Lipopolyamines of spermine type for construction of liposomal transfection systems

Patent metadata

Field	Value
Publication number	US-9393200-B2
Application number	US-201314370526-A
Country	US
Kind code	B2
Filing date	Jan 14, 2013
Priority date	Jan 13, 2012
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

Abstract

The invention provides new lipopolyamines of spermine type of the general formula I, wherein X is C—N bond or aminopolyethyleneglycolcarboxamide linker or o-hydroxy-alkylcarboxamide linker or ω-hydroxyalkylcarboxamidopolyethyleneglycol-carboxamide linker, and wherein a hydrophobic domain Y is an acyl symmetrically branched in the position C(2) or cholesteryl. The invention further provides a method of preparation of said lipopolyamines and their use for construction of polycationic liposomal drug carriers.

First claim

The invention claimed is:

1. Lipopolyamines of spermine type of general formula I

wherein X is selected from the group containing
C—N bond;
aminopolyethyleneglycol carboxamide linker of general formula II

wherein n 1 =1-13;

and a hydrophobic domain Y is selected from an acyl having general formula V

wherein n 5 =5-30.

2. Lipopolyamines of spermine type of general formula I according to claim 1 , characterized in that X is C—N bond or the linker of general formula II wherein n 1 =3, and Y is the acyl of general formula V wherein n 5 =13.

3. A method of preparation of the lipopolyamines of spermine type of general formula I according to claim 1 , characterized in that
in a first step, acids selected from the group containing
fatty acids of general formula VII

wherein n 1 =5-30;
acids of general formula VIII

wherein n 1 =1-13 and n 5 =5-30;

are converted into their pentafluorophenyl esters by reaction with (pentafluorophenyl)carbonate in the presence of organic base in polar aprotic solvent,
in a second step, the acid pentafluorophenyl esters obtained in the first step are converted by reaction with N 2 N 3 N 4 -tri-(tert-butoxycarbonyl)spermine in organic aprotic solvent in the presence of organic base into protected polycationic lipids of general formula XI

wherein X and Y are as defined in claim 1 ,
in a third step, the protected polycationic lipids of general formula XI obtained in the second step are converted by debocylation into lipopolyamines of general formula I as defined in claim 1 .

4. The method according to claim 3 , wherein the acids of general formula VIII are prepared by basic catalysed reaction of pentafluorophenyl esters of the acids of general formula VII with aminopolyethyleneglycol carboxylic acids of formula H 2 N—(CH 2 ) 2 —O—[(CH 2 ) 2 —O] n —(CH 2 )—COOH, wherein n=1-13, in organic aprotic solvent.

5. A method drug delivery, comprising the steps of:
making a polycationic self-assembling system, further comprising the step of providing a lipopolyamine of spermine type of general formula I, as described in claim 1 ;
providing a drug;
using the polycationic self-assembling system as a carrier for the drug; and
delivering the drug to a subject in need thereof.

Assignees

• Ustav Organicke Chemie A Biochemie Av Cr V V I
• Vyzk Ustav Vet Lekarstvi

Inventors

• Drasar Lukas
• Ledvina Miroslav
• Korvasova Zina
• Turanek Jaroslav

Classifications

• C12N15/88

  using microencapsulation, e.g. using {amphiphile} liposome vesicle · CPC title

• C07C233/35

  with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom · CPC title

• A61K9/1272 Primary

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• C07J9/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane · CPC title