Claims for Patent: 6,124,495

Summary for Patent: 6,124,495

Title:	Unsaturated 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 and inducing tolerance to an antigen. The methods of the invention use unsaturated oxyalkylene esters.
Inventor(s):	Neiss; Edward (New Canaan, CT), Loev; Bernard (Medford, NJ)
Assignee:	Beacon Laboratories, Inc. (Phoenix, MD)
Application Number:	08/814,366
Patent Claims:	1. A method of treating, preventing or ameliorating cancer or other proliferative disorder in a subject which comprises administering an amount of a compound effective to treat, prevent or ameliorate said cancer or said disorder, wherein said compound is represented by the formula: ##STR32## wherein R is C.sub.2 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, C.sub.2 to C.sub.10 alkynyl, aryl or heteroaryl, any of which can be optionally substituted with halo, trifluoromethyl, hydroxy, alkoxy, cyano, nitro or carbonyl, wherein the heteroatom of said heteroaryl is oxygen or sulfur; R.sup.1 and R.sup.2 are independently H, 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, any of which can be optionally substituted with halo, alkoxy, amino, trifluoromethyl, aryl or heteroaryl; A is ##STR33## R.sup.3 is independently ##STR34## R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are independently H, alkyl or alkenyl; B is aryl or heteroaryl, wherein the heteroatom of said heteroaryl is oxygen or sulfur; m and n are independently 0 to 5; the sum of m and n is 1 to 5; p, q and r are independently 0 to 2; or a pharmaceutically-acceptable salt thereof; with the proviso that when p, q and r are 0, each R.sup.3 is --CR.sup.6 .dbd.CR.sup.7 --, R.sup.6 is H or methyl and R.sup.7 is H or methyl, then the sum of m and n can not be 4 or 5. 2. The method of claim 1, wherein R.sup.2 is H. 3. The method of claim 1, wherein m is 1 to 5; n is 0 to 5; and p is 0. 4. The method of claim 2, wherein R.sup.2 is H. 5. The method of claim 4, wherein in R is n-propyl, 2-chloroethyl, 2-propenyl; R.sup.1 is H or alkyl; R.sup.3 is ##STR35## R.sup.6 and R.sup.7 are independently H or alkyl; and n, q and r are 0. 6. The method of claim 1, wherein said compound is cinnamoyloxymethyl butyrate, 3,4-dimethoxycinnamoyloxymethyl butyrate or 1-(3,4-dimethoxycinnamoyl)oxyethyl butyrate. 7. The method of any one of claims 1 to 6 wherein said disorder is leukemia, squamous cell carcinoma, prostate carcinoma, breast carcinoma, colon carcinoma, pancreatic carcinoma, lung carcinoma, renal carcinoma, neuroblastoma or melanoma. 8. The method of any one of claims 1 to 6 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 9. The method of any one of claims 1 to 6, wherein said effective amount is an amount effective to inhibit histone deacetylase in said subject. 10. A method of differentiating or blocking proliferation of cancerous or neoplastic cells comprising administering to said cells an amount of a compound of any one of claims 1 to 6 effective to cause differentiation of or to block proliferation of cancerous or neoplastic cells. 11. The method of claim 10 wherein said cells are in vivo. 12. The method of claim 10 wherein said cells are in vitro. 13. The method of claim 10 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 14. A method of increasing hemoglobin content in blood which comprises administering a therapeutically-effective amount of a compound of any one of claims 1 to 6 to a subject. 15. The method of claim 14 wherein said hemoglobin is fetal hemoglobin. 16. The method of claim 14 wherein said composition is administered orally or parenterally. 17. A method of treating a blood disorder in a subject which comprises administering a therapeutically-effective amount of a compound of any one of claims 1 to 6 to a subject. 18. The method of claim 17, wherein treating said blood disorder comprises increasing the hemoglobin content in cells of said subject. 19. The method of claim 17 wherein said disorder is selected from the group consisting of thalassemias, sickle cell anemias, infectious anemias, aplastic anemias, hypoplastic and hypoproliferative anemias, sideroblastic anemias, myelophthisic anemias, antibody-mediated anemias, anemias due to chronic diseases and enzyme-deficiencies, and anemias due to blood loss, radiation therapy and chemotherapy. 20. The method of claim 17 wherein said composition is administered orally or parenterally. 21. A method of modulating an immune response in a host which comprises administering an amount of a compound of any one of claims 1 to 6 effective to modulate said immune response. 22. The method of claim 21 wherein modulating said immune response is enhancing cytokine secretion, inhibiting or delaying apoptosis in polymorphonuclear cells, enhancing polymorphonuclear cell function by augmenting hematopoietic growth factor secretion, inducing expression of cell surface antigens in tumor cells, enhancing progenitor cell recovery after bone marrow transplantation. 23. The method of claim 21 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 24. A method of treating, preventing or ameliorating cancer or other proliferative disorder in a subject in need of such treatment which comprises administering an amount of a compound of any one of claims 1 to 6 effective to induce cellular apoptosis of the cancer cells or of the cells of the proliferative disorder. 