Details for Patent: 6,060,459

Title:	Enhancing blood cell count with oxypurine nucleosides
Abstract:	The invention relates to certain oxypurine nucleosides, congeners of such oxypurine nucleosides, and acyl derivatives thereof, and compositions which contain at least one of these compounds. The invention also relates to methods of treating or preventing hematopoietic disorders and modifying hematopoiesis, and treating or preventing inflammatory diseases and bacterial infections by administering a compound or composition of the present invention to an animal.
Inventor(s):	von Borstel; Reid W. (Potomac, MD), Bamat; Michael K. (Potomac, MD), Hiltbrand; Bradley M. (Columbia, MD), Butler; James C. (Gaithersburg, MD), Shirali; Shyam (Gaithersburg, MD)
Assignee:	Pro-Neuron, Inc. (Gaithersburg, MD)
Filing Date:	Jun 05, 1995
Application Number:	08/465,016
Claims:	1. A method for treating or preventing cytopenia comprising administering to an animal a pharmaceutically effective amount of one or more compounds having the formula: ##STR29## where: R.sub.A =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkylphosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and R.sub.B =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and Z=H; OH; .dbd.O divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or NHR.sub.C where R.sub.C =H or an acyl radical of a carboxylic acid with 2 to 30 carbon atoms, or an alkyl radical with 2-30 carbon atoms, and L=H or OR.sub.D, where R.sub.D =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and M=H or OR.sub.E, where R.sub.E =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, a radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, with the proviso that at least one of L and M is H, and Q=H; a halogen; NHR.sub.F where R.sub.F is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; S divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; SR.sub.G where R.sub.G is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; O divalently bound to the carbon, in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or OR.sub.H where R.sub.H is H or an acyl or alkyl radical containing 1 to 10 carbon atoms, and the C--C bond between the 2' and 3' positions of the aldose moiety is optionally present, ##STR30## where Z=NHR.sub.C where R.sub.C =H or an acyl radical of a carboxylic acid with 2 to 30 carbon atoms, or an alkyl radical with 2-30 carbon atoms, and Q=H; a halogen; NHR.sub.F where R.sub.F is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; S divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; SR.sub.G where R.sub.G is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; O divalently bound to the carbon, in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen, or OR.sub.H where R.sub.H is H or an acyl or alkyl radical containing 1 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof. 2. A method as in claim 1 wherein said cytopenia is due to ionizing radiation. 3. A method as in claim 1 wherein said cytopenia is due to pharmaceutical drugs which reduce blood cell counts. 4. A method as in claim 1 wherein said cytopenia is due to antineoplastic agents. 5. A method as in claim 1 wherein said cytopenia is due to antiviral agents. 6. A method as in claim 1 wherein said cytopenia is due to AIDS. 7. A method as in claim 1 wherein said cytopenia is due to cancer. 8. A method as in claim 7 wherein prior to, during, or after said administering step is the step of administering irradiation or chemotherapy. 9. A method as recited in claim 1 wherein said cytopenia is anemia, neutropenia, thrombocytopenia, or lymphocytopenia. 10. A method as recited in claim 1 wherein said cytopenia is due to damaged bone marrow. 11. A method for modifying blood cell counts comprising administering to an animal a pharmaceutically effective amount of one or more compounds having the formula: ##STR31## where: R.sub.A =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkylphosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and R.sub.B =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and Z=H; OH; .dbd.O divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or NHR.sub.C where R.sub.C =H or an acyl radical of a carboxylic acid with 2 to 30 carbon atoms, or an alkyl radical with 2-30 carbon atoms, and L=H or OR.sub.D, where R.sub.D =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and M=H or OR.sub.E, where R.sub.E =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, a radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, with the proviso that at least one of L and M is H, and Q=H; a halogen; NHR.sub.F where R.sub.F is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; S divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; SR.sub.G where R.sub.G is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; O divalently bound to the carbon, in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or OR.sub.H where R.sub.H is H or an acyl or alkyl radical containing 1 to 10 carbon atoms, and the C--C bond between the 2' and 3' positions of the aldose moiety is optionally present, or the formula: ##STR32## where Z=NHR.sub.C where R.sub.C =H or an acyl radical of a carboxylic acid with 2 to 30 carbon atoms, or an alkyl radical with 2-30 carbon atoms, and Q=H; a halogen; NHR.sub.F where R.sub.F is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; S divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; SR.sub.G where R.sub.G is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; O divalently bound to the carbon, in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or OR.sub.H where R.sub.H is H or an acyl or alkyl radical containing 1 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof. 12. A method for treating or preventing infection comprising administering to an animal a pharmaceutically effective amount of one or more compounds having the formula: ##STR33## where: R.sub.A =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkylphosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and