WO1995018972A1 - Production modulaire systematique de molecules a base d'aminimide et d'oxazolone ayant des proprietes choisies - Google Patents

Production modulaire systematique de molecules a base d'aminimide et d'oxazolone ayant des proprietes choisies Download PDF

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Publication number
WO1995018972A1
WO1995018972A1 PCT/US1994/000199 US9400199W WO9518972A1 WO 1995018972 A1 WO1995018972 A1 WO 1995018972A1 US 9400199 W US9400199 W US 9400199W WO 9518972 A1 WO9518972 A1 WO 9518972A1
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compound
structural diversity
array
structural
compounds
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PCT/US1994/000199
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English (en)
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Joseph C. Hogan, Jr.
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Arqule, Inc.
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Priority to CA002180526A priority Critical patent/CA2180526A1/fr
Priority to AU60221/94A priority patent/AU704183B2/en
Priority to PCT/US1994/000199 priority patent/WO1995018972A1/fr
Priority to EP94906537A priority patent/EP0740791A4/fr
Priority to JP7518446A priority patent/JPH09507487A/ja
Publication of WO1995018972A1 publication Critical patent/WO1995018972A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/08—Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support

Definitions

  • the present invention relates to a method for the modular development of aminimide- and oxazolone-derived synthetic organic molecules, posessing selected properties for a particular application.
  • This method involves 1.) the synthesis of an array generated from modules of aminimide-forming, oxzolone, oxazolone-forming and/or oxazolone-derived molecules containing a chosen set of substituent groups which confer structural diversity and/or the reaction of these modules with other appropriate reactive groups to produce an array of molecules posessing a chosen set of diverse structural moieties; 2.) the screening of these molecules for the desired set of properties in a target application.
  • the iterative application of this method enables molecules to be produced, having an optimum balance of properties for the particular application.
  • the synthetic chemist must subsequently find ways to synthesize structural variants of this lead molecule to optimize its properties in the desired application.
  • the "lead” molecule is a synthetized organic species or a natural product
  • the chemist is usually limited to certain structural themes and synthetic reaction schemes. These are dictated largely by the structural composition of the "lead” molecule and by the requirements of the specific application. For example, in cases where the "lead” posesses a functionally important aromatic ring, various electrophillic and nucleophillic substitutions are typically be carried out on the ring to produce variants. Each such case must be approached as a specific independent design and synthesis problem, starting each time from the beginning, because of the lack of availability of an appropriate chemistry to simply alter the structure of the lead compound to produce the variant.
  • 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 regulation of gene expression.
  • a biologically active molecule referred to as a ligand
  • binds with another mole ule usually a macromolecule referred to as ligand-acceptor (e.g.
  • ligand and ligand-acceptor are geometrically characteristic and extraordinarily specific, involving appropriate three-dimensional structural arrangements and chemical interactions.
  • 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.
  • 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.
  • peptidic ligands belonging to a certain biochemical class have been converted by groups of organic chemists and pharmacologists to specific peptidomimetics; however, in the majority of cases 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. 114:9699-9701; Hirschmann, R. et al., 1992 J. Am. Chem. Soc. 114:9217-9218); however, the success of this approach remains to be seen.
  • peptides are then screened for activity without removing them from the pins.
  • Houghton (1985, Proc. Natl. Acad. Sci. USA 82:5131 ; and U.S. Patent No. 4,631,211) utilizes individual polyethylene bags ("tea bags") containing C-terminal amino acids bound to a solid support. These are mixed and coupled with the requisite amino acids using solid phase synthesis techniques. The peptides produced are then recovered and tested individually.
  • Fodor et al. (1991, Science 251 :767) described light-directed, spatially addressable parallel-peptide synthesis on a silicon wafer to generate large arrays of addressable peptides that can be directly tested for binding to biological targets.
  • 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.
  • This synthetic scheme exponentially increasing numbers of peptides were produced in uniform amounts which were then separately screened for a biological activity of interest.
  • the invention relates to a method for obtaining compounds having selected properties for a particular application by forming base modules TM having at least two structural diversity elements from the reaction of a first compound having at least one structural diversity element and a first reactive group, with a second compound having at least one structural diversity element and a second reactive group, wherein the first and second groups combine by an addition reaction; producing a first array of molecules by varying at least one of the structural diversity elements of the compounds when producing the base modules; and screening the array to determine a first suitable compound for the particular application.
  • the method can be repeated by producing a second array of molecules through the formation of base modules having structural diversity elements that are modified from those of the first suitable compound; and screening the second array of molecules to determine a second suitable compound for the particular application.
  • the second array can be produced by forming base modules having at least two structural diversity elements in the same manner as the first array, except that the structural diversity elements are modified from those of the first suitable compound.
  • the second array producing and screening steps can be repeated as often as necessary to achieve an optimum compound for the particular application.
  • the first compound is produced by forming an oxazolone compound having at least one structural diversity element attached thereto and reacting it with a nucleophile or carbonyl compound which contains at least one structural diversity element to form a base module having one of the following structures:
  • the first compound as an aminimide-forming compound having at least one structural diversity element attached thereto and to react it with an oxazolone or ether compound which contains at least one structural diversity element to form a base module having one of the following structures:
  • the first and second structural diversity elements can be one of the following: an amino acid derivative of the form (AA) n . a nucleotide derivative of the form (NUCL) n ; a carbohydrate deri ,r "tive of the form (CH) n ; an organic moiety o_ an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, or of a naturally occurring or synthetic organic structural motif, optionally containing a reporter element, an electrophilic group, a nucleophilic group or a polymerizable group; or a macromolecular component.
  • At least one of the first and second compounds can be provided with two or more structural diversity elements, two of which can form a ring structure.
  • the invention relates to a method for obtaining compounds havin ⁇ cted properties for a particular application by producing a first structurally diverse array of molecules having at least two orthogonal reactivity elements wherein a first orthogonal reactivity element is held constant for each molecule and a second orthogonal reactivity element is varied; screening the array to determine a first suitable compound for the intended application; and modifying the first suitable compound to form a second structurally diverse array of molecules.
  • the first suitable compound has at least two orthogonal reactivity elements, so that the method further includes modifying the first suitable compound by holding a first orthogonal reactivity element constant while varying the second orthogonal reactivity element to produce the second structurally diverse array; and screening the second structurally diverse array of molecules to determine a second suitable compound for the intended application.
  • the method further comprises repeating the modifying and screening steps as often as necessary to achieve the optimum compound for the intended application.
  • the first structurally diverse array of molecules is advantageously produced by reacting either an oxazolone or aminimide compound, or combinations thereof, with first and second components which provide the orthogonal reactivity elements. It is useful for the first structurally diverse array of molecules to have one of the specific structures disclosed herein. These structures may include components such as an amino acid derivative, a nucleotide derivative, a carbohydrate derivative, an organic structural motif, a reporter element, a polymerizable organic moeity, or a macromolecular component.
  • This method is useful for a wide variety of applications, including the development of new biopharmaceutical agents, new monomeric species for the modular construction of separations tools, including chiral selectors, industrial detergents and additives and for the development of modular chemical intermediates for the production new materials and polymers.
  • the method relates to the selection of molecular modules containing appropriate structural diversity elements, the connecting of these modules together via facile high-yield addition reactions which produce discrete highly pure molecules in less than milligram quantities, in a manner such that the properties of these molecules are determined by the contributions of the individual building modules.
  • the molecular modules of the invention may be chiral, and can be used to synthesize new compounds, structures and 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 industrial and materials science.
  • Figure 1 is a flow chart for the reaction disclosed in Example 2.
  • the present invention is able to generate a number of different molecules for screening purposes by first forming a base module that contains at least two structural diversity elements attached thereto. These modules are formed by reacting first and second compounds, each of which has at least one structural diversity element and a reactive group. The reactive groups of the first and second compounds are such that they react with each other to form the base module by an additional reaction. By fixing one of the positions and structures of the structural diversity elements and by varying at least one of the others, an array of different molecules is easily generated. These molecules can then be screened to determine which are suitable for a particular application or target use. Once a suitable compound is identified, it can be selected for generating a further array of molecules. This is done by modifying the particular structural diversity elements that are found to be suitable, or by combining the chosen structural diversity element with an expanded or different set of second compounds or elements. This process can be repeated as often as necessary to develop the optimum compound for the particular use.
