# US 7,411,065 B2 · PNA monomer and precursor

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- Number: US 7,411,065 B2
- Document ID: US7411065B2
- Status: Granted
- Kind: B2
- Application number: 11/182,977
- Filed: 2005-07-15
- Published: 2005-11-10
- Granted: 2008-08-12
- Earliest claimed: 2005-07-15
- Assignees: Panagene Inc.
- Inventors: Sung Kee Kim; Hyunil Lee; Jong Chan Lim; Hoon Choi; Jae Hoon Jeon; Sang Youl Ahn; Sung Hee Lee; Won Jun Yoon
- Web page: https://patentgrep.com/patent/US7411065B2

## CPC

- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- A61P 35/00: Antineoplastic agents
- C07D 277/80: to a nitrogen atom
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07B 2200/11: Compounds covalently bound to a solid support
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

This application relates to monomers of the general formula (I) for the preparation of PNA (peptide nucleic acid) oglimers and provides method for the synthesis of both predefined sequence PNA oligomers and random sequence PNA oligomers: wherein E is nitrogen or C—R′; J is sulfur or oxygen; R′, R1, R2, R3, R4 is independently H, halogen, alkyl, nitro, nitrile, alkoxy, halogenated alkyl, halogenated alkoxy, phenyl or halogenated phenyl, R5 is H or protected or unprotected side chain of natural or unnatural α-amino acid; and B is a natural or unnatural nucleobase, wherein when said nucleobase has an exocyclic amino function, said function is protected by protecting group which is labile to acids but stable to weak to medium bases in the presence of thiol.

## Claims

### Claim 1

A compound represented by formula I:
wherein
E is nitrogen or C-R′; J is sulfur or oxygen;
R′, R1, R2, R3, R4 is independently H, halogen, alkyl, nitro, cyano, alkoxy, halogenated alkyl, halogenated alkoxy, phenyl or halogenated phenyl;
R5 is H or protected or unprotected side chain of a naturally occurring α-amino acid; and
R7 is represented by the formula:
wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10 is independently selected from hydrogen, halogen, alkyl, and alkoxy;
or
wherein Z1, Z2, Z3, Z4, Z5 is independently selected from hydrogen, halogen, alkyl, alkoxy, and methylene dioxy of adjacent two residues;
or
wherein R8 is alkyl or phenyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein E is nitrogen and J is sulfur.

### Claim 3 (depends on 1)

The compound of claim 1, wherein E is nitrogen and J is oxygen.

### Claim 4 (depends on 1)

The compound of claim 1, wherein E is CH and J is sulfur.

### Claim 5 (depends on 1)

The compound of claim 1, wherein E is CH and J is oxygen.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R5 is H or protected or unprotected side chain of a naturally occurring α-amino acid.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R′ is H, CF3, F, Cl, Br, I, methyl, phenyl, nitro, or cyano.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R7 is represented by the formula:
wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10 is independently selected from hydrogen, halogen, alkyl, and alkoxy.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R7 is represented by the formula:
wherein Z1, Z2, Z3, Z4, Z5 is independently selected from hydrogen, halogen, alkyl, alkoxy, and methylene dioxy of adjacent two residues.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R7 is represented by the formula;
wherein R8 is alkyl or phenyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R7 is benzyl, benzhydryl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, piperonyl, or 2-methylthioethyl.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R1, R2, R3, and R4 are H.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R2 is Cl, and R1, R3 and R4 are H.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R1 is C1l, R2 is methoxy, and R3, R4 and R5 are H.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R1, R2, R3, and R4 are H; E is nitrogen; and J is sulfur.

### Claim 16 (depends on 1)

A method of making the compound of claim 1, said method comprising
cyclizing a compound represented by formula VI in the presence of a coupling reagent that is customarily used in peptide synthesis or an anhydride, wherein the formula VI is as follows:
wherein
E is nitrogen or C—R′; J is sulfur or oxygen;
R′, R1, R2, R3, R4 is independently H, halogen, alkyl, nitro, cyano, alkoxy, halogenated alkyl, halogenated alkoxy, phenyl or halogenated phenyl;
R5 is H, a side chain of a naturally occurring α-amino acid, or a protected side chain of a naturally occurring α-amino acid; and
R7 is represented by the formula:
wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10 is independently selected from hydrogen, halogen, alkyl, and alkoxy;
or
wherein Z1, Z2, Z3, Z4, Z5 is independently selected from hydrogen, halogen, alkyl, alkoxy, and methylene dioxy of adjacent two residues;
or
wherein R8 is alkyl or phenyl.

### Claim 17 (depends on 1)

A method of making the compound of claim 1, comprising coupling reaction of a compound represented by formula IV with a nucleobase acetic acid moiety in the presence of non-nucleophilic organic base and a coupling reagent that is customarily used in peptide synthesis, wherein said formula IV is as follows:
wherein
HX is an organic or inorganic acid;
E is nitrogen or C— R′; J is sulfur or oxygen;
R′, R1, R2, R3, R4 is independently H, halogen, alkyl, nitro, cyano, alkoxy, halogenated alkyl, halogenated alkoxy, phenyl or halogenated phenyl; and
R5 is H, a side chain of a naturally occurring α-amino acid, or a protected side chain of a naturally occurring α-amino acid, and
wherein said nucleobase acetic acid moiety is represented as follows:
wherein R7 is represented by the formula:
wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10 is independently selected from hydrogen, halogen, alkyl, and alkoxy;
or
wherein Z1, Z2, Z3, Z4, Z5 is independently selected from hydrogen, halogen, alkyl, alkoxy, and methylene dioxy of adjacent two residues;
or
wherein R8 is alkyl or phenyl.