R.sub.B =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and Z=H; OH; .dbd.O divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or NHR.sub.C where R.sub.C =H or an acyl radical of a carboxylic acid with 2 to 30 carbon atoms, or an alkyl radical with 2-30 carbon atoms, and L=H or OR.sub.D, where R.sub.D =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and M=H or OR.sub.E, where R.sub.E =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, a radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, with the proviso that at least one of L and M is H, and Q=H; a halogen; NHR.sub.F where R.sub.F is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; S divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; SR.sub.G where R.sub.G is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; O divalently bound to the carbon, in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or OR.sub.H where R.sub.H is H or an acyl or alkyl radical containing 1 to 10 carbon atoms, and the C--C bond between the 2' and 3' positions of the aldose moiety is optionally present, or the formula: ##STR34## where Z=NHR.sub.C where R.sub.C =H or an acyl radical of a carboxylic acid with 2 to 30 carbon atoms, or an alkyl radical with 2-30 carbon atoms, and Q=H; a halogen; NHR.sub.F where R.sub.F is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; S divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; SR.sub.G where R.sub.G is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; O divalently bound to the carbon, in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or OR.sub.H where R.sub.H is H or an acyl or alkyl radical containing 1 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof. 13. A method for accelerating or improving recovery after bone marrow transplantation comprising administering to an animal a pharmaceutically effective amount of one or more compounds having the formula: ##STR35## where: R.sub.A =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkylphosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and R.sub.B =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and Z=H; OH; =O divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or NHR.sub.C where R.sub.C =H or an acyl radical of a carboxylic acid with 2 to 30 carbon atoms, or an alkyl radical with 2-30 carbon atoms, and L=H or OR.sub.D, where R.sub.D =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and M=H or OR.sub.E, where R.sub.E =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, a radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, with the proviso that at least one of L and M is H, and Q=H; a halogen; NHR.sub.F where R.sub.F is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; S divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; SR.sub.G where R.sub.G is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; O divalently bound to the carbon, in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or OR.sub.H where R.sub.H is H or an acyl or alkyl radical containing 1 to 10 carbon atoms, and the C--C bond between the 2' and 3' positions of the aldose moiety is optionally present, or the formula: ##STR36## where Z=NHR.sub.C where R.sub.C =H or an acyl radical of a carboxylic acid with 2 to 30 carbon atoms, or an alkyl radical with 2-30 carbon atoms, and Q=H; a halogen; NHR.sub.F where R.sub.F is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; S divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; SR.sub.G where R.sub.G is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; O divalently bound to the carbon, in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or OR.sub.H where R.sub.H is H or an acyl or alkyl radical containing 1 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof. 14. A method for inhibiting apoptosis of blood cells comprising administering to an animal a pharmaceutically effective amount of one or more compounds having the formula: ##STR37## where: R.sub.A =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkylphosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and R.sub.B =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and Z=H; OH; .dbd.O divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or NHR.sub.C where R.sub.C =H or an acyl radical of a carboxylic acid with 2 to 30 carbon atoms, or an alkyl radical with 2-30 carbon atoms, and L=H or OR.sub.D, where R.sub.D =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, an acyl radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, and M=H or OR.sub.E, where R.sub.E =H or an acyl radical of a carboxylic, alkylphosphonic, or alkylsulfonic acid, a radical of an alkyl phosphate or alkyl sulfate, or an alkyl radical, with 2 to 30 carbon atoms, with the proviso that at least one of L and M is H, and Q=H; a halogen; NHR.sub.F where R.sub.F is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; S divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; SR.sub.G where R.sub.G is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; O divalently bound to the carbon, in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or OR.sub.H where R.sub.H is H or an acyl or alkyl radical containing 1 to 10 carbon atoms, and the C--C bond between the 2' and 3' positions of the aldose moiety is optionally present, or the formula: ##STR38## where Z=NHR.sub.C where R.sub.C =H or an acyl radical of a carboxylic acid with 2 to 30 carbon atoms, or an alkyl radical with 2-30 carbon atoms, and Q=H; a halogen; NHR.sub.F where R.sub.F is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; S divalently bound to the carbon in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; SR.sub.G where R.sub.C is H or an acyl or alkyl radical containing 1 to 10 carbon atoms; O divalently bound to the carbon, in which case the adjacent carbon-nitrogen double bond is a single bond and an H is then attached to that nitrogen; or OR.sub.H where R.sub.H is H or an acyl or alkyl radical containing 1 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof.