Endosomolytic agents for gene therapy

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 with a gene therapy vector.

18. A method according to claim 1 , wherein the compound according to claim 1 is administered simultaneously, sequentially or separately from the gene therapy vector.

19. A method according to claim 17 , wherein the gene therapy vector is polyplex, lipoplex or lipopolyplex.

20. A method according to claim 19 , wherein the lipoplex or lipopolyplex comprises liposomes.

21. A pharmaceutical composition comprising a gene therapy vector according to claim 13 and a pharmaceutically acceptable carrier or diluent.