Note: Descriptions are shown in the official language in which they were submitted.
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ANTICANCER COMPOUND AND ENANTIOMER SEPARATION METHOD USEFUL
FOR SYNTHESIZING SAID COMPOUND
Background of the Invention
This is a divisional application of Canadian
Application S/N 2,398,353, filed on November 29, 2000.
This invention relates to a compound that can be
used in the treatment of hyperproliferative disease, such as
cancer, in mammals. This invention also relates to a method
of separating enantiomers in a racemic mixture from one
another to obtain a specific enantiomer. The invention
further relates to a synthesis method to directly obtain the
same enantiomer.
Oncogenes frequently encode protein components of
signal transduction pathways which lead to stimulation of
cell growth and mitogenesis. Oncogene expression in
cultured cells leads to cellular transformation,
characterized by the ability of cells to grow in soft agar
and the growth of cells as dense foci lacking the contact
inhibition exhibited by non-transformed cells. Mutation
and/or overexpression of certain oncogenes is frequently
associated with human cancer.
To acquire transforming potential, the precursor
of the Ras oncoprotein must undergo farnesylation of the
cysteine residue located in a carboxyl-terminal
tetrapeptide. Inhibitors of the enzyme that catalyzes this
modification, farnesyl protein transferase, have therefore
been suggested as agents to combat tumors in which Ras
contributes to transformation. Mutated, oncogenic forms of
Ras are frequently found in many human cancers, most notably
in more than 50% of colon and pancreatic carcinomas (Kohl
et al., Science, Vol. 260, 1834 to 1837, 1993). The
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compound of the present invention exhibits activity as an
inhibitor of the enzyme farnesyl protein transferase and
therefore is believed to be useful as an anti-cancer and
anti-tumor agent. Further, the compound of the present
invention may be active against any tumors that proliferate
by virtue of farnesyl protein transferase.
The racemate 6-[amino-(6-chloro-pyridin-3-yl)-(3-
methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-
cyclopropylmethyl-lH-quinolin-2-one and other compounds that
can inhibit farnesyl protein transferase are disclosed in
United States Patent No. 6,258,824 and in International
Publication No. WO 00/47574.
Other compounds that are indicated as having
activity inhibiting farnesyl protein transferase are
referred to in International Publication Number WO 97/21701,
entitled "Farnesyl Protein Transferase Inhibiting (Imidazol-
5-yl)methyl-2-quinolinone Derivatives", which has an
International Publication Date of June 19, 1997; in
International Publication Number WO 97/16443, entitled
"Farnesyl Transferase Inhibiting 2-Quinolone Derivatives",
which has an International Publication Date of May 9, 1997;
WO 00/012498 entitled "2-Quinolone derivatives Useful as
Anticancer Agents"; and WO 00/012499 entitled "Alkynyl-
Substituted Quinolin-2-one Derivatives Useful as Anticancer
Agents".
Summary of the Invention
The parent application is directed to the compound
(+)-6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-
4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-lH-
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quinolin-2-one and to pharmaceutically acceptable salts and
solvates thereof, and to prodrugs thereof.
"(+)-6-[Amino-(6-chloro-pyridin-3-yl)-(3-methyl-
3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-
cyclopropylmethyl-1H-quinolin-2-one" refers to the
dextrorotatory isomer of 6-[amino-(6-chloro-pyridin-3-yl)-
(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-
cyclopropylmethyl-1H-quinolin-2-one. The dextrorotatory
isomer of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-
imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-l-
cyclopropylmethyl-1H-quinolin-2-one has been found to have
greater activity in inhibiting the enzyme farnesyl protein
transferase than the levorotatory isomer. The term "(+)-6-
[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-
methyl]-4-(3-chloro-phenyl)-l-cyclopropylmethyl-lH-quinolin-
2-one" for purposes of the present invention and unless
.otherwise indicated herein, however, also refers to
compositions consisting essentially of (+)-6-[amino-(6-
chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-
(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one
substantially free of (-)-6-[amino-(6-chloro-pyridin-3-yl)-
(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-
cyclopropylmethyl-1H-quinolin-2-one, the levorotatory isomer
of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-
yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-lH-
quinolin-2-one. The term "substantially free" means that
the amount of the dextrorotatory isomer predominates the
composition relative to the levorotatory isomer of 6-[amino-
(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-
4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one.
More specifically, this means that the amount of the
dextrorotatory isomer relative to the levorotatory isomer by
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weight is at least about 90%, preferably greater than
about 95%, more preferably greater than about 99%.
The phrases "racemate", "racemic mixture", and
other like phrases refer to generally equimolar proportions
of a levorotatory isomer and a dextrorotatory isomer of a
compound in a composition.
The parent application is also directed to a
method of inhibiting abnormal cell growth in a mammal
comprising administering to the mammal an amount of the
aforementioned compound of the invention, or a
pharmaceutically acceptable salt or solvate or prodrug
thereof, that is effective in inhibiting farnesyl protein
transferase.
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The parent application is also directed to a
method of inhibiting abnormal cell growth in a mammal
comprising administering to said mammal an amount of the
aforementioned compound of the invention, or a
pharmaceutically acceptable salt or solvate or prodrug
thereof, that is effective in inhibiting abnormal cell
growth.
The parent application is further directed to a
method of inhibiting abnormal cell growth in a mammal which
comprises administering to said mammal an amount of the
aforementioned compound of the invention, or a
pharmaceutically acceptable salt or solvate or prodrug
thereof, in combination with an amount of a
chemotherapeutic, wherein the amounts of the compound, salt,
solvate, or prodrug, and the chemotherapeutic are together
effective in inhibiting abnormal cell growth. Several
chemotherapeutics are known in the art, and these can be
used in the present invention. In one embodiment, the
chemotherapeutic is selected from the group consisting of
mitotic inhibitors, alkylating agents, anti-metabolites,
intercalating antibiotics, growth factor inhibitors, cell
cycle inhibitors, enzymes, topoisomerase inhibitors,
biological response modifiers, anti-hormones, e.g. anti-
androgens.
The parent application is further directed to a
method for inhibiting abnormal cell growth in a mammal which
method comprises administering to the mammal an amount of
the aforementioned compound of the invention, or a
pharmaceutically acceptable salt or solvate or prodrug
thereof, in combination with radiation therapy, wherein the
amount of the compound, salt, solvate or prodrug is in
combination with the radiation therapy effective in
inhibiting abnormal cell growth in the mammal. Techniques
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for administering radiation therapy are known in the art,
and these techniques can be used in the combination therapy
described herein. The administration of the compound of the
invention in this combination therapy can be determined as
described herein.
It is believed that the compound of the parent
application can render abnormal cells more sensitive to
treatment with radiation for purposes of killing and/or
inhibiting the growth of such cells. Accordingly, this
invention further relates to a method for sensitizing
abnormal cells in a mammal to treatment with radiation which
comprises administering to the mammal an amount of the
compound of the invention, pharmaceutically acceptable salt
or solvate thereof, or prodrug thereof, which amount is
effective in sensitizing abnormal cells to treatment with
radiation. The amount of the compound, salt, solvate, or
prodrug in this method can be determined according to the
means for ascertaining effective amounts of the compound of
the invention described herein.
The parent application is further directed to a
pharmaceutical composition for inhibiting abnormal cell
growth in a mammal comprising an amount of the
aforementioned compound of the invention, or a
pharmaceutically acceptable salt or solvate or prodrug
thereof, that is effective in inhibiting farnesyl protein
transferase, and a pharmaceutically acceptable carrier.
The parent application is further directed to a
pharmaceutical composition for inhibiting abnormal cell
growth in a mammal comprising an amount of the
aforementioned compound of the invention, or a
pharmaceutically acceptable salt or solvate or prodrug
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thereof, that is effective in inhibiting abnormal cell
growth, and a pharmaceutically acceptable carrier.
The parent application is also directed to a
pharmaceutical composition for inhibiting abnormal cell
growth in a mammal which comprises an amount of the
aforementioned compound of the invention, or a
pharmaceutically acceptable salt or solvate or prodrug
thereof, in combination with an amount of a
chemotherapeutic, wherein the amounts of the compound, salt,
solvate, or prodrug, and of the chemotherapeutic are
together effective in inhibiting abnormal cell growth. Many
chemotherapeutics are presently known in the art. In one
embodiment, the chemotherapeutic is selected from the group
consisting of mitotic inhibitors, alkylating agents, anti-
metabolites, intercalating antibiotics, growth factor
inhibitors, cell cycle inhibitors, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones,
e.g. anti-androgens, and a pharmaceutically acceptable
carrier.
The parent application is also directed to a
method of and to a pharmaceutical composition for inhibiting
abnormal cell growth in a mammal which comprises an amount
of the compound of the invention, a pharmaceutically
acceptable salt or solvate thereof, a prodrug thereof, or an
isotopically-labelled derivative thereof, and an amount of
one or more substances selected from anti-angiogenesis
agents, signal transduction inhibitors, and
antiproliferative agents.
Anti-angiogenesis agents, such as MMP-2 (matrix-
metalloproteinase 2) inhibitors, MMP-9 (matrix-
metalloproteinase 9) inhibitors, and COX-II
(cyclooxygenase II) inhibitors, can be used in conjunction
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with the compounds described in the parent application in
the methods and pharmaceutical compositions described
herein. Examples of useful COX-II inhibitors include
CELEBREXTM (celecoxib), valdecoxib, and rofecoxib. Examples
of useful matrix metalloproteinase inhibitors are described
in WO 96/33172 (published October 24, 1996), WO 96/27583
(published March 7, 1996), EP 0,818,442, EP 1,004,578,
WO 98/07697 (published February 26, 1998), WO 98/03516
(published January 29, 1998), WO 98/34918 (published
August 13, 1998), WO 98/34915 (published August 13, 1998),
WO 98/33768 (published August 6, 1998), WO 98/30566
(published July 16, 1998), European Patent Publication
606,046 (published July 13, 1994), European Patent
Publication 931,788 (published July 28, 1999), WO 90/05719
(published May 31, 1990), WO 99/52910 (published
October 21, 1999), WO 99/52889 (published October 21, 1999),
WO 99/29667 (published June 17, 1999), WO 99/007675,
U.S. Patent No. 7,030,242, United States Patent 5,863,949
(issued January 26, 1999), United States Patent 5,861,510
(issued January 19, 1999), and European Patent
Publication 780,386 (published June 25, 1997). Preferred
MMP-2 and MMP-9 inhibitors are those that have little or no
activity inhibiting MMP-1.
More preferred, are those that selectively inhibit
MMP-2 and/or MMP-9 relative to the other matrix-
metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,
MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
According to one aspect of the invention, the
present divisional application provides a method of
separating (+) and (-) enantiomers of a compound of
formula 1 in a racemic mixture,
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(R20)n
a
R
R R s
R9
2 N
R '14 R7 Z
O N R6
R
wherein:
the dashed line indicates an optional second bond
connecting C-3 and C-4 of the quinolin-2-one ring;
R1 is selected from H, C1-Clo alkyl,
- (CR13R14) qC (0) R12 , - (CR13R14) qC (0) OR15 , - (CR13R14) gOR12 ,
- (CR13R14) gCS02R15, - (CR13R14) t (C3-C10 cycloalkyl) ,
- (CR13R14) t (C6-Clo aryl) , and - (CR13R14) t (4-10 membered
heterocyclic), wherein said cycloalkyl, aryl and
heterocyclic R1 groups are optionally fused to a C6-Clo aryl
group, a C5-C8 saturated cyclic group, or a 4-10 membered
heterocyclic group; and the foregoing R1 groups, except H but
including any optional fused rings referred to above, are
optionally substituted by 1 to 4 R6 groups;
R2 is halo, cyano, -C(O) OR15, or a group selected
from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently
selected from H, C1-C1o alkyl, C2-Clo alkenyl, C2-Clo alkynyl,
halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
azido, -OR12, C(O)R12, -C (0) OR12, -NR13C (0) OR15, -OC (0) R12,
-NR 13S02R15, -S02NR12R13, -NR13C (0) R12, -C (O)NR 12 R 13 r -NR 12R13,
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-CH=NOR 12, -S (O) jR12 wherein j is an integer from 0 to 2,
- (CR13R14) t (C6-Clo aryl) , - (CR13R19) t(4-10 membered
heterocyclic), - (CR13R14) t (C3-C10 cycloalkyl) , and
- (CR13R19) tC=CR16; and wherein the cycloalkyl, aryl and
heterocyclic moieties of the foregoing groups are optionally
fused to a C6-Clo aryl group, a C5-C8 saturated cyclic group,
or a 4-10 membered heterocyclic group; and said alkyl,
alkenyl, cycloalkyl, aryl and heterocyclic groups are
optionally substituted by 1 to 3 substituents independently
selected from halo, cyano, nitro, trifluoromethyl,
trifluoromethoxy, azido, -NR 13SO2R15, -SO2NR12R13, -C (0) R12,
-C (0) OR12, -OC (0) R12, -NR13C (0) OR15, -NR13C (O)R'2, -C (0) NR12R13,
-NR 12R13, -OR12, C1-Clo alkyl, C2-Clo alkenyl, C2-Clo alkynyl,
- (CR13R19) t (C1-Clo aryl) , and - (CR13R14) t(4-10 membered
heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group,
substituted by 1 to 4 R6 substituents;
R9 is - (CR13R14) t (imidazolyl) or
-(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl
moiety is substituted by 1 or 2 R6 substituents;
each R12 is independently selected from H,
C,-Clo alkyl, - (CR13R14) t (C3-Clo cycloalkyl) ,
- (CR13R14) t (C6-Cio aryl) , and - (CR13R14) t(4-10 membered
heterocyclic); said cycloalkyl, aryl and heterocyclic
R12 groups are optionally fused to a C6-Clo aryl group, a
C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic
group; and the foregoing R12 substituents, except H but
including any optional fused rings, are optionally
substituted by 1 to 3 substituents independently selected
from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
azido, -0(0) R13, -C (0) OR13, -00(0) R13, -NR 13C (0) R14,
-C(O)NR 13 R 14 1 -NR 13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
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each t is independently an integer from 0 to 5 and
each q is independently an integer from 1 to 5;
each R13 and R14 is independently H or C1-C6 alkyl,
and where R13 and R14 are as - 13 R 19 13 14
(CR ) q or -(CR R ) t each is
independently defined for each iteration of q or t in excess
of 1;
R15 is selected from the substituents provided in
the definition of R12 except R15 is not H;
R16 is selected from the list of substituents
provided in the definition of R12 and -SiR17R18R19;
R17, R18 and R19 are each independently selected
from the substituents provided in the definition of
R12 except at least one of R17, R18 and R19 is not H;
R20 is H, C,-C10 alkyl, C2-C,0 alkenyl,
C2-C10 alkynyl, halo, nitro, trifluoromethyl,
trifluoromethoxy, -OR'2, -OC (0) R12, -C(O)R12 , -NR12R13,
13 12 1213 13, -12
-NRC (0) R, -C (0) NRR, cyano, -C (0) OR SR, or
- (CR13R14) t (C6-C10 aryl) , wherein said aryl R20 group is
substituted by 1 to 4 R6 groups; and
n is an integer selected from 1 to 3;
which method comprises applying a portion or all
of said racemic mixture to a chiral separation apparatus,
under conditions suitable for separation of chiral
molecules,
and obtaining the separated (+) and (-)
enantiomers of formula 1 from said apparatus, subsequent to
said conditions.
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According to another aspect of the invention, the
present divisional application provides a method of
synthesizing a (+) or (-) enantiomer of formula 2
4
8 R9
RZ R7
IN
R' R6
2
wherein:
the dashed line indicates an optional second bond
connecting C-3 and C-4 of the quinolin-2-one ring;
R1 is selected from H, C1-O1o alkyl,
- (CR13R14) qC (0) R12 , - (CR13R14) qC (0) OR15 , - (CR13R19 ) 4OR12
~
- (CR13R14) gCS02R15, - (CR13R14) t (C3-C10 cycloal kyl) ,
- (CR13R14) t (C6-Clo aryl) , and - (CR13R14) t(4-10 membered
heterocyclic), wherein said cycloalkyl, aryl and
heterocyclic R1 groups are optionally fused to a C6-Clo aryl
group, a C5-C8 saturated cyclic group, or a 4-10 membered
heterocyclic group; and the foregoing R1 groups, except H but
including any optional fused rings referred to above, are
optionally substituted by 1 to 4 R6 groups;
R2 is halo, cyano, -C(O)OR 15, or a group selected
from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently
selected from H, C1-Clo alkyl, C2-Clo alkenyl, C2-C10 alkynyl,
halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
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azido, -OR12, -C (0) R12, -C (0) OR12, -NR13C (0) OR", -OC (0) R12,
-NR 13SO2R15, -SO2NR12R13, -NR13C (0) R12, -C (0) NR12R13, -NR 12R13,
-CH=NOR12, -S(O)jR12 wherein j is an integer from 0 to 2,
- (CR13R14) t (C6-C10 aryl) , - (CR13R14) t(4-10 membered
heterocyclic), - (CR13R14) t (C3-C10 cycloalkyl) , and
- (CR13R14) tC=CR16; and wherein the cycloalkyl, aryl and
heterocyclic moieties of the foregoing groups are optionally
fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group,
or a 4-10 membered heterocyclic group; and said alkyl,
alkenyl, cycloalkyl, aryl and heterocyclic groups are
optionally substituted by 1 to 3 substituents independently
selected from halo, cyano, nitro, trifluoromethyl,
trifluoromethoxy, azido, -NR 13SO2R15, -SO2NR12R13, -C (0) R12,
_C(O)OR 12, -OC (0) R12, -NR13C (O)OR 15, -NR13C (0) R12, -C(O)NR 12 R 13,
-NR 12R13, -OR 12, C,-C,o alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
- (CR13R14) t (C6-C10 aryl) , and - (CR13R14) t(4-10 membered
heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group,
substituted by 1 to 4 R6 substituents;
R8 is -NH2, -NH (C1-C10 alkyl) , or
-N (C,-C10 alkyl) (C,-C10 alkyl) ;
R9 is - (CR13R14) t (imidazolyl) or
-(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl
moiety is substituted by 1 or 2 R6 substituents;
each R12 is independently selected from H,
C1-C10 alkyl, - (CR13R14) t (C3-C10 cycloalkyl) ,
- (CR13R14) t (C6-C10 aryl) , and - (CR13R14) t (4 -10 membered
heterocyclic); said cycloalkyl, aryl and heterocyclic
R12 groups are optionally fused to a C6-C10 aryl group, a
C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic
group; and the foregoing R12 substituents, except H but
including any optional fused rings, are optionally
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substituted by 1 to 3 substituents independently selected
from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
azido, -C (0) R13, -C(O)OR 13 , -00(0) R13, -NR 13C (0) R19,
-C(O)NR 13 R 14, -NR13R14, hydroxy, C,-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5 and
each q is independently an integer from 1 to 5;
each R13 and R14 is independently H or C1-C6 alkyl,
and where R13 and R14 are as - (CR13R14) q or - (CR13R14) t each is
independently defined for each iteration of q or t in excess
of 1;
R15 is selected from the substituents provided in
the definition of R12 except R15 is not H;
R16 is selected from the list of substituents
provided in the definition of R12 and -SiR17R18R19; and
R17, R18 and R19 are each independently selected
from the substituents provided in the definition of
R12 except at least one of R17, R18 and R19 is not H;
which method comprises
a) obtaining a racemic mixture comprising
(+) and (-) enantiomers of a compound of formula 1
(R20)n
R4
3 R5
~R R9
2 N
R 4 7 Z
N R6
I1
1
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wherein R20 is H, C,-C10 alkyl, C2-C10 alkenyl,
C2-C10 alkynyl, halo, nitro, trifluoromethyl,
trifluoromethoxy, -OR12, -OC (0) R12, -C(O)R12 , -NR12R'3,
13 12 1213 3, -12
-NRC (0) R, -C (0) NRR, cyano, -C (0) OR1 SR, or
- (CR13R14) t (C6-C10 aryl) , said aryl R20 group being substituted
by 1 to 4 R6 groups, n is an integer selected from 1 to 3,
and wherein R1, R2 R3 R4 R5 R6 R7 R9 R12 and R13 are as
defined above;
b) applying a portion or all of the racemic
mixture from step (a) to a chiral separation apparatus,
under conditions suitable for separation of chiral
molecules, and obtaining separated (+) and (-) enantiomers
of formula 1 from said apparatus, subsequent to said
conditions; and
c) converting the benzylidine moiety of either the
separated (+) or the separated (-) enantiomer of formula 1
from step (b) with an amine moiety R8, wherein R8 is as
defined above, thereby obtaining a separated (+) or (-)
enantiomer of a compound of formula 2.
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Some specific examples of MMP inhibitors useful in the present invention are
AG-3340,
RG 32-3555, RS 13-0830, and the compounds recited in the following list
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-
amino]-propionic acid;
3-exo-3-[4-(4-flu oro-phenoxy)-benzenesulfonylamino]-8-oxa-
bicyclo[3.2.1]octane-
3 carboxylic acid hydroxyamide;
(2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-
methyl-
piperidine-2-carboxylic acid hydroxyamide;
4-[4-(4-fl uoro-phenoxy)-benzenes ulfonylamino]-ietrahydro-pyran-4-carboxylic
acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-
amino]-propionic acid;
4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-ietrahydro-pyran-4-carboxylic
acid hydroxyamide;-
(R) 3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-
carboxylic
acid hydroxyamide;
(2R, 3R) 1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-
methyl-piperidine-2-carboxylic acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-
amino]-propionic acid;
3-[j4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-
4-yl)-amino]-propionic acid;
3-exo- 3-j4-(4-chloro-phe noxy)-benzenesulfonylamino]-8-oxa-
bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide;
3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-
bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; and
(R) 3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-
carboxylic
acid hydroxyamide;
and pharmaceutically acceptable salts and solvates of said compounds.
