Reversible pegylated drugs

Patent metadata

Field	Value
Publication number	US-9433683-B2
Application number	US-201514795974-A
Country	US
Kind code	B2
Filing date	Jul 10, 2015
Priority date	Apr 8, 2003
Publication date	Sep 6, 2016
Grant date	Sep 6, 2016

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 compound of the formula:
(X) n —Y

wherein
Y is a moiety of a drug bearing at least one functional group selected from free amino, carboxyl, phosphate, hydroxyl and/or mercapto;
X is a radical selected from the group of radicals consisting of the formulas (ii), (iii) or (iv):

wherein:
R 1 is a radical containing a protein or a polymer carrier moiety;
A is a covalent bond when the radical is linked to a carboxyl, phosphate or mercapto group of the drug Y, or A is OCO— when the radical is linked to an amino or hydroxyl group of the drug Y; and
n is an integer of at least one,
and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein said protein carrier is selected from the group consisting of albumin, a modified albumin, and a protein containing globin-like domains having long half-life in circulation.

3. The compound of claim 2 , wherein said albumin is human serum albumin (HSA), said modified albumin is cationized bovine serum albumin (CBSA) or cationized human serum albumin (CHSA), and said protein containing globin-like domains having long half-life in circulation is hemoglobin A or S.

4. The compound of claim 1 , wherein said polymer carrier has suitable functional groups, and is selected from the group consisting of linear or branched polyethylene glycol (PEG) or copolymers thereof; poly(lactic acid) or copolymers thereof; polyesters having suitable functional groups based on polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL), or their copolymers; and polyamides based on polymethacrylamide or their copolymers.

5. The compound of claim 4 , wherein (i) said polymer carrier is poly(lactic acid)-block-polyethylene glycol, N-(2-hydroxypropyl)methacrylamide (HMPA) copolymer, or poly-D,L-lactide-co-glycolide (PLGA) nanoparticles; or (ii) the functional groups of said polymer carrier are selected from the group consisting of hydroxy, mercapto, amino, carboxyl, sulfonic acid group, and combinations thereof.

6. The compound of claim 1 , wherein said polymer carrier is liposomes containing phospholipids with covalently attached polyethylene glycol; or said polymer carrier is in the form of nanoparticles.

7. The compound of claim 1 , wherein the polymer carrier is a linear or branched PEG.

8. The compound of claim 7 , wherein R 1 is a radical of the formula:
—R 5 —R 6 -PEG

wherein
R 5 is selected from the group consisting of —NH—, —S—, —CO—, —COO—, —CH 2 —, —SO 2 —, —SO 3 —, —PO 2 —, and —PO 3 —; and
R 6 is a bond or a radical through which the PEG moiety is covalently attached to R 5 .

9. The compound of claim 8 , wherein:
(i) R 5 is —NH—;
R 6 is selected from the group consisting of —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,

Z is O, S or NH that is linked to the PEG moiety; and
R 7 is selected from the group consisting of C 1 -C 18 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; or

(ii) R 5 is —S—; and
R 6 is selected from the group consisting of

 and
Z is O, S or NH; or

(iii) R 5 is —CO;
R 6 is selected from the group consisting of O—, —NH—, —NH—R 7 —COO—, —NH—R 7 —NH, —NH—R 7 —CO—NH,

Z is O, S or NH; and
R 7 is selected from the group consisting of C 1 -C 18 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; or

(iv) R 5 is —CH 2 —; and
R 6 is —(CH 2 ) n —S— or —(CH 2 ) n —NH—, wherein n is 0 to 18; or

(v) R 5 is —SO 2 —; and
R 6 is —O—, —NH— or —CH 2 —CH 2 —S; or

(vi) R 5 is —PO 2 —; and
R 6 is —O— or —NH—.

10. The compound of claim 7 , wherein the radical R 1 contains a linear or branched PEG moiety having a molecular weight in the range of 200 to 200,000.

11. The compound of claim 10 , wherein the PEG moiety has a molecular weight in the range of 5000 to 40000 Da.

12. The compound of claim 11 , wherein the PEG moiety is a branched molecule of 40000 Da or 5000 Da.

13. The compound of claim 9 , wherein Y is a moiety of a drug containing at least one amino group.

14. The compound of claim 13 , wherein said drug is an antibiotic aminoglycoside or an antineoplastic drug; or said drug is a peptide or a protein drug of low or medium molecular weight.

15. The compound of claim 14 , wherein said antibiotic aminoglycoside is gentamicin or amphotericin; said antineoplastic drug is aminolevulinic acid, daunorubicin or doxorubicin; and said peptide or protein is selected from the group consisting of insulin, an interferon, a PYY agonist, an exendin, an exendin analogue or exendin agonist, atrial natriuretic peptide (ANP), human growth hormone (hGH), erythropoietin, TNF-α, calcitonin, gonadotropin releasing hormone (GnRH), a GnRH analogue, hirudin, glucagon, and a monoclonal antibody fragment.

16. The compound of claim 15 , wherein said interferon is IFN-α2, said PYY agonist is the peptide PYY 3-36 , said exendin is exendin-3 or exendin-4, and said monoclonal antibody fragment is anti-TNF-α monoclonal antibody fragment.

17. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17 , wherein R 1 is a protein carrier moiety.

19. The pharmaceutical composition of claim 17 , wherein R 1 is a radical containing a polymer carrier moiety.

20. The pharmaceutical composition of claim 19 , wherein said polymer carrier moiety is a linear or branched PEG.

21. The pharmaceutical composition of claim 20 , wherein R 1 is a radical of the formula:
—R 5 —R 6 -PEG

wherein
R 5 is selected from the group consisting of —NH—, —S—, —CO—, —COO—, —CH 2 —, —SO 2 —, —SO 3 —, —PO 2 —, and —PO 3 —; and
R 6 is a bond or a radical through which the PEG moiety is covalently attached to R 5 .

22. The pharmaceutical composition of claim 21 , wherein:
R 5 is —NH—;
R 6 is selected from the group consisting of —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,

Z is O, S or NH that is linked to the PEG moiety; and
R 7 is selected from the group consisting of C 1 -C 18 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

Assignees

• Yeda Res & Dev

Inventors

• Shechter Yoram
• Fridkin Matityahu
• Tsubery Haim

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P5/02

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

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title