Reversible pegylated drugs

Patent metadata

Field	Value
Publication number	US-9956295-B2
Application number	US-201615216870-A
Country	US
Kind code	B2
Filing date	Jul 22, 2016
Priority date	Apr 8, 2003
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

Reversible pegylated drugs are provided by derivatization of free functional groups of the drug selected from amino, hydroxyl, mercapto, phosphate and/or carboxyl with groups sensitive to mild basic conditions such as 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS), to which group a PEG moiety is attached. In these pegylated drugs, the PEG moiety and the drug residue are not linked directly to each other, but rather both residues are linked to different positions of the scaffold Fmoc or FMS structure that is highly sensitive to bases and is removable under physiological conditions. The drugs are preferably drugs containing an amino group, most preferably peptides and proteins of low or medium molecular weight. Similar molecules are provided wherein a protein carrier or another polymer carrier replaces the PEG moiety.

First claim

The invention claimed is:

1. A method for treatment of a viral disease treatable by IFN-α2, said method comprising administering to an individual in need an effective amount of a conjugate of the formula:
(X) n —Y

wherein
Y is a IFN-α2, and
X is a radical of the formula (i):

wherein
R 1 is a radical of the formula —R 5 —R 6 -PEG, wherein PEG is a linear or branched polyethylene glycol (PEG) moiety;
R 2 is selected from the group consisting of hydrogen, (C1-C8)alkyl, (C1-C8) alkoxy, (C1-C8)alkoxyalkyl, (C6-C10)aryl, (C1-C8)alkaryl, (C6-C10)ar(C1-C8)alkyl, halogen, nitro, —SO 3 H, —SO 2 NHR, amino, ammonium, carboxyl, PO 3 H 2 , and OPO 3 H 2 , and R is selected from the group consisting of hydrogen, (C1-C8)alkyl and (C6-C10)aryl;
R 3 and R 4 , the same or different, are each selected from the group consisting of hydrogen, (C1-C8)alkyl and (C6-C10)aryl;
R 5 is selected from the group consisting of —NH—, —S—, —CO—, —CH 2 —, —SO 2 —, and —PO 2 —; and
A is OCO-linked to an amino group of the PYY agonist; and
n is an integer of at least one,
provided that:
(i) when R 5 is —NH—, R 6 is —CO—, —COO—, —CH 2 —, —CH(CH 3 )—, —CO—NH—, —CS—NH, —CO—CH 2 —NH—CO—, —CO—CH(CH 3 )—NH—CO—, —CO—CH 2 —NH—CO—NH,

or

Z is O, S or NH that is linked to the PEG moiety; and R 7 is selected from the group consisting of C1-C18 straight or branched alkylene, phenylene, an oxyalkylene radical having 3-18 carbon atoms in the backbone, a residue of a peptide containing 2-10 amino acid residues, and a residue of a saccharide containing 1-10 monosaccharide residues;
(ii) when R 5 is —S—, R 6 is

or

and Z is O, S or NH;
(iii) when R 5 is —CO—, R 6 is —O—, —NH—, —NH—R 7 —COO—, —NH—R 7 —NH, —NH—R 7 —CO—NH,

or

Z is O, S or NH; and R 7 is selected from the group consisting of C1-C18 straight or branched alkylene, phenylene, an oxyalkylene radical having 3-18 carbon atoms in the backbone, a residue of a peptide containing 2-10 amino acid residues, and a residue of a saccharide containing 1-10 monosaccharide residues;
(iv) when R 5 is —CH 2 —, R 6 is —(CH 2 ) n —S— or —(CH 2 ) n —NH—, wherein n is 0 to 18; (v) when R 5 is —SO 2 —, R 6 is —O—; —NH— or —CH 2 —CH 2 —S; and (vi) when R 5 is —PO 2 —, R 6 is —O— or —NH—.

2. The method of claim 1 , wherein (i) R 2 , R 3 and R 4 each is hydrogen; or (ii) R 2 is —SO 3 H at position 2 of the fluorene ring, and R 3 and R 4 each is hydrogen.

3. The method of claim 1 , wherein R 5 is —NH—.

4. The method of claim 3 , comprising administering a conjugate of the formula:

5. The method of claim 4 , wherein n is an integer from 1 to 3.

6. The method of claim 5 , wherein the PEG moiety has a molecular weight in the range of 5,000 to 40,000 Da.

7. The method of claim 6 , wherein the PEG moiety is a branched molecule of 40,000 Da or 5,000 Da.

8. The method of claim 5 , wherein R 2 is —SO 3 H at position 2 of the fluorene ring, and the PEG moiety is a branched molecule of 40,000 Da.

9. The method of claim 3 , comprising administering a conjugate of the formula:

wherein R 2 is H or —SO 3 H at position 2 of the fluorene ring, and PEG is a linear or branched PEG moiety of molecular weight in the range of 200 to 200,000 Da.

10. The method of claim 9 , wherein the PEG moiety has a molecular weight in the range of 5,000 to 40,000 Da.

11. The method of claim 10 , wherein the PEG moiety is a branched molecule of 40,000 Da or 5,000 Da.

12. The method of claim 1 , wherein said viral disease treatable by IFN-α2 is hepatitis B or hepatitis C.

Assignees

• Yeda Res & Dev
• Yeda Res & Dev

Inventors

• Shechter Yoram
• Fridkin Matityahu
• Tsubery Haim

Classifications

• A61P5/02

  of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P35/00

  Antineoplastic agents · CPC title