Disulfide compounds for delivery of pharmaceutical agents

Patent metadata

Field	Value
Publication number	US-9765022-B2
Application number	US-201414770327-A
Country	US
Kind code	B2
Filing date	Feb 28, 2014
Priority date	Feb 28, 2013
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

A compound of formula the following formula: (I). In this formula, moieties A, B, X, R 1 , R 2 , and R 3 are defined herein. Also disclosed are a nanocomplex that is formed of such a compound and a pharmaceutical agent, and a nanocomplex that is formed of a protein and a bioreducible compound.

First claim

What is claimed is:

1. A compound of formula (I):

wherein
A, a hydrophilic head, is

in which each of R a , R a ′, R a ″, and R a ′″, independently, is H, a C 1 -C 20 monovalent aliphatic radical, a C 1 -C 20 monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical; and Z is a C 1 -C 20 bivalent aliphatic radical, a C 1 -C 20 bivalent heteroaliphatic radical, a bivalent aryl radical, or a bivalent heteroaryl radical;
B is a C 1 -C 24 monovalent aliphatic radical, a C 1 -C 24 monovalent heteroaliphatic radical, a monovalent aryl radical, a monovalent heteroaryl radical, or

in which R 4 , R 5 , R 6 , and Y are defined below;
each of R 1 and R 4 , independently, is a C 1 -C 10 bivalent aliphatic radical, a C 1 -C 10 bivalent heteroaliphatic radical, a bivalent aryl radical, or a bivalent heteroaryl radical;
each of R 2 and R 5 , independently, is a bond, a C 1 -C 20 bivalent aliphatic radical, a C 1 -C 20 bivalent heteroaliphatic radical, a bivalent aryl radical, or a bivalent heteroaryl radical;
each of R 3 and R 6 , independently, is a C 1 -C 20 monovalent aliphatic radical; a C 1 -C 20 monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical;
each of

 a hydrophobic tail, and

 also a hydrophobic tail, has 8 to 24 carbon atoms; and
each of X, a linker, and Y, also a linker, independently, is

in which each of m, n, p, q, and t, independently, is 1-6; W is O, S, or NR c ; each of L 1 , L 3 , L 5 , L 7 , and L 9 , independently, is a bond, O, S, or NR d ; each of L 2 , L 4 , L 6 , L 8 , and L 10 , independently, is a bond, O, S, or NR e ; and V is OR f , SR g , or NR h R i , each of R b , R c , R d , R e , R f , R g , R h , and R i , independently, being H, OH, C 1 -C 10 oxyaliphatic radical,
C 1 -C 10 monovalent aliphatic radical, C 1 -C 10 monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical.

2. The compound of claim 1 , wherein A is

in which each of R a and R a ′, independently, is, H, a C 1 -C 10 monovalent aliphatic radical, a C 1 -C 10 monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical; and Z is a C 1 -C 10 bivalent aliphatic radical, a C 1 -C 10 bivalent heteroaliphatic radical, a bivalent aryl radical, or a bivalent heteroaryl radical.

3. The compound of claim 2 , wherein B is a C 8 -C 20 monovalent aliphatic radical, a C 8 -C 20 monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical; R 1 is a C 1 -C 6 bivalent aliphatic radical, or a C 1 -C 6 bivalent heteroaliphatic radical; the total carbon number of R 2 and R 3 is 12-20; and X is

4. The compound of claim 2 , wherein B is

each of R 1 and R 4 is a C 1 -C 6 bivalent aliphatic radical or a C 1 -C 6 bivalent heteroaliphatic radical; the total carbon number of R 2 and R 3 is 12-20; the total carbon number of R 5 and R 6 is 12-20; and each of X and Y, independently, is

5. The compound of claim 1 , wherein B is a C 8 -C 20 monovalent aliphatic radical, a C 8 -C 20 monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical; R 1 is a C 1 -C 6 bivalent aliphatic radical or a C 1 -C 6 bivalent heteroaliphatic radical; the total carbon number of R 2 and R 3 is 12-20; and X is

6. The compound of claim 1 , wherein B is

each of R 1 and R 4 is a C 1 -C 6 bivalent aliphatic radical or a C 1 -C 6 bivalent heteroaliphatic radical; the total carbon number of R 2 and R 3 is 12-20; the total carbon number of R 5 and R 6 is 12-20; and each of X and Y, independently, is

7. The compound of claim 1 , wherein R 1 is a C 1 -C 4 bivalent aliphatic radical or a C 1 -C 4 bivalent heteroaliphatic radical; and the total carbon number of R 2 and R 3 is 14-18.

8. The compound of claim 1 , wherein X is

9. The compound of claim 1 , wherein X is

10. The compound of claim 1 , wherein X is

in which m is 2-6.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a nanocomplex formed of a compound of claim 1 and a pharmaceutical agent, wherein the nanocomplex has a particle size of 50 nm to 1000 nm; the compound binds to the pharmaceutical agent via a non-covalent interaction, a covalent bond, or both; and the pharmaceutical agent is a small molecule, a protein, a peptide, a nucleic acid, or a combination thereof.

12. The pharmaceutical composition of claim 11 , wherein A is

in which each of R a and R a ′, independently, is a C 1 -C 10 monovalent aliphatic radical, a C 1 -C 10 monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical; and Z is a C 1 -C 10 bivalent aliphatic radical, a C 1 -C 10 bivalent heteroaliphatic radical, a bivalent aryl radical, or a bivalent heteroaryl radical.

13. The pharmaceutical composition of claim 12 , wherein B is a C 8 -C 20 monovalent aliphatic radical, a C 8 -C 20 monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical; R 1 is a C 1 -C 6 bivalent aliphatic radical or a C 1 -C 6 bivalent heteroaliphatic radical; the total carbon number of R 2 and R 3 is 12-20; and X is

14. The pharmaceutical composition of claim 12 , wherein B is

each of R 1 and R 4 is a C 1 -C 6 bivalent aliphatic radical or a C 1 -C 6 bivalent heteroaliphatic radical; the total carbon number of R 2 and R 3 is 12-20; the total carbon number of R 5 and R 6 is 12-20; and each of X and Y, independently, is

Assignees

• Univ Tufts

Inventors

• Xu Qiaobing
• Wang Ming

Classifications

• A61K47/48046

  Human Necessities · mapped topic

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K47/48869

  Human Necessities · mapped topic

• C07B45/06

  of mercapto or sulfide groups · CPC title