ARYL PYRIDINE AS ALDOSTERONE SYNTHASE INHIBITORS

• US 20100292225A1
• Filed: 05/14/2010
• Published: 11/18/2010
• Est. Priority Date: 05/15/2009
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Chamoin, Sylvie, Hu, Qi-Ying, Papillon, Julien
• Granted Patent: US 8,383,827 B2
• Time in Patent Office: Days
• US Class Current: 514/226.5
• 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 or 2 having Formula II:

4. The compound of claim 1 having Formula III:

5. The compound of claim 1 having formula IV:

6. The compound of claim 1 having Formula V:

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein C is phenyl.

8. 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:

9. 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.

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

11. 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.

12. The compound of claim 1 selected from:

N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)ethanesulfonamide;

N-[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-4-methoxy-benzene-sulfonamide;

N-[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-4-fluoro-benzene-sulfonamide;

N-[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-4-ethyl-benzene-sulfonamide;

N-[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-4-cyano-benzene-sulfonamide;

N-[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-4-trifluoromethyl-benzenesulfonamide;

N-[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-4-fluoro-2-methyl-benzenesulfonamide;

N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)-2,2,2-trifluoroethanesulfonamide;

N-[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-1-phenyl-methanesulfonamide;

N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)-2-phenoxyethanesulfonamide;

N-[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-4-methyl-benzenesulfonamide;

N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)-1-(2-chlorophenyl)methanesulfonamide;

N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)-1-(4-fluorophenyl)methanesulfonamide;

Cyclopropanesulfonic acid [5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-amide;

N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)propane-1-sulfonamide;

N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)butane-1-sulfonamide;

N-(5-(4-cyano-3-methoxyphenyl)pyridin-3-yl)-2,2,2-trifluoroethanesulfonamide;

N-(5-(4-cyano-3-methoxyphenyl)pyridin-3-yl)ethanesulfonamide;

N-(5-(4-cyano-3-methoxyphenyl)pyridin-3-yl)cyclopropane-sulfonamide;

N-((5-(4-cyano-3-methoxyphenyl)pyridin-3-yl)methyl)methane-sulfonamide;

N-((5-(4-cyano-3-methoxyphenyl)pyridin-3-yl)methyl)ethanesulfonamide;

N-((5-(4-cyano-3-methoxyphenyl)pyridin-3-yl)methyl)-1,1,1-trifluoromethanesulfonamide;

N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)methyl)ethanesulfonamide;

N-((5-(4-cyano-3-ethoxyphenyl)pyridin-3-yl)methyl)ethanesulfonamide;

N-(1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)-2-methylpropyl)ethanesulfonamide;

N-(1-(5-(4-cyano-3-methoxyphenyl)pyridin-3-yl)ethyl)ethanesulfonamide;

N-(1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)ethyl)ethanesulfonamide;

N-(1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)butyl)ethanesulfonamide;

(R)—

N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

(S)—

N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)methanesulfonamide;

N-((5-(4-cyano-3-methoxyphenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

(S)—

N-((5-(4-cyano-2-methoxyphenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

(R)—

N-((5-(4-cyano-2-methoxyphenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide

(R)—

N-((5-(4-cyano-3-fluorophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

(S)—

N-((5-(4-cyano-3-fluorophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide

N-((5-(4-cyano-2-fluorophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopentyl)methyl)ethanesulfonamide;

N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)propane-2-sulfonamide;

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

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

N-((5-(4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

N-(2-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)propan-2-yl)ethanesulfonamide;

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

N-(cyclopropyl(5-(4-methoxyphenyl)pyridin-3-yl)methyl)ethanesulfonamide;

N-(cyclopropyl(5-(4-ethoxyphenyl)pyridin-3-yl)methyl)ethanesulfonamide;

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

N-(cyclopropyl(5-(4-fluorophenyl)pyridin-3-yl)methylethanesulfonamide;

N-(cyclopropyl(5-(2,4-dichlorophenyl)pyridin-3-yl)methylethanesulfonamide;

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

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

N-((5-(4-chlorophenyl)pyridin-3-yl)(cyclopropyl)methyl)-ethanesulfonamide;

N-(cyclopropyl(5-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl)ethanesulfonamide;

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

N-((5-(3-chloro-4-fluorophenyl)pyridin-3-yl)(cyclopropyl)methyl)-ethanesulfonamide;

N-(cyclopropyl(5-(6-methoxynaphthalen-2-yl)pyridin-3-yl)methyl)ethanesulfonamide;

N-((5-(6-chloro-1-methyl-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)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-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)-N-methylethanesulfonamide;

N-(cyclopropyl(5-(4-fluoro-3-methyl-phenyl)pyridin-3-yl)methyl)ethanesulfonamide;

N-(cyclopropyl(5-(4-ethylsulfanyl-phenyl)pyridin-3-yl)methyl)ethanesulfonamide;

N-(cyclopropyl(5-(3-fluoro-4-methoxy-phenyl)pyridin-3-yl)methyl)ethanesulfonamide;

N-(cyclopropyl(5-(2,4-dimethoxy-phenyl)pyridin-3-yl)methyl)ethanesulfonamide;

N-(cyclopropyl(5-(4-methylsulfanyl-phenyl)pyridin-3-yl)methyl)ethanesulfonamide;

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-(2,4,6-trimethyl-phenyl)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;

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

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

Ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]cyclopropyl-methyl}-ethyl-amide;

Ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-(3-methyl-butyl)-amide;

({[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-ethanesulfonyl-amino)-acetic acid methyl ester;

Ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-isobutyl-amide;

Ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-(2-hydroxy-ethyl)-amide;

N-(1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)cyclopropyl)ethane-sulfonamide;

N-((4-chloro-5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)-N-methylmethanesulfonamide;

N-((5-(6-cyanonaphthalen-2-yl)pyridin-3-yl)(cyclopropyl)methyl)ethane-sulfonamide;

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

(R)—

N-((5-(4-cyano-3-methylphenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide;

(S)—

N-((5-(4-cyano-3-methylphenyl)pyridin-3-yl)(cyclopropyl)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;

N-((5-(4-cyano-3-methylphenyl)pyridin-3-yl)(4-fluorophenyl)methyl)ethane-sulfonamide;

N-(1-(5-(4-cyano-3-methylphenyl)pyridin-3-yl)-2,2,2-trifluoroethyl)ethane-sulfonamide;

N-(2-(5-(2,3-dichlorophenyl)pyridin-3-yl)ethyl)ethanesulfonamide;

N-(2-(5-(2,3-dichlorophenyl)pyridin-3-yl)cyclopropyl)ethane-sulfonamide;

or a pharmaceutically acceptable salt thereof.

13. 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.

14. A combination, in particular 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 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.

15. A method of inhibiting aldosterone synthase 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.

16. 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.

17. A method according to claim 16, wherein the disorder or the disease is selected from hypokalemia, hypertension, Conn'"'"'s disease, renal failure, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction, cardiovascular diseases, renal dysfunction, liver diseases, cerebrovascular diseases, vascular diseases, retinopathy, neuropathy, insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction, migraine headaches, heart failure such as congestive heart failure, arrhythmia, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, impaired diastolic filling, systolic dysfunction, ischemia, hypertrophic cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, impaired arterial compliance, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, decreased ejection fraction, cardiac lesions, vascular wall hypertrophy, endothelial thickening, and fibrinoid necrosis of coronary arteries.

22. The compound of claim 3, 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.

23. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 3, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

24. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 22, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

25. A method of treating a disorder or a disease in a subject mediated by aldosterone synthase, wherein the disorder or the disease is selected from hypokalemia, hypertension, Conn'"'"'s disease, renal failure, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction, cardiovascular diseases, renal dysfunction, liver diseases, cerebrovascular diseases, vascular diseases, retinopathy, neuropathy, insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction, migraine headaches, heart failure such as congestive heart failure, arrhythmia, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, impaired diastolic filling, systolic dysfunction, ischemia, hypertrophic cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, impaired arterial compliance, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, decreased ejection fraction, cardiac lesions, vascular wall hypertrophy, endothelial thickening, and fibrinoid necrosis of coronary arteries comprising:

administering to the subject a therapeutically effective amount of the compound according to claim 3 or a pharmaceutically acceptable salt thereof.

26. A method of treating a disorder or a disease in a subject mediated by aldosterone synthase, wherein the disorder or the disease is selected from hypokalemia, hypertension, Conn'"'"'s disease, renal failure, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction, cardiovascular diseases, renal dysfunction, liver diseases, cerebrovascular diseases, vascular diseases, retinopathy, neuropathy, insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction, migraine headaches, heart failure such as congestive heart failure, arrhythmia, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, impaired diastolic filling, systolic dysfunction, ischemia, hypertrophic cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, impaired arterial compliance, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, decreased ejection fraction, cardiac lesions, vascular wall hypertrophy, endothelial thickening, and fibrinoid necrosis of coronary arteries comprising:

administering to the subject a therapeutically effective amount of the compound according to claim 22 or a pharmaceutically acceptable salt thereof.

18-21. -21. (canceled)