WO1995018186A1 - Structure et synthese modulaire de molecules contenant l'aminimide - Google Patents

Structure et synthese modulaire de molecules contenant l'aminimide Download PDF

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Publication number
WO1995018186A1
WO1995018186A1 PCT/US1993/012612 US9312612W WO9518186A1 WO 1995018186 A1 WO1995018186 A1 WO 1995018186A1 US 9312612 W US9312612 W US 9312612W WO 9518186 A1 WO9518186 A1 WO 9518186A1
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WIPO (PCT)
Prior art keywords
different
group
aminimide
chemical bond
same
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PCT/US1993/012612
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English (en)
Inventor
Joseph C. Hogan, Jr.
David Casebier
Paul Furth
Cheng Tu
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Arqule Partners, L.P.
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Priority to PCT/US1993/012612 priority Critical patent/WO1995018186A1/fr
Priority to CA002179983A priority patent/CA2179983A1/fr
Priority to AU60159/94A priority patent/AU689764B2/en
Priority to EP94906465A priority patent/EP0737232A4/fr
Priority to JP7517995A priority patent/JPH09510693A/ja
Publication of WO1995018186A1 publication Critical patent/WO1995018186A1/fr

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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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    • C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C—CHEMISTRY; METALLURGY
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    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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    • 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
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    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
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    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to the logical development of biochemical and biopharmaceutical agents and of new materials including fabricated materials such as fibers, beads, films, and gels. Specifically, the invention relates to the development of molecular modules based on aminimide and related structures, and to the use of these modules in the assembly of simple and complex molecules, polymers and fabricated materials with tailored properties; where said properties can be planned and are determined by the
  • molecular modules of the invention are preferably chiral, and can be used to synthesize new compounds and fabricated materials which are able to recognize biological receptors, enzymes, genetic materials, and other chiral molecules, and are thus of great interest in the fields of biopharmaceuticals, separation and materials science.
  • the discovery of new peptide hormones has involved work with peptides; the discovery of new therapeutic steroids has involved work with the steroid nucleus; the discovery of new surfaces to be used in the construction of computer chips or sensors has involved work with inorganic materials, etc.
  • the discovery of new functional molecules being ad hoc in nature and relying predominantly on serendipity, has been an extremely time-consuming, laborious, unpredictable, and costly enterprise.
  • nucleotides can form complementary base pairs so that complementary single-stranded molecules hybridize resulting in double- or triple-helical structures that appear to be involved in
  • a biologically active molecule binds with another molecule, usually a macromolecule referred to as ligand-acceptor (e.g. , a receptor or an enzyme), and this binding elicits a chain of molecular events which ultimately gives rise to a physiological state, e.g., normal cell growth and differentiation, abnormal cell growth leading to carcinogenesis, blood-pressure regulation, nerve-impulse-generation and -propagation, etc.
  • ligand-acceptor e.g., a receptor or an enzyme
  • the binding between ligand and ligand-acceptor is geometrically characteristic and extraordinarily specific, involving appropriate three-dimensional structural arrangements and chemical interactions.
  • oligonucleotides that can be used to block or suppress gene expression via an antisense, ribozyme or triple helix
  • sequence of the native target DNA or RNA molecule is characterized and standard methods are used to synthesize oligonucleotides representing the
  • disaccharides and four dissimilar monosaccharides can give rise to up to 35,560 unique tetramers, each capable of
  • the gangliosides are examples of the versatility and effect with which organisms can use saccharide structures.
  • glycolipids sucgar-lipid composites
  • these molecules are able to position themselves at strategic locations on the cell wall: their lipid component enables them to anchor in the hydrophobic interior of the cell wall, positioning their hydrdphilic component in the aqueous extracellular milieu.
  • gangliosides like many other saccharides
  • they are involved in both the inactivation of bacterial toxins and in contact inhibition, the latter being the complex and poorly understood process by which normal cells inhibit the growth of adjacent cells, a property lost in most tumor cells.
  • the structure of ganglioside GM, a potent inhibitor of the toxin secreted by the cholera organism, featuring a branched complex pentameric structure is shown below.
  • glycoproteins saliva-protein composites
  • human blood-group antigens the A, B, and O blood classes
  • glycoproteins on red blood cells belonging to incompatible blood classes cause formation of aggregates, or clusters and are the cause for failed transfusions of human blood.
  • glycosylation i.e., the covalent linking with sugars.
  • deglycosylation of erythropoetin causes loss of the hormone's biological activity
  • deglycosylation of human gonadotropic hormone increases receptor binding but results in almost complete loss of biological activity
  • TPA tissue plasminogen activating factor
  • glycopolypeptide which is 30% more active than the
  • a currently favored strategy for the development of agents which can be used to treat diseases involves the discovery of forms of ligands of biological receptors, enzymes, or related macromolecules, which mimic such ligands and either boost, i.e., agonize, or suppress, i.e., antagonize, the activity of the ligand.
  • boost i.e., agonize
  • suppress i.e., antagonize
  • the discovery of such desirable ligand forms has traditionally been carried out either by random screening of molecules (produced through chemical synthesis or isolated from natural sources), or by using a so-called
  • rational approach involving identification of a lead-structure, usually the structure of the native ligand, and optimization of its properties through numerous cycles of structural redesign and biological testing. Since most useful drugs have been discovered not through the “rational” approach but through the screening of randomly chosen compounds, a hybrid approach to drug discovery has recently emerged which is based on the use of combinatorial chemistry to construct huge libraries of randomly-built chemical structures which are screened for specific biological activities. (S. Brenner and R.A. Lerner, 1992,
  • peptide mimetics bind tightly, preferably in the nanomolar range, and can withstand the chemical and
  • peptidomimetics in the majority of cases the results in one biochemical area, e.g., peptidase inhibitor design using the enzyme substrate as a lead, cannot be transferred for use in another area, e.g., tyrosine-kinase inhibitor design using the kinase substrate as a lead.
  • the peptidomimetics that result from a peptide structural lead using the "rational" approach comprise unnatural alpha-amino acids. Many of these mimetics exhibit several of the troublesome features of native peptides (which also comprise alpha-amino acids) and are, thus, not favored for use as drugs.
  • nonpeptidic scaffolds such as steroidal or sugar structures, to anchor specific receptor-binding groups in fixed geometric relationships have been described (see for example Hirschmann, R. et al., 1992 J. Am. Chem. Soc.
  • V. D. Huebner and D.V. Santi utilized functionalized polystyrene beads divided into portions each of which was acylated with a desired amino acid; the bead portions were mixed together, then divided into portions each of which was re-subjected to acylation with a second desirable amino acid producing dipeptides, using the techniques of solid phase peptide synthesis.
  • antisense nucleotide mimetics Hoogstein-type binders or minor groove binding compounds such as those pioneered by Dervan and coworkers, have employed a variety of derivatives and variants of the naturally occuring sugar-phosphate backbone. Polyamide backbones have also been employed to support the base complements. While binding and desired functionality is observed in vitro withthese systems, they have inherent design drawbacks for in vivo use for hybridization against a rogue gene or its insidious RNA. The two main drawbacks of these polyamide systems are in (a) the persistent reliance upon an amide bond which is susceptible to proteolytic cleavage, and (b) the inability of the compound either as a class, or even singularly show efficient membrane
  • nucleotide bases other than guanosine, cytosine, thymidine, adenine, or uridine, to efficiently hydrogen bond (hybridize) to another, natural base or nucleotide.
  • these natural nucleotide mimetics are showdomycin ( 1 ) and pseudouridine (2) and the synthetic compounds (3) and (4).
  • rational drug discovery is the structure of the biological ligand acceptor which, often in conjunction with molecular modelling calculations, is used to simulate modes of binding of the ligand with its acceptor; information on the mode of binding is useful in optimizing the binding properties of the lead-structure.
  • finding the structure of the ligand acceptor, or preferably the structure of a complex of the acceptor with a high affinity ligand requires the isolation of the acceptor or complex in the pure, crystalline state, followed by x-ray crystallographic analysis. The isolation and
  • polypeptide substrates thereof are time-consuming, laborious, and expensive. Success in this important area of biological chemistry depends on the effective utilization of sophisticated separation technologies.
  • Crystallization can be valuable as a separation technique but in the majority of cases, especially in cases involving isolation of a biomolecule from a complex biological milieu, successful separation is chromatographic.
  • Chromatographic separations are the result of reversible differential binding of the components of a mixture as the mixture moves on an active natural, synthetic, or semisynthetic surface; tight-binding components in the moving mixture leave the surface last en masse resulting in separation.
  • substrates or supports to be used in separations has involved either the polymerizationcrosslinking of monomeric molecules under various conditions to produce fabricated materials such as beads, gels, or films, or the chemical modification of various commercially available fabricated materials e.g., sulfonation of polystyrene beads, to produce the desired new materials.
  • prior art support materials have been developed to perform specific separations or types of separations and are thus of limited utility. Many of these materials are incompatible with biological macromolecules, e.g., reverse-phase silica frequently used to perform high pressure liquid chromatography can denature hydrophobic proteins and other polypeptides.
  • chromatography and remains an extremely effective and widely used separation technique. It is certainly much more selective than traditional chromatographic techniques, e.g chromatography on silica, alumina, silica or alumina coated with long-chain hydrocarbons, polysaccharide and other types of beads or gels which in order to attain their maximum separating efficiency need to be used under conditions that are damaging to biomolecules, e.g., conditions involving high pressure, use of organic solvents and other denaturing agents, etc.
  • a and B are the same or different, and each represents a chemical bond; hydrogen; an electrophillic group; a nucleophillic group; R; R'; an amino acid derivative; a nucleotide derivative; a carbohydrate derivative; an organic structural motif; a reporter element; an organic moiety
  • X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen, phosphorous, silicon or combinations thereof; c.
  • R and R' are the same or different and each represents A, B, cyano, nitro, halogen, oxygen, hydroxy, alkoxy, thio, straight or branched chain alkyl, carbocyclic aryl and substituted or heterocyclic derivatives thereof, wherein R and R', may be the same or different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attached; d.
  • G is a chemical bond or a connecting group that includes a terminal carbon atom for attachment to the quarternary nitrogen and G may be different in adjacent n units; and e. n is greater than or equal to 1 ; provided that, (1) if G is a chemical bond, Y includes a terminal carbon atom for attachment to the
  • Aminimides are zwitterionic structures described by the resonance hybrid of the two energetically comparable Lewis structures shown below:
  • the tetrasubstituted nitrogen of the aminimide group can be asymetric rendering aminimides chiral as shown by the two enantiomers below:
  • Dilute aqueous solutions of aminimides are neutral and of very low conductivity; the conjugate acids of simple aminimides are weakly acidic, pKa of ca. 4.5.
  • a striking property of aminimides is their hydrolytic stability, under acidic, basic, or enzymatic conditions. For example, boiling trimethyl amine benzamide in 6 N NaOH for 24 hrs leaves the aminimide unchanged. Upon thermolytic treatment, at temperatures exceeding 180_C, aminimides decompose to give isocyanates as follows.
  • the aminimide building blocks of the invention can be used to synthesize novel molecules designed to mimic the three-dimensional structure and function of native ligands, and/or interact with the binding sites of a native receptor.
  • This logical approach to molecular construction is applicable to the synthesis of all types of molecules, including but not limited to mimetics of peptides, proteins, oligonucleotides, carbohydrates, lipids, polymers and to fabricated materials useful in materials science. It is analogous to the modular construction of a mechanical device that performs a specific operation wherein each module performs a specific task contributing to the overall operation of the device.
  • All ligands share a single universal architectural feature: they consist of a scaffold structure, made e.g., of amide, carbon-carbon, or
  • a continuum of fabricated materials exists spanning a dimensional range from 100
  • Angstroms to 1 cm in diameter comprising various materials of varied construction, geometries, morphologies and functions, all of which possess the common feature of a functional surface which is presented to a biologically active molecule or a mixture of molecules to achieve recognition between the molecule (or the desired molecule in a mixture) and the surface.
  • Aminimide structures which have remained relatively unexplored in the design and synthesis of
  • biologically active compounds and especially of drugs would be ideal building blocks for constructing backbones or scaffolds bearing the appropriate functional groups, that either mimic desired ligands and/or interact with appropriate receptor binding sites; furthermore, aminimide modules may be utilized in a variety of ways across the continuum of fabricated materials described above to produce new materials capable of specific molecular recognition. These aminimide building blocks may be chirally pure and can be used to synthesize molecules that mimic a number of biologically active molecules, including but not limited to peptides, proteins, oligonucleotides,
  • polynucleotides polynucleotides, carbohydrates, lipids, and a variety of polymers and fabricated materials that are useful as new materials, including but not limited to solid supports useful in column chromatography, catalysts, solid phase immunoassays. drug delivery vehicles, films, and "intelligent" materials designed for use in selective separations of various components of complex mixtures.
  • the molecular structures include functionalized silica surfaces useful in the optical resolution of racemic mixtures; peptide mimetics which inhibit human elastase, protein-kinase, and the HIV protease: polymers formed via free-radical or condensation polymerization of aminimide-containing monomers; and lipid-mimetics useful in the detection, isolation, and purification of a variety of receptors. Accordingly, the present invention relates to a novel class of aminimide compounds and their use in the construction of simple and complex molecules and macromolecular
  • the present invention also relates to the use of said aminimide compounds in biochemical and biopharmaceutical applications as well as their use in materials such as fibers, beads, films and gels.
  • the present invention also relates to the use of the inventive class of compounds to logically develop intelligent molecules and fabricated materials which are able to recognize biological receptors, enzymes, genetic materials and chiral molecules.
  • the present invention relates to the synthesis of libraries of aminimide-based molecules employing techniques herein disclosed or other techniques well known to those skilled in the art.
  • the present invention relates to chirally pure compounds, that may be synthesized chirally pure and can be used to recognize other chiral compounds.
  • the present invention relates to a class of aminimide compounds that can be used as mimetics for numerous biologically active agents.
  • the present invention also relates to aminimide molecules which posess enhanced hydrolytic and enzymatic stabilities, and in the case of biologically active materials, are transported to target ligand-acceptor macromolecules in vivo without causing serious side effects.
  • the invention is also directed to a method of making a polymer having a particular water solubility comprising the steps of; a) choosing a first monomer having the formula
  • R and R' are the same or different and are chosen from those organic moieties exhibiting hydrophobicity; b) choosing a second monomer having the formula
  • R and R' are the same or different and are chosen from those organic moieties exhibiting hydrophilicity; and c) reacting said monomers to provide an effective amount of each monomer in a developing polymer chain until a polymer having the desired water solubility is created.
  • said hydrophobic organic moieties can include those which do not have carboxyl, amino or ester functionality. Also said hydrophilic moieties can include those which do have carboxyl, amino or ester functionality.
  • This invention is further directed to using said method of preparing a synthetic compound to produce a compound that mimics or complements the structure of a biologically active compound of the formula.
  • This method can be used to produce pharmacaphores, peptide mimetics, nucleotide mimetics, carbohydrate mimetics, and reporter compounds, for example.
  • This invention is also further directed to a method of preparing a combinatorial library which comprises: a) preparing a compound having the formula;
  • this invention is directed to a method of separating a desired compound from a plurality of
  • the aminimide group mimics several key structural features of the amide group, such as overall geometry (e.g., both functional groups contain a planar carbonyl unit and a tetrahedral atom linked to the acylated nitrogen) and aspects of charge distribution (e.g., both functional groups contain a carbonyl with significant negaJive charge development on the oxygen). These structural relationships can be seen below, where the resonance hybrids of the two groups are drawn.
  • aminimides Being hydrolytically and enzymatically more stable than amides and possessing novel solubility properties due to their zwitterionic structures, aminimides are valuable building blocks for the construction of mimetics of biologically active molecules with superior pharmacological properties.
  • biological activity is defined as having a beneficial biological effect.
  • the aminimide backbone is used as a scaffold for the geometrically precise attachment of structural units possessing desired stereochemical and
  • aminimide units can be linked in a variety of modes, using likers of diverse structures, to produce polymers of a great variety of structures. Specific molecular forms are chosen for screening and further study using several criteria. In one instance, a certain aminimide structure is chosen because it is novel and has never been tested for activity as a biopharmaceutical agent or as material for device construction. In a preferable instance, an aminimide ligand is chosen because it incorporates structural features and
  • the aminimide structure is the result of assembly of molecular modules each making a specific desirable contribution to the overall properties of the
  • aminimides are functional groups with unusual and very desirable physiochemical properties, which can be used as molecular modules for the construction of molecular structures that are useful as biopharmaceutical agents and as new materials for high technological applications 4.2 General Synthetic Routes to Aminimides
  • Aminimides can be synthesized in a variety of different ways.
  • the compounds of the present invention can be synthesized by many routes. It is well known in the art of organic synthesis that many different synthetic protocols can be used to prepare a given compound. Different routes can involve more or less expensive reagents, easier or more difficult separation or purification procedures, straightforward or cumbersome scale-up, and higher or lower yield.
  • the skilled synthetic organic chemist knows well how to balance the competing characteristics of competing strategies.
  • the compounds of the present invention are not limited by the choice of synthetic strategy and any synthetic strategy that yields the compounds described above can be used.
  • the scope of this invention is intended to encompass each species of the aforementioned Markush genus. Thus, for example, where there is a numeric designation in the claim, that can be an integer, i.e. m or n, the scope of this invention is intended to cover each species that would be represented by every different integer.
  • This alkylation is carried out in a suitable solvent, such as a hydroxylic solvent, e.g., water, ethanol, isopropanol or a dipolar aprotic solvent, e.g., DMF, DMSO, acetonitrile, usually with heating.
  • a suitable solvent such as a hydroxylic solvent, e.g., water, ethanol, isopropanol or a dipolar aprotic solvent, e.g., DMF, DMSO, acetonitrile
  • the hydrazide to be used in the above synthesis is produced by the reaction of a 1,1-disubstituted hydrazine with an activated acyl derivative or an isocyanate, in a suitable organic solvent, e.g., methylene chloride, toluene, ether, etc. in the presence of a base such as triethylamine to neutralize the haloacid generated during the acylation.
  • a suitable organic solvent e.g., methylene chloride, toluene, ether, etc.
  • a base such as triethylamine
  • Activated acyl derivatives include acid chlorides,
  • the desired 1 , 1 -disubstituted hydrazines may be readily prepared in a number of ways well known in the art; for example, the reaction of a secondary amine with NH2CI in an inert organic solvent.
  • a second synthetic route for the preparation of hydrazines is alkylation of monoalkyl hydrazines, shown below for methyl hydrazine:
  • acyl derivatives for the acylation reaction are the same as those required for the synthesis of the hydrazides outlined above.
  • This hydrazinium salt synthesis method can be subject to the possibility of rearrangements and side reactions which compete with the formation of the aminimide.
  • the conditions under which these rearrangements can take place are highly dependent on the specific substituents on the quarternary nitrogen and, thus, the application of this .synthetic route for the production of aminamide-derived species needs to take into consideration the specific nature of the desired R groups at this position.
  • Two basic rearrangements are possible: a. Migration of a substituent group from the quaternary nitrogen to form a hydrazide (Wawazoneck rearrangement - cf. Chem. Rev., 73, 255, 1972; Ind. Eng. Chem. Prod. Res. Devel., 19, 338, 1980).
  • the required hydrazinium salts may be prepared by routine alkylation of a 1 , 1-disubstituted hydrazines or by treatment of a tertiary amine with a haloamine (see 78 J. Am. Chem. Soc. 121 1 ( 1956)).
  • a tertiary amine may be reacted with hytiroxylamine-O-sulfonic acid (prepared by the method of Goesl and Meuwsen; Chem. Ber., 92, 2521 , 1959), as shown:
  • This reaction is carried out by reacting a suspension of the tertiary amine in a vigorously stirred cold aqueous solution of an equivalent amount of potassium carbonate sesquihydrate, containing a small amount of EDTA, with a cold solution of an equivalent amount of hydroxylamine-O-sulfonic acid in water, added over a 1 hour period. Methanol is added, and the precipitated K2SO4 is removed by filtration. The filtrate is adjusted to pH. 7 with hydrochloric acid and the solvent is removed on a rotary evaporator. The hydrazinium salt is isolated by precipitation from the thick glassy residue by the addition of acetone.
  • Hydrazinium salts being chiral at nitrogen, may be resolved, e.g. , by treatment with a chiral acid followed by separation of the diastereomers (e.g., using chromatography or fractional crystallization and the resulting enantiomers used in stereoselective syntheses of aminimides.
  • the ester may be saponified efficiently using LiOH in a mixture of methanol and water, producing a useful - hydrazinium acid after neutralization of the reaction mixture with an acid.
  • Suitably protected hydrazinium carboxylates may be used in condensation reactions to produce aminimides.
  • Procedures analogous to those known to be useful in effecting peptide bond formation are expected to be useful; e.g. DCC or other carbodiimides may be used as condensing agents in solvents such as DMF.
  • the hydrazinium carboxylate units may be coupled with alpha-amino-acids or with other nucleophiles, such as amines, thiols, alcohols, etc., using standard techniques, to produce molecules of wide utility as ligand mimetics and new materials for high technological applications.
  • the alpha-hydrazinium esters may, in turn, be produced by the alkylation of a 1 , 1-disubstituted hydrazine with a haloester under standard reaction conditions, such as those given above for the alkylation of hydrazides.
  • protected hydrazinium carboxylates may be used in condensation reactions to produce aminimides.
  • the hydrazinium carboxylate units may be coupled with alpha-amino-acids or with other nucleophiles, such as amines, thiols, alcohols, etc., using standard techniques. to produce molecules of wide utility as ligand mimetics and new materials for high technological applications.
  • the alpha-hydrazinium esters may, in turn, be produced by the alkylation of a 1 , 1-disubstituted hydrazine with a haloester under standard reaction conditions, such as those given above for the alkylation of hydrazides.
  • these hydrazinium esters may be produced by standard alkylation of the appropriate alpha-hydrazino ester.
