IP Library › Granted Patent US 9,714,242

Granted Patent B2

US 9,714,242 · App. 14/299,750 · Granted Jul 25, 2017

Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists

Inventors: Timo Fleβner (Wuppertal, DE); Frank-Gerhard Böβ (Frankfurt, DE); Christina Erb (Wiesbaden, DE); Frank-Thorsten Hafner (Wuppertal, DE); Katrin Schnizler (Rodenbach, DE); Dieter Lang (Velbert, DE); Joachim Luithle (Berlin, DE); Marja Van Kampen (Dusseldorf, DE); Franz-Josef Van Der Staay (Dronten, NL)

Assignee: Bayer Intellectual Property GmbH

C07D453/02

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Quick Facts

Patent No.: US 9,714,242
App. No.: 14/299,750
Granted: Jul 25, 2017
Kind: B2

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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 (146)

1. A method of treating a cognitive impairment in a patient in need thereof, comprising administering to the patient a compound represented by Formula (I):

wherein:

R 1 represents 1-azabicyclo[2.2.2]oct-3-yl;

R 2 represents hydrogen or C 1 -C 6 -alkyl;

R 3 represents hydrogen, halogen, amino, hydroxy or C 1 -C 6 -alkyl;

R 4 represents hydrogen or C 1 -C 6 -alkyl which is optionally substituted by a radical selected from the group of hydroxy, halogen, cyano, C 1 -C 6 -alkoxy, trifluoromethyl, or trifluoromethoxy;

R 5 represents hydrogen or C 1 -C 6 -alkyl; or R 4 and R 5 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 C 1 -C 6 -alkyl, C 1 -C 4 -acyl, oxo, thioxo;

R 6 represents (i) hydrogen, (ii) C 1 -C 6 -alkyl, (iii) C 3 -C 8 -cycloalkyl, (iv) C 6 -C 10 -aryl, (v) 5- to 10-membered heteroaryl, or (vi) C 6 -C 10 -arylcarbonyl, where (ii) is optionally substituted by phenyl, C 1 -C 6 -alkoxycarbonyl or C 1 -C 6 -alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkylamino, or C 1 -C 6 -acylamino; or R 5 and R 6 together with the nitrogen atom to which they are bonded are a 3- to 10-membered heterocycle which is optionally substituted by C 1 -C 6 -alkyl or C 1 -C 6 -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, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy;

or a salt thereof.

2. The method of claim 1 , wherein:

R 6 represents (i) hydrogen, (ii) C 1 -C 6 -alkyl, (iii) C 3 -C 8 -cycloalkyl, (iv) C 6 -C 10 -aryl, or (v) 5- to 10-membered heteroaryl, where (ii) is optionally substituted by phenyl, or C 1 -C 6 -alkoxy, and (iv) and (v) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkylamino, or C 1 -C 6 -acylamino; or R 5 and R 6 together with the nitrogen atom to which they are bonded are a 3- to 8-membered heterocycle which is optionally substituted by C 1 -C 6 -alkyl or C 1 -C 6 -hydroxyalkyl; and

A represents oxygen.

3. The method of claim 1 , wherein:

R 2 represents hydrogen or C 1 -C 4 -alkyl:

R 3 represents hydrogen, halogen, amino, hydroxy or C 1 -C 4 -alkyl;

R 4 represents hydrogen or C 1 -C 4 -alkyl which is optionally substituted by a radical selected from the group of hydroxy, halogen, cyano, C 1 -C 3 -alkoxy, trifluoromethyl or trifluoromethoxy;

R 5 represents hydrogen or C 1 -C 4 -alkyl, or R 4 and R 5 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 C 1 -C 6 -alkyl, C 1 -C 4 -acyl, oxo, thioxo;

R 6 represents (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) C 5 -C 6 -cycloalkyl, (iv) phenyl, (v) 5- to 6-membered heteroaryl, or (vi) C 6 -C 10 -arylcarbonyl, where (ii) is optionally substituted by phenyl, C 1 -C 4 -alkoxycarbonyl or C 1 -C 3 -alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 3 -alkylamino, or C 1 -C 3 -acylamino, or R 5 and R 6 together with the nitrogen atom to which they are bonded are a 3- to 10-membered heterocycle which is optionally substituted by C 1 -C 3 -alkyl or C 1 -C 3 -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, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy.

4. The method of claim 3 , wherein:

R 4 represents hydrogen or C 1 -C 4 -alkyl which is optionally substituted by a radical selected from the group of hydroxy, C 1 -C 3 -alkoxy, trifluoromethyl, trifluoromethoxy; and

R 6 represents (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) C 5 -C 6 -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 C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, hydroxy, chlorine, fluorine, cyano, C 1 -C 3 -alkoxy, C 1 -C 6 -acyl, trifluoromethyl, trifluoromethoxy, amino, C 1 -C 3 -alkylamino, or C 1 -C 3 -acylamino, or R 5 and R 6 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by C 1 -C 3 -alkyl or C 1 -C 3 -hydroxyalkyl.

