Granted Patent B2

US 12,630,509 · App. 17/755,907 · Granted May 19, 2026

Inventors: Shuhei Ikeda (Fujisawa, JP); Makoto Kamata (Fujisawa, JP); Yuya Oguro (Fujisawa, JP); Jumpei Aida (Fujisawa, JP); Taisuke Tawaraishi (Fujisawa, JP); Takeshi Wakabayashi (Fujisawa, JP); Norio Oyabu (Fujisawa, JP); Atsuko Ochida (Fujisawa, JP); Kouichi Iwanaga (Fujisawa, JP); Satoshi Yamamoto (Fujisawa, JP); Masataka Murakami (Fujisawa, JP); Minoru Nakamura (Fujisawa, JP); Fumie Yamaguchi (Fujisawa, JP); Takafumi Yukawa (Fujisawa, JP)

Assignee: Takeda Pharmaceutical Company Limited

C07D207/263A61P25/18C07D401/06

Abstract

Claims (63)

1 . A compound of formula (I):

or a pharmacologically acceptable salt thereof, wherein:

R 1 is chosen from halogens and C 1-3 alkyl groups optionally substituted with at least one fluorine;

R 2 is chosen from unsubstituted C 1-3 alkyl groups;

R 3 is chosen from hydrogen and hydroxyl groups;

ring A is chosen from groups of the formula:

wherein:

R v is chosen from halogens; and

R w is chosen from hydrogen and halogens;

ring B is

wherein:

X is nitrogen and Y is C—H;

ring B 1 is unsubstituted; and

Z is CH 2 .

2 . The compound according to claim 1 , or a pharmacologically acceptable salt thereof, which is chosen from:

Name

Structure

(4S,5S)-1-{[6-(2-fluoro-4- methylphenoxy)pyridin-3-yl]methyl}-4- hydroxy-5-methyl pyrrolidin-2-one

(4S,5S)-4-hydroxy-5-methyl-1-{[6- (2,4,6-trifluorophenoxy)pyridin-3- yl]methyl}pyrrolidin-2-one

(4S,5S)-1-{[6-(2,6-difluoro-4- methylphenoxy)pyridin-3-yl]methyl}-4- hydroxy-5-methyl pyrrolidin-2-one

(4S,5S)-1-{[6-(2,4- difluorophenoxy)pyridin-3-yl]methyl}-4- hydroxy-5-methyl pyrrolidin-2-one

(4S,5S)-1-({6-[2-fluoro-4- (trifluoromethyl)phenoxy]pyridin-3- yl}methyl)-4-hydroxy-5- methylpyrrolidin-2-one

(4S,5S)-1-{[6-(4-chloro-2- fluorophenoxy)pyridin-3-yl]methyl}-4- hydroxy-5- methylpyrrolidin-2-one

(5S)-1-({6-[4-(difluoromethyl)-2- fluorophenoxy]pyridin-3-yl}methyl)-5- methylpyrrolidin-2-one

(5S)-1-{[6-(2,4- difluorophenoxy)pyridin-3-yl]methyl}- 5-methylpyrrolidin-2-one

and pharmacologically acceptable salts thereof.

3 . A pharmaceutical composition comprising at least one entity chosen from compounds according to claim 1 and pharmacologically acceptable salts thereof.

4 . A method for antagonizing an NMDA receptor containing an NR2B subunit in a mammal, comprising administering an effective dose of at least one entity chosen from compounds according to claim 1 and pharmacologically acceptable salts thereof to the mammal.

5 . A method for treating depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia in a mammal, comprising administering an effective dose of at least one entity chosen from compounds according to claim 1 and pharmacologically acceptable salts thereof to the mammal.

6 . A process for preparing a compound of Formula (Ia), or a pharmacologically acceptable salt thereof:

wherein:

Z a is CH 2 ; and

R 1 , R 2 , R 3 , ring A and ring B are as defined in claim 1 , comprising subjecting compound (7):

wherein X is chosen from halogens;

to an alkylation reaction together with compound (8):

to provide the compound of Formula (Ia).

7 . The process of claim 6 , wherein compound (7):

is prepared by:

(i) subjecting compound (2):

wherein:

X is halogen; and

R a is C 1-3 alkyl optionally substituted with one to three substituents chosen from halogens;

to an aromatic nucleophilic substitution reaction together with compound (3):

to provide compound (4):

(iia) subjecting compound (4) to a reduction reaction to provide compound (6):

or

(iib) hydrolyzing compound (4) to provide compound (5)

and

subjecting compound (5) to a reduction reaction to provide compound (6):

and

(iii) halogenating a hydroxyl group of compound (6)

to provide compound (7).

8 . A process for preparing a compound of Formula (Ib), or a pharmacologically acceptable salt thereof:

wherein:

R 1 , R 2 , ring A, and ring B are as defined in claim 1 ;

comprising:

(i) subjecting compound (7):

wherein X is chosen from halogens;

to an alkylation reaction together with compound (9):

wherein P 1 is an alcoholic hydroxyl protecting group,

to provide compound (10):

and

(ii) deprotecting compound (10) to provide the compound of Formula (Ib).

Priority Claims (1)

Continuity (1)

References Cited (147)