4-Amino-7,8-Dihydropteridines, Pharmaceutical Compositions Containing Them and Their Use For The Treatment Of Diseases Which Are Caused By An Increased Nitric Oxide Level

• US 20080027062A1
• Filed: 12/30/2003
• Published: 01/31/2008
• Est. Priority Date: 12/30/2003
• Status: Active Grant

• Current Assignee: Vasopharm GmbH
• Original Assignee: Vasopharm Biotech GmbH
• Inventors: Tegtmeier, Frank, Doblhofer, Robert
• Granted Patent: US 7,541,360 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 475/08 with a nitrogen atom directly attached in position 2

Abstract

The present invention relates to the area of NO synthase inhibition and, more particularly, relates to novel 4-amino-7,8-dihydropteridines, pharmaceutical compositions containing said compounds, and the use of said compounds in the treatment of a disorder characterized by a disturbed nitric oxide level.

Claims

1-22. -22. (canceled)

23. A compound of formula I, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and physiologically tolerated salts, hydrates and esters thereof:

24. The compound of claim 23, wherein:

R₁ is hydrogen,

R₂ is chosen from hydrogen, (C₁-C₂₀)-alkyl and cycloalkylalkyl,

R₄ is chosen from phenyl, (C₁-C₂₀)-alkylphenyl and (C₁₂-C₂₀)-alkyl which is optionally substituted with —

OH, alkyloxy or halogen, and

R₁₁, R₁₂ and R₁₃ are independently of each other chosen from hydrogen and methyl.

25. The compound of claim 23, wherein:

R₁ is chosen from cycloalkylalkyl, optionally substituted with (C₁-C₅)-alkyl, and (C₁-C₅)—

O-alkyl,

R₂ is hydrogen,

R₄ is 1,2-dihydroxypropyl and

R₁₁, R₁₂ and R₁₃ are independently of each other chosen from hydrogen and methyl.

26. The compound of claim 25, wherein R₁ is chosen from cyclohexylmethyl and cylcohexylethyl.

27. The compound of claim 23, wherein:

R₁ is hydrogen,

R₂ is chosen from hydrogen, (C₁-C₂₀)-alkyl and cycloalkylalkyl,

R₄ is chosen from phenyl, (C₁-C₂₀)-alkylphenyl and (C₁-C₂₀)-alkyl which is optionally substituted with —

OH, (C₁-C₂₀)-alkyloxy or halogen,

R₁₁ is (C₁-C₅)-alkyl, which is optionally substituted,

R₁₂ and R₁₃ are independently of each other chosen from hydrogen and (C₁-C₅)-alkyl, which is optionally substituted.

28. The compound of claim 27, wherein:

R₁ and R₂ are hydrogen,

R₄ is 1,2-dihydroxypropyl

R₁₁ is chosen from methyl and ethyl, and

R₁₂ and R₁₃ are independently of each other chosen from hydrogen and methyl.

29. The compound of claim 23, wherein:

R₁ is chosen from cycloalkylalkyl, optionally substituted with (C₁-C₅)-alkyl, and (C₁-C₅)—

O-alkyl,

R₂ is hydrogen,

R₄ is 1,2-dihydroxypropyl, and

R₁₂ and R₁₃ are independently of each other chosen from hydrogen and methyl.

30. The compound of claim 29, wherein R₁ is chosen from cyclohexylmethyl and cyclohexylethyl.

31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to claim 23, or a pharmaceutically acceptable acid addition salt thereof.

32. A method of treating a disorder associated with an increased nitric oxide (NO) level, comprising administering to the subject a therapeutically sufficient amount of a compound of formula I, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and physiologically tolerated salts, hydrates and esters thereof,:

33. The method of claim 32, wherein in the compound of formula (I)

R₁ is hydrogen,

R₂ is chosen from hydrogen, (C₁-C₂₀)-alkyl and cycloalkylalkyl,

R₄ is chosen from phenyl, (C₁-C₂₀)-alkylphenyl and (C₁₂-C₂₀)-alkyl which is optionally substituted with —

OH, alkyloxy or halogen, and

R₁₁, R₁₂ and R₁₃ are independently of each other chosen from hydrogen and methyl.

34. The method of claim 32, wherein in the compound of formula (I)

R₁ is chosen from cycloalkylalkyl, optionally substituted with (C₁-C₅)-alkyl, and (C₁-C₅)—

O-alkyl,

R₂ is hydrogen,

R₄ is 1,2-dihydroxypropyl and

R₁₁, R₁₂ and R₁₃ are independently of each other chosen from hydrogen and methyl.

35. The method of claim 34, wherein in the compound of formula (I) R₁ is chosen from cyclohexylmethyl and cyclohexylethyl.

36. The method of claim 32, wherein in the compound of formula (I)

R₁ is hydrogen,

R₂ is chosen from hydrogen, (C₁-C₂₀)-alkyl and cycloalkylalkyl,

R₄ is chosen from phenyl, (C₁-C₂₀)-alkylphenyl and (C₁-C₂₀)-alkyl which is optionally substituted with —

OH, (C₁-C₂₀)-alkyloxy or halogen,

R₁₁, is (C₁-C₅)-alkyl, which is optionally substituted,

R₁₂ and R₁₃ are independently of each other chosen from hydrogen and (C₁-C₅)-alkyl, which is optionally substituted.

37. The method of claim 36, wherein in the compound of formula (I)

R₁ and R₂ are hydrogen,

R₄ is 1,2-dihydroxypropyl

R₁₁, is chosen from methyl and ethyl, and

R₁₂ and R₁₃ are independently of each other chosen from hydrogen and methyl.

38. The method of claim 32, wherein in the compound of formula (I)

R₁ is chosen from cycloalkylalkyl, optionally substituted with (C₁-C₅)-alkyl, and (C₁-C₅)—

O-alkyl,

R₂ is hydrogen,

R₄ is 1,2-dihydroxypropyl and

R₁₂ and R₁₃ are independently of each other chosen from hydrogen and methyl.

39. The method of claim 38, wherein in compound of formula (I) R₁ is chosen from cyclohexylmethyl and cyclohexylethyl.

40. The method of claim 32, wherein said disorder associated with an increased NO level is chosen from:

(a) disorders characterized by pathological blood pressure decreases;

(b) inflammatory disorders;

(c) insulin-dependent diabetes mellitus;

(d) transplant rejection reactions;

(e) cardiovascular disorders;

(f) disorders of the nervous system/central nervous system;

(g) disorders of the kidney.

41. The method of claim 32, wherein the subject is a mammal.

42. The method of claim 41, wherein the subject is a human.