Substituted aminobutyric derivatives as neprilysin inhibitors
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Abstract
The present invention provides a compound of formula I′;
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, X and n 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 a combination of pharmacologically active agents and a pharmaceutical composition.
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Citations
16 Claims
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1. A compound of the formula (IIB):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
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2. The compound according to claim 1, having Formula IIC
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3. The compound according to claim 1 wherein A1 has the following Formulae:
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4. The compound according to claim 3 wherein A1 is selected from the group consisting of:
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5. The compound according to claim 1 wherein A1 has the following Formula:
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6. The compound according to claim 5 wherein A1 is selected from the group consisting of:
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7. The compound according to claim 1 wherein each R2 is independently halo, alkyl, alkoxy, hydroxy, haloalkyl;
- or a pharmaceutically acceptable salt thereof.
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8. The compound according to claim 1 wherein X and X1 are independently OH or —
- O—
C1-7alkyl;
or a pharmaceutically acceptable salt thereof.
- O—
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9. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
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10. 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.
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11. 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 a pharmaceutically acceptable salt thereof.
- administering to the subject a therapeutically effective amount of the compound according to claim 1;
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12. A method of slowing or arresting the development of, or alleviating or ameliorating at least one physical parameter of, or stabilizing a discernible symptoms of a disorder or a disease associated with 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 a pharmaceutically acceptable salt 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, reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders, depression and 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.
- administering to the subject a therapeutically effective amount of the compound according to claim 1;
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13. A pharmaceutical composition comprising a compound according to claim 6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
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14. A combination comprising:
- a compound according to claim 6 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.
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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 6;
or a pharmaceutically acceptable salt thereof.
- administering to the subject a therapeutically effective amount of the compound according to claim 6;
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16. A method of slowing or arresting the development of, or alleviating or ameliorating at least one physical parameter of, or stabilizing a discernible symptoms of a disorder or a disease associated with 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 6;
or a pharmaceutically acceptable salt 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, reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders, depression and 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.
- administering to the subject a therapeutically effective amount of the compound according to claim 6;
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2. The compound according to claim 1, having Formula IIC
Specification
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Current AssigneeNovartis Ag
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Original AssigneeNovartis Ag
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InventorsKarki, Rajeshri, Coppola, Gary Mark, Iwaki, Yuki, Kawanami, Toshio, Ksander, Gary Michael, Mogi, Muneto, Sun, Robert
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Primary Examiner(s)SHTERENGARTS, SAMANTHA L
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Application NumberUS14/635,311Publication NumberTime in Patent Office757 DaysField of SearchNoneUS Class Current1/1CPC Class CodesA61K 31/194 having two or more carboxyl...A61K 45/06 Mixtures of active ingredie...A61P 1/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 13/02 of urine or of the urinary ...A61P 13/12 of the kidneysA61P 15/00 Drugs for genital or sexual...A61P 15/04 for inducing labour or abor...A61P 15/06 Antiabortive agents; Labour...A61P 15/08 for gonadal disorders or fo...A61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 25/04 Centrally acting analgesics...A61P 25/08 Antiepileptics; Anticonvuls...A61P 25/18 Antipsychotics, i.e. neurol...A61P 25/20 Hypnotics; SedativesA61P 25/24 AntidepressantsA61P 25/28 for treating neurodegenerat...A61P 27/02 Ophthalmic agentsA61P 27/06 Antiglaucoma agents or mioticsA61P 27/16 : OtologicalsA61P 29/00 : Non-central analgesic, anti...A61P 3/00 : Drugs for disorders of the ...A61P 3/04 : Anorexiants; Antiobesity ag...A61P 3/10 : for hyperglycaemia, e.g. an...A61P 31/02 : Local antisepticsA61P 35/02 : specific for leukemiaA61P 43/00 : Drugs for specific purposes...A61P 7/00 : Drugs for disorders of the ...A61P 7/10 : Antioedematous agents; Diur...A61P 9/00 : Drugs for disorders of the ...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/06 : AntiarrhythmicsA61P 9/08 : Vasodilators for multiple i...A61P 9/10 : for treating ischaemic or a...A61P 9/12 : AntihypertensivesC07C 233/47 : having the carbon atom of t...C07C 233/63 : having the nitrogen atom of...C07C 233/87 : of a carbon skeleton contai...C07C 235/52 : having the nitrogen atom of...C07C 235/74 : of a saturated carbon skeletonC07C 235/82 : with the carbon atom of at ...C07C 251/12 : being acyclicC07C 257/06 : having carbon atoms of imin...C07C 2601/02 : with a three-membered ringC07C 2601/04 : with a four-membered ringC07C 2601/14 : The ring being saturatedC07C 271/12 : to hydrogen atoms or to car...C07C 275/16 : being further substituted b...C07C 311/19 : to an acyclic carbon atom o...C07C 317/44 : having sulfone or sulfoxide...C07D 207/34 : with hetero atoms or with c...C07D 209/18 : Radicals substituted by car...C07D 213/56 : AmidesC07D 213/81 : Amides; ImidesC07D 213/82 : in position 3C07D 231/14 : with hetero atoms or with c...C07D 239/28 : with hetero atoms or with c...C07D 261/18 : Carbon atoms having three b...C07D 271/10 : 1,3,4-Oxadiazoles; Hydrogen...C07D 277/64 : with only hydrocarbon or su...C07D 285/12 : 1,3,4-Thiadiazoles; Hydroge...C07D 303/48 : with hetero atoms or with c...C07D 307/68 : Carbon atoms having three b...C07D 309/40 : Oxygen atoms attached in po...C07D 333/24 : Radicals substituted by car...C07D 333/40 : Thiophene-2-carboxylic acid