Endosomolytic agents for gene therapy

Patent metadata

Field	Value
Publication number	US-10842884-B2
Application number	US-201716337243-A
Country	US
Kind code	B2
Filing date	Sep 27, 2017
Priority date	Sep 29, 2016
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

Compounds of formula (I), wherein Ar is an aryl group optionally further substituted with one or more groups R 3 ; A is a lipophilic, hydrophobic moiety; R 1 is a phosphodiester, phosphotriester, thioether or amide group; X is an unsubstituted or substituted C 6 to C 24 alkylene or alkenylene group, which is optionally interrupted by one or more —NR 9 —, —O— or —S— linkages, R 2 is —YC(R 4 )(R 5 )CO 2 R 6 ; and pharmaceutically acceptable salts or solvates thereof are useful as endosomolytic agents particularly for the delivery of nucleic acids useful in gene therapy.

First claim

The invention claimed is:

1. A compound of formula (1),

wherein
Ar is an aryl group optionally further substituted with one or more groups R 3 ;
A is a lipophilic, and hydrophobic moiety;
R 1 is a phosphodiester, phosphotriester, thioether or amide group;
X is an unsubstituted or substituted C 6 to C 24 alkylene or alkenylene group,
which is optionally interrupted by one or more —NR 9 —, —O— or —S— linkages,
wherein R 9 is a C 1 to C 6 alkyl group;
R 2 is —YC(R 4 )(R 5 )CO 2 R 6 ;
Y is a covalent bond or —(CH 2 ) m —, wherein m is 1, 2 or 3;
R 4 and R 5 are the same or different and each is a substituted or unsubstituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl or C 2 to C 6 alkenyl group;
R 6 is a hydrogen atom or an unsubstituted or substituted C 1 to C 6 alkyl group;
each R 3 moiety is the same or different and each is selected from a halogen atom, a C 1 to C 6 alkyl group, a C 1 to C 6 alkenyl group, a C 1 to C 6 alkynl group,
a C 1 to C 6 alkoxy group, and —YC(R 4 )(R 5 )CO 2 R 6 , and wherein when an R 3 moiety is —YC(R 4 )(R 5 )CO 2 R 6 it may be the same or different to R 2 ;

wherein R 4 , R 5 and R 6 are unsubstituted or substituted with 1, 2 or 3 substituents selected from a halogen atom, a hydroxyl group, C 1 to C 6 alkoxy and NR 7 R 8 , wherein R 7 and R 8 are the same or different and each is a C 1 to C 6 alkyl group;
or a pharmaceutically acceptable salt or solvate thereof.

2. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein either A is —R 10 CH(OR 12 )R 11 CH(OR 13 )Z, wherein R 12 and R 13 are the same or different and each is a C 10 to C 24 alkyl or alkenyl group, R 10 and R 11 are the same or different and each is a covalent bond or a —(CH 2 ) s — group wherein s is 1, 2 or 3, Z is a hydrogen atom or a C 1 to C 3 alkyl group: or A is an unsubstituted or substituted C 17 to C 35 group comprising the fused ring system of a steroid.

3. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein A is (R)-2,3-di(octadecyloxy)propyl or cholesteryl.

4. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the aryl group Ar is a phenyl group.

5. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, which comprises at least one R 3 group which is of the formula —YC(R 4 )(R 5 )CO 2 R 6 and is the same or different to the group R 2 .

6. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure

wherein
A is a lipophilic, and hydrophobic moiety;
R 1 is a phosphodiester, phosphodiester, thioether or amide group;
X is an unsubstituted or substituted C 6 to C 24 alkylene or alkenylene group,
which is optionally interrupted by one or more —NR 9 —, —O— or —S— linkages,
wherein R 9 is a C 1 to C 6 alkyl group;
R 2 is —YC(R 4 )(R 5 )CO 2 R 6 ;
R 3a is of the formula —YC(R 4 )(R 5 )CO 2 R 6 and is the same or different to the group R 2 , and each R 3b is the same or different and each is selected from a hydrogen atom, a halogen atom, a C 1 to C 6 alkyl group, a C 1 to C 6 , alkenyl group, a C 1 to C 6 alkynl group or a C 1 to C 6 alkoxy group;
Y is a covalent bond or —(CH 2 ) m —, wherein m is 1, 2 or 3;
R 4 and R 5 are the same or different and each is a substituted or unsubstituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl or C 2 to C 6 alkynyl group;
R 6 is a hydrogen atom or an unsubstituted or substituted C 1 to C 6 alkyl group;
each R 3 moiety is the same or different and each is selected from a halogen atom, a C 1 to C 6 alkyl group, a C 1 to C 6 alkenyl group, a C 1 to C 6 alkynl group, a C 1 to C 6 alkoxy group and —YC(R 4 )(R 5 )CO 2 R 6 , and wherein when an R 3 moiety is —YC(R 4 )(R 5 )CO 2 R 6 it may be the same or different to R 2 ; and

wherein R 4 , R 5 and R 6 are unsubstituted or substituted with 1, 2 or 3 substituents selected from a halogen atom, a hydroxyl group, C 1 to C 6 alkoxy and NR 7 R 8 , wherein R 7 and R 8 are the same or different and each is a C 1 to C 6 alkyl group.

7. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a phosphodiester or phosphotriester group.

8. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is —CH 2 —.

9. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 and R 5 are an unsubstituted C 1 to C 6 alkyl group.

10. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is a hydrogen atom or an unsubstituted C 1 to C 3 alkyl group.

11. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is —(CH 2 ) n — wherein n is 10 to 20.

12. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is one of the following:
dimethyl 3,3′-(5-(11-(((2-chlorophenoxy)(((3R,10R,13R)-10,13-dimenthyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)phosphoryl)oxy)undecyl)-1,3-phenylene)bis(2,2-dimethylpropanoate);
3,3′-(5-(11-(((((3R,10R,13R)-10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)(hydroxy)phosphoryl)oxy)undecyl)-1,3-phenylene)bis(2,2-dimethylpropanoic acid), ammonium salt;
dimethyl 3,3′-(5-(11-((((S)-2,3-bis(octadecyloxy)propoxy)(2-chlorophenoxy)phosphoryl)oxy)undecyl)-1,3-phenylene)bis(2,2-dimethylpropanoate);
3,3′-(5-(11-((((S)-2,3-bis(octadecyloxy)propoxy)(hydroxy)phosphoryloxy)undecyl)-1,3-phenylene)bis(2,2-dimethylpropanoic acid), ammonium salt;
dimethyl 3,3′-(5-(17-(((2-chlorophenoxy)(((3R,10R,13R)-10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)phosphoryl)oxy)heptadecyl)-1,3-phenylene)bis(2,2-dimethylpropanoate); or
3,3′-(5-(17-(((((3R,10R,13R)-10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)(hydroxy)phosphoryl)oxy)heptadecyl)-1,3-phenylene)bis(2,2-dimethylpropanoic acid), ammonium salt.

13. A gene therapy vector comprising the compound as defined in claim 1 .

14. A gene therapy vector according to claim 13 , which is a polyplex, lipoplex or lipopolyplex.

15. A gene therapy vector according to claim 14 , wherein the lipoplex or lipopolyplex comprises liposomes.

16. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

17. A method for the treatment of a disorder for which the administration of a gene therapy vector is indicated, which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 1 in conjunction wi

Assignees

• UCB Biopharma SRL

Inventors

• Baker Terence Seward
• Eaton Michael Anthony William
• Norman Timothy John
• Turner James Petrie

Classifications

• C07F9/106

  Adducts, complexes, salts of phosphatides · CPC title

• C07J51/00 Primary

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

• C07F9/117

  with cycloaliphatic alcohols · CPC title

• A61K48/0083

  characterised by an aspect of the administration regime · CPC title

• C07F9/12

  with hydroxyaryl compounds · CPC title