CA2210949A1 - A method of generating a plurality of chemical compounds in a spatially arranged array - Google Patents
A method of generating a plurality of chemical compounds in a spatially arranged arrayInfo
- Publication number
- CA2210949A1 CA2210949A1 CA002210949A CA2210949A CA2210949A1 CA 2210949 A1 CA2210949 A1 CA 2210949A1 CA 002210949 A CA002210949 A CA 002210949A CA 2210949 A CA2210949 A CA 2210949A CA 2210949 A1 CA2210949 A1 CA 2210949A1
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- Canada
- Prior art keywords
- array
- compounds
- molecular
- reaction site
- chemical
- Prior art date
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- Abandoned
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Classifications
-
- 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
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
-
- 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
- C40B30/00—Methods of screening libraries
- C40B30/04—Methods of screening libraries by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
-
- 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
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/773—Nanoparticle, i.e. structure having three dimensions of 100 nm or less
- Y10S977/774—Exhibiting three-dimensional carrier confinement, e.g. quantum dots
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/778—Nanostructure within specified host or matrix material, e.g. nanocomposite films
- Y10S977/779—Possessing nanosized particles, powders, flakes, or clusters other than simple atomic impurity doping
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/788—Of specified organic or carbon-based composition
- Y10S977/789—Of specified organic or carbon-based composition in array format
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/788—Of specified organic or carbon-based composition
- Y10S977/789—Of specified organic or carbon-based composition in array format
- Y10S977/79—Of specified organic or carbon-based composition in array format with heterogeneous nanostructures
- Y10S977/791—Molecular array
Abstract
This invention is directed to an m x n array of different chemical compounds wherein each of said compounds has at least one structural diversity element selected from a group of amines and ketones and wherein the scaffold structure is selected from a group consisting of aminimide, imidazolone, sulfonylaminimide and phosphonylaminimide.
Description
W O 96/22529 PCTrUS96/01005 A METHOD OF ~N~R~TING A PLURU~LITY OF
CHEMICAL COMPOUND8 IN A SPATIALLY ~RR~NGED ARRAY
Backqround of the Invention The discovery of new molecules has traditionally focused in two broad areas, biologically active molecules, which are used as drugs for the treatment of life-threatening diseases, and new materials, which are used in commercial, especially high technological applications. In both areas, the strategy 10 used to discover new molecules has involved two basic operations: (i) a more or less random choice of a molecular candidate, prepared either via chemical synthesis or isolated from natural sources, and (ii) the testing of the molecular candidate for the property or properties of interest. This 15 discovery cycle is repeated indefinitely until a molecule possessing the desirable properties is located. In the majority of cases, the molecular types chosen for testing have belonged to rather narrowly defined chemical classes.
For example, the discovery of new peptide hormones has 20 involved work with peptides; the discovery of new therapeutic steroids has involved work with the steroid nucleus; the discovery of new surfaces to be used in the construction of computer chips or sensors has involved work with inorganic materials, etc. (for example, see R. Hirschmann, Angew.
25 Chem., Int. Ed. in Engl. 1991, 30, 1278-1301). As a result, the discovery of new functional molecules, being, ad hoc in nature and relying predominantly on serendipity, has been an extremely time-consuming, laborious, unpredictable, and costly enterprise.
A brief account of the strategies and tactics used in the discovery of new molecules is described below. The emphasis is on biologically interesting molecules. However, as discussed below, there are technical problems encountered in the discovery of molecules and in the development of 35 fabricated materials which can serve as new materials for high technological applications.
Modern theories of biological activity state that R~FJ~D SHEET (RULE 91) PCTrUS9G/0100 biological activities, and therefore physiological states, are the result of molecular recognition events. For example, nucleotides can form complementary base pairs so that complementary single-stranded molecules hybridize resulting 5 in double- or triple-helical structures that appear to be involved in regulation of gene expression. In another example, a biologically active molecule, referred to as a ligand, binds with another molecule, usually a macromolecule referred to as ligand-acceptor (e.g. a receptor or an 10 enzyme), and this binding elicits a chain of molecular events which ultimately gives rise to a physiological state, e.g.
normal cell growth and differentiation, abnormal cell growth leading to carcinogenesis, blood-pressure regulation, nerve-impulse-generation and -propagation, etc. The binding 15 between ligand and ligand-acceptor is geometrically characteristic and extraordinarily specific, involving appropriate three-dimensional structural arrangements and chemical interactions.
20 Desiqn and S~nthesis of Mimetics o~ Bioloqical Liqands A currently favored strategy for development of agents which can be used to treat diseases involves the discovery of forms of ligands of biological receptors, enzymes, or related macromolecules, which mimic such ligands and either boost 25 (i.e., agonize) or suppress (i.e., antagonize) the activity of the ligand. The discovery of such desirable ligand forms has traditionally been carried out either by random screening of molecules (produced through chemical synthesis or isolated from natural source's, for example, see K. NakAn;~h;, Acta 30 Pharm. Nord., 1992, 4, 319-328.), or by using a so-called "rational" approach involving identification of a lead-structure, usually the structure of the native ligand, and optimization of its properties through numerous cycles of structural redesign and biological testing (for example see 35 Testa, B. & Kier, L. B. Med. Res. Rev. 1991, 11, 35-48 and Rotstein, S. H. & Murcko, M. A. J. Med. Chem. ~ 993, 36, 1700-1710.). Since most useful drugs have been discovered not RECI IFIEl~ Sl IEET (RULE 91) F
through the "rational" approach but through the screening of randomly chosen compounds, a hybrid approach to drug discovery has recently emerged which is based on the use of combinatorial chemistry to construct huge libraries of 5 randomly-built chemical structures which are screened for specific biological activities. (Brenner, S. & Lerner, R. A.
Proc. Natl. Acad. Scl. USA 1992, 89, 5381) Most lead-structures which have been used in "rational"
drug design are native polypeptide ligands of receptors or 10 enzymes. The majority of polypeptide ligands, especially the small ones, are relatively unstable in physiological fluids, due to the tendency of the peptide bond to undergo facile hydrolysis in acidic media or in the presence of peptidases.
Thus, such ligands are decisively inferior in a ~5 pharmacokinetic sense to nonpeptidic compounds, and are not favored as drugs. An additional limitation of small peptides as drugs is their low affinity for ligand acceptors. This phenomenon is in sharp contrast to the affinity demonstrated by large, folded polypeptides, e.g., proteins, for specific 20 acceptors, e.g., receptors or enzymes, which can be in the subnanomolar range. For peptides to become effective drugs, they must be transformed into nonpeptidic organic structures, i.e., peptide mimetics, which bind tightly, preferably in the nanomolar range, and can withstand the chemical and 25 biochemical rigors of coexistence with biological fluids.
Despite numerous incremental advances in the art of peptidomimetic design, no general solution to the problem of converting a polypeptide-ligand structure to a peptidomimetic has been defined. At present, "rational" peptidomimetic 30 design is done on an ad hoc basis. Using numerous redesign-synthesis-screening cycles, peptidic ligands belonging to a certain biochemical class have been converted by y~OUpS of organic chests and pharmacologists to specific peptidomimetics; however, in the majority of cases the 35 results in one biochemical area e.g., peptidase inhibitor design using the enzyme substrate as a lead, cannot be transferred for use in another area, e.g., tyrosine-kinase ltU SHEET (RULE 91) W 096/22529 PCTrUS96/01005 inhibitor design using the kinase substrate as a lead.
In many cases, the peptidomimetics that result from a peptide structural lead using the "rational" approach comprise unnatural amino acids. Many of these mimetics 5 exhibit several of the troublesome features of native peptides (which also comprise alpha-amino acids) and are, thus, not favored for use as drugs. Recently, fundamental research on the use of nonpeptide scaffolds, such as steroidal or sugar structures, to anchor specific receptor-10 binding groups in fixed geometric relationships have beendescribed (see for example Hirschmann, R. et al. ~. Am. Chem.
Soc. 1992, 114, 9699-9701; Hirschmann, R. et al., ~. Am.
Chem. Soc., 1992, 114, 9217-9218); however, the success of this approach remains to be seen.
In an attempt to accelerate the identification of lead-structures, and also the identification of useful drug candidates through screening of randomly chosen compounds, researchers have developed automated methods for the generation of large combinatorial libraries of peptides and 20 certain types of peptide mimetics, called "peptoids", which are screened for a desirable biological activity (see Gordon, E. M. et al. ~. Med. Chem. 1994, 37, 1385-1401). For example, the method of H. M. Geysen, (Bioorg. Med. Chem.
Letters, 1993, 3, 397-404; Proc. Natl. Acad. sci. USA 1984, 25 81, 3998) employs a modification of Merrifield peptide synthesis, wherein the C-terminal amino acid residues of the peptides to be synthesized are linked to solid-support particles shaped as polyethylene pins; these pins are treated individually or collectively in sequence to -ntroduce 30 additional amino-acid residues forming the desired peptides.
The peptides are then screened for activity without removing them from the pins. Houghton, (Proc. Natl. Acad. Sci. USA
1985, 82, 5131; Eichler, J. ~ Houghton, R. A. Biochemi ~try, 1993, 32, 11035-11041, and U.S. Patent ~o. 4,631,211) 35 utilizes individual polyethylene bags ( tea bags") containing C-terminal amino acids bound to a solid support. These are mixed and coupled with the requisite amino acids usir.g solid RECTIFIED SHEET (RULE 91' W096/22529 PCT~S9610100S
phase synthesis t~chn;ques. The peptides produced are then recovered and tested individually. S. P. A. Fodor et al., (Science 1991, 2~1, 767) described light-directed, spatially addressable parallel-peptide synthesis on a silicon wafer to ~ 5 generate large arrays of addressable peptides that can be directly tested for binding to biological targets. These ~ workers have also developed recombinant DNA/genetic engineering methods for expressing huge peptide libraries on the surface of phages (Cwirla et al. Proc. Natl. Acad. Sci.
10 USA 1990, 87, 6378; Barbas, et al. Proc. Natl. Acad. Sci. USA
1991, 881, 7978-7~82).
In another combinatorial approach, V. D. Huebner and D.V. Santi (U.S. Patent No. 5,182,366) utilized functionalized polystyrene beads divided into portions each 15 of which was acylated with a desired amino acid; the bead portions were mixed together, then divided into portions each of which was re-subjected to acylation with a second desirable amino acid producing dipeptides, using the techniques of solid phase peptide synthesis. By using this 20 synthetic scheme, exponentially increasing numbers of peptides were produced in uniform amounts which were then separately screened for a biological activity of interest.
Zuckermann and coworkers (For examples, see Zuckermann, et al. J. Med. Chem. 1994, 37, 2678-2685 ~ Zuckermann, et al.
25 Int. J. Peptide Protein ~es. 1992, 91, 1) also have developed similar methods for the synthesis o~ peptide libraries and applied these methods to the automation of a modular synthetic chemistry for the production of libraries of N-alkyl glycine peptide derivatives, called "peptoids", which 30 are screened for activity against a variety of biochemical targets. (See also, Symon et al., Proc . Natl . Acad . Sci .
USA, 1992, 89, 9367). Encoded combinatorial chemical syntheses have been described recently (Brenner, S. & Lerner, R. A. Proc. Natl. Acad. Sci. USA 1992, 89, 5381; Barbas, C.
35 F. et al. Proc. Natl. Acad. Sci. USA '992, 89, 4 57-4461; see also Borchardt, A. & Still, W. C. J. Am. Chem. Soc. 1994, 116, 373-374; Kerr, J. et al. J. Am. Chem. Soc. 1993, 115, ~C~ u SHEEr (RULE 91) W096/22529 PCT~S96/01005 2529-2531).
M. J. Kurth and his group (Chen, C. et al. ~. Am. Chem .
Soc. 1994, 116, 2661-2662.) have applied organic synthetic strategies to develop non-peptide libraries synthesized using 5 multi-step processes on a polymer support. Although the method demonstrates the utility of standard organic synthesis in the application and development of chemical libraries, the synthetic conditions are limited by compatibility with the solid support.
The development of substrates or supports to be used in separations has involved either the polymerization/crosslinking of monomeric molecules under various conditions to produce fabricated materials such as beads, gels, or films, or the chemical modification of 15 various commercially available fabricated materials e.g., sulfonation of polystyrene beads, to produce the desired new materials. In the majority of cases, prior art support materials have been developed to perform specific separations or types of separations and are thus of limited utility.
20 Many of these materials are incompatible with biological macromolecules, e.g., reverse-phase silica frequently used to perform high pressure liquid chromatography can denature hydrophobic proteins and other polypeptides. Furthermore, many supports are used under conditions which are not 25 compatible with sensitive biomolecules, such as proteins, enzymes, glycoproteins, etc., which are readily denaturable and sensitive to extreme pH's. An additional difficulty with separations carried out using these supports is that the separation results are often support-batch dependent, i.e.
30 they are irreproducible.
Rec~ntly a variety of coatings and composite-forming materials have been used to modify commercially available fabricated materials into articles with improved properties;
however the success of this approach remains to be seen.
If a chromatographic support is equipped with molec~les which bind specifically with a component of a complex mixture, that component will be separated from the mixture tL) SHEET (RULE 91) W 096/22529 PCTrUS9G/0100~
and may be released subsequently by changing the experimental conditions (e.g., buffers, stringency, etc.) This type of separation is appropriately called "affinity chromatography"
and remains an extremely effective and widely used separation 5 ter-hn;que (see Perry, E. S. in Techniques of Chemistry, Vol.
12 (J. Wiley) & May, S. W. in Separations and Purification 1978, 3rd ed.). It is certainly much more selective than traditional chromatographic tec-hn;ques, e.g chromatography on silica, alumina, silica or alumina coated with long-r-hA;n 10 hydrocarbons, polysaccharide and other types of beads or gels which in order to attain their maximum separating efficiency need to be used under conditions that are damaging to biomolecules, e.g., conditions involving high pressure, use of organic solvents and other denaturing agents, etc. (for 15 example see Stewart, D. J., et al. ~. Biotechnology 1989, 11, 253-266; Brown, E., et al. Int. Symp. Affinity.
Chromatography & Mo7ecular Interactions 1979, 86, 37-50).
The development of more powerful separation technologies depends significantly on breakthroughs in the field of 20 materials science, specifically in the design and construct-on of materials that have the power to recognize specific molecular shapes under experimental conditions resembling those found in physiological media, i.e. , these experimental conditions must involve an aqueous medium whose temperature 25 and pH are close to the physiological levels and which contains none of the agents known to damage or denature biomolecules. The construction of these "intelligent"
materials freguently involves the introduction of small molecules capable of specifically recognizing others into 30 existing materials, e.g. surfaces, films, gels, beads, etc., by a wide variety of chemical modifications; alternatively molecules capable of recognition are converted to monomers and used to create the "intelligent" materials through polymerization reactions.
Advances in the ability to synthesize large numbers of peptides have made it possible to create a vast array of combinations of microenvironments within which different D SHEET(RU~E 91) W096/22529 PCT~S96/OlOOS
proteins may interact in equally. Kauvar (U.S. Patent 5,340,474) has developed a chromatographic method to obtain ligands which have the required affinity specific for a selected member of an array of analytes by providing maximal 5 diversity in the choice of these ligands. A key to this technology is the use of a flow-through 96-well plate compatible for assaying large numbers of parallel samples.
Their short peptide-based ligands as paratope analogs (or "paralogs") contain an N-terminal amino acid spacer used for 10 coupling to the sorbent. The C-terminal is capped with an amide group. Diversity is then created with the use of hydrophobic amino acids, enantiomeric amino acids, positively charged, negatively charged, and neutral (hydrophilic) residues, as well as intra-chain cyclization via the 15 formation of disulfide bonds between cysteine residues.
Protein is then loaded onto each column in the sorbent plate, and the proteins that are bound to the chromatographic sorbents are eluted, then collected into a second pretreated microplate (Benedek, K. et al. ~. Chromatography 1992, 627, 20 51-61). Sets of paralogs are constructed by systématically varying five independent parameters drawn from protein structure literature: 1. a hydrophobic index; 2. an isoelectric point derived from overall charge by averaging the pKa values of the ionizable side chains in solution at pH
25 7; 3. a hydrophobic moment; 4. an analogous lateral dipole moment; S. a corrugation factor, defined as the measure of the scattering in the distribution of bulky side ch~i n~ along the helical backbone (see Villar, H. O. & Kauvar, L. M. FEBS
Letters 1994, 349, 125-130) and to defined reproducible 30 patterns of cross-reaction which represent distinctive spectra of the primary antigen and its analogs using an immunoassay of molecular analogs against panels of antibodies (Cheung, P. Y. K., et al . Analytlca Chimica Acta 1993, 283, 181-192) Definitions This invention discloses a system for the design, R~Cr~lEI) SHEET (RULE 91) W O 96/22529 PCTrUS96/01005 synthesis and use of logically arranged collections of synthetic product molecules called "molecular constructs"
from structural elements in such a manner that the collection of molecular constructs possesses a constant structural 5 element and a variable structural element. The definitions are shown below.
A "construct" is a molecule which is a member of a collection of molecules cont~;ning a common constant structural element and a common variable structural element.
An "array" is a logical positional ordering of molecular constructs in Cartesian coordinates.
A "bond" or ~chemical bond" is used to describe a group of electrons that is shared between two atoms. This term also denotes an ionic, covalent or other attractive force 15 between two atoms.
A "building block" is any molecule useful in the assembly of a molecular construct.
The terms "fragment" or "structural diversity element"
refer to the common variable s ructural element of a 20 molecular construct.
The "molecular core" is the common constant structural element of a molecular construct.
A "spatial address" is a position in the array defined by unique Cartesian coordinates.
A "sub-array" is a set of spatial addresses within a given array cont~;n;ng those molecular constructs having a common molecular core and differ from each other by O (zero) or 1 (one) change in a fragment.
A "relative address" refers to a location within the 30 array or sub array comparable to any selected address, and differing by O (zero) or only 1 (one) change in the common variable structural element.
An "operator" is a simultaneous and/or concurrent change in the condition of at least two spatial addresses in 35 individual cells residing in an array or a sub-array that results in a structural change in at least one molecular construct in the array. In particular, an operator in terms _ g f~t~ tlJ SHEET (RULE 91) PCT~US96/01005 of this invention can be the reaction of at least one site on the molecular core capable of becoming or providing attachment for a structural diversity element, to add or change a structural motif thereon. Other operators which can 5 be performed according to the patent include but are not limited to: addition of reagents or solvents; quality control protocols such as gas chromatography, high performance liquid chromatography, mass spectrometry, infrared spectroscopy, ultraviolet spectroscopy, nuclear magnetic resonance 10 spectroscopy, fluorescence spectroscopy, melting point, mass balance, combustion analysis and thin layer chromatography;
biological and enzymological assays such as ELISA, spectroscopic inhibition assays, disc assays and binding affinity assays; mechanical motions or manipulations; passage ~5 of time which includes resting & evaporation; heating and cooling; iteration of previous steps in a synthesis;
dilution and dispensation of products in a form suitable for the design purpose.
RtCI~IElJ SHEET (RIJLE 91) W 096/22529 PCTrUS96/01005 SU~n~ARY OF THE INVENTION
This invention is directed to an m x n array of different chemical compounds wherein each of said compounds - has at least one structural diversity elements chosen from 5 the group consisting of:
~ ~N ~N / 9[~--l--~ NN~
} ~ ~CI~D N ~
~\~NH2 ~ C~ F3C~¢~N~/ \~3 [~1 o J ~1 ~N~ ~ , J
~ ,, 1~: 1 ,~ 1~ ~ \N N~H
and wherein the scaffold structure is selected from the group consisting of:
~ G~ o o ~ ~
This invention is still further directed to an m x n array of different chemical compounds wherein each of said compounds has at least one of the structural diversity elements defined herein and wherein the scaffold structure may be a chemical molecule having at least three carbon atoms and at least two sites on the molecule capable of undergoing RECTIFIED SHEET (RULE 91) W O 96/22529 PCTrUS9G/0100~
a reaction to change the structure, usually by the addition of other molecules to a site capable of reacting to form or attach a structural diversity element.
This invention is still yet further directed to an n x m 5 array of chemical compounds called molec~ r constructs possessing a logical ordering of molecular constructs comprising at least one k x 1 sub array within the array wherein each sub array is comprised of a) at least k.l molecular constructs having a common molecular core and differing from the other k.l molecular constructs in the sub array by at least one change in the structural diversity element attached to the molecular core; and b) each sub array within the array is related to all other sub arrays in that all corresponding molecular constructs within each sub array has at least one change in the structural diversity elements.
Also, the array of chemical compounds above encompasses those circumstances wherein n, m, k and 1 are all integers greater than 1.
The above array of chemical compounds can also be directed to those circumstances wherein n > 5 and m > 1, or n > 10 and m > 1, or even wherein n > 5 and m > 5. The specific integers used for m and n are not critical and any can be selected depending upon the desired form of the array.
The above defined array of chemical compounds is also directed to arrays wherein m multiplied by n is greater than 10, greater than 20, greater than 100, greater than 200, greater than 500, greater than 1000 or aven greater than 5000. Again, the final number can be any multiple of the selected m and n values.
Still yet further the present invention is directed to an n x m array of chemical compounds called molecular constructs possessing a logical ordering of molecular constructs comprising at least one ~ x 1 sub array within the array the wherein each sub array is comprised of ~t~ lt~ SHEET (RULE 91) W 096/22529 PCT~US96/0100 a) at least ~.1 molecular constructs having a common molecular core and differing from other k.l molecular constructs in the sub array by at least one change in the structural diversity element attached to the molecular core;
b) each sub array within the array is related to ~ all other sub arrays in that all corresponding molecular constructs with each sub array has at least one change in the structural diversity elements; and c) and wherein each molecular construct is equidistant from at least two of its neighboring molecular constructs.
A preferred array is that defined immediately above wherein when n and m are greater than 3 and the chemical compounds are ~ ounded on four sides by four e~uidistant neighboring other chemical compounds.
Also the present invention covers n x m arrays of chemical compounds called molecular constructs possessinq a logical ordering of molecular constructs comprising at least one k x l sub array within the array wherein each sub array is comprised of a) at least k.l molecular constructs having a common molecular core and differing from the other k.l molecular constructs in the sub array by at least one change in the structural diversity element attached to the mol~c~ r core;
b) each sub array within the array is related to all other sub arrays in that all corresponding molecular constructs within each sub array has at least one change in the structural diversity elements; and c) and wherein each molecular construct is separated from all other molecular constructs by a container material.
The contained materials for the above cited array may employ glass, polymers, silicon, or any other material known REClIFIEL~ SHEET (RULE 91) _ W 096/22529 PCT~US96/01005 by those of ordinary skill in the art.
Further, the present invention is directed to an n x m x q array of chemical compounds called molecular constructs possessing a logical ordering of molecular constructs 5 comprising at least one k x l sub array within the array wherein each sub array is comprised of a) at least k.l molecular constructs having a common molecular core and differing from the other k.l molecular constructs in the sub array by at least one change in the structural diversity element attached to the molecular core;
b) each sub array within the array is related to all other sub arrays in that all corresponding molecular constructs within each sub array has at least one change in the structural diversity elements; and c) and wherein q is an integer > 1 and each array designated ql...q5 where s is an integer > than 1, differs from the other q arrays by at least one ~0 function.
In addition, the present invention is directed to an n x m x q array wherein the function is the addition of an organic structure selected from the group consisting of an amine, an aldehyde, an alcohol, a ketone, a carboxylic acids, an ether and an epoxy, and wherein the function may or may not be an analytic technique.
The reactions which are the subject of this inventio;
may be performed simultaneously by using a mer-h~n;cal apparatus such as multiple pipettes attached to an apparatus and other methods known to the skilled artisan.
REC~I~IED SHEET IRUEE 91) W O 96/22529 PCTrUS9G/01005 Brief DescriPtion of Drawinqs Figure 1 is a graphical representation of an array vertex illustrating the relationship between the building blocks, their addresses and the various operators therefor;
5 and Figure 2 is a schematic diagram representing the sequence of events for combining the building blocks to form the array.
Detailed DescriPtion of the Invention This invention pertains to the logical layout, 15 construction and testing of arrays of chemical compound for one of a variety of applications, in which the desired properties of the compound can be measured and correlated to specific ordered changes in the fragments use to construct them. The array is ordered in such a fashion as to expedite 20 assembly, to maximize the informational content derived from the testing and to facilitate the rapid extraction of that data from the testing process. This method has great utility in accelerating the development of compounds have the optimal properties for the desired application.
The arrays are constructed from logically ordered and arranged sub-arrays of compounds. Each sub-array consists of spatially addressable sets of structurally related individual chemical compounds, ranging in number from one to 10l2 and possessing the following properties: (l) a common structural 30 scaffold element referred to as a "molecular core" and (2) a variable structural diversity element referred to as a fragment, in such a manner that the variation between any two - compounds within a given sub-array consists only of either zero (0) or one (1) change in a fragment. These arrays may 35 in turn be arrar~ed in such a manner to form higher order arrays consisting of sets of arrays and tested to provide information regarding the optimum structural features RECTIFI~D SHEET (RIJLE gl) PCTrUS9G/01005 available for the application.
The sub-arrays are arranged in such a manner that the direct comparisons of compounds automatically yields information regarding the effect known fragments have on a 5 desired application, as well as on the effect on changes in physical and reactive properties. As provided by simple set theory for any number of independently variable structural diversity elements n, there exists ~ logical higher order array arrangements, such that relational information on the 10 effect of variation of each of the ~ structural diversity elements can be obtained in a similar manner by comparison of testing data from the relative addresses in appropriately arranged sub-arrays.
An application of this invention is the rapid 15 determination and optimization of desired biological or physical activity. An array is screened and the optimum candidate is chosen. This process can be continued in n dimensions to provide an absolute structure activity relationship ("SAR") picture of the candidate and selection 20 in speeded by the rapid modular synthesis of arrays for use in testing. Thus in one light the invention is the most powerful tool to date for the rapid synthesis, screening and testing of compounds for IND candidacy. This method is facilitated by virtue of selecting fragments based solely 25 upon their ability to react and participate in the process of assembly.
These arrays may be assembled to form a "super array"
for exhaustive testing. This approach provides a large scale view over different structures, functionalities and spatial 30 arrangements for exploring biological activity.
The physical construction of the array also permits the logical and rapid analysis of synthetic results for the assurance of purity and quality. By testing a series of loci within any given sub-array, it becomes possible to determine 35 the efficacy of construc.ion of that core, and eliminate those fragments (i.e., process development within the assembly) which do not provide satisfactory results. This RECrlElED SHEET (RULE 91) W 096/22529 PCTrUS96/01005 system, therefore possesses the ability to learn the utility of given reagents from previous results, and either delete them from further use or alter general conditions for their efficient incorporation into the array. Thus, both positive 5 and negative results are of value in the ultimate construction of the array, and there is no ambiguity in regards to the inclusion or exclusion of fragments.
A further application of this invention is the facilitation of the optimal analyte or epitope b;~in~ ligand 10 for attachment to a chromatographic ~u~pOL L for separation or purification applications. A further application of this invention pertains to the ability to construct materials in a modular fashion, so as to facilitate their selection for such properties as strength, stability, reactivity or any other 15 desired physical property. Whereas many methods rely upon logical choice for fragment candidates in such efforts, this method provides for the construction and testing of all candidates, thereby eliminating any compromises which traditional methods make based on the limits of time, 20 manpower, and cost. ~y the scroo~;~g of all possible synthetic variations the selection of the optimal candidate is a matter of data and not chemical intuition. The desired affinity can be rapidly optimized and directly correlated and attributed to the singular change made within a given sub-25 array. Therefore the selection of a ligand is no longer arandom, intuitive process, but one of complete confidence providing exhaustive data (cf. Kauvar, L.M. U.S. Patent 5,340,474)-Furthermore the invention providos for the development 30 of seamless technology between plAnn; n~, logisticaldevelopment, execution of assembly in either an arrayed or subarrayed manner, quality analysis, packaging, distribution, testing, interpretation and iteration. The invention provides for the integrated desi~n and delivery of a unified 35 chemical discovery system, which by application of logic and implementation of information management, has been heretofore unknown. The invention provides for the occupation of all R~ FIED SHEET (RUI.E 91) possible spatial addresses and therefore allows for complete analysis of desired properties. This concept can be extended toward the design and manufacture of appropriate hardware and software to support the integrated aspect of this modular 5 construction.
The logically arranged arrays of the present invention are fundamentally different from all known prior art.
Testing of these arrays automatically results in the generation of complete relational structural information such 10 that a positive result provides: (1) information on a compound within any given spatial address; (2) simultaneous juxtaposition of this information upon a set of systematically structural congeners; (3) the ability to extract relational structural information from negative 15 results in the presence of positive results.
All known prior art is universally directed toward the maximization of structural diversity. By definition this has excluded the acquisition of maximal data. In these cases, the relationship between individual structural variations and 20 any resulting changes in a measurable property of the compounds can not be directly obtained from the testing results. The process of obt~; n; ng a compound having a desired physical property using methods of the prior art, while guided by intuition, is a random statistical process at 25 best. Thus a positive result is not designed to give any additional information about the relationship between a specific structural modification and the corresponding change in the desired property, and a negative result can not provide any information at all. Methods in the prior art 30 universally require extensive further experimentation to elucidate any relational information in a process which is costly, time consuming and one in which success is difficult to predict.
These arrays may be constructed from a wide variety of 35 molecular cores, several examples of whi~h are shown below.
The criteria for core candidates are that the scaffold a) present attachment points for at least two structural IED SHEET (RULE 9~) CA 022l0949 l997-07-2l W 096/22529 PCT~US96/01005 diversity elements; b) is able to present these structural diversity elements in controlled, varying spatial arrangements; c) can be constructed in a rapid concerted fashion.
In general the molecular cores are linear, branched or cyclic organic compounds. In particular, the molecular cores comprise a chemical molecule having at least three carbon atoms and at least two sites on the molecule capable of undergoing a reaction to change the structure, usually by the 10 addition of other molecules to a site capable of reacting to form or attach a structural diversity element.
One example of a molecular core is an aminimide molecule. This is a technology which has been previously described. ~ ~
~N~3 These compounds may be synthesized in a number of ways, from 20 the reaction of an epoxide, an ester, and a hydrazine, as well as alkylation of a hydrazide, as shown below.
¦¦ ~QN~N~ ~ ~ o (~ ~ OH
CHEMICAL COMPOUND8 IN A SPATIALLY ~RR~NGED ARRAY
Backqround of the Invention The discovery of new molecules has traditionally focused in two broad areas, biologically active molecules, which are used as drugs for the treatment of life-threatening diseases, and new materials, which are used in commercial, especially high technological applications. In both areas, the strategy 10 used to discover new molecules has involved two basic operations: (i) a more or less random choice of a molecular candidate, prepared either via chemical synthesis or isolated from natural sources, and (ii) the testing of the molecular candidate for the property or properties of interest. This 15 discovery cycle is repeated indefinitely until a molecule possessing the desirable properties is located. In the majority of cases, the molecular types chosen for testing have belonged to rather narrowly defined chemical classes.
For example, the discovery of new peptide hormones has 20 involved work with peptides; the discovery of new therapeutic steroids has involved work with the steroid nucleus; the discovery of new surfaces to be used in the construction of computer chips or sensors has involved work with inorganic materials, etc. (for example, see R. Hirschmann, Angew.
25 Chem., Int. Ed. in Engl. 1991, 30, 1278-1301). As a result, the discovery of new functional molecules, being, ad hoc in nature and relying predominantly on serendipity, has been an extremely time-consuming, laborious, unpredictable, and costly enterprise.
A brief account of the strategies and tactics used in the discovery of new molecules is described below. The emphasis is on biologically interesting molecules. However, as discussed below, there are technical problems encountered in the discovery of molecules and in the development of 35 fabricated materials which can serve as new materials for high technological applications.
Modern theories of biological activity state that R~FJ~D SHEET (RULE 91) PCTrUS9G/0100 biological activities, and therefore physiological states, are the result of molecular recognition events. For example, nucleotides can form complementary base pairs so that complementary single-stranded molecules hybridize resulting 5 in double- or triple-helical structures that appear to be involved in regulation of gene expression. In another example, a biologically active molecule, referred to as a ligand, binds with another molecule, usually a macromolecule referred to as ligand-acceptor (e.g. a receptor or an 10 enzyme), and this binding elicits a chain of molecular events which ultimately gives rise to a physiological state, e.g.
normal cell growth and differentiation, abnormal cell growth leading to carcinogenesis, blood-pressure regulation, nerve-impulse-generation and -propagation, etc. The binding 15 between ligand and ligand-acceptor is geometrically characteristic and extraordinarily specific, involving appropriate three-dimensional structural arrangements and chemical interactions.
20 Desiqn and S~nthesis of Mimetics o~ Bioloqical Liqands A currently favored strategy for development of agents which can be used to treat diseases involves the discovery of forms of ligands of biological receptors, enzymes, or related macromolecules, which mimic such ligands and either boost 25 (i.e., agonize) or suppress (i.e., antagonize) the activity of the ligand. The discovery of such desirable ligand forms has traditionally been carried out either by random screening of molecules (produced through chemical synthesis or isolated from natural source's, for example, see K. NakAn;~h;, Acta 30 Pharm. Nord., 1992, 4, 319-328.), or by using a so-called "rational" approach involving identification of a lead-structure, usually the structure of the native ligand, and optimization of its properties through numerous cycles of structural redesign and biological testing (for example see 35 Testa, B. & Kier, L. B. Med. Res. Rev. 1991, 11, 35-48 and Rotstein, S. H. & Murcko, M. A. J. Med. Chem. ~ 993, 36, 1700-1710.). Since most useful drugs have been discovered not RECI IFIEl~ Sl IEET (RULE 91) F
through the "rational" approach but through the screening of randomly chosen compounds, a hybrid approach to drug discovery has recently emerged which is based on the use of combinatorial chemistry to construct huge libraries of 5 randomly-built chemical structures which are screened for specific biological activities. (Brenner, S. & Lerner, R. A.
Proc. Natl. Acad. Scl. USA 1992, 89, 5381) Most lead-structures which have been used in "rational"
drug design are native polypeptide ligands of receptors or 10 enzymes. The majority of polypeptide ligands, especially the small ones, are relatively unstable in physiological fluids, due to the tendency of the peptide bond to undergo facile hydrolysis in acidic media or in the presence of peptidases.
Thus, such ligands are decisively inferior in a ~5 pharmacokinetic sense to nonpeptidic compounds, and are not favored as drugs. An additional limitation of small peptides as drugs is their low affinity for ligand acceptors. This phenomenon is in sharp contrast to the affinity demonstrated by large, folded polypeptides, e.g., proteins, for specific 20 acceptors, e.g., receptors or enzymes, which can be in the subnanomolar range. For peptides to become effective drugs, they must be transformed into nonpeptidic organic structures, i.e., peptide mimetics, which bind tightly, preferably in the nanomolar range, and can withstand the chemical and 25 biochemical rigors of coexistence with biological fluids.
Despite numerous incremental advances in the art of peptidomimetic design, no general solution to the problem of converting a polypeptide-ligand structure to a peptidomimetic has been defined. At present, "rational" peptidomimetic 30 design is done on an ad hoc basis. Using numerous redesign-synthesis-screening cycles, peptidic ligands belonging to a certain biochemical class have been converted by y~OUpS of organic chests and pharmacologists to specific peptidomimetics; however, in the majority of cases the 35 results in one biochemical area e.g., peptidase inhibitor design using the enzyme substrate as a lead, cannot be transferred for use in another area, e.g., tyrosine-kinase ltU SHEET (RULE 91) W 096/22529 PCTrUS96/01005 inhibitor design using the kinase substrate as a lead.
In many cases, the peptidomimetics that result from a peptide structural lead using the "rational" approach comprise unnatural amino acids. Many of these mimetics 5 exhibit several of the troublesome features of native peptides (which also comprise alpha-amino acids) and are, thus, not favored for use as drugs. Recently, fundamental research on the use of nonpeptide scaffolds, such as steroidal or sugar structures, to anchor specific receptor-10 binding groups in fixed geometric relationships have beendescribed (see for example Hirschmann, R. et al. ~. Am. Chem.
Soc. 1992, 114, 9699-9701; Hirschmann, R. et al., ~. Am.
Chem. Soc., 1992, 114, 9217-9218); however, the success of this approach remains to be seen.
In an attempt to accelerate the identification of lead-structures, and also the identification of useful drug candidates through screening of randomly chosen compounds, researchers have developed automated methods for the generation of large combinatorial libraries of peptides and 20 certain types of peptide mimetics, called "peptoids", which are screened for a desirable biological activity (see Gordon, E. M. et al. ~. Med. Chem. 1994, 37, 1385-1401). For example, the method of H. M. Geysen, (Bioorg. Med. Chem.
Letters, 1993, 3, 397-404; Proc. Natl. Acad. sci. USA 1984, 25 81, 3998) employs a modification of Merrifield peptide synthesis, wherein the C-terminal amino acid residues of the peptides to be synthesized are linked to solid-support particles shaped as polyethylene pins; these pins are treated individually or collectively in sequence to -ntroduce 30 additional amino-acid residues forming the desired peptides.
The peptides are then screened for activity without removing them from the pins. Houghton, (Proc. Natl. Acad. Sci. USA
1985, 82, 5131; Eichler, J. ~ Houghton, R. A. Biochemi ~try, 1993, 32, 11035-11041, and U.S. Patent ~o. 4,631,211) 35 utilizes individual polyethylene bags ( tea bags") containing C-terminal amino acids bound to a solid support. These are mixed and coupled with the requisite amino acids usir.g solid RECTIFIED SHEET (RULE 91' W096/22529 PCT~S9610100S
phase synthesis t~chn;ques. The peptides produced are then recovered and tested individually. S. P. A. Fodor et al., (Science 1991, 2~1, 767) described light-directed, spatially addressable parallel-peptide synthesis on a silicon wafer to ~ 5 generate large arrays of addressable peptides that can be directly tested for binding to biological targets. These ~ workers have also developed recombinant DNA/genetic engineering methods for expressing huge peptide libraries on the surface of phages (Cwirla et al. Proc. Natl. Acad. Sci.
10 USA 1990, 87, 6378; Barbas, et al. Proc. Natl. Acad. Sci. USA
1991, 881, 7978-7~82).
In another combinatorial approach, V. D. Huebner and D.V. Santi (U.S. Patent No. 5,182,366) utilized functionalized polystyrene beads divided into portions each 15 of which was acylated with a desired amino acid; the bead portions were mixed together, then divided into portions each of which was re-subjected to acylation with a second desirable amino acid producing dipeptides, using the techniques of solid phase peptide synthesis. By using this 20 synthetic scheme, exponentially increasing numbers of peptides were produced in uniform amounts which were then separately screened for a biological activity of interest.
Zuckermann and coworkers (For examples, see Zuckermann, et al. J. Med. Chem. 1994, 37, 2678-2685 ~ Zuckermann, et al.
25 Int. J. Peptide Protein ~es. 1992, 91, 1) also have developed similar methods for the synthesis o~ peptide libraries and applied these methods to the automation of a modular synthetic chemistry for the production of libraries of N-alkyl glycine peptide derivatives, called "peptoids", which 30 are screened for activity against a variety of biochemical targets. (See also, Symon et al., Proc . Natl . Acad . Sci .
USA, 1992, 89, 9367). Encoded combinatorial chemical syntheses have been described recently (Brenner, S. & Lerner, R. A. Proc. Natl. Acad. Sci. USA 1992, 89, 5381; Barbas, C.
35 F. et al. Proc. Natl. Acad. Sci. USA '992, 89, 4 57-4461; see also Borchardt, A. & Still, W. C. J. Am. Chem. Soc. 1994, 116, 373-374; Kerr, J. et al. J. Am. Chem. Soc. 1993, 115, ~C~ u SHEEr (RULE 91) W096/22529 PCT~S96/01005 2529-2531).
M. J. Kurth and his group (Chen, C. et al. ~. Am. Chem .
Soc. 1994, 116, 2661-2662.) have applied organic synthetic strategies to develop non-peptide libraries synthesized using 5 multi-step processes on a polymer support. Although the method demonstrates the utility of standard organic synthesis in the application and development of chemical libraries, the synthetic conditions are limited by compatibility with the solid support.
The development of substrates or supports to be used in separations has involved either the polymerization/crosslinking of monomeric molecules under various conditions to produce fabricated materials such as beads, gels, or films, or the chemical modification of 15 various commercially available fabricated materials e.g., sulfonation of polystyrene beads, to produce the desired new materials. In the majority of cases, prior art support materials have been developed to perform specific separations or types of separations and are thus of limited utility.
20 Many of these materials are incompatible with biological macromolecules, e.g., reverse-phase silica frequently used to perform high pressure liquid chromatography can denature hydrophobic proteins and other polypeptides. Furthermore, many supports are used under conditions which are not 25 compatible with sensitive biomolecules, such as proteins, enzymes, glycoproteins, etc., which are readily denaturable and sensitive to extreme pH's. An additional difficulty with separations carried out using these supports is that the separation results are often support-batch dependent, i.e.
30 they are irreproducible.
Rec~ntly a variety of coatings and composite-forming materials have been used to modify commercially available fabricated materials into articles with improved properties;
however the success of this approach remains to be seen.
If a chromatographic support is equipped with molec~les which bind specifically with a component of a complex mixture, that component will be separated from the mixture tL) SHEET (RULE 91) W 096/22529 PCTrUS9G/0100~
and may be released subsequently by changing the experimental conditions (e.g., buffers, stringency, etc.) This type of separation is appropriately called "affinity chromatography"
and remains an extremely effective and widely used separation 5 ter-hn;que (see Perry, E. S. in Techniques of Chemistry, Vol.
12 (J. Wiley) & May, S. W. in Separations and Purification 1978, 3rd ed.). It is certainly much more selective than traditional chromatographic tec-hn;ques, e.g chromatography on silica, alumina, silica or alumina coated with long-r-hA;n 10 hydrocarbons, polysaccharide and other types of beads or gels which in order to attain their maximum separating efficiency need to be used under conditions that are damaging to biomolecules, e.g., conditions involving high pressure, use of organic solvents and other denaturing agents, etc. (for 15 example see Stewart, D. J., et al. ~. Biotechnology 1989, 11, 253-266; Brown, E., et al. Int. Symp. Affinity.
Chromatography & Mo7ecular Interactions 1979, 86, 37-50).
The development of more powerful separation technologies depends significantly on breakthroughs in the field of 20 materials science, specifically in the design and construct-on of materials that have the power to recognize specific molecular shapes under experimental conditions resembling those found in physiological media, i.e. , these experimental conditions must involve an aqueous medium whose temperature 25 and pH are close to the physiological levels and which contains none of the agents known to damage or denature biomolecules. The construction of these "intelligent"
materials freguently involves the introduction of small molecules capable of specifically recognizing others into 30 existing materials, e.g. surfaces, films, gels, beads, etc., by a wide variety of chemical modifications; alternatively molecules capable of recognition are converted to monomers and used to create the "intelligent" materials through polymerization reactions.
Advances in the ability to synthesize large numbers of peptides have made it possible to create a vast array of combinations of microenvironments within which different D SHEET(RU~E 91) W096/22529 PCT~S96/OlOOS
proteins may interact in equally. Kauvar (U.S. Patent 5,340,474) has developed a chromatographic method to obtain ligands which have the required affinity specific for a selected member of an array of analytes by providing maximal 5 diversity in the choice of these ligands. A key to this technology is the use of a flow-through 96-well plate compatible for assaying large numbers of parallel samples.
Their short peptide-based ligands as paratope analogs (or "paralogs") contain an N-terminal amino acid spacer used for 10 coupling to the sorbent. The C-terminal is capped with an amide group. Diversity is then created with the use of hydrophobic amino acids, enantiomeric amino acids, positively charged, negatively charged, and neutral (hydrophilic) residues, as well as intra-chain cyclization via the 15 formation of disulfide bonds between cysteine residues.
Protein is then loaded onto each column in the sorbent plate, and the proteins that are bound to the chromatographic sorbents are eluted, then collected into a second pretreated microplate (Benedek, K. et al. ~. Chromatography 1992, 627, 20 51-61). Sets of paralogs are constructed by systématically varying five independent parameters drawn from protein structure literature: 1. a hydrophobic index; 2. an isoelectric point derived from overall charge by averaging the pKa values of the ionizable side chains in solution at pH
25 7; 3. a hydrophobic moment; 4. an analogous lateral dipole moment; S. a corrugation factor, defined as the measure of the scattering in the distribution of bulky side ch~i n~ along the helical backbone (see Villar, H. O. & Kauvar, L. M. FEBS
Letters 1994, 349, 125-130) and to defined reproducible 30 patterns of cross-reaction which represent distinctive spectra of the primary antigen and its analogs using an immunoassay of molecular analogs against panels of antibodies (Cheung, P. Y. K., et al . Analytlca Chimica Acta 1993, 283, 181-192) Definitions This invention discloses a system for the design, R~Cr~lEI) SHEET (RULE 91) W O 96/22529 PCTrUS96/01005 synthesis and use of logically arranged collections of synthetic product molecules called "molecular constructs"
from structural elements in such a manner that the collection of molecular constructs possesses a constant structural 5 element and a variable structural element. The definitions are shown below.
A "construct" is a molecule which is a member of a collection of molecules cont~;ning a common constant structural element and a common variable structural element.
An "array" is a logical positional ordering of molecular constructs in Cartesian coordinates.
A "bond" or ~chemical bond" is used to describe a group of electrons that is shared between two atoms. This term also denotes an ionic, covalent or other attractive force 15 between two atoms.
A "building block" is any molecule useful in the assembly of a molecular construct.
The terms "fragment" or "structural diversity element"
refer to the common variable s ructural element of a 20 molecular construct.
The "molecular core" is the common constant structural element of a molecular construct.
A "spatial address" is a position in the array defined by unique Cartesian coordinates.
A "sub-array" is a set of spatial addresses within a given array cont~;n;ng those molecular constructs having a common molecular core and differ from each other by O (zero) or 1 (one) change in a fragment.
A "relative address" refers to a location within the 30 array or sub array comparable to any selected address, and differing by O (zero) or only 1 (one) change in the common variable structural element.
An "operator" is a simultaneous and/or concurrent change in the condition of at least two spatial addresses in 35 individual cells residing in an array or a sub-array that results in a structural change in at least one molecular construct in the array. In particular, an operator in terms _ g f~t~ tlJ SHEET (RULE 91) PCT~US96/01005 of this invention can be the reaction of at least one site on the molecular core capable of becoming or providing attachment for a structural diversity element, to add or change a structural motif thereon. Other operators which can 5 be performed according to the patent include but are not limited to: addition of reagents or solvents; quality control protocols such as gas chromatography, high performance liquid chromatography, mass spectrometry, infrared spectroscopy, ultraviolet spectroscopy, nuclear magnetic resonance 10 spectroscopy, fluorescence spectroscopy, melting point, mass balance, combustion analysis and thin layer chromatography;
biological and enzymological assays such as ELISA, spectroscopic inhibition assays, disc assays and binding affinity assays; mechanical motions or manipulations; passage ~5 of time which includes resting & evaporation; heating and cooling; iteration of previous steps in a synthesis;
dilution and dispensation of products in a form suitable for the design purpose.
RtCI~IElJ SHEET (RIJLE 91) W 096/22529 PCTrUS96/01005 SU~n~ARY OF THE INVENTION
This invention is directed to an m x n array of different chemical compounds wherein each of said compounds - has at least one structural diversity elements chosen from 5 the group consisting of:
~ ~N ~N / 9[~--l--~ NN~
} ~ ~CI~D N ~
~\~NH2 ~ C~ F3C~¢~N~/ \~3 [~1 o J ~1 ~N~ ~ , J
~ ,, 1~: 1 ,~ 1~ ~ \N N~H
and wherein the scaffold structure is selected from the group consisting of:
~ G~ o o ~ ~
This invention is still further directed to an m x n array of different chemical compounds wherein each of said compounds has at least one of the structural diversity elements defined herein and wherein the scaffold structure may be a chemical molecule having at least three carbon atoms and at least two sites on the molecule capable of undergoing RECTIFIED SHEET (RULE 91) W O 96/22529 PCTrUS9G/0100~
a reaction to change the structure, usually by the addition of other molecules to a site capable of reacting to form or attach a structural diversity element.
This invention is still yet further directed to an n x m 5 array of chemical compounds called molec~ r constructs possessing a logical ordering of molecular constructs comprising at least one k x 1 sub array within the array wherein each sub array is comprised of a) at least k.l molecular constructs having a common molecular core and differing from the other k.l molecular constructs in the sub array by at least one change in the structural diversity element attached to the molecular core; and b) each sub array within the array is related to all other sub arrays in that all corresponding molecular constructs within each sub array has at least one change in the structural diversity elements.
Also, the array of chemical compounds above encompasses those circumstances wherein n, m, k and 1 are all integers greater than 1.
The above array of chemical compounds can also be directed to those circumstances wherein n > 5 and m > 1, or n > 10 and m > 1, or even wherein n > 5 and m > 5. The specific integers used for m and n are not critical and any can be selected depending upon the desired form of the array.
The above defined array of chemical compounds is also directed to arrays wherein m multiplied by n is greater than 10, greater than 20, greater than 100, greater than 200, greater than 500, greater than 1000 or aven greater than 5000. Again, the final number can be any multiple of the selected m and n values.
Still yet further the present invention is directed to an n x m array of chemical compounds called molecular constructs possessing a logical ordering of molecular constructs comprising at least one ~ x 1 sub array within the array the wherein each sub array is comprised of ~t~ lt~ SHEET (RULE 91) W 096/22529 PCT~US96/0100 a) at least ~.1 molecular constructs having a common molecular core and differing from other k.l molecular constructs in the sub array by at least one change in the structural diversity element attached to the molecular core;
b) each sub array within the array is related to ~ all other sub arrays in that all corresponding molecular constructs with each sub array has at least one change in the structural diversity elements; and c) and wherein each molecular construct is equidistant from at least two of its neighboring molecular constructs.
A preferred array is that defined immediately above wherein when n and m are greater than 3 and the chemical compounds are ~ ounded on four sides by four e~uidistant neighboring other chemical compounds.
Also the present invention covers n x m arrays of chemical compounds called molecular constructs possessinq a logical ordering of molecular constructs comprising at least one k x l sub array within the array wherein each sub array is comprised of a) at least k.l molecular constructs having a common molecular core and differing from the other k.l molecular constructs in the sub array by at least one change in the structural diversity element attached to the mol~c~ r core;
b) each sub array within the array is related to all other sub arrays in that all corresponding molecular constructs within each sub array has at least one change in the structural diversity elements; and c) and wherein each molecular construct is separated from all other molecular constructs by a container material.
The contained materials for the above cited array may employ glass, polymers, silicon, or any other material known REClIFIEL~ SHEET (RULE 91) _ W 096/22529 PCT~US96/01005 by those of ordinary skill in the art.
Further, the present invention is directed to an n x m x q array of chemical compounds called molecular constructs possessing a logical ordering of molecular constructs 5 comprising at least one k x l sub array within the array wherein each sub array is comprised of a) at least k.l molecular constructs having a common molecular core and differing from the other k.l molecular constructs in the sub array by at least one change in the structural diversity element attached to the molecular core;
b) each sub array within the array is related to all other sub arrays in that all corresponding molecular constructs within each sub array has at least one change in the structural diversity elements; and c) and wherein q is an integer > 1 and each array designated ql...q5 where s is an integer > than 1, differs from the other q arrays by at least one ~0 function.
In addition, the present invention is directed to an n x m x q array wherein the function is the addition of an organic structure selected from the group consisting of an amine, an aldehyde, an alcohol, a ketone, a carboxylic acids, an ether and an epoxy, and wherein the function may or may not be an analytic technique.
The reactions which are the subject of this inventio;
may be performed simultaneously by using a mer-h~n;cal apparatus such as multiple pipettes attached to an apparatus and other methods known to the skilled artisan.
REC~I~IED SHEET IRUEE 91) W O 96/22529 PCTrUS9G/01005 Brief DescriPtion of Drawinqs Figure 1 is a graphical representation of an array vertex illustrating the relationship between the building blocks, their addresses and the various operators therefor;
5 and Figure 2 is a schematic diagram representing the sequence of events for combining the building blocks to form the array.
Detailed DescriPtion of the Invention This invention pertains to the logical layout, 15 construction and testing of arrays of chemical compound for one of a variety of applications, in which the desired properties of the compound can be measured and correlated to specific ordered changes in the fragments use to construct them. The array is ordered in such a fashion as to expedite 20 assembly, to maximize the informational content derived from the testing and to facilitate the rapid extraction of that data from the testing process. This method has great utility in accelerating the development of compounds have the optimal properties for the desired application.
The arrays are constructed from logically ordered and arranged sub-arrays of compounds. Each sub-array consists of spatially addressable sets of structurally related individual chemical compounds, ranging in number from one to 10l2 and possessing the following properties: (l) a common structural 30 scaffold element referred to as a "molecular core" and (2) a variable structural diversity element referred to as a fragment, in such a manner that the variation between any two - compounds within a given sub-array consists only of either zero (0) or one (1) change in a fragment. These arrays may 35 in turn be arrar~ed in such a manner to form higher order arrays consisting of sets of arrays and tested to provide information regarding the optimum structural features RECTIFI~D SHEET (RIJLE gl) PCTrUS9G/01005 available for the application.
The sub-arrays are arranged in such a manner that the direct comparisons of compounds automatically yields information regarding the effect known fragments have on a 5 desired application, as well as on the effect on changes in physical and reactive properties. As provided by simple set theory for any number of independently variable structural diversity elements n, there exists ~ logical higher order array arrangements, such that relational information on the 10 effect of variation of each of the ~ structural diversity elements can be obtained in a similar manner by comparison of testing data from the relative addresses in appropriately arranged sub-arrays.
An application of this invention is the rapid 15 determination and optimization of desired biological or physical activity. An array is screened and the optimum candidate is chosen. This process can be continued in n dimensions to provide an absolute structure activity relationship ("SAR") picture of the candidate and selection 20 in speeded by the rapid modular synthesis of arrays for use in testing. Thus in one light the invention is the most powerful tool to date for the rapid synthesis, screening and testing of compounds for IND candidacy. This method is facilitated by virtue of selecting fragments based solely 25 upon their ability to react and participate in the process of assembly.
These arrays may be assembled to form a "super array"
for exhaustive testing. This approach provides a large scale view over different structures, functionalities and spatial 30 arrangements for exploring biological activity.
The physical construction of the array also permits the logical and rapid analysis of synthetic results for the assurance of purity and quality. By testing a series of loci within any given sub-array, it becomes possible to determine 35 the efficacy of construc.ion of that core, and eliminate those fragments (i.e., process development within the assembly) which do not provide satisfactory results. This RECrlElED SHEET (RULE 91) W 096/22529 PCTrUS96/01005 system, therefore possesses the ability to learn the utility of given reagents from previous results, and either delete them from further use or alter general conditions for their efficient incorporation into the array. Thus, both positive 5 and negative results are of value in the ultimate construction of the array, and there is no ambiguity in regards to the inclusion or exclusion of fragments.
A further application of this invention is the facilitation of the optimal analyte or epitope b;~in~ ligand 10 for attachment to a chromatographic ~u~pOL L for separation or purification applications. A further application of this invention pertains to the ability to construct materials in a modular fashion, so as to facilitate their selection for such properties as strength, stability, reactivity or any other 15 desired physical property. Whereas many methods rely upon logical choice for fragment candidates in such efforts, this method provides for the construction and testing of all candidates, thereby eliminating any compromises which traditional methods make based on the limits of time, 20 manpower, and cost. ~y the scroo~;~g of all possible synthetic variations the selection of the optimal candidate is a matter of data and not chemical intuition. The desired affinity can be rapidly optimized and directly correlated and attributed to the singular change made within a given sub-25 array. Therefore the selection of a ligand is no longer arandom, intuitive process, but one of complete confidence providing exhaustive data (cf. Kauvar, L.M. U.S. Patent 5,340,474)-Furthermore the invention providos for the development 30 of seamless technology between plAnn; n~, logisticaldevelopment, execution of assembly in either an arrayed or subarrayed manner, quality analysis, packaging, distribution, testing, interpretation and iteration. The invention provides for the integrated desi~n and delivery of a unified 35 chemical discovery system, which by application of logic and implementation of information management, has been heretofore unknown. The invention provides for the occupation of all R~ FIED SHEET (RUI.E 91) possible spatial addresses and therefore allows for complete analysis of desired properties. This concept can be extended toward the design and manufacture of appropriate hardware and software to support the integrated aspect of this modular 5 construction.
The logically arranged arrays of the present invention are fundamentally different from all known prior art.
Testing of these arrays automatically results in the generation of complete relational structural information such 10 that a positive result provides: (1) information on a compound within any given spatial address; (2) simultaneous juxtaposition of this information upon a set of systematically structural congeners; (3) the ability to extract relational structural information from negative 15 results in the presence of positive results.
All known prior art is universally directed toward the maximization of structural diversity. By definition this has excluded the acquisition of maximal data. In these cases, the relationship between individual structural variations and 20 any resulting changes in a measurable property of the compounds can not be directly obtained from the testing results. The process of obt~; n; ng a compound having a desired physical property using methods of the prior art, while guided by intuition, is a random statistical process at 25 best. Thus a positive result is not designed to give any additional information about the relationship between a specific structural modification and the corresponding change in the desired property, and a negative result can not provide any information at all. Methods in the prior art 30 universally require extensive further experimentation to elucidate any relational information in a process which is costly, time consuming and one in which success is difficult to predict.
These arrays may be constructed from a wide variety of 35 molecular cores, several examples of whi~h are shown below.
The criteria for core candidates are that the scaffold a) present attachment points for at least two structural IED SHEET (RULE 9~) CA 022l0949 l997-07-2l W 096/22529 PCT~US96/01005 diversity elements; b) is able to present these structural diversity elements in controlled, varying spatial arrangements; c) can be constructed in a rapid concerted fashion.
In general the molecular cores are linear, branched or cyclic organic compounds. In particular, the molecular cores comprise a chemical molecule having at least three carbon atoms and at least two sites on the molecule capable of undergoing a reaction to change the structure, usually by the 10 addition of other molecules to a site capable of reacting to form or attach a structural diversity element.
One example of a molecular core is an aminimide molecule. This is a technology which has been previously described. ~ ~
~N~3 These compounds may be synthesized in a number of ways, from 20 the reaction of an epoxide, an ester, and a hydrazine, as well as alkylation of a hydrazide, as shown below.
¦¦ ~QN~N~ ~ ~ o (~ ~ OH
2 5 (~OMe (~ H ~ X
35 ~ NH
REC~ ED SHEET (RULE 91) -W 096/22529 PCTrUS96/01005 An example of a scaffold capable of forming a molecular core of an oxazolone molecule. Methylidene amides are formed from the sequential reaction of aldehydes, then amines with oxazolones. These compounds and their congeners may be in 5 turn transformed into imidazolones:
N4 ~H
,,H He~t,dch~l-bon These compounds and their methods of manufacture are described in PCT Publications W094/00509 and W094/01102.
Sulfonylaminimides and phosphonylaminimides are still 20 further examples of molecular cores which can be constructed in an analogous manner as their carbon-based counterparts, with the exception of sulfonate esters not participating in the reaction of an epoxide and hydrazine in the desired manner.
o~
While the aminimide, oxazolone, sulphonylaminimide, and phosphonylaminimide are several examples of the concept of a molecular core, other molecular cores are possible according to the teachings of this invention. Further examples of possible molecular cores include, but are not limited to:
35 alkaloids, quinolines, isoquinolines, benzimidazoles, benzothiazoles, purines, pyrimidines, thiazolidines, imidazopyrazinones, oxazolopyridines, pyrroles, pyrrolidines, RECTIF~ED SHEET (RULE 91) PCT~US96/0100 imidazolidones, quinolones, amino acids, macrolides, penems, saccharides, xanthins, benzothiadiazine, anthracyclines, dibenzocycloheptadienes, inositols, porphyrins, corrins, and carboskeletons presenting geometric solids (e.g., dodecahedrane).
Diels-Alder reactions, Darzens glycidic ester condensations, Simmons-Smith cyclopropanations, rhodium catalyzed carbene additions, Ugi and Passerini reactions may all be done in such a manner, as to construct these arrays as described above. The application of this ~ech~ology is facile and the format in which it is constructed is amenable to most organic transformations and reaction se~uences.
The structural diversity elements may be the same or different, may be of a variety of structures and may differ markedly in their physical or functional properties, or may be the same; they may also be chiral or symmetric or from a compound which is chiral or symmetric. The structural diversity elements are preferably selected from:
1) amino acid derivatives of the form (AA) n~ which would include, for example, natural and synthetic amino acid residues (n = 1) including all of the naturally occurring alpha amino acids, especially alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine; the naturally occurring disubstituted amino acids, such as amino isobutyric acid, and isovaline, etc.; a variety of synthetic amino acid residues, including alpha-disubstituted variants, species with olefinic substitution at the alpha position, species having derivatives, variants or mimetics of the naturally occurring side chains; N-substituted glycine residues; natural and synthetic species known to functionally mimic amino acid residues, such as statine, bestatin, etc. Peptides (n = 2 - 30) constructed from the amino acids listed above, such as angiotensinogen and its family of physiologically important angiotensin hydrolysis products, as well as derivatives, variants and ~El;lll 1~1) SHEET (RULE 9"
CA 022l0949 l997-07-2l PCT~US96/01005 mimetics made from various combinations and permutations of all the natural and synthetic residues listed above.
Polypeptides (n = 31 - 70), such as big endothelin, pancreastatin, human growth hormone releasing factor and human pancreatic polypeptide. Proteins (n > 70) including structural proteins such as collagen, functional proteins such as hemoglobin, regulatory proteins such as the dopamine and thrombin receptors.
2) a nucleotide derivative of the ~orm (NUCL)n, which 10 includes natural and synthetic nucleotides (n = 1), such as adenosine, thymine, guanidine, uridine, cytosine, derivatives of these and a variety of variants and mimetics of the purine ring, the sugar ring, the phosphate linkage and combinations of some or all of these. Nucleotide probes (n = 2 - 25) and 15 oligonucleotides (n > 25) including all of the various possible; homo and hetero-synthetic combinations and permuta'ions of the naturally occurring nucleotides;
derivatives and variants cont~i n; ng synthetic purine or pyrimidine species, or mimics of these; various sugar ring 20 mimetics; and a wide variety of alternate backbone analogs, including but not limited to phosphodiester, phosphorothionate, phosphorodithionate, phosphoramidate, alkyl phosphotriester, sulfamate, 3'-thioformacetal, methylene(methylimino), 3-N-carbamate, morpholino carbamate 25 and peptide nucleic acid analogs.
35 ~ NH
REC~ ED SHEET (RULE 91) -W 096/22529 PCTrUS96/01005 An example of a scaffold capable of forming a molecular core of an oxazolone molecule. Methylidene amides are formed from the sequential reaction of aldehydes, then amines with oxazolones. These compounds and their congeners may be in 5 turn transformed into imidazolones:
N4 ~H
,,H He~t,dch~l-bon These compounds and their methods of manufacture are described in PCT Publications W094/00509 and W094/01102.
Sulfonylaminimides and phosphonylaminimides are still 20 further examples of molecular cores which can be constructed in an analogous manner as their carbon-based counterparts, with the exception of sulfonate esters not participating in the reaction of an epoxide and hydrazine in the desired manner.
o~
While the aminimide, oxazolone, sulphonylaminimide, and phosphonylaminimide are several examples of the concept of a molecular core, other molecular cores are possible according to the teachings of this invention. Further examples of possible molecular cores include, but are not limited to:
35 alkaloids, quinolines, isoquinolines, benzimidazoles, benzothiazoles, purines, pyrimidines, thiazolidines, imidazopyrazinones, oxazolopyridines, pyrroles, pyrrolidines, RECTIF~ED SHEET (RULE 91) PCT~US96/0100 imidazolidones, quinolones, amino acids, macrolides, penems, saccharides, xanthins, benzothiadiazine, anthracyclines, dibenzocycloheptadienes, inositols, porphyrins, corrins, and carboskeletons presenting geometric solids (e.g., dodecahedrane).
Diels-Alder reactions, Darzens glycidic ester condensations, Simmons-Smith cyclopropanations, rhodium catalyzed carbene additions, Ugi and Passerini reactions may all be done in such a manner, as to construct these arrays as described above. The application of this ~ech~ology is facile and the format in which it is constructed is amenable to most organic transformations and reaction se~uences.
The structural diversity elements may be the same or different, may be of a variety of structures and may differ markedly in their physical or functional properties, or may be the same; they may also be chiral or symmetric or from a compound which is chiral or symmetric. The structural diversity elements are preferably selected from:
1) amino acid derivatives of the form (AA) n~ which would include, for example, natural and synthetic amino acid residues (n = 1) including all of the naturally occurring alpha amino acids, especially alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine; the naturally occurring disubstituted amino acids, such as amino isobutyric acid, and isovaline, etc.; a variety of synthetic amino acid residues, including alpha-disubstituted variants, species with olefinic substitution at the alpha position, species having derivatives, variants or mimetics of the naturally occurring side chains; N-substituted glycine residues; natural and synthetic species known to functionally mimic amino acid residues, such as statine, bestatin, etc. Peptides (n = 2 - 30) constructed from the amino acids listed above, such as angiotensinogen and its family of physiologically important angiotensin hydrolysis products, as well as derivatives, variants and ~El;lll 1~1) SHEET (RULE 9"
CA 022l0949 l997-07-2l PCT~US96/01005 mimetics made from various combinations and permutations of all the natural and synthetic residues listed above.
Polypeptides (n = 31 - 70), such as big endothelin, pancreastatin, human growth hormone releasing factor and human pancreatic polypeptide. Proteins (n > 70) including structural proteins such as collagen, functional proteins such as hemoglobin, regulatory proteins such as the dopamine and thrombin receptors.
2) a nucleotide derivative of the ~orm (NUCL)n, which 10 includes natural and synthetic nucleotides (n = 1), such as adenosine, thymine, guanidine, uridine, cytosine, derivatives of these and a variety of variants and mimetics of the purine ring, the sugar ring, the phosphate linkage and combinations of some or all of these. Nucleotide probes (n = 2 - 25) and 15 oligonucleotides (n > 25) including all of the various possible; homo and hetero-synthetic combinations and permuta'ions of the naturally occurring nucleotides;
derivatives and variants cont~i n; ng synthetic purine or pyrimidine species, or mimics of these; various sugar ring 20 mimetics; and a wide variety of alternate backbone analogs, including but not limited to phosphodiester, phosphorothionate, phosphorodithionate, phosphoramidate, alkyl phosphotriester, sulfamate, 3'-thioformacetal, methylene(methylimino), 3-N-carbamate, morpholino carbamate 25 and peptide nucleic acid analogs.
3) a carbohydrate derivative of the form (CH)nr which would include natural physiologically active carbohydrates;
related compounds, such as glucose, galactose, sialic acids, ~-D-glucosylamine and nojorimycin, which are both inhibitors 30 of glucosidase; pseudo sugars, such as 5a-carba-2-D-galactopyranose, which is known to inhibit the growth of Klebsiella pneumonia (n = 1); synthetic carbohydrate residues and derivatives of these (n = 1) and all of the complex oligomeric permutations of these as found in nature, 35 including high mannose oligosaccharides, the known antibiotic streptomycin (n > 1).
related compounds, such as glucose, galactose, sialic acids, ~-D-glucosylamine and nojorimycin, which are both inhibitors 30 of glucosidase; pseudo sugars, such as 5a-carba-2-D-galactopyranose, which is known to inhibit the growth of Klebsiella pneumonia (n = 1); synthetic carbohydrate residues and derivatives of these (n = 1) and all of the complex oligomeric permutations of these as found in nature, 35 including high mannose oligosaccharides, the known antibiotic streptomycin (n > 1).
4) a naturally occurring or synthetic organic kt~ U SHEET (RUlE gl) -PCTrUS96/01005 structural motif. The term "motif" is defined as an organic molecule having or cont~; n; ng a specific structure that has biological activity, such as a molecule having a complementary structure to an enzyme active site, for 5 example. This term includes any of the well known basic structures of pharmaceutical compounds including pharmacophores, or metabolites thereof. These basic structures include beta-lactams, such as penicillin, known to inhibit bacterial cell wall biosynthesis; dibenzazepines, 10 known to bind to CNS receptors and used as antidepressants;
polyketide macrolides, known to bind to bacterial ribosymes, etc. These structural motifs are generally known to have specific desirable binding properties to ligand acceptors.
5) a reporter element, such as a natural or synthetic 15 dye or a residue capable of photographic amplification which possesses reactive groups that may be synthetically incorporated into the sulfam;n;r;de structure or reaction scheme, and may be attached through the groups without adversely interfering or affecting with the reporting 20 functionality of the group. Preferred reactive groups are amino, thio, hydroxy, carboxylic acid, carboxylic acid ester, particularly methyl ester, acid chloride, isocyanate alkyl halides, aryl halides and oxirane groups.
polyketide macrolides, known to bind to bacterial ribosymes, etc. These structural motifs are generally known to have specific desirable binding properties to ligand acceptors.
5) a reporter element, such as a natural or synthetic 15 dye or a residue capable of photographic amplification which possesses reactive groups that may be synthetically incorporated into the sulfam;n;r;de structure or reaction scheme, and may be attached through the groups without adversely interfering or affecting with the reporting 20 functionality of the group. Preferred reactive groups are amino, thio, hydroxy, carboxylic acid, carboxylic acid ester, particularly methyl ester, acid chloride, isocyanate alkyl halides, aryl halides and oxirane groups.
6) an organic moiety cont~;n;ng a polymerizable group 25 such as a double bond, or other functionalities capable of undergoing condensation polymerization or copolymerization.
Suitable groups include vinyl groups, oxirane groups, carboxylic acids, acid chlorides, esters, amides, azlactones, lactones and lactams. Other organic moiety such as those 30 defined for R and R' may also be used.
Suitable groups include vinyl groups, oxirane groups, carboxylic acids, acid chlorides, esters, amides, azlactones, lactones and lactams. Other organic moiety such as those 30 defined for R and R' may also be used.
7) a macromolecular component, such as a macromolecular surface or structures which may be attached to the sulfA~;n;mide modules via the various reactive groups outlined above, in a manner where the binding of the attached 35 species to a ligand-receptor molecule is not adversely affected and the interactive activity of the attached functionality is determined or limited by the macromolecule.
RE(~f~F~El~ S,YEE~ ~UL~ ~) CA 022l0949 l997-07-2l PCTrUS96/01005 Examples of macromolecular components include porous and non-porous inorganic components, such as, for example, silica, alumina, zirconia, titania and the like, as commonly used for various applications, such as normal and reverse phase 5 chromatographic separations, water purification, pigments for paints, etc.; porous and non-porous organic macromolec~ r components, including synthetic components such as styrenedivinyl benzene beads, various methacrylate beads, PVA
beads, and the like, commonly used for protein purification, 10 water softening; and a variety of other applications, natural components such as native and functionalized celluloses, such as, for example, agarose and chitin, sheet and hollow fiber membranes made from nylon, polyether sulfone or any of the materials mentioned above. The molecular weight of these 15 macromolecules may range from about 1000 Daltons to as high as possible. They may take the form of nano-particles (dp =
1000 - 5000 Angstroms), latex particles (dp = lOOo - 5000 Angstroms), porous or non-porous beads (dp = 0.5 - 1000 microns), membranes, gels, macroscopic surfaces or 20 functionalized or coated versions or composites.
Structural diversity elements may also be a chemical bond to a suitable organic moiety, a hydrogen atom, an organic moiety which contains a suitable electrophilic group, such as an aldehyde, ester, alkyl halide, ketone, nitrile, 25 epoxide or the like; a suitable nucleophilic group, such as a hydroxyl, amino, carboxylate, amide, carbanion, urea or the like; or one of the other structural diversity elements defined below. In addition, structural diversity elements may join to form a ring, bi-cyclic or tri-cyclic ring system;
30 or structure which connects to the ends of the repeating unit of the compound defined by the preceding formula; or may be separately connected to other moieties.
Structural diversity elements on a scaffold may be the same or different and each may be one or more atoms of 3s carbon, nitrogen, sulfur, oxygen, any other inorganic elements or combinations thereof. The structural diversity elements may be cyano, nitro, halogen, oxygen, hydroxy, R~CI~ltu SHET (R~)LE 91) PCTrUS96/01005 alkoxy, thio, straight or branched chain alkyl, carbocyclic aryl and substituted or heterocyclic derivatives thereof.
Structural diversity elements may be different in adjacent molecular cores and have a selected stereochemical 5 arrangement about the carbon atom to which they are attached.
As used herein, the phrase linear chain or branched chained alkyl groups means any substituted or unsubstituted acyclic carbon-cont~; n; ng compounds, including A lk~nes, alkenes and alkynes. Alkyl groups having up to 30 carbon 10 atoms are preferred. Examples of alkyl groups include lower alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; upper alkyl, for example, octyl, nonyl, decyl, and the like; lower alkylene, for example, ethylene, propylene, propyldiene, butylene, 15 butyldiene; upper alkenyl such as l-decene, 1-nonene, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl or beptenyl, and the like; alkynyl such as 1-ethynyl, 2-butynyl, 1-pentynyl and the like. The ordinary skilled artisan is familiar with numerous linear and branched alkyl groups, which are within 20 the scope of the present invention.
In addition, such alkyl group may also contain various substituents in which one or more hydrogen atoms has been replaced by a functional group. Functional groups include but are not limited to hydroxyl, amino, carboxyl, amide, 25 ester, ether, and halogen (fluorine, chlorine, bromine and iodine), to mention but a few. Specific substituted alkyl groups can be, for example, alkoxy such as methoxy, ethoxy, butoxy, pentoxy and the like, polyhydroxy such as 1,2-dihydroxypropyl, 1,4-dihydroxy-l-butyl, and the like;
30 methylamino, ethylamino, dimethylamino, diethylamino, triethylamino, cyclopentylamino, benzylamino, dibenzylamino, and the like; propionic, butanoic or pentanoic acid groups, and the like; formamido, acetamido, butanamido, and the like, methoxycarbonyl, ethoxycarbonyl or the like, chloroformyl, 35 bromoformyl, 1, 1-chloroethyl, bromoethyl, and the like, or dimethyl or diethyl ether groups or the like.
As used herein, substituted and unsubstituted IED SHEET (RULE 9~) W096/22529 PCT~S96/01005 carbocyclic groups of up to about 20 carbon atoms means cyclic carbon-containing compounds, including but not limited to cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. Such cyclic groups may also contain various 5 substituents in which one or more hydrogen atoms has been replaced by a functional group. Such functional groups include those described above, and lower alkyl groups as described above. The cyclic groups of the invention may further comprise a heteroatom. For example, in a specific lO embodiment, structural diversity element A is cyclohexanol.
As used herein, substituted and unsubstituted aryl groups means a hydrocarbon ring bearing a system of conjugated double bonds, usually comprising (4p - 2) pi bond electrons, where p is an integer equal to or greater than l.
l5 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anisyl, toluyl, xylenyl and the like.
According to the present invention, aryl also includes aryloxy, aralkyl, aralkyloxy and heteroaryl groups, e.g., pyrimidine, morpholine, piperazine, piperidine, benzoic acid, ~o toluene or thiophene and the like. These aryl groups may also be substituted with any number of a variety of functional groups. In addition to the functional groups described above in connection with substituted alkyl groups and carbocyclic groups, functional groups on the aryl groups 25 can be nitro groups.
As mentioned above, structural diversity elements can also represent any combination of alkyl, carbocyclic or aryl groups; for example, l-cyclohexylpropyl, benzylcyclohexylmethyl, 2-cyclohexyl-propyl, 30 2,2-methylcyclohexylpropyl, 2,2methylphenylpropyl, 2,2-methylphenylbutyl, and the like.
The structural diversity element may also be a connecting group that includes a terminal carbon atom for attachment to the quaternary nitrogen and may be different in 35 ~djacent n units.
In one embodiment of the invention, at least one of the structural diversity elements represents an organic or U SHEET (RULE 91) W O 96/22529 PCT~US96/01005 inorganic macromolecular surface. Examples of preferred macromolecular surfaces include ceramics such as silica and alumina, porous and non-porous beads, polymers such as a latex in the form of beads, membranes, gels, macroscopic 5 surfaces or coated versions or composites or hybrids thereof.
All publications, patents, and patent applications are herein specifically incorporated by reference to their relevant portions (cf. The Merck Tn~, 11th Ed., Budavari, S. Ed., Merck & Co., Rahway, NJ, 1989; Physicians Desk 10 Reference, 44th Ed., Barnhart, E. D. Publ., Medical Economics Company Inc., Oradell, NJ, 1990.
The following experimentals are meant to exemplify but one embodiment of the present invention and are not intended to limit the invention thereto.
Examples A 10,240-component array is synthesized according to the teaching of the invention, from eight oxazolones (Building Block A), 32 aldehydes (Building Block B), and ~0 amines 20 (Building Block C).
AN 1001 Protocol: Tetrahydrofuran (THF) solutions of the building blocks are prepared according to the protocols generated on the spread sheets entitled "AN 1001 SOLUTION
PROTOCOLS. CALCULATIONS, AND BUILDING BLOCK SELECTION". The 25 Building Block solutions are 250 mM in "A", 250 mM in "B", and 500 mM in "C". Sufficient volumes of each solution are prepared to allow for the production of one row of reaction plates (Px, where x= 1-128 for AN 1001). A reaction plate contains 80 spatial addresses each (8 X 10) and a row 30 contains 16 reaction plates. The entire array consists of 8 rows of these reaction plates which are recycled 16 at a time to complete production of the array. The initial cycle's first operator is spatial delivery of 200 ~l (1 eq., 50 ~moles) of the "A" building block solution according to the 35 spread ~eet entitled "AN 1001 SPATIAL LAYOUT, "A" BUILDING
BLOCKSII starting at Pl and ending at P16. The second operator is spatial delivery of 200 ~l (l eq., 50 ~moles) of RECrlF~ED SHEEr (RULE 9t) W O 96/22529 PCTrUS96/01005 the "B" Building Blocks to the same reaction plates according to the spread sheet entitled "AN 1001 SPATIAL LAYOUT, "B"
BUILDING BLOCKS." The third operator is addition to the same reaction plates of 50 ~L of a I M (1 eq., 50 ~moles) solution 5 of triethylamine in THF to all the spatial addresses that "A"
and "B" building Blocks were added. The forth operator is placement of the reaction blocks on an agitator at 60 degrees centigrade for 1.5 hrs. The fifth operator is spatial addition of 100 ~l (1 eq., 50 ~moles) of the "C" building, 10 ~lock solutions according to the spread sheet entitled "AN
1001 SPATIAL LAYOUT, "C" BUILDING BLOCKS." The sixth operator is addition of 200 ~L of THF to all the spatial addresses in the row or cycle. The seventh operator allows the reaction plates to stand at 25 decrees centigrade for 16 15 hrs. enabling evaporation of THF and completion of the synthesis of the molecular constructs. The following operators are then applied to distribute and reformat the molecular constructs for delivery and quality control. Heat the reaction plates to 60 degrees centigrade for 10 minutes 20 and add 400 ~l of dimethylsulfoxide (DMSO) to dissolve the molecular constructs (operator 8). Remove the solution from the reaction plates and place in a plastic microtiter plates in a special manner (operator 9). Specially wash the reaction plates (each address) with 4 times 325 ~L of DMSO
25 and place in the same microtiter plates (operator 10). This affords 2g.4 mM solutions of the molecular constructs in DMSO
ready for further spacial distribution. Remove a 10 ~L
aliquot following a unique address pattern layout from each microtiter plate for quality control (operator 11).
30 Specially reformat these aliquots, dilute with 300 ~L of acetonitrile and subject these samples to analysis by High Performance Liquid Chromatography and Mass Spectrometry for quality control of the molecular constructs in the each microtiter plate (operator 12). The above cycles and 35 operators are re~oated 7 more times to finish production and quality controlled validation of the array, AN 1001.
RE~TIFIED SHEET (RllLL 91) W O g6/22529 - AN 100 OOL~TION rnu,~CùL~, C~rBr~ION8 AND B~ILDING BLOC~ ~r.
AT THEORY, ENTER
~M uM/Well Equ~v.
nAn 8UI~DING B~OC~S ~ 8 250 50 ~Bn B m LDINC B } S 32 250 50 ~C" Bm~DING B}S 40 500 S0 t ~n~ .,.~R~p~ ~R 80 r~rr~ q'R~ AC!I~ PJER ADDRRSS
Uu UB ~M
PER ~A~ 50 200 250 PER ~B" 50 200 250 PER "C" 50 100 500 ~ AnL~K~.q~ ~ t ~R ~ PLATES
Tu~~AL RûW CûL~M ~OTAL Rû~ CûLVMN
N
PER ~A" 1280 1280 80 16 16 PER "B" 320 40 320 4 0.5 4 PER ~C~ 256 32 16 3.2 0.4 0.2 ~1 used ~ole5 us~d TOTAL ROW COLUM TOTAL ROW COLUMN
PER nAn 256 256 16 64 64 4 PER "B" 64 8 64 16 2 16 PER nc" 25.6 3.2 1.6 12.8 1.6 0.8 ENTER ACTUAL AMOU~TS DESIRE~ FROM ABOVE ~T~T~Tn~S
VOL (~1) m~ Excess ~
PER nAn 250 250 20 PER nBn 10 250 20 PER ncn 10 S00 200 D SH~ET (RULE 91 , PCTrUS9G/01005 W 096/22~29 '~1 CO 10 ~o r~ N N ~ ,N~ N
_~ N N N N N N N N 0 ~( ~ It~ . N, N ~D ~D N N 1 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~J ~r ~ ~D ~O ~0 . . . .
E; ~i H ~-~ P
~ c:, c~ a c~ a o c~ c~ O
g g $ g g g g g ,~ N N ~'1 N N ,~ ,~ ~I N N
~, 111 U7 ~q N N N 'D ~D
O 11~ 0It) O
O ~ O O ~ ~ ~ q CO ~ I~ r ~l ~1 ~( ~ .( ~ ~ O ~ O U~ '~D
o o o o o o o o ~
p p - p p ~J ~ N N N ~r ~/ ~ U~ ~0 '.0 Q a a a a a a a ' I~ N o 1~
N ~1 --( ~q N O O O
~ It' O C ~ 1~ N N It~
~D ~1 ~ N N ~ N ~ r O O O
N N ,~ t' I' r N N <Y
r ~q N ~ ~ r 1 r~ OO t' ~ ~ ~I L 1' 1' 0 o~ ~
~ ~ ~ O - 'I O o o o o O OO ~ O .- O O O O O O
m m m m m m m m m m ~
K K
~ O ~ ~ O
H ~
D . , , . . ~, ~ D C
X ~ rl ~ ~ h P ~ h P h C~ -- ~ 11N ~ ~ N Q~ ~ _ N ~ N ~ r . . . O ~ Q~
RECTIFI~D SHEET (RULE 91) W O 96/22529 .. PCT~US96/01005 N N N N~-I N N'( N ~ _~ N N NN N NN N N N N
~ N ~ 10 IY ~r CO ~ ~ .r~r N ~ eo C
1~ C 1~ 0 P N Y~ gCO In 1~_( tq O~1 0 pg g 1 p ~( _I P ,~ PP P ~1 .i ~1 N N N N N N N N N N NN N N NN N NN N N N
0~ t' It) ~'ICO Ct' ~I t~ ~o N N ~)CO ~ It') ~'- O 0 CD 1'~
~I N N ~~r7 N CO t~ ~O\ N ~r~r t~l N N Iq tO CO ~ 01 ~ 0 ~ 0~ r N N r~
1~ N N N ,~ ~ 01 ~r 1~ ~,~N ~ t~~ ~ N 0~ N
U~ 0 ~I~q ~ . ~I gt~ 0 r' . N Oo~ N g P g O O ~r a~ 0 ~i o ~ ~ o ~ 0 Ul 0 0P In N~ ~ ~ ,i N _I
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fltCl~U SHEE~ (RULL 91) W O 96/22529 PCTrUS96/0100 EXPANDED VIEW OF A SINGLE REACTION PLATE LAYOUl~ / TEMPLATE
ARRAY, A~ 1001 ~Sp~ial Address ~' = = = = =
C
D
F
G
=
R 1 C 1, _ P 1 ~
Column number in Array of the plate Reaction Plate number Row number in Array of the plate rt~ SHEET (RULE 91) "A"BUILDnNG BLOCKS
ARRAY, AN 1001 ~ ~,CO ~0 ~ ~
1 rh..
m~
2~
6~ F,C~ c~ 6 T ' ~ r 2,~n~
~-T ' mT.' CA 022l0949 l997-07-2l W 096/22529 "B"BUlLDn~G BLOCK~ PCT~US96/01005 CHO CHO
~"F ~ F ~ ~F
2,4~-- . ,,,, 2-r ' '' ~,~ 3 F ' ~ 2-r CHO
CHO CHO ¦ CHO
~CF, ~ ~CH~
B5 B6 CF, B7 B8 T -c ~ ~a.T "~T.' ~ ~.T ~ F ~ o-Tolualdehyde CHO CHO
~C/~J ~ ~ ~
CH, H,C B 11 m-Tolu~ldehydep-Tolualdehyde 1 r ~ r ~ ~ ~ ,d~
CHO
CHO CHO ¦ CHO
O
2-(~ ' ' ' ' ', 1~ 3~ ~ ' ' ' ' ,.' 2,4 n ~ . ,,, m ~
"B"B~lLDnNG BLOCKS PCTrUS9610100S
W 096/22529 Y,A~1001 CHO
CHO
~_ ~CHO
CHO
SCH, B18 B19 OcF, B20 ) L , ~ T y) J-CHO F/~F
3 ~ 2~ 3~~ 3~5--n ' ~ ~ ~ Ic CHO
CHO
~CHO ~ ~ ~ ~CHO
3 r; ~ ~ ~ b, '_1 P; ' ' ' ~ ~ ~ ,J, 3-'2 ,J~
~ ¢~C~ C~o I Q ~ 2-F. ' ~ 3-F. ' ' ' ,J. 51 b, "C"BU~LDnNG BLOCKS PCTrUS96/01005 W 096/22529 A~URAY,AI~ 1001 I--\o ~~ ,l NHz /~ O--NH2 H2N Cl a C3 C~
T ' ,,' - ~ (~)-s~c-autyl~snine C~
/~\ HO~NH2 H2N~<H
C~ ' ' ' ' I _ . ~ . Eth~tnolurune (S) (I) I A 2 i --NH2 ~ ~ ~OH
C9 OH C10 OH Cl I C12 2 ~ ~ .(tP~,25) ( ) ~ ' ' ' (rR)-(-)-Lcucinol Pipcddinc n- Cl~l =
1 B.,.. ~ , " Morpholinc l-Mothyl-3; ' ,~ ,, 3-Phenyl-l-propyla~runc ~NH2 ~NH2 ~ \C--NH2 C~9 ao B~n~yl rtune Fh.. Ih~ 1.7.3,1 T~ h, ' I ., ' ,' 2-(p-Tolyl)cthyl; tninc W 096/22529 "C"BUILDnNG BLOCKS PCT~US96/01005 ARRAY, AN1001 3~ ~ ~ ~J\HR
A 'i, ' ,: ' 2.2 ri~ minod~n (l ): '' ' ,"
~ ¢~ NH2 H~COJ~--~NHZ ~H~ C28 C25 H2N C26 OCH3 C27 o~o~CH~
I r 1 r J 3 4 n 1 Elhyl l-pipe~azine tarbo~tylate CN~-- ~N~ H ~N~ HN~ X >
1-(2-Aminoethyl)pytroadine I n~ ,!~', ' 1~8 ' I ! ~ ?i, ~
l~N~ NH2 ~N~NH2 ~ --~\ H2 ~1--~NH2 4-(3~ ', ,,I)-motpholine 4-(2-Aminocthyl)-mopholine 1~3~ ', ,JI)imithzol~ 3n , ,, F,C N HH ~NIi2 G ~NH2 HN ~_ C37 C3~ C39 C ~0 a~;t~T~ ~: 'yl)-piper~'n~ 2~ ?ryridine , 1-(2-Aminoethyl~pipeHoine 1~
PCTrUS96/01005 OE~
W O 96/22S29 PCTrUS96/01005 A~ A A1 A A' A A A~ A A'B A1 A A A1 A A
A~ A A A A A~ A A~ A~ A~C A1 A~ A A1 A~ A
A~ A~ A~ A' A~ A~ A1 A A A~~ A A A A1 A1 A~
A~ A A~ A A~ A' A1 A A~ AA' A~ A~ A1 A1 A' A' A1 A' A1 A~ A' A1 A' A' A'A' A~ A' A1 A' A~
G A' A1 A A1 A A' A1 A1 A' A~G A' A~ A' A1 A' A' H A' A1 A' A1 A1 A1 A1 A1 A' A1 H A1 A1 A' A1 A' A' A A2 A2 A2 A2 A2 A2 A2 A2 A2 A' A A2 A2 A2 A2 A2 A2 B A2 A2 A2 A2 A2 A2 A2 A2 A2 A~ B A2 A2 A~. A2 A2 A.
