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EP0296522A2 Expired / Lapsed EP ⏱️ 0.0 years remaining

Functionalized polyamine chelants and rhodium complexes thereof and process for their preparation

Assignee: Dow Chemical Co
•
Filing: 1988-06-20
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Granted: —
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Expires: 2008-06-20
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Abstract

Abstract A group of functionalized polyamine chelants that form complexes with rhodium are disclosed. The rhodium complexes can be attached to an antibody or antibody fragment and used for therapeutic or diagnostic purposes.

Inventors

  • 👤 William J. Kruper Jr.
  • 👤 Douglas K. Pollock
  • 👤 William A. Fordyce
  • 👤 Michael J. Fazio
  • 👤 Muthiah N. Inbasekaran

Bibliographic Details

Application Number —
Jurisdiction EP
Data Source google_patents
Last Synchronized 2026-11-08 07:31
CPC Classifications
C; C07; C07C; C07C263/00; C07C263/10; C07D; C07D257/00; C07D257/02; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K47/6835; A61K47/6887; A61K49/00; A61K49/0002; A61K51/00; A61K51/02; A61K51/04; A61K51/08; A61K51/10; A61K51/1093; C07F; C07F15/00; C07F15/0006; C07F15/0073; C07F15/008; A61K2123/00

Claims Analysis

Total Claims: 38
Claim 1
Independent Claim 315 words
A compound of the formula: wherein: each R independently represents a straight-­chained or branched alkylene group of 2 to 10 carbon atoms inclusive, with the proviso that for any two adjacent nitrogens connected by an R group, the R group must provide at least three single bonds between the nitrogens it connects; each R¹ independently represents hydrogen or a straight-chained or branched alkylene group of 1 to 10 carbon atoms inclusive; X and X¹ represent hydrogen, or X and X¹ taken together complete a bridging straight-chained or branched alkylene group of 2 to 10 carbon atoms inclusive or a bridging aralkylene group wherein the alkylene is a straight-chained or branched alkylene group of 2 to 10 carbon atoms inclusive, with the proviso that when X and X¹ are taken together the group it represents must provide at least three single bonds between the adjacent nitrogens it connects; n is an integer of 0 or 1, provided that when the L group is bonded to the same nitrogen atom, n must be 0, otherwise n must be 1; y is an integer of 1 through 3 inclusive; and L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of, any one of the nitrogen or carbon atoms, said linker/spacer group being represented by the formula wherein: s represents an integer of 0 or 1; t represents an integer of 0 through 20 inclu­sive; R² represents 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; and 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; provided that the compound of formula I is not 3-(4-­aminobutyl)-1,5,8,12-tetraazacyclotetradecane.
Claim 2
Dependent Claim 315 words
A compound of the formula: wherein: each R independently represents a straight-­chained or branched alkylene group of 2 to 10 carbon atoms inclusive, with the proviso that for any two adjacent nitrogens connected by an R group, the R group must provide at least three single bonds between the nitrogens it connects; each R¹ independently represents hydrogen or a straight-chained or branched alkylene group of 1 to 10 carbon atoms inclusive; X and X¹ represent hydrogen, or X and X¹ taken together complete a bridging straight-chained or branched alkylene group of 2 to 10 carbon atoms inclusive or a bridging aralkylene group wherein the alkylene is a straight-chained or branched alkylene group of 2 to 10 carbon atoms inclusive, with the proviso that when X and X¹ are taken together the group it represents must provide at least three single bonds between the adjacent nitrogens it connects; n is an integer of 0 or 1, provided that when the L group is bonded to the same nitrogen atom, n must be 0, otherwise n must be 1; y is an integer of 1 through 3 inclusive; and L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of, any one of the nitrogen or carbon atoms, said linker/spacer group being represented by the formula wherein: s represents an integer of 0 or 1; t represents an integer of 0 through 20 inclu­sive; R² represents 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; and 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; provided that the compound of formula I is not 3-(4-­aminobutyl)-1,5,8,12-tetraazacyclotetradecane.
Claim 3
Dependent Claim 27 words
The compound of Claim 1 wherein L is R² and s are defined as in Claim 1; and t is an integer of 0 through 6 inclusive.
Claim 4
Dependent Claim 48 words
The compound of Claim 1 or 2 wherein R is an alkylene group having 2 or 3 carbon atoms; R¹ is hydrogen or methyl; X and X¹ represent hydrogen, or X and X¹ taken together represent a benzyl or an alkylene group having 2 or 3 carbon atoms.
