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US 5,593,994 AGranted
Prostaglandin synthase inhibitors
AssigneeThe DuPont Merck Pharmaceutical Company
InventorsDouglas G. Batt, Donald J. P. Pinto, Michael J. Orwat, Joseph J. Petraitis, William J. Pitts
Life of this patent
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Abstract
This invention relates to ortho substituted phenyl compounds as inhibitors of prostaglandin synthase, to pharmaceutical compositions comprising such compounds and to methods of using such compounds as antiinflammatory and antipyretic agents. The class of compounds useful in this method of treatment is represented by Formula I below: ##STR1##
Claims13
A pharmaceutical composition comprising an antiinflammatory amount of a compound of Formula I:
- ##STR30## or a pharmaceutically acceptable salt or prodrug form thereof, wherein:
- J, K, and L are independently CR.sup.3, CR.sup.4 or N;
- X is a single bond, --(CHR.sup.5).sub.2 --, --CH.dbd.CR.sup.5 --, --CR.sup.5 .tbd.CH--, --C.tbd.C--, --(CHR.sup.5).sub.p Z--, --Z(CHR.sup.5).sub.p --, --C(.dbd.O)CH.sub.2, or --CH.sub.2 C(.dbd.O)--;
- Z is O or S;
- R.sup.1 is:
- phenyl substituted with 0-2 R.sup.7,
- 2-naphthyl substituted with 0-2 R.sup.7,
- C.sub.5 -C.sub.7 cycloalkyl substituted with 0-1 R.sup.9,
- C.sub.5 -C.sub.7 cycloalkenyl, provided that when R.sup.1 is attached directly to a heteroatom, said heteroatom is not attached to a carbon bearing a double bond in the cycloalkene ring,
- a 5- to 10-membered heterocyclic ring system selected from furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, 3-pyridinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzoisothiazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, or piperidinyl, said heterocyclic ring system being substituted with 0-2 R.sup.7 ;
- R.sup.2 is:
- ##STR31## Y is --CH.sub.3 or NH.sub.2 ;
- R.sup.3 is:
- H, F, Br, Cl, I, CN, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.12, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkenyl substituted with 0-1 R.sup.13, NO.sub.2, NR.sup.15 R.sup.16, S(O).sub.m R.sup.11, SO.sub.2 NR.sup.15a R.sup.16, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15a R.sup.16, or OR.sup.18 ;
- R.sup.4 is H, F, Br, Cl, I, C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2 alkoxy, C.sub.1 -C.sub.2 haloalkyl, --CF.sub.3, --SR.sup.10a, or
- alternately, when R.sup.3 and R.sup.4 are substituents on adjacent carbon atoms, R.sup.3 and R.sup.4 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or heterocyclic ring system, said heterocyclic ring system containing from 1-3 heteroatoms selected from N, O or S;
- R.sup.5 is C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2 alkoxy, or C.sub.1 -C.sub.2 haloalkyl;
- R.sup.6 is
- hydrogen,
- C.sub.1 -C.sub.6 alkyl substituted with 0-1 R.sup.14,
- phenyl substituted with 0-2 R.sup.9,
- C.sub.5 -C.sub.7 cycloalkyl substituted with 0-1 R.sup.9,
- a 5- to 10-membered heterocyclic ring system selected from furyl, thienyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, said heterocyclic ring system being substituted with 0-2 R.sup.7 ;
- R.sup.7 is a substituent on carbon that is selected from:
- H, F, Br, Cl, I, C.sub.1 -C.sub.4 alkyl, phenyl, CH.sub.2 OH, CH.sub.2 OCH.sub.3, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 haloalkyl, --SR.sup.10, NR.sup.15 R.sup.16, --C(.dbd.O)R.sup.10, CH.sub.2 COOR.sup.17, or OR.sup.19 ;
- provided that when X is a single bond then R.sup.7 is not ortho to X;
- R.sup.8 is H, F, Br, Cl, I, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --(CH.sub.2).sub.n COOR.sup.17, or --CH.dbd.CHCOOR.sup.17 ;
- R.sup.9 is H, F, Br, Cl, I, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.10 is H or C.sub.1 -C.sub.4 alkyl;
- R.sup.10a is C.sub.1 -C.sub.4 alkyl;
- R.sup.11 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.2 fluoroalkyl, phenyl, or benzyl;
