US 8,026,244 B2Granted

Thioxanthine derivatives and their use as inhibitors of MPO

AssigneeAstraZeneca AB

InventorsAnna-Karin Tiden, Jenny Viklund

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Abstract

There are disclosed novel compounds of Formula (I) wherein L, R1, X and Y are as defined in the specification, and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors of the enzyme MPO and are thereby particularly useful in the treatment or prophylaxis of neuroinflammatory disorders, cardio- and cerebrovascular atherosclerotic disorders and peripheral artery disease and respiratory disorders.

Claims7

Dependent claims

A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein
at least one of X and Y is S, and the other is O or S;
L is ethylene, methylene, —CH2CH(CH3)OCH2—, —CH2CH(C6H5)—, —CH2CH2NHCH2—, —CH2CH2N(CH3)CH2—, —CH2CH(CH3)NHCH2—, or —CH2CH(CH3)NHC(O)—;
R1 selected from indole, isoindole, benzimidazole, quinoline, naphthyridine, imidazo[1,2-a]pyridine, pyrazole, pyrazine, oxadiazole, pyridine, isoxazole, pyrimidine, pyrrole, imidazole, furazan and triazole;
wherein each R1 is independently and optionally substituted with one or more substituents independently selected from halogen, CHF2, CH2F, CF3, SO(n)R9, SO(n)NR9R10, (CH2)nR3, NR4R5, OH, C1 to 7 alkyl, C1 to 7 alkoxy, phenoxy, aryl, CN, C(O)NR2R3, NR2C(O)R3, C(O)R3, a 5- or 6-membered saturated or partially saturated ring containing one or more atoms selected from C, N, O, and S, and a mono- or bicyclic heteroaromatic ring system containing one or more heteroatoms selected from N, S, and O;
and wherein said C1 to 7 alkoxy is optionally substituted with C1 to 6 alkoxy or aryl;
wherein said C1 to 7 alkyl is optionally substituted with hydroxy or C1 to 6 alkoxy;
wherein said C1 to 7 alkyl is optionally incorporating a carbonyl at any position in the C1 to 7 alkyl;
and wherein said phenoxy is optionally substituted with C1 to 6 alkyl, halogen or C1 to 6 alkoxy;
at each occurrence, R2, R3, R4, R5, R9 and R10 are independently selected from hydrogen, C1 to 6 alkyl, C1 to 6 alkoxy, aryl, and phenoxy;
and said C1 to 6 alkyl is optionally substituted with halogen, C1 to 6 alkoxy, CHO, C2 to 6 alkanoyl, OH, C(O)NR7R8 or NR7C(O)R8;
and said aryl or said phenoxy is optionally substituted with C1 to 6 alkyl, halogen or C1 to 6 alkoxy;
or the groups NR2R3, NR4R5 and NR9R10 each independently represents a 5 to 7 membered saturated azacyclic ring optionally incorporating one additional heteroatom selected from O, S and NR11, said ring being optionally further substituted with halogen, C1 to 6 alkoxy, CHO, C2 to 6 alkanoyl, OH, C(O)NR7R8 or NR7C(O)R8;
at each occurrence R7, R8 and R11 independently represent hydrogen or C1 to 6 alkyl, or the group NR7R8 represents a 5 to 7 membered saturated azacyclic ring optionally incorporating one additional heteroatom selected from O, S, and NR11;
and
n is 0, 1 or 2.

13 more elements

A compound selected from:

3-[2-(1H-Benzimidazol-2-yl)ethyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(1H-Pyrazol-3-ylmethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[(5-Methylpyrazin-2-yl)methyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[(3-Isopropylisoxazol-5-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[(4-Methyl-1,2,5-oxadiazol-3-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[(6-Butoxypyridin-2-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[(4-Butoxypyridin-2-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[(3-Butoxypyridin-2-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[2-(Pyridin-2-ylmethoxy)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[(3,5-Dimethylisoxazol-4-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[(1-Methyl-1H-indol-2-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(2-Phenyl-2-pyridin-2-ylethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(Quinolin-4-ylmethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[(6-Phenoxypyridin-3-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-{2-[(Quinolin-4-ylmethyl)amino]ethyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(2-{[(1-Methyl-1H-indol-3-yl)methyl]amino}ethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-{2-[Methyl(quinolin-4-ylmethyl)amino]ethyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(2-Aminopropyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate;
3-{2-[(Pyridin-2-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate;
3-{2-[(Pyridin-3-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-{2-[(Pyridin-4-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(2-{[(6-Chloropyridin-3-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate;
3-[2-({[6-(Trifluoromethyl)pyridin-3-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate;
3-(2-{[(4,6-Dichloropyrimidin-5-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[2-({[2-(Dimethylamino)pyrimidin-5-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-{2-[(Quinolin-2-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate;
3-{2-[(Quinolin-3-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(2-{[(1-tert-Butyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[2-({[1-(1,1-Dioxidotetrahydro-3-thienyl)-3,5-dimethyl-1H-pyrazol-4-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-{2-[(1H-Benzoimidazol-2-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[2-({[1-(Phenylsulfonyl)-1H-pyrrol-2-yl]methyl}amino]propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate;
3-{2-[({1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-2-yl}methyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate;
3-(2-{[(1-methyl-1H-pyrrol-2-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[2-({[1-(4-sec-Butylphenyl)-1H-pyrrol-2-yl]methyl}amino)propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[2-({[1-(3-Methoxyphenyl)-1H-pyrrol-2-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[2-({[2,5-Dimethyl-1-(1,3-thiazol-2-yl)-1H-pyrrol-3-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[2-({[4-(3-Chlorobenzoyl)-1-methyl-1H-pyrrol-2-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-{2-[(1H-Imidazol-2-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(2-{[(1-Methyl-1H-imidazol-2-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(2-{[(4-Bromo-1-methyl-1H-imidazol-5-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(2-{[(1-Methyl-1H-indol-3-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
2-Thioxo-3-{2-[(1H-1,2,3-triazol-5-ylmethyl)amino]propyl}-1,2,3,7-tetrahydro-6H-purin-6-one;
3-[2-({[1-(Benzyloxy)-1H-imidazol-2-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-(2-{[(6-Bromo-2-methylimidazo[1,2-a]pyridin-3-yl)methyl]amino}propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
3-{2-[({1-[2-(2-Methoxyphenoxy)ethyl]-1H-pyrrol-2-yl}methyl)amino]propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one;
N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]pyridine-2-carboxamide;
N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]nicotinamide;
N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)-ethyl] isonicotinamide;
N-[1-methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]-1,8-naphthyridine-2-carboxamide;
N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]quinoline-2-carboxamide;
N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]pyrimidine-2-carboxamide;
and
N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]-1H-imidazole-2-carboxamide trifluoroaceate;
or a pharmaceutically acceptable salt thereof.