25. The method of claim 24 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 26. A method for enhancing the actions of a pharmaceutical agent useful for the treatment of cancer and other proliferative disorders, comprising co-administering a therapeutically-effective amount of a compound of any one of claims 1 to 6 with a therapeutically-effective amount of said agent, wherein said agent is selected from the group consisting of a cytokine, an interleukin, an anti-cancer agent or an anti-neoplastic agent, a chemotherapeutic agent, an antibody, a conjugated antibody, an immune stimulant, an antibiotic, a hormone antagonist or a growth stimulant. 27. The method of claim 26, wherein said antibiotic selected from the group consisting of ganciclovir, acyclovir, and famciclovir. 28. The method of claim 26, wherein said chemotherapeutic agent is selected from the group consisting of an alkylating agent, a purine analog, a pyrimidine analog, a vinca alkaloid, a vinca-like alkaloid, etoposide, an etoposide-like drug, 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 26 wherein said cytokine is an interferon. 30. The method of claim 26 wherein said immune stimulant is Corynebacterium parvum or a sarcolectin. 31. The method of claim 26 wherein the chemotherapeutic agent is selected from the group consisting of tamoxifen, doxorubicin, L-asparaginase, dacarbazine, amascrine, procarbazine, hexamethylmelamine, mitosantrone and gemcitabine. 32. The method of claim 26 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 33. A method of ameliorating the effects of a cytotoxic agent which comprises administering a therapeutically-effective amount of said cytotoxic agent with a compound of any one of claims 1 to 6 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. 34. The method of claim 33, wherein said rapidly-proliferating epithelial cells are in hair follicles, gastrointestinal tract or bladder. 35. The method of claim 33, wherein said rapidly-proliferating epithelial cells are hair follicle cells, or intestinal cryt cells. 36. The method of claim 33 wherein administering is simultaneous. 37. The method of claim 33 wherein administering comprises administering said agent before or after said compound. 38. The method of claim 33 wherein said administration is systemic or topical. 39. A method of treating gastrointestinal disorders which comprises administering a therapeutically-effective amount of a compound of any one of claims 1 to 6 to a subject. 40. The method of claim 39 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 41. A method of treating cutaneous ulcers which comprises administering a therapeutically-effective amount of a compound of any one of claims 1 to 6 to a subject. 42. The method of claim 41 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 43. A method of inducing wound healing which comprises administering a therapeutically-effective amount of a compound of any one of claims 1 to 6 to a subject. 44. The method of claim 43 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intrasally, rectally or topically. 45. A method of enhancing recombinant gene expression which comprises treating a recombinant host cell containing an expression system for a gene product of interest with an expression-enhancing amount of a compound of any one of claims 1 to 6, wherein said gene product is encoded by a butyric acid-responsive gene. 46. The method of claim 45, wherein said host cell is a mammalian cell, an insect cell, a yeast cell or a bacterial cell. 47. The method of claim 45, wherein said gene product is a tumor suppressor gene or fetal hemoglobin. 48. A method of treating, preventing or ameliorating symptoms in insulin-dependent patients which comprises administering an amount of a compound of any one of claims 1 to 6 effective to enhance insulin expression. 49. The method of claim 48 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 50. A method of treating, preventing or ameliorating symptoms in cystic fibrosis patients which comprises administering an amount of a compound of any one of claims 1 to 6 effective to enhance chloride channel expression. 51. The method of claim 50 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 52. 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 to 6 effective to decrease the basal level telomerase activity is said cells and thereby inhibit malignant progression of said cells. 53. The method of claim 52 wherein said cells are in vivo. 54. The method of claim 53 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 55. The method of claim 52 wherein said cells are in vitro. 56. A method of treating, preventing or ameliorating virus-associated tumors which comprises co-administering a therapeutically-effective amount of a compound of any one of claims 1 to 6 with a therapeutically-effective amount of an antiviral agent. 57. The method of claim 56 wherein said antiviral agent is ganciclovir, acyclovir, or famciclovir. 58. The method of claim 56 wherein said virus-associated tumor is an EBV-associated malignancy, Kaposi's sarcoma, an AIDS-related lymphoma, an hepatitis B-associated malignancy or an hepatitis C-associated malignancy. 59. The method of claim 58 wherein said EBV-associated malignancy is nasopharyngeal carcinoma or non-Hodgkin's lymphoma. 60. The method of claim 56 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 61. A method of modulating gene expression which comprises treating a host or host cells with an amount of a compound of any one of claims 1 to 6 effective to enhance, augment or repress expression of a gene of interest. 62. The method of claim 61 wherein expression of said gene is enhanced or augmented. 63. The method of claim 62 wherein said gene encodes a gene product which is or acts as repressor, a tumor suppressor, an inducer of apoptosis or an inducer of differentiation. 64. The method of claim 63 wherein said host is a cancer patient and said gene is a tumor suppressor gene. 65. The method of claim 64 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 66. The method of claim 61 wherein expression of said gene is repressed. 67. The method of claim 66 wherein said gene encodes a gene product which is or acts as an oncogene or an inhibitor of apoptosis. 68. The method of claim 67 wherein said gene is bcl-2. 69. The method of claim 61 wherein said host cells are undergoing ex vivo gene therapy. 70. The method of claim 61 wherein said host is a patient receiving in vivo gene therapy. 71. The method of claim 70 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 72. A method of inducing tolerance to an antigen which comprises administering a therapeutically-effective amount of compound of any one of claims 1 to 6. 73. The method of claim 72 wherein said antigen is a self-antigen. 74. The method of claim 73 wherein said self-antigen is associated with an autoimmune disease. 75. The method of claim 74 wherein said autoimmune disease is systemic lupus erythromatosus, rheumatoid arthritis, multiple sclerosis, myasthenia gravis or diabetes. 76. The method of claim 72 wherein said antigen is present on a transplanted organ or cells. 77. The method of claim 72 wherein said compound is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically. 78. A method for treating, preventing, or ameliorating protozoan infection in a subject which comprises administering to said subject an effective amount of a compound of any one of claims 1 to 6. 79. The method of claim 78, wherein said protozoan infection is malaria, cryptosporidiosis, toxoplasmosis, or coccidiosis. 80. The method of claim 78 wherein said compound is administered orally, parenterally, transmucosally, intranasally or rectally. 81. The method of claim 78, wherein said effective amount is an amount of said compound effective to inhibit protozoan histone deacetylase in said subject. 82. A method of inhibiting histone deacetylase in cells which comprises administering an effective amount of a compound of any one of claims 1 to 6 to said cells. 83. A compound represented by the formula: ##STR36## wherein R is C.sub.2 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, C.sub.2 to C.sub.10 alkynyl, aryl or heteroaryl, any of which can be optionally substituted with halo, trifluoromethyl, hydroxy, alkoxy, cyano, nitro or carbonyl, wherein the heteroatom of said heteroaryl is oxygen or sulfur; R.sup.1 and R.sup.2 are independently H, 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, any of which can be optionally substituted with halo, alkoxy, amino, trifluoromethyl, aryl or heteroaryl; A is ##STR37## R.sup.3 is independently ##STR38## R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are independently H, alkyl or alkenyl; B is aryl or heteroaryl, wherein the heteroatom of said heteroaryl is oxygen or sulfur; m and n are independently 0 to 5; the sum of m and n is 1 to 5; p, q and r are independently 0 to 2; or a pharmaceutically-acceptable salt thereof; with the provisos that (1) that when R is p-hydroxyphenyl, then A and B taken together cannot be 2-(3-hydroxy-4-methoxyphenyl)ethenyl; and (2) that when p, q and r are 0, each R.sup.3 is --CR.sup.6 .dbd.CR.sup.7 --, R.sup.6 is H or methyl and R.sup.7 is H or methyl, then the sum of m and n can not be 4 or 5. 84. The compound of claim 83, wherein R.sup.2 is H. 85. The compound of claim 83, wherein m is 1 to 5; n is 0 to 5; and p is 0. 86. The compound of claim 85, wherein R.sup.2 is H. 87. The compound of claim 86, wherein in R is n-propyl, benzyl, 2-chloroethyl, 2-propenyl; R.sup.1 is H or alkyl; R.sup.3 is ##STR39## R.sup.6 and R.sup.7 are independently H or alkyl; and n, q and r are 0. 88. The compound of claim 87, wherein said compound is cinnamoyloxymethyl butyrate, 3,4-dimethoxycinnamoyloxymethyl butyrate or 1-(3,4-dimethoxycinnamoyl)oxyethyl butyrate. 89. A pharmaceutical composition comprising a therapeutically-effective amount of a compound of any one of claims 83 to 88 and a pharmaceutically-effective carrier or diluent. 90. A pharmaceutical composition comprising a therapeutically-effective amount of a compound of any one of claims 83 to 88 with 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 and a growth stimulant. 91. The composition of claim 90 wherein said pharmaceutical agent comprises a cytotoxic agent. 92. The composition of claim 90 wherein said antibiotic is an antiviral nucleoside antibiotic selected from the group consisting of ganciclovir, acyclovir, and famciclovir. 93. The composition of claim 90 wherein said antibiotic is ganciclovir. 94. The composition of claim 90 wherein said chemotherapeutic agent is selected from the group consisting of alkylating agents, purine and pyrimidine analogs, vinca and vinca-like alkaloids, etoposides and etoposide-like drugs, corticosteroids, nitrosoureas, antimetabolites, platinum based cytotoxic drugs, hormonal antagonists, anti-androgens and antiestrogens. 95. The composition of claim 90, wherein said cytokine is an interferon. 96. The composition of claim 90, wherein said immune stimulant is Corynebacterium parvum or a sarcolectin. 97. The composition of claim 90, wherein the chemotherapeutic agent is selected from the group consisting of tamoxifen, doxorubicin, L-asparaginase, dacarbazine, amsacrine, procarbazine, hexamethylmelamine, mitoxantrone and gemcitabine.

Details for Patent 6,124,495

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