ZA200502337B - Synthesis of epothilones, intermediates thereto, analogues and uses thereof - Google Patents
Synthesis of epothilones, intermediates thereto, analogues and uses thereof Download PDFInfo
- Publication number
- ZA200502337B ZA200502337B ZA200502337A ZA200502337A ZA200502337B ZA 200502337 B ZA200502337 B ZA 200502337B ZA 200502337 A ZA200502337 A ZA 200502337A ZA 200502337 A ZA200502337 A ZA 200502337A ZA 200502337 B ZA200502337 B ZA 200502337B
- Authority
- ZA
- South Africa
- Prior art keywords
- cyclic
- aryl
- orp
- compound
- heteroaryl
- Prior art date
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- 229930013356 epothilone Natural products 0.000 title claims description 63
- 230000015572 biosynthetic process Effects 0.000 title description 33
- 238000003786 synthesis reaction Methods 0.000 title description 28
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 title description 19
- 239000000543 intermediate Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 169
- -1 cyclic acetal Chemical class 0.000 claims description 131
- 229910052739 hydrogen Inorganic materials 0.000 claims description 119
- 239000001257 hydrogen Substances 0.000 claims description 116
- 125000003118 aryl group Chemical group 0.000 claims description 102
- 125000001072 heteroaryl group Chemical group 0.000 claims description 85
- 125000001931 aliphatic group Chemical group 0.000 claims description 78
- 206010028980 Neoplasm Diseases 0.000 claims description 67
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- 125000004122 cyclic group Chemical group 0.000 claims description 67
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 66
- 125000002015 acyclic group Chemical group 0.000 claims description 64
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 52
- 150000002367 halogens Chemical class 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 47
- 125000006239 protecting group Chemical group 0.000 claims description 47
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 46
- 150000003883 epothilone derivatives Chemical group 0.000 claims description 44
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
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- 238000000034 method Methods 0.000 claims description 40
- 229960001592 paclitaxel Drugs 0.000 claims description 40
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 40
- 238000011282 treatment Methods 0.000 claims description 40
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 32
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
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- 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 17
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
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- 125000004104 aryloxy group Chemical group 0.000 claims description 6
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- 239000008389 polyethoxylated castor oil Substances 0.000 claims description 5
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- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 claims description 3
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- 108020005497 Nuclear hormone receptor Proteins 0.000 claims 5
- LSMWOQFDLBIYPM-UHFFFAOYSA-N 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-2h-imidazol-1-ium-2-ide Chemical group CC1=CC(C)=CC(C)=C1N1[C-]=[N+](C=2C(=CC(C)=CC=2C)C)CC1 LSMWOQFDLBIYPM-UHFFFAOYSA-N 0.000 claims 1
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- IREVRWRNACELSM-UHFFFAOYSA-J ruthenium(4+);tetrachloride Chemical compound Cl[Ru](Cl)(Cl)Cl IREVRWRNACELSM-UHFFFAOYSA-J 0.000 claims 1
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Description
SYNTHESIS OF EPOTHILONES, INTERMEDIATES THERETO, Co
ANALOGUES AND USES THEREOF
Epothilones A and B (2a and 2b, Scheme 1) are naturally occurring cytotoxic macrolides that were isolated from a cellulose degrading mycobacterium, Sorangium cellulosum (Hofle et al. Angew. Chem., Int. Ed Engl. 1996, 35, 1567 and J. Antibiot. 1996, 49, 560; each of which is incorporated herein by reference). Despite their vastly different structures, epothilones A and B share the same mechanism of action as paclitaxel (Taxol®) which involves growth inhibition of tumor cells by tubulin polymerization and stabilization of microtubule assemblies (Bollag er al. Cancer Res. 1995, 55, 2325; incorporated by reference). In spite of its unquestioned clinical value as a front-line chemotherapeutic agent, Taxol® is far from an ideal drug. Its marginal water solubility necessitates recourse to formulation vehicles such as Cremophores that pose their own risks and management issues (Essayan et al. J. Allergy Clin. Immunol. 1996, 97, 42; incorporated herein by reference). Moreover, Taxol® is vulnerable to deactivation through multiple drug resistance (MDR) (Giannakakou et al. J. Biol.
Chem. 1997, 272, 17118; incorporated herein by reference). However, it has also been demonstrated that epothilones A and B retain remarkable potency against MDR tumor cells (Kowalski et al. Mol. Biol. Cell 1995, 6, 2137; incorporated herein by reference).
Additionally, the increased water solubility in comparison to paclitaxel may be useful for the formulability of epothilones. While the naturally occurring compound, epothilone B (2b, EpoB, in Scheme 1), is a potent member of the epothilone family of natural products, it unfortunately possesses, at least in xenograft mice, a worrisomely narrow therapeutic index (Su ef al. Angew. Chem. Int. Ed. Engl. 1997, 36, 1093; Harris etal J. Org. Chem. 1999, 64, 8434; each of which is incorporated herein by reference). o 20S
Ro 0 Vg, = Alo. a
SITE R= ~N
HO B85 AcO 8
OH
I HE oT
Scheme 1: Taxoids and Epothilones
Given the limited therapeutic index of EpoB, other epothilone analogues, in ” particular the 12,13-desoxyepothilones, were investigated for their ability to provide an improved therapeutic profile (see, U.S. Patent No.: 6,242,469, 6,284,781, 6,300,355, 6,369,234, 6,204,388, 6,316,630; each of which is incorporated herein by reference).
Invivo experiments conducted on various mouse models demonstrated that 12,13- desoxyepothilone B (3b, dEpoB in Scheme 2) possesses therapeutic potential against various sensitive and resistant human tumors in mice xenografts (Chou et al. Proc.
Natl. Acad. Sci. U.S.A. 1998, 95, 9642 and 15798; incorporated herein by reference).
Recently, the therapeutic superiority of these desoxyepothilones over other anticancer agents has been conclusively demonstrated by thorough comparative studies (Chou et al. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 8113; incorporated herein by reference). oo Due to its impressive in vivo profile, dEpoB has been advanced through toxicology evaluations in dogs, and is now in human trials as an anticancer drug.
JOH OH OH
R= rR R—\ 0} 0}
OH OH OH sas Sg Sun Deion Cr, SG LO Be Ef Con STR SRT or en 3fRy = CHy, Re = NH;, Desmethylamino-dEpoB (dadEpoB) Af R, = CHy, Re = NH;, Desmethylamino-ddEpoB 5fR, = CHy, Re = NH;, Desmethylamino-iso-dEpoB
LRA Bho hth nee
Scheme 2. Various Desoxyepothilone Analogues
In light of the promising therapeutic utility of the 12,13-desoxyepothilones, it would be desirable to investigate additional analogues as well as additional synthetic methodologies for the synthesis of existing epothilones, desoxyepothilones, and
A analogues thereof, as well as novel analogues thereof. In particular, given the interest in the therapeutic utility of this class of compounds, it would also be desirable to develop methodologies capable of providing significant quantities of any epothilones or desoxyepothilones previously described, or those described herein, for clinical trials and for large-scale preparation.
Figure 1 is a table of ICs values of epothilones against CCRF-CEM, CCRF-
CEM/VBL, and CCRF-CEM/Taxol cell growth. Cell growth inhibition was measured by XTT tetrazonium assay after 72-hour incubation for cell growth, as described previously (Scudiero et al. Cancer Res. 46:4827-4833, 1988; incorporated herein by reference). ICs, values were determined from dose-effect relationship at six or seven concentrations of each drug, by using a computer program (Chou et al. Adv. Enzyme
Regul. 22:27-55, 1984; Chou et al. CalcuSyn for Windows (Biosoft, Cambridge, UK), 1997; each of which is incorporated herein by reference) as described earlier (Chou ef al. Proc. Natl. Acad. Sci. USA 95:15798-15802, 1998; incorporated herein by reference). :
Figure 2 is a "H NMR spectrum of trans-9,10-dehydro-12,13-desoxyEpoB.
Figure 3 is a >C NMR spectrum of rans-9,10-dehydro-12,13-desoxyEpoB.
Figure 4 shows a scheme for synthesis of 11-R and 14-R epothilones using
LACDAC-ring closing olefin methathesis, and illustrates certain substitutions available with synthetic strategies that pass through a 9,10-dehydro epothilone.
Figure 5 presents relative cytotoxicity data against human leukemic cells in vitro for a variety of epothilone compounds and derivatives including certain 9,10- dehydro compounds (e.g., compound 7 in Figure SA and compound 88 and 89 in
Figure 5B).
Figure 6 depicts alternative synthetic strategies for preparing 9,10-dehydro epothilone analogs. Figure 6A illustrates a Macro-Stille strategy, a sp>-sp° coupling strategy, and B-Suzuki strategy. Figure 6B illustrates a Julia olefination strategy, a
Wadsworth-Emmons strategy, and a Macro-Reformatosky strategy. Figure 6C illustrates a McMurry coupling strategy and a lactam analog synthesis.
Figure 7 shows various analogs of 9,10-dehydro-12,13-desoxy EpoB. . Figure 8 shows the therapeutic effect of 9,10-dehydro-dEpoB and dEpoB in nude mice bearing human mammary carcinoma MX-1 xenograft (iv infusion, Q2Dx3).
Figure 9 shows the stability of epothilone analogs in murine plasma. Epo 1 is 12,13-desoxyEpoB, Epo 2 is 26-F3-12,13-desoxyEpoB, Epo 3 is (E)-9,10-dehydro- 12,13-desoxyEpoB, and Epo 4 is 26-F3-(£)-9,10-dehydro-12,13-desoxyEpoB.
Figure 10 depicts the therapeutic effect of epothilone analogs in nude mice bearing HCT-116 xenograft (iv infusion, Q2Dx7, n=3). Arrows indicate drug administration. Epo 3 is (E)-9,10-dehydro-12,13-desoxyEpoB.
Figure 11 shows the potencies of various epothilone analogues against tumor cell growth in vitro and therapeutic index, as compared to paclitaxel and vinblastine.
Figure 12s a table summarizing the effect of dEpoB, Taxol, and 26-triF-9,10- deH-dEpoB against MX-1 xenograft in nude mice.
Figure 13 shows the therapeutic effect of 26-trifluoro-9,10-dehydro-dEpoB and 9,10-dehydro-EpoB on tumor size in nude mice bearing MX-1 xenografts (6 hour iv infusion, Q2Dx6 & Q2Dx9, respectively).
Figure 14 shows body weight changes of nude mice bearing human mammary carcinoma tumor MX-1 xenograft following treatment with 26-trifluoro-9, 1 0-dehydro- dEpoB and 9,10~dehydro-EpoB (6 hour infusion, Q2Dx6 & Q2Dx9, respectively).
Figure 15 shows the therapeutic effect of 26-trifluoro-9,10-dehydro-dEpoB and 9,10-dehydroEpoB on tumor size in nude mice bearing MX-1 xenografts (6 hour iv infusion, Q2Dx6 & Q2Dx9, respectively).
Figure 16 shows body weight changes of nude mice bearing human mammary carcinoma tumor MX-1 xenograft following treatment with 26-trifluoro-9,10-dehydro- dEpoB and 9,10-dehydro-EpoB (6 hour iv infusion, Q2Dx6 & Q2Dx9, respectively).
Figure 17 shows the therapeutic effect of 9,10-dehydro-dEpoB on tumor size in nude mice bearing HCT-116 xenografts (iv infusion, Q2Dx7).
Figure 18 shows the effect of 9,10-dehydro-dEpoB on tumor size in nude mice bearing human colon carcinoma HCT-116 xenografts (iv infusion, Q3Dx5).
Figure 19 shows the effect of 9,10-dehydro-dEpoB on tumor size in nude mice bearing A549/Taxol xenografts (6 hour iv infusion, Q3Dx7).
Figure 20 shows changes in body weight of nude mice bearing A549/Taxol xenograft treated with 26-trifluoro-9,10-dehydro-dEpoB and 9,10-dehydro-dEpoB (6 hour iv infusion, Q3Dx7).
Figure 21 shows the effect of 26-trifluoro-9,10-dehydro-dEpoB and 9,10- dehydro-dEpoB on tumor size in nude mice bearing A549/Taxol xenografts (6 hour iv ’ infusion, Q2Dx7). :
Figure 22 shows changes in body weight of nude mice bearing A549/Taxol xenografts treated with 26-trifluoro-9,10-dehydro-dEpoB and 9,10-dehydro-dEpoB (6 hour iv infusion, Q2Dx7).
Figure 23 shows the effect of 9,10-dehydro-EpoB on tumor size in nude mice bearing human colon carcinoma HCT-116 tumor xenografts (6 hour iv infusion).