  • the required 1 , 1 -disubstituted hydrazine for the above reaction may be obtained by acid or base hydrolysis of the corresponding hydrazone (see 108 J. Am. Chem. Soc. 6394 ( 1986)); the alkylated hydrazone is produced from the monosubstituted hydrazide by the method of Hinman and Flores (24 J. Org. Chem. 660 ( 1958)).
  • the monosubstituted hydrazided required above may be obtained by reduction of the Schiff base formed from an alpha-keto ester and a suitable hydrazide. This reduction may also be carried out stereoselectively, if desired, using DuPHOS-Rhodium catalysis ( 1 14 J. Am. Chem. Soc. 6266 ( 1992); 259 Science 479 ( 1993)), as shown:
  • omega- halo aminimides are prepared using an omega-halo acyl halide (prepared by acylation of the trisubstituted hydrazinium tosylate salt with a haloalkyl acyl halide, such as ClCH2COCl) These halo aminimides may be reacted with nucleophiles containing reactive hydroxyl, thio, or amino groups to give aminimide derivatized molecules.
  • omega-halo acyl halide prepared by acylation of the trisubstituted hydrazinium tosylate salt with a haloalkyl acyl halide, such as ClCH2COCl
  • a very useful and versatile synthesis of aminimides involves the one-pot reaction of an epoxide, an asymetricalh disubstituted hydrazine, ahd an ester in a hydroxylic solvent, usually water or an alcohol, which is allowed to proceed usuall y at room temperature over several hours to several days.
  • R1 , R2 and R3 are selected from a set of diverse structural types (e.g. alkyl, carbocyclic. aryl, aralkyl. alkaryl or many substituted versions thereof), and R4 and R5 are alkyl, carbocyclic. cycloalkyl, aryl or alkaryl.
  • substituent R4 of the ester component in the above aminimide formation contains a double bond
  • an aminimide with a terminal double bond results which may be epoxidized, e.g. using a peracid under standard reaction conditions, and the resulting epoxide used as starting material for a new aminimide formation.
  • a structure containing two aminimide subunits results. If the aminimide-formation and epoxidation sequence is repeated n times, a structure containing n aminimide subunits results; thus when R4 is propene, n repetition of the sequence results in the structure shown below:
  • a related aminimide polymerization sequence utilizes an ester moiety bonded directly to the epoxide group.
  • An additional related polymerization sequence involves the use of bifunctional epoxides and esters of the following form and
  • X and Y are alkyl, carbocyclic, aryl, aralkyl or alkaryl linkers.
  • This reaction is carried out by heating equimolar amounts of the pyridinium salt and the hydrazine with a slight excess of triethylamine in an alcohol, such as ethanol, for 12 hours.
  • the desired product is obtained from the precipitated solid produced by extraction with dioxane/water, removal of the dioxane in vacuo, followed by acidification with HCI, filtration to remove salts and neutralizetion with NaOH.
  • the mixture is cooled, the crystallized product is collected by filtration and purified by recrystallization from ethanol (yields 65-85%).
  • Enantiomerically-pure aminimides may be produced by acylation of chiral hydrazinium salts as shown in the example below.
  • Chirally-pure hydrazinium salts may be obtained by resolution of the racemates; resolution can be effected by forming salts with optically pure acids, e.g. tartaric acid, and separating the resulting diastereomers by means of
  • Enantiomerically-pure aminimides may also be obtained by resolution of the racemic modifications using one of the techniques described above for the resolution of racemic hydrazinium salts (for an example, see 28 J. Org. Chem. 2376
  • Chirally-pure aminimide molecular building blocks are especially preferred since they can be used to produce a vast array of molecules useful as new materials for high
  • substituents A and B may be the same or different and may be of a variety of structures and may differ markedly in their physical or functional properties, or may be the same; they may also be chiral or symmetric.
  • a and B are preferably selected from:
  • Peptides constructed from the amino acids listed above, such as angiotensinogen and its family of physiologically important angiotensin hydrolysis products, as well as derivatives, variants and mimetics made from various combinations and permutations of all the natural and synthetic residues listed above.
  • Proteins including structural proteins such as collagen, functional proteins such as hemoglobin, regulatory proteins such as the dopamine and thrombin receptors.
  • Nucleotide probes (N 2-25 ) and
  • oligonucleotides including all of the various possible homo and heterosynthetic combinations and permutations of the naturally occuring nucleotides, derivatives and variants containing synthetic purine or pyrimidine species or mimics of these, various sugar ring mimetics, and a wide variety of alternate backbone analogues including but not limited to phosphodiester, phosphorothionate, phosphorodithionate, phosphoramidate, alkyl phosphotriester, sulfamate, 3'-thioformacetal, methylene(methylimino), 3-N-carbamate, morpholino carbamate and peptide nucleic acid analogues.
  • beta-lactams such as pennicillin, known to inhibit bacterial cell wall biosynthesis
  • dibenzazepines known to bind to CNS receptors, used as antidepressants
  • polyketide macrolides known to bind to bacterial ribosymes, etc.
  • a reporter element such as a natural or synthetic, dye or a residue capable of photographic
  • reactive groups which may be synthetically incorporated into the aminimide structure or reaction scheme and may be attached through the groups without adversely interfering with the reporting functionality of the group.
  • Preferred reactive groups are amino, thio, hydroxy, carboxylic acid, carboxylic acid ester, particularly methyl ester, acid chloride, isocyanate alkyl halides, aryl halides and oxirane groups.
  • an organic .moiety containing a polymerizabie group such as a double bond or other functionalities capable of undergoing condensation polymerization or copolymerization Suitable groups include vinyl groups, oxirane groups, carboxylic acids, acid chlorides, esters, amides, lactones and lactams.
  • a macromolecular component such as a macromolecular surface or structures which may be attached to the aminimide modules via the various reactive groups outlined above in a manner where the binding of the attached species to a ligand-receptor molecule is not adversely affected and the interactive activity of the attached functionality is determined or limited by the macromolecule.
  • porous and non-porous inorganic macromolecular components such as, for example, silica, alumina, zirconia, titania and the like, as commonly used for various applications, such as normal and reverse phase chromatographic separations, water purification, pigments for paints, etc.
  • porous and non-porous organic macromolecular components including synthetic components such as styrene-divinyl benzene beads, various methacrylate beads, PVA beads, and the like, commonly used for protein purification, water softening and a variety of other applications, natural components such as native and
  • celluloses such as, for example, agarose and chitin, sheet and hollow fiber membranes made from nylon, polyether sulfone or any of the materials mentioned above.
  • dp 1000-5000Angstroms
  • membranes gels, macroscopic surfaces or functionalized or coated versions or composites of these .
  • a and/or B may be a chemical bond to a suitable organic moiety, a hydrogen atom, an organic moiety which contains a suitable electrophilic group, such as an aldehyde, ester, alkyl halide, ketone, nitrile, epoxide or the like, a suitable nucleophilic group, such as a hydroxyl, amino, carboxylate, amide, carbanion, urea or the like, or one of the R groups defined below.
  • a and B may join to form a ring or structure which connects to the ends of the repeating unit of the compound defined by the preceding formula or may be separately connected to other moieties.
  • composition of this invention is defined by the following formula:
  • a and B are as defined above and A and B are optionally connected to each other or to other compounds ;
  • X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or combinations thereof;
  • R and R' are the same or different and each represents B, cyano, nitro, halogen, oxygen, hydroxy, alkoxy, thio, straight or branched chain alkyl, carbocyclic aryl and substituted or heterocyclic derivatives thereof, wherein R and R' may be different in adjacent n units and have a selected stereochemical arrangement about the carbon atom to which they are attached;
  • linear chain or branched chained alkyl groups means any substituted or unsubstituted acyclic carbon-containing compounds, including alkanes, alkenes and alkynes. Alkyl groups having up to 30 carbon atoms are preferred. Examples of alkyl groups include lower alkyl, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl.
  • alkyl for example, cotyl, nonyl, decyl, and the like
  • lower alkylene for example, ethylene, propylene, propyldiene, butylene, butyldiene
  • upper alkenyl such as 1-decene, 1-nonene, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl or heptenyl, and the like
  • alkynyl such as 1-ethynyl. 2-butynyl, 1-pentynyl and the like.
  • the ordinary skilled artisan is familiar with numerous linear and branched alkyl groups, which are within the scope of the present invention.
  • alkyl group may also contain various substituents in which one or more hydrogen atoms has been replaced by a functional group.
  • Functional groups include but are not limited to hydroxyl, amino, carboxyl, amide, ester. ether, and halogen (fluorine, chlorine, bromine and iodine), to mention but a few.
  • Specific substituted alkyl groups can be, for example, alkoxy such as methoxy, ethoxy, butoxy, pentoxy and the like, polyhydroxy such as 1 ,2-dihydroxypropyl, 1 ,4-dihydroxy- 1-butyl , and the like; methylamino, ethylamino, dimethylamino, diethylamino, triethylamino, cyclopentylamino. benzylamino, dibenzylamino, and the like; propanoic, butanoic or pentanoic acid groups, and the like; formamido, acetamido.
  • alkoxy such as methoxy, ethoxy, butoxy, pentoxy and the like
  • polyhydroxy such as 1 ,2-dihydroxypropyl, 1 ,4-dihydroxy- 1-butyl , and the like
  • butanamido, and the like methoxycarbonyl, ethoxycarbonyl or the like, chloroformyl, bromoformyl, 1 ,1-chloroethyl, bromo ethyl and the like, or dimethyl or diethyl ether groups or the like.
  • substituted and unsubstituted carbocyclic groups of up to about 20 carbon atoms means cyclic carbon-containing compounds, including but not limited to cyclopentyl, cyclohexyl, cycloheptyl, admantyl, and the like, such cyclic groups may also contain various substituents in which one or more hydrogen atoms has been replaced by a functional group.
  • Such functional groups include those
  • cyclic groups of the invention may further comprise a heteroatom.
  • R 2 is cycohexanol.
  • substituted and unsubstituted aryl groups means a hydrocarbon ring bearing a system of
  • aryl groups include, but are not limited to, phenyl, naphthyl, anisyl, toluyl, xylenyl and the like. According to the present invention, aryl also includes aryloxy, aralkyl, aralkyloxy and heteroaryl groups, e.g., pyrimidine, morpholine, piperazine, piperidine, benzoic acid, toluene or thiophene and the like. These aryl groups may also be substituted with any number of a variety of functional groups. In addition to the functional groups described above in connection with substituted alkyl groups and carbocylic groups, functional groups on the aryl groups can be nitro groups.
  • R2 can also represent any combination of alkyl, carbocyclic or aryl groups, for example, 1-cyclohexylpropyl, benzylcyclohexylmethyl, 2-cyclohexylpropyl, 2,2-methylcyclohexylpropyl, 2,2methylphenylpropyl, 2,2-methylphenylbutyl, and the like.
  • G is a chemical bond or a connecting group that includes a terminal carbon atom for attachment to the quaternary nitrogen and G may be different in adjacent n units; and d. G is a chemical bond or a connecting group that includes a terminal carbon atom for attachment to the quaternary nitrogen and G may be different in adjacent n units; a n d
  • n is equal to or greater tha1l .
  • G is a chemical bond
  • Y includes a terminal carbon atom for attachment to the quaternary
  • At least one of A and B represents an organic or inorganic macromolecular surface.
  • preferred macromolecular surfaces include ceramics such as silica and alumina, porous and
  • nonporous beads polymers such as a latex in the form of beads, membranes, gels, macroscopic surfaces or coated
  • This functionalized surface may be represented as follows:
  • either A, B, or both contain one or more double bonds capable of undergoing free-radical polymerization or copolymerization to produce achiral or chiral oligomers, polymers, copolymers. etc .
  • W is -H or -H2X- where X- is an anion, such as a halogen or tosyl anion.
  • Yet another aspect of the invention relates to a lipid mimetic composition having the structure
  • Q is a chemical bond; hydrogen; an electrophilic group: a nucleophilic group; R; an amino acid derivative; a nucleotide derivative; a carbohydrate derivative; an organic structural motif; a reporter element; an organic moiety containing a polymerizable group; a macromolecular component; or the substituent X(T) or X(T)2; wherein R is an alkyl, carbocyclic, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, and T is a linear or branched hydrocarbon having between 12 and 20 carbon atoms some of which are optionally substituted with oxygen, nitrogen or sulfur atoms or by an aromatic ring; and provided that at least two T
  • Rn where n is an integer will be used to designate a group from the definition of R and R1.
  • Another aspect of the invention relates to functionalized polymers having the structure:
  • X and Y are connecting groups
  • n is equal to or greater than 1.
  • These functionalized polymers may be made according to known techniques for attaching terminal groups to the surface or by attaching a monomer unit to the surface and then building the polymer, for instance.
  • the invention also encompasses various methods of producing an aminimide-functional support.
  • One method comprises the steps of reacting a polymer or oligomer containing pendant moieties of OH, NH or SH with a compound of the formula:
  • R1 and R2 each represent alkyl, carbocyclic, aryl, aralkyl or alkaryl, and R3 is an amino acid derivative; a nucleotide derivative; a carbohydrate derivative ; an organic structural motif; a reporter element; an organic moiety containing a polymerizable group; or a macromolecular component; coating the reacted polymer or oligomer onto a support to form a film thereon; and heating the coated . support to crosslink the film.
  • Another method comprises the steps of coating a mixture of multifunctional esters and multifunctional epoxides onto a support to form a film thereon; and reacting the coated support with 1 ,1'-dialkylhydrazine to crosslink the film.
  • a third method comprises the steps of coating a mixture of an aminimide-functional vinyl monomer, a
  • difunctional vinyl monomer and a vinyl polymerization initiator onto a support to form a film thereon; and heating the coating support to form a crosslinked film.
  • the aminimide-functionalized support prepared according to the previous methods are another aspect of the invention.
  • Chiral recognition is a process whereby chiral enantiomers display differential binding energies with an enantiomerically pure chiral target or recognition agent.
  • This agent may be attached to a surface to produce a chiral stationary phase (CSP) for chromatographic use or may be used to form diastereomeric complexes with the racemic target.
  • CSP chiral stationary phase
  • These complexes have differing physiochemical propereties which allow them to be separated using standard unit processes, such as fractional crystallization.
  • aminimide building blocks possessing functional groups capable of establishing predictable binding interactions with target molecules, and by using synthetic techniques such as those broadly described above to effect catenation (linking) of the building blocks, it is possible to construct sequences of aminimide subunits mimicking selected native oligomers or polymers, e.g., peptides and polypeptides. oligonucleotides, carbohydrates, as well as any other
  • substituents found in the side chains of naturally occuring amino acids include purine and pyrimidine groups, as well as derivatives and variants of these; natural and synthetic carbohydrate recognition groups, such as sialic acids; groups containing organic structures with known pharmacological activities, such as beta lactam antibiotic moities, which are known to be efficient inhibitors of bacterial cell wall
  • the experimental conditions e.g. reaction-solvent, temperature and time, and purification procedures for
  • reaction solvents such as DMF, or N-methyl pyrollidone
  • chaotropic (aggregate-breaking) agents such as urea
  • the aminimine is normally not isolated, but used directly for the following reactioh.
  • B 1 is an appropriate protecting group such as BOC (t-butyl carbamate), particularly suitable for this purpose, readily cleaved by acid hydrolysis; 2,4-dichlorobenzene carbamate, cleaved by acid hydrolysis, but more stable than BOC; 2-(biphenylyl)isopropyl carbamate, cleaved more easily than BOC by dilute acid; FMOC (9-fluorenylmethyl carbamate), cleaved by ß-elimination with base; isonicotinyl carbamate, cleaved by reduction with zinc in acetic acid; 1-adamantyl carbamate, readily cleaved by trifluoroacetic acid; 2-phenylisopropyl carbamate, cleaved by acid hydrolysis but slightly more stable than BOC; imines and enamines, readily cleaved by acid hydrolysis; mono and bis trialkylsilyl derivatives, cleaved by
  • the alpha-hydrazinium carboxylic acids may be obtained by treatment of the esters with LiOH in MeOH/H2O at room temperature, as described above, and coupled with each other using condensation reactions promoted by DCC or other agents.
  • Protecting groups used in traditional peptide synthesis are expected to be useful here as well.
  • An alternate strategy is to catenate sequences of substituted hydrazides to obtain ligands with the desired side-chain substitution patterns, and subsequently convert all of the hydrazide groups to aminimides by multiple simultaneous alkylation followed by neutralization. This approach, which is outlined below, does not allow stereochemical control of the chiral center and, as a result, each aminimide center formed will exist as a racemic mixture.
  • the hydrazide oligomers themselves may, in fact, serve as useful binding ligands.
  • Aminimide subunits may be introduced into any position of a polypeptide via chemical synthesis, using one of the procedures outlined above, including the techniques for dealing with problematic reactions of high molecular weight species.
  • the resulting hybrid molecules have improved properties over the native molecules; for example, the aminimide group can confer greater hydrolytic and enzymatic stability to the hybrid molecule over its native counterpart.
  • moiety B contains a functional group which can be used to link additional aminimide and natural or unnatural amino acid subunits, e.g. via acylation reactions, complex hybrid structures may be obtained using the experimental procedures outlined above.
  • Our strategy is to append natural and/or unnatural bases (e.g. thymine, guanidine, 5-fluorouricil(5FU)) onto aminimide backbones to form an antisense strand, or nucleotide mimetic.
  • bases e.g. thymine, guanidine, 5-fluorouricil(5FU)
  • the resulting linkages and backbones are superior in their resistance to base, acid and proteolytic/phospholytic activity.
  • the bases can be attached using appropriate spacers and the stereochemistry and periodiocity of substitution geometry and rigidity of the backbone scaffold can be designed such that the bases are geometrically arrayed and projected to provide the optimum arrangement and orientation of the bases to hybridize with their targeted counterparts.
  • Aminimide oligonucleotide mimetics can be
  • backbones having natural or synthetic bases attached as side chain substituents to the backbone via appropriate spacers, i.e. R or R' in the general structural formulas described above designates the Base-spacer grouping.
  • these reactions may be carried out in a concerted manner with mixtures of base-functionalized hydrazines to produce random oligonucleotide sequences which can be screened for activity, as outlined: a.)
  • carbohydrates increasingly are being viewed as the components of living systems with the enormously complex structures required for the encoding of the massive amounts of information needed to orchestrate the processes of life, e.g., cellular recognition, immunity, embryonic development, carcinogenesis and cell- death.
  • This information is contained and utilized through highly specific binding interactions mediated by the detailed three dimensional-topological form of the specific carbohydrate. It is of great value to be able to arrange and to connect these moities in various arrays in a controlled manner. This may be done either by connecting carbohydrate recognition groups along an oligomeric backbone, as done by for random vinyl copolymers containing functionalized sialic acid groups, which were shown to inhibit hemagluttinin binding (J. Am. Chem.
  • Aminimide-derived carbohydrate mimetics may be synthesized from carbohydrate derivatives containing functional groups, such as epoxide groups, ester groups, hydrazine groups or alkylating groups, which are compatible with the aminimide forming and catenating reactions outlined above, thus allowing the following functional groups, such as epoxide groups, ester groups, hydrazine groups or alkylating groups, which are compatible with the aminimide forming and catenating reactions outlined above, thus allowing the
  • carbohydrates to be attached to a basic scaffold, or to be arrayed along a backbone in a precise controlled manner.
  • the physical principle governing the binding of a natural ligand or substrate to a receptor or active site of an enzyme, nucleotide or carbohydrate are the same principles governing the binding of non-peptide, non-nucleotide and non- carbohydrate compounds (competitive inhibitors or agonists).
  • the modification of a known biologically active compound as a lead or prototype, then synthesizing and testing its structural congers, homologues or analogues is a basic strategy for the development of new therapeutic agents. Several advantages of this method are: • Greater probability of theses modified derivatives to possess physiological properties most similar to those of the prototype than those tested at random.
  • a biologically active compound for example a protein or polypeptide
  • a solid support such as a resin or glass surface.
  • linked compounds show diverse inhibitory activity, an indication that linked molecules are able to retain their binding properties despite the partial loss of mobility.
  • the polymer can be arranged so as to be homogeneous, that is, the entire polymer is made from the same monomers, or heterogeneous, that is, the polymer can be made with any varying sequences of monomers in a controllable fashion.
  • the length of the linker, the molecular fragment that connects the pharmacophoric portion to the quatenary nitrogen of the aminimide polymer can be of various lengths and shapes, such as but not limited to a linear alkyl chain. As such, the arrangement and the geometric configuration of the pharmacophores on the backbone polymer can be controlled.
  • Additional monomeric structures useful in preferred free radical polymerizations include those shown below; they produce polymeric chains capable of being
  • the monomers shown below may be prepared using the synthetic procedures outlined above, and the polymerization/crosslinking reactions may be run using standard polymerization techniques. See, for example, Practical Macromolecular Organic Chemistry, Braun, Cherdron and Kern, trans, by K. Ivin, 3ed., Vol Z, Harwood
  • the monomers shown above may be polymerized with other alkenes or dienes, which are either commercially available or readily prepared using standard synthetic
  • Sequential condensations of aminimide-forming molecules may be used to produce a variety of novel polymers of controlled size.
  • An example involving dimeric epoxides and esters is given below; processes involving trimeric and more complex epoxides and esters are also contemplated; and experimental conditions for running these polymerizations (including techniques for resolving experimental difficulties as product molecular weight increases) have been described, above.
  • condensation polymerization may be carried out by reacting alpha carboxyester derivatized hydrazines (prepared as outlined above) with chiral epoxides to produce the novel polymers shown:
  • a support e.g. silica
  • a support capable of specific molecular recognition is produced; an example of such a support is given below:
  • Aminimide conjugate structures containing a single long-chain hydrocarbon group can be used as amphiphillic surface active materials which have great utility as delivery systems for the administration of drugs.
  • the attachment of a "recognition group" to the aminimide moiety gives a material which is highly compatible with lipophillic structures, such as cell wall membranes, and which itself will form micellular structures in water with the recognition group pointed out or "displayed " on the surface of the micelle. This may be
  • Aminimide structures possessing two long-chain alkyl groups capable of producing bilayer membrane structures are preferred embodiments of the present invention. Because of the presence of the double tail on the amphiphilic group, these molecules prefer to form continuous bilayer membrane structures, such as those found in cell wall membranes rather than micelles. As such they may function as "cell wall- mimicking'" components. This is schematically illustrated below:
  • Substituents R may be chosen from a variety of structures of various sizes including structures of ligands of biological receptors or enzymes; a preferred combination of substituents involves sterically small groups for R1 and R2 and a group such as A or B described above for R3; the long-chain alkyl groups are 4-30 carbons in length; group X is a linker composed of atoms chosen from the set of C, H, N, O, S, P and Si.
  • X is a linker group (e.g., CH); one or more substituents R are chosen from the group of structures A and B described above and the remaining
  • substituent(s) in preferably a sterically small group, e.g., H, or CH3.
  • An additional desirable amphiphilic structure is shown below; substituent structures are similar to those listed above.
  • Lipid mimetics are illustrated in the Examples that follow.
  • aminimide molecular building blocks may be utilized to construct new macromolecular structures capable of recognizing specific molecules ("intelligent macromolecules").
  • the "intelligent macromolecules” may be represented by the following general formula:
  • R is a structure capable of molecular
  • L is a linker
  • P is a macromolecular structure serving as a supporting platform
  • C is a polymeric structure serving as a coating which surrounds P.
  • Structure R may be a native ligand or a biological ligand-acceptor or a mimetic thereof, such as those described above.
  • Linker L may be a chemical bond or one of the linker structures listed above, or a sequence of subunits such as amino acids, aminimide monomers, oxazolohe-derived chains of atoms, etc.
  • Polymeric coating C may be attached to the supporting platform either via covalent bonds or "shrink wrapping," i.e. the bonding that results when a surface is subjected to coating polymerization is well known to those skilled in the art.
  • This coating element may be 1 ) a thin crosslinked polymeric film 10 - 50
  • the controlled microporosity gel may be engineered to completely fill the porous structure of the support platform.
  • the polymeric coatings may be constructed in a controlled way by carefully controlling a variety of reaction parameters such as the nature and degree of coating crosslinking, polymerization initiator, solvent, concentration of reactants, and other reaction conditions, such as temperature, agitation, etc., in a manner that is well known to those skilled in the art.
  • the support platform P may be a pellicular - material having a diameter (dp) from 100 Angstroms to 1000 microns, a latex particle (dp 0.1 - 0.2 microns), a microporous bead (dp 1 -1000 microns), a porous membrane, a gel, a fiber, or a
  • polymeric materials such as silica, polystyrene, polyacrylates, polysulfones, agarose, cellulose, etc. or synthetic aminimide-containing polymers such as those described below.
  • any of the elements P, C, L, or R containing an aminimide-based structure is derived from a form of the element containing a precursor to the aminimide-based structure.
  • the multisubunit recognition agents above are expected to be very useful in the development of targeted therapeutics, drug delivery systems, adjuvants, diagnostics, chiral selectors, separation systems, and tailored catalysts.
  • surface refers to either P, P linked to C or P linked to C and L as defined above.
  • another aspect of the invention relates to a three-dimensional crosslinked random copolymer containing, in copolymerized form about 1 to 99 parts of a free-radically polymerizable monomer containing an aminimide group; up to 98 parts of a free-radically addition-polymerizable comonomer; and about 1 to 50 parts of at least one crosslinking monomer.
  • the comonomer used in this copolymer may be water-soluble or water-insoluble, and the copolymer is fashioned into a water-insoluble bead, a water-insoluble membrane or a latex particle, or can be a swollen aqueous gel suitable for use as an electrophoresis gel.
  • This copolymer is preferably the reaction product of about 1 to 99 parts of a condensation-polymerizable
  • monomer containing a moiety, cluster selected from the group consisting of ( 1 ) at least three epoxy groups, (2) at least three ester groups, (3) at least one epoxy and at least two ester groups and (4) at least one ester and at least two epoxy groups; about 1 to 99 parts of a second condensation-polymerizable monomer containing a moiety cluster selected from the group consisting of (1) at least two ester groups, (2) at least two epoxy groups and (3) at least one ester and one epoxy group; and an amount of 1, 1-dialkylhydrazine equivalent, on a molar basis, substantially equal to the total molar content of epoxy groups.
  • chromatographic support materials for chromatographic and other applications, as well as other fabricated materials can be derivatized with tailored aminimide moieties, through chemical modification, producing novel materials capable of recognizing specific molecular structures.
  • A is selected from the group consisting of amino acids, oligopeptides, polypeptides and proteins, nucleotides, oligonucleotides, polynucleotides, carbohydrates, molecular structures associated with therapeutic agents, metabolites, dyes, photographically active chemicals, and organic structures having desired steric, charge, hydrogen-bonding or hydrophobicity elements;
  • X and Y are chemical bonds or groups consisting of atoms selected from the set of C, H, N, O, S;
  • R1 and R2 are chosen from the group of alkyl, carbocyclic, aryl, aralkyl, alkaryl and, preferably, structures mimicking the side-chains of naturally-occurring amino acids.
  • R1...n and R' 1...n are used to illustrate the manner in which the hydrazine substituents R1 and R2 can be varied in each polymerization step described above to produce a functional supported oligomer or polymer.
  • a surface bearing ester groups can be treated with an epoxide, containing desired group B, and a disubstituted hydrazine to form an aminimide surface as follows:
  • the surface is treated with a solution containing a 10% molar excess of the epoxide (based on the calculated number of reactive ester groups of the surface), and a stoichiometric amount of the hydrazine (with respect to the amount of the epoxide) in an appropriate solvent, such as an alcohol, with shaking.
  • an appropriate solvent such as an alcohol
  • the surface is treated with a solution containing a 10% molar excess of the ester (based on the calculated number of reactive epoxide groups of the support), and a stoichiometric amount of the hydrazine (with respect to the amount of the ester used), in an appropriate solvent, such as an alcohol, with shaking.
  • an appropriate solvent such as an alcohol
  • the foregoing reaction can be modified by utilizing an ester whose substituent B contains a double bond.
  • the double bond of the ester can be epoxidized using one of a variety of reactions including the asymetric epoxidation of Sharpies (e.g., utilizing a peracid under suitable reaction conditions well-known in the art), and the product used as the epoxide in a new repetition of the aminimide-forming reaction.
  • the overall process can be repeated to form oligomers and polymers.
  • R2...n .and R3...n are used to illustrate the manner in which the hydrazine substituents R2 and R3 are varied in each polymerization step, if desired, to produce an oligomer or polymer.
  • Y is a linker as defined above, to form desirable polymers. If an ester-functionalized surface is reacted with bifunctional esters and epoxides, the resulting surface will have the following general structure.
  • An amine-functionalized surface can be converted to an ester-bearing surface by reaction with an acrylic ester as shown in sequence (a) below. This reaction is followed by reaction with hydrazine and an epoxide as shown in sequence (b).
  • reaction (a) For reaction (a), a 10% molar excess of methyl acrylate (based on the number of reactive amino groups the surface as determined by a titration with acid) is dissolved in an appropriate solvent, such as an alcohol, and added to the surface. After addition is complete, the mixture is shaken at room temperature for 2 days. The solvent is then removed by decantation and the surface is washed thoroughly with fresh solvent in preparation for the next step.
  • an appropriate solvent such as an alcohol
  • reaction (b) the stoichiometric amount of a 1 : 1 mixture of the hydrazine and the epoxide, is combined in an appropriate solvent, such as an alcohol, and quickly added to the solvent-wet surface from reaction (a). The mixture is shaken at room temperature for 3 days. The solvent is then removed by decantation, and the surface is washed thoroughly with fresh solvent and dried.
  • an appropriate solvent such as an alcohol
  • reaction sequence can also be employed with an epoxide-functionalized surface, in which case
  • substituent B in the structure above represents the surface and the desired functional group bears the amine moiety.
  • One way of obtaining such a surface is to react a silica surface with a silicic ester containing an epoxide group to produce a so-called “epoxy silica", as shown below.
  • a surface functionalized with a carboxylic acid group can be reacted with an 1 ,1 -dialkylhydrazine and a coupling agent, such as dicyclohexyl carbodiimide (DCC), to form a hydrazone-containing surface as shown in step (a) below.
  • This surface can then be coupled with a desired group B bearing a substituent capable of alkylating the hydrazone to give an aminimide structure (after treatment with base), as shown in step (b): / ' /
  • Substituent B is a surface functionalized with an alkylating agent capable of reacting with a hydrazone.
  • the surface is treated with a 10% molar excess equimolar amounts of the N,N-dimethylhydraz ⁇ ne and DCC in a suitable solvent, such as methylene chloride, and the mixture is shaken for 2 hours at room temperature.
  • a suitable solvent such as methylene chloride
  • the slurry is then removed by decantation and the surface is washed thoroughly with fresh solvent to remove any residual precipitated dicyclohexyl urea.
  • the surface is then treated with a stoichiometric amount of the alkylating agent in a suitable solvent, warmed to 70 _C and held at this temperature for 6 hours.
  • the mixture is then cooled, the solvent is removed by decantation, and the surface is washed witn fresh solvent and dried.
  • a surface bearing a group capable of alkylating acyl hydrazones can be functionalized to contain aminimide groups as follows:
  • Z and W are linkers composed of atoms selected from the set of C, N, H, O, S, and X is a suitable leaving group, such as a halogen or tosylate.
  • a hydrazone bearing a desired group B is produced by reacting the appropriate 1,1'-dialkylhydrazine with any of a variety of derivatives containing B via reactions that are well- known in the art. These derivatives may be acid halides, azlactones (oxazolones), isocyanates, chloroformates, or chlorothioformates.
  • the required chloromethyl aminimides can be prepared by known literature procedures (See, e.g., 21 J Polvmer Sci.. Polymer Chem. Ed. 1 159 ( 1983)). or by using the techniques described above.
  • Oxazolone-containing surfaces can be functionalized by first reacting them with 1,1'-dialkylhydrazine as shown in step (a) below followed by alkylation of the resulting
  • step (b) hydrazone with an alkylating agent B-CH2-X as shown in step (b); reaction conditions similar to those described above are expected to be effective in carrying out these modifications.
  • R3 and R4 are derived from the five membered azlactone ring denoted by Az.
  • aminimide-functionalized composite support materials by coating various soluble aminimide formulations on the surfaces of existing supports, and subsequently crosslinking the resulting coatings in place to form mechanically stable surfaces.
  • the coating may be engineered for a particular application (e.g.. to take the form of a thin non-porous film or to possess localized microporosity for enhanced surface area) by judicious selection of process conditions, monomer loading levels, the crosslinking
  • any of the foregoing reactions can be carried out with a vinyl aminimide in contact with a selected surface, which is polymerized according to well-known techniques (see, e.g., U.S. Patent No. 4,737,560).
  • a vinyl aminimide in contact with a selected surface, which is polymerized according to well-known techniques (see, e.g., U.S. Patent No. 4,737,560).
  • new surfaces and other materials can be fabricated de novo from aminimide precursors bearing polymerizable groups by polymerizations and/or copolymerizations in the presence or absence of crosslinking agents.
  • crosslinking agents Depending upon the properties for the desired material, various combinations of monomers, crosslinkers, and ratios thereof may be employed.
  • the resultant support materials may be latex particles, porous or non-porous beads, membranes, fibers, gels, electrophoresis gels, or hybrids thereof.
  • the monomers and crosslinking agents may or may not all be aminimides.
  • Vinyl or condensation polymerizations may be advantageously employed to prepare the desired aminimide-containing materials.
  • copolymerizable with aminimides suitable examples include styrene, vinyl acetate, and acrylic monomers.
  • suitable non-aminimide crosslinkers such as divinyl benzene, may be employed (either singly or in combination as the other such agents).
  • Condensation polymerization may be accomplished using multifunctional epoxides and multifunctional esters with the appropriate amounts of an 1,1'-dialkylhydrazine, using the reaction conditions described above. Either the ester
  • component or the epoxide component should be at least trifunctional to obtain three-dimensionally crosslinked polymer structures; preferably, both components are trifunctional.
  • the ratio of the various monomers and the ratio of crosslinker to total monomer content can be varied to produce a variety of product structures (e.g., beads, fibers, membranes, gels, or hybrids of the foregoing) and to tailor the mechanical and surface
  • properties of the final product e.g., particle size and shape, porosity, and surface area. Appropriate parameters for a particular application are readily selected by those skilled in the art.
  • solid phase libraries i.e., libraries in which the ligand-candidates remain attached to the solid support particles used for their synthesis
  • the bead-staining technique of Lam may be used.
  • the technique involves tagging the ligand-candidate acceptor (e.g., an enzyme or cellular receptor of interest) with an enzyme (e.g., alkaline phosphatase) whose activity can give rise to color production thus staining library support particles which contain active ligand-candidates and leaving support particles containing inactive ligand-candidates colorless.
  • Stained support particles are physically removed from the library (e.g., using tiny forceps that are coupled to a
  • micromanipulator with the aid of a microscope) and used to structurally identify the biologically active ligand in the library after removal of the ligand acceptor from the complex by e.g.. washing with 8M guanidine hydrochloride.
  • affinity selection techniques described by Zuckermann above may be employed.
  • An especially preferred type of combinatorial library is the encoded combinatorial library, which involves the synthesis of a unique chemical code (e.g., an oligonucleotide or peptide), that is readily decipherable (e.g., by sequencing using traditional analytical methods), in parallel with the synthesis of the ligand-candidates of the library.
  • a unique chemical code e.g., an oligonucleotide or peptide
  • the structure of the code is fully descriptive of the structure of the ligand and used to structurally characterize biologically active ligands whose structures are difficult or impossible to elucidate using
  • saccharide and polysaccharide structural motifs incorporating aminimide structures are contemplated including, but not limited to, the following.
  • nucleotide and oligonucleotide structural motifs incorporating aminimide-based structures are contemplated including, but not limited to, the following.
  • This example illustrates the alkylation of 1 , 1-dimethyl-2-acryloylhydrazide by treatment with an equimolar amount of methyl iodide in acetonitrile.
  • This reaction is carried out with equimolar quantities of the reactants dissolved in acetonitrile (0.1 mol ea/100 mL) under gentle reflux overnight.
  • the mixture is concentrated on a rotary evaporator, methanol is added and the pH is adjusted to the phenolphthalein end point with methanolic KOH.
  • the solvents are removed in vacuo, the residue is dissolved in the minimum amount of benzene, the precipitated salts are removed by filtration and the crude product is isolated by removal of solvents to dryness. Purified monomer is obtained by recrystallization from ethyl acetate.
  • N- ( 2 - trifluoroacetamidoisobutyryl)-N'-benzyl-methylhydrazine N- ( 2-trifluoroacetamidoisobutyryl)-N',N'-dimethylhydrazine, and N-( 2-trifluoroacetamidoisobutyryl)-N',N'-pentamethylene- hydrazine are prepared in comparable yields from 2- trifluoroacetamido-isobutyric acid and the respective 1 , 1 - dialkylhydrazines.
  • 1-isopropyl- 1-methylhydrazine 12.3g, 42%); 1-(tert-butyl 2-acetyl)- 1 -methylhydrazine (3.40g, 42%); 1 -isobutyl- 1 -methylhydrazine (9.80g, 29%), and 1-(2-(3-indolyl)-ethyl)- 1-methylhydrazine ( 1.32g, 69%) are prepared from the respective alkyl bromides and characterized.
  • This reaction is carried out by stirring equimolar amounts of the 1 , 1 , 1-trialkylhydrazinium tosylate (prepared from 1-methyl- 1-phenyl hydrazine and p-toluenesulfonic acid in toluene) in t-butanol at room temperature overnight.
  • An equimolar amount of 2-vinyl-4,4-dimethylazlactone (SNPE Chemical Inc.) is added and, the solution is stirred an additional 6 hours.
  • An equal volume of toluene is added.
  • the system is filtered and the filtrate is concentrated in vacuo on a rotary evaporator to yield the product as a thick oil. Pure crystalline product is obtained by crystallization from acetone.
  • This example is illustrated for functionizing commercially available 6% crosslinked agarose with 1 -benzyl- 1 , 1-dimethyl chloromethyl aminimide (prepared from 1 -benzyl- 1 , 1-dimethylhydrazinium chloride [from 1 , 1 -dimethylhydrazine and benzyl chloride in toluene] to produce the aminimide functionalized agarose, useful as a hydrophobic interaction support material for the chromatographic
  • This reaction is carried out by steeping the agarose with potassium t-butoxide in a mixture of t-butanol and DMF under nitrogen for one hour at room temperature.
  • the hydrazinium salt is added, and the mixture is stirred for 24 hours.
  • the functionalized agarose is collected by filtration, washed with t-butanol, methanol and finally with water. This material is stored in water for future use.
  • This epoxide (0.095 mole) is treated with 1 , 1-dimethylhydrazine (5.73 g, 0.095 mole) in methanol ( 100 mL and is refluxed for eight hours. The mixture is cooled and methyl 4-pentenoate ( 10.87 g, 0.095 mole) in methanol ( 100 mL) is added. The resultant solution is stirred at room temperature for 48 h. The solvent is removed to provide a pale yellow solid (45.6 g, 1 14%). Treatment of this material with m-CPBA (ca. 1.5 eq) in methylene chloride provides, after recrystallization, colorless crystals of the epoxydiaminimide (38.2 g, 0.091 mole, 96%).
  • a slurry of epoxy silica ( 10.0 g, 15 m Exsil C-200 silica, vide infra) in methanol ( 100 mL) is treated with 1 , 1-dimethylhydrazine (6.01 g, 1.0 mole), and stirred at room temperature for two hours (mechanical stirring provides a more efficient preparative procedure, as well as a superior product).
  • methyl 4-pentenoate 1 1.41 g, 0.1 mole
  • the functionalized silica is collected by filtration and washed by repeatedly suspending in methanol and filtering to removed the soluble material. After six washings, the solid obtained is dried overnight in a vacuum oven (60°C/0.1 mm Hg) to afford 9.86 g of product.
  • This material is suspended in methylene chloride and treated with m-CPBA (51.8 g, 50-60%, ca. 1.05 mole). The suspension is stirred mechanically overnight at room temperature and washed with methanol, as before, to remove the unreacted and spent reagents. The solid is dried overnight in a vacuum oven (60 °C/ 1.0 mm Hg) to afford 9.83 g of product.
  • This homologous epoxy silica is slurried in methanol
  • the diastereomers from the above reaction are separated on a C- 18 reverse phase silica media with an acetonitrile- water gradient.
  • the fractions containing the desired diastereomer are pooled, and the product is isolated by removal of the solvents in vacuo.
  • the resulting dried powder from the above reaction is dissolved in benzene and pyridine ( 1.59 g, 20 mmol, 1.61 mL or Amberlite IR-45 resin, vide supra), then cooled to 0 °C while a solution of bromoacetyl chloride ( 1.13 g, 7.2 mmol,. 0.59 mL) in benzene ( 10 mL) is added. The mixture is stirred overnight at room temperature. The pyridinium salts are subsequently removed by filtration and the filtrate is concentrated to afford a pale yellow solid ( 1.87 g). The pure material is obtained by recrystallization of the yellow solid from ethyl acetate.
  • Acetyl chloride (8.64 g, 1.01 mole) is added to an ice-cooled solution of N-amino-N-methylglycine tert-butyl ester (11.6 g, 1.00 mole) in pyridine (10 mL) and THF (250 mL). The mixture is stirred at 0 °C for 30 minutes, then room temperature for three hours. The mixture is concentrated on a rotary evaporator and the remaining volatiles are removed in vacuo . The residue is recrystallized from ether to afford the hydrazide ester ( 14.54 g, 0.092 mole).
  • the precipitate (dicyclohexylurea) is removed by filtration and the filtrate is concentrated on a rotary evaporator to afford an amorphous mass, which yields white crystals (27.06 g, 89%, 0.082 mole) after recrystallization from ethyl acetate.
  • the suspension is treated with Amberlite IR-45 (or an equivalent basic resin) for three hours at room temperature, then filtered to remove both the resin and precipitated dicyclohexylurea. The filtrate is concentrated, and the residue is recrystallized from ethyl acetate to afford the bis hydrazinium inner salt (3.56 g, 78%).
  • the pyrimidyl hydrazine (2.14 g, 10 mmol) is treated with an excess of anhydrous ammonia in methanol at 0 °C, then stirred at room temperature overnight. Removal of the solvent on a rotary evaporator afforded a residue which was chromatographed on silica gel (gradient elution with chloroform-methanol), providing the pure 1 -(3-( 1 -cytidyl)-propyl)- 1 -methylhydrazine ( 1.62 g, 87%).
  • Stepwise assemblage of a modular scaffold which presents a known sequence of nucleotides to a desired target.
  • this series of reaction can be repeated, substituting the five natural bases as well as other bases for each step as the desired sequence dictates or warrants.
  • This material also can be elongated using silyl protected purines. which prevents inter and intramolecular binding of the bases.
  • the ring amine of the cytidyl hydrazine is protected as well, by a trialkylsilyl group prior to incorporation into the backbone.
  • a three neck round-bottom flask is charged with 10 mL of a suitable solvent, such as CH 2 CI 2 , and oxalyl chloride (540 mL, 6.2 mmol, 1.2 equiv).
  • a suitable solvent such as CH 2 CI 2
  • oxalyl chloride 540 mL, 6.2 mmol, 1.2 equiv.
  • the solution is stirred and cooled to -60 °C as DMSO (740 ⁇ L, 810 mg, 10.4 mmol, 2 equiv) in dichloromethane (5 mL) is added dropwise at a rapid rate. After 5 min, 6 (1 g, 51.8 mmol, 1.0 equiv) is added dropwise over 10 min period, maintaining the temperature at -60 °C.
  • methyltriphenylphosphonium iodide ( l . lg, 2.74 mmol, 1.1 equiv) and THF (10 mL), then flushed with argon.
  • the flask is cooled in an ice bath, and the suspension is stirred under a positive pressure of argon while 5 ⁇ L to 14 ⁇ L of 1.8 M
  • phenyllithium in 30:70 ether.cyclohexane is added dropwise until the suspension develops a permanent yellow color.
  • 1.6 mL of 1.8 M phenyllithium is added dropwise over 10 min.
  • the ice bath is removed, and the orange suspension containing excess phosphonium salt is stirred at room temperature for 30 min.
  • the reaction mixture is stirred and cooled to 0-5 °C.
  • a strong base such as n-butyllithium (2.5 M solution in hexanes, 25.0 mL, 62.5 mmol
  • a solution of dibenzosuberenone ( 12.5 g, 60.6 mmole) in an appropriate anhydrous solvent, such as THF ( 100 mL) is added dropwise, with stirring, over a period of 30 minutes.
  • the reaction is stirred at 0 °C for another two hours, then quenched with the addition of water ( 150 mL), made basic such as with the addition of concentrated aqueous NaOH ( 10 mL).
  • the volume of the resulting mixture is partially reduced in vacuo, then extracted with ether (2 ⁇ 150 mL).
  • the combined organic layers are washed with saturated aqueous NaHCO 3 (2 ⁇ 150 mL), then brine ( 1 ⁇ 100 mL), dried over anhydrous MgSO 4 , and concentrated by rotary evaporation to afford 29 g of a yellow oil.
  • the crude material is purified with column chromatography on a suitable stationary phase such as normal phase silica gel and eluted with an appropriate mobile phase, such as hexanes-ethyl acetate mixtures, to afford the desired compound (14.2 g, 85%). A portion is repurified to yield a sample for analysis.
  • Lithium aluminum anhydride ( 1.87 g, 49.3 mmole) is added, slowly, to a stirring solution of 4-hydroxy-N-(N-(N- methylhydrazino)-2-ethanamidyl)-4-phenylpiperidine in a suitable anhydrous solvent, such as THF or diethyl ether ( 100 mL), at 0 °C.
  • a suitable anhydrous solvent such as THF or diethyl ether ( 100 mL)
  • Ethyl acetate (40 mL) is added, with vigorous stirring, to quench the reaction, followed by the careful addition of a saturated aqueous solution of sodium sulfate to neutralize the mixture.
  • the white aluminum salts are filtered, and washed thoroughly with an appropriate solvent such as diethyl ether or ethyl acetate.
  • the filtrate is concentrated on a rotary evaporator to yield the desired product as a solid (3.63 g, 89%).
  • a portion is recrystallization to give a sample for analysis.
  • 1,2-Epoxydodecane (2.68g, 0.01 mol), 1 , 1- dimethylhydrazine (0.6 g, 0.01 mol) and sialic acid methyl ester (3.23 g, 0.01 mol) are dissolved in methanol (50 mL).
  • methanol 50 mL
  • the resulting clear yellow solution is stirred at room temperature for 96 hours.
  • the solution was concentrated on a rotary evaporator in vacuo, then subjected to vacuum (1.0 torr), to remove any residual solvent, leaving a quantitative yield of the waxy solid sialic acid derivative, characterized by 1 H-NMR and FTIR spectroscopy.
  • 1,2-Epoxydodecane (26.75 g, 1.0 mol), 1 ,1-dimethylhydrazine (6.01 g, 1.0 mol), and S-ketoprofen (26.8 g, 1.0 mol) were dissolved in 150 mL of methanol. The resulting clear yellow solution was stirred at room temperature for 96 hours. The solution was concentrated on a rotary evaporator in vacuo, then subjected to vacuum (1.0 torr) to remove any residual solvent, leaving a waxy solid ketoprofen aminimide derivative (59.23 g), characterized by its 1 H-NMR and FTIR spectra.
  • 1,2-Epoxydodecane (26.75 g, 1.045 mol), 1 , 1-dimethylhydrazine (8.72 g, 1.045 mol) and ethyl acetate ( 12.78 g, 1.045 mol) were dissolved in methanol (50 mL). The resulting clear yellow solution was stirred at room temperature for 96 hours. The solution was concentrated on a rotary evaporator in vacuo, then subjected to vacuum (1.0 torr) to remove any residual solvent. The resulting thick glass was cooled to 0 °C and scratched with a glass rod to initiate
  • a suitable solid phase synthesis support e.g., the chloromethyl resin of Merrifield is treated with 4-hydroxyl butyric acid in the presence of Cs 2 CO 3 followed by tosylation with p-toluenesulfonyl chloride, under conditions known in the art:
  • the resulting resin is divided into three equal portions. Each portion is coupled with one of the hydrazines shown above to give the hydrazinium resin which is converted to the aminimide by reaction with chloroacetyl chloride using the experimental conditions described above.
  • the aminimide resin portions are mixed" thoroughly and divided again into three equal portions. Each resin portion is coupled with a different hydrazine followed by a coupling with ⁇ -chloracetyl chloride producing a resin with two linked aminimide subunits. The resin portions are then mixed thoroughly and divided into three equal portions.
  • the resin portions are mixed producing a library containing 27 types of beads each bead type containing a single trimeric aminimide species for screening using the bead-stain method described above.
  • the aminimides may be detached from the support via acidolysis producing a
  • This mimetic was synthesized by reacting styrene oxide or propylene oxide, ethyl acetate or methyl benzoate with four commercially available cyclic hydrazines (as mimetics of proline) in isopropanol in 16 individual sample vials, as shown below:
  • 1,2-epoxydodecane (I) ( 1.84 g, 0.01 mol) in a suitable solvent, such as n-propanol, is added, with stirring, 1,1-dimethylhydrazine (0.61 g, 0.01 mol).
  • a suitable solvent such as n-propanol
  • 1,1-dimethylhydrazine (0.61 g, 0.01 mol)
  • the solution is stirred for 1 hour at room temperature, cooled to 10 °C in an ice bath, and a solution of vincamine (II) (3.54 g, 0.01 mol), dissolved in the minimum amount of the same solvent, is added.
  • the reaction mixture is stirred at 0 °C for 2 hours, then stirred at room temperature for 3 days.
  • the solvent is removed under high vacuum (0.2 torr) and the crude product is isolated.
  • the conjugate (II) is useful as a stabilization agent for the isolation and purification of receptor proteins which are acted upon by vincamine
  • V conjugate (V), which is useful as a ligand for the discovery, stabilization and isolation of serotonin-binding membrane receptor proteins.
  • Rhodamine B (49.74 g, 1.0 mol, prepared from rhodamine B by the standard techniques for preparing acid chlorides from carboxylic acids), dissolved in a suitable solvent (500 mL), are added, with stirring, over a 1-hour period to a solution of 1,1-dimethylhydrazine (6.01 g, 1.0 mol) in 100 mL of the same solvent. The temperature is kept at 10 °C. After the addition is complete, the mixture is stirred at room temperature for 12 hours, and the solvent is removed in vacuo to yield the Rhodamine B dimethylhydrazine (VII).
  • Rhodamine B dimethylhydrazine (VII) (5.21 g, 0.01 mol) is dissolved in a suitable solvent, such as benzene
  • Disperse blue 3 tosylate (XII) (0.466 g, 0.001 mol, prepared by the standard tosylation techniques from a pure sample of the dye obtained from the commercial material by standard normal-phase silica chromatography), is added and the mixture is heated at 70 °C for 2 more hours.
  • the solvent is removed in vacuo, the residue is redissolved in an appropriate alcohol solvent and titrated to pH 8 (measured with moist pH paper) with 10% (w/v) methanolic KOH.
  • the precipitated salts are then removed by filtration.
  • the filtrate is concentrated in vacuo to give conjugate (XIII), useful as a probe for the location and isolation of receptor proteins that bind codeine and similar molecules.
  • the dodecamer peptide (BEAD)-Asp-His-Ile-Ala-Asn-Arg-Arg-Gly-Thr-Arg-Gly-Ser-NH 2 is attached to the solid support as shown using standard FMOC peptide synthesis techniques, after deprotection of the terminal FMOC group.
  • This peptide is shaken with a solution of an equivalent molar amount of CICH 2 COCI in a suitable solvent at 50 °C for 6 hours.
  • the solvent is removed by decanting, leaving a terminal -NH-CO-CH 2 CI group attached to the peptide.
  • the precipitated N,N'-dicyclohexylurea is removed by centrifuging and decanting, and the solution is added to the functionalized beads prepared in a. above.
  • the mixture is heated to 50 °C and shaken overnight. After cooling, the solvent is removed by decanting, and the peptide is released from the bead to yield the aminimide mimetic H 2 N -Thr-Thr-Tyr-Ala-Asp-Phe-Ile-CO-N-N(CH 3 )2-CH 2 -Ser-Gly-Arg-Thr-Gly-Arg-Asn-Ala-Ile-His-Asp-COOH.
  • This mimetic has the aminimide in place of alanine in the naturally occurring protein-kinase binding peptide, UK (5-24), and is useful as a synthetic binding peptide with enhanced proteolytic stability.
  • This example teaches the synthesis of a competitive inhibitor for human elastase based on the structure of known N-trifluoroacetyl dipeptide analide inhibitors (see 162 J. Mol.
  • chloracetyl chloride (1.24 g, 0.011 mol), contained in a micro reaction flask equipped with a drying tube, was heated in an oil bath to 105°C for 1 hour.
  • the solid substance was purified by recrystallization from ethanol/ether to yield the desired pure diastereomeric salt, which was subsequently converted to the iodide form by precipitation from a water-ethanol solution of the tartrate (made alkaline by the addition of sodium
  • chloroacetyl chloride (1.24 g, 0.011 mol), contained in a micro reaction flask equipped with a drying tube, was heated to 105 °C for 1 hour with an oil bath. The homogeneous reaction mixture was cooled to room temperature, then extracted with diethyl ether (4 ⁇ 20 mL) to remove chloracetyl chloride and chloroacetic acid. The residual semi-solid mass was dissolved in the minimum amount of methanol, and titrated with 10 % KOH in methanol to the phenolphthalein end point. The precipitated salts were filtered and the filtrate was evaporated to dryness on a rotary evaporator at 40 °C. The residue was then taken up in benzene and filtered. The solvent was removed on a rotary
  • N-methylurea 74.08 g, 1 mol
  • diethylethoxymethylenemalonate 216.2 g, 1 mol
  • This example teaches the synthesis of a competitive inhibitor for the HIV protease with enhanced stability, based on the in
  • the product is recrystallized from ethyl acetone at -30°C to yield pure crystalline momomer, useful for fabricating crosslinked chiral gels, beads, membranes and composites for chiral separations, particularly for operation at high pH.
  • NMR CDCl3 chemical shifts, presence of vinyl groups in 6 ppm region, vinyl splitting patterns, peak integrations and D20 experiments diagnostic for structure.
  • silica functionalized with the Michael-addition product of (S)-4-ethyl-4-benzyl-2-vinyl- 5-oxazolone to mercaptopropyl-functional silica is stirred at room temperature for 8 hours.
  • the functionalized silica is collected by filtration and successively reslurried and refiltered using 100-ml portions of toluene (twice), methanol (four times) and water (twice).
  • the resulting wet cake is dried in a vacuum oven at 60 ⁇ C under 30" vacuum to constant weight, yielding 4.98 g of chiral-aminimide-functionalized silica, useful for the separation of racemic mixtures of carboxylic acids, such as ibuprofen, ketoprofen and the like.
  • the functionalized silica is then collected by filtration, re-slurried in 100 ml methanol and re-filtered a total of five times, then dried in a vacuum oven at 60 ⁇ C/30" overnight to give 9.68 g of the product.
  • This functionalized silica is slurry packed from methanol into a 0.46 x 15 cm stainless steel column and used to separate mixtures of mandelic acid derivatives under standard conditions.
  • Exsil silica (SA 250 M2/g) is added to 650 ml toluene in a two-liter three-necked round-bottomed flask equipped with a Teflon paddle stirrer, a thermometer and a vertical condenser set up with a Dean-Stark trap through a claisen adaptor.
  • the slurry is stirred, heated to a bath temperature of 140 ⁇ C and the water is azeotropically removed by distillation and collection in the Dean-Stark trap.
  • This example describes preparation of an aminimide-functionalized ion-exchange silica matrix using epoxy silica as the support to be modified.
  • the reaction sequence is:
  • the diethylaminoethyl (DEAE) functionalized silica is collected by filtration, re-slurried in 100 ml methanol and re-filtered a total of five times. The packing is dried in a vacuum oven at 60_C/30" overnight. A 1.0 ml bed of this material is then packed in a 15 mM NaAc buffer at pH 7.7. The column is then equilibrated with 15 mM NaAc buffer at pH 5.6, and a solution of 1 mg/ml ovalbumin in this buffer run through the bed at a flow rate of 1.6 ml/min. A total of 59.2 ml of protein solution is run.
  • This example describes preparation of an aminimide-functionalized size-exclusion silica matrix using the epoxy silica support described in Example _.
  • the functionalized silica is then collected by filtration, re-slurried in 100 ml methanol, re-filtered a total of five times and dried in a vacuum oven at 60 ⁇ C/30" overnight.
  • the functionalized silica is slurry packed from methanol into a 10 mm interior-diameter jacketed glass column with adjustable pistons to provide an 8 cm-long packed bed. This packing is used to separate mixtures of polyethylene glycol polymers of varying molecular weight with good
  • This example describes preparation of an aminimide-functionalized crosslinked PVA matrix.
  • the bulk packing is used to selectively adsorb polyethylene-glycol functionalized hemoglobin from serum samples taken from test animals that had been treated with this derivative as a blood substitute. Filtration of the serum, after treatment with the bulk packing, gave a serum free from the functionalized hemoglobin, thus allowing blood screening or testing by means of standard methods.
  • This example describes preparation of a second type of aminimide-functionalized crosslinked PVA matrix.
  • the bulk packing is used to selectively adsorb polyethylene-glycol functionalized hemoglobin from serum samples taken from test animals that had been treated with this derivative as a blood substitute. Filtration of the serum, after treatment with the bulk packing, gave a serum free from the functionalized hemoglobin, thus allowing blood screening or testing by means of standard methods.
  • Hydroxypropylcellulose is mono-functionalized by reaction, under strong alkaline conditions (preferably provided by a strong base, such as potassium t-butoxide) with C1CH2CON-N+(CH3)3.
  • strong alkaline conditions preferably provided by a strong base, such as potassium t-butoxide
  • C1CH2CON-N+(CH3)3 a strong base
  • the resulting aminimide derivative is coated onto a surface (e.g., silica).
  • a surface e.g., silica
  • the N(CH3)3 group leaves, resulting in formation of an isocyanate moiety:
  • the isocyanate groups then react with unreacted hydroxyl groups on the saccharide units to produce a cross-linked coating.
  • the cellulose can be coated onto the surface and immobilized using standard techniques (e.g., reaction with bisoxiranes), and then mono, di- or tri- substituted with desired aminimide derivatives as described above .
  • reaction sequence can also be employed with polymers or oligomers bearing NH or SH groups instead of hydroxyl groups and can also be utilized to fabricate structures such as crosslinked cellulose membranes.
  • This example illustrates an alternative immobilization technique, namely, polymerizing aminimide precursors containing vinyl groups and which have been coated onto a surface.
  • the chemistry resembles the approach
  • the mixture is stirred in a rotary at room temperature for 15 min and then stripped using a bath temperature of 44°C to a volatiles content of 15% as measured by weight loss (from 25-200°C with a sun gun).
  • the coated silica is slurried in 100 ml of isooctane containing 86 mg of VAZO-64 dissolved in 1.5 ml toluene which had been de- aerated with nitrogen. The slurry is thoroughly de-aerated wtih nitrogen and then stirred at 70°C for two hours.
  • coated silica is collected by filtration and washed three times in 100 ml methanol and air dried. The silica is heated at 120o C for 2 hours to cure the coating. 13.1 g of coated silica are obtained. A 1 ml bed of this material is packed in an adjustable glass column and successfully used to separate BSA from lactoglobulin:
  • an epoxy-functionalized surface is reacted with disubstituted hydrazine, a bisepoxide and a triester to form a crosslinked network of aminimide chains attached covalently to the surface as follows:
  • the reaction can be carried out in water at room temperature without special conditions.
  • This example describes preparation of three-dimensional cross-linked porous copolymeric aminimide ion-exchange beads. It involves reaction of three monomers:
  • This material is triturated with diethylether and hot benzene and dissolved in the minimum amount of methanol.
  • the mixture is then treated with charcoal, filtered, heated to boiling and brought to the cloud point with ethyl acetate.
  • the resulting solution is allowed to stand at 0°C for a week.
  • the white crystals that formed are collected by filtration, washed with cold ethyl acetate and dried in a vacuum oven at room
  • the beads obtained at the conclusion of the foregoing steps had a mean diameter of approximately 75 u and an ion-exchange capacity of 175 ueq/ml.
  • the gel is overlayed with isobutanol and allowed to polymerize overnight.
  • Tris 1.5M 6.06 g Tris base, 8 ml 10% SDS, volume adjusted to 90 ml with double-distilled water. The pH is adjusted to 6.0 with concentrated HCI, and the final volume adjusted to 100 ml with DD water.
  • SDS 10% w/v 10 g of SDS is dissolved in DD water and adjusted to a volume of 100 ml.
  • Ammonium persulfate 10% 0.1 g ammonium persulfate is dissolved in 0.9 ml DD water. The solution is used within 4 hours of preparation.
  • 591.1 ml of distilled water is charged to a three-necked round-bottomed flask.
  • a nitrogen dip tube is placed below the liquid level and the nitrogen flow rate set to 2 cm3/min.
  • the solution is mechanically agitated with a Teflon paddle at 250 RPM and heated to 80° C over a half-hour period.

Abstract

L'invention se rapporte à la structure et à la synthèse de nouveaux modules moléculaires dérivés de l'aminimide et à l'utilisation de ces modules dans la formation de nouvelles molécules et aux matériaux fabriqués grâce à ce procédé. Les nouvelles molécules et les matériaux produits sont des agents de reconnaissance moléculaire utilisés dans l'élaboration et la synthèse de médicaments et s'appliquent à des techniques de séparation et aux sciences des matériaux.
PCT/US1993/012612 1993-12-28 1993-12-28 Structure et synthese modulaire de molecules contenant l'aminimide WO1995018186A1 (fr)

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PCT/US1993/012612 WO1995018186A1 (fr) 1993-12-28 1993-12-28 Structure et synthese modulaire de molecules contenant l'aminimide
CA002179983A CA2179983A1 (fr) 1993-12-28 1993-12-28 Structure et synthese modulaire de molecules contenant l'aminimide
AU60159/94A AU689764B2 (en) 1993-12-28 1993-12-28 Modular design and synthesis of aminimide containing molecules
EP94906465A EP0737232A4 (fr) 1993-12-28 1993-12-28 Structure et synthese modulaire de molecules contenant l'aminimide
JP7517995A JPH09510693A (ja) 1993-12-28 1993-12-28 アミンイミド含有分子のモジュール設計および合成

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EP0743857A1 (fr) * 1994-01-05 1996-11-27 Arqule, Inc. Procede de preparation de polymeres ayant des proprietes specifiques
EP1053238A1 (fr) * 1998-01-29 2000-11-22 Monash University Composes therapeutiques
WO2003018557A1 (fr) * 2001-08-27 2003-03-06 Centre National De La Recherche Scientifique Hydrazinopeptoides et leurs utilisations dans le traitement des cancers
US6545057B2 (en) 2000-09-26 2003-04-08 The Brigham And Women's Hospital Inc. Tricyclic antidepressants and their analogues as long-acting local anesthetics and analgesics
US7074961B2 (en) 2000-09-26 2006-07-11 The Brigham And Women's Hospital, Inc. Antidepressants and their analogues as long-acting local anesthetics and analgesics
US10351661B2 (en) 2015-12-10 2019-07-16 Ppg Industries Ohio, Inc. Method for producing an aminimide
US10377928B2 (en) 2015-12-10 2019-08-13 Ppg Industries Ohio, Inc. Structural adhesive compositions

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JP5700203B2 (ja) * 2010-12-22 2015-04-15 スリーボンドファインケミカル株式会社 アミンイミド化合物、およびそれを用いた組成物およびその硬化方法

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0743857A1 (fr) * 1994-01-05 1996-11-27 Arqule, Inc. Procede de preparation de polymeres ayant des proprietes specifiques
EP0743857A4 (fr) * 1994-01-05 1998-07-15 Arqule Inc Procede de preparation de polymeres ayant des proprietes specifiques
EP1053238A1 (fr) * 1998-01-29 2000-11-22 Monash University Composes therapeutiques
EP1053238A4 (fr) * 1998-01-29 2003-09-03 Univ Monash Composes therapeutiques
US6784186B1 (en) 1998-01-29 2004-08-31 Roy W. Jackson Therapeutic compounds
US6545057B2 (en) 2000-09-26 2003-04-08 The Brigham And Women's Hospital Inc. Tricyclic antidepressants and their analogues as long-acting local anesthetics and analgesics
US7074961B2 (en) 2000-09-26 2006-07-11 The Brigham And Women's Hospital, Inc. Antidepressants and their analogues as long-acting local anesthetics and analgesics
WO2003018557A1 (fr) * 2001-08-27 2003-03-06 Centre National De La Recherche Scientifique Hydrazinopeptoides et leurs utilisations dans le traitement des cancers
US10351661B2 (en) 2015-12-10 2019-07-16 Ppg Industries Ohio, Inc. Method for producing an aminimide
US10377928B2 (en) 2015-12-10 2019-08-13 Ppg Industries Ohio, Inc. Structural adhesive compositions
US11518844B2 (en) 2015-12-10 2022-12-06 Ppg Industries Ohio, Inc. Method for producing an aminimide
US11674062B2 (en) 2015-12-10 2023-06-13 Ppg Industries Ohio, Inc. Structural adhesive compositions

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EP0737232A1 (fr) 1996-10-16
JPH09510693A (ja) 1997-10-28
AU6015994A (en) 1995-07-17
CA2179983A1 (fr) 1995-07-06
AU689764B2 (en) 1998-04-09

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