Benzhydrol derivatives for the management of conditions related to hypoxia inducible factors

Patent metadata

Field	Value
Publication number	US-10772858-B2
Application number	US-201615570969-A
Country	US
Kind code	B2
Filing date	May 2, 2016
Priority date	May 1, 2015
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

This disclosure relates to benzhydrol derivatives for managing conditions related to the Hypoxia Inducible Factor (HIF) pathway such as uses in treating cancer. In certain embodiment, the disclosure contemplates compounds and pharmaceutical compositions. In certain embodiment, the disclosure contemplates compounds disclosed herein as prodrugs, optionally substituted with one or more substituents, derivatives, or salts thereof.

First claim

What is claimed is:

1. A compound having Formula I

or pharmaceutically acceptable salts thereof, wherein:
A is an aryl ring;
n is 1, 2, or 3;
R 4 and R 7 are each, individually and independently, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) 2 amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
R 5 and R 6 are each alkoxy;
R 9 is alkoxy substituted with R 20 ;
R 20 is carbocyclyl, aryl, or heterocyclyl, wherein R 20 is substituted with one or more, the same or different, R 21 ; and
R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydoxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

2. The compound according to claim 1 , wherein A is phenyl.

3. The compound according to claim 1 , wherein R 9 is (2-piperidin-4-yl)ethoxy or (2-(N-alkoxycarbonyl)piperidin-4-yl)ethoxy.

4. A compound having Formula II

or pharmaceutically acceptable salts thereof wherein,
X is —CH 2 O— or —CH 2 CH 2 O—;
R 12 is carbocyclyl, aryl, or heterocyclyl, wherein R 12 is substituted with one or more, the same or different, R 20 ;
R 20 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, hydroxyalkyl, alkoxy, thioalkyl, alkylthio, aminoalkyl, alkylamino, (alkyl) 2 amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 20 is optionally substituted with one or more, the same or different, R 21 ;
R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydoxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R 2 is hydrogen, alkyl, halogen, or alkoxy;
R 3 is hydrogen, alkyl, halogen, or alkoxy;
R 4 , R 7 , and R 8 are each hydrogen;
R 10 is alkyl, formyl, alkanoyl, carbamoyl, hydroxyalkyl, aminoalkyl, or thioalkyl wherein R 10 is optionally substituted with one or more, the same or different, R 20 ; and
R 15 is alkyl, formyl, alkanoyl, carbamoyl, hydroxyalkyl, aminoalkyl, or thioalkyl wherein R 5 is optionally substituted with one or more, the same or different, R 20 .

5. The compound according to claim 4 , wherein X is —CH 2 CH 2 O—.

6. The compound according to claim 5 , wherein R 12 is heterocyclyl.

7. The compound according to claim 1 , selected from the group consisting of
tert-butyl 4-(2-(4-(hydroxy(3,4-dimethoxyphenyl)methyl)-3-methylphenoxy)ethyl)piperidine-1-carboxylate; and
tert-butyl 4-(2-(4-(hydroxy(3, 4,5-trimethoxyphenyl)methyl)-3-methylphenoxy)ethyl)piperidine-1-carboxylate.

8. A pharmaceutical composition, comprising a compound according to claim 1 , or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

9. The compound according to claim 1 , wherein R 9 is ((piperidin-4-yl)oxy)methyl.

10. The compound according to claim 1 , wherein the compound is tert-butyl 4-(2-(4-(hydroxy(3,4-dimethoxyphenyl)methyl)-3-methylphenoxy)ethyl)piperidine-1-carboxylate.

Assignees

• Georgia State Univ Research Foundation
• Univ Emory
• Univ Georgia State Res Found

Inventors

• Wang Binghe
• Van Meir Erwin
• Holmes Ferguson Jalisa
• Kaluz Stefan
• Ji Xingyue

Classifications

• A61K31/352

  condensed with carbocyclic rings, e.g. methantheline  {(cannabinoids A61K31/658)} · CPC title

• C07D211/46 Primary

  having a hydrogen atom as the second substituent in position 4 · CPC title

• A61K31/341

  not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine · CPC title

• A61K31/166

  having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol · CPC title

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title