Claims
- 1. A multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers, wherein each of said ligands comprises, independently of each other, a muscarinic receptor antagonist or an allosteric modulator of a muscarinic receptor and pharmaceutically acceptable salts thereof, provided that at least one of said ligands is a muscarinic receptor antagonist, and further provided that when the multibinding compound comprises of 2 or 3 ligands, then only one of the ligands is 11-acetyl-5,11-dihydro-6H-pyrido[2,3b][1,4]-benzodiazepin-6-one, N-methylquinuclidine, or a compound of formula:
- 2. A multibinding compound of Formula (I):
- 3. The multibinding compound of claim 2 wherein q is less than p.
- 4. The multibinding compound of claim 3 wherein each ligand, L, that is a muscarinic receptor antagonist in the multibinding compound of Formula (I) is independently selected from the group consisting of:
(1) a compound of formula (a): 656wherein:
A is an aryl or a heteroaryl ring; B″ is —CH2—, —O— or —NRa— where Ra is hydrogen, alkyl, or substituted alkyl; R1 is hydrogen or alkyl; R2 is selected from a group consisting of formula (i), (ii), (iii), or “Het”: 657wherein: - - - - - is an optional double bond; n1 is an integer of from 1 to 4; n2 is an integer of from 1 to 3; V is —CH—, —O—, —S(O)n3— (where n3 is an integer of from 0 to 2), or —NR4— (wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl); “Het” is a heteroaryl ring which optionally attaches the ligand to a linker; R3 is hydrogen, alkyl, amino, substituted amino, —ORa (where Ra is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker; R5 is hydrogen, alkyl, amino, substituted amino, —ORb (where Rb is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand to a linker; R6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; K is a bond or an alkylene group; K″ is a bond, —C(O)—, —S(O)n4— (where n4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and B is a heterocycloamino group which optionally attaches the ligand to a linker; provided that at least one of the R5, R6, R7, R8, “Het”, or the heterocycloarnino group attaches the ligand to a linker; (2) a compound of formula (b): 658wherein:
C is an aryl or heteroaryl ring which optionally attaches the ligand to a linker; R9 is hydrogen, hydroxy, cyano, aminocarbonyl which optionally links the ligand to a linker, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; R10 is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; Q is a single bond, —O—, —COCH2—, —C(O)NH—, —NHC(O)O—, —NHC(O)NH—, or —C(O)O—; Q″ is selected from the group consisting of:
(i) monoaalkylaminoalkyl, monoalkylaminoalkenyl, monoalkylaminoalkynyl wherein the amino group optionally links the ligand to a linker; (ii) carboxy which optionally links the ligand to a linker; (iii) a group of formula (iv): 659(iv) where: E is hydrogen, a covalent bond attaching the ligand to a linker, or —CH2—W—R11 wherein W is a single bond or alkylene wherein one of the carbon atoms may optionally be replaced by —O—, —S—, or —NRg — (wherein Rg is hydrogen or alkyl); and R11 is a group of formula (v), (vi), or “Het”: 660wherein: - - - - - is an optional bond; T and U are, independently of each other, —O— or —CH2—; n5 is an integer of from 1 to 3; and “Het” is heteroaryl; and
(iv) a group of formula (vii), (viii) or (ix): 661wherein: n6 is 0 or 1; M− is a counterion; R12 is a covalent bond attaching the ligand to a linker; R13 is alkyl, alkenyl, cycloalkyl, or a covalent bond attaching the ligand to a linker; R14 is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker; R15 is hydrogen or alkyl and J is: 662provided that at least one of the C, R9, R10, and Q″ attaches the ligand to a linker; (3) a compound of formula (c): 663wherein:
G′ is pyrrolidine, piperidine, or 664wherein said G′ groups optionally attach the ligand to a linker; n7 is an 0 or 1, provided that when the nitrogen atom of the quinclidine ring attaches the ligand to the linker then n7 is 0; n8 is 1 or 2; g is an integer of from 0 to 3; each R15 is, independently of each other, hydrogen, halogen, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, methylenedioxy, ethylenedioxy, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino, or a covalent bond attaching the ligand to a linker; G is aryl, heteroaryl, heterocyclyl, or cycloalkyl which optionally attach the ligand to a linker; and G″ is a single bond or an alkylene group provided that at least one of the R15, G, G′, and G″ attaches the ligand to a linker; (4) a compound of formula (d): 665wherein:
n9 is 1 or 2; n10is 0 or 1 provided that n9+n10 is 1 or 2; P is an aryl or heteroaryl ring which optionally attaches the ligand to a linker; P″ is a single bond or an alkylene group; S is a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the P and S attaches the ligand to a linker; (5) a compound of formula (e): 666wherein:
n14 is 0, 1, or 2; n52 is 0 or 1; R16 is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker; R17, R18, and R19 are, independently of each other, hydrogen, alkyl, alkoxy, hydroxy, carbamoyl, sulfanoyl, halo, or a covalent bond attaching the ligand to a linker; R20 and R21 are, independently of each other, hydrogen, alkyl or a covalent bond attaching the ligand to a linker; or R20 and R21 together with the nitrogen atom to which they are attached form a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the R16, R17, R18, R19, R20, and R21 attaches the ligand to a linker; or (6) a compound of formula (f): 667wherein:
R22 is hydrogen or halo; R23 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclylalkyl; R24 is hydroxy, halo, or a covalent bond attaching the ligand to a linker; R25 and R26 are, independently of each other, hydrogen, alkyl, aralkyl, or a covalent bond attaching the ligand to a linker, or R25 and R26 together with the nitrogen atom to which they are attached form a heterocycloamino group which optionally attaches the ligand to a linker provided that at least one of the R24, R25, and R26 attaches the ligand to a linker; and each ligand, L, that is an allosteric modulator of a muscarinic receptor in the multibinding compound of Formula (I) is independently selected from a group consisting of: (7) a compound of formula (g): 668wherein:
D″ is alkylene; D is —NR31R32, —N+(R33R34R35) or —OR32 where R31, R33, and R34 are, independently of each other, hydrogen, alkyl, or aralkyl; and R32 and R35 represent a covalent bond attaching the ligand to a linker; R27 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R28 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbarnoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R29 and R30 are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono-or dialkylamino; or one of R27, R28, R29, or R30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group; (8) a compound of formula (h): 669wherein:
n11 is an integer of from 1 to 7; n12 is 0 to 7; F is —NR40—, —O—, —S—, or —CHR41— (wherein R40 and R41 are, independently of each other, hydrogen, alkyl, or substituted alkyl); F″ is a covalent bond, —OR43, —NR42R43 or —N+R43R44R45 wherein R42 is hydrogen or alkyl, R44 and R45 are alkyl, and R43 is a covalent bond attaching the ligand to a linker; R36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R37 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; and R38 is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R38 and R43 attaches the ligand to a linker; R39 is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; or (9) a compound of formula (i): 670wherein:
R46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle; R47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR49 where R49 is alkyl; or R46 and R47 together with the nitrogen atom to which they are attached form heterocycle; R48 is a covalent bond that attaches the ligand to a linker; R49 is alkyl; and pharmaceutically acceptable salts, individual isomers, mixture of isomers, and prodrugs thereof provided that at least one of the ligands is a muscarinic receptor antagonist.
- 5. The multibinding compound of claim 3 wherein each ligand, L, that is a muscarinic receptor antagonist in the multibinding compound of Formula (I) is independently selected from a group consisting of:
(1) a compound of formula (a): 671wherein:
A is an aryl or a heteroaryl ring; R1 is hydrogen or alkyl; R2 is selected from a group consisting of formula (i), (ii), (iii), or “Het”: 672wherein: - - - - - is an optional double bond; n1 is an integer of from 1 to 4; n2 is an integer of from 1 to 3; V is —CH—, —O—, —S(O)n3— (where n3 is an integer of from 0 to 2), or —NR4— (wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl); “Het” is a heteroaryl ring which optionally attaches the ligand to a linker; R3 is hydrogen, alkyl, amino, substituted amino, —ORa (where Ra is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker; R5 is hydrogen, alkyl, amino, substituted amino, —ORb (where Rb is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand to a linker; R6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; K is a bond or an alkylene group; K″ is a bond, —C(O)—, —S(O)n4— (where n4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and B is a heterocycloamino group which optionally attaches the ligand to a linker; provided that at least one of the R5, R6, R7, R8, “Het”, or the heterocycloarnino group attaches the ligand to a linker; (2) a compound of formula (b): 673wherein:
C is an aryl or heteroaryl ring which optionally attaches the ligand to a linker; R9 is hydrogen, hydroxy, cyano, aminocarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; R10 is hydrogen, aryl, heteroaryl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; Q is a single bond or —C(O)O— such that:
when Q is a bond then, Q″ is a group of formula (iv): 674where: E is hydrogen, a covalent bond attaching the ligand to a linker, or —CH2—W—R11 wherein W is a single bond or alkylene wherein one of the carbon atoms may optionally be replaced by —O—, —S—, or —NRg— (wherein Rg is hydrogen or alkyl); and R11 is a group of formula (v), (vi), or “Het”: 675wherein: T and U are, independently of each other, —O— or —CH2—; n5 is an integer of from 1 to 3; and “Het” is heteroaryl provided that at least one of C, E, R9, and R10 attaches the ligand to a linker; and when Q is —C(O)O— or —NHC(O)O— then, Q″ is a group of formula (vii) or (viii): 676wherein n6 is 0 or 1; M− is a counterion; R12 is a covalent bond attaching the ligand to a linker; R13 is alkyl alkenyl, cycloalkyl, or a covalent bond attaching the ligand to a linker; R14 is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker; and J is: 677provided that at least one of the C, R9, R10, R12, R13, and R14 attaches the ligand to a linker; (3) a compound of formula (c): 678wherein:
G′ is pyrrolidine, piperidine, or 679wherein M− is a counterion and further wherein said G′ groups optionally attach the ligand to a linker; n7 is an 0 or 1, provided that when the nitrogen atom of the quinclidine ring attaches the ligand to the linker then n7 is 0; ng is 1 or 2; g is an integer of from 0 to 3; each R5 is, independently of each other, hydrogen, halogen, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, methylenedioxy, ethylenedioxy, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino, or a covalent bond attaching the ligand to a linker; G is aryl, heteroaryl, heterocyclyl, or cycloalkyl which optionally attach the ligand to a linker; and G″ is a single bond or an alkylene group provided that at least one of the R15, G, G′, and G″ attaches the ligand to a linker; (4) a compound of formula (d): 680wherein:
n9 is 1 or 2; n10 is 0 or 1 provided that n9+n10 are 1 or 2; P is an aryl or heteroaryl ring which optionally attaches the ligand to a linker; P″ is a single bond or an alkylene group; S is a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the P and S attaches the ligand to a linker; (5) a compound of formula (e): 681wherein:
R16 is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker; R17, R18, and R19 are, independently of each other, hydrogen, alkyl, alkoxy, hydroxy, carbamoyl, sulfanoyl, halo, or a covalent bond attaching the ligand to a linker; R20 and R21 are, independently of each other, hydrogen, alkyl or a covalent bond attaching the ligand to a linker; or R20 and R21 together with the nitrogen atom to which they are attached form a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the R16, R17, R18, R19, R20, and R21 attaches the ligand to a linker; or (6) a compound of formula (f): 682wherein:
R22 is hydrogen or halo; R23 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclylalkyl; R24 is hydroxy, halo, or a covalent bond attaching the ligand to a linker; R25 and R26 are, independently of each other, hydrogen, alkyl, aralkyl, or a covalent bond attaching the ligand to a linker, or R25 and R26 together with the nitrogen atom to which they are attached form a heterocycloamino group which optionally attaches the ligand to a linker provided that at least one of the R24, R25, and R26 attaches the ligand to a linker; each ligand, L, that is an allosteric modulator of a muscarinic receptor is independently selected from a group consisting of: (7) a compound of formula (g): 683wherein:
D″ is alkylene; D is —NR31R32, —N+(R33R34R35) or —OR32 where R31, R33, and R34 are, independently of each other, hydrogen, alkyl, or aralkyl; and R32 and R35 represent a covalent bond attaching the ligand to a linker; R27 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R28 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R29 and R30 are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono-or dialkylamino; or one of R27, R28, R29, or R30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group; and (8) a compound of formula (h): 684wherein:
n11 is an integer of from 1 to 7; n12 is an integer of from 0 to 7; F is —NR40—, —O—, —S—, or —CHR41— (wherein R40 and R41 are, independently of each other, hydrogen or alkyl); F″ is a covalent bond, —OR43, —NR42R43, or —N+R43R44R45 wherein 42 is hydrogen or alkyl, R44 and R45 are alkyl, and R43 is a covalent bond attaching the ligand to a linker; R36 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R37 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; and R38 is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R38 and R43 attaches the ligand to a linker; and each linker independently has the formula: —Xa—Z—(Ya—Z)m—Yb—Z—Xa—wherein: m is an integer of from 0 to 20; Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Ya and Yb at each separate occurrence are selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)n—, —C(O)NR′—, —NR′ C(O)—, —NR′ C(O)NR′—, —NR′ C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—, —N═C(Xa)—NR′—, —NR′—C(Xa)═N—, —P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O)nCR′ R″—, —S(O)n—NR′—, —NR′—S(O)n—, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.
- 6. The multibinding compound of claim 5 wherein p is 2 and q is 1.
- 7. A bivalent multibinding compound of formula:
- 8. The multibinding compound of claim 7 wherein:
La is a compound of formula (a): 695wherein:
A is an phenyl; B″ is —CH2—, —O— or —NH—; R1 is hydrogen; R2 is: 696where R6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; K and K″ are a bond; and B is:
(i) pyrrolidine, piperidine, 4-methylpiperidine, or hexahydroazepine where the nitrogen atom in said rings attaches the ligand to a linker; Lb is selected from a group consisting of: (1) a compound of formula (g): 697wherein:
D″ is alkylene; D is —NR31R32 or —N+(R33R34R35) where R31, R33, and R34 are, independently of each other, hydrogen or alkyl; and R32 and R35 represent a covalent bond attaching the ligand to a linker; (2) a compound of formula (h): 698wherein:
n12 is 2 to 7; F″ is —NR42R43 or —N+R43R44R45 wherein R42 is hydrogen or alkyl, R44 and R45 are alkyl, and R43 is a covalent bond attaching the ligand to a linker; and R36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, amino, or substituted amino; and (3) a compound of formula (i): 699wherein:
R46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle; R47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR49 where R49 is alkyl; or R46 and R47 together with the nitrogen atom to which they are attached form heterocycle; R48 is a covalent bond that attaches the ligand to a linker; R49 is alkyl.
- 9. The multibinding compound of claim 8 wherein La is selected from the group consisting of:
- 10. The multibinding compound of claim 8 wherein Lb is selected from the group consisting of:
- 11. The multibinding compound of claim 8 wherein X is selected from the group consisting of:
- 12. The multibinding compound of claim 7 wherein:
La is a compound of formula (b): 719wherein: C is an aryl or heteroaryl ring; R9 is hydrogen, hydroxy, aminocarbonyl which optionally links the ligand to a linker via the amino group, alkyl optionally substituted with one, two or three substituents selected from hydroxy, carboxy, alkoxycarbonyl, amino, and substituted amino, or R9 is a covalent bond attaching the ligand to a linker; R10 is hydrogen, aryl, or cycloalkyl; Q is a single bond, —O—, —COCH2—, —C(O)NH—, —NHC(O)O—, —NHC(O)NH—, or —C(O)O—; Q″ is selected from the group consisting of:
(i) monoaalkylaminoalkyl, monoalkylaminoalkenyl, monoalkylaminoalkynyl wherein the amino group optionally links the ligand to a linker; (ii) carboxy which optionally links the ligand to a linker; (iii) a group of formula (iv): 720where: E is a covalent bond attaching the ligand to a linker, or —CH2—W—R11 wherein W is alkylene; and R11 is: 721and
(iv) a group of formula: 722wherein: n6 is 0 or 1; R14 is a covalent bond attaching the ligand to a linker; R51 is hydrogen or alkyl; and J is —(CH2)2—: provided that at least one of the R9 and Q″ group attaches the ligand to a linker; Lb is selected from a group consisting of: (1) a compound of formula (g): 723wherein: D″ is alkylene; D is —NR31R32 or —N+(R33R34R35) where R31, R33, and R34 are, independently of each other, hydrogen or alkyl; and R32 and R35 represent a covalent bond attaching the ligand to a linker; (2) a compound of formula (h): 724wherein: n12 is 2 to 7; F″ is —NR42R43 or —N+R43R44R45 wherein R42 is hydrogen or alkyl, R44 and R45 are alkyl, and R43 is a covalent bond attaching the ligand to a linker; and R36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, amino, or substituted amino; and (3) a compound of formula (i): 725wherein: R46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle; R47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR49 where R49 is alkyl; or R46 and R47 together with the nitrogen atom to which they are attached form heterocycle; R48 is a covalent bond that attaches the ligand to a linker; and R49 is alkyl.
- 13. The multibinding compound of claim 12 wherein:
La is a compound of formula (b): 726wherein:
C is phenyl, 2-hydroxy-5-methylphenyl, or pyridine; R9 is hydrogen, hydroxy, aminocarbonyl which optionally links the ligand to a linker via the amino group, or hydroxymethyl; R10 is hydrogen, phenyl, cyclopentyl, or cyclohexyl; Q is a single bond, —O—, —COCH2—, —C(O)NH—, —NHC(O)O—, —NHC(O)NH—, or —C(O)O—; Q″ is selected from the group consisting of:
(i) 2-N-methylaminoethyl, 2-N-ethylaminoethyl, 3-methylaminobutyl, 2-N-isopropylaminoethyl, 4-ethylaminobutyn-1-yl, or 5-N-ethylamino-2-methylpentyn-2-yl wherein the nitrogen atom of the amino group links the ligand to a linker; (ii) carboxy which links the ligand to a linker; (iii) a group of formula (iv): 727where: E is a covalent bond attaching the ligand to a linker, or —CH2—W—R11 wherein W is —CH2—; and R11 is: 728and
(iv) a group of formula: 729wherein: n6 is 0 or 1; R14 is a covalent bond attaching the ligand to a linker; R51 is hydrogen or methyl; and J is —(CH2)2—:
provided that at least one of the R9 and Q″ group attaches the ligand to a linker; Lb is an allosteric modulator of a muscarinic receptor and is selected from a group consisting of: (1) a compound of formula (g): 730wherein:
D″ is alkylene; D is —NR31R32 or —N+(R33R34R35) where R31, R33, and R34 are, independently of each other, hydrogen or alkyl; and R32 and R35represent a covalent bond attaching the ligand to a linker; (4) a compound of formula (h): 731wherein:
n12 is 2 to 7; F″ is —NR42R43 or —N+R43R44R45 wherein R42 is hydrogen or alkyl, R44 and R45 are alkyl, and R43 is a covalent bond attaching the ligand to a linker; and R36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, amino, or substituted amino; and (5) a compound of formula (i): 732wherein:
R46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle; R47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR49 where R49 is alkyl; or R46 and R47 together with the nitrogen atom to which they are attached form heterocycle; R48 is a covalent bond that attaches the ligand to a linker; R49 is alkyl.
