U.S. patent application number 11/839136 was filed with the patent office on 2007-11-29 for cytokine inhibitors.
Invention is credited to Ronald A. Aungst, Derek Cogan, Amy L. Davis, Daniel R. Goldberg, Ming-Hong Hao, Zhaoming Xiong.
Application Number | 20070275946 11/839136 |
Document ID | / |
Family ID | 35229785 |
Filed Date | 2007-11-29 |
United States Patent
Application |
20070275946 |
Kind Code |
A1 |
Aungst; Ronald A. ; et
al. |
November 29, 2007 |
Cytokine Inhibitors
Abstract
Disclosed are compounds of formula (I) ##STR1## which inhibit
production of cytokines involved in inflammatory processes and are
thus useful for treating diseases and pathological conditions
involving inflammation such as chronic inflammatory disease. Also
disclosed are processes for preparing these compounds and
pharmaceutical compositions comprising these compounds.
Inventors: |
Aungst; Ronald A.; (Clifton
Park, NY) ; Cogan; Derek; (Sandy Hook, CT) ;
Davis; Amy L.; (Schoharie, NY) ; Goldberg; Daniel
R.; (Redding, CT) ; Hao; Ming-Hong;
(Ridgefield, CT) ; Xiong; Zhaoming; (Danbury,
CT) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY RD
P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Family ID: |
35229785 |
Appl. No.: |
11/839136 |
Filed: |
August 15, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11119524 |
Apr 29, 2005 |
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11839136 |
Aug 15, 2007 |
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60567693 |
May 3, 2004 |
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Current U.S.
Class: |
514/210.02 ;
514/252.18; 514/253.09; 514/333; 514/339; 540/362; 544/297;
544/364; 546/256; 546/278.1 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 401/12 20130101; A61P 35/00 20180101; A61P 43/00 20180101;
C07D 401/14 20130101 |
Class at
Publication: |
514/210.02 ;
514/252.18; 514/253.09; 514/333; 514/339; 540/362; 544/297;
544/364; 546/256; 546/278.1 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61K 31/444 20060101 A61K031/444; C07D 401/12
20060101 C07D401/12; C07D 401/14 20060101 C07D401/14 |
Claims
1. A compound of the formula (I) ##STR50## wherein: Ar.sup.1 is
chosen from rings (i), (ii) and (iii) below: ##STR51## wherein one
of A or B is nitrogen and the other is carbon, R.sup.1 is
covalently attached to either A or B, and when nitrogen is
N--R.sup.1 the double bond between A and B is not present; R.sub.1
is chosen from hydrogen, NO.sub.2, --N(R.sup.c).sub.2,
J-C(O)--N(R.sup.c)--, J-S(O).sub.m--N(R.sup.c)--, or R.sup.1 is
chosen from C.sub.1-6 alkyl, C.sub.3-7 cylcoalkyl, C.sub.1-5
alkoxyl or C.sub.3-7 cycloalkoxyl, C.sub.1-5 alkylthiol or
C.sub.3-7 cycloalkylthiol, C.sub.1-5 acyl, C.sub.1-5
alkoxycarbonyl, C.sub.1-5 acyloxy, C.sub.1-5 acylamino, C.sub.2-5
alkenyl, C.sub.2-5 alkynyl, heterocycle, heteroaryl and nitrile,
each of the aforementioned where possible are optionally partially
or fully halogenated or are optionally further substituted with
alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,
hydroxyl, oxo, nitro or nitrile; or R.sup.1 is, where P can be O,
>CR.sup.9 or >NR.sup.9 ##STR52## wherein z is 1 to 4; R.sup.9
is chosen from C.sub.1-6 alkyl, C.sub.3-7 cylcoalkyl, C.sub.1-5
alkoxyl or C.sub.3-7 cycloalkoxyl, C.sub.1-5 alkylthiol or
C.sub.3-7 cycloalkylthiol, C.sub.1-5 acyl, C.sub.1-5
alkoxycarbonyl, C.sub.1-5 acyloxy, C.sub.1-5 acylamino, C.sub.2-5
alkenyl, C.sub.2-5 alkynyl, heterocycle, heteroaryl and nitrile,
each of the aforementioned where possible are optionally partially
or fully halogenated or are optionally further substituted with
alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,
hydroxyl, oxo, nitro or nitrile; R.sup.2 is chosen from hydrogen,
halogen, C.sub.1-5 alkyl, C.sub.1-5 alkoxy, C.sub.1-5
alkylC.sub.1-5 alkoxy, hydroxy, hydroxy C.sub.1-5 alkyl, oxo,
C.sub.1-5 alkylS(O).sub.m-- and amino optionally mono- or
di-substituted by C.sub.1-5 alkyl, aryl or aryl C.sub.1-5 alkyl;
##STR53## wherein R.sup.1' is chosen from hydrogen, C.sub.1-5
alkylS(O).sub.m--, C.sub.1-6 alkyl, C.sub.3-7 cylcoalkyl, C.sub.1-5
alkoxyl or C.sub.3-7 cycloalkoxyl, C.sub.1-5 alkylthiol C.sub.3-7
cycloalkylthiol, C.sub.1-5 acyl, C.sub.1-5 alkoxycarbonyl,
C.sub.1-5 acyloxy, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl,
heterocycle, heterocycleC.sub.1-6 alkyl, heteroaryl,
heteroarylC.sub.1-6 alkyl and nitrile, each of the aforementioned
where possible are optionally partially or fully halogenated or are
optionally further substituted with alkylsulfonylamino, alkoxyl,
amino, alkylamino, dialkylamino, hydroxyl, oxo, nitro or nitrile;
R.sup.2' is chosen from nitrile, C.sub.1-5 alkylS(O).sub.m--,
J-O--C(O)--O--, NH.sub.2--C(O)--(CH.sub.2).sub.m--, H, halogen,
C.sub.1-5 alkyl, C.sub.1-5 alkoxy, C.sub.1-5 alkylC.sub.1-5 alkoxy,
hydroxy, hydroxy C.sub.1-5 alkyl and amino optionally mono- or
di-substituted by C.sub.1-5 alkyl, aryl or aryl C.sub.1-5 alkyl;
##STR54## wherein c is a benzo ring fused to ring d which is a 5-7
membered heterocyclic ring; each R.sup.x is chosen from C.sub.1-6
alkyl or C.sub.3-7 cycloalkyl each being optionally substituted by
C.sub.1-3 alkyl and optionally partially or fully halogenated,
C.sub.1-4 acyl, aroyl, C.sub.1-4 alkoxy, which may optionally be
partially or fully halogenated, halogen, C.sub.1-6 alkoxycarbonyl,
carbocyclesulfonyl and --SO.sub.2--CF.sub.3; each J is
independently chosen from C.sub.1-10 alkyl and carbocycle each
optionally substituted by R.sup.b; R.sup.b is chosen from hydrogen,
C.sub.1-5 alkyl, hydroxyC.sub.1-5 alkyl, C.sub.2-5 alkenyl,
C.sub.2-5 alkynyl, carbocycle, heterocycle, heteroaryl, C.sub.1-5
alkoxy, C.sub.1-5 alkylthio, amino, C.sub.1-5 alkylamino, C.sub.1-5
dialkylamino, C.sub.1-5 acyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5
acyloxy, C.sub.1-5 acylamino, each of the aforementioned are
optionally partially or fully halogenated, or R.sup.b is chosen
from C.sub.1-5 alkylsulphonylamino, hydroxy, oxo, halogen, nitro
and nitrile; Q is a N; Y is >CR.sup.pR.sup.v,
--CR.sup.p.dbd.C(R.sup.V)--, --O-- or >S(O).sub.m; each R.sup.c,
R.sup.p, R.sup.V and R.sup.y are each independently hydrogen or
C.sub.1-5 alkyl; X is --CH.sub.2--, --N(R.sup.c)--, --O-- or --S--;
W is N or CH; each m independently 0, 1 or 2; n is 1-4; each
R.sup.3, R.sup.4 and R.sup.5 are independently chosen from
hydrogen, C1-6 alkyl and halogen; R.sup.6 is optionally attached at
a position ortho or meta to the N atom of the indicated ring, and
is chosen from a bond, --O--, --O--(CH.sub.2).sub.1-5--, >C(O),
--NH--, --C(O)--NH--, --S--, C.sub.1-5 alkyl branched or
unbranched, C.sub.2-5 alkenyl, C.sub.1-3 acyl, C.sub.1-3 alkyl(OH),
heterocycle selected from morpholinyl, piperazinyl, piperidinyl,
pyrrolidinyl and tetrahydrofuranyl, heteroaryl selected from
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, thiazolyl,
oxazolyl and isothiazolyl or aryl each alkyl, alkenyl, acyl,
heterocycle, heteroaryl and aryl are optionally substituted by one
to three hydroxy, oxo, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-5
alkoxycarbonyl, --NR.sup.7R.sup.8 or NR.sup.7R.sup.8--C(O)--;
wherein each R.sup.6 is further optionally covalently attached to
groups chosen from: hydrogen, NR.sup.7R.sup.8, C.sub.1-3 alkyl,
C.sub.3-6 cycloalkylC.sub.0-2alkyl, hydroxy, C.sub.1-3 alkoxy,
phenoxy, benzyloxy, arylC.sub.0-4 alkyl, heteroaryl C.sub.0-4 alkyl
and heterocycle C.sub.0-4alkyl, each above-listed heterocycle,
heteroaryl and aryl group is optionally substituted by one to three
hydroxy, oxo, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, C.sub.1-5
alkoxycarbonyl, NR.sup.7R.sup.8--C(O)-- or C.sub.1-4 acyl; each
R.sup.7 and R.sup.8 are independently hydrogen,
phenylC.sub.0-3alkyl optionally substituted by halogen, C.sub.1-3
alkyl or diC.sub.1-5 alkyl amino, or R.sup.7 and R.sup.8 are
C.sub.1-2 acyl, benzoyl or C.sub.1-5 branched or unbranched alkyl
optionally substituted by C.sub.1-4 alkoxy, hydroxy or mono or
diC.sub.1-3 alkyl amino; or the pharmaceutically acceptable salts
and/or isomers thereof.
2. The compound according to claim 1 and wherein: if Ar.sup.1 is
(i) then: R.sup.1 is chosen from hydrogen, C.sub.1-6 alkyl,
C.sub.3-7 cylcoalkyl, C.sub.1-5 alkoxyl and nitrile, each of the
aforementioned where possible are optionally partially or fully
halogenated or are optionally further substituted with
alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,
hydroxyl, oxo, nitro or nitrile; R.sup.2 is chosen from hydrogen,
halogen, C.sub.1-5 alkyl, C.sub.1-5 alkoxy, C.sub.1-5
alkylC.sub.1-5 alkoxy, hydroxy, hydroxy C.sub.1-5 alkyl, oxo,
C.sub.1-5 alkylS(O).sub.m-- and amino optionally mono- or
di-substituted by C.sub.1-5 alkyl, phenyl or phenyl C.sub.1-5
alkyl; if Ar.sup.1 is (ii) then: R.sup.1' is chosen from H,
C.sub.1-6 alkyl, C.sub.1-5 alkylS(O).sub.m--, C.sub.1-5 alkoxyl
C.sub.1-5 alkylthiol, NH.sub.2--C(O)--(CH.sub.2).sub.n--,
heterocycle, heterocycleC.sub.1-6 alkyl, heteroaryl and nitrile,
each of the aforementioned where possible are optionally partially
or fully halogenated or are optionally further substituted with
alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,
hydroxyl, oxo, nitro and nitrile; R.sup.2' is chosen from C.sub.1-5
alkylS(O).sub.m--, J-O--C(O)--O--, C.sub.1-5 alkyl and C.sub.1-5
alkoxy; or if Ar.sup.1 is (iii) then: ring d is a 5-6 membered
heterocyclic ring; and z is 1 to 2.
3. The compound according to claim 2 and wherein: if Ar.sup.1 is
(i) then: R.sup.1 is chosen from hydrogen, C.sub.1-6 alkyl or
nitrile; R.sup.2 is chosen from hydrogen, halogen, C.sub.1-5 alkyl,
C.sub.1-5 alkoxy, oxo or C.sub.1-5 alkylS(O).sub.m--; if Ar.sup.1
is (ii) then: R.sup.1' is chosen from hydrogen, C.sub.1-6 alkyl,
C.sub.1-5 alkylS(O).sub.m--, C.sub.1-5 alkoxyl C.sub.1-5
alkylthiol, NH.sub.2--C(O)--(CH.sub.2).sub.n--, morpholino
C.sub.1-6 alkyl, heteroaryl chosen from pyrazole, triazole,
imidazole and tetrazole, and nitrile; R.sup.2' is chosen from
C.sub.1-5 alkylS(O).sub.m--, J-O--C(O)--O--, C.sub.1-5 alkyl and
C.sub.1-5 alkoxy; or if Ar.sup.1 is (iii) then: ring d is a 5-6
membered heterocyclic ring such that rings c and d fuse to form the
following: ##STR55## where each R is independently H or C.sub.1-3
alkyl.
4. The compound according to claim 3 and wherein: J is chosen from
C.sub.1-10 alkyl, aryl and C.sub.3-7 cycloalkyl each optionally
substituted by R.sup.b; R.sup.x is independently chosen from
C.sub.1-6 alkyl which may optionally be partially or fully
halogenated, C.sub.3-6 cycloalkyl optionally substituted by
C.sub.1-3 alkyl and optionally partially or fully halogenated,
acetyl, aroyl, C.sub.1-4 alkoxy, which may optionally be partially
or fully halogenated, halogen, methoxycarbonyl, phenylsulfonyl and
--SO.sub.2--CF.sub.3; R.sup.b is chosen from hydrogen, C.sub.1-5
alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, C.sub.3-8
cycloalkylC.sub.0-2 alkyl, aryl, C.sub.1-5 alkoxy, C.sub.1-5
alkylthio, amino, C.sub.1-5 alkylamino, C.sub.1-5 dialkylamino,
C.sub.1-5 acyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 acyloxy,
C.sub.1-5 acylamino, C.sub.1-5 sulphonylamino, hydroxy, halogen,
trifluoromethyl, nitro, nitrile, or R.sup.b is chosen from
heterocycle chosen from pyrrolidinyl, pyrrolinyl, morpholinyl,
thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl
sulfone, dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone,
1,3-dioxanone, 1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl,
pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene
sulfone, tetramethylene sulfide, tetramethylene sulfoxide and
tetramethylene sulfone and heteroaryl chosen from aziridinyl,
thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl,
tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl,
indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,
benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl,
triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl,
pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,
oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl; and R.sup.7 is
hydrogen.
5. The compound according to claim 4 and wherein: Y is --O-- or
--S--; X is --N(R.sup.a)-- or --O--; each R.sup.3, R.sup.4 and
R.sup.5 are hydrogen; R.sup.b is chosen from hydrogen, C.sub.1-5
alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, C.sub.3-8
cycloalkylC.sub.0-2 alkyl, aryl, C.sub.1-5 alkoxy, C.sub.1-5
alkylthio, amino, C.sub.1-5 alkylamino, C.sub.1-5 dialkylamino,
C.sub.1-5 acyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 acyloxy,
C.sub.1-5 acylamino, C.sub.1-5 sulphonylamino, hydroxy, halogen,
trifluoromethyl, nitro, nitrile or R.sup.b is chosen from;
heterocycle chosen from pyrrolidinyl, pyrrolinyl, morpholinyl,
thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl
sulfone, dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone,
1,3-dioxanone, 1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl,
pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene
sulfone, tetramethylene sulfide, tetramethylene sulfoxide and
tetramethylene sulfone and heteroaryl chosen from aziridinyl,
thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl,
tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl,
indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,
benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl,
triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl,
pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,
oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl.
6. The compound according to claim 5 and wherein: R.sup.6 is
present, and is chosen from a bond, --O--,
--O--(CH.sub.2).sub.1-5--, --NH--, --C(O)--NH--, C.sub.1-5 alkyl
branched or unbranched, C.sub.2-5 alkenyl, C.sub.1-3 alkyl(OH),
heterocycle selected from morpholinyl, piperazinyl, piperidinyl,
pyrrolidinyl and tetrahydrofuranyl, or aryl chosen from phenyl and
naphthyl, each alkyl, alkenyl, heterocycle and aryl are optionally
substituted by one to three hydroxy, C.sub.1-3 alkyl, C.sub.1-3
alkoxy, mono or diC.sub.1-3 alkyl amino, amino or C.sub.1-5
alkoxycarbonyl; wherein each R.sup.6 is further optionally
covalently attached to groups chosen from: hydrogen,
NR.sup.7R.sup.8, C.sub.1-3 alkyl, C.sub.3-6
cycloalkylC.sub.0-2alkyl, hydroxy, C.sub.1-3 alkoxy, phenoxy,
benzyloxy, phenylC.sub.0-4 alkyl, piperazinylC.sub.0-4 alkyl,
piperidinyl C.sub.0-4alkyl, pyrrolidinylC.sub.0-4 alkyl,
morpholinylC.sub.0-4 alkyl, tetrahydrofuranylC.sub.0-4 alkyl,
triazolyl C.sub.0-4alkyl, imidazolyl C.sub.0-4alkyl and pyridinyl
C.sub.0-4alkyl, each above listed heterocycle, heteroaryl and
phenyl group is optionally substituted by one to three hydroxy,
oxo, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, C.sub.1-5 alkoxycarbonyl,
--NR.sup.7R.sup.8, NR.sup.7R.sup.8--C(O)-- or C.sub.1-4 acyl; each
R.sup.7 and R.sup.8 are independently hydrogen,
phenylC.sub.0-3alkyl optionally substituted by halogen, C.sub.1-3
alkyl or diC.sub.1-5 alkyl amino, or R.sup.7 and R.sup.8 are
C.sub.1-2 acyl, benzoyl or C.sub.1-5 branched or unbranched alkyl
optionally substituted by C.sub.1-4 alkoxy, hydroxy or mono or
diC.sub.1-3 alkyl amino.
7. The compound according to any one of claims 1-6 and wherein: if
Ar.sup.1 is (i), then Ar.sup.1 is: ##STR56## ##STR57## if Ar.sup.1
is (ii), then Ar.sup.1 is: ##STR58## ##STR59## ##STR60## where R in
these structures is C.sub.1-5alkyl.
8. A pharmaceutical composition containing a pharmaceutically
effective amount of a compound according to claim 1 and one or more
pharmaceutically acceptable carriers and/or adjuvants.
9. A method of treating an oncological disease comprising
administering to a patient a pharmaceutically effective amount of a
compound according to claim 1.
10. A method of treating a disease or condition chosen from
osteoarthritis, atherosclerosis, contact dermatitis, bone
resorption diseases, reperfusion injury, asthma, multiple
sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative
colitis, psoriasis, graft versus host disease, systemic lupus
erythematosus, insulin-dependent diabetes mellitus, rheumatoid
arthritis, toxic shock syndrome, Alzheimer's disease, diabetes,
inflammatory bowel diseases, acute and chronic pain, stroke,
myocardial infarction alone or following thrombolytic therapy,
thermal injury, adult respiratory distress syndrome (ARDS),
multiple organ injury secondary to trauma, acute
glomerulonephritis, dermatoses with acute inflammatory components,
acute purulent meningitis, syndromes associated with hemodialysis,
leukopherisis, granulocyte transfusion associated syndromes,
necrotizing enterocolitis, restenosis following percutaneous
transluminal coronary angioplasty, traumatic arthritis, sepsis,
chronic obstructive pulmonary disease and congestive heart failure,
said method comprising administering to a patient a
pharmaceutically effective amount of a compound according to claim
1.
Description
APPLICATION DATA
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/119,524, filed Apr. 29, 2005 the entirety
of which is incorporated herein by reference, and claims benefit of
U.S. Provisional Application No. 60/567,693, filed May 3, 2004.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] This invention relates to compounds of formula (I)
##STR2##
[0004] The compounds of the invention inhibit production of
cytokines involved in inflammatory processes and are thus useful
for treating diseases and pathological conditions involving
inflammation such as chronic inflammatory disease. This invention
also relates to processes for preparing these compounds and to
pharmaceutical compositions comprising these compounds.
[0005] 2. Background Information
[0006] Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are
important biological entities collectively referred to as
proinflammatory cytokines which play a role in cytokine mediated
diseases. These, along with several other related molecules,
mediate the inflammatory response associated with the immunological
recognition of infectious agents. The inflammatory response plays
an important role in limiting and controlling pathogenic
infections.
[0007] Elevated levels of proinflammatory cytokines are also
associated with a number of diseases of autoimmunity such as toxic
shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and
inflammatory bowel disease (Dinarello, C. A., et al., 1984, Rev.
Infect. Disease 6:51). In these diseases, chronic elevation of
inflammation exacerbates or causes much of the pathophysiology
observed. For example, rheumatoid synovial tissue becomes invaded
with inflammatory cells that result in destruction to cartilage and
bone (Koch, A. E., et al., 1995, J. Invest. Med. 43: 28-38).
Studies suggest that inflammatory changes mediated by cytokines may
be involved in endothelial cell pathogenesis including restenosis
after percutaneous transluminal coronary angioplasty (PTCA)
(Tashiro, H., et al., 2001 March, Coron Artery Dis 12(2):107-13).
An important and accepted therapeutic approach for potential drug
intervention in these diseases is the reduction of proinflammatory
cytokines such as TNF (also referred to in its secreted cell-free
form as TNF.alpha.) and IL-1.beta.. A number of anti-cytokine
therapies are currently in clinical trials. Efficacy has been
demonstrated with a monoclonal antibody directed against TNF.alpha.
in a number of autoimmune diseases (Heath, P., "CDP571: An
Engineered Human IgG4 Anti-TNF.alpha. Antibody" IBC Meeting on
Cytokine Antagonists, Philadelphia, Pa., Apr. 24-5, 1997). These
include the treatment of rheumatoid arthritis, Crohn's disease and
ulcerative colitis (Rankin, E. C. C., et al., 1997, British J.
Rheum. 35: 334-342 and Stack, W. A., et al., 1997, Lancet 349:
521-524). The monoclonal antibody is thought to function by binding
to both soluble TNF.alpha. and to membrane bound TNF.
[0008] A soluble TNF.alpha. receptor has been engineered that
interacts with TNF.alpha.. The approach is similar to that
described above for the monoclonal antibodies directed against
TNF.alpha.; both agents bind to soluble TNF.alpha., thus reducing
its concentration. One version of this construct, called Enbrel
(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase
III clinical trial for the treatment of rheumatoid arthritis
(Brower et al., 1997, Nature Biotechnology 15: 1240). Another
version of the TNF.alpha. receptor, Ro 45-2081 (Hoffman-LaRoche
Inc., Nutley, N.J.) has demonstrated efficacy in various animal
models of allergic lung inflammation and acute lung injury. Ro
45-2081 is a recombinant chimeric molecule constructed from the
soluble 55 kDa human TNF receptor fused to the hinge region of the
heavy chain IgG1 gene and expressed in eukaryotic cells (Renzetti,
et al., 1997, Inflamm. Res. 46: S143).
[0009] IL-1 has been implicated as an immunological effector
molecule in a large number of disease processes. IL-1 receptor
antagonist (IL-1ra) had been examined in human clinical trials.
Efficacy has been demonstrated for the treatment of rheumatoid
arthritis (Antril, Amgen). In a phase III human clinical trial
IL-1ra reduced the mortality rate in patients with septic shock
syndrome (Dinarello, 1995, Nutrution 11, 492). Osteoarthritis is a
slow progressive disease characterized by destruction of the
articular cartilage. IL-1 is detected in synovial fluid and in the
cartilage matrix of osteoarthritic joints. Antagonists of IL-1 have
been shown to diminish the degradation of cartilage matrix
components in a variety of experimental models of arthritis
(Chevalier, 1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO)
is a mediator of cardiovascular homeostasis, neurotransmission and
immune function; recently it has been shown to have important
effects in the modulation of bone remodeling. Cytokines such as
IL-1 and TNF are potent stimulators of NO production. NO is an
important regulatory molecule in bone with effects on cells of the
osteoblast and osteoclast lineage (Evans, et al., 1996, J Bone
Miner Res. 11, 300). The promotion of beta-cell destruction leading
to insulin dependent diabetes mellitus shows dependence on IL-1.
Some of this damage may be mediated through other effectors such as
prostaglandins and thromboxanes. IL-1 can effect this process by
controlling the level of both cyclooxygenase II and inducible
nitric oxide synthetase expression (McDaniel et al., 1996, Proc Soc
Exp Biol Med. 211, 24).
[0010] Inhibitors of cytokine production are expected to block
inducible cyclooxygenase (COX-2) expression. COX-2 expression has
been shown to be increased by cytokines and it is believed to be
the isoform of cyclooxygenase responsible for inflammation (M. K.
O'Banion et al., Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.)
Accordingly, inhibitors of cytokines such as IL-1 would be expected
to exhibit efficacy against those disorders currently treated with
COX inhibitors such as the familiar NSAIDs. These disorders include
acute and chronic pain as well as symptoms of inflammation and
cardiovascular disease.
[0011] Elevation of several cytokines have been demonstrated during
active inflammatory bowel disease (IBD). A mucosal imbalance of
intestinal IL-1 and IL-1ra is present in patients with IBD.
Insufficient production of endogenous IL-1ra may contribute to the
pathogenesis of IBD (Cominelli, et al., 1996, Aliment Pharmacol
Ther. 10, 49). Alzheimer disease is characterized by the presence
of beta-amyloid protein deposits, neurofibrillary tangles and
cholinergic dysfunction throughout the hippocampal region. The
structural and metabolic damage found in Alzheimer disease is
possibly due to a sustained elevation of IL-1 (Holden, et al.,
1995, Med Hypotheses, 45, 559). A role for IL-1 in the pathogenesis
of human immunodeficiency virus (HIV) has been identified. IL-1ra
showed a clear relationship to acute inflammatory events as well as
to the different disease stages in the pathophysiology of HIV
infection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54). IL-1
and TNF are both involved in periodontal disease. The destructive
process associated with periodontal disease may be due to a
disregulation of both IL-1 and TNF (Howells, 1995, Oral Dis. 1,
266).
[0012] Proinflammatory cytokines such as TNF.alpha. and IL-1.alpha.
are also important mediators of septic shock and associated
cardiopulmonary dysfunction, acute respiratory distress syndrome
(ARDS) and multiple organ failure. In a study of patients
presenting at a hospital with sepsis, a correlation was found
between TNF.alpha. and IL-6 levels and septic complications
(Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNF.alpha. has
also been implicated in cachexia and muscle degradation, associated
with HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85,
289). Obesity is associated with an increase incidence of
infection, diabetes and cardiovascular disease. Abnormalities in
TNF.alpha. expression have been noted for each of the above
conditions (Loffreda, et al., 1998, FASEB J. 12, 57). It has been
proposed that elevated levels of TNF.alpha. are involved in other
eating related disorders such as anorexia and bulimia nervosa.
Pathophysiological parallels are drawn between anorexia nervosa and
cancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). An
inhibitor of TNF.alpha. production, HU-211, was shown to improve
the outcome of closed brain injury in an experimental model
(Shohami, et al., 1997, J Neuroimmunol. 72, 169). Atherosclerosis
is known to have an inflammatory component and cytokines such as
IL-1 and TNF have been suggested to promote the disease. In an
animal model an IL-1 receptor antagonist was shown to inhibit fatty
streak formation (Elhage et al., 1998, Circulation, 97, 242).
[0013] TNF.alpha. levels are elevated in airways of patients with
chronic obstructive pulmonary disease and it may contribute to the
pathogenesis of this disease (M. A. Higham et al., 2000, Eur.
Respiratory J., 15, 281). Circulating TNF.alpha. may also
contribute to weight loss associated with this disease (N.
Takabatake et al., 2000, Amer. J. Resp. & Crit. Care Med., 161
(4 Pt 1), 1179). Elevated TNF.alpha. levels have also been found to
be associated with congestive heart failure and the level has been
correlated with severity of the disease (A. M. Feldman et al.,
2000, J. Amer. College of Cardiology, 35, 537). In addition,
TNF.alpha. has been implicated in reperfusion injury in lung
(Borjesson et al., 2000, Amer. J. Physiol., 278, L3-12), kidney
(Lemay et al., 2000, Transplantation, 69, 959), and the nervous
system (Mitsui et al., 1999, Brain Res., 844, 192).
[0014] TNF.alpha. is also a potent osteoclastogenic agent and is
involved in bone resorption and diseases involving bone resorption
(Abu-Amer et al., 2000, J. Biol. Chem., 275, 27307). It has also
been found highly expressed in chondrocytes of patients with
traumatic arthritis (Melchiorri et al., 2000, Arthritis and
Rheumatism, 41, 2165). TNF.alpha. has also been shown to play a key
role in the development of glomerulonephritis (Le Hir et al., 1998,
Laboratory Investigation, 78, 1625).
[0015] The abnormal expression of inducible nitric oxide synthetase
(iNOS) has been associated with hypertension in the spontaneously
hypertensive rat (Chou et al., 1998, Hypertension, 31, 643). IL-1
has a role in the expression of iNOS and therefore may also have a
role in the pathogenesis of hypertension (Singh et al., 1996, Amer.
J. Hypertension, 9, 867).
[0016] IL-1 has also been shown to induce uveitis in rats which
could be inhibited with IL-1 blockers. (Xuan et al., 1998, J.
Ocular Pharmacol. and Ther., 14, 31). Cytokines including IL-1, TNF
and GM-CSF have been shown to stimulate proliferation of acute
myelogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65).
IL-1 was shown to be essential for the development of both irritant
and allergic contact dermatitis. Epicutaneous sensitization can be
prevented by the administration of an anti-IL-1 monoclonal antibody
before epicutaneous application of an allergen (Muller, et al.,
1996, Am J Contact Dermat. 7, 177). Data obtained from IL-1 knock
out mice indicates the critical involvement in fever for this
cytokine (Kluger et al., 1998, Clin Exp Pharmacol Physiol. 25,
141). A variety of cytokines including TNF, IL-1, IL-6 and IL-8
initiate the acute-phase reaction which is stereotyped in fever,
malaise, myalgia, headaches, cellular hypermetabolism and multiple
endocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62,
813). The production of these inflammatory cytokines rapidly
follows trauma or pathogenic organism invasion.
[0017] Other proinflammatory cytokines have been correlated with a
variety of disease states. IL-8 correlates with influx of
neutrophils into sites of inflammation or injury. Blocking
antibodies against IL-8 have demonstrated a role for IL-8 in the
neutrophil associated tissue injury in acute inflammation (Harada
et al., 1996, Molecular Medicine Today 2, 482). Therefore, an
inhibitor of IL-8 production may be useful in the treatment of
diseases mediated predominantly by neutrophils such as stroke and
myocardial infarction, alone or following thrombolytic therapy,
thermal injury, adult respiratory distress syndrome (ARDS),
multiple organ injury secondary to trauma, acute
glomerulonephritis, dermatoses with acute inflammatory components,
acute purulent meningitis or other central nervous system
disorders, hemodialysis, leukopherisis, granulocyte transfusion
associated syndromes, and necrotizing enterocolitis.
[0018] Rhinovirus triggers the production of various
proinflammatory cytokines, predominantly IL-8, which results in
symptomatic illnesses such as acute rhinitis (Winther et al., 1998,
Am J Rhinol. 12, 17).
[0019] Other diseases that are effected by IL-8 include myocardial
ischemia and reperfusion, inflammatory bowel disease and many
others.
[0020] The proinflammatory cytokine IL-6 has been implicated with
the acute phase response. IL-6 is a growth factor in a number in
oncological diseases including multiple myeloma and related plasma
cell dyscrasias (Treon, et al., 1998, Current Opinion in Hematology
5: 42). It has also been shown to be an important mediator of
inflammation within the central nervous system. Elevated levels of
IL-6 are found in several neurological disorders including AIDS
dementia complex, Alzheimer's disease, multiple sclerosis, systemic
lupus erythematosus, CNS trauma and viral and bacterial meningitis
(Gruol, et al., 1997, Molecular Neurobiology 15: 307). IL-6 also
plays a significant role in osteoporosis. In murine models it has
been shown to effect bone resorption and to induce osteoclast
activity (Ershler et al., 1997, Development and Comparative
Immunol. 21: 487). Marked cytokine differences, such as IL-6
levels, exist in vivo between osteoclasts of normal bone and bone
from patients with Paget's disease (Mills, et al., 1997, Calcif
Tissue Int. 61, 16). A number of cytokines have been shown to be
involved in cancer cachexia. The severity of key parameters of
cachexia can be reduced by treatment with anti IL-6 antibodies or
with IL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins
Mol. Ther. 1, 107). Several infectious diseases, such as influenza,
indicate IL-6 and IFN alpha as key factors in both symptom
formation and in host defense (Hayden, et al., 1998, J Clin Invest.
101, 643). Overexpression of IL-6 has been implicated in the
pathology of a number of diseases including multiple myeloma,
rheumatoid arthritis, Castleman's disease, psoriasis and
post-menopausal osteoporosis (Simpson, et al., 1997, Protein Sci.
6, 929). Compounds that interfered with the production of cytokines
including IL-6, and TNF were effective in blocking a passive
cutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem.,
41, 1050).
[0021] GM-CSF is another proinflammatory cytokine with relevance to
a number of therapeutic diseases. It influences not only
proliferation and differentiation of stem cells but also regulates
several other cells involved in acute and chronic inflammation.
Treatment with GM-CSF has been attempted in a number of disease
states including burn-wound healing, skin-graft resolution as well
as cytostatic and radiotherapy induced mucositis (Masucci, 1996,
Medical Oncology 13: 149). GM-CSF also appears to play a role in
the replication of human immunodeficiency virus (HIV) in cells of
macrophage lineage with relevance to AIDS therapy (Crowe et al.,
1997, Journal of Leukocyte Biology 62, 41). Bronchial asthma is
characterised by an inflammatory process in lungs. Involved
cytokines include GM-CSF amongst others (Lee, 1998, J R Coll
Physicians Lond 32, 56).
[0022] Interferon .gamma. (IFN .gamma.) has been implicated in a
number of diseases. It has been associated with increased collagen
deposition that is a central histopathological feature of
graft-versus-host disease (Parkman, 1998, Curr Opin Hematol. 5,
22). Following kidney transplantation, a patient was diagnosed with
acute myelogenous leukemia. Retrospective analysis of peripheral
blood cytokines revealed elevated levels of GM-CSF and IFN .gamma..
These elevated levels coincided with a rise in peripheral blood
white cell count (Burke, et al., 1995, Leuk Lymphoma. 19, 173). The
development of insulin-dependent diabetes (Type 1) can be
correlated with the accumulation in pancreatic islet cells of
T-cells producing IFN .gamma. (Ablumunits, et al., 1998, J
Autoimmun. 11, 73). IFN .gamma. along with TNF, IL-2 and IL-6 lead
to the activation of most peripheral T-cells prior to the
development of lesions in the central nervous system for diseases
such as multiple sclerosis (MS) and AIDS dementia complex (Martino
et al., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result
in arterial disease that can lead to cardiac and cerebral
infarction. Many activated immune cells are present in these
lesions, mainly T-cells and macrophages. These cells produce large
amounts of proinflammatory cytokines such as TNF, IL-1 and IFN
.gamma.. These cytokines are thought to be involved in promoting
apoptosis or programmed cell death of the surrounding vascular
smooth muscle cells resulting in the atherosclerotic lesions (Geng,
1997, Heart Vessels Suppl 12, 76). Allergic subjects produce mRNA
specific for IFN .gamma. following challenge with Vespula venom
(Bonay, et al., 1997, Clin Exp Immunol. 109, 342). The expression
of a number of cytokines, including IFN .gamma. has been shown to
increase following a delayed type hypersensitivity reaction thus
indicating a role for IFN .gamma. in atopic dermatitis
(Szepietowski, et al., 1997, Br J Dermatol. 137, 195).
Histopathologic and immunohistologic studies were performed in
cases of fatal cerebral malaria. Evidence for elevated IFN .gamma.
amongst other cytokines was observed indicating a role in this
disease (Udomsangpetch et al., 1997, Am J Trop Med. Hyg. 57, 501).
The importance of free radical species in the pathogenesis of
various infectious diseases has been established. The nitric oxide
synthesis pathway is activated in response to infection with
certain viruses via the induction of proinflammatory cytokines such
as IFN .gamma. (Akaike, et al., 1998, Proc Soc Exp Biol Med. 217,
64). Patients, chronically infected with hepatitis B virus (HBV)
can develop cirrhosis and hepatocellular carcinoma. Viral gene
expression and replication in HBV transgenic mice can be suppressed
by a post-transcriptional mechanism mediated by IFN A, TNF and IL-2
(Chisari, et al., 1995, Springer Semin Immunopathol 17, 261). IFN
.gamma. can selectively inhibit cytokine induced bone resorption.
It appears to do this via the intermediacy of nitric oxide (NO)
which is an important regulatory molecule in bone remodeling. NO
may be involved as a mediator of bone disease for such diseases as:
rheumatoid arthritis, tumor associated osteolysis and
postmenopausal osteoporosis (Evans, et al., 1996, J Bone Miner Res.
11, 300). Studies with gene deficient mice have demonstrated that
the IL-12 dependent production of IFN .gamma. is critical in the
control of early parasitic growth. Although this process is
independent of nitric oxide the control of chronic infection does
appear to be NO dependent (Alexander et al., 1997, Philos Trans R
Soc Lond B Biol Sci 352, 1355). NO is an important vasodilator and
convincing evidence exists for its role in cardiovascular shock
(Kilboum, et al., 1997, Dis Mon. 43, 277). IFN .gamma. is required
for progression of chronic intestinal inflammation in such diseases
as Crohn's disease and inflammatory bowel disease (IBD) presumably
through the intermediacy of CD4+ lymphocytes probably of the TH1
phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). An
elevated level of serum IgE is associated with various atopic
diseases such as bronchial asthma and atopic dermatitis. The level
of IFN .gamma. was negatively correlated with serum IgE suggesting
a role for IFN .gamma. in atopic patients (Teramoto et al., 1998,
Clin Exp Allergy 28, 74).
[0023] WO 01/01986 discloses particular compounds alleged to having
the ability to inhibit TNF-alpha. Certain compounds disclosed in WO
01/01986 are indicated to be effective in treating the following
diseases: dementia associated with HIV infection, glaucoma,
optic-neuropathy, optic neuritis, retinal ischemia, laser induced
optic damage, surgery or trauma-induced proliferative
vitreoretinopathy, cerebral ischemia, hypoxia-ischemia,
hypoglycemia, domoic acid poisoning, anoxia, carbon monoxide or
manganese or cyamide poisoning, Huntington's disease, Alzheimer's
disease, Parkinson's disease, meningitis, multiple sclerosis and
other demyelinating diseases, amyotrophic lateral sclerosis, head
and spinal cord trauma, seizures, convulsions, olivopontocerebellar
atrophy, neuropathic pain syndromes, diabetic neuropathy,
HIV-related neuropathy, MERRF and MELAS syndromes, Leber's disease,
Wernicke's encephalophathy, Rett syndrome, homocysteinuria,
hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia,
hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined
systems disease, lead encephalopathy, Tourett's syndrome, hepatic
encephalopathy, drug addiction, drug tolerance, drug dependency,
depression, anxiety and schizophrenia. WO 02/32862 discloses that
inhibitors of pro-inflammatory cytokines including TNF.alpha. are
allegedly useful for treating acute and chronic inflammation in the
lung caused by inhalation of smoke such as cigarette smoke.
TNF.alpha. anatagonists are apparently also useful for the
treatment of endometriosis, see EP 1022027 A1. Infliximab, in
clinical trials for RA, has also been indicated to be useful for
treating various inflammatory diseases including Behcet's disease,
uveitis and ankylosing spondylitis. Pancreatitis may also be
regulated by inflammatory mediator production, see J Surg Res 2000
May 15 90(2)95-101; Shock 1998 Sep. 10(3):160-75. p38MAP kinase
pathway plays an role in B. burgdorferi-elicited inflammation and
may be useful in treating inflammation induced by the Lyme disease
agent. Anguita, J. et. al., The Journal of Immunology, 2002,
168:6352-6357.
[0024] Compounds which modulate release of one or more of the
aforementioned inflammatory cytokines can be useful in treating
diseases associated with release of these cytokines. For example,
WO 98/52558 discloses heteroaryl urea compounds which are indicated
to be useful in treating cytokine mediated diseases. WO 99/23091
discloses another class of urea compounds which are useful as
anti-inflammatory agents. WO 99/32463 relates to aryl ureas and
their use in treating cytokine diseases and proteolytic enzyme
mediated disease. WO 00/41698 discloses aryl ureas said to be
useful in treating p38 MAP kinase diseases.
[0025] Compounds active against p38 MAP kinase can also be useful
for treating various types of cancers as described in WO
03/068223.
[0026] U.S. Pat. No. 5,162,360 discloses N-substituted
aryl-N'-heterocyclic substituted urea compounds which are described
as being useful for treating hypercholesterolemia and
atherosclerosis. Di-substituted aryl and heteroaryl compounds are
also disclosed in U.S. Pat. Nos. 6,080,763; 6,319,921; 6,297,381
and 6,358,945. The compounds in the patents are alleged to possess
anti-cytokine activity and are therefore useful in treating
diseases associated with inflammation.
[0027] The work cited above supports the principle that inhibition
of cytokine production will be beneficial in the treatment of
cytokine mediated diseases. Therefore a need exists for small
molecule inhibitors for treating these diseases with optimized
efficacy, pharmacokinetic and safety profiles.
BRIEF SUMMARY OF THE INVENTION
[0028] The work cited above supports the principle that inhibition
of cytokine production with small molecule compounds will be
beneficial in the treatment of various disease states.
[0029] It is therefore an object of the invention to provide
compounds of formula (I) ##STR3##
[0030] It is a further object of the invention to provide methods
for treating cytokine mediated diseases and pathological conditions
involving inflammation such as chronic inflammatory disease, using
the novel compounds of the invention.
[0031] It is yet a further object of the invention to provide
pharmaceutical compositions and processes of preparation of the
above-mentioned novel compounds.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0032] In a broad generic aspect of the invention there is provided
a compound of the formula (I) ##STR4## [0033] wherein: [0034]
Ar.sup.1 is chosen from rings (i), (ii) and (iii) below: ##STR5##
[0035] wherein one of A or B is nitrogen and the other is carbon,
R.sup.1 is covalently attached to either A or B, and when nitrogen
is N--R.sup.1 the double bond between A and B is not present;
[0036] R.sub.1 is chosen from hydrogen, NO.sub.2,
--N(R.sup.c).sub.2, J-C(O)--N(R.sup.c)--,
J-S(O).sub.m--N(R.sup.c)--, [0037] or R.sup.1 is chosen from
C.sub.1-6 alkyl, C.sub.3-7 cylcoalkyl, C.sub.1-5 alkoxyl or
C.sub.3-7 cycloalkoxyl, C.sub.1-5 alkylthiol or C.sub.3-7
cycloalkylthiol, C.sub.1-5 acyl, C.sub.1-5 alkoxycarbonyl,
C.sub.1-5 acyloxy, C.sub.1-5 acylamino, C.sub.2-5 alkenyl,
C.sub.2-5 alkynyl, heterocycle, heteroaryl and nitrile, each of the
aforementioned where possible are optionally partially or fully
halogenated or are optionally further substituted with
alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,
hydroxyl, oxo, nitro or nitrile; [0038] or R.sup.1 is, where P can
be O, >CR.sup.9 or >NR.sup.9 ##STR6## [0039] wherein z is 1
to 4, preferably 1 to 2, [0040] R.sup.9 is chosen from C.sub.1-6
alkyl, C.sub.3-7 cylcoalkyl, C.sub.1-5 alkoxyl or C.sub.3-7
cycloalkoxyl, C.sub.1-5 alkylthiol or C.sub.3-7 cycloalkylthiol,
C.sub.1-5 acyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 acyloxy,
C.sub.1-5 acylamino, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl,
heterocycle, heteroaryl and nitrile, each of the aforementioned
where possible are optionally partially or fully halogenated or are
optionally further substituted with alkylsulfonylamino, alkoxyl,
amino, alkylamino, dialkylamino, hydroxyl, oxo, nitro or nitrile;
[0041] R.sup.2 is chosen from hydrogen, halogen, C.sub.1-5 alkyl,
C.sub.1-5 alkoxy, C.sub.1-5 alkylC.sub.1-5 alkoxy, hydroxy, hydroxy
C.sub.1-5 alkyl, oxo, C.sub.1-5 alkylS(O).sub.m-- and amino
optionally mono- or di-substituted by C.sub.1-5 alkyl, aryl or aryl
C.sub.1-5 alkyl; ##STR7## [0042] wherein [0043] R.sup.1' is chosen
from hydrogen, C.sub.1-5 alkylS(O).sub.m--, C.sub.1-6 alkyl,
C.sub.3-7 cylcoalkyl, C.sub.1-5 alkoxyl or C.sub.3-7 cycloalkoxyl,
C.sub.1-5 alkylthiol C.sub.3-7 cycloalkylthiol, C.sub.1-5 acyl,
C.sub.1-5 alkoxycarbonyl, C.sub.1-5 acyloxy, C.sub.2-5 alkenyl,
C.sub.2-5 alkynyl, heterocycle, heterocycleC.sub.1-6 alkyl,
heteroaryl, heteroarylC.sub.1-6 alkyl and nitrile, each of the
aforementioned where possible are optionally partially or fully
halogenated or are optionally further substituted with
alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,
hydroxyl, oxo, nitro or nitrile; [0044] R.sup.2' is chosen from
nitrile, C.sub.1-5 alkylS(O).sub.m--, J-O--C(O)--O--,
NH.sub.2--C(O)--(CH.sub.2).sub.n--, H, halogen, C.sub.1-5 alkyl,
C.sub.1-5 alkoxy, C.sub.1-5 alkylC.sub.1-5 alkoxy, hydroxy, hydroxy
C.sub.1-5 alkyl and amino optionally mono- or di-substituted by
C.sub.1-5 alkyl, aryl or aryl C.sub.1-5 alkyl; ##STR8## [0045]
wherein c is a benzo ring fused to ring d which is a 5-7 membered
heterocyclic ring; [0046] each R.sup.x is chosen from C.sub.1-6
alkyl or C.sub.3-7 cycloalkyl each being optionally substituted by
C.sub.1-3 alkyl and optionally partially or fully halogenated,
C.sub.1-4 acyl, aroyl, C.sub.1-4 alkoxy, which may optionally be
partially or fully halogenated, halogen, C.sub.1-6 alkoxycarbonyl,
carbocyclesulfonyl and --SO.sub.2--CF.sub.3; [0047] each J is
independently chosen from C.sub.1-10 alkyl and carbocycle each
optionally substituted by R.sup.b; [0048] R.sup.b is chosen from
hydrogen, C.sub.1-5 alkyl, hydroxyC.sub.1-5 alkyl, C.sub.2-5
alkenyl, C.sub.2-5 alkynyl, carbocycle, heterocycle, heteroaryl,
C.sub.1-5 alkoxy, C.sub.1-5 alkylthio, amino, C.sub.1-5 alkylamino,
C.sub.1-5 dialkylamino, C.sub.1-5 acyl, C.sub.1-5 alkoxycarbonyl,
C.sub.1-5 acyloxy, C.sub.1-5 acylamino, each of the aforementioned
are optionally partially or fully halogenated, or R.sup.b is chosen
from C.sub.1-5 alkylsulphonylamino, hydroxy, oxo, halogen, nitro
and nitrile; [0049] Q is a N or CR.sup.p; [0050] Y is
>CR.sup.pR.sup.v, --CR.sup.p.dbd.C(R.sup.V)--, --O--,
--N(R.sup.c)-- or >S(O).sub.m; [0051] each R.sup.c, R.sup.p,
R.sup.V and R.sup.y are each independently hydrogen or C.sub.1-5
alkyl; [0052] X is --CH.sub.2--, --N(R.sup.c)--, --O-- or --S--;
[0053] W is N or CH; [0054] each m independently 0, 1 or 2; n is
1-4; [0055] each R.sup.3, R.sup.4 and R.sup.5 are independently
chosen from hydrogen, C1-6 alkyl and halogen; [0056] R.sup.6 is
optionally attached at a position ortho or meta to the N atom of
the indicated ring, and is chosen from [0057] a bond, --O--,
--O--(CH.sub.2).sub.1-5--, >C(O), --NH--, --C(O)--NH--, --S--,
C.sub.1-5 alkyl branched or unbranched, C.sub.2-5 alkenyl,
C.sub.1-3 acyl, C.sub.1-3 alkyl(OH), heterocycle selected from
morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl and
tetrahydrofuranyl, heteroaryl selected from pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl,
furyl, isoxazolyl, thiazolyl, oxazolyl and isothiazolyl or aryl
each alkyl, alkenyl, acyl, heterocycle, heteroaryl and aryl are
optionally substituted by one to three hydroxy, oxo, C.sub.1-3
alkyl, C.sub.1-3 alkoxy, C.sub.1-5 alkoxycarbonyl,
--NR.sup.7R.sup.8 or NR.sup.7R.sup.8--C(O)-- [0058] wherein each
R.sup.6 is further optionally covalently attached to groups chosen
from: [0059] hydrogen, NR.sup.7R.sup.8, C.sub.1-3 alkyl, C.sub.3-6
cycloalkylC.sub.0-2alkyl, hydroxy, C.sub.1-3 alkoxy, phenoxy,
benzyloxy, arylC.sub.0-4 alkyl, heteroaryl C.sub.0-4 alkyl and
heterocycle C.sub.0-4alkyl, each above-listed heterocycle,
heteroaryl and aryl group is optionally substituted by one to three
hydroxy, oxo, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, C.sub.1-5
alkoxycarbonyl, NR.sup.7R.sup.8--C(O)-- or C.sub.1-4 acyl; [0060]
each R.sup.7 and R.sup.8 are independently hydrogen,
phenylC.sub.0-3alkyl optionally substituted by halogen, C.sub.1-3
alkyl or diC.sub.1-5 alkyl amino, or R.sup.7 and R.sup.8 are
C.sub.1-2 acyl, benzoyl or C.sub.1-5 branched or unbranched alkyl
optionally substituted by C.sub.1-4 alkoxy, hydroxy or mono or
diC.sub.1-3 alkyl amino; or the pharmaceutically acceptable salts
and/or isomers thereof.
[0061] In another embodiment there is provided a compound of the
invention as described immediately above and wherein:
if Ar.sup.1 is (i) then:
[0062] R.sup.1 is chosen from hydrogen, C.sub.1-6 alkyl, C.sub.3-7
cylcoalkyl, C.sub.1-5 alkoxyl and nitrile, each of the
aforementioned where possible are optionally partially or fully
halogenated or are optionally further substituted with
alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,
hydroxyl, oxo, nitro or nitrile; [0063] R.sup.2 is chosen from
hydrogen, halogen, C.sub.1-5 alkyl, C.sub.1-5 alkoxy, C.sub.1-5
alkylC.sub.1-5 alkoxy, hydroxy, hydroxy C.sub.1-5 alkyl, oxo,
C.sub.1-5 alkylS(O).sub.m-- and amino optionally mono- or
di-substituted by C.sub.1-5 alkyl, phenyl or phenyl C.sub.1-5
alkyl; if Ar.sup.1 is (ii) then: R.sup.1' is chosen from H,
C.sub.1-6 alkyl, C.sub.1-5 alkylS(O).sub.m--, C.sub.1-5 alkoxyl
C.sub.1-5 alkylthiol, NH.sub.2--C(O)--(CH.sub.2).sub.n--,
heterocycle, heterocycleC.sub.1-6 alkyl, heteroaryl and nitrile,
each of the aforementioned where possible are optionally partially
or fully halogenated or are optionally further substituted with
alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,
hydroxyl, oxo, nitro and nitrile; R.sup.2' is chosen from C.sub.1-5
alkylS(O).sub.m--, J-O--C(O)--O--, C.sub.1-5 alkyl and C.sub.1-5
alkoxy; or if Ar.sup.1 is (iii) then: ring d is a 5-6 membered
heterocyclic ring.
[0064] In another embodiment, there are provided compounds of the
formula (I) as described immediately above and wherein
if Ar.sup.1 is (i) then:
R.sup.1 is chosen from hydrogen, C.sub.1-6 alkyl or nitrile;
R.sup.2 is chosen from hydrogen, halogen, C.sub.1-5 alkyl,
C.sub.1-5 alkoxy, oxo or C.sub.1-5 alkylS(O).sub.m--;
if Ar.sup.1 is (ii) then:
R.sup.1' is chosen from hydrogen, C.sub.1-6 alkyl, C.sub.1-5
alkylS(O).sub.m--, C.sub.1-5 alkoxyl C.sub.1-5 alkylthiol,
NH.sub.2--C(O)--(CH.sub.2).sub.n--, morpholino C.sub.1-6 alkyl,
heteroaryl chosen from pyrazole, triazole, imidazole and tetrazole,
and nitrile;
R.sup.2' is chosen from C.sub.1-5 alkylS(O).sub.m--,
J-O--C(O)--O--, C.sub.1-5 alkyl and C.sub.1-5 alkoxy;
or if Ar.sup.1 is (iii) then:
[0065] ring d is a 5-6 membered heterocyclic ring such that rings c
and d fuse to form the following: ##STR9## [0066] where each R is
independently H or C.sub.1-3 alkyl.
[0067] In yet another embodiment, there are provided compounds of
the formula (I) as described in any of the embodiments shown above
and wherein
J is chosen from C.sub.1-10 alkyl, aryl and C.sub.3-7 cycloalkyl
each optionally substituted by R.sup.b;
[0068] R.sup.x is independently chosen from C.sub.1-6 alkyl which
may optionally be partially or fully halogenated, C.sub.3-6
cycloalkyl optionally substituted by C.sub.1-3 alkyl and optionally
partially or fully halogenated, acetyl, aroyl, C.sub.1-4 alkoxy,
which may optionally be partially or fully halogenated, halogen,
methoxycarbonyl, phenylsulfonyl and --SO.sub.2--CF.sub.3;
[0069] R.sup.b is chosen from hydrogen, C.sub.1-5 alkyl, C.sub.2-5
alkenyl, C.sub.2-5 alkynyl, C.sub.3-8 cycloalkylC.sub.0-2 alkyl,
aryl, C.sub.1-5 alkoxy, C.sub.1-5 alkylthio, amino, C.sub.1-5
alkylamino, C.sub.1-5 dialkylamino, C.sub.1-5 acyl, C.sub.1-5
alkoxycarbonyl, C.sub.1-5 acyloxy, C.sub.1-5 acylamino, C.sub.1-5
sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro,
nitrile,
[0070] or R.sup.b is chosen from heterocycle chosen from
pyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl,
thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxalanyl,
piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl,
piperidinonyl, tetrahydropyrimidonyl, pentamethylene sulfide,
pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene
sulfide, tetramethylene sulfoxide and tetramethylene sulfone and
heteroaryl chosen from aziridinyl, thienyl, furanyl, isoxazolyl,
oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl,
imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl,
benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl,
naphthyridinyl, indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidinyl,
purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl,
tubercidinyl, oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl;
and
R.sup.7 is hydrogen.
[0071] In another embodiment, there are provided compounds of the
formula (I) as described immediately above and wherein
Y is --O--, --S--, --NH--, --N(CH.sub.2CH.sub.3)-- or
--N(CH.sub.3)--;
X is --N(R.sup.a)-- or --O--;
Q is CH;
each R.sup.3, R.sup.4 and R.sup.5 are hydrogen;
[0072] R.sup.b is chosen from hydrogen, C.sub.1-5 alkyl, C.sub.2-5
alkenyl, C.sub.2-5 alkynyl, C.sub.3-8 cycloalkylC.sub.0-2 alkyl,
aryl, C.sub.1-5 alkoxy, C.sub.1-5 alkylthio, amino, C.sub.1-5
alkylamino, C.sub.1-5 dialkylamino, C.sub.1-5 acyl, C.sub.1-5
alkoxycarbonyl, C.sub.1-5 acyloxy, C.sub.1-5 acylamino, C.sub.1-5
sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro,
nitrile
[0073] or R.sup.b is chosen from; heterocycle chosen from
pyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl,
thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxalanyl,
piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl,
piperidinonyl, tetrahydropyrimidonyl, pentamethylene sulfide,
pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene
sulfide, tetramethylene sulfoxide and tetramethylene sulfone and
heteroaryl chosen from aziridinyl, thienyl, furanyl, isoxazolyl,
oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl,
imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl,
benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl,
naphthyridinyl, indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidinyl,
purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl,
tubercidinyl, oxazo[4,5-b]pyridinyl and
imidazo[4,5-b]pyridinyl.
[0074] In yet another embodiment, there are provided compounds of
the formula (I) as described immediately above and wherein
Y is --O--, --S-- or --N(CH.sub.3)--;
R.sup.6 is present, and is chosen from
[0075] a bond, --O--, --O--(CH.sub.2).sub.1-5--, --NH--,
--C(O)--NH--, C.sub.1-5 alkyl branched or unbranched, C.sub.2-5
alkenyl, C.sub.1-3 alkyl(OH), heterocycle selected from
morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl and
tetrahydrofuranyl, or aryl chosen from phenyl and naphthyl, each
alkyl, alkenyl, heterocycle and aryl are optionally substituted by
one to three hydroxy, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, mono or
diC.sub.1-3 alkyl amino, amino or C.sub.1-5 alkoxycarbonyl;
wherein each R.sup.6 is further optionally covalently attached to
groups chosen from:
[0076] hydrogen, NR.sup.7R.sup.8, C.sub.1-3 alkyl, C.sub.3-6
cycloalkylC.sub.0-2alkyl, hydroxy, C.sub.1-3 alkoxy, phenoxy,
benzyloxy, phenylC.sub.0-4 alkyl, piperazinylC.sub.0-4 alkyl,
piperidinyl C.sub.0-4alkyl, pyrrolidinylC.sub.0-4 alkyl,
morpholinylC.sub.0-4 alkyl, tetrahydrofuranylC.sub.0-4 alkyl,
triazolyl C.sub.0-4alkyl, imidazolyl C.sub.0-4alkyl and pyridinyl
C.sub.0-4alkyl, each above listed heterocycle, heteroaryl and
phenyl group is optionally substituted by one to three hydroxy,
oxo, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, C.sub.1-5 alkoxycarbonyl,
--NR.sup.7R.sup.8, NR.sup.7R.sup.8--C(O)-- or C.sub.1-4 acyl; each
R.sup.7 and R.sup.8 are independently hydrogen,
phenylC.sub.0-3alkyl optionally substituted by halogen, C.sub.1-3
alkyl or diC.sub.1-5 alkyl amino, or R.sup.7 and R.sup.8 are
C.sub.1-2 acyl, benzoyl or C.sub.1-5 branched or unbranched alkyl
optionally substituted by C.sub.1-4 alkoxy, hydroxy or mono or
diC.sub.1-3 alkyl amino.
[0077] In yet another embodiment, there are provided compounds of
the formula (I) as described immediately above and wherein
X is --O--;
Y is --N(CH.sub.3)--;
R.sup.6 is chosen from
[0078] a bond, --O--, --O--(CH.sub.2).sub.1-5--, --NH--,
--C(O)--NH--, C.sub.1-5 alkyl branched or unbranched, C.sub.2-5
alkenyl, C.sub.1-3 alkyl(OH), heterocycle selected from
morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl or phenyl,
each alkyl, alkenyl, heterocycle and phenyl are optionally
substituted by one to three hydroxy, C.sub.1-3 alkyl, C.sub.1-3
alkoxy, mono or diC.sub.1-3 alkyl amino, amino or C.sub.1-5
alkoxycarbonyl;
wherein each R.sup.6 is further optionally covalently attached to
groups chosen from:
[0079] hydrogen, --NR.sup.7R.sup.8, C.sub.1-3 alkyl, C.sub.3-6
cycloalkylC.sub.0-2alkyl, benzyloxy, phenylC.sub.0-4 alkyl,
piperazinylC.sub.0-4 alkyl, piperidinyl C.sub.0-4alkyl,
pyrrolidinylC.sub.0-4 alkyl, morpholinylC.sub.0-4 alkyl, triazolyl
C.sub.0-4alkyl, imidazolyl C.sub.0-4alkyl and pyridinyl
C.sub.0-4alkyl, each above-listed heterocycle, heteroaryl and
phenyl group is optionally substituted by one to three hydroxy,
oxo, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, C.sub.1-5 alkoxycarbonyl,
amino, NR.sup.7R.sup.8--C(O)-- or C.sub.1-4 acyl; each R.sup.7 and
R.sup.8 are independently hydrogen, phenylC.sub.0-2alkyl optionally
substituted by halogen, C.sub.1-3 alkyl or diC.sub.1-5 alkyl amino,
or R.sup.7 and R.sup.8 are C.sub.1-5 branched or unbranched alkyl
optionally substituted by C.sub.1-4 alkoxy, hydroxy or mono or
diC.sub.1-3 alkyl amino; R.sup.b is chosen from hydrogen, C.sub.1-5
alkyl, C.sub.3-7 cycloalkylC.sub.0-2 alkyl, aryl, C.sub.1-5 alkoxy,
amino, C.sub.1-5 alkylamino, C.sub.1-3 dialkylamino, C.sub.1-3
acyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-3 acyloxy, C.sub.1-3
acylamino, C.sub.1-3 sulphonylamino, hydroxy, halogen,
trifluoromethyl, nitro, nitrile; or R.sup.b is chosen from
pyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl,
thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperidinyl,
piperazinyl, piperidinonyl, tetrahydropyrimidonyl, aziridinyl,
isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl,
pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl
and pyridazinyl.
[0080] In yet still another embodiment, there are provided
compounds of the formula (I) as described immediately above and
wherein
R.sup.6 is chosen from
[0081] a bond, --O--, --O--(CH.sub.2).sub.1-5--, --NH--,
--C(O)--NH--, C.sub.1-5 alkyl branched or unbranched, C.sub.2-5
alkenyl, C.sub.1-3 alkyl(OH), heterocycle selected from
morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl or phenyl,
each alkyl, alkenyl, heterocycle and phenyl are optionally
substituted by one to three hydroxy, C.sub.1-3 alkyl, C.sub.1-3
alkoxy, mono or diC.sub.1-3 alkyl amino, amino or C.sub.1-5
alkoxycarbonyl;
wherein each R.sup.6 is further optionally covalently attached to
groups chosen from:
[0082] hydrogen, --NR.sup.7R.sup.8, C.sub.1-3 alkyl, C.sub.3-6
cycloalkylC.sub.0-2alkyl, benzyloxy, phenylC.sub.0-4 alkyl,
piperazinyl, piperazinylC.sub.1-2 alkyl, piperidinyl, piperidinyl
C.sub.1-2alkyl, pyrrolidinyl, pyrrolidinyl C.sub.1-2 alkyl,
morpholinyl, morpholinylC.sub.1-2 alkyl, triazolyl, triazolyl
C.sub.1-12alkyl, imidazolyl, imidazolyl C.sub.1-2alkyl, pyridinyl
and pyridinyl C.sub.1-2alkyl, each above-listed heterocycle,
heteroaryl and phenyl group is optionally substituted by one to
three hydroxy, oxo, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, C.sub.1-5
alkoxycarbonyl, amino, NR.sup.7R.sup.8--C(O)-- or C.sub.1-4
acyl.
[0083] In yet another embodiment, there are provided compounds of
the formula (I) as described immediately above and wherein
R.sup.b is chosen from hydrogen, C.sub.1-5 alkyl, C.sup.3-6
cycloalkylC.sub.0-2 alkyl, phenyl, C.sub.1-5 alkoxy, amino,
C.sub.1-5 alkylamino, C.sub.1-3 dialkylamino, C.sub.1-3 acyl,
C.sub.1-5 alkoxycarbonyl, C.sub.1-3 acyloxy, C.sub.1-3 acylamino,
hydroxy, halogen;
or R.sup.b is chosen from morpholinyl, thiomorpholinyl,
thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperidinyl,
piperidinonyl, pyridinyl, pyrimidinyl, pyrazinyl and
pyridazinyl.
[0084] In yet another embodiment, there are provided compounds of
the formula (I) as described immediately above and wherein
R.sup.b is chosen from amino, C.sub.1-5 alkylamino, C.sub.1-3
dialkylamino;
or R.sup.b is chosen morpholinyl, piperidinyl and pyridinyl.
[0085] In yet another embodiment, there are provided compounds of
the formula (I) as described immediately above and wherein Rx is
chosen from: ##STR10##
[0086] For any of the above described embodiments, preferred
embodiments where Ar1 is (i) and includes: ##STR11## ##STR12##
[0087] For any of the above described embodiments, preferred
embodiments where Ar.sup.1 is (ii) include: ##STR13## ##STR14##
##STR15## where R in these structures is C.sub.1-5alkyl.
[0088] The following are representative compounds of the invention:
TABLE-US-00001 TABLE 1 ##STR16##
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid
(2-tert-butyl-5-methoxy-pyridin-4-yl)- amide ##STR17##
1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid
(5-tert-butyl-2- methanesulfinyl-phenyl)-amide ##STR18##
1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid
(5-tert-butyl-2- methanesulfonyl-phenyl)-amide ##STR19##
1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid
(5-tert-butyl-2-oxo-1,2- dihydro-pyridin-3-yl)-amide ##STR20##
1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid
(5-tert-butyl-1-methyl-2-oxo- 1,2-dihydro-pyridin-3-yl)-amide
##STR21## 1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid
(5-tert-butyl-2-methyl-pyridin- 3-yl)-amide ##STR22##
1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid
(5-tert-butyl-3-cyano-2- methoxy-phenyl)-amide ##STR23##
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-2-methyl-pyridin-3-yl)- amide ##STR24##
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-cyano-2-methoxy-phenyl)- amide ##STR25##
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-2-methanesulfinyl-phenyl)- amide ##STR26##
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyridin-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-2-methyl-pyridin-3-yl)-amide ##STR27##
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyridin-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-2-methanesulfinyl-phenyl)-amide ##STR28##
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyridin-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-cyano-2-methoxy-phenyl)- amide ##STR29##
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyridin-4-yloxy]-1H-indole-2-carboxylic acid
(2-tert-butyl-5-methanesulfinyl-pyridin-4-yl)- amide ##STR30##
1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid
[5-tert-butyl-2-methoxy-3-(2- oxo-pyrrolidin-1-yl)-phenyl]-amide
##STR31## 1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid
[5-tert-butyl-2-methoxy-3-(2- oxo-azetidin-1-yl)-phenyl]-amide
##STR32## 1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyridin-4-yloxy]-1H-indole-2-carboxylic acid
(2-amino-6-tert-butyl-3-methoxy-pyridin-4- yl)-amide ##STR33##
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyridin-4-yloxy]-1H-indole-2-carboxylic acid
[3-methanesulfonylamino-2-methoxy-5-(1-
methyl-cyclopropyl)-phenyl]-amide ##STR34##
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-
pyridin-4-yloxy]-1H-indole-2-carboxylic acid
[3-methanesulfonylamino-2-methoxy-5-(1-
methyl-cyclopropyl)-phenyl]-amide or the pharmaceutically
acceptable salts and/or isomers thereof.
[0089] In all the compounds disclosed hereinabove in this
application, in the event the nomenclature is in conflict with the
structure, it shall be understood that the compound is defined by
the structure.
[0090] Of particular importance according to the invention are
compounds of formula (I), for use as pharmaceutical compositions
with an anti-cytokine activity.
[0091] The invention also relates to the use of a compound of
formula (I), for preparing a pharmaceutical composition for the
treatment and/or prevention of a cytokine mediated disease or
condition.
[0092] The invention also relates to pharmaceutical preparations,
containing as active substance one or more compounds of formula
(I), or the pharmaceutically acceptable derivatives thereof,
optionally combined with conventional excipients and/or
carriers.
[0093] Compounds of the invention also include their
isotopically-labelled forms. An isotopically-labelled form of an
active agent of a combination of the present invention is identical
to said active agent but for the fact that one or more atoms of
said active agent have been replaced by an atom or atoms having an
atomic mass or mass number different from the atomic mass or mass
number of said atom which is usually found in nature. Examples of
isotopes which are readily available commercially and which can be
incorporated into an active agent of a combination of the present
invention in accordance with well established procedures, include
isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
fluorine and chlorine, e.g., .sup.2H, .sup.3H, .sup.13C, .sup.14C,
.sup.15N, .sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S,
.sup.18F, and .sup.36Cl, respectively. An active agent of a
combination of the present invention, a prodrug thereof, or a
pharmaceutically acceptable salt of either which contains one or
more of the above-mentioned isotopes and/or other isotopes of other
atoms is contemplated to be within the scope of the present
invention.
[0094] The invention includes the use of any compounds of described
above containing one or more asymmetric carbon atoms may occur as
racemates and racemic mixtures, single enantiomers, diastereomeric
mixtures and individual diastereomers. Isomers shall be defined as
being enantiomers and diastereomers. All such isomeric forms of
these compounds are expressly included in the present invention.
Each stereogenic carbon may be in the R or S configuration, or a
combination of configurations.
[0095] Some of the compounds of formula (I) can exist in more than
one tautomeric form. The invention includes methods using all such
tautomers.
[0096] All terms as used herein in this specification, unless
otherwise stated, shall be understood in their ordinary meaning as
known in the art. For example, "C.sub.1-4alkoxy" is a
C.sub.1-4alkyl with a terminal oxygen, such as methoxy, ethoxy,
propoxy, butoxy. All alkyl, alkenyl and alkynyl groups shall be
understood as being branched or unbranched where structurally
possible and unless otherwise specified. Other more specific
definitions are as follows:
[0097] Carbocycles include hydrocarbon rings containing from three
to twelve carbon atoms. These carbocycles may be either aromatic
either aromatic or non-aromatic ring systems. The non-aromatic ring
systems may be mono- or polyunsaturated. Preferred carbocycles
include but are not limited to cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,
cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,
benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,
decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl.
Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl
shall be used interchangeably.
[0098] The term "heterocycle" refers to a stable nonaromatic 4-8
membered (but preferably, 5 or membered) monocyclic or nonaromatic
8-11 membered bicyclic heterocycle radical which may be either
saturated or unsaturated. Each heterocycle consists of carbon atoms
and one or more, preferably from 1 to 4 heteroatoms chosen from
nitrogen, oxygen and sulfur. The heterocycle may be attached by any
atom of the cycle, which results in the creation of a stable
structure. Unless otherwise stated, heterocycles include but are
not limited to, for example pyrrolidinyl, pyrrolinyl, morpholinyl,
thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl
sulfone, dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone,
1,3-dioxanone, 1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl,
pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene
sulfone, tetramethylene sulfide, tetramethylene sulfoxide and
tetramethylene sulfone.
[0099] The term "heteroaryl" shall be understood to mean an
aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring
containing 1-4 heteroatoms such as N, O and S. Unless otherwise
stated, such heteroaryls include aziridinyl, thienyl, furanyl,
isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl,
pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyranyl, quinoxalinyl, indolyl, benzimidazolyl,
benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl,
quinazolinyl, naphthyridinyl, indazolyl, triazolyl,
pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl,
pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl and
imidazo[4,5-b]pyridinyl.
[0100] The term "heteroatom" as used herein shall be understood to
mean atoms other than carbon such as O, N, S and P.
[0101] In all alkyl groups or carbon chains one or more carbon
atoms can be optionally replaced by heteroatoms: O, S or N, it
shall be understood that if N is not substituted then it is NH, it
shall also be understood that the heteroatoms may replace either
terminal carbon atoms or internal carbon atoms within a branched or
unbranched carbon chain. Such groups can be substituted as herein
above described by groups such as oxo to result in definitions such
as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.
[0102] The term "aryl" as used herein shall be understood to mean
aromatic carbocycle or heteroaryl as defined herein. Each aryl or
heteroaryl unless otherwise specified includes it's partially or
fully hydrogenated derivative. For example, quinolinyl may include
decahydroquinolinyl and tetrahydroquinolinyl, naphthyl may include
it's hydrogenated derivatives such as tetrahydranaphthyl. Other
partially or fully hydrogenated derivatives of the aryl and
heteroaryl compounds described herein will be apparent to one of
ordinary skill in the art.
[0103] As used herein, "nitrogen" and "sulfur" include any oxidized
form of nitrogen and sulfur and the quaternized form of any basic
nitrogen. For example, for an --S--C.sub.1-6 alkyl radical, unless
otherwise specified, this shall be understood to include
--S(O)--C.sub.1-6 alkyl and --S(O).sub.2--C.sub.1-6 alkyl.
[0104] The term "halogen" as used in the present specification
shall be understood to mean bromine, chlorine, fluorine or iodine,
preferably fluorine. The definitions "partially or fully
halogenated"; partially or fully fluorinated; "substituted by one
or more halogen atoms", includes for example, mono, di or tri halo
derivatives on one or more carbon atoms. For alkyl, a nonlimiting
example would be --CH.sub.2CHF.sub.2, --CF.sub.3 etc.
[0105] The compounds of the invention are only those which are
contemplated to be `chemically stable` as will be appreciated by
those skilled in the art. For example, a compound which would have
a `dangling valency`, or a `carbanion` are not compounds
contemplated by the inventive methods disclosed herein.
[0106] The invention includes pharmaceutically acceptable
derivatives of compounds of formula (I). A "pharmaceutically
acceptable derivative" refers to any pharmaceutically acceptable
salt or ester, or any other compound which, upon administration to
a patient, is capable of providing (directly or indirectly) a
compound useful for the invention, or a pharmacologically active
metabolite or pharmacologically active residue thereof. A
pharmacologically active metabolite shall be understood to mean any
compound of the invention capable of being metabolized
enzymatically or chemically. This includes, for example,
hydroxylated or oxidized derivative compounds of the formula
(I).
[0107] Pharmaceutically acceptable salts include those derived from
pharmaceutically acceptable inorganic and organic acids and bases.
Examples of suitable acids include hydrochloric, hydrobromic,
sulfuric, nitric, perchloric, fumaric, maleic, phosphoric,
glycolic, lactic, salicylic, succinic, toluene-p-sulfuric,
tartaric, acetic, citric, methanesulfonic, formic, benzoic,
malonic, naphthalene-2-sulfuric and benzenesulfonic acids. Other
acids, such as oxalic acid, while not themselves pharmaceutically
acceptable, may be employed in the preparation of salts useful as
intermediates in obtaining the compounds and their pharmaceutically
acceptable acid addition salts. Salts derived from appropriate
bases include alkali metal (e.g., sodium), alkaline earth metal
(e.g., magnesium), ammonium and N--(C.sub.1-C.sub.4
alkyl).sub.4.sup.+ salts.
[0108] In addition, within the scope of the invention is use of
prodrugs of compounds of the formula (I). Prodrugs include those
compounds that, upon simple chemical transformation, are modified
to produce compounds of the invention. Simple chemical
transformations include hydrolysis, oxidation and reduction.
Specifically, when a prodrug is administered to a patient, the
prodrug may be transformed into a compound disclosed hereinabove,
thereby imparting the desired pharmacological effect.
General Synthetic Methods
[0109] The invention additionally provides for methods of making
the compounds of the formula (I). The compounds of the invention
may be prepared by the general methods and examples presented
below, and methods known to those of ordinary skill in the art.
Further reference in this regard may be made to U.S. Pat. No.
6,358,945, U.S. application Ser. Nos. 09/714,539, 09/834,797,
10/120,028, 10/143,322 and 10/147,675. U.S. application Ser. No.
10/264,689 teaches additional methods for preparation of
sulfonamide intermediates. Each of the aforementioned US cases are
incorporated in their entirety.
[0110] In all schemes, unless otherwise specified, Ar.sup.1, X, Y,
W and R.sup.3-R.sup.6 in the formulas shown below shall have the
meanings defined for these groups in the definition of the formula
(I) of the invention, described hereinabove. Intermediates used in
the syntheses below are either commercially available or easily
prepared by methods known to those skilled in the art. Reaction
progress may be monitored by conventional methods such as thin
layer chromatography (TLC). Intermediates and products may be
purified by methods known in the art, including column
chromatography, HPLC or recrystallization.
[0111] Compounds of the invention where Q is a carbon atom, may be
prepared as described in Schemes I and II. Compounds of the
invention wherein Q is a nitrogen atom, may be prepared by
analogous methods which will be apparent to one of ordinary skill
in the art. ##STR35##
[0112] As illustrated in Scheme I an amine bearing Ar.sup.1 is
coupled with carboxylic acid III, where P is a protecting group,
using standard coupling conditions known in the art (see for
example M. Bodanszky, 1984, The Practice of Peptide Synthesis,
Springer-Verlag). For example, one may couple III and II by
treating with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (EDC) followed by 1-hydroxybenzotriazole hydrate
(HOBT) in a suitable solvent such as DMF. Removal of the protecting
group P to provide V may be achieved by standard procedures known
in the art. For example, if P is a benzyl group, it may be removed
by treatment of IV with hydrogen gas in the presence of a catalyst
such as palladium on carbon in a suitable solvent such as EtOH. The
resulting intermediate V may then be coupled with the desired halo
heterocycle VI (Z=halogen) bearing R.sup.6 in the presence of a
suitable base to provide I. Ar.sup.1 and R.sup.6 may be further
modified by standard synthetic methods known in the art to produce
additional compounds of formula (I). Several examples are described
in the Synthetic Examples section below.
[0113] In a modification of the above method, the order of coupling
VI and Ar.sup.1NH.sub.2 with the central heterocycle may be
reversed. This is illustrated in Scheme II. ##STR36##
[0114] As illustrated above, the ester VII (R=lower alkyl such as
methyl or ethyl, P=a protecting group) is deprotected as described
above and the resulting intermediate VIII is coupled, as described
above to provide ester IX. This is hydrolyzed using standard
hydrolysis conditions and the resulting acid coupled with
Ar.sup.1NH.sub.2 to provide I. As above, Ar.sup.1 and R.sup.6 may
be further modified by standard synthetic methods known in the art
to produce additional compounds of formula (I). Several examples
are described in the Synthetic Examples section below.
SYNTHETIC EXAMPLES
Example 1
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carbo-
xylic acid
(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide
[0115] For a similar procedure to form the indole core, see R.
Albrecht et al. Eur. J. Med. Chem. Chim. Ther. 1985, 20, 59-60.
##STR37## ##STR38##
Preparation of 1-Benzyloxy-3-methyl-2-nitro-benzene (Compound
2)
[0116] To a mechanically stirred solution of 1 (760 g, 4.96 mol) in
acetonitrile (12.1 L) was added potassium carbonate (857 g, 6.2
mol). Benzyl bromide (590 mL, 4.96 mol) was added to the dark red
suspension over 5 h which raised the temperature slightly. The
reaction was heated to 75.degree. C. over 45 min and then held at
75.degree. C. for 2 h over which time the reaction turned orange.
The reaction was allowed to cool to 40.degree. C. and water (6.2 L)
was added. The reaction was transferred to a separatory funnel and
the reaction flask washed with ethyl acetate (1 L) to complete the
transfer. The layers were separated and the aqueous layer extracted
with ethyl acetate (6 L). The combined organics were washed with
brine (5 L) and then dried over sodium sulfate. The mixture was
filtered through celite and concentrated to an orange oil. The oil
was redissolved in ethyl acetate and filtered through celite a
second time to remove residual solids. The solution was then
concentrated and dried under vacuum to give 2 (1199 g, 99%) as an
orange oil.
Preparation of 3-(3-Benzyloxy-2-nitro-phenyl)-2-hydroxy-acrylic
acid ethyl ester potassium salt (Compound 3)
[0117] To a stirred solution of MTBE (16 L) was added a 1 M
solution of potassium t-butoxide in THF (4.9 L, 4.9 mol). Diethyl
oxalate (667 mL, 4.9 mol) was added via addition funnel causing a
slight exotherm. A solution of 2 (1199 g, 4.9 mol) in MTBE (2 L)
was added over 1 h. The reaction was stirred at room temperature
for 3 h and then heated at reflux overnight. The reaction was
allowed to cool to room temperature and the solids were collected
by vacuum filtration, washed with MTBE, and dried under vacuum to
give compound 3 as an orange solid (1398 g, 74%).
Preparation of 7-Benzyloxy-1H-indole-2-carboxylic acid ethyl ester
(Compound 4)
[0118] A suspension of iron powder (2783 g, 50 mol) in acetic acid
(12.3 L) was heated to 50.degree. C. A solution of 3 (1422 g, 3.72
mol) in acetic acid (4.2 L) was added over 3.5 h in an exothermic
reaction. The reaction was heated at 80.degree. C. for 12 h. The
reaction was cooled to 50.degree. C. and ethyl acetate (16 L) was
added and the suspension stirred for 0.5 h. The suspension was
filtered through celite and washed through with ethyl acetate (8
L). The filtrate was concentrated to a brown paste. The paste was
redissolved in ethyl acetate (16 L) and a 0.4 M solution of
tetrasodium EDTA (16 L) was added. The solution was saturated with
solid sodium bicarbonate and stirred overnight. The layers were
separated and the aqueous layer extracted with ethyl acetate (4 L).
The combined organics were washed with saturated sodium bicarbonate
(2.times.7 L) and then washed with a 0.4 M solution of tetrasodium
EDTA (7 L). The organics were dried over sodium sulfate for 5 h and
then filtered through a pad of silica gel washing through with
ethyl acetate. The filtrate was concentrated to give compound 4
(905 g, 82%) as a dark brown solid.
Preparation of 7-Benzyloxy-1-methyl-1H-indole-2-carboxylic acid
ethyl ester (Compound 5)
[0119] A suspension of sodium hydride (132 g, 3.43 mol, 60%
dispersion in mineral oil) was cooled to 10.degree. C. in an ice
bath. A solution of 4 (844 g, 2.86 mol) in DMF (1.9 L) was added
over 4.5 h with a slight exotherm raising the temperature to
13.degree. C. The reaction was stirred for an additional 0.5 h.
Methyl iodide (180 mL, 2.86 mol) was added over 1 h raising the
temperature from 12.6.degree. C. to 18.8.degree. C. The reaction
was stirred overnight under nitrogen. The reaction was quenched
with saturated ammonium chloride (700 mL) causing a tan precipitate
and an exotherm. Water (3 L) was added and the solids were
collected by vacuum filtration and washed with water (2 L). The
solids (.about.1.5 kg) were dissolved in ethyl acetate (4 L) and
washed with brine (1 L). The ethyl acetate solution was treated
with sodium sulfate and charcoal for 1 h. The mixture was filtered
through celite and concentrated to a brown solid. The solid (964 g)
was mostly dissolved in 2% ethyl acetate in heptane (4.8 L),
decanted from the oily residue, and the solution was filtered and
concentrated a dark yellow solid. The oily residue was dissolved in
ethyl acetate (5 volumes) and diluted with heptane (5 volumes based
on ethyl acetate) and the resulting precipitate collected by vacuum
filtration. The solids were combined and slurried with heptane (3
volumes), filtered, and dried under vacuum for 2 days to give
compound 5 (686 g, 76%) as a tan powder: mp 59-61.degree. C.
Preparation of 7 7-Hydroxy-1-methyl-1H-indole-2-carboxylic acid
ethyl ester (Compound 6)
[0120] 5 (82.2 g, 266 mmol) and Pearlman's catalyst (2.0 g; 20%
Pd(OH).sub.2/C, wet, Aldrich) were suspended in EtOH (300 mL) in a
Parr Shaker jar. The jar was purged with H.sub.2 and shaken at RT
(Parr shaker) under a constant 10 psi of H.sub.2 for 5 h. The final
solution was filtered through Celite 545 and concentrated to give
the product (58.15 g; 99%) as an analytically pure, off-white
solid.
Preparation of
7-(2-Chloro-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
ethyl ester (Compound 7)
[0121] The indole substrate (135.0 g, 602 mmol) and
2-chloro-4-iodopyridine (147 g, 614 mmol) were dissolved in
anhydrous DMF (150 mL) under an atmosphere of N.sub.2. DBU 144 mL,
963 mmol) was added in one portion. The reaction was stirred at
110.degree. C. for 16 hours, then cooled and concentrated under
high vacuum. The dark residue was taken up in EtOAc (1500 ml) and
washed successively with 50% brine (300 mL), 5% aqueous citric acid
(2.times.300 mL), saturated aqueous sodium bicarbonate (2.times.300
mL), and brine (300 ml). The organic layer was dried over
MgSO.sub.4/decolorizing charcoal, filtered, and concentrated to
give a dark red-purple solid. Recrystallization from MeCN (260 mL)
gave the product as pale purple crystals (199 g, 67%).
Preparation of
7-(2-Chloro-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(Compound 8)
[0122] The ester (53.2 g, 161 mmol) was dissolved in 1:1 THF/EtOH
(1000 mL). 1M aqueous NaOH (370 mL, 370 mmol) was added over 30
minutes with vigorous stirring. The solution was stirred at RT for
5 hours. Water (500 mL) was then added, and the bulk of the organic
solvents removed by rotary evaporation (60.degree. C.). The
resulting aqueous solution was washed with Et.sub.2O (2.times.200
mL) and the organic extracts discarded. The dark aqueous solution
was acidified to pH 5.2 (pH meter) with 10% HCl and then extracted
with EtOAc (4.times.400 mL). The combined organic extracts were
washed with brine (300 mL), dried over MgSO.sub.4, filtered, and
concentrated. The residue was dissolved in the minimum amount of
hot acetonitrile and decolorizing carbon added. The solution was
refluxed for 5 minutes, and then filtered through a pad of Celite
which was subsequently washed with hot acetonitrile (2.times.100
mL). The product crystallized on cooling and was collected by
filtration giving the desired acid as an off-white, analytically
pure solid (46 g, 95%).
Preparation of
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carb-
oxylic acid (Compound 9)
[0123] Flush with N.sub.2 a 3-neck 250 mL round bottom flask
equipped with an overhead stirrer, reflux condensor, thermocouple
thermometer, heating mantle and N.sub.2 line. Charge 8 (6 g, 19
mmol) into the flask followed by t-BuONa (69 mmol) and toluene (99
mL). Charge piperazine (39.6 mmol) into the flask. A mild exotherm
brings the internal temperature to 30.degree. C. Purge the solution
by sparging with N.sub.2 5-10 min. Charge Xantphos (69 mmol)
followed by Pd (0.3 mmol). Purge the mixture again by sparging with
N.sub.2 for 5-10 min. Heat the mixture to 95-100.degree. C. and
stir under N.sub.2 for 4 h. Cool the mixture to 22-25.degree. C.
and add water (60 mL). Stir for 2-5 min and set aside the aqueous
portion. Extract the organic portion with 0.3 M NaOH (35 mL). The
combined aqueous portions were filtered through a pad of Darco G-60
charcoal and celite. The pad was filtered with 2 mL 0.3 M NaOH.
Place the combined aqueous portions over a bath at 20-25.degree. C.
and neutralize the solution to pH=6-7 with 2N HCl. The solution is
stirred for 20 min to 30 min the solid by is collected by
filtration. The cake is rinsed with MTBE (20 mL) and air-dried
overnight. The solid is dried by azeotropic distillation of a
slurry with THF (3.times.75 mL) and then in a vacuum oven at
50.degree. C. for a minimum of 6 h to afford 7.83 g (87%) of an
off-white solid.
Preparation of
1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carb-
oxylic acid
(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide
(Compound 10)
[0124] Charge 9 (6.0 g, 16.4 mmol) into a flask followed by THF
(96.0 mL) and DMF (0.05 mL). Add oxalyl chloride (1.5 mL) slowly
keeping the internal temperature at 20-25.degree. C. Stir for
approx. 1.5 h. Aniline (18 mmol) and DMAP (catalytic) were added in
one portion followed by Et.sub.3N (2.65 mL). The mixture is stirred
at ambient temperature for 2 hours.
[0125] The mixture was quenched with 5% NaHCO.sub.3 (70 mL) and
stirred for 10 min. The organic portion was removed and the aqueous
was extracted with ethyl acetate (1.times.70 mL) and MeTHF
(1.times.70 mL). The combined organic portions were washed with 5%
NaCl (70 mL), dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure to afford a brown oil. The resulting oil was
dissolved in acetonitrile (55.0 mL) at 55.degree. C., allowed to
reach 25-30.degree. C. and filtered. The cake was rinsed with 5 mL
acetonitrile. The mixture was then concentrated to an oil (approx.
30-40% by weight), diluted with acetonitrile at 50.degree. C. The
resulting solid was collected by filtration. The cake was washed
with acetonitrile (2.times.12 mL) and air dried for 1 h. The
product was dried in a vacuum over at 50.degree. to afford 3.52 g
(34.7%) of an off-white solid.
Example 2
Synthesis of
1-methyl-7-[2-(4-methyl-piperizin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-ca-
rboxylic acid (2-tert-butyl-5-methoxy-pyidin-4-yl)-amide
[0126] ##STR39##
[0127] To a solution of 2-tert-butyl-5-hydroxy-isonicotinonitrile
(10.0 g, 73.5 mmol) in acetonitrile/methanol (9:1, 20 mL) was added
N,N-diisopropylethylamine (1.48 mL, 8.52 mmol) followed by
(trimethylsilyl)diazomethane (2.0M in hexane, 4.30 mL, 8.52 mmol).
The red solution was stirred for 18 h at room temperature and then
concentrated in vacuo. The residue was dissolved in methylene
chloride, washed with saturated aqueous NaHCO.sub.3 dried over
sodium sulfate, filtered, and concentrated in vacuo to provide
2-tert-butyl-5-methoxy-isonicotinonitrile (1.10 g, 99%) as a pale
yellow oil which was utilized without further purification.
[0128] The above nitrile (1.10 g, 5.68 mmol) was dissolved in
aqueous sulfuric acid (9.0 M in water, 6.0 mL) and heated to
120.degree. C. for 8 h. The solution was cooled to room temperature
and NaOH (.about.2.0 g) was added slowly to neutralize the
solution. The mixture was then diluted with an equal volume of
saturated aqueous KH.sub.2PO.sub.4 and extracted several times with
25% 2-propanol in chloroform. The extracts were combined, dried
over sodium sulfate, filtered, and concentrated in vacuo to provide
2-tert-butyl-5-methoxy-isonicotinic acid (1.09 g, 92%) as a pale
brown solid which was utilized without further purification.
[0129] Ethyl chloroformate (101 microL, 1.05 mmol) was added
dropwise to a solution of the above acid (200 mg, 0.96 mmol) and
N,N-diisopropylethylamine (183 microL, 1.05 mmol) in acetone (1.0
mL) at 0.degree. C. The mixture was stirred for 0.5 h at 0.degree.
C. then warmed to room temperature and stirred an additional 0.5 h.
Lastly, a solution of sodium azide (5.0 M in water, 400 .mu.L, 2.00
mmol) was added and the resultant slurry was stirred at room
temperature for 1 h. Water was added to the reaction mixture and
the aqueous phase was extracted with methylene chloride. Toluene (2
mL) was added to the combined extracts which were subsequently
dried over sodium sulfate, filtered, and concentrated in vacuo to a
volume of 1 mL (Caution was taken to avoid complete concentration).
The resultant toluene solution of the acyl azide was then added
dropwise to a refluxing solution of benzyl alcohol (120 microL,
1.15 mmol) in toluene (1 mL) and the mixture was refluxed an
additional 1.5 h. Concentration in vacuo, followed by filtration of
the residue through a plug of silica-gel with diethyl ether
provided the crude Cbz-protected aniline. This crude product was
immediately dissolved in ethanol/water (10:1, 3.0 mL) in a Parr
hydrogenation vessel and Pd(OH).sub.2 (20% on carbon, 20 mg) was
added. The reaction was placed under a hydrogen atmosphere (50 psi)
and shaken at room temperature for 0.25 h. The solution was then
filtered through diatomaceous earth, concentrated and the residue
was purified by silica-gel chromatography (ethyl acetate) to
provide 2-tert-butyl-5-methoxy-pyridin-4-ylamine (95 mg, 56%) as a
white solid.
[0130] To a slurry of 7-benzyloxy-1-methyl-1H-indole-2-carboxylic
acid (163 mg, 0.58 mmol) in methylene chloride (2 mL) at 0.degree.
C. was added oxalyl chloride (72 microL, 0.84 mmol) followed by a
drop of N,N-dimethylformamide. The solution immediately bubbled and
became clear after a period of 0.75 h. The mixture was concentrated
and redissolved in methylene chloride (1.5 mL). The acid chloride
solution was added to a solution of N,N-diisopropylethylamine (202
microL, 1.16 mmol) and 2-tert-butyl-5-methoxy-pyridin-4-ylamine (95
mg, 0.52 mmol) in methylene chloride (1.5 mL). The solution was
stirred at room temperature for 3 h then poured onto saturated
aqueous NaHCO.sub.3. The aqueous layer was extracted with methylene
chloride and the combined extracts were washed with saturated
aqueous NaHCO.sub.3, followed by saturated aqueous
KH.sub.2PO.sub.4, and again with saturated aqueous NaHCO.sub.3. The
organic extracts were dried over sodium sulfate, filtered through a
plug of silica-gel with diethyl ether, and concentrated in vacuo to
provide pure 7-benzyloxy-1-methyl-1H-indole-2-carboxylic acid
(2-tert-butyl-5-methoxy-pyidin-4-yl)-amide (231 mg, 99%) as a white
solid.
[0131] Pd(OH).sub.2 (20% on C, 24 mg) was added to a solution of
the above indole (231 mg, 0.52 mmol) in ethanol/ethyl acetate (3:2,
5.0 mL) at room temperature. The solution was placed under a
hydrogen atmosphere (1 atm) and stirred at room temperature for 18
h. The mixture was filtered through diatomaceous earth and
concentrated in vacuo to provide
7-hydroxy-1-methyl-1H-indole-2-carboxylic acid
(2-tert-butyl-5-methoxy-pyidin-4-yl)-amide (199 mg, 99%) as a pale
brown solid.
[0132] A solution of the above indole amide (93 mg, 0.26 mmol) and
DBU (40 micro L, 0.26 mmol) in acetonitrile (1.0 mL) was added
dropwise to a slurry of 2,4-dichloropyrimidine (39 mg, 0.26 mmol)
in acetonitrile (1.0 mL). The solution was stirred for 18 h at
30.degree. C. and an additional equivalent of DBU (40 microL, 0.26
mmol) was added to the solution, followed by 1-methylpiperizine
(146 microL, 1.32 mmol). The mixture was heated to 60.degree. C.
for 1 h then concentrated in vacuo. The residue was partitioned
between saturated aqueous NaHCO.sub.3 and methylene chloride. The
aqueous layer was extracted with methylene chloride. The combined
organic extracts were dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by semi-prep HPLC
to provide the title compound, (22 mg, 16%) as a white solid (.3TFA
salt): mp: 72-74.degree. C. (dec.); ESI MS m/z 530
[C.sub.29H.sub.35N.sub.7O.sub.3+H].sup.+; HPLC >95%,
t.sub.R=13.68 min.
Example 3
Synthesis of 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic
acid (5-tert-butyl-2-methanesulfinyl-phenyl)-amide
[0133] ##STR40##
[0134] Triflic anhydride (4.14 mL, 24.6 mmol) was added dropwise to
a solution of 4-tert-butyl-2-nitrophenol (4.00 g, 20.5 mmol) and
pyridine (2.16 mL, 26.7 mmol) in methylene chloride (50 mL) at
0.degree. C. The yellow solution was stirred 0.25 h at 0.degree.
C., poured onto saturated aqueous NaHCO.sub.3 and extracted with
methylene chloride. The combined extracts were washed with
saturated aqueous NaHCO.sub.3, dried over sodium sulfate, filtered,
and concentrated in vacuo. The residue was purified by filtration
through a plug of silica-gel (methylene chloride) to provide
trifluoro-methanesulfonic acid 4-tert-butyl-2-nitro-phenyl ester
(5.82 g, 87%) as a pale yellow oil which was utilized without
further purification.
[0135] Sodium thiomethoxide (1.86 g, 26.6 mmol) was added to a
cooled solution of the above triflate (5.80 g, 17.7 mmol) in DMF
(35 mL) at 0.degree. C. The red solution was warmed to room
temperature and stirred at that temperature for 0.75 h, poured onto
saturated aqueous NaHCO.sub.3 and the aqueous layer was extracted
with hexane. The combined extracts were washed with saturated
aqueous NaHCO.sub.3, dried over sodium sulfate, filtered, and
concentrated in vacuo to provide a mixture (1:1) of the desired
product and starting phenol. The residue was purified
recrystallization from hexane to provide a yellow precipitate which
was filtered off and washed with hexane. The remaining filtrate was
concentrated in vacuo and repurified by silica-gel chromatography
(3% diethyl ether in hexanes). The purified products were combined
to provide 4-tert-butyl-1-methylsulfanyl-2-nitro-benzene (2.19 g,
55%) as a bright yellow solid.
[0136] Sodium periodate (1.23 g, 5.76 mmol) in water (2.0 mL) was
added to a solution of the above thioether (1.08 g, 4.80 mmol) in
methanol/THF (2:1, 15 mL). The mixture was stirred at 50.degree. C.
for 24 h, then the solvent was concentrated in vacuo. The residue
was diluted with diethyl ether and washed with water and saturated
aqueous NaHCO.sub.3, dried over sodium sulfate, filtered, and
concentrated in vacuo. Purification of the crude product by
silica-gel chromatography (methylene chloride--50% ethyl acetate in
methylene chloride) provided
4-tert-butyl-1-methanesulfinyl-2-nitro-benzene (1.05 g, 91%) as a
white solid.
[0137] Tin(II)chloride dihydrate (2.84 g, 12.6 mmol) was added to a
solution of the above sulfoxide (1.01 g, 4.19 mmol) in ethyl
acetate (20 mL). The mixture was heated to reflux for 0.25 h upon
which the solution became red in color. The solution was cooled to
room temperature and poured onto aqueous 2.0 M NaOH. The aqueous
phase was extracted with diethyl ether and the combined organic
layers were washed with saturated aqueous NaHCO.sub.3. The combined
organic extracts were dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was redissolved in diethyl ether
and extracted (3.times.) with 1.0 M HCl. The pH of the combined
aqueous layers was adjusted to pH=10 with NaHCO.sub.3 and extracted
with methylene chloride. The combined organic layers were dried
over sodium sulfate, filtered and concentrated in vacuo to provide
5-tert-butyl-2-methanesulfinyl-phenylamine (693 mg, 78%) as a white
solid.
[0138] 1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(127 mg, 0.473 mmol) and HATU (180 mg, 0.473 mmol) were combined in
DMF (900 microL) and stirred for 5 min at room temperature. The
above aniline (100 mg, 0.473 mmol) was added to the reaction
mixture followed by N,N-diisopropylethylamine (247 microL, 1.42
mmol). The solution was stirred at room temperature for 18 h then
poured onto saturated aqueous NaHCO.sub.3. The aqueous layer was
extracted with methylene chloride and the combined extracts were
dried over sodium sulfate, filtered, and concentrated in vacuo.
Purification by silica-gel chromatography (diethyl ether--1%
methanol in diethyl ether) provided the title compound, in 92%
purity. Trituration with diethyl ether provided pure
1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-2-methanesulfinyl-phenyl)-amide (63 mg, 33%) as a
white solid, mp: 88-92.degree. C. (dec.); ESI MS m/z 462
[C.sub.26H.sub.27N.sub.3O.sub.3S+H].sup.+; HPLC >96%,
t.sub.R=15.89 min.
Example 4
Synthesis of 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic
acid (5-tert-butyl-2-methanesulfonyl-phenyl)-amide
[0139] ##STR41##
[0140] 3-Chloroperoxybenzoic acid (77%, 1.84 g, 10.6 mmol) was
added to a solution of
4-tert-butyl-1-methylsulfanyl-2-nitro-benzene (800 mg, 3.55 mmol)
in methylene chloride (7.0 mL) at 0.degree. C. The mixture was
stirred at room temperature for 5 h, diluted with diethyl ether and
poured onto saturated aqueous NaHCO.sub.3. The organic layer was
washed twice with saturated aqueous NaHCO.sub.3, twice with
saturated aqueous Na.sub.2CO.sub.3, dried over sodium sulfate,
filtered, and concentrated in vacuo. Purification by silica-gel
chromatography (20% ethyl acetate in hexane) provided
4-tert-butyl-1-methanesulfonyl-2-nitro-benzene (781 mg, 86%) as a
white solid.
[0141] Tin(II)chloride dihydrate (2.73 g, 12.1 mmol) was added to a
solution of the above sulfone (777 mg, 3.02 mmol) in ethyl acetate
(15 mL). The mixture was heated to reflux for 0.5 h then cooled to
room temperature and poured onto aqueous 2.0 M NaOH. The aqueous
phase was extracted with diethyl ether and the combined organic
layers were washed with saturated aqueous NaHCO.sub.3, dried over
sodium sulfate, filtered and concentrated in vacuo to provide pure
5-tert-butyl-2-methanesulfonyl-phenylamine (618 mg, 90%) as a white
solid.
[0142] 1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(47 mg, 0.177 mmol) and the above aniline (50 mg, 0.194 mmol) were
dissolved in pyridine (600 microL) at room temperature. Phosphorus
oxychloride (18 micro L, 0.194 mmol) was added dropwise to the
solution and the reaction mixture was stirred at room temperature
for 0.5 h. The solvent was concentrated and the residue was
partitioned between saturated aqueous NaHCO.sub.3 and methylene
chloride. The aqueous layer was extracted with methylene chloride
and the combined organic extracts were dried over sodium sulfate,
filtered, and concentrated in vacuo. Purification by silica-gel
chromatography (1% methanol in diethyl ether) provided
1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-2-methanesulfonyl-phenyl)-amide (54 mg, 34%) as a
white solid: mp: 158-159.degree. C. (dec.); ESI MS m/z 478
[C.sub.26H.sub.27N.sub.3O.sub.4S+H].sup.+; HPLC >97%,
t.sub.R=18.07 min.
Example 5
Synthesis of 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic
acid (5-tert-butyl-2-oxo-1,2-dihydropyridin-3-yl)-amide
[0143] ##STR42##
[0144] 3-Nitro-5-tert-butyl-1H-pyidin-2-one (360 mg, 1.83 mmol) was
dissolved in methanol/ethyl acetate (2:1, 3 mL) and placed in a
Parr hydrogenation vessel. Pd (10% on carbon, 36 mg) was added and
the reaction was placed under a hydrogen atmosphere (50 psi) and
shaken at room temperature for 2 h. The solution was then filtered
through diatomaceous earth and concentrated in vacuo. The residue
was redissolved in diethyl ether and extracted (3.times.) with 1.0
M HCl. The pH of the combined aqueous layers was adjusted to 10
with NaHCO.sub.3 and extracted with methylene chloride. The
combined organic layers were dried over sodium sulfate, filtered
and concentrated in vacuo to provide
3-amino-5-tert-butyl-1H-pyidin-2-one (195 mg, 64%) as a pale green
solid: ESI MS m/z 166 [C.sub.9H.sub.14N.sub.2O+H].sup.+.
[0145] 1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(145 mg, 0.542 mmol) and HATU (206 mg, 0.542 mmol) were combined in
DMF (1 mL) and stirred 5 min at room temperature. The above
aminopyridinone (90 mg, 0.542 mmol) was added to the reaction
mixture followed by N,N-diisopropylethylamine (283 microL, 1.63
mmol). The solution was stirred at room temperature for 72 h then
poured into saturated aqueous NaHCO.sub.3. The aqueous layer was
extracted with chloroform and the combined extracts were dried over
sodium sulfate, filtered, and concentrated in vacuo. Purification
by silica-gel chromatography (2% ammonium hydroxide, 50% ethyl
acetate in hexane) provided
1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-2-oxo-1,2-dihydropyridin-3-yl)-amide (163 mg, 73%) as
a white solid: mp: 236-238.degree. C. (dec.); ESI MS m/z 417
[C.sub.24H.sub.24N.sub.4O.sub.3+H].sup.+; HPLC >97%,
t.sub.R=14.74 min.
Example 6
Synthesis of 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic
acid
(5-tert-butyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-amide
[0146] ##STR43##
[0147] Ethyl nitroacetate (1.64 g, 12.3 mmol) was added to a
solution of methylamine (33% in methanol, 7.7 mL, 61.6 mmol) and
the solution was stirred at room temperature for 18 h. The solvent
was concentrated in vacuo and the residue was dissolved in aqueous
1.0 M HCl. The aqueous layer was washed with diethyl ether and the
organic washings were discarded. The aqueous layer was then
extracted with ethyl acetate and the combined organic layers were
dried over sodium sulfate, filtered and concentrated in vacuo to
provide N-methyl-2-nitro-acetamide (961 mg, 66%) as a pale yellow
solid.
[0148] To a solution of 2-tert-butyl-malonaldehyde (385 mg, 3.00
mmol) and the above amide (355 mg, 3.00 mmol) dissolved in ethanol
(6.0 mL) was added pyrrolidine (63 microL, 0.750 mmol). The mixture
was heated at reflux for 18 h and concentrated in vacuo.
Purification by silica-gel chromatography (75% ethyl acetate in
hexanes) provided 5-tert-butyl-1-methyl-3-nitro-1H-pyridin-2-one
(186 mg, 30%) as an orange solid.
[0149] The above nitro pyridine (186 mg, 0.886 mmol) was dissolved
in methanol/ethyl acetate (2:1, 3 mL) and placed in a Parr
hydrogenation vessel. Pd (10% on carbon, 20 mg) was added and the
reaction was placed under a hydrogen atmosphere (50 psi) and shaken
at room temperature for 1 h. The solution was then filtered through
diatomaceous earth and concentrated in vacuo. The residue was
redissolved in diethyl ether and extracted (3.times.) with 1.0 M
HCl. The pH of the combined aqueous layers was adjusted to 10 with
NaHCO.sub.3 and extracted with methylene chloride. The combined
organic layers were dried over sodium sulfate, filtered and
concentrated in vacuo to provide
3-amino-5-tert-butyl-1-methyl-1H-pyridin-2-one (110 mg, 69%) as a
blue solid: .sup.1ESI MS m/z 180
[C.sub.10H.sub.16N.sub.2O.sub.3+H].sup.+.
[0150] 1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(125 mg, 0.466 mmol) and the above aminopyridinone (84 mg, 0.466
mmol) were dissolved in pyridine (1.5 mL) at room temperature.
Phosphorus oxychloride (48 micro L, 0.513 mmol) was added dropwise
to the solution and the reaction mixture was stirred at room
temperature for 0.5 h. The solvent was concentrated in vacuo and
the residue was partitioned between saturated aqueous NaHCO.sub.3
and methylene chloride. The aqueous layer was extracted with
methylene chloride and the combined organic extracts were dried
over sodium sulfate, filtered, and concentrated in vacuo.
Purification by silica-gel chromatography (50% ethyl acetate in
methylene chloride) provided
1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-amide (65 mg,
33%) as a pale pink solid: mp: 74-76.degree. C. (dec.); ESI MS m/z
431 [C.sub.25H.sub.26N.sub.4O.sub.3+H].sup.+; HPLC >97%,
t.sub.R=15.69 min.
Example 7
Synthesis of 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic
acid (5-tert-butyl-2-methyl-pyridin-3-yl)-amide
[0151] ##STR44##
[0152] To a solution of 5-tert-butyl-2-chloro-3-nitro-pyridine (554
mg, 2.58 mmol) dissolved in 10% aqueous dioxane (5.0 mL) was added
potassium carbonate (1.07 g, 7.74 mmol), trimethylboroxine (395 mL,
2.84 mmol), and lastly tetrakis-(triphenylphosphine)palladium (149
mg, 0.129 mmol). The solution was heated in a sealed tube to
100.degree. C. for 18 h, cooled to room temperature and diluted
with ether. The organic layer was washed twice with saturated
aqueous NaHCO.sub.3, dried over sodium sulfate, filtered, and
concentrated in vacuo. Purification by silica-gel chromatography
(10% ethyl acetate in hexane) provided
5-tert-butyl-2-methyl-3-nitro-pyridine (388 mg, 75%) as colorless
oil.
[0153] The above pyridine (388 mg, 1.99 mmol) was dissolved in
ethanol (6 mL) and placed in a Parr hydrogenation vessel. Pd (10%
on carbon, 20 mg) was added and the reaction was placed under a
hydrogen atmosphere (50 psi) and shaken at room temperature for 18
h. The solution was then filtered through diatomaceous earth,
concentrated in vacuo to provide
5-tert-butyl-2-methyl-pyidin-3-ylamine (340 mg, 99%) as a pale
orange solid: ESI MS m/z 164 [C.sub.10H.sub.16N.sub.2+H].sup.+.
[0154] 1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(183 mg, 0.683 mmol) and HATU (259 mg, 0.683 mmol) were combined in
DMF (1.2 mL) and stirred 5 min at room temperature. The above
aminopyridine (102 mg, 0.621 mmol) was added to the reaction
mixture followed by N,N-diisopropylethylamine (326 microL, 1.86
mmol). The solution was stirred at room temperature for 18 h then
poured onto saturated aqueous NaHCO.sub.3. The aqueous layer was
extracted with methylene chloride and the combined extracts were
dried over sodium sulfate, filtered, and concentrated in vacuo.
Purification by silica-gel chromatography (1% ammonium hydroxide,
50% ethyl acetate in methylene chloride) provided
1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-2-methyl-pyridin-3-yl)-amide (163 mg, 63%) as a pale
yellow solid: mp: 52-56.degree. C. (dec.); ESI MS m/z 415
[C.sub.25H.sub.26N.sub.4O.sub.2+H].sup.+; HPLC >95%,
t.sub.R=12.29 min.
Example 8
Synthesis of 3-Amino-5-tert-butyl-2-methoxy-benzonitrile
[0155] ##STR45##
[0156] To a solution of 5-tert-butyl-2-hydroxybenzaldehyde (1.25 g,
7.0 mmol) in ethyl acetate (15 mL) was added (NO).sup.+
18-crown-6-H(NO.sub.3).sub.2 (2.64 g, 6.3 mmol). The solution
turned yellow and was stirred at room temperature for 5 h. The
solvent was evaporated, giving a residue which was taken up in
ether. The ether was washed 4.times. with saturated NH.sub.4Cl,
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to
give 5-tert-butyl-2-hydroxyl-3-nitro-benzaldehyde (1.56 g, 99%) as
a yellow solid.
[0157] The above aldehyde (1.4 g, 6.3 mmol), hydroxylamine
hydrochloride (0.438 g, 6.3 mmol), and sodium formate (0.771 g,
11.3 mmol) in formic acid (20 mL) were heated overnight, at reflux,
then cooled to room temperature. The reaction was diluted with
water, and the resulting precipitate was filtered. The solid was
taken up in ether, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to yield
5-tert-butyl-2-hydroxyl-3-nitro-benzonitrile (1.21 g, 87%) as a
yellow solid.
[0158] The above nitrile (0.5 g, 2.27 mmol) was taken up in 1:9
methanol/acetonitrile (20 mL). N,N-diisopropylethylamine (1.1 mL,
6.35 mmol) was added dropwise followed by
(trimethylsilyl)diazomethane (3.2 mL, 6.35 mmol). The reaction was
stirred until the bubbling stopped (20 min) and the reaction was
quenched with water. The water was extracted 3.times. with
methylene chloride, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo to give
5-tert-butyl-2-methoxy-3-nitro-benzonitrile (0.531 g, 99%) as a
yellow solid.
[0159] The above benzonitrile (100 mg, 0.427 mmol) was dissolved in
1:1 ethyl acetate/methanol (10 mL) in a nitrogen-flushed flask.
Ammonium formate (270 mg, 4.27 mmol) and palladium on carbon (30
mg, 10% wet) were added and the mixture was heated to reflux for 30
min. The reaction was cooled to room temperature and filtered
through a pad of diatomaceous earth, eluting with ethyl acetate.
The ethyl acetate was evaporated under vacuum. The resulting
residue was purified by chromatography on silica gel (1:1 ethyl
acetate/hexanes) to afford the title compound, (67 mg, 77%) as a
colorless oil.
Example 9
Synthesis of 6-tert-butyl-3-methoxy-pyridine-2,4-diamine
[0160] ##STR46##
[0161] 2-tert-Butyl-5-ethoxy-oxazole (16.6 g, 98.1 mmol) was
dissolved in freshly distilled ethyl acrylate (11.7 mL, 108 mmol).
The solution was heated in a sealed tube to 100.degree. C. for 24
h. Upon cooling, the remaining starting materials were distilled
away from the product which was further purified by filtration
through a plug of silica-gel (methylene chloride) and concentrated
to provide 2-tert-butyl-5-hydroxy-isonicotinic acid ethyl ester
(11.2 g, 54%) as a pale yellow oil.
[0162] To a solution of the above isonicotinic acid ethyl ester
(2.0 g, 9.47 mmol) in DMF (20 mL) was added N-bromosuccinimide
(1.85 g, 10.4 mmol). The solution was stirred at room temperature
for 0.5 h then poured into saturated aqueous NaHCO.sub.3. The
aqueous layer was extracted with diethyl ether and the combined
organic layers were washed with saturated aqueous NaHCO.sub.3,
dried over sodium sulfate, filtered, and concentrated in vacuo to
provide 2-bromo-6-tert-butyl-3-hydroxy-isonicotinic acid ethyl
ester (2.74 g, 96%) as a pale yellow oil which was utilized without
further purification.
[0163] To a solution of the above bromopyridine (2.74 g, 9.07 mmol)
in acetonitrile/methanol (9:1, 33 mL) was added
N,N-diisopropylethylamine (2.50 mL, 14.2 mmol) followed by
(trimethylsilyl)diazomethane (2.0M in hexane, 7.0 mL, 14.2 mmol).
The red solution was stirred 0.5 h at room temperature then
concentrated in vacuo. The residue was dissolved in methylene
chloride, washed with saturated aqueous NaHCO.sub.3, dried over
sodium sulfate, filtered, and concentrated in vacuo to provide
2-bromo-6-tert-butyl-3-methoxy-isonicotinic acid ethyl ester (2.65
g, 93%) as a red oil which was utilized without further
purification.
[0164] To a solution of the above bromide (2.65 g, 8.39 mmol) in
DMF (18 mL) was added copper(I)cyamide (3.8 g, 42 mmol). The
mixture was heated to 100.degree. C. for 18 h then cooled to room
temperature. The resultant black solution was poured into saturated
aqueous NaHCO.sub.3 and the aqueous layer was extracted with
diethyl ether. The combined organic extracts were washed with
saturated aqueous NaHCO.sub.3, dried over sodium sulfate, filtered
through a plug of silica gel (methylene chloride), and concentrated
in vacuo to provide 6-tert-butyl-2-cyano-3-methoxy-isonicotinic
acid ethyl ester (1.55 g, 70%) as a yellow oil which was utilized
without further purification.
[0165] To a solution of the above nitrile (616 mg, 2.35 mmol) in
ethanol (8.0 mL) was added NaOH (2.0 M in water, 8.3 mL, 16.5
mmol). The mixture was heated to reflux for 20 h then cooled to
room temperature and the ethanol was concentrated in vacuo. The
basic solution was neutralized with 12 N HCl to a pH=6 then
extracted with chloroform/isopropanol (3:1). The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated
in vacuo to provide
6-tert-butyl-3-methoxy-pyridine-2,4-dicarboxylic acid (402 mg, 68%)
as a yellow solid which was utilized without further
purification.
[0166] To a solution of the above diacid (123 mg, 0.49 mmol) in
methylene chloride/THF (3:1, 1.0 mL) was added oxalyl chloride (104
microL, 1.21 mmol) followed by 1 drop of DMF. The solution
initially bubbled and was stirred at room temperature for 3 h, then
concentrated in vacuo. The residue was dissolved in dry acetone
(1.0 mL) and a solution of sodium azide (2 M in water, 1.45 mL, 3.9
mmol) was added all at once. The mixture was immediately poured
onto water and the aqueous layer extracted with methylene chloride.
To the combined extracts was added toluene (4.0 mL) and the organic
layer was dried over sodium sulfate, filtered, and concentrated in
vacuo to approximately 1 mL of toluene remaining. An additional
amount of toluene (5.0 mL) was added and this was again
concentrated in vacuo to about 1.0 mL of toluene remaining. The
resulting solution of diacyl azide was added dropwise to a
refluxing solution of benzyl alcohol (116 microL, 1.12 mmol) in
toluene (1.0 mL) which immediately evolved nitrogen. After heating
the solution at reflux for 2 h, the mixture was cooled to room
temperature and concentrated in vacuo to provide
(4-benzyloxycarbonylamino-6-tert-butyl-3-methoxy-pyridin-2-yl)-carbamic
acid benzyl ester.
[0167] To a solution of the crude dicarbamate from above in ethanol
(3.0 mL) was added Pd(OH).sub.2 (20% on carbon, 20 mg). The mixture
was placed in a Parr shaker and hydrogenated (50 psi) for 18 h. The
solution was filtered and concentrated in vacuo. The resultant
residue was purified by silica gel chromatography (1% concentrated
ammonium hydroxide-5% methanol in chloroform) to provide the title
compound, (43 mg, 45% over 2 steps) as a white solid: ESI MS m/z
196 [C.sub.10H.sub.17N.sub.3O+H].sup.+.
Example 10
Synthesis of 1-methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic
acid
[5-tert-butyl-2-methoxy-3-(2-oxo-azetidin-1-yl)-phenyl]-amide
[0168] ##STR47##
[0169] 2-Bromo-4-tert-butylanisole (4.54 g, 18.67 mmol) was
dissolved in acetic anhydride (15 mL) and the solution was cooled
to 0.degree. C. A solution of nitric acid (70%, 2.5 mL) in acetic
anhydride (2.5 mL) was prepared by the dropwise addition of
HNO.sub.3 (70%, 2.5 mL) to Ac.sub.2O at 0.degree. C. The HNO.sub.3
solution was pre-cooled to 0.degree. C., and added dropwise to the
stirred solution of the 2-bromo-4-tert-butylanisole over 5 min. The
mixture was stirred at 0.degree. C. for 1 h, then allowed to warm
to room temperature and stirred overnight. The reaction mixture was
diluted with EtOAc (150 mL) and saturated NaHCO.sub.3 (50 mL) This
mixture was then neutralized by gradual addition of solid
NaHCO.sub.3 until the pH was between 7-8. The organic layer was
separated, washed with brine (50 mL) and dried over anhydrous
Na.sub.2SO.sub.4. The solvents were removed in vacuo, the residue
was purified by column chromatography (eluting with 3:1
hexane-EtOAc) to give 2-bromo-4-tert-butyl-6-nitroanisole (2 g,
37%).
[0170] An oven-dried Schlenk tube was charged with the above
nitroanisole (500 mg, 1.74 mmol), 2-azetidinone (150 mg, 2.1 mmol),
tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.1 mmol)
and cesium carbonate (795 mg, 2.44 mmol). The tube was capped with
a rubber septum, purged with argon and 1,4-dioxane (7 mL) was then
added through the septum via a syringe. The tube was sealed with a
teflon screwcap and the reaction mixture was stirred at 100.degree.
C. for 20 h. The reaction mixture was cooled to room temperature,
diluted with EtOAc (100 mL), washed with water, brine and dried
over anhydrous Na.sub.2SO.sub.4. The solvent was removed in vacuo,
and the crude product was purified by column:chromatography (2:1
hexane-EtOAc) to give
1-(5-tert-butyl-2-methoxy-3-nitro-phenyl)-azetidin-2-one (516 mg,
quantitative).
[0171] A mixture of the above coupled nitroanisole (250 mg, 0.90
mmol) and Pd (10% on carbon, 60 mg) in absolute EtOH (5 mL) was
stirred under H.sub.2 (1 atm) overnight. The reaction mixture was
filtered through diatomaceous earth, and solid residue was rinsed
with EtOAc (20 mL). The filtrate was concentrated in vacuo to give
1-(3-amino-5-tert-butyl-2-methoxy-phenyl)-azetidin-2-one (210 mg,
94%), which was used in next step without further purification.
[0172] To a suspension of
1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (40 mg,
0.15 mmol) in DMF (1 mL) was added Hunig's base (52 microL, 0.3
mmol) resulting in a clear solution. After 5 min, HATU (90 mg, 0.23
mmol) and HOAT (3 mg, 0.02 mmol) were added followed by the above
anisidine (37 mg, 0.15 mmol). The mixture was stirred overnight.
The reaction mixture was diluted with EtOAc (30 mL), washed with
water, brine, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated in vacuo. The crude product was purified by column
chromatography (eluting with 30-80% EtOAc in hexane) to give the
title compound (50 mg, 75%).
Example 11
Synthesis of 1-methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic
acid
[5-tert-butyl-2-methoxy-3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide
[0173] ##STR48##
[0174] An oven-dried Schlenk tube was charged with
2-bromo-4-tert-butyl-6-nitroanisole (500 mg, 1.74 mmol),
2-pyrrolidinone (158 .mu.L, 2.09 mmol), Pd.sub.2(dba).sub.3 (32 mg,
0.035 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58
mg, 0.1 mmol) and Cs.sub.2CO.sub.3 (795 mg, 2.44 mmol). The tube
was capped with a rubber septum, purged with argon and 1,4-dioxane
(7 mL) was then added through the septum via a syringe. The tube
was sealed with a teflon screwcap, and the reaction mixture was
stirred at 100 C for 20 h. The reaction mixture was cooled to room
temperature, diluted with EtOAc (100 mL), washed with water, brine
and dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed
in vacuo, and crude product was purified by column chromatography
(2:1 hexane-EtOAc) to give
1-(5-tert-butyl-2-methoxy-3-nitro-phenyl)-pyrrolidin-2-one (150 mg,
30%).
[0175] A mixture of the above coupled nitroanisole (145 mg, 0.50
mmol) and Pd (10% on carbon, 40 mg) in EtOAc (5 mL) was stirred
under H.sub.2 (1 atm) overnight. The reaction mixture was filtered
through diatomaceous earth and solid residue was rinsed with EtOAc
(20 mL). The filtrate was concentrated in vacuo to give
1-(3-amino-5-tert-butyl-2-methoxy-phenyl)-pyrrolidin-2-one (100 mg,
77%), which was used in the next step without further
purification.
[0176] To a suspension of
1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (40 mg,
0.15 mmol) in DMF (1 mL) was added Hunig's base (52 microL, 0.3
mmol) resulting in a clear solution. After 5 min, HATU (90 mg, 0.23
mmol) and HOAT (3 mg, 0.02 mmol) were added followed by the above
anisidine (39 mg, 0.15 mmol). The mixture was stirred overnight.
The reaction mixture was diluted with EtOAc (30 mL), washed with
water, brine, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated in vacuo. The crude product was purified by column
chromatography (eluting with 30-80% EtOAc in hexane) to give the
title compound (60 mg, 78%).
Example 12
Synthesis of
N-[3-amino-2-methoxy-5-(1-methylcyclopropyl)-phenyl]-methanesulfonamide
[0177] ##STR49##
[0178] To a solution of 4-hydroxyacetophenone (10.0 g, 73.5 mmol)
in DMF (74 mL) was added imidazole (12.0 g, 176.3 mmol) and
tert-butyldimethylsilyl chloride (13.3 g, 88.1 mmol). The colorless
solution was stirred for 0.75 h at room temperature then quenched
with saturated aqueous NaHCO.sub.3. The aqueous phase was extracted
with hexanes and the combined organic layers were washed with
saturated aqueous NaHCO.sub.3. The organic layers were dried over
sodium sulfate, filtered, and concentrated to provide the silyl
ether (18.0 g, 98%) as a white solid which was utilized without
further purification.
[0179] Methyl(triphenylphosphonium)bromide (17.1 g, 48.0 mmol) was
suspended in THF (96 mL) and cooled to 0.degree. C. n-Butyllithium
(2.5 M in hexane, 19.2 mL, 48.0 mmol) was added dropwise to the
mixture. The red solution was stirred at room temperature for 0.5
h. The acetophenone silyl ether (10.0 g, 40.0 mmol) from above was
added. The solution turned bright yellow and a white precipitate
formed. The mixture was stirred for 1 h at room temperature and
then the solution was quenched with saturated aqueous NaHCO.sub.3.
The aqueous phase was extracted with diethyl ether and the combined
organic layers were washed with saturated aqueous NaHCO.sub.3. The
organic layers were dried over sodium sulfate, filtered and
concentrated. The resulting mixture was eluted through a plug of
silica gel (hexanes) and the filtrate was concentrated to provide
the styrene (8.36 g, 84%) as a colorless oil.
[0180] Diethylzinc (1.0 M in hexanes, 69 mL, 69 mmol) was added to
a solution of the above styrene intermediate (6.85 g, 27.6 mmol) in
dichloroethane at 0.degree. C. Diiodomethane (11.2 mL, 138 mmol)
was then added dropwise to the solution and the resulting mixture
was stirred at 0.degree. C. for 0.5 h and allowed to warm to room
temperature for 2 h. The opaque mixture was quenched with saturated
aqueous NH.sub.4Cl. The aqueous phase was extracted with methylene
chloride and the combined organic layers were washed with saturated
aqueous NaHCO.sub.3. The organic layers were dried over sodium
sulfate, filtered through diatomaceous earth, and concentrated. The
crude residue was dissolved in THF (50 mL) and TBAF (1.0 M in THF,
28 mL, 28 mmol) was added at room temperature. The solution was
stirred for 2 h and then quenched with aqueous 1.0 M HCl. The
aqueous phase was extracted with EtOAc and the combined organic
layers were washed with saturated aqueous NaHCO.sub.3. The organic
layers were dried over sodium sulfate, filtered and concentrated.
Purification by silica-gel chromatography (1% 2-propanol/12% EtOAc
in hexanes) provided the phenol intermediate (2.77 g, 68%) as a
white solid:
[0181] (NO)18-crown-6-H(NO.sub.3).sub.2.sup.1 (18.0 g, 43.0 mmol)
was added to a solution of the above phenol intermediate (2.77 g,
18.7 mmol) in EtOAc. The reaction mixture was heated to reflux for
5 min and then cooled to room temperature. The mixture was poured
into aqueous 1.0 M HCl. The aqueous phase was extracted with
diethyl ether. The combined organic layers were dried over sodium
sulfate, filtered and concentrated. The residue was dissolved in
acetonitrile/MeOH (9:1, 62 mL), cooled to 0.degree. C. and
N,N-diisopropylethylamine (13 mL, 74.8 mmol) was added slowly. The
deep red solution was warmed to room temperature and
trimethylsilyldiazomethane (2.0 M in hexane, 18.7 mL, 37.4 mmol)
was added slowly to control nitrogen evolution. After stirring at
room temperature for 0.5 h, the mixture was concentrated and
partitioned between methylene chloride and saturated aqueous
NH.sub.4Cl. The aqueous layer was extracted with methylene chloride
and the combined extracts were dried over sodium sulfate, filtered
and concentrated. Purification by silica-gel chromatography (6%
EtOAc in hexanes) provided the dinitroanisole (2.21 g, 47%) as a
red oil.
[0182] Tin(II)chloride dihydrate (11.9 g, 52.6 mmol) was added to a
solution of the above dinitroanisole (2.21 g, 8.76 mmol) in EtOAc
(30 mL). The mixture was heated to reflux for 0.25 h upon which the
solution became red in color. The solution was cooled to room
temperature and poured into aqueous 2.0 M NaOH. The aqueous phase
was extracted with EtOAc and the combined organic layers were
washed with saturated aqueous NaHCO.sub.3. The organic layers were
dried over sodium sulfate, eluted through a plug of silica gel (1%
ammonium hydroxide in methylene chloride), and the filtrate was
concentrated. The residue was dissolved in diethyl ether and
extracted (3.times.) with 1.0 M HCl. The pH of the combined aqueous
layers was adjusted to pH=12 with 2.0 M NaOH and extracted with
methylene chloride. The combined organic layers were dried over
sodium sulfate, filtered and concentrated to provide diaminoanisole
(860 mg, 52%) as a red oil.
[0183] Triethylamine (521 .mu.L, 3.74 mmol) was added to a solution
of the above diaminoanisole (718 mg, 3.74 mmol) in methylene
chloride at -10.degree. C. Methanesulfonyl chloride (290 .mu.L,
3.74 mmol) was then added dropwise over a 10 min period and the
resulting solution was allowed to slowly warm to room temperature
over 2 h. The mixture was quenched with saturated aqueous
NaHCO.sub.3 and the aqueous layer was extracted with methylene
chloride. The combined organic layers were dried over sodium
sulfate, filtered and concentrated. Purification by silica gel
chromatography (1% ammonium hydroxide/35% EtOAc in hexanes to 1%
ammonium hydroxide/50% EtOAc in hexanes) provided a red solid which
was triturated with diethyl ether/hexanes (1:1) to yield the title
compound (510 mg, 51%) as a pale brown solid, mp 144-146.degree.
C.
[0184] This intermediate can then be coupled to the indole core and
reacted further by the procedures described in the examples above,
to form desired analogous indole amides.
Methods of Use
[0185] In accordance with the invention, there are provided novel
methods of using the compounds of the formula (I). The compounds
disclosed therein effectively block inflammatory cytokine
production from cells. The inhibition of cytokine production is an
attractive means for preventing and treating a variety of cytokine
mediated diseases or conditions associated with excess cytokine
production, e.g., diseases and pathological conditions involving
inflammation. Thus, the compounds are useful for the treatment of
diseases and conditions as described in the Background section,
including the following conditions and diseases:
[0186] osteoarthritis, atherosclerosis, contact dermatitis, bone
resorption diseases, reperfusion injury, asthma, multiple
sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative
colitis, psoriasis, graft versus host disease, systemic lupus
erythematosus and insulin-dependent diabetes mellitus, rheumatoid
arthritis, toxic shock syndrome, Alzheimer's disease, diabetes,
inflammatory bowel diseases, acute and chronic pain as well as
symptoms of inflammation and cardiovascular disease, stroke,
myocardial infarction, alone or following thrombolytic therapy,
thermal injury, adult respiratory distress syndrome (ARDS),
multiple organ injury secondary to trauma, acute
glomerulonephritis, dermatoses with acute inflammatory components,
acute purulent meningitis or other central nervous system
disorders, syndromes associated with hemodialysis, leukopherisis,
granulocyte transfusion associated syndromes, and necrotizing
enterocolitis, complications including restenosis following
percutaneous transluminal coronary angioplasty, traumatic
arthritis, sepsis, chronic obstructive pulmonary disease and
congestive heart failure. The compounds of the invention may also
be useful for anticoagulant or fibrinolytic therapy (and the
diseases or conditions related to such therapy) as described in the
U.S. application Ser. No. 10/630,599.
[0187] The compounds of the invention are also p38 MAP kinase
inhibitors. Activity can be demonstrated by using methods known in
the art. See for example Branger et al., (2002) J Immunol. 168:
4070-4077, and the 46 references cited therein, each incorporated
herein by reference in their entirety. As disclosed in the
Background of the Invention, the compounds of the invention will
therefore be useful for treating inflammatory and oncological
diseases. These diseases include but are not limited to solid
tumors, such as cancers of the breast, respiratory tract, brain,
reproductive organs, digestive tract, urinary tract, eye, liver,
skin, head and neck, thyroid, parathyroid and their distant
metastases. Those disorders also include lymphomas, sarcomas, and
leukemias.
[0188] Examples of breast cancer include, but are not limited to
invasive ductal carcinoma, invasive lobular carcinoma, ductal
carcinoma in situ, and lobular carcinoma in situ.
[0189] Examples of cancers of the respiratory tract include, but
are not limited to small-cell and non-small-cell lung carcinoma, as
well as bronchial adenoma and pleuropulmonary blastoma and
mesothelioma.
[0190] Examples of brain cancers include, but are not limited to
brain stem, optic and hypothalamic glioma, cerebella and cerebral
astrocytoma, medulloblastoma, ependymoma, as well as pituitary
neuroectodermal and pineal tumor.
[0191] Examples of peripheral nervous system tumors include, but
are not limited to neuroblastoma, ganglioneuroblastoma, and
peripheral nerve sheath tumors.
[0192] Examples of tumors of the endocrine and exocrine system
include, but are not limited to thyroid carcinoma, adrenocortical
carcinoma, pheochromocytoma, and carcinoid tumors.
[0193] Tumors of the male reproductive organs include, but are not
limited to prostate and testicular cancer.
[0194] Tumors of the female reproductive organs include, but are
not limited to endometrial, cervical, ovarian, vaginal, and vulvar
cancer, as well as sarcoma of the uterus.
[0195] Tumors of the digestive tract include, but are not limited
to anal, colon, colorectal, esophageal, gallblader, gastric,
pancreatic, rectal, small-intestine, and salivary gland
cancers.
[0196] Tumors of the urinary tract include, but are not limited to
bladder, penile, kidney, renal pelvis, ureter, and urethral
cancers.
[0197] Eye cancers include, but are not limited to intraocular
melanoma and retinoblastoma.
[0198] Examples of liver cancers include, but are not limited to
hepatocellular carcinoma (liver cell carcinomas with or without
fibrolamellar variant), hepatoblastoma, cholangiocarcinoma
(intrahepatic bile duct carcinoma), and mixed hepatocellular
cholangiocarcinoma.
[0199] Skin cancers include, but are not limited to squamous cell
carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin
cancer, and non-melanoma skin cancer.
[0200] Head-and-neck cancers include, but are not limited to
laryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and
lip and oral cavity cancer.
[0201] Lymphomas include, but are not limited to AIDS-related
lymphoma, non-Hodgkin's lymphoma, Hodgkins lymphoma, cutaneous
T-cell lymphoma, and lymphoma of the central nervous system.
[0202] Sarcomas include, but are not limited to sarcoma of the soft
tissue, osteosarcoma, Ewings sarcoma, malignant fibrous
histiocytoma, lymphosarcoma, angiosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia,
acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic
myelogenous leukemia, and hairy cell leukemia.
[0203] Plasma cell dyscrasias include, but are not limited to
multiple myeloma, and Waldenstrom's macroglobulinemia.
[0204] These disorders have been well characterized in man, but
also exist with a similar etiology in other mammals, and can be
treated by pharmaceutical compositions of the present
invention.
[0205] For therapeutic use, the compounds may be administered in
any conventional dosage form in any conventional manner. Routes of
administration include, but are not limited to, intravenously,
intramuscularly, subcutaneously, intrasynovially, by infusion,
sublingually, transdermally, orally, topically or by inhalation.
The preferred modes of administration are oral and intravenous.
[0206] The compounds may be administered alone or in combination
with adjuvants that enhance stability of the inhibitors, facilitate
administration of pharmaceutic compositions containing them in
certain embodiments, provide increased dissolution or dispersion,
increase inhibitory activity, provide adjunct therapy, and the
like, including other active ingredients. Advantageously, such
combination therapies utilize lower dosages of the conventional
therapeutics, thus avoiding possible toxicity and adverse side
effects incurred when those agents are used as monotherapies. The
above described compounds may be physically combined with the
conventional therapeutics or other adjuvants into a single
pharmaceutical composition. Reference is this regard may be made to
Cappola et al.: U.S. patent application Ser. No. 09/902,822, PCT/US
01/21860 and U.S. application Ser. No. 10/214,782, each
incorporated by reference herein in their entirety. Advantageously,
the compounds may then be administered together in a single dosage
form. In some embodiments, the pharmaceutical compositions
comprising such combinations of compounds contain at least about
5%, but more preferably at least about 20%, of a compound of
formula (I) (w/w) or a combination thereof. The optimum percentage
(w/w) of a compound of the invention may vary and is within the
purview of those skilled in the art. Alternatively, the compounds
may be administered separately (either serially or in parallel).
Separate dosing allows for greater flexibility in the dosing
regime.
[0207] As mentioned above, dosage forms of the compounds described
herein include pharmaceutically acceptable carriers and adjuvants
known to those of ordinary skill in the art. These carriers and
adjuvants include, for example, ion exchangers, alumina, aluminum
stearate, lecithin, serum proteins, buffer substances, water, salts
or electrolytes and cellulose-based substances. Preferred dosage
forms include, tablet, capsule, caplet, liquid, solution,
suspension, emulsion, lozenges, syrup, reconstitutable powder,
granule, suppository and transdermal patch. Methods for preparing
such dosage forms are known (see, for example, H. C. Ansel and N.
G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems,
5th ed., Lea and Febiger (1990)). Dosage levels and requirements
are well-recognized in the art and may be selected by those of
ordinary skill in the art from available methods and techniques
suitable for a particular patient. In some embodiments, dosage
levels range from about 1-1000 mg/dose for a 70 kg patient.
Although one dose per day may be sufficient, up to 5 doses per day
may be given. For oral doses, up to 2000 mg/day may be required.
Reference in this regard may also be made to U.S. application Ser.
No. 10/313,667. As the skilled artisan will appreciate, lower or
higher doses may be required depending on particular factors. For
instance, specific dosage and treatment regimens will depend on
factors such as the patient's general health profile, the severity
and course of the patient's disorder or disposition thereto, and
the judgment of the treating physician.
Biological Assays
Inhibition of TNF Production in THP Cells
[0208] The inhibition of cytokine production can be observed by
measuring inhibition of TNF.alpha. in lipopolysaccharide stimulated
THP cells (for example, see W. Prichett et al., 1995, J.
Inflammation, 45, 97). All cells and reagents were diluted in RPMI
1640 with phenol red and L-glutamine, supplemented with additional
L-glutamine (total: 4 mM), penicillin and streptomycin (50 units/ml
each) and fetal bovine serum (FBS, 3%) (GIBCO, all conc. final).
Assay was performed under sterile conditions; only test compound
preparation was nonsterile. Initial stock solutions were made in
DMSO followed by dilution into RPMI 1640 2-fold higher than the
desired final assay concentration. Confluent THP.1 cells
(2.times.10.sup.6 cells/ml, final conc.; American Type Culture
Company, Rockville, Md.) were added to 96 well polypropylene round
bottomed culture plates (Costar 3790; sterile) containing 125 .mu.l
test compound (2 fold concentrated) or DMSO vehicle (controls,
blanks). DMSO concentration did not exceed 0.2% final. Cell mixture
was allowed to preincubate for 30 min, 37.degree. C., 5% CO.sub.2
prior to stimulation with lipopolysaccharide (LPS; 1 .mu.g/ml
final; Siga L-2630, from E. coli serotype 0111.B4; stored as 1
mg/ml stock in endotoxin screened distilled H.sub.2O at -80.degree.
C.). Blanks (unstimulated) received H.sub.2O vehicle; final
incubation volume was 250 .mu.l. Overnight incubation (18-24 hr)
proceeded as described above. Assay was terminated by centrifuging
plates 5 min, room temperature, 1600 rpm (400.times.g);
supernatants were transferred to clean 96 well plates and stored
-80.degree. C. until analyzed for human TNF.alpha. by a
commercially available ELISA kit (Biosource #KHC3015, Camarillo,
Calif.). Data was analyzed by non-linear regression (Hill equation)
to generate a dose response curve using SAS Software System (SAS
institute, Inc., Cary, N.C.). The calculated IC.sub.50 value is the
concentration of the test compound that caused a 50% decrease in
the maximal TNF.alpha. production.
[0209] Preferred compounds have an IC.sub.50<1 uM in this
assay.
Inhibition of Other Cytokines
[0210] By similar methods using peripheral blood monocytic cells,
appropriate stimuli, and commercially available ELISA kits (or
other method of detection such as radioimmunoassay), for a
particular cytokine, inhibition of IL-1beta, GM-CSF, IL-6 and IL-8
can be demonstrated for preferred compounds (for example, see J. C.
Lee et al., 1988, Int. J. Immunopharmacol., 10, 835).
[0211] All references cited in this application are incorporated
herein by reference in their entirety.
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