Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-10-26
2001-10-02
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S347000, C514S445000, C546S338000, C549S065000, C564S082000
Reexamination Certificate
active
06297282
ABSTRACT:
The invention relates to novel compounds having anti-inflammatory activity.
Prostaglandins play a decisive role in inflammatory processes and inhibition of the formation of prostaglandin, especially the formation of PGG
2
, PGH
2
and PGE
2
, is the common characteristic of compounds with anti-inflammatory activity. The known non-steroidal anti-inflammatory drugs (NSAIDs), which reduce prostaglandin-induced pain and swelling during the inflammation process, also influence prostaglandin-regulated processes which do not accompany inflammation processes. For this reason, most known NSAIDs cause undesirable side-effects in high doses, often even dangerous ulcers, especially stomach ulcers, gastric haemorrhages and such like. For this reason, the therapeutic potential of these compounds is decisively reduced.
Most known NSAIDs prevent the formation of prostaglandins by the inhibition of enzymes in human arachidonic acid metabolism, especially by inhibiting the enzyme cyclooxygenase (COX). The enzyme cyclooxygenase II (COX-2) is an enzyme of human arachidonic acid metabolism which has only been discovered recently. (Proc. Natl. Acad. Sci. USA, 89, 7384, 1992). COX-2 is induced by cytokines or endotoxins.
The discovery of this inducible enzyme, which plays a decisive role in inflammation processes, offers the possibility of searching for selectively effective compounds with an anti-inflammatory activity, which inhibit the inflammation process in a more effective manner without influencing other prostaglandin-regulated processes, and thus having fewer and fewer serious side-effects.
5-methylsulphonamide-1-indanones, which inhibit the enzyme cyclooxygenase II and which can therefore be utilised during the treatment of inflammation processes, are known from WO 94/13635. The potential of these compounds, and their side-effects, have not yet been fully clarified. Furthermore, these known compounds dissolve poorly, and thus have decisive disadvantages with regard to their formulation and application. Hence there is still a demand for new cyclooxygenase II-selective compounds, which, due to their effect and side-effect profiles, are safe and efficient in applications for the treatment of inflammatory processes.
The objective of the present invention was thus the provision of new non-steroidal anti-inflammatory drugs (NSAIDs), which selectively inhibit cyclooxygenase II (COX-2) and thus have fewer and fewer serious undesired side effects.
This objective could be unexpectedly solved by the provision of new derivatives of benzenesulphonic acid. As a result of their selective effect on the enzyme Cyclooxygenase II, these new compounds have excellent anti-inflammatory, analgesic, antipyretic and anti-allergic effects, but without the extremely undesirable side-effects of known anti-inflammatory agents.
The subject matter of the invention are thus compounds of formula I
wherein
A denotes oxygen, sulphur or NH,
R
1
is an optionally unsaturated alkyl or alkyloxyalkyl group, optionally mono- or polysubstituted or mixed substituted by halogen, alkoxy, oxo or cyano, a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted or mixed substituted by halogen, alkyl, CF
3
, cyano or alkoxy,
R
2
and R
3
, independently from one another, denote hydrogen, an optionally polyfluorised alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH
2
)
n
—X,
or
R
2
and R
3
, together with the N- atom denotes a 3 to 7-membered, saturated, partially or completely unsaturated heterocycle with one or more heteroatoms N, O or S, which can optionally be substituted by oxo, an alkyl, alkylaryl or aryl group, or a group (CH
2
)
n
—X,
X denotes halogen, NO
2
, —OR
4
, —COR
4
, —CO
2
R
4
, —OCO
2
R
4
, —CN, —CONR
4
OR
5
, —CONR
4
R
5
, —SR
4
, —S(O)R
4
, —S(O)
2
R
4
, —NR
4
R
5
, —NHC(O)R
4
, —NHS(O)
2
R
4
,
n denotes a whole number from 0 to 6,
R
6
denotes a straight-chained or branched alkyl group with 1-10 C- atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group, aralkyl group, a heteroaryl or heteroaralkyl group which can optionally be mono- or polysubstituted or mixed substituted by halogen or alkoxy,
R
7
denotes halogen, hydroxy, a straight-chained or branched alkyl, alkoxy, acyloxy or alkyloxycarbonyl group with 1-6 C- atoms, which can optionally be mono- or polysubstituted by halogen, NO
2
, —OR
4
, —COR
4
, —CO
2
R
4
, —OCO
2
R
4
, —CN, —CONR
4
OR
5
, —CONR
4
R
5
, —SR
4
, —S(O)R
4
, —S(O)
2
R
4
, —NR
4
R
5
, —NHC(O)R
4
, —NHS(O)
2
R
4
, or a polyfluoroalkyl group,
R
4
and R
5
, independently from one another, denote hydrogen, alkyl, aralkyl or aryl, and
m denotes a whole number from 0 to 2, and the pharmaceutically-acceptable salts thereof.
A denotes oxygen, sulphur or NH.
R
1
denotes an optionally unsaturated alkyl or alkyloxyalkyl group, each with 1-12 C-atoms in the alkyl chain, for example a methyl, an ethyl, a propyl, an isopropyl, a butyl, an isobutyl, a tertiary-butyl, a pentyl, an isopentyl, a hexyl or an isohexyl group and the like, or for example unsaturated alkyl groups such as ethenyl, butenyl, or alkyoxyalkyl groups such as methoxymethyl, ethoxymethyl and the like. These groups can optionally be substituted by halogen, for example F, Cl or Br, by alkoxy, oxo or cyano. Furthermore, R
1
can denote a cycloalkyl group, for example a cyclohexyl or a cyclopentyl group, an aryl group, for example a phenyl group, or heteroaryl group, for example a furyl, thienyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyridinyl or pyrazolyl group. These groups can optionally be mono- or polysubstituted or mixed substituted by halogen, for example Cl, F, Br or by CF
3
or alkyl with 1-4 C-atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tertiary-butyl or alkoxy with 1-4 C-atoms, for example methoxy, ethoxy, propoxy or butoxy or cyano.
R
2
and R
3
, independently from one another, denote hydrogen, an optionally polyfluorized alkyl group with 1-6 C-atoms, for example methyl, an ethyl, a propyl, an isopropyl, a butyl, an isobutyl, a tertiary-butyl, a pentyl, an isopentyl, a hexyl or an isohexyl group, a CF
3
group or C
2
F
5
, an aralkyl group with 1-4 C-atoms in the alkyl chain, for example a benzyl group, an ethylphenyl group, an aryl group, for example a phenyl group or a heteroaryl group, for example a pyridyl group, a pyridazinyl group, a thienyl group, a thiazolyl group or an isothiazolyl group.
R
2
and R
3
can also, independently from one another, denote a group —(CH
2
)
n
—X, whereby X is halogen, —NO
2
, —OR
4
, —COR
4
, —CO
2
R
4
, —OCO
2
R
4
, —CN, —CONR
4
OR
5
, —CONR
4
R
5
, —SR
4
, —S(O)R
4
, —S(O)
2
R
4
, —NR
4
R
5
, —NHC(O)R
4
, —NHS(O)
2
R
4
, and n is a whole number from 0 to 6.
Examples of such groups are halogen alkyl groups, for example chloromethyl, chloroethyl, the group —CN, nitroalkyl groups, for example nitromethyl, nitroethyl or cyanoalkyl groups, for example cyanomethyl, cyanopropyl, cyanohexyl, a hydroxy group or hydroxyalkyl groups, for example hydroxymethyl, hydroxyethyl, hydroxypropyl bishydroxymethyl-methyl. Other examples are alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, pentoxy, the groups methyloxy-ethyl, ethyloxy-methyl, carboxylic acid groups such as ethoxycarbonyl, methoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl groups and their alkyl-, aralkyl- or aryl esters, carbamoyl groups, oxycarbonyloxy groups, for example the ethoxycarbonyloxy group, carboxymide acid groups, thiocarboxy groups and such like.
R
4
and R
5
denote, independently of one another, hydrogen, alkyl with 1-6 C-atoms, aralkyl with 1-4 C-atoms in the alkyl chain, for example benzyl, ethylphenyl or aryl, for example phenyl.
Furthermore, R
2
and R
3
, together with the N-atom, can form a 3- to 7-membered, saturated, partially or completely unsaturated heterocycle with one or more heteroatoms N, O or S, which may optionally be substituted by oxo, an alkyl, alkylaryl or aryl group or a group —(CH
2
)
n
—X, whereby X denotes halogen, NO
2
, —OR
4
, —COR
4
, —CO
2
R
4
, —OCO
2
R
4
, —CN, —CONR
4
OR
5
, —CONR
4
R
5
, —SR
4
, —S(O)R
4
, —S(O)
Blaschke Heinz
Fellier Harald
Hartmann Michael
Kremminger Peter
Rovenszky Franz
Nycomed Austria GmbH
O'Sullivan Peter
Wenderoth Lind & Ponack LLP
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