US 6,022,884 AGranted

Substituted pyridine compounds and methods of use

AssigneeAmgen Inc.

InventorsNathan B. Mantlo, Stephen T. Schlachter, John A. Josey

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Abstract

Selected novel substituted pyridine compounds are effective for prophylaxis and treatment of diseases, such as TNF-.alpha., IL-1.beta., IL-6 and/or IL-8 mediated diseases, and other maladies, such as pain and diabetes. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving inflammation, pain, diabetes, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Claims18

Dependent claims

A compound of the formula ##STR29## or a pharmaceutically acceptable salt thereof, wherein X is O, S, S(O), S(O).sub.2 or NR.sup.2 ;

Y is --C(O)--NR.sup.3 R.sup.4 or --NR.sup.4 --C(O)--R.sup.3 ;
R.sup.1 is a cycloalkyl or aryl radical which is optionally substituted by 1-4 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 -alkyl;
provided that the total number of aryl and cycloalkyl radicals in R.sup.1 is 1-3;
R.sup.2 is a hydrogen or alkyl radical;
R.sup.3 is an aryl radical which is optionally substituted by 1-5 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R.sup.19 --Z.sup.19 -- or R.sup.19 --Z.sup.19 -alkyl;
provided that the total number of aryl radicals in R.sup.3 is 1-3;
and provided when Y is --C(O)--NR.sup.3 R.sup.4, then R.sup.3 is other than an optionally substituted phenyl or naphthyl having an amino, nitro, cyano or --CO.sub.2 R.sup.19 substituent bonded to the ring carbon atom adjacent to the ring carbon atom bonded to --NR.sup.4 --;
when Y is --NR.sup.4 --C(O)--R.sup.3 and X is O or S, then R.sup.3 is other than an optionally substituted 2-hydroxyphenyl or 2-(alkylcarbonyloxy)phenyl radical;
and when R.sup.4 is a hydrogen radical and X is O or S, then R.sup.3 is other than a tert-butylphenyl radical;
R.sup.4 is a hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or R.sup.20 --Z.sup.20 -alkyl radical;
wherein R.sup.18, R.sup.19 and R.sup.20 are each independently a hydrogen, alkyl, haloalkyl, aryl or arylalkyl radical;
wherein the aryl radicals of R.sup.4, R.sup.18, R.sup.19 and R.sup.20 are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
and
Z.sup.18, Z.sup.19 and Z.sup.20 are each independently --O--, --S--, --S(O)--, --S(O).sub.2 --, --CO.sub.2 --, --C(O)--, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --;
wherein each R.sup.21 is independently a hydrogen or alkyl radical;
R.sup.5 and R.sup.6 are each independently a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;
and
R.sup.7 is a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;
provided when Y is --C(O)--NR.sup.3 R.sup.4 and X is O or S, then R.sup.7 is other than an aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;
and
wherein cycloalkyl is a monocyclic, bicyclic or tricyclic carbocyclic alkyl radical of 5-12 ring members, which is optionally partially unsaturated or benzo fused;
and aryl is a phenyl or biphenyl radical which is optionally benzo fused.

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Dependencies are inferred from the claim text.

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Abstract

A compound of the formula ##STR29## or a pharmaceutically acceptable salt thereof, wherein X is O, S, S(O), S(O).sub.2 or NR.sup.2 ;

Y is --C(O)--NR.sup.3 R.sup.4 or --NR.sup.4 --C(O)--R.sup.3 ;
R.sup.1 is a cycloalkyl or aryl radical which is optionally substituted by 1-4 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 -alkyl;
provided that the total number of aryl and cycloalkyl radicals in R.sup.1 is 1-3;
R.sup.2 is a hydrogen or alkyl radical;
R.sup.3 is an aryl radical which is optionally substituted by 1-5 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R.sup.19 --Z.sup.19 -- or R.sup.19 --Z.sup.19 -alkyl;
provided that the total number of aryl radicals in R.sup.3 is 1-3;
and provided when Y is --C(O)--NR.sup.3 R.sup.4, then R.sup.3 is other than an optionally substituted phenyl or naphthyl having an amino, nitro, cyano or --CO.sub.2 R.sup.19 substituent bonded to the ring carbon atom adjacent to the ring carbon atom bonded to --NR.sup.4 --;
when Y is --NR.sup.4 --C(O)--R.sup.3 and X is O or S, then R.sup.3 is other than an optionally substituted 2-hydroxyphenyl or 2-(alkylcarbonyloxy)phenyl radical;
and when R.sup.4 is a hydrogen radical and X is O or S, then R.sup.3 is other than a tert-butylphenyl radical;
R.sup.4 is a hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or R.sup.20 --Z.sup.20 -alkyl radical;
wherein R.sup.18, R.sup.19 and R.sup.20 are each independently a hydrogen, alkyl, haloalkyl, aryl or arylalkyl radical;
wherein the aryl radicals of R.sup.4, R.sup.18, R.sup.19 and R.sup.20 are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
and
Z.sup.18, Z.sup.19 and Z.sup.20 are each independently --O--, --S--, --S(O)--, --S(O).sub.2 --, --CO.sub.2 --, --C(O)--, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --;
wherein each R.sup.21 is independently a hydrogen or alkyl radical;
R.sup.5 and R.sup.6 are each independently a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;
and
R.sup.7 is a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;
provided when Y is --C(O)--NR.sup.3 R.sup.4 and X is O or S, then R.sup.7 is other than an aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;
and
wherein cycloalkyl is a monocyclic, bicyclic or tricyclic carbocyclic alkyl radical of 5-12 ring members, which is optionally partially unsaturated or benzo fused;
and aryl is a phenyl or biphenyl radical which is optionally benzo fused.

19 more elements