C A2 A2 A2 A2 A' A2 A2 A2 A2 A_ C A2 A2 A' A2 A2 A-A2 A2 A2 A2 A2 A2 A2 A2 A2 A. D A2 A2 A~. A2 A2 A~, A2 A2 A2 A2 A'.A2 A' A2 A2 A', E A' A2 A' A2 A2 A, A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 F A'.A2 A2 A2 A2 A2 G A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 G A'.A2 A2 A2 A2 A2 A A3 A A~ A3 A3 A3 A3 A3 A3 A3 A A3 A3 A3 A3 A3 A3 B A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 B A3 A3 A3 A3 A3 A3 C A3 A3 A3 A3 A3 A3 A3 A3 A~' A3 C A3 AV A3 A3 A3 A3 . A3 A3 A~' A3 A3 A3 A3 A3 A3 A3 D A'~A3 A3 A A~ A:
A3 A3 A~' A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A~ A3 A A3 A~ A3 A3 A~ A~ A3 A3 A3 A3 A3 A3 A~ A3 A3 H A3 A A3 A3 AJ A3 A3 A~ A~ A3 H A3 A3 A3 A3 A3 A3 A A~ A4 A~ A4 A4 A4 A4 A4 A4 A4 A A4 A4 A4 A4 A4 A4 - B A~ A4 A~ A4 A4 A4 A4 M A4 A4 B A4 A4 A4 A4 A4 A4 C A~ A4 A~ A4 A4 A4 A4 A4 A4 A4 C A4 A4 A4 A4 A4 A4 ~ A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 D A~ A4 A4 A4 A4 A4 - A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 E A~ A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 F A~ A4 A4 A4 A4 A4 G A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 G A4 A4 A4 A4 A4 A4 H A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 H A4 A4 A4 A4 A4 A4 -W 096/22529 PCTrUS96/01005 B A5 A5 A A A A. A. A5 A5 A5 B A5 A5 A A5 A. A
l A5 A5 A. A A A A A A5 A5 D A A5 A A5 A;. A5 A. A A A A A5 A A A5 A5 E A A5 A5 A5 A5 A5 A A_ A A A A5 A A A5 A F A5 A5 A5 A5 A5 A5 ~ G A A. A A A. A5 A5 A5 A5 A G A5 A5 A5 A5 A5 A5 E A7 A7 A7 A, A7 A7 A7 A, A7 A. A7 A7 A7 A7 A7 A7 F A7 A7 A7 A- A, A7 A7 A7 A7 A- A7 A7 A7 A7 A7 A7 W O 96/22529 PC~fUS96/01005 A' A1 A1 A' B A' A' A1 A' A' A1 A1 A1 A1 A1 B A1 A' A1 A1 AC A' A A' A A A A A1 A1 A C A
A A1 A A~ A A A A' A1 A' A A1 A' A ~ A
A' A1 A A1A1 A1 A' A' A1 A' A A1 A' A A
A1 A1 A A1 G A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 G A' A2 A2 A2 A2 C A2 A2A2 A2 A2 A2 A2 A2 A' A2 C A2 A2 A2 A2 A' D A2 A2A2 A2 A2 A2 A2 A2 A2 A2 ~ A2 A2 A2 A2 A2 A2 A2A~' A2 A2 A2 A2 A2 A2 A' A2 A3 A~ A3 A3 A A3 A~A3 A3 A3 A3 A3 A3 A3 A~ A A~
A' A3 A3 A3 B A3 A3A3 A3 A_ A3 A3 A3 A3 A3 B A' A3 A~ A3 A3 C A3 A~A3 A' A3 A3 A3 A3 A3 A C A' A3 A~ A3 A3 D A3 A3A3 A3 A3 A3 A3 A3 A3 A D A' A3 A~ A3 A3 E A3 A3A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A~ A3 A~ F A3 A3A3 A3 A3 A3 Av A3 A3 A3 A3 Aé A~ A3 A'- G A' A3A3 A3 A3 A3 A3 A3 A3 A' G A3 A~ A3 A3 A H A3 A3A3 A3 A3 A3 A3 A3 A3 A~ H A3 P 34 R 3 C 3 P 3~ R 3 A4 A4 A4 A4 A A4 A4A4 A4 A4 A4 A4 A4 A4 A~ A A4 A~ A4 A4 A4 B A4 A4A4 A4 A4 A4 A4 A4 A4 A~ B A4 A~ A4 A4 A4 C A4 A4A4 A4 A4 A4 A4 A4 A4 A~ C A4 A~ A4 A4 A4 D A4 A4A4 A~ A4 A4 A4 A4 A4 A~ D A4 A~ A4 A4 A4 E A4 A4A4 A~ A4 A4 A4 A4 A4 A~ E A4 A4 A4 A4 A4 F A4 A4A4 A~ A4 A4 A4 A4 A4 A~ FA4 CA 022l0949 l997-07-2l W O 96/22529 PCT~US96/01005 A5A5 A5 A ~ A5 A5 A5 A5 A5 A A5 A A A5 D A
A7A7 A7 A7 ~ C A7 A7 A- A7 A7 A7 A7 A- A7 A7 C A7 A7A7 A7 A7 E A, A7 A. A, A7 A7 A7 A- A- A7 E A7 A7A7 A7 A7 G A- A7 A7 A, A7 A7 A7 A7 A- A7 G A7 A7A7 A7 A7 H A, A7 A7 A7 A7 A7 A7 A7 A7 A7 H A7 8 9 10 11 2 3 ~ 5 6 7 8 9 10 1 2 -CA 022l0949 l997-07-2l W O 96/22529 PCTfUS96/01005 A' A A1 A A A1 A' A A C A1 A1 A1 A1 A1 A1 A1 A1 A' A' A1 A' A' A1 A' A' A' D A1 A' A1 A1 A1 A1 A A' A1 A' A1 A' A A1 A' A1 A A1 A A1 A1 A1 A1 A A' A1 A' A1 A' A' A1 A' A1 A' A1 A' A1 A1 A1 A1 A A' A1 A' A1 A1 A1 A1 A1 A1 A' G A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A' H A1 A1 A1 A1 A1 A1 A1 A1 A2 A2 A2 A2 A2 A2 A2 A2 A2 c A2 A2 A2 A2 A2 A2 A2 A2 A., A3 A3 A3 A3 A3 A3 A3 A3 A A3 A3 A3 A3 A3 A3 A3 A3 Av A3 A3 A3 A3 A3 A3 A3 A3 B A3 A3 A3 A3 A3 A3 A3 A' A~ A~ A3 A3 A3 A3 A3 A3 A3 c A3 A3 A3 A3 A3 A3 A3 A3 A', A3 A3 A3 A3 A3 A3 A3 A D A3 A3 A3 A3 A~ A3 A3 A' A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 A' A' A3 A3 A3 A3 A3 A3 A3 A3 A3 G A3 Av A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 H A3 A~ A3 A3 A3 A3 A3 A' A4 A4 A4 A~ A4 A4 A4 A4 A~ A A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 A~ A~ A4 A4 A4 A4 A~ B A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 A~ A~ A4 A4 A4 A4 A~ C A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 D A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 E A4 A4 A4 A4 A4 A4 A4 A~
A4 A4 A4 A4 A4 A4 A4 A4 A4 F A4 A4 A4 A4 A4 A4 A4 A~
A4 A4 A4 A4 A4 A4 A4 A4 A4 G A4 A4 A4 A4 A4 A4 A4 A~
A4 A4 A4 A4 A4 A4 A4 A4 A4 H A4 A4 A4 A4 A4 A4 A4 A~
W 096/22529 PCTrUS9610100S
3 4 5 6 7 8 9 10 1~ _ 3 4 5 6 7 8 9 A. A. A5 A5 A5 A5 A5 A A5 B A A A A A A A5 A
A~ A A5 A5 A5 A5 A5 A5 A ~ A A A A A5A~ A A
A A5 A5 A5 A5 A5 A5 A A A5 A5 A A A5A-' A A
A A5 A- A5 A~ A5 A5 A A A5 A5 A A A5 A A A-' A .A5 A-' A5 A A5 A5 A A5 G A5 A5 A5 A A5A5 A5 A5 A A A6 A6 A6 A6 A6 A6 A B A .A A A6 A A6 A6 A
A A A6 A6 A6 A6 A6 A6 A C A A A A6 A A~ A6 A
A A6 A6 A6 A6 A6 A6 A A6 F A6 A6 A6 A A~ A A6 A
A, A7 A7 A7 A7 A7 A7 A7 A. D A7 A7 A7 A7 A7A7 A7 A7 CA 022l0949 l997-07-2l W O 96/22529 PCTrUS96/01005 A- A- C A1 A' A1 A- A1 A- A1 A1 A1 A C A1 A1 A
A- A-~ A1 A- A1 A A1 A' A' A- A- A' ~ A1 A' A' A A'A1 A' A1 A- A1 A- A- A A' A A1 A- A' A' A'A1 A' A1 A1 A' A' A' A' A' A' A1 A' A' A' A1 G A1 A1 A1 A1 A' A' A1 A1 A' A1 G A1 A1 A1 A' A1 H A1 A1 A1 A1 A' A- A1 A1 A' A1 H A1 A1 A1 A2 A2 ~ A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 D A2 A2 A2 A2 A2 A, A2 A, A2 A2 A2 A2 A2 A2 A. E A, A, A2 A2 A2 A.' A2 A'' A2 A2 A2 A2 A2 A2 A' F A, A, A2 A2 A2 G A' A2 A, A2 A2 A2 A2 A2 A2 A~ G A, A, A2 A2 A2 H A, A2 A, A2 A2 A2 A2 A2 A2 A_ H A, A, A2 A3 A3 A A3 A3 A~ A3 A3 A3 A3 A3 Av A3 A A3 A~ A3 A3 A3 B A3 A3 A3 A3 A3 A3 Av A3 -A3 A3 B A3 A3 A3 A3 A3 C A3 A3 A3 A3 A3 A3 A3 A3 A~ A3 C A3 A~ A3 Av A3 D A3 A3 A3 A3 A3 A3 A3 A3 A3 A' ~ A3 A3 A3 A3 A3 E A3 A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 Av A3 F A3 A3 A3 A3 A3 A3 A3 A3 A. A3 A3 A' A3 A' A' G A3 A3 A3 A3 A3 A3 A3 A3 A' A~ G A3 A3 A3 A3 A3 H A3 A3 A3 A3 A3 A3 A3 A3 A3 A. H A3 A3 A3 A~ A4 A A~ A~ A4 A4 A4 A4 A4 A4 A4 A4 A A4 A4 A4 A~ A4 B A~ A~ A4 A~ A4 A4 A4 A4 A4 A4 B A4 A4 A4 A~ A4 C A~ A~ A4 A~ A~ A4 A4 A4 A4 A~ C A4 A4 A4 A~ A4 ~ A4 A' A4 A~ A~ A4 A4 A4 A4 A~ D A4 A4 A4 A4 A4 A4 A4 A4 A~ A~ A4 A4 A4 A4 A~ E A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 ~4 F A4 A4 A4 CA 022l0949 l997-07-2l PCTrUS96/01005 A A A A A A. A5 A A A5 AA5 A5 A A5A5 A5 A A C A A A-' A5 A A-' A5 AA5 A5 c A5A5 A5 A5 A5 G A.A5 A5 A5 A5 A5 A5 A5A5 A G A5A5 A5 A7 A7 H A7A7 A7 A7 A- A7 A7 A7 A- A, H A7A7 A7 CA 022l0949 l997-07-2l PCT~US96/01005 A
A A1 A1 A A1 A1 A C A1 A A1 A A1 A1 A- A' A A1 A1 A1 A1 A1 A A1 A1 E A1 A' A' A1 A' A1 A- A1 A1 A1 A1 A1 A1 A1 A- A1 A1 F A1 A- A' A1 A- A1 A- A1 A1 A1 A1 A1 A1 A1 A A1 A1 G A1 A A A1 A' A1 A A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 H A1 A1 A' A1 A1 A1 A' A1 A1 A1 A2 A2 A2 A2 A2 A2 A2 A A2 A2 A2 A, A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A,' B A2 A2 A2 A2 A2 A2 A2 A.' A2 A2 A2 A2 A2 A2 A2 A2 A, C A2 A2 A2 A2 A2 A2 A2 A, A2 A2 A2 A2 A2 A2 A2 A2 A2 D A2 A2 A2 A, A2 A, A.' A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 E A2 A2 A2 A2 A2 A, A2 A, A2 A2 A2 A2 A2 A2 A2 A2 A2 F A2 A2 A2 A2 A2 A. A2 A, A2 A2 A2 A2 A2 A2 A2 A2 A2 G A2 A2 A2 A2 A2 A2 A2 A, A2 A2 A3 A3 A3 A3 A3 A3 A3 A A3 A3 A3 A3 A3 A_ A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 C A3 A3 A3 A3 A~ A3 A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 D Av A3 A3 A3 A: A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A3 A3 E A3 A3 A~ A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A3 F A~ A3 A3 A3 A3 A3 A' A3 Av A3 A~ A_ A3 A3 A3 A3 A3 G A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A~ A~ A~ H A3 A3 A~ A' A3 A' A3 A_ A~ A3 A4 A4 A4 A4 A4 A4 A4 C A~ A4 A' A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 D A' A4 A' A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 EA' A4 A' A4 A' A4 A4 A4 A4 A4 A' A4 A4 A4 A4 A4 A4 FA4 A4 A4 A4 A' A4 A4 A4 A4 A4 A' A4 A4 A4 A4 A4 A4 G A4 A4 A4 A4 A' A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 H A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 PCTrUS96/01005 A. A5 A A A5 A A5 c A5 A A5 A5 A5 A5 A A A A
A. A5 A5 A5 A A5 A H A5 A5 A5 A5 A5 A5 A5 A5 A5 A5 A7 A7 A7 A7 A7 A7 A7 ~ A7 A7 A- A7 A7 A7 A7 A7 A7 A7 A, A7 A7 A7 A7 A7 A- A7 A7 A- A7 A7 A7 A7 A7 A- A7 A- A7 A7 A7 A7 A7 A. G A7 A7 A7 A7 A7 A7 A7 A7 A- A7 P 1t3 R 7 C 8 P 10 . A 8 A8 A8 A A8 A8 A8 A8 . 8 A8 A A A8 A8 A8 A8 A A8 A8 P~T~US96/01005 B A A1 A1 A1 A1 A1 A1 A' A1 A1 B A1 A1 A1A1 A1 C A' A1 A1 A1 A1 A1 A1 A' A' A1 C A' A' A1A1 A1 D A A1 A A1 A1 A1 A1 A A A1 D A' A' A1A1 A1 E A A1 A A1 A1 A1 A1 A A A1 E A' A' A1A1 A
F A A1 A A1 A1 A1 A1 A A A1 F A1 A' A1A1 A
A A A2 A2 A2 A2 A2 A2 A2 A. A2 A A2 A2 A2A2 A2 B A2 A2 A2 A2 A2 A2 A2 A2 A, A2 B A2 A2 A2A2 A2 C A3 A3 A3 A3 A3 A3 A3 A3 Av A3 C A3 A3 A3- A3 A3 D A3 A3 A3 A3 A3 Av A3 A3 A3 A3 D A3 A3 A3 A3 A' E A3 A3 A3 A3 A3 A~ Av A3 Av A_ E A3 A3 A3 A~ A.
F A3 A3 A~ A3 A' Av Av Av Av A', F A' A. A~ A_ A3 G A3 A3 Av A3 Av A3 A~ A3 A3 A' G Av Av Av A', Av H A3 A3 A3 A3 A3 A3 A3 A~ A3 A3 HAv Av AvA3 Av C A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 c A4 A4 A4A4 A4 D A4 A4 A~ A4 A4 A4 A4 A4 A4 A4 D A4 A4 A4A4 A4 E A4 A4 A' A4 A4 A4 A4 A4 A4 A4 E A4 A4 A4A4 A4 F A4 A4 A~ A4 A4 A4 A4 A4 A4 A4 FA4 A4 A4A4 A4 CA 022l0949 l997-07-2l W O 96/22529 PCTrUS96/01005 C A A5 A A5 A A5 A A A A c A A A A A
D A A5 A. A5 A A5 A. A A A D A A A A A
A5 A5 A A5 A5 A A A A A F A A A A. A
H A5 A5 A5 A5 A5 A A A. A A H A A A A A
R 5 C 9 P 7. R 5 C 10 A A7 A7 A7 A7 A7 A7 A7 A7 A, A7 A A7 A7 A7A7 A7 C A7 A7 A7 A7 A7 A7 A7 A7 A. A7 C A7 A7 A7A7 A7 A7 A7 A7 A7 A7 A7 A7 A7 A7 A7 ~ A7 A7 A7A7 A7 R 7 C 9 ' P 105 R 7 C 10 PCTrUS96101005 A
A1A' A1 A1 A B A1 A1 A1 A1 A A1 A1 A' A1 A1 B
A1A' A1 A1 A' C A1 A1 A1 A1 A A1 A1 A' A1 A1 C
A1A1 A1 A1 A1 D A1 A1 A1 A1 A1 A1 A1 A' A1 A1 D
A1A' A A A' A A1 A1 A1 A1 A1 A1 A' A1 A1 E
A A' A A' A' A A' A' A1 A1 A1 A1 A1 A1 A1 F
A'A' A A A G A' A' A A1 A1 A1 A1 A1 A1 A1 G
A'A' A1 A1 A1 H A' A' A' A1 A1 A1 A1 A1 A1 A1 H
A2 A2 A2 A2 A2 B A2 A, A2 A2 A2 A2 A2 A2 A2 A2 B
A2 A2 A2 A2 A2 D A. A2 A2 A2 A2 A2 A2 A2 A2 A2 D
A3 A3 A3 A3 A3 A A3 A3 A3 A3 A~ A3 A~ A3 A3 A3 A
A3 A3 A~ A3 A~ B A3 A' A3 A3 A3 A3 A3 A3 A3 A3 B
A~ A3 A~ A3 A~ C A: A' A'- A3 A~ A3 A' A3 A3 A3 C
Av A3 A3 A3 A3 D A3 A3 A~ A3 A~ A3 A3 A3 A3 A3 D
A3 A3 A3 A3 A3 E A3 A3 A~ A3 A3 A3 A3 A~ A3 A3 E
A3 A3 A3 A3 A3 F A3 A3 A3 A3 A3 A3 Av A3 A3 A3 F
A~ A3 A~ A3 A~ G A3 A. A3 A3 A3 A3 A3 A3 A3 A3 G
A3 A3 A3 A3 A3 H A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 H
A~ A4 A4 A4 A' D A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 D
A~ A4 A4 A4 A~ E A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 E
A~ A4 A4 A4 A~ F A4 A4 A4 A4 A4 A~ A4 A~ A4 A4 F
A~ A4 A4 A4 A4 G A4 A4 A4 A4 A4 A~ A4 A~ A4 A4 G
A~ A4 A4 A4 A4 H A4 A4 A4 A4 A4 A~ A4 A~ A4 A4 H
: =
CA 022l0949 1997-07-21 PCT~US96101005 A5 A5 A5 A5 A A A5 A5 A5 A... A A A5 A5 A A A
A5 A. A5 A A E A5 A5 A A5 A5 A5 A A5 A5 A
A5 A A A A F A5 A. A5 A5 A5 A5 A5 A5 A5 A
A5 A_ A A A G A5 A A5 A5 A5 A5 A5 A5 A5 A G
P 74 R 5 C 11 p 75 R
A6 A6 A6 A A G A6 A6 A6 A6 A6 A~ A6 A6 A6 A6 G
A6 A6 A6 A~ A H A6 A6 A6 A6 A6 A A6 A6 A6 A6 H
A7 A7 A7 ~7 A7 C A7 A7 A7 A, A- A- A7 A7 A7 A- C
A A8 A8 A A8 D A8 A8 A8 A A8 A8 A8 A8 A8 A8 .D
CA 022l0949 l997-07-2l W O 96/22529 PCTnUS96/01005 A A1 A1 A1 A1 A1 A A1 A1 A1 c A1 A1 A1 A1 A1 A1 A1 A'A' A A1 A1 A1 A1 A1 A1 A' ~ A1 A1 A1 A1 A1 A1 A' A' A A A1 A1 A1 A1 A A A A1 A A1 A1 A1 A1 A' A A A A1 A1 A1 A1 A A A' A' A A' A1 A1 A1 A
A A A' A1 A1 A1 A1 A' A A' G A A A A1 A1 A1 A1 A'A1 A' A1 A1 A1 A1 A1 A1 A1 H A' A1 A' A1 A1 A1 A1 A2A. A2 A, A2 A2 A2 A2 A2 A2 A A2 A2 A2 A2 A2 A2 A2 A2A' A2 A, A2 A2 A2 A2 A2 A2 B A2 A2 A2 A'' A2 A2 A2 A2A, A2 A, A2 A2 A2 A2 A2 A2 C A2 A2 A2 A2 A2 A2 A2 A2A2 A2 A2 A2 A2 A2 A2 A2 A2 D A2 A2 A2 A. A2 A2 A2 A2A2 A2 A2 A2 A2 A2 A2 A2 A2 E A2 A2 A, A2 A2 A2 A2 A2A2 A2 A2 A2 A2 A2 A2 A2 A2 F A2 A2 A' A. A2 A2 A2 A2A2 A2 A2 A2 A2 A2 A2 A2 A2 G A2 A2 A, A. A2 A2 A2 A2A2 A2 A2 A2 A2 A2 A2 A2 A2 H A2 A2 A. A, A2 A2 A2 A3A3 A3 A3 A3 A3 A3 A3 A3 A3 A A3 A~ A3 A3 A3 A3 A3 A~A3 A3 A~ A3 A3 A3 A3 A3 A3 C A3 A3 A3 A3 A3 A~ A3 A'A3 A3 A3 A3 A3 A3 A3 A3 A3 ~A3 A3 A3 A' A3 A' A3 A3A3 A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A3 A3 A3 A3A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A3 A3 A_ A~ A3 A3A3 A3 A' A3 A3 A3 A' A3 A3 G A3 A3 A3 A3 A' A3 A3 A3A3 A3 A3 A3 A3 A3 A3 A3 A3 H A3 A3 A3 A3 A~ A3 A~
A4A4 A4 A4 A4 A4 A4 A4 A4 A4 FA~ A4 A~A4 A~ A4 A4 A4A4 A4 A4 A4 A4 A4 A4 A4 A4 G A~ A4 A~A4 A' A4 A4 A4A4 A4 A4 A4 A4 A4 A4 A4 A4 HA~ A4 A~A4 A~ A4 A4 W O 96/22529 PCTrUS96/01005 A A5 A5 A A A A A5 A A. B A5 A5 A5 A A A5A5 A A5 A5 A A A A A5 A A c A5 A5 A A A. A5A5 A. A5 A5A5 A A5 A A5 A5 A D A A5 A A A AA5 A7 A7 A7A7 A7 A- A- A7 A- A7 G A7 A7 A.A7 A- A7A7 A7 A7 A7A7 A7 A- A, A7 A- A7 H A7 A7 A7A7 A7 A7A7 -t .
RE(~f~F~El~ S,YEE~ ~UL~ ~) CA 022l0949 l997-07-2l PCTrUS96/01005 Examples of macromolecular components include porous and non-porous inorganic components, such as, for example, silica, alumina, zirconia, titania and the like, as commonly used for various applications, such as normal and reverse phase 5 chromatographic separations, water purification, pigments for paints, etc.; porous and non-porous organic macromolec~ r components, including synthetic components such as styrenedivinyl benzene beads, various methacrylate beads, PVA
beads, and the like, commonly used for protein purification, 10 water softening; and a variety of other applications, natural components such as native and functionalized celluloses, such as, for example, agarose and chitin, sheet and hollow fiber membranes made from nylon, polyether sulfone or any of the materials mentioned above. The molecular weight of these 15 macromolecules may range from about 1000 Daltons to as high as possible. They may take the form of nano-particles (dp =
1000 - 5000 Angstroms), latex particles (dp = lOOo - 5000 Angstroms), porous or non-porous beads (dp = 0.5 - 1000 microns), membranes, gels, macroscopic surfaces or 20 functionalized or coated versions or composites.
Structural diversity elements may also be a chemical bond to a suitable organic moiety, a hydrogen atom, an organic moiety which contains a suitable electrophilic group, such as an aldehyde, ester, alkyl halide, ketone, nitrile, 25 epoxide or the like; a suitable nucleophilic group, such as a hydroxyl, amino, carboxylate, amide, carbanion, urea or the like; or one of the other structural diversity elements defined below. In addition, structural diversity elements may join to form a ring, bi-cyclic or tri-cyclic ring system;
30 or structure which connects to the ends of the repeating unit of the compound defined by the preceding formula; or may be separately connected to other moieties.
Structural diversity elements on a scaffold may be the same or different and each may be one or more atoms of 3s carbon, nitrogen, sulfur, oxygen, any other inorganic elements or combinations thereof. The structural diversity elements may be cyano, nitro, halogen, oxygen, hydroxy, R~CI~ltu SHET (R~)LE 91) PCTrUS96/01005 alkoxy, thio, straight or branched chain alkyl, carbocyclic aryl and substituted or heterocyclic derivatives thereof.
Structural diversity elements may be different in adjacent molecular cores and have a selected stereochemical 5 arrangement about the carbon atom to which they are attached.
As used herein, the phrase linear chain or branched chained alkyl groups means any substituted or unsubstituted acyclic carbon-cont~; n; ng compounds, including A lk~nes, alkenes and alkynes. Alkyl groups having up to 30 carbon 10 atoms are preferred. Examples of alkyl groups include lower alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; upper alkyl, for example, octyl, nonyl, decyl, and the like; lower alkylene, for example, ethylene, propylene, propyldiene, butylene, 15 butyldiene; upper alkenyl such as l-decene, 1-nonene, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl or beptenyl, and the like; alkynyl such as 1-ethynyl, 2-butynyl, 1-pentynyl and the like. The ordinary skilled artisan is familiar with numerous linear and branched alkyl groups, which are within 20 the scope of the present invention.
In addition, such alkyl group may also contain various substituents in which one or more hydrogen atoms has been replaced by a functional group. Functional groups include but are not limited to hydroxyl, amino, carboxyl, amide, 25 ester, ether, and halogen (fluorine, chlorine, bromine and iodine), to mention but a few. Specific substituted alkyl groups can be, for example, alkoxy such as methoxy, ethoxy, butoxy, pentoxy and the like, polyhydroxy such as 1,2-dihydroxypropyl, 1,4-dihydroxy-l-butyl, and the like;
30 methylamino, ethylamino, dimethylamino, diethylamino, triethylamino, cyclopentylamino, benzylamino, dibenzylamino, and the like; propionic, butanoic or pentanoic acid groups, and the like; formamido, acetamido, butanamido, and the like, methoxycarbonyl, ethoxycarbonyl or the like, chloroformyl, 35 bromoformyl, 1, 1-chloroethyl, bromoethyl, and the like, or dimethyl or diethyl ether groups or the like.
As used herein, substituted and unsubstituted IED SHEET (RULE 9~) W096/22529 PCT~S96/01005 carbocyclic groups of up to about 20 carbon atoms means cyclic carbon-containing compounds, including but not limited to cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. Such cyclic groups may also contain various 5 substituents in which one or more hydrogen atoms has been replaced by a functional group. Such functional groups include those described above, and lower alkyl groups as described above. The cyclic groups of the invention may further comprise a heteroatom. For example, in a specific lO embodiment, structural diversity element A is cyclohexanol.
As used herein, substituted and unsubstituted aryl groups means a hydrocarbon ring bearing a system of conjugated double bonds, usually comprising (4p - 2) pi bond electrons, where p is an integer equal to or greater than l.
l5 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anisyl, toluyl, xylenyl and the like.
According to the present invention, aryl also includes aryloxy, aralkyl, aralkyloxy and heteroaryl groups, e.g., pyrimidine, morpholine, piperazine, piperidine, benzoic acid, ~o toluene or thiophene and the like. These aryl groups may also be substituted with any number of a variety of functional groups. In addition to the functional groups described above in connection with substituted alkyl groups and carbocyclic groups, functional groups on the aryl groups 25 can be nitro groups.
As mentioned above, structural diversity elements can also represent any combination of alkyl, carbocyclic or aryl groups; for example, l-cyclohexylpropyl, benzylcyclohexylmethyl, 2-cyclohexyl-propyl, 30 2,2-methylcyclohexylpropyl, 2,2methylphenylpropyl, 2,2-methylphenylbutyl, and the like.
The structural diversity element may also be a connecting group that includes a terminal carbon atom for attachment to the quaternary nitrogen and may be different in 35 ~djacent n units.
In one embodiment of the invention, at least one of the structural diversity elements represents an organic or U SHEET (RULE 91) W O 96/22529 PCT~US96/01005 inorganic macromolecular surface. Examples of preferred macromolecular surfaces include ceramics such as silica and alumina, porous and non-porous beads, polymers such as a latex in the form of beads, membranes, gels, macroscopic 5 surfaces or coated versions or composites or hybrids thereof.
All publications, patents, and patent applications are herein specifically incorporated by reference to their relevant portions (cf. The Merck Tn~, 11th Ed., Budavari, S. Ed., Merck & Co., Rahway, NJ, 1989; Physicians Desk 10 Reference, 44th Ed., Barnhart, E. D. Publ., Medical Economics Company Inc., Oradell, NJ, 1990.
The following experimentals are meant to exemplify but one embodiment of the present invention and are not intended to limit the invention thereto.
Examples A 10,240-component array is synthesized according to the teaching of the invention, from eight oxazolones (Building Block A), 32 aldehydes (Building Block B), and ~0 amines 20 (Building Block C).
