WO1998027087A1 - Procede combinatoire de realisation d'echantillotheques de pyrimidines fondues - Google Patents

Procede combinatoire de realisation d'echantillotheques de pyrimidines fondues Download PDF

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Publication number
WO1998027087A1
WO1998027087A1 PCT/US1997/022839 US9722839W WO9827087A1 WO 1998027087 A1 WO1998027087 A1 WO 1998027087A1 US 9722839 W US9722839 W US 9722839W WO 9827087 A1 WO9827087 A1 WO 9827087A1
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WIPO (PCT)
Prior art keywords
library
formula
compounds
compound
fused
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Application number
PCT/US1997/022839
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English (en)
Inventor
Gunnar E. Jagdmann, Jr.
Original Assignee
Eli Lilly And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to EP97953179A priority Critical patent/EP0946549A1/fr
Priority to CA002274022A priority patent/CA2274022A1/fr
Priority to AU56983/98A priority patent/AU5698398A/en
Priority to JP52784798A priority patent/JP2001508049A/ja
Publication of WO1998027087A1 publication Critical patent/WO1998027087A1/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
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • the present invention relates to libraries of fused pyrimidine compounds, methods of making such libraries, and an apparatus for storing and providing a readily accessible source of diverse fused pyrimidine compounds .
  • the apparatus harboring the present combinatorial libraries is a useful component of assay systems for identifying compounds for drug development.
  • combinatorial chemistry to generate large numbers (10 2 - 10°) of compounds generically referred to as "libraries".
  • An important objective of combinatory chemistry is to generate a large number of novel compounds that can be screened to generate lead compounds for pharmaceutical research. Theoretically 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.
  • a single reaction product is prepared in each separate vessel.
  • 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/assaying .
  • Combinatorial chemistry is typically conducted on a solid support, normally a polymer.
  • the library scaffold is releasably tethered to the solid support through a chemically cleavable divalent linking group.
  • Reactions are carried out to modify the scaffold while it remains tethered to the solid support.
  • the product is cleaved and released from the solid support.
  • combinatorial libraries can also be prepared in solution phase. To ensure the completion of the solution phase reactions one reagent is typically added in considerable excess. Thus completion of the reaction produces a soluble product with at least one soluble unreacted reactant . Accordingly, as a final step a polymer scavenger having functional groups reactive with the excess reagent is used to remove the excess reagent .
  • 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 fused pyrimidines useful in the identification of new lead compounds.
  • the library is created, stored and used as an apparatus comprising a 2-dimensional array of reservoirs, each reservoir containing one predetermined compound of the library differing from those in laterally adjacent reservoirs in only one substituent group.
  • the present invention provides combinatorial arrays of structurally related compounds having fused pyrimi )
  • R is an organic group derived from a primary amine of the formula RNH2
  • the fusion ring (“A") is an aromatic ring or a non-aromatic ring, either of which can be heterocylic.
  • the invention further provides a method for generating fused pyrimidine libraries generally in accordance with Scheme 1 or Scheme 2 as set forth below.
  • One embodiment the present invention provides an assay kit for the identification of pharmaceutical lead fused pyrimidine compounds, said kit 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 member of the fused pyrimidine library.
  • the well plate apparatus is used to provide multiple reaction zones for making the library and to store and provide a readily accessible source of library member compounds .
  • assay kit refers to an assemblage of two cooperative elements, namely (1) a well plate apparatus and (2) biological assay materials.
  • Bio 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 “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 fused pyrimidine 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”).
  • a “diverse library” means a library where the substituents on the fused pyrimidine combinatorial library scaffold 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”).
  • “Lead compound” means a compound in a selected combinatorial library for which the assay kit has revealed significant activity 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 fused pyrimidine ring system.
  • a “library compound” is an individual reaction product (usually a single compound) in a combinatorial library.
  • Paraallel array synthesis refers to the method of conducting combinatorial chemical synthesis of libraries wherein the individual combinatorial library reaction products 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 wellplate apparatus.
  • scaffold refers to the invariable region (a fused pyrimidine core in the present invention) of the compounds which are members of the combinatorial library.
  • “Simultaneous synthesis” means making of a library of compounds within one production cycle of a combinatorial method (not making all library compounds at the same instant in time) .
  • Substituents are chemical radicals which are bonded to or incorporated in the 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 biologically 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.
  • ellplate apparatus refers to the structure capable of holding a plurality of library compounds of dimensionally fixed and defined positions.
  • Non-interfering substituent are those groups that do not significantly impede the process of the invention and yield stable fused pyrimidine library compounds.
  • Suitable non-interfering radicals 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, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, phenyl, substituted phenyl, toluoyl, xylenyl, biphenyl, 2- 12 alkoxyalkyl, C1-C6 alkylsulfinyl, C1-C10 alkylsulfonyl, - (CH2 )m ⁇ 0- (C1-C10 alkyl), aryl, substituted aryl, substituted alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclic radical, substituted heterocyclic radical, and nitroalkyl, where m is from 1 to 8.
  • Preferred non-interfering radicals are C ⁇ -C ⁇ o alkyl, C2-C10 alkenyl, C1-C10 alkoxy, C7-C12 aralkyl, C7- C12 alkaryl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, phenyl, - (CH2 )m ⁇ 0- (C1-C10 alkyl), aryl, and substituted aryl .
  • Aryl means one or more aromatic rings, each of 5 or 6 carbon atoms. Multiple aryl rings may be fused, as in naphthyl or unfused, as in biphenyl.
  • Substituted aryl is aryl having one or more non-interfering groups as substituents.
  • Alkyl means straight or branched chain or cyclic hydrocarbon having, typically 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” means one or more rings of 5, 6 or 7 atoms with or without unsaturation or aromatic character 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 of benzofuran.
  • Substituted heterocycle is heterocycle having one or more side chains formed from non-interfering substituents.
  • a diverse library of fused pyrimidines is provided in accordance with the present invention.
  • the fused pyrimidine library embodied as an apparatus of this invention serves as a readily accessible source of a wide variety of structurally related compounds for use in identifying new biologically active compounds through drug/agricultural candidate screening assays, for use in defining structure activity relationship studies, and/or for use in clinical investigation.
  • the method comprises the steps of preparing aromatic or aliphatic formamidine or formamidate intermediates from the illustrated cyanoamine compounds and reacting each intermediate with a series of primary amines (RNH2) to prepare a library of fused pyrimidine compounds. While dimethylformamide and trimethylorthoformate are preferred reactants for forming the respective intermediates, other formamidine and formimidate forming reactants, e.g., di(C ⁇ -C4 alkyl) formamide acetals and tri (C1-C4 alkyl) orthoformates, can be employed.
  • Each formamidine/formimidate intermediate is prepared and further reacted with a primary amine in a separate reaction chamber (i.e. parallel array synthesis), and the reaction product is identified by the reaction well number.
  • the fused ring A is an aromatic ring or a non- aromatic ring, either of which can be heterocyclic.
  • Illustrative of the divalent group A forming the ring structure above and in the other formulas defining the present invention, including Formulas I and II above, include, but are not intended to be limited to, the following groups :
  • Li and 2 are the points of bonding with the rest of the molecule.
  • the primary amines used in accordance with the process of this invention in preparation of the present fused pyrimidine libraries are compounds of the formula RNH2 wherein R is an alkyl or substituted alkyl group having substituents which do not interfere with the pyrimidine forming reaction.
  • R is an alkyl or substituted alkyl group having substituents which do not interfere with the pyrimidine forming reaction.
  • the primary amine reactants have a molecular weight of about 30 to about 600.
  • R groups in the definition of the present invention include, but are not intended to be limited to, the following radicals:
  • L is the point of bonding to the nitrogen atom to which the group is bound.
  • exemplary of primary amines useful in the process of this invention are the compounds represented by those formulas wherein L is - NH2.
  • (+/-) -exo-2-aminonorbornane (s) - (+) -2- (aminomethyl) pyrrolidine 3-amino-l-propanol vinyl ether geranylamine
  • Additional primary amines suitable for use in the process of the invention for preparing fused pyrimidine libraries are those represented by the following formulae:
  • the preparation of the fused pyrimidine library compounds of Formula II comprises a two step process wherein a formamidine intermediate is first formed and subsequently reacted with a primary amine to prepare a broad array of fused pyrimidine compounds in accordance with scheme 1.
  • those compounds can be prepared in accordance with Scheme 2 via a formimidate intermediate and thermal rearrangement of the library compounds of Formula I .
  • a library of fused pyrimidines of Formula I are prepared, and a portion of each of the product compounds are converted to the corresponding compounds of Formula II to produce a separate library.
  • the completion of the reactions between the primary amine and the formamidine/formimidate intermediates and the conversion of the compounds of Formula I to those of Formula II can be determined by a number of conventional techniques including thin layer chromatography (TLC) .
  • TLC thin layer chromatography
  • the process of the present invention may be carried out in any vessel capable of holding the liquid reaction medium and having an inlet and outlet means. In one embodiment the process of the invention is carried out in containers adaptable to parallel array synthesis.
  • the process of this invention is carried out in an apparatus providing multiple reaction zones, most typically a two-dimensional array of defined reservoirs, wherein one member of the fused pyrimidine libraries of this invention is prepared in each reservoir.
  • the diverse fused pyrimidine library of the present invention comprises a plurality, of reservoir arrays, e,g., well plates, each reservoir or well containing a unique member of the fused pyrimidine library. Accordingly the library compounds are 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 to prepare multiple copies of the library apparatus or to subject the library to additional reaction conditions.
  • Copies of the library apparatus (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 fused pyrimidine 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.
  • an assay kit for the identification of pharmaceutical lead compounds.
  • the assay kit comprises as essential parts, (1) a well plate apparatus (containing one of the fused pyrimidine 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: In vitro assays such as:
  • 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 [125 ⁇ ] SPA assay,
  • HIV proteinase [ 125 I] SPA enzyme assay, Cholesteryl ester transfer (CETP) [ 3 H] SPA assay, Fluorescence Polarization Assays, Fluorescence Correlation Spectroscopy,
  • Colorimeric biosensors Ca ⁇ + -EGTA for Cell-based assays, Receptor Gene Constructs for cell based assays, Cellular reporter assays utilizing, for example, reporters such as luciferase, green fluorescent protein, B-lactamase, and the like; Electrical cell impedance sensor assays, and the like.
  • the titled compounds were prepared from the appropriate acid chloride and aminomalononitrile tosylate in N-methylpyrrolidin-2-one according to the general procedure of Freeman, F.; Kim, D. S. H. L. Tetrahedron Let t . 1989, 30, 2631-2.
  • the titled compounds were prepared from the appropriate primary amine, aminomalononitrile tosylate, triethyl orthoformate, triethylamine, and acetonitrile according to the general procedure of Birkett, P. R. ; Chapleo, C. B.: Mackenzie, G. Synthesis 1991, 822 - 4.
  • a 96-well 1 mL deep well glass well titer plate was charged with 50 uMol of each formamidine solution in rows, with care taken that all liquid was added to the bottom of the wells, with minimum splattering.
  • the solvents were evacuated, then acetonitrile (200 uL) was added to each well, and the plate was gently heated in a 96-well heat block (USA Scientific) with moderate shaking at 60°C with no caps for about 15 min in order to dissolve most material.
  • a 96-well deep well glass plate was charged with 0.25N solutions of eight different aminonitriles in methanol or methylene chloride/methanol, by rows (300 uL, 75 uMol per well) .
  • the plate was evacuated of solvent, and each well was charged with a slurry (400 uL, 10 mg contained) made from taking up 1.5g of dried sulfonic acid resin (DOWEX® type, 5 mmol/g dry loading) in 9 mL of methanol and diluting the mixture to 60 mL with methylene chloride.
  • DOWEX® type dried sulfonic acid resin
  • the wells were again evacuated of solvent, then charged with trimethyl orthoformate (400 uL/well) , and the plate was capped with strip caps, clamped into a heat block, and shaken at 65 - 70°C for 40 -72 h.
  • the plate was cooled and uncapped, and the contents were transferred by robot through a 96-well filter plate into another 96-well deep well glass plate. Methylene chloride (250 uL per well) was added to the original plate, and the contents were again transferred into the filter plate.
  • the receiving plate was evacuated of solvent, then acetonitrile (200 uL per well) was added.
  • the plate was cooled and uncapped, and the contents were transferred by robot through a 96-well filter plate into another 96-well deep well glass plate. Methylene chloride (250 uL per well, DMF substituted if solubility is a problem) was added to the original plate, and the contents were again transferred into the filter plate.
  • the receiving plate was evacuated of solvent, then each well was treated with a slurry made by suspending 3.5g of polystyrene carboxaldehyde resin (1.7 mmol/g) in 5:1 dichloroethane/methanol (70 mL) . Strip caps were added, and the plate was clamped into the heat block and shaken at 50-55°C for 4-6h, then at room temperature for 16h.
  • each well was transferred by robot through a 96-well filter plate into a plate suitable for compound storage, then methylene chloride (250 uL per well) or DMF (if needed) was added to the original plate, and the contents were again transferred into the filter plate. TLC analysis was performed on each well, and the product plate was evacuated of solvent.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle échantillothèque combinatoire diversifiée de composés de pyrimidines fondues et un dispositif donnant facilement accès aux différents éléments de l'échantillothèque. Le dispositif peut s'utiliser pour des trousses d'essais et comme élément de remplacement dans des machines de dosage automatisé.
PCT/US1997/022839 1996-12-18 1997-12-15 Procede combinatoire de realisation d'echantillotheques de pyrimidines fondues WO1998027087A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP97953179A EP0946549A1 (fr) 1996-12-18 1997-12-15 Procede combinatoire de realisation d'echantillotheques de pyrimidines fondues
CA002274022A CA2274022A1 (fr) 1996-12-18 1997-12-15 Processus combinatoire de preparation de bibliotheques de pyrimidines fondues
AU56983/98A AU5698398A (en) 1996-12-18 1997-12-15 Combinatorial process for preparing fused pyrimidine libraries
JP52784798A JP2001508049A (ja) 1996-12-18 1997-12-15 縮合ピリミジンライブラリーの組合せ的製造法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3429596P 1996-12-18 1996-12-18
US60/034,295 1996-12-18

Publications (1)

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WO1998027087A1 true WO1998027087A1 (fr) 1998-06-25

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PCT/US1997/022839 WO1998027087A1 (fr) 1996-12-18 1997-12-15 Procede combinatoire de realisation d'echantillotheques de pyrimidines fondues

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EP (1) EP0946549A1 (fr)
JP (1) JP2001508049A (fr)
AU (1) AU5698398A (fr)
CA (1) CA2274022A1 (fr)
WO (1) WO1998027087A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064033A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Medicaments modulateurs de la phosphodiesterase-5 et leurs utilisations

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3948913A (en) * 1971-04-27 1976-04-06 Ciba-Geigy Corporation New 5-nitrofuryl derivatives
US4044130A (en) * 1974-07-03 1977-08-23 Ciba-Geigy Corporation Compositions for the control of microorganisms
US4053474A (en) * 1976-04-21 1977-10-11 E. R. Squibb & Sons, Inc. Pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine
US4146716A (en) * 1975-11-28 1979-03-27 Imperial Chemical Industries Limited Thienopyrimidines
US4189483A (en) * 1977-03-23 1980-02-19 Imperial Chemical Industries Limited Pesticidal compounds, compositions and processes
US4196207A (en) * 1977-05-23 1980-04-01 Ici Australia Limited Process for controlling eradicating or preventing infestations of animals by Ixodid ticks
US4562193A (en) * 1982-07-21 1985-12-31 Sankyo Company Limited 4-[2-(Di- or trisubstitutedphenoxy)ethyl amino]thienodipyrimidines and insecticidal and acaricidal composition containing said pyrimidines
US4659727A (en) * 1984-09-11 1987-04-21 May & Baker Limited Ethene derivatives

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3948913A (en) * 1971-04-27 1976-04-06 Ciba-Geigy Corporation New 5-nitrofuryl derivatives
US4044130A (en) * 1974-07-03 1977-08-23 Ciba-Geigy Corporation Compositions for the control of microorganisms
US4146716A (en) * 1975-11-28 1979-03-27 Imperial Chemical Industries Limited Thienopyrimidines
US4053474A (en) * 1976-04-21 1977-10-11 E. R. Squibb & Sons, Inc. Pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine
US4189483A (en) * 1977-03-23 1980-02-19 Imperial Chemical Industries Limited Pesticidal compounds, compositions and processes
US4196207A (en) * 1977-05-23 1980-04-01 Ici Australia Limited Process for controlling eradicating or preventing infestations of animals by Ixodid ticks
US4562193A (en) * 1982-07-21 1985-12-31 Sankyo Company Limited 4-[2-(Di- or trisubstitutedphenoxy)ethyl amino]thienodipyrimidines and insecticidal and acaricidal composition containing said pyrimidines
US4659727A (en) * 1984-09-11 1987-04-21 May & Baker Limited Ethene derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064033A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Medicaments modulateurs de la phosphodiesterase-5 et leurs utilisations

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EP0946549A1 (fr) 1999-10-06
CA2274022A1 (fr) 1998-06-25
AU5698398A (en) 1998-07-15
JP2001508049A (ja) 2001-06-19

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