- 14. The multibinding compound of claim 13 wherein La is selected from the group consisting of:
- 15. The multibinding compound of claim 13 wherein:
Lb is selected from the group consisting of: 737738739740741742743744745746747748749750751752753wherein the nitrogen atom of the secondary aliphatic amino group is attached to a linker via a covalent bond and is optionally substituted with a methyl group to form a quaternary ammonium salt.
- 16. The multibinding compound of claim 13 wherein X is selected from the group consisting of:
- 17. A multibinding compound of formula:
- 18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of Formula (I):
- 19. The pharmaceutical composition of claim 18 wherein each ligand that is a muscarinic receptor antagonist is independently selected from a group consisting of:
(1) a compound of formula (a): 767wherein:
A is an aryl or a heteroaryl ring; B″ is —CH2—, —O— or —NRa — where Ra is hydrogen, alkyl, or substituted alkyl; R1 is hydrogen or alkyl; R2 is selected from a group consisting of formula (i), (ii), (iii), or “Het”: 768wherein: - - - - - is an optional double bond; n1 is an integer of from 1 to 4; n2 is an integer of from 1 to 3; V is —CH—, —O—, —S(O)n3— (where n3 is an integer of from 0 to 2), or —NR4— (wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl); “Het” is a heteroaryl ring which optionally attaches the ligand to a linker; R3 is hydrogen, alkyl, amino, substituted amino, —ORa (where Ra is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker; R5 is hydrogen, alkyl, amino, substituted amino, —ORb (where Rb is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand to a linker; R6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; K is a bond or an alkylene group; K″ is a bond, —C(O)—, —S(O)n4— (where n4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and B is a heterocycloarnino group which optionally attaches the ligand to a linker; provided that at least one of the R5, R6, R7, R8, “Het”, or the heterocycloamino group attaches the ligand to a linker; (2) a compound of formula (b): 769wherein:
C is an aryl or heteroaryl ring which optionally attaches the ligand to a linker; R9 is hydrogen, hydroxy, cyano, aminocarbonyl which optionally links the ligand to a linker, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; R10 is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; Q is a single bond, —O—, —COCH2—, —C(O)NH—, —NHC(O)O—, —NHC(O)NH—, or —C(O)O—; Q″ is selected from the group consisting of:
(i) monoaalkylaminoalkyl, monoalkylaminoalkenyl, monoalkylaminoalkynyl wherein the amino group optionally links the ligand to a linker; (ii) carboxy which optionally links the ligand to a linker; (iii) a group of formula (iv): 770where: E is hydrogen, a covalent bond attaching the ligand to a linker, or —CH2—W—R11 wherein W is a single bond or alkylene wherein one of the carbon atoms may optionally be replaced by —O—, —S—, or —NRg— (wherein Rg is hydrogen or alkyl); and R11 is a group of formula (v), (vi), or “Het”: 771wherein: - - - - - is an optional bond; T and U are, independently of each other, —O— or —CH2—; n5 is an integer of from 1 to 3; and “Het” is heteroaryl; and
(iv) a group of formula (vii), (viii) or (ix): 772wherein: n6 is 0 or 1; M− is a counterion; R12 is a covalent bond attaching the ligand to a linker; R13 is alkyl, alkenyl, cycloalkyl, or a covalent bond attaching the ligand to a linker; R14 is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker; R51 is hydrogen or alkyl; and J is: 773provided that at least one of the C, R9, R10, and Q″ attaches the ligand to a linker; (3) a compound of formula (c): 774wherein:
G′ is pyrrolidine, piperidine, or 775wherein said G′ groups optionally attach the ligand to a linker; n7 is an 0 or 1, provided that when the nitrogen atom of the quinuclidine ring attaches the ligand to the linker then n7 is 0; n8 is 1 or 2; g is an integer of from 0 to 3. each R15 is, independently of each other, hydrogen, halogen, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, methylenedioxy, ethylenedioxy, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino, or a covalent bond attaching the ligand to a linker; G is aryl, heteroaryl, heterocyclyl, or cycloalkyl which optionally attach the ligand to a linker; and G″ is a single-bond or an alkylene group provided that at least one of the R15, G, G′, and G″ attaches the ligand to a linker; (4) a compound of formula (d): 776wherein:
n9 is 1 or 2; n10 is 0 or 1 provided that n9+n10 is 1 or 2; P is an aryl or heteroaryl ring which optionally attaches the ligand to a linker; P″ is a single bond or an alkylene group; S is a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the P and S attaches the ligand to a linker; (5) a compound of formula (e): 777wherein:
n14 is 0, 1, or 2; n52 is 0 or 1; R16 is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker; R17, R18, and R19 are, independently of each other, hydrogen, alkyl, alkoxy, hydroxy, carbamoyl, sulfanoyl, halo, or a covalent bond attaching the ligand to a linker; R20 and R21 are, independently of each other, hydrogen, alkyl or a covalent bond attaching the ligand to a linker; or R20 and R21 together with the nitrogen atom to which they are attached form a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the R16, R17, R18, R19, R20, and R21 attaches the ligand to a linker; or (6) a compound of formula (f): 778wherein:
R22 is hydrogen or halo; R23 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclylalkyl; R24 is hydroxy, halo, or a covalent bond attaching the ligand to a linker; R25 and R26 are, independently of each other, hydrogen, alkyl, aralkyl, or a covalent bond attaching the ligand to a linker, or R25 and R26 together with the nitrogen atom to which they are attached form a heterocycloamino group which optionally attaches the ligand to a linker provided that at least one of the R24, R25, and R26 attaches the ligand to a linker; and each ligand, L, that is an allosteric modulator of a muscarinic receptor in the multibinding compound of Formula (I) is independently selected from a group consisting of: (7) a compound of formula (g): 779wherein:
D″ is alkylene; D is —NR31R32, —N+(R33R34R35) or —OR32 where R31, R33, and R34 are, independently of each other, hydrogen, alkyl, or aralkyl; and R32 and R35 represent a covalent bond attaching the ligand to a linker; R27 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R28 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R29 and R30 are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono-or dialkylamino; or one of R27, R28, R29, or R30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group; (8) a compound of formula (h): 780wherein:
n11 is an integer of from 1 to 7; n12 is 0 to 7; F is —NR40—, —O—, —S—, or —CHR41— (wherein R40 and R41 are, independently of each other, hydrogen, alkyl, or substituted alkyl); F″ is a covalent bond, —OR43, —NR42R43 or —N+R43R44R45 wherein R42 is hydrogen or alkyl, R44 and R45 are alkyl, and R43 is a covalent bond attaching the ligand to a linker; R36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R37 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R38 is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R38 and R43 attaches the ligand to a linker; and R39 is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; and (9) a compound of formula (i): 781wherein:
R46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle; R47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR49 where R49 is alkyl; or R46 and R47 together with the nitrogen atom to which they are attached form heterocycle; R48 is a covalent bond that attaches the ligand to a linker; R49 is alkyl; each X is independently of each other a compound of formula: —Xa—Z—(Ya—Z)m—Yb—Z—Xa—wherein: m is an integer of from 0 to 20; Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Ya and Yb at each separate occurrence are selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)n—, —C(O)NR′—, —NR′ C(O)—, —NR′ C(O)NR′—, —NR′ C(S)NR′—, —C(═NR′)—NR′—, —NR′ C(═NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—, —N═C(Xa)—NR′—, —NR′—C(Xa)═N—,—P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O)nCR′ R″—, —S(O)n—NR′—, —NR′—S(O)n—, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic; and pharmaceutically acceptable salts, individual isomers, mixture of isomers, and prodrugs thereof provided that at least one of the ligands is a muscarinic receptor antagonist.
- 20. The pharmaceutical composition of claim 19 wherein p is 2 and q is 1.
- 21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of claim 7.
- 22. A method for treating diseases mediated by a muscarinic 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 comprising from 2 to 10 ligands covalently attached to one or more linkers, wherein each of said ligands, comprises, independently of each other, a muscarinic receptor antagonist or an allosteric modulator of a muscarinic receptor provided that at least one of said ligands is a muscarinic receptor antagonist, and pharmaceutically acceptable salts thereof.
- 23. A method for treating diseases mediated by a muscarinic 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 identifying multimeric ligand compounds possessing multibinding properties for a muscarinic 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 a muscarinic receptor.
- 25. A method for identifying multimeric ligand compounds possessing multibinding properties for a muscarinic 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 a muscarinic receptor.
- 26. The method according to claim 24 or 25 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).
- 27. The method according to claim 26 wherein the multimeric ligand compounds comprising the multimeric ligand compound library are dimeric.
- 28. The method according to claim 27 wherein the dimeric ligand compounds comprising the dimeric ligand compound library are heterodimeric.
- 29. The method according to claim 28 wherein the heterodimeric ligand compound library is prepared by sequential addition of a first and second ligand.
- 30. The method according to claim 24 or 25 wherein, prior to procedure (d), each member of the multimeric ligand compound library is isolated from the library.
- 31. The method according to claim 30 wherein each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS).
- 32. The method according to claim 24 or 25 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.
- 33. The method according to claim 32 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups.
- 34. The method according to claim 33 wherein the linkers are selected to have different linker lengths ranging from about 2 to 100 Å.
- 35. The method according to claim 24 or 25 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands.
- 36. The method according to claim 35 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.
- 37. The method according to claim 24 or 25 wherein the multimeric ligand compound library comprises homomeric ligand compounds.
- 38. The method according to claim 24 or 25 wherein the multimeric ligand compound library comprises heteromeric ligand compounds.
- 39. A library of multimeric ligand compounds which may possess multivalent properties for a muscarinic 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.
- 40. A library of multimeric ligand compounds which may possess multivalent properties for a muscarinic 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.
- 41. The library according to claim 39 or 40 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.
- 42. The library according to claim 41 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups.
- 43. The library according to claim 42 wherein the linkers are selected to have different linker lengths ranging from about 2 to 100 Å.
- 44. The library according to claim 39 or 40 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands.
- 45. The library according to claim 44 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.
- 46. The library according to claim 40 or 41 wherein the multimeric ligand compound library comprises homomeric ligand compounds.
- 47. The library according to claim 39 or 40 wherein the multimeric ligand compound library comprises heteromeric ligand compounds.
- 48. An iterative method for identifying multimeric ligand compounds possessing multibinding properties for a muscarinic 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 a muscarinic receptor; (c) repeating the process of (a) and (b) above until at least one multimeric compound is found to possess multibinding properties for a muscarinic 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 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.
- 49. The method according to claim 48 wherein steps (e) and (f) are repeated from 2-50 times.
- 50. The method according to claim 49 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. patent application Ser. No. 09/325,725, filed on Jun. 4, 1999 which claims the benefit of U.S. patent application No. 60/088,466, filed Jun. 8, 1998; U.S. Patent Application No. 60/092,938, filed Jul. 15, 1998; and U.S. Patent Application No. 60/120,287, filed Feb. 16, 1999; the disclosures of which are incorporated herein by reference in their entirety.
Provisional Applications (1)
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Continuations (2)
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