Details for Patent: 5,470,838
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Title: | Method of delivering exogenous uridine or cytidine using acylated uridine or cytidine |
Abstract: | Methods of delivering exogenous uridine or cytidine to the tissue of an animal comprising the administration of acyl derivatives of uridine or cytidine, respectively, are disclosed. Also disclosed are methods for treating cardiac insufficiency, myocardial infarction, cirrhosis of the liver, each comprising administration of acyl derivatives of uridine or cytidine. |
Inventor(s): | von Borstel; Reld W. (Darnestown, MD), Bamat; Michael K. (Darnestown, MD) |
Assignee: | Pro-Neuron, Inc. (Rockville, MD) |
Filing Date: | Dec 30, 1992 |
Application Number: | 07/997,657 |
Claims: | 1. A method of delivering exogenous uridine to the tissue of an animal, comprising the step of administering to said animal an acyl derivative of uridine having the formula (I) ##STR4## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a carboxylic acid selected from the group consisting of glycolic acid, pyruvic acid, lactic acid, enolpyruvic acid, an amino acid, a fatty acid of 2 to 22 carbon atoms, lipoic acid, pantothenic acid, succinic acid, fumaric acid, adipic acid, acetoacetic acid, p-aminobenzoic acid, betahydroxybutyric acid, orotic acid, and creatine, provided that at least one of said R substituents is not hydrogen, or a pharmaceutically acceptable salt thereof. 2. A method as recited in claim 1 wherein said acyl derivative of uridine is administered orally. 3. A method as in claim 1 wherein said acyl derivative of uridine has the formula (I) wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a fatty acid of 2 to 22 carbon atoms , provided that at least one of said R substituents is not hydrogen. 4. A method as recited in claim 3 wherein said acyl derivative of uridine is selected from the group consisting of 2', 3', 5'-tri-O-acetyl uridine, 2', 3', 5'-tri-O-propionyl uridine, and 2', 3', 5'-tri-O-butyryl uridine. 5. A method as recited in claim 4 wherein said acyl derivative of uridine is 2', 3', 5'-tri-acetyl uridine. 6. A method as in claim 5 wherein said acyl derivative of uridine is administered orally. 7. A method as in claim 1 wherein said acyl derivative of uridine is administered in a dose of 15-4500 mg. 8. A method as in claim 7 wherein said acyl derivative of uridine is 2', 3', 5'-tri-acetyl uridine, and said dose is administered 1-3 times per day. 9. A method of delivering exogenous cytidine to the tissue of an animal, comprising the step of administering to said animal an acyl derivative of cytidine having the formula (III) ##STR5## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a carboxylic acid selected from the group consisting of glycolic acid, pyruvic acid, lactic acid, enolpyruvic acid, an amino acid, a fatty acid of 2 to 22 carbon atoms, lipoic acid, pantothenic acid, succinic acid, fumaric acid, adipic acid, acetoacetic acid, p-aminobenzoic acid, betahydroxybutyric acid, orotic acid, and creatine, provided that at least one of said R substituents is not hydrogen, and that R.sub.4 is not a fatty acid, or a pharmaceutically acceptable salt thereof. 10. A method as recited in claim 9 wherein said acyl derivative of cytidine is administered orally. 11. A method as in claim 9 wherein said acyl derivative of cytidine has the formula (III) wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a fatty acid of 2 to 22 carbon atoms, provided that at least one of said R substituents is not hydrogen. 12. A method as recited in claim 11 wherein said acyl derivative of cytidine is selected from the group consisting of 2', 3', 5'-tri-O-acetyl cytidine, 2', 3', 5'-tri-O-propionyl cytidine, and 2', 3', 5'-tri-O-butyryl cytidine. 13. A method as in claim 12 wherein said acyl derivative of cytidine is administered orally. 14. A method for treating cardiac insufficiency, comprising administering to an animal in need of such treatment a composition in an amount to effect said treatment, said composition comprising an acyl derivative of uridine having the formula (I) ##STR6## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a carboxylic acid selected from the group consisting of glycolic acid, pyruvic acid, lactic acid, enolpyruvic acid, an amino acid, a fatty acid of 2 to 22 carbon atoms, lipoic acid, pantothenic acid, succinic acid, fumaric acid, adipic acid, acetoacetic acid, p-aminobenzoic acid, betahydroxybutyric acid, orotic acid, and creatine, provided that at least one of said R substituents is not hydrogen, or a pharmaceutically acceptable salt thereof. 15. A method as recited in claim 14 wherein said acyl derivative of uridine is administered orally. 16. A method as in claim 14 wherein said acyl derivative of uridine has the formula (I) wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a fatty acid of 2 to 22 carbon atoms, provided that at least one of said R substituents is not hydrogen. 17. A method as recited in claim 16 wherein said acyl derivative of uridine is selected from the group consisting of 2', 3', 5'-tri-O-acetyl uridine, 2', 3', 5'-tri-O-propionyl uridine, and 2', 3', 5'-tri-O-butyryl uridine. 