WO1995034813A1 - Resines pour synthese a l'etat solide - Google Patents

Resines pour synthese a l'etat solide Download PDF

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Publication number
WO1995034813A1
WO1995034813A1 PCT/US1995/007150 US9507150W WO9534813A1 WO 1995034813 A1 WO1995034813 A1 WO 1995034813A1 US 9507150 W US9507150 W US 9507150W WO 9534813 A1 WO9534813 A1 WO 9534813A1
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Prior art keywords
optionally substituted
optionally
resin
compound
substimted
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PCT/US1995/007150
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English (en)
Inventor
Dimitri E. Gaitanopoulos
Joseph Weinstock
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Smithkline Beecham Corporation
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Priority to JP8502297A priority Critical patent/JPH10502102A/ja
Priority to EP95922224A priority patent/EP0765477A4/fr
Publication of WO1995034813A1 publication Critical patent/WO1995034813A1/fr

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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00Chemical modification by after-treatment
    • C08F8/34Introducing sulfur atoms or sulfur-containing groups
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00Chemical modification by after-treatment
    • C08F8/30Introducing nitrogen atoms or nitrogen-containing groups
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00497Features relating to the solid phase supports

Definitions

  • This invention relates to novel polymer resins, methods for their preparation and their use in the synthesis of libraries of compounds to be screened as pharmaceutical agents.
  • the standard method for conducting a search is to screen a variety of chemical moieties, for example, naturally occurring compounds, specifically synthesized compounds or compounds which exist in synthetic libraries or data banks.
  • the biological activity of the chemical moieties is determined by employing the moieties in a suitable assay which has been designed to test for 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 or to exhibit activity at an enzyme.
  • the instant novel polymer resins are useful in the preparation of either a single compound or a library of molecularly diverse compounds.
  • the present resins are useful in preparing compounds through resin-bound synthesis, wherein (i) a resin-bound compound intermediate is formed by coupling the instant novel resin with a compound having at least one heteroatom, (ii) the compound portion of the resin-bound compound intermediate is derivatized and (iii) the resin-bound compound intermediate subjected to mild cleavage conditions so that the derivatized compound thus cleaved can have a -COOH, cyclic or acyclic amide, cyclic or acyclic sulfonamide, hydroxy, -NH or -SH group at the position of cleavage from the resin-bound compound intermediate.
  • the instant resins and linker moieties allow for efficient preparation and derivatization of compounds to be screened for pharmacological activity.
  • the compounds or libraries of compounds prepared according to this invention may be screened for activity as ligands (either as an agonist or as an antagonist of the receptor) of various receptor sites, including, but not Umited to, G-protei coupled receptor sites, and as enzyme inhibitors, in suitable assays for determining such activity.
  • the methods disclosed herein may be applied to obtain libraries of compounds that are enzyme inhibitors, receptor ligands or channel blockers.
  • This invention relates to novel polymer resins, methods for preparing said resins an intermediates used in the preparation of said resins.
  • the resin comprises the structure of formula (I):
  • X is O, S, or N-R, wherein R is hydrogen, alkyl, aryl or arylalkyl; P is a polymer support; Z is a bond, optionally substituted aryl or optionally substituted heteroaryl, wherein the optional substituents are alkyl, aryl, nitro, halogen or methoxy, or Z is -COO wherein R' is (C2 to C20) alkyl optionally having one or more intervening aryl groups; W i a leaving group that is readily displaceable by an oxygen, nitrogen or sulfur anion, including, but not limited to, chlorine, bromine, iodine, -OSO2R", wherein R" is alkyl, optionally substituted aryl, or perfluoroalkyl; R 1 , R 2 , R 3 and R 4 are, independently from one another, hydrogen, (C to C 4 ) alkyl, (C 3 to C 10 ) cyclic alkyl or optionally substituted aryl
  • One aspect of this invention relates to a novel linker of formula (IA) , '-Z-(CR 1 R 2 ) n -X-(C*R 3 R 4 W)", wherein moieties W, X, Z, R 1 , R 2 , R3, R4, an d n ⁇ defined as described above.
  • the novel resin of this invention is the entire compound of formula (I) which comprises the polymer support P, bound to the linker of formula (IA), as defined above.
  • Another aspect of this invention relates to methods for utilizing solid-phase chemistry to make a compound of formula (II).
  • a resin-bound compound intermediate is formed by coupling the resin of formula (I) with a compound to be derivatized. Additional synthetic chemistry is performed on the compound portion of the resin-bound compound intermediate, after which a derivatized resin-bound compound intermediate is formed and subjected to cleavage, which cleavage product is the derivatized compound of formula (II).
  • the resin of formul (I) comprises the following structure:
  • A is A ] , A2, A3, A4, A5, A6, A7, or Ag;
  • a j is -OR 5 , wherein R 5 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substitute heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl;
  • a 2 is -NR 6 R 7 , wherein R 6 and R 7 are the same or different and are hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substitute heterocyclic, optionally substitute
  • A3 is -SR 8 , wherein R 8 is optionally substituted alkyl, optionally substituted alkenyl optionally substituted cycloalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl;
  • A4 is R 9 -COO", wherein R 9 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl;
  • A5 is -NR 10 -C(O)R 11 , wherein R 10 and R 11 are the same or different and are optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substitute heterocyclic, optionally substituted heteroal
  • Ag is -NR 12 -SO2R 13 , wherein R 12 and R 13 are the same or different and are optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substitute heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl; or wherein R 12 and R 13 , together with the nitrogen and sulfone to which they are bound, form an optionally substituted, saturated or unsaturated, 4-, 5-, 6- or 7-membered ring;
  • a 7 is -O-(CH 2 ) m -C(O)R 14 , wherein m is an integer from 0 to 10; and R 14 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl; or wherein when m is an integer from 1 to 10, R 14 may form an optionally substituted, saturated or unsaturated, 4-, 5-, 6- or 7-membered ring together with one of the methylene carbons; and
  • a 8 is -O-(CH 2 ) r -A'-C(0)R 15 , wherein r is an integer from 0 to 10; A' is O, N, or S; and R 15 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl; or R 15 may form an optionally substituted, saturated or unsaturated, 4-, 5-, 6- or 7-membered ring together with one of the methylene carbons; provided that when A' is O or S, r
  • Yet another aspect of this invention relates to methods for preparing resin-bound compounds of formula (II). Still another aspect is this invention relates to methods for utilizing novel polymer resin intermediates for preparing the compounds of this invention. Yet further, this invention relates to methods for preparing a library of molecularly diverse compounds of formula (II), wherein said methods utilize the polymer resins of this invention in combinatorial synthesis methods. Still further, this invention relates to methods for screening the compounds synthesized by the methods of this invention as pharmaceutical agents.
  • 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 of formula (II) or a library of molecularly diverse compounds of formula (II), wherein the chemical reactions are performed on a compound to be derivatized, which compound is bound to a polymer support through a novel linkage, in particular, a linkage moiety comprised of any combination of any two of N, O or S heteroatoms which are separated by a carbon atom, wherein any one of the N, O or S heteroatoms is part of the compound to be derivatized.
  • the heteroatoms are separated by a methylene group.
  • compound intermediate or "resin-bound compound intermediate” are used herein at all occurrences to mean an intermediate formed by the displacement of leaving group W of formula (I) with a compound to be derivatized comprising at least one heteroatom, which heteroatom is bound directly to a carbon atom (C*) to form a carbon atom-heteroatom bond, wherein this carbon is directly bound to a second heteroatom (variable X), which second heteroatom joins the carbon atom (C*), through a moiety -Z-CCR ⁇ 2 ) ⁇ , to a polymer backbone, P.
  • the leaving group W is being displaced by an oxygen, nitrogen or sulfur heteroatom of the compound to be derivatized thus forming the carbon atom-heteroatom bond/linkage.
  • the carbon atom C* is depicted as such in order to indicate the position of attachment of the compound to be derivatized to the resin, thus forming the resin-bound compound intermediate.
  • the carbon atom C* may or may not be a chir al center.
  • polymeric resin polymer support or polymer backbone
  • polymer backbone polymer backbone
  • the terms may include a bead or other solid support such as pellets, disks, capillaries, hollow fibers, needles, solid fibers, pins, cellulose beads, pore-glass beads, silica gels, or latex beads, made of, for example, a crosslinked polystyrene resin, a polyethylene glycol-polystyrene based resin, a polypropylene glycol based resin, polyamide, polysulfamide, phenolic resins, polysaccharides 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.
  • a crosslinked polystyrene resin such as pellets, disks, capillaries, hollow fibers, needles, solid fibers, pins, cellulose beads, pore-glass beads, silica gels, or latex beads, made of, for example, a crosslinked polystyrene resin, a polyethylene glycol-polystyrene based resin, a polyprop
  • Preferred polymeric resins for use herein are cross-linked polystyrene based resins, polyethylene glycol-polystyrene based resins and polypropylene glycol based resins.
  • the desired compound (or library of compounds) is synthesized as part of a resin-bound compound intermediate, it may then be cleaved from the resin- bound compound intermediate (hereinafter referred to as a "soluble compound” or a "soluble library”).
  • the compounds made by the instant methods may also remain bound as a resin-bound compound intermediate which is used to perform the resin-bound synthesis (hereinafter referred to as "resin-bound compounds” or "resin-bound libraries").
  • additional synthetic chemistry is used herein at all occurrences to mean chemical reactions which are performed on the resin-bound compound intermediate in order to derivatize the compound portion of the intermediate.
  • the additional synthetic chemistry is performed after attachment of the compound to be derivatized to the resin of formula (I), and prior to cleavage of the derivatized compound from the polymeric resin. It will be understood that said chemical reactions are compatible with and non-reactive with the resin-bound compound intermediate and may be used to derivatize the compound bound to the resin in order to produce compounds of formula (II) which are the final products after cleavage of the resin-bound compound intermediate.
  • acetals, hemithioacetals, dithioacetals and aminoacetals may be used for preparing resin-bound compound intermediates from a resin of formula (I) and for cleaving the resin-bound compound intermediates in order to produce compounds of formula (II).
  • Suitable methods of cleaving the resin-bound organic compounds disclose herein from the linkage to the resin may be found in Protective Groups in Organic Svnthesis.2nd Edition, T. Greene and P.G.M. Wuts, pp. 17-24; 47-55; 149-150; 156-158; 279-282; 393-394; 413-416; 437-440; and 449-452 (1991).
  • 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 this invention is disclosed by Lerner et al., Pro c. Natl. Acad. Sci. U.SA., 91(5), pp. 1614- 1618 (1994).
  • alkyl is used herein at all occurrences to mean a straight or branched chain radical of 1 to 20 carbon atoms, unless the 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.
  • 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.
  • alkenyl is used herein at all occurrences to mean a straight or branched chain radical of 2 to 20 carbon atoms, unless the length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain, 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 to 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.
  • the unsaturated linkage i.e., the vinylene or acetylene linkage is preferably not directly attached to the nitrogen, oxygen or sulfur moieties.
  • 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 alkyl chain of the alkoxy moiety is 1 to 10 carbon atoms in length; more preferably 1 to 8 carbon atoms in length.
  • aryl is used herein at all occurrences to mean 5-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri- cyclic systems, including, but not limited to phenyl, naphthyl, and the like.
  • heteroatom is used herein at all occurrences to mean an oxygen atom, a sulfiir atom or a nitrogen atom. It will be recognized that when the heteroatom is nitrogen, it may form an NR a R ⁇ moiety, wherein R a and R 0 are, independently, 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, including, but not limited to, pyrrolidine, piperidine piperazine, morpholine, pyridine, and the like. It will be recognized that the saturated or unsaturated 5-, 6- or 7-membered ring may optionally have one or more additional heteroatoms in the ring.
  • heteroaryl is used herein at all occurrences to mean 5-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri- cyclic systems in which one or more of the rings comprise one or more heteroatoms.
  • Representative examples include, but are not limited to, pyrrole, thiophene, pyridine, pyrimidine, oxazole, quinoline, thiazole, isoquinoline, imidazole, benzimidazole, furanyl, 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, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, benzodiazepines, and the like.
  • arylalkyl preferably Ci to C10; more preferably Ci to Cg alkyl moiet as defined above, for example, benzyl or phenethyl, and the like.
  • heteroalkyl is used herein at all occurrences to mean a straight or branched chain radical of 1 to 20 carbon atoms (preferably Ci to C 1 0; more preferably Ci to Cg), unless the chain is limited thereto, wherein the chain comprises one or more heteroatoms.
  • Representative examples include, but are not limited to, Ai is OR 5 , wherein R 5 is heteroalkyl, and may be represented by the formula -CH2-S-CH2-NH2.
  • heteroatom of the heteroalkyl moiety when the heteroatom of the heteroalkyl moiety is oxygen or sulfur, it is not directly attached to the oxygen atom of Ai, A7 or Ag; or when the heteroatom of the heteroalkyl moiety is oxygen, it is not directly attached to the sulfur atom of A3.
  • alkylheteroalkyl is used herein at all occurrences to mean a straight or branched chain radical of 1 to 20 carbon atoms (preferably Ci to C10; more preferably Q to Cg), unless the length is limited thereto, wherein the chain comprises one or more heteroatoms.
  • Representative examples include, but are not limited to, methylethyl ether, ethyl propyl sulfide, isopropylthiobutane, dimethyl amine, diethylmethylamine, dimethyl sulfone, dimethyl sulfoxide, and the like.
  • halogen is used herein at all occurrences to mean chloro, fluoro, iodo and bromo.
  • cyclic amide is used herein at all occurrences to mean that the nitrogen and the carbonyl of an amide moiety, together with the R groups to which they are attached, form a saturated or unsaturated 4-, 5-, 6- or 7-membered ring. It will be recognized that the saturated or unsaturated 4-, 5-, 6- or 7-membered ring may optionally have one or more additional heteroatoms in the ring.
  • cyclic sulfonamide is used herein at all occurrences to mean that the nitrogen and the sulfone of a sulfonamide, together with the R groups to which they are attached, form a saturated or unsaturated 4-, 5-, 6- or 7-membered ring. It will be recognized that the saturated or unsaturated 4-, 5-, 6- or 7-membered ring may optionally have one or more additional heteroatoms in the ring.
  • R' is hydrogen, (Cj - C 6 ) alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, including, but not limited to, phenyl, benzyl, pyridyl, and the like.
  • R' is hydrogen, (Cj - C 6 ) alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, including, but not limited to, phenyl, benzyl, pyridyl, and the like.
  • R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 or R 15 is alkyl, aryl, cycloalkyl, arylalkyl, alkylheteroalkyl, heteroarylalkyl, -OR'", -SR'", -N(R"') 2 , -NHC(O)R"', SO 2 N(R"')2. -C0 2 R"' or -CON(R"') 2 .
  • alkyl, aryl, cycloalkyl, arylalkyl, alkylheteroalkyl, heteroarylalkyl moiety or the moiety R'" may be optionally substituted with one to five various optionally substituted functional groups including alkyl, alkenyl, aryl, cycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclic or heterocyclicalkyl.
  • combinatorial library or "library of molecularly diverse compounds” are used herein at all occurrences to mean a collection of diverse compounds of formula (II) which have been synthesized simultaneously starting from a core compound structure.
  • the library contains a discrete number of independently variable substituents, functional groups or structural elements. Further, 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 may be present in the library.
  • a compound to be derivatized into a compound of formula (II) contains three independently variable substituents, labeled X, Y and Z, and if X is taken from m different chemical moieties, Y from n different chemical moieties and Z from p different chemical moieties (wherein m, n and/? are integers which define the size of the library, and which range between 1 and 100,000; between 1 and 10,000; between 1 and 1,000; between 1 and 100; and between 1 and 50), then the library may contain m x n x p different chemical compounds and all possible combinations of X, Y and Z could be present on the compounds 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.
  • 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, IL-8R receptors, dopamine receptors, endothelin receptors, histamine receptors, calcitonin receptors, angiotensin receptors and the like.
  • optionally substituted compounds of formula (II) can be prepared by resin-bound synthesis, wherein said compound, after cleavage from a novel polymeric resin-bound compound intermediate, has a -COOH, cyclic or acyclic amide, cyclic or acyclic sulfonamide, hydroxy, -NH or -SH group on the carbon where it was bound to the resin.
  • the compound of formula (II) is as follows:
  • Aj is -OR 5 , wherein R 5 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl.
  • a preferred embodiment of this invention comprises a compound of formula (II), wherein A is Ai, i.e., -OR 5 , wherein R 5 is optionally substituted aryl, and one of the optional substituents is CON(R'")2 wherein at least one of the R'" moieties attached to the amide nitrogen is optionally substituted heterocyclicalkyl, including, but not limited to, N-ethyl pyrrolidine.
  • Another preferred embodiment of this invention comprises a compound of formula (II), wherein A is Ai, i.e., -OR 5 , wherein R 5 is optionally substituted cycloalkyl, preferably optionally substituted 1,2,3,4 -tetrahydronaphthyl, wherein one the optional substituents on the cycloalkyl ring is - N(R'")2 and wherein R"', independently, is C ⁇ to Cg alkyl and optionally substituted C j to Cg alkyl, wherein the optional substituent on the alkyl moiety is aryl, preferably phenyl.
  • A2 is -NR 6 R 7 , wherein R 6 and R 7 are the same or different and are hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substitute heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl, provided that R 6 and R 7 cannot both be hydrogen; or wherein R 6 and R 7 , together with the nitrogen to which they are bound, form an optionally substituted, saturated or unsaturated, 4-, 5-, 6- or 7-membered ring.
  • A3 is -SR 8 , wherein R 8 is optionally substituted alkyl, optionally substituted alkenyl optionally substituted cycloalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl.
  • R 8 is optionally substituted alkyl, optionally substituted alkenyl optionally substituted cycloalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl.
  • a 4 is R 9 -COO", wherein R 9 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl.
  • a preferred embodiment of this invention comprises a compound of formula (II) wherein A is A4, i.e., R 9 -COO " , wherein R 9 is optionally substituted aryl, and one of the optional substituents is heteroarylalkyl which is further substituted by a (Ci to Cg) alkyl and an optionally substituted (C2 to Cg) alkenyl moiety, wherein the optional substituents on the alkenyl moiety are -CO2R'", wherein R'" is (Cj to Cg) alkyl; and a heteroaryl moiety, for example, thiophene.
  • a 5 is -NR 10 -C(O)R ⁇ , wherein R 10 and R 11 are the same or different and are optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substitute heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl; or wherein R 10 and R 11 , together with the nitrogen and carbonyl to which they are bound, form an optionally substituted, saturated or unsaturated, 4-, 5-, 6- or 7-membered ring.
  • Ag is -NR 12 -SO2R 1 , wherein R 12 and R 13 are the same or different and are optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substitute heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl; or wherein R 12 and R 13 , together with the nitrogen and sulfone to which they are bound, form an optionally substituted, saturated or unsaturated, 4-, 5-, 6- or 7-membered ring.
  • a 7 is -O-(CH 2 ) m -C(O)R 14 , wherein m is an integer from 0 to 10; and R 14 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl; or wherein when m is an integer from 1 to 10, R 14 may form an optionally substituted, saturated or unsaturated, 4-, 5-, 6- or 7-membered ring together with one of the methylene carbons.
  • a 8 is -0-(CH 2 ) r -A'-C(0)R 15 , wherein r is an integer from 0 to 10; A' is O, N, or S; and R 15 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, optionally substituted heteroalkyl, optionally substituted heterocyclicalkyl, or optionally substituted alkylheteroalkyl; or R 15 may form an optionally substituted, saturated or unsaturated, 4-, 5-, 6- or 7-membered ring together with one of the methylene carbons; provided that when A' is O or S, r must be an integer from 1 to 10.
  • the instant polymer resins and linkage moieties are particularly useful in preparing compounds of formula (II) by resin-bound synthesis.
  • the instant resin may be coupled with a compound (or a plurality of compounds) in order to form a resin-bound compound intermediate (or a plurality of resin- bound compound intermediates). Because of the structure of the resin of formula (I), cleavage of the carbon atom-heteroatom bond of the resin-bound compound intermediate to yield a compound of formula (II) which has a -COOH, cyclic or acyclic amide, cyclic or acyclic sulfonamide, hydroxy, -NH or -SH group at the cleavage position, is synthetically possible.
  • each of these groups offers its own unique pharmacological properties.
  • the instant resins and linkage moieties allow a variety of chemical reactions, or additional synthetic chemistry, to be conducted on compounds attached thereto, without cleavage of the compound from the resin until the attached compounds are fully derivatized.
  • the attached compounds may be cleaved from the resin by cleaving the carbon atom-heteroatom bond of the resin-bound compound intermediate, for example, using mild acid conditions, in order to produce compounds of formula (II).
  • polymer resins of this invention also allow the successful preparation of libraries of molecularly diverse compounds which, upon cleavage from the resin, have a -COOH, cyclic or acyclic amide, cyclic or acyclic sulfonamide, hydroxy, -NH or -SH group at the cleavage position.
  • the compounds 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 of formula (II by resin-bound synthesis, said method comprising the steps of: (i) attaching a compound comprising at least one heteroatom to a polymeric resin of formula (I):
  • X is O, S, or N-R, wherein R is hydrogen, alkyl, aryl or arylalkyl; P is a polymer support; Z is a bond, optionally substituted aryl or optionally substituted heteroaryl, wherein the optional substituents are alkyl, aryl, nitro, halogen or methoxy, or Z is -COOR', wherein R' is (C2 to C20) alkyl optionally having one or more intervening aryl groups; W is a leaving group that is readily displaceable by an oxygen, nitrogen or sulfur anion, including, but not limited to, chlorine, bromine, iodine, -OSO 2 R", wherein R" is alkyl, optionally substituted aryl, or perfluoroalkyl; R 1 , R 2 , R 3 and R 4 are, independently from one another, hydrogen, (C j to C 4 ) alkyl, (C 3 to CJ Q ) cyclic alkyl or optionally
  • one suitable method according to this invention for attaching the compound to be derivatized to a resin of formula (I), is by an S N 2 displacement of moiety W with the heteroatom used to link the compound to the resin.
  • 3-Scheme 1 is attached to the resin of formula (I) wherein P is a polystyrene backbone; Z is phenyl; X is O; W is chlorine; and R 1 , R 2 , R 3 and R 4 are each hydrogen, i.e., 2-Scheme 1.
  • the compound to be derivatized in order to produce a compound of formula (II) is bound to a polymer resin through a carbon-heteroatom bond to give a resin-bound compound intermediate.
  • the compound to be derivatized will comprise at least one heteroatom which is to be linked to the polymer support through a carbon atom of a linker group (i.e., C*).
  • the compound is bound to the polymer support through a linker group of formula (IA) comprising the following moiety - ,, -Z-(CR 1 R 2 ) n -X-(C*R 3 R 4 W)", wherein Z is defined as an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein the optional substituents are alkyl, aryl, nitro, halogen or methoxy, or Z is -COOR', wherein R' is (C2 to C20) lkyl optionally having one or more intervening aryl groups; X is a heteroatom; W is a leaving group that is readily displaceable by an oxygen, nitrogen or sulfur anion, including, but not limited to, chlorine, bromine, iodine, -OSO2R", wherein R" is alkyl, optionally substituted aryl, or perfluoroalkyl; R 1 , R 2 , R 3 and R 4 are, independently from one another, hydrogen
  • Z is preferably an optionally substituted aryl moiety, more preferably, an optionally substituted phenyl moiety.
  • Preferred optional substituents on moiety Z are nitro, halogen and/or methoxy.
  • the heteroatom of the compound in order for the compound to be linked to the resin, the heteroatom of the compound must displace moiety W of the linker, so that a resin- bound compound intermediate is produced.
  • conventional procedures may be used in order to attach the linker to the polymer support P, so that a compound of formula (I) is produced.
  • the linker may be reacted with a chloromethyl cross-linked divinylbenzene polystyrene resin.
  • Preferred linker groups of formula (IA), i.e., Z-(C-R 1 R 2 ) n -X-(C*-R 3 R 4 W), for use in the methods disclosed herein include, but are not limited to, the following linker groups: -Ph-CH 2 -O-CH 2 ⁇ -, wherein Z is phenyl ("Ph"); X is O; and R 1 , R 2 , R 3 and R 4 are each hydrogen; W is CI and n is 1; or -Ph-CH2-S-CH 2 C1-, wherein Z is phenyl; X is S; and R 1 , R 2 , R 3 and R 4 are each hydrogen; W is CI and n is 1.
  • the polymer support is polystyrene-based, e.g., a chloromethylpolystyrene resin known as the Merrifield resin
  • the optionally substituted phenyl moiety that is Z is also pan of the polymer resin.
  • the polymer support is then further functionalized in order to couple the remaining portion of the linker to the polymer support using methods such as those shown in Schemes 1 and 2, below.
  • cleavage may be accomplished by treating the resin-bound compound intermediate with a strong protic acid.
  • the acidic cleavage conditions include, but are not limited to, treatment with trifluoroacetic acid ("TFA”), hydrofluoric acid (“HF”), hydrochloric acid (“HCl”), hydrobromic acid (“HBr”), pyridinium hydrofluoride, sulfuric acid (“H2SO4"), trifluormethanesulfonic acid (commonly referred to as triflic acid), boron trifluoride (“BF3”), methanesulfonic acid or mixtures thereof.
  • Cleavage methods may be carried out in solution or by applying the acid to the resin-bound compound intermediate(s), neat Preferred cleavage conditions utilize 25% TFA. Further, an addition of 1% veratrol or ethanedithiol to the cleavage mixture may be used to prevent undesirable side reactions of the liberated compound of formula (II).
  • cleavage of the carbon-heteroatom bond for linker groups with sulfur heteroatoms may be accomplished with silver or mercury salts using conditions known to one of ordinary skill in the art.
  • A is A 3 , i.e.,-SR 8
  • the end-product compound of formula (II) may be desulfurized using conditions known in the art, such as treatment with Raney nickel, in order to produce a compound which contains a hydrogen at the position where the compound was attached to the resin.
  • the invention is in a method for preparing a compound of formula (II) which is resin-bound, said process comprising the steps of:
  • the resin-bound compound intermediate may be derivatized immediately by modifying the compound with additional synthetic chemistry or stored for future derivatization of the resin-bound compound. If the compound intermediate is derivatized, the resulting derivatized resin-bound compound intermediate is a precursor to the compound of formula (II), wherein after cleavage, the compound is a compound of formula (II), i.e., it has a -COOH, cyclic or acyclic amide, cyclic or acyclic sulfonamide, hydroxy, -NH or -SH group on the carbon where it was bound to a polymeric resin.
  • the resin-bound compounds prepared according to this invention may be screened as pharmaceutical agents in the assays described below.
  • this invention is in a method for preparing a library of molecularly diverse compounds, each comprising at least one heteroatom, by resin-bound synthesis, said method comprising the steps of:
  • 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 are prepared on the polymer resins using the linkers described herein. For example, a plurality of compounds comprising at least one heteroatom, are each attached to an individual polymer resin support of formula (I) through a carbon-heteroatom bond to give a plurality of resin-bound compound intermediates.
  • the plurality of resin-bound compound intermediates may be reacted with one or more reagents, in one reaction vessel.
  • aliquots of the resin-bound compound intermediates may be reacted with one or more reagents; each one of which will modify the compound attached to the resin as a resin-bound compound intermediate; and then the resultant product in each separate aliquot is mixed together with the products formed in the other aliquots to form the library of derivatized compounds.
  • This first modified/derivatized library may then be further derivatized by repeating the process of dividing and recombining the derivatized resin- bound compound intermediates formed by the additional synthetic chemistry.
  • each polymer support unit for example, a bead, bears a single derivatized compound species created by the additional synthetic chemistry performed on the resin-bound compound intermediate.
  • the steps of optionally dividing and recombining the resin-bound compound intermediates into portions are for purposes of varying the derivatization on the compounds which are generated by the combinatorial synthesis. See, for example, Moss et al., Ann. Rep. Med. Chem., 28, p. 315 (1993) for the split-synthesis method of preparing peptide libraries of compounds, variations on which may be used to prepare the non-peptide libraries of this invention. It will also be obvious to the skilled artisan that the resin-bound compound 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. Therefore, it will be obvious to the skilled artisan that the steps of dividing the portions, performing additional synthetic chemistry and recombining the portions, may each be carried out more than once.
  • the steps of optionally dividing and recombining the resin- bound compound intermediates into portions are for purposes of varying the derivatization, depending upon the type of diversity required for the hbrary of end-product compounds being prepared.
  • the compounds can be separated and characterized by conventional analytical techniques known to the skilled artisan, for example infrared spectroscopy or mass spectroscopy.
  • the compounds may be characterized while remaining resin-bound or they can be cleaved from the resin using the conditions described above, and then analyzed.
  • a portion of resin-bound compound intermediates may be cleaved so that only a portion of the compound members are cleaved from the resin, characterized and analyzed, while leaving the remaining portion of the compound members of the library bound to the resin as derivatized resin-bound compound intermediates.
  • this library is considered to be a "partially cleaved" library of derivatized compounds, i.e., the library comprises (a) derivatized compounds which are cleaved from the resin and (b) derivatized compounds which remain resin-bound.
  • the library comprises (a) derivatized compounds which are cleaved from the resin and (b) derivatized compounds which remain resin-bound.
  • a chloromethoxymethylpolystyrene resin of the formula (I) wherein P is polystyrene; Z is phenyl; X is O; W is chlorine; and R 1 , R 2 , R 3 and R 4 are each hydrogen (see 2- Scheme 1. is prepared as shown in Scheme 1 by reaction of commercially available hydroxymethylpolystyrene resin (1 -Scheme 1. with, e.g., trioxane and hydrochloric acid in a suitable nonprotonic solvent. Further reaction with the anion of a phenol, such as 2z Scheme 1. provides resin-bound compound intermediates such as 4-Scheme 1. These may be further derivatized by additional synthetic chemistry to form further compounds of interest which are also bound to the resin. The derivatized resin-bound compounds may be liberated from the resin to produce compounds of formula (II) by, e.g., treatment with an acid such as TFA.
  • Scheme 3 shows the attachment of several dopaminergics to a resin of formula (I), wherein P is polystyrene; Z is phenyl; X is S; W is chlorine; and R 1 , R 2 , R 3 and R 4 are each hydrogen (see 1 -Scheme 3). via thioacetal linkages.
