Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors

• US 9,480,693 B2
• Filed: 09/10/2015
• Issued: 11/01/2016
• Est. Priority Date: 02/14/2013
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Barnes, David Weninger, Cohen, Scott Louis, Rigel, Dean Franklin
• Primary Examiner(s): CRUZ, KATHRIEN ANN
• Application Number:
  US14/850,224
• Publication Number:
  US 20150374726A1
• Time in Patent Office: 418 Days
• Field of Search: 514/89, 514/119, 514/101, 514/91, 549/221, 558/275, 560/41, 562/15, 546/22, 548/413
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/665 having oxygen as a ring hetero atom, e.g. fosfomycin
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/08 : Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• 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 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07F 9/3808 : Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/572 : Five-membered rings
• CPC Class Codes: C07F 9/59 : Hydrogenated pyridine rings
• CPC Class Codes: C07F 9/65515 : the oxygen atom being part of a five-membered ring

Abstract

The present invention provides a compound of formula I;

or a pharmaceutically acceptable salt thereof, wherein R¹, R² and R³ are defined herein. The invention also relates to a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides pharmaceutical composition of the compounds of the invention and a combination of pharmacologically active agents and a compound of the invention.

Claims

1. A method of treating a disorder or a disease associated with neutral endopeptidase activity in a subject in need thereof, comprising:

administering to the subject a therapeutically effective amount of a compound of the formula (I);

2. The method according to claim 1 wherein the compound is of Formula II:

3. The method according to claim 1 wherein R² is Cl and R³ is F;

or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 wherein the compound is of Formula III:

5. The method according to claim 1 wherein the compound is of Formula IV:

6. The method of claim 1 wherein R¹ is —

C_1-7alkyl or C_6-10aryl;

wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of —

O—

C(O)—

O—

C_3-7cycloalkyl, —

O—

C(O)—

C_3-7cycloalkyl, —

O—

C(O)—

C_6-10aryl, —

O—

C(O)—

O—

C_6-10aryl, —

O—

C(O)—

O—

C_1-7alkyl, —

O—

C(O)—

C_1-7alkyl, heteroaryl, heterocyclyl, —

C(O)—

heterocyclyl, —

C(O)NH₂, —

C(O)NH—

C_1-7alkyl, and —

C(O)N(C_1-7alkyl)₂;

or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1 wherein R¹ is —

C_1-4alkyl or R¹ is selected from the following groups;

8. The method according to claim 1 wherein R¹ is Me, Et or is selected from a group of the following Formulae:

9. The method compound to claim 1 -wherein R¹ is Me, Et or is selected from a group of the following Formulae:

11. The method according to claim 1, wherein the disorder or the disease is selected from renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, contrast-induced nephropathy, nephrotic syndrome and end-stage renal disease (ESRD).

12. The method according to claim 1 wherein the compound is (3-(((R)-1-(5′

-chloro-2′

-fluoro-[1,1′

-biphenyl]-4-yl)-4-((S)-1-(((cyclohexyloxy)carbonyl)oxy)ethoxy)-4-oxobutan-2-yl)amino)-3-oxopropyl)phosphonic acid;

or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12, wherein the disorder or the disease is selected from, renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, contrast-induced nephropathy, nephrotic syndrome and end-stage renal disease (ESRD).

10. A method of inhibiting neutral endopeptidase activity in a subject in need thereof, comprising:

administering to the subject a therapeutically effective amount of a compound of Formula (I);