Substituted aminobutyric derivatives as neprilysin inhibitors

• US 8,263,629 B2
• Filed: 05/27/2010
• Issued: 09/11/2012
• Est. Priority Date: 05/28/2009
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Coppola, Gary Mark, Iwaki, Yuki, Karki, Rajeshri Ganesh, Kawanami, Toshio, Ksander, Gary Michael, Mogi, Muneto, Sun, Robert
• Primary Examiner(s): Anderson, Rebecca
• Assistant Examiner(s): Shterengarts, Samantha
• Application Number:
  US12/788,794
• Publication Number:
  US 20100305145A1
• Time in Patent Office: 838 Days
• Field of Search: 514/364, 514/374, 514/378, 514/381, 548/131, 548/143, 548/215, 548/240, 548/250
• US Class Current: 514/364
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• 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 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 15/04 for inducing labour or abortion; Uterotonics
• 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 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 25/04 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 25/20 Hypnotics; Sedatives
• 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 27/16 : Otologicals
• 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 31/02 : Local antiseptics
• 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 7/00 : 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 9/08 : Vasodilators for multiple indications
• 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: 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 233/63 : 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 233/87 : of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/52 : 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 235/74 : of a saturated carbon skeleton
• CPC Class Codes: C07C 235/82 : with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 251/12 : being acyclic
• CPC Class Codes: C07C 257/06 : having carbon atoms of imino-carboxyl groups bound to hydrogen atoms, to acyclic carbon atoms, or to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 2601/02 : with a three-membered ring
• CPC Class Codes: C07C 2601/04 : with a four-membered ring
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 271/12 : to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07C 275/16 : being further substituted by carboxyl groups
• CPC Class Codes: C07C 311/19 : to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 317/44 : having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07D 207/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 209/18 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/56 : Amides
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• 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 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 271/10 : 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 277/64 : with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• CPC Class Codes: C07D 285/12 : 1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
• CPC Class Codes: C07D 303/48 : 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, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 309/40 : Oxygen atoms attached in positions 3 and 4, e.g. maltol
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/40 : Thiophene-2-carboxylic acid

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.

Claims

1. A compound of the formula (I′

);

2. The compound of claim 1 wherein:

R¹ is C_1-7alkyl;

for each occurrence, R² is independently C_1-7alkyl, halo, C_3-7cycloalkyl, hydroxy, C_1-7alkoxy, halo-C_1-7alkyl, NR^bR^c, C_6-10aryl, heteroaryl or heterocyclyl;

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

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, C_1-7alkoxy, halo, C_1-7alkyl, halo-C_1-7alkyl, C_6-10aryl, heteroaryl, —

NHS(O)_2-C_1-7alkyl, —

SO₂C_1-7alkyl and benzyl;

R⁵ is H; and

X is OH, —

O—

C_1-7alkyl or NR^bR^c;

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

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;

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.

3. The compound according to claim 1 having Formulae VI or VIA:

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, C_1-7alkyl, C_1-7alkoxy, halo, halo-C_1-7alkyl and benzyl;

or a pharmaceutically acceptable salt or tautomer thereof.

5. The compound of claim 1 wherein R¹ is methyl, R² is independently halo, C_1-7alkyl, halo-C_1-7alkyl, hydroxy and C_1-7alkoxy, n is 0, 1 or 2 and X is OH or —

O—

C_1-7alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

6. The compound of claim 1 wherein n is 1 or 2;

R² is meta-chloro and the other optional R² group is halo, C_1-7alkyl, halo-C_1-7alkyl, hydroxy and C_1-7alkoxy;

or a pharmaceutically acceptable salt or tautomer thereof.

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.

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.

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.

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.

11. The compound of claim 4 wherein n is 1 or 2;

R² is meta-chloro and the other optional R² group is halo, C_1-7alkyl, halo-C_1-7alkyl, hydroxy and C_1-7alkoxy;

or a pharmaceutically acceptable salt or tautomer thereof.

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.

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.

14. A compound according to claim 1 selected from the group consisting of:

(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.

15. A compound according to claim 1 selected from the group consisting of:

(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.