Dihydrochromene derivatives

Patent metadata

Field	Value
Publication number	US-12398149-B2
Application number	US-202318187124-A
Country	US
Kind code	B2
Filing date	Mar 21, 2023
Priority date	Mar 20, 2018
Publication date	Aug 26, 2025
Grant date	Aug 26, 2025

Abstract

The present invention relates to the compound of formula (I) wherein R 1A , R 1B , R 1C , and R 1D are hydrogen atom, etc., R 2A and R 2B are hydrogen atom, etc., R 3A , R 3B , R 3C , and R 3D are hydrogen atom, etc., L is bond, etc., V is C 1-6 alkylene, Q is optionally-substituted imidazole, or a pharmaceutically acceptable salt thereof, as a novel anti-tumor agent that targets CSCs which are thought to be closely involved in the persistent proliferation of malignant tumor, metastasis or recurrence of cancer, and resistance to anti-tumor agents.

First claim

The invention claimed is:

1. A process for preparing a compound of Formula (1a):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1A , R 1B , R 1C , and R 1D are each independently hydrogen atom, halogen atom, azide, or cyano, provided that all of R 1A , R 1B , R 1C , and R 1D are not hydrogen atom;
R 2A and R 2B are each independently hydrogen atom or C 1-6 alkyl;
R 3A , R 3B , R 3C , and R 3D are each independently hydrogen atom, halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, —CO 2 R 4 , —NR 5 R 6 , or —NR 7 COR 8 , or any two of R 3A , R 3B , R 3C , and R 3D may be taken together at the common carbon atom to which they are attached to form ═O;
R 4 and R 8 are each independently C 1-3 alkyl, and
R 5 , R 6 , and R 7 are each independently hydrogen atom or C 1-3 alkyl, or when R 5 and R 6 are both C 1-3 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocyclyl,

comprising the following steps:
A1) reacting a compound of Formula (7a):

wherein:
P is an amino-protecting group; and
R 3A , R 3B , R 3C , and R 3D are as defined above;

with a compound of Formula (7b):

wherein:
LG 2 is a leaving group; and
R 2A and R 2B are as defined above;

to give a compound of Formula (7c):

wherein P, R 2A , R 2B , R 3A , R 3B , R C , and R 3D are as defined above;

A2) reducing the compound of Formula (7c) above, to give the compound of Formula (6b):

wherein P, R 2A , R 2B , R 3A , R 3B , R 3C , and R 3D are as defined above;

A3) reacting the compound of Formula (6b) above with a compound of Formula (6a):

wherein R 1A , R 1B , R 1C , and R 1D are as defined above;

to give the compound of Formula (6b):

wherein P, R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 3A , R 3B , R 3C , and R 3D are as defined above; and

A4) deprotecting the compound of Formula (6c) above, to give the compound of Formula (1a) above.

2. A process for preparing a compound of Formula (5c):

or a pharmaceutically acceptable salt thereof,
wherein:
V is C 1-6 alkylene which may be substituted with 1 to 3 substituents selected independently from the group consisting of fluorine atom, hydroxy, C 1-6 alkoxy, C 3-7 cycloalkyl, 3- to 7-membered saturated heterocyclyl, cyano, and azide;
Q is optionally-substituted imidazole group;
R 1A , R 1B , R 1C , and R 1D are each independently hydrogen atom, halogen atom, azide, or cyano, provided that all of R 1A , R 1B , R 1C , and R 1D are not hydrogen atom;
R 2A and R 2B are each independently hydrogen atom or C 1-6 alkyl;
R 3A , R 3B , R 3C , and R 3D are each independently hydrogen atom, halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, —CO 2 R 6 , —NR 5 R 6 , or —NR 7 COR 8 , or any two of R 3A , R 3B , R 3C , and R 3D may be taken together at the common carbon atom to which they are attached to form ═O;
R 4 and R 8 are each independently C 1-3 alkyl, and
R 5 , R 6 , and R 7 are each independently hydrogen atom or C 1-3 alkyl, or when R 5 and R 6 are both C 1-3 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocyclyl,

comprising the following steps:
B1) reacting a compound of Formula (1a):

or a pharmaceutically acceptable salt thereof,
wherein R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 3A , R 3B , R 3C , and R 3D are as defined above;

with a compound of Formula (5a):

wherein:
LG 2 denotes a leaving group; and
V is as defined above;

to give a compound of Formula (5b):

wherein LG 2 , V, R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 3A , R 3B , R 3C , and R 3D are as defined above; and

B2) reacting the compound of Formula (5b) above with an imidazole derivate (QH) to give the compound of Formula (5c) above.

3. The method of claim 2 wherein the compound of Formula (5c) or a pharmaceutically acceptable salt thereof is at least one selected from the group consisting of:
(4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran];
(4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran];
(4′aR,10′bR)-8′-chloro-1-(2-(1H-imidazol-1-yl)ethyl)-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran];
(4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran];
(4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran]; and
(4′aR,10′bR)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].

4. A process for preparing a compound of Formula (4b):

or a pharmaceutically acceptable salt thereof,
wherein:
V is C 1-6 alkylene which may be substituted with 1 to 3 substituents selected independently from the group consisting of fluorine atom, hydroxy, C 1-6 alkoxy, C 3-7 cycloalkyl, 3- to 7-membered saturated heterocyclyl, cyano, and azide;
Q is optionally-substituted imidazole group;
R 1A , R 1B , R 1C , and R 1D are each independently hydrogen atom, halogen atom, azide, or cyano, provided that all of R 1A , R 1B , R 1C , and R 1D are not hydrogen atom;
R 2A and R 2B are each independently hydrogen atom or C 1-6 alkyl;
R 3A , R 3B , R 3C , and R 3D are each independently hydrogen atom, halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, —CO 2 R 4 , —NR 5 R 6 , or —NR 7 COR 8 , or any two of R 3A , R 3B , R 3C , and R 3D may be taken together at the common carbon atom to which they are attached to form ═O;
R 4 and R 8 are each independently C 1-3 alkyl, and
R 5 , R 6 , and R 7 are each independently hydrogen atom or C 1-3 alkyl, or when R 5 and R 6 are both C 1-3 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocyclyl,

comprising the following step:

Assignees

• Sumitomo Pharma Co Ltd

Inventors

• Ban Hitoshi
• Kamioka Seiji
• Sawayama Yusuke
• Hashizume Miki

Classifications

• A61K31/438

  The ring being spiro-condensed with carbocyclic or heterocyclic ring systems · CPC title

• A61K31/436

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D491/20 Primary

  Spiro-condensed systems · CPC title