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WO1998017695A1 - Composes et procedes - Google Patents

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Publication number
WO1998017695A1
WO1998017695A1 PCT/US1997/019450 US9719450W WO9817695A1 WO 1998017695 A1 WO1998017695 A1 WO 1998017695A1 US 9719450 W US9719450 W US 9719450W WO 9817695 A1 WO9817695 A1 WO 9817695A1
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WO
WIPO (PCT)
Prior art keywords
scheme
resin
bound
alkyl
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US1997/019450
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English (en)
Inventor
Balan Chenera
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
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SmithKline Beecham Corp
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Filing date
Publication date
Priority claimed from GB939325621A external-priority patent/GB9325621D0/en
Priority claimed from PCT/US1994/014414 external-priority patent/WO1995016712A1/fr
Priority claimed from US08/663,148 external-priority patent/US5773512A/en
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Priority to JP10519697A priority Critical patent/JP2001502354A/ja
Priority to CA002269737A priority patent/CA2269737A1/fr
Priority to EP97947288A priority patent/EP0934345A4/fr
Publication of WO1998017695A1 publication Critical patent/WO1998017695A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/42—Introducing metal atoms or metal-containing groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports

Definitions

  • the standard method for conducting a search is to screen a variety of pre-existing chemical moieties, for example, naturally occurring compounds or compounds which exist in synthetic libraries or databanks.
  • the biological activity of the pre-existing chemical moieties is determined by applying the moieties to an assay which has been designed to test a particular property of the chemical moiety being screened, for example, a receptor binding assay which tests the ability of the moiety to bind to a particular receptor site.
  • an assay which has been designed to test a particular property of the chemical moiety being screened, for example, a receptor binding assay which tests the ability of the moiety to bind to a particular receptor site.
  • silicon-based polymer resins are useful in the preparation of a single compound, e.g., an aromatic carbocycle, or a library of molecularly diverse compounds which are aromatic carbocycles, each comprising an aromatic carbon atom and at least one substituent that is not hydrogen or alkyl, said aromatic carbons having a hydrogen, halogen, hydroxy or acyloxy group bound to them after cleavage from the resin.
  • non-peptide compounds each comprised of a core structure, bind to a variety of receptors, in particular, G-protein coupled receptors.
  • the core structures including aromatic carbocycles, may be used as templates for developing libraries of non- peptide compounds which are analogs of the core structures. Therefore, rather than synthesizing individual analogs of these non-peptide compounds for screening, large numbers of non-peptide compounds which may be receptor ligands, in particular G- protein coupled receptor ligands, can be synthesized by the combinatorial methods described herein and screened in assays developed for determining lead compounds as pharmaceutical agents.
  • the methods disclosed herein may also be applied to obtain libraries of compounds, including aromatci carbocycles, that are enzyme inhibitors, receptor ligands or channel blockers.
  • the present invention is directed to non-peptide compounds, each comprised of a core structure.
  • the present invention is also directed to the use of these core structures as templates for developing libraries of non-peptide compounds which are analogs of the core structures.
  • this invention is directed to libraries of compounds which comprise receptor ligands, in particular, G-protein coupled receptor ligands, enzyme inhibitors and channel blockers and the combinatorial synthetic methods for making such libraries of compounds.
  • receptor ligands in particular, G-protein coupled receptor ligands, enzyme inhibitors and channel blockers and the combinatorial synthetic methods for making such libraries of compounds.
  • this invention relates to novel silicon-based polymer resins, methods for preparing said resins and intermediates used in the preparation of said resins.
  • one aspect of this invention relates to methods for preparing one or a plurality of derivatized compounds by resin-bound synthesis, wherein the compounds are aromatic carbocycles each comprising an aromatic carbon atom and at least one substituent X, A, B or C that is not hydrogen or alkyl, said aromatic carbons having a hydrogen, halogen, hydroxy or acyloxy group bound to them after cleavage from the resin.
  • this aspect of the invention relates to methods for utilizing silicon chemistry to effectuate the cleavage of an aromatic carbocycle from a polymer resin while leaving a hydrogen, halogen, hydroxy or acyloxy group on the aromatic carbocycle at the cleavage position.
  • the present invention is directed to methods for screening a compound or plurality of compounds made according to the synthetic methods disclosed herein, which comprise using the compounds in suitable assays developed for detecting the compounds' utility as pharmaceutical agents.
  • this invention relates to a method of screening G-protein coupled receptors with ligands that are known to bind other G-protein coupled receptors, or that are related to ligands that are known to bind other G- protein coupled receptors.
  • core structure(s) is used herein at all occurrences to mean a core molecular structure(s) which is derived from compounds which have been shown to interact with a receptor, in particular, a G-protein coupled receptor, and which is used as a template for designing the libraries of compounds to be made.
  • Core structures may be aromatic carbocycles as defined below.
  • library of compounds is used herein at all occurrences to mean a series or plurality of compounds derivatized from their core structure.
  • the core structure used for designing a library of compounds is an aromatic carbocycle.
  • combinatorial library is used herein at all occurrences to mean a collection of compounds based upon a core structure, for example, an aromatic carbocycle structure, wherein the library contains a discrete number of independently variable substituents, functional groups or structural elements, and further, wherein the library is designed so that, for the range of chemical moieties selected for each of the independently variable substituents, compounds containing all possible permutations of those substituents will be present in the library.
  • a core structure labeled R
  • X is taken from m different chemical moieties
  • Y from n different chemical moieties
  • Z from p different chemical moieties
  • m, n and p are integers which define the size of the library, and which range between 1 to 1000; preferably between 1 to 100; most preferably between 1 to 20
  • the library would contain m x n xp different chemical compounds and all possible combinations of X, Y and Z would be present on the core structure R within that library.
  • the methods for preparing combinatorial libraries of compounds are such that the molecularly diverse compound members of the libraries are synthesized simultaneously.
  • aromatic carbocycle is used herein at all occurrences to mean a compound which comprises a single ring or a fused ring system, preferably 5-14 membered ring systems, and, for purposes herein, includes an optionally substituted biphenyl, composed of carbon atoms having aromatic character, e.g., characterized by delocalized electron resonance and the ability to sustain a ring current and which ring or ring systems may include one or more heteroatoms selected from oxygen, nitrogen or sulfur.
  • the aromatic carbocycle may be optionally substituted by one or more substituents herein described as "substituent X", "substituent A", “substituent B” or "substituent C".
  • the aromatic carbocycle is a biphenyl
  • the substituents X, A, B or C may be, independently, on one or both rings. This is similarly so for other aromatic carbocyclic rings or ring systems as defined above. It will be recognized by the skilled artisan that a large number of aromatic carbocycles may be made using the silane linkers of this invention, provided that the chemistry used to prepare the aromatic carbocycles is compatible with the aryl silane bond, defined below.
  • Suitable aromatic carbocycles include, but are not limited to, optionally substituted phenyl rings, optionally substituted naphthyl rings, optionally substituted tetrahydronaphthyl rings, optionally substituted anthracenyl rings, optionally substituted 1-, 2- or 3- tetrahydrobenzazepines; optionally substituted 1,4-, 1,5-, or 2,4- tetrahydrobenzodiazepines; optionally substituted biphenyl tetrazoles; optionally substituted 1,3- or 1,4-diaminobenzene compounds; or optionally substituted 1,3- or 1,4-aminocarboxyphenyl compounds.
  • the aromatic carbocycles described herein may serve as core structures, and therefore, as templates for designing libraries of compounds to be screened as pharmaceutical agents.
  • the aromatic carbocycles are G-protein coupled receptor ligands, channel blockers and/or enzyme inhibitors.
  • reaction-bound synthesis and “solid phase synthesis” are used herein interchangeably to mean one or a series of chemical reactions used to prepare either a single compound or a library of molecularly diverse compounds, wherein the chemical reactions are performed on a compound, suitably, an aromatic carbocycle, which is bound to a polymeric resin support through an appropriate linkage, suitably, an silane linker.
  • resin inert resin
  • polymeric resin polymeric resin support
  • bead or other solid support such as beads, pellets, disks, capillaries, hollow fibers, needles, solid fibers, cellulose beads, pore-glass beads, silica gels, grafted co-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N'-bis- acryloyl ethylene diamine, glass particles coated with a hydrophobic polymer, etc., i.e., a material having a rigid or semi-rigid surface.
  • the solid support is suitably made of, for example, cross linked polystyrene resin, polyethylene glycol- polystyrene resin, benzyl ester resins or benzhydrylamine resins and any other substance which may be used as such and which would be known or obvious to one of ordinary skill in the art.
  • the linker to the resin is silicon-based, the above terms mean any aliphatic or aromatic polymer which lacks functionality known to participate in the additional synthetic chemistry for generation of the derivatized compounds of this invention, and which is stable to conditions for protodesilylation.
  • Preferred polymer resins for use herein are the Merrifield resin (available commercially from Nova Biochem) and the Wang resin (synthesis described below).
  • the compounds (or libraries of compounds) made by the instant methods may either remain bound to the resin which is used to perform the resin-bound synthesis (hereinafter referred to as "resin-bound compounds (or libraries)”) or not bound to a resin (hereinafter referred to as “soluble compounds (or libraries)").
  • silane linker or “silane linker group” are used herein at all occurrences to mean the moiety which binds the aromatic carbocycle to the polymeric resin support, which linker comprises a silicon atom bound to an alkyl chain comprising one or more methylene groups, said alkyl chain optionally having one or more intervening heteroatoms and/or aryl groups, or combinations thereof.
  • Suitable silane linkers for use in this invention comprise a moiety of the following formula: -D-CH 2 -Si-R"R'", wherein R" and R'" are independently, Ci to C alkyl, and D is a C j to C20 alkyl chain optionally having one or more intervening heteroatoms and/or optionally substituted aryl groups. It will be recognized that the alkyl chain may contain both intervening heteroatoms and intervening optionally substituted aryl groups.
  • R" and R" are independently, C to C4 alkyl, more preferably, R" and R"' are both methyl or ethyl, more preferably methyl.
  • aryl silane compound is used herein at all occurrences to mean an intermediate compound comprising an aromatic carbocycle having an aromatic carbon and at least one substituent X, A, B or C that is not hydrogen or alkyl, wherein the aromatic carbon is bound to a silane linker through an aryl silane bond.
  • an aryl silane compound within the scope of this invention is defined by a compound of Formula (LB).
  • aryl silane bond is used herein at all occurrences to mean the bond between the aromatic carbon of an aromatic carbocycle and the silicon atom of a silane linker.
  • this bond is cleaved in order to decouple the aromatic carbocycle from the resin-bound aryl silane intermediate.
  • resin-bound aryl silane intermediate is used herein at all occurrences to mean an intermediate wherein an aromatic carbocycle is directly bound to a silane linker, which linker is directly bound to a polymeric resin support. Therefore, it will be recognized that a resin-bound aryl silane intermediate is a moiety which couples an aromatic carbocycle to a polymeric resin support through a silane linker.
  • C are used herein at all occurrences to mean a non-nucleophilic substituent, including, but not limited to, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether (e.g., -alkyl-S -alkyl-), alkylthio (e.g., alkyl-SH), C(O)R a , wherein R a is hydrogen or alkyl, t-butoxyamino-carbonyl, cyano, nitro (-NO 2 ), aryl, heteroaryl, arylalkyl, alkyl disulfide (e.g., alkyl-S-S-), aryl disulfide (e.g., aryl-S-S-), acetal (alkyl(O-alkyl)2), thioacetal (alkyl(S-alkyl)2), fluorenylmefhoxycarbonyl or
  • the substituents X, A, B and C are chosen independently from one another.
  • X, A, B and C can not all be hydrogen and X, A, B and C can not all be alkyl.
  • the aromatic carbocycle is a biphenyl
  • the substituents X, A, B or C may be, independently, on one or both rings. This is similarly so for other aromatic carbocyclic rings or ring systems as defined above.
  • modification of the substituents produces a derivatized aromatic carbocycle.
  • the nature of the substituents X, A, B and C must be compatible with the reaction conditions used for modifying said substituents without said conditions being capable of cleaving the aryl silane bond of the resin- bound aryl silane intermediate.
  • synthetic chemistry conventional in the art may then be performed on the cleaved derivatized aromatic carbocycle to convert the strong electron withdrawing group into a different functionality, e.g., conversion of a nitro group into an amino group using known reaction conditions.
  • synthetic chemistry which are compatible with the goal of derivatizing the resin-bound aromatic carbocycle, without also cleaving the aryl silane bond of the resin-bound aryl silane intermediate, will be obvious to one of ordinary skill in the art.
  • additional synthetic chemistry is used herein at all occurrences to mean one or a series of chemical reactions which are performed on the resin-bound aryl silane intermediate, in particular to modify or derivatize substituents X, A, B and C, prior to cleavage of the aromatic carbocycle from the resin-bound aryl silane intermediate, wherein said chemical reactions are compatible with and non-reactive with the aryl silane bond and may be used to prepare derivatives of the aromatic carbocycle. It will be recognized by the skilled artisan that the additional synthetic chemistry performed on the resin-bound aryl silane intermediate is done so prior to cleavage of the aryl silane bond.
  • Chemical reactions which are compatible with the resin-bound aryl silane intermediate are reactions which effectuate the swelling of the polymeric resin thereby allowing penetration of the reagents to react with the aromatic carbocycle.
  • Chemical reactions which are reactive with the aryl silane bond i.e., they cause cleavage of the aryl silane bond, and therefore are not among the additional synthetic chemistry that may be used in the methods of this invention, are for example, chemical reactions which use strongly acidic conditions or strong electrophilic oxidizing agents (e.g., benzoyl peroxide under acidic conditions).
  • G-protein coupled receptor(s) is used herein at all occurrences to mean a membrane receptor using G-proteins as part of their signaling mechanism, including, but not limited to muscarinic acetylcholine receptors, adenosine receptors, adrenergic receptors, LL-8R receptors, dopamine receptors, endothelin receptors, histamine receptors, calcitonin receptors, angiotensin receptors and the like.
  • assay is used herein at all occurrences to mean a binding assay or a functional assay known or obvious to one of ordinary skill in the art, including, but not limited to, the assays disclosed herein.
  • a particularly suitable assay for use according to the invention is disclosed by Lerner et al., Proc. Natl. Acad. Sci. U.S.A., 91 (5), pp. 1614-1618 (1994).
  • batches or “pools” are used herein at all occurrences to mean a collection of compounds or compound intermediates.
  • alkyl is used herein at all occurrences to mean a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, and the like.
  • the alkyl chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
  • alkenyl is used herein at all occurrences to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl, and the like.
  • the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length.
  • alkynyl is used herein at all occurrences to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2-propylene, and the like.
  • the alkynyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length.
  • alkenyl or alkynyl moiety there is an alkenyl or alkynyl moiety as a substituent group
  • unsaturated linkage i.e., the vinylene or acetylene linkage is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
  • alkoxy is used herein at all occurrences to mean a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
  • the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
  • cycloalkyl and “cyclic alkyl” are used herein at all occurrences to mean cyclic radicals, preferably comprising 3 to 10 carbon atoms which may be mono- or bicyclo- fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4- tetrahydronaphthyl, and the like.
  • aryl or “heteroaryl” are used herein at all occurrences to mean 5-
  • aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems and one or more heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen or sulfur.
  • Representative examples include, but are not limited to, phenyl, naphthyl, pyridyl, quinolinyl, thiazinyl, isoquinoline, imidazole, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4- dimethoxybenzyl, 3,4-methylenedioxy-benzyl, benzhydryl, 1-naphthylmethyl, 2- naphthylmethyl, fluorenyl, biphenyl-4-methyl, furanyl, and the like.
