Claims for Patent: 6,030,961

Summary for Patent: 6,030,961

Title:	Oxyalkylene phosphate compounds 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 hearing, 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 in particular, augmenting expression of tumor suppressor genes, inducing tolerance to antigens, treating, preventing or ameliorating protozoan infection, or inhibiting histone deacetylase in cells. The compositions of the invention are to and the methods of the invention use oxyalkalene phosphate compounds.
Inventor(s):	Nudelman; Abraham (Rehovot, IL), Rephaeli; Ada (North Caldwell, NJ)
Assignee:	Bar-Ilan Research & Development Co., Ltd. (Ramat-Gan, IL) Mor Research Applications Ltd. (Givat Shmuel, IL)
Application Number:	08/814,386
Patent Claims:	1. A compound represented by the formula: ##STR11## wherein A is ##STR12## and wherein R is C.sub.3 -C.sub.10 straight chain alkyl, optionally substituted with one amino, acylamino, halo, trifluoromethyl, hydroxy, alkoxy, alkyl, acyl, aryl, heteroaryl or substituted heteroaryl group; or C.sub.2 -C.sub.10 alkenyl or C.sub.2 -C.sub.10 alkynyl, each optionally substituted with at least one amino, acylamino, halo, trifluoromethyl, hydroxy, alkoxy, alkyl, carbonyl, aryl, heteroaryl, substituted heteroaryl group or combination thereof; R.sup.1 and R.sup.2 are each independently H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl wherein the alkyl, alkenyl or alkynyl group or combination thereof is optionally substituted with halo or alkoxy; X is R.sup.4 or OR.sup.5, and R.sup.3 and R.sup.5 are both H or each is independently C.sub.1 -C.sub.6 alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl or heteroaralkyl; R.sup.4 is C.sub.1 -C.sub.6 alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl or heteroaralkyl; with the proviso that when R is n-propyl and R.sup.1 or R.sup.2 is H and the other is trichloromethyl, then X is not methoxy and R.sup.3 is not methyl. 2. The compound of claim 1 wherein R is C.sub.3 -C.sub.6 alkyl or alkenyl, optionally substituted with halo, alkyl, aryl or heteroaryl; R.sup.1 is H or alkyl and R.sup.2 is H; and X and --OR.sup.3 are each independently alkyloxy, alkenyloxy, alkynyloxy, aryloxy, arylalkyloxy, heteroaryloxy, or heteroarylalkyloxy. 3. The compound of claim 1 wherein said compound is butyroyloxymethyl diethyl phosphate, 1-(1-butyroyloxy)ethyl diethyl phosphate, mono(butyroyloxymethyl) phosphate or 1{1-(4-phenylbutyroyloxy)ethyl} diethyl phosphate. 4. A compound represented by the formula: ##STR13## wherein A is ##STR14## and wherein R is C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl or C.sub.2 -C.sub.10 alkynyl, each optionally substituted with at least one amino, acylamino, halo, trifluoromethyl, hydroxy, alkoxy, alkyl, acyl, aryl, heteroaryl, substituted heteroaryl group or combination thereof; R.sup.1 and R.sup.2 are each independently H or C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl wherein the alkyl, alkenyl or alkynyl group or combination thereof is optionally substituted with halo or alkoxy; X is A, R.sup.4 or OR.sup.5, wherein R.sup.3 and R.sup.5 are both H or each is independently C.sub.1 -C.sub.6 alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl or heteroaralkyl; and R.sup.4 is C.sub.1 -C.sub.6 alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl or heteroaralkyl; or both X and OR.sup.3 are A. 5. A pharmaceutical composition comprising a therapeutically-effective amount of a compound represented by the formula: ##STR15## wherein A is ##STR16## and wherein R is C.sub.3 -C.sub.10 straight chain alkyl, C.sub.2 -C.sub.10 alkenyl or C.sub.2 -C.sub.10 alkynyl, each optionally substituted with at least one amino, acylamino, halo, trifluoromethyl, hydroxy, alkoxy, alkyl, acyl, aryl, heteroaryl, substituted heteroaryl group or combination thereof; R.sup.1 and R.sup.2 are each independently H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl, wherein the alkyl, alkenyl or alkynyl group or combination thereof is optionally substituted with halo or alkoxy; X is R.sup.4 or OR.sup.5, and R.sup.3 and R.sup.5 are both H or each is independently C.sub.1 -C.sub.6 alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl or heteroaralkyl; R.sup.4 is C.sub.1 -C.sub.6 alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl or heteroaralkyl; with the proviso that when R is n-propyl and R.sup.1 or R.sup.2 is H and the other is trichloromethyl, then X is not methoxy and R.sup.3 is not methyl; and a pharmaceutically acceptable carrier or diluent. 6. The pharmaceutical composition of claim 5 wherein R is C3-C6 alkyl or alkenyl, optionally substituted with halo, alkyl, aryl or heteroaryl; R.sup.1 is H or alkyl and R.sup.2 is H; X and --OR.sup.3 are each independently alkyloxy, alkenyloxy, alkynyloxy, aryloxy, arylalkyloxy, heteroaryloxy, or heteroarylalkyloxy. 7. The pharmaceutical composition of claim 5 wherein said compound is butyroyloxymethyl diethyl phosphate, 1-(1-butyroyloxy)ethyl diethyl phosphate, mono(butyroyloxymethyl) phosphate or 1{1-(4-phenylbutyroyloxy)ethyl} diethyl phosphate. 8. A pharmaceutical compsition comprising a therapeutically effective amount of a compound represented by the formula: ##STR17## wherein A is ##STR18## and wherein R is C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl or C.sub.2 -C.sub.10 alkynyl, each optionally substituted with at least one amino, acylamino, halo, trifluoromethyl, hydroxy, alkoxy, alkyl, acyl, aryl, heteroaryl, substituted heteroaryl group or combination thereof; R.sup.1 and R.sup.2 are each independently H or C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl wherein the alkyl, alkenyl or alkynyl group or combination thereof is optionally substituted with halo or alkoxy; X is A, R.sup.4 or OR.sup.5 wherein R.sup.3 and R.sup.5 each is independently H, C.sub.1 -C.sub.6 alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl; R.sup.4 is C.sub.1 -C.sub.6 alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or both X and OR.sup.3 are A; and a pharmaceutically acceptable carrier or diluent. 9. The pharmaceutical composition of claim 5 or 8 further comprising a cytotoxic agent. 10. The pharmaceutical composition of claim 5 or 8 further comprising an antiviral nucleoside antibiotic selected from the group consisting of ganciclovir, acyclovir, and famciclovir. 11. The pharmaceutical composition of claim 10 wherein said antibiotic is ganciclovir. 12. The pharmaceutical composition of claim 5 or 8 further comprising a chemotherapeutic agent selected from the group consisting of alkylating agents, purine and pyrimidine analogs, vinca and vinca-like alkaloids, etoposide and etoposide-like drugs, corticosteroids, nitrosoureas, antimetabolites, platinum based cytotoxic drugs, hormonal antagonists, anti-androgens and antiestrogens. 13. The pharmaceutical composition of claim 5 or 8 further comprising a cytokine. 14. The pharmaceutical composition of claim 13 wherein the cytokine is an interferon. 15. The pharmaceutical composition of claim 5 or 8 further comprising an immune stimulant. 16. The pharmaceutical composition of claim 15 wherein said immune stimulant is Corynebactedum parvum or a sarcolectin. 17. 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 effective to treat the cancer or disorder. 18. The method of claim 17 wherein the disorder is leukemia, squamous cell carcinoma, prostate carcinoma, breast carcinoma, colon carcinoma, pancreatic carcinoma, lug carcinoma, renal carcinoma, neuroblastoma or melanoma. 19. The method of claim 17 wherein said compound is administrated orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 20. The method of claim 17 wherein said effective amount is an amount effective to inhibit histone deacetylase in the patient. 21. A method of differentiating or blocking proliferation of cancerous or neoplastic cells comprising administering to said cells a compound of any one of claims 1-4 in an amount effective to cause differentiation of or to block proliferation of said cancerous or neoplastic cells. 22. The method of claim 21 wherein the compound is administered to said cells in vivo. 23. The method of claim 21 wherein the compound is administered to said cells in vitro. 24. The method of claim 21 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 25. 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 claims 1-4 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 of anti-neoplastic agent, a chemotherapeutic agent, an antibody, a conjugated antibody, an immune stimulant, antibiotic, a hormone antagonist and a growth stimulant. 26. The method of claim 25 wherein said pharmaceutical agent is an antibiotic. 27. The method of claim 25 wherein said antibiotic is selected from the group consisting of ganciclovir, acyclovir, and famciclovir. 28. The method of claim 25 wherein said pharmaceutical agent is a chemotherapeutic agent. 29. The method of claim 27 wherein said pharmaceutical agent is a chemotherapeutic agent 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. 30. The method of claim 29 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 29 wherein said chemotherapeutic agent is an interferon. 32. The method of claim 25 wherein said pharmaceutical agent is an immune stimulant. 33. The method of claim 32 wherein said immune stimulant is Corynebacterium parvum or a sarcolectin. 34. 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. 35. The method of claim 25 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 36. A method of ameliorating the effects of a cytotoxic agent in a mammalian patient which comprises administering to the patient a therapeutically-effective amount of said cytotoxic agent and a compound of any one of claims 1-4 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. 37. The method of claim 36 wherein said rapidly proliferating epithelial cells are in hair follicles, gastrointestinal tract or bladder of said patient. 38. The method of claim 36 wherein said rapidly-proliferating epithelial cells are hair follicle cells or intestinal cryt cells of said patient. 39. The method of claim 36 wherein said cytotoxic agent and said compound are administered simultaneously. 40. The method of claim 36 wherein said cytotoxic agent is administered prior to or after administration of the compound. 41. The method of claim 36 wherein said cytotoxic agent and said compound are administered systemically or topically. 42. A method of inhibiting telomerase activity in cancer cells which comprises administering to said cells an amount of a compound of any one of claims 1-4 effective to decrease the basal level of telomerase activity in said cells and thereby inhibit malignant progression of said cells. 43. The method of claim 42 wherein said compound is administered to the cells in vivo. 44. The method of claim 43 wherein said compound is administered to the patient orally, parentally, transdermally, transmucosally, intranasally, rectally or topically. 45. The method of claim 42 wherein said compound is administered to the cells in vitro. 46. 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 claims 1-4 and a therapeutically-effective amount of an antiviral agent. 47. The method of claim 46 wherein said antiviral agent is ganciclovir, acyclovir, or famciclovir. 48. The method of claim 46 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. 49. The method of claim 46 wherein said EBV-associated malignancy is nasopharyngeal carcinoma or non-Hodgkin's lymphoma. 50. The method of claim 46 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 51. 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 in an amount effective to induce cellular apoptosis of the cancer cells or of the cells of the proliferative disorder. 52. The method of claim 51 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically.

Details for Patent 6,030,961

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2039-02-26