US5326856A
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Bifunctional isothiocyanate derived thiocarbonyls as ligands for metal binding
Assignee: Cytogen Corp
•
Filing: 1992-04-09
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Granted: 1994-07-05
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Expires: 2012-04-09
Abstract
Abstract This invention relates to chelating agents useful for coupling metal ions to biologically active molecules. In particular, isothiocyanate derived thiocarbonyls for chelating metals such as technetium are provided that can be conjugated to a targeting molecule such as an antibody, a peptide or a protein.
Inventors
- 👤 Daniel J. Coughlin
- 👤 Benjamin A. Belinka, Jr.
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-08 05:15
CPC Classifications
C; C07; C07D; C07D207/00; C07D207/02; C07D207/44; C07D207/444; C07D207/448; C07D207/452; A; A61; A61K; A61K47/00; A61K47/50; A61K51/00; A61K51/02; A61K51/04; A61K51/08; A61K51/082; A61K51/088; A61K51/10; A61K51/1093; C07C; C07C335/00; C07C335/04; C07C335/16; C07C335/22; C07C337/00; C07C337/06; C07D213/00; C07D213/02; C07D213/04; C07D213/60; C07D213/62; C07D213/70; C07D213/71; A61K2121/00; A61K2123/00
Claims Analysis
Total Claims: 47
Claim 1
Independent Claim
134 words
A chelating agent of the formula: ##STR11## in which NHCSNHR is in the 2,3- or 3,4-positions, and R is H or a substituent of the general formula: R=--(NH).sub.a (CH.sub.2).sub.b CY(NH).sub.d (CH.sub.2).sub.e --Z in which a=0 or 1; b=0-10; CY is C═S, C═O or CH 2 ; d=0-2; e=1-10; Z=is H, N(R') 3 + X - , SO 3 H, CO 2 H, OH, H 2 PO 3 ; in which X - is a counterion such as a halide or an acid salt and R' is a C 1 to C 4 lower alkyl; and L comprises a reactive linker group selected from the group consisting of a primary amine, hydrazide, acid hydrazide, thioacid hydrazide, semicarbazide, thiosemicarbazide, reactive disulfide group, p-mercuribenzoate group, maleimide group, carboxylic acid, a carboxylic acid ester, an isothiocyanate, and succinate.
Claim 2
Dependent Claim
134 words
A chelating agent of the formula: ##STR11## in which NHCSNHR is in the 2,3- or 3,4-positions, and R is H or a substituent of the general formula: R=--(NH).sub.a (CH.sub.2).sub.b CY(NH).sub.d (CH.sub.2).sub.e --Z in which a=0 or 1; b=0-10; CY is C═S, C═O or CH 2 ; d=0-2; e=1-10; Z=is H, N(R') 3 + X - , SO 3 H, CO 2 H, OH, H 2 PO 3 ; in which X - is a counterion such as a halide or an acid salt and R' is a C 1 to C 4 lower alkyl; and L comprises a reactive linker group selected from the group consisting of a primary amine, hydrazide, acid hydrazide, thioacid hydrazide, semicarbazide, thiosemicarbazide, reactive disulfide group, p-mercuribenzoate group, maleimide group, carboxylic acid, a carboxylic acid ester, an isothiocyanate, and succinate.
Claim 3
Dependent Claim
15 words
The chelating agent of claim 1 in which the NHCSNHR groups are in the 3,4-positions.
Claim 4
Dependent Claim
21 words
The chelating agent of claim 1 in which L is spaced from 0 to about 20 atoms from the benzene ring.
Claim 5
Dependent Claim
31 words
The chelating agent of claim 1 in which the reactive group of L is selected from the group consisting of a primary amine, hydrazide, acid hydrazide, thioacid hydrazide, semicarbazide or thiosemicarbazide.
Claim 6
Dependent Claim
31 words
The chelating agent of claim 1 in which the reactive group of L is selected from the group consisting of a reactive disulfide group, a p-mercuribenzoate group and a maleimide group.
Claim 7
Dependent Claim
32 words
The chelating agent of claim 1 in which the reactive group of L is selected from the group consisting of a carboxylic acid, a carboxylic acid ester, an isothiocynate, and a succinate.
Claim 8
Dependent Claim
75 words
The chelating agent of claim 1 in which R is: --(NH).sub.a CY(CH.sub.2).sub.e Z in which a=0 or 2, e=1-10, CY is C═S, C═O or CH 2 ; and Z is H, N(R') 3 + X - , SO 3 H, CO 2 H, OH, H 2 PO 3 ; in which X - is a counterion such as a halide or an acid salt and R' is a C 1 to C 4 lower alkyl.
Claim 9
Dependent Claim
31 words
The chelating agent of claim 7 in which Z is selected from the group consisting of an amine or salt thereof, an acid or a salt thereof, and a hydroxy group.
Claim 10
Dependent Claim
18 words
The chelating agent of claim 8 in which the amine-salt is trimethylammonium chloride, trimethylammonium acetate, or trimethylammonium trifluoroacetate.
Claim 11
Dependent Claim
13 words
A complex comprising the chelating agent of claim 1 and a metal ion.
Claim 12
Dependent Claim
26 words
The complex of claim 10 in which the metal ion is an isotope selected from the group consisting of technetium, rhenium, copper, mercury, lead and bismuth.
Claim 13
Dependent Claim
12 words
The complex of claim 11 in which the metal ion is technetium-99m.
Claim 14
Dependent Claim
42 words
A conjugate comprising the chelating agent of claim 1 and a targeting molecule capable of specific interaction with a target molecule, said targeting molecule selected from the group consisting of an antibody, a protein, a peptide, a nucleic acid, and a steroid.
Claim 15
Dependent Claim
27 words
The conjugate of claim 13 in which the targeting molecule is an antibody, an Fab fragment of an antibody, or an F(ab') 2 fragment of an antibody.
Claim 16
Dependent Claim
13 words
The conjugate of claim 13 in which the targeting molecule is a peptide.
Claim 17
Dependent Claim
12 words
The conjugate of claim 13 in which the targeting molecule is protein.
Claim 18
Dependent Claim
12 words
The complex comprising the conjugate of claim 13 and a metal ion.
Claim 19
Dependent Claim
26 words
The complex of claim 17 in which the metal ion is an isotope selected from the group consisting of technetium, rhenium, copper, mercury, lead and bismuth.
Claim 20
Dependent Claim
12 words
The complex of claim 18 in which the metal ion is technetium-99m.
Claim 21
Dependent Claim
136 words
A chelating agent of the formula: ##STR12## in which the NHCSNHR groups are in the 2,4- or 3,5-positions; and R is hydrogen or a substituent of the general formula: R=--(NH).sub.a (CH.sub.2).sub.b CY(NH).sub.d (CH.sub.2).sub.e --Z in which a=0 or 1; b=0-10; CY is C═S, C═O or CH 2 ; d=0-2; e=1-10; Z=is H, N(R') 3 + X - , SO 3 H, CO 2 H, OH, H 2 PO 3 ; in which X - is a counterion such as a halide or an acid melt and R' is a C 1 to C 4 lower alkyl; and L comprises a reactive linker group selected from the group consisting of a primary amine, hydrazide, acid hydrazide, thioacid hydrazide, semicarbazide, thiosemicarbazide, reactive disulfide group, p-mercuribenzoate group, maleimide group, carboxylic acid, a carboxylic acid ester, an isothiocyanate, and succinate.
Claim 22
Dependent Claim
136 words
A chelating agent of the formula: ##STR12## in which the NHCSNHR groups are in the 2,4- or 3,5-positions; and R is hydrogen or a substituent of the general formula: R=--(NH).sub.a (CH.sub.2).sub.b CY(NH).sub.d (CH.sub.2).sub.e --Z in which a=0 or 1; b=0-10; CY is C═S, C═O or CH 2 ; d=0-2; e=1-10; Z=is H, N(R') 3 + X - , SO 3 H, CO 2 H, OH, H 2 PO 3 ; in which X - is a counterion such as a halide or an acid melt and R' is a C 1 to C 4 lower alkyl; and L comprises a reactive linker group selected from the group consisting of a primary amine, hydrazide, acid hydrazide, thioacid hydrazide, semicarbazide, thiosemicarbazide, reactive disulfide group, p-mercuribenzoate group, maleimide group, carboxylic acid, a carboxylic acid ester, an isothiocyanate, and succinate.
Claim 23
Dependent Claim
15 words
The chelating agent of claim 20 in which the NHCSNHR groups are in the 3,5-positions.
Claim 24
Dependent Claim
21 words
The chelating agent of claim 20 in which L is spaced from 0 to about 20 atoms from the benzene ring.
Claim 25
Dependent Claim
31 words
The chelating agent of claim 20 in which the reactive group of L is selected from the group consisting of a primary amine, hydrazide, acid hydrazide, thioacid hydrazide, semicarbazide or thiosemicarbazide.
Claim 26
Dependent Claim
31 words
The chelating agent of claim 20 in which the reactive group of L is selected from the group consisting of a reactive disulfide group, a p-mercuribenzoate group and a maleimide group.
Claim 27
Dependent Claim
32 words
The chelating agent of claim 20 in which the reactive group of L is