Cannabinoid receptor modulators

Patent metadata

Field	Value
Publication number	US-9597340-B2
Application number	US-201214001132-A
Country	US
Kind code	B2
Filing date	Feb 24, 2012
Priority date	Feb 25, 2011
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

Provided are certain methods useful in the treatment of cancer comprising administering a compound of Formula Ia and pharmaceutical compositions thereof that modulate the activity of the cannabinoid CB 2 receptor;

First claim

The invention claimed is:

1. A composition comprising a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:

wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H and C 1 -C 6 alkyl;
X is NR 7 and Y is CC(O)N(R 8 )R 9 ; or
X is CC(O)N(R 8 )R 9 and Y is NR 7 ;
R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:
R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;
R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R 11 is absent;
R 12 is C 1 -C 6 alkylene; or R 12 is absent; and
R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, amino, C 3 -C 7 cycloalkyl, cyano, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkyl, halogen, and hydroxyl;
R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:
R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, carboxy, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl and aryl are optionally substituted with one substituent selected from: C 1 -C 6 alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R 14 is absent;
R 15 is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with C 1 -C 6 alkyl; or R 15 is absent;
R 16 is C 1 -C 6 alkylene; or R 16 is absent; and
R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, amino, aryl, arylamino, aryloxy, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylamino, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, amino, aryl, carboxy, cyano, C 3 -C 7 cycloalkyl, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and
R 9 is selected from: H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or
R 8 and R 9 together with the nitrogen atom to which they are both bonded form a group selected from: heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, carbo-C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C 1 -C 6 alkyl, and heteroaryl are optionally substituted with one substituent selected from: C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, halogen, and hydroxyl,
and one or more known pharmaceutical agents selected from: inhibitors of inherent multidrug resistance, anti-emetic agents, agents useful in the treatment of anemia, agents useful in the treatment of neutropenia, immunologic-enhancing agents, and anticancer agents.

2. A composition comprising a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:

wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H and C 1 -C 6 alkyl;
X is NR 7 and Y is CC(O)N(R 8 )R 9 ; or
X is CC(O)N(R 8 )R 9 and Y is NR 7 ;
R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:
R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;
R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R 11 is absent;
R 12 is C 1 -C 6 alkylene; or R 12 is absent; and
R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, amino, C 3 -C 7 cycloalkyl, cyano, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkyl, halogen, and hydroxyl;
R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:
R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, carboxy, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl and aryl are optionally substituted with one substituent selected from: C 1 -C 6 alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R 14 is absent;
R 15 is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with C 1 -C 6 alkyl; or R 15 is absent;
R 16 is C 1 -C 6 alkylene; or R 16 is absent; and
R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, amino, aryl, arylamino, aryloxy, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylamino, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, amino, aryl, carboxy, cyano, C 3 -C 7 cycloalkyl, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and
R 9 is selected from: H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or
R 8 and R 9 together with the nitrogen atom to which they are both bonded form a group selected from: heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, carbo-C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C 1 -C 6 alkyl, and heteroaryl are optionally substituted with one substituent selected from: C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, halogen, and hydroxyl,
one or more known pharmaceutical agents selected from: inhibitors of inherent multidrug resistance, anti-emetic agents, agents useful in the treatment of anemia, agents useful in the treatment of neutropenia, immunologic-enhancing agents, and anticancer agents, and
a pharmaceutically acceptable carrier.

Assignees

• Thatte Jayant
• Blackburn Anthony C
• Han Sangdon
• Jones Robert M
• Jung Jae-Kyu
• Montalban Antonio Garrido
• Pal Biman B
• Rueter Jaimie Karyn
• Strah-Pleynet Sonja
• THORESEN Lars
• Xiong Yifeng
• Yue Dawei
• Zhu Xiuwen
• Arena Pharm Inc

Inventors

• Thatte Jayant
• Blackburn Anthony C
• Han Sangdon
• Jones Robert M
• Jung Jae-Kyu
• Montalban Antonio Garrido
• Pal Biman B
• Rueter Jaimie Karyn
• Strah-Pleynet Sonja
• THORESEN Lars
• Xiong Yifeng
• Yue Dawei
• Zhu Xiuwen

Classifications

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/416

  condensed with carbocyclic ring systems, e.g. indazole · CPC title

• A61K31/675 Primary

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4439

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