Other anti-angiogenesis agents, including other COX-11 inhibitors and other
MMP
inhibitors, can also be used in the present invention.
The compound of the present invention can also be used with signal
transduction
inhibitors, such as agents that can inhibit EGFR (epidermal growth factor
receptor)
responses, such as EGFR antibodies, EGF antibodies, and molecules that are
EGFR
inhibitors; VEGF (vascular endothelial growth factor) inhibitors, such as VEGF
receptors and
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molecules that can inhibit VEGF; and erbB2 receptor
inhibitors, such as organic molecules or antibodies that
bind to the erbB2 receptor, for example, HERCEPTINT"
(Genentech, Inc. of South San Francisco, California, USA).
EGFR inhibitors are described in, for example in
WO 95/19970 (published July 27, 1995), WO 98/14451
(published April 9, 1998), WO 98/02434 (published
January 22, 1998), and United States Patent 5,747,498
(issued May 5, 1998), and such substances can be used in the
present invention as described herein. EGFR-inhibiting
agents include, but are not limited to, the monoclonal
antibodies C225 and anti-EGFR 22Mab (ImClone Systems
Incorporated of New York, New York, USA), the compounds
ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim),
MDX-447 (Medarex Inc. of Annandale, New Jersey, USA), and
OLX-103 (Merck & Co. of Whitehouse Station, New Jersey,
USA), VRCTC-310 (Ventech Research) and EGF fusion toxin
(Seragen Inc. of Hopkinton, Massachusetts). These and other
EGFR-inhibiting agents can be used in the present invention.
VEGF inhibitors, for example SU-5416 and SU-6668
(Sugen Inc. of South San Francisco, California, USA), can
also be combined with the compound of the present invention.
VEGF inhibitors are described in, for example in WO 99/24440
(published May 20, 1999), WO 99/062890, WO 95/21613
(published August 17, 1995), WO 99/61422 (published
December 2, 1999), United States Patent 5,834,504 (issued
November 10, 1998), WO 98/50356 (published November 12,
1998), United States Patent 5,883,113 (issued March 16,
1999), United States Patent 5,886,020 (issued March 23,
1999), United States Patent 5,792,783 (issued August 11,
1998), WO 99/10349 (published March 4, 1999), WO 97/32856
(published September 12, 1997), WO 97/22596 (published
June 26, 1997), WO 98/54093 (published December 3, 1998),
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WO 98/02438 (published January 22, 1998), WO 99/16755
(published April 8, 1999), and WO 98/02437 (published
January 22, 1998). Other examples of some specific VEGF
inhibitors useful in the present invention are IM862 (Cytran
Inc. of Kirkland, Washington, USA); anti-VEGF monoclonal
antibody of Genentech, Inc. of South San Francisco,
California; and angiozyme, a synthetic ribozyme from
Ribozyme (Boulder, Colorado) and Chiron (Emeryville,
California). These and other VEGF inhibitors can be used in
the present invention as described herein.
ErbB2 receptor inhibitors, such as GW-282974
(Glaxo Wellcome plc), and the monoclonal antibodies AR-209
(Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA)
and 2B-1 (Chiron), can furthermore be combined with the
compound of the invention, for example those indicated in
WO 98/02434 (published January 22, 1998), WO 99/35146
(published July 15, 1999), WO 99/35132 (published July 15,
1999), WO 98/02437 (published January 22, 1998), WO 97/13760
(published April 17, 1997), WO 95/19970 (published July 27,
1995), United States Patent 5,587,458 (issued December 24,
1996), and United States Patent 5,877,305 (issued March 2,
1999). ErbB2 receptor inhibitors useful in the present.
invention are also described in United States Patent
Nos. 6,465,449 and 6,284,764. The erbB2 receptor inhibitor
compounds and substance described in the aforementioned PCT
publications and U.S. patents, as well as other compounds
and substances that inhibit the erbB2 receptor, can be used
with the compound of the present invention in accordance
with the present invention.
The compound of the invention can also be used
with other agents useful in treating abnormal cell growth or
cancer, including, but not limited to, agents capable of
enhancing antitumor immune responses, such as CTLA4
CA 02586175 2007-05-09
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(cytotoxic lymphocyte antigen 4) antibodies, and other
agents capable of blocking CTLA4; and anti-proliferative
agents such as other farnesyl protein transferase
inhibitors, for example the farnesyl protein transferase
inhibitors described in the references cited in the
"Background" section, supra. Specific CTLA4 antibodies
that can be used in the present invention include those
described in WO 00/037504, however other CTLA4 antibodies
can be used in the present invention.
"Abnormal cell growth", as used herein, refers to
cell growth that is independent of normal regulatory
mechanisms (e.g., loss of contact inhibition), including the
abnormal growth of normal cells and the growth of abnormal
cells. This includes, but is not limited to, the abnormal
growth of: (1) tumor cells (tumors), both benign and
malignant, expressing an activated Ras oncogene; (2) tumor
cells, both benign and malignant, in which the Ras protein
is activated as a result of oncogenic mutation in another
gene; (3) benign and malignant cells of other proliferative
diseases in which aberrant Ras activation occurs. Examples
of such benign proliferative diseases are psoriasis, benign
prostatic hypertrophy, human papilloma virus (HPV), and
restenosis. "Abnormal cell growth" also refers to and
includes the abnormal growth of cells, both benign and
malignant, resulting from activity of the enzyme farnesyl
protein transferase.
The term "treating", as used herein, unless
otherwise indicated, means reversing, alleviating,
inhibiting the progress of, or preventing the disorder or
condition to which such term applies, or one or more
symptoms of such disorder or condition. The term
"treatment", as used herein, refers to the act of treating,
as "treating" is defined immediately above.
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The term "pharmaceutically acceptable salt(s)", as
used herein, unless otherwise indicated, includes salts of
groups of the compound of the invention, which groups are
capable of forming salts. For example, pharmaceutically
acceptable salts include hydrochloride salts of the amino
group and/or the imidazolyl group of the compound. Other
pharmaceutically acceptable salts of the amino group and/or
imidazolyl group are hydrobromide, sulfate, hydrogen
sulfate, phosphate, hydrogen phosphate, dihydrogen
CA 02586175 2007-05-09
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phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate,
methanesulfonate
(mesylate) and p-toluenesulfonate (tosylate) salts. The preparation of such
salts is described
below.
The subject invention also includes isotopically-labelled compounds, which
compounds are identical to the above recited compound of the invention, but
for the fact that
one or more atoms thereof are replaced by an atom having an atomic mass or
mass number
different from the atomic mass or mass number usually found in nature.
Examples of
isotopes that can be incorporated into the compound of the invention include
isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such
as 2H, 3H, 13C,
14C, 15N, 180, 170, 3'P, 32P, 3S, 18F, and 36C1, respectively. Compounds of
the present
invention, and pharmaceutically acceptable salts of said compounds which
contain the
aforementioned isotopes -andlor other isotopes of other atoms are within the
scope of this
invention. Certain isotopically-labelled compounds of the present invention,
for example
those into which radioactive isotopes such as 3H and 14C are incorporated, are
useful in drug
and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-
14, i.e., 14C,
isotopes are particularly preferred for their ease of preparation and
detectability. Further,
substitution with heavier isotopes such as deuterium, i.e., 2H, can afford
certain therapeutic
advantages resulting from greater metabolic stability, for example increased
in vivo half-life or
reduced dosage requirements and, hence, may be preferred in some
circumstances.
Isotopically labelled compounds of this invention can generally be prepared by
carrying out
the procedures disclosed in the Schemes and/or in the Examples below, by
substituting a
readily available isotopically labelled reagent for a non-isotopically
labelled reagent.
Accordingly, reference to the compound of the invention for use in the
therapeutic methods
and pharmaceutical compositions described herein also encompasses isotopically-
labelled
forms of the compound.
This invention also encompasses prodrugs of the compound (+)-6-[amino-(6-
chloro-
pyridin-3-yl)-(3-methyl-3H-imidazol-4-yi)-methyl]-4-(3-chloro-phenyl)-1-
cyclopropylmethyl-1 H-
quinolin-2-one, and pharmaceutical compositions containing and methods of
treatment through
administering such prodrugs. For example, the free amino group of the compound
can be
converted into a prodrug. Such prodrugs include compounds wherein an amino
acid residue, or
a polypeptide chain of two or more (e.g., two, three or four). amino acid
residues is covalently
joined through an amide or ester bond to the free amino group. The amino acid
residues
include but are not limited to the 20 naturally occurring amino acids commonly
designated by
three letter symbols and also includes 4-hydroxyproline, hydroxylysine,
demosine, isodemosine,.
3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline
homocysteine,
homoserine, omithine and methionine sulfone. A prodrug comprising a carbamate
of the amino
group is also included as part of the invention. The free amine can also be
derivatized as an
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amide, sulfonamide or phosphonamide to four a prodrug. All of these prodrug
moieties may
incorporate groups including but not limited to ether, amine and carboxylic
acid functionalities.
Patients that can be treated with the compound of the invention, or
pharmaceutically
acceptable salts or solvates thereof, or a prodrug thereof, or isotopically
labelled compounds
of the invention, according to the methods of this invention include, for
example, patients that
have been diagnosed as having lung cancer, NSCLC (non small cell lung cancer),
bone
cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous
or
intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of
the anal
region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g.,
uterine
sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium,
carcinoma of the
cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's Disease,
cancer of the
esophagus, cancer of the small intestine, cancer of the endocrine system
(e.g., cancer of the
thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of
the urethra,
cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors
of childhood,
lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter
(e.g., renal cell
carcinoma, carcinoma of the renal pelvis), pediatric malignancy, neoplasms of
the central
nervous system (e.g., primary CNS lymphoma, spinal axis tumors, brain stem
giiomas or
pituitary adenomas), neoplastic cutaneous diseases (e.g. psoriasis, mycoses
fungoides), or
Barrett's esophagus (pre-malignant syndrome).
The compound of the invention, its pharmaceutically acceptable salts and
solvates,
its prodrugs, and its radioactively-labelled derivatives can all independently
also furthermore
be used in a palliative neo-adjuvantladjuvant therapy in alleviating the
symptoms associated
with the diseases recited in the preceding paragraph as well as the symptoms
associated
with abnormal cell growth. Such therapy can be a monotherapy or can be in a
combination
with chemotherapy and/or immunotherapy.
Patients that can be treated according to the methods of this invention also
include
patients suffering from abnormal cell growth, as defined above.
