Substituted Aminopropionic Derivatives as Neprilysin inhibitors

• US 20100305131A1
• Filed: 05/27/2010
• Published: 12/02/2010
• Est. Priority Date: 05/28/2009
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Ksander, Gary Michael, Sun, Robert, Coppola, Gary Mark, Mogi, Muneto, Kawanami, Toshio, Karki, Rajeshri Ganesh, Iwaki, Yuki
• Granted Patent: US 8,394,853 B2
• Time in Patent Office: Days
• US Class Current: 514/239.2
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/421 1,3-Oxazoles, e.g. pemoline, trimethadione
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 : Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/08 : for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 : for impotence
• CPC Class Codes: A61P 15/12 : for climacteric disorders
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• 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 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 3/00 : 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 3/10 : 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 5/24 : of the sex hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• 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 9/10 : 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: C07B 2200/05 : Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 233/47 : having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/49 : having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
• CPC Class Codes: C07C 233/51 : having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/56 : having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
• CPC Class Codes: C07C 233/63 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/12 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/78 : the carbon skeleton containing rings
• CPC Class Codes: C07C 237/16 : the carbon skeleton being acyclic and unsaturated
• CPC Class Codes: C07C 237/22 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 255/60 : at least one of the singly-bound nitrogen atoms being acylated
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2602/08 : the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 271/22 : to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 275/24 : containing six-membered aromatic rings
• CPC Class Codes: C07C 311/08 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/51 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 239/28 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/34 : One oxygen atom
• CPC Class Codes: C07D 239/36 : as doubly bound oxygen atom or as unsubstituted hydroxy radical
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 263/32 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 265/30 : not condensed with other rings
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 295/15 : to an acyclic saturated chain
• CPC Class Codes: C07D 309/32 : having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 317/34 : Oxygen atoms

Abstract

The present invention provides a compound of formula I′;

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁵, B¹, X and n are defined herein. The invention also relates a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Claims

1. A compound of Formula I′

;

2. A compound according to claim 1 of Formula I:

3. The compound of claim 1 wherein:

R¹ is H or C_1-7alkyl;

R² for each occurrence, is independently C_1-7alkyl, halo, C_3-7cycloalkyl, hydroxy, C_1-7alkoxy, haloC_1-7alkyl, —

NR^aR^b, C_6-20aryl, heteroaryl or heterocyclyl;

wherein R^a and R^b for each occurrence are independently H or C_1-7alkyl;

R³ is A¹-C(O)X¹ or A²-R⁴;

R⁴ is C_6-20aryl or a heteroaryl, each of which can be monocyclic or bicyclic and each of which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C_1-7alkoxy, halo, C_1-7alkyl, halo-C_1-7alkyl, C_6-10aryl, heteroaryl, —

NHSO₂—

C_1-7alkyl and benzyl;

R⁵ is H; and

X and X¹ are independently OH, —

O—

C_1-7alkyl or NR^aR^b;

B′

is —

C(O)NH—

or —

NHC(O)—

;

A¹ is a linear or branched C_1-7alkylene;

which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C_3-7cycloalkyl, C_1-7alkoxy, hydroxy and O-acetate;

in which two geminal alkyl can optionally combine to form a C_3-7cycloalkyl;

or

A¹ is a phenyl or a heteroaryl;

each of which is optionally substituted with one or more substituents independently selected from the group consisting of C_1-7alkyl, C_3-7cycloalkyl, hydroxy, C_1-7alkoxy, halo, —

NR^aR^b, —

OCH₂CO₂H, and —

OCH₂C(O)NH₂; and

A² is a bond or a linear or branched C_1-7 alkylene;

which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C_1-7alkoxy, hydroxy, O-Acetate and C_3-7cycloalkyl; and

n is 0, 1, 2, 3, 4 or 5;

wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and

each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 having Formula II or IIA:

5. The compound of claim 1 having formula III or IIIA:

6. The compound of claim 1 or 4 wherein A¹ is an optionally substituted linear or branched C_1-7 alkylene, or a pharmaceutically acceptable salt thereof.

7. The compounds of claim 1 or 4 wherein A¹ is CH₂CH₂, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein A¹ is an optionally substituted phenyl or heteroaryl, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 having Formula VII or VIIA:

10. The compound of claim 9 wherein A² is a bond or CH₂ or CH₂—

CH₂, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 or 4 wherein R¹ is H, R² is independently halo, C_1-7alkoxy, hydroxy, C_1-7alkyl or halo-C_1-7alkyl, n is 0, 1 or 2 and X and X¹ are independently OH or —

O—

C_1-7alkyl, or a pharmaceutically acceptable salt thereof.

12. The compounds of claim 11 wherein n is 1 or 2;

R² is meta-chloro or meta-fluoro and the other optional R² group is halo, C_1-7alkyl, hydroxy and C_1-7alkoxy, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

14. A combination comprising:

a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents selected from HMG-Co-A reductase inhibitor, an anigiotensin receptor blocker, angiotensin converting enzyme Inhibitor, a calcium channel blocker, an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-I mimic, an anti-diabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, an aldosterone synthase inhibitors, a CETP inhibitor and a phosphodiesterase of type 5 (PDE5) inhibitor.

15. A method of inhibiting neutral endopeptidase EC. 3.4.24.11. activity in a subject in need thereof, comprising:

administering to the subject a therapeutically effective amount of the compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof.

16. The method according to claim 15, wherein the disorder or the disease is selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (MI), renal fibrosis, polycystic kidney disease (PKD), pulmonary arterial hypertension, renal failure, cyclical oedema, Meniè

res disease, hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders, depression, psychotic condition, dementia, geriatric confusion, obesity and gastrointestinal disorders, wound healing, septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications, atherosclerosis, male and female sexual dysfunction.

20. The compounds of claim 7 wherein n is 1 or 2;

R² is meta-chloro or meta-fluoro and the other optional R² group is halo, C_1-7alkyl, halo-C_1-7alkyl, hydroxy and C_1-7alkoxy, and X and X¹ are independently OH or —

O—

C_1-7alkyl, or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound according to claim 7, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

22. A pharmaceutical composition comprising a compound according to claim 20, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

23. A method of inhibiting neutral endopeptidase EC. 3.4.24.11. activity in a subject in need thereof, wherein the disorder or the disease is selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (MI), renal fibrosis, polycystic kidney disease (PKD), pulmonary arterial hypertension, renal failure, cyclical oedema, Meniè

res disease, hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders, depression, psychotic condition, dementia, geriatric confusion, obesity and gastrointestinal disorders, wound healing, septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications, atherosclerosis, male and female sexual dysfunction;

comprising;

administering to the subject a therapeutically effective amount of the compound according to claim 7, or a pharmaceutically acceptable salt thereof.

24. A method of inhibiting neutral endopeptidase EC. 3.4.24.11. activity in a subject in need thereof, wherein the disorder or the disease is selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (MI), renal fibrosis, polycystic kidney disease (PKD), pulmonary arterial hypertension, renal failure, cyclical oedema, Meniè

res disease, hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders, depression, psychotic condition, dementia, geriatric confusion, obesity and gastrointestinal disorders, wound healing, septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications, atherosclerosis, male and female sexual dysfunction;

comprising;

administering to the subject a therapeutically effective amount of the compound according to claim 20, or a pharmaceutically acceptable salt thereof.

17-19. -19. (canceled)