Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-16
2003-02-11
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S460000, C549S292000, C549S294000, C549S293000
Reexamination Certificate
active
06518303
ABSTRACT:
This invention relates to new therapeutically useful 2-phenylpyran-4-one derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
It is known that nonselective inhibition of the enzyme cyclooxygenase (COX) prevents the overproduction of prostaglandins associated with inflammation, which are mediated by cyclooxygenase-2 (COX-2) bu., at the same time, deprives tissues of basal levels of prostaglandins necessary for the health of certain tissues mediated largely by cyclooxygenase-1 (COX-1). Non steroidal anti-inflammatory drugs are non-selective inhibitors of COX and for that reason, have side effects of decreased renal blood flow, decreased platelet function, dyspepsia and gastric ulceration.
We have now found that certain 2-phenylpyran-4-one derivatives selectively inhibit COX-2 in preference to COX-1 and are useful in the treatment of COX-2 mediated diseases, such as inflammation, pain, fever and asthma with fewer side effects.
Accordingly the present invention provides a 2-phenylpyran-4-one compound of formula (I):
wherein
R
1
represents an alkyl or —NR
4
R
5
group, wherein R
4
and R
5
each independently represents a hydrogen atom or an alkyl group;
R
2
represents an alkyl, C
3
-C
7
cycloalkyl, pyridyl, thienyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups;
R
3
represents a methyl, hydroxymethyl, alkoxymethyl, C
3
-C
7
cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile, trifluoromethyl or difluoromethyl group or a CH
2
—R
6
group wherein R
6
represents an alkyl group; and
X represents a single bond, an oxygen atom, a sulfur atom or a methylene group;
or a pharmaceutically acceptable salt thereof.
The alkyl groups and moieties such as those present in the alkoxy, hydroxyalkyl, mono- or di-alkylamino groups, mentioned in relation to the groups R
1
to R
6
are usually “lower” alkyl that is containing from 1 to 6 particularly from 1 to 4 carbon atoms, the hydrocarbon chain being branched or straight. Preferred alkyl groups, and where relevant alkyl moieties, include methyl, ethyl, propyl including i-propyl, and butyl including n-butyl, t-butyl and sec-butyl.
In a phenyl group substituted by one or more halogen atoms or alkyl, trifluoroalkyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkyl amino, hydroxyalkyl or hydroxycarbonyl groups, the phenyl ring may be substituted by 1, 2, 3, 4 or 5 substituents, preferably 1, 2 or 3 substituents, each being independently selected from the possible substituents set out above. The phenyl group (attached to X or the pyran-4-one ring through its 1-position) may be substituted at any of the remaining positions, that is to say the 2, 3, 4, 5 or 6-positions. A phenyl group having more than one substituent may be substituted at any combination of positions. For example a phenyl group having two substituents may be substituted at the 2 and 3, 2 and 4, 2 and 5, 2 and 6, 3 and 4 or 3 and 5 positions.
In particular, it is preferred that R
2
represents a branched alkyl, C
3
-C
7
(preferably C
3
, C
5
or C
6
) cycloalkyl, napthyl, tetrahydronaphthyl or indanyl group, an unsubstituted phenyl group or a phenyl group substituted by one or more halogen atoms, alkoxy groups, preferably methoxy groups, and/or alkyl groups, preferably methyl groups. The phenyl group preferably has 1, 2 or 3 substituents, more preferably 1 or 2 substituents. Halogen atoms are preferably selected from fluorine, chlorine and bromine atoms. When R
2
as a phenyl group substituted by one or more halogen atoms, alkoxy groups and/or alkyl groups, preferably one of the substitutions is at the 4-position of the phenyl group. When R
2
is a phenyl group substituted by one or two halogen atoms at least one of the substitutions is preferably on the 2- or the 4-position.
It is preferred that R
1
independently represents an unsubstituted alkyl croup such as methyl, ethyl, propyl or butyl, preferably methyl, or an NH
2
group (i.e. PR
4
and R
5
in the above formula both independently represent an H atom)
It is also preferred that R
3
independently represents an unsubstituted alkyl group such as methyl, ethyl, propyl or butyl, preferably methyl, a nitrile group, a hydroxymethyl group, a methoxymethyl group, a difluoromethyl group or a hydroxycarbonyl group.
It is further preferred that X independently represents a single bond, an oxygen atom or a methylene group more preferably a single bond or an oxygen atom.
Specific examples of the 2-phenylpyran-4-one derivatives of the present intention include:
2-(4-methanesulfonylphenyl) -6-methyl-3-phenylpyran-4-one,
3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-bromophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-p-tolylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-m-tolylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-o-tolylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-(4-trifluoromethylphenyl)pyran-4-one,
3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3,4-difluorophenyl)-2-(4 -methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3,5-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4- one,
3-(2,5-difluorophenyl)-2-(4 -methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2,6-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2,4-dichlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3,4-dichlorophenyl)-2-(4 -methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3-fluoro-4-methoxyplenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chloro-3-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-chloro-4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6 -methylpyran-4-one,
3-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one
3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-cyclohexyl-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylyphenyl)-6- methyl-3-naphthalen-2-ylpyran-4-one,
4-(6-methyl-4-oxo-3-phenyl-4H-pyran-2-yl) benzenesulfonamide,
4-[3 (4-fluorophenyl)-6-methyl-4-oxo-4H-pyran-2-yl]benzenesulfonamide,
4-[3-(3,4-dichlorophenyl)-6-methyl-4-oxo-4H-pyran-2-yl]benzenesulfonamide,
5-(2,4-difluorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4-pyran-2-carbontrile
3-(2-fluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2,5-difluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3-chloro-4-methylphenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-phenoxypyran-4-one,
3-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-(4-methylphenoxy) pyran-4-one,
3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-methoxymethylpyran-4-one,
3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonyl-phenyl) pyran-4 -one,
and anyone of the compounds specifically identified in Table 4, and pharmaceutically acceptable salts thereof.
Of outstanding interest are:
3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-bromophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4 -one,
3-(3,4-dichl
Crespo Crespo Maria Isabel
Duran Carles Puig
Jimenez Mayorga Juan Miguel
Soca Pueyo Lidia
Almirall Prodesfarma S.A.
Nixon & Vanderhye
Robinson Binta
Rotman Alan L.
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