EP1206429A2 - Stilbenes with vascular damaging activity - Google Patents

Stilbenes with vascular damaging activity

Info

Publication number
EP1206429A2
EP1206429A2 EP00951727A EP00951727A EP1206429A2 EP 1206429 A2 EP1206429 A2 EP 1206429A2 EP 00951727 A EP00951727 A EP 00951727A EP 00951727 A EP00951727 A EP 00951727A EP 1206429 A2 EP1206429 A2 EP 1206429A2
Authority
EP
European Patent Office
Prior art keywords
compounds
cis
stilbene
formula
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00951727A
Other languages
German (de)
English (en)
French (fr)
Inventor
Peter David Davis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Angiogene Pharmaceuticals Ltd
Original Assignee
Angiogene Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Angiogene Pharmaceuticals Ltd filed Critical Angiogene Pharmaceuticals Ltd
Publication of EP1206429A2 publication Critical patent/EP1206429A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds

Definitions

  • Neovascularisation is also a clinical feature of skin lesions in psoriasis, of the invasive pannus in the joints of rheumatoid arthritis patients and of atherosclerotic plaques
  • Retinal neovascularisation is pathological in macular degeneration and in diabetic retinopathy In all these diseases reversal of neovascularisation by damaging the newly-formed vascular endothelium is expected to have a beneficial therapeutic effect
  • tumour vasculature has several important advantages over a direct attack on the tumour
  • the endothelial cells of tumour vasculature are more genetically stable than those of the tumour itself and are therefore less likely to become resistant to the damaging agent
  • vascular damaging agents are able to attack a wide range of tumour types
  • tubulin-binding agents including the stilbenes combretastatin Al, combretastatin A4 (D J Chaplin et al , British J Cancer 27, S86-S88 (1996))and combretastatin A4 phosphate (D J Chaplin et al , Anticancer Research 19, 189-196, (1999)) are known to selectively damage neovasculature of solid tumours in animal models.
  • vascular-damaging stilbenes combretastatin Al, combretastatin A4 and combretastatin A4 phosphate have a 4-methoxy group in the "B" ring.
  • the compounds of the invention lack a 4-methoxy group in the ring corresponding to the "B" ring of combretastatin A4.
  • substituting alternative groups for the 4-methoxy group in the B-ring of combretastatin A4 would considerably reduce biological activity:
  • Woods et al. disclose analogues of combretastatin with reduced potency.
  • the 4-methyl compound shows 3.5 to 36-fold reduction in potency against four cell lines compared to the 4-methoxy compound.
  • R',R 2 and R 3 are each independently alkyl
  • R 4 is alkyl, haloalkyl, alkenyl, alkynyl, alkylthio, alkylsulphinyl, alkylsulphonyl or halo
  • R 5 is hydrogen, alkoxy, alkyl, alkylthio, hydroxy or halo, and the pharmaceutically acceptable salts, solvates, hydrates and prodrugs thereof.
  • alkyl alone or in combinations, means a straight or branched-chain alkyl group containing from one to seven, preferably a maximum of four, carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl and pentyl.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy.
  • halogen means fluorine, chlorine, bromine or iodine.
  • An alkenyl group may be for example an olefinic group containing from two to seven carbon atoms for example methylene, ethylene, n-propylene, i-propylene, n-butylene, i- butylene, s-butylene and t-butylene.
  • An alkynyl group may be for example an ethynyl , propynyl or butynyl group.
  • salts include pharmaceutically acceptable salts for example acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates, salts derived from inorganic bases including alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and salts derived from organic amines such as morpholine, piperidine or dimethylamine salts.
  • acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates
  • salts derived from inorganic bases including alkali metal salt
  • Prodrugs of the invention are compounds which upon administration to a mammal produce compounds of formula (1). Such prodrugs can be for example converted within the mammal by hydrolysis. Prodrugs are preferably ester derivatives of the phenolic hydroxy group contained in compounds of formula (1) such as, for example, phosphate esters, carboxylate esters, sulphate esters and carbonates.
  • Preferred compounds of the invention are those of formula 1 in which R 1 , R 2 and R 3 are all methyl, and prodrugs thereof Further preferred compounds of the invention are those of formula 1 in which R 1 , R 2 and R 3 are all methyl and R 5 is hydrogen and prodrugs thereof
