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
15 Claims
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1. A compound of the formula (I′
- );
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
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2. The compound of claim 1 wherein:
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R1 is C1-7alkyl; for each occurrence, R2 is independently C1-7alkyl, halo, C3-7cycloalkyl, hydroxy, C1-7alkoxy, halo-C1-7alkyl, NRbRc, C6-10aryl, heteroaryl or heterocyclyl;
wherein Rb and Rc, for each occurrence, are independently H or C1-7alkyl;R3 is A2-R4; R4 is aryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C1-7alkoxy, halo, C1-7alkyl, halo-C1-7alkyl, C6-10aryl, heteroaryl, —
NHS(O)2-C1-7alkyl, —
SO2C1-7alkyl and benzyl;R5 is H; and X is OH, —
O—
C1-7alkyl or NRbRc;A2 is a bond or a linear or branched C1-7alkylene;
optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-7alkoxy, hydroxy, O-Acetate and C3-7cycloalkyl;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 heterocyclyl is independently selected from O, N and S; or a pharmaceutically acceptable salt or tautomer thereof.
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3. The compound according to claim 1 having Formulae VI or VIA:
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4. The compound according to claim 3 wherein A2 is a bond, R4 is a 5-membered ring heteroaryl selected from the group consisting of oxazole, pyrrole, pyrazole, isooxazole, triazole, tetrazole, oxadiazole, oxadiazolone, thiazole, isothiazole, thiophene, imidazole and thiadiazole, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from hydroxy, C1-7alkyl, C1-7alkoxy, halo, halo-C1-7alkyl and benzyl;
- or a pharmaceutically acceptable salt or tautomer thereof.
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5. The compound of claim 1 wherein R1 is methyl, R2 is independently halo, C1-7alkyl, halo-C1-7alkyl, hydroxy and C1-7alkoxy, n is 0, 1 or 2 and X is OH or —
- O—
C1-7alkyl;
or a pharmaceutically acceptable salt or tautomer thereof.
- O—
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6. The compound of claim 1 wherein n is 1 or 2;
- R2 is meta-chloro and the other optional R2 group is halo, C1-7alkyl, halo-C1-7alkyl, hydroxy and C1-7alkoxy;
or a pharmaceutically acceptable salt or tautomer thereof.
- R2 is meta-chloro and the other optional R2 group is halo, C1-7alkyl, halo-C1-7alkyl, hydroxy and C1-7alkoxy;
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7. A pharmaceutical composition comprising a compound according to claim 1 or 4, or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers.
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8. A combination comprising:
- a compound according to claim 1 or a pharmaceutically acceptable salt or tautomer 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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9. 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 or tautomer thereof.
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10. A method of treating a disorder or a disease associated with neutral endopeptidase EC. 3.4.24.11. activity in a subject having a disorder or a disease associated with neutral endopeptidase EC.3.4.24.11. activity, comprising:
administering to the subject a therapeutically effective amount of the compound according to claim 1, or 4, or a pharmaceutically acceptable salt or tautomer thereof, wherein the disorder or disease is selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, congestive heart failure or pulmonary arterial hypertension.
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11. The compound of claim 4 wherein n is 1 or 2;
- R2 is meta-chloro and the other optional R2 group is halo, C1-7alkyl, halo-C1-7alkyl, hydroxy and C1-7alkoxy;
or a pharmaceutically acceptable salt or tautomer thereof.
- R2 is meta-chloro and the other optional R2 group is halo, C1-7alkyl, halo-C1-7alkyl, hydroxy and C1-7alkoxy;
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12. A pharmaceutical composition comprising a compound according to claim 11 or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers.
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13. A method of treating a disorder or a disease associated with neutral endopeptidase EC.3.4.24.11. activity in a subject having a disorder or a disease associated with neutral endopeptidase EC.3.4.24.11. activity, comprising:
- administering to the subject a therapeutically effective amount of the compound according to claim 11, or a pharmaceutically acceptable salt or tautomer thereof, wherein the disorder or disease is selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, congestive heart failure or pulmonary arterial hypertension.
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14. A compound according to claim 1 selected from the group consisting of:
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(2R,4S)-5-(3′
-Chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester;(2R,4S)-5-(3′
-Chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid;(2S,4S)-5-(3′
-Chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid;(2R,4S)-5-(3′
-chlorobiphenyl-4-yl)-2-methyl-4-(2H-tetrazole-5-carboxamido)pentanoic acid;(2R,4S)-5-(2′
,5′
-dichlorobiphenyl-4-yl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid;(2R,4S)-5-(3′
-Chloro-biphenyl-4-yl)-2-methyl-4-[(2H-tetrazole-5-carbonyl)-amino]-pentanoic acid ethyl ester;(2R,4S)-5-(3′
-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamido)pentanoic acid;(2R,4S)-5-(3′
-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoic acid;(2R,4S)-ethyl 5-(3′
-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoate;(2R,4S)-5-(3′
-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)-2-methylpentanoic acid;(2S,4S)-4-(2-ethyloxazole-5-carboxamido)-5-(5′
-fluoro-2′
-methoxybiphenyl-4-yl)-2-methylpentanoic acid;(2R,4S)-5-(2′
,5′
-dichlorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)-2-methylpentanoic acid;(2R,4S)-5-(2′
,5′
-dichlorobiphenyl-4-yl)-2-methyl-4-(oxazole-5-carboxamido)pentanoic acid;(2S,4S)-5-(5′
-chloro-2′
-fluorobiphenyl-4-yl)-2-methyl-4-(oxazole-5-carboxannido)pentanoic acid;(2R,4S)-5-(5′
-chloro-2′
-fluorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)-2-methylpentanoic acid;(2S,4S)-5-(2′
,5′
-dichlorobiphenyl-4-yl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid;(2R,4S)-ethyl 5-(5′
-fluoro-2′
-methoxybiphenyl-4-yl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoate;(2R,4S)-ethyl 5-(2′
,5′
-dichlorobiphenyl-4-yl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoate; and(2R,4S)-5-(5′
-chloro-2′
-fluorobiphenyl-4-yl)-2-methyl-4-(oxazole-5-carboxamido)pentanoic acid;
or a pharmaceutically acceptable salt or tautomer thereof.
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15. A compound according to claim 1 selected from the group consisting of:
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(2R,4S)-5-(3′
-Chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid;(2R,4S)-5-(5′
-chloro-2′
-fluorobiphenyl-4-yl)-2-methyl-4-(oxazole-5-carboxamido)pentanoic acid;(2R,4S)-5-(3′
-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoic acid;(2S,4S)-5-(3′
-Chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid;(2R,4S)-5-(3′
-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamido)pentanoic acid; and(2R,4S)-5-(2′
,5′
-dichlorobiphenyl-4-yl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid;
or a pharmaceutically acceptable salt or tautomer thereof.
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2. The compound of claim 1 wherein:
- );
Specification
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Current AssigneeNovartis Ag
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Original AssigneeNovartis Ag
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InventorsCoppola, Gary Mark, Iwaki, Yuki, Karki, Rajeshri Ganesh, Kawanami, Toshio, Ksander, Gary Michael, Mogi, Muneto, Sun, Robert
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Primary Examiner(s)Anderson, Rebecca
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Assistant Examiner(s)Shterengarts, Samantha
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Application NumberUS12/788,794Publication NumberTime in Patent Office838 DaysField of Search514/364, 514/374, 514/378, 514/381, 548/131, 548/143, 548/215, 548/240, 548/250US Class Current514/364CPC 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