Fusogenic compounds for delivery of biologically active molecules

Patent metadata

Field	Value
Publication number	US-11413243-B2
Application number	US-201816182571-A
Country	US
Kind code	B2
Filing date	Nov 6, 2018
Priority date	Nov 6, 2017
Publication date	Aug 16, 2022
Grant date	Aug 16, 2022

Abstract

This invention includes fusogenic compounds, and compositions and methods of use thereof. The fusogenic compounds can be used for making nanoparticle compositions for use in biopharmaceuticals and therapeutics. More particularly, this invention relates to compounds, compositions and methods for providing nanoparticles to incorporate or encapsulate active agents, to deliver and distribute the active agents to cells, tissues, organs, and subjects.

First claim

What is claimed is:

1. A fusogenic compound having Formula I

wherein each AA is independently an amino acid selected from the following structures, and any stereoisomer thereof:

wherein the amino acid is attached to an amphiphile at each of its amino groups and is attached to the linker at its C terminus;

wherein linker has the structure
—NH CH 2 n OCH 2 CH 2 m CH 2 p NH—

or

wherein Q 2 is

wherein Q 3 is

wherein X is —O—, —S—, or —NH—;
wherein n, p, q and t are independently for each occurrence 1 to 3;
wherein m is independently 1 to 10;
wherein r and s are independently for each occurrence 1 to 5; and
wherein each amphiphile is independently selected from Formula (II), Formula (IV), Formula (V), and Formula (VI), as follows:

wherein R 1 in Formula (II) is CH 2 (CH 2 ) n O(C═O)R 4 , CH 2 (CH 2 ) n NH(C═O)R 4 , CH 2 (CH 2 ) n (C═O)OR 4 , or CH 2 (CH 2 ) n (C═O)NHR 4 ;
wherein R 2 in Formula (II) is CH 2 (CH 2 ) m O(C═O)R 5 , CH 2 (CH 2 ) m NH(C═O)R 5 , CH 2 (CH 2 ) m (C═O)OR 5 , or CH 2 (CH 2 ) m (C═O)NHR 5 ;
wherein n and m in Formula (II) are each independently from 1 to 2; and R 4 and R 5 are independently for each occurrence a C(12-20) alkyl group, or a C(12-20) alkenyl group; and
wherein R 3 in Formula (II) is branched or unbranched C(1-8) alkandiyl;

wherein R 1 in Formula (IV) is (C═O)R 4 ;
wherein R 2 in Formula (IV) is (C═O)OR 5 ;
wherein R 4 and R 5 in Formula (IV) are independently for each occurrence a C(12-20) alkyl group, or a C(12-20) alkenyl group;
wherein Z in Formula (IV) is NH;
wherein p in Formula (IV) is 1 to 4;
wherein R 3 in Formula (IV) is
—C(1-12) alkyl group that is substituted with a —(C═O)— which is attached to AA;

wherein R 1 in Formula (V) is (C═O)OR 4 ;
wherein R 2 in Formula (V) is NH(C═O)R 5 ;
wherein R 4 and R 5 in Formula (V) are independently for each occurrence a C(12-20) alkyl group, or a C(12-20) alkenyl group;
wherein R 3 in Formula (V) is branched or unbranched —O(C═O)—C(1-8)alkandiyl-(C═O)— which is attached to AA;

wherein R 1 in Formula (VI) is O(C═O)R 4 ;
wherein R 2 in Formula (VI) is O(C═O)R 5 ;
wherein R 4 and R 5 in Formula (VI) are independently for each occurrence a C(12-20) alkyl group, or a C(12-20) alkenyl group;
wherein R 3 in formula (VI) is

which is attached to AA
wherein one or two of the amphiphiles may optionally be absent and replaced by a pharmaceutically acceptable organic chemical group selected from an alkyl group, alkenyl, alkynyl, acetyl, Boc, Fmoc, TFA, and CBZ, having 1-400 atoms selected from carbon, oxygen, nitrogen, sulfur, fluorine, and hydrogen.

2. The fusogenic compound of claim 1 , wherein one or two of the amphiphiles are absent and replaced by the pharmaceutically acceptable organic chemical group.

3. The fusogenic compound of claim 2 , wherein the pharmaceutically acceptable organic chemical group is alkyl, alkenyl, alkynyl, acetyl, Boc, Fmoc, TFA, or CBZ.

4. The fusogenic compound of claim 2 , wherein the compound is selected from the following:

5. The fusogenic compound of claim 1 , wherein R 3 in Formula (II) is
branched or unbranched C(2-8)alkandiyl.

6. The fusogenic compound of claim 1 , wherein the compound is selected from the following:

7. The fusogenic compound of claim 1 , wherein R 4 and R 5 in Formula (IV) are independently for each occurrence a C(14-18) alkyl group, or a C(14-18) alkenyl group.

8. The fusogenic compound of claim 1 , wherein the compound is compound T10:

9. The fusogenic compound of claim 1 , wherein R 4 and R 5 in Formula (V) are independently for each occurrence a C(14-18) alkyl group, or a C(14-18) alkenyl group.

10. The fusogenic compound of claim 1 , wherein the compound is compound T12:

11. The fusogenic compound of claim 1 , wherein R 4 and R 5 in Formula (VI) are

Assignees

• Nitto Denko Corp

Inventors

• Tsang Kwok Yin
• Majeti Bharat
• Gaudette John
• Adami Roger
• Bai Hao
• Ying Wenbin

Classifications

• 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

• C07C201/00

  Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton · CPC title

• A61K47/6911

  the form being a liposome · CPC title

• C07C235/74

  of a saturated carbon skeleton · CPC title

• C07C275/14 Primary

  being further substituted by nitrogen atoms not being part of nitro or nitroso groups · CPC title