Substituted naphtho[2,3-b]furans as water-soluble prodrugs for preventing and/or treating cancer

Patent metadata

Field	Value
Publication number	US-10800752-B2
Application number	US-201816194525-A
Country	US
Kind code	B2
Filing date	Nov 19, 2018
Priority date	Mar 27, 2015
Publication date	Oct 13, 2020
Grant date	Oct 13, 2020

Abstract

The present invention provides compounds represented by formula (1A), or pharmaceutically acceptable salts. Compounds represented by formula (1A), or pharmaceutically acceptable salts thereof, wherein A 1 and A 2 are identical or different, and each independently —C(═O)B, —C(═O)CR 3A R 3B B, —CO 2 B, —C(═S)OB, —CONR 3C B, —C(═S)NR 3C B, a hydrogen atom, or the like, wherein A 1 and A 2 are not both hydrogen atoms, wherein B is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocyclic group, an optionally substituted 3- to 12-membered cyclic amino group, or a group represented by the following formula (B), wherein the 3- to 12-membered monocyclic or polycyclic heterocyclic group and the 3- to 12-membered cyclic amino group have at least one or more secondary nitrogen atoms in the ring; R 1 is a hydrogen atom or the like; R 2A , R 2B , R 2C , and R 2D are identical or different, and each independently a hydrogen atom or the like; and R 8 is alkyl.

wherein * denotes a bonding position.

First claim

The invention claimed is:

1. A method for treating at least one cancer in a patient, wherein the at least one cancer is selected from the group consisting of acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, malignant lymphoma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, hepatoma, pancreatic cancer, colon cancer, cervical cancer, malignant melanoma, osteosarcoma, Ewing's sarcoma, and soft tissue sarcoma, comprising administering to a patient in need thereof a therapeutically and prophylactically effective amount of a compound represented by formula (1A):

or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof,
wherein:
A 1 is H, —C(O)CR 3A R 3B B, —C(O)NR 3C B, —C(O) 2 B, —C(O)B, —C(S)NR 3C B, —C(S)OB, —P(O)(CR 3A R 3B B) 2 , —P(O)(NR 3C B) 2 , —P(O)(OB) 2 , —P(O)(B) 2 , —S(O) 2 CR 3A R 3B B, —S(O) 2 NR 3C B, —S(O) 2 OB, or —S(O) 2 B;
A 2 is H, —C(O)CR 3A R 3B B, —C(O)NR 3C B, —C(O) 2 B, —C(O)B, —C(S)NR 3C B, —C(S)OB, —P(O)(CR 3A R 3B B) 2 , —P(O)(NR 3C B) 2 , —P(O)(OB) 2 , —P(O)(B) 2 , —S(O) 2 CR 3A R 3B B, —S(O) 2 NR 3C B, —S(O) 2 OB, or —S(O) 2 B;
R 1 is H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)C 1-6 alkyl, C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 3-10 cycloalkyl, C(O)O-(3- to 12-membered heterocyclyl), C(O)OC 6-10 aryl, C(O)C 3-10 cycloalkyl, C(O)-(3- to 12-membered heterocyclyl), C(O)C 6-10 aryl, NH 2 , OH, OC 1-6 alkyl, SC 1-6 alkyl, SC 3-10 cycloalkyl, S-(3- to 12-membered heterocyclyl), SC 6-10 aryl, S(O)C 1-6 alkyl, S(O)NH 2 , S(O)OH, S(O)C 3-10 cycloalkyl, S(O)-(3- to 12-membered heterocyclyl), S(O)C 6-10 aryl, S(O) 2 C 1-6 alkyl, S(O) 2 NH 2 , S(O) 2 OH, S(O) 2 OC 1-6 alkyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 -(3- to 12-membered heterocyclyl), S(O) 2 C 6-10 aryl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-10 aryl;
R 2A is H, halogen, CN, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 3-10 cycloalkyl, C(O)O-(3- to 12-membered heterocyclyl), C(O)OC 6-10 aryl, C(O)C 3-10 cycloalkyl, C(O)-(3- to 12-membered heterocyclyl), C(O)C 6-10 aryl, NH 2 , OH, OC 1-6 alkyl, OC 3-10 cycloalkyl, O-(3- to 12-membered heterocyclyl), OC 6-10 aryl, SC 1-6 alkyl, SC 3-10 cycloalkyl, S-(3- to 12-membered heterocyclyl), SC 6-10 aryl, S(O)C 1-6 alkyl, S(O)NH 2 , S(O)OH, S(O)C 3-10 cycloalkyl, S(O)-(3- to 12-membered heterocyclyl), S(O)C 6-10 aryl, S(O) 2 C 1-6 alkyl, S(O) 2 NH 2 , S(O) 2 OC 1-6 alkyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 -(3- to 12-membered heterocyclyl), S(O) 2 C 6-10 aryl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-10 aryl;
R 2B is H, halogen, CN, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 3-10 cycloalkyl, C(O)O-(3- to 12-membered heterocyclyl), C(O)OC 6-10 aryl, C(O)C 3-10 cycloalkyl, C(O)-(3- to 12-membered heterocyclyl), C(O)C 6-10 aryl, NH 2 , OH, OC 1-6 alkyl, OC 3-10 cycloalkyl, O-(3- to 12-membered heterocyclyl), OC 6-10 aryl, SC 1-6 alkyl, SC 3-10 cycloalkyl, S-(3- to 12-membered heterocyclyl), SC 6-10 aryl, S(O)C 1-6 alkyl, S(O)NH 2 , S(O)OH, S(O)C 3-10 cycloalkyl, S(O)-(3- to 12-membered heterocyclyl), S(O)C 6-10 aryl, S(O) 2 C 1-6 alkyl, S(O) 2 NH 2 , S(O) 2 OC 1-6 alkyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 -(3- to 12-membered heterocyclyl), S(O) 2 C 6-10 aryl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-10 aryl;
R 2C is H, halogen, CN, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 3-10 cycloalkyl, C(O)O-(3- to 12-membered heterocyclyl), C(O)OC 6-10 aryl, C(O)C 3-10 cycloalkyl, C(O)-(3- to 12-membered heterocyclyl), C(O)C 6-10 aryl, NH 2 , OH, OC 1-6 alkyl, OC 3-10 cycloalkyl, O-(3- to 12-membered heterocyclyl), OC 6-10 aryl, SC 1-6 alkyl, SC 3-10 cycloalkyl, S-(3- to 12-membered heterocyclyl), SC 6-10 aryl, S(O)C 1-6 alkyl, S(O)NH 2 , S(O)OH, S(O)C 3-10 cycloalkyl, S(O)-(3- to 12-membered heterocyclyl), S(O)C 6-10 aryl, S(O) 2 C 1-6 alkyl, S(O) 2 NH 2 , S(O) 2 OC 1-6 alkyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 -(3- to 12-membered heterocyclyl), S(O) 2 C 6-10 aryl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-10 aryl;
R 2D is H, halogen, CN, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 3-10 cycloalkyl, C(O)O-(3- to 12-membered heterocyclyl), C(O)OC 6-10 aryl, C(O)C 3-10 cycloalkyl, C(O)-(3- to 12-membered heterocyclyl), C(O)C 6-10 aryl, NH 2 , OH, OC 1-6 alkyl, OC 3-10 cycloalkyl, O-(3- to 12-membered heterocyclyl), OC 6-10 aryl, SC 1-6 alkyl, SC 3-10 cycloalkyl, S-(3- to 12-membered heterocyclyl), SC 6-10 aryl, S(O)C 1-6 alkyl, S(O)NH 2 , S(O)OH, S(O)C 3-10 cycloalkyl, S(O)-(3- to 12-membered heterocyclyl), S(O)C 6-10 aryl, S(O) 2 C 1-6 alkyl, S(O) 2 NH 2 , S(O) 2 OC 1-6 alkyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 -(3- to 12-membered heterocyclyl), S(O) 2 C 6-10 aryl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-10 aryl;
R 3A is H, optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl;
R 3B is H, optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl;
R 3C is H, optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl;
B is optionally substituted 3- to 12-membered heterocyclyl; or
B is formula (B):

