# US 8,541,404 B2 · Inhibitors of the human aldosterone synthase CYP11B2

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- Number: US 8,541,404 B2
- Document ID: US8541404B2
- Status: Granted
- Kind: B2
- Application number: 12/938,581
- Filed: 2010-11-03
- Published: 2011-05-12
- Granted: 2013-09-24
- Earliest claimed: 2009-11-09
- Assignees: ElexoPharm GmbH
- Applicants: Rolf W. Hartmann; Ralf Heim; Simon Lucas
- Inventors: Rolf W. Hartmann; Ralf Heim; Simon Lucas
- Web page: https://patentgrep.com/patent/US8541404B2

## CPC

- C07D 401/10: linked by a carbon chain containing aromatic rings
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D 471/06: Peri-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 1

A method of treating hyperaldosteronism in a mammal in need thereof, the method comprising administering to the mammal a pharmaceutically effective amount of a compound of formula (I):
wherein:
Z is C═O or C═S;
U is CR5R6, NR7, O, S, SO, or SO2;
X is independently CR5R6, NR7, O, or S;
Y is CR5R6, NR7, O, or S;
b is 0;
n is 0;
m is 0 or 1;
provided that when U is SO or SO2: not more than one of U, X, and Y is NR7,O, or S; and X and Y are not O or S; and X or Y is NR7 in a position vicinal to U,
wherein, when m is 1, the bond between U and X or U and Y, respectively, or X and Y can be a C═C or C═N double bond;
Het is a ring system containing 1 or 2 rings, and at least one of the rings is aromatic and contains 5 or 6 ring atoms, of which at least one is nitrogen, and the other ring can be saturated or unsaturated and comprises from 5 to 7 ring atoms; while the ring system can contain additional 1 to 5 heteroatoms selected from the group consisting of N, S, and O, provided that not more than two heteroatoms are selected from the group consisting of S and O; and the ring system can be substituted by from one to four substituents R11,
with the provisos that:
3-pyridyl has at position 6 no substituents other than H, when Het is 3-pyridyl; and,
when Z is C═O; m is 1; X is CR5R6 and U is CR5R6; or the bond between U and X is a C═C double bond; R1 is H, C1-4 alkyl or 2-hydroxyethyl; and R2 is other than NO2; then Het is not an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group;
R1 is selected from the group consisting of H; C1-4 alkyl; C2-4 alkenyl; C3-7 cycloalkyl; C1-4 alkylcarbonyl; and C1-4 alkoxycarbonyl; each of which can be substituted by from one to three substituents Ra, wherein Ra is independently selected from the group consisting of optionally partially or completely halogenated C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, and C1-4 alkylcarbonyl and also hydroxyl, nitro, and cyano, or can be partially or completely halogenated with independent halogen atoms; aryl C1-4 alkyl and heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb, wherein Rb is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, C1-4 alkylsulfonyl, whose alkyl moieties may be partially or completely halogenated with independent halogen atoms, halogen, hydroxyl, nitro, cyano, —NRc2, —CONRc2, and SO2NRc2,
wherein Rc is independently selected from the group consisting of H and C1-4 alkyl;
R2, R3 and R4 are independently selected from the group consisting of H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, C1-4 alkoxy, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylsulfonyl, which in each case can be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms; aryl C1-4 alkyl, aryl C0-4 alkylsulfonyl, heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb; halogen, hydroxyl, nitro, cyano, —NRc2, —CONRc2, and —SO2NRc2;
or
R1 and R2 form, together with the atoms to which they are bonded, an unsaturated nitrogen-containing five membered to seven membered ring comprising 1 or 2 unsaturated bonds and may, in addition to the nitrogen atom to which the R1 group is bonded, also contain a hetero atom or a heteroatom-containing group selected from the group consisting of O, S and NR7, and can be substituted by from one to four substituents R12;
R5 and R6 are independently selected from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl, hydroxyl C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylthio, whose alkyl moieties can be partially or completely halogenated with independent halogen atoms; halogen, hydroxyl, nitro, cyano, —NRc2, and NRcCORd, and Rd is selected from the group consisting of C1-4 alkyl, C3-7 cycloalkyl, C1-4 alkoxy, whose alkyl moieties can be partially or completely halogenated with independent halogen atoms, and wherein R5 or R6 may be bonded to a carbon atom forming part of a double bond,
R7 is selected from the group consisting of H, C1-4 alkyl, and C3-7 cycloalkyl, which in each case can be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms; and aryl C1-4 alkyl, which can be substituted on the ring or at least on one ring by from one to four substituents Rb;
R8 and R9 are independently selected from the group consisting of H; C1-4 alkyl, C3-7 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, which can in each case be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms; halogen, hydroxyl; aryl, aryl C1-4 alkyl, heterocyclyl, heterocyclyl C1-4 alkyl, which can be substituted on the ring or at least on one ring by from one to four substituents Rb;
or
R8 and R9 form, together with the carbon atom to which they are bonded, a cyclopropane ring;
R10 is selected from the group consisting of H; C1-4 alkyl, C3-7 cycloalkyl, which in each case can be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms; aryl, aryl C1-4 alkyl, heterocyclyl, and heterocyclyl C1-4 alkyl, each of which can be substituted on the or at least one ring by from one to four substituents Rb;
R11 is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylsulfonyl, which can in each case be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms; aryl, heterocyclyl, aryl C0-4 alkylsulfonyl, aryl C1-4 alkyl, and heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb, halogen, hydroxyl, nitro, cyano, —NRc2, —CONRc2, and —SO2NRc2; and
R12 is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, which can in each case be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms; aryl, heterocyclyl, aryl C1-4 alkyl, and heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb; optionally partially or completely halogenated C1-4 alkoxy, hydroxyl, halogen, nitro, cyano, and NRc2 when R12 is bonded to a carbon atom;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein treating hyperaldosteronism comprises treating at least one selected from the group consisting of hypokalaemia, hypertension, congestive heart failure, ventricular fibrillation, renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, postmyocardial infarction syndrome, coronary cardiac diseases, inflammation, increased collagen formation, vasculitis, fibrosis, remodeling following hypertension, endothelial dysfunction and edema.

### Claim 3 (depends on 1)

The method according to claim 1, wherein
R1 is selected from the group consisting of H; C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, C1-4 alkylcarbonyl, and C1-4 alkoxycarbonyl, each of which can be substituted by from one to three substituents Ra, wherein Ra is independently selected from the group consisting of optionally partially or completely halogenated C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, and C1-4 alkylcarbonyl and also hydroxyl, nitro, and cyano, or can be partially or completely halogenated with independent halogen atoms; aryl C1-4 alkyl and heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb, wherein Rb is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, C1-4 alkylsulfonyl, whose alkyl moieties may be partially or completely halogenated with independent halogen atoms, halogen, hydroxyl, nitro, cyano, —NRc2, —CONRc2, and SO2NRc2, wherein Rc is independently selected from the group consisting of H and C1-4 alkyl; and
R2 is selected from the group consisting of H; C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, C1-4 alkoxy, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylsulfonyl, which in each case can be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms; aryl C1-4 alkyl, aryl C0-4 alkylsulfonyl, heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb; halogen, hydroxyl, nitro, cyano, —NRc2, —CONRc2, and —SO2NRc2.

### Claim 4 (depends on 1)

The method of 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.

### Claim 5 (depends on 1)

The method of claim 1, wherein Z is C═O, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The method of claim 1, wherein R1 is H or C1-4 alkyl, or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The method of 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, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The method of 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.

### Claim 9 (depends on 1)

The method of claim 1, wherein U is S or CR5R6, wherein R5 and R6 are independently selected from H and C1-4 alkyl, X is CH2, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein Het is pyridyl, isoquinolinyl, pyrimidyl or imidazolyl, optionally substituted with a substituent R11, or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of:
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-tetra-hydropyrrolo[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-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.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound is administered to the mammal as part of a composition that further comprises a pharmaceutically acceptable carrier or excipient.

### Claim 13

A method of treating hyperaldosteronism in a mammal in need thereof, the method comprising administering to the mammal a pharmaceutically effective amount of a compound of formula (I):
wherein:
Z is C═O;
U is CH2;
X is CH2;
Y is absent;
A is CR8R9;
b is 1;
n is 0;
m is 1;
Het is 4-pyridinyl;
R1 and R2 form, together with the atoms to which they are bonded, a 2,3-dihydropyrrole ring,
R3 and R4 are independently selected from the group consisting of H; C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, C1-4 alkoxy, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylsulfonyl, which in each case can be substituted by from one to three substituents Ra, or can be partially or completely halogenated with independent halogen atoms; aryl C1-4 alkyl, aryl C0-4 alkylsulfonyl, heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb; halogen, hydroxyl, nitro, cyano, —NRc2, —CONRc2, and —SO2NRc2;
wherein Rc is independently selected from the group consisting of H and C1-4 alkyl,
R8 is phenyl, and,
R9 is H or OH,
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein treating hyperaldosteronism comprises treating at least one selected from the group consisting of hypokalaemia, hypertension, congestive heart failure, ventricular fibrillation, renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, postmyocardial infarction syndrome, coronary cardiac diseases, inflammation, increased collagen formation, vasculitis, fibrosis, remodeling following hypertension, endothelial dysfunction and edema.