Claims for Patent: 6,573,296

Summary for Patent: 6,573,296

Title:	Therapeutic quassinoid preparations with antineoplastic, antiviral, and herbistatic activity
Abstract:	The present invention includes purified and isolated quassinoids and synthetically derived quassinoid analogs based on a picrasane carbon skeleton. Novel sidechains at C-15 incorporating water solubilizing agents such as glycine are discussed. Therapeutic methods taking advantage of anticancer, antiviral, and herbistatic properties of these quassinoids are disclosed, including use against solid tumors and human immunodeficiency virus infected cells.
Inventor(s):	Grieco; Paul A. (Gosport, IN), Morre; D. James (West Lafayette, IN), Corbett; Thomas H. (Gross Pointe Park, MI), Valeriote; Frederick A. (Utica, MI)
Assignee:	Advanced Research and Technology Institute, Inc. (Indianapolis, IN)
Application Number:	09/293,606
Patent Claims:	1. A therapeutic composition comprising a compound represented by the formula: ##STR14## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble side chain, and Y is a side chain comprising lipids, nucleic acids, derivatized polymeric substances which have from 1 to about 1,000 monomeric units and which enhance the impermeance of said compound, immunoglobulins, growth hormones, insulin, interferons, plasma albumin, fibrinogen, plasminogen activator, heparin, chondroitin, sulfate, soybean trypsin inhibitor, L-asparaginase, and ribonuclease, wherein any of the foregoing optionally is attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage and a pharmaceutically effective carrier therefor, with the proviso that said compound is not glaucarubinone, castelanone, soularubinone, or simalikalactone D. 2. A method of treating a non-retroviral viral infection in a host comprising the steps of administering to said host a compound represented by the formula: ##STR15## wherein R.sub.1 represents a hydroxyl, R.sub.2 and R.sub.4 represent double bonded oxygen, R.sub.3 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble side chain, and Y is a side chain comprising hydrogen, oxygen, halogen, hydroxyl, ester, carbonyl, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances which have from 1 to about 1,000 monomeric units and which enhance the impermeance of said compound, immunoglobulins, growth hormones, insulin, interferons, plasma albumin, fibrinogen, plasminogen activator, heparin, chondroitin, sulfate, soybean trypsin inhibitor, L-asparaginase, ribonuclease, and protein, wherein any of the foregoing optionally is attached to the C-15 carbon by an ether, ester. carbonyl, or glycosidic linkage, with the proviso that said compound is not chaparrinone, glaucarubolone, glaucarubinone, castelanone, soularubinone, or simalikalactone D. 3. A method according to claim 2 wherein Y comprises an ester sidechain represented by the formula ##STR16## wherein R.sub.5, R.sub.6, and R.sub.7 represent hydrogen, halogen, methyl, ethyl, alkyl, aryl, hydroxyl, carboxyl, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, protein, and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage. 4. A method according to claim 3, wherein R.sub.5 represents a methyl group, R.sub.6 represents an ethyl group, and R.sub.7 represents a hydroxyl group. 5. A method according to claim 2, wherein Y represents a hydroxyl group. 6. A method according to claim 2, wherein Y represents hydrogen. 7. A method according to claim 2 wherein Y comprises an ester sidechain represented by the formula ##STR17## wherein R.sub.5, R.sub.6, and R.sub.7 represent hydrogen, halogen, methyl, ethyl, alkyl, aryl, hydroxyl, carboxyl, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, protein, and any of the foregoing attached to the central carbon by an ether, ester, carbonyl, or glycosidic linkage. 8. A method according to claim 7, wherein R.sub.5 represents an ethyl group, R.sub.6 represents an ethyl group, and R.sub.7 represents a hydroxyl group. 9. A method of treating a viral infection in a host comprising the steps of administering to said host an antiviral effective amount of a compound represented by the formula: ##STR18## wherein R.sub.1 represents a hydroxyl, R.sub.2 and R.sub.4 represent double bonded oxygen, R.sub.3 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and Y is a sidechain comprising hydrogen, oxygen, halogen, hydroxyl, ester, carbonyl, alkyl, hydroxyalkyl, aryl, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances which have from 1 to about 1,000 monomeric units and which enhance the impermeance of said compound, immunoglobulins, growth hormones, insulin, interferons, plasma albumin, fibrinogen, plasminogen activator, heparin, chondroitin, sulfate, soybean trypsin inhibitor, L-asparaginase, ribonuclease, and protein, wherein any of the foregoing optionally is attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage, with the proviso that said compound is not chaparrinone, glaucarubolone, glaucarubinone, castelanone, soularubinone, or simalikalactone D. 10. A method according to claim 9 wherein Y comprises an ester sidechain represented by the formula ##STR19## wherein R.sub.5, R.sub.6, and R.sub.7 represent hydrogen, halogen, methyl, ethyl, alkyl, aryl, hydroxyl, carboxyl, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, protein, and any of the foregoing attached to the central carbon by an ether, ester, carbonyl, or glycosidic linkage. 11. A method according to claim 10, wherein R.sub.5 represents a methyl group, R.sub.6 represents hydrogen, and R.sub.7 represents an ethyl group. 12. A method of treating a viral infection in a host comprising the step of administering to said host an antiviral effective amount of a composition according to claim 1. 