6-pyridin-3-yl-3,4-dihydro-1h-quinolin-2-one derivatives and related compounds as inhibitors of the human aldosterone synthase CYP11B2

• US 8,685,960 B2
• Filed: 05/05/2009
• Issued: 04/01/2014
• Est. Priority Date: 05/06/2008
• Status: Active Grant

• Current Assignee: Elexopharm GmbH
• Original Assignee: Elexopharm GmbH
• Inventors: Hartmann, Rolf W., Heim, Ralf, Lucas, Simon
• Primary Examiner(s): NORTHINGTON DAVI, ZINNA
• Application Number:
  US12/990,909
• Publication Number:
  US 20110118241A1
• Time in Patent Office: 1,792 Days
• Field of Search: None
• US Class Current: 514/211.06
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 3/04 Anorexiants; Antiobesity agents
• 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 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 215/227 only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 221/06 Ring systems of three rings
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The invention provides compounds of the general formula (I) which are inhibitors of the human aldosterone synthase, and also pharmaceutical compositions containing these compounds, and the use of these compounds and other heteroaryl substituted quinolinone derivatives for the treatment of hyperaldosteronism and/or disorders or diseases that are mediated by 11 β-hydroxylase (CYP11 B1).

Claims

1. A compound of formula (I):

2. A compound according to claim 1, wherein Z is C═

O, or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, wherein U is S or CR⁵R⁶, wherein R⁵ and R⁶ are independently selected from H and C_1-4 alkyl, X is CH₂, or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, wherein the unsaturated nitrogen containing ring is an unsubstituted 5- or 6-membered ring having one or two unsaturated bond(s) and no further heteroatom, or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1, wherein Het is for pyridinyl, isoquinolinyl, pyrimidinyl or imidazolyl, optionally substituted with a substituent R¹¹, wherein R¹¹ is defined as in claim 1, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 selected from

8-Pyridin-3-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

9-Pyridin-3-yl-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one

8-(5-Methoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-Isoquinolin-4-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

9-(5-Methoxypyridin-3-yl)-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one

9-Isoquinolin-4-yl-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one

8-Pyridin-3-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinoline-4-thione

8-(5-Hydroxypyridin-3-yl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one

6,6-Dimethyl-8-pyridin-3-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-(5-Ethoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-(5-Trifluoromethylpyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-(5-Fluoropyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-Imidazol-1-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-Pyridin-4-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-Pyrimidin-5-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-(Pyridin-4-carbonyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-(Pyridin-3-carbonyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-(5-Phenylpyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-(5-Isopropoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-(1-Imidazol-1-yl-ethyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-[5-(4-Fluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-[5-(3-Fluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-[5-(4-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-[5-(3-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-[5-(2-Fluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-[5-(3-Trifluoromethylphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-[5-(3,4-Difluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

8-[5-(3-Trifluoromethoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]-quinolin-4-one

8-[5-(2-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one

or a pharmaceutically acceptable salt thereof.

7. A compound of formula (I):

8. A compound according to claim 7, wherein Z is C═

O, or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 7, wherein R¹ is H or C_1-4 alkyl, or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 7, wherein U is S or CR⁵R⁶, wherein R⁵ and R⁶ are independently selected from H and C_1-4 alkyl, X is CH₂, or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 7, wherein Het is isoquinolinyl optionally substituted with a substituent R¹¹, wherein R¹¹ is defined as in claim 7, or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 7 selected from

6-Isoquinolin-4-yl-3,4-dihydro-1H-quinolin-2-one,

6-Isoquinolin-4-yl-1-methyl-3,4-dihydro-1H-quinolin-2-one,

or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 13, wherein Het is for pyridinyl, pyrimidinyl or imidazolyl, optionally substituted with a substituent R¹¹, wherein R¹¹ is defined as in claim 12, or a pharmaceutically acceptable salt thereof.

13. A compound of formula (I):

14. A compound according to claim 13, wherein R¹ is H or C_1-4 alkyl, or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 13, wherein U is S or CR⁵R⁶, wherein R⁵ and R⁶ are independently selected from H and C_1-4 alkyl, X is CH₂, or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 13 selected from

8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione,

8-Fluoro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-thione,

7-Fluoro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-thione,

or a pharmaceutically acceptable salt thereof.