# US 8,772,511 B2 · Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists

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- Number: US 8,772,511 B2
- Document ID: US8772511B2
- Status: Granted
- Kind: B2
- Application number: 13/441,407
- Filed: 2012-04-06
- Published: 2013-03-07
- Granted: 2014-07-08
- Earliest claimed: 2002-07-29
- Assignees: Bayer Intellectual Property GmbH
- Applicants: Timo Fleβner; Frank-Gerhard Böβ; Christina Erb; Frank-Thorsten Hafner; Katrin Schnizler; Dieter Lang; Joachim Luithle; Marja Van Kampen; Franz-Josef Van der Staay
- Inventors: Timo Fleβner; Frank-Gerhard Böβ; Christina Erb; Frank-Thorsten Hafner; Katrin Schnizler; Dieter Lang; Joachim Luithle; Marja Van Kampen; Franz-Josef Van der Staay
- Web page: https://patentgrep.com/patent/US8772511B2

## CPC

- C07D 453/02: containing not further condensed quinuclidine ring systems
- A61P 25/00: Drugs for disorders of the nervous system
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to novel benzothiophene-, benzofuran-, and indole ureas and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning, and/or memory.

## Claims

### Claim 1

A pharmaceutical composition, comprising a compound represented by formula (I):
wherein:
R1 represents 1-azabicyclo[2.2.2]oct-3-yl;
R2 represents hydrogen or C1-C6-alkyl;
R3 represents hydrogen, halogen, amino, hydroxy or C1-C6-alkyl;
R4 represents hydrogen or C1-C6-alkyl which is optionally substituted by a radical selected from the group of hydroxy, halogen, cyano, C1-C6-alkoxy, trifluoromethyl, or trifluoromethoxy,
R5 represents hydrogen or C1-C6-alkyl; or R4 and R5 represent together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by up to 2 substituents independently of one another selected from the group of C1-C6-alkyl, C1-C4-acyl, oxo, thioxo;
R6 represents (i) hydrogen, (ii) C1-C6-alkyl, (iii) C3-C8-cycloalkyl, (iv) C6-C10-aryl, (v) 5- to 10-membered heteroaryl, or (vi) C6-C10-arylcarbonyl, where (ii) is optionally substituted by phenyl, C1-C6-alkoxycarbonyl or C1-C6-alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C1-C6-alkyl, C1-C6-hydroxyalkyl, 3- to 8-membered heterocyclyl, C6-C10-aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano, C1-C6-alkoxy, C1-C6-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkylamino, or C1-C6-acylamino; or R5 and R6 represent together with the nitrogen atom to which they are bonded are a 3- to 10-membered heterocycle which is optionally substituted by C1-C6-alkyl or C1-C6-hydroxyalkyl;
A represents oxygen or sulfur;
X represents oxygen or sulfur;
ring B represents benzo which is optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy;
or a salt thereof; and
a pharmaceutically acceptable carrier.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein:
R6 represents (i) hydrogen, (ii) C1-C6-alkyl, (iii) C1-C8-cycloalkyl, (iv) C6-C10-aryl, or (v) 5- to 10-membered heteroaryl, where (ii) is optionally substituted by phenyl, or C1-C6-alkoxy, and (iv) and (v) are optionally substituted by up to 3 radicals selected independently of one another from the group of C1-C6-alkyl, C1-C6-hydroxyalkyl, 3- to 8-membered heterocyclyl, C6-C10-aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano, C1-C6-alkoxy, C1-C6-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkylamino, or C1-C6-acylamino; or R5 and R6 together with the nitrogen atom to which they are bonded are a 3- to 8-membered heterocycle which is optionally substituted by C1-C6-alkyl or C1-C6-hydroxyalkyl; and
A represents oxygen.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein:
R2 represents hydrogen or C1-C4-alkyl;
R3 represents hydrogen, halogen, amino, hydroxy or C1-C4-alkyl;
represents hydrogen or C1-C4-alkyl which is optionally substituted by a radical selected from the group of hydroxy, halogen, cyano, C1-C3-alkoxy, trifluoromethyl or trifluoromethoxy;
R5 represents hydrogen or C1-C4-alkyl, or R4 and R5 represents together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by up to 2 substituents independently of one another selected from the group of C1-C6-alkyl, C1-C4-acyl, oxo, thioxo;
R6 represents (i) hydrogen, (ii) C1-C4-alkyl, (iii) C5-C6-cycloalkyl, (iv) phenyl, (v) 5- to 6-membered heteroaryl, or (vi) C6-C10-arylcarbonyl, where (ii) is optionally substituted by phenyl, C1-C4-alkoxycarbonyl or C1-C3-alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C1-C4-alkyl, C1-C4-hydroxyalkyl, 3- to 8-membered heterocyclyl, C6-C10-aryl, 5- to 10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano, C1-C3-alkoxy, C1-C3-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C3-alkylamino, or C1-C3-acylamino, or R5 and R6 together with the nitrogen atom to which they are bonded are a 3- to 10-membered heterocycle which is optionally substituted by C1-C3-alkyl or C1-C3-hydroxyalkyl;
A represents oxygen;
X represents oxygen; and
ring B represents benzo which is optionally substituted by radicals from the series chlorine, fluorine, cyano, trifluoromethyl, trifluoromethoxy, amino, C1-C4-alkyl and C1-C4-alkoxy.

### Claim 4 (depends on 3)

The pharmaceutical composition of claim 3, wherein:
R4 represents hydrogen or C1-C4-alkyl which is optionally substituted by a radical selected from the group of hydroxy, C1-C3-alkoxy, trifluoromethyl, trifluoromethoxy; and
R6 represents (i) hydrogen, (ii) C1-C4-alkyl, (iii) C5-C6-cycloalkyl, (iv) phenyl, or (v) 5- to 6-membered heteroaryl, where (ii) is optionally substituted by phenyl, and (iv) and (v) are optionally substituted by up to 3 radicals selected independently of one another from the group of C1-C4-alkyl, C1-C4-hydroxyalkyl, hydroxy, chlorine, fluorine, cyano, C1-C3-alkoxy, C1-C6-acyl, trifluoromethyl, trifluoromethoxy, amino, C1-C3-alkylamino, or C1-C3-acylamino, or R5 and R6 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by C1-C3-alkyl or C1-C3-hydroxyalkyl.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein:
R2-R4 each represents hydrogen;
R5 represents hydrogen or C1-C4-alkyl, or R4 and R5 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by up to 2 substituents independently of one another selected from the group of C1-C4-alkyl, C1-C4-acyl, oxo, thioxo;
R6 represents (i) hydrogen, (ii) C1-C4-alkyl, (iii) C5-C6-cycloalkyl, (iv) phenyl, (v) pyridyl, (vi) C6-C10-arylcarbonyl, where (ii) is optionally substituted by phenyl, C1-C4-alkoxycarbonyl or C1-C3-alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C1-C4-alkyl, C1-C4-hydroxyalkyl, 3- to 8-membered heterocyclyl, C6-C10-aryl, 5- to 10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano, C1-C3-alkoxy, C1-C3-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C3-alkylamino, or C1-C3-acylamino, or R5 and R6 together with the nitrogen atom to which they are bonded are a 3- to 10-membered heterocycle which is optionally substituted by C1-C3-alkyl or C1-C3-hydroxyalkyl;
A represents oxygen;
X represents oxygen; and
ring B represents benzo.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein:
R2 represents hydrogen;
R3 represents hydrogen, chlorine, fluorine, amino or C1-C3-alkyl;
R4 represents hydrogen, methyl or ethyl, where methyl and ethyl are optionally substituted by a radical selected from the group of hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, or R4 and R5 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by up to 2 substituents independently of one another selected from the group of C1-C3-alkyl, C1-C4-acyl, oxo, thioxo;
R5 represents hydrogen or C1-C3-alkyl;
R6 represents (i) hydrogen, C1-C4-alkyl, (iii) cyclohexyl, (iv) phenyl, benzyl, or (vi) phenethyl, where (iv) to (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of hydroxy, chlorine, fluorine, cyano, methoxy, ethoxy, C1-C4-acyl, trifluoromethyl, trifluoromethoxy, amino, C1-C3-alkylamino;
A represents oxygen;
X represents oxygen; and
ring B represents benzo which is optionally substituted by radicals from the series chlorine, fluorine, cyano, trifluoromethyl, trifluoromethoxy, C1-C4-alkyl, methoxy and ethoxy.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein the compound is represented by formula:
wherein to R1 to R6, A, and X have the meanings indicated in claim 1, or a salt thereof.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein the compound is represented by formula:
wherein R1 to R6, A, and X have the meanings indicated in claim 1, or a salt thereof.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein the compound is represented by formula:
wherein R1 to R6 have the meanings indicated in claim 1, or a salt thereof.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the compound is represented by formula:
wherein R1 to R6 have the meanings indicated in claim 1, or a salt thereof.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, wherein:
R2-R5 each represents hydrogen;
R6 represents (i) hydrogen, (ii) C1-C6-alkyl, (iii) C3-C8-cycloalkyl, (iv) C6-C10-aryl, (v) 5- to 10-membered heteroaryl, (vi) C6-C10-arylcarbonyl, where (ii) is optionally substituted by phenyl, C1-C6-alkoxycarbonyl or C1-C6-alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C1-C6-alkyl, C1-C6-hydroxyalkyl, 3- to 8-membered heterocyclyl, C6-C10-aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano, C1-C6-alkoxy, C1-C6-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkylamino, or C1-C6-acylamino;
A represents sulfur;
X represents oxygen; and
ring B represents benzo.

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, wherein:
R6 (i) hydrogen, (ii) C1-C6-alkyl, (iii) C3-C8-cycloalkyl, (iv) C6-C10-aryl, (v) 5- to 10-membered heteroaryl, where (ii) is optionally substituted by phenyl, or C1-C6-alkoxy, and (iv) and (v) are optionally substituted by up to 3 radicals selected independently of one another from the group of C1-C6-alkyl, C1-C6-hydroxyalkyl, 3- to 8-membered heterocyclyl, C6-C10-aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano, C1-C6-alkoxy, C1-C6-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkylamino, or C1-C6-acylamino.

### Claim 13 (depends on 11)

The pharmaceutical composition of claim 11, wherein:
R6 represents (i) hydrogen, (ii) C1-C4-alkyl, (iii) C5-C6-cycloalkyl, (iv) phenyl, (v) 5- to 6-membered heteroaryl, (vi) C6-C10-arylcarbonyl, where (ii) is optionally substituted by phenyl, C1-C4-alkoxycarbonyl or C1-C3-alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C1-C4-alkyl, C1-C4-hydroxyalkyl, 3- to 8-membered heterocyclyl, C6-C10-aryl, 5- to 10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano, C1-C3-alkoxy, C1-C3-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C3-alkylamino, or C1-C3-acylamino.

### Claim 14 (depends on 11)

The pharmaceutical composition of claim 11, wherein:
R6 represents (i) hydrogen, (ii) C1-C4-alkyl, (iii) C5-C6-cycloalkyl, (iv) phenyl, (v) 5- to 6-membered heteroaryl, where (ii) is optionally substituted by phenyl, and (iv) and (v) are optionally substituted by up to 3 radicals selected independently of one another from the group of C1-C4-alkyl, C1-C4-hydroalkyl, hydroxy, chlorine, fluorine, cyano, C1-C3-alkoxy, C1-C6-acyl, trifluoromethyl, trifluoromethoxy, amino, C1-C3-alkylamino, or C1-C3-acylamino.

### Claim 15 (depends on 11)

The pharmaceutical composition of claim 11, wherein:
R6 represents (i) hydrogen, (ii) C1-C4-alkyl, (iii) C5-C6-cycloalkyl, (iv) phenyl, (v) pyridyl, (vi) C6-C10-arylcarbonyl, where (ii) is optionally substituted by phenyl, C1-C4-alkoxycarbonyl or C1-C3-alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C1-C4-alkyl, C1-C4-hydroxyalkyl, 3- to 8-membered heterocyclyl, C6-C10-aryl, 5- to 10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano, C1-C3-alkoxy, C1-C3-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C3-alkylamino, or C1-C3-acylamino.

### Claim 16 (depends on 11)

The pharmaceutical composition of claim 11, wherein:
R6 represents (i) hydrogen, (ii) C1-C4-alkyl, (iii) cyclopentyl, cyclohexyl, (iv) phenyl, (v) benzyl, (vi) phenethyl, where (iv) to (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of hydroxy, chlorine, fluorine, cyano, methoxy, ethoxy, C1-C4-acyl, trifluoromethyl, trifluoromethoxy, amino, C1-C3-alkylamino.

### Claim 17 (depends on 11)

The pharmaceutical composition of claim 11, wherein the compound is represented by formula:
wherein R1 to R6, A, and X have the meanings indicated in claim 11, or a salt thereof.

### Claim 18 (depends on 11)

The pharmaceutical composition of claim 11, wherein the compound is represented by formula:
wherein R1 to R6, A, and X have the meanings indicated in claim 11, or a salt thereof.

### Claim 19 (depends on 11)

The pharmaceutical composition of claim 11, wherein the compound is represented by formula:
wherein R1 to R6 have the meanings indicated in claim 11, or a salt thereof.

### Claim 20 (depends on 11)

The pharmaceutical composition of claim 11, wherein the compound is represented by formula:
wherein R1 to R6 have the meanings indicated in claim 11, or a salt thereof.