Details for Patent: 6,605,599

Title:	Epothilone derivatives
Abstract:	The present invention relates to epothilone derivatives, having the following formula ##STR1## in which the variables G, W, Q, X, Y, B.sub.1, B.sub.2, Z.sub.1, Z.sub.2, and R.sub.1 -R.sub.7 are as defined herein, methods for the preparation of the derivatives and intermediates thereof.
Inventor(s):	Vite; Gregory D. (Titusville, NJ), Kim; Soong-Hoon (Lawrenceville, NJ), Borzilleri; Robert M. (Lawrenceville, NJ), Johnson; James A. (Lawrenceville, NJ)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Filing Date:	May 26, 1998
Application Number:	09/084,542
Claims:	1. A compound of the formula: ##STR50## wherein: Q is selected from the group consisting of: ##STR51## G is selected from the group consisting of alkyl; substituted alkyl; substituted aryl; a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; ##STR52## W is O or NR.sub.15 ; X is O or H, H; Y is selected from the group consisting of O; H, OR.sub.16 ; OR.sub.17, OR.sub.17 ; NOR.sub.18 ; H,NHOR.sub.19 ; H, NR.sub.20 R.sub.21 ; H, H; and CHR.sub.22 ; wherein OR.sub.17, OR.sub.17 can be a cyclic ketal; Z.sub.1 and Z.sub.2 are independently CH.sub.2 ; B.sub.1 and B.sub.2 are independently selected from the group consisting of OR.sub.24, OCOR.sub.25, and O--C(.dbd.O)--NR.sub.26 R.sub.27, and when B.sub.1 is OH and Y is OH, H, they can form a six-membered ring ketal or acetal; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.7, R.sub.13, R.sub.14, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.22, R.sub.26 and R.sub.27 are selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R.sub.1 and R.sub.2 are alkyl can be joined to form a cycloalkyl, and when R.sub.3 and R.sub.4 are alkyl can be joined to form a cycloalkyl; R.sub.6 is methyl; R.sub.9, R.sub.10, R.sub.16, R.sub.17, R.sub.24, R.sub.25 and R.sub.31 are selected from the group consisting of H, alkyl, and substituted alkyl; R.sub.11, R.sub.12, R.sub.28, R.sub.30, R.sub.32, and R.sub.33 are selected from the group consisting of H; alkyl; substituted alkyl; aryl; substituted aryl; cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C.sub.3 -C.sub.7 carbocyclic ring; and a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R.sub.8 is hydrogen or methyl; R.sub.15, R.sub.23 and R.sub.29 are selected from the group consisting of H; alkyl; substituted alkyl; aryl; substituted aryl; cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C.sub.3 -C.sub.7 carbocyclic ring; a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R.sub.32 C.dbd.O; R.sub.33 SO.sub.2 ; hydroxy; O-alkyl or O-substituted alkyl; or pharmaceutically acceptable salts thereof, hydrates, solvates or geometric, optical or stereoisomers thereof; with the proviso that compounds wherein W and X are both O; and R.sub.1, R.sub.2 and R.sub.7 are H; and R.sub.3, R.sub.4 and R.sub.6 are methyl; and R.sub.8 is H or methyl; and G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and Q is as defined above are excluded. 2. The compound of claim 1 wherein Q is ##STR53## X is O; Y is O; Z.sub.1, and Z.sub.2, are CH.sub.2 ; and W is NR.sub.15. 3. A compound selected from the group consisting of: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[1 4.1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramet hyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14. 1.0]heptadecane-5,9-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-m ethyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-di one; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-meth yl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione ; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[1 4.1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramet hyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14. 1.0]heptadecane-5,9-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-m ethyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-di one; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-meth yl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione ; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1. 0]heptadecane-9-one; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramet hyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1. 0]heptadecane-9-one; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3,8,8,10,12,16-hex amethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14. 1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3,8,8,10,12-pentam ethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1. 0]heptadecane-5,9-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13,16-hexamethyl-16-[1 -methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione ; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,16-pentamethyl-16-[1-m ethyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1. 0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-6,8,8,10,12-pentam ethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1. 0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14. 1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramet hyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1. 0]heptadecane-5,9-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-m ethyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-meth yl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-4,8,8,10,12,16-hex amethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14 .1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-4,8,8,10,12-pentam ethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14. 1.0]heptadecane-5,9-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-1,5,5,7,9,13-hexamethyl-16-[1- methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-1,5,5,7,9-pentamethyl-16-[1-me thyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicycl o[14.1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramet hyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[1 4.1.0]heptadecane-5,9-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-m ethyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6- dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-meth yl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dio ne; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicycl o[14.1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramet hyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[1 4.1.0]heptadecane-5,9-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-m ethyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6- dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-meth yl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dio ne; [1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-Phenyl-7,11-dihydroxy-8,8,10,12,16 -pentamethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide; [1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-Phenyl-7,11-dihydroxy-8,8,10,12-te tramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide; [4S-[4R*,7S*,8R*,9R*,15R*]]-N-Phenyl-4,8-dihydroxy-5,5,7,9,13-pentamethyl-2 ,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide; [4S-[4R*,7S*,8R*,9R*,15R*]]-N-Phenyl-4,8-dihydroxy-5,5,7,9-tetramethyl-2,6- dioxo-1-oxa-13-cyclohexadecene-16-carboxamide; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[1 4.1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramet hyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14. 1.0]heptadecane-5,9-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-m ethyl-2-(2-hydroxymethyl-4-thiazolyl)ethenyl]-1-aza-13(Z)-cyclohexadecene-2 ,6-dione; and the pharmaceutically acceptable salts, solvates and hydrates thereof. 4. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 1. 5. The method of claim 4, wherein the cancer is cancer of the breast, ovary, or colon. 6. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 2. 7. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 3. 8. A compound having the formula: ##STR54## or a pharmaceutically acceptable salt, hydrate, solvate, geometrical isomer, optical isomer or stereoisomer thereof. 9. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 8. 10. The method of claim 9, wherein the cancer is cancer of the breast, ovary, or colon. 11. The method of claim 6, wherein the cancer is cancer of the breast, ovary, or colon. 12. The method of claim 7, wherein the cancer is cancer of the breast, ovary, or colon. 13. The compound of claim 1, wherein G is 1-methyl-2-(substituted-4-thiazolyl) ethenyl group. 14. The compound of claim 1, wherein Q is ##STR55## 15. The compound of claim 1, wherein W is NR.sub.15. 16. The compound of claim 1, wherein X and Y are each O. 17. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 13. 18. The method of claim 17, wherein the cancer is cancer of the breast, ovary, or colon. 19. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 14. 20. The method of claim 19, wherein the cancer is cancer of the breast, ovary, or colon. 21. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 15. 22. The method of claim 21, wherein the cancer is cancer of the breast, ovary, or colon. 23. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 16. 24. The method of claim 23, wherein the cancer is cancer of the breast, ovary, or colon. 25. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1. 26. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 2. 27. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 3. 28. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 8. 29. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 13. 30. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 14. 31. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 15. 32. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 16. 33. The method of claim 4, further comprising administering one or more of an additional anti-cancer agent. 34. The method of claim 33, wherein the additional anti-cancer agent acts in a phase of the cell cycle other than the G.sub.2 -M phase. 35. The method of claim 34, wherein the additional anti-cancer is a thymidilate synthase inhibitor, a DNA cross linking agent, a topoisomerase I or II inhibitor, a DNA alkylating agent, a ribonuclase reductase inhibitor, a cytotoxic factor, or a growth factor inhibitor. 36. The method of claim 4, further comprising administering radiation therapy. 37. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle or diluent. 38. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable vehicle or diluent. 39. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable vehicle or diluent. 40. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable vehicle or diluent. 41. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable vehicle or diluent. 42. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable vehicle or diluent. 43. A pharmaceutical composition comprising the compound of claim 15 and a pharmaceutically acceptable vehicle or diluent. 44. A pharmaceutical composition comprising the compound of claim 16 and a pharmaceutically acceptable vehicle or diluent. 45. A method of treating melanoma, non-Hodgkin's lymphoma, multiple myeloma, or Karposi's sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 1. 46. A method of treating melanoma, non-Hodgkin's lymphoma, multiple myeloma, or Karposi's sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 2. 47. A method of treating melanoma, non-Hodgkin's lymphoma, multiple myeloma, or Karposi's sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 3. 48. A method of treating melanoma, non-Hodgkin's lymphoma, multiple myeloma, or Karposi's sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 8. 49. A method of treating melanoma, non-Hodgkin's lymphoma, multiple myeloma, or Karposi's sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 13. 50. A method of treating melanoma, non-Hodgkin's lymphoma, multiple myeloma, or Karposi's sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 14. 51. A method of treating melanoma, non-Hodgkin's lymphoma, multiple myeloma, or Karposi's sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 15. 52. A method of treating melanoma, non-Hodgkin's lymphoma, multiple myeloma, or Karposi's sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 16. 53. A compound of the formula: ##STR56## wherein: Q is selected from the group consisting of: ##STR57## G is selected from the group consisting of alkyl; substituted alkyl; substituted aryl; a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; ##STR58## X is O or H, H; Y is selected from the group consisting of O; H, OR.sub.16 ; OR.sub.17, OR.sub.17 ; NOR.sub.18 ; H, NHOR.sub.19 ; H, NR.sub.20 R.sub.21 ; H, H; and CHR.sub.22 ; wherein OR.sub.17, OR.sub.17 can be a cyclic ketal; Z.sub.1 and Z.sub.2 are independently CH.sub.2 ; B.sub.1 and B.sub.2 are independently selected from the group consisting of OR.sub.24, OCOR.sub.25, and O--C(.dbd.O)-NR.sub.26 R.sub.27, and when B.sub.1 is OH and Y is OH, H, they can form a six-membered ring ketal or acetal; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.7, R.sub.13, R.sub.14, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.22, R.sub.26 and R.sub.27 are selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R.sub.1 and R.sub.2 are alkyl can be joined to form a cycloalkyl, and when R.sub.3 and R.sub.4 are alkyl can be joined to form a cycloalkyl; R.sub.6 is methyl; R.sub.9, R.sub.10, R.sub.16, R.sub.17, R.sub.24, R.sub.25 and R.sub.31 are selected from the group consisting of H, alkyl, and substituted alkyl; R.sub.11, R.sub.12, R.sub.28, R.sub.30, R.sub.32, and R.sub.33 are selected from the group consisting of H; alkyl; substituted alkyl; aryl; substituted aryl; cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C.sub.3 -C.sub.7 carbocyclic ring; and a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R.sub.8 is hydrogen or methyl; R.sub.15, R.sub.23 and R.sub.29 are selected from the group consisting of H; alkyl; substituted alkyl; aryl; substituted aryl; cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C.sub.3 -C.sub.7 carbocyclic ring; a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R.sub.32 C.dbd.O; R.sub.33 SO.sub.2 ; hydroxy; O-alkyl or O-substituted alkyl; or pharmaceutically acceptable salts, hydrates, solvates or geometric, optical or steroisomers thereof. 54. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 53. 55. The method of claim 54 wherein the cancer is cancer of the breast, ovary, or colon. 56. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 53. 57. The method of claim 54 further comprising administering one or more of an additional anti-cancer agent. 58. The method of claim 57 wherein the additional anti-cancer agent acts in a phase of the cell cycle other than the G.sub.2 -M phase. 59. The method of claim 58 wherein the additional anti-cancer is a thymidilate synthase inhibitor, a DNA cross linking agent, a topoisomerase I or II inhibitor, a DNA alkylating agent, a ribonuclase reductase inhibitor, a cytotoxic factor, or a growth factor inhibitor. 60. A method of treating melanoma, non-Hodgkin's lymphoma, multiple myeloma, or Karposi's sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 53. 61. A pharmaceutical composition comprising the compound of claim 53 and a pharmaceutically acceptable vehicle or diluent. 62. A compound of the formula: ##STR59## wherein: Q is selected from the group consisting of: ##STR60## G is selected from the group consisting of alkyl; substituted alkyl; substituted aryl; a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; ##STR61## W is O or NR.sub.15 ; X is O or H, H; Y is selected from the group consisting of O; H, OR.sub.16 ; OR.sub.17, OR.sub.17 ; NOR.sub.18 ; H, NHOR.sub.19 ; H, NR.sub.20 R.sub.21 ; H, H; and CHR.sub.22 ; wherein OR.sub.17, OR.sub.17 can be a cyclic ketal; Z.sub.1 and Z.sub.2 are independently CH.sub.2 ; B.sub.1 and B.sub.2 are independently selected from the group consisting of OR.sub.24, OCOR.sub.25, and O--C(.dbd.O)--NR.sub.26 R.sub.27, and when B.sub.1 is OH and Y is OH, H, they can form a six-membered ring ketal or acetal; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.7, R.sub.13, R.sub.14, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.22, R.sub.26 and R.sub.27 are selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R.sub.1 and R.sub.2 are alkyl can be joined to form a cycloalkyl, and when R.sub.3 and R.sub.4 are alkyl can be joined to form a cycloalkyl; R.sub.6 is methyl; R.sub.9, R.sub.10, R.sub.16, R.sub.17, R.sub.24, R.sub.25 and R.sub.31 are selected from the group consisting of H, alkyl, and substituted alkyl; R.sub.11, R.sub.12, R.sub.28, R.sub.30, R.sub.32, and R.sub.33 are selected from the group consisting of H; alkyl; substituted alkyl; aryl; substituted aryl; cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C.sub.3 -C.sub.7 carbocyclic ring; and a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R.sub.8 is hydrogen or methyl; R.sub.15, R.sub.23 and R.sub.29 are selected from the group consisting of H; alkyl; substituted alkyl; aryl; substituted aryl; cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C.sub.3 -C.sub.7 carbocyclic ring; a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R.sub.32 C.dbd.O; R.sub.33 SO.sub.2 ; hydroxy; O-alkyl or O-substituted alkyl; or pharmaceutically acceptable salts, hydrates, solvates or geometric, optical or steroisomers thereof; wherein substituted alkyl is an alkyl group substituted with from one to four substituents selected from the group consisting of halo; trifluoromethyl; trifluoromethoxy; hydroxy; alkoxy; cycloalkoxy; heterocyclooxy; oxo; alkanoyl; aryloxy; alkanoyloxy; amino; alkylamino; arylamine; aralkylamino; cycloalkylamino; heterocycloamino; disubstituted amines wherein the substituents are selected from alkyl, aryl, and aralkyl; alkanoylamino; optionally substituted with halogen, alkyl, alkoxy, aryl, or araralkyl; arylamino optionally substituted with halogen, alkyl, alkoxy, aryl, or araralkyl; aralkanoylamino optionally substituted with halogen, alkyl, alkoxy, aryl, or araralkyl; thio; alkylthio; aralkylthio; cycloalkylthio; heterocyclothio; alkylthiono; arylthiono; aralkylthiono; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; sulfonamido optionally substituted with halogen, alkyl, alkoxy, aryl, or araralkyl; nitro; cyano; carboxy; carbamyl optionally substituted with halogen, alkyl, alkoxy, aryl, or araralkyl; alkoxycarbonyl; aryl; substituted aryl; guanidino; and heterocyclo; and substituted aryl is an aryl group substituted with from one to four substituents selected from the group consisting of alkyl; substituted alkyl; halo; trifluoromethyl; trifluoromethoxy; hydroxy; alkoxy; cycloalkoxy; heterocyclooxy; alkanoyl; alkanoyloxy; amino; alkylamino; aralkylamino; cycloalkylamino; heterocycloamino; dialkylamino; alkanoylamino; thio; alkylthio; cycloalkylthio; heterocyclothio; ureido; nitro; cyano; carboxy; carboxyalkyl; carbamyl; alkoxycarbonyl; alkylthiono; arylthiono; alkylsulfonyl; sulfonamido; and aryloxy each of which may be optionally substituted with halo, hydroxy, alkyl, alkoxy, substituted aryl, substituted alkyl, or substituted aralkyl; with the proviso that compounds wherein W and X are both O; and R.sub.1, R.sub.2 and R.sub.7 are H; and R.sub.3, R.sub.4 and R.sub.6 are methyl; and R.sub.8 is H or methyl; and G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and Q is as defined above are excluded.