Methods for treatment of neuro- and nephro- disorders and therapeutic toxicities using aminothiol compounds

• US 20060270636A1
• Filed: 08/09/2006
• Published: 11/30/2006
• Est. Priority Date: 12/09/1997
• Status: Abandoned Application

• Current Assignee: Medimmune LLC (Astrazeneca PLC)
• Original Assignee: Arizona State of University, MedImmune Oncology, Inc. (Astrazeneca PLC)
• Inventors: Stogniew, Martin, Alberts, David S., Kaplan, Edward H.
• Application Number:
  US11/501,949
• Publication Number:
  US 20060270636A1
• Time in Patent Office: Days
• US Class Current: 514/114
• 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 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/145 having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2) isothiourea A61K31/155
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/16 : Otologicals
• 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 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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

Abstract

The present invention relates to new uses of S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate, (amifostine) and other aminothiol compounds to treat and reverse toxicities caused by therapeutic agents, radiation treatment or diabetes. In particular, the invention provides a method for treating neurotoxicity and nephrotoxicity associated with the administration of chemotherapeutic agents.

Claims

1. A method for treating toxicities associated with the administration of a therapeutic agent to a mammal which comprises administering a therapeutically effective amount of one or more aminothiol compounds, or a pharmaceutically acceptable salt thereof, to said mammal after the occurrence of one or more of said toxicities.

2. The method of claim 1 wherein said aminothiol compound is a compound of the formula:

R₁NH(CH₂)_nNH(CH₂)_mSR₂ 

 

(I)

or a pharmaceutically acceptable addition salt or hydrate thereof, wherein

R₁ is hydrogen, C₅-C₇ aryl, C₂-C₇ acyl, or C₁-C₇ alkyl;

R₂ is hydrogen, PO₃H₂ or R₃ wherein R₃ is R₁NH(CH₂)_nNH(CH₂)_mS—

;

n is an integer from 1 to 10; and

m is an integer from 1 to 10.

3. The method of claim 2 wherein said compound is selected from the group consisting of WR-1065, WR-151326, WR-151327, WR-638, WR-3689, WR-2822, WR-2529, WR-77913, WR-255591, WR-2823, WR-255709 and salts and hydrates thereof;

and mixtures thereof.

4. The method of claim 1 wherein said aminothiol is amifostine.

5. The method of claim 1 wherein said aminothiol is WR-33278.

6. The method of claim 1 wherein said aminothiol is an active metabolite of WR-2721.

7. The method of claim 1 wherein said aminothiol is a prodrug of a active metabolite of WR-2721.

8. The method of claim 1 wherein said toxicity is selected from the group consisting of neurotoxicity, nephrotoxicity, ototoxicity, cardiotoxicity, alopecia, mucositis, xerostomia, infertility, pulmonary toxicity and renal failure.

9. The method of claim 1 wherein said aminothiol is administered one or more days after the occurrence of said toxicity.

10. The method of claim 1 wherein two or more aminothiol compounds are administered.

11. The method of claim 1 wherein said therapeutically effective amount administered is from about 10 mg/m² to about 2,000 mg/m².

12. The method of claim 1 wherein said mammal is a human.

13. The method of claim 12 wherein said human is a cancer patient, an AIDS patient, a diabetic, or hypertensive patient.

14. The method of claim 1 wherein said therapeutic agent is an antiviral, an antibiotic, an antifungal, a contrast agent or a antineoplastic agent.

15. The method of claim 14 wherein said antibiotic is an aminoglycoside.

16. The method of claim 14 wherein said antiviral agent is 3′

-azido-3′

-deoxythymidine (AZT), d4T (stavadine), ddI (didanosine), ddC (zalcitabine), 3TC (lamivudine), or a combination thereof.

17. The method of claim 14 wherein said antibiotic is gentamicin, tobramicin, kanamicin, amikacin, vaucamicin, or a combination thereof.

18. The method of claim 14 wherein said antineoplastic agent is cisplatin, carboplatin, paclitaxel, docetaxel, vinblastine, vincristine, navelbine, gemcytobin, etoposide, doxorubicin, daunorubicin or a combination thereof.

19. The method of claim 14 wherein said antifungal is amphotericin B.

43. The method of claim 1 wherein said aminothiol compound is administered intravenously, subcutaneously, intramuscularly, intradermally, topically or orally.

20-33. -33. (canceled)

34. A method for treating a neuro-disorder in a human which comprises administering a therapeutically effective amount of one or more aminothiol compounds, or a pharmaceutically acceptable salt thereof, to a human in need of such treatment after the occurrence of said neuro-disorder, wherein said aminothiol compound is a compound of the formula:

R₁NH(CH₂)_nNH(CH₂)_mSR₂

or a pharmaceutically acceptable addition salt or hydrate thereof, wherein

R₁ is hydrogen, C₅-C₇ acyl, or C₂-C₇ acyl, or C₁-C₇ alkyl;

R₂ is PO₃H₂ or R₃ wherein R₃ is R₁NH(CH₂)_nNH(CH₂)_mS—

;

n is an integer from 1 to 10; and

m is an integer from 1 to 10.

35. The method of claim 34, wherein said neuro-disorder is chemically induced, drug induced, induced by aging, induced by exposure to radiation, induced by diabetes or induced by an unknown etiology.

36. The method of claim 35 wherein said neuro-disorder is induced by diabetes.

37. The method of claim 34, wherein said neuro-disorder is a neurotoxicity or nephrotoxicity associated with the administration of radiation therapy of one or more therapeutic agent(s).

38. The method of claim 34 wherein said neuro-disorder is a peripheral neuropathy, autonomic neuropathy, central neuropathy, muscle weakness, arthralgia or myalgia.

40. The method of claim 37 wherein said therapeutic agent is an antiviral, an antibiotic, an antifungal, an antineoplastic agent, a contrast agent or a combination thereof.

41. The method of claim 34 wherein said neuro-disorder is a result of the administration of cisplatin, carboplatin, pactitaxel, docetaxel, vincristine, navelbine, gemcytobin, etoposide, doxorubicin, daunorubicin or a combination thereof.

42. The method of claim 34 wherein said neuro-disorder is a result of the administration of 3′

-azido-3′

-deoxythymidine (AZT), d4T (stavadine), ddI (didanosine), ddC (zalcitabine), 3TC (lamivudine), gentamicin, tobramicin, kanamicin, amikacin, vancamicin, amphotericin B or a combination thereof.

44. The method of claim 34 wherein said human is a cancer patient, AIDS patient, diabetic, or hypertensive patient.

47. The method of claim 34, wherein said aminothiol compound is administered intravenously, subcutaneously, intramuscularly, intradermally, topically or orally.

39. (canceled)

45. A method of treating the clinical symptoms and disorders associated with Type I or Type II diabetes in a human which comprises administering to a diabetic human a therapeutically effective amount of one or more aminothiol compounds or a salt, hydrate or metabolite thereof.

46. The method of claim 45 wherein said symptom or disorder is a neurotoxicity.

48. The method of claim 45, wherein said aminothiol compound is administered intravenously, subcutaneously, intramuscularly, intradermally, topically or orally.