# US 8,541,605 B2 · Lipid conjugated cyclic carbonate derivatives, their synthesis, and uses

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- Number: US 8,541,605 B2
- Document ID: US8541605B2
- Status: Granted
- Kind: B2
- Application number: 12/599,407
- Filed: 2008-05-11
- Published: 2010-12-02
- Granted: 2013-09-24
- Earliest claimed: 2007-05-09
- Assignees: Siolab Ltd.; Yissum Research Development Company of the Hebrew University of Jerusalem
- Applicants: Aaron Garzon; Jean Hildesheim
- Inventors: Aaron Garzon; Jean Hildesheim
- Web page: https://patentgrep.com/patent/US8541605B2

## CPC

- C07D 319/04: 1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07C 269/04: from amines with formation of carbamate groups
- C07C 269/06: by reactions not involving the formation of carbamate groups
- C07C 269/08: Separation; Purification; Stabilisation; Use of additives
- C07D 263/14: with radicals substituted by oxygen atoms
- A61K 9/1272: 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})
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present disclosure provides processes for the preparation of lipid conjugated cyclic carbonate derivatives. More specifically, the present disclosure is based on the finding that reacting lipids, such as, ceramides, with N,N′-disuccinimidyl derivative, resulted in the formation of, isolatable, substituted cyclic [1,3]-dioxan-2-one and [1,3]-dioxan-2-thione compounds. These isolatable cyclic substituted compounds and derivatives thereof may be used for various applications, such as in vaccination.

## Claims

### Claim 1

A cyclic compound of general formula (I):
wherein
W represents O, S, NH, or CH2;
X1, X2, X3, and X4 represent independently O or S; and
R1 and R2 independently represent a C1-C24 aliphatic moiety selected from the group consisting of alkyl, alkenyl and alkynyl, and at least one of R1 and R2 is an alkenyl chain.

### Claim 2 (depends on 1)

The cyclic compound of claim 1, wherein R1 and R2 independently represent one of a branched and a linear C8-C24 chain.

### Claim 3 (depends on 2)

The cyclic compound of claim 2, wherein R1 and R2 independently represent one of a branched and a linear C12-C18 chain.

### Claim 4 (depends on 2)

The cyclic compound of claim 2, wherein R1 is an alkenyl chain.

### Claim 5 (depends on 1)

The cyclic compound of claim 1, wherein R1 is an alkenyl chain and R2 is an alkyl chain.

### Claim 6 (depends on 1)

The cyclic compound of claim 1, wherein W represents NH.

### Claim 7 (depends on 1)

The cyclic compound of claim 1, wherein X1, X2, X3, and X4 independently represent O.

### Claim 8 (depends on 1)

The cyclic compound of claim 1, wherein R1 is —CH═CH—C13H27 and R2 is —C15H31.

### Claim 9 (depends on 1)

The cyclic compound of claim 1, further comprising a first stereogenic carbon on position 4 and a second stereogenic carbon on position 5, each of the first and the second stereogenic carbon being independently in one of (R) and (S) configuration.

### Claim 10 (depends on 1)

The cyclic compound of claim 1, wherein at least one of R1 and R2 is in one of (E) and (Z) configuration.

### Claim 11

The cyclic compound (4R, 5S)-5-(hexadecanoylamido)-4-[(1E)-pentadecene]-[1,3]-dioxanone-2-one having formula (I):

### Claim 12

A process for preparation of a compound of general formula (I):
wherein
W represents O, S, NH, or CH2;
X1, X2, X3, and X4 represent independently O or S; and
R1 and R2 independently represent a C1-C24 aliphatic moiety selected from the group consisting of alkyl, alkenyl and alkynyl, and at least one of R1 and R2 is an alkenyl chain;
the process comprising:
(a) providing a lipid of the following general formula (II):
wherein
W represents O, S, NH, or CH2;
X1, X2, X3 and X4 represent independently O or S; and
R1 and R2 independently represent a C1-C24 aliphatic moiety selected from the group consisting of alkyl, alkenyl and alkynyl, and at least one of R1 and R2 is an alkenyl chain
(b) allowing the lipid to react in a presence of a basic catalyst with a N,N′-disuccinimidyl derivative of general formula (III)
wherein X1′, X2′, and X3 represent independently O or S;
to obtain a substituted [1,3]-dioxan-2-one or a [1,3]-dioxan-2-thione (I).

### Claim 13 (depends on 12)

The process of claim 12, wherein the lipid is an N-acyl sphingosine.

### Claim 14 (depends on 13)

The process of claim 13, wherein the N-acyl sphingosine is selected from the group consisting of ceramide, dihydroceramide, phytoceramide, dihydrophytoceramide, ceramine, dihydroceramine, phytoceramine, dihydrophytoceramine and derivatives thereof.

### Claim 15 (depends on 14)

The process of claim 14, wherein the ceramide is a C2 to C24 ceramide.

### Claim 16 (depends on 15)

The process of claim 15, wherein the ceramide is a C8 to C24 ceramide.