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WO1998046631A1 - Echantillotheques combinatoires de macrocycles peptidomimetiques et procedes correspondants - Google Patents

Echantillotheques combinatoires de macrocycles peptidomimetiques et procedes correspondants Download PDF

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Publication number
WO1998046631A1
WO1998046631A1 PCT/US1998/007135 US9807135W WO9846631A1 WO 1998046631 A1 WO1998046631 A1 WO 1998046631A1 US 9807135 W US9807135 W US 9807135W WO 9846631 A1 WO9846631 A1 WO 9846631A1
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group
hydrogen
formula
chloride
acid
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PCT/US1998/007135
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English (en)
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David Mendel
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Eli Lilly And Company
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Priority to JP54406098A priority Critical patent/JP2002506423A/ja
Priority to CA002286867A priority patent/CA2286867A1/fr
Priority to EP98914651A priority patent/EP1015479A4/fr
Priority to AU68955/98A priority patent/AU6895598A/en
Publication of WO1998046631A1 publication Critical patent/WO1998046631A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • the present invention relates to diverse libraries of peptidomimetic organopeptide macrocyclic compounds, combinatorial methods of making such libraries, and an apparatus for storing and providing a readily accessible source of such libraries.
  • the apparatus harboring the present combinatorial libraries is a useful component of assay systems for identifying compounds for drug development.
  • Synthesis of compounds is an expensive and time consuming phase of research and development. Historically, research chemists individually synthesized and analyzed high purity compounds for biological screening to develop pharmaceutical leads. Although such methods were successful in bringing new drugs to the market, the limitations of individual synthesis and complete compound characterization considerably slowed the discovery of new pharmaceutically active compounds. The need for more rapid and less expensive drug discovery methodology is increasingly important in today's competitive pharmaceutical industry. Recently, modern drug discovery has utilized combinatorial chemistry to generate large numbers (10 ⁇ - 10 ⁇ ) of compounds generally referred to as "libraries”. An important objective of combinatorial chemistry is to generate a large number of novel compounds that can be screened to identify lead compounds for pharmaceutical research.
  • the total number of compounds which may be produced for a given library is limited only by the number of reagents available to form substituents on the variable positions on the library's molecular scaffold.
  • the combinatorial process lends itself to automation, both in the generation of compounds and in their biological screening, thereby greatly enhancing the opportunity and efficiency of drug discovery.
  • Combinatorial chemistry may be performed in a manner where libraries of compounds are generated as mixtures with complete identification of the individual compounds postponed until after positive screening results are obtained.
  • a preferred form of combinatorial chemistry is "parallel array synthesis", where individual reaction products are simultaneously synthesized, but are retained in separate vessels.
  • the individual library compounds can be prepared, stored, and assayed in separate wells of a microtiter plate, each well containing one member of the parallel array.
  • the use of standardized microtiter plates or equivalent apparatus is advantageous because such an apparatus is readily accessed by programmed robotic machinery, both during library synthesis and during library sampling or assaying.
  • Combinatorial chemistry can be carried out in solution phase where both reactants are dissolved in solution or in solid phase where one of the reactants is covalently bound to a solid support.
  • completion of the solution phase reactions in combinatorial chemistry schemes are ensured by selecting high yielding chemical reactions and/or by using one reagent in considerable excess.
  • one reagent is used in excess, completion of the reaction produces a mixture of a soluble product with at least one soluble unreacted reagent.
  • Solid phase synthesis offers the advantage that the solid support-bound products are easily washed free of excess reagent.
  • Solution phase synthesis typically requires use of one or more reaction mixture work-up procedures to separate reaction product from unreacted excess reagent.
  • Combinatorial chemistry may be used at two distinct phases of drug development.
  • discovery phase diverse libraries are created to find lead compounds.
  • second optimization phase strong lead compounds are more narrowly modified to find optimal molecular configurations .
  • peptidomimetics are frequently used to redeploy important peptide main chain and side chain pharmacophores onto less peptide-like scaffolds. Peptidomimetics vary greatly in their resemblance to peptides. Success has been achieved with peptides containing hydrolytically stable amide surrogates, mixed organo-peptide frameworks, and with non-peptide scaffolds alike.
  • Benzodiazepines, penicillins and cephalosporins are well-established peptidomimetic drugs and it is easy to see that organo- peptide chimeras are essential to both rational design and combinatorial chemistry approaches to drug discovery.
  • Conformational restriction is important in drug pharmacology and efficacy because i) less flexible molecules usually bind with much higher affinity to their targets because less energy is expended in freezing out non-active conformations and ii) conformationally restricted peptides are usually less susceptible to digestion by proteases, hence are expected to be more active drugs.
  • preparation of cyclic compounds has been an important drug discovery tactic to take advantage of those features. [See Hruby, Life Sciences, 31, 189-199 (1982); Kates et al .
  • the present invention is directed to the construction of a series of novel structurally related macrocyclic compounds from one or more aminothioether compounds or one or more of their corresponding sulfoxide or sulfone derivatives, collectively referred to herein as "ATAs".
  • ATA compounds are used in combination with other ATAs and other organic compounds that bear amine and acid functionality, to generate the present novel, diverse macrocyclic compounds having at least 2 sulfur linkages in the macrocycle ring structure, wherein the oxidation state of those linkages may vary.
  • ATAs By linking ATAs together in sequence, one may generate an oligomer with a backbone alternating between sulfur and amide linkages.
  • the flexibility of the present process for preparing the macrocyclic libraries enables construction of peptidomimetics that are not constrained to the normal spacing or "register" found in normal peptides.
  • the process also enables facile synthesis of macrocycle libraries having the same number or a different number of ring atoms of from about 12 to about 40 ring atoms. Libraries of these macrocyclic ATA compounds are screened to identify lead compounds through their biological activity.
  • ATAs are dipeptides where a thioether bridge replaces the central amide linkage, such as, for example, those described by Spatola, A.F., in Chemistry and Biochemistry of Amino Acids, Peptides and Proteins , B. Weinstein, Ed.; Marcel Dekker: New York, 1983; Vol. 7; pages 267-357.
  • a facile synthesis of such compounds from commercially available amino acids or amino alcohols and mercapto acids provides a diverse array of ATA compounds for use in preparation of novel macrocycle libraries described in the present invention.
  • the diverse ATA compounds are used in combination with other organic compounds that bear amine and acid functionality, including both proteiogenic amino acids and non- proteiogenic amino acids, to construct diverse libraries of peptidomi etic macrocyclic compounds of the present invention.
  • the present invention is also directed to a simple and direct process for the production of diverse libraries of novel macrocyclic organo-peptide compounds useful in the identification of new pharmaceutical lead compounds.
  • the present library compounds may be easily prepared using solid phase synthesis techniques via carbodiimide-mediated coupling of one or more ATAs with proteiogenic and non-proteiogenic amino acids, followed by solid phase or solution phase cyclization by a thioetherforming intramolecular nucleophilic displacement reaction.
  • the anchor residue and the terminal bromoacid, as well as the identity, number and coupling order of the intervening amino acid and ATA components all contribute to the unique structural identity of the macrocycle product .
  • TFA trifluoroacetic acid
  • the library is created, stored, and used as an apparatus comprising a two-dimensional array of reservoirs, each reservoir containing a predetermined library reaction product differing from those in adjacent reservoirs .
  • kits for the identification of pharmaceutical lead compounds comprising assay materials and a well plate apparatus or equivalent apparatus providing a two- dimensional array of defined reservoirs.
  • the well plate apparatus provides a diverse combinatorial library, wherein each well (reservoir) contains a unique macrocycle compound, or stereoisomers and/or regioisomers thereof.
  • the well plate apparatus is used to provide multiple reaction zones for making the library, to store the library and to provide a readily accessible source of library compounds .
  • Fig. 1 is a top view of a well plate in accordance with this invention.
  • Fig. 2 is a side view of a well plate apparatus for use in the process of this invention.
  • test kit refers to an assemblage of two cooperative elements, namely (1) a well plate apparatus and (2) biological assay materials.
  • Biological assay materials are materials necessary to conduct a biological evaluation of the efficacy of any library compound in a screen relevant to a selected disease state.
  • a "library” is a collection of compounds created by a combinatorial chemical process, said compounds having a common scaffold with one or more variable substituents.
  • a “library compound” is an individual reaction product, a single compound or a mixture of isomers, in a combinatorial library.
  • a “Lead compound” is a library compound in a selected combinatorial library for which the assay kit has revealed significant activity relevant to a selected disease state.
  • a “diverse library” means a library where the substituents on the combinatorial library scaffold or core structure, are highly variable in constituent atoms, molecular weight, and structure, and the library, considered in its entirety, is not a collection of closely related homologues or analogues (compare to "directed library”) .
  • a “directed library” is a collection of compounds created by a combinatorial chemical process, for the purpose of optimization of the activity of a lead compound, wherein each library compound has a common scaffold, and the library, considered in its entirety, is a collection of closely related homologues or analogues to the lead compound (compare with "diverse library”).
  • scaffold as used in accordance with the present invention comprises a peptido imetic macrocycle bearing at least two sulfur linking groups.
  • the scaffold may be further derivatized using conventional combinatorial techniques.
  • Substituents are chemical radicals which are bonded to or incorporated onto the scaffold through the combinatorial synthesis process.
  • the different functional groups account for the diversity of the molecules throughout the library and are selected to impart diversity of structure, function and biological activity to the scaffold in the case of diverse libraries, and optimization of a particular biological activity in the case of directed libraries.
  • Reagent means any chemical compound used in the combinatorial synthesis process to incorporate substituents on the scaffold of a library.
  • Paraallel array synthesis refers to the method of conducting combinatorial chemical synthesis of libraries wherein the individual combinatorial library compounds are separately prepared and stored without prior and subsequent intentional mixing.
  • “Simultaneous synthesis” means making of library compounds within one production cycle of a combinatorial method (not making all library compounds at the same instant in time) .
  • reaction zone refers to the individual vessel location where the combinatorial chemical library compound preparation process of the invention is carried out and where the individual library compounds are synthesized.
  • Suitable reaction zones include, but are not intended to be limited to the individual wells of a well plate apparatus .
  • Well plate apparatus refers to the structure capable of holding one or more library compounds in dimensionally fixed and defined positions.
  • Non-interfering substituents are those chemical radicals that do not significantly impede the process of the invention and yield stable aminothioether macrocyclic library compounds .
  • Aryl means one or more aromatic rings, each of 5 or
  • alkyl means straight or branched chain or cyclic hydrocarbon having 1 to 20 carbon atoms.
  • Substituted alkyl is alkyl having one or more non- interfering substituents.
  • Halo means chloro, fluoro, iodo or bromo .
  • Heterocycle or “heterocyclic radical” means one or more rings of 5, 6 or 7 atoms with or without unsaturation or aromatic character, optionally substituted with one or more non-interfering substituents, and at least one ring atom which is not carbon.
  • Preferred heteroatoms include sulfur, oxygen, and nitrogen. Multiple rings may be fused, as in quinoline or benzofuran, or unfused as in 4- phenylpyridine .
  • Suitable substituents on the heterocyclic ring structure include, but are not limited to halo, C ⁇ Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, C1-C10 alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyi, C3-C10 cycloalkenyl, di (C1-C10) -alkylamino, C2-C12 alkoxyalkyl, Ci-C ⁇ alkylsulfinyl, C1-C10 alkylsulfonyl, arylsulfonyl, aryl, hydroxy, hydroxy (C ⁇ -C ⁇ o) alkyl, aryloxy (C1-C10 ) alkyl , Cl-Cio alkoxycarbonyl , aryloxycarbon
  • Organic moiety means a substituent comprising a non-interfering substituent covalently bonded through at least one carbon atom.
  • Suitable substituents onto a connecting carbon atom include, but are not limited to hydrogen, halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, Cl-Cio alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyi, C3-C10 cycloalkenyl, di (Cl-Cio ) -alkylamino, C2-C12 alkoxyalkyl, Ci-C ⁇ alkylsulfinyl , C1-C10 alkylsulfonyl, arylsulfonyl , aryl, hydroxy, hydroxy (C ⁇ Cio
  • amino acid as used in accordance with the present invention includes the 20 proteiogenic amino acids encoded by the genetic code, as well as hydroxyproline, alpha-aminoisobutyric acid, sarcosine, citrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, beta-alanine, 4-aminobutyric acid and other compounds of the general formula:
  • R n is hydrogen or an organic moiety
  • Q is an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from 0, N and S; or R n taken together with Q and the nitrogen atom to which they are bound form a 4 to 7-membered ring.
  • Proteiogenic amino acids are those amino acids of the formula
  • Rn wherein Ri is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, sulfhydrylmethyl, 2 (methylthio) ethyl, benzyl, 4-hydroxybenzyl , 3-indolylmethyl, carboxymethyl, 2-carboxyethyl, carbamidomethy1, 2-carbamidoethyl, 4-aminobutyl, 3-guanadinylpropyl and 4-imidazolylmethyl, and R n is hydrogen, or R n and Ri taken together with the common bonded nitrogen atom form a pyrrolidine ring.
  • Activated acid or “activated acid group” refers to a carboxylic acid that has been reacted to form a group - C(0)X wherein X is a leaving group subject to nucleophilic displacement by nucleophiles.
  • exemplary of the group X is chloro (an acid chloride), -0C(0)R ⁇ (an anhydride), or -
  • Acid reactive groups refer to those nucleophilic groups capable of reacting with activated acids to form a covalent bond.
  • Exemplary of acid reactive groups are -OH, -SH or -NHR r , where R r is hydrogen or an organic moiety, and stabilized carbon anions.
  • Solid support refers to a solvent insoluble substrate having acid reactive groups for forming cleavable covalent bonds with acid reagents, such as S- protected amino-protected mercapto amino acids for use in preparing the present library compounds .
  • ring atoms in defining this invention refers to those atoms or “ring members” covalently bonded serially, one to another, to form a ring structure.
  • a diverse library of macrocyclic compounds is provided in accordance with the present invention.
  • the macrocycle library embodied as an apparatus of this invention serves as a readily accessible source of diverse macrocyclic compounds for use in identifying new biologically active macrocyclic compounds through pharmaceutical and agricultural candidate screening assays, for use in studies defining structure/activity relationships, and/or for use in clinical investigation.
  • L is a divalent group of the formula - (CH 2 ) 0 - ⁇ -C 6 H 4 CH 2 - or -CHR a - wherein R a is hydrogen or an organic moiety;
  • R z is hydrogen or methyl
  • B is hydroxy, or a group of the formula -NRyRt wherein Ry is hydrogen, alkyl, aryl or heterocycle, and R is hydrogen, a solid support, or Rt is a group of the formula
  • E is hydrogen, a solid support or a substituent derived from an electrophilic reagent
  • T is a divalent linking group
  • Ry is hydrogen or a substituent derived from an electrophilic reagent
  • R and Ry taken together with the atoms to which they are bonded form a 6- to 7-membered ring or a bicyclic or tricyclic ring comprising 6 to 12 carbon atoms
  • Ry or Ry taken together with -T- and the atoms to which they are commonly bonded form a 4- to 7-membered ring
  • Ry and Ry each taken together with T and the nitrogen atom to which they are respectively bonded form a 5- to 7- membered ring
  • E is hydrogen, a solid support or a substituent derived from an electrophilic reagent
  • T is a divalent linking group
  • Ry is hydrogen or a substituent derived from an electrophilic reagent
  • Z is a divalent group of the formula
  • each of AAi- ⁇ is independently a divalent group of the formula
  • each of ATA ⁇ -3 is independently a divalent sulfur- linked group of the formula
  • Q and Q' are each independently an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from 0, N and S; m is 0 , 1 or 2 ;
  • R s is hydrogen or an organic moiety
  • R n ' is hydrogen, or an organic moiety, or R n taken together with Q and the atoms to which they are bonded form a 4- to 7-membered ring;
  • Rn ' and R s taken together with -Q ' - and the atoms to which they are bonded form a 4- to 7-membered ring or a bicyclic or tricyclic ring comprising 6 to 12 carbon atoms; or Rn ' or R s taken together with -Q ' - and the atoms to which they are commonly bonded form a 4- to 7-membered ring.
  • the library compounds of this invention have a molecular weight of about 200 to about 1500, more typically about 250 to about 1250.
  • the present macrocycle library compounds as represented by Formula I include 12 to 40 ring atoms.
  • the library compounds are constructed to have 12 to 24 ring atoms, at least two of which are sulfur.
  • the ring atoms are derived from four types of reactants during the solid phase synthesis: 1) a solid suppor -anchored orthogonally protected trifunctional (protected thiol, protected amino, carboxy) compound (viz.
  • cysteine or penicillamine ; 2) aminoacids, selected from proteiogenic amino acids and non- proteiogenic amino acids; 3) ATAs (a inothioether acids and their corresponding sulfoxide and sulfone derivatives) ; and 4) alpha-halo acids, preferably alpha- bromo acids or carboxy- or carboxymethyl-substituted benzyl bromides.
  • macrocycle synthesis is initiated by deprotecting the support anchored amine functional group.
  • the linear (or at least acyclic) macrocycle precursor is synthesized by serial peptide coupling of at least one ATA and zero, one or more amino acids .
  • the resulting terminal amine functionality is finally coupled, by peptide bond formation, to an alpha- halo acid or a carboxy/carboxymethyl substituted benzyl bromide to provide an electrophilic (bromomethyl) terminus.
  • an alpha- halo acid or a carboxy/carboxymethyl substituted benzyl bromide to provide an electrophilic (bromomethyl) terminus.
  • the support bound orthogonally protected cysteine or penicillamine contributes 4 ring atoms to the macrocycle structure
  • use of an alpha-halo acid contributes two ring atoms
  • use of a carboxy/carboxymethyl substituted benzyl bromide contributes 4 to 7 ring atoms to the macrocycle structure.
  • the remaining ring members are determined by the nature, coupling order and number of the amino acids and ATAs coupled during synthesis of the acyclic support bound macrocycle precursor.
  • the libraries in accordance with this invention can be synthesized to have diversity in the number of ring atoms, or they can be prepared so that each member of the library has the same number of ring atoms with diversity in the library being introduced by the nature and coupling order of the component amino acids (AA ⁇ -6) and ATAs.
  • Additional elements of diversity can be introduced into the present macrocycle library by the preparation and use of solid supports having selected acid reactive groups such as, for example, those acid reactive groups derived from reaction of diamines with p-nitrophenylcarbonate
  • Such library compounds are derived from the corresponding library compounds wherein B is a solid support, particularly a Rink-Amide AM resin or Rink-Amide MBHA resin by trifluoracetic acid mediated cleavage of the covalently bound library compound or its acyclic precursor from the solid support.
  • Another embodiment of the present invention provides macrocycle library compounds of Formula I wherein B is a group of the formula -NRyRt wherein is hydrogen, alkyl, aryl or heterocycle and Rt is hydrogen, a solid support, or Rt is a group of the formula
  • T, Ry" and E are as defined above.
  • the compounds where E is hydrogen can be derived from corresponding library compounds wherein E is a solid support, particularly a Wang resin, by trifluoroacetic acid mediated cleavage, or they can be derived by cyclization of the corresponding acyclic polymers.
  • the library compounds of Formula I wherein E is hydrogen are useful as core structures for the synthesis of directed macrocycle libraries having diversity in the group E through reactions with various electrophilic reagents to construct variable "side chain" functionality on the macrocycle library compounds.
  • the library compounds of Formula I wherein the group B or E is a covalently bonded solid support (and the corresponding acyclic precursor compounds) also represent embodiments of the present invention.
  • a general compilation of solid supports (resins) can be found in "Supports for Solid Phase Organic Synthesis, " Martin Winter, pp 465-510, in Combinatorial Peptide and Non- peptide Libraries, edited by G ⁇ nther Jung (1996) , VCH
  • solid supports having acid reactive groups such as hydroxy and primary or secondary amino groups (or precursors thereto) are commercially available.
  • the acid reactive groups covalently bound to solid supports are typically designed to have selectively cleavable covalent bonds linking it to the solid support.
