Methods and compositions for selective and targeted cancer therapy

Patent metadata

Field	Value
Publication number	US-9789096-B2
Application number	US-201414916644-A
Country	US
Kind code	B2
Filing date	Sep 4, 2014
Priority date	Sep 4, 2013
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

Provided herein are methods and compositions for selective and targeted cancer therapy, in particular certain benzothiophenes, benzothiazoles, oxalamides, N-acyl ureas and chromones, and their use in selectively treating certain adenocarcinomas. In some embodiments, the selective toxicity of the compounds may be mediated through SCD1 and/or CYP450 such as CYP4F11.

First claim

The invention claimed is:

1. A method for selectively treating cancer or killing a cancer cell, comprising administering a prodrug of formula (IV), or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein said prodrug is activated by a cytochrome P450 enzyme, and the activated drug inhibits SCD1:

wherein:
R 1a is attached to any one or more of C4, C5, C6 and C7 position, and at each occurrence is selected from: hydrogen; halo; hydroxyl; C 1-6 alkoxyl optionally substituted with 1 or more hydroxyl, cyano and/or halo; C 1-6 carbonyl; C 1-6 alkoxycarbonyl; cyano; nitro; amine; —(O(CH 2 ) 1-3 ) n —CCH wherein n is an integer selected from 1-5; and R A ;
m is an integer selected from 0-4; and
Y 1 is selected from: azide; —C(O)R a , —CH(OH)R a , —CH(NH 2 )R a , —NHR a , —C(O)NH(CH 2 ) 0-6 R a and —C(O)N(R b )(R c ), each optionally substituted with 1 or more R A ;
wherein R A is selected from C 1-6 (e.g., C 1-3 ) alkyl, C 2-6 (e.g., C 2-3 ) alkenyl and C 2-6 (e.g., C 2-3 ) alkynyl, each optionally substituted with 1 or more halo, hydroxyl, C 1-6 (e.g., C 1-3 ) alkoxyl, C 1-6 (e.g., C 1-3 ) carbonyl, C 1-6 (e.g., C 1-3 ) alkoxycarbonyl, cyano, nitro, and/or amine;
wherein R a is, at each occurrence, independently selected from C 3-12 cycloalkyl, C 2-6 heterocyclyl, C 6-12 aryl and C 4-12 heteroaryl, each optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl, C 1-6 (e.g., C 1-3 ) alkoxyl, C 1-6 (e.g., C 1-3 ) alkoxycarbonyl, cyano, nitro and/or amine;
wherein R b and R c are each independently selected from R a and R A ; or R b and R c together with the nitrogen they are attached to form a C 2-6 heterocyclyl or C 4-12 heteroaryl ring.

2. The method of claim 1 , wherein said cytochrome P450 enzyme is CYP4F11.

3. The method of claim 2 , wherein said CYP4F11 is overexpressed in the cancer cell in the patient.

4. The method of claim 1 , wherein said cancer is non-small cell lung cancer.

5. The method of claim 1 , wherein Y 1 is at the para position.

6. The method of claim 1 , wherein R 1a is methoxy, m is 1, and Y 1 is —CH(NH 2 )Ph.

Assignees

• Univ Texas

Inventors

• Ready Joseph M
• Nijhawan Deepak
• Gonzales Stephen S
• Theodoropoulos Pano

Classifications

• C07C2601/18

  with a ring being at least seven-membered · CPC title

• C07D215/48

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07C235/38

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C235/56

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C271/48

  to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms · CPC title