AN 1001 Protocol: Tetrahydrofuran (THF) solutions of the building blocks are prepared according to the protocols generated on the spread sheets entitled "AN 1001 SOLUTION
PROTOCOLS. CALCULATIONS, AND BUILDING BLOCK SELECTION". The 25 Building Block solutions are 250 mM in "A", 250 mM in "B", and 500 mM in "C". Sufficient volumes of each solution are prepared to allow for the production of one row of reaction plates (Px, where x= 1-128 for AN 1001). A reaction plate contains 80 spatial addresses each (8 X 10) and a row 30 contains 16 reaction plates. The entire array consists of 8 rows of these reaction plates which are recycled 16 at a time to complete production of the array. The initial cycle's first operator is spatial delivery of 200 ~l (1 eq., 50 ~moles) of the "A" building block solution according to the 35 spread ~eet entitled "AN 1001 SPATIAL LAYOUT, "A" BUILDING
BLOCKSII starting at Pl and ending at P16. The second operator is spatial delivery of 200 ~l (l eq., 50 ~moles) of RECrlF~ED SHEEr (RULE 9t) W O 96/22529 PCTrUS96/01005 the "B" Building Blocks to the same reaction plates according to the spread sheet entitled "AN 1001 SPATIAL LAYOUT, "B"
BUILDING BLOCKS." The third operator is addition to the same reaction plates of 50 ~L of a I M (1 eq., 50 ~moles) solution 5 of triethylamine in THF to all the spatial addresses that "A"
and "B" building Blocks were added. The forth operator is placement of the reaction blocks on an agitator at 60 degrees centigrade for 1.5 hrs. The fifth operator is spatial addition of 100 ~l (1 eq., 50 ~moles) of the "C" building, 10 ~lock solutions according to the spread sheet entitled "AN
1001 SPATIAL LAYOUT, "C" BUILDING BLOCKS." The sixth operator is addition of 200 ~L of THF to all the spatial addresses in the row or cycle. The seventh operator allows the reaction plates to stand at 25 decrees centigrade for 16 15 hrs. enabling evaporation of THF and completion of the synthesis of the molecular constructs. The following operators are then applied to distribute and reformat the molecular constructs for delivery and quality control. Heat the reaction plates to 60 degrees centigrade for 10 minutes 20 and add 400 ~l of dimethylsulfoxide (DMSO) to dissolve the molecular constructs (operator 8). Remove the solution from the reaction plates and place in a plastic microtiter plates in a special manner (operator 9). Specially wash the reaction plates (each address) with 4 times 325 ~L of DMSO
25 and place in the same microtiter plates (operator 10). This affords 2g.4 mM solutions of the molecular constructs in DMSO
ready for further spacial distribution. Remove a 10 ~L
aliquot following a unique address pattern layout from each microtiter plate for quality control (operator 11).
30 Specially reformat these aliquots, dilute with 300 ~L of acetonitrile and subject these samples to analysis by High Performance Liquid Chromatography and Mass Spectrometry for quality control of the molecular constructs in the each microtiter plate (operator 12). The above cycles and 35 operators are re~oated 7 more times to finish production and quality controlled validation of the array, AN 1001.
RE~TIFIED SHEET (RllLL 91) W O g6/22529 - AN 100 OOL~TION rnu,~CùL~, C~rBr~ION8 AND B~ILDING BLOC~ ~r.
AT THEORY, ENTER
~M uM/Well Equ~v.
nAn 8UI~DING B~OC~S ~ 8 250 50 ~Bn B m LDINC B } S 32 250 50 ~C" Bm~DING B}S 40 500 S0 t ~n~ .,.~R~p~ ~R 80 r~rr~ q'R~ AC!I~ PJER ADDRRSS
Uu UB ~M
PER ~A~ 50 200 250 PER ~B" 50 200 250 PER "C" 50 100 500 ~ AnL~K~.q~ ~ t ~R ~ PLATES
Tu~~AL RûW CûL~M ~OTAL Rû~ CûLVMN
N
PER ~A" 1280 1280 80 16 16 PER "B" 320 40 320 4 0.5 4 PER ~C~ 256 32 16 3.2 0.4 0.2 ~1 used ~ole5 us~d TOTAL ROW COLUM TOTAL ROW COLUMN
PER nAn 256 256 16 64 64 4 PER "B" 64 8 64 16 2 16 PER nc" 25.6 3.2 1.6 12.8 1.6 0.8 ENTER ACTUAL AMOU~TS DESIRE~ FROM ABOVE ~T~T~Tn~S
VOL (~1) m~ Excess ~
PER nAn 250 250 20 PER nBn 10 250 20 PER ncn 10 S00 200 D SH~ET (RULE 91 , PCTrUS9G/01005 W 096/22~29 '~1 CO 10 ~o r~ N N ~ ,N~ N
_~ N N N N N N N N 0 ~( ~ It~ . N, N ~D ~D N N 1 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~J ~r ~ ~D ~O ~0 . . . .
E; ~i H ~-~ P
~ c:, c~ a c~ a o c~ c~ O
g g $ g g g g g ,~ N N ~'1 N N ,~ ,~ ~I N N
~, 111 U7 ~q N N N 'D ~D
O 11~ 0It) O
O ~ O O ~ ~ ~ q CO ~ I~ r ~l ~1 ~( ~ .( ~ ~ O ~ O U~ '~D
o o o o o o o o ~
p p - p p ~J ~ N N N ~r ~/ ~ U~ ~0 '.0 Q a a a a a a a ' I~ N o 1~
N ~1 --( ~q N O O O
~ It' O C ~ 1~ N N It~
~D ~1 ~ N N ~ N ~ r O O O
N N ,~ t' I' r N N <Y
r ~q N ~ ~ r 1 r~ OO t' ~ ~ ~I L 1' 1' 0 o~ ~
~ ~ ~ O - 'I O o o o o O OO ~ O .- O O O O O O
m m m m m m m m m m ~
K K
~ O ~ ~ O
H ~
D . , , . . ~, ~ D C
X ~ rl ~ ~ h P ~ h P h C~ -- ~ 11N ~ ~ N Q~ ~ _ N ~ N ~ r . . . O ~ Q~
RECTIFI~D SHEET (RULE 91) W O 96/22529 .. PCT~US96/01005 N N N N~-I N N'( N ~ _~ N N NN N NN N N N N
~ N ~ 10 IY ~r CO ~ ~ .r~r N ~ eo C
1~ C 1~ 0 P N Y~ gCO In 1~_( tq O~1 0 pg g 1 p ~( _I P ,~ PP P ~1 .i ~1 N N N N N N N N N N NN N N NN N NN N N N
0~ t' It) ~'ICO Ct' ~I t~ ~o N N ~)CO ~ It') ~'- O 0 CD 1'~
~I N N ~~r7 N CO t~ ~O\ N ~r~r t~l N N Iq tO CO ~ 01 ~ 0 ~ 0~ r N N r~
1~ N N N ,~ ~ 01 ~r 1~ ~,~N ~ t~~ ~ N 0~ N
U~ 0 ~I~q ~ . ~I gt~ 0 r' . N Oo~ N g P g O O ~r a~ 0 ~i o ~ ~ o ~ 0 Ul 0 0P In N~ ~ ~ ,i N _I
~( O ~-r Ul P 0 N P,t ~~ N ~O H 0 O~p p p ~ ~O 0 N Cl N N ~~ ~ N N (7 a~ ~ 0 ~ Ir N 0 Il'~ N~ 'a ~ ~D .1 1 a~ o N N O ~ I
0 N 1~ 1~ ~1 ~ N N 0 NN U') tt) ~ '1 1~ t' 1' tJ~
.1 Y~ In o ~ N ~ N _( ~1 ~ ~1~1U) ~ --~ O O ~ 1 ~r ~0 O O In ~ N 0 ~D 0 0 NN N ~~ O t~ 1~ ~o Q 0 S I S S S I i I I I I ~ , S S I
0 o ~ ~ N ~ ~117 ' ~ ~I N
r-l N O o "' ~-~ L 1' N - ~ N
O O O O O O O O O O O 0 0~ ' O 0~
~I N t''~ .D 1' 0 O~ O_I N ~ O 1' 0 O~ O _I N
~I r r r I N N NN Q Q NQ QN N N 1'~
0 O~ ') Ul 0~D U') 0 0 0 0\ 0 ~ 0 - t' O'. O~ O~
;; .~
~ ~,,,; '_ r ~ ~ ; C
~r I N ~ N ~ r O ~ ~ N r ~) ~ r n ~TI~iED ~ r ~
PCTrUS9~/01005 . ~I N N N N N N N N NN N N N N NN N N N N N N
a~ O
~U~ .
d ~ D r ~ ~~rN ~ 0~ t''S In 1' ~ N
O 0~ ~ ~1 ~ O P~' ~ O 1') t' 0~ N d V~ O Y~ O p r ~ N N O ~ ~ r ou~ O~~
N N N N N N N N ~ NN N N N N N~ N N N ~'1 O O O O O O O O O O ~ ~ ~ ~ ~ O O O O O O O
L
P
N N N ~0 ~' N 1~ CO1~~D ~ N ~0 0ID ~
N ~ '1 cqO ~ '1 0 ~7 N
~DO 0 1~ 0 ~ U')~-1 ~Oa~ o ~D ~ 1'~ ~ O~ '.D ~0 It~~1 ~1 0 ICI ~q N 0 1~7 t' N~ 0 ~ ~0 N O eD O
~1~1 ~1 ~ ~ 0~ NN~t ~ N NN ~1 ~ N N N ~'1 ~ ~ ~ ~ d . .. ~ t' ~~ '~ N ~ r C 0 ~I 0 ~q t~ ~ pN1~ D N 0r 1~) o G N
~1 ~1~1 ~1 ~1 ~1 0~ ~(~1~ N ~1 ~ N~I N N ~1 ~l N N N
C~ .0 d Ul ~(N~1 ~ N 1~ 0 N 0 ,~ O O O O .i 0 U~ ~~ O O O O O O O O ~i ~ ~( 0~~
It7 ~r~r N CO 1' ~~ l N~ N ~( 10 0 ~ 1 ~1~1 ~1 o .( ~N_( ~I N .--1 N N ~ ~I N N N N
o ~ 0 ~ 0 r C~ o N ~r ~1 0 O~
N ~ I N ~I N N NH ~ 1 N ~ H N H _I N H ~( N _ N d In H ~ ~1~1~ _I N H O ~~ ' 0 H ~r ~; ~r 0 ~q N t~ 1~ ~ t~ N N ~~ r ~ N H 0 ~ $ O $ o 0--I ~ N 0 _ $ _I O
O O O O O O O O O O O ~ O ~ O O ~~
O _IN ~ ~ 0 1~ 0 ~ O H N
t) S U C~ U C ) C ) C 1 C ) C ~ C ) c~ t I t I N N
t~ O~ O~ 0 ~n 0 ~ 0 o~ 0 c~ 1~ 0 o~ ~ eo r~ ~ 'D
N
m , . , -- -~ N ' ~ . ~ ~~ ~ ~ Q~ Cl I
H ~ ~ r~ _I p _ ~ N ~ _ p ~ H N ~ _. N
fflCllFl~L) SHEE~ ~RULE 91) -PCT~US96/01005 ~ ~ ~ ~ ~ a~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ a~ a~
.~ N N N ~ N N N N N N N ~ N N ~ N N N N N N N
--I
14 U~
o ~ ~ ~ ~ ~ a~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ o ~ o g N N O ~ ~ r o L ~ ~ ~ a~ ~ o a~ a ~ a; a~ a~ ~ al ~ r a~ ~ ~ a~ ~ ~ a~ a~
1~ N N N N N N N t~ N N N N ~1 N N N N 4 O O O O O O O O O O O O O O O O O O O O O O
N N N ~ ~ ~ ~ a~ ~ ~ ~ ~ ~ o a~
a~ a; N ~ ~ ~ ~ ~ ~ ~ ~ ~ r ~ ~ ~ ~ o o o a~ o ~ ~ ~ ~ o ~ ~ ~ ~ o ~ ~ ~ ~ ~ ~ a, o ~ a~ ~ o a~ o ~1 ~ N N ~1 --I N N N ~ N N ~q ~ ~ ~ a~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ N ~ ~ ~ ~ ~ ~
~0 U7 ~ ~ '7 ' N ~ 1~ ~ 0 ~ ~i 0 ~ 1~ N tD ,~
~ o ~ o r a~ ~ ~ ~ N ~ ~ ~ N O ~ ~ O, - ~ ~
N _ _I N ~I N N _; ~1 ~ N
0 ~D N ~ t~ 0 ,~ ~ ~ ~N 1' 'D 0~ O N m al ~ N C'~
~ ~ . a~ a~ ~ o ~ ~ ~ ~ a~ G ~ ~ C ~ ~ O . o ~
,~ O O O O _i O ~O_iO O O O O O O O ~( ~ _i ~0 N~,~ t' o'I .(NC ~- ~ 0 N _ 0 N .-1 N N
ot~ a~ D ~ a~ t~ a~ c r O N ~ ~~ a~ a~
P3 N _I _I _I N_( N N N~ ~ N ~~ . N ~ ~ N ~ ~( N ~ N ~ O ~ t' ~ N~1-- -- 1 ~ ' a, .
O '~ ~D _( O N 0 _I ~ O N O-- O ~ ~1 o o O '. O O O O O O OO O O O O~ O '~ O O O
O l O O O O O O OO O O O O'' O ~ ' O O O
O ~I N 1''1 ~ 10 ~.0 1' 0 ~ o ,( N
~ ~ ~ a~ ~ a~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
0 A~ ~
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fltCl~U SHEE~ (RULL 91) W O 96/22529 PCTrUS96/0100 EXPANDED VIEW OF A SINGLE REACTION PLATE LAYOUl~ / TEMPLATE
ARRAY, A~ 1001 ~Sp~ial Address ~' = = = = =
C
D
F
G
=
R 1 C 1, _ P 1 ~
Column number in Array of the plate Reaction Plate number Row number in Array of the plate rt~ SHEET (RULE 91) "A"BUILDnNG BLOCKS
ARRAY, AN 1001 ~ ~,CO ~0 ~ ~
1 rh..
m~
2~
6~ F,C~ c~ 6 T ' ~ r 2,~n~
~-T ' mT.' CA 022l0949 l997-07-2l W 096/22529 "B"BUlLDn~G BLOCK~ PCT~US96/01005 CHO CHO
~"F ~ F ~ ~F
2,4~-- . ,,,, 2-r ' '' ~,~ 3 F ' ~ 2-r CHO
CHO CHO ¦ CHO
~CF, ~ ~CH~
B5 B6 CF, B7 B8 T -c ~ ~a.T "~T.' ~ ~.T ~ F ~ o-Tolualdehyde CHO CHO
~C/~J ~ ~ ~
CH, H,C B 11 m-Tolu~ldehydep-Tolualdehyde 1 r ~ r ~ ~ ~ ,d~
CHO
CHO CHO ¦ CHO
O
2-(~ ' ' ' ' ', 1~ 3~ ~ ' ' ' ' ,.' 2,4 n ~ . ,,, m ~
"B"B~lLDnNG BLOCKS PCTrUS9610100S
W 096/22529 Y,A~1001 CHO
CHO
~_ ~CHO
CHO
SCH, B18 B19 OcF, B20 ) L , ~ T y) J-CHO F/~F
3 ~ 2~ 3~~ 3~5--n ' ~ ~ ~ Ic CHO
CHO
~CHO ~ ~ ~ ~CHO
3 r; ~ ~ ~ b, '_1 P; ' ' ' ~ ~ ~ ,J, 3-'2 ,J~
~ ¢~C~ C~o I Q ~ 2-F. ' ~ 3-F. ' ' ' ,J. 51 b, "C"BU~LDnNG BLOCKS PCTrUS96/01005 W 096/22529 A~URAY,AI~ 1001 I--\o ~~ ,l NHz /~ O--NH2 H2N Cl a C3 C~
T ' ,,' - ~ (~)-s~c-autyl~snine C~
/~\ HO~NH2 H2N~<H
C~ ' ' ' ' I _ . ~ . Eth~tnolurune (S) (I) I A 2 i --NH2 ~ ~ ~OH
C9 OH C10 OH Cl I C12 2 ~ ~ .(tP~,25) ( ) ~ ' ' ' (rR)-(-)-Lcucinol Pipcddinc n- Cl~l =
1 B.,.. ~ , " Morpholinc l-Mothyl-3; ' ,~ ,, 3-Phenyl-l-propyla~runc ~NH2 ~NH2 ~ \C--NH2 C~9 ao B~n~yl rtune Fh.. Ih~ 1.7.3,1 T~ h, ' I ., ' ,' 2-(p-Tolyl)cthyl; tninc W 096/22529 "C"BUILDnNG BLOCKS PCT~US96/01005 ARRAY, AN1001 3~ ~ ~ ~J\HR
A 'i, ' ,: ' 2.2 ri~ minod~n (l ): '' ' ,"
~ ¢~ NH2 H~COJ~--~NHZ ~H~ C28 C25 H2N C26 OCH3 C27 o~o~CH~
I r 1 r J 3 4 n 1 Elhyl l-pipe~azine tarbo~tylate CN~-- ~N~ H ~N~ HN~ X >
1-(2-Aminoethyl)pytroadine I n~ ,!~', ' 1~8 ' I ! ~ ?i, ~
l~N~ NH2 ~N~NH2 ~ --~\ H2 ~1--~NH2 4-(3~ ', ,,I)-motpholine 4-(2-Aminocthyl)-mopholine 1~3~ ', ,JI)imithzol~ 3n , ,, F,C N HH ~NIi2 G ~NH2 HN ~_ C37 C3~ C39 C ~0 a~;t~T~ ~: 'yl)-piper~'n~ 2~ ?ryridine , 1-(2-Aminoethyl~pipeHoine 1~
PCTrUS96/01005 OE~
W O 96/22S29 PCTrUS96/01005 A~ A A1 A A' A A A~ A A'B A1 A A A1 A A
A~ A A A A A~ A A~ A~ A~C A1 A~ A A1 A~ A
A~ A~ A~ A' A~ A~ A1 A A A~~ A A A A1 A1 A~
A~ A A~ A A~ A' A1 A A~ AA' A~ A~ A1 A1 A' A' A1 A' A1 A~ A' A1 A' A' A'A' A~ A' A1 A' A~
G A' A1 A A1 A A' A1 A1 A' A~G A' A~ A' A1 A' A' H A' A1 A' A1 A1 A1 A1 A1 A' A1 H A1 A1 A' A1 A' A' A A2 A2 A2 A2 A2 A2 A2 A2 A2 A' A A2 A2 A2 A2 A2 A2 B A2 A2 A2 A2 A2 A2 A2 A2 A2 A~ B A2 A2 A~. A2 A2 A.
C A2 A2 A2 A2 A' A2 A2 A2 A2 A_ C A2 A2 A' A2 A2 A-A2 A2 A2 A2 A2 A2 A2 A2 A2 A. D A2 A2 A~. A2 A2 A~, A2 A2 A2 A2 A'.A2 A' A2 A2 A', E A' A2 A' A2 A2 A, A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 F A'.A2 A2 A2 A2 A2 G A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 G A'.A2 A2 A2 A2 A2 A A3 A A~ A3 A3 A3 A3 A3 A3 A3 A A3 A3 A3 A3 A3 A3 B A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 B A3 A3 A3 A3 A3 A3 C A3 A3 A3 A3 A3 A3 A3 A3 A~' A3 C A3 AV A3 A3 A3 A3 . A3 A3 A~' A3 A3 A3 A3 A3 A3 A3 D A'~A3 A3 A A~ A:
A3 A3 A~' A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A~ A3 A A3 A~ A3 A3 A~ A~ A3 A3 A3 A3 A3 A3 A~ A3 A3 H A3 A A3 A3 AJ A3 A3 A~ A~ A3 H A3 A3 A3 A3 A3 A3 A A~ A4 A~ A4 A4 A4 A4 A4 A4 A4 A A4 A4 A4 A4 A4 A4 - B A~ A4 A~ A4 A4 A4 A4 M A4 A4 B A4 A4 A4 A4 A4 A4 C A~ A4 A~ A4 A4 A4 A4 A4 A4 A4 C A4 A4 A4 A4 A4 A4 ~ A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 D A~ A4 A4 A4 A4 A4 - A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 E A~ A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 F A~ A4 A4 A4 A4 A4 G A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 G A4 A4 A4 A4 A4 A4 H A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 H A4 A4 A4 A4 A4 A4 -W 096/22529 PCTrUS96/01005 B A5 A5 A A A A. A. A5 A5 A5 B A5 A5 A A5 A. A
l A5 A5 A. A A A A A A5 A5 D A A5 A A5 A;. A5 A. A A A A A5 A A A5 A5 E A A5 A5 A5 A5 A5 A A_ A A A A5 A A A5 A F A5 A5 A5 A5 A5 A5 ~ G A A. A A A. A5 A5 A5 A5 A G A5 A5 A5 A5 A5 A5 E A7 A7 A7 A, A7 A7 A7 A, A7 A. A7 A7 A7 A7 A7 A7 F A7 A7 A7 A- A, A7 A7 A7 A7 A- A7 A7 A7 A7 A7 A7 W O 96/22529 PC~fUS96/01005 A' A1 A1 A' B A' A' A1 A' A' A1 A1 A1 A1 A1 B A1 A' A1 A1 AC A' A A' A A A A A1 A1 A C A
A A1 A A~ A A A A' A1 A' A A1 A' A ~ A
A' A1 A A1A1 A1 A' A' A1 A' A A1 A' A A
A1 A1 A A1 G A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 G A' A2 A2 A2 A2 C A2 A2A2 A2 A2 A2 A2 A2 A' A2 C A2 A2 A2 A2 A' D A2 A2A2 A2 A2 A2 A2 A2 A2 A2 ~ A2 A2 A2 A2 A2 A2 A2A~' A2 A2 A2 A2 A2 A2 A' A2 A3 A~ A3 A3 A A3 A~A3 A3 A3 A3 A3 A3 A3 A~ A A~
A' A3 A3 A3 B A3 A3A3 A3 A_ A3 A3 A3 A3 A3 B A' A3 A~ A3 A3 C A3 A~A3 A' A3 A3 A3 A3 A3 A C A' A3 A~ A3 A3 D A3 A3A3 A3 A3 A3 A3 A3 A3 A D A' A3 A~ A3 A3 E A3 A3A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A~ A3 A~ F A3 A3A3 A3 A3 A3 Av A3 A3 A3 A3 Aé A~ A3 A'- G A' A3A3 A3 A3 A3 A3 A3 A3 A' G A3 A~ A3 A3 A H A3 A3A3 A3 A3 A3 A3 A3 A3 A~ H A3 P 34 R 3 C 3 P 3~ R 3 A4 A4 A4 A4 A A4 A4A4 A4 A4 A4 A4 A4 A4 A~ A A4 A~ A4 A4 A4 B A4 A4A4 A4 A4 A4 A4 A4 A4 A~ B A4 A~ A4 A4 A4 C A4 A4A4 A4 A4 A4 A4 A4 A4 A~ C A4 A~ A4 A4 A4 D A4 A4A4 A~ A4 A4 A4 A4 A4 A~ D A4 A~ A4 A4 A4 E A4 A4A4 A~ A4 A4 A4 A4 A4 A~ E A4 A4 A4 A4 A4 F A4 A4A4 A~ A4 A4 A4 A4 A4 A~ FA4 CA 022l0949 l997-07-2l W O 96/22529 PCT~US96/01005 A5A5 A5 A ~ A5 A5 A5 A5 A5 A A5 A A A5 D A
A7A7 A7 A7 ~ C A7 A7 A- A7 A7 A7 A7 A- A7 A7 C A7 A7A7 A7 A7 E A, A7 A. A, A7 A7 A7 A- A- A7 E A7 A7A7 A7 A7 G A- A7 A7 A, A7 A7 A7 A7 A- A7 G A7 A7A7 A7 A7 H A, A7 A7 A7 A7 A7 A7 A7 A7 A7 H A7 8 9 10 11 2 3 ~ 5 6 7 8 9 10 1 2 -CA 022l0949 l997-07-2l W O 96/22529 PCTfUS96/01005 A' A A1 A A A1 A' A A C A1 A1 A1 A1 A1 A1 A1 A1 A' A' A1 A' A' A1 A' A' A' D A1 A' A1 A1 A1 A1 A A' A1 A' A1 A' A A1 A' A1 A A1 A A1 A1 A1 A1 A A' A1 A' A1 A' A' A1 A' A1 A' A1 A' A1 A1 A1 A1 A A' A1 A' A1 A1 A1 A1 A1 A1 A' G A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A' H A1 A1 A1 A1 A1 A1 A1 A1 A2 A2 A2 A2 A2 A2 A2 A2 A2 c A2 A2 A2 A2 A2 A2 A2 A2 A., A3 A3 A3 A3 A3 A3 A3 A3 A A3 A3 A3 A3 A3 A3 A3 A3 Av A3 A3 A3 A3 A3 A3 A3 A3 B A3 A3 A3 A3 A3 A3 A3 A' A~ A~ A3 A3 A3 A3 A3 A3 A3 c A3 A3 A3 A3 A3 A3 A3 A3 A', A3 A3 A3 A3 A3 A3 A3 A D A3 A3 A3 A3 A~ A3 A3 A' A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 A' A' A3 A3 A3 A3 A3 A3 A3 A3 A3 G A3 Av A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 H A3 A~ A3 A3 A3 A3 A3 A' A4 A4 A4 A~ A4 A4 A4 A4 A~ A A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 A~ A~ A4 A4 A4 A4 A~ B A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 A~ A~ A4 A4 A4 A4 A~ C A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 D A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 E A4 A4 A4 A4 A4 A4 A4 A~
A4 A4 A4 A4 A4 A4 A4 A4 A4 F A4 A4 A4 A4 A4 A4 A4 A~
A4 A4 A4 A4 A4 A4 A4 A4 A4 G A4 A4 A4 A4 A4 A4 A4 A~
A4 A4 A4 A4 A4 A4 A4 A4 A4 H A4 A4 A4 A4 A4 A4 A4 A~
W 096/22529 PCTrUS9610100S
3 4 5 6 7 8 9 10 1~ _ 3 4 5 6 7 8 9 A. A. A5 A5 A5 A5 A5 A A5 B A A A A A A A5 A
A~ A A5 A5 A5 A5 A5 A5 A ~ A A A A A5A~ A A
A A5 A5 A5 A5 A5 A5 A A A5 A5 A A A5A-' A A
A A5 A- A5 A~ A5 A5 A A A5 A5 A A A5 A A A-' A .A5 A-' A5 A A5 A5 A A5 G A5 A5 A5 A A5A5 A5 A5 A A A6 A6 A6 A6 A6 A6 A B A .A A A6 A A6 A6 A
A A A6 A6 A6 A6 A6 A6 A C A A A A6 A A~ A6 A
A A6 A6 A6 A6 A6 A6 A A6 F A6 A6 A6 A A~ A A6 A
A, A7 A7 A7 A7 A7 A7 A7 A. D A7 A7 A7 A7 A7A7 A7 A7 CA 022l0949 l997-07-2l W O 96/22529 PCTrUS96/01005 A- A- C A1 A' A1 A- A1 A- A1 A1 A1 A C A1 A1 A
A- A-~ A1 A- A1 A A1 A' A' A- A- A' ~ A1 A' A' A A'A1 A' A1 A- A1 A- A- A A' A A1 A- A' A' A'A1 A' A1 A1 A' A' A' A' A' A' A1 A' A' A' A1 G A1 A1 A1 A1 A' A' A1 A1 A' A1 G A1 A1 A1 A' A1 H A1 A1 A1 A1 A' A- A1 A1 A' A1 H A1 A1 A1 A2 A2 ~ A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 D A2 A2 A2 A2 A2 A, A2 A, A2 A2 A2 A2 A2 A2 A. E A, A, A2 A2 A2 A.' A2 A'' A2 A2 A2 A2 A2 A2 A' F A, A, A2 A2 A2 G A' A2 A, A2 A2 A2 A2 A2 A2 A~ G A, A, A2 A2 A2 H A, A2 A, A2 A2 A2 A2 A2 A2 A_ H A, A, A2 A3 A3 A A3 A3 A~ A3 A3 A3 A3 A3 Av A3 A A3 A~ A3 A3 A3 B A3 A3 A3 A3 A3 A3 Av A3 -A3 A3 B A3 A3 A3 A3 A3 C A3 A3 A3 A3 A3 A3 A3 A3 A~ A3 C A3 A~ A3 Av A3 D A3 A3 A3 A3 A3 A3 A3 A3 A3 A' ~ A3 A3 A3 A3 A3 E A3 A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 Av A3 F A3 A3 A3 A3 A3 A3 A3 A3 A. A3 A3 A' A3 A' A' G A3 A3 A3 A3 A3 A3 A3 A3 A' A~ G A3 A3 A3 A3 A3 H A3 A3 A3 A3 A3 A3 A3 A3 A3 A. H A3 A3 A3 A~ A4 A A~ A~ A4 A4 A4 A4 A4 A4 A4 A4 A A4 A4 A4 A~ A4 B A~ A~ A4 A~ A4 A4 A4 A4 A4 A4 B A4 A4 A4 A~ A4 C A~ A~ A4 A~ A~ A4 A4 A4 A4 A~ C A4 A4 A4 A~ A4 ~ A4 A' A4 A~ A~ A4 A4 A4 A4 A~ D A4 A4 A4 A4 A4 A4 A4 A4 A~ A~ A4 A4 A4 A4 A~ E A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 ~4 F A4 A4 A4 CA 022l0949 l997-07-2l PCTrUS96/01005 A A A A A A. A5 A A A5 AA5 A5 A A5A5 A5 A A C A A A-' A5 A A-' A5 AA5 A5 c A5A5 A5 A5 A5 G A.A5 A5 A5 A5 A5 A5 A5A5 A G A5A5 A5 A7 A7 H A7A7 A7 A7 A- A7 A7 A7 A- A, H A7A7 A7 CA 022l0949 l997-07-2l PCT~US96/01005 A
A A1 A1 A A1 A1 A C A1 A A1 A A1 A1 A- A' A A1 A1 A1 A1 A1 A A1 A1 E A1 A' A' A1 A' A1 A- A1 A1 A1 A1 A1 A1 A1 A- A1 A1 F A1 A- A' A1 A- A1 A- A1 A1 A1 A1 A1 A1 A1 A A1 A1 G A1 A A A1 A' A1 A A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 H A1 A1 A' A1 A1 A1 A' A1 A1 A1 A2 A2 A2 A2 A2 A2 A2 A A2 A2 A2 A, A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A,' B A2 A2 A2 A2 A2 A2 A2 A.' A2 A2 A2 A2 A2 A2 A2 A2 A, C A2 A2 A2 A2 A2 A2 A2 A, A2 A2 A2 A2 A2 A2 A2 A2 A2 D A2 A2 A2 A, A2 A, A.' A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 E A2 A2 A2 A2 A2 A, A2 A, A2 A2 A2 A2 A2 A2 A2 A2 A2 F A2 A2 A2 A2 A2 A. A2 A, A2 A2 A2 A2 A2 A2 A2 A2 A2 G A2 A2 A2 A2 A2 A2 A2 A, A2 A2 A3 A3 A3 A3 A3 A3 A3 A A3 A3 A3 A3 A3 A_ A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 C A3 A3 A3 A3 A~ A3 A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 D Av A3 A3 A3 A: A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A3 A3 E A3 A3 A~ A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A3 F A~ A3 A3 A3 A3 A3 A' A3 Av A3 A~ A_ A3 A3 A3 A3 A3 G A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A~ A~ A~ H A3 A3 A~ A' A3 A' A3 A_ A~ A3 A4 A4 A4 A4 A4 A4 A4 C A~ A4 A' A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 D A' A4 A' A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 EA' A4 A' A4 A' A4 A4 A4 A4 A4 A' A4 A4 A4 A4 A4 A4 FA4 A4 A4 A4 A' A4 A4 A4 A4 A4 A' A4 A4 A4 A4 A4 A4 G A4 A4 A4 A4 A' A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 H A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 PCTrUS96/01005 A. A5 A A A5 A A5 c A5 A A5 A5 A5 A5 A A A A
A. A5 A5 A5 A A5 A H A5 A5 A5 A5 A5 A5 A5 A5 A5 A5 A7 A7 A7 A7 A7 A7 A7 ~ A7 A7 A- A7 A7 A7 A7 A7 A7 A7 A, A7 A7 A7 A7 A7 A- A7 A7 A- A7 A7 A7 A7 A7 A- A7 A- A7 A7 A7 A7 A7 A. G A7 A7 A7 A7 A7 A7 A7 A7 A- A7 P 1t3 R 7 C 8 P 10 . A 8 A8 A8 A A8 A8 A8 A8 . 8 A8 A A A8 A8 A8 A8 A A8 A8 P~T~US96/01005 B A A1 A1 A1 A1 A1 A1 A' A1 A1 B A1 A1 A1A1 A1 C A' A1 A1 A1 A1 A1 A1 A' A' A1 C A' A' A1A1 A1 D A A1 A A1 A1 A1 A1 A A A1 D A' A' A1A1 A1 E A A1 A A1 A1 A1 A1 A A A1 E A' A' A1A1 A
F A A1 A A1 A1 A1 A1 A A A1 F A1 A' A1A1 A
A A A2 A2 A2 A2 A2 A2 A2 A. A2 A A2 A2 A2A2 A2 B A2 A2 A2 A2 A2 A2 A2 A2 A, A2 B A2 A2 A2A2 A2 C A3 A3 A3 A3 A3 A3 A3 A3 Av A3 C A3 A3 A3- A3 A3 D A3 A3 A3 A3 A3 Av A3 A3 A3 A3 D A3 A3 A3 A3 A' E A3 A3 A3 A3 A3 A~ Av A3 Av A_ E A3 A3 A3 A~ A.
F A3 A3 A~ A3 A' Av Av Av Av A', F A' A. A~ A_ A3 G A3 A3 Av A3 Av A3 A~ A3 A3 A' G Av Av Av A', Av H A3 A3 A3 A3 A3 A3 A3 A~ A3 A3 HAv Av AvA3 Av C A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 c A4 A4 A4A4 A4 D A4 A4 A~ A4 A4 A4 A4 A4 A4 A4 D A4 A4 A4A4 A4 E A4 A4 A' A4 A4 A4 A4 A4 A4 A4 E A4 A4 A4A4 A4 F A4 A4 A~ A4 A4 A4 A4 A4 A4 A4 FA4 A4 A4A4 A4 CA 022l0949 l997-07-2l W O 96/22529 PCTrUS96/01005 C A A5 A A5 A A5 A A A A c A A A A A
D A A5 A. A5 A A5 A. A A A D A A A A A
A5 A5 A A5 A5 A A A A A F A A A A. A
H A5 A5 A5 A5 A5 A A A. A A H A A A A A
R 5 C 9 P 7. R 5 C 10 A A7 A7 A7 A7 A7 A7 A7 A7 A, A7 A A7 A7 A7A7 A7 C A7 A7 A7 A7 A7 A7 A7 A7 A. A7 C A7 A7 A7A7 A7 A7 A7 A7 A7 A7 A7 A7 A7 A7 A7 ~ A7 A7 A7A7 A7 R 7 C 9 ' P 105 R 7 C 10 PCTrUS96101005 A
A1A' A1 A1 A B A1 A1 A1 A1 A A1 A1 A' A1 A1 B
A1A' A1 A1 A' C A1 A1 A1 A1 A A1 A1 A' A1 A1 C
A1A1 A1 A1 A1 D A1 A1 A1 A1 A1 A1 A1 A' A1 A1 D
A1A' A A A' A A1 A1 A1 A1 A1 A1 A' A1 A1 E
A A' A A' A' A A' A' A1 A1 A1 A1 A1 A1 A1 F
A'A' A A A G A' A' A A1 A1 A1 A1 A1 A1 A1 G
A'A' A1 A1 A1 H A' A' A' A1 A1 A1 A1 A1 A1 A1 H
A2 A2 A2 A2 A2 B A2 A, A2 A2 A2 A2 A2 A2 A2 A2 B
A2 A2 A2 A2 A2 D A. A2 A2 A2 A2 A2 A2 A2 A2 A2 D
A3 A3 A3 A3 A3 A A3 A3 A3 A3 A~ A3 A~ A3 A3 A3 A
A3 A3 A~ A3 A~ B A3 A' A3 A3 A3 A3 A3 A3 A3 A3 B
A~ A3 A~ A3 A~ C A: A' A'- A3 A~ A3 A' A3 A3 A3 C
Av A3 A3 A3 A3 D A3 A3 A~ A3 A~ A3 A3 A3 A3 A3 D
A3 A3 A3 A3 A3 E A3 A3 A~ A3 A3 A3 A3 A~ A3 A3 E
A3 A3 A3 A3 A3 F A3 A3 A3 A3 A3 A3 Av A3 A3 A3 F
A~ A3 A~ A3 A~ G A3 A. A3 A3 A3 A3 A3 A3 A3 A3 G
A3 A3 A3 A3 A3 H A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 H
A~ A4 A4 A4 A' D A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 D
A~ A4 A4 A4 A~ E A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 E
A~ A4 A4 A4 A~ F A4 A4 A4 A4 A4 A~ A4 A~ A4 A4 F
A~ A4 A4 A4 A4 G A4 A4 A4 A4 A4 A~ A4 A~ A4 A4 G
A~ A4 A4 A4 A4 H A4 A4 A4 A4 A4 A~ A4 A~ A4 A4 H
: =
CA 022l0949 1997-07-21 PCT~US96101005 A5 A5 A5 A5 A A A5 A5 A5 A... A A A5 A5 A A A
A5 A. A5 A A E A5 A5 A A5 A5 A5 A A5 A5 A
A5 A A A A F A5 A. A5 A5 A5 A5 A5 A5 A5 A
A5 A_ A A A G A5 A A5 A5 A5 A5 A5 A5 A5 A G
P 74 R 5 C 11 p 75 R
A6 A6 A6 A A G A6 A6 A6 A6 A6 A~ A6 A6 A6 A6 G
A6 A6 A6 A~ A H A6 A6 A6 A6 A6 A A6 A6 A6 A6 H
A7 A7 A7 ~7 A7 C A7 A7 A7 A, A- A- A7 A7 A7 A- C
A A8 A8 A A8 D A8 A8 A8 A A8 A8 A8 A8 A8 A8 .D
CA 022l0949 l997-07-2l W O 96/22529 PCTnUS96/01005 A A1 A1 A1 A1 A1 A A1 A1 A1 c A1 A1 A1 A1 A1 A1 A1 A'A' A A1 A1 A1 A1 A1 A1 A' ~ A1 A1 A1 A1 A1 A1 A' A' A A A1 A1 A1 A1 A A A A1 A A1 A1 A1 A1 A' A A A A1 A1 A1 A1 A A A' A' A A' A1 A1 A1 A
A A A' A1 A1 A1 A1 A' A A' G A A A A1 A1 A1 A1 A'A1 A' A1 A1 A1 A1 A1 A1 A1 H A' A1 A' A1 A1 A1 A1 A2A. A2 A, A2 A2 A2 A2 A2 A2 A A2 A2 A2 A2 A2 A2 A2 A2A' A2 A, A2 A2 A2 A2 A2 A2 B A2 A2 A2 A'' A2 A2 A2 A2A, A2 A, A2 A2 A2 A2 A2 A2 C A2 A2 A2 A2 A2 A2 A2 A2A2 A2 A2 A2 A2 A2 A2 A2 A2 D A2 A2 A2 A. A2 A2 A2 A2A2 A2 A2 A2 A2 A2 A2 A2 A2 E A2 A2 A, A2 A2 A2 A2 A2A2 A2 A2 A2 A2 A2 A2 A2 A2 F A2 A2 A' A. A2 A2 A2 A2A2 A2 A2 A2 A2 A2 A2 A2 A2 G A2 A2 A, A. A2 A2 A2 A2A2 A2 A2 A2 A2 A2 A2 A2 A2 H A2 A2 A. A, A2 A2 A2 A3A3 A3 A3 A3 A3 A3 A3 A3 A3 A A3 A~ A3 A3 A3 A3 A3 A~A3 A3 A~ A3 A3 A3 A3 A3 A3 C A3 A3 A3 A3 A3 A~ A3 A'A3 A3 A3 A3 A3 A3 A3 A3 A3 ~A3 A3 A3 A' A3 A' A3 A3A3 A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A3 A3 A3 A3A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A3 A3 A_ A~ A3 A3A3 A3 A' A3 A3 A3 A' A3 A3 G A3 A3 A3 A3 A' A3 A3 A3A3 A3 A3 A3 A3 A3 A3 A3 A3 H A3 A3 A3 A3 A~ A3 A~
A4A4 A4 A4 A4 A4 A4 A4 A4 A4 FA~ A4 A~A4 A~ A4 A4 A4A4 A4 A4 A4 A4 A4 A4 A4 A4 G A~ A4 A~A4 A' A4 A4 A4A4 A4 A4 A4 A4 A4 A4 A4 A4 HA~ A4 A~A4 A~ A4 A4 W O 96/22529 PCTrUS96/01005 A A5 A5 A A A A A5 A A. B A5 A5 A5 A A A5A5 A A5 A5 A A A A A5 A A c A5 A5 A A A. A5A5 A. A5 A5A5 A A5 A A5 A5 A D A A5 A A A AA5 A7 A7 A7A7 A7 A- A- A7 A- A7 G A7 A7 A.A7 A- A7A7 A7 A7 A7A7 A7 A- A, A7 A- A7 H A7 A7 A7A7 A7 A7A7 -t .
A' A1 A1B A A' A1 A A A' A A1 A1 A1 B A A
A A1 A'C A A A A A A' A' A A1 A1 C A A
A A1 A'~ A' A' A A A A' A1 A' A A1 ~ A A
A' A' A'A' A' A' A' A' A' A1 A' A A1 A' A
A' A' A'A' A A' A' A' A' A' A' A' A1 A' A
A' A' AG A1 A' A' A A' A' A' A A A1 G A' A' A' A A'H A1 A A' A' A' A' A' A1 A1 A1 H A' A' A. A2 A2 C A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 C A2 A.
A. A2 A2 D A~ A2 A2 A2 A2 A2 A2 A2 A2 A2 D A2 A.
A. A2 A2 A. A2 A2 A2 A2 A2 A2 A2 A2 A2 E A2 A.
A2 A2 A2 A. A. A2 A2 A2 A2 A2 A2 A2 A2 F A2 A.
A2 A2 A2 G A2 A~' A2 A2 A2 A2 A2 A2 A2 A2 G A2 A2 A2 A2 A2 H A2 A. A2 A2 A2 A2 A2 A2 A2 A2 H A2 A2 A3 A3 A3 A A3 Av A3 A3 A3 A3 A3 A3 A~ A3 A A3 A3 A3 A3 A3 B A3 A3 A3 Av A3 A3 A3 A3 Av A3 B A~ A3 A3 A3 A3 C A3 Av A3 A~ A~ Av Av A3 A3 A3 C Av Av A3 A3 A3 D A3 Av A3 Av Av A3 A' A3 A3 A3 D A' Av A3 A3 A3 Av A~ A3 Av Av A3 Av A3 A3 Av E A3 A3 A3 A3 A3 Av Av A' A3 A3 A3 Av Av A_ A~ F A~ A3 A3 A3 A3 G Av A3 Av Av A' A3 A3 Av A_ A3 G A3 A3 A3 A3 Av H A3 A3 Av A3 A3 A3 Av A3 A3 A3 H A3 A3 P 45 R 3 C 14 , P 46 R 3 C
A4 A4 A4 A A4 A4 A~ A~ A4 A4 A4 A4 A4 A~ A A4 A4 A4 A4 A4 B A4 A4 A~ A~ A~ A4 A4 A4 A4 A~ B A4 A~
A4 A4 A4 C A4 A4 A~ A~ A~ A4 A4 A4 A4 A~ C A4 A~
A4 A4 A4 D A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 D A4 A~
A4 A4 A4 E A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 E A4 A4 PCTrUS96/0100 r ~ L
A A A. A A. A A A A~ A A_ A. A5 A A A A5 A A A B A. A A A A A A A A5 A B A A
A A A C A A A A A A A A A A C A A
A5 A5 A E A5 A A A A~ A A A A A5 E A A
A A5 A5 F A5 A. A A A. A A A A A5 F A A
A A5 A5 H A5 A5 A5A5 A5 A5 .A5A5 A5 A5 H A5 A5 A6 A A D A6 A6 A A A A A A A6 A ~ A A6 A6 A A~ F A6 A6 A A A A A A A6 A6 A6 A
A7 A7 A7 C A7 A7 A- A- A7 A7 A7 A7 A7 A- c A7 A7 A7 A7 A7 D A7 A7 A, A- A7 A7 A7 A7 A7 A, D A7 A7 A- A- A- E A7 A- A- A- A7 A7 A7 A- A7 A7 E.A7 A7 A- A7 A7 H A- A- A,A, A- A7 A7 A, A7 A7 H A7 A7 W O 96/22529 PCTrUS96/01005 A
A A' A' A' A' A A A1 B A A A' A A' A A1 A1 A' A' A' A' A A' A A' A' C A A' A' A A A A1 A1 A
A' A1 A' A1 A' A1 A' A ~ A' A' A' A A A1 A1 A' A' A' A1 A' A1 A A1 A' A A' A' A' A A1 A1 A1 A A
A A1 A' A1 A1 A1 A1 A' A' A1 A A1 A1 A1 A1 A' A1 A A1 A1 A1 A1 A1 A1 A' G A A1 A' A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A' H A' A1 A' A1 A1 A1 A1 A1 A1 A2 A2 A2 A2 A2 A2 A2 A2 B A. A, A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 C A2 A2 A. A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A, D A2 A, A' A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A. E A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 F A. A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 G A2 A2 A~ A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A. H A. A2 A2 A2 A2 A2 A2 A2 A2 A3 A3 A3 A3 A3 A3 A3 A A A3 A3 Av A3 A~ A3 A3 A3 A3 A3 A~ A3 A3 A3 A' A3 A~ B A3 A3 A~ A3 A~ A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 C A3 A3 A3 A3 A_ A3 A3 A3 A3 A3 A_ A~ A3 A3 A~ A3 A' D A3 Av A3 A3 A3 A3 A3 A3 A3 A~ A' A3 A3 A3 A~ A3 A3 A3 Av A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A~ A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 A' A3 A3 A3 A' A3 A' G A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A3 A3 A3 H A3 A~ A3 A~ A3 A3 A3 A3 A~
A~ A4 A4 A4 A4 A4 A4 A4 B A4 A4 A4 A4 A~ A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A4 C A4 A4 A4 A4 A~ A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A~ D A4 A4 A4 A4 A~ A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A~ A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A~ G A4 A4 A4 A4 A4 A4 A4 A4 A4 P 63 R 4 C 16 p W 096/22529 PCT~US96/01005 A A. A A A A A A5 C A A5 A5 A5 A5 A5 A5 A5 A5 A A. A5 A A A5 A5 A5 E A A5 A5 A5 A5 A5 A5 A5 A5 A A6 A A A A~ A6 A6 A6 A A A A6 A6 A6 A6 A6 A- A7 A7 A7 A7 A7 A7 A7 H A7 A7 A7 A7 A7 A, A7 A7 A7 P 111 R 7 C 16 p P 127 R 8 C 16 p PCTrUS96/01005 A
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CA 022l0949 l997-07-2l W O 96/22529 PCTrUS9G/01005 A _ A _ A~_ A _ A _ A-A, A _ A
- W 096/22529 PCT~US96/01005 B 1 B1 B1 B~ B 2 B2 B22 B2 B B3B3 B3 B3 B3 B4 C 1 B1 B1 B B 2 B2 B22 B2 C B3B3 B_ B3 B3 B4 D 1 B1 B1 BB' 2 B2 B22 B2 D B3B3 BB~ B3 B~
E B1 B1 B1 B1 B1 B2 B2 B2 B2 B2 E B3B3 B3B' B3 B~
F B1 B1 B1 B1 B1 B2 B2 B2 B2 B2 F B3B3 B~B_ B3 B~
2 3 4 5 6 7 8 9 10 11 2 ~ 456 7 A B1 B1 B1 B1 B1 B2 B2 B2 B2 B2 A B~ ' B3B~ B~
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C B1 B1 B1 B1 B1 B2 B2 B2 B2 B2 C B~Bv B~Bs v B~
D B1 B1 B1 B1 B1 B2 B2 B2 B2 B2 D B3B~ B3B3 B3 B4 B' 1 B1 B1 B1 B2 B2 B2 B2 B2 E B3B3 B3B3 B3 B4 B' 1 B1 B1 B1 B2 B2 B2 B2 B2 F B3B3 B3B3 B3 B4 G B' 1 B1 B1 B1 B2 B2 B2 B2 B2 G B~B3 B3B3 B3 B4 B B~ B B1 B1 B1 B2 B2 B2 B2 B. B B3B3 B3B3 B3 B4 C B B B1 B B' B2 B2 B2 B2 B. C B~B3 B3B3 B~ B4 D B1 B B1 B B2 B2 B2 B22 ~ B3B3 B3B3 B' B4 E B1 B B1 B B2 B2 B2 B22 B~B3 B3B3 ' B4 F B11 B~ 11 B22 B,2 ' B~B3 B3 B33 B4 G B11 B' 11 B22 B,2 B~ G B3B3 B3 B33 B4 H B11 B B11 B22 B,2 B, H B~B3 B3B3 B3 B4 A BB1 B11 B1 B2 B2 B2 B, B2 A B3B3 B3B3 B3 B4 B BB1 B11 B12 B, B2 B2 B2 B 3B3 B3B3 B3 B4 C B 1 B11 B12 B, B2 B, B2 c 3B3 B3B3 B3 B4 D B'1 B11 B12 B, B, B, B2 D 3B3 B3B3 B3 B4 E B 1 B1 B1 B1 B2 B2 B. B2 B2 E B3B3 B3B3 B3 B4 F B1B1 B1 B1 B1 B2 B2 B. B2 B2 F B3B3 B3B3 B3 B4 ;
W O 96/22529 PCTrUS96/01005 B4B4 B4B' A B B5 B5 B5 B5 B6 B6 B6 B6B6 AB7 B~ 4 B4~' B B B5 B5 B5 B5 B6 B6 B6 B6 B BB7 B~ 4 B4~ C .B~ B B~ B6 B6 B6 B6 B CB7 B' ~ B4~' ~ B B~ ~ B B B6 B6 B6 B DB7 B4B'~ B4~ B . B B 6 E
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B4B~ B4B4 H 5 B B 5 B. B B6 6 H 7 B4B4 B4B4 D B B_ B5 B B B B6 B6 B6B6 DB7 B4B4 B4B4 G B. B B5 B B5 B B6 B6B6 GB7 B4B4 B4B4 A B5B5 B B~ B5 B B6 B6 B6B6 AB7 B4B4 B4B4 C B5B5 B B. B B B B6 B6 6 CB7 B'B' B4B4 D B5B5 B5 B B B B B6 B6 6 DB7 B~B~ B4B4 E B5B5 B5 B B B B B6 B6 6 EB7 ~ B'~ B~B~ F B5 5 5 B~ B B B B6 B6B6 F B-B~ B~B~ G B5 5 5 B B B B B6 B6B6 G B-B~ B~B~ H B5 5 5 B B B B6 B6 B6B6 HB, B4B~ B4B4 F B5B5 B5 B B5 B B B6B6 F 7 B4B' B4B4 G B5B5 B5 B5 B5 B B B6B6 G 7 B4B~ B4B4 H B5B5 B5 B5 B5 B B B6B6 H 7 B4B4 B4 B4 A B5 5 B B5 B5 B6 B6 6 B A B, B~B4 B4 B4 B B5 B5 B5 B6 B6 6 B B B-B~B4 B4 B4 C B5 . B5 5 6 B 6 B C B, B~B4 B4 B4 D B5 B 5 B5 5 B D
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B4B4 B4 B4 A B: B5 B5 B B B B 6 6 B A B7 B4B4 B4 B4 B B B5 B5 B~ B B B 6 B B B7 B4B4 B4 B4 C B B5 B B~ B B 6 C B7 B4B4 B4 B4 D B5 B5 B B B~ B B 6 ~ B7 B4B4 B4 B4 F B5 B. B. B B 6 B B-B4B4 B4 B4 G B5 B B5 B B 6 B G B, B4 B4 B4 B4 H B5 B. B5 B B B 6 B 6 H B7 4 B~ B4 B4 A B5 B5 B~ B6 6 6 B B A B7 4 B~ B4 B4 B B5 B5 B B~ 6 B B B B7 4 B- B4 B4 C B5 B5 B B 6 B~ B C B7 B4 B4 B4 B4 D B5 B5 B5 B B B6 !B B6 B6 D B7 4 B4 B4 B4 H B5 B5 B5 B5 5 B6 B6 B B6 B6 : H B7 PCTrUS96/0100 ~ 3 4 5 6 7 8 9 10 11 2 3 4 5 6 7 8 9 B7 B7 B7B7 B8 B8 B B8 B8 C B9B9 9 B B10 B10 B'0 B7 B7 B7B7 B8 B8 B8 B8 B8 D B9B3 9 B B B10 B10 B~0 B7 B7 B7B7 B8 B8 B8 B8 B8 E B9B3 9 B B10 B10 B'0 B7 B7 B7B7 B8 B8 B8 B8 B8 F B9B3 B9 B3 B10 B10 '0 B7 B7 B7B7 B8 B8 B8 B8 B8 G B9B9 B9 B9 3 B10 B10 '0 B7 B7 B7B7 B8 B8 B8 B8 B8 H B9B9 B9 B9 B9 B10 B10 '0 B7 B7 B7 7 B B8 B8 B8 B8 D B9 9 9 B9 B9 B10 B'0 B'0 B7 B7 B7B7 B B8 B8 B8 B8 E B9 9 9 B3 B9 B10 B'0 B 0 B7 B7 B7B7 B8 B8 B8 B8 B8 G B9 B9 B9 B B9 B10 B10 B'0 7 B 8 B g B 10 B7 B7 B7B7 B8 B8 B8 B8 B8 B B9B9 B9 B9 B9 B10 ~0 10 B7 B7 B7B7 B8 B8 B8 B8 B8 C B9B9 B9 B9 B9 B10 '0 10 B7 B7 B7B7 B B8 B B8 B8 D B9B9 B9 B3 B9 B10 '0 10 B7 B7 B7B7 B B8 B B8 B8 E B9B9 B9 B B9 B10 B'0 '0 B7 B7 B7B7 B B8 B B8 8 F B9B9 9 B B9 B 0 B'0 '0 B7 B7 B7B7 B B8 B B8 8 G B9B9 9 B9 B9B'0 B'0 B~0 B7 B7 B7B7 B8 B8 B8 B8 8 H B9B9 9 B9 B9B'0 B'0 B'0 7 B 8 B g B 10 B7 B7 B7B7 B B8 B8 B8 B8 B B9B9 B3 B9 B9B'0 B10 B 0 B7 B7 B7B7 B B8 B8 B8 B8 C B9B9 B B9 B9B'0 B10 B 0 CA 022l0949 l997-07-2l W 096/22529 PCTrUS96/01005 B7B7 B7 B- 8 B B 8 B c B9 B3B9 B9 B9B10 B10 B10 B7 7 B7 , B B 8 ~ B9 B B9 B9 B10 B10 B10 B- B7 B7 B7 B8 B8 B8 B8 B8 c B9 B9B3 B9 B9B10 B10 B10 B,B7 B7 B7 8 B8 B8 B8 B8 D B9 B9B9 B9 B9B10 B10 B10 7 B 8 B g B 10 B7B7 B7 B- B8 B8 B8 B8 B B B9 B~B9 B3 B9B'0 B10 B10 B7B7 B7 B7 B8 B8 B8 B8 B c B9 B B9 B3 B3B'0 B1Q B10 B7B7 B7 B7 B8 B8 B8 B8 B D B9 B9 9 B BB'0 B10 B10 B7B7 B7 B7 B8 B8 B8 B8 B8 E B9 B9 9 BB'0 B10 B10 B7B7 B7 B7 B8 8 B B8 B8 c B9 B B9 B9 B9B10 B10 B10 B7B7 B7 B7 B8 B8 B8 B8 B8 E B9 B9B9 B9 .B9 B10 B10 B10 W 096/22529 PCTrUS96/01005 0 10 B B'' B 1 B'1 B1 1 B 2 B12 12 B12 B12 B B13 B13 B13 0 '0 C B'' 1 B' B 1 B 2 B12 12 B12 B'2 C B13 B13 B13 0 B 0 D '1 '1 B'' B ' B'2 B12 12 B12 B 2 D B13 B13 B13 0 B 0 E '1 1 B'' B B' B 2 B12 B'2 '2 ', E B13 B13 B13 B'0 B'0 F '1 11 ''B1 B'' B'2 B12 B 2 2 , F B1~ B13 B13 B10 B10 G11 B11 1 B1 B'' B 2 B12 B'2 '2 ', G B1~ B13 B13 B10 B10 HB11 B11 1'B1 B'' B 2 B12 B'2 B'2 '2 H B13 B13 B13 B10 B10 C11 B B'1 B11 B1 B12 B12 B12 B12 B12 C B13 B13 B13 10 B10 D1' B B 1 B11 B11 B , B12 B12 B12 B1, D B13 B13 B13 10 B10 E 1 B B'1 B 'B11 B ' B12 B12 B12 B1, E B13 B13 B13 10 B10 F1' B B B''B11 B . B12 B12 B12 B12 F B13 B13 B13 B10 B10 GB11 B1 B'' BB11 B12 B12 B12 B12 B12 G B13 B13 B13 B10 B10 HB11 B1' B1' B1B11 B12 B12 B12 B12 B12 H B13 B13 B13 B10 B 0 A B11 B11 B 1 B11 B11 B12 B 2 B12 B12 B 2 A B 3 B1v B13 B10 B 0 B B 1 B11 B 11 11 B1' B',12 B12 B'2 B 3 B1 B13 B10 B 0 C B'1 B11 B'' 11 11 B1. B'''12 B12 B'2 C 3 B1~ B13 B10 B 0 DB 1 B1 B1 111' B12 B _1' B12 B 2 D 13 B1~ B13 B10 B'0 EB11 B1' B1' 1'B1' B1, B''', B12 B 2 E B13 B13 B 3 B 0 B'0 F11 B1 B1' 1 1' B1, B'.', B12 B 2 F B13 B13 B'' B'0 B10 G11 B1 B11 B1 1 B12 B12 B 2 B12 B12 G B13 B13 B 3 B'0 B10 H11 B1' B11 B11 1' B12 B12 B12 B12 B12 H B13 B13 B13 B 0 B10 A 1 B11 B1 B1 B1 B12 B 212 B12 B 2 A B1~ B13 B13 B'0 B10 B 1' B11 B1 B''B1 B12 B 212 B12 B 2 B B13 B13 B13 B'0 B10 C 1 B1 B1' B B1' B ~ B 212 B12 B'2 C B13 B13 B13 B10 B10 D B11 B1 B11 B B11 B , B 2 B12 B12 B12 D B13 B13 B13 PCTrUS96/01005 0 B o A 1 1 B1B1' B 2 B 2 B12 B12 A B13 B13 B1~
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C140 C1-40 C1~0 C3 C11 C19 C27 C35 cC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 C
W O 96/22529 PCT~US96101005 t 5 C1-40 C1-40 c1-40 C1-40 C3 C11 C19 C27 C35 C3 C11 C19 C27 C35 c C3 C11 C19 C27 C35 C3 C11 C3 C11 C19 C27 C35 C3 C11 C19 C27 C35 c C3 C11 C19 C27 C35 C3 C11 3 C 12 i P 44 R 3 C 13 2 3 4 5 6 7 8 9 10 11 2 . 3 4 5 6 7 8 C3 C11 C19 C27 C35 C3 C11 C19 C27 C35 c C3 C11 C19 C27 C35 C3 C11 4 C 12 , P 60 R 4 C 13 W O 96/22529 PCTrUS96/01005 C1~0 C1~0 C1-40 C1-40 -CA 022l0949 l997-07-2l W O96/22529 PCT~US96/01005 C1~0 C1~0 C1-40 C1~0 C1-40 C110 C19 C27 C35 cC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 CC3 C11 C140 C1-40 C1~0 CA 022l0949 l997-07-2l W O96/22529 PCT~US96/OlOOS
C1~0 C1-40 C1-40 C19 C27 C35 cC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 CC3 C11 C1~0 C140 C1-40 C1-40 C140 C1~0 C19 C27 C35 CC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 cC3 C11 CA 022l0949 l997-07-2l PCTrUS96/01005 PCTrUS96/01005 C19 C27 C35 C3 C11 C19 C27 C35 c C3 C11 C19 C27 C35 C3 C11 C19 C27 15 P 79 R5 C 16 p C1-40 C1~0 C1-40 CA 022l0949 l997-07-2l PCTrUS96/01005 C~5 C~6 C~7 .
W O 96/22529 PCT~US96101005 =
A A1 A'C A A A A A A' A' A A1 A1 C A A
A A1 A'~ A' A' A A A A' A1 A' A A1 ~ A A
A' A' A'A' A' A' A' A' A' A1 A' A A1 A' A
A' A' A'A' A A' A' A' A' A' A' A' A1 A' A
A' A' AG A1 A' A' A A' A' A' A A A1 G A' A' A' A A'H A1 A A' A' A' A' A' A1 A1 A1 H A' A' A. A2 A2 C A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 C A2 A.
A. A2 A2 D A~ A2 A2 A2 A2 A2 A2 A2 A2 A2 D A2 A.
A. A2 A2 A. A2 A2 A2 A2 A2 A2 A2 A2 A2 E A2 A.
A2 A2 A2 A. A. A2 A2 A2 A2 A2 A2 A2 A2 F A2 A.
A2 A2 A2 G A2 A~' A2 A2 A2 A2 A2 A2 A2 A2 G A2 A2 A2 A2 A2 H A2 A. A2 A2 A2 A2 A2 A2 A2 A2 H A2 A2 A3 A3 A3 A A3 Av A3 A3 A3 A3 A3 A3 A~ A3 A A3 A3 A3 A3 A3 B A3 A3 A3 Av A3 A3 A3 A3 Av A3 B A~ A3 A3 A3 A3 C A3 Av A3 A~ A~ Av Av A3 A3 A3 C Av Av A3 A3 A3 D A3 Av A3 Av Av A3 A' A3 A3 A3 D A' Av A3 A3 A3 Av A~ A3 Av Av A3 Av A3 A3 Av E A3 A3 A3 A3 A3 Av Av A' A3 A3 A3 Av Av A_ A~ F A~ A3 A3 A3 A3 G Av A3 Av Av A' A3 A3 Av A_ A3 G A3 A3 A3 A3 Av H A3 A3 Av A3 A3 A3 Av A3 A3 A3 H A3 A3 P 45 R 3 C 14 , P 46 R 3 C
A4 A4 A4 A A4 A4 A~ A~ A4 A4 A4 A4 A4 A~ A A4 A4 A4 A4 A4 B A4 A4 A~ A~ A~ A4 A4 A4 A4 A~ B A4 A~
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A4 A4 A4 E A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 E A4 A4 PCTrUS96/0100 r ~ L
A A A. A A. A A A A~ A A_ A. A5 A A A A5 A A A B A. A A A A A A A A5 A B A A
A A A C A A A A A A A A A A C A A
A5 A5 A E A5 A A A A~ A A A A A5 E A A
A A5 A5 F A5 A. A A A. A A A A A5 F A A
A A5 A5 H A5 A5 A5A5 A5 A5 .A5A5 A5 A5 H A5 A5 A6 A A D A6 A6 A A A A A A A6 A ~ A A6 A6 A A~ F A6 A6 A A A A A A A6 A6 A6 A
A7 A7 A7 C A7 A7 A- A- A7 A7 A7 A7 A7 A- c A7 A7 A7 A7 A7 D A7 A7 A, A- A7 A7 A7 A7 A7 A, D A7 A7 A- A- A- E A7 A- A- A- A7 A7 A7 A- A7 A7 E.A7 A7 A- A7 A7 H A- A- A,A, A- A7 A7 A, A7 A7 H A7 A7 W O 96/22529 PCTrUS96/01005 A
A A' A' A' A' A A A1 B A A A' A A' A A1 A1 A' A' A' A' A A' A A' A' C A A' A' A A A A1 A1 A
A' A1 A' A1 A' A1 A' A ~ A' A' A' A A A1 A1 A' A' A' A1 A' A1 A A1 A' A A' A' A' A A1 A1 A1 A A
A A1 A' A1 A1 A1 A1 A' A' A1 A A1 A1 A1 A1 A' A1 A A1 A1 A1 A1 A1 A1 A' G A A1 A' A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A' H A' A1 A' A1 A1 A1 A1 A1 A1 A2 A2 A2 A2 A2 A2 A2 A2 B A. A, A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 C A2 A2 A. A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A, D A2 A, A' A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A. E A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 F A. A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 G A2 A2 A~ A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A2 A. H A. A2 A2 A2 A2 A2 A2 A2 A2 A3 A3 A3 A3 A3 A3 A3 A A A3 A3 Av A3 A~ A3 A3 A3 A3 A3 A~ A3 A3 A3 A' A3 A~ B A3 A3 A~ A3 A~ A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 C A3 A3 A3 A3 A_ A3 A3 A3 A3 A3 A_ A~ A3 A3 A~ A3 A' D A3 Av A3 A3 A3 A3 A3 A3 A3 A~ A' A3 A3 A3 A~ A3 A3 A3 Av A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A~ A3 A3 A3 A3 A3 A~ A3 A3 A3 A3 A3 A3 A' A3 A3 A3 A' A3 A' G A3 A~ A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 A3 Av A3 A3 A3 H A3 A~ A3 A~ A3 A3 A3 A3 A~
A~ A4 A4 A4 A4 A4 A4 A4 B A4 A4 A4 A4 A~ A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A4 C A4 A4 A4 A4 A~ A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A~ D A4 A4 A4 A4 A~ A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A~ A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A4 A4 A4 A~ A4 A4 A4 A4 A4 A4 A~ G A4 A4 A4 A4 A4 A4 A4 A4 A4 P 63 R 4 C 16 p W 096/22529 PCT~US96/01005 A A. A A A A A A5 C A A5 A5 A5 A5 A5 A5 A5 A5 A A. A5 A A A5 A5 A5 E A A5 A5 A5 A5 A5 A5 A5 A5 A A6 A A A A~ A6 A6 A6 A A A A6 A6 A6 A6 A6 A- A7 A7 A7 A7 A7 A7 A7 H A7 A7 A7 A7 A7 A, A7 A7 A7 P 111 R 7 C 16 p P 127 R 8 C 16 p PCTrUS96/01005 A
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D B1 B1 B1 B1 B1 B2 B2 B2 B2 B2 D B3B~ B3B3 B3 B4 B' 1 B1 B1 B1 B2 B2 B2 B2 B2 E B3B3 B3B3 B3 B4 B' 1 B1 B1 B1 B2 B2 B2 B2 B2 F B3B3 B3B3 B3 B4 G B' 1 B1 B1 B1 B2 B2 B2 B2 B2 G B~B3 B3B3 B3 B4 B B~ B B1 B1 B1 B2 B2 B2 B2 B. B B3B3 B3B3 B3 B4 C B B B1 B B' B2 B2 B2 B2 B. C B~B3 B3B3 B~ B4 D B1 B B1 B B2 B2 B2 B22 ~ B3B3 B3B3 B' B4 E B1 B B1 B B2 B2 B2 B22 B~B3 B3B3 ' B4 F B11 B~ 11 B22 B,2 ' B~B3 B3 B33 B4 G B11 B' 11 B22 B,2 B~ G B3B3 B3 B33 B4 H B11 B B11 B22 B,2 B, H B~B3 B3B3 B3 B4 A BB1 B11 B1 B2 B2 B2 B, B2 A B3B3 B3B3 B3 B4 B BB1 B11 B12 B, B2 B2 B2 B 3B3 B3B3 B3 B4 C B 1 B11 B12 B, B2 B, B2 c 3B3 B3B3 B3 B4 D B'1 B11 B12 B, B, B, B2 D 3B3 B3B3 B3 B4 E B 1 B1 B1 B1 B2 B2 B. B2 B2 E B3B3 B3B3 B3 B4 F B1B1 B1 B1 B1 B2 B2 B. B2 B2 F B3B3 B3B3 B3 B4 ;
W O 96/22529 PCTrUS96/01005 B4B4 B4B' A B B5 B5 B5 B5 B6 B6 B6 B6B6 AB7 B~ 4 B4~' B B B5 B5 B5 B5 B6 B6 B6 B6 B BB7 B~ 4 B4~ C .B~ B B~ B6 B6 B6 B6 B CB7 B' ~ B4~' ~ B B~ ~ B B B6 B6 B6 B DB7 B4B'~ B4~ B . B B 6 E
B4B~ B44 5 B B 6 F
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B'B4 B4 B4 E B5 B B5 B5 ~ B B B 6 E
B4B4 B4 B4 F B5 B, B5 B5 B B B B B F
B4B4 B4 B4 B B5 B. B5 B B B6 B B B6 B6 B B7 B4B4 B4 B4 D B5 B. .B5 B. B B6 B6 B B6 B6 D B7 4 B 5 , B 6 . B
B4B4 B4 B4 A B: B5 B5 B B B B 6 6 B A B7 B4B4 B4 B4 B B B5 B5 B~ B B B 6 B B B7 B4B4 B4 B4 C B B5 B B~ B B 6 C B7 B4B4 B4 B4 D B5 B5 B B B~ B B 6 ~ B7 B4B4 B4 B4 F B5 B. B. B B 6 B B-B4B4 B4 B4 G B5 B B5 B B 6 B G B, B4 B4 B4 B4 H B5 B. B5 B B B 6 B 6 H B7 4 B~ B4 B4 A B5 B5 B~ B6 6 6 B B A B7 4 B~ B4 B4 B B5 B5 B B~ 6 B B B B7 4 B- B4 B4 C B5 B5 B B 6 B~ B C B7 B4 B4 B4 B4 D B5 B5 B5 B B B6 !B B6 B6 D B7 4 B4 B4 B4 H B5 B5 B5 B5 5 B6 B6 B B6 B6 : H B7 PCTrUS96/0100 ~ 3 4 5 6 7 8 9 10 11 2 3 4 5 6 7 8 9 B7 B7 B7B7 B8 B8 B B8 B8 C B9B9 9 B B10 B10 B'0 B7 B7 B7B7 B8 B8 B8 B8 B8 D B9B3 9 B B B10 B10 B~0 B7 B7 B7B7 B8 B8 B8 B8 B8 E B9B3 9 B B10 B10 B'0 B7 B7 B7B7 B8 B8 B8 B8 B8 F B9B3 B9 B3 B10 B10 '0 B7 B7 B7B7 B8 B8 B8 B8 B8 G B9B9 B9 B9 3 B10 B10 '0 B7 B7 B7B7 B8 B8 B8 B8 B8 H B9B9 B9 B9 B9 B10 B10 '0 B7 B7 B7 7 B B8 B8 B8 B8 D B9 9 9 B9 B9 B10 B'0 B'0 B7 B7 B7B7 B B8 B8 B8 B8 E B9 9 9 B3 B9 B10 B'0 B 0 B7 B7 B7B7 B8 B8 B8 B8 B8 G B9 B9 B9 B B9 B10 B10 B'0 7 B 8 B g B 10 B7 B7 B7B7 B8 B8 B8 B8 B8 B B9B9 B9 B9 B9 B10 ~0 10 B7 B7 B7B7 B8 B8 B8 B8 B8 C B9B9 B9 B9 B9 B10 '0 10 B7 B7 B7B7 B B8 B B8 B8 D B9B9 B9 B3 B9 B10 '0 10 B7 B7 B7B7 B B8 B B8 B8 E B9B9 B9 B B9 B10 B'0 '0 B7 B7 B7B7 B B8 B B8 8 F B9B9 9 B B9 B 0 B'0 '0 B7 B7 B7B7 B B8 B B8 8 G B9B9 9 B9 B9B'0 B'0 B~0 B7 B7 B7B7 B8 B8 B8 B8 8 H B9B9 9 B9 B9B'0 B'0 B'0 7 B 8 B g B 10 B7 B7 B7B7 B B8 B8 B8 B8 B B9B9 B3 B9 B9B'0 B10 B 0 B7 B7 B7B7 B B8 B8 B8 B8 C B9B9 B B9 B9B'0 B10 B 0 CA 022l0949 l997-07-2l W 096/22529 PCTrUS96/01005 B7B7 B7 B- 8 B B 8 B c B9 B3B9 B9 B9B10 B10 B10 B7 7 B7 , B B 8 ~ B9 B B9 B9 B10 B10 B10 B- B7 B7 B7 B8 B8 B8 B8 B8 c B9 B9B3 B9 B9B10 B10 B10 B,B7 B7 B7 8 B8 B8 B8 B8 D B9 B9B9 B9 B9B10 B10 B10 7 B 8 B g B 10 B7B7 B7 B- B8 B8 B8 B8 B B B9 B~B9 B3 B9B'0 B10 B10 B7B7 B7 B7 B8 B8 B8 B8 B c B9 B B9 B3 B3B'0 B1Q B10 B7B7 B7 B7 B8 B8 B8 B8 B D B9 B9 9 B BB'0 B10 B10 B7B7 B7 B7 B8 B8 B8 B8 B8 E B9 B9 9 BB'0 B10 B10 B7B7 B7 B7 B8 8 B B8 B8 c B9 B B9 B9 B9B10 B10 B10 B7B7 B7 B7 B8 B8 B8 B8 B8 E B9 B9B9 B9 .B9 B10 B10 B10 W 096/22529 PCTrUS96/01005 0 10 B B'' B 1 B'1 B1 1 B 2 B12 12 B12 B12 B B13 B13 B13 0 '0 C B'' 1 B' B 1 B 2 B12 12 B12 B'2 C B13 B13 B13 0 B 0 D '1 '1 B'' B ' B'2 B12 12 B12 B 2 D B13 B13 B13 0 B 0 E '1 1 B'' B B' B 2 B12 B'2 '2 ', E B13 B13 B13 B'0 B'0 F '1 11 ''B1 B'' B'2 B12 B 2 2 , F B1~ B13 B13 B10 B10 G11 B11 1 B1 B'' B 2 B12 B'2 '2 ', G B1~ B13 B13 B10 B10 HB11 B11 1'B1 B'' B 2 B12 B'2 B'2 '2 H B13 B13 B13 B10 B10 C11 B B'1 B11 B1 B12 B12 B12 B12 B12 C B13 B13 B13 10 B10 D1' B B 1 B11 B11 B , B12 B12 B12 B1, D B13 B13 B13 10 B10 E 1 B B'1 B 'B11 B ' B12 B12 B12 B1, E B13 B13 B13 10 B10 F1' B B B''B11 B . B12 B12 B12 B12 F B13 B13 B13 B10 B10 GB11 B1 B'' BB11 B12 B12 B12 B12 B12 G B13 B13 B13 B10 B10 HB11 B1' B1' B1B11 B12 B12 B12 B12 B12 H B13 B13 B13 B10 B 0 A B11 B11 B 1 B11 B11 B12 B 2 B12 B12 B 2 A B 3 B1v B13 B10 B 0 B B 1 B11 B 11 11 B1' B',12 B12 B'2 B 3 B1 B13 B10 B 0 C B'1 B11 B'' 11 11 B1. B'''12 B12 B'2 C 3 B1~ B13 B10 B 0 DB 1 B1 B1 111' B12 B _1' B12 B 2 D 13 B1~ B13 B10 B'0 EB11 B1' B1' 1'B1' B1, B''', B12 B 2 E B13 B13 B 3 B 0 B'0 F11 B1 B1' 1 1' B1, B'.', B12 B 2 F B13 B13 B'' B'0 B10 G11 B1 B11 B1 1 B12 B12 B 2 B12 B12 G B13 B13 B 3 B'0 B10 H11 B1' B11 B11 1' B12 B12 B12 B12 B12 H B13 B13 B13 B 0 B10 A 1 B11 B1 B1 B1 B12 B 212 B12 B 2 A B1~ B13 B13 B'0 B10 B 1' B11 B1 B''B1 B12 B 212 B12 B 2 B B13 B13 B13 B'0 B10 C 1 B1 B1' B B1' B ~ B 212 B12 B'2 C B13 B13 B13 B10 B10 D B11 B1 B11 B B11 B , B 2 B12 B12 B12 D B13 B13 B13 PCTrUS96/01005 0 B o A 1 1 B1B1' B 2 B 2 B12 B12 A B13 B13 B1~
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B1~ B13 B14 B14 B14 B14 B14 A B1 B15 B15 B15 B15 B16 B16 B1 B16 B 6 B1' B13 B14 B14 B14 B14 B14 B B1~ B15 B15 B15 B15 B'6 B16 B1~ B16 B 6 B1~ 1_ B14 B14 B14 B14 B14 CB1 ~ B15 B15 B15 B 6 B16 B B16 B 6 B13 1' B14 B14 B14 B14 B14 DB15B1 B15 B15 B 6 B16 B 6 B16 B16 B13 1~ B14 B14 B14 B14 B14 EB'5' B1~ B1 B'5 B16 B16 B' B16 B16 B13 B13 B14 B14 B14 B14 B14 FB 5 ~ B~ B 5 B16 B 6 B1 B16 B16 B13 B13 B14 B14 B14 B14 B14 GB'5 1 B'_' B'5 B16 B 6 B1 B16 B16 B13 B13 B14 B14 B14 B14 B14 HB'5 1 B''5 B'5 B16 B'6 B16 B16 B16 B1~ B13 B14 B14 B14 B14 B14 AB1 5 B1~ B1~ 1 B16 B16 B 6 B13 B13 B14 B14 B14 B14 B14 BB1~ 5 ~ B~ B1_ ~ B1 B16 B'6 B1~ B13 B14 B14 B14 B14 B14 CB1 15 'B'~ B1 ' B1 B16 B'6 B13 B13 B14 B14 B14 B14 B14 DB1 B~ BB~ B . ' 1B1 B16 B16 B13 B13 B14 B14 B14 B14 B14 EB'~ B B1B1~ B'B16 B16 B'6 B'6 B16 B13 B13 B14 14 B14 B14 14 F B B~ B1 B1~ B~ B16 B16 B'6 B 6 B16 B1., B13 B14 14 B14 B14 14 GB'~ B1 B1 B1~ B1 B16 B16 B 6 B 6 B16 B1v B13 B14 14 B14 B14 14 HB' B1. B1_ B1 B1 B16 B16 B'6 B 6 B16 P 103 R7 C 8 p 104 B13 B13 B14 B14 B14 B14 B14 A B1' B 5 B15 B ~ 1 B B B 6 B 6 B13 B13 B14 B14 B14 B14 B14 B B1B 5 B1 B~ ~ 1 B B B 6 B 6 B13 B13 B14 B14 B14 B14 B14 C B'.~ B' ' ' 1 B' B' B 6 B'6 B1~ B13 B14 B14 B14 B14 B14 ~ B~ B'~ ~ B1 B16 B 6 B1~ 16 B'6 B13 B13 B14 B14 B14 B14 B14 B'~1 B'B15 B'6 B 6 B1 1 B'6 B13 B13 B14 B14 B14 B14 B14 B~15 B1~ B15 B~6 B16 B1 1 B~
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W 096/22529 PCTrUS96101005 B23 B23 B23 23 B2~ B24 B24 B24 B24 B24 A B25 B2_ B25 B2 B2 B26 B, B2v B23 B23 23 B23 B24 B24 B24 B24 B24 B B2 B2 B25 B2 B, B26 B' B23 B23 B23 23 B23 B24 B24 B24 B24 B24 C B2 B2 B25 B2. B~ B26 B, B,~ B2~ B23 B23 B23 B24 B24 B24 B24 B24 D B2 B25 B25 B25 B,5 B26 B2 ,~ B2~ B23 B2. B23 B24 B24 B24 B2~ B24 F B25 B25 B25 B25 B25 B26 B26 23 B23 B23 B2' B23 B24 B24 B24 B2' B24 G B25 B25 B25 B25 B25 B26 B26 2v B23 B23 B23 B23 B24 B24 B24 B2~ B24 H B25 B25 B25 B25 B25 B26 B26 B23 B23 B23 B23 B23 B24 B,~ B24 B24 B,~ A B2_25 .. B,5 B,5 B, ,6 B.3 B2.- B23 B23 B23 B24 B2~ B'4 B24 B~ B B2.2~'~ B,5 B~5 B, 26 B23 B23 B23 B23 B23 B24 B,~ B,4 B24 B~' C B,. 2,;~ B,5 B,5 B, 26 B23 B23 B23 B23 B23 B24 B24 B24 B24 B,~ D B,. 2B25 B,5 B,5 B,6 23 B23 B23 B23 B23 B24 B24 B24 B24 B,4 E B, B2.B25 B25 B,5 B26 2 23 B23 B23 B23 B23 B24 B24 B24 B24 B,4 F B2 B25 B25 B25 B25 B26 2 23 B23 B23 B23 B23 B24 B24 B24 B24 B,4 G B2 B25 B25 B25 B25 B26 B26 ,. B23 B23 B23 B23 B24 B24 B24 B24 B24 A B25 B25 B25 B25 B25 B26 B26 ~' B23 B23 B23 B23 B24 B24 B24 B24 B24 B B25 B25 B25 B25 B25 B26 B26 ~v B23 B23 B23 B23 B24 B24 B24 B24 B,4 C B25 B25 B25 B25 B25 B26 B26 B23 B23 B23 B23 B23 B24 B24 B 4 B2~ B24 D B2 B2~ B25 B25 B,5 B26 B2F
B23 B23 B23 B23 B23 B24 B24 B,4 B2~ B~4 E B2~ B2 B25 B25 B~5 B26 B2 B23 B:3 B23 B23 B23 B24 B24 B2~ B.~ B~ F B2 2 B2 B25 B, B,6 B2 B23 B,3 B23 B2~ B23 B24 B24 B2~ B~' B2~ G B2~ 2. B2 B25 B2 B,6 B2 B23 B,3 B23 B23 B2~ B24 B24 B2~ B,4 B~ H B2 2. B2. B25 B2 B,6 B2 2~ B23 B23 B23 B23 B24 B24 B24 B24 B24 A B25 B25 B25 B25 B25 B26 B26 2~ B23 B23 B23 B23 B24 B24 B24 B24 B24 B B25 B25 B25 B25 B25 B26 B26 ,3 B23 B23 B23 B23 B24 B24 B24 B24 B24 C B25 B25 B25 B25 B25 B26 B26 B,3 B23 B23 B23 B23 B24 B24 B24 B24 B24 D B25 B25 B25 B25 B25 B26 B26 B,_ B23 B23 B23 B23 B24 B24 B24 B24 B24 E B25 B25 B25 B25 B25 B26 B26 B2~ B23 B23 B23 B23 B24 B24 B24 B24 B,4 F B25 B25 B25 B25 B25 B26 B26 B23 B23 B23 B23 B23 B24 B24 B24 B24 B,4 G B25 B25 B25 B25 B25 B26 B26 B2~ B23 B23 B23 B2~ B24 B24 B24 B24 B,4 H B25 B25 B25 B25 B25 B26 B26 CA 022l0949 1997-07-21 B2~ B23 B23 B23 B23 B24 B24 B24 2~ B2~ A ,. ,5 B25 B25 B25 B26 B26 B2v B23 B23 B23 B,~ 24 B24 24 2/ B~ B 2 ~5 B25 B25 B2 B26 B26 B2~ B2~ BX B23 B2~ 24 B24 2~ 2~ B,.~ C ~' B' 2 B2 B2 B,6 B2v B2~ B2~ B23 B,3 24 B24 2~ 2~ B2~ B2 2. B2 B2 B,6 B23 B2v B2v B23 B23 B24 B24 B2' B24 B,4 B2. B2 B'. 2 B25 B2 B,6 B23 B,3 2~ B2v B23 B24 B24 B24 B24 B24 B2 B2 B2 B2 B25 B26 B,6 B23 B,3 2' B2~ B23 B24 B24 B24 B24 B,4 G B25 B25 B25 B2 B25 B26 B26 B23 B,3 2' B23 B23 B24 B24 B24 B24 B,4 H B25 B25 B25 B25 B25 B26 B26 B23 B23 B23 B2v B23 B24 B24 B24 B24 B24 A B25 B25 B25 B25 B25 B26 B26 B23 B23 B23 B2v B23 B24 B24 B24 24 B24 B B2 B25 B25 B25 B25 B26 B26 B,3 23 B23 B2v B23 B24 B24 B24 24 B,4 C 2~ B2. B25 B25 B25 B26 B2 B,3 23 B23 B23 B2v B24 B24 B24 24 B24 D 2 B, B,5 B25 B2~ B2 B2 B,3 ,3 B2~ B2: B2: B24 B24 B24 B24 B,4 E ,_ ' B,5 B,5 B,. 2 2 B,3 B,3 B2v B2v B2: B24 B24 B24 B24 24 F B, , B,5 B,5 B, 2 2 B23 B,3 B2~ B2v B23 B24 B24 B24 B24 24 G B, , B,5 B,5 B, 2 2 B23 B,3 B23 B23 B23 B24 B24 B24 B24 24 H B2 ,. B,5 B,5 B2 2 2 B23 B23 B23 B23 B23 B24 B24 B24 B24 B2~ A 2 2 B25 B25 B25 B26 B26 B,3 B23 B2v B23 B23 B24 B24 B24 B24 B2~ B 2~ 2~ B25 B25 B25 B26 B26 B,3 B23 2' B23 B23 B24 B24 B24 B24 B,~ C 2 2 B25 B25 B25 B26 B26 B,3 B2~ 2v B,3 B23 B24 B24 B24 B,4 B,4 ~ 2~ 2 B25 B25 B25 26 B26 23 B2~ 23 ,~ B2. B2' B24 B24 B,~ B,4 -~ 25 2~ B25 B25 26 B26 ,' B2~ 23 ,3 B23 B2' B24 B24 B,~ B24 B,- 25 2 B25 B25 26 B26 23 B2~ B23 2~ B2v B2~ B24 B24 B2~ B24 G B'5 B25 2. B25 B25 B26 B26 B23 B2~ B23 23 B23 B2~ B24 B24 B24 B24 H B~5 B25 2 B25 B25 B26 B26 B23 B2 23 B_3 B23 B24 24 B24 B2~ 24 A 2 2 B,5 B25 B,5 B26 B2 B23 B2~ ,3 B,3 B23 B24 24 B24 B2' 24 B 2. 2~ B,5 B25 B,5 B26 B2 B23 B23 ,3 B,3 B23 B24 24 B24 B2~ 24 C 2 2 B,5 B25 B,5 B26 B2 B23 B23 B,~ B23 B23 B24 B24 B24 B24 B24 D 2 B25 B25 B25 B25 B26 B2 B23 B23 B2v B23 B23 B24 B24 B24 B24 B24 E 2 B25 B25 B25 B25 B26 B26 B2~B23 B2~ B23 B2' B24 B24 B24 B24 B24 F B25 B25 B25 B25 B25 B26 B26 B2~B23 B2~ B23 B2: B24 B24 B24 B24 B24 G B25 B25 B25 B25 B25 B26 B26 B2~B23 B2V B23 B2v B24 B24 B24 B24 B24 H B25 B25 B25 B25 B25 B26 B26 PCTrUS96/01005 B2 26 B, A B27 B27 B27 B27 B27 B28 B28 B28 B28 B28 A B2 B.3 2 2 B. B B27 B.7 B27 B27 B27 B228 B~8 B2 B28 B B2 B2 _ 2 B_ C B27 B27 B27 B27 27 B2,8 B,8 B2 B,8 CB2~ B' 2 , , D ,- ,7 B27 B27 27 B2,8 B,8 B2 B, DB2 B_ ,6 , '. E ,- 27 B27 B27 27 B2,8 B28 B2 B, EB23 B, 2 , ~ F ,, ,7 B27 B27 B27 B2,8 B28 B2 B, FB23 B2 , 2 ' G ,7 B,7 B27 B27 B27 B228 B28 B2 B2 GB29 B2 2 2 , H 27 B,7 B27 B27 B27 B228 B28- B2 B,8 HB29 B2 B2 2 B,6 A B27 B27 B27 B27 B27 B28 B28 2 ,8 B2 A B23 B,9 B2 2 B,6 B B27 B27 B27 B27 B2- 2 2 2 , 2 B, B29 B2 2~ B26 ~ B27 B27 B27 B27 B2- 2 2 2 , 2 C2~ B,9 2 2 B,6 ~ 27 B27 B27 B27 B2. 2 2 2 2 2 D,9 B,9 2 2 ,6 27 B27 B27 B27 B27 B28 B2B2 28 28 E,9 B,9 2 2 26 27 B27 B27 B27 B,7 B28 B2B2 28 2 FB29 B,9 ,6 B26 26 G B27 B27 B27 B27 B,7 B28 B2 B28 B28 2 GB29 B29 B,6 B26 B26 H B27 B27 B27 B27 B,7 B28 B2B28 B28 B2 HB29 B29 B 27 B 28 .- B 29 B2f B26 B26 A B27 B27 B27 B27 B27 B2828 B28 B28 B,8 AB29 B29 2 2 B26 B B27 B27 B27 B27 B27 B28 28 B2 2 B,8 B29 B29 2 2 B26 C B27 B27 B27 B27 B27 B28 28-B2 2 B,8 C'9 B29 2 2 B26 ~ B27 B27 B27 B27 B27 B28 B,8 B, 2 B, ~29 B29 2 B2 B2 27 B27 B2- B27 B27 2 B'8 B'. ' B2 B, B, , B2 B. 27 B~7 B2- 27 B27 2 B B ~ B2 B, B' 2 B2 B. G 27 B,7 B2- 27 B27 2 B~ B- , B2 GB2 B, ,6 B2 B. H B27 B,7 B2- 27 B27 2 B_ B, , B2 H B2 B, B2 B2 B26 B B27 B27 B27 B27 B27 B28 B2 , B2 B28 BB29 B29 B2 B2 B26 C B27 B27 B27 B27 B27 B28 B2 , B2 B28 CB29 B,9 B2 B2 B26 ~ B27 B27 B27 B27 B27 B28 B2 2 B.8 , ~ ,9 B'9 2 2 B2 B27 B27 B27 B27 B27 B28 B2 2 B,8 , ,9 B29 2 ,6 _ B27 B27 B27 B2- B27 B2 2 28 B,8 , ,3 B,9 2 ,6 , G B27 B27 B27 B2- B27 B2 2 28 B28'8 GB'.3 B29 2 ,6 ,6 H B27 B27 B27 B27 B27 B2 2 28 B28 B_8 H B,3 B29 ~ 79 W 096122529 PCTrUS96/01005 B26 B2 B2 A ,- ,7 .7 B,7 B27 2 2 B28 B2 B,8 A B29 B29 B26 B2 B2 B ,- ,- ,7 B.7 B,7 2 2 2 B2 ' B B29 B29 B26 B2 B2~ C .- 2- 27 27 B,7 2 2 2 B2 , CB29 B29 B26 B26 B26 D B27 2- ,- 27 B27 2 B2 2 2 2 DB29 B29 B26 B26 B26 E B27 27 2- 27 B27 28 B' 2 2 2 EB29 B,9 B26 B26 B26 F B27 B2- 27 B27 B27 B28 B~8 28 2 B28 F29 B29 B26 B26 B26 G B27 B2- B27 B27 B27 B28 B28 28 2 B,8 G29 B,9 B26 B26 B26 H B27 B27 B27 B27 B27 B28 B28 B28 2 B,8 H29 B29 B26 B26 26 D2 B27 2, B27 27 28 2 B,8 B2 2 DB29 B29 B26 B26 B26 E27 B,7 27 B27 27 ,8 2 B,8 2 , EB29 B29 B26 B26 B26 FB27 B,7 27 B27 27 ,8 28 B28 2 2 FB29 B29 B26 B26 B26 GB27 B,7 27 B27 27 28 B28 B28 2 B28 GB29 B29 B26 B26 B26 H B27 B27 B27 B27 B27 B28 B28 B,8 B2B,8 HB29 B29 B26 B26 B26 AB27 2- B27 B2- B~7 2 B,8 B, B2 B~8 AB,9 B29 B26 B26 B26 BB,7 ,- B27 B2- B,7 , B28 B, B2 B28 BB,3 29 26 B26 B26 CB,7 ,- 27 B2 ,7 , B, , B2 B,8 CB,~ ,9 26 B26 B2 D B,7 B,7 27 B27 27 B,8 B, 2 B28 B28 DB23 ,9 26 B26 B2~ E B27 B27 27 B27 27 B,8 B, 28 B2 B28 E B29 B.9 B26 B26 B2 F B27 B27 B27 B27 B27 B,8 B,28 B2 B28 F B29 B29 B26 B26 B26 B B27 27 B27 B27 B27 B' B2 B28 B28 B'8 B 29 B29 B26 B26 B26 C B27 27 B27 B27 B27 B, B2 B28 B28 B,8 C29 B29 B26 B26 B26 D B27 27 B27 B27 B27 B; B2 B28 B28 B,8 D 29 B29 B26 B26 B26 E B27 27 B27 B27 B27 B, B2 B28 B28 B28 E B29 B29 2 B26 B26 G B.7 B27 B27 B27 B27 B28 B28 B28 B28 B2 GB2~ B29 2f B26 B26 H B27 B27 B27 B27 B27 B28 B28 B28 B28 B2 H B2 B29 CA 022l0949 l997-07-2l W 096/22529 PCTrUS96/OlOOS
~ 4 5 6 7 8 9 10 11 2 3 4 5 6 7 8 9 10 B23 B29 B29 B30 B30 B30 B30 B30 A 31 B_1 B3 B31 B31 B32 Bv2 32 B32 B23 B29 B29 B_0 B30 B30 B30 B30 B 31 BV1 B3- B31 B 1 B32 B32 32 B32 B2 B29 B29 B.0 B30 B30 B30 B30 C 31 B~1 B3 B31 B~1 B32 B~2 32 B32 B2 B29 B29 BvO B30 B30 B30 B30 D B31 B31 B31 B31 B31 B32 B~2 B32 B~2 29 B29 B29 B30 B30 '0 B30 B30 E BV1 B31 B31 B31 B31 B32 B32 B32 B~2 B23 B29 B29 B30 B30 B30 B30 B30 H B'1 B31 B31 B31 B31 B32 B32 B32 B32 B29 B29 B29 B30 B'0 BvO B30 B30 A 31 B~1 B31 B.1 B31 B~2 B32 B32 B32 B29 B29 B29 B30 B~0 B30 B30 B30 B 31 B~1 B31 B31 B3' B32 B32 B32 B32 B29 B29 B29 B30 BvO B30 B30 B30 C 31 Bv1 B31 B~1 B0' B~2 B'2 B32 B32 B29 B29 B29 B30 B30 B30 B30 B30 D 31 Bv1 B31 B~1 B3' B~2 B~2 B32 B32 B29 B29 B29 B30 B30 B30 B30 B30 E B31 B~1 B~1 B31 B31 B32 B32 B32 B32 B29 B29 B29 B30 B30 B30 B30 B30 F B31 B31 B_1 B31 B31 B32 B'2 B32 B32 B29 B29 B29 B30 B30 B30 B30 B30 G B31 B31 B~1 B31 B31 B32 B32 B32 B32 4 5 6 7 8 9 10 11 2 3 4 5 6 7 8 9 10B,9 B29 B29 B30 B~0 B~0 B30 B30 A B31 B~1 B31 B31 B31 B~2 B32 B32 B32 B'9 B29 B'9 B30 B30 B~0 B30 B30 B B31 B~1 31 B31 B3' Bv2 B32 B32 B32 B,B29 B2 B30 B~0 B30 B~0 30 c 31 31 31 B31 B3' B32 B32 B32 B32 B,B29 B23 B30 B'0 B~0 B30 30 D 31 _1 31 B31 B3 B~2 B32 B32 B32 B,B29 B23 B30 B~0 B30 B30 30 E 31 31 B31 B31 B3' B.2 02 B~2 B32 B2B29 B29 B30 B~0 B30 B~0 B'0 F B~1 B31 B31 31 B~ B'2 ~2 B32 B'2 B2B29 B29 B30 B_0 B_0 B30 B~0 G B31 B'1 B31 31 B0 B~2 ~2 B32 B~2 B2B29 B29 B30 B30 B30 B30 B30 H B31 B~1 B31 31 B~' B32 32 B.2 B_2 B29 B29 B29 B30 B30 B30 B30 B30 AB31 B31 B31 B31 B31 B32 B32 Bv2 B32 B29 B29 B29 B30 B30 B30 B30 B30 CB31 B31 B31 B3 31 B32 B32 B~2 B32 B29 B29 B29 B30 B30 B30 B30 B30 DB31 B31 B31 B3 31 B32 B32 B'2 B32 B29 B23 B29 B30 B30 B30 B30 B30 EB31 B31 B31 B3 31 B32 B32 B~2 B32 B29 B23 B29 B30 B30 B'0 B~0 B30 FB31 B31 B31 B31 B31 B32 B32 B32 B~2 B29 B2 B29 B30 B_0 B~0 B_0 B30 GB31 B31 B31 B31 B31 B32 B32 B32 Bv2 B29 B29 B29 B30 B~0 B30 B'-0 B30 HB31 B31 B31 B31 B31 B32 B32 B32 B'2 W 096/22529 PCTrUS96/0100 B2 B,9 B29 B30 B30 B30 B30 B30 B B~1 B31 B31 B31 B31 B32 B32 B32 B~2 B2 B,9 B29 B30 B30 B30 B30 BvO C BV1 B31 B31 B31 B31 B32 B32 B32 B32 B2 B,9 B29 B30 B30 B30 B30 BvO ~ B'1 B31 Bv1 B31 B31 B32 B32 Bv2 ;2 B,g B29 B2 B~0 30 ~0 B~0 B~0 Bv' B~ B'1 Bv1 B31 32 32 Bv2 ;2 ,9 B'9 B2 B~0 30 30 B~0 B.0 - B~ B' 31 B'1 31 3~ 32'2 32 ,9 B,9 B2 B~0 30 30 B~0 B'0 G B3' Bv' 31 B~1 31 32 3232 B32 ,9 B.9 B21 BvO B30 BvO BvO BvO H Bv' Bv' 31 B~1 31 32 3232 B~2 29 B29 B29 B30 B30 B30 B30 B30 B B31 B31 B31 B31 B31 B32 B32 B32 ;2 29 B29 B29 B30 B30 B30 B30 B30 C B31 B31 B31 B31 B31 B32 B32 B32 v2 29 B29 B29 B30 B30 B30 B30 B30 D B31 B31 B31 B31 B31 B32 B32 B.2 ~2 B2~ B,9 B29 B.0 30 B30 30 B~0 E B31 B31 B31 B31 B31 B32 B32 Bv2 32 B2 B,9 B29 B30 30 B30 30 B~0 F B31 B31 B31 B31 B31 B32 B32 B~2 32 B2~ B,9 B29 BvO 30 B30 30 B_0 G B31 B31 B31 B31 B31 B32 B32 B32 B32 B2 B,9 B29 B30 B30 B30 B30 B30 H B31 B31 B31 B31 B31 B32 B32 B32 B32 P 95 R6 C 16 p B,9 B21 29 B30 B30 B30 B30 BvO A B~1 B31 B3 B3 B31 32 B~2 32 B32 B, B21 2~ BvO B30 B'0 B30 B30 B 31 31 B3 B3 B31 32 B~2 32 B~2 B, B2 2 BvO B30 B~0 B30 B~0 Cv1 31 B3 B3 B31 32 B~2 ~2 _2 B2~ B2 23 B30 B30 B30 B30 B30 Dv1 31 B3 B31 B31 32 B32 B~, ~2 B29 B29 B29 B30 B30 B30 B30 B30 EBv1 B31 B3' B31 B31 B32 B32 Bv2 32 B2929 B29 B30 B~0 B30 B30 B30 F B31 B31 B31 B31 B31 B3, B32 B3~ 3, B2929 B29 B30 BvO B30 B30 B30 G B31 B31 B31 B31 B31 B32 B32 B'-2 3, B2929 B29 B30 BvO B30 B30 B30 H B31 B31 B31 B31 B31 B3, B32 B~2 3, B2B29 B29 B30 B30 B30 30 B'0 A B31 B31 B31 B31 B31 B32 B32 B~2 B~2 B2B29 B29 B30 B30 B30 30 B'0 B B31 B31 B31 B31 B~1 B32 B32 Bv2 B~2 B2~ B29 B29 B30 B30 B30 30 B'0 cB3 B31 B31 B31 Bv1 B32 B32 v2 Bv2 B29 B29 B29 B30 B30 B30 B30 B30 DB3 B31 B31 B31 Bv B32 B32 ~2 B32 B29 B29 B29 B30 B30 B30 B30 B30 EB3 B~1 B31 B31 B3' B~2 B32 32 B~2 B29 B29 B29 B30 B30 B30 B30 B30 FB31 B31 B31 B31 B3 Bv2 B3, 32 B32 B29 B29 B29 B30 B30 B30 B30 B30 GB31 Bv1 B31 B31 B3 B~2 B3, B32 Bv2 W 096/22529 PCTrUS96/01005 y B~.
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f , ~ -C1~0 C W0 C1~0 C1-4 C1~0 c1~0 c1~0 C1 CC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 cC3 C11 C19 C27 C35 C3 CC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 cC3 C11 C19 C27 C35 C3 C1~0 C1-40 c1-40 C1-4 CA 022l0949 l997-07-2l C140 c1-40 C1-4 C1-40 c140 C14 CA 022l0949 l997-07-2l C1-40 C1-40 C1-4 r C11 C19 C27 C35 C3 C11 C19 C27 C35 c C3 C11 C19 C27 C35 C3 C11 C19 CA 022 l 0949 l 997 - 07 - 2 l PCTrUS96/01005 C11 C19 C27 C35 C3 C11 C19 C27 C35 c C3 C11 C19 C27 C35 C3 C11 C19 CA 022l0949 1997-07-21 W O 96122529 PCTnUS96101005 C28 C36 Dc4 C12 C20 C28 C36 C4 C12 C20 C28 C36 DC4 C12 C20 C29 C37 EC5 C13 C21 C29 C37 C5 C13 C21 C29 C37 E ' C5 C13 C21 CA 022l0949 l997-07-2l W O96/22529 PCTnUS96101005 C1~0 C1-40 C1-40 C1~0 C1-40 C1-40 C27 C35 CC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 cC3 C11 C19 C27 C35 CC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 cC3 C11 C19 , PCTrUS9G/01005 =r ~' C140 C1-40 C1~0 C1~0 C1-40 C1-40 C1~0 C1-40 C1-40 CA 022l0949 1997-07-21 PCT~US96/01005 W 0~6/22529 C25 C33 C1 Cg C17 C25 C33 A C1 C9 C17 C25 C33 C1 C9 C17 C25 C33 C1-40 C1~0 C1-40 C27 C35 C3 C11 C19 C27 C35 cC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 C1~0 C1~0 C1-40 C30 C38 C6 C14 C22 C30 C38 F ~ C6 C14 C22 C30 C38 C6 C14 C22 C30 C38 C27 C35 C3 C11 C19 C27 C35 cC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 i p 119 R8 C 8 P 120 , CA 022l0949 l997-07-2l PCT~US96/01005 ~ - BB3 CA 022l0949 l997-07-2l W O96/22S29 PCTrUS96/01005 ~ BB3 C1~0 C1~0 C140 GC7 C15 C23 C31 e39 C7 C15 C23 C31 C39 GC7 C15 C23 C31 C39 CA 022l0949 l997-07-2l PCTrUS96/01005 C1~0 C1~0 C1-40 7 8 9 10 11 2 3 4' 5 6 7 8 9 10 11 C1~0 C1~0 C1-40 CA 022l0949 l997-07-2l W O 96/22529 PCT~US96/01005 C1~0 C1-40 C1~0 C1~0 C1-40 C1-40 C1~0 C1-40 C1-40 C6 C14 C22 C3-~ C38 FC6 C14 C22 C30 C38 C6 C14 C22 C30 C38 F
