WO1998027427A1 - Combinatorial process for preparing tetrahydroquinoline libraries - Google Patents
Combinatorial process for preparing tetrahydroquinoline libraries Download PDFInfo
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- WO1998027427A1 WO1998027427A1 PCT/US1997/022869 US9722869W WO9827427A1 WO 1998027427 A1 WO1998027427 A1 WO 1998027427A1 US 9722869 W US9722869 W US 9722869W WO 9827427 A1 WO9827427 A1 WO 9827427A1
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- Prior art keywords
- library
- amino
- compounds
- formula
- hydrogen
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- 0 *Nc(c([N+]([O-])[O-])cc(O)c1)c1I Chemical compound *Nc(c([N+]([O-])[O-])cc(O)c1)c1I 0.000 description 11
- UCCUXODGPMAHRL-UHFFFAOYSA-N Brc(cc1)ccc1I Chemical compound Brc(cc1)ccc1I UCCUXODGPMAHRL-UHFFFAOYSA-N 0.000 description 1
- YFXVWZUFEKALBO-UHFFFAOYSA-N CC(C(CC=C1I)OC2=CCCC=C2)C1NI Chemical compound CC(C(CC=C1I)OC2=CCCC=C2)C1NI YFXVWZUFEKALBO-UHFFFAOYSA-N 0.000 description 1
- SBWWMXXVEUMTTD-UHFFFAOYSA-N COC(C=C1I)=CC(CI)C1NI Chemical compound COC(C=C1I)=CC(CI)C1NI SBWWMXXVEUMTTD-UHFFFAOYSA-N 0.000 description 1
- GNIKLVDGDUKVGK-UHFFFAOYSA-N COc(c(I)c(c(C=[IH])c1)NI)c1[NH+]([O-])O Chemical compound COc(c(I)c(c(C=[IH])c1)NI)c1[NH+]([O-])O GNIKLVDGDUKVGK-UHFFFAOYSA-N 0.000 description 1
- DBFJAUGZOAKTOR-UHFFFAOYSA-N COc(c(N[I]=C)c1I)ccc1Cl Chemical compound COc(c(N[I]=C)c1I)ccc1Cl DBFJAUGZOAKTOR-UHFFFAOYSA-N 0.000 description 1
- WBYVNDUCUMNZPM-UHFFFAOYSA-N Fc(cc1)cc(I)c1F Chemical compound Fc(cc1)cc(I)c1F WBYVNDUCUMNZPM-UHFFFAOYSA-N 0.000 description 1
- RAGHRFWZOUPKFJ-UHFFFAOYSA-N Ic(cccc1)c1NI Chemical compound Ic(cccc1)c1NI RAGHRFWZOUPKFJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
- C40B50/08—Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support
Definitions
- the present invention relates to diverse libraries of tetrahydroquinoline compounds, methods of making such libraries, and an apparatus for storing and providing a readily accessible source of diverse tetrahydroquinoline compounds .
- the apparatus harboring the present combinatorial libraries is a useful component of assay systems for identifying compounds for drug development.
- the total number of compounds which may be produced for a given library is limited only by the number of reagents available to form substituents on the variable positions on the library's molecular scaffold.
- the combinatorial process lends itself to automation, both in the generation of compounds and in their biological screening, thereby greatly enhancing the opportunity and efficiency of drug discovery.
- Combinatorial chemistry may be performed in a manner where libraries of compounds are generated as mixtures with complete identification of the individual compounds postponed until after positive screening results are obtained.
- a preferred form of combinatorial chemistry is "parallel array synthesis", where individual reaction products are simultaneously synthesized, but are retained in separate vessels.
- the individual library compounds can be prepared, stored, and assayed in separate wells of a microtiter plate, each well containing one member of the parallel array.
- the use of standardized microtiter plates or equivalent apparatus is advantageous because such an apparatus is readily accessed by programmed robotic machinery, both during library synthesis and during library sampling or assaying.
- Combinatorial chemistry may be used at two distinct phases of drug development.
- discovery phase diverse libraries are created to find lead compounds.
- second optimization phase strong lead compounds are more narrowly modified to find optimal molecular configurations .
- the method of the present invention is based on the preparation of a novel diverse library of tetrahydroquinolines useful in the identification of new lead compounds.
- the library is created, stored, and used as an apparatus comprising of a two-dimensional array of reservoirs, each reservoir containing a predetermined library reaction product differing from those in adjacent reservoirs .
- the present invention provides combinatorial libraries of structurally related compounds having tetrahydroquinoline core structures of the general formula (I) :
- Ri and Rl ' are substituents derived from an optionally substituted aniline of the formula and R2 s hydrogen or an organic moiety derived from an aldehyde of the formula R2CHO.
- the invention further provides a method for preparing tetrahydroquinoline libraries generally in accordance with Scheme 1 as set forth below.
- kits for the identification of pharmaceutical lead tetrahydroquinoline compounds comprising assay materials and a well plate apparatus or equivalent apparatus providing a two-dimensional array of defined reservoirs.
- the well plate apparatus provides a diverse combinatorial library, wherein each well (reservoir) contains a unique reaction product of the tetrahydroquinoline library.
- the well plate apparatus is used to provide multiple reaction zones for making the library, to store the library and to provide a readily accessible source of library compounds.
- Fig. 1 is a top view of a well plate in accordance with this invention.
- Fig. 2 is a side view of a well plate apparatus for use in the process of this invention.
- Assay kit refers to an assemblage of two cooperative elements, namely (1) a well plate apparatus and (2) biological assay materials.
- Biological assay materials are materials necessary to conduct a biological evaluation of the efficacy of any library compound in a screen relevant to a selected disease state.
- a "library” is a collection of compounds created by a combinatorial chemical process, said compounds having a common scaffold with one or more variable substituents.
- the scaffold of the present invention is a tetrahydroquinoline .
- a "library compound” is an individual reaction product, a single compound or a mixture of isomers, in a combinatorial library.
- a "Lead compound” is a library compound in a selected combinatorial library for which the assay kit has revealed significant activity relevant to a selected disease state.
- a “diverse library” means a library where the substituents on the combinatorial library scaffold or core structure, are highly variable in constituent atoms, molecular weight, and structure, and the library, considered in its entirety, is not a collection of closely related homologues or analogues (compare to "directed library”).
- a “directed library” is a collection of compounds created by a combinatorial chemical process, for the purpose of optimization of the activity of a lead compound, wherein each library compound has a common scaffold, and the library, considered in its entirety, is a collection of closely related homologues or analogues to the lead compound (compare with “diverse library”).
- the term "scaffold” as used in accordance with the present invention refers to the invariable region (a tetrahydroquinoline core in the present invention) of the compounds which are members of the combinatorial library.
- “Substituents” are chemical radicals which are bonded to or incorporated onto the tetrahydroquinoline scaffold through the combinatorial synthesis process.
- the different functional groups account for the diversity of the molecules throughout the library and are selected to impart diversity of biological activity to the scaffold in the case of diverse libraries, and optimization of a particular biological activity in the case of directed libraries.
- Reagent means a reactant, any chemical compound used in the combinatorial synthesis to place substituents on the scaffold of a library.
- Paraallel array synthesis refers to the method of conducting combinatorial chemical synthesis of libraries wherein the individual combinatorial library compounds are separately prepared and stored without prior and subsequent intentional mixing.
- reaction zone refers to the individual vessel location where the combinatorial chemical library compound preparation process of the invention is carried out and where the individual library compounds are synthesized. Suitable reaction zones are the individual wells of a well plate apparatus.
- Well plate apparatus refers to the structure capable of holding a plurality of library compounds in dimensionally fixed and defined positions.
- Non-interfering substituents are those groups that do not significantly impede the process of the invention and yield stable tetrahydroquinoline library compounds.
- Aryl means one or more aromatic rings, each of 5 or 6 ring carbon atoms and includes substituted aryl having one or more non-interfering substituents. Multiple aryl rings may be fused, as in naphthyl, or unfused, as in biphenyl .
- Alkyl means straight or branched chain or cyclic hydrocarbon having 1 to 20 carbon atoms.
- Substituted alkyl is alkyl having one or more non- interfering substituents.
- Halo means chloro, fluoro, iodo or bromo .
- Heterocycle or “heterocyclic radical” means one or more rings of 5, 6 or 7 atoms with or without unsaturation or aromatic character, optionally substituted, and at least one ring atom which is not carbon. Preferred heteroatoms include sulfur, oxygen, and nitrogen. Multiple rings may be fused, as in quinoline or benzofuran, or unfused as in 4- phenylpyridine .
- “Substituted heterocycle” or “Substituted heterocyclic radical” is heterocycle having one or more non-interfering substituents.
- Suitable radicals for substitution on the heterocyclic ring structure include, but are not limited to halo, Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, C1-C10 alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl , di(C ⁇ _- C10) -alkylamino, C2-C12 alkoxyalkyl, Ci-C ⁇ alkylsulfinyl, Cl-Cio alkylsulfonyl, arylsulfonyl, aryl, hydroxy, hydroxy (C1-
- Organic moiety means a substituent comprising a non-interfering substituent covalently bonded through at least one carbon atom.
- Suitable radicals for substitution onto the connecting carbon atom include, but are not limited to hydrogen, halo, Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, C1-C10 alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, di (C ⁇ ⁇ C10) -alkylamino, C2-C12 alkoxyalkyl, Ci-Cg alkylsulfinyl, Cl-Cio alkylsulfonyl, arylsulfonyl, aryl, hydroxy, hydroxy (C1-C10) alkyl
- Optionally substituted aniline means aniline or aniline having at least one non-interfering substituent covalently bound to the benzene ring.
- Suitable radicals for substitution on the benzene ring include, but are not limited to halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, Cl-Cio alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, di (C1-C10 ) -alkylamino, C2-C12 alkoxyalkyl, C1-C6 alkylsulfinyl , C1-C10 alkylsulfonyl, arylsulfonyl, aryl, hydroxy, hydroxy (
- a diverse library of tetrahydroquinolines is provided in accordance with the present invention.
- the tetrahydroquinoline library embodied as an apparatus of this invention serves as a readily accessible source of diverse tetrahydroquinoline compounds for use in identifying new biologically active tetrahydroquinoline compounds through pharmaceutical and agricultural candidate screening assays, for use in studies defining structure/activity relationships, and/or for use in clinical investigation.
- the library provided in accordance with the present invention includes tetrahydroquinoline compounds of the formula (I) :
- Rx and Rx ' are independently hydrogen or non- interfering substituents derived from an optionally substituted aniline of the formula
- R2 is hydrogen or an organic moiety derived from an aldehyde of the formula R2CHO.
- Rx and Rx ' are independently selected from the group consisting of hydrogen and non-interfering substituents and R2 is alkyl, substituted alkyl, or aryl.
- Rx and Rx ' are independently selected from hydrogen and non-interfering substituents and R2 is C ⁇ C ⁇ o alkyl, substituted (C ⁇ -C ⁇ o alkyl), or aryl.
- Rx and Rx ' are independently hydrogen or non-interfering substituents selected from the group consisting of halo, C ⁇ -C ⁇ o alkyl, C2-C ⁇ o alkenyl, C2-C ⁇ o alkynyl, C ⁇ -C ⁇ o alkoxy, C7-CX2 aralkyl, C7-CX2 alkaryl, Cl-C ⁇ o alkylthio, arylthio, aryloxy, arylamino, C3-CX0 cycloalkyl, C3-CX0 cycloalkenyl, di (C ⁇ -C ⁇ rj ) -alkylamino, C2- I2 alkoxyalkyl, C ⁇ -C6 alkylsulfinyl, C ⁇ -C ⁇ o alkylsulfonyl , arylsulfonyl, aryl, hydroxy, hydroxy (C ⁇ )
- the present invention also provides a method for preparing the library of tetrahydroquinoline compounds of Formula I using combinatorial chemistry in a parallel array synthesis technique illustrated in the following reaction scheme:
- the method comprises the steps of reacting series of optionally substituted anilines, optionally substituted aldehydes and cyclopentadiene in the presence of a protic acid, for example trifluoroacetic acid, to prepare a library of tetrahydroquinoline compounds with three sites of diversity, Rx and Rl ' , derived from the aniline reagent, and R2 derived from the aldehyde reagent.
- a protic acid for example trifluoroacetic acid
- aniline and aldehyde reagents are either commercially available or prepared from commercially available starting materials.
- Anilines for use in accordance with this invention are compounds of the formula
- Rx and Rx ' are non-interfering groups, i.e., substituents which do not interfere with the reaction of the the aniline, aldehyde and cyclopentadiene.
- the aniline reactants typically have a molecular weight of about 100 to about 600.
- Suitable anilines for use in preparation of the tetrahydroquinoline library of this invention include, but are not intended to be limited to:
- Ethyl 3-aminobenzoate, methanesulfonic acid salt 4-Amino-3 -nitrobenzonitrile 2-Bromo-4, 5, 6-trifluoroaniline 4-Bromo-2 , 6-difluoroaniline 5-Amino-2-nitrobenzotrifluoride 2-Amino-6-fluorobenzonitrile 4-Amino-3-methoxybenzoic acid 2-Amino-4, 5-dimethoxyacetophenone 2-Amino-5-nitrobenzoic acid 3 , 5-Dibromoanthranilic acid 3 , 5-Dichloroanthranilic acid
- Suitable anilines for use in preparation of the tetrahydroquinoline library of this invention include, but are not intended to be limited to, those which are illustrated by the following formulas, wherein Lx and L2 are hydrogen:
- aldehyde reagents for use in the process for preparing the present library are represented by the general formula R2CHO, wherein R2 is hydrogen or an organic moiety.
- R2 is hydrogen or an organic moiety.
- aldehyde reagents have a molecular weight ranging from about 50 to about 600.
- aldehydes useful for forming the imine intermediates in preparation of the present tetrahydroquinoline libraries are further illustrated by the following formulas, wherein L is -CHO:
- the preparation of the tetrahydroquinoline library compounds of Formula I above comprises a one-step process wherein an optionally substituted aniline, an optionally substituted aldehyde and cyclopentadiene are allowed to react in the presence of acid, typically a protic acid and/or a Lewis acid, for example, trifluoroacetic .
- acid typically a protic acid and/or a Lewis acid, for example, trifluoroacetic .
- the progress/completion of the reactions can be determined by a number of conventional techniques including thin layer chromatography (TLC) .
- reaction is carried out at ambient temperature in acetonitrile, preferably in a single reaction step.
- reaction can be carried out as a two step process: (1) an intermediate imine forming step by reaction of equivalent amounts of an aldehyde and an optionally substituted aniline and (2) protic acid catalyzed cycloaddition of the intermediate imine with cyclopentadiene.
- aldehyde (about 1 molar equivalent per amount of aniline reactant) .
- reaction zone is then sealed and shaken at ambient temperature for about 12 to about 24 hours.
- the reaction mixture is then evaporated by vacuum to provide a library compound in each reaction zone.
- the product is dissolved in a mixture of acetone, methanol and methylene chloride and the resulting solution is evaporated to promote removal of residual volatiles.
- Samples of each library compound can be analyzed by chromatographic, or more preferably chromatographic and mass spectral techniques.
- the process of the present invention utilized in preparation of a library of tetrahydroquinolines of Formula I above may be carried out in any vessel capable of holding the liquid reaction medium.
- the process of the invention is carried out in containers adaptable to parallel array synthesis.
- the tetrahydroquinoline library of this invention can be formed in a 96-well plate as illustrated in Figures 1 and 2. That apparatus provides multiple reaction zones most typically in a two-dimensional array of defined reservoirs, wherein one member of the tetrahydroquinoline library of this invention is prepared in each reservoir.
- the diverse tetrahydroquinoline library of the present invention comprises a plurality of reservoir arrays (e.g.
- each reservoir or well containing a library compound of the tetrahydroquinoline library is typically identified by reference to their well plate number and their X column and Y row well plate coordinates .
- the compounds can be transferred in whole or in part to other reservoir arrays (e.g. well plates), to prepare multiple copies of the library apparatus or to subject the library to additional reaction conditions.
- Copies of the library apparatus (daughter well plates, each comprising a 2- dimensional array of defined reservoirs with each reservoir containing a predetermined member of the library) are useful as replaceable elements in automated assay machines.
- the apparatus of this invention allows convenient access to a wide variety of structurally related tetrahydroquinoline compounds.
- One preferred reservoir array for use in making and using this invention is a multi-well titer plate, typically a 96- well microtiter plate.
- Figure 1 illustrates the top surface of a well plate apparatus of the present invention.
- the well plate (1) is a plastic plate with 96-wells (depressions) capable of holding liquids for parallel array synthesis.
- Individual reaction products are prepared in each well and are labeled by the well plate coordinates.
- the library compound at location (2) is identified by the alpha numeric coordinate, "A6".
- FIG. 2 illustrates a side view of a modified well plate apparatus for use in preparation of the library of the present invention.
- Well plate (3) contains wells (4) with a filter (5), and a retaining frit (6), and a liquid reaction medium used in carrying out the process (7) .
- the wells have an outlet at the bottom which is sealed by gasket (8) held in place by a top cover (9) and bottom cover (10) maintained in position by clamps (11) .
- Such well plates are typically prepared using standard 96-well plates. A hole is drilled in the bottom of each well in the plates and a porous frit is placed in the bottom of each well. The plate is then placed in the clamp assembly to seal the bottom of the wells.
- Synthesis is initiated by adding reagents to their individual wells according to their assigned plate coordinates .
- the plate is then capped and tumbled to mix the reagents.
- the solvent and residual volatile reagents are evaporated with a Speed-vac.
- the residual products are redissolved in appropriate liquid solvent and the reaction products analyzed, for example, by thin layer chromatography, mass spectrometry and/or nuclear magnetic resonance spectrometry.
- the assay kit comprises as essential parts, (1) a well plate apparatus (containing one of the tetrahydroquinoline compounds in each of its individual wells), and (2) biological assay materials.
- the biological assay materials are generally known to be predictive of success for an associated disease state.
- Illustrative of biological assay materials useful in the kit of this invention are those required to conduct assays known in the art, which include, but are not intended to be limited to:
- Receptor-ligand binding Protein-Protein interaction, Protein-DNA interaction, and the like;
- Cell based, functional assays such as: Transcriptional regulation, Signal transduction/Second messenger, Viral Infectivity, and the like;
- Add, Incubate, & Read assays such as: Scintillation Proximity Assays, Angiotensin II IPA receptor binding assay, Endothelia converting enzyme [125j_] gp ⁇ assay, HIV proteinase [ ⁇ 5 ] gp ⁇ enzyme assay, Cholesteryl ester transfer (CETP) [ 3 H] SPA assay, Fluorescence Polarization Assays, Fluorescence Correlation Spectroscopy, Calorimetric biosensors,
- Receptor Gene Constructs for cell based assays Cellular reporter assays utilizing, for example, reporters such as luciferase, green fluorescent protein, Beta-lactamase, and the like
- Example 1 Tetrahydroquinoline Library Plates: General Procedure. A different optionally substituted aniline reagent (100 ⁇ L of a 0.5 M solution in CH3CN) was added to the wells of each row of a (several) 96-well glass titer plate (well volume of 1 mL) , with care taken that all liquid was added to the bottom of the wells and with minimum splattering. Trifluoroacetic acid was then added to each well (100 ⁇ L of a 0.45 M solution in CH3CN) , followed by a freshly prepared solution of cyclopentadiene (125 ⁇ L of a 1.6 M solution in CH3CN) . A different aldehyde (100 ⁇ L of a 0.5 M solution in
- CH3CN CH3CN
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP52785598A JP2001526633A (en) | 1996-12-18 | 1997-12-15 | Combination method for producing tetrahydroquinoline library |
EP97953185A EP1019720A1 (en) | 1996-12-18 | 1997-12-15 | Combinatorial process for preparing tetrahydroquinoline libraries |
CA002273882A CA2273882A1 (en) | 1996-12-18 | 1997-12-15 | Combinatorial process for preparing tetrahydroquinoline libraries |
AU56988/98A AU5698898A (en) | 1996-12-18 | 1997-12-15 | Combinatorial process for preparing tetrahydroquinoline libraries |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3249496P | 1996-12-18 | 1996-12-18 | |
US60/032,494 | 1996-12-18 |
Publications (1)
Publication Number | Publication Date |
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WO1998027427A1 true WO1998027427A1 (en) | 1998-06-25 |
Family
ID=21865229
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1997/022869 WO1998027427A1 (en) | 1996-12-18 | 1997-12-15 | Combinatorial process for preparing tetrahydroquinoline libraries |
Country Status (5)
Country | Link |
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EP (1) | EP1019720A1 (en) |
JP (1) | JP2001526633A (en) |
AU (1) | AU5698898A (en) |
CA (1) | CA2273882A1 (en) |
WO (1) | WO1998027427A1 (en) |
Families Citing this family (1)
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SE0301320D0 (en) * | 2003-05-06 | 2003-05-06 | Astrazeneca Ab | Positive modulators of nicotinic acetylcholine receptors |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5324483A (en) * | 1992-10-08 | 1994-06-28 | Warner-Lambert Company | Apparatus for multiple simultaneous synthesis |
-
1997
- 1997-12-15 AU AU56988/98A patent/AU5698898A/en not_active Abandoned
- 1997-12-15 CA CA002273882A patent/CA2273882A1/en not_active Abandoned
- 1997-12-15 EP EP97953185A patent/EP1019720A1/en not_active Withdrawn
- 1997-12-15 WO PCT/US1997/022869 patent/WO1998027427A1/en not_active Application Discontinuation
- 1997-12-15 JP JP52785598A patent/JP2001526633A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5324483A (en) * | 1992-10-08 | 1994-06-28 | Warner-Lambert Company | Apparatus for multiple simultaneous synthesis |
US5324483B1 (en) * | 1992-10-08 | 1996-09-24 | Warner Lambert Co | Apparatus for multiple simultaneous synthesis |
Non-Patent Citations (1)
Title |
---|
SYNTHESIS, September 1995, Vol. 9, KOBAYASHI et al., "Lanthanide Triflate Catalyzed Imino Diels-Alder Reactions; Convenient Syntheses of Pyridine and Quinoline Derivatives", pages 1195-1202. * |
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JP2001526633A (en) | 2001-12-18 |
CA2273882A1 (en) | 1998-06-25 |
EP1019720A1 (en) | 2000-07-19 |
AU5698898A (en) | 1998-07-15 |
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