Benzophenones as inhibitors of IL-1&bgr; and TNF-&agr;

Details Benzophenones as inhibitors of IL-1&bgr; and TNF-&agr; Benzophenones as inhibitors of IL-1&bgr; and TNF-&agr;

2001-05-21

2002-08-13

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S256000, C514S261100, C514S310000, C514S313000, C514S352000, C514S370000, C514S394000, C514S395000, C546S146000, C546S161000, C546S312000, C544S277000, C544S311000, C544S336000, C548S161000

Reexamination Certificate

active

06432962

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel class of compounds, including heteroaryl aminobenzophenone derivatives, which show anti-inflammatory effects, to pharmaceutical compositions containing these compounds, and to their use in the treatment and prophylaxis of inflammatory diseases.
BACKGROUND OF THE INVENTION
A series of aminobenzophenones (e.g. 4-(2-amino-4-nitrophenylamino)benzophenone) have been described previously (Hussein, F. A. et al., Iraqi J. Sci., 22, 54-66 (1981)). In this publication, however, there is no description of any potential therapeutic use of such compounds. WO 98/32730 discloses aminobenzophenone inhibitors of interleukin 1&bgr; (IL-1&bgr;) and tumour necrosis factor &agr; (TNF-&agr;) secretion in vitro, and indicates the potential utility of these compounds in the treatment of inflammatory diseases in which the production of pro-inflammatory cytokines is involved in the pathogenesis, e.g. asthma, rheumatoid arthritis, psoriasis, contact dermatitis, and atopic dermatitis. Furthermore the A compounds disclosed in WO 98/32730 were tested in vivo for anti-inflammatory properties in the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced murine chronic skin inflammation model (De Young, L. M. et al.,
Agents Actions
26, 335-341 (1989); Carlson, R. P. et al.,
Agents Actions
17, 197-204 (1985); Alford, J. G. et al.,
Agents Action
37, (1992); Stanley, P. L. et al.,
Skin Pharmacol
. 4, 262-271 (1991)). In this chronic skin inflammation model the compounds had the same potency compared to the reference compound hydrocortisone.
It is the object of the present invention is to provide further pharmacologically active benzophenone derivatives which differ structurally from those disclosed in WO 98/32730.
SUMMARY OF THE INVENTION
It has surprisingly been found that novel benzophenone derivatives are potent inhibitors of interleukin 1&bgr; (IL-1&bgr;) and tumour necrosis factor &agr; (TNF-&agr;) secretion in vitro, making them potentially useful for the treatment and/or prevention of inflammatory diseases and other conditions in which the secretion and regulation of cytokines or more specifically interleukin 1&bgr; (IL-1&bgr;) and tumour necrosis factor &agr; (TNF-&agr;) are involved in the pathogenesis. The inhibition or downregulation of the cytokines is possibly due to an inhibition of MAP kinases, more specifically the p38 MAP kinase, a stress-activated protein which is an important element in the signal transduction pathway leading to the production of pro-inflammatory cytokines.
Accordingly, the present invention relates to a compound with the general formula I
wherein R
1
is selected from the group consisting of halogen, haloalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy, mercapto, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, alkylaryl, alkoxy, aralkoxy, alkylthio, alkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy, alkylsulfonyloxy, alkyloxysulfonyl, alkylcarbonylamino, aminocarboaminoalkyl, aminosulfonyl, alkylsulfonylamino, alkanoyl, alkylcarbonyl, —NR
9
R
10
or —CONR
9
R
10
, wherein R
9
and R
10
are the same or different and individually represent hydrogen, alkyl or aryl;
R
2
represents one or more, same or different substituents selected from the group consisting of hydrogen, halogen, haloalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy, mercapto, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, alkylaryl, alkoxy, aralkoxy, alkylthio, alkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy, alkylsulfonyloxy, alkyloxysulfonyl, alkylcarbonylamino, aminocarboaminoalkyl, aminosulfonyl, alkylsulfonylamino, alkanoyl, alkylcarbonyl, —NR
