WO2004099139A1 - Composes contenant de l'indole a activite anti-tubuline et de ciblage vasculaire - Google Patents

Composes contenant de l'indole a activite anti-tubuline et de ciblage vasculaire Download PDF

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WO2004099139A1
WO2004099139A1 PCT/US2004/013616 US2004013616W WO2004099139A1 WO 2004099139 A1 WO2004099139 A1 WO 2004099139A1 US 2004013616 W US2004013616 W US 2004013616W WO 2004099139 A1 WO2004099139 A1 WO 2004099139A1
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compound
cancer
tubulin
mmol
tumor
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PCT/US2004/013616
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English (en)
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Kevin Pinney
Feng Wang
Mallinath Hadimani
Maria Del Pilar Mejia
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Baylor University
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Priority to US10/555,352 priority Critical patent/US20070082872A1/en
Publication of WO2004099139A1 publication Critical patent/WO2004099139A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms

Definitions

  • tubulin binding agents or anti-tubulin agents exhibit potent tumor cell cytotoxicity by efficiently inhibiting the polymerization of ⁇ -tubulin heterodimers into the microtubule structures that are required to facilitate mitotic cell division (Hamel, Medicinal Research Reviews, 1996).
  • Vinca Alkaloids such as Vinblastine and Vincristine (Owellen et al, Cancer Res., 1976;
  • tubulin binding agents exploit the relatively rapid mitosis that occurs in proliferating tumor cells. By binding to tubulin and inhibiting the formation of the spindle apparatus in a tumor cell, the Tubulin Binding Agent can cause significant tumor cell cytotoxicity with relatively minor effects on the slowly dividing normal cells of the patient.
  • tubulin binding site interactions remain largely unknown, and they definitely vary between each class of Tubulin Binding Agent.
  • Photoaffinity labeling and other binding site elucidation tecliniques have identified three key binding sites on tubulin: 1) the colchicine site (Floyd et al, Biochemistry, 1989; Staretz et al, J. Org. Chem., 1993; Williams et al, J. Biol. Chem., 1985; Wolff et al, Proc. Natl. Acad. Sci.
  • Antivascular chemotherapy is an emerging area of cancer chemotherapy which centers on the development of drugs that target the proliferation of the vasculature the supports tumor growth.
  • Much of the research in anti- vascular cancer therapy has focused on understanding the process of new blood vessel formation, known as angiogenesis, and identifying anti-angiogenic agents which inhibit the formation of new blood vessels.
  • Angiogenesis is characterized by the proliferation of tumor endothelial cells and generation of new vasculature to support the growth of a tumor. This growth is stimulated by certain growth factors produced by the tumor itself.
  • VEGF Vascular Endothelial Growth Factor
  • VEGF Vascular Endothelial Growth Factor
  • Various anti-angiogenic strategies have been developed to inhibit this signaling process at one or more steps in the biochemical pathway in order to prevent the growth and establishment of the tumor vasculature.
  • anti-angiogenic therapies act slowly and must be chronically administered over a period of months to years in order to produce a desired effect.
  • Vascular Targeting Agents (“VTAs”) or vascular damaging agents, are a separate class of antivascular chemotherapeutics.
  • VTAs attack solid tumors by selectively targeting the established tumor vasculature and causing extensive shutdown of tumor blood flow.
  • a single dose of a VTA can cause a rapid and selective shutdown of the tumor neovasculature within a period of minutes to hours, leading eventually to tumor necrosis by induction of hypoxia and nutrient depletion.
  • This vascular-mediated cytotoxic mechanism of VTA action is quite divorced from that of anti-angiogenic agents that inhibit the formation of new tumor vascularization, rather than interfering with the existing tumor vasculature.
  • VTAs have been known to disrupt tumor vasculature, but differ in that they also manifest substantial normal tissue toxicity at their maximum tolerated dose. In contrast, genuine VTAs retain their vascular shutdown activity at a fraction of their maximum tolerated dose. It is thought that Tubulin-binding VTAs selectively destabilize the microtubule cytoskeleton of tumor endothelial cells, causing a profound alteration in the shape of the cell which ultimately leads to occlusion of the tumor blood vessel and shutdown of blood flow to the tumor (Kanthou et al, Blood, 2002).
  • Combretastatin A4 phosphate prodrug (“CA4P) is one of the leading new candidates from among a relatively small collection of known world compounds with vascular targeting activity (U.S. Pat. No. 5,561,122; Chaplin et al, Anticancer Res., 1999; Tozer et al, Cancer Res., 1999; Pettit and Rhodes, Anti-Cancer Drug Des., 1998; Iyer et al, Cancer Res., 1998; Dark et al, Cancer Res., 1997). Its parent phenol compound, Combretastatin A-4 (“CA4") was discovered by Professor George R. Pettit (Arizona State University) as an isolate from South African bush willow (Combretum caffrum) in the 1970s.
  • CA4 is a potent inhibitor of tubulin assembly and binds to the colchicine site on ⁇ -tubulin. Interestingly, CA4 itself does not demonstrate destruction of tumor vasculature, while CA4P is very active in terms of tumor vasculature destruction. Therefore, the phosphate ester portion of CA4P undergoes dephosphorylation to reveal the potent tubulin binder CA4 that destroys the tumor cell through an inhibition of tubulin assembly.
  • CA4P is currently the lead drug in a group of tubulin-binding VTAs under clinical development.
  • Other tubulin binding VTAs that have been discovered include the Colchicinoid ZD6126 (Davis et al., Cancer Research, 2002 ) and the Combretastatin analog AVE8032 (Lejeune et al, Proceedings of the AACR., 2002).
  • An aggressive chemotherapeutic strategy for the treatment and maintenance of solid tumor cancers continues to rely on the development of architecturally new and biologically more potent compounds.
  • the present invention addresses this urgent need by providing a structurally novel class of Tubulin Binding Agent compositions with potent antiproliferative activity and tumor cell cytotoxicity.
  • the present invention provides the important discovery that corresponding prodrug constructs of these agents have selective effects on the tumor vasculature that are independent of any antimitotic effect on the cells of the tumor. These agents are capable of selectively shutting down the flow of blood to a tumor and causing secondary tumor cell death.
  • the present compositions have expanded clinical utility over known tubulin binding agents.
  • the present invention relates to a discovery of indole compounds that result from the judicious combination of a non-tubulin binding molecular template which, when suitably modified with structural features such as hydroxyl moieties and arylalkoxy groups, are found to function as tubulin binding agents capable of inhibiting tubulin assembly and tumor cell proliferation.
  • the present invention provides indole compounds of the following general formula I:
  • Ri is independently selected from OH, nitro, amine, lower alkyl, lower alkoxy, phosphate, or halogen; n is 0, 1, 2, 3, or 4;
  • Y ⁇ , Y 2 , are Y 3 are optionally a covalent bond, -CO-, -O-, -S-, -CH 2 -, or -CH 2 O-; and A, B, and C are alkyl, aryl or H, wherein at least two of A, B, or C are aryl.
  • n is desirably 1 or 2.
  • A is desirably a substituted aryl group.
  • A is trisubstituted; two or three of the substituents may be identical.
  • the substituents may be the same, or different.
  • the substituents are alkoxy, e.g., methoxy, ethoxy; or hydroxyl.
  • Y 3 is a carbonyl group.
  • A may be a substituted aryl group.
  • A is di- or tri-substituted; two or three of the substituents may be identical.
  • the substituents may be the same, or different.
  • the substituents are alkoxy e.g., methoxy, ethoxy; hydroxyl or amino.
  • Y 3 is a covalent bond in this embodiment.
  • B is desirably a substituted aryl group. In an embodiment, B is di- or tri-substituted.
  • substituents may be identical.
  • the substituents may be the same, or different.
  • the substituents are alkoxy e.g., methoxy, ethoxy; or hydroxyl.
  • Y 2 is a covalent bond.
  • B is desirably a substituted aryl group.
  • A is trisubstituted; two or three of the substituents may be identical.
  • the substituents may be the same, or different.
  • the substituents are alkoxy, e.g., methoxy, ethoxy; or hydroxyl.
  • Y 2 is a carbonyl group.
  • C is desirably H or methyl.
  • C is a substituted aryl group.
  • C is trisubstituted; two or three of the substituents may be identical.
  • the substituents may be the same, or different.
  • the substituents are alkoxy, e.g., methoxy, ethoxy; or hydroxyl.
  • Yi is a carbonyl group.
  • the compounds of the invention also include prodrug forms of the compound, e.g., phosphate prodrugs.
  • the invention provides 2-aryl, 3-aroyl indoles of the following structural formula la:
  • n and o may independently be 0, 1, 2 or 3
  • Ri, R 2 and R may be independently selected from OH, nitro, amine, lower alkyl, lower alkoxy, phosphate, or halogen;
  • R 4 may be H or lower alkyl, or a substituted aryl group.
  • the invention provides 2-aroyl, 3 -aryl indoles of the following structural formula lb: b)
  • n and o may independently be 0, 1, 2 or 3
  • Ri, R 2 and R 3 may be independently selected from OH, nitro, amine, lower alkyl, lower alkoxy, phosphate, or halogen;
  • R may be H or lower alkyl, or a substituted aryl group.
  • the invention provides N-aroyl, 2-aryl indoles of the following structural formula Ic:
  • R 2 and R 3 may be independently selected from OH, nitro, amine, lower alkyl, lower alkoxy, phosphate, or halogen.
  • the invention provides 2,3-diaryl indoles of the following structural formula Id:
  • n and o may independently be 0, 1, 2 or 3
  • R 1 ⁇ R 2 and R 3 may be independently selected from OH, nitro, amine, lower alkyl, lower alkoxy, phosphate, or halogen;
  • R t may be H or lower alkyl, or a substituted aryl group.
  • the invention provides N-aryl, 2-aryl indoles of the following structural formula Ie:
  • R 2 and R 3 may be independently selected from OH, nitro, amine, lower alkyl, lower alkoxy, phosphate, or halogen.
  • the invention contemplates methods of contacting a tubulin- containing system with an effective amount of a compound of Formula I. Methods are also provided for treating a warm-blooded animal afflicted with a neoplastic disease comprising administering an effective amount of compound capable of inliibiting the proliferation of the neoplastic disease.
  • the antiproliferative effect has the direct result of causing tumor cell cytotoxicity due to inhibition of mitosis.
  • the invention broadly contemplates the provision of a method for treating a warm-blooded animal having a vascular proliferative disorder comprising administering an effective amount of a compound of the present invention to achieve targeted vascular toxicity at a locality of proliferating vasculature, wherein the proliferating vasculature is malignant or nonmalignant.
  • the invention broadly contemplates the provision of a method for administering an effective amount of a compound of the present invention to selectively reduce the flow of blood to at least a portion of a neoplastic region, thereby causing substantial necrosis of tissue in the neoplastic region without substantial necrosis of tissue in adjoining regions.
  • the effect of reduced tumor blood flow is reversible so that normal tumor blood flow is restored following cessation of treatment.
  • Figure 1 A depicts 2-aryl, 3-aroyl-substituted benzo[b]thiophene and benzofuran tubulin binding agents; B) hydroxylated analogs; and C) phosphate prodrugs thereof.
  • Figure 2 illustrated the in vivo tumor growth control of the Benzo[b]thiophene prodrug 3-(3', 4', 5' - trimethoxybenzoyl)-2-(4'-methoxyphenyl)-6-methoxybenzo[j]thiophene.
