Claims for Patent: 6,719,540

Summary for Patent: 6,719,540

Title:	C3-cyano epothilone derivatives
Abstract:	The present invention relates to compounds useful in the treatment of cancer or other proliferative diseases represented by formula I: ##STR1## wherein: Q is selected from the group consisting of ##STR2## M is O, NR.sub.9, or CR.sub.10 R.sub.11 ; X is O or NH; and the R groups are as defined, and therapeutic compositions containing them alone or in combination with other therapeutic agents useful in the treatment of cancer or other proliferative diseases.
Inventor(s):	Regueiro-Ren; Alicia (Middletown, CT), Kim; Soong-Hoon (Titusville, NJ)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:	10/386,072
Patent Claims:	1. A compound represented by formula I: ##STR20## wherein: Q is selected from the group consisting of ##STR21## M is O, NR.sub.9, CR.sub.10 R.sub.11 ; X is O or NH; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently selected from the group consisting of hydrogen or lower alkyl; R.sub.6 is selected from the group consisting of aryl, substituted aryl, and heterocyclo; R.sub.7 and R.sub.8 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, and cyano; R.sub.9 is selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, substituted aryl, cycloalkyl, heterocyclo, R.sub.12 C.dbd.O, R.sub.13 OC.dbd.O, R.sub.14 SO.sub.2, R.sub.15 R.sub.16 NC.dbd.O, R.sub.17 R.sub.18 NSO.sub.2, and NR.sub.19 R.sub.20 ; R.sub.10 and R.sub.11 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, cycloalkyl, heterocyclo, R.sub.21 C.dbd.O, R.sub.22 OC.dbd.O, R.sub.23 NHC.dbd.O, and NR.sub.24 R.sub.25 ; and R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.22, R.sub.23, R.sub.24, and R.sub.25 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo with the proviso that R.sub.13 and R.sub.14 cannot be hydrogen; R.sub.15 and R.sub.16, R.sub.17 and R.sub.18, R.sub.19 and R.sub.20, R.sub.24 and R.sub.25 can each independently be taken together to form a heterocyclic ring; and somers, clathrates, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof. 2. A compound which is a regioisomer or stereoisomer of a compound of claim 1 or pharmaceutically acceptable salts, solvates or hydrates thereof. 3. The compound of claim 1 wherein R.sub.6 is selected from the group consisting of: ##STR22## pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, imidazolyl, oxazolyl, oxazolidinyl, thiazolyl, furyl, thienyl, piperidinyl, piperazinyl, azepinyl, pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, thietanyl, thiiranyl, triazinyl, and triazolyl or pharmaceutically acceptable salts, solvates or hydrates thereof. 4. The compound of claim 1 wherein X is O. 5. The compound of claim 1 wherein X is NH. 6. The compound of claim 1 wherein M is O. 7. The compound of claim 1 wherein M is NR.sub.9. 8. The compound of claim 1 wherein M is CR.sub.10 R.sub.11. 9. The compound of claim 1 wherein said compound is selected from the group consisting of: ##STR23## ##STR24## and mixtures or pharmaceutically acceptable salts, solvates or hydrates thereof. 10. The compound of claim 1 wherein said compound is selected from the group consisting of: 11-Hydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-thiazol-4-yl)-viny l]-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadecane-7-carbonitrile; 11-Hydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-thiazol-4-yl)-v inyl]-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadecane-7-carbonitrile; and 8-Hydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-thiazol-4-yl)-vin yl]-2,6-dioxo-azacyclohexadec-13-ene-4-carbonitrile; and pharmaceutically acceptable salts, solvates or hydrates thereof. 11. A pharmaceutical composition comprising as an active ingredient at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and diluents. 12. The pharmaceutical composition of claim 11 additionally comprising as a further active ingredient a therapeutic agent useful in the treatment of cancer or other proliferative diseases. 13. The pharmaceutical composition of claim 12 wherein said therapeutic agent useful in the treatment of cancer or other proliferative diseases is selected from the group consisting of adriamycin, cisplatin, carboplatin, cimetidine, carminomycin, mechlorethamine hydrochloride, pentamethylmelamine, thiotepa, teniposide, cyclophosphamide, chlorambucil, demethoxyhypocrellin A, melphalan, ifosfamide, trofosfamide, Treosulfan, podophyllotoxin or podophyllotoxin derivatives, etoposide phosphate, teniposide, etoposide, leurosidine, leurosine, vindesine, 9-aminocamptothecin, camptoirinotecan, crisnatol, Chloroambucil, megestrol, methopterin, mitomycin C, ecteinascidin 743, busulfan, carmustine (BCNU), lomustine (CCNU), lovastatin, 1-methyl-4-phenylpyridinium ion, semustine, staurosporine, streptozocin, thiotepa, phthalocyanine, dacarbazine, aminopterin, methotrexate, trimetrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine (ara C), porfiromycin, 5-fluorouracil, 6-mercaptopurine, doxorubicin hydrochloride, leucovorin, mycophenoloc acid, daunorubicin, deferoxamine, floxuridine, doxifluridine, ratitrexed, idarubicin, epirubican, pirarubican, zorubicin, mitoxantrone, bleomycin sulfate, mitomycin C, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, vertoporfin, paclitaxel, tamoxifen, raloxifene, tiazofuran, thioguanine, ribavirin, EICAR, estramustine, estramustine phosphate sodium, flutamide, bicalutamide, buserelin, leuprolide, pteridines, diyneses, levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethosone, gemcitabine hydrochloride, verapamil, VP-16, altretamine, thapsigargin and topotecan. 14. A method for treating cancer or other proliferative diseases in a mammal in need thereof which comprises administering an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof to said mammal. 15. The method of claim 14 wherein said cancer is responsive to microtubule-stabilization. 16. A method for inhibiting angiogenesis in a mammal in need thereof which comprises administering an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof to said mammal. 17. A method for inducing apoptosis in a mammal in need thereof which comprises administering an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof to said mammal. 18. The method of claim 14 wherein said compound of claim 1 is administered simultaneously or sequentially with a therapeutic agent useful in the treatment of cancer or other proliferative diseases. 19. The method of claim 18 wherein said compound of claim 1 is administered prior to the administration of the therapeutic agent. 20. The method of claim 18 wherein said compound of claim 1 is administered after the administration of the therapeutic agent. 21. The method of claim 18 wherein said therapeutic agent useful in the treatment of cancer or other proliferative diseases is selected from the group consisting of adriamycin, cisplatin, carboplatin, cimetidine, carminomycin, mechlorethamine hydrochloride, pentamethylmelamine, thiotepa, teniposide, cyclophosphamide, chlorambucil, demethoxyhypocrellin A, melphalan, ifosfamide, trofosfamide, Treosulfan, podophyllotoxin or podophyllotoxin derivatives, etoposide phosphate, teniposide, etoposide, leurosidine, leurosine, vindesine, 9-aminocamptothecin, camptoirinotecan, crisnatol, Chloroambucil, megestrol, methopterin, mitomycin C, ecteinascidin 743, busulfan, carmustine (BCNU), lomustine (CCNU), lovastatin, 1-methyl-4-phenylpyridinium ion, semustine, staurosporine, streptozocin, thiotepa, phthalocyanine, dacarbazine, aminopterin, methotrexate, trimetrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine (ara C), porfiromycin, 5-fluorouracil, 6-mercaptopurine, doxorubicin hydrochloride, leucovorin, mycophenoloc acid, daunorubicin, deferoxamine, floxuridine, doxifluridine, ratitrexed, idarubicin, epirubican, pirarubican, zorubicin, mitoxantrone, bleomycin sulfate, mitomycin C, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, vertoporfin, paclitaxel, tamoxifen, raloxifene, tiazofuran, thioguanine, ribavirin, EICAR, estramustine, estramustine phosphate sodium, flutamide, bicalutamide, buserelin, leuprolide, pteridines, diyneses, levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethosone, gemcitabine hydrochloride, verapamil, VP-16, altretamine, thapsigargin and topotecan. 22. The method of claim 14 wherein said compound of claim 1 is administered simultaneously or sequentially with a therapeutic agent useful inhibiting angiogenesis. 23. The method of claim 22 wherein said compound of claim 1 is administered prior to the administration of the therapeutic agent. 24. The method of claim 22 wherein said compound of claim 1 is administered after the administration of the therapeutic agent. 25. The method of claim 22 wherein said therapeutic agent useful in inhibiting angiogenesis is selected from the group consisting of indolinethiones, pyridopyrimidines, quinoazolines, phenyl-pyrrolo-pyrimidines, trastuzumab, IMC-C225, AG 1571 (SU 5271), SU 5416, SU 6668, Interferon-alpha, Interleuken-12, IM 862, EMD-121974, calcium influx inhibitor (CAI), neomycin, squalamine, endostatin, SI-27, MMI-166, marimastat, BAY-129556, prinomastat (AG-3340), metastat (COL-3), CGS-27023A and BMS-275291. 26. The method of claim 14 wherein said mammal is human. 27. The method of claim 16 wherein said mammal is human. 28. The method of claim 17 wherein said mammal is human. 29. The method of claim 14 wherein said cancer is a cancer of the brain, breast, central nervous system, stomach, bladder, prostate, colon, rectum, liver, lung (both small cell and non-small cell), pancreas, esophagus, mouth, pharynx, kidney, bone, pituitary, ovary, uterine, skin, head and neck, cervix or larynx. 30. The method of claim 14 wherein said cancer is a solid tumor. 31. The method of claim 14 wherein said cancer is a metastatic tumor. 32. A unit dosage form comprising a compound of claim 1. 33. A sterile injectable unit dosage form comprising a compound of claim 1. 34. The unit dosage form of claim 32 wherein said dosage form is lyophilized. 35. The unit dosage form of claim 33 wherein said dosage form is lyophilized.

Details for Patent 6,719,540

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Clinigen, Inc.	PROLEUKIN	aldesleukin	For Injection	103293	05/05/1992		2022-03-12
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	02/20/1991		2022-03-12
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	06/28/2000		2022-03-12