U.S. patent application number 10/940053 was filed with the patent office on 2005-02-10 for prodrugs of cox-2 inhibitors.
Invention is credited to Carter, Jeffery S..
Application Number | 20050032852 10/940053 |
Document ID | / |
Family ID | 26962690 |
Filed Date | 2005-02-10 |
United States Patent
Application |
20050032852 |
Kind Code |
A1 |
Carter, Jeffery S. |
February 10, 2005 |
Prodrugs of cox-2 inhibitors
Abstract
A compound of Formula (I), or a pharmaceutically-acceptable salt
thereof, suitable for use in the treatment of a cyclooxygenase-2
mediated disease is provided. 1 Also provided is a pharmaceutical
composition comprising a compound of Formula (I), or a
pharmaceutically-acceptable salt thereof, and a method for
treatment of a cyclooxygenase-2 mediated disease by administering
to a subject in need thereof a therapeutically-effective amount of
the pharmaceutical composition.
Inventors: |
Carter, Jeffery S.;
(Chesterfield, MO) |
Correspondence
Address: |
PHARMACIA CORPORATION
GLOBAL PATENT DEPARTMENT
POST OFFICE BOX 1027
ST. LOUIS
MO
63006
US
|
Family ID: |
26962690 |
Appl. No.: |
10/940053 |
Filed: |
September 14, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10940053 |
Sep 14, 2004 |
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10439023 |
May 15, 2003 |
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6809111 |
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10439023 |
May 15, 2003 |
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10123730 |
Apr 16, 2002 |
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6613790 |
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60284589 |
Apr 17, 2001 |
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60357959 |
Feb 19, 2002 |
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Current U.S.
Class: |
514/357 ;
514/408; 514/602; 546/335; 548/577; 564/86 |
Current CPC
Class: |
A61K 47/22 20130101;
A61K 31/415 20130101; A61K 47/38 20130101; A61P 29/00 20180101;
A61K 9/0019 20130101; C07D 231/12 20130101; C07D 413/12 20130101;
A61P 43/00 20180101; A61K 9/4866 20130101; A61K 47/12 20130101;
A61K 9/4858 20130101; A61K 31/42 20130101; A61K 31/635 20130101;
A61K 47/02 20130101; A61K 47/60 20170801; C07D 261/08 20130101;
A61P 25/06 20180101 |
Class at
Publication: |
514/357 ;
514/408; 514/602; 564/086; 546/335; 548/577 |
International
Class: |
C07D 213/55; C07D
207/46; A61K 031/18; A61K 031/44 |
Claims
1-26. (canceled).
27. A compound of Formula 33or a pharmaceutically-acceptable salt
thereof, wherein: A is an isoxazole group optionally substituted at
a substitutable position with one or more radicals independently
selected at each occurrence from the group consisting of
alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro,
carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl,
cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy,
alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl,
alkenyl heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl,
cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl,
arylcarbonyl, aralkylcarbonyl aralkenyl, alkoxyalkyl,
arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl,
N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl- , alkylamino, N-arylamino, N-aralkylamino,
N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl
alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalky- l, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,
aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl and N-alkyl-N-arylaminosulfonyl; R.sup.1 is selected
from the group consisting of heteroaryl, heterocyclyl, cycloalkyl,
and cycloalkenyl, wherein R.sup.1 is optionally substituted at a
substitutable position with one or more radicals independently
selected at each occurrence from the group consisting of alkyl,
haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl,
haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl,
alkylsulfinyl, halo, alkoxy and alkylthio; R.sup.2 and R.sup.3 are
independently selected from the group consisting of hydrido, alkyl,
alkylcarbonyl, hydroxyalkyl, heterocyclyl, heteroaryl,
monosaccharide, disaccharide, polysaccharide, alkylphosphate,
acyloxyalkyl, alkylaminocarbonyl, alkoxyaralkyl and carboxyalkyl,
wherein R.sup.3 is optionally substituted at a substitutable
position with one or more radicals independently selected at each
occurrence from the group consisting of alkylcarbonyl, formyl,
halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy,
aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl,
hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl,
carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl,
heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl,
cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl,
arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl,
arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl,
N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl, alkylamino, N-arylamino, N-aralkylamino,
N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl,
alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,
aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl, and N-alkyl-N-arylaminosulfonyl; wherein at least one
of R.sup.2 and R.sup.3 is other than hydrido; wherein R.sup.2 is
other than alkyl, carboxyalkyl or alkylcarbonyl when R.sup.3 is
hydrido; and wherein R.sup.3 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.2 is hydrido; or, R.sup.2 and R.sup.3 are
taken together along with the nitrogen to which they are attached
to form a three to seven membered saturated, partially unsaturated
or unsaturated heterocyclic ring and may optionally be substituted
at a substitutable position with one or more R.sup.5 radicals,
wherein the R.sup.5 radicals are independently selected at each
occurrence from the group consisting of alkylcarbonyl, formyl,
halo, alkyl, haloalkyl, alkylphosphate, phosphate, oxo, cyano,
nitro, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl,
cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy,
alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl,
alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl,
heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl,
alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino,
N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl;
and R.sup.4 is selected from hydrido and fluoro.
28. A compound according to claim 27 wherein R.sup.1 is selected
from the group consisting of 5- or 6-membered heteroaryl and
heterocyclyl, lower cycloalkyl, and lower cycloalkenyl, where
R.sup.1 is optionally substituted at a substitutable position with
one or more radicals independently selected at each occurrence from
the group consisting of lower alkyl, lower haloalkyl, cyano,
carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower
haloalkoxy, amino, lower alkylmino, phenylamino, nitro, lower
alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower
alkylthio.
29. A compound according to claim 27 wherein R.sup.1 is selected
from the group consisting of thienyl, oxazolyl, isoxazolyl, furyl,
thiazolyl, pyridyl, pyrrolidinyl, imidazolidinyl, piperidino,
piperazinyl, morpholinyl, thiazolidinyl, dihydrothiophenyl,
dihydropyranyi, dihydrofuranyl, dihydrothiazole, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl,
and cyclohexenyl, where R.sup.1 is optionally substituted at a
substitutable position with one or more radicals independently
selected at each occurrence from the group consisting of methyl,
trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, nitro,
methoxymethyl, fluoro, chloro, bromo, methoxy and methylthio.
30. A compound according to claim 27 that is a
pharmaceutically-acceptable metal salt.
31. A compound according to claim 30 wherein the metal salt is an
alkali metal salt or an alkaline earth metal salt.
32. A compound according to claim 31 wherein the metal salt is
selected from the group consisting of sodium and potassium
salts.
33. A pharmaceutical composition comprising a compound according to
claim 27 or pharmaceutically-acceptable salt thereof, and at least
one pharmaceutically-acceptable carrier, adjuvant or diluent.
34. A compound according to claim 27 represented by Formula II:
34or a pharmaceutically-acceptable salt thereof wherein: R.sup.1 is
selected from heteroaryl, heterocyclyl, cycloalkyl, and
cycloalkenyl, wherein R.sup.1 is optionally substituted at a
substitutable position with one or more radicals indepedently
selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl,
hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino,
nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R.sup.2 and R.sup.3 are independently selected from the group
consisting of hydrido, alkyl, alkylcarbonyl, hydroxyalkyl,
heterocyclyl, heteroaryl, monosaccharide, disaccharide,
polysaccharide, alkylphosphate, acyloxyalkyl, alkylaminocarbonyl,
alkoxyaralkyl and carboxyalkyl, wherein R.sup.3 is optionally
substituted at a substitutable position with one or more radicals
independently selected at each occurrence from the group consisting
of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano,
nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl,
carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy,
alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl,
alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl,
heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl,
alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl- , alkylamino,
N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalky- l, aryloxy, aralkoxy, arylthio,
aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,
alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and
N-alkyl-N-arylaminosulfonyl; and R.sup.4 is selected from hydrido
and fluoro; wherein at least one of R.sup.2 and R.sup.3 is other
than hydrido; wherein R.sup.2 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.3 is hydrido; and wherein R.sup.3 is other
than alkyl, carboxyalkyl or alkylcarbonyl when R.sup.2 is
hydrido.
35. A compound according to claim 34 that is a
pharmaceutically-acceptable metal salt.
36. A compound according to claim 35 wherein the metal salt is an
alkali metal salt or an alkaline earth metal salt.
37. A compound according to claim 36 wherein the metal salt is
selected from the group consisting of sodium and potassium
salts.
38. A pharmaceutical composition comprising a compound according to
claim 34 or pharmaceutically-acceptable salt thereof, and at least
one pharmaceutically-acceptable carrier, adjuvant or diluent.
Description
[0001] This application claims priority of U.S. provisional patent
application Ser. No. 60/284,589 filed on Apr. 17, 2001, and of U.S.
provisional patent application Ser. No. 60/357,959 filed on Feb.
19, 2002.
FIELD OF THE INVENTION
[0002] This invention is in the field of antiinflammatory
pharmaceutical agents and specifically relates to prodrugs of
compounds which selectively inhibit cyclooxygenase-2.
BACKGROUND OF THE INVENTION
[0003] The use of non-steroidal antiinflammatory drugs (NSAIDs) in
treating pain and the swelling associated with inflammation also
produce severe side effects, including life threatening ulcers. The
recent discovery of an inducible enzyme associated with
inflammation ("prostaglandin G/H synthase II" or "cyclooxygenase-2
(COX-2)") provides a viable target of inhibition which more
effectively reduces inflammation and produces fewer and less
drastic side effects.
[0004] Compounds which selectively inhibit cyclooxygenase-2 have
been described. U.S. Pat. No. 5,380,738 and WO94/27980 describe
oxazoles which selectively inhibit cyclooxygenase-2. U.S. Pat. No.
5,344,991 describes cyclopentenes which selectively inhibit
cyclooxygenase-2. U.S. Pat. No. 5,393,790 describes spiro compounds
which selectively inhibit cyclooxygenase-2. WO94/15932 describes
thiophene and furan derivatives which selectively inhibit
cyclooxygenase-2. WO94/13635 and WO94/20480 describe compounds
which selectively inhibit cyclooxygenase-2. WO95/15316 describes
pyrazolyl sulfonamide derivatives which selectively inhibit
cyclooxygenase-2. However, in some circumstances, prodrugs of
antiinflammatory compounds are advantageous, especially where the
prodrugs have increased water solubility or delayed onset of
action.
[0005] Substituted sulfonamides have been described.
Pyrazolyl-sulfonylureas have been described as having possible
hypoglycemic activity [H. Faid-Allah and H. Mokhtar, Ind. J Chem,
27, 245 (1988)]. JP 1,045,374 describes water soluble tetrazolium
compounds useful in assays for determining reducing substances. D.
Mukerjee et. al. [Acta. Pharma. Jugosl., 31, 151 (1981)] describe
tetrazolium sulfonamides as antiviral agents. JP 4,277,724
describes triphenyl pyrazolines as nonlinear optical material. JP
5,323,522 describes the use of heterocyclic compounds in black and
white photographic material. U.S. Pat. No. 5,389,635 describes
substituted imidazoles as angiotensin II antagonists. U.S. Pat. No.
5,387,592 describes substituted benzimidazole derivatives as
angiotensin II antagonists. G. Dorofeenko et. al. [Khim. Farm. Zh.,
16, 920 (1982)] describe pyridinium salts as antiviral agents. U.S.
Pat. No. 5,338,749 describes diaryl-substituted heterocyclyl
compounds as antiarthritis agents. WO94/26731 describes thiophene
compounds which selectively inhibit cyclooxygenase-2. WO95/00501
describes compounds which selectively inhibit cyclooxygenase-2, and
specifically,
3-(4-(trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluoropheny-
l)thiophene is described. T. Ivanov [Mh. Chem., 97, 1499 (1966)]
describes the preparation of diarylindone derivatives as possible
indicators, and 2-(4-(N-methylaminosulfonyl)phenyl)-3-phenylindone
is specifically described.
[0006] J. Larsen and H. Bundgaard [Int. J. Pharmaceutics, 37, 87
(1987)] describe the evaluation of N-acylsulfonamides as potential
prodrug derivatives. J. Larsen et. al. [Int. J. Pharmaceutics, 47,
103 (1988)] describe the evaluation of N-methylsulfonamides as
potential prodrug derivatives.
[0007] There currently exists a need for compounds suitable for use
in antiinflammatory compositions which can readily penetrate across
biological membranes to provide improved drug absorption. Further,
there currently exists a need for compounds which are more soluble
and stable. The compounds of the present invention are found to
show usefulness as prodrugs.
SUMMARY OF THE INVENTION
[0008] The present invention provides a compound of Formula (I):
2
[0009] or a pharmaceutically-acceptable salt thereof wherein:
[0010] A is a ring substituent selected from the group consisting
of heterocyclyl, heteroaryl, cycloalkenyl and aryl, wherein A is
optionally substituted at a substitutable position with one or more
radicals independently selected at each occurrence from the group
consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo,
cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl,
carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy,
alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl,
alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl,
heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl,
alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino,
N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl and
N-alkyl-N-arylaminosulfonyl;
[0011] R.sup.1 is selected from the group consisting of heteroaryl,
heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R.sup.1 is
optionally substituted at a substitutable position with one or more
radicals independently selected at each occurrence from the group
consisting of alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl,
hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino,
nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
[0012] R.sup.2 and R.sup.3 are independently selected from the
group consisting of hydrido, alkyl, alkylcarbonyl, hydroxyalkyl,
heterocyclyl, heteroaryl, monosaccharide, disaccharide,
polysaccharide, alkylphosphate, acyloxyalkyl, alkylaminocarbonyl,
alkoxyaralkyl and carboxyalkyl, wherein R.sup.3 is optionally
substituted at a substitutable position with one or more radicals
independently selected at each occurrence from the group consisting
of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano,
nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl,
carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy,
alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl,
alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl,
heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl,
alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino,
N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl, and
N-alkyl-N-arylaminosulfonyl;
[0013] wherein at least one of R.sup.2 and R.sup.3 is other than
hydrido;
[0014] wherein R.sup.2 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.3 is hydrido; and
[0015] wherein R.sup.3 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.2 is hydrido;
[0016] or, R.sup.2 and R.sup.3 are taken together along with the
nitrogen to which they are attached to form a three to seven
membered saturated, partially unsaturated or unsaturated
heterocyclic ring and may optionally be substituted at a
substitutable position with one or more R.sup.5 radicals, wherein
the R.sup.5 radicals are independently selected at each occurrence
from the group consisting of alkylcarbonyl, formyl, halo, alkyl,
haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, alkoxy,
aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl,
hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl,
carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl,
heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl,
cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl,
arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl,
arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl,
N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl- , alkylamino, N-arylamino, N-aralkylamino,
N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl,
alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalky- l, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,
aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl and N-alkyl-N-arylaminosulfonyl; and
[0017] R.sup.4 is selected from hydrido and fluoro;
[0018] wherein R.sup.5 is other than methyl when A is isoxazole,
R.sup.1 is phenyl and R.sup.2 and R.sup.3 are taken together to
form a pyrrole ring.
[0019] The present invention also provides a pharmaceutical
composition comprising a therapeutically-effective amount of a
compound of Formula (1), and a method of treating a
cyclooxygenase-2 mediated disease such as inflammation or an
inflammation-related disorder in a subject.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Compounds of Formula (I) would be useful for, but not
limited to, the treatment of inflammation in a subject, and for
treatment of other cyclooxygenase-2 mediated disorders, such as, as
an analgesic in the treatment of pain and headaches, or as an
antipyretic for the treatment of fever. For example, compounds of
the invention would be useful to treat arthritis, including but not
limited to rheumatoid arthritis, spondyloarthropathies, gouty
arthritis, osteoarthritis, systemic lupus erythematosus and
juvenile arthritis. Such compounds of the invention would be useful
in the treatment of asthma, bronchitis, menstrual cramps, premature
labor, tendinitis, bursitis, skin-related conditions such as
psoriasis, eczema, burns and dermatitis, and from post-operative
inflammation including from ophthalmic surgery such as cataract
surgery and refractive surgery. Compounds of the invention also
would be useful to treat gastrointestinal conditions such as
inflammatory bowel disease, Crohn's disease, gastritis, irritable
bowel syndrome and ulcerative colitis. Compounds of the invention
would be useful for the prevention or treatment of cancer, such as
colorectal cancer, and cancer of the breast, lung, prostate,
bladder, cervix and skin. Compounds of the invention would be
useful in treating inflammation in such diseases as vascular
diseases, migraine headaches, periarteritis nodosa, thyroiditis,
aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever,
type I diabetes, neuromuscular junction disease including
myasthenia gravis, white matter disease including multiple
sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,
polymyositis, gingivitis, nephritis, hypersensitivity, swelling
occurring after injury, myocardial ischemia, and the like. The
compounds would also be useful in the treatment of ophthalmic
diseases, such as retinitis, retinopathies, uveitis, ocular
photophobia, and of acute injury to the eye tissue. The compounds
would also be useful in the treatment of pulmonary inflammation,
such as that associated with viral infections and cystic fibrosis.
The compounds would also be useful for the treatment of certain
central nervous system disorders, such as cortical dementias
including Alzheimer's disease, and central nervous system damage
resulting from stroke, ischemia and trauma. The compounds of the
invention are useful as antiinflammatory agents, such as for the
treatment of arthritis, with the additional benefit of having
significantly less harmful side effects. These compounds would also
be useful in the treatment of allergic rhinitis, respiratory
distress syndrome, endotoxin shock syndrome, and atherosclerosis.
The compounds would also be useful in the treatment of pain, but
not limited to postoperative pain, dental pain, muscular pain, and
pain resulting from cancer. The compounds would be useful for the
prevention of dementias, such as Alzheimer's disease.
[0021] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of companion animals,
exotic animals and farm animals, including mammals, rodents, and
the like. More preferred animals include horses, dogs, and
cats.
[0022] The present compounds may also be used in co-therapies,
partially or completely, in place of other conventional
antiinflammatories, such as together with steroids, NSAIDs,
5-lipoxygenase inhibitors, LTB.sub.4 antagonists and LTA.sub.4
hydrolase inhibitors.
[0023] Suitable LTB.sub.4 inhibitors include, among others,
ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo
Denmark compound ETH-615, Lilly compound LY-293111, Ono compound
ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024,
264086 and 292728, ONO compound ONO-LB457, Searle compound
SC-53228, calcitrol, Lilly compounds LY-210073, LY223982, LY233469,
and LY255283, ONO compound ONO-LB-448, Searle compounds SC-41930,
SC-50605 and SC-51146, and SK&F compound SKF-104493.
Preferably, the LTB.sub.4 inhibitors are selected from ebselen,
Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark
compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057,
and Terumo compound TMK-688.
[0024] Suitable 5-LO inhibitors include, among others, masoprocol,
tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine
hydrochloride, enazadrem phosphate, and bunaprolast.
[0025] The present compounds may also be used in combination
therapies with opioids and other analgesics, such as morphine,
meperidine or codeine.
[0026] The present invention may also be used in combination with a
5-hydroxytriptamine (5-HT) receptor agonist. Amino compounds such
as, for example but not limited to, sumatriptan, zolmitriptan,
naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan,
ergotamine, dihydroergotamine.
[0027] The term "cyclooxygenase-2 inhibitor" embraces compounds
which selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
Preferably, the compounds have a cyclooxygenase-2 IC.sub.50 of less
than about 0.5 .mu.M, and also have a selectivity ratio of
cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at
least 50, and more preferably of at least 100. Even more
preferably, the compounds have a cyclooxygenase-1 IC.sub.50 of
greater than about 1 .mu.M, and more preferably of greater than 20
.mu.M. Such preferred selectivity may indicate an ability to reduce
the incidence of common NSAID-induced side effects.
[0028] The phrase "therapeutically-effective" is intended to
qualify the amount of each agent for use in the combination therapy
which will achieve the goal of improvement in severity and the
frequency of incidence over treatment of each agent by itself,
while avoiding adverse side effects typically associated with
alternative therapies.
[0029] The phrase "combination therapy" (or "co-therapy"), in
defining use of a cyclooxygenase-2 inhibitor agent and another
agent, is intended to embrace administration of each agent in a
sequential manner in a regimen that will provide beneficial effects
of the drug combination, and is intended as well to embrace
coadministration of these agents in a substantially simultaneous
manner, such as in a single capsule having a fixed ratio of these
active agents or in multiple, separate capsules for each agent.
[0030] The term "prodrug" refers to compounds which are drug
precursors which, following administration to a subject and
subsequent absorption, is converted to an active species in vivo
via some process, such as a metabolic process. Other products from
the conversion process are easily disposed of by the body. More
preferred prodrugs produce products from the conversion process
which are generally accepted as safe.
[0031] In one embodiment, compounds which inhibit cyclooxygenase-2
consists of compounds of Formula (I) wherein A is selected from
partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl,
lower cycloalkenyl and phenyl, wherein A is optionally substituted
at a substitutable position with one or more radicals independently
selected at each occurence from formyl, lower alkylcarbonyl, halo,
lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower
alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl,
lower cyanoalkyl, lower hydroxyalkyl, lower haloalkylsulfonyloxy,
lower alkoxyalkyloxyalkyl, lower carboxyalkoxyalkyl, lower
cycloalkylalkyl, lower alkenyl, lower alkynyl, heterocyclyloxy,
lower alkylthio, lower cycloalkyl, phenyl, 5-6 membered
heterocyclyl, lower cycloalkenyl, lower phenylalkyl, 5-6 membered
heterocyclylalkyl, lower alkylthioalkyl, phenylcarbonyl, lower
phenylalkylcarbonyl, lower phenylalkenyl, lower alkoxyalkyl, lower
phenylthioalkyl, lower phenyloxyalkyl, lower phenylalkylthioalkyl,
lower phenylalkoxyalkyl, lower alkoxycarbonylalkyl, lower
aminocarbonylalkyl, lower alkylaminocarbonyl,
N-phenylaminocarbonyl, lower N-alkyl-N-phenylaminocarbonyl, lower
alkylaminocarbonylalkyl, lower alkylamino, N-phenylamino, lower
N-phenylalkylamino, lower N-alkyl-N-phenalkylamino, lower
N-alkyl-N-phenylamino, lower aminoalkyl, lower alkylaminoalkyl,
lower N-phenylaminoalkyl, lower N-phenalkylaminoalkyl, lower
N-alkyl-N-phenalkylaminoalkyl, lower N-alkyl-N-phenylaminoalkyl,
phenyloxy, lower phenylalkoxy, lower phenylthio, lower
phenalkylthio, lower alkylsulfinyl, lower alkylsulfonyl,
aminosulfonyl, lower alkylaminosulfonyl, N-phenylaminosulfonyl,
phenylsulfonyl, and lower N-alkyl-N-phenylaminosul- fonyl; and
[0032] R.sup.1 is selected from 5- or 6-membered heteroaryl and
heterocyclyl, lower cycloalkyl, lower cycloalkenyl and phenyl,
where R.sup.1 is optionally substituted at a substitutable position
with one or more radicals independently selected at each occurence
from lower alkyl, lower haloalkyl, cyano, carboxyl, lower
alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy,
amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl,
lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio.
[0033] In another embodiment, compounds which inhibit
cyclooxygenase-2 consists of compounds of Formula (1) wherein A is
a radical selected from thienyl, oxazolyl, furyl, pyrrolyl,
thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl,
isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl,
benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl, wherein A
is optionally substituted at a substitutable position with one or
more radicals independently selected at each occurence from formyl,
methylcarbonyl, fluoro, chloro, bromo, methyl, trifluoromethyl,
difluoromethyl, oxo, cyano, carboxyl, methoxy, aminocarbonyl,
methoxycarbonyl, ethoxycarbonyl, carboxypropyl, hydroxymethyl,
cyanomethyl, phenyl, phenylmethyl, methoxycarbonyl, phenylcarbonyl,
methoxymethyl, phenyloxymethyl, aminocarbonylmethyl, carboxymethyl,
and phenyloxy; and
[0034] R.sup.1 is selected from thienyl, oxazolyl, isoxazolyl
(heteroaryl was never in claim 1 for this substituent), furyl,
thiazolyl, pyridyl, and phenyl, where R.sup.1 is optionally
substituted at a substitutable position with one or more radicals
independently selected at each occurence from methyl,
trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, nitro,
methoxymethyl, fluoro, chloro, bromo, methoxy and methylthio.
[0035] In yet another embodiment, A is other than tetrazolium or
pyridinium. In still another embodiment, A is other than indanone
when R.sup.3 is carboxyalkyl.
[0036] A family of specific compounds of particular interest within
Formula (1) consists of compounds and pharmaceutically-acceptable
salts thereof as follows:
[0037]
1-{[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl}-L-proline;
sodium
1-{[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl}-L-prolinate-
; and
[0038] methyl
1-{[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl}-L-pro-
linate.
[0039] Within Formula (I) there is a subclass of compounds of high
interest represented by Formula (II): 3
[0040] or a pharmaceutically-acceptable salt thereof wherein:
[0041] R.sup.1 is selected from heteroaryl, heterocyclyl,
cycloalkyl, cycloalkenyl and aryl, wherein R.sup.1 is optionally
substituted at a substitutable position with one or more radicals
indepedently selected from alkyl, haloalkyl, cyano, carboxyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo,
alkoxy and alkylthio;
[0042] R.sup.2 and R.sup.3 are independently selected from the
group consisting of hydrido, alkyl, alkylcarbonyl, hydroxyalkyl,
heterocyclyl, heteroaryl, monosaccharide, disaccharide,
polysaccharide, alkylphosphate, acyloxyalkyl, alkylaminocarbonyl,
alkoxyaralkyl and carboxyalkyl, wherein R.sup.3 is optionally
substituted at a substitutable position with one or more radicals
independently selected at each occurrence from the group consisting
of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano,
nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl,
carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy,
alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl,
alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl,
heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl,
alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino,
N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl;
and
[0043] R.sup.4 is selected from hydrido and fluoro;
[0044] wherein at least one of R.sup.2 and R.sup.3 is other than
hydrido;
[0045] wherein R.sup.2 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.3 is hydrido; and
[0046] wherein R.sup.3 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.2 is hydrido.
[0047] A family of specific compounds of particular interest within
Formulae (I) and (II) consists of compounds and
pharmaceutically-acceptab- le salts thereof as follows:
[0048]
N,N-dimethyl-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide;
and
[0049]
N-ethyl-4-(5-methyl-3-phenylisoxazol-4-yl)-N-propionylbenzenesulfon-
amide.
[0050] Another subclass of compounds of high interest within
Formula (I) are compounds represented by Formula (III): 4
[0051] or a pharmaceutically-acceptable salt thereof wherein:
[0052] R.sup.1 is selected from heteroaryl, heterocyclyl,
cycloalkyl, cycloalkenyl and aryl, wherein R.sup.1 is optionally
substituted at a substitutable position with one or more radicals
indepedently selected from alkyl, haloalkyl, cyano, carboxyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo,
alkoxy and alkylthio;
[0053] R.sup.2 and R.sup.3 are independently selected from the
group consisting of hydrido, alkyl, alkylcarbonyl, hydroxyalkyl,
heterocyclyl, heteroaryl, monosaccharide, disaccharide,
polysaccharide, alkylphosphate, acyloxyalkyl, alkylaminocarbonyl,
alkoxyaralkyl and carboxyalkyl, wherein R.sup.3 is optionally
substituted at a substitutable position with one or more radicals
independently selected at each occurrence from the group consisting
of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano,
nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl,
carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy,
alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl,
alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl,
heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl,
alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino,
N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl;
and
[0054] R.sup.4 is selected from hydrido and fluoro;
[0055] wherein at least one of R.sup.2 and R.sup.3 is other than
hydrido;
[0056] wherein R.sup.2 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.3 is hydrido; and
[0057] wherein R.sup.3 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.2 is hydrido.
[0058] A compound of particular interest within Formula (III) is
N,N-bis(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]benzenesulfonamide.
[0059] Another compound of particular interest within Formula (III)
is
N-(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide.
[0060] In another embodiment, compounds which inhibit
cyclooxygenase-2 consists of compounds of Formula (I): 5
[0061] or a pharmaceutically-acceptable salt thereof wherein:
[0062] R.sup.2 and R.sup.3 are independently selected from the
group consisting of hydrido, alkyl, alkylcarbonyl, hydroxyalkyl,
heterocyclyl, heteroaryl, monosaccharide, disaccharide,
polysaccharide, alkylphosphate, acyloxyalkyl, alkylaminocarbonyl,
alkoxyaralkyl and carboxyalkyl, wherein R.sup.3 is optionally
substituted at a substitutable position with one or more radicals
independently selected at each occurrence from the group consisting
of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano,
nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl,
carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy,
alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl,
alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl,
heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl,
alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino,
N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl, and
N-alkyl-N-arylaminosulfonyl;
[0063] wherein at least one of R.sup.2 and R.sup.3 is other than
hydrido;
[0064] wherein R.sup.2 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.3 is hydrido; and
[0065] wherein R.sup.3 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.2 is hydrido;
[0066] or, R.sup.2 and R.sup.3 are taken together along with the
nitrogen to which they are attached to form a three to seven
membered saturated, partially unsaturated or unsaturated
heterocyclic ring and may optionally be substituted at a
substitutable position with one or more R.sup.5 radicals, wherein
the R.sup.5 radicals are independently selected at each occurrence
from the group consisting of alkylcarbonyl, formyl, halo, alkyl,
haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, alkoxy,
aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl,
hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl,
carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl,
heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl,
cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl,
arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl,
arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl,
N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl- , alkylamino, N-arylamino, N-aralkylamino,
N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl,
alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalky- l, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,
aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl and N-alkyl-N-arylaminosulfonyl; and
[0067] X is any ligand such that when R.sup.2 and R.sup.3 are
hydrido the compound of Formula (I) is a selective COX-2
inhibitor.
[0068] The term "hydrido" denotes a single hydrogen atom (H). This
hydrido radical may be attached, for example, to an oxygen atom to
form a hydroxyl radical or two hydrido radicals may be attached to
a carbon atom to form a methylene (--CH.sub.2--) radical.
[0069] Where used, either alone or within other terms such as
"haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", the
term "alkyl" embraces linear or branched radicals having one to
about twenty carbon atoms or, preferably, one to about twelve
carbon atoms. More preferred alkyl radicals are "lower alkyl"
radicals having one to about ten carbon atoms. Most preferred are
lower alkyl radicals having one to about six carbon atoms. Examples
of such radicals include methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl
and the like.
[0070] The term "alkenyl" embraces linear or branched radicals
having two to about twenty carbon atoms and at least one
carbon-carbon double bond or, preferably, two to about twelve
carbon atoms and at least one carbon-carbon double bond. More
preferred alkenyl radicals are "lower alkenyl" radicals having two
to about six carbon atoms. The terms "alkenyl" and "lower alkenyl",
embrace radicals having "cis" and "trans" orientations, or
alternatively, "E" and "Z" orientations. Examples of alkenyl
radicals include ethenyl, propenyl, allyl, propenyl, butenyl and
4-methylbutenyl.
[0071] The term "alkynyl" denotes linear or branched radicals
having at least one carbon-carbon triple bond, and having two to
about twenty carbon atoms or, preferably, two to about twelve
carbon atoms. More preferred alkynyl radicals are "lower alkynyl"
radicals having two to about ten carbon atoms. Most preferred are
lower alkynyl radicals having two to about six carbon atoms.
Examples of such radicals include propargyl, butynyl, and the
like.
[0072] The term "cycloalkyl" embraces saturated carbocyclic
radicals having three to about twelve carbon atoms. More preferred
cycloalkyl radicals are "lower cycloalkyl" radicals having three to
about eight carbon atoms. Examples of such radicals include
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0073] The term "cycloalkenyl" embraces partially unsaturated
carbocyclic radicals having three to twelve carbon atoms. More
preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals
having four to about eight carbon atoms. Examples of such radicals
include cyclobutenyl, cyclopentenyl and cyclohexenyl.
[0074] The term "halo" means halogens such as fluorine, chlorine,
bromine or iodine. The term "haloalkyl" embraces radicals wherein
any one or more of the alkyl carbon atoms is substituted with halo
as defined above. Specifically embraced are monohaloalkyl,
dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical,
for one example, may have either an iodo, bromo, chloro or fluoro
atom within the radical. Dihalo and polyhaloalkyl radicals may have
two or more of the same halo atoms or a combination of different
halo radicals. "Lower haloalkyl" embraces radicals having one to
six carbon atoms. Examples of haloalkyl radicals include
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and
dichloropropyl.
[0075] The term "hydroxyalkyl" embraces linear or branched alkyl
radicals having one to about ten carbon atoms any one of which may
be substituted with one or more hydroxyl radicals. More preferred
hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one
to six carbon atoms and one or more hydroxyl radicals. Examples of
such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,
hydroxybutyl and hydroxyhexyl.
[0076] The terms "alkoxy" and "alkyloxy" embrace linear or branched
oxy-containing radicals each having alkyl portions of one to about
ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy"
radicals having one to six carbon atoms. Examples of such radicals
include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
[0077] The term "alkoxyalkyl" embraces alkyl radicals having one or
more alkoxy radicals attached to the alkyl radical, that is, to
form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy"
radicals may be further substituted with one or more halo atoms,
such as fluoro, chloro or bromo, to provide haloalkoxy radicals.
More preferred haloalkoxy radicals are "lower haloalkoxy" radicals
having one to six carbon atoms and one or more halo radicals.
Examples of such radicals include fluoromethoxy, chloromethoxy,
trifluoromethoxy, trifluoroethoxy, fluoroethoxy and
fluoropropoxy.
[0078] The term "aryl", alone or in combination, means a
carbocyclic aromatic system containing one, two or three rings
wherein such rings may be attached together in a pendent manner or
may be fused. The term "aryl" embraces aromatic radicals such as
phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl
moieties may also be substituted at a substitutable position with
one or more substituents selected independently from alkyl,
alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro,
alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and
aralkoxycarbonyl.
[0079] The term "heterocyclyl" embraces saturated, partially
unsaturated and unsaturated heteroatom-containing ring-shaped
radicals, where the heteroatoms may be selected from nitrogen,
sulfur and oxygen. Examples of saturated heterocyclyl radicals
include saturated 3 to 6-membered heteromonocylic group containing
1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl,
piperidino, piperazinyl, etc.); saturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially
unsaturated heterocyclyl radicals include dihydrothiophene,
dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl
radicals may include a pentavalent nitrogen, such as in tetrazolium
and pyridinium radicals.
[0080] The term "heteroaryl" embraces unsaturated heterocyclyl
radicals. Examples of heteroaryl radicals include unsaturated 3 to
6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.)
tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.),
etc.; unsaturated 3 to 6-membered heteromonocyclic group containing
an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to
6-membered heteromonocyclic group containing a sulfur atom, for
example, thienyl, etc.; unsaturated 3- to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl
(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
etc.) etc.; unsaturated condensed heterocyclyl group containing 1
to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl,
benzoxadiazolyl, etc.); unsaturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.)
etc.; unsaturated condensed heterocyclyl group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl,
benzothiadiazolyl, etc.) and the like. The term "heteroaryl" also
embraces radicals where heterocyclyl radicals are fused with aryl
radicals. Examples of such fused bicyclic radicals include
benzofuran, benzothiophene, and the like. Said "heterocyclyl group"
may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy,
oxo, amino and alkylamino.
[0081] The term "alkylthio" embraces radicals containing a linear
or branched alkyl radical, of one to about ten carbon atoms
attached to a divalent sulfur atom. More preferred alkylthio
radicals are "lower alkylthio" radicals having alkyl radicals of
one to six carbon atoms. Examples of such lower alkylthio radicals
are methylthio, ethylthio, propylthio, butylthio and hexylthio.
[0082] The term "alkylthioalkyl" embraces radicals containing an
alkylthio radical attached through the divalent sulfur atom to an
alkyl radical of one to about ten carbon atoms. More preferred
alkylthioalkyl radicals are "lower alkylthioalkyl" radicals having
alkyl radicals of one to six carbon atoms. Examples of such lower
alkylthioalkyl radicals include methylthiomethyl.
[0083] The term "alkylsulfinyl" embraces radicals containing a
linear or branched alkyl radical, of one to about ten carbon atoms,
attached to a divalent --S(.dbd.O)-- radical. More preferred
alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having
alkyl radicals of one to six carbon atoms. Examples of such lower
alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl,
butylsulfinyl and hexylsulfinyl.
[0084] The term "sulfonyl", whether used alone or linked to other
terms such as "alkylsulfonyl", denotes a divalent radical,
--SO.sub.2--. "Alkylsulfonyl" embraces alkyl radicals attached to a
sulfonyl radical, where alkyl is defined as above. More preferred
alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having
one to six carbon atoms. Examples of such lower alkylsulfonyl
radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
The "alkylsulfonyl" radicals may be further substituted with one or
more halo atoms, such as fluoro, chloro or bromo, to provide
haloalkylsulfonyl radicals.
[0085] The terms "sulfamyl", "aminosulfonyl" and "sulfonamidyl"
denote NH.sub.2O.sub.2S--.
[0086] The term "acyl" denotes a radical provided by the residue
after removal of hydroxyl from an organic acid. Examples of such
acyl radicals include alkanoyl and aroyl radicals. Examples of such
alkanoyl radicals include formyl, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals
formed from succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic,
pantothenic, .beta.-hydroxybutyric, galactaric and galacturonic
acids.
[0087] The term "aroyl" embraces aryl radicals with a carbonyl
radical as defined below. Examples of aroyl include benzoyl,
naphthoyl, phenylacetyl, and the like, and the aryl in said aroyl
may be additionally substituted, such as in p-hydroxybenzoyl, and
salicylyl.
[0088] The term "carbonyl", whether used alone or with other terms,
such as "alkoxycarbonyl", denotes --(C.dbd.O)--.
[0089] The terms "carboxy" or "carboxyl", whether used alone or
with other terms, such as "carboxyalkyl", denotes --CO.sub.2H. The
term "carboxyalkyl" embraces alkyl radicals substituted with a
carboxy radical. More preferred are "lower carboxyalkyl" which
embrace lower alkyl radicals as defined above, and may be
additionally substituted on the alkyl radical with halo. Examples
of such lower carboxyalkyl radicals include carboxymethyl,
carboxyethyl and carboxypropyl.
[0090] The term "alkoxycarbonyl" means a radical containing an
alkoxy radical, as defined above, attached via an oxygen atom to a
carbonyl radical. More preferred are "lower alkoxycarbonyl"
radicals with alkyl portions having one to six carbons. Examples of
such lower alkoxycarbonyl (ester) radicals include substituted or
unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
butoxycarbonyl and hexyloxycarbonyl.
[0091] The terms "alkylcarbonyl", "arylcarbonyl" and
"aralkylcarbonyl" include radicals having alkyl, hydroxylalkyl,
aryl, arylalkyl and aryl-hydroxylalkyl radicals, as defined herein,
attached to a carbonyl radical. Examples of such radicals include
substituted or unsubstituted methylcarbonyl, ethylcarbonyl,
propylcarbonyl, butylcarbonyl, pentylcarbonyl,
hydroxymethylcarbonyl, hydroxyethylcarbonyl, phenylcarbonyl,
benzylcarbonyl, and phenyl(hydroxymethyl)carbonyl.
[0092] The term "carboxyalkylcarbonyl" embraces alkylcarbonyl
radicals substituted with a carboxy radical. More preferred are
"lower carboxyalkylcarbonyl" which embrace lower alkyl radicals as
defined above, and may be additionally substituted on the alkyl
radical with hydroxyl. Examples of such lower carboxyalkylcarbonyl
radicals include carboxymethylcarbonyl, carboxyethylcarbonyl,
carboxypropylcarbonyl, HO.sub.2C(CHOH).sub.4C(O)--,
HO.sub.2C(CHOH).sub.2C(O)--, HO.sub.2C(CH.sub.2)(CHOH)C(O)--, and
HO.sub.2CCH.sub.2C(OH)(CO.sub.2H)C(O- )--.
[0093] The term "carboxyalkenylcarbonyl" embraces derivatives of
maleic and fumaric acids. Examples of such carboxyalkenylcarbonyl
radicals include (Z)-carboxyethenylcarbonyl and
(E)-carboxyethenylcarbonyl.
[0094] The term "aralkyl" embraces aryl-substituted alkyl radicals
such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and
diphenylethyl. The aryl in said aralkyl may be additionally
substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The terms benzyl and phenylmethyl are interchangeable.
[0095] The term "heterocyclylalkyl" embraces saturated and
partially unsaturated heterocyclyl-substituted alkyl radicals, such
as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals,
such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl,
and quinolylethyl. The heteroaryl in said heteroaralkyl may be
additionally substituted with halo, alkyl, alkoxy, halkoalkyl and
haloalkoxy.
[0096] The term "aryloxy" embraces aryl radicals attached through
an oxygen atom to other radicals. The term "arylthio" embraces aryl
radicals attached to a sulfur atom.
[0097] The term "aralkoxy" embraces aralkyl radicals attached
through an oxygen atom to other radicals.
[0098] The term "heterocyclyloxy" embraces heterocyclyl radicals
attached through an oxygen atom to other radicals.
[0099] The term "aralkoxyalkyl" embraces aralkoxy radicals attached
through an oxygen atom to an alkyl radical.
[0100] The term "aralkylthio" embraces aralkyl radicals attached to
a sulfur atom. The term "aralkylthioalkyl" embraces aralkylthio
radicals attached through a sulfur atom to an alkyl radical.
[0101] The term "aminoalkyl" embraces alkyl radicals substituted
with amino radicals. More preferred are "lower aminoalkyl"
radicals. Examples of such radicals include aminomethyl,
aminoethyl, and the like.
[0102] The term "alkylamino" denotes amino groups which are
substituted with one or two alkyl radicals. Preferred are "lower
alkylamino" radicals having alkyl portions having one to six carbon
atoms. Suitable lower alkylamino may be monosubstituted
N-alkylamino or disubstituted N,N-alkylamino, such as
N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or
the like.
[0103] The term "arylamino" denotes amino groups which are
substituted with one or two aryl radicals, such as N-phenylamino.
The "arylamino" radicals may be further substituted on the aryl
ring portion of the radical.
[0104] The term "aralkylamino" embraces amino groups which are
substituted with one or two aralkyl radicals.
[0105] The terms "N-arylaminoalkyl" and "N-aryl-N-alkyl-aminoalkyl"
denote aminoalkyl groups which are substituted with one aryl
radical or one aryl and one alkyl radical, respectively. Examples
of such radicals include N-phenylaminomethyl and
N-phenyl-N-methylaminomethyl.
[0106] The term "aminocarbonyl" denotes an amide group of the
formula --C(.dbd.O)NH.sub.2. The term "alkylaminocarbonyl" denotes
an aminocarbonyl group which has been substituted with one or two
alkyl radicals on the amino nitrogen atom. Preferred are
"N-alkylaminocarbonyl" and "N,N-dialkylaminocarbonyl" radicals.
More preferred are "lower N-alkylaminocarbonyl" and "lower
N,N-dialkylaminocarbonyl" radicals with lower alkyl portions as
defined above. The term "alkylaminoalkyl" embraces radicals having
one or more alkyl radicals attached to an aminoalkyl radical.
[0107] The term "aryloxyalkyl" embraces radicals having an aryl
radicals attached to an alkyl radical through a divalent oxygen
atom.
[0108] The term "arylthioalkyl" embraces radicals having an aryl
radicals attached to an alkyl radical through a divalent sulfur
atom.
[0109] The term "monosaccharide" embraces radicals of allose,
altrose, arabinose, erythrose, erythrulose, fructose, D-fucitol,
L-fucitol, fucosamine, fucose, galactosamine, D-galactosaminitol,
galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde,
glycerol, glycerone, gulose, idose, lyxose, mannosamine, annose,
psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine,
rhamnose, ribose, ribulose, sorbose, tagatose, tartaric acid,
threose, xylose and xylulose. Further, the term "monosaccharide"
also includes modified monosaccharide radicals.
[0110] The terms "disaccharide" and "polysaccharide" embrace
radicals of abequose, amicetose, amylose, apiose, arcanose,
ascarylose, ascorbic acid, boivinose, cellobiose, cellotriose,
chacotriose, chalcose, cladinose, colitose, cymarose,
2-deoxyribose, 2-deoxyglucose, diginose, digitalose, digitoxose,
evalose, evemitrose, gentianose, gentiobiose, hamamelose, inulin,
isolevoglucosenone, isomaltose, isomaltotriose, isopanose,
kojibiose, lactose, lactosamine, lactosediamine, laminarabiose,
levoglucosan, levoglucosenone, .beta.-maltose, manninotriose,
melezitose, melibiose, muramic acid, mycarose, mycinose, neuraminic
acid, nigerose, nojirimycin, noviose, oleandrose, panose, paratose,
planteose, primeverose, raffinose, rhodinose, rutinose, sarmentose,
sedoheptulose, sedoheptulosan, solatriose, sophorose, stachyose,
streptose, sucrose, .alpha.,.alpha.-trehalose, trehalosami,
turanose, tyvelose and umbelliferose. Further, the terms
"disaccharide" and "polysaccharide" include modified disaccharide
and polysaccharide radicals.
[0111] "Amino acid residue" means any of the naturally occurring
alpha-, beta- and gamma-amino carboxylic acids, including their D
and L optical isomers and racemic mixtures thereof, synthetic amino
acids, and derivatives of these natural and synthetic amino acids.
The amino acid residue is bonded either through an amino or an acid
functional group of the amino acid. The naturally occurring amino
acids which can be incorporated in the present invention include,
but are not limited to, alanine, arginine, asparagine, aspartic
acid, cysteine, glutamic acid, glutamine, glycine, histidine,
isoleucine, leucine, lysine, methionine, ornithine, phenylalanine,
proline, serine, threonine, cyclohexylalanine, tryptophan,
tyrosine, valine, .beta.-alanine, and .gamma.-aminobutyric acid.
Derivatives of amino acids which can be incorporated in the present
invention include, but are not limited to amino acids having
protected and modified carboxylic acids, including acid esters and
amides, protected amines, and substituted phenyl rings, including
but not limited to alkyl, alkoxy and halo substituted tyrosine and
phenylalanine.
[0112] The present invention further provides a pharmaceutical
composition comprising a therapeutically-effective amount of a
compound of Formula (I) in association with at least one
pharmaceutically-acceptable carrier, adjuvant or diluent.
[0113] The present invention also provides a method of treating a
cyclooxygenase-2 mediated disease in a subject comprising the step
of administering to the subject a pharmaceutical composition
comprising a therapeutically-effective amount of a compound of
Formula (I): 6
[0114] or a pharmaceutically-acceptable salt thereof wherein:
[0115] A is a ring substituent selected from the group consisting
of heterocyclyl, heteroaryl, cycloalkenyl and aryl, wherein A is
optionally substituted at a substitutable position with one or more
radicals independently selected at each occurrence from the group
consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo,
cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl,
carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy,
alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl,
alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl,
heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl,
alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino,
N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl and
N-alkyl-N-arylaminosulfonyl;
[0116] R.sup.1 is selected from the group consisting of heteroaryl,
heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R.sup.1 is
optionally substituted at a substitutable position with one or more
radicals independently selected at each occurrence from the group
consisting of alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl,
hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino,
nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
[0117] R.sup.2 and R.sup.3 are independently selected from the
group consisting of hydrido, alkyl, alkylcarbonyl, hydroxyalkyl,
heterocyclyl, heteroaryl, monosaccharide, disaccharide,
polysaccharide, alkylphosphate, acyloxyalkyl, alkylaminocarbonyl,
alkoxyaralkyl and carboxyalkyl, wherein R.sup.3 is optionally
substituted at a substitutable position with one or more radicals
independently selected at each occurrence from the group consisting
of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano,
nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl,
carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy,
alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl,
alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl,
heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl,
alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino,
N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl, and
N-alkyl-N-arylaminosulfonyl;
[0118] wherein at least one of R.sup.2 and R.sup.3 is other than
hydrido;
[0119] wherein R.sup.2 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.3 is hydrido; and
[0120] wherein R.sup.3 is other than alkyl, carboxyalkyl or
alkylcarbonyl when R.sup.2 is hydrido;
[0121] or, R.sup.2 and R.sup.3 are taken together along with the
nitrogen to which they are attached to form a three to seven
membered saturated, partially unsaturated or unsaturated
heterocyclic ring and may optionally be substituted at a
substitutable position with one or more R.sup.5 radicals, wherein
the R.sup.5 radicals are independently selected at each occurrence
from the group consisting of alkylcarbonyl, formyl, halo, alkyl,
haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, alkoxy,
aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl,
hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl,
carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl,
heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl,
cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl,
arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl,
arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl,
N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl- , alkylamino, N-arylamino, N-aralkylamino,
N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl,
alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalky- l, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,
aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl and N-alkyl-N-arylaminosulfonyl; and
[0122] R.sup.4 is selected from hydrido and fluoro;
[0123] wherein R.sup.5 is other than methyl when A is isoxazole,
R.sup.1 is phenyl and R.sup.2 and R.sup.3 are taken together to
form a pyrrole ring.
[0124] The method of the present invention also includes
prophylactic treatment. A preferred method of the invention is the
administration of a compound of Formula (I) parenterally. In one
embodiment, the compound of Formula (I) is administered
intravenously. In another embodiment, the compound of Formula (I)
is administered intramuscularly.
[0125] Also included in the family of compounds of Formula (I) are
the stereoisomers thereof. Compounds of the present invention can
possess one or more asymmetric carbon atoms and are thus capable of
existing in the form of optical isomers as well as in the form of
racemic or nonracemic mixtures thereof. Accordingly, some of the
compounds of this invention may be present in racemic mixtures
which are also included in this invention. The optical isomers can
be obtained by resolution of the racemic mixtures according to
conventional processes, for example by formation of
diastereoisomeric salts by treatment with an optically active acid
or base. Examples of appropriate acids are tartaric,
diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and
camphorsulfonic acid and then separation of the mixture of
diastereoisomers by crystallization followed by liberation of the
optically active bases from these salts. A different process for
separation of optical isomers involves the use of a chiral
chromatography column optimally chosen to maximize the separation
of the enantiomers. Still another available method involves
synthesis of covalent diastereoisomeric molecules by reacting an
amine functionality of precursors to compounds of Formula (I) with
an optically pure acid in an activated form or an optically pure
isocyanate. Alternatively, diastereomeric derivatives can be
prepared by reacting a carboxyl functionality of precursors to
compounds of Formula I with an optically pure amine base. The
synthesized diastereoisomers can be separated by conventional means
such as chromatography, distillation, crystallization or
sublimation, and then hydrolyzed to deliver the enantiomerically
pure compound. The optically active compounds of Formula I can
likewise be obtained by utilizing optically active starting
materials. These isomers may be in the form of a free acid, a free
base, an ester or a salt.
[0126] Also included in the family of compounds of Formula (I) are
the pharmaceutically-acceptable salts thereof. The term
"pharmaceutically-acceptable salts" embraces salts commonly used to
form alkali metal salts and to form addition salts of free acids or
free bases. The nature of the salt is not critical, provided that
it is pharmaceutically-acceptable. Suitable
pharmaceutically-acceptable acid addition salts of compounds of
Formula (I) may be prepared from an inorganic acid or from an
organic acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric
acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and
sulfonic classes of organic acids, example of which are formic,
acetic, propionic, succinic, glycolic, gluconic, lactic, malic,
tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,
aspartic, glutamic, benzoic, anthranilic, mesylic, stearic,
salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic
(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic,
pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,
cyclohexylaminosulfonic, algenic, .beta.-hydroxybutyric, galactaric
and galacturonic acid. Suitable pharmaceutically-acceptable base
addition salts of compounds of Formula (I) include metallic salts
and organic salts. More preferred metallic salts include, but are
not limited to appropriate alkali metal (group Ia) salts, alkaline
earth metal (group IIa) salts and other physiological acceptable
metals. Such salts can be made from aluminum, calcium, lithium,
magnesium, potassium, sodium and zinc. Preferred organic salts can
be made from tertiary amines and quanternary ammonium salts,
including in part, trometamine, diethylamine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. All of these salts may be prepared by conventional means
from the corresponding compound of Formula (I) by reacting, for
example, the appropriate acid or base with the compound of Formula
(I).
General Synthetic Procedures
[0127] The cyclooxygenase-2 inhibitor prodrugs of the invention can
be synthesized according to the following procedures of Schemes
I-XVII, wherein the R.sup.1-R.sup.8 substituents are as defined for
Formula (I), above, except where further noted. 7
[0128] Synthetic Scheme I shows the preparation of cyclooxygenase-2
inhibitor compounds, as described in WO95/15316, which is
incorporated herein by reference. In step 1, ketone 1 is treated
with a base, preferably NaOMe or NaH, and an ester, or ester
equivalent, to form the intermediate diketone 2 (in the enol form)
which is used without further purification. In step 2, diketone 2
in an anhydrous protic solvent, such as absolute ethanol or acetic
acid, is treated with the hydrochloride salt or the free base of a
substituted hydrazine at reflux to afford a mixture of pyrazoles 3
and 4. Recrystallization or chromatography affords 3 usually as a
solid. Similar pyrazoles can be prepared by methods described in
U.S. Pat. Nos. 5,401,765, 5,434,178, 4,146,721, 5,051,518,
5,134,142 and 4,914,121 which also are incorporated herein by
reference. 8
[0129] Scheme II shows the four step procedure for forming
cyclooxygenase-2 inhibitor pyrazoles 8 as described in U.S. Pat.
No. 5,486,534 (where R.sup.c is hydrido or alkyl) from ketones 5.
In step 1, ketone 5 is reacted with a base, such as lithium
bis(trimethylsilyl)amide or lithium diisopropylamide (LDA) to form
the anion. In step 2, the anion is reacted with an acetylating
reagent to provide diketone 6. In step 3, the reaction of diketone
6 with hydrazine or a substituted hydrazine, gives pyrazole 7. In
step 4, the pyrazole 7 is oxidized with an oxidizing reagent, such
as Oxone.RTM. (potassium peroxymonosulfate), 3-chloroperbenzoic
acid (MCPBA) or hydrogen peroxide, to give a mixture of the desired
3-(alkylsulfonyl)phenyl-pyrazole 8 and the
5-(alkylsulfonyl)phenyl-pyrazole isomer. Sulfonamides 9 can be
prepared such as by the Huang method [Tet. Lett., 35, 7201-04
(1994)].
[0130] Alternatively, diketone 6 can be formed from ketone 5 by
treatment with a base, such as sodium hydride, in a solvent, such
as dimethylformamide, and further reacting with a nitrile to form
an aminoketone. Treatment of the aminoketone with acid forms the
diketone 6. Similar pyrazoles can be prepared by methods described
in U.S. Pat. No. 3,984,431 which is incorporated herein by
reference. 9
[0131] Cyclooxygenase-2 inhibitor diaryl/heteroaryl thiophenes
(where T is S, and R.sup.b
[0132] is alkyl) can be prepared by the methods described in U.S.
Pat. Nos. 4,427,693, 4,302,461, 4,381,311, 4,590,205, and
4,820,827, and PCT documents WO 95/00501 and WO94/15932, which are
incorporated herein by reference. Similar pyrroles (where T is N),
furanones and furans (where T is O) can be prepared by methods
described in PCT documents WO 95/00501 and WO94/15932. 10
[0133] Cyclooxygenase-2 inhibitor diaryl/heteroaryl oxazoles can be
prepared by the methods described in U.S. Pat. Nos. 5,380,738,
3,743,656, 3,644,499 and 3,647,858, and PCT documents WO 95/00501
and WO94/27980, which are incorporated herein by reference. 11
[0134] Cyclooxygenase-2 inhibitor diaryl/heteroaryl isoxazoles can
be prepared by the methods described in PCT application Serial No.
US96/01869, PCT documents WO92/05162, and WO92/19604, and European
Publication EP 26928, which are incorporated herein by reference.
Sulfonamides 27 can be formed from the hydrated isoxazole 26 in a
two step procedure. First, hydrated isoxazole 26 is treated at
about 0.degree. C. with two or three equivalents of chlorosulfonic
acid to form the corresponding sulfonyl chloride. In step two, the
sulfonyl chloride thus formed is treated with concentrated ammonia
to provide the sulfonamide derivative 27. 12
[0135] Scheme VI shows a three step preparation of the
cyclooxygenase-2 inhibitor imidazoles 33. In step 1, the reaction
of substituted nitriles (R.sup.aCN) 28 with primary phenylamines 29
in the presence of alkylaluminum reagents such as
trimethylaluminum, triethylaluminum, dimethylaluminum chloride,
diethylaluminum chloride in the presence of inert solvents such as
toluene, benzene, and xylene, gives amidines 30. In step 2, the
reaction of amidine 30 with 2-haloketones (where X is Br or Cl) in
the presence of bases, such as sodium bicarbonate, potassium
carbonate, sodium carbonate, potassium bicarbonate or hindered
tertiary amines such as N,N-diisopropylethylamine, gives the
4,5-dihydroimidazoles 31 (where R.sup.b is alkyl). Some of the
suitable solvents for this reaction are isopropanol, acetone and
dimethylformamide. The reaction may be carried out at temperatures
of about 20.degree. C. to about 90.degree. C. In step 3, the
4,5-dihydroimidazoles 31 may be dehydrated in the presence of an
acid catalyst such as 4-toluenesulfonic acid or mineral acids to
form the 1,2-disubstituted imidazoles 32 of the invention. Suitable
solvents for this dehydration step are e.g., toluene, xylene and
benzene. Trifluoroacetic acid can be used as solvent and catalyst
for this dehydration step. Sulfonamides 33 can be prepared such as
by the Huang method [Tet. Lett., 35, 7201-04 (1994)].
[0136] In some cases (e.g., where R.sup.c=methyl or phenyl) the
intermediate 31 may not be readily isolable. The reaction, under
the conditions described above, proceeds to give the targeted
imidazoles directly.
[0137] Similarly, imidazoles can be prepared having the
sulfonylphenyl moiety attached at position 2 and R.sup.a attached
at the nitrogen atom at position 1. Diaryl/heteroaryl imidazoles
can be prepared by the methods described in U.S. Pat. No. 4,822,805
and PCT documents WO 93/14082 and WO96/03388, which are
incorporated herein by reference. 13
[0138] Imidazole cyclooxygenase-2 inhibitor compounds 41 may be
synthesized according to the sequence outlined in Scheme VII.
Aldehyde 34 may be converted to the protected cyanohydrin 35 by
reaction with a trialkylsilyl cyanide, such as trimethylsilyl
cyanide (TMSCN) in the presence of a catalyst such as zinc iodide
(ZnI.sub.2) or potassium cyanide (KCN). Reaction of cyanohydrin 35
with a strong base followed by treatment with benzaldehyde 36 and
using both acid and base treatments, in that order, on workup gives
benzoin 37. Examples of strong bases suitable for this reaction are
lithium diisopropylamide (LDA) and lithium hexamethyldisilazane.
Benzoin 37 may be converted to benzil 38 by reaction with a
suitable oxidizing agent, such as bismuth oxide or manganese
dioxide, or by a Swern oxidation using dimethyl sulfoxide (DMSO)
and trifluoroacetic anhydride. Benzil 38 may be obtained directly
by reaction of the anion of cyanohydrin 35 with a substituted
benzoic acid halide. Any of compounds 37 and 38 may be used as
intermediates for conversion to imidazoles 39 according to chemical
procedures known by those skilled in the art and described by M. R.
Grimmett, "Advances in Imidazole Chemistry" in Advances in
Heterocyclic Chemistry, 12, 104 (1970). The conversion of 38 to
imidazoles 39 is carried out by reaction with ammonium acetate and
an appropriate aldehyde (R.sup.bCHO) in acetic acid. Benzoin 37 may
be converted to imidazoles 39 by reaction with formamide. In
addition, benzoin 37 may be converted to imidazoles by first
acylating with an appropriate acyl group (R.sup.bCO--) and then
treating with ammonium hydroxide. Those skilled in the art will
recognize that the oxidation of the sulfide to the sulfone may be
carried out at any point along the way beginning with compounds 36,
and including oxidation of imidazoles 39, using, for examples,
reagents such as hydrogen peroxide in acetic acid,
m-chloroperoxybenzoic acid (MCPBA) and potassium peroxymonosulfate
(OXONE.RTM.). Sulfonamides 41 can be prepared such as by the Huang
method [Tet. Lett., 35, 7201-04 (1994)].
[0139] Diaryl/heteroaryl imidazoles can be prepared by the methods
described in U.S. Pat. Nos. 3,707,475, 4,686,231, 4,503,065,
4,472,422, 4,372,964, 4,576,958, 3,901,908, PCT application Serial
No. US95/09505, European publication EP 372,445, and PCT document
WO 95/00501, which are incorporated herein by reference. 14
[0140] Diaryl/heteroaryl cyclopentene cyclooxygenase-2 inhibitors
can be prepared by the methods described in U.S. Pat. No.
5,344,991, and PCT document WO 95/00501, which are incorporated
herein by reference. 15
[0141] Similarly, Synthetic Scheme IX shows the procedure for the
preparation of 1,2-diarylbenzene cyclooxygenase-2 inhibitor agents
51 from 2-bromo-biphenyl intermediates 49 (prepared similar to that
described in Synthetic Scheme VIII) and the appropriate substituted
phenylboronic acids. Using a coupling procedure similar to the one
developed by Suzuki et al. [Synth. Commun., 11, 513 (1981)],
intermediates 49 are reacted with the boronic acids in
toluene/ethanol at reflux in the presence of a Pd.degree. catalyst,
e.g., tetrakis(triphenylphosphine)palladium(0), and 2M sodium
carbonate to give the corresponding 1,2-diarylbenzene
antiinflammatory agents 50 of this invention. Sulfonamides 51 can
be prepared such as by the Huang method [Tet. Lett., 35, 7201-04
(1994)]. Such terphenyl compounds can be prepared by the methods
described in U.S. application Ser. No. 08/346,433, which is
incorporated herein by reference. 16
[0142] Diaryl/heteroaryl thiazole cyclooxygenase-2 inhibitors can
be prepared by the methods described in U.S. Pat. Nos. 4,051,250,
4,632,930, European document EP 592,664, and PCT documents
WO96/03392, and WO 95/00501, which are incorporated herein by
reference. Isothiazoles can be prepared as described in PCT
document WO 95/00501.
[0143] Diaryl/heteroaryl pyridine cyclooxygenase-2 inhibitors can
be prepared by the methods described in U.S. Pat. Nos. 5,169,857,
4,011,328, 4,533,666, PCT application Serial No. US96/01110 and PCT
application Serial No. US96/01111, which are incorporated herein by
reference. 17
[0144] Synthetic Scheme XI illustrates a method for the preparation
of acylated sulfonamides 57. The method involves treatment of an
unsubstituted sulfonamide 56 with a suitable acylating agent such
as an anhydride, acid chloride, acyl imidazole, or active ester, in
the presence of base and a suitable solvent, such as
tetrahydrofuran (THF), to afford the acylated sulfonamide 57. The
product 57 can then be isolated by chromatography or by
crystallization. 18
[0145] Synthetic Scheme XII shows the method for the preparation of
the corresponding salt form of 57. Treatment of 57 with a suitable
strong base such as sodium hydroxide, potassium hydroxide, calcium
hydroxide and the like produces the corresponding salt form 58. A
wide variety of solvents can be used so long as they do not react
with the added strong base, such solvents as ethanol and
tetrahydrofuran are preferred. 19
[0146] Synthetic Scheme XIII shows the method used for the
preparation of substituted sulfonamides 60. The step involves
treatment of a suitable sulfonyl chloride 59 with an amine to
produce the substituted sulfonamide 59. The amine may be either a
primary amine (R.sup.bNH.sub.2) or a secondary amine
(R.sup.bR.sup.cNH). The reaction is generally conducted in the
presence of added base. The reaction may also be conducted in the
presence of excess amine. Under the conditions of excess amine, the
amine functions as both nucleophile and base. 20
[0147] Synthetic Scheme XIV shows the method used for the synthesis
of N-substituted acyl sulfonamides 61. The procedure involves
treatment of the salt of an acylated sulfonamide 58 with an alkyl
halide (R.sup.cX) to produce the corresponding N-alkylated acyl
sulfonamide 61. This process may be conducted in a wide variety of
solvents with a wide array of electrophiles. 21
[0148] Synthetic Scheme XV illustrates the method used for the
synthesis of certain N-acylated sulfonamides 57. The procedure
involves treatment of the sulfonamide 56 with an excess of an
anhydride, acid chloride or carbamyl chloride in the presence of a
tertiary amine base to provide the corresponding
bis(N-acylated)sulfonamide 62. The bis(N-acylated)sulfonami- de 62
is then treated with two equivalents of a strong base such as
sodium hydroxide to provide the sodium salt 58. 22
[0149] Synthetic Scheme XVI illustrates the method used for the
synthesis of certain N-alkylated pyrrole sulfonamides. Alcohol 65
is synthesized by following the literature procedure (J. Org. Chem.
57, 2195,1992). The alcohol 65 is oxidized such as by treatment
with oxalyl chloride in an appropriate solvent, such as methylene
chloride or DMSO. Addition, such as by Grignard reagents, produces
the alcohol 67. Oxidation with pyridinium chlorochromate produces
the ketones 68. Condensation with a [(N-substituted
amino)sulfonyl]benzeneamine in the presence of p-toluenesulfonic
acid (produces the substituted pyrrole sulfonamide 69. 23
[0150] Synthetic Scheme XVII illustrates the method for the
preparation of acylated isoxazole sulfonamides 71. The step
involves treatment of an unsubstituted sulfonamide 70 with a
suitable acylating agent such as an anhydride, acid chloride, acyl
imidazole, or active ester to afford the acylated sulfonamide 71.
The product 71 can be isolated by chromatography or by
crystallization. 24
[0151] Synthetic Scheme XVIII illustrates a method for the
preparation of N-substituted sulfonamides 72. The method involves
acylation of the unsubstituted sulfonamide 56 with an acylating
agent such as an anhydride, acid chloride, acyl imidazole, or
active ester, in the presence of base and a suitable solvent such
as tetrahydrofuran (THF). A catalyst such as dimethylaminopyridine
(DMAP) may be added. The acylated sulfonamide 57 can be alkylated
by treatment with an appropriate base and an alkylating agent such
as an alkylhalide. The resulting N-acyl-N-alkylsulfonamide 61, upon
treatment with an nucleophilic base such as hydroxide, a thiol, or
an amine under appropriately basic conditions will yield an
N--H--N-alkyl sulfonamide 72. The product 72 can be isolated by
chromatography or crystallization. 25
[0152] Synthetic Scheme XIX shows a direct alklyation of the
sulfonamide 56 using an appropriate base such as sodium hydride
with an aklylating agent such as an alkyl halide, aralkyl halide,
an alkyl sulfonate, or a cyclic alkly sulfonate in an appropriate
solvent such as dimethylformamide (DMF), dimthyl sulfoxide (DMSO),
or tetrahydrofuran (THF). By choice of the appropriate conditions
and number of equivalents of alkylating agent, the N-monoalkyl or
N,N-dialkyl substitution can be obtained. 26
[0153] Scheme XX illustrates the reductive alkylation of
sulfonamide 56 using an aldehyde, a hydride source such as sodium
triacetoxyborohydride or sodium cyanoborohydridein and an
appropriate solvent mixture which may include tetrahydrofuran and
acetic acid or trifluoroacetic acid to form a N-alkyl or N-aryl
sulfonamide 72. 27
[0154] Scheme XXI shows the reaction of an primary or secondary
sulfonamide 72, wherein R.sup.b must include H or alkyl, with an
appropriate carbamoylating agent such as an N-alkyl-S-alkyl
xanthate, N-aklyl-carbamoyl chloride or an n-alkyl isocyanate in
the presence of a base such as triethylamine and optionally a
catalyst such as dimethylaminopyridine (DMAP) in a solvent such as
dimethyl formamide (DMF), dichloromethane (DCM), tetrahydrofuran
(THF), or dimethyl sulfoxide (DMSO) to yield N-sulfonylcarbamate
73. 28
[0155] Scheme XXII illustrates the conversion of sulfonyl chloide
59 via its reaction with an appropriately substituted
hydroxylamine, wherein R.sup.b must include H or alkyl and R.sup.c
is either a protecting group or H, in the presence of a base such
as triethyl amine in a solvent such as dimethyl formamide (DMF),
dichloromethane (DCM), tetrahydrofuran (THF), or dimethyl sulfoxide
(DMSO) to yield the substituted N-hydroxy sulfonamide 74. Where
R.sup.c is a protecting group such as a tetrahydropyran (THP), it
can be removed under acidic conditions such as by the treatment
with toluenesulfonic acid in an appropriate solvent such as
tetrahydrofuran with an alcohol or water present.
[0156] The following examples contain detailed descriptions of the
methods of preparation of compounds of Formula (I). These detailed
descriptions fall within the scope, and serve to exemplify, the
above described General Synthetic Procedures which form part of the
invention. These detailed descriptions are presented for
illustrative purposes only and are not intended as a restriction on
the scope of the invention. All parts are by weight and
temperatures are in Degrees centigrade unless otherwise indicated.
All compounds showed NMR spectra consistent with their assigned
structures.
[0157] The following abbreviations are used:
[0158] HCl--hydrochloric acid
[0159] DMSO--dimethylsulfoxide
[0160] DMSOd6--deuterated dimethylsulfoxide
[0161] CDCl.sub.3--deuterated chloroform
[0162] MgSO.sub.4--magnesium sulfate
[0163] NaHCO.sub.3--sodium bicarbonate
[0164] KHSO.sub.4--potassium hydrogen sulfate
[0165] DMF--dimethylformamide
[0166] NaOH--sodium hydroxide
[0167] BOC--tert-butyloxycarbonyl
[0168] CD.sub.3OD--deuterated methanol
[0169] EtOH--ethanol
[0170] LiOH--lithium hydroxide
[0171] CH.sub.2Cl.sub.2--methylene chloride
[0172] h--hour
[0173] hr--hour
[0174] min--minutes
[0175] THF--tetrahydrofuran
[0176] TLC--thin layer chromatography
[0177] Et.sub.3N--triethylamine
[0178] DBU--1,8-diazabicyclo[5.4.0]undec-7-ene
[0179] DMAP--4-dimethylaminopyridine
EXAMPLE 1
[0180] 29
[0181] N-ethyl-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide
(5.0 g) and propionic anhydride (20 mL) were added together and
heated to 50.degree. C. at which point 20 .mu.L of sulfuric acid
was added. The temperature of the mixture was then increased to
80.degree. C. and stirred for 15 minutes. The mixture was then
cooled to 50.degree. C. at a rate of 0.3.degree. C./minute. If
crystallization did not occur, then the mixture was cooled until
crystallization was observed. The mixture was then held at
50.degree. C. for 30 minutes followed by cooling to 0.degree. C. at
a rate of 0.3.degree. C./minute. The mixture was held at 0.degree.
C. for about 30 minutes, filtered, washed with 10 mL MTBE at room
temperature and vacuum dried for about 5 minutes. The washing
procedure was repeated once again, and the product was then vacuum
dried overnight at room temperature to provide
N-ethyl-4-(5-methyl-3-phenylisox-
azol-4-yl)-N-propionylbenzenesulfonamide (4.7 g).
EXAMPLE 2
[0182] 30
[0183] A mixture of
4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide (3.14 g, 0.01
mol) and potassium carbonate (5.53 g, 0.04 mol) in DMF (50 mL) was
stirred at room temperature for 5 hours. 4-methylbenzylchloride
(3.45 g, 0.022 mol) was then added and the resulting mixture was
stirred overnight. Ethyl acetate (50 mL) and sat. water (100 mL)
were then added and the layers were separated. The organic layer
was washed with NaHCO3 (50 mL), brine, 1 N HCl (25 mL) and water
(2.times.25 mL). Then the organic layer was then dried over
MgSO.sub.4, filtered and concentrated under vacuum. The resulting
product was crystallized from boiling ethanol to afford 5.2 g of
the product as a white solid: mp, 133.8-135.2.degree. C.
EXAMPLE 3
[0184] 31
[0185] Preparation of methyl
N-(tert-butoxycarbonyl)-N-({4-[5-(4-methylphe-
nyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}sulfonyl)glycinate
[0186] A mixture of celecoxib (1.00 g, 2.62 mmol), DMAP (0.160 g,
(1.31 mmol), di-t-butyl dicarbonate (1.72 g, 7.87 mmol) and
triethylamine (0.318 g, 3.14 mmol) in anhydrous THF (10.0 mL) was
stirred at room temperature for 1 hour. Methyl bromoacetate (1.00
g, 6.55 mmol) and K.sub.2CO.sub.3 (0.724 g, 5.24 mmol) was then
added and the resulting mixture was stirred at room temperature for
21.5 hours. The reaction mixture was poured into sat. NaHCO.sub.3
and extracted with ethyl acetate (2.times.100 mL). The organic
layers were combined, washed with sat. NaCl (50 mL), dried over
MgSO.sub.4, filtered and concentrated under vacuum. The resulting
yellow glass was purified by flash chromatography (silica gel, 9:1
hexanes:ethyl acetate) to afford 1.32 g (91% yield) of the product
as a white powder: mp, 88.5.degree. C.; .sup.1H NMR
(dmso-d.sub.6/300 MHz) .delta. 8.06 (d, 2H, J=8.7 Hz), 7.61 (d, 2H,
J=8.9 Hz), 7.22-7.16 (m, 5H), 4.59 (s, 2H), 3.69 (s, 3H), 2.30 (s,
3H), 1.23 (s, 9H); HRMS (M+H)+calcd. for
C.sub.25H.sub.27F.sub.3O.sub.6S: 554.1573; found: 554.1601.
[0187] Preparation of
N-(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluor-
omethyl)-1H-pyrazol-1-yl]benzenesulfonamide
[0188] To a solution of methyl
N-(tert-butoxycarbonyl)-N-({4-[5-(4-methylp-
henyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}sulfonyl)glycinate
(1.18 g, 2.13 mmol) in 50 ml anhydrous methanol (50 mL) was added
NaBH.sub.4 (0.8 g, 21.1 mmol) and the mixture was stirred at room
temperature. At 30 minutes, additional MeOH (50 mL) was added and
then NaBH.sub.4 (3.6 g, 95.1 mmol) was added in portions over 5.5
hours and the mixture was stirred at room temperature for an
additional 18 hours. The solvent was removed under vacuum and ethyl
acetate (100 mL) was added. The mixture was then poured into sat.
NaHCO.sub.3 (200 mL) and the layers were separated. The aqueous
layer was then extracted with ethyl acetate (100 mL). The organic
layers were combined, washed with sat. NaHCO.sub.3 (100 mL), dried
over MgSO.sub.4, filtered and concentrated under vacuum. The
resulting pale yellow glass was dissolved in TFA (100 mL) and the
mixture was allowed to stand at room temperature for 2 hours. The
TFA was removed under vacuum, and remaining traces of TFA were
removed by addition and removal under vacuum of CH.sub.2Cl.sub.2
(several portions) to give a yellow oil. The crude product was
purified by flash chromatography (silica gel, 1:1 hexanes:ethyl
acetate) to afford 0.365 g (40% yield) of the product as a white
powder: mp, 57.8.degree. C.; .sup.1H NMR (dmso-d.sub.6/300 MHz)
.delta. 7.86-7.83 (m, 2H), 7.76 (exchangeable with D.sub.2O, t,
1H), J=5.9 Hz), 7.56-7.53 (m, 2H), 7.22-7.17 (m, 5H), 4.70
(exchangeable with D.sub.2O, t, 1H, J=5.6 Hz), 3.37-3.32 (m, 2H),
2.84-2.79 (m, 2H), 2.30 (s 3H); HRMS (M+H).sup.+ calcd. for
C.sub.19H.sub.9F.sub.3N.sub.3O.sub.3S: 426.1099; found
426.1071.
EXAMPLE 4
[0189] 32
[0190] Preparation of methyl
N-(2-methoxy-2-oxoethyl)-N-({4-[5-(4-methylph-
enyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}sulfonyl)glycinate
[0191] A mixture of Celecoxib (0.500 g, 1.31 mmol), methyl
bromoacetate (0.501 g, 3.28 mmol) and K.sub.2CO.sub.3 (0.362 g,
2.62 mmol) in anhydrous DMF (5.0 mL) was stirred at room
temperature for 21 hours. The mixture was then poured into sat.
NaHCO.sub.3 (200 mL) and extracted with ethyl acetate (200 mL). The
ethyl acetate solution was then washed with sat NaCl (50 mL), dried
over MgSO.sub.4, filtered and concentrated under vacuum. The crude
product was purified by flash chromatography (silica gel, 98:2
methylene chloride:methanol) to afford 0.350 g (51% yield) of the
product as a colorless glass: .sup.1H NMR (dmso-d.sub.6/300 MHz)
.delta. 7.90 (d, 2H, J=8.7 Hz), 7.53 (d, 2H, J=8.7 Hz), 7.23-7.17
(m, 5H), 4.19 (s, 4H), 3.54 (s, 6H), 2.30 (s, 3H); HRMS
(M+NH.sub.4).sup.+ calcd. for
C.sub.23H.sub.26F.sub.3N.sub.4O.sub.6S: 543.1525; found:
543.1526.
[0192] Preparation of
N,N-bis(2-hydroxyethyl)-4-[5-(4-methylphenyl-3-(trif-
luoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
[0193] To a solution of methyl
N-(2-methoxy-2-oxoethyl)-N-({4-[5-(4-methyl-
phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}sulfonyl)glycinate
prepared as in example 2.A. (0.330 g, 0.628 mmol) in anhydrous
methanol (50 mL), was added NaBH.sub.4 (0.4 g, 10.6 mmol) and the
mixture was allowed to stand at room temperature for 2 hours.
Additional NaBH.sub.4 (0.4 g, 10.6 mmol) was then added and after 1
hour, the solvent was removed in vacuo. The residue was dissolved
in water (100 mL), saturated with NaCl and the pH was adjusted to 2
with 1N HCl. The solution was extracted with ethyl acetate (200
mL). The organic solution was washed with sat. NaCl (50 mL), dried
over MgSO.sub.4, filtered and concentrated under vacuum to afford
0.285 g (97% yield) of the product as a white powder: mp,
79.1.degree. C.; .sup.1H NMR (dmso-d.sub.6/300 MHz) .delta. 7.87
(d, 2H, J=8.7 Hz), 7.54 (d, 2H, J=8.7 Hz), 7.23-7.16 (m, 5H), 4.81
(exchangeable with D.sub.2O, t, 2H, J=5.4 Hz), 3.52-3.46 (m, 4H),
3.20 (t, 4H, J=6.0 Hz), 2.30 (s, 3H); HRMS (M+H).sup.+ calcd. for
C.sub.21H.sub.23F.sub.3N.sub.3O.sub.4S: 470.1361; found
470.1330.
Biological Evaluation
Air-Pouch Model of Inflammation
[0194] Male Lewis rats (175-200 g) were used. Air cavities were
produced by subcutaneous injection of 20 mL of sterile air into the
intrascapular area of the back. An additional 10 mL of air was
injected into the cavity every 3 days to keep the space open. Seven
days after the initial air injection, 2 mL of a 1% solution of
carrageenan (Sigma) dissolved in saline was injected directly into
the pouch to produce an inflammatory response. The volume of
exudate was measured with a Coulter Counter.
[0195] The differential cell count was determined by Wright-Giemsa
staining. PGE.sub.2 and 6-keto-PGF.sub.1.alpha. were determined in
the pouch exudates by specific ELISAs (Cayman Chemicals, Ann Arbor,
Mich.). Results are shown in Table I.
1 TABLE I AIR POUCH TEST % Inhibition Example @ 20 mg/kg body
weight 3 59 4 10
[0196] Also embraced within this invention is a class of
pharmaceutical compositions comprising the active compounds of this
combination therapy in association with one or more non-toxic,
pharmaceutically-acceptable carriers and/or diluents and/or
adjuvants (collectively referred to herein as "carrier" materials)
and, if desired, other active ingredients. The active compounds of
the present invention may be administered by any suitable route,
preferably in the form of a pharmaceutical composition adapted to
such a route, and in a dose effective for the treatment intended.
The active compounds and composition may, for example, be
administered orally, intravascularly (IV), intraperitoneally,
subcutaneously, intramuscularly (IM) or topically.
[0197] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, hard or soft capsule,
lozenges, dispensable powders, suspension or liquid. The
pharmaceutical composition is preferably made in the form of a
dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or
capsules.
[0198] The active ingredient may also be administered by injection
(IV, IM, subcutaneous or jet) as a composition wherein, for
example, saline, dextrose, or water may be used as a suitable
carrier. The pH of the composition may be adjusted, if necessary,
with suitable acid, base, or buffer. Suitable bulking, dispersing,
wetting or suspending agents, including mannitol and PEG 400, may
also be included in the composition. A suitable parenteral
composition can also include a compound formulated as a sterile
solid substance, including lyophilized powder, in injection vials.
Aqueous solution can be added to dissolve the compound prior to
injection.
[0199] The amount of therapeutically active compounds that are
administered and the dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
depends on a variety of factors, including the age, weight, sex and
medical condition of the subject, the severity of the inflammation
or inflammation related disorder, the route and frequency of
administration, and the particular compound employed, and thus may
vary widely. The prodrug compositions should include similar
dosages as for the parent compounds. The pharmaceutical
compositions may contain active ingredients in the range of about
0.1 to 1000 mg, preferably in the range of about 0.5 to 250 mg and
most preferably between about 1 and 60 mg. A daily dose of about
0.01 to 100 mg/kg body weight, preferably between about 0.05 and
about 20 mg/kg body weight and most preferably between about 0.1 to
10 mg/kg body weight, may be appropriate. The daily dose can be
administered in one to four doses per day.
[0200] In the case of skin conditions, it may be preferable to
apply a topical preparation of compounds of this invention to the
affected area two to four times a day.
[0201] For disorders of the eye or other external tissues, e.g.,
mouth and skin, the formulations are preferably applied as a
topical gel, spray, ointment or cream, or as a suppository,
containing the active ingredients in a total amount of, for
example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most
preferably 0.4 to 15% w/w. When formulated in an ointment, the
active ingredients may be employed with either paraffinic or a
water-miscible ointment base. Alternatively, the active ingredients
may be formulated in a cream with an oil-in-water cream base. If
desired, the aqueous phase of the cream base may include, for
example at least 30% w/w of a polyhydric alcohol such as propylene
glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene
glycol and mixtures thereof. The topical formulation may desirably
include a compound which enhances absorption or penetration of the
active ingredient through the skin or other affected areas.
Examples of such dermal penetration enhancers include
dimethylsulfoxide and related analogs. The compounds of this
invention can also be administered by a transdermal device.
Preferably topical administration will be accomplished using a
patch either of the reservoir and porous membrane type or of a
solid matrix variety. In either case, the active agent is delivered
continuously from the reservoir or microcapsules through a membrane
into the active agent permeable adhesive, which is in contact with
the skin or mucosa of the recipient. If the active agent is
absorbed through the skin, a controlled and predetermined flow of
the active agent is administered to the recipient. In the case of
microcapsules, the encapsulating agent may also function as the
membrane. The transdermal patch may include the compound in a
suitable solvent system with an adhesive system, such as an acrylic
emulsion, and a polyester patch.
[0202] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it may comprise a mixture
of at least one emulsifier with a fat or an oil or with both a fat
and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,
among others.
[0203] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters may be used. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0204] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier, especially an aqueous solvent for
the active ingredients. The antiinflammatory active ingredients are
preferably present in such formulations in a concentration of 0.5
to 20%, advantageously 0.5 to 10% and particularly about 1.5%
w/w.
[0205] For therapeutic purposes, the active compounds of this
combination invention are ordinarily combined with one or more
adjuvants appropriate to the indicated route of administration. If
administered per os, the compounds may be admixed with lactose,
sucrose, starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium stearate,
magnesium oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose. Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules having one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
[0206] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations.
* * * * *