Asymmetric ureas and medical uses thereof

• US 9,751,836 B2
• Filed: 01/08/2014
• Issued: 09/05/2017
• Est. Priority Date: 02/25/2011
• Status: Active Grant

• Current Assignee: Helsinn Healthcare SA
• Original Assignee: Helsinn Healthcare SA
• Inventors: Garcia Rubio, Silvina, Pietra, Claudio, Giuliano, Claudio, Li, Zhigang
• Primary Examiner(s): Chang, Celia
• Application Number:
  US14/150,360
• Publication Number:
  US 20140121210A1
• Time in Patent Office: 1,336 Days
• Field of Search: 5142372, 514314, 514318, 514319, 514321, 514329
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/4525 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• 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 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• 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: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 211/60 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/94 : Oxygen atom, e.g. piperidine N-oxide
• CPC Class Codes: C07D 211/96 : Sulfur atom
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links

Abstract

Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the ghrelin receptor. The compounds have the general formula (I):

Claims

1. A method of treating cachexia or gastroparesis by agonizing activity of a ghrelin receptor in a human subject comprising administering to said subject an effective amount of a ghrelin receptor agonist selected from the group consisting of 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, 1-hydroxy-3-(1-(4-methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, and 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, for the treatment of cachexia resulting from cancer, congestive heart failure, wasting due to ageing, or AIDS.

3. The method of claim 1, wherein said cachexia results from cancer.

4. The method of claim 3, wherein said cachexia results from congestive heart failure.

5. The method of claim 1, wherein said cachexia results from wasting due to ageing.

6. The method of claim 1, wherein said cachexia results from AIDS.

7. The method of claim 1, wherein said agonist or a pharmaceutically acceptable salt thereof, is administered by one or more routes selected from the group consisting of rectal, buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral and topical administration.

8. The method of claim 7, wherein said administration is accomplished by administering an oral form of said agonist or a pharmaceutically acceptable salt thereof.

9. The method of claim 1, wherein said agonist or a pharmaceutically acceptable salt thereof, is administered in an amount of from about 0.01 microgram per Kg g/Kg) body weight per day to about 100 mg/Kg body weight per day, from about 0.1 μ

g/Kg/day to about 10 mg/Kg/day, from about 1 μ

g/Kg/day to about 5 mg/Kg/day, from about 10 μ

g/Kg/day to about 5 mg/Kg/day, from about 100 μ

g/Kg/day to about 5 mg/Kg/day, or from about 500 μ

g/Kg/day to about 5 mg/Kg/day.

10. The method of claim 1, wherein the subject has been identified as needing treatment for the disease or the administration.

11. The method of claim 1 for the treatment of gastroparesis.

12. The method of claim 1 wherein said compound is 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 wherein said compound is 1-hydroxy-3-(1-(4-methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 wherein said compound is 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, or a pharmaceutically acceptable salt thereof.

15. A method of treating cachexia or gastroparesis by agonizing activity of a ghrelin receptor in a human subject comprising administering to said subject an effective amount of a ghrelin receptor agonist represented by formula (I):

16. The method of claim 15, for the treatment of cachexia from cancer, congestive heart failure, wasting due to ageing or AIDS.

17. The method of claim 16, wherein said cachexia results from cancer.

18. The method of claim 16, wherein said cachexia results from congestive heart failure.

19. The method of claim 16, wherein said cachexia results from wasting due to ageing.

20. The method of claim 15, wherein said cachexia results from AIDS.

21. The method of claim 15, wherein said compound or a pharmaceutically acceptable salt thereof, is administered by one or more routes selected from the group consisting of rectal, buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral and topical administration.

22. The method of claim 21, wherein said administration is accomplished by administering an oral form of said compound or a pharmaceutically acceptable salt thereof.

23. The method of claim 15, wherein said compound or a pharmaceutically acceptable salt thereof, is administered in an amount of from about 0.01 microgram per Kg g/Kg) body weight per day to about 100 mg/Kg body weight per day, from about 0.1 μ

g/Kg/day to about 10 mg/Kg/day, from about 1 μ

g/Kg/day to about 5 mg/Kg/day, from about 10 μ

g/Kg/day to about 5 mg/Kg/day, from about 100 μ

g/Kg/day to about 5 mg/Kg/day, or from about 500 μ

g/Kg/day to about 5 mg/Kg/day.

24. The method of claim 22, wherein the subject has been identified as needing treatment for the disease or the administration.

25. The method of claim 15, wherein R is aryl.

26. The method of claim 15, wherein R is phenyl or naphthalene which is optionally independently substituted with from one to six substituents independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, trifluoromethyl, cyano, methoxy, ethoxy, methyl and ethyl.

27. The method of claim 15, wherein R₁ is selected from the group consisting of alkoxy, alkoxyalkyl, —

OR¹⁰¹, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl.

28. The method of claim 15, wherein R₁ is selected from the group consisting of alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl and heteroarylalkyl.

29. The method of claim 15, wherein R₁ is selected from the group consisting of methyl, —

CH₂OH, and —

CH₂—

O—

CH₂-phenyl.

30. The method of claim 15, wherein R₃ is hydrogen, alkyl or cycloalkyl.

31. The method of claim 15, wherein R₄ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amino, alkoxy, alkylamino, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and aminoalkyl.

32. The method of claim 15, wherein R₄ is methyl, ethyl, benzyl, or benzyl substituted with from one to five substituents independently selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl, methoxy, cyano and hydroxy.

33. The method of claim 15, wherein R₅ is selected from the group consisting of alkyl, cycloalkyl, oxide (═

O), aryl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —

C(O)R¹⁰¹, —

C(O)OR¹⁰¹ and —

C(O)NR¹⁰¹R¹⁰².

34. The method of claim 15, wherein R₅ is methyl.

35. The method of claim 15, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, —

C(O)OR¹⁰¹, and -alkylOR¹⁰³.

36. The method of claim 15, wherein R₈ and R₉ are each independently hydrogen, alkyl, cycloalkyl, —

C(O)OR¹⁰¹, or -alkylOR¹⁰³.

37. The method of claim 15, wherein R₈ and R₉ are each independently hydrogen, methyl, ethyl, —

C(═

O)OEt, or —

CH₂OH.

38. The method of claim 15 for the treatment of gastroparesis.

39. A method of treating cachexia or gastroparesis by agonizing activity of a ghrelin receptor in a human subject comprising administering to said subject an effective amount of a ghrelin receptor agonist selected from one of the following compounds, or a pharmaceutically acceptable salt thereof:

40. The method of claim 39, for the treatment of cachexia from cancer, congestive heart failure, wasting due to ageing or AIDS, chronic liver failure, chronic obstructive pulmonary disease, gastrointestinal disease, or gastric disorder.

41. The method of claim 39, wherein said cachexia results from cancer.

42. The method of claim 40, wherein said cachexia results from congestive heart failure.

43. The method of claim 40, wherein said cachexia results from wasting due to ageing.

44. The method of claim 39, wherein said cachexia results from AIDS.

45. The method of claim 39, wherein said compound or a pharmaceutically acceptable salt thereof, is administered by one or more routes selected from the group consisting of rectal, buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral and topical administration.

46. The method of claim 39, wherein said administration is accomplished by administering an oral form of said compound or a pharmaceutically acceptable salt thereof.

47. The method of claim 39, wherein said compound or a pharmaceutically acceptable salt thereof, is administered in an amount of from about 0.01 microgram per Kg g/Kg) body weight per day to about 100 mg/Kg body weight per day, from about 0.1 μ

g/Kg/day to about 10 mg/Kg/day, from about 1 μ

g/Kg/day to about 5 mg/Kg/day, from about 10 μ

g/Kg/day to about 5 mg/Kg/day, from about 100 μ

g/Kg/day to about 5 mg/Kg/day, or from about 500 μ

g/Kg/day to about 5 mg/Kg/day.

48. The method of claim 39, wherein the subject has been identified as needing treatment for the disease or the administration.

49. The method of claim 39 for the treatment of gastroparesis.