EP1976505A1 - Derives de combretastatine et methodes therapeutiques associees - Google Patents

Derives de combretastatine et methodes therapeutiques associees

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Publication number
EP1976505A1
EP1976505A1 EP06837549A EP06837549A EP1976505A1 EP 1976505 A1 EP1976505 A1 EP 1976505A1 EP 06837549 A EP06837549 A EP 06837549A EP 06837549 A EP06837549 A EP 06837549A EP 1976505 A1 EP1976505 A1 EP 1976505A1
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European Patent Office
Prior art keywords
compound according
compound
groups
carbon atoms
acid
Prior art date
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EP06837549A
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German (de)
English (en)
Inventor
Chunlin Tao
Qinwei Wang
Tapas De
Neil P. Desai
Patrick Soon-Shiong
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Abraxis Bioscience LLC
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Abraxis Bioscience Inc USA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds

Definitions

  • the present invention relates the derivatives of combretastatin and related therapeutic methods.
  • antiangiogenesis is aimed at preventing the growth of new blood vessels in a tumor.
  • vascular targeting utilizes agents which destroy the existing neo vasculature of a tumor in an effort to cause the selective shutdown of tumor blood vessels and extensive ischemic necrosis. See Thorpe et al. Cancer Res. 2003, 63, 1144; U.S. Patent No. 6,538,038.
  • angiogenesis and blood supply as necessary requirements for primary tumor growth (e.g., invasiveness and metastasis), and that adequate vasculature is important to the growth of tumors.
  • one blood vessel nourishes thousands of tumor cells, targeting tumor vasculature as a molecular approach to cancer chemotherapy is becoming an important area of research.
  • two drug models are emerging: a first model which prevents the formation of new blood vessels in the tumor (antiangiogenesis), and a second which targets vascular destruction as a means of limiting tumor nourishment and/or the impermeability of the luminal surface of vessel endothelial cells to cancer drugs such as immunotherapies. See New England Journal of Medicine 1998, 339, 473.
  • the antiangiogenic model is basically a cytostatic approach wherein angiogenic factors generally produced by tumors, such as vascular endothelial growth factor (VEGF) and platelet derived endothelial cell growth factor, are blocked by antiangiogenic compounds, such as the natural polypeptides angiostatin and endostatin, thereby preventing new blood vessel growth.
  • VEGF vascular endothelial growth factor
  • antiangiogenic compounds such as the natural polypeptides angiostatin and endostatin
  • TWs property is of value in the treatment of disease states associated with angiogenesis such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • angiogenesis such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • the combretastatins are a group of anti-mitotic agents isolated from the bark of the South African tree Comhretum cqffrum.
  • the most potent member is combretastatin A-4, referred to herein as CA-4.
  • CA-4 was found to be a potent inhibitor of micro tubulin assembly; significantly active against murine L1210 and P338 lymphocytic leukemia as well as multidrug resistant (MDR) cancer cell lines, and displaying potent and selective toxicity toward tumor vasculature. See U.S. Patent No. 4,996,237; Pettit et al., Experimentia, 1989, 45, 209; Lin et al., MoI.
  • CA-4 has been demonstrated to elicit selective and irreversible shutdown of blood flow to neoplastic cells while permitting the blood supply to reach healthy cells.
  • CA-4 is able to inhibit cell growth at low concentrations (IC5 0 , P388 murine leukaemia cell line 2.6 nM), thereby destroying tumor blood vessels and effectively starving the tumors of nutrients.
  • CA-4 as an antimitotic agent showed poor antitumor effects in in vivo models.
  • CA-4 as a clinically useful anticancer agent has been limited. See Brown et al, J Chem. Soc, Perkin Tram. 1995, 1, 577.
  • prodrug derivatives of combretastatin A-4 that will regenerate combretastatin A-4 when exposed to physiological conditions.
  • Ohsumi et al. describe the synthesis of amino acid HCl prodrugs of a combretastatin analog, wherein an amino acid salt is attached to the amino group of a combretastatin derivative containing a basic amino group. See Ohsumi et al., Anti-Cancer Drug Design, 1999, 14, 539.
  • prodrugs may have an increased solubility compared to CA-4, they possess an inherent limitation in that the regeneration of CA-4 is dependent upon endogenous aminopeptidase in the blood of the subject to whom the prodrug is administered.
  • U.S. Patent No. 5,561,122 and U.S. Published Patent Application No. 20020072507A1 also describe CA-4 water-soluble prodrugs.
  • a disodium phosphate prodrug (CA-4P) displayed potent antivascular and antitumor effects in a wide range of preclinical tumor models.
  • CA-4P is currently in Phase II clinical trials. See Pettit et al., Anti-Cancer DrugDes., 1995, 10, 299; Hadimani et al., Bioorg. Med. Chem. Lett. 2003, 13(9), 1505.
  • both CA-4 and CA-4P target tubulin, binding strongly at or close to the colchicine binding site, preventing polymerization of ⁇ , ⁇ -tubulin heterodimer to microtubules.
  • the inhibition of microtubule formation prevents mitosis and is important in disrupting the growth of new vascular epithelial cells.
  • disruption of the intracellular microtubule networks by CA-4 leads to the destruction of microvessels within the tumor. This antivascular activity offers therapeutic possibilities, as the destruction of microvessels results in the death of all tumor cells which depend on the vessel for nutrients and oxygen.
  • the multi-functional role of tubulin in both healthy and cancer cells highlights the need for selectively targeted drugs.
  • CA-4P causes rapid, extensive and irreversible vascular shutdown in experimental tumor models following the administration of a single dose at 1/lOth the maximum tolerated dose (MTD).
  • MTD maximum tolerated dose
  • tubulin binding agents such as the combretastatins and taxane analogs
  • tubulin binding agents are water-insoluble and require formulation before evaluation in the clinic.
  • biolabile water-soluble prodrugs such as the phosphate salt derivatives of CA-4 and taxane, which allow metabolic conversion back into the water in soluble form. See Anticancer Drug Des. 1998, 13(3), 183; U.S. Patent No. 5,561,122; Bioorganic Med. Chem. Lett. 1993, 3, 1766; Bioorganic Med. Chem. Lett. 1993, 3, 1357.
  • CA-4 may be prepared from (3,4,5-trimethoxybenzyl)triphenylphosphonium salts which are condensed with a 3-hydroxy-4-methoxybenzaldehyde (the hydroxy 1 group of which is protected) in the presence of sodium hydride or of lithium derivatives, after which the desired product may be purified with standard chemical protocol.
  • a novel synthetic method of CA-4 analogs also has been reported. See Gaukroger et al, J. Org.
  • CA-4 and its derivatives can be used effectively to enhance immune responsiveness without causing vascular destruction (WO02058535A2) and in the treatment of diabetic retinopathy. See Cirla et al., Nat. Prod. Rep. 2003, 20(6),
  • the prodrug is non-toxic even though the parent combretastatin compound may be substantially more toxic.
  • the prodrug is hydrolyzed to the parent combretastatin compound after administration, thereby reducing the overall toxicity experienced by the patient during combretastatin therapy.
  • the present invention provides a compound of the fo ⁇ nula:
  • R wherein R), R 5 , R 6 , R 7 and Rio are H, wherein R 2 , R 3 , R 4 and R 8 are OMe, and wherein R 9 is -X-CO-R", R" is an unsubstituted or a substituted alkyl, alkenyl or aryl group comprising 5-21 carbon atoms and does not include N, and X is O, S or NH, with the proviso that when X is O, R" is not an optionally substituted 9-fluorenyl or 9- xanthenyl. [0020] Another aspect of the present invention provides a compound of the formula:
  • R 1 , R 5 , R 6 , R 7 and R] 0 are H; wherein R 3 , R 4 , Rs, R 9 are OMe, and wherein R 2 is -X-CO-R", R" is an unsubstituted or a substituted alkyl, alkenyl or aryl group comprising 2-21 carbon atoms, and X is O, S or NH.
  • a further aspect of the present invention provides a compound of the formula:
  • Ri, R 5 , R 6 , R 7 and Rio are H; wherein R 4 and Rs are OMe; wherein R 2 and R 3 form -OCH2-O; and wherein R 9 is -X-CO-R", R" is an unsubstituted or a substituted alkyl, alkenyl or aryl group comprising 2-21 carbon atoms and does not include N, and X is O 5 S or NH.
  • the present invention provides a compound of the formula:
  • Ri, R 5 , R 6 and R 7 are H; wherein R 2 , R 3 , R 4 and R 8 are OMe; and wherein R 9 and R ]0 are -X-CO-R", R" is an unsubstituted or a substituted alkyl, alkenyl or aryl group comprising 2-21 carbon atoms, and X is O, S or NH.
  • R 1 , R 5 , R 6 , R 7 and Rio are H; wherein R 3 , R 4 and R 8 are OMe; and wherein R 2 and R 9 are -X-CO-R", R" is an unsubstituted or a substituted alkyl, alkenyl or aryl group comprising 2-21 carbon atoms, and X is O, S or NH.
  • the present invention contemplates a method of modulating tumor growth or metastasis in an animal comprising identifying an animal afflicted with a tumor growth or metastasis and administering at least one of the aforesaid compounds to the afflicted animal.
  • the present invention further provides pharmaceutical formulations which include one or more of the aforesaid compounds and a pha ⁇ naceutically-acceptable carrier, as well as formulations in which the one or more compounds, when introduced into the earner, possess an average particle size of no more than about 500 nm.
  • the compounds and pharmaceutical formulations of the present invention may administered simultaneously with other pharmaceuticals, separately or at intervals so as to obtain the maximum efficacy of the combination; it being possible for each administration to vary in its duration from a rapid administration to a continuous perfusion.
  • the present invention also contemplates combination therapy, wherein the compounds of the present invention and at least one other anticancer agent are prepared as two separate pharmaceutical preparations and administered to a patient in need thereof, simultaneously, semi-simultaneously, separately or at intervals .
  • the Figure is a graph of the percentage of CA4 concentration produced over time, for Compounds 3, 4, 5, and 6.
  • the compounds of the present invention are those combretastatin derivatives of formula (I):
  • Ri, R 2 , R 3 , R 4 , R 5 , R ⁇ , R7, Rs, R 9 and Rio are respectively hydrogen, halogen atom, OH, OMe, OEt, OCH 2 CH 2 CH 3 , and one or more of them are: X-R', wherein,
  • X is O, NH or S
  • R' represents a group of formula R"-CO-, where R" represents: a hydrogen atom, alkyl, alkoxy, alkylthiol, alkylamino, alkenyl, alkynyl, having from 1 to 30 carbon atoms and which are unsubstituted or which is substituted by at least one of the substitutes (a), as defined below; an aryl group which has from 6 to 14 ring atoms and which is unsubstituted or which is substituted by at least one of substituents (b), as defined below; a heterocyclic group which has 5 or 6 ring atoms, of wliich from 1 to 3 are nitrogen and/or oxygen and/or sulphur hetero-atoms, said heterocyclic group being unsubstituted or being substituted by at least one of substituents (c), defined below; wherein the substituents (a) are: hydroxy groups; alkoxy groups wliich have from 1 to 20 carbon atoms and which are unsubsti
  • R" is an alkyl group
  • this group desirably has from 1 to 30 carbon atoms, and may be a straight or branched chain group, or natural or unnatural fatty acid.
  • examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 3-methylbutyl, 2,2- dimethylpropyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 4-methylpentyl, heptyl, 1- methylhexyl, 2-methylhexyl, 5-methylhexyl, 3-ethylpentyl, octyl, 2-methylheptyl, 6- methylheptyl, 2-ethylhexyl, 2-ethyl-3-methylpentyl, 3-ethyl-2-methylpentyl, nony
  • Substituents (a) may desirably include aryl groups, the latter which may be as defined above and exemplified below. Wherein R" is an alkyl group, the latter may be substituted to provide aralkyl groups, these groups preferably having from 1 to 4 carbon atoms in the alkyl part and from 6 to 10 carbon atoms in the aryl part.
  • the aryl part may be substituted or unsubstituted.
  • aralkyl groups include the benzyl, phenethyl, l-phenylethyl, 1-, 2- and 3-phenylpropyI, 1-, 2-, 3-, 4- and 5- ⁇ henylpentyl and the 1- and 2-naphthylmethyl groups.
  • R" is an alkoxy group
  • this group may desirably comprise from 1 to 20 carbon atoms, and further may be a straight or branched chain group.
  • examples of such groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t- butoxy, pentoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1,1-dimethylpropoxy, hexyloxy, 1-methylpentyloxy, 4-methylpentyloxy, heptyloxy, l-methylhexyloxy 5 2- methylhexyloxy, 5-methylhexyloxy, 3-ethylpentyloxy, octyloxy, 2-methylheptyloxy, 6- methylheptyloxy, 2-ethylhexyloxy, 2-ethyl-3-methylpentyloxy, 3-ethyl-2- methylpentyloxy, nonyloxy, 2-methyloct
  • R" is an alkenyl group
  • this group desirably includes from 2 to 30 carbon atoms, and further may be a straight or branched chain group and, preferably, is a natural or unnatural fatty acid. It may have 1 or more, and preferably from 2 to 6, double bonds.
  • Examples of such groups include vinyl, allyl, 1-propenyl, isopropenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 8-nonenyl, 1-nonenyl, 1-decenyl, 9-decenyl, 8-tridecenyl, cis-8- pentadecenyl, fr ⁇ r ⁇ -8-pentadecenyl, 8-heptadecenyl, 8-heptadecenyl, 8,11- heptadecadienyl, 8,11,14-heptadecatrieny
  • R" is an alkynyl group, it desirably possesses from 2 to 10 carbon atoms, and may be a straight or branched chain group. Examples of such groups include ethynyl, 1-propynyl, propargyl, 1-heptynyl, 1-octynyl and 1-decynyl groups.
  • R" represents an aryl group, it desirably has from 6 to 14 ring atoms, in a single ring or in multiple rings. Examples include phenyl, 1-naphthyl, 2-naphthyl, fluorenyl, 1-anthryl and 1-phenanthryl groups.
  • Such groups may be substituted or unsubstituted, and, if substituted, the substituents may be selected from substituents (a), as defined above. Examples include phenoxy, 1-naphthyloxy, 2-naphthyloxy, fluorenyloxy, 1-anthryloxy and 1-phenanthryloxy groups.
  • R" is a heterocyclic group, it desirably possesses 5 or 6 ring atoms. Of these atoms, it is preferable that 1 to 3 are nitrogen and/or oxygen and/or sulphur hetero- atoms. Where there are 3 hetero-atoms, it is desirable that at least one (and more desirably 2) be a nitrogen atom and one or two should be nitrogen, oxygen or sulphur atoms (and, where there are two, they may be the same or different).
  • hetero-atoms When it is desired to include two hetero-atoms, these may be the same or different and they are nitrogen and/or oxygen and/or sulphur atoms; however, more preferably one is a nitrogen atom and the other is a nitrogen, oxygen or sulphur atom.
  • Such groups may be unsubstituted or they may be substituted by at least one (preferably from 1 to 3) of substituents (c), as defined and exemplified above.
  • unsubstituted groups include furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, thiazolinyl, isothiazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, pyrazolidinyl, piperazinyl, dioxopiperazinyl, tetrahydropyrimidinyl, dihydropyridazinyl, morpholinyl, tlii
  • R" is a cycloalkyl group
  • the latter desirably possesses from 3 to 8 carbon atoms, and may be unsubstituted or substituted. If substituted, it may be substituted by at least one of substituents (c), as defined above and exemplified below. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl groups and substituted analogues thereof.
  • R" represents a cycloalkenyl group
  • the latter desirably has from 5 to 8 carbon atoms, and also may be unsubstituted or substituted.
  • substituents (c) include 1-cyclopenten-l- yl, 2-cyclopenten-l-yl, 1-cyclohexen-l-yl, 2-cyclohexen-l-yl, 3-cyclohexen-l-yl, 1- cylohepten-1-yl, 2-cyclohepten-l-yl, 1-cycloocten-l-yl and 3-cycloocten-l-yl groups and substituted analogues thereof.
  • substituents examples include: Hydroxy groups; chlorine, fluorine, bromine and iodine atoms; cyano group; mercapto groups; carboxy groups; alkoxy groups which have from 1 to 20 carbon atoms and which are unsubstituted or are substituted by at least one alkoxy group having from 1 to 4 carbon atoms and/or alkylthio group having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, methoxymethoxy, 1-methoxyethoxy, 2-methoxy ethoxy, butoxymethoxy, 2- butoxyethoxy, 3-ethoxypropoxy, 3 -methyl butoxy, 2,2-dimethylpropoxy, 1,1- dimethylpropoxy, hexyloxy, 1-methylpentyloxy, 4-methylpenty
  • substituents (b) examples include: alkyl groups having from 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 3-methylbutyl, 2,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 4-methylpentyl, heptyl, 1 -methylhexyl, 2- methylhexyl, 5 -methylhexyl, 3-ethylpentyl, octyl, 2-methylheptyl, 6-methylheptyl, 2- ethylhexyl, 2-ethyl-3-methylpentyl and 3-ethyl-2-methylpentyl groups; and hydroxy, alkoxy, aryl, aryloxy, aliphatic
  • Preferred classes of compounds of the present invention include those compounds of formula (I) in which among of Ri, R 2 , R 3 , R 4 , R 5 , R ⁇ R7, Rg, R9 and Rio at least one of them represents a group of formula R"-CO-, wherein the group represented by R" is selected from: unsubstituted alkyl, alkenyl, or alkynyl groups having from 6 to 22 carbon atoms; substituted alkyl " , alkenyl, or alkynyl groups having from 6 to 22 carbon atoms and substituted by at least one of substituents: such as hydroxy groups, protected hydroxy groups, amino groups, protected amino groups, groups of formula -NR 3 R 4 , wherein:
  • R 3 and R 4 are the same or different and each represents an alkyl group having from 1 to 4 carbon atoms, an alkylcarbonyl group having a total of from 2 to 5 carbon atoms, a benzoyl group, a substituted benzoyl group in which the substituents are selected from substituents (b) as defined above; mercapto groups, protected mercapto groups, alkoxy groups having from 1 to 8 carbon atoms, alkylthio groups having 1 or 2 carbon atoms, phenyl groups, substituted phenyl groups in which the substituents are selected from substituents (b) as defined above, phenoxy groups, substituted phenoxy groups in which the substituents are selected from substituents (b) as defined above, cyano groups, alkylcarbonyl groups having from 2 to 9 carbon atoms, benzoyl groups, carbamoyloxy groups, heterocyclic groups having 5 or 6 ring atoms, of which 1 is a nitrogen and/or oxygen and/or
  • More preferred classes of compounds of the present invention include those compounds of formula (I), R 1 , R 2 , R 3 , R t , R 5 , R O , R7, R S5 R 9 and R 10 that are hydrogen or methoxy and at least one of them represents a group of formula R" -CO-, wherein the group represented by R" is selected from: unsubstituted alkyl, alkenyl, or alkynyl groups having from 3 to 25 carbon atoms; substituted alkyl, alkenyl, or alkynyl groups having from 3 to 25 carbon atoms and substituted by at least one of substituents: hydroxy groups, protected hydroxy groups, amino groups, protected amino groups, carboxy groups, protected carboxy groups, mercapto groups, protected mercapto groups, alkoxy groups having from 1 to 8 carbon atoms and alkylthio groups having 1 or 2 carbon atoms.
  • Various embodiments of the present invention include compounds of formula 1, wherein R b R 5 , R 6 , and R 7 are H; R 2 is OMe, -X-CO-R" (wherein X and R" are, independently, as defined herein) or, together with R 3 , forms -OCH 2 -O; R 3 is OMe or, together with R 2 , forms -OCH 2 -O; R 4 and Rs are OMe; R 9 is OMe, or -X-CO-R" (wherein X and R" are, independently, as defined herein); and Rio is H or -X-CO-R" (wherein X and R" are, independently, as defined herein).
  • Preferred compounds useful in the embodiments of the present invention as described herein include:
  • R 1 , R 5 , R 6 , R 7 and Rio are H, wherein R 2 , R 3 , R 4 and Rs are OMe 5 and wherein R 9 is -X-CO-R",
  • R" is an unsubstituted or a substituted alkyl, alkenyl or aryl group comprising 5-21 carbon atoms (with the alky and alkenyl being most preferred) and, desirably, does not include N
  • X is O, S or NH, with the proviso that when X is O 5 R" is not an optionally substituted 9-fluorenyl or 9-xanthenyl.
  • X is O and/or R" is one of
  • R h R 5 , R 65 R 7 and Ri 0 are H; wherein R 3 , R 4 , Rg, R 9 are OMe, and wherein R 2 is -X-CO-R", R" is an unsubstituted or a substituted alkyl, alkenyl or aryl group comprising 2-21, and more desirably 5-21, carbon atoms(with the alky and alkenyl being most preferred), and X is O 5 S or NH. Of these compounds, it is more preferable if X is O and/or R" is one of-CH 2 (CH 2 ) 3 CH 3 ,
  • Preferred compounds include those in which R" comprises 2-21, and more preferably 5-21, carbon atoms and/or does not include N;
  • Preferred compounds include those in which R" comprises 2-21, and more preferably 5-21, carbon atoms and/or does not include N; (d) compounds of the formula:
  • R 1 , R 5 , R 6 and R 7 are H; wherein R 2 , R 3 , R 4 and R 8 are OMe; and wherein Rg and Rio are -X-CO-R", R" is an unsubstituted or a substituted alkyl, alkenyl or aryl group comprising 2-21, and desirably 5-12, carbon atoms (with the alky and alkenyl being most preferred), and X is O, S or NH. Of these compounds, it is more preferable if X is O and/or R" is one of-CH 2 (CH 2 ) 3 CH 3 ,
  • Preferred compounds include those in which R" comprises 2-21, and more preferably 5-21, carbon atoms and/or does not include N; and (e) compounds of the formula:
  • Ri, Rs, R 6 , R 7 and R 10 are H; wherein R3, R 4 and R 8 are OMe; and wherein R 2 and R 9 are -X-CO-R", R" is an unsubstituted or a substituted alkyl, alkenyl or aryl group comprising 2-21, and desirably 5-21, carbon atoms (with the alky and alkenyl being most preferred), and X is O, S or NH.
  • Preferred compounds include those in which R" comprises 2-21, and more preferably 5-21, carbon atoms and/or does not include N. [0046] In any of the compounds of the present invention which include a hydroxy, amino, mercapto or carboxy group, any of these groups may be protected by a suitable protecting group.
  • protecting group is on a compound intended for use merely as a chemical intermediate, its nature is not critical to the invention; and any of the well known protecting groups may be employed. Where the resulting compound is intended for therapeutic use, the protecting group should be pharmaceutically acceptable.
  • hydroxy-protecting groups include: formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl.
  • the most preferred classes of compounds of the present invention include those compounds of formula (I), wherein Ri, R 2 , R 3 , R 4 , Rs, R ⁇ 5, R7 > Rs 5 Rg and R 1 O are hydrogen or methoxy and at least one of them represents a group of formula R"-CO-, wherein the group represented by R" is selected from: unsubstituted alkyl, alkenyl, or alkynyl groups having from 7 to 21 carbon atoms; preferably the natural or unnatural fatty acids.
  • the compounds of the invention may contain asymmetric carbon atoms and/or carbon-carbon double bonds and can, therefore, form optical and/or cisl trans isomers. Although these are all referred to herein by a single formula, the present invention envisages both mixtures of the isomers as well as the individual isolated isomers. [0050] Many of the compounds of the present invention have anti -tumor activity, as referred to herein. Others may be of value as intermediates in the preparation of other compounds of the present invention, which may have greater relative activity. [0051] Examples of specific compounds of the present invention are those compounds of formula (I), as described above, in which R of formula (II) are defined in the following Table 1.
  • the lipophilic combretastatin analogs are preferred:
  • Fatty acids as constituents of phospholipids, make up the bulk of cell membranes. Due to their lipophilic nature, fatty acids can easily partition into and interact with the cell membrane in a non-toxic way. In general, increased lipophilicity has been suggested as a mechanism for enhancing intestinal uptake of drugs into the lymphatic system, thereby enhancing the entry of the conjugate into the brain and also thereby avoiding first-pass metabolism of the conjugate in the liver.
  • the type of lipophilic molecules employed have included phospholipids, non-naturally occurring branched and unbranched fatty acids, and naturally occurring branched and unbranched fatty acids ranging from as few as 4 carbon atoms to more than 30 carbon atoms.
  • Fatty acids of specific types are of considerable interest both for the maintenance of healthy tissue and in the treatment of various diseases. Some fatty acids are of interest in themselves, some because they give rise to particular metabolites such as prostaglandins or other oxygenated derivatives, and some for both reasons. Among them, are the essential fatty acids (EFAs) not made by the body and therefore constituting essential nutrients. Among the EFAs of particular interest for both reasons are gamma- linolenic acid (GLA), dihomogammalinolenic acid (DGLA) and eicosapentaenoic acid (EPA).
  • GLA gamma- linolenic acid
  • DGLA dihomogammalinolenic acid
  • EPA eicosapentaenoic acid
  • DGLA is an important component of cell membranes and is also the precursor of prostaglandin Ei (PGEi); PGEi has many desirable effects being an antithrombotic, antiinflammatory, vasodilator, immunomodulating and cholesterol lowering agent.
  • GLA is an immediate precursor of DGLA and is rapidly converted to DGLA within the body.
  • EPA is also a component of cell membranes and is a precursor of PGE 3 which has actions similar to those of PGEi.
  • a further fatty acid which is of particular interest as a component of cell membranes is docosahexaenoic acid (DHA), which is also an important constituent of the brain.
  • DHA docosahexaenoic acid
  • 6,602,902 disclosed DHA- pharmaceutical agent conjugates to improve tissue selectivity relative to the unconjugated pharmaceutical agents.
  • the conjugates in general, render the activity of these compounds selective for colon tissue, breast tissue and central nervous system tissue.
  • Fatty acids previously have been conjugated with drugs to help the drugs as conjugates cross the blood brain barrier.
  • a major goal in the pharmacological arts has been the development of methods and compositions to facilitate the specific delivery of therapeutic and other agents to the appropriate cells and tissues that would benefit from such treatment, and the avoidance of the general physiological effects of the inappropriate delivery of such agents to other cells or tissues of the body.
  • the conjugate be of a single fatty acid molecule and the covalent attachment be directly to the combretastatin derivatives through a linkage or directly conjugating to the combretastatin skeleton. It was postulated that the lipid molecule interacted with the phospholipid membrane to act as a distill anchor for the receptor ligand in the membrane micro environment of the receptor. [0059]
  • the preparation of combretastatin A-4 is illustrated in Scheme 1. The synthesis of the stilbenes using the Perkin condensation (Perkin, W. H. J. Chem. Soc. 1868, 21, 181; Perkin, W. H. J. Chem. Soc, 1877, 31, 388.), described by Letcher et al.
  • the compounds of the present invention may be prepared by a variety of methods well known for preparing acylated compounds from the corresponding hydroxy compound.
  • acylation products as in formula (I) of the present invention are prepared by reaction of a compound of fo ⁇ nula (II):
  • R 3 ' represents any of the groups or atoms represented by R" or any such group in which any active group or atom is protected, and R" is as defined above or with a reactive derivative thereof, and, if required, removing any protecting group, to give said compound of formula (I).
  • a carboxylic acid of formula (IV) is used in the form of the free acid
  • the reaction is preferably effected in the presence of a suitable condensation agent, for example l,r-oxalyldiimidazole, 2,2'-dipyridyl disulphide, N 9 N'- dicyclohexylcarbodiimide, N,N'-disuccinimidyl carbonate, N,N'-bis(2-oxo-3- oxazolidinyl)phosphinic chloride, N,N'-carbodiimidazole, N,N'-disuccinimidyl oxalate, N,N'-diphthalimide oxalate, N,N'-bis(norbornenylsuccinimidyl) oxalate, 1,1'- bis(benzotriazolyl)oxalate, l,r-bis(6-chlorobenzotriazolyl) oxa
  • the reaction is preferably conducted in the presence of an inert solvent.
  • an inert solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aliphatic hydrocarbons, such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, especially aromatic and aliphatic hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and the dichlorobenzenes; esters, such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane.
  • aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether
  • aromatic hydrocarbons such as benzene, toluene and
  • ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone
  • nitro compounds which may be nitroalkanes or nitroaranes, such as nitroethane and nitrobenzene
  • nitriles such as acetonitrile and isobutyronitrile
  • amides which may be fatty acid amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide
  • sulphoxides such as dimethyl sulphoxide and sulpholane.
  • the reaction may take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it was found convenient to cany out the reaction at a temperature of from 0 0 C to 100 0 C.
  • the compound of the present invention may be obtained by reaction of a compound of formula (III) as defined above with one and more equivalents of a carboxylic acid and a condensation agent or of a reactive derivative of the carboxylic acid.
  • Any acid can be used for the invention to obtain the desired product, such as aliphatic acids, aromatic carboxylic acids, and heterocyclic carboxylic acids, preferably, the fatty acids.
  • These acids may contain one or more unsaturated bonds in the molecule and carry one or more substituents such as halogen atoms, amino groups and hydroxyl groups, such as various kinds of fart)' acid and amino acids.
  • the illustrative examples are fatty acids with 5 to 30 carbons and their derivatives.
  • Unbranched, naturally occurring fatty acids embraced by aspects of the invention include propionic acid (C3), butyric acid (C4), valeric acid (C5), hexanoic acid
  • C6 4-methylhexanoic acid (C6), octanoic acid (C8), decanoic acid (ClO), lauric acid
  • C 12 myristic acid (C 14), palmitic acid (C 16), palmitoleic acid (C 16), stearic acid
  • CIS oleic acid
  • CIS vaccenic acid
  • CIS linoleic acid
  • CIS ⁇ -linolenic acid
  • CIS eleostearic acid
  • C 18 6-linolenic acid
  • C20 cis-l 1-eicosenoic acid
  • C20 11,14-eicosadienoic acid
  • C20 cis-S,l 1,14-eicosatrienoic acid (20)
  • C28 triacontanoic acid
  • Highly preferred unbranched, naturally occurring fatty acids are those with between 12 and 22 carbon atoms.
  • Examples of reactive derivatives of the carboxylic acid of formula (IV) include: acid halides, such as the acid chloride and the acid bromide; and acid anhydrides.
  • acid halides such as the acid chloride and the acid bromide
  • acid anhydrides include: acid halides, such as the acid chloride and the acid bromide; and acid anhydrides.
  • the reaction is preferably carried out in the presence of an inert organic solvent, or in the absence of an inert organic solvent by using an excess of the acid anhydride.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; and ethers, such as dioxane, tetrahydrofuran and diethylene glycol dimethyl ether.
  • the reaction may be carried out with a compound in Formula (III), 2 to 10 molar equivalent of the acid anhydride, and a base (such as tetraethyl amine and pyridine).
  • a base such as tetraethyl amine and pyridine.
  • any anhydrides can be used for the invention to obtain the desired product in Formula (I), such as aliphatic, aromatic carboxylic, and heterocyclic carboxylic anhydride.