  • these compounds are readily liberated from the resin by treatment with acid to give a compound of formula (II).
  • reaction of the phenol 2-Scheme 3 with a base, e.g., CS2CO3 to form its anion followed by reaction with chloromethylthiomethylpolystyrene (1-Scheme 3) gave the resin bound compound 2r Scheme 3.
  • Scheme 5 shows the attachment of a thiol to a resin via a dithioacetal and a thioacetal linkages.
  • the cesium mercaptide was reacted with the resin l Scheme 3 to give 2-Scheme 5 wherein the compound, 1-Scheme 5. is bound to the resin (j Scheme 3 " ) by a dithioacetal linkage.
  • the mercaptide of 1-Scheme 5 was reacted with the chloromethoxymethyl resin, 2-Scheme 1. to give 3-Scheme 5 wherein the compound, 1-Scheme 5. is bound to the resin (2-Scheme 1. by a thioacetal linkage.
  • the thioacetal linkage was readily cleaved by acid, but the dithioacetal linkage required prolonged treatment with strong acid or metal ions such as silver or mercury for cleavage.
  • This differentiation may be useful in that the compound of interest may be attached via the thioacetal linker while a tag for recording the chemical history of the bead could be attached via the dithioacetal linker.
  • the compound could be released first for biological assays, and the tags of the active beads could be read later to identify the active compound. See, for example, a description of synthesis using tags in WO 9408051, published April 14, 1994, the relevant subject matter of which is incorporated herein by reference.
  • liberated compound of formula (II) is a thiol
  • desulfurization after release from the resin for example with Raney nickel, gives the compound with a hydrogen at the position which was attached to the resin.
  • Example 1 Preparation of chlorornethoxvmethvlpolvstvrene resin (2-Scheme 1.
  • Example 4 Preparation of the chloromethylthiomethylpolystyrene resin (4-Scheme 2) (a. Thiouroniummethylpolvstyrene hvdrochloride (2-Scheme 2. A mixture of Merrifield's peptide resin (available from Aldrich; 2% crosslinked, 1.015 mM Cl g) (5.00 g, 5.075 mM) and thiourea (1.55 g, 20.362 mM) in DMF (50 mL) were gently stirred at ambient temperature for 48 hr.
  • 4-Scheme 2 a. Thiouroniummethylpolvstyrene hvdrochloride (2-Scheme 2.
  • a mixture of Merrifield's peptide resin available from Aldrich; 2% crosslinked, 1.015 mM Cl g) (5.00 g, 5.075 mM) and thiourea (1.55 g, 20.362 mM) in DMF (50 mL) were gently stir
  • Example 5 Preparation of ethyl 4-phenoxythiomethylmethylpolystyrenebenzoate resin (5- Scheme 21 A mixture of ethyl 4-hydroxybenzoate (0.0532 g, 0.3024 mM) and cesium carbon ⁇ ate (0.1310 g, 0.4022 nM) in DMF (5 mL) was stirred at ambient temperature for 4 hr. Chloromethylthiomethylpolystyrene resin (4-Scheme 21 (0.8066 mM Cl/g) (0.1250 g, 0.1008 mM) was added in one portion and stirred at ambient temperature for 18 hr.
  • the resin-intermediate was collected on a coarse fritted glass filter, washed successively with 3x30 mL portions of DMF, 1 :1 DMF/H 2 O, water, DMF, THF, methylene chloride, and methanol, and then air-dried to provide 0.1000 g (72%) of product.
  • IR (KBr) 1700 cm" 1 (C O).
  • a small sample of 5-Scheme 2 was treated with 25% TFA/methylene chloride at ambient temperature for 5 min.
  • TLC sica gel, 10% methanol/chloroform
  • Example 6 Preparation of 6-(methoxythiomethylpolvstyrene1-S(-1-eticlopride resin
  • S(-)-eticlopride hydrochloride S(-)-3-chloro-5-ethyl-N-[(l-ethyl-2- pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride
  • cesium carbonate 0.64477 g, 1.9880 mM
  • Example 7 Preparation of ester of (E1- ⁇ -rr2-butvl-l-r4-carboxvphenvl1methvn-l-H- imidazol-5-vl1methvlene-2-thiophenepropanoic acid ethvl ester and hvdroxymethylthiomethyl-polystyrene resin
  • Example 3 The procedure of Example 3 was used except that the esterification was carried out using DMF as the solvent and the reaction was heated at 45°C for 48 hr. The resin product was obtained in 96% yield.
  • This resin also cleaved to liberate the starting acid when exposed to vapors of methylene chloride, ethanedithiol, and TFA.
  • linkers and polymer resins of this invention may be used in a variety of combinatorial methods for synthesizing and identifying 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
  • 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 compound, 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) and Still et al., WO 94/08051, published April 14, 1994.
  • 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 performe 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 MgCl2 and 1.5 mM EDTA.
  • an appropriate incubation buffer e.g. 75 mM TriS ' HCl, pH 7.4 containing 12.5 mM MgCl2 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. at 37°C.
  • 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 competed with by a high concentration of unlabeled receptor ligand.
  • the presence of a competing ligand in the Ubrary test mixture is evidenced by a reduction in specific binding of the radiolabeled receptor hgand in the presence of the library test mixture.

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Abstract

La présente invention concerne de nouvelles résines polymères, des procédés pour leur préparation et leur utilisation dans la synthèse de composés ou de bibliothèques de composés destinés à être criblés comme agents pharmaceutiques.
PCT/US1995/007150 1994-06-14 1995-06-05 Resines pour synthese a l'etat solide WO1995034813A1 (fr)

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WO1999007751A1 (fr) * 1997-08-05 1999-02-18 Akzo Nobel N.V. Polymere modifie de sulfone de vinyle
WO1999009073A1 (fr) * 1997-08-13 1999-02-25 Akzo Nobel N.V. Supports de phase solide
WO1999028356A1 (fr) * 1997-11-28 1999-06-10 Active Materials Inc. Polymeres fonctionnels portant des derives oxacides non metalliques sur des bras dimethylene
WO1999032508A1 (fr) * 1997-12-22 1999-07-01 Avecia Limited Preparation de composites polymeres solides
WO2000026262A2 (fr) * 1998-11-05 2000-05-11 Mitokor Substrats polymeres fonctionnalises destines a lier des fractions moleculaires
WO2000053578A1 (fr) * 1999-03-11 2000-09-14 Kuraray Co., Ltd. Derives de la vitamine d et leur procede de preparation
WO2001090203A1 (fr) * 2000-05-25 2001-11-29 Institut Francais De Recherche Pour L'exploitation De Mer (Ifremer) Copolymeres statistiques insolubles presentant une affinite specifique envers un protiste donne, leurs utilisations et leur procede de selection
FR2826454A1 (fr) * 2001-06-26 2002-12-27 Bio Merieux Cartes d'analyse
US9371284B2 (en) 2007-06-04 2016-06-21 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses
US9872846B2 (en) 2006-07-09 2018-01-23 Techfields Pharma Co., Ltd. High penetration compositions and uses thereof
US11135153B2 (en) 2006-07-09 2021-10-05 Techfields Pharma Co., Ltd. High penetration composition and uses thereof
US11541029B2 (en) 2008-12-04 2023-01-03 Techfields Pharma Co., Ltd. High penetration compositions and their applications
US11813256B2 (en) 2012-05-16 2023-11-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical compositon thereof for treatment of pulmonary conditions

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WO2008007171A1 (fr) * 2006-07-09 2008-01-17 Techfields Biochem Co. Ltd Promédicaments hydrosolubles à charge positive de l'aspirine

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999007751A1 (fr) * 1997-08-05 1999-02-18 Akzo Nobel N.V. Polymere modifie de sulfone de vinyle
WO1999009073A1 (fr) * 1997-08-13 1999-02-25 Akzo Nobel N.V. Supports de phase solide
US6486354B1 (en) 1997-08-13 2002-11-26 Akzo Nobel N.V. Solid phase supports
US6448344B1 (en) 1997-11-28 2002-09-10 Active Materials, Inc. Functional polymers bearing non-metal oxyacid derivatives on dimethylene spaces
WO1999028356A1 (fr) * 1997-11-28 1999-06-10 Active Materials Inc. Polymeres fonctionnels portant des derives oxacides non metalliques sur des bras dimethylene
WO1999032508A1 (fr) * 1997-12-22 1999-07-01 Avecia Limited Preparation de composites polymeres solides
WO2000026262A2 (fr) * 1998-11-05 2000-05-11 Mitokor Substrats polymeres fonctionnalises destines a lier des fractions moleculaires
WO2000026262A3 (fr) * 1998-11-05 2000-07-27 Chiron Corp Substrats polymeres fonctionnalises destines a lier des fractions moleculaires
WO2000053578A1 (fr) * 1999-03-11 2000-09-14 Kuraray Co., Ltd. Derives de la vitamine d et leur procede de preparation
FR2809405A1 (fr) * 2000-05-25 2001-11-30 Ifremer Copolymeres statistiques insolubles presentant une affinite specifique envers un protiste donne, leurs utilisations et leur procede de selection
WO2001090203A1 (fr) * 2000-05-25 2001-11-29 Institut Francais De Recherche Pour L'exploitation De Mer (Ifremer) Copolymeres statistiques insolubles presentant une affinite specifique envers un protiste donne, leurs utilisations et leur procede de selection
FR2826454A1 (fr) * 2001-06-26 2002-12-27 Bio Merieux Cartes d'analyse
WO2003000748A1 (fr) * 2001-06-26 2003-01-03 bioMérieux Cartes d'analyse
US9872846B2 (en) 2006-07-09 2018-01-23 Techfields Pharma Co., Ltd. High penetration compositions and uses thereof
US11135153B2 (en) 2006-07-09 2021-10-05 Techfields Pharma Co., Ltd. High penetration composition and uses thereof
US9371284B2 (en) 2007-06-04 2016-06-21 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses
US10233198B2 (en) 2007-06-04 2019-03-19 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAs with very high skin and membranes penetration rates and their new medicinal uses
US11541029B2 (en) 2008-12-04 2023-01-03 Techfields Pharma Co., Ltd. High penetration compositions and their applications
US11813256B2 (en) 2012-05-16 2023-11-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical compositon thereof for treatment of pulmonary conditions

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EP0765477A4 (fr) 2004-11-17
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