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C1~0 C1-40 C1-40 C19 C27 C35 cC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 CC3 C11 C1~0 C140 C1-40 C1-40 C140 C1~0 C19 C27 C35 CC3 C11 C19 C27 C35 C3 C11 C19 C27 C35 cC3 C11 CA 022l0949 l997-07-2l PCTrUS96/01005 PCTrUS96/01005 C19 C27 C35 C3 C11 C19 C27 C35 c C3 C11 C19 C27 C35 C3 C11 C19 C27 15 P 79 R5 C 16 p C1-40 C1~0 C1-40 CA 022l0949 l997-07-2l PCTrUS96/01005 C~5 C~6 C~7 .
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Claims (28)
1. A method for constructing an array of synthetic molecular constructs, comprising the steps of:
a. forming a plurality of molecular constructs;
b. laying out an array possessing a logical ordering of sub-arrays of said molecular constructs;
c. providing each sub-array with molecular constructs having a common molecular core and at least one structured diversity element which is different from the others; and d. relating each sub-array within the array to all other sub arrays by said difference in said structural diversity elements.
a. forming a plurality of molecular constructs;
b. laying out an array possessing a logical ordering of sub-arrays of said molecular constructs;
c. providing each sub-array with molecular constructs having a common molecular core and at least one structured diversity element which is different from the others; and d. relating each sub-array within the array to all other sub arrays by said difference in said structural diversity elements.
2. The method of Claim 1 where the molecular constructs are functionalized beads, plates, membranes, composites or combinations thereof.
3. A method of optimizing the ability of a first chemical compound to bind to a reaction site comprising the steps of:
a) ascertaining the three dimensional and electrostatic configuration of the reaction site;
b) selecting a scaffold backbone for attaching at least one structural diversity element that is complementary to the reaction site;
c) forming an n x m array of different chemical compounds, wherein each chemical compound comprises said scaffold and at least one structural diversity element; and d) simultaneously screening each of the compounds in the n x m array against the reaction site to determine the chemical compound having the most reactivity to the reaction site.
a) ascertaining the three dimensional and electrostatic configuration of the reaction site;
b) selecting a scaffold backbone for attaching at least one structural diversity element that is complementary to the reaction site;
c) forming an n x m array of different chemical compounds, wherein each chemical compound comprises said scaffold and at least one structural diversity element; and d) simultaneously screening each of the compounds in the n x m array against the reaction site to determine the chemical compound having the most reactivity to the reaction site.
4. A method according to claim 3 which further comprises (e) ascertaining which chemical compounds in the n x m array have any reactivity to the reaction site and assigning those compounds a location designated by (n,m).
5. A method according to claim 4 which further comprises (f) forming an o x p array comprising at least one of the compounds having reactivity to the reaction site and forming at least one homolog, isomer or analog of each of said at least one compound to form the o x p array.
6. A method according to claim 5 which further comprises (g) simultaneously screening each of the compounds in the o x p array to determine their reactivity to the reaction site.
7. A method according to claim 6 wherein steps (e) through (g) are repeated at least twice.
8. A method according to claim 1 which further comprises selecting the scaffold backbone to have the following structure:
9. A method according to claim 1 which further comprises selecting the scaffold backbone to have the following structure:
10. A method according to claim 1 which further comprises selecting the scaffold backbone to have the following structure:
11. A method according to claim 1 which further comprises selecting the scaffold backbone to have the following structure:
12. A method according to claim 1 which further comprises selecting the structural diversity elements is selected from the group consisting of but not limited to:
13. A method according to claim 3 wherein each compound having a binding ability is assigned a location in the array, which also provides structural and chemical data for that compound.
14. A method of ascertaining the spatial orientation of an n x m array of different chemical compounds comprising the steps of:
a) forming an n x m array of oriented wells;
b) adding reactive ingredients capable of forming chemical compounds into the wells;
c) determining the molecular weights of all ingredients added to each well and assigning each well a location (n,m);
d) allowing the reactive ingredients to combine to form a chemical compound in each well, and determining the molecular weight of the chemical compositions in any two wells;
e) matching the molecular weights of the chemical compounds in the any two wells with the molecular weights of the chemical ingredients added to each well (n,m) to determine the spatial orientation of the array.
a) forming an n x m array of oriented wells;
b) adding reactive ingredients capable of forming chemical compounds into the wells;
c) determining the molecular weights of all ingredients added to each well and assigning each well a location (n,m);
d) allowing the reactive ingredients to combine to form a chemical compound in each well, and determining the molecular weight of the chemical compositions in any two wells;
e) matching the molecular weights of the chemical compounds in the any two wells with the molecular weights of the chemical ingredients added to each well (n,m) to determine the spatial orientation of the array.
15. A method according to claim 14 wherein the molecular weight is determined by mass spectroscopy.
16. A method of determining the structure of a chemical compound capable of binding to a reaction site comprising the steps of:
a) ascertaining the three dimensional structure and electrostatic configuration of the reaction site;
b) selecting a scaffold backbone for attaching structural diversity elements that is capable of being complementary to the reaction site;
c) forming an n x m array of different chemical compounds, wherein each chemical compound comprises the scaffold backbone and at least one structural diversity element;
d) simultaneously screening each of the compounds in the n x m array against the reaction site to determine the chemical compound having the most reactivity to the molecular recognition site.
a) ascertaining the three dimensional structure and electrostatic configuration of the reaction site;
b) selecting a scaffold backbone for attaching structural diversity elements that is capable of being complementary to the reaction site;
c) forming an n x m array of different chemical compounds, wherein each chemical compound comprises the scaffold backbone and at least one structural diversity element;
d) simultaneously screening each of the compounds in the n x m array against the reaction site to determine the chemical compound having the most reactivity to the molecular recognition site.
17. A method according to claim 16 wherein the scaffold has the structure:
18. A method according to claim 16 wherein the scaffold has the structure:
19. A method according to claim 16 wherein the scaffold has the structure:
20. A method according to claim 16 wherein the scaffold has the structure:
21. A method according to claim 16 wherein at least one of the structural diversity elements is selected from the group consisting of but not limited to:
22. A method of determining the structure of at least a portion of a reaction site comprising the steps of a) selecting a scaffold backbone for attaching structural diversity elements;
b) forming an n x m array of different chemical compounds, wherein each chemical compound comprises the scaffold backbone and at least one structural diversity element;
c) simultaneously screening the n x m array against the reaction site to determine the chemical compound having the most reactivity to the reaction site;
d) determining the structure of the compound (n,m) in the array having the greatest reactivity;
e) forming a second k x l array comprising the reactive compound having the greatest reactivity from the n x m array and its isomers, homologs and analogs;
f) simultaneously screening the k x l array of compounds against the reaction site to determine the chemical compound having the greatest reactivity to the reaction site;
g) determining the structure and electrostatic configuration of the compound from the k x l array having the greatest reactivity;
f) forming at least one homolog, isomer or analog of each compound (n,m) having a reactivity to form the o x p array.
b) forming an n x m array of different chemical compounds, wherein each chemical compound comprises the scaffold backbone and at least one structural diversity element;
c) simultaneously screening the n x m array against the reaction site to determine the chemical compound having the most reactivity to the reaction site;
d) determining the structure of the compound (n,m) in the array having the greatest reactivity;
e) forming a second k x l array comprising the reactive compound having the greatest reactivity from the n x m array and its isomers, homologs and analogs;
f) simultaneously screening the k x l array of compounds against the reaction site to determine the chemical compound having the greatest reactivity to the reaction site;
g) determining the structure and electrostatic configuration of the compound from the k x l array having the greatest reactivity;
f) forming at least one homolog, isomer or analog of each compound (n,m) having a reactivity to form the o x p array.
23. The rational development of a chemical compound capable of reacting with a molecular recognition site comprising the steps of:
a) selecting a scaffold for attaching structural diversity elements;
b) simultaneously forming an n x m array of different chemical compounds, wherein each chemical compounds comprises a scaffold and at least one structural diversity element; and c) simultaneously screening the n x m array of compounds against a molecular recognition site to determine the chemical compound having the most reactivity to the molecular recognition site;
a) selecting a scaffold for attaching structural diversity elements;
b) simultaneously forming an n x m array of different chemical compounds, wherein each chemical compounds comprises a scaffold and at least one structural diversity element; and c) simultaneously screening the n x m array of compounds against a molecular recognition site to determine the chemical compound having the most reactivity to the molecular recognition site;
24. A method of forming an n x m array of chemical compounds comprising the steps of:
a) Forming an n x m array of the same molecular construct having a common molecular core and X, where X is greater than or equal to three, sites capable of undergoing chemical transformations;
b) simultaneously and/or concurrently performing an operation on each molecular construct in the n x m array to create a reaction on at least one site on each of the n x m molecules to form at least one different molecular construct;
c) performing either overlaid or orthogonal operations on the product of b. for sufficient cycles to produce an ordered, fully-addressable array of novel compounds.
a) Forming an n x m array of the same molecular construct having a common molecular core and X, where X is greater than or equal to three, sites capable of undergoing chemical transformations;
b) simultaneously and/or concurrently performing an operation on each molecular construct in the n x m array to create a reaction on at least one site on each of the n x m molecules to form at least one different molecular construct;
c) performing either overlaid or orthogonal operations on the product of b. for sufficient cycles to produce an ordered, fully-addressable array of novel compounds.
25. A method of determining the structure of a chemical compound capable of binding to a reaction site comprising the steps of;
a) ascertaining the three dimensional structure and electrostatic configuration of the reaction site;
b) selecting a scaffold backbone for attaching structural diversity elements that is capable of being complementary to the reaction site;
c) forming an n x m array of different chemical compounds, wherein each chemical compound comprises the scaffold backbone and at least one structural diversity element; and d) simultaneously screening each of the compounds in the n x m array against the reaction site to determine the chemical compound having the most reactivity to the molecular recognition site.
a) ascertaining the three dimensional structure and electrostatic configuration of the reaction site;
b) selecting a scaffold backbone for attaching structural diversity elements that is capable of being complementary to the reaction site;
c) forming an n x m array of different chemical compounds, wherein each chemical compound comprises the scaffold backbone and at least one structural diversity element; and d) simultaneously screening each of the compounds in the n x m array against the reaction site to determine the chemical compound having the most reactivity to the molecular recognition site.
26. A method according to claim 25 which further comprises the following steps:
e) simultaneously screening each of the compounds in the o x p array f) determining the molecular weight of all ingredients added to each well and assigning each well a location (n,m);
g) allowing the reactive ingredients to combine to form a chemical compound in each well and determining the molecular weight of the chemical compositions in any two wells;
h) adding reactive ingredients capable of forming chemical compounds into the wells, is performed;
and i) simultaneously screening each of the compounds in the o x p array against a reactive site.
e) simultaneously screening each of the compounds in the o x p array f) determining the molecular weight of all ingredients added to each well and assigning each well a location (n,m);
g) allowing the reactive ingredients to combine to form a chemical compound in each well and determining the molecular weight of the chemical compositions in any two wells;
h) adding reactive ingredients capable of forming chemical compounds into the wells, is performed;
and i) simultaneously screening each of the compounds in the o x p array against a reactive site.
27. A method of determining the structure of at least a portion of a reaction site comprising the steps of:
a) selecting a scaffold backbone for attaching structural diversity elements;
b) forming an n x m array of different chemical compounds, wherein each chemical compound comprises the scaffold backbone and at least one structural diversity element;
c) simultaneously screening each compound in the n x m array against the reaction site to determine the chemical compound having the most reactivity to the reaction site;
d) determining the structure of the compound (n,m) in the array having the greatest reactivity;
e) forming a second k x l array comprising the most reactive compound from the n x m array and its isomers, homologs and analogs;
f) simultaneously screening the k x l array of compounds against the reaction site to determine the chemical compound having the greatest reactivity to the reaction site; and g) determining the structure and electrostatic configuration of the compound from the k x l array having the greatest reactivity.
a) selecting a scaffold backbone for attaching structural diversity elements;
b) forming an n x m array of different chemical compounds, wherein each chemical compound comprises the scaffold backbone and at least one structural diversity element;
c) simultaneously screening each compound in the n x m array against the reaction site to determine the chemical compound having the most reactivity to the reaction site;
d) determining the structure of the compound (n,m) in the array having the greatest reactivity;
e) forming a second k x l array comprising the most reactive compound from the n x m array and its isomers, homologs and analogs;
f) simultaneously screening the k x l array of compounds against the reaction site to determine the chemical compound having the greatest reactivity to the reaction site; and g) determining the structure and electrostatic configuration of the compound from the k x l array having the greatest reactivity.
28. A method for constructing an array of synthetic molecular constructs, comprising the steps of:
a. forming a plurality of molecular constructs;
b. laying out an array possessing a logical ordering of sub-arrays of said molecular constructs;
c. providing each sub-array with molecular constructs having a common molecular core of one of and at least one structural diversity element which is different from the others, and;
d. relating each sub-array within the array to all other sub arrays by said difference in said structural diversity elements.
g) determining the structure and electrostatic configuration of the compound from the k x l array having the greatest reactivity.
a. forming a plurality of molecular constructs;
b. laying out an array possessing a logical ordering of sub-arrays of said molecular constructs;
c. providing each sub-array with molecular constructs having a common molecular core of one of and at least one structural diversity element which is different from the others, and;
d. relating each sub-array within the array to all other sub arrays by said difference in said structural diversity elements.
g) determining the structure and electrostatic configuration of the compound from the k x l array having the greatest reactivity.
Applications Claiming Priority (2)
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| US08/375,838 US5712171A (en) | 1995-01-20 | 1995-01-20 | Method of generating a plurality of chemical compounds in a spatially arranged array |
| US375,838 | 1995-01-20 |
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|---|---|
| CA2210949A1 true CA2210949A1 (en) | 1996-07-25 |
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| CA002210949A Abandoned CA2210949A1 (en) | 1995-01-20 | 1996-01-19 | A method of generating a plurality of chemical compounds in a spatially arranged array |
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| US (4) | US5712171A (en) |
| EP (1) | EP0804726A4 (en) |
| JP (1) | JPH11503720A (en) |
| KR (1) | KR100414424B1 (en) |
| AU (1) | AU719584C (en) |
| CA (1) | CA2210949A1 (en) |
| CZ (1) | CZ232297A3 (en) |
| HU (1) | HUP9802293A3 (en) |
| IL (1) | IL116838A0 (en) |
| NO (1) | NO973335L (en) |
| NZ (1) | NZ301594A (en) |
| PL (1) | PL327437A1 (en) |
| WO (1) | WO1996022529A1 (en) |
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1995
- 1995-01-20 US US08/375,838 patent/US5712171A/en not_active Expired - Fee Related
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1996
- 1996-01-19 KR KR1019970704928A patent/KR100414424B1/en not_active IP Right Cessation
- 1996-01-19 NZ NZ301594A patent/NZ301594A/en unknown
- 1996-01-19 CZ CZ972322A patent/CZ232297A3/en unknown
- 1996-01-19 JP JP8522446A patent/JPH11503720A/en not_active Ceased
- 1996-01-19 PL PL96327437A patent/PL327437A1/en unknown
- 1996-01-19 WO PCT/US1996/001005 patent/WO1996022529A1/en not_active Application Discontinuation
- 1996-01-19 IL IL11683896A patent/IL116838A0/en unknown
- 1996-01-19 HU HU9802293A patent/HUP9802293A3/en unknown
- 1996-01-19 CA CA002210949A patent/CA2210949A1/en not_active Abandoned
- 1996-01-19 AU AU47059/96A patent/AU719584C/en not_active Ceased
- 1996-01-19 EP EP96902775A patent/EP0804726A4/en not_active Withdrawn
- 1996-05-17 US US08/649,371 patent/US5736412A/en not_active Expired - Lifetime
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- 1997-07-18 NO NO973335A patent/NO973335L/en not_active Application Discontinuation
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1998
- 1998-01-20 US US09/009,846 patent/US6878557B1/en not_active Expired - Fee Related
- 1998-01-26 US US09/013,709 patent/US5962736A/en not_active Expired - Fee Related
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| EP0804726A1 (en) | 1997-11-05 |
| NZ301594A (en) | 1999-01-28 |
| EP0804726A4 (en) | 2004-07-07 |
| US5736412A (en) | 1998-04-07 |
| PL327437A1 (en) | 1998-12-07 |
| KR100414424B1 (en) | 2004-07-07 |
| US6878557B1 (en) | 2005-04-12 |
| HUP9802293A2 (en) | 1999-02-01 |
| KR19980703097A (en) | 1998-10-15 |
| AU719584C (en) | 2001-07-26 |
| CZ232297A3 (en) | 1998-06-17 |
| WO1996022529A1 (en) | 1996-07-25 |
| US5712171A (en) | 1998-01-27 |
| NO973335D0 (en) | 1997-07-18 |
| HUP9802293A3 (en) | 1999-03-29 |
| AU719584B2 (en) | 2000-05-11 |
| AU4705996A (en) | 1996-08-07 |
| US5962736A (en) | 1999-10-05 |
| IL116838A0 (en) | 1996-07-23 |
| JPH11503720A (en) | 1999-03-30 |
| NO973335L (en) | 1997-08-21 |
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