Novel Quinoline-Hepcidine Antagonists

• US 20120196853A1
• Filed: 08/19/2010
• Published: 08/02/2012
• Est. Priority Date: 08/20/2009
• Status: Abandoned Application

• Current Assignee: Vifor (International) AG (CSL Limited)
• Original Assignee: Vifor (International) AG (CSL Limited)
• Inventors: Geisser, Peter O., Buhr, Wilm, Funk, Felix, Dürrenberger, Franz, Burckhardt, Susanna, Corden, Vincent A., Davenport, Tara, Jaeger, Stefan, Slack, Mark, Yarnold, Christopher J., Yau, Wei Tsung, Courtney, Stephen M.
• Application Number:
  US13/390,785
• Publication Number:
  US 20120196853A1
• Time in Patent Office: Days
• US Class Current: 514/232.5
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 19/04 for non-specific disorders of the connective tissue
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 215/26 Alcohols; Ethers thereof
• CPC Class Codes: C07D 215/28 with halogen atoms or nitro radicals in positions 5, 6 or 7
• CPC Class Codes: C07D 215/32 Esters
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention relates to novel hepcidin antagonists of the general formula (I), pharmaceutical compositions comprising them and the use thereof as medicaments, in particular for treatment of disorders in iron metabolism, such as, in particular, iron deficiency diseases and anaemias, in particular anaemias in connection with chronic inflammatory diseases (ACD: anaemia of chronic disease and AI: anaemia of inflammation).

Claims

1. A method of treating at least one disorder including iron metabolism disorders, comprising, administering to a patient in need, a preparation including compounds of the general formula (I)

2. The method according to claim 1, wherein

R¹, R² and R⁷ are identical or different and are each chosen from the group consisting of:

hydrogen,

hydroxyl,

halogen,

optionally substituted alkyl,

optionally substituted alkoxy,

optionally substituted aryl,

optionally substituted heteroaryl;

R⁶ is chosen from the group consisting of;

hydrogen,

optionally substituted alkyl,

optionally substituted aryl,

optionally substituted heteroaryl;

R³ is chosen from the group consisting of;

hydrogen,

optionally substituted alkyl,

optionally substituted aryl,

optionally substituted heteroaryl;

optionally substituted acyl; and

R⁴ and R⁵ are identical or different and are each chosen from the group consisting of;

hydrogen,

optionally substituted alkyl,

optionally substituted aryl,

optionally substituted heteroaryl;

or R⁴ and R⁵ together with the nitrogen atom to which they are bonded form a saturated or unsaturated, optionally substituted 5- to 8-membered ring which can optionally contain further hetero atoms;

or pharmaceutically acceptable salts.

3. The method according to claim 1, wherein

R¹, R² and R⁷ are identical or different and are each chosen from the group consisting of:

hydrogen,

hydroxyl,

halogen,

optionally substituted alkyl,

optionally substituted alkoxy;

R⁶ is chosen from the group consisting of;

hydrogen,

optionally substituted alkyl,

optionally substituted aryl,

optionally substituted heteroaryl;

R³ is chosen from the group consisting of;

hydrogen,

optionally substituted alkyl,

optionally substituted acyl; and

R⁴ and R⁵ are identical or different and are each chosen from the group consisting of

hydrogen,

optionally substituted alkyl,

optionally substituted aryl,

optionally substituted heteroaryl,

or wherein R⁴ and R⁵ together with the nitrogen atom to which they are bonded form a saturated or unsaturated, optionally substituted 5- to 6-membered ring which can optionally contain further hetero atoms;

or pharmaceutically acceptable salts thereof.

4. The method according to claim 1, wherein

R¹, R² and R⁷ are identical or different and are each chosen from the group consisting of:

hydrogen,

hydroxyl,

halogen,

optionally substituted alkyl,

optionally substituted alkoxy;

R⁶ is chosen from the group consisting of;

hydrogen,

optionally substituted alkyl,

optionally substituted aryl,

optionally substituted heteroaryl;

R³ is chosen from the group consisting of;

hydrogen,

optionally substituted alkyl,

optionally substituted acyl; and

R⁴ and R⁵ are identical or different and are each chosen from the group consisting of;

hydrogen,

optionally substituted aryl,

optionally substituted heteroaryl,

or wherein R⁴ and R⁵ together with the nitrogen atom to which they are bonded form a saturated or unsaturated, optionally substituted 5- to 6-membered ring which can optionally contain further hetero atoms;

or pharmaceutically acceptable salts thereof.

5. The method according to claim 1, with the meanings:

R¹;

hydrogen;

R²;

hydrogen,

halogen or

optionally substituted alkyl, in particular or cycloalkyl-substituted alkyl;

R³;

hydrogen,

optionally substituted alkyl, or optionally substituted arylalkyl or optionally substituted heteroarylalkyl, or

optionally substituted acyl, or optionally substituted aroyl or optionally substituted heteroaroyl;

R⁴ and R⁵ are identical or different and denote;

hydrogen,

optionally substituted alkyl,

optionally substituted aryl,

optionally substituted heteroaryl, or

R⁴ and R⁵ together with the nitrogen atom to which they are bonded form a saturated or unsaturated, optionally substituted 6-membered ring which can contain further hetero atoms;

R⁶;

hydrogen,

optionally substituted aryl, or

optionally substituted heteroaryl; and

R⁷;

hydrogen;

or pharmaceutically acceptable salts thereof.

6. The method according to claim 1, with the meanings:

R¹;

hydrogen;

R²;

hydrogen or

halogen;

R³;

hydrogen, or

optionally substituted acyl, in particular optionally substituted aroyl or optionally substituted heteroaroyl;

R⁴ and R⁵ are identical or different and denote;

hydrogen,

optionally substituted aryl,

optionally substituted heteroaryl, or

R⁴ and R⁵ together with the nitrogen atom to which they are bonded form a saturated or unsaturated, optionally substituted 6-membered ring which can contain further hetero atoms;

R⁶;

hydrogen,

optionally substituted aryl, or

optionally substituted heteroaryl; and

R⁷;

hydrogen;

or pharmaceutically acceptable salts thereof.

7. The method according to claim 1, wherein

R¹ is hydrogen,

R² is chosen from

hydrogen,

chlorine or

morpholinylalkyl, such as morpholinylmethyl;

R³ is chosen from

hydrogen,

optionally substituted benzyl or

optionally substituted furoyl or optionally substituted benzoyl;

R⁴ and R⁵ are identical or different and denote;

hydrogen,

optionally substituted alkyl,

optionally substituted heteroaryl, or

R⁴ and R⁵ together with the nitrogen atom to which they are bonded form a saturated, optionally substituted 6-membered ring which contains one or no further hetero atom;

R⁶ denotes;

hydrogen,

optionally halogen-, alkyl-, alkoxy-, aminocarbonyl- or cyano-substituted phenyl or

optionally substituted pyridinyl, pyrazinyl, imidazolyl or thienyl; and

R⁷ is hydrogen,

or pharmaceutically acceptable salts thereof.

8. The method according to claim 1, wherein

R¹ is hydrogen,

R² is chosen from

hydrogen or

chlorine

R³ is chosen from

hydrogen, or

optionally substituted furoyl or optionally substituted benzoyl;

R⁴ and R⁵ are identical or different and denote;

hydrogen,

optionally substituted heteroaryl, or

R⁴ and R⁵ together with the nitrogen atom to which they are bonded form a saturated, optionally substituted 6-membered ring which contains a further hetero atom;

R⁶ denotes;

hydrogen,

optionally halogen-substituted phenyl or

pyridinyl; and

R⁷ is hydrogen,

or pharmaceutically acceptable salts thereof.

10. The method of claim 1, wherein the preparation includes compounds chosen from

15. The method according to claim 1 further comprising treating at least a second disorder, the second disorder selected from the group consisting of anaemias, anaemias with cancer, anaemia induced by chemotherapy, anaemia induced by inflammation, anaemias with congestive cardiac insufficiency anaemia with chronic renal insufficiency stage 3-5 anaemia induced by chronic inflammation anaemia with rheumatic arthritis anaemia with systemic lupus erythematosus and anaemia with inflammatory intestinal diseases.

16. The method of claim 1, further comprising administering one or more pharmaceutical carriers together with at least one of auxiliary substances and solvents.

17. The method of claim 1, wherein the preparation further comprises at least one further pharmaceutically active compound, wherein the pharmaceutically active compound is a compound for treatment of disorders in iron metabolism and the accompanying symptoms, wherein said pharmaceutically active compound is an iron-containing compound.

9. (canceled)

11-14. -14. (canceled)

18-20. -20. (canceled)

21. A method of preparing a medicament for oral or parental administration comprising combining:

(a) at least one compound of the general formula (I),

22. A method of treating disorders in iron metabolism comprising administering:

(a) at least one compound of the general formula (I)