Polyamine analog-amino acid conjugates useful as anticancer agents

• US 7,312,244 B2
• Filed: 11/08/2001
• Issued: 12/25/2007
• Est. Priority Date: 04/30/1999
• Status: Expired due to Fees

• Current Assignee: Cellgate, Inc. (Tbg Diagnostics Limited)
• Original Assignee: Cellgate, Inc. (Tbg Diagnostics Limited)
• Inventors: Marton, Laurence J., Valasinas, Aldonia L., Reddy, Venodhar K.
• Primary Examiner(s): Witherspoon, Sikarl A.
• Application Number:
  US10/415,377
• Publication Number:
  US 20040133013A1
• Time in Patent Office: 2,238 Days
• Field of Search: 514/477, 514/478, 514/479, 514/642, 514/740
• US Class Current: 514/477
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 237/10 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups

Abstract

Conjugates in which polyamine analogs are conjugated to an amino acid are provided, as well as compositions comprising these conjugates. Methods of using these conjugates as anticancer treatments are also provided.

Claims

1. A composition comprising a polyamine or polyamine analog conjugated to at least one amino acid, wherein two amino acids are conjugated to the polyamine or polyamine analog, where each amino acid is conjugated to an exterior nitrogen of the polyamine or polyamine analog.

2. A composition comprising a polyamine or polyamine analog conjugated to at least one amino acid, wherein the polyamine- or polyamine analog-amino acid conjugates are of the formula:

3. A composition comprising a polyamine or polyamine analog conjugated to at least one amino acid, wherein the polyamine- or polyamine analog-amino acid conjugates are of the formula:

4. A composition comprising a polyamine or polyamine analog conjugated to at least one amino acid, wherein the polyamine- or polyamine analog-amino acid conjugates are of the formula:

5. A composition comprising a polyamine or polyamine analog conjugated to at least one amino acid, wherein the polyamine- or polyamine analog-amino acid conjugates are of the formula:

21. The composition of claim 5 wherein the polyamine analog amino acid conjugate is of the formula

22. The composition of claim 5 wherein the polyamine analog amino acid conjugate is of the formula

23. The composition of claim 21, further comprising a pharmaceutically acceptable carrier.

24. The composition of claim 22, further comprising a pharmaceutically acceptable carrier.

6. A composition comprising a polyamine or polyamine analog conjugated to at least one amino acid, wherein the polyamine- or polyamine analog-amino acid conjugates are of the formula:

7. A composition comprising a polyamine or polyamine analog conjugated to at least one amino acid, further comprising a pharmaceutically acceptable carrier, wherein the polyamine- or polyamine analog-amino acid conjugates are of the formula:

8. A composition comprising a polyamine or polyamine analog conjugated to at least one amino acid, further comprising a pharmaceutically acceptable carrier, wherein the polyamine- or polyamine analog-amino acid conjugates are of the formula:

9. A composition comprising a polyamine or polyamine analog conjugated to at least one amino acid, wherein the amino acid is chosen from D-glutamine or L-glutamine, and all salts thereof.

10. A composition according to claim 9, wherein the amino acid is chosen from L-glutamine, and all salts thereof.

11. A composition comprising a polyamine analog-amino acid conjugate of the formula:

CH₃CH₂—

N(R₁₀₀)—

J—

N(R₁₀₀)—

CH₂CH_3, where each R₁₀₀ is independently chosen from H, C₁–

C₈ alkyl, and an amino acid, with the proviso that at least one R₁₀₀ be an amino acid; and

where J is selected from {C₁–

C₈ alkyl-[N(R₁₀₀)-(C₁–

C₈ alkyl)]_k}, where each R₁₀₁ is independently selected from H and C₁–

C₈ alkyl, and where k is an integer between 0 and 15.

12. The composition of claim 11, wherein one and only one R₁₀₀ is an amino acid.

13. The composition of claim 11, wherein one and only one R₁₀₀ is an amino acid and the other R₁₀₀ is H.

14. The composition of claim 11, where the amino acid is chosen from amino acids with either amide-containing or basic side chains, and all stereoisomers and salts thereof.

15. The composition of claim 11, where the amino acid is chosen from glutamine, asparagine, lysine, ornithine, arginine, histidine, or citrulline, and all stereoisomers and salts thereof.

16. The composition of claim 11, where the amino acid is D-glutamine or L-glutamine, and all salts thereof.

17. The composition of claim 11, where the amino acid is L-glutamine, and all salts thereof.

19. The composition of claim 11, further comprising a pharmaceutically acceptable carrier.

18. A composition comprising a polyamine analog-amino acid conjugate of the formula:

CH₃CH₂—

N(R₁₀₀)—

(CH₂)₄—

N(R₁₀₁)—

(CH₂)₄—

N(R₁₀₁)—

(CH₂)₄—

N(R₁₀₁)—

(CH₂)₄—

N(R₁₀₀)—

CH₂CH₃

where each R₁₀₀ is independently chosen from H, C₁–

C₈ alkyl, and an amino acid, with the proviso that at least one R₁₀₀ be an amino acid; and

each R₁₀₁ is independently chosen from H and C₁–

C₈ alkyl.

20. The composition of claim 18, further comprising a pharmaceutically acceptable carrier.