Acetyl pyrrolidinyl indole derivative
The present invention relates to compounds, which are useful for treatment and/or prevention of diabetes mellitus, diabetes mellitus complications or obesity, since the compounds have glucokinase-activating effects, and are presented in Formula (I): wherein R 1 represents a lower alkylsulfonyl group; R 2 represents a hydrogen atom; R 20 represents, e.g., a hydrogen atom; m represents an integer of from 1 to 3; and n represents zero or 1, or relates to a pharmaceutically acceptable salts thereof.
1. A compound, or a pharmaceutically acceptable salt thereof, presented in Formula (I):
wherein R 1 represents a group selected from the group consisting of: a lower alkylsulfonyl group; lower alkyl groups substituted with a hydroxy or lower alkoxy group; a lower alkoxy group substituted with a hydroxy group; and a group of Formula (II):
wherein R 3 and R 4 independently represent a hydrogen atom or a lower alkyl group optionally substituted with a hydroxy group, or R 3 and R 4 together with a nitrogen atom to which they are attached represent a four- to seven-membered nitrogen-containing aliphatic ring;
R 2 represents a hydrogen atom;
R 20 is a branched lower alkyl group substituted with a hydroxy group or a group of Formula (III):
wherein R 5 and R 6 independently represent a hydrogen atom, or a lower alkyl group, or R 5 and R 6 together with a nitrogen atom to which they are attached represent a four- to seven-membered nitrogen-containing aliphatic ring;
m represents an integer of from 1 to 3;
n represents zero or 1; and
Formula (IV):
represents a heteroaryl group selected from the group consisting of: pyridinyl, pyrazinyl, and pyrazolyl.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n represents zero.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 20 represents a branched lower alkyl group substituted with a hydroxy group.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 20 is a group of Formula (III):
wherein R 5 and R 6 independently represent a hydrogen atom, or a lower alkyl group, or R 5 and R 6 together with a nitrogen atom to which they are attached represent a four- to seven-membered nitrogen-containing aliphatic ring.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 represents a lower alkylsulfonyl group.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the group represented by Formula (IV) is:
wherein
shows a site attached to an indole ring.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
6-[(R)-1-acetylpyrrolidin-2-yl]-2-[5-(N-methylcarbamoyl)pyridin-2-yl]-5-(6-methylsulfonylpyridin-3-yloxy)-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-2-[5-(1,1-dimethylhydroxymethyl)pyridin-2-yl]-5-(6-hydroxymethylpyridin-3-yloxy)-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-2-[5-(1,1-dimethylhydroxymethyl)pyridin-2-yl]-5-(6-methylsulfonylpyridin-3-yloxy)-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-5-[6-(azetidin-1-ylcarbonyl)pyridin-3-yloxy]-2-[5-(1,1-dimethylhydroxymethyl)pyrazin-2-yl]-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-2-[5-(1,1-dimethylhydroxymethyl)pyrazin-2-yl]-5-(6-methylsulfonylpyridin-3-yloxy)-1H-indole, and
6-[(R)-1-acetylpyrrolidin-2-yl]-5-[6-(azetidin-1-ylcarbonyl)pyridin-3-yloxy]-2-[5-(1,1-dimethylhydroxymethyl)pyridin-2-yl]-1H-indole.
8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
9. A method of treating type 2 diabetes in a mammalian patient in need of such treatment, comprising administering to the patient a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount effective to treat type 2 diabetes.
10. A compound, or a pharmaceutically acceptable salt thereof, presented in Formula (I):
wherein R 1 is a lower alkoxy group substituted with a hydroxy group or a group of Formula (II):
wherein R 3 and R 4 each represent a lower alkyl group optionally substituted with a hydroxy group, or R 3 and R 4 together with a nitrogen atom to which they are attached represent a four- to seven-membered nitrogen-containing aliphatic ring;
R 2 represents a hydrogen atom;
R 20 independently represents a group selected from the group consisting of: hydrogen atoms, lower alkyl groups optionally substituted with hydroxy groups, lower alkoxy groups, and groups of Formula (III):
wherein R 5 and R 6 independently represent a hydrogen atom, or a lower alkyl group, or R 5 and R 6 together with a nitrogen atom to which they are attached represent a four- to seven-membered nitrogen-containing aliphatic ring;
m represents an integer of from 1 to 3;
n represents zero or 1; and
Formula (IV):
represents a heteroaryl group selected from the group consisting of: pyridinyl, pyrazinyl, and pyrazolyl.
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 1 is a lower alkoxy group substituted with a hydroxy group.
12. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 1 is a group of Formula (II):
wherein R 3 and R 4 each represent a lower alkyl group optionally substituted with a hydroxy group.
13. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 1 is a group of Formula (II):
wherein R 3 and R 4 together with a nitrogen atom to which they are attached represent a four- to seven-membered nitrogen-containing aliphatic ring.
14. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein n represents zero.
15. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the group represented by Formula (IV):
wherein
shows a site attached to an indole ring.
16. The compound of claim 10 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
6-[(R)-1-acetylpyrrolidin-2-yl]-5-[6-(2-hydroxyethoxy)pyridin-3-yloxy]-2-(pyridin-2-yl)-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-5-[6-(2-hydroxyethoxy)pyridin-3-yloxy]-2-(pyrazin-2-yl)-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-5-[6-(2-hydroxyethoxy)pyridin-3-yloxy]-2-(5-methylpyrazin-2-yl)-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-5-[6-(2-hydroxyethoxy)pyridin-3-yloxy]-2-(5-hydroxymethylpyrazin-2-yl)-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-5-[6-(azetidin-1-ylcarbonyl)pyridin-3-yloxy]-2-(pyrazin-2-yl)-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-5-[6-(azetidin-1-ylcarbonyl)pyridin-3-yloxy]-2-[5-(1,1-dimethylhydroxymethyl)pyrazin-2-yl]-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-5-[6-(azetidin-1-ylcarbonyl)pyridin-3-yloxy]-2-(5-hydroxymethylpyridin-2-yl)-1H-indole,
6-[(R)-1-acetylpyrrolidin-2-yl]-5-[6-(azetidin-1-ylcarbonyl)pyridin-3-yloxy]-2-[5-(1,1-dimethylhydroxymethyl)pyridin-2-yl]-1H-indole; and
6-[(R)-1-acetylpyrrolidin-2-yl]-5-{6-[N-(2-hydroxyethyl)]-N-methylcarbamoyl]pyridin-3-yloxy}-2-(pyrazin-2-yl)-1H-indole.
17. A pharmaceutical composition comprising a compound of claim 10 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
18. A method of treating type 2 diabetes in a mammalian patient in need of such treatment, comprising administering to the patient a compound of claim 10 , or a pharmaceutically acceptable salt thereof, in an amount effective to treat type 2 diabetes.