- R.sup.12 is F, OR.sup.18, NR.sup.15 R.sup.16, phenyl substituted with 0-2 R.sup.9, --CN, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15 R.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, pyridinyl, piperidazinyl, pyrimidinyl, pyrazinyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- R.sup.13 is --CN, --C(.dbd.O)R.sup.6, --COOR.sup.17, --NO.sub.2, or NR.sup.15 R.sup.16 ;
- R.sup.14 is F, OH, C.sub.1 -C.sub.4 alkoxy, NH.sub.2, phenyl substituted with 0-2 R.sup.9, alkylcarbonyl, arylcarbonyl, --COOR.sup.17, or --C(.dbd.O)NH.sub.2 ;
- R.sup.15 is H, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.23, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.7 -C.sub.14 arylalkoxycarbonyl, C.sub.6 -C.sub.10 aryloxycarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.6 -C.sub.10 arylcarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl, C.sub.6 -C.sub.10 arylsulfonyl, C.sub.7 -C.sub.14 alkylarylsulfonyl, C.sub.7 -C.sub.14 arylalkylsulfonyl;
- R.sup.15a is H, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.23, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy;
- R.sup.16 is H, or C.sub.1 -C.sub.4 alkyl;
- alternately, R.sup.15 and R.sup.16 can be taken together to be --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --, or --(CH.sub.2).sub.2 NR.sup.21 (CH.sub.2).sub.2 --,
- R.sup.17 is C.sub.1 -C.sub.4 alkyl, or arylalkyl;
- R.sup.18 is C.sub.1 -C.sub.4 alkyl substituted with 0-2 R.sup.24, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.7 -C.sub.14 arylalkylcarbonyl, or C.sub.6 -C.sub.10 arylcarbonyl substituted with 0-2 R.sup.9 ;
- R.sup.19 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxyalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.7 -C.sub.14 arylalkylcarbonyl, or C.sub.6 -C.sub.10 arylcarbonyl substituted with 0-2 R.sup.9 ;
- R.sup.21 is C.sub.1 -C.sub.4 alkyl or benzyl;
- R.sup.23 is H, F, phenyl substituted with 0-2 R.sup.9, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NHR.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- R.sup.24 is H, F, NR.sup.15 R.sup.16, phenyl substituted with 0-2 R.sup.9, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15 R.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, piperidinyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- m is 0-2;
- p is 0-1;
- provided that when J and L are both nitrogen and K is CR.sup.4, then R.sup.4 cannot be SR.sup.10 ;
- and
- a pharmaceutically acceptable carrier.
49 more elements
A method of inhibiting prostaglandin H synthase in a mammal comprising administering to the mammal an effective amount of a compound of Formula I:
- ##STR33## or a pharmaceutically acceptable salt or prodrug form thereof, wherein:
- J, K, and L are independently CR.sup.3, CR.sup.4 or N;
- X is a single bond, (i.e. X is absent), --(CHR.sup.5).sub.2 --, --CH.dbd.CR.sup.5 --, --CR.sup.5 .dbd.CH--, --C.tbd.C--, --(CHR.sup.5).sub.p Z--, --Z (CHR.sup.5).sub.p --, --C(.dbd.O)CH.sub.2, or --CH.sub.2 C(.dbd.O)--;
- Z is O or S;
- R.sup.1 is:
- phenyl substituted with 0-2 R.sup.7,
- 2-naphthyl substituted with 0-2 R.sup.7,
- C.sub.5 -C.sub.7 cycloalkyl substituted with 0-1 R.sup.9,
- C.sub.5 -C.sub.7 cycloalkenyl, provided that when R.sup.1 is attached directly to a heteroatom, said heteroatom is not attached to a carbon bearing a double bond in the cycloalkene ring,
- a 5- to 10-membered heterocyclic ring system selected from furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, 3-pyridinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzoisothiazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, or piperidinyl, said heterocyclic ring system being substituted with 0-2 R.sup.7 ;
- R.sup.2 is:
- ##STR34## Y is --CH.sub.3 or NH.sub.2 ;
- R.sup.3 is:
- H, F, Br, Cl, I, CN, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.12, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkenyl substituted with 0-1 R.sup.13, NO.sub.2, NR.sup.15 R.sup.16, S(O).sub.m R.sup.11, SO.sub.2 NR.sup.15a R.sup.16, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15a R.sup.16, or OR.sup.18 ;
- R.sup.4 is H, F, Br, Cl, I, C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2 alkoxy, C.sub.1 -C.sub.2 haloalkyl, --CF.sub.3, --SR.sup.10a, or
- alternately, when R.sup.3 and R.sup.4 are substituents on adjacent carbon atoms, R.sup.3 and R.sup.4 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or heterocyclic ring system, said heterocyclic ring system containing from 1-3 heteroatoms selected from N, O or S;
- R.sup.5 is C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2 alkoxy, or C.sub.1 -C.sub.2 haloalkyl;
- R.sup.6 is
- hydrogen,
- C.sub.1 -C.sub.6 alkyl substituted with 0-1 R.sup.14,
- phenyl substituted with 0-2 R.sup.9,
- C.sub.5 -C.sub.7 cycloalkyl substituted with 0-1 R.sup.9,
- a 5- to 10-membered heterocyclic ring system selected from furyl, thienyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, said heterocyclic ring system being substituted with 0-2 R.sup.7 ;
- R.sup.7 is a substituent on carbon that is selected from:
- H, F, Br, Cl, I, C.sub.1 -C.sub.4 alkyl, phenyl, CH.sub.2 OH, CH.sub.2 OCH.sub.3, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 haloalkyl, --SR.sup.10, NR.sup.15 R.sup.16, --C(.dbd.O)R.sup.10, CH.sub.2 COOR.sup.17, or OR.sup.19 ;
- provided that when X is a single bond then R.sup.7 is not ortho to X;
- R.sup.8 is H, F, Br, Cl, I, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --(CH.sub.2).sub.n COOR.sup.17, or --CH.dbd.CHCOOR.sup.17 ;
- R.sup.9 is H, F, Br, Cl, I, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.10 is H or C.sub.1 -C.sub.4 alkyl;
- R.sup.10a is C.sub.1 -C.sub.4 alkyl;
- R.sup.11 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.2 fluoroalkyl, phenyl, or benzyl;
- R.sup.12 is F, OR.sup.18, NR.sup.15 R.sup.16, phenyl substituted with 0-2 R.sup.9, --CN, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15 R.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, pyridinyl, piperidazinyl, pyrimidinyl, pyrazinyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- R.sup.13 is --CN, --C(.dbd.O)R.sup.6, --COOR.sup.17, --NO.sub.2, or NR.sup.15 R.sup.16 ;
- R.sup.14 is F, OH, C.sub.1 -C.sub.4 alkoxy, NH.sub.2, phenyl substituted with 0-2 R.sup.9, alkylcarbonyl, arylcarbonyl, --COOR.sup.17, or --C(.dbd.O)NH.sub.2 ;
- R.sup.15 is H, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.23, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.7 -C.sub.14 arylalkoxycarbonyl, C.sub.6 -C.sub.10 aryloxycarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.6 -C.sub.10 arylcarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl, C.sub.6 -C.sub.10 arylsulfonyl, C.sub.7 -C.sub.14 alkylarylsulfonyl, C.sub.7 -C.sub.14 arylalkylsulfonyl;
- R.sup.15a is H, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.23, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy;
- R.sup.16 is H, or C.sub.1 -C.sub.4 alkyl;
- alternately, R.sup.15 and R.sup.16 can be taken together to be --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --, or --(CH.sub.2).sub.2 NR.sup.21 (CH.sub.2).sub.2 --,
- R.sup.17 is C.sub.1 -C.sub.4 alkyl, or arylalkyl;
- R.sup.18 is C.sub.1 -C.sub.4 alkyl substituted with 0-2 R.sup.24, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.7 -C.sub.14 arylalkylcarbonyl, or C.sub.6 -C.sub.10 arylcarbonyl substituted with 0-2 R.sup.9 ;
- R.sup.19 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxyalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.7 -C.sub.14 arylalkylcarbonyl, or C.sub.6 -C.sub.10 arylcarbonyl substituted with 0-2 R.sup.9 ;
- R.sup.21 is C.sub.1 -C.sub.4 alkyl or benzyl;
- R.sup.23 is H, F, phenyl substituted with 0-2 R.sup.9, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NHR.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- R.sup.24 is H, F, NR.sup.15 R.sup.16, phenyl substituted with 0-2 R.sup.9, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15 R.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, piperidinyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- m is 0-2;
- p is 0-1;
- provided that when J and L are both nitrogen and K is CR.sup.4, then R.sup.4 cannot be SR.sup.10.
