U.S. patent application number 11/727044 was filed with the patent office on 2007-07-26 for pyridinic sulfonamide derivatives method of production and use thereof.
This patent application is currently assigned to Universite de Liege. Invention is credited to Xavier de Leval, Jacques Delarge, Jean-Michel Dogne, Fabien Julemont, Bernard Pirotte.
Application Number | 20070173534 11/727044 |
Document ID | / |
Family ID | 8180983 |
Filed Date | 2007-07-26 |
United States Patent
Application |
20070173534 |
Kind Code |
A1 |
Delarge; Jacques ; et
al. |
July 26, 2007 |
Pyridinic sulfonamide derivatives method of production and use
thereof
Abstract
New pyridinic sulfonamide derivatives represented by a general
formula (I), wherein R.sub.1 represents a mono- or polyhalogenated
C.sub.1-12-alkyl or a mono- or polyhalogenated C.sub.3-8-cycloalkyl
group. The method of production of such derivatives and their use
as active therapeutic substance in the treatment of diseases such
as inflammation, arthrosis, cancer, angiogenesis and asthma are
also reported.
Inventors: |
Delarge; Jacques;
(Dolembreux, BE) ; Pirotte; Bernard; (Oupeye,
BE) ; Dogne; Jean-Michel; (Grivegnee, BE) ; de
Leval; Xavier; (Louveigne, BE) ; Julemont;
Fabien; (Verviers, BE) |
Correspondence
Address: |
JACOBSON HOLMAN PLLC
400 SEVENTH STREET N.W.
SUITE 600
WASHINGTON
DC
20004
US
|
Assignee: |
Universite de Liege
|
Family ID: |
8180983 |
Appl. No.: |
11/727044 |
Filed: |
March 23, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10488553 |
Mar 4, 2004 |
7226936 |
|
|
11727044 |
Mar 23, 2007 |
|
|
|
Current U.S.
Class: |
514/347 ;
546/294 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 213/89 20130101; C07D 213/76 20130101; A61P 29/00
20180101 |
Class at
Publication: |
514/347 ;
546/294 |
International
Class: |
C07D 213/62 20060101
C07D213/62; A61K 31/4412 20060101 A61K031/4412 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 27, 2001 |
EP |
01203683.6 |
Claims
1. A pyridinic sulfonamide derivative acts as COX-2 selective
inhibitor, said pyridinic sulfonamide derivative being represented
by a formula (I): ##STR2## wherein A represents a Nitrogen or a
--N.dbd.O group; X represents Oxygen, Sulphur or an element
selected from the group consisting of --NR.sub.3,
--CR.sub.3R.sub.4, --SO, --SO.sub.2, and --CO; wherein R.sub.3 and
R.sub.4 which can be identical or different, denotes each
independently one element selected from the group consisting of
hydrogen, a mono- or polyhalogenated C.sub.1-2-alkyl, a mono- or
polyhalogenated C.sub.3-8-cycloalkyl, a C.sub.1-12-alkyl and a
C.sub.3-8-cycloalkyl; R.sub.1 represents a mono- or polyhalogenated
C.sub.1-12-alkyl or a mono or polyhalogenated C.sub.3-8-cycloalkyl
group; R.sub.2 represents a C.sub.3-8-cycloalkyl group or a
non-substituted aryl group or an aryl group wherein one or more of
hydrogen atom(s) of the aryl group is/are substituted by one of the
elements selected from the group consisting of halogen,
C.sub.1-12-alkyl, C.sub.3-8-cycloalkyl, R.sub.1, hydroxy,
C.sub.1-6-alkoxy, C.sub.1-6-alkoxy-C.sub.1-6-alkyl, nitro, amino,
cyano, cyanomethyl; perhalomethyl, C.sub.1-6-monoalkyl- or
dialkylamino, sulfamoyl, C.sub.1-6-alkylthio,
C.sub.1-6-alkylsulfonyl, C.sub.1-6-alkylsulfinyl, formyl,
C.sub.1-6-alkylcarbonylamino, R.sub.5-arylthio,
R.sub.5-arylsulfinyl, R.sub.5-arylsulfonyl,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl;
carbamyl; carbamylmethyl; C.sub.1-6-monoalkyl- or
dialkylaminocarbonyl, C.sub.1-6-monoalkyl- or
dialkylaminothiocarbonyl, ureido, C.sub.1-6-monoalkyl- or
dialkylaminocarbonylamino, thioureido, C.sub.1-6-monoalkyl- or
dialkylaminothiocarbonylamino, C.sub.1-6-monoalkyl- or
dialkylaminosulfonyl, carboxy, carboxy-C.sub.1-.sub.6-alkyl, acyl,
R.sub.5-aryl, R.sub.5-arylalkyl, and R.sub.5-aryloxy, where R.sub.5
denotes one or several elements selected from the group consisting
of hydrogen, C.sub.1-6-alkyl, halogen, hydroxy and
C.sub.1-6-alkoxy.
2. A method of preparing an active substance in a drug, said method
comprising the step of utilizing a pyridinic sulfonamide
derivatives, or a pharmaceutically acceptable salt thereof with a
pharmaceutically acid or base or any optical isomer or mixture of
optical isomers, including a racemic mixture, or any tautomeric
form, said pyridinic sulfonamide derivative being represented by a
formula (I): ##STR3## wherein A represents a Nitrogen or a
--N.dbd.O group; X represents Oxygen, Sulphur or an element
selected from the group consisting of --NR.sub.3,
--CR.sub.3R.sub.4, --SO, --SO.sub.2, and --CO; wherein R.sub.3 and
R.sub.4 which can be identical or different, denotes each
independently one element selected from the group consisting of
hydrogen, a mono- or polyhalogenated C.sub.1-12-alkyl, a mono- or
polyhalogenated C.sub.3-8-cycloalkyl , a C.sub.1-12-alkyl and a
C.sub.3-8-cycloalkyl; R.sub.1 represents a mono- or polyhalogenated
C.sub.1-12-alkyl or a mono or polyhalogenated C.sub.3-8-cycloalkyl
group; R.sub.2 represents a C.sub.3-8-cycloalkyl group or a
non-substituted aryl group or an aryl group wherein one or more of
hydrogen atom(s) of the aryl group is/are substituted by one of the
elements selected from the group consisting of halogen,
C.sub.1-12-alkyl, C.sub.3-8-cycloalkyl, R.sub.1, hydroxy,
C.sub.1-6-alkoxy, C.sub.1-6-alkoxy-C.sub.1-6-alkyl, nitro, amino,
cyano, cyanomethyl; perhalomethyl, C.sub.1-6-monoalkyl- or
dialkylamino, sulfamoyl, C.sub.1-6-alkylthio,
C.sub.1-6-alkylsulfonyl, C.sub.1-6-alkylsulfinyl, formyl,
C.sub.1-6-alkylcarbonylamino, R.sub.5-arylthio,
R.sub.5-arylsulfinyl, R.sub.5-arylsulfonyl,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl;
carbamyl; carbamylmethyl; C.sub.1-6-monoalkyl- or
dialkylaminocarbonyl, C.sub.1-6-monoalkyl- or
dialkylaminothiocarbonyl, ureido, C.sub.1-6-monoalkyl- or
dialkylaminocarbonylamino, thioureido, C.sub.1-6-monoalkyl- or
dialkylaminothiocarbonylamino, C.sub.1-6-monoalkyl- or
dialkylaminosulfonyl, carboxy, carboxy-C.sub.1-6-alkyl, acyl,
R.sub.5-aryl, R.sub.5-arylalkyl, and R.sub.5-aryloxy, where R.sub.5
denotes one or several elements selected from the group consisting
of hydrogen, C.sub.1-6-alkyl, halogen, hydroxy and
C.sub.1-6-alkoxy.
3. A method of preparing a medicament comprising the step of
utilizing of a pyridinic sulfonamide derivative or a
pharmaceutically acceptable salt thereof with a pharmaceutically
acid or base or any optical isomer or mixture of optical isomers,
including a racemic mixture, or any tautomeric form, said pyridinic
sulfonamide derivative being represented by a formula (I): ##STR4##
wherein A represents a Nitrogen or a --N.dbd.O group; X represents
Oxygen, Sulphur or an element selected from the group consisting of
--NR.sub.3, --CR.sub.3R.sub.4, --SO, --SO.sub.2, and --CO; wherein
R.sub.3 and R.sub.4 which can be identical or different, denotes
each independently one element selected from the group consisting
of hydrogen, a mono- or polyhalogenated C.sub.1-12-alkyl, a mono-
or polyhalogenated C.sub.3-8-cycloalkyl , a C.sub.1-12-alkyl and a
C.sub.3-8-cycloalkyl; R.sub.1 represents a mono- or polyhalogenated
C.sub.1-12-alkyl or a mono or polyhalogenated C.sub.3-8-cycloalkyl
group; R.sub.2 represents a C.sub.3-8-cycloalkyl group or a
non-substituted aryl group or an aryl group wherein one or more of
hydrogen atom(s) of the aryl group is/are substituted by one of the
elements selected from the group consisting of halogen,
C.sub.1-12-alkyl, C.sub.3-8-cycloalkyl, R.sub.1, hydroxy,
C.sub.1-6-alkoxy, C.sub.1-6-alkoxy-C.sub.1-6-alkyl, nitro, amino,
cyano, cyanomethyl; perhalomethyl, C.sub.1-6-monoalkyl- or
dialkylamino, sulfamoyl, C.sub.1-6-alkylthio,
C.sub.1-6-alkylsulfonyl, C.sub.1-6-alkylsulfinyl, formyl,
C.sub.1-6-alkylcarbonylamino, R.sub.5-arylthio,
R.sub.5-arylsulfinyl, R.sub.5-arylsulfonyl,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl;
carbamyl; carbamylmethyl; C.sub.1-6-monoalkyl- or
dialkylaminocarbonyl, C.sub.1-6-monoalkyl- or
dialkylaminothiocarbonyl, ureido, C.sub.1-6-monoalkyl- or
dialkylaminocarbonylamino, thioureido, C.sub.1-6-monoalkyl- or
dialkylaminothiocarbonylamino, C.sub.1-6-monoalkyl- or
dialkylaminosulfonyl, carboxy, carboxy-C.sub.1-6-alkyl, acyl,
R.sub.5-aryl, R.sub.5-arylalkyl, and R.sub.5-aryloxy, where R.sub.5
denotes one or several elements selected from the group consisting
of hydrogen, C.sub.1-6-alkyl, halogen, hydroxy and
C.sub.1-6-alkoxy.
4. A method of preparing a medicament comprising the step of
utilizing a pyridinic sulfonamide derivative to prepare a
medicament, said pyridinic sulfonamide derivative being represented
by a formula (I): ##STR5## wherein A represents a Nitrogen or a
--N.dbd.O group; X represents Oxygen, Sulphur or an element
selected from the group consisting of --NR.sub.3,
--CR.sub.3R.sub.4, --SO, --SO.sub.2, and --CO; wherein R.sub.3 and
R.sub.4 which can be identical or different, denotes each
independently one element selected from the group consisting of
hydrogen, a mono- or polyhalogenated C.sub.1-12-alkyl, a mono- or
polyhalogenated C.sub.3-8-cycloalkyl , a C.sub.1-12-alkyl and a
C.sub.3-8-cycloalkyl; R.sub.1 represents a mono- or polyhalogenated
C.sub.1-12-alkyl or a mono or polyhalogenated C.sub.3-8-cycloalkyl
group; R.sub.2 represents a C.sub.3-8-cycloalkyl group or a
non-substituted aryl group or an aryl group wherein one or more of
hydrogen atom(s) of the aryl group is/are substituted by one of the
elements selected from the group consisting of halogen,
C.sub.1-12-alkyl, C.sub.3-8-cycloalkyl, R.sub.1, hydroxy,
C.sub.1-6-alkoxy, C.sub.1-6-alkoxy-C.sub.1-6-alkyl, nitro, amino,
cyano, cyanomethyl; perhalomethyl, C.sub.1-6-monoalkyl- or
dialkylamino, sulfamoyl, C.sub.1-6-alkylthio,
C.sub.1-6-alkylsulfonyl, C.sub.1-6-alkylsulfinyl, formyl,
C.sub.1-6-alkylcarbonylamino, R.sub.5-arylthio,
R.sub.5-arylsulfinyl, R.sub.5-arylsulfonyl,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl;
carbamyl; carbamylmethyl; C.sub.1-6-monoalkyl- or
dialkylaminocarbonyl, C.sub.1-6-monoalkyl- or
dialkylaminothiocarbonyl, ureido, C.sub.1-6-monoalkyl- or
dialkylaminocarbonylamino, thioureido, C.sub.1-6-monoalkyl- or
dialkylaminothiocarbonylamino, C.sub.1-6-monoalkyl- or
dialkylaminosulfonyl, carboxy, carboxy-C.sub.1-6-alkyl, acyl,
R.sub.5-aryl, R.sub.5-arylalkyl, and R.sub.5-aryloxy, where R.sub.5
denotes one or several elements selected from the group consisting
of hydrogen, C.sub.1-6-alkyl, halogen, hydroxy and
C.sub.1-6-alkoxy.
Description
[0001] This is a divisional application of application Ser. No.
10/488,553, filed Mar. 4, 2004.
[0002] The present invention relates to new pyridinic sulfonamides,
to their method of production, to pharmaceutical compositions
comprising such derivatives and their use as active therapeutic
substance in the treatment of diseases.
