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Compounds for targeting drug delivery and enhancing siRNA activity

A compound and drug technology, applied in the field of cationic lipids and fat-soluble vitamin compounds, can solve the problems of cytotoxicity and lack of stability

Active Publication Date: 2014-06-11
NITTO DENKO CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But some disadvantages of using cationic polymers include their toxicity to cells and / or their lack of stability

Method used

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  • Compounds for targeting drug delivery and enhancing siRNA activity
  • Compounds for targeting drug delivery and enhancing siRNA activity
  • Compounds for targeting drug delivery and enhancing siRNA activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0233] Example 1: Preparation of 2-(bis(2-(tetradecyloxy)ethyl)amino)-N-(2-hydroxyethyl)-N,N-dimethyl-2-oxoethylaminium Bromide (HEDC)

[0234]

[0235] Preparation of Intermediate 1: 2,2'-(tert-butoxycarbonylazanediyl)bis(ethane-2,1-diyl)ditetradecanoate (HEDC-BOC-IN)

[0236]

[0237] A solution of N-BOC-diethanolamine (194 g, 0.946 mol), triethylamine (201 g, 2.03 mol) and diaminopyridine (23.1 g, 0.19 mol) in DCM (1750 mL) was cooled to 0°C. A solution of myristoyl chloride (491 g, 1.99 mol) in DCM (440 mL) was added at 0-10 °C over a period of 50 minutes and the mixture was allowed to warm to ambient temperature. TLC showed complete conversion after 1.5 hours at 20-24°C. Water (1750 mL) was added and the pH was measured to be 8.3 by pH meter. Separate the organic phase, use (1) 6% NaHCO 3 (500 mL), (2) 0.3M HCl (1700 mL), (3) 12.5% ​​sodium chloride (1700 mL) and dried over anhydrous magnesium sulfate (120 g). Evaporation of the filtrate at 50°C and 50 mBar aff...

Embodiment 2

[0247] Example 2: Preparation of 2-(bis(3-(tetradecyloxy)propyl)amino)-N-(2-hydroxyethyl)-N,N-dimethyl-2-oxo-ethylamine Onium Bromide (Pr-HEDC)

[0248]

[0249] Preparation of Intermediate 1: 3,3'-Azanediylbis(propan-1-ol)

[0250]

[0251] 3-amino-1-propanol (14.5mL, 19.0mmol), 1-chloro-3-hydroxypropane (8mL, 95.6mmol) and H 2 The mixture of O (~50 mL) was refluxed for more than 24 hours. Potassium hydroxide (5.40 g) was then added. After dissolution, all the H 2 The O evaporates to leave a viscous oil and a lot of potassium chloride. These were filtered and washed with anhydrous acetone and dichloromethane. Na 2 SO 4 The organic phase was dried, filtered and concentrated. The product was then purified by silica gel chromatography with a DCM / MeOH gradient to obtain 12.5 g of 3,3'-azanediylbis(propan-1-ol).

[0252] Preparation of intermediate 2: tert-butylbis(3-hydroxypropyl)carbamate

[0253]

[0254] 3,3'-Azanediylbis(propan-1-ol) (12.5 g, 95.4 mmol) was...

Embodiment 3

[0267] Example 3: Preparation of 2-(bis(3-(oleoyloxy)propyl)amino)-N-(2-hydroxyethyl)-N,N-dimethyl-2-oxoethylaminium bromide compound (Pr-HE-DODC)

[0268]

[0269] Preparation of Intermediate 1: (Z)-((tert-butoxycarbonyl)azanediyl)bis(propane-3,1-diyl)dioleate

[0270]

[0271] tert-Butylbis(3-hydroxypropyl)carbamate (synthesized above), triethylamine and DMAP were dissolved in chloroform. While stirring in an ice bath, the oleoyl chloride solution was added over 15 minutes. The addition is carried out in such a way that the reaction temperature does not exceed 30°C. The reaction was allowed to stir overnight at room temperature. The next day, MeOH (50 mL) and 0.9% saline solution (50 mL) were added to quench the reaction. Separate the organic layer and wash with 1M NaHCO 3 cleaning. use Na 2 SO 4 The solvent was dried, filtered and concentrated in vacuo to obtain an oil. (Z)-((tert-butoxycarbonyl)azanediyl)bis(propane-3,1-diyl)dioleate was used as such without...

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Abstract

Here described are compounds of formula I: wherein R1 and R2 is independently selected from a group consisting of C10 to C18 alkyl, C12 to C18 alkenyl, and oleyl group; wherein R3 and R4 are independently selected from a group consisting of C1 to C6 alkyl, and C2 to C6 alkanol; wherein X is selected from a group consisting of -CH2-, -S-, and -O- or absent; wherein Y is selected from -(CH2)n, -S(CH2)n, -O(CH2)n-, thiophene, -SO2(CH2)n-, and ester, wherein n = 1 -4; wherein a = 1 -4; wherein b=l -4; wherein c=l-4; and wherein Z is a counterion; and compounds consisting of the structure (targeting molecule)m-linker-(targeting molecule)n, wherein the targeting molecule is a retinoid or a fat soluble vitamin having a specific receptor on the target cell; wherein m and n are independently 0, 1, 2 or 3; and wherein the linker comprises a polyethylene glycol (PEG) or PEG-like molecule, as well as compositions and pharmaceutical formulations including one or both of these compounds which are useful for the delivery of therapeutic agents; and methods of using these compositions and pharmaceutical formulations.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application Nos. 61 / 494,840 and 61 / 494,710, filed June 8, 2011, the entire contents of which are incorporated herein by reference. technical field [0003] The present invention relates to the use of cationic lipids and fat-soluble vitamin compounds to target and enhance the activity of siRNA-containing therapeutic molecules. Background technique [0004] Liver fibrosis can be caused by activated hepatic stellate cells (HSCs), resulting in the deposition of various collagen molecules and fibronectin on the interstitial tissue. This can cause cirrhosis, liver failure, and / or hepatocellular carcinoma. In addition long-term pancreatitis occurs due to pancreatic fibrosis by the same mechanism as that of liver fibrosis (Madro et al., 2004; Med Sci Monit. 10:RA166-70; Jaster, 2004, Mol Cancer. 6:26). Additionally, astrocytes are present in vocal cord disorders of the v...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/08A61K31/16A61P1/16C07C237/22C07C323/60C07C333/04
CPCA61K9/1271C07C333/04C07C237/08C07C237/22C07C323/60C07C213/06C07C213/08C07C231/02C07C231/12C07C319/20C07F9/10C07C323/52C07C219/06A61P1/00A61P1/16A61P1/18A61P11/04A61P35/00A61P43/00A61K47/08A61K47/14C07C237/06A61K47/10C07C235/34A61K31/16
Inventor 新津洋司郎J·E·佩恩侯铮J·A·高德特C·N·斯里达尔V·克诺波夫R·P·维特M·艾哈麦丁L·A·佩雷尔曼田中康进V·阿科皮扬P·卡尔玛里
Owner NITTO DENKO CORP
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