Conformationally restricted polyamine analogs as disease therapies

• US 7,186,825 B2
• Filed: 06/21/2004
• Issued: 03/06/2007
• 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: Basu, Hirak S., Valasinas, Aldonia L., Blokhin, Andrei V., Reddy, Venodhar K., Frydman, Benjamin, Marton, Laurence J.
• Primary Examiner(s): DAVIS, BRIAN J
• Application Number:
  US10/873,100
• Publication Number:
  US 20040235962A1
• Time in Patent Office: 988 Days
• Field of Search: 540/145
• US Class Current: 540/145
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 211/09 : Diamines
• CPC Class Codes: C07C 211/18 : containing at least two amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 211/22 : containing at least two amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 211/23 : the carbon skeleton containing carbon-to-carbon triple bonds
• CPC Class Codes: C07C 211/36 : containing at least two amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 215/14 : the nitrogen atom of the amino group being further bound to hydrocarbon groups substituted by amino groups
• CPC Class Codes: C07C 257/18 : having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 2601/04 : with a four-membered ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 45/46 : Friedel-Crafts reactions
• CPC Class Codes: C07C 47/575 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 67/343 : by increase in the number of carbon atoms
• CPC Class Codes: C07C 69/734 : Ethers
• CPC Class Codes: C07D 207/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 219/10 : attached in position 9
• CPC Class Codes: C07D 235/18 : with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 307/79 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 307/92 : Naphthofurans; Hydrogenated naphthofurans
• CPC Class Codes: C07D 311/92 : Naphthopyrans; Hydrogenated naphthopyrans
• CPC Class Codes: C07D 317/70 : condensed with ring systems containing two or more relevant rings
• CPC Class Codes: C07D 487/22 : in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 493/04 : Ortho-condensed systems
• CPC Class Codes: C07K 5/1013 : the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids

Abstract

Novel conformationally restricted polyamine analogs are provided, as well as compositions comprising these novel polyamine analogs. Methods of using the novel polyamine analogs in treatment of diseases such as cancer are also provided. Also provided is a method of delivering these analogs specifically to tumor cells by covalently attaching polyamine analogs to porphyrin compounds, along with novel polyamine-porphyrin covalent conjugates.

Claims

1. A composition comprising a porphyrin-polyamine conjugate or porphyrin-polyamine analog conjugate, wherein the conjugate comprises a polyamine compound or polyamine analog compound covalently linked to a porphyrin compound, and a pharmaceutically acceptable carrier, wherein the composition comprises a therapeutic amount of the porphyrin-polyamine conjugate or porphyrin-polyamine analog conjugate for treatment of cancer or uncontrolled cell proliferation, and with the proviso that the polyamine or polyamine analog is not spermine, and the proviso that the polyamine or polyamine analog does not have a tertiary amino group.

2. The composition of claim 1, wherein the covalent link is an amide bond or a amine bond.

8. A method of treating aberrant cell growth in an individual comprising the step of administering to the individual a therapeutic amount of the composition of claim 1.

9. A method of inhibiting proliferation of diseased cells in an individual comprising the step of administering to the individual a therapeutic amount of the composition of claim 1.

10. The method of claim 8, wherein the aberrant cell growth is cancer.

3. A porphyrin-polyamine conjugate or porphyrin-polyamine analog conjugate of the formula

4. The composition of claim 3, wherein K₁ and each A are independently selected from the group consisting of C₁–

C₈ alkyl, K₂ is independently selected from the group consisting of H and C₁–

C₈ alkyl, and the remainder of the groups J₁–

J₈ are each independently selected from the group consisting of H, K₃, or K₄-COOH, where K₃ and K₄ are independently selected from the group consisting of C₁–

C₈ alkyl.

5. The composition of claim 4, wherein K₁ is —

CH₂—

CH₂—

or —

CH₂—

CH₂—

CH₂—

.

6. The composition of claim 4, wherein n is 4.

7. The composition of claim 4, wherein J₃, J₄, J₇ and J₈ are independently selected from the group consisting of C₁–

C₃ alkyl;

J₅ and J₆ are independently selected from the group consisting of C₁–

C₃ alkyl and C₁–

C₃ alkyl-COOH;

and J₁ and J₂ are independently selected from the group consisting of C₁–

C₃ alkyl-G-N(P₁)-A-(NH-A)_n1-K₅;

wherein G is —

(C═

O)—

or a nonentity;

P₁ is independently selected from H or C₁–

C₃ alkyl;

each A is independently selected from the group consisting of C₁–

C₈ alkyl;

n₁ is 3 or 4;

and K₅ is independently selected from the group consisting of H and C₁–

C₈ alkyl.

11. The composition of claim 3 wherein the porphyrin-polyamine conjugate or porphyrin-polyamine analog conjugate is of the formula:

12. The composition of claim 3 wherein the porphyrin-polyamine conjugate or porphyrin-polyamine analog conjugate is of the formula:

13. The composition of claim 3 wherein the porphyrin-polyamine conjugate or porphyrin-polyamine analog conjugate is of the formula:

14. The composition of claim 3 wherein the porphyrin-polyamine conjugate or porphyrin-polyamine analog conjugate is of the formula:

15. The composition of claim 3 wherein the porphyrin-polyamine conjugate or porphyrin-polyamine analog conjugate is of the formula:

16. The composition of claim 3 wherein the porphyrin-polyamine conjugate or porphyrin-polyamine analog conjugate is of the formula:

17. A method of treating aberrant cell growth in an individual comprising the step of administering to the individual a therapeutic amount of the composition of claim 3.

18. A method of inhibiting proliferation of diseased cells in an individual comprising the step of administering to the individual a therapeutic amount of the composition of claim 3.

19. A composition comprising a porphyrin-polyamine analog conjugate, wherein the conjugate comprises a polyamine analog compound covalently linked to a porphyrin compound, and a pharmaceutically acceptable carrier, wherein the composition comprises a therapeutic amount of the porphyrin-polyamine analog conjugate for treatment of cancer or uncontrolled cell proliferation, and with the proviso that the polyamine analog is conformationally restricted.

20. The composition of claim 19, wherein the covalent link is an amide bond or a amine bond.