5. The method of claim 1 , wherein:

R 2 -R 4 each represents hydrogen;

R 6 represents (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) C 5 -C 6 -cycloalkyl, (iv) phenyl, (v) pyridyl, (vi) C 6 -C 10 -arylcarbonyl, where (ii) is optionally substituted by phenyl, C 1 -C 4 -alkoxycarbonyl or C 1 -C 3 -alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 3 -alkylamino, or C 1 -C 3 -acylamino, or R 5 and R 6 together with the nitrogen atom to which they are bonded are a 3- to 10-membered heterocycle which is optionally substituted by C 1 -C 3 -alkyl or C 1 -C 3 -hydroxyalkyl;

A represents oxygen;

X represents oxygen; and

ring B represents benzo.

6. The method of claim 1 , wherein:

R 2 represents hydrogen;

R 3 represents hydrogen, chlorine, fluorine, amino or C 1 -C 3 -alkyl;

R 4 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 R 4 and R 5 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 C 1 -C 3 -alkyl, C 1 -C 4 -acyl, oxo, thioxo;

R 5 represents hydrogen or C 1 -C 3 -alkyl;

R 6 represents (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) cyclopentyl, cyclohexyl, (iv) phenyl, (v) 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, C 1 -C 4 -acyl, trifluoromethyl, trifluoromethoxy, amino, C 1 -C 3 -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, C 1 -C 4 -alkyl, methoxy and ethoxy.

7. The method of claim 1 , wherein the cognitive impairment is Alzheimer's disease.

8. The method of claim 1 , wherein the cognitive impairment is Schizophrenia.

9. The method of claim 1 , wherein the method improves perception, concentration, learning, or memory.

10. The method of claim 1 , wherein the compound, or salt thereof, is selected from the group consisting of:

6-[(Anilino carbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-chlorophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-phenylethyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-bromophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-ethoxyphenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-(dimethylamino)phenyl)amino]-carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-nitrophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,6-difluorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,4-dichlorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-(trifluoromethyl)phenyl]amino)-carbonyl}amino]-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4,5-trimethoxyphenyl)amino]-carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[4-methoxy-3-(trifluoromethyl)phenyl]-amino}carbonyl)amino]-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-methoxyphenyl]amino}carbonyl)-amino]-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-trifluoromethoxyphenyl]amino}-carbonyl)amino]-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)carbonyl]amino}-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclohexyl amino)carbonyl]amino}-1-benzothiophene-2-carboxamide hydrochloride;

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[(1S)-1-phenylethyl]amino}carbonyl)-amino]-1-benzothiophene-2-carboxamide hydrochloride;

7-[(Anilinocarbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride; and

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methoxyphenyl)amino]carbonyl}-amino)-1-benzofuran-2-carboxamide hydrochloride.

11. The method of claim 10 , wherein the cognitive impairment is Alzheimer's disease.

12. The method of claim 10 , wherein the cognitive impairment is Schizophrenia.

13. The method of claim 10 , wherein the method improves perception, concentration, learning, or memory.

14. A method of treating a cognitive impairment in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising:

i) a compound represented by Formula (I):

wherein:

R 1 represents 1-azabicyclo[2.2.2]oct-3-yl;

R 2 represents hydrogen or C 1 -C 6 -alkyl:

R 3 represents hydrogen, halogen, amino, hydroxy or C 1 -C 6 -alkyl;

R 4 represents hydrogen or C 1 -C 6 -alkyl which is optionally substituted by a radical selected from the group of hydroxy, halogen, cyano, C 1 -C 6 -alkoxy, trifluoromethyl, or trifluoromethoxy;

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, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy;

or a salt thereof; and

ii) a pharmaceutically acceptable carrier.

15. The method of claim 14 , wherein:

A represents oxygen.

16. The method of claim 14 , wherein:

R 2 represents hydrogen or C 1 -C 4 -alkyl;

R 3 represents hydrogen, halogen, amino, hydroxy or C 1 -C 4 -alkyl;

R 4 represents hydrogen or C 1 -C 4 -alkyl which is optionally substituted by a radical selected from the group of hydroxy, halogen, cyano, C 1 -C 3 -alkoxy, trifluoromethyl or trifluoromethoxy;

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, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy.

17. The method of claim 14 , wherein:

R 4 represents hydrogen or C 1 -C 4 -alkyl which is optionally substituted by a radical selected from the group of hydroxy, C 1 -C 3 -alkoxy, trifluoromethyl, trifluoromethoxy; and

18. The method of claim 14 , wherein:

R 2 -R 4 each represents hydrogen;

A represents oxygen;

X represents oxygen; and

ring B represents benzo.

19. The method of claim 14 , wherein:

R 2 represents hydrogen;

R 3 represents hydrogen, chlorine, fluorine, amino or C 1 -C 3 -alkyl;

R 5 represents hydrogen or C 1 -C 3 -alkyl;

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, C 1 -C 4 -alkyl methoxy and ethoxy.

20. The method of claim 14 , wherein the cognitive impairment is Alzheimer's disease.

21. The method of claim 14 , wherein the cognitive impairment is Schizophrenia.

22. The method of claim 14 , wherein the method improves perception, concentration, learning, or memory.

23. The method of claim 14 , wherein the compound, or salt thereof, is selected from the group consisting of: