Platinum-polymer complexes and their use as antitumor agents

• US 4,931,553 A
• Filed: 05/11/1988
• Issued: 06/05/1990
• Est. Priority Date: 05/11/1988
• Status: Expired due to Fees

• Current Assignee: Andrulis Pharmaceuticals Corporation
• Original Assignee: Andrulis Research Corporation
• Inventors: Andrulis, Peter J. Jr., Gill, Devinder S.
• Primary Examiner(s): Griffin, Ronald W.
• Application Number:
  US07/192,451
• Time in Patent Office: 755 Days
• Field of Search: 536/121, 514/492, 514/908, 424/78, 556/137
• US Class Current: 424/78.26
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/28 Compounds containing heavy metals
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 15/0093 without a metal-carbon linkage
• CPC Class Codes: C08F 8/44 Preparation of metal salts or ammonium salts
• CPC Class Codes: C08G 79/00 Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule

Abstract

Platinum(amine) complexes, when covalently linked to a water-soluble, biodegradable or biostable polymer, exhibit high antitumor activity at low dosages of platinum against L1210 and solid tumors. The complexes are platinum square planar complexes and octahedral structures of the formulae ##STR1## wherein A₂ represents either 2 ammonia ligands, 2 monodentate amine ligands or a single bidentate amine ligand; P is either a biodegradable or a biostable but biocompatible polymer having pendent anionic groups which form covalent linkages with Pt; o is a positive integer and X is an anionic ligand.

Claims

1. A polymeric platinum-amine complex of the formula ##STR9## wherein each A independently represents a monodentate amine ligand or NH₃ or A₂ represents a single bidentate amine ligand;

n is a positive integer up to 500;

P is a divalent ligand of a physiologically acceptable homopolymer or copolymer bearing at least 2×

n pendant anionic groups, pairs of which form covalent linkages with the Pt(II)A₂ or Pt(IV)A₂ group; and

X is an anionic ligand.

2. A platinum complex according to claim 1, wherein the platinum is Pt(II).

3. A platinum complex according to claim 1, wherein A₂ is the bidentate 1,2-diaminocyclohexane ligand.

4. A platinum complex according to claim 1, wherein n is about 100 to 500.

5. A platinum complex according to claim 1, wherein the physiologically acceptable polymer is a biostable polymer having a weight average molecular weight of about 10,000 to 50,000 or a biodegradable polymer having a weight average molecular weight of about 5,000 to about 200,000 and containing only C, H and O atoms.

6. A platinum complex according to claim 1, wherein the physiologically acceptable polymer is a biodegradable polycarboxylic acid derivative of amylose, amylopectin, dextran, alginic acid or polygalacturonic acid.

7. A platinum complex according to claim 1, wherein the physiologically acceptable polymer is complexed with 1,2-diaminocyclohexane platinum.

8. A platinum complex according to claim 7, wherein the platinum is Pt(II).

9. A platinum complex according to claim 8, wherein the physiologically acceptable polymer is a biostable polymer having a weight average molecular weight of about 10,000 to 50,000 or a biodegradable polymer having a weight average molecular weight of about 5,000 to about 200,000 and containing only C, H and O atoms and wherein n is about 100 to 500.

10. A Pt(trans-DACH)carboxy amylose platinum complex according to claim 1.

11. A Pt(trans-DACH)carboxyamylopectin platinum complex according to claim 1.

12. A Pt(trans-DACH)carboxydextran platinum complex according to claim 1.

13. A Pt(trans-DACH)Co-oxyalginic acid platinum complex according to claim 1.

14. A Pt(trans-DACH)carboxy polygalacturonic acid platinum complex according to claim 1.

15. A Pt(trans-DACH)pyran copolymer platinum complex according to claim 1.

16. A platinum complex according to claim 1, wherein the physiologically acceptable polymer is a biostable polymer having a weight average molecular weight of about 10,000 to 50,000 or a biodegradable polymer having a weight average molecular weight of about 5,000 to about 200,000 and containing only C, H, and O atoms, and wherein the physiologically acceptable polymer is a biodegradable polycarboxylic acid derivative or amylose, amylopectin, dextran, alginic acid, or polygalacturonic acid.

18. In a method of treating a patient with a tumor susceptible to platinum therapy by administering thereto an antitumor-effective amount of a platinum complex the improvement wherein the complex is a platinum complex according to claim 1.

19. In a method of treating a patient with a tumor susceptible to platinum therapy by administering thereto an antitumor-effective amount of a platinum complex the improvement wherein the complex is a platinum complex according to claim 8.

20. In a method of treating a patient with a tumor susceptible to platinum therapy by administering thereto an antitumor-effective amount of a platinum complex the improvement wherein the complex is a platinum complex according to claim 9.

21. In a method of treating a patient with a tumor susceptible to platinum therapy by administering thereto an antitumor-effective amount of a platinum complex the improvement wherein the complex is a platinum complex according to claim 10.

22. In a method of treating a patient with a tumor susceptible to platinum therapy by administering thereto an antitumor-effective amount of a platinum complex the improvement wherein the complex is a platinum complex according to claim 11.

23. In a method of treating a patient with a tumor susceptible to platinum therapy by administering thereto an antitumor-effective amount of a platinum complex the improvement wherein the complex is a platinum complex according to claim 12.

24. In a method of treating a patient with a tumor susceptible to platinum therapy by administering thereto an antitumor-effective amount of a platinum complex the improvement wherein the complex is a platinum complex according to claim 13.

25. In a method of treating a patient with a tumor susceptible to platinum therapy by administering thereto an antitumor-effective amount of a platinum complex the improvement wherein the complex is a platinum complex according to claim 14.

26. A method of increasing the percentage of Pt ions of a diaminocyclohexane platinum (II) moiety which are delivered to the tumor cells of a tumor susceptible to platinum (II) therapy in a mammal, which method comprises administering to the mammal an amount effective to deliver an antitumor effective amount of said moiety to said tumor of a platinum complex according to claim 8.

17. A method of treating a patient with a tumor susceptible to platinum therapy by administering thereto a platinum-amine complex which exhibits anti-tumor activity against L1210 tumors and solid tumors, which comprises administering the platinum-amine complex to the affected host as a conjugate with a water-soluble, physiologically acceptable anionic polymer, thereby reducing the amount of the complex required to be administered thereto to manifest the anti-tumor activity thereof in the patient.