# US 2008/0188477 A1 · Substituted heterocycles, their use as medicament, and pharmaceutical preparations comprising them

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- Number: US 2008/0188477 A1
- Document ID: US20080188477A1
- Status: Published application
- Kind: A1
- Application number: 11/954,396
- Filed: 2007-12-12
- Published: 2008-08-07
- Earliest claimed: 2005-06-22
- Assignees: Sanofi-Aventis
- Inventors: Joachim BRENDEL; Heinrich Christian ENGLERT; Klaus WIRTH; Michael WAGNER; Jean-Marie RUXER; Fabienne PILORGE
- Web page: https://patentgrep.com/patent/US20080188477A1

## CPC

- C07D 213/64: attached in position 2 or 6
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/12: for electrolyte homeostasis
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/06: Antiarrhythmics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 35/00: Antineoplastic agents
- C07D 237/14: Oxygen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to compounds of formula I in which R1, R2, R3, R4, R5, R6 and X have the meanings stated in the claims. The compounds are particularly suitable as antiarrhythmic active ingredients, in particular for the treatment and prophylaxis of atrial arrhythmias, for example atrial fibrillation (AF) or atrial flutter.

## Claims

### Claim 1

A compound of formula I,
in which:
R1 is phenyl, pyridyl, thienyl, naphthyl, quinolinyl, pyrimidinyl or pyrazinyl,
where each of these aryl radicals is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, alkoxy having 1, 2, 3 or 4 carbon atoms, OCF3, methylsulfonyl, CF3, alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, acetyl, and methylsulfonylamino;
R2 is phenyl, pyridyl, thienyl, naphthyl, quinolinyl, pyrimidinyl or pyrazinyl,
where each of these aryl radicals is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, COOMe, CONH2, alkoxy having 1, 2, 3 or 4 carbon atoms, OCF3, OH, methylsulfonyl, CF3, alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, acetyl, and methylsulfonylamino;
R3 is CpH2p—R7;
p is 0, 1, 2, 3, 4 or 5;
R7 is CH3, CH2F, CHF2, CF3, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, C≡CH, C≡C—CH3, alkoxy having 1, 2, 3 or 4 carbon atoms, phenyl or 2-pyridyl,
where phenyl and 2-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R4 is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R5 is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R6 is hydrogen, F, Cl, CF3 or alkyl having 1, 2 or 3 carbon atoms;
X is CH or N;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.

### Claim 2 (depends on 1)

A compound of formula I as claimed in claim 1, in which:
R1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl,
where each of these aryl radicals is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, alkoxy having 1, 2, 3 or 4 carbon atoms, OCF3, methylsulfonyl, CF3, alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, acetyl, and methylsulfonylamino;
R2 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl,
where each of these aryl radicals is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, COOMe, CONH2, alkoxy having 1, 2, 3 or 4 carbon atoms, OCF3, OH, methylsulfonyl, CF3, alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, acetyl, and methylsulfonylamino;
R3 is CpH2p—R7;
p is 0, 1, 2, 3, 4 or 5;
R7 is CH3, CH2F, CHF2, CF3, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, C≡CH, C≡C—CH3, alkoxy having 1, 2, 3 or 4 carbon atoms, phenyl or 2-pyridyl,
where phenyl and 2-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R4 is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R5 is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R6 is hydrogen, F, Cl, CF3 or alkyl having 1, 2 or 3 carbon atoms;
X is CH or N;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.

### Claim 3 (depends on 1)

A compound of formula I as claimed in claim 1, in which:
R1 is phenyl,
which is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, alkoxy having 1, 2, 3 or 4 carbon atoms, OCF3, methylsulfonyl, CF3, alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, acetyl, and methylsulfonylamino;
R2 is phenyl,
which is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, COOMe, CONH2, alkoxy having 1, 2, 3 or 4 carbon atoms, OCF3, OH, methylsulfonyl, CF3, alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, acetyl, and methylsulfonylamino;
R3 is CpH2p—R7;
p is 0, 1, 2, 3, 4 or 5;
R7 is CH3, CH2F, CHF2, CF3, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, C≡CH, C≡C—CH3, alkoxy having 1, 2, 3 or 4 carbon atoms, phenyl or 2-pyridyl,
where phenyl and 2-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen, F or alkyl having 1, 2, or 3 carbon atoms;
X is CH or N;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.

### Claim 4 (depends on 1)

A compound of formula I as claimed in claim 1, in which:
R1 is phenyl,
which is unsubstituted or substituted by 1 substituent from the group consisting of F, Cl, Br, I, CN and alkoxy having 1 or 2 carbon atoms;
R2 is phenyl,
which is unsubstituted or substituted by 1 substituent from the group consisting of F, Cl, Br, I, CN and alkoxy having 1 or 2 carbon atoms;
R3 is CpH2p—R7;
p is 0, 1, 2, 3;
R7 is CH3, cycloalkyl having 3 or 4 carbon atoms or phenyl,
where phenyl is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CN, alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen, F or alkyl having 1 or 2 carbon atoms;
X is CH or N;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.

### Claim 5 (depends on 1)

A compound of formula I as claimed in claim 1, in which:
R1 is phenyl,
which is unsubstituted or substituted by one substituent from the group consisting of F, Cl, Br, I, CN and alkoxy having 1 or 2 carbon atoms;
R2 is phenyl,
which is unsubstituted or substituted by one substituent from the group consisting of F, Cl, Br, I, CN and alkoxy having 1 or 2 carbon atoms;
R3 is CpH2p—R7;
p is 0, 1, 2 or 3;
R7 is CH3, cycloalkyl having 3 or 4 carbon atoms or phenyl,
where phenyl is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CN, alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen, F or alkyl having 1 or 2 carbon atoms;
X is N;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.

### Claim 6 (depends on 1)

A compound of formula I as claimed in claim 1, selected from:
1R′, 2R′-1-(2-Cyclopropylmethoxy-1,2-diphenylethyl)-1H-pyridin-2-one,
1R′, 2S′-1-[2-Cyclopropylmethoxy-1-(4-fluorophenyl)-2-(4-methoxyphenyl)ethyl]-1H-pyridin-2-one,
1-(2-Cyclopropylmethoxy-1,2-diphenylethyl)-5-fluoro-1H-pyridin-2-one,
2-[2-(4-Chlorophenyl)-2-cyclopropylmethoxy-1-phenylethyl]-2H-pyridazin-3-one,
1R′, 2R′-5-Fluoro-1-(2-p-cyanophenoxy-1,2-di-p-fluorophenylethyl)-1H-pyridin-2-one,
1-[2-Cyclopropoxy-1,2-bis(4-fluorophenyl)ethyl]-5-fluoro-1H-pyridin-2-one,
1-[2-(4-Chlorophenyl)-2-cyclopropylmethoxy-1-phenylethyl]-1H-pyridin-2-one,
1R′, 2R′-1-[2-Cyclopropylmethoxy-1,2-bis(4-fluorophenyl)ethyl]-1H-pyridin-2-one,
1R′, 2S′-1-[2-Cyclopropylmethoxy-1,2-bis-(4-fluorophenyl)ethyl]-1H-pyridin-2-one,
1-[2-(4-Bromophenyl)-2-cyclopropylmethoxy-1-(4-fluorophenyl)ethyl]-1H-pyridin-2-one,
4-[1-Cyclopropylmethoxy-2-(4-fluorophenyl)-2-(2-oxo-2H-pyridin-1-yl)ethyl]benzonitrile,
1R′, 2R′-1-(2-Cyclopropylmethoxy-1,2-diphenylethyl)-5-fluoro-1H-pyridin-2-one,
1R′, 2R′-1-[1-(4-Fluorophenyl)-2-(4-methoxybenzyloxy)-2-(4-methoxyphenyl)ethyl]-1H-pyridin-2-one,
1-[2-Cyclopropylmethoxy-1,2-bis-(4-fluorophenyl)ethyl]-1H-pyridin-2-one,
4-[1-(4-Chlorophenyl)-2-(2-oxo-2H-pyridin-1-yl)-2-phenylethoxymethyl]benzonitrile,
1-[2-Cyclopropylmethoxy-1,2-bis-(4-fluorophenyl)ethyl]-5-fluoro-1H-pyridin-2-one,
1R′, 2R′-1-[2-Cyclopropylmethoxy-1-(4-fluorophenyl)-2-(4-methoxyphenyl)ethyl]-1H-pyridin-2-one
and
1R′, 2S′-1-[1-(4-Fluorophenyl)-2-(4-methoxybenzyloxy)-2-(4-methoxyphenyl)ethyl]-1H-pyridin-2-one,
and the pharmaceutically acceptable salts and trifluoroacetates thereof.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as active ingredient, together with one or more pharmaceutically acceptable carriers or additives.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as active ingredient, together with one or more pharmaceutically acceptable carriers or additives, and in combination with one or more other pharmacologically active ingredients or pharmaceuticals.

### Claim 9 (depends on 1)

A method for the therapy or prophylaxis of one or more K+ channel-mediated diseases, the method comprising the administration of a K+ channel-blocking effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A method for the therapy or prophylaxis of cardiac arrhythmias which can be abolished by prolonging action potential, the method comprising the administration of a pharmaceutically effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

A method for the therapy or prophylaxis of reentry arrhythmias, the method comprising the administration of a pharmaceutically effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A method for the therapy or prophylaxis of supraventricular arrhythmias, the method comprising the administration of a pharmaceutically effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A method for the therapy or prophylaxis of atrial fibrillation or atrial flutter, the method comprising the administration of a pharmaceutically effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

A method for the therapy or prophylaxis of respiratory disorders, neurodegenerative disorders or cancers, the method comprising the administration of a pharmaceutically effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

A method for the therapy or prophylaxis of sleep-related respiratory disorders, central and obstructive sleep apneas, Cheyne-Stoke's breathing, snoring, impaired central respiratory drive, sudden infant death syndrome, postoperative hypoxia and apnea, muscle-related respiratory disorders, respiratory disorders following long-term ventilation, respiratory disorders associated with altitude adaptation, acute and chronic pulmonary disorders with hypoxia and hypercapnia, neurodegenerative disorders, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, breast cancer, lung cancer, colon cancer or prostate cancer, the method comprising the administration of a pharmaceutically effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

A method for the therapy or prophylaxis of heart failure and for increasing atrial contractility, the method comprising the administration of a pharmaceutically effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

The method of claim 16 wherein the heart failure is diastolic heart failure.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and a beta blocker as active ingredients, together with one or more pharmaceutically acceptable carriers or additives.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and an IKs channel blocker as active ingredients, together with one or more pharmaceutically acceptable carriers or additives.