Heterocyclic compound and use thereof

Patent metadata

Field	Value
Publication number	US-11655241-B2
Application number	US-201916973320-A
Country	US
Kind code	B2
Filing date	Jun 27, 2019
Priority date	Jun 29, 2018
Publication date	May 23, 2023
Grant date	May 23, 2023

Abstract

The present invention provides a heterocyclic compound having an orexin type 2 receptor agonist activity.
A compound represented by the formula (I):

wherein each symbol is as described in the specification, or a salt thereof has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy.

First claim

The invention claimed is:

1. A compound represented by the formula (I)

wherein
R 1 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted mono- or di-C 1-6 alkylamino group, an acyl group, or an optionally substituted 3- to 6-membered cyclic group;
R 2 is a hydrogen atom, an acyl group, or an optionally substituted 3- to 6-membered cyclic group;
R 3 and R 4 are each independently a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, or a hydroxy group;
Ring A is an optionally further substituted pyrrolidine ring;
Ring B is an optionally further substituted 4- to 7-membered ring; and
Ring C is a benzene ring optionally further substituted by 1 to 3 halogen atoms;
or a salt thereof.

2. The compound or salt according to claim 1 , wherein
R 1 is
(1) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a hydroxy group, and
(iii) a C 1-6 alkoxy group,

(2) a C 1-6 alkoxy group,
(3) a mono- or di-C 1-6 alkyl-carbamoyl group,
(4) a C 3-6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a cyano group,
(iii) a hydroxy group, and
(iv) a C 1-6 alkoxy group, or

(5) a 3- to 6-membered monocyclic non-aromatic heterocyclic group;
R 2 is
(1) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from
(i) a hydroxy group, and
(ii) a C 1-6 alkoxy group,

(2) a C 3-10 cycloalkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a cyano group,
(iii) a hydroxy group,
(iv) an optionally halogenated C 1-6 alkyl group, and
(v) a C 1-6 alkoxy group, or

(3) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group; R 3 and R 4 are both hydrogen atoms;
Ring A is
a pyrrolidine ring having no additional substituent;
Ring B is
(1) a benzene ring having no additional substituent, or
(2) a 5- to 6-membered monocyclic aromatic heterocycle having no additional substituent; and
Ring C is a benzene ring optionally further substituted by 1 to 3 halogen atoms.

3. The compound or salt according to claim 1 , wherein
R 1 is
(1) a mono- or di-C 1-6 alkyl-carbamoyl group, or
(2) a 3- to 6-membered monocyclic non-aromatic heterocyclic group;
R 2 is
(1) a C 3-10 cycloalkyl-carbonyl group, or
(2) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl group;
R 3 and R 4 are both hydrogen atoms;
Ring A is a pyrrolidine ring having no additional substituent; Ring B is a benzene ring having no additional substituent; and Ring C is a benzene ring further substituted by 1 to 3 halogen atoms.

4. The compound or salt according to claim 1 , wherein
R 1 is
(1) a mono- or di-C 1-6 alkyl-carbamoyl group, or
(2) a tetrahydrofuryl group;
R 2 is
(1) a cyclobutylcarbonyl group, or
(2) an azetidinylcarbonyl group;
R 3 and R 4 are both hydrogen atoms;
Ring A is a pyrrolidine ring having no additional substituent; Ring B is a benzene ring having no additional substituent; and Ring C is a benzene ring further substituted by 1 to 3 halogen atoms.

5. A compound which is N ˜ 2 ˜ -{(2S,3S)-1-(Azetidine-1-carbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N ˜ 1 ˜ ,N ˜ 1 ˜ -dimethylethanediamide, or a salt thereof.

6. A compound which is (2S)—N-{(2S,3S)-1-(Azetidine-1-carbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide, or a salt thereof.

7. A compound which is (2S)—N-{(2S,3S)-1-(Cyclobutanecarbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide, or a salt thereof.

8. A medicament comprising the compound or salt according to claim 1 .

9. A method of activating an orexin type 2 receptor in a mammal, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.

10. A method for the prophylaxis or treatment of narcolepsy in a mammal, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.

11. A compound represented by the formula (I):

wherein
R 1 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted mono- or di-C 1-6 alkylamino group, an acyl group, or an optionally substituted 3- to 6-membered cyclic group;
R 2 is a hydrogen atom, an acyl group, or an optionally substituted 3- to 6-membered cyclic group;
R 3 and R 4 are each independently a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, or a hydroxy group;
Ring A is an optionally further substituted piperidine ring;
Ring B is an optionally further substituted 4- to 7-membered ring; and
Ring C is a benzene ring optionally further substituted by 1 to 3 halogen atoms,
or a salt thereof.

12. The compound or salt according to claim 11 , wherein
R 1 is
(1) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a hydroxy group, and
(iii) a C 1-6 alkoxy group,

(2) a C 1-6 alkoxy group,
(3) a mono- or di-C 1-6 alkyl-carbamoyl group,
(4) a C 3-6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a cyano group,
(iii) a hydroxy group, and
(iv) a C 1-6 alkoxy group, or

(5) a 3- to 6-membered monocyclic non-aromatic heterocyclic group;
R 2 is
(1) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from
(i) a hydroxy group, and
(ii) a C 1-6 alkoxy group,

(2) a C 3-10 cycloalkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a cyano group,
(iii) a hydroxy group,
(iv) an optionally halogenated C 1-6 alkyl group, and
(v) a C 1-6 alkoxy group, or

(3) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group;
R 3 and R 4 are both hydrogen atoms;
Ring A is a piperidine ring having no additional substituent;
Ring B is
(1) a benzene ring having no additional substituent, or
(2) a 5- to 6-membered monocyclic aromatic heterocycle having no additional substituent; and
Ring C is a benzene ring optionally further substituted by 1 to 3 halogen atoms.

13. A medicament comprising the compound or salt according to claim 11 .

14. A method of activating an orexin type 2 receptor in a mammal, which comprises administering an effective amount of the compound or salt according to claim 11 to the mammal.

15. A method for the prophylaxis or treatment of narcolepsy in a mammal, which comprises administering an effective amount of the compound or salt according to claim 11 to the mammal.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Oda Tsuneo
• Ito Yoshiteru
• Miyazaki Tohru
• Takeuchi Kohei
• Tokunaga Norihito
• Hoashi Yasutaka
• Hattori Yasushi
• Imamura Keisuke
• Kajita Yuichi
• Miyanohana Yuhei
• Sugimoto Takahiro
• Koike Tatsuki
• Uyghur Dilhumar

Classifications

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K31/4523

  containing further heterocyclic ring systems · CPC title