Back to results
US 6,093,742 AGranted
Inhibitors of p38
AssigneeVertex Pharmaceuticals Incorporated
InventorsFrancesco Gerald Salituro, Guy W. Bemis, Jeremy Green, James L. Kofron
Life of this patent
Estimating the term…
Abstract
The present invention relates to inhibitors of p38, a mammalian protein kinase involved in cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
Claims22
A compound of the formula:
- ##STR153## wherein:
- W is an aromatic monocyclic, bicyclic or tricyclic ring system wherein W optionally comprises up to 4 substituents independently selected from R.sup.1 and R.sup.4 ;
- wherein R.sup.1 is halogen, OH, OR.sup.3, NO.sub.2, NH.sub.2, N(R.sup.3).sub.2, CO.sub.2 H, CO.sub.2 R.sup.3, CONH.sub.2, CON(R.sup.3).sub.2, COH, COR.sup.3, NHCOH, NHCOR.sup.3, SO.sub.2 NH, SO.sub.2 NR.sup.3, CN, SH, SR.sup.3, 1,2-methyleneoxy, 1,2-ethylenedioxy, phenyl or CF.sub.3 ;
- Y is O or NH;
- X.sub.1 and X.sub.2 are NR.sup.2 ;
- wherein R.sup.2 is selected from H or C.sub.1 -C.sub.6 straight or branched alkyl, C.sub.2 -C.sub.6 straight or branched alkenyl or alkynyl, wherein R.sup.2 is optionally substituted with --OH, --N(R.sup.3).sub.2, --Z, --CO.sub.2 H, --CO.sub.2 R.sup.3 or --CO--N(R.sup.3).sub.2 ;
- R.sup.3 is selected from phenyl, C.sub.1 -C.sub.6 straight or branched alkyl, C.sub.2 -C.sub.6 straight or branched alkenyl or alkynyl, wherein R.sup.3 is optionally substituted with halo, --OH, --OR.sup.4, --NO.sub.2, --NH.sub.2, --N(R.sup.4).sub.2, --CO.sub.2 R.sup.4, --CO--N(R.sup.4).sub.2, --Z, --CN, --SR.sup.4, CF.sub.3 or --SO.sub.2 NR.sup.4 ;
- provided that when Y is O and R.sup.2 is H, then R.sup.3 is not substituted with OH or NH.sub.2 and R.sup.1 is not OH, CO.sub.2 H, COH, NHCOH, SH or SO.sub.2 NH;
- R.sup.4 is independently (C.sub.1 -C.sub.6)-straight or branched alkyl, (C.sub.2 -C.sub.6)-straight or branched alkenyl or alkynyl;
- Z is selected from a monocyclic, bicyclic or tricyclic aromatic ring system comprising 5-7 members per ring, and wherein Z optionally comprises up to 4 substituents independently selected from R.sup.1 and R.sup.4 ;
- provided that when Y is O and R.sup.2 is H, then W and Z are not both simultaneously substituted or unsubstituted aromatic monocyclic or bicyclic ring systems comprising up to 3 substituents.
8 more elements
A compound selected from the following:
- ______________________________________ compound number Stucture ______________________________________ 1 #STR154## - 2 #STR155## - 3 #STR156## - 4 #STR157## - 5 #STR158## - 6 #STR159## - 7 #STR160## - 8 #STR161## - 9 #STR162## - 10 #STR163## - 11 #STR164## - 12 #STR165## - 13 #STR166## - 14 #STR167## - 15 #STR168## - 17 #STR169## - 19 #STR170## - 20 #STR171## - 21 #STR172## - 22 #STR173## - 23 #STR174## - 24 #STR175## - 25 #STR176## - 27 #STR177## - 28 #STR178## - 29 #STR179## - 30 #STR180## - 31 #STR181## - 33 #STR182## - 34 #STR183## - 35 #STR184## - 36 #STR185## - 37 #STR186## - 38 #STR187## - 39 #STR188## - 41 #STR189## - 44 #STR190## - 45 #STR191## - 46 #STR192## - 47 #STR193## - 52 #STR194## - 53 #STR195## - 54 #STR196## - 55 #STR197## - 61 #STR198## - 62 #STR199## - 63 #STR200## - 64 #STR201## - 65 #STR202## - 66 #STR203## - 67 #STR204## - 68 #STR205## - 69 #STR206## - 70 #STR207## - 71 #STR208## - 76 #STR209## - 77 #STR210## - 78 #STR211## - 79 #STR212## - 83 #STR213## - 84 #STR214## - 87 #STR215## - 88 #STR216## - 89 #STR217## - 90 #STR218## - 91 #STR219## - 92 #STR220## - 93 #STR221## - 94 #STR222## - 95 #STR223## - 96 #STR224## - 97 #STR225## - 98 #STR226## - 99 #STR227## - 100 #STR228## - 103 #STR229## - 104 #STR230## - 105 #STR231## - 106 #STR232## - 107 #STR233## - 108 #STR234## - 109 #STR235## - 110 #STR236## - 111 #STR237## - 112 #STR238## - 113 #STR239## - 114 #STR240## - 115 #STR241## - 116 #STR242## - 118 #STR243## - 119 #STR244## - 120 #STR245## - 121 #STR246## - 122 #STR247## - 123 #STR248## - 124 #STR249## - 125 #STR250## - 127 #STR251## - 128 #STR252## - 129 ##STR253## ______________________________________
A method of treating or preventing a p38-mediated condition, comprising the step of administering an amount of a compound effective to treat or prevent a p38-mediated condition, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, to a human or animal in need thereof, wherein the compound has the formula:
- ##STR254## wherein:
- W is an aromatic monocyclic or bicyclic ring system wherein W optionally comprises up to 4 substituents independently selected from R.sup.1 and R.sup.4 ;
- wherein R.sup.1 is halogen, OH, OR.sup.3, NO.sub.2, NH.sub.2, N(R.sup.3).sub.2, CO.sub.2 H, CO.sub.2 R.sup.3, CONH.sub.2, CON(R.sup.3).sub.2, COR.sup.3, NHCOR.sup.3, SO.sub.2 NH.sub.2, SO.sub.2 NR.sup.3, CN, SR.sup.3, 1,2-methyleneoxy, 1,2-ethylenedioxy, phenyl or CF.sub.3 ;
- Y is O or NH;
- X.sub.1 and X.sub.2 are NR.sup.2 ;
- wherein R.sup.2 is selected from H or C.sub.1 -C.sub.6 straight or branched alkyl, C.sub.2 -C.sub.6 straight or branched alkenyl or alkynyl, wherein R.sup.2 is optionally substituted with --OH, --N(R.sup.3).sub.2, --Z, --CO.sub.2 H, --CO.sub.2 R.sup.3 or --CO--N(R.sup.3).sub.2 ;
- R.sup.3 is selected from phenyl, C.sub.1 -C.sub.6 straight or branched alkyl, C.sub.2 -C.sub.6 straight or branched alkenyl or alkynyl, wherein R.sup.3 is optionally substituted with halo, --OH, --OR.sup.4, --NO.sub.2, --NH.sub.2, --N(R.sup.4).sub.2, --CO.sub.2 R.sup.4, --CO--N(R.sup.4).sub.2, --Z, --CN, --SR.sup.4, CF.sub.3 or --SO.sub.2 NR.sup.4 ;
- provided that when Y is O and R.sup.2 is H, then R.sup.3 is not substituted with OH or NH.sub.2 ;
- R.sup.4 is independently (C.sub.1 -C.sub.6)-straight or branched alkyl, (C.sub.2 -C.sub.6)-straight or branched alkenyl or alkynyl;
- and
- Z is selected from monocyclic or bicyclic, aromatic ring systems comprising 5-7 members per ring, and wherein Z optionally comprises up to 4 substituents independently selected from R.sup.1 and R.sup.4.
8 more elements
Dependencies are inferred from the claim text.