  • Figure 3 A) illustrates a synthetic route for preparation of phenylindole derivatives involving aryl migration
  • B) a COSY NMR spectra for the aromatic region of a 2-phenylindole derivative
  • C a cyclized isomer without aryl migration (no evidence for its formation).
  • Figure 4 illustrates a synthetic route for the preparation of a 2-phenylindole in a one-pot reaction and further derivatization with benzoyl chloride to produce the indole-based analog.
  • Figure 5 illustrates a synthetic route for the preparation of a hydroxyl-substituted indole-based ligand and corresponding phosphate prodrug salt.
  • Figure 6 illustrates a synthetic route for the preparation of a ammo-substituted indole based ligand and corresponding phosphoramidate prodrug salt.
  • Figure 7A depicts exemplary 2-aryl, 3-aroyl-substituted indoles and B) corresponding prodrugs.
  • Figure 8A depicts exemplary 3-aryl, 2-aroyl-substituted indoles and B) corresponding prodrugs.
  • Figure 9A) depicts exemplary di- and tri-hydroxylated indole -based ligands; B) depicts exemplary N-substituted indole-based ligands; C) depicts exemplary 2,3-diaryl-substituted indole-based ligands; and D) depicts exemplary 2,3'diaryl ether-substituted indole-based ligands.
  • Figure 10 illustrates a synthetic routes for the preparation of dihydroxyl-substituted indole-based ligand and corresponding phosphate prodrug salt.
  • Figure 11 illustrates a synthetic route for the preparation of an N-methyl substituted 2- aryl, 3-aroyl-substituted indole prodrug.
  • Figure 12 illustrates a synthetic route for the preparation of an N-aroyl, 2-aryl substituted indole prodrug.
  • Figure 13 illustrates a synthetic route for the preparation of an exemplary 2,3-diaryl substituted indole and its corresponding diphosphate prodrug.
  • Figure 14 illustrates the effect of an exemplary 2-aryl, 3-aroyl-substituted indole phosphate prodrug (Oxi8007) on tumor vasculature over a 24 hour period.
  • Figure 15 illustrates the effect of an exemplary 2-aryl, 3-aroyl-substituted indole phosphate prodrug (Oxi8007) on tumor growth.
  • Estradiol is perhaps the most important estrogen in humans, and it is interesting and instructive that the addition of the methoxy aryl motif to this compound makes it interactive with tubulin. It is also noteworthy that 2-methoxyestradiol is a natural mammalian metabolite of estradiol and may play a cell growth regulatory role especially prominent during pregnancy.
  • the novel indole compounds described in this application are the first to incorporate the 3,4,5-trimethoxyaryl motif reminiscent of colchicine and CA4 arranged in an appropriate molecular conformation such that a pseudo aryl- aryl pi stacking interaction can take place.
  • Such an aryl-aryl interaction of the appropriate centroid-to-centroid distance (approximately 4.7 Angstroms) is believed to be important for enhanced binding affinity to the colchicine site on ⁇ -tubulin. It is this binding that ultimately leads to an inliibition of tubulin assembly which manifests itself as a cytotoxic event or antivascular event.
  • the indole compounds of the present invention demonstrate remarkable cytotoxicity against a variety of human cancer cell lines.
  • the ability of an agent to inhibit tubulin assembly and microtubule formation is an important property of many anticancer agents. Disruption of microtubules that comprise the cytoskeleton and mitotic spindle apparatus can interfere dramatically with the ability of a cell to successfully complete cell division.
  • the compounds of the present invention are highly cytotoxic to actively proliferating cells, inhibiting their mitotic division and often causing their selective apoptosis while leaving normal quiescent cells relatively unaffected.
  • Nonmalignant Vascular Proliferative Disorders The invention provides the discovery that the compounds of the invention as well as analogs thereof, are vascular targeting agents (VTAs), and thus are useful for the treatment of malignant vascular proliferative disorders, such as solid tumor cancers, as well as other nonmalignant vascular proliferative disorders, such as retinal neovascularization and restenosis.
  • VTAs vascular targeting agents
  • the present invention is directed to the administration of a vascular targeting agent, particularly a tubulin binding VTA, for the treatment of malignant or nonmalignant vascular proliferative disorders in ocular tissue.
  • Neovascularization of ocular tissue is a pathogenic condition characterized by vascular proliferation and occurs in a variety of ocular diseases with varying degrees of vision failure.
  • the administration of a VTA for the pharmacological control of the neovascularization associated with non-malignant vascular proliferative disorders such as wet macular degeneration, proliferative diabetic retinopathy or retinopathy of prematurity would potentially benefit patients for which few therapeutic options are available.
  • the invention provides the administration of a VTA for the pharmacological control of neovascularization associated with malignant vascular proliferative disorders such as ocular tumors.
  • the blood-retinal barrier is composed of specialized nonfenestrated tightly- joined endothelial cells that form a transport barrier for certain substances between the retinal capillaries and the retinal tissue.
  • the nascent vessels of the cornea and retina associated with the retinopathies are aberrant, much like the vessels associated with solid tumors.
  • Tubulin binding agents, inhibitors of tubulin assembly and vascular targeting agents may be able to attack the aberrant vessels because these vessels do not share architectural similarities with the blood retinal barrier.
  • Tubulin binding agents may halt the progression of the disease much like they do with a tumor-vasculature.
  • the compounds of the present invention are also contemplated for use in the treatment of vascular disease, particularly atherosclerosis and restenosis.
  • Atherosclerosis is the most common form of vascular disease and leads to insufficient blood supply to critical body organs, resulting in heart attack, stroke, and kidney failure. Additionally, atherosclerosis causes major complications in those suffering from hypertension and diabetes, as well as tobacco smokers.
  • Atherosclerosis is a form of chronic vascular injury in which some of the normal vascular smooth muscle cells ("VSMC") in the artery wall, which ordinarily control vascular tone regulating blood flow, change their nature and develop "cancer-like" behavior.
  • VSMC normal vascular smooth muscle cells
  • VSMC become abnormally proliferative, secreting substances (growth factors, tissue-degradation enzymes and other proteins) which enable them to invade and spread into the inner vessel lining, blocking blood flow and making that vessel abnormally susceptible to being completely blocked by local blood clotting, resulting in the death of the tissue served by that artery.
  • Restenosis is due to a complex series of fibroproliferative responses to vascular injury involving potent growth-regulatory molecules, including platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), also common to the later stages in atherosclerotic lesions, resulting in vascular smooth muscle cell proliferation, migration and neointimal accumulation.
  • PDGF platelet-derived growth factor
  • bFGF basic fibroblast growth factor
  • Restenosis occurs after coronary artery bypass surgery (CAB), endarterectomy, and heart transplantation, and particularly after heart balloon angioplasty, atherectomy, laser ablation or endovascular stenting (in each of which one-third of patients redevelop artery- blockage (restenosis) by 6 months), and is responsible for recurrence of symptoms (or death), often requiring repeat revascularization surgery.
  • CAB coronary artery bypass surgery
  • atherectomy laser ablation or endovascular stenting
  • endovascular stenting in each of which one-third of patients redevelop artery- blockage (restenosis) by 6 months
  • recurrence of symptoms or death
  • the most effective way to prevent this disease is at
  • amino acid acyl group in the amino acid acylamino group includes an acyl group derived from the amino acid.
  • the amino acids may be enumerated by ⁇ -amino acids, ⁇ -amino acids and ⁇ -amino acids.
  • preferred amino acids include glycine, alanine, leucine, serine, lysine, glutamic acid, aspartic acid, threonine, valine, isoleucine, ornithine, glutamine, asparagines, tyrosine, phenylalanine, cysteine, methionine, arginine, ⁇ -alanine, tryptophan, proline, histidine, etc.
  • the preferred amino acid is serine and the preferred amino acid acyl group is a serinamide.
  • “Amine” includes a free amine NH 2 or a lower alkylamino.
  • “Animal” includes any warm-blooded mammal, preferably a human.
  • Alkyl includes a group containing from 1 to 8 carbon atoms and may be straight chained or branched.
  • An alkyl group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group.
  • alkyl groups may be substituted with up to four substituent groups, R as defined, at any available point of attachment.
  • R substituent groups
  • Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4- trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.
  • substituents may include but are not limited to one or more of the following groups: halo (such as F, Cl, Br, I), haloalkyl (such as CC1 3 or CF ), alkoxy, alkylthio, hydroxy, carboxy (-COOH), alkyloxycarbonyl (-C(O)R), alkylcarbonyloxy (-OCOR), amino (-NH 2 ), carbamoyl (-
  • Alkyl groups as defined may also comprise one or more carbon to carbon double bonds or one or more carbon to carbon triple bonds.
  • Aryl includes groups with aromaticity, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, as well as multicyclic systems with at least one aromatic ring.
  • aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, etc.
  • the preferred aryl group of the present invention is an optionally-substituted benzene ring of the following structure
  • Ri is OH, nitro, amine, lower alkyl, lower alkoxy, carboxyl, or halogen and n is 0, 1, 2, 3, 4, or 5.
  • Cycloalkyl is a species of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings. Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc. Exemplary substituents include one or more of the following groups: halogen, alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and/or alkylthio.
  • Halogen or “Halo” includes chlorine, bromine, fluorine or iodine.
  • “Lower alkoxy” includes -O-alkyl groups, wherein alkyl is as defined hereinabove.
  • the alkoxy group is bonded to the core compound through the oxygen bridge.
  • the alkoxy group may be straight chained or branched; although the straight-chain is preferred. Examples include methoxy, ethyloxy, propoxy, butyloxy, t-butyloxy, i-propoxy, and the like.
  • Preferred alkoxy groups contain 1-4 carbon atoms, especially preferred alkoxy groups contain 1-3 carbon atoms. The most preferred alkoxy group is methoxy.
  • “Lower alkylamino” includes a group wherein one or two alkyl groups is bonded to an amino nitrogen, i.e., NH(alkyl).
  • the nitrogen is the bridge connecting the alkyl group to the core compound. Examples include NHMe, NHEt, NHPr, and the like.
  • Prodrug includes a precursor form of the drug which is metabolically converted in vivo to produce the active drug.
  • Preferred prodrugs of the present invention include phosphate, phosphoramidate, or amino acid acyl groups as defined herein.
  • the phosphate ester salt moiety may also include (-OP(O)(O-alkyl) 2 or (-OP(O)(O-NH 4 + ) 2 ).
  • Phenolic moiety means herein a hydroxy group when it refers to an R group on an aryl ring.
  • Phosphate “Phosphate moiety”, or “Phosphate prodrug salt” includes phosphate ester salt moiety (-OP(O)(O " M + ) 2 ), a phosphate triester moiety (-OP(O)(OR) 2 ) or a phosphate diester moiety (-OP(O)(OR)(O " M + ), where M is a salt and R is chosen to be any appropriate alkyl or branched alkyl substituent (the two R groups may be the same alkyl group or may be mixed), or benzyl, or aryl groups.
  • the salt M is advantageously Na, K and Li, but the invention is not limited in this respect.
  • Phosphoramidate includes a phosphoamidate ester salt moiety (-NP(O)(O " M + ) 2 ), a phosphoramidate diester moiety (-NP(O)(OR) 2 ), or a phosphamidate disalt moiety (-
  • M is a salt and R is chosen to be any appropriate alkyl or branched alkyl substituent (the two R groups may be the same alkyl group or may be mixed), or benzyl, or aryl groups.
  • the salt M is advantageously Na, K and Li, but the invention is not limited in this respect.
  • Salt is a pharmaceutically acceptable salt and can include acid addition salts such as the hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Na, K, Li, alkaline earth metal cations such as Mg +2 or Ca +2 , or organic amine salts such as those disclosed in PCT International Application Nos.WO02/22626 or WO00/48606.
  • acid addition salts such as the hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, and tartrates
  • alkali metal cations such as
  • Tubulin Binding Agent shall refer to a ligand of tubulin or a compound capable of binding to either ⁇ -tubulin heterodimers or microtubules and interfering with the assembly or disassembly of microtubules.
  • Tumors Tumors
  • Cancers or “Neoplastic Disease” shall be used interchangeably and include (but are not limited to) the following:
  • carcinomas including that of the bladder, breast, colon, rectum, kidney, liver, lung (including small cell lung cancer), pharynx, esophagus, gall bladder, urinary tract, ovaries, cervix, uterus, pancreas, stomach, endocrine glands (including thyroid, adrenal, and pituitary), prostate, testicles and skin, including squamous cell carcinoma;
  • hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma; 3) hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;
  • tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma
  • tumors of the central and peripheral nervous system and meninges including astrocytoma, neuroblastoma, glioma, schwannomas, retinoblastomas, neuroma, glioma, gliobalstoma; and
  • tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer, anaplastic thyroid cancer and Kaposi's sarcoma.
  • Vascular toxicity includes the selective destruction, damage, or occlusion, whether reversible or irreversible, partial or complete, of proliferating vasculature.
  • Malignant proliferating vasculature includes the endothelium, artery, blood vessel, or neovasculature formed by a malignant disease state, such as a tumor.
  • Nonmalignant proliferating vasculature includes the endothelium, artery, blood vessel, or neovasculature formed by undesirable or pathological angiogenesis and that is associated with disease states other than a malignant disease state, including without limitation, ocular diseases such as wet or age-related macular degeneration, myopic macular degeneration, diabetic retinopathy, retinopathy of prematurity, diabetic molecular edema, uveitis, neovascular glaucoma, rubeosis, retrolental fibroplasias, angioid streaks, ocular histoplasmosis, and corneal neovascularization, or other nonocular disease states such as atherosclerosis, endometriosis, psoriasis, rheumatoid arthritis, Osier- Webber Syndrome, wound granulation, atheroma, restenosis, Kaposi's sarcoma, haemangiom
  • Antiproliferative or “antimitotic” refer to the ability of the compounds of the present invention to directly inhibit the proliferation of tumor cells and impart direct cytotoxicity towards tumor cells.
  • Treating includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing the progression or severity of a resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration. "Effective amount” includes the amount or dose of the compound, upon single or multiple dose administration to the patient, which provides the desired effect in the patient under diagnosis or treatment.
  • an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • determining the effective amount or dose of compound administered a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of, involvement, or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • a typical daily dose will contain from about 0.1 mg/kg to about 1000 mg/kg of the active compound of this invention. Preferably, daily doses will be about 10 mg/kg to about 100 mg/kg, and most preferably about 10 mg.
  • a compound of the present invention can be administered systemically in any form or mode which makes the compound bioavailable in effective amounts. Systemic administration may be accomplished by administration of a compound of the present invention into the bloodstream at a site which is separated by a measurable distance from the diseased or affected organ or tissue.
  • compounds of the present invention can be administered orally, parenterally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, buccally, and the like.
  • Oral or intravenous administration is generally preferred for treating neoplastic disease or cancer.
  • the compound may be administered non-systemically by local administration of the compound of the present invention directly at the diseased or affected organ or tissue.
  • Treatment of ocular diseases characterized by the presence of non-malignant proliferative vasculature or neovascularization can be achieved using non-systemic administration methods such as intravitreal injection, sub- Tenon's injection, ophthalmic drops, iontophoresis, topical formulation, and implants and/or inserts.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the disease state to be treated, the stage of the disease, and other relevant circumstances.
  • the present invention provides a pharmaceutical composition, which comprises a compound of the present invention or a pharmaceutically acceptable salt thereof as defined hereinabove and a pharmaceutically acceptable diluent or carrier.
  • compositions are prepared by known procedures using well-known and readily available ingredients.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragcanth, gelatin, calcium silicate, micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well know in the art.
  • the compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg, more preferably about 5 mg to about 300 mg (for example 25 mg) of the active ingredient.
  • unit dosage form includes a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predete ⁇ nined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • suitable pharmaceutical carrier diluent, or excipient.
  • compositions of the present invention may be fo ⁇ nulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal, transdermal (e.g. , patch), intianasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl chorines (lecithins), both natural and synthetic. Methods to form liposomes are well known in the art (see for example, Prescott Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY, 1976, p 33).
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose of calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose of calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or
  • Liquid preparations for oral administration may take the form, of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • composition may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. , in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in a powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension form a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch. Tablets or capsules of the compounds may be administered singly or two or more at a time as appropriate. It is also possible to administer the compounds in sustained release formulations.
  • the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case. There can of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the compounds of the present invention can be administered by inhalation or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • An alternative means of transdermal administration is by use of a skin patch.
  • they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
  • Administration means any of the standard methods of administering a compound to a subject, known to those skilled in the art. Examples include, but are not limited to, intravenous, intramuscular or intraperitoneal administration.
  • pharmaceutically acceptable carriers means any of the standard pharmaceutical carriers.
  • suitable carriers are well known in the art and may include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solutions, including phosphate buffered saline solutions containing POLYSORB 80, water, emulsions such as oil/water emulsion, and various type of wetting agents.
  • Other carriers may also include sterile solutions, tablets, coated tablets, and capsules.
  • Such carriers typically contain excipients such as starch, milk, sugar, certain types of clay gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols, or other known excipients.
  • excipients such as starch, milk, sugar, certain types of clay gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols, or other known excipients.
  • Such carriers may also include flavor and color additives or other ingredients.
  • Compositions comprising such carriers are formulated by well known conventional methods.
  • the compounds of the present invention may also be useful for the treatment of solid tumor described above when used either alone or in combination with radiotherapy and/or other chemotherapeutic treatments conventionally administered to patients for treating solid tumor cancers.
  • compounds of the present invention may be administered with chemotherapeutic agents selected from one of the following functional classes:
  • All viating agents compounds that donate an alkyl group to nucleotides. Alkylated DNA is unable to replicate itself and cell proliferation is stopped.
  • Exemplary alkylating agents include Melphalan, Chlorambucil, cyclophosphamide, ifosfamide, busulfan, dacarbaine, methotrexate, 5-FU, cytosine arabinsoide, and 6-thioguanine.
  • Antiangiogeneic agents compounds that inhibit the formation of tumor vasculature.
  • Exemplary anti-angiogenic agents include TNP-470 and AvastinTM.
  • Antitumor Antibiotics compounds having antimicrobial and cytotoxic activity. Such compounds also may interfere with DNA by chemically inhibiting enzymes and mitosis or altering cellular membranes.
  • Exemplary antitumor antibiotics include Actinomycin-D, bleomycin, mitomycin-C, Dactinomycin, Daunorubicin, and Doxorubicin.
  • Topoisomerase Inhibitors agents which interfere with topoisomerase activity thereby inhibiting DNA replication. Such agents include CPT-11 and Topotecan.
  • Hormonal Therapy includes, but is not limited to anti-estrogens.
  • An exemplary antiestrogen is Tamoxifen.
  • Antimicrotubule compounds Vincristine, paclitaxel, taxotere, etoposide, vinblastine, etc.
  • Indole-based ligand 9 was synthesized as shown in Figures 3 and 4.
  • Secondary amine 6 was prepared by treatment of -anisidine and 2-bromo-4- methoxyacetophenone under basic conditions (ethanolic potassium hydroxide) at 0°C.
  • ethanolic potassium hydroxide ethanolic potassium hydroxide
  • trimethoxybenzoylchloride (0.692 g, 3.00 mmol). The reaction mixture was heated to reflux for 12 hours. Solvent was removed by distillation under reduced pressure. After cooling down to room temperature, a dark solid formed which was dissolved in chloroform and purified by silica gel column chromatography with chloroform as the eluent. The collected mixture was again purified by column chromatography (50:50 hexanes:EtOAc) affording trimethoxybenzoyl indole 9 (0.744 g, 1.66 mmol, 84%) as a yellow oily gel. Pale yellow-green crystals were obtained by recrystallization from a mixture of ethanol and hexanes.
  • reaction proceeded for about 30 minutes and TLC analysis (silica gel, hexanes/EtOAc: 30/70) showed no starting material.
  • TLC analysis sica gel, hexanes/EtOAc: 30/70
  • the reaction mixture was then filtered and concentrated under reduced pressure to give greenish-yellow foam.
  • Example 3 Synthesis of amine functionalized 2-Aryl, 3-Aroyl substituted Indoles and corresponding phosphoramidate prodrugs
  • phosphorous based prodrug derivatives of the nitrogenated indoles may have therapeutic advantages as selective tumor vasculature destruction agents. These compounds are primarily serinamides, phosphoramidates, and related phosphate dianions that are assembled on the amino substituent of tubulin binding indole analogs of CA4.
  • phosphoramidate analogs When utilized in vivo, phosphoramidate analogs are able to provide a more soluble compound than the corresponding amine, thereby increasing the bioavailability of the parent drug.
  • the P-N bond can be enzymatically cleaved by serum phosphatases releasing the amine which can inhibit tubulin assembly in a manner analogous to CA4P.
  • the amine-based prodrugs of the invention can be synthesized according to the scheme provided in Figure 6.
  • the filtered solid was further purified by recrystallization from EtOAc-hexanes and was characterized to be the desired product.
  • Example 4 Synthesis of N-substituted Indoles: In addition to the lH-Indole-based anti-mitotic agents described in this application, we have discovered that the nitrogen of the above indoles can be substituted with retention of tubulin binding activity. Similarly, the 2,3-diaroyl or diaryl substitution pattern of the indole ring can be shifted to a 1(N), 2 disubstitution pattern while retaining activity. Exemplary N- substituted diar(o)yl indoles are depicted in Figure 9B. These compounds may be prepared by an addition elimination reaction utilizing the trimethoxyphenolic anion as a nucleophile as described by us for the benzo[ ⁇ ]thiophene compounds. Other linkage atoms between the aryl rings are conceivable as well.
  • the reaction mixture was heated to reflux at 160°C for 12 hours. Then excess of o-dichlorobenzene was distilled off under reduced pressure and the resulting dark-colored solid was subjected to flash chromatography.
  • 2-(3,4,5-trimethoxyphenyl)-6-methoxyindole will be prepared Fischer indole synthesis starting from 3-methoxyphenylhydrazine and 3,4,5-trimethoxyacetophenone using the methods described by Liu (Liu et al, j. Am. Chem. Soc, 2003).
  • the resulting derivatized indole will then be reacted with N-bromosuccinimide in dimethylformamide to yield 3-bromo-2-(3,4,5- trimethoxyphenyl)-6-methoxyindole (Bunker et al, Bioorg. Med. Chem. Lett., 1996; Masanobu et al, Heterocycles, 1992).
  • the product obtained will then be reacted (through a Suzuki coupling reaction) with 3-isopropoxy-4-methoxyphenylboronic acid to obtain the expected 2,3-diaryl substituted indole derivative (Liu et al, Tetrahedron Letters, 2000).
  • the isopropyl group, in the resulting 2,3-diarylindole will be removed by treatment with aluminum trichloride.
  • the resulting hydroxy group will then be converted to the disodiumphosphate functionality leading to the prodrug.
  • linkage atoms between the aryl rings are conceivable as well, including thioethers (-S-), secondary alcohols (-CH(OH)-, and methylenes (-CH2-). These compounds are intended to form a one-atom bridge between the substituted aryl and the indole ring.
  • a single covalent bond can substitute for the 1-atom linker (see Figure 9C).
  • IC 50 values for tubulin assembly were determined according to a previously described
  • IC 50 is the amount of inhibitor needed to inhibit tubulin assembly 50% with respect to the amount of inhibition that occurs in the absence of inhibitor.
  • Example 7 In vitro Cytotoxicity Activity Against Cancer Cell Lines Newly prepared compounds were evaluated for cytotoxic activity against a variety of cell lines derived from human tumors using an assay system similar to the National Cancer Institute procedure previously described (Monks et al, J. Natl. Cancer Inst., 1991). Briefly, the cell suspensions, diluted according to the particular cell type and the expected target cell density (5,000-40,000 cells per well based on cell growth characteristics), were added by pipet (100 ⁇ l) to 96-well microtiter plates. Inoculates were allowed a preincubation time of 24-28 hours at 37 C for stabilization. Incubation with the inhibitor compounds lasted for 48 hours in 5% CO 2 atmosphere and 100% humidity.
  • Determination of cell growth was performed by in situ fixation of cells, followed by staining with a protein-binding dye sulforhodamine B (SRB), which binds to the basic amino acids of cellular macromolecules.
  • SRB protein-binding dye sulforhodamine B
  • Seveial compounds were evaluated for cytotoxic activity against human P388 leukemia cell lines.
  • the effective dose or ED 50 value (defined as the effective dosage required to inhibit 50% of cell growth) was measured.
  • These and additional compounds were evaluated in terms of growth inhibitory activity against several other human cancer cell lines including: central nervous system ("CNS", SF-295), pancreas (BXPC-3), non-small cell lung cancer ("lung-NSC”, NCI-H460), breast (MCF-7), colon (KM20L2), ovarian (OVCAR-3), and prostate (DU-145).
  • the results are described in Table 2 below.
  • the growth inhibition GI 50 (defined as the dosage required to inhibit tumor cell growth by 50%) is listed for each cell line. Table 2.
  • Example 8 Inhibition of Tumor Blood Flow
  • the antivascular effects of the indole phosphate prodrug Oxi-8007 was assessed in tumor-bearing mice using a Fluorescent Bead Assay.
  • a MHEC-5T hemangioendothelioma tumor model was established by subcutaneous injection of 0.5x106 cultured transformed cell murine myocardial vascular endothelial cell line (“MHEC5-T”) cells into the right flank of Fox Chase CB-17 Severe Combined Immunodeficient (“SCID”) mice.
  • MHEC5-T myocardial vascular endothelial cell line
  • mice When transplanted tumors reached a size of 500 mm 3 (a size without development of necrosis), the mice received a single intraperitoneal (i.p.) injection of saline control or compound at doses ranging from 3.2 to 25 mg/kg.
  • mice were injected intravenously with 0.25ml of diluted FluoSphere beads (1:6 in physiological saline) in the tail vein, sacrificed after 3 minutes, and tumor was excised for cryosectioning. Tumor cryosections at a thickness of 8um were directly examined using quantitative fluorescent microscopy. Blood vessels were indicated by blue fluorescence from injected beads.
  • Example 9 Evaluation of Tumor Growth Control in vivo
  • the antitumor activity of indole phosphate prodrug, Oxi-8007 was assessed in tumor- bearing mice by measuring its effects on tumor volume.
  • the dosage effects of Oxi-com 197 is illustrated in Figure 15. Administration of X mg/kg doses of the drug significantly inhibited tumor growth relative to control treatment.
  • compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
  • the compounds of the subject invention can be synthesized in the alternative by previously described coupling methods such as the palladium- catalyzed coupling method of Flynn that involves multicomponent coupling of an o- iodoacetanilide and a methoxyphenylethyne in the presence of a palladium catalyst and methylmagnesium chloride to give an o-alkynylphenolate intermediate.
  • the intermediate Upon heating in a nitrogen or carbon monoxide atmosphere, the intermediate undergoes cyclization and reductive elimination in the presence of a methoxy-substituted aryl iodide to afford 2,3-diarylindole or 2- aryl, 3-aroyl indoles, respectively (Chaplin JH et al, Chem. Commun., 2001; Flynn et al, J. Med. Chem., 2002, PCT Pub. No. WO02/060872).
  • the indole ligands of the invention can be obtained at room temperature in a one-pot reaction described by Cacchi, in which an o-iodotrifluoroacetanilide is coupled to the alkyne under Sonogashira conditions in acetonitrile to give an alkynylphenolate that, when treated with K 2 CO 3 under the appropriate atmospheric conditions, affords the 2,3-diarylindole or 2-aryl,3-aroyl indoles of the invention (Arcadi et al, Tetrahedron Lett., 1992; Arcadi et al, Tetrahedron, 1994).
  • trimethoxyaryl motif seems optimal for enhanced tubulin binding, it is also very possible that another combination of alkoxy substituents (such as ethoxy, propoxy, isopropoxy, allyloxy, etc.) either as a trisubstituted pattern or as disubstituted (with one type of alkoxy moiety) and monosubstituted (with a different alkoxy moiety), or with three distinct types of alkoxy moieties may also have good tubulin binding characteristics. It is also conceivable that instead of having aryl alkoxy groups, it may be possible to substitute simply aryl-alkyl and aryl-alkenyl moieties and still maintain the enhanced cytotoxicity profile.
  • alkoxy substituents such as ethoxy, propoxy, isopropoxy, allyloxy, etc.
  • Phenolic groups may also have activity on these described indole ligands.
  • the synthesis of any of these modified indole-ligands will be very straightforward for anyone skilled in the art, and often will only involve a different choice of initial starting materials.
  • To prepare these alternative ligands the same synthetic schemes as disclosed herein or similar schemes with only slight modifications may be employed.
  • Pettit, G. R. Kamano, Y., Herald, C. L., Tuinman, A. A., Boettner, F. E., Kizu, H., Schmidt, J. M., Baczynskyj, L., Tomer, K. B., Bontems, R. J., The Isolation and Structure of a Remarkable Marine Animal Antineoplastic Constituent: Dolastatin 10, J. Am. Chem. Soc, 1987, 109, 6883-6885.
  • Pettit, G. R.; Singh, S. B.; Cragg, G. M. Synthesis of Natural (-)Combretastatin, J. Org. Chem. 1985, 50, 3404.

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Abstract

L'invention concerne des ligands d'indole substitués par triméthoxyphényle qui présentent une cytotoxicité exceptionnelle, ainsi qu'une remarquable capacité d'inhibition de l'ensemble de tubuline. De tels composés ainsi que leurs dérivés constituent d'excellents candidats cliniques pour le traitement de cancer chez les êtres humains. En outre, certains de ces ligands, en tant que promédicaments, peuvent s'avérer être des agents chimiothérapeutiques de ciblage vasculaire sélectif tumoral ou présenter une activité de ciblage vasculaire débouchant sur la prévention et/ou la destruction sélective de vaisseaux proliférants non malins.
PCT/US2004/013616 1999-09-17 2004-05-03 Composes contenant de l'indole a activite anti-tubuline et de ciblage vasculaire WO2004099139A1 (fr)

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Cited By (9)

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EP1819338A2 (fr) * 2004-11-22 2007-08-22 Threshold Pharmaceuticals, Inc. Agents anticancereux de liaison à la tubuline et leurs prodrogues
JP2008526756A (ja) * 2004-12-31 2008-07-24 ナショナル・ヘルス・リサーチ・インスティテューツ 抗腫瘍化合物、癌の治療方法および製剤学的組成物
JP2009531281A (ja) * 2006-02-03 2009-09-03 バイオノミックス リミテッド 置換ベンゾフラン、ベンゾチオフェン、ベンゾセレノフェンおよびインドールおよびそれらのチューブリン重合阻害剤としての使用
ITRM20100151A1 (it) * 2010-04-01 2011-10-02 Consiglio Nazionale Ricerche Derivati indolici e loro uso in campo medico.
CN102391164A (zh) * 2011-09-23 2012-03-28 中南大学 一种二芳基硫醚化合物、制备方法及其抗肿瘤应用
CN104003918A (zh) * 2011-09-23 2014-08-27 中南大学 一种二芳基硫醚化合物、制备方法及其抗肿瘤应用
CN104098499A (zh) * 2013-04-08 2014-10-15 上海医药工业研究院 5-苄氧基-2-(4-苄氧基苯基)-3-甲基-1h-吲哚的制备方法
CN104262229A (zh) * 2014-08-18 2015-01-07 山东希尔康泰药业有限公司 一种2-苯基取代-3-苯甲酰基取代吲哚的制备方法
US10012656B2 (en) 2012-08-13 2018-07-03 Otago Innovation Limited NT-proCNP as a biomarker of vascular disorders and pregnancy complication

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US6162930A (en) * 1998-03-06 2000-12-19 Baylor University Anti-mitotic agents which inhibit tubulin polymerization

Patent Citations (1)

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US6162930A (en) * 1998-03-06 2000-12-19 Baylor University Anti-mitotic agents which inhibit tubulin polymerization

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1819338A2 (fr) * 2004-11-22 2007-08-22 Threshold Pharmaceuticals, Inc. Agents anticancereux de liaison à la tubuline et leurs prodrogues
EP1819338A4 (fr) * 2004-11-22 2009-11-04 Threshold Pharmaceuticals Inc Agents anticancereux de liaison à la tubuline et leurs prodrogues
JP2008526756A (ja) * 2004-12-31 2008-07-24 ナショナル・ヘルス・リサーチ・インスティテューツ 抗腫瘍化合物、癌の治療方法および製剤学的組成物
JP2009531281A (ja) * 2006-02-03 2009-09-03 バイオノミックス リミテッド 置換ベンゾフラン、ベンゾチオフェン、ベンゾセレノフェンおよびインドールおよびそれらのチューブリン重合阻害剤としての使用
ITRM20100151A1 (it) * 2010-04-01 2011-10-02 Consiglio Nazionale Ricerche Derivati indolici e loro uso in campo medico.
WO2011121629A1 (fr) 2010-04-01 2011-10-06 Universita' Degli Studi Dl Roma "La Sapienza" Dérivés indoliques et utilisation de celles-ci dans le domaine médical
CN102391164A (zh) * 2011-09-23 2012-03-28 中南大学 一种二芳基硫醚化合物、制备方法及其抗肿瘤应用
CN102391164B (zh) * 2011-09-23 2014-08-13 中南大学 一种二芳基硫醚化合物、制备方法及其抗肿瘤应用
CN104003918A (zh) * 2011-09-23 2014-08-27 中南大学 一种二芳基硫醚化合物、制备方法及其抗肿瘤应用
US10012656B2 (en) 2012-08-13 2018-07-03 Otago Innovation Limited NT-proCNP as a biomarker of vascular disorders and pregnancy complication
CN104098499A (zh) * 2013-04-08 2014-10-15 上海医药工业研究院 5-苄氧基-2-(4-苄氧基苯基)-3-甲基-1h-吲哚的制备方法
CN104098499B (zh) * 2013-04-08 2016-05-04 上海医药工业研究院 5-苄氧基-2-(4-苄氧基苯基)-3-甲基-1h-吲哚的制备方法
CN104262229A (zh) * 2014-08-18 2015-01-07 山东希尔康泰药业有限公司 一种2-苯基取代-3-苯甲酰基取代吲哚的制备方法

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