Claim 5
Dependent Claim 14 words
The compound of Claim 3 wherein R² is isothiocyanate, semicarbazide, thiosemicarbazide, amino, or carboxyl.
Claim 6
Dependent Claim 11 words
The compound of Claim 4 wherein y is the integer 1.
Claim 7
Dependent Claim 8 words
The compound of Claim 1 which is 3-[4-­-(aminophenyl)methyl]-1,5,8,12-tetraazacyclotetradecane.
Claim 8
Dependent Claim 8 words
The compound of Claim 1 which is 6-[4-­-(aminophenyl)methyl]-1,4,8,11-tetraazaundecane.
Claim 9
Dependent Claim 8 words
The compound of Claim 1 which is 6-(3-­-aminopropyl)-1,4,8,11-tetraazaundecane.
Claim 10
Dependent Claim 8 words
The compound of Claim 1 which is 1,4,7,10-­-tetraaza-1-[(4-aminophenyl)methyl]cyclododecane.
Claim 11
Dependent Claim 8 words
The compound of Claim 1 which is 3-[4-­(aminophenyl)methyl]-1,5,8,12-tetraaza-2,4,9-trioxo­cyclotetradecane.
Claim 12
Dependent Claim 8 words
The compound of Claim 1 which is 3-[4-­(aminophenyl)methyl]-1,5,8,12-tetraaza-2,4,9,11-­-tetraoxocyclotetradecane.
Claim 13
Dependent Claim 8 words
The compound of Claim 1 which is 6-[4-­(aminophenyl)methyl]-1,4,8,11-tetraaza-5,7-dioxoundecane.
Claim 14
Dependent Claim 313 words
A rhodium complex which comprises rhodium complexed with a compound of the formula: wherein: each R independently represents a straight-­chained or branched alkylene group of 2 to 10 carbon atoms inclusive, with the proviso that for any two adjacent nitrogens connected by an R group, the R group must provide at least three single bonds between the nitrogens it connects. each R¹ independently represents hydrogen or a straight-chained or branched alkylene group of 1 to 10 carbon atoms inclusive; X and X¹ represent hydrogen, or X and X¹ taken together complete a bridging straight-chained or branched alkylene group of 2 to 10 carbon atoms inclusive or a bridging aralkylene group wherein the alkylene is a straight-chained or branched alkylene group of 2 to 10 carbon atoms inclusive with the proviso that when X and X¹ are taken together the group it represents must provide at least three single bonds between the adjacent nitrogens it connects; n is an integer of 0 or 1, provided that when the L group is bonded to the same nitrogen atom, n must be 0, otherwise n must be 1; y is an integer of 1 through 3 inclusive; and L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of, any one of the nitrogen or carbon atoms, said linker/spacer group being represented by the formula wherein: s represents an integer of 0 or 1; t represents an integer of 0 through 20 inclu­sive; R² represents 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; and 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.
Claim 15
Dependent Claim 313 words
A rhodium complex which comprises rhodium complexed with a compound of the formula: wherein: each R independently represents a straight-­chained or branched alkylene group of 2 to 10 carbon atoms inclusive, with the proviso that for any two adjacent nitrogens connected by an R group, the R group must provide at least three single bonds between the nitrogens it connects. each R¹ independently represents hydrogen or a straight-chained or branched alkylene group of 1 to 10 carbon atoms inclusive; X and X¹ represent hydrogen, or X and X¹ taken together complete a bridging straight-chained or branched alkylene group of 2 to 10 carbon atoms inclusive or a bridging aralkylene group wherein the alkylene is a straight-chained or branched alkylene group of 2 to 10 carbon atoms inclusive with the proviso that when X and X¹ are taken together the group it represents must provide at least three single bonds between the adjacent nitrogens it connects; n is an integer of 0 or 1, provided that when the L group is bonded to the same nitrogen atom, n must be 0, otherwise n must be 1; y is an integer of 1 through 3 inclusive; and L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of, any one of the nitrogen or carbon atoms, said linker/spacer group being represented by the formula wherein: s represents an integer of 0 or 1; t represents an integer of 0 through 20 inclu­sive; R² represents 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; and 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.
Claim 16
Dependent Claim 44 words
A rhodium complex of Claim 13, which comprises rhodium complexed with the compound of formula I as defined in Claim 13 wherein L is wherein: R² and s are defined as in Claim 13; and t is an integer of 0 through 6 inclusive.
Claim 17
Dependent Claim 65 words
A rhodium complex of Claim 13 or 14 which comprises rhodium complexed with the compound of formula I as defined in Claim 13 wherein R is an alkylene group having 2 or 3 carbon atoms; R¹ is a hydrogen or methyl; X and X¹ represent hydrogen, or X and X¹ taken together represent a benzyl or an alkylene group having 2 or 3 carbon atoms.
Claim 18
Dependent Claim 27 words
A rhodium complex of Claim 15 which comprises rhodium complexed with the compound of formula I as defined in Claim 12 wherein y is the integer 1.
Claim 19
Dependent Claim 30 words
A rhodium complex of Claim 15 which comprises rhodium complexed with the compound of formula I as defined in Claim 12 wherein R² is isothiocyanate, semicarbazide, thiosemicarbazide, amino, or carboxyl.
Claim 20
Dependent Claim 16 words
A rhodium complex of Claim 13 which comprises rhodium complexed with 3-[4-(amino­phenyl)methyl]-1,5,8,12-tetraazacyclotetradecane, 6-[4-­-(aminophenyl)methyl]-1,4,8,11-tetraazaundecane, 6-(3-­-aminopropyl)-1,4,8,11-tetraazaundecane, or 1,4,7,10-­-tetraaza-1-[(4-aminophenyl)methyl]cyclododecane.
Claim 21
Dependent Claim 15 words
A rhodium complex of Claim 13 which comprises rhodium complexed with 3-[4-(amino­phenyl)methyl]-1,5,8,12-tetraaza-2,4,9-trioxocyclo­tetradecane, 3-[4-(aminophenyl)methyl]-1,5,8,12-tetraaza-­2,4,9,11-tetraoxocyclotetradecane, or 6-[4-(amino­phenyl)methyl]-1,4,8,11-tetraaza-5,7-dioxoundecane.
Claim 22
Dependent Claim 87 words
A rhodium complex of the formula [RhChP₁P₂]A      (II) wherein: Rh represents a rhodium atom; Ch represents a compound of formula I as defined in Claim 13; P₁ and P₂ each represent the same or different monodentate ligand, or P₁ and P₂ taken together represent a bidentate ligand; provided, however, that: (a) if y is 2 then P₂ is absent, or (b) if y is 3 then P₁ and P₂ are absent; and A represents one or more anions of sufficient charge to render the rhodium complex neutral.
Claim 23
Dependent Claim 20 words
The rhodium complex of Claim 13 or 20 in which at least a portion of the rhodium is radioactive rhodium.
Claim 24
Dependent Claim 18 words
The rhodium complex of Claim 13 or 20 wherein at least a portion of the rhodium is ¹⁰⁵Rh.
Claim 25
Dependent Claim 15 words
The rhodium complex of Claim 20 wherein the compound is 3-[4-(aminophenyl)methyl]-1,5,8,12-tetraaza­cyclotetradecane, 6-[4-(aminophenyl)methyl]-1,4,8,11-­tetraazaundecane, 6-(3-aminopropyl)-1,4,8,11-tetraaza­undecane, or 1,4,7,10-tetraaza-1-[(4-aminophenyl)methyl]-­cyclododecane.
Claim 26
Dependent Claim 11 words
The rhodium complex of Claim 20 which is [Rh(BA-2,3,2-tet)Cl₂]Cl·HCl or [Rh(BA-cyclam)Cl₂]Cl·HCl.
Claim 27
Dependent Claim 12 words
The rhodium complex of Claim 13 covalently attached to a polymeric support.
Claim 28
Dependent Claim 22 words
A rhodium chelate/antibody conjugate which comprises the rhodium complex of Claim 21 or 22 covalently attached to an antibody or antibody fragment.
Claim 29
Dependent Claim 19 words
The rhodium chelate/antibody conjugate of Claim 25 wherein the antibody or antibody fragment is B72.3, CC-49, or CC-49 (Fab′)₂.
Claim 30
Dependent Claim 20 words
The rhodium chelate/antibody conjugate of Claim 26 wherein the antibody or antibody fragment is a monoclonal antibody or fragment thereof.
Claim 31
Dependent Claim 17 words
A rhodium chelate/antibody composition comprising the rhodium chelate/antibody conjugate of Claim 26 and a pharmaceutically acceptable carrier.
Claim 32
Dependent Claim 15 words
The rhodium chelate/antibody composition of Claim 28 wherein the pharmaceutically acceptable carrier is a liquid.
Claim 33
Dependent Claim 27 words
A method for the diagnosis or treatment of a disease state in a mammal by the administration of the composition of Claim 26, 27, 28 or 29.
Claim 34
Dependent Claim 11 words
The method of Claim 31 wherein the disease state is cancer.
Claim 35
Dependent Claim 16 words
The rhodium chelate/antibody conjugate of Claim 26, 27, or 28 for use in diagnosis or treatment.
Claim 36
Dependent Claim 13 words
The rhodium chelate/antibody composition of Claim 29 for use in diagnosis or treatment.
Claim 37
Dependent Claim 141 words
A process for preparing a rhodium complex of the formula [RhChP₁P₂]A      (II) wherein: Rh represents a rhodium atom; Ch represents a compound of formula I as defined in Claim 13; P₁ and P₂ each represent the same or different monodentate ligand or, if taken together, a bidentate ligand (P, P₂); provided, however, that: (a) P₂ is absent if y is 2 in the compound of formula I as defined in Claim 13; and (b) P₁ and P₂ are absent if y is 3 in formula I as defined in Claim 13; and A represents one or more anions of sufficient charge to render the complex neutral; which comprises reacting RhA·nH₂O wherein: A is defined as above; n is an integer from 0 to the number required to form the hydrate; with ChP₁P₂ wherein: Ch, P₁ and P₂ are defined as above.
Claim 38
Dependent Claim 23 words
The process of Claim 35 wherein the reaction is conducted at reflux, in an aqueous solution, and at a pH of about 7.

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