This invention also relates a method of separating (-r) and (-) enantiomers of
a
compound of formula I in a racemic mixture,
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-10-
(020)
4 n
R3 R5
R2 N Rs
3 R7 Z
0 R 6
1 R~
wherein: the dashed line indicates an optional second bond connecting C-3 and
C-4
of the quinolin-2-one ring;
R' is selected from H, C1-C10 alkyl, -(CR13R14)gC(O)R12, -(CR13R14)gC(O)OR15,
-(CR13R14)gOR12, -(CR13R14)gCS02R16, -(CR13R14)i(C3-C10 cycloalkyl), -
(CR13R'4)t(C6-C1o aryl),
and -CR13R14)t(4_10 membered heterocyclic), wherein said c cloal
( y icyl, aryl and heterocyclic
R1 groups are optionally fused to a C6-C10 aryl group, a C5-C5 saturated
cyclic group,-or a 4-
membered heterocyclic group; and the foregoing R1 groups, except H but
including any
10 optional fused rings referred to above, are optionally substituted by 1 to
4 R6 groups;
R2 is halo, cyano, -C(O)OR15, or a group selected from the substituents
provided in
the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-
C10
alkenyl, C2-C10 alkynyl, = halo, cyano, nitro, trifluoromethyl,
trifluoromethoxy, azido, -OR12,
-C(O)R12, -C(O)OR12, -NR13C(O)OR15, -OC(O)R14, -NR'3SO2R15, -S02NR12R13,
-NR13C(0)R12, -C(O)NR12R13, -NR12R'3, -CH=NOR'2, -S(O))Ri2 wherein j is an
integer from 0
to 2, -(CR13R14)1(C5-C1D aryl), -(CR13R14)1(4-10 membered heterocyclic), -
(CR13R14) (C -C10
cycloalkyl), and -(CR13R14)tC=CR16; and wherein the cycloalkyl, aryl and
heterocyclic moieties
of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8
saturated cyclic
group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl,
cycloalkyl, aryl and
heterocyclic groups are optionally substituted by I to 3 substituents
independently selected
from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR
t3SO2R15, -S02NR72R"3,
-C(O)R12, -C(O)OR12, -OC(O)R12, -NR13C(O)OR15, -NR'3C(O)R12, -C(O)NR'2R13, -
NR12R13,
-OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C70 alkynyl, -(CR13R14)t(C6-C10 aryl),
and -(CR73R14)t(4-
10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by I to 4 R6
substituents;
R9 is -(CR13R14),(imidazolyl) or -(CR13R14)1(pyridinyl) wherein said
imidazolyl or
pyridinyl moiety is substituted by I or 2 R6 substituents
CA 02586175 2007-05-09
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-11-
each R12 is independently selected from H, C1-C10 alkyl, -(CRt3R14),(C3-C10
cycloalkyl), -(CR13R14),(C6-C10 aryl), and -(CR13R14)1(4-10 membered
heterocyclic); said
cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10
aryl group, a C5-
C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the
foregoing R12
substituents, except H but including any optional fused rings, are optionally
substituted by 1 to
3 substituents independently selected from halo, cyano, nitro,
trifluoromethyl,
trifluoromethoxy, azido, -C(O)R13, -C(O)OR13, -OC(O)R'3, -NR'3C(O)R14, -
C(O)NR13R14,
-NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5 and each q is independently an
integer
from 1 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are
as
-(CR13R14)q or -(CR'3R'4), each is independently defined for each iteration of
q or t in excess
of 1;
R15 is selected from the substituents provided in the definition of R12 except
R15 is not
H;
R16 is selected from the list of substituents provided in the definition of
R12 and
SiR17R18R19;
R17, R18 and R19 are each independently selected from the substituents
provided in
the definition of R12 except at least one of R17, Rib and R19 is not H;
R20 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, nitro,
trifluoromethyl,
trifluoromethoxy, -OR12, -OC(O)R12, -C(O)R12, -NR'2R13, -NR13C(O)R12, -
C(O)NR'2R'3, cyano,
-C(O)OR13, -SR12, or -(CR'3R14),(C6-C70 aryl), wherein said aryl R2 group is
substituted by I
to 4 R6 groups; and
n is an integer selected from 1 to 3;
which method comprises applying a portion or all of said racemic mixture to a
chiral
separation apparatus, under conditions suitable for separation of chiral
molecules, and
obtaining the separated (+) and (-) enantiomers of formula 1 from said-
apparatus, subsequent
to said conditions.
The compounds of formula I have utility in that they are believed to inhibit
the
enzyme farnesyl protein transferase. Also, the compounds of formula I
encompass
intermediate compounds useful for synthesizing (+)-6-[amino-(6-chloro-pyridin-
3-yl)-(3-
methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1 H-
quinolin-2-one,
the compound of the invention.
The phrase "chiral separation apparatus" includes apparatuses capable of
separating
chiral molecules. Apparatuses capable of separating chiral molecules are known
in the art,
including columns containing material capable of binding (+) and (-)
enantiomers of a given
chiral compound differentially such that the (+) and (-) enantiomers elute
from the column at
different rates. Several columns useful for separation of (+) and (-)
enantiomers of chiral
CA 02586175 2007-05-09
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-12-
molecules are commercially available, and any of these could be used in the
present
invention. Examples of such columns include, but are not limited to,
CHIRALCELT"' OD and
CHIRALPAKT"" AD (both from Daicel Chemical Industries, LTD (Osaka, Japan)).
Conditions suitable for separation of chiral molecules are conditions such as
temperature and eluent, and such conditions are related to the particular
apparatus selected
for separating the enantiomers. Such conditions can be determined by a person
of ordinary
skill in the art.
The subject invention also relates to a method of synthesizing a (+) or (-)
enantiomer
of formula 2
R4
R R5
R8 R9
2
R7 Z
O N Rs
IR1
2
wherein:
the dashed line indicates an optional second bond connecting C-3 and C-4 of
the
quinolin-2-one ring;
R1 is selected from H, C1-C10 alkyl, -(CR13R14),C(0)R12, -(CR13R14)gC(O)OR15,
-(CR13R14)gOR12, -(CR13R14)gCSO2R15, -(CR13R14)-(C3-C1o cycloalkyl), -
(CR13R14)t(C6-C10 aryl),
and -(CR13R14)1(4-10 membered heterocyclic), wherein said cycloalkyl, aryl and
heterocyclic
R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated
cyclic group, or 'a 4-
10 membered heterocyclic group; and the foregoing R1 groups, except H but
including any
optional fused rings referred to above, are optionally substituted by 1 to 4
Rs groups;
R2 is halo, cyano, -C(O)OR15, or a group selected from the substituents
provided in
the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-
C10
alkenyl, Cz-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
azido, -OR12,
-C(O)R 12, -C(O)OR12, -NR13C(O)OR15, -OC(O)R 12, -NR13SO2R15, -SO2NR12R13;
NR13C(O)R12, -C(0)NR12R13, -NR12R13, -CH=NOR 12, -S(O)iR12 wherein j is an
integer from 0
to 2, -(CR73R14)t(C6-C10 aryl), -(CR13R14)t(4-10 membered heterocyclic), -
(CR13R14)t(C3-C1o
cycloalkyl), and -(CR13R14)tC=CR16; and wherein the cycloalkyl, aryl and
heterocyclic moieties
CA 02586175 2007-05-09
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of the foregoing groups are optionally fused to a Cs-C10 aryl group, a C5-C8
saturated cyclic
group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl,
cycloalkyl, aryl and
heterocyclic groups are optionally substituted by 1 to 3 substituents
independently selected
from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -
NR13S02R15, -S02NR12R13,
-C(0)R12, -C(O)OR12, -OC(O)R12, -NR 13C(O)OR15, -NR13C(O)R12, -C(O)NR12R13, -
NR 12R'3,
-OR12, C1-C10 alkyl, C2-Ci0 alkenyl, C2-C10 alkynyl, -(CR13R1A)t(C6-C10 aryl),
and -(CR13R14),(4-
membered heterocyclic);
Z is an, aromatic 4-10 membered heterocyclic group, substituted by I to 4 R6
substituents;
10 R8 is -NH2, -NH(C1-C10 alkyl), or -N(C1-C10 alkyl)(Cj-C10 alkyl);
R9 is -(CR13R14)1(imidazolyl) or -(CR13R14),(pyridinyl) wherein said
imidazolyl or
pyridinyl moiety is substituted by 1 or 2 R6 substituents;
each R12 is independently selected from H, C1-C10 alkyl, -(CR13R4)j(C3-C10
cycloalkyl), -(CR13R14)L(CG-C10 aryl), and -(CR13R14)t(4-10 membered
heterocyclic); said
cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10
aryl group, a C5-
C8 saturated cyclic group, or a 4-10 membered. heterocyclic group; and the
foregoing R12
substituents, except H but including any optional fused rings, are optionally
substituted by I to
3 substituents independently selected from halo, cyano, nitro, trdiuoromethyl,
trifluoromethoxy, azido, -C(O)R13, -C(O)OR13, -OC(O)R13, -NR13C(O)Rt4, -
C(O)NR13R14,
-NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5 and each q is independently an
integer
from 1 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are
as
-(CR13R14)q or -(CR13R14)I each is independently defined for each iteration of
q or t in excess
oft;
R15 is selected from the substituents provided in the definition of R12 except
R15 is not
H;
R16 is selected from the list of substituents' provided in the definition of
R12 and
-SiR17R18R19; and,
Ri7, R18 and R19 are each independently selected from the substituents
provided in
the definition of R12 except at least one of R17, R1B and R19 is not H;
which method comprises a) obtaining a racemic mixture comprising (+) and ( )
enantiomers of a compound of formula I
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-14
4
R3 R
N
2 9
a I R~ Z
O R 6
1 R~
wherein R20 is H, C1-Ct0 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, nitro,
trifluoromethyl, trifluoromethoxy, -OR12, -OC(O)R12, -C(O)R12, -NR 12 W 3. -NR
13C(O)R'2,.
-C(O)NR12R13, cyano, -C(O)OR19, -SR12, or -(CR13R14)j(C6-C10 aryl), said aryl
R20 group being
substituted by I to 4 R6 groups, n is an integer selected from I to 3, and
wherein R1, R2, R3,
W. R6, R6, R7, R9, R12, and R18 are as defined above; b) applying a portion or
all of the
racemic mixture from step (a) to a chiral separation apparatus, under
conditions suitable for
separation of chiral molecules, and obtaining separated (+) and (-)
enantiomers of formula I
from said apparatus, subsequent to said conditions; and c) converting the
benzylidine moiety
of either the separated (+) or the separated (-) enantiomer of formula I from
step (b) with an
amine moiety R8, wherein R8 is as defined above, thereby obtaining a separated
(+). or (-)
enantiomer of a compound of formula 2.
The compounds of formula 2 possess utility in that they are inhibitors of the
enzyme
famesyl protein transferase. The compounds of formula 2 encompass the compound
of the
invention (+)-6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-
methyl]-4-(3-chloro-
phenyl}1-cyclopropylmethyl-1 H-quinolin-2-one, and hence the method described
in the
preceding paragraph can be used to synthesize (+)-6-[amino-(6-chloro-pyridin-3-
yl)-(3-
methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyi-1 H-
quinolin-2-one.
In one embodiment of the above-described method, the racemic mixture of step
(a) is,
obtained by converting to (+) and (-) enantiomers of formula 1, (+) and (-)
enantiomers, of
formula 2 in a racemic mixture
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-15-
R4
R3 ~ Rs
2 R Rs
R 7 Z
O N Rs
2 R
wherein Z, R1, R2, R3, R4, R5, R6, R7, and R9 are the same as those selected
for Z, R1,
R2, R3, R4, R5, R6, R7, and R9 in claim 9, and wherein R8 is NR12R13, R12
being selected from
H, C1-C10 alkyl, -(CR73R14)c(C3-C10 cycloalkyl), -(CR13R14),(C6-C10 aryl), and
-(CR13R14)t(4-10
membered heterocyclic), said cycloalkyl, aryl and heterocyclic R12 groups
being optionally
fused to a C6-C10 aryl group, a C5-C8-saturated cyclic group, or a 4-10
membered heterocyclic
group, and said R12,substituents, except H but including any optional fused
rings, optionally
being substituted by 1 to. 3 substituents independently selected from halo,
cyano, nitro,
trifluoromethyl, trifluoromethoxy, azido, -C(O)R13, -C(O)OR13, -OC(O)R13, -
NR19C(O)R14,
-C(O)NR13R14, -NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy,
each R 13 and R14 being independently H or C1-C6 alkyl, and where R13 and R14
are
-(CR13R14)q or -(CR'3R14)t each being independently defined for each iteration
of q or t in
excess of 1, and each t being independently an integer from 0 to 5 and each q
being
independently an integer from 1 to 5.
The conversion of the (+) and (-) enantiomers of formula 2 to the (+) and (-)
enantiomers of formula 1 in one embodiment comprises reacting the racemic
mixture
comprising the (+) and (-) enantiomers of formula 2 with a benzaldehyde of the
formula 3
(R20)~ . ...
3
wherein R20 is H, C1-C10 alkyl, C2-CIO alkenyl, C2-C10 alkynyl, halo, nitro,
trifluoromethyl, trifluoromethoxy, -OR12, -OC(O)R22, -C(O)R12, -NR 12R13, -
NR13C(O)R12,
-C(O)NR12R13, cyano, -C(O)OR13, -SR12, or -(CR13R14),(C6-C10 aryl), said aryl
R20 group being
substituted by I to 4 Rs groups; n is an integer selected from 1 to 3; each
R12 is
independently selected from H, C1-C10 alkyl, -(CR13R14)~(C3-C10 cycloalkyl), -
(CR13R14),(C6-C10
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aryl), and -(CR 13 R 14 ),(4-10 membered heterocyclic); said cycloalkyl, aryl
and heterocyclic R12
groups optionally being fused to a C6-C10 aryl group, a C$-C6 saturated cyclic
group, or a 4-10
membered heterocyclic group; and the foregoing R12 substituents, except H but
including any
optional fused rings, optionally being substituted by 1 to 3 substituents-
independently
selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -
C(O)R13, -C(O)OR13,
-OC(O)R13, -NR13C(O)R14, -C(O)NR13R14, -NR13R14, hydroxy, C1-C6 alkyl, and C1-
C6 alkoxy;
each t is independently an integer from 0 to 5 end each q is independently an
integer from 1
to 5; and each R13 and R14 is independently H or C1-C6 alkyl, and where R13
and R14 are as
-(CR13R14)q or -(CR13R14)1 each is independently defined for each iteration of
q or t in excess
of 1.
In one embodiment, for the compound of formula 3, R20 is H or -OR 12, and R12
is C1-
C10 alkyl. For example, R20 is methoxy or ethoxy. In another embodiment, n is
I or 2. In
another embodiment, n is 1 and R20 is not H.
The reaction of the compound of formula 2 with the benzaldehyde molecule of
formula 3 to form a racemate of formula I can be by condensation at ambient
temperature
under acidic conditions, for example in acetic acid. The removal of the
benzylidine group of
one of the separated enantiomers of the corrlpound of formula I subsequent to
chiral
molecule separation of the racemate of the compound of formula I to form an
amino group is
by acidic conditions, such as by addition of hydrochloric acid.
The term "halo', as used herein, unless otherwise indicated, means fluoro,
chloro,
bromo or iodo. Preferred halo groups are fluoro,cchloro and bromo.=
The term "alkyl", as used herein, unless otherwise indicated, includes
saturated
monovalent hydrocarbon radicals having straight or branched moieties. Examples
of alkyl
groups include, but are not limited to, methyl, ethyl, piopyl, isopropyl, and
t-butyl.
The term "cycloalkyl", as used herein, unless otherwise indicated, includes
cyclic alkyl
moieties wherein alkyl is as defined above. Multicyclic, such as bicyclic and
tricyclic, groups
are included in this definition.
The term "alkenyl",= as used herein, unless otherwise indicated, includes
alkyl
moieties having at least one carbon-carbon double bond wherein alkyl is as
defined above.
The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl
moieties having at least one carbon-carbon triple bond wherein alkyl is as
defined above.
Examples of alkynyl groups include, but are no limited to, ethynyl and 2-
propynyt.
The term "alkoxy", as used herein, unless otherwise indicated, includes 0-
alkyl
groups wherein alkyl is as defined above.
The term "aryl", as used herein, -unless otherwise indicated, includes an
organic.
radical derived from an aromatic hydrocarbon by removal of one hydrogen, such
as phenyl or
naphthyl.
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The term "heterocyclic", as used herein, unless otherwise indicated, means
aromatic
and non-aromatic heterocyclic groups (including saturated heterocyclic groups)
containing one
or more heteroatoms each selected from 0, S and N, wherein each ring of a
heterocyclic group
has from 4 to 10 atoms. Non-aromatic heterocyclic groups may include rings
having only 4
atoms, but aromatic heterocyclic rings must have at least 5 atoms.
Heterocyclic groups. of this
invention. unless otherwise indicated may contain one ring or more than one
ring, i.e. they may
be monocyclic or multicyclic, for example bicyclic (which may comprise non-
aromatic and/or
aromatic rings). Preferably, bicyclic heterocyclic groups of this invention
contain 6-9 members in
their ring systems. Monocyclic heterocyclic groups of this invention
preferably contain 5 or 6
members. Aromatic multicyclic heterocyclic groups include benzo-fused ring
systems. The
heterocyclic groups of this invention can also include ring systems
substituted with one or more
oxo moieties. An example of a 4 membered heterocyclic group is azetidinyl
(derived from
azetidine). An example of a 5 membered heterocyclic group is thiazolyl and-an
example of a
10 membered heterocyclic group is quinolinyl. Examples of non-aromatic
heterocyclic groups
are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
tetrahydrothiopyranyl, .
piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl,
piperidinyl, 1,2,3,6-
tetrahydropyridinyl, pyrrolinyi, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl,
pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,
imidazolinyl,
imidazolidinyl, 3-azabicycio[3.1,0]hexanyl, 3-azabicyclo[4.1.O]heptanyl, 3H-
indolyl and
quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,
imidazolyl, pyrimidinyl,
pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,
thiazolyl, oxazolyl,
isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,
benzofuranyl,.cinnolinyl,
indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
purinyl, oxadiazolyl,
thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,
benzoxazolyl,
quinazolinyl, quinoxaiinyl, naphthyridinyl, and furopyridinyl. The foregoing
groups, as .derived
from the compounds listed above, may be C-attached or N-attached where such Is
possible.
For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or
pyrr6l-3-yl (C-
attached).
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Detailed Description of the Invention
In the following Schemes and Examples, "Et" represents an ethyl moiety, and
"Me"
represents a methyl moiety. Hence, for example, "OEt" means ethoxy. Also,
"THF" means
tetrahydrofuran, and "DMF" means dimethylformamide. The term "rt" stands for
room
temperature. "HOAc" mean acetic acid. "DCM" is dichloromethane.
Compounds of formula 1 and formula 2, and enantiomers thereof, including the
compound- of the invention (+)-6-jamino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-
imidazol-4-yl)-
methylJ-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one, may be
prepared
according to the following Schemes 1 through 4:
Scheme 1
N CI \ /xN p \ /=N
1. SOC12 -N / M.0-Q-CHO
N 2. NH3 , N HOAc,11 N N
I
Me0 N OH CI O H C1 O cl
Example I Br OMe
CI I\ -N1--N
r N
N N
Mao--CHO Chiral
N HOAc, rt N N separation
OH CI O
1 (Scheme 3)
Example 2
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Scheme 2
cl N cl -N N
G I N Sr Chiral
separation
I,
Ct -------=
N S002- N p o
OR ----`r' H (Scheme 3)
Meo N 2=N~oMe ome
Example 5
NaBH
Example 2
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Scheme 3
cl i N
Example 3 chiralcel OD H chiralcel OD Example 4
Enantiomer 2
b N ~ Enantiomer 2
OMe
CI
Example 2
HCI, THE-H20
HCI, THE-H20 it
N
Example 6 chiralpak AD I -N chiralpak AD Example 7
N __, Enantiomer 2
Enantiomer) ~cxtc.
CIO
I
~
OMe
TFA, DCM, d Example 5 TFA, DCM, d
q P-MN Q N
-N _N
N W2 N a o f \ NH= N
b
Example 9 Example 8
Enantiomer 2 Enantiomer I
Scheme 4
p I -N N c 1 -N N
Chiral
separation
N NaN02, H2SO4 off N Example 12 and Example 13
0 / LA 0 N q
OMe
Example 2
The above Schemes 1 through 4 illustrate non-limiting examples of the claimed
methods of the invention.
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Referring to Scheme 1, compounds of formula 2,
exemplified by Example 1 in the Scheme, can be prepared from
corresponding 2-alkoxy quinoline compounds by addition of
thionyl chloride under an atmosphere of N2-
Compounds of formula 2 can also be prepared as
described in U.S. Patent No. 6,258,824 and published as
WO 00/47574.
The compound of formula 2 is condensed with a
benzaldehyde compound of formula 3, such as p-anisaldehyde,
to form a racemate of formula 1. The condensation can be in
acidic conditions, such as in acetic acid, at ambient
temperature. This racemate of formula 1 can optionally be
derivatized to form other racemates of formula 1, such as
the title compound of Example 2, prior to chiral molecule
separation (Scheme 3).
As an alternative to chiral molecule separation of
the benzylidine molecule of formula 1, a compound of
formula 2 wherein R8 comprises a benzylamino group can be
separated on a chiral column (see Scheme 2), for subsequent
formation of a compound of formula 2 wherein R8 is -NH2,
-NH (C1-Clo alkyl) , or -N (C1-C10 alkyl) (C1-C10 alkyl) (as in
Scheme 3). Referring to Scheme 2, the benzylamino compound
of formula 2 can be prepared from the corresponding
benzylidine compound, exemplified by Example 2 in Scheme 2,
by addition of sodium borohydride to the benzylamino
compound in methanol. Alternatively, the benzylamino
compound of formula 2 can be prepared by treating the
(6-hydroxymethyl)2-alkoxy quinoline compound with thionyl
chloride under an atmosphere of dry nitrogen to form the
quinolinone, followed by condensation with a benzylamino
compound optionally substituted on the phenyl group, such as
p-methoxybenzylamine. This condensation can occur at a
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temperature of about -78 C, under an atmosphere of dry
nitrogen.
Referring to Scheme 3, either the benzylamino
compound of formula 2, or the benzylidine of formula 1, can
be applied to a chiral molecule separation column. The
resulting (+) and/or (-) enantiomer of either the
benzylamino compound of the benzylidine compound can be
converted to an enantiomer of a compound of formula 2
wherein R8 is -NH2, -NH (C1-C10 alkyl) , or -N (C1-Clo
alkyl) (C1-C10 alkyl) . The benzylidine moiety is converted to
an amino group under acidic conditions, for example by
addition of hydrochloric acid. The benzylamino group is
converted to an amino group also under acidic conditions,
for example by addition of TFA.
Scheme 4 illustrates preparation of the
dihydrochloride salt of an enantiomer of a compound of
formula 2 wherein RB is -NH2, -NH (C1-C10 alkyl), or -N (C1-Clo
alkyl) (C1-C10 alkyl) directly from chiral separation of the
corresponding 6-hydroxymethyl quinolinone to (+) and (-)
enantiomers.
In Schemes 1 through 4, Example 8 is (+)-6-[amino-
(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-
4-(3-chloro-phenyl)-1-cyclopropylmethyl-lH-quinolin-2-one,
the compound of the invention.
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The compound (+)-6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-
methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyi-1 H-quinolin-2-one, and its
pharmaceutically
acceptable salts and solvates, and prodrugs of the compound, can be
administered orally,
transdermally (e.g., through the use of a patch), parenterally or topically.
Oral administration
is preferred. In general, the compound, and its pharmaceutically acceptable
salts and
solvates, and its prodrugs, are most desirably administered in dosages ranging
from about
1.0 mg up to about 500 mg per day, preferably from about 1 to about 100 mg per
day in
single or divided (i.e., multiple) doses. The compound, or its salt or
solvate, or a prodrug
thereof, will ordinarily be administered in daily dosages ranging from about
0.01 to about 10
mg per kg body weight per day, in single or divided doses. Variations may
occur depending
on the weight and condition of the person being treated and the particular
route of
administration chosen. In some instances, dosage levels below the lower limit
of the
aforesaid range may be more than adequate, while in other cases still larger
doses may be
employed without causing any harmful side effect, provided that such larger
doses are first
divided into several small doses for administration throughout the day.
For the combination therapies and pharmaceutical compositions described
herein,
the effective amounts of the compound of the invention and of the
chemotherapeutic or other
agent useful for inhibiting abnormal cell growth (e.g., other
antiproliferative agent, anti-
angiogenic, signal transduction inhibitor or immune-system enhancer) can be
determined by
those of ordinary skill in the art, based on the effective amounts for the
compound described
herein and those known or described for the chemotherapeutic or other agent.
The
formulations and routes of administration for such therapies and compositions
can be based
on the information described herein for compositions and therapies comprising
the compound
of the invention as the sole active agent and on information provided for the
chemotherapeutic or other agent in combination therewith.
The compound.of the invention, or its salt or solvate or prodrug, may be
administered
alone or in combination with pharmaceutically acceptable carriers or diluents
by any of the
routes previously indicated, and such administration may be carried out in
single or multiple
doses. More particularly, the compound of this invention or its salt or
solvate or prodrug can
be administered in a wide variety of different dosage forms, i.e., combined
with various
pharmaceutically acceptable inert carriers in the form of tablets, capsules,
lozenges, troches,
hard candies, powders, sprays, creams, salves, suppositories, jellies, gels,
pastes, lotions,
ointments, elixirs, syrups, and the like. Such carriers include solid diluents
or fillers, sterile
aqueous media and various non-toxic organic solvents, etc. Moreover, oral
pharmaceutical
compositions can be suitably sweetened and/or flavored.
For oral administration, tablets containing various excipients such as
microcrystalline
cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine
may be
employed along with various disintegrants such as starch (and preferably com,
potato or
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tapioca starch), alginic acid and certain complex silicates, together with
granulation binders
like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as
magnesium stearate, sodium lauryl sulfate and talc are often very useful for
tabletting
purposes. Solid compositions of a similar type may also be employed as fillers
in gelatin
capsules; preferred materials in this connection also include lactose or milk
sugar as well as
high molecular weight polyethylene glycols. When aqueous suspensions and/or
elixirs are
desired for oral administration, the active ingredient may be combined with
various
sweetening or flavoring agents, coloring matter or dyes, and, if so desired,
emulsifying and/or
suspending agents as well, together with such diluents as water, ethanol,
propylene glycol,
glycerin and various like combinations thereof.
For parenteral administration, solutions of the compound of the invention, or
salt
thereof, in either sesame or peanut oil or in aqueous propylene glycol may be
employed. The
aqueous solutions should be suitably buffered if necessary and the liquid
diluent first
rendered isotonic. These aqueous solutions are suitable for intravenous
injection purposes.
The oily solutions are suitable for intra-articular, intra-muscular and
subcutaneous injection
purposes. The preparation of all these solutions under sterile conditions is
readily
accomplished by standard pharmaceutical techniques well-known to those skilled
in the art.
Additionally, it is also possible to administer the compound, salt, or solvate
topically
and this may preferably be done by way of creams, jellies, gels, pastes,
ointments and the
like, in accordance with standard pharmaceutical practice.
The compound of the invention may also be administered to a mammal other than
a
human. The dosage to be administered to a mammal will depend on the animal,
species and
the disease or disorder being treated. The compound may be administered to
animals in the-
form of a capsule, bolus, tablet or liquid drench. The compound may also be
administered to
animals by injection or as an implant. Such formulations are prepared in a
conventional
manner in accordance with standard veterinary practice. As an alternative, the
compound
may be administered with the animal feedstuff, and for this purpose a
concentrated feed
additive or premix may be prepared for mixing with the normal animal feed.
The compounds of formula 1 and formula 2, including the compound of the
invention
(+)-6-(amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methylj-4-(3-
chloro-phenyl)-1-
cyclopropylmethyl-1 H-quinolin-2-one, exhibit activity as Ras famesylation
inhibitors and are
useful in the treatment of cancer and the inhibition of abnormal cell growth
in mammals,
including humans. The activity of the compounds of formula 1 and formula 2 as
Ras
farnesylation inhibitors may be determined by their ability, relative to a
control, to inhibit Ras
farnesyl transferase in vitro. An example of one such procedure is described
below.
A crude preparation of human famesyl transferase (FTase) comprising the
cytosolic
fraction of homogenized brain tissue is used for screening compounds in a 96-
well assay
format. The cytosolic fraction is prepared by homogenizing approximately 40
grams of fresh
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tissue in 100 MI of sucrose/MgCI2/EDTA buffer (using a Dounce homogenizer; 10-
15 strokes),
.centrifuging the homogenates at 1000 g for 10 minutes at 4 C, re-centrifuging
the supernatant at
17,000 g for 15 minutes at 4 C, and then collecting the resulting supernatant,
This supematant
is diluted to contain a final concentration of 50 mM Tris HCI (pH 7.5), 5 mM
DTT, 0.2 M KCI, 20
M ZnC12i 1 mM PMSF and re-centrifuged at 178,000 g for 90 minutes at 4 C. The
supernatant,
termed "crude FTase" is assayed for protein concentration, aliquoted, and
stored at -70 C.
The assay used to measure in vitro inhibition of human FTase is a modification
of the
method described by Amersham LifeScience for using their Farnesyl transferase
(3H)
Scintillation Proximity Assay (SPA) kit (TRKQ 7010). FTase enzyme activity is
determined in a
volume of 100 l containing 50 mM N-(2-hydroxy ethyl) piperazine-N-(2-ethane
sulfonic acid)
(HEPES), pH 7.5, 30 mM MgCI2i 20 mM KCI, 25 mM Na2HPO4, 5 mM dithiothreitol
(DTT),
0.01% Triton X-100, 5% dimethyl sulfoxide (DMSO), 20 mg of crude FTase, 0.12
mM 13H)-
famesyl pyrophosphate ([3H]-FPP; 36000 dpm/pmole, Amersham LifeScience), and
0.2 M of
biotinylated Ras peptide KTKCVIS .(Bt-KTKCVIS) that is 'N-temiinally
biotinylated at its alpha
amino group and was synthesized and purified by HPLC in house. The reaction is
initiated by
addition of the enzyme and terminated by addition of EDTA (supplied as the
STOP reagent in lot
TRKQ 7010) following a 45 minute incubation at 37 C. Prenylated and
unprenylated Bt-
KTKCVIS is captured by adding 150 l of streptavidin-coated SPA beads (TRKQ
7010) per well
and incubating the reaction mixture for 30 minutes at room temperature. The
amount of
radioactivity bound to the SPA beads is determined using a MicroBetaa 1450
plate counter.
Under these assay conditions, the enzyme activity is linear with respect to
the concentrations of
the prenyl group acceptor, Bt-KTKCVIS, and crude FTase, and inhibition of BI-
KTKCVIS
interaction with FTase can be detected. The enzyme activity is saturating with
respect'to the
prenyl donor, FPP. The assay reaction time is also in the linear range.
The test compounds are routinely dissolved in 100% DMSO. Inhibition of famesyl
transferase activity is determined by calculating percent incorporation of
tritiated-famesyl in the
presence of the test compound versus its incorporation in control wells
(absence of inhibitor).
ICS values, that is, the concentration required to produce half maximal
famesylation of Bt
KTKCVIS, is determined from the dose-responses obtained.
The compound (+)-6-[amino-(6-chloro-py(diri-3-yl)-(3-methyl-3H-imidazoi-4-yi)-
methyl}-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one was found to
have an ICBD
value for inhibiting famesylation of the biotinylated KTKCVIS-peptide of less
than 500 nM using
the above-described assay.
The following Examples are provided to illustrate aspects of the subject
invention.
They are not intended, nor should they be construed, to limit the invention as
more fully
described herein and set forth in the claims.
