WO2000046211A1 - Procede de synthese de derives d'acide barbiturique et utilisation de ces derives d'acide barbiturique pour la synthese de bibliotheques chimiques - Google Patents

Procede de synthese de derives d'acide barbiturique et utilisation de ces derives d'acide barbiturique pour la synthese de bibliotheques chimiques Download PDF

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WO2000046211A1
WO2000046211A1 PCT/US2000/002998 US0002998W WO0046211A1 WO 2000046211 A1 WO2000046211 A1 WO 2000046211A1 US 0002998 W US0002998 W US 0002998W WO 0046211 A1 WO0046211 A1 WO 0046211A1
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aryl
alkyl
substituted
formula
template
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PCT/US2000/002998
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English (en)
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Adnan M. M. Mjalli
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Transtech Pharma
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Priority to MXPA01007869A priority Critical patent/MXPA01007869A/es
Priority to AU32232/00A priority patent/AU3223200A/en
Priority to CA002362085A priority patent/CA2362085A1/fr
Priority to JP2000597281A priority patent/JP2002536368A/ja
Priority to EP00910081A priority patent/EP1155002A4/fr
Publication of WO2000046211A1 publication Critical patent/WO2000046211A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention relates to method of synthesis of compounds of Formula 1 (referred to herein as support templates) as follows:
  • solid support synthesis is carried out on a substrate made of a polymer, cross-linked polymer, functionalized polymeric pin, or other insoluble material.
  • These polymers or insoluble materials have been described in the literature and are known to those who are skilled in the art of solid phase synthesis (see, Stewart JM, Young J.D., Solid Phase Peptide Synthesis, 2nd Ed, Pierce Chemical Company, Rockford, Illinois, United States of America, 1984).
  • Some of the supports are based on polymeric organic substrates such as polyethylene, polystyrene, polypropylene, polyethylene glycol, polyacrylamide, and cellulose.
  • Additional types of supports include composite structures such as grafted copolymers and polymeric substrates such as polyacrylamide supported within an inorganic matrix such as kieselghuhr particles, silica gel, and controlled pore glass.
  • Such polymers are substituted with linkers that modulate the stability of the linkage to the support resin.
  • the linkers incorporate reactive functionalities (e.g. amino, hydroxy, oximo, phenolic, silyl, etc.) for loading of monomers suitable for carrying out a plurality of further reactions to synthesize the desired products (see, Hemkens, P. H. H., Ottenheijm, H. C. J., and Rees, D., Tetrahedron Lett., 1996, Vol. 52, pp. 4527-4554).
  • reactive functionalities e.g. amino, hydroxy, oximo, phenolic, silyl, etc.
  • hydroxymethyl polystyrene resin Wang resin, hydroxymethylbenzoic acid resin (HMBA resin), hydroxymethylphenoxy functionalized TentagelTM resin, ArgogelTM resin, oxime resin, 4-hydroxymethyl-3-methoxyphenoxybutyric acid-BHA resin (HPPB-BHA resin), and polyethylene glycol type A resin (PEGA resin).
  • HMBA resin hydroxymethylbenzoic acid resin
  • HPPB-BHA resin 4-hydroxymethyl-3-methoxyphenoxybutyric acid-BHA resin
  • PEGA resin polyethylene glycol type A resin
  • pin method a type of solid phase synthesis method referred to as the "pin method” which was developed by Geysen et al. and is useful for combinatorial solid-phase peptide synthesis (see, Geysen et al., J. Immunol. Meth., 1987, Vol. 102, pp. 259-274).
  • a series of 96 polymeric pins are mounted on a block, in an arrangement and a spacing which correspond to a 96-well microtiter reaction plate, and the surface of each polymeric pin is functionalized (also referred to as derivatized) to contain a terminal functional group linker.
  • the polymeric pin block is then lowered into the 96-well microtiter reaction plate to immerse the pins in the wells of the plate where coupling (i.e., linking) with a compound occurs at the terminal functional group linkers.
  • a plurality of further reactions are carried out in a similar fashion on each compound by having reagents varying in their substituent groups occupy the wells of the plate in a predetermined array, in order to achieve as ultimate products, a unique product on each pin.
  • Each product is then cleaved from each polymeric pin.
  • tea bag method containing the functionalized solid phase resins referred to above (see, Houghton, R.A., et al., Nature, Vol. 354, pp. 84-86, 1991).
  • These tea bags of resin can be moved from one reaction vessel to another in order to undergo a series of reaction steps for the synthesis of libraries of products.
  • solubilizable resins that can be rendered insoluble during the synthesis process as solid phase supports. This may be achieved by attachment of linkers to resins that can be solubilized under certain solvent and reaction conditions and rendered insoluble for isolation of reaction products from reagents, for instance, by use of high molecular weight polyethyleneglycol as a solubilizable polymeric support (see, Vandersteen, A. M., Han, H., and Janda, K. D., Molecular Diversity, 1996, Vol. 2, pp. 89-96).
  • solid support synthesis is known to provide several advantages over solution chemistry, as shown by the ease of purification and automation of solid support synthesis of peptides (see, Atherton, E. and Sheppard, RC, Solid Phase Peptide Synthesis: A Practical Approach, IRL Press at Oxford University Press, Oxford, 1989) as well as by the ease of purification and automation of non-peptide-based molecules (see, Lenzoff, C.C, Ace. Chem. Res., 1978, Vol. 11, pp. 327-333). Moreover, solid support synthesis of combinatorial libraries has yielded many biologically active compounds (see, Moos, W. H. et al., Annu. Rep. Med. Chem., 1993, Vol. 28, pp.
  • the present invention provides a support template comprising a compound of Formula 1 as follows:
  • x of the template comprises a linker for linking to the remainder of the template
  • x and the remainder of the template comprise a chemical library
  • R 2 , R 3 , and R 11 are the same or different and are selected from: (a) H,
  • (c) C1-C10 alkyl, C ⁇ -C ⁇ 0 substituted alkyl, C 1 -C 10 substituted alkyl-aryl, C1-C10 substituted alkenyl, and C 1 -C 10 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C 1 -C 10 alkyloxy, C 1 -C 10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C-C 1 0 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C- 1 -C 1 0 thioalkyl, d- C 1 0 thioalkyl-aryl, C1-C10 alkylsulfoxide, C 1 -C 1 0
  • ⁇ of the template comprises a material suitable for a support
  • x of the template comprises a linker for linking to the remainder of the template
  • x and the remainder of the template comprise a chemical library
  • R 2 , R 3 , and R 11 are the same or different and are selected from: (a) H, (b) mono-, di- and tri-substituted aryl, and
  • (c) C1-C10 alkyl, C1-C10 substituted alkyl, d-C 10 substituted alkyl-aryl, C1-C1 0 substituted alkenyl, and C1-C1 0 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, Ci-do alkyloxy, C-i-do alkyloxy aryl, C1-C10 aminoalkyl, d-do alkylamino, C1-C10 aminoalkyl aryl,
  • C10 thioalkyl-aryl C C ⁇ 0 alkylsulfoxide, d-C 10 alkylsulfone, d-Cio alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C 1 -C 1 0 alkylsulfoxide aryl, Cr C 10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C 1 -C 1 0 alkyl, C1-C 1 0 alkyl aminocarbonylamino C 1 -C 1 0 alkyl aryl, C 1 -C- 10 alkyloxycarbonyl C 1 -C 1 0 alkyl, C 1 -C 1 0 alkyloxycarbonyl C1-C10 alkyl aryl, C 1 -C 1 0 carboxyalkyl, C 1 -C 1 0 carboxyalkyl aryl, C 1 -C10 carbonylal
  • R 4 and R 5 are the same or different and are selected from: H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ, in the presence of an amide-bond forming reagent, (2) amine-deprotecting the resultant by replacing R 5 with H, and reacting the deprotected resultant with an amine R 11 NH 2 or an isocyanate R 11 NCO under urea-forming reaction conditions to provide a urea-bound solid support resin of Formula 4 as follows:
  • the present invention relates to carbonyl-esters or carbonyl-amides linked to insoluble materials as depicted in Formula 1 , and methods for producing chemical libraries generated through a plurality of chemical reactions utilizing support templates of Formula 1.
  • R 2 and R 3 in Formula 1 may be joined together to form cyclic compounds of Formula 1a with ring size of 3-8 as follows:
  • the ring system may be selected from:
  • Scheme 1 is performed as follows.
  • a material suitable for a support (which may be any of the polymers suitable for a support, which may be a solid support, as mentioned in the referenced literature that is described above), functionalized with xH (such as amino, hydroxy, oximo, phenolic, or silyl) where x is a linker (such as NH, O, CHNO, PhO, or SiH 2 , respectively), provided a functionalized polymer support as shown in Formula 2 (i.e., the functionalized ⁇ also may be any of the funtionalized polymer supports, which may be solid supports, as mentioned in the referenced literature that is described above), which was then reacted with a N-protected alpha-amino acid of Formula A (defined below and in Provisional U.S.
  • N-protected alpha-amino acids of Formula A have one or two substituents (R 2 and/or R 3 ) at the alpha position and are defined as follows:
  • R 2 and R 3 are the same or different and are selected from:
  • R 4 and R 5 are the same or different and are selected from: H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ and the like.
  • R 2 and R 3 in Formula A are joined together to form cyclic compounds of Formula Aa with a ring size of 3-8 as follows:
  • the ring system may be selected from substituted- cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl as shown in compounds of Formulae Ab and Ac as follows:
  • Formula Ab selected from substituted- cyciopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl as in compounds of Formula Ad as follows:
  • R 6 and R 7 , R 6 and R 10 , or R 9 and R 10 may be joined together as a ring to form a fused system with the cyclopentene ring, where the aryl and its substituents are as defined below vis-a-vis (e) and (f), or selected from substituted heterocyclic compounds, where A is O, S, SO, SO 2 , NH, SO 2 NHR 8 , NCONHR 8 , NCOOR 8 , or NR 8 inserted in the ring systems as in compounds of Formulae Ae and Af as follows:
  • substituents R 4 and R 5 in Formulae Aa-Af are as defined above and where the substituents (R 6 , R 7 , R 8 , R 9 , and R 10 ) in Formulae Aa-Af are the same or different and are selected from: (d) H,
  • Formula A, 1 may be performed prior to 2), 2) may be performed prior to 1), or 1 ) and 2) may be performed concurrently.
  • an appropriate aldehyde or ketone such as but not limited to phenylacetaldehyde or cyclo
  • the desired alpha-amino acid of Formula B has a removable amino acid/chiral auxiliary and preferably is selected from compounds where R is mono, di-, tri-, tetra- or penta-substituted aryl, where the aryl is selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, and the like, and the substituents are selected from: H, cyano, amino, C1-C 10 alkyl, C 1 -C 10 alkyloxy, d-do alkyloxy aryl, d-C 10 aminoalkyl, C1-C10 alkylamino, C 1 -C 10 aminoalkyl aryl, and the like.
  • dialkylcarbodiimide with an additive such as 1-hydroxybenzotriazole; especially diispropylcarbodiimide/1 -hydroxy-7-azabenzotriazole (DIC/HABT); benzotriazol-1 -yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP); O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU); bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP); and Fmoc amino acid fluorides (see for instance, Carpino, L.A., et al., "9-Fluorenylmethyloxycarbonyl Amino Acid Fluorides, Convenient New Peptide Coupling Reagents Applicable to the Fmoc/Tert-But
  • any of the wide variety of available amino protecting groups for R 5 may be used such as tert-butyloxycarbonyl (BOC), fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (CBZ), and the like.
  • BOC tert-butyloxycarbonyl
  • Fmoc fluorenylmethyloxycarbonyl
  • CBZ benzyloxycarbonyl
  • the choice of a particular protecting group will depend on the specific nature of the substituents and reactions contemplated. Also, more than one type of protecting group may be necessary at any given point in the synthesis (see, e.g., Green, T. and Wuts, P. G. M., Protective Groups In Organic Synthesis 2 nd Ed, Wiley, 1991, and references cited therein).
  • Support templates of Formula 1 may be solid support templates
  • Support templates of Formula 1 may be reacted with plurality of chemical transformations followed by cleavage from the support ⁇ of the desired heterocycle compounds under appropriate conditions (such as by trichloroacetic acid/dichloromethane).
  • Some examples of these transformations provided desired heterocycle compounds of Formulae B-J, which are referred to as "libraries" prior to cleavage from the support ⁇ , as shown below in Scheme 2.
  • reaction of Formula 1 with an acid chloride (R 12 COCI, or equivalent) or an alkyl halide (R 12 Br, R 12 CI, R 12 F, or equivalent) using standard conditions followed by cleaving the product from the support (under standard conditions described above) provided compounds of Formula A and Formula C, respectively, after cleavage from the support.
  • reaction of compounds of Formula B (prior to cleavage from the support) with a hydrazine (R 13 NHNH 2 ) provided compounds of Formula G, after cleavage from the support.
  • reaction of Formula 1 with an alpha-halomethyl ketone provided compounds of Formula E, after cleavage from the support.
  • reaction of Formula E (prior to cleavage from the support) with a hydrazine (R 13 NHNH 2 ) provided compounds of Formula D, after cleavage from the support.
  • R 7 in Formula B was -CH(CH 2 NHR 17 )NHR 16 , compounds of
  • X 1 halogen, hydroxy, alkoxy, acyloxy
  • reactivity of the amide nitrogen in Formula 4 is enhanced by treatment with N,O-bis(trimethylsilyl)acetamide or instead the carbonyl moiety in Formula 6 is activated by formation of chloroanhydrides, mixed anhydrides, or active esters. Ring closure occurs via an intermediate compound of Formula 5, which may be isolated, if desired.
  • Compounds of Formula 5 were cyclized in the presence of a condensation reagent, such as acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, or 1 ,1'- carbonyldiimidazole, to provide compounds of Formula 1.
  • a condensation reagent such as acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, or 1 ,1'- carbonyldiimidazole
  • R 2 , R 3 , and R 11 are as defined above;
  • X 3 H, alkyl, arylalkyl, acyl, or N,N'-substituted amidine;
  • N-Fmoc-phenylalanyl-Wang resin (1 g, loading 1.0 mmol/g, Wang resin supplied by NovaBiochem) was treated with piperidine/dimethylformamide (1 :1 ) for 3 h. The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The resulting resin was swelled in dichloromethane/tetrahydrofuran (1 :1 ), treated with 4-nitrophenyl chloroformate (1.039 g, 5 mmol) and N,N-diisopropylethylamine (0.348 ml, 2 mmol), and stirred at rt for 45 min.
  • the resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol). Propylamine (0.411 ml, 5 mmol) was then added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times). The resulting resin was dried in vacuum.
  • N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-(propylcarbamoyl)phenylalanine on Wang resin.
  • the slurry was heated at 50°C for 5 h.
  • the resulting resin was filtered and washed with 1 ,2-dichloroethane.
  • 1 M solution of Meldrum's acid in 1 ,2- dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight.
  • the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
  • a sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1 :1) for LC/MS analysis: m/z 337 (M+H) + .
  • N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-((4-methylbenzyl)carbamoyl)phenylalanine on Wang resin.
  • the slurry was heated at 50°C for 5 h.
  • the resulting resin was filtered and washed with 1 ,2-dichloroethane.
  • 1 M solution of Meldrum's acid in 1 ,2-dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight.
  • the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
  • a sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1 :1) for LC/MS analysis: m/z 399 (M+H) + .
  • N-Fmoc-alanyl-Wang resin (1 g, loading 1.0 mmol/g, NovaBiochem) was treated with piperidine/dimethylformamide (1:1 ) for 3 h. The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The resulting resin was swelled in dichloromethane/tetrahydrofuran (1 :1), treated with 4- nitrophenyl chloroformate (1.039 g, 5 mmol), and N,N-diisopropylethylamine (0.348 ml, 2 mmol), and then stirred at rt for 45 min.
  • the resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol). Propylamine (0.411 ml, 5 mmol) was added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times). The resulting resin was dried in vacuum. A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1 :1) for LC/MS analysis: m/z 175 (M+H) + .
  • N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-(propylcarbamoyl)alanine on Wang resin.
  • the resulting slurry was heated at 50°C for 5 h.
  • the resulting resin was filtered and washed with 1 ,2-dichloroethane.
  • 1 M solution of Meldrum's acid in 1 ,2- dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight.
  • the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
  • a sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1) for LC/MS analysis: m/z 261 (M+H) + .
  • N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)alanine on Wang resin 500 mg was swelled in 1 M acetic anhydride/1 ,2-dichloroethane (10 ml). The resulting mixture was agitated by bubbling of nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then suspended in 1 M acetic anhydride/1 ,2-dichloroethane (10 ml). The resulting mixture was again agitated by bubbling of nitrogen overnight, washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
  • EXAMPLE 8 1 -(1 -carboxy-2-phenyl)ethyl-5-(3-phenyl-2-((9-fluorenylmethoxycarbonyl) amino)pro-pionyl)-3-propylbarbituric acid
  • 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene (100 mg, loading 0.5 mmol/g, Novabiochem) was mixed with triethyl orthoformate (1 ml) and 1 M 2-phenylethylamine in 1 ,2-dichloroethane (1 ml). Nitrogen was bubbled into the resulting slurry for 2 h. The resulting solution was removed by suction, and the resulting resin was treated with 1 M sodium cyanoborohydride in tetrahydrofuran (1 ml) and 1% acetic acid in N,N-dimethylformamide (1 ml) overnight under nitrogen.
  • the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
  • the resulting resin was treated with 0.25 M symmetric anhydride prepared in situ from N-(9- fluorenylmethoxycarbonyl)phenylalanine and 1 ,3-diisopropylcarbodiimide in 3 ml 1-methyl-2-pyrrolidinone overnight.
  • the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried.
  • the resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried.
  • a sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichioromethane/triethylsilane (25:75:1) for LC/MS analysis: m/z 402 (M+H) + .
  • N,O-bis(trimethylsilyl)acetamide (1 ml) and tetrahydrofuran (1 ml) were added to the obtained resin.
  • the resulting slurry was heated at 50°C for 5 h.
  • the resulting resin was filtered and washed with 1 ,2-dichloroethane.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un modèle de substrat représenté par la formule (1) ci-après.
PCT/US2000/002998 1999-02-04 2000-02-04 Procede de synthese de derives d'acide barbiturique et utilisation de ces derives d'acide barbiturique pour la synthese de bibliotheques chimiques WO2000046211A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
MXPA01007869A MXPA01007869A (es) 1999-02-04 2000-02-04 Metodo de sintesis de compuestos de la formula 1 y su uso para la sintesis de bibliotecas quimicas.
AU32232/00A AU3223200A (en) 1999-02-04 2000-02-04 Method of synthesizing barbituric acid derivatives and their use for the synthesis of chemical libraries
CA002362085A CA2362085A1 (fr) 1999-02-04 2000-02-04 Procede de synthese de derives d'acide barbiturique et utilisation de ces derives d'acide barbiturique pour la synthese de bibliotheques chimiques
JP2000597281A JP2002536368A (ja) 1999-02-04 2000-02-04 化学式１の化合物の合成方法およびケミカルライブラリー構築のためのそれらの使用
EP00910081A EP1155002A4 (fr) 1999-02-04 2000-02-04 Procede de synthese de derives d'acide barbiturique et utilisation de ces derives d'acide barbiturique pour la synthese de bibliotheques chimiques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11854799P 1999-02-04 1999-02-04
US60/118,547 1999-02-04

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WO2000046211A1 true WO2000046211A1 (fr) 2000-08-10

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JP (1) JP2002536368A (fr)
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CA (1) CA2362085A1 (fr)
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WO (1) WO2000046211A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4833148A (en) * 1987-04-09 1989-05-23 Washington University Method of using alkenyl- or alkynyl-substituted thiobarbiturates to reduce neurotoxic injury

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3247127A (en) * 1960-04-14 1966-04-19 Eastman Kodak Co Light-absorbing water-permeable colloid layer containing an oxonol dye
DE68927541T2 (de) * 1988-09-01 1997-05-15 Fuji Photo Film Co Ltd Photographische Silberhalogenidemulsionen
JPH04505973A (ja) * 1989-12-22 1992-10-15 イーストマン コダック カンパニー 高銀イオン活量において改良された性能の写真乳剤
JPH05249593A (ja) * 1992-03-04 1993-09-28 Konica Corp ハロゲン化銀写真感光材料
JPH07276810A (ja) * 1994-04-04 1995-10-24 Fuji Photo Film Co Ltd ジアゾ感熱記録材料

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4833148A (en) * 1987-04-09 1989-05-23 Washington University Method of using alkenyl- or alkynyl-substituted thiobarbiturates to reduce neurotoxic injury

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
J. MED. CHEM.: "Highly selective aldose reductase inhibitors, 3 structural diversity of 3-(arylmethyl)-2,4,5-trioxoimidazolidine- 1-acetic acids", KOTANI ET. AL., vol. 40, 1997, pages 684 - 694, XP002929246 *
LENZOFF, C. C.: "The use of insoluble polymer supports in general organic synthesis", ACC. CHEM. RES., vol. 11, no. 9, September 1978 (1978-09-01), pages 327 - 333, XP002929247 *
See also references of EP1155002A4 *

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EP1155002A4 (fr) 2003-03-19
MXPA01007869A (es) 2003-06-04
EP1155002A1 (fr) 2001-11-21
JP2002536368A (ja) 2002-10-29
CA2362085A1 (fr) 2000-08-10
AU3223200A (en) 2000-08-25

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