Lipid raft, caveolin protein, and caveolar function modulation compounds and associated synthetic and therapeutic methods

• US 20080286316A1
• Filed: 05/19/2008
• Published: 11/20/2008
• Est. Priority Date: 05/18/2007
• Status: Active Grant

• Current Assignee: Heidi Kay
• Original Assignee: Heidi Kay
• Inventors: Kay, Heidi
• Granted Patent: US 8,026,382 B2
• Time in Patent Office: Days
• US Class Current: 424/278.1
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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 31/18 for HIV
• CPC Class Codes: C07F 15/0093 without a metal-carbon linkage

Abstract

The present invention is directed to the modulation of lipid rafts, caveolin proteins, or caveolar functions and processes by platinum(IV) compounds. Caveolae and/or lipid rafts are associated with cell transcription regulation, membrane and cellular transport, cell membrane receptor function, cellular trafficking, antigen presentation, cell differentiation and activation, cytokine modulation, membrane structure and function, and protein modulation. Caveolae, caveolin proteins and lipid rafts are known therapeutic targets for numerous biological functions. Diseases and disorders currently known to be therapeutically targeted through caveolae and/or lipid rafts include diabetes, cancer, cardiovascular diseases, atherosclerosis, pulmonary fibrosis, multiple sclerosis, viral and prion diseases, neuronal disorders, degenerative muscular dystrophies, and autoimmune disorders.

Claims

1. A method for synthesizing a target trichloronitroplatinum(IV) compound, the method comprising:

dissolving a predetermined molar amount of solid K₂Pt(II)Cl₄ in a solvent to form a solution;

stirring an equimolar amount of solid silver(I) nitrite into the solution;

removing an AgCl precipitate from the solution, leaving in the solution a trichloronitroplatinum(IV) compound having two open Pt substitution positions; and

adding to the solution an equimolar amount of a metal-coordinating ligand for each of the two open Pt substitution positions of the trichloronitroplatinum(IV) compound to synthesize a target trichloronitroplatinum(IV) compound.

2. The method recited in claim 1, wherein the solvent is water.

3. The method recited in claim 1, wherein the metal-coordinating ligand is at least one of a ligand selected from a group consisting of a sulfur-, a nitrogen-, an oxygen- or a phosphorus-containing ligand.

4. The method recited in claim 1, wherein the target trichloronitroplatinum(IV) compound is diamminotrichloronitroplatinum(IV) and the metal-coordinating ligand is NH₄OH.

9. Use of the compound of claim 4 in the manufacture of a medicament for the treatment of an oncological disorder, an immune evasion response, cancer metastasis, cancer or tumor development, cardiovascular disease, multiple sclerosis, muscular dystrophy, rheumatoid arthritis, infectious disease, myelosuppression, diabetes, autoimmune disease, AIDS development, retinitis pigmentosa, asthma, Alzheimers disease, endometriosis, conditions associated with Lyme neuroboreliosis, irritable bowel syndrome, optical diseases, or diabetic retinopathy.

5. A platinum(IV) compound having the structure shown in at least one of formula (I), (II), (III), and (IV):

wherein X and Y are, independently, any halogen, —

CN, —

SCN, —

NCS, —

NO₂, —

ONO, —

OHSO₃, —

OH₂PO₃, —

OHSO₂, —

SO₃H, —

OH, —

OR², —

OS(CH₃)₂, —

OCOR², —

OCOOR², —

OSO₂CH₃, —

SH, —

SR², —

S₂CN(R²)₂, —

OSiO₃, OBO₂H, —

OHSeO₂, —

NHCOH, —

NH₂CHO, —

NH₂CH₂OH, —

NH₂C(OH)₃, or —

NH₂CH(OH)₂, or —

NHCOR², or X and Y together form a ring structure selected from the group consisting of cyclobutane dicarboxylate (CBDCA) (OCOC₄H₆OCO)²⁻

;

oxalate (C₂O₄)²⁻

, malanato (OOCCH₂COO)²⁻

, dithiocarbamate ((R²)₂NCS₂)⁻

, acetylacetonate (CH₃COCHCOCH₃)⁻

, carboxylate (CO₂R²)⁻

, sulfate (SO₄)², phosphate (HPO₄)²⁻

, selenate (SeO₄)²⁻

, silicate (SiO₄)²⁻

, diborate (B₂O₅)⁴⁻

, (acetylacetonate (OCCH₃CH₂CH₃O)⁻

, ethylene diamine (H₂C₂H₄NH₂), bis(diphenylphosphino)ethane (dppe) ((C₆H₅)₂PC₂H₄P(C₆H₅)₂), bis(dimethylphosphino)ethane (dmpe) ((CH₃)₂PC₂H₄P(CH₃)₂), 2,2′

-bipyridine ((NC₅H₄)₂) and glyme (CH₃OCH₂CH₂OCH₃);

R¹ is —

NO₂, —

ONO, —

CN, —

SCN, —

NCS, —

COOH, COOR², —

CHO, —

COR or —

SO₃H;

R² is any halogen, —

COOH, —

OH, —

NH₂, —

HSO₃, —

OHSO₃, —

OH₂PO₃, —

OBO₂, —

OHSiO₃, —

OHSeO₂, an alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl, any of which can be optionally substituted with any halogen, —

COOH, —

OH, —

NO₂, —

NH₂, —

HSO₃, —

OHSO₃, —

OH₂PO₃, —

OBO₂, —

OHSiO₃, —

OHSeO₂, N-alkyl, alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl;

R³ is —

NH₃, —

NH₂R², —

NH(R²)₂, —

N(R²)₃, —

NH₂COR², —

NH₂COH, —

NH₂CHO, —

NH₂CH₂OH, —

NH₂C(OH)₃, —

NH₂CH(OH)₂, —

OCH₃ or —

OR²,

or R³, R³, X, and Y together comprise porphyrin or phthalocyanine;

or R³, R², X, and Y together comprise porphyrin or phthalocyanine;

or a pharmaceutically acceptable salt thereof.

6. The platinum(IV) compound or pharmaceutically acceptable salt thereof recited in claim 5, wherein X and Y are independently selected from the group consisting of F, Cl, Br, and I;

R¹ is —

NO₂;

R² is Cl; and

R³ is —

NH₃.

7. The platinum(IV) compound or pharmaceutically acceptable salt thereof recited in claim 6, wherein X and Y are Cl.

8. A platinum(IV) compound having the structure shown in formula I, II, III, or IV:

wherein X and Y are, independently, any halogen, —

CN, —

SCN, —

NCS, —

NO₂, —

ONO, —

OHSO₃, —

OH₂PO₃, —

OHSO₂, —

SO₃H, —

OH, —

OR², —

OS(CH₃)₂, —

OCOR², —

OCOOR², —

OSO₂CH₃, —

SH, —

SR², —

S₂CN(R²)₂, —

OSiO₃, —

OBO₂H, —

OHSeO₂, —

NHCOH, —

NH₂CHO, —

NH₂CH₂OH, —

NH₂C(OH)₃ or —

NH₂CH(OH)₂ or —

NHCOR², or X and Y together form a ring structure selected from the group consisting of cyclobutane dicarboxylate (CBDCA) (OCOC₄H₆OCO)²⁻

;

oxalate (C₂O₄)²⁻

, malanato (OOCCH₂COO)²⁻

, dithiocarbamate ((R²)₂NCS₂)⁻

, acetylacetonate (CH₃COCHCOCH₃)⁻

, carboxylate (CO₂R²)⁻

, sulfate (SO₄)², phosphate (HPO₄)²⁻

, selenate (SeO₄)²⁻

, silicate (SiO₄)²⁻

, diborate (B₂O₅)⁴⁻

, (acetylacetonate (OCCH₃CH₂CH₃O)⁻

, ethylene diamine (H₂C₂H₄NH₂), bis(diphenylphosphino)ethane (dppe) ((C₆H₅)₂PC₂H₄P(C₆H₅)₂), bis(dimethylphosphino)ethane (dmpe) ((CH₃)₂PC₂H₄P(CH₃)₂), 2,2′

-bipyridine ((NC₅H₄)₂) and glyme (CH₃OCH₂CH₂OCH₃);

R¹ is —

NO₂, —

ONO, —

CN, —

SCN, —

NCS, —

COOH, COOR², —

CHO, —

COR or —

SO₃H;

R² is chloride, bromide, fluoride or iodide;

