U.S. patent application number 11/932269 was filed with the patent office on 2008-08-14 for inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas.
Invention is credited to Jacques Dumas, David E. Gunn, Holia Hatoum-Mokdad, Uday Khire, Timotthy B. Lowinger, Mary-Katherine Monahan, Bernd Riedl, William J. Scott, Robert N. Sibley, Roger A. Smith, Jill E. Wood.
Application Number | 20080194580 11/932269 |
Document ID | / |
Family ID | 46322161 |
Filed Date | 2008-08-14 |
United States Patent
Application |
20080194580 |
Kind Code |
A1 |
Dumas; Jacques ; et
al. |
August 14, 2008 |
Inhibition Of Raf Kinase Using Quinolyl, Isoquinolyl Or Pyridyl
Ureas
Abstract
This invention relates to a group of quinolyl, isoquinolyl and
pyridyl ureas, their the use in treating raf mediated diseases, and
pharmaceutical compositions which contain these ureas for use in
such therapy.
Inventors: |
Dumas; Jacques; (Orange,
CT) ; Riedl; Bernd; (Wuppertal, DE) ; Khire;
Uday; (Hamden, CT) ; Sibley; Robert N.; (North
Haven, CT) ; Hatoum-Mokdad; Holia; (Hamden, CT)
; Monahan; Mary-Katherine; (Hamden, CT) ; Gunn;
David E.; (Hamden, CT) ; Lowinger; Timotthy B.;
(Nishinomiya City, JP) ; Scott; William J.;
(Guilford, CT) ; Smith; Roger A.; (Madison,
CT) ; Wood; Jill E.; (Hamde, CT) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO, & BRANIGAN, P.C.;Arlington Courthouse Plaza I
Suite 1400, 2200 Clarendon Boulevard
Arlington
VA
22201
US
|
Family ID: |
46322161 |
Appl. No.: |
11/932269 |
Filed: |
October 31, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11158048 |
Jun 22, 2005 |
7371763 |
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11932269 |
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10125369 |
Apr 19, 2002 |
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11158048 |
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60367376 |
Apr 20, 2001 |
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Current U.S.
Class: |
514/253.05 ;
514/310; 514/313; 514/332; 514/352 |
Current CPC
Class: |
C07D 213/40 20130101;
A61P 35/00 20180101 |
Class at
Publication: |
514/253.05 ;
514/332; 514/352; 514/310; 514/313 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/444 20060101 A61K031/444; A61K 31/44 20060101
A61K031/44; A61P 35/00 20060101 A61P035/00; A61K 31/47 20060101
A61K031/47 |
Claims
1-20. (canceled)
21. A method for inhibiting raf kinase in a patient, comprising
administering an effective amount of a compound of one of the
following formulae A-D-B (I) A'-D-B' (II) and A''-D-B'' (III) or a
pharmaceutically acceptable salt thereof, wherein D is
--NH--C(O)--NH--, A is selected from the group consisting of
substituted t-butylpyridyl groups, unsubstituted t-butylpyridyl
groups, substituted (trifluoromethyl)pyridyl groups, unsubstituted
(trifluoromethyl) pyridyl groups, substituted isopropylpyridyl
groups, unsubstituted isoproplpyridyl groups, substituted
(2-methyl-2-butyl)pyridyl groups, unsubstituted (2-methyl-2-butyl
pyridyl) groups, substituted (3-methyl-3-pentyl)pyridyl groups, and
unsubstituted (3-methyl-3-pentyl)pyridyl groups, substituted
(3-ethyl-3-pentyl)pyridyl groups and unsubstituted
(3-ethyl-3-pentyl)pyridyl groups A' is a substituted isoquinolinyl
group or unsubstituted isoquinolinyl group or an unsubstituted
quinolinyl group, A'' is a substituted quinolinyl group, B, B' and
B'' are each, independently, a substituted or unsubstituted bridged
cyclic structure of up to 30 carbon atoms of the formula
-L-(ML.sup.1).sub.q wherein L comprises a cyclic moiety having at
least 5 members and is bound directly to D, L.sup.1 comprises a
cyclic moiety having at least 5 members, M is a bridging group
selected from the group consisting of --O--, --S--, --N(R.sup.7)--,
--(CH--).sub.m--, --C(O)--, --CH(OH)--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mS--, --(CH.sub.2).sub.mN(R.sup.7)--,
--O(CH.sub.2).sub.m, CHX.sup.a--, --CX.sup.a.sub.2--,
--S--(CH.sub.2).sub.m-- and --N(R.sup.7)(CH.sub.2).sub.m--, where
m=1-3 X.sup.a is halogen, and R.sup.7 is as defined below, q is an
integer of from 1-3, and each cyclic structure of L and L.sup.1
contains 0-4 members of the group consisting of nitrogen, oxygen
and sulfur, subject to the provisos that B is not ##STR00076## and
B'' is not ##STR00077## wherein the substituents for A'' and the
substituted isoquinolyl groups of A' are selected from the group
consisting of halogen, up to per-halo, and Wn, where n is 0-3 and
each W is independently selected from the group consisting of
C.sub.1-10 alkyl, C.sub.1-10 alkoxy, at least a five membered
C.sub.3-10 cycloalkyl having 0-3 heteroatoms, C.sub.2-10 alkenyl,
C.sub.1-10 alkenoyl, substituted C.sub.1-10 alkyl, substituted
C.sub.1-10 alkoxy, at least a five-membered substituted C.sub.3-10
cycloalkyl having 0-3 heteroatoms selected from N, S and O; --CN,
up to per halo substituted C.sub.6-C.sub.14 aryl, up to per halo
substituted C.sub.7-C.sub.24 alkaryl, up to per halo substituted
C.sub.7-4 aralkyl, up to per halo substituted C.sub.3-C.sub.12
heteroaryl having at least 5 members and 1-3 heteratoms selected
from O, N and S, up to per halo substituted C.sub.4-C.sub.24
alkylheteroaryl having at least 5 members and 1-3 heteroatoms
selected from O, N and S, C.sub.6-C.sub.14 aryl, C.sub.1-C.sub.24
alkaryl, C.sub.1-C.sub.24 aralkyl, C.sub.3-C.sub.12 heteroaryl
having at least 5 cyclic members and 1-3 heteroatoms selected from
O, N and S, C.sub.4-C.sub.24 alkylheteroaryl having at least 5
cyclic members and 1-3 heteroatoms selected from O, N and S;
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently selected from hydrogen, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl,
up to per halosubstituted C.sub.1-10 alkyl, up to per
halosubstituted C.sub.1-10 alkoxy, up to per halosubstituted
C.sub.2-10 alkenyl and up to per halosubstituted C.sub.1-10
alkenoyl; wherein the substitutents for the substituted t-butyl
pyridyl groups substituted trifluoromethyl pyridyl groups,
substituted isopropyl pyridyl groups, substituted 2-methyl-2-butyl
pyridyl groups and substituted 3-methyl-3-pentyl pyridyl groups of
A are selected from the group consisting of halogen, up to
per-halo, and Zn, where n is 0-3 and each Z is independently
selected from the group consisting of C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently as defined above for W; where B and B'
are substituted, the substituents are selected from the group
consisting of halogen, up to per-halo, and Jn, where n is 0-3 and
each J is independently selected from the group consisting of --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently as defined above for W, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, at least a five-membered C.sub.3-10
cycloalkyl having 0-3 heteroatoms, C.sub.2-10 alkenyl, C.sub.1-10
alkenoyl, C.sub.6-12 aryl, at least a five-membered C.sub.3-12
hetaryl having 1-3 heteroatoms selected from N, S and O, C.sub.7-24
aralkyl, C.sub.7-24 alkaryl, substituted C.sub.1-10 alkyl,
substituted C.sub.1-10 alkoxy, at least a five-membered substituted
C.sub.3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and
O, substituted C.sub.6-C.sub.14 aryl, at least a five-membered
substituted C.sub.3-12 hetaryl having 1-3 heteroatoms selected from
N, S and O, substituted C.sub.7-24 alkaryl and substituted
C.sub.7-C.sub.24 aralkyl, where B'' is substituted, the
substituents are selected from the group consisting of halogen,
--CN, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7, --NO.sub.2,
--OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7'' independently as defined above for W, C.sub.1-10
alkyl, at least a five-membered C.sub.3-10 cycloalkyl having 0-3
heteroatoms, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, C.sub.6-12
aryl, at least a five-membered C.sub.3-12 hetaryl having 1-3
heteroatoms selected from N, S and O, C.sub.7-4 aralkyl, C.sub.7-24
alkaryl, substituted C.sub.1-10 alkyl, substituted C.sub.1-10
alkoxy, at least a five-membered substituted C.sub.3-10 cycloalkyl
having 0-3 heteroatoms selected from N, S and O, substituted
C.sub.6-C.sub.14 aryl, at least a five-membered substituted
C.sub.3-12 hetaryl having 1-3 heteroatoms selected from N, S and O,
substituted C.sub.7-24 alkaryl and substituted C.sub.7-C.sub.24
aralkyl, subject to the proviso that where B, B' or B'' is
-L(ML.sup.1).sub.q, L.sup.1 is not substituted by the substituents
--C(O)R.sup.a, --C(NR.sup.a)R.sup.b, --C(O)NR.sup.aR.sup.b and
--SO.sub.2R.sup.a wherein each R.sup.a and R.sup.b are
independently hydrogen or a carbon based moiety of up to 24 carbon
atoms, optionally containing heteroatoms selected from N, S and O,
where J is a substituted group, it is substituted by halogen, up to
per halo, or by one or more substituents independently selected
from the group consisting of --CN, --CO.sub.2R.sup.7, --OR.sup.7,
--SR.sup.7, --NR.sup.7R.sup.7', --NO.sub.2, --NR.sup.7C(O)R.sup.7'
and --NR.sup.7C(O)OR.sup.7'; with each R.sup.7 and R.sup.7'
independently as defined above for W, a patient in need
thereof.
22. A method as in claim 21 for inhibiting raf kinase in a patient,
comprising administering an effective amount of a compound of one
of the following formulae A-D-B, A'-D-B', A''-D-B'', ##STR00078## R
is selected from the group consisting of halogen, C.sub.1-10 alkyl,
C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', or a
pharmaceutically acceptable salt thereof wherein D is
--NH--C(O)--NH-- A is selected from the group consisting of
substituted t-butylpyridyl groups, unsubstituted t-butylpyridyl
group, substituted (trifluoromethyl)pyridyl group, unsubstituted
(trifluoromethyl) pyridyl group, substituted isopropylpyridyl
group, unsubstituted isopropylpyridyl group, substituted
(2-methyl-2-butyl)pyridyl group, unsubstituted (2-methyl-2-butyl)
pyridyl group, substituted (3-methyl-3-pentyl) pyridyl group,
unsubstituted (3-methyl-3-pentyl) pyridyl group, substituted
(3-ethyl-3-pentyl)pyridyl group, unsubstituted (3-ethyl-3-pentyl)
pyridyl group, A' is a substituted isoquinolinyl group or
unsubstituted isoquinolinyl group or an unsubstituted quinolinyl
group, A'' is a substituted quinolinyl group, B, B' and B'' are
each independently of the formula -L-(ML.sup.1).sub.q, wherein L is
phenyl or substituted phenyl and L.sup.1 is phenyl, substituted
phenyl, pyridinyl or substituted pyridinyl, q is an integer of from
1-2 and M is selected from the group consisting of --O--, --S--,
--N(R.sup.7)--, --(CH.sub.2).sub.m--, --C(O)--, --CH(OH)--,
--(CH.sub.2).sub.mO--, --(CH.sub.2).sub.mS--,
--(CH.sub.2).sub.mN(R.sup.7)--, --O(CH.sub.2).sub.m, CHX.sup.a--,
CX.sup.a.sub.2--, --S--(CH.sub.2)-- and
--N(R.sup.7)(CH.sub.2).sub.m--, where m=1-3, X.sup.a is halogen,
and R.sup.7 is as defined below; subject to the provisos that B' is
not ##STR00079## B is not ##STR00080## wherein the substituents for
the substituted t-butyl pyridyl groups, substituted trifluoromethyl
pyridyl groups, substituted isopropyl pyridyl groups, substituted
2-methylbutyl pyridyl groups and 3-methylpentyl pyridyl groups, of
A are selected from the group consisting of halogen, up to
per-halo, and Zn, where n is 0-3 and each Z is independently
selected from the group consisting of C.sub.1-10 alkyl C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently selected from hydrogen, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl,
up to per halosubstituted C.sub.1-10 alkyl, up to per
halosubstituted C.sub.1-10 alkoxy, up to per halosubstituted
C.sub.2-10 and up to per halosubstituted C.sub.1-10 alkenoyl;
wherein the substituents for A'' and the substituted isoquinolinyl
groups of A' are selected from the group consisting of halogen, up
to per-halo, and Wn, where n is 0-3 and each W is independently
selected from the group consisting. of C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, substituted
C.sub.1-10 alkyl, substituted C.sub.1-10 alkoxy, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently selected from hydrogen, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl,
up to per halosubstituted C.sub.1-10 alkyl, up to per
halosubstituted C.sub.1-10 alkoxy, up to per halosubstituted
C.sub.2-10 alkenyl and up to per halosubstituted C.sub.1-10
alkenoyl; wherein B and B' are substituted, the substituents are
selected from the group consisting of halogen, up to per-halo, and
Jn, where n is 0-3 and each J is independently selected from the
group consisting of --CN, --CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7, --NO.sub.2, --OR.sup.7,
--SR.sup.7, --NR.sup.7R.sup.7', --NR.sup.7C(O)OR.sup.7',
--NR.sup.7C(O)R.sup.7', with each R.sup.7 and R.sup.7'
independently as defined above for W, C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, substituted
C.sub.1-10 alkyl, and substituted C.sub.1-10 alkoxy, subject to the
proviso that where B, B' or B'' is -L(ML.sup.1).sub.q, L.sup.1 is
not substituted by the substituents --C(O)R.sup.a,
--C(NR.sup.a)R.sup.b, --C(O)NR.sup.aR.sup.b and --SO.sub.2R.sup.a
wherein R.sup.a and R.sup.b are each independently hydrogen or a
carbon based moiety of up to 24 carbon atoms, optionally containing
heteroatoms selected from N, S and O, wherein B'' is substituted,
the substituents are selected from the group consisting of halogen,
--CN, --C(O)NR.sup.7R.sup.7', --NO.sub.2, --OR.sup.7, --SR.sup.7,
--NR.sup.7R.sup.7', --NR.sup.7C(O)OR.sup.7',
--NR.sup.7C(O)R.sup.7', with each R.sup.7 and R.sup.7'
independently as defined above for W, C.sub.1-10 alkyl, C.sub.2-10
alkenyl, C.sub.1-10 alkenoyl, substituted C.sub.1-10 alkyl, and
substituted C.sub.1-10 alkoxy, subject to the proviso that where B,
B' or B'' is -L(ML.sup.1).sub.q, L.sup.1 is not substituted by the
substituents --C(O)R.sup.a, --C(NR.sup.a)R.sup.b,
C(O)NR.sup.aR.sup.b and --SO.sub.2R.sup.a wherein R.sup.a and
R.sup.b are each independently, hydrogen or a carbon based moiety
of up to 24 carbon atoms, optionally containing heteroatoms
selected from N, S and O to a patient in need thereof.
23. A method as in claim 21 for inhibiting raf kinase in a patient,
comprising administering an effective amount of a compound which is
N-(4-tert-butylpyridinyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-phenoxyphenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-(4-methylphenoxy)phenyl) or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-(4-chlorophenoxy)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-(4-pyridinyloxy)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-4-tert-butylpyridinyl)-N'-(4-(4-pyridinylthio)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-3-(4-pyridinylthio)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(3-isoquinolinyl)-N'-(4-(4-pyridinyloxy)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N,N'-(bis(3-(2-methoxyquinolinyl)) urea) or a pharmaceutically
acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-pyridinylmethyl)phenyl)) urea
or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-pyridinylcarbonyl)phenyl)) urea
or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-pyridinyloxy)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-methoxyphenyl)methylamino)phenyl)urea
or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(3-(4-pyridinylthio)phenyl))urea or a
pharmaceutically acceptable salt thereof; or
N-(1-(4-methylpiperazinyl)-3-isoquinolinyl)-N'
(4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable
salt thereof to a patient in need thereof.
24-40. (canceled)
41. A method for treating a solid tumor with cell growth mediated
by raf kinase in a patient, comprising administering a
therapeutically effective amount of a compound of one of the
following formulae A-D-B (I) A'-D-B' (II) and A''-D-B'' (III) or a
pharmaceutically acceptable salt thereof, wherein D is
--NH--C(O)--NH--, A is selected from the group consisting of
substituted t-butylpyridyl group, unsubstituted t-butylpyridyl
group, substituted (trifluoromethyl)pyridyl group, unsubstituted
(trifluoromethyl) pyridyl group, substituted isopropylpyridyl
group, unsubstituted isopropylpyridyl group, substituted
(2-methyl-2-butyl)pyridyl group, unsubstituted (2-methyl-2-butyl
pyridyl) group, substituted (3-methyl-3-pentyl)pyridyl group, and
unsubstituted(3-methyl-3-pentyl) pyridyl groups, substituted
(3-ethyl-3-pentyl)pyridyl group and unsubstituted
(3-ethyl-3-pentyl)pyridyl group, A' is a substituted isoquinolinyl
group or unsubstituted isoquinolinyl group or an unsubstituted
quinolinyl group, A'' is a substituted quinolinyl group, B, B' and
B'' are each, independently, a substituted or unsubstituted bridged
cyclic structure of up to 30 carbon atoms of the formula
-L-(ML.sup.1).sub.q wherein L comprises a cyclic moiety having at
least 5 members and is bound directly to D, L.sup.1 comprises a
cyclic moiety having at least 5 members, M is a bridging group
selected from the group consisting of --O--, --S--, --N(R.sup.7)--,
--(CH.sub.2).sub.m--, --C(O)--, --C(OH)--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mS--, --(CH.sub.2).sub.mN(R.sup.7)--,
--O(CH.sub.2).sub.m, --CHX.sup.a--, --CX.sup.a.sub.2--,
--S--(CH.sub.2).sub.m-- and --N(R.sup.7)(CH.sub.2).sub.m--, where
m=1-3, X.sup.a is halogen, and R.sup.7 is as defined below, q is an
integer of from 1-3, and each cyclic structure of L and L.sup.1
contains 0-4 members of the group consisting of nitrogen, oxygen
and sulfur, subject to the provisos that B is not ##STR00081## and
B' is not ##STR00082## wherein the substituents for A'' and the
substituted isoquinolyl groups of A' are selected from the group
consisting of halogen, up to per-halo, and Wn, where n is 0-3 and
each W is independently selected from the group consisting of
C.sub.1-10 alkyl, C.sub.1-10 alkoxy, at least a five membered
C.sub.3-10 cycloalkyl having 0-3 heteroatoms, C.sub.2-10 alkenyl,
C.sub.1-10 alkenoyl, substituted C.sub.1-10 alkyl, substituted
C.sub.1-10 alkoxy, at least a five-membered substituted C.sub.3-10
cycloalkyl having 0-3 heteroatoms selected from N, S and O; --CN,
up to per halo substituted C.sub.6-C.sub.14 aryl, up to per halo
substituted C.sub.7-C.sub.24 alkaryl, up to per halo substituted
C.sub.7-4 aralkyl, up to per halo substituted C.sub.3-C.sub.12
heteroaryl having at least 5 members and 1-3 heteratoms selected
from O, N and S, up to per halo substituted C.sub.4-C.sub.24
alkylheteroaryl having at least 5 members and 1-3 heteroatoms
selected from O, N and S, C.sub.6-C.sub.14 aryl, C.sub.1-C.sub.24
alkaryl, C.sub.1-C.sub.24 aralkyl, C.sub.3-C.sub.12 heteroaryl
having at least 5 cyclic members and 1-3 heteroatoms selected from
O, N and S, C.sub.4-C.sub.24 alkylheteroaryl having at least 5
cyclic members and 1-3 heteroatoms selected from O, N and S;
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently selected from hydrogen, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl,
up to per halosubstituted C.sub.1-10 alkyl, up to per
halosubstituted C.sub.1-10 alkoxy, up to per halosubstituted
C.sub.2-10 alkenyl and up to per halosubstituted C.sub.1-10
alkenoyl; wherein the substitutents for the substituted t-butyl
pyridyl groups substituted trifluoromethyl pyridyl groups,
substituted isopropyl pyridyl groups, substituted 2-methyl-2-butyl
pyridyl groups and substituted 3-methyl-3-pentyl pyridyl groups of
A are selected from the group consisting of halogen, up to
per-halo, and Zn, where n is 0-3 and each Z is independently
selected from the group consisting of C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently as defined above for W; where B and B'
are substituted, the substituents are selected from the group
consisting of halogen, up to per-halo, and Jn, where n is 0-3 and
each J is independently selected from the group consisting of --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently as defined above for W, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, at least a five-membered C.sub.3-10
cycloalkyl having 0-3 heteroatoms, C.sub.2-10 alkenyl, C.sub.1-10
alkenoyl, C.sub.6-12 aryl, at least a five-membered C.sub.3-12
hetaryl having 1-3 heteroatoms selected from N, S and O, C.sub.7-24
aralkyl, C.sub.7-24 alkaryl, substituted C.sub.1-10 alkyl,
substituted C.sub.1-10 alkoxy, at least a five-membered substituted
C.sub.3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and
O, substituted C.sub.6-C.sub.14 aryl, at least a five-membered
substituted C.sub.3-12 hetaryl having 1-3 heteroatoms selected from
N, S and O, substituted C.sub.7-24 alkaryl and substituted
C.sub.7-C.sub.24 aralkyl, where B'' is substituted, the
substituents are selected from the group consisting of halogen,
--CN, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7, --NO.sub.2,
--OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7'' independently as defined above for W, C.sub.1-10
alkyl, at least a five-membered C.sub.3-10 cycloalkyl having 0-3
heteroatoms, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, C.sub.6-12
aryl, at least a five-membered C.sub.3-12 hetaryl having 1-3
heteroatoms selected from N, S and O, C.sub.7-24 aralkyl,
C.sub.7-24 alkaryl, substituted C.sub.1-10 alkyl, substituted
C.sub.1-10 alkoxy, at least a five-membered substituted C.sub.3-10
cycloalkyl having 0-3 heteroatoms selected from N, S and O,
substituted C.sub.6-C.sub.14 aryl, at least a five-membered
substituted C.sub.3-12 hetaryl having 1-3 heteroatoms selected from
N, S and O, substituted C.sub.7-24 alkaryl and substituted
C.sub.7-C.sub.24 aralkyl, subject to the proviso that where B, B'
or B'' is -L(ML.sup.1).sub.q, L.sup.1 is not substituted by the
substituents --C(O)R.sup.a, --C(NR.sup.a)R.sup.b,
--C(O)NR.sup.aR.sup.b and --SO.sub.2R.sup.a wherein each R.sup.a
and R.sup.b are independently hydrogen or a carbon based moiety of
up to 24 carbon atoms, optionally containing heteroatoms selected
from N, S and O, where J is a substituted group, it is substituted
by halogen, up to per halo, or by one or more substituents
independently selected from the group consisting of --CN,
--CO.sub.2R.sup.7, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NO.sub.2, --NR.sup.7C(O)R.sup.7' and --NR.sup.7C(O)OR.sup.7';
with each R.sup.7 and R.sup.7' independently as defined above for
W, to treat said patient.
42. A method for the treatment of carcinomas of the lungs,
pancreas, thyroid, bladder or colon, myeloid leukemia or villous
colon adenoma, comprising administering a therapeutically effective
amount of a compound of one of the following formulae A-D-B (I)
A'-D-B' (II) and A''-D-B'' (III) or a pharmaceutically acceptable
salt thereof, wherein D is --NH--C(O)--NH--, A is selected from the
group consisting of substituted t-butylpyridyl group, unsubstituted
t-butylpyridyl group, substituted (trifluoromethyl)pyridyl group,
unsubstituted (trifluoromethyl) pyridyl group, substituted
isopropylpyridyl group, unsubstituted isopropylpyridyl group,
substituted (2-methyl-2-butyl)pyridyl group, unsubstituted
(2-methyl-2-butyl pyridyl) group, substituted
(3-methyl-3-pentyl)pyridyl group, and unsubstituted
(3-methyl-3-pentyl) pyridyl groups, substituted
(3-ethyl-3-pentyl)pyridyl group and unsubstituted
(3-ethyl-3-pentyl)pyridyl group, A' is a substituted isoquinolinyl
group or unsubstituted isoquinolinyl group or an unsubstituted
quinolinyl group, A'' is a substituted quinolinyl group, B, B' and
B'' are each, independently, a substituted or unsubstituted bridged
cyclic structure of up to 30 carbon atoms of the formula
-L-(ML.sup.1).sub.q wherein L comprises a cyclic moiety having at
least 5 members and is bound directly to D, L.sup.1 comprises a
cyclic moiety having at least 5 members, M is a bridging group
selected from the group consisting of --O--, --S--, --N(R.sup.7)--,
--(CH.sub.2).sub.m--, --C(O)--, --C(OH)--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mS--, --(CH.sub.2).sub.mN(R.sup.7)--,
--O(CH.sub.2).sub.m, --CHX.sup.a--, --CX.sup.a.sub.2--,
--S--(CH.sub.2).sub.m-- and --N(R.sup.7)(CH.sub.2).sub.m--, where
m=1-3, X.sup.a is halogen, and R.sup.7 is as defined below, q is an
integer of from 1-3, and each cyclic structure of L and L.sup.1
contains 0-4 members of the group consisting of nitrogen, oxygen
and sulfur, subject to the provisos that B is not ##STR00083## and
B' is not ##STR00084## wherein the substituents for A'' and the
substituted isoquinolinyl groups of A' are selected from the group
consisting of halogen, up to per-halo, and Wn, where n is 0-3 and
each W is independently selected from the group consisting of
C.sub.1-10 alkyl, C.sub.1-10 alkoxy. at least a five membered
C.sub.3-10 cycloalkyl having 0-3 heteroatoms, C.sub.2-10 alkenyl,
C.sub.1-10 alkenoyl, substituted C.sub.1-10 alkyl, substituted
C.sub.1-10 alkoxy, at least a five-membered substituted C.sub.3-10
cycloalkyl having 0-3 heteroatoms selected from N, S and O; --CN,
up to per halo substituted C.sub.6-C.sub.14 aryl, up to per halo
substituted C.sub.7-C.sub.24 alkaryl, up to per halo substituted
C.sub.7-4 aralkyl, up to per halo substituted C.sub.3-C.sub.12
heteroaryl having at least 5 members and 1-3 heteratoms selected
from O, N and S, up to per halo substituted C.sub.4-C.sub.24
alkylheteroaryl having at least 5 members and 1-3 heteroatoms
selected from O, N and S, C.sub.6-C.sub.14 aryl, C.sub.1-C.sub.24
alkaryl, C.sub.1-C.sub.24 aralkyl, C.sub.3-C.sub.12 heteroaryl
having at least 5 cyclic members and 1-3 heteroatoms selected from
O, N and S, C.sub.4-C.sub.24 alkylheteroaryl having at least 5
cyclic members and 1-3 heteroatoms selected from O, N and S;
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently selected from hydrogen, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl,
up to per halosubstituted C.sub.1-10 alkyl, up to per
halosubstituted C.sub.1-10 alkoxy, up to per halosubstituted
C.sub.2-10 alkenyl and up to per halosubstituted C.sub.1-10
alkenoyl; wherein the substitutents for the substituted t-butyl
pyridyl groups substituted trifluoromethyl pyridyl groups,
substituted isopropyl pyridyl groups, substituted 2-methyl-2-butyl
pyridyl groups and substituted 3-methyl-3-pentyl pyridyl groups of
A are selected from the group consisting of halogen, up to
per-halo, and Zn, where n is 0-3 and each Z is independently
selected from the group consisting of C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently as defined above for W; where B and B'
are substituted, the substituents are selected from the group
consisting of halogen, up to per-halo, and Jn, where n is 0-3 and
each J is independently selected from the group consisting of --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently as defined above for W, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, at least a five-membered C.sub.3-10
cycloalkyl having 0-3 heteroatoms, C.sub.2-10 alkenyl, C.sub.1-10
alkenoyl, C.sub.6-12 aryl, at least a five-membered C.sub.3-12
hetaryl having 1-3 heteroatoms selected from N, S and O, C.sub.7-24
aralkyl, C.sub.7-24 alkaryl, substituted C.sub.1-10 alkyl,
substituted C.sub.1-10 alkoxy, at least a five-membered substituted
C.sub.3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and
O, substituted C.sub.6-C.sub.14 aryl, at least a five-membered
substituted C.sub.3-12 hetaryl having 1-3 heteroatoms selected from
N, S and O, substituted C.sub.7-24 alkaryl and substituted
C.sub.7-C.sub.24 aralkyl, where B'' is substituted, the
substituents are selected from the group consisting of halogen,
--CN, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7, --NO.sub.2,
--OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7'' independently as defined above for W, C.sub.1-10
alkyl, at least a five-membered C.sub.3-10 cycloalkyl having 0-3
heteroatoms, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, C.sub.6-12
aryl, at least a five-membered C.sub.3-12 hetaryl having 1-3
heteroatoms selected from N, S and O, C.sub.7-4 aralkyl, C.sub.7-24
alkaryl, substituted C.sub.1-10 alkyl, substituted C.sub.1-10
alkoxy, at least a five-membered substituted C.sub.3-10 cycloalkyl
having 0-3 heteroatoms selected from N, S and O, substituted
C.sub.6-C.sub.14 aryl, at least a five-membered substituted
C.sub.3-12 hetaryl having 1-3 heteroatoms selected from N, S and O,
substituted C.sub.7-24 alkaryl and substituted C.sub.7-C.sub.24
aralkyl, subject to the proviso that where B, B' or B'' is
-L(ML.sup.1).sub.q, L.sup.1 is not substituted by the substituents
--C(O)R.sup.a, --C(NR.sup.a)R.sup.b, --C(O)NR.sup.aR.sup.b and
--SO.sub.2R.sup.a wherein each R.sup.a and R.sup.b are
independently hydrogen or a carbon based moiety of up to 24 carbon
atoms, optionally containing heteroatoms selected from N, S and O,
where J is a substituted group, it is substituted by halogen, up to
per halo, or by one or more substituents independently selected
from the group consisting of --CN, --CO.sub.2R.sup.7, --OR.sup.7,
--SR.sup.7, --NR.sup.7R.sup.7', --NO.sub.2, --NR.sup.7C(O)R.sup.7'
and --NR.sup.7C(O)OR.sup.7'; with each R.sup.7 and R.sup.7'
independently as defined above for W, to treat said patient.
43. A method as in claim 41 for the treatment of a solid tumor with
cell growth mediated by raf kinase in a patient, comprising
administering a therapeutically effective amount of a compound of
one of the following formulae A-D-B, A'-D-B', A''-D-B''.
##STR00085## R is selected from the group consisting of halogen,
C.sub.1-10 alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10
alkenoyl, --CN, --CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7',
--C(O)--R.sup.7, --NO.sub.2, --OR.sup.7, --SR.sup.7,
--NR.sup.7R.sup.7', --NR.sup.7C(O)OR.sup.7'',
--NR.sup.7C(O)R.sup.7', or a pharmaceutically acceptable salt
thereof wherein D is --NH--C(O)--NH-- A is selected from the group
consisting of substituted t-butylpyridyl groups, unsubstituted
t-butylpyridyl group, substituted (trifluoromethyl)pyridyl group,
unsubstituted (trifluoromethyl) pyridyl group, substituted
isopropylpyridyl group, unsubstituted isopropylpyridyl group,
substituted (2-methyl-2-butyl)pyridyl group, unsubstituted
(2-methyl-2-butyl) pyridyl group, substituted (3-methyl-3-pentyl)
pyridyl group, unsubstituted (3-methyl-3-pentyl) pyridyl group,
substituted (3-ethyl-3-pentyl)pyridyl group, unsubstituted
(3-ethyl-3-pentyl) pyridyl group, A' is a substituted isoquinolinyl
group or unsubstituted isoquinolinyl group or an unsubstituted
quinolinyl group, A'' is a substituted quinolinyl group, B, B' and
B'' are each independently of the formula -L-(ML.sup.1).sub.q,
wherein L is phenyl or substituted phenyl and L.sup.1 is phenyl,
substituted phenyl, pyridinyl or substituted pyridinyl, q is an
integer of from 1-2 and M is selected from the group consisting of
--O--, --S--, --N(R.sup.7)--, --(CH.sub.2).sub.m--, --C(O)--,
--CH(OH)--, --(CH.sub.2).sub.mO--, --(CH.sub.2).sub.mS--,
--(CH.sub.2).sub.mN(R.sup.7)--, --O(CH.sub.2).sub.m, CHX.sup.a--,
CX.sup.a.sub.2--, --S--(CH.sub.2)-- and
--N(R.sup.7)(CH.sub.2).sub.m--, where m=1-3, X.sup.a is halogen,
and R.sup.7 is as defined below; subject to the provisos that B' is
not ##STR00086## B is not ##STR00087## wherein the substituents for
the substituted t-butyl pyridyl groups, substituted trifluoromethyl
pyridyl groups, substituted isopropyl pyridyl groups, substituted
2-methylbutyl pyridyl groups and 3-methylpentyl pyridyl groups, of
A are selected from the group consisting of halogen, up to
per-halo, and Zn, where n is 0-3 and each Z is independently
selected from the group consisting of C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.1-10 alkenyl, C.sub.1-10 alkenoyl, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently selected from hydrogen, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl,
up to per halosubstituted C.sub.1-10 alkyl, up to per
halosubstituted C.sub.1-10 alkoxy, up to per halosubstituted
C.sub.2-10 and up to per halosubstituted C.sub.1-10 alkenoyl;
wherein the substituents for A'' and the substituted isoquinolinyl
groups of A' are selected from the group consisting of halogen, up
to per-halo, and Wn, where n is 0-3 and each W is independently
selected from the group consisting of C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, substituted
C.sub.1-10 alkyl, substituted C.sub.1-10 alkoxy, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently selected from hydrogen, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl,
up to per halosubstituted C.sub.1-10 alkyl, up to per
halosubstituted C.sub.1-10 alkoxy, up to per halosubstituted
C.sub.2-10 alkenyl and up to per halosubstituted C.sub.1-10
alkenoyl; wherein B and B' are substituted, the substituents are
selected from the group consisting of halogen, up to per-halo, and
Jn, where n is 0-3 and each J is independently selected from the
group consisting of --CN, --CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7, --NO.sub.2, --OR.sup.7,
--SR.sup.7, --NR.sup.7R.sup.7', --NR.sup.7C(O)OR.sup.7',
--NR.sup.7C(O)R.sup.7', with each R.sup.7 and R.sup.7'
independently as defined above for W, C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, substituted
C.sub.1-10 alkyl, and substituted C.sub.1-10 alkoxy, subject to the
proviso that where B, B' or B'' is -L(ML.sup.1).sub.q, L.sup.1 is
not substituted by the substituents --C(O)R.sup.a,
--C(NR.sup.a)R.sup.b, --C(O)NR.sup.aR.sup.b and --SO.sub.2R.sup.a
wherein R.sup.a and R.sup.b are each independently hydrogen or a
carbon based moiety of up to 24 carbon atoms, optionally containing
heteroatoms selected from N, S and O, wherein B'' is substituted,
the substituents are selected from the group consisting of halogen,
--CN, --C(O)NR.sup.7R.sup.7', --NO.sub.2, --OR.sup.7, --SR.sup.7,
--NR.sup.7R.sup.7', --NR.sup.7C(O)OR.sup.7',
--NR.sup.7C(O)R.sup.7', with each R.sup.7 and R.sup.7'
independently as defined above for W, C.sub.1-10 alkyl, C.sub.2-10
alkenyl, C.sub.1-10 alkenoyl, substituted C.sub.1-10 alkyl, and
substituted C.sub.1-10 alkoxy, subject to the proviso that where B,
B' or B'' is -L(ML.sup.1).sub.q, L.sup.1 is not substituted by the
substituents --C(O)R.sup.a, --C(NR.sup.a)R.sup.b,
C(O)NR.sup.aR.sup.b and --SO.sub.2R.sup.a wherein R.sup.a and
R.sup.b are each independently, hydrogen or a carbon based moiety
of up to 24 carbon atoms, optionally containing heteroatoms
selected from N, S and O to a patient in need thereof.
44. (canceled)
45. A method as in claim 42 for the treatment of carcinomas of the
lungs, pancreas, thyroid, bladder or colon, myeloid leukemia or
villous colon adenoma in a patient mediated by raf kinase,
comprising administering a therapeutically effective amount of a
compound of one of the following formulae A-D-B, A'-D-B',
A''-D-B'', ##STR00088## R is selected from the group consisting of
halogen, C.sub.1-10 alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl,
C.sub.1-10 alkenoyl, --CN, --CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7, --NO.sub.2, --OR.sup.7,
--SR.sup.7, --NR.sup.7R.sup.7', --NR.sup.7C(O)OR.sup.7'',
--NR.sup.7C(O)R.sup.7', or a pharmaceutically acceptable salt
thereof wherein D is --NH--C(O)--NH-- A is selected from the group
consisting of substituted t-butylpyridyl groups, unsubstituted
t-butylpyridyl group, substituted (trifluoromethyl)pyridyl group,
unsubstituted (trifluoromethyl) pyridyl group, substituted
isopropylpyridyl group, unsubstituted isopropylpyridyl group,
substituted (2-methyl-2-butyl)pyridyl group, unsubstituted
(2-methyl-2-butyl) pyridyl group, substituted (3-methyl-3-pentyl)
pyridyl group, unsubstituted (3-methyl-3-pentyl) pyridyl group,
substituted (3-ethyl-3-pentyl)pyridyl group, unsubstituted
(3-ethyl-3-pentyl) pyridyl group, A' is a substituted isoquinolinyl
group or unsubstituted isoquinolinyl group or an unsubstituted
quinolinyl group, A'' is a substituted quinolinyl group, B, B' and
B'' are each independently of the formula -L-(ML.sup.1).sub.q,
wherein L is phenyl or substituted phenyl and L.sup.1 is phenyl,
substituted phenyl, pyridinyl or substituted pyridinyl, q is an
integer of from 1-2 and M is selected from the group consisting of
--O--, --S--, --N(R.sup.7)--, --(CH.sub.2).sub.m--, --C(O)--,
--CH(OH)--, --(CH.sub.2).sub.mO--, --(CH.sub.2).sub.mS--,
--(CH.sub.2).sub.mN(R.sup.7)--, --O(CH.sub.2).sub.m, CHX.sup.a--,
CX.sup.a.sub.2--, --S--(CH.sub.2)-- and
--N(R.sup.7)(CH.sub.2).sub.m--, where m=1-3, X.sup.a is halogen,
and R.sup.7 is as defined below; subject to the provisos that B' is
not ##STR00089## B is not ##STR00090## wherein the substituents for
the substituted t-butyl pyridyl groups, substituted trifluoromethyl
pyridyl groups, substituted isopropyl pyridyl groups, substituted
2-methylbutyl pyridyl groups and 3-methylpentyl pyridyl groups, of
A are selected from the group consisting of halogen, up to
per-halo, and Zn, where n is 0-3 and each Z is independently
selected from the group consisting of C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently selected from hydrogen, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl,
up to per halosubstituted C.sub.1-10 alkyl, up to per
halosubstituted C.sub.1-10 alkoxy, up to per halosubstituted
C.sub.2-10 and up to per halosubstituted C.sub.1-10 alkenoyl;
wherein the substituents for A'' and the substituted isoquinolinyl
groups of A' are selected from the group consisting of halogen, up
to per-halo, and Wn, where n is 0-3 and each W is independently
selected from the group consisting of C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, substituted
C.sub.1-10 alkyl, substituted C.sub.1-10 alkoxy, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently selected from hydrogen, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl,
up to per halosubstituted C.sub.1-10 alkyl, up to per
halosubstituted C.sub.1-10 alkoxy, up to per halosubstituted
C.sub.2-10 alkenyl and up to per halosubstituted C.sub.1-10
alkenoyl; wherein B and B' are substituted, the substituents are
selected from the group consisting of halogen, up to per-halo, and
Jn, where n is 0-3 and each J is independently selected from the
group consisting of --CN, --CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7, --NO.sub.2, --OR.sup.7,
--SR.sup.7, --NR.sup.7R.sup.7', --NR.sup.7C(O)OR.sup.7',
--NR.sup.7C(O)R.sup.7', with each R.sup.7 and R.sup.7'
independently as defined above for W, C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, substituted
C.sub.1-10 alkyl, and substituted C.sub.1-10 alkoxy, subject to the
proviso that where B, B' or B'' is -L(ML.sup.1).sub.q, L.sup.1 is
not substituted by the substituents --C(O)R.sup.a,
--C(NR.sup.a)R.sup.b, --C(O)NR.sup.aR.sup.b and --SO.sub.2R.sup.a
wherein R.sup.a and R.sup.b are each independently hydrogen or a
carbon based moiety of up to 24 carbon atoms, optionally containing
heteroatoms selected from N, S and O, wherein B'' is substituted,
the substituents are selected from the group consisting of halogen,
--CN, --C(O)NR.sup.7R.sup.7', --NO.sub.2, --OR.sup.7, --SR.sup.7,
--NR.sup.7R.sup.7', --NR.sup.7C(O)OR.sup.7',
--NR.sup.7C(O)R.sup.7', with each R.sup.7 and R.sup.7'
independently as defined above for W, C.sub.1-10 alkyl, C.sub.2-10
alkenyl, C.sub.1-10 alkenoyl, substituted C.sub.1-10 alkyl, and
substituted C.sub.1-10 alkoxy, subject to the proviso that where B,
B' or B'' is -L(ML.sup.1).sub.q, L.sup.1 is not substituted by the
substituents --C(O)R.sup.a, --C(NR.sup.a)R.sup.b,
C(O)NR.sup.aR.sup.b and --SO.sub.2R.sup.a wherein R.sup.a and
R.sup.b are each independently, hydrogen or a carbon based moiety
of up to 24 carbon atoms, optionally containing heteroatoms
selected from N, S and O to treat said patient.
46. A method as in claim 41 for the treatment of a solid tumor with
cell growth mediated by raf kinase in a patient, comprising
administering a therapeutically effective amount of a compound
which is
N-(4-tert-butylpyridinyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-phenoxyphenyl)urea or a
pharmaceutically acceptable salt thereof:
N-(4-tert-butylpyridinyl)-N'-(4-(4-methylphenoxy)phenyl) or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-(4-chlorophenoxy)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-(4-pyridinyloxy)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-(4-pyridinylthio)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(3-(4-pyridinylthio)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(3-isoquinolinyl)-N'-(4-(4-pyridinyloxy)phenyl) urea or a
pharmaceutically acceptable salt thereof;
N,N'-(bis(3-(2-methoxyquinolinyl)) urea) or a pharmaceutically
acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-pyridinylmethyl)phenyl)) urea
or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-pyridinylcarbonyl)phenyl)) urea
or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-pyridinyloxy)phenyl))urea or a
pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-((4-methoxyphenyl)methylamino)phenyl)
urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(3-(4-pyridinylthio)phenyl)) urea or
a pharmaceutically acceptable salt thereof; or
N-(1-(4-methylpiperazinyl)-3-isoquinolinyl)-N'
(4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable
salt thereof, to treat said patient.
47. A method as in claim 42 for the treatment of carcinomas of the
lungs, pancreas, thyroid, bladder or colon, myeloid leukemia or
villous colon adenoma, comprising administering a therapeutically
effective amount of a compound which is
N-(4-tert-butylpyridinyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-phenoxyphenyl) urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-(4-methylphenoxy)phenyl) or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-(4-chlorophenoxy)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-(4-pyridinyloxy)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(4-(4-pyridinylthio)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N'-(3-(4-pyridinylthio)phenyl)urea or a
pharmaceutically acceptable salt thereof;
N-(3-isoquinolinyl)-N'-(4-(4-pyridinyloxy phenyl)urea or a
pharmaceutically acceptable salt thereof;
N,N'-(bis(3-(2-methoxy-quinolinyl))urea) or a pharmaceutically
acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-pyridinylmethyl)-phenyl)) urea
or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-pyridinylcarbonyl)phenyl)) urea
or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-pyridinyloxy)phenyl)) urea or a
pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(4-((4-methoxyphenyl)methylamino)phenyl))
urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N'-(3-(4-pyridinylthio)phenyl)) urea or
a pharmaceutically acceptable salt thereof; or
N-(1-(4-methylpiperazinyl)-3-isoquinolinyl)-N'
(4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable
salt thereof to treat said patient.
48. A method as in claim 47 for the treatment of carcinomas of the
lungs.
49. A method as in claim 47 for the treatment of carcinomas of the
pancreas.
50. A method as in claim 47 for the treatment of carcinomas of the
thyroid.
51. A method as in claim 47 for the treatment of carcinomas of the
bladder.
52. A method as in claim 47 for the treatment of carcinomas of the
colon.
53. A method as in claim 47 for the treatment of myeloid
leukemia.
54. A method as in claim 47 for the treatment of villous colon
adenoma.
Description
[0001] This application is a continuation of U.S. non-provisional
application Ser. No. 10/125,369, filed Apr. 19, 2002, which claims
the benefit of U.S. provisional application No. 60/367,376 filed
Apr. 20, 2001. The contents of U.S. non-provisional application
Ser. No. 10/125,369 filed Apr. 19, 2002 and U.S. provisional
application No. 60/367,376, filed Apr. 20, 2001 are incorporated by
reference herein.
FIELD OF THE INVENTION
[0002] This invention relates to the use of a group of aryl ureas
in treating raf mediated diseases, and pharmaceutical compositions
for use in such therapy.
BACKGROUND OF THE INVENTION
[0003] The p21.sup.ras oncogene is a major contributor to the
development and progression of human solid cancers and is mutated
in 30% of all human cancers (Bolton et al. Ann. Rep. Med. Chem.
1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its
normal, unmutated form, the ras protein is a key element of the
signal transduction cascade directed by growth factor receptors in
almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19,
279-83). Biochemically, ras is a guanine nucleotide binding
protein, and cycling between a GTP-bound activated and a GDP-bound
resting form is strictly controlled by ras' endogenous GTPase
activity and other regulatory proteins. In the ras mutants in
cancer cells, the endogenous GTPase activity is alleviated and,
therefore, the protein delivers constitutive growth signals to
downstream effectors such as the enzyme raf kinase. This leads to
the cancerous growth of the cells which carry these mutants
(Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been
shown that inhibiting the effect of active ras by inhibiting the
raf kinase signaling pathway by administration of deactivating
antibodies to raf kinase or by co-expression of dominant negative
raf kinase or dominant negative MEK, the substrate of raf kinase,
leads to the reversion of transformed cells to the normal growth
phenotype (see: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80;
Fridman et al. J. Biol. Chem. 1994, 269, 30105-8. Kolch et al.
(Nature 1991, 349, 426-28) have further indicated that inhibition
of raf expression by antisense RNA blocks cell proliferation in
membrane-associated oncogenes. Similarly, inhibition of raf kinase
(by antisense oligodeoxynucleotides) has been correlated in vitro
and in vivo with inhibition of the growth of a variety of human
tumor types (Monia et al., Nat. Med. 1996, 2, 668-75).
SUMMARY OF THE INVENTION
[0004] The present invention provides compounds which are
inhibitors of the enzyme raf kinase. Since the enzyme is a
downstream effector of p21.sup.ras, the instant inhibitors are
useful in pharmaceutical compositions for human or veterinary use
where inhibition of the raf kinase pathway is indicated, e.g., in
the treatment of tumors and/or cancerous cell growth mediated by
raf kinase. In particular, the compounds are useful in the
treatment of human or animal, e.g., murine cancer, since the
progression of these cancers is dependent upon the ras protein
signal transduction cascade and therefore susceptible to treatment
by interruption of the cascade, i.e., by inhibiting raf kinase.
Accordingly, the compounds of the invention are useful in treating
solid cancers, such as, for example, carcinomas (e.g., of the
lungs, pancreas, thyroid, bladder or colon, myeloid disorders
(e.g., myeloid leukemia) or adenomas (e.g., villous colon
adenoma).
[0005] The present invention, therefore, provides compounds
generally described as aryl ureas, including both aryl and
heteroaryl analogues, which inhibit the raf pathway. The invention
also provides a method for treating a raf mediated disease state in
humans or mammals. Thus, the invention is directed to compounds
which inhibit the enzyme RAF kinase and also to compounds,
compositions and methods for the treatment of cancerous cell growth
mediated by raf kinase wherein a compound of one of the formulae I,
II or III, or a pharmaceutically acceptable salt thereof, is
administered.
A-D-B (I)
A'-D-B' (II)
A''D-B'' (III)
In formulae I-III,
[0006] D is --NH--C(O)--NH--,
[0007] A is selected from the group consisting of substituted or
unsubstituted t-butylpyridyl groups, (trifluoromethyl) pyridyl
groups, isopropylpyridyl groups, (2-methyl-2-butyl)pyridyl groups,
(3-methyl-3-pentyl)pyridyl groups and (3-ethyl-3-pentyl)pyridyl
groups,
[0008] A' is a substituted isoquinolinyl group or unsubstituted
isoquinolinyl group or an unsubstituted quinolinyl group,
[0009] A'' is a substituted quinolinyl group,
[0010] B and B' are each, independently, a substituted or
unsubstituted bridged cyclic structure of up to 30 carbon atoms of
the formula -L-(ML.sup.1).sub.q wherein L comprises a cyclic moiety
having at least 5 members and is bound directly to D, L.sup.1
comprises a cyclic moiety having at least 5 members, M is a
bridging group having at least one atom, q is an integer of from
1-3, and each cyclic structure of L and L.sup.1 contains 0-4
members of the group consisting of nitrogen, oxygen and sulfur,
[0011] subject to the provisos that B is not
##STR00001##
[0012] and B' is not
##STR00002##
[0013] B'' is a substituted or unsubstituted, up to tricyclic aryl
or heteroaryl moiety of up to 30 carbon atoms with a cyclic
structure bound directly to D containing at least 5 members with
0-4 members of the group consisting of nitrogen, oxygen and
sulfur.
[0014] The moiety B'' is preferably either a substituted or
unsubstituted bridged cyclic structure of up to 30 carbon atoms of
the formula -L-(ML.sup.1).sub.q, a substituted or unsubstituted 6
member cyclic aryl moiety or 5 membered hetaryl moiety or a
substituted or unsubstituted fused aryl ring or hetaryl ring of
from 2-3 fused rings. For Example, B'' can be phenyl, substituted
phenyl, napthyl substituted napthyl, pyridinyl, substituted
pyridinyl, pyrimidinyl, substituted pyrimidinyl, quinolinyl,
substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl or
of the formula -L(ML.sup.1).sub.q.
[0015] The substituents for A'' and the substituted isoquinolinyl
groups of A' are selected from the group consisting of halogen, up
to per-halo, and Wn, where n is 0-3 and each W is independently
selected from the group consisting of C.sub.1-10 alkyl, C.sub.1-10
alkoxy, at least a five membered C.sub.3-10 cycloalkyl having 0-3
heteroatoms, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, substituted
C.sub.1-10 alkyl, substituted C.sub.1-10 alkoxy, a substituted
C.sub.3-10 cycloalkyl having at least 5 cyclic members and 0-3
heteroatoms selected from N, S and O; C.sub.6-C.sub.14 aryl,
C.sub.7-C.sub.24 alkaryl, C.sub.7-C.sub.24 aralkyl,
C.sub.3-C.sub.12 heteroaryl having 1-3 heteroatoms selected from O,
N and S, C.sub.4-C.sub.23 alkheteroaryl having 1-3 heteroatoms
selected from O, N and S, up to per halo substituted
C.sub.6-C.sub.12 aryl, up to per halo substituted C.sub.3-C.sub.12
hetaryl having at least 5-members and 1-3 heteroatoms selected from
O, N and S, up to per halo substituted C.sub.7-C.sub.24 aralkyl, up
to per halo substituted C.sub.7-C.sub.24 alkaryl, up to per halo
substituted C.sub.4-C.sub.23 alkheteroaryl having at least 5 cyclic
members and 1-3 heteroatoms selected from O, N and S, --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7,
--NO.sub.2, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NR.sup.7C(O)OR.sup.7', --NR.sup.7C(O)R.sup.7', with each R.sup.7
and R.sup.7' independently selected from hydrogen, C.sub.1-10
alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl,
up to per halosubstituted C.sub.1-10 alkyl, up to per
halosubstituted C.sub.1-10 alkoxy, up to per halosubstituted
C.sub.2-10 alkenyl and up to per halosubstituted C.sub.1-10
alkenoyl.
[0016] The substituents for the substituted t-butylpyridyl,
(trifluoromethyl)pyridyl, isopropylpyridyl,
(2-methyl-2-butyl)pyridyl, (3-methyl-3-pentyl)pyridyl groups and
(3-ethyl-3-pentyl)pyridyl groups, of A are selected from the group
consisting of halogen, up to per-halo, and Zn, where n is 0-3 and
each Z is independently selected from the group consisting of
C.sub.1-10 alkyl, C.sub.1-10 alkoxy, C.sub.2-10 alkenyl, C.sub.1-10
alkenoyl, --CN, --CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7',
--C(O)--R.sup.7, --NO.sub.2, --OR.sup.7, --SR.sup.7,
--NR.sup.7R.sup.7', --NR.sup.7C(O)OR.sup.7',
--NR.sup.7C(O)R.sup.7', with each R.sup.7 and R.sup.7'
independently as defined above.
[0017] Where B, B' and B'' are substituted, the substituents are
selected from the group consisting of halogen, up to per-halo, and
Jn, where n is 0-3 and each J is independently selected from the
group consisting of --CN, --CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.7', --C(O)--R.sup.7, --NO.sub.2, --OR.sup.7,
--SR.sup.7, --NR.sup.7R.sup.7', --NR.sup.7C(O)OR.sup.7',
--NR.sup.7C(O)R.sup.7', C.sub.1-10 alkyl, C.sub.1-10 alkoxy,
C.sub.3-10 cycloalkyl having at least five cyclic members and 0-3
heteroatoms, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, C.sub.6-12
aryl, C.sub.3-12 hetaryl having at least five cyclic members and
1-3 heteroatoms selected from N, S and O, C.sub.7-24 aralkyl,
C.sub.7-24 alkaryl, substituted C.sub.1-10 alkyl, substituted
C.sub.1-10 alkoxy, substituted C.sub.3-10 cycloalkyl having at
least five cyclic members and 0-3 heteroatoms selected from N, S
and O, substituted C.sub.6-C.sub.14 aryl, substituted C.sub.3-12
hetaryl having at least five cyclic members and 1-3 heteroatoms
selected from N, S and O, substituted C.sub.7-24 alkaryl,
substituted C.sub.7-C.sub.24 aralkyl and -Q-Ar, subject to the
proviso that where B, B' or B'' is -L(ML.sup.1).sub.q, L.sup.1 is
not substituted by the substituents --C(O)R.sup.a,
--C(NR.sup.a)R.sup.b, --C(O)NR.sup.aR.sup.b and --SO.sub.2R.sup.a
wherein R.sup.a and R.sup.b are each, independently, hydrogen or a
carbon based moiety of tip to 24 carbon atoms, optionally
containing heteroatoms selected from N, S and O.
[0018] R.sup.a and R.sup.b are preferably C.sub.1-10 alkyl,
C.sub.1-10 alkoxy, C.sub.3-10 cycloalkyl having 0-3 heteroatoms,
C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, C.sub.6-12 aryl,
C.sub.3-12 hetaryl having 1-3 heteroatoms selected from N, S and O,
C.sub.7-24 aralkyl, C.sub.7-24 alkaryl, substituted C.sub.1-10
alkyl, substituted C.sub.1-10 alkoxy, substituted C.sub.3-10
cycloalkyl having 0-3 heteroatoms selected from N, S and O,
substituted C.sub.6-C.sub.14 aryl, substituted C.sub.3-12 hetaryl
having 1-3 heteroatoms selected from N, S and O, substituted
C.sub.7-24 alkaryl or substituted C.sub.7-C.sub.24 aralkyl, where
R.sup.a is a substituted group, it is substituted by halogen up to
per halo.
[0019] Where B'' of Formula III is a substituted pyridyl,
substituted quinolinyl or isoquinolinyl group, B'' is preferably
substituted 1 to 3 times by 1 or more substituents selected from
the group consisting of --CN, halogen, C.sub.1-C.sub.10 alkyl,
C.sub.1-C.sub.10 alkoxy, --OH, up to per halo substituted
C.sub.1-C.sub.10 alkyl, up to per halo substituted C.sub.1-C.sub.10
alkoxy or phenyl substituted by halogen up to per halo.
[0020] Where J is a substituted group, it is substituted by
halogen, up to per halo, or by one or more substituents
independently selected from the group consisting of --CN,
--CO.sub.2R.sup.7, --OR.sup.7, --SR.sup.7, --NR.sup.7R.sup.7',
--NO.sub.2, --NR.sup.7C(O)R.sup.7', --NR.sup.7C(O)OR.sup.7; with
each R.sup.7 and R.sup.7' independently as defined above.
[0021] Where the substituents for B, B' and B'' are -Q-Ar, Q is
--O--, --S--, --N(R.sup.7)--, --(CH.sub.2).sub.m--, --C(O)--,
--O--[C(R.sup.9)(R.sup.9')].sub.m--, --CH(OH)--,
--(CH.sub.2).sub.mO--, --(CH.sub.2).sub.mS--,
--(CH.sub.2).sub.mN(R.sup.7)--, --O(CH.sub.2).sub.m--,
--CHX.sup.a--, --CX.sup.a.sub.2--, --S--(CH.sub.2).sub.m and
--N(R.sup.7)(CH.sub.2).sub.m, where m=1-3, R.sup.9 and R.sup.9' are
each, independently, hydrogen, C.sub.1-C.sub.4 alkyl and halogen,
and X.sup.a is halogen and each R.sup.7 is as defined above,
and
[0022] Ar is a 5- or 6-member aromatic structure. This aromatic
structure of Ar [0023] a) contains 0-2 members selected from the
group consisting of nitrogen, oxygen and sulfur, [0024] b) is free
of the substituents --C(O)R.sup.a, --C(NR.sup.a)R.sup.b,
--C(O)NR.sup.aR.sup.b, and --SO.sub.2R.sup.a, wherein R.sup.a and
R.sup.b are as defined above; [0025] c) is optionally substituted
by halogen, up to per-halo, and [0026] d) is optionally substituted
by Mp, wherein p is 0 to 3 and each M is independently selected
from the group consisting of --CN, --NO.sub.2, --OR.sup.7,
--SR.sup.7, --NR.sup.7R.sup.7', --NR.sup.7C(O)(O)R.sup.7',
--NR.sup.7C(O)R.sup.7', with each R.sup.7 and R.sup.7'
independently as defined above, C.sub.1-10 alkyl, C.sub.1-10
alkoxy, C.sub.2-10 alkenyl and C.sub.1-10 alkenoyl halo substituted
C.sub.1-10 alkyl up to per halo, halo substituted C.sub.1-10 alkoxy
up to per halo, halosubstituted C.sub.2-10 alkenyl up to per halo
and halosubstituted C.sub.1-10 alkenoyl up to per halo.
[0027] The bridging group M in the formula -L-(ML.sup.1).sub.q, for
B, B' and B'' is preferably selected from the group consisting of
--O--, --S--, --N(R.sup.7)--, --(CH.sub.2).sub.m--, --C(O)--,
--CH(OH)--, --(CH.sub.2).sub.mO--, --(CH.sub.2).sub.mS--,
--(CH.sub.2).sub.m N(R.sup.7)--, --O(CH.sub.2).sub.m--CHX.sup.a--,
--CX.sup.a.sub.2--, S--(CH.sub.2).sub.m-- and
--N(R.sup.7)(CH.sub.2).sub.m, where m=1-3, X.sup.a is hydrogen and
R.sup.7 is as defined above and q is 1. More preferably, M is
--O--, --CH.sub.2--, --S--, --NH--, --C(O)--, --O--CH.sub.2-- and
--CH.sub.2--O--.
[0028] The moieties L and L.sup.1 in the formula
-L-(ML.sup.1).sub.q for B, B' and B'' are typically each,
independently, a substituted aryl moiety having at least 6 cyclic
members, a substituted hetaryl moiety having at least 5 cyclic
members, an substituted aryl moiety having at least 6 cyclic
members or an unsubstituted hetaryl moiety having at least 5 cyclic
members. The hetaryl moieties for L and L' typically have 1 to 4
members selected from the group of hetaryl atoms consisting of
nitrogen, oxygen and sulfur with the balance of the hetaryl moiety
being carbon. More typical moieties for L.sup.1 and L are selected
from the group consisting of thiophene, phenyl, substituted phenyl,
pyridinyl, substituted pyridinyl, pyrimidinyl substituted
pyrimidinyl quinolyl, substituted quinolyl isoquinolyl, substituted
isoquinolyl, napthyl and substituted napthyl.
[0029] The substituted t-butylpyridyls, (trifluoromethyl)pyridyls,
isopropylpyridyls, (2-methyl-2-butyl)pyridyls,
(3-methyl-3-pentyl)pyridyls and (3-ethyl-3-pentyl)pyridyls of A,
the substituted isoquinolinyls of A' and the substituted
quinolinyls of A'' preferably have 1-3 substituents selected from
the group consisting of C.sub.1-10 alkyl, up to per halo
substituted C.sub.1-10alkyl, --CN, --OH, halogen, C.sub.1-10
alkoxy, up to per halo substituted C.sub.1-10 alkoxy and C3-C10
heterocyclic moieties comprising 1 to 2 heteroatoms selected from
the group of consisting of nitrogen, oxygen and sulfur.
[0030] Preferred compounds of Formula I include those wherein the
cyclic structures of B and L bound directly to D are not
substituted in the ortho position by --OH.
[0031] In Formulae I, II and III suitable hetaryl groups include,
but are not limited to, 5-12 carbon-atom aromatic rings or ring
systems containing 1-3 rings, at least one of which is aromatic, in
which one or more, e.g., 1-4 carbon atoms in one or more of the
rings can be replaced by oxygen, nitrogen or sulfur atoms. Each
ring typically has 3-7 atoms. For example, B can be 2- or 3-furyl,
2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-,
4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or
5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-
or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or
6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-,
-3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,
1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,
1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,
1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-,
4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or
4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-,
3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or
7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or
7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-6- or
7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-,
5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or
7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-,
3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4- or
9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-,
4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally
substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl,
3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B can be
4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl,
1-methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or
5-methyl-1,2,4-thiadiazol-2-yl.
[0032] Suitable alkyl groups and alkyl portions of groups, e.g.,
alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc.,
including all straight-chain and branched isomers such as
isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
[0033] Suitable aryl groups which do not contain heteroatoms
include, for example, phenyl and 1- and 2-naphthyl.
[0034] The term "cycloalkyl", as used herein, refers to cyclic
structures with or without alkyl substituents such that, for
example, "C.sub.4 cycloalkyl" includes methyl substituted
cyclopropyl groups as well as cyclobutyl groups. The term
"cycloalkyl", as used herein also includes saturated heterocyclic
groups.
[0035] Suitable halogen groups include F, Cl, Br, and/or I, from
one to per-substitution (i.e. all H atoms on a group replaced by a
halogen atom) being possible where an alkyl group is substituted by
halogen, mixed substitution of halogen atom types also being
possible on a given moiety.
[0036] The invention also relates to compounds per se, of formula
I, II and III.
[0037] The present invention is also directed to pharmaceutically
acceptable salts of formulae I, II and III. Suitable
pharmaceutically acceptable salts are well known to those skilled
in the art and include basic salts of inorganic and organic acids,
such as hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic
acid, benzenesulphonic acid, p-toluenesulfonic acid,
1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic
acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid,
lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid,
benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid.
In addition, pharmaceutically acceptable salts include acid salts
of inorganic bases, such as salts containing alkaline cations
(e.g., Li.sup.+ Na.sup.+ or K.sup.+), alkaline earth cations (e.g.,
Mg.sup.+2, Ca.sup.+2 or Ba.sup.+2), the ammonium cation, as well as
acid salts of organic bases, including aliphatic and aromatic
substituted ammonium, and quaternary ammonium cations, such as
those arising from protonation or peralkylation of triethylamine,
N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine,
N,N-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane
(DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
[0038] A number of the compounds of Formula I, II and III possess
asymmetric carbons and can therefore exist in racemic and optically
active forms. Methods of separation of enantiomeric and
diastereomeric mixtures are well known to one skilled in the art.
The present invention encompasses any racemic or optically active
form of compounds described in Formulae I, II and III which possess
progesterone receptor binding activity.
General Preparative Methods
[0039] The compounds of Formulae I, II and III may be prepared by
the use of known chemical reactions and procedures, some from
starting materials which are commercially available. Nevertheless,
general preparative methods are provided below to aid one skilled
in the art in synthesizing these compounds, with more detailed
examples being provided in the Experimental section which
follows.
[0040] Substituted and unsubstituted aminoquinolines,
aminoisoquinolines and aminopyridines may be prepared using
standard methods (see, for example: A. R. Katritzky et al. (Eds.).
Comprehensive Heterocyclic Chemistry II, Vol. 5. M. H. Palmer.
Heterocyclic Compounds; Arnold Ltd., London (1967). C. K. Esser et
al. WO 96/18616. C. J. Donahue et al. Inorg. Chem. 30, 1991, 1588.
E. Cho et al. WO 98/00402. A. Cordi et al. Bioorg Med. Chem. 3,
1995, 129). In addition, many aminoquinolines, aminoisoquinolines
and aminopyridines are commercially available.
[0041] Substituted anilines may be generated using standard methods
(March. Advanced Organic Chemistry, 3.sup.rd Ed.; John Wiley: New
York (1985). Larock. Comprehensive Organic Transformations; VCH
Publishers: New York (1989)). As shown in Scheme I, aryl amines are
commonly synthesized by reduction of nitroaryls using a metal
catalyst, such as Ni, Pd, or Pt, and H.sub.2 or a hydride transfer
agent, such as formate, cyclohexadiene, or a borohydride (Rylander.
Hydrogenation Methods; Academic Press: London, UK (1985)).
Nitroaryls may also be directly reduced using a strong hydride
source, such as LiAlH.sub.4 (Seyden-Penne. Reductions by the
Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New
York (1991)), or using a zero valent metal, such as Fe, Sn or Ca,
often in acidic media. Many methods exist for the synthesis of
nitroaryls (March. Advanced Organic Chemistry, 3.sup.rd Ed.; John
Wiley. New York (1985). Larock. Comprehensive Organic
Transformations; VCH Publishers: New York (1989)).
##STR00003##
[0042] Nitroaryls are commonly formed by electrophilic aromatic
nitration using HNO.sub.3, or an alternative NO.sub.2.sup.+ source.
Nitroaryls may be further elaborated prior to reduction. Thus,
nitroaryls substituted with
##STR00004##
potential leaving groups (e.g. F, Cl, Br, etc.) may undergo
substitution reactions on treatment with nucleophiles, such as
thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may
also undergo Ullman-type coupling reactions (Scheme II).
##STR00005##
[0043] Nitroaryls may also undergo transition metal mediated cross
coupling reactions. For example, nitroaryl electrophiles, such as
nitroaryl bromides, iodides or triflates, undergo palladium
mediated cross coupling reactions with aryl nucleophiles, such as
arylboronic acids (Suzuki reactions, exemplified below), aryltins
(Stille reactions) or arylzincs (Negishi reaction) to afford the
biaryl (5).
##STR00006##
[0044] Either nitroaryls or anilines may be converted into the
corresponding arenesulfonyl chloride (7) on treatment with
chlorosulfonic acid. Reaction of the sulfonyl chloride with a
fluoride source, such as KF then affords sulfonyl fluoride (8).
Reaction of sulfonyl fluoride 8 with trimethylsilyl
trifluoromethane in the presence of a fluoride source, such as
tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF)
leads to the corresponding trifluoromethylsulfone (9).
Alternatively, sulfonyl chloride 7 may be reduced to the arenethiol
(10), for example with zinc amalgum. Reaction of thiol 10 with
CHClF.sub.2 in the presence of base gives the difluoromethyl
mercaptan (11), which may be oxidized to the sulfone (12) with any
of a variety of oxidants, including CrO.sub.3-acetic anhydride
(Sedova et al. Zh. Org. Khim. 1970, 6, (568),
##STR00007##
[0045] As shown in Scheme IV, non-symmetrical urea formation may
involve reaction of an aryl isocyanate (14) with an aryl amine
(13). The heteroaryl isocyanate may be synthesized from a
heteroaryl amine by treatment with phosgene or a phosgene
equivalent, such as trichloromethyl chloroformate (diphosgene),
bis(trichloromethyl) carbonate (triphosgene) or
N,N'-carbonyldiimidazole (CDI). The isocyanate may also be derived
from a heterocyclic carboxylic acid derivative, such as an ester,
an acid halide or an anhydride by a Curtius-type rearrangement.
Thus, reaction of acid derivative 16 with an azide source, followed
by rearrangement affords the isocyanate. The corresponding
carboxylic acid (17) may also be subjected to Curtius-type
rearrangements using dephenylphosphoryl axide (DPPA) or a similar
reagent.
##STR00008##
[0046] Finally, ureas may be further manipulated using methods
familiar to those skilled in the art.
[0047] The invention also includes pharmaceutical compositions
including at least one compound of Formula I, II or III and a
physiologically acceptable carrier.
[0048] The compounds may be administered orally, dermally,
parenterally, by injection, by inhalation or spray, or
sublingually, rectally or vaginally in dosage unit formulations.
The term `administration by injection` includes intravenous,
intraarticular, intramuscular, subcutaneous and parenteral
injections, as well as use of infusion techniques. Dermal
administration may include topical application or transdermal
administration. One or more compounds may be present in association
with one or more non-toxic pharmaceutically acceptable carriers and
if desired other active ingredients.