13. A therapeutic composition for treatment of viral diseases comprising an antiviral effective amount of a compound represented by the formula: ##STR20## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble side chain, R.sub.2 and R.sub.4 represent double bonded oxygen, R.sub.3 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble side chain, and Y is a side chain comprising hydrogen, oxygen, halogen, hydroxyl, ester, carbonyl, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glycosaceharides, water soluble sidechains, amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances which have from 1 to about 1,000 monomeric units and which enhance the impermeance of said compound, immunoglobulins, growth hormones, insulin, interferons, plasma albumin, fibrinogen, plasminogen activator, heparin, chondroitin, sulfate, soybean trypsin inhibitor, L-asparaginase, ribonuclease, and protein, wherein any of the foregoing optionally is attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage and a pharmaceutically effective carrier therefor, with the proviso that said compound is not chaparrinone, glaucarubolone, glaucarubinone, castelanone, soularubinone, or simalikalactone D. 14. The therapeutic composition of claim 13, wherein Y includes a water soluble sidechain selected from the group consisting of dextrans, dextrins, cyclodextrins, polyethyleneglycols, polymers of ethyleneglycol, polymers of propyleneglycol, carbohydrate polymers, carboxymethylcellulose, polyamines, polyglutamine, N-(2-hydroxypropyl)methacrylamide copolymers, polyoxamines, polyoxyethylene block polymers, and polyoxypropylene block polymers. 15. The therapeutic composition of claim 13, wherein Y includes a protein selected from the group consisting of: antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease. 16. A method of treating a viral infection in a host comprising the step of administering to said host an antiviral effective amount of a composition according to claim 13. 17. The method of claim 9, wherein Y includes a water soluble sidechain selected from the group consisting of dextrans, dextrins, cyclodextrins, polyethyleneglycols, polymers of ethyleneglycol, polymers of propyleneglycol, carbohydrate polymers, carboxymethylcellulose, polyamines, polyglutamine, N-(2-hydroxypropyl)methacrylamide copolymers, polyoxamines, polyoxyethylene block polymers, and polyoxypropylene block polymers. 18. The method of claim 9, wherein Y includes a protein selected from the group consisting of antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease. 19. A therapeutic composition comprising a compound represented by the formula: ##STR21## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulib, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and wherein Y includes a sidechain selected from the group consisting of dextrans, dextrins, cyclodextrins, polyethyleneglycols, polymers of ethyleneglycol, polymers of propyleneglycol, carboxymethylcellulose, polyamines, polyglutamine, N-(2-hydroxypropyl)methacrylamide copolymers, polyoxamines, polyoxyethylene block polymers, and polyoxypropylene block polymers, wherein any of the foregoing optionally is attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage and a pharmaceutically effective carrier therefor. 20. A therapeutic composition comprising a compound represented by the formula: ##STR22## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and wherein Y includes a protein selected from the group consisting of antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease, wherein any of the foregoing optionally is attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage and a pharmaceutically effective carrier therefor. 21. A method of treating a viral infection in a host comprising the steps of administering to said host a compound represented by the formula: ##STR23## wherein R.sub.1 represents a hydroxyl, R.sub.2 and R.sub.4 represent double bonded oxygen, R.sub.3 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and Y includes a water soluble sidechain selected from the group consisting of dextrans, dextrins, cyclodextrins, polyethyleneglycols, polymers of ethyleneglycol, polymers of propyleneglycol, carbohydrate polymers, carboxymethylcellulose, polyamines, polyglutamine, N-(2-hydroxypropyl)methacrylamide copolymers, polyoxamines, polyoxyethylene block polymers, and polyoxypropylene block polymers, wherein any of the foregoing optionally is attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage. 22. A method of treating a viral infection in a host comprising the steps of administering to said host a compound represented by the formula: ##STR24## wherein R.sub.1 represents a hydroxyl, R.sub.2 and R.sub.4 represent double bonded oxygen, R.sub.3 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and Y includes a protein selected from the group consisting of antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease, wherein any of the foregoing optionally is attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage. 23. A method of treating a viral infection in a host comprising the steps of administering to said host a compound represented by the formula: ##STR25## wherein R.sub.1 represents a hydroxyl, R.sub.2 and R.sub.4 represent double bonded oxygen, R.sub.3 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble side chain, and Y is a side chain comprising cycloalkanes, cycloalkenes, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances which have from 1 to about 1,000 monomeric units and which enhance the impermeance of said compound, immunoglobulins, growth hormones, insulin, interferons, plasma albumin, fibrinogen, plasminogen activator, heparin, chondroitin, sulfate, soybean trypsin inhibitor, L-asparaginase, ribonuclease, and protein, wherein any of the foregoing optionally is attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage, with the proviso that said compound is not chaparrinone, glaucarubolone, glaucarubinone, castelanone, soularubinone, or simalikalactone D. 24. A method according to claim 23, further comprising the step of contacting HIV infected cells with said pharmaceutically active composition. 25. A method of treating a viral infection in a host comprising the steps of administering to said host a compound represented by the formula: ##STR26## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble side chain, and Y is a side chain comprising oxygen, halogen, carbonyl, carboxyl, aryl, cycloalkanes, cycloalkenes, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances which have from 1 to about 1,000 monomeric units and which enhance the impermeance of said compound, immunoglobulins, growth hormones, insulin, interferons, plasma albumin, fibrinogen, plasminogen activator, heparin, chondroitin, sulfate, soybean trypsin inhibitor, L-asparaginase, ribonuclease, and protein, wherein any of the foregoing optionally is attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage and a pharmaceutically effective carrier therefor, with the proviso that said compound is not glaucarubinone, castelanone, soularubinone, or simalikalactone D.

Details for Patent 6,573,296

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2015-11-03