51 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/295,306Filed 12 Apr 2007 · us provisional application
Priority: 13 Apr 2006
Published: US 2009/0149475 A111 Jun 2009
Granted: 27 Sep 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 473/20
With oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6: two sulfur atoms
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/04
Drugs for disorders of the cardiovascular system: inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Family

Application60/791,667Us provisional application · filed 13 Apr 2006
US 2009/0149475 A1Pre-grant publication · published 11 Jun 2009
US 8,026,244 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein
at least one of X and Y is S, and the other is O or S;
L is ethylene, methylene, —CH2CH(CH3)OCH2—, —CH2CH(C6H5)—, —CH2CH2NHCH2—, —CH2CH2N(CH3)CH2—, —CH2CH(CH3)NHCH2—, or —CH2CH(CH3)NHC(O)—;
R1 selected from indole, isoindole, benzimidazole, quinoline, naphthyridine, imidazo[1,2-a]pyridine, pyrazole, pyrazine, oxadiazole, pyridine, isoxazole, pyrimidine, pyrrole, imidazole, furazan and triazole;
wherein each R1 is independently and optionally substituted with one or more substituents independently selected from halogen, CHF2, CH2F, CF3, SO(n)R9, SO(n)NR9R10, (CH2)nR3, NR4R5, OH, C1 to 7 alkyl, C1 to 7 alkoxy, phenoxy, aryl, CN, C(O)NR2R3, NR2C(O)R3, C(O)R3, a 5- or 6-membered saturated or partially saturated ring containing one or more atoms selected from C, N, O, and S, and a mono- or bicyclic heteroaromatic ring system containing one or more heteroatoms selected from N, S, and O;
and wherein said C1 to 7 alkoxy is optionally substituted with C1 to 6 alkoxy or aryl;
wherein said C1 to 7 alkyl is optionally substituted with hydroxy or C1 to 6 alkoxy;
wherein said C1 to 7 alkyl is optionally incorporating a carbonyl at any position in the C1 to 7 alkyl;
and wherein said phenoxy is optionally substituted with C1 to 6 alkyl, halogen or C1 to 6 alkoxy;
at each occurrence, R2, R3, R4, R5, R9 and R10 are independently selected from hydrogen, C1 to 6 alkyl, C1 to 6 alkoxy, aryl, and phenoxy;
and said C1 to 6 alkyl is optionally substituted with halogen, C1 to 6 alkoxy, CHO, C2 to 6 alkanoyl, OH, C(O)NR7R8 or NR7C(O)R8;
and said aryl or said phenoxy is optionally substituted with C1 to 6 alkyl, halogen or C1 to 6 alkoxy;
or the groups NR2R3, NR4R5 and NR9R10 each independently represents a 5 to 7 membered saturated azacyclic ring optionally incorporating one additional heteroatom selected from O, S and NR11, said ring being optionally further substituted with halogen, C1 to 6 alkoxy, CHO, C2 to 6 alkanoyl, OH, C(O)NR7R8 or NR7C(O)R8;
at each occurrence R7, R8 and R11 independently represent hydrogen or C1 to 6 alkyl, or the group NR7R8 represents a 5 to 7 membered saturated azacyclic ring optionally incorporating one additional heteroatom selected from O, S, and NR11;
and
n is 0, 1 or 2.

13 more elements

Facts

Application

12/295,306Filed 12 Apr 2007 · us provisional application

Priority

13 Apr 2006

Published

US 2009/0149475 A111 Jun 2009

Granted

27 Sep 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 473/20
With oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6: two sulfur atoms
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/04
Drugs for disorders of the cardiovascular system: inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure