# US 7,745,392 B2 · Multi-valent guanidinium compounds for enhancing molecular translocation across cellular membranes and epithelial tissues

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- Number: US 7,745,392 B2
- Document ID: US7745392B2
- Status: Granted
- Kind: B2
- Application number: 11/525,512
- Filed: 2006-09-21
- Published: 2007-04-05
- Granted: 2010-06-29
- Earliest claimed: 2005-09-23
- Assignees: Nitto Denko Corporation
- Inventors: Zheng Hou; Jian Liu; Lei Yu
- Web page: https://patentgrep.com/patent/US7745392B2

## CPC

- C07K 7/02: Linear peptides containing at least one abnormal peptide link
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- C07K 7/64: Cyclic peptides containing only normal peptide links
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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

Disclosed herein are guanidinium containing compounds consisting of a core moiety with a plurality of side chains containing guanidinium groups. Such compounds have enhanced translocation across cellular membranes and epithelial tissues. The compounds may also have a therapeutic or other biologically active moiety attached so that these moieties may be effectively transported into a cell by the guanidinium containing compound.

## Claims

### Claim 1

A compound having the formula:
wherein C is selected from the group consisting of:
wherein R is selected from the group consisting of hydrogen, optionally substituted C1-12 alkyl, optionally substituted C2-C12 alkenyl, and optionally substituted C2-C12 alkynyl;
wherein Y is a group of the formula:
wherein 2 to 6 Y groups are attached to C;
wherein Z has the formula:
wherein one Z is attached to C or is absent;
wherein each L is separately selected to be a linker moiety comprising a molecular fragment having a molecular weight less than 1000;
wherein each BB is separately selected to be a backbone moiety comprising an organic fragment having a molecular weight less than 5000;
wherein each G is separately selected to be a guanidinium group covalently attached to BB and has the formula:
or each G is separately selected from the group consisting of:
each R1, R2, R3, and R4 is hydrogen;
wherein each T is a terminal group separately selected from the group consisting of hydrogen, an amine group, a carboxylic group, a N-terminal peptide or group that forms an N-terminal peptide bond with BB, a C-terminal peptide or group that forms a C-terminal peptide bond with BB, a reporting moiety, a targeting moiety, and a therapeutic moiety, or each T is separately absent; and
wherein each n is separately selected to be an integer from 1 to 8.

### Claim 2 (depends on 1)

The compound of claim 1, wherein each L is separately selected from the group consisting of: —C(═O)NH—, —C(═O)NHO—, —C(═O)NHNH—, —S(═O)(═O)NR—, —P(═O)(—OR)NR′—, —SS—, —CH2NR—, —CH2NR—, —CH2C(═O)NR—, —C(═O)O—, —C(═S)NR—, —S(═O)(═O)CH2—, —SOCH2— and —OC(═O)NR—, wherein each R and R′ are separately selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, and optionally substituted C2-C12 alkynyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein at least two Y groups attached to C are different from each other.

### Claim 4 (depends on 1)

The compound of claim 1, wherein each BB-G is separately selected from the group consisting of:

### Claim 5 (depends on 1)

The compound of claim 1, wherein at least one T comprises a polypeptide.

### Claim 6 (depends on 5)

The compound of claim 5, wherein at least one T comprises a protein antigen.

### Claim 7 (depends on 6)

The compound of claim 6, wherein at least one T comprises a tumor antigen.

### Claim 8 (depends on 1)

The compound of claim 1, wherein at least one T comprises an antimicrobial agent.

### Claim 9 (depends on 1)

The compound of claim 1, wherein at least one T comprises a cleavable linker.

### Claim 10 (depends on 9)

The compound of claim 9, wherein said cleavable linker comprises an ester group.

### Claim 11 (depends on 9)

The compound of claim 9, wherein said cleavable linker comprises a disulfide group.

### Claim 12

A compound selected from the group consisting of:
wherein Z has the formula:
wherein each T is a terminal group separately selected from the group consisting of hydrogen, an amine group, a carboxylic group, a N-terminal peptide or group that forms an N-terminal peptide bond with BB, a C-terminal peptide or group that forms a C-terminal peptide bond with BB, a reporting moiety, a targeting moiety, and a therapeutic moiety, or each T is separately absent; and
wherein each L is separately selected to be a linker moiety comprising a molecular fragment having a molecular weight less than 1000.

### Claim 13 (depends on 1)

A method for enhancing transport of a biologically active moiety across a biological membrane, comprising contacting a biological membrane with a compound of claim 1, wherein at least one T comprises the biologically active moiety, whereby said contacting is effective to promote transport of said compound across said biological membrane at a rate that is greater than a trans-membrane transport rate of the biologically active moiety in non-conjugated form.

### Claim 14 (depends on 13)

The method of claim 13, wherein said biological membrane is a eukaryotic cell membrane.

### Claim 15 (depends on 13)

The method of claim 13, wherein said biological membrane is a prokaryotic cell membrane.

### Claim 16 (depends on 13)

The method of claim 13, wherein said biological membrane is a cancer cell membrane.

### Claim 17 (depends on 13)

The method of claim 13, wherein said biologically active moiety is a therapeutic moiety.

### Claim 18 (depends on 13)

The method of claim 13, wherein said therapeutic moiety is an anti-cancer agent.

### Claim 19 (depends on 1)

A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

### Claim 20 (depends on 12)

The compound of claim 12, wherein each L is separately selected from the group consisting of: an oligopeptide comprising 1 to 12 amino acid residues, an optionally substituted C1-C12 alkyl, an optionally substituted C2-C12 alkenyl, an optionally substituted C2-C12 alkynyl, and an optionally substituted C3-C12 cyclic alkyl, alkenyl, alkynyl, or aromatic moiety.

### Claim 21 (depends on 12)

The compound of claim 12, wherein each L is separately selected from the group consisting of: —C(═O)NH—, —C(═O)NHO—, —C(═O)NHNH—, —S(═O)(═O)NR—, —P(═O)(—OR)NR′—, —SS—, —CH2NR—, —CH2NR—, —CH2C(═O)NR—, —C(═O)O—, —C(═S)NR—, —S(═O)(═O)CH2—, —SOCH2— and —OC(═O)NR—, wherein each R and R′ are separately selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, and optionally substituted C2-C12 alkynyl.

### Claim 22 (depends on 12)

The compound of claim 12, wherein each T is a terminal group separately selected from the group consisting of a reporting moiety, a targeting moiety, and a therapeutic moiety.