Inhibitors of the Human Aldosterone Sythase CYP11B2

• US 20110112067A1
• Filed: 11/03/2010
• Published: 05/12/2011
• Est. Priority Date: 11/09/2009
• Status: Active Grant

• Current Assignee: Elexopharm GmbH
• Original Assignee: Universität des Saarlandes
• Inventors: Lucas, Simon, Heim, Ralf, Hartmann, Rolf W.
• Granted Patent: US 8,541,404 B2
• Time in Patent Office: Days
• US Class Current: 514/211.06
• 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 7/00 Drugs for disorders of the blood or the extracellular fluid
• 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 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 471/06 Peri-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 a method of treating of hyperaldosteronism and/or disorders or diseases that are mediated by 11β-hydroxylase (CYP11B1) with these compounds.

Claims

1. A compound of the general formula (I)

2. A compound according to claim 1, wherein

R¹ is selected from the group consisting of H;

C_1-4 alkyl, C_2-4 alkenyl, C_3-7 cycloalkyl, C_1-4 alkylcarbonyl, and C_1-4 alkoxycarbonyl, each of which can be substituted by from one to three substituents R^a, wherein R^a is independently selected from the group consisting of optionally partially or completely halogenated C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, and C_1-4 alkylcarbonyl and also hydroxyl, nitro, and cyano, or can be partially or completely halogenated with independent halogen atoms;

aryl C_1-4 alkyl and heterocyclyl C_1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents R^b, wherein R^b is selected from the group consisting of C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkylcarbonyl, C_1-4 alkylsulfonyl, whose alkyl moieties may be partially or completely halogenated with independent halogen atoms, halogen, hydroxyl, nitro, cyano, —

NR^c₂, CONR^c₂, and SO₂NR^c₂, wherein R^o is independently selected from the group consisting of H and C_1-4 alkyl; and

R² is selected from the group consisting of H;

C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_5-7 cycloalkenyl, C_1-4 alkoxy, C_1-4 alkylcarbonyl, C_1-4 alkoxycarbonyl, C_1-4 alkylsulfonyl, which in each case can be substituted by from one to three substituents R^a, wherein R^a has the meanings stated above, or can be partially or completely halogenated with independent halogen atoms;

aryl C_1-4 alkyl, aryl C_0-4 alkylsulfonyl, heterocyclyl C_1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents R^b, wherein R^b has the meanings stated above;

halogen, hydroxyl, nitro, cyano, —

NR^c₂, —

CONR^c₂, and —

SO₂NR^c₂, wherein R^c has the meanings stated above;

3. A compound according to claim 1, wherein the bond between U and X and U and Y, respectively, or X and Y, is a single bond, or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, wherein Z stands for C═

O, or a pharmaceutically acceptable salt thereof.

5. A compound according to any of claims 1, wherein R¹ stands for H or C_1-4 alkyl, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1, wherein R¹ and R² together with the atoms, to which they are bound, form an unsaturated nitrogen-containing five to seven membered ring having 1 or 2 unsaturated bond(s) and, in addition to the nitrogen atom, to which R¹ is bound, may contain a heteroatom or a heteroatom-containing group selected from the group consisting of O, S and NR⁷ and may be substituted with one to four substituents R¹², wherein R¹² is as defined in claim 1, or a pharmaceutically acceptable salt thereof.

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

8. A compound according to claim 1, wherein U stands for S or CR⁵R⁶, wherein R⁵ and R⁶ are independently selected from H and C_1-4 alkyl, X stands for CH₂, and n=0, or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1, wherein A stands for C═

O or CR⁸R⁹, wherein R⁸ and R⁹ independently stand for H or C_1-4 alkyl or A is absent, i.e. b=0, or a pharmaceutically acceptable salt thereof.

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

11. A compound according to claim 1 selected from

5-Pyridin-3-yl-1,3-dihydroindol-2-one

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

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

6-Pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione

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

8-Nitro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one

7-Pyridin-3-yl-4H-benzo[1,4]thiazin-3-one

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

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

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-Isopropoxpyridin-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.

12. Pharmaceutical composition, containing a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

13. A method of treating hyperaldosteronism in a mammal wherein a pharmaceutically effective amount of a compound according to claim 1 is administered to a patient in need thereof.

14. The method according to claim 13, wherein the treating of hyperaldosteronism includes the treating of hypokalaemia, hypertension, congestive heart failure, ventricular fibrillation, renal failure, including chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, postmyocardial infarction syndrome, coronary cardiac diseases, inflammation, increased collagen formation, vasculitis, fibrosis, including cardiac or myocardial fibrosis, remodeling following hypertension, endothelial dysfunction and/or edema.

15. A method of treating hyperaldosteronism in a mammal wherein a pharmaceutically effective amount of a composition according to claim 12 is administered to a patient in need thereof.

16. The method according to claim 15, wherein the treating of hyperaldosteronism includes the treating of hypokalaemia, hypertension, congestive heart failure, ventricular fibrillation, renal failure, including chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, postmyocardial infarction syndrome, coronary cardiac diseases, inflammation, increased collagen formation, vasculitis, fibrosis, including cardiac or myocardial fibrosis, remodeling following hypertension, endothelial dysfunction and/or edema.