[0049] Compositions intended for oral use may be prepared according
to any suitable method known to the art for the manufacture of
pharmaceutical compositions. Such compositions may contain one or
more agents selected from the group consisting of diluents,
sweetening agents, flavoring agents, coloring agents and preserving
agents in order to provide palatable preparations. Tablets contain
the active ingredient in admixture with non-toxic pharmaceutically
acceptable excipients which are suitable for the manufacture of
tablets. These excipients may be, for example, inert diluents, such
as calcium carbonate, sodium carbonate, lactose, calcium phosphate
or sodium phosphate; granulating, and disintegrating agents, for
example, corn starch, or alginic acid; and binding agents, for
example magnesium stearate, stearic acid or talc. The tablets may
be uncoated or they may be coated by known techniques to delay
disintegration and adsorption in the gastrointestinal tract and
thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or
glyceryl distearate may be employed. These compounds may also be
prepared in solid, rapidly released form.
[0050] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0051] Aqueous suspensions containing the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions may also be used. Such excipients are suspending
agents, for example sodium carboxymethylcellulose, methylcellulose,
hydroxypropyl-methylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example, lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl,
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0052] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example,
sweetening, flavoring and coloring agents, may also be present.
[0053] The compounds may also be in the form of non-aqueous liquid
formulations, e.g., oily suspensions which may be formulated by
suspending the active ingredients in a vegetable oil, for example
arachis oil, olive oil, sesame oil or peanut oil, or in a mineral
oil such as liquid paraffin. The oily suspensions may contain a
thickening agent, for example beeswax, hard paraffin or cetyl
alcohol, Sweetening agents such as those set forth above, and
flavoring agents may be added to provide palatable oral
preparations. These compositions may be preserved by the addition
of an anti-oxidant such as ascorbic acid.
[0054] Pharmaceutical compositions of the invention may also be in
the form of oil-in-water emulsions. The oil phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters;
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0055] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents.
[0056] The compounds may also be administered in the form of
suppositories for rectal or vaginal administration of the drug.
These compositions can be prepared by mixing the drug with a
suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal or vaginal temperature and
will therefore melt in the rectum or vagina to release the drug.
Such materials include cocoa butter and polyethylene glycols.
[0057] Compounds of the invention may also be administered
transdermally using methods known to those skilled in the art (see,
for example: Chien; "Transdermal Controlled Systemic Medications";
Marcel Dekker Inc.; 1987. Lipp et al. WO94/04157 3 Mar. 1994). For
example, a solution or suspension of a compound of Formula I in a
suitable volatile solvent optionally containing penetration
enhancing agents can be combined with additional additives known to
those skilled in the art, such as matrix materials and
bacteriocides. After sterilization, the resulting mixture can be
formulated following known procedures into dosage forms. In
addition, on treatment with emulsifying agents and water, a
solution or suspension of a compound of Formulae I, II or III may
be formulated into a lotion or salve.
[0058] Suitable solvents for processing transdermal delivery
systems are known to those skilled in the art, and include lower
alcohols such as ethanol or isopropyl alcohol, lower ketones such
as acetone, lower carboxylic acid esters such as ethyl acetate,
polar ethers such as tetrahydrofuran, lower hydrocarbons such as
hexane, cyclohexane or benzene, or halogenated hydrocarbons such as
dichloromethane, chloroform, trichlorotrifluoroethane, or
trichlorofluoroethane. Suitable solvents may also include mixtures
one or more materials selected from lower alcohols, lower ketones,
lower carboxylic acid esters, polar ethers, lower hydrocarbons,
halogenated hydrocarbons.
[0059] Suitable penetration enhancing materials for transdermal
delivery systems are known to those skilled in the art, and
include, for example, monohydroxy or polyhydroxy alcohols such as
ethanol, propylene glycol or benzyl alcohol, saturated or
unsaturated C.sub.8-C.sub.18 fatty alcohols such as lauryl alcohol
or cetyl alcohol, saturated or unsaturated C.sub.8-C.sub.18 fatty
acids such as stearic acid, saturated or unsaturated fatty esters
with up to 24 carbons such as methyl, ethyl, propyl, isopropyl,
n-butyl, sec-butyl isobutyl tert-butyl or monoglycerin esters of
acetic acid, capronic acid, lauric acid, myristinic acid, stearic
acid, or palmitic acid, or diesters of saturated or unsaturated
dicarboxylic acids with a total of up to 24 carbons such as
diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate,
diisopropyl maleate, or diisopropyl fumarate. Additional
penetration enhancing materials include phosphatidyl derivatives
such as lecithin or cephalin, terpenes, amides, ketones, ureas and
their derivatives, and ethers such as dimethyl isosorbid and
diethyleneglycol monoethyl ether. Suitable penetration enhancing
formulations may also include mixtures one or more materials
selected from monohydroxy or polyhydroxy alcohols, saturated or
unsaturated C.sub.8-C.sub.18 fatty alcohols, saturated or
unsaturated C.sub.8-C.sub.18 fatty acids, saturated or unsaturated
fatty esters with up to 24 carbons, diesters of saturated or
unsaturated dicarboxylic acids with a total of up to 24 carbons,
phosphatidyl derivatives, terpenes, amides, ketones, ureas and
their derivatives, and ethers.
[0060] Suitable binding materials for transdermal delivery systems
are known to those skilled in the art and include polyacrylates,
silicones, polyurethanes, block polymers, styrene-butadiene
copolymers, and natural and synthetic rubbers. Cellulose ethers,
derivatized polyethylenes, and silicates may also be used as matrix
components. Additional additives, such as viscous resins or oils
may be added to increase the viscosity of the matrix.
[0061] For all regimens of use disclosed herein for compounds of
Formulae I, II and III, the daily oral dosage regimen will
preferably be from 0.01 to 200 mg/Kg of total body weight. The
daily dosage for administration by injection, including
intravenous, intramuscular, subcutaneous and parenteral injections,
and use of infusion techniques will preferably be from 0.01 to 200
mg/Kg of total body weight. The daily rectal dosage regimen will
preferably be from 0.01 to 200 mg/Kg of total body weight. The
daily vaginal dosage regimen will preferably be from 0.01 to 200
mg/Kg of total body weight. The daily dosages for oral
administration, administration by injection, rectal administration
and vaginal administration can be achieved by multiple
administrations per day or by administration as infrequently as
once every 14 days. The long term dosage, can range from 100-800
mg/Kg of total body weight, more preferably 200-600 mg/Kg of total
body weight. The daily topical dosage regimen will preferably be
from 0.1 to 200 mg administered between one to four times daily.
The transdermal concentration will preferably be that required to
maintain a daily dose of from 0.01 to 200 mg/Kg of total body
weight. The daily inhalation dosage regimen will preferably be from
0.01 to 10 mg/Kg of total body weight.
[0062] It will be appreciated by those skilled in the art that the
particular method of administration will depend on a variety of
factors, all of which are considered routinely when administering
therapeutics. It will also be understood, however, that the
specific dose level for any given patient will depend upon a
variety of factors, including, but not limited to the activity of
the specific compound employed, the age of the patient, the body
weight of the patient, the general health of the patient, the
gender of the patient, the diet of the patient, time of
administration, route of administration, rate of excretion, drug
combinations, and the severity of the condition undergoing therapy.
It will be further appreciated by one skilled in the art that the
optimal course of treatment, i.e., the mode of treatment and the
daily or weekly number of doses of a compound of Formulae I, II or
III or a pharmaceutically acceptable salt thereof given for a
defined number of days, can be ascertained by those skilled in the
art using conventional treatment tests.
[0063] The entire disclosure of all applications, patents and
publications cited above and below are hereby incorporated by
reference.
[0064] The compounds of Figure I, II and III are producible from
known compounds (or from starting materials which, in turn, are
producible from known compounds), e.g., through the general
preparative methods shown below. The activity of a given compound
to inhibit raf kinase can be routinely assayed, e.g., according to
procedures disclosed below. The following examples are for
illustrative purposes only and are not intended, nor should they be
construed to limit the invention in any way.
EXAMPLES
[0065] All reactions were performed in flame-dried or oven-dried
glassware under a positive pressure of dry argon or dry nitrogen,
and were stirred magnetically unless otherwise indicated. Sensitive
liquids and solutions were transferred via syringe or cannula, and
introduced into reaction vessels through rubber septa. Unless
otherwise stated, the term `concentration under reduced pressure`
refers to use of a Buchi rotary evaporator at approximately 15
mmHg. Unless otherwise stated, the term `under high vacuum` refers
to a vacuum of 0.4-1.0 mmHg.
[0066] All temperatures are reported uncorrected in degrees Celsius
(.degree. C.). Unless otherwise indicated, all parts and
percentages are by weight.
[0067] Commercial grade reagents and solvents were used without
further purification.
N-cyclohexyl-N'-(methylpolystyrene)carbodiimide was purchased from
Calbiochem-Novabiochem Corp. 5-(Trifluoromethyl)-2-aminopyridine,
3-aminoquinioline, 3-aminoisoquinoline,
1-(4-methylpiperazinyl)-3-aminoisoquinoline, ethyl
4-isocyanatobenzoate,
N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline,
4-(4-nitrobenzyl)pyridine, 4-phenoxyaniline,
4-(4-methylphenoxy)aniline, 4-(4-chlorophenoxy)aniline and
4-chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and
used without further purification. Syntheses of
2-amino-4-tert-butylpyridine (C. K. Esser et al. WO 96/18616; C. J.
Donahue et al. Inorg. Chem. 30, 1991, 1588),
3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et
al. EP 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129),
4-(3-carbamoylphenoxy)-1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79,
1959, 760; Chem, Abstr. 53, 1959, 12761b),
4-[(4-methoxyphenyl)methylamino]aniline (P. Brenneisen et al. U.S.
Pat. No. 3,755,406; IBID U.S. Pat. No. 3,839,582; IBID DE
1,935,388), 4-(4-pyridylcarbonyl)aniline (M. L. Carmello et al.
Pestic. Sci. 45, 1995, 227), 3-tert-butylphenyl isocyanate (O. Rohr
et al. DE 2,436,108) and 2-methoxy-5-(trifluoromethyl)phenyl
isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku
Zasshi 70, 1967, 491) have previously been described.
[0068] Thin-layer chromatography (TLC) was performed using
Whatman.RTM. pre-coated glass-backed silica gel 60A F-254 250 .mu.m
plates. Visualization of plates was effected by one or more of the
following techniques: (a) ultraviolet illumination, (b) exposure to
iodine vapor, (c) immersion of the plate in a 10% solution of
phosphomolybdic acid in ethanol followed by heating, (d) immersion
of the plate in a cerium sulfate solution followed by heating,
and/or (e) immersion of the plate in an acidic ethanol solution of
2,4-dinitrophenylhydrazine followed by heating. Column
chromatography (flash chromatography) was performed using 230-400
mesh EM Science.RTM. silica gel.
[0069] Melting points (mp) were determined using a Thomas-Hoover
melting point apparatus or a Mettler FP66 automated melting point
apparatus and are uncorrected. Fourier transform infrared spectra
were obtained using a Mattson 4020 Galaxy Series spectrophotometer.
Proton (.sup.1H) nuclear magnetic resonance (NMR) spectra were
measured with a General Electric GN-Omega 300 (300 MHz)
spectrometer with either Me.sub.4Si (.delta. 0.00) or residual
protonated solvent (CHCl.sub.3 .delta.7.26; MeOH .delta. 3.30; DMSO
.delta. 2.49) as standard. Carbon (.sup.13C) NMR spectra were
measured with a General Electric GN-Omega 300 (75 NMz) spectrometer
with solvent (CDCl.sub.3 .delta. 77.0; MeOD-d.sub.3; .delta. 49.0;
DMSO-d.sub.6 .delta. 39.5) as standard. Low resolution mass spectra
(MS) and high resolution mass spectra (HRMS) were either obtained
as electron impact (EI) mass spectra or as fast atom bombardment
(FAB) mass spectra. Electron impact mass spectra (EI-MS) were
obtained with a Hewlett Packard 5989A mass spectrometer equipped
with a Vacumetrics Desorption Chemical Ionization Probe for sample
introduction. The ion source was maintained at 250.degree. C.
Electron impact ionization was performed with electron energy of 70
eV and a trap current of 300 .mu.A. Liquid-cesium secondary ion
mass spectra (FAB-MS), an updated version of fast atom bombardment
were obtained using a Kratos Concept 1-H spectrometer. Chemical
ionization mass spectra (CI-MS) were obtained using a Hewlett
Packard MS-Engine (5989A) with methane or ammonia as the reagent
gas (1.times.10.sup.-4 torr to 2.5.times.10.sup.-4 torr). The
direct insertion desorption chemical ionization (DCI) probe
(Vacuumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held
at 10 amps until all traces of the sample disappeared (.about.1-2
min). Spectra were scanned from 50-800 amu at 2 sec per scan.
HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a
Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a
variable wavelength detector, a C-18 column, and a Finnigan LCQ ion
trap mass spectrometer with electrospray ionization. Spectra were
scanned from 120-800 amu using a variable ion time according to the
number of ions in the source. Gas chromatography--ion selective
mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas
chromatograph equipped with an HP-1 methyl silicone column (0.33 mM
coating; 25 m.times.0.2 mm) and a Hewlett Packard 5971 Mass
Selective Detector (ionization energy 70 eV). Elemental analyses
were conducted by Robertson Microlit Labs, Madison N.J.
[0070] All compounds displayed NMR spectra, LRMS and either
elemental analysis or HRMS consistant with assigned structures.
LIST OF ABBREVIATIONS AND ACRONYMS
[0071] AcOH acetic acid anh anhydrous atm atmosphere(s) BOC
tert-butoxycarbonyl CDI 1,1'-carbonyl diimidazole conc concentrated
dec decomposition
DMAC N,N-dimethylacetamide
[0072] DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
DMF N,N-dimethylformamide
[0073] DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EtOAc ethyl acetate
EtOH ethanol (100%) Et.sub.2O diethyl ether Et.sub.3N triethylamine
HOBT 1-hydroxybenzotriazole m-CPBA 3-chloroperoxybenzoic acid MeOH
methanol pet. ether petroleum ether (boiling range 30-60.degree.
C.) THF tetrahydrofuran TFA trifluoroacetic acid Tf
trifluoromethanesulfonyl
A. General Methods for Synthesis of Substituted Anilines
A1. General Method for Substituted Aniline Formation Via
Hydrogenation of a Nitroarene
##STR00009##
[0075] 4-(4-Pyridinylmethyl)aniline: To a solution of
4-(4-nitrobenzyl)pyridine (7.0 g, 32.68 mmol) in EtOH (200 mL) was
added 10% Pd/C (0.7 g) and the resulting slurry was shaken under a
H.sub.2 atmosphere (50 psi) using a Parr shaker. After 1 h, TLC and
.sup.1H-NMR of an aliquot indicated complete reaction. The mixture
was filtered through a short pad of Celite.RTM.. The filtrate was
concentrated in vacuo to afford a white solid (5.4 g, 90%):
.sup.1H-NMR (DMSO-d.sub.6) .delta. 3.74 (s, 2H), 4.91 br s, 2H),
6.48 (d, J=8.46 Hz, 2H), 6.86 (d, J=8.09 Hz, 2H), 7.16 (d, J=5.88
Hz, 2H), 8.40 (d, J=5.88 Hz, 2H); EI-MS m/z 184 (M.sup.+). This
material was used in urea formation reactions without further
purification.
A2, General Method for Substituted Aniline Formation Via Dissolving
Metal Reduction of a Nitroarene
##STR00010##
[0077] 4-(2-Pyridinylthio)aniline; To a solution of
4-(2-pyridinylthio)-1-nitrobenzene (Menai ST 3355A; 0.220 g 0.95
mmol) and H.sub.2O (0.5 mL) in AcOH (5 mL) was added iron powder
(0.317 g, 5.68 mmol) and the resulting slurry stirred for 16 h at
room temp. The reaction mixture was diluted with EtOAc (75 mL) and
H.sub.2O (50 mL), basified to pH 10 by adding solid K.sub.2CO.sub.3
in portions (Caution: foaming). The organic layer was washed with a
saturated NaCl solution, dried (MgSO.sub.4), concentrated in vacuo.
The residual solid was purified by MPLC (30% EtOAc/70% hexane) to
give the desired product as a thick oil (0.135 g, 70%); TLC (30%
EtOAc/70% hexanes) R.sub.f 0.20.
A3a. General Method for Substituted Aniline Formation via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00011##
[0078] Step 1. 1-Methoxy-4-(4-nitrophenoxy)benzene: To a suspension
of NaH (95%, 1.50 g, 59 mmol) in DMF (100 mL) at room temp. was
added dropwise a solution of 4-methoxyphenol (7.39 g, 59 mmol) in
DMF (50 mL). The reaction was stirred 1 h, then a solution of
1-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was added
dropwise to form a dark green solution. The reaction was heated at
95.degree. C. overnight, then cooled to room temp., quenched with
H.sub.2O and concentrated in vacuo. The residue was partitioned
between EtOAc (200 mL) and H.sub.2O (200 mL). The organic layer was
sequentially washed with H.sub.2O (2.times.200 mL), a saturated
NaHCO.sub.3 solution (200 mL), and a saturated NaCl solution (200
mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The
residue was triturated (Et.sub.2O/hexane) to afford
t-methoxy-4-(4-nitrophenoxy)benzene (12.2 g, 100%); .sup.1H-NMR
(CDCl.sub.3) .delta. 3.83 (s, 3H), 6.93-7.04 (m, 6H), 8.18 (d,
J=9.2 Hz, 2H); EI-MS m/z 245 (M.sup.+).
