Compounds
AssigneeAstraZeneca AB
InventorsChristophe B. Barlaam, Robert I. Dowell, Maurice R.V. Finlay, Nicholas J. Newcombe, Howard Tucker, David Waterson
Life of this patent
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Abstract
Compounds of the formula I 1 useful as metalloproteinase inhibitors, especially as inhibitors of MMP 13.
Claims22
A compound of the formula I or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof
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- wherein
- B is a phenyl group monosubstituted at the 3- or 4-position by halogen or trifluoromethyl, or disubstituted at the 3- and 4-positions by halogen (which may be the same or different);
- or B is a 2-pyridyl or 2-pyridyloxy group monosubstituted at the 4-, 5- or 6-position by halogen, trifluoromethyl, cyano or C1-4 alkyl;
- or B is a 4-pyrimidinyl group optionally substituted at the 6-position by halogen or C1-4 alkyl;
- X is a carbon or nitrogen atom;
- R1 is a trimethyl-1-hydantoin C2-4alkyl or a trimethyl-3-hydantoin C2-4alkyl group;
- or R1 is phenyl or C2-4alkylphenyl monosubstituted at the 3- or 4-position by halogen, trifluoromethyl, thio or C1-3alkyl or C1-3 alkoxy;
- or R1 is phenyl-SO2NHC2-4alkyl;
- or R1 is 2-pyridyl or 2-pyridyl C2-4alkyl;
- or R1 is 3-pyridyl or 3-pyridyl C2-4alkyl;
- or R1 is 2-pyrimidine-SCH2CH2;
- or R1 is 2- or 4-pyrimidinyl C2-4alkyl optionally monosubstituted by one of halogen, trifluoromethyl, C1-3 alkyl, C1-3 alkyloxy, 2-pyrazinyl optionally substituted by halogen or 2-pyrazinyl C2-4alkyl optionally substituted by halogen.
A compound as claimed in any one of the previous claims or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof wherein X is a nitrogen atom.
A compound as claimed in any one of the previous claims or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof wherein R1 is selected from 3-chlorophenyl, 4-chlorophenyl, 3-pyridyl, 2-pyridylpropyl, 2- or 4-pyrimidinylethyl (optionally monosubstituted by fluorine), 2- or 4-pyrimidinylpropyl, 2-(2-pyrimidinyl)propyl (optionally monosubstituted by fluorine).
A compound as claimed in any one of the previous claims or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof wherein the compound of formula I is the most active enantiomer.
A compound as claimed in any one of the previous claims or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof wherein the compound of formula I is the S enantiomer or the S,S enantiomer.
A method of treating a metalloproteinase mediated disease condition which comprises administering to a warm-blooded animal a therapeutically effective amount of a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
The use of a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in the treatment of a disease condition mediated by one or more metalloproteinase enzymes.
The use of a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in the treatment of arthritis.
The use of a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in the treatment of atherosclerosis.
The use of a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in the treatment of chronic obstructive pulmonary diseases.
A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof which process comprises reacting a compound of the formula II with a compound of the formula R1CHO to yield an alkene of the formula III, converting the alkene to a compound of the formula IV, and then converting the compound of formula IV to a compound of the formula I, and optionally thereafter forming a pharmaceutically acceptable salt or in vivo hydrolysable ester of the compound of formula I, all as set out below:
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A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof which process comprises reacting a compound of the formula II with a compound of the formula R1COOR to yield a compound of the formula VIII, converting the compound of formula VIII to a compound of the formula IX, converting the compound of formula IX to an alkene of the formula III, converting the alkene to a compound of the formula IV, and then converting the compound of formula IV to a compound of the formula I, and optionally thereafter forming a pharmaceutically acceptable salt or in vivo hydrolysable ester of the compound of formula I, all as set out below:
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Dependencies are inferred from the claim text.