Therapeutic Quassinoid preparations with antineoplastic, antiviral, and herbistatic activity
AssigneesAdvanced Research and Technology Institute, Inc., Board of Governors of Wayne State University, Purdue Reseach Foundation
InventorsPaul A. Grieco, D. James Morre, Thomas H. Corbett, Frederick A. Valeriote
Life of this patent
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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.
Claims42
A compound characterized by the formula ##STR14## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or water soluble sidechain, and Y is a sidechain comprising hydrogen, alkyl (excluding holocanthone, castelanone and ailanthinone), hydroxyalkyl (excluding soularubinone and glaucarubinone), carboxyl (excluding glaucarubinone-2'-acetate), substituted aryl, alkenyl, cycloalkanes, cycloalkenes, glycosaccharides, water soluble sidechains 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,
- amino acid, peptide, polypeptide, protein selected from the group consisting of:
- antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease,
- and any of the foregoing attached by an ether, ester, carbonyl, or glycosidic linkage.
A therapeutic composition for treatment of viral diseases comprising a combination of a compound characterized by the formula ##STR15## wherein R.sub.1 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, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glycosaccharides, water soluble sidechains 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,
- amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances, naturally occurring macromolecules, protein selected from the group consisting of:
- antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease,
- and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage and a pharmaceutically acceptable carrier therefor.
A therapeutic preparation comprising a pharmaceutically effective carrier and a compound represented by the formula ##STR16## 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 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,
- amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances, naturally occurring macromolecules, protein selected from the group consisting of:
- antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase and ribonuclease,
- and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage.
A method for inhibiting plant growth comprising the steps of preparing a herbistat composition containing a quassinoid represented by the formula ##STR17## 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, naturally occurring macromolecules, protein, and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage, and
- contacting plants with said herbistatic composition to control plant growth rate.
A method for inhibiting plant growth comprising the steps of preparing a herbistat composition containing a quassinoid represented by the formula ##STR18## wherein R 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, naturally occurring macromolecules, protein, and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage and
- contacting plants with said herbistatic composition to control plant growth rate.
A method for treating solid tumors comprising the steps of preparing a pharmaceutically active composition containing a quassinoid represented by the formula ##STR20## 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, naturally occurring macromolecules, protein, and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage, and
- contacting the solid tumors with said pharmaceutically active composition.
A method for treating solid tumors comprising the steps of preparing a pharmaceutically active composition containing a quassinoid represented by the formula ##STR23## wherein R.sub.1 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, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glycosaccharides, water soluble sidechains 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,
- amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances, naturally occurring macromolecules, protein selected from the group consisting of:
- antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease,
- and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage and
- contacting the solid tumors with said pharmaceutically active composition.
A compound characterized by the formula ##STR24## wherein R.sub.1 represents hydrogen, oxygen, an alkyl having at least two carbons, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and Y is a sidechain comprising hydrogen, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, protein, and any of the foregoing attached by an ether, ester, carbonyl, or glycosidic linkage.
A compound characterized by the formula ##STR25## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or water soluble sidechain, and Y is a sidechain comprising hydrogen, carboxyl, aryl (excluding glaucarubolone-15-benzoate), cycloalkanes, cycloalkenes, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, protein, lipids, nucleic acids, derivatized polymeric substances, naturally occurring macromolecules, and any of the foregoing attached by an ether, ester, carbonyl, or glycosidic linkage.
A compound characterized by the formula ##STR26## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or water soluble sidechain, and Y is a sidechain comprising hydrogen, alkyl, hydroxyalkyl, carboxyl, substituted aryl, alkenyl, cycloalkanes, cycloalkenes, glycosaccharides, water soluble sidechains 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,
- amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances, naturally occurring macromolecules, protein selected from the group consisting of:
- antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease,
- and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage, with the proviso that said compound is not ailanthinone, glaucarubinone, chaparrinone, glaucarubolone, castelanone, soularubinone, holacanthone, glaucarubolone-15-benzoate, 2'-acetylglaucarubinone, or glaucarubolone-15-tiglate, and with the further proviso that said Y is not a C.sub.5 to C.sub.18 2-alkenoate or a C.sub.5 to C.sub.16 3-methylalkenoate.
A therapeutic preparation comprising a pharmaceutically effective carrier and a compound represented by the formula ##STR27## wherein R.sub.1 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 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,
- amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances, naturally occurring macromolecules, protein selected from the group consisting of:
- antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease,
- and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage, with the proviso that said compound is not ailanthinone, glaucarubinone, chaparrinone, glaucarubolone, castelanone, soularubinone, holacanthone, glaucarubolone-15-benzoate, 2'-acetylglaurarubinone, or glaucarubolone-15-tiglate, and with the further proviso that said Y is not a C.sub.5 to C.sub.18 2-alkenoate or a C.sub.5 to C.sub.16 3-methylalkenoate.
A method for treating solid tumors comprising the steps of preparing a pharmaceutically active composition containing a quassinoid represented by the formula ##STR28## wherein R.sub.1 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, naturally occurring macromolecules, protein, and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage, with the proviso that said quassinoid is not ailanthinone, glaucarubinone, chaparrinone, glaucarubolone, castelanone, soularubinone, holacanthone, glaucarubolone-15-benzoate, 2'-acetyglaucarubinone, or glaucarubolone-15-tiglate, and with the further proviso that said Y is not a C.sub.5 to C.sub.18 2-alkenoate or a C.sub.5 to C.sub.16 3-methylalkenoate, and
- contacting the solid tumors with said pharmaceutically active composition.
A method for treating solid tumors comprising the steps of preparing a pharmaceutically active composition containing a quassinoid represented by the formula ##STR31## wherein R.sub.1 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, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glycosaccharides, water soluble sidechains 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,
- amino acid, peptide, polypeptide, lipids, nucleic acids derivatized polymeric substances, naturally occurring macromolecules, protein selected from the group consisting of:
- antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease,
- and any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage, with the proviso that said quassinoid is not ailanthinone, glaucarubinone, chaparrinone, glaucarubolone, castelanone, soularubinone, holacanthone, glaucarubolone-15-benzoate, 2'-acetylglaucarubinone, or glaucarubolone-15-tiglate, and with the further proviso that said Y is not a C.sub.5 to C.sub.18 2-alkenoate or a C.sub.5 to C.sub.16 3-methylalkenoate, and
- contacting the solid tumors with said pharmaceutically active composition.
A compound characterized by the formula ##STR32## wherein R.sub.1 represents hydrogen, oxygen, an alkyl having at least two carbons, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and Y is a sidechain comprising hydrogen, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycosaccharides, water soluble sidechains, polymers, amino acid, peptide, polypeptide, protein, and any of the foregoing attached by an ether, ester, carbonyl, or glycosidic linkage, with the proviso that said quassinoid is not ailanthinone, glaucarubinone, chaparrinone, glaucarubolone, castelanone, soularubinone, holacanthone, glaucarubolone-15-benzoate, 2'-acetylglaucarubinone, or glaucarubolone-15tiglate, and with the further proviso that said Y is not a C.sub.5 to C.sub.18 2-alkenoate or a C.sub.5 to C.sub.16 3-methylalkenoate.
A compound characterized by the formula ##STR33## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or water soluble sidechain, and Y is a sidechain comprising hydrogen, carboxyl, aryl, cycloalkanes, cycloalkenes, glycosaccharides, water soluble sidechains, amino acid, polymers, peptide, polypeptide, protein, lipids, nucleic acids, derivatized polymeric substances, naturally occurring macromolecules, and any of the foregoing attached by an ether, ester, carbonyl, or glycosidic linkage, with the proviso that said quassinoid is not ailanthinone, glaucarubinone, chaparrinone, glaucarubolone, castelanone, soularubinone, holacanthone, glaucarubolone-15-benzoate, 2'-acetylglaucarubinone, or glaucarubolone-15-tiglate, and with the further proviso that said Y is not a C.sub.5 to C.sub.18 2-alkenoate or a C.sub.5 to C.sub.16 3-methylalkenoate.
Dependencies are inferred from the claim text.