##STR00012##
[0079] Step 2. 4-(4-Methoxyphenoxy)aniline: To a solution of
1-methoxy-4-(4-nitrophenoxy)benzene (12.0 g, 49 mmol) in EtOAc (250
mL) was added 5% Pt/C (1.5 g) and the resulting slurry was shaken
under a H.sub.2 atmosphere (50 psi) for 18 h. The reaction mixture
was filtered through a pad of Celite.RTM. with the aid of EtOAc and
concentrated in vacuo to give an oil which slowly solidified (10.6
g, 100%): .sup.1H-NMR (CDCl.sub.3) .delta. 3.54 (br s, 2H), 3.78
(s, 3H), 6.65 (d, J=8.8 Hz, 2H), 6.79-6.92 (m, 6H); EI-MS m/z 215
(M.sup.+).
A3b. General Method for Substituted Aniline Formation Via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00013##
[0080] Step 1. 3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene:
A solution of 4-mercaptopyridine (2.8 g, 24 mmoles),
2-fluoro-5-nitrobenzotrifluoride (5 g, 23.5 mmoles), and potassium
carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) was stirred
at room temperature and under argon overnight. TLC showed complete
reaction. The mixture was diluted with Et.sub.2O (100 mL) and water
(100 mL) and the aqueous layer was back-extracted with Et.sub.2O
(2.times.100 mL). The organic layers were washed with a saturated
NaCl solution (100 mL), dried (MgSO.sub.4), and concentrated under
reduced pressure. The solid residue was triturated with Et.sub.2O
to afford the desired product as a tan solid (3.8 g, 54%): TLC (30%
EtOAc/70% hexane) R.sub.f 0.06; .sup.1H-NMR (DMSO-d.sub.6) .delta.
7.33 (dd, J=1.2, 4.2 Hz, 2H), 7.78 (d, J=8.7 Hz, 1H), 8.46 (dd,
J=2.4, 8.7 Hz, 1H), 8.54-8.56 (m, 3H).
##STR00014##
[0081] Step 2. 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline: A
slurry of 3-trifluoromethyl-4-(4-pyridinylthio)nitrobenzene (3.8 g,
12.7 mmol), iron powder (4.0 g, 71.6 mmol), acetic acid (100 mL),
and water (1 mL) were stirred at room temp. for 4 h. The mixture
was diluted with Et.sub.2O (100 mL) and water (100 mL). The aqueous
phase was adjusted to pH 4 with a 4 N NaOH solution. The combined
organic layers were washed with a saturated NaCl solution (100 mL),
dried (MgSO.sub.4), and concentrated under reduced pressure. The
residue was filtered through a pad of silica (gradient from 50%
EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the desired
product (3.3 g); TLC (50% EtOAc/50% hexane) R.sub.f 0.10;
.sup.1H-NMR (DMSO-d.sub.6) .delta. 6.21 (s, 2H), 6.84-6.87 (m, 3H),
7.10 (d, J=2.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=6.3 Hz,
2H).
A3c. General Method for Substituted Aniline Formation Via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00015##
[0082] Step 1. 4-(2-(4-Phenyl)thiazolyl)thio-1-nitrobenzene: A
solution of 2-mercapto-4-phenylthiazole (4.0 g, 20.7 mmoles) in DMF
(40 mL) was treated with 1-fluoro-4-nitrobenzene (2.3 mL, 21.7
mmoles) followed by K.sub.2CO.sub.3 (3.18 g, 23 mol), and the
mixture was heated at approximately 65.degree. C. overnight. The
reaction mixture was then diluted with EtOAc (100 mL), sequentially
washed with water (100 mL) and a saturated NaCl solution (100 mL),
dried (MgSO.sub.4) and concentrated under reduced pressure. The
solid residue was triturated with a Et.sub.2O/hexane solution to
afford the desired product (6.1 g): TLC (25% EtOAc/75% hexane)
R.sub.f 0.49; .sup.1H-NMR (CDCl.sub.3) .delta. 7.35-7.47 (m, 3H),
7.58-7.63 (m, 3H), 7.90 (d, J=6.9 Hz, 2H), 8.19 (d, J==9.0 Hz,
2H).
##STR00016##
[0083] Step 2. 4-(2-(4-Phenyl)thiazolyl)thioaniline:
4-(2-(4-Phenyl)thiazolyl)thio-1-nitro-benzene was reduced in a
manner analagous to that used in the preparation of
3-(trifluoromethyl)-4-(4-pyridinylthio)aniline: TLC (25% EtOAc/75%
hexane) R.sub.f 0.18; .sup.1H-NMR (CDCl.sub.3) .delta. 3.89 (br s,
2H), 6.72-6.77 (m, 2H), 7.26-7.53 (m, 6H), 7.85-7.89 (m, 2H).
A3d. General Method for Substituted Aniline Formation Via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00017##
[0084] Step 1. 4-(6-Methyl-3-pyridinyloxy)-1-nitrobenzene: To a
solution of 5-hydroxy-2-methylpyridine (5.0 g, 45.8=mol) and
1-fluoro-4-nitrobenzene (6.5 g, 45.8 mmol) in anh DMF (50 mL) was
added K.sub.2CO.sub.3 (13.0 g, 91.6 mmol) in one portion. The
mixture was heated at the reflux temp. with stirring for 18 h and
then allowed to cool to room temp. The resulting mixture was poured
into water (200 mL) and extracted with EtOAc (3.times.150 mL). The
combined organics were sequentially washed with water (3.times.100
mL) and a saturated NaCl solution (2.times.100 mL), dried
(Na.sub.2SO.sub.4), and concentrated in vacuo to afford the desired
product (8.7 g, 83%). This material was carried to the next step
without further purification.
##STR00018##
[0085] Step 2. 4-(6-Methyl-3-pyridinyloxy)aniline: A solution of
4-(6-methyl-3-pyridinyloxy)-1-nitrobenzene (4.0 g, 17.3 mmol) iii
EtOAc (150 mL) was added to 10% Pd/C (0.500 g, 0.47 mmol) and the
resulting mixture was placed under a H.sub.2 atmosphere (balloon)
and was allowed to stir for 18 h at room temp. The mixture was then
filtered through a pad of Celite.RTM. and concentrated in vacuo to
afford the desired product as a tan solid (3.2 g, 92%): EI-MS m/z
200 (M.sup.+).
A3e. General Method for Substituted Aniline Formation Via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00019##
[0086] Step 1. 4-(3,4-Dimethoxyphenoxy)-1-nitrobenzene: To a
solution of 3,4-dimethoxyphenol (1.0 g, 6.4 mmol) and
1-fluoro-4-nitrobenzene (700 .mu.L, 6.4 mmol) in anh DMF (20 mL)
was added K.sub.2CO.sub.3 (1.8 g, 12.9 mmol) in one portion. The
mixture was heated at the reflux temp with stirring for 18 h and
then allowed to cool to room temp. The mixture was then poured into
water (100 mL) and extracted with EtOAc (3.times.100 mL). The
combined organics were sequentially washed with water (3.times.50
mL) and a saturated NaCl solution (2.times.50 mL), dried
(Na.sub.2SO.sub.4), and concentrated in vacuo to afford the desired
product (0.8 g, 54%). The crude product was carried to the next
step without further purification.
##STR00020##
[0087] Step 2. 4-(3,4-Dimethoxyphenoxy)aniline: A solution of
4-(3,4-dimethoxy-phenoxy)-1-nitrobenzene (0.8 g, 3.2 mmol) in EtOAc
(50 mL) was added to 10% Pd/C (0.100 g) and the resulting mixture
was placed under a H.sub.2 atmosphere (balloon) and was allowed to
stir for 18 h at room temp. The mixture was then filtered through a
pad of Celite.RTM. and concentrated in vacuo to afford the desired
product as a white solid (0.6 g, 75%): EI-MS m/z 245 (M.sup.+).
[0088] A3f. General Method for Substituted Aniline Formation via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00021##
[0089] Step 1. 3-(3-Pyridinyloxy)-1-nitrobenzene: To a solution of
3-hydroxypyridine (2.8 g, 29.0 mmol), 1-bromo-3-nitrobenzene (5.9
g, 29.0 mmol) and copper(I) bromide (5.0 g, 34.8 mmol) in anh DMF
(50 mL) was added K.sub.2CO.sub.3 (8.0 g, 58.1 mmol) in one
portion. The resulting mixture was heated at the reflux temp. with
stirring for 18 h and then allowed to cool to room temp. The
mixture was then poured into water (200 mL) and extracted with
EtOAc (3.times.150 mL). The combined organics were sequentially
washed with water (3.times.100 mL) and a saturated NaCl solution
(2.times.100 mL), dried (Na.sub.2SO.sub.4), and concentrated in
vacuo. The resulting oil was purified by flash chromatography (30%
EtOAc/70% hexane) to afford the desired product (2.0 g, 32%). This
material was used in the next step without further
purification.
##STR00022##
[0090] Step 2. 3-(3-Pyridinyloxy)aniline: A solution of
3-(3-pyridinyloxy)-1-nitrobenzene (2.0 A, 9.2 mmol) in EtOAc (100
mL) was added to 10% Pd/C (0.200 g) and the resulting mixture was
placed under a H.sub.2 atmosphere (balloon) and was allowed to stir
for 18 h at room temp. The mixture was then filtered through a pad
of Celite.RTM. and concentrated in vacuo to afford the desired
product as a red oil (1.6 g, 94%): EI-MS m/z 186 (M.sup.+).
A3 g. General Method for Substituted Aniline Formation via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00023##
[0091] Step 1. 3-(5-Methyl-3-pyridinyloxy)-1-nitrobenzene: To a
solution of 3-hydroxy-5-methylpyridine (5.0 g, 45.8 mmol),
1-bromo-3-nitrobenzene (12.0 g, 59.6 mmol) and copper(I) iodide
(10.0 g, 73.3 mmol) in anh DMF (50 mL) was added K.sub.2CO.sub.3
(13.0 g, 91.6 mmol) in one portion. The mixture was heated at the
reflux temp. with stirring for 18 h and then allowed to cool to
room temp. The mixture was then poured into water (200 mL) and
extracted with EtOAc (3.times.150 mL). The combined organics were
sequentially washed with water (3.times.100 mL) and a saturated
NaCl solution (2.times.100 mL), dried (Na.sub.2SO.sub.4), and
concentrated in vacuo. The resulting oil was purified by flash
chromatography (30% EtOAc/70% hexane) to afford the desired product
(1.2 g, 13%).
##STR00024##
[0092] Step 2. 3-(5-Methyl-3-pyridinyloxy)-1-nitrobenzene: A
solution of 3-(5-methyl-3-pyridinyloxy)-1-nitrobenzene (1.2 g,
5.2=mol) in EtOAc (50 mL) was added to 10% Pd/C (0.100 g) and the
resulting mixture was placed under a H.sub.2 atmosphere (balloon)
and was allowed to stir for 18 h at room temp. The mixture was then
filtered through a pad of Celite.RTM. and concentrated in vacuo to
afford the desired product as a red oil (0.9 g, 86%): CI-MS m/z 201
((M+H).sup.+).
A3 h. General Method for Substituted Aniline Formation via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00025##
[0093] Step 1. 5-Nitro-2-(4-methylphenoxy)pyridine: To a solution
of 2-chloro-5-nitropyridine (6.34 g, 40 mmol) in DMF (200 mL) were
added of 4-methylphenol (5.4 g, 50 mmol, 1.25 equiv) and
K.sub.2CO.sub.3 (8.28 g, 60 mmol, 1.5 equiv). The mixture was
stirred overnight at room temp. The resulting mixture was treated
with water (600 mL) to generate a precipitate. This mixture was
stirred for 1 h, and the solids were separated and sequentially
washed with a 1 N NaOH solution (25 mL), water (25 mL) and pet
ether (25 mL) to give the desired product (7.05 g, 76%); mp
80-82.degree. C.; TLC (30% EtOAc/70% pet ether) R.sub.f 0.79;
.sup.1H-NMR (DMSO-d.sub.6) .delta. 2.31 (s, 3H), 7.08 (d, f=8.46
Hz, 2H), 7.19 (d, J=19.20 Hz, 1H), 7.24 (d, J=8.09 Hz, 2H), 8.58
(dd, J=2.94, 8.82 Hz, 1H), 8.99 (d, J=2.95 Hz, 1H); FAB-MS m/z (rel
abundance) 231 ((M+H).sup.+), 100%).
##STR00026##
[0094] Step 2. 5-Amino-2-(4-methylphenoxy)pyridine Dihydrochloride;
A solution 5-nitro-2-(4-methylphenoxy)pyridine (6.94 g, 30 mmol, 1
eq) and EtOH (10 mL) in EtOAc (190 mL) was purged with argon then
treated with 10% Pd/C (0.60 g). The reaction mixture was then
placed under a H.sub.2 atmosphere and was vigorously stirred for
2.5 h. The reaction mixture was filtered through a pad of
Celite.RTM.. A solution of HCl in Et.sub.2O was added to the
filtrate was added dropwise. The resulting precipitate was
separated and washed with EtOAc to give the desired product (7.56
g, 92%): mp 208-210.degree. C. (dec); TLC (50% EtOAc/50% pet ether)
R.sub.f 0.42; .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.25 (s, 3H).sub.,
6.98 (d, J=8.45 Hz, 2H), 7.04 (d, J=8.82 Hz, 1H), 7.19 (d, J=8.09
Hz, 2H), 8.46 (dd, J=2.57, 8.46 Hz, 1H), 8.63 (d, J=2.57 Hz, 1H);
EI-MS m/z (rel abundance) (M.sup.+, 100%).
A3i. General Method for Substituted Aniline Formation via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00027##
[0095] Step 1. 4-(3-Thienylthio)-1-nitrobenzene; To a solution of
4-nitrothiophenol (80% pure, 1.2 g, 6.1 mmol), 3-bromothiophene
(1.0 g, 6.1 mmol) and copper(II) oxide (0.5 g, 3.7 mmol) in
anhydrous DMF (20 mL) was added KOH (0.3 g, 6.1 mmol), and the
resulting mixture was heated at 130.degree. C. with stirring for 42
h and then allowed to cool to room temp. The reaction mixture was
then poured into a mixture of ice and a 6N HCl solution (200 mL)
and the resulting aqueous mixture was extracted with EtOAc
(3.times.100 mL). The combined organic layers were sequentially
washed with a 1M NaOH solution (2.times.100 mL) and a saturated
NaCl solution (2.times.100 mL), dried (MgSO.sub.4), and
concentrated in vacuo. The residual oil was purified by MPLC
(silica gel; gradient from 10% EtOAc/90% hexane to 5% EtOAc/95%
hexane) to afford of the desired product (0.5 g, 34%). GC-MS m/z
237 (M.sup.+).
##STR00028##
[0096] Step 2. 4-(3-Thienylthio)aniline:
4-(3-Thienylthio)-1-nitrobenzene was reduced to the aniline in a
manner analogous to that described in Method A1.
A3j. General Method for Substituted Aniline Formation via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00029##
[0097] 4-(5-Pyrimininyloxy)aniline: 4-Aminophenol (1.0 g, 9.2 mmol)
was dissolved in DMF (20 .mu.L) then 5-bromopyrimidine (1.46 g, 9.2
mmol) and 1(2CO.sub.3 (1.9 g, 13.7 mmol) were added. The mixture
was heated to 100.degree. C. for 18 h and at 130.degree. C. for 48
h at which CC-MS analysis indicated some remaining starting
material. The reaction mixture was cooled to room temp. and diluted
with water (50 mL). The resulting solution was extracted with EtOAc
(100 mL). The organic layer was washed with a saturated NaCl
solution (2.times.50 mL), dried (MgSO.sub.4), and concentrated in
vacuo. The residual solids were purified by MPLC (50% EtOAc/50%
hexanes) to give the desired amine (0.650 g, 38%).
A3k. General Method for Substituted Aniline Formation via
Nitroarene Formation through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00030##
[0098] Step 1. 5-Bromo-2-methoxypyridine: A mixture of
2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6
mmol) in MeOH (60 mL) was heated at 70.degree. C. in a sealed
reaction vessel for 42 h, then allowed to cool to room temp. The
reaction mixture was treated with water (50 mL) and extracted with
EtOAc (2.times.100 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to give
a pale yellow, volatile oil (4.1 g, 95% yield): TLC (10% EtOAc/90%
hexane) R.sub.f 0.57.
##STR00031##
[0099] Step 2. 5-Hydroxy-2-methoxypyridine: To a stirred solution
of 5-bromo-2-methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at
-78.degree. C. was added an n-butyllithium solution (2.5 M in
hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was
allowed to stir at -78.degree. C. for 45 min. Trimethyl borate
(7.06 mL, 62.2 mmol) was added via syringe and the resulting
mixture was stirred for an additional 2 h. The bright orange
reaction mixture was warmed to 0.degree. C. and was treated with a
mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen
peroxide solution (30%; approx. 50 mL). The resulting yellow and
slightly turbid reaction mixture was warmed to room temp. for 30
min and then heated to the reflux temp. for 1 h. The reaction
mixture was then allowed to cool to room temp. The aqueous layer
was neutralized with a 1N HCl solution then extracted with
Et.sub.2O (2.times.100 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to give
a viscous yellow oil (3.5 g, 60%).
##STR00032##
[0100] Step 3. 4-(5-(2-Methoxy)pyridyl)oxy-1-nitrobenzene: To a
stirred slurry of NaH (97%, 1.0 g, 42 mmol) in anh DMF (100 mL) was
added a solution of 5-hydroxy-2-methoxypyridine (3.5 g, 28 mmol) in
DMF (100 mL). The resulting mixture was allowed to stir at room
temp. for 1 h, 4-fluoronitrobenzene (3 mL, 28 mmol) was added via
syringe. The reaction mixture was heated to 95.degree. C.
overnight, then treated with water (25 mL) and extracted with EtOAc
(2.times.75 mL). The organic layer was dried (MgSO.sub.4) and
concentrated under reduced pressure. The residual brown oil was
crystallized EtOAc/hexane) to afford yellow crystals (5.23 g,
75%).
