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Last Updated: October 21, 2019

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Claims for Patent: 6,110,955

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Summary for Patent: 6,110,955
Title: Metabolically stabilized oxyalkylene esters and uses thereof
Abstract:This invention relates to compositions for and methods of treating, preventing or ameliorating cancer and other proliferative diseases as well as methods of inducing wound healing, treating cutaneous ulcers, treating gastrointestinal disorders, treating blood disorders such as anemias, immunomodulation, enhancing recombinant gene expression, treating insulin-dependent patients, treating cystic fibrosis patients, inhibiting telomerase activity, treating virus-associated tumors, especially EBV-associated tumors, modulating gene expression and particularly augmenting expression of a tumor suppressor gene, inducing tolerance to an antigen and treating, ameliorating or preventing protozoan infection. The methods of the invention use metabolically stabilized oxyalkylene esters.
Inventor(s): Nudelman; Abraham (Rehovot, IL), Rephaeli; Ada (North Caldwell, NJ), Neiss; Edward (New Canaan, CT), Loev; Bernard (Medford, NJ)
Assignee: Beacon Laboratories, Inc. (Phoenix, MD)
Application Number:08/814,975
Patent Claims:1. A compound represented by the formula: ##STR18## wherein R is a C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl or C.sub.2 to C.sub.10 alkynyl group, optionally substituted with an alkoxy, halo, trifluoromethyl, amino, acylamino, carboxyl, carboxamide, carbalkoxy, hydroxy, acyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group;

R.sup.1 and R.sup.2 are each independently H, C.sub.1 to C.sub.6 straight or branched chain alkyl, C.sub.2 to C.sub.6 branched or straight chain alkenyl or C.sub.2 to C.sub.6 branched or straight chain alkynyl wherein the alkyl, alkenyl or alkynyl group is optionally substituted with halo or alkoxy; and

R.sup.3 CO is an acyl moiety of a carboxylic acid-containing compound that inhibits beta-oxidation of fatty acids;

with the proviso that when said acyl moiety is the acyl moiety of a NSAID compound, the NSAID is selected from the group consisting of ketoprofen, diflunisal, salsalate, etodolac, tolmetin, ibuprofen, naproxen, oxaprozin, salicylic acid, acetylsalicylic acid, indomethacin, flurbiprofen, diclofenac, mefenamic acid, meclofenamic acid, ketorolac and sulindac; and wherein when the acyl moiety is that of ibuprofen, R is not methyl or ethyl; when the acyl moiety is that of oxaprozin, R is not methyl; when the acyl moiety is that of sulindac or naproxen, R is not alkyl; when the acyl moiety is that of salicylic acid or acetylsalicylic acid, R is C.sub.3 to C.sub.10 alkenyl or lower haloalkyl; and when the acyl moiety is that of indomethacin, flurbiprofen, mefenamic acid, meclofenamic acid or diclofenac, R is C.sub.3 to C.sub.10 haloalkyl, aralkyl, heteroaralkyl, 2-, 3- or 4-arylpropyl or 2-, 3- or 4heteroarylpropyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R.sup.3 CO is the acyl group of a NSAID.

3. The compound of claim 1 wherein the NSAID is selected from the group consisting of etodolac, tolmetin, salsalate, diflunisal and ketoprofen.

4. The compound of claim 1 wherein R.sup.2 is H.

5. A pharmaceutical composition comprising a therapeutically-efective amount of a compound of any one of claims 1 to 4 and a pharmaceutically-effective carrier or diluent.

6. A pharmaceutical composition comprising a therapeutically-efective amount of a compound of any one of claims 1 to 4 and a therapeutically-effective amount of a pharmaceutical agent, wherein said agent is selected from the group consisting of a cytokine, an interleukin, an anti-cancer agent or anti-neoplastic agent, a chemotherapeutic agent, an antibody, a conjugated antibody, an immune stimulant, an antibiotic, a hormone antagonist, a growth stimulant or a combination thereof.

7. The composition of claim 6 wherein said pharmaceutical agent comprises a cytotoxic agent.

8. The composition of claim 6 wherein said antibiotic is an antiviral nucleoside antibiotic selected from the group consisting of ganciclovir, acyclovir, and famciclovir.

9. The composition of claim 6 wherein said antibiotic is ganciclovir.

10. The composition of claim 6 wherein said chemotherapeutic agent is selected from the group consisting of alkylating agents, purine and pyrimidine analogs, vinca and vinca-like alkaloids, etopside and etopside-like drugs, corticosteroids, nitrosoureas, antimetabolites, platinum based cytotoxic drugs, hormonal antagonists, anti-androgens and antiestrogens.

11. The composition of claim 6, wherein said cytokine is an interferon.

12. The composition of claim 6, wherein said immune stimulant is Corynebactedum parvum or a sarcolectin.

13. The composition of claim 6, wherein the chemotherapeutic agent is selected from the group consisting of tamoxifen, doxorubicin, I-asparaginase, dacarbazine, amacrine, procarbazine, hexamethylmelamine, mitoxantrone and gemcitabine.

14. The composition of claim 5 wherein said compound is .alpha.-methyl-4-(2-methylpropyl)-benzeneacetyloxymethyl butyrate, 1-{.alpha.-methyl-4(2-methylpropyl)-benzeneacetyloxy}-ethyl butyrate, 1-{.alpha.-methyl-4(2-methylpropyl)-benzeneacetyloxy}-butyl butyrate, 6-methoxy-.alpha.-methyl-2-naphthaleneacetyloxylmethyl butyrate, 1-{6-methoxy-.alpha.-methyl-2-naphthaleneacetyloxy}-ethyl butyrate or 1-{6-methoxy-.alpha.-methyl-2-naphthaleneacetyloxy}butyl butyrate.

15. The composition of claim 5 wherein the R.sup.3 CO moiety of the compound is that of valproic acid or 2-valproenic acid and R is not C.sub.2 to C.sub.10 alkenyl substituted with an aryl group, C.sub.1 to C.sub.10 alkyl or hydroxy propyl.

16. A method of treating cancer or other proliferative disorder in a patient which comprises administering to the patient an amount of a compound of any one of claims 1-4 or the composition of claim 14 effective to treat the cancer or disorder.

17. The method of claim 16 wherein the disorder is leukemia, squamous cell carcinoma, prostate carcinoma, breast carcinoma, colon carcinoma, pancreatic carcinoma, lung carcinoma, renal carcinoma, neuroblastoma or melanoma.

18. The method of claim 16 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically.

19. The method of claim 16 wherein said effective amount is an amount effective to inhibit histone deacetylase in the patient.

20. A method of differentiating or blocking proliferation of cancerous or neoplastic cells comprising administering to said cells a compound of any one of claim 1-4 or the composition of claim 14 in an amount effective to cause differentiation of or to block proliferation of said cancerous or neoplastic cells.

21. The method of claim 20 wherein the compound is administered to said cells in vivo.

22. The method of claim 20 wherein the compound is administered to said cells in vitro.

23. The method of claim 20 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically.

24. A method of enhancing the action of a pharmaceutical agent useful for the treatment of cancer or other proliferative disorder, comprising co-administering to a patient a therapeutically-effective amount of a compound of any one of claim 1-4 or the composition of claim 14 and a therapeutically effective amount of said pharmaceutical agent, wherein said pharmaceutical agent is selected from the group consisting of a cytokine, an interleukin, an anti-cancer agent or anti-neoplastic agent, a chemotherapeutic agent, an antibody, a conjugated antibody, an immune stimulant, an antibiotic, a hormone antagonist and a growth stimulant.

25. The method of claim 24 wherein said pharmaceutical agent is an antibiotic.

26. The method of claim 25 wherein said antibiotic is an antiviral nucleoside antibiotic selected from the group consisting of ganciclovir, acyclovir, and famciclovir.

27. The method of claim 24 wherein said pharmaceutical agent is a chemotherapeutic agent.

28. The method of claim 27 wherein said chemotherapeutic agent is selected from the group consisting of an alkylating agent, a purine analog, a pyrimidine analog, a vinca alkaloid, an etoposide, a corticosteroid, a nitrosourea, an antimetabolite, a platinum-based cytotoxic drug, a hormonal antagonist, an anti-androgen and an anti-estrogen.

29. The method of claim 24 wherein said cytokine is an interferon.

30. The method of claim 27 wherein said chemotherapeutic agent is selected from the group consisting of tamoxifen, doxorubicin, 1-asparaginase, dacarbazine, amsacrine, procarbazine, hexamethylmelamine, mitoxantrone and gemcitabine.

31. The method of claim 24 wherein said pharmaceutical agent is an immune stimulant.

32. The method of claim 31 wherein said immune stimulant is Corynebacterium parvum or a sarcolectin.

33. The method of claim 24 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranassaly, rectally or topically.

34. A method of ameliorating the effects of a cytotoxic agent which comprises administering a therapeutically-effective amount of said cytotoxic agent and a compound of any one of claims 1-4 or the composition of claim 14 to a mammalian patient for a time and in an amount to induce growth arrest of rapidly-proliferating epithelial cells or bone marrow stem cells of said patient and thereby protecting said cells from cytotoxic effects of said agent.

35. The method of claim 34 wherein said rapidly proliferating epithelial cells are in hair follicles, gastrointestinal tract, gladder or bone marrow of said patient.

36. The method of claim 34 wherein said rapidly-proliferating epithelial cells are hair follicle cells or intestinal cryt cells of said patient.

37. The method of claim 34 wherein said compound is administered simultaneously with the cytotoxic agent.

38. The method of claim 34 wherein said cytotoxic agent is administered before or after administration of the compound.

39. The method of claim 34 wherein said compound is administered systemically or topically.

40. A method of inhibiting telomerase activity in cancer cells which comprises administering to said cells an amount of a compound of any one of claim 1-4 or the composition of claim 14 effective to decrease the basal level of telomerase activity in said cells and thereby inhibit malignant progression of said cells.

41. The method of claim 40 wherein said cells are treated in vivo.

42. The method of claim 41 wherein said compound is administered to the patient orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically.

43. The method of claim 40 wherein said compound is administered to the cells in vitro.

44. A method of treating virus-associated tumors which comprises co-administering to a patient a therapeutically-effective amount of a compound of any one of claim 1-4 or the composition of claim 14 and a therapeutically-effective amount of an antiviral agent.

45. The method of claim 44 wherein said antiviral agent is ganciclovir, acyclovir, or famciclovir.

46. The method of claim 44 wherein said virus-associated tumor is an EBV-associated malignancy, Kaposi's sarcoma, an AIDS-related lymphoma, a hepatitis B-associated malignancy or a hepatitis C-associated malignancy.

47. The method of claim 44 wherein said EBV-associated malignancy is nasopharyngeal carcinoma or non-Hodgkin's lymphoma.

48. The method of claim 44 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically.

49. A method of treating cancer or other proliferative disorder in a patient in need of such treatment which comprises administering to the patient a compound of any one of claims 1-4 or the composition of claim 14

in an amount effective to induce cellular apoptosis of the cancer cells or of the cells of the proliferative disorder.

50. The method of claim 49 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically.

Details for Patent 6,110,955

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Merck ELSPAR asparaginase VIAL 101063 001 1978-01-10   Start Trial Beacon Laboratories, Inc. (Phoenix, MD) 2039-02-26 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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