(19) TZZ _¥_T (11) EP 2 146 963 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 213/64 (2006.01) C07D 233/64 (2006.01) 17.12.2014 Bulletin 2014/51 C07D 233/68 (2006.01) C07D 233/70 (2006.01) C07D 401/10 (2006.01) C07D 401/12 (2006.01) (2006.01) (2006.01) (21) Application number: 08743204.3 C07D 409/06 A61K 31/4164 A61K 31/4178 (2006.01) A61K 31/4412 (2006.01) A61P 9/00 (2006.01) C07D 231/14 (2006.01) (22) Date of filing: 23.04.2008 A61K 45/00 (2006.01) A61K 31/415 (2006.01) A61K 31/417 (2006.01) A61K 31/4196 (2006.01) C07D 213/89 (2006.01) C07D 233/90 (2006.01) C07D 403/10 (2006.01) (86) International application number: PCT/US2008/005219 (87) International publication number: WO 2008/133896 (06.11.2008 Gazette 2008/45) (54) DUAL-ACTING ANTIHYPERTENSIVE AGENTS BLUTDRUCKSENKENDE MITTEL MIT DUALER WIRKUNG AGENTS ANTIHYPERTENSIFS À DOUBLE ACTION (84) Designated Contracting States: • MCKINNELL, Robert Murray AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Half Moon Bay, California 94019 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • MCMURTRIE, Darren RO SE SI SK TR Foster City, California 94404 (US) Designated Extension States: • OLSON, Brooke AL BA MK RS San Francisco, California 94110 (US) (30) Priority: 24.04.2007 US 925931 P (74) Representative: Scott, Susan Margaret et al Abel & Imray (43) Date of publication of application: 20 Red Lion Street 27.01.2010 Bulletin 2010/04 London WC1R 4PQ (GB) (73) Proprietor: Theravance Biopharma R&D IP, LLC (56) References cited: South San Francisco, CA 94080 (US) EP-A- 0 437 103 EP-A- 0 505 954 US-A- 5 616 599 (72) Inventors: • ALLEGRETTI, Paul • MIDDLEMISS D., ET AL.: "BENZOFURAN BASED Fort Collins, CO 80526 (US) ANGIOTENSIN II ANTAGONISTS RELATED TO • CHOI, Seok-ki GR117289: PART II; AMINOACID AMIDES" Palo Alto, California 94301 (US) BIOORGANIC & MEDICINAL CHEMISTRY • GENDRON, Roland LETTERS, vol. 3, no. 10, 1993, pages 2043-2046, San Francisco, California 94110 (US) XP002514917 • FATHEREE, Paul R. San Francisco, California 94107 (US) Remarks: • JENDZA, Keith Thefile contains technical information submitted after San Francisco, California 94114 (US) the application was filed and not included in this specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 146 963 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 146 963 B1 Description BACKGROUND OF THE INVENTION 5 FIELD OF THE INVENTION [0001] The present invention relates to novel compounds having angiotensin II type 1 (AT 1) receptor antagonist activity and neprilysin-inhibition activity. The invention also relates to pharmaceutical compositions comprising such compounds, processes and intermediates for preparing such compounds, and finds utility in methods of using such compounds to 10 treat diseases such as hypertension. STATE OF THE ART [0002] The aim of antihypertensive therapy is to lower blood pressure and prevent hypertension-related complications 15 such as myocardial infarction, stroke, and renal disease. For patients with uncomplicated hypertension (that is, no risk factors, target organ damage, or cardiovascular disease), it is hoped that reducing blood pressure will prevent develop- ment of cardiovascular and renal comorbidities, conditions that exist at the same time as the primary condition in the same patient. For those patients with existing risk factors or comorbidities, the therapeutic target is the slowing of comorbid disease progression and reduced mortality. 20 [0003] Physicians generally prescribe pharmacological therapies for patients whose blood pressure cannot be ade- quately controlled by dietary and/or lifestyle modifications. Commonly used therapeutic classes act to promote diuresis, adrenergic inhibition, or vasodilation. A combination of drugs is often prescribed, depending upon what comorbidities are present. [0004] There are five common drug classes used to treat hypertension: diuretics, which include thiazide and thiazide- 25 like diuretics such as hydrochlorothiazide, loop diuretics such as furosemide, and potassium-sparing diuretics such as triamterene; β1 adrenergic receptor blockers such as metoprolol succinate and carvedilol; calcium channel blockers such as amlodipine; angiotensin-converting enzyme (ACE) inhibitors such as captopril, benazepril, enalapril, enalaprilat, lisinopril, quinapril, and ramipril; and AT1 receptor antagonists, also known as angiotensin II type t receptor blockers (ARBs), such as candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan medoxomil, telmisartan, and valsar- 30 tan. Combinations of these drugs are also administered, for example, a calcium channel blocker (amlodipine) and an ACE inhibitor (benazepril), or a diuretic (hydrochlorothiazide) and an ACE inhibitor (enalapril). All of these drugs, when used appropriately, are effective in the treatment of hypertension. Nevertheless, both efficacy and tolerability should be further improved in new drugs targeting hypertension. Despite the availability of many treatment options, the recent National Health And Nutrition Examination Survey (NHANES) demonstrated that only about 50% of all treated patients 35 with hypertension achieve adequate blood pressure control. Furthermore, poor patient compliance due to tolerability issues with available treatments further reduces treatment success. [0005] In addition, each of the major classes of antihypertensive agents have some drawbacks. Diuretics can adversely affect lipid and glucose metabolism, and are associated with other side effects, including orthostatic hypotension, hy- pokalemia, and hyperuricemia. Beta blockers can cause fatigue, insomnia, and impotence; and some beta blockers can 40 also cause reduced cardiac output and bradycardia, which may be undesirable in some patient groups. Calcium channel blockers are widely used but it is debatable as to how effectively these drugs reduce fatal and nonfatal cardiac events relative to other drug classes. ACE inhibitors can cause coughing, and rarer side effects include rash, angioedema, hyperkalemia, and functional renal failure. AT1 receptor antagonists are equally effective as ACE inhibitors but without the high prevalence of cough. 45 [0006] EP 437,103, EP 505,954, US 5,616,599 and Bioorg. & Med. Chem. Lett. 3(10) 2043-2046 all disclose hetero- cyclic compounds having ATI receptor antagonist activity. [0007] Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is an endothelial membrane bound Zn 2+metallopepti- dase found in many tissues, including the brain, kidney, lungs, gastrointestinal tract, heart, and peripheral vasculature. NEP is responsible for the degradation and inactivation of a number of vasoactive peptides, such as circulating bradykinin 50 and angiotensin peptides, as well as the natriuretic peptides, the latter of which have several effects including vasodilation and diuresis. Thus, NEP plays an important role in blood pressure homeostasis. NEP inhibitors have been studied as potential therapeutics and include thiorphan, candoxatril, and candoxatrilat. In addition, compounds have also been designed that inhibit both NEP and ACE, and include omapatrilat, gempatrilat, and sampatrilat. Referred to as vasopepti- dase inhibitors, this class of compounds are described in Robl et al. (1999) Exp. Opin. Ther. Patents 9(12): 1665-1677. 55 [0008] There may be an opportunity to increase anti-hypertensive efficacy when combining AT 1 receptor antagonism and NEP inhibition, as evidenced by AT1 receptor antagonist/NEP inhibitor combinations described in WO 9213564 to Darrow et al (Schering Corporation); US20030144215 to Ksander et al.; Pu et al., Abstract presented at the Canadian Cardiovascular Congress (October 2004); and Gardiner et al. (2006) JPET 319:340-348; and WO 2007/045663 (Novartis 2 EP 2 146 963 B1 AG) to Glasspool et al. [0009] Recently, WO 2007/056546 (Novartis AG) to Feng et aL has described complexes of an AT 1 receptor antagonist and a NEP inhibitor, where an AT 1 receptor antagonist compound is non-covalently bound to a NEP inhibitor compound, or where the antagonist compound is linked to the inhibitor compound by a cation. 5 [0010] In spite of the advances in the art, there remains a need for a highly efficacious monotherapy with multiple mechanisms of action leading to levels of blood pressure control that can currently only be achieved with combination therapy. Thus, although various hypertensive agents are known, and administered in various combinations, it would be highly desirable to provide compounds having both AT1 receptor antagonist activity and NEP inhibition activity in the same molecule. Compounds possessing both of these activities are expected to be particularly useful as therapeutic 10 agents since they would exhibit antihypertensive activity through two independent modes of action while having single molecule pharmacokinetics. [0011] In addition, such dual-acting compounds are also expected to have utility to treat a variety of other diseases that can be treated by antagonizing the AT1 receptor and/or inhibiting the NEP enzyme. 15 SUMMARY OF THE INVENTION [0012] The present invention provides novel compounds that have been found to possess AT1