Claims for Patent: 6,462,041

Summary for Patent: 6,462,041

Title:	Gambogic acid, analogs and derivatives as activators of caspases and inducers of apoptosis
Abstract:	The present invention is directed to gambogic acid, analogs and derivatives thereof, represented by the general Formulae I-III: ##STR1## wherein R.sub.1 -R.sub.5 are defined herein. The present invention also relates to the discovery that compounds having Formula I-III are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled cell growth and spread of abnormal cells occurs.
Inventor(s):	Cai; Sui Xiong (San Diego, CA), Zhang; Han-Zhong (San Diego, CA), Wang; Yan (San Diego, CA), Tseng; Ben (San Diego, CA), Kasibhatla; Shailaja (San Diego, CA), Drewe; John A. (Costa Mesa, CA)
Assignee:	Cytovia, Inc. (San Diego, CA)
Application Number:	09/495,120
Patent Claims:	1. A method of inducing cell apoptosis in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound having one of the Formulae I-III: ##STR103## or a pharmacuetically acceptable salt or prodrug thereof, wherein: the dotted lines are single bonds, double bonds or epoxy groups; X together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; Y together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; R.sub.1 is formyl, methylenehydroxy, carboxy, acyl (R.sub.a CO), optionally substituted alkoxycarbonyl (R.sub.a OCO), optionally substituted alkylthiocarbonyl, optionally substituted aminocarbonyl (carbamyl, R.sub.b R.sub.c NCO) or hydroxyaminocarbonyl, where R.sub.a is optionally substituted lower alkyl; R.sub.b and R.sub.c are independently hydrogen, optionally substituted heteroalkyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted lower aralkyl groups; or R.sub.b and R.sub.a may be taken together with the attached N to form an optionally substituted, saturated or partially saturated 5-7 membered heterocyclo group; R.sub.2 is hydrogen, optionally substituted alkyl, acyl (R.sub.a CO), carbamyl (R.sub.b R.sub.c NCO) or sulfonyl (R.sub.d SO.sub.2), where R.sub.a, R.sub.b, and R.sub.a are defined above; R.sub.d is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted lower aralkyl groups; R.sub.3 is hydrogen or prenyl; R.sub.4 is hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, alkoxy, alkylthio or amino; and R.sub.5 is hydrogen, optionally substituted alkyl, acyl (R.sub.a CO), carbamyl (R.sub.b R.sub.c NCO) or sulfonyl (R.sub.d SO.sub.2), where R.sub.a, R.sub.b, R.sub.c and R.sub.d are defined above; with the provisos that when said mammal has cancer, then (a) said compound is not gambogic acid, isogambogic acid, morellinol, isomorellinol or gambogin, (b) said compound is of Formula I or II, and (c) R.sub.3 is prenyl. 2. The method of claim 1, wherein the dotted lines between C-9 and C-10 of a compound of Formula I or III represent a double bond, R.sub.4 is not a cycloalkyl group, the other dotted lines are not epoxy groups, and R.sub.b and R.sup.c are not heteroalkyl groups. 3. A method according to claim 1, wherein R.sub.1 is formyl, acetyl, propionyl, carboxy, methoxycarbonyl, ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N'-piperazinylcarbonyl, 2(dimethylamino)-ethylcarbamyl or N-morpholinylcarbonyl, and the dotted lines represent double bonds. 4. A method according to claim 1, wherein R.sub.2 is hydrogen, formyl, acetyl, dimethylcarbamyl, diethylcarbamyl, 2-(dimethylamino)ethyl-carbamyl, N-piperidinylcarbonyl, N-methyl-N'-piperazinylcarbonyl, N-morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, methyl, ethyl, 2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl, or 2-(diethylamino)ethyl, and the dotted lines represent double bonds. 5. A method according to claim 1, wherein R.sub.4 is methyl, ethyl, phenyl, chloro, bromo, hydroxy, hydrogen, methoxy, ethoxy, methylthio, ethylthio, butylthio, dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, N-methylpiperazinyl, 2-(dimethylamino)ethylamino or morpholinyl, and the dotted lines represent double bonds. 6. A method according to claim 1, wherein R.sub.5 is hydrogen, acetyl, dimethylcarbamyl, diethylcarbamyl, 2-(dimethylamino)ethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N'-piperazinylcarbonyl, N-morpholinyl-carbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, methyl, ethyl, 2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl, or 2-(diethylamino)ethyl. 7. The method according to claim 1, wherein said compound is selected from the group consisting of: Methyl gambogate ester; 9,10-Dihydrogambogyl (4-methylpiperazine); 9,10-Dihydrogambogyl (2-dimethylaminoethylamine); 9,10-Dihydro-12-hydroxygambogic acid; Gambogyl diethylamine; Gambogyl dimethylamine; Gambogyl amine; Gambogyl hydroxyamine; Gambogyl piperidine; 6-Methoxy-gambogic acid; 6-(2-Dimethylaminoethoxy)-gambogic acid; 6-(2-Piperidinylethoxy)-gambogic acid; 6-(2-Morpholinylethoxy)-gambogic acid; 6-Methoxy-gambogyl piperidine; Gambogyl morpholine; Gambogyl (2-dimethylaminoethylamine); 9,10-Dihydro-10-morpholinyl-gambogyl morpholine; 9,10-Dihydro-10-morpholinyl-gambogyl piperidine; 9,10-Dihydro-10-(4-methylpiperazinyl)-gambogyl piperidine; 9,10-Dihydro-10-(4-methylpiperazinyl)-gambogyl morpholine; 9,10-Dihydro-10-piperidinyl-gambogyl piperidine; 9,10-Dihydro-10-(4-methylpiperazinyl)-gambogyl (4-methylpiperazine); 10-Cyclohexyl-9,10-dihydrogambogic acid; 9,10-Dihydro-10-methyl gambogic acid; Gambogyl (4-methylpiperazine); Methyl-6-Methoxy-gambogate; 9,10-Dihydro-10-methoxy-gambogic acid; 10-Butylthio-9,10-dihydrogambogic acid; 9,10-Dihydro-10-(4-methylpiperazinyl)-gambogic acid; 9,10-Dihydro-10-pyrrolidinyl-gambogic acid; Methyl-9,10-dihyrdro-10-morpholinyl-gambogate; 9,10-Dihydro-10-piperidinyl-gambogic acid; 9,10-Dihydro-10-morpholinyl-gambogic acid; N-(2-Gambogylamido-ethyl)biotinamide; Gambogyl (2-(4-morpholinyl)ethylamine); 9,10-Epoxygambogic acid; Gambogyl (4-(2-pyridyl)piperazine); 9,10-Dihydro-10-(4-(2-pyridyl)piperazinyl)gambogyl (4-(2-pyridyl)piperazine); 6-Acetylgambogic acid; 9,10-Dihydro-10-(4-(2-pyridyl)piperazinyl)gambogic acid; 8-(Gambogylamido)octanoic acid; 6-(Gambogylamido)hexanoic acid; 12-(Gambogylamido)dode canoic acid ; 9,10-Dihydro-10-methoxy-gambogyl piperidine; Gambogyl (4-(2-pyrimidyl)piperazine); Gambogyl (bis(2-pyridylmethyl)amine); Gambogyl (N-(3-pyridyl)-N-(2-hydroxybenzyl)amine); Gambogyl (4-benzylpiperazine); Gambogyl (4-(3,4-methylenedioxybenzyl)piperazine); Gambogyl (-methyl-5-(methylamino)-3-oxapentylamine); Gambogyl (N-methyl-8-(methylamino)-3,6-dioxaoctylamine); Gambogyl (N-ethyl-2-(ethylamino)ethylamine); Gambogyl (4-isopropylpiperazine); Gambogyl (4-cyclopentylpiperazine); Gambogyl (N-(2-oxo-2-ethoxyethyl)-(2-pyidyl)methylamine); Gambogyl (2,5-dimethylpiperazine); Gambogyl (3,5-dimethylpiperazine); Gambogyl (4-(4-acetylphenyl)piperazine); Gambogyl (4-ethoxycarbonylpiperazine); Gambogyl (4-(2-oxo-2-pyrrolidylethyl)piperazine); Gambogyl (4-(2-hydroxyethyl)piperazine); Gambogyl (N-methyl-2-(methylamino)ethylamine); Gambogyl (N-methyl-2-(benzylamino)ethylamine); Gambogyl (N-methyl-(6-methyl-2-pyridyl)methylamine); Gambogyl (N-ethyl-2-(2-pyridyl)ethylamine); Gambogyl (N-methyl-(2-pyridyl)methylamine); Gambogyl (N-methyl-4-(3-pyridyl)butylamine); Gambogyl (bis(3-pyridylmethyl)amine); Gambogyl (2,4-dimethyl-2-imidazoline); Gambogyl (4-methyl-homopiperazine); Gambogyl (4-(5-hydroxy-3-oxapentyl)piperazine); Gambogyl (3-dimethylaminopyrrolidine); Gambogyl ((2-furanyl)methylamine); Gambogyl (2-hydroxy-1-methyl-2-phenylethylamine); Gambogyl (3,4,5-trimethoxybenzylamine); Gambogyl (2-(.sup.2 -methoxyphenyl)ethylamine); Gambogyl (2-methoxybenzylamine); Gambogyl (3,4-methylenedioxybenzylamine); Gambogyl (2-(2,5-dimethoxyphenyl)ethylamine); Gambogyl (2-(3-methoxyphenyl)ethylamine); Gambogyl (3-(piperidinyl)propylamine); Gambogyl (2-(piperidinyl)ethylamine); Gambogyl (3,4-dimethoxybenzylamine); Gambogyl ((2-tetrahydrofuranyl)methylamine); Gambogyl ((N-ethyl-2-pyrrolidinyl)methylamine); Gambogyl (2-diethylaminoethylamine); Gambogyl (2,2-dimethyl-3-dimethylaminopropylamine); Gambogyl ((N-ethoxycarbonyl-4-piperidinyl)amine); Gambogyl (2-carbamylpyrrolidine); Gambogyl (3-(homopiperidinyl)propylamine); Gambogyl ((N-benzyl-4-piperidinyl)amine); Gambogyl (2-(4-methoxyphenyl)ethylamine); Gambogyl (4-oxa-hex-5-enylamine); Ganbogyl (6-hydroxyhexylamine); Gambogyl (2-(3,5-dimethoxyphenyl)ethylamine); Gambogyl (3,5-dimethoxybenzylamine); and Gambogyl (2-carbamyl-2-(4-hydroxyphenyl)ethylamine). 8. A method for treating cancer, comprising administering to an animal in need of such treatment an effective amount of a compound having the Formula I or II: ##STR104## or a pharmacuetically acceptable salt or prodrug thereof, wherein: the dotted lines are single bonds or epoxy groups; X together with the attache carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; Y together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; R.sub.1 is formyl, methylenehydroxy, carboxy, acyl (R.sub.a CO), optionally substituted alkoxycarbonyl (R.sub.a OCO), optionally substituted alkylthiocarbonyl, optionally substituted aminocarbonyl (carbamyl, R.sub.b R.sub.c NCO) or hydroxyaminocarbonyl, where R.sub.a is optionally substituted lower alkyl; R.sub.b and R.sub.a are independently hydrogen, optionally substituted heteroalkyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted lower aralkyl groups; or R.sub.b and R.sub.c may be taken together with the attached N to form an optionally substituted, saturated or partially saturated 5-7 membered heterocyclo group; R.sub.2 is hydrogen, optionally substituted alkyl, acyl (R.sub.a CO), carbamyl (R.sub.b R.sub.a NCO) or sulfonyl (R.sub.d SO.sub.2), where R.sub.a, R.sub.b and R.sub.c are defined above; R.sub.d is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted lower aralkyl groups; R.sub.3 is prenyl; and R.sub.4 is hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, alkoxy, alkylthio or amino; with the proviso that said compound is not gambogic acid, isogambogic acid, morellinol, isomorellinol or gambogin. 9. The method of claim 8, wherein in the compound the dotted lines between C-9 and C-10 of a compound of Formula I or III represent a double bond, R.sub.4 is not a cycloalkyl group, the other dotted lines are not epoxy groups, and R.sub.b and R.sub.c are not heteroalkyl groups. 10. The method according to claim 8, wherein the method is for treating Hodgkin's disease, non-Hodgkin's lymphomas, acute and chronic lymphocytic leukemias, multiple myeloma, neuroblastoma, breast carcinomas, ovarian carcinomas, lung carcinomas, Wilms'tumor, cervical carcinomas, testicular carcinomas, soft-tissue sarcomas, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinomas, chronic granulocytic leukemia, primary brain carcinomas, malignant melanoma, small-cell lung carcinomas, stomach carcinomas, colon carcinomas, malignant pancreatic insulinoma, malignant carcinoid carcinomas, malignant melanomas, choriocarcinomas, mycosis fungoides, head and neck carcinomas, osteogenic sarcoma, pancreatic carcinomas, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinomas, thyroid carcinomas, esophageal carcinomas, malignant hypercalcemia, cervical hyperplasia, renal cell carcinomas, endometrial carcinomas, polycythemia vera, essential thrombocytosis, adrenal cortex carcinomas, skin cancer, or prostatic carcinomas. 11. A method for the treatment of drug resistant cancer, comprising administering to an animal in need of such treatment an effective amount of a compound having one of the Formulae I-III: ##STR105## or a pharmaceutically acceptable salt or prodrug thereof, wherein: the dotted lines are single bonds, double bonds or epoxy groups; X together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; Y together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; R.sub.1 is formyl, methylenehydroxy, carboxy, acyl (R.sub.a CO), optionally substituted alkoxycarbonyl (R.sub.a OCO), optionally substituted alkylthiocarbonyl, optionally substituted aminocarbonyl (carbamyl, R.sub.b R.sub.c NCO) or hydroxyaminocarbonyl, where R.sub.a is optionally substituted lower alkyl; R.sub.b and R.sub.c are independently hydrogen, optionally substituted heteroalkyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted lower aralkyl groups; or R.sub.b and R.sub.c may be taken together with the attached N to form an optionally substituted, saturated or partially saturated 5-7 membered heterocyclo group; R.sub.2 is hydrogen, optionally substituted alkyl, acyl (R.sub.a CO), carbamyl (R.sub.b R.sub.c NCO) or sulfonyl (R.sub.d SO.sub.2), where R.sub.a, R.sub.b and R.sub.c are defined above; R.sub.d is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted lower aralkyl groups; R.sub.3 is hydrogen or prenyl; R.sub.4 is hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, alkoxy, alkylthio or amino; and R.sub.5 is hydrogen, optionally substituted alkyl, acyl (R.sub.a CO), carbamyl (R.sub.b R.sub.c NCO) or sulfonyl (R.sub.d SO.sub.2), where R.sub.a, R.sub.b, R.sub.c and R.sub.d are defined above; with the proviso that said compound is not gambogic acid, isogambogic acid, morellinol, or isomorellinol. 12. The method of claim 11, wherein in the compound the dotted lines between C-9 and C-10 of a compound of Formula I or III represent a double bond, R.sub.4 is not a cycloalkyl group, the other dotted lines are not epoxy groups, and R.sub.b and R.sub.c are not heteroalkyl groups. 13. The method according to claim 8 or 11, wherein said compound is administered together with at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent. 14. The method according to claim 13, wherein said known cancer chemotherapeutic agent is selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin.RTM. (trastuzumab), Rituxan.RTM. (rituximab) and alanosine. 15. The method according to claim 8 or 11, wherein said animal is also treated with radiation-therapy. 16. The method according to claim 8 or 11, wherein said compound(s) are administered after surgical treatment for cancer. 17. The method according to claim 1, wherein the mammal has an autoimmune disease. 18. The method according to claim 1, wherein the mammal has rheumatoid arthritis. 19. The method according to claim 1, wherein the mammal has inflammation or inflammatory bowel disease. 20. The method according to claim 1, wherein the mammal has a skin disease. 21. The method according to claim 20, wherein said skin disease is psoriasis. 22. A compound having the Formula I: ##STR106## or a pharmaceutically acceptable salt or prodrug thereof, wherein: the dotted lines are single bonds, double bonds or epoxy groups; X together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; Y together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; R.sub.1 is formyl, methylenehydroxy, carboxy, acyl (R.sub.a CO), optionally substituted alkoxycarbonyl (R.sub.a OCO), optionally substituted alkylthiocarbonyl, optionally substituted aminocarbonyl (carbamyl, R.sub.b R.sub.c NCO) or hydroxyaminocarbonyl, where R.sub.a is optionally substituted lower alkyl; R.sub.b and R.sub.c are independently hydrogen, optionally substituted heteroalkyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted lower aralkyl groups; or R.sub.b and R.sub.c may be taken together with the attached N to form an optionally substituted, saturated or partially saturated 5-7 membered heterocyclo group; R.sub.2 is hydrogen, optionally substituted alkyl, acyl (R.sub.a CO), carbamyl (R.sub.b R.sub.c NCO) or sulfonyl (R.sub.d SO.sub.2), where R.sub.a, R.sub.b and R.sub.c are defined above; R.sub.d is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted lower aralkyl groups; and R.sub.3 is prenyl; with the proviso that if R.sub.1 is methyl, carboxy or methoxycarbonyl, and X and Y are O, then R.sub.2 is not a hydrogen, acetyl or methyl. 