  • the particular base module chosen for use in accordance with the present invention is not critical and can be any one of a wide variety of structures. It has been found, however, that two particular structures which are known in the art are highly useful as such base modules, these known compounds being the oxazolones and aminamides. Thus, it is preferred to utilize compounds which are aminamide forming, oxazolone forming, oxazolone or oxazolone-derived molecules for use as the base module. Depending upon the specific structure selected, these base modules can have between two and six structural diversity elements. The specific chemistry of these molecules, as well as an identification of the structural diversity elements and reactivity groups, follows. Oxazolones
  • Oxazolones, or azlactones are structures of the general formula:
  • A, R, and R' are functional groups and n is 0-3.
  • Oxazolones may posess two substituents at the 4- position. When these substituents are not equivalent, the carbon atom at the 4-position is asymmetric and two non- superimposable oxazolone structures (azlactones) result:
  • Chiral oxazolones possessing a single 4-position non hydrogen substituent also known as 5(4H)-oxazolones
  • 5(4H)-oxazolones also known as 5(4H)-oxazolones
  • Chiral oxazolones possessing a single 4-position non hydrogen substituent also known as 5(4H)-oxazolones
  • derived from (chiral) natural amino acid derivatives including activated acylamino acyl structures
  • Oxazolones having at least one hydrogen substituent at the 4-position can also undergo a variety of rearrangements and side-reactions ( cf., 23 Tetrahedron 3363 (1967)), which may interfere with other desired transformations. This is illustrated for the case of the oxazolone formed from the cyclization of N-acryloyl glycine:
  • Oxazolones containing two non-hydrogen substituents at the four position are structurally pre l uded from undergoing these racemizations and side-reactions. These disubstituted oxazolones may be obtained chirally pure and may be subjected to the transformations which are the subject of this invention with retention of the chirality at this position.
  • Oxazolones may be prepared from the appropriate amino acid using any of a number of standard acylation and cyclization techniques well-known to those skilled in the art, e.g.:
  • oxazolones may be isolated in the pure state or may be generated in-situ from the acyl amino acid by treatment, for example, with equivalent amounts of triethyl amine and ethyl chloroformate in benzene. Following the evolution of carbon monoxide and the removal of the triethyl ammonium chloride formed by filtration, the solution of the oxazolone may be utilized directly for subsequent transformations.
  • Oxazolones may be subjected to ring opening reactions with a variety of nucleophiles, as shown below:
  • Y represents an oxygen, sulfur, or nitrogen atom.
  • R and R ⁇ differ from one another and taken alone each signifies one of the following: alkyl including carbocyclic and substituted forms thereof; aryl, araikyl, alkaryl, and substituted or heterocyclic versions thereof.
  • the above ring-opening reaction can be carried out either in an organic solvent such as methylene chloride, ethyl acetate, dimethyl formamide (DMF) or in water at room or higher temperatures, in the presence or absence of acids, such as carboxylic, other proton or Lewis-acids, or bases, such as tertiary amines or hydroxides, serving as catalysts.
  • organic solvent such as methylene chloride, ethyl acetate, dimethyl formamide (DMF)
  • acids such as carboxylic, other proton or Lewis-acids, or bases, such as tertiary amines or hydroxides, serving as catalysts.
  • This reaction may be used to generate an array of adducts, posessing combinations of the structural diversity elements A and C, as shown:
  • the compound shown can have from two to four structural diversity elements attached to the base module as desired.
  • both substituents in the 4-position are hydrogen, i.e., the oxazolone is formed from cyclization of an acyl glycine
  • the ring may undergo a high yield condensation addition reaction with aldehyde or ketone-containing structural groups at the 4-position. This reaction may be used to generate an array of adducts, posessing combinations of the structural diversity elements A and B, as shown:
  • the R group can be selected to be a diversity element to provide an additional structural diversity group on the oxazolone molecule.
  • the resulting adduct may subsequently undergo a high yield ring-opening addition reactrion with a wide variety of SH, NH and OH containing nucleophiles.
  • This reaction sequence may, thus, be used to generate an array of adducts, posessing combinations of the structural diversity elements A, B and C, as shown
  • the R group can be selected to be a diversity element to provide an additional structural diversity group on the oxazolone molecule.
  • 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.
  • 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.
  • 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
  • a very useful and versatile synthesis of aminimides involves the one-pot reaction of an epoxide, an asymetrically disubstituted hydrazine, and an ester in a hydroxylic solvent, usually water or an alcohol, which is allowed to proceed usually at room temperature over several hours to several days.
  • Rl, 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.
  • Any of the various R groups illustrated in all of these aminimide and aminimide-forming structures may be selected to be structural diversity elements.
  • a particularly useful embodiment of the invention is the synthesis of mixed aminimide-oxazolone molecules, as shown below.
  • T'.is scenario allows the incorporation of multiple structural diversity elements as shown:
  • R and methyl groups can be replaced with additional structural diversity elements so that a total of six can be provided on the mixed aminamide-oxazolone base module.
  • 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 (N>70) including structural proteins such as collagen, functional proteins such as hemoglobin, regulatory proteins such as the dopamine and thrombin receptors.
  • natural physiologically active carbohydrates such as including related compounds such as glucose, galactose, sialic acids, beta-D-glucosylamine and nojorimycin which are both inhibitors of glucosidase, pseudo sugars, such as 5a-carba-2-D-galactopyranose, which is known to inhibit the growth of
  • a naturally occurring or synthetic organic structural motif is defined as meaning an organic molecule having a specific structure that has biological activity, such as having a complementary structure to an enzyme, for instance.
  • This term includes any of the well known base structures of pharmaceutical compounds including pharmacophores or metabolites thereof. These include 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. These structural motifs are generally known to have specific desirable binding properties to ligand acceptors.
  • a reporter element such as a natural or synthetic dye or a residue capable of photographic amplification which possesses reactive groups which may be synthetically incorporated into the oxazolone structure or reaction scheme and may be attached through the groups without adversely interfering with the reporting functionality of the group.
  • reactive groups are amino, thio, hydroxy, carboxylic acid, carboxylic acid ester, particularly methyl ester, acid chloride, isocyanate alkyl halides, aryl halides and oxirane groups.
  • a macromolecular component such as a macromolecular surface or structures which may be attached to the oxazolone 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 functionalized 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.
  • 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
  • a structural moiety selected from the group including 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.
  • alkyl groups include lower alkyl, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl; upper 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.
  • alkynyl such as 1-ethynyl, 2-butynyl, 1- pentynyl and the like.
  • the ordinary skilled artisan is familiar with numerous linear and
  • 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- l -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, 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 described above, and lower alkyl groups as described above.
  • the cyclic groups of the invention may further comprise a heteroatom.
  • R2 is cycohexanol.
  • substituted and unsubstituted aryl groups means a hydrocarbon ring bearing a system of conjugated double bonds, usually comprising an even number of 6 or more (pi) electrons.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anisyl, toluyl, xylenyl and the like.
  • 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.
  • functional groups on the aryl groups can be nitro groups.
  • these structural moieties can also be any combination of alkyl, carbocyclic or aryl groups, for example, 1-cyclohexylpropyl, benzylcyclohexylmethyl, 2- cyclohexyl-propyl, 2,2-methylcyclohexylpropyl, 2,2methylphenylpropyl, 2,2-methylphenylbutyl, and the like.
  • a key element of the present method is the presence of at least two compounds, each having a reactive group capable of forming an addition compound with the other and carrying at least one of the structural diversity groups. These compounds are used to form the aminimide and the oxazolone base modules. These compounds may take the form of either A.) multiple reactive groups which are capable of being "turned on” independently of each other or B.) groups with multiple states with differing reactivities which may be addressed or brought into being at different times or under different conditions in a reaction sequence. It is highly desirable, although not absolutely necessary, that each individual reaction be a high-yielding addition reaction hout possible interfering side-reactions , so that isolation and purification steps are not necessaryy, or, at least, are held to a minimum.
  • This example describes the generation of a matrix of 16 molecules around the following aryl-heterocycle-alicyclic amine structural theme.
  • 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 in figure 1.

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne un procédé pour obtenir des composés ayant des propriétés choisies pour une application particulière, consistant à former des modules de base ayant au moins deux éléments de diversité structurels différents, provenant de la réaction d'un premier composé ayant au moins un premier élément de diversité structurel et un premier groupe réactif, avec un second composé ayant au moins un élément de diversité structurel différent et un second groupe réactif, où le premier et le second groupes se combinent par une réaction d'addition. On produit un premier ensemble de molécules en modifiant au moins un des éléments de diversité structurels des composés, lorsqu'on produit les modules de base. Puis, on trie l'ensemble pour déterminer un premier composé convenant à une application particulière. Les modules de base sont constitués de préférence de composés dérivés de l'oxazolone et d'un aminimide. Lorsque cela est souhaité, le procédé peut être répété par production d'un second ensemble de molécules par la formation de modules de base ayant des éléments de diversité structurels différents, lesquels sont modifiés par rapport à ceux du premier composé approprié. Ensuite, on trie le second ensemble de molécules pour trouver un second composé approprié à l'application particulière. Les étapes de production et de tri du second ensemble peuvent être répétées le nombre de fois nécessaire, jusqu'à obtention d'un composé optimal pour l'application particulière en question.
PCT/US1994/000199 1994-01-05 1994-01-05 Production modulaire systematique de molecules a base d'aminimide et d'oxazolone ayant des proprietes choisies WO1995018972A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002180526A CA2180526A1 (fr) 1994-01-05 1994-01-05 Methode d'identification de composes chimiques ayant des proprietes selectionnees pour des applications particulieres
AU60221/94A AU704183B2 (en) 1994-01-05 1994-01-05 Systematic modular production of aminimide- and oxazolone-based molecules having selected properties
PCT/US1994/000199 WO1995018972A1 (fr) 1994-01-05 1994-01-05 Production modulaire systematique de molecules a base d'aminimide et d'oxazolone ayant des proprietes choisies
EP94906537A EP0740791A4 (fr) 1994-01-05 1994-01-05 Production modulaire systematique de molecules a base d'aminimide et d'oxazolone ayant des proprietes choisies
JP7518446A JPH09507487A (ja) 1994-01-05 1994-01-05 選ばれた性質を有するアミンイミドおよびオキサゾロンをベースとした分子の系統的モジュール製造

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CA002180526A CA2180526A1 (fr) 1994-01-05 1994-01-05 Methode d'identification de composes chimiques ayant des proprietes selectionnees pour des applications particulieres
PCT/US1994/000199 WO1995018972A1 (fr) 1994-01-05 1994-01-05 Production modulaire systematique de molecules a base d'aminimide et d'oxazolone ayant des proprietes choisies

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AU (1) AU704183B2 (fr)
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WO1997039722A2 (fr) * 1996-04-25 1997-10-30 T Cell Sciences, Inc. Procede pour isoler les regulateurs de l'activation des lymphocytes t
WO1998056028A1 (fr) * 1997-06-03 1998-12-10 Arqule, Inc. Procede automatise a haut debit permettant de cribler une pluralite de composes par spectrometrie de masse
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US6497820B1 (en) 1998-02-03 2002-12-24 Arqule, Inc. Rapid method for separation of small molecules using reverse phase high performance liquid chromatography
US6919178B2 (en) 2000-11-21 2005-07-19 Sunesis Pharmaceuticals, Inc. Extended tethering approach for rapid identification of ligands
US6998233B2 (en) 1998-06-26 2006-02-14 Sunesis Pharmaceuticals, Inc. Methods for ligand discovery
US7514263B2 (en) 2001-04-02 2009-04-07 3M Innovative Properties Company Continuous process for the production of combinatorial libraries of materials
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Publication number Publication date
AU704183B2 (en) 1999-04-15
CA2180526A1 (fr) 1995-07-13
JPH09507487A (ja) 1997-07-29
EP0740791A1 (fr) 1996-11-06
EP0740791A4 (fr) 2000-04-05
AU6022194A (en) 1995-08-01

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