  • the anhydride can be commercial available, or the anhydride can be prepared from the corresponding acid with the general synthetic method in the prior art.
  • the reaction is preferably conducted in an inert organic solvent in the presence of an acid binding agent.
  • the acid binding agent may be any such compound which binds to an acid and does not interfere with the reaction, and examples include: alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as sodium carbonate and potassium carbonate; and organic bases, such as triethylamine, pyridine, 4-dimethylaminopyridine and 1-methylimidazole.
  • the reaction is carried out with the corresponding acid chloride in the presence of acid binding agent in anhydrous solvent.
  • solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as chloroform, methylene chloride and trichloroethane; ethers, such as diethyl ether, tetrahydrofuran and dioxane; aliphatic dialkylamides, which may be fatty acid amides, such as dimethylformamide and dimethylacetamide; nitriles, such as acetonitrile; ketones, such as acetone; dimethyl sulphoxide; and pyridine.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons especially halogenated aliphatic hydrocarbons, such as chloroform, methylene chloride and trichloroethane
  • ethers such as diethyl ether, tetrahydrofuran
  • any acid chloride can be used for the invention to obtain the desired product in Formula (III), such as aliphatic, aromatic carboxylic, and heterocyclic carboxylic acid chloride.
  • the acid chloride can be commercial available or, the acid chloride can be prepared from the corresponding acid with the general synthetic method in the prior art.
  • the acid chloride derivative of the fatty acid can be prepared by reacting the pure fatty acid with thionyl chloride.
  • the combretastatin fatty acid ester can be made by mixing the fatty acid chloride with combretastatin in the presence of dichloromethane and pyridine. After workup, the residue can then be subjected to column chromatography. Other methods of preparation may be used by those skilled in the art.
  • the desired compound of formula (I) can be obtained by its removal, if necessary.
  • the reaction employed will, as is well known in the art.
  • a silyl group is employed as the hydroxy-protecting group, it can generally be removed by treatment with a compound capable of forming fluorine anions, such as tetrabutylammonium fluoride.
  • the reaction is preferably carried out in the presence of a solvent.
  • a solvent There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • the compounds of the present invention may be prepared by a variety of methods well known for preparing acylated compounds from the corresponding hydroxy compound.
  • compounds of formula (I) may be prepared by reacting a compound of formula (III):
  • R 3 ' represents any of the groups or atoms represented by R" or any such group in which any active group or atom is protected, and R" is as defined above or with a reactive derivative thereof, and, if required, removing any protecting group, to give said compound of formula (I).
  • reaction of a compound of formula (III) with a compound of formula (V) can be carried out by methods known in the art.
  • the reaction is preferably conducted in the presence of an inert solvent.
  • an inert solvent There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aliphatic hydrocarbons, such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, especially aromatic and aliphatic hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, ethyl acetate, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane.
  • aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons especially aromatic and aliphatic hydrocarbons, such as methylene chloride, chloroform, carbon tetrachlor
  • Dimethoxyethane diethylene glycol dimethyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, formamide, dimethylformamide, dimethylacetamide, dimethyl and sulphoxide.
  • the reaction may take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it was found convenient to cany out the reaction at a temperature of from O 0 C to 100 0 C.
  • the reaction of a compound of fo ⁇ nula (III) with a compound of formula (VI) may be canned out by methods known in the art.
  • the reaction is preferably conducted in an inert organic solvent in the presence of an acid binding agent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as chloroform, methylene chloride and trichloroethane; ethers, such as diethyl ether, tetrahydrofuran and dioxane; aliphatic dialkylamides, which may be fatty acid amides, such as dimethylformamide and dimethylacetamide; nitriles, such as acetonitrile; ketones, such as acetone; dimethyl sulphoxide; and pyridine.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons especially halogenated aliphatic hydrocarbons, such as chloroform, methylene chloride and trichloroethane
  • ethers such as diethyl ether, tetrahydrofur
  • the acid binding agent may be any such compound which binds to an acid and does not interfere with the reaction, and examples include: alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as sodium carbonate and potassium carbonate; and organic bases, such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and 1-methylimidazole.
  • alkali metal hydroxides such as sodium hydroxide and potassium hydroxide
  • alkali metal carbonates such as sodium carbonate and potassium carbonate
  • organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and 1-methylimidazole.
  • the reaction may take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it was found convenient to carry out the reaction at a temperature of from -10 0 C to 100 0 C.
  • X' is chloride, imidazole, or 4-nitrophenyloxy
  • Y is OH, NH 2 , or SH, with R 3 ' representing any of the groups or atoms represented by R" or any such group in which any active group or atom is protected, and R" is as defined above or with a reactive derivative thereof, and, if required, removing any protecting group, to give said compound of formula (I).
  • the intermediates of Formula (VII) can be prepared by the reaction of a compound in Formula (III) with phosgene, triphosgen, diimidazolecabonate, or A- nitrophenyl chlorformate in the presence of a base, preferably an organic base such as triethylamine, in an inert organic solvent such as dichloromethane.
  • a base preferably an organic base such as triethylamine
  • an inert organic solvent such as dichloromethane.
  • the reaction is usually carried out in a temperature range of -60° C to 90° C, most commonly at around ambient temperature.
  • reaction of a compound of formula (VII) with a compound of formula (VIII) can be earned out by methods known in the art.
  • the reaction is preferably conducted in an inert organic solvent, or in the presence of an acid binding agent.
  • an inert organic solvent or in the presence of an acid binding agent.
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as chloroform, methylene chloride and trichloroethane; ethers, such as diethyl ether, tetrahydrofuran and dioxane; aliphatic dialkylamides, which may be fatty acid amides, such as dimethylformamide and dimethylacetamide; nitriles, such as acetonitrile; ketones, such as acetone; dimethyl sulphoxide; and pyridine.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons especially halogenated aliphatic hydrocarbons, such as chloroform, methylene chloride and trichloroethane
  • ethers such as diethyl ether, tetrahydrofur
  • the acid binding agent may be any such compound which binds to an acid and does not interfere with the reaction, and examples include: alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as sodium carbonate and potassium carbonate; and organic bases, such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and 1- methylimidazole.
  • alkali metal hydroxides such as sodium hydroxide and potassium hydroxide
  • alkali metal carbonates such as sodium carbonate and potassium carbonate
  • organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and 1- methylimidazole.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. Ln general, we find it convenient to carry out the reaction at a temperature of from -10 0 C to 100 0 C.
  • hydroxy-protecting, amino-protecting group, mercapto-protecting or carboxy-protecting group need to be removed to generate the desired products in Formula (I), it can be carried out with the methods in the prior art. See Greene et al., Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, 1999.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent, and any solvent commonly used for hydrolysis reactions may equally be used here.
  • suitable solvents include: water; and mixtures of water with an alcohol, such as methanol, ethanol or propanol, or with an ether, such as tetrahydrofuran or dioxane.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the compounds of the present invention may be administered as a pharmaceutical composition containing the compounds and a pharmaceutically acceptable earner or diluent.
  • the active materials can also be mixed with other active materials which do not impair the desired action and/or supplement the desired action.
  • the active materials according to the present invention can be administered by any acceptable route including, but not limited to, orally, parenterally, intravenously, intradermal Iy, subcutaneously, through an inhaler or topically, in liquid or solid form.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • the tablets, pills, capsules and the like may contain the following ingredients: a binder such as macrocrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, corn starch and the like; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added.
  • a binder such as macrocrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, corn starch and the like
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin or flavoring agent such as peppermint, methyl salicylate
  • dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically or veterinarially pure and non-toxic in the amounts used.
  • the active ingredient may be incorporated into a solution or suspension.
  • the solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as ethylenediaminetetraacetic acid
  • the pharmaceutical forms suitable for injectable use include sterile solutions, dispersions, emulsions, and sterile powders.
  • the final form must be stable under conditions of manufacture and storage. Furthermore, the final pharmaceutical form must be protected against contamination and must, therefore, be able to inhibit the growth of microorganisms such as bacteria or fungi.
  • a single intravenous or intraperitoneal dose can be administered. Alternatively, a slow long te ⁇ n infusion or multiple short term daily infusions may be utilized, typically lasting from 1 to 8 days. Alternate day or dosing once every several days may also be utilized.
  • Sterile, injectable solutions are prepared by incorporating a compound in the required amount into one or more appropriate solvents to which other ingredients, listed above or known to those skilled in the art, may be added as required.
  • Sterile injectable solutions are prepared by incorporating the compound in the required amount in the appropriate solvent with various other ingredients as required. Sterilizing procedures, such as filtration, then follow.
  • dispersions are made by incorporating the compound into a sterile vehicle which also contains the dispersion medium and the required other ingredients as indicated above. In the case of a sterile powder, the preferred methods include vacuum drying or freeze drying to which any required ingredients are added.
  • Suitable pharmaceutical earners include sterile water; saline, dextrose; dextrose in water or saline; condensation products of castor oil and ethylene oxide combining about 30 to about 35 moles of ethylene oxide per mole of castor oil; liquid acid; lower alkanols; oils such as com oil; peanut oil, sesame oil and the like, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxymethylcellulose; sodium alginate; poly(vinylpyrolidone); and the like, alone, or with suitable dispensing agents such as lecithin; polyoxyethylene stearate; and the like.
  • a suspending agent for example, sodium carboxymethylcellulose; sodium alginate; poly(vinylpyrolidone); and
  • the carrier may also contain adjuvants such as preserving stabilizing, wetting, emulsifying agents and the like together with the penetration enhancer.
  • adjuvants such as preserving stabilizing, wetting, emulsifying agents and the like together with the penetration enhancer.
  • the final form must be sterile and must also be able to pass readily through an injection device such as a hollow needle.
  • the proper viscosity may be achieved and maintained by the proper choice of solvents or excipients.
  • the use of molecular or particulate coatings such as lecithin, the proper selection of particle size in dispersions, or the use of materials with surfactant properties may be utilized.
  • compositions of combretastatin derivative and methods useful for the in vivo delivery of combretastatin derivatives in the form of nanoparticles which are suitable for aforesaid any route administrations.
  • U. S. Patent Nos. 5,916,596, 6,506,405 and 6,537,579 teach the preparation of nanoparticles from the biocompatible polymers, such as albumin. These are incorporated by reference in there entirety.
  • methods for the formation of nanoparticles of present invention by a solvent evaporation technique from an oil-in- water emulsion prepared under conditions of high shear forces (e.g., sonication, high pressure homogenization, or the like).
  • combretastatin derivative is dissolved in a water miscible organic solvent (e.g., a solvent having greater than about 10% solubility in water, such as, for example, ethanol) is added to the oil phase at a final concentration in the range of about l%-99% v/v, more preferably in the range of about 5%-25% v/v of the total organic phase.
  • a water miscible organic solvent e.g., a solvent having greater than about 10% solubility in water, such as, for example, ethanol
  • the water miscible organic solvent can be selected from such solvents as ethyl acetate, ethanol, tetrahydrofuran, dioxane, acetonitrile, acetone, dimethyl sulfoxide, dimethyl formamide, methyl pyrrolidinone, and the like.
  • the mixture of water immiscible solvent with the water miscible solvent is prepared first, followed by dissolution of the pharmaceutically active agent in the mixture.
  • a protein e.g., human serum albumin
  • Protein is added (into the aqueous phase) to act as a stabilizing agent for the formation of stable nanodroplets.
  • Protein is added at a concentration in the range of about 0.05 to 25% (w/v), more preferably in the range of about 0.5%-5% (w/v).
  • no surfactant e.g. sodium lauryl sulfate, lecithin, tween 80, pluronic F-68 and the like
  • a sufficient amount of the first organic solvent e.g. chloroform
  • the first organic solvent e.g. chloroform
  • a separate, measured amount of the organic phase (which now contains the pharmacologically active agent, the first organic solvent and the second organic solvent) is added to the saturated aqueous phase, so that the phase fraction of the organic phase is between about 0.5%- 15% v/v, and more preferably between 1% and 8% v/v.
  • An emulsion is formed by homogenization under high pressure and high shear forces. Such homogenization is conveniently carried out in a high pressure homogenizer, typically operated at pressures in the range of about 3,000 up to 30,000 psi. Preferably, such processes are earned out at pressures in the range of about 6,000 up to 25,000 psi.
  • the resulting emulsion comprises very small nanodroplets of the nonaqueous solvent (containing the dissolved pharmacologically active agent) and very small nanodroplets of the protein stabilizing agent.
  • Acceptable methods of homogenization include processes imparting high shear and cavitation such as high pressure homogenization, high shear mixers, sonication, high shear impellers, and the like.
  • a colloidal system composed of protein coated nanoparticles of pharmacologically active combretastatin derivative and protein.
  • Acceptable methods of evaporation include the use of rotary evaporators, falling film evaporators, spray driers, freeze driers, and the like.
  • a colloidal dispersion system (pharmacologically active agent and protein) in the form of nanoparticles of about 10-500 nm is obtained.
  • extremely small nanoparticles i.e., particles in the range of about 10 nm-200 nm diameter are obtained that can be sterile-filtered.
  • the preferred size range of the particles is between about 50 nm-150 nm, depending on the formulation and operational parameters.
  • Colloidal systems prepared in accordance with the present invention may be further converted into powder form by removal of the water, e.g., by lyophilization at a suitable temperature-time profile.
  • the protein e.g., human serum albumin
  • the powder is easily reconstituted by addition of water, saline or buffer, without the need to use such conventional cryoprotectants as mannitol, sucrose, glycine, and the like. While not required, it is of course understood that conventional cryoprotectants may be added to invention formulations if so desired.
  • the polymeric shell containing solid or liquid cores of pharmaco logically active agent allows for the delivery of high doses of the pharmacologically active agent in relatively small volumes. This minimizes patient discomfort at receiving large volumes of fluid and minimizes hospital stay.
  • the walls of the polymeric shell or coating are generally completely degradable in vivo by proteolytic enzymes (e.g., when the polymer is a protein), resulting in no side effects from the delivery system as is the case with current formulations.
  • biocompatible materials may be employed in the practice of the present invention for the formation of a polymeric shell.
  • Several biocompatible materials may be employed in the practice of the present invention for the formation of a polymeric shell.
  • naturally occurring biocompatible materials such as proteins, polypeptides, oligopeptides, polynucleotides, polysaccharides (e.g., starch, cellulose, dextrans, alginates, chitosan, pectin, hyaluronic acid, and the like), lipids, and so on, are candidates for such modification.
  • biocompatible materials naturally occurring or synthetic proteins
  • suitable biocompatible materials include albumin, insulin, hemoglobin, lysozyme, immunoglobulins, a-2-macroglobulin, fibronectin, vitronectin, fibrinogen, casein and the like, as well as combinations of any two or more thereof.
  • synthetic polymers are also good candidates for preparation of the drug formulation.
  • polyalkylene glycols e.g., linear or branched chain
  • polyvinyl alcohol polyacrylates, polyhydroxyethyl methacrylate, polyacrylic acid, polyethyloxazoline, polyacrylamides, polyisopropyl acrylamides, polyvinyl pyrrolidinone, polylactide/glycolide and the like, and combinations thereof, are good candidates for the biocompatible polymer in the invention formulation.
  • biocompatible materials may also be employed in several physical forms such as gels, crosslinked or uncrosslinked to provide matrices from which the pharmacologically active ingredient, for example paclitaxel, may be released by diffusion and/or degradation of the matrix.
  • Temperature sensitive materials may also be utilized as the dispersing matrix for the invention formulation.
  • the camptothecin diester may be injected in a liquid formulation of the temperature sensitive material (e.g., copolymers of polyacrylamides or copolymers of polyalkylene glycols and polylactide/glycolides) which gel at the tumor site and provide slow release of combretastatin derivatives.
  • Particles of biologic substantially completely contained within a polymeric shell, or associated therewith, prepared as described herein, are delivered neat, or optionally as a suspension in a biocompatible medium.
  • This medium may be selected from water, buffered aqueous media, saline, buffered saline, optionally buffered solutions of amino acids, optionally buffered solutions of proteins, optionally buffered solutions of sugars, optionally buffered solutions of carbohydrates, optionally buffered solutions of vitamins, optionally buffered solutions of synthetic polymers, lipid-containing emulsions, and the like.
  • the polymeric shell can optionally be modified by a suitable agent, wherein the agent is associated with the polymeric shell through an optional covalent bond.
  • Covalent bonds contemplated for such linkages include ester, ether, urethane, diester, amide, secondary or tertiary amine, phosphate ester, sulfate ester, and the like bonds.
  • Suitable agents contemplated for this optional modification of the polymeric shell include synthetic polymers (polyalkylene glycols (e.g., linear or branched chain polyethylene gfycol), polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylic acid, polyethyloxazoline, polyacrylamide, polyvinyl pyrrolidinone, and the like), phospholipids (such as phosphatidyl choline (PC) 5 phosphatidyl ethanolamine (PE), phosphatidyl inositol (PI) 5 sphingomyelin, and the like), proteins (such as enzymes, antibodies, and the like), polysaccharides (such as starch, cellulose, dextrans, alginates, chitosan, pectin, hyaluronic acid, and the like), chemical modifying agents (such as pyridoxal 5'-phosphate, derivatives of pyridoxal, dialdehydes, diaspirin
  • the prepared nanoparticle with this invention can be administered by any acceptable route including, but not limited to, orally, intramuscularly, transdermally, intravenously, through an inhaler or other air bome delivery systems, and the like.
  • the continuous phase preferably comprises an aqueous solution of tonicity modifiers, buffered to a pH below 7, more preferably below 6.
  • the prepared nanoparticles of this invention may be enclosed in a hard or soft capsule, may be compressed into tablets, or may be incorporated with beverages, food or otherwise into the diet. Capsules may be formulated by mixing the nanoparticle with a pharmaceutical diluent which is inert and inserting this mixture into a hard gelatin capsule having the appropriate size. If soft capsules are desired a slurry of the compound with an acceptable vegetable, light petroleum, or other inert oil can be encapsulated by machine into a gelatin capsule.
  • the percentage of the final composition and the preparations may, of course, be varied and may conveniently range between 1 and 90% of the weight of the final fo ⁇ n, e.g., tablet. The amount in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Preferred compositions according to the current invention are prepared so that an oral dosage unit form contains between about 5 to about 50% by weight (% w) in dosage units weighing between 50 and 1000 mg.
  • the lipophilic compounds in this invention will be more easily passed through the cell membranes and distributed tissues and cross the blood brain barrier.
  • the tissue can be tissue of the Blood and Blood Forming system: including platelets, blood vessel wall, and bone marrow; Cardiovascular system: including heart and vascular system; Digestive and excretory system: including alimentary tract, biliary tract, kidney, liver, pancreas and urinary tract; Endocrine system: including adrenal gland, kidney, ovary, pituitary gland, renal gland, salivary gland, sebaceous gland, testis, thymus gland and thyroid gland; Muscular system: including muscles that move the body.
  • Reproductive System including breast, ovary, penis and uterus;
  • Respiratory system including bronchus, lung and trachea;
  • Skeletal system including bones and joints;
  • Tissue, fiber, and integumentary system including adipose tissue, cartilage, connective tissue, cuticle, dermis, epidermis, epithelium, fascia, hair follicle, ligament, bone marrow, melanin, melanocyte, mucous membrane, skin, soft tissue, synovial capsule and tendon.
  • the combretastatin derivatives of the present invention can be used in warm-blooded animals, including humans, as an anti-tumor agent against these kinds of tumoral diseases.
  • the compounds may be administered by any convenient route, for example by parenteral administration methods, such as intravenous injection, subcutaneous injection, intramuscular injection or by suppositories; or oral administration by using, for example, capsules, powders or granules.
  • parenteral administration methods such as intravenous injection, subcutaneous injection, intramuscular injection or by suppositories
  • oral administration by using, for example, capsules, powders or granules.
  • the dosage to an adult human may vary depending on the nature of the disease, the route of administration and the administration frequency and period. However, a daily dosage of from 1 to 100 mg in a single dose or in divided doses may be given.
  • compositions for injection can be provided in the form of ampoules, each containing a unit dose amount, or in the form of a container containing multiple doses.
  • the composition may sometimes contain additives such as emulsifiers, stabilizers and/or dispersants, and may often be in the form of a powder which is intended to be dissolved by the pharmacist in a suitable solvent, such as a pyrogen-free sterilized aqueous solvent, just before use.
  • a suitable solvent such as a pyrogen-free sterilized aqueous solvent
  • compositions for oral administration can be provided by means of capsules, powders, granules or syrups each containing a suitable amount of one or more of the radicicol derivatives of the present invention.
  • the compounds of the present invention are used to treat cancers which include but are not limited to tumors of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas.
  • the compounds of the present invention are used to treat cancers of the liver and biliary tree (particularly hepatocellular carcinoma), intestinal cancers, particularly colorectal cancer, ovarian cancer, small cell and non-small cell lung cancer, breast cancer, sarcomas (including fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma), neoplasms of the central nervous systems (particularly brain cancer), lymphomas (including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B- lineage large cell lymphoma, Burkitt's lymphoma, and T-
  • the antiangiogenic treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • the other component(s) of such conjoint treatment in addition to the antiangiogenic treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy.
  • Such chemotherapy may include the following categories of therapeutic agent:
  • VEGF vascular endothelial growth factor
  • RTKIs vascular endothelial growth factor receptor tyrosine kinase inhibitors
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, vorazole, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilulamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, luprolide), inl ⁇ ibitors of testosterone 5.alpha.-dihydroreductase (for example finasteride), anti-invasion agents (for example metalloproteinase inhibitors like marimastat
  • biological response modifiers for example interferon
  • antibodies for example edrecolomab
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as antimetabolites (for example antifolates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); antirumour antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic agents (for example vinca alkaloids like vincristine and taxoids like taxol, taxotere); enzymes (for example asparagina), antigen
  • the compounds defined in the present invention are of interest for their vascular damaging effects.
  • Such compounds of the invention are expected to be useful in the prophylaxis and treatment of a wide range of disease states where inappropriate angiogenesis occurs including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumors of, for example, the colon, breast, prostate, lungs and skin.
  • the compounds of formula (I) and their pharmaceutically acceptable salts, solvates or pro-drugs are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of vascular damaging agents in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • kits for the administration of the compounds, nanoparticles and compositions described herein.
  • the kits may include a unit dosage amount of at least one of the therapeutic compounds or composition as disclosed herein. Kits may further comprise suitable packaging and/or instructions for use of the compound or composition. Kits may also comprise a means for the delivery of the inventive compounds or compositions, such as a syringe for injection or other device as described herein and known to those of skill in the art.
  • kits may provide the compounds or compositions thereof and reagents to prepare a pharmaceutical composition for administration.
  • the composition may be in a dry or lyophilized form, or in a solution, particularly a sterile solution.
  • the reagent may comprise a pharmaceutically acceptable diluent for preparing a liquid formulation.
  • diluents include those known to those of skill in the art and are additionally described herein.
  • the kit may also contain a device for administration or for dispensing the compositions, including, but not limited to syringe, pipette, or other device known to those of skill. When in a wet form, the composition may be stored in an ampoule or other sterile sealed container, including those known to persons of skill in the art.
  • the kits may include other therapeutic compounds for use in conjunction with the compounds described herein.
  • the therapeutic agents are other anticancer agents. These agents may be provided in a separate form, or mixed with the compounds of the present invention, provided such mixing does not reduce the effectiveness of either the additional therapeutic agent of the compositions and formulations described herein. Similarly the kits may include additional agents for adjunctive therapy.
  • kits will include appropriate instructions for preparation and administration of the compound/composition, side effects of the compound/compositions, and any other relevant information.
  • the instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, or optical disc.
  • kits for treating an individual who suffers from or is susceptible to the conditions described herein comprising a first container comprising a dosage amount of the inventive compounds or compositions as disclosed herein, and instructions for use.
  • the container may be any of those known in the art and appropriate for storage and delivery of intravenous formulations.
  • the kit further comprises a second container comprising a pharmaceutically acceptable earner, diluent, adjuvant, etc. for preparation of the composition to be administered to the individual.
  • Kits may also be provided that contain sufficient dosages of the compounds or compositions as disclosed herein to provide effective treatment for an individual for an extended period, such as a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, S weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more.
  • Kits may also include multiple unit doses of the inventive compounds and compositions and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pha ⁇ nacies.
  • the kit may comprise appropriately packaged oral dosage forms and instructions for use.
  • the kits comprise a at last one inventive compound or a composition thereof, wherein the compound is an inventive compound listed in Tables 1 or 2.
  • This example illustrates the preparation of Compound 1.
  • a mixture of 3- hydroxy-4-methoxybenzaldehyde (9.0Og, 59.15 mmol), 3,4,5-trimethoxyphenyl acetic acid (6.0Og, 26.52 mmol), acetic anhydride (12.0 mL), and triethylamine (6.0 mL) was heated under reflux for 5 hours. After acidification with concentrated hydrochloric acid (18.0 mL), water (100 mL) was added and the mixture was extracted by ethyl acetate. The organic layer was dried by sodium sulfate and concentrated to leave a gum.
  • This example illustrates the preparation of Compound 2.
  • a solution of Compound 1 (1.0Og, 2.49 mmol) in dioxane (1OmL) and ethanol (ImL)
  • a solution of NaOH (0.50Og) in water (3 mL)
  • the solution was acidified with dilute HCl (IN, 50 mL) and a
  • This example illustrates the preparation of CA-4.
  • Compound 1 (1.61 g, 3.99 mmol) was treated with acetic anhydride (15.0 mL)-pyridine (15 mL) for 2 hours at 90 0 C and the solvents were evaporated to give a gum.
  • the resulting gum was mixed with quinoline (15 mL) and copper chromite (0.41 g, 1.30 mmol), and heated under reflux for 15 minutes under argon. Ethyl acetate was added and the product was filtered off through Celite. The filtrate was washed with dilute hydrochloric acid until pH 1 ⁇ 2, water, dried (Na 2 SO4) and concentrated to leave a residue.
  • TMs example illustrates the preparation of Compound 3.
  • thiethylamine (0.21 mL, 1.51 mmol) and the mixture was cooled to 0 0 C.
  • Hexanoly chloride (0.13 mL, 0.91 mmol) was added and the mixture was stirred at 0 0 C to room temperature overnight.
  • Ethyl acetate was added and the mixture was washed by 5% NaHCO 3 , water, dried (Na 2 SO 4 ) and concentrated to leave a residue.
  • This example illustrates the preparation of Compound 4.
  • thiethylamine (0.18 mL, 1.26 mmol) and the mixture was cooled to 0 0 C.
  • Lauroyl chloride (0.18 mL, 0.76 mmol) was added and the mixture was stirred at room temperature for 2.5 hours.
  • Ethyl acetate was added and the mixture was washed by 5% NaHCO 3 , water, dried (Na 2 SO 4 ) and concentrated to leave a residue.
  • This example illustrates the preparation of Compound 5.
  • linoleic acid (0.25 mL, 0.79 mmol)
  • DMAP catalytic amount
  • a solution of DCC (0.16 g, 0.79 mmol) in anhydrous dichloromethane (2 mL) was added to the above mixture and the resulting solution was stirred at room temperature for 2.5 hours. Hexane was added and the product was filtered off by gravity filtration.
  • This example illustrates the preparation of Compound 6.
  • oleic acid (0.21 mL, 0.66 mmol)
  • DMAP catalytic amount
  • EDC N-(3- dimethylaminopiOpyl)-N'-ethylcarbodiimide hydrochloride
  • This example illustrates the preparation of albumin nanoparticle compositions from Compound 6.
  • 30 Mg of Compound 6 (as prepared in Example 7) was dissolved in 3.0 ml methylene chloride/methanol (9/1). The solution was then added into 27.0 ml of human serum albumin solution (3% w/v). The mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer model: Tempest LQ.) in order to form a crude emulsion, and then transferred into a high-pressure homogenizer (Avestin). The emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • This example showed the in vitro growth inhibition experiments for several compounds described herein on MX-I (human breast carcinoma) cells.
  • the cytotoxicity assay was quantitated using the Promega CellTiter Blue Cell Viability Assay. Briefly, cells (5000 cells/well) were plated onto 96-well microliter plates in RPMI 1640 medium supplemented with 10% FBS and incubated at 37°C in a humidified 5% CO 2 atmosphere. After 24 h, cells were exposed to various concentrations of compound in DMSO and cultured for another 72 h. 10OuI of media were removed and 20ul of Promega CellTiter Blue reagent were added to each well and shaken to mix.
  • a standard solution of each of Compounds 3, 4, 5, and 6 was prepared at 6 mg/mL in acetonitrile. Sample solutions of each compound were then prepared by spiking the standard solution into human serum or human liver microsome to obtain a solution at 50 ⁇ g/mL. Each sample solution was aliquoted and then incubated at 37 0 C for 48 hours. The samples were retrieved as the indicated time and extracted with acetonitrile at a ratio of 1 :2, then centrifuged at 14,000 rpm for 10 min. The supernatant was injected to HPLC to obtain the percent CA4 generated from each sample with reference to time (see the Figure). The compounds in the invention can be converted to CA4 in the presence of microsome and can used as its prodrugs.

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Abstract

L'invention concerne des composés représentés par la formule (I) dans laquelle R1, R5, R6, R7 et R10 sont H, dans laquelle R2, R3, R4 et R8 sont OMe, et dans laquelle R9 est -X-CO-R', R' est un groupe alkyle, alcényle ou aryle non substitué ou substitué comprenant de 5 à 21 atomes de carbone et ne comprenant pas N, et X est O, S ou N. L'invention concerne également des composés associés, et leurs méthodes d'utilisation, en particulier dans la modulation de la croissance tumorale ou de la métastase chez un animal.
EP06837549A 2005-11-14 2006-11-14 Derives de combretastatine et methodes therapeutiques associees Withdrawn EP1976505A1 (fr)

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WO2009059448A1 (fr) * 2007-11-05 2009-05-14 Zhiquan Yong Dérivé styrène-acide et utilisation dans la fabrication de médicaments de type agent ciblé sur les vaisseaux sanguins
FR2923717B1 (fr) * 2007-11-15 2015-01-16 Caudalie Compositions de derives polyphenoliques stilbeniques et leurs applications pour lutter contre les pathologies et le veillissement des organismes vivants
EP2266546A1 (fr) 2009-06-08 2010-12-29 Advancell Advanced in Vitro Cell Technologies,S.A. Procédé pour la préparation de systèmes colloïdaux pour la livraison de composés actifs
GB201113815D0 (en) * 2011-08-10 2011-09-28 Univ Salford The Multi-photon isomerisation of transcombretastatins
CN105566100B (zh) * 2014-10-29 2018-11-02 东莞安好医药科技有限公司 一种苯乙烯酸类化合物，包含其的组合物及其应用
CN106580945B (zh) * 2015-10-14 2019-11-08 上海天氏利医药科技有限公司 一种考布他汀a4衍生物及其制剂
CN106236752A (zh) * 2016-07-29 2016-12-21 浙江大学 联合用药抗肿瘤药物、制备方法及应用
CN106242972B (zh) * 2016-07-29 2019-02-26 浙江大学 康普瑞汀药物前体、药物制剂和制备方法

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