Aminosteroid derivatives and process for producing same

Patent metadata

Field	Value
Publication number	US-11174282-B2
Application number	US-201716302237-A
Country	US
Kind code	B2
Filing date	Jun 2, 2017
Priority date	Jun 2, 2016
Publication date	Nov 16, 2021
Grant date	Nov 16, 2021

Abstract

Estrane-based and androstane-based aminosteroid derivatives are described herein. More specifically, the following piperazinyl-steroid compounds of Formula I, Formula II, Formula III, and Formula IV are described. The compounds display cytotoxicity on a variety of cancer cell lines. A process for producing the compounds and their use in the manufacture of pharmaceutical formulations and/or combinations is also disclosed.

First claim

The invention claimed is:

1. An aminosteroid derivative of Formula I:

wherein:
represents a single or a double bond, provided that two double bonds are not adjacent each other;
A is C, N or NR 1 ;
B is CO, SO, SO 2 , CH 2 , C(X 1 ) 2 , or absent;
Y 1 is chosen from OH, halogen, OR 2 , OCOR 3 , OCONR 4 R 5 and OSO 2 NR 4 R 5 ;
Y 2 is chosen from H, halogen, OH, OR 2 , OMOM (O-methoxymethyl ether), OCOR 3 , OCONR 4 R 5 , OSO 2 NH 2 , OPO(OH) 2 , when Y 2 C is Y 2 —C and
Y 2 is O or S when Y 2 C is Y 2 ═C,
Y 3 is H 2 or O;
Z is H, halogen or C≡CR 6 ;
V is an amino acid,

W is CO, SO 2 , CH 2 , CONH, CSNH, or

X is chosen from alkyl, alkylsulfinyl, alkylthio, alkylsulfonyl, alkoxy, alkenyl, alkynyl, aryl, alkaryl, alkheterocyclyl, aryloxy, alkoxyalkyl, alkoxyaryl, alkthioalkyl, alkthioaryl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclyloxy and thioalkoxy;
X 1 is halogen;
R 1 is H or alkyl;
R 2 is alkyl;
R 3 is H, alkyl or heterocyclyl;
R 4 and R 5 are independently chosen from H and alkyl; and
R 6 is H or alkyl;

or a pharmaceutically acceptable salt, or an N-oxide thereof.

2. The aminosteroid derivative of claim 1 , having the structure:

wherein:
B is CO, SO, SO 2 , CH 2 , C(X 1 ) 2 , or absent;
Y 1 is chosen from OH, halogen, OR 2 , OCOR 3 , OCONR 4 R 5 ; and OSO 2 NR 4 R 5 ;
Y 2 is chosen from H, halogen, OH, OR 2 , OMOM (0-methoxymethyl ether), OCOR 3 , OCONR 4 R 5 , OSO 2 NH 2 and OPO(OH) 2 ;
Y 3 is H 2 or O;
Z is H, halogen or C≡CR 6 ;
V is an amino acid,

W is CO, SO 2 , CH 2 , CONH, CSNH, or

X is chosen from alkyl, alkylsulfinyl, alkylthio, alkylsulfonyl, alkoxy, alkenyl, alkynyl, aryl, alkaryl, alkheterocyclyl, aryloxy, alkoxyalkyl, alkoxyaryl, alkthioalkyl, alkthioaryl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclyloxy and thioalkoxy;
X 1 is halogen;
R 2 is alkyl;
R 3 is H, alkyl or heterocyclyl;
R 4 and R 5 are independently chosen from H and alkyl; and
R 6 is H or alkyl;

or a pharmaceutically acceptable salt, or an N-oxide thereof.

3. The aminosteroid derivative of claim 1 , wherein V is proline and wherein the variables W and X are linked to form the linkage W-X, wherein W-X is chosen from

or a pharmaceutically acceptable salt, or an N-oxide thereof.

4. An aminosteroid derivative of having at least one of the following structures:

5. An aminosteroid derivative of Formula II:

wherein:
A is CHR 1 , NR 1 , O or S;
B is CO, SO, SO 2 , CH 2 , C(X 1 ) 2 , or absent;
Y 1 is chosen from OH, halogen, OR 2 , OCOR 3 , OCONR 4 R 5 and OSO 2 NR 4 R 5 ;
Y 2 is chosen from O and S;
Y 3 is H 2 or O;
Z is H, halogen or C≡CR 6 ;
V is an amino acid,

W is CO, SO 2 , CH 2 , CONH, CSNH, or

X is chosen from alkyl, alkylsulfinyl, alkylthio, alkylsulfonyl, alkoxy, alkenyl, alkynyl, aryl, alkaryl, alkheterocyclyl, aryloxy, alkoxyalkyl, alkoxyaryl, alkthioalkyl, alkthioaryl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclyloxy and thioalkoxy;
X 1 is halogen;
R 1 is H or alkyl;
R 2 is alkyl;
R 3 is H, alkyl or heterocyclyl;
R 4 and R 5 are independently chosen from H and alkyl; and
R 6 is H or alkyl;

or a pharmaceutically acceptable salt, or an N-oxide thereof.

6. The aminosteroid derivative of claim 5 , having the structure:

wherein:
B is CO, SO, SO 2 , CH 2 , C(X 1 ) 2 , or absent;
Y 1 is chosen from OH, halogen, OR 2 , OCOR 3 , OCONR 4 R 5 and OSO 2 NR 4 R 5 ;
Y 2 is chosen from O and S;
Y 3 is H 2 or O;
Z is H, halogen or C≡CR 6 ;
V is an amino acid,

W is CO, SO 2 , CH 2 , CONH, CSNH, or

X is chosen from alkyl, alkylsulfinyl, alkylthio, alkylsulfonyl, alkoxy, alkenyl, alkynyl, aryl, alkaryl, alkheterocyclyl, aryloxy, alkoxyalkyl, alkoxyaryl, alkthioalkyl, alkthioaryl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclyloxy and thioalkoxy;
X 1 is halogen;
R 2 is alkyl;
R 3 is H, alkyl or heterocyclyl;
R 4 and R 5 are independently chosen from H and alkyl; and
R 6 is H or alkyl;

or a pharmaceutically acceptable salt, or an N-oxide thereof.

7. The aminosteroid derivative of claim 5 , wherein V is proline and wherein the variables W and X are linked to form the linkage W-X, wherein W-X is chosen from

or a pharmaceutically acceptable salt, or an N-oxide thereof.

8. The aminosteroid derivative of claim 5 , having at least one of the following structures

9. An aminosteroid derivative of Formula III:

Assignees

• Univ Laval

Inventors

• Poirier Donald
• Maltais René
• Perreault Martin

Classifications

• C07J73/005 Primary

  by nitrogen as hetero atom · CPC title

• A61K31/58

  containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048}) · CPC title

• C07J43/003 Primary

  not condensed · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07J51/00

  Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00 · CPC title