Improvements in or relating to modified haptens useful as imaging and therapeutic agents

Claim 2

A diagnostic or therapeutic formulation which comprises as an active ingredient a compound of Formula (I): wherein R. is or R 2 is hydrogen, an amino group, -OC(̵Y), -p-phenyl-CH 2 -Y, an unsubstituted C 1 to Cso branched or straight chain alkyl group; a substituted C 1 to C 30 branched or straight chain alkyl, cycloalkyl, aryl or arylalkyl group, in which the substituents are one or more of any of: hydroxy, carboxy, = 0 , =S, -S-, -SR 4 , fluoro, chloro, bromo, iodo, amino, nitro, -SO 3 H, -NHR 3 , -NHR 4 , -N(R 3 ) 2 , -CONHRs, -COOR 3 , -S0 4 , -P0 4 , phenyl, benzyl, imidazolo, or a group of the formulae: wherein R 3 is hydrogen, a C 1 to C so straight or branched chain alkyl group, -p-phenyl-CH 2 -Y, or a non-reactive functional group; Y is EDTA, DTPA, DOTA, HETA, TRITA orTETA; R 4 is H or and, M is a metalion, or a pharmaceutically-acceptable salt thereof, associated with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.

Claim 3

A diagnostic or therapeutic formulation which comprises as an active ingredient a compound of Formula (la): wherein R 1 is in which R 2 is hydrogen; NH 2 ; an unsubstituted Ci-C3o branched or straight chain alkyl group; or a C 1 -C 30 branched or straight chain alkyl, cycloalkyl, aryl or arylalkyl group substituted by one or more substituents independently selected from the group consisting of: -OH; -COOH; =O; =S; -S-; -CI; -F; -Br; -I; -NH 2 ; -N0 2 ; -SO 3 H; -NH-R 3 ; -CONHR 3 ; -COOR 3 ; -S0 4 ; -P0 4 ; phenyl; and benzyl; R 3 is H; an alkyl group; or a non-reactive functional group; and M is a metal ion, or a pharmaceutically-acceptable salt thereof, associated with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.

Claim 4

A diagnostic or therapeutic formulation which comprises as an active ingredient a compound of Formula (la): wherein R 1 is in which R 2 is hydrogen; NH 2 ; an unsubstituted Ci-C3o branched or straight chain alkyl group; or a C 1 -C 30 branched or straight chain alkyl, cycloalkyl, aryl or arylalkyl group substituted by one or more substituents independently selected from the group consisting of: -OH; -COOH; =O; =S; -S-; -CI; -F; -Br; -I; -NH 2 ; -N0 2 ; -SO 3 H; -NH-R 3 ; -CONHR 3 ; -COOR 3 ; -S0 4 ; -P0 4 ; phenyl; and benzyl; R 3 is H; an alkyl group; or a non-reactive functional group; and M is a metal ion, or a pharmaceutically-acceptable salt thereof, associated with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.

Claim 5

A diagnostic or therapeutic formulation which comprises as an active ingredient a compound of Formula (Ib): wherein R 1 is R 2 is -p-phenyl-CH 2 -Y, -OC(̵Y), a substituted C 1 to C so branched or straight chain alkyl, cycloalkyl, aryl or arylalkyl group, in which the substituents are one or more of any of: hydroxy, - -SR 4 , -NHR 3 , -NHR 4 , -N(R 3 ) 2 , imidazolo, or a group of the formulae: wherein R 3 is -p-phenyl-CH 2 -Y, or Y is EDTA, DTPA, DOTA, HETA, TRITA or TETA; R 4 is H or and, M is a metal ion, or a pharmaceutically-acceptable salt thereof, associated with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.

Claim 6

A diagnostic or therapeutic formulation which comprises as an active ingredient a compound of Formula (Ib): wherein R 1 is R 2 is -p-phenyl-CH 2 -Y, -OC(̵Y), a substituted C 1 to C so branched or straight chain alkyl, cycloalkyl, aryl or arylalkyl group, in which the substituents are one or more of any of: hydroxy, - -SR 4 , -NHR 3 , -NHR 4 , -N(R 3 ) 2 , imidazolo, or a group of the formulae: wherein R 3 is -p-phenyl-CH 2 -Y, or Y is EDTA, DTPA, DOTA, HETA, TRITA or TETA; R 4 is H or and, M is a metal ion, or a pharmaceutically-acceptable salt thereof, associated with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.

