Enkephalin conjugates

• US 6,956,051 B1
• Filed: 10/29/1999
• Issued: 10/18/2005
• Est. Priority Date: 08/14/1998
• Status: Expired due to Fees

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Nobex Corporation (Biocon Incorporated)
• Inventors: Ekwuribe, Nnochiri N., Price, Christopher H., Ansari, Aslam M., Rhadakrishnan, Balasingam, Anderson, Wes Jr.
• Primary Examiner(s): Tate, Christopher R.
• Assistant Examiner(s): AUDET, MAURY A
• Application Number:
  US09/429,798
• Time in Patent Office: 2,181 Days
• Field of Search: 514/402
• US Class Current: 514/402
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
• CPC Class Codes: A61P 5/10 of the posterior pituitary hormones, e.g. oxytocin, ADH
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/18 of the parathyroid hormones

Abstract

The present invention relates to amphiphilic drug-oligomer conjugates capable of traversing the blood-brain barrier (“BBB”) and to methods of making and using such conjugates. An amphiphilic drug-oligomer conjugates comprise a therapeutic compound conjugated to an oligomer, wherein the oligomer comprises a lipophilic moiety coupled to a hydrophilic moiety. The conjugates of the invention further comprise therapeutic agents such as proteins, peptides, nucleosides, nucleotides, antiviral agents, antineoplastic agents, antibiotics, etc., and prodrugs, precursors, derivatives and intermediates thereof, chemically coupled to amphiphilic oligomers.

Claims

1. An amphiphilic drug-oligomer conjugate comprising a therapeutic compound consisting of an enkephalin compound selected from the group consisting of SEQ ID NOS:

1 or 48 conjugated to an oligomer, wherein the oligomer comprises a lipophilic moiety coupled to a hydrophilic moiety, and wherein the oligomer has the formula;

CH₃(CH₂)_x(CH₂CH═

CH)_y(CH₂)_zA(OC₂H₄)_m(OC₂H₄)_nE

wherein

m=1 to 6;

n=0 or 1;

x=0, 3 or 6;

y=1, 2, 3 or 6;

z=2, 3, 7 or 8;

A=single bond, CO or CONHCH₂CH₂; and

E=OH or OCH₂COOH.

2. The amphiphilic drug-oligomer conjugate of claim 1, wherein the amphiphilic drug-oligomer conjugate exhibits the biological activity of the therapeutic compound without cleavage of the therapeutic compound from the oligomer.

3. The amphiphilic drug-oligomer conjugate of claim 1, wherein the amphipilic drug-oligomer conjugate does not exhibit the biological activity of the therapeutic compound without cleavage of the therapeutic compound from the oligomer.

4. The amphiphilic drug-oligomer conjugate of claim 1, wherein the lipophilic moiety is coupled to the hydrophilic moiety by a hydrolyzable bond.

5. The amphiphilic drug-oligomer conjugate of claim 1, wherein the lipophilic moiety is coupled to the hydrophilic moiety by a non-hydrolyzable bond.

6. The amphiphilic drug-oligomer conjugate of claim 1, wherein the lipophilic moiety is coupled to the hydrophilic moiety by a bond selected from the group consisting of:

amide bond, carbamate bond, carbonate bond and ester bond.

7. The amphiphilic drug-oligomer conjugate of claim 1, wherein the oligomer is coupled to the therapeutic compound by a bond selected from the group consisting of amide bond, carbamate bond, carbonate bond and ester bond.

8. The amphiphilic drug-oligomer conjugate of claim 1, wherein the enkephalin compound comprises an added N-terminal residue selected from the group consisting of proline and alanine.

9. The amphiphilic drug-oligomer conjugate of claim 1, wherein the enkephalin compound is met-enkephalin-lys (SEQ ID NO:

1) or an analog thereof.

10. The amphiphilic drug-oligomer conjugate of claim 1, wherein the enkephalin compound is met⁵-enkephalin (SEQ ID NO:

48) or an analog thereof.

11. The amphiphilic drug-oligomer conjugate of claim 1, wherein the therapeutic compound is met-enkephalin-lys (SEQ ID NO:

1) and the oligomer has the formula;

CH₃(CH₂)_x(CH₂CH═

CH)_y(CH₂)_zA(OC₂H₄)_m(OC₂H₄)_nE

wherein m=1, n=0, A=CONHCH₂CH₂, E=OH, x=0, y=6, and z=2.

12. The amphiphilic drug-oligomer conjugate of claim 1, wherein the therapeutic compound is met-enkephalin-lys (SEQ ID NO:

1) and the oligomer has the formula;

CH₃(CH₂)_x(CH₂CH═

CH)_y(CH₂)_zA(OC₂H₄)_m(OC₂H₄)_nE

wherein m=1, n=0, A=CONHCH₂CH₂, E=OH, x=3, y=2, and z=7.