23. A compound of claim 22, wherein the dotted lines between C-9 and C-10 represent a double bond, the other dotted lines are not epoxy groups, and R.sub.b and R.sub.a are not heteroalkyl groups. 24. A compound according to claim 22, wherein R.sub.1 is formyl, acetyl, propionyl, carboxy, methoxycarbonyl, ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N'-piperazinylcarbonyl, 2-(dimethylamino)-ethylcarbamyl or N-morpholinylcarbonyl, and the dotted lines represent double bonds. 25. A compound according to claim 22, wherein R.sub.2 is hydrogen, formyl, acetyl, dimethylcarbamyl, diethylcarbamyl, 2-(dimethylamino)ethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N'-piperazinylcarbonyl, N-morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, methyl, ethyl, 2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl, or 2-(diethylamino)ethyl, and the dotted lines represent double bonds. 26. A compound having the Formula II: ##STR107## or a pharmaceutically acceptable salt or prodrug thereof, wherein: the dotted lines are single bonds, double bonds or epoxy groups; X together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; Y together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; R.sub.1 is formyl, methylenehydroxy, carboxy, acyl (R.sub.a CO), optionally substituted alkoxycarbonyl (R.sub.a OCO), optionally substituted alkylthiocarbonyl, optionally substituted aminocarbonyl (carbamyl, R.sub.b R.sub.c NCO) or hydroxyaminocarbonyl, where R.sub.a is optionally substituted lower alkyl; R.sub.b and R.sub.c are independently hydrogen, optionally substituted heteroalkyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted lower aralkyl groups; or R.sub.b and R.sub.c may be taken together with the attached N to form an optionally substituted, saturated or partially saturated 5-7 membered heterocyclo group; R.sub.2 is hydrogen, optionally substituted alkyl, acyl (R.sub.a CO), carbamyl (R.sub.b R.sub.c NCO) or sulfonyl (R.sub.d SO.sub.2), where R.sub.a, R.sub.b and R.sub.c are defined above; R.sub.d is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted lower aralkyl groups; R.sub.3 is hydrogen or prenyl; and R.sub.4 is hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, alkoxy, alkylthio or amino; with the proviso that if R.sub.1 is formyl or carboxy, R.sub.2 is hydrogen, R.sub.3 is hydrogen, and X and Y are O, then R.sub.4 is not a hydrogen, hydroxy, methoxy or ethoxy. 27. A compound of claim 26, wherein R.sub.4 is not a cycloalkyl group, the dotted lines are not epoxy groups, and R.sub.b and R.sub.c are not heteroalkyl groups. 28. A compound according to claim 26, wherein R.sub.1 is formyl, acetyl, propionyl, carboxy, methoxycarbonyl, ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N'-piperazinylcarbonyl, 2-(dimethylamino)-ethylcarbamyl or N-morpholinylcarbonyl, and the dotted lines represent double bonds. 29. A compound according to claim 26, wherein R.sub.2 is hydrogen, formyl, acetyl, dimethylcarbamyl, diethylcarbamyl, 2-(dimethylamino)ethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N'-piperazinylcarbonyl, N-morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, methyl, ethyl, 2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl, or 2-(diethylamino)ethyl, and the dotted lines represent double bonds. 30. A compound according to claim 26, wherein R.sub.4 is methyl, ethyl, phenyl, chloro, bromo, hydroxy, hydrogen, methoxy, ethoxy, methylthio, ethylthio, butylthio, dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, N-methylpiperazinyl, 2-(dimethylamino)ethylamino or morpholinyl, and the dotted lines represent double bonds. 31. A compound according to claim 22, wherein said compound is selected from the group consisting of: Gambogyl dimethylamine; Gambogyl amine; Gambogyl diethylamine; Gambogyl hydroxyamine; Gambogyl piperidine; 6-Methoxy-gambogic acid; 6-(2-Dimethylaminoethoxy)-gambogic acid; 6-(2-Piperidinylethoxy)-gambogic acid; 6-(2-Morpholinylethoxy)-gambogic acid; 6-Methoxy-gambogyl piperidine; Gambogyl morpholine; Gambogyl (2-dimethylaminoethylamine); Gambogyl (4-methylpiperazine); N-(2-Gambogylamido-ethyl)biotinamide; Gambogyl (2-(4-morpholinyl)ethylamine); Gambogyl (4-(2-pyridyl)piperazine); 6-Acetylgambogic acid; N-Hydroxysuccinimidyl gambogate; 8-(Gambogylamido)octanoic acid; 6-(Gambogylamido)hexanoic acid; 12-(Gambogylamido)dodecanoic acid; N-Hydroxysuccinimidyl-8-(gambogylamido)octanoate; N-Hydroxysuccinimidyl-6-(gambogylamido)hexanoate; N-Hydroxysuccinimidyl-12-(gambogylamido)dodecanoate; Gambogyl (4-(2-pyrimidyl)piperazine); Gambogyl (bis(2-pyridylmethyl)amine); Gambogyl (N-(3-pyridyl)-N-(2-hydroxybenzyl)amine); Gambogyl (4-benzylpiperazine); Gambogyl (4-(3,4-methylenedioxybenzyl)piperazine); Gambogyl (N-methyl-5-(methylamino)-3-oxapentylamine); Gambogyl (N-methyl-8-(methylamino)-3,6-dioxaoctylarnine); Gambogyl (N-ethyl-2-(ethylamino)ethylamine); Gambogyl (4-isopropylpiperazine); Gambogyl (4-cyclopentylpiperazine); Gambogyl (N-(2-oxo-2-ethoxyethyl)-(2-pyridyl)methylamine); Gambogyl (2,5-dimethylpiperazine); Gambogyl (3,5-dimethylpiperazine); Gambogyl (4-(4-acetylphenyl)piperazine); Gambogyl (4-ethoxycarbonylpiperazine); Gambogyl (4-(2-oxo-2-pyrrolidylethyl)piperazine); Gambogyl (4-(2-hydroxyethyl)piperazine); Gambogyl (N-methyl-2-(methylamino)ethylamine); Gambogyl (N-methyl-2-(benzylamino)ethylamine); Gambogyl (N-methyl-(6-methyl-2-pyridyl)methylamine); Gambogyl (N-methy-2-(2-pyridyl)ethylamine); Gambogyl (N-methyl-(2-pyridyl)methylamine); Gambogyl (N-methyl-4-(3-pyridyl)butylamine); Gambogyl (bis(3-pyridylmethyl)amine); Gambogyl (2,4-dimethyl-2-imidazoline); Gambogyl (4-methyl-homopiperazine); Gambogyl (4-(5-hydroxy-3-oxapentyl)piperazine); Gambogyl (3-dimethylaminopyrrolidine); Gambogyl ((2-furanyl)methylamine); Gambogyl (2-hydroxy-1-methyl-2-phenylethylamine); Gambogyl (3,4,5-trimethoxybenzylamine); Gambogyl (2-(2-methoxyphenyl)ethylamine); Gambogyl (2-methoxybenzylamine); Gambogyl (3,4-methylenedioxybenzylamine); Gambogyl (2-(2,5-dimethoxyphenyl)ethylamine); Gambogyl (2-(3-methoxyphenyl)ethylamine); Gambogyl (3-(piperidinyl)propylamine); Gambogyl (2-(piperidinyl)ethylamine); Gambogyl (3,4-dimethoxybenzylamine); Gambogyl ((2-tetrahydrofuranyl)methylamine); Gambogyl ((N-ethyl-2-pyrrolidinyl)methylamine); Gambogyl (2-diethylaminoethylamine); Gambogyl (2,2-dimethyl-3-dimethylaminopropylamine); Gambogyl ((N-ethoxycarbonyl-4-piperidinyl)amine); Gambogyl (2-carbamylpyrrolidine); Gambogyl (3-(homopiperidinyl)propylamine); Gambogyl ((N-benzyl-4-piperidinyl)amine); Gambogyl (2-(4-methoxyphenyl)ethylamine); Gambogyl (4-oxa-hex-5-enylamine); Ganbogyl (6-hydroxyhexylamine); Gambogyl (2-(3,5-dimethoxyphenyl)ethylamine); Gambogyl (3,5-dimethoxybenzylamine); and Gambogyl (2-carbamyl-2-(4-hydroxyphenyl)ethylamine). 