WO2000027627A1 - Lieurs d'aryloxime dans la synthese de la phase solide de 3-aminobenzisoxazoles - Google Patents

Lieurs d'aryloxime dans la synthese de la phase solide de 3-aminobenzisoxazoles Download PDF

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Publication number
WO2000027627A1
WO2000027627A1 PCT/US1999/026803 US9926803W WO0027627A1 WO 2000027627 A1 WO2000027627 A1 WO 2000027627A1 US 9926803 W US9926803 W US 9926803W WO 0027627 A1 WO0027627 A1 WO 0027627A1
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alkyl
aryl
arylalkyl
compound
resin
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PCT/US1999/026803
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English (en)
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Michael Robert Wiley
Salvatore Donato Lepore
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Eli Lilly And Company
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Priority to AU18184/00A priority Critical patent/AU1818400A/en
Publication of WO2000027627A1 publication Critical patent/WO2000027627A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a solid support mediated method for the synthesis of polycyclic heterocycle compounds, as well as intermediate compounds, a library of polycyclic heterocycle compounds, a method for the synthesis of a library of diverse polycyclic heterocycles and an assay kit for the identification of compounds having biological or other activity.
  • VIM benzisoxazole scaffold
  • Suh et al. teach compounds having the benzisoxazole scaffold that are potent LTB receptor antagonists. (Suh, H.; Jeong, S.;Han, Y.N.; Lee, H.; Ryu, J. Bioorg. Med. Chem. Lett., 1997, 7, 389).
  • polycyclic heterocycles have been synthesized according to chemistry known in the art by several groups. Much of the synthesis has relied on conventional "solvent" based chemistry.
  • Solvent defined chemistry relies on the collision of discrete reactants within a solvent cage. The movement of reactants is controlled by kinetic and thermodynamic molecular fluid energetics. For example, Shutske et al. generated benzisoxazoles according to Scheme A, through the solvent defined NOT FURNISHED UPON FILING
  • the desired product is isolated from a refluxing 1 :1 ethanol:5% HCI solution of the corresponding aryl oxime.
  • Cyclorelease or cyclization and release are terms applied to a reaction that forms a cyclized system with simultaneous release of product from a solid support.
  • the phrase, cyclization and displacement of product from a solid support is used to mean the same reaction.
  • Combinatorial chemistry allows researchers to make collections, or libraries, of compounds by parallel synthesis of large numbers of derivatives of selected classes of organic compounds that can be screened for biological and other activities. By screening these compounds against key receptors or enzymes, useful structure-function data can be obtained, speeding the search for new therapeutic agents.
  • a solid support mediated method for the synthesis of polycyclic heterocycle compounds and the use of this solid support mediated method for the synthesis of a library of diverse polycyclic heterocycles is desirable.
  • One aspect of this invention relates to a solid support mediated method for the synthesis of polycyclic heterocycle compounds (V):
  • n is an integer > 0, preferably 0, 1 , 2, or 3 and most preferably 0 or 1.
  • polycyclic heterocycles of the general Formula (V) are synthesized according to a procedure comprising the steps of:
  • intermediate (IV) is optionally chemically derivatized where at least one of R 1 , R 2 , R 3 or R 4 is chemically altered to form a corresponding intermediate (IV):
  • a second aspect of the invention is an intermediate compound of formula IV or IV above. Because this intermediate may be chemically derivatized before cyclization and displacement to thereby provide further options for the groups R 1 , R 2 , R 3 and R 4 ; the intermediate is preferably stable to a wide range of chemical conditions.
  • a third aspect of the invention is directed to a library of polycyclic heterocycle compounds where this library contains a plurality of diverse compounds (V):
  • a fourth aspect of the invention is directed to a method for the synthesis of a library of diverse polycyclic heterocycles by the general method described above.
  • a fifth aspect of the invention is directed to an assay kit for the identification of compounds having biological or other activity, this kit comprising assay materials and well plate apparatus where each well in this apparatus contains a compound of the library described above.
  • solid support is intended to have a relatively broad meaning including, but not limited to, a resin, a polymer, a gel, glass beads, silica gel, a ceramic solid support or other solid composition.
  • solid support bound oxime means a solid support that at least has one oxime moiety chemically attached thereto.
  • this compound may be represented by the formula (IX):
  • g represents a solid support, such as defined above.
  • solid support bound member means a solid support that has at least one functional moiety chemically attached thereto.
  • this may be represented by the formula (III):
  • oxime resin means a solid support where the functional moiety is an oxime, and the solid support is a resin.
  • Kaiser resin means an oxime functionalized polystyrene resin, an example of that is defined by E.T.Kaiser in a 1980 publication (Degrado, W.F.;Kaiser. E.T.; J.Org. Chem., 1980, 45, 1295).
  • a preferred resin is an oxime functionalized polystyrene, such as an oxime-polystyrene resin derived from p-nitrobenzophenone polystyrene resin according to the following formula.
  • halo means a member selected from the group consisting of fluoro, chloro, bromo and iodo.
  • Alkyl is the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl group, and that groups may include one or more double or triple bonds.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone, and more preferably 20 or fewer and most preferred 10 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure.
  • Particularly preferred alkyl substituents include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, tert-butyl, sec- butyl, cyclobutyl, pentyl, hexyl, cyclohexyl, etc.
  • "lower alkyl” as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure.
  • the aliphatic cyclic groups can be single or polycyclic containing between about 3 to 12 carbons per ring, but preferably between 3 and 9 carbons per ring.
  • Haloalkyl and “alkylhalo” both refer to mono- or poly- halogen radical substituted alkyl radicals, with the alkyl radicals having the analogous length and possible substitution as described above. Typically, these terms refer to groups of the formula X n -(CX'X") m -, where n and m are each independently an integer > 1 , and X, X' and X" are each independently hydrogen or halogen (so long as at least one of X, X and X" are halogen).
  • Hydroxyalkyl and “alkylhydroxide” and “alkyl alcohol” all refer to a mono or poly hydroxide radical substituted alkyl radical, with the alkyl radicals having the analogous length and possible substitution as described above.
  • Alkyloxyalkyl ether and “alkyloxyaryl ether” both refer to ether functional radicals of either the dialkyl radical or the alkyl, aryl radical configuration, with the alkyl radicals and the aryl radicals having the analogous length and possible substitution to the alkyl and aryl radicals defined herein.
  • Alkenyl and “alkynyl” refer to unsaturated aliphatic substituents analogous in length and possible substitution to the alkyl radicals described above, but that contain at least one double or triple bond, respectively.
  • Amino means an amino radical substituted with up to 2 alkyl radicals as defined above or with 1 alkyl radical and a hydrogen radical, or with two or more hydrogen radicals or with the substitution required to complete the nitrogen's valence requirements.
  • Aryl as used herein includes 5-10 membered aromatic monocyclic or fused polycyclic moieties that may include from zero to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthyline, benzathiazoline, benzothiapene, benzofurans, indole, quinoline, etc.
  • the aryl group can be substituted at one or more positions with halo, alkyl, alkoxy, alkoxy carbonyl, haloalkyl, cyano, amino sulfonyl, aryl, sulfonyl, aminocarbonyl, carboxy, acylamino, alkyl sulfonyl, amino and substituted or unsubstituted substituents.
  • heteroaryl is a mono-, bi- or tricyclic, -N-, -O- or -S- heteroaryl substituent, such as benzofuran, benzothiophene, furan, imidazole, indole, isothiazole, oxazole, piperazine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, thiazole and thiophene.
  • a "library” means a large number of chemical derivatives used in screening for biological activity or other activity.
  • a library will have greater than 20 members, preferably the library will have at least 50 members, more preferably the library will have at least 96 members and most preferably the library will have at least 1000 members.
  • chemically derivatized means the chemical manipulation such as addition to, oxidation of, substitution for, reduction of, or cyclization of the selected R group or R groups of the intermediate. Chemical derivatization also means the manipulation of two or more groups of the intermediate such that additional aryl or alkyl rings are formed and that rings may be fused or unfused to the intermediate ring, and that new ring may be substituted with further chemically derivatizable substituents.
  • pharmaceutically acceptable salt and “salts thereof means organic or inorganic salts of the pharmaceutically important molecule.
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion.
  • the counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically important organic molecule may have more than one charged atom in its structure. Situations where multiple charged atoms are part of the molecule may have multiple counterions.
  • the molecule of a pharmaceutically acceptable salt may contain one or more than one charged atoms and may also contain, one or more than one counterion.
  • the desired charge distribution is determined according to methods of drug administration.
  • Examples of pharmaceutically acceptable salts are well known in the art but, without limiting the scope of the present invention, exemplary presentations can be found in the Physician's Desk Reference, The Merck Index, The Pharmacopoeia and Goodman & Gilman's The Pharmacological Basis of Therapeutics.
  • TFA means trifluoro acetic acid
  • HCI means hydrochloric acid
  • THF means tetrahydrofuran
  • DMF means dimethylformamide
  • DIPEA diisopropylethyl amine
  • TMS means a trimethyl silyl radical
  • TBS means a f-butyldimethyl silyl radical.
  • leaving group means halo, oxo, thioxo radicals and activated alcohols such as a p-toluene sulfonyl activated alcohols and other groups that are susceptible to displacement and replacement by a nucleophile under selected conditions of temperature, solvent and time.
  • scaffold means a common chemical structure found within a library of organic compounds. Similarly, within a combinatorial chemical library the scaffold forms the basis for a diverse series of chemical derivatization, additions and subtractions. Importantly, regardless of the extent of the chemical derivatization performed on the scaffold, the product is within the scope of the combinatorial library.
  • a general method for making polycyclic heterocyles according to the first aspect of the invention involves the following method.
  • each of R 1 , R 2 , R 3 and R 4 is a stable moiety independently selected from the group consisting of halo, haloalkyl, cyano, nitro, R a -Q-, R a -Q-alkyl, R a -Q- alkenyl, R a -Q-alkynyl, R a -Q-arylalkyl and R a -Q-aryl;
  • R a is hydrogen, alkyl, aryl or arylalkyl;
  • R b is hydrogen, alkyl, aryl or arylalkyl, where R a and R may together with the nitrogen to that they are attached form a ring, R 5 is selected from the group consisting of halo, nitro, and haloalkyl.
  • each of R 1 , R 2 , R 3 and R 4 may be substituted one to three times with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, halo, hydroxy, alkoxy, alkylthio, sulfonyl, aryl, heteroaryl and where the substituents of the moieties substituted can themselves be substituted with one to three further substituents, if desired.
  • a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, halo, hydroxy, alkoxy, alkylthio, sulfonyl, aryl, heteroaryl and where the substituents of the moieties substituted can themselves be substituted with one to three further substituents, if desired.
  • R , R 2 , R 3 or R 4 is an haloalkyl, more particularly either R 1 , R 3 or R 4 is a CF 3 radical and most particularly R 3 is a
  • R 1 , R 2 , R 3 or R 4 is an hydroxyalkyl, more particularly one of R 1 , R 2 , R 3 or R 4 is methoxy and most particularly R 3 is a methoxy radical.
  • R 1 , R 2 , R 3 or R 4 is halo, cyano or nitro.
  • R 1 , R 2 , R 3 or R 4 is bromo, and most particularly R 3 is bromo.
  • R 3 is most particularly a cyano radical.
  • R 3 is most particularly a nitro radical.
  • R 5 is selected from fluoro, chloro or nitro. If a 5,6 polycycle is desired, then R 5 is a halo. Also, R 5 is between C- ⁇ to C ⁇ 2 haloalkyl, particularly R 5 is between Ci to C 6 haloalkyl and more particularly R 5 is a halomethyl and most particularly R 5 is bromomethyl.
  • R 6 of formula (I) is selected from the group consisting of cyano and a radical of formula (II) where L is selected from the group consisting of -0-, -S- and -NH-.
  • L is preferably -O- or -S- and most preferably -O-.
  • R 7 of formula (II) is selected from the group consisting of alkyl, aryl, arylalkyl, alkyloxyalkyl, aryloxyalkyl, alkylamino, dialkylamino, arylamino, alkoxy carbonyl, amino, alkoxy, hydroxy and heteroaryl.
  • R 6 is a radical of formula (II)
  • R 7 is preferably aryl and most preferably R 7 is phenyl.
  • R 5 is halomethyl and R 6 is cyano.
  • R 5 is halo
  • R 6 is formula (II)
  • L is oxygen and R 7 is a phenyl radical.
  • R 5 is halo and R 6 is cyano.
  • the compound (I) is reacted with the solid support bound member (III) under suitable conditions for a desired period of time and at a desired temperature such that the compound (I) is reacted with the compound (III).
  • g is a solid support selected from the group consisting of a resin, a polymer, a gel, glass beads, silica gel, a ceramic solid support or other solid composition. More preferably the solid support is a resin and most preferably the solid support is a polystyrene resin.
  • h is selected from the group consisting of alkyl and aryl.
  • h is aryl, more preferably h is a substituted aryl and most preferably h is p-nitrophenyl.
  • R 13 is selected from the group consisting of -
  • R 13 is -O-.
  • Suitable conditions for this reaction include having a suitable solvent mixture, a suitable temperature and reacting for a suitable period of time.
  • a suitable solvent mixture is preferably of basic pH.
  • the base is an alkoxide, more preferably the base is an alkoxide of fewer than 5 carbons and most preferably the base is K + OBu*.
  • a suitable solvent is either protic or aprotic, preferably the solvent is aprotic and even more preferably the solvent is aprotic and anhydrous and most preferably the solvent is THF.
  • the reaction temperature is preferably between about 0° C and 85° C but more preferably between about 30° C and about 70° C and most preferably at about 55° C.
  • the reaction time is preferably between about 1 minute and 2 days, more preferably between about 1 hour and 1 day and most preferably between about 8 hours and 14 hours.
  • the compounds (I) and (III) react forming an intermediate (IV) where n > 0, and g, h, R 1 , R 2 , R 3 , R 4 , R 6 and R 13 are as defined above.
  • This intermediate (IV) is optionally chemically derivatized prior to the cyclization and displacement procedure.to form a corresponding intermediate (IV):
  • R 1 , R 2 , R 3 and R 4 substituents are each independently the same as substituents R 1 , R 2 , R 3 and R 4 respectively if not derivatized or are each independently the chemically derivatized substituents respectively.
  • Examples of chemical derivatization reactions include, but are not limited to, the following general derivatizations procedures.
  • R' , R , R° and R 4 substituents are each independently the same as substituents R 1 , R 2 , R 3 and R 4 respectively if not derivatized or are each independently the chemically derivatized substituents respectively.
  • each of R 1 , R 2 , R 3 and R 4 may be correspondingly the same as R 1 , R 2 , R 3 and R 4 or may represent the result of the optional chemical derivatization of the corresponding substituent, prior to cyclization and displacement.
  • chemical derivatization includes other ring formation or ring closure reactions such as where any two of R 1 , R 2 , R 3 and R 4 together form an aryl or an alkyl ring of between about 5 and 14 atoms.
  • R 7 is amino, hydroxy or the same as R 7 above.
  • the temperature for the cyclization and displacement procedure may be between about 0° and 85° C but is preferably between about 30° and 70° and is most preferably at about 55° C.
  • the solvents suitable for the cyclization and displacement procedure include protic and aprotic solvent mixtures, aqueous and anhydrous solvent mixtures.
  • a preferred solvent is TFA
  • a more preferred solvent mixture is TFA:H O
  • a most preferred solvent mixture is TFA:5 N HCI/H 2 0.
  • the ratio of this TFA:5 N HCI/H 2 O mixture may vary between about 1 :1 to about 99:1 TFA:5 N HCI/H 2 0, but preferably is between about 80:1 to 1 :1 TFA:5 N HCI/H 2 O, and is most preferably at about 4:1 TFA:5 N HCI/H 2 O.
  • the time for the cyclization and displacement reaction may vary, but generally is between about 1 minute and 4 days but preferably between about 1 hour and 20 hours.
  • a second aspect of the invention is directed to a solid support bound intermediate (IV) above.
  • the intermediate (IV) can be derivatized before the cyclization and displacement procedure to thereby provide further options for the groups R 1 , R 2 , R 3 and R 4 in the final product.
  • the preferred, yet optional, derivatizations of the intermediate compound (IV), and preferred conditions whereby optional derivatizations occur are as described above.
  • a third aspect of the invention is directed to a library of polycyclic heterocycle compounds where the library contains a plurality of diverse compounds (V):
  • each of R 1 , R 2 , R 3 and R 4 is a stable moiety independently selected from the group consisting of halo, haloalkyl, cyano, nitro, R a -Q-, R a -Q-alkyl, R a -Q- alkenyl, R a -Q-alkynyl, R a -Q-arylalkyl and R a -Q-aryl;
  • R a is hydrogen, alkyl, aryl or arylalkyl
  • R b is hydrogen, alkyl, aryl or arylalkyl, where R a and R b may together with the nitrogen to that they are attached form a ring, and n > 0; and R 7 is selected from the group consisting of alkyl, aryl, arylalkyl, alkyloxyalkyl, aryloxyalkyl, alkylamino, dialkylamino, arylamino, alkoxy carbonyl, amino, alkoxy, hydroxy and heteroaryl; and
  • R 13 is selected from the group consisting of -NH-, -O- and -S-.
  • Preferred substituents for R 1 , R 2 , R 3 , R 4 , R 7 , and values for n are as described above, in the included examples and the appended claims.
  • a fourth aspect according to the present invention preferably produces a library of compounds where the compounds comprise a diverse chemical library according to the general methods discussed above. All of the compounds in such a library have a common scaffold, e.g., compound (V).
  • R 1' , R 2 , R 3 , R 4 , R 7 , and R 13 substituents are selected to allow the creation of a chemically diverse library that, as one goal, maximizes the exploration of molecular spatial properties. Such maximization increases the likelihood of creating compounds that will be biologically active against selected targets.
  • a fifth aspect of the invention is directed to an assay kit for the identification of biologically active compounds, the kit comprising assay materials and a well plate apparatus where each well in the apparatus contains a compound of the library described above.
  • the fourth and fifth aspects of the solid support mediated method of the invention may be carried out by way of parallel synthesis in any reaction vessel capable of holding the liquid reaction medium and having, preferably, inlet and outlet means.
  • the solid support mediated method of the invention is preferably carried out in containers adaptable to parallel array syntheses.
  • parallel array synthesis individual reaction products are prepared in each of multiple reaction zones.
  • the reaction zones are physically separated from one another in a reaction vessel.
  • Compounds can be added to the reaction vessel by multiple delivery apparatus, automated or robotic apparatus, any of that may be either manually or computer controlled.
  • a preferred parallel synthesis embodiment of the present invention is a diverse polycyclic heterocycle compound library in the form of a plurality of wellplates, each wellplate having wells containing a separate reaction product (library compound).
  • libraries compound a separate reaction product
  • their wellplate number and "x" column and "y" wellplate row coordinates conveniently identify the library compounds.
  • the process of making the library of polycyclic heterocycle compounds may be conveniently carried out in a conventional wellplate apparatus. It is particularly advantageous to carry out the method of the invention in a standard wellplate apparatus such as a plastic 96 well microtiter plate.
  • the wellplate apparatus is in the form of a rigid or semi-rigid plate, the plate having a common surface containing openings of a plurality of reservoirs arranged in rows and columns.
  • a standard form of wellplate apparatus is a rectangular plastic plate having 8 rows and 12 columns (total 96) of liquid retaining depressions, or reservoirs, on its surface.
  • a wellplate apparatus may optionally have other elements of structure such as a top or cover (e.g., plastic or foil), a bottom in a form such as a plate or reservoir, clamping means to secure the wellplate and prevent loss of its contained compounds.
  • the polycyclic heterocycle library of compounds formed using the solid support mediated method aspects of the invention can be used to screen compounds for biological or other activity.
  • Myriad biological assays are known in the art and can be used to screen the polycyclic heterocycle library of compounds.
  • the libraries of diverse polycyclic heterocycle according to the solid support mediated method of the present invention may be screened for biological activity.
  • the library to be screened is exposed to a biological substance, usually a protein such as a receptor, enzyme, membrane binding protein or antibody, and the presence or absence of an interaction between the heterocycle derivative and the biological substance is determined.
  • a biological substance usually a protein such as a receptor, enzyme, membrane binding protein or antibody
  • this will comprise determining whether the biological substance is bound to one or more of the members of the library.
  • binding may be determined by attaching a label to the biological substance.
  • Commonly used labels include fluorescent labels. Other methods of labeling may be used, such as radioactive labels.
  • the degree of binding affinity may be determined by quantitating the amount or intensity of the bound label.
  • various biologically active compounds may be selected by identifying that compounds bind the particular biological substance most effectively.
  • additional assays include but are not limited to in vitro assays such as enzymatic inhibition, receptor - ligand binding, protein - protein interaction, andprotein - DNA interaction; cell based, functional assays such as transcriptional regulation, signal transduction / second messenger, and viral infectivity; add, incubate & read assays such as scintillation proximity assays (SPA), fluorescence polarization assay, fluorescence correlation spectroscopy, colorimetric biosensors, cellular reporter assays using reporter genes such as luciferase, green fluorescent protein, ⁇ -lactamase, and the like; and electrical cell impedance sensor assays.
  • in vitro assays such as enzymatic inhibition, receptor - ligand binding, protein - protein interaction, andprotein - DNA interaction
  • cell based, functional assays such as transcriptional regulation, signal transduction / second messenger, and
  • Table A lists representative moieties that are substituted for R on the designated position of the starting compound. Because the moieties are representative of a general class of organic substituents, it is meant that other organic substituents are chemically equivalent to those given in Table A and are within the scope of the invention and appended claims.
  • the CF 3 radical replaces R 3
  • the placement of the same group in position 4, 5 or 6 is an equivalent analogue.
  • the CF 3 placed at each of positions 3, 4, 5, 6 or any combination thereof is within the scope of this invention and appended claims.
  • the CF 3 group is, optionally, meant to represent an electron withdrawing group and can therefor be replaced by other electron withdrawing groups such as polyhalo-alkyl and be within the scope of this invention.
  • the solid support bound oxime is reacted with the fluorobenzonitrile of Example 1 under suitable conditions to form the solid support bound intermediate.
  • the solid support bound intermediate is optionally isolated and finally subjected to the cyclization and displacement procedure.
  • the nitrogen and oxygen of the solid support bound oxime are involved in the cyclization and displacement reaction and become part of the polycyclic heterocycle.
  • the solid support mediated method includes analogues involving substituents at each available position of the aromatic scaffold, such as a tri or tetra substituted phenyl.
  • analogues involving substituents at each available position of the aromatic scaffold, such as a tri or tetra substituted phenyl.
  • R is methoxy
  • a Ci to C ⁇ 2 alkoxy is considered an equivalent analogue.
  • the substituent group is Br
  • another halo substituent such as -F or -CI is an equivalent analogue.
  • the solid support mediated method according to the present invention further allows for the optional chemical derivatization of none, any, or all of R 1 , R 2 , R 3 R 4 substituents of the solid support bound intermediate as provided above.
  • the solid support bound intermediate is preferably stable to a broad range of reaction conditions.
  • Table B lists substituted aromatic compounds (I), which are reacted with the solid support bound member, thereby forming the solid support bound intermediate (IV), are chemically derivatized with final cyclization and displacement of the corresponding polycyclic heterocycle.
  • the compounds of Table B are synthesized according to the solid support mediated method of the present invention. This list is intended to demonstrate the diversity of compounds that are synthesized according to this invention and is not intended to limit the scope in any way.
  • the resin bound intermediates of the present invention were surprisingly stable to conditions suitable for optional derivatizations such as, BOC removal/acylation, TBS removal and Mitsunobu coupling, Suzuki coupling, Sonogashira coupling, Hoerner-Emmons olefination, and ester hydrolysis/amidation reaction conditions. These and other reactions discussed were performed according to the following detailed chemical procedure.
  • the loaded resin was removed from the oven and allowed to cool for 1 h and rinsed with 2 x 5 mL of CH 2 CI 2 , 2 x 5 mL of 5% TFA/CH 2 CI 2 , 2 x 5 mL of isopropanol and 4 x 5 mL of MeOH. This was dried in a 35° C vacuum oven for 12 h. Next, 4 mL of TFA and 1mL of aqueous 5 N HCI were then added to the resin followed by turning for 2 h in a 55° C oven. The TFA/H 2 O was collected and the resin was rinsed with 2 x 5 mL of CH 2 CI 2 .
  • the loaded resin was removed from the oven and allowed to cool for 1 h and rinsed with 2 x 5 mL of CH 2 CI 2 , 2 x 5 mL of 5% TFA/CH 2 CI 2 , 2 x 5 mL of isopropanol 4 x 5 mL of MeOH. This was dried in a 35° C vacuum oven for 12 h. Next, 4 mL of TFA and 1mL of aqueous 5 N HCI were then added to the resin followed by turning for 8 h in a 55° C oven. The TFA/H 2 O was collected and the resin was rinsed with 2 x 5 mL of CH 2 CI 2 .
  • This reaction vessel was placed in a 55 °C oven fitted with a rotating device for 12 h. This was removed from the oven and allowed to cool for 1 h and rinsed with 2 x 5 mL of CH 2 CI 2, 2 x 5 mL of isopropanol, and 4 x 5 mL of isopropanol, and 4 x 5 mL of MeOH. This was dried in a 35 °C vacuum oven for 12 h. BOC-deprotection was achieved using 25% TFA/CH 2 CI 2 (7 mL) followed by shaking for 2 h.
  • Resin was again rinsed with 2 x 5 mL of CH 2 CI 2 , 2 x 5 mL of isopropanol, and 4 x 5 mL of MeOH.
  • the resin was suspended in DMF followed by addition of acetic anhydride and diisopropylethylamine. This was allowed to shake for 3h and was rinsed with 2 x 5 mL of CH 2 CI 2 , 2 x 5 mL of isopropanol, and 4 x 5 mL of MeOH. 4 mL of TFA and 1 mL of aqueous 5 N HCI were then added to the resin followed by turning for 2 h in a 55° C oven.
  • the resin was rinsed with 2 x 5 mL of CH 2 CI 2 , 2 x 5 mL H 2 O, 4 x 5 mL of MeOH. This was dried in a 35° C vacuum oven for 12 h.
  • the resin was suspended in 8 mL of 1:1 THF/CH 2 CI 2 followed by addition of triphenylphosphine (700mg, 5 equiv.) and 4-chlorophenol (690 mg, 10 equiv.). This was shaken by hand followed by the slow addition of diisopropyl azodicarboxylate (0.53mL 5 equiv).
  • Method A 4: 1 TFA/5N HCI, 55 °C.
  • Method B 99: 1 TFA/H 2 0, 55 °C.
  • Method C 25% THF/CH 2 C1 2 , room temp.
  • Method D TFA, 55 °C.
  • Method E AcOH/THF/H 2 0, 55 °C.
  • Method F TsOH/THF/H 2 0, 55 °C. isolated yield after chromatography and based on loading. Crude purity based on HPLC analysis.
  • Acid 6 was then coupled to 4-chlorobenzylamine to give the on-resin amide. Both the resin weight increase and chlorine analysis of the intermediate suggested that the coupling reaction went essentially to completion within 12 h. The resin was then treated with the standard cyclorelease conditions to give the desired amide 7 in a 3 step yield of 81% (93% crude purity).
  • the reaction vessel was rotated at 55 °C in a Robbins oven for 12 h to give resin 5 followed by cooling for 1 h.
  • the resin was then rinsed with 2 x 5 mL of CH 2 CI 2 , 2 x 5 mL of MeOH, 2 x 5 mL of H 2 0, and 4 * 5 mL of MeOH.
  • the resin was then suspended in THF (7 mL) followed by the addition of LiOH (39 mg, 1.61 mmol) dissolved in MeOH/H 2 O (1 :1 , 2 mL) and rotated at room temp, for 12 h.
  • the resin was then rinsed with 2 * 5 mL of CH 2 CI 2 , 2 x 5 mL of MeOH, 2 x 5 mL of H 2 O, 2 x 5 mL of MeOH, and 2 x 5 mL of DMF.
  • the resin was then suspended in DMF (7 mL) and to this was added p- chlorobenzylamine (261 ⁇ L, 2.14 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (289 mg, 2.14 mmol), benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (947 mg, 2.14 mmol), and diisopropylethylamine (DIPEA) (467 ⁇ L, 2.68 mmol). The reaction was allowed to proceed for 12 h at room temp.
  • the resin was then rinsed 2 5 mL of CH 2 CI 2 , 2 5 mL of MeOH, 2 x 5 mL of H 2 0, and 4 5 mL of MeOH.
  • TFA (4 mL) and 5 N HCI aq (1 mL) were then added to the resin and the vessel was rotated for 2 h in a 55 °C oven. The TFA/HCI aq was collected and the resin was rinsed with 2 x 5 mL of CH2CI2.
  • Phenolic Mitsunobu reaction On-resin carbon-oxygen bond formation via the Mitsunobu reaction has been identified as an important tool in combinatorial chemistry (Kaldor, S.W.; Siegel, M.G. Comb. Chem. Mol. Diversity Drug Discovery 1998, 307-335. Editors: Gordon, Eric M.; Kerwin, James F., Jr. Publisher: Wiley- Liss, New York, N. Y).
  • Application of this reaction to an aryl oxime-linked substrate is shown in Scheme 3.
  • Resin 8 was prepared by reacting the potassium anion of the Kaiser resin 1 with 2-fluoro-4-( -butyl-dimethylsilyloxymethyl)-benzonitrile.
  • the TBS- protecting group was removed using TBAF in THF.
  • the on-resin alcohol was then treated with p-chlorophenol, triphenylphosphine and diisopropylazodicarboxylate (DIAD) in THF.
  • DIAD diisopropylazodicarboxylate
  • the best results were observed for reactions times of 3 h. Longer reaction times generally led to decreased purity in the crude cyclization product. Cyclitive removal using the standard conditions then gave aryl ether 9 in a 77% yield (3 steps) and 83% crude purity.
  • the resin was then suspended in THF (6 mL) followed by the addition of TBAF (562 ⁇ L, 1 M in THF, 0.562 mmol) and rotated at room temperature for 12 h.
  • the resin was then rinsed with 2 5 mL of CH 2 CI 2 , 2 x 5 mL of MeOH, 2 x 5 mL of H 2 O, 2 5 mL of MeOH, and 2 5 mL of CH 2 CI 2 .
  • the resin was then suspended in CH 2 CI 2 (7 mL) and to this was added p-chlorophenol (690 mg, 5.35 mmol), triphenylphosphine (700 mg, 2.68 mmol), and diisopropyl-azodicarboxylate (DIAD) (530 ⁇ L, 2.68 mmol). The reaction was allowed to proceed for 1 h at room temp. The resin was then rinsed 2 5 mL of CH 2 CI 2 , 2 5 mL of MeOH, 2 x 5 mL of H 2 O, and 4 5 mL of MeOH. The resin was dried in a 35 °C vacuum oven for 12 h.
  • the resin loading reaction may be quite selective for the 2-position, giving primarily 12, and then subsequently 14a upon cyclorelease.
  • mixtures of the two isomeric aryloxime adducts could be formed with the hydrolysis of intermediate 12 occurring much more rapidly than 13.
  • Scheme 5 depicts a solution phase model study for the loading reaction of 2,4- difluorobenzonitrile.
  • the potassium salt of acetone oxime was treated with 2,4-difluorobenzonitrile and showed only a slight preference for the addition to the 2-position (1.4:1).
  • Scheme 6 illustrates a comparison of the relative rates of hydrolysis for analogous 2- vs 4-substituted aryloximes. Since the isolation of pure 12 and pure 13 was not practical, model resins 3a and 15 were prepared from 2-fluorobenzonitrile and 4-fluorobenzonitrile respectively. As described previously, when resin 3a was treated with the standard cyclitive removal conditions, complete conversion to 3- aminobenzisoxazole was observed after 2h.
  • IR analysis of the resin shows a nitrile stretching peak at 2230.3 cm "1 .
  • TFA (4 mL) and 5 N HCI aq (1 mL) were then added to the resin and the vessel was rotated for 2 h in a 55 °C oven.
  • the TFA/HCI aq was collected and the resin was rinsed with 2 x 5 mL of CH 2 CI 2 .
  • An IR analysis of the resin after the cyclorelease reaction shows a diminished nitrile stretching peak.
  • a - D all use 4.0 eq of boronic acid and 5% Pd(PPh 3 ) 4 , and 36 h.
  • A 2.5 eq 2 M Na ⁇ O-,, DME, reflux;
  • B 1.0 eq 2 M Na 2 C0 3 , THF, 55 °C;
  • C 1.3 eq 2 M Na 2 C0 3 , THE, 55 °C;
  • D 1.5 eq 2 M Na 2 C0 3 , THF, 55 °C isolated yield after chromatography and based on loading. Crude purity based on HPLC analysis. Major impurity in all cases is 6-bromo-3-aminobenzisoxazole.
  • the vessel was then rotated for 36 h in a 55 °C oven followed by rinsing with 2 x 5 mL of CH 2 CI 2 , 2 x 5 mL of MeOH, 2 5 mL of H 2 0, and 4 x 5 mL of MeOH.
  • the resin was dried in a 35 °C vacuum oven for 3 h.
  • TFA (4 mL) and 5 N HCI aq (1 mL) were then added to the resin and the vessel was rotated for 2 h in a 55 °C oven.
  • the TFA/HCI aq was collected and the resin was rinsed with 2 x 5 mL of CH 2 CI 2 .
  • aldehyde resin 18 (Scheme 9) from the Suzuki reaction with 3b (Table 5, entry 4) provided an opportunity to evaluate the compatibility of the aryloxime linker with the Horner-Emmons olefination.
  • treatment of 18 with the anion of trimethylphosphonoacetate in THF preformed with n-BuLi at 0

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Dans une première variante, l'invention porte sur un procédé, induit par un support solide, de synthèse de divers hétérocycles polycycliques selon la formule générale (V). Dans une deuxième variante, l'invention porte sur un composé intermédiaire lié à un support solide qui peut être éventuellement dérivatisé avant qu'une procédure de cyclisation et de déplacement génère un produit. L'intermédiaire est de préférence stable par rapport à une large plage de conditions chimiques, ce qui permet, si souhaité, la dérivatisation chimique de l'intermédiaire. Dans un troisième aspect, l'invention porte sur une bibliothèque de divers composés qui contient une pluralité de composés divers de la formule générale (V). Dans un quatrième variante, l'invention porte sur un procédé de synthèse d'une bibliothèque de divers hétérocycles polycycliques. Dans une cinquième variante, l'invention porte sur un kit de dosage utilisé dans l'identification de têtes de série de la bibliothèque précitée.
PCT/US1999/026803 1998-11-12 1999-11-12 Lieurs d'aryloxime dans la synthese de la phase solide de 3-aminobenzisoxazoles WO2000027627A1 (fr)

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US60/108,208 1998-11-12
US14549299P 1999-07-22 1999-07-22
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EP1135023A1 (fr) * 1998-11-12 2001-09-26 Eli Lilly And Company Composes aminobenzisoxazole et banques contenant de tels composes
US6569879B2 (en) * 2000-02-18 2003-05-27 Merck & Co., Inc. Aryloxyacetic acids for diabetes and lipid disorders
WO2004113304A1 (fr) * 2003-05-22 2004-12-29 Abbott Laboratories Inhibiteurs de kinases de type indazole, benzisoxazole et benzisothiazole
DE102005038947A1 (de) * 2005-05-18 2006-11-30 Grünenthal GmbH Substituierte Benzo[d]isoxazol-3-yl-amin-Verbindungen und deren Verwendung in Arzneimitteln
US7297709B2 (en) 2003-05-22 2007-11-20 Abbott Laboratories Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
US7435731B2 (en) 2004-02-27 2008-10-14 Roche Palo Alto Llc Substituted pyrazolo[3,4-d]pyrimadines and methods of using the same
US7452880B2 (en) 2004-02-27 2008-11-18 Nidhi Arora Substituted pyrazolo [3,4-d] pyrimidines and methods of using the same
US7473701B2 (en) 2002-03-11 2009-01-06 Aventis Pharma S.A. Substituted indazoles, compositions containing them, method of production and use
US7495015B2 (en) 2004-02-27 2009-02-24 Roche Palo Alto Llc Indazole derivatives and methods for using the same
US7563799B2 (en) 2005-08-25 2009-07-21 Roche Palo Alto Llc Substituted pyrazolo[3,4-D]pyrimidines as p38 map kinase inhibitors
JP2010533731A (ja) * 2007-07-16 2010-10-28 アボット・ラボラトリーズ タンパク質キナーゼ阻害薬としてのインダゾール類、ベンゾイソオキサゾール類およびベンゾイソチアゾール類
US8293738B2 (en) 2010-05-12 2012-10-23 Abbott Laboratories Indazole inhibitors of kinase

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1135023A4 (fr) * 1998-11-12 2003-03-05 Lilly Co Eli Composes aminobenzisoxazole et banques contenant de tels composes
EP1135023A1 (fr) * 1998-11-12 2001-09-26 Eli Lilly And Company Composes aminobenzisoxazole et banques contenant de tels composes
US6569879B2 (en) * 2000-02-18 2003-05-27 Merck & Co., Inc. Aryloxyacetic acids for diabetes and lipid disorders
US7473701B2 (en) 2002-03-11 2009-01-06 Aventis Pharma S.A. Substituted indazoles, compositions containing them, method of production and use
US7598283B2 (en) 2003-05-22 2009-10-06 Abbott Laboratories, Inc. Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
JP2011088918A (ja) * 2003-05-22 2011-05-06 Abbott Lab インダゾール、ベンズイソオキサゾールおよびベンズイソチアゾールキナーゼ阻害剤
US7297709B2 (en) 2003-05-22 2007-11-20 Abbott Laboratories Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
US8940778B2 (en) 2003-05-22 2015-01-27 Abbvie Inc. Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
US8642776B2 (en) 2003-05-22 2014-02-04 Abbvie Inc. Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
US8299243B2 (en) 2003-05-22 2012-10-30 Abbvie Inc. Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
JP2007500226A (ja) * 2003-05-22 2007-01-11 アボット・ラボラトリーズ インダゾール、ベンズイソオキサゾールおよびベンズイソチアゾールキナーゼ阻害剤
US8063091B2 (en) 2003-05-22 2011-11-22 Abbott Laboratories Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
WO2004113304A1 (fr) * 2003-05-22 2004-12-29 Abbott Laboratories Inhibiteurs de kinases de type indazole, benzisoxazole et benzisothiazole
AU2004249675B2 (en) * 2003-05-22 2010-04-15 Abbvie Bahamas Ltd. Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
KR100976076B1 (ko) 2003-05-22 2010-08-17 아보트 러보러터리즈 인다졸, 벤즈이속사졸 및 벤즈이소티아졸 키나제 억제제
JP4810427B2 (ja) * 2003-05-22 2011-11-09 アボット・ラボラトリーズ インダゾール、ベンズイソオキサゾールおよびベンズイソチアゾールキナーゼ阻害剤
EP2246333A1 (fr) * 2003-05-22 2010-11-03 Abbott Laboratories Nhibiteurs de kinases de type indazole, benzisoxazole et benzisothiazole
US7495015B2 (en) 2004-02-27 2009-02-24 Roche Palo Alto Llc Indazole derivatives and methods for using the same
US7452880B2 (en) 2004-02-27 2008-11-18 Nidhi Arora Substituted pyrazolo [3,4-d] pyrimidines and methods of using the same
US7435731B2 (en) 2004-02-27 2008-10-14 Roche Palo Alto Llc Substituted pyrazolo[3,4-d]pyrimadines and methods of using the same
US7977360B2 (en) 2005-05-18 2011-07-12 Gruenenthal Gmbh Benzo[d]isoxazol-3-yl-amine compounds and their use as vanilloid receptor ligands
DE102005038947A1 (de) * 2005-05-18 2006-11-30 Grünenthal GmbH Substituierte Benzo[d]isoxazol-3-yl-amin-Verbindungen und deren Verwendung in Arzneimitteln
US7563799B2 (en) 2005-08-25 2009-07-21 Roche Palo Alto Llc Substituted pyrazolo[3,4-D]pyrimidines as p38 map kinase inhibitors
JP2010533731A (ja) * 2007-07-16 2010-10-28 アボット・ラボラトリーズ タンパク質キナーゼ阻害薬としてのインダゾール類、ベンゾイソオキサゾール類およびベンゾイソチアゾール類
US8293738B2 (en) 2010-05-12 2012-10-23 Abbott Laboratories Indazole inhibitors of kinase

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