MACROCYCLIC GHRELIN RECEPTOR MODULATORS AND METHODS OF USING THE SAME

• US 20080194672A1
• Filed: 02/08/2008
• Published: 08/14/2008
• Est. Priority Date: 02/09/2007
• Status: Active Grant

• Current Assignee: Ocera Therapeutics, Inc. (Mallinckrodt plc)
• Original Assignee: Tranzyme Pharma, Inc. (Mallinckrodt plc)
• Inventors: Drutz, David, Peterson, Mark L., Fraser, Graeme L., Hoveyda, Hamid, Brassard, Martin, Marsault, Eric, Ouellet, Luc, Beauchemin, Sophie, Benakli, Kamel, Wang, Zhigang
• Granted Patent: US 9,371,297 B2
• Time in Patent Office: Days
• US Class Current: 514/450
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• 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 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• 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 3/00 : 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/06 : Antianaemics
• 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 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07C 215/42 : having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
• CPC Class Codes: C07C 215/54 : linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 271/16 : to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07D 273/00 : Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/16 : Peri-condensed systems

Abstract

The present invention provides novel conformationally-defined macrocyclic compounds that can function as selective modulators of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, central nervous system disorders, bone disorders, genetic disorders, hyperproliferative disorders and inflammatory disorders.

Claims

1. A compound of formula I:

7. A pharmaceutical composition comprising:

(a) a compound of formula I of claim 1; and

(b) a pharmaceutically acceptable carrier, excipient or diluent.

20. A kit comprising one or more containers containing pharmaceutical dosage units comprising an effective amount of one or more compounds of claims 1, 10, 11 or 12.

2. The compound of formula I, wherein

R₁ is cyclopropyl, cyclohexyl, —

CH₂CH₃, —

CH₂CH₂CH₃, —

CH₂CH₂CH₂CH₃, —

CH(CH₃)₂, —

CH(OH)CH₃, —

CH(OCH₃)CH₃, —

CH₂CH(CH₃)₂, or —

CH(CH₃)CH₂CH₃;

R₂ is methyl, fluoromethyl or hydroxymethyl;

R₃ is —

CH₂CH(CH₃)₂, —

C(CH₃)₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxyphenyl, —

C(OR₁₄)R₁₅R₁₆, wherein R₁₄, R₁₅ and R₁₆ are independently selected from hydrogen and lower alkyl; and

—

CR_11aR_11bR₁₂, wherein R_11a and R_11b are independently hydrogen or methyl and R₁₂ is selected from the group consisting of

3. The compound of formula I having the following structure:

4. A compound of formula II:

5. The compound of formula II having the following structure:

6. A macrocyclic compound comprising:

(a) a building block structure; and

(b) a compound of formula II, or a derivative thereof.

9. A method of treating a gastrointestinal disorder comprising administering to a subject in need thereof an effective amount of a compound of formula I:

8. A pharmaceutical composition comprising:

(a) a compound of claim 10; and

(b) a pharmaceutically acceptable carrier, excipient or diluent.

10. The method of claim 9, wherein the compound has the following structure:

11. The method of claim 9, wherein the gastrointestinal disorder is characterized by gastrointestinal dysmotility.

12. The method of claim 9, wherein the gastrointestinal disorder is postoperative ileus, gastroparesis, opioid-induced bowel dysfunction, chronic intestinal pseudo-obstruction, acute colonic pseudo-obstruction (Ogilvie'"'"'s syndrome), short bowel syndrome, emesis, constipation-predominant irritable bowel syndrome (IBS), chronic constipation, cancer-associated dyspepsia syndrome, delayed gastric emptying, gastrointestinal dysfunction or delayed gastric emptying in patients with Parkinson'"'"'s disease, gastrointestinal dysfunction or delayed gastric emptying in myotonic muscular dystrophy, gastrointestinal dysfunction or delayed gastric emptying in patients with scerloderma, gastroesophageal reflux disease (GERD), gastric ulcers or Crohn'"'"'s disease.

13. The method of claim 12, wherein the gastroparesis is diabetic gastroparesis or postsurgical gastroparesis syndrome.

14. The method of claim 9, wherein the compound is administered orally.

15. The method of claim 9, wherein the compound is administered parenterally.

16. The method of claim 9, wherein the subject is a mammal.

17. The method of claim 9, wherein the subject is a human.

18. The method of claim 9, wherein the subject is a horse.

19. The method of claim 9, wherein the compound is co-administered with an additional agent useful for stimulating gastrointestinal motility.

21. A method of treating a metabolic or endocrine disorder comprising administering to a subject in need thereof an effective amount of a compound of formula I:

22. The method of claim 21, wherein the compound has the following structure:

23. The method of claim 21, wherein the metabolic or endocrine disorder is characterized by lack of appetite, decrease in food intake, reduced energy expenditure, or muscle wasting.

24. The method of claim 23, wherein the metabolic or endocrine disorder is cachexia.

25. A method of treating a cardiovascular disease comprising administering to a subject in need thereof an effective amount of a compound of formula I:

26. The method of claim 25, wherein the compound has the following structure:

27. The method of claim 25, wherein the cardiovascular disease is chronic heart failure.

28. A method of treating a central nervous system disorder comprising administering to a subject in need thereof an effective amount of a compound of formula I:

29. The method of claim 28, wherein the central nervous system disorder is Alzheimer'"'"'s disease, Parkinson'"'"'s disease, anxiety, stress, insomnia, or is characterized by reduced cognitive function or by disruption of normal sleep patterns.

30. A method of treating an inflammatory disorder comprising administering to a subject in need thereof an effective amount of a compound of formula I:

31. The method of claim 30, wherein the inflammatory disorder is ulcerative colitis, inflammatory bowel disease, Crohn'"'"'s disease, pancreatitis, rheumatoid arthritis, osteoarthritis, asthma, vasculitis, psoriasis, allergic rhinitis, peptic ulcer disease, postoperative intra-abdominal sepsis, ischemia-reperfusion injury, pancreatic and liver damage, sepsis and septic shock, gastric damage caused by certain drugs, stress-induced gastric damage, gastric damage caused by H. pylori, inflammatory pain, chronic kidney disease or intestinal inflammation.

32. A method of treating a hyperproliferative disorder comprising administering to a subject in need thereof an effective amount of a compound of formula I:

33. The method of claim 32, wherein the hyperproliferative disorder is cancer.

34. A method of treating a bone disorder comprising administering to a subject in need thereof an effective amount of a compound of formula I:

35. The method of claim 34, wherein the bone disorder is osteoporosis.

36. A method of treating a patient suffering from reduced or dysfunctional gastrointestinal motility caused by an agent, the method comprising administering a compound of formula I:

37. The method of claim 36 wherein the metabolic disorder is selected from type 1 diabetes, type II diabetes, obesity or metabolic syndrome.

38. The method of claim 36 wherein the hyperproliferative disorder is selected from multiple myeloma, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, small lymphocytic lymphoma, chronic lymphocytic lymphoma, follicular lymphoma, mantle cell lymphoma, neuroendocrine carcinoma, heptacellular carcinoma, non-small-cell carcinoma, hematological tumors, solid tumors, tumors of the prostate or colon, lung, stomach, ovary or breast cancer.

39. The method of claim 36 wherein the agent is selected from a GLP-1 receptor agonist, an amylin receptor agonist, a peptide YY (PYY) receptor agonist, a proteasome inhibitor, an anti-cholinergic agent, a tricyclic antidepressant, a monoamine uptake blocker antidepressant, a cancer chemotherapy agent, an adrenergic agonist, a dopaminergic agent, an antimalarial or an antispasmodic.

40. The method of claim 36 wherein the agent is selected from GLP-1, GLP-1 (7-36) amide, exenatide (exendin-4), liraglutide (NN2211), gilatide, albiglutide (GSK-716155, albugon), GLP1-I.N.T., AC2592, AC2993 LAR, ARI-2255, ARI-2651, BRX-0585 (GLP-1-Tf), CJC-1131, PC-DAC™

;

Exendin-4, CS-872, AVE-0010 (ZP-10), BIM-51077 (R-1583), BIM-51182, ITM-077, SUN E7001, TH-0318, TH-0396, TTP-854, LY-315902, LY-307161, amylin, pramlintide, MBP-0250, PX811016, peptide YY, peptide YY 3-36 (AC-162352), bortezomib, carfilzomib (PR-171), MLN-273, MLN-519 (LDP-519), NPI-0052, (salinosporamide A), MG-132, MG-162, PR39, CEP-18770, atropine, benzotropine, hyoscine, propantheline, scopolamine, trihexyphenidyl, phenothiazines, amitriptyline, nortryptyline, desipramine, fluoxetine, citalopram, nomifensine, other psychoactive medications, vincristine), isoproterenol, salbutamol, lidamidine, clonidine, levodopa, bromocriptine, apomorphine, chloroquine or mepacrine.

41. The method of claim 36 wherein the compound is administered concurrently with the agent causing reduced or dysfunctional gastrointestinal motility.

42. The method of claim 36 wherein the compound is administered subsequent to the agent causing reduced or dysfunctional gastrointestinal motility.

43. The method of claim 36 wherein the compound is administered prior to administration of the agent causing reduced or dysfunctional gastrointestinal motility.

44. A pharmaceutical composition comprising:

(a) a ghrelin receptor agonist;

(b) a GLP-1 receptor agonist; and

(c) a pharmaceutically acceptable carrier, excipient or diluent.

45. The pharmaceutical composition of claim 44, wherein the ghrelin receptor agonist is a compound of formula I:

46. The pharmaceutical composition of claim 44, wherein the ghrelin receptor agonist is selected from ghrelin, hexarelin, GHRP-1, GHRP-2, GHRP-6, ipamorelin, tesamorelin, MK-0677, NN703, capromorelin, G7039, G7134, G7203, G7502, SM-130686, BMS-604992, RC-1141, RC-1239, RC-1291, EX-1314, GTP-200, SUN 11031, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187 or NNC-26-1291.

47. The pharmaceutical composition of claim 44, wherein the GLP-1 receptor agonist is selected from GLP-1, GLP-1 (7-36) amide, exenatide (exendin-4), liraglutide (NN2211), gilatide, albiglutide (GSK-716155, albugon), GLP1-I.N.T., AC2592, AC2993 LAR, ARI-2255, ARI-2651, BRX-0585 (GLP-1-Tf), CJC-1131, PC-DAC™

;

Exendin-4, CS-872, AVE-0010 (ZP-10), BIM-51077 (R-1583), BIM-51182, ITM-077, SUN E7001, TH-0318, TH-0396, TTP-854, LY-315902 or LY-307161.

57. A method of treating a metabolic disorder comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of claims 44, 48 or 51.

58. The method of claim 57 wherein the metabolic disorder is type 1 diabetes, type II diabetes, obesity or metabolic syndrome, is characterized by hyperinsulinemia, or is complicated by GI dysmotility.

59. The method of claim 57, wherein the pharmaceutical composition is administered orally.

60. The method of claim 57, wherein the pharmaceutical composition is administered parenterally.

61. The method of claim 57, wherein the subject is a mammal.

62. The method of claim 57, wherein the subject is a human.

63. A kit comprising one or more containers containing pharmaceutical dosage units comprising an effective amount of a pharmaceutical composition of claims 44, 48 or 51.

48. A pharmaceutical composition comprising:

(a) a ghrelin receptor agonist;

(b) an amylin receptor agonist; and

(c) a pharmaceutically acceptable carrier, excipient or diluent.

49. The pharmaceutical composition of claim 48, wherein the ghrelin receptor agonist is selected from ghrelin, hexarelin, GHRP-1, GHRP-2, GHRP-6, ipamorelin, tesamorelin, MK-0677, NN703, capromorelin, G7039, G7134, G7203, G7502, SM-130686, BMS-604992, RC-1141, RC-1239, RC-1291, EX-1314, GTP-200, SUN 11031, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187 or NNC-26-1291.

50. The pharmaceutical composition of claim 48, wherein the amylin receptor agonist is selected from amylin, pramlintide, MBP-0250 or PX811016.

51. A pharmaceutical composition comprising:

(a) a ghrelin receptor agonist;

(b) a peptide YY (PYY) receptor agonist; and

(b) a pharmaceutically acceptable carrier, excipient or diluent.

52. The pharmaceutical composition of claim 51, wherein the ghrelin receptor agonist is selected from ghrelin, hexarelin, GHRP-1, GHRP-2, GHRP-6, ipamorelin, tesamorelin, MK-0677, NN703, capromorelin, G7039, G7134, G7203, G7502, SM-130686, BMS-604992, RC-1141, RC-1239, RC-1291, EX-1314, GTP-200, SUN 11031, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-11136, NNC-26-11137, NNC-26-1187 or NNC-26-1291.

53. The pharmaceutical composition of claim 51, wherein the peptide YY receptor agonist is selected from peptide YY or peptide YY 3-36 (AC-162352).

54. A pharmaceutical composition comprising:

(a) a ghrelin receptor agonist;

(b) a proteasome inhibitor; and

(b) a pharmaceutically acceptable carrier, excipient or diluent.

55. The pharmaceutical composition of claim 54, wherein the ghrelin receptor agonist is selected from ghrelin, hexarelin, GHRP-1, GHRP-2, GHRP-6, ipamorelin, tesamorelin, MK-0677, NN703, capromorelin, G7039, G7134, G7203, G7502, SM-130686, BMS-604992, RC-1141, RC-1239, RC-1291, EX-1314, GTP-200, SUN 11031, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187 or NNC-26-1291.

56. The pharmaceutical composition of claim 54, wherein the proteasome inhibitor is selected from bortezomib, carfilzomib (PR-171), MLN-273, MLN-519 (LDP-519), NPI-0052, (salinosporamide A), MG-132, MG-162, PR39 or CEP-18770.

64. A method of treating a hyperproliferative disorder comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of claim 54.

65. The method of claim 64 wherein the hyperproliferative disorder is selected from multiple myeloma, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, small lymphocytic lymphoma, chronic lymphocytic lymphoma, follicular lymphoma, mantle cell lymphoma, neuroendocrine carcinoma, heptacellular carcinoma, non-small-cell carcinoma, hematological tumors, solid tumors, tumors of the prostate or colon, lung, stomach, ovary or breast cancer.

66. The method of claim 64 wherein the hyperproliferative disorder is complicated by GI dysmotility.

67. The method of claim 64, wherein the pharmaceutical composition is administered orally.

68. The method of claim 64, wherein the pharmaceutical composition is administered parenterally.

69. The method of claim 64, wherein the subject is a mammal.

70. The method of claim 64, wherein the subject is a human.

71. A kit comprising one or more containers containing pharmaceutical dosage units comprising an effective amount of a pharmaceutical composition of claim 54.