Prodrug compounds with isoleucine

• US 7,696,313 B2
• Filed: 01/16/2008
• Issued: 04/13/2010
• Est. Priority Date: 06/14/2000
• Status: Expired due to Fees

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: Medarex Incorporated (Bristol-Myers Squibb Company)
• Inventors: Gangwar, Sanjeev, Lobl, Thomas J., Yarranton, Geoffrey T., Pickford, Lesley B., Nieder, Matthew H.
• Primary Examiner(s): Russel; Jeffrey E
• Application Number:
  US12/009,031
• Publication Number:
  US 20080255248A1
• Time in Patent Office: 818 Days
• Field of Search: None
• US Class Current: 530/344
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/101 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/1024 with the first amino acid being heterocyclic

Abstract

The compounds of the invention are modified forms of therapeutic agents. A typical prodrug compound of the invention comprises a therapeutic agent, an oligopeptide having an isoleucine residue, a stabilizing group and, optionally, a linker group. The prodrug is cleavable by an enzyme associated with the target cell. Methods of making and using the compounds are also disclosed.

Claims

1. In a method of making a prodrug, a method of removing free therapeutic agent comprising:

(1) coupling an optionally protected stabilizing group-oligopeptide conjugate with the free therapeutic agent,

(2) contacting the product of step (1) with a polymeric resin to bind free therapeutic agent remaining after step (1) and to form a therapeutic agent-polymeric resin complex, wherein the polymeric resin is polystyrene methylisocyanate, or polystyrene sulfonyl chloride, and

(3) removing the therapeutic agent-polymeric resin complex.

2. The method of claim 1 wherein the optionally protected stabilizing group-oligopeptide conjugate includes an oligopeptide of the formula (AA)_n-AA³-AA²-AA¹, wherein:

each AA independently represents an amino acid,

n is 0 or 1, and when n is 1, then (AA)_n is AA⁴ which represents any amino acid,

AA³ represents isoleucine,

AA² represents any amino acid, and

AA¹ represents any amino acid.

3. The method of claim 1, wherein the therapeutic agent is selected from the group consisting of Doxorubicin, Daunorubicin, Vinblastine, Vincristine, Calicheamicin, Etoposide, Etoposide phosphate, CC-1065, Duocarmycin, KW-2189, Methotrexate, Methopterin, Aminopterin, Dichloromethotrexate, Docetaxel, Paclitaxel, Epithiolone, Combretastatin, Combretastatin A4 Phosphate, Dolastatin 10, Dolastatin 11, Dolastatin 15, Topotecan, Camptothecin, Mitomycin C, Porfiromycin, 5-Fluorouracil, 6-Mercaptopurine, Fludarabine, Tamoxifen, Cytosine arabinoside, Adenosine Arabinoside, Colchicine, Cisplatin, Carboplatin, Bleomycin, Melphalan, chloroquine, and cyclosporin A.

4. The method of claim 1, wherein the therapeutic agent is Daunorubicin or Doxorubicin.

5. The method of claim 1, wherein the therapeutic agent is Doxorubicin.

6. In a method of making a prodrug, a method of removing free therapeutic agent comprising:

(1) coupling an optionally protected stabilizing group-oligopeptide conjugate with the free therapeutic agent to produce a product mixture comprising a prodrug of the therapeutic agent and remaining free therapeutic agent,

(2) contacting the product of step (1) with a polymeric resin having isocyanate or sulfonyl groups to bind free therapeutic agent remaining after step (1) and to form a therapeutic agent-polymeric resin complex, wherein the polymeric resin is selected from the group consisting of polystyrene isocyanate, polystyrene thioisocyanate, polystyrene methylthioisocyanate, polystyrene methylsulfonyl chloride and polystyrene benzaldehyde; and

(3) removing the therapeutic agent-polymeric resin complex.

7. The method of claim 6 wherein the optionally protected stabilizing group-oligopeptide conjugate includes an oligopeptide of the formula (AA)_n-AA³-AA²-AA¹, wherein:

each AA independently represents an amino acid,

n is 0 or 1, and when n is 1, then (AA)_n is AA⁴ which represents any amino acid,

AA³ represents isoleucine,

AA² represents any amino acid, and

AA¹ represents any amino acid.

8. The method of claim 6, wherein the therapeutic agent is selected from the group consisting of Doxorubicin, Daunorubicin, Vinblastine, Vincristine, Calicheamicin, Etoposide, Etoposide phosphate, CC-1065, Duocarmycin, KW-2189, Methotrexate, Methopterin, Aminopterin, Dichloromethotrexate, Docetaxel, Paclitaxel, Epithiolone, Combretastatin, Combretastatin A4 Phosphate, Dolastatin 10, Dolastatin 11, Dolastatin 15, Topotecan, Camptothecin, Mitomycin C, Porfiromycin, 5-Fluorouracil, 6-Mercaptopurine, Fludarabine, Tamoxifen, Cytosine arabinoside, Adenosine Arabinoside, Colchicine, Cisplatin, Carboplatin, Bleomycin, Melphalan, chloroquine, and cyclosporin A.

9. The method of claim 6, wherein the therapeutic agent is Doxorubicin.

10. The method of claim 6, wherein the therapeutic agent is linked to the resin by a urea or sulfonamide group.