Claim 7

A formulation as claimed in Claim 2 in which R 1 of the active ingredient is -NH(C=S)NH-R 2 in which R 2 is selected from -H, -CH 2 CH 3 , -(CH 2 ) 3 CH 3 , -(CH 2 ) 7 CH 3 , -CH 2 CH 2 0H, -CH 2 CH 2 NH 2 , -C 6 H 5 , -CH 2 C 6 H 5 , -4-(C 6 H 4 )CH 2 C0 2 H, -(CH 2 ) 2 C0 2 H, -(CH 2 ) 3 CO 2 H, -(CH 2 ) 4 CH(NHCOCH 3 )CONH 2 , -(CH 2 ) 2 NHCO(CH 2 ) 3 C0 2 H, or a pharmaceutically-acceptable salt thereof.

Claim 8

A formulation as claimed in Claim 4 in which R 2 of the active ingredient is -CH 2 CH 2 0H.

Claim 9

A formulation as claimed in Claim 3 in which R 1 of the active ingredient is -NH(C=S)NH-R 2 in which R 2 is -C 6 H 4 -CH 2 -DTPA, -CH 2 CH 2 -NH(C=S)NH-C 6 H 4 -CH 2 DTPA, or -(CH 2 ) 4 -NH(C=S)NH-C 6 H 4 -CH 2 DTPA.

Claim 10

A formulation as claimed in Claim 6 in which R 2 of the active ingredient is -C 6 H 4 -CH 2 -DTPA. 8. A formulation as claimed in Claim 3 in which the active ingredient is a compound of the Formula: X-CH 2 -CO-NH-CeH 4 -CH 2 -EDTA-M, in which X is -NH-C 6 H 4 -CH 2 -DTPA, -S(CH 2 ) 4 SCH 2 (C=O)NHC 6 H 4 CH 2 DTPA, -SCH 2 CH(OH)CH(OH)CH 2 SCH 2 (C=O)NHC 6 H 4 CH 2 DTPA, or-NHCH 2 CH(OH)CH 2 NHCH 2 (C=O)NHC 6 H 4 CH 2 DTPA.

Claim 11

A formulation as claimed in Claim 8 in which X of the active ingredient is -NH-C 6 H 4 -CH 2 -DTPA.

Claim 12

A formulation as claimed in any one of Claims 1 to 9, in which the metal ion is indium or yttrium.

Claim 13

A formulation, as claimed in Claim 10, in which the metal ion is 111 ln or 90 Y.

Claim 14

A process for preparing a formulation as claimed in any one of Claims 1 to 11 which comprises admixing a compound of Formulae (I), (la), or (Ib), or a pharmaceutically acceptable salt thereof, as defined in any one of Claims 1 to 11, with a pharmaceutically acceptable carrier, diluent or excipient therefor.

Claim 15

A kit adapted for the administration, simultaneously, sequentially, or as a complex, of an immunodiagnostic or immunotherapeutic agent, which comprises a compound of any one of Claims 1 to 11 and an antibody, or fragment thereof, said antibody or fragment capable of complexing with said compound.

Claim 16

A kit as claimed in Claim 13 in which the antibody is a monoclonal antibody, or fragment thereof.

Claim 17

A kit as claimed in Claim 13 in which the antibody is a bifunctional antibody, or fragment thereof.

Claim 18

A kit as claimed in Claim 13 in which the antibody is a chimeric antibody, or fragment thereof.

Claim 19

A kit as claimed in Claim 16 in which the antibody is a humanized antibody, or fragment thereof.

Claim 20

A kit as claimed in Claim in Claim 16 or 17 in which the antibody is a chimeric-bifunctional antibody, or fragment thereof.

Claim 21

A kit as claimed in any one of Claims 15 to 18 in which the antibody is a synthetic cross-linked antibody, or a fragment thereof.

Claim 22

A process for preparinq a compound of Formula (I) : wherein R 1 is or R 2 is hydrogen, an amino group, -p-phenyl-CH 2 -Y, an unsubstituted C 1 to C 30 branched or straight chain alkyl group; a substituted C 1 to C 30 branched or straight chain alkyl, cycloalkyl, aryl or arylalkyl group, in which the substituents are one or more of any of: hydroxy, carboxy, =O, =S,

Claim 23

A process for preparinq a compound of Formula (I) : wherein R 1 is or R 2 is hydrogen, an amino group, -p-phenyl-CH 2 -Y, an unsubstituted C 1 to C 30 branched or straight chain alkyl group; a substituted C 1 to C 30 branched or straight chain alkyl, cycloalkyl, aryl or arylalkyl group, in which the substituents are one or more of any of: hydroxy, carboxy, =O, =S,

Claim 24

-S-, -SR 4 , fluoro, chloro, bromo, iodo, amino, nitro, -SO 3 H, -NHRs, -NHR 4 , -N(R 3 ) 2 , -CONHRs, -COOR 3 , -S0 4 , -P0 4 , phenyl, benzyl, imidazolo, or a group of the formulae: wherein R 3 is hydrogen, a C 1 to C 30 straight or branched chain alkyl group, -p-phenyl-CH 2 -Y, or a non-reactive functional group; Y is EDTA, DTPA, DOTA, HETA, TRITA orTETA; R 4 is H or and, M is a metal ion, or a pharmaceutically acceptable salt thereof, which comprises, (A) in the case in which R 1 is -NH(C=S)NH-R 2 , or-NH(C=O)NH-R 2 , (1) reacting isothiocyanatobenzyl EDTA, isocyanatobenzyl EDTA, as appropriate, or a metal chelate thereof, with a compound of the formula H 2 N-R 2 , in which R 2 is as described above; or, (2) reacting a compound of the formula R 2 -N = C = S, R 2 -N = C = 0, as appropriate, or a metal chelate thereof, with a compound of the formula: EDTA-CH 2 -C 6 H 4 -(NH(C=S)NH) m -(X) n -NH 2 , or EDTA-CH 2 -CeH 4 -(NH(C=O)NH) m -(X) n -NH 2 . or a metal chelate thereof, in which X is a C 1 to C 30 branched or straight chain alkyl, aryl or arylalkyl group optionally substituted with one or more of the substituents allowed in the definition of R 2 above, and n and m, independently, are 0 or 1; (B) if R 1 is -NH(C=O)CH 2 -S-R 2 , reacting p-bromoacetamidobenzyl-EDTA ("BABE"), or a metal chelate thereof, with a compound of the formula HS-R 2 , in which R 2 is as defined above; (C) if R 1 is -NH(C=O)CH 2 -NH-R 2 , reacting p-bromoacetamidobenzyl EDTA ("BABE") with a compound of the formula H 2 N-R 2 , in which R 2 is as defined above; or, if R 1 is -NH(C=O)CH 2 -NH-R 2 in which a substituent of R 2 is NHR 4 , reacting p-bromoacetamidobenzyl-Y in which Y is EDTA, DTPA, DOTA, HETA, TRITA or TETA, or a metal chelate thereof, with a compound of the formula: EDTA-CH 2 -C 6 H 4 -NH(C=O)CH 2 -NH-X-NH 2 , or a metal chelate thereof, in which X is a C 1 to C 30 branched or straight chain alkyl, aryl, or arylalkyl group optionally substituted with one or more of the substituents allowed in the definition of R 2 , above; and, (D) if desired, salifying or preparing the metal chelate of the product obtained.

