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WO1995019974A2 - Composes a base de calixarene presentant une activite antibacterienne, antifongique, anticancereuse et anti-vih - Google Patents

Composes a base de calixarene presentant une activite antibacterienne, antifongique, anticancereuse et anti-vih Download PDF

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WO1995019974A2
WO1995019974A2 PCT/IE1995/000008 IE9500008W WO9519974A2 WO 1995019974 A2 WO1995019974 A2 WO 1995019974A2 IE 9500008 W IE9500008 W IE 9500008W WO 9519974 A2 WO9519974 A2 WO 9519974A2
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compound
arene
following
prepared
derivative
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WO1995019974B1 (fr
WO1995019974A3 (fr
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Stephen J. Harris
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Harris Stephen J
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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    • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C245/08—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene
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    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/16—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
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    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/40—Esters thereof
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Definitions

  • the present invention relates to compounds having biological activity, particularly calixarene-based compounds, having anti- bacterial, anti-fungal, anti-cancer and anti-viral, particularly anti-HIV activity.
  • the virus that causes AIDS, the human immunodeficiency virus HIV is believed to be one of the major threats to human life and health worldwide. Even back in 1988 an article in Scientific American by J. M. Mann, J. Chin, P. Piot and T. Quinn estimated that more than a quarter of a million AIDS cases had occurred up to then and that 5-10 million people were infected with HIV worldwide.
  • HIV has been studied more intensively than any other virus and we now have a general picture of how the genes and proteins in the HIV virus particle operate, although we don't have a clear understanding of what controls the replication and how it destroys the human immune system.
  • the life cycle of the virus is described below in some detail since for a drug to be effective it has to interfere with at least one stage of its life cycle.
  • the HIV virus particle is roughly spherically shaped and is about a thousandth of a millimetre across. Its outer membrane consists of lipid molecules which possess many viral protein spikes projecting outwards. Each spike is thought to consist of four molecules of glycoprotein gpl20 with the same number of glycoprotein gp41 molecules embedded in the membrane itself. These envelope proteins come into play when HIV binds and then enters target cells. Gp120 can bind tightly to CD4 proteins sited in the membranes of immune system cells especially T lymphocytes also called T cells.
  • the virus core is surrounded by matrix protein called pl7 and is itself in the shape of a hollow cone made of another protein p24 containing the genetic material of the virus.
  • RNA Ribonucleic acid
  • RNA strands RNA strands.
  • RNA Ribonucleic acid
  • RNA strands RNA strands.
  • RNA Ribonucleic acid
  • integrase a protease
  • ribonuclease a ribonuclease and other enzymes.
  • Once in the cell the viral RNA is converted to DNA which then enters the cell nucleus.
  • the next step is integration of viral DNA into host chromosomes. This is followed by cell proteins binding to DNA initiating transcription. Short RNA molecules then leave the nucleus and make viral regulatory proteins followed by medium length and long RNA which generate structural and enzymatic proteins. These assemble to form new viruses (replication-viral budding) (1).
  • the drug of choice in AIDS treatment up to this time has been Wellcome's Retrovir or Zidovudine which is 3'-Azido-2',3'- dideoxythymidine or AZT for short:
  • This compound is of the dideoxynucleoside type and blocks HIV replication by inhibiting reverse transcriptase. (Such compounds are actually modified in vivo in the target cell to active 5'-triphosphates (2). Other nucleoside drugs believed to work in a similar way are Didanosine dd1 (or Videx) which has been developed by Bristol-Myers Squibb and dideoxycytidine ddC of Roche.
  • AZT can give rise to anaemia although this undesirable side effect may be counteracted by co-administration of drugs such as erythropoietin.
  • AZT Triton Bioscience's 3'-azido-dideoxy-uridine AzdU but being structurally similar to AZT may have similar resistance problems (3). Indeed apart from the toxic side effects associated with the use of AZT the virus quickly develops resistance to this drug (4). researchers had hoped for several years that using a combination of these nucleoside inhibitors would provide benefits over individual drugs used alone. However, recent such results presented in Berlin were very disappointing. A large recent controversial French and British Study of AZT indicates that its early use in HIV-infected individuals provided no survival benefits (5).
  • New non-nucleoside reverse transcriptase inhibitors which have selective anti HIV-1 activity are certain benzodiazepine analogs and thione derivatives developed by Pauwels and coworkers (2) but again resistance to these compounds develops very rapidly blunting their clinical usefulness.
  • oligodeoxynucleosides short segments of DNA that may hybridize to messenger RNA and inhibit translation. In any event they have been demonstrated to possess in vitro anti HIV activity (2).
  • a very late stage in the HIV life cycle which has been targetted is that of viral budding which has at least been partially blocked by use of interferon alpha.
  • the concentration at which an HIV-1 drug is effective is designated EC 50 which represents when the number of cells protected from HIV injection is half of the total.
  • the antigen Agp120 assay - the virus related antigen - is related to the number of virus particles produced by measuring glycoprotein gp 120 in infected cell cultures uM (micromolar).
  • EC 50 represents the concentration which reduces required Antigen gp 120 by 50% in infected cell cultures.
  • the concentration of the drug which reduces cell growth by 50% is designated TC 50 ⁇ M.
  • AZT Therapeutic index which is TC 50 /EC 50 ratio so as not to damage healthy cells.
  • human beings and animals are more than a collection of cells and in spite of the high Therapeutic Index, AZT is quite toxic, giving rise to nerve damage and anaemia among other things (3). Nevertheless such tests on cell cultures indicate what is a potential anti HIV drug.
  • Such compounds are cyclic and acyclic phenol-aldehyde oligomers and their wide range of derivatives preferably carboxylic acid salt derivatives which renders them water soluble. These compounds have shown surprisingly good anti-HIV activity, particularly against HIV-1.
  • the first class of compounds are derived from cyclic phenol -formaldehyde calixarenes and oxacalixarenes.
  • the present invention provides calixarene or oxacalixarene derivatives of the formula I
  • n 0 - 8
  • R is H, halogen, hydrocarbyl, aryl, hydrocarbylaryl or a substituted
  • X is halogen, NO 2 , CO 2 H, CN or other electron withdrawing group.
  • R 3 is alkyl or a substituted derivative thereof
  • M is a metal or ammonium ion
  • P is the charge on the metal ion
  • R 4 or R 5 may be the same or different, or both may be part of amino acid ester or poly(amino acid ester) of one or more of the same or different amino acids or part of a cyclic polyene antibiotic/antifungal drug or part of a cyclic nitrogen heterocycle,
  • R 1 is preferably NO 2 or a halogen, particularly bromine , R 3 is
  • R 2 is preferably CH 2 CO 2 K or
  • the cyclic polyene drug may be Amphotericin B or a lactam antibiotic such as a penicillin derivative or the aminoglucoside sinefungin.
  • the cyclic nitrogen heterocycle may be an aminotetrazole or aminotriazole.
  • the invention provides open chain, i.e. acyclic phenol-formaldehyde oligomers of formula II
  • R is H or CH 2 CO 2 M p where p is the charge on the metal ion ,
  • M is a metal ion
  • R 6 i s preferably halogen .
  • M i s preferably an al kal ine metal or alkal ine earth metal .
  • R i s preferably CH 2 CO 2 K.
  • Phenolic oligomers may be made by the procedure of B. Dhawan and CD. Gutsche, J. Org. Chem 1983 48 p.1536, and the ester modified oligomers by the procedure of U.K. Pat. Appln. GB 2,200,124 A1 by S.J. Harris and B.J. Kneafsey assigned to Loctite (Ireland).
  • R 8 is H or CH 2 CO 2 R 9 or CH 2 CO 2 M p
  • R is alkyl, aryl, alkaryl or a substituted derivative thereof
  • M is metal ion
  • p is the charge on the metal ion
  • Y is halogen and R 8 is CH 2 CO 2 K.
  • M is preferably an alkaline metal or alkaline earth metal.
  • the parent cyclotriveratrylene may be synthesised by the process of J.Org.
  • R 11 is the same as R 8 defined above, Z is halogen or nitro
  • R 10 is alkyl, aryl, alkaryl or a substituted derivative thereof.
  • Z is halogen and R 11 is CH 2 CO 2 K.
  • the invention provides cyclic tetrameric
  • R 12 is the same as R 8 defined above,
  • L is H, halogen or nitro, or other electron withdrawing group
  • R 13 is alkyl, aryl, alkaryl or a substituted derivative thereof or when
  • L is halogen e.g. Bromine
  • R 12 is CH 2 CO 2 NH 4 ,
  • the present invention provides in a sixth aspect calixarene or
  • n 0-8
  • a which may be the same or different on each aryl group, is 0 or 1;
  • R' which may be the same or different on each aryl group, is -H or hydrocarbyl, aminohydrocarbyl aryl , hydrocarbylaryl or a substituted derivative or salt thereof;
  • R 2 which may be the same or different on each aryl group, is
  • R 4 and R 5 which may be the same or different, are -H or
  • hydrocarbyl, aryl, hydrocarbylaryl or a substituted derivative thereof and R 4 and R 5 may form a cycloaliphatic ring, which may in turn be
  • R 5 may be /
  • R 6 and R 7 which may be the same or different are H or
  • R 5 is OR 4 wherein R 4 is as defined above; or R 5 is a residue of a
  • R 3 which may be the same or different on each aryl group, is -H, halogen, hydrocarbyl, aryl, hydrocarbylaryl or a substituted derivative thereof;
  • X is -OH, -OM (wherein M is a salt forming metal), or a group containing an acrylate or methacrylate functional group;
  • Z is O or S or NOH
  • Preferred embodiments of the invention include:
  • hydrocarbyl as used herein means aliphatic hydrocarbyl including alkyl, alkenyl and alkynyl and also includes alkylene and alkenylene groups in the case where R 4 and R 5 together form a cycloaliphatic ring.
  • Hydrocarbyl groups shall preferably contain from 1 to 12 carbon atoms, more preferably from 1 to 5 carbon atoms, and aryl and hydrocarbylaryl groups shall preferably have from 6 to 20 carbon atoms, more preferably from 6 to 10 carbon atoms. Hydrocarbyl groups are preferred, especially alkyl or alkenyl groups. A substituted derivative of the foregoing may suitably be substituted with one or more halo groups or radicals containing nitrogen or substituted or interrupted by one or more oxo groups.
  • Radicals containing nitrogen may or may not form part of a heterocyclic ring; a suitable radical may contain an amino or amide group, or may be a heterocyclic ring which may be saturated or unsaturated, aliphatic or aromatic, for example a 5- or 6-membered ring containing 1 or 2 nitrogen atoms.
  • a suitable radical may contain an amino or amide group, or may be a heterocyclic ring which may be saturated or unsaturated, aliphatic or aromatic, for example a 5- or 6-membered ring containing 1 or 2 nitrogen atoms.
  • Halogen may be chlorine, bromine, fluorine or iodine.
  • calixarene derivatives The preparation of calixarene derivatives is known and is described, for example, in C. Gutsche et. al., Ace. Chem. Res., 16, 161-170 (1983); in U.S. Patents 4,556,700 Harris et. al., 4,866,198 Harris,
  • the aryl groups having the -OCH 2 C(O)X side chain may be
  • the methylene and ether bridges may or may not alternate within the oxacalixarene molecule.
  • Oxacalixarene compounds may be readily synthesised by methods described in C. Gutsche et. al., J. Am. Chem. Soc. 103, 3782 (1981); B. Dhawan et. al., J. Org. Chem., 48, 1536 (1983), U.S. Patent 4,098,717 Buriks et. al., U.S.
  • X is a group containing an acrylate or methacrylate functional group, said group is preferably of the formula
  • R" is H or CH 3 .
  • the invention also relates to a method for the synthesis of compounds of formula V defined above wherein pyrogallol is condensed with an aldehyde.
  • the resulting tetramer is halogenated.
  • This tetramer may be converted to its alkyl acetate derivative and optionally base - hydrolysed to give a potassium acetate derivative.
  • the potassium salt may then be converted to the acid and subsequently to the ammonium salt.
  • pyrogallol is condensed with an aldehyde in equimolar quantities in refluxing 37% aqueous HCl/ethanol 1/4 by volume following the method of J. Holmes et al, European Patent No. 400,773 5th December 1990 for I.C.I.
  • the precipitated tetramer is washed with a minimum quantity of cold ethanol then brominated with one equivalent of bromine in CHCl 3 then
  • the invention also provides anti-bacterial, anti-fungal, anti-viral and anti-cancer agents comprising as active ingredient calixarene or oxacalixarene derivatives of formulae I, II, III, IV, V or VI.
  • the invention further provides pharmaceutical compositions comprising a pharmaceutically effective amount of any of the above defined compounds, either singly or in combination.
  • the invention also provides use of any of the above defined compounds, either singly or in combination, in the
  • the invention also provides a method of medical treatment comprising administering a therapeutically effective amount of any of the above defined compounds to a patient, either singly or in combination.
  • Particularly preferred compounds with antibiotic activity are those of
  • R 2 is CH 2 CO 2 K, m is 0, n is 5, X is hydrogen and R 1 is Br; or (b) R 2 i s CH 2
  • n 3 , m i s 1 , X i s hydrogen , R 1 i s t-butyl , and R 4 i s the same as R 5 and i s CH 2 CH 3 ; or (d) R 2 is
  • n 3
  • m 3
  • X is hydrogen
  • R 1 is Br
  • R 4 is the same as R 5 and is (CH 2 ) 7 CH 3 ; or
  • n 2 CH 2 OCH 3 ;
  • n 7
  • X is hydrogen
  • R 1 is ethyl
  • R 4 is the same as R 5 and is
  • Particularly preferred compounds with anti-cancer activity are compounds of Formula I in which
  • n 0 and X is hydrogen
  • R 1 is t-butyl, n is 4, m is 0, X is hydrogen, R 2 is
  • R 4 is the same as R 5 and is CH 2 CH 3 , CH 2 CH 2 OCH 3 ;
  • R 1 is t-butyl, n is 5, m is 0, X is hydrogen, R 2 is
  • R 4 is the same as R 5 and is CH 2 CH 3 ;
  • R 1 is t-butyl, n is 2, m is 2, X is hydrogen, R 2 is where R 4 is the same as R 5 and is CH 2 CH 3 .
  • R 1 is t-butyl, n is 4, m is 0, R 4 is phenyl and R is cholesterol.
  • P-T-Butylcalix-7-arene was prepared following the procedure of Y.
  • Calix-7-arene from the above example was converted to its p.nitro derivative by treating with concentrated sulphuric acid then nitric acid following the method of S. Shinkai, T. Tsubaki, T. Sone and 0. Manabe
  • P-T-Butylcalix-5-arene was prepared following the method of A. Ninagawa and H. Matsuda Makromol Chem Rapid Commun 3 p.65 1982 and dealkylated with aluminium chloride, phenol and toluene as in the first example to give calix-5-arene as a pale pink solid.
  • 1.0g (0.0019 mole) of calix-5-arene in 25 ml chloroform was treated overnight with 1.28g, (0.008)mole bromine in 5 ml chloroform at room temperature with stirring under nitrogen. Subsequent removal of all volatiles gave 1.7g, 97% yield of p-bromo-calix-5-arene as a pale pink solid.
  • This compound was prepared as a pale orange solid following the method of Example 3.
  • the p-t-butylcalix-6-arene starting material was prepared following the method of C.D. Gutsche, B. Dhawan, K. H. No and R.
  • Calix-7-arene prepared as in Example 1 was treated with octadecanocyl chloride following the method of Y. Nakamoto, G. Kallinowski, V. Bohmer and W. Vogt. Langmuir 5 p.116 1989 in 80% yield as an off-white solid
  • P-T-Butylcalix-8-arene was prepared following the method of C. D.
  • Example 8 P-Sodiumsulphonatecalix-4-arene P-Sodiumsulphonatecalix-4-arene was prepared following the method of J.
  • P-T-Butyldihomooxacalix-4-arene was prepared by the method of B. Dhawan and C.D. Gutsche J. Org Chem 48 p. 1536 1983, then dealkylated by the method of Ex. 1 but reaction time was 10min instead of 1h and at 0oC instead of room temp., to give dihomooxacalix-4-arene.
  • P-T-Butylcalix-4-arene tetraacetic acid was prepared following the method of S. J. Harris U.S. Patent 4,882,449 November 21 1989 by hydrolysis of its ethyl acetate derivative with potassium hydroxide but with ethanol only (no water) which after neutralisation with aqueous HCl and filtering off and drying was treated with excess thionyl chloride under reflux for 2 hours after which all volatiles were removed to give p-t-butylcalix-4-arene tetraacetyl chloride which was not purified on account of its moisture sensitivity.
  • P-Nitrocalix-4-arene tetracetic acid was prepared in the following way.
  • Cone conformational calix-4-arene t-butyl acetate derivative was prepared following the method of S. J. Harris, M. A. McKervey, G. Svehla and D. Diamond U.S. Patent 5,132,345 July 21 1992.
  • cone Compound 13a was dissolved in 10 ml glacial acetic acid which was cooled to 0°C To this stirred solution was added a mixture of 5 ml concentrated nitric acid and 5 ml concentrated sulphuric acid dropwise to the solution which attained a purple colour. Stirring was continued for 2 hours at 0°C during which the reaction mixture thickened. The reaction mixture was stirred overnight at room temperature to give a clear green solution which was subsequently cooled to 0°C and 25 ml water was added dropwise to give an off-white solid precipitate which was filtered off and allowed to dry overnight after washing with minimum amount cold water to give 0.4g cone p-nitrocalix-4-arene tetracetic acid.
  • Example 16 Compound 16: 1g Compound 16a was treated with 1g potassium hydroxide in ethanol 10 ml which was refluxed for 2 hours, volatiles were then removed and the residue was treated with HCl following the method of S. J. Harris U.S. Patent
  • Example 17 Compound 17: During the preparation of Compound 17a in J. Am Chem Soc. 111 p.8681 1989 by S. J. Harris, F. Arnand-Neu, E. M. Collins, M. Deasy, G. Ferguson, B.
  • P-Bromocalix-6-arene prepared in Example 4 was treated with ethyl bromoacetate, anhydrous potassium carbonate in refluxing dry acetone following the method described in Example 14. Subsequent conversion of the Compound 18a to acid following the method in Example 12 and thence acid chloride also in Example 12, then treatment with methoxyethanol in the presence of pyridine in dry THF following the method given in Example 12, gave the title product in 80% yield as a pale yellow solid.
  • Calix-8-arene was obtained from dealkylation of its t-butyl derivative following the method in Example 7, then etherified with ethyl bromoacetate and potassium carbonate in refluxing acetone following the method in Example 14, then converted to its methoxyethyl ester derivative following the method of Example 18.
  • Calix-7-arene prepared as in Example 1 was converted to its methoxyethyl ester derivative following the method of Example 18.
  • Example 22 Compound 22: Calix-7-arene prepared as in Example 1 was converted to its
  • P-T-Butylcalix-7-arene was prepared following the method in Example 1, then converted to its methoxy ethyl ester derivative following the method in Example 18 and obtained as a colourless solid.
  • P-Octadecanoylcalix-7-arene was prepared as in Example 5, then treated with ethyl bromoacetate in the presence of anhydrous potassium carbonate in refluxing acetone following the method of Example 14 to give the title product in 85% yield as a yellow solid.
  • Example 26 P-Qctadecylcalix-7-arene Hepta-ethyl Acetate Derivative P-0ctadecanoylcalix-7-arene prepared as in Example 5 was treated with triethylsilane/trifluoroacetic acid following the method of Y. Nakamoto, G. Kallinowski, V. Bohmer and W. Vogt, Langmuir 5 p.116 1989 to give
  • Example 27 P-Octadecylcalix-7-arene Hepta-methoxy Ethyl Acetate Derivative The ethylacetate p-octadecylcalix-7-arene was converted to its
  • P-Ethylcalix-7-arene was prepared following the method of Z. Asfari and J. Vicens Makromol Chem Rapid Commun 10 p.177 1989. Treatment with ethyl bromoacetate in the presence of anhydrous potassium carbonate in refluxing dry acetone following the procedure of Example 14 gave the title product in 82% yield as a heavy colourless oil.
  • the procedure followed is given in more detail in U.S. Patent 5,132,345 July 21 1992 by S. J. Harris, M. A. McKervey, G. Svehla and D. Diamond.
  • P-Ethylcalix-7-arene hepta-ethyl acetate from Example 29 was converted to its methoxyethyl acetate derivative in 90% yield as a colourless oil by refluxing 24 hours with excess methoxyethanol in the presence of catalytic (few mg per lg starting material) quantity of p-toluene sulphonic acid to give the title product after removal of all volatiles under reduced pressure.
  • Example 32 P-Ethylcalix-7-arene Hepta-n-butyloxyethyl Acetate Derivative
  • P-Ethylcalix-7-arene hepta-ethyl acetate from Example 29 was converted to its n-butyloxyethyl acetate derivative as a pale yellow oil via its acid, and acid chloride and final treatment with n-butyloxyethanol in THF in the presence of pyridine following the method of Example 12.
  • Example 29 P-Ethycalix-7-arene hepta-ethyl acetate from Example 29 was hydrolysed to its acid following the method of Example 12, followed by conversion to its acid chloride in the same Example. Treatment then with methoxy
  • P-Ethylcalix-7-arene hepta-ethyl acetate from Example 29 was converted to its methylthioethyl acetate derivative as a pale yellow oil by treatment of its acid chloride derivative with methylthioethanol following the method of Example 12.
  • P-0ctadecylcalix-4-arene was prepared following the method of Y.
  • P-Bromocalix-4-arene was prepared following the method of Example 3. To 0.55g (0.00074 mole) of p-bromocalix-4-arene was added 0.61g (0.0044 mole) anhydrous potassium carbonate and 0.98g (0.0059 mole) ethyl bromoacetate and 10ml dry analar acetone and the entire was stirred under reflux for 168 hours. After removal of solvent the product was taken up into 10 ml dichloromethane which was washed with 3% aqueous sulphuric acid, then with water, after which the organic layer was dried with dried magnesium sulphate. Removal of solvent gave 0.81g (ca 100% yield) product which was recrystallised from ethanol to give 0.71g 89% yield pure ethyl acetate product mp
  • Example 38 P-Bromocalix-4-arene Tetra-acetic Acid Derivative
  • the tetra-potassium acetate salt of p-bromocalix-4-arene prepared in Example 37 was treated with 37% HCl and then washed with ice cold water and dried overnight at room temperature to give the title product as a pale yellow solid.
  • Example 39 P-Nitrocalix-4-arene Tetra-acetic Acid Derivative (Cone
  • the title compound was prepared as described in Example 13 as a red brown solid.
  • Example 39 Treatment of p-nitrocalix-4-arene tetra-acetic acid prepared in Example 39 was treated with 4 equivalents of potassium hydroxide in ethanol to give the title product in quantitative yield, after removal of volatiles under reduced pressure, as a pale yellow solid which was readily water soluble.
  • Partial cone calix-4-arene tetra-t-butyl acetate derivative prepared following the procedure of S. J. Harris, M. A. McKervey, G. Svehla and D. Diamond U.S. Pat. 5,132,345 July 21 1992, was treated following the method of Ex. 13 with concentrated nitric acid/concentrated sulphuric acid to give partial cone p-nitrocalix-4-arene acetic acid as a pale yellow solid. I.r. ⁇ 1450 M Nitro stretching band cm -1 .
  • Partial cone p-nitrocalix-4-arene tetra-acetic acid from Ex. 41 was treated with potassium hydroxide in ethanol following the method in Ex. 40 to give the title compound as a yellow solid readily soluble in water.
  • Example 44 P-Sodium Sulphonate Calix-4-arene Tetra-methyl Ether Derivative This compound was prepared following the method of Chemistry Letters p.1033 1985.
  • P-Sodiumsulphonatecalix-4-arene was prepared following the method in Example 8.
  • Treatment with ethyl bromoacetate and anhydrous potassium carbonate in refluxing analar dry acetone following the procedure of Example 14 gave p-sulphonic acid calix-4-arene tetra-ethyl acetate derivative upon acid work up.
  • Treatment with potassium hydroxide in ethanol following the method in Example 36 gave the title compound as a colourless solid upon removal of all volatiles under reduced pressure.
  • P-Potassium oxyacetate calix-4-arene tetra-potassium acetate derivative prepared in Example 47 was treated with 37% aqueous HCl, then the resulting solid was washed with a minimum amount of cold water as in Example 46 to give colourless solid the title product in near quantitative yield.
  • P-Oxyacetic Acid calix-4-arene tetra-acetic acid prepared in Example 48 was treated with excess 25% analar aqueous ammonium hydroxide following the method of Example 43 giving a colourless solid the title product in
  • Example 50 O,O'-Dibromo-P-Potassium Oxyacetate Calix-4-arene Tetra-potassium Acetate Derivative
  • Example 51 O,O'-Dibromo-P-Oxyacetic Acid Calix-4-arene Tetra-acetic Acid Derivative 0,0'-Dibromo-p-potassium oxyacetate calix-4-arene tetra-potassium acetate derivative prepared in Example 50 was treated with 37% aqueous HCl to give the title product as a grey-yellow solid after washing with a minimum quantity of ice cold water following the method in Example 38.
  • P-t-butyldihomooxacalix-4-arene tetra-ethyl acetate derivative was prepared following the method of S. J. Harris and M. G. MacManus, U.S. Patent 4,855,461 August 8 1989. Treatment with ethanolic potassium hydroxide following the method in Example 36 gave colourless solid the title product which was readily water soluble.
  • P-t-Butyldihomooxacalix-4-arene tetra-potassium acetate derivative prepared in Example 52 was neutralised with 37% aqueous HCl following the method of Example 38 to give the parent acetic acid derivative which was treated then with 4 equivalents NaOH in ethanol to give the title product after removal of all volatiles, as a colourless solid.
  • Example 54 Replacement of lithium hydroxide with caesium hydroxide in Example 54 gave the title product as a colourless solid.
  • Example 58 P-T-Butyldihomooxacalix-4-arene 1.33-aluminium Acetate Derivative
  • Example 67 Dihomooxacalix-4-arene Tetra-potassium Acetate Derivative
  • Dihomooxacalix-4-arene prepared by dealkylation of its t-butyl derivative of Example 9 was etherified with ethyl bromoacetate following the method of Example 14 to give its ethyl acetate derivative as a colourless oil.
  • Example 68 P-Nitrodihomooxacalix-4-arene Tetra-potassium Acetate Dihomooxacalix-4-arene prepared in Example 67 was treated with
  • Example 69 P-Bromodihomooxacalix-4-arene Tetra-potassium Acetate
  • P-Bromodihomooxacalix-4-arene was prepared following the method of Example 9 as a pale orange solid, then treated with ethyl bromoacetate following the method in Example 14 to give the ethyl acetate derivative as a pale yellow solid.
  • Treatment with potassium hydroxide in ethanol following the method of Example 36 gave the title product as a yellow-brown solid.
  • Example 70 P-Bromodihomooxacalix-4-arene Tetra-acetic Acid
  • Example 69 P-Bromodihomooxacalix-4-arene Potassium Acetate prepared in Example 69 was treated with 37% aqueous HCl to give the title product as a pale yellow solid following the method in Example 38.
  • Example 70 P-Bromodihomooxacalix-4-arene acetic acid prepared in Example 70 was treated with 4 equivalents of tetra-n-butyl ammonium hydroxide in methanol following the method in Example 66 to give the title product as pale brown solid.
  • P-t-Butylcalix-5-arene prepared following the method described in Example 3 was etherified with ethyl bromoacetate following the method in Example 14 to give its ethyl acetate derivative as a colourless solid.
  • P-Bromocalix-5-arene prepared in Example 3 was etherified with ethyl bromoacetate following the method in Example 14.
  • P-Nitrocalix-5-arene was prepared following the method of Example 2 from calix-5-arene prepared following the method in Example 3. Treatment with ethyl bromoacetate following the method in Example 14 gave
  • Example 77 P-Nitrocalix-5-arene Penta-acetic Acid P-Nitrocalix-5-arene penta-potassium acetate from Example 76 was treated with aqueous HCl following the method given in Example 38 to give the title acid as a pale yellow solid as the title product.
  • Example 79 P-Bromocalix-6-arene hexa-acetic acid prepared in Example 79 was treated with ammonium hydroxide following the method in Example 43 to give the title product as pale yellow solid.
  • Example 79 P-Bromocalix-6-arene hexa-acetic acid prepared in Example 79 was treated with 6 equivalents tetra-n-butyl ammonium hydroxide following the method in Example 66 to give the title product as pale brown solid.
  • Example 84 P-Nitrocalix-7-arene Hepta-potassium Acetate
  • P-Nitrocalix-7-arene hepta-ethyl acetate was prepared following the method in Example 24 which was then hydrolysed with ethanolic potassium hydroxide following the method of Example 36 to give the title product as a brown solid.
  • Example 86 P-Nitrocalix-7-arene Hepta-ammonium Acetate P-Nitrocalix-7-arene hepta-acetic acid from Example 85 was treated with NH 4 OH following the method of Example 43 to give the title product as a pale brown solid.
  • Example 87 P-Bromocalix-7-arene Hepta-potassium Acetate
  • P-Bromocalix-7-arene hepta-ethyl acetate was prepared following the method in Example 22 which was then treated with ethanol ic potassium hydroxide following the method in Example 36 to give the title product as a pale yellow solid.
  • Example 88 P-Bromocalix-7-arene Hepta-acetic Acid P-Bromocalix-7-arene hepta-potassium acetate prepared in Example 87 was treated with HCl following Example 38 to give the title product as pale yellow solid.
  • Example 90 P-Bromocalix-7-arene Hepta-tetra-n-butyl-ammonium Acetate
  • P-Bromocalix-7-arene hepta-acetic acid prepared in Example 88 was treated with 7 equivalents of tetra-n-butyl-ammonium hydroxide in methanol following the method in Example 66 to give the title product as a brown solid.
  • P-Octadecanoylcalix-8-arene prepared in Example 7 was converted to p-octadecylcalix-8-arene by treatment with triethylsilane and trifluoroacetic acid in method quoted in Example 26 which was obtained as a grey waxy solid.
  • Calix-8-arene octa-ethyl acetate was prepared following the method in Example 20 and was subsequently treated with ethanolic potassium hydroxide following the method in Example 36 to give the title product as a pale colourless solid.
  • P-Bromocalix-8-arene octa-ethyl acetate was prepared following the method in Example 19 which was then converted to its the title product as a pale yellow solid by treatment with ethanolic potassium hydroxide following the method of Example 36.
  • Calix-8-arene was prepared following the method in Example 7, then treated with sulphuric acid, then nitric acid following the procedure in
  • Example 98 Compound 98:
  • Example 100 Compound 100: The title compound was prepared as a pale brown solid by treatment of its ethyl acetate derivative prepared in Example 99 with ethanolic potassium hydroxide following the procedure in Example 36.
  • Example 103 Compound 103: Treatment of p-t-butylcalix-4-arene tetra-acetyl chloride as in Example 102 with aminotetrazole gave the title product as a colourless solid.
  • Example 104 Compound 104:
  • Example 110 Compound 110: Treatment of p-t-butyl cal ix-4-arene tetra-acetyl chloride from Example
  • Example 126 Cone Compound 126: Treatment of cone p-nitrocalix-4-arene tetra-acetyl chloride of Example 114 with Compound 126a gave the title product as pale brown solid.
  • Example 127, Cone Compound 127 Treatment of cone p-nitrocalix-4-arene acetyl chloride of Example 114 with Compound 127a gave the title product as a pale brown solid.
  • Example 48 Compound 132a was prepared as Example 48 which was then converted to its acid chloride by treatment with thionyl chloride following the method in Example 12. This product was then reacted with bis-methoxyethyl amine in
  • Example 134 Compound 134:
  • P-Nitrocalix-6-arene hexa-acetic acid from Example 83 was converted to its acid chloride with thionyl chloride following the method of Example 12 and then converted to the title product as a bright red-brown solid by treatment with Compound 134a as in Example 102.
  • P-Ethylcalix-7-arene hepta-acetyl chloride prepared in Example 32 was converted to the title product by treatment with NH 2 CH 2 CH 2 OH as a
  • Example 92 P-calix-8-arene octa-potassium acetate prepared in Example 92 was treated with HCl following the method of Example 38 to give its acid which was then converted to its acid chloride with thionyl chloride following Example 12. This product was then treated with Compound 137a to give the title product as an off white solid.
  • the tetra-ethyl acetate derivative of p-t-butyldioxacalix-4-arene was prepared fol l owi ng method of US Patent 4855461 August 8 1989 by S . J . Harri s and M.G. MacManus which was then hydrolysed to its acid via its potassium salt by treatment with alcoholic potassium hydroxide following the method of Examples 36/38.
  • the acid derivative was converted to its acid chloride with thionyl chloride following the method in Example 12 which was then reacted with bis hydroxyethyl amine with pyridine in THF following the method in Example 102 to give the title product as an off-white solid.
  • P-t-butycalix-4-arene tetra-acetyl chloride of Example 12 was treated with the lactam antibiotic aminocephalosporanic acid from Fluka following the method in Example 102 to give the title product as an off-white solid.
  • Example 141 Cone Compound 141: Cone P-Nitrocalix-4-arene tetra-acetyl chloride of Example 114 was treated with Amphotericin B to give the title amide product as a red-brown solid.
  • P-Bromcalix-6-arene hexa-acetic acid was prepared by the method in
  • Example 79 which was converted to its acid chloride with thionyl chloride as in Example 12. Subsequent reaction with the lactam antibiotic
  • aminocephalosporanic acid gave the title product as a very pale-yellow solid.
  • P-Nitrocalix-6-arene hexa-acetic acid was prepared following the method in Example 83 which was converted to its acid chloride employing thionyl chloride as in Example 12. Subsequent treatment with the lactam
  • aminocephalosporanic acid gave the title product as a yellow solid.
  • Example 150 Compound 150: Cyclotriveratryline was converted to its parent phenolic derivative by treatment with boron tribromide in dry dichloromethane under nitrogen following the method of J.A. Hyatt, J Org Chem 43 (9) p1808 1978. This compound was subsequently reacted with 6 equivalents of bromine in dry chloroform under nitrogen at room temperature overnight to give after removal of volatiles its hexabromo derivative as a pale brown solid. This product was subsequently treated with ethyl bromoacetate following the method in Example 14 to give its ethyl acetate as a heavy brown oil which was then treated with ethanol ic KOH following the method of Example 36 to give the title product as a dark-grey solid.
  • Example 150 The Compound 150 prepared in Example 150 was treated with HCl to give its acid title product, following the method of Example 38, as a dark-brown solid.
  • Compound 153 was prepared following the method of A.G.S. Hogberg, J Org
  • Example 155 Compound 155:
  • Example 162 Compound 162:
  • Example 163 The title compound was prepared as a pale pink solid by the reaction of n-butyraldehyde and pyrogallol in 1:4, 37% aqueous HCl to ethanol under nitrogen under reflux for 90 minutes following the method of J. Holmes and P. Tasker, European Patent Application EP 400,773 5th December 1990 assigned to ICI.
  • Example 163 The cyclic tetramer of pyrogallol and butyraldehyde prepared in Example 163 was treated with 4 equivalents of bromine in chloroform following the method of Example 3 to give a pale grey-brown solid as the title compound after removal of all volatiles.
  • Example 165 prepared in Example 165 was treated with ethanolic potassium hydroxide following the method of Example 36 to give off white title product, which was soluble in water, as were all acid salts which follow.
  • This compound was tested i.v. in mice with no toxic effect at 200 mg per kg body weight.
  • Example 177 Compound 177:
  • Example 178 Compound 178:
  • the title compound was prepared as an off white solid following synthesis of the tetramer from pyrogallol and phenyl acetaldehyde and conversion steps in Examples 163, 164, 166, and 169.
  • Example 180 Compound 180:
  • the title compound was prepared as a pale yellow solid by treatment of the acid derivative from Example 179 with NH 4 OH following the method Example 171.
  • the title compound was prepared as an off-white solid following synthesis of the tetramer from pyrogallol and m-bromobenzaldehyde and conversion steps in Examples 163, 164,166, and 169.
  • Example 182 Compound 182: The title compound was prepared as a brown solid by treatment of its potassium salt from Example 181 with HCl following the method of Example 170.
  • Example 183, Compound 183 The title compound was prepared as a pale brown solid by treatment of the acid derivative from Example 182 with NH 4 OH following the method of Example 171.
  • Example 185 Compound 185:
  • Example 186 Compound 186:
  • Example 187 Compound 187:
  • Example 188, Compound 188 The title compound was prepared as a pale brown solid by treatment of its potassium salt in Example 187 with HCl following the method of Example 170.
  • Example 189 Compound 189: The title compound was prepared as a pale yellow-brown solid by treatment of its acid derivative from Example 188 with ammonium hydroxide following the method of Example 171.
  • Example 192 Compound 192:
  • the title compound was prepared as an off-white solid by treatment of its acid derivative of Example 191 with ammonium hydroxide following the method in Example 171.
  • the title compound was prepared as a pale buff coloured solid following synthesis of tetramer from pyrogallol and 1-naphthaldehyde as a pale grey-pink solid and conversion steps in Examples 163, 164, 166 and 169.
  • Example 194 The title compound was prepared as a buff-coloured solid by treatment of its potassium salt in Example 193 with HCl following the method of Example 170.
  • Example 195 Compound 195: The title compound was prepared as a buff-coloured solid by treatment of its acid derivative from Example 194 with ammonium hydroxide following the method in Example 171.
  • Example 198 Compound 198:
  • the title compound was prepared as a pale yellow-brown solid by treatment of its acid derivative from Example 197 with ammonium hydroxide following the method in Example 171.
  • the title compound was prepared as a red solid by treatment of its potassium salt of Example 199 with HCl following the method of Example 170.
  • the title compound was prepared as a brown solid by treatment of its acid derivative with ammonium hydroxide following the method in Example 171.
  • the title compound was prepared as a purple-brown solid by reacting together pyrogallol and 9-(10-chloro)anthracene carboxaldehyde to give the tetramer and thence its conversion by steps in Examples 163, 164, 166 and 169.
  • the title compound was prepared as a purple-brown solid by treatment of its potassium salt of Example 202 with HCl following the method in Example 170.
  • the title compound was prepared as a red-brown solid by treatment of its acid derivative of Example 203 with ammonium hydroxide following the method in Example 171.
  • Example 205 Compound 205: The title compound was prepared as a buff solid by treatment of the tetramer from reaction of pyrogallol and pyrene carboxaldehyde, a grey-brown solid, and then its conversion in steps in Examples 163, 164, 166, and 169.
  • Example 207 Compound 207:
  • the title compound was prepared as a brown solid by treatment of its acid derivative with ammonium hydroxide following the method in Example 171.
  • the title compound was prepared as a brown solid by treatment of the sulphonic acid tetramer, a pale pink solid, from reaction of pyrogallol and Compound 208a and then its conversion in steps in Examples 163, 164, 166 and 169.
  • Example 209 Compound 209: The title compound was prepared as a brown solid by reaction of its potassium salt in Example 208 with HCl following the method of Example 170.
  • Example 210 Compound 210: The title compound was prepared as a brown solid by reaction of its acid derivative in Example 209 with NH.OH following the procedure in Example 171.
  • Example 211 Compound 211: The title compound was prepared as a pale yellow solid by treatment of the tetramer from reaction of pyrogallol with p-bromobenzaldehyde to give a pale orange-pink solid by conversion steps in Examples 163, 164, 166 and 169.
  • the title compound was prepared as a pale brown solid by reaction of its potassium salt of Example 211 with HCl following the method of Example 170.
  • Example 214 Compound 214:
  • the title compound was prepared as a brown solid by treatment of the tetramer, a dark pink solid, from reaction of pyrogallol and Compound 214a and then its conversion in steps in Examples 163, 164, 166, and 169.
  • the title compound was prepared as a brown solid by treatment of its potassium salt derivative from Example 214 with HCl following the method in Example 170.
  • Example 216, Compound 216 The title compound was prepared as a pale orange-brown solid by treatment of its acid derivative from Example 215 with NH 4 OH following the method in Example 171.
  • the title compound was prepared as a colourless solid by firstly
  • Example 219 Compound 219:
  • the title product was obtained as a grey-blue solid by firstly preparing the tetramer from pyrogallol and p-carboxybenzaldehyde (ca only 10% yield) and thence its conversion by steps in Examples 163, 164, 166 then 169.
  • Example 221 Compound 221: The title product was obtained as a brown solid by treatment of its potassium salt from Example 220 with HCl following the method in Example 170.
  • Example 222 Compound 222: The title compound was prepared as a buff solid by treatment of its acid derivative from Example 221 with NH 4 OH following the method in Example 171.
  • the title compound was prepared as a pale brown solid by treating its potassium salt with HCl following the method in Example 170.
  • Example 227, Compound 227 The title product was prepared as an orange solid by treatment of its respective potassium salt in Example 226 with HCl following the method in Example 170.
  • the title compound was prepared as a yellow solid by reaction of 3, 4, 5-trihydroxybenzaldehyde with pyrogallol to give the cyclic bright purple-red tetramer and similar conversion to the isomeric product in Example 226 by bromination with 12 equivalents of bromine to give a black solid,
  • Example 231 Compound 231:
  • Example 230 The title compound was prepared as a pale orange-brown solid by treatment of its acid derivative in Example 230 with ammonium hydroxide following the method of Example 171.
  • Example 232 Compound 232: The title compound was prepared as a buff coloured solid by reaction of pyrogallol with 3, 5-dibromo-4-hydroxybenzaldehyde to give an orange solid product, bromination following the method of Example 164 etherification with 32 equivalents of ethyl bromacetate following the method in Example 166, then treatment with ethanolic potassium hydroxide following the method in Example 169.
  • Example 232 The title compound was prepared as a brown solid by treatment of its potassium salt in Example 232 with HCl following the method in Example 170.
  • the title compound was prepared as a pale red-brown solid by treatment of its acid derivative with NH 4 OH following the method in Example 171.
  • Example 238 P-T-Butylcalix-4-arene Tetraacetic Acid
  • the compound was prepared as a colourless solid from its ethyl acetate derivative following the method in Example 12 after filtration and washing with ice cold water and allowing to air-dry overnight.
  • I.r.l)l730 S C 0cm .
  • the title compound was prepared as a colourless solid by hydrolysis of its ethyl acetate derivative, prepared following the method in U.S. Patent No. 4,556,700 by S. J. Harris, M.A. Kervey, D. P. Melody, J. Woods and J. M.
  • Example 243 P-T-Butylcalix-6-arene Hepta-potassium Acetate
  • Example 250 P-T-Butylcalix-4-arene Tetra-ethyl Acetate Derivative
  • Example 255 P-T-Butylcalix-8-arene Octa-ethyl Acetate Derivative
  • Example 256 P-T-Butyldihomooxacalix-4-arene Tetra-acetic Acid
  • Example 257 P-T-Butycalix-4-arene Tetra-t-butylketone
  • Example 259, Compound 259 The title compound was prepared following the procedure given in U.K. Patent Application No. 2,200,909 by S. J. Harris, August 17th 1988.
  • Example 260 Compound 260: The title compound was prepared as a colourless solid from
  • the title compound was prepared as a soluble linear polymer following the method cited in European Patent Application No. 0,309,291 by S. J. Harris, M. G. MacManus and J. Guthrie, 29th March 1989 .
  • the title compound was prepared as a colourless solid by treatment of cone calix-4-arene t-butyl acetate derivative with ethanolic KOH thence HCl following the method in Example 12.
  • P-Ethylcalix-7-arene heptaacetic Acid prepared in Example 240 was treated with thionyl chloride as in Example 12 to give its acetyl chloride then bis(hydroxyethyl) amine following the method cited in Example 246 to give the title product.
  • the title product was prepared by treating p-t-butylcalix-4-arene tetra-acetyl chloride with di-n-octylamine and triethylamine following the method cited in Example 246/8.
  • Example 70 P-Bromodihomooxacalix-4-arene tetra-acetic acid prepared in Example 70 was treated with thionyl chloride then di-n-octylamine following the method cited in Example 271 to give the title product.
  • Example 274, Compound 274 The title compound was prepared following the method of Example 138 bis (methoxyethyl) amine being used in place of bis(hydroxyethyl) amine.
  • Example 275 Compound 275: The title compound was prepared following the method cited in Example 271 substituting di-n-decylamine for di-n-octylamine.
  • P-T-Butylcalix-5-arene was prepared following the method cited in Example 3 then etherified with ethyl bromoacetate following the method cited in Example 14 to give its pentaethyl acetate derivative which was then converted to its acid salt, acid, acid chloride thence amide following the method cited in Example 246.
  • Compound 163 from Example 163 was quantitatively converted to its chloro derivative compound 280a by bubbling chlorine gas into a chloroform solution of same for 2 hr at room temperature and thence removal of all volatiles then converted to the title product, following the method in Example 166 and 167, as a pale yellow solid.
  • the anti-HIV and anti-SIV (Simian immunodeficiency virus) activities and toxicities of compounds were assessed in C8166 cells infected with
  • HIV-1 111B HIV-1 111B
  • HIV-2 ROD HIV-2 ROD
  • SIV MAC SIV MAC
  • the cells are cultured in RPM1 1640 with 10% calf serum.
  • a microtiter antigen capture ELISA was developed using lectin (GNA) from Galanthus nivalis (Vector Laboratories, Peterborough, U.K.) and human antibodies (12).
  • the plates were coated with lectin (0.5ug), and after blocking with 10% calf serum, dilutions of virus supernatant in 0.25% detergent solution (Empigen, Albright and Wilson Ltd., Whitehaven, U.K.) were added to the wells and incubated at 4°C for 12-16 hours.
  • Bound antigen was captured using human anti-HIV antibodies, and finally detected with anti-human Ig antibodies conjugated to horseradish peroxidase. The results are shown in Table 1.
  • Table 2 shows the effect of the compound of Example 169 on viral infectivity. Virus was incubated at room temperature with dilutions of the compound to be tested, and the compound was then removed by dilution to a virus non-inhibiting concentration. The viral infectivity was determined by adding C6166 cells and compared with untreated controls. The compound did not reduce the virus titre indicating:-
  • the compound does not inhibit infection by binding to viral envelope proteins, or
  • Table 3 describes the results of preliminary experiments to determine the mode of action of the compounds of the present invention. Antiviral activity is pronounced for the compounds tested when the compound is present during virus absorption, then when added 4 hours after infection suggesting that the compound of Example 169 is inhibiting infection at an early stage of virus replication (e.g. virus absorption, fusion, uncoating or reverse transcriptase activity), similarly to heparin.
  • an early stage of virus replication e.g. virus absorption, fusion, uncoating or reverse transcriptase activity
  • the compound was tested for inhibition of reverse transcriptase in vitro but was found to have no effect on it's activity.
  • the compounds tested appear to be highly active against HIV-1 and less so against HIV-2 and SIV.
  • Example 169 and 171 did not induce any signs of toxicity as shown by observation of behaviour over 5 days, in groups of three male and three female mice, after intravenous administration at 50mg/kg. Similarly there was no apparent toxicity at a dose of 200mg/kg following intravenous injection in groups of 2 male mice.
  • Table 4 shows how the determination of EC 50 and TC 50 was made for the compounds shown in Tables 5 to 13. The results for AZT are shown as a control.
  • EC 50 represents the concentration which reduces the Ag gp120 by 50% in infected cell cultures.
  • TC 50 represents the concentration of drug which reduces cell growth by 50%.
  • Viral titre was determined by serially diluting the compound/virus mixture before mixing with C8166 cells. The end point was measured by examining syncytia and by the MTT Formazan assay after five days of infection.
  • Heparin 100 100 31 52 2 100
  • EC 50 represents the concentration which reduced the Ag gp120 by 50% in infected cell cultures.
  • EC 50 is the concentration which reduces the Ag gp120 by 50% in infected cell cultures.
  • TC 50 is the concentration of drug which reduces cell growth by 50%.
  • Fusarium oxysporum, Fusarium graminearum. Pyricularia versicolor and coriolous versicolor were all grown on (Oxoid) potato dextrose agar. Trichophyton mentaoarophytes was grown on potato dextrose agar with 0.5% yeast extract (Difco) added. Trichophyton rubrum was grown on (Oxoid) szabaraud dextrose agar.
  • Sample compounds and bis (tributyltin oxide) were prepared in acetone and CuSO 4 in water. From the data obtained by Yagi et al (13) it was decided to look at concentrations of 10, 100 and 1,000 ⁇ M samples in the case of bis (tributyltin oxide) and CuSO 4 and concentrations of 1, 10 and 100 ⁇ M samples in the case of the test compound were tested.
  • the appropriate growth media were prepared and autoclaved in 100 ml lots. These were then cooled to 50°C and 1 ml of respective samples at concn. ⁇ 100 was added, i.e. for concn. of 1,000 ⁇ M, 1 ml of 100 mM sample solution was added.
  • Controls were set up for each fungus, one set with no addition, and one set with 1 ml of acetone added. All tests were carried out in quadruplicate.
  • Example 240 Example 241 Example 242 Example 243
  • Samples were dissolved in sterile water, and diluted again in sterile water as below.2ml aliquots of each sample was added to petri dishes, 18 ml of molten SD agar was then added to each plate, producing a 1/10 dilution of sample.

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Abstract

Composés à base de calixarène présentant une activité biologique et notamment antibactérienne, antifongique, anticancéreuse et antivirale. Il s'avère que certains composés présentent une activité anti-VIH. Les composés sont des calixarènes ou oxacalixarènes, des oligomères acycliques de phényle-formol, des dérivés de cyclotrivératrylène, des dérivés cycliques tétramères de résorcinol-aldéhyde appelés composés de Hogberg, et des dérivés cycliques tétramères de pyrogallol-aldéhyde.
PCT/IE1995/000008 1994-01-24 1995-01-24 Composes a base de calixarene presentant une activite antibacterienne, antifongique, anticancereuse et anti-vih WO1995019974A2 (fr)

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997015566A1 (fr) * 1994-04-28 1997-05-01 Georghiou Paris E Oligomeres nouveaux, procede de preparation et procedes d'utilisation
NL1008988C2 (nl) * 1998-04-24 1999-10-26 Stichting Tech Wetenschapp Calixareenverbinding en een selectief molecuul voorzien van een dergelijke verbinding.
EP1005356A1 (fr) * 1998-06-08 2000-06-07 Advanced Medicine, Inc. Agents antibacteriens
EP1038871A1 (fr) * 1997-12-09 2000-09-27 Cosmo Research Institute Derives sulfones de sulfures phenoles cycliques, leur procede de preparation, agents de separation et de recuperation contenant des sulfures phenoles cycliques, procedes de separation et de recuperation utilisant ces agents, et compositions de medicaments contenant lesdits sulfures
WO2002044121A1 (fr) * 2000-12-01 2002-06-06 Aids Care Pharma Limited Composes antiviraux
EP1367044A1 (fr) * 2002-05-31 2003-12-03 Aids Care Pharma Limited Dérivés du calixarène à activité antivirale
DE10226099A1 (de) * 2002-06-12 2004-01-08 Jörg Martin Dipl.-Chem. Dormann Filtermaterial für Toxine, Bakterien, Viren und andere physiologische Schadstoffe
WO2004085441A1 (fr) * 2003-03-24 2004-10-07 Centre National De La Recherche Scientifique Nouveaux composes de calix arenes, leur procede de preparation et leur utilisation, notamment en tant que mimes enzymatiques
WO2006042104A2 (fr) * 2004-10-04 2006-04-20 Regents Of The University Of Minnesota Mimetiques a conformation peptidique a base de calixarene, procedes d'utilisation, et procedes d'elaboration
US7338977B2 (en) * 2003-11-25 2008-03-04 Aids Care Pharma Limited Anti-viral compounds
WO2009025335A1 (fr) * 2007-08-23 2009-02-26 Jsr Corporation Composition et composé sensibles au rayonnement
FR2939666A1 (fr) * 2008-12-17 2010-06-18 Inst Radioprot Et De Surete Nu Formulations cosmetiques et pharmaceutiques de molecules de calix[6]arenes
AU2005208771B2 (en) * 2004-01-23 2011-11-24 The Trustees Of The University Of Pennsylvania Facially amphiphilic polyaryl and polyarylalkynyl polymers and oligomers and uses thereof
US8236800B2 (en) 2003-03-17 2012-08-07 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers and oligomers and uses thereof
WO2012140364A1 (fr) * 2011-04-12 2012-10-18 Universite De Lorraine Utilisation de calixarenes dans le traitement des infections bacteriennes
WO2012140365A1 (fr) * 2011-04-12 2012-10-18 Universite De Lorraine Utilisation de calixarenes associes avec un antibiotique dans le traitement des infections bacteriennes
WO2013024777A1 (fr) * 2011-08-12 2013-02-21 三菱瓦斯化学株式会社 Composé cyclique ainsi que procédé de fabrication de celui-ci, composition, et procédé de formation de motif de réserve
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CN115252869A (zh) * 2022-08-18 2022-11-01 南通大学 一种促进血管再生的纳米敷料及其制备方法

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5043415A (en) * 1987-09-24 1991-08-27 Loctite (Ireland) Ltd. Nitrogen-containing oxacalixarene and calixarene derivatives, polymers including groups related to such derivatives, and use of such compounds
IE59509B1 (en) * 1987-01-21 1994-03-09 Loctite Ireland Ltd Functionalised oxacalixarenes, their preparation and use in instant adhesive compositions
IE68312B1 (en) * 1989-12-13 1996-06-12 Loctite Ireland Ltd Calixarene and oxacalixarene derivatives and use thereof for sequestration of metals
US5210216A (en) * 1985-03-28 1993-05-11 Loctite (Ireland) Limited Calixarene and oxacalixarene derivatives and use thereof of sequestration metals
US4604404A (en) * 1985-04-03 1986-08-05 A. H. Robins Company, Inc. Antiviral sulfonated naphthalene formaldehyde condensation polymers
EP0259016B1 (fr) * 1986-08-29 1990-07-04 LOCTITE (IRELAND) Ltd. Dérivés de la calixarène et leur utilisation comme accélérateurs pour compositions adhésives instantanées
IE862567L (en) * 1986-09-29 1988-03-29 Loctite Ireland Ltd Encapsulating compositions
IE893986A1 (en) * 1989-12-13 1991-06-19 Loctite Ireland Ltd Polymerisable calixarene and oxacalixarene derivatives,¹polymers thereof, and use of such derivatives and polymers¹for sequestration of metals
US5132345A (en) * 1990-12-10 1992-07-21 Harris Stephen J Ion-selective electrodes
US5312837A (en) * 1991-01-29 1994-05-17 Genelabs Technologies, Inc. Method of treating viral infections with aryl macrocyclic compounds
FR2672214A1 (fr) * 1991-01-31 1992-08-07 Rhone Poulenc Rorer Sa Application de polymeres biologiquement actifs, pour l'obtention d'un medicament pour le traitement d'infections a retrovirus.
WO1994003164A1 (fr) * 1992-08-06 1994-02-17 Genelabs Technologies, Inc. Inhibition et traitement de l'infection par un virus a enveloppe avec des composes de calix(n) arene

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* Cited by examiner, † Cited by third party
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EP1038871A1 (fr) * 1997-12-09 2000-09-27 Cosmo Research Institute Derives sulfones de sulfures phenoles cycliques, leur procede de preparation, agents de separation et de recuperation contenant des sulfures phenoles cycliques, procedes de separation et de recuperation utilisant ces agents, et compositions de medicaments contenant lesdits sulfures
EP1038871A4 (fr) * 1997-12-09 2001-09-19 Cosmo Res Inst Derives sulfones de sulfures phenoles cycliques, leur procede de preparation, agents de separation et de recuperation contenant des sulfures phenoles cycliques, procedes de separation et de recuperation utilisant ces agents, et compositions de medicaments contenant lesdits sulfures
US6355671B1 (en) 1997-12-09 2002-03-12 Cosmo Research Institute Sulfonated derivatives of cyclic phenol sulfides, process for the preparation thereof, separating and recovering agents containing cyclic phenol sulfides, methods for separation and recovery therewith, and drug compositions containing the sulfides
NL1008988C2 (nl) * 1998-04-24 1999-10-26 Stichting Tech Wetenschapp Calixareenverbinding en een selectief molecuul voorzien van een dergelijke verbinding.
EP1005356A1 (fr) * 1998-06-08 2000-06-07 Advanced Medicine, Inc. Agents antibacteriens
EP1005356A4 (fr) * 1998-06-08 2001-08-22 Advanced Medicine Inc Agents antibacteriens
WO2002044121A1 (fr) * 2000-12-01 2002-06-06 Aids Care Pharma Limited Composes antiviraux
US8889163B2 (en) 2001-03-08 2014-11-18 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers as anti-infective agents
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US8455490B2 (en) 2003-03-17 2013-06-04 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers and oligomers and uses thereof
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US9241917B2 (en) 2003-03-17 2016-01-26 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers and oligomers and uses thereof
WO2004085441A1 (fr) * 2003-03-24 2004-10-07 Centre National De La Recherche Scientifique Nouveaux composes de calix arenes, leur procede de preparation et leur utilisation, notamment en tant que mimes enzymatiques
WO2004085442A3 (fr) * 2003-03-24 2004-12-16 Centre Nat Rech Scient Nouveaux composes calix arenes, leur procede de preparation et leur utilisation, en particulier comme mimes de sites enzymatiques
US7338977B2 (en) * 2003-11-25 2008-03-04 Aids Care Pharma Limited Anti-viral compounds
US8222456B2 (en) 2004-01-23 2012-07-17 The Trustees Of The University Of Pennsylvania Facially amphiphilic polyaryl and polyarylalkynyl polymers and oligomers and uses thereof
AU2005208771B2 (en) * 2004-01-23 2011-11-24 The Trustees Of The University Of Pennsylvania Facially amphiphilic polyaryl and polyarylalkynyl polymers and oligomers and uses thereof
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WO2006042104A3 (fr) * 2004-10-04 2007-01-18 Univ Minnesota Mimetiques a conformation peptidique a base de calixarene, procedes d'utilisation, et procedes d'elaboration
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EP2404895A1 (fr) * 2004-10-04 2012-01-11 Regents of the University of Minnesota Mimétiques à conformation peptidique à base de calixarene, procédés d'utilisation et procédés de fabrication
WO2006042104A2 (fr) * 2004-10-04 2006-04-20 Regents Of The University Of Minnesota Mimetiques a conformation peptidique a base de calixarene, procedes d'utilisation, et procedes d'elaboration
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JPWO2013024777A1 (ja) * 2011-08-12 2015-03-05 三菱瓦斯化学株式会社 環状化合物、その製造方法、組成物及びレジストパターン形成方法
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US9122153B2 (en) 2011-08-12 2015-09-01 Mitsubishi Gas Chemical Company, Inc. Cyclic compound, method for producing same, composition, and method for forming resist pattern
WO2013024777A1 (fr) * 2011-08-12 2013-02-21 三菱瓦斯化学株式会社 Composé cyclique ainsi que procédé de fabrication de celui-ci, composition, et procédé de formation de motif de réserve
KR20140104949A (ko) * 2011-11-18 2014-08-29 미쯔비시 가스 케미칼 컴파니, 인코포레이티드 환상 화합물, 그 제조방법, 감방사선성 조성물 및 레지스트 패턴 형성방법
KR20140093239A (ko) * 2011-11-18 2014-07-25 미쯔비시 가스 케미칼 컴파니, 인코포레이티드 환상 화합물, 그 제조 방법, 감방사선성 조성물 및 레지스트 패턴 형성 방법
KR101986544B1 (ko) 2011-11-18 2019-06-07 미쯔비시 가스 케미칼 컴파니, 인코포레이티드 환상 화합물, 그 제조 방법, 감방사선성 조성물 및 레지스트 패턴 형성 방법
KR102004692B1 (ko) 2011-11-18 2019-07-29 미쯔비시 가스 케미칼 컴파니, 인코포레이티드 환상 화합물, 그 제조방법, 감방사선성 조성물 및 레지스트 패턴 형성방법
WO2015196086A1 (fr) * 2014-06-20 2015-12-23 The University of Montana, Missoula, MT Nouveaux inhibiteurs du système xc(-)
CN107043364A (zh) * 2016-02-05 2017-08-15 徐州医学院 氧杂杯[4]芳烃衍生物及其应用
CN107043364B (zh) * 2016-02-05 2020-04-03 徐州医学院 氧杂杯[4]芳烃衍生物及其应用
CN107325810A (zh) * 2017-06-29 2017-11-07 广东医科大学 一种穴状多羟基荧光化合物及其应用
CN112771042A (zh) * 2018-09-28 2021-05-07 重庆复创医药研究有限公司 作为蛋白激酶抑制剂的萘啶酮和吡啶基嘧啶酮类化合物
WO2020074776A1 (fr) * 2018-10-08 2020-04-16 Aalto University Foundation Sr Composés macrocycliques et leurs utilisations
CN113164412A (zh) * 2018-10-08 2021-07-23 阿尔托大学基金会 大环化合物及其用途
CN115252869A (zh) * 2022-08-18 2022-11-01 南通大学 一种促进血管再生的纳米敷料及其制备方法

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