  • Still further preferred compounds of the invention are those of formula 1 in which R 1 , R 2 and R 3 are all methyl, R 5 is hydrogen and R 4 is alkyl or halo and prodrugs thereof
  • Preferred prodrugs of the invention are phosphate esters Particularly preferred prodrugs of the invention are dihydrogen phosphate esters
  • compounds of formula (1) can be prepared by Wittig olefin synthesis involving reaction of a phosphonium salt of formula (2) with a strong base, for example an alkyllithium such as n-butyllithium or t-butyllithium or a metal hydride such as sodium hydride in a solvent such as an ether solvent for example diethyl ether or tetrahydrofuran or in a solvent such as a hydrocarbon solvent for example toluene at a temperature of between about -100°C to about 30°C followed by treatment with an aldehyde of formula (3) in which R 6 is a protecting group, to give an intermediate of formula (4) The synthesis of compounds of formula (1) is then completed by removal of the group R 6 .
  • a strong base for example an alkyllithium such as n-butyllithium or t-butyllithium or a metal hydride such as sodium hydride in a solvent such as an ether solvent for example diethyl
  • Suitable protecting groups R 6 include trialkylsilyl, for example t- butyldimethylsilyl, and allyl
  • R 6 is a trialkylsilyl group it may be removed, for example, by treatment with a quaternary ammonium fluoride such as tetrabutylammonium fluoride in an ether solvent such as tetrahydrofuran at a temperature of about -30°C to about 40°C conveniently at or near ambient temperature
  • R 6 is an allyl group it may be removed for example by treatment with a palladium(O) complex such as tetrakis(triphenylphosphine)Pd(0) in a solvent such as a chlorinated solvent, for example dichloromethane, at a temperature of about - 40°C to about 40°C conveniently at or near ambient temperature, in the presence of an allyl scavenger such as morpholine.
  • Aldehydes of formula (3) can be prepared by any process known to a person skilled in the art.
  • an aldehyde of formula (3) can be prepared from an alcohol of formula (5) by oxidation with a suitable oxidising agent Suitable oxidising agents include the Dess-Martin reagent and manganese dioxide Alcohols of formula (5) can be prepared by application of standard methods of organic synthesis including the selective protection of phenols of formula (6).
  • alcohols of formula (5) may be prepared, for example, by treatment of a phenol of formula (6) with a strong base, for example an alkyllithium such as n-butyllithium or t-butyllithium or a metal hydride such as sodium hydride in a solvent such as an ether solvent for example diethyl ether or tetrahydrofuran or in a solvent such as a hydrocarbon solvent for example toluene at a temperature of between about -100°C to about 40°C followed by treatment with tert- butylchlorodimethylsilane.
  • a strong base for example an alkyllithium such as n-butyllithium or t-butyllithium or a metal hydride such as sodium hydride in a solvent such as an ether solvent for example diethyl ether or tetrahydrofuran or in a solvent such as a hydrocarbon solvent for example toluene at a temperature of between about
  • Phenols of formula (6) are either known or may be prepared from known compounds using standard methods of organic synthesis.
  • Compounds of formula ( 1) may also be prepared from other compounds of formula (1) by chemical modification. Examples of such chemical modifications that may be applied are standard alkylation, halogenation, oxidation and coupling reactions. These reactions may be used to add new substituents or to modify existing substituents.
  • Prodrugs of compounds of formula (1) can be prepared by any process known to a person skilled in the art. Processes for the preparation of prodrugs of compounds of formula 1 include standard acylation, sulphation and phosphorylation reactions.
  • dihydrogen phosphate esters of compounds of formula (1) can be prepared by treatment of the corresponding di-t-butylphosphate esters with an acid, for example hydrochloric acid or trifluoroacetic acid, in a solvent such as a chlorinated solvent, for example dichloromethane, at a temperature of from about -20°C to about 40°C, conveniently at room temperature.
  • Compounds according to the invention are able to destroy tumour vasculature and vasculature that has been newly formed while leaving unaffected normal, mature vasculature.
  • the ability of the compounds to act in this way may be determined by the tests described hereinafter.
  • the compounds according to the invention are thus of particular use in the prophylaxis and treatment of cancers involving solid tumours and in the prophylaxis and treatment of diseases where inappropriate angiogenesis occurs such as diabetic retinopathy, psoriasis, rheumatoid arthritis, atherosclerosis and macular degeneration.
  • compositions for the treatment of neovascularisation which compositions contain an effective amount of a cis-stilbene or prodrugs thereof as hereinbefore defined.
  • the invention also includes the use in the preparation of a composition for the treatment of neovascularisation of a cis-stilbene or prodrugs therof as hereinbefore defined.
  • compounds of the invention may be administered in combination with radiotherapy or in combination with other anti-tumour substances for example those selected from mitotic inhibitors, for example vinblastine, vincristine, vinorelbine, paclitaxel and docetaxel; platinum derivatives for example cisplatin and carboplatin; alkylating agents, for example melphalan, chlorambucil, busulphan, ifosfamide and cyclophosphamide; antimetabolites, for example methotrexate, 5-fluorouracil, cytosine arabinoside, gemcitabine and hydroxyurea; antitumour antibiotics for example bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C, dactinomycin and mithramycin ; enzymes, for example aspariginase; topoisomerase inhibitors for example etoposide,teniposide, topotecan and
  • Such combination treatment may involve simultaneous or sequential application of the individual components of the treatment.
  • the compounds according to the invention may be administered as pharmaceutical compositions selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Such pharmaceutical compositions may take a form suitable for oral, buccal, nasal, topical, rectal or parenteral administration and may be prepared in a conventional manner using conventional excipients
  • the pharmaceutical compositions may take the form of tablets or capsules
  • Topical administration may be as an ointment or cream and rectal administration may be as a suppository
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • the composition may take the form of, for example, a sterile solution, suspension or emulsion
  • the dose of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, the route of administration, the form and severity of the condition and whether the compound is to be administered alone or in combination with another drug Thus the precise dose will be determined by the administering physician but in general daily dosages may be in the range 0 001 to l OOmg/kg preferably 0 1 to lOmg/kg
  • Tumour functional vascular volume in CaNT tumour-bearing mice was measured using the fluorescent dye Hoechst 33342 according to the method of Smith et al (Brit J Cancer 57, 247-253, 1988) At least three animals were used in control and treated groups.
  • the fluorescent dye was dissolved in saline at 6.25 mg/ml and injected intravenously at 10 mg/kg 24 hours after intraperitoneal drug treatment. One minute later, animals were killed and tumours excised and frozen; 10 ⁇ m sections were cut at 3 different levels and observed under UV illumination using an Olympus microscope equipped with epifluorescence.
  • aqueous phase was extracted with diethylether (5 portions of 20ml) and the combined extracts were washed with aqueous sodium thiosulphate solution (3 portions of 10ml), water (3 portions of 10ml) and brine (2 portions of 10ml), dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. Purification by chromatography on silica gel, eluting with petroleum ether / diethyl ether (50:50) gave 3-tert-butyldimethylsilyIoxy-4- methylbenzaldehyde (85mg).
  • Trifluoroacetic acid (0.22mL, 2.95mmol) was added dropwise to a stirred solution of (Z)-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl di-tcvtbutyl phosphate (401mg, 0.82mmol) and dichloromethane (16mL). The mixture was stirred at room temperature overnight. Solvent was removed in vacuo, and the residue azeotroped four times with toluene. The colourless oil was triturated with ether to give the title compound as a white solid (18 l g, 58%) m.p. 109-1 13°C.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP00951727A 1999-08-12 2000-08-09 Stilbenes with vascular damaging activity Withdrawn EP1206429A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9918912 1999-08-12
GBGB9918912.8A GB9918912D0 (en) 1999-08-12 1999-08-12 New stilbenes with vascular damaging activity
PCT/GB2000/003067 WO2001012579A2 (en) 1999-08-12 2000-08-09 New stilbenes with vascular damaging activity

Publications (1)

Publication Number Publication Date
EP1206429A2 true EP1206429A2 (en) 2002-05-22

Family

ID=10858950

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00951727A Withdrawn EP1206429A2 (en) 1999-08-12 2000-08-09 Stilbenes with vascular damaging activity

Country Status (6)

Country Link
EP (1) EP1206429A2 (it)
JP (1) JP2003507356A (it)
CA (1) CA2379544A1 (it)
GB (1) GB9918912D0 (it)
NZ (1) NZ517069A (it)
WO (1) WO2001012579A2 (it)

Families Citing this family (19)

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Publication number Priority date Publication date Assignee Title
EP1068870B1 (en) 1998-04-03 2006-06-07 Ajinomoto Co., Inc. Antitumor agents
GB0019944D0 (en) 2000-08-15 2000-09-27 Angiogene Pharm Ltd Compositions with vascular damaging activity
AU2002216228A1 (en) 2000-12-21 2002-07-01 Cancer Research Ventures Limited Substituted stilbenes, their reactions and anticancer activity
FR2838437B1 (fr) 2002-04-11 2004-06-04 Aventis Pharma Sa Procedes de preparation de combretastatines
GB0306908D0 (en) * 2003-03-26 2003-04-30 Angiogene Pharm Ltd Bioreductively activated stilbene prodrugs
TW200533636A (en) 2003-12-16 2005-10-16 Gtx Inc Prodrugs of selective androgen receptor modulators and methods of use thereof
CN1723884A (zh) * 2004-07-21 2006-01-25 中国人民解放军军事医学科学院放射医学研究所 顺式－1，2－取代的二苯乙烯衍生物用于制备治疗或预防糖尿病的药物的用途
CN101085743B (zh) * 2006-06-06 2012-02-15 浙江大德药业集团有限公司 含氟烷氧基康普立停衍生物及制法和用途
JP5302328B2 (ja) 2007-11-21 2013-10-02 オキシジーン， インコーポレイテッド 造血性新生物を治療するための方法
JP2011016777A (ja) * 2009-07-10 2011-01-27 Nipro Corp 新規システイン誘導体
EP2609089A1 (en) 2010-08-27 2013-07-03 Universität des Saarlandes Selective 17beta-hydroxysteroid dehydrogenase type 1 inhibitors
US9353150B2 (en) 2012-12-04 2016-05-31 Massachusetts Institute Of Technology Substituted pyrazino[1′,2′:1 ,5]pyrrolo[2,3-b]-indole-1,4-diones for cancer treatment
US10201623B2 (en) 2013-03-15 2019-02-12 Memorial Sloan Kettering Cancer Center HSP90-targeted cardiac imaging and therapy
EP3337495A4 (en) 2015-08-18 2019-04-10 Mateon Therapeutics, Inc. USE OF VDA TO ENHANCE IMMUNOMODULATION THERAPIES AGAINST TUMORS
WO2017197045A1 (en) 2016-05-11 2017-11-16 Movassaghi Mohammad Convergent and enantioselective total synthesis of communesin analogs
WO2018209239A1 (en) 2017-05-11 2018-11-15 Massachusetts Institute Of Technology Potent agelastatin derivatives as modulators for cancer invasion and metastasis
US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers
WO2020092134A1 (en) 2018-10-29 2020-05-07 Cepheid Exponential base-3 nucleic acid amplification with reduced amplification time using nested overlapping primers
US11535634B2 (en) 2019-06-05 2022-12-27 Massachusetts Institute Of Technology Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9106177D0 (en) * 1991-03-22 1991-05-08 Aston Molecules Ltd Substituted diphenylethylenes and analogues or derivatives thereof
TW325458B (en) * 1993-09-08 1998-01-21 Ajinomoto Kk Stilbene derivatives and pharmaceutical compositions comprising the same for anti-cancer
US5561122A (en) * 1994-12-22 1996-10-01 Arizona Board Of Regents Acting On Behalf Of Arizona State University Combretastatin A-4 prodrug
GB9903403D0 (en) * 1999-02-16 1999-04-07 Angiogene Pharm Ltd Substituted stilbene compounds with vascular damaging activity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0112579A2 *

Also Published As

Publication number Publication date
WO2001012579A2 (en) 2001-02-22
CA2379544A1 (en) 2001-02-22
WO2001012579A3 (en) 2001-10-11
NZ517069A (en) 2004-04-30
GB9918912D0 (en) 1999-10-13
JP2003507356A (ja) 2003-02-25

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