7-amino-2-alkylthiopteridin-4-yl-amines for the treatment of chemokine-related diseases

• US 20040102447A1
• Filed: 07/31/2003
• Published: 05/27/2004
• Est. Priority Date: 10/20/2000
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Bonnert, Roger, Walters, Iain
• Granted Patent: US 7,071,193 B2
• Time in Patent Office: Days
• US Class Current: 514/251
• 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 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 35/00 Antineoplastic agents
• CPC Class Codes: C07D 475/06 with a nitrogen atom directly attached in position 4

Abstract

Pteridine compounds of formula (I) in which R¹, R², R³ and R⁴ are as specified in the claims, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in the treatment of inflammatory diseases such as psoriasis, rheumatoid arthritis, diseases in which angiogenesis is assocated with raised CXCR2 chemokine levels (diabetic retinopathy) and COPD. The compounds are ligands for chemokine receptors and medical indications mentioned in the description include: diseases of the respiratory tract (COPDD, asthma, bronchitis, rhinitis, fibroid lung, pneumonia, etc.), diseases of the bones and joints (arthritis, etc.), skin-diseases (psoriasis, etc), diseases of the gastrointestinal tract, diseases in other tissues and systemic disease (multipe sclerosis, atherosclerosis, AIDS, type 1 diabetes, leprosy, sepsis, etc.), allograft rejection, cancers, cystic fibrosis, stroke, burn wounds, skin ulcers, reproductive disease and more.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

2. A compound according to claim 1, wherein R¹ represents an optionally substituted benzyl group.

3. A compound according to claim 1 or claim 2, wherein one of R² and R³ is hydrogen and the other is C₁-C₈ alkyl substituted by hydroxy and one or more methyl or ethyl groups.

4. A compound according to any one of claims 1 to 3, wherein R⁴ is hydrogen.

5. A compound according to claim 1 selected from:

(2R)-2-[[7-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol,

2-[[7-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pteridinyl]amino]-1,3-propanediol,

2-[[7-Amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pteridinyl]amino]-2-methyl-1-propanol,

(2R)-2-[[7-Amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pteridinyl]amino]-1-butanol,

2-[[7-Amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pteridinyl]amino]-2-methyl-1,3-propanediol,

(2R)-2-[[7-amino-2-[(phenylmethyl)thio]-4-pteridinyl]amino]-1-propanol,

(2R)-2-[[7-amino-2-[[(2-fluorophenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol,

(2R)-2-[[7-amino-2-[[(3-chloro-4-methoxyphenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol,

(2R)-2-[[7-amino-2-[[(3-chlorophenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol,

(2R)-2-[[7-amino-2-[[(5-methyl-2-furanyl)methyl]thio]-4-pteridinyl]amino]-1-propanol,

(2R)-2-[[7-amino-2-[(2-thienylmethyl)thio]-4-pteridinyl]amino]-1-propanol,

(2R)-2-[[7-amino-2-[[(2-fluoro-4-methoxyphenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol,

(2R)-2-[[7-amino-2-[[(3-chloro-2-fluorophenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol,

and their pharmaceutically acceptable salts and solvates.

6. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises:

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

where R¹ is as defined in formula (I) with with an amine R²R ³NH and optionally thereafter forming a pharmaceutically acceptable salt.

8. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 5 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

9. A process for the preparation of a pharmaceutical composition as claimed in claim 8 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 5 with a pharmaceutically acceptable adjuvant, diluent or carrier.

10. A compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of claims 1 to 5 for use in therapy.

11. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 5 in the manufacture of a medicament for use in therapy.

12. A method of treating a chemokine mediated disease wherein the chemokine binds to one or more chemokine receptors, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 5.

13. A method according to claim 12 in which the chemokine receptor belongs to the CXC chemokine receptor subfamily.

14. A method according to claim 12 or 13 in which the chemokine receptor is the CXCR2 receptor.

15. A method of treating an inflammatory 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 of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 5.

16. A method according to claim 15, wherein the disease is psoriasis, rhumatoid arthritis, a disease in which angiogenesis is associated with raised CXCR2 chemokine levels, or COPD.

17. A method according to claim 15, wherein the disease is rhumatoid arthritis.

7. A compound of formula (II) where R¹ is as defined in formula (I).