Preparation and biological evaluation of viridicatumtoxin analogs

Patent metadata

Field	Value
Publication number	US-10065924-B2
Application number	US-201515327912-A
Country	US
Kind code	B2
Filing date	Jul 22, 2015
Priority date	Jul 22, 2014
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

In one aspect, the present invention provides novel derivatives of viridicatumtoxin of the formula wherein the variables are as defined herein. The application also provides compositions, methods of treatment, and methods of synthesis thereof.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
X 1 is absent such that atoms 16 and 17 are only connected by the shown single bond, a covalent bond such that a double bond is formed between atoms 16 and 17, —O—, alkanediyl (C≤8) , or substituted alkanediyl (C≤8) ;
Y 1 , Y 2 , and Y 3 are each independently alkyl (C≤12) or substituted alkyl (C≤12) ;
R 1 is hydrogen, hydroxy, alkoxy (C≤8) , substituted alkoxy (C≤8) , or oxo, provided that when R 1 is oxo, the bond between R 1 and atom number 5 is a double bond;
R 2 is hydrogen, amino, carboxy, cyano, halo, hydroxy, nitro, or sulfo;
alkyl (C≤12) , alkoxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤18) , or a substituted version of any of these groups;
R 3 , R 6 , R 7 , and R 10 are each independently selected from: hydrogen,
alkyl (C≤8) , alkenyl (C≤8) , aryl (C≤12) , aralkyl (C≤12) , acyl (C≤8) , or a substituted version of any of these groups;
R 4 and R 5 are each independently selected from: hydrogen,
alkyl (C≤8) , alkanediyl (C≤8) -heterocycloalkyl (C≤8) , alkanediyl (C≤8) -heteroaryl (C≤8) , alkanediyl (C≤8) -alkylamino (C≤8) , alkanediyl (C≤8) -dialkylamino (C≤8) , or a substituted version of any of these groups;
R 8 is hydrogen,
alkyl (C≤8) , alkenyl (C≤8) , aryl (C≤12) , aralkyl (C≤12) , acyl (C≤8) , or a substituted version of any of these groups; or —X 2 —R 11 , wherein:
X 2 is alkanediyl (C≤12) or substituted alkanediyl (C≤12) ; and
R 11 is hydroxy, amino, azido, carboxy, or cyano,
alkenyl (C≤6) , alkynyl (C≤6) , heterocycloalkyl (C≤12) , alkylamino (C≤8) , dialkylamino (C≤8) , alkoxy (C≤8) , or a substituted version of any of these groups; or
a -linker-biomolecule wherein the biomolecule is a protein, a polypeptide, an amino acid, a cofactor, an imaging agent, an antibody, a fatty acid, a nucleic acid, or a small molecule therapeutic agent; and

R 9 is hydrogen, amino, carboxy, cyano, halo, hydroxy, nitro, or sulfo;
alkyl (C≤12) , alkoxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤18) , amido (C≤12) , or a substituted version of any of these groups; or —NR 12 C(O)R 13 —NR 14 R 15 ;
wherein:
R 12 is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ;
R 13 is alkanediyl (C≤8) or substituted alkanediyl (C≤8) ; and
R 14 and R 15 are each independently selected from:
hydrogen,
alkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , acyl (C≤12) , or a substituted version of any of these groups; or
R 14 and R 15 are taken together and are alkanediyl (C≤8) , alkoxydiyl (C≤8) , alkylaminodiyl (C≤8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

2. The compound of claim 1 further defined as:

wherein:
X 1 is absent such that atoms 16 and 17 are only connected by the shown single bond, a covalent bond such that a double bond is formed between atoms 16 and 17, —O—, alkanediyl (C≤8) , or substituted alkanediyl (C≤8) ;
Y 1 , Y 2 , and Y 3 are each independently alkyl (C≤12) or substituted alkyl (C≤12) ;
R 1 is hydrogen, hydroxy, alkoxy (C≤8) , substituted alkoxy (C≤8) , or oxo, provided that when R 1 is oxo, the bond between R 1 and atom number 5 is a double bond;
R 2 is hydrogen, amino, carboxy, cyano, halo, hydroxy, nitro, or sulfo;
alkyl (C≤12) , alkoxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤8) , or a substituted version of any of these groups;
R 4 and R 5 are each independently selected from: hydrogen,
alkyl (C≤8) , alkanediyl (C≤8) -heterocycloalkyl (C≤8) , alkanediyl (C≤8) -heteroaryl (C≤8) , alkanediyl (C≤8) -alkylamino (C≤8) , alkanediyl (C≤8) -dialkylamino (C≤8) , or a substituted version of any of these groups;
R 8 is hydrogen,
alkyl (C≤8) , alkenyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , acyl (C≤8) , or a substituted version of any of these groups; or —X 2 —R 11 , wherein:
X 2 is alkanediyl (C≤12) or substituted alkanediyl (C≤12) ; and
R 11 is hydroxy, amino, azido, carboxy, or cyano,
alkenyl (C≤6) , alkynyl (C≤6) , heterocycloalkyl (C≤12) , alkylamino (C≤8) , dialkylamino (C≤8) , alkoxy (C≤8) , or a substituted version of any of these groups; or
a -linker-biomolecule wherein the biomolecule is a protein, a polypeptide, an amino acid, a cofactor, an imaging agent, an antibody, a fatty acid, a nucleic acid, or a small molecule therapeutic agent; and

R 9 is hydrogen, amino, carboxy, cyano, halo, hydroxy, nitro, or sulfo;
alkyl (C≤12) , alkoxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤18) , amido (C≤12) , or a substituted version of any of these groups; or —NR 12 C(O)R 13 —NR 14 R 15 ;
wherein:
R 12 is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ;
R 13 is alkanediyl (C≤8) or substituted alkanediyl (C≤8) ; and
R 14 and R 15 are each independently selected from:
hydrogen,
alkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , acyl (C≤12) , or a substituted version of any of these groups; or
R 14 and R 15 are taken together and are alkanediyl (C≤8) , alkoxydiyl (C≤8) , alkylaminodiyl (C≤8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

3. The compound of claim 1 further defined as:

wherein:
R 1 is hydrogen, hydroxy, alkoxy (C≤8) , substituted alkoxy (C≤8) , or oxo, provided that when R 1 is oxo, the bond between R 1 and atom number 5 is a double bond and when the bond between R 1 and atom number 5 is a double bond then R 1 is oxo;
R 2 is hydrogen, amino, carboxy, cyano, halo, hydroxy, nitro, or sulfo;
alkyl (C≤12) , alkoxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤18) , or a substituted version of any of these groups;
R 4 and R 5 are each independently selected from: hydrogen,
alkyl (C≤8) , alkanediyl (C≤8) -heterocycloalkyl (C≤8) , alkanediyl (C≤8) -heteroaryl (C≤8) , alkanediyl (C≤8) -alkylamino (C≤8) , alkanediyl (C≤8) -dialkylamino (C≤8) , or a substituted version of any of these groups;
R 8 is hydrogen,
alkyl (C≤8) , alkenyl (C≤8) , aryl (C≤12) , aralkyl (C≤12) , acyl (C≤8) , or a substituted version of any of these groups; or —X 2 —R 11 , wherein:
X 2 is alkanediyl (C≤12) or substituted alkanediyl (C≤12) ; and
R 11 is hydroxy, amino, azido, carboxy, or cyano,
alkenyl (C≤6) , alkynyl (C≤6) , heterocycloalkyl (C≤12) , alkylamino (C≤8) , dialkylamino (C≤8) , alkoxy (C≤8) , or a substituted version of any of these groups; or
a -linker-biomolecule wherein the biomolecule is a protein, a polypeptide, an amino acid, a cofactor, an imaging agent, an antibody, a fatty acid, a nucleic acid, or a small molecule therapeutic agent; and

R 9 is hydrogen, amino, carboxy, cyano, halo, hydroxy, nitro, or sulfo;
alkyl (C≤12) , alkoxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤18) , amido (C≤12) , or a substituted version of any of these groups; or —NR 12 C(O)R 13 —NR 14 R 15 ;
wherein:
R 12 is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ;
R 13 is alkanediyl (C≤8) or substituted alkanediyl (C≤8) ; and
R 14 and R 15 are each independently selected from:
hydrogen,
alkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , acyl (C≤12) , or a substituted version of any of these groups; or
R 14 and R 15 are taken together and are alkanediyl (C≤8) , alkoxydiyl (C≤8) , alkylaminodiyl (C≤8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

4. The compound of claim 1 further defined as:

wherein:

Assignees

• Univ Rice William M

Inventors

• Nicolaou Kyriacos C
• Hale Christopher R H
• Nilewski Christian
• Ioannidou Heraklidia
• El Marrouni Abdellatif

Classifications

• C07D261/20

  condensed with carbocyclic rings or ring systems · CPC title

• C07D295/15

  to an acyclic saturated chain · CPC title

• C07C235/82 Primary

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

• C07C2603/94

  containing "free" spiro atoms · CPC title

• A61K45/06

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