wherein:
X is a single bond, optionally substituted C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, optionally substituted C 3-10 cycloalkylene, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 arylene, or C 5-10 heteroarylene;
Y is a single bond, —C(O)—, —C(O)NR 4A —, —C(O)O—, —NR 4A —, —NR 4A C(O)—, —NR 4A C(O)NR 4B —, —NR 4A C(O)O—, —NR 4A S(O) 2 —, —NR 4A S(O) 2 NR 4B —, —NR 4A S(O) 2 O—, —O—, —OC(O)—, —OC(O)NR 4A —, —OC(O)O—, —OS(O) 2 —, —OS(O) 2 NR 4A —, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 NR 4A —, —S(O) 2 O—, or 3- to 12-membered cyclic aminylene;
R 4A is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl;
R 4B is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl;
Z is a single bond, optionally substituted C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, optionally substituted C 3-10 cycloalkylene, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 arylene, or C 5-10 heteroarylene;
V is —NHR 5 or optionally substituted 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl has at least one secondary nitrogen atom in the ring;
R 5 is H, optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, optionally substituted 3- to 12-membered heterocyclyl, C 6-10 aryl, or C 5-10 heteroaryl, wherein the 3- to 12-membered heterocyclyl has at least one secondary nitrogen atom in the ring;
n is 0, 1, or 2; and
* denotes a bonding position; and
R 8 is optionally substituted C 1-10 alkyl;

wherein in B, R 3A , R 3B , R 3C , R 5 , R 8 , V, X, and Z, the optionally substituted 3- to 12-membered heterocyclyl, C 1-10 alkyl, C 1-10 alkylene, and C 3-10 cycloalkylene is optionally substituted with one, two, three, four, or five substituents

Assignees

• Boston Biomedical Inc
• Sumitomo Dainippon Pharma Co Ltd

Inventors

• Ban Hitoshi
• Kamioka Seiji
• Sawayama Yusuke
• Li Chiang Jia

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D307/92 Primary

  Naphthofurans; Hydrogenated naphthofurans · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title