  • heteroatom is used herein at all occurrences to mean an oxygen atom ("O"), a sulfur atom ("S”) or a nitrogen atom (“N”). It will be recognized that when the heteroatom is nitrogen, it may form an NRiR 2 moiety, wherein R 1 and R 2 are, independently from one another, hydrogen or C j to Cg alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7- membered ring.
  • arylalkyl and heteroarylalkyl are used herein at all occurrences to mean an aryl or heteroaryl moiety, respectively, that is connected to a Cj.g alkyl moiety as defined above, such as, but not limited to, benzyl.
  • 5- 6-, or 7-membered ring is used herein at all occurrences to mean that substituents R 1 and R 2 , together with the nitrogen to which they are bound, form a saturated or unsaturated ring structure containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur, including, but not limited to morpholine, piperazine, piperidine, pyrolidine, pyridine, and the like.
  • heterocyclic is used herein at all occurrences to mean a saturated or wholly or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of O, N, or S; including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, benzodiazepines, and the like.
  • halogen is used herein at all occurrences to mean chloro, fluoro, iodo and bromo.
  • Ph is used herein at all occurrences to mean phenyl.
  • substituents may be further substituted by groups similar to those indicated above herein to give substituents such as halo- substituted alkyl (e.g., -CF3), aryl-substituted alkyl, alkoxy-substituted alkyl and the like.
  • substituents such as halo- substituted alkyl (e.g., -CF3), aryl-substituted alkyl, alkoxy-substituted alkyl and the like.
  • Preferred optional substituents for use herein include alkyl, alkenyl, alkoxy, cyano, NO 2 , halogen, preferably bromine, -(CR 1 1 R 12 ) n C(O)R, -(CR 1 1 R 1 ) n -SR' ) -(CR 1 1 R 12 ) n -N(R') and aryl, preferably phenyl. More preferably, the optional substituents are C ⁇ to CJQ alkyl, Ci to C 10 alkoxy, cyano, C(O)R', NO 2 , halogen, and aryl.
  • polypeptide is used herein at all occurrences to mean a polymer of amino acids (i.e., acid units chemically bound together with amide linkages (CONH)), forming a chain that consists of 1 to 20 amino acid residues.
  • non-peptide compounds bind to a variety of receptors, particularly, G-protein coupled receptors.
  • the following core structures may be used as templates for designing libraries of non-peptide compounds which may be tested for binding to a variety of receptors, specifically, G-protein coupled receptors.
  • the libraries can be prepared on a solid support, e.g., a resin, or they can be prepared in solution.
  • the variable substituents can be added by reacting core structure, labeled R, with a mixture of reagents designed to introduce substituents Xl- collectively or by reacting aliquots of R with individual reagents each one of which will introduce a single substituent R; and then mixing the resultant products together (wherein i,j and k are used herein to represent any of the substituents on the compound members of the combinatorial library).
  • the components of the library are screened in groups of multiple compounds. Therefore, once the library of compounds has been synthesized, there must be some method to deconvolute the results of screening such that individual active compounds can be identified. Based upon the disclosure herein, it will be clear to the skilled artisan that there are many methods for decon volution of the combinatorial library. For example, if the compounds of the library are screened on a solid support, they may be physically segregated so that individual active compounds may be directly selected and identified.
  • the library may be deconvoluted in an iterative approach, which involves resynthesis of mixtures of decreasing complexity until a single compound is identified, or in a scanning approach, in which the various substituents on the core structure R, are evaluated independently and the structure of active compounds are determined deductively. Both the iterative and scanning approaches to deconvolution of the combinatorial libraries of this invention are described in more detail below.
  • the iterative approach to deconvoluting the combinatorial library involves separation of the combinatorial library of compounds immediately prior to the introduction of the last variable substituent.
  • R is the core structure, etc., as used above
  • m Yi- is partitioned into p aliquots (wherein m, n and p are integers which define the size of the library, and which range between 1 to 1000; preferably between 1 to 100; most preferably between 1 to 20). Each of those aliquots is reacted with reagents designed to introduce a single substituent, labeled Z.
  • the library is prepared again, this time splitting the mixture of compounds RXi- into n aliquots for introduction of the n different Y substituents (as used herein " “, “b” and “c” refer to specific acceptable substituents which have been determined to be active by screening in a binding or functional assay).
  • the Z ⁇ substituent is introduced into each of the still separated aliquots.
  • the library now consists of n pools RX ⁇ .
  • the appropriate X substituent, labeled X c is determined by beginning with m different aliquots of core structure R and sequentially introducing Xjt, Yfr and Z a to give m different pools RXfcY£Z fl , each of which contains a single compound.
  • Xjt, Yfr and Z a m different pools
  • RXfcY£Z fl m different pools
  • m + n +p syntheses are required to decon volute a library containing m x n xp compounds.
  • the iterative approach is specific for a single target which is determined after the first round of screening, since subsequent library preparations do not contain the full complement of substituents.
  • the application of the scanning approach to deconvoluting the combinatorial library requires that the variable substituents X, Y and Z can be introduced synthetically independently of each other.
  • the library is first prepared as
  • RXl- Yl- w Z exactly as in the iterative approach to give p pools RXi- Y ⁇ _ n Z , each of which contains m x n compounds with all possible variation of X and Y represented but only one particular Z. Screening this library defines the appropriate Z substituents for the desired activity. Since Y can be introduced independently from X and Z, the library is then prepared as RXi- Y Zi- ⁇ , giving n pools of compounds each containing m p compounds in which all substituents X and Z are represented with a particular Y substituent. Screening this library in a binding or functional assay defines the appropriate Y substituents for the desired activity.
  • the library is then prepared as RXjfcYi- n Zi- , giving m batches or pools of compounds, each of which contains n xp compounds in which all substituents Y and Z are represented with a particular X substituent. Screening this library in a binding or functional assay defines the appropriate X substituents for the desired activity.
  • each library contains all the possible permutations of X, Y and Z and can be utilized to screen against a number of different biological targets.
  • the Use of Silicon Chemistry in Preparing Combinatorial Libraries The use of the instant silicon-based resins has been discovered to be particularly effective in preparing, by resin-bound synthesis, core structure(s) which are substituted aromatic carbocycle(s), wherein said aromatic carbocycle(s) comprises an aromatic carbon which carbon has a hydrogen, halogen, hydroxy or acyloxy group bound to it after the resin-bound synthesis is completed.
  • the aromatic carbocycle prepared by resin-bound synthesis utilizing silicon chemistry may be useful as receptor ligands, particularly G-protein coupled receptor ligands, enzyme inhibitors and channel blockers.
  • the instant polymeric resins and silane linkers are particularly useful in effectuating the cleavage of an aromatic carbocycle from a polymeric resin support while leaving a hydrogen at the cleavage position.
  • the silicon linkers, polymeric resin supports and intermediates of this invention effectuate the successful preparation of a single aromatic carbocycle or a plurality of molecularly diverse aromatic carbocycles which, upon cleavage from a polymeric resin support, have a halogen, hydroxy or acyloxy group at the cleavage position.
  • the aromatic carbocycles prepared by the methods described herein can be screened in assays developed for determining lead compounds as pharmaceutical agents.
  • the invention is in a method for preparing a compound by resin-bound synthesis, wherein said compound is an aromatic carbocycle comprising an aromatic carbon atom and at least one substituent that is not hydrogen or alkyl, said method comprising the steps of: (i) attaching the aromatic carbon to a polymeric resin support through a silane linker to give a resin-bound aryl silane intermediate; and (ii) performing additional synthetic chemistry on the substituent so that the aromatic carbocycle is derivatized.
  • the derivatized resin-bound aryl silane intermediate may be stored for further derivatization of the substituents.
  • the aromatic carbocycle is biphenyl, phenyl, naphthyl or anthracenyl.
  • the aromatic carbocycle has at least one substituent that is X, A, B or C, as defined above, to be derivatized by additional synthetic chemistry.
  • a compound prepared by this method remains as a resin-bound aryl silane intermediate, which resin-bound intermediate may be screened in a suitable assay developed for determining pharmaceutical activity.
  • the derivatized aromatic carbocycle may be decoupled from the resin-bound aryl silane intermediate by a further step comprising cleaving the resin-bound aryl silane intermediate at the aryl silane bond so that the decoupled aromatic carbocycle resulting from the cleavage has a hydrogen, halogen, hydroxy or acyloxy group on the aromatic carbon where it was bound through the silane linker. After this step, the decoupled aromatic carbocycle may be screened in a suitable assay developed for determining pharmaceutical activity.
  • the additional synthetic chemistry performed in order to modify the substituents X, A, B or C must be such that the aromatic carbocycle is derivatized without cleaving the aryl silane bond of the resin-bound aryl silane intermediate.
  • the aromatic carbocycle is bound to a polymeric resin support through a silane linker to give a resin-bound aryl silane intermediate.
  • the aromatic carbocycle is bound to the resin through a silane linker group comprising the following moiety: D-CH 2 -Si-R"R"', wherein D is defined as a C j to C 20 alkyl chain optionally having one or more intervening heteroatoms and/or optionally substituted aryl groups, and R" and R'" are independently, Ci to C ⁇ alkyl.
  • Preferred silane linker groups of formula D-CH2-Si-R"R'" for use in the methods disclosed herein include, but are not limited to, the following linker groups: -(CH2)4-Si-R"R'", wherein D is -(CH 2 )3-; -O-CH 2 -Ph-O-CH 2 -Si-R"R'", wherein D is -O-CH 2 -Ph-O-; -O-Ph-O- CH 2 -SiR"R'", wherein D is -O-Ph-O-; or -O-Ph-CH2-O-CH 2 -Si-R"R'", wherein D is - O-PI1-CH2-O-.
  • a preferred silane linker group for preparing aromatic carbocycles wherein a substituent X, A, B, or C is cyano is a linker group of formula D-CH2 ⁇ Si- R"R'", wherein D is -O-Ph-O-.
  • the aromatic carbon atom of the aromatic carbocycle is bound directly to a silicon atom of the silane linker.
  • R" and R'" are independently, C1 to C4 alkyl, more preferably, R" and R'" are both methyl or ethyl, more preferably R" and R'" are both methyl.
  • Useful intermediates of the invention are the novel aryl silane compounds of Formula (LB).
  • the compounds of Formula (LB) are reacted with an appropriate polymer resin in order to make a resin-bound aryl silane intermediate which will be further modified by performing additional synthetic chemistry thereon.
  • an aryl silane compound is formed as a first intermediate, which intermediate is then coupled to a polymeric resin support.
  • a suitable resin-bound aryl silane intermediate is prepared by combining an aryl silane compound of Formula (LB):
  • R" and R' independently from one another, are Cj to Cg alkyl;
  • X, A, B and C are, independently from one another, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, C(O)R a , wherein R a is hydrogen or alkyl, t-butoxyaminocarbonyl, cyano, nitro, aryl, heteroaryl, arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl or orthoester group, provided that X, A, B and C can not all be hydrogen and X, A, B and C can not all be alkyl; and n is an integer from 1 to 10, with an appropriate polymeric resin, using conventional techniques.
  • a preferred embodiment of this inventive intermediate is a compound of Formula (IB) wherein R" and R'", independently from one another, are Cj to C4 alkyl; X is bromine or iodine; A, B and C are hydrogen; and n is 1 to 4.
  • R" and R"' are each methyl; X is bromine; A, B and C are hydrogen; and n is 1.
  • the compound of Formula (LB) may then be reacted with a suitable polymeric resin support to form a resin-bound aryl silane intermediate.
  • suitable resins for use herein are a cross-linked polystyrene resin, a polyethylene glycol- polystyrene based resin, or a polypropylene glycol based resin.
  • a preferred resin for reaction with a compound of Formula (LB) is a chloromethyl cross-linked divinylbenzene polystyrene resin.
  • Suitable additional synthetic chemistry may be performed on this resin-bound aryl silane intermediate, particularly on the substituents X, A, B or C, as described above, in order to modify the substituents X, A, B or C.
  • the derivatized aromatic carbocycle may be cleaved from the resin-bound aryl silane intermediate at the aryl silane bond or it may remain as a resin-bound aryl silane intermediate.
  • the intermediate compounds of Formula (IB) may be prepared by utilizing another useful intermediate of this invention, i.e., a compound of Formula (LLB):
  • R" and R"' independently from one another, are C j to Cg alkyl;
  • X, A, B and C are, independently from one another, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, C(O)R a , wherein R a is hydrogen or alkyl, t-butoxyaminocarbonyl, cyano, nitro, aryl, heteroaryl, arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl or an orthoester group, provided that X, A, B and C can not all be hydrogen and X, A, B and C can not all be alkyl; Y is halogen or hydroxyl; and n is an integer from 1 to 10.
  • a preferred embodiment of this aspect of the invention is a compound of Formula (LIB) wherein R" and R'", independently from one another, are Cj to C4 alkyl; X is halogen; A, B and C are hydrogen; Y is bromine; and n is 1 to 4.
  • a more preferred embodiment of this aspect of the invention is a compound of Formula (LLB) wherein R" and R'" are each methyl; X is bromine; A, B and C are hydrogen; Y is bromine; and n is 1.
  • the novel intermediates of Formula (LLB) may easily be prepared from compound 1 -Scheme 1. or appropriate analogs thereof, by reaction with an alkyl lithium compound.
  • a compound of Formula (LLB) may be prepared by forming a Grignard reagent of compound 1 -Scheme 1. or appropriate analogs thereof.
  • An illustrative method for preparing an intermediate of Formula (LLB) is disclosed by Morikawa et al., Polym. J., 24, p. 573 (1992), the relevant parts of which are incorporated herein by reference.
  • substituents X, A, B and C aside from being compatible with the additional synthetic chemistry to be performed on the resin-bound aryl silane intermediate, substituents X, A, B and C must also be compatible with the alkyl lithium chemistry utilized to make the intermediates of Formulae (LB) and ( LB).
  • a number of suitable conditions may be used, for example, treatment of the resin- bound aryl silane intermediate with a strong protic acid.
  • the acidic cleavage conditions include, but are not limited to, treatment with 100% trifluoroacetic acid ("TFA”), hydrofluoric acid (“HF”), hydrochloric acid (“HCl”), pyridinium hydrofluoride, sulfuric acid (“H2SO4"), trifluoromethanesulfonic acid (commonly referred to as triflic acid), boron trifluoride ("BF 3 "), methanesulfonic acid or mixtures thereof.
  • TFA trifluoroacetic acid
  • HF hydrofluoric acid
  • HCl hydrochloric acid
  • pyridinium hydrofluoride pyridinium hydrofluoride
  • sulfuric acid H2SO4
  • trifluoromethanesulfonic acid commonly referred to as triflic acid
  • boron trifluoride boron trifluoride
  • methanesulfonic acid or mixtures thereof Preferred cleavage conditions utilize 100% TFA.
  • base catalyzed cleavage conditions include, but are not limited to, cleavage with NaOH in DMSO (dimethylsulfoxide) or methanol. See, for example, Cretney et al., J. Organometal. Chem., 28, pp. 49-52 (1971).
  • a number of suitable conditions may be used, for example, treatment of the resin- bound aryl silane intermediate with bromine, chlorine or iodine.
  • a number of suitable conditions may be used, for example, treatment of the resin-bound aryl silane intermediate with benzoyl peroxide to give a benzoate ester at the cleavage site.
  • the resulting aromatic carbocycle which is substituted with an ester functionality may be subsequently hydrolyzed using known conditions to yield an aromatic carbocycle which is substituted with a hydroxy group.
  • a number of suitable conditions may be used, for example, treatment of the resin-bound aryl silane intermediate with acetyl peroxide or any suitable acyl peroxide using conventional conditions known to the skilled artisan.
  • this invention is in a method for preparing a library of diverse resin-bound aromatic carbocycles each comprising an aromatic carbon atom and at least one substituent that is not hydrogen or alkyl, said method comprising the steps of: (i) attaching the aromatic carbon atom of each of a plurality of aromatic carbocycles to an individual polymeric resin support through a silane linker to give a plurality of resin-bound aryl silane intermediates; (ii) optionally dividing said resin-bound aryl silane intermediates into a plurality of portions; (iii) performing additional synthetic chemistry on the substituents so that the aromatic carbocycle is derivatized; and (iv) optionally recombining the portions.
  • the substituents on the aromatic carbocycle which are to be derivatized are X, A, B or C as defined above.
  • the libraries are considered to be combinatorial libraries because the compounds generated from the synthetic methods are molecularly diverse and are prepared simultaneously.
  • the libraries may be prepared on polymeric resin supports using the silane linkers described herein above. For example, a plurality of aromatic carbocycles each comprising an aromatic carbon atom and having at least one substituent X, A, B or C that is not hydrogen or alkyl, are each attached to an individual polymer resin support through a silane linker to give a plurality of resin-bound aryl silane intermediates.
  • the plurality of resin-bound aryl silane intermediates may be reacted with one or more reagents in one reaction vessel.
  • aliquots of the resin- bound aryl silane intermediates may be reacted with one or more reagents and then the resultant products are mixed together to form a library of derivatized aromatic carbocycles.
  • the reagent(s) used in this first step modification will modify only a single substituent X, A, B or C.
  • This first modified/derivatized library may then be further derivatized by repeating the process of dividing and recombining the derivatized resin-bound aryl silane intermediates formed by the additional synthetic chemistry.
  • the resin-bound aryl silane intermediates may be divided into portions at any point during the synthetic scheme. The portions may be recombined at any point during the scheme or, further iterations may be applied if more derivatization is required.
  • the derivatized aliquots may be recombined and reacted with one or more additional reagents in one reaction vessel.
  • each aliquot may be subdivided into further aliquots and reacted as described herein.
  • each polymeric resin support bears a single (derivatized) aromatic carbocycle species created by the additional synthetic chemistry performed on the resin-bound aryl silane intermediate.
  • the desired library is one that comprises an N- methylated compound of formula 8 and an N-ethylated compound of formula 8, the following variation on the split-synthesis method of Moss et al., Ann. Rep. Med. Chem., 28, p. 315 (1993), for preparing libraries of compounds may be used.
  • the steps depicted in Scheme 6 are followed, without dividing the resin-bound aryl silane intermediates of formulae 1 through 5 into portions.
  • said resin-bound formula 6 is divided into a number of portions, for example, two portions, labeled for purposes of illustration as portion 1 and portion 2.
  • Each of the two portions contains resin-bound aryl silane intermediate 6-Scheme 6.
  • Portion 1 is reacted under standard conditions with, e.g., methyl iodide, in order to obtain a compound 7_z Scheme 6. wherein R 4 is methyl.
  • Portion 2 is reacted under standard conditions, with, e.g., ethyl bromide, in order to obtain compound 7-Scheme 6. wherein R 4 is ethyl.
  • the two separate portions are recombined to form a library of two compounds, wherein each polymer resin is linked through a silane linker group, to a distinct aromatic carbocycle which is the product of a specific reaction sequence.
  • the methods and linkers described herein may be applied to the preparation of a large variety of core structures, including aromatic carbocycles.
  • the silicon linker group (which comprises D-CH2-Si-R"R') is suitably bound to an aromatic carbon on the aromatic portion of the core structure, such as in a benzodiazepine derivative or in a tetrahydronaphthyl derivative.
  • the compounds can be separated and characterized by conventional analytical techniques known to the skilled artisan, for example infrared spectrometry or mass spectrometry.
  • the compounds may be characterized while remaining resin-bound or they can be cleaved from the resin- bound aryl silane intermediates using the conditions described above, and then analyzed.
  • some of the compound members of the library may be cleaved from the resin-bound aryl silane intermediates while other members of the library remain resin bound to give a "partially cleaved" library of compounds.
  • a "fully cleaved" library of compounds is created.
  • aromatic carbocycles coupled to the polymerc resins through the silane linkers illustrated below can be optionally substituted at any appropriate site, depending upon the type of derivatization required.
  • the aromatic carbocycle is a biphenyl
  • the substituents X, A, B or C may be, independently, on one or both rings. This is similarly so for other aromatic carbocyclic rings or ring systems, as defined above.
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • LRMS low resolution mass spectrometry
  • DLEA diisopropylethylamine
  • THF tetrahydrofuran
  • n-BuLi n-butyllithium
  • min is minutes
  • mL is milliliters
  • BnBr is benzylbromide
  • 'OAc is acetate.
  • the resin-bound aryl silane intermediate 4-Scheme 1. wherein X is bromine and A, B and C are each hydrogen, is prepared by reacting Merrifield chloromethyl resin (available from Nova Biochem, 1.4 mM/g of Cl) with the resin-bound aryl silane intermediate alcohol 3-Scheme 1. wherein X is bromine and A, B and C are each hydrogen, in an SN2 displacement as described in Scheme 1.
  • 2-Scheme 1 (or the appropriate analogs) is reacted with a base, (such as sodium methoxide or potassium carbonate) in an aprotic solvent (dimethyl formamide, dimethyl acetamide or DMSO if sodium methoxide is the base; acetone or ethyl methyl ketone if potassium carbonate is the base) to displace the halogen on the silane moiety for coupling with optionally substituted hydroxybenzyl alcohol to prepare an aryl silane compound 3 ⁇ Scheme 1 (i.e., a compound of Formula (LB) wherein R" and R'" are methyl; X is bromine; A, B and C are hydrogen; and n is 1).
  • a base such as sodium methoxide or potassium carbonate
  • an aprotic solvent dimethyl formamide, dimethyl acetamide or DMSO if sodium methoxide is the base; acetone or ethyl methyl ketone if potassium carbonate is the base
  • X, A, B and C are, independently from one another, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether, alkylthio, C(O)R a , wherein R a is hydrogen or alkyl, t-butoxyamino- carbonyl, cyano, nitro (-NO2), aryl, heteroaryl, arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl or orthoester (-C(OR)3, wherein R is Cj to C4 alkyl), provided that X, A, B and C can not all be hydrogen and X, A, B and C can not all be alkyl.
  • Scheme 2 wherein X is bromine and A, B and C are hydrogen, is depicted starting from the Wang resin 1 -Scheme 2.
  • Scheme 2 depicts the preparation of an aromatic carbocycle (4-Scheme 2. wherein X is bromine) from a resin-bound aryl silane intermediate (2-Scheme 2. wherein X is bromine), wherein the aromatic carbocycle has a hydrogen atom at the site of cleavage from the resin.
  • the Wang resin 1 -Scheme 2 is prepared according to the published procedure of Su-Sun Wang, JACS, 95, p. 1328 (1973) starting from the Merrifield resin. Elemental analysis of 2-Scheme 2. wherein X is bromine and A, B and C are hydrogen, indicated a conversion of approximately 70%.
  • X, A, B and C are, independently from one another, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether, alkylthio, C(O)R a , wherein R a is hydrogen or alkyl, t-butoxyamino-carbonyl, cyano, nitro (- NO2), aryl, heteroaryl, arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl or orthoester (-C(OR)3, wherein R is C j to C4 alkyl), provided that X, A, B and C can not all be hydrogen and X, A, B and C can not all be alkyl.
  • Reaction sequence (a) depicts the preparation of an aromatic carbocycle 2c Scheme 3.
  • X is, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether, alkylthio, C(O)R a , wherein R a is hydrogen or alkyl, t- butoxyaminocarbonyl, cyano, nitro (-NO 2 ), aryl, heteroaryl, arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl or orthoester (-C(OR) 3 , wherein R is Cj to C4 alkyl), preferably halogen, and most preferably bromine, and wherein A, B and C are hydrogen.
  • 2-Scheme 3. wherein there is a hydrogen atom left on the aromatic carbocycle at the cleavage site, is synthesized through an aryl silane intermediate which is bound to a suitable resin (such as the Merrifield resin or the Wang resin), wherein cleavage of 2-Scheme 3 from the resin is accomplished using strong acidic conditions.
  • a suitable resin such as the Merrifield resin or the Wang resin
  • Preparation of an aromatic carbocycle 3-Scheme 3. wherein there is a halogen atom left on the aromatic carbocycle at the site of cleavage from the silane resin intermediate is accomplished by reacting the resin- bound aryl silane intermediate with an elemental halogen compound (such as Br2, 12 or CI2) in a suitable aprotic solvent (such as methylene chloride).
  • reaction sequences may be applied, wherein X, A, B and C are, independently from one another, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether, alkylthio, C(O)R a , wherein R a is hydrogen or alkyl, t-butoxyaminocarbonyl, cyano, nitro (-NO2), aryl, heteroaryl, arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl or orthoester (-C(OR)3, wherein R is C ⁇ to C4 alkyl), provided that X, A, B and C can not all be hydrogen and X, A, B and C can not all be alkyl.
  • n-BuLi, THF, Phthalic anhydride available from Aldrich
  • n-BuLi, THF, CO2 available from Aldrich
  • n-BuLi, THF, Diethyloxalate available from Aldrich
  • Reaction sequence (a) depicts the preparation of 2a-Scheme 4. wherein the para-bromine moiety on resin-bound aryl silane intermediate 1 -Scheme 4 is substituent X which is then modified by additional synthetic chemistry (such as creation of an alkyl lithium species in an aprotic solvent such as THF) to gi e 2a- Scheme 4. wherein X is defined as shown in Scheme 4.
  • Reaction sequence (b) depicts the preparation of 2b-Scheme 4.
  • reaction sequence (c) depicts the preparation of 2c-Scheme 4. wherein the para-bromine moiety on resin-bound aryl silane intermediate 1 -Scheme 4 is substituent X which is then modified by additional synthetic chemistry (such as creation of an alkyl lithium species in an aprotic solvent such as THF) to give 2b-Scheme 4. wherein X is a carboxylic acid moiety.
  • Reaction sequence (c) depicts the preparation of 2c-Scheme 4. wherein the para-bromine moiety on resin-bound aryl silane intermediate 1 -Scheme 4 is substituent X which is then modified by additional synthetic chemistry (such as creation of an alkyl lithium species in an aprotic solvent such as THF) to give Z z Scheme 4. wherein X is a ketoester moiety.
  • the moieties A, B and C may be as defined above.
  • Scheme 5 illustrates additional synthetic chemistry that was successfully performed in order to prepare an aromatic carbocycle (biphenyl) with a hydrogen left at the cleavage site, according to this invention.
  • the resin-bound aryl silane intermediate 1 -Scheme 5 (prepared similarly to 4-Scheme 1). wherein X is bromine, and A, B and C are hydrogen, is reacted with phenylboronic acid and (Pb ⁇ P ⁇ Pd (available from Aldrich) in a mixture of an aprotic and a protic solvent to yield the resin-bound aryl silane intermediate 2c Scheme 5. Subsequent cleavage of resin-bound aryl silane intermediate 2-Scheme 5 under strong acidic conditions produces the aromatic carbocycle biphenyl, 3-Scheme 5. This key reaction is used according to this invention in order to synthesize a variety of biphenyls substituted with various functional groups with conventional chemistry that will be obvious to the skilled artisan.
  • X, A, B and C are, independently from one another, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether, alkylthio, - C(O)R a , wherein R a is hydrogen or alkyl, t-butoxyaminocarbonyl, cyano, nitro (- NO 2 ), aryl, heteroaryl, arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxy-carbonyl or orthoester (-C(OR) 3 , wherein R is Cj to C alkyl), provided that X, A, B and C can not all be hydrogen and X, A, B and C can not all be alkyl, and provided that the chemistry is compatible with modifying the substituent
  • n-BuLi THF, optionally substituted phthalic anhydride
  • (b) (i) (PhO)2P(O)N 3 , Et3N, Toluene; (ii) NaOH, MeOH; (c) (i) peptide coupling; (ii) Deprotection with 20% piperidine in DMF; (d) DMF, 5% acetic acid; (e) 4-benzyl lithium oxazolidinone, THF, R 4 -Z; (f) TFA.
  • the resin-bound aryl silane intermediate 3-Scheme 6 is prepared using the general procedure outlined above for preparing 2a-Scheme 4. using optionally substituted phthalic anhydride, wherein the optional substituent(s) is Y', and Y' is hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether, alkylthio, C(O)R a , wherein R a is hydrogen or alkyl, t-butoxyaminocarbonyl, cyano, nitro (- NO2), aryl, heteroaryl, arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmeth-oxycarbonyl or orthoester (-C(OR)3, wherein R is Cj to C4 alkyl).
  • substituent R 3 is hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether, alkylthio, C(O)R a , wherein R a is hydrogen or alkyl, t-butoxyamino-carbonyl, cyano, nitro (-NO 2 ), aryl, heteroaryl arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl or orthoester (-C(OR)3, wherein R is Cj to C4 alkyl).
  • Deprotection of 4-Scheme 6 is accomplished with conventional techniques (such as 20% piperidine in DMF) to produce 5-Scheme 6.
  • Cyclization of 5-Scheme 6 is accomplished with an organic acid (such as acetic acid) in an aprotic solvent (such as DMF) to produce 6-Scheme 6.
  • Analogs of 6-Scheme 6 may be N-alkylated at the position- 1 nitrogen of the benzodiazepine ring (depicted in the scheme as R 4 ), using conventional techniques, for example, reaction with a base (such as 4-benzyl lithium oxazolidinone) in an aprotic solvent and alkylation with an alkyl halide or alkyl tosylate (such as R 4 -Z, wherein R 4 is alkyl; and Z is Br, I or tosylate).
  • a base such as 4-benzyl lithium oxazolidinone
  • alkyl halide or alkyl tosylate such as R 4 -Z, wherein R 4 is alkyl; and Z is Br, I or tosylate.
  • Cleavage of the resin-bound aryl silane intermediate 7-Scheme 6 to produce an optionally substituted aromatic carbocycle, i.e., the benzodiazepine &z Scheme 6. is accomplished by treatment with strong acid
  • X is Br and A, B and C are hydrogen.
  • substituents X, A, B and C on the staring material are as defined more broadly, above.
  • 4b-Scheme 6 may be synthesized through a nitrobenzophenone intermediate.
  • Scheme 7 illustrates a method for preparing 1,3- or 1 ,4-diaminobenzene compounds, one of the various types of aromatic carbocycles that may be prepared using the silane linkers of this invention:
  • R" and R'" are methyl; the substituents X and A are bromine and nitro, respectively; B and C are hydrogen; Y is bromine; and n is 1, is prepared by forming a lithium species of 2,4- dibromonitrobenzene (Aldrich) and subsequent reaction with a silane compound (such as bromomethyl chlorodimethyl silane available from Aldrich) in an aprotic solvent (such as THF or ether).
  • aprotic solvent such as THF or ether
  • a strong base such as sodium methoxide or potassium carbonate
  • an optionally substituted benzyl alcohol in an aprotic solvent (such as THF, dimethyl formamide, dimethyl acetamide or DMSO if sodium methoxide is the base; acetone or ethyl methyl ketone if potassium carbonate is the base) to prepare the aryl silane intermediate of 3-Scheme 7.
