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US 2004.0024032A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0024032A1 Voi et al. (43) Pub. Date: Feb. 5, 2004

(54) COMBINATION OF (22) Filed: Jun. 12, 2003 ANALOGS AND CHEMOTHERAPEUTIC AGENTS FOR THE TREATMENT OF Related U.S. Application Data PROLIFERATIVE DISEASES (60) Provisional application No. 60/388,702, filed on Jun. (76) Inventors: Maurizio Voi, Bruxelles (BE); David 14, 2002. Lebwohl, Madison, NJ (US (US) Publication Classification Correspondence Address: STEPHEN B. DAVIS (51) Int. Cl...... A61K 31/427 BRISTOL-MYERS SQUIBB COMPANY (52) U.S. Cl...... 514/365 PATENT DEPARTMENT PO BOX 4000 (57) ABSTRACT PRINCETON, NJ 08543-4000 (US) Compositions and methods are disclosed which are useful of (21) Appl. No.: 10/459,972 the treatment and prevention of proliferative diseases. US 2004/0024032A1 Feb. 5, 2004

COMBINATION OF EPOTHILONE ANALOGS AND Significant advantage over taxol in that exhibit a CHEMOTHERAPEUTICAGENTS FOR THE much lower drop in potency compared to taxol against a TREATMENT OF PROLIFERATIVE DISEASES multiple drug-resistant cell line (Bollaget al. (1995)). Fur thermore, epothilones are considerably less efficiently CROSS-REFERENCE TO RELATED exported from the cells by P-glycoprotein than is taxol APPLICATIONS (Gerth et al. (1996)). 0001. This application claims priority from provisional 0009. It is an object of the invention to provide effica U.S. Application Serial No. 60/388,702, filed on Jun. 14, cious combination chemotherapeutic treatment regimens 2002, incorporated herein by reference in its entirety. wherein epothilone analogs are combined with other anti neoplastic agents for the treatment of proliferative diseases. FIELD OF THE INVENTION SUMMARY OF THE INVENTION 0002 This invention relates to the fields of oncology and improved regimens. 0010. The present invention provides a method for the treatment of anti-proliferative diseases, including cancer, BACKGROUND OF THE INVENTION which comprises administering to a mammalian Specie in need thereof, a therapeutically effective amount of: (1) a 0003. The disclosure of each literature article and pub compound of formula I and (2) at least one anti-proliferative lished patent document referred to herein is incorporated by agent. reference in its entirety. 0004. The National Cancer Institute has estimated that in the United States alone, 1 in 3 people will be struck with cancer during their lifetime. Moreover, approximately 50% to 60% of people contracting cancer will eventually Suc cumb to the disease. The widespread occurrence of this disease underScores the need for improved anticancer regi mens for the treatment of malignancy. 0005. Due to the wide variety of cancers presently observed, numerous anticancer agents have been developed to destroy cancer within the body. These compounds are administered to cancer patients with the objective of destroying or otherwise inhibiting the growth of malignant 0011 wherein: cells while leaving normal, healthy cells undisturbed. Anti 0012 Q is selected from the group consisting of cancer agents have been classified based upon their mecha nism of action. 0006. One type of chemotherapeutic is referred to as a R8 metal coordination complex. It is believed this type of chemotherapeutic forms predominantly inter-strand DNA croSS links in the nuclei of cells, thereby preventing cellular Pyry ry replication. As a result, tumor growth is initially repressed, and then reversed. Another type of chemotherapeutic is R10O. R8 R10O R8 R8 referred to as an alkylating agent. These compounds func RoO RoO tion by inserting foreign compositions or molecules into the s and DNA of dividing cancer cells. As a result of these foreign moieties, the normal functions of cancer cells are disrupted and proliferation is prevented. Another type of chemothera peutic is an antineoplastic agent. This type of agent prevents, kills, or blocks the growth and spread of cancer cells. Still 0013 G is selected from the group consisting of other types of anticancer agents include nonsteroidal aro alkyl, Substituted alkyl, aryl, Substituted aryl, hetero mastase inhibitors, bifunctional alkylating agents, etc. cyclo, 0007 represents one of the major classes of antimicrotubule agents that promotes polymerization R12 R12 R12 and, presumably, mitotic arrest during cell division. Taxol (paclitaxel) has been shown to have excellent antitumor activity in Vivo and has been employed in the treatment of to-y 's-y "N-y a variety of cancers, including breast, ovarian and lung cancer. Unfortunately, many tumors develop resistance to R12 O paclitaxel. R13 0008 Epothilones mimic the biological effects of taxol, -y and NN s (Bollaget al., Cancer Research 55: 2325-2333 (1995), and in competition Studies act as competitive inhibitors of taxol binding to . However, epothilones enjoy a US 2004/0024032A1 Feb. 5, 2004

0014 W is O or NR; melamine, Triethylenethiophosphoramine, , Car mustine, , Streptozocin, , and Temo 0.015 X is O or H, H; Zolomide, (including, without limitation, 0016 Y is selected from the group consisting of O; folic acid antagonists, pyrimidine analogs, purine analogs H, OR, OR, OR, NOR; H, NHOR; H, and adenosine deaminase inhibitors), , 5-Fluo NRR, H, H; and CHR, wherein OR7, OR, rouracil, , , 6-, can be a cyclic ketal; 6-Thioguanine, phosphate, Pentostatine, and 0017 Z, and Z are independently selected from the ; natural products and their derivatives (for group consisting of CH, O, NR, S, and SO2, example, Vinca alkaloids, antitumor antibiotics, enzymes, wherein only one of Z, and Z can be a heteroatom; lymphokines and epipodophyllotoxins): , Vinc ristine, Vindesline, , , Daunorubi 0018) B and B are independently selected from the cin, , , , Ara-C, paclitaxel group consisting of OR2, OCORs, and (paclitaxel is commercially available as Taxol(R), Mithra O-C(=O)-NRR, and when B is H and Y is mycin, Deoxyco-formycin, Mitomycin-C, L-, OH, H, they can form a six-membered ring ketal or Interferons (especially IFN-a), , and ; acetal; navelbene, CPT-11, anastraZole, letrazole, , 0019 D is selected from the group consisting of reloxafine, , ifosamide, and droloxafine NRR, NRCOR and Saturated heterocycle; and radiation. 0020 R, R2, R3, R, Rs, R6, R7, R13, R14, R18, Rio, 0027 According to the present invention, the antiprolif Rao, R2, R22, R2 and R27 are independently Selected from the group consisting of H, alkyl, erative agent is administered prior to, Simultaneously with, Substituted alkyl, and aryl, and when R and R are or after the administration of a compound of Formula I, Such alkyl can be joined to form a cycloalkyl, and when as the compound of Formula Ia. R and R are alkyl can be joined to form a cycloalkyl, DETAILED DESCRIPTION OF THE INVENTION 0021) Ro, Rio, R16, R17, R2, R2s and Rs1, are independently Selected from the group consisting of 0028. In accordance with the present invention, methods H, alkyl, and substituted alkyl; for the Scheduled administration of epothilone analogs in 0022 Rs, R, R2, R2s, Rao, Rs, and Rs are combination(s) with at least one additional anti-neoplastic independently selected from the group consisting of agent for the treatment and prevention of proliferative H, alkyl, Substituted alkyl, aryl, Substituted aryl, diseases are provided. cycloalkyl and heterocyclo; 0029. Epothilones mimic the biological effects of taxol, 0023 Rs, R2 and Rao are independently selected (Bollaget al., Cancer Research 55: 2325-2333 (1995), and from the group consisting of H, alkyl, Substituted in competition Studies act as competitive inhibitors of taxol alkyl, aryl, Substituted aryl, cycloalkyl, heterocyclo, binding to microtubules. However, epothilones enjoy a RC=O, RSO, hydroxy, O-alkyl or O-substi Significant advantage over taxol in that epothilones exhibit a tuted alkyl, and much lower drop in potency compared to taxol against a 0024 pharmaceutically acceptable salts thereof and multiple drug-resistant cell line (Bollaget al. (1995)). Fur any hydrates, Solvates or geometric, optical and thermore, epothilones are considerably less efficiently Steroisomers thereof. exported from the cells by P-glycoprotein than is taxol (Gerth et al. (1996)). 0.025. An example of a compound of Formula I is the compound of Formula Ia (“Compound 1”): 0030. In one embodiment of the present invention, the chemotherapeutic method of the invention comprises the Ia administration of an epothilone analog of Formula I in combination with at least one other anti-cancer or anti proliferative agent. The epothilone analogs disclosed herein, when used in combination with at least one other anti-cancer agent, demonstrate Superior cytotoxic activity. 0031 Epothilone analogs for use in the methods of the invention are compounds of Formula I:

9-N-17N,1.

0.026 Suitable anti-proliferative agents for use in the methods of the invention, include, without limitation, alky lating agents (including, without limitation, nitrogen mus tards, ethylenimine derivatives, alkyl Sulfonates, and triaZenes): Uracil mustard, , Cyclophosphamide (Cytoxan), , , , , , Triethylene US 2004/0024032A1 Feb. 5, 2004

0032) wherein: H, alkyl, Substituted alkyl, aryl, Substituted aryl, 0033 Q is selected from the group consisting of cycloalkyl and heterocyclo; 0044 Ris, R2 and Rao are independently selected from the group consisting of H, alkyl, Substituted R8 R8 alkyl, aryl, Substituted aryl, cycloalkyl, heterocyclo, O RC=O, RSO, hydroxy, O-alkyl or O-substi tuted alkyl, and Py s A s 0045 pharmaceutically acceptable salts thereof and r/ any hydrates, Solvates or geometric, optical and R10O. R8 R10O. R8 R8 Steroisomers thereof. RoO s and 0046 According to the present invention, the anti-prolif y erative agent may be administered prior to, Simultaneously with, or after the administration of an epothilone analog of Formula I. 0034) G is selected from the group consisting of 0047 Examples of compounds of Formula I include 1S alkyl, Substituted alkyl, aryl, Substituted aryl, hetero 1R*,3R*(E).7R*,10S*,11R*,12R*,16S*I-7,11-dihydroxy cyclo, 8,8,10,12,16-pentamethyl-3-1-methyl-2-(2-methyl-4-thiaz olyl)ethenyl-4-aza-17oxabicyclo14.1.0-heptadecane-5.9- dione (Formula Ia; Compound 1) and pharmaceutically R12 R12 R12 acceptable Salts thereof. Compound 1 has the following to-y 's-y "N-y chemical Structure: R12 O Ia

-y and R13 NN s

0035 W is O or NR; 0.036 X is O or H, H; 0037 Y is selected from the group consisting of O; H, OR; OR, OR, NOR; H, NHOR; H, NRR, H, H; and CHR, wherein OR7, OR, can be a cyclic ketal; 0.038 Z and Z are independentlv Selected from the 0048 When describing the compounds of the present 1. 2 p y invention, the phrase “lower alkyl” or “lower alk” (as part of group consisting of CH, O, NR, S, and S, another group) refers to an unsubstituted alkyl group of 1 to wherein only one of Z and Z can be a heteroatom; 6, Such as 1 to 4, carbon atoms. 0039 B and B are independently selected from the group consisting of OR2, OCORs, and 0049. The term “aralkyl” refers to an aryl group bonded O-C(=O)-NRR, and when B is H and Y is directly through a lower alkyl group. An example of an OH, H, they can form a six-membered ring ketal or aralkyl group is benzyl. acetal; 0050. The term “aryl” refers to a monocyclic or bicyclic 0040 D is selected from the group consisting of aromatic hydrocarbon group having 6 to 12 carbon atoms in NRR, NRCOR and Saturated heterocycle; the ring portion. Exemplary of aryl herein are phenyl, naphthyl and biphenyl groups. 0041) R, R2, R3, R, Rs, R6, R7, R13, R14, R18, Rio, Rao, R, R2, R2 and R27 are independently 0051) The term “heterocyclo” refers to a fully saturated Selected from the group consisting of H, alkyl, or unsaturated, aromatic or nonaromatic cyclic group which Substituted alkyl, and aryl, and when R and R are is a 4 to 7 membered monocyclic, 7 to 11 membered alkyl can be joined to form a cycloalkyl, and when bicyclic, or 10 to 15 membered tricyclic ring system which R and R are alkyl can be joined to form a has at least one heteroatom in at least one carbon atom cycloalkyl, containing ring. Each ring of the heterocyclic group con taining a heteroatom may have 1, 2, 3 or 4 heteroatoms 0042 Ro, Rio, Re, R7, R, R2s and R are inde Selected from nitrogen, oxygen and Sulfur where the nitro pendently Selected from the group consisting of H, gen and Sulfur heteroatoms may also optionally be oxidized alkyl, and Substituted alkyl, and the nitrogen heteroatoms may also optionally be quat 0.043 Rs, R1, R12, R2s, Rao, R32, and Ras are ernized. The heterocyclo group may be attached at any independently Selected from the group consisting of heteroatom or carbon atom. US 2004/0024032A1 Feb. 5, 2004

0.052 Exemplary monocyclic heterocyclo groups include larly embrace the racemic forms and the isolated optical pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazoli isomers having the Specified activity. nyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, 0056 An example of an epothilone analog of Formula I Oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiaz for use in the methods of the invention is Compound 1: olyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tet 1S-1R*,3R*(E).7R*,10S*,11R*,12R*,16S*Il-7,11-dihy rahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, droxy-8,8,10,12,16-pentamethyl-3-1-methyl-2-(2-methyl 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-thiazolyl)ethenyl-4-aza-17-oxabicyclo14.1.0) heptade 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-py cane-5,9-dione. Compound 1 is described in WO99/02514, ridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydrothiopy published Jan. 21, 1999, the entire contents of which are ranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, herein incorporated by reference. thiamorpholinyl Sulfoxide, tetrahydrothiopyranylsulfone, 0057 Compound 1, an exemplary epothilone analog of thiamorpholinyl Sulfone, 1,3-dioxolane, tetrahydro-1,1-di the invention, is a Semi-Synthetic epothilone analog and has OXothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiranyl, a mode of action analogous to paclitaxel (i.e., triazinyl, triazolyl, and the like. Stabilization). However, in preclinical pharmacology Stud 0.053 Exemplary bicyclic heterocyclo groups include ies, Compound 1 has demonstrated Significant improvement benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, over paclitaxel in Several critical aspects. Compound 1 quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, exhibits a very impressive and broad Spectrum of antitumor benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, activity against paclitaxel-sensitive (A2780, HCT116 and chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, LS174T) and, more importantly, as well as paclitaxel pyrrolopyridyl, furopyridinyl (Such as furo2,3-cpyridinyl, resistant human colon tumors (HCT116/VM46), ovarian furo3,1-bipyridinyl or furo2,3-bpyridinyl), dihydroisoin carcinoma (Pat-7 and A2780Tax) and breast carcinoma dolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo (Pat-21) models. Compound 1 is orally efficacious; the quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazi antitumor activity produced after oral administration is nyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, comparable to that produced by parenteral administration of benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, the drug. These preclinical efficacy data indicate that Com dihydrobenzothiopyranyl, dihydrobenzothiopyranyl Sul pound 1 demonstrates improved clinical efficacy in fone, dihydrobenzopyranyl, indolinyl, isochromanyl, isolin TAXOL(R)-insensitive and sensitive disease types. dolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, 0058 As used herein, the phrase “anti-neoplastic agent” pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofu is Synonymous with “chemotherapeutic agent' and/or “anti ryl, thienopyridyl, thienothienyl, and the like. proliferative agent' and refers to compounds that prevent cancer, or hyperproliferative cells, from multiplying. Anti 0.054 When a group is referred to as being optionally proliferative agents prevent cancer cells from multiplying substituted, it may be substituted with one to five, preferably by: (1) interfering with the cell's ability to replicate DNA one to three, substituents such as F, Cl, Br, I, trifluoromethyl, and (2) inducing cell death and/or apoptosis in the cancer trifluoromethoxy, hydroxy, lower alkoxy, cycloalkoxy, het cells. erocyclooxy, OXO, lower alkanoyl, aryloxy, lower alkanoy loxy, amino, lower alkylamino, arylamino, aralkylamino, 0059 Classes of compounds that may be used as anti cycloalkylamino, heterocycloamino, disubstituted amines in proliferative cytotoxic agents include the following: which the two amino Substituents independently are Selected 0060 Alkylating agents (including, without limitation, from lower alkyl, aryl or aralkyl, lower alkanoylamino, nitrogen mustards, ethylenimine derivatives, alkyl Sul aroylamino, aralkanoylamino, Substituted lower alkanoy fonates, nitroSoureas and triaZenes): Uracil mustard, Chlo lamino, Substituted arylamino, Substituted aralkylanoy rmethine, Cyclophosphamide (Cytoxan), Ifosfamide, Mel lamino, thiol, lower alkylthio, arylthio, aralkylthio, phalan, Chlorambucil, Pipobroman, Triethylene-melamine, cycloalkylthio, heterocyclothio, lower alkylthiono, arylth Triethylenethiophosphoramine, BuSulfan, , iono, aralkylthiono, lower alkylsulfonyl, arylsulfonyl, Lomustine, Streptozocin, Dacarbazine, and . aralkylsulfonyl, Sulfonamide (e.g., SONH2), Substituted 0061 Antimetabolites (including, without limitation, Sulfonamide, nitro, cyano, carboxy, carbamyl (e.g., folic acid antagonists, pyrimidine analogs, purine analogs CONH), Substituted carbamyl (e.g., CONH-lower alkyl, and adenosine deaminase inhibitors): Methotrexate, 5-Fluo CONH-aryl, CONH-aralkyl or cases where there are two rouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, Substituents on the nitrogen independently Selected from 6-Thioguanine, Fludarabine phosphate, Pentostatine, and lower alkyl, aryl or aralkyl), lower alkoxycarbonyl, aryl, Gemcitabine. Substituted aryl, guanidino, and heterocycloS (e.g., indolyl, 0062 Natural products and their derivatives (for imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, example, Vinca alkaloids, antitumor antibiotics, enzymes, pyrimidyl and the like). Where noted above that the substi lymphokines and epipodophyllotoxins): Vinblastine, Vinc tutuent is further Substituted, it will be substituted with F, Cl, ristine, Vindesline, Bleomycin, Dactinomycin, Daunorubi Br, I, optionally Substituted lower alkyl, hydroxy, optionally cin, Doxorubicin, Epirubicin, Idarubicin, Ara-C, paclitaxel Substituted lower alkoxy, optionally Substituted aryl, or (paclitaxel is commercially available as Taxol(R), Mithra optionally Substituted aralkyl. mycin, Deoxyco-formycin, Mitomycin-C, L-ASparaginase, 0.055 All stereoisomers of the Formula I compounds of Interferons (especially IFN-a), Etoposide, and Teniposide. the instant invention are contemplated, either in admixture 0063. Other anti-proliferative cytotoxic agents are navel or in pure or substantially pure form. The definition of the bene, CPT-11, anastrazole, letrazole, capecitabine, carbopl formula I compounds embraces all possible Stereoisomers atin, reloxafine, cyclophosphamide, ifosamide, and drolox and their mixtures. The Formula I definitions very particu afine. US 2004/0024032A1 Feb. 5, 2004

0064. The phrase “radiation therapy” includes, but is not dent carcinomas non-proliferative. Yet another example of a limited to, X-rays or gamma rays which are delivered from cytostatic agent is the antiestrogen Tamoxifen which inhibits either an externally applied Source Such as a beam or by the proliferation or growth of estrogen dependent breast implantation of Small radioactive Sources. cancer. Inhibitors of the transduction of cellular proliferative 0065 Microtubule affecting agents interfere with cellular Signals are cytostatic agents. Examples are epidermal mitosis and are well known in the art for their anti-prolif growth factor inhibitors, Her-2 inhibitors, MEK-1 kinase erative cytotoxic activity. Microtubule affecting agents use inhibitors, MAPK kinase inhibitors, PI3 inhibitors, Src ful in the invention include, but are not limited to, allo kinase inhibitors, and PDGF inhibitors. colchicine (NSC 406042), Halichondrin B (NSC 609395), 0069. As mentioned, certain anti-proliferative agents are colchicine (NSC 757), colchicine derivatives (e.g., NSC anti-angiogenic and antivascular agents and, by interrupting 33410), dolastatin 10 (NSC 376128), maytansine (NSC blood flow to Solid tumors, render cancer cells quiescent by 153858), rhizoxin (NSC 332598), paclitaxel (Taxolg, NSC depriving them of nutrition. Castration, which also renders 125973), Taxol(R) derivatives (e.g., derivatives (e.g., NSC androgen dependent carcinomas non-proliferative, may also 608832), thiocolchicine NSC 361792), trityl (NSC be utilized. Starvation by means other than Surgical disrup 83265), vinblastine sulfate (NSC 49842), sulfate tion of blood flow is another example of a cytostatic agent. (NSC 67574), natural and synthetic epothilones including, One exemplary class of antivascular cytostatic agents is the but not limited to, epothilone A, epothilone B, epothilone C, combretastatins. Other exemplary cytostatic agents include epothilone D, desoxyepothilone A, desoxyepothilone B, MET kinase inhibitors, MAP kinase inhibitors, inhibitors of 1S-1R*,3R*(E).7R*,10S*,11R*,12R*,16S*Il-7-11-dihy non-receptor and receptor tyrosine kinases, inhibitors of droxy-8,8,10,12,16-pentamethyl-3-1-methyl-2-(2-methyl integrin Signaling, and inhibitors of insulin-like growth 4-thiazolyl)ethenyl-4-aza-17 oxabicyclo 14.1.0 heptade factor receptorS. cane-5,9-dione (disclosed in WO 99/02514, published Jan. 21, 1999, entire contents of which are herein incorporated by 0070 Thus, the present invention provides methods for reference), 1S-1R*,3R*(E).7R*,10S*,11R*,12R*,16S*- the treatment of a variety of cancers including, but not 3-2-2-(aminomethyl)-4-thiazolyl-1-methylethenyl-7,11 limited to, the following: dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabicyclo 0071 carcinoma including that of the bladder 14.1.0-heptadecane-5,9-dione (disclosed in U.S. Pat. No. (including accelerated and metastatic bladder can 6,262,094, issued Jul. 17, 2001, entire contents of which are cer), breast, colon (including colorectal cancer), kid herein incorporated by reference, and examples 7 and 8 ney, liver, lung (including Small and non-Small cell therein), and derivatives thereof; and other microtubule lung cancer and lung adenocarcinoma), ovary, pros disruptor agents. Additional antineoplastic agents include tate, testes, genitourinary tract, lymphatic System, (see Service, (1996) Science, 274:2009) rectum, larynx, pancreas (including exocrine pancre estramustine, , MAP4, and the like. Examples of atic carcinoma), esophagus, Stomach, gall bladder, Such agents are also described in the Scientific and patent cervix, thyroid, and skin (including Squamous cell literature, see, e.g., Bulinski (1997) J. Cell Sci. 110:3055 carcinoma); 3064; Panda (1997) Proc. Natl. Acad. Sci. USA94:10560 10564; Muhlradt (1997) Cancer Res. 57:3344-3346; Nico 0072 hematopoietic tumors of lymphoid lineage laou (1997) Nature 387:268-272; Vasquez (1997) Mol. Biol. including leukemia, acute lymphocytic leukemia, Cell. 8:973-985; Panda (1996) J. Biol. Chem 271:29807 acute lymphoblastic leukemia, B-cell lymphoma, 2.9812. T-cell lymphoma, Hodgkins lymphoma, non Hodgkins lymphoma, hairy cell lymphoma, histio 0.066. In cases where it is desirable to render aberrantly cytic lymphoma, and Burketts lymphoma; proliferative cells quiescent in conjunction with or prior to treatment with the chemotherapeutic methods of the inven 0073 hematopoietic tumors of myeloid lineage tion, hormones and steroids (including Synthetic analogs): including acute and chronic myelogenous leukemias, 17a-, Diethylstilbestrol, Testosterone, Pred myelodysplastic Syndrome, myeloid leukemia, and nisone, Fluoxymesterone, DromoStanolone propionate, Tes promyelocytic leukemia; tolactone, Megestrolacetate, , Methyl testosterone, , Triamcinolone, 0074 tumors of the central and peripheral nervous Chlorotrianisene, Hydroxyprogesterone, Aminoglutethim System including astrocytoma, neuroblastoma, ide, Estramustine, Medroxyprogesteroneacetate, Leupro glioma, and Schwannomas, lide, Flutamide, Toremifene, ZoladeX can also be adminis 0075 tumors of mesenchymal origin including fib tered to the patient. rosarcoma, rhabdomyOScarcoma, and Osteosarcoma; 0067. Also suitable for use in the combination chemo and therapeutic methods of the invention are antiangiogenics 0076 other tumors including melanoma, Xenoderma such as matrix metalloproteinase inhibitors, and other VEGF pigmentosum, keratoactanthoma, Seminoma, thyroid inhibitors, such as anti-VEGF antibodies and Small mol follicular cancer, and teratocarcinoma. ecules Such as ZD6474 and SU6668 are also included. Anti Her2 antibodies from Genetech may also be utilized. A 0077. For example, in one embodiment, the invention is suitable EGFR inhibitor is EKB-569 (an irreversible inhibi used to treat accelerated or metastatic cancers, Such as tor). Also included are Imclone antibody C225 immunospe bladder cancer, pancreatic cancer, prostate cancer, non-Small cific for the EGFR, and Src inhibitors. cell lung cancer, colorectal cancer and . 0068 Also suitable for use as an antiproliferative cyto 0078. In another embodiment of this invention, methods Static agent is CasodeX' which renders androgen-depen are provided for the treatment of cancerous tumors. Advan US 2004/0024032A1 Feb. 5, 2004

tageously, the method of this invention reduces the devel excess of the desired Salt-forming inorganic or organic acid opment of tumors, reduces tumor burden, or produces tumor or base, in a Suitable Solvent or Solvent combination. regression in a mammalian host. 0086 The present invention also encompasses a pharma 0079 Methods for the safe and effective administration ceutical composition useful in the treatment of cancer, of most of these chemotherapeutic agents are known to those comprising the administration of a therapeutically effective skilled in the art. In addition, their administration is amount of the combinations of this invention, with or described in the Standard literature. without pharmaceutically acceptable carriers or diluents. The pharmaceutical compositions of this invention comprise 0080 For example, the administration of many of the an anti-proliferative agent or agents, a formula I compound, chemotherapeutic agents is described in the “Physicians and a pharmaceutically acceptable carrier. The methods Desk Reference” (PDR), e.g., 1996 edition (Medical Eco entail the use of a neoplastic agent in combination with a nomics Company, Montvale, N.J. 07645-1742, USA); the Formula I compound. The compositions of the present disclosure of which is incorporated herein by reference invention may further comprise one or more pharmaceuti thereto. cally acceptable additional ingredient(s) Such as alum, sta bilizers, antimicrobial agents, buffers, coloring agents, fla 0081. The Formula I compounds may be prepared by the Voring agents, adjuvants, and the like. The antineoplastic procedures described in WO 99/02514, published Jan. 21, agents, Formula I compounds and compositions of the 1999. present invention may be administered orally or parenterally 0082 The compounds of Formulas I are useful in various including the intravenous, intramuscular, intraperitoneal, pharmaceutically acceptable Salt forms. The term “pharma Subcutaneous, rectal and topical routes of administration. ceutically acceptable salt” refers to those salt forms which 0087. For oral use, the antineoplastic agents, Formula I would be apparent to the pharmaceutical chemist, i.e., those compounds and compositions of this invention may be which are substantially non-toxic and which provide the administered, for example, in the form of tablets or capsules, desired pharmacokinetic properties, palatability, absorption, powders, dispersible granules, or cachets, or as aqueous distribution, metabolism or excretion. Other factors, more Solutions or Suspensions. In the case of tablets for oral use, practical in nature, which are also important in the Selection, carriers which are commonly used include lactose, corn are cost of the raw materials, ease of crystallization, yield, Starch, magnesium carbonate, talc, and Sugar, and lubricat Stability, hygroscopicity and flowability of the resulting bulk ing agents Such as magnesium Stearate are commonly added. drug. Conveniently, pharmaceutical compositions may be For oral administration in capsule form, useful carriers prepared from the active ingredients or their pharmaceuti include lactose, corn Starch, magnesium carbonate, talc, and cally acceptable Salts in combination with pharmaceutically Sugar. When acqueous Suspensions are used for oral admin acceptable carriers. istration, emulsifying and/or Suspending agents are com 0.083 Pharmaceutically acceptable salts of the Formula I monly added. compounds which are Suitable for use in the methods and 0088. In addition, Sweetening and/or flavoring agents compositions of the present invention include, but are not may be added to the oral compositions. For intramuscular, limited to, Salts formed with a variety of organic and intraperitoneal, Subcutaneous and intravenous use, Sterile inorganic acids Such as hydrogen chloride, hydroxymethane Solutions of the active ingredient(s) are usually employed, Sulfonic acid, hydrogen bromide, methaneSulfonic acid, and the pH of the solutions should be suitably adjusted and Sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, buffered. For intravenous use, the total concentration of the benzeneSulfonic acid, toluenesulfonic acid, Sulfamic acid, Solute(s) should be controlled in order to render the prepa glycolic acid, Stearic acid, lactic acid, malic acid, pamoic ration isotonic. acid, Sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methaneSulfonic acid, ethanedisul 0089 For preparing suppositories according to the inven fonic acid, oxalic acid, isethonic acid, and include various tion, a low melting wax Such as a mixture of fatty acid other pharmaceutically acceptable Salts, Such as, e.g., glycerides or cocoa butter is first melted, and the active nitrates, phosphates, borates, tartrates, citrates, Succinates, ingredient is dispersed homogeneously in the wax, for benzoates, ascorbates, Salicylates, and the like. Cations Such example by Stirring. The molten homogeneous mixture is as quaternary ammonium ions are contemplated as pharma then poured into conveniently sized molds and allowed to ceutically acceptable counterions for anionic moieties. cool and thereby solidify. 0084 Examples of salts of compounds of Formula I 0090 Liquid preparations include solutions, suspensions include, for example, hydrochloride Salts, methaneSulfonic and emulsions. Such preparations are exemplified by water acid Salts and trifluoroacetic acid Salts. In addition, pharma or water/propylene glycol Solutions for parenteral injection. ceutically acceptable Salts of the Formula I compounds may Liquid preparations may also include Solutions for intranasal be formed with alkali metals. Such as Sodium, potassium and administration. lithium; alkaline earth metals. Such as calcium and magne 0091 Aerosol preparations suitable for inhalation may sium; organic bases Such as dicyclohexylamine, tributy include Solutions and Solids in powder form, which may be lamine, and pyridine, and amino acids Such as arginine, in combination with a pharmaceutically acceptable carrier, lysine and the like. Such as an inert compressed gas. 0085. The pharmaceutically acceptable salts of the 0092 Also included are solid preparations which are present invention can be Synthesized by conventional chemi intended for conversion, shortly before use, to liquid prepa cal methods. Generally, the Salts are prepared by reacting the rations for either oral or parenteral administration. Such free base or acid with Stoichiometric amounts or with an liquid forms include Solutions, Suspensions and emulsions. US 2004/0024032A1 Feb. 5, 2004

0093. The compounds of Formula I, as well as the anti-neoplastic agents, described herein may also be deliv TABLE 1-continued ered transdermally. The transdermal compositions can take CHEMOTHERAPEUTIC DOSAGE the form of creams, lotions, aerosols and/or emulsions and COMBINATION mg/m (per dose) can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. Formula I + 5-5000 mg/m2 SFU, CPT-11 and 4-400 mg/m2 optionally + leucovorin 5-1000 mg/m2 0094. The combinations of the present invention may Compound O 0.1-100 mg/m2 also be used in conjunction with other well known therapies Formula I + 5-5000 mg/m2 that are Selected for their particular usefulneSS against the 5FU + radiation 200–8000 cGy condition that is being treated. Compound O 0.1-100 mg/m2 Formula I + 200–8000 cGy 0.095 If formulated as a fixed dose, the active ingredients radiation + 5-5000 mg/m2 5FU + 5-150 mg/m2 of the combination compositions of this invention are Compound O 0.1-100 mg/m2 employed within the dosage ranges described below. Alter Formula I + 5-200 mg/m2 natively, the anti-neoplastic, and Formula I compounds may +5FU and 5-5000 mg/m2 be administered Separately in the dosage ranges described optionally + Leucovorin 5-1000 mg/m2 Compound of Formula I 0.1-100 mg/m2 below. In a preferred embodiment of the present invention, +paclitaxe 40–250 mg/m2 the antineoplastic agent is administered in the dosage range CPT 11 4-400 mg/m2 described below following administration of the Formula I Compound of Formula I 0.1-100 mg/m2 compound in the dosage range described below. paclitaxel 40–250 mg/m2 --5-FU 5-5000 mg/m2 0.096 Table I sets forth preferred chemotherapeutic com Compound of Formula I 0.1-100 mg/m2 --UFT 50-800 mg/m2 binations and exemplary dosages for use in the methods of +CPT-1 I and optionally 4-400 mg/m2 the present invention. Where “Compound of Formula I' +leucovorin 5-1000 mg/m2 appears, any of the variations of Formula I Set forth herein are contemplated for use in the chemotherapeutic combina tions. For example, Compound 1 may be employed. 0097. In the above Table I, “5FU” denotes 5-, "Leucovorin' can be employed as leucoVorin calcium, TABLE 1. “UFT is a 1:4 molar ratio of :uracil, and As an example, “epothilone” is a compound described in WO CHEMOTHERAPEUTIC DOSAGE 99/02514 or WO 00/50423, both of which are incorporated COMBINATION mg/m (per dose) by reference herein in their entirety. Compound O 0.1-100 mg/m2 Formula I + Cisplatin 5-150 mg/m2 0098. While Table I provides exemplary dosage ranges of Compound O 0.1-100 mg/m2 the Formula I compounds and certain anticancer agents of Formula I + Carboplatin 5-1000 mg/m2 the invention, when formulating the pharmaceutical com Compound O 0.1-100 mg/m2 positions of the invention the clinician may utilize other Formula I + Radiation 200–8000 cGy Compound O 0.1-100 mg/m2 dosages as warranted by the condition of the patient being Formula - CPT-11 5-400 mg/m2 treated. For example, when Compound 1 is administered in Compound O 0.1-100 mg/m2 combination with carboplatin, Compound 1 may be admin Formula I + Paclitaxel 40–250 mg/m2 istered at 5 mg/m to 60 mg/m every 3 weeks and dosages Compound O 0.1-100 mg/m2 Formula I + Paclitaxel + 40–250 mg/m2 for carboplatin may be within the range of 5 mg/m' to 1000 Carboplatin 5-1000 mg/m2 mg/m or an AUC of 0.5-8 mg/mlxmin. (dosage calculated Compound O 0.1-100 mg/m2 per Calvert formula; Calvert et al., J. Clin. Oncol., 1989, 7, Formula I +5FU and 5-5000 mg/m2 1748-1756), such as an AUC of 4-6 mg/mlxmin. optionally + Leucovorin 5-1000 mg/m2 Compound O 0.1-100 mg/m2 0099. A compound of Formula I may be administered as Formula I + Epothilone -500 mg/m2 a 10-minute to 3-hour infusion, for example, as a 60-minute Compound O 0.1-100 mg/m2 Formula I + Gemcitabine 100-3000 mg/m2 infusion. The anti-proliferative agent may be administered Compound O 0.1-100 mg/m2 as a 5-minute to 2-hour infusion, for example, as a Formula I + UFT and 50-800 mg/m2 30-minute infusion. optionally + leucovorin 5-1000 mg/m2 Compound O 0.1-100 mg/m2 0100. A compound of Formula I may be administered Formula I + 100-3000 mg/m2 daily, weekly for 1-5 consecutive weeks, or every 2-5 weeks, Gemcitabine + Cisplatin 5-150 mg/m2 for example, every 3 weeks. The compound of Formula I Compound O 0.1-100 mg/m2 Formula I + 50-800 mg/m2 may also be administered in divided doses during each UFT + Leucovorin 5-1000 mg/m2 treatment cycle. For example, a compound of Formula I may Compound O 0.1-100 mg/m2 be administered on day 1 and day 8 of the treatment cycle Formula I + 5-150 mg/m2 and repeated every 3 weeks. Cisplatin + paclitaxel 40–250 mg/m2 Compound O 0.1-100 mg/m2 0101 The anti-proliferative agent may be administered Formula I + 5-150 mg/m2 daily, weekly for 1-5 consecutive weeks, or every 2-5 weeks, Cisplatin +5FU 5-5000 mg/m2 for example, every 3 weeks. For example, the anti-prolif Compound O 0.1-100 mg/m2 Formula I + 5-200 mg/m2 erative agent may be administered on day 1 of the treatment Oxaliplatin + CPT-11 4-400 mg/m2 cycle and repeated every 3 weeks. The anti-proliferative Compound of Formula I 0.1-100 mg/m2 agent may also be administered in divided doses during each treatment cycle. US 2004/0024032A1 Feb. 5, 2004

0102) A treatment cycle comprises that duration of time the condition that is being treated. Combinations of the in which the desired doses (either single or split) of a instant invention may alternatively be used Sequentially with compound of Formula I and an anti-proliferative agent are known pharmaceutically acceptable agent(s) when a mul administered, before administration of these compounds is tiple combination formulation is inappropriate. repeated in Subsequent rounds of treatment. Thus, a patient 0108. The chemotherapeutic agent(s) and/or radiation may undergo Several rounds of treatment, or treatment therapy can be administered according to therapeutic pro cycles, as determined necessary by the clinician or physi tocols well known in the art. It will be apparent to those C. skilled in the art that the administration of the chemothera 0103) In one embodiment of the present invention, Com peutic agent(s) and/or radiation therapy can be varied pound 1 may be administered as a 60-minute infusion, depending on the disease being treated and the known effects 30-minutes prior to a 30-minute carboplatin infusion on day of the chemotherapeutic agent(s) and/or radiation therapy on 1. This combination is administered every three weeks for at that disease. Also, in accordance with the knowledge of the least one treatment cycle. A treatment cycle, which in this skilled clinician, the therapeutic protocols (e.g., dosage embodiment is 3 weeks in duration, comprises one round of amounts and times of administration) can be varied in view chemotherapy using the compound of Formula I and the of the observed effects of the administered therapeutic anti-proliferative agent. Treatment on this Schedule may agents (i.e., antineoplastic agent(s) or radiation) on the occur in, but is not limited to, four dose cycles. In another patient, and in View of the observed responses of the disease embodiment of the present invention, the dosage of Com to the administered therapeutic agents. pound 1 is between 5 and 60 mg/m and the dosage of 0109 The attending clinician or physician, in judging carboplatin is between 5 and 1000 mg/m or between AUC whether treatment is effective at the dosage administered, 4 and 8. In yet another embodiment of the present invention, will consider the general well-being of the patient as well as the dosage of Compound 1 is between 25 and 50 mg/m and more definite signs. Such as relief of disease-related Symp the dosage of carboplatin is between 5 and 1000 mg/m or toms, inhibition of tumor growth, actual shrinkage of the between AUC 5 and 6. tumor, or inhibition of metastasis. Size of the tumor can be 0104. As another example of the present invention, the measured by Standard methods Such as radiological Studies, doses of Compound 1 are split on days 1 and 8 with e.g., CAT or MRI scan, and Successive measurements can be carboplatin being administered on day 1. This combination used to judge whether or not growth of the tumor has been of agents is administered every three weeks for at least one retarded or even reversed. Relief of disease-related Symp treatment cycle. A treatment cycle in this case comprises toms Such as pain, and improvement in overall condition can administration of Compound 1 on days 1 and 8 with admin also be used to help judge effectiveness of treatment. istration of carboplatin on day 1. This is followed by 2 weeks of no therapy where neither Compound I nor an anti 0110. In order to facilitate a further understanding of the proliferative agent is administered. This 3-week period invention, the following examples are presented primarily comprises one treatment cycle. Such treatment cycles are for the purpose of illustrating more Specific details thereof. continued for as long as needed. In one embodiment of the The scope of the invention should not be deemed limited by present invention, the dosage of Compound 1 is between 5 the examples, but to encompass the entire Subject matter and 60 mg/m and the dosage of carboplatin is between 5 defined by the claims. and 1000 mg/m or between AUC 4 and 8 (dosage calculated per Calvert formula; Calvert et al., J. Clin. Oncol., 1989, 7, EXAMPLES 1748-1756). In another embodiment of the present inven 0111 Compounds: tion, the dosage of Compound 1 is between 15 and 30 mg/m and the dosage of carboplatin is between 5 and 1000 mg/m 0112 The following designations are used to identify the or between AUC 5 and 6. test compounds throughout the examples: 0105 The actual dosage employed may be varied 0113 Compound 1: depending upon the requirements of the patient and the 0114) 1S-1R*,3R*(E).7R*,10S*,11R*,12R*,16S*I-7, severity of the condition being treated. Determination of the 11-dihydroxy-8,8,10,12,16-pentamethyl-3-1-methyl-2-(2- proper dosage for a particular situation is within the skill of methyl-4-thiazolyl)ethenyl-4-aza-17-oxabicyclo14.1.0) the art. Generally, treatment is initiated with Smaller dosages heptadecane-5,9-dione (compound of Formula Ia). which are less than the optimum dose of the compound. Thereafter, the dosage is increased by Small amounts until 0115 Chemicals and Solutions: the optimum effect under the circumstances is reached. For 0116. Unless specified, chemicals and solutions used for convenience, the total daily dosage may be divided and the maintenance of cell culture were obtained from GIBCO/ administered in portions during the day if desired. Intermit BRL. Sterile tissue culture ware was obtained from Corning, tent therapy (e.g., one week out of three weeks or three out N.Y. All other reagents were from Sigma or Fisher at the of four weeks) may also be used. highest grade available. 0106 When employing the methods or compositions of 0117 Drug Administration: the present invention, other agents used in the modulation of 0118 For administration of Compound 1 (an epothilone), tumor growth or metastasis in a clinical Setting, Such as two different excipients have been used: (1) ethanol/water antiemetics, can also be administered as desired. (1:9, V/v) and (2) Cremophor(R/ethanol/water (1:1:8, V/v). 0107 The combinations of the instant invention may also Compound 1 was first dissolved in ethanol or a mixture of be co-administered with other well known therapeutic Cremophor(R/ethanol (50:50). Final dilution to the required agents that are Selected for their particular usefulness against dosage Strength is made less than 1 h before drug adminis US 2004/0024032A1 Feb. 5, 2004 tration. For parenteral administration (IV), dilution was (range 31-74). Fifty-six percent (56%) of patients had made with water So that the dosing Solutions contain the received prior chemotherapy (3 or fewer regimens) and 51% Specified excipient composition described above. had prior radiotherapy. Major toxicities were myeloSuppres Sion, myalgia and peripheral neuropathy. Eleven patients Example 1 withdrew from the study because of study drug toxicity, with 0119) Pharmacological Studies of compound 1 in Com peripheral neuropathy being reported in all these patients. bination with Carboplatin in Patients with Advanced Cancer 0.126 The regimen was active: partial responses were 0120 Compound 1 followed by carboplatin was given reported in five (5) patients (2 breast, neuro-endocrine, intravenously every 3 weeks to patients with advanced Solid unknown primary carcinomas and mesothelioma), 48% of tumors treated with S2 prior chemotherapy regimens. Phar patients showed disease Stabilization for more than two macokinetics of both drugs were measured on the first months. Analysis of Compound 1 plasma levels show that course. Twenty-five (25) patients were treated at four dose C and AUC increase with dose, the volume of distribution levels-combining Compound 1 (30 or 40 mg/m) with is high and half-life is ~30 hours. Thus, Compound 1 can 5-1000 mg/m or AUC 5 or 6 (Calvert formula; Calvert et safely be combined with carboplatin, with the major toxici al., J. Clin. Oncol., 1989, 7, 1748-1756) of carboplatin. A ties being neutropenia and peripheral neuropathy. Dividing total of 91 courses were given. Transient CTC grade 4 the dose of Compound 1 allows a higher dose intensity to be neutropenia was noted at all dose levels and was dose achieved. limiting at 40 mg/m/AUC 6 (2/2 patients with complicated grade 4 neutropenia). The major non-haematological toxici What is claimed is: ties were myalgia on day 4 and cumulative peripheral 1. A method for the treatment of a proliferative disease neuropathy. Seven patients withdrew from the trial because which comprises administering to a mammalian Specie in of neurotoxicity, grade 2/3 Sensory neuropathy after at least need thereof a therapeutically effective amount of (1) a 3 courses but grade 3 motor neuropathy in one patient on the compound of formula I and (2) at least one anti-proliferative first course. The regimen was active with 3/25 confirmed agent, partial responses (breast, neuroendocrine and unknown pri mary carcinomas) and 12 patients have disease Stabilization and clinical benefit from treatment. 0121 The maximum tolerated dose of Compound 1 was 40 mg/m with carboplatin AUC 5 (dosage calculated per Calvert formula, which allows determination of dosage based upon renal function of patient, Calvert et al., J. Clin. Oncol., 1989, 7, 1748-1756). Example 2 0122) Pharmacological Studies of Compound 1 in Com bination with Carboplatin in Patients with Advanced Caancer wherein: 0123 Compound 1 was assessed in Phase I studies in combination with other chemotherapeutic agents. Com Q is Selected from the group consisting of pound 1 was given as a 60-minute infusion, 30 minutes prior to a 30-minute carboplatin infusion on day 1 every three weeks (or 21 days). Pharmacokinetic Samples were taken 8 R 8 R8 during the first cycle. Twenty-five (25) patients were treated O on this schedule at 4 dose levels (Compound 1 doses of 30 mg/m or 40 mg/m with carboplatin doses of 5-1000 mg/m, or AUC 5 or 6). Dose limiting toxicity (DLT) occurred with 40 mg/m’ of Compound 1 and carboplatin AUC 6 (per Calvert formula) on this schedule, with myelo RoO RoO Suppression as the major toxicity. s and 0.124. A further 14 patients were recruited onto an amended Schedule with Compound 1 doses being split and administered on days 1 and 8 every three weeks (or 21 days) and carboplatin being administered on day 1. DLT on this G is Selected from the group consisting of alkyl, Substi schedule was observed with carboplatin AUC 6 and with tuted alkyl, aryl, Substituted aryl, heterocyclo, Compound 1 at 25 mg/m being administered on days 1 and 8. The preceding dose level (carboplatin AUC 6 and Com pound 1 at 20 mg/m on days 1 and 8) was expanded and a total of 8 patients were treated. 0125) Thirty-nine (39) patients (18 male/19 female/2 missing) were treated over seven (7) dose level; 92% were WHO performance status 0 or 1 at entry; mean age 55 years US 2004/0024032A1 Feb. 5, 2004

6. The method of claim 5 wherein the anti-proliferative -continued agent is carboplatin. R12 O 7. The method of claim 1 wherein the compound of formula I is 1S-1R*,3R*(E).7R*,10S*,11R*,12R*,16S*- D and Rians 7,11-dihydroxy-8,8,10,12,16-pentamenthyl-3-1-methyl-2- (2-methyl-4-thiazolyl)ethenyl-4-aza-17-oxabicyclo14.1.0) R14 heptadecane-5,9-dione (Compound 1). 8. The method of claim 2 wherein the compound of W is O or N Rs; formula I is 1S-1R*,3R*(E).7R*,10S*,11R*,12R*,16S*- 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-1-methyl-2- X is O or H, H; (2-methyl-4-thiazolyl)ethenyl-4-aza-17-oxabicyclo14.1.0) Y is Selected from the group consisting of O, H, OR; heptadecane-5,9-dione (Compound 1). OR, OR, NOR, H, NHOR; H, NRR, H, H; 9. The method of claim 1 wherein the compound of and CHR, wherein OR7, OR, can be a cyclic ketal; formula I is 1S-1R*,3R*(E).7R*,10S*,11R*,12R*,16S*- 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-1-methyl-2- Z, and Z are independently selected from the group (2-methyl-4-thiazolyl)ethenyl-4-aza-17-oxabicyclo14.1.0) consisting of CH, O, NR, S, and SO2, wherein only heptadecane-5,9-dione (Compound 1) and the anti one of Z, and Z can be a heteroatom; proliferative agent is carboplatin. B and B are independently Selected from the group 10. The method of claim 2 wherein the compound of consisting of OR1, OCORs, and O-C(=O)- formula I is 1S 1R*,3R*(E).7R*,10S*,11R*,12R*,16S*- NRR-7, and when B is H and Y is OH, H, they can 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-1-methyl-2- form a six-membered ring ketal or acetal; (2-methyl-4-thiazolyl)ethenyl-4-aza-17-oxabicyclo14.1.0) D is selected from the group consisting of NRR, heptadecane-5,9-dione (Compound 1) and the anti NRCORs and Saturated heterocycle; proliferative agent is carboplatin. 11. A method for modulating tumor growth in a human in R1, R2, R3, R1, Rs. R6, R7, R13, R1, R1s, Rio, Rao, R21, need thereof, comprising Sequential or simultaneous admin R, R2 and R27 are independently Selected from the istration of 1S 1R*,3R*(E).7R*,10S*,11R*,12R*,16S*- group consisting of H, alkyl, Substituted alkyl, and aryl, 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-1-methyl-2- and when R and R are alkyl can be joined to form a (2-methyl-4-thiazolyl)ethenyl-4-aza-17-Oxabicyclo14.1.0) cycloalkyl, and when R and R are alkyl can be joined heptadecane-5,9-dione (Compound 1) and carboplatin. to form a cycloalkyl, 12. The method of claim 11 wherein said 1S 1R*,3R*(E), Ro, Rio, Re, R7, R2, R2s and Rs are independently 7R*,10S*,11R*, 12R*,16S*I-7,11-dihydroxy-88,10,12, Selected from the group consisting of H, alkyl, and 16-pentamethyl-3-1-methyl-2-(2-methyl-4-thiazolyl)ethe Substituted alkyl; nyl-4-aza-17-oxabicyclo14.1.0 heptadecane-5,9-dione (Compound 1) is administered first, followed by adminis Rs, R1, R12, R2s, Rao, R32, and Ras are independently tration of carboplatin, and wherein this combination of Selected from the group consisting of H, alkyl, Substi Compound 1 and carboplatin is administered every three tuted alkyl, aryl, Substituted aryl, cycloalkyl and het weeks for at least one treatment cycle. erocyclo; 13. The method of claim 12 wherein said 1S 1R*,3R*(E), Rs, R2 and Rao are independently Selected from the 7R*,10S*,11R*, 12R*,16S*I-7,11-dihydroxy-88,10,12, group consisting of H, alkyl, Substituted alkyl, aryl, 16-pentamethyl-3-1-methyl-2-(2-methyl-4-thiazolyl)ethe Substituted aryl, cycloalkyl, heterocyclo, RC=O, nyl-4-aza-17-oxabicyclo14.1.0 heptadecane-5,9-dione RSO, hydroxy, O-alkyl or O-substituted alkyl; and (Compound 1) is administered as a 60-minute infusion, 30 pharmaceutically acceptable Salts thereof and any minutes prior to a 30-minute infusion of carboplatin. hydrates, Solvates or geometric, optical and Steroiso 14. The method of claim 12 wherein the dosage of said mers thereof, wherein Said compound of formula I and 1S 1R*,3R*(E).7R*,10S*,11R*,12R*,16S*I-7,11-dihy Said anti-proliferative agent are administered simulta droxy-8,8,10,12,16-pentamethyl-3-1-methyl-2-(2-methyl neously or Sequentially. 4-thiazolyl)ethenyl-4-aza-17-oxabicyclo14.1.0 heptade 2. The method of claim 1 wherein the antiproliferative cane-5,9-dione (Compound 1) is between 5 mg/m and 60 agent is administered after administration of the compound mg/m and the dosage of carboplatin is between 5 mg/m and of formula I. 1000 mg/ml. 3. The method of claim 2 for the treatment of cancerous 15. The method of claim 14 wherein the dosage of said Solid tumors. 1S 1R*,3R*(E).7R*,10S*,11R*,12R*,16S*I-7,11-dihy 4. The method of claim 2 for the treatment of refractory droxy-8,8,10,12,16-pentamethyl-3-1-methyl-2-(2-methyl tumorS. 4-thiazolyl)ethenyl-4-aza-17-oxabicyclo14.1.0 heptade 5. The method of claim 1 wherein the anti-proliferative cane-5,9-dione (Compound 1) is between 25 mg/m and 50 agent is Selected from the group consisting of a microtubule mg/m and the dosage of carboplatin is between 5 mg/m affecting agent, an alkylating agent, an anti-metabolite, and 1000 mg/m. epidophyllotoxin, an antineoplastic enzyme, a topoi 16. The method of claim 11 wherein said 1S 1 R*, Somerase inhibitor, , , inhibitors 3R*(E).7R*,10S*,11R*, 12R*, 16S*I-7,11-dihydroxy-88, of cell cycle progression, radiation and a platinum coordi 10,12,16-pentamethyl-3-1-methyl-2-(2-methyl-4-thiaz nation complex. olyl)ethenyl-4-aza-17-oxabicyclo14.1.0heptadecane-5.9- US 2004/0024032A1 Feb. 5, 2004 dione (Compound 1) is administered on day 1 and again on cane-5,9-dione (Compound 1) is between 5 mg/m and 60 day 8, and carboplatin is administered on day 1, for at least mg/m and the dosage of carboplatin is between 5 mg/m and one treatment cycle. 1000 mg/ml. 17. The method of claim 16 wherein said 1S 1R*,3R*(E), 19. The method of claim 18 wherein the dosage of said 7R*,10S*,11R*, 12R*,16S*7,11-dihydroxy-8,8,10,12,16 1S 1R*,3R*(E).7R*,10S *,11R*,12R*,16S *-7,11-dihy pentamethyl-3-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl droxy-8,8,10,12,16-pentamethyl-3-1-methyl-2-(2-methyl 4-aza-17-oxabicyclo14.1.0heptadecane-5,9-dione 4-thiazolyl)ethenyl-4-aza-17-oxabicyclo14.1.0 heptade (Compound 1) is administered as a 60-minute infusion, 30 2 minutes prior to a 30-minute infusion of carboplatin. cane-5,9-dione (Compound 1) is between 15 and 30 mg/m 18. The method of claim 16 wherein the dosage of said and the dosage of carboplatin is between 5 mg/m° and 1000 1S 1R*,3R*(E).7R*,10S*,11R*,12R*,16S*I-7,11-dihy mg/m. droxy-8,8,10,12,16-pentamethyl-3-1-methyl-2-(2-methyl 4-thiazolyl)ethenyl-4-aza-17-oxabicyclo14.1.0 heptade