Chemical compounds

• US 20040171623A1
• Filed: 01/08/2004
• Published: 09/02/2004
• Est. Priority Date: 07/19/2001
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Reynolds, Rachel Heulwen, Ingall, Anthony Howard
• Granted Patent: US 7,361,660 B2
• Time in Patent Office: Days
• US Class Current: 514/260.1
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The invention relates to a compound of formula (1)(A chemical formula should be inserted here—please see paper copy enclosed) wherein Q is —CO— or —C(R⁴)(R⁵)— (wherein R⁴ is a hydrogen atom or C_1-4alkyl and R⁵ is a hydrogen atom or hydroxy group) and Ar is a 5- to 10-membered aromatic ring system wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents as defined in the specification. It also relates to methods of preparing, pharmaceutical compositions containing and methods of using the compound of the formula (1), particularly in the modulation of autoimmune disease.

Claims

1. A compound of formula (1)

2. A compound according to claim 1 wherein R² is methyl or ethyl.

3. A compound according to either claim 1 or claim 2 wherein R¹ is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl or 3,3,3-trifluoropropyl.

4. A compound according any one of claims 1 to 3 wherein Q is —

CO—

of —

CH₂—

.

5. A compound according any one of claims 1 to 4 wherein R¹⁰ is C_1-4alkyl optionally substituted by hydroxy.

6. A compound according any one of claims 1 to 5 wherein R¹¹ is C_1-4alkyl optionally substituted by hydroxy.

7. A compound according any one of claims 1 to 6 wherein Y is O.

8. A compound according any one of claims 1 to 7 wherein R³ is —

CON(Me)OMe, —

CON(Et)OMe, —

CON(OEt)Me, —

CON(Et)OEt, —

CON(CH₂CH₂OH)OEt, —

CON(CH₂CH₂OH)Me, —

CON(OCH₂CH₂OH)Me or —

CON(OCH₂CH₂OH)Et.

9. A compound according any one of claims 1 to 8 wherein Ar contains at least 1 ring nitrogen.

10. A compound according any one of claims 1 to 9 wherein Ar contains at least 2 ring nitrogen.

11. A compound according any one of claims 1 to 8 wherein Ar is selected from imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to claim 1.

12. A compound according any one of claims 1 to 11 wherein Ar is substituted by 1, 2 or 3 substituents independently selected from C_1-4alkyl (optionally substituted by 1 or 2 hydroxy groups), C_1-4alkoxy, halogen, trihaloalkyl, C_1-4alkylthio, C_1-4alkoxycarbonyl, C_2-4alkanoyl, oxo, thioxo, cyano, —

NHR⁷ and —

(CH₂)pN(R⁸)R⁹ (wherein p is 1 or

     2), hydroxy, C_1-4alkylsulphonyl, carbamoyl, C_1-4alkylcarbamoyl, di-C_1-4alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from nitrogen, oxygen and sulphur.

13. A compound according to claim 1 which is:

6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-6-(1H-indol-3-ylmethyl)-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-6-(1H-indol-3-ylcarbonyl)-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-6-(1H-indazol-3-ylmethyl)-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxamide;

1-(2,2-dimethylpropyl)-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-6-[[2-(1-methylethyl)-1H-imidazol-1-yl]methyl]-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[[2-(methylthio)-1H-imidazol-1-yl]methyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

6-[(2-chloro-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[2-(methylthio)-1H-benzimidazol-1-yl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-(2-hydroxyethyl)-N-methoxy-3-methyl-1-(2-methylpropyl)-6-[[2-(methylthio)-1H-imidazol-1-yl]methyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-6-[[2-(methylamino)-1H-benzimidazol-1-yl]methyl]-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-[(2,3-dihydro-3-methyl-2-oxo-1H-benzimidazol-1-yl)methyl]-thieno[2,3-d]pyrimidine-5-carboxamide;

6-[(2,3-dihydro-2-oxo-benzothiazol-3-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

6-[(1-acetyl-1H-indol-3-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

6-[(3-chloroquinolin-4-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

N-methoxy-N,3-dimethyl-2,4-dioxo-1-propyl-6-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide;

1-ethyl-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide;

1-(cylopropylmethyl)-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide;

N-methoxy-N,3-dimethyl-2,4-dioxo-1-propyl-6-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide;

1-ethyl-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide;

1-(cyclopropylmethyl)-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide;

6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(1-methylethyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-[2-(trifluoromethyl)phenylmethyl]thieno[2,3-d)pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-(benzyl)thieno[2,3-d]pyrimidine-5-carboxamide;

methyl 4-[1,2,3,4-tetrahydro-5-[(N-methoxy-N-methylamino)carbonyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl](hydroxy)methyl]-1-methyl-1H-pyrrole-2-carboxylate;

methyl 1-methyl-4-[1,2,3,4-tetrahydro-5-[(methoxymethylamino)carbonyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl]-1H-pyrrole-2-carboxylate;

methyl 2,5-dimethyl-4-[1,2,3,4-tetrahydro-5-[(N-methoxy-N-methyl amino)carbonyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl]-1H-pyrrole-3-carboxylate;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-[2-oxo-3(2H)-benzoxazolylmethyl]-thieno[2,3-d]pyrimidine-5-carboxamide;

1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-[(2,4,5-trichloro-1H-imidazol-1-yl)methyl]-thieno[2,3-d]pyrimidine-5-carboxamide;

6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-(2-hydroxyethyl)-1-isobutyl-N-methoxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide;

6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-(2-hydroxyethoxy)-1-isobutyl-N,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide; and

6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-ethyl-1,2,3,4-tetrahydro-N-methoxy-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;

or a pharmaceutically-acceptable salt thereof.

14. A process for the preparation of a compound of the formula (1) as defined in claim 1, or a compound of the formula (1) as defined in claim 1 wherein at least 1 functional group is protected, using one of the following processes:

a) when R^3.is of the formula —

CON(R¹⁰Y(R¹¹), reacting a compound of the formula (10);

with a compound of the formula HN(R¹⁰)Y(R¹¹);

b) when R³ is of the formula —

SO₂N(R¹⁰)Y(R¹¹), reacting a compound of the formula (11);

with a compound of the formula HN(R¹⁰)Y(R¹¹);

c) when Q is methylene, reacting a compound of the formula (12);

with a compound of the formula Ar;

d) when Q is methylene, reducing a compound of the formula (13);

e) reacting a compound of the formula (14);

with a compound of the formula L′

-R¹⁰;

or

f) converting one compound of the formula (1) into another compound of the formula (1);

wherein L and L′

are leaving groups, X is —

CO—

or —

SO₂— and

R¹, R², R³, R¹⁰, Q and Ar are as hereinabove defined and any functional groups are optionally protected;

and optionally after a), b), c), d), e) or f), converting the compound of the formula (1) into a further compound of formula (1) and/or forming a pharmaceutically-acceptable salt and/or prodrug thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable adjuvant, diluent or carrier.

16. A compound according to any one of claims 1 to 13 for use in therapy.

17. The use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for use in inhibiting the proliferation of T cells.

18. A method of inhibiting the proliferation of T cells, which comprises administering to a patient a therapeutically effective amount of a compound according to claim 1.

19. A method of effecting immunosuppression, which comprises administering to a patient a therapeutically effective amount of a compound according to claim 1.

20. A method of treating or reducing the risk of a reversible obstructive airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound according to claim 1.