##STR00033##
[0101] Step 4. 4-(5-(2-Methoxy)pyridyl)oxyaniline:
4-(5-(2-Methoxy)pyridyl)oxy-1-nitrobenzene was reduced to the
aniline in a manner analogous to that described in Method A3d, Step
2.
A4a. General Method for Substituted Aniline Synthesis via
Nucleophilic Aromatic Substitution Using a Halopyridine
##STR00034##
[0102] 3-(4-Pyridinylthio)aniline: To a solution of
3-aminothiophenol (3.8 mL, 34 mmoles) in anh DMF (90 mL) was added
4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles) followed by
K.sub.2CO.sub.3 (16.7 g, 121 mmoles). The reaction mixture was
stirred at room temp. for 1.5 h, then diluted with EtOAc (100 mL)
and water (100 mL). The aqueous layer was back-extracted with EtOAc
(2.times.100 mL). The combined organic layers were washed with a
saturated NaCl solution (100 mL), dried (MgSO.sub.4), and
concentrated under reduced pressure. The residue was filtered
through a pad of silica (gradient from 50% EtOAc/50% hexane to 70%
EtOAc/30% hexane) and the resulting material was triturated with a
Et.sub.2O/hexane solution to afford the desired product (4.6 g,
66%): TLC (100% ethyl acetate) R.sub.f 0.29; .sup.1H-NMR
(DMSO-d.sub.6) .delta. 5.41 (s, 2H), 6.64-6.74 (m, 3H), 7.01 (d,
J=4.8, 2H), 7.14 (t, J=7.85 Hz, 1H), 8.32 (d, J=4.8, 2H).
A4b. General Method for Substituted Aniline Synthesis Via
Nucleophilic Aromatic Substitution Using a Halopyridine
##STR00035##
[0103] 4-(2-Methyl-4-pyridinyloxy)aniline: To a solution of
4-aminophenol (3.6 g, 32.8 mmol) and 4-chloropicoline (5.0 g, 39.3
mmol) in art DMPU (50 mL) was added potassium tert butoxide (7.4 g,
65.6 mmol) in one portion. The reaction mixture was heated at
100.degree. C. with stirring for 18 h, then was allowed to coot to
room temp. The resulting mixture was poured into water (200 mL) and
extracted with EtOAc (3.times.150 mL). The combined extracts were
sequentially washed with water (3.times.100 mL) and a saturated
NaCl solution (2.times.100 mL), dried (Na.sub.2SO.sub.4), and
concentrated in vacuo. The resulting oil was purified by flash
chromatography (50% EtOAc/50% hexane) to afford the desired product
as a yellow oil (0.7 g, 9%): CI-MS m/z 201 ((M+H).sup.+).
A4c. General Method for Substituted Aniline Synthesis Via
Nucleophilic Aromatic Substitution Using a Halopyridine
##STR00036##
[0104] Step 1. Methyl(4-nitrophenyl)-4-pyridylamine: To a
suspension of N-methyl-4-nitroaniline (2.0 g, 13.2 mmol) and
K.sub.2CO.sub.3 (7.2 g, 52.2 mmol) in DMPU (30 mL) was added
4-chloropyridine hydrochloride (2.36 g, 15.77 mmol). The reaction
mixture was heated at 90.degree. C. for 20 h, then cooled to room
temperature. The resulting mixture was diluted with water (100 mL)
and extracted with EtOAc (100 mL). The organic layer was washed
with water (100 mL), dried (Na.sub.2SO.sub.4) and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, gradient from 80% EtOAc/20% hexanes to
100% EtOAc) to afford methyl(4-nitrophenyl)-4-pyridylamine (0.42
g)
##STR00037##
[0105] Step 2. Methyl(4-aminophenyl)-4-pyridylamine:
Methyl(4-nitrophenyl)-4-pyridylamine was reduced in a manner
analogous to that described in Method A1.
A5. General Method of Substituted Aniline Synthesis Via Phenol
Alkylation Followed by Reduction of a Nitroarene
##STR00038##
[0107] Step 1. 4-(4-Butoxyphenyl)thio-1-nitrobenzene: To a solution
of 4(4-nitrophenyl-thio)phenol (1.50 g, 6.07 mmol) in anh DMF (75
ml) at 0.degree. C. was added NaH (60% in mineral oil, 0.267 g,
6.67 mmol). The brown suspension was stirred at 0.degree. C. until
gas evolution stopped (15 min), then a solution of iodobutane (1.12
g, 690 ml, 6.07 mmol) in anh DMF (20 mL) was added dropwise over 15
min at 0.degree. C. The reaction was stirred at room temp. for 18 h
at which time TLC indicated the presence of unreacted phenol, and
additional iodobutane (56 mg, 9.035 mL, 0.303 mmol, 0.05 equiv) and
NaH (13 mg, 0.334 mmol) were added. The reaction was stirred an
additional 6 h at room temp., then was quenched by the addition of
water (400 mL). The resulting mixture was extracted with Et.sub.2O
(2.times.500 mL). The combined organics were washed with water
(2.times.400 mL), dried (MgSO.sub.4), and concentrated under
reduced pressure to give a clear yellow oil, which was purified by
silica gel chromatography (gradient from 20% EtOAc/80% hexane to
50% EtOAc/50% hexane) to give the product as a yellow solid (1.24
g, 67%): TLC (20% EtOAc/80% hexane) R.sub.f 0.75; .sup.1H-NMR
(DMSO-d.sub.6) .delta. 0.92 (t, J=7.5 Hz, 3H), 1.42 (app hex, J=7.5
Hz, 2H), 1.70 (m, 2H), 4.01 (t, 16.6 Hz, 2H), 7.08 (d J=8.7 Hz,
2H), 7.17 (d, J=9 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 8.09 (d, J=9 Hz,
2H).
##STR00039##
[0108] Step 2. 4-(4-Butoxyphenyl)thioaniline:
4-(4-Butoxyphenyl)thio-1-nitrobenzene was reduced to the aniline in
a manner analagous to that used in the preparation of
3-(trifluoromethyl)-4-(4-pyridinylthio)aniline (Method A3b, Step
2): TLC (33% EtOAc/77% hexane) R.sub.f 0.38.
A6. General Method for Synthesis of Substituted Anilines by the
Acylation of Diaminoarenes
##STR00040##
[0110] 4-(4-tert-Butoxycarbamoylbenzyl)aniline: To a solution of
4,4'-methylenedianiline (3.00 g, 15.1 mmol) in anh THF (50 mL) at
room temp was added a solution of di-tert-butyl dicarbonate (3.30
g, 15.1 mmol) in anh THF (10 mL). The reaction mixture was heated
at the reflux temp. for 3 h, at which time TLC indicated the
presence of unreacted methylenedianiline. Additional di-tert-butyl
dicarbonate (0.664 g, 3.03 mmol, 0.02 equiv) was added and the
reaction stirred at the reflux temp. for 16 h. The resulting
mixture was diluted with Et.sub.2O (200 mL), sequentially washed
with a saturated NaHCO.sub.3 solution (100 ml), water (100 mL) and
a saturated NaCl solution (50 mL), dried (MgSO.sub.4), and
concentrated under reduced pressure. The resulting white solid was
purified by silica gel chromatography (gradient from 33% EtOAc/67%
hexane to 50% EtOAc/50% hexane) to afford the desired product as a
white. solid (2.09 g, 46%); TLC (50% EtOAc/50% hexane) R.sub.f0.45;
.sup.1H-NMR (DMSO-d.sub.6) .delta. 1.43 (s, 9H), 3.63 (s, 2H), 4.85
(br s, 2H), 6.44 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.1 Hz, 2H), 7.00
(d, J=8.4 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 9.18 (hr s, 1H); FAB-MS
m/z 298 (M.sup.+).
A7. General Method for the Synthesis of Aryl Amines Via
Electrophilic Nitration Followed by Reduction
##STR00041##
[0112] Step 1. 3-(4-Nitrobenzyl)pyridine: A solution of
3-benzylpyridine (4.0 g, 23.6 mmol) and 70% nitric acid (30 mL) was
heated overnight at 50.degree. C. The resulting mixture was allowed
to cool to room temp. then poured into ice water (350 mL). The
aqueous mixture then made basic with a 1N NaOH solution, then
extracted with Et.sub.2O (4.times.100 mL). The combined extracts
were sequentially washed with water (3.times.100 mL) and a
saturated NaCl solution (2.times.100 mL), dried (Na.sub.2SO.sub.4),
and concentrated in vacuo. The residual oil was purified by MPLC
(silica gel; 50% EtOAc/50% hexane) then recrystallization
(EtOAc/hexane) to afford the desired product (1.0 g, 22%): CC-MS
m/z 214 (M.sup.+).
##STR00042##
[0113] Step 2. 3-(4-Pyridinyl)methylaniline:
3-(4-Nitrobenzyl)pyridine was reduced to the aniline in a manner
analogous to that described in Method A1.
A8. General Method for Synthesis of Aryl Amines Via Substitution
with Nitrobenzyl Halides Followed by Reduction
##STR00043##
[0114] Step 1. 4-(1-Imidazolylmethyl)-1-nitrobenzene: To a solution
of imidazole (0.5 g, 7.3 mmol) and 4-nitrobenzyl bromide (1.6 g,
7.3 mmol) in anh acetonitrile (30 mL) was added K.sub.2CO.sub.3
(1.0 g, 7.3 mmol). The resulting mixture was stirred at room temp.
for 18 h and then poured into water (200 mL) and the resulting
aqueous solution was extracted with EtOAc (3.times.50 mL). The
combined organic layers were sequentially washed with water
(3.times.50 mL) and a saturated NaCl solution (2.times.50 mL),
dried (MgSO.sub.4), and concentrated in vacuo. The residual oil was
purified by MPLC (silica gel; 25% EtOAc/75% hexane) to afford the
desired product (1.0 g, 91%): EI-MS m/z 203 (M.sup.+).
##STR00044##
[0115] Step 2. 4-(1-Imidazolylmethyl)aniline:
4-(1-Imidazolylmethyl)-1-nitrobenzene was reduced to the aniline in
a manner analogous to that described in Method A2.
A9. Formation of Substituted Hydroxymethylanilines by Oxidation of
Nitrobenzyl Compounds Followed by Reduction
##STR00045##
[0117] Step 1. 4-(1-Hydroxy-1-(4-pyridyl)methyl-1-nitrobenzene: To
a stirred solution of 3-(4-nitrobenzyl)pyridine (6.0 g, 28 mmol) in
CH.sub.2Cl.sub.2 (90 mL) was added m-CPBA (5.80 g, 33.6 mmol) at
10.degree. C., and the mixture was stirred at room temp. overnight.
The reaction mixture was successively washed with a 10% NaHSO.sub.3
solution (50 mL), a saturated K.sub.2CO.sub.3 solution (50 mL) and
a saturated NaCl solution (50 mL), dried (MgSO.sub.4) and
concentrated under reduced pressure. The resulting yellow solid
(2.68 g) was dissolved in anh acetic anhydride (30 mL) and heated
at the reflux temperature overnight. The mixture was concentrated
under reduced pressure. The residue was dissolved in MeOH (25 mL)
and treated with a 20% aqueous NH.sub.3 solution (30 mL). The
mixture was stirred at room temp. for 1 h, then was concentrated
under reduced pressure. The residue was poured into a mixture of
water (50 mL) and CH.sub.2Cl.sub.2 (50 mL). The organic layer was
dried (MgSO.sub.4), concentrated under reduced pressure, and
purified by column chromatography (80% EtOAc/20% hexane) to afford
the desired product as a white solid. (0.53 g, 8%); mp
110-118.degree. C.; TLC (80% EtOAc/20% hexane) R.sub.f 0.12; FAB-MS
m/z 367 ((M+H).sup.+, 100%).
##STR00046##
[0118] Step 2. 4-(1-Hydroxy-1-(4-pyridyl)methylaniline:
4-(1-Hydroxy-1-(4-pyridyl)-methyl-1-nitrobenzene was reduced to the
aniline in a manner analogous to that described in Method A3d, Step
2.
A10. Formation of 2-(N-methylcarbamoyl)pyridines Via the Menisci
reaction
##STR00047##
[0119] Step 1. 2-(N-methylcarbamoyl)-4-chloropyridine. (Caution:
this is a highly hazardous, potentially explosive reaction.) To a
solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL)
under argon at ambient temp was added conc. H.sub.2SO.sub.4 (3.55
mL) (exotherm). To this was added H.sub.2O.sub.2 (17 mL, 30% wt in
H2O) followed by FeSO.sub.47H.sub.2O (0.55 g) to produce an
exotherm. The reaction was stirred in the dark at ambient temp for
1 h then was heated slowly over 4 h at 45.degree. C. When bubbling
subsided, the reaction was heated at 60.degree. C. for 16 h. The
opaque brown solution was diluted with H2O (700 mL) followed by a
10% NaOH solution (250 mL). The aqueous mixture was extracted with
EtOAc (3.times.500 ml) and the organic layers were washed
separately with a saturated NaCl solution (3.times.150 mL. The
combined organics were dried (MgSO.sub.4) and filtered through a
pad of silica gel eluting with EtOAc. The solvent was removed in
vacuo and the brown residue was purified by silica gel
chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20%
hexane). The resulting, yellow oil crystallized at 0.degree. C.
over 72 h to give 2-(N-methylcarbamoyl)-4-chloropyridine in yield
(0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) R.sub.f 0.50; MS;
.sup.1H NMR (CDCl.sub.3): .delta.d 8.44 (d, 1H, J=5.1 Hz, CNN),
8.21 (s, 1H, CHCCO), 7.96 bs, 5H, NH), 7.43 (dd, 1H, J=2.4, 5.4 Hz,
ClCHCN), 3.04 (d, 3H, J=5.1 Hz, methyl); CI-MS m/z 171
((M+H)+).
A11. General Method for the Synthesis of .delta.-Sulfonylphenyl
Anilines
##STR00048##
[0121] Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene: To a
solution of 4-(4-methylthiophenoxy)-1-nitrobenzene (2 g, 7.66 mmol)
in CH.sub.2Cl.sub.2 (75 mL) at 0.degree. C. was slowly added mCPBA
(57-86%, 4 g), and the reaction mixture was stirred at room
temperature for 5 h. The reaction mixture was treated with a 1 N
NaOH solution (25 mL). The organic layer was sequentially washed
with a 1N NaOH solution (25 mL), water (25 mL) and a saturated NaCl
solution (25 mL), dried (MgSO.sub.4), and concentrated under
reduced pressure to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene
as a solid (2.1 g).
[0122] Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline:
4-(4-Methylsulfonylphenoxy)-1-nitrobenzene was reduced to the
aniline in a manner analogous to that described in Method A3d, step
2.
A12. General Method for Synthesis of
.delta.-Alkoxy-.delta.-carboxyphenyl Anilines
##STR00049##
[0123] Step 1.
4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene: To a
solution of .delta.-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene
(prepared in a manner analogous to that described in Method A3a,
step 1, 12 mmol) in acetone (50 mL) was added K.sub.2CO.sub.3 (5 g)
and dimethyl sulfate (3.5 mL). The resulting mixture was heated at
the reflux temperature overnight, then cooled to room temperature
and filtered through a pad of Celite.RTM.. The resulting solution
was concentrated under reduced pressure, absorbed onto silica gel,
and purified by column chromatography (50% EtOAc/50% hexane) to
give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a
yellow powder (3 g): mp 115-118.degree. C.
##STR00050##
[0124] Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene: A
mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene
(1.2 g), KOH (0.33 g), and water (5 mL) in MeOH (45 mL) was stirred
at room temperature overnight and then heated at the reflux
temperature for 4 h. The resulting mixture was cooled to room
temperature and concentrated under reduced pressure. The residue
was dissolved in water (50 mL), and the aqueous mixture was made
acidic with a 1N HCl solution. The resulting mixture was extracted
with EtOAc (50 mL). The organic layer was dried (MgSO.sub.4) and
concentrated under reduced pressure to give
4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).
B. General Methods of Urea Formation
[0125] B1. Reaction of a Heterocyclic Amine with an Aryl
Isocyanate
##STR00051##
[0126] N-(4-tert-butylpyridyl)-N'-(2,3-dichlorophenyl)urea: A
solution of 2-amino-4-tert-butylpyridine (192 mg) and
2,3-dichlorophenyl isocyanate (240 mg) in anh. toluene (15 mL) was
heated at 70.degree. C. under argon for 24 h. The resulting mixture
was diluted with EtOAc (200 mL) then washed with water (125 mL).
The organic layer was dried (MgSO.sub.4) and concentrated tinder
reduced pressure to give a gum. Trituration of the gum with hexanes
afforded N-(4-tert-butylpyridyl)-N'-(2,3-dichlorophenyl)urea as a
white solid (394 mg, 91%): TLC (2:1 hexanes/ethyl acetate) R.sub.f
0.40; FAB-MS m/z 338 ((M+H).sup.+).
B2a. Reaction of a Heterocyclic Amine with N,N'-Carbonyldiimidazole
Followed by Reaction with a Substituted Aniline
##STR00052##
[0127] N-(4-tert-butylpyridyl)-N'-(4-(4-pyridinylmethyl)phenyl
urea: To a stirring solution of 4-tert-butyl-2-aminopyridine (192
mg) in anh. CH.sub.2Cl.sub.2 (15 mL) under argon at 0.degree. C.
was added CDI (207 mg). The resulting solution was allowed to warm
to ambient temp over 2 h. To this mixture was added
4-(4-pyridylmethyl)aniline (prepared according to Method A1, 235
mg). The resulting solution was stirred at room temperature for 24
h, then was quenched with water (125 ml). The resulting mixture was
extracted with EtOAc (200 mL). The organic layer was washed with
water (100 mL), dried (MgSO.sub.4) and concentrated under reduced
pressure. The residue was purified by chromatography (SiO.sub.2,
EtOAc) to afford
N-(4-tert-butylpyridyl)-N'-(4-(4-pyridinylmethyl)phenyl urea as a
white solid (200 mg, 43%): TLC (EtoAc) R.sub.f 0.47; FAB-MS m/z 361
((M+H).sup.+).
