Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors

• US 8,877,786 B2
• Filed: 12/02/2013
• Issued: 11/04/2014
• Est. Priority Date: 11/20/2009
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Iwaki, Yuki, Kawanami, Toshio, Ksander, Gary Michael, Moji, Muneto
• Primary Examiner(s): SAEED, KAMAL A
• Application Number:
  US14/093,956
• Publication Number:
  US 20140088165A1
• Time in Patent Office: 337 Days
• Field of Search: None
• US Class Current: 514/380
• 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 31/42 Oxazoles
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• 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 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 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 15/10 for impotence
• 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 3/02 : Nutrients, e.g. vitamins, minerals
• 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 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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 5/28 : Antiandrogens
• 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 9/10 : 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: C07D 231/40 : Acylated on said nitrogen atom
• CPC Class Codes: C07D 257/06 : with nitrogen atoms directly attached to the ring carbon atom
• CPC Class Codes: C07D 261/14 : Nitrogen atoms

Abstract

The present invention provides a compound of formula I;

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, R⁶, A¹, A², X¹, s and m 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 method of treating 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 a compound of the formula (I′

);

2. The method according to claim 1 wherein the compound is of Formula I:

3. The method of claim 1 wherein the compound is of Formula II:

4. The method of claim 1 wherein the compound is of Formula III:

5. The method according to claim 4 wherein the compound is of formula IV:

6. The method according to claim 1 wherein

X¹ represent OH or O—

C_1-6-alkyl;

R¹ is H or C_1-6 alkyl;

R² for each occurrence is independently C_1-6-alkoxy, hydroxy, halo, C_1-6-alkyl, cyano or trifluoromethyl;

R⁴ and R⁵ are independently H or C_1-6 alkyl;

A¹ is a bond or C_1-3alkylene chain;

R³ is a 5- or 6-membered heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of C_1-6alkyl, halo, haloC_1-6alkyl, C_1-6alkoxy, hydroxy, CO₂H and CO₂C_1-6alkyl;

R⁶ for each occurrence is independently halo, hydroxy, C_1-7alkoxy, halo, C_1-7alkyl or halo-C_1-7alkyl;

m is 0 or an integer of 1 to 5;

s is 0 or an integer of 1 to 4;

or

a pharmaceutically acceptable salt thereof.

7. The method of claim 1 wherein A¹ is a bond or CH₂;

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 wherein R¹ is methyl or ethyl, R⁵ and R⁴ are H;

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 wherein R³ is a 5-membered ring heteroaryl selected from the group consisting of oxazole, pyrrole, pyrazole, isooxazole, triazole, tetrazole, oxadiazole, thiazole, isothiazole, thiophene, imidazole and thiadiazole;

each of which is optionally substituted with one or more substituents independently selected from the group consisting of C_1-6alkyl, halo, haloC_1-6alkyl, C_1-6alkoxy, hydroxy, CO₂H and CO₂C_1-6alkyl;

or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 wherein R³ is tetrazole;

or a pharmaceutically acceptable salt thereof.

11. The method of claim 5 wherein X² is Cl, or a pharmaceutically acceptable salt thereof.

12. The method according to claim 1 wherein the compound is selected from the group consisting of:

(S)-2-[(S)-2-(3′

-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester

(S)-2-[(S)-2-(2′

,5′

-Dichloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid tert-butyl ester;

(S)-2-[(S)-2-Biphenyl-4-yl-1-(1-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester;

(S)-2-[(S)-2-(5′

-Fluoro-2′

-methoxy-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]propionic acid tert-butyl ester;

5-[(S)-3-Biphenyl-4-yl-2-((S)-1-tert-butoxycarbonyl-ethylamino)-propionylamino]-1H-pyrazole-3-carboxylic acid methyl ester;

(S)-2-[(S)-2-(3′

-Chloro-biphenyl-4-yl)-1-(3-hydroxy-isoxazol-5-ylcarbamoyl)-ethylamino]propionic acid tert-butyl ester;

(S)-2-[(S)-2-(3′

-Chloro-biphenyl-4-yl)-1-(1-methyl-1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester;

(S)-2-[(S)-2-(3′

-Chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-4-phenyl-butyric acid ethyl ester;

(S)-2-[(S)-2-(3′

-Chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-butyric acid tert-butyl ester;

2-[2-(3′

-Chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-phenyl-propionic acid ethyl ester;

(S)-2-{(S)-2-(3′

-chloro-biphenyl-4-yl)-1-[methyl-(1H-tetrazol-5-yl)-carbamoyl]ethylamino}-propionic acid ethyl ester;

(S)-3-benzyloxy-2-[(S)-2-(3′

-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester;

(S)-2-[(S)-2-(3′

-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-methoxy-propionic acid ethyl ester;

(S)-2-[(S)-2-(3′

-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethoxy]-propionic acid ethyl ester;

(S)-2-[(R)-2-(3′

-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester;

(S)-2-[(R)-2-(2′

,5-Dichloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid tert-butyl ester;

(S)-2-[(R)-2-(3′

-Chloro-biphenyl-4-yl)-1-(3-hydroxy-isoxazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester;

(S)-2-[(R)-2-(3′

-Chloro-biphenyl-4-yl)-1-(1-methyl-1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester;

(S)-2-[(S)-2-(3′

-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid

(S)-2-[(S)-2-(2′

,5′

-dichloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid;

(S)-2-[(R)-2-(2′

,5-Dichloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid;

(S)-2-[(S)-2-Biphenyl-4-yl-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid;

(S)-2-[(S)-2-(5′

-Fluoro-2′

-methoxy-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid;

5-[(S)-3-Biphenyl-4-yl-2-((S)-1-carboxy-ethylamino)-propionylamino]-1H-pyrazole-3-carboxylic acid;

(S)-2-[(S)-2-(3′

-Chloro-biphenyl-4-yl)-1-(3-hydroxy-isoxazol-5-ylcarbamoyl)-ethylamino]-propionic acid;

(S)-2-[(S)-2-(3′

-Chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-4-phenyl-butyric acid;

(S)-2-[(R)-2-(3′

-Chloro-biphenyl-4-yl)-1-(3-hydroxy-isoxazol-5-ylcarbamoyl)-ethylamino]-propionic acid;

(S)-2-{2-(3′

-Chloro-biphenyl-4-yl)-1-[methyl-(1H-tetrazol-5-yl)-carbamoyl]-ethylamino}-propionic acid;

(S)-2-[(S)-2-(3′

-Chloro-biphenyl-4-yl)-1-(1-methyl-1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid;

(S)-2-[(R)-2-(3′

-Chloro-biphenyl-4-yl)-1-(1-methyl-1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid;

(S)-2-[(S)-2-(3′

-Chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-butyric acid;

(S)-2-[(S)-2-(3′

-Chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-phenyl-propionic acid;

(S)-2-[(R)-2-(3′

-Chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-phenyl-propionic acid;

(S)-3-benzyloxy-2-[(S)-2-(3′

-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid;

(S)-2-[(S)-2-(3′

-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-methoxy-propionic acid;

(S)-2-[(S)-2-(3′

-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethoxy]-propionic acid;

(S)-2-[(S)-2-(3′

-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-hydroxy-propionic acid;

(S)-2-[(S)-2-biphenyl-4-yl-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-hydroxy-propionic acid; and

(S)-3-(3′

-chloro-biphenyl-4-yl)-2-((S)-2-methanesulfonylamino-1-methyl-2-oxo-ethylamino)-N-(1H-tetrazol-5-yl)-propionamide;

or a pharmaceutically acceptable salt thereof.