Substituted pyrrolidine compound and use thereof

Patent metadata

Field	Value
Publication number	US-11059780-B2
Application number	US-201816491811-A
Country	US
Kind code	B2
Filing date	Mar 7, 2018
Priority date	Mar 8, 2017
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

The present invention provides a substituted pyrrolidine 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:

wherein
X 1 , X 2 , X 3 and X 4 are each independently a nitrogen atom, or CR a ;
Y and Z are each independently an oxygen atom, NR b , or CR c R d ;
R 1 and R 2 are each independently an optionally substituted C 1-6 alkyl group, or an optionally substituted cyclic group; or
R 1 and R 2 in combination form an optionally further substituted nitrogen-containing heterocycle, together with the adjacent nitrogen atom;
R 3 is an optionally substituted C 1-6 alkyl group, an optionally substituted cyclic group, a group represented by the formula: —C(═O)—R e , or a group represented by the formula: —C(═O)O—R e ;
Ring A is an optionally further substituted pyrrolidine ring;
R a , R c and R d are each independently a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group;
R b is a hydrogen atom, or an optionally substituted C 1-6 alkyl group; and
R e is an optionally substituted C 1-6 alkyl group, or an optionally substituted cyclic group,
or a salt thereof.

2. The compound or salt according to claim 1 , wherein
X 1 is CR a wherein R a is a hydrogen atom or a halogen atom;
X 2 is CR a wherein R a is a hydrogen atom or a halogen atom;
X 3 is CR a wherein R a is a hydrogen atom, a halogen atom or a C 1-6 alkyl group;
X 4 is a nitrogen atom, or CH;
Y is an oxygen atom, NR b wherein R b is a hydrogen atom or a C 1-6 alkyl group, or CR c R d wherein R c and R d are each independently a hydrogen atom, a halogen atom or a C 1-6 alkyl group;
Z is an oxygen atom;
R 1 and R 2 are each independently
(1) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a pyridyl group and a tetrahydrofuryl group,
(2) a pyridyl group,
(3) an oxetanyl group, a tetrahydrofuryl group, a tetrahydropyranyl group or a 8-oxabicyclo[3.2.1]octanyl group, each optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom, and
(ii) a C 1-6 alkyl group, or

(4) a C 3-10 cycloalkyl group, or
R 1 and R 2 in combination form, together with the adjacent nitrogen atom, azetidine, pyrrolidine, pyrroline, piperidine, azepane, morpholine, isoxazolidine, oxazepane, dihydropyrrolopyridine, dihydroimidazopyrazine, indoline, isoindoline, octahydropyrrolopyridine, 6-oxa-1-azaspiro[3.4]octane, 6-oxa-1-azaspiro[3.5]nonane, 7-oxa-1-azaspiro[3.5]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 6-oxa-1-azaspiro[3.3]heptane, 5-azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.4]octane, 2-oxa-7-azaspiro[4.4]nonane, 4-oxa-7-azaspiro[2.5]octane, 2,5-dioxa-8-azaspiro[3.5]nonane, 8-oxa-3-azabicyclo[3.2.1]octane, 2-azabicyclo[3.1.0]hexane, 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane, 6-oxa-3-azabicyclo[3.1.1]heptane or 3-azabicyclo[3.2.0]heptane, each 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 hydroxy group,
(ii) a C 1-6 alkoxy group, and
(iii) a pyridyl group,

(b) a C 1-6 alkyl-carbonyl group,
(c) a C 1-6 alkoxy-carbonyl group,
(d) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a C 1-6 alkyl group, and
(iii) a C 1-6 alkoxy group, and

(e) a pyridyl group, a pyrimidinyl group, a pyrazinyl group and a thiazolyl group, each optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom, and
(ii) a C 1-6 alkyl group;

R 3 is
(1) a C 1-6 alkyl group optionally substituted by 1 to 3 C 6-14 aryl groups,
(2) a C 6-14 aryl group,
(3) a benzothiazolyl group,
(4) a group represented by the formula: —C(═O)—R e
wherein R e is
(a) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a C 1-6 alkyl group,
(iii) a C 1-6 alkoxy group, and
(iv) a C 3-10 cycloalkyl group,

