Claims
- 1. A multibinding compound of Formula (I):
- 2. The multibinding compound of claim 2 wherein q is less than p.
- 3. The multibinding compound of claim 2 wherein each linker, X, in the multibinding compound of Formula (I) independently has the formula:
- 4. A multibinding compound of Formula (II):
- 5. The bivalent multibinding compound of claim 4, wherein:
X is —O—, —O-alkylene, —O-(arylene)-NH-(substituted alkylene), —O-(alkylene)-O-(arylene)-(alkylene)-O-(alkylene)-NH-(substituted alkylene)-, —O-(alkylene)-O-(arylene)-, or -(alkylene)-(cycloalkylene)-NH-(substituted alkylene); and Q is a covalent bond.
- 6. The multibinding compound of claim 5, wherein:
Ar1 is:
(i) a phenyl ring of formula (c): 57wherein: R4 is hydrogen, methyl, fluoro, chloro, or methoxy; R5 is hydrogen, hydroxy, fluoro, chloro, amino, or —NHSO2CH3; R6 is hydrogen, chloro, fluoro, hydroxy, methoxy, hydroxymethyl, —CH2SO2CH3, —NHSO2CH3, —NHCHO, —CONH2, or —NHCONH2; Ar2 is phenyl wherein the W and the X groups are attached at the 1, 4 position of the phenyl ring; and Ar3 is either:
(i) a phenyl ring of formula (c) as defined in claim 6 above; or (ii) a phenyl ring of formula (d): 58wherein: R7 is hydrogen, methyl, propen-2-yl, fluoro, chloro, methoxy, —OCH2CO2Me, —OCON(NCH3)2, hydroxy, —CH2CONH2, —NHCOCH3, imidazol-1-yl, or 1-methyl-4-trifluoromethyl-imidazol-2-yl; and R8 is hydrogen, fluoro, chloro, methoxy, —OCH2CO2Me, —OCON(CH3)2, or —CONH2; or
(iii) naphthyl, pyridyl, benzimidazol-1-yl, indolyl, 2-cyanoindolyl, carbazolyl, 4-methylindanyl, 5-(CH3CO2CH2O—)-1,2,3,4-tetrahydronaphthyl, 1H-2-oxoindole, 2,3,4-trihydrothianaphthalene, or 4-oxo-2,3-dihydrothianapthalene.
- 7. The multibinding compound of claim 6 wherein:
Ar1 is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-dichlorophenyl, 2-chloro-3,4-dihydroxyphenyl, 2-fluoro-3,4-dihydroxyphenyl, 2-chloro-3,5-dihydroxyphenyl, 2-fluoro-3,5-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3-(HCONH—)phenyl, 4-hydroxy-3-(NH2CO—)phenyl, 3-chlorophenyl, 2,5-diethoxyphenyl, 4-(CH3SO2NH—)-phenyl, 4-hydroxy-3-(CH3SO2CH2—)phenyl, 4-hydroxy-3-(CH3SO2NH—)phenyl, 4-hydroxy-3-(NH2CONH—)phenyl, or 3,5-dichloro-4-aminophenyl; W is a bond, methylene, ethylene, propylene, —(CH2)6—O—(CH2)3—, —(CH2)6—O—, or —CH2CH(OH)CH2—O—; X is —O—; —O—(CH2)4—; —O-(1,4-phenylene)-NH—CH2—CH(OH)—; —O—(CH2)10—O-(1,4-phenylene)-(CH2)3—O—(CH2)6—NH—CH2—CH(OH)—; —O-(CH2)6—O-(1,4-phenylene)-(CH2)3—O—(CH2)5—NH—CH2—CH(OH)—; —O—(CH2)6—O-(1,4-phenylene)-; or —CH2-(1,4-cyclohexyl)-NH—CH2—CH(OH)—; and Ar3 is: 59
- 8. The multibinding compound of claim 4, wherein:
X is a covalent bond; and Q is a substituted alkylene group wherein one or more of the carbon atoms in said substituted alkylene group is optionally replaced by a heteroatom selected from the group consisting of—NRa— (where Ra is hydrogen, alkyl, or acyl) and —O—.
- 9. The multibinding compound of claim 8, wherein:
Ar1 is:
(i) a phenyl ring of formula (c): 60wherein: R4 is hydrogen, methyl, fluoro, chloro, or methoxy; R5 is hydrogen, hydroxy, fluoro, chloro, amino, or —NHSO2CH3; and R6 is hydrogen, chloro, fluoro, hydroxy, methoxy, hydroxymethyl, —CH2SO2CH3, —NHSO2CH3, —NHCHO, —CONH2, or —NHCONH2; Ar2 is phenyl wherein the W and the X groups are attached at the 1, 4 position of the phenyl ring; and Ar3 is either:
(i) a phenyl ring of formula (c) as defined in claim 9 above; or (ii) a phenyl ring of formula (d): 61wherein: R7 is hydrogen, methyl, propen-2-yl, fluoro, chloro, methoxy, —OCH2CO2Me, —OCON(CH3)2, hydroxy, —CH2CONH2, —NHCOCH3, imidazol-1-yl, or 1-methyl-4-trifluoromethyl-imidazol-2-yl; and R8 is hydrogen, fluoro, chloro, methoxy, —OCH2CO2Me, —OCON(CH3)2, or —CONH2; or
(iii) naphthyl, pyridyl, benzimidazol-1-yl, indolyl, 2-cyanoindolyl, carbazolyl, 4-methylindanyl, 5-(CH3CO2CH2O—)-1,2,3,4-tetrahydronaphthyl, 1H-2-oxoindole, 2,3,4-trihydrothianaphthalene, or 4-oxo-2,3-dihydrothianapthalene.
- 10. The multibinding compound of claim 9 wherein:
Ar1 is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-dichlorophenyl, 2-chloro-3,4-dihydroxyphenyl, 2-fluoro-3,4-dihydroxyphenyl, 2-chloro-3,5-dihydroxyphenyl, 2-fluoro-3,5-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3-(HCONH—)phenyl, 4-hydroxy-3-(NH2CO—)phenyl, 3-chlorophenyl, 2,5-dimethoxyphenyl, 4-(CH3SO2NH—)-phenyl, 4-hydroxy-3-(CH3SO2CH2—)phenyl, 4-hydroxy-3-(CH3SO2NH—)phenyl, 4-hydroxy-3-(NH2CONH—)phenyl, or 3,5-dichloro-4-aminophenyl; W is a bond, methylene, ethylene, propylene, —(CH2)6—O—(CH2)3—, —(CH2)6—O—, or —CH2CH(OH)CH2—O—; Q is —NH—CH2—CH(OH)—; —NH—CH(CH2OH)—; —CH2—NH—CH2—CH(OH)—; —C(CH3)2—NH—CH2—CH(OH)—; —(CH2)3—NH—CH2—CH(OH)—; —(CH2)3—O—(CH2,6—NH—CH2—CH(OH)—; —(CH2)2—NH—CH213 CH(OH)—; or —O—(CH2)—CH(OH)—CH2—NH—CH2—CH(OH)—; and Ar3 is: 62
- 11. The multibinding compound of claim 10 wherein the compound is:
- 12. The multibinding compound of claim 10 wherein the compound is:
- 13. The multibinding compound of claim 10 wherein the compound is:
- 14. The multibinding compound of claim 8 wherein:
Ar3 is phenyl; and Q is —NH—CH2—*CH(OH)-(where * is RS, R, or S stereochemistry).
- 15. The multibinding compound of claim 8 wherein:
Ar3 is phenyl, 4-hydroxy-3-(NH2CONH—)phenyl, or 3,5-dichloro-4-aminophenyl.
- 16. The multibinding compound of claim 8 wherein:
Ar1 is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-dichlorophenyl, 2-chloro-3,4-dihydroxyphenyl, 2-fluoro-3,4dihydroxyphenyl, 2-chloro-3,5-dihydroxyphenyl, 2-fluoro-3,5-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3-(HCONH—)phenyl, 4-hydroxy-3-(NH2CO—)phenyl, 3-chlorophenyl, 2,5-dimethoxyphenyl, 4-(CH3SO2NH—)-phenyl, 4-hydroxy-3-(CH3SO2CH2—)phenyl, 4-hydroxy-3-(CH3SO2NH—)phenyl, 4-hydroxy-3-(NH2CONH—)phenyl, or 3,5-dichloro-4-aminophenyl; W is a bond, methylene, ethylene, propylene, —(CH2)6—O—(CH2)3—, —(CH2)6—O—, or —CH2CH(OH)CH2—O—; Ar2 is phenyl wherein the W and the X groups are attached at the 1,4-position of the phenyl ring; Q is —NH—CH2—CH(OH)—CH2—O—; and Ar3 is: 66
- 17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of Formula (I):
- 18. The pharmaceutical composition of claim 17 wherein q is less than p.
- 19. The pharmaceutical composition of claim 18 wherein each linker independently has the formula:
- 20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of claim 7.
- 21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of claim 10.
- 22. A method for treating diseases mediated by a β2 adrenergic receptor in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a multibinding compound of Formula (I):
- 23. A method for treating diseases mediated by a β2 adrenergic receptor in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a multibinding compound of claim 7.
- 24. A method for treating diseases mediated by a β2 adrenergic receptor in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a multibinding compound of claim 10.
- 25. The method of claim 24 wherein the disease is a respiratory disease.
- 26. The method of claim 25 wherein the disease is asthma or chronic pulmonary obstructive disease.
- 27. A method for identifying multimeric ligand compounds possessing multibinding properties for β2 adrenergic receptor which method comprises:
(a) identifying a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and (d) assaying the multimeric ligand compounds produced in the library prepared in (c) above to identify multimeric ligand compounds possessing multibinding properties for β2 adrenergic receptor.
- 28. A method for identifying multimeric ligand compounds possessing multibinding properties for β2 adrenergic receptor which method comprises:
(a) identifying a library of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and (d) assaying the multimeric ligand compounds produced in the library prepared in (c) above to identify multimeric ligand compounds possessing multibinding properties for β2 adrenergic receptor.
- 29. The method according to claim 27 or 28 wherein the preparation of the multimeric ligand compound library is achieved by either the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers identified in (b).
- 30. The method according to claim 29 wherein the multimeric ligand compounds comprising the multimeric ligand compound library are dimeric.
- 31. The method according to claim 30 wherein the dimeric ligand compounds comprising the dimeric ligand compound library are heterodimeric.
- 32. The method according to claim 31 wherein the heterodimeric ligand compound library is prepared by sequential addition of a first and second ligand.
- 33. The method according to claim 27 or 28 wherein, prior to procedure (d), each member of the multimeric ligand compound library is isolated from the library.
- 34. The method according to claim 33 wherein each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS).
- 35. The method according to claim 27 or claim 28 wherein the linker or linkers employed are selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization and amphiphilic linkers.
- 36. The method according to claim 35 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups.
- 37. The method according to claim 36 wherein the linkers are selected to have different linker lengths ranging from about 2 to 100 Å.
- 38. The method according to claim 27 or 28 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands.
- 39. The method according to claim 38 wherein said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof wherein the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand.
- 40. The method according to claim 27 or claim 28 wherein the multimeric ligand compound library comprises homomeric ligand compounds.
- 41. The method according to claim 27 or claim 28 wherein the multimeric ligand compound library comprises heteromeric ligand compounds.
- 42. A library of multimeric ligand compounds which may possess multivalent properties for β2 adrenergic receptor which library is prepared by the method comprising:
(a) identifying a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.
- 43. A library of multimeric ligand compounds which may possess multivalent properties for β2 adrenergic receptor which library is prepared by the method comprising:
(a) identifying a library of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.
- 44. The library according to claim 42 or claim 43 wherein the linker or linkers employed are selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization and/or polarizability, and amphiphilic linkers.
- 45. The library according to claim 44 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups.
- 46. The library according to claim 45 wherein the linkers are selected to have different linker lengths ranging from about 2 to 100 Å.
- 47. The library according to claim 42 or 43 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands.
- 48. The library according to claim 47 wherein said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof wherein the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand.
- 49. The library according to claim 42 or claim 43 wherein the multimeric ligand compound library comprises homomeric ligand compounds.
- 50. The library according to claim 42 or claim 43 wherein the multimeric ligand compound library comprises heteromeric ligand compounds.
- 51. An iterative method for identifying multimeric ligand compounds possessing multibinding properties for β2 adrenergic receptor which method comprises:
(a) preparing a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which target a receptor with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand wherein said contacting is conducted under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; (b) assaying said first collection or iteration of multimeric compounds to assess which if any of said multimeric compounds possess multibinding properties for β2 adrenergic receptor; (c) repeating the process of (a) and (b) above until at least one multimeric compound is found to possess multibinding properties for β2 adrenergic receptor; (d) evaluating what molecular constraints imparted multibinding properties to the multimeric compound or compounds found in the first iteration recited in (a)-(c) above; (e) creating a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints imparting multibinding properties for β2 adrenergic receptor to the multimeric compound or compounds found in said first iteration; (f) evaluating what molecular constraints imparted enhanced multibinding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above; (g) optionally repeating steps (e) and (f) to further elaborate upon said molecular constraints.
- 52. The method according to claim 51 wherein steps (e) and (f) are repeated from 2-50 times.
- 53. The method according to claim 52 wherein steps (e) and (f) are repeated from 5-50 times.
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. application Ser. No. 09/323,943, filed on Jun. 2, 1999 which claims the benefit of U.S. patent application Ser. No. 60/088,466, filed Jun. 8, 1998; and U.S. patent application Ser. No. 60/092,938, filed Jul. 15, 1998; the disclosures of which are incorporated herein by reference in their entirety.
Continuations (2)
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10108945 |
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09457618 |
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Continuation in Parts (1)
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