U.S. patent application number 13/539914 was filed with the patent office on 2012-10-25 for inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas.
This patent application is currently assigned to BAYER HEALTHERCARE LLC. Invention is credited to Catherine BRENNAN, Jacques DUMAS, David E. GUNN, Holia HATOUM-MOKDAD, Uday KHIRE, Timothy B. LOWINGER, Scott MILLER, Martin OSTERHOUT, Marell RODRIGUEZ, William J. SCOTT, Robert SIBLEY, Roger A. SMITH, Tiffany TURNER, Ming WANG, Jill E. WOOD.
Application Number | 20120270878 13/539914 |
Document ID | / |
Family ID | 46298784 |
Filed Date | 2012-10-25 |
United States Patent
Application |
20120270878 |
Kind Code |
A1 |
MILLER; Scott ; et
al. |
October 25, 2012 |
INHIBITION OF P38 KINASE USING SYMMETRICAL AND UNSYMMETRICAL
DIPHENYL UREAS
Abstract
This invention relates to the use of a group of aryl ureas in
treating cytokine mediated diseases and proteolytic enzyme mediated
diseases, and pharmaceutical compositions for use in such
therapy.
Inventors: |
MILLER; Scott; (Exton,
PA) ; OSTERHOUT; Martin; (Raleigh, NC) ;
DUMAS; Jacques; (Orange, CT) ; KHIRE; Uday;
(Hamden, CT) ; LOWINGER; Timothy B.; (Nishinomiya,
JP) ; SCOTT; William J.; (Guilford, CT) ;
SMITH; Roger A.; (Madison, CT) ; WOOD; Jill E.;
(Hamden, CT) ; GUNN; David E.; (Hamden, CT)
; HATOUM-MOKDAD; Holia; (Hamden, CT) ; RODRIGUEZ;
Marell; (Guilford, CT) ; SIBLEY; Robert;
(North Haven, CT) ; WANG; Ming; (Stanford, CT)
; TURNER; Tiffany; (Pittsburgh, PA) ; BRENNAN;
Catherine; (Milford, CT) |
Assignee: |
BAYER HEALTHERCARE LLC
Tarrytown
NY
|
Family ID: |
46298784 |
Appl. No.: |
13/539914 |
Filed: |
July 2, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11932397 |
Oct 31, 2007 |
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13539914 |
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10060396 |
Feb 1, 2002 |
7517880 |
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11932397 |
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09458015 |
Dec 10, 1999 |
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10060396 |
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09285522 |
Dec 22, 1998 |
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09458015 |
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60126439 |
Dec 22, 1997 |
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Current U.S.
Class: |
514/237.5 ;
514/336; 514/357; 514/367; 514/411; 514/587; 514/598 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 31/44 20130101; A61K 31/341 20130101; A61P 19/02 20180101;
A61K 31/5375 20130101; A61K 31/4035 20130101; A61P 19/10 20180101;
A61P 11/00 20180101; A61P 1/00 20180101; A61P 41/00 20180101; Y02A
50/411 20180101; A61K 31/381 20130101; A61K 31/17 20130101 |
Class at
Publication: |
514/237.5 ;
514/336; 514/357; 514/367; 514/411; 514/587; 514/598 |
International
Class: |
A61K 31/17 20060101
A61K031/17; A61K 31/4436 20060101 A61K031/4436; A61K 31/4409
20060101 A61K031/4409; A61K 31/428 20060101 A61K031/428; A61P 41/00
20060101 A61P041/00; A61P 29/00 20060101 A61P029/00; A61P 19/02
20060101 A61P019/02; A61P 19/10 20060101 A61P019/10; A61P 11/00
20060101 A61P011/00; A61P 1/00 20060101 A61P001/00; A61K 31/5375
20060101 A61K031/5375; A61K 31/403 20060101 A61K031/403 |
Claims
1. A method of treating a disease, other than cancer, mediated by
p-38, comprising administering a compound of formula I ##STR00326##
wherein A is ##STR00327## B is a substituted or unsubstituted, up
to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms
with at least one 6-member aromatic structure containing 0-4
members of the group consisting of nitrogen, oxygen and sulfur,
wherein if B is substituted, it is substituted by one or more
substituents selected from the group consisting of halogen, up to
per-halo, and W.sub.n, wherein n is 0-3 and each W 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-C.sub.10 alkyl, C.sub.1-10-alkenyl,
C.sub.1-10-alkoxy, C.sub.3-C.sub.10 cycloalkyl, C.sub.6-C.sub.14
aryl, C.sub.7-C.sub.24 alkaryl, C.sub.3-C.sub.13 heteroaryl,
C.sub.4-C.sub.23 alkheteroaryl, substituted C.sub.1-C.sub.10 alkyl,
substituted C.sub.2-10-alkenyl, substituted C.sub.1-10-alkoxy,
substituted C.sub.3-C.sub.10 cycloalkyl, substituted
C.sub.4-C.sub.23 alkheteroaryl and Q-Ar; wherein if W is a
substituted group, it is substituted by one or more substituents
independently selected from the group consisting of --CN,
--CO.sub.2R.sup.7, --C(O)R.sup.7, --C(O)NR.sup.7R.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 and halogen up to
per-halo; wherein each R.sup.7 is independently selected from H,
C.sub.1-C.sub.10 alkyl, C.sub.2-10-alkenyl, C.sub.3-C.sub.10
cycloalkyl, C.sub.6-C.sub.14 aryl, C.sub.3-C.sub.13 hetaryl,
C.sub.7-C.sub.24 alkaryl, C.sub.4-C.sub.23 alkheteroaryl, up to
per-halosubstituted C.sub.1-C.sub.10 alkyl, up to per-halo
substituted C.sub.2-10-alkenyl, up to per-halo substituted
C.sub.3-C.sub.10 cycloalkyl, up to per-halosubstituted
C.sub.6-C.sub.14 aryl and up to per-halosubstituted
C.sub.3-C.sub.13 hetaryl, wherein Q is --O--, --S--,
--N(R.sup.7)--, --(CH.sub.2)--.sub.m, --C(O)--, --CH(OH)--,
--(CH.sub.2).sub.mO--, --NR.sup.7C(O)NR.sup.7R.sup.7'--,
--NR.sup.7C(O)--, --C(O)NR.sup.7--, --(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--, m=1-3, and X.sup.a is halogen; and
Ar is a 5-10 member aromatic structure containing 0-2 members of
the group consisting of nitrogen, oxygen and sulfur, which is
unsubstituted or substituted by halogen up to per-halo and
optionally substituted by Z.sub.n1, wherein .sub.n1 is 0 to 3 and
each Z is independently selected from the group consisting of --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7, --C(O)--NR.sup.7,
--COR.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-C.sub.10
alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.6-C.sub.14 aryl,
C.sub.3-C.sub.13 hetaryl, C.sub.7-C.sub.24 alkaryl,
C.sub.4-C.sub.23 alkheteroaryl, substituted C.sub.1-C.sub.10 alkyl,
substituted C.sub.3-C.sub.10 cycloalkyl, substituted
C.sub.7-C.sub.24 alkaryl and substituted C.sub.4-C.sub.23
alkheteroaryl; wherein the one or more substituents of Z is
selected from the group consisting of --CN, --CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.7, --OR.sup.7, --SR.sup.7, --NO.sub.2,
--NR.sup.7R.sup.7, --NR.sup.7C(O)R.sup.7, --NR.sup.7C(O)OR.sup.7,
R.sup.3', R.sup.4', R.sup.5' are each independently H,
C.sub.1-10-alkyl, optionally substituted by halogen, up to perhalo,
C.sub.1-10 alkoxy, optionally substituted by halogen, up to
perhaloalkoxy, halogen; NO.sub.2 or NH.sub.2; R.sup.6 is H,
C.sub.1-10-alkyl, C.sub.1-10 alkoxy, --NHCOR.sup.1;
--NR.sup.1COR.sup.1; NO.sub.2; ##STR00328## one of R.sup.4, R.sup.5
or R.sup.6 can be --X--Y, or 2 adjacent R.sup.4'-R.sup.6' can
together be an aryl or hetaryl ring with 5-12 atoms, optionally
substituted by C.sub.1-10-alkyl, C.sub.1-10 alkoxy, C.sub.3-10
cycloalkyl, C.sub.2-10 alkenyl, C.sub.1-10 alkanoyl, C.sub.6-12
aryl, C.sub.5-12 hetaryl or C.sub.6-12 aralkyl; R.sup.1 is
C.sub.1-10-alkyl optionally substituted by halogen, up to perhalo;
X is --CH.sub.2--, --S--, --N(CH.sub.3)--, --NHC(O)--,
--CH.sub.2--S--, --S--CH.sub.2--, --C(O)--, or --O--; and X is
additionally a single bond where Y is pyridyl; Y is phenyl,
pyridyl, naphthyl, pyridone, pyrazine, benzodioxane, benzopyridine,
pyrimidine or benzothiazole, each optionally substituted by
C.sub.1-10-alkyl, C.sub.1-10-alkoxy, halogen, OH, --SCH.sub.3 or
NO.sub.2 or, where Y is phenyl, by ##STR00329## or a
pharmaceutically acceptable salt thereof.
2. A method according to claim 1, comprising administering a
compound of formula Ia ##STR00330## wherein R.sup.3, R.sup.4,
R.sup.5, and R.sup.6 are each independently H; halogen;
C.sub.1-10-alkyl optionally substituted by halogen up to perhalo;
C.sub.1-10-alkoxy optionally substituted by at least one hydroxy
group or halogen up to perhalo, C.sub.6-12 aryl, optionally
substituted by C.sub.1-10 alkoxy or halogen, C.sub.5-12 hetaryl,
optionally substituted by C.sub.1-10 alkyl, C.sub.1-10 alkoxy or
halogen; NO.sub.2; SO.sub.2F; --SO.sub.2CH.sub.pX.sub.3-p;
--COOR.sup.1; --OR.sup.1CONHR.sup.1; --NHCOR.sup.1; --SR.sup.1;
NH.sub.2; --N(SO.sub.2R.sup.1).sub.2; furyloxy; ##STR00331## 2
adjacent R.sup.3-R.sup.6 can together form an aryl or hetaryl ring
with 5-12 atoms, optionally substituted by C.sub.1-10-alkyl,
C.sub.1-10-alkoxy, C.sub.3-10-cycloalkyl, C.sub.2-10-alkenyl,
C.sub.1-10-alkanoyl, C.sub.6-12-aryl, C.sub.5-12-hetaryl,
C.sub.6-12-aralkyl, C.sub.6-12-alkaryl, halogen; --NR.sup.1;
--NO.sub.2; --CF.sub.3; --COOR.sup.1; --NHCOR.sup.1; --CN;
--CONR.sup.1R.sup.1; --SO.sub.2R.sup.2; --SOR.sup.2; --SR.sup.2; in
which R.sup.1 is H or C.sub.1-10-alkyl and R.sup.2 is
C.sub.1-10-alkyl optionally substituted by halogen, up to perhalo,
with --SO.sub.2-- optionally incorporated in the aryl or hetaryl
ring; p is 0 or 1; one of R.sup.3, R.sup.4, R.sup.5 or R.sup.6 can
be --X--Y, with the proviso that if R.sup.3 and R.sup.6 are both H,
one of R.sup.4 or R.sup.5 is not H, and R.sup.3'-R.sup.6' are as
defined in claim 1.
3. A method according to claim 2, wherein R.sup.3 is H; halogen;
C.sub.1-10-alkyl optionally substituted by halogen, up to perhalo,
NO.sub.2, --SO.sub.2F or --SO.sub.2CF.sub.3; R.sup.4 is H,
C.sub.1-10-alkyl, C.sub.1-10-alkoxy, halogen or NO.sub.2; R.sup.5
is H, C.sub.1-10-alkyl optionally substituted by halogen, up to
perhalo; R.sup.6 is H, hydroxy, C.sub.1-10-alkoxy optionally
substituted by at least one hydroxy group; --COOR.sup.1;
--OR.sup.1CONHR.sup.1; --NHCOR.sup.1; --SR.sup.1; phenyl optionally
substituted by halo or C.sub.1-10-alkoxy; NH.sub.2;
--N(SO.sub.2R.sup.1).sub.2, furyloxy, thiophene, pyrole or methyl
substituted pyrole, ##STR00332##
4. A method according to claim 2, wherein R.sup.3 is Cl, F,
C.sub.4-5-branched alkyl, --SO.sub.2F or --SO.sub.2CF.sub.3; and
R.sup.6 is hydroxy; C.sub.1-10-alkoxy optionally substituted by at
least one hydroxy group; --COOR.sup.1; --OR.sup.1CONHR.sup.1;
--NHCOR.sup.1; --SR.sup.1; phenyl optionally substituted by halo or
C.sub.1-10-alkoxy; NH.sub.2; --N(SO.sub.2R.sup.1).sub.2, furyloxy,
##STR00333##
5. A method according to claim 2, wherein R.sup.4' is
C.sub.1-10-alkyl or halogen; R.sup.5' is H, C.sub.1-10-alkyl,
halogen, CF.sub.3, halogen, NO.sub.2 or NH.sub.2; and R.sup.6' is
H, C.sub.1-10-alkyl, halogen, --NHCOCH.sub.3,
--N(CH.sub.3)COCH.sub.3, NO.sub.2, ##STR00334##
6. A method according to claim 2, wherein R.sup.5' is
C.sub.1-10-alkyl, halogen, CF.sub.3, halogen, NO.sub.2 or
NH.sub.2.
7. A method according to claim 2, wherein R.sup.6' is
C.sub.1-10-alkyl, halogen, --NHCOCH.sub.3, --N(CH.sub.3)COCH.sub.3,
NO.sub.2, ##STR00335##
8. A method according to claim 4, wherein R.sup.3 is t-butyl or
CF.sub.3 and R.sup.6 is --OCH.sub.3.
9. A method according to claim 2, wherein the disease is mediated
by a cytokine or protease regulated by p38.
10. A method according to claim 2, wherein the disease is mediated
by TNF.alpha., MMP-1, MMP-3, IL-1, IL-6 or IL-8.
11. A method according to claim 2, wherein the disease is an
inflammatory or immunomodulatory disease.
12. A method according to claim 2, wherein the disease is
osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, septic
shock, inflammatory bowel disease, or the result of
host-versus-graft reactions.
13. A method according to claim 1, wherein the compound of formula
I is N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-phenyloxyphenyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-methoxyphenyloxy)phenyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-pyridinyloxy)phenyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-pyridinylmethyl)phenyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-pyridinylthio)phenyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-(4,7-methano-1H-isoindole-1,3(2H-
)-dionyl)methyl)phenyl)urea;
N-(5-tert-Butyl-2-phenylphenyl)-N-(2,3-dichlorophenyl)urea;
N-(5-tert-Butyl-2-(3-thienyl)phenyl)-N-(2,3-dichlorophenyl)urea;
N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N-(2,3-dichloroph-
enyl)urea;
N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N-(1-na-
phthyl)urea;
N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N-(2,3-dichlorophe-
nyl)urea;
N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N-(1-naph-
thyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(3-pyridinyl)methylpheny-
l)urea;
N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N-(2,3-dichlorop-
henyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-methylphenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-methyl-2-fluorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-fluoro-3-chlorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-methyl-3-chlorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-methyl-3-fluorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(2,4-difluorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-phenyloxy-3,5-dichlorophenyl)u-
rea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-(4-pyridinylmethyl)phenyl)-
urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-(4-pyridinylthio)phenyl)u-
rea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-(4-pyridinyloxy)phenyl)ure-
a;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(3-(4-pyridinylthio)phenyl)urea-
;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-(3-(N-methylaminocarbonyl)-ph-
enyloxy)phenyl)-urea;
N-(5-Fluorosulfonyl)-2-methoxyphenyl)-N-(4-methylphenyl)urea;
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-methylphenyl)urea;
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-fluorophenyl)urea;
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-methyl-2-fluoropheny-
l)urea;
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-methyl-3-fluo-
rophenyl)urea;
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-methyl-3-chloropheny-
l)urea;
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-fluoro-3-chlo-
rophenyl)urea;
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-fluoro-3-methylpheny-
l)urea;
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(2,3-dimethylphe-
nyl)urea;
N-(5-(Trifluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-methylphen-
yl)urea; N-(3-methoxy-2-naphthyl)-N'-(2-fluorophenyl)urea);
N-(3-Methoxy-2-naphthyl)-N-(4-methylphenyl)urea;
N-(3-Methoxy-2-naphthyl)-N-(3-fluorophenyl)urea;
N-(3-Methoxy-2-naphthyl)-N-(4-methyl-3-fluorophenyl)urea;
N-(3-Methoxy-2-naphthyl)-N-(2,3-dimethylphenyl)urea;
N-(3-Methoxy-2-naphthyl)-N-(1-naphthyl)urea;
N-(3-Methoxy-2-naphthyl)-N-(4-(4-pyridinylmethyl)phenyl)urea;
N-(3-Methoxy-2-naphthyl)-N-(4-(4-pyridinylthio)phenyl)urea;
N-(3-Methoxy-2-naphthyl)-N-(4-(4-methoxyphenyloxy)phenyl)urea; and
N-(3-Methoxy-2-naphthyl)-N-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl-
)methyl)phenyl)urea.
N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N-(phenyl)urea; or
N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N-(4-(4-pyridinylmethly)phenyl)ur-
ea.
14.-22. (canceled)
Description
FIELD OF THE INVENTION
[0001] This invention relates to the use of a group of aryl ureas
in treating cytokine mediated diseases and proteolytic enzyme
mediated diseases, and pharmaceutical compositions for use in such
therapy.
BACKGROUND OF THE INVENTION
[0002] Two classes of effector molecules which are critical for the
progression of rheumatoid arthritis are pro-inflammatory cytokines
and tissue degrading proteases. Recently, a family of kinases was
described which is instrumental in controlling the transcription
and translation of the structural genes coding for these effector
molecules.