Figure 24 shows changes in body weight of nude mice bearing human colon carcinoma HCT-116 tumor xenograft following treatment with 9,10-dehydro-EpoB (6 hour iv infusion).
Figure 25 shows microtubule formation from tubulin in the presence of various epothilone analogues at 37 °C
Figure 26 shows microtubule formation from tubulin in the presence of various epothilone analogues at 4 °C.
Figure 27 shows the effect of 9,10-dehydro-dEpoB and dEpoB on tumor size in nude mice bearing HCT-116 xenografts (iv infusion, Q2Dx6).
Figure 28 shows changes in body weight of nude mice bearing HCT-116 xenografts after treatment with 9,10-dehydro-dEpoB and dEpoB (iv infusion, Q2Dx6).
Figure 29 shows the effect of 9,10-dehydro-dEpoB on tumor size in nude mice bearing human colon carcinoma HCT-116 xenografts (iv infusion, Q3Dx4).
Figure 30 shows changes in body weight of nude mice bearing human colon carcinoma tumor HCT-116 xenografts following treatment with 9,10-dehydro-dEpoB (5 mg/kg, iv infusion, X3Dx4).
Figure 31 is a table with ICs values for epothilone analogues against CCRF-
CEM cell growth.
Figure 32 shows the metabolic stability of epothilone analogues in vitro.
Figure 33 is a table detailing the therapeutic effects of various epothilone analogues against human tumor xenografts in mice with 6 hour iv infusion.
Figure 34 shows the effect of 9,10-dehydro-EpoB on tumor size in nude mice bearing human colon carcinoma HCT-116 tumor xenograft (6 hour iv infusion,
Q2Dx7).
Figure 35 shows changes in body weight of nude mice bearing human colon carcinoma HCT-116 tumor xenografts following treatment with 9,10-dehydro-EpoB and oxazole-EpoD (6 hour infusion, Q2Dx7).
Figure 36 shows the effect of 26-trifluoro-9,10-dehydro-dEpoB and 9,10- dehydro-dEpoB on tumor size in nude mice bearing A549/Taxol xenografts (6 hour iv infusion, Q2Dx4).
Figure 37 shows the effect of 9,10-dehydro-dEpoB on tumor size in nude mice bearing A549/Taxol xenografts (6 hour iv infusion, Q3Dx3).
Figure 38 shows the stability of epothilone analogues in 20% mouse plasma/PBS.
. Figure 39 shows the stability of epothilone analogues in 10% Men Liver ~ S9/PBS.
Figure 40 shows EpoD stability chromatogram in 10% Men Liver S9/PBS.
Figure 41 are tables describing the effect of various epothilone analogues on in vitro microtubule polymerization at 37 °C in the absence of GTP (A) and the
Cytotoxicity of various epothilone analogs in the human lung cell line A549 (B).
Figure 42 shows the stabilization of microtubule formation by epothilones at 35 °C and 4 °C.
Figure 43 shows the therapeutic effect of 9,10-dehydro-dEpoB in nude mice bearing T human mammary carcinoma (MX-1) xenograft (6 hour infusion, Q2Dx5).
Figure 44 shows the change in body weight of nude mice bearing human mammary carcinoma (MX-1) xenograft following treatment with 9,10-dehydro-dEpoB (6 hour infusion, Q2Dx8).
Figure 45 shows the change in body weight of nude mice bearing HCT-116 xenograft following treatment with 9,10-dehydro-dEpoB (iv infusion, Q2Dx7).
Figure 46 shows the therapeutic effect of 9,10-dehydro-dEpoF, dEpoB, and
Taxol on tumor size in nude mice bearing human mammary carcinoma (MX-1) tumor xenograft (6 hour iv infusion, Q2Dx6).
Figure 47 shows the changes in body weight of nude mice bearing human mammary carcinoma (MX-1) tumor xenograft following treatment with 9,10-dehydro- dEpoF, dEpoB, and Taxol (6 hour infusion, Q2Dx6).
Figure 48 shows the therapeutic effect of 9,10-dehydo-dEpoF and dEpoB in nude mice bearing human colon carcinoma HCT-116 xenograft (6 hour infusion,
Q2Dx8).
Figure 49 shows the changes in body weight of nude mice bearing HCT-116 xenograft following treatment with 9,10-dehydro-dEpoF and dEpoB (6 hour infusion,
Q2Dx8).
Figure 50 shows the therapeutic effect of 9,10-dehydro-dEpoF and dEpoB in nude mice bearing Taxol-resistant human lung carcinoma (A549/Taxol) xenograft (6 hour infusion, Q2DxS5).
Figure 51 shows changes in body weight of nude mice bearing Taxol-resistant human lung carcinoma (A549/Taxol) xenograft following treatment with 9,10-dehydro- dEpoF and dEpoB (6 hour infusion, Q2Dx5).
Figure 52 is a table comparing the potency of various epothilone analogs with respect to inhibition of tumor growth in vitro and relative therapeutic index.
Figure 53 shows the therapeutic effect of 9,10-dehydro-dEpoB in nude mice bearing MX-1 xenograft (Q3Dx9, 6 hr.-iv infusion).
J Figure 54 shows changes in body weight of nude mice bearing an MX-1 xenograft following treatment with 9,10-dehydro-dEpoB (Q3Dx9, 6 hr-iv infusion).
Figure 55 shows the therapeutic effect of 9,10-dehydro-epothilone B in nude mice bearing MX-1 xenograft (Q3Dx9, 6 hour infusion).
Figure 56 shows changes in body weight of nude mice bearing MX-1 xenograft following treatment with 9,10-dehydro-epothilone B (Q3Dx9, 6hr.-iv infusion).
Figure 57 shows the therapeutic effect at low doses of 26-trifluoro-9,10- dehydro-dEpoB in nude mice bearing MX-1 xenograft (6 hr.-i.v. infusion, Q2Dx12).
Figure 58 shows changes in body weight of nude mice bearing a MX-1 xenograft following treatment with low doses of 26-trifluoro-9,10-dehydro-dEpoB (6hr.-i.v. infusion, Q2Dx12).
Figure 59 shows the chemotherapeutic effect of epothilone analogs against : human tumor xenografts in nude mice. Tumor tissue (40-50 mg) was implanted s.c. on
Day 0. Treatment was started when tumor size reached about 100 mm” or greater as indicated. All treatments as indicated by arrows were carried out with 6-hr-i.v. infusion via tail vein using a mini-catheter and programmable pump as described earlier (Su, D.-
S. et al, Angew. Chem. Int. Ed. 1997, 36,2093; Chou, T. C. et al. Proc. Natl. Acad. Sci.
USA. 1998, 95, 15798; each of which is incorporated herein by reference). Each dose group consisted of four or more mice. Body weight was referred to as the total body weight minus tumor weight assuming 1 mm’ of tumor equals 1 mg of tumor tissue. A.
Mammary carcinoma MX-1 xenograft treated with a low dose of 25-trifluoro-(£)-9,10- dehydro-12,13-desoxyEpoB (10 mg/kg) when compared with those in Table 1 (20 mg/kg and 30 mg/kg). B. MX-1 large xenografts (500 mm’) were treated with 25- trifluoro-(£)-9,10-dehydro-12,13-desoxyEpoB (25 mg/kg) and dEpoB (30 mg/kg). C.
Slow growing A549 lung carcinoma xenograft treated with 25-trifluoro-(£)-9,10- dehydro-12,13-desoxyEpoB (25 mg/kg) and dEpoB (30 mg/kg). D. A549/Taxol (44- fold resistance to paclitaxel in vitro) xenograft treated with 25-trifluoro-(£)-9,10- dehydro-12,13-desoxyEpoB (20 mg/kg) and (£)-9,10-dehydro-12,13-desoxyEpoB (4 mg/kg). The treatment for deH-dEpoB on day 28 was skipped due to marked and rapid body weight decreases.
Figure 60 depicts the synthesis of C-21 modified 9,10-(E)-dehydro-epothilones.
Figure 60A shows the synthesis of 26-trifluoro-21-methylamino-9,10-(E)-dehydro- 12,13-desoxyepothilone B. Figure 60B is a synthetic scheme for the preparation to 26- SI trifluoro-21-amino-9,10-(E)-dehydro-12,13-desoxyepothilone B as an intermediate in the synthesis of 26-trifluoro-21-dimethylamino-9,10-()-dehydro-12,13- desoxyepothilone B.
Figure 61 is table with ICsp values for C-21 modified epothilones against tumor cell line CCRF-CEM and its drug-resistant sublines.
Figure 62 shows the therapeutic effect of 26-trifluoro-9,10-dehydro-dEpoB and
Taxol in nude mice bearing human T-cell lymphoblastic leukemia CCRF-CEM xenograft (6 hour iv infusion, Q2Dx8).
Figure 63 shows the changes in body weight changes of nude mice bearing human T-cell lymphoblastic leukemia CCRF-CEM xenograft following treatment with 25-trifluoro-9,10-dehydro-dEpoB and Taxol (6 hour iv infusion, Q2Dx8).
Figure 64 shows the therapeutic effect of 26-trifluoro-9,10-dehydro-dEpoB and
Taxol in nude mice bearing human T-cell lymphoblastic leukemia CCRF-CEM/Taxol xenograft (Taxol resistant) (6 hour iv infusion, Q2Dx7, x5).
Figure 65 shows the changes in body weight changes of nude mice bearing human T-cell lymphoblastic leukemia CCRF-CEM/Taxol xenograft (Taxol resistant) following treatment with 26-trifluoro-9,10-dehydro-dEpoB and Taxol (6 hour iv infusion, Q2Dx7, x5).
Figure 66 shows the therapeutic effect of 26-trifluoro-9,10-dehydro-dEpoB and
Taxol in nude mice bearing human colon carcinoma HCT-116 xenograft (Q2Dx4, x2, 6 hour iv infusion).
Figure 67 shows the changes in body weight of nude mice bearing human colon carcinoma HCT-116 xenograft following treatment with 26-trifluoro-9,10-dehydro- dEpoB and Taxol (Q2Dx4, x2, 6 hour iv infusion).
Figure 68 shows the therapeutic effect of 9,10-dehydro-EpoB in nude mice bearing MX-1 xenograft (6 hour iv infusion).
Figure 69 shows the changes in body weight of nude mice bearing human mammary carcinoma MX-1 xenograft following treatment with 9,10-dehydro-EpoB (6 hour iv infusion).
Figure 70 shows the therapeutic effect of 9,10-dehydro-EpoB in nude mice bearing human T-cell lymphoblastic leukemia CCRF-CEM/Taxol xenograft (Taxol resistant) (6 hour iv infusion, Q3Dx5, x2).
Figure 71 shows the changes in body weight of nude mice bearing human T- cell lymphoblastic leukemia CCRF-CEM/Taxol xenograft (Taxol resistant) following treatment with 9,10-dehydro-EpoB (6 hour iv infusion, Q3DxS5, x2).
Figure 72 shows the therapeutic effect of 26-trifluoro-dEpoB and 26-trifluoro- 9,10-dehydro-dEpoF in nude mice bearing human mammary carcinoma MX-1 xenograft (Q2Dx11, iv injection).
Figure 73 shows the changes in body weight of nude mice bearing human mammary carcinoma MX-1 xenograft following treatment with 26-trifiuoro-dEpoB and 26-trifluoro-9,10-dehydro-dEpoF (Q2Dx11, iv injection).
Figure 74 shows the therapeutic effect of 9,10-dehydro-dEpoB in nude mice bearing human mammary carcinoma MX-1 xenograft (Q3Dx9, 6 hour iv infusion).
Figure 75 shows the changes in body weight of nude mice bearing human mammary carcinoma MX-1 xenograft following treatment with 9,10-dehydro-dEpoB (Q3Dx9, 6 hour iv infusion).
Figure 76 shows the therapeutic effect of 26-trifluoro-9,10-dehydro-dEpoF in nude mice bearing human lung carcinoma (MX-1) xenograft (6 hour iv infusion and iv injection).
Figure 77 shows the changes in body weight of nude mice bearing MX-1 xenograft following treatment with 26-trifluoro-9,10-dehydro-dEpoF (6 hour iv infusion and iv injection).
Certain compounds of the present invention, and definitions of specific functional groups are also described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75" Ed., inside cover, and specific functional groups are generally defined as described therein.
Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell,
University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference. Furthermore, it will be appreciated by one of 9
A ordinary skill in the art that the synthetic methods, as described herein, utilize a variety of protecting groups. By the term “protecting group”, as used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. In preferred embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be : selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other funcational groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction. As detailed herein, oxygen, sulfur, nitrogen and carbon protecting groups may be utilized. Exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can : be readily identified using the above criteria and utilized in the method of the present invention. Additionally, a variety of protecting groups are described in “Protective
Groups in Organic Synthesis” Third Ed. Greene, T.W. and Wuts, P.G., Eds., John
Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example of proliferative disorders, including, but not limited to cancer. , The term “stable”, as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the « compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
The term “aliphatic”, as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, as used herein, the term “alkyl” includes straight, branched and cyclic alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like. Furthermore, as used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the like encompass both substituted and unsubstituted groups.
In certain embodiments, as used herein, "lower alkyl" is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.
In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CHa- cyclopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH,-cyclobutyl, ’ 30 n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH,-cyclopentyl, n-hexyl, sec- . hexyl, cyclohexyl, -CH;-cyclohexyl moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
The term "alkoxy", or "thioalkyl" as used herein refers to an alkyl group, as “ previously defined, attached to the parent molecular moiety through an oxygen atom or through a sulfur atom. In certain embodiments, the alkyl group contains 1-20 alipahtic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkoxy, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert- butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
The term "alkylamino" refers to a group having the structure -NHR' wherein R' is alkyl, as defined herein. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.
Some examples of substituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl;
Br; I; -OH; -NO,; -CN; -CF3; ~CH,CF;; -CHCl; -CH,OH; -CH2CHOH; -CHoNHy; -
CH,S0,CHjs; -C(O)Ry; -CO2(Ry); -CON(R)2; -OC(O)Ry; -OCO2Rx; <-OCON(Ry)2; -
N(R); -S(O)2Ry; -NRx(CO)Rx wherein each occurrence of Ry independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or . heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted.
Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein. ) In general, the terms “aryl” and “heteroaryl”, as used herein, refer to stable
N mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or i» unsubstituted. Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound. In certain embodiments of the present invention, "aryl" refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. In certain embodiments of the present invention, the term “heteroaryl”, as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
It will be appreciated that aryl and heteroaryl groups (including bicyclic aryl groups) can be unsubstituted or substituted, wherein substitution includes replacement of one, two or three of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO;; -CN; -CF;; -CH,CF;; -CHClp; -CH,0H; -CH,CH,0H; -CH,NH;; -CH,SO,CHjs; -C(O)Ry; -
CO2(Rx); ~CON(Ry)z; -OC(O)Ry; -OCO2Rx; -OCON(R)2; -N(Rx)2; -S(O)2Ry; -
NR(CO)R, wherein each occurrence of Ry independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described \ above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substitutents are illustrated by the specific embodiments shown in the Examples that are described herein.
The term “cycloalkyl”, as used herein, refers specifically to groups having three . to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not : limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, vr which, as in the case of other aliphatic, heteroaliphatic or hetercyclic moieties, may optionally be substituted with substituents including, but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroaryithio; F; Cl;
Br; I; -OH; -NOj; -CN; -CF3; -CH,CF3; -CHCl,; -CH,0H; -CH,CH,0H; -CH,NH3; -
CH,S0,CHj; -C(O)Ry; -CO2(Ry); -CON(Rx)z2; -OC(O)Rx; -OCO2Ry; -OCON(Ry)z; -
NRy)2; -S(0)2Rx; -NR(CO)Rx wherein each occurrence of Ry independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted.
Additional examples of generally applicable substitutents are illustrated by the specific embodiments shown in the Examples that are described herein.
The term “heteroaliphatic”, as used herein, refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc. In certain embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; CL; Br; I; -OH; -NO,; -CN; -CF3; -CH.CFj3; -CHCly; -CH,0H; -CH>CH,0H; -CH2NH;; -CH,SO,CHs; -C(O)Rx; -CO2(Ry); -
CON(Ry)2; -OC(O)Ry; -OCO2Ry; -OCON(Ry)z; -N(Rx)2; -S(0)2Rx; -NR(CO)R ¢ wherein each occurrence of Ry independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic,
and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable . substitutents are illustrated by the specific embodiments shown in the Examples that are
N described herein.
The terms “halo” and “halogen” as used herein refer to an atom selected from w fluorine, chlorine, bromine and iodine.
The term “haloalkyl” denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term “heterocycloalkyl” or “heterocycle”, as used herein, refers to a non- aromatic 5-, 6-, or 7- membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to a benzene ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. In certain embodiments, a “substituted heterocycloalkyl or heterocycle” group is utilized and as used herein, refers - to a heterocycloalkyl or heterocycle group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO3; -CN; -CF3; -CH,CF3; -CHC),; -CH,0H; -
CH2CH,OH; -CHaNHa; -CH2S0,CHj; -C(O)Ry; -CO2(Ry); -CON(Rx)2; -OC(O)Ry; -
OCO,Ry; “OCON(RL)2; -N(Ry)2; -S(0)2Rx; -NRx(CO)R wherein each occurrence of Ry independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, ’ 30 arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or " heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted.
Additional examples of generally applicable substitutents are illustrated by the specific embodiments shown in the Examples which are described herein. : “Labeled”: As used herein, the term “labeled” is intended to mean that a . compound has at least one element, isotope or chemical compound attached to enable the detection of the compound.
In general, labels fall into three classes: a) isotopic » labels, which may be radioactive or heavy isotopes, including, but not limited to, 2H, *H, 2p, 3S, Ga, #™Tc (Tc-99m), In, 21, 21, "Yb and **Re; b) immune labels, : which may be antibodies or antigens; and c) colored or fluorescent dyes.
It will be appreciated that the labels may be incorporated into the compound at any position that does not interfere with the biological activity or characteristic of the compound that is being detected.
In certain embodiments of the invention, photoaffinity labeling is utilized for the direct elucidation of intermolecular interactions in biological systems (e.g., to probe the epothilone binding site in a tubulin dimer). A variety of known photophores can be employed, most relying on photoconversion of diazo compounds, azides, or diazirines to nitrenes or carbenes (See, Bayley, H., Photogenerated Reagents in Biochemistry and Molecular Biology (1983), Elsevier, Amsterdam.), the entire contents of which are hereby incorporated by reference.
In certain embodiments of the invention, the photoaffinity labels employed are o-, m~ and p-azidobenzoyls, substituted with one or more halogen moieties, including, but not limited to 4-azido- 2,3,5,6-tetrafluorobenzoic acid.
"Polymer": The term "polymer", as used herein, refers to a composition comprising chains that may be open, closed, linear, branched or cross-linked of repeating units (monomers) that may be the same or different.
It will be appreciated that in certain embodiments the term polymer refers to biopolymers, which, as used herein, is intended to refer to polymeric materials found in nature or based upon those : materials found in nature, including, but not limited to nucleic acids, peptides, and mimetics thereof.
In certain other embodiments, the term polymer refers to synthetic polymers, such as biodegradable polymers or other polymeric materials.
It will be appreciated that polymeric solid supports are also encompassed by the polymers of the ’ 30 present invention.
Inventive compounds can be attached to polymeric supports and thus certain synthetic modifications can be conducted on the solid phase.
As used herein, the term "solid support” is meant to include, but is not limited to, pellets, disks, capillaries, hollow fibers, needles, pins, solid fibers, cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally cross-linked with divinylbenzene, grafted co-
poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally crosslinked with N-N'-bis-acryloylethylenediamine, and glass particles coated with a hydrophobic polymer. One of ordinary skill in the art will realize that the choice of “ particular solid support will be limited by the compatability of the support with the reaction chemistry being utilized. An exemplary solid support is a Tentagel amino ” resin, a composite of 1) a polystyrene bead crosslinked with divinylbenzene and 2)
PEG (polyethylene glycol). Tentagel is a particularly useful solid support because it provides a versatile support for use in on-bead or off-bead assays, and it also undergoes excellent swelling in solvents ranging from toluene to water.
In recognition of the need to develop novel and effective cancer therapies, the present invention provides novel synthetic methodologies enabling access to macrocycles having a broad range of biological and pharmacological activity, as well as novel compounds with such activity, novel therapeutic compositions, and methods of using these compounds and compositions.
In certain embodiments, the inventive compounds are useful in the treatment of cancer. Certain compounds of the invention exhibit cytotoxic or growth inhibitory effects on cancer cells lines, exhibit an ability to polymerize tubulin and stabilize microtubule assemblies, and/or lead to shrinkage or diappearance of tumors in cancer cell xenograft models. In certain embodiments, the compounds may have reduced or minimal side effects including toxicity to vital organs, nausea, vomiting, diarrhea, allopecia, weight loss, weight gain, liver toxicity, skin disorders, etc. The compounds may also be easier to formulate due to increased water solubility, decreased toxicity, increased therapeutic range, increased efficacy, efc.
General Description of Compounds of the Invention
Compounds of the invention include compounds of the general formula (0) and ¢ (0%) as further defined below:
Ro X lo) Ro X 0)
ORg ORg
Y-
Rs 4 Rg Ro Rg Rg Ro . Rio Rio m > m | > ) Re 7 “ORs Re 7 “ORs
Ra Rs or Rs %, 0) 0”) wherein Ry is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; in certain embodiments, Ry is a arylalkyl, arylalkenyl, heteroarylalkyl, or heteroarylalkenyl moiety; in other embodiments, Ry is a heteroarylalkenyl moiety; in certain embodiments, Ry is a heteroarylalkyl moiety; in other embodiments, Rg is a 5-7 membered aryl or heteroaryl moiety; in yet other embodiments, Ro is an 8-12 membered bicyclic aryl or heteroaryl moiety; in still other embodiments, Ry is a bicyclic moiety wherein a phenyl ring is fused to a heteroaryl or aryl moiety; in other embodiments, Rg is a bicyclic moiety wherein a phenyl ring is fused to a thiazole, oxazole, or imidazole moiety; in yet other embodiments, Ry is a substituted or unsubstituted phenyl moiety;
Rs and Ry are each independently hydrogen; or substituted or unsubstituted, linear or branched, cyclic or acyclic aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety, optionally substituted by one or more of hydroxy, protected hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, amino, protected amino, amino substituted with one or two alkyl or aryl moieties, N-hydroximino, or N-alkoxyimino; in certain embodiments, R; and Ry are each independently hydrogen, fluorine, or lower alkyl; in other embodiments, Rj and Ry are each independently hydrogen or methyl; in still other embodiments, Rj is methyl, and Ry is hydrogen;
Rs and Rg are each independently hydrogen or a protecting group; in certain ; embodiments, Rs and Rg are both hydrogen; # 25 X is O, S, C(R7),, or NR, wherein each occurrence of Ry is independently hydrogen or lower alkyl; in certain embodiments, X is O; in other embodiments, X is
NH; :
Y is O, S, NH, C(R7)2, CHa, N(R), or NH, wherein each occurrence of Ry is oo independently hydrogen or lower alkyl; in certain embodiments, Y is O; in other embodiments, Y is NH; in yet other embodiments, Y is CH; o each Rg is independently hydrogen; halogen, hydroxy, alkoxy, amino, dialkylamino, alkylamino, fluoro, cyano, or substituted or unsubstituted, linear or : v branched, cyclic or acyclic aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, or heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl moiety, optionally substituted by one or more of hydroxy, protected hydroxy, alkoxy, carboxy, caboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, amino, protected amino, amino substituted with one or two alkyl or aryl moieties, N- hydroximino, or N-alkoxyimino; in certain embodiments, Rs is hydrogen; in other embodiments, Rg is hydroxy; in yet other embodiments, Rg is fluorine; in still other embodiments, Rg is lower alkyl such as methyl; in other embodiments Rg is —CF3, -
CF,H, or —CFH,; in other embodiments, Rg is perfluorinated or fluorinated alkyl group; in yet other embodiments, Rs is halogentated or perhalogenated alkyl group;
Ro and Ry are each indenpendently hydrogen; or substituted or unsubstituted, linear or branched, cyclic or acyclic aliphatic, heteroaliphatic, aryl, heteroaryl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety, optionally substituted by one or more of hydroxy, protected hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, amino, protected amino, amino substituted with one or two alkyl or aryl moieties, N-hydroximino, or N-alkoxyimino; in certain embodiments, one of Rg and
Rio is methyl; in other embodiments, both Rg and Ry are methyl; in yet other embodiments, one of Rg and Rp is methyl, and the other is hydrogen; in other embodiments, both Rg and Ryo are hydrogen;
Rp is, independently for each occurrence, hydrogen; halogen; -ORp:; -SRp-; -
N(R p)2; -C(O)ORg’; -C(O)R p; -CONHR p'; -O(C=0)Rp’; -O(C=0)ORp’; -
NRp'(C=O)Rz; N3; N;R p'; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORg’; -SRa'; “N(R 5')2; -C(O)ORg; -C(O)Rp; -CONHRp'; - . O(C=0)Rp’; -O(C=0)ORp’; -NRg(C=0)Rp’; N3; NJR p-; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; in certain embodiments, Rp
0 is hydrogen, ~J , methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, : cyclobutyl, cyclopentyl, or cyclohexyl, each unsubstituted or optionally substituted . with one or more occurrences of halogen, -OH, -ORg:, NH, or N(Rp-),, or any combination thereof, wherein each occurrence of Rp: is independently hydrogen, alkyl, - 5 aryl, or a protecting group, in other embodiments, Rpg is hydrogen, methyl, or ethyl, in still other embodiments, Rp is methyl, in other embodiments, -CY3, -CHY>, -CH,Y, where Y is F, Br, Cl, I, ORp:, NHRp', N(Rp')2, or SRp in yet other embodiments, Rp is —CF3, -CH,F, or CHF»; in other embodiments, Rp is perfluorinated or fluorinated alkyl group; in yet other embodiments, Rp is halogentated or perhalogenated alkyl group; 10 each occurrence of Rp: is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; mis 1,2, 3,or4, mis 1 or2 in certain embodiments, m is 1 in other 15 embodiments; and pharmaceutically acceptable derivatives thereof.
The compounds of the invention include compounds of the general formula (T) or (I’) as further defined below:
Ry Rq
Ra A X O Raw _~# X o}
ORg ORs 0
Rs / Rg | 5
Ye ORs ORs
Rs % or R3 Y : @ a?) wherein R,; is hydrogen or lower alkyl; in certain embodiments, R, is methyl; in : certain embodiments, R; is —CF3, -CF>H, or CHF; in other embodiments, R; is perfluorinated or fluorinated alkyl group; in yet other embodiments, R| is halogentated or perhalogenated alkyl group;
: R, is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety; in certain embodiments, R; is substituted or unsubstituted oxazole; in other : embodiments, Rj is substituted or unsubstituted thiazole;
R3 and Ry are each independently hydrogen; or substituted or unsubstituted, 5 linear or branched, cyclic or acyclic aliphatic, heteroaliphatic, aryl, heteroaryl, a arylalkyl, or heteroarylalkyl moiety, optionally substituted by one or more of hydroxy, protected hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, amino, protected amino, amino substituted with one or two alkyl or aryl moieties, N-hydroximino, or N-alkoxyimino; in certain embodiments, R3 and R4 are each independently hydrogen, fluorine, or lower alkyl; in other embodiments, R; and Ry are each independently hydrogen or methyl; in still other embodiments, R3 is methyl, and Rs is hydrogen;
Rs and Re are each independently hydrogen or a protecting group; in certain embodiments, Rs and Rg are both hydrogen;
X is O, S, C(Ry)2, or NR», wherein each occurrence of Ry is independently hydrogen or lower alkyl; in certain embodiments, X is O; in other embodiments, X is
NH;
Rp is, independently for each occurrence, hydrogen; halogen; -ORp-; -SRp’; -
N(R p)2; -C(O)ORp’; -C(O)R g’; -CONHR p; -O(C=0)Rp’; -O(C=0)ORp’; -
NRp(C=0)Rp-; N3; N2R p; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORgp’; -SRp’; -N(R »')2; -C(O)ORp'; -C(O)Rp'; -CONHRp'; -
O(C=0)Rp’; -O(C=0)ORg’; -NRg(C=0)Rp"; N3; N2R p’; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; in certain embodiments, Rg 0. is hydrogen, A , methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, . cyclobutyl, cyclopentyl, or cyclohexyl, each unsubstituted or optionally substituted with one or more occurrences of halogen, -OH, -ORg:, NH, or N(Rp'),, or any - 30 combination thereof, wherein each occurrence of Rp’ is independently hydrogen, alkyl, aryl, or a protecting group, in other embodiments, Rp is hydrogen, methyl, or ethyl, in still other embodiments, Rp is methyl, in yet other embodiments, Rg is —CF3, -CHyF, or :
CHF>; and pharmaceutically acceptable derivatives thereof.
In certain embodiments, the compounds of the invention include compounds of - the general formula (IT) or (IT’) with the stereochemistry defined as shown:
R4 Ry
Raw _Z X 0) Ro A X 0)
ORs OFs $ 0 $
Rp / Re 5 | 3
Z ORs Z ORs
Rs Ra or R3 Ra 41) (I) wherein X, Ry, Ra, Rs, Rs, Rs, Rg, Rp, and X are as defined above.
In certain embodiments, X is O. In other embodiments, X is NH. In other embodiments, X is CHa.
In some embodiments, R; is a substituted or unsubstituted thiazole. In certain embodiments, Ry is 2-methyl-thiazo-4-yl. In other embodiments, Rj is 2- hydroxylmethyl-thiazo-4-yl. In yet other embodiments, R; is 2-aminomethyl-thiazo-4- yl. In other embodiments, R; is 2-thiolmethyl-thiazo-4-yl.
In certain embodiments Rj; is a substituted or unsubstituted oxazole. In certain ° embodiments, Ry is 2-methyl-oxazo-4-yl. In other embodiments, R; is 2- hydroxylmethyl-oxazo-4-yl. In yet other embodiments, R; is 2-aminomethyl-oxazo-4- : yl. In other embodiments, R; is 2-thiolmethyl-oxazo-4-yl. ; In certain embodiments, Rg is hydrogen, methyl, ethyl, -CF3, -CH,F, -CF,H. In certain embodiments, Rp is methyl. In yet other embodiments, Rp is ~CF3. In certain embodiments, Rp is hydrogen. In other embodiments, Rg is ethyl.
Certain preferred compounds include, for example:
S. O. y= 0. o fo)
N o N o \ , kt OH ()
Ss wone—( vone—( \ JF O, fo] \ Va O. o] oH ™ / 4
Y S
OH OH
S. 0.
O. 0 C O. eo]
MM a 4 J , | Y
OH OH
Ss. [o] q Ya O. Oo $ Va 0. [o]
Re ™
FyC: 4 FaC / [o] [eo]
OH OH
S. fo! rowe— ame— \ yy 0. fe) \ 0. 0
El . Nai
J 4 b \
OH OH
Ss [o)
F © © on | a 0 ° on 0; N o § “ | \ | Y
OH OH } wone—( | : vone— \ PP 0. 1) \ = ° ° on & $ o § \ | N oH OH s 0. 0 q o
Sa o \ | \
OH oH s o
N | a - 0° y | a 0
FC: [GX
Y | N
OH OH
S. wwne—( wme—q
N a ©. ° \ 7 0 & Ne \ | \
OH oH
S [ol
JF O. oO q | LF 0. o] , . [ZX / FyC: / a o o
OH OH
© S o. one—( woare—( \ a O. {o] \; FZ O. {o] oo SH
FiC 4 FsC J > | Y (cL} OH
S. rene—( | vone—g \ A o \ JF 0. fe) of SH
FC [2X : | :
OH OH
S
— | . —<
No ZF N FF o
Ru H
FC: FC [+] ]
OH OH wone—( rone—( \ F 0. o \ PZ 0
SM Fal
FyC FsC ) | S
OH OH
Ss i“ N FF © ° N | ra ° ¢ on oH . FC: FyC o [2]
OH OH
S O. \ Vz 0. 0 S A (e) o oH oO | [eo]
OH OH
) S ne rone—( = a O. (o] he ZZ O. Oo
SH Ka > | )
OH OH
S.
O. 0 C O. re}
SM oH
N | >
OM OH ' 3. ol ya 0. Oo g . ZF 0
Cl oH
FyC FiC b | S oH od
S mwo—( | wwe \ LF {o] " JF (e] ie}
Ne & b | N
OH OH
Compounds of this invention include those specifically set forth above and ‘ described herein, and are illustrated in part by the various classes, subgenera and species disclosed elsewhere herein.
It will be appreciated by one of ordinary skill in the art that asymmetric centers may exist in the compounds of the present invention. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer,
diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
In certain embodiments, the compounds of the invention are enantiopure compounds. :
In certain other embodiments, a mixtures of stereoisomers or diastereomers are wo provided.
It will be appreciated that some of the foregoing classes and subclasses of
H compounds can exist in various isomeric forms. The invention encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. Additionally, the invention encompasses both (Z) and (E) double bond isomers unless otherwise specifically designated. Thus, compounds of the invention generally depicted in structure (0), (0°), (DO), (1%), (IL), and (11°) encompass those structures in which double bonds are (Z) or (E). In certain preferred embodiments, the double bond at the C12-
C13 position is in the cis or Z configuration. In some embodiments, the double bond at the C9-C10 position is in the trans or E configuration. In still other embodiments, the double bond at the C12-C13 position is in the cis or Z configuration, and the double bond at the C9-C10 position is in the trans or E configuration. The invention also encompasses tautomers of specific compounds as described above.
Additionally, the present invention provides pharmaceutically acceptable derivatives of the inventive compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents. The phrase, “pharmaceutically acceptable derivative”, as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof.
Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro- drug is a derivative of a compound, usually with significantly reduced pharmacological ) activity, which contains an additional moiety that is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a . pro-drug is an ester that is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below. . Compounds of this invention which are of particular interest include those which: = e exhibit cytotoxic or growth inhibitory effect on cancer cell lines maintained in vitro or in animal studies using a scientifically acceptable cancer cell xenograft model; e exhibit an ability to polymerize tubulin and stabilize microtubule assemblies; o exhibit minimal levels of toxicity to vital organs; e lead to tumor disappearance in scientifically acceptable cancer cell xenograft models; e lead to tumor shrinkage in scientifically acceptable cancer cell xenograft models; e lead to tumor disappearance in scientifically acceptable cancer cell xenograt models and delayed/or no recurrence of the tumor after stopping treatment; » exhibit transient and reversible body weight decreases and show therapeutic effects in scientifically acceptable cancer cell xenograft models; » exhibit enhanced water solubility over epothilones A, B, C or D, or paclitaxel, or additionally or alternatively exhibit sufficient solubility to be formulated in an aqueous medium using reduced proportion of chremophor; and/or » exhibit a therapeutic profile (e.g., optimum safety and curative effect) that is superior to that of epothilone B, epothilone D, or paclitaxel.
A variety of epothilone analogs as described supra have been prepared, characterized, and tested as exemplified herein. 9,10-dehydro-epothilone analogs have been found to be useful in the treatment of cancer, and in particular compounds have been prepared and found to possess one or more of the desired characteristics listed above, ; Synthetic Methodology
The synthesis of certain epothilones, desoxyepothilones and analogues thereof g have been previously described (see, U.S. Patents 6,242,469, 6,284,781, 6,300,355, 6,204,388, 6,316,630, and 6,369,234; U.S. Patent Applications 09/797,027, 09/796,959, and 10/236,135; and PCT Publication Nos. WO 99/01124, WO 99/43653, and WO
01/64650, the entire contents of which are hereby incorporated by reference). In recognition of the need for improved or additional synthetic methodologies to efficiently generate epothilones, desoxyepothilones and analogues thereof in large . quantities, the present invention provides an efficient and modular route for the synthesis of epothilones, desoxyepothilones and analogues thereof. Although the o synthesis of certain exemplary compounds is described in the Exemplification herein, it will be appreciated that this methodology is generally applicable to the generation of analogues and conjugates as discussed above for each of the classes and subclasses described herein.
In particular, the 9,10-dehydroepothilone compounds of the present invention may be prepared in a variety of ways using synthetic methodologies useful in the synthesis of epothilones. In certain embodiments, the compounds are prepared using a convergent synthetic route. For example, the epothilone may be synthesized by preparing two or three intermediates which are brought together to yield the desired compound. In one embodiment, one of the intermediates is an acy! portion containing carbons 1-9, and another intermediate contains carbons 10-15 and may also contain the thiazole side chain. These two roughly equal portions of the epothilone may be brought together first using an esterification reaction between C-1 and an oxygen off C-15. The macrocycle may then be closed using a carbon-carbon coupling reaction such as a
Suzuki coupling or ring closing metathesis reaction. In one embodiment, the final ring closing step is accomplished using a ring closing metathesis reaction to form the 9,10- double bond and close the macrocycle. The ring closing metathesis reaction is accomplished using an organometallic catalyst such as the Grubbs catalyst as shown in
Scheme 8 below. In certain embodiments, the 9,10-double bond is reduced or oxidized, or the 9,10-double bond may be further functionalized to prepare additional epothilone derivatives.
In other embodiments, the final ring closing step is accomplished using a ring closing metathesis reaction to form the 12,13-double bond and close the macrocycle.
