Heterocyclic compound
The present invention provides a compound having an MAGL inhibitory action, and useful as an agent for the prophylaxis or treatment of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, glaucoma, multiple sclerosis etc.), anxiety disorder, pains (e.g., inflammatory pain, cancerous pain, neurogenic pain etc.), epilepsy, depression and the like. The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.
1. A compound represented by the formula (I):
wherein
Ring A is a 3- to 14-membered non-aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from
(a) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a C 6-14 aryloxy group optionally substituted by 1 to 3 substituents selected from
(I) a halogen atom,
(II) an optionally halogenated C 1-6 alkyl group,
(III) a C 3-10 cycloalkyl group,
(IV) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms, and
(V) a cyano group,
(ii) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from
(I) a halogen atom, and
(II) an optionally halogenated C 1-6 alkyl group,
(iii) a halogen atom, and
(iv) a C 7-16 aralkyloxy group optionally substituted by 1 to 3 substituents selected from
(I) a halogen atom, and
(II) a C 1-6 alkyl group,
(b) a C 7-16 aralkyloxy group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) an optionally halogenated C 1-6 alkyl group, and
(iii) an optionally halogenated C 1-6 alkoxy group,
(c) a C 2-6 alkenyl group optionally substituted by 1 to 3 substituents selected from
(i) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from
(I) a halogen atom, and
(II) an optionally halogenated C 1-6 alkyl group, and
(ii) a halogen atom,
(d) a C 6-14 aryloxy group optionally substituted by 1 to 3 halogen atoms, and
(e) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom, and
(ii) an optionally halogenated C 1-6 alkyl group;
Ring D is a C 4-5 cycloalkane;
n is 1 or 2;
X is —O—, —CH 2 — or —O—CH 2 —; and
R a and R b are both hydrogen atoms,
or a salt thereof.
2. The compound or salt of claim 1 , wherein
Ring D is a cyclobutane ring;
n is 1;
X is —O—; and
R a and R b are both hydrogen atoms.
3. The compound or salt of claim 1 , wherein
Ring A is
(1) an azetidine ring optionally further substituted by 1 to 3 substituents selected from
(a) a benzyloxy group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom, and
(ii) an optionally halogenated C 1-6 alkyl group,
(2) a piperidine ring optionally further substituted by 1 to 3 substituents selected from
(a) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a phenoxy group optionally substituted by 1 to 3 substituents selected from
(I) a halogen atom,
(II) an optionally halogenated C 1-6 alkyl group, and
(III) an azetidinyl group optionally substituted by 1 to 3 halogen atoms,
(ii) a phenyl group optionally substituted by 1 to 3 halogen atoms, and
(iii) a halogen atom, and
(b) a dihydrobenzofuryl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom, and
(ii) an optionally halogenated C 1-6 alkyl group, or
(3) a 7-azaspiro[3.5]nonane ring optionally further substituted by 1 to 3 substituents selected from
(a) a phenoxy group optionally substituted by 1 to 3 halogen atoms;
Ring D is a cyclobutane ring;
n is 1;
X is —O—; and
R a and R b are both hydrogen atoms.
4. The compound or salt of claim 1 , wherein
Ring A is
(1) an azetidine ring further substituted by 1 to 3 substituents selected from
(a) a benzyloxy group substituted by 1 to 3 substituents selected from
(i) a halogen atom, and
(ii) an optionally halogenated C 1-6 alkyl group;
Ring D is a cyclobutane ring;
n is 1;
X is —O—;and
R a and R b are both hydrogen atoms.
5. (2s,4s)-2-((3-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)azetidin-1-yl)carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, or a salt thereof.
6. (2s,4s)-2-((3-((2-Methyl-4-(trifluoromethyl)benzyl)oxy)azetidin-1-yl)carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, or a salt thereof.
7. (25,45)-2-((3-((3-Chloro-4-methylbenzyl)oxy)azetidin-1-yl)carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, or a salt thereof.
8. A medicament comprising the compound or salt of claim 1 .
9. The medicament of claim 8 , which is a monoacylglycerol lipase inhibitor.
10. A method of inhibiting monoacylglycerol lipase in a mammal, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal.