WO2009126947A2 - Heteroaryl-substituted bicyclic smac mimetics and the uses thereof - Google Patents
Heteroaryl-substituted bicyclic smac mimetics and the uses thereof Download PDFInfo
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- WO2009126947A2 WO2009126947A2 PCT/US2009/040312 US2009040312W WO2009126947A2 WO 2009126947 A2 WO2009126947 A2 WO 2009126947A2 US 2009040312 W US2009040312 W US 2009040312W WO 2009126947 A2 WO2009126947 A2 WO 2009126947A2
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- 0 *[C@@](C1OC1N[C@@](CCC*C(CC1)N2[C@@]1C(*1)=Nc3c1c(*)c(*)c(*)c3*)C2=O)N* Chemical compound *[C@@](C1OC1N[C@@](CCC*C(CC1)N2[C@@]1C(*1)=Nc3c1c(*)c(*)c(*)c3*)C2=O)N* 0.000 description 16
- QPQLAQQNAPKJRY-JJOWMTMRSA-N C[C@@H](C(N[C@@H](CN(CC[C@@H](CC1)N2[C@@H]1c([nH]c1ccc3)nc1c3-c(cc1)ccc1F)C(Cc(cc1)ccc1F)=O)C2=O)=O)NC Chemical compound C[C@@H](C(N[C@@H](CN(CC[C@@H](CC1)N2[C@@H]1c([nH]c1ccc3)nc1c3-c(cc1)ccc1F)C(Cc(cc1)ccc1F)=O)C2=O)=O)NC QPQLAQQNAPKJRY-JJOWMTMRSA-N 0.000 description 1
- AWOGJDHMSMDFKJ-RZNYTTDSSA-N C[C@@H](C(N[C@@H](CN(CC[C@@H](CC1)N2[C@@H]1c([nH]c1ccc3)nc1c3-c1ccccc1)C(Cc1ccccc1)=O)C2=O)=O)NC Chemical compound C[C@@H](C(N[C@@H](CN(CC[C@@H](CC1)N2[C@@H]1c([nH]c1ccc3)nc1c3-c1ccccc1)C(Cc1ccccc1)=O)C2=O)=O)NC AWOGJDHMSMDFKJ-RZNYTTDSSA-N 0.000 description 1
- IWDLFZDNZCPYQM-GAGAFAOGSA-N C[C@@H](C(N[C@@H](CNCC[C@@H](CC1)N2[C@@H]1c1nc(c(-c3ccccc3)ccc3)c3[nH]1)C2=O)=O)N(C)C(OC(C)(C)C)=O Chemical compound C[C@@H](C(N[C@@H](CNCC[C@@H](CC1)N2[C@@H]1c1nc(c(-c3ccccc3)ccc3)c3[nH]1)C2=O)=O)N(C)C(OC(C)(C)C)=O IWDLFZDNZCPYQM-GAGAFAOGSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention is in the field of medicinal chemistry.
- the invention relates to heteroaryl-substituted bicyclic Smac mimetics of the N-terminal sequence of
- Smac which function as inhibitors of Inhibitor of Apoptosis Proteins.
- the invention also relates to the use of these mimetics for inducing or sensitizing cells to the induction of apoptotic cell death.
- the aggressive cancer cell phenotype is the result of a variety of genetic and epigenetic alterations leading to deregulation of intracellular signaling pathways (Ponder,
- the second class of central negative regulators of apoptosis is the inhibitor of apoptosis proteins (IAPs) (Deveraux et al., Genes Dev. 13:239 (1999); Salvesen et al.,
- This class includes proteins such as XIAP, cIAP-1, cIAP-2, ML-IAP, HIAP, KIAP, TSIAP, NAIP, survivin, livin, ILP-2, apollon, and BRUCE.
- IAP proteins potently suppress apoptosis induced by a large variety of apoptotic stimuli, including chemotherapeutic agents, radiation, and immunotherapy in cancer cells.
- X-linked IAP is the most potent inhibitor in suppressing apoptosis among all of the IAP members (Holcik et al., Apoptosis 6:253 (2001); LaCasse et al., Oncogene 17:3247 (1998); Takahashi et al., J. Biol. Chem. 275:7787 (1998); Deveraux et al., Nature 388:300 (1997); Sun et al., Nature 407:818 (1999); Deveraux et al., EMBO J. 75:5242 (1999); Asselin et al, Cancer Res. 61:1862 (2001)).
- XIAP plays a key role in the negative regulation of apoptosis in both the death receptor-mediated and the mitochondria-mediated pathways.
- XIAP functions as a potent endogenous apoptosis inhibitor by directly binding and potently inhibiting three members of the caspase family of enzymes, caspase-3, -7, and -9 (Takahashi et al, J. Biol. Chem. 275:7787 (1998); Deveraux et al, Nature 388:300 (1997); Sun et al, Nature 407:818 (1999); Deveraux et al, EMBO J. 18:5242 (1999); Asselin et al., Cancer Res. 67:1862 (2001); Riedl et al, Cell 104:191 (2001); Chai et al, Cell 104:769 (2001); Huang et al, Cell 104:781 (2001)).
- XIAP contains three baculovirus inhibitor of apoptosis repeat (BIR) domains as well as a C-terminal RING finger.
- BIR3 baculovirus inhibitor of apoptosis repeat
- BIR3 selectively targets caspase-9, the initiator caspase in the mitochondrial pathway, whereas the linker region between BIRl and BIR2 inhibits both caspase-3 and caspase-7 (Salvesen et al, Nat. Rev. MoI Cell. Biol. 5:401 (2002)).
- binding to XIAP prevents the activation of all three caspases, it is apparent that the interaction with caspase-9 is the most critical for its inhibition of apoptosis (Ekert et al, J. Cell Biol.
- XIAP protein was found to be expressed in most of the NCI 60 human cancer cell lines (Tamm et al, Clin. Cancer Res. 6:1796 (2000)). Analysis of tumor samples in 78 previously untreated patients showed that those with lower levels of XIAP had significantly longer survival (Tamm et al, Clin. Cancer Res. 6:1796 (2000)). XIAP was found to be expressed in human malignant glioma (Wagenknecht et al, Cell Death Differ. 6:370 (1999); Fulda et al, Nature Med. 5:808 (2002)).
- XIAP was found to be expressed in human prostate cancer cells and blocks Apo2 ligand/tumor necrosis factor-related apoptosis inducing ligand-mediated apoptosis of prostate cancer cells in the presence of mitochondrial activation (McEleny et al, Prostate 57:133 (2002); Ng et al, MoI Cancer
- XIAP is overexpressed in non-small cell lung cancer (NSCLC) in patients and has been implicated in pathogenesis of NSCLC (Hofmann et al, J. Cancer Res. Clin. Oncol. 128:554 (2002)).
- NSCLC non-small cell lung cancer
- Expression of XIAP and lack of down-regulation of XIAP upon treatment with cisplatin have been implicated in cisplatin resistance of human ovarian cancer (Li et al., Endocrinology 142:370 (2001); Cheng et al., Drug Resist. Update 5:131 (2002)).
- XIAP may play an important role in resistance of several human cancers to current therapeutic agents.
- Integrity of the blood vessel wall is essential for vascular homeostasis and organ function.
- a dynamic balance between endothelial cell survival and apoptosis contributes to this integrity during vascular development and pathological angiogenesis. It has been shown that cIAP-1 is essential for maintaining endothelial cell survival and blood vessel homeostasis during vascular development (Santoro et al, Nature Genetics 39: 1397
- cIAP-1 may play an important role in the control of angiogenesis and blood vessel homeostasis during embryogenesis, regeneration and tumorigenesis.
- Apoptosis is not a single process, rather, it is involved with a number of different, sometimes interconnected, signaling pathways leading to cell degradation.
- the pathways involved in a particular form of apoptosis depend on many factors, such as the insult or insults that initiate the process. Other factors include the activation or overactivation of specific receptors, such as the activation of "death" receptors by tumor necrosis factor alpha (TNF ⁇ ), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L), or FAS ligand.
- TNF ⁇ tumor necrosis factor alpha
- TRAIL or Apo2L tumor necrosis factor-related apoptosis-inducing ligand
- FAS ligand Another determining factor is the type of cell which is involved, since different signaling pathways are shown for so called type I and type II cells after
- TRAIL Apo2L has been shown to be a selective and potent inducer of apoptosis in cancer cells (but not normal cells) upon binding to either of two pro-apoptotic TRAIL receptors, TRAIL-Rl (or DR4) (Pan et al, Science 276:111 (1997)) or TRAIL-R2 (KILLER, or DR5) (Wu et al., Nat. Genet. 77:141-143 (1997); Pan et al., Science
- DISC death inducing signaling complex
- TRAIL has generated significant interest as a potential cancer therapeutic (French et al, Nat. Med. 5:146 (1999)) because of its selective targeting of cancer cells, whereas most normal cells appear to be resistant to TRAIL (Ashkenazi et al, Science 281: 1305 (1998); Walczak et al, Nat. Med. 5:157 (1999)).
- Systemic administration of TRAIL has proven to be safe and effective at killing breast or colon xenografted tumors and prolonging survival in mice (Walczak et al., Nat. Med.5:157 (1999)).
- TRAIL can specifically kill many types of cancer cells, many others display TRAIL-resistance (Kim et al., Clin. Cancer Res. 6:335 (2000); Zhang et al., Cancer Res. 59:2141 (1999)). In addition, cancer cells have been killed by application of antibodies (monoclonal or polyclonal) that specifically recognize either TRAIL-Rl or TRAIL-R2.
- TRAIL-resistance Such mechanisms exist at a number of levels, including at the receptor level, mitochondria level, post-mitochondria level, and at the DISC level. For example, loss of caspase-8 expression (Teitz et al., Nat. Med. 6:529 (2000); Griffith et al., J. Immunol. 161:2833 (1998)), or high expression of the cellular FLICE inhibitor protein
- cFLIP cFLIP-deficient embryonic mouse fibroblasts
- cFLIP-S short splice variant
- cFLIP-L longer splice variant
- TRAIL represents a potentially promising candidate for tumor-selective death receptor activation (i.e., it induces apoptosis preferentially in tumor cells but not in normal tissues), many cancer cells are resistant to apoptosis-inducing drugs, as discussed above. As a result, treatment with such drugs often requires co-treatment with irradiation and/or cytotoxic chemicals to achieve a therapeutic effect. However, both radiation and chemotherapy have significant side effects, and are generally avoided if possible. [0016] Thus, a need exists for an agent that can selectively and efficiently sensitize tumor cells to selective, apoptosis-inducing drugs such as TRAIL or TRAIL receptor antibodies, without also sensitizing surrounding normal cells. Such an agent would also be useful for reducing or preventing the drug resistance commonly associated with the use of receptor- mediated apoptotic cancer drugs, thus improving their effectiveness and eliminating the need for combination therapies.
- Smac/DIABLO second mitochondria-derived activator of caspases
- Smac-XIAP interaction is mediated by only four amino acid residues on the Smac protein and a well-defined surface groove on the BIR3 domain of XIAP.
- This well-defined interaction site is ideal for the design of non-peptide, drug-like small molecules that mimic the binding of Smac to XIAP.
- a cell permeable Smac peptide which consists of the first four amino acid residues (AVPI (SEQ ID NO: I)) of the N-terminus of Smac tethered to a carrier peptide to facilitate intracellular delivery, was recently shown to sensitize various tumor cells in vitro and malignant glioma cells in vivo to apoptosis induced by death receptor ligation or cytotoxic drugs (Fulda et ah, Nature Med. 5:808 (2002)). Importantly, this Smac peptide strongly enhanced the anti-tumor activity of Apo2L/TRAIL in an intracranial malignant glioma xenograft model in vivo. Complete eradication of established tumors and survival of mice was only achieved upon combined treatment with Smac peptides and
- Smac peptide does not have detectable toxicity to normal brain tissue.
- a second recent independent study also showed that peptides consisting of the first four to eight amino acid residues of the N-terminus of Smac tethered to a different carrier peptide enhanced the induction of apoptosis and the long term anti-pro liferative effects of diverse chemotherapeutic drugs, including paclitaxel, etoposide, SN-38, and doxorubicin in MCF-7 and other human breast cancer cell lines (Arnt et ah, J. Biol. Chem. 277:44236 (2002).
- This study conclusively showed that XIAP and cIAP-1 are the primary molecular targets for these peptides in cells.
- a third study showed that a Smac peptide of the first seven N-terminal residues tethered to polyarginine restored the apoptosome activity and reversed the apoptosis resistance in non-small cell lung cancer H460 cells (Yang et ah, Cancer Res. (53:831 (2003)).
- XIAP was shown to be responsible for the defect in apoptosome activity and suppression of caspase activity in H460 cells.
- the cell-permeable Smac peptide regressed tumor growth in vivo with little murine toxicity.
- Peptide-based inhibitors are useful tools to elucidate the anti-apoptotic function of IAPs and the role of IAPs in response of cancer cells to chemotherapeutic agents.
- peptide-based inhibitors in general have intrinsic limitations as potentially useful therapeutic agents. These limitations include their poor cell-permeability and poor in vivo stability. Indeed, in these three published studies using Smac-based peptide inhibitors, the peptides had to be fused to carrier peptides to make them relatively cell-permeable.
- the present invention provides conformationally constrained Smac mimetics having heteroaromatic substitution on the bicyclic scaffold.
- the present invention contemplates that exposure of animals suffering from cancer or other hyperproliferative disorders or diseases associated with dysregulation of apoptosis to therapeutically effective amounts of drug(s) (e.g., small molecules) that inhibit the function(s) of IAPs will kill the diseased cells or supporting cells outright
- drug(s) e.g., small molecules
- inhibitors of IAPs satisfy an unmet need for the treatment of multiple cancer types, either when administered as monotherapy to induce apoptosis in cancer cells dependent on IAP function, or when administered in a temporal relationship with other cell death-inducing cancer therapeutic drugs or radiation therapies so as to render a greater proportion of the cancer cells or supportive cells susceptible to executing the apoptosis program compared to the corresponding proportion of cells in an animal treated only with the cancer therapeutic drug or radiation therapy alone.
- the present invention also contemplates that treatment of animals suffering from endothelial cell-associated diseases (e.g., tumor angiogenesis, retinopathies and atherosclerosis) with therapeutically effective amounts of drug(s) (e.g., small molecules) that inhibit the function(s) of IAPs (e.g., cIAP-1) may prevent or inhibit angiogenesis and disrupt blood vessel homeostasis during vascular development in pathological conditions.
- drug(s) e.g., small molecules
- IAPs e.g., cIAP-1
- disorders that may be treated with the compounds of the invention include macular degeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neo vascular glaucoma, retrolental fibroplasia, rubeosis, Osier- Webber Syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, wound granulation, intestinal adhesions, atherosclerosis, scleroderma and hypertrophic scars.
- combination treatment of animals with a therapeutically effective amount of a compound of the present invention and a course of an anticancer agent or radiation is expected to produce a greater tumor response and clinical benefit in such animals compared to those treated with the compound or anticancer drugs/radiation alone.
- the compounds of the present invention lower the apoptotic threshold of all cells that express IAPs, the proportion of cells that successfully execute the apoptosis program in response to the apoptosis inducing activity of anticancer drugs/radiation is increased.
- the compounds of the present invention are expected to allow administration of a lower, and therefore less toxic and more tolerable, dose of an anticancer agent and/or radiation to produce the same tumor response/clinical benefit as the conventional dose of the anticancer agent/radiation alone. Since the doses for all approved anticancer drugs and radiation treatments are known, the present invention contemplates the various combinations of them with the compounds of the present invention. Also, since the compounds of the present invention act at least in part by inhibiting IAPs, the exposure of cancer cells and supporting cells to therapeutically effective amounts of the compounds can be temporally linked to coincide with the attempts of cells to execute the apoptosis program in response to the anticancer agent or radiation therapy.
- compositions of the present invention in connection with certain temporal relationships, is expected to provide especially efficacious therapeutic practices.
- the present invention relates to Smac mimetics that are useful for inhibiting the activity of IAP proteins and inter alia increasing the sensitivity of cells to inducers of apoptosis.
- the Smac mimetics are compounds of Formula I:
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O; W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl;
- Y is selected from the group consisting Of CON(R 1 ), N(R ⁇ )CO, C(O)O, OC(O), (CH 2 )L 3 , wherein one or more CH 2 groups can be replaced by O, S, or NR 1 , optionally substituted aryl and optionally substituted heteroaryl;
- Z is (CR 2a R 2b ) r ;
- D is (CR 3a R 3b ) n -U-(CR 4a R 4b ) m ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ;
- J is (CR 7a R 7b ) p -L-(CR 8a R 8b ) q ;
- T is optionally substituted heteroaryl;
- n, m, p and q are independently selected from the group consisting of 0-5;
- r is 0-3;
- R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; each R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 7a , R 7b , R 8a , R 8b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; or pharmaceutically acceptable salt or prodrug thereof.
- Smac mimetics are compounds of Formula II:
- a 1 , A 2 , V, Z, W, X, Y, D, J and T have the meanings as described above for Formula I; or a pharmaceutically acceptable salt or prodrug thereof.
- Smac mimetics are compounds of Formula III:
- Smac mimetics are compounds of Formula IV:
- Ai, A 2 , X, U, and T have the meanings as described above for Formula I, and m is 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.
- Smac mimetics are compounds of Formula V:
- Smac mimetics are compounds of Formula VI:
- Smac mimetics are compounds of Formula VII:
- Ai and X are optionally substituted alkyl, R 9 is optionally substituted alkyl or aralkyl, and T is optionally substituted heteroaryl; or a pharmaceutically acceptable salt or prodrug thereof.
- Smac mimetics are compounds of Formulae I-
- R 12 is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo
- R 1Oa , R 10b , R lla , R l lb , R l lc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamid
- Smac mimetics are compounds of Formula
- Ai and X are optionally substituted alkyl, m is 1 or 2 , Q is O, S or NR 12 , R 12 is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo, and R 1Oa and R 10b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido; or a pharmaceutically
- Ai and X are optionally substituted alkyl, m is 1 or 2, Q is O, S or NR 12 , R 12 is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo, and R l la , R llb , R l lc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido
- R 9 is optionally substituted alkyl or aralkyl
- m is 1 or 2
- Q is O, S or NR 12
- R 12 is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo
- R 1Oa and R 10b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxa
- Ai and X are optionally substituted alkyl, R is optionally substituted alkyl or aralkyl, m is 1 or 2, Q is O, S or NR 12 , R 12 is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo, and R lla , R l lb , R l lc and R lld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, aryl
- the invention relates to compounds represented by Formulae I-XIa which are inhibitors of IAP proteins.
- the invention relates to the use of the compounds of the invention to induce apoptosis in cells and inhibit angiogenesis.
- the invention also relates to the use of the compounds of the invention for sensitizing cells to inducers of apoptosis.
- the compounds are useful for the treatment, amelioration, or prevention of disorders responsive to induction of apoptotic cell death, e.g., disorders characterized by dysregulation of apoptosis, including hyperproliferative diseases such as cancer.
- the compounds can be used to treat, ameliorate, or prevent cancer that is characterized by resistance to cancer therapies (e.g., those which are chemoresistant, radiation resistant, hormone resistant, and the like).
- the compounds can be used to treat hyperproliferative diseases characterized by overexpression of IAPs.
- the compounds can be used as a method of preventing or inhibiting angiogenesis in animals in need thereof.
- the present invention provides pharmaceutical compositions comprising compounds of Formulae I-XIa in a therapeutically effective amount to induce apoptosis in cells or to sensitize cells to inducers of apoptosis.
- kits comprising a compound of Formula I and instructions for administering the compound to an animal.
- the kits may optionally contain other therapeutic agents, e.g., anticancer agents or apoptosis-modulating agents.
- the present invention also provides a process for preparing a compound of
- R 13 is selected from the group consisting OfN(H)P 1 and
- P 1 is an amine protecting group
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O; W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl;
- Y is selected from the group consisting Of CON(R 1 ), N(R ⁇ CO, C(O)O, OC(O), (CH 2 )i_ 3 , wherein one or more CH 2 groups can be replaced by O, S, or NR 1 , optionally substituted aryl and optionally substituted heteroaryl;
- Z is (CR 2a R 2b ) r ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ;
- m is 1 or 2;
- r is 0-3;
- R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; each R 2a , R 2b , R 5a and R 5b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; and [0046] R 1Oa and R 10b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo.
- the present invention also provides a process for preparing a compound of
- XVIII comprising: a) condensing ; a compound of Formula XIII
- R 13 is selected from the group consisting OfN(H)P 1 and ;
- P 1 is an amine protecting group
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O; W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl;
- Y is selected from the group consisting Of CON(R 1 ), N(R ⁇ CO, C(O)O, OC(O), (CH 2 )L 3 , wherein one or more CH 2 groups can be replaced by O, S, or NR 1 , optionally substituted aryl and optionally substituted heteroaryl;
- Z is (CR 2a R 2b ) r ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ; m is 1 or 2; r is 0-3; R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; each R 2a , R 2b , R 5a and R 5b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- R l la , R l lb , R l lc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido, and
- R 12 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo.
- the present also provides a process for preparing a compound of Formula XXI
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O;
- W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl; Z is (CR 2a R 2b ) r ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ; m is 1 or 2; r is 0-3; each R 2a , R 2b , R 5a and R 5b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; and T is optionally substituted heteroaryl.
- Fig. 1 is a graph illustrating competitive binding curves of Smac mimetics to the XIAP BIR3 domain.
- Fig. 2 is a graph illustrating competitive binding curves of Smac mimetics to the cIAPl domain.
- Fig. 3 is a bar graph showing the induction of cell death by SM- 1238 in the human breast cancer MDA-MB-231 and human ovarian cancer SK-O V-3 cell lines.
- the present invention relates to conformationally constrained compounds represented by Formulae I-XIa, which are mimetics of Smac and function as inhibitors of IAPs.
- Smac mimetics of Formula I-XIa display potent in vitro inhibitory activity in cancer cell lines.
- the invention relates to methods of sensitizing cells to inducers of apoptosis and to methods of inducing apoptosis in cells, comprising contacting the cells with a compound of Formulae I-XIa alone or in combination with an inducer of apoptosis.
- the invention further relates to methods of treating, ameliorating, or preventing disorders in an animal that are responsive to induction of apoptosis comprising administering to the animal a compound of Formulae I-XIa and an inducer of apoptosis.
- disorders include those characterized by a dysregulation of apoptosis and those characterized by overexpression of IAPs.
- the invention further relates methods of preventing or inhibiting angiogenesis in an animal in need thereof comprising administering to an animal a compound of Formulae I-XIa.
- IAP proteins refers to any known member of the
- Inhibitor of Apoptosis Protein family including, but not limited to, XIAP, cIAP-1, cIAP-2, ML-IAP, HIAP, TSIAP, KIAP, NAIP, survivin, livin, ILP-2, apollon, and BRUCE.
- mRNAs encoding for an IAP protein(s) and/or to elevated levels of IAP protein(s) in cells as compared to similar corresponding non-pathological cells expressing basal levels of mRNAs encoding IAP proteins or having basal levels of IAP proteins.
- Methods for detecting the levels of mRNAs encoding IAP proteins or levels of IAP proteins in a cell include, but are not limited to, Western blotting using IAP protein antibodies, immunohistochemical methods, and methods of nucleic acid amplification or direct RNA detection.
- IAP proteins in cells As important as the absolute level of IAP proteins in cells is to determining that they overexpress IAP proteins, so also is the relative level of IAP proteins to other pro-apoptotic signaling molecules (e.g., pro-apoptotic Bcl-2 family proteins) within such cells.
- pro-apoptotic signaling molecules e.g., pro-apoptotic Bcl-2 family proteins
- the pro-apoptotic signaling molecules would be sufficient to cause the cells to execute the apoptosis program and die, said cells would be dependent on the IAP proteins for their survival. In such cells, exposure to an inhibiting effective amount of an IAP protein inhibitor will be sufficient to cause the cells to execute the apoptosis program and die.
- an IAP protein also refers to cells that, due to the relative levels of pro-apoptotic signals and anti-apoptotic signals, undergo apoptosis in response to inhibiting effective amounts of compounds that inhibit the function of IAP proteins.
- anticancer agent and “anticancer drug,” as used herein, refer to any therapeutic agents (e.g., chemotherapeutic compounds and/or molecular therapeutic compounds), radiation therapies, or surgical interventions, used in the treatment of hyperproliferative diseases such as cancer (e.g., in mammals).
- therapeutic agents e.g., chemotherapeutic compounds and/or molecular therapeutic compounds
- radiation therapies or surgical interventions, used in the treatment of hyperproliferative diseases such as cancer (e.g., in mammals).
- prodrug refers to a pharmacologically inactive derivative of a parent "drug” molecule that requires biotransformation (e.g., either spontaneous or enzymatic) within the target physiological system to release, or to convert (e.g., enzymatically, physiologically, mechanically, electromagnetically) the prodrug into the active drug.
- Prodrugs are designed to overcome problems associated with stability, toxicity, lack of specificity, or limited bioavailability.
- Exemplary prodrugs comprise an active drug molecule itself and a chemical masking group (e.g., a group that reversibly suppresses the activity of the drug).
- Some preferred prodrugs are variations or derivatives of compounds that have groups cleavable under metabolic conditions. Exemplary prodrugs become pharmaceutically active in vivo or in vitro when they undergo solvolysis under physiological conditions or undergo enzymatic degradation or other biochemical transformation (e.g., phosphorylation, hydrogenation, dehydrogenation, glycosylation).
- Prodrugs often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism. (See e.g., Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam (1985); and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA (1992)).
- Common prodrugs include acid derivatives such as esters prepared by reaction of parent acids with a suitable alcohol (e.g., a lower alkanol), amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative (e.g., a lower alkylamide).
- salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
- acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, sulfonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like.
- Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
- bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW 4 + , wherein W is Ci_ 4 alkyl, and the like.
- alkali metal e.g., sodium
- alkaline earth metal e.g., magnesium
- W is Ci_ 4 alkyl
- salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
- salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a Ci_ 4 alkyl group), and the like.
- a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a Ci_ 4 alkyl group), and the like.
- salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
- salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
- the term "therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to result in amelioration of one or more symptoms of a disorder, or prevent advancement of a disorder, or cause regression of the disorder.
- a therapeutically effective amount preferably refers to the amount of a therapeutic agent that decreases the rate of tumor growth, decreases tumor mass, decreases the number of metastases, increases time to tumor progression, or increases survival time by at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
- sensitize and “sensitizing,” as used herein, refer to making, through the administration of a first agent (e.g., a compound of Formula I), an animal or a cell within an animal more susceptible, or more responsive, to the biological effects (e.g., promotion or retardation of an aspect of cellular function including, but not limited to, cell division, cell growth, proliferation, invasion, angiogenesis, or apoptosis) of a second agent.
- a first agent e.g., a compound of Formula I
- biological effects e.g., promotion or retardation of an aspect of cellular function including, but not limited to, cell division, cell growth, proliferation, invasion, angiogenesis, or apoptosis
- the sensitizing effect of a first agent on a target cell can be measured as the difference in the intended biological effect (e.g., promotion or retardation of an aspect of cellular function including, but not limited to, cell growth, proliferation, invasion, angiogenesis, or apoptosis) observed upon the administration of a second agent with and without administration of the first agent.
- the response of the sensitized cell can be increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least
- the term "dysregulation of apoptosis,” as used herein, refers to any aberration in the ability of (e.g., predisposition) a cell to undergo cell death via apoptosis.
- Dysregulation of apoptosis is associated with or induced by a variety of conditions, including for example, autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, graft-versus-host disease, myasthenia gravis, or Sjogren's syndrome), chronic inflammatory conditions (e.g., psoriasis, asthma or Crohn's disease), hyperproliferative disorders (e.g., tumors, B cell lymphomas, or T cell lymphomas), viral infections (e.g., herpes, papilloma, or HIV), and other conditions such as osteoarthritis and atherosclerosis.
- autoimmune disorders e.g., systemic lupus erythe
- angiogenesis means the generation of new blood vessels into a tissue or organ.
- antiangiogenesis refers to prevention or reduction of the growth of new blood vessels.
- diseases or disorders associated with angiogenesis include macular degeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neo vascular glaucoma, retrolental fibroplasia, rubeosis, Osier-Webber Syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, wound granulation, intestinal adhesions, atherosclerosis, scleroderma and hypertrophic scars.
- hyperproliferative disease refers to any condition in which a localized population of proliferating cells in an animal is not governed by the usual limitations of normal growth.
- hyperproliferative disorders include, but are not restricted to cancers (e.g., tumors, neoplasms, lymphomas and the like) or autoimmune disorders.
- a neoplasm is said to be benign if it does not undergo invasion or metastasis and malignant if it does either of these.
- a "metastatic" cell means that the cell can invade and destroy neighboring body structures.
- Hyperplasia is a form of cell proliferation involving an increase in cell number in a tissue or organ without significant alteration in structure or function.
- Metaplasia is a form of controlled cell growth in which one type of fully differentiated cell substitutes for another type of differentiated cell.
- the hyperproliferative disease is rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, leiomyomas, adenomas, lipomas, hemangiomas, f ⁇ bromas, vascular occlusion, restenosis, atherosclerosis, pre-neoplastic lesions (such as adenomatous hyperplasia and prostatic intraepithelial neoplasia), carcinoma in situ, oral hairy leukoplakia, or psoriasis.
- autoimmune disorder refers to any condition in which an organism produces antibodies or immune cells which recognize the organism's own molecules, cells or tissues.
- Non- limiting examples of autoimmune disorders include autoimmune hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac sprue, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft versus host disease, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatic arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, and the like.
- neoplastic disease refers to any abnormal growth of cells being either benign (non-cancerous) or malignant (cancerous).
- anti-neoplastic agent refers to any compound that retards the proliferation, growth, or spread of a targeted (e.g., malignant) neoplasm.
- the terms “prevent,” “preventing,” and “prevention,” as used herein, refer to a decrease in the occurrence of pathological cells (e.g., hyperproliferative or neoplastic cells) in an animal. The prevention may be complete, e.g., the total absence of pathological cells in a subject. The prevention may also be partial, such that the occurrence of pathological cells in a subject is less than that which would have occurred without the present invention.
- apoptosis-modulating agents refers to agents which are involved in modulating (e.g., inhibiting, decreasing, increasing, promoting) apoptosis.
- the apoptosis-modulating agent is an inducer of apoptosis.
- inducer of apoptosis refers to an agent that induces apoptosis in cells (e.g., cancer cells), rendering those cells more susceptible to executing the apoptosis program.
- an agent that induces apoptosis is an anticancer agent.
- apoptosis-modulating agents include proteins which comprise a death domain such as, but not limited to, Fas/CD95, TRAMP, TNF RI, DRl, DR2, DR3, DR4, DR5, DR6, FADD, and RIP.
- apoptotic-modulating agents include, but are not limited to, TNF ⁇ , Fas ligand, antibodies to Fas/CD95 and other TNF family receptors, TRAIL (also known as Apo2 Ligand or Apo2L/TRAIL), agonists (e.g., monoclonal or polyclonal agonistic antibodies) of TRAIL-Rl or TRAIL-R2, Bcl-2, p53, BAX, BAD, Akt, CAD, PB kinase, PPl, and caspase proteins.
- Modulating agents broadly include agonists and antagonists of TNF family receptors and TNF family ligands.
- Apoptosis-modulating agents may be soluble or membrane bound (e.g.
- apoptosis-modulating agents are inducers of apoptosis, such as TNF or a TNF-related ligand, particularly a TRAMP ligand, a Fas/CD95 ligand, a TNFR-I ligand, or TRAIL
- the inhibitors of IAPs of the present invention are Smac mimetics having the general Formula I:
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O; W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl;
- Y is selected from the group consisting Of CON(R 1 ), N(R ⁇ CO, C(O)O, OC(O), (CH 2 )i. 3 , wherein one or more CH 2 groups can be replaced by O, S, or NR 1 , optionally substituted aryl and optionally substituted heteroaryl;
- Z is (CR 2a R 2b ) r ;
- D is (CR 3a R 3b ) n -U-(CR 4a R 4b ) m ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ;
- J is (CR 7a R 7b ) p -L-(CR 8a R 8b ) q ;
- T is optionally substituted heteroaryl;
- n, m, p and q are independently selected from the group consisting of 0-5;
- r is 0-3;
- R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; each R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 7a , R 7b , R 8a and R 8b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- Smac mimetics are compounds of Formula I wherein n is
- Smac mimetics are compounds of Formula I wherein R 3a , R 3b , R 4a , R 4b , R 7a , R 7b , R 8a and R 8b are hydrogen.
- Smac mimetics are compounds of Formula I wherein Y is
- Smac mimetics are compounds of Formula I wherein Y is CON(H), W is CH, r is 1, V is N, R 2a is optionally substituted alkyl, R 2b is hydrogen and X is hydrogen. [0072] In another particular embodiment, Smac mimetics are compounds of Formula II:
- a 1 , A 2 , V, Z, W, X, Y, D, J and T having the meanings as described above for Formula I; or a pharmaceutically acceptable salt or prodrug thereof.
- Smac mimetics are compounds of Formula II wherein n is 1, m is 1 or 2, p is 0, L is CH 2 and q is 1.
- Smac mimetics are compounds of Formula II wherein R 3a , R 3b , R 4a , R 4b , R 7a , R 7b , R 8a and R 8b are hydrogen.
- Smac mimetics are compounds of Formula II wherein Y is CON(H), W is CH, r is 0 and V is N.
- Smac mimetics are compounds of Formula II wherein Y is CON(H), W is CH, r is 1 , V is N, R 2a is optionally substituted alkyl, R 2b is hydrogen and X is hydrogen.
- Smac mimetics are compounds of Formula III:
- a 1 , A 2 , V, Z, W, X, Y, U, and T have the meanings as described above for Formula I, and m is 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.
- Smac mimetics are compounds of Formula III wherein Y is CON(H), W is CH, r is 1, V is N, R 2a is optionally substituted alkyl, R 2b is hydrogen and X is hydrogen.
- m is 1. In another embodiment, m is 2.
- Smac mimetics are compounds of Formula IV: IV
- Smac mimetics are compounds of Formula IV wherein m is 1. In another embodiment, m is 2. [0078] In another particular embodiment, Smac mimetics are compounds of Formula V:
- a 1 , A 2 , X, U and T have the meanings as described above for Formula I, and m is
- Smac mimetics are compounds of Formula V wherein Ai is optionally substituted alkyl and A 2 is hydrogen.
- X is optionally substituted alkyl.
- U is CH 2 .
- Smac mimetics are compounds of Formula V wherein Ai is optionally substituted alkyl and A 2 is hydrogen.
- X is optionally substituted alkyl.
- U is CH 2 .
- U is NR 6 .
- R 6 is COR 9 .
- R 9 is optionally substituted alkyl or aralkyl.
- R 9 is -CH 2 CH(CHs) 2 .
- m is 2. In another embodiment, m is 1.
- Smac mimetics are compounds of Formula VI:
- Ai and X are optionally substituted alkyl and T is optionally substituted heteroaryl; or a pharmaceutically acceptable salt or prodrug thereof.
- Ai and X are independently optionally substituted C 1 -C 4 alkyl. In another embodiment, Ai and X are independently Ci-C 4 alkyl. In another embodiment, Ai and X are independently selected from the group consisting of methyl and ethyl. In one embodiment, Ai and X are methyl. In one embodiment, Ai is hydroxyalkyl and X is optionally substituted alkyl. In another embodiment, Ai is HOCH 2 CH 2 -.
- Smac mimetics are compounds of Formula VII:
- Ai and X are optionally substituted alkyl, R is optionally substituted alkyl or aralkyl, and T is optionally substituted heteroaryl; or a pharmaceutically acceptable salt or prodrug thereof.
- Ai and X are independently optionally substituted Ci-C 4 alkyl. In another embodiment, Ai and X are independently Ci-C 4 alkyl. In another embodiment, Ai and X are independently selected from the group consisting of methyl and ethyl. In one embodiment, Ai and X are methyl. In another embodiment, Ai is hydroxyalkyl and X is optionally substituted alkyl. In another embodiment, Ai is HOCH 2 CH 2 -. In another particular embodiment, Smac mimetics are compounds of Formulae I-
- R 12 is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo
- R 1Oa , R 10b , R lla , R l lb , R l lc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamid
- R 1Oa , R 10b , R lla , R l lb , R l lc and R l ld is optionally substituted phenyl, aralkyl, or optionally substituted alkyl.
- R 12 is hydrogen or optionally substituted alkyl.
- R 12 is hydrogen.
- R 1Oa is optionally substituted phenyl.
- R l la is optionally substituted phenyl.
- Smac mimetics are compounds of Formulae I-
- Smac mimetics are compounds of Formulae I-
- R 1Oa is optionally substituted aryl, aralkyl, or optionally substituted alkyl.
- R 10b is hydrogen.
- R 1Oa is optionally substituted aryl and R 10b is hydrogen.
- Q is S.
- Q is O.
- Q is NR 12 .
- R 12 is hydrogen or optionally substituted alkyl. In another embodiment R 12 is hydrogen.
- Smac mimetics are compounds of Formulae I-
- R l la is optionally substituted aryl, aralkyl, or optionally substituted alkyl.
- R l lb , R l lc and R l ld are hydrogen.
- R l la is optionally substituted aryl and R l lb , R l lc and R lld are hydrogen.
- R l ld is optionally substituted aryl and R lla , R l lb , and R llc are hydrogen.
- Q is S.
- Q is O.
- Q is NR 12 .
- R 12 is hydrogen or optionally substituted alkyl. In another embodiment, R 12 is hydrogen.
- Smac mimetics are compounds of Formulae
- R l la is optionally subsituted aryl, aralkyl, or optionally substituted alkyl and at least one of Z 1 , Z 2 , and Z 3 is N. In one embodiment, R l la is optionally subsituted aryl. In one embodiment, Z 1 is N and Z 2 and Z 3 are CH. In one embodiment, Z 2 is N and Z 1 and Z 3 are CH. In one embodiment, Z 3 is N and Z 1 and Z 2 are CH. In one embodiment, Z 1 and Z 3 are N and Z 2 is CH. In one embodiment, Q is S. In one embodiment, Q is O. In one embodiment, Q is NR 12 . In one embodiment, R 12 is hydrogen or optionally substituted alkyl. In another embodiment, R 12 is hydrogen. [0093] In another particular embodiment, Smac mimetics are compounds of Formula
- Ai and X are optionally substituted alkyl, m is 1 or 2 , Q is O, S or NR 12 , R 12 is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo, and R 1Oa and R 10b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido; or a pharmaceutically
- R 1Oa is optionally substituted aryl.
- R 10b is hydrogen.
- R 1Oa is optionally substituted aryl and R 10b is hydrogen.
- R 9 is hydrogen or optionally substituted alkyl.
- Q is S. [0095] In another particular embodiment, Smac mimetics are compounds of Formula IX:
- Ai and X are optionally substituted alkyl, m is 1 or 2, Q is O, S or NR 12 , R 12 is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo, and R l la , R llb , R l lc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido
- R l la is optionally substituted aryl, aralkyl, or optionally substituted alkyl.
- R l lb , R l lc and R lld are hydrogen.
- R lla is optionally substituted aryl and R l lb , R l lc and R l ld are hydrogen.
- R l ld is optionally substituted aryl and R l la , R llb , and R l lc are hydrogen.
- Q is NR 12 .
- R 12 is hydrogen or optionally substituted alkyl.
- R 12 is hydrogen.
- Q is S.
- Q is O.
- Smac mimetics are compounds of Formula X:
- Ai and X are optionally substituted alkyl, R 9 is optionally substituted alkyl or aralkyl,, m is 1 or 2, Q is O, S or NR 12 , R 12 is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo, and R 1Oa and R 10b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamid
- n is 2. In another embodiment, m is 1. In one embodiment,
- R 1Oa is optionally substituted aryl.
- R 10b is hydrogen.
- R 1Oa is optionally substituted aryl and R 10b is hydrogen.
- R 12 is hydrogen or optionally substituted alkyl.
- R 9 is -CH 2 CH(CHs) 2 .
- Q is S.
- Smac mimetics are compounds of Formula XI:
- Ai and X are optionally substituted alkyl, R 9 is optionally substituted alkyl or aralkyl, m is 1 or 2, Q is O, S or NR 12 , R 12 is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo, and R lla , R l lb , R l lc and R lld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, ary
- n is 2. In another embodiment, m is 1. In one embodiment,
- R l la is optionally substituted aryl, aralkyl, or optionally substituted alkyl.
- R l lb , R l lc and R lld are hydrogen.
- R lla is optionally substituted aryl and R l lb , R l lc and R l ld are hydrogen.
- R l ld is optionally substituted aryl and R l la , R llb , and R l lc are hydrogen.
- Q is NR 12 .
- R 12 is hydrogen or optionally substituted alkyl.
- R 12 is hydrogen.
- Q is S.
- Q is O.
- R 9 is -CH 2 CH(CH 3 ) 2 .
- Smac mimetics are compounds of Formula X wherein Ai and X are methyl, m is 1 , R 9 is optionally substituted alkyl or aralkyl, R 1Oa is optionally substituted aryl, R 10b is hydrogen, and Q is S.
- Smac mimetics are compounds of Formula
- R 9 is optionally substituted alkyl or aralkyl and R l la is optionally substituted aryl.
- alkyl as used herein by itself or part of another group refers to a straight-chain or branched saturated aliphatic hydrocarbon having from one to eighteen carbons or the number of carbons designated (e.g., C 1 -C 18 means 1 to 18 carbons).
- the alkyl is a Ci-Cg alkyl.
- the alkyl is a Ci-C 6 alkyl.
- the alkyl is a C 1 -C 4 alkyl.
- Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyi, n-pentyl, n- hexyl, isohexyl, n-heptyl, 4,4-dimethylpentyl, n-octyl, 2,2,4-trimethylpentyl, nonyl, decyl and the like.
- optionally substituted alkyl as used herein by itself or part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two or three substituents independently selected from hydroxy (i.e., -OH), nitro (i.e., -NO 2 ), cyano (i.e., -CN), optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido.
- the optionally substituted alkyl is substituted with two substituents.
- the optionally substituted alkyl is substituted with one substituents.
- the substituents are selected from hydroxyl (i.e., a hydroxyalkyl) or amino (i.e., an aminoalkyl).
- exemplary optionally substituted alkyl groups include -CH 2 OCH 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CN, -CH 2 SO 2 CH 3 , hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.
- alkylenyl as used herein by itself or part of another group refers to a divalent alkyl radical containing one, two, three or four joined methylene groups.
- alkylenyl groups include -(CH 2 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 - and -(CH 2 ) 4 -.
- haloalkyl as used herein by itself or part of another group refers to an alkyl as defined above having one to six halo substituents. In one embodiment, the haloalkyl has one, two or three halo substituents. Exemplary haloalkyl groups include trifluoromethyl, -CH 2 CH 2 F and the like.
- hydroxyalkyl as used herein by itself or part of another group refers to an alkyl as defined above having one, two or three hydroxy substituents. In one embodiment, the hydroxyalkyl has one hydroxy substituent.
- exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.
- aralkyl refers to an optionally substituted alkyl as defined above having one, two or three optionally substituted aryl substituents. In one embodiment, the aralkyl has two optionally substituted aryl substituents. In another embodiment, the aralkyl has one optionally substituted aryl substituent. In another embodiment, the aralkyl is an aryl(Ci-C 4 alkyl).
- the aryl(Ci-C 4 alkyl) has two optionally substituted aryl substituents. In another embodiment, the aryl(Ci-C4 alkyl) has one optionally substituted aryl substituent.
- exemplary aralkyl groups include, for example, benzyl, phenylethyl, (4- fluorophenyl)ethyl, phenylpropyl, diphenylmethyl (i.e., Ph 2 CH-), diphenylethyl
- cycloalkyl refers to saturated and partially unsaturated (containing one or two double bonds) cyclic hydrocarbon groups containing one to three rings having from three to twelve carbon atoms (i.e., C 3 -Ci 2 cycloalkyl) or the number of carbons designated.
- the cycloalkyl has one ring.
- the cycloalkyl is a C 3 -C 7 cycloalkyl.
- Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl and the like.
- optionally substituted cycloalkyl as used herein by itself or part of another group means the cycloalkyl as defined above is either unsubstituted or substituted with one, two or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido.
- optionally substituted cycloalkyl also means the cycloalkyl as defined above may be fused to an optionally substituted aryl.
- Exemplary optionally substituted cycloalkyl groups include
- alkenyl as used herein by itself or part of another group refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds.
- the alkenyl has one carbon-to-carbon double bond.
- alkenyl as used herein by itself or part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido.
- cycloalkenyl as used herein by itself or part of another group refers to a cycloalkyl group as defined above containing one, two or three carbon-to-carbon double bonds. In one embodiment, the cycloalkenyl has one carbon-to-carbon double bond.
- Exemplary cycloalkenyl groups include cyclopentene, cyclohexene and the like.
- cycloalkenyl as used herein by itself or part of another group means the cycloalkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido.
- alkynyl as used herein by itself or part of another group refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-to-carbon triple bond.
- alkynyl as used herein by itself or part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido.
- Exemplary optionally substituted alkenyl groups include -C ⁇ CPh, -ClHkC ⁇ CPh and the like.
- aryl as used herein by itself or part of another group refers to monocyclic and bicyclic aromatic ring systems having from six to fourteen carbon atoms (i.e., Ce-Cu aryl) such as phenyl (abbreviated as Ph), 1-naphthyl and 2-naphthyl and the like.
- aryl as used herein by itself or part of another group means the aryl as defined above is either unsubstituted or substituted with one to five substituents independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido.
- the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent.
- Exemplary substituted aryl groups include 2- methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3- methylphenyl, 3-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 4-methylphenyl, A- ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6- di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di- methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl and 3,5-dimethoxy, A- methylphenyl and the like.
- the term optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and
- heteroaryl as used herein by itself or part of another group refers to monocyclic and bicyclic aromatic ring systems having from five to fourteen carbon atoms
- heteroaryl i.e., C5-C14 heteroaryl
- the heteroaryl has three heteroatoms. In one embodiment, the heteroaryl has two heteroatoms. In one embodiment, the heteroaryl has one heteroatom.
- heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, purinyl, 2-benzimidazolyl, 4- benzimidazolyl, 5-benzimidazolyl, 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 5- indolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 1-isoquinolyl, 5-
- heteroaryl as used herein by itself or part of another group means the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, typically one or two substituents, independently selected from halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido or sulfonamido.
- the optionally substituted heteroaryl has one substituent.
- the substituent is an optionally substituted aryl, aralkyl, or optionally substituted alkyl.
- the substituent is an optionally substituted phenyl. Any available carbon or nitrogen atom my be substituted.
- Exemplary optionally substituted heteroaryl groups include
- heterocyclo refers to saturated and partially unsaturated (containing one or two double bonds) cyclic groups containing one to three rings having from two to twelve carbon atoms (i.e., C 2 -Ci 2 heterocyclo) and one or two oxygen, sulfur or nitrogen atoms.
- the heterocyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.
- exemplary heterocyclo groups include
- An optionally substituted heterocyclo may be fused to an aryl group to provide an optionally substituted aryl as described above.
- alkoxy refers to a haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom.
- aryloxy as used herein by itself or part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom.
- exemplary aryloxy groups include phenoxy and the like.
- aralkyloxy refers to an aralkyl attached to a terminal oxygen atom.
- exemplary aralkyloxy groups include benzyloxy and the like.
- alkylthio refers to a haloalkyl, aralkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal sulfur atom.
- exemplary alkyl groups include -SCH 3 and the like.
- halo or halogen as used herein by itself or part of another group refers to fluoro, chloro, bromo or iodo. In one embodiment, the halo is fluoro or chloro.
- amino refers to a radical of formula -NR a R b wherein R a and R b are independently hydrogen, haloalkyl, aralkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl or optionally substituted heteroaryl; or R a and R b taken together with the nitrogen atom to which they are attached form a four to seven membered optionally substituted heterocyclo.
- Exemplary amino groups include - NH 2 , -N(H)CH 3 , -N(CHs) 2 , N(H)CH 2 CH 3 , N(CH 2 CH 3 ), -N(H)CH 2 Ph and the like.
- the term "carboxamido" as used herein by itself or part of another group refers to a radical of formula -CO-amino.
- Exemplary carboxamido groups include -CONH 2 , -
- sulfonamido as used herein by itself or part of another group refers to a radical of formula -SO 2 -amino.
- exemplary sulfonamido groups include -SO 2 NH 2 , - SO 2 N(H)CH 3 , -SO 2 N(H)Ph and the like.
- leaving group refers to an atom or group that becomes detached from an atom or group in what is considered to be the residual or main part of the substrate in a specified reaction.
- exemplary leaving groups i.e., leaving groups designated L 1
- leaving groups include -F, -Cl, -Br, -OH, -OC 6 F 5 , - O(CO)alkyl and the like.
- the leaving group, L 1 is -Cl.
- the leaving group, L 1 is an activated form of -OH (e.g., OBt, O-acylisourea).
- An activating agent e.g., dicyclohexylcarbodiimide (DCC), l-ethyl-3- (3-dimethylaminopropyl)carbodiimide (EDC), benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBop)
- DCC dicyclohexylcarbodiimide
- EDC l-ethyl-3- (3-dimethylaminopropyl)carbodiimide
- benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate PyBop
- Such activating agents are well known to those of skill in the art of organic synthesis.
- Other additives such as N-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), may also be added to optimize reaction parameters (e.g., rate, yield, purity, racem
- nucleophilic displacement reactions e.g., S N 2 reactions
- exemplary leaving groups e.g., S N 2 reactions
- leaving groups designated L 2 include -Cl, -Br, -I, -OSO 2 Me (mesylate), -OSO 2 CF 3 (triflate), -OSO 2 C 6 H 5 (besylate), -OSO 2 CH 3 C 6 H 4 (tosylate) and the like.
- the leaving group, L 2 is -Cl or -Br. In another embodiment, the leaving group, L 2 , is -Br.
- amine protecting group refers to group that blocks (i.e., protects) the amine functionality while reactions are carried out on other functional groups or parts of the molecule.
- amine protecting group refers to group that blocks (i.e., protects) the amine functionality while reactions are carried out on other functional groups or parts of the molecule.
- Those skilled in the art will be familiar with the selection, attachment, and cleavage of amine protecting groups and will appreciate that many different protective groups are known in the art, the suitability of one protective group or another being dependent on the particular the synthetic scheme planned. Treatises on the subject are available for consultation, such as Greene and Wuts,
- Suitable amine protecting groups include the carbobenzyloxy (Cbz), te/t-butyloxycarbonyl (BOC), 9- fluorenylmethyloxycarbonyl (FMOC) and benzyl (Bn) group.
- Cbz carbobenzyloxy
- BOC te/t-butyloxycarbonyl
- FMOC 9- fluorenylmethyloxycarbonyl
- Bn benzyl
- Certain of the compounds of the present invention may exist as stereoisomers including optical isomers.
- the invention includes all stereoisomers, both as pure individual stereoisomer preparations and enriched preparations of each, and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of skill in the art.
- the compound of Formula I is:
- the compound of Formula I is:
- the compound of Formula I is selected from the group consisting of:
- the present invention also pertains to a process for the preparation of a compound of Formula XII
- R 13 is selected from the group consisting OfN(H)P 1 and ;
- P 1 is an amine protecting group;
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O;
- W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl;
- Y is selected from the group consisting Of CON(R 1 ), N(R ⁇ )CO, C(O)O, OC(O), (CH 2 )L 3 , wherein one or more CH 2 groups can be replaced by O, S, or NR 1 , optionally substituted aryl and optionally substituted heteroaryl;
- Z is (CR 2a R 2b ) r ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ;
- m is 1 or 2;
- r is 0-3;
- R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; each R 2a , R 2b , R 5a and R 5b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; and
- R 1Oa and R 10b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo.
- R 13 is -N(H)P 1 .
- P 1 is selected from the group consisting of carbobenzyloxy, te/t-butyloxycarbonyl and benzyl.
- P 1 is selected from the group consisting of carbobenzyloxy and tert- butyloxycarbonyl. In one embodiment, P 1 is carbobenzyloxy. In one embodiment, P 1 is tert-butyloxycarbonyl. In one embodiment, U is CH 2 . In one embodiment, U is NCOR 9 . In another embodiment, R 9 is optionally substituted alkyl. In one embodiment, m is 2. In one embodiment, m is 1.
- L 2 is selected from the group consisting of Cl, -Br, -I,
- L 2 is selected from the group consisting of -Cl and -Br. In another embodiment, L 2 is Br. In oonnee eemmbbooidiment, R 1Oa is optionally substituted phenyl. In one embodiment, R 10b is hydrogen.
- R 13 is .
- Y is CON(H)
- W is CH, r is O and V is N.
- U is CH 2 .
- U is NCOR 9 .
- R 9 is optionally substituted alkyl.
- m is 2. In one embodiment, m is 1.
- ammonia is condensed with a compound of Formula XIII in the presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N- hydroxybenzotriazole in an inert organic solvent (e.g., acetonitrile, tetrahydrofuran, dimethylformamide, etc.) at a temperature of about -2O 0 C to about 25 0 C.
- an inert organic solvent e.g., acetonitrile, tetrahydrofuran, dimethylformamide, etc.
- a compound of XIV is converted to a compound of Formula XV using P 4 S 10 in an inert organic solvent (e.g., dichloromethane, etc.) at a temperature of about -2O 0 C to about 45 0 C.
- the condensation of a compound of Formula XV with a compound of Formula XVI is carried out in an inert organic solvent (e.g., acetonitrile, tetrahydrofuran, dimethylformamide, etc.) at a temperature of about O 0 C to about 5O 0 C.
- an inert organic solvent e.g., acetonitrile, tetrahydrofuran, dimethylformamide, etc.
- a compound of Formula XVII is cyclized in methanol, ethanol, propanol, isopropanol, or butanol. In one embodiment, the cyclization of a compound of Formula XVII is carried out at a temperature of about 25 0 C to about 100 0 C, in one embodiment, above 3O 0 C. In one embodiment, the cyclization of a compound of Formula XVIII is carried out in refluxing solvent. In one embodiment, the cyclization of a compound of Formula XVIII is carried out in refluxing ethanol.
- a compound of Formula XII, as well as any synthetic intermediates i.e., a compound of Formula XIV, XV or XVII
- a compound of Formula XIV, XV or XVII can be isolated and purified by any means known in the art such normal- and reverse-phase column chromatography (e.g., column chromatography on silica gel or reverse-phase HPLC), crystallization, extraction, etc.
- the product thus isolated can be subjected to further purification (e.g., recrystallization) until the desired level of purity is achieved.
- a compound of Formula XII has a purity of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more.
- the invention pertains to a process for the preparation of a compound of Formula XVIII
- XVIII comprising: a) condensing a compound of Formula XIII
- R 13 is selected from the group consisting OfN(H)P 1 and ;
- P 1 is an amine protecting group
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O; W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl;
- Y is selected from the group consisting Of CON(R 1 ), N(R ⁇ CO, C(O)O, OC(O), (CH 2 )L 3 , wherein one or more CH 2 groups can be replaced by O, S, or NR 1 , optionally substituted aryl and optionally substituted heteroaryl;
- Z is (CR 2a R 2b ) r ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ; m is 1 or 2; r is 0-3; R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; each R 2a , R 2b , R 5a and R 5b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- R l la , R l lb , R l lc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido, and
- R 12 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo. [00146] In one embodiment, R l la is optionally substituted phenyl. In one embodiment,
- R l lb , R l lc and R l ld are hydrogen.
- R l la is optionally substituted phenyl
- R l lb , R l lc and R lld are hydrogen.
- m is 2.
- m is 1.
- U is CH 2 .
- U is NCOR 9 .
- R 9 is optionally substituted alkyl.
- R 12 is hydrogen.
- R 13 is -N(H)P 1 .
- P 1 is selected from the group consisting of carbobenzyloxy, te/t-butyloxycarbonyl and benzyl.
- P 1 is selected from the group consisting of carbobenzyloxy and tert- butyloxycarbonyl.
- P 1 is carbobenzyloxy.
- P 1 is tert-butyloxycarbonyl.
- U is CH 2 . In one embodiment, U is NCOR 9 .
- R 9 is optionally substituted alkyl.
- m is 2. In one embodiment, m is 1.
- W is CH, r is 0 and V is N.
- U is CH 2 .
- U is NCOR 9 .
- R 9 is optionally substituted alkyl.
- m is 2. In one embodiment, m is 1.
- a compound of Formula XIII is condensed with a compound of Formula XIX in the presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxybenzotriazole in an inert organic solvent (e.g., acetonitrile, tetrahydrofuran, dimethylformamide, etc.) at a temperature of about -2O 0 C to about 25 0 C.
- an inert organic solvent e.g., acetonitrile, tetrahydrofuran, dimethylformamide, etc.
- a compound of Formula XX is cyclized in acetic acid at a temperature of about 25 0 C to about 118 0 C.
- a compound of Formula XX is cyclized in refluxing acetic acid.
- a compound of Formula XVIII, as well as any synthetic intermediate(s) can be isolated and purified by any means known in the art such normal- and reverse-phase column chromatography (e.g., column chromatography on silica gel or reverse-phase HPLC), crystallization, extraction, etc.
- the product thus isolated can be subjected to further purification (e.g., recrystallization) until the desired level of purity is achieved.
- a compound of Formula XVIII has a purity of 90%, 91%, 92%, 93%,
- the present invention also pertains to a process for preparing a compound of Formula XXI
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O;
- W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl;
- Z is (CR 2a R 2b ) r ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ; m is 1 or 2; r is 0-3; each R 2a , R 2b , R 5a and R 5b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; and T is optionally substituted heteroaryl.
- W is CH and V is N.
- T is selected from the group consisting of
- Q is selected from the group consisting of O, S and NR 12 ;
- R 12 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; and R 1Oa , R 10b , R l la , R l lb , R llc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido.
- U is CH 2 . In one embodiment, U is NCOR 9 . In one embodiment, R 9 is optionally substituted alkyl. In one embodiment, m is 2. In one embodiment, m is 1. [00153] In one embodiment, L 1 is selected from the group consisting of -Cl and -OH. In one embodiment, L 1 is -OH and the reaction is carried out in the presence of an activating agent.
- a compound of Formula XXIII is prepared by removing P 1 from a compound of Formula XXII
- P 1 is a leaving group.
- P 1 is carbobenzyloxy, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyl.
- P 1 is carbobenzyloxy or te/t-butyloxycarbonyl.
- P 1 is carbobenzyloxy.
- P 1 is or te/t-butyloxycarbonyl.
- the condensation reaction is conducted in an inert organic solvent such as acetonitrile, benzene, chloroform, 1 ,2-dichloroethane, 1,2,- dimethoxy ethane, dimethylformamide, dimethylsulfoxide, dioxane, dichloromethane, N- methyl-2-pyrrolidinone or tetrahydrofuran.
- the condensation reaction is carried out in tetrahydrofuran.
- the condensation reaction is carried out in dichloromethane.
- the condensation reaction is carried out at about -2O 0 C to about 35 0 C.
- the condensation reaction is carried out at about 25 0 C.
- the condensation reaction is complete in about 1 hour to about 48 hours. In another embodiment, the condensation reaction is complete in about 12 hours.
- L 1 is Cl, -OH or -OBt. In one embodiment, L 1 is -OH or
- the condensation reaction is carried out in the presence of an activating agent.
- the activating agent is dicyclohexylcarbodiimide, 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide or benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate.
- the activating agent is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
- the condensation reaction is carried out in the presence of an activating agent and an additive that optimize reaction parameters such as purity and yield.
- the additive is N-hydroxybenzotriazole.
- a compound of Formula XXI can be isolated and purified by any means known in the art such normal- and reverse-phase column chromatography (e.g., column chromatography on silica gel or reverse-phase HPLC), crystallization, extraction, etc.
- the product thus isolated can be subjected to further purification (e.g., recrystallization) until the desired level of purity is achieved.
- a compound of Formula XXI has a purity of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more.
- the invention pertains to a compound having Formula
- T is optionally substituted heteroaryl; m is 1 or 2;
- U is CH 2 or NR 6
- R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; and
- P 1 is an amine protecting group.
- P 1 is selected from the group consisting of t-butoxycarbonyl and benzyloxycarbonyl.
- the invention pertains to a compound having Formula
- U is CH 2 or NR 6
- R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl, and aralkyl;
- Ai is selected from the group consisting of hydrogen an optionally substituted alkyl
- P 1 is an amine protecting group.
- P 1 is selected from the group consisting of t-butoxycarbonyl and benzyloxycarbonyl.
- the compounds of this invention may be prepared using methods known to those of skill in the art. Specifically, compounds of the invention can be prepared as illustrated by the exemplary reactions in the Examples.
- An important aspect of the present invention is that compounds of Formulae I-XIa induce apoptosis and also potentiate the induction of apoptosis in response to apoptosis induction signals. Therefore, it is contemplated that these compounds will sensitize cells to inducers of apoptosis, including cells that are resistant to such inducers.
- the IAP inhibitors of the present invention can be used to induce apoptosis in any disorder that can be treated, ameliorated, or prevented by the induction of apoptosis.
- the present invention provides compositions and methods for targeting animals characterized as overexpressing an IAP protein.
- the cells e.g., cancer cells
- the cells will show elevated expression levels of IAP proteins as compared to non-pathological samples (e.g., non-cancerous cells).
- the cells operationally will manifest elevated expression levels of IAP proteins by virtue of executing the apoptosis program and dying in response to an inhibiting effective amount of a compound of Formulae I-XIa, said response occurring, at least in part, due to the dependence in such cells on IAP protein function for their survival.
- the invention pertains to modulating an apoptosis- associated state which is associated with one or more apoptosis-modulating agents.
- apoptosis-modulating agents include, but are not limited to, Fas/CD95, TRAMP, TNF RI, DRl, DR2, DR3, DR4, DR5, DR6, FADD, RIP, TNF ⁇ , Fas ligand, TRAIL, antibodies to TRAIL-Rl or TRAIL-R2, Bcl-2, p53, BAX, BAD, Akt, CAD, PB kinase, PPl, and caspase proteins. Other agents involved in the initiation, decision and degradation phase of apoptosis are also included. Examples of apoptosis-modulating agents include agents, the activity, presence, or change in concentration of which, can modulate apoptosis in a subject.
- apoptosis-modulating agents are inducers of apoptosis, such as TNF or a TNF-related ligand, particularly a TRAMP ligand, a Fas/CD95 ligand, a TNFR-I ligand, or TRAIL.
- the compositions and methods of the present invention are used to treat diseased cells, tissues, organs, or pathological conditions and/or disease states in an animal (e.g., a mammalian subject including, but not limited to, humans and veterinary animals).
- an animal e.g., a mammalian subject including, but not limited to, humans and veterinary animals.
- various diseases and pathologies are amenable to treatment or prophylaxis using the present methods and compositions.
- a non- limiting exemplary list of these diseases and conditions includes, but is not limited to, breast cancer, prostate cancer, lymphoma, skin cancer, pancreatic cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, le
- infections suitable for treatment with the compositions and methods of the present invention include, but are not limited to, infections caused by viruses, bacteria, fungi, mycoplasma, prions, and the like.
- Some embodiments of the present invention provide methods for administering an effective amount of a compound of Formulae I-XIa and at least one additional therapeutic agent (including, but not limited to, chemotherapeutic antineoplastics, apoptosis- modulating agents, antimicrobials, antivirals, antifungals, and anti-inflammatory agents) and/or therapeutic technique (e.g., surgical intervention, and/or radiotherapies).
- additional therapeutic agent including, but not limited to, chemotherapeutic antineoplastics, apoptosis- modulating agents, antimicrobials, antivirals, antifungals, and anti-inflammatory agents
- therapeutic technique e.g., surgical intervention, and/or radiotherapies.
- anticancer agents are contemplated for use in the methods of the present invention. Indeed, the present invention contemplates, but is not limited to, administration of numerous anticancer agents such as: agents that induce apoptosis; polynucleotides (e.g., anti-sense, ribozymes, siRNA); polypeptides (e.g., enzymes and antibodies); biological mimetics (e.g., gossypol or BH3 mimetics); agents that bind (e.g., oligomerize or complex) with a Bcl-2 family protein such as Bax; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (e.g., antibodies conjugated with anticancer drugs, toxins, defensins), toxins; radionuclides; biological response modifiers (e.g., interferons (e.g., IFN- ⁇ ) and
- anticancer agents comprise agents that induce or stimulate apoptosis.
- Agents that induce apoptosis include, but are not limited to, radiation (e.g., X-rays, gamma rays, UV); tumor necrosis factor (TNF)-related factors (e.g., TNF family receptor proteins, TNF family ligands, TRAIL, antibodies to TRAIL-Rl or TRAIL-R2); kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitor, vascular growth factor receptor (VGFR) kinase inhibitor, fibroblast growth factor receptor (FGFR) kinase inhibitor, platelet-derived growth factor receptor (PDGFR) kinase inhibitor, and Bcr-Abl kinase inhibitors (such as GLEEV
- compositions and methods of the present invention provide a compound of Formulae I-XIa and at least one anti-hyperproliferative or antineoplastic agent selected from alkylating agents, antimetabolites, and natural products
- Alkylating agents suitable for use in the present compositions and methods include, but are not limited to: 1) nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan (L-sarcolysin); and chlorambucil); 2) ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa); 3) alkyl sulfonates (e.g., busulfan); 4) nitrosoureas (e.g., carmustine (BCNU); lomustine (CCNU); semustine (methyl-CCNU); and streptozocin (streptozotocin)); and 5) triazenes (e.g., dacarbazine (DTIC; dimethyltriazenoimid-azolecarboxamide).
- nitrogen mustards e.g., mechlorethamine, cyclophosphamide,
- antimetabolites suitable for use in the present compositions and methods include, but are not limited to: 1) folic acid analogs (e.g., methotrexate (amethopterin)); 2) pyrimidine analogs (e.g., fluorouracil (5-fluorouracil; 5-FU), floxuridine (fluorode-oxyuridine; FudR), and cytarabine (cytosine arabinoside)); and 3) purine analogs (e.g., mercaptopurine (6-mercaptopurine; 6-MP), thioguanine (6- thioguanine; TG), and pentostatin (2'-deoxycoformycin)).
- folic acid analogs e.g., methotrexate (amethopterin)
- pyrimidine analogs e.g., fluorouracil (5-fluorouracil; 5-FU), floxuridine (fluorode-oxyuridine; FudR), and cytara
- chemotherapeutic agents suitable for use in the compositions and methods of the present invention include, but are not limited to: 1) vinca alkaloids (e.g., vinblastine (VLB), vincristine); 2) epipodophyllotoxins (e.g., etoposide and teniposide); 3) antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin (daunomycin; rubidomycin), doxorubicin, bleomycin, plicamycin (mithramycin), and mitomycin (mitomycin C)); 4) enzymes (e.g., L-asparaginase); 5) biological response modifiers (e.g., interferon-alfa); 6) platinum coordinating complexes (e.g., cisplatin (cis-DDP) and carboplatin); 7) anthracenediones (e.g., mitoxantrone
- vinca alkaloids e
- any oncolytic agent that is routinely used in a cancer therapy context finds use in the compositions and methods of the present invention.
- the U.S. Food and Drug Administration maintains a formulary of oncolytic agents approved for use in the United States. International counterpart agencies to the U.S.F.D.A. maintain similar formularies.
- Table 1 provides a list of exemplary antineoplastic agents approved for use in the U.S. Those skilled in the art will appreciate that the "product labels" required on all U.S. approved chemotherapeutics describe approved indications, dosing information, toxicity data, and the like, for the exemplary agents.
- Anticancer agents further include compounds which have been identified to have anticancer activity but are not currently approved by the U.S. Food and Drug Administration or other counterpart agencies or are undergoing evaluation for new uses. Examples include, but are not limited to, 3-AP, 12-0-tetradecanoylphorbol- 13 -acetate, 17AAG, 852A, ABI-007, ABR-217620, ABT-751, ADI-PEG 20, AE-941, AG-013736, AGROlOO, alanosine, AMG 706, antibody G250, antineoplastons, AP23573, apaziquone, APC8015, atiprimod, ATN-161, atrasenten, azacitidine, BB- 10901, BCX- 1777, bevacizumab, BGOOOOl, bicalutamide, BMS 247550, bortezomib, bryostatin-1, buserelin, calcitriol, CCI-779, CDB-2914, cefix
- the anticancer agent is selected from the group consisting of taxotere, gemcitabine, lapatinib (Tykerb ® ) and etoposide.
- the present invention provides methods for administering a compound of
- Formulae I-XIa with radiation therapy is not limited by the types, amounts, or delivery and administration systems used to deliver the therapeutic dose of radiation to an animal.
- the animal may receive photon radiotherapy, particle beam radiation therapy, other types of radiotherapies, and combinations thereof.
- the radiation is delivered to the animal using a linear accelerator.
- the radiation is delivered using a gamma knife.
- the source of radiation can be external or internal to the animal.
- External radiation therapy is most common and involves directing a beam of high-energy radiation to a tumor site through the skin using, for instance, a linear accelerator. While the beam of radiation is localized to the tumor site, it is nearly impossible to avoid exposure of normal, healthy tissue. However, external radiation is usually well tolerated by animals.
- Internal radiation therapy involves implanting a radiation-emitting source, such as beads, wires, pellets, capsules, particles, and the like, inside the body at or near the tumor site including the use of delivery systems that specifically target cancer cells (e.g., using particles attached to cancer cell binding ligands). Such implants can be removed following treatment, or left in the body inactive.
- a radiation-emitting source such as beads, wires, pellets, capsules, particles, and the like
- Such implants can be removed following treatment, or left in the body inactive.
- Types of internal radiation therapy include, but are not limited to, brachytherapy, interstitial irradiation, intracavity irradiation, radioimmuno therapy, and the like.
- the animal may optionally receive radiosensitizers (e.g., metronidazole, misonidazole, intra-arterial Budr, intravenous iododeoxyuridine (IudR), nitroimidazole,
- radiosensitizers e.g., metronidazole, misonidazole, intra-arterial Budr, intravenous iododeoxyuridine (IudR), nitroimidazole,
- Radiotherapy Any type of radiation can be administered to an animal, so long as the dose of radiation is tolerated by the patient without unacceptable negative side-effects.
- Suitable types of radiotherapy include, for example, ionizing (electromagnetic) radiotherapy (e.g.,
- Ionizing radiation is defined as radiation comprising particles or photons that have sufficient energy to produce ionization, i.e., gain or loss of electrons (as described in, for example, U.S. 5,770,581 incorporated herein by reference in its entirety).
- the effects of radiation can be at least partially controlled by the clinician.
- the dose of radiation is preferably fractionated for maximal target cell exposure and reduced toxicity. [00183]
- the total dose of radiation administered to an animal preferably is about .01 Gray
- Gy to about 100 Gy. More preferably, about 10 Gy to about 65 Gy (e.g., about 15 Gy, 20 Gy, 25 Gy, 30 Gy, 35 Gy, 40 Gy, 45 Gy, 50 Gy, 55 Gy, or 60 Gy) are administered over the course of treatment. While in some embodiments a complete dose of radiation can be administered over the course of one day, the total dose is ideally fractionated and administered over several days. Desirably, radiotherapy is administered over the course of at least about 3 days, e.g., at least 5, 7, 10, 14, 17, 21, 25, 28, 32, 35, 38, 42, 46, 52, or 56 days (about 1-8 weeks).
- a daily dose of radiation will comprise approximately 1-5 Gy (e.g., about 1 Gy, 1.5 Gy, 1.8 Gy, 2 Gy, 2.5 Gy, 2.8 Gy, 3 Gy, 3.2 Gy, 3.5 Gy, 3.8 Gy, 4 Gy, 4.2 Gy, or 4.5 Gy), preferably 1-2 Gy (e.g., 1.5-2 Gy).
- the daily dose of radiation should be sufficient to induce destruction of the targeted cells.
- radiation preferably is not administered every day, thereby allowing the animal to rest and the effects of the therapy to be realized.
- radiation desirably is administered on 5 consecutive days, and not administered on 2 days, for each week of treatment, thereby allowing 2 days of rest per week.
- radiation can be administered 1 day/week, 2 days/week, 3 days/week, 4 days/week, 5 days/week, 6 days/week, or all 7 days/week, depending on the animal's responsiveness and any potential side effects.
- Radiation therapy can be initiated at any time in the therapeutic period.
- radiation is initiated in week 1 or week 2, and is administered for the remaining duration of the therapeutic period.
- radiation is administered in weeks 1-6 or in weeks 2-6 of a therapeutic period comprising 6 weeks for treating, for instance, a solid tumor.
- radiation is administered in weeks 1-5 or weeks 2- 5 of a therapeutic period comprising 5 weeks.
- Antimicrobial therapeutic agents may also be used as therapeutic agents in the present invention. Any agent that can kill, inhibit, or otherwise attenuate the function of microbial organisms may be used, as well as any agent contemplated to have such activities. Antimicrobial agents include, but are not limited to, natural and synthetic antibiotics, antibodies, inhibitory proteins (e.g., defensins), antisense nucleic acids, membrane disruptive agents and the like, used alone or in combination. Indeed, any type of antibiotic may be used including, but not limited to, antibacterial agents, antiviral agents, antifungal agents, and the like.
- a compound of Formulae I-XIa and one or more therapeutic agents or anticancer agents are administered to an animal under one or more of the following conditions: at different periodicities, at different durations, at different concentrations, by different administration routes, in a single composition, in separate compositions, etc.
- the compound is administered prior to the therapeutic or anticancer agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, 1, 2, 3, or 4 weeks prior to the administration of the therapeutic or anticancer agent.
- the compound is administered after the therapeutic or anticancer agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, 1, 2, 3, or 4 weeks after the administration of the anticancer agent.
- the compound and the therapeutic or anticancer agent are administered concurrently but on different schedules, e.g., the compound is administered daily while the therapeutic or anticancer agent is administered once a week, once every two weeks, once every three weeks, or once every four weeks.
- the compound is administered once a week while the therapeutic or anticancer agent is administered daily, once a week, once every two weeks, once every three weeks, or once every four weeks.
- compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
- the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for disorders responsive to induction of apoptosis. For example, about 0.01 to about 25 mg/kg is orally administered to treat, ameliorate, or prevent such disorders.
- the dose is generally about one-half of the oral dose.
- a suitable intramuscular dose would be about 0.0025 to about 25 mg/kg, e.g., from about 0.01 to about 5 mg/kg.
- the unit oral dose may comprise from about 0.01 to about 1000 mg, e.g., about 0.1 to about 100 mg of the compound.
- the unit dose may be administered one or more times daily as one or more tablets or capsules each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.
- the compound may be present at a concentration of about
- the compound is present at a concentration of about 0.07-1.0 mg/ml, e.g., about 0.1-0.5 mg/ml, e.g., about 0.4 mg/ml.
- the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically.
- the preparations particularly those preparations which can be administered orally or topically and which can be used for the preferred type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, injection, topically orally, contain from about 0.01 to 99 percent, e.g., from about 0.25 to 75 percent of active compound(s), together with the excipient.
- compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention.
- animals are mammals, e.g., humans, although the invention is not intended to be so limited.
- Other animals include veterinary animals (cows, sheep, pigs, horses, dogs, cats and the like).
- the compounds and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose.
- administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
- administration may be by the oral route.
- the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
- compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
- pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
- Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
- fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
- disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
- Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
- Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
- concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
- suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used.
- Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
- Other pharmaceutical preparations which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
- the push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
- suitable liquids such as fatty oils, or liquid paraffin.
- stabilizers may be added.
- Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
- Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
- gelatin rectal capsules which consist of a combination of the active compounds with a base.
- Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
- Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
- suspensions of the active compounds as appropriate oily injection suspensions may be administered.
- Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400.
- Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
- the suspension may also contain stabilizers.
- the topical compositions of this invention are formulated preferably as oils, creams, lotions, ointments and the like by choice of appropriate carriers.
- Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12).
- the preferred carriers are those in which the active ingredient is soluble.
- Emulsif ⁇ ers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
- transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in
- Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil such as almond oil, is admixed.
- a typical example of such a cream is one which includes about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.
- Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool.
- a vegetable oil such as almond oil
- a typical example of such an ointment is one which includes about 30% almond oil and about 70% white soft paraffin by weight.
- Lotions may be conveniently prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.
- a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A2 is absent when V is O; V is selected from the group consisting of N, CH and O;
- W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl;
- Y is selected from the group consisting of CON(R 1 ), N(R ⁇ )CO, C(O)O, OC(O), (CH 2 )i-3, wherein one or more CH 2 groups can be replaced by O, S, or NR 1 , optionally substituted aryl and optionally substituted heteroaryl;
- Z is (CR 2a R 2b );
- D is (CR 3a R3b) n -U-(CR 4a R 4b ) m ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ;
- J is (CR 7a R 7b ) p -L-(CR 8a R 8b ) q ;
- T is optionally substituted heteroaryl
- n, m, p and q are independently selected from the group consisting of 0-5; r is 0-3;
- Rl is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; each R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 7a , R 7b , R 8a , R 8b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; or pharmaceutically acceptable salt or prodrug thereof.
- n 1, m is 1 or 2
- p is 0, L is CR 7a R 7b , q is 1, and R 3a , R 3b , R 4a , R 4b , R 7a , R 7b , R 8a , R 8b are hydrogen.
- III The compound of II, wherein Y is CON(H), W is CH, r is 0 and V is N.
- Q is selected from the group consisting of O, S and NR 12 ;
- R 12 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- R 1Oa , R 10b , R l la , R l lb , R l lc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido;
- Z 1 , Z 2 , and Z 3 are independently selected from the group consisting of CR l le and N, wherein at least one of Z 1 , Z 2 , and Z 3 is CR l le , and at least one of Z 1 , Z 2 , and Z 3 is N; and
- R l le is selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido.
- T is selected from the group consisting of
- Q is selected from the group consisting of O, S and NR 12 ;
- R 12 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- R 1Oa , R 10b , R l la , R l lb , R l lc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido.
- XIX The compound of XVIII wherein T is
- XXII The compound of XXI, wherein R l la is selected from the group consisting of optionally substituted aryl, aralkyl, and optionally substituted alkyl; and R l lb , R l lc and
- R l ld are each hydrogen.
- XXIII The compound of XXI, wherein R l ld is selected from the group consisting of optionally substituted aryl, aralkyl, and optionally substituted alkyl; R lla , R llb and R l lc are each hydrogen.
- XXIV The compound of XXII having Formula XIa:
- XXVI A pharmaceutical composition comprising the compound of any one of I- XXV and a pharmaceutically acceptable carrier.
- XXVII A method of inducing apoptosis in a cell comprising contacting the cell with the compound of any one of I-XXV.
- XXVIII A method of rendering a cell sensitive to an inducer of apoptosis comprising contacting the cell with the compound of any one of I-XXV.
- XXIX The method of XXVIII, further comprising contacting the cell with an inducer of apoptosis.
- XXX The method of XXIX, wherein said inducer of apoptosis is a chemotherapeutic agent.
- XXXI The method of XXIX, wherein said inducer of apoptosis is radiation.
- XXXII The method of XXIX, wherein said inducer of apoptosis is a tumor necrosis factor (TNF), a TNF-related ligand, or an agonist of TRAIL-Rl or TRAIL-R2.
- TNF tumor necrosis factor
- XXXIII The method of XXXII, wherein said TNF-related ligand is selected from the group consisting of a TRAMP ligand, a Fas/CD95 ligand, a TNFR-I ligand, and
- TRAIL [00235] XXXIV. The method of XXXIII, wherein said TNF-related ligand is
- TRAIL [00236] XXXV. The method of XXXIV, wherein said agonist of TRIAL-Rl or
- TRAIL-R2 is an antibody.
- XXXVI A method of treating, ameliorating, or preventing a disorder responsive to the induction of apoptosis in an animal, comprising administering to said animal a therapeutically effective amount of the compound of any one of I-XXV.
- XXXVII The method of XXXVI, further comprising administering an inducer of apoptosis.
- XXXVIII The method of XXXVII, wherein said inducer of apoptosis is a chemotherapeutic agent.
- XXXIX The method of XXVIII, wherein said inducer of apoptosis is radiation.
- XL The method of XXXVII, wherein said inducer of apoptosis is a TNF, a
- TNF-related ligand or an agonist of TRAIL-Rl or TRAIL-R2.
- TNF-related ligand is selected from the group consisting of a TRAMP ligand, a Fas/CD95 ligand, a TNFR-I ligand, and TRAIL.
- XLII The method of XLI, wherein said TNF-related ligand is TRAIL.
- XLIII The method of XLII, wherein said agonist of TRAIL-Rl or TRAIL-R2 is an antibody.
- XLIV The method of XXXVI, wherein said disorder responsive to the induction of apoptosis is a hyperproliferative disease.
- XLV The method of XLIV, wherein said hyperproliferative disease is cancer.
- XLVI The method of XXXVI, wherein said compound of I-XXV is administered prior to said inducer of apoptosis.
- XLVII The method of XXXVI, wherein said compound of I-XXV is administered after said inducer of apoptosis.
- XLIX A method of treating, ameliorating, or preventing a hyperproliferative disease in an animal, comprising administering to said animal a therapeutically effective amount of the compound of any one of I-XXV.
- LII The method of LI, wherein said inducer of apoptosis is a chemotherapeutic agent.
- LIII The method of LII, wherein said inducer of apoptosis is radiation.
- LIV The method of LI, wherein said inducer of apoptosis is a TNF, a TNF- related ligand, or an agonist of TRAIL-Rl or TRAIL-R2.
- LV The method of LIV, wherein said TNF-related ligand is selected from the group consisting of a TRAMP ligand, a Fas/CD95 ligand, a TNFR-I ligand, and TRAIL.
- LVI The method of LIV, wherein said TNF-related ligand is TRAIL.
- LVII The method of LIV, wherein said agonist of TRAIL-Rl or TRAIL-R2 is an antibody.
- LX The method of L, wherein said compound of I-XXV is administered after said anticancer agent.
- LXI The method of L, wherein said compound of I-XXV is administered concurrently with said anticancer agent.
- LXII The method of L, wherein said anticancer agent is selected from the group consisting of taxotere, lapatinib and gemcitabine.
- LXIII A method of preventing or inhibiting angiogenesis in an animal in need thereof, comprising administering to said animal a therapeutically effective amount of the compound of any one of I-XXV.
- LXIV The method of LXIII wherein said animal has a disease or disorder selected from the group consisting of macular degeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, Osier-Webber Syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, wound granulation, intestinal adhesions, atherosclerosis, scleroderma and hypertrophic scars.
- LXV A kit comprising the compound of any one of I-XXV and instructions for administering said compound to an animal.
- LXVI The kit of LXV, further comprising an anticancer agent.
- LXVII The kit of LXVI, wherein said anticancer agent is an inducer of apoptosis.
- LXVIII The kit of LXVII wherein said inducer of apoptosis is a chemotherapeutic agent.
- LXIX The kit of LXVII, wherein said inducer of apoptosis is a TNF, a TNF- related ligand, or an agonist of TRAIL-Rl or TRAIL-R2.
- LXX The kit of LXIX, wherein the TNF-related ligand is selected from the group consisting of a TRAMP ligand, a Fas/CD95 ligand, a TNFR-I ligand, and TRAIL.
- LXXI The kit of LXX, wherein said TNF-related ligand is TRAIL.
- LXXII The kit of LXIX, wherein said agonist of TRAIL-Rl or TRAIL-R2 is an antibody.
- LXXIII The kit of LXV, wherein said instructions are for administering said compound to an animal having a hyperproliferative disease.
- LXXIV The kit of LXXIII, wherein said hyperproliferative disease is cancer.
- LXXV A process for preparing a compound of Formula XII
- R , 13 is selected from the group consisting of N(H)Pl and P 1 is an amine protecting group;
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O; W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl;
- Y is selected from the group consisting of CON(R 1 ), N(R ⁇ CO, C(O)O, OC(O), (CH 2 )i_ 3 , wherein one or more CH 2 groups can be replaced by O, S, or NR 1 , optionally substituted aryl and optionally substituted heteroaryl;
- Z is (CR 2a R 2b ) r ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ; m is 1 or 2; r is 0-3;
- R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; each R 2a , R 2b , R 5a and R 5b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; and
- R 1Oa and R 10b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo, comprising: a) condensing a compound of Formula XIII
- LXXVI The process of LXXV, wherein L 2 is selected from the group consisting of Cl and Br.
- LXXVII The process of LXXVI, wherein L 2 is Br.
- LXXVIII The process of LXXVI, wherein R 1Oa is optionally substituted aryl.
- LXXIX The process of LXXV, wherein m is 1.
- LXXX The process of LXXV, wherein R 13 is -N(H)P 1 .
- LXXXI The process of LXXX, wherein P 1 is selected from the group consisting of t-butoxycarbonyl and benzyloxycarbonyl.
- LXXXII The process of LXXV, wherein Rl 3 is A 1 x
- LXXXIII The process of LXXXII, wherein Y is CON(H), W is CH, r is 0 and V is N.
- LXXXIV The process of LXXV, wherein U is NR 6 and R 6 is COR 9 .
- R 13 is selected from the group consisting OfN(H)P 1 and
- P 1 is an amine protecting group
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O; W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl;
- Y is selected from the group consisting of CON(R 1 ), N(R ⁇ CO, C(O)O, OC(O), (CH 2 )i-3, wherein one or more CH 2 groups can be replaced by O, S, or NR 1 , optionally substituted aryl and optionally substituted heteroaryl;
- Z is (CR 2a R 2b ) r ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ; m is 1 or 2; r is 0-3;
- R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; each R 2a , R 2b , R 5a and R 5b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- R l la , R l lb , R l lc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido, and
- R 12 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo, comprising: a) condensing a compound of Formula XIII
- LXXXVI The process of LXXXV, wherein R 12 is hydrogen.
- LXXXVII The process of LXXXV, wherein R l la is optionally substituted phenyl.
- LXXXVIII The process of LXXXV, wherein m is 1.
- LXXXIX The process of LXXXV, wherein R 13 is -N(H)P 1 .
- XCI The process of LXXXV, wherein R . 1"3 is A 1 X
- XCII The process of XCI, wherein Y is CON(H), W is CH, r is 0 and V is N.
- XCIII The process of LXXXV, wherein U is NR 6 and R 6 is COR 9 .
- XCIV A process for preparing a compound of Formula XXI XXI
- Ai and A 2 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, wherein A 2 is absent when V is O;
- V is selected from the group consisting of N, CH and O; W is selected from the group consisting of CH and N;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl and aralkyl; Z is (CR 2a R 2b ) r ;
- U is selected from the group consisting of CR 5a R 5b and NR 6 ; m is 1 or 2; r is 0-3; each R 2a , R 2b , R 5a and R 5b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; and T is optionally substituted heteroaryl, comprising: reacting a compound of Formula XXIII XXIII
- Q is selected from the group consisting of O, S and NR , 1 1 2 Z ;.
- R 12 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; and R 1Oa , R 10b , R l la , R l lb , R l lc and R l ld are independently selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido. [00
- P 1 is an amine protecting group
- T is optionally substituted heteroaryl
- m is 1 or 2
- U is CH 2 or NR 6
- R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo; and
- P 1 is an amine protecting group.
- CV. The compound of CIV, wherein P 1 is selected from the group consisting of t-butoxycarbonyl and benzyloxycarbonyl.
- CVI. A compound having Formula XXV
- T is optionally substituted heteroaryl; m is 1 or 2;
- U is CH 2 or NR 6
- R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo and COR 9 ;
- R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclo;
- X is selected from the group consisting of hydrogen, optionally substituted alkyl, and aralkyl
- Ai is selected from the group consisting of hydrogen an optionally substituted alkyl
- P 1 is an amine protecting group.
- CVII The compound of CVI, wherein P 1 is selected from the group consisting of t-butoxycarbonyl and benzyloxycarbonyl.
- CVIII The compound of CVII having the structure:
- Reagents and conditions (a) i. 4 N HCI in 1 ,4-dioxane, methanol; ii. Boc-Dap(Z)-OH, EDC, HOBt, ⁇ /, ⁇ /-diisopropylethylamine, CH 2 CI 2 , 52% over two steps; (b) O 3 , then PPh 3 , CH 2 CI 2 , 90%; (c) H 2 , 10% Pd-C, /-PrOH, 41 %; (d) H 2 , 10% Pd-C, /-PrOH; (e) NaBH(OAc) 3 , THF; (f) 9-BBN (2 eq), THF, reflux, 12h, then 3 N NaOH (2 eq), 35% H 2 O 2 (2.5 eq), O 0 C - rt, 85%; (f) i.
- Compound 6 can be prepared according to methods reported in the literature
- Selective transformation of the primary amide to thioamide c can be realized by reaction of b with P 4 S io in CH 2 Cl 2 at room temperature. Reaction of c with d, wherein L 2 is a leaving group, furnishes e. L 2 is a leaving group. In one embodiment, d is an ⁇ -bromoketone. Cyclization of e by refluxing in ethanol provides thiozole of Formula A.
- Formula B [00327] A compound represented by Formula B, wherein m is 1-2, R l la , R llb , R l lc and
- R l ld are independently hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, nitro, cyano, hydroxy, amino, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido and sulfonamido
- R 12 is hydrogen, optionally substituted alkyl, haloalkyl, aralkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, and U has the meaning as described above for Formula I, may be prepared as described in
- a compound represented by Formula C wherein m is 1 or 2, and A 1 , A 2 , Z, X, T and U have the meanings as described above for Formula I, may be prepared as shown in Scheme 7. Briefly, removal of the Boc protecting group in a provides amine b.
- a compound represented by Formula D wherein m is 1 or 2, and T and R 9 have the meanings as described above for Formula I, may be prepared as described in Scheme 8. Briefly, reaction of amine a with carboxylic acid R 9 CO 2 H or carboxylic acid chloride
- Reagents and conditions (a) 3-bromo-1 ,2-diamine, EDC, HOBt, N,N-diisopropylethylamine, CH 2 CI 2 ; (b) HOAc, 70 0 C, 10 h; (c) arylboronic acid, dba Pd, tri-tert-butylphosphine, K 2 CO 3 , methylene glycol dimethyl ether, refulx, overnight; (d) i. 4 N HCI in 1 ,4-dioxane, methanol; ii.
- a compound represented by Formula E wherein m is 1 or 2, and R has the meaning as described for Formula I, may be prepared as described in Scheme 9. Briefly, reaction of acid 1 with 3-bromo-l,2-diamine gives amide 2.
- a sensitive and quantitative in vitro binding assay using the fluorescence polarization (FP) based method was used to determine the binding affinity of Smac mimetics to XIAP protein (Nikolovska-Coleska et al., Anal. Biochem. 332:261-73 (2004)).
- FP fluorescence polarization
- 5-carboxyfluorescein (5 -F am) was coupled to the lysine side chain of the mutated Smac peptide, AbuRPF-K-(5-Fam)-NH 2 (termed SM5F).
- Another fluorescently tagged Smac mimetic (termed SM-Fl) with higher affinities than SM5F was also used.
- SM-Fl As one example for the SM-Fl tracer, to each well, SM-Fl (2nM, InM, and InM for experiments with XIAP-BIR3, cIAPl-BIR3, and cIAP2-BIR3, respectively) and different concentrations of proteins were added to a final volume of 125 ⁇ l in the assay buffer (10OmM potassium phosphate, pH 7.5, 100 ⁇ g/ml bovine ⁇ -globulin, 0.02% sodium azide, Invitrogen, with 4% DMSO). Plates were mixed and incubated at room temperature for 3 hours with gentle shaking to assure equilibrium.
- assay buffer 10OmM potassium phosphate, pH 7.5, 100 ⁇ g/ml bovine ⁇ -globulin, 0.02% sodium azide, Invitrogen, with 4% DMSO.
- the K d values of SM-Fl to recombinant XAIP-BIR3 protein was determined to be 4.7 nM.
- IC50 values the inhibitor concentration at which 50% of bound peptide is displaced, will be determined from a plot using nonlinear least-squares analysis. Curve fitting will be performed using
- GRAPHPAD PRISM software GraphPad Software, Inc., San Diego, CA.
- IC50 values the inhibitor concentration at which 50% of bound peptide is displaced, will be determined from a plot using nonlinear least-squares analysis. Curve fitting will be performed using
- WST-8 was added at a final concentration of 10% to each well, and then the plates were incubated at 37 0 C for 2-3 hrs.
- the absorbance of the samples was measured at 450 nm using a ULTRA Tecan Reader (Molecular Device).
- the concentration of the tested compound that inhibited cell growth by 50% was calculated by comparing absorbance in untreated cells and the cells treated with the tested compound.
- MB-231 and ovarian cancer SK-OV-3 cell lines (Fig. 3). Cells were treated with SM- 1238 for 48 hours and cell viability was determined using the trypan blue exclusion assay. SM-1238 induced cell death in both cell lines in a concentration-dependant fashion.
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US12/937,114 US8445473B2 (en) | 2008-04-11 | 2009-04-13 | Heteroaryl-substituted bicyclic Smac mimetics and the uses thereof |
CN200980122992.2A CN102066361B (en) | 2008-04-11 | 2009-04-13 | Heteroaryl-substituted bicyclic SMAC mimetics and the uses thereof |
JP2011504232A JP5887134B2 (en) | 2008-04-11 | 2009-04-13 | Bicyclic Smac mimetics substituted by heteroaryl |
AU2009234280A AU2009234280A1 (en) | 2008-04-11 | 2009-04-13 | Heteroaryl-substituted bicyclic Smac mimetics and the uses thereof |
EP09729584A EP2265604A4 (en) | 2008-04-11 | 2009-04-13 | Heteroaryl-substituted bicyclic smac mimetics and the uses thereof |
CA2725398A CA2725398A1 (en) | 2008-04-11 | 2009-04-13 | Heteroaryl-substituted bicyclic smac mimetics and the uses thereof |
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EP (1) | EP2265604A4 (en) |
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Cited By (5)
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WO2011050068A3 (en) * | 2009-10-23 | 2011-09-29 | The Regents Of The University Of Michigan | Bivalent diazo bicyclic smac mimetics and the uses thereof |
WO2015187998A3 (en) * | 2014-06-04 | 2016-02-04 | Sanford-Burnham Medical Research Institute | Use of inhibitor of apoptosis protein (iap) antagonists in hiv therapy |
US10441654B2 (en) | 2014-01-24 | 2019-10-15 | Children's Hospital Of Eastern Ontario Research Institute Inc. | SMC combination therapy for the treatment of cancer |
US10870663B2 (en) | 2018-11-30 | 2020-12-22 | Glaxosmithkline Intellectual Property Development Limited | Compounds useful in HIV therapy |
US11618751B1 (en) | 2022-03-25 | 2023-04-04 | Ventus Therapeutics U.S., Inc. | Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives |
Families Citing this family (5)
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ES2504216T3 (en) * | 2007-04-13 | 2014-10-08 | The Regents Of The University Of Michigan | Bicyclic Smac diazo mimetics and their uses |
US9546174B2 (en) | 2012-11-30 | 2017-01-17 | Sanford-Burnham Medical Research Institute | Inhibitor of apoptosis protein (IAP) antagonists |
WO2016079527A1 (en) | 2014-11-19 | 2016-05-26 | Tetralogic Birinapant Uk Ltd | Combination therapy |
WO2016097773A1 (en) | 2014-12-19 | 2016-06-23 | Children's Cancer Institute | Therapeutic iap antagonists for treating proliferative disorders |
CN110028508B (en) * | 2019-05-16 | 2021-05-28 | 南京华威医药科技集团有限公司 | Antitumor diazo bicyclic apoptosis protein inhibitor |
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MXPA06008095A (en) * | 2004-01-16 | 2007-03-28 | Univ Michigan | Conformationally constrained smac mimetics and the uses thereof. |
ES2525585T3 (en) * | 2006-05-05 | 2014-12-26 | The Regents Of The University Of Michigan | Intermediates for the preparation of bivalent SMAC mimetics |
CN101096363B (en) * | 2006-06-27 | 2011-05-11 | 中国人民解放军军事医学科学院毒物药物研究所 | 2,4,5-three-substituted thiazole compound, preparation method, medicament composition and pharmacy use thereof |
US7985735B2 (en) * | 2006-07-24 | 2011-07-26 | Tetralogic Pharmaceuticals Corporation | Dimeric IAP inhibitors |
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2011050068A3 (en) * | 2009-10-23 | 2011-09-29 | The Regents Of The University Of Michigan | Bivalent diazo bicyclic smac mimetics and the uses thereof |
US8815927B2 (en) | 2009-10-23 | 2014-08-26 | The Regents Of The University Of Michigan | Bivalent diazo bicyclic Smac mimetics and the uses thereof |
US10441654B2 (en) | 2014-01-24 | 2019-10-15 | Children's Hospital Of Eastern Ontario Research Institute Inc. | SMC combination therapy for the treatment of cancer |
WO2015187998A3 (en) * | 2014-06-04 | 2016-02-04 | Sanford-Burnham Medical Research Institute | Use of inhibitor of apoptosis protein (iap) antagonists in hiv therapy |
US10300074B2 (en) | 2014-06-04 | 2019-05-28 | Sanford Burnham Prebys Medical Discovery Institute | Use of inhibitor of apoptosis protein (IAP) antagonists in HIV therapy |
US10864217B2 (en) | 2014-06-04 | 2020-12-15 | Sanford Burnham Prebys Medical Discovery Institute | Use of inhibitor of apoptosis protein (IAP) antagonists in HIV therapy |
US10870663B2 (en) | 2018-11-30 | 2020-12-22 | Glaxosmithkline Intellectual Property Development Limited | Compounds useful in HIV therapy |
US11492361B2 (en) | 2018-11-30 | 2022-11-08 | Glaxosmithkline Intellectual Property Development Limited | Compounds useful in HIV therapy |
US11873310B2 (en) | 2018-11-30 | 2024-01-16 | Glaxosmithkline Intellectual Property Development Limited | Compounds useful in HIV therapy |
US11618751B1 (en) | 2022-03-25 | 2023-04-04 | Ventus Therapeutics U.S., Inc. | Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives |
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US8445473B2 (en) | 2013-05-21 |
US20110046189A1 (en) | 2011-02-24 |
JP5887134B2 (en) | 2016-03-16 |
JP2011516581A (en) | 2011-05-26 |
CN102066361A (en) | 2011-05-18 |
CN102066361B (en) | 2014-08-06 |
EP2265604A4 (en) | 2011-10-26 |
AU2009234280A1 (en) | 2009-10-15 |
EP2265604A2 (en) | 2010-12-29 |
WO2009126947A3 (en) | 2009-12-17 |
CA2725398A1 (en) | 2009-10-15 |
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