Chemically modified small molecules

Patent metadata

Field	Value
Publication number	US-9388104-B2
Application number	US-201414248245-A
Country	US
Kind code	B2
Filing date	Apr 8, 2014
Priority date	Dec 16, 2003
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

Provided are methods of preparing a monodisperse oligo (ethylene glycol) reagent composition.

First claim

What is claimed is:

1. A method of preparing a monodisperse oligo (ethylene glycol) reagent composition, comprising:
reacting a halo-terminated oligo (ethylene glycol) having (m) monomer subunits and a methoxy end-capping group with a first hydroxyl-terminated oligo (ethylene glycol) having (n) monomer subunits, wherein the first hydroxyl-terminated oligo (ethylene glycol) structure is HO—(CH 2 CH 2 O) n —H, under conditions effective to displace said halo group to thereby form an oligo (ethylene glycol) having (m)+(n) monomer subunits (OEG m+n ), wherein reacting the halo-terminated oligo(ethylene glycol) with the first hydroxyl-terminated oligo (ethylene glycol) comprises adding a 1:1 molar ratio of the halo-terminated oligo(ethylene glycol) to the first hydroxyl-terminated oligo (ethylene glycol) in a solution;
converting the terminal hydroxyl group of OEG m+n into a halo group, —X, to form OEG m+n -X; and
reacting OEG m+n -X with a second hydroxyl-terminated oligo (ethylene glycol) having (n) monomer subunits, wherein the second hydroxyl-terminated oligo structure is HO—(CH 2 CH 2 O) n —H, under conditions effective to displace said halo group to thereby form an oligo(ethylene glycol) having (m)+2(n) monomer subunits (OEG m+2n ), wherein reacting the OEG m+n -X with the second hydroxyl-terminated oligo (ethylene glycol) comprises adding a 1:1 molar ratio of the OEG m+n -X to the second hydroxyl-terminated oligo (ethylene glycol) in a solution;
wherein (m) and (n) each independently range from 1-10, and
wherein (OEG m+2n ) corresponds to the structure CH 3 O(CH 2 CH 2 O) m+2n H, and is present as part of a monodisperse composition of CH 3 O(CH 2 CH 2 O) m+2n H.

2. A method of preparing a monodisperse oligo (ethylene glycol) reagent composition, comprising:
reacting a halo-terminated oligo (ethylene glycol) having (m) monomer subunits and a methoxy end-capping group with a first hydroxyl-terminated oligo (ethylene glycol) having (n) monomer subunits, wherein the first hydroxyl-terminated oligo (ethylene glycol) structure is HO—(CH 2 CH 2 O) n —H, under conditions effective to displace said halo group to thereby form an oligo (ethylene glycol) having (m)+(n) monomer subunits (OEG m+n ), wherein reacting the halo-terminated oligo(ethylene glycol) with the first hydroxyl-terminated oligo (ethylene glycol) comprises adding a 1:1 molar ratio of the halo-terminated oligo(ethylene glycol) to the first hydroxyl-terminated oligo (ethylene glycol) in a solution;
converting the terminal hydroxyl group of OEG m+n into a halo group, —X, to form OEG m+n -X;
reacting OEG m+n -X with a second hydroxyl-terminated oligo (ethylene glycol) having (n) monomer subunits under conditions effective to displace said halo group to thereby form an oligo(ethylene glycol) having (m)+2(n) monomer subunits (OEG m+2n ), wherein OEG m+2n possesses a primary or secondary hydroxyl group, wherein reacting the OEG m+n -X with the second hydroxyl-terminated oligo (ethylene glycol) comprises adding a 1:1 molar ratio of the OEG m+n -X to the second hydroxyl-terminated oligo (ethylene glycol) in a solution;
converting said primary or secondary hydroxyl group into a halo group, —X, to form OEG m+2n -X; and
reacting OEG m+2n -X with a third hydroxyl-terminated oligo (ethylene glycol) having (n) monomer subunits under conditions effective to displace said halo group to thereby form an oligo (ethylene glycol) having m+3n monomer subunits (OEG m+3n ), wherein reacting the OEG m+2n -X with the third hydroxyl-terminated oligo (ethylene glycol) comprises adding a 1:1 molar ratio of the OEG m+2n -X to the third hydroxyl-terminated oligo (ethylene glycol) in a solution;
wherein (m) and (n) each independently range from 1-10; and
wherein (OEG m+3n ) corresponds to the structure CH 3 O(CH 2 CH 2 O) m+3n H, and is present as a monodisperse composition of CH 3 O(CH 2 CH 2 O) m+3n H.

3. The method of claim 1 , wherein (m) ranges from 1-3 and (n) ranges from 2-6.

4. The method of claim 2 , wherein (m) ranges from 1-3 and (n) ranges from 2-6.

5. The method of claim 1 , wherein each reacting step is carried out in the presence of a strong base.

6. The method of claim 2 , wherein each reacting step is carried out in the presence of a strong base.

7. The method of claim 1 , wherein each of the halo groups is Br.

8. The method of claim 2 , wherein each of the halo groups is Br.

Assignees

• Nektar Therapeutics

Inventors

• Bentley Michael D
• Viegas Tacey X
• Goodin Richard R
• Cheng Lin
• Zhao Xuan

Classifications

• C07C41/24 Primary

  by elimination of halogens, e.g. elimination of HCl · CPC title

• A61K9/007 Primary

  Pulmonary tract; Aromatherapy · CPC title

• A61K31/485

  Morphinan derivatives, e.g. morphine, codeine · CPC title

• A61P25/36

  Opioid-abuse · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title