In certain embodiments, the 12,13-double bond is reduced or oxidized. In other ’ 30 embodiments, a macroaldolization or macrolactonization reaction is used to form the macrocycle.
Certain exemplary syntheses of the compounds of the invention are provided in the Figures and in the Examples. As would be appreciated by one of ordinary skill in the art, a variety of analogs and derivatives may be prepared using the synthetic procedures described herein. For example, one could accomplish many of the synthetic steps with different protecting groups or different substituents on the 16-membered ring. “
Pharmaceutical Compositions
This invention also provides a pharmaceutical preparation comprising at least one of the compounds as described above and herein, or a pharmaceutically acceptable derivative thereof, which compounds are capable of inhibiting the growth of or killing cancer cells, and, in certain embodiments of special interest are capabie of inhibiting the growth of or killing multidrug resistant cancer cells. In certain embodiments, the pharmaceutical preparation also comprises as solubilizing or emulsifying agent such as
Cremophor (polyoxyl 35 castor oil) or Solutol (polyethylene glycol 660 12- hydroxystrearate).
As discussed above, the present invention provides novel compounds having antitumor and antiproliferative activity, and thus the inventive compounds are useful for the treatment of cancer. Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, wherein these compositions comprise any one of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In certain other embodiments, the additional therapeutic agent is an anticancer agent, as discussed in more detail herein.
It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof, e.g., a prodrug.
As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact ) with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of . pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric . acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and ary! sulfonate.
Additionally, as used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, ‘ 30 acrylates and ethylsuccinates.
Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo . to yield the parent compound of the above formula, for example by hydrolysis in blood.
A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel 2 Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and
Pergamon Press, 1987, both of which are incorporated herein by reference.
As described above, the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the anti-cancer compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; Cremophor; Solutol; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesjum hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic } compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
Uses of Compounds and Pharmaceutical Compositions
The invention further provides a method for inhibiting tumor growth and/or ’ tumor metastasis. In certain embodiments of special interest, the invention provides a method of treating cancers by inhibiting tumor growth and/or tumor metastasis for ) tumors multidrug resistant cancer cells. The method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. In certain embodiments, specifically for treating cancers comprising multidrug resistant cancer cells, the therapeutically effective amount is an amount sufficient to kill or inhibit the growth of multidrug resistant cancer cell lines. In certain embodiments, the inventive compounds are useful for the treatment of solid tumors.
The compounds and pharmaceutical compositions of the present invention may be used in treating or preventing any disease or conditions including proliferative diseases (e.g., cancer), autoimmune diseases (e.g., rheumatoid arthritis), and infections (e.g., bacterial, fungal, etc.). The compounds and pharmaceutical compositions may be administered to animals, preferably mammals (e.g., domesticated animals, cats, dogs, mice, rats), and more preferably humans. Any method of administration may be used to deliver the compound of pharmaceutical compositions to the animal. In certain embodiments, the compound or pharmaceutical composition is administered parenterally.
In yet another aspect, according to the methods of treatment of the present invention, tumor cells are killed, or their growth is inhibited by contacting the tumor cells with an inventive compound or composition, as described herein. Thus, in still another aspect of the invention, a method for the treatment of cancer is provided comprising administering a therapeutically effective amount of an inventive compound, or a pharmaceutical composition comprising an inventive compound to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired ¢ result. In certain embodiments of the present invention a "therapeutically effective amount" of the inventive compound or pharmaceutical composition is that amount ’ effective for killing or inhibiting the growth of tumor cells. The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for killing or inhibiting the growth of tumor cells. Thus, the expression "amount effective to kill or inhibit the growth of tumor cells", as used herein, refers to a sufficient amount of agent to kill or inhibit the growth of tumor cells. The exact amount required will vary from subject to
Co subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular anticancer agent, its mode of administration, and the like. - The anticancer compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of anticancer agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
Furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments of the invention, the inventive compounds as described herein are formulated by conjugating with water soluble chelators, or water soluble polymers such as polyethylene glycol as poly (1-glutamic acid), or poly (1- aspartic acid), as described in U.S. Patent 5,977,163, the entire contents of which are hereby incorporated by reference. In certain embodiments, the compounds of the ] invention may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about . 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 ‘mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. The desired dosage may delivered as delivered every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
In certain embodiments, the desired dosage may be delivered using multiple . administrations (e.g., two, three, four, five, six, seven, eight, nine, or ten administrations). . Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile ‘ 30 injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot : forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to » polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, ¢) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. ] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as . high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a
: composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid : compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high ¢ molecular weight polethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
As discussed above, the compounds of the present invention are useful as anticancer agents, and thus may be useful in the treatment of cancer, by effecting tumor cell death or inhibiting the growth of tumor cells. In general, the inventive anticancer agents are useful in the treatment of cancers and other proliferative disorders, including, ‘but not limited to breast cancer, brain cancer, skin cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's . lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer, to 5S name a few. In certain embodiments, the inventive anticancer agents are active against
E leukemia cells and melanoma cells, and thus are useful for the treatment of leukemias (e.g., myeloid, lymphocytic, promyelocytic, myelocytic and lymphoblastic leukemias, whether acute or chromic forms) and malignant melanomas. In still other embodiments, the inventive anticancer agents are active against solid tumors and also kill and/or inhibit the growth of multidrug resistant cells (MDR cells). In certain embodiments, the inventive anticancer agents are active against cancers which are resistant to other known anti-neoplastic agents or which have been found not to respond clinically to other known anti-neoplastic agents. In other embodiments, the inventive anticancer agents are active against cancer which are resistant to other anti-neoplastic microtubule-stabilizing agents (e.g., paclitaxel).
It will also be appreciated that the compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another anticancer agent), or they may achieve different effects (e.g., control of any adverse effects).
For example, other therapies or anticancer agents that may be used in combination with the inventive anticancer agents of the present invention include surgery, radiotherapy (in but a few examples, y-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive . isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6- . Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel, Docetaxel), podophyllotoxins - (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), to name a few. For a more comprehensive discussion of updated cancer therapies see, http://www.nci.nih.gov/, a list of the FDA approved oncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual,
Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by reference.
In still another aspect, the present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention, and in certain embodiments, includes an additional approved therapeutic agent for use as a combination therapy. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
EQUIVALENTS
The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the ‘ examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art. The following examples contain important additional information, exemplification and guidance which can be adapted to the practice of this invention in its various embodiments and equivalents thereof.
EXEMPLIFICATION
Example 1: Synthesis of 9,10-dehydro-12,13-desoxy-epothilones
This Example describes the synthesis of trans-9,10-dehydro-12,13- desoxyepothilone B, 26-trifluoro-trans-9,10-dehydro-12,13-desoxyepothilone B, 26- trifluoro-12,13-desoxyepothilone B, and 12,13-desoxyepothilone B and biological testing of these compounds.
Fluorinated derivatives of epothilones were prepared and tested given the enhanced pharmacokinetics and chemotherapeutic indices of other medicinal agents with fluorine substitutions (Ojima, 1.; Inoue, T.; Chakravarty, S.; J. Fluorine Chem. 1999, 97; Newman, R. A.; Yang, J.; Finlay, M. R. V,; Cabral, F., Vourloumis, D.;
Stephens, L. C.; Troncoso, P.; Wu, X.; Logothetis, C. J.; Nicolaou, K. C.; Navone, N.
M. Cancer Chemother. Pharmacol. 2001, 48, 319-326; each of which is incorporated herein by reference). \ X “OH »OH 4 Xd 1 [16]dEpoB 2 26-F5-{16]dEpoB
To reach compound 2, we sought to take advantage of a highly convergent route recently reported from our laboratory for the synthesis of epothilone 490 (6, dehydrodeoxy Epo B) en route to dEpoB (1, Scheme 3) (Biswas, K.; Lin, H,;
Njardarson, J. T.; Chappell, M.D., Chou, T.C., Guan, Y.; Tong, W. P., He, L.; Horwitz,
S.B., Danishefsky, S.J. J. Am. Chem. Soc. 2002, 124 (33); 9825-9832; Rivkin, A.; ’ 25 Njardarson, J. T.; Biswas, K; Chou, T.C.; Danishefsky, S. J. J. Org. Chem. 2002, 67, 7737-7740; each of which is incorporated herein by reference). In that synthesis, we ) introduced a flanking vinyl group to compound 4 via a stereospecific Stille coupling of a vinyl iodide precursor 3 with tri-n-butylvinylstannane. Ring closing metathesis followed by deprotection led to 6, which was then transformed to dEpoB (1) via a regioselective diimide reduction. : Scheme 3. Synthesis of Epothilone 490 : OTES
OES / . —_— : — = —_ ¢ 3R=1 5 4 R = viny) [ 0
OH a \ ———> dEpoB(1)
OH
6
Attention was first directed to the synthesis of 15 (Scheme 4). Alkylation of the previously reported lithium enolate of 7 (Chappell, M. D.; Stachel, S. J.; Lee, C. B.;
Danishefsky, S. J. Org. Lett. 2000, 2(11), 1633-1636; incorporated herein by reference) with iodide 8 (synthesized from the known alcohol 16 using TMSI in methylene chloride) afforded 9 in 78% yield and high diastereoselectivity (>25:1 de). Compound 9 was advanced in three steps to 10 as shown. Attempts to accomplish addition of methylmagnesium bromide to the Weinreb amide linkage of 10 failed. The breakdown of this reaction was attributed to the presence of the iodoalkene linkage. However we could accomplish our goal by changing the order of these two C-C bond forming steps.
Thus, reaction of 10 with vinyltributyltin under Stille conditions could then be followed by addition of methyl Grignard reagent to give the desired ketone 11. Condensation of ‘ ketone 11 with phosphine oxide 12, followed by deprotection of the triethylsilyl ether, afforded fragment 13 in good yield. Esterification of the resulting 13 with C1-C10 acid ) 20 fragment 14 (Biswas, K.; Lin, H.; Njardarson, J. T.; Chappell, M.D., Chou, T.C., Guan,
Y.; Tong, W. P., He, L.; Horwitz, S.B., Danishefsky, S.J. J. Am. Chem. Soc. 2002, 124 (33); 9825-9832; Rivkin, A.; Njardarson, J. T.; Biswas, K; Chou, T.C.; Danishefsky, S.
J. J Org. Chem. 2002, 67, 7737-7740; incorporated herein by reference), provided the desired 15, in 75% yield (Scheme 4). . Scheme 4. Synthesis of the RCM precursor 15 . Jo ors \ : OTES a / + I — —_— ‘Bn 1” CF, ‘Bn ]
CFa 7 8 9
OTES mE
MeO. OTES oie => NE 10 1© CF, 1 Foe \ 5 d 3 I Z JOTES — OH EDCI, DMAP FO \ > 3 : 14 Pp N 75%
F OTroc 13 Fs 15 lo}
H OTES
— 14 17 CF, ; "CF, (a) LHMDS, 78 °C, 78%; (b) i) HOAC:THF:H,0 (3:1:1); ii) CH3ONHCH3, AlMe,; iii) TESCI, imidazole, DMF, 79% overall; (c) i) Vinyltributyltin, Pd(dba), DMF, 80 °C, 3h 43%; ii) MeMgBr, 0 °C, 94%; (d) i) n-BuLi, THF, —78 °C, 30 min., ii) 12, —78 °C to #, 81%; iii) HOAC:THF:H,0 5 (3:1:1), 94%; (6) TMSI, CH,Ch, 0 °C, 92%
Unfortunately, attempts to carry out the ring-closing metathesis reaction of 15 using the second generation Grubbs catalyst (Reviews: Grubbs, R. H.; Miller, S. J.; Fu,
G. C. Acc. Chem. Res. 1995, 28, 446; Trka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18; Alkene Metathesis in Organic Chemistry Ed.: Fiirstner, A.; Springer, . Berlin, 1998; Fiirstner, A. Angew. Chem. Int. Ed. Engl. 2000, 39, 3012; Schrock, R. R.
Top. Organomet. Chem. 1998, I, 1; each of which is incorporated herein by reference) ¢ in methylene chloride led primarily to apparent dimerization of the starting material (Equation 1). Given the fact that the RCM works quite well in the related setting of § —
6, we naturally attributed the failure in the case of 15 to the presence of the trifluoromethyl group at Cys. . pe \ 0 | o
SOTES OTES rod > a ©
NS Grubbs EG 15 17
It was conjectured that the detrimental impact of the resident 26-trifluoro substitutent on the desired reaction, might be alleviated by adding a carbon spacer between the RCM reaction center and the trifluoromethyl group. Accordingly, we undertook a synthesis of 19 (Equation 2) via the ring-closing metathesis of 18, which would present the trifluoromethyl group in the context of a 17-membered ring containing a shipped (1,4)-diene.
Je: CI 3 Ly
OES JOH
FG ap: —_— Ex @
Nore “NAY
OH
18 19
The synthesis program directed to 19 commenced with the preparation of compound 21, which corresponds to the O-alkyl sector of our proposed RCM substrate (Scheme 5). We began with allylation of 10, this time under radical reaction conditions as shown (Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829; review: Curran,
D. P. Synthesis 1988, Part 1, pp 417-439; Part 2, pp. 489; each of which is incorporated herein by reference). This conversion was followed by reaction of the alkylated product with methyl magnesium bromide, thus affording the required ketone 20.
Condensation of this compound with phosphine oxide 12, followed by deprotection of the triethylsilyl ether function provided 21 in good yield.
Scheme S. Synthesis of the alcohol fragment 21
Ph Ph
Me OTES OES ] a + . TT a, 10 1 CF, 20 CFs 12 - 1 b —_— OH 2
Fs x (a) i) Allyltributyltin, AIBN, Benzene, 8 °C, 3h 74%; ii)
MeMgBr, 0 °C, 93%: (b) i) 12, n-BuLi, THF, =78 °C, 30 min., ii) 20, ~78 °C to it, 85%; iii) HOAG:THF:H,0 (3:1:1), 98%; (c) TMSI, CHCl, 0 °C, 92%
Esterification of 21 with the C1-C10 acid fragment 14, provided the proposed
RCM precursor 18 in 75% yield (Scheme 6). Happily in this case, the ring-closing metathesis reaction of 18 could be accomplished using the second generation Grubbs catalyst in methylene chloride. As in the case of the conversion of 5—6, the reaction provided exclusively the trans isomer 22 in 57% yield.® Finally, reductive cleavage of the trichloro ethoxycarbonyl protecting group with zinc and acetic acid, followed by deprotection of the TES ether with HF-pyridine, provided the desired 19 containing a trifluoromethyl function at C,5, albeit in the context of the 17-membered ring series.
Scheme 6. Synthesis 27-F3;-ddEpoB (19)
N\ ) 2 OH = 7 ~OTES [2 / red EDCL DMAP Fs 14 2 75% 18 OTroc
Mes 1 a | © Cozi
Cc h : bon 57%
Nn ) \ o. 0 | o. 0
AOH 1. Zn, AcOH, ~OTES yas THF Fa 2. HF Py, THF — o —
OH 73% OTroc 19R = CF, 22 23 R = Me (Previously synthesized)
Synthetic 19 was evaluated as to its cytotoxic activity. As shown in Table 1-1 below, direct comparison of the previously reported [17]ddEpoB (23) with 27-F;-
[17]ddEpoB (19) indicated that the new perfluorinated compound possessed a comparably high cytotoxic potency.
Table 1-1. In vitro Cytotoxicities (ICs) with tumor cell lines”
Compound CCRF-CEM CCRF-CEM/ VBL (ACso (UM)? | (ACso (1M)*) 27-F3-[17]ddEpoB (19) 0.068 0.191
CR
[16]ddEpoB (6) 0.020 0.068
XTT assay following 72 h inhibition. CCRF-CEM is a human T-cell acute lymphoblastic leukemia cell line. The CCRF-CEM/vaL100, CCRF-CEM/vpm; and . CCRF- CEM/raxol cell lines all overexpress P-glycoprotein and display a multidrug resistance phenotype to MDR associated oncolytics (Ojima, L.; Inoue, T.; Chakravarty, : 15 S.; J. Fluorine Chem. 1999, 97; Newman, R. A.; Yang, J.; Finlay, M. R. V.; Cabral, F.,
Vourloumis, D.; Stephens, L. C.; Troncoso, P.; Wu, X_; Logothetis, C. J.; Nicolaou, K.
: C.; Navone, N. M. Cancer Chemother. Pharmacol. 2001, 48, 319-326; each of which is - incorporated herein by reference). : Though the trifluoromethyl isoteric substitution had little effect on the gross cytotoxic activity, preliminary data from metabolic degradation studies in mouse ¢ plasma showed 19 to be notably more stable than is the parent 23. Exposure of epothilones 19 and 23 to nude mouse and human plasma led to degradation of 23 within 30 minutes, while epothilone 19 remained mostly intact. Since pharmokinetic issues are likely to be critical in the actual use of any epothilone agent as a drug, we take this finding to be quite encouraging.
The synthesis of 26-Fs-dEpoB (2) could be accomplished via a highly convergent strategy, related to that employed in the synthesis of 27-F3-{17]ddEpoB (19). Accordingly, fragments of similar complexity would serve as key building blocks (Scheme 7). We envisioned that the acyl sector 25, could serve as the polypropionate domain and the alkyl sector 21 or 24 would be prepared as previously described in the introduction. The union of the two fragments 21(24) and 25 would be initiated through an esterification and consumated via a subsequent ring-closing metathesis. Finally, cleavage of the protecting groups would provide the desired analogs 28 and 29.
Chemoselective reduction of the 9,10-olefin of 28 and 29 would furnish dEpoB (1) and the desired 26-F3-12,13-desoxyEpoB (2).
Scheme 7 a RSS vy 0 res
I~ * L/L
IRE Rs
R:CF3(21), Me (24) 25 R: CF; (26), Me (27)
OH OH
. Ses _— 0 0
OH OH
To bans. Toe Te debope (28) 264-1213 deBonyRoB (2)
The synthesis of 1 and 2 commenced with the preparation of acyl sector 25.
Ketone 30,previously reported, was subjected to an aldol rection with the readily available aldehyde 31. Upon deprotonation and reaction of “lithio” 30 with 31, smooth . condensation gave rise to a 5.3:1 mixture of aldol products 32 and 33. The major diastereoisomer 32 was easily separated by flash chromatography and protected as a } TBS silyl ether. Hydrolysis of the diisopropyl acetal group under acid catalysis gave keto aldehyde 34, setting the stage for the second aldol reaction. Following the previously practiced “titano” tert-butyl ester method, with the new aldehyde 34 as the coupling partner, the desired aldo! product 35 was obtained in high diastereoselectivity (dr>20:1) and yield (86%). Protection of the C3 alcohol of 35 with a TES silyl group was followed by deprotection of the benzyl ether. Oxidation of the resultant primary hydroxy provided the corresponding aldehyde, which was then converted to a terminal olefin via a Wittig reaction to provide 36 in high yield. Finally, hydrolysis of the t-butyl ester of 36 with TESOT( provided the acyl sector 25 (82%) along with side-product 37 (14%), which was converted to acyl sector 38 in high yield. Spectral and chromatographic properties of 38 were identical to previously obtained material from other programs in Dr. Sinha’s laboratories (Scripps).
Scheme 8. j-Pr BR a i-P H je QH — + 2 rreodor + ¥ ~O0Bn rod ee tro Pog ose 30 3 32 ©3:1) 33 i H x pTES . OH TBS
TU — LILI — IESE 32 34 35
QTES OTES OH
EN oz SS , Q £0 os oo =U 0 OBS tBu x HO x HO x 36 ) 25 ) 37 : Reagents and Conditions: (a) LDA, THF, -90 °C, 79%; (b) (i) TBSOT{, | f 2,6-lutidine CH,Cl,, —40 to -20 °C, 97%, (ii) 2) p-TsOH-H,0 (cat.)THF-H,0 (4:1), 64 °C, 86%; (c) t-butyl acetate, LDA, chirak-Ti OTES complex, Et,0, -78 °C, 92%, (dr = >20:1); (d) (i) TESCI, imidazole, DMF, z TBS : 0 °C to rt, 99%, (ii) H, Pd/C (10%), EtOH, 83%, (iii) TPAP, NMO, z
CHCl, , 93%, (iv) MePPhyl, n-BuLi, THF, -78 to 5 °C, 78%; (e) AAILI
TESOTY, 2,6-lutidine, CH,Cly, 0 °C to rt 82%; (f) (i) TBSOTY, 2,6-lutidine, H
CHCl, 0 °C to rt, (ii) sat. NaHCO; (aq.), MeOH, THF, rt, 99%. 38
Esterification of the allylic alcohols 21 and 24 with C;-Cy acid fragment 25 provided the corresponding RCM cyclization precursors 26 and 27, respectively (Scheme 9).
Scheme 9.
MesN,__NMe
H 0 es 2] °
Reb YL on (OTES RAM o EA (10 moi%)
EDCI, g at Ph + DMAP 4 PCy,
Rd — R — (o} CHCl toluene, 110 °C
N & ores 0°Gtort \ lo} 5 min 7 oTBS 25 1 2 21 (R'=Me, R®=H), 24 (R'=CF, R’=H), R' =Me, R“ =H, { 26, 79%) 53 pS NN > R} = CFy, R= H (27, 70%) ’ R' = Me, R?= OTBS (54, 92% from ester) rR 4 4, PR 0 0} C u
OTES LOTES NPNES 0 i R OH
R + < 0 | 0 oTBS TBS lo) 41 OH » 39a (R'=Me, R? =H, 38%), 39b (R'=Me, R?= H, 62%) Dr. White's proposed und
HE-Pyrdine, | 40a (R'=CF,, R2= H, 22%), 40b (R'=CF;, R® = H, 60%) oS Propose oe 0°C tort 55 (R'=Me, R? = OTBS, 27%), 66 (R'=Me, R? = OTBS, 57%)
R= ! Rl \
B H
N E lo) N £ 0)
NNN OH | KOLC-N=N-COK NNN OH
N ACOH, CICH,CH.C
R' 74 45 °C R! 4 ——— eee o o
OH OH
R'=Me, R2=H, ( 28, 77%) R' = Me, R%=H (1, 60% + recovery of starting material in 36%)
R'=CF3, R2=H (29, 79%) R'= CF,, RZ =H (2, 37% + recovery of starting material in 60%)
R'=Me, R®= OH (67, 77%)
The ring-closing metathesis reactions 26, 27 and 54 were then carried out using the second generation Grubbs catalyst in toluene, which provided, as in our earlier study, exclusively the trans isomer 39a, 40a, and 55 along with the corresponding side products 39b, 40b, and 56. F inally, deprotection of silyl ethers with HF-pyridine led to the desired compounds 28, 29, and 57. Spectral and chromatographic properties of 28 were not identical to previously obtained material from the epothilone program in Dr,
James D. White’s laboratories (Oregon State University). Dr. James D. White thought he had synthesized 28, however inadvertently he made the 12,13E isomer 41 instead, which would explain the poor biological activity he observed. Consequently, we are i} the first ones to have synthesized 28 and tested this compound for its antitumor activity.
The fully synthetic 28, 29, and 2 have been evaluated against a variety of cell : types to determine their antitumor potential. As shown in Table 1-2, all three compounds exhibited high cytotoxic activity against a variety of sensitive and resistant tumor cell lines. Direct comparison of 28 with the previously reported dEpoB (1) indicates that the new compound possesses nearly three times more potency.
Table 1-2. In vitro Cytotoxicities (ICs) with tumor cell lines”.
Tumor Cell Lines ICso (HM)® —3® 29 dmpeB(M 5m ~ CCRF-CEM 00014 0.0035 00036 _ 000051
CCRF-CEM/VBL tp 0.0065 0.0210 0.014 0.0106
CCRF-CEM/Taxol 0.0017 0.0057 0.0057 0.00073 . “XTT assay following 72 h inhibition. CCRF-CEM is a human T-cell acute lymphoblastic leukemia cell line. The CCRF-CEM/ypy 190, CCRF-CEM/ym; and
CCRF- CEM/taxal cell lines all overexpress P-glycoprotein and display a multidrug resistance phenotype to MDR associated oncolytics (Prié, G.; Thibonnet, J.; Abarbri,
M.; Duchéne, A.; Parrain, J. Synlett 1998, 839; incorporated herein by reference).
To improve the overall yield of our synthesis of 28, 29, and 2, we decided to carry out the RCM reaction in the absense of the thiazole subsituted olefin and in so doing avoid the formation of the undesired side product 39b and 40b. Deprotection of the silyl ether of the previously reported 42 and 20 provided hydroxyketones 43 and 44.
Esterification of the resultant hydroxyketones 43 and 44 with C;-Cs acid fragment 25 provided the corresponding RCM cyclization precursors 45 and 46, respectively . 25 (Scheme 10). The ring-closing metathesis reaction of 45 and 46 was then carried out using the second generation Grubbs catalyst in toluene, which provided, as in our earlier study, exclusively the trans isomer 47 and 48 in high yields. Installation of the thiazole moiety gave 39a, 40a, and 55 in high yield. Deprotection of the two silyl ethers with HF-pyridine led to 28 and 29. Finally, selective reduction of the C9-C10
Claims (1)
- ; L. A compound of the formula: R2 x Hx PQ . ORs m| 0 OR5 wherein R, is hydrogen or lower alkyl; R; is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety; Rs and Rg are each independently hydrogen or a protecting group; X is O, S, C(Ry),, or NR7, wherein each occurrence of Rj is independently hydrogen or lower alkyl; Rp is, independently for each occurrence, hydrogen; halogen; -ORg; -SRp'; -NRp); -CY3, -CHY3, -CH2Y, where Y is F, Br, Cl, I, ORp:, NHRp, N(Rg*),, or SRp’; ~C(O)ORp’; -C(O)R g'; -CONHR p:; -O(C=0)Rp’; -O(C=0)ORp’; - NRp:(C=0O)Rp-; N3; N2R p+; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORp:; -SRp-; -N(R 5-)2; -C(O)ORp’; -C(O)R p’; -CONHR 3; - O(C=0)Rg’; -O(C=0)ORg'; -NRp(C=0)Rp'; N3; N2R p:; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of Rp’ is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylatkenyl, or heteroarylalkynyl : moiety; and mis 1,2, 3,or4.2. A compound of the formula:S Re N GZ X Oo ORe wd . | \ ORs wherein X is O, S, C(Ry)2, or NR;, wherein each occurrence of Ry is independently hydrogen or lower alkyl; Rs and Rg are each independently hydrogen or a protecting group; Rp is hydrogen; halogen; -ORg’; -SRp’; -N(R p')2; -CY3, -CHY3, -CH,Y, where Y is F, Br, CL, I, ORg:, NHRp:, N(Rp')2, or SRyp’, -C(O)ORp'; -C(O)R p'; -CONHR p'; - O(C=0)Rp’; -O(C=0)ORp’; -NRg'(C=0)Rp'; N3; NaR p’; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORp’; -SRp*; -N(R p*)2; - C(O)ORg'; -C(O)R p'; -CONHR pg’; -O(C=O)Rp’; -O(C=0)ORp’; -NRg(C=0)Rp’; N3; N2R p; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of Rg: is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; Rg is independently hydrogen, halogen, -ORg, -SRg, -N(Ro)s, -CY3, -CHY>, - CH,Y, where Y is F, Br, Cl, I, ORp’, NHRp:, N(Rp")2, or SRg’; -(CV2)nORo, - (CV)NR9)2, -(CV2)aSRy, -(C=0)Ry, -O(C=0)Ry, -(C=0)ORy, -O(C=0)ORg;- : NH(C=0)Ry, -NH(C=0)ORy, -(C=0)NHRy, or a cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety ] 25 optionally substituted with one or more occurrences of halogen, -ORy, -SRy, -N(Ry)2, - (CV2aORy, -(CV2)aN(Ry),, -(CV2)nSRy, -(C=0)Rg, -O(C=0)Rs, -(C=0)ORy, - O(C=0)ORy;-NH(C=0)Rg, -NH(C=0)ORy, -(C=O)NHR, or a cyclic or acyclic, linear or branched, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety, wherein each occurrence of Ry is independently hydrogen; a protecting group; a cyclic or acyclic, linear or branched, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone or ¢ analogues thereof; a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of V is independently hydrogen, halogen, hydroxyl, thio, amino, alkylamino, or protected hydroxyl, thio or amino; each occurrence of t is independently 0, 1 or 2; and each occurrence of n is independently 0-10; and pharmaceutically acceptable derivatives thereof.3. The compound of claim 2 wherein Rg is methyl.4. The compound of claim 2 wherein Rp is ~CF;.5. The compound of claim 2, 3, or 4, wherein Rg is methyl.8. The compound of claim 2, 3, or 4, wherein Rg is -CH,0H.Oo. The compound of claim 2, 3, or 4, wherein Rg is -CH,NH,.10. A compound of the formula: Oo Re—4 N = X O ra—d 5 ORs whereinX is O, S, C(R7)2, or NRy, wherein each occurrence of Ry is independently hydrogen or lower alkyl; Rs and Re are each independently hydrogen or a protecting group; Rp is hydrogen; halogen; -ORp'; -SRp:; -N(R pg); -CY3, -CHY>, -CH,Y, where YisF,Br, Cl, 1, ORp, NHRp:, N(Rp'),, or SRp'; -C(O)ORp:; -C(O)R p’; -CONHR p; - : - O(C=0)Rp’; -O(C=0)ORp’; -NRp:(C=0)Rp'; N3; N2R p'; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORgp:; -SRp'; -N(R B)2; = C(O)ORg'; -C(O)R p'; -CONHR p'; -O(C=0)Rgp'; -O(C=0)ORg:; -NRp-(C=0)Rp"; N3; NR; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of Rp: is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, beteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; Rg is independently hydrogen, halogen, ORs, -SRg, -N(Rg),; -CY3, -CHYo>, -CH.Y, where Y is F, Br, Cl, I, ORg’, NHRp, N(Rg')2, or SRp'; ~(CV2),ORo, - (CV2)aNRGo)2, -(CV2)nSRg, -(C=0)Ry, -O(C=0)Ry, -(C=0)ORy, -O(C=0)ORy;- NH(C=0)Rs, -NH(C=0)O0Ry, -(C=0O)NHRy, or a cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety optionally substituted with one or more occurrences of halogen, -ORy, -SRy, ~N(Ro),, - (CV2)nORy, -(CV2)aN(Ro)2, -(CV2)nSRy, -(C=0)Ry, -O(C=0)Ry, -(C=0O)ORy, - O(C=0)ORy;-NH(C=0)Rg, -NH(C=0)ORy, -(C=0)NHRsy, or a cyclic or acyclic, linear or branched, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety, wherein each occurrence of Ry is independently hydrogen; a protecting group; a cyclic or acyclic, linear or branched, substituted or unsubstituted aliphatic, : heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone or analogues thereof; a polymer; carbohydrate; photoaffinity label; or radiolabel; ) wherein each occurrence of V is independently hydrogen, halogen, hydroxyl, thio, amino, alkylamino, or protected hydroxyl, thio or amino; each occurrence of t is independently 0, 1 or 2; and each occurrence of n is independently 0-10; and pharmaceutically acceptable derivatives thereof.11. The compound of claim 10, wherein Rp is methyl. ] 12. The compound of claim 10, wherein Rp is ~CF. CG 13. The compound of claim 10, 11, or 12, wherein Rg is methyl.14. The compound of claim 10, 11, or 12, wherein Rg is -CH,OH.15. The compound of claim 10, 11, or 12, wherein Rg is -CH,NH.16. A compound of the formula: S Rg—< Hx 0 N Y OR 5 Rg—C 0 ORs wherein Rs and Re are each independently hydrogen or a protecting group; Rs is independently hydrogen, halogen, -ORg, -SRy, -N(Rg)3, -CY3, -CHY>, - CHY, where Y is F, Br, Cl, I, ORp’, NHRg, N(Rp-)2, or SRg’; -(CV2)aOR, - (CV2)aNRo)2, -(CV2)aSRg, -(C=0)Ry, -O(C=0)Ry, -(C=0)ORy, -O(C=0)ORy;- NH(C=0)Ry, -NH(C=0)ORy, -(C=0)NHRy, or a cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety optionally substituted with one or more occurrences of halogen, -ORg, -SRg, -N(Ro),, - (CV2)yORy, -(CV2)aN(Ry)2, -(CV2)aSRg, (C=0)Ry, -O(C=0)Ry, -(C=0)ORy, - O(C=0)0ORy;-NH(C=0)Ry, -NH(C=0)ORy, -(C=0O)NHRGy, or a cyclic or acyclic, linear or branched, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety, wherein each occurrence of Ry is independently hydrogen; a protecting group; a } cyclic or acyclic, linear or branched, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone or analogues thereof; a polymer; carbohydrate; photoaffinity label; or radiolabel;wherein each occurrence of V is independently hydrogen, halogen, hydroxyl, thio, amino, alkylamino, or protected hydroxyl, thio or amino; X is O, S, C(R7)2, or NR, wherein each occurrence of R; is independently . hydrogen or lower alkyl; Rp 1s, independently for each occurrence, hydrogen; halogen; -ORp'; -SRp'; Md -N(R p)2; -CY3, -CHY>, -CH,Y, where Y is F, Br, Cl, I, ORp:, NHRp:, N(Rp),, or SR’; -C(O)ORg’; -C(O)R p’; -CONHR g; -O(C=O)Rp’; -O(C=0)ORp'; -NRp(C=O)Rp’; N3; N2R p’; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; - ORp’; -SRp’; -N(R p)2; -C(O)ORg; -C(O)R p'; -CONHR p:; -O(C=0)Rp’; - O(C=0)0Rp’; -NRp'(C=0)Rp; N3; N2R p-; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of Rp: is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; and pharmaceutically acceptable derivatives thereof.17. The compound of claim 16, wherein Rp is methyl.18. The compound of claim 16, wherein Rg is —CFs.19. The compound of claim 16, 17, or 18, wherein Rg is methyl.20. The compound of claim 16, 17, or 18, wherein Rg is -CH,OH.21. The compound of claim 16, 17, or 18, wherein Rg is -CH,NH,.. 22. A compound of the formula:Ry x Hx 0 oo ORs 0 : Re ORs wherein R; is hydrogen or lower alkyl; R; is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety; Rs and Re are each independently hydrogen or a protecting group; X is O, S, C(Ry)2, or NRy, wherein each occurrence of Ry is independently hydrogen or lower alkyl; Rg is, independently for each occurrence, hydrogen; halogen; -ORg'; ~-SRp’; -N(Rp); -CY3, -CHY,, -CH2Y, where Y is F, Br, Cl, I, ORp:, NHRp:, N(Rp'),, or SRp’; -C(O)ORp’; -C(O)R 5’; -=CONHR p; -O(C=0)Rp’; -O(C=0)ORp’; - NRp(C=0)Rp-; N3; N2R pg; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORg; -SRp*; -N(R p')2; -C(O)ORp'; -C(O)R p'; -CONHR g-; - O(C=0O)Rp:; -O(C=0)ORp’; -NRp:(C=0)Rp; N3; NaR p’; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of Rp is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety.23. A compound of the formula:S Re — N GF 0 0) ORs 0) N , Rg . Y ORs wherein Rp is hydrogen; halogen; -ORg'; -SRp’; -N(R p)2; -CY3, -CHY, -CH,Y, where YisF,Br, Cl I, ORp,, NHRp, NRp)2, or SRp'; -C(O)ORg:; -C(O)R 5; -CONHR p; - O(C=0)Rp:; -O(C=0)ORg’; -NRp:(C=0)Rg; N3; N2R p'; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORp'; -SRa'; -N(R p')s; - C(O)ORp'; -C(O)R p'; -CONHR p-; -O(C=0)Rp’; -O(C=0)ORp; -NRg(C=0)Rp; Ns; N:zR py; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of Rp: is independently hydrogen, alkyl, aryl, or a protecting group; wherein each occurrence of Rg: is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; Rs and Rg are each independently hydrogen or a protecting group; Rg is independently hydrogen, halogen, -ORg, -SRg, -N(Rg)s, -CY3, -CHY>, - CH,Y, where Y is F, Br, Cl, I, ORs’, NHRg’, N(Rp')2, or SRp’; -(CV2),0Ry, - (CV2)aNRg)a, -(CV2)nSRy, -(C=0)Rg, -O(C=0)Ry, -(C=0)ORs, -O(C=0)ORy;- NH(C=0)Rs, -NH(C=0)ORy, -(C=0)NHRs, or a cyclic or acyclic, linear or branched : aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety optionally substituted with one or more occurrences of halogen, ~-ORy, -SRo, -N(Ro)y, - ’ 25 (CV2)ORy, -(CV2)aN(Ro)2, -(CV2)sSRg, -(C=0)Rs, -O(C=0)Ry, -(C=0)ORy, - O(C=0)ORg;-NH(C=0)Ry, -NH(C=0)ORy, -(C=O)NHRs, or a cyclic or acyclic, linear or branched, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalky! moiety, wherein each occurrence of Ry is independently hydrogen; a protecting group; a - cyclic or acyclic, linear or branched, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone or - analogues thereof; a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of V is independently hydrogen, halogen, hydroxyl, thio, amino, alkylamino, or protected hydroxyl, thio or amino; each occurrence of t is independently 0, 1 or 2; and each occurrence of n is independently 0-10; and 10, pharmaceutically acceptable derivatives thereof.24. The compound of claim 23 wherein Ry is methyl.25. The compound of claim 23 wherein Rg is —CFs.26. The compound of claim 23, 24, or 25, wherein Rg is methyl.27. The compound of claim 23, 24, or 25, wherein Rg is —-CH,OH.28. The compound of claim 23, 24, or 25, wherein Rg is -CH,NH,.29. A compound of the formula: O Re— N P= \O) Oo ORs (8) > Rg PU ORg whereinRp is hydrogen; halogen; -ORp'; -SRp’; -N(R p')2; -CY3, -CHY,, -CH,Y, where Y is F, Br, Cl, I, ORp,, NHRp’, N(Rp-)2, or SRp; -C(O)ORp; -C(O)Rg'; -CONHRgp:; - O(C=0)Rp’; -O(C=0)ORp-; -NRp(C=0)Rz’; N3; N,R B’; Cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally i 5 substituted with one or more of hydrogen; halogen; -ORy; -SRp; -N(Rp'); - . C(O)ORg'; -C(O)R p; -CONHR p’; -O(C=0)Rp’; -O(C=0)ORp:; -NRp(C=0)Rp"; N3; N2R p:; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of Ry: is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; Rs and Re are each independently hydrogen or a protecting group; Rs is independently hydrogen, halogen, -ORsy, -SRo, -N(Ro),, -CY3, -CHY>, - CHyY, where Y is F, Br, Cl, I, OR, NHRp, N(Rs");, or SRp -(CV3)uORy, - (CV2)uNRog)z2, -(CV2)uSRg, ~(C=O)Ry, -O(C=O)Rs, -(C=0O)ORs, -O(C=0)ORg;- NH(C=0)Ry, -NH(C=0)ORy, -(C=0)NHRs, or a cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety optionally substituted with one or more occurrences of halogen, -ORg, -SRg, -N(Rg),, - (CV2)iORg, -(CV2)N(Ro)z, ~(CV3)uSRg, -(C=O)Ry, -O(C=O)Ry, -(C=O)ORs, - O(C=0)ORg;-NH(C=0O)Ry, -NH(C=0)ORy, -(C=0)NHRs, or a cyclic or acyclic, linear or branched, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety, wherein each occurrence of Ry is independently hydrogen; a protecting group; a cyclic or acyclic, linear or branched, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone or analogues thereof: a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of V is independently hydrogen, halogen, hydroxyl, i 30 thio, amino, alkylamino, or protected hydroxyl, thio or amino; each occurrence of t is independently 0, 1 or 2; and each occurrence of n is independently 0-10; and pharmaceutically acceptable derivatives thereof.30. The compound of claim 29 wherein Rg is methyl.31. The compound of claim 29 wherein Rp is —~CFs. ) 32. The compound of claim 29, 30, or 31, wherein Rg is methyl. - 33. The compound of claim 29, 30, or 31, wherein Rg is -CH,0H.34. The compound of claim 29, 30, or 31, wherein Rg is <CH,NHo.35. A compound of the formula: S ve—g N P= O (0) OH F3C / . OH36. A compound of the formula: S ve— N FF O) (0) OH Me / > OH. 37. A compound of the formula:S ve—( N GZ Oo. _.0O ° oH ” FaC * 3 OH38. A compound of the formula: S Me—( N FZ O Oo OH 8) SS Me 3 OH38a. A compound of the formula: S HoMe—( ’ = 0 6) OH od 5 OH ¢ 38b. A compound of the formula:S me—( N ZZ Oo Oo oH ¥ FiC / ’ Oo OH39. A trans-9,10-dehydro-cis-12,13-dehydroepothilone analog.40. The trans-9,10-dehydro-cis-12,13-dehydroepothilone analog, wherein the analog is characterized by an ICs of less than 0.01 in a CCRF-CEM cell line.41. The frans-9,10-dehydro-cis-12,13-dehydroepothilone analog, wherein the analog is characterized by an ICs of less than 0.05 in a CCRF-CEM cell line.42. The trans-9,10-dehydro-cis-12,13-dehydroepothilone analog, wherein the analog is characterized by an ICs of less than 0.01 in a CCRF-CEM cell line resistant to Taxol.43. The trans-9,10-dehydro-cis-12,13-dehydroepothilone analog, wherein the analog is characterized by an ICs of less than 0.05 in a CCRF-CEM cell line resistant to Taxol. 44, A pharmaceutical composition comprising a trans-9,10-dehydro-cis-12,13- dehydroepothilone analog and a pharmaceutically acceptable excipient.45. A pharmaceutical composition for the treatment of cancer comprising a “ compound of any one of claims 1-32 and a pharmaceutically acceptable excipient.46. The pharmaceutical composition of claim 44 or 45 further comprising Cremophor.47. The pharmaceutical composition of claim 44 or 45 further comprising Cremophor and ethanol. : ) 48. The pharmaceutical composition of claim 44 or 45, wherein the compound is ’ 5 suspended in 1:1 Cremophor/EtOH. >)49. The pharmaceutical composition of claim 44 or 45 further comprising an additional cytotoxic agent.50. A pharmaceutical composition for the treatment of cancer comprising: a therapeutically effective amount of a compound of any one of claims 1-43, or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier or diluent, wherein the therapeutically effective amount of the compound is an amount sufficient to deliver about 0.001 to about 40 mg compound per kg body weight of a subject.51. A method of treating cancer comprising: administering a therapeutically effective amount of a compound of any one of claims 1-32 to a subject in need thereof.52. The method of claim 51, wherein the therapeutically effective amount of the compound is an amount sufficient to deliver about 0.001 mg to about 40 mg compound per kg body weight.53. The method of claim 51, wherein the therapeutically effective amount of the compound is an amount sufficient to deliver about 0.1 mg to about 25 mg compound per kg body weight. § 30 54. A method of preparing a compound of formula:Ro Py Hx 0 ORs Sa: con” m| 0 vy ORs @ wherein R; is hydrogen or lower alkyl; 4 R; is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety; Rs and Rg are each independently hydrogen or a protecting group; X is O, S, C(R7)2, or NR, wherein each occurrence of R; is independently hydrogen or lower alkyl; Rp is, independently for each occurrence, hydrogen; halogen; -ORp’; -SRp’; -N(R p')2; -CY3, -CHY>, -CH,Y, where Y is F, Br, Cl, I, ORp:, NHRp, N(Rp*)2, or SRp’; -C(O)ORp’; -C(O)R p; -CONHR pg’; -O(C=0)Rp’; -O(C=0)ORg’; - NRg(C=0)Rp’; N3; NaR p'; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORp’; -SRp’; -N(R p°)2; -C(O)ORp’; -C(O)R p’; -CONHR p; - O(C=0)Rp:; -O(C=0)ORp'; -NRp:(C=0)Rp"; N3; N2R p’; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of Rp is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; and mis 1, 2, 3, or 4, the method comprising steps of: subjecting a compound of the formula: Ry By Hx _P i ay SR fe y Zz ORg to conditions of a ring closing metathesis reaction.55. A method of preparing a compound of formula: iy io xX.O ° 7 ORs A) m| 'e) ORs wherein R; is hydrogen or lower alkyl; R; is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety; Rs and Rg are each independently hydrogen or a protecting group; X is O, 8, CRs), or NR, wherein each occurrence of R; is independently hydrogen or lower alkyl, Rp is, independently for each occurrence, hydrogen; halogen; -ORp:; -SRp'; -NR p’)2; -CY3, -CHY,, -CH,Y, where Y is F, Br, Cl, I, ORp’, NHRp, N(Rp'),, or SRp'; -C(O)ORg'; -C(O)R p; -CONHR p'; -O(C=0)Rp; -O(C=0)ORp; - NRp(C=0)Rp:; N3; N2R 5; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORp'; -SRp’; -N(R p°)2; -C(O)ORp; -C(O)R gp’; -CONHR pg; - O(C=0)Rg’; -O(C=0)ORp’; -NRp:(C=0)Rg’; N3; N2R »’; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of Rp is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; and mis 1, 2, 3, or 4, the method comprising steps of: . 25 subjecting a compound of the formula:R B 1 «0 oO \ ORs Re—<. * m\\ o} = ORs «© to conditions of a ring closing metathesis reaction.56. The method of claim 54, wherein the conditions of a ring closing metathesis reaction include a Grubbs catalyst.57. The method of claim 565, wherein the Grubbs catalyst is tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2- ylidene][benzilydene]ruthenium (IV) chloride.58. A method of preparing a compound of formula: Rq © Rox : X 0 ORs Re—<. m (0) ORs wherein R; is hydrogen or lower alkyl; R; is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety; Rs and Rg are each independently hydrogen or a protecting group; X is O, S, C(Ry)2, or NRy, wherein each occurrence of Ry is independently hydrogen or lower alkyl; Rp is, independently for each occurrence, hydrogen; halogen; -ORg’; -SRp; -N(Rp)2; -CY3, -CHY>, -CH,Y, where Y is F, Br, Cl, I, ORg’, NHRp:, N(Rp")2, or fo SRg’; ~C(O)ORp’; -C(O)R p’; -CONHR p’; -O(C=0)Rg’; -O(C=0)ORp’; - NRp/(C=O)Rp:; N3; NoRp’; cyclic acetal; or cyclic or acyclic, linear or branched “ aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORp’; -SRp:; -N(R p-),; -C(O)ORp:; -C(O)R 5; -CONHR p’; - O(C=O)Rp’; -O(C=0)ORp’; -NRp:(C=0)Rp'; N3; N2R p:; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of Rp is independently hydrogen; a protecting group; a linear or branched, substituted or ’ 5 unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, Cw arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; and mis 1, 2, 3, or 4, the method comprising steps of: reducing a compound of the formula: Ro x Hx 0 ORe Re—C 9) Rs59. A method of preparing a compound of formula: 0 ; Re 0 ORs wherein R; is hydrogen or lower alkyl; R; is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety; Rs and Rg are each independently hydrogen or a protecting group; X is O, §, C(Ry)2, or NRy, wherein each occurrence of Ry is independently hydrogen or lower alkyl; Rg is, independently for each occurrence, hydrogen; halogen; -ORg-; -SRp; I” NR p'); -CY3, -CHY>, -CHyY, where Y is F, Br, Cl, I, ORp:, NHRg:, N(Rp')2, or SRp; -C(O)ORgz; -C(O)R p'; -CONHR g-; -O(C=0)Rp’; -O(C=0)ORp’; - ’ NRp:(C=0)Rp; N3; NaR pr; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORp’; -SRp’; -N(R p')2; -C(O)ORp’; -C(O)R p’; -CONHR p’; ~O(C=0)Rp’; -O(C=0)ORp’; -NRp(C=0)Rp’; N3; NaR p’; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is . a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of } 5 Rp is independently hydrogen; a protecting group; a linear or branched, substituted or © unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; and mis 1, 2, 3, or 4, the method comprising steps of: oxidizing a compound of the formula: Rz Py Hx 0 ORs m |] 0 ORs60. A method of preparing a compound of formula: R, I XC Oe Rg / m| 0 ORs wherein R; is hydrogen or lower alkyl; R is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety; Rs and Re are each independently hydrogen or a protecting group; X is O, S, C(R7)2, or NRy, wherein each occurrence of Rj is independently hydrogen or lower alkyl, (\ Rp is, independently for each occurrence, hydrogen; halogen; -ORg'; -SRp-; -NR p)2; -CY3, -CHY2, -CH,Y, where Y is F, Br, Cl, I, ORp:, NHRp:, N(Rp'),, or ) SRp; -C(O)ORp'; -C(O)R p>; -CONHR p’; -O(C=0)Rp’; -O(C=0)ORg’; - NRg(C=O)Rp’; N3; N2R p'; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -ORs"; -SRp’; -N(R p°); -C(O)ORp'; -C(O)R B; -CONHR p'; - O(C=0)Rg’; -O(C=0)ORp’; -NRp(C=0)Rz’; N3; N2R p’; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, . or heteroaryl moiety; or is an epothilone, desoxyepothilone, or analogues thereof; or is a polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of “ Rp is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroalliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; and mis 1, 2, 3, or 4, the method comprising steps of: condensing a phosphine oxide or Wittig reagent having the structure: « * we fe AR Ng or Ne wherein R' and R" are independently Cy. linear or branched chain alkyl, or a substitutedor unsubstituted phenyl, aryl, alkoxy or aryloxy; and X is a counteranion such as choride or bromide; with a ketone having the structure: 1 H Xx.O Oo Y ORs m]| 0 ORs Hy
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