32. A compound according to claim 26, wherein said compound is selected from the group consisting of: 9,10-Dihydrogambogyl (4-methylpiperazine); 9,10-Dihydrogambogyl (dimethylamino)ethylamine; 9,10-Dihydro-1 2-hydroxygambogic acid; 9,10-Dihydro-10-(4-methylpiperazinyl)-gambogyl piperidine; 9,10-Dihydro-10-(4-methylpiperazinyl)-gambogyl morpholine; 9,10-Dihydro-10-piperidinyl-gambogyl piperidine; 9,10-Dihydro-10-(4-methylpiperazinyl)-gambogyl (4-methylpiperazine); 9,10-Dihydro-10-(4-methylpiperazinyl)-gambogic acid; 9,10-Dihydro-10-pyrrolidinyl-gambogic acid; Methyl-9,10-dihydro-10-morpholinyl-gambogate; 9,10-Dihydro-10-morpholinyl-gambogyl morpholine; 9,10-Dihydro-10-morpholinyl-gambogyl piperidine; 9,10-Dihydro-10-methoxy-gambogic acid; 10-Butylthio-9,10-dihydrogambogic acid; 9,10-Dihydro-10-piperidinyl-gambogic acid; 9,10-Dihydro-10-morpholinyl-gambogic acid; 10-Cyclohexyl-9,10-dihydro-gambogic acid; 9,10-Dihydro-10-methyl-gambogic acid; 9,10-Dihydro-10-methoxy-gambogyl piperidine; 9,10-Dihydro-10-(4-(2-pyridyl)piperazinyl)gambogyl (4-(2-pyridyl)piperazine); 9,10-Dihydro-10-(4-(2-pyridyl)piperazinyl)gambogic acid; and 9,10-Epoxygambogic acid. 33. A pharmaceutical composition, comprising a compound of claim 22 or 26, and a pharmaceutically acceptable carrier. 34. The pharmaceutical composition of claim 33, further comprising at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent. 35. The pharmaceutical composition of claim 34, wherein said known cancer chemotherapeutic agent is selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, caiptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea, thioguanine, meiphalan, chorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin.RTM. (trastuzumab), Rituxan.RTM. (rituximab) and alanosine. 36. The method of claim 1, wherein said compound is of Formula I. 37. The method of claim 36, wherein R.sub.3 is prenyl. 38. The method of claim 1, wherein said compound is of Formula II. 39. The method of claim 38, wherein R.sub.3 is prenyl. 40. The method of claim 1, wherein said compound is of Formula III. 41. The method of claim 40, wherein R.sub.3 is prenyl. 42. The method of claim 1, with the further proviso that said disorder is other than cancer, (a) said compound is not gambogic acid, isogambogic acid, morellinol, isomorellinol or gambogin, (b) the compound is of Formula I or II, and (c) R.sub.3 is prenyl. 43. The method of claim 1, wherein said disorder is other than cancer. 44. The method of claim 8, wherein said compound is of Formula I. 45. The method of claim 8, wherein said compound is of Formula II. 46. The method of claim 11, wherein said compound is of Formula I. 47. The method of claim 11, wherein said compound is of Formula II. 48. The method of claim 11, wherein (a) said compound is of Formula I or II, and (b) R.sub.3 is prenyl. 49. The compound of claim 26, wherein R.sub.3 is prenyl. 50. The compound of claim 26, wherein Y is O. 51. A method of inducing cell apoptosis in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound having the Formula I: ##STR108## or a pharmaceutically acceptable salt or prodrug thereof, wherein: the dotted lines are single bonds, double bonds or epoxy groups; X together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; Y together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; R.sub.1 is optionally substituted alkylthiocarbonyl, optionally substituted aminocarbonyl (carbamyl, R.sub.b R.sub.c NCO) or hydroxyaminocarbonyl, where R.sub.b and R.sub.c are independently hydrogen, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted lower aralkyl groups; or R.sub.b and R.sub.c may be taken together with the attached N to form an optionally substituted, saturated or partially saturated 5-7 membered heterocyclo group; and when at least one of X and Y together with the attached carbon is a methylene, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; then R.sub.1 is additionally optionally substituted lower alkyl, formyl, methylenehydroxy, carboxy, acyl (R.sub.a CO), or optionally substituted alkoxycarbonyl (R.sub.a OCO), where R.sub.a is optionally substituted lower alkyl; R.sub.2 is hydrogen, optionally substituted alkyl, acyl (R.sub.a CO), carbamyl (R.sub.b R.sub.c NCO) or sulfonyl (R.sub.d SO.sub.2), where R.sub.a, R.sub.b, and R.sub.c are defined above; R.sub.d is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted lower aralkyl groups; and R.sub.3 is hydrogen or prenyl. 