US 5,705,693 AGranted

Cationic lipids

AssigneeGilead Sciences, Inc.

InventorsRandolph B. DePrince, Kevin L. Facchine, George S. Lewis, Jason G. Lewis, Kuei-Ying Lin, Mark D. Matteucci, Robert A. Mook, Jr., Richard W. Wagner

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Abstract

The present invention is directed to new cationic lipids and intermediates in their synthesis that are useful for transfecting nucleic acids or peptides into prokaryotic or eukaryotic cells. The lipids comprise one or two substituted arginine, lysine or ornithine residues, or derivatives thereof, linked to a lipophilic moiety. The lipids form a complex when mixed with polyanions such as nucleic acids or peptides. The complexes permit efficient transfer of polyanions into cells, usually without significant toxicity to the cells.

Claims23

Dependent claims

A compound having the structure ##STR24## wherein each R.sup.1 is independently alkyl (10-22 C) or a mono unsaturated alkenyl (10-22 C) group;

each R.sup.4 is independently hydrogen or is a protecting group;
R.sup.5 is H, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2 CH.sub.3, CH.sub.2 C.sub.6 H.sub.5, CH.sub.2 C.sub.6 H.sub.4 -p-OH, CH.sub.2 OH, CH(OH)CH.sub.3, (CH.sub.2).sub.4 NHR.sup.4, (CH.sub.2).sub.3 NHR.sup.4 or (CH.sub.2).sub.3 NR.sup.4 C(NH)NHR.sup.4 ;
R.sup.15 is alkyl;
alkyl substituted with halogen, hydroxyl, S(O).sub.2, O-alkyl or O-aryl;
alkenyl;
alkenyl substituted with halogen, hydroxyl, S(O).sub.2, O-alkyl or O-aryl;
aryl;
aryl substituted with halogen, hydroxyl, alkyl, or alkyl substituted with halogen, hydroxyl, S(O).sub.2, O-alkyl or O-aryl;
heteroaryl;
heteroaryl substituted with halogen, hydroxyl, alkyl, or alkyl substituted with halogen, hydroxyl, S(O).sub.2, O-alkyl or O-aryl;
N(H)alkyl;
N(alkyl).sub.2 wherein each alkyl group is independently chosen;
O-alkyl;
O-aryl;
alkylaryl;
O-alkylaryl;
alkylheteroaryl;
or O-alkylheteroaryl;
L is an integer having a value of 2, 3, 4, 5, 6 or 7;
m is an integer having a value of 1;
n is an integer having a value of 0 or 1;
provided that when L is 3, n is 1, each R.sup.1 is independently alkyl (12-22C) or alkenyl (12-22C), and R.sup.15 together with the C(O) group to which it is linked, is a protecting group, then R.sup.4 is hydrogen;
and the salts, solvates, resolved and unresolved enantiomers and diastereomers thereof.

20 more elements

A composition comprising a polyanion and a lipid having the structure F ##STR30## wherein each R.sup.1 is independently alkyl (10-22 C) or a mono unsaturated alkenyl (10-22 C) group;

each R.sup.4 is independently hydrogen or is a protecting group;
R.sup.5 is H, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2 CH.sub.3, CH.sub.2 C.sub.6 H.sub.5, CH.sub.2 C.sub.6 H.sub.4 -p-OH, CH.sub.2 OH, CH(OH)CH.sub.3, (CH.sub.2).sub.4 NHR.sup.4, (CH.sub.2).sub.3 NHR.sup.4 or (CH.sub.2).sub.3 NR.sup.4 C(NH)NHR.sup.4 ;
R.sup.15 is alkyl;
alkyl substituted with halogen, hydroxyl, S(O).sub.2, O-alkyl or O-aryl;
alkenyl;
alkenyl substituted with halogen, hydroxyl, S(O).sub.2, O-alkyl or O-aryl;
aryl;
aryl substituted with halogen, hydroxyl, alkyl, or alkyl substituted with halogen, hydroxyl, S(O).sub.2, O-alkyl or O-aryl;
heteroaryl;
heteroaryl substituted with halogen, hydroxyl, alkyl, or alkyl substituted with halogen, hydroxyl, S(O).sub.2, O-alkyl or O-aryl;
N(H)alkyl;
N(alkyl).sub.2 wherein each alkyl group is independently chosen;
O-alkyl;
O-aryl;
alkylaryl;
O-alkylaryl;
alkylheteroaryl;
or O-alkylheteroaryl;
L is an integer having a value of 2, 3, 4, 5, 6 or 7;
m is an integer having a value of 1;
n is an integer having a value of 0 or 1;
provided that when L is 3, n is 1, each R.sup.1 is independently alkyl (12-22C) or alkenyl (12-22C), and R.sup.15 together with the C(O) group to which it is linked, is a protecting group, then R.sup.4 is hydrogen;
and
and the salts, solvates, resolved and unresolved enantiomers and diastereomers thereof.

21 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/499,699Filed 7 Jul 1995 · continuation in part
Priority: 8 Jul 1994
Granted: 6 Jan 1998
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07K 5/06095
With the first amino acid being basic: arg-amino acid
A61K 9/1272
Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers: comprising non-phosphatidyl surfactants as…
C07C 237/06
The carbon skeleton being acyclic and saturated: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon…
C07C 237/20
Having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton: the carbon skeleton containing…

Family

Serial273,045Parent of this continuation-in-part · filed 8 Jul 1994
US 5,705,693 AThis patent

From the US filing history. Foreign family members aren’t listed.

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