Claims
- 1. A method for recording the reaction history of a reaction series on each of a plurality of unique solid supports, wherein said reaction series involves at least two stages requiring differing agents or reaction conditions resulting in a different modification as to a plurality of said unique solid supports, resulting in a plurality of different final products on different unique solid supports, employing a combination of identifiers for recording said reaction history, said identifiers characterized by defining the choice of agent or reaction condition and the stage in said reaction series and being capable of being analyzed as to the choice and stage, said method comprising:
reacting, at a first or intermediate stage of said series, a different agent or employing a different reaction condition with each of a group of said unique solid supports, said group comprising at least one of said unique solid supports, and a combination of identifiers wherein said combination of identifiers defines the choice of agent and the stage in said series as to each group of said unique solid supports, each of said identifiers being individually bound to said unique solid support directly or through other than a prior identifier; mixing said groups together and then dividing said plurality of unique solid supports into a plurality of groups for a second intermediate or final stage; and repeating said reacting at least once to provide a plurality of final products, having different products on the different individual unique solid supports.
- 2. A method according to claim 1, wherein at least 100 unique solid supports and at least 2 groups are employed in each said reacting.
- 3. A method according to claim 1, including the additional stages of screening said final products on said unique solid supports for a characteristic of interest; and identifying the reaction history of at least one final product having said characteristic of interest.
- 4. A method of claim 1, further comprising cleaving the final product from the solid support and screening said final product.
- 5. A method of claim 1, further comprising treating the identifiers so as to detach tag components from the solid supports and reacting said tag components with a moiety capable of detection by fluorescence or electron capture.
- 6. A method of claim 5, wherein the detaching is done photochemically or oxidatively and the detectable moiety is derived from dansyl chloride or a polyhalobenzoylhalide.
- 7. A method of claim 1, wherein the identifier comprises tag components which have two characteristics, a characteristic capable of separation and a characteristic capable of detection.
- 8. A method according to claim 7, wherein said characteristic capable of detection is the ability to be detected by electron capture.
- 9. A method according to claim 7, wherein said characteristic capable of detection is the ability to be detected by mass spectroscopy.
- 10. A method of claim 9, wherein the mass spectropscopy detects the presence of deuterium atoms.
- 11. A method according to claim 7, wherein said characteristic capable of detection is radioactivity.
- 12. A method according to claim 7, wherein said characteristic capable of detection is fluorescence.
- 13. A method according to claim 7, wherein said tags may be separated by means of chromatography.
- 14. A kit comprising a plurality of different separated organic compounds, each of the compounds characterized by having a distinguishable composition, encoding at least one bit of different information which can be determined by a physical measurement and sharing at least one common functionality.
- 15. A kit of claim 14, comprising at least 4 different functional organic compounds.
- 16. A kit according to claim 14, wherein said functional organic compounds are of the formula:
- 17. A kit according to claim 16, wherein said functional organic compounds differ by the number of methylene groups and/or halogens, nitrogens or sulfurs present.
- 18. A kit according to claim 16, wherein the C—E—C′ portion can be removed photochemically.
- 19. A kit according to claim 16, wherein the C—E—C′ portion can be removed oxidatively, hydrolytically, thermolytically, or reductively.
- 20. A solid support characterized by having a ligand bound thereto and having a combination of identifiers bound to said solid support.
- 21. A solid support according to claim 20, wherein said ligand is an oligomer which is an oligopeptide, oligonucleotide, oligosaccharide, polylipid, polyester, polyamide, polyurethane, polyurea, polyether, poly (phosphorus derivative) which is a phosphate, phosphonate, phosphoramide, phosphonamidey, phosphite, or phosphinamide, poly (sulfur derivative) which is a sulfone, sulfonate, sulfite, sulfonamide, or sulfenamide, where for the phosphorous and sulfur derivatives the indicated heteroatom for the most part will be bonded to C, H, N, O or S, and combinations thereof.
- 22. A solid support according to claim 20, wherein said ligand is a non-oligomer which is heterocyclic, aromatic, alicyclic, or aliphatic, and combinations thereof.
- 23. A solid support of claim 22, wherein the non-oligomer is a diazabicyclic, an azatricyclic, or a branched amide compound.
- 24. A solid support of claim 20, wherein the ligand is linked to the support through a non-labile linkage.
- 25. A solid support of claim 20, wherein the ligand is linked to the support through a cleavable linkage.
- 26. A solid support according to claim 20, wherein the identifier comprises tags, the tags being radioisotopes, or haloalkyl or haloarylallyl containing compounds.
- 27. A solid support of claim 20, which is a bead of about 10-2000 μm in diameter, and wherein the identifiers comprise tag components which after cleavage from the bead can be separated by gas chromatography and or liquid chromatography detected by electron capture, mass spectroscopy, fluorescence, or atomic emission techniques.
- 28. A library comprising a plurality of solid supports according to claim 23.
- 29. A library of claim 28, wherein the final products have been cleaved from the solid support.
- 30. A library of claim 29, wherein the final products are a diazabicyclic, azatricyclic, or branched amide compounds.
- 31. A process for identifying compounds having a characteristic of interest which comprises screening a library of claim 28.
- 32. A process of claim 31, wherein the compounds have been cleaved from the solid surface.
- 33. A process of claim 32, wherein the compound is a diazabicyclic, azatricyclic, or branched amide compound.
- 34. A method for producing a ligand involving a reaction series employing a method for recording the reaction history of a reaction series on each of a plurality of unique solid supports, wherein said reaction series involves at least two stages requiring differing agents and/or reaction conditions resulting in a different modification as to a plurality of said unique solid supports, resulting in a plurality of different final products on different unique solid supports, employing a combination of identifiers for recording said reaction history, said identifiers characterized by defining the choice of agent or reaction condition and the stage in said series and being capable of being analyzed as to the choice and stage, said method comprising:
reacting, at a first or intermediate stage of said series, a different agent or employing a different reaction condition with each of a group of said unique solid supports, said group comprising at least one of said unique solid supports, and a combination of identifiers wherein said combination of identifiers defines the choice of agent and the stage in said series as to each group of said unique solid supports, each of said identifiers being individually bound to said unique solid support directly or through other than a prior identifier; mixing said groups together and then dividing said plurality of unique solid supports into a plurality of groups for a second intermediate or final stage; repeating said reacting at least once to provide a plurality of ligands, having different products on the different individual unique solid surfaces; and identifying said reaction history of at least one selected unique solid surface by means of said combination of identifiers.
- 35. A ligand according to claim 34, wherein said identifying includes the stage of screening said ligands for a characteristic of interest.
- 36. A method for producing a ligand involving a reaction series employing a method for recording the reaction history of a reaction series on each of a plurality of unique solid surfaces, wherein said reaction series involves at least two stages requiring differing agents and/or reaction conditions resulting in a different modification as to each of a plurality of said unique solid surfaces, resulting in a plurality of different ligands on different unique solid surfaces, employing combinations of identifiers for recording said reaction history, said combination of identifiers characterized by defining the choice of agent and/or reaction condition and the stage in said series and being capable of being analyzed as to the choice and stage, said method comprising:
reacting, at a first or intermediate stage of said series, a different agent and/or employing a different reaction condition with each of a group of said unique solid surfaces, said group comprising at least one of said unique solid surfaces, and a combination of identifiers wherein said combination of identifiers defines the choice of agent and the stage in said series as to each group of said unique solid surfaces, each of said identifiers being individually bound to said unique solid surface through other than a prior identifier by a cleavable link; mixing said groups together and then dividing said plurality of unique solid surfaces into a plurality of groups for a second intermediate or final stage; repeating said reacting to provide a plurality of ligands having different ligands on the different individual unique solid surfaces; screening the ligands from a plurality of each of said unique solid surfaces for a characteristic of interest; and identifying said reaction history of at least one selected unique solid surface having ligand having said characteristic of interest by detaching the tag members from said unique solid surface and identifying said tag members by means of a differing characteristic.
- 37. A method according to claim 36, wherein said tags differ in an homologous series and are detected by electron capture gas chromatography or mass spectroscopy.
- 38. A compound of the Formula I:
- 39. A compound of claim 38, having the formula:
- 40. A compound of claim 39, wherein:
F1 is
CO2H, OH, CHN2, C(O)CHN2, C(O)X, NCS, or CH2X: 66C and C′ is each independently C1-C20 alkylene unsubstituted or substituted by 1-40 F or Cl, or [O—(CH2)2-3]p; E is C1-C10 alkyl substituted by 1-20 F or Cl; Q-aryl where aryl is a bi-cyclic aromatic ring substituted by 1-7 F or Cl; or Q-phenyl substituted by 1-5 F, Cl, NO2, or SO2R5; and Q is a bond, O, —NR5 C(O)—, or —OC(O)—.
- 41. A compound of claim 39, having the formula:
- 42. A compound of claim 39, wherein:
E—C′ is H, OH, or NH2.
- 43. A composition of the formula
- 44. A composition of claim 43, wherein:
S is a capillary, hollow fiber, needle, solid fiber, cellulose bead, pore-glass bead, silica gel, polystyrene bead optionally cross-linked with divinylbenzene, grafted co-poly bead, poly-acrylamide bead, latex bead, dimethylacrylamide bead optionally cross-linked with N,N′-bis-acryloyl ethylene diamine, glass particles coated with a hydrophobic polymer, or low molecular weight non-cross-linked polystyrene; and F1′—F2—C—E—C′ is the residue of Formula I attached to S.
- 45. The method of claim 1, wherein the combination of identifiers defines a binary coding scheme.
- 46. The method of claim 1, wherein the identifiers are of claim 38.
- 47. The method of claim 1, wherein the identifiers are of claim 39.
- 48. The method of claim 1, wherein the identifiers are of claim 40.
- 49. The method of claim 1, wherein the identifiers are of claim 42.
- 50. The method of claim 1, further comprising detaching the tag members from said unique solid surfaces.
- 51. The method of claim 50, wherein the tag members are detached photochemically, oxidatively, hydrolytically, thermolytically, or reductively.
- 52. The method of claim 1, further comprising detaching non-oligomer ligands from said unique solid surfaces photochemically.
- 53. A compound of the formula
- 54. A method of synthesizing a chemical compound so that the structure of the compound is readily determinable, which comprises synthesizing the compound on the surface of a solid support under conditions such that the solid support at the completion of the synthesis of the compound has bound to it a plurality of identifiers which encode the reaction stages associated with the synthesis of the compound.
- 55. A method of synthesizing a library of chemical compounds so that the structure of each compound in the library is readily determinable which comprises synthesizing each compound on the surface of a unique solid support under conditions such that each such unique support at the completion of the synthesis of the library of compounds has bound to it a plurality of identifiers which encode the reaction stages associated with the synthesis of the compound synthesized on such solid support.
- 56. A method of determining the structure of a chemical compound which comprises synthesizing the compound by the method of claim 54 or 55, isolating the solid support upon which the compound was synthesized, treating the solid support so isolated so as to cause the tag components of each of the identifiers bound to the solid support to be released, determining the identity or quantity or both of each tag component so released, and deriving the structure of the compound from the identities or quantities or both of all such tag components.
- 57. A method of identifying a compound having a desired characteristic which comprises synthesizing a library of chemical compounds by the method of claim 55, separately testing each of the compounds in the resulting library in an assay which identifies compounds having the desired characteristic so as to identify any compounds present in the library which has the desired characteristic.
- 58. A method of claim 57, further comprising determining the structure of the compound so identified.
- 59. A library of chemical compounds, each compound in the library being bound to a unique solid support and each such solid support having bound to it a plurality of identifiers which encode the reaction stages associated with the synthesis of the compound bound to such solid support.
- 60. A library of claim 59, wherein compounds in the library are diazabicyclic compounds.
- 61. A library of claim 59, wherein compounds in the library are azatricyclic compounds.
- 62. A library of claim 59, wherein compounds in the library are branched amide compounds.
- 63. A library of claim 59, wherein compound in the library are peptides.
- 64. A method of identifying a compound having a desired characteristic which comprises testing a library of chemical compounds according to claim 58 in an assay which identifies compounds having the desired characteristic so as to identify any compound present in the library which have the desired characteristic.
- 65. A method of claim 64, further comprising determining the structure of the compound so identified.
- 66. A compound identified by the method of claim 64.
- 67. A method of claim 64, wherein the desired characteristic is antagonism for the human neurokinin 1/brandykin receptor and the library of chemical compounds comprises azatricyclic compounds.
- 68. A method of claim 64, wherein the desired characteristic in usefulness as a muscle relaxant, a tranquilizer or a sedative and the library of chemical compounds comprises bezodiazepines.
- 69. A method of claim 64, wherein the desired characteristic is useful in the treatment of hypertension or Raynaud's syndrome and the library of chemical compounds comprises branched amides.
- 70. A composition comprising at least 6 different components, said components being associated in a kit or in a common medium, each component having a distinguishable moiety, said components being characterized by:
each distinguishable moiety being substantially chemically inert, differing in molecular weight, and having and identifiable characteristic different from each of the other distinguishable moieties other than light emission; each moiety joined to a linking group having an active functionality capable of forming a covalent bond, through a linking unit to individually separable solid surfaces, or joined to a group which is detectable at less than 1 nanomole, with the proviso that when said moieties are joined to said linking group, said components are physically segregated.
- 71. A composition according to claim 70, wherein said solid supports are beads.
- 72. A composition according to claim 70, wherein each component comprises molecules of different compounds bound to individual separable solid surfaces, wherein said distinguishable moieties encode the synthetic protocol used to synthesize said molecules on said solid surfaces.
- 73. A composition according to claim 70, wherein said distinguishable moieties define an homologous series and/or a series of substituents on a core molecule.
- 74. A composition comprising at least 6 different markers said markers being associated in a kit or in a common medium, each marker having a distinguishable moiety which is substantially chemically inert, differing from each other in molecular weight, said markers of the formula:
- 75. A composition according to claim 74, wherein the markers are of the formula (1).
- 76. A composition according to claim 74, wherein the markers are of the formula (2).
- 77. A composition according to claim 74, wherein the markers are of the formula (3).
- 78. A composition according to claim 74, wherein the markers are of the formula (4).
- 79. A composition according to claim 74, wherein Δ is bound to Λ.
- 80. A compound library comprising at least one hundred unique solid supports characterized by:
each solid support having (1) an individual compound bound to said solid support as the major compound bound to said support; and (2) a plurality of nonsequencable markers, where said markers are individual molecules which are physically distinguishable in being physically separable, differing in molecular weight and being distinguishable by other than fluorescence and are substituted so as to be detectable at less than about a nanomole or have a functional group for bonding to a substituent which is detectable at less than about a nanomole.
- 81. A compound library according to claim 80, wherein each solid support has at least about 6 markers.
- 82. A compound library according to claim 80, wherein said markers define a binary or higher code encoding the synthetic protocol used for synthesizing said compound on said solid support.
- 83. The compound of claim 38, wherein F1 is CHN2, C(O)CHN2, S(O2)CHN2, N3, NO2, or SO2N3.
- 84. The compound of claim 38, wherein F1 is COOH, CHN2, C(O)CHN2, S(O2)CHN2, COCl, OH, SH, CH2X, or NHR1;
wherein F2 is 70wherein A is —O— or —OC(O)O—; C(E—C′)a is —(CR42)1-15—(O)0-1—Ar, —(CR42)0-15—(CF2)1-15—F, —(CR42)0-15—(CF2)1-15—(CR42)0-15—H, or —(CH2)1-20—((O)0-1—(CH2)1-19)0-24—(CH2)0-24—(O)0-1—Ar,
wherein Ar is pentafluoro-, pentachloro-, or pentabromophenyl, 2,3,5,6-tetrafluoro-4(2,3,4,5,6-pentafluorophenyl)phenyl, 2,4,6-trichlorophenyl, 2,4,5-trichlorophenyl, 2,6-dichloro-4-fluorophenyl, or 2,3,5,6-tetrafluorophenyl.
Parent Case Info
[0001] This application is a continuation-in-part of U.S. Ser. No. 08/227,007, filed Apr. 13, 1994 the contents of which are hereby incorporated by reference into the subject application.
Continuations (1)
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Number |
Date |
Country |
Parent |
08722014 |
Feb 1997 |
US |
Child |
10150141 |
May 2002 |
US |