47 more elements
A method of treating an inflammatory disease in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of Formula I:
- ##STR35## or a pharmaceutically acceptable salt or prodrug form thereof, wherein:
- J, K, and L are independently CR.sup.3, CR.sup.4 or N;
- X is a single bond, (i.e. X is absent), --(CHR.sup.5).sub.2 --, --CH.dbd.CR.sup.5 --, --CR.sup.5 .dbd.CH--, --C.tbd.C--, --(CHR.sup.5).sub.p Z--, --Z(CHR.sup.5).sub.p --, --C(.dbd.O)CH.sub.2, or --CH.sub.2 C(.dbd.O)--;
- Z is O or S;
- R.sup.1 is:
- phenyl substituted with 0-2 R.sup.7,
- 2-naphthyl substituted with 0-2 R.sup.7,
- C.sub.5 -C.sub.7 cycloalkyl substituted with 0-1 R.sup.9,
- C.sub.5 -C.sub.7 cycloalkenyl, provided that when R.sup.1 is attached directly to a heteroatom, said heteroatom is not attached to a carbon bearing a double bond in the cycloalkene ring,
- a 5- to 10-membered heterocyclic ring system selected from furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, 3-pyridinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzoisothiazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, or piperidinyl, said heterocyclic ring system being substituted with 0-2 R.sup.7 ;
- R.sup.2 is:
- ##STR36## Y is --CH.sub.3 or NH.sub.2 ;
- R.sup.3 is:
- H, F, Br, Cl, I, CN, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.12, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkenyl substituted with 0-1 R.sup.13, NO.sub.2, NR.sup.15 R.sup.16, S(O).sub.m R.sup.11, SO.sub.2 NR.sup.15a R.sup.16, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15a R.sup.16, or OR.sup.18 ;
- R.sup.4 is H, F, Br, Cl, I, C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2 alkoxy, C.sub.1 -C.sub.2 haloalkyl, --CF.sub.3, --SR.sup.10a, or
- alternately, when R.sup.3 and R.sup.4 are substituents on adjacent carbon atoms, R.sup.3 and R.sup.4 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or heterocyclic ring system, said heterocyclic ring system containing from 1-3 heteroatoms selected from N, O or S;
- R.sup.5 is C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2 alkoxy, or C.sub.1 -C.sub.2 haloalkyl;
- R.sup.6 is
- hydrogen,
- C.sub.1 -C.sub.6 alkyl substituted with 0-1 R.sup.14,
- phenyl substituted with 0-2 R.sup.9,
- C.sub.5 -C.sub.7 cycloalkyl substituted with 0-1 R.sup.9,
- a 5- to 10-membered heterocyclic ring system selected from furyl, thienyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, said heterocyclic ring system being substituted with 0-2 R.sup.7 ;
- R.sup.7 is a substituent on carbon that is selected from:
- H, F, Br, Cl, I, C.sub.1`-C.sub.4 alkyl, phenyl, CH.sub.2 OH, CH.sub.2 OCH.sub.3, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 haloalkyl, --SR.sup.10, NR.sup.15 R.sup.16, --C(.dbd.O)R.sup.10, CH.sub.2 COOR.sup.17, OR.sup.19 ;
- provided that when X is a single bond then R.sup.7 is not ortho to X;
- R.sup.8 is H, F, Br, Cl, I, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --(CH.sub.2).sub.n COOR.sup.17, or --CH.dbd.CHCOOR.sup.17 ;
- R.sup.9 is H, F, Br, Cl, I, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.10 is H or C.sub.1 -C.sub.4 alkyl;
- R.sup.10a is C.sub.1 -C.sub.4 alkyl;
- R.sup.11 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.2 fluoroalkyl, phenyl, or benzyl;
- R.sup.12 is F, OR.sup.18, NR.sup.15 R.sup.16, phenyl substituted with 0-2 R.sup.9, --CN, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15 R.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, pyridinyl, piperidazinyl, pyrimidinyl, pyrazinyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- R.sup.13 is --CN, --C(.dbd.O)R.sup.6, --COOR.sup.17, --NO.sub.2, or NR.sup.15 R.sup.16 ;
- R.sup.14 is F, OH, C.sub.1 -C.sub.4 alkoxy, NH.sub.2, phenyl substituted with 0-2 R.sup.9, alkylcarbonyl, arylcarbonyl, --COOR.sup.17, or --C(.dbd.O)NH.sub.2 ;
- R.sup.15 is H, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.23, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.7 -C.sub.14 arylalkoxycarbonyl, C.sub.6 -C.sub.10 aryloxycarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.6 -C.sub.10 arylcarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl, C.sub.6 -C.sub.10 arylsulfonyl, C.sub.7 -C.sub.14 alkylarylsulfonyl, C.sub.7 -C.sub.14 arylalkylsulfonyl;
- R.sup.15a is H, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.23, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy;
- R.sup.16 is H, or C.sub.1 -C.sub.4 alkyl;
- alternately, R.sup.15 and R.sup.16 can be taken together to be --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --, or --(CH.sub.2).sub.2 NR.sup.21 (CH.sub.2).sub.2 --,
- R.sup.17 is C.sub.1 -C.sub.4 alkyl, or arylalkyl;
- R.sup.18 is C.sub.1 -C.sub.4 alkyl substituted with 0-2 R.sup.24, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.7 -C.sub.14 arylalkylcarbonyl, or C.sub.6 -C.sub.10 arylcarbonyl substituted with 0-2 R.sup.9 ;
- R.sup.19 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxyalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.7 -C.sub.14 arylalkylcarbonyl, or C.sub.6 -C.sub.10 arylcarbonyl substituted with 0-2 R.sup.9 ;
- R.sup.21 is C.sub.1 -C.sub.4 alkyl or benzyl;
- R.sup.23 is H, F, phenyl substituted with 0-2 R.sup.9, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NHR.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- R.sup.24 is H, F, NR.sup.15 R.sup.16, phenyl substituted with 0-2 R.sup.9, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15 R.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, piperidinyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- m is 0-2;
- p is 0-1;
- provided that when J and L are both nitrogen and K is CR.sup.4 then R.sup.4 cannot be SR.sup.10.
47 more elements
A method of treating pyresis in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of Formula I:
- ##STR37## or a pharmaceutically acceptable salt or prodrug form thereof, wherein:
- J, K, and L are independently CR.sup.3, CR.sup.4 or N;
- X is a single bond, (i.e. X is absent), --(CHR.sup.5).sub.2 --, --CH.dbd.CR.sup.5 --, --CR.sup.5 .dbd.CH--, --C.tbd.C--, --(CHR.sup.5).sub.p Z--, --Z(CHR.sup.5).sub.p --, --C(.dbd.O)CH.sub.2, or --CH.sub.2 C(.dbd.O)--;
- Z is O or S;
- R.sup.1 is:
- phenyl substituted with 0-2 R.sup.7,
- 2-naphthyl substituted with 0-2 R.sup.7,
- C.sub.5 -C.sub.7 cycloalkyl substituted with 0-1 R.sup.9,
- C.sub.5 -C.sub.7 cycloalkenyl, provided that when R.sup.1 is attached directly to a heteroatom, said heteroatom is not attached to a carbon bearing a double bond in the cycloalkene ring,
- a 5- to 10-membered heterocyclic ring system selected from furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, 3-pyridinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzoisothiazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, or piperidinyl, said heterocyclic ring system being substituted with 0-2 R.sup.7 ;
- R.sup.2 is:
- ##STR38## Y is --CH.sub.3 or NH.sup.2 ;
- R.sup.3 is:
- H, F, Br, Cl, I, CN, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.12, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkenyl substituted with 0-1 R.sup.13, NO.sub.2, NR.sup.15 R.sup.16, S(O).sub.m R.sup.11, SO.sub.2 NR.sup.15a R.sup.16, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15a R.sup.16, or OR.sup.18 ;
- R.sup.4 is H, F, Br, Cl, I, C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2 alkoxy, C.sub.1 -C.sub.2 haloalkyl, --CF.sub.3, --SR.sup.10a, or
- alternately, when R.sup.3 and R.sup.4 are substituents on adjacent carbon atoms, R.sup.3 and R.sup.4 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or heterocyclic ring system, said heterocyclic ring system containing from 1-3 heteroatoms selected from N, O or S;
- R.sup.5 is C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2 alkoxy, or C.sub.1 -C.sub.2 haloalkyl;
- R.sup.6 is
- hydrogen,
- C.sub.1 -C.sub.6 alkyl substituted with 0-1 R.sup.14,
- phenyl substituted with 0-2 R.sup.9,
- C.sub.5 -C.sub.7 cycloalkyl substituted with 0-1 R.sup.9,
- a 5- to 10-membered heterocyclic ring system selected from furyl, thienyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, said heterocyclic ring system being substituted with 0-2 R.sup.7 ;
- R.sup.7 is a substituent on carbon that is selected from:
- H, F, Br, Cl, I, C.sub.1 -C.sub.4 alkyl, phenyl, CH.sub.2 OH, CH.sub.2 OCH.sub.3, C.sub.1 -C.sub.4 alkyoxy, C.sub.1 -C.sub.4 haloalkyl, --SR.sup.10, NR.sup.15 R.sup.16, --C(.dbd.O)R.sup.10, CH.sub.2 COOR.sup.17, or OR.sup.19 ;
- provided that when X is a single bond then R.sup.7 is not ortho to X;
- R.sup.8 is H, F, Br, Cl, I, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --(CH.sub.2).sub.n COOR.sup.17, or --CH.dbd.CHCOOR.sup.17 ;
- R.sup.9 is H, F, Br, Cl, I, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.10 is H or C.sub.1 -C.sub.4 alkyl;
- R.sup.10a is C.sub.1 -C.sub.4 alkyl;
- R.sup.11 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.2 fluoroalkyl, phenyl, or benzyl;
- R.sup.12 is F, OR.sup.18, NR.sup.15 R.sup.16, phenyl substituted with 0-2 R.sup.9, --CN, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15 R.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, pyridinyl, piperidazinyl, pyrimidinyl, pyrazinyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- R.sup.13 is --CN, --C(.dbd.O)R.sup.6, --COOR.sup.17, --NO.sup.2, or NR.sup.15 R.sup.16 ;
- R.sup.14 is F, OH, C.sub.1 -C.sub.4 alkoxy, NH.sub.2, phenyl substituted with 0-2 R.sup.9, alkylcarbonyl, arylcarbonyl, --COOR.sup.17, or --C(.dbd.O)NH.sup.2 ;
- R.sup.15 is H, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.23, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.7 -C.sub.14 arylalkoxycarbonyl, C.sub.6 -C.sub.10 aryloxycarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.6 -C.sub.10 arylcarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl, C.sub.6 -C.sub.10 arylsulfonyl, C.sub.7 -C.sub.14 alkylarylsulfonyl, C.sub.7 -C.sub.14 arylalkylsulfonyl;
- R.sup.15a is H, C.sub.1 -C.sub.4 alkyl substituted with 0-1 R.sup.23, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy;
- R.sup.16 is H, or C.sub.1 -C.sub.4 alkyl;
- alternately, R.sup.15 and R.sup.16 can be taken together to be --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --, or --(CH.sub.2).sub.2 NR.sup.21 (CH.sub.2).sub.2 --,
- R.sup.17 is C.sub.1 -C.sub.4 alkyl, or arylalkyl;
- R.sup.18 is C.sub.1 -C.sub.4 alkyl substituted with 0-2 R.sup.24, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.7 -C.sub.14 arylalkylcarbonyl, or C.sub.6 -C.sub.10 arylcarbonyl substituted with 0-2 R.sup.9 ;
- R.sup.19 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxyalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylaminocarbonyl, C.sub.7 -C.sub.14 arylalkylcarbonyl, or C.sub.6 -C.sub.10 arylcarbonyl substituted with 0-2 R.sup.9 ;
- R.sup.21 is C.sub.1 -C.sub.4 alkyl or benzyl;
- R.sup.23 is H, F, phenyl substituted with 0-2 R.sup.9, --C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NHR.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- R.sup.24 is H, F, NR.sup.15 R.sup.16, phenyl substituted with 0-2 R.sup.9, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, C(.dbd.O)R.sup.6, --COOR.sup.17, --C(.dbd.O)NR.sup.15 R.sup.16, or
- a heterocyclic ring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, piperidinyl, or tetrahydropyridinyl, said heterocyclic ring system being substituted with 0-2 R.sup.9 ;
- m is 0-2;
- p is 0-1;
- provided that when J and L are both nitrogen and K is CR.sup.4, then R.sup.4 cannot be SR.sup.10.
47 more elements
The compounds which are:
- 2-(4-methylsulfonylphenyl)-3-phenylnaphthalane,
- 3-(4-methylsulphonylphenyl)-2-phenylpyridine, and
- 2-(4-aminosulfonylphenyl)-1-biphenyl.
Dependencies are inferred from the claim text.