Macrocyclic ghrelin receptor modulators and methods of using the same

• US 10,258,602 B2
• Filed: 03/28/2018
• Issued: 04/16/2019
• Est. Priority Date: 02/09/2007
• Status: Active Grant

• Current Assignee: Ocera Therapeutics, Inc. (Mallinckrodt plc)
• Original Assignee: Ocera Therapeutics, Inc. (Mallinckrodt plc)
• Inventors: Hoveyda, Hamid, Fraser, Graeme, Benakli, Kamel, Marsault, Eric, Peterson, Mark L.
• Primary Examiner(s): Lieb, Jeanette M
• Application Number:
  US15/938,038
• Publication Number:
  US 20180228768A1
• Time in Patent Office: 384 Days
• Field of Search: None
• 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 method of treating gastroparesis comprising administering to a subject in need thereof an effective amount of a compound having the following structure:

2. The method of claim 1, wherein the gastroparesis is diabetic gastroparesis or postsurgical gastroparesis syndrome.

3. The method of claim 1, wherein the compound is administered orally.

4. The method of claim 1, wherein the compound is administered parenterally.

5. The method of claim 1, wherein the subject is a mammal.

6. The method of claim 1, wherein the subject is a human.

7. The method of claim 1, wherein the subject is a horse.

8. The method of claim 1, wherein the compound is co-administered with an additional agent useful for stimulating gastrointestinal motility.

9. A method of treating gastroparesis comprising administering to a subject in need thereof an effective amount of a compound having the following structure:

10. The method of claim 9, wherein the gastroparesis is diabetic gastroparesis or postsurgical gastroparesis syndrome.

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

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

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

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

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

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