WO2001042228A1 - Composes macrocycliques et utilisation de ces derniers - Google Patents

Composes macrocycliques et utilisation de ces derniers Download PDF

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Publication number
WO2001042228A1
WO2001042228A1 PCT/GB2000/004725 GB0004725W WO0142228A1 WO 2001042228 A1 WO2001042228 A1 WO 2001042228A1 GB 0004725 W GB0004725 W GB 0004725W WO 0142228 A1 WO0142228 A1 WO 0142228A1
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WO
WIPO (PCT)
Prior art keywords
compound
mmol
dcm
meoh
triazine
Prior art date
Application number
PCT/GB2000/004725
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English (en)
Inventor
Dennis Lowik
Christopher Robin Lowe
Original Assignee
Prometic Biosciences 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 Prometic Biosciences Ltd. filed Critical Prometic Biosciences Ltd.
Priority to US10/149,508 priority Critical patent/US6998272B2/en
Priority to CA002394580A priority patent/CA2394580A1/fr
Priority to EP00988964A priority patent/EP1240150A1/fr
Priority to JP2001543528A priority patent/JP2003516398A/ja
Priority to AU25295/01A priority patent/AU2529501A/en
Publication of WO2001042228A1 publication Critical patent/WO2001042228A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • the invention relates to macrocylic compounds and their use.
  • Background of the Invention There is a growing interest in macrocyclic molecules that may be used as scaffolds in the combinatorial synthesis of receptor molecules. Many macrocyclic molecules have been synthesised. However, in many cases, their synthesis is difficult and/or relatively inflexible towards functionalisation.
  • unsymmet cally substituted macrocycles see Rasmussen etal, J. Tet. Lett. (1999) 40: 3511 ; H ⁇ ger ef a/, Chem. Eur. J. (1999) 5: 1686; Shu et al, J. Org. Chem. (1999) 64: 2673; and Cho etal, Bioorg. Med. Chem.
  • Mathias et al discloses linear triazine-based macromolecules, capable of supramolecular aggregation
  • lchihara et al discloses t azine-linked porphyrins
  • Lipkowski et al discloses compounds that form a [2x2] hydrogen-bonded grid.
  • Known macrocycles include those of the formula
  • Rasmussen et al discloses compounds in which X is a benzene ring, R 1 is H, Y is peptidic, R 2 is a functional group, and m is 3, for combinatorial applications.
  • Anelli et al discloses compounds in which X is triazine, R is Cl and m is 2, as intermediates to triply-bridged derivatives, capable of molecular recognition and of use as phase-transfer catalysts.
  • the present invention is based on a stepwise approach to the combinatorial synthesis of macromolecules having a desired/defined stereochemistry and also functional groups effectively predefined both for the potential uses of the molecule and for its synthesis (which can be done on a solid phase).
  • compounds are of the formula given above, wherein X is a ring bearing an optionally-protected functional group R 1 , Y is a linker optionally bearing an optionally-protected functional or solid phase group R 2 , and m is at least 3; each of X, Y, R 1 and R 2 may be the same or different.
  • Compounds of this invention provide, typically by choice of the functional group R , an effective recognition element.
  • compounds of the invention have a variety of uses, for example depending on their binding properties, for diagnostics and therapeutics. They may be used for affinity binding, phase-transfer agents and ionophors.
  • Compounds of the invention may also be used for molecular imprinting and for other purposes such as removing pesticides from water and for high performance chromatography.
  • compounds of the invention may be constructed to recognise portions of proteins, and thereby have value for targeting or separation purposes. Their utility may also depend on characteristics of the molecule other than R 1 , e.g. the value of m (which determines the "hole" in which foreign molecules may be bound).
  • the characteristics of compounds of the invention may be extended by using them in a multi-layer format. Description of the Invention
  • X is preferably triazine. It may also be any ring that bears or can readily be reacted to form the three given substituents on X, i.e. R 1 and two linkers Y. Y may be any suitable linker, of any desired length; it will often be preferred that the molecule forming the linker terminates in a functional groups such as NH, which can readily be reacted with a carbon atom in the ring X. By this means of synthesis, any group R 1 or
  • R 2 may already be present on X/Y. This allows a wide selection of suitable functional groups, according to the desired end purpose. Suitable protecting groups, their introduction and removal, are well known to those in the art, and will be used as necessary for protection during synthesis. The primary purpose of the functional group
  • R 1 will be with respect to foreign molecules to be bound by macrocycles of the invention; for this purpose, the groups R 1 may be the same or different. R 1 may also be used as a point of attachment to a solid phase. R 2 may be absent; if present, it will generally be chosen with a view to ready immobilisation of the linker, to facilitate synthesis and/or use of the macrocycles. As indicated below, this invention allows effective solid phase chemistry to be used. m will typically be 3. It may however be a higher integer, e.g. 4, 5 or 6, depending on the desired size of the macrocycle.
  • the solid phase may be any material that may conveniently be used to separate macrocyclic compounds of the invention from solutes in a contacting solution.
  • suitable solid phase support materials include, but are not limited to, polysaccharides such as agarose, cellulose, dextran, starch, alginate and carrageenan; synthetic polymers such as polystyrene, styrene-divinylbenzene copolymers, polymethacrylates, (e.g. poly(hydroxyethylmethacrylate), polyvinyl alcohol, poiyamides, polyacrylamides and perfluorocarbons; inorganic materials such as glass, silica and metal oxides; and composite materials.
  • libraries of macrocyclic compounds of the invention with differing X, Y, R 1 and R 2 groups may be constructed and subsequently screened for binding activity towards target compounds.
  • Macrocyclic compounds of the invention have general utility for the capture of complementary molecules. It will be appreciated that such compounds have many potential applications. Applications of compounds of the invention include, but are not limited to, the analysis, separation, isolation, purification, quantification, characterisation, or identification of chemical, biological or therapeutic compounds, the diagnosis of disease, and the treatment of disease.
  • compounds that can be separated from admixture with others include organic heterocycles such as cyanuric acid and saccharide-containing compounds such as octylglucosides .
  • Examples of therapeutic application are in the treatment of immune disorders and metabolic disorders by capture or clearance of carbohydrates and glycoproteins, and the removal of toxic substances from blood.
  • the invention will now be described with reference to the synthesis of macrocycles based on the triazine unit as a building block, with each unit comprising a triazine ring and a linker moiety (piperazine or diamine).
  • the chain can be either elongated or cyclised to the macrocycle of interest.
  • the use of two orthogonal protective groups (P 1 , P 2 ) on either side of the oligomers, allows control of the length of triazine-piperazine chain.
  • each triazine unit in the chain it is possible to functionalise each triazine unit in the chain differently by reaction with particular amines.
  • piperazine was used as the linker, in order to create relatively rigid macrocycles. It will be evident to those skilled in the art that larger rings may be prepared and that other linkers may be used, thereby increasing the diversity even further.
  • Example 1 Preparation of macrocyclic triazine compounds in solution The synthesis of the basic macrocyclic structures commenced with mono-Boc protection of piperazine 1 using a modification of the procedure described by Carpino et al, J.Org. Chem (1983) 48:661. Reaction of monoprotected piperazine 2 with cyanuric chloride gave the monosubstituted product 3 in 93% yield, using the procedures of Koopman etal, J. Rec. Trav. Chim. Pays-Bas (1958) 77:235 and Beech, Chem. Soc. C. (1967) 466.
  • Compound 3 can be used throughout the synthesis as a convenient building block for the elongation of triazine-piperazine oligomers.
  • Mono-Z protected piperazine was chosen as the second substituent on the triazine 3, since it provided a second piperazine moiety, orthogonally protected.
  • the mono-Z-protected piperazine was obtained by subsequent reaction of 2 with Z-chloride and TFA to give a quantitative yield of piperazine 5. This route is convenient and gives high yield.
  • the reaction of piperazine with Z-chloride only gave the bisubstituted product.
  • triazines 7 are also the starting point for the preparation of a series of functionalized triazine-pipera;:ine oligomers that can be eventually cyclised. At this point, compound 7a was chosen to continue the work: either the Boc or the Z-group could be removed to functionalise further this compound.
  • compound 7 was subjected to subsequent hydrogenolysis and a reaction with cyanuric chloride to afford dichloride 8 in a yield of 43%.
  • Elongation of bis-triazine 10 was obtained by subsequent reaction with TFA and building block 3 to produce tris-triazine 12 in a yield of 93%. The remaining chlorine was displaced with cyclohexylamine to give tris-triazine 13 in 92% yield. Repetition of these steps also afforded the precursors for the tetra-, penta- and hexa-triazine-piperazine macrocycles 14, 17 and 20 in 62%, 46% and 43% overall yields, respectively, from compound 13.
  • the triazine-piperazine oligomers 8, 11 , 14, 17 and 20 were used to prepare their respective macrocycles by subsequent treatment with acid and base (scheme 4).
  • Example 2 Preparation of immobilised macrocyclic triazine compounds by solid phase synthesis Having shown that it is possible to synthesise macrocycles based on triazine- piperazine building blocks in solution, the next step was to repeat this or similar chemistry on a solid phase. Synthesising the macrocycles on a solid phase allows the possibility to generate many variants that may be screened easily for their binding properties. However, in order to attach the compounds to a resin, appropriate coupling chemistry or a 'handle' is required.
  • a flexible way to achieve this without having to use one of the triazine rings was to use an additional functionality on one of the piperazine rings, as found in piperazine 30 It was also considered beneficial to have a linker between the resin and the triazine-piperazine based molecules, in order to permit detachment from the solid phase and analysis of their structure This may be achieved by inserting a methionine residue between the piperazine 30 and the resin, in order to give a linkage that is stable to the conditions (acids, bases and nucleophiles) under which the macrocycles are synthesised The methionine linkage may be subsequently cleaved with cyanogen bromide Alternatives include a photocleavable bond or one involving a vicinal diol and cleavable by pe ⁇ odate oxidation, Furthermore, instead of building block 3, N-protected triazine-piperazine 32 was used, in which a tntyl protective group is used such that it may be removed without
  • the solid phase synthesis proceeded by selective removal of the tntyl group, followed by a reaction with 32 which elongated the triazine-piperazine chain
  • the additional triazine was functionalised by a reaction with amyl amine
  • the synthesis was concluded by a reaction of the di-t ⁇ azine with cyanuric chloride followed by ring closure and a final reaction with a third amine, after removal of the Boc group, to provide compound 44
  • a combinatorial library of 48 macrocyclic compounds was synthesised Diversity was obtained by functionalisation of the tnazines using various commercially available amines
  • the solid phase synthesis is an efficient way to obtain a library of macrocycles that may act as receptor molecules towards a variety of complementary ligands
  • Example 3 Preparation of macrocyclic compounds incorporating xylenediamine spacer groups
  • other diamines such as xylenediamine were used to create novel macrocyclic structures
  • a new building block 46 was required and easily prepared from monoprotected xylenediamine 45 and cyanuric chloride in 85% yield, as illustrated in Scheme 7.
  • orthogonally protected linker 47 (96% yield)
  • the remaining chlorine in triazine 48 was substituted using an excess of amylamine to afford triazine 49 in 98% yield.
  • Compound 49 can be regarded as a starting point for the preparation of xylene-triazine oligomers.
  • Monotriazine 49 was elongated by subsequent reactions with TFA and building block 46 to give bis-triazine 50 in 83% yield. Refluxing this compound with an excess of either amyl- or iso-butylamine afforded oligomers 51a and 51b both in 97% yield.
  • the Z- group from compounds 51 was removed and the resulting free amine was subsequently used in a reaction with cyanuric chloride.
  • the crude dichlorotriazines obtained were used directly for cyclisation to afford macrocycles 52a and 52b. Yields of 36% and 34%, respectively were obtained for the cyclisation affording rings 52a and 52b.
  • 53a and 53b should be able to completely encircle one molecule of cyanuric acid.
  • compound 53b was titrated with 0.1 to 2 equivalents of cyanuric acid. After the addition of the appropriate amount of cyanuric acid, each sample was sonicated for three hours. Compound 53b was able to dissolve at least one equivalent of cyanuric acid in CDCI 3 , which was otherwise poorly soluble in this solvent. The addition of cyanuric acid to compound 53b generates new signals in the NMR spectrum that were assigned to the newly-formed complex. The equilibrium established between the free and the bound state is slow on the NMR time scale, as both the free and bound state were visible. A binding constant of 2.5 x 10" M "1 was calculated by non-linear regression of binding isotherms. The curve obtained was consistent with the postulated 1 :1 stoichiometry.
  • Electron Spray Mass Spectrometry (ESI), Fast Atom Bombardment (FAB) and Liquid secondary Ion Mass Spectrometry (LSIMS) were carried out on a Bruker Bio-Apex II FT-ICR, Micromass Q-TOF or MSI Concept.
  • ESI Electron Spray Mass Spectrometry
  • FAB Fast Atom Bombardment
  • LIMS Liquid secondary Ion Mass Spectrometry
  • Compound 19 was prepared from Compound 18 (0.24 g, 0.16 mmol) and 2- phenylethylamine (303 ⁇ L, 2.42 mmol) according to the procedure described for Compound 12, except that the reaction time was 5 hours, to yield 241 mg of product (94%). R, 0.17 (3% MeOH in DCM), 0.72 (EtOAc/hexanes 2:1). HRMS (ESI) calcd for C 81 H 114 N 32 NaO 4 (M+Na) + : 1621.9598, found m/z: 1621.9646. Compound 20
  • Compound 47 was prepared from Compound 45 (1.57 g, 6.64 mmol) according to the procedures described for Compound 4 and Compound 5, to give 1.36 g product (94%). R, 0.18 (10% MeOH and 1% Et 3 N in DCM). Compound 48 To a solution of 807 mg Compound 47 (2.99 mmol) in 20 mL water/acetone 1:1 ,
  • Compound 50 was prepared from Compound 49 (1.03 g, 1.54 mmol) and Compound 26 (563 mg, 1.54 mmol) according to the procedure described for Compound 9, except that the reaction time was extended to 4 hours. Column chromatography (eluent: 4% MeOH in DCM) afforded 1.17 g of product (83%). R f 0.50 (10% MeOH in DCM). HRMS (ESI) calcd for C 48 H 59 CIN 13 O 4 (M+H) + : 916.4501 , found m/z: 916.4511.
  • Compound 51a was prepared from Compound 50 (0.50 g, 0.52 mmol) and isobutylamine (414 mL, 4.17 mmol) according to the procedure described for Compound 10, to afford 500 mg of the title compound (97%). R f 0.47 (10% MeOH in DCM). HRMS (LSIMS) calcd for C 52 H 69 N 14 O 4 (M+H) + : 953.5626, found m/z: 953.5637. Compound 51 b

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés macrocycliques prévus pour recueillir un soluté dans une solution et qui présentent la formule (I). Dans cette dernière, X est une chaîne supportant un groupe fonctionnel éventuellement protégé ou un groupe de phase solide R1, Y est un lieur supportant éventuellement un groupe fonctionnel éventuellement protégé ou un groupe de phase solide R2, m est au moins égale à 3, et chaque élément parmi X, Y, R1 et R2 peut être semblable ou différent.
PCT/GB2000/004725 1999-12-10 2000-12-11 Composes macrocycliques et utilisation de ces derniers WO2001042228A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US10/149,508 US6998272B2 (en) 1999-12-10 2000-12-11 Macrocyclic compounds and their use
CA002394580A CA2394580A1 (fr) 1999-12-10 2000-12-11 Composes macrocycliques et utilisation de ces derniers
EP00988964A EP1240150A1 (fr) 1999-12-10 2000-12-11 Composes macrocycliques et utilisation de ces derniers
JP2001543528A JP2003516398A (ja) 1999-12-10 2000-12-11 大環状化合物およびそれらの使用
AU25295/01A AU2529501A (en) 1999-12-10 2000-12-11 Macrocyclic compounds and their use

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GB9929318.5 1999-12-10
GBGB9929318.5A GB9929318D0 (en) 1999-12-10 1999-12-10 Macrocyclic compounds and their use

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052870A1 (fr) 2002-12-09 2004-06-24 Prometic Biosciences Ltd. Composes de triazine et leur utilisation dans la formation de bibliotheques multidimensionnelles pour la chromatographie d'affinite
US7683061B2 (en) * 2003-11-24 2010-03-23 Prometic Biosciences Inc. Triazine dimers for the treatment of autoimmune diseases
CN103193784A (zh) * 2013-04-07 2013-07-10 东华大学 一种含嘧啶基团刚性共轭大环化合物及其制备方法和应用
CN103819479A (zh) * 2014-03-10 2014-05-28 东华大学 一种含嘧啶基团刚性共轭大环化合物及其制备方法和应用
US9181298B2 (en) 2003-06-18 2015-11-10 Ocera Therapeutics, Inc. Intermediates for macrocyclic compounds
CN108218803A (zh) * 2018-01-12 2018-06-29 首都医科大学 一种六元亚胺环化合物及一锅法合成六元亚胺环化合物的方法

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DE3932914A1 (de) * 1989-10-03 1991-04-11 Sandoz Ag Aufhellersalze
EP0560567A1 (fr) * 1992-03-09 1993-09-15 Texaco Development Corporation Calix-arène encapsulation de s-triazines et leur utilisation pour diminuer les oxides d'azote dans les gaz d'échappement provenant de carburant diesel

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DE3932914A1 (de) * 1989-10-03 1991-04-11 Sandoz Ag Aufhellersalze
EP0560567A1 (fr) * 1992-03-09 1993-09-15 Texaco Development Corporation Calix-arène encapsulation de s-triazines et leur utilisation pour diminuer les oxides d'azote dans les gaz d'échappement provenant de carburant diesel

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C.-M. SHU ET AL.: "Synthesis of Calix[4]arenes with Four Different "Lower Rim" Substituents", J. ORG. CHEM., vol. 64, no. 8, 1999, pages 2673 - 2679, XP002165630 *
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J. P. MATHIAS ET AL.: "Self-Assembly through Hydrogen Bonding: Peripheral Crowding - A New Strategy for the Preparation of Stable Supramolecular Aggregates Based on Parallel, Connected Ca(3).M(3) Rosettes", J. AM. CHEM. SOC., vol. 116, no. 10, 1994, pages 4326 - 4340, XP000942081 *
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P. H. RASMUSSEN, J. REBEK, JR.: "A Pseudopeptide Platform with Side Chains Addressable for Combinatorial Applications", TETRAHEDRON LETT., vol. 40, 1999, pages 3511 - 3514, XP002165631 *
P. L. ANELLI ET AL.: "Doubly and Triply Bridged Polyoxapolyazaheterophanes Derived from 2,4,6-Trichloro-s-triazine", J. ORG. CHEM., vol. 49, no. 22, 1984, pages 4197 - 4203, XP000615835 *
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052870A1 (fr) 2002-12-09 2004-06-24 Prometic Biosciences Ltd. Composes de triazine et leur utilisation dans la formation de bibliotheques multidimensionnelles pour la chromatographie d'affinite
AU2003288447B2 (en) * 2002-12-09 2008-02-21 Prometic Biosciences Ltd. Triazine compounds and their use in forming multidimensional libraries for affinity chromatography
US7723335B2 (en) 2002-12-09 2010-05-25 Prometic Biosciences Ltd. Triazine compounds and their use in forming multidimensional libraries for affinity chromatography
CN1788003B (zh) * 2002-12-09 2011-04-06 普罗米蒂克生物科学有限公司 三嗪化合物及其在形成用于亲合色谱的多维库中的应用
US9181298B2 (en) 2003-06-18 2015-11-10 Ocera Therapeutics, Inc. Intermediates for macrocyclic compounds
US10040751B2 (en) 2003-06-18 2018-08-07 Ocera Therapeutics, Inc. Intermediates for macrocyclic compounds
US7683061B2 (en) * 2003-11-24 2010-03-23 Prometic Biosciences Inc. Triazine dimers for the treatment of autoimmune diseases
CN103193784A (zh) * 2013-04-07 2013-07-10 东华大学 一种含嘧啶基团刚性共轭大环化合物及其制备方法和应用
CN103193784B (zh) * 2013-04-07 2015-10-28 东华大学 一种含嘧啶基团刚性共轭大环化合物及其制备方法和应用
CN103819479A (zh) * 2014-03-10 2014-05-28 东华大学 一种含嘧啶基团刚性共轭大环化合物及其制备方法和应用
CN103819479B (zh) * 2014-03-10 2017-01-04 东华大学 一种含嘧啶基团刚性共轭大环化合物及其制备方法和应用
CN108218803A (zh) * 2018-01-12 2018-06-29 首都医科大学 一种六元亚胺环化合物及一锅法合成六元亚胺环化合物的方法

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GB9929318D0 (en) 2000-02-02
CA2394580A1 (fr) 2001-06-14
AU2529501A (en) 2001-06-18
JP2003516398A (ja) 2003-05-13

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