52. A method of inducing cell apoptosis in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound having the Formula II: ##STR109## or a pharmaceutically acceptable salt or prodrug thereof, wherein: the dotted lines are single bonds, double bonds or epoxy groups; X together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; Y together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; R.sub.1 is optionally substituted alkylthiocarbonyl, optionally substituted aminocarbonyl (carbamyl, R.sub.b R.sub.c NCO) or hydroxyaminocarbonyl, where R.sub.b and R.sub.c are independently hydrogen, optionally substituted heteroalkyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted lower aralkyl groups; or R.sub.b and R.sub.c may be taken together with the attached N to form an optionally substituted, saturated or partially saturated 5-7 membered heterocyclo group; R.sub.2 is hydrogen, optionally substituted alkyl, acyl (R.sub.a CO), carbamyl (R.sub.b R.sub.c NCO) or sulfonyl (R.sub.d SO.sub.2), where R.sub.a, R.sub.b, and R.sub.c are defined above; R.sub.d is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted lower aralkyl groups; R.sub.3 is hydrogen or prenyl; and R.sub.4 is hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, alkoxy, alkylthio or amino. 53. A method of inducing cell apoptosis in a mammal in need thereof comprising administering to said mammal an effective amount of a compound having the Formula II: ##STR110## or a pharmaceutically acceptable salt or prodrug thereof, wherein: the dotted lines are single bonds, double bonds or epoxy groups; X together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; Y together with the attached carbon is a methylene, carbonyl, hydroxymethinyl, alkoxymethinyl, aminomethinyl, an oxime, a hydrazone, an arylhydrazone or semicarbazone; R.sub.1 is optionally substituted alkylthiocarbonyl, optionally substituted aminocarbonyl (carbamyl, R.sub.b R.sub.c NCO) or hydroxyaminocarbonyl, where R.sub.b and R.sub.c are independently hydrogen, optionally substituted heteroalkyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted lower aralkyl groups; or R.sub.b and R.sub.c may be taken together with the attached N to form an optionally substituted, saturated or partially saturated 5-7 membered heterocyclo group; R.sub.2 is hydrogen, optionally substituted alkyl, acyl (R.sub.a CO), carbamyl (R.sub.b R.sub.c NCO) or sulfonyl (R.sub.d SO.sub.2), where R.sub.a, R.sub.b, and R.sub.c are defined above; R.sub.d is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted lower aralkyl groups; R.sub.3 is hydrogen or prenyl; R.sub.4 is hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, alkoxy, alkylthio or amino; and when R.sub.4 is halogen, cycloalkyl, alkylthio or amino, then R.sub.1 additionally is optionally substituted lower alkyl, formyl, methylenehydroxy, carboxy, acyl (R.sub.a CO), or optionally substituted alkoxycarbonyl (R.sub.a OCO), where R.sub.a is optionally substituted lower alkyl. 54. The method of any one of claims 51-53, wherein said disorder is cancer.

Details for Patent 6,462,041

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2019-05-21
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2019-05-21
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2019-05-21
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2019-05-21
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2019-05-21
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2019-05-21