[0003] The new pyridinic sulfonamide derivatives, according to the
invention, are represented by a general formula (I): ##STR1##
wherein [0004] A represents a Nitrogen or a --N.dbd.O group; [0005]
X represents Oxygen, Sulphur or an element selected from the group
consisting of (--NR.sub.3, --CR.sub.3R.sub.4, --SO, --SO.sub.2, or
--CO); wherein R.sub.3 and R.sub.4 which can be identical or
different, denotes each independently one element selected from the
group consisting of (hydrogen , a mono- or polyhalogenated
C.sub.1-12-alkyl, a mono- or polyhalogenated C.sub.3-8-cycloalkyl ,
a C.sub.1-12-alkyl or a C.sub.3-8-cycloalkyl); [0006] R.sub.1
represents a mono- or polyhalogenated C.sub.1-12-alkyl, or a mono-
or polyhalogenated C.sub.3-8-cycloalkyl group; [0007] R.sub.2
represents a C.sub.3-8-cycloalkyl group or an aryl group
substituted or not by one or several elements selected from the
group consisting of (halogen, C.sub.1-12-alkyl,
C.sub.3-8-cycloalkyl, R.sub.1, hydroxy, C.sub.1-6-alkoxy,
C.sub.1-6-alkoxy-C.sub.1-6-alkyl, nitro, amino, cyano, cyanomethyl,
perhalomethyl, C.sub.1-6-monoalkyl- or dialkylamino, sulfamoyl,
C.sub.1-6-alkylthio, C.sub.1-6-alkylsulfonyl,
C.sub.1-6-alkylsulfinyl, formyl, C.sub.1-6-alkylcarbonylamino,
R.sub.5arylthio, R.sub.5arylsulfinyl, R.sub.5arylsulfonyl,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl,
carbamyl, carbamylmethyl, C.sub.1-6-monoalkyl- or
dialkylaminocarbonyl, C.sub.1-6-monoalkyl- or
dialkylaminothiocarbonyl, ureido, C.sub.1-6-monoalkyl- or
dialkylaminocarbonylamino, thioureido, C.sub.1-6-monoalkyl- or
dialkylaminothiocarbonylamino, C.sub.1-6-monoalkyl- or
dialkylaminosulfonyl, carboxy, carboxy-C.sub.1-6-alkyl, acyl,
R.sub.5aryl, R.sub.5arylalkyl, R.sub.5aryloxy), where R.sub.5
denotes one or several elements selected from the group consisting
of (hydrogen, C.sub.1-6-alkyl, halogen, hydroxy or
C.sub.1-6-alkoxy).
[0008] "C.sub.1-6-alkyl" as used herein, alone or in combination,
refers to a straight or branched, saturated hydrocarbon chain
having 1 to 6 carbon atoms such as methyl, propyl, butyl,
isopentyl, hexyl, 1-methylbutyl, 1,2-dimethylbutyl, 2-ethylbutyl,
2-methylpentyl, 3-methylpentyl and the like.
[0009] "C.sub.1-12-alkyl" as used herein, alone or in combination,
refers to a straight or branched, saturated hydrocarbon chain
having 1 to 12 carbon atoms.
[0010] "C.sub.3-8-cycloalkyl" as used herein refers to a radical of
a saturated cyclic hydrocarbon chain having 3 to 8 carbon atoms
such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the
like.
[0011] "C.sub.1-6-alkoxy" as used herein, alone or in combination,
refers to a straight or branched monovalent substituent comprising
a C.sub.1-6-alkyl group linked through an ether oxygen having its
free valence bond from the ether oxygen and having 1 to 6 carbon
atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
pentoxy, tert-butoxy and the like.
[0012] "C.sub.1-6-alkoxy-C.sub.1-6-alkyl" as used herein refers to
a group of 2-12 carbon atoms interrupted by an oxygen atom such as
--CH.sub.2--O--CH.sub.3, --CH.sub.2CH.sub.2O--CH.sub.3,
--CH.sub.2--O--CH.sub.2CH.sub.3, --CH.sub.2--O--CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2--O--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)CH.sub.2--O--CH.sub.3 and the like.
[0013] "halogen" means fluorine, chlorine, bromine or iodine.
[0014] "perhalomethyl" means trifluoromethyl, trichloromethyl,
tribromomethyl or triiodomethyl.
[0015] "C.sub.1-6-monoalkylamino" as used herein refers to an amino
group wherein one of the hydrogen atoms is substituted with a
straight or branched, saturated hydrocarbon chain having 1 to 6
carbon atoms such as methylamino, ethylamino, propylamino,
isopropylamino, butylamino, tert-butylamino, isopentylamino,
hexylamino and the like.
[0016] "C.sub.1-6-dialkylamino" as used herein refers to an amino
group wherein the two hydrogen atoms independently are substituted
with a straight or branched, saturated hydrocarbon chain having 1
to 6 carbon atoms such as dimethylamino, N-ethyl-N-methylamino,
N-methyl-N-isopropylamino, N-butyl-N-methylamino, dihexylamino and
the like.
[0017] "C.sub.1-6-alkylthio" as used herein, alone or in
combination, refers to a straight or branched monovalent
substituent comprising a C.sub.1-6-alkyl group linked through a
divalent sulfur atom having its free valence bond from the sulfur
atom and having 1 to 6 carbon atoms such as methylthio, ethylthio,
propylthio, isopropylthio, butylthio, pentylthio,
3-methylpentylthio and the like.
[0018] "C.sub.1-6-alkylsulfonyl" as used herein refers to a
monovalent substituent comprising a C.sub.1-6-alkyl group linked
through a sulfonyl group (--S(.dbd.O).sub.2--) such as
methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,
butylsulfonyl, pentylsulfonyl, 2-methylpentylsulfonyl and the
like.
[0019] "C.sub.1-6-alkylsulfinyl" as used herein refers to a
monovalent substituent comprising a C.sub.1-6-alkyl group linked
through a sulfinyl group (--S(.dbd.O)--) such as methylsulfinyl,
ethylsulfinyl, propylsulfinyl, isopropylsulfinyl,
tert-butylsulfinyl, pentylsulfinyl, 2-ethylbutylsulfinyl and the
like.
[0020] "acyl" as used herein refers to a monovalent substituent
comprising a C.sub.1-6-alkyl group linked through a carbonyl group
such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl
and the like.
[0021] "C.sub.1-6-alkylcarbonylamino" as used herein refers to an
amino group wherein one of the hydrogen atoms is substituted with
an acyl group such as acetamido, propionamido,
iospopropylcarbonylamino 2-ethylbutylcarbonylamino and the
like.
[0022] "aryl" as used herein refers to phenyl, 1-naphthyl, or
2-naphthyl.
[0023] "arylthio" as used herein, alone or in combination, refers
to an aryl group linked through a divalent sulfur atom having its
free valence bond from the sulfur atom, the aryl group is
substituted or not by one or several elements of R.sub.5 such as
phenylthio, 1-naphthylthio, 2-methylphenylthio, 3-methoxyphenylthio
and the like.
[0024] "arylsulfinyl" as used herein, alone or in combination,
refers to an aryl group linked through a sulfinyl group
(--S(.dbd.O)--), the aryl group is substituted or not by one or
several elements of R.sub.5 such as phenylsulfinyl,
2-methylphenylsulfinyl, 3-chloro-1-naphthylsulfinyl and the
like.
[0025] "arylsulfonyl" as used herein, alone or in combination,
refers to an aryl group linked throug a sulfonyl group
(--S(.dbd.O).sub.2--), the aryl group is substituted or not by one
or several elements of R.sub.5 such as phenylsulfonyl,
2-methylphenylsulfonyl, 4-iodophenylsulfonyl, 2-naphthylsulfonyl
and the like.
[0026] "C.sub.1-6-alkoxycarbonyl" as used herein refers to a
monovalent substituent comprising a C.sub.1-6-alkoxy group linked
through a carbonyl group such as methoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,
2-methylpentoxycarbonyl and the like.
[0027] "C.sub.1-6-monoalkylaminocarbonyl" as used herein refers to
a monovalent substituent comprising a C.sub.1-6-monoalkylamino
group linked through a carbonyl group such as methylaminocarbonyl,
isopropylaminocarbonyl, butylaminocarbonyl,
2-methylbutylaminocarbonyl and the like.
[0028] "C.sub.1-6-dialkylaminocarbonyl" as used herein refers to a
monovalent substituent comprising a C.sub.1-6-dialkylamino group
linked through a carbonyl group such as dimethylaminocarbonyl,
diethylaminocarbonyl N-methyl-N-isopropylaminocarbonyl,
N-methyl-N-butylaminocarbonyl,
N-propyl-N-2-methylbutylaminocarbonyl and the like.
[0029] "C.sub.1-6-monoalkylaminothiocarbonyl" as used herein refers
to a monovalent substituent comprising a C.sub.1-6-monoalkylamino
group linked through a thiocarbonyl group such as
methylaminothiocarbonyl, isopropylaminothiocarbonyl,
butylaminothiocarbonyl, 3-methylpentylaminothiocarbonyl,
1,2-dimethylbutylaminothiocarbonyl and the like.
[0030] "C.sub.1-6-dialkylaminothiocarbonyl" as used herein refers
to a monovalent substituent comprising a C.sub.1-6-dialkylamino
group linked through a thiocarbonyl group such as
dimethylaminothiocarbonyl, diethylaminothiocarbonyl
N-methyl-N-isopropylaminothiocarbonyl,
N-methyl-N-butylaminothiocarbonyl
N-tert-butyl-N-hexylaminothiocarbonyl and the like.
[0031] "C.sub.1-6-monoalkylaminocarbonylamino" as used herein
refers to an amino group wherein one of the hydrogen atoms is
substituted with a C.sub.1-6-monoalkylaminocarbonyl group such as
methylaminocarbonylamino, ethylaminocarbonylamino,
propylaminocarbonylamino, 3-methylbutylaminocarbonylamino,
1,2-dimethylbutylaminocarbonylamino and the like.
[0032] "C.sub.1-6-dialkylaminocarbonylamino" as used herein refers
to an amino group wherein one of the hydrogen atoms is substituted
with a C.sub.1-6-dialkylaminocarbonyl group such as
dimethylaminocarbonylamino, diethylaminocarbonylamino,
N-methyl-N-ethylaminocarbonylamino,
N-methyl-N-isopropylaminocarbonylamino,
N-propyl-N-pentylaminocarbonylamino and the like.
[0033] "C.sub.1-6-monoalkylaminothiocarbonylamino" as used herein
refers to an amino group wherein one of the hydrogen atoms is
substituted with a C.sub.1-6-monoalkylaminothiocarbonyl group such
as methylaminothiocarbonylamino, ethylaminothiocarbonylamino,
propylaminothiocarbonylamino, 3-methylpentylaminothiocarbonylamino
and the like.
[0034] "C.sub.1-6-dialkylaminothiocarbonylamino" as used herein
refers to an amino group wherein one of the hydrogen atoms is
substituted with a C.sub.1-6-dialkylaminothiocarbonyl group such as
dimethylaminothiocarbonylamino, diethylaminothiocarbonylamino,
N-methyl-N-ethylaminothiocarbonylamino,
N-methyl-N-propylaminothiocarbonylamino,
N-isopropyl-N-hexylaminothiocarbonylamino,
N-3-methylpentyl-N-pentylaminothiocarbonylamino and the like.
[0035] "C.sub.1-6-monoalkylaminosulfonyl" as used herein refers to
a monovalent substituent comprising a C.sub.1-6-monoalkylamino
group linked through a sulfonyl group such as methylaminosulfonyl,
ethylaminosulfonyl, propylaminosulfonyl, hexylaminosulfonyl,
tert-butylaminosulfonyl, 1,2-dimethylbutylaminosulfonyl and the
like.
[0036] "C.sub.1-6-dialkylaminosulfonyl" as used herein refers to a
monovalent substituent comprising a C.sub.1-6-dialkylamino group
linked through a sulfonyl group such as dimethylaminosulfonyl,
diethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl
N-methyl-N-propylaminosulfonyl,
N-hexyl-N-3-methylbutylaminosulfonyl and the like.
[0037] "ureido" as used herein means --NH--CO--NH.sub.2.
[0038] "thioureido" as used herein means --NH--CS--NH.sub.2.
[0039] "arylalkyl" as used herein refers to a straight or branched
saturated carbon chain containing from 1 to 6 carbons substituted
with an aromatic carbohydride. The aryl group is substituted or not
by one or several elements of R.sub.5.
[0040] "aryloxy" as used herein refers to phenoxy, 1-naphthyloxy or
2-naphthyloxy, the aryl group is substituted or not by one or
several elements of R.sub.5.
[0041] "R.sub.5aryl" as used herein refers to aryl substituted or
not by R.sub.5.
[0042] This invention also refers to all optical isomers of
pyridinic sulfonamides derivatives covered by the formula (I),
particularly the optically active isomers and their mixtures
including racemic mixtures thereof.
[0043] When in the general formula (I), one has an asymetrical
carbon atom, the invention refers as well to pure optical isomers
than to racemic mixture.
[0044] The invention refers also to tautomeric forms of the
pyridinic sulfonamide derivatives and to pharmacologically
acceptable salts of the derivatives covered by formula (I).
[0045] By pharmacologically acceptable salts of the derivatives,
one means pharmaceutically acceptable acid addition salts,
pharmaceutically acceptable metal salts or optionally alkylated
ammonium salts.
[0046] Preferred classes of pyridine sulfonamides derivatives
according to the general formula are especially those in which
R.sub.1 is trifluoromethyl.
[0047] The most preferred pyridine sulfonamide is
N-(3-phenoxy-4-pyridinyl)trifluoromethanesulfonamide.
[0048] In another aspect, the invention also relates to a method of
producing the above mentioned derivatives. The method comprises the
steps of [0049] a) converting into pyridine N-oxide, a pyridinic
compound unsubstituted in position 4 and [0050] b) reacting the
resulted pyridine N-oxide with a nitration reagent to obtain a
4-nitrosubstituted pyridine N-oxide derivative.
[0051] The pyridinic compound may be any pyridinic derivative
unsubstituted in position 4 and susceptible to react with an
oxydant such as H.sub.2O.sub.2.
[0052] The pyridinic compound unsubstituted in the 4-position may
be for example 3-bromopyridine or 3-methylpyridine as illustrated
in FIGS. 1 and 2.
[0053] Conversion of pyridinic compound into the pyridine N-oxyde
is described for example in Organic Syntheses, Coll. Vol. IV, p
828, 1963.
[0054] By nitration agent one means a mixture from 1:1 to 1:2 parts
of concentrated nitric acid and concentrated sulphuric acid to be
added between RT to 100.degree. C. and under continuous stirring to
the pyridine N-oxide.
[0055] The method of production of the pyridinic sulfonamide
derivatives is illustrated in FIGS. 1 and 2 wherein.
[0056] FIG. 1 represents a schematic synthesis of compounds with an
O, S, SO, SO.sub.2, NR.sub.3 and CR.sub.3R.sub.4 linkage and
[0057] FIG. 2 represents a schematic synthesis of compounds with a
CO and CH.sub.2 linkage.
FIG. 1
[0058] The pyridine N-oxide of formula 1amay be prepared from
3-bromopyridine which can be oxidized using several oxidants such
as H.sub.2O.sub.2. The nitration at the 4-position of the pyridine
N-oxide can be achieved by a mixture of nitric and sulphuric acids
to form 1b. The synthesis of 1c may be realized by reaction of 1b
with a cycloalkane derivative such as a cyclopentane, a
cyclohexane, a cycloheptane derivative or a benzene derivative in
presence of a suitable inorganic base such as K.sub.2CO.sub.3 or
NaOH in an inert solvent such as acetonitrile or dichloromethane.
The nitropyridine N-oxide 1c is converted into the aminopyridine 1d
via a reduction reaction using a reductant such as iron in presence
of acetic acid. For this reaction, water may be added to the
mixture and the temperature may be ranging from room temperature to
the reflux of the solvent. The synthesis of the sulfonamide 1e is
completed by reaction of the amino-substituted pyridine derivative
1d and the appropriate sulfonyl derivative such as sulfonyl
chloride, sulfonyl fluoride or sulfonic anhydride in presence of a
suitable inorganic base such as K.sub.2CO.sub.3 or NaOH in an inert
anhydrous solvent such as acetonitrile, dioxane or dichloromethane.
The oxidation of 1e use an oxidant such as H.sub.2O.sub.2 to form
1f.
[0059] The synthesis of the sulfoxide and the sulfone family 1i and
1j is realized throughout oxidation of the thio derivative 1c by an
oxidant such as meta-chloroperbenzoic acid to form 1g. This
oxidation is followed by a reduction (1h) and the formation of the
sulfonamide (1i) and finally by an oxidation (1j) of the pyridine
comparable to the methods used for the preparation of 1d, 1e and
1f.
FIG. 2
[0060] The synthesis of the ceto derivatives is achieved by the
pathway of scheme 2. This scheme begins by an oxidation of
3-methylpyridine by hydrogen peroxide in presence of acetic acid
(2a). Nitration by nitric acid and sulphuric acid at the 4-position
of the N-oxide lead to the formation of 2b. The methyl group of 2b
is oxidized by KMnO.sub.4 to produce the carboxylic acid 2c. The
synthesis of the cyano derivative 2d is achieved in three steps.
The first one is a conversion of carboxylic acid into carboxylic
halide by SOCl.sub.2. The second is the formation of carboxamide
and the last step is a deshydration of the amide to form the
nitrile 2d. The ceto linkage is prepared by reaction between 2d and
an organosmagnesium compound such as an alkyl magnesium bromide or
an aryl magnesium bromide. The ceto group is then protected as an
acetal by reaction of 2e and ethyleneglycol in an acidic medium.
After that, the nitro group and the N-oxide of 2f is reduced by
iron in presence of acetic acid to produce 2g. This compound reacts
with the appropriate sulfonyl chloride such as an alkyl or an aryl
sulfonyl chloride to form the sulfonamide 2h. The acetal may be
hydrolysed to generate the ceto compound 2i. The last step is an
oxidation of the pyridine 2i by H.sub.2O.sub.2 to form 2j.
Conversion of the ceto compounds into the corresponding methylene
derivatives is achieved by a Wolff-Kishner reaction as described in
Organic Reactions, Vol IV, p 378, 1948.
[0061] The method of production is also illustrated by examples
hereafter.
[0062] Elemental analyses (C, H, N, S) have been realised and
correspond to the theoretical formula (+/-0.4%). IR and .sup.1H-NMR
spectra are in accordance with proposed formulas.
[0063] The Infra-red spectra (IR) made on 1 mg of different
substances have been recorded by means of a FT-IR Perkin Elmer 1750
and KBr pellets of 250 mg.
[0064] After dissolution in DMSO-d.sub.6, the .sup.1H-NMR spectrum
of different molecules has been recorded on a Bruker 400
apparatus.
[0065] Melting points of obtained molecules have been determined on
a Buchi-Tottoli apparatus.
EXAMPLE 1
Preparation of
N-(3-phenoxy-4-pyridinyl)trifluoromethane-sulfonamide (Compound
1)
[0066] Step 1:
[0067] To 1.58 g of 3-bromopyridine (10 mmol) dissolved in 6 mL of
glacial acetic acid, 4 mL of 30% hydrogen peroxide are added. The
solution is heated with reflux for 48 hours. The solvent is
evaporated under depression. The residue is purified by column
chromatography using ethyl acetate as eluent.
[0068] Yield : 64% (oil).
[0069] IR (KBr): 3109 (C--H), 1595 (C.dbd.N), 1468 (C.dbd.C), 1292
(N--O) cm.sup.-1
[0070] Step 2:
[0071] To 1.74 g of 3-bromopyridine N-oxide dissolved in 4 mL of
concentrated sulphuric acid, a mixture of 4 mL of concentrated
sulphuric acid and 6.7 mL of concentrated nitric acid is added
under continuous stirring. The solution is heated at 90.degree. C.
for 90 minutes. Then the solution is poured into ice and
supplemented with a 50% aqueous solution of NaOH until complete
precipitation of the final compound. The yellow solid is filtered
off and washed with water to give 1.51 g of 3-bromo-4-nitropyridine
N-oxide.
[0072] Yield: 69%. mp: 149.degree. C. IR (KBr): 3099 (C--H), 1589
(C.dbd.N), 1552, 1338 (NO.sub.2), 1295 (N--O), 643 (C--Br)
cm.sup.-1
[0073] Step 3:
[0074] 4.8 mL of 10% aqueous solution of NaOH are added to 1.12 g
of phenol. After stirring for 5 minutes, water is evaporated under
reduced pressure. A white solid is obtained and taken up by 10 mL
of acetonitrile and the resulting suspension is supplemented with
2.19 g of 3-bromo-4-nitropyridine N-oxide. The obtained mixture is
heated under reflux during 5 minutes. The mixture is further poured
into ice and extracted with ethyl acetate. Organic layers are
collected and dried over anhydrous magnesium sulphate. After
evaporation of the solvent , a solid residue is purified by column
chromatography using ethyl acetate as eluent to give 1.27 g of a
yellow solid.
[0075] Yield: 54%. mp: 109.degree. C. IR (KBr): 3109 (C--H), 1606
(C.dbd.N), 1507, 1313 (NO.sub.2), 1219 (N--O) cm.sup.-1
[0076] Step 4:
[0077] 2.32 g of 4-nitro-3-phenoxypyridine N-oxide dissolved in 55
mL of acetic acid and 14 mL of water are heated under reflux. Then
3.48 g of iron powder are added and the reflux is maintained for 12
hours. The solution is filtered and evaporated under reduced
pressure. An oily residue is taken up with water and pH adjusted to
10 by addition of a 10% aqueous solution of NaOH. The suspension is
filtered and the filtrate is extracted by ethyl acetate. Organic
layers are collected and dried over anhydrous magnesium sulfate.
After evaporation, 4-amino-3-phenoxypyridine is obtained as a
yellow oil.
[0078] Yield: 80-90%.
[0079] Step 5:
[0080] To 1.81 g of 4-amino-3-phenoxypyridine dissolved in 112 mL
of dry acetonitrile are added 8.29 g anhydrous potassium carbonate.
The suspension is stirred for 5 minutes and 2.02 mL of
trifluoromethanesulfonyl chloride are added. The mixture is stirred
for 12 h, then filtered and the solvent evaporated under reduced
pressure. The residue is taken up with 10% aqueous solution of NaOH
and the pH of the solution is adjusted to 5 with 1N HCl to separate
2.53 g of a final compound as a white solid.
[0081] Yield: 80%; mp: 239.degree. C.; IR (KBr): 2807, 2728, 2648
(N.sup.+'H), 1633 (C.dbd.N), 1473 (C.dbd.C), 1343, 1129 (SO.sub.2)
cm.sup.-1; NMR .sup.1H (DMSO-d.sub.6): .delta. 6.95 (d, 2H,
H-2'+H-6'), 7.11 (t, 1H, H-4'), 7.36 (t, 2H, H-3'+H-5'), 7.81 (d,
1H, H-5), 8.30 (d, 1H, H-6), 8.43 (s, 1H, H-2), 13,90 (bs, N--H);
Anal (C.sub.12H.sub.9N.sub.2O.sub.3SF.sub.3) C, H, N, S.
EXAMPLE 2
Preparation of
N-(3-(4-chlorophenoxy)-4-pyridinyl)trifluoromethanesulfonamide
[0082] Step 1 and Step 2:
[0083] Similar to example 1
[0084] Step 3:
[0085] 4 mL of a 10% aqueous solution of NaOH are added to 1.4 g of
4-chlorophenol. After stirring for 5 minutes, water is evaporated
under reduced pressure. A white solid is obtained and taken up by
10 mL of acetonitrile and the resulting suspension is supplemented
with 2 g of 3-bromo-4-nitropyridine N-oxide to obtain a mixture
which is then heated under reflux for 5 minutes. The mixture is
further filtered and the filtrate is concentrated under reduced
pressure. A solid is obtained and is dissolved in a minimum of
methanol and 4-nitro-3-(4-chlorophenoxy)-pyridine N-oxide is
precipitated by addition of water. The precipitate is collected by
filtration to give 1.15 g of a yellow solid.
[0086] Yield: 47%. mp: 101-102.degree. C. IR (KBr): 3117, 3029
(C--H), 1610 (C.dbd.N), 1213 (N--O), 1100 cm.sup.-1
[0087] Step 4:
[0088] 0.37 g of 4-nitro-3-(4-chlorophenoxy)-pyridine N-oxide
dissolved in 9 mL of acetic acid and 2 mL of water are heated under
reflux. To such warm solution are added 0.5 g of iron powder and
the reflux is maintained for 1 hour. A suspension is obtained and
filtered and the filtrate is evaporated under reduced pressure. An
oily residue is obtained and taken up with water and pH adjusted to
10 by addition of a 10% aqueous solution of NaOH. The resulting
suspension is filtered and the filtrate is extracted by ethyl
acetate. Organic layers are collected and dried over anhydrous
magnesium sulfate. After evaporation,
4-amino-3-(4-chlorophenoxy)pyridine is obtained as a yellow
oil.
[0089] Yield: 80-90%.
[0090] Step 5:
[0091] To 0.56 g of 4-amino-3-(4-chlorophenoxy)pyridine dissolved
in 20 mL of dry acetonitrile is added 1 g of anhydrous potassium
carbonate. The suspension is stirred for 5 minutes and 0.794 mL of
trifluoromethanesulfonyl chloride are added. The mixture is stirred
for 15 minutes, then filtered and the filtrate concentrated under
reduced pressure. The residue is taken up with a 10% aqueous
solution of NaOH and the pH of the solution is adjusted to 7 with
1N HCl to separate 0.61 g of the final compound as a white solid
which is filtered, washed with water and dried.
[0092] Yield: 68%; mp: 222-223.degree. C.; IR (KBr): 2810, 2732,
2648 (N.sup.+--H), 1636 (C.dbd.N), 1474 (C.dbd.C), 1344, 1130
(SO.sub.2) cm.sup.-1
EXAMPLE 3
Preparation of
N-(3-(3,5-dichlorophenoxy)-4-pyridinyl)trifluoromethanesulfonamide
[0093] Step 1 and Step 2:
[0094] Similar to example 1
[0095] Step 3:
[0096] 4.32 mL of a 10% aqueous solution of NaOH are added to 1.76
g of 3,5-dichlorophenol. After stirring for 5 minutes, water is
evaporated under reduced pressure. A white solid is obtained and
taken up by 10 mL of acetonitrile and the suspension is
supplemented with 2 g of 3-bromo-4-nitropyridine N-oxide and then
heated under reflux for 20 hours. The mixture is filtered and the
filtrate is concentrated under reduced pressure. A solid is
obtained and is suspended in a minimum of cold methanol and
4-nitro-3-(3,5-dichlorophenoxy)pyridine N-oxide is collected by
filtration to give 1.25 g of a yellow final solid.
[0097] Yield: 47%. mp : 160-161.degree. C. IR (KBr): 3051, 3014
(C--H), 1610 (C.dbd.N), 1584, 1309 (NO.sub.2), 1227 (N--O)
cm.sup.-1
[0098] Step 4:
[0099] 0.95 g of 4-nitro-3-(3,5-dichlorophenoxy)pyridine N-oxide
dissolved in 18 mL of acetic acid and 5 mL of water are heated
under reflux. To the warm solution are added 1.12 g of iron powder
and the reflux is maintained for 12 hours. The solution is filtered
and the filtrate is evaporated under reduced pressure. An oily
residue is obtained and taken up with water and the pH adjusted to
10 by addition of a 10% aqueous solution of NaOH. The suspension is
filtered and the filtrate is extracted by ethyl acetate. Organic
layers are collected and dried over anhydrous magnesium sulfate.
After evaporation, 4-amino-3-(3,5-dichlorophenoxy)pyridine is
obtained as a yellow oil.
[0100] Yield: 80-90%.
[0101] Step 5:
[0102] To 0.45 g of 4-amino-3-(3,5-dichlorophenoxy)pyridine
dissolved in 20 mL of dry acetonitrile are added 0.73 g anhydrous
potassium carbonate. The suspension is stirred for 5 minutes and
0.551 mL of trifluoromethanesulfonyl chloride are added. The
mixture is stirred for 30 minutes, then filtered and the filtrate
concentrated under reduced pressure. A residue is obtained and
taken up with a 10% aqueous solution of NaOH and the pH of the
solution is adjusted to 7 with 1N HCl to separate 0.33 g of the
final compound as a white solid which is filtered, washed with
water and dried.
[0103] Yield: 49%; mp: 219-220.degree. C.; IR (KBr): 2921, 2820,
2653 (N.sup.+--H), 1633 (C.dbd.N), 1486 (C.dbd.C), 1344, 1126
(SO.sub.2) cm.sup.-1.
EXAMPLE 4
Preparation of
N-(3-(4-bromophenoxy)-4-pyridinyl)trifluoromethanesulfonamide
[0104] Step 1 and Step 2:
[0105] Similar to example 1
[0106] Step 3:
[0107] 5.5 mL of a 10% aqueous solution of NaOH are added to 1.88 g
of 4-bromophenol. After stirring for 5 minutes, water is evaporated
under reduced pressure. A white solid is obtained and taken up by
10 mL of acetonitrile and the suspension is supplemented with 2 g
of 3-bromo-4-nitropyridine N-oxide and then heated under reflux 5
minutes. The mixture is filtered and the filtrate is evaporated
under reduced pressure. A solid is obtained and is dissolved in a
minimum of methanol and 4-nitro-3-(4-bromophenoxy)-pyridine N-oxide
is precipitated by addition of water. The precipitated is collected
by filtration, washed with water and dried, to give 0.96 g of a
yellow solid.
[0108] Yield: 34%. mp: 124-125.degree. C. IR (KBr): 3106 (C--H),
1605 (C.dbd.N), 1565, 1312 (NO.sub.2), 1212 (N--O) cm.sup.-1
[0109] Step 4:
[0110] 3 g of 4-nitro-3-(4-bromophenoxy)-pyridine N-oxide dissolved
in 72 mL of acetic acid and 18 mL of water are heated under reflux.
To the warm solution are added 4.2 g of iron powder and the reflux
is maintained for 12 hours. The solution is filtered and the
filtrate is evaporated under reduced pressure. Oily residue is
obtained and is taken up with water and the pH adjusted to 10 by
addition of a 10% aqueous solution of NaOH. The suspension is
filtered and the filtrate is extracted by ethyl acetate. Organic
layers are collected and dried over anhydrous magnesium sulfate.
After evaporation, 4-amino-3-(4-bromophenoxy)-pyridine is obtained
as a yellow oil.
[0111] Yield: 80-90%.
[0112] Step 5:
[0113] To 0.2 g of 4-amino-3-(4-bromophenoxy)-pyridine dissolved in
20 mL of dry acetonitrile are added 2.25 g anhydrous potassium
carbonate. The suspension is stirred for 5 minutes and 0.235 mL of
trifluoromethanesulfonyl chloride are added. The mixture is stirred
for 1 hour, then filtered and the filtrate concentrated under
reduced pressure. A residue is taken up with a 10% aqueous solution
of NaOH and the pH of the solution is adjusted to 7 with 1N HCl to
separate 0.21 g of the final compound as a white solid.
[0114] Yield : 70%; mp: 245-246.degree. C.; IR (KBr) : 2809, 2732,
2648 (N.sup.+--H), 1635 (C.dbd.N), 1473 (C.dbd.C), 1344, 1130
(SO.sub.2) cm.sup.-1.
EXAMPLE 5
Preparation of
N-(3-(3-chlorophenoxy)-4-pyridinyl)trifluoromethanesulfonamide
[0115] Step 1 and Step 2:
[0116] Similar to example 1
[0117] Step 3:
[0118] 4 mL of a 10% aqueous solution of NaOH are added to 1.4 g of
3-chlorophenol. After stirring for 5 minutes, water is evaporated
under reduced pressure. A white solid is obtained and taken up by
40 mL of acetonitrile and the suspension is supplemented with 2 g
of 3-bromo-3-nitropyridine N-oxide and then heated under reflux for
5 minutes. The mixture is filtered and the filtrate is concentrated
under reduced pressure. A solid is obtained and is dissolved in a
minimum of cold methanol and 4-nitro-3-(3-chlorophenoxy)-pyridine
N-oxide is collected by filtration to give 1.06 g of a yellow
solid.
[0119] Yield: 42%. mp: 105-106.degree. C. IR (KBr): 3056 (C--H),
1604 (C.dbd.N), 1568, 1318 (NO.sub.2), 1219 (N--O) cm.sup.-1
[0120] Step 4:
[0121] 1 g of 4-nitro-3-(3-chlorophenoxy)-pyridine N-oxide
dissolved in 20 mL of acetic acid and 6 mL of water are heated
under reflux. To the warm solution are added 2.98 g of iron powder
and then heated under reflux for 3 hours. The suspension is
filtered and the filtrate is concentrated under reduced pressure.
Oily residue is obtained and taken up with water and the pH
adjusted to 10 by addition of a 10% aqueous solution of NaOH. The
suspension is filtered and the filtrate is extracted by ethyl
acetate. Organic layers are collected and dried over anhydrous
magnesium sulfate. After evaporation,
4-amino-3-(3-chlorophenoxy)pyridine is obtained as a yellow
oil.
[0122] Yield: 90%.
[0123] Step 5:
[0124] To 0.2 g of 4-amino-3-(3-chlorophenoxy)pyridine dissolved in
15 mL of dry dichloromethane are added 0.5 mL of triethylamine. The
solution is stirred for 5 minutes and 0.19 mL of
trifluoromethanesulfonyl chloride are added. The mixture is stirred
for 12 h, then filtered and the filtrate concentrated under reduced
pressure. The residue is taken up with a 10% aqueous solution of
NaOH and the pH of the solution is adjusted to 7 with 1N HCl to
separate 0.2 g of the final compound as a white solid which is
filtered, washed with water and dried.
[0125] Yield: 73%; mp: 198-199.degree. C.; IR (KBr): 2896, 2815,
2650 (N.sup.+--H), 1632 (C.dbd.N), 1473 (C.dbd.C), 1343, 1129
(SO.sub.2) cm.sup.-1.
EXAMPLE 6
Preparation of
N-(3-thiophenoxy-4-pyridinyl)trifluoromethanesulfonamide
[0126] Step 1 and Step 2:
[0127] Similar to example 1
[0128] Step 3:
[0129] 2 mL of thiophenol is dissolved in 80 mL of toluene. 2.5 g
of K.sub.2CO.sub.3 is added and the suspension is heated until
reflux occur. Then, 4 g of 3-bromo-4-nitropyridine N-oxide is added
and the reflux is maintained for 2 hours. The mixture is filtered
and the filtrate is concentrated under reduced pressure. A residue
is taken up by a minimum of cold ethanol and
4-nitro-3-thiophenoxypyridine N-oxide is collected by filtration to
give 2.52 g of a yellow solid.
[0130] Yield: 55%. mp: 147-148.degree. C. IR (KBr): 3065 (C--H),
1588 (C.dbd.N), 1548, 1329 (NO.sub.2), 1230 (N--O) cm.sup.-1
[0131] Step 4:
[0132] 0.5 g of 4-nitro-3-thiophenoxypyridine N-oxide dissolved in
20 mL of glacial acetic acid are heated under reflux. To the warm
solution are added 0.37 g of iron powder and the reflux is
maintained for 2 hours. The solution is filtered and the filtrate
concentrated under reduced pressure. Oily residue is obtained and
taken up with water and the pH adjusted to 10 by addition of a 10%
aqueous solution of NaOH solution. The suspension is filtered and
the filtrate is extracted by ethyl acetate. Organic layers are
collected and dried over anhydrous magnesium sulfate. After
evaporation, 4-amino-3-thiophenoxypyridine is obtained as a yellow
oil.
[0133] Yield: 90%.
[0134] Step 5:
[0135] To 0.45 g of 4-amino-3-thiophenoxypyridine dissolved in 20
mL of dry acetonitrile are added 1.84 g anhydrous potassium
carbonate. The suspension is stirred for 5 minutes and 0.47 mL of
trifluoromethanesulfonyl chloride are added. The mixture is stirred
for 4 h, then filtered and acetonitrile is evaporated under reduced
pressure. The residue is taken up with a 10% aqueous solution of
NaOH and the pH of the solution is adjusted to 5 with 1N HCl to
separate 0.36 g of the final compound as a white solid which is
filtered, washed with water and dried.
[0136] Yield: 50%; mp: 188-189.degree. C.; IR (KBr): 2807, 2728,
2648 (N.sup.+--H), 1633 (C.dbd.N), 1473 (C.dbd.C), 1343, 1129
(SO.sub.2
[0137] The invention also refers to the use of the pyridinic
sulfonamides derivatives covered by formula (1) and their salts for
drug manufacture for treatment and/or prevention of diseases such
as inflammation, arthrosis, cancer, angiogenesis and asthma and for
other pathologies in which they can play a role of COX-2 selective
inhibitor.
[0138] Prostaglandins (PG) are key mediators involved in the
inflammation processes. According to Bergstrom, S.; Ryhage, R.;
Samuelsson, B.; Sjovall, J. in J. Biol. Chem., 1963, 238,
3555-3563. prostaglandins are synthesized by cyclooxygenases (COXs)
from arachidonic acid.
[0139] Different classes of anti-inflammatory drugs on the market
inhibit the synthesis of PG by inhibiting those enzymes.
[0140] The COX enzymes exist under two distinct isoforms. COX-1 is
a constitutive enzyme responsible for physiological production of
PG. This enzyme is involved in several homeostatic processes and is
thus considered as a "house keeping" enzyme. In contrast, COX-2 is
an inducible enzyme which is mainly produced during inflammation
processes. Furthermore, according to Crofford L., Lipsky P., Brooks
P., Abramson S., Simon L., van de Putte L. in Arthritis Rheum.,
2000, 43, 4-13, COX-2 is expressed during different pathologies
such as arthrosis, angiogenesis and asthma.
[0141] A problem with the inhibition of COX-1 by common
non-steroidal anti-inflammatory drugs (NSAID) is its side effects
such as gastric ulceration.
[0142] The present invention deals with the use of new COX-2
selective inhibitors represented by the pyridinic sulfonamide
derivatives described above. Such new COX-2 selective inhibitors
advantageously does not exhibit such side effects.
[0143] The pyridinic sulfonamide derivatives described above have
been evaluated as COX inhibitors on one in vitro test and on one in
vivo test. For the in vitro assay the methodology is described by
X. de Leval, J. Delarge, P. Devel, P. Neven, C. Michaux, B.
Masereel, B. Pirotte, J.-L. David, Y. Henrotin, J.-M. Dogne. in
Prostaglandins, Leukot., Essent. Fatty Acids, 2001, 64,
211-216.
[0144] Pharmacological evaluations of
N-(3-phenoxy-4-pyridinyl)trifluoro-methanesulfonamide (compound 1)
are recorded in
[0145] Table 1 which describes Estimated IC.sub.50 for compound 1
on whole blood assay TABLE-US-00001 IC.sub.50 COX-1 IC.sub.50 COX-2
IC.sub.50 COX-1/ compound (.mu.M) (.mu.M) IC.sub.50 COX-2 1 2.2 0.4
5.28
[0146] The activity of the derivatives has also been evaluated by
using a rat paw oedema pharmacological model.
[0147] In Carrageenin-induced rat paw oedema model, Wistar rats
were used. The mean weight of the animals was 250 g. The animals
were treated with an intraperitoneal injection of the drug at the
appropriate concentration (solution at the concentration of 10
mg/mL in DMSO). Lambda carrageenin (0.1 mL; 1%) was injected one
hour later in the plantar region of the right hand paw. Three hours
thereafter, the rats were euthanasied by injection of nembutal (100
mg/kg) and the paws were cutted at the ankle. The swelling was
calculated as a percentage increase in the weight of the control
paw. TABLE-US-00002 compound 5 (mg/kg) 10 (mg/kg) 30 (mg/kg)
Control 1 101.0 .+-. 8.1 74.7 .+-. 7.2 54.1 .+-. 17.5 96 .+-. 8.7
Results are expressed as percentage of growth of the paw after
injection of carrageneen (mean .+-. standard deviation, n = 6).
[0148] Those tables clearly show that compound 1 is active as COX-2
inhibitor and presents an anti-inflammatory effect in vivo.
[0149] The invention also refers to a Pharmaceutical composition
comprising a pyridinic sulfonamide derivative or a pharmaceutical
acceptable salt thereof with a pharmaceutical acceptable acid or
base, or any optical isomer or mixture of optical isomers,
including a racemic mixture or any tautomeric form together with
one or more acceptable carriers or diluents.
[0150] The pharmaceutical composition may be in a form of an oral
dosage unit or parenteral dosage unit.
* * * * *