(b) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a C 6-14 aryl group optionally substituted by 1 to 3 C 1-6 alkoxy groups, and
(ii) a halogen atom,

(c) a pyridyl group or a pyrazolyl group, each optionally substituted by 1 to 3 substituents selected from
(i) a C 1-6 alkyl group,
(ii) a C 1-6 alkoxy group, and
(iii) a C 6-14 aryl group,

(d) a tetrahydropyranyl group or a pyrrolidinyl group, each optionally substituted by 1 to 3 C 1-6 alkyl groups, or
(e) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 C 6-14 aryl groups, or

(5) a group represented by the formula: —C(═O)O—R e
wherein R e is
(a) a C 1-6 alkyl group optionally substituted by 1 to 3 C 6-14 aryl groups, or
(b) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from
(i) a C 1-6 alkyl group, and
(ii) a C 1-6 alkoxy group; and

Ring A is a pyrrolidine ring optionally further substituted by 1 to 3 C 1-6 alkoxy groups.

3. The compound or salt according to claim 1 , wherein
X 1 is CH;
X 2 is CR a wherein R a is a hydrogen atom or a halogen atom;
X 3 is CR a wherein R a is a hydrogen atom, a halogen atom or a C 1-6 alkyl group;
X 4 is a nitrogen atom, or CH;
Y is an oxygen atom, NH, or CR c R d wherein R c is a hydrogen atom, and R d is a hydrogen atom or a halogen atom;
Z is an oxygen atom;
R 1 and R 2 are each independently
(1) a C 1-6 alkyl group, or
(2) a tetrahydropyranyl group, or
R 1 and R 2 in combination form, together with the adjacent nitrogen atom, pyrrolidine, 6-oxa-1-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane or 3-azabicyclo[3.1.0]hexane, each optionally further substituted by 1 to 3 substituents selected from
(a) a C 1-6 alkyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups,
(b) a phenyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups, and
(c) a pyridyl group and a thiazolyl group, each optionally substituted by 1 to 3 C 1-6 alkyl groups;

R 3 is a group represented by the formula: —C(═O)—R e
wherein R e is a phenyl group optionally substituted by 1 to 3 substituents selected from
(a) a C 1-6 alkyl group,
(b) a C 1-6 alkoxy group, and
(c) a cyclopropyl group; and

Ring A is a pyrrolidine ring further substituted by one C 1-6 alkoxy group.

4. The compound or salt according to claim 1 , wherein
X 1 is CH;
X 2 is CH;
X 3 is CH;
X 4 is CH;
Y is NH or CH 2 ;
Z is an oxygen atom;
R 1 and R 2 are each independently
(1) a C 1-6 alkyl group, or
(2) a tetrahydropyranyl group, or
R 1 and R 2 in combination form 3-azabicyclo[3.1.0]hexane, together with the adjacent nitrogen atom;
R 3 is a group represented by the formula: —C(═O)—R e
wherein R e is a phenyl group optionally substituted by 1 to 3 C 1-6 alkyl groups; and

Ring A is a pyrrolidine ring further substituted by one C 1-6 alkoxy group.

5. N-(3-(((3R,4R)-1-(2,5-Dimethylbenzoyl)-4-methoxypyrrolidin-3-yl)oxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-sulfonamide or a salt thereof.

6. N-(3-(((3R,4R)-1-(2-Ethyl-6-methylbenzoyl)-4-methoxypyrrolidin-3-yl)oxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-sulfonamide or a salt thereof.

7. 1-(3-(((3R,4R)-1-(2-Ethyl-6-methylbenzoyl)-4-methoxypyrrolidin-3-yl)oxy)phenyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)methanesulfonamide or a salt thereof.

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

9. The medicament according to claim 8 , which is an orexin type 2 receptor agonist.

10. The

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Daini Masaki
• Miyanohana Yuhei
• Mikami Satoshi
• Kajita Yuichi
• Ogino Masaki
• Koike Tatsuki
• Takeuchi Kohei

Classifications

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• A61K31/403

  condensed with carbocyclic rings, e.g. carbazole · CPC title

• A61P25/26 Primary

  Psychostimulants, e.g. nicotine, cocaine · CPC title

• A61K31/4439

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