  • Illustrative of commercially available solid supports include, but are not intended to be limited to, the following resins:
  • T and Ry ' are as defined above and E is a solid support, are derived from the modified Wang resin bearing acid reactive groups of the formula
  • the modified Wang resin is prepared by reacting Wang p-nitrophenylcarbonate resin with an excess of diamine of the formula
  • Ky Ry Exemplary of diamine compounds suitable for preparing modified Wang resins for use in preparing library compounds of this invention wherein E is a solid support or hydrogen (after cleavage) include, but are not intended to be limited to the following:
  • Illustrative of the divalent group Z in those embodiments include, but are not intended to be limited to:
  • One preferred embodiment of the invention is a library of macrocyclic compounds of the formula
  • L is a divalent group of the formula ⁇ (CH 2 ) 0 - 1 -C 6 H 4 CH 2 1 or -CHR a - wherein R a is hydrogen or an organic moiety;
  • R z is hydrogen or methyl
  • B is hydroxy or a group of the formula -NRyRt wherein Ry is hydrogen, alkyl, aryl or heterocycle, and Rt is hydrogen, a solid support, or Rt is a group of the formula
  • Ry wherein E is hydrogen, a solid support or a substituent derived from an electrophilic reagent, T is a divalent linking group, and Ry" is hydrogen or a substituent derived from an electrophilic reagent; or Ry and Ry" taken together with the atoms to which they are bonded form a 4- to 7-membered ring or a bicyclic or tricyclic ring comprising 6 to 12 carbon atoms; or Ry or Ry» taken together with -T- and the atoms to which they are commonly bonded form a 6- to 7-membered ring or Ry and Ry" each taken together with T and the nitrogen atom to which they are respectively bonded form a 5- to 7-membered ring;
  • Z is a divalent group of the formula
  • AAi and AA3 are independently a divalent group of the formula
  • ATA is a divalent sulfur group of the formula
  • W is a divalent organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from the group consisting of 0, N and S;
  • Q and Q' are each independently an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from 0, N and S;
  • m is 0, 1 or 2 ;
  • R n ' is hydrogen, or an organic moiety, or R n taken together with Q and the atoms to which they are bonded form a 4- to 7-membered ring; R n ' and R s taken together with -Q ' - and the atoms to which they are bonded form a 4- to 7-membered ring or a bicyclic or tricyclic ring comprising 6 to 12 carbon atoms ; or R n ' or Rs taken together with -Q ' - and the atoms to which they are commonly bonded form a 4- to 7-membered ring.
  • Another embodiment of this invention provides a library of macrocycle compounds of Formula I wherein each amino acid used to form the macrocycle is a proteiogenic amino acid.
  • Ri is hydrogen, or a non-interfering substituent
  • R2 is hydrogen or an organic moiety; or Rl taken together with R n forms a 4- to 7-membered ring, or Ri taken together with R s forms a 4- to 7- membered ring; or Ri taken together with R2 forms a 3- to 6-membered ring.
  • W is a divalent organic group selected from the group consisting of -CHR8-, -CR4R5CR6R7- , and a 5- or 6- membered aromatic ring containing 0 to 4 heteroatoms selected from 0, N and S; wherein R8 is hydrogen or an organic group;
  • R4, Rs, and R6 are independently hydrogen or alkyl
  • R7 is hydrogen, hydroxy, protected hydroxy, amino or protected amino or substituted amino wherein the substituent is derived from an electrophilic group.
  • the present library compounds can be prepared using combinatorial synthesis protocols, or individual macrocycle library compounds can be prepared by standard chemical synthesis techniques and used as core structure for preparation of directed libraries.
  • R z is defined as above, and P s and P are thiol- and amino-protecting groups, respectively, to a solid support including acid reactive groups;
  • L is as defined above and X is a leaving group subject to nucleophilic displacement
  • Each of the reaction steps is carried out using a dry, inert, polar, aprotic solvent at a temperature of about 0° to about 30°C.
  • a dry, inert, polar, aprotic solvent at a temperature of about 0° to about 30°C.
  • solution phase reactions stoichiometrically equivalent amounts or near stoichiometric amounts of reactants are typically employed.
  • the use of solid phase synthesis for most of the process steps (the cyclization step can be conducted in solid phase or solution phase) allows the flexibility of using excess reagents to optimize yield without complicating product isolation.
  • effective work-up to remove any excess reagents comprises washing the solid support bound product one or more times with reaction solvent.
  • Suitable solvents for carrying out the process steps include dimethylformamide, dimethylsulfide, tetahydrofuran, N-methylpyrrolidone, dioxane, ethyl acetate, diethyl ether and the like.
  • the reaction steps can be carried out using standard combinatorial chemistry protocols to produce arrays of the present library compounds, or they can be carried out on larger scale using standard chemical synthesis, work-up, and product isolation and purification procedures .
  • the initial step in the process for preparation of the present library compounds of formula I comprises covalently bonding to a solid support an amino-protected, thiol-protected starting material of the formula
  • NHP wherein R z is defined as above, and P s and P are thiol- protecting and amino-protecting groups, respectively, wherein the solid support includes covalently bound acid reactive groups (e.g. hydroxy or primary or secondary amino) .
  • Suitable thiol-protecting groups include, but are not intended to be limited to, trityl (triphenylmethyl) , 4-methoxypheny1-diphenylmethy1 , di (4- methoxyphenyl ) phenylmethyl , and the like.
  • Exemplary of monovalent amino-protecting groups include, but are not intended to be limited to:
  • Covalent coupling of orthogonally protected cysteine or penicillamine to the solid support is carried out by forming an activated form of the acid, such as an active ester, and reacting the activated form with the solid support, typically using an excess (2-10 fold) of the activated form to optimize yield of the support-coupled product. Excess reagent is washed from the reacted solid support .
  • the support-coupled product is then reacted to remove amino-protecting groups using the protecting group dependent cleavage conditions.
  • the fluorenylmethyloxycarbonyl group a preferred amino- protecting group for solid phase synthesis, is removed by treatment of the solid support bound product with from about 20% to about 30% piperidine in dimethylformamide.
  • R Plant R wherein P is an amino-protecting group and R n , Rn ' Q, Q ' , R s , m and W are as defined above.
  • the coupling reaction is carried out under conditions paralleling those described above for coupling the orthogonally protected cysteine or penicillamine to the solid support using a 2- 10 fold excess of an activated form of the protected amino acid or ATA.
  • the protected amino acids typically have a molecular weight of about 75 to about 800.
  • Exemplary of such amino acid reactants (and protected derivatives thereof) suitable for use in this process include, but are not intended to be limited to, the following:
  • (+/- ) -TRANS-3-AZABICYCLO (3.1.0) HEXANE-2-CARBOXYLIC ACID 3-AZETIDINECARBOXYLIC ACID N-CARBOBENZYLOXY-L-TYROSINE HYDRATE 4-HYDROXY-2 , 2 , 6, 6-TETRAMETHYL-4-PIPERIDINECARBOXYLIC
  • amino acids utilized according to the present invention can also be selected from proteiogenic amino acids or optical isomers thereof.
  • ATAs for use in the process of this invention for preparation of macrocycle libraries are readily available by synthesis from available amino alcohols, more particularly protected-amino alcohol mesylates or tosylates, and mercapto acids.
  • Rn is reacted with about 1 to about 1.2 stoichiometric equivalents of a mercaptide salt of a mercapto compound of the formula
  • the reaction is typically carried out in solution phase, and a solution of the compound of Formula II is added slowly to a solution of the mercaptide salt.
  • the mercaptide salt is most typically generated by reacting the corresponding mercaptan in solution with about two stoichiometric equivalent amounts of an alkali metal alkoxide base, for example sodium methoxide.
  • alkali metal alkoxide base for example sodium methoxide.
  • Other mercaptide forming bases can be used (e.g. alkali metal dimsylates or hydrides), but without advantage.
  • suitable mercapto acids for use in preparing the library compounds of this invention include, but are not intended to be limited to, the following:
  • the substituent X is a good leaving group subject to nucleophilic displacement by the mercaptide salt.
  • exemplary of suitable X groups include, but are not intended to be limited to, mesylate, tosylate, halo, and the like.
  • Compounds of Formula II are typically derived from an amino alcohol or protected-amino alcohol of the formula p N Q CH0H
  • the amino alcohol is selected to have a molecular weight of about 60 to about 450, most typically about 60 to about 300.
  • the amino alcohol starting material is reacted with methane sulfonyl chloride to provide the corresponding mesylate in high yield using the mesylation protocol of Crossland and Servis [JOC 35, 1952- 6 (1970)].
  • Suitable amino alcohols for use in preparing the present library compounds include, but are not intended to be limited to, the following:
  • Amino alcohol starting materials can also be prepared in high yield from available amino acids and protected amino acids of the formula
  • R s when R s is hydrogen these compounds can be obtained from sodium borohydride reduction of the mixed carbonate formed, for example, between the starting acid and isobutyryl chloroformate.
  • Any of the above exemplified amino acids are available for conversion to the corresponding amino alcohols for use in preparing amino thioether acids for use in this invention.
  • the excess reagent frequently migrates with the thioether acid product on a flash silica column and cannot be removed by simple extraction.
  • the excess acid can be separated from the product by dissolving the reaction mixture in ethyl acetate and adding a 2-fold molar excess of solid mercuric acetate to the solution.
  • the resulting slurry is filtered through a celite pad, the filtrate containing the desired thioether product is subjected to flash chromatography on silica, and the chromatographed material is evaporated to provide the purified reaction product .
  • the oxidation can be accomplished in high yields using stoichiometric amounts of any one of several oxidizing agents including m- chloroperbenzoic acid, periodate, and oxone (a mixture of potassium hydrogen persulfate, potassium bisulfate and potassium sulfate) .
  • the oxidation reaction is carried out in any one of a wide variety of solvents at a temperature of about -10_C to about 30°C.
  • the preparation of sulfoxides and sulfones by oxidation of thioethers are well known in the art. Oxidation of a sulfide to its corresponding sulfoxide:
  • Amino-protected ATAs useful in the present process have a molecular weight of about 150 to about 800.
  • a preferred amino-protecting group for the amino acids and ATAs used in this process is 9-fluorenyloxymethylcarbonyl .
  • process step (d) following the first amino acid or ATA coupling reaction of process step (c) as described above, in process step (d) the amino-protecting group is removed from the solid support coupled product following the same procedures as described above for process step (b) . Thereafter, process step (c) and process step (d) may be repeated one or more times using the same or a different amino-protected amino acid or amino-protected ATA. However, at least one of the process steps (c) and (e) is carried out using an amino- protected ATA.
  • the coupling of the organic acid with the terminal amino group on the solid support bound product is carried out under essentially the same reaction conditions and stoichiometry described above for the coupling of the protected amino acids or the protected ATAs in steps (c) and (e) above except that the hydroxybenzotriazole (HOBT) reagent typically used with carbodiimides to form the intermediate "active" HOBT ester is not used in the coupling reaction mixture due to the fact that HOBT is sufficiently nucleophilic that it reacts to displace the terminal leaving group.
  • the coupling reaction proceeds without added HOBT via the active ester formed by the reaction of the organic acid and the carbodiimide reactant .
  • the support- bound product from step (f) above is cyclized and cleaved from the solid support. While those two reactions can be conducted in either order, i.e., cyclization before cleavage, or cleavage before cyclization, it is preferred that cyclization be conducted in solution phase after cleavage of the acyclic precursor from the solid support.
  • cyclization be conducted in solution phase after cleavage of the acyclic precursor from the solid support.
  • the optimum reaction conditions for cleavage of the product of step (f) or of the pre-cyclized product from the solid support are dependent on the nature of the acid reactive groups on the support.
  • cleavage reactions are carried out by treating the solid support with trifluoroacetic acid in the presence of water, optionally in the presence of triethylsilane, conditions which also effect removal of the thio-protecting group from the acyclic precursor product.
  • the cleavage product is isolated by separation of the "cleavage cocktail” solution from the solid support and lyophilization of the "cleavage cocktail". Cyclization of the acyclic macrocycle precursor product can be efficiently carried out in solution in the presence of a non-nucleophilic base such as, for example, 2, 6-lutidine, diisopropylethylamine (DIPEA) , and the like.
  • DIPEA diisopropylethylamine
  • the acid reactive group on the solid support comprises a covalently bound group of the formula
  • Such library compounds are optionally reacted with an electrophilic agent having a molecular weight of about 30 to about 600 to provide library compounds of Formula I wherein E is a substituent derived from an electrophilic reagent.
  • electrophilic agents include, but are not intended to be limited to, organic halides, acyl halides, sulfonic acid esters, organohaloformates, organosulfonyl halides, organic isocyanates, organic isothiocyanates, aldehydes, ketones, and the like. Examples of such electrophilic agents include, but are not intended to be limited to:
  • 11-eicosenoyl chloride behenoyl chloride petroselinoyl chloride palmitoleoyl chloride tridecanoyl chloride
  • Sulfonic Acid Esters ethyl trifluoromethanesulfonate 2,2, 2-trifluoroethyl p-toluenesulfonate 2-chloroethyl-p-toluenesulfonate 1 , 3 -propane sultone 5 ' -tosyladenosine

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Abstract

La présente invention concerne une échantillothèque diversifiée de composés macrocycliques peptidomimétiques, les procédés de préparation correspondants et un dispositif permettant de constituer une source facilement accessible de chacun des différents membres de l'échantillothèque. Ce dispositif convient à des nécessaires de dosage et comme élément remplaçable dans des machines à doser automatisées.
PCT/US1998/007135 1997-04-11 1998-04-08 Echantillotheques combinatoires de macrocycles peptidomimetiques et procedes correspondants WO1998046631A1 (fr)

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JP54406098A JP2002506423A (ja) 1997-04-11 1998-04-08 ペプチド模倣型大員環のコンビナトリアルライブラリーとそのための方法
CA002286867A CA2286867A1 (fr) 1997-04-11 1998-04-08 Echantillotheques combinatoires de macrocycles peptidomimetiques et procedes correspondants
EP98914651A EP1015479A4 (fr) 1997-04-11 1998-04-08 Echantillotheques combinatoires de macrocycles peptidomimetiques et procedes correspondants
AU68955/98A AU6895598A (en) 1997-04-11 1998-04-08 Combinatorial libraries of peptidomimetic macrocycles and processes therefor

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001025257A3 (fr) * 1999-10-04 2001-12-06 Neokimia Inc Synthese combinatoire de bibliotheques de composes macrocycliques utilisables dans la recherche medicamenteuse
WO2005012332A1 (fr) * 2003-07-31 2005-02-10 Tranzyme Pharma Composes macrocycliques definis spatialement incorporant des substituts de liaison peptidique
WO2005012331A1 (fr) * 2003-07-31 2005-02-10 Tranzyme Pharma Composes macrocycliques definis spatialement utiles pour la decouverte de medicaments
WO2008076904A1 (fr) * 2006-12-14 2008-06-26 Aileron Therapeutics, Inc. Systèmes de macrocyclisation bis-sulfhydryle
US7521420B2 (en) 2003-06-18 2009-04-21 Tranzyme Pharma, Inc. Macrocyclic antagonists of the motilin receptor
EP2067787A1 (fr) 2007-12-06 2009-06-10 Boehringer Ingelheim International GmbH Procédé pour le contrôle de populations d'insectes
US7981999B2 (en) 2007-02-23 2011-07-19 Aileron Therapeutics, Inc. Triazole macrocycle systems
US7981998B2 (en) 2006-12-14 2011-07-19 Aileron Therapeutics, Inc. Bis-sulfhydryl macrocyclization systems
US8088733B2 (en) 2006-07-06 2012-01-03 Tranzyme Pharma Inc. Methods of using macrocyclic agonists of the ghrelin receptor for treatment of gastrointestinal motility disorders
US9096684B2 (en) 2011-10-18 2015-08-04 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9527896B2 (en) 2007-01-31 2016-12-27 Dana-Farber Cancer Institute, Inc. Stabilized p53 peptides and uses thereof
US9604919B2 (en) 2012-11-01 2017-03-28 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US9951099B2 (en) 1999-05-18 2018-04-24 President And Fellows Of Harvard College Stabilized compounds having secondary structure motifs
US9957299B2 (en) 2010-08-13 2018-05-01 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10022422B2 (en) 2009-01-14 2018-07-17 Alleron Therapeutics, Inc. Peptidomimetic macrocycles
US10023613B2 (en) 2015-09-10 2018-07-17 Aileron Therapeutics, Inc. Peptidomimetic macrocycles as modulators of MCL-1
US10059741B2 (en) 2015-07-01 2018-08-28 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10213477B2 (en) 2012-02-15 2019-02-26 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10227380B2 (en) 2012-02-15 2019-03-12 Aileron Therapeutics, Inc. Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
US10253067B2 (en) 2015-03-20 2019-04-09 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10301351B2 (en) 2007-03-28 2019-05-28 President And Fellows Of Harvard College Stitched polypeptides
US10300109B2 (en) 2009-09-22 2019-05-28 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10471120B2 (en) 2014-09-24 2019-11-12 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10905739B2 (en) 2014-09-24 2021-02-02 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and formulations thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019567A1 (fr) * 1994-01-13 1995-07-20 The Trustees Of Columbia University In The City Of New York Recepteurs de synthese, leurs bibliotheques et leurs utilisations
US5510240A (en) * 1990-07-02 1996-04-23 The Arizona Board Of Regents Method of screening a peptide library

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0677060A1 (fr) * 1993-01-08 1995-10-18 Tanabe Seiyaku Co., Ltd. Inhibiteurs peptidiques de l'adhesion cellulaire
JPH10512570A (ja) * 1995-01-20 1998-12-02 モレキュメティックス リミテッド コンホメーション的に制限された逆ターンライブラリおよびそれらに関連する方法
WO1996040781A1 (fr) * 1995-06-07 1996-12-19 Tanabe Seiyaku Co., Ltd. INHIBITEURS PEPTIDIQUES CYCLIQUES D'ADHERENCE CELLULAIRE INDUITE PAR INTEGRINE β1 ET β¿2?

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5510240A (en) * 1990-07-02 1996-04-23 The Arizona Board Of Regents Method of screening a peptide library
WO1995019567A1 (fr) * 1994-01-13 1995-07-20 The Trustees Of Columbia University In The City Of New York Recepteurs de synthese, leurs bibliotheques et leurs utilisations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GILON C., ET AL.: "BACKBONE CYCLIZATION: A NEW METHOD FOR CONFERRING CONFORMATIONAL CONSTTAINT ON PEPTIDES.", BIOPOLYMERS, JOHN WILEY & SONS, INC., US, vol. 31., no. 06., 1 March 1991 (1991-03-01), US, pages 745 - 750., XP002912704, ISSN: 0006-3525, DOI: 10.1002/bip.360310619 *
HIRSCHMANN R., ET AL.: "SYNTHESIS OF POTENT CYCLIC HEXAPEPTIDE NK-1 ANTAGONISTS. USE OF A MINILIBRARY IN TRANSFORMING A PEPTIDAL SOMATOSTATIN LIGAND INTO A NK-1 RECEPTOR LIGANF VIA A POLYVALENT PEPTIDOMIMETIC.", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 39., 1 June 1996 (1996-06-01), US, pages 2441 - 2448., XP002912705, ISSN: 0022-2623, DOI: 10.1021/jm960281e *
See also references of EP1015479A4 *

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WO2001025257A3 (fr) * 1999-10-04 2001-12-06 Neokimia Inc Synthese combinatoire de bibliotheques de composes macrocycliques utilisables dans la recherche medicamenteuse
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JP2003511387A (ja) * 1999-10-04 2003-03-25 ネオキミア・インコーポレイテッド 創薬に有用な大環状化合物ライブラリーのコンビナトリアル合成
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US9409945B2 (en) 1999-10-04 2016-08-09 Ocera Therapeutics, Inc. Combinatorial synthesis of libraries of macrocyclic compounds useful in drug discovery
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