Heterocyclic compound and use thereof
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.
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.