EP0353450A1 — Macrocyclic bifunctional chelants, complexes ther…

Claim 1

Independent Claim 288 words

A compound of the formula wherein: each Q is independently hydrogen or (CHR⁵) p CO₂R; Q¹ is hydrogen or (CHR⁵) w CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of the sum of Q and Q¹ must be other than hydrogen; each R⁵ independently is hydrogen or C₁-C₄ alkyl; X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond; n is 0 or 1; m is an integer from 0 to 10 inclusive; p = 1 or 2; r = 0 or 1; w = 0 or 1; with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1; L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula wherein: s is an integer of 0 or 1; t is an integer of 0 to 20 inclusive; R¹ is an electrophilic or nucleophilic moiety which allows for covalent attachment to an antibody or fragment thereof, or a synthetic linker which can be attached to an antibody or fragment thereof, or a precursor thereof; and Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to an antibody or antibody fragment; with the proviso that when s, t, m, r and n are 0, then R¹ is other than carboxyl; or a pharmaceutically acceptable salt thereof,.

Claim 2

Dependent Claim 288 words

A compound of the formula wherein: each Q is independently hydrogen or (CHR⁵) p CO₂R; Q¹ is hydrogen or (CHR⁵) w CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of the sum of Q and Q¹ must be other than hydrogen; each R⁵ independently is hydrogen or C₁-C₄ alkyl; X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond; n is 0 or 1; m is an integer from 0 to 10 inclusive; p = 1 or 2; r = 0 or 1; w = 0 or 1; with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1; L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula wherein: s is an integer of 0 or 1; t is an integer of 0 to 20 inclusive; R¹ is an electrophilic or nucleophilic moiety which allows for covalent attachment to an antibody or fragment thereof, or a synthetic linker which can be attached to an antibody or fragment thereof, or a precursor thereof; and Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to an antibody or antibody fragment; with the proviso that when s, t, m, r and n are 0, then R¹ is other than carboxyl; or a pharmaceutically acceptable salt thereof,.

Claim 3

Dependent Claim 27 words

A compound of Claim 1 wherein the pharmaceutically acceptable salt is selected from the group consisting of potassium, sodium, lithium, ammonium, calcium, magnesium, and hydrogen chloride adducts.

Claim 4

Dependent Claim 12 words

A compound of Claim 1 wherein R and R⁵ are both hydrogen.

Claim 5

Dependent Claim 16 words

A compound of Claim 1 wherein R is hydrogen, R⁵ is methyl and w is 0.

Claim 6

Dependent Claim 18 words

A compound of Claim 1 wherein n and r are both 0 and m is 0 through 5.

Claim 7

Dependent Claim 96 words

A compound of the formula: wherein: X, Y, Q, Q¹, n, m, and r are defined as in Claim 1; R² is selected from the group consisting of hydrogen, nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; R³ is selected from the group consisting of C₁-C₄ alkoxy, -OCH₂CO₂H, hydroxy and hydrogen; R⁴ is selected from the group consisting of hydrogen, nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; with the proviso that R² and R⁴ cannot both be hydrogen but one of R² and R⁴ must be hydrogen; or a pharmaceutically acceptable salt thereof.

Claim 8

Dependent Claim 11 words

A compound of Claim 6 wherein R³ and R⁴ are hydrogen.

Claim 9

Dependent Claim 132 words

A compound of Claim 6 having the formula wherein: each Q is independently hydrogen or CHR⁵CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of Q must be other than hydrogen; m is an integer from 0 to 5 inclusive; R² is selected from the group consisting of hydrogen, nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; R³ is selected from the group consisting of C₁-C₄ alkoxy, -OCH₂CO₂H, hydroxy and hydrogen; R⁴ is selected from the group consisting of hydrogen, nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; each R⁵ independently is hydrogen or C₁-C₄ alkyl; with the proviso that R² and R⁴ cannot both be hydrogen but one of R² and R⁴ must be hydrogen; or a pharmaceutically acceptable salt thereof.