[0003] The mitogen-activated protein (MAP) kinase family is made up
of a series of structurally related proline-directed
serine/threonine kinases which are activated either by growth
factors (such as EGF) and phorbol esters (ERK), or by IL-1,
TNF.alpha. or stress (p38, INK). The MAP kinases are responsible
for the activation of a wide variety of transcription factors and
proteins involved in transcriptional control of cytokine
production. A pair of novel protein kinases involved in the
regulation of cytokine synthesis was recently described by a group
from SmithKline Beecham (Lee et al. Nature 1994, 372, 739). These
enzymes were isolated based on their affinity to bond to a class of
compounds, named CSAIDSs (cytokine suppressive anti-inflammatory
drugs) by SKB. The CSALDs, bicyclic pyridinyl imidazoles, have been
shown to have cytokine inhibitory activity both in vitro and in
vivo. The isolated enzymes, CSBP-1 and -2 (CSAID binding protein 1
and 2) have been cloned and expressed. A murine homologue for
CSBP-2, p38, has also been reported (Han et al. Science 1994, 265,
808).
[0004] Early studies suggested that CSAIDs function by interfering
with m-RNA translational events during cytokine biosynthesis
Inhibition of p38 has been shown to inhibit both cytokine
production (eg., TNF.alpha., IL-1, IL-6, IL-8) and proteolytic
enzyme production (eg., MMP-1, MMP-3) in vitro and/or in vivo.
[0005] Clinical studies have linked TNF.alpha. production and/or
signaling to a number of diseases including rheumatoid arthritis
(Main. J. Royal Coll. Physicians London 1996, 30, 344). In
addition, excessive levels of TNF.alpha. have been implicated in a
wide variety of inflammatory and/or immunomodulatory diseases,
including acute rheumatic fever (Yegin et al. Lancet 1997, 349,
170), bone resorption (Pacifici et al. J. Clin. Endocrinol.
Metabol. 1997, 82, 29), postmenopausal osteoperosis (Pacifici et
al. J. Bone Mineral Res. 1996, 11, 1043), sepsis (Blackwell et al.
Br. J. Anaesth. 1996, 77, 110), gram negative sepsis (Debets et al.
Prog. Clin. Biol. Res. 1989, 308, 463), septic shock (Tracey et al.
Nature 1987, 330, 662; Girardin et al. New England J. Med. 1988,
319, 397), endotoxic shock (Beutler et al. Science 1985, 229, 869;
Ashkenasi et al. Proc. Nat'l. Acad. Sci. USA 1991, 88, 10535),
toxic shock syndrome, (Saha et al. J. Immunol. 1996, 157, 3869;
Lina et al. FEMS Immunol. Med. Microbiol. 1996, 13, 81), systemic
inflammatory response syndrome (Anon. Crit. Care Med. 1992, 20,
864), inflammatory bowel diseases (Stokkers et al. J. Inflamm.
1995-6, 47, 97) including Crohn's disease (van Deventer et al.
Aliment. Pharmacol. Therapeu. 1996, 10 (Suppl. 2), 107; van
Dullemen et al. Gastroenterology 1995, 109, 129) and ulcerative
colitis (Masuda et al. J. Clin. Lab. Immunol. 1995, 46, 111),
Jarisch-Herxheimer reactions (Fekade et al. New England J. Med.
1996, 335, 311), asthma (Amrani et al. Rev. Malad. Respir. 1996,
13, 539), adult respiratory distress syndrome (Roten et al. Am.
Rev. Respir. Dis. 1991, 143, 590; Suter et al. Am. Rev. Respir.
Dis. 1992, 145, 1016), acute pulmonary fibrotic diseases (Pan et
al. Pathol. Int. 1996, 46, 91), pulmonary sarcoidosis (Ishioka et
al. Sarcoidosis Vasculitis Diffuse Lung Dis. 1996, 13, 139),
allergic respiratory diseases (Casale et al. Am. J. Respir. Cell
Mol. Biol. 1996, 15, 35), silicosis (Gossart et al. J. Immunol.
1996, 156, 1540; Vanhee et al. Eur. Respir. J. 1995, 8, 834), coal
worker's pneumoconiosis (Boren et al. Am. Rev. Respir. Dis. 1988,
138, 1589), alveolar injury (Horinouchi et al. Am. J. Respir. Cell
Mol. Biol. 1996, 14, 1044), hepatic failure (Gantner et al. J.
Pharmacol. Exp. Therap. 1997, 280, 53), liver disease during acute
inflammation (Kim et al. J. Biol. Chem. 1997, 272, 1402), severe
alcoholic hepatitis (Bird et al. Ann. Intern. Med. 1990, 112, 917),
malaria (Grau et al. Immunol. Rev. 1989, 112, 49; Taverne et al.
Parasitol. Today 1996, 12, 290) including Plasmodium falciparum
malaria (Perlmann et al. Infect. Immunit. 1997, 65, 116) and
cerebral malaria (Rudin et al. Am. J. Pathol. 1997, 150, 257),
non-insulin-dependent diabetes mellitus (NIDDM; Stephens et al. J.
Biol. Chem. 1997, 272, 971; Ofei et al. Diabetes 1996, 45, 881),
congestive heart failure (Doyama et al. Int. J. Cardiol. 1996, 54,
217; McMurray et al. Br. Heart J. 1991, 66, 356), damage following
heart disease (Malkiel et al. Mol. Med. Today 1996, 2, 336),
atherosclerosis (Parums et al. J. Pathol. 1996, 179, A46),
Alzheimer's disease (Fagarasan et al. Brain Res. 1996, 723, 231;
Aisen et al. Gerontology 1997, 43, 143), acute encephalitis
(Ichiyama et al. J. Neural. 1996, 243, 457), brain injury (Cannon
et al. Crit. Care Med. 1992, 20, 1414; Hansbrough et al. Surg.
Clin. N. Am. 1987, 67, 69; Marano et al. Surg. Gynecol. Obstetr.
1990, 170, 32), multiple sclerosis (M. S.; Coyle. Adv.
Neuroimmunol. 1996, 6, 143; Matusevicius et al. J. Neuroimmunol.
1996, 66, 115) including demyelation and oligiodendrocyte loss in
multiple sclerosis (Brosnan et al. Brain Pathol. 1996, 6, 243),
advanced cancer (MucWierzgon et al. J. Biol. Regulators Homeostatic
Agents 1996, 10, 25), lymphoid malignancies (Levy et al. Crit. Rev.
Immunol. 1996, 16, 31), pancreatitis (Exley et al. Gut 1992, 33,
1126) including systemic complications in acute pancreatitis (McKay
et al. Br. J. Surg. 1996, 83, 919), impaired wound healing in
infection inflammation and cancer (Buck et al. Am. J. Pathol. 1996,
149, 195), myelodysplastic syndromes (Raza et al. Int. J. Hematol.
1996, 63, 265), systemic lupus erythematosus (Maury et al.
Arthritis Rheum. 1989, 32, 146), biliary cirrhosis (Miller et al.
Am. J. Gasteroenterolog. 1992, 87, 465), bowel necrosis (Sun et al.
J. Clin. Invest. 1988, 81, 1328), psoriasis (Christophers. Austr.
J. Dermatol. 1996, 37, S4), radiation injury (Redlich et al. J.
Immunol. 1996, 157, 1705), and toxicity following administration of
monoclonal antibodies such as OKT3 (Brod et al. Neurology 1996, 46,
1633). TNF.alpha. levels have also been related to
host-versus-graft reactions (Pignet et al. Immunol. Ser. 1992, 56,
409) including ischemia reperfusion injury (Colletti et al. J.
Clin. Invest. 1989, 85, 1333) and allograft rejections including
those of the kidney (Maury et al. J. Exp. Med. 1987, 166, 1132),
liver (Imagawa et al. Transplantation 1990, 50, 219), heart
(Bolling et al. Transplantation 1992, 53, 283), and skin (Stevens
et al. Transplant. Proc. 1990, 22, 1924), lung allograft rejection
(Grossman et al. Immunol. Allergy Clin. N. Am. 1989, 9, 153)
including chronic lung allograft rejection (obliterative
bronchitis; LoCicero et al. J. Thorac. Cardiovasc. Surg. 1990, 99,
1059), as well as complications due to total hip replacement
(Cirino et al. Life Sci. 1996, 59, 86). TNF.alpha. has also been
linked to infectious diseases (review: Beutler et al. Crit. Care
Med. 1993, 21, 5423; Degre. Biotherapy 1996, 8, 219) including
tuberculosis (Rook et al. Med. Malad. Infect. 1996, 26, 904),
Helicobacter pylori infection during peptic ulcer disease (Beales
et al. Gastroenterology 1997, 112, 136), Chaga's disease resulting
from Trypanosoma cruzi infection (Chandrasekar et al. Biochem.
Biophys. Res. Commun. 1996, 223, 365), effects of Shiga-like toxin
resulting from E. coli infection (Hanel et al. J. Clin. Invest.
1992, 56, 40), the effects of enterotoxin A resulting from
Staphylococcus infection (Fischer et al. J. Immunol. 1990, 144,
4663), meningococcal infection (Waage et al. Lancet 1987, 355;
Ossege et al. J. Neurolog. Sci. 1996, 144, 1), and infections from
Borrelia burgdorferi (Brandt et al. Infect. Immunol. 1990, 58,
983), Treponema pallidum (Chamberlin et al. Infect. Immunol. 1989,
57, 2872), cytomegalovirus (CMV; Geist et al. Am. J. Respir. Cell
Mol. Biol. 1997, 16, 31), influenza virus (Beutler et al. Clin.
Res. 1986, 34, 491a), Sendai virus (Goldfield et al. Proc. Nat'l.
Acad. Sci. USA 1989, 87, 1490), Theiler's encephalomyelitis virus
(Sierra et al. Immunology 1993, 78, 399), and the human
immunodeficiency virus (HIV; Poli. Proc. Nat'l. Acad. Sci. USA
1990, 87, 782; Vyakaram et al. AIDS 1990, 4, 21; Badley et al. J.
Exp. Med. 1997, 185, 55).
[0006] Because inhibition of p38 leads to inhibition of TNF.alpha.
production, p38 inhibitors will be useful in treatment of the above
listed diseases.
[0007] A number of diseases are thought to be mediated by excess or
undesired matrix-destroying metalloprotease (MMP) activity or by an
imbalance in the ratio of the MMPs to the tissue inhibitors of
metalloproteinases (TIMIPs). These include osteoarthritis (Woessner
et al. J. Biol. Chem. 1984, 259, 3633), rheumatoid arthritis
(Mullins et al. Biochim. Biophys. Acta 1983, 695, 117; Woolley et
al. Arthritis Rheum. 1977, 20, 1231; Gravallese et al. Arthritis
Rheum. 1991, 34, 1076), septic arthritis (Williams et al. Arthritis
Rheum. 1990, 33, 533), tumor metastasis (Reich et al. Cancer Res.
1988, 48, 3307; Matrisian et al. Proc. Nat'l. Acad. Sci., USA 1986,
83, 9413), periodontal diseases (Overall et al. J. Periodontal Res.
1987, 22, 81), corneal ulceration (Burns et al. Invest. Opthalmol.
Vis. Sci. 1989, 30, 1569), proteinuria (Baricos et al. Biochem. J.
1988, 254, 609), coronary thrombosis from atherosclerotic plaque
rupture (Henney et al. Proc. Nat'l. Acad. Sci., USA 1991, 88,
8154), aneurysmal aortic disease (Vine et al. Clin. Sci. 1991, 81,
233), birth control (Woessner et al. Steroids 1989, 54, 491),
dystrophobic epidermolysis bullosa (Kronberger et al. J. Invest.
Dermatol. 1982, 79, 208), degenerative cartilage loss following
traumatic joint injury, osteopenias mediated by MMP activity,
tempero mandibular joint disease, and demyelating diseases of the
nervous system (Chantry et al. J. Neurochem. 1988, 50, 688).
[0008] Because inhibition of p38 leads to inhibition of MAP
production, p38 inhibitors will be useful in treatment of the above
listed diseases.
[0009] Inhibitors of p38 are active in animal models of TNF.alpha.
production, including a muirne lipopolysaccharide (LPS) model of
TNF.alpha. production. Inhibitors of p38 are active in a number of
standard animal models of inflammatory diseases, including
carrageenan-induced edema in the rat paw, arachadonic acid-induced
edema in the rat paw, arachadonic acid-induced peritonitis in the
mouse, fetal rat long bone resorption, murine type II
collagen-induced arthritis, and Fruend's adjuvant-induced arthritis
in the rat. Thus, inhibitors of p38 will be useful in treating
diseases mediated by one or more of the above-mentioned cytokines
and/or proteolytic enzymes.
[0010] The need for new therapies is especially important in the
case of arthritic diseases. The primary disabling effect of
osteoarthritis, rheumatoid arthritis and septic arthritis is the
progressive loss of articular cartilage and thereby normal joint
function. No marketed pharmaceutical agent is able to prevent or
slow this cartilage loss, although nonsteroidal antiinflammatory
drugs (NSAIDs) have been given to control pain and swelling. The
end result of these diseases is total loss of joint function which
is only treatable by joint replacement surgery. P38 inhibitors will
halt or reverse the progression of cartilage loss and obviate or
delay surgical intervention.
[0011] Several patents have appeared claiming polyarylimidazoles
and/or compounds containing polyarylimidazoles as inhibitors of p38
(for example, Lee et al. WO 95/07922; Adams et al. WO 95/02591;
Adams et al. WO 95/13067; Adams et al. WO 95/31451). It has been
reported that arylimidazoles complex to the ferric form of
cytochrome P450.sub.cam. (Harris et al. Mol. Eng. 1995, 5, 143, and
references therein), causing concern that these compounds may
display structure-related toxicity (Howard-Martin et al. Toxicol.
Pathol. 1987, 15, 369). Therefore, there remains a need for
improved p38 inhibitors.
SUMMARY OF THE INVENTION
[0012] This invention provides compounds, generally described as
aryl ureas, including both aryl and heteroaryl analogues, which
inhibit p38 mediated events and thus inhibit the production of
cytokines (such as TNF.alpha., IL-1 and IL-8) and proteolytic
enzymes (such as MMP-1 and MMP-3). The invention also provides a
method of treating a cytokine mediated disease state in humans or
mammals, wherein the cytokine is one whose production is affected
by p38. Examples of such cytokines include, but are not limited to
TNF.alpha., IL-1 and IL-8. The invention also provides a method of
treating a protease mediated disease state in humans or mammals,
wherein the protease is one whose production is affected by p38.
Examples of such proteases include, but are not limited to
collagenase (MMP-1) and stromelysin (MMP-3).
[0013] Accordingly, these compounds are useful therapeutic agents
for such acute and chronic inflammatory and/or immunomodulatory
diseases as rheumatoid arthritis, osteoarthritis, septic arthritis,
rheumatic fever, bone resorption, postmenopausal osteoperosis,
sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic
shock syndrome, systemic inflammatory response syndrome,
inflammatory bowel diseases including Crohn's disease and
ulcerative colitis, Jarisch-Herxheimer reactions, asthma, adult
respiratory distress syndrome, acute pulmonary fibrotic diseases,
pulmonary sarcoidosis, allergic respiratory diseases, silicosis,
coal worker's pneumoconiosis, alveolar injury, hepatic failure,
liver disease during acute inflammation, severe alcoholic
hepatitis, malaria including Plasmodium falciparum malaria and
cerebral malaria, non-insulin-dependent diabetes mellitus (NIDDM),
congestive heart failure, damage following heart disease,
atherosclerosis, Alzheimer's disease, acute encephalitis, brain
injury, multiple sclerosis including demyelation and
oligiodendrocyte loss in multiple sclerosis, advanced cancer,
lymphoid malignancies, tumor metastasis, pancreatitis, including
systemic complications in acute pancreatitis, impaired wound
healing in infection, inflammation and cancer, periodontal
diseases, corneal ulceration, proteinuria, myelodysplastic
syndromes, systemic lupus erythematosus, biliary cirrhosis, bowel
necrosis, psoriasis, radiation injury, toxicity following
administration of monoclonal antibodies such as OKT3,
host-versus-graft reactions including ischemia reperfusion injury
and allograft rejections including kidney, liver, heart, and skin
allograft rejections, lung allograft rejection including chronic
lung allograft rejection (obliterative bronchitis) as well as
complications due to total hip replacement, and infectious diseases
including tuberculosis, Helicobacter pylori infection during peptic
ulcer disease, Chaga's disease resulting from Trypanosoma cruzi
infection, effects of Shiga-like toxin resulting from E. coli
infection, effects of enterotoxin A resulting from Staphylococcus
infection, meningococcal infection, and infections from Borrelia
burgdorferi, Treponema pallidum, cytomegalovirus, influenza virus,
Theiler's encephalomyelitis virus, and the human immunodeficiency
virus (HIV).
[0014] The present invention, therefore, provides compounds
generally described as aryl ureas, including both aryl and
heteroaryl analogues, which inhibit the p38 pathway. The invention
also provides a method for treatment of p38-mediated disease states
in humans or mammals, e.g., disease states mediated by one or more
cytokines or proteolytic enzymes produced and/or activated by a p38
mediated process. Thus, the invention is directed to compounds and
methods for the treatment of diseases mediated by p38 kinase
comprising administering a compound of Formula I
##STR00001##
wherein [0015] A is
##STR00002##
[0016] B is a substituted or unsubstituted, up to tricyclic aryl or
heteroaryl moiety of up to 30 carbon atoms with at least one
6-member aromatic structure containing 0-4 members of the group
consisting of nitrogen, oxygen and sulfur, wherein if B is
substituted, it is substituted by one or more substituents selected
from the group consisting of halogen, up to per-halo, and W.sub.n,
wherein n is 0-3 and each W 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-C.sub.10 alkyl, C.sub.2-10-alkenyl, C.sub.1-10-alkoxy,
C.sub.3-C.sub.10 cycloalkyl, C.sub.6-C.sub.14 aryl,
C.sub.7-C.sub.24 alkaryl, C.sub.3-C.sub.13 heteroaryl,
C.sub.4-C.sub.23 alkheteroaryl, substituted C.sub.1-C.sub.10 alkyl,
substituted C.sub.2-10-alkenyl, substituted C.sub.1-10-alkoxy,
substituted C.sub.3-C.sub.10 cycloalkyl, substituted
C.sub.4-C.sub.23 alkheteroaryl and Q-Ar; [0017] wherein if W is a
substituted group, it is substituted by one or more substituents
independently selected from the group consisting of --CN,
--CO.sub.2R.sup.7, --C(O)R.sup.7, --C(O)NR.sup.7R.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)R.sup.7 and halogen up to
per-halo; [0018] wherein each R.sup.7 is independently selected
from H, C.sub.1-C.sub.10 alkyl, C.sub.2-10-alkenyl,
C.sub.3-C.sub.10 cycloalkyl, C.sub.6-C.sub.14 aryl,
C.sub.3-C.sub.13 hetaryl, C.sub.7-C.sub.24 alkaryl,
C.sub.4-C.sub.23 alkheteroaryl, up to per-halosubstituted
C.sub.1-C.sub.10 alkyl, up to per-halosubstituted
C.sub.2-40-alkenyl, up to per-halosubstituted C.sub.3-C.sub.10
cycloalkyl, up to per-halosubstituted C.sub.6-C.sub.14 aryl and up
to per-halosubstituted C.sub.3-C.sub.13 hetaryl, [0019] wherein Q
is --O--, --S--, --(CH.sub.2)--, --C(O)--, --CH(OH)--,
--(CH.sub.2)O--, --NR.sup.7C(O)NR.sup.7R.sup.7'--,
--NR.sup.7C(O)--, --C(O)NR.sup.7--, --(CH.sub.2).sub.mS--,
--(CH.sub.2).sub.mN(R.sup.7)--, --O(CH.sub.2).sub.m, --CHX.sup.a,
--CHX.sup.a.sub.2--S--(CH.sub.2).sub.m-- and
--N(R.sup.7)(CH.sub.2).sub.m--, [0020] m=1-3, and X.sup.a is
halogen; and
[0021] Ar is a 5-10 member aromatic structure containing 0-2
members of the group consisting of nitrogen, oxygen and sulfur,
which is unsubstituted or substituted by halogen up to per-halo and
optionally substituted by Z.sub.n1, wherein .sub.n1 is 0 to 3 and
each Z is independently selected from the group consisting of --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7, --C(O)--NR.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-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.6-C.sub.14 aryl, C.sub.3-C.sub.13 hetaryl, C.sub.7-C.sub.24
alkaryl, C.sub.4-C.sub.23 alkheteroaryl, substituted
C.sub.1-C.sub.10 alkyl, substituted C.sub.3-C.sub.10 cycloalkyl,
substituted C.sub.7-C.sub.24 alkaryl and substituted
C.sub.4-C.sub.23 alkheteroaryl; wherein the one or more
substituents of Z is selected from the group consisting of --CN,
--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.7, --SR.sup.7, --NO.sub.2,
--NR.sup.7R.sup.7, --NR.sup.7C(O)R.sup.7, --NR.sup.7C(O)OR.sup.7,
[0022] R.sup.3', R.sup.4', R.sup.5' are each independently H,
C.sub.1-10-alkyl, optionally substituted by halogen, up to perhalo,
C.sub.1-1a alkoxy, optionally substituted by halogen, up to
perhaloalkoxy, halogen; NO.sub.2 or NH.sub.2; [0023] R.sup.6' is H,
C.sub.1-10-alkyl, C.sub.1-10 alkoxy, --NHCOR.sup.1;
--NR.sup.1COR.sup.1; NO.sub.2;
[0023] ##STR00003## [0024] one of R.sup.4', R.sup.5' or R.sup.6'
can be --X--Y, [0025] or 2 adjacent R.sup.4'-R.sup.6' can together
be an aryl or hetaryl ring with 5-12 atoms, optionally substituted
by C.sub.1-10-alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkyl,
C.sub.2-10 alkenyl, C.sub.1-10 alkanoyl, C.sub.6-12 aryl,
C.sub.5-12 hetaryl or C.sub.6-12 aralkyl; [0026] R.sup.1 is
C.sub.1-10-alkyl optionally substituted by halogen, up to perhalo;
[0027] X is --CH.sub.2--, --S--, --N(CH.sub.3)--, --NHC(O)--,
--CH.sub.2--S--, --S--CH.sub.2--, --C(O)--, or --O--; and [0028] X
is additionally a single bond where Y is pyridyl; [0029] Y is
phenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodioxane,
benzopyridine, pyrimidine or benzothiazole, each optionally
substituted by [0030] C.sub.1-10-alkyl, C.sub.1-10-alkoxy, halogen,
OH, --SCH.sub.3 or NO.sub.2 or, where Y is phenyl, by
##STR00004##
[0030] or a pharmaceutically acceptable salt thereof.
[0031] Preferably, the compounds of formula I are of formula Ia
##STR00005##
wherein
[0032] R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently
H, halogen, C.sub.1-10-alkyl optionally substituted by halogen, up
to perhalo, C.sub.1-10-alkoxy, optionally substituted by at least
one hydroxy group or by halogen, up to perhalo; C.sub.5-12 aryl,
optionally substituted by C.sub.1-10 alkoxy or halogen, C.sub.5-12
hetaryl, optionally substituted by C.sub.1-10 alkyl, C.sub.1-10
alkoxy or halogen; NO.sub.2, SO.sub.2F or
--SO.sub.2CH.sub.pX.sub.3-p; --COOR.sup.1; --OR.sup.1CONHR.sup.1;
--NHCOR.sup.1; --SR.sup.7; phenyl optionally substituted by halo or
C.sub.1-10-alkoxy; NH.sub.2; --N(SO.sub.2R.sup.1).sub.2,
furyloxy,
##STR00006##
[0033] 2 adjacent R.sup.3-R.sup.6 can together form an aryl or
hetaryl ring with 5-12 atoms, optionally substituted by
C.sub.1-10-alkyl, C.sub.1-10-alkoxy, C.sub.3-10-cycloalkyl,
C.sub.2-10-alkenyl, C.sub.1-10-alkanoyl, C.sub.6-42-aryl,
C.sub.5-12-hetaryl, C.sub.6-12-aralkyl, C.sub.6-42-alkaryl,
halogen; --NR.sup.1; --NO.sub.2; --CF.sub.3; --COOR.sup.1;
--NHCOR.sup.1; --CN; --CONR.sup.1R.sup.1; --SO.sub.2R.sup.2;
--SOR.sup.2; --SR.sup.2; in which R.sup.1 is H or C.sub.1-10-alkyl
and R.sup.2 is C.sub.1-10-alkyl; optionally substituted by halogen,
up to perhalo, with --SO.sub.2-optionally incorporated in the aryl
or hetaryl ring; [0034] one of R.sup.4, R.sup.5 or R.sup.6 can be
--X--Y, [0035] R.sup.1 is C.sub.1-10-alkyl, optionally substituted
by halogen, up to perhalo; [0036] p is 0 or 1; [0037] X is
--CH.sub.2, --S--, N(CH.sub.3)--, --NHC(O), --C(O)--, or --O--; and
[0038] Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine,
benzodixane, benzopyridine, pyrimidine or benzothiazole, each
optionally substituted by C.sub.1-10-alkyl, C.sub.1-10-alkoxy,
halogen or NO.sub.2 or, where Y is phenyl, by
##STR00007##
[0038] with the proviso that if R.sup.3 and R.sup.6 are both H, one
of R.sup.4 or R.sup.5 is not H.
[0039] In formula I, suitable hetaryl groups B 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-, T- 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.
[0040] 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.
[0041] Suitable aryl groups include, for example, phenyl and 1- and
2-naphthyl.
[0042] The term "cycloalkyl", as used herein, refers to cyclic
structures with or without alkyl substitutents such that, for
example, "C.sub.4 cycloakyl" includes methyl substituted
cyclopropyl groups as well as cyclobutyl groups. The term
"cycloalkyl" also includes saturated heterocyclic groups.
[0043] 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.
[0044] Preferred compounds of formula I include those where R.sup.3
is H, halogen or C.sub.1-10-alkyl, optionally substituted by
halogen, up to perhalo, NO.sub.2, --SO.sub.2F, --SO.sub.2CHF.sub.2;
or --SO.sub.2CF.sub.3; R.sup.4 is H, C.sub.1-10-alkyl,
C.sub.1-10-alkoxy, halogen or NO.sub.2; R.sup.5 is H,
C.sub.1-10-alkyl optionally substituted by halogen, up to perhalo;
R.sup.6 is H, hydroxy, C.sub.1-40-alkoxy, optionally substituted by
at least one hydroxy group; --COOR.sup.1; --OR.sup.1CONHR.sup.1;
--NHCOR.sup.1; --SR.sup.1; phenyl optionally substituted by halo or
C.sub.1-10-alkoxy; NH.sub.2; --N(SO.sub.2R.sup.1).sub.2,
furyloxy,
[0045] Preferably, R.sup.3 is Cl, F, C.sub.4-5-branched alkyl,
--SO.sub.2F or --SO.sub.2CF.sub.3; and R.sup.6 is hydroxy;
C.sub.1-10-alkoxy optionally substituted by at least one hydroxy
group; --COOR.sup.1; --OR.sup.1CONBR.sup.1; --NHCOR.sup.1;
--SR.sup.1; phenyl optionally substituted by halo or
C.sub.1-10-alkoxy; NH.sub.2; --N(SO.sub.2R.sup.1).sub.2,
furyloxy,
[0046] More preferably, R.sup.6 is t-butyl or CF.sub.3 and R.sup.6
is --OCH.sub.3. Preferably, R.sup.4' is C.sub.1-10-alkyl or
halogen; R.sup.5' is H, C.sub.1-10-alkyl, halogen, CF.sub.3,
halogen, NO.sub.2 or NH.sub.2; and leis H, C.sub.1-10-alkyl,
halogen, --NHCOCH.sub.3, --N(CH.sub.3)COCH.sub.3, NO.sub.2,
##STR00008##
[0047] The invention also relates to compounds per se, of formula
II
##STR00009##
wherein
[0048] R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently
H, halogen, C.sub.1-10-alkyl optionally substituted by halogen up
to perhalo, C.sub.1-10-alkoxy, optionally substituted by at least
one hydroxy group or halogen, up to perhalo; NO.sub.2, SO.sub.2F or
--SO.sub.2CH.sub.nX.sub.3-n, C.sub.1-10-alkoxy; --COOR.sup.1;
--OR.sup.1CONHR.sup.1; --NHCOR.sup.1; --SR.sup.1; C.sub.6-12 aryl,
optionally substituted by C.sub.1-10-alkyl, C.sub.1-10 alkoxy or
halogen, C.sub.5-12 hetaryl, optionally substituted by C.sub.1-10
alkyl, C.sub.1-10 alkoxy or halogen; NH.sub.2;
--N(SO.sub.2R.sup.1).sub.2; furyloxy;
##STR00010##
[0049] 2 adjacent R.sup.3-R.sup.6 can together form an aryl or
hetaryl ring with 5-12 atoms, optionally substituted by
C.sub.1-10-alkyl, C.sub.3-10-cycloalkyl, C.sub.2-10-alkenyl,
C.sub.1-10-alkanoyl, C.sub.6-12-aryl, C.sub.5-12-hetaryl,
C.sub.6-12-aralkyl, C.sub.6-12-alkaryl, halogen; --NR.sup.1;
--NO.sub.2; --CF.sub.3; --COOR.sup.1; --NHCOR.sup.1; --CN;
--CONR.sup.1R.sup.1; --SO.sub.2R.sup.2; --SOR.sup.2; --SR.sup.2; in
which R.sup.1 is H or C.sub.1-10-alkyl and R.sup.2 is
C.sub.1-10-alkyl; [0050] R.sup.3' R.sup.4' and R.sup.5' are each
independently H, C.sub.1-10-alkyl, optionally substituted by
halogen, up to perhalo; NO.sub.2 or NH.sub.2; [0051] R.sup.6' is H,
C.sub.1-10-alkyl, halogen, --NHCOR.sup.1; --NR.sup.1COR.sup.1;
NO.sub.2;
##STR00011##
[0052] 2 adjacent R.sup.4'-R.sup.6' can together be an aryl or
hetaryl ring with 5-12 atoms;
[0053] R.sup.1 is C.sub.1-10-alkyl, optionally substituted by
halogen, up to perhalo;
[0054] n is 0 or 1;
with the provisos that [0055] (a) if R.sup.3 and R.sup.6 are both
H, one of R.sup.4 or R.sup.5 is not H, and [0056] (b) that R.sup.6
is phenyl substituted by alkoxy or halogen, alkoxy substituted by
hydroxy, --SO.sub.2CF.sub.2H, --OR.sup.1CONBR.sup.1,
##STR00012##
[0056] furyloxy or --N(SO.sub.2R.sup.1).sub.2;
or R.sup.6' is
##STR00013##
[0057] and (c) if R.sup.6 is phenyl substituted by alkoxy or
halogen, the compounds have a pKa greater than 10, e.g., greater
than 12, preferably greater than 15. Preferred 5-tert-butylphenyl
ureas are: [0058]
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-phenyloxyphenyl)urea; [0059]
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(4-methoxyphenyloxy)phenyl)urea;
[0060]
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(4-pyridinyloxy)phenyl)urea-
; [0061]
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(4-pyridinylmethyl)phenyl)-
urea; [0062]
N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-pyridinylthio)phenyl)urea;
[0063]
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(4-(4,7-methano-1H-isoindol-
e-1,3(2H)-dionyl)methyl)phenyl)urea; [0064]
N-(5-tert-Butyl-2-phenylphenyl)-N'-(2,3-dichlorophenyl)urea; [0065]
N-(5-tert-Butyl-2-(3-thienyl)phenyl)-N'-(2,3-dichlorophenyl)urea;
[0066]
N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N'-(2,3-dichlorop-
henyl)urea; [0067]
N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N-(1-naphthyl)ure-
a; [0068]
N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N'-(2,3-d-
ichlorophenyl)urea; [0069]
N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N'-(1-naphthyl)ure-
a; [0070]
N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N-(2,3-dichlor-
ophenyl)urea; and [0071]
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(3-pyridinyl)methylphenyl)urea.
Preferred 5-trifluoromethylphenyl ureas are: [0072]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-methylphenyl)urea;
[0073]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-methyl-2-fluorophenyl)urea;
[0074]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-fluoro-3-chlorophenyl)-
urea; [0075]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-methyl-3-chlorophenyl)urea;
[0076]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-methyl-3-fluorophenyl)-
urea; [0077]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(2,4-difluorophenyl)urea;
[0078]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-phenyloxy-3,5-dichlorophenyl)-
urea; [0079]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-(4-pyridinylmethyl)phenyl)ure-
a; [0080]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-(4-pyridinylthio)phe-
nyl)urea; [0081]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-(4-pyridinyloxy)phenyl)urea;
[0082]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(3-(4-pyridinylthio)phenyl-
)urea; and [0083]
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-(3-(N-methylaminocarbonyl)-ph-
enyloxy)phenyl)-urea. Preferred 5-sulfonylphenyl ureas are: [0084]
N-(5-Fluorosulfonyl)-2-methoxyphenyl)-N'-(4-methylphenyl)urea;
[0085]
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methylphenyl)ureaN--
(5-(Difluorornethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluorophenyl)urea;
[0086]
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-2-flu-
orophenyl)urea; [0087]
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-3-fluorophen-
yl)urea; [0088]
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-3-chlorophen-
yl)urea; [0089]
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluoro-3-chlorophen-
yl)urea; [0090]
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluoro-3-methylphen-
yl)urea; [0091]
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N'-(2,3-dimethylphenyl)ur-
ea; and [0092]
N-(5-(Trifluoromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methylphenyl)urea.
Preferred 2-naphthyl ureas are: [0093]
N-(3-Methoxy-2-naphthyl)-N'-(2-fluorophenyl)urea; [0094]
N-(3-Methoxy-2-naphthyl)-N'-(4-methylphenyl)urea; [0095]
N-(3-Methoxy-2-naphthyl)-N'-(3-fluorophenyl)urea; [0096]
N-(3-Methoxy-2-naphthyl)-N'-(4-methyl-3-fluorophenyl)urea; [0097]
N-(3-Methoxy-2-naphthyl)-N'-(2,3-dimethylphenyl)urea; [0098]
N-(3-Methoxy-2-naphthyl)-N'-(1-naphthyl)urea; [0099]
N-(3-Methoxy-2-naphthyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;
[0100] N-(3-Methoxy-2-naphthyl)-N'-(4-(4-pyridinylthio)phenyl)urea;
[0101]
N-(3-Methoxy-2-naphthyl)-N'-(4-(4-methoxyphenyloxy)phenyl)urea; and
[0102]
N-(3-Methoxy-2-naphthyl)-N'-(4-(4-(4,7-methano-1H-isoindole-1,3(2H-
)-dionyl)methyl)phenyl)urea.
[0103] Other preferred ureas are: [0104]
N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N'-(phenyl)urea; and [0105]
N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea-
.
[0106] The present invention is also directed to pharmaceutically
acceptable salts of formula I. 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, sulphonic 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, 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).
[0107] A number of the compounds of Formula I 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 isolated racemic or optically active form
of compounds described in Formula I which possess p38 kinase
inhibitory activity.
General Preparative Methods
[0108] The compounds of Formula I may be prepared by use of known
chemical reactions and procedures, some from starting materials
which are commercially available. Nevertheless, the following
general preparative methods are presented to aid one of skill in
the art in synthesizing these compounds, with more detailed
particular examples being presented in the experimental section
describing the working examples.
##STR00014##
[0109] Nitroaryls are commonly fowled 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
##STR00015##
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).
##STR00016##
[0110] 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).
##STR00017##
[0111] 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
mercaptam (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).
##STR00018##
[0112] 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 diphenylphosphoryl azide (DPPA) or a similar
reagent.
##STR00019##
[0113] Finally, ureas may be further manipulated using methods
familiar to those skilled in the art.
[0114] The invention also includes pharmaceutical compositions
including a compound of Formula I, and a physiologically acceptable
carrier.
[0115] The compounds may be administered orally, topically,
parenterally, by inhalation or spray, vaginally, rectally or
sublingually in dosage unit formulations. The term `administration
by injection` includes intravenous, 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.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] Compounds of the invention may also be administrated
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. 94). 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 Formula I may be formulated
into a lotion or salve.
[0122] 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
of one or more materials selected from lower alcohols, lower
ketones, lower carboxylic acid esters, polar ethers, lower
hydrocarbons, halogenated hydrocarbons.
[0123] Suitable penetration enhancing materials for transdermal
delivery system 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 tertbutyl 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 of 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 discarboxylic acids with a
total of up to 24 carbons, phosphatidyl derivatives, terpenes,
amides, ketones, ureas and their derivatives, and ethers.
[0124] Suitable binding materials for transdermal delivery systems
are known to those skilled in the art and include polyacrylates,
silicones, polyurethanes, block polymers, styrenebutadiene
coploymers, 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.
[0125] 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.
[0126] 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.
[0127] The compounds may also be administered in the form of
suppositories for rectal 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.
[0128] For all regimens of use disclosed herein for compounds of
Formula I, 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 vaginal dosage regimen 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 transdermal concentration will preferably be that
required to maintain a daily dose of from 0.01 to 200 mg/Kg. The
daily topical dosage regimen will preferably be from 0.1 to 200 mg
administered between one to four times daily. The daily inhalation
dosage regimen will preferably be from 0.01 to 10 mg/Kg of total
body weight.
[0129] 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 a given patient depends on a variety of
factors, including specific activity of the compound administered,
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 combination, and the severity of the condition
undergoing therapy, etc. 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 number of doses of a compound of
Formula I or a pharmaceutically acceptable salt thereof given for a
defined number of days, can be ascertained by those skilled in the
art using conventional course of treatment tests.
[0130] The compounds of Figure I 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 above. 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
construde to limit the invention in any way.
[0131] The entire disclosure of all applications, patents and
publications cited above and below are hereby incorporated by
reference, including provisional application serial number attorney
docket number Bayer 10-V1, filed on Dec. 22, 1997 as Ser. No.
08/995,749, and converted on Dec. 22, 1998.
[0132] 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
[0133] 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.
[0134] All temperatures are reported uncorrected in degrees Celsius
(.degree. C.). Unless otherwise indicated, all parts and
percentages are by weight.
[0135] Commercial grade reagents and solvents were used without
further purification. 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.
[0136] 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 sprectra
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 (d 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 MHz) 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 (FIRMS) 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 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
are conducted by Robertson Microlit Labs, Madison N.J.
[0137] All compounds displayed NMR spectra, LRMS and either
elemental analysis or HRMS consistant with assigned structures.
LIST OF ABBREVIATIONS AND ACRONYMS
[0138] AcOH acetic acid anh anhydrous BOC tert-butoxycarbonyl cone
concentrated dec decomposition DMPU
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
DMF N,N-dimethylformamide
[0139] DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EtOAc
ethyl acetate EtOH ethanol (100%) Et.sub.2O diethyl ether Et.sub.3N
triethylamine 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. Synthesis of 2,5-Dioxopyrrolidinylartilines
##STR00020##
[0141] Step 1.
4-tert-Butyl-1-(2,5-dioxo-1-pyrrolidinyl)-2-nitrobenzene:
[0142] To a solution of 4-tert-butyl-2-nitroaniline (1.04 g, 5.35
mmol) in xylene (25 mL) was added succinic anhydride (0.0535 g,
5.35 mmol) and triethylamine (0.75 mL, 5.35 mmol). The reaction
mixture was heated at the reflux temp. for 24 h, cooled to room
temp. and diluted with Et.sub.2O (25 mL) The resulting mixture was
sequentially washed with a 10% HCl solution (50 mL), a saturated
NH.sub.4Cl solution (50 mL) and a saturated NaCl solution (50 mL),
dried (MgSO.sub.4), and concentrated under reduced pressure. The
residue was purified by flash cromatography (60% EtOAc/40% hexane)
to yield the succinimide as a yellow solid (1.2 g, 86%): mp
135-138.degree. C.; .sup.1H NMR(CHCl.sub.3) .delta. 1.38 (s, 9H),
2.94-2.96 (m, 4H), 7.29-7.31 (m, 1H), 7.74-7.78 (m, 1H), 8.18-8.19
(m, 1H).
##STR00021##
[0143] Step 2.
5-tert-Butyl-2-(2,5-dioxo-1-pyrrolidinyl)aniline:
[0144] To a solution of
4-tert-butyl-1-(2,5-dioxo-1-pyrrolidinyl)-2-nitrobenzene (1.1 g,
4.2 mmol) in EtOAc (25 mL) was added a 10% Pd/C (0.1 g). The
resulting slurry was placed under a H.sub.2 atmosphere using 3
cycles of an evacuate-quench protocol and was allowed to stir under
a H.sub.2 atmosphere for 8 h. The reaction mixture was filtered
through a pad of Celite.RTM. and the residue was washed with
CHCl.sub.3. The combined filtrate was concentrated under reduced
pressure to yield the desired aniline as an off-white solid (0.75
g, 78%): mp 208-211.degree. C.; .sup.1H-NMR (DMSO-d.sub.6) .delta.
1.23 (s, 9H), 2.62-2.76 (m, 4H), 5.10 (br s, 2H), 6.52-6.56 (m,
1H), 6.67-6.70 (m, 2H).
A2. General Method for the Synthesis of
Tetrahydrofuranyloxyanilines
##STR00022##
[0146] Step 1.
4-tert-Butyl-1-(3-tetrahydrofuranyloxy)-2-nitrobenzene:
[0147] To a solution of 4-tert-butyl-2-nitrophenol (1.05 g, 5.4
mmol) in anh THF (25 mL) was added 3-hydroxytetrahydrofuran (0.47
g, 5.4 mmol) and triphenylphosphine (1.55 g, 5.9 mmol) followed by
diethyl azodicarboxylate (0.93 ml, 5.9 mmol) and the mixture was
allowed to stir at room temp. for 4 h. The resulting mixture was
diluted with Et.sub.2O (50 mL) and washed with a saturated
NH.sub.4Cl solution (50 mL) and a saturated NaCl solution (50 mL),
dried (MgSO.sub.4), and concentrated under reduced pressure. The
residue was purified by flash cromatography (30% EtOAc/70% hexane)
to yield the desired ether as a yellow solid (1.3 g, 91%):
.sup.1H-NMR(CHCl.sub.3) .delta. 1.30 (s, 9H), 2.18-2.24 (m, 2H),
3.91-4.09 (m, 4H), 5.00-5.02 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.52
(dd, J=2.6, 8.8 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H).
##STR00023##
[0148] Step 2. 5-tert-Butyl-2-(3-tetrahydrofuranyloxy)aniline:
[0149] To a solution of
4-tert-butyl-1-(3-tetrahydrofuranyloxy)-2-nitrobenzene (1.17 g, 4.4
mmol) in EtOAc (25 mL) was added 10% Pd/C (0.1). The resulting
slurry was placed under a H.sub.2 atmosphere using 3 cycles of an
evacuate-quench protocol and was allowed to stir under a H.sub.2
atmosphere for 8 h. The reaction mixture was filtered through a pad
of Celite.RTM. and washed with CHCl.sub.3. The combined filtrate
was concentrated under reduced pressure to yield of the desired
aniline as a yellow solid (0.89 g, 86%): mp 79-82.degree. C.;
(CHCl.sub.3) .delta. 1.30 (s, 9H), 2.16-2.20 (m, 2H), 3.78 (br s,
2H), 3.85-4.10 (m, 4H), 4.90 (m, 1H), 6.65-6.82 (m, 3H).
A3. General Method for the Synthesis of
Trilluoromethanesulfonylanilines
##STR00024##
[0151] Step 1. 2-Methoxy-5-(fluorosulfonyl)acetanilide:
[0152] Acetic anhydride (0.90 mL, 9.6 mmol) was added to a solution
of 4-methoxymetanilyl fluoride (1.0 g, 4.8 mmol) in pyridine (15
mL). After being stirred at room temp. for 4 h, the reaction
mixture was concentrated under reduced pressure. The resulting
residue was dissolved in CH.sub.2Cl.sub.2 (25 mL), washed with a
saturated NaHCO.sub.3 solution (25 mL), dried (Na.sub.2SO.sub.4),
and concentrated under reduced pressure to give a foam which was
triturated with a Et.sub.2O/hexane solution to provide the title
compound (0.85 g): .sup.1H-NMR (CDCl.sub.3) .delta. 2.13 (s, 3H),
3.98 (s, 3H), 7.36 (d, J=8.5 Hz, 1H), 7.82 (dd, J=2.6, 8.8 Hz, 1H),
8.79 (d, S=2.2 Hz, 1H), 9.62 (br s, 11-1).
##STR00025##
[0153] Step 2.
2-Methoxy-5-(trilluoromethanesulfonyl)acetanilide:
[0154] To an ice-cooled suspension of tris(dimethylamino)sulfonium
difluorotrimethylsiliconate (0.094 g, 0.34 mmol) in THF (4 mL) was
added a solution of (trifluoromethyl)trimethylsilane (1.0 mL, 6.88
mmol) in TIT (3 mL) followed by a solution of
2-methoxy-5-(fluorosulfonyl)acetanilide (0.85 g, 3.44 mmol) in THF
(3 mL). The reaction mixture was stirred for 2 h on an ice bath,
then was allowed to warm to room temp. and was then concentrated
under reduced pressure. The resulting residue was dissolved in
CH.sub.2Cl.sub.2 (25 mL), washed with water (25 mL), dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure. The
resulting material was purified by flash chromatography (3%
MeOH/97% CH.sub.2Cl.sub.2) to provide the title compound as a white
solid (0.62 g): .sup.1H-NMR (CDCl.sub.3) .delta. 2.13 (s, 3H) 4.00
(s, 3H), 7.42 (d, J=8.8 Hz, 1H), 7.81 (dd, j--2.6, 8.8 Hz, 1H),
8.80 (d, J=2.2 Hz, 1H), 9.64 (br s, 1H); FAB-MS m/z 298
((M+1).sup.+).
##STR00026##
[0155] Step 3. 2-Methoxy-5-(trifluoromethanesulfonyl)aniline:
[0156] A solution of
2-methoxy-5-(trifluoromethanesulfonyl)acetanilide (0.517 g, 1.74
mmol) in EtOH (5 mL) and a 1 N HCl solution (5 mL) was heated at
the reflux temp. for 4 h and the resulting mixture was concentrated
under reduced pressure. The residue was dissolved in
CH.sub.2Cl.sub.2 (30 mL), washed with water (30 mL), dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure to
afford the title compound as a gum (0.33 g): .sup.1H-NMR
(CDCl.sub.3) .delta. 3.90 (s, 3H) 5.57 (br s, 2H), 7.11-7.27 (m,
3H); FAB-MS m/z 256 ((M+1).sup.+). This material was used in urea
formation without further purification.
A4. General Method for Aryl Amine Formation Via Phenol Nitration
Followed by Ether Formation and Reduction
##STR00027##
[0158] Step 1. 2-Nitro-5-tert-butylphenol:
[0159] A mixture of fuming nitric acid (3.24 g, 77.1 mmol) in
glacial HOAc (10 mL) was added dropwise to a solution of
m-tert-butylphenol (11.58 g, 77.1 mmol) in glacial HOAc (15 mL) at
0.degree. C. The mixture was allowed to stir at 0.degree. C. for 15
min then warmed to room temp. After 1 h the mixture was poured into
ice water (100 mL) and extracted with Et.sub.2O (2.times.50 mL).
The organic layer was washed with a saturated NaCl solution (100
mL), dried (MgSO.sub.4) and concentrated in vacuo. The residue was
purified by flash chromatography (30% EtOAc/70% hexane) to give the
desired phenol (4.60 g, 31%): .sup.1H-NMR. (DMSO-d.sub.6) .delta.
1.23 (s, 9H), 7.00 (dd, J=1.84, 8.83 Hz, 1H), 7.07 (d, J=1.84 Hz,
1H), 7.82 (d, J=8.83 Hz, 1H), 10.74 (s, 1H).
##STR00028##
[0160] Step 2. 2-Nitro-5-tert-butylanisole:
[0161] A slurry of 2-nitro-5-tert-butylphenol (3.68 g, 18.9 mmol)
and K.sub.2CO.sub.3 (3.26 g, 23.6 mmol) in anh DMF (100 mL) was
stirred at room temp with stirring for 15 min then treated with
iodomethane (2.80 g, 19.8 mmol) via syringe. The reaction was
allowed to stir at room temp for 18 h., then was treated with water
(100 mL) and extracted with EtOAc (2.times.100 mL). The combined
organic layers were washed with a saturated NaCl solution (50 mL),
dried (MgSO.sub.4) and concentrated in vacuo to give the desired
ether (3.95 g, 100%): .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.29 (s,
9H), 3.92 (s, 3H), 7.10 (dd, J=1.84, 8.46 Hz, 1H), 7.22 (d, J=1.84
Hz, 1H), 7.79 (d, J=8.46 Hz, 1H). This material was used in the
next step without further purification.
##STR00029##
[0162] Step 3. 4-tert-Butyl-2-methoxy aniline:
[0163] A solution of 2-nitro-5-tert-butylanisole (3.95 g, 18.9
mmol) in MeOH (65 mL) and added to a flask containing 10% Pd/C in
MeOH (0.400 g), then placed under a H.sub.2 atmosphere (balloon).
The reaction was allowed to stir for 18 h at room temp, then
filtered through a pad of Celite.RTM. and concentrated in vacuo to
afford the desired product as a dark sticky solid (3.40 g, 99%):
.sup.1H-NMR (DMSO-d.sub.6) .delta. 1.20 (s, 9H), 3.72 (s, 3H), 4.43
(br s, 2H), 6.51 (d, J=8.09 Hz, 1H), 6.64 (dd, J=2.21, 8.09 Hz,
1H), 6.76 (d, J=2.21 Hz, 1H).
A5. General Method for Aryl Amine Formation Via Carboxylic Acid
Esterification Followed by Reduction
##STR00030##
[0165] Step 1. Methyl 2-Nitro-4-(trifluoromethyl)benzoate:
[0166] To a solution of 2-nitro-4-(trifluoromethyl)benzoic acid
(4.0 g, 17.0 mmol) in MeOH (150 mL) at room temp was added cone
H.sub.2SO.sub.4 (2.5 mL). The mixture was heated at the reflux temp
for 24 h., cooled to room temp and concentrated in vacuo. The
residue was diluted with water (100 mL) and extracted with EtOAc
(2.times.100 mL). The combined organic layers were washed with a
saturated NaCl solution, dried (MgSO.sub.4), concentrated in vacuo.
The residue was purified by flash chromatography (14% EtOAc/86%
hexane) to give the desired ester as a pale yellow oil (4.17 g,
98%): .sup.1H-NMR. (DMSO-d.sub.6) .delta. 3.87 (s, 3H), 8.09 (d,
J=7.72 Hz, 1H), 8.25 (dd, J=1.11, 8.09 Hz, 1H), 8.48 (d, J=1.11 Hz,
1H).
##STR00031##
[0167] Step 2. Methyl 2-Amino-4-(trifluoromethyl)benzoate:
[0168] A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate
(3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask
containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under
a H.sub.2 atmosphere (balloon). The reaction was allowed to stir
for 18 h at room temp, then was filtered through Celite.RTM. and
concentrated in vacuo to afford the desired product as a white
crystalline solid (3.20 g, 93%): .sup.1H-NMR (DMSO-d.sub.6) .delta.
3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11
(d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
A6. General Method for Aryl Amine Formation Via Ether Formation
Followed Ester Saponification, Curtius Rearrangement, and Carbamate
Deprotection
##STR00032##
[0170] Step 1. Methyl 3-Methoxy-2-naphthoate:
[0171] A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1
mmol) and K.sub.2CO.sub.3 (7.96 g, 57.6 mmol) in DMF (200 mL) was
stirred at room temp for 15 min, then treated with iodomethane
(3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp
overnight, then was treated with water (200 mL). The resulting
mixture was extracted with EtOAc (2.times.200 mL). The combined
organic layers were washed with a saturated NaCl solution (100 mL),
dried (MgSO.sub.4), concentrated in vacuo (approximately 0.4 mmHg
overnight) to give the desired ether as an amber oil (10.30 g):
.sup.1H-NMR (DMSO-d.sub.6) .delta. 2.70 (s, 3H), 2.85 (s, 3H), 7.38
(app t, j=8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J=8.09 Hz, 1H),
7.84 (d, J=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
##STR00033##
[0172] Step 2. 3-Methoxy-2-naphthoic Acid:
[0173] A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10
mmol) and water (10 mL) in MeOH (100 mL) at room temp was treated
with a 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture was
heated at the reflux temp for 3 h, cooling to room temp, and made
acidic with a 10% citric acid solution. The resulting solution was
extracted with EtOAc (2.times.100 mL). The combined organic layers
were washed with a saturated NaCl solution, dried (MgSO.sub.4) and
concentrated in vacuo. The residue was triturated with hexanes and
washed several times with hexanes to give the desired carboxylic
acid as a white crystalline solid (5.40 g, 92%): .sup.1H-NMR
(DMSO-d.sub.6) .delta. 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54
(m, 1H), 7.83 (d, J=8.09 Hz, 1H), 7.91 (d, J=8.09 Hz, 1H), 8.19 (s,
1H), 12.83 (br s, 1H).
##STR00034##
[0174] Step 3. 2-(N-(Carbobenzyloxy)amino-3-methoxynaphthalene:
[0175] A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol)
and Et.sub.3N (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was
stirred at room temp. for 15 min., then treated with a solution of
diphenylphosphoryl azide (5.12 g, 18.6 mmol) in toluene (10 mL) via
pipette. The resulting mixture was heated at 80.degree. C. for 2 h.
After cooling the mixture to room temp. benzyl alcohol (2.06 mL, 20
mmol) was added via syringe. The mixture was then warmed to
80.degree. C. overnight. The resulting mixture was cooled to room
temp., quenched with a 10% citric acid solution, and extracted with
EtOAc (2.times.100 mL) The combined organic layers were washed with
a saturated NaCl solution, dried (MgSO.sub.4), and concentrated in
vacuo. The residue was purified by flash chromatography (14%
EtOAc/86% hexane) to give the benzyl carbamate as a pale yellow oil
(5.1 g, 100%): .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.89 (s, 3H),
5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H),
8.76 (s, 1H).
##STR00035##
[0176] Step 4. 2-Amino-3-methoxynaphthalene:
[0177] A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene
(5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70 mL) was
maintained under a H.sub.2 atmospheric (balloon) at room temp.
overnight. The resulting mixture was filtered through Celite.RTM.
and concentrated in vacuo to give the desired amine as a pale pink
powder (2.40 g, 85%): .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.86 (s,
3H), 6.86 (s, .sup.2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0 Hz, 1H),
7.56 (d, J=8.0 Hz, 1H); EI-MS m/z 173 (M.sup.+).
A7. General Method for the Synthesis of Aryl Amines Via
Metal-Mediated Cross Coupling Followed by Reduction
##STR00036##
[0179] Step 1.
5-tert-Butyl-2-(trifluoromethanesulfonyl)oxy-1-nitrobenzene:
[0180] To an ice cold solution of 4-tert-butyl-2-nitrophenol (6.14
g, 31.5 mmol) and pyridine (10 mL, 125 mmol) in CH.sub.2Cl.sub.2
(50 mL) was slowly added trifluoromethanesulfonic anhydride (10 g,
35.5 mmol) via syringe. The reaction mixture was stirred for 15
min, then allowed to warm up to room temp. and diluted with
CH.sub.2Cl.sub.2 (100 mL). The resulting mixture was sequentially
washed with a 1M NaOH solution (3.times.100 mL), and a 1M HCl
solution (3.times.100 mL), dried (MgSO.sub.4), and concentrated
under reduced pressure to afford the title compound (8.68 g, 84%):
.sup.1H-NMR (CDCl.sub.3) .delta. 1.39 (s, 9H), 7.30-8.20 (m,
3H).
##STR00037##
[0181] Step 2. 5-tert-Butyl-2-(3-fluorophenyl)-1-nitrobenzene:
[0182] A mixture of 3-fluorobenzeneboronic acid (3.80 g, 27.5
mmol), KBr (2.43 g, 20.4 mmol), K.sub.3PO.sub.4 (6.1 g, 28.8 mmol),
and Pd(PPh.sub.3).sub.4 (1.0 g, 0.9 mmol) was added to a solution
of 5-tert-butyl-2-(trifluoromethanesulfonyl)oxy-1-nitrobenzene (6.0
g, 18.4 mmol) in dioxane (100 mL). The reaction mixture was heated
at 80.degree. C. for 24 h, at which time TLC indicated complete
reaction. The reaction mixture was treated with a saturated
NH.sub.4Cl solution (50 mL) and extracted EtOAc (3.times.100 mL).
The combined organic layers were dried (MgSO.sub.4) and
concentrated under reduced pressure. The residue was purified by
flash chromatography (3% EtOAc/97% hexane) to give the title
compound (4.07 g, 81%): .sup.1H-NMR (CDCl.sub.3) .delta. 1.40 (s,
9H), 6.90-7.90 (m, 7H).
##STR00038##
[0183] Step 3. 5-tert-Butyl-2-(3-fluorophenyl)aniline:
[0184] To a solution of
5-tert-butyl-2-(3-fluorophenyl)-1-nitrobenzene (3.5 g, 12.8 mmol)
and EtOH (24 mL) in EtOAc (96 mL) was added 5% Pd/C (0.350 g) and
the resulting slurry was stirred under a H.sub.2 atmosphere for 24
h, at which time TLC indicated complete consumption of starting
material. The reaction mixture was filtered through a pad of
Celite.RTM. to give the desired product (2.2 g, 72%): .sup.1H-NMR
(CDCl.sub.3) .delta. 1.35 (s, 9H), 3.80 (br s, 2H), 6.90-7.50 (m,
7H).
A8. General Method for the Synthesis of Nitroanilines
##STR00039##
[0186] Step 1.
4-(4-(2-Propoxycarbonylamino)phenyl)methylaniline:
[0187] A solution of di-tert-butyl dicarbonate (2.0 g, 9.2 mmol)
and 4,4'-methylenedianiline (1.8 g, 9.2 mmol) in DMF (100 mL) was
heated at the reflux temp. for 2 h, then cooled to room temp. This
mixture was diluted with EtOAc (200 mL) sequentially washed with a
saturated NH.sub.4Cl (200 mL) and a saturated NaCl solution (100
mL), and dried (MgSO.sub.4). The residue was purified by flash
chromatography (30% EtOAc/70% hexane) to give the desired carbamate
(1.3 g, 48%): .sup.1H-NMR (CDCl.sub.3) .delta. 1.51 (s, 9H), 3.82
(s, 2H), 6.60-7.20 (m, 8H).
##STR00040##
[0188] Step 2.
4-(4-(2-Propoxycarbonylamino)phenyl)methyl-1-nitrobenzene:
[0189] To an ice cold solution of
4-(4-(2-propoxycarbonylamino)phenyl)methylaniline (1.05 g, 3.5
mmol) in CH.sub.2Cl.sub.2 (15 mL) was added m-CPBA (1.2 g, 7.0
mmol). The reaction mixture was slowly allowed to warm to room
temp. and was stirred for 45 min, at which time TLC indicated
disappearance of starting material. The resulting mixture was
diluted with EtOAc (50 mL), sequentially washed with a 1M NaOH
solution (50 mL) and a saturated NaCl solution (50 mL), and dried
(MgSO.sub.4). The residue was purified by flash chromatography (20%
EtOAc/80% hexane) to give the desired nitrobenzene (0.920 g):
FAB-MS m/z 328 (M.sup.+).
##STR00041##
[0190] Step 3. 4-(4-Nitrophenyl)methylaniline:
[0191] To a solution of
4-(4-(2-propoxycarbonylamino)phenyl)methyl-1-nitrobenzene (0.920 g,
2.8 mmol in dioxane (10 mL) was added a conc. HCl solution (4.0 mL)
and the resulting mixture was heated at 80.degree. C. for 1 h at
which time TLC indicated disappearance of starting material. The
reaction mixture was cooled to room temp. The resulting mixture was
diluted with EtOAc (50 mL), then washed with a 1M NaOH solution
(3.times.50 mL), and dried (MgSO.sub.4) to give the desired aniline
(0.570 mg, 89%): .sup.1H-NMR (CDCl.sub.3) .delta. 3.70 (br s, 2H),
3.97 (s, 2H), 6.65 (d, J=8.5 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 7.32
(d, J=8.8 Hz, 2H), 8.10 (d, J=8.8 Hz, 2H).
A9. General Method for Synthesis of Aryl Anilines Via Alkylation of
a Nitrophenol Followed by Reduction
##STR00042##
[0193] Step 1. 4-(.alpha.-Bromoacetyl)morpholine:
[0194] To an ice cold solution of morpholine (2.17 g, 24.9 mmol)
and diisopropylethylamine (3.21 g, 24.9 mmol) in CH.sub.2Cl.sub.2
(70 mL) was added a solution of bromoacetyl bromide (5.05 g, 25
mmole) in CH.sub.2Cl.sub.2 (8 mL) via syringe. The resulting
solution was kept at 0.degree. C. for 45 min, then was allowed to
warm to room temp. The reaction mixture was diluted with EtOAc (500
mL), sequentially washed with a 1M HCl solution (250 mL) and a
saturated NaCl solution (250 mL), and dried (MgSO.sub.4) to give
the desired product (3.2 g, 62%): .sup.1H-NMR (DMSO-d.sub.6)
.delta. 3.40-3.50 (m, 4H), 3.50-3.60 (m, 4H), 4.11 (s, 2H),
##STR00043##
[0195] Step 2.
2-(N-Morpholinylcarbonyl)methoxy-5-tert-butyl-1-nitrobenzene:
[0196] A slurry of 4-tert-butyl-2-nitrophenol (3.9 g, 20 mmol) and
K.sub.2CO.sub.3 (3.31 g, 24 mmol) in DMF (75 mL) was stirred at
room temp. for 15 minutes, then a solution of
4-.alpha.-bromoacetyl)morpholine (4.16 g, 20 mmol) in DMF. (10 mL)
was added. The reaction was allowed to stir at room temp.
overnight, then was diluted with EtOAc (500 mL) and sequentially
washed with a saturated NaCl solution (4.times.200 mL) and a 1M
NaOH solution (400 mL). The residue was purified by flash
chromatography (75% EtOAc/25% hexane) to give the nitrobenzene
(2.13 g, 33%): .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.25 (s, 9H),
3.35-3.45 (m, 4H), 3.50-3.58 (m, 4H), 5.00 (s, 2H), 7.12 (d, J=8.8
Hz, 1H), 7.50-7.80 (m, 2H).
##STR00044##
[0197] Step 3.
2-(N-Morpholinylcarbonyl)methoxy-5-tert-butylaniline:
[0198] To a solution of
2-(N-morpholinylcarbonyl)methoxy-5-tert-butyl-1-nitrobenzene (2.13
g, 6.6 mmol) and EtOH (10 mL) in EtOAc (40 mL) was added 5% Pd/C
(0.215 g). The resulting slurry was stirred under a H.sub.2
atmosphere for 6 h, at which time TLC indicated complete
consumption of starting material. The reaction mixture was filtered
through a pad of Celite.RTM. to give the desired product (1.9 g,
98%): .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.18 (s, 9H), 3.40-3.50
(m, 4H), 3.50-3.60 (m, 4H), 4.67 (br s, 2H), 4.69 (s, 2H),
6.40-6.70 (m, 3H).
A10. General Method for Aryl Amine Formation Via Nitrophenol
Alkylation Followed by Reduction
##STR00045##
[0200] Step 1. 5-tert-Butyl-2-(2-hydroxyethoxy)-1-nitrobenzene:
[0201] A solution of 4-tert-butyl-2-nitrophenol (30 g, 0.15 mol)
and tetra-n-butylammonium fluoride (0.771 g, 3.0 mmol) in ethylene
carbonate (10.24 mL. 0.15 mol) was heated at 150.degree. C. for 18
h, then cooled to room temp. and separated between water (50 mL)
and CH.sub.2Cl.sub.2 (50 mL). The organic layer was dried
(MgSO.sub.4) and concentrated under reduced pressure. The residue
was purified by column chromatography (20% EtOAc/80% hexane) to
afford the desired product as a brown oil (35.1 g, 90%):
.sup.1H-NMR (DMSO-d.sub.6) .delta. 1.25 (s, 9H), 3.66-3.69 (m, 2H),
4.10-4.14 (t, J=5.0 Hz, 2H), 4.85 (t, J=5.0 Hz, 1H), 7.27 (d, J=8.8
Hz, 1H), 7.60-7.64 (m, 1H), 7.75 (d, J=2.6 Hz, 1H).
##STR00046##
[0202] Step 2.
5-tert-Butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)-1-nitrobenzene:
[0203] A solution of
5-tert-butyl-2-(2-hydroxyethoxy)-1-nitrobenzene (0.401 g, 1.68
mmol), di-tert-butyl dicarbonate (0.46 mL, 2.0 mmol) and
dimethylaminopyridine (0.006 g, 0.05 mmol) in CH.sub.2Cl.sub.2 (15
mL) was stirred at room temp. for 30 min, at which time TLC
indicated consumption of starting material. The resulting mixture
was washed with water (20 mL), dried (MgSO.sub.4) and concentrated
under reduced pressure. The residue was purified by column
chromatography (3% MeOH/97% CH.sub.2Cl.sub.2) to give the desired
product as a yellow oil (0.291 g, 51%): .sup.1H-NMR (DMSO-d.sub.6)
.delta. 1.25 (s, 9H), 1.38 (s, 9H), 4.31 (br s, 4H), 7.27 (d, J=9.2
Hz, 1H) 7.64 (dd, J=2.6, 8.8 Hz, 1H) 7.77 (d, J=2.6 Hz, 1H).
##STR00047##
[0204] Step 3.
5-tert-Butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)aniline:
[0205] To a mixture of
5-tert-butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)-1-nitrobenzene
(0.290 g, 0.86 mmol) and 5% Pd/C (0.058 g) in MeOH (2 mL) was
ammonium formate (0.216 g, 3.42 mmol), and the resulting mixture
was stirred at room temp. for 12 h, then was filtered through a pad
of Celite.RTM. with the aid of EtOH. The filtrate was concentrated
under reduced pressure and the residue was purified by column
chromatography (2% MeOH/98% CH.sub.2Cl.sub.2) tp give the desired
product as a pale yellow oil (0.232 g, 87%): TLC (20% EtOAc/80%
hexane) R.sub.f 0.63; .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.17 (s,
9H), 1.39 (s, 9H), 4.03-4.06 (m, 2H), 4.30-4.31 (m, 2H), 4.54 (br
s, 2H), 6.47 (dd, J=2.2, 8.1 Hz, 1H) 6.64-6.67 (m, 2H).
A11. General Method for Substituted Aniline Formation Via
Hydrogenation of a Nitroarene
##STR00048##
[0207] 4-(4-Pyridinylmethyl)aniline:
[0208] 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 (11,e). This material was used in urea formation reactions
without further purification.
A12. General Method for Substituted Aniline Formation Via
Dissolving Metal Reduction of a Nitroarene
##STR00049##
[0209] 4-(2-Pyridinylthio)aniline:
[0210] 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.f0.20. A13a. General Method for Substituted Aniline Formation
Via Nitroarene Formation Through Nucleophilic Aromatic
Substitution, Followed by Reduction
##STR00050##
[0211] Step 1. 1-Methoxy-4-(4-nitrophenoxy)benzene:
[0212] 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 1-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); ELMS m/z 245
(M.sup.+).
##STR00051##
[0213] Step 2. 4-(4-Methoxyphenoxy)aniline:
[0214] 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.+).
A13b. General Method for Substituted Aniline Formation Via
Nitroarene Formation Through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00052##
[0215] Step 1.
3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene:
[0216] 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.f0.06; .sup.1H-NMR (DMSO-d.sub.6) .delta.
7.33 (dd, 0.1=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).
##STR00053##
[0217] Step 2. 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline:
[0218] 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.f0.10;
.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).
A13c. General Method for Substituted Aniline Formation Via
Nitroarene Formation Through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00054##
[0219] Step 1. 4-(2-(4-Phenyl)thiazolyl)thio-1-nitrobenzene:
[0220] 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
mmol), 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.f0.49; .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).
##STR00055##
[0221] Step 2. 4-(2-(4-Phenyl)thiazolyl)thioaniline:
[0222] 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, 21-1).
A13d. General Method for Substituted Aniline Formation Via
Nitroarene Formation Through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00056##
[0223] Step 1. 4-(6-Methyl-3-pyridinyloxy)-1-nitrobenzene:
[0224] To a solution of 5-hydroxy-2-methylpyridine (5.0 g, 45.8
mmol) 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%). The this material was carried to the
next step without further purification.
##STR00057##
[0225] Step 2. 4-(6-Methyl-3-pyridinyloxy)aniline:
[0226] A solution of 4-(6-methyl-3-pyridinyloxy)-1-nitrobenzene
(4.0 g, 17.3 mmol) in 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.+).
A13e. General Method for Substituted Aniline Formation Via
Nitroarene Formation Through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00058##
[0227] Step 1. 4-(3,4-Dimethoxyphenoxy)-1-nitrobenzene:
[0228] 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.
##STR00059##
[0229] Step 2. 4-(3,4-Dimethoxyphenoxy)aniline:
[0230] 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 1-1, atmosphere (balloon)
and was allowed to stir for 18 h at room temp. The mixture was then
filtered through a pad of Celiteu and concentrated in vacuo to
afford the desired product as a white solid (0.6 g, 75%): EI-MS m/z
245 (M.sup.+).
A13f. General Method for Substituted Aniline Formation Via
Nitroarene Formation Through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00060##
[0231] Step 1. 3-(3-Pyridinyloxy)-1-nitrobenzene:
[0232] 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.
##STR00061##
[0233] Step 2. 3-(3-Pyridinyloxy)aniline:
[0234] A solution of 3-(3-pyridinyloxy)-1-nitrobenzene (2M g, 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.+).
A13g. General Method for Substituted Aniline Formation Via
Nitroarene Formation Through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00062##
[0235] Step 1. 3-(5-Methyl-3-pyridinyloxy)-1-nitrobenzene:
[0236] 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,
(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%).
##STR00063##
[0237] Step 2. 3-(5-Methyl-3-pyridinyloxy)-1-nitrobenzene:
[0238] A solution of 3-(5-methyl-3-pyridinyloxy)-1-nitrobenzene
(1.2 g, 5.2 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 red oil
(0.9 g, 86%): CI-MS m/z 201 ((M+H).sup.+).
A13h. General Method for Substituted Aniline Formation Via
Nitroarene Formation Through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00064##
[0239] Step 1. 5-Nitro-2-(4-methylphenoxy)pyridine:
[0240] 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, (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, J=8.46
Hz, 2H), 7.19 (d, J=9.20 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%).
##STR00065##
[0241] 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), 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%).
A13i. General Method for Substituted Aniline Formation Via
Nitroarene Formation Through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00066##
[0242] Step 1. 4-(3-Thienylthio)-1-nitrobenzene:
[0243] 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.4'').
##STR00067##
[0244] Step 2. 4-(3-Thienylthio)aniline
[0245] 4-(3-Thienylthio)-1-nitrobenzene was reduced to the aniline
in a manner analogous to that described in Method B1.
A13j. General Method for Substituted Aniline Formation Via
Nitroarene Formation Through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00068##
[0246] 4-(5-Pyrimininyloxy)aniline:
[0247] 4-Aminophenol (1.0 g, 9.2 mmol) was dissolved in DMF (20 mL)
then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K.sub.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 GC-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 residular solids
were purified by MPLC (50% EtOAc/50% hexanes) to give the desired
amine (0.650 g, 38%).
A13k. General Method for Substituted Aniline Formation Via
Nitroarene Formation Through Nucleophilic Aromatic Substitution,
Followed by Reduction
##STR00069##
[0248] Step 1. 5-Bromo-2-methoxypyridine:
[0249] 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 190% hexane) R.sub.f0.57.
##STR00070##
[0250] Step 2. 5-Hydroxy-2-methoxypyridine:
[0251] 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%).
##STR00071##
[0252] Step 3. 4-(5-(2-Methoxy)pyridyl)oxy-1-nitrobenzene:
[0253] 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%).
##STR00072##
[0254] Step 4. 4-(5-(2-Methoxy)pyridyl)oxyaniline:
[0255] 4-(5-(2-Methoxy)pyridyl)oxy-1-nitrobenzene was reduced to
the aniline in a manner analogous to that described in Method B3d,
Step 2.
A14a. General Method for Substituted Aniline Synthesis Via
Nucleophilic Aromatic Substitution Using a Halopyridine
##STR00073##
[0256] 3-(4-Pyridinylthio)aniline:
[0257] 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, 2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d, 2H).
A14b. General Method for Substituted Aniline Synthesis Via
Nucleophilic Aromatic Substitution Using a Halopyridine
##STR00074##
[0258] 4-(2-Methyl-4-pyridinyloxy)aniline:
[0259] To a solution of 4-aminophenol (3.6 g, 32.8 mmol) and
4-chloropicoline (5.0 g, 39.3 mmol) in anh 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 cool 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.+).
A14c. General Method for Substituted Aniline Synthesis Via
Nucleophilic Aromatic Substitution Using a Halopyridine
##STR00075##
[0260] Step 1. Methyl(4-nitrophenyl)-4-pyridylamine:
[0261] 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)
##STR00076##
[0262] Step 2. Methyl(4-aminophenyl)-4-pyridylamine:
[0263] Methyl(4-nitrophenyl)-4-pyridylamine was reduced in a manner
analogous to that described in Method B1.
A15. General Method of Substituted Aniline Synthesis Via Phenol
Alkylation Followed by Reduction of a Nitroarene
##STR00077##
[0265] Step 1. 4-(4-Butoxyphenyl)thio-1-nitrobenzene:
[0266] 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 mill), then a
solution of iodobutane (1.12 g, 0.690 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,
0.035 mL, 0.303 mmol, 0.05 equiv) and NaH (13 mg, 0.334 mmol) were
added. The reaction was stirred an additional 6 h 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.f0.75; .sup.1H-NMR (DMSO-d.sub.6) 0.92 (t,
J=7.5 Hz, 3H), 1.42 (app hex, J=7.5 Hz, 2H), 1.70 (m, 2H), 4.01 (t,
J=6.6 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).
##STR00078##
[0267] Step 2. 4-(4-Butoxyphenyl)thioaniline:
[0268] 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 B3b, Step
2): TLC (33% EtOAc/77% hexane) R.sub.f 0.38.
A16. General Method for Synthesis of Substituted Anilines by the
Acylation of Diaminoarenes
##STR00079##
[0270] 4-(4-tert-Butoxycarbamoylbenzyl)aniline:
[0271] 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 THY (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-cert-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 (br s, 1H); FAB-MS m/z 298
(M.sup.+).
A17. General Method for the Synthesis of Aryl Amines Via
Electrophilic Nitration Followed by Reduction
##STR00080##
[0273] Step 1. 3-(4-Nitrobenzyl)pyridine:
[0274] 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%): GC-MS m/z 214 (M.sup.+).
##STR00081##
[0275] Step 2. 3-(4-Pyridinyl)methylaniline:
[0276] 3-(4-Nitrobenzyl)pyridine was reduced to the aniline in a
manner analogous to that described in Method B1.
A18. General Method for Synthesis of Aryl Amines Via Substitution
with Nitrobenzyl Halides Followed by Reduction
##STR00082##
[0277] Step 1. 4-(1-Imidazolylmethyl)-1-nitrobenzene:
[0278] 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%): ELMS m/z 203
(M.sup.+).
##STR00083##
[0279] Step 2. 4-(1-Imidazolylmethyl)aniline:
[0280] 4-(1-Imidazolylmethyl)-1-nitrobenzene was reduced to the
aniline in a manner analogous to that described in Method B2.
A19. Formation of Substituted Hydroxymethylanilines by Oxidation of
Nitrobenzyl Compounds Followed by Reduction
##STR00084##
[0282] Step 1. 4-(1-Hydroxy-1-(4-pyridyl)methyl-1-nitrobenzene:
[0283] 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.f0.12; FAB-MS
m/z 367 ((M+H).sup.+, 100%).
##STR00085##
[0284] Step 2. 4-(1-Hydroxy-1-(4-pyridyl)methylaniline:
[0285] 4-(1-Hydroxy-1-(4-pyridyl)-methyl-1-nitrobenzene was reduced
to the aniline in a manner analogous to that described in Method
B3d, Step 2.
A20. Formation of 2-(N-methylcarbamoyl)pyridines Via the Menisci
Reaction
##STR00086##
[0287] Step 1. 2-(N-methylcarbamoyl)-4-chloropyridine.
[0288] (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.4.7H2O
(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 120% 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):
d 8.44 (d, 1H, J=5.1 Hz, CHIN), 8.21 (s, 1H, CHCCO), 7.96 (b s,
111, 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)+).
A21. General Method for the Synthesis of .omega.-Sulfonylphenyl
Anilines
##STR00087##
[0290] Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene:
[0291] 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).
[0292] Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline:
[0293] 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene was reduced to
the aniline in a manner anaologous to that described in Method B3d,
step 2.
A22. General Method for Synthesis of
.omega.-Alkoxy-.omega.-Carboxyphenyl Anilines
##STR00088##
[0295] Step 1.
4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene:
[0296] To a solution of
-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared in a manner
analogous to that described in Method B3a, 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.
##STR00089##
[0297] Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene:
[0298] 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
[0299] B1a. General Method for the Reaction of an Aryl Amine with
an Aryl Isocyanate
##STR00090##
[0300]
N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N'-(4-methylpheny-
l)urea:
[0301] To a solution of
5-tert-butyl-2-(3-tetrahydrofuranyloxy)aniline (0.078 g, 0.33 mmol)
in toluene (2.0 mL) was added p-tolyl isocyanate (0.048 g, 0.36
mmol) and the resulting mixture was allowed to stir at room temp.
for 8 h to produce a precipitate. The reaction mixture was filtered
and the residue was sequentially washed with toluene and hexanes to
give the desired urea as a white solid (0.091 g, 75%): nip
229-231.degree. C.; .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.30 (s,
9H), 1.99-2.03 (m, 1H), 2.19-2.23 (m, 4H), 3.69-3.76 (m, 1H),
3.86-3.93 (m, 3H), 4.98-5.01 (m, 1H), 6.81-6.90 (m, 2H), 7.06 (d,
J=8.09 Hz, 2H, 7.32 (d, J=8.09 Hz, 21-1), 7.84 (s, 1H), 8.22 (d,
J=2.21 Hz, 1H), 9.26 (s, 1H).
B1b. General Method for the Reaction of an Aryl Amine with an Aryl
Isocyanate
##STR00091##
[0302]
N-(2-Methoxy-5-(trifluoromethanesulfonyl)phenyl)-N'(4-methylphenyl)-
urea:
[0303] p-Tolyl isocyanate (0.19 ml, 1.55 mmol) was added to a
solution of 2-methoxy-5-(trifluoromethanesulfonyl)aniline (0.330 g,
1.29 mmol) in EtOAc (5 mL), and the reaction mixture was stirred at
room temp. for 18 h. The resulting precipitate was collected by
filtration and washed with Et.sub.2O to give a white solid (0.28
g). This material was then purified by HPLC(C-18 column, 50%
CH.sub.3CN/50% H.sub.2O) and the resulting solids were triturated
with Et.sub.2O to provide the title compound (0.198 g): .sup.1H-NMR
(CDCl.sub.3) .delta. 7.08 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz,
2H), 7.40 (d, J=8.8 Hz, 1H), 7.71 (dd, J=2.6, 8.8 Hz, 1H), 8.66 (s,
1H), 8.90 (d, J=2.6 Hz, 1H), 9.36 (s, 1H); FAB-MS m/z 389
((M+1).sup.+).
B1c. General Method for the Reaction of an Aryl Amine with an Aryl
Isocyanate
##STR00092##
[0304]
N-(2-Methoxy-5-(difluoromethanesulfonyl)phenyl)-N'-(4-methylphenyl)-
urea:
[0305] p-Tolyl isocyanate (0.058 mL, 0.46 mmol) was added to a
solution of 2-methoxy-5-(difluoromethanesulfonyl)aniline (0.100 g,
0.42 mmol) in EtOAc (0.5 mL) and the resulting mixture was stirred
at room temp. for 3 d. The resulting precipitate was filtered and
washed with Et.sub.2O to provide the title compound as a white
solid (0.092 g): .sup.1H-NMR (CDCl.sub.3) .delta. 2.22 (s, 3H) 4.01
(s, 3H), 7.02-7.36 (m, 6H), 7.54 (dd, J=2.4, 8.6 Hz, 1H), 8.57 (s,
1H), 8.79 (d, J=2.6 Hz, 1H), 9.33 (s, 1H); ELMS m/z 370
(M.sup.+).
B1d. General Method for the Reaction of an Aryl Amine with an Aryl
Isocyanate
##STR00093##
[0306]
N-(2,4-Dimethoxy-5-(trifluoromethyl)phenyl)-N'-(4-methylphenyl)urea-
:
[0307] p-Tolyl isocyanate (0.16 mL, 1.24 mmol) was added to a
solution of 2,4-dimethoxy-5-(trifluoromethyl)aniline (0.25 g, 1.13
mmol) in EtOAc (3 mL) and the resulting mixture was stirred at room
temp. for 18 h. A resulting precipitate was washed with Et.sub.2O
to give the title compound as a white solid (0.36 g): .sup.1H-NMR
(CDCl.sub.3) .delta. 2.21 (s, 3H). 3.97 (s, 31-1), 3.86 (s, 3H),
6.88 (s, 1H), 7.05 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 8.13
(s, 1H), 8.33 (s, 1H), 9.09 (s, 1H); FAB-MS m/z 355
((M+1).sup.+).
B1e. General Method for the Reaction of an Aryl Amine with an Aryl
Isocyanate
##STR00094##
[0308] N-(3-Methoxy-2-naphthyl)-N'-(1-naphthyl)urea:
[0309] To a solution of 2-amino-3-methoxynaphthalene (0.253 g, 1.50
mmol) in CH.sub.2Cl.sub.2 (3 mL) at room temp. was added a solution
of 1-naphthyl isocyanate (0.247 g, 1.50 mmol) in CH.sub.2Cl.sub.2
(2 mL) and the resulting mixture was allowed to stir overnight. The
resulting precipitate was separated and washed with
CH.sub.2Cl.sub.2 to give the desired urea as a white powder (0.450
g, 90%): mp 235-236.degree. C.; .sup.1H-NMR (DMSO-d.sub.6) .delta.
4.04 (s, 3H), 7.28-7.32 (m, 2H), 7.38 (s, 1H), 7.44-7.72 (m, 6H),
7.90-7.93 (m, 1H), 8.05-8.08 (m, 1H), 8.21-8.24 (m, 1H), 8.64 (s,
1H), 9.03 (s, 1H), 9.44 (s, 1H); FAB-MS m/z 343 ((M+11).sup.+).
B1f. General Method for the Reaction of an Aryl Amine with an Aryl
Isocyanate
##STR00095##
[0310]
N-(5-tert-Butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)phenyl)-N'-(4-me-
thylphenyl)urea:
[0311] A mixture of
5-tert-butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)aniline (Method
A10, 0.232 g, 0.75 mmol) and p-tolyl isocyanate (0.099 mL, 0.79
mmol) in EtOAc (1 mL) was stirred at room temp. for 3 d to produce
a solid, which was separated. The filtrate was purified by column
chromatography (100% CH.sub.2Cl.sub.2) and the residue was
triturated (Et.sub.2O/hexane) to give the desired product (0.262 g,
79%): mp 155-156.degree. C.; TLC (20% EtOAc/80% hexane)
R.sub.f0.49; .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.22 (s, 9H), 1.37
(s, 9H), 2.21 (s, 3H), 4.22-4.23 (m, 2H), 4.33-4.35 (m, 2H),
6.89-7.00 (m, 4H), 7.06 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H),
7.96 (s, 1H); 8.22 (d, J=1.5 Hz, 1H), 9.22 (s, 1H); FAB-MS m/z (rel
abundance) 443 ((M+H).sup.+, 6%).
B2a. General Method for Reaction of an Aryl Amine with Phosgene
Followed by Addition of a Second Aryl Amine
##STR00096##
[0312]
N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(4-pyridinylthio)phen-
yl)urea:
[0313] To a solution of pyridine (0.61 mL, 7.5 mmol, 3.0 equiv) and
phosgene (20% in toluene; 2.65 mL, 5.0 mmol, 2.0 equiv) in
CH.sub.2Cl.sub.2 (20 mL) was added
2-methoxy-5-(trifluoromethyl)aniline (0.48 g, 2.5 mmol) at
0.degree. C. The resulting mixture was allowed warm to room temp.
stirred for 3 h, then treated with anh. toluene (100 mL) and
concentrated under reduced pressure. The residue was suspended in a
mixture of CH.sub.2Cl.sub.2 (10 mL) and anh. pyridine (10 mL) and
treated with 3-(4-pyridinylthio)aniline (0.61 g, 2.5 mmol, 1.0
equiv). The mixture was stirred overnight at room temp., then
poured into water (50 mL) and extracted with CH.sub.2Cl.sub.2
(3.times.25 mL). The combined organic layers were dried
(MgSO.sub.4) and concentrated under reduced pressure. The residue
was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and treated
with pet. ether to give the desired product as a white precipitate
(0.74 g, 70%): mp 202.degree. C.; TLC (5% acetone/95%
CH.sub.2Cl.sub.2) R.sub.f0.09; .sup.1H -NMR (DMSO-d.sub.6) .delta.
7.06 (d, J=5.5 Hz, 2H), 7.18 (dd, J=2.4, 4.6 Hz, 2H), 7.31 (dd,
J=2.2, 9.2 Hz, 1H), 7.44 (d, J=5.7 Hz, 1H), 7.45 (s, 1H), 7.79 (d,
J=2.2 Hz, 1H), 8.37 (s, 2H), 8.50 (dd, J=2.2, 9.2 Hz, 2H), 9.63 (s,
1H), 9.84 (s, 1H); FAB-MS m/z 420 ((M+H).sup.+, 70%).
[0314] B2b. General Method for Reaction of an Aryl Amine with
Phosgene Followed by Addition of a Second Aryl Amine
##STR00097##
[0315]
N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(4-pyridinylthio)phen-
yl)urea:
[0316] To a solution of pyridine (0.61 mL, 7.5 mmol, 3.0 equiv) and
phosgene (20% in toluene; 2.65 mL, 5.0 mmol, 2.0 equiv) in
CH.sub.2Cl.sub.2 (20 mL) was added 4-(4-pyridinylthio)aniline
(0.506 g, 2.5 mmol) at 0.degree. C. After stirring for 3 h at room
temp., the mixture was treated with anh. toluene (100 mL) then
concentrated under reduced pressure. The residue was suspended in a
mixture of CH.sub.2Cl.sub.2 (10 mL) and anh. pyridine (10 mL) and
treated with 2-methoxy-5-(trifluoromethyl)aniline (0.50 g, 2.5
mmol, 1.0 equiv). After stirring the mixture overnight at room
temp., it was poured into a 1 N NaOH solution (50 mL) and extracted
with CH.sub.2Cl.sub.2 (3.times.25 mL). The combined organic layers
were dried (MgSO.sub.4) and concentrated under reduced pressure to
give the desired urea (0.74 g, 71%): mp 215.degree. C.; TLC (5%
acetone/95% CH.sub.2Cl.sub.2) R.sub.f 0.08; .sup.1H-NMR.
(DMSO-d.sub.6) .delta. 3.96 (s, 3H), 6.94 (dd, J=1.1, 4.8 Hz, 2H),
7.19 (d, J=8.4 Hz, 1H), 7.32 (dd, J=2.2, 9.3 Hz, 1H), 7.50 (d,
J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 8.32 (d, J=5.1 Hz, 2H), 8.53
(d, J=0.7 Hz, 1H), 8.58 (s, 1H), 9.70 (s, 1H); FAB-MS m/z 420
((M+H).sup.+).
B3a. General Method for the Reaction of an Aryl Amine with Phosgene
with Isolation of the Isocyanate, Followed by Reaction with a
Second Aryl Amine
##STR00098##
[0317] Step 1. 5-(Difluoromethanesulfonyl)-2-methoxyphenyl
isocyanate:
[0318] To a solution of phosgene (1.95 M in toluene; 3.0 mL, 5.9
mmol) in CH.sub.2Cl.sub.2 (40 mL) at 0.degree. C. was added a
solution of 5-(difluoromethanesulfonyl)-2-methoxyaniline (0.70 g,
2.95 mmol) and pyridine (0.44 mL, 8.85 mmol) in CH.sub.2Cl.sub.2
(10 mL) dropwise. After being stirred at 0.degree. C. for 30 min
and at room temp. for 3 h, the reaction mixture was concentrated
under reduced pressure, then treated with toluene (50 mL). The
resulting mixture was concentrated under reduced pressure, then was
treated with Et.sub.2O (50 mL) to produce a precipitate (pyridinium
hydrochloride). The resulting filtrate was concentrated under
reduced pressure to provide the title compound as a white solid
(0.33 g). This material was used in the next step without further
purification.
##STR00099##
[0319] Step 2.
N-(2-Methoxy-5-(difluoromethanesulfonyl)phenyl)-N'-(2-fluoro-4-methylphen-
yl)urea:
[0320] 2-Fluoro-4-methylaniline (0.022 mL, 0.19 mmol) was added to
a solution of 5-(difluoromethanesulfonyl)-2-methoxyphenyl
isocyanate (0.046 g, 0.17 mmol) in EtOAc (1 mL). The reaction
mixture was stirred at room temp. for 3 d. The resulting
precipitate was washed with Et.sub.2O to provide the title compound
as a white solid (0.055 g): .sup.1H-NMR (CDCl.sub.3) .delta. 2.24
(s, 3H), 4.01 (s, 3H), 6.93 (d, J=8.5 Hz, 1H), 7.01-7.36 (m, 3H),
7.56 (dd, J=2.4, 8.6 Hz, 1H), 7.98 (app t, J=8.6 Hz, 1H), 8.79 (d,
J=2.2 Hz, 1H), 9.07 (s, 1H), 9.26 (s, 1H); FAB-MS m/z 389
((M+1).sup.+).
B3b. General Method for the Reaction of an Aryl Amine with Phosgene
with Isolation of the Isocyanate, Followed by Reaction with a
Second Aryl Amine
##STR00100##
[0321] Step 1. 2-Methoxy-5-trifluoromethylphenyl Isocyanate:
[0322] To a solution of phosgene (1.93 M in toluene; 16 mL, 31.4
mmol) in CH.sub.2Cl.sub.2 (120 mL) at 0.degree. C. was added a
solution of 2-methoxy-5-(trifluoromethyl)aniline (3.0 g, 15.7 mmol)
and pyridine (2.3 mL, 47.1 mmol) in CH.sub.2Cl.sub.2 (30 mL)
dropwise. The resulting mixture was stirred at 0.degree. C. for 30
min and at room temp for 3 h, then concentrated under reduced
pressure. The residue was diluted with toluene (30 mL),
concentrated under reduced pressure, and treated with Et.sub.2O.
The resulting precipitate (pyridinium hydrochloride) was removed
and the filtrate, was concentrated under reduced pressure to give
the title compound as a yellow oil (3.0 g) which crystallized upon
standing at room temp. for a few days.
##STR00101##
[0323] Step 2.
N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-fluorophenyl)urea:
[0324] 4-Fluoroaniline (0.24 mL, 2.53 mmol) was added to a solution
of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.50 g, 2.30
mmol) in EtOAc (6 mL) and the reaction mixture was stirred at room
temp. for 3 d. The resulting precipitate was washed with Et.sub.2O
to give the title compound as a white solid (0.60 g): NMR: 3.94 (s,
3H). 7.13-7.18 (m, 3H), 7.30 (dd, J=1.5, 8.4 Hz, 1H), 7.44 (m, 2H),
8.45 (s, 1H), 8.52 (d, 0.1=2.2 Hz, 1H), 9.42 (s, 1H); FAB-MS m/z
329 ((M+1).sup.+).
B4. General Method for Urea Formation Via Curtius Rearrangement,
Followed By Trapping with an Amine
##STR00102##
[0325] N-(3-Methoxy-2-naphthyl)-N'-(4-methylphenyl)urea:
[0326] To a solution of 3-methoxy-2-naphthoic acid (Method A6, Step
2; 0.762 g, 3.80 mmol) and Et.sub.3N (0.588 mL, 4.2 mmol) in anh
toluene (20 mL) at room temp. was added a solution of
diphenylphosphoryl azide (1.16 g, 4.2 mmol) in toluene (5 mL). The
resulting mixture was heated to 80.degree. C. for 2 h, cooled to
room temp., and p-toluidine (0.455 g, 4.1 mmol) was added. The
mixture was heated at 80.degree. C. overnight, cooled to room
temp., quenched with a 10% citric acid solution, and extracted with
EtOAc (2.times.25 mL). The combined organic layers were washed with
a saturated NaCl solution (25 mL), dried (MgSO.sub.4), and
concentrated in vacuo. The residue was triturated with
CH.sub.2Cl.sub.2 to give the desired urea as white powder (0.700 g,
61%): nip 171-172.degree. C.; .sup.1H-NMR (DMSO-d.sub.6) .delta.
2.22 (s, 3H), 3.99 (s, 3H), 7.07 (d, J---8.49 Hz, 2H), 7.27-7.36
(m, 5H), 7.67-7.72 (m, 2H), 8.43 (s, 1H), 8.57 (s, 1H), 9.33 (s,
1H); FAB-MS m/z 307 ((M+H).sup.+).
B5. General Method for the Reaction of Substituted Aniline with
N,N'-Carbonyldiimidazole Followed by Reaction with a Second
Amine
##STR00103##
[0327]
N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N'-(4-(4-pyridinylmethyl)pheny-
l)urea:
[0328] A solution of 4-(4-pyridinylmethyl)aniline (0.300 g, 1.63
mmol) and N,N'-carbonyldiimidazole (0.268 g, 1.65 mmol) in
CH.sub.2Cl.sub.2 (10 mL) was stirred at room temp. for 1 h at which
time TLC analysis indicated no starting aniline. The reaction
mixture was then treated with 2-amino-4-chloro-5-nitrophenol (0.318
g, 1.65 mmol) and stirred at 40-45.degree. C. for 48 h. The
resulting mixture was cooled to room temp. and diluted with EtOAc
(25 mL). The resulting precipitate was separated to give the
desired product (0.416 g, 64%): TLC (50% acetone/50%
CH.sub.2Cl.sub.2) R.sub.f 0.40; .sup.1H-NMR (DMSO-d.sub.6) .delta.
3.90 (s, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.21 (d, J=6 Hz, 2H), 7.38
(d, J=8.4 Hz, 2H), 7.54 (s, 1H), 8.43-8.45 (m, 3H), 8.78 (s, 1H),
9.56 (s, 1H), 11.8 (br s, 1H); FAB-MS m/z (rel abundance) 399
((M+H).sup.+, 10%).
B6. General Method for the Synthesis of Symmetrical Diphenyl Ureas
as Side-Products of Urea Forming Reactions
##STR00104##
[0330] Bis(4-chloro-3-(trifluoromethyl)phenyl)urea:
[0331] To a solution of 5-amino-3-tert-butylisoxazole (0.100 g) in
anh toluene (5 mL) was added 4-chloro-3-(trifluoromethyl)phenyl
isocyanate (0.395 g). The reaction vessel was sealed, heated at
85.degree. C. for 24 h, and cooled to room temp. The reaction
mixture was added to a slurry of Dowex.RTM. 50WX2-100 resin (0.5 g)
in CH.sub.2Cl.sub.2 (40 mL), and the resulting mixture was stirred
vigorously for 72 h. The mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography (gradient form 100% CH.sub.2Cl.sub.2 to 5%
MeOH/95% CH.sub.2Cl.sub.2) to give
bis(4-chloro-3-(trifluoromethyl)phenyl)urea followed by
N-(3-tert-butyl-5-isoxazolyl)-N'-(4-chloro-3-(trifluoromethyl)phenyl)urea-
. The residue from the symmetrical urea fractions was triturated
(Et.sub.2O/hexane) to give the urea as a white solid (0.110 g): TLC
(3% MeOH/97/0 CH.sub.2Cl.sub.2) R.sub.f 0.55; FAB-MS m/z 417
((M+H).sup.+).
C. Urea Interconversions and Misc. Reactions
C1. General Method for Alkylation of Hydroxyphenyl Ureas
##STR00105##
[0333] Step 1.
N-(2-Hydroxy-5-(trifluoromethylthio)phenyl)-N'-(4-methylphenyl)urea:
[0334] p-Tolyl isocyanate (0.066 mL, 0.52 mmol) was added to a
solution of 2-hydroxy-5-(trifluoromethylthio)aniline (0.100 g, 0.48
mmol) in EtOAc (2 mL) and the reaction mixture was stirred at room
temp. for 2 d. The resulting precipitate was washed with EtOAc to
provide the title compound (0.13 g): .sup.1H-NMR (CDCl.sub.3)
.delta. 2.24 (s, 3H). 7.44-7.03 (m, 6H), 8.46 (s, 1H), 8.60 (d,
J=1.8 Hz, 1H), 9.16 (s, 1H), 10.41 (s, 11-1); FAB-MS m/z 343
((M+1).sup.+). This material was used in the next step without
purification.
##STR00106##
[0335] Step 2.
N-(2-Methoxy-5-(trifluoromethylthio)phenyl)-N'-(4-methylphenyl)urea:
[0336] A solution of
N-(2-hydroxy-5-(trifluoromethylthio)phenyl)-N'-(4-methylphenyl)urea
(0.125 g, 0.36 mmol), iodomethane (0.045 mL, 0.73 mmol), and
K.sub.2CO.sub.3 (100 mg, 0.73 mmol) in acetone (2 mL) was heated at
the reflux temp. for 6 h, then was cooled to room temp. and
concentrated under reduced pressure. The residue was dissolved in a
minimal amount of MeOH, absorbed onto silica gel, and then purified
by flash chromatography (3% Et.sub.2O/97% CH.sub.2Cl.sub.2) to
provide the title compound as a white solid (68 mg): .sup.1H-NMR
(CDCl.sub.3) .delta. 2.22 (s, 3H), 3.92 (s, 3H), 7.05-7.32 (m, 6H),
8.37 (s, 1H), 8.52 (d, J=2.2 Hz, 1H), 9.27 (s, 1H); FAB-MS m/z 357
((M+1).sup.+).
C2. General Method for the Reduction of Nitro-Containing Ureas
##STR00107##
[0338]
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(2-amino-4-methylphenyl)urea:
[0339] A solution of
N-(5-tert-butyl-2-methoxyphenyl)-N'-(2-nitro-4-methylphenyl)urea
(prepared in a manner analogous to Method B1a; 4.0 g, 11.2 mmol) in
EtOH (100 mL) was added to a slurry of 10% Pd/C (0.40 g) in EtOH
(10 mL), and the resulting mixture was stirred under an atmosphere
of H.sub.2 (balloon) at room temp. for 18 h. The mixture was
filtered through a pad of Celite.RTM. and concentrated in vacuo to
afford the desired product (3.42 g, 94%) as a powder: mp
165-166.degree. C.; .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.30 (s,
9H), 2.26 (s, 3H), 3.50 (br s, 2H), 3.71 (s, 3H), 6.39 (br s, 1H),
6.62 (s, 1H), 6.73 (d, J=8.46 Hz, 1H), 6.99 (dd, J=2.21, 8.46 Hz,
1H), 7.05 (d, J=8.46 Hz, 1H), 7.29 (s, 1H), 8.22 (d, J=2.57 Hz,
1H); FAB-MS m/z 328 ((M+H).sup.+).
C3. General Method of Thiourea Formation by Reaction with a
Thioisocyanate
##STR00108##
[0340]
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(1-naphthyl)thiourea:
[0341] To a solution of 5-tert-butyl-2-methoxyaniline (0.372 g,
2.07 mmol) in toluene (5 mL) was added 1-naphthyl thioisocyanate
(0.384 g, 2.07 mmol) and the resulting mixture was allowed to stir
at room temp. for 8 h to produce a precipitate. The solids were
separated and sequentially washed with toluene and hexane to give
the desired product as an off-white powder (0.364 g, 48%): mp
158-160.degree. C.; .sup.113-NMR (DMSO-d.sub.6) .delta. 1.31 (s,
9H), 3.59 (s, 3H), 6.74 (d, J=8.46 Hz, 1H), 7.13 (dd, J=2.21, 8.46
Hz, 1H), 7.53-7.62 (m, 4H), 7.88-7.95 (m, 4H), 8.06-8.08 (m, 1H),
8.09 (br s, 1H); FAB-MS m/z 365 ((M+H).sup.+).
C4. General Method for Deprotection of Cert-Butyl
Carbonate-Containing Ureas
##STR00109##
[0343]
N-(5-tert-Butyl-2-(2-hydroxyethoxy)phenyl)-N'-(4-methylphenyl)urea:
[0344] A solution of
N-(5-tert-butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)phenyl)-N'-(4-methylph-
enyl)urea (Method B1f; 0.237 g, 0.54 mmol) and TFA (0.21 mL, 2.7
mmol) in CH.sub.2Cl.sub.2 (2 mL) was stirred at room temp for 18 h,
then was washed with a saturated NaHCO.sub.3 solution (2 mL). The
organic layer was dried by passing through 1PS filter paper
(Whatman.RTM.) and concentrated under reduced pressure. The
resulting white foam was triturated (Et.sub.2O/hexane), then
recrystallized (Et.sub.2O) to give the desired product (3.7 mg):
TLC (50% EtOAc/50% hexane) R.sub.f 0.62; .sup.1H-NMR (DMSO-d.sub.6)
.delta. 1.22 (s, 9H), 3.75-3.76 (m, 2H), 4.00-4.03 (m, 2H), 4.80
(t, J=5.0 Hz, 1H), 6.88-6.89 (m, 4H), 7.06 (d, J=8.5 Hz, 2H), 7.33
(d, J=8.1 Hz, 2H), 7.97 (s, 1H), 8.20 br s, 1H), 9.14 (s, 1H);
FAB-MS m/z (rel abundance) 343 ((M+H).sup.+, 100%).
[0345] The following compounds have been synthesized according to
the General Methods listed above:
TABLE-US-00001 TABLE 1 2-Substituted-5-tert-butylphenyl Ureas
##STR00110## Ex- am- mp TLC Solvent Mass Synth. ple R.sup.1 R.sup.2
(.degree. C.) R.sub.f System Spec. Source Method 1 OH ##STR00111##
0.54 2% MeOH/ 98% CH2Cl2 299 (M + H)+ FAB B1d 2 OMe ##STR00112##
199- 200 313 (M + H)+ FAB B1d 3 OMe ##STR00113## 208- 209 390 (M+)
EI B1d 4 OMe ##STR00114## 192- 194 389 (M + H)+ FAB B1d 5 OMe
##STR00115## 0.58 50% EtOAc/ 50% hexane 347 (M + H)+ FAB B3b 6 OMe
##STR00116## 0.62 50% EtOAc/ 50% hexane 351 (M + H)+ FAB B3b 7 OMe
##STR00117## 0.71 50% EtOAc/ 50% hexane 331 (M + H)+ FAB B1d 8 OMe
##STR00118## 0.74 50% EtOAc/ 50% hexane 331 (M + H)+ FAB B3b 9 OMe
##STR00119## 0.66 20% EtOAc/ 80% hexane 327 (M + H)+ FAB B1d 10 OMe
##STR00120## 0.62 20% EtOAc/ 80% hexane 331 (M + H)+ FAB B1d 11 OMe
##STR00121## 0.42 13% EtOAc/ 87% hexane 335 (M + H)+ FAB B1d 12 OMe
##STR00122## 0.52 2% MeOH/ 98% CH2Cl2 327 (M + H)+ FAB B1d 13 OMe
##STR00123## 0.56 2% MeOH/ 98% CH2Cl2 335 (M + H)+ FAB B1d 14 OMe
##STR00124## 0.48 2% MeOH/ 98% CH2Cl2 351 (M + H)+ FAB B1d 15 OMe
##STR00125## 0.50 2% MeOH/ 98% CH2Cl2 347 (M + H)+ FAB B1d 16 OMe
##STR00126## 201- 202 390 (M + H)+ FAB B2a 17 OMe ##STR00127## 199-
200 390 (M + H)+ FAB B2a 18 OMe ##STR00128## 198- 199 0.45 25%
EtOAc/ 75% hexane B1a 19 OMe ##STR00129## 181- 182 389 (M + H)+ CI
B2a 20 OMe ##STR00130## 181- 183 390 (M+) EI B1a 21 OMe
##STR00131## 175- 177 358 (M + H)+ FAB B1a 22 OMe ##STR00132## 219-
220 358 (M + H)+ FAB B1a 23 OMe ##STR00133## 165- 166 328 (M + H)+
FAB C2 24 OMe ##STR00134## 102- 104 271 (M + H)+ FAB C2 25 OMe
##STR00135## 236- 238 349 (M + H)+ FAB B1a 26 OMe ##STR00136## 192-
194 367 (M + H)+ FAB B1a 27 OMe ##STR00137## 137- 140 550 (M + H)+
FAB B2a 28 OMe ##STR00138## 197- 199 434 (M + H)+ CI A8, B2a 29 OMe
##STR00139## 212- 215 416 (M + H)+ FAB B2a 30 OMe ##STR00140## 195
405 (M + H)+ FAB B1e 31 OMe ##STR00141## 110 0.07 5% acetone/ 95%
CH2Cl2 408 (M + H)+ FAB B2b 32 OMe ##STR00142## 185 067 5% acetone/
95% CH2Cl2 425 (M + H)+ FAB B2a 33 OMe ##STR00143## 214- 215 0.54
5% acetone/ 95% CH2Cl2 448 (M + H)+ FAB B2a 34 OMe ##STR00144## 180
0.56 5% acetone/ 95% CH2Cl2 421 (M + H)+ FAB B2a 35 ##STR00145##
##STR00146## 0.67 50% EtOAc/ 50% hexane 343 (M + H)+ FAB A10, B1f,
C4 36 ##STR00147## ##STR00148## 0.45 50% EtOAc/ 50% hexane 340 (M +
H)+ FAB B1d 37 ##STR00149## ##STR00150## 222- 223 354 (M + H)+ ES
B1c 38 ##STR00151## ##STR00152## 203- 205 366 (M + H)+ FAB B1d 39
##STR00153## ##STR00154## 230- 232 367 (M + H)+ FAB B1d 40
##STR00155## ##STR00156## 197- 198 406 (M + H)+ FAB A9, B1a 41
##STR00157## ##STR00158## 204- 205 392 (M + H)+ FAB A9, B1a 42
##STR00159## ##STR00160## 217- 218 424 (M + H)+ FAB A9, B1a 43
##STR00161## ##STR00162## 187- 188 370 (M + H)+ FAB A9, B1a 44
##STR00163## ##STR00164## 118- 120 462 (M + H)+ FAB A9, B1a 45
##STR00165## ##STR00166## 146- 148 448 (M + H)+ FAB A9, B1a 46
##STR00167## ##STR00168## 110- 113 480 (M + H)+ FAB A9, B1a 47
##STR00169## ##STR00170## 95- 100 400 (M + H)+ FAB A9, B1a 48
##STR00171## ##STR00172## 107- 110 398 (M + H)+ FAB A9, B1a 49
##STR00173## ##STR00174## 180- 182 472 (M + H)+ FAB A9, B1a 50
##STR00175## ##STR00176## 217- 219 388 (M + H)+ FAB A9, B1a 51
##STR00177## ##STR00178## 116- 120 420 (M + H)+ FAB A9, B1a 52
##STR00179## ##STR00180## 100- 105 406 (M + H)+ FAB A9, B1a 53
##STR00181## ##STR00182## 103- 105 438 (M + H)+ FAB A9, B1a 54
##STR00183## ##STR00184## 118- 120 384 (M + H)+ FAB A9, B1a 55
##STR00185## ##STR00186## 125- 128 394 (M + H)+ FAB A1, B1a 56
##STR00187## ##STR00188## 227- 230 468 (M + H)+ FAB A1, B1a 57
##STR00189## ##STR00190## 154- 156 434 (M + H)+ FAB A1, B1a 58
##STR00191## ##STR00192## 169- 171 373 (M + H)+ FAB A2, B1a 59
##STR00193## ##STR00194## 157- 159 423 (M + H)+ FAB A2, B1a 60
##STR00195## ##STR00196## 229- 231 369 (M + H)+ FAB A2, b1a 61
##STR00197## ##STR00198## 200- 204 468 (M + H)+ FAB B2a 62
##STR00199## ##STR00200## 187- 188 508 (M + H)+ FAB B2a 63
##STR00201## ##STR00202## 204- 206 413 (M + H)+ FAB B1a 64
##STR00203## ##STR00204## 192- 194 389 (M + H)+ FAB A7, B1a 65
##STR00205## ##STR00206## 183- 185 425 (M + H)+ FAB A7, B1a 66
##STR00207## ##STR00208## 159- 160 443 (M + H)+ FAB A7, B1a 67
##STR00209## ##STR00210## 179- 180 411 (M + H)+ FAB A7, B1a 68
##STR00211## ##STR00212## 0.06 10% EtOAc/ 90% hexane 408 (M + H)+
FAB A7, B1a 69 ##STR00213## ##STR00214## 227- 229 377 (M + H)+ FAB
A7, B1a 70 ##STR00215## ##STR00216## 216- 217 381 (M + H)+ FAB A7,
B1a 71 ##STR00217## ##STR00218## 213- 214 431 (M + H)+ FAB A7, B1a
72 ##STR00219## ##STR00220## 200- 201 399 (M + H)+ FAB A7, B1a 73
##STR00221## ##STR00222## 134- 136 443 (M+) EI A7, B1a 74
##STR00223## ##STR00224## 185- 186 459 (M + H)+ FAB A7, B1a 75
##STR00225## ##STR00226## 207- 208 419 (M + H)+ FAB A7, B1a
##STR00227##
TABLE-US-00002 TABLE 2 2-Substituted-5-(trifluoromethyl)phenyl
Ureas ##STR00228## mp TLC Solvent Mass Synth. Example R.sup.1
R.sup.2 (.degree. C.) R.sub.f System Spec. Source Method 76 OMe
##STR00229## 185- 186 325 (M + H)+ FAB B1d 77 OMe ##STR00230## 0.22
20% EtOAc/ 80% hexane 329 (M + H)+ FAB B3b 78 OMe ##STR00231## 0.49
20% EtOAc/ 80% hexane 343 (M + H)+ FAB B3b 79 OMe ##STR00232## 0.32
20% EtOAc/ 80% hexane 343 (M + H)+ FAB B3b 80 OMe ##STR00233## 0.37
20% EtOAc/ 80% hexane 359 (M + H)+ FAB B3b 81 OMe ##STR00234## 0.44
20% EtOAc/ 80% hexane 363 (M + H)+ FAB B3b 82 OMe ##STR00235## 0.68
50% EtOAc/ 50%+ hexane 339 (M + H)+ FAB B1d 83 OMe ##STR00236##
0.68 50% EtOAc/ 50% hexane 343 (M + H)+ FAB B1d 84 OMe ##STR00237##
0.60 50% EtOAc/ 50% hexane 347 (M + H)+ FAB B1d 85 OMe ##STR00238##
0.53 2% MeOH/ 98% CH2Cl2 339 (M + H)+ FAB B1d 86 OMe ##STR00239##
0.29 2% MeOH/ 98% CH2Cl2 347 (M + H)+ FAB B1d 87 OMe ##STR00240##
0.27 2% MeOH/ 98% CH2Cl2 363 (M + H)+ FAB B1d 88 OMe ##STR00241##
0.45 2% MeOH/ 98% CH2Cl2 359 (M + H)+ FAB B1d 89 OMe ##STR00242##
184- 185 401 (M + H)+ FAB B2a 90 OMe ##STR00243## 176- 178 402 (M+)
EI B1a 91 OMe ##STR00244## 231- 233 361 (M + H)+ FAB B1a 92 OMe
##STR00245## 192- 194 379 (M + H)+ FAB B1a 93 OMe ##STR00246## 198
417 (M + H)+ FAB B1e 94 OMe ##STR00247## 206 0.58 5% acetone/ 95%
CH2Cl2 437 (M + H)+ FAB B2a 95 OMe ##STR00248## 98-99 0.50 5%
acetone/ 95% CH2Cl2 B2a 96 OMe ##STR00249## 190 0.65 5% acetone/
95% CH2Cl2 B2a 97 OMe ##STR00250## 194 0.76 5% acetone/ 95% CH2Cl2
464 (M + H)+ FAB B2a 98 OMe ##STR00251## 210- 211 0.07 5% acetone/
95% CH2Cl2 402 (M + H)+ FAB B2a 99 OMe ##STR00252## 202 0.09 5%
acetone/ 95% CH2Cl2 420 (M + H)+ FAB B2a 100 OMe ##STR00253## 215
0.08 5% acetone/ 95% CH2Cl2 420 (M + H)+ FAB B2a 101 OMe
##STR00254## 206 0.05 5% acetone/ 95% CH2Cl2 404 (M + H)+ FAB B2a
102 OMe ##STR00255## 0.78 5% acetone/ 95% CH2Cl2 471 (M + H)+ FAB
B1a 103 OMe ##STR00256## 471 (M + H)+ FAB B1a 104 OMe ##STR00257##
487 (M + H)+ FAB B1a 105 ##STR00258## ##STR00259## 0.65 20% EtOAc/
80% hexane 352 (M + H)+ FAB B1d 106 ##STR00260## ##STR00261## 159-
160 0.33 25% EtOAc/ 75% hexane 353 (M + H)+ FAB A5, B1a 107
##STR00262## ##STR00263## 152- 153 0.35 25% EtOAc/ 75% hexane 339
(M + H)+ FAB A5, B1a 108 SMe ##STR00264## 246- 247 0.30 25% EtOAc/
75% hexane 377 (M + H)+ FAB B1a 109 SMe ##STR00265## 210- 211 0.35
25% EtOAc/ 75% hexane 345 (M + H)+ CI B1a 110 SMe ##STR00266## 195-
196 0.35 25% EtOAc/ 75% hexane 314 (M + H)+ FAB B1a 111 SMe
##STR00267## 196- 197 0.40 25% EtOAc/ 75% hexane 395 (M + H)+ FAB
B1a
TABLE-US-00003 TABLE 3 S-Substituted 2-Methoxy-5-sulfonylphenyl
Ureas ##STR00268## mp TLC Solvent Mass Synth. Example R.sup.2
R.sup.3 (.degree. C.) R.sub.f System Spec. Source Method 112
##STR00269## F 205- 207 339 (M + H)+ HPLC ES-MS B1d 113
##STR00270## CHF.sub.2 195- 196 370 (M+) EI B1d 114 ##STR00271##
CHF.sub.2 0.46 50% EtOAc/ 50% hexane 389 (M + H)+ FAB B3a 115
##STR00272## CHF.sub.2 0.21 50% EtOAc/ 50% hexane 405 (M + H)+ FAB
B3a 116 ##STR00273## CHF.sub.2 0.23 20% EtOAc/ 80% hexane 409 (M +
H)+ FAB B3a 117 ##STR00274## CHF.sub.2 0.40 50% EtOAc/ 50% hexane
389 (M + H)+ FAB B3a 118 ##STR00275## CHF.sub.2 0.53 50% EtOAc/ 50%
hexane 375 (M + H)+ FAB B3a 119 ##STR00276## CHF.sub.2 0.58 50%
EtOAc/ 50% hexane 389 (M + H)+ FAB B1c 120 ##STR00277## CHF.sub.2
0.48 50% EtOAc/ 50% hexane 389 (M + H)+ FAB B1d 121 ##STR00278##
CHF.sub.2 0.44 50% EtOAc/ 50% hexane 393 (M + H)+ FAB B1c 122
##STR00279## CHF.sub.2 0.33 5% MeOH/ 95% CH2Cl2 385 (M + H)+ FAB
B1c 123 ##STR00280## CHF.sub.2 393 (M + H)+ FAB B1c 124
##STR00281## CHF.sub.2 409 (M + H)+ FAB B1c 125 ##STR00282##
CHF.sub.2 405 (M + H)+ FAB B1c 126 ##STR00283## CHF.sub.2 0.56 50%
EtOAc/ 50% hexane 385 (M + H)+ FAB B1c 127 ##STR00284## CF.sub.3
0.56 50% EtOAc/ 50% hexane 389 (M + H)+ FAB A3, B1d
TABLE-US-00004 TABLE 4 3-Substituted-2-naphthyl Ureas ##STR00285##
mp TLC Solvent Mass Synth. Example R.sup.1 R.sup.2 (.degree. C.)
R.sub.f System Spec. Source Method 128 OMe ##STR00286## 171- 172
0.40 25% EtOAc/ 75% hexane 307 (M + H)+ FAB B4 129 OMe ##STR00287##
197- 199 0.40 14% EtOAc/ 86% hexane 325 (M + H)+ FAB B4 130 OMe
##STR00288## 235- 236 0.45 25% EtOAc/ 75% hexane 343 (M + H)+ FAB
A6, B1a 131 OMe ##STR00289## 236- 237 0.45 25% EtOAc/ 75% hexane
311 (M + H)+ FAB A6, B1a 132 OMe ##STR00290## 209- 211 311 (M + H)+
FAB A6, B1a 133 OMe ##STR00291## 225- 226 321 (M + H)+ FAB A6, B1a
134 OMe ##STR00292## 199- 200 395 (M + H)+ FAB A6, B1a 135 OMe
##STR00293## 227- 228 361 (M + H)+ FAB A6, B1a 136 OMe ##STR00294##
207- 208 327 (M + H)+ FAB A6, B1a 137 OMe ##STR00295## 234- 235 361
(M + H)+ FAB A6, B1a 138 OMe ##STR00296## 228- 229 352 (M + H)+ FAB
A6, B1a 139 OMe ##STR00297## 190- 195 323 (M + H)+ FAB A6, B1a 140
OMe ##STR00298## 203- 205 310 (M + H)+ FAB A6, B1a 141 OMe
##STR00299## 209- 210 307 (M + H)+ FAB A6, B1a 142 OMe ##STR00300##
200- 201 323 (M + H)+ FAB A6, B1a 143 OMe ##STR00301## 201- 202 307
(M + H)+ FAB A6, B1a 144 OMe ##STR00302## 216- 218 385 (M + H)+ FAB
A6, B1a 145 OMe ##STR00303## 181- 182 361 (M + H)+ FAB A6, B1a 146
OMe ##STR00304## 238- 239 0.25 25% EtOAc/ 75% hexane 402 (M + H)+
FAB B4 147 OMe ##STR00305## 199- 200 0.20 25% EtOAc/ 75% hexane 384
(M + H)+ FAB B4 148 OMe ##STR00306## 175- 176 321 (M + H)+ FAB A6,
B1a 149 OMe ##STR00307## 164- 166 544 (M + H)+ FAB A6, B1a 150 OMe
##STR00308## 206- 209 446 (M + H)+ FAB A6, B1a 151 OMe ##STR00309##
234- 237 410 (M + H)+ FAB B2a 152 OMe ##STR00310## 209- 211 0.40
25% EtOAc/ 75% hexane 414 (M+) EI B4
TABLE-US-00005 TABLE 5 Misc. Ureas mp TLC Solvent Mass Synth.
Example R.sup.2 (.degree. C.) R.sub.f System Spec. Source Method
153 ##STR00311## 183- 184 327 (M + H)+ FAB B1d 154 ##STR00312##
156- 157 312 (M+) EI B1d 155 ##STR00313## 0.46 50% EtOAc/ 50%
hexane 291 (M + H)+ FAB B1d 156 ##STR00314## 157 ##STR00315## 0.40
50% acetone/ 50% CH2Cl2 399 (M + H)+ FAB B5 158 ##STR00316## 219-
221 336 (M + H)+ FAB B1d 159 ##STR00317## 204- 205 305 (M + H)+ FAB
B1d 160 ##STR00318## 208- 210 302 (M + H)+ FAB B1d 161 ##STR00319##
226- 228 355 (M + H)+ FAB B1d 162 ##STR00320## 160- 162 328 (M +
H)+ FAB B1a 163 ##STR00321## 0.85 50% EtOAc/ 50% hexane 291 (M +
H)+ FAB B1b 164 ##STR00322## 225- 226 0.60 25% EtOAc/ 75% hexane
367 (M + H)+ FAB A4, B1a 165 ##STR00323## 0.55 3% MeOH/ 97% CH2Cl2
417 (M + H)+ FAB B6 166 ##STR00324## 169- 171 407 (M + H)+ FAB B1a
167 ##STR00325## 158- 160 C3 365 (M + H)+ FAB C3
BIOLOGICAL EXAMPLES
P38 Kinase Assay:
[0346] The in vitro inhibitory properties of compounds were
determined using a p38 kinase inhibition assay. P38 activity was
detected using an in vitro kinase assay run in 96-well microliter
plates. Recombinant human p38 (0.5 .mu.g/mL) was mixed with
substrate (myelin basic protein, 5 .mu.g/mL) in kinase buffer (25
mM Hepes, 20 mM MgCl.sub.2 and 150 mM NaCl) and compound. One
.mu.Ci/well of .sup.33P-labeled ATP (10 .mu.M) was added to a final
volume of 100 .mu.L. The reaction was run at 32.degree. C. for 30
min. and stopped with a 1M HCl solution. The amount of
radioactivity incorporated into the substrate was determined by
trapping the labeled substrate onto negatively charged glass fiber
filter paper using a 1% phosphoric acid solution and read with a
scintillation counter. Negative controls include substrate plus ATP
alone.
[0347] All compounds exemplified displayed p38 IC.sub.50s of
between 1 nM and 10 .mu.M.
LPS Induced TNF.alpha. Production in Mice:
[0348] The in vivo inhibitory properties of selected compounds were
determined using a murine LPS induced TNF.alpha. production in vivo
model. BALB/c mice (Charles River Breeding Laboratories; Kingston,
N.Y.) in groups of ten were treated with either vehicle or compound
by the route noted. After one hour, endotoxin (E. coli
lipopolysaccharide (LPS) 100 .mu.g) was administered
intraperitoneally (i.p.). After 90 min, animals were euthanized by
carbon dioxide asphyxiation and plasma was obtained from individual
animals by cardiac puncture ionto heparinized tubes. The samples
were clarified by centrifugation at 12,500.times.g for 5 min at
4.degree. C. The supernatants were decanted to new tubes, which
were stored as needed at -20.degree. C. TNF.alpha. levels in sera
were measured using a commercial murine TNF ELISA kit
(Genzyme).
[0349] The preceeding examples can be repeated with similar success
by substituting the generically of specifically described reactants
and/or operating conditions of this invention for those used in the
preceeding examples
[0350] From the foregoing discussion, 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.
* * * * *