  • a strong base such as sodium methoxide or potassium carbonate
  • an aprotic solvent such as THF, dimethyl formamide, dimethyl acetamide or DMSO if sodium methoxide is the base; acetone or ethyl methyl ketone if potassium carbonate is the base
  • This intermediate is coupled with a polymer resin (such as Merrifield resin, Wang resin, or any other suitable resin described herein) in an aprotic solvent (such as THF) using a base (such as sodium hydride, sodium methoxide in THF, dimethyl formamide, dimethyl acetamide or DMSO, or potassium carbonate in acetone or ethyl methyl ketone) to produce 4-Scheme 7.
  • a base such as sodium hydride, sodium methoxide in THF, dimethyl formamide, dimethyl acetamide or DMSO, or potassium carbonate in acetone or ethyl methyl ketone
  • substituents B, C, R 5 and R 6 are, independently from one another, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether, alkylthio, C(O)R a , wherein R a is hydrogen or alkyl, t-butoxyaminocarbonyl, cyano, nitro (-NO 2 ), aryl, heteroaryl, arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl or orthoester (-C(OR) 3 , wherein R is Cj to C 4 alkyl).
  • Scheme 8 illustrates a method for preparing amino carboxy compounds, another class of aromatic carbocycles that may be prepared using the silane linkers of this invention:
  • substituents B, C, R 7 and R 8 are, independently from one another, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether, alkylthio, C(O)R a , wherein R a is hydrogen or alkyl, cyano, t-butoxyaminocarbonyl, nitro (-NO2), aryl, heteroaryl, arylalkyl, alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl or orthoester (-C(OR) 3 , wherein R is Cj to C4 alkyl), is accomplished under strongly acidic conditions (such as treatment with TFA).
  • Scheme 9 illustrates a method for preparing biphenyltetrazole compounds, yet another class of aromatic carbocycles that may be prepared using the silane linkers of this invention.
  • 2-Scheme 9 (wherein X and A are bromine and B and C are defined as described above) prepared by reacting 1 -Scheme 9 (prepared from 2,4- dibromobenzoic acid which is available from Aldrich, by reaction with methanesulfonyl chloride and ammonia) with sodium azide in the presence of a Lewis acid, and then N-alkylating the intermediate previously formed, using conventional techniques, for example, reaction with a base (such as NaH, potassium carbonate or trialkylamines) in an aprotic solvent, and alkylation with an alkyl halide or an alkyl tosylate (such as R 9 -Z', wherein R 9 is alkyl; and Z' is Cl, Br, I or tosylate).
  • a base such as NaH, potassium carbonate or trialkylamines
  • alkylation with an alkyl halide or an alkyl tosylate such as R 9 -Z', wherein R 9 is alkyl; and
  • 2-Scheme 9 is coupled with a silane compound and then with a polymer resin to prepare 4-Scheme 9. as described previously. Additional synthetic chemistry is performed in order to modify the aromatic carbocycle bound to the resin. Cleavage of the substituted aromatic carbocycle is accomplished using strong acid conditions. It will be clear that X and A can be other than bromide and as defined above, provided that X, A, B and C can not all be hydrogen and not all X, A, B and C can be alkyl.
  • Scheme 10 illustrates the preparation of an aromatic carbocycle 3-Scheme
  • Scheme 11 illustrates the preparation of an amine substituted biphenyl compound using the resin-bound aryl silane intermediate 1 -Scheme 11 (prepared according to step (a) of Scheme 10 above) as a starting material.
  • 1 -Scheme 11 is reacted with an optionally substituted primary amine (such as benzyl amine, Aldrich ®, Milwauke, WI ) in an aprotic or protic solvent (such as toluene, methylene chloride, ethanol or methanol) to give a resin-bound aryl silane intermediate substituted with a benzyl imine (2-Scheme 11).
  • an optionally substituted primary amine such as benzyl amine, Aldrich ®, Milwauke, WI
  • an aprotic or protic solvent such as toluene, methylene chloride, ethanol or methanol
  • the optionally substituted primary amine is substituted with alkyl, aryl heteroaryl, arylalkyl or heteroarylalkyl; preferably arylalkyl; more preferably, benzyl.
  • Additional synthetic chemistry specifically a Grignard reaction using allylmagnesium bromide (made conventionally) in an aprotic solvent (such as ether and toluene), is performed on resin-bound aryl silane intermediate 2-Scheme 11 to convert the benzyl imine to 3 ⁇ Scheme 11. an aminobenzyl substituted alkenyl moiety.
  • Compounds analogous to 3-Scheme 11. but wherein the alkenyl moiety is varied, may be prepared prepared by using a different Grignard reagent under the same reaction conditions. Standard cleavage conditions are used to give 4-Scheme 11.
  • Scheme 12 illustrates the preparation of another substituted biphenyl compound using the resin-bound aryl silane intermediate 1 -Scheme 12 (prepared according to step (a) of Scheme 10 above) as a starting material.
  • an aprotic solvent such
  • the vinyl ester 2c scheme 12 is modified to a thiol addition moiety by reaction with an optionally substituted thiol (such as thiophenol, Aldrich) in a tertiary amine base (such as triethylamine) in an aprotic or protic solvent (such as toluene or ethanol) to give resin-bound aryl silane intermeidate 3-Scheme 12. which intermediate is cleaved to give the desired derivatized aromatic carbocycle, 4-Scheme 12. It will be recognized that various additional synthetic chemistry can be performed on intermediate 2c Scheme 12 in order to derivatize across the alkenyl bond, for example by performing a Wadsworth-Emmons reaction as disclosed by Patios, Tet.
  • an optionally substituted thiol such as thiophenol, Aldrich
  • a tertiary amine base such as triethylamine
  • aprotic or protic solvent such as toluene or ethanol
  • Phj P CHCOOEt, THF, 60°; b) PhSH, EN, Toluene, 25° ; c) TFA, Neat
  • Schemes 13a and 13b illustrate other types of additional synthetic chemistry which are compatible with the aryl silane bond of various resin-bound aryl silane intermediates.
  • Scheme 14 merely illustrates the standard reaction conditions for making dibromobenzonitrile (starting material 1 -Scheme 15).
  • Scheme 15 illustrates the reaction conditions for making a cyano, bromo- substituted aryl silane compound 4-Scheme 15.
  • Scheme 16 illustrates the preparation of a resin 2-Scheme 16. starting from the Merrifield chloromethyl resin 1 -Scheme 16.
  • Scheme 17 illustrates the preparation of a cyano-substituted aromatic carbocycle using the cyano, bromo-substituted aryl silane compound 2-Scheme 17 (prepared per Scheme 15) and resin 1 -Scheme 17 (prepared per Scheme 16) as starting materials.
  • Ph3P is triphenylphosphine (Aldrich);
  • DEAD is diethylazodicarboxylate (Aldrich);
  • NMM is N-methyl mo ⁇ holine (Aldrich).
  • the instant invention includes a silane linker of formula D-CH 2 -Si-R"R" ⁇ wherein D is -(CH2)3-, i.e., -(CH2)4-Si-R"R' M , as an appropriate silane linker to carry out solid phase synthesis of increasing complexity, particularly when the possibility of undesired side products upon cleavage of the final product from the resin-bound aryl silane intermediate, exists.
  • Scheme 18 illustrates the preparation of a resin-bound aryl silane intermediate 3-Scheme 18. utilizing an all carbon silane linker of formula D-CH -Si- R"R'", wherein D is -(CH 2 )3-, i.e., -(CH 2 )4-Si-R"R'", wherein R" and R'" are each methyl.
  • Scheme 18(a) illustrates the preparation of 2-Scheme 18(a) which is a reagent used in the preparation of 3-Scheme 18. described above.
  • Scheme 19 illustrates the preparation of a sulfonamide aromatic carbocycle ., 1 -Scheme 19) as the starting material.
  • Scheme 20 illustrates the use of an acid labile MOM protecting group with the all carbon silane linker.
  • the usefullness of this reaction scheme is the demonstartion that 10% TFA is useful in deprotecting 2-Scheme 20. however, 10% TFA does not cleave the aromatic carbocycle from the resin-bound aryl silane intermediate 3-Scheme 20.
  • Resin-bound aryl silane intermediate 4-Scheme 1 (0.5 g) was swelled in methylene chloride(5 mL). Bromine(0.1 mL) was added and stirred overnight. Reaction mixture, after filtering, washing with ether and removal of solvents in vacuo, gave an oil (175 mg) which solidified on standing. It was found to be dibromobenzene by l NMR and m. pt.
  • Resin-bound aryl silane intermediate 4-Scheme 1 (500 mg) was suspended in methylene chloride (5 mL). Gaseous HBr was then passed through the suspension cooled in an ice bath for 5 minutes. The cooling bath was removed and the reaction mixture stirred for 30 minutes. Excess HBr was purged from the suspension by passing Argon until no HBr was detected with pH paper. The resin was filtered off, washed with ether and the solvents removed in vacuo to give 230 mg of an oil. MPLC (silica, ethyl acetate: hexane 1:10) provided the product. MS (DCI, NH3) 428 (M+ +NH4). Reaction resin-bound aryl silane intermediate 4-Scheme 1 with trifluoroacetic acid (See Scheme 3(a))
  • Resin-bound aryl silane intermediate 4-Scheme 1 (500 mg) was stirred in trifluoroacetic acid (2 mL) and the product was analyzed by GC(SE-30, 50°C) room temperature 5.14 minutes. The formation of bromobenzene was confirmed by co- injection with authentic bromobenzene. Preparation of resin-bound aryl silane intermediate 2a-Scheme 4
  • the resin-bound aryl silane intermediate 2a-Scheme 4 was suspended in toluene and allowed to swell for 30 minutes. To this was added diphenylphosphoryl azide and the mixture is heated in an oil bath maintained at 90°C for 16 h. The reaction mixture was cooled and filtered, washed with methanol, methylene chloride, methanol and finally dried in vacuo to give the isocyanate. IR 2100 cm -1 .
  • the resin-bound aryl silane intermediate 5-Scheme 19 was treated with TFA:DMS:H2 ⁇ (90:5:5) for 16 h.
  • the solvents were removed under vacuo to provide a pale yellow oil which was compared with an authentic sample prepared earlier.
  • silicon linkers and silicon based polymer resins of this invention may be used in a variety of combinatorial methods for synthesizing a large number of molecularly diverse compounds, simultaneously.
  • the instant invention may be applied to (i) the "multi-pin" method described in Geysen et al., Proc. Natl. Acad. Sci. USA., 81, p. 3998 (1984); U.S. Patent 4,708,871 (1987); Geysen et al., Bioorg. Med. Chem. Lett, 3, p.397 (1993); and European Patent 138,855 (1991); (ii) the "tea-bag” approach described in Houghten, R.A., Proc. Natl. Acad. Sci. USA., 82, p. 5131 (1985); and Houghten et al., Nature, 354, p. 84 (1991); and (iii) chemical synthesis on a "chip” described in Fodor et al., Science, 251, p. 767 (1991) and U.S. Patent 5,143,854 (1992).
  • the compounds may be screened in assays which have been developed for determining lead compounds as pharmaceutical agents.
  • the components of the library are screened in groups of multiple compounds. Therefore, once the library of compounds has been synthesized, there must be some method to deconvolute the results of screening such that individual active compounds can be identified. Based upon the disclosure herein, it will be clear to the skilled artisan that there are many methods for deconvolution of the combinatorial library. For example, if the compounds of the library are screened on a solid support, they may be physically segregated so that individual active compounds may be directly selected and identified.
  • the library may be deconvoluted in an iterative approach, which involves resynthesis of mixtures of decreasing complexity until a single compound is identified, or in a scanning approach, in which the various substituents on the aromatic carbocycle, are evaluated independently and the structure of active compounds are determined deductively.
  • iterative and scanning approaches to deconvolution of a combinatorial library of compounds see, for example, Houghten et al., Nature, 354, p. 84 (1991).
  • a representative binding assay is as follows. Other binding assays or functional assays that are known by, or that would be obvious to the skilled artisan, may be performed as well. Tissue containing the appropriate target receptor are homogenized, filtered through cheesecloth and centrifuged at 1500 x g for 10 minutes. The supernatant is decanted and the pellet is resuspended in an appropriate incubation buffer, e.g. 75 mM Tris.HCl, pH 7.4 containing 12.5 mM MgCl and 1.5 mM EDTA. Membranes equivalent to 100 g protein are incubated with 50 pmol radiolabeled receptor ligand and an appropriate amount of the test library mixture in a total volume of 5001 for 1 hr.
  • an appropriate incubation buffer e.g. 75 mM Tris.HCl, pH 7.4 containing 12.5 mM MgCl and 1.5 mM EDTA.
  • the binding reaction is terminated by dilution with the addition of 5 mL of cold incubation buffer and the bound tracer is separated from free by filtration on Whatman GF/C filter paper. The filter paper is washed several times with cold incubation buffer and then counted to determine the amount of bound ligand.
  • Specific binding is defined as the portion of radiolabeled receptor ligand binding which can be completed by a high concentration of unlabeled receptor ligand.
  • the presence of a competing ligand in the library test mixture is evidenced by a reduction in specific binding of the radiolabeled receptor ligand in the presence of the library test mixture.

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  • Chemical & Material Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)

Abstract

Cette invention se rapporte à de nouvelles résines polymères à base de silicone et à des bras de silane, à des procédés pour leur préparation et leur utilisation dans la synthèse de banques de composés devant être triés en tant qu'agents pharmaceutiques.
PCT/US1997/019450 1993-12-15 1997-10-24 Composes et procedes Ceased WO1998017695A1 (fr)

Priority Applications (3)

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JP10519697A JP2001502354A (ja) 1996-10-25 1997-10-24 化合物および方法
CA002269737A CA2269737A1 (fr) 1996-10-25 1997-10-24 Composes et procedes
EP97947288A EP0934345A4 (fr) 1996-10-25 1997-10-24 Composes et procedes

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GB939325621A GB9325621D0 (en) 1993-12-15 1993-12-15 Compounds and methods
US23562494A 1994-04-29 1994-04-29
PCT/US1994/014414 WO1995016712A1 (fr) 1993-12-15 1994-12-15 Composes et procedes
US08/663,148 US5773512A (en) 1994-12-15 1994-12-15 Compounds and methods
US73837996A 1996-10-25 1996-10-25
US08/738,379 1996-10-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6147159A (en) * 1998-09-30 2000-11-14 Argonaut Technologies Compositions for organic synthesis on solid phase and methods of using the same
US6416861B1 (en) 1999-02-16 2002-07-09 Northwestern University Organosilicon compounds and uses thereof
US7985882B1 (en) 2002-08-23 2011-07-26 Biotage Ab Compositions for reductive aminations utilizing supported tricarboxyborohydride reagents and methods of using the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4933391A (en) * 1989-02-16 1990-06-12 Eastman Kodak Company Functionalized polymers

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4933391A (en) * 1989-02-16 1990-06-12 Eastman Kodak Company Functionalized polymers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0934345A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6147159A (en) * 1998-09-30 2000-11-14 Argonaut Technologies Compositions for organic synthesis on solid phase and methods of using the same
US6416861B1 (en) 1999-02-16 2002-07-09 Northwestern University Organosilicon compounds and uses thereof
US7985882B1 (en) 2002-08-23 2011-07-26 Biotage Ab Compositions for reductive aminations utilizing supported tricarboxyborohydride reagents and methods of using the same

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