Claim 10

Dependent Claim 72 words

A compound of Claim 8 having the formula wherein: each Q is independently hydrogen or CHR⁵CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of Q must be other than hydrogen; m is an integer from 0 to 5 inclusive; R² is selected from the group consisting of nitro, amino, isothiocyanato, and semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; or a pharmaceutically acceptable salt thereof.

Claim 11

Dependent Claim 14 words

The compound of Claim 9 which is 1-[2-(4-aminophenyl)ethyl]-1 ,4,7, 10-tetraazacyclododecane-4,7,10-triacetic acid, 4,7, 10-trimethyl ester.

Claim 12

Dependent Claim 11 words

The compound of Claim 9 which is 1-[2-(4-aminophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid, hydrochloride salt.

Claim 13

Dependent Claim 10 words

The compound of Claim 9 which is 1-[2-(4-isothiocyanatophenyl)ethyl]-1 ,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid.

Claim 14

Dependent Claim 11 words

The compound of Claim 9 which is 1-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid, hydrochloride salt.

Claim 15

Dependent Claim 92 words

A compound of Claim 8 having the formula wherein: each Q is independently hydrogen or CHR⁵CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of Q must be other than hydrogen; m is an integer from 0 to 5 inclusive; R³ is selected from the group consisting of C₁-C₄ alkoxy, -OCH₂CO₂H and hydroxy; R⁴ is selected from the group consisting of nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; each R⁵ independently is hydrogen or C₁-C₄ alkyl; or a pharmaceutically acceptable salt thereof.

Claim 16

Dependent Claim 9 words

The compound of Claim 14 which is 1-(2-methoxy-5-aminobenzyl)-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid.

Claim 17

Dependent Claim 9 words

The compound of Claim 14 which is 1-(2-hydroxy-5-aminobenzyl)-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid.

Claim 18

Dependent Claim 155 words

A compound of Claim 6 having the formula wherein: each Q is independently hydrogen or CHR⁵CO₂R; Q¹ is hydrogen or (CHR⁵) w CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of the sum of Q and Q¹ must be other than hydrogen and one of Q is hydrogen; m is an integer from 0 to 5 inclusive; w is 0 or 1; R² is selected from the group consisting of hydrogen, nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; R³ is selected from the group consisting of C₁-C₄ alkoxy, -OCH₂CO₂H, hydroxy and hydrogen; R⁴ is selected from the group consisting of hydrogen, nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; each R⁵ independently is hydrogen or C₁-C₄ alkyl; with the proviso that R² and R⁴ cannot both be hydrogen but one of R² and R⁴ must be hydrogen; or a pharmaceutically acceptable salt thereof.

Claim 19

Dependent Claim 14 words

The compound of Claim 17 wherein R is hydrogen and R⁵ is C₁₋₄ alkyl.

Claim 20

Dependent Claim 131 words

A compound of Claim 6 having the formula wherein: each Q is independently hydrogen or CHR⁵CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least one Q must be other than hydrogen; m is an integer from 0 to 5 inclusive; R² is selected from the group consisting of hydrogen, nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; R³ is selected from the group consisting of C₁-C₄ alkoxy, -OCH₂CO₂H, hydroxy and hydrogen; R⁴ is selected from the group consisting of hydrogen, nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; each R⁵ independently is hydrogen or C₁-C₄ alkyl; with the proviso that R² and R⁴ cannot both be hydrogen but one of R² and R⁴ must be hydrogen; or a pharmaceutically acceptable salt thereof.

Claim 21

Dependent Claim 78 words

A compound of Claim 19 having the formula wherein: each Q is independently hydrogen or CHR⁵CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least one Q must be other than hydrogen; m is an integer from 0 to 5 inclusive; R² is selected from the group consisting of nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; each R⁵ independently is H or C₁-C₄ alkyl; or a pharmaceutically acceptable salt thereof.

Claim 22

Dependent Claim 12 words

The compound of Claim 20 which is α-[2-(4-aminophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1-(R,S)-acetic 4,7,10-tris-(R-methylacetic) acid, 1-isopropyl-4,7,10-trimethyl ester.

Claim 23

Dependent Claim 10 words

The compound of Claim 20 which is α-[2-(4-aminophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1-(R,S)-acetic 4,7,10-tris-(R-methylacetic) acid.

Claim 24

Dependent Claim 9 words

The compound of Claim 20 which is α-[2-(4-isothiocyanatophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1-(R,S)-acetic-4,7,10-tris-(R-methylacetic) acid.

Claim 25

Dependent Claim 13 words

The compound of Claim 20 which is α-[2-(4-aminophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,10-triacetic acid, mixed ammonium, potassium salt.

Claim 26

Dependent Claim 9 words

The compound of Claim 20 which is α-(4-aminophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.

Claim 27

Dependent Claim 9 words

The compound of Claim 20 which is α-(4-aminophenyl)-1,4,7,10-tetraazacyclododecane-1,4,10-triacetic acid.

Claim 28

Dependent Claim 9 words

The compound of Claim 20 which is α-(4-aminophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

Claim 29

Dependent Claim 9 words

The compound of Claim 20 which is α-(4-isothiocyanatophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

Claim 30

Dependent Claim 11 words

The compound of Claim 20 which is α-[2-(4-nitrophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, 1,4,7,10-tetramethyl ester.

Claim 31

Dependent Claim 11 words

The compound of Claim 20 which is α-[2-(4-aminophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, 1,4,7,10-tetramethyl ester.

Claim 32

Dependent Claim 9 words

The compound of Claim 20 which is α-[2-(4-aminophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

Claim 33

Dependent Claim 9 words

The compound of Claim 20 which is α-[2-(4-isothiocyanatophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

Claim 34

Dependent Claim 92 words

A compound of Claim 6 having the formula wherein: each Q is independently hydrogen or CHR⁵CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least one Q must be other than hydrogen; m is an integer from 0 to 5 inclusive; R³ is selected from the group consisting of C₁-C₄ alkoxy, -OCH₂CO₂H, hydroxy and hydrogen; R⁴ is selected from the group consisting of nitro, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido and carboxyl; each R⁵ independently is hydrogen or C₁-C₄ alkyl; or a pharmaceutically acceptable salt thereof.

Claim 35

Dependent Claim 9 words

The compound of Claim 32 which is α-(2-methoxy-5-nitrophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

Claim 36

Dependent Claim 11 words

The compound of Claim 32 which is α-(2-methoxy-5-aminophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, tetraamonium salt.

Claim 37

Dependent Claim 11 words

The compound of Claim 32 which is α-(2-methoxy-5-isothiocynatophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, tetraamonium salt.

Claim 38

Dependent Claim 322 words

A complex which comprises a compound of the formula wherein: each Q is independently hydrogen or (CHR⁵) p CO₂R; Q¹ is hydrogen or (CHR⁵) w CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of the sum of Q and Q¹ must be other than hydrogen; each R⁵ independently is hydrogen or C₁-C₄ alkyl; X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond; n is 0 or 1; m is an integer from 0 to 10 inclusive; p = 1 or 2; r = 0 or 1; w = 0 or 1; with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1; L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula wherein: s is an integer of 0 or 1; t is an integer of 0 to 20 inclusive; R¹ is an electrophilic or nucleophilic moiety which allows for covalent attachment to an antibody or fragment thereof, or a synthetic linker which can be attached to an antibody or fragment thereof, or precursor thereof; and Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to an antibody or antibody fragment; with the proviso that when s, t, m, r and n are 0, then R¹ is other than carboxyl; or a pharmaceutically acceptable salt thereof; complexed with an ion of a metal selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y and Sc.

Claim 39

Dependent Claim 322 words

A complex which comprises a compound of the formula wherein: each Q is independently hydrogen or (CHR⁵) p CO₂R; Q¹ is hydrogen or (CHR⁵) w CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of the sum of Q and Q¹ must be other than hydrogen; each R⁵ independently is hydrogen or C₁-C₄ alkyl; X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond; n is 0 or 1; m is an integer from 0 to 10 inclusive; p = 1 or 2; r = 0 or 1; w = 0 or 1; with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1; L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula wherein: s is an integer of 0 or 1; t is an integer of 0 to 20 inclusive; R¹ is an electrophilic or nucleophilic moiety which allows for covalent attachment to an antibody or fragment thereof, or a synthetic linker which can be attached to an antibody or fragment thereof, or precursor thereof; and Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to an antibody or antibody fragment; with the proviso that when s, t, m, r and n are 0, then R¹ is other than carboxyl; or a pharmaceutically acceptable salt thereof; complexed with an ion of a metal selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y and Sc.

Claim 40

Dependent Claim 14 words

A complex of Claim 36 wherein the metal ion is Sm, Lu or Y.

Claim 41

Dependent Claim 21 words

A complex of Claim 36 wherein the metal ion is ¹⁵³Sm, ¹⁶⁶Ho, ⁹⁰Y, ¹⁴⁹Pm, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁷⁷Lu, ¹⁷⁵Yb, ⁴⁷Sc, or ¹⁴²Pr.

Claim 42

Dependent Claim 14 words

A complex of Claim 38 wherein the metal ion is ¹⁵³Sm, ¹⁷⁷Lu or ⁹⁰Y.

Claim 43

Dependent Claim 22 words

A complex of any one of Claims 36 through 39 wherein the metal ion is complexed with the compound of Claim 6.

Claim 44

Dependent Claim 22 words

A complex of any one of Claims 36 through 39 wherein the metal ion is complexed with the compound of Claim 8.

Claim 45

Dependent Claim 22 words

A complex of any one of Claims 36 through 39 wherein the metal ion is complexed with the compound of Claim 9.

Claim 46

Dependent Claim 22 words

A complex of any one of Claims 36 through 39 wherein the metal ion is complexed with the compound of Claim 14.

Claim 47

Dependent Claim 22 words

A complex of any one of Claims 36 through 39 wherein the metal ion is complexed with the compound of Claim 17.

Claim 48

Dependent Claim 22 words

A complex of any one of Claims 36 through 39 wherein the metal ion is complexed with the compound of Claim 19.

Claim 49

Dependent Claim 22 words

A complex of any one of Claims 36 through 39 wherein the metal ion is complexed with the compound of Claim 20.

Claim 50

Dependent Claim 22 words

A complex of any one of Claims 36 through 39 wherein the metal ion is complexed with the compound of Claim 32.

Claim 51

Dependent Claim 17 words

A complex of Claim 38 wherein the metal ion is complexed with the compound of Claim 27.

Claim 52

Dependent Claim 18 words

A complex of Claim 48 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 27.

Claim 53

Dependent Claim 18 words

A complex of Claim 48 wherein the metal ion is ⁹⁰Y complexed with the compound of Claim 27.

Claim 54

Dependent Claim 17 words

A complex of Claim 38 wherein the metal ion is complexed with the compound of Claim 28.

Claim 55

Dependent Claim 18 words

A complex of Claim 51 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 28.

Claim 56

Dependent Claim 17 words

A complex of Claim 38 wherein the metal ion is complexed with the compound of Claim 31.

Claim 57

Dependent Claim 18 words

A complex of Claim 53 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 31.

Claim 58

Dependent Claim 18 words

A complex of Claim 53 wherein the metal ion is ⁹⁰Y complexed with the compound of Claim 31.

Claim 59

Dependent Claim 18 words

A complex of Claim 53 wherein the metal ion is ¹⁷⁷Lu complexed with the compound of Claim 31.

Claim 60

Dependent Claim 17 words

A complex of Claim 38 wherein the metal ion is complexed with the compound of Claim 32.

Claim 61

Dependent Claim 18 words

A complex of Claim 57 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 32.

Claim 62

Dependent Claim 18 words

A complex of Claim 57 wherein the metal ion is ⁹⁰Y complexed with the compound of Claim 32.

Claim 63

Dependent Claim 18 words

A complex of Claim 57 wherein the metal ion is ¹⁷⁷Lu complexed with the compound of Claim 32.

Claim 64

Dependent Claim 17 words

A complex of Claim 38 wherein the metal ion is complexed with the compound of Claim 11.

Claim 65

Dependent Claim 18 words

A complex of Claim 61 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 11.

Claim 66

Dependent Claim 17 words

A complex of Claim 38 wherein the metal ion is complexed with the compound of Claim 12.

Claim 67

Dependent Claim 18 words

A complex of Claim 63 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 12.

Claim 68

Dependent Claim 17 words

A complex of Claim 38 wherein the metal ion is complexed with the compound of Claim 34.

Claim 69

Dependent Claim 18 words

A complex of Claim 65 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 34.

Claim 70

Dependent Claim 17 words

A complex of Claim 38 wherein the metal ion is complexed with the compound of Claim 35.

Claim 71

Dependent Claim 18 words

A complex of Claim 67 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 35.

Claim 72

Dependent Claim 17 words

A complex of Claim 38 wherein the metal ion is complexed with the compound of Claim 22.

Claim 73

Dependent Claim 18 words

A complex of Claim 69 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 22.

Claim 74

Dependent Claim 18 words

A complex of Claim 69 wherein the metal ion is ⁹⁰Y complexed with the compound of Claim 22.

Claim 75

Dependent Claim 18 words

A complex of Claim 69 wherein the metal ion is ¹⁷⁷Lu complexed with the compound of Claim 22.

Claim 76

Dependent Claim 17 words

A complex of Claim 38 wherein the metal ion is complexed with the compound of Claim 23.

Claim 77

Dependent Claim 18 words

A complex of Claim 73 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 23.

Claim 78

Dependent Claim 18 words

A complex of Claim 73 wherein the metal ion is ⁹⁰Y complexed with the compound of Claim 23.

Claim 79

Dependent Claim 17 words

A complex of Claim 73 wherein the metal ion ¹⁷⁷Lu complexed with the compound of Claim 23.

Claim 80

Dependent Claim 330 words

A conjugate comprising a compound of the formula wherein: each Q is independently hydrogen or (CHR⁵) p CO₂R; Q¹ is hydrogen or (CHR⁵) w CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of the sum of Q and Q¹ must be other than hydrogen; each R⁵ independently is hydrogen or C₁-C₄ alkyl; X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond; n is 0 or 1; m is an integer from 0 to 10 inclusive; p = 1 or 2; r = 0 or 1; w = 0 or 1; with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1;; L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula wherein: s is an integer of 0 or 1; t is an integer of 0 to 20 inclusive; R¹ is an electrophilic or nucleophilic moiety which allows for covalent attachment to an antibody or fragment thereof, or a synthetic linker which can be attached to an antibody or fragment thereof, or precursor thereof; and Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to an antibody or antibody fragment; with the proviso that when s, t, m, r and n are 0, then R¹ is other than carboxyl; or a pharmaceutically acceptable salt thereof; complexed with an ion of a metal selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y and Sc; and covalently attached to an antibody or antibody fragment.

Claim 81

Dependent Claim 330 words

A conjugate comprising a compound of the formula wherein: each Q is independently hydrogen or (CHR⁵) p CO₂R; Q¹ is hydrogen or (CHR⁵) w CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of the sum of Q and Q¹ must be other than hydrogen; each R⁵ independently is hydrogen or C₁-C₄ alkyl; X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond; n is 0 or 1; m is an integer from 0 to 10 inclusive; p = 1 or 2; r = 0 or 1; w = 0 or 1; with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1;; L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula wherein: s is an integer of 0 or 1; t is an integer of 0 to 20 inclusive; R¹ is an electrophilic or nucleophilic moiety which allows for covalent attachment to an antibody or fragment thereof, or a synthetic linker which can be attached to an antibody or fragment thereof, or precursor thereof; and Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to an antibody or antibody fragment; with the proviso that when s, t, m, r and n are 0, then R¹ is other than carboxyl; or a pharmaceutically acceptable salt thereof; complexed with an ion of a metal selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y and Sc; and covalently attached to an antibody or antibody fragment.

Claim 82

Dependent Claim 20 words

The conjugate of Claim 77 wherein the metal is ¹⁵³Sm, ¹⁶⁶Ho, ⁹⁰Y, ¹⁴⁹Pm, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁷⁷Lu, ¹⁷⁵Yb, ⁴⁷Sc or ¹⁴²Pr.

Claim 83

Dependent Claim 13 words

The conjugate of Claim 78 wherein the metal is ¹⁵³Sm, ⁹⁰Y or ¹⁷⁷Lu.

Claim 84

Dependent Claim 23 words

A conjugate of any one of Claims 77 through 79 wherein the antibody or antibody fragment is a monoclonal antibody or fragment thereof.

Claim 85

Dependent Claim 20 words

A conjugate of Claim 80 wherein the antibody or antibody fragment is CC-49, CC-49 F(ab′)₂, CC-83, CC-83 F(ab′)₂ or B72.3.

Claim 86

Dependent Claim 19 words

A conjugate of any one of Claims 77 through 81 wherein the compound is as defined in Claim 6.

Claim 87

Dependent Claim 19 words

A conjugate of any one of Claims 77 through 81 wherein the compound is as defined in Claim 8.

Claim 88

Dependent Claim 19 words

A conjugate of any one of Claims 77 through 81 wherein the compound is as defined in Claim 9.

Claim 89

Dependent Claim 19 words

A conjugate of any one of Claims 77 through 81 wherein the compound is as defined in Claim 14.

Claim 90

Dependent Claim 19 words

A conjugate of any one of Claims 77 through 81 wherein the compound is as defined in Claim 17.

Claim 91

Dependent Claim 19 words

A conjugate of any one of Claims 77 through 81 wherein the compound is as defined in Claim 19.

Claim 92

Dependent Claim 19 words

A conjugate of any one of Claims 77 through 81 wherein the compound is as defined in Claim 20.

Claim 93

Dependent Claim 19 words

A conjugate of any one of Claims 77 through 81 wherein the compound is as defined in Claim 32.

Claim 94

Dependent Claim 23 words

A conjugate of any one of Claims 78 through 81 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 28.

Claim 95

Dependent Claim 23 words

A conjugate of any one of Claims 78 through 81 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 32.

Claim 96

Dependent Claim 23 words

A conjugate of any one of Claims 78 through 81 wherein the metal ion is ⁹⁰Y complexed with the compound of Claim 32.

Claim 97

Dependent Claim 23 words

A conjugate of any one of Claims 78 through 81 wherein the metal ion is ¹⁷⁷Lu complexed with the compound of Claim 32.

Claim 98

Dependent Claim 23 words

A conjugate of any one of Claims 78 through 81 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 35.

Claim 99

Dependent Claim 23 words

A conjugate of any one of Claims 78 through 81 wherein the metal ion is ¹⁵³Sm complexed with the compound of Claim 23.

Claim 100

Dependent Claim 23 words

A conjugate of any one of Claims 78 through 81 wherein the metal ion is ⁹⁰Y complexed with the compound of Claim 23.

Claim 101

Dependent Claim 23 words

A conjugate of any one of Claims 78 through 81 wherein the metal ion is ¹⁷⁷Lu complexed with the compound of Claim 23.

Claim 102

Dependent Claim 297 words

A conjugate comprising a compound of the formula wherein: each Q is independently hydrogen or (CHR⁵) p CO₂R; Q¹ is hydrogen or (CHR⁵) w CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of the sum of Q and Q¹ must be other than hydrogen; each R⁵ independently is hydrogen or C₁-C₄ alkyl; X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond; n is 0 or 1; m is an integer from 0 to 10 inclusive; p = 1 or 2; r = 0 or 1; w = 0 or 1; with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1;; L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula wherein: s is an integer of 0 or 1; t is an integer of 0 to 20 inclusive; R¹ is an electrophilic or nucleophilic moiety which allows for covalent attachment to an antibody or fragment thereof, or a synthetic linker which can be attached to an antibody or fragment thereof, or precursor thereof; and Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to an antibody or antibody fragment; with the proviso that when s, t, m, r and n are 0, then R¹ other than carboxyl; or a pharmaceutically acceptable salt thereof; covalently attached to an antibody or antibody fragment.

Claim 103

Dependent Claim 297 words

A conjugate comprising a compound of the formula wherein: each Q is independently hydrogen or (CHR⁵) p CO₂R; Q¹ is hydrogen or (CHR⁵) w CO₂R; each R independently is hydrogen, benzyl or C₁-C₄ alkyl; with the proviso that at least two of the sum of Q and Q¹ must be other than hydrogen; each R⁵ independently is hydrogen or C₁-C₄ alkyl; X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond; n is 0 or 1; m is an integer from 0 to 10 inclusive; p = 1 or 2; r = 0 or 1; w = 0 or 1; with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1;; L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula wherein: s is an integer of 0 or 1; t is an integer of 0 to 20 inclusive; R¹ is an electrophilic or nucleophilic moiety which allows for covalent attachment to an antibody or fragment thereof, or a synthetic linker which can be attached to an antibody or fragment thereof, or precursor thereof; and Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to an antibody or antibody fragment; with the proviso that when s, t, m, r and n are 0, then R¹ other than carboxyl; or a pharmaceutically acceptable salt thereof; covalently attached to an antibody or antibody fragment.

Claim 104

Dependent Claim 18 words

A conjugate of Claim 98 wherein the antibody or antibody fragment is a monoclonal antibody or fragment thereof.

Claim 105

Dependent Claim 20 words

A conjugate of Claim 99 wherein the antibody or antibody fragment is CC-49, CC-49 F(ab′)₂, CC-83, CC-83 F(ab′)₂ or B72.3.

Claim 106

Dependent Claim 19 words

A conjugate of any one of Claims 98 through 100 wherein the compound is as defined in Claim 6.

Claim 107

Dependent Claim 19 words

A conjugate of any one of Claims 98 through 100 wherein the compound is as defined in Claim 8.

Claim 108

Dependent Claim 19 words

A conjugate of any one of Claims 98 through 100 wherein the compound is as defined in Claim 9.

Claim 109

Dependent Claim 19 words

A conjugate of any one of Claims 98 through 100 wherein the compound is as defined in Claim 14.

Claim 110

Dependent Claim 19 words

A conjugate of any one of Claims 98 through 100 wherein the compound is as defined in Claim 17.

Claim 111

Dependent Claim 19 words

A conjugate of any one of Claims 98 through 100 wherein the compound is as defined in Claim 19.

Claim 112

Dependent Claim 19 words

A conjugate of any one of Claims 98 through 100 wherein the compound is as defined in Claim 20.

Claim 113

Dependent Claim 19 words

A conjugate of any one of Claims 98 through 100 wherein the compound is as defined in Claim 32.

Claim 114

Dependent Claim 21 words

A pharmaceutical formulation comprising a conjugate as claimed in any one of Claims 77 through 97 with a pharmaceutically acceptable carrier.

Claim 115

Dependent Claim 29 words

A method for the diagnosis and/or treatment of a disease state in a mammal which comprises administering to said mammal an effective amount of the formulation of Claim 109.

Claim 116

Dependent Claim 11 words

A method of Claim 110 wherein the disease state is cancer.

Macrocyclic bifunctional chelants, complexes thereof and their antibody conjugates

Abstract

Inventors

Bibliographic Details

Claims Analysis

References Cited (Backward Citations)

USPTO Annuity & Maintenance Windows

Assigned Categories & Tags

Assign Category Tag