18. A method as recited in claim 17 wherein said acyl derivative of uridine is 2', 3', 5'-tri-acetyl uridine. 19. A method as in claim 18, wherein said acyl derivative of uridine is administered orally. 20. A method as in claim 14 wherein said acyl derivative of uridine is administered in a dose of 15-4500 mg. 21. A method as in claim 20 wherein said acyl derivative of uridine is 2', 3', 5'-tri-acetyl uridine, and said dose is administered 1-3 times per day. 22. A method for treating myocardial infarction, comprising administering to an animal in need of such treatment a composition in an amount to effect said treatment, said composition comprising an acyl derivative of uridine having the formula (I) ##STR7## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a carboxylic acid selected from the group consisting of glycolic acid, pyruvic acid, lactic acid, enolpyruvic acid, an amino acid, a fatty acid of 2 to 22 carbon atoms, lipoic acid, pantothenic acid, succinic acid, fumaric acid, adipic acid, acetoacetic acid, p-aminobenzoic acid, betahydroxybutyric acid, orotic acid, and creatine, provided that at least one of said R substituents is not hydrogen, or a pharmaceutically acceptable salt thereof. 23. A method as recited in claim 22 wherein said acyl derivative of uridine is administered orally. 24. A method as in claim 22 wherein said acyl derivative of uridine has the formula (I) wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a fatty acid of 2 to 22 carbon atoms, provided that at least one of said R substituents is not hydrogen. 25. A method as recited in claim 24 wherein said acyl derivative of uridine is selected from the group consisting of 2', 3', 5'-tri-O-acetyl uridine, 2', 3', 5'-tri-O-propionyl uridine, and 2', 3', 5'-tri-O-butyryl uridine. 26. A method as recited in claim 25 wherein said acyl derivative of uridine is 2', 3', 5'-tri-acetyl uridine. 27. A method as in claim 26 wherein said acyl derivative of uridine is administered orally. 28. A method as in claim 22 wherein said acyl derivative of uridine is administered in a dose of 15-4500 mg. 29. A method as in claim 28 wherein said acyl derivative of uridine is 2', 3', 5'-tri-acetyl uridine, and said dose is administered 1-3 times per day. 30. A method for treating cirrhosis of the liver, comprising administering to an animal in need of such treatment a composition sufficient in an amount to effect said treatment, said composition comprising an acyl derivative of uridine having the formula (I) ##STR8## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a carboxylic acid selected from the group consisting of glycolic acid, pyruvic acid, lactic acid, enolpyruvic acid, an amino acid, a fatty acid of 2 to 22 carbon atoms, lipoic acid, pantothenic acid, succinic acid, fumaric acid, adipic acid, acetoacetic acid, p-aminobenzoic acid, betahydroxybutyric acid, orotic acid, and creatine, provided that at least one of said R substituents is not hydrogen, or a pharmaceutically acceptable salt thereof. 31. A method as recited in claim 30 wherein said acyl derivative of uridine is administered orally. 32. A method as in claim 30 wherein said acyl derivative of uridine has the formula (I) wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a fatty acid of 2 to 22 carbon atoms, provided that at least one of said R substituents is not hydrogen. 33. A method as recited in claim 32 wherein said acyl derivative of uridine is selected from the group consisting of 2', 3', 5'-tri-O-acetyl uridine, 2', 3', 5'-tri-O-propionyl uridine, and 2', 3', 5'-tri-O-butyryl uridine. 34. A method as recited in claim 33 wherein said acyl derivative of uridine is 2', 3', 5'-tri-acetyl uridine. 35. A method as in claim 34 wherein said acyl derivative of uridine is administered orally. 36. A method as in claim 30 wherein said acyl derivative of uridine is administered in a dose of 15-4500 mg. 37. A method as in claim 30 wherein said acyl derivative of uridine is 2', 3', 5'-tri-acetyl uridine, and said dose is administered 1-3 times per day. 38. A method as recited in claim 14, 22, or 30 wherein said administering step further comprises administering to an animal an effective amount of a composition comprising an acyl derivative of cytidine having the formula (III) ##STR9## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is an acyl radical of a carboxylic acid selected from the group consisting of glycolic acid, pyruvic acid, lactic acid, enolpyruvic acid, an amino acid, a fatty acid of 2 to 22 carbon atoms, lipoic acid, pantothenic acid, succinic acid,. fumaric acid, adipic acid, acetoacetic acid, p-aminobenzoic acid, betahydroxybutyric acid, orotic acid, and creatine, or a pharmaceutically acceptable salt thereof. 39. A method of claim 38, wherein said administering step comprises administering at least one acyl derivative of cytidine selected from the group consisting of 2', 3', 5'-tri-O-propionyl cytidine, and 2', 3', 5'-tri-O-butyryl cytidine, and at least one acyl derivative of uridine selected from the group consisting of 2', 3', 4'-tri-O-acetyl uridine, 2', 3', 5'-tri-O-propionyl uridine, and 2', 3', 5'-tri-O-butyryl uridine. 40. A method of claim 38, wherein the dose of each acyl derivative of uridine is 15-4500 mg and the dose of each acyl derivative of cytidine is 15-4500 mg. 41. A method for treating cardiac insufficiency, comprising administering to an animal in need of such treatment a composition in an amount to effect said treatment, said composition comprising an acyl derivative of cytidine, having the formula (III) ##STR10## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is a acyl radical of a carboxylic acid selected from the group consisting of glycolic acid, pyruvic acid, lactic acid, enolpyruvic acid, an amino acid, a fatty acid of 2 to 22 carbon atoms, lipoic acid, pantothenic acid, succinic acid, fumaric acid, adipic acid, acetoacetic acid, p-aminobenzoic acid, betahydroxybutyric acid, orotic acid, and creatine, provided that at least one of said R substituents is not hydrogen, or a pharmaceutically acceptable salt thereof. 42. A method as recited in claim 41 wherein said acyl derivative of cytidine is administered orally. 43. A method as in claim 41 wherein said acyl derivative of cytidine has the formula (III) wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a fatty acid of 2 to 22 carbon atoms, provided that at least one of said R substituents is not hydrogen. 44. A method as recited in claim 43 wherein said acyl derivative of cytidine is selected from the group consisting of 2', 3', 5'-tri-O-acetyl cytidine, 2', 3', 5'-tri-O-propionyl cytidine, and 2', 3', 5'-tri-O-butyryl cytidine. 45. A method as in claim 44 wherein said acyl derivative of cytidine is administered orally. 46. A method for treating myocardial infarction, comprising administering to an animal in need of such treatment a composition in an amount to effect said treatment, said composition comprising an acyl derivative of cytidine, having the formula (III) ##STR11## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is a acyl radical of a carboxylic acid selected from the group consisting of glycolic acid, pyruvic acid, lactic acid, enolpyruvic acid, an amino acid, a fatty acid of 2 to 22 carbon atoms, lipoic acid, pantothenic acid, succinic acid, fumaric acid, adipic acid, acetoacetic acid, p-aminobenzoic acid, betahydroxybutyric acid, orotic acid, and creatine, provided that at least one of said R substituents is not hydrogen, or a pharmaceutically acceptable salt thereof. 47. A method as recited in claim 46 wherein said acyl derivative of cytidine is administered orally. 48. A method as in claim 46 wherein said acyl derivative of cytidine has the formula (III) wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a fatty acid of 2 to 22 carbon atoms, provided that at least one of said R substituents is not hydrogen. 49. A method as recited in claim 48 wherein said acyl derivative of cytidine is selected from the group consisting of 2', 3', 5'-tri-O-acetyl cytidine, 2', 3', 5'-tri-O-propionyl cytidine, and 2', 3', 5'-tri-O-butyryl cytidine. 50. A method as in claim 49 wherein said acyl derivative of cytidine is administered orally. 51. A method for treating cirrhosis of the liver, comprising administering to an animal in need of such treatment a composition in an amount to effect said treatment, said composition comprising an acyl derivative of cytidine, having the formula (III) ##STR12## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is a acyl radical of a carboxylic acid selected from the group consisting of glycolic acid, pyruvic acid, lactic acid, enolpyruvic acid, an amino acid, a fatty acid of 2 to 22 carbon atoms, lipoic acid, pantothenic acid, succinic acid, fumaric acid, adipic acid, acetoacetic acid, p-aminobenzoic acid, betahydroxybutyric acid, orotic acid, and creatine, provided that at least one of said R substituents is not hydrogen, or a pharmaceutically acceptable salt thereof. 52. A method as recited in claim 51 wherein said acyl derivative of cytidine is administered orally. 53. A method as in claim 51 wherein said acyl derivative of cytidine has the formula (III) wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same or different and each is hydrogen or an acyl radical of a fatty acid of 2 to 22 carbon atoms, provided that at least one of said R substituents is not hydrogen. 54. A method as recited in claim 52 wherein said acyl derivative of cytidine is selected from the group consisting of 2', 3', 5'-tri-O-acetyl cytidine, 2', 3', 5'-tri-O-propionyl cytidine, and 2', 3', 5'-tri-O-butyryl cytidine. 55. A method as in claim 54 wherein said acyl derivative of cytidine is administered orally. 56. A method as in claim 14 wherien said composition further comprises a pharmaceutically acceptable carrier. 57. A method as in claim 22 wherein said composition further comprises a pharmaceutically acceptable carrier. 58. A method as in claim 30 wherein said composition further comprises a pharmaceutically acceptable carrier. 59. A method as in claim 41 wherein said composition further comprises a pharmaceutically acceptable carrier. 60. A method as in claim 46 wherein said composition further comprises a pharmaceutically acceptable carrier. 61. A method as in claim 51 wherein said composition further comprises a pharmaceutically acceptable carrier. |