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WO1998037078A1 - CHIMIE EN PHASE SOLIDE ET SYNTHESE COMBINATOIRE DE THIOPHENES SUBSTITUES ET DE SERIES DE CES thiofènes SUBSTITUES - Google Patents

CHIMIE EN PHASE SOLIDE ET SYNTHESE COMBINATOIRE DE THIOPHENES SUBSTITUES ET DE SERIES DE CES thiofènes SUBSTITUES Download PDF

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WO1998037078A1
WO1998037078A1 PCT/DK1998/000035 DK9800035W WO9837078A1 WO 1998037078 A1 WO1998037078 A1 WO 1998037078A1 DK 9800035 W DK9800035 W DK 9800035W WO 9837078 A1 WO9837078 A1 WO 9837078A1
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alkyl
substrate
halogen
aryl
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Florencio Zaragoza DÖRWALD
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Novo Nordisk AS
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Novo Nordisk AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring

Definitions

  • the present invention relates to the field of solid phase chemistry. More specifically, the invention provides a method for solid phase and combinatorial synthesis of organic compounds, and most particularly, a therapeutically important class of compounds, namely diversely substituted thiophenes.
  • the synthetic sequence disclosed in this invention is a variant of related thiophene syntheses (ref. 11-16), adapted and optimized for its realization on a solid support.
  • Linker a molecule with at least two reactive sites, which permit its covalent attachment to other molecules or to a substrate. Either the bond of the linker to the substrate or the bond of the linker to other molecules attached to it or the linker itself must be cleavable upon selective exposure to an activator such as a selected chemical activator or other specific conditions, e.g. by treatment with a strong acid or by exposure to electromagnetic radiation or by metal catalysis.
  • an activator such as a selected chemical activator or other specific conditions, e.g. by treatment with a strong acid or by exposure to electromagnetic radiation or by metal catalysis.
  • Protecting group A material which is chemically bound to a molecule or a substrate and which may be removed upon selective exposure to an activator such as a selected chemical activator or other specific conditions, e.g. by treatment with a strong acid or by exposure to electromagnetic radiation or by metal catalysis.
  • Combinatorial synthesis an ordered strategy for parallel synthesis of arrays of single compounds or mixtures, by sequential addition of reagents.
  • Receptor A material that has an affinity for a given ligand.
  • Receptors may be naturally- occurring or synthetic molecules or aggregates of molecules. Also, they can be employed in their unaltered state or as aggregates with other species. Receptors may be attached, covalently or non-covalently, to a binding material or a substrate, either directly or via a linking substance.
  • the invention provides a rapid approach for combinatorial synthesis and screening of arrays of thiophene derivatives as a therapeutically important class of compounds. It provides a solid phase synthesis of these derivatives, which eliminates purification and isolation steps and thus highly increases synthesis efficiency.
  • This patent disclosure also describes an important extension of solid phase synthesis methods to nonoligomeric organic compounds.
  • the application of the present invention is the rapid preparation and screening, preferably in parallel and simultaneous fashion, of a large number of differently substituted thiophenes of the general formula I
  • A is a electron-withdrawing group of formula
  • Y is an amino group or an aryl group, such as phenyl
  • E is a group of formula
  • R is alkylene optionally substituted with hydrogen, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cyano, hydroxy, dialkylamino, arylalkylamino, diarylamino or halogen, such as methylene, 1 ,2-ethylene, 1 ,4-butylene, or 1 ,3-pentylene,
  • R is hydrogen, alkyl optionally substituted with hydroxy, halogen, cyano, alkoxy, aryloxy, dialkylamino, arylalkylamino or diarylamino; or aralkyi, n and m are integers between 0 and 15, preferentially between 0 and 3;
  • R is hydrogen, alkyl, alkyl substituted with hydroxy, alkoxy, aryloxy, alkylthio, arylhio, dialkylamino, arylalkylamino or diarylamino; aralkyi, aryl, aryl substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl; such as benzyl
  • R is hydrogen, alkyl optionally substituted with hydroxy, halogen, cyano, alkoxy, aryloxy, dialkylamino, arylalkylamino or diarylamino; or aralkyi; such as hydrogen
  • 1 4 5 6 1 1 R may be covalently linked to E, R , R and/or R , in which case -R -E- or -R -
  • R - represents low alkylene, preferentially methylene, ethylene or propylene, unsubstituted or substituted with alkyl, hydroxy, alkoxycarbonyl, alkoxy or dialkylamino; -
  • R -R - represents ethylene or propylene, unsubstituted or substituted with alkyl, hydroxy, alkoxy or dialkylamino; and/or -R -R - represents methylene, propylene or butylene unsubstituted or substituted with alkyl, hydroxy, alkoxycarbonyl, alkoxy or dialkylamino;
  • R is alkyl optionally substituted with aryl, heteroaryl, alkoxy, aryloxy, cyano, dialkylamino, arylalkylamino, diarylamino or halogen; aryl optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl; such as 4-chlorophenyl, methyl or isopropyl, and R 2 is cyano, -CO-R', -CO 2 R', -CONHR', -CONR'R", or
  • Su is a substrate, such as 1% crosslinked polystyrene beads
  • L is a chemical bond or a linker, such as 4-hydroxybenzylalcohol (Wang linker),
  • A is a electron-withdrawing group of formula
  • Y is an amino group or an aryl group, such as phenyl
  • E' is a chemical bond or a group of formula
  • G' may be -O-, -NH-, -NH-peptide-O- or -NH-peptide-NH-
  • R is alkylene optionally substituted with hydrogen, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cyano, hydroxy, dialkylamino, arylalkylamino, diarylamino or halogen, such as methylene, 1 ,2-ethylene, 1 ,4-butylene, or 1 ,3-pentylene,
  • R is hydrogen, alkyl optionally substituted with hydroxy, halogen, cyano, alkoxy, aryloxy, dialkylamino, arylalkylamino or diarylamino; or aralkyi; n and m are integers between 0 and 15, preferentially 0 and 3;
  • R is hydrogen, alkyl, alkyl substituted with hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aralkyi, aryl, aryl substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl; such as benzyl,
  • R is hydrogen, alkyl optionally substituted with hydroxy, halogen, cyano, alkoxy, aryloxy, dialkylamino, arylalkylamino or diarylamino; or aralkyi, such as hydrogen,
  • R - represents low alkylene, preferentially methylene, ethylene or propylene, unsubstituted or substituted with alkyl, hydroxy, alkoxycarbonyl, alkoxy or dialkylamino; -
  • R -R - represents ethylene or propylene, unsubstituted or substituted with alkyl, hydroxy,
  • R is alkyl optionally substituted with aryl, heteroaryl, alkoxy, aryloxy, cyano, dialkylamino, arylalkylamino, diarylamino or halogen; aryl optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl; such as 4-chlorophenyl, methyl or isopropyi; and
  • R 2 is cyano, -CO-R', -CO 2 R', -CONHR', -CONR'R", or -C(OH)-R ⁇ R' being alkyl, alkyl substituted with halogen, aryl, aryl substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl or heteroaryl; and R" being alkyl or substituted or unsubstituted aryl; such as benzoyi, 2,4-dichlorobenzoyl, 4-chloro-3-methylbenzoyl, 4-phenylbenzoyl, 2- naphthoyl or 4-(methylsulfonylamino)benzoyl; and
  • High throughput screening generally incorporates automation and robotics, thus making it possible to screen thousands of compounds in one or more bioassays in a short period of time. This technique has created the need for an automated production of large numbers of different compounds for being screened.
  • a robotic, fully automated system for the production and screening of highly diverse compounds as potential lead-candidates will dramatically speed up the discovery and optimization of new leads for all types of human diseases.
  • Linear syntheses involve the sequential reactions of several separate reactants in order to obtain the final product.
  • Linear syntheses require the isolation, purification and characterization by spectroscopic and other analytical tools of the intermediate reaction products.
  • Such a linear synthesis is therefore a very time consuming process, which requires a high skill in the synthetic organic chemical art. Since this traditional way of producing compounds is too inefficient for fully exploiting the screening-potential of presently available systems for high throughput screening, synthetic methodology is required, which permits the automated synthesis of large numbers of different compounds.
  • Thiophenes are important core structures for biologically active compounds. (S. Gronowitz, Adv. Heterocycl. Chem. 1963, 7, 1 ; H. D. Hartough, Chem. Heterocycl. Compd. 1952, 3, 1 ; M. Chaykovsky et al., J. Med. Chem. 1973, 6, 188; A. Michiel van Rhee et. al, J. Med. Chem. 1996, 39, 398-406).
  • Thiophene derivatives have for instance also been used as analgetics (tinoridine, diethylthiambutene), anti-inflammatories (suprofen, tiaprofenic acid), antihelmintics (morantel, pyrantel, thenium chlosylate), anticholinergics (heteronium bromide, oxitefonium bromide, penthienate bromide, tiquizinium bromide, thihexinol methylbromide, thiemonium bromide), antihistaminics (chlorothen, thenalidine, methaphenilene, methapyrilene, thenyldiamine) and antiussives (tipepidine).
  • analgetics tinoridine, diethylthiambutene
  • anti-inflammatories suprofen, tiaprofenic acid
  • antihelmintics morantel, pyrantel, thenium
  • Thiophene derivatives have been used as anticholesteremics (Bryant, H. U.; Grese, T. A., Can. Pat. Appl. CA 2,117,853 (1995), Chemical Abstracts 1995, 123, 339713y) or for the treatment of disorders associated with amyloidogenic peptides (Lunn, W. H. W., PCT Int. Appl. WO 95 17,095 (1995), Chemical Abstracts 1995, 723, 339715a).
  • the present invention provides a solid phase synthesis for thiophenes in which variable substituent groups are independently attached to a common central thiophene ring.
  • the generally recognized advantages of solid phase synthesis are the absence of purification steps of intermediates or the final product, as well as the possibility of automation. Due to these features, a solid phase synthesis of thiophenes dramatically increases the synthesis efficiency for these therapeutically important compounds.
  • Alkyl is intended to mean lower straight, cyclic, fused or branched alkyl having 1 to 15 carbon atoms, preferentially 1 to 6 carbon atoms.
  • Aryl is intended to mean phenyl or phenyl substituted with alkyl or phenyl, or phenyl fused with cycloalkyl, or polycyclic aromatic systems such as naphthyl, anthracenyl, phenanthrenyl, fluorenyl, etc.
  • Alkylene is intended to mean lower straight, cyclic, fused or branched alkylene having 1 to 15 carbon atoms, preferentially 1 to 6 carbon atoms.
  • Heteroaryl is intended to mean any of the possible isomeric, unsubstituted or alkyl-substituted pyrrolyl, furyl, thienyi, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyi, pyrimidinyl and pyridazinyl, as well as the corresponding benzo and dibenzo derivatives or other fused ring-systems thereof. Heteroaryl is also intended to mean the partially or fully hydrogenated derivatives of the heterocyclic systems enumerated above.
  • Alkylthio is intended to mean -S-alkyl and arylthio is intended to mean -S-aryl.
  • Alkoxycarbonyl is intended to mean -CO- O-alkyl and aminocarbonyl is intended to mean -CO-N(alkyl)2, -CO-N(alkyl)(aryl) or -CO- N(aryl)2- Acylamino is intended to mean -N(alkyl)-CO-alkyl or -N(alkyl)-CO-aryl.
  • a leaving group is intended to be a group or atom capable of existing in solution as a negatively charged species, or a positively charged group or atom.
  • HO2C-CH(R 6 )-N(R 1 )H or HO 2 C-peptide-N(R 1 )H is attached to or prepared on a substrate Su via a linker L by well precedented methods, in such a way, that a free primary or secondary amino group is generated on the support.
  • the substrate may be any insoluble or partially insoluble material, to which compounds may be covalently attached.
  • the substrates may be selected from the group consisting of polystyrene, polyethylene glycol (PEG), polyethylene glycol attached to polystyrene (e.g. TentaGel), poiyamides, polysaccharides and silicates.
  • PEG polyethylene glycol
  • TentaGel polyethylene glycol attached to polystyrene
  • poiyamides e.g. TentaGel
  • polysaccharides e.g., polysaccharides and silicates.
  • different types of solvents or protecting groups may be used.
  • a polystyrene resin or TentaGel covalently attached to a Rink linker
  • a polystyrene resin or TentaGel covalently attached to a Rink linker
  • a Rink linker H. Rink, Tetrahedron Lett. 1987, 28, 3787
  • may be acylated with a derivative of a side-chain and nitrogen-protected e.g.
  • the nitrogen protecting group may be removed by well established methods, such as treatment with piperidine in DMF in the case of an FMoc-protecting group, to give a substrate-bound amino acid of the general formula [polystyrene or fi 1
  • a base preferentially a tertiary amine
  • the resulting intermediate is then reacted with a compound of the general formula A-CH 2 - CN, A being an electron-withdrawing group, in the presence of a base, preferentially 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU).
  • DBU diazabicyclo[5.4.0]undec-7-ene
  • R 3 being straight or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, including n-butyl, sec-butyl, iso- butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc., and their variants, straight or branched alkylene chains such as methylene, 1 ,2-ethylene, 1 ,1-ethylene, propylene, etc.
  • substituted or unsubstituted aryl groups such as phenyl, naphthyl, biphenylyl or monovalent radicals of substituted or unsubstituted heterocycles and heteroaromatics such as pyridyl, thienyl, pyrrolyl, furyl, piperidinyl, pyrrolidinyl, etc.
  • R may be substituted or unsubstituted aryl groups or substituted or unsubstituted heterocycles or heteroaromatics. All these groups may also be substituted with functional groups such as F, Cl, Br, I, CONR2, CO2R, CN, NO2 . SR, SOR, SO2R, SO2NR2, OR or NR2, R being low alkyl or aryl.
  • the resulting substrate-bound thioamide 2 may now be alkylated at sulfur with a compound of the general formula R 2 -CH 2 -X, X being -OH or a leaving group for nucleophilic displacement, such as chloride or bromide and R 2 being an electron- withdrawing group as e.g.
  • aryl groups such as phenyl, naphthyl, biphenylyl or monovalent radicals of substituted or unsubstituted heterocycles and heteroaromatics such as pyridyl, thienyl, pyrrolyl, furyl, piperidinyl,
  • R may be substituted or unsubstituted aryl groups or substituted or unsubstituted heterocycles or heteroaromatics. All these groups may also be substituted with functional groups such as F, Cl, Br, I, CONR2, CO2R, CN, NO2, SR, SOR, SO2R, SO2NR2, OR or NR2, R being low alkyl or aryl.
  • This alkylation is carried out in an appropriate solvent such as DMF, DCM, acetonitrile or THF, either under neutral or acidic conditions.
  • the leaving group X may be, for instance
  • the resulting, S-alkylated intermediate may be treated with a base, such as DBU, guanidines, potassium hexamethyldisilazide or alcoholates, in an appropriate solvent such as DMF, THF, toluene, alcohols or acetonitrile, thereby inducing a Thorpe-Ziegler-cyclization to the substrate-bound thiophene II.
  • a base such as DBU, guanidines, potassium hexamethyldisilazide or alcoholates
  • an appropriate solvent such as DMF, THF, toluene, alcohols or acetonitrile
  • Cleavage of the linker of the substrate-bound thiophene II may release the 3- aminothiophene derivative I into solution. Cleavage conditions will depend upon the type of substrate and linker chosen. E. g., in the case of a polystyrene resin with a Wang linker or a Rink linker, treatment of the support-bound thiophene II with neat TFA or TFA/DCM mixtures may lead to a cleavage of the linker.
  • further chemical transformations may be carried out with the substrate- bound thiophene II.
  • These comprise the acylation at the 3-amino group with e.g. carboxylic acid derivatives, sulfonic acid derivatives, isocyanates or isothiocyanates.
  • R -COR', R' being hydrogen or substituted or unsubstituted alkyl or aryl
  • the reduction of the keto group in the resin bound thiophene II may yield a primary or secondary alcohol, which may be cleaved from the support or first acylated with carboxylic acid derivatives, sulfonic acid derivatives, isocyanates or isothiocyanates either at the hydroxy group or at the amino group, the site of acylation depending on the precise 2 reaction conditions, and then cleaved from the support.
  • R -COR', R' being hydrogen or substituted or unsubstituted alkyl or aryl
  • keto- or formyl-group of the substrate-bound thiophene II may be chemically transformed in numerous ways, obvious to those skilled in the art. It may be converted into a hydrazone or an oxime, it may be reductively aminated or reacted with organometallic reagents or condensed with CH-acidic compounds such as nitroaikanes, 1 ,3-dicarbonyl compounds, malononitrile, disulfonyl methanes, etc. Each of these reactions may be performed by conventional means, readily apparent to those skilled in the art.
  • the thiophenes of formula I wherein Y is an aryl, such as phenyl may be prepared by a method analogous to that outlined above and shown in scheme 1 , wherein the acceptor- substituted acetonitrile A-CH 2 -CN is replaced by either an acyiacetonitrile of the general formula Y-CO-CH 2 -CN or a ketone of the general formula Y-CO-CH 2 -Z, Z being an electron-withdrawing group such as -N0 2 , -O 2 R 4 , -C0 2 R 4 , -CONR 4 R 5 or -COR 4 .
  • thiophenes of formula I and II appear as 3- aminothiophenes it is not ment as a limitation and should be construed as also including such thiophenes of formula I and II wherein Y is aryl, preferably phenyl.
  • arrays of thiophene derivatives 11 or I may be constructed with the help of a device for parallel solid phase synthesis.
  • a device for parallel solid phase synthesis This may be either the pin method developed by Geysen et al. (J Immunol. Meth. 1987, 702, 259-274) or a device with several reactors for solid phase synthesis (containers with a permeable wall), which permits the automated addition of reagents and solvents, as well as the removal of the solvents from the reactors by simultaneous or individual application of a pressure difference between the inside and the outside of the permeable wall of the reactors.
  • Such an array may be prepared on a multiple organic synthesizer (e.g. "ACT 496” of “Advanced ChemTech”) by individually reacting under the conditions specified below different amines attached to a substrate and located in individual containers, with carbondisulfide and p-toluenesulfonylchloride or thiophosgene or a thiophosgene equivalent in the presence of a base, followed by treatment with different acceptor- substituted acetonitriles of the general formula A-CH 2 -CN, also in the presence of a base.
  • ACT 496 of "Advanced ChemTech”
  • the resulting substrate-bound thioamides 2 may now be alkylated at sulfur with different alkylating agents of the general formula R 2 -CH 2 -X to give, after treatment with a base and optional cleavage from the support, an array of different thiophene derivatives I or II.
  • the present invention also permits the synthesis of arrays of mixtures of thiophene derivatives. This can be achieved either by the "split and mix” method (Sepetov, N.F., Krchnak, V., Stankova, M., Wade, S., Lam, K.S., and Lebl Proc. Natl. Acad. Sci. USA 1995, 92, 5426-5430) or by using mixtures of the corresponding reagents.
  • FCA fully combinatorial arrays
  • NFCA not-fully combinatorial arrays
  • FCA we refer to arrays of substituted thiophenes, in which all the possible combinations of a set of selected building blocks are realized.
  • the selection of building blocks may be done with regard to the expected properties of the members of the array.
  • NFCA By NFCA we refer to arrays of substituted thiophenes, in which only a selection of the possible combinations of a set of selected building blocks is realized.
  • a NFCA of N thiophenes may be prepared by first selecting n diamines, m acceptor- substituted acetonitriles and p haloketones so that n x m x p > N.
  • N thiophenes from all the n x m x p theoretically possible thiophenes is done by grouping all the n x m x p possible thiophenes into N groups of thiophenes with similar expected properties and selecting from each of these groups one thiophene, which is then synthesized.
  • the selection of building blocks and of thiophenes may be done with regard to the expected properties of the members of the array.
  • the exact positions of the substrate does, by itself, not give any structural information about the compound prepared on this particular batch of substrate. For this reason, the spatial arrangement of the substrate is irrelevant. Structural information will be accessible from the records of the sequences of reagents added to each batch of substrate. In every step of the preparation of a FCA or a NFCA, the exact location of one substrate-container within the array of containers and the structure of the different reagents added to this container is recorded, so that the precise structure of the thiophene resulting from one given container can always be deduced.
  • the resulting arrays of 2-aminothiophenes may then be screened by comparing the individual thiophenes in terms of their ability to bind to a particular receptor or to induce a particular biological process or to catalyze a biological or chemical reaction.
  • This can be achieved basically in two different ways.
  • One possibility may be the screening of the substrate-bound thiophenes II, e.g. against a soluble receptor. This could for instance be a radioactively labelled peptide or enzyme, which would easily permit to determine the binding-strength of a given substrate-bound thiophene II to this peptide by washing away the excess of radioiigand used and determining the remaining radioactivity of each substrate-bound thiophene ll-peptide complex.
  • catalytic activity of the different substrate-bound thiophenes II for a given biological process or a chemical reaction may be measured by comparing the speed at which this biological process or a chemical reaction takes place in the presence and in the absence of a given substrate-bound thiophene II.
  • the second option for screening may consist in screening the thiophenes I, after having cleaved the linker of the substrate-bound thiophenes II and using appropriately charged and indexed Microtiter plates of similar multiwell arrangements, in solution against an optionally substrate-bound receptor or enzyme.
  • the screening of soluble small molecules is conventional and well known.
  • radioassays are being used, in which the competitive binding of the radioiabelled, natural ligand of a given receptor and the compound to be tested for binding to this receptor is investigated.
  • cholecystokinine receptors which are widely distributed throughout the central and peripheral nervous system and mediate numerous physiological responses.
  • Crude membrane homogenates may be prepared according to the procedure described by Chang et al. (Proc. Natl. Acad. Sci. 1986, 4923- 4926) and radiolabelled cholecystokinine can be purchased from New England Nuclear, Massachusetts, U.S.A.
  • Other examples will be readily apparent to those skilled in the arts of physiology, biology and biotechnology. These could for instance be the somatostatine receptors, the glucagon receptors, the insulin receptor, the opiate receptors, the dopamine receptors, the acetylcholine receptors, the histamine receptors, etc.
  • functional or other assays may be used, in which for example the biological response of a cell or a genetically modified or unmodified organism is measured as a function of the amount of test-substance added to this organism.
  • the catalytic activity of the different thiophenes I for a given biological process or a chemical reaction may be measured by comparing the speed at which this biological process or a chemical reaction takes place in the presence and in the absence of a given thiophene I.
  • Zaragoza, F Solid-phase Synthesis of substituted 3-Aminothiophenes and 2- Methylene-2,3-dihydrothiazoles, Tetrahedron Lett. 1996, 37, 6213-6216.
  • ChemTech the four diamines 1 ,2-diaminoethane, 1 ,4-diaminobutane, 1 ,3-diamino-2,2- dimethylpropane and 1 ,3-diaminopentane, previously attached to a Wang resin via a carbamate-group, were equally distributed [150 mg (approx. 0.14 mmol) of each resin- bound diamine into each of twenty reactors].
  • the array of reactors was shaken for 15 h, the resins filtered and washed with 1 ,2-dichloroethane and then reacted with four different acceptor-substituted acetonitriles [malonodinitrile, (4-chiorophenyl)sulfonylacetonitrile, methylsulfonyl-acetonitrile, isopropylsulfonylacetonitrile] in the presence of DBU (as described above) in such a way, that all possible combinations of diamines and acceptor-substituted acetonitriles was realized.
  • acceptor-substituted acetonitriles malonodinitrile, (4-chiorophenyl)sulfonylacetonitrile, methylsulfonyl-acetonitrile, isopropylsulfonylacetonitrile

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  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention a trait à un procédé en phase solide aux fins de la synthèse de plusieurs thiofènes différemment substitués par une large gamme de substituants à chaîne latérale et se présentant en tant que composés potentiellement intéressants du point de vue thérapeutique. On prépare ces thiofènes en faisant réagir une amine, primaire ou secondaire, liée à un substrat avec un équivalent thiophosgène et en faisant ensuite réagir l'intermédiaire résultant avec un acétonitrile substitué par accepteur et ce, en présence d'une base. Une alkylation par un halogénure d'alkyle approprié, suivie d'une cyclisation de Thorpe-Ziegler, donne lieu à des 3-amino-thiofènes, liés à un support, substitués de diverses manières. Ces amino-thiofènes peuvent être éprouvés sur le substrat ou coupés du substrat et ensuite éprouvés en solution. Il est possible, dans une variante, de soumettre les 3-amino-thiofènes liés à une résine ou les intermédiaires de synthèse à d'autres transformation par voie de synthèse (N-acylation, réduction) sur le support, ce qui permet de préparer d'autres composés intéressants du point de vue thérapeutique. La synthèse productive d'une large gamme de thiofène faisant intervenir les techniques automatisées de l'invention fait de ces composés des candidats intéressants aux fins de la production et du criblage rapide de banques variées axées sur les thiofènes. Le procédé ici présenté, susceptible d'une automatisation, offre un accès facile et rapide à divers composé hétérocycliques présentant un intérêt thérapeutique.
PCT/DK1998/000035 1997-02-20 1998-01-29 CHIMIE EN PHASE SOLIDE ET SYNTHESE COMBINATOIRE DE THIOPHENES SUBSTITUES ET DE SERIES DE CES thiofènes SUBSTITUES Ceased WO1998037078A1 (fr)

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AU56518/98A AU5651898A (en) 1997-02-20 1998-01-29 Solid phase and combinatorial synthesis of substituted thiophenes and of arrays of substituted thiophenes

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DK0177/97 1997-02-20
DK17797 1997-02-20

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WO1998037078A1 true WO1998037078A1 (fr) 1998-08-27

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Publication number Priority date Publication date Assignee Title
EP1242080A4 (fr) * 1999-09-27 2003-01-22 Univ Georgetown Inhibiteurs du transporteur de dopamine et leur utilisation
WO2006078287A3 (fr) * 2004-05-06 2007-03-29 Plexxikon Inc Inhibiteurs de pde4b
US7932213B2 (en) 1999-05-11 2011-04-26 President And Fellows Of Harvard College Small molecule printing

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Title
EDUARD R. FELDER, "The Challenge of Preparing and Testing Combinatorial Compound Libraries in the Fast Lane, at the Front End of Drug Development", CHIMIA, Volume 48, 1994, pages 531-541. *
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FLORENCIO ZARAGOZA, "Solid-Phase Synthesis of Substituted 3-Aminothiophenes and 2-Methylene-2,3-Dihydrothiazoles", TETRAHEDRON LETTERS, Volume 37, No. 34, 1996, pages 6213-6216. *
HENRIK STEPHENSEN et al., "Resin-Bound Isothiocyanates and Their Synthetic Equivalents as Intermediates for the Solid-Phase Synthesis of Substituted Thiophenes", J. ORG. CHEM., Volume 62, Sept. 1997, pages 6096-6097. *
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7932213B2 (en) 1999-05-11 2011-04-26 President And Fellows Of Harvard College Small molecule printing
EP1242080A4 (fr) * 1999-09-27 2003-01-22 Univ Georgetown Inhibiteurs du transporteur de dopamine et leur utilisation
WO2006078287A3 (fr) * 2004-05-06 2007-03-29 Plexxikon Inc Inhibiteurs de pde4b
JP2008503446A (ja) * 2004-05-06 2008-02-07 プレキシコン，インコーポレーテッド Ｐｄｅ４ｂ阻害剤及びその使用
US7585859B2 (en) * 2004-05-06 2009-09-08 Plexxikon, Inc. PDE4B inhibitors and uses therefor
US8470821B2 (en) 2004-05-06 2013-06-25 Plexxikon Inc. PDE4B inhibitors and uses therefor

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