Aryl pyridine as aldosterone synthase inhibitors

• US 8,519,142 B2
• Filed: 09/14/2012
• Issued: 08/27/2013
• Est. Priority Date: 05/15/2009
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Chamoin, Sylvie, Hu, Qi-Ying, Papillon, Julien
• Primary Examiner(s): Grazier, Nyeemah A
• Application Number:
  US13/615,902
• Publication Number:
  US 20130035354A1
• Time in Patent Office: 347 Days
• Field of Search: None
• US Class Current: 546/312
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/542 ortho- or peri-condensed with heterocyclic ring systems
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/40 Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
• CPC Class Codes: A61P 5/42 : for decreasing, blocking or antagonising the activity of mineralocorticosteroids
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• 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: C07D 213/46 : Oxygen atoms
• CPC Class Codes: C07D 213/76 : to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 401/02 : containing two hetero rings
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

The present invention provides a compound of formula I;

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. The compound of claim 1, having Formula I:

3. The compound of claim 1 having Formula III:

4. The compound of claim 1 having Formula V:

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C or Ring C together with 2 R⁴ groups, is selected from:

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is independently selected from C_1-4alkyl, C_1-4alkoxy, CN, halo, halo-C_1-4alkyl or halo-C_1-7alkoxy.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is CHR⁵.

8. The compound of claim 1, or a pharmaceutically salt thereof wherein R¹ is C_1-4alkyl, R² is H, R³ is H, A is CHR⁵, R⁵ is C_1-4alkyl or C_3-6cycloalkyl, p is 1 or 2;

and each R⁴ is independently C_1-4alkyl, halo-C_1-4alkyl, C_1-4alkoxy, CN, halo or halo-C_1-4alkoxy.

9. The compound of claim 1 selected from:

N-((5-(6-chloro-1-methyl-1H-benzo[d]imidazol-2-yl)pyridin-3yl)methyl)ethanesulfonamide;

Ethanesulfonic acid [5-(6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-pyridin-3-ylmethyl]-amide;

Ethanesulfonic acid [5-(6-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyridin-3-ylmethyl]-amide;

N-(cyclopropyl(5-benzo-[1,3]-dioxol-5-yl-pyridin-3-yl)methyl)ethanesulfonamide;

N-(cyclopropyl(5-(2,3-dihydro-benzofuran-5-yl)pyridin-3-yl)methyl)ethanesulfonamide;

N-(cyclopropyl(5-(1H-indol-5-yl)pyridin-3-yl)methyl)ethanesulfonamide;

N-(cyclopropyl(5-benzo[b]thiophen-2-yl-pyridin-3-yl)methyl)ethanesulfonamide;

N-(cyclopropyl(5-(1-methyl-1H-indol-5-yl)pyridin-3-yl)methyl)ethanesulfonamide;

2-Chloro-4-[5-(1,1-dioxo-isothiazolidin-2-ylmethyl)-pyridin-3-yl]-benzonitrile;

N-(cyclopropyl(5-(quinolin-6-yl)pyridin-3-yl)methyl)ethanesulfonamide;

N-((5-(5-cyanobenzofuran-2-yl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

N-((5-(benzo[d]thiazol-5-yl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

N-((5-(benzofuran-5-yl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

11. A pharmaceutical combination, comprising a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents selected from the group consisting of an HMG-Co-A reductase inhibitor, an angiotensin II receptor antagonist, angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker (CCB), a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, 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, and a CETP inhibitor.

12. A method of treating a disorder or a disease in a subject mediated by aldosterone synthase, 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 hypertension.