Cationic sulfonamide amino lipids and amphiphilic zwitterionic amino lipids

Patent metadata

Field	Value
Publication number	US-10562849-B2
Application number	US-201715597049-A
Country	US
Kind code	B2
Filing date	May 16, 2017
Priority date	May 16, 2016
Publication date	Feb 18, 2020
Grant date	Feb 18, 2020

Abstract

The present disclosure provides one or more amino lipids such as an amino lipids containing a sulfonic acid or sulfonic acid derivative of the formulas:

wherein the variables are as defined herein. These amino lipids may be used in compositions with one or more helper lipids and a nucleic acid therapeutic agent. These compositions may be used to treat a disease or disorder such as cancer, cystic fibrosis, or other genetic diseases.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
X 1 is —S(O) 2 O − or —OP(O)OR e O − , wherein:
R e is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ;

Y 1 is alkanediyl (C≤12) , alkenediyl (C≤12) , or a substituted version of either of these groups;
Z 1 is —N + R 3 R 4 − ;
A is —NR a —, —S—, or —O—; wherein:
R a is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) , or R a is taken together with either R 3 or R 4 and is alkanediyl (C≤8) , or a substituted version thereof;

R 1 is a group of the formula:

wherein:
R 5 , R 6 , and R 2 are each independently hydrogen or alkyl (C≤8) , -alkanediyl (C≤6) -NH 2 , -alkanediyl (C≤6) -alkylamino (C≤8) , -alkanediyl (C≤6) -dialkylamino (C≤12) , -alkanediyl (C≤6) —NR′R″, or a substituted version of any of these groups wherein:
R′ and R″ are each independently hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , or -Z 2 A′R 7 ; wherein:
Z 2 is alkanediyl (C≤6) or substituted alkanediyl (C≤6) ;
A′ is —CHR j —, —C(O)O—, or —C(O)NR b —;
R b is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
R j is hydrogen, halo, hydroxy, acyloxy (C≤24) , or substituted acyloxy (C≤24) ;

R 7 is alkyl (C6-24) , substituted alkyl (C6-24) , alkenyl (C6-24) , substituted alkenyl (C6-24) ; or

R 5 , R 6 , and R 2 are each independently -Z 3 A″R 8 ; wherein:
Z 3 is alkanediyl (C≤6) or substituted alkanediyl (C≤6) ;
A″ is —CHR k —, —C(O)O—, or —C(O)NR l —;
R l is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
R k is hydrogen, halo, hydroxy, acyloxy (C≤24) , or substituted acyloxy (C≤24) ; and

R 8 is alkyl (C6-24) , substituted alkyl (C6-24) , alkenyl (C6-24) , substituted alkenyl (C6-24) ;

q is 1 or 2; and
r is 1, 2, or 3;

R 1 is a group of the formula:

wherein:
Y 2 is heterocycloalkanediyl (C≤12) , or a substituted version thereof;
R 9 , R 10 , and R 11 are each independently hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , or -Z 4 A′″R 12 ; wherein:
Z 4 is alkanediyl (C≤6) , or substituted alkanediyl (C≤6) ;
A′″ is —CHR k —, —C(O)O—, or —C(O)NR l —;
R l is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
R k is hydrogen, halo, hydroxy, acyloxy (C≤24) , or substituted acyloxy (C≤24) ; and

R 12 is alkyl (C6-24) , substituted alkyl (C6-24) , alkenyl (C6-24) , substituted alkenyl (C6-24) ; and

x and y are 1, 2, or 3;

R 3 and R 4 are each independently hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) , or R 3 or R 4 are taken together with R a and is alkanediyl (C≤8) , or a substituted version thereof; and
m, n, and p are each independently an integer selected from 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 further defined as:

wherein:
Y 1 is alkanediyl (C≤12) , or a substituted version thereof;
A is —NR a —, —S—, or —O—; wherein:
R a is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) , or R a is taken together with either R 3 or R 4 and is alkanediyl (C≤8) , or a substituted version thereof;

R 1 is a group of the formula:

wherein:
R 5 , R 6 , and R 2 are each independently hydrogen or alkyl (C≤8) , -alkanediyl (C≤6) -NH 2 , -alkanediyl (C≤6) -alkylamino (C≤8) , -alkanediyl (C≤6) -dialkylamino (C≤12) , -alkanediyl (C≤6) —NR′R″, or a substituted version of any of these groups wherein:
R′ and R″ are each independently hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , or -Z 2 A′R 7 ; wherein:
Z 2 is alkanediyl (C≤4) or substituted alkanediyl (C≤4) ;
A′ is —CHR j —, —C(O)O—, or —C(O)NR b —;
R b is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
R j is hydrogen, halo, hydroxy, acyloxy (C≤24) , or substituted acyloxy (C≤24) ;

R 7 is alkyl (C6-24) , substituted alkyl (C6-24) , alkenyl (C6-24) , substituted alkenyl (C6-24) ; or

R 5 , R 6 , and R 2 are each independently —Z 3 A″R 8 ; wherein:
Z 3 is alkanediyl (C≤4) or substituted alkanediyl (C≤4) ;
A″ is —CHR k —, —C(O)O—, or —C(O)NR l —;
R l is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
R k is hydrogen, halo, hydroxy, acyloxy (C≤24) , or substituted acyloxy (C≤24) ; and

R 8 is alkyl (C6-24) , substituted alkyl (C6-24) , alkenyl (C6-24) , substituted alkenyl (C6-24) ;

q is 1 or 2; and
r is 1, 2, or 3;

R 1 is a group of the formula:

wherein:
Y 2 is arenediyl (C≤12) , heterocycloalkanediyl (C≤12) , heteroarenediyl (C≤12) , alkoxydiyl (C≤12) , or a substituted version of any of these groups;
R 9 , R 10 , and R 11 are each independently selected from hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , or -Z 4 A′″R 12 ; wherein:
Z 4 is alkanediyl (C≤4) or substituted alkanediyl (C≤4) ;
A′″ is —CHR k —, —C(O)O—, or —C(O)NR l —;
R l is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
R k is hydrogen, halo, hydroxy, acyloxy (C≤24) , or substituted acyloxy (C≤24) ; and

R 12 is alkyl (C6-24) , substituted alkyl (C6-24) , alkenyl (C6-24) , substituted alkenyl (C6-24) ; and

x and y are 1, 2, 3, or 4;

R 3 and R 4 are each independently hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) , or R 3 or R 4 are taken together with R a and is alkanediyl (C≤8) , or a substituted version thereof; and
m, n, and p are each independently an integer selected from 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 further defined as:

wherein:
Y 1 is alkanediyl (C≤12) , or a substituted version thereof;
A is —NR a - or —O—; wherein:
R a is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) , or R a is taken together with either R 3 or R 4 and is alkanediyl (C≤8) , or a substituted version thereof;
R 1 is a group of the formula:

wherein:
R 5 , R 6 , and R 2 are each independently hydrogen or alkyl (C≤8) , -alkanediyl (C≤6) -NH 2 , -alkanediyl (C≤6) -alkylamino (C≤8) , -alkanediyl (C≤6) -dialkylamino (C≤12) , -alkanediyl (C≤6) —NR′R″, or a substituted version of any of these groups wherein:
R′ and R″ are each independently hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , or -Z 2 A′R 7 ; wherein:
Z 2 is alkanediyl (C≤4) or substituted alkanediyl (C≤4) ;
A′ is —CHR j —, —C(O)O—, or —C(O)NR b —;
R b is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
R j is hydrogen, halo, hydroxy, acyloxy (C≤24) , or substituted acyloxy (C≤24) ;

R 7 is alkyl (C6-24) , substituted alkyl (C6-24) , alkenyl (C6-24) , substituted alkenyl (C6-24) ; or

R 5 , R 6 , and R 2 are each independently —Z 3 A″R 8 ; wherein:
Z 3 is alkanediyl (C≤4) or substituted alkanediyl (C≤4) ;
A″ is —CHR k —, —C(O)O—, or —C(O)NR l —;
R l is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
R k is hydrogen, halo, hydroxy, acyloxy (C≤24) , or substituted acyloxy (C≤24) ; and

R 8 is alkyl (C6-24) , substituted alkyl (C6-24) , alkenyl (C6-24) , substituted alkenyl (C6-24) ;

q is 1 or 2; and
r is 1, 2, or 3;

R 1 is a group of th

Assignees

• Univ Texas

Inventors

• Siegwart Daniel J
• Miller Jason B

Classifications

• C07F9/106

  Adducts, complexes, salts of phosphatides · CPC title

• C07C229/06

  having only one amino and one carboxyl group bound to the carbon skeleton · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title