Thienopyrimidinediones and their use in the modulation of autoimmune disease

• US 7,384,951 B2
• Filed: 01/15/2004
• Issued: 06/10/2008
• Est. Priority Date: 01/17/2003
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Guile, Simon David
• Primary Examiner(s): Coleman; Brenda L.
• Assistant Examiner(s): Moore; Susanna
• Application Number:
  US10/542,197
• Publication Number:
  US 20060052400A1
• Time in Patent Office: 1,608 Days
• Field of Search: 544/278, 514/260.1
• US Class Current: 514/260.1
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The invention relates to thienopyrimidinediones of formula (1) wherein R¹ and R² each independently represent a C_1-6alkyl, C_3-6alkyl, C_3-6alkenyl, C_3-5cycloalkylC_1-3alkyl or C_3-6cycloalkyl; each of which may be optionally substituted by 1 to 3 halogen atoms R³ is a group CO-G or SO₂-G where G is a 5- or 6-membered ring containing a nitrogen atom and a second heteroatom selected from oxygen and sulphur adjacent to the nitrogen; the ring being substituted by at least one group as defined in the specification, Q is CR⁴R⁵ where R⁴ is hydrogen, fluorine or C_1-6 alkyl and R⁵ is hydrogen, fluorine or hydroxy; and Ar is a 5-10-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 groups defined in the specification; as well as pharmaccutically acceptable salts and solvates thereof. Processes for their preparation of the compounds, pharmaceutical compositions containing them and their use in therapy, in particular in immunosuppressive therapy are also described

Claims

1. A compound of formula (1):

2. A compound according to claim 1 in which R¹ is ethyl, propyl, butyl or cyclopropyl.

3. A compound according to claim 1 in which R² is methyl.

4. A compound according to claim 1 in which R³ a group CO-G.

5. A compound according to claim 1 in which Q is CH₂.

6. A compound according to claim 1 in which Ar is a 5-membered aromatic ring containing two heteroatoms optionally substituted as defined in claim 1 or Ar is a 9- or 10-membered bicyclic ring containing one, two or three heteroatoms and optionally substituted as defined in claim 1, or phenyl, optionally substituted as defined in claim 1.

7. A compound according to claim 1 in which Ar is a thienyl, pyrazole or thiazole ring each substituted by two or three C_1-4alkyl, halogen, trifluoromethyl substituents and/or also substituted by a 2-pyrimidinyl or 2-pyridyl group.

8. A compound according to claim 6 wherein Ar is a group of sub-formula (i)

9. A compound according to claim 8 wherein R¹⁰ and R¹¹ are methyl.

10. A compound according to claim 9 wherein R¹² is is selected from H, C_1-3alkyl or a 5- to 6-membered aromatic ring system wherein up to 3 ring atoms may be heteroatoms independently selected from oxygen, sulphur and nitrogen, optionally substituted by hydroxyl.

12. A pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof as defined in claim 1 and a pharmaceutical carrier.

13. A method of treating asthma in a patient suffering from asthma, which comprises administering to the patient a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof as defined in claim 1.

14. A process for the preparation of a compound of formula (1) according to claim 1 which comprises one of the following reactions:

a) when R³ is a group COG, reacting a compound of the formula (10);

11. A compound selected from the group consisting of:

(S)-2-[[6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,

(S)-2-[[6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,

1-Cyclopropyl-6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(S)-2-[[6-[(1H-1,2,3-Benzotriazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,

(S)-2-[[6-[(4,5-Dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-1-ethyl-3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,

5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

(4S)-4-methyl-2-[[1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propyl-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinol,

(4S)-2-[[6-[(2,4-Dichloro-5-thiazolyl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,

(4S)-2-[[6-[(3-Bromo-2-thienyl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,

5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[[3,5-Dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[[(4S)-4-Hydroxy-4-methyl-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(4S)-2-[[6-[[3,5-Dimethyl-1-(4-pyridinyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,

(4S)-2-[[6-[[3,5-Dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,

5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6-[(1-phenyl-1H-pyrazol-4-yl)methyl]-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

6-[(8-Fluoroquinolin-4-yl)methyl]-5-{[(4S)-4-hydroxy-4-methylisoxazolidin-2-yl]carbonyl}-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

5-{[(4S)-4-Hydroxy-4-methylisoxazolidin-2-yl]carbonyl}-1-isopropyl-3-methyl-6-(4-pyrimidin-2-ylbenzyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6-[(5-(2-pyridinyl)-2-thienyl)methyl]-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

6-[(1,3-Dimethyl-1H-5-pyrazolyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

6-[(3,5-Dimethyl-4-isothiozolyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6-[[1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

6-[(4-Fluorophenyl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[[(4S)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6-(1H-1,2,3-triazol-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

6-[(6-Chloroimidazo[1,2-a]pyridin-3-yl)methyl]-5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[[(4S)-4-hydroxy-4-methylisoxazolidin-2-yl]carbonyl]-3-methyl-1-(1-methylethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(4S)-4-Methyl-2-[[1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-6-[[5-methyl-1-(2-pyrimidinyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinol,

(4S)-2-[[6-[[3,5-Dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-ethyl-4-isoxazolidinol,

(4S)-2-[[6-[[1-(2,3-Dihydro-2-oxo-4-pyrimidinyl)-3,5-dimethyl-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-methyl-4-isoxazolidinol,

5-[[(4R)-4-Hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

and pharmaceutically acceptable salts thereof.