9
R
10
or —CONR
9
R
10
, wherein R
9
and R
10
are the same or different and individually represent hydrogen, alkyl or aryl;
R
3
represents one or more, same or different substituents selected from the group consisting of hydrogen, halogen, haloalkyl, hydroxy, hydroxyalkyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, alkylaryl, alkoxy, aralkoxy, alkylthio, alkoxycarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl —NR
9
R
10
or —CONR
9
R
10
, wherein R
9
and R
10
are the same or different and individually represent hydrogen, alkyl or aryl;
R
4
represents hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl, cycloalkenyl, carboxy or aryl;
R
5
represents a heteroaromatic mono- or bicyclic ring system comprising 1-4 heteroatoms, except for triazine, said ring system being optionally substituted by hydrogen, halogen, haloalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy, mercapto, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, alkylaryl, alkoxy, aralkoxy, alkylthio, alkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy, alkylsulfonyloxy, alkyloxysulfonyl, alkylcarbonylamino, aminocarboaminoalkyl, aminosulfonyl, alkylsulfonylamino, alkanoyl, alkylcarbonyl, —NR
9
R
10
or —CONR
9
R
10
, wherein R
9
and R
10
are the same or different and individually represent hydrogen, alkyl or aryl;
X represents oxygen, sulphur, N—OH or NR
11
wherein R
11
is hydrogen or alkyl;
or pharmaceutically acceptable salts hydrates, solvates or esters thereof as well as N-oxides wherein an N-atom of R
5
is oxidised.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
In the present context, the term “alkyl” is intended to indicate a univalent radical derived from straight or branched alkane by removing a hydrogen atom from any carbon atom. The alkyl chain typically comprises 1-10 carbon atoms, in particular 1-6 carbon atoms. The term includes the subclasses normal alkyl (n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, hexyl and isohexyl.
The term “haloalkyl” is intended to indicate an alkyl radical as defined above substituted by one or more halogens such as chloro, fluoro, bromo or iodo.
The term “hydroxyalkyl” is intended to indicate an alkyl radical as defined above substituted by one or more hydroxy groups.
The term “alkoxy” is intended to indicate a radical of formula OR′, wherein R′ is alkyl as defined above, e.g. methoxy, ethoxy, propoxy, butoxy, etc.
The term “hydroxyalkyloxy” is intended to indicate an alkoxy group as defined above substituted by one or more hydroxy groups.
The term “alkenyl” is intended to indicate a mono-, di-, tri-, tetra- or pentaunsaturated alkane radical typically comprising 2-10 carbon atoms, in particular 2-6 carbon atoms, e.g. ethenyl, propenyl, butenyl, pentenyl or hexenyl. The term “alkynyl” is intended to indicate an alkane radical comprising 1-5 triple C—C bonds, the alkane chain typically comprising 2-10 carbon atoms, in particular 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl or hexynyl.
The term “alkoxycarbonyl” is intended to indicate a radical of formula —COOR′ wherein R′ is alkyl as defined above, e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc.
The term “cycloalkyl” is intended to indicate a saturated cycloalkane radical typically comprising 3-10 carbon atoms, in particular 3-8 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term “cycloalkenyl” is intended to indicate mono-, di- tri- or tetraunsaturated cycloalkane radicals, e.g. cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl. The term “heterocycloalkyl” is intended to indicate a cycloalkane radical as defined above, comprising one or more heteroatoms selected from O, N, or S.
The term “aryl” is intended to include radicals of carbocyclic aromatic rings, in particular 5- or 6-membered rings, optionally fused bicyclic rings, e.g. phenyl or naphthyl. The term “heteroaryl” is intended to include radicals of heterocyclic aromatic rings, in particular 5- or 6-membered rings with 1-4 heteroatoms selected from O, S and N, or optionally fused bicyclic rings with 1-4

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