Thioxanthine Derivatives as Myeloperoxidase Inhibitors
AssigneeAstraZeneca AB
InventorsSverker Hanson, Gunnar Nordvall, Anna-Karin Tiden
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Abstract
There is disclosed the use of a compound of formula (Ia) or (Ib) wherein R1, R2, R3, R4, X and Y are as defined in the specification, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of the enzyme myeloperoxidase (MPO) is beneficial. Certain novel compounds of formula (Ia) or (Ib) and pharmaceutically acceptable salts thereof are disclosed, together with processes for their preparation. The compounds of formulae (Ia) and (Ib) are MPO inhibitors and are thereby particularly useful in the treatment or prophylaxis of neuroinflammatory disorders.
Claims23
A compound of formula (Ia) or (Ib)
- wherein:
- X is S, and Y is O;
- R1 is hydrogen or C1 to 6 alkyl;
- R2 is C1 to 6 alkyl substituted by
- a saturated or partially unsaturated 3- to 7-membered ring optionally incorporating one or two heteroatoms selected independently from O, N and S, said ring being optionally substituted by one or more substituents selected from halogen, hydroxy, C1 to 6 alkoxy and C1 to 6 alkyl;
- R3 and R4 independently represent hydrogen or C1 to 6 alkyl;
- or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof.
A compound selected from:
- 1,3-diisobutyl-8-methyl-6-thioxanthine;
- 1,3-dibutyl-8-methyl-6-thioxanthine;
- 3-isobutyl-1,8-dimethyl-6-thioxanthine;
- 3-(2-methylbutyl)-6-thioxanthine;
- 3-isobutyl-8-methyl-6-thioxanthine;
- 3-isobutyl-2-thioxanthine;
- 3-isobutyl-2,6-dithioxanthine;
- 3-isobutyl-8-methyl-2-thioxanthine;
- 3-isobutyl-7-methyl-2-thioxanthine;
- 3-cyclohexylmethyl-2-thioxanthine;
- 3-(3-methoxypropyl)-2-thioxanthine;
- 3-cyclopropylmethyl-2-thioxanthine;
- 3-isobutyl-1-methyl-2-thioxanthine;
- 3-(2-methoxy-ethyl)-2-thioxanthine;
- 3-(3-(1-morpholinyl)-propyl)-2-thioxanthine;
- 3-(2-furyl-methyl)-2-thioxanthine;
- 3-(4-methoxybenzyl)-2-thioxanthine;
- 3-(4-fluorobenzyl)-2-thioxanthine;
- 3-phenethyl-2-thioxanthine;
- 3-n-butyl-2-thioxanthine;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof.
A method for treating neuroinflammatory disorders or conditions, comprising administering to a person in need thereof a therapeutically effective amount of a compound of formula (Ia) or (Ib)
- wherein:
- one of X and Y is S, and the other is O or S;
- R1 is hydrogen or C1 to 6 alkyl;
- R2 is hydrogen or C1 to 6 alkyl;
- said alkyl group being optionally substituted by:
- i) a saturated or partially unsaturated 3- to 7-membered ring optionally incorporating one or two heteroatoms selected independently from O, N and S, and optionally incorporating a carbonyl group;
- said ring being optionally substituted by one or more substituents selected from halogen, hydroxy, C1 to 6 alkoxy and C1 to 6 alkyl;
- said alkyl being optionally further substituted by hydroxy or C1 to 6 alkoxy;
- or
- ii) C1 to 6 alkoxy;
- or
- iii) an aromatic ring selected from phenyl, furyl or thienyl;
- said aromatic ring being optionally further substituted by halogen, C1 to 6 alkyl or C1 to 6 alkoxy;
- R3 and R4 independently represent hydrogen or C1 to 6 alkyl;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof.
8-12. (canceled)
A method for treating neuroinflammatory disorders or conditions, comprising administering to a person in need thereof a therapeutically effective amount of a compound selected from:
- 1,3-diisobutyl-8-methyl-6-thioxanthine;
- 1,3-dibutyl-8-methyl-6-thioxanthine;
- 3-isobutyl-1,8-dimethyl-6-thioxanthine;
- 3-(2-methylbutyl)-6-thioxanthine;
- 3-isobutyl-8-methyl-6-thioxanthine;
- 3-isobutyl-2-thioxanthine;
- 3-isobutyl-2,6-dithioxanthine;
- 3-isobutyl-8-methyl-2-thioxanthine;
- 3-isobutyl-7-methyl-2-thioxanthine;
- 3-cyclohexylmethyl-2-thioxanthine;
- 3-(3-methoxypropyl)-2-thioxanthine;
- 3-cyclopropylmethyl-2-thioxanthine;
- 3-isobutyl-1-methyl-2-thioxanthine;
- 3-(2-methoxy-ethyl)-2-thioxanthine;
- 3-(3-(1-morpholinyl)-propyl)-2-thioxanthine;
- 3-(2-furyl-methyl)-2-thioxanthine;
- 3-(4-methoxybenzyl)-2-thioxanthine;
- 3-(4-fluorobenzyl)-2-thioxanthine;
- 3-phenethyl-2-thioxanthine;
- 3-(2-tetrahydrofuryl-methyl)-2-thioxanthine;
- 3-n-butyl-2-thioxanthine;
- and
- pharmaceutically acceptable salts, enantiomers, diastereomers, and racemates thereof.
Dependencies are inferred from the claim text.