Thienopyrimidinedinones and their use in modulation of autoimmune disease

• US 7,393,854 B2
• Filed: 01/15/2004
• Issued: 07/01/2008
• Est. Priority Date: 01/17/2003
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Guile, Simon David, Ingall, Anthony Howard
• Primary Examiner(s): Coleman; Brenda L.
• Assistant Examiner(s): Moore; Susanna
• Application Number:
  US10/542,457
• Publication Number:
  US 20060135539A1
• Time in Patent Office: 1,629 Days
• Field of Search: 544/278, 514/260.1
• US Class Current: 514/260.1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

The invention relates to thienopyrimidinediones of formula (I):

wherein:

• R¹, R², Q are as defined in the specification, and Ar and Ar² are selected from certain aromatic ring systems which may be optionally substituted, as defined in the specification.

Processes for the preparation of compounds of formula (I), pharmaceutical compositions containing them and their use in therapy are also described and claimed.

Claims

1. A compound of formula (I):

2. A compound according to claim 1 in which R¹ is C_1-6alkyl.

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

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

5. A compound according to claim 1 in which Ar is a 5 or 6-membered aromatic ring system wherein up to 2 ring atoms are optionally heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from C_1-4alkyl, C_1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, cyano and C_1-4alkylsulphonyl.

6. A compound according to claim 5 wherein Ar is a group of sub-formula (i)

7. A compound according to claim 1 wherein Ar² is other than phenyl.

8. A compound according to claim 7 wherein Ar² contains at least one heteroatom.

9. A compound according to claim 1 in which Ar² is a 5 or 6-membered aromatic ring system wherein up to 3 ring atoms are optionally heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from C_1-4alkyl, C_1-4alkoxy, halogen, dihaloalkyl, trihaloalkyl, cyano and C_1-4alkylsulphonyl.

10. A compound according to claim 9 wherein Ar² is pyridinyl or pyrimidinyl.

11. A compound according to claim 9 wherein Ar² is thiazolyl.

12. A compound according to claim 1 selected from:

(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-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-isoxazolidinol

and pharmaceutically acceptable salts thereof.

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

14. 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 (I) or a pharmaceutically-acceptable salt thereof as defined in claim 1.

15. A process for the preparation of a compound of formula (I) according to claim 1 which comprises:

(a) reaction of a compound of formula (II);

16. A compound according to claim 1, wherein the compound is:

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

or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 1, wherein the compound is:

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

or a pharmaceutically acceptable salt thereof.