Novel lipids and lipid nanoparticle formulations for delivery of nucleic acids

Patent metadata

Field	Value
Publication number	US-2017157268-A1
Application number	US-201715432771-A
Country	US
Kind code	A1
Filing date	Feb 14, 2017
Priority date	Jun 25, 2014
Publication date	Jun 8, 2017
Grant date	—

Abstract

Compounds are provided having the following structure:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , L 2 , a, b, c, d and e are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.

First claim

1 - 47 . (canceled)

48 . A pegylated lipid having the following structure (II):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and
z has a mean value ranging from 30 to 60;

provided that R 10 and R 11 are not both n-octadecyl when z is 42.

49 . The pegylated lipid of claim 48 , wherein R 10 and R 11 are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.

50 . The pegylated lipid of claim 48 , wherein z is about 45.

51 . The pegylated lipid of claim 48 , having one of the following structures:

wherein n has a mean value ranging from 40 to 50.

52 . A composition comprising the pegylated lipid of claim 48 and a cationic lipid.

53 . The composition of claim 52 , wherein the cationic lipid has a structure of Formula I:

or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
L 1 and L 2 are each independently —O(C═O)—, —(C═O)O— or a carbon-carbon double bond;
R 1a and R 1b are, at each occurrence, independently either (a) H or C 1 -C 12 alkyl, or (b) R 1a is H or C 1 -C 12 alkyl, and R 1b together with the carbon atom to which it is bound is taken together with an adjacent R 1b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 2a and R 2b are, at each occurrence, independently either (a) H or C 1 -C 12 alkyl, or (b) R 2a is H or C 1 -C 1 , alkyl, and R 2b together with the carbon atom to which it is bound is taken together with an adjacent R 2b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 3a and R 3b are, at each occurrence, independently either (a) H or C 1 -C 12 alkyl, or (b) R 3a is H or C 1 -C 12 alkyl, and R 3b together with the carbon atom to which it is bound is taken together with an adjacent R 3b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 4a and R 4b are, at each occurrence, independently either (a) H or C 1 -C 12 alkyl, or (b) R 4a is H or C 1 -C 12 alkyl, and R 4b together with the carbon atom to which it is bound is taken together with an adjacent R 4b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 5 and R 6 are each independently methyl or cycloalkyl;
R 7 is, at each occurrence, independently H or C 1 -C 12 alkyl;
R 8 and R 9 are each independently unsubstituted C 1 -C 12 alkyl; or R 8 and R 9 , together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring comprising one nitrogen atom,
a and d are each independently an integer from 0 to 24;
b and c are each independently an integer from 1 to 24; and
e is 1 or 2.

54 . The composition of claim 53 , wherein one of L 1 or L 2 is —O(C═O)—.

55 . The composition of claim 53 , wherein one of L 1 or L 2 is —(C═O)O—.

56 . The composition of claim 53 , wherein the cationic lipid has one of the following structures (Ia), (lb) or (Ic):

57 . The composition of claim 56 , wherein a, b, c and d are each independently an integer from 2 to 12.

58 . The composition of claim 56 , wherein a, b, c and d are each independently an integer from 5 to 9.

59 . The composition of claim 56 , wherein at least one of R 1a , R 2a , R 3a and R 4a is H.

60 . The composition of claim 56 , wherein at least one of R 1a , R 2a , R 3a and R 4a is C 1 -C 8 alkyl.

61 . The composition of claim 60 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

62 . The composition of claim 56 , wherein each of R 5 and R 6 is methyl.

63 . The composition of claim 56 , wherein e is 2.

64 . The composition of claim 56 , wherein each of R 8 and R 9 is methyl.

65 . The composition of claim 52 , wherein the cationic lipid has one of the following structures:

66 . The composition of claim 52 , further comprising a nucleic acid.

67 . The composition of claim 66 , wherein the nucleic acid is selected from antisense and messenger RNA

68 . The composition of claim 52 , further comprising one or more excipient selected from neutral lipids and steroids.

69 . The composition of claim 68 , wherein the composition comprises one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.

70 . The composition of claim 69 , wherein the neutral lipid is DSPC.

71 . The composition of claim 68 , wherein the steroid is cholesterol.

72 . The pegylated lipid of claim 48 , wherein R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing 12 carbon atoms.

73 . The pegylated lipid of claim 48 , wherein R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing 14 carbon atoms.

74 . The pegylated lipid of claim 48 , wherein R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing 16 carbon atoms.

Assignees

• Acuitas Therapeutics Inc

Inventors

• Ansell Steven M
• Du Xinyao

Classifications

• A61P43/00

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

• C07C227/16

  by reactions not involving the amino or carboxyl groups · CPC title

• A61K47/22

  Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones · CPC title

• C07C229/16

  to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids · CPC title

• C07C229/24 Primary

  having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid · CPC title