Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-29
2001-10-09
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...
C514S202000, C546S255000, C546S256000, C546S210000, C546S193000
Reexamination Certificate
active
06300347
ABSTRACT:
This Application is a 371 of Application No. PCT/EP98/03930, filed Jun. 26, 1998.
This invention relates to 2-substituted 4,5-diaryl imidazoles and to their use for treatin TNF&agr; and IL-1 mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis.
Accordingly the present invention provides novel 2-substituted 4,5-diaryl imidazoles in which:
i) the nitrogen atom at the 1 position is substituted by a trialkylsilyl-containing substituent, or
ii) the substituent at the 2 position is arylalkyl, arylsulfonyl, aryithio aryiseleno, aryltelluro, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyly, amino or hydrazino, or mono- or bicyclic N-heterocyclyl in which the N containing ring has six ring members, provided that the substituent at the 2 position is not piperidin-4-yl, 1-carboxylic-acid-tert-butyl-ester-4-benzyl-piperidin-4-yl, 1,4-dimethyl-piperidin-4-yl, 4-benzyl-piperidin-4-yl, or piperidinyl which is further substituted only at the N atom, and further provided that neither of the 4- or 5-aryl substituents is phenyl substituted with a radical selected from alkyisulfonyl or aminosulfonyl.
and pharmaceutically-acceptable acid addition salts thereof and physiologically-cleavable esters thereof.
The 4- or 5-aryl substituent may be any of those known in the art; for instance, as described in WO 95/03297 and WO 97/12876. For example, the 4- and 5-aryl substituents may be as hereinafter defined for R
1
and R
2
of formula I and include heteroaryl substituents.
When the nitrogen atom at the 1 position is substituted by a trialkylsiyl-containing substituent, the substituent is suitably a trialkylsilylalkoxyalkyl substituent.
When the substituent at the 2 position is arylalkyl, it is conveniently phenylalkyl.
When the substituent at the 2 position is arylalkyl, arylsulfonyl, arylthio arylseleno, aryltelluro, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, amino or hydrazino, or mono- or bicyclic N-heterocyclyl, it may be further substituted, e.g. by up to 6 substituents selected from halo, OH, C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, C
1-4
thioalkoxy, nitro, amino, C
1-4
alkylsulphinyl, C
1-4
alkylsulphonyl, carboxylate or ester.
Above and elsewhere in the present description the terms halo or halogen denote I, Br, Cl or F, preferably F.
In particular embodiments the invention provides a compound of formula I
wherein
R
1
is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolyl, 1-imidazolyl or 1-benzamidazolyl, which is optionally substituted with one or two substituents each of which is independently selected from
C
1-4
alkyl, halogen, C
1-4
alkoxy, C
1-4
alkylthio, NR
5
R
6
, or an N-heterocyclyl ring having 5 to 7 ring atoms and optionally containing an additional heteroatom selected from O, S, or N
wherein R
5
and R
6
is each independently C
1-4
alkyl;
R
2
is phenyl, naphth-1-yl or naphth-2-yl which is optionally substituted by up to 5 substituents;
R
3
is hydrogen,
heterocyclyl,
heterocyclylC
1-10
alkyl,
triC
1-4
alkylsilylC
1-10
alkoxyC
1-4
alkyl,
optionally halo substituted C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-10
alkyl, C
5-7
cycloalkenyl, aryl, arylC
1-10
alkyl, heteroaryl, or heteroarylC
1-10
alkyl,
optionally mono- or di-C
1-4
alkyl-substitutedC
0-10
alkyl-oxycarbonyl or -oxythiocarbonyl optionally substituted by C
1-10
alkyl, C
3-7
cycloalkyl, heterocyclyl, heterocyclylC
1-10
alkyl, aryl, arylC
1-10
alkyl, heteroaryl, heteroarylC
1-10
alkyl, or
mono- or di-C
1-4
alkyl-substitutedC
1-10
alkyl optionally substituted by
cyano,
nitro,
hydroxy, C
1-10
alkoxy, C
3-7
cycloalkoxy, heterocycloxy,
heterocyclylC
1-10
alkoxy, aryloxy, arylC
1-10
alkoxy, heteroaryloxy,
heteroarylC
1-10
alkoxy,
optionally substituted amino, carboxylate, thiocarboxylate,
carbonyl or thiocarbonyl, sulphinyl or suiphonyl,
R
4
is mono- or di-C
3-7
cycloalkyl-C
0-4
alkyl optionally substituted by -halo, —OH, —C
1-4
alky, —C
1-4
alkoxy, —C
1-4
thioalkoxy, -nitro, -amino, —C
1-4
alkylsulphinyl, —C
1-4
alkylsulphonyl, -carboxylate or -ester,
—NR
7
R
8
, NHNHR
9
,
wherein independently each R
7
, R
8
or R
9
, is C
1-4
alkyl, C
2-4
alkenyl, C
2-6
alkynyl,
—X—C
5-10
aryl (including heteroaryl)
wherein X is S, SO
2
, Se, Te or C
1-4
alkyl,
mono- or bicyclic N-heterocyclyl in which the N containing ring has six ring members,
or aryl or heteroaryl optionally substituted by up to 4 substituents, provided that
when R
3
is not triC
1-4
alkylsilylC
1-10
alkoxyC
1-4
alkyl,
R
4
is not aryl or heteroaryl optionally substituted by up to 3 substituents, except when R
4
is mono- or bicyclic N-heterocyclyl in which the N containing ring has six ring members,
further provided that
R
4
is not piperidin-4-yl, 1-carboxylic-acid-tert-butyl-ester-4-benzyl-piperidin-4-yl, 1,4-dimethyl-piperidin-4-yl, 4-benzyl-piperidin-4-yl, or piperidinyl which is further substituted only at the N atom, and
yet further provided that R
2
is not phenyl substituted with a radical selected from alkylsulfonyl or aminosulfonyl,
and pharmaceutically-acceptable acid addition salts thereof and physiologically-cleavable esters thereof.
R
2
is substituted by up to 5 substituents which may be any of the substituents known in the art; for instance, as described for R
4
in WO 95/03297 and the substituent R of WO 97/12876.
When R
4
is —X—C
5-10
aryl, the C
5-10
aryl or X, when it is C
1-4
alkyl, may be substituted by up to 6 substituents selected from halo, OH, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
thioalkoxy, nitro, amino, C
1-4
alkylsulphinyl, C
1-4
alkylsulphonyl, carboxylate or ester.
When R
4
is mono- or bicyclic N,-heterocyclyl in which the N containing ring has six ring members, it may be saturated or unsaturated, e.g. aromatic, heterocyclyl.
When R
4
is aryl or heteroaryl optionally substituted by up to 4 substituents, R
4
may comprise one of the customary aryl or heteroaryl substituents used in the art; for instance as defined for the substituent R
3
of WO 93/03297.
Imidazoles with a 2-substituent, e.g. R
4
as defined above, and with also aryl substituents at both positions 4 and 5, e.g. as defined for R
1
and R
2
above, in which the nitrogen atom at the 1 position is substituted by a trialkylsilyl-containing substituent are entirely novel.
Accordingly in a further aspect the invention provides a compound of formula I′
wherein
R
3
′ is triC
1-4
alkylsilylC
1-10
alkoxyC
1-4
alkyl, and R
1
, R
2
and R
4
are as defined above, and pharmaceutically-acceptable acid addition salts thereof and physiologically-cleavable esters thereof.
Compounds of formula I′ in which R
4
is H and R
2
, R
3
′ and R
4
as defined above are key intermediates for the synthesis of other compounds of formula I in which R
3
is not triC
1-4
alkylsilylC
1-10
alkoxyC
1-4
alkyl, as hereinafter described.
The substituents R
1
, R
2
, R
3
, R
3
′ and R
4
′ independently have the following preferred significances.
Preferably R
1
is 4-pyridyl or pyrimidinyl, especially 4-pyridyl.
R
2
is preferably phenyl, including substituted phenyl.
Most preferably R
3
′ is trimethylsilylethoxymethyl.
When R
3
is triC
1-4
alkylsilylC
1-10
alkoxyC
1-4
alkyl, R
1
is preferably 4-pyridyl.
When R
3
is triC
1-4
alkylsilylC
1-10
alkoxyC
1-4
alkyl, R
2
is preferably 4-fluorophenyl.
When R
3
is triC
1-4
alkylsilylC
1-10
alkoxyC
1-4
alkyl, R
4
is preferably H.
In a further preferred aspect of the invention R
4
is —X—C
5-10
aryl, preferably —X—phenyl, wherein X is as previously defined, e.g. a compound of formula III
wherein R
1
, R
2
, R
3
and X are as defined above and R
11
represent from 1-4, substituents independently selected from H, halo, OH, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
thioalkoxy, nitro, amino, C
1-4
alkylsulphinyl, C
1-4
alkylsulphonyl, carboxylate or ester, and pharmaceutically-acceptable acid addition salts thereof and physiologically-cleavable esters thereof.
In a yet further preferred aspect of the invention R
4
is cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalk
Desai Rita
Loeschorn Carol
Novartis AG
Rotman Alan L.
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