Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N31/00—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/44—Resins; rubber; leather
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00281—Individual reactor vessels
  • B01J2219/00283—Reactor vessels with top opening
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
  • B01J2219/00308—Reactor vessels in a multiple arrangement interchangeably mounted in racks or blocks
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
  • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
  • B01J2219/00315—Microtiter plates
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00479—Means for mixing reactants or products in the reaction vessels
  • B01J2219/00484—Means for mixing reactants or products in the reaction vessels by shaking, vibrating or oscillating of the reaction vessels
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00495—Means for heating or cooling the reaction vessels
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
  • B01J2219/00547—Bar codes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00585—Parallel processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/0059—Sequential processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00599—Solution-phase processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/0068—Means for controlling the apparatus of the process
  • B01J2219/00686—Automatic
  • B01J2219/00689—Automatic using computers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/0068—Means for controlling the apparatus of the process
  • B01J2219/00695—Synthesis control routines, e.g. using computer programs
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/0068—Means for controlling the apparatus of the process
  • B01J2219/007—Simulation or vitual synthesis
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00718—Type of compounds synthesised
  • B01J2219/0072—Organic compounds
• • 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
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
  • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B70/00—Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes

Definitions

• the invention relates to the production of large catalogued libraries of reaction products for use, for example, in screening for pharmacological activity, providing pharmacological leads, and optimization of lead selection. More specifically, the invention provides methods for producing such libraries having a plurality of reaction products using solution-phase chemistry, and also provides an electronic database so that individual reaction products may be readily identified and characterized by their structure.
• the cost per compound is high.
• a chemist may typically produce between 50 and 100 purified compounds per year through conventional methods. This means that the cost per compound is in the range from $2,250.00 to $4,500.00 (assuming a conservative annual cost for chemist, including overhead, of $225,000.00). Because only a very small proportion of the total number of chemical compounds produced are found to have pharmacological uses, the cost per useful compound is even higher. Therefore, there exists a strong identified need to reduce the cost per chemical compound produced.
• the invention provides highly efficient methods for producing very large chemical libraries, especially chemical libraries of relatively small organic compounds Typically, such libraries find use in pharmacological activity screening, as pharmaceutical leads, in agricultural chemistry for testing as herbicides or pesticides, in food chemistry for use in flavors or fragrances, and the like.
• chemical libraries find use in pharmacological activity screening, as pharmaceutical leads, in agricultural chemistry for testing as herbicides or pesticides, in food chemistry for use in flavors or fragrances, and the like.
• the chemical libraries of the invention are accompanied by a coding and tracking system that enables the ready identification of the compound present in any of the large number of reaction products, along with its chemical structure, method of synthesis, substrate and reactants used in the synthesis, and other useful data.
• a method for producing a library of reaction products for screening for pharmacological activity In this method, the predetermined class of compounds to be screened for pharmacological activity is first established. Then, the method requires selecting at least one substrate able to produce reaction products that fall within the predetermined classes, when the substrate is reacted with reactants. A plurality of reactants, able to react with the substrate, to produce reaction products in the predetermined classes of compounds, is selected.
• a reaction pathway for reacting each of a multiplicity of individual samples of the substrate with at least one of the plurality of reactants, to produce a multiplicity of reaction products is determined.
• a reaction matrix for combining each of the samples of the substrate with an amount of a reactant through the selected reaction pathway is then developed.
• the invention provides for preparing a plurality of separate samples of the substrate and combining a predetermined amount of each of the reactants with a separate sample of the substrate, in accordance with the reaction matrix developed.
• these separate samples of the substrate are placed in separate vials, which are held in trays, able to hold many vials, placed upon shakers, so that the multiplicity of individual substrate samples with added reactant all simultaneously undergo reaction through desired reaction pathways.
• the reactions in each of the separate vials are quenched by adding a quenching agent. Thereafter, according to the invention, reaction products are extracted from the quenched solutions using a solvent.
• the extract produced, containing the reaction products desired, are each distributed into individual storage containers. Samples are then taken from each of these individual containers and redissolved in a suitable solvent in a sample container. The solvent is then removed from the sample product to produce dried reaction products ready for use in pharmacological activity screening.
• a reaction matrix may include, for example, x substrates, each of which must be reacted with y reactants, through a number of pathways, such as z pathways.
• x substrates each of which must be reacted with y reactants
• z pathways a number of pathways, such as z pathways.
• this multiplicity of reaction products is rapidly and efficiently produced by the synthesis method summarized above, and describe in more detail below.
• the invention provides a method of identification and an electronic database of information that supplies the chemical structure of the compound in the reaction product, and its method of synthesis, including substrates and reactants.
• a machine-readable code such as a bar code which may be readable by a laser reader.
• Reaction products formed are also tagged to allow subsequent identification of the chemical compound present, its chemical structure, substrate and reactant used to produce the reaction product, as well as the reaction pathway.
• the reaction matrix which includes the structure of the organic compound present in each reaction product, and the substrate and reactant used in making the reaction product, together with the reaction pathway, is retrievably stored in an electronic database.
• a reaction product has been identified as useful, its chemical structure and other particulars may readily be accessed from the database.
• the invention also provides a method for producing a chemical library for providing or optimizing pharmaceutical leads.
• These libraries are created in substantially the same manner as the screening libraries discussed above, except that the selection of substrate, reactants, and chemical pathways is determined by other factors.
• libraries of chemical leads are generally focused around a particular chemical that has already been found to have pharmacological activity and the development of other compounds with functional groups and structure varying to a limited extent from the known active compound.
• the method of identifying individual reaction products of the chemical library is the same as for the screening library.
• the combinatorial organic synthesis method of the invention for producing large chemical libraries is especially useful for use in pharmacological screening, and the provision of pharmacological leads or the selection of optimum leads, although other applications are also feasible.
• the organic compounds produced as reaction products have molecular weights in the range from about 200 to about 500 daltons, although larger or smaller compounds may also be produced.
• the invention also provides for the production of libraries of peptide-like compounds.
• reaction product refers to a relatively unrefined product of the reaction of a selected substrate with a selected reactant through a selected reaction pathway, which after one step of purification, such as solvent extraction, produces predominantly a desired chemical compound.
• the desired chemical compound is present in the reaction product, it is usually not present in highly purified form.
• the chemical libraries of the invention may be divided into two types, for ease of explanation.
• the chemical libraries may be developed for initial pharmacological lead identification.
• the molecular structural objective is undefined, except that the resultant chemical compound should be pharmacologically active.
• the production of "free" compounds is favored, although certain biological assays will accommodate compounds that are coupled to solid supports. Because of the large number of samples that must be screened to find a lead, a low cost per sample is desirable.
• the chemical library in order to develop, for example, a more optimal pharmacologically active compound, the chemical library must be more focused and the molecular diversity of the library is consequently more restricted.
• a more focused synthesis strategy is employed using specific building blocks and specific reactions and reaction orders. A free compound is almost always preferred for lead follow up, and a higher cost per sample is tolerated, because some biological activity has already been identified.
• a further advantage of the invention is that each reaction product is produced separately, in a small reaction vial container and samples of each can subsequently be transferred, for testing, to an even smaller container, such as a well in a microtiter plate.
• the reaction product is readily identifiable, both because it is separate and also because of the identification, cataloguing, and tracking methodology of the invention.
• a method of producing a chemical library for pharmacological activity testing proceeds with first determining the class of compounds to be tested for activity. Once the class or classes of compounds have been determined, a substrate, or substrates, are selected that are able to produce compounds within the predetermined class or classes, when each are reacted with a reactant. Reactants are then selected to react with the selected substrate, or substrates, through at least one, and possibly more, reaction pathways to produce reaction products in the predetermined classes of compounds.
• reaction matrix for example, as follows:
• n is the number of reaction pathways.
• the reaction product may not be AB, as shown but A' and a byproduct.
• the substrate or the reactant may be the reaction product of a prior chemical library, according to the invention.
• the reaction matrix may be entered into an electronic database which will then uniquely identify for each reaction product at least the substrate, reactant, and chemical pathway for producing the reaction product. Also, since the reaction product is produced by solution chemistry, the chemical structure of the reaction product is known and is preferably also entered into the electronic database, along with the aforementioned information.
• An exemplary database is ISIS, sold by MDL Information Systems of California.
• a single substrate and reaction pathway is exemplary and illustrates the methodology according to the invention which is readily adaptable to more substrates and reaction pathways by a person of ordinary skill in the art.
• the selected substrate is tagged with an identifying marking, preferably a bar code that is readable by a laser reader, although other tagging methods may also be used.
• the reactants are likewise marked, and a code is selected for the reaction pathway selected. This information is also entered into the electronic database, as explained above. The separate reactions between the substrate and reactants must now be physically performed.
• reaction vials In order to carry out these reactions, and produce separate reaction products, separate amounts of solutions of the substrate in a suitable nonreactive solvent must be placed into individual reaction vials. In order to identify these vials, they are either individually marked, or they may be placed within a tray, in an array of rows and columns, so that each vial is uniquely identified by the position that it occupies in the array. In the event that the row and column identifying method is used, then it is only necessary to identify the individual tray by a bar code. Thus, reaction vials may be placed in trays that are each individually marked with a bar code, while each individual vial on the tray is identified by its location by row and column.
• Solvents, reactive starting materials, and any additional chemicals such as catalysts, are added to the reaction vials according to the chosen reaction matrix.
• solution aliquots are preferably made of the reactants so that predetermined needed aliquots are added to each of the plurality of reaction vials, preferably in an automated or semi-automated liquid transfer process.
• reaction vials still in their marked trays, are then placed on orbital shakers where they are shaken for a predetermined amount of time according to the reaction matrix in order to allow chemical reaction to proceed to the desired extent for the production of desired reaction products.
• the manifolds of the shakers that hold the trays or reaction vials may be modified to control the temperature of the reaction vials within desired limits. Further, the reactions may proceed under an inert atmosphere, such as nitrogen or helium, if desirable or necessary.
• a quenching agent is added to each of the reaction vials.
• the quenching agent is also in solution to facilitate ready automated addition of an aliquot thereof to each of the reaction vials.
• a preselected extract solvent for the reaction products is added to each of the reaction vials and the reaction product is dissolved in this solvent.
• the extract, containing the reaction product, is removed from the reaction vial and transferred to storage vials.
• the reaction vials each contain one millimole of reaction product, then four replicate storage vials may each contain about 250 micromoles of reaction product.
• the storage vials are stripped of extraction solvent and any volatile components using an automated vacuum dryer, such as a Savant Speed Vac made by Savant Corp.
• an automated vacuum dryer such as a Savant Speed Vac made by Savant Corp.
• the reaction products are not subject to heat, or any other condition that may result in decomposition or altering the reaction product.
• a random sampling of reaction products from the storage vials is analyzed by a reliable method, such as ion spray mass spectroscopy to ensure successful reactions.
• a reliable method such as ion spray mass spectroscopy to ensure successful reactions.
• from about five to about ten percent of the reaction products should be sampled and tested.
• one of the storage vials of each reaction product is redissolved in an appropriate solvent and an aliquot of the solution sufficient to provide about 25 micromoles of reaction product is distributed into a well of a bar-coded microtiter plate, preferably a standard 96-well microtiter plate wherein the wells are arrayed by row and column.
• This operation can be carried out using a multi-probe automated multi-channel liquid handling system, such as a Packard multi-probe supplied by Packard Instrument Co.
• the microtiter plates are stripped of solvent, preferably in an automated vacuum solvent-removing process, taking care not to decompose the reaction product by exposure to heat or other decomposing conditions.
• reaction product is only placed in about 72 wells, leaving the remaining wells for use by the end user carrying out screening or lead optimization.
• a record is kept of the location of a particular reaction product on a particular microtiter plate, by row and column of the array of wells on the bar coded microtiter plate, so that the reaction product may be tracked back to the storage vial from which it originated, and thence back to the reaction vial and the original substrate, reactant, reaction pathway, and chemical structure of the desired chemical compound present in the reaction product, as recorded in the reaction matrix.
• the method of producing a chemical library is capable of providing a very large number of reaction products.
• each of these reaction products is identified by row and column of its position on a microtiter plate supplied to a chemical library user and its chemical structure, molecular weight, as well as the original substrate and reactant from which it is made through a particular pathway, is readily accessible from the electronic database.
• reaction vials containing reaction products it may be desirable to provide the reaction vials containing reaction products directly to the end user thereby eliminating subsequent steps of transferring to storage vials and thence to microtiter plates.
• the library is also catalogued, as described above, so that reaction products in each vial are uniquely identified.
• reaction may proceed directly in microtiter plate wells on orders of magnitude smaller scale.
• the plates are each bar coded and the location of each reaction product by row and column on each coded plate is recorded in an electronic data base.
• the reaction products are dried, as described above, by vacuum solvent removal and are then available for the end user.
• the methods of the invention eliminate the storage vials and transfer reaction products directly to wells in microtiter plates from the reaction vials. Again, as before, reaction products are tagged to ensure identification of each product in each well by recording identifying data in an electronic database. In making the transfer of reaction products to microtiter plate well, the reaction products are each extracted from the reaction vial product, the extract is transferred to the appropriate well, and the extract solvent is removed under vacuum.
• Example 1 A chemical library of 600 reaction products of amines and acid chlorides were produced. These products were the result of reacting 60 amines (listed in Table 1) with 10 acid chlorides (listed in Table 2) by a single reaction pathway. Each of the substrates, reactants and reaction pathway were assigned a bar code identifier which was recorded in an electronic database.
• samples of each of the substrates were dissolved in an appropriate solvent, anhydrous methylene chloride, to form a solution. Aliquots of each of these solutions were placed in 10 reaction vials to provide 600 reaction vials of substrate, contained in arrays of rows and columns on 50 vial capacity trays, each tray being marked with a bar-code identifier, recorded on an electronic database. The tray bar codes and location of vials by row and column on each tray were recorded on an electronic database.
• Ten solutions were prepared from individual samples of each of the ten acid chloride reactants in anhydrous methylene chloride as a solvent, and an aliquot of one of these solutions was added to each of the reaction vials, according to a predetermined reaction matrix, so that each of the ten vials containing a particular amine substrate received an aliquot of a different one of the ten reactant solutions.
• the trays containing the reaction vials were each placed on an orbital shaker, and shaken for about 240 minutes. At this point, the reactions were quenched with an aqueous saturated solution of sodium bicarbonate. Reaction product was extracted from each of the reaction vials using anhydrous methylene chloride as an extraction solvent. The extracts, containing the reaction products, were each transferred to storage vials, also contained in arrays on trays marked with a bar-code identifier which was recorded on an electronic database. The reaction product in each storage vial, identified by row and column, was recorded on an electronic database so that it could be traced back to the original reaction vial from which it came. The trays containing the storage vials were subjected to a vacuum until a dried reaction product was obtained.
• Table 4 An example of the output obtainable from the electronic database for each of the reaction products is shown in Table 4. It should be understood that, for 600 reaction products, 600 such outputs will be generated.
• Table 4 provides the chemical structure of the reaction product, shown in two-dimensional drawing in the upper left-hand corner of the outputs, substrate identification (Sub ID), and reagent identification (Reag ID), which are bar-code numbers assigned to the substrate and reagent starting materials.
• the reaction identification is also given, as "Rxn ED.” This number correlates to the reaction number given in the reaction summaries, exemplified in Table 3.
• the reaction center is also identified, as "Rxn Ctr.” Physical characteristics of the reaction product are given, as required, in the space headed "Phys. Charact.”
• the approximate date of synthesis of the reaction product is given under "Syn. Date.”
• the heading "QC” indicates whether the particular sample was one that was tested for quality control purposes.
• the molecular formula and weight of the theoretical reaction product is given.
• the bar-code number identifying the storage vial plate is given under "Master ID.”
• the space reserved for “Master Column” records the number identifying the location of a particular storage vial according to the column of the storage tray.
• the row in which the particular storage file is located on the storage tray is given under "Row.”
• the "client plate ID” records the bar-code number and well location of the reaction product in the microtiter plate.
• the remaining codes such as “Client ED,” “Project ID,” and “Comments” are self-explanatory.
• the invention has been described with reference to its preferred embodiments and as being exemplified in the above example. A person of ordinary skill in the art, having read the disclosure, will appreciate modifications and variations that are within the scope of the invention as described above and as claimed hereafter.

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• 1996
  • 1996-01-11 KR KR1019970704738A patent/KR19980701349A/ko not_active Application Discontinuation
  • 1996-01-11 WO PCT/US1996/000094 patent/WO1996021859A1/en not_active Application Discontinuation
  • 1996-01-11 AU AU46522/96A patent/AU697473B2/en not_active Ceased
  • 1996-01-11 CN CN96191914A patent/CN1173921A/zh active Pending
  • 1996-01-11 EP EP96902071A patent/EP0803063A4/de not_active Withdrawn
  • 1996-01-11 CA CA002210071A patent/CA2210071A1/en not_active Abandoned
  • 1996-01-11 JP JP8521733A patent/JPH11500419A/ja active Pending

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