B2b. Reaction of a Heterocyclic Amine with N,N'-Carbonyldiimidazole
Followed by Reaction with a Substituted Aniline
##STR00053##
[0128] N,N'-(Bis(3-(2-methoxyquinolinyl)) urea): To a stirring
solution of: 3-amino-2-methoxyquinoline (133 mg) in anh.
CH.sub.2Cl.sub.2 (15 mL) under argon at 0.degree. C. was added CDI
(128 mg). The resulting solution was warmed to ambient temp over 1
h. After 16 h 4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline (175 mg)
was added and the resulting yellow solution was stirred at room
temperature under argon for 72 h. The solution was treated with
water (125 mL) and the resulting mixture was extracted with EtOAc
(2.times.150 mL). The combined organics were washed with a
saturated NaCl solution (100 mL), dried (MgSO.sub.4) and
concentrated under reduced pressure. The residue was triturated
with a 10% hexane/90% EtOAc solution. The resulting white crystals
were washed with EtOAc. The resulting filtrate was purified by
chromatography (SiO.sub.2, 50% EtOAc/50% hexane) to give
N,N'-(bis(3-(2-methoxyquinolinyl)) urea) (30 mg, 20% yield): TLC
(50% EtOAc/50% hexane) R.sub.f 0.45; HPLC ES-MS m/z 375
((M+H).sup.+).
B2c. Reaction of a Heterocyclic Amine with N,N-Carbonyldiimidazole
Followed by Reaction with a Substituted Aniline
##STR00054##
[0129] N-(4-tert-Butylpyridyl)-N'-(4-(4-chlorophenoxy)phenyl)urea:
A solution of 4-tert-butyl-2-aminopyridine (0.177 g, 1.18 mmol, 1
equiv.) in 1.2 mL of anh. CH.sub.2Cl.sub.2 (1.2 mL) was added to
CDI (0.200 g, 1.24 mmol, 1.05 equiv) and the mixture was allowed to
stir under argon at room temperature 1d. To the resulting solution
was added 4-(4-chlorophenoxy)aniline (0.259 g, 1.18 mmol, 1 equiv.)
in one portion. The resulting mixture was stirred at room
temperature for 1d, then was treated with a 10% citric acid
solution (2 mL) and allowed to stir for 1 h. The resulting organic
layer was extracted with EtOAc (3.times.5 mL). The combined organic
layers were dried (MgSO.sub.4) and concentrated in vacuo. The
resultant residue was treated with CH.sub.2Cl.sub.2 (10 mL) and a 1
N aqueous NaOH solution. This mixture was allowed to stir
overnight. The resulting organic layer was extracted with
CH.sub.2Cl.sub.2 (3.times.5 mL). The combined organic layers were
(MgSO.sub.4) and concentrated in vacuo. The resultant solids were
suspended in diethyl ether (10 mL) and sonicated for 15 minutes.
The resulting white solids were dried to give
N-(4-tert-butylpyridyl)-N'-(4-(4-chlorophenoxy)phenyl)urea (42 mg,
9%): mp 198-199.degree. C.
B3. Reaction of Substituted Aniline with N,N'-Carbonyldiimidazole
Followed by Reaction with a Heterocyclic Amine
##STR00055##
[0130]
N-(2-(5-trifluoromethyl)pyridyloxy)-N'-(3-(4-pyridylthio)phenyl)ure-
a: A solution of 3-(4-pyridylthio)aniline (300 mg, 1.48 mmoles) in
CH.sub.2Cl.sub.2 (12 mL) was treated with CDI (253 mg, 1.56
mmoles). The solution was stirred at room temperature and under
argon for 2 h. The resulting mixture was treated with
2-amino-5-(trifluoromethyl)pyridine (238 mg, 1.47 mmoles) and
heated at 40.degree. C. overnight. The reaction mixture was then
diluted with EtOAc (25 mL), washed with water (10 mL) and a
saturated NaCl solution m(25 mL), dried (MgSO.sub.4), and
concentrated under reduced pressure. The residue was purified by
column chromatography (SiO.sub.2; gradient from 70% EtOAc/30%
CH.sub.2Cl.sub.2 to 100% EtOAc to give
N-(2-(5-trifluoromethyl)pyridyloxy)-N'-(3-(4-pyridylthio)phenyl)urea
(103 mg): TLC (50% EtOAc/50% CH.sub.2Cl.sub.2) R.sub.f 0.33;
.sup.1H-NMR (DMSO-d.sub.6) .delta. 6.06 (d, J=6 Hz, 2H), 7.25 (dt,
J=1.2, 7.8 Hz, 1H), 7.48 (t, J=8.1 Hz, 1H), 7.59-7.63 (m, 1H), 7.77
(d, J=8.7 Hz, 1H), 7.86 (t, J=1.8 Hz, 1H), 8.12 (dd, J=2.7, 9.3 Hz,
1H), 8.37 (d, J=6.3 Hz, 2H), 8.67 (bs, 1H), 9.88 (s, 1H), 10.26 (s,
1H); FAB-MS m/z 391 ((M+H).sup.+).
B4. Reaction of a Heterocyclic Amine with Phosgene, Followed by
Reaction with a Substituted Aniline
##STR00056##
[0131]
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-(2-N-Methylcarbamyl-4-pyridylox-
y)phenyl) urea: To a stirring solution of phosgene (20% in toluene,
1.38 mL) in anh. CH.sub.2Cl.sub.2 (20 ml) at 0.degree. C. under
argon was added anh. pyridine (207 mg) followed by
3-amino-2-methoxyquinoline (456 mg). The resulting solution was
warned to ambient temperature over 1 h, then concentrated in vacuo
at ambient temperature to give a white solid. The solid was dried
under vacuum for 15 min then suspended in art toluene (20 mL). To
the resulting slurry was added
4-(4-(2-(methylcarbamoyl)pyridyloxy)aniline (prepared according to
Method A2, 300 mg) and the reaction heated under argon at
80.degree. C. for 20 h. The resulting mixture was diluted with
water (200 mL), then treated with a saturated NaHCO.sub.3 solution
(10 mL) and extracted with EtOAc (2.times.300 mL). The combined
organic layers were washed with a saturated NaCl solution (100 mL),
dried (MgSO.sub.4) and concentrated under reduced pressure. The
solid yellow residue was purified by chromatography (SiO.sub.2,
gradient from 50% EtOAc/50% hexane 100% EtOAc), followed by
recrystallization from diethyl ether and hexane to give
N-(3-(2-methoxyquinolinyl)-N'-(4-(4-(2-N-Methylcarbamyl-4-pyridyloxy-
)phenyl)urea as a white solid (140 mg, 25%): TLC (EtOAc) R.sub.f
0.52; FAB-MS m/z 430 ((M.sup.++H).sup.+),
Specific Compound Preparations
[0132] Descriptions of the detailed preparative steps used to
prepare the specific compounds listed in Tables 1-4 are provided
below. Many of the compounds listed in the Tables can be
synthesized following a variety of methods. The specific examples
below are therefore provided by way of illustration only and should
not be construed to limit the scope of the invention in any
way.
Entry 5: N-(4-tert-Butylpyridyl)-N'-(4-(4-pyridinylmethyl)phenyl
urea was prepared according to Method B2a. Entry 6:
4-tert-Butyl-2-aminopyridine was reacted with 4-phenoxyaniline
according to Method B2c to afford the urea. Entry 7:
4-tert-Butyl-2-aminopyridine was reacted with
4-(4-methylphenoxy)aniline according to Method B2c to afford the
urea, Entry 8:
N-(4-tert-Butylpyridyl)-N'-(4-(4-chlorophenoxy)phenyl)urea was
prepared according to Method B2c. Entry 10:
4-(4-Aminophenoxy)pyridine was prepared starting from
4-hydroxypyridine and 1-bromo-3-nitrobenzene according to Method
A3F. 4-tert-Butyl-2-aminopyridine was reacted with
4-(4-aminophenoxy)pyridine according to Method B2a to afford the
urea. Entry 11: 4-(4-Pyridylthio)amine was prepared starting from
4-aminothiophenol and 4-chloropyridine hydrochloride according to
Method A4a. 4-tert-Butyl-2-aminopyridine was reacted with
4-(4-pyridylthio)aniline according to Method B2c to afford the
urea. Entry 12: 4-(4-Pyridylthio)aniline was prepared starting from
4-aminothiophenol and 4-chloropyridine hydrochloride according to
Method A4a. 4-tert-Butyl-2-aminopyridine was reacted with
3-(4-pyridylthio)aniline according to Method B2c to afford the
urea. Entry 20: 4-(4-Aminophenoxy)pyridine was prepared starting
from 4-hydroxypyridine and 1-bromo-3-nitrobenzene according to
Method A3f. 3-Aminoisoquinoline was reacted with
4-(4-aminophenoxy)pyridine according to Method B2a to afford the
urea. Entry 22: N,N'-(Bis(3-(2-methoxyquinolinyl)) urea) was
prepared according to Method B2b. Entry 23:
3-Amino-2-methoxyquinoline and 4-(4-pyridylmethyl)aniline were
reacted according to Method B3 to afford the urea. Entry 24:
3-Amino-2-methoxyquinoline was reacted with
4-(4-pyridylcarbonyl)aniline according to Method B4 to afford the
urea. Entry 25: 4-(4-Pyridyloxy)aniline was prepared starting from
4-hydroxypyridine and 1-fluoro-4-nitrobenzene according to Method
A3d. 3-Amino-2-methoxyquinoline was reacted with
4-(4-pyridyloxy)aniline according to Method B2c to afford the urea.
Entry 26: 3-Amino-2-methoxyquinoline was reacted with 4-((4
methoxyphenyl)methylamino)aniline according to Method B4 to afford
the urea. Entry 27: 3-(4-Pyridylthio)aniline was prepared according
to Method A4a. 3-Amino-2-methoxyquinoline and
3-(4-pyridylmethyl)aniline were reacted according to Method B3 to
afford the urea. Entry 28: 4-(4-Pyridyloxy)aniline was prepared
starting from 4-hydroxypyridine and 1-fluoro-4-nitrobenzene
according to Method A3d.
1-(4-Methylpiperazinyl)-3-aminoisoquinoline was reacted with
4-(4-aminophenoxy)pyridine according to Method 82a to afford the
urea.
[0133] The following compounds have been synthesized according to
the General Methods listed above:
TABLE-US-00001 TABLE 1 4-tert-Butyl-2-pyridyl Ureas ##STR00057##
TLC Mass mp HPLC TL Solvent Spec. Entry R (.degree. C.) (min.) C
R.sub.f System [Source] 5 ##STR00058## 0.47 100%EtOAc 361(M + H)
+(FAB) 6 ##STR00059## 179-180 0.58 5%MeOH/95%CH2Cl2 362(M + H)
+(FAB) 7 ##STR00060## 190-191 0.46 5%MeOH/95%CH2Cl2 376(M + H)
+(FAB) 8 ##STR00061## 198-199 0.76 5%MeOH/95%CH2Cl2 396(M + H)
+(FAB) 10 ##STR00062## 0.40 100%EtOAc 363(M + H) +(FAB) 11
##STR00063## 208-212 0.39 5%MeOH/95%CH2Cl2 379(M + H) +(HPLCES-MS)
12 ##STR00064## 196-197 0.37 5%MeOH/95%CH2Cl2 379(M + H) +(FAB)
TABLE-US-00002 TABLE 2 3-Isoquinolyl Ureas ##STR00065## TLC Mass mp
HPLC TL Solvent Spec. Entry R (.degree. C.) (min.) C R.sub.f System
[Source] 20 ##STR00066## 0.27 100%EtOAc 357(M + H) +(FAB)
TABLE-US-00003 TABLE 3 2-Methoxy-3-quinolyl Ureas ##STR00067## TLC
Mass mp HPLC TL Solvent Spec. Entry R (.degree. C.) (min.) C
R.sub.f System [Source] 22 ##STR00068## 0.45 50%EtOAc/50%hexane
375(M + H) +(HPLCES-MS) 23 ##STR00069## 0.56 50%EtOAc/50%hexane
385(M + H) +(FAB) 24 ##STR00070## 0.45 100%EtOAc 399(M + H) +(FAB)
25 ##STR00071## 207-208 0.24 5%MeOH/95%CH2Cl2 387(M + H) +(FAB) 26
##STR00072## 126-130 27 ##STR00073## 0.39 50%acetone/50%CH2Cl2
403(M + H) +(FAB)
TABLE-US-00004 TABLE 4 3-Quinolyl Ureas ##STR00074## TLC Mass mp
HPLC TL Solvent Spec. Entry R (.degree. C.) (min.) C R.sub.f System
[Source] 28 ##STR00075## 0.20 30%MeOH/70%EtOAc 455(M + H)
+(HPLCES-MS)
Biological Examples
In Vitro raf Kinase Assay
[0134] In an in vitro kinase assay, raf was incubated with MEK in
20 mM Tris-HCl, pH 8.2 containing 2 mM 2-mercaptoethanol and 100 mM
NaCl. This protein solution (20 .mu.L) was mixed with water (5
.mu.L) or with compounds diluted with distilled water from 10 mM
stock solutions of compounds dissolved in DMSO. The kinase reaction
was initiated by adding 25 .mu.L [.lamda.-.sup.33P]ATP (1000-3000
dpm/pmol) in 80 mM Tris-HCl, pH 7.5, 120 mM NaCl, 1.6 mM DTT, 16 mM
MgCl.sub.2. The reaction-mixtures were incubated at 32.degree. C.,
usually for 22 min. Incorporation of .sup.33P into protein was
assayed by harvesting the reaction onto phosphocellulose mats,
washing away free counts with a 1% phosphoric acid solution and
quantitating phosphorylation by liquid scintillation counting. For
high throughput screening, 10 .mu.M ATP and 0.4 .mu.M MEK was used.
In some experiments, the kinase reaction was stopped by adding an
equal amount of Laemmli sample buffer. Samples were boiled 3 min
and the proteins resolved by electrophoresis on 7.5% Laemmli gels.
Gels were fixed, dried and exposed to an imaging plate (Fuji).
Phosphorylation was analyzed using a Fujix Bio-Imaging Analyzer
System.
[0135] All compounds exemplified displayed IC.sub.50s of between 10
nM and 10 .mu.M.
Cellular Assay:
[0136] For in vitro growth assay, human tumor cell lines, including
but not limited to HCT116 and DLD-1, containing mutated K-ras genes
were used in standard proliferation assays for anchorage dependent
growth on plastic or anchorage independent growth in soft agar.
Human tumor cell lines were obtained from ATCC (Rockville M) and
maintained in RPMI with 10% heat inactivated fetal bovine serum and
200 mM glutamine. Cell culture media and additives were obtained
from Gibco/BRL (Gaithersburg, Md.) except for fetal bovine serum
(JR Biosciences, Lenexa, Kans.). In a standard proliferation assay
for anchorage dependent growth, 3.times.10.sup.3 cells were seeded
into 96-well tissue culture plates and allowed to attach overnight
at 37.degree. C. in a 5% CO.sub.2 incubator. Compounds were
titrated in media in dilution series and added to 96-well cell
cultures. Cells were allowed to grow 5 days typically with a
feeding of fresh compound containing media on day three
Proliferation was monitored by measuring metabolic activity with
standard XTT colorimetric assay (Boehringer Mannheim) measured by
standard ELISA plate reader at OD 490/560, or by measuring
.sup.3H-thymidine incorporation into DNA following an 8 h culture
with 1 .mu.Cu .sup.3H-thymidine, harvesting the cells onto glass
fiber mats using a cell harvester and measuring-.sup.3H-thymidine
incorporation by liquid scintillant counting.
[0137] For anchorage independent cell growth, cells were plated at
1.times.10.sup.3 to 3.times.10.sup.3 in 0.4% Seaplaque agarose in
RPMI complete media, overlaying a bottom layer containing only
0.64% agar in PRMI complete media in 24-well tissue culture plates.
Complete media plus dilution series of compounds were added to
wells and incubated at 37.degree. C. in a 5% CO.sub.2 incubator for
10-14 days with repeated feedings of fresh media containing
compound at 3-4 day intervals. Colony formation was monitored and
total cell mass, average colony size and number of colonies were
quantitated using image capture technology and image analysis
software (Image Pro Plus, media Cybernetics).
[0138] These assays established that the compounds of formula I are
active to inhibit raf kinase activity and to inhibit oncogenic cell
growth.
In Vivo Assay;
[0139] An in vivo assay of the inhibitory effect of the compounds
on tumors (e.g., solid cancers) mediated by raf kinase can be
performed as follows;
[0140] CDI nu/nu mice (6-8 weeks old) are injected subcutaneously
into the flank at 1.times.10.sup.6 cells with human colon
adenocarcinoma cell line. The mice are dosed i.p., i.v. or p.o. at
10, 30, 100, or 300 mg/Kg beginning on approximately day 10, when
tumor size is between 50-100 mg. Animals are dosed for 14
consecutive days once a day; rumor size was monitored with calipers
twice a week.
[0141] The inhibitory effect of the compounds on raf kinase and
therefore on tumors (e.g., solid cancers) mediated by raf kinase
can further be demonstrated in vivo according to the technique of
Monia et al. (Nat. Med. 1996, 2, 668-75).
[0142] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0143] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *