U.S. patent application number 09/906765 was filed with the patent office on 2002-08-22 for heterocyclic aromatic oxazole compounds and use thereof.
Invention is credited to Haruta, Junichi, Hashimoto, Hiromasa, Matsushita, Mutsuyoshi.
Application Number | 20020115701 09/906765 |
Document ID | / |
Family ID | 27468109 |
Filed Date | 2002-08-22 |
United States Patent
Application |
20020115701 |
Kind Code |
A1 |
Haruta, Junichi ; et
al. |
August 22, 2002 |
Heterocyclic aromatic oxazole compounds and use thereof
Abstract
A heterocyclic aromatic oxazole compound of the formula (I) 1
wherein Z is an oxygen atom; one of R and R.sub.1 is a group of the
formula 2 wherein R.sub.3 is lower alkyl, amino or lower
alkylamino, and R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are the same
or different and each is hydrogen atom, halogen atom, lower alkyl,
lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at
least one of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is not hydrogen
atom, and the other is an optionally substituted cycloalkyl, an
optionally substituted heterocyclic group or an optionally
substituted aryl; and R.sub.2 is a lower alkyl or a halogenated
lower alkyl, and a pharmaceutically acceptable salt thereof. The
heterocyclic aromatic oxazole compound and pharmaceutically
acceptable salts thereof have antipyretic action, analgesic action,
anti-inflammatory action, and particularly, selective inhibitory
action on cyclooxygenase-2 (COX-2), and are expected to be useful
as anti-inflammatory agents with less side-effects such as
digestive tract disorders.
Inventors: |
Haruta, Junichi; (Osaka,
JP) ; Hashimoto, Hiromasa; (Osaka, JP) ;
Matsushita, Mutsuyoshi; (Osaka, JP) |
Correspondence
Address: |
Stephen B. Maebius
FOLEY & LARDNER
Suite 500
3000 K Street, N.W.
Washington
DC
20007-5109
US
|
Family ID: |
27468109 |
Appl. No.: |
09/906765 |
Filed: |
July 18, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09906765 |
Jul 18, 2001 |
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09398997 |
Sep 17, 1999 |
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09398997 |
Sep 17, 1999 |
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08693051 |
Aug 19, 1996 |
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08693051 |
Aug 19, 1996 |
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PCT/JP95/02600 |
Dec 18, 1995 |
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Current U.S.
Class: |
514/374 ;
548/235 |
Current CPC
Class: |
C07C 49/567 20130101;
C07C 2601/14 20170501; C07D 263/32 20130101; C07C 45/004 20130101;
C07C 69/007 20130101; C07C 311/29 20130101; C07C 45/004 20130101;
C07C 311/32 20130101; C07C 317/24 20130101; A61P 25/04 20180101;
C07C 49/567 20130101; C07C 311/37 20130101; C07C 317/32 20130101;
A61P 29/00 20180101; C07C 251/42 20130101; A61P 43/00 20180101;
C07C 233/31 20130101; C07D 413/04 20130101; C07C 311/16 20130101;
C07C 49/813 20130101; C07C 233/47 20130101 |
Class at
Publication: |
514/374 ;
548/235 |
International
Class: |
C07D 263/30; A61K
031/421 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 20, 1994 |
JP |
335838/1994 |
Mar 27, 1995 |
JP |
93099/1995 |
Jun 6, 1995 |
JP |
164656/1995 |
Nov 20, 1995 |
JP |
326571/1995 |
Claims
What is claimed is:
1. A heterocyclic aromatic oxazole compound of the formula (I)
58wherein Z is an oxygen atom; one of R and R.sub.1 is a group of
the formula 59wherein R.sub.3 is lower alkyl, amino or lower
alkylamino, and R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are the same
or different and each is hydrogen atom, halogen atom, lower alkyl,
lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at
least one of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is not hydrogen
atom, and the other is optionally substituted cycloalkyl,
optionally substituted heterocyclic group or optionally substituted
aryl; and R.sub.2 is a lower alkyl or a halogenated lower alkyl, or
a pharmaceutically acceptable salt thereof:
2. The heterocyclic aromatic oxazole compound of claim 1, wherein
R.sub.1 is a group of the formula 60wherein R.sub.3' is lower alkyl
or amino, at least one of R.sub.4', R.sub.5', R.sub.6' and R.sub.7'
is halogen atom or lower alkyl and the rest is hydrogen atom or
halogen atom, or a pharmaceutically acceptable salt thereof.
3. The heterocyclic aromatic oxazole compound of claim 1, wherein
R.sub.1 is a group of the formula 61wherein R.sub.3" is methyl or
amino, R.sub.5" is fluorine atom and R.sub.6" is hydrogen atom or
fluorine atom, and R.sub.2 is methyl, or a pharmaceutically
acceptable salt thereof.
4. The heterocyclic aromatic oxazole compound of claim 1, wherein
R.sub.1 is a group of the formula 62wherein R.sub.3", R.sub.5" and
R.sub.6" are as defined in claim 3; R is optionally substituted
cycloalkyl having 5 to 7 carbon atoms, optionally substituted
thienyl, optionally substituted furyl, optionally substituted
pyrrolyl, optionally substituted morpholino, optionally substituted
piperazinyl, optionally substituted piperidyl, optionally
substituted phenyl, optionally substituted naphthyl or optionally
substituted biphenyl, and R.sub.2 is methyl, or a pharmaceutically
acceptable salt thereof.
5. The heterocyclic aromatic oxazole compound of claim 4, wherein
R.sub.3" is amino, or a pharmaceutically acceptable salt
thereof.
6. The heterocyclic aromatic oxazole compound of claim 4, wherein R
is optionally substituted cycloalkyl having 5 to 7 carbon atoms,
optionally substituted phenyl or optionally substituted thienyl, or
a pharmaceutically acceptable salt thereof.
7. The heterocyclic aromatic oxazole compound of claim 4, wherein R
is cyclohexyl or 4-fluorophenyl, and R.sub.1 is
4-aminosulfonyl-3-fluorophen- yl,
4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl
or 3,5-difluoro-4-methylsulfonylphenyl, or a pharmaceutically
acceptable salt thereof.
8. The heterocyclic aromatic oxazole compound of claim 1, which is
selected from the group consisting of:
4-cyclohexyl-5-(3-fluoro-4-methyls- ulfonylphenyl)-2-methyloxazole,
5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclo- hexyl-2-methyloxazole,
5-(4-aminosulfonyl-3,5-difluorophenyl)-4-cyclohexyl-
-2-methyloxazole,
4-cyclohexyl-5-(3,5-difluoro-4-methylsulfonylphenyl)-2-m-
ethyloxazole, and
5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2--
methyloxazole, or a pharmaceutically acceptable salt thereof.
9. An oxime compound of the following formula (XI') 63wherein
R.sub.1" is 64wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are as
defined in claim 1, and R" is optionally substituted cycloalkyl or
optionally substituted aryl.
10. The oxime compound of claim 9 wherein R.sub.1" is
3-fluorophenyl or 3,5-difluorophenyl, and R" is cyclohexyl or
4-fluorophenyl.
11. A ketone compound of the following formula (IV") 65wherein
R.sub.1" and R" are respectively as defined in claim 9.
12. The ketone compound of claim 11, wherein R.sub.1" is
3-fluorophenyl or 3,5-difluorophenyl, and R" is cyclohexyl or
4-fluorophenyl.
13. A ketomethylene compound of the following formula (IV'")
66wherein R'" is an optionally substituted cycloalkyl having 5 to 7
carbon atoms, an optionally substituted phenyl or an optionally
substituted thienyl, and R.sub.1'" is a group of the formula
67wherein R.sub.3', R.sub.4', R.sub.5', R.sub.6' and R.sub.7' are
as defined in claim 2.
14. The ketomethylene compound of claim 13, wherein R'" is
cyclohexyl, and R.sub.1'" is 4-aminosulfonyl-3-fluorophenyl,
4-aminosulfonyl-3,5-difluoro- phenyl,
3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylph-
enyl.
15. An ester compound of the following formula (V) 68wherein R,
R.sub.1, R.sub.2 and Z are as defined in claim 1.
16. The ester compound of claim 15, wherein R is cycloalkyl and
R.sub.2 is lower alkyl.
17. An amide compound of the following formula (XVIII') 69wherein
R.sub.1" and R" are respectively as defined in claim 9, and Z and
R.sub.2 are as defined in claim 1.
18. The amide compound of claim 17, wherein R.sub.1" is
3-fluorophenyl or 3,5-difluorophenyl, R" is cyclohexyl or
4-fluorophenyl, and R.sub.2 is lower alkyl.
19. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier, and a heterocyclic aromatic oxazole compound of
claim 1 or a pharmaceutically acceptable salt thereof.
20. A cyclooxygenase-2 inhibitor comprising a pharmaceutically
acceptable carrier, and a heterocyclic aromatic oxazole compound of
claim 1 or a pharmaceutically acceptable salt thereof as an active
ingredient.
21. An anti-inflammatory agent comprising a pharmaceutically
acceptable carrier, and a heterocyclic aromatic oxazole compound of
claim 1 or a pharmaceutically acceptable salt thereof as an active
ingredient.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel heterocyclic aromatic
oxazole compounds. More particularly, the present invention relates
to heterocyclic aromatic oxazole compounds having antipyretic
activity, analgesic activity, anti-inflammatory activity, and in
particular, selective inhibitory activity against cyclooxygenase-2
(COX-2), pharmaceutically acceptable salts thereof, intermediates
for producing them and pharmaceuticals useful as anti-inflammatory
agents causing less side-effects such as disorders in the digestive
tract, which comprise these heterocyclic aromatic oxazole
compounds.
BACKGROUND ART
[0002] It has been conventionally known that arachidonic acid
metabolites, prostaglandin E.sub.2 (PGE.sub.2), prostaglandin
I.sub.2 (PGI.sub.2) and thromboxane B.sub.2 (TXB.sub.2) are deeply
involved in inflammations. An important enzyme in this arachidonic
acid metabolism is cyclooxygenase. Cyclooxygenase is a synthase
which produces prostaglandin H.sub.2 (PGH.sub.2) from arachidonic
acid via prostaglandin G.sub.2 (PGG.sub.2), and includes
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
[0003] With respect to COX-1, cDNA cloning was performed in 1988
and its primary structure and induction by various factors have
been clarified [Yokoyama, C. et al.: Biochem. Biophys. Res.
Commun., 165: 888-894 (1989); Smith, W. L. et al.: Biochim.
Biophys. Acta, 1083: 1-17 (1991); DeWitt, D. L.: Biochim. Biophys.
Acta, 1083: 121-134 (1991)]. On the other hand, the existence of an
isozyme of COX-1, namely, COX-2, was suggested in 1989 [Holtzman,
M. J. et al.: J. Biol. Chem., 267: 21438-21445 (1992)], and cDNAs
of COX-2 of chicken, mouse and human have been cloned since 1991
[Xie, W. et al.: Proc. Natl. Acad. Sci. USA, 88:-2692-2696 (1991);
Kujubu, D. A. et al.: J. Biol. Chem., 266: 12866-12872 (1991); Hla,
T. et al.: Proc. Natl. Acad. Sci. USA, 89: 7384-7388 (1992)]. COX-2
is quickly induced by phorbol ester, lipopolysaccharide (LPS) and
the like, and the relationship with inflammation and bronchial
asthma has been inferred.
[0004] COX-1 systemically and constantly exists in almost all cells
and is physiologically concerned with the generation of
prostaglandin (PG) necessary for the functions of, for example,
stomach and kidney. Therefore, when COX-1 is inhibited, the
biosynthesis of PG by vasodilative PGE.sub.2 and PGI.sub.2, which
protect gastric mucosa, is suppressed, and the protective action on
the gastric mucosa becomes degraded, as a result of which ulcer is
caused. With regard to a symptom associated with a decrease in
renal blood flow, in general terms, the renal blood flow can be
increased by promoting the production of vasodilative PGE.sub.2 in
the body, thereby to appropriately maintain glomerular filtration
rate. However, if the production of such vasodilative PG is
suppressed due to the inhibition of COX-1, the renal blood flow
becomes less, so that a side-effect such as the onset of ischemic
acute renal insufficiency is sometimes caused.
[0005] On the other hand, COX-2 exists in particular sites such as
monocytes, synovial cells, granulosa cells and intravenous
endothelial cells, and is topically expressed when inflammation is
caused. It is therefore considered that PG generated by COX-2 is
deeply concerned with inflammation and tissue disorders.
[0006] Currently, non-steroidal anti-inflammatory drugs (NSAID)
such as aspirin, mefenamic acid, diclofenac, indomethacin,
ibuprofen and naproxen have been widely used in clinical
situations. Most of these NSAIDs are anti-inflammatory drugs which
selectively inhibit cyclooxygenase (COX) and are associated with
side-effects such as disorders in the digestive tract. Such
side-effects are considered to be caused by the fact that they,
though certainly selectively inhibit COX, inhibit both COX-1 and
COX-2.
[0007] It follows therefrom that selective inhibition, without
inhibition of COX-1, of solely COX-2 which is specifically induced
at the inflammatory sites, would enable provision of a superior
anti-inflammatory drug free of side-effects such as disorders in
the digestive tract (e.g., ulcer).
[0008] There are various reports on anti-inflammatory drugs having
selective COX-2 inhibitory activity, which aim at reducing
side-effects such as disorders in the digestive tract.
[0009] For example, WO94/15932 discloses, as COX-2 inhibitors,
5-membered heterocyclic compounds substituted by bisaryl, such as
thiophene, furan and pyrrole, which are specifically exemplified by
3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene. However,
this publication merely shows a 5-membered heterocyclic compound
such as thiophene having aryl or heteroaryl at the 3-position or
4-position.
[0010] Moreover, various reports deal with anti-inflammatory drugs
having cyclooxygenase-inhibitory action, prostaglandin
synthesis-inhibitory action or thromboxane A.sub.2
synthesis-inhibitory action.
[0011] For example, Japanese Patent Unexamined Publication No.
141261/1991 discloses pyrazole derivatives such as ethyl
1-(4-fluorophenyl)-5-[4-(met-
hylsulfonyl)phenyl]pyrazole-3-carboxylate; Japanese Patent
Unexamined Publication No. 183767/1982 discloses thiazole
derivatives such as 2-methylthio-5-phenyl-4-(3-pyridyl)-thiazole;
and Japanese Patent Unexamined Publication No. 58981/1985 discloses
thiazole derivatives such as
2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole. These
publications mention that they are useful as anti-inflammatory
drugs, whereas they do not disclose if they have selective
inhibitory action on COX-2 to reduce side-effects, or any
suggestion of it.
[0012] There are other reports on the following heterocyclic
aromatic compounds.
[0013] For example, U.S. Pat. No. 4,632,930 discloses oxazole
compounds such as
5-cyclohexyl-4-(4-methylsulfonylphenyl)-.alpha.,.alpha.-bis(trifl-
uoromethyl)oxazole-2-methanol. Yet, the compounds disclosed therein
are effective for hypertension and their usefulness as
anti-inflammatory drugs or any suggestion to that effect are not
included.
[0014] Japanese Patent Application under PCT laid-open under Kohyo
No. 500054/1984 discloses oxazole derivatives having heteroaryl or
carbon ring aryl at the 4-position or 5-position of oxazole ring
and having carboxy, ester or amidized carboxy via lower alkylene at
the 2-position thereof, such as ethyl
2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionate; and Japanese
Patent Application under PCT laid-open under Kohyo No. 500055/1984
discloses imidazole derivatives having heteroaryl and/or carbon
ring aryl at the 4-position or 5-position of imidazole ring and
having formyl or acetalized formyl via lower alkylene at the
2-position thereof, such as
2-[4-phenyl-5-(3-pyridyl)-imidazol-2-yl]-acetaldehyde dimethyl
acetal. These publications teach that these compounds are effective
as dermal antiphlogistic or mucosal antiphlogistic for inflammatory
dermal diseases, but do not teach or even suggest that they have
selective inhibitory action on COX-2.
[0015] Japanese Patent Unexamined Publication No. 70446/1993
discloses N-thiazolylsulfonamide derivatives such as
N-[5-cyclohexyl-4-(4-methoxyph-
enyl)thiazol-2-yl]trifluoromethanesulfonamide; and Japanese Patent
Unexamined Publication No. 83372/1990 discloses cyclohexylimidazole
derivatives such as 4-cyclohexyl-5-phenyl-2-t-butyl-imidazole.
These publications only exemplify cyclohexyl as a substituent and
include no suggestion as to the substitution with phenyl
substituted by aminosulfonyl, lower alkylaminosulfonyl or lower
alkylsulfonyl.
[0016] WO94/27980 discloses oxazole compounds such as
2-phenyl-4-cyclohexyl-5-(4-methylsulfonylphenyl)oxazole as COX-2
inhibitors. However, the compounds described in this publication
are mainly characterized by 4-fluorophenyl and
4-methylsulfonylphenyl at the 4-position and 5-position of oxazole
ring, and do not suggest the compounds having specific substituents
in combination, as in the present invention.
[0017] Not only in COX-2 inhibitors but also in the field of
anti-inflammatory drugs, preferable phenyl substituent for
5-membered heterocyclic ring skeleton has been conventionally
considered to be monosubstituted phenyl such as
4-methylsulfonylphenyl and 4-methoxyphenyl, and di-substituted
phenyl has been barely tried (e.g., UK Patent No. 1206403).
DISCLOSURE OF THE INVENTION
[0018] The present inventors have intensively studied with the aim
of providing a novel compound having antipyretic activity,
analgesic activity and anti-inflammatory activity, which is free of
side-effects such as disorders in the digestive tract.
Surprisingly, they have found that a compound having a secondary
substituent such as halogen atom, in particular, fluorine atom,
introduced into phenyl such as 4-lower alkylsulfonylphenyl,
4-aminosulfonylphenyl or 4-lower alkylaminosulfonylphenyl, as a
substituent for oxazole, has superior selective inhibitory action
on COX-2, which resulted in the completion of the present
invention.
[0019] That is, the present invention relates to heterocyclic
aromatic oxazole compounds as shown in the following (1) to (21),
pharmaceutically acceptable salts thereof, intermediate compounds
for producing such compounds and pharmaceutical compositions
comprising such heterocyclic aromatic oxazole compound.
[0020] (1) Heterocyclic aromatic oxazole compounds of the formula
(I) 3
[0021] wherein
[0022] Z is an oxygen atom;
[0023] one of R and R.sub.1 is a group of the formula 4
[0024] wherein R.sub.3 is lower alkyl, amino or lower alkylamino,
and R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are the same or different
and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy,
trifluoromethyl, hydroxy or amino, provided that at least one of
R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is not hydrogen atom, and the
other is optionally substituted cycloalkyl, optionally substituted
heterocyclic group or optionally substituted aryl; and
[0025] R.sub.2 is a lower alkyl or a halogenated lower alkyl, and
pharmaceutically acceptable salts thereof.
[0026] (2) Heterocyclic aromatic oxazole compounds of the above
(1), wherein R.sub.1 is a group of the formula 5
[0027] wherein R.sub.3' is lower alkyl or amino, at least one of
R.sub.4', R.sub.5', R.sub.6' and R.sub.7' is halogen atom or lower
alkyl and the rest is hydrogen atom or halogen atom, and
pharmaceutically acceptable salts thereof.
[0028] (3) Heterocyclic aromatic oxazole compounds of the above
(1), wherein R.sub.1 is a group of the formula 6
[0029] wherein R.sub.3" is methyl or amino, R.sub.5" is fluorine
atom and R.sub.6" is hydrogen atom or fluorine atom, and R.sub.2 is
methyl, and pharmaceutically acceptable salts thereof.
[0030] (4) Heterocyclic aromatic oxazole compounds of the above
(1), wherein R.sub.1 is a group of the formula 7
[0031] wherein R.sub.3", R.sub.5" and R.sub.6" are as defined in
the above (3); R is optionally substituted cycloalkyl having 5 to 7
carbon atoms, optionally substituted thienyl, optionally
substituted furyl, optionally substituted pyrrolyl, optionally
substituted morpholino, optionally substituted piperazinyl,
optionally substituted piperidyl, optionally substituted phenyl,
optionally substituted naphthyl or optionally substituted biphenyl,
and R.sub.2 is methyl, and pharmaceutically acceptable salts
thereof.
[0032] (5) Heterocyclic aromatic oxazole compounds of the above
(4), wherein R.sub.3" is amino, and pharmaceutically acceptable
salts thereof.
[0033] (6) Heterocyclic aromatic oxazole compounds of the above
(4), wherein R is optionally substituted cycloalkyl having 5 to 7
carbon atoms, optionally substituted phenyl or optionally
substituted thienyl, and pharmaceutically acceptable salts
thereof.
[0034] (7) Heterocyclic aromatic oxazole compounds of the above
(4), wherein R is cyclohexyl or 4-fluorophenyl, and R.sub.1 is
4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl,
3-fluoro-4-methylsulfonylphenyl or
3,5-difluoro-4-methylsulfonylphenyl, and pharmaceutically
acceptable salts thereof.
[0035] (8) Heterocyclic aromatic oxazole compounds of the above
(1), which are selected from the group of:
[0036]
4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole,
[0037]
5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole,
[0038]
5-(4-aminosulfonyl-3,5-difluorophenyl)-4-cyclohexyl-2-methyloxazole-
,
[0039]
4-cyclohexyl-5-(3,5-difluoro-4-methylsulfonylphenyl)-2-methyloxazol-
e, and
[0040]
5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazo-
le,
[0041] and pharmaceutically acceptable salts thereof.
[0042] (9) Oxime compounds of the following formula (XI') 8
[0043] wherein R.sub.1" is 9
[0044] wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are as defined
in the above (1), and R" is optionally substituted cycloalkyl or
optionally substituted aryl.
[0045] (10) Oxime compounds of the above (9) wherein R.sub.1" is
3-fluorophenyl or 3,5-difluorophenyl, and R" is cyclohexyl or
4-fluorophenyl.
[0046] (11) Ketone compounds of the following formula (IV") 10
[0047] wherein R.sub.1" and R" are respectively as defined in the
above (9).
[0048] (12) Ketone compounds of the above (11) wherein R.sub.1" is
3-fluorophenyl or 3,5-difluorophenyl, and R" is cyclohexyl or
4-fluorophenyl.
[0049] (13) Ketomethylene compounds of the following formula (IV'")
11
[0050] wherein R'" is optionally substituted cycloalkyl having 5 to
7 carbon atoms, optionally substituted phenyl or optionally
substituted thienyl, and R.sub.1'" is a group of the formula 12
[0051] wherein R.sub.3', R.sub.4', R.sub.5', R.sub.6' and R.sub.7'
are as defined in the above (2).
[0052] (14) Ketomethylene compounds of the above (13) wherein R'"
is cyclohexyl, and R.sub.1'" is 4-aminosulfonyl-3-fluorophenyl,
4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl
or 3,5-difluoro-4-methylsulfonylphenyl.
[0053] (15) Ester compounds of the following formula (V) 13
[0054] wherein R, R.sub.1, R.sub.2 and Z are as defined in the
above (1).
[0055] (16) Ester compounds of the above (15) wherein R is
cycloalkyl and R.sub.2 is lower alkyl.
[0056] (17) Amide compounds of the following formula (XVIII')
14
[0057] wherein R.sub.1" and R" are respectively as defined in the
above (9), and Z and R.sub.2 are as defined in the above (1).
[0058] (18) Amide compounds of the above (17) wherein R.sub.1" is
3-fluorophenyl or 3,5-difluorophenyl, R" is cyclohexyl or
4-fluorophenyl, and R.sub.2 is lower alkyl.
[0059] (19) Pharmaceutical compositions comprising a
pharmaceutically acceptable carrier, and a heterocyclic aromatic
oxazole compound of the above (1) or a pharmaceutically acceptable
salt thereof.
[0060] (20) Cyclooxygenase-2 inhibitors comprising a
pharmaceutically acceptable carrier, and a heterocyclic aromatic
oxazole compound of the above (1) or a pharmaceutically acceptable
salt thereof as an active ingredient.
[0061] (21) Anti-inflammatory agents comprising a pharmaceutically
acceptable carrier, and a heterocyclic aromatic oxazole compound of
the above (1) or a pharmaceutically acceptable salt thereof as an
active ingredient.
[0062] As used herein, lower alkyl means an optionally branched all
having 1 to 4 carbon atoms, which is exemplified by methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, with
preference given to methyl.
[0063] Lower alkylamino is that wherein amino group is substituted
by the above-mentioned lower alkyl, and is exemplified by
methylamino, dimethylamino, ethylamino, diethylamino, propylamino,
isopropylamino, butylamino, isobutylamino, sec-butylamino and
tert-butylamino. Preferred are methylamino and dimethylamino.
[0064] Halogen atom means chlorine atom, bromine atom, fluorine
atom and the like, with preference given to chlorine atom and
fluorine atom. Particularly preferred is fluorine atom.
[0065] Lower alkoxy is an optionally branched alkoxy having 1 to 4
carbon atoms, which is exemplified by methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, with
preference given to methoxy.
[0066] Cycloalkyl means a cycloalkyl having 3 to 8 carbon atoms,
which is exemplified by cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl, with preference given to
cycloalkyl having 5 to 7 carbon atoms, such as cyclopentyl,
cyclohexyl and cycloheptyl. Particularly preferred is
cyclohexyl.
[0067] Heterocyclic group is a 5- or 6-membered aromatic
heterocyclic ring, saturated heterocyclic ring or condensed
heterocyclic ring of these heterocyclic rings and benzene ring, all
having, besides carbon atom, 1 to 3 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom as atom(s) constituting
the ring. Examples thereof include thienyl, furyl, pyrrolyl,
imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, morpholino, piperazinyl, piperidyl, pyranyl,
thiopyranyl, pyridyl, benzothienyl, benzofuranyl, indole,
4,5,6,7-tetrahydroindole, 4,5,6,7-tetrahydrobenzothienyl and
4,5,6,7-tetrahydrobenzofuranyl, with preference given to thienyl,
furyl, pyrrolyl, morpholino, piperazinyl and piperidyl, and
particular preference given to thienyl.
[0068] Aryl is, for example, phenyl, naphthyl or biphenyl.
Preferred is phenyl.
[0069] Halogenated lower alkyl is that wherein lower alkyl is
substituted by the above-mentioned halogen atom, and is exemplified
by fluoromethyl, chloromethyl, bromomethyl, iodomethyl,
difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl,
fluoroethyl, chloroethyl, difluoroethyl, dichloroethyl,
trifluoroethyl, trichloroethyl, tetrachloroethyl, pentafluoroethyl
and fluoropropoyl, with preference given to fluoromethyl,
chloromethyl, dichloromethyl, difluoromethyl, trichloromethyl and
trifluoromethyl. "Optionally substituted" means that the group may
be substituted by 1 to 3 substituents wherein said substituents may
be the same or different. The position of the substituents is
optional and is not particularly limited. Specific examples include
lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl and
tert-butyl; hydroxy; lower alkoxy such as methoxy, ethoxy, propoxy
and butoxy; halogen atom such as fluorine, chlorine and bromine;
nitro; cyano; acyl such as formyl, acetyl and propionyl; acyloxy
such as formyloxy, acetyloxy and propionyloxy; mercapto; alkylthio
such as methylthio, ethylthio, propylthio, butylthio and
isobutylthio; amino; alkylamino such as methylamino, ethylamino,
propylamino and butylamino; dialkylamino such as dimethylamino,
diethylamino, dipropylamino and dibutylamino; carbonyl;
alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and
propoxycarbonyl; amide; trifluoromethyl; alkylsulfonyl such as
methylsulfonyl and ethanesulfonyl; aminosulfonyl; cycloalkyl such
as cyclopentyl and cyclohexyl; phenyl; and acylamide such as
acetamide and propionylamide. Preferred are hydroxy, lower alkyl,
lower alkoxy, mercapto, lower alkylthio, halogen atom,
trifluoromethyl, alkylcarbonyl, alkoxycarbonyl and acylamide.
[0070] More specifically, optionally substituted aryl means an aryl
which may be substituted by halogen atom, hydroxy, lower alkyl,
lower alkoxy, lower alkylsulfonyl and aminosulfonyl, particularly
phenyl, and is exemplified by phenyl, fluorophenyl, methylphenyl,
methoxyphenyl, methylsulfonylphenyl and aminosulfonylphenyl, with
preference given to phenyl and 4-fluorophenyl.
[0071] Optionally substituted heterocyclic group means a
heterocyclic group which may be substituted by halogen atom,
hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl and
aminosulfonyl, and particularly means thienyl, furyl,
5-methylthienyl and 5-chlorothienyl. Optionally substituted
cycloalkyl means a cycloalkyl which may be substituted by the same
substituents as above, with preference given to cyclohexyl.
[0072] Examples of preferable R of the heterocyclic aromatic
oxazole compounds of the present invention include cyclohexyl,
4-fluorophenyl and 5-chlorothienyl, with particular preference
given to cyclohexyl. Preferred as R.sub.1 is a group of the formula
15
[0073] wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are
as defined above, with particular preference given to a group
wherein R.sub.3 is amino or methyl, R.sub.4 and R.sub.7 are
hydrogen atoms and at least one of R.sub.5 and R.sub.6 is fluorine
atom. Specific examples include 4-aminosulfonyl-3-fluorophenyl,
3-fluoro-4-methylsulfonylphenyl, 4-aminosulfonyl-3,5-difluorophenyl
and 3,5-difluoro-4-methylsulfonylpheny- l, with particular
preference given to 4-aminosulfonyl-3-fluorophenyl. Preferred as
R.sub.2 is methyl.
[0074] Pharmaceutically acceptable salt may be any as long as it
forms a non-toxic salt with the oxazole derivative of the formula
(I). Alkali metal salts such as sodium salt and potassium salt,
alkaline earth metal salts such as magnesium salt and calcium salt,
ammonium salt, organic base salts such as trimethylamine salt,
triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine
salt and N,N'-dibenzylethylenediam- ine salt, and amino acid salts
such as lysine salt and arginine salt are among the examples. It
may be a hydrate as the case demands.
[0075] The compound of the present invention has particularly
superior selective inhibitory action on COX-2 and is expected to
make a therapeutic drug useful for antipyresis, pain relief and
anti-inflammation, which is free of side-effects such as digestive
tract disorders.
[0076] When the compound of the formula (I) of the present
invention or a pharmaceutically acceptable salt thereof is used as
a pharmaceutical preparation, it is generally admixed with
pharmacologically acceptable carriers, excipients, diluents,
extenders, disintegrators, stabilizers, preservatives, buffers,
emulsifying agents, aromatics, colorings, sweeteners, thickeners,
flavorings, solubilizers and other additives known per se, such as
water, vegetable oil, alcohol such as ethanol and benzyl alcohol,
polyethylene glycol, glycerol triacetate gelatin, carbohydrates
such as lactose and starch, magnesium stearate, talc, lanolin and
petrolatum, and formulated into, by a conventional method, tablets,
pills, powders, granules, suppositories, injections, eye drops,
liquids, capsules, troches, aerosols, elixirs, suspensions,
emulsions, syrups and the like, which can be administered orally or
parenterally.
[0077] While the dose varies depending on the kind and severity of
the disease, compound to be administered, administration route, and
age, sex, body weight etc. of patients, 0.1 mg-1,000 mg,
particularly 1 mg-300 mg of compound (I) is generally administered
orally to an adult per day.
[0078] The compounds of the present invention can be produced, for
example, by the following methods. It is needless to say that the
method for producing the compounds of the present invention is not
limited to these methods. 16
[0079] wherein R.sub.2' is lower alkyl or halogenated lower alkyl
wherein R.sub.2' may be the same with or different from R.sub.2, X
and X' are the same or different and each is halogen atom such as
bromine atom and chlorine atom, X.sub.1 is halogen atom or hydroxy,
X.sub.1' is halogen atom or hydroxy or alkali metal derivative
thereof, and R, R.sub.1, R.sub.2 and Z are as defined above.
[0080] Step 1
[0081] Compound (IV) can be synthesized by reacting compound (II)
with compound (III) in the presence of a metal such as zinc and
magnesium in an inert solvent such as 1,2-dimethoxyethane, dioxane,
ether, tetrahydrofuran, methylene chloride, benzene and toluene at
room temperature. In this case, a catalyst such as palladium(O)
complex and copper(I) complex may be added.
[0082] Step 2
[0083] Compound (V) can be synthesized by reacting compound (IV) in
acetic acid solvent in the presence of lead tetraacetate, or by
refluxing compound (IV) under heating in the presence of a complex
such as manganese acetate, in lower alkanecarboxylic acid such as
acetic acid and propionic acid corresponding to R.sub.2COOH wherein
R.sub.2 is as defined above and benzoic acid and a solvent such as
benzene as necessary.
[0084] Step 3
[0085] Compound (I) can be synthesized by refluxing compound (V)
under heating in the presence of ammonium salt (e.g., lower
alkanecarboxylic acid ammonium such as ammonium acetate and
ammonium formate), and inorganic ammonium such as ammonium
carbonate in an acidic solvent such as lower alkanecarboxylic acid
(e.g., formic acid, acetic acid and propionic acid). In this
reaction, when R or R.sub.1 is aromatic heterocycle, isomers may be
produced wherein the 4-position R and the 5-position R.sub.1 are
reversed.
[0086] Compound (I) can be also synthesized by the following
route.
[0087] Step 4 Wherein X.sub.1 is Hydroxy
[0088] This step, Step 6 and Step 7 are advantageous when R.sub.2
(e.g., methyl) is converted to other R.sub.2 (e.g., R.sub.2' such
as ethyl).
[0089] When X.sub.1 is hydroxy, compound (VI) can be synthesized by
reacting compound (V) in the presence of a base such as potassium
carbonate, lithium hydroxide, sodium hydroxide and potassium
hydroxide in an organic solvent such as methanol, ethanol and
dioxane, water or a mixed solvent thereof from under cooling to
under heating.
[0090] Compound (VI) can be also synthesized by the following Step
5.
[0091] Step 5 Wherein X.sub.1 is Halogen Atom or Hydroxy
[0092] Compound (VI) can be synthesized by reacting compound (IV)
in the presence of a halogenating agent such as bromine, chlorine
and N-bromosuccinimide in an inert solvent such as acetic acid,
1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene
chloride, benzene and toluene to give compound (VI) wherein X.sub.1
is halogen atom. Compound (VI) wherein X.sub.1 is hydroxy can be
synthesized by oxidizing compound (IV) with an oxidizing agent such
as benzene iodoacetate, or by treating the halogenated compound
(VI) obtained above with water in an inert solvent such as acetone,
1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, benzene and
toluene.
[0093] Step 6
[0094] Compound (V') can be obtained by reacting compound (VI) and
compound (VII') by a known method. Specifically, compound (VI)
wherein X.sub.1 is hydroxy and compound (VII') wherein X.sub.1' is
halogen atom, or compound (VI) wherein X.sub.1 is halogen atom and
compound (VII') wherein X.sub.1' is hydroxy are reacted in
pyridine, or in the presence of a base such as triethylamine and
sodium hydroxide, in an organic solvent such as methylene chloride,
chloroform and ethanol, from under cooling to under heating. When
X.sub.1 is halogen atom, alkali metal salt such as sodium acetate
may be used instead of carboxylic acid compound (VII'). In this
case, a base may or may not be added.
[0095] Step 7
[0096] Compound (I') can be obtained by treating compound (V') in
the same manner as in Step 3.
[0097] When a compound wherein either R or R.sub.1 is
4-aminosulfonyl-3-fluorophenyl is desired, the compound can be
produced from a compound having 3-fluoro-4-methylsulfonylphenyl
corresponding to the objective compound by a known method.
[0098] Instead of obtaining compound (IV) using, as mentioned
above, compound (II) or (III) having, as R or R.sub.1, 17
[0099] wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are
as defined above, compound (II') or (III') having 18
[0100] wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are as defined
above, may be used as a starting material to give compound (IV')
according to Step 10, which compound is then converted to
aminosulfonyl or methylsulfonyl according to the method of Step 15
to give compound (IV). Alternatively, such starting materials (II')
and (III') may be used to give a non-sulfonylated oxazole compound
(XIII) corresponding to the ultimate compound (I) or (I') according
to Step 1 to Step 7, and the obtained compound (XIII) may be
subjected to sulfonylation in the same manner as in Step 15 to give
the objective compound (I) or (I').
[0101] When a compound wherein either R or R.sub.1 is phenyl
substituted by alkylaminosulfonyl or aminosulfonyl is desired,
compound (X) wherein either R.sub.8 or R.sub.9 is
methoxysulfonylphenyl is subjected to the following Step 8 and Step
9 to synthesize compound (IV). 19
[0102] wherein either R.sub.8 or R.sub.9 is methoxysulfonylphenyl
of the formula 20
[0103] wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are as defined
above, and the other is optionally substituted cycloalkyl,
optionally substituted heterocyclic group or optionally substituted
aryl, and R, R.sub.1, X and X' are as defined above.
[0104] Step 8
[0105] Compound (X) can be synthesized in the same manner as in
Step 1, using compound (VIII) and compound (IX).
[0106] Step 9
[0107] When at least one of R and R.sub.1 is phenyl having
aminosulfonyl or alkylsulfonyl at the 4-position, compound (IV) can
be synthesized by heating compound (X) in pyridine, or refluxing
compound (X) under heating in the presence of sodium iodide,
potassium iodide, lithium iodide and the like, in an organic
solvent such as acetone and tetrahydrofuran, after which the
obtained compound is reacted with thionyl chloride or oxalyl
chloride under heating. Then, the resulting product is aminated or
alkylaminated or alkylated by a known method. More specifically,
amination or alkylamination is carried out by reacting the
resulting product in the presence of aqueous ammonia or alkylamine,
or a base such as sodium acetate and ammonium salt such as
alkylamine hydrochloride, in an organic solvent such as
tetrahydrofuran, ether, toluene, benzene, methylene chloride and
dioxane from under cooling to under heating. The alkylation can be
carried out by the method described in J. Org. Chem., 56: 4974-4976
(1991).
[0108] Compound (I) can be also synthesized by the method of the
following Step 10 to Step 15.
[0109] This method is directed to finally introducing sulfonyl
group in the last Step 15. 21
[0110] wherein either R' or R.sub.1' is phenyl of the formula
22
[0111] wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are as defined
above, and the other is a group corresponding to one of R and
R.sub.1, cycloalkyl which may be substituted by a substituent such
as lower alkyl, heterocyclic group such as thienyl and furyl, which
may be substituted by a substituent lower alkyl or halogen atom, or
aryl which may be substituted by a substituent such as halogen
atom, lower alkyl and lower alkoxy, and R, R.sub.1, X, X' and Z are
as defined above.
[0112] Step 10
[0113] Compound (IV') can be synthesized in the same manner as in
Step 1, wherein compound (II') and compound (III') are reacted in
the presence of a metal such as zinc and magnesium in an inert
solvent such as 1,2-dimethoxyethane, dioxane, ether,
tetrahydrofuran, methylene chloride, benzene and toluene at room
temperature. In this case, a catalyst such as palladium(O) complex
and copper(I) iodide complex may be added.
[0114] Step 11
[0115] Compound (XI) can be synthesized by refluxing under heating
compound (IV') and hydroxylammine hydrochloride in the presence of
a base such as sodium acetate, sodium hydroxide and potassium
carbonate in an organic solvent such as methanol, ethanol and
tetrahydrofuran, water or a mixed solvent thereof.
[0116] Step 12
[0117] Compound (XII) can be synthesized by reacting compound (XI)
in the presence of an acylating agent such as acetic anhydride and
acetyl chloride, in pyridine, or in the presence of a base such as
triethylamine in an organic solvent such as methylene chloride and
chloroform from under cooling to under heating.
[0118] Step 13
[0119] Compound (XIII) can be synthesized by refluxing under
heating compound (XII) in an acidic solvent such as formic acid and
acetic acid. In this case, a dehydrating agent such as magnesium
sulfate and sodium sulfate may be added.
[0120] Step 14
[0121] This step is for the synthesis of compound (XIII) from
compound (XI) in a single step, and compound (XIII) can be
synthesized from compound (XI) and carboxylic acid chloride such as
acetyl chloride by the method described in Indian J. Chem., 20B:
322-323 (1981). When R.sub.2 is methyl, compound (XIII) can be
synthesized by reacting compound (XI) and acetic anhydride while
heating in acetic acid.
[0122] Step 15
[0123] Compound (I) can be synthesized by reacting compound (XIII)
in the presence of a chlorosulfonylating agent such as
chlorosulfonic acid in an organic solvent such as chloroform and
methylene chloride, or without solvent, and subjecting the
resulting product to amination, alkylamination or alkylation by a
known method. The amination and alkylamination in Step 15
specifically comprise reacting in the presence of aqueous ammonia,
alkylamine or a base such as sodium acetate and ammonium salt such
as alkylamine hydrochloride in an organic solvent such as
tetrahydrofuran, ether, toluene, benzene, methylene chloride and
dioxane from under cooling to under heating. When alkylsulfonation
is carried out, the method described in J. Org. Chem., 56:
4974-4976 (1991) can be used for the synthesis.
[0124] In the above description, alkylsulfonation or
aminosulfonation in the final Step 15 has been exemplarily
discussed. It is possible to use compound (II) and compound (III)
instead of the starting materials (II') and (III') to give compound
(IV), which is followed by Step 11 to Step 14 to give an oxazole
compound (I). In this case, Step 15 is not necessary.
[0125] Compound (XIII) used in Step 15 can be also synthesized by
the following route. 23
[0126] wherein R', R.sub.1', R.sub.2 and Z are as defined
above.
[0127] Step 16
[0128] Compound (V") can be synthesized in the same manner as in
Step 2 wherein compound (IV') is reacted in the presence of lead
tetraacetate in acetic acid solvent, or by heating compound (IV')
in the presence of a complex such as manganese acetate in lower
alkanecarboxylic acid such as acetic acid-and propionic acid
corresponding to R.sub.2COOH wherein R.sub.2 is as defined above,
and benzoic acid and in a solvent such as benzene as necessary.
[0129] Step 17
[0130] Compound (XIII) can be synthesized in the same manner as in
Step 3 wherein compound (V") is refluxed under heating in the
presence of ammonium salt such as lower alkanecarboxylic acid
ammonium (e.g., ammonium acetate and ammonium formate) and
inorganic ammonium (e.g., ammonium carbonate) in an acidic solvent
of lower alkanecarboxylic acid such as formic acid, acetic acid and
propionic acid. In this reaction, when R' or R.sub.1' is an
aromatic heterocycle, isomers may be produced wherein the
4-position R' and the 5-position R.sub.1' are reversed.
[0131] Compound (I) can be also synthesized by the method shown in
the following Step 18 to Step 21. 24
[0132] wherein X.sub.2 is halogen atom, and R, R.sub.1, R',
R.sub.1', R.sub.2 and Z are as defined above.
[0133] Step 18
[0134] Compound (XV) can be synthesized by reacting compound (XIV)
with chlorocarbonate such as ethyl chlorocaronate in an inert
solvent such as tetrahydrofuran, toluene and ethyl acetate in the
presence of a base such as triethylamine, or by heating compound
(XIV) in acetic anhydride.
[0135] Step 19
[0136] Compound (XVII) can be synthesized by reacting compound (XV)
with compound (XVI) or an acid anhydride corresponding to compound
(XVI) in an inert solvent such as tetrahydrofuran, acetonitrile,
ethyl acetate and toluene in the presence of magnesium salt such as
magnesium chloride and a base such as triethylamine, pyridine and
potassium carbonate. Compound (XVII) can be also synthesized by the
method described in Chem. Ber., 102: 883-898 (1969).
[0137] Step 20
[0138] Compound (XVIII) can be synthesized by treating compound
(XVII) with an acid such as 1N-4N hydrochloric acid, oxalic solid
and dilute sulfuric acid in an inert solvent such as
tetrahydrofuran, dioxane, methylene chloride and toluene, or
heating compound (XVII) in the presence of pyridine and acetic
acid.
[0139] Step 21
[0140] Compound (I) is obtained by reacting compound (XVIII) with a
chlorosulfonylating agent such as chlorosulfonic acid in an organic
solvent such as chloroform and methylene chloride, or without
solvent. Then, the obtained product is reacted with aqueous ammonia
or alkylamine in an orgnic solvent such as tetrahydrofuran, ether,
toluene, methylene chloride and dioxane, or reacted with ammonium
salt such as alkylamine hydrochloride in the presence of a base
such as sodium acetate, pyridine and sodium hydroxide.
[0141] Compound (I) can be also synthesized from compound (XVIII)
by the following Step 22 and Step 23.
[0142] Step 22
[0143] Compound (XIII) can be synthesized by reacting compound
(XVIII) with inorganic acid such as concentrated sulfuric acid and
polyphosphoric acid in acetic anhydride, or without solvent, at
room temperature to under heating.
[0144] Step 23
[0145] Compound (I) can be synthesized by reacting compound (XIII)
in the same manner as in the aforementioned Step 15.
[0146] In the above Step 22 and Step 23, alkylsulfonylation or
aminosulfonylation in the final Step 23 has been exemplarily
discussed. It is possible to subject a compound having R and
R.sub.1 instead of R' and R.sub.1' to the reaction according to
Step 18 to Step 20, followed by Step 22 to give an oxazole compound
(I). In this case, Step 23 is not necessary.
[0147] The compound (I) thus obtained can be isolated and purified
by a known method for separation and purification, such as
concentration, concentration under reduced pressure, solvent
extraction, crystal precipitation, recrystallization and
chromatography.
[0148] The present invention is described in more detail in the
following by illustrative Examples and Experimental Examples, to
which the present invention is not limited.
EXAMPLE 1
[0149] Synthesis of
5-(2-chloro-4-methylsulfonylphenyl)-4-cyclohexyl-2-met- hyloxazole
(formula (I'); R=cyclohexyl, R.sub.1=2-chloro-4-methylsulfonylp-
henyl, R.sub.2'=methyl, Z=oxygen atom)
[0150] Step 1) 2-Chloro-4-methylsulfonylbenzyl cyclohexyl ketone
(formula (IV); R=cyclohexyl,
R.sub.1=2-chloro-4-methylsulfonylphenyl) 25
[0151] To a solution of tetrakis(triphenylphosphine)palladium (1.29
g) and zinc powder (2.19 g) in 1,2-dimethoxyethane (10 ml) was
added a solution of cyclohexanecarbonyl chloride (3.60 g) in
1,2-dimethoxyethane (10 ml) at room temperature under a nitrogen
atmosphere. A solution of 2-chloro-4-methylsulfonylbenzyl bromide
(9.40 g) in 1,2-dimethoxyethane (20 ml) was gradually added
dropwise to the mixture at room temperature with stirring. The
mixture was further stirred at room temperature for 3 hours. The
insoluble matter was removed by filtration and the filtrate was
concentrated under reduced pressure. Then, ethyl acetate (200 ml)
was added to the residue, and the mixture was washed with 1N
hydrochloric acid, and then with saturated aqueous sodium
hydrogencarbonate solution and saturated brine, and dried over
anhydrous sodium sulfate. The solvent was evaporated, and ethyl
acetate and diisopropyl ether were added. The precipitated solid
was collected by filtration to give 3.47 g of the title compound as
a white solid.
[0152] Step 5)
2-Bromo-2-(2-chloro-4-methylsulfonylphenyl)-1-cyclohexyl-1--
ethanone (formula (VI); R=cyclohexyl,
R.sub.1=2-chloro-4-methylsulfonylphe- nyl, X.sub.1=bromine atom)
26
[0153] To a solution of the compound (3.40 g) obtained in the above
Step 1) in benzene (20 ml) was dropwise added a solution of bromine
(1.73 g) in benzene (20 ml) with stirring under ice-cooling, and
the mixture was stirred for one hour. This solution was poured into
water and extracted with ethyl acetate. The organic layer was
washed with saturated aqueous sodium hydrogencarbonate solution and
saturated brine, and dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure to give 4.20 g of the
title compound.
[0154] Step 6)-
1-(2-Chloro-4-methylsulfonylphenyl)-2-cyclohexyl-2-oxoethy- l
acetate (formula (V'); R=cyclohexyl,
R.sub.1=2-chloro-4-methylsulfonylph- enyl, R.sub.2'=methyl,
Z=oxygen atom) 27
[0155] Sodium acetate (1.06 g) and ethanol (40 ml) were added to
the compound (4.20 g) obtained in the above Step 5). The mixture
was refluxed under heating for 4 hours, and the solvent was
evaporated under reduced pressure. Ethyl acetate was added to the
residue. The mixture was washed with water and saturated brine, and
dried over anhydrous sodium sulfate. The solvent was evaporated to
give 3.85 g of a crude product of the title compound.
[0156] Step 7)
5-(2-Chloro-4-methylsulfonylphenyl)-4-cyclohexyl-2-methylox- azole
(formula (I'); R=cyclohexyl,
R.sub.1=2-chloro-4-methylsulfonylphenyl- , R.sub.2'=methyl,
Z=oxygen atom) 28
[0157] A solution of the compound (3.85 g) obtained in the above
Step 6) and ammonium acetate (2.08 g) in acetic acid (40 ml) was
refluxed under heating for 5 hours. The solvent was evaporated
under reduced pressure, and ethyl acetate was added to the residue.
The mixture was washed with water, saturated aqueous sodium
hydrogencarbonate solution and saturated brine, and dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure to give 1.95 g of the title compound (yield 53%).
EXAMPLE 2
[0158] Synthesis of
5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-meth- yloxazole
(formula (I); R=cyclohexyl, R.sub.1=4-aminosulfonyl-3-fluorophen-
yl, R.sub.2-methyl, Z=oxygen atom)
[0159] Step 10) Cyclohexyl 3-fluorobenzyl ketone (formula (IV');
R'=cyclohexyl, R.sub.1'=3-fluorophenyl) 29
[0160] To a solution of tetrakis(triphenylphosphine)palladium (2.00
g) and zinc powder (17.98 g) in 1,2-dimethoxyethane (50 ml) was
added a solution of cyclohexanecarbonyl chloride (20.00 g) in
1,2-dimethoxyethane (50 ml) at room temperature under a nitrogen
atmosphere. A solution of 3-fluorobenzyl bromide (26.00 g) in
1,2-dimethoxyethane (100 ml) was gradually added dropwise to the
mixture with stirring under ice-cooling. The mixture was stirred
under ice-cooling for 30 minutes, and at room temperature for 2
hours. The insoluble matter was removed by filtration and the
filtrate was concentrated under reduced pressure. Then, ethyl
acetate (200 ml) was added to the residue, and the mixture was
washed with 1N hydrochloric acid, and then with saturated aqueous
sodium hydrogencarbonate solution and saturated brine, and dried
over anhydrous sodium sulfate. The solvent was evaporated to give
29.20 g of an oily crude product.
[0161] Step 16) 2-Cyclohexyl-1-(3-fluorophenyl)-2-oxoethyl acetate
(formula (V"); R'=cyclohexyl, R.sub.1'=3-fluorophenyl,
R.sub.2'=methyl, Z=oxygen atom) 30
[0162] Lead tetraacetate (75.00 g) was added to a solution of the
compound (29.20 g) obtained in the above Step 10) in acetic acid
(300 ml). The mixture was refluxed under heating for 1.5 hours, and
the solvent was evaporated under reduced pressure. Ethyl acetate
was added to the residue. The mixture was washed with water, a
saturated aqueous sodium hydrogencarbonate solution and saturated
brine, and dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column chromatography (developing solvent; hexane:ethyl
acetate=9:1) to give 18.30 g of the title compound as an oil (yield
50%).
[0163] Step 17) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole
(formula (XIII); R'=cyclohexyl, R.sub.1'=3-fluorophenyl,
R.sub.2=methyl, Z=oxygen atom) 31
[0164] A solution of the compound (18.00 g) obtained in the above
Step 16) and ammonium acetate (15.00 g) in acetic acid (100 ml) was
refluxed under heating for 5 hours, and the solvent was evaporated
under reduced pressure. Ethyl acetate was added to the residue. The
mixture was washed with water, saturated aqueous sodium
hydrogencarbonate solution and saturated brine, and dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure to give 17.20 g of an oily crude product.
[0165] Step 15)
5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2methyloxa- zole
(formula (I); R=cyclohexyl, R.sub.1=4-aminosulfonyl-3-fluorophenyl,
R.sub.2=methyl, Z=oxygen atom) 32
[0166] To a solution of the compound (17.00 g) obtained in the
above Step 17) in chloroform (80 ml) was added dropwise
chlorosulfonic acid (27 ml) with stirring under ice-cooling, and
the mixture was heated at 100.degree. C. for 3 hours. The reaction
mixture was cooled to room temperature, and dropwise added to
ice-water (300 ml) with stirring. The organic layer was separated,
washed with saturated brine, and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure to give
20.31 g of a crude product.
[0167] Aqueous ammonia (28%) was added to a solution of the
obtained compound (10.00 g) in tetrahydrofuran (40 ml) with
stirring at room temperature, and the mixture was stirred at room
temperature for one hour. The solvent was evaporated under reduced
pressure and ethyl acetate was added to the residue. The mixture
was washed with water and saturated brine, and dried over anhydrous
sodium sulfate. The solvent was evaporated, and the residue was
separated and purified by silica gel column chromatography
(developing solvent; dichloromethane:ethyl acetate=6:1) to give
5.74 g of the title compound (yield 61%).
EXAMPLE 2'
[0168] The compound of Example 2 (formula (I); R=cyclohexyl,
R.sub.1=4-aminosulfonyl-3-fluorophenyl, R.sub.2=methyl, Z=oxygen
atom) was synthesized according to another synthetic method.
[0169] Step 11) Cyclohexyl 3-fluorobenzyl ketone oxime (formula
(XI); R'=cyclohexyl, R.sub.1'=3-fluorophenyl) 33
[0170] To a solution of the compound (353 g) obtained according to
a method similar to that of the above Example 2, Step 10) in
ethanol (1300 ml) were added hydroxylamine hydrochloride (123 g)
and sodium acetate (158 g). The mixture was refluxed under heating
for 2 hours, and the solvent was evaporated under reduced pressure.
Ethyl acetate was added to the residue. The mixture was washed with
water, saturated aqueous sodium hydrogencarbonate solution and
saturated brine, and dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure, and the crude
product was recrystallized from n-heptane to give 160 g of the
title compound (yield 42%).
[0171] Step 14) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole
(formula (XIII); R'=cyclohexyl, R,.sub.1=3-fluorophenyl,
R.sub.2=methyl, Z=oxygen atom) 34
[0172] Acetic anhydride (95 ml) was dropwise added to a solution of
the compound (158 g) obtained in the above Step 11) in acetic acid
(900 ml) with stirring at room temperature, and the mixture was
refluxed under heating for 7 hours. The solvent was evaporated
under reduced pressure and n-heptane was added to the residue. The
mixture was washed with water, saturated aqueous sodium
hydrogencarbonate solution, saturated brine and acetonitrile. The
solvent was evaporated under reduced pressure to give 119 g of the
title compound as an oil.
[0173] Then, the obtained compound (119 g) was reacted in the same
manner as in the above Example 2, Step 15) to give a compound of
Example 2 (formula (I); R=cyclohexyl,
R.sub.1=4-aminosulfonyl-3-fluorophenyl, R.sub.2=methyl, Z=oxygen
atom).
EXAMPLE 3
[0174] Synthesis of
4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-met- hyloxazole
(formula (I); R=cyclohexyl, R.sub.1=3-fluoro-4-methylsulfonylph-
enyl, R.sub.2=-methyl, Z=oxygen atom)
[0175] Step 15)
4-Cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methylo- xazole
(formula (I); R=cyclohexyl,
R.sub.1=3-fluoro-4-methylsulfonylphenyl- , R.sub.2=methyl, Z=oxygen
atom) 35
[0176] To a solution of the compound (17.00 g) obtained in the
above Example 2, Step 17) in chloroform (80 ml) was dropwise added
chlorosulfonic acid (27 ml) with stirring under ice-cooling. The
mixture was heated at 100.degree. C. for 3 hours. The reaction
mixture was cooled to room temperature and dropwise added to
ice-water (300 ml) with stirring. The organic layer was separated,
washed with saturated brine, and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure to give
20.31 g of a crude product.
[0177] Water (25 ml) was added to the obtained compound (3.66 g).
To the mixture were added sodium sulfite (1.42 g) and sodium
hydrogencarbonate (1.89 g) successively with stirring at room
temperature. The mixture was heated at 70.degree. C. for 2 hours.
Ethanol (25 ml) and methyl iodide (2.20 g) were added to the
mixture, and the mixture was heated at 100.degree. C. for 2 hours.
The mixture was cooled to room temperature and extracted with ethyl
acetate. The extract was washed with saturated brine and dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure, and the residue was saparated and purified by silica gel
column chromatography (developing solvent; hexane:ethyl
acetate=2:1) to give 0.82 g of the title compound (yield 24%).
EXAMPLES 4-6
[0178] The compounds of Examples 4-6 were obtained in the same
manner as in Examples 1-3 or Example 7 to be mentioned below.
[0179] The structures and properties of the compounds of Examples
1-6 are shown in the following Tables. In the Tables, Me means
methyl.
1TABLE 1 Ex. Compound m.p. .sup.1H NMR (.delta.) ppm IR cm.sup.-1
MS Elem. analysis 1 36 119.about.121.degree. C. white crystals
CDCl.sub.3 300 MHz 1.1-1.2 (3H, m) 1.6-1.8 (7H, m) 2.48 (1H, m)
2.51 (3H, s) 3.12 (3H, s) 7.55 (1H, d, J = 8.1 Hz) 7.88 (1H, dd, J
= 1.8, 8.1 Hz) 8.07 (1H, d, J = 1.8 Hz) # neat 2928 1578 1317 1155
1100 960 FAB +354 (MH.sup.+) 2 37 166.about.167.degree. C. white
crystals CDCl.sub.3 300 MHz 1.3-1.5 (3H, m) 1.6-1.9 (7H, m) 2.51
(3H, s) 2.79 (1H, tt, J = 3.7, 11.3 Hz) 5.11 (2H, s) 7.36-7.44 (2H,
m) 7.94 (1H, t, J = 7.9 Hz) # neat 3280 2929 1613 1343 1170 FAB
+339 (MH.sup.+) Calculated C 56.79% H 5.66% N 8.28% Found C 56.41%
H 5.73% N 8.19% 3 38 111.about.112.degree. C. white crystals CDCl3
300 MHz 1.3-1.5 (3H, m) 1.6-1.8 (7H, m) 2.52 (3H, s) 2.80 (1H, tt,
J = 4.0, 11.4 Hz) 3.25 (3H, s) 7.40 (1H, dd, J = 1.6, 11.2 Hz) 7.48
(1H, dd, J = 1.6, 8.3 Hz) 7.99 # (1H, dd, J = 8.3, 8.4 Hz) neat
2929 1612 1320 1161 1144 769 FAB +338 (MH.sup.+) Calculated C
60.52% H 5.97% N 4.15% Found C 60.70% H 6.10% N 4.12%
[0180]
2TABLE 2 Ex. Compound m.p. .sup.1H NMR (.delta.) ppm IR cm.sup.-1
MS Elem. analysis 4 39 200.about.201.degree. C. white crystals
CDCl.sub.3 300 MHz 1.28-1.44 (4H, m) 1.62-1.92 (6H, m) 2.51 (3H,s)
2.72-2.83 (1H, m) 5.18 (2H, s) 7.53 (1H, dd, J = 8.4, 1.6 Hz) 7.69
(1H, d, J = 1.6 Hz) 8.13 (1H, d, J = # 8.4 Hz) KBr 3353 3255 2928
1606 1342 1166 FAB +355 (MH.sup.+) Calculated C 54.16% H 5.40% N
7.89% Found C 54.11% H 5.45% N 7.78% 5 40 183.2.about.184.2.degree.
C. white crystals CDCl.sub.3 300 MHz 1.3-1.5 (3H, m) 1.7-1.9 (7H,
m) 2.50 (3H, s) 2.73 (3H, s) 2.80 (1H, m) 4.92 (2H, s) 7.43-7.49
(2H, m) 8.05 (1H, d, J = 8.3 Hz) # KBr 3294 2929 1609 1299 1170 FAB
+335 (MH.sup.+) Calculated C 61.05% H 6.63% N 8.38% Found C 61.24%
H 6.73% N 8.43% 6 41 amorphous CDCl.sub.3 300 MHz 1.28-1.47 (3H, m)
1.57-1.95 (7H, m) 2.51 (3H, s) 2.68-2.80 (1H, m) 5.37 (2H, brs)
7.18 (2H, ddd, J = 9.9, 1.7, 1.4 Hz) KBr 2931 1622 1557 1422 1359
1175 1035 FAB +357 (MH.sup.+)
EXAMPLE 7
[0181] Synthesis of
5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)--
2-methyloxazole (formula (I); R=4-fluorophenyl,
R.sub.1=4-aminosulfonyl-3-- fluorophenyl, R.sub.2=methyl, Z=oxygen
atom) 42
[0182] A solution of
5-(3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole (1.10 g)
obtained by the method as mentioned above and chlorosulfonic acid
(1.6 ml) in chloroform (2 ml) was heated with stirring at
90.degree. C. for 2 hours. The reaction mixture was poured into
ice-water and extracted with chloroform. The organic layer was
washed with water and saturated brine, dried over anhydrous
magnesium sulfate, and concentrated to give 1.06 g of a crude
product of 5-(4-chlorosulfonyl-3-fluorophenyl)--
4-(4-fluorophenyl)-2-methyloxazole.
[0183] To a solution of this crude product (1.06 g) in
tetrahydrofuran (6 ml) was added 28% aqueous ammonia (0.6.ml) and
the mixture was stirred at room temperature for 2 hours. The
reaction mixture was concentrated, added with ethyl acetate, and
washed with water and saturated brine. The ethyl acetate solution
was dried over anhydrous magnesium sulfate, and concentrated to
give 981 mg of a crude product. This crude product was
recrystallized from ethanol to give 629 mg of the title compound
(yield 44%). The structure and properties of this compound are
shown in the following Table.
3TABLE 3 Ex. Compound m.p. .sup.1H NMR (.delta.) ppm IR cm.sup.-1
MS Elem. analysis 7 43 208.degree. C. white crystals CDCl.sub.3 300
MHz 2.58 (3H, s) 5.07 (2H, s) 7.14 (2H, tt, J = 2.2, 8.8 Hz) 7.36
(1H, dd, J = 1.5, 11.0 Hz) 7.47 (1H, dd, J = 1.8, 7.7 Hz) 7.59 (2H,
ddd, J = 2.2, 5.5, 8.8 Hz) 7.88 (1H, t, J = 7.7 Hz) # neat 3278
2359 1613 1562 1510 1342 1171 FAB +351 (M.sup.+ + 1) Calculated C
54.74% H 3.86% N 7.66% Found C 54.40% H 3.74% N 7.59%
EXAMPLE 2"
[0184] The compound of Example 2 (formula (I); R=cyclohexyl,
R.sub.1=4-aminosulfonyl-3-fluorophenyl, R.sub.2=methyl, Z=oxygen
atom) was synthesized according to another synthetic method.
[0185] Step 18) 4-Cyclohexyl-2-methyl-5-oxazolone (formula (XV);
R'=cyclohexyl, R.sub.2=methyl) 44
[0186] Triethylamine (8.39 ml) was added to a suspension of
DL-N-acetyl-2-cyclohexylglycine (10.00 g) obtained from
.alpha.-aminophenylacetic acid according to a known method
[Collect. Czeck. Chem. Commun., 31: 4563 (1996)] in ethyl acetate
(50 ml). Ethyl chlorocarbonate (5.28 ml) was dropwise added to the
mixture under ice-cooling. The mixture was stirred under
ice-cooling for one hour, added with ethyl acetate (150 ml), and
washed successively with water and saturated brine. The ethyl
acetate solution was concentrated under reduced pressure to give
9.86 g of the title compound as an oil.
[0187] Step 19)
4-Cyclohexyl-4-(3-fluorobenzoyl)-2-methyl-5-oxazolone (formula
(XVII); R'=cyclohexyl, R.sub.1'=3-fluorophenyl, R.sub.2=methyl,
Z=oxygen atom) 45
[0188] A solution of the compound (9.86 g) obtained in the above
Step 18) in tetrahydrofuran (15 ml) was added to a suspension of
magnesium chloride (3.56 g) in tetrahydrofuran (20 ml).
Triethylamine (9.49 ml) was added with stirring under ice-cooling,
and the mixture was stirred for 15 minutes. 3-Fluorobenzoyl
chloride (4.55 ml) was dropwise added to the mixture, and the
mixture was stirred under ice-cooling for one hour. The reaction
mixture was diluted with ethyl acetate, washed with water, and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give 11.69 g of the title compound as an
oil.
[0189] Step 20) 2-N-Acetylamino-2-cyclohexyl-3'-fluoroacetophenone
(formula (XVIII); R'=cyclohexyl, R.sub.1'=3-fluorophenyl,
R.sub.2=methyl, Z=oxygen atom) 46
[0190] To a solution of the compound (527 mg) obtained in the above
Step 19) in tetrahydrofuran (3.5 ml) was added 1N hydrochloric acid
(0.35 ml). The mixture was stirred at room temperature for one
hour, added with ethyl acetate, and washed successively with water,
saturated aqueous sodium hydrogencarbonate solution and saturated
brine. The organic layer was dried over anhydrous sodium sulfate,
and the solvent was evaporated under reduced pressure to give 404
mg of the title compound as a solid (yield 84%). The solid was
recrystallized from n-heptane to give white crystals, melting point
116-117.degree. C.
[0191] Step 21)
5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methylox- azole
(formula (I); R=cyclohexyl, R.sub.1=4-aminosulfonyl-3-fluorophenyl,
R.sub.2=methyl, Z=oxygen atom) 47
[0192] Chlorosulfonic acid (0.34 ml) was added to a solution of the
compound (200 mg) obtained in the above Step 20) in chloroform (2
ml) with stirring under ice-cooling, and the mixture was refluxed
under heating for 5 hours. The reaction mixture was diluted with
chloroform and poured into ice-water. The organic layer was
separated, washed successively with water and saturated brine, and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give 181 mg of a crude product.
[0193] To a solution of the obtained compound (169 mg) in
tetrahydrofuran (2 ml) was added 28% aqueous ammonia (0.1 ml) with
stirring at room temperature, and the mixture was stirred for 30
minutes. The solvent was evaporated under reduced pressure. Ethyl
acetate was added to the residue, and the mixture was washed
successively with water and saturated brine, which was followed by
drying over anhydrous sodium sulfate. The solvent was evaporated,
and the residue was separated and purified by silica gel column
chromatography (developing solvent; dichloromethane:ethyl
acetate=6:1) to give 126 mg of the title compound (yield 55%).
EXAMPLE 2'"
[0194] The compound of Example 2 (formula (I); R=cyclohexyl,
R.sub.1=4-aminosulfonyl-3-fluorophenyl, R.sub.2=methyl, Z=oxygen
atom) was synthesized according to another synthetic method.
[0195] Step 22) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole
(formula (XIII); R'=cyclohexyl, R.sub.1'=3-fluorophenyl,
R.sub.2=methyl) 48
[0196] Concentrated sulfuric acid (30 .mu.l) was added to a
suspension of the compound (141 mg) obtained in the above Example,
Step 20) in acetic anhydride (2 ml), and the mixture was stirred at
100.degree. C. for 30 minutes. The reaction mixture was
concentrated under reduced pressure, added with aqueous potassium
carbonate solution, and extracted with ethyl acetate. The organic
layer was washed with water and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure to give
135 mg of the title compound as an oil.
[0197] Step 23)
5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methylox- azole
(formula (I); R=cyclohexyl, R.sub.1=4-aminosulfonyl-3-fluorophenyl,
R.sub.2=methyl, Z=oxygen atom) 49
[0198] In the same manner as in the above Example 2, Step 15), the
compound obtained in the above Step 22) was reacted to give the
compound of Example 2 (formula (I); R=cyclohexyl,
R.sub.1=4-aminosulfonyl-3-fluoro- phenyl, R.sub.2=methyl, Z=oxygen
atom).
[0199] Experimental Example 1 (Inhibitory Action on
Cyclooxygenase)
[0200] The enzymatic activity was determined from the percent
conversion of .sup.14C arachidonic acid into prostaglandin H.sub.2
(PGH.sub.2) and the decomposed product thereof. That is, a test
sample (20 .mu.l), an enzyme solution (20 .mu.l) and distilled
water (10 .mu.l ) were added to 100 mM Tris-HCl buffer (pH 8, 140
.mu.l) containing hematin (2 .mu.M) and tryptophan (5 mM), and the
mixture was thoroughly stirred, which was followed by preincubation
at 24.degree. C. for 5 minutes. Then, a .sup.14C arachidonic acid
solution (10 .mu.l) was added and the mixture was reacted at
24.degree. C., whereafter a solution (40 .mu.l) of ethyl
ether/methanol/1M citric acid (30/4/1) ice-cooled to -20.degree. C.
was added to stop the reaction. The reaction mixture was
centrifuged for 5 minutes at 3,000 rpm to give an ether layer which
was placed on a thin plate, and developed with ethyl
ether/methanol/acetic acid (90/2/0.1) to determine percent
conversion (A) from arachidonic acid to PGH.sub.2 and the
decomposed product thereof. The percent conversion (B) without a
test sample was also determined, based on which percent inhibition
was calculated from the following formula, and a concentration
(IC.sub.50) necessary for 50% inhibition of the test sample was
determined.
Inhibition (%)=(1-A/B).times.100
[0201] An enzyme prepared from human platelets was used as an
enzyme solution of cyclooxygenase-1, and an enzyme expressed by a
yeast, into which EDNA of human cyclooxygenase-2 had been
introduced using a kit of Invitrogen Corp., was used as an enzyme
solution of cyclooxygenase-2. As used herein, control compound 1
was 5-(4-aminosulfonylphenyl)-4-cyclohexy- l-2-methyloxazole, a
patent application to which has been previously filed by us, and
control compound 2 was a known analogous compound,
5-(4-aminosulfonylphenyl)-4-(4-fluorophenyl)-2-methyloxazole.
[0202] The results are shown in Table 4.
[0203] As is evident from the comparison of control compound 1 and
the compound of Example 2, as well as control compound 2 and the
compound of Example 7, a remarkable reduction of the action on
COX-1 while retaining the activity on COX-2 has become possible
particularly by introducing fluorine atom.
4TABLE 4 Experimental Example 1 (inhibitory action on
cyclooxygenase) Structural IC.sub.50 (.mu.M) Example formula COX-2
COX-1 COX-1/COX-2 2 50 0.07 >100 >1,428 3 51 0.3 >100
>333 4 52 >10 5 53 >10 6 54 0.16 >100 >625 7 55 0.03
37 1,233 Indomethacin 8 0.5 0.063 Control 1 56 0.07 45 643 Control
2 57 0.02 5 250
[0204] Experimental Example 2 (Effects on Carrageenin-induced
Podedema)
[0205] Carrageenin (1%, 0.05 ml) dissolved in physiological saline
was subcutaneously injected to the left hindlimb of male Donryu
rats to induce podedema. The degree of podedema was evaluated by
measuring the volume of the limb 3 hours after carrageenin
administration. A test compound (1, 3, 10 or 30 mg/kg) was orally
administered one hour before carrageenin administration, and
suppression thereby was studied. Inhibitory activity was expressed
by the dose (ED.sub.30) of the test compound necessary for
inhibiting by 30% relative to the control group. The results are
shown in Table 5.
5 carrageenin-induced podedema Example in rats, ED.sub.30 (mg/kg
p.o.) 2 5.5 indomethacin 2.9
INDUSTRIAL APPLICABILITY
[0206] The compound of the present invention, in particular, a
compound wherein R.sub.3 is methyl or amino, R.sub.5 is fluorine
atom, R.sub.6 is hydrogen atom or fluorine atom, and R.sub.4 and
R.sub.7 are hydrogen atom, and pharmaceutically acceptable salts
thereof surprisingly selectively inhibit COX-2 alone, while
scarcely inhibiting COX-1. Accordingly, the compound of the present
invention possesses superior antipyretic action, analgesic action
and anti-inflammatory action that the conventional products cannot
afford, and scarcely show side-effects in the digestive tract.
[0207] Consequently, the development of a superior
anti-inflammatory agent heretofor not existed has been enabled,
which in turn produces great expectation of the provision of a
practical therapeutic agent for the diseases possibly caused by
COX-2 product, such as asthma and rheumatism.
* * * * *