κ opioid receptor agonist comprising 2-phenylbenzothiazoline derivative
View Patent ↗A compound or a salt thereof having the following formula wherein R 1 is acyl, R 2 is hydrogen, halogen, unsubstituted alkyl or alkyl substituted by halogen; R 3 is halogen or alkoxy; R 4 is cycloalkyl, unsubstituted alkyl or alkyl substituted by cycloalkyl, aryl or hydroxyl or an ester thereof or alkoxy; R 5 is hydroxyl or an ester thereof, alkoxy or alkoxyalkyl; or R 4 and R 5 are bonded with each other to form a pyrrolidine ring substituted by hydroxyl or an ester thereof, alkoxy or alkoxyalkyl; R 6 is hydroxyl or an ester thereof, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, mercapto or alkylthio; and A 1 and A 2 , are the same or different, and are alkylene, provided that (i) when R 4 and R 5 are bonded to each other to form the pyrrolidine ring substituted by hydroxyl or an ester thereof, R 2 is halogen; (ii) when R 4 and R 5 are bonded to each other to form the pyrrolidine ring substituted by alkoxyalkyl, R 2 is hydrogen; (iii) when R 6 is hydroxyl or an ester thereof, R 4 is isopropyl.
1. A compound or a salt thereof represented by the following formula [III],
wherein R 1 is acyl;
R 2 is hydrogen, halogen, unsubstituted alkyl or alkyl substituted by halogen;
R 3 is halogen or alkoxy;
R 4 is cycloalkyl, unsubstituted alkyl or alkyl substituted by cycloalkyl, aryl or hydroxyl or an ester thereof or alkoxy;
R 5 is hydroxyl or an ester thereof, alkoxy or -A 2 -R 6 ; or
R 4 and R 5 are bonded with each other to form a pyrrolidine ring substituted by hydroxyl or an ester thereof, alkoxy or alkoxyalkyl;
R 6 is hydroxyl or an ester thereof, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, mercapto or alkylthio; and
A 1 and A 2 , are the same or different, and are alkylene, provided that (i) when R 4 and R 5 are bonded to each other to form the pyrrolidine ring substituted by hydroxyl or an ester thereof, R 2 is halogen; (ii) when R 4 and R 5 are bonded to each other to form the pyrrolidine ring substituted by alkoxyalkyl, R 2 is hydrogen; (iii) when R 6 is hydroxyl or an ester thereof, R 4 is isopropyl.
2. The compound or a salt thereof as claimed in claim 1 , wherein
R 1 is acyl,
R 2 is hydrogen,
R 3 is alkoxy,
R 4 is alkyl,
R 5 is hydroxyl or an ester thereof, alkoxy or -A 2 -R 6 , or
R 4 and R 5 are bonded with each other to form a pyrrolidine ring substituted by alkoxy or alkoxyalkyl,
R 6 is alkoxy, alkoxyalkoxy or alkoxyalkoxyalkoxy, and
A 1 and A 2 , are the same or different, and are alkylene.
3. The compound or a salt thereof as claimed in claim 1 , wherein
R 1 is acyl,
R 2 is halogen,
R 3 is alkoxy,
R 4 is alkyl,
R 5 is hydroxyl or an ester thereof, alkoxy or -A 2 -R 6 , or
R 4 and R 5 are bonded with each other to form a pyrrolidine substituted by hydroxyl or an ester thereof or alkoxy,
R 6 is alkoxy, alkoxyalkoxy or alkoxyalkoxyalkoxy, and
A 1 and A 2 , are the same or different, and are alkylene.
4. The compound or a salt thereof as claimed in claim 1 , wherein
R 1 is acyl,
R 2 is hydrogen or halogen,
R 3 is alkoxy,
R 4 is isopropyl,
R 5 is -A 2 -R 6 ,
R 6 is hydroxyl or an ester thereof, and
A 1 and A 2 , are the same or different, and are alkylene.
5. A κ opioid receptor agonist comprising a compound or a salt thereof, the compound being selected from the group consisting of
3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-(2-methylpropyl)-amino)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-((2S)-2-hydroxymethylazolan-1-yl)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-((3S)-hydroxyazolan-1-yl)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(2-methoxyethyl)amino)-propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-(furan-2-ylmethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]-5-trifluoromethylbenzothiazoline,
3-acetyl-5-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-1-methylpropoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-2-[2-(3-(N-isopropyl-N-(2-methoxyethyl)amino)propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(2-methoxyethyl)amino)-propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(thiophen-2-ylmethyl)-amino)propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-(furan-2-ylmethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-ethyl-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N,N-diisopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-methylamino)propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-(hydroxyethyl)-N-methylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
(−)-3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(2-methoxyethyl)amino)-propoxy)-5-methoxyphenyl]benzothiazoline,
(−)-3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
(−)-3-acetyl-6-chloro-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(2-methoxymethyloxyethyl))-amino)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(2-(2-methoxyethoxy-methoxy)ethyl) amino)propoxy)-5-methoxyphenyl]benzothiazoline,
2-[2-(3-(N-(2-acetoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]-3-acetyl-6-chlorobenzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(2-phenylcarboxyethyl)-amino)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-hydroxy-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-cyclohexyl-N-(2-hydroxyethyl)amino)-propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-ethyl-N-(2-hydroxyethyl)amino)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline and
(+)-3-acetyl-2-[2-(3-(N-isopropyl-N-(2-methoxyethyl)amino)propoxy)-5-methoxyphenyl]benzothiazoline.
6. A compound or a salt thereof, the compound being selected from the group consisting of
3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-hydroxy-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(2-methoxyethyl)amino)-propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-5-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-1-methylpropoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(2-methoxyethyl)amino)-propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-6-chloro-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline,
(+)-3-acetyl-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-(N-(2-methoxymethyloxy-ethyl))amino)propoxy)-5-methoxyphenyl]benzothiazoline,
3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(2-(2-methoxyethoxy-methoxy)ethyl)amino)propoxy)-5-methoxyphenyl]benzothiazoline,
2-[2-(3-(N-(2-Acetoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]-3-acetyl-6-chlorobenzothiazoline and
3-acetyl-6-chloro-2-[2-(3-(N-isopropyl-N-(2-phenylcarboxyethyl)-amino)propoxy)-5-methoxyphenyl]benzothiazoline.
7. A composition comprising an effective pharmaceutical amount of the κ opioid receptor agonist as claimed in claim 5 as an active ingredient in combination with a pharmaceutical acceptable carrier.
8. A method of treating pain or pruritus comprising administering to a patient in need thereof a pharmaceutically effective amount of the kappa opioid receptor agonist according to claim 5 .
9. A method of treating pain or pruritus comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound or salt according to claim 1 .
10. A method of treating pain or pruritus comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound or salt according to claim 2 .
11. A method of treating pain or pruritus comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound or salt according to claim 3 .
12. A method of treating pain or pruritus comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound or salt according to claim 4 .
13. A method of treating pain or pruritus comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound or salt according to claim 6 .
14. The method as claimed in claim 8 , wherein the method is for treating pain caused by a rheumatic disease.
15. The method as claimed in claim 9 , wherein the method is for treating pain caused by a rheumatic disease.
16. The method as claimed in claim 10 , wherein the method is for treating pain caused by a rheumatic disease.
17. The method as claimed in claim 11 , wherein the method is for treating pain caused by a rheumatic disease.
18. The method as claimed in claim 12 , wherein the method is for treating pain caused by a rheumatic disease.
19. The method as claimed in claim 13 , wherein the method is for treating pain caused by a rheumatic disease.