—

COOH, —

OH, —

NH₂, —

HSO₃, —

OHSH₃, —

OH₂PO₃, —

OBO₂, —

OHSiO₃, —

OHSeO₂, folate, N-acetylcysteine, taurine, ethanolamine, safranin, riboflavin, 7-ethoxycoumarin, methylene blue, thiamine, caffeine, N-acetyl galactosamine, naringin, N-acetyl neuraminic acid, methyl alpha-D-mannopyranoside, xanthine, hydantoin, 6-aminonicotinamide, theophylline, N-acetyl glucosamine, alpha-aminoisobutyric acid, cytarabine, pantothenic acid, nicotinamide, fluorescein, rhodamine, biotin, inosine, theobromine, histidine, niacine, eosin, luminol, pyrimidine, thiosalicylic acid, 7-amino-4-methylcoumarin, tris, nicotine, 2,6-dichloro-4-nitropyridine, 2,6-dimethyl-4-nitropyridine, quinoline, pyridoxine, nicotinic acid, carbazole, morpholine, pyrimidinecarboxylic acid, imidazole, thiazole, oxazole, succinimidyl ester, pyridine, benzimidazole, benzoxazole, 2-(2-aminophenyl)-benzothiazole, 2-(4-aminophenyl)-benzothiazole, benzothiazole, hydroorotic acid, palmitate, purine, adenine, guanine, hypoxanthine, uric acid, isoguanine, serine, cytosine, thymidine, uracil, myristic acid, oleic acid, succinimide, triethanolamine, diethanolamine, thiazolidinedione, flavin, anthranilic acid, methionine, cysteine, tyrosine, threonine, N-acetyl mannose;

R³ is —

NH₃, —

NH₂R², —

NH(R²)₂, —

N(R²)₃, —

NH₂COR², —

NH₂COH, —

NH₂CHO, —

NH₂CH₂OH, —

NH₂C(OH)₃, —

NH₂CH(OH)₂, —

OCH₃ or —

OR²,

or R³, R³, X, and Y together comprise porphyrin or phthalocyanine;

or R³, R², X, and Y together comprise porphyrin or phthalocyanine;

or a pharmaceutically acceptable salt thereof.

10. A method for increasing the effectiveness of a drug subject to multidrug resistance or upregulated p53 in a patient in need thereof, the method comprising administering to the patient an effective amount of a platinum (IV) compound with the drug.

11. A method for inhibiting the development of TH17 thymus lymphocytes or the production of associated inflammatory cytokines IL-17, IL-6, or IL-22, the method comprising administering in vivo or ex vivo an effective amount of a platinum(IV) compound to a patient in need thereof.

12. A method for modulating stem cell activities, the method comprising contacting the lipid rafts, caveolae, or caveolin proteins of a stem cell with an effective amount of a platinum(IV) compound in vivo, ex vivo, or in vitro.

13. A method for reducing infiltration into the central nervous system associated with leakage of cells across the blood brain barrier, the method comprising administering an effective amount of a platinum(IV) compound to a patient in need thereof.

14. A method for regenerating liver tissue or of supporting a liver transplant in a patient in need thereof, the method comprising administering an effective amount of a platinum(IV) compound to a patient in need thereof.

15. A method for modulating or characterizing lipid raft or caveolar structure, function, or activity in a cell, the method comprising contacting said cell with an effective amount of a platinum(IV) compound, wherein the cell is in vitro, in vivo, or ex vivo, and the cell is bacterial, viral, or derived from any living animal.

16. An adjuvant for enhancing antigen presentation in the adaptive immune response system of a subject, the adjuvant comprising an effective amount of a platinum(IV) compound.

17. A method for treating or preventing an oncological disorder in a patient in need thereof, the disorder selected from the group consisting of a cancer, a tumor, a tumor immune evasion response, metastasis, viral cell transformation, and tumor-associated angiogenesis, the method comprising administering an effective amount of a platinum(IV) compound to the patient.

18. A method for treating or preventing an autoimmune or inflammatory disease in a patient in need thereof, the autoimmune disease selected from the group consisting of a TH17-associated disease, multiple sclerosis, rheumatoid arthritis, myelosuppression, diabetes, asthma, Alzheimers disease, or diabetic retinopathy, the method comprising administering an effective amount of a platinum(IV) compound to the patient.

19. A method for preventing or treating infection of a pathogen in a patient in need thereof, the pathogen selected from a group consisting of a virus, a prion, a viral protein, toxin, and a bacteria, the method comprising administering an effective amount of a platinum (IV) compound to the patient.

20. A method for reducing matrix metalloproteinases (MMP) in a patient in need thereof, including MT-MMP-1 (transmembrane MMP-1 or MMP14), MMP-2, and MMP-9, the method comprising administering an effective amount of a platinum(IV) compound to the patient.

21. A method for preventing or treating HIV-associated dementia (HAD) or HIV-Encephalitis in a patient in need thereof, the method comprising administering an effective amount of a platinum (IV) compound to said patient.

22. A method for modulating caveolin-associated proteins, transport of ions or molecules across or within cell membranes, cellular excretions or cell receptors that associate with lipid rafts or caveolae in a cell, the method comprising contacting the cell with an effective amount of a platinum(IV) compound, wherein the cell is in vitro, in vivo, or ex vivo, wherein the cell is bacterial, viral, or derived from any living animal.