* Trade-mark
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EXAMPLE I
6 TAmino-(6-chloro-pyridin-3-vll-(3-methyl.3H-imidazol-4-yl)-methyl]-4-(3-
chloro-
phenyll-1 H-quinolin-2-one
To [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(6-chloro-py(din-3-yl)-(3-
methyl-3H-
imidazol-4-yl)-methanol (20.95 g, 42.76 mmol) in toluene (150 ml) under an
atmosphere of
dry N2 was added thionyl chloride (31.19 ml, 427 mmol) dropwise. The reaction
mixture was
heated at 85 C for 15 hours. Solvent and the excess thionyl chloride were
removed under
reduced pressure. The crude chloride was taken up in toluene and concentrated
under
vacuum. The resulting solid was dissolved in THF (10 ml) and to this solution
at -78 C was
bubbled ammonia gas (NH3) for 10 minutes. The reaction mixture was stirred at
ambient
temperature under an atmosphere of N2 for an additional 1.5 hours. After
removal of THF, the
product mixture was partitioned between CHCI3 and water. The organic layer was
washed,
dried over MgSO4 and concentrated under vacuum to give the crude product. It
was
chromatographed on silica gel with CHCI3 then MeOH-CHCI3-NH4OH (2 : 98: 0.1 to
7 : 93 :
0.1) as eluents to afford the title compound (17.89 g, 88 % yield).
C.I. m/z 473.8 [M+1].
EXAMPLE 2
4-(3-Chloro-phenvll-6-1(6-chloro-pyridin-3-v1)-1(4-methoxv-benzylidene)-aminol
(3-methyl-3H-imidazol-4-vi)-methvll-l-cyclopropylmethyl-1 H-quinolin-2-one
2A. 4-(3-Chloro-pheny11-6-r(6-chloro-pyridin-3-yi)-T(4-methoxv-benzviidene)
aminol-(3-methyl-3H-imidazol-4-vn-methvll-1 H-quinolin-2-one
To a solution of thetitle compound of Example 1 (11.89 g, 25.03 mmol) in
acetic acid
(75 ml) was added p-anisaldehyde (6.09 ml, 50.06 mmol) dropwise. The reaction
mixture
was stirred at ambient temperature for 4 hours after which time it was cooled
to 0 C. '10 ml of
ammonia hydroxide was added followed by addition of ethyl acetate. After
separation, the
organic layer was washed with brine, dried over MgSO4 and concentrated under
vacuum to
yield the crude product. It was chromatographed on silica gel with MeOH-CHCI3-
NH4OH (1 :
99: 0.1 to 5 : 95 : 0.1) as eluents to afford the title compound of Example 2A
as a white solid
(11.58 g, 78 % yield).
CI-MS: m/z 594.1, 596.1 [M + 1].
2B. 4-(3-Chloro-phenvll-6-r(6-chloro-pyridin-3-y1)-1(4-methoxv-benzylidene)
ami nol-(3-methyl. 3H-imidazol-4-vl)-methvll-l -cyclopropylmethyl-1 H-quinolin-
2-one
To a solution of the title compound of Example 2A (10.78 g, 18.14 mmol) in THF
(2.5
ml) was added (bromomethyl)cyclopropane (2.42 ml, 24.96 mmol),
benzyltriethylammonium
chloride (2.59 =g, 11.34 mmol), sodium. iodide (0.85 g, 5.67 mmol) and a
solution of 40 %
.aqueous NaOH (30 ml). The reaction mixture was heated at 65 C for 4 hours
after which
time THF was removed. The crude product mixture was partitioned between CHC13
and
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water. The organic layer was washed with brine, dried over MgSO4 and
concentrated under
vacuum to give the crude product. It. was chromatographed on silica gel McOH-
CHCI3-
NH40H (1.5 : 98.5 : 0.1 to) as the eluents to afford the title compound as a
white solid (8.49 g,
13.10 mmol, 72 % yield).
5. Cl-MS: m/z 648.1 [M+1]. =
EXAMPLE 3 and EXAMPLE 4
+) and (-) Enantiomers of 4-(3-Chloro-phenyl)-6-i(6-chloro-pvridin-3-vll-f(4-
methoxy-benzylidene)-aminol-(3-methyl-3H-im idazol-4-yl)-methvll-l -
cyclopropylmethyl-
1 H-auinolin-2-one
The title compound of Example 2 (1.322 g) was separated into its enantiomers
and
purified by high-performance liquid chromatography over CHIRALCELTM OD
(manufactured
by Daicel Chemical Industries, LTD, Osaka, Japan) (2.2 cm x 25 cm, 10 lam;
eluents
Hexane/ethanol/methanol/diethylamine 80/10/10/0.1; 25 C). Under these
conditions, 0.595'g
of the faster eluting enantiomer A (Example 3): (+)-4-(3-chloro-phenyl)-6-[(6-
chloro-pyridin-3-
15= yl)-[(4-methoxy-benzylidene)-amino]-(3-methyl-3H-imidazol-4-yl}methyl]-1-
cyclopropylmethyl-IH-quinolin-2-one, and 0.511 g of the slower moving
enantiomer B
(Example 4): (-)-4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-[(4-methoxy-
benzylidene)-
amino]-(3-methyl-3H-imidazoi-4-yi)-methyl}1-cyclopropylmethyl-lH-quinolin-2-
one were
obtained. Both enantiomers were >99% optical pure.
EXAMPLE 5
4-(3-Chloro-phenyl)-6-f(6-chloro-pvridin-3-yll-(4-methoxv-benz:ylamino)43-
methyl-3H=imidazol-4-vl)-methvll-1-cyclopropylmethyl-1H-Quinolin-2-one
5A. 4-(3-Chloro-phenyl)-64(6-chloro-pvridin-3-y1)-(4-methoxv-benzylamino)-(3-
methy$-
3H-imidazol-4-yil-methvll-1 H-auinolin-2-one
To [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(6-chloro-py(din-3-yl}(3-
methyl-3H-
imidazol-4=yi)-methanol (1.08 g, 2.21 mmol) in toluene (8.5 ml) under an
atmosphere of dry
N2 was added thionyl chloride (1.61 ml, 22.06 mmol) dropwise. The reaction
mixture was
heated at 85 C for 15 hours. Solvent and the excess thionyl chloride were
removed under
reduced pressure. The crude chloride was taken up in toluene and concentrated
under
vacuum. The resulting solid was dissolved in THE (10 ml) and to this solution
at 78 C was
added p-methoxybenzylamine (1.44 ml, 11.03 mmol) in THE (2 ml). The reaction
mixture was
stirred at -78 C for 3 hours under an atmosphere of N2 for 3 hours. After
removal of THF,
the product mixture, was partitioned between CHC13 and. water. The organic
layer was
washed, dried over MgSO4 and concentrated under vacuum to give the crude
product. It was
chromatographed on silica gel with MeOH-CHCI3-NH4OH (2 : 98 : 0.1 as eluents
to afford
the title compound of Example 5A(6.482 g, 52 % yield).
C.I. m/z 596.1 [M+1].
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56. 4-(3-Chloro-phenyl)-6-1(6-chloro-pvridin-3-yl)-(4-methoxy-benzvlamino)-(3-
methyl-3H-im idazol-4-yl)-methvll-1-cvclopropvlmethvl-1 H-quinolin-2-one
The same procedure was used as that described in Example 2B, except that 4-(3-
chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-(4-methoxy-benzylamino)-(3-methyl-3H-
imidazol-4-
yi)-methyl)-1 H-quinolin-2-one (0.682 g, 1.14 mmol) was used in the place of 4-
(3-chloro-
phenyl)-6-[(6-chloro-pyridin-3-yi)-[(4-methoxy-benzylidene)-amino]-(3-methyl-
3H-imidazol-4-
yl)-methyl]-1 H-quinolin-2-one to give the title compound (0.315 g, 0.485
mmol, 43 % yield).
C.I. m/z 650.1 [M+1].
EXAMPLE 6 and EXAMPLE 7
( ) and (-) Enantiomers of 4-(3-chloro-phenyl)-6-f(6-chloro-pvridin-3-yll-(4-
methoxy-benzvlamino)-(3-methyl-3H-imidazol-4-yl)-methvll-1-cvclopropvlmethvl-1
H-
guinolin-2-one
The title compound of Example 5, 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-
yl)-(4-
methoxy-benzylamino)-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1
H-quinolin-
2-one (3.05 g) was separated into its enantiomers and purified by high-
performance liquid
chromatography over CHIRALPAKTm AD (manufactured by Daicel Chemical
Industries, LTD,
Osaka, Japan) (2.2 cm x 25 cm, 10 m; eluent: -Hexane/ethanol/methanol/
diethylamine
80/10/10/0.1; 25 C). Under these conditions, 1.56 g of the faster eluting
enantiomer A
(Example 6): (+)-4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-y()-(4-methoxy-
benzylamino)-(3-
methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one, and
1.07 g of the
slower moving enantiomer B (Example 7): (-)-4-(3-chloro-phenyl)-6-[(6-chloro-
pyridin-3-yl}(4
methoxy-benzytamino)-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropytmethyl-1
H-quinolin-
2-one were obtained. Both enantiomers were >99% optical pure.
EXAMPLE 8
(+)-6-(Amino-(6-chloro-pvridin-3-yl)-(3-methvl-3H-imidazol-4-yl)-methvll-4-(3-
chloro-phenyl)-1-cvclopropvlmethvl-1 H-q uinolin-2-o ne
Procedure 1, Conversion of Example 4
To a solution of the title compound of Example 4, the slower moving enantiomer
of 4-
(3-chloro-phenyl)-6-[(6-ch)oro-pyridin-3-yl)-[(4-methoxy-benzylidene)-amino]-
(3-methyl-3H-
imidazol-4-yi)-methyl]-1-cyclopropytmethyl-1H-quinolin-2-one (1.41 g, 1.74
mmol) in THE
(200 ml) was added 2N hydrochloric acid (20 ml) slowly. The reaction mixture
was stirred at
ambient temperature for 1.5 hour after which time it was cooled to 0 C. An
aqueous solution
of potassium carbonate was added followed by addition of ethyl acetate. After
separation, the
organic layer was washed with brine, dried over MgSO4 and concentrated under
vacuum to
= give the crude product It was chromatographed on silica gel with MeOH-CHCI3-
NH4OH (1:
99 : 0.1 to 2 : 98 : 0.1) as the eluents to afford the title compound as a
white solid ( 0.844 g,
1.59 mmol, 90 % yield). It is the faster eluting enantiomer of 6-[amino-(6-
chloro-pyridin-3-yi)-
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(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1
H-quinolin-2-
one with >99 % optical purity.
C.I. m/z: 530.1, 532.1 [M+1].
Procedure 2, Conversion of Example 7
To a solution of the title compound of Example 7 -(the slower moving
enantiomer),
(-)4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-(4-m eth oxy-benzyl-amino)-
(3-methyl-3H-
imidazol-4-yl)-methyl)-1-cyclopropylmethyl-1H-quinolin-2-one (1.07 g, 1.64
mmol) in
dichloromethane (6.5 ml) was added trifluoroacetic acid (TFA, 6.5 ml) slowly
at 0 C. The
reaction mixture was stirred at ambient temperature for 80 minutes after which
time it was
diluted with DCM (10 ml) and was poured into a chilled aqueous solution of
potassium
carbonate. After separation, the organic layer was washed with brine, dried
over MgSO4 and
concentrated under vacuum to give the crude product. It was chromatographed on
silica gel
with McOH-CHCl3-NH4OH (1.5: 98.5 : 0.15) as the eluents to afford the title
compound as a
white solid (0.588 g, 1.11 mmol, 68 % yield). It is the faster eluting
enantiomer of 6-[amino-
(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl}-4-(3-chloro-
phenyl)-1-
cyclopropylmethyl-1H-quinolin-2-one with >99 % optical purity.
C.I. mtz: 530.1, 532.1 [M+1]. .
EXAMPLE 9
(-)-6-(Amino-(6-chloro-pyridin-3-vl)-(3-methyl-3H-imidazol-4-y1)-methyll-4-(3-
chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one
Procedure 1, Conversion of Example 3
Following the same procedure as that described in Example 8 for the conversion
of
Example 4, the title compound of Example 3, the faster eluting enantiomer of 4-
(3-chloro-
phenyl}-6-[(6-chloro-pyridin-3-yl)-[(4-methoxy-benzylidene)-amino]-(3-methyl-3
H-imidazol-4-
yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (1.98 g, 3.05 mmol) afforded
the title
compound as a white solid (1.51 g, 2.85 mmol, 93 % yield). It is the slower
moving
enantiomer of 6-[amino=(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-
methyl]-4-(3-
chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one with >99 % optical
purity.
W. m/z: 530.1, 532.1 [M+1].
Procedure 2, Conversion of Example 6
Following the same procedure as that described in Example 8 for the conversion
of
Example 7, the title compound of Example 6 (the faster eluting enantiomer, (+)-
4-(3-chloro-
phenyl)-6-[(6-chloro-pyridin-3-yi)-(4-methoxy-benzylamino)-(3-methyl-3H-
imidazol-4-yl)-
methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (0.249 g, 0.384 mmol) afforded
the He 35 compound as a white solid (0.137 g, 0.252 mmol, 66 % yield). It is
the slower moving
=enantiomer of , 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-
methyl}-4-(3-
chloro-phenyl)-1-cyclopropylmethyl-MH-quinolin-2-one with >98 % optical
purity.
W. m/z: 530.1, 532.1 [M+1].
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EXAMPLE 10 and EXAMPLE 11
(+) and (-1 Enantiomers of 4-(3-Chloro-phenyl)-6-T(6-chloro-pvridin-3-vl)-
hydroxy-(3-methyl-3H-imidazol-4-yil-methvll-l-cvclopropvlmethvl-1 H-guinofin-2-
one
To a solution of the title compound of Example 2 (4.31 g, 6.64 mmol) in THE
(30 ml)
was added 38 -ml of 1 N sulfuric acid, After the mixture was cooled to 0 C, a
solution of
sodium nitrite (NaN02, 1.45 g, 20.99 mmol) in water (10 ml) was added
dropwise. The
reaction mixture was stirred at ambient temperature for 7 hours after which
time ethyl acetate
was added. The organic layer was washed with saturated potassium carbonate,
brine, dried
over MgSO4 and concentrated under vacuum to give the crude product. It was
chromatographed on silica gel with MeOH-CHCI3-NH4OH (2: 98: 0.1) as the
eluents to afford
4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-
yl)-methyl]-1-
cyclopropylmethyl-1 H-quinolin-2-one as a white solid (3.32 g, 94 % yield).
CI-MS: m/z 530.9 [M+1].
(+/-)-4-(3-Chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-
imidazol-4-
yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (3.002 g) was separated into
its
enantiomers and purified by high-performance liquid chromatography over
CHIRALCELT" OD
(manufactured by Daicel Chemical Industries, LTD, Osaka, Japan) (2.2 cm x 25
cm, 10 m;
eluent: Hexane/ethanol/methanol 8517.5/7.5; 25 C). Under these conditions,
1.14 g of the
faster eluting enantiomer A, (Example 10): (-)-4-(3-chloro-phenyl)-6-[(6-
chloro-pyridin-3-yl)-
hydroxy-(3-methyl-3H-imidazol-4-yi)-methyl]-1-cyclopropylmethyl-lH-quinolin-2-
one and 0.7 g
of the slower moving enantiomer B (Example 11): (+-4-(3-chloro-phenyl)-6-[(6-
chloro-py(din-
3=yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1 H-
quinolin-2-one
were obtained.
Both enantiomers-were >98 % optically pure.
- EXAMPLE 12
(+)-6-TAm i no-(6-ch loro-pyridi n-3-yl)-(3-methyl-3 H-imidazol-4-yl)-methvll-
4-(3-
chloro-phenyl)-1-cyclopropylmethyl-1H-guinolin-2-one, dihvdrochloride salt
To a solution of (+)-4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-
methyl-
3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1 H-quinolin-2-one (0.844 g,
1.59 mmol) in
DCM (10 ml) was added a solution of HCI in ethyl ether (1M, 4,77 ml, 4.77
mmol). The slurry
solution 'was stirred for '2 hours. After filtration, the title compound of
Example 12 was
obtained as a white solid (0.78 g, 1.29 mmol, 81.4 % yield).
EXAMPLE 13
(-).6-TAm i no-(6-ch loco-pvridin-3-vi)-(3-methyl-3H-imidazol-4-vll-methvll-4-
(3-
chloro-phenyl)-1=cvclopropvlmethvl-1H-quinofin-2-one, dihvdrochloride salt
Following the same procedure as that described in Example 12, (-)-4-(3-chloro-
phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yi)-methyl]-
1-
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cyclopropylmethyl-1 H-quinolin-2-one (0.252 g, 0.474 mmol) generated the
dihydrochloride
salt as a white solid (0.167 g, 0.28 mmol, 58 % yield).
EXAMPLE 14
6-[Amino-(6-methyl-pvridin-3-yl)-(3-methyl-3H-imidazol-4-y1)-methvll-4-(3-
chloro-phenyl)-1-methyl-IH-quinolin-2-one
14A. 6-[Amino-(6-methyl-pvridin-3-vl)-(3-methyl-3H-imidazol-4-yll-methvll-4-(3-
chloro-phenyl)-1 H-quinolin-2-one
To j4-(3-chloro-phenylr2-methoxy-quinolin-6-yl]-(6-methyl-pyridin-3-yl)-(3-
methyl-3H-
imidazol-4-yl)-methanol (0.118 g, 0.251 mmol) in toluene (5 ml) under an
atmosphere of dry N2
was added thionyl chloride (0.18 ml, 2.51 mmol) dropwise. The reaction mixture
was heated
at 85 C for 15 hours. Solvent and the excess thionyl chloride were removed
under reduced
pressure. The crude chloride was taken up in toluene and concentrated under
vacuum. The
resulting solid was dissolved in THF (10 mL) and to this solution at -78 C was
bubbled
ammonia gas (NH3) for 10 minutes. The reaction mixture was stirred at ambient
temperature
15' under an atmosphere of N2 for additional 1.5 hours. After removal of THF,
the product mixture
was partitioned between CHCI3 and water. The organic layer was washed, dried
over MgSO4
and concentrated under vacuum to give a brown solid. This was chromatographed
on silica gel
with CHC13 then MeOH-CHCI3-NH4OH (5 : 95 : 0.1 to 10 : 89:1) as eluents to
afford the title
compound of Example 14A as a white solid (53 mg, 0.116 mmol, 46.4 % yield).
C.I. m/z 456.3 jM+11.
14B. 6-[Amino-(6-methyl-pvridin-3-yll-(3-methyl-3H-im idazol-4-vfl-methvll-4-
(3-
chloro-phenyl)-1-methyl-1 H-quinolin-2-one
To a solution of the title compound of Example 14A (26 mg, 0.057 mmol) in THE
(2.5
ml) was added a solution of 40 % aqueous NaOH (0.1 ml),=benzyltriethylammonium
chloride
(6.5 mg. 0.074 mmol) and methyl iodide (0.0046 ml, 0.0743 mmol). The reaction
mixture was
stirred at ambient temperature for 3 hours after which time THE was removed.
The crude
product mixture was partitioned between CHCI3 and water. The organic layer was
washed
with brine, dried over MgSO4 and concentrated under vacuum to give the crude
product It
was purified by thin layer chromatography with MeOH-CHCI3-NH40H (5 : 95 : 0.1)
as the
mobile phase to afford the title compound as a white solid (14.1 mg, 0.031
mmol, 54 % yield).
Cl-MS: m/z 470.0 IM+1].
EXAMPLE 15
6;(Amino-(6-methyl-pyridi n-3-yi)-(3-methyl-3H-imidazol-4-yi)-methvll-4-(3-
chloro-phenyi)-1-cyclopropylmethyl-1 H-quinolin-2-one
To a solution of the title compound of Example 51A (26 mg, 0.057 mmol) in THF
(2.5
ml) was added (bromomethyl)cyclopropane (0.0075 mi, 0.080 mmol),
benzyltriethylammonium chloride (6.5 mg. 0.0286 mmol), sodium iodide (2.57 mg,
0.0171
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mmol) and a solution of 40% aqueous NaOH (0.57 mi). The reaction mixture was
heated at
65 C for 3 hours after which time THE was removed. The crude product mixture
was
partitioned between CHC13 and water. The organic layer was washed with brine;
dried over
NIgSO4 and concentrated under vacuum to give the crude product. It was
chromatographed
on silica gel with MeOH-CHCI3-NH40H (2 : 98 : 0.1 to 5: 95 : 0.1) as. the
eluents to afford the
title compound as a white solid (11 mg, 0.022 mmol, 38 % yield).
CI-MS: m/z 510.3 [M-Fi].
EXAMPLE 16
6-(Amino-(pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyll-4-(3-chIoro-
phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one
To a solution of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazoi-4-y1)-
methyl}-
4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one (0.408 g, 0.77 mmol)
in pyridine
(0.77 ml) was added trichloroethyl chloroformate (0.159 ml, 1.15 mmol) at 0 C.
The reaction
mixture was gradually warmed to room temperature and stirred overnight. After
removal of
pyridine, the product mixture was taken into dichloromethane and water. After
separation, the
organic layer was washed with brine, dried over MgSO4 and concentrated under
vacuum to
give the crude product. It was chromatographed on silica gel with M6OH-CHCI3-
NH40H (1 :
99 : 0.1) as the eluents to afford the trichloroethyl carbamate as a white
solid (0.451 g, 0.64
mmol, 83 % yield).
Cl-MS: m1z 705.8, 708.0 [M+1].
To a solution of the trichloroethyl carbamate (34 mg, 0.048 mmol) in formic
acid (0.96
ml) was added zinc powder (87 mg). The reaction mixture was stirred at ambient
temperature for 15 minutes. After addition of methanol, the mixture was
filtered through the
Celite*, followed by a saturated solution of potassium carbonate. The
filtrated was evaporated
and was extracted with chloroform. The organic layer was washed with brine,
dried over
MgSO4 and concentrated under vacuum to give the crude product. It was
chromatographed
on silica gel with MeOH-CHCI3-NH40H (2: 98: 0.) as the eluents to afford the
title compound
as a white solid (25 mg, 100 % yield).
CI-MS: m/z 496.1 [M+1].
* Trade-mark