Claim 25

-S-, -SR 4 , fluoro, chloro, bromo, iodo, amino, nitro, -SO 3 H, -NHRs, -NHR 4 , -N(R 3 ) 2 , -CONHRs, -COOR 3 , -S0 4 , -P0 4 , phenyl, benzyl, imidazolo, or a group of the formulae: wherein R 3 is hydrogen, a C 1 to C 30 straight or branched chain alkyl group, -p-phenyl-CH 2 -Y, or a non-reactive functional group; Y is EDTA, DTPA, DOTA, HETA, TRITA orTETA; R 4 is H or and, M is a metal ion, or a pharmaceutically acceptable salt thereof, which comprises, (A) in the case in which R 1 is -NH(C=S)NH-R 2 , or-NH(C=O)NH-R 2 , (1) reacting isothiocyanatobenzyl EDTA, isocyanatobenzyl EDTA, as appropriate, or a metal chelate thereof, with a compound of the formula H 2 N-R 2 , in which R 2 is as described above; or, (2) reacting a compound of the formula R 2 -N = C = S, R 2 -N = C = 0, as appropriate, or a metal chelate thereof, with a compound of the formula: EDTA-CH 2 -C 6 H 4 -(NH(C=S)NH) m -(X) n -NH 2 , or EDTA-CH 2 -CeH 4 -(NH(C=O)NH) m -(X) n -NH 2 . or a metal chelate thereof, in which X is a C 1 to C 30 branched or straight chain alkyl, aryl or arylalkyl group optionally substituted with one or more of the substituents allowed in the definition of R 2 above, and n and m, independently, are 0 or 1; (B) if R 1 is -NH(C=O)CH 2 -S-R 2 , reacting p-bromoacetamidobenzyl-EDTA ("BABE"), or a metal chelate thereof, with a compound of the formula HS-R 2 , in which R 2 is as defined above; (C) if R 1 is -NH(C=O)CH 2 -NH-R 2 , reacting p-bromoacetamidobenzyl EDTA ("BABE") with a compound of the formula H 2 N-R 2 , in which R 2 is as defined above; or, if R 1 is -NH(C=O)CH 2 -NH-R 2 in which a substituent of R 2 is NHR 4 , reacting p-bromoacetamidobenzyl-Y in which Y is EDTA, DTPA, DOTA, HETA, TRITA or TETA, or a metal chelate thereof, with a compound of the formula: EDTA-CH 2 -C 6 H 4 -NH(C=O)CH 2 -NH-X-NH 2 , or a metal chelate thereof, in which X is a C 1 to C 30 branched or straight chain alkyl, aryl, or arylalkyl group optionally substituted with one or more of the substituents allowed in the definition of R 2 , above; and, (D) if desired, salifying or preparing the metal chelate of the product obtained.

Claim 26

A process as claimed in Claim 20 for preparing a compound of formula (I) in which R 1 is -NH(C=S)NH-R 2 in which R 2 is selected from -H, -CH 2 CH 3 , -(CH 2 ) 3 CH 3 , -(CH 2 ) 7 CH 3 , -CH 2 CH 2 0H, -CH 2 CH 2 NH 2 , -C 6 H 5 , -CH 2 C 6 Hs, -4-(C 6 H 4 )CH 2 CO 2 H, -(CH 2 ) 2 CO 2 H, -(CH 2 ) 3 C0 2 H, -(CH 2 ) 4 CH(NHCOCH 3 )CONH 2 , -(CH 2 ) 2 NHCO(CH 2 ) 3 CO 2 H, or a pharmaceutically-acceptable salt thereof.

Claim 27

A process as claimed in Claim 21 for preparing a compound in which R 2 is -CH 2 CH 2 0H.

Claim 28

A process as claimed in Claim 20 for preparing a compound in which R 1 is -NH(C=S)NH-R 2 in which R 2 is -C 6 H 4 -CH 2 -DTPA, -CH 2 CH 2 -NH(C=S)NH-C 6 H 4 -CH 2 DTPA, or -(CH 2 ) 4 -NH(C=S)NH-C 6 H 4 -CH 2 DTPA.

Claim 29

A process as claimed in Claim 23 for preparing a compound in which R 2 is -C 6 H 4 -CH 2 -DTPA.

Claim 30

A process as claimed in Claim 20 for preparing a compound of the Formula: X-CH 2 -CO-NH-C 6 H 4 -CH 2 -EDTA-M, in which X is -NH-C 6 H 4 -CH 2 -DTPA, -S(CH 2 ) 4 SCH 2 (C = O)NHC 6 H 4 CH 2 DTPA, -SCH2CH(OH)CH(OH)CH2SCH2(C=0)NHC6H4CH2DTPA, or-NHCH 2 CH(OH)CH 2 NHCH 2 (C=O)NHC 6 H 4 CH 2 DTPA.

Claim 31

A process as claimed in Claim 25 in which X is -NH-C 6 H 4 -CH 2 -DTPA.

Claim 32

A process as claimed in any one of Claims 20 to 25 in which the metal ion is indium or yttrium.

Claim 33

A process as claimed in Claim 27, in which the metal ion is 111 ln or 9 °Y.

Claim 34

A process as claimed in any one of Claims 20 to 28 in which the pH of the reaction is between about 6 and about 12.

Claim 35

A process as claimed in Claim 29 in which the pH of the reaction is between about 8 and about 11.

Claim 36

A process as claimed in Claim 30 in which the temperature of the reaction is between about 0° C. and about 60° C.

Claim 37

A process as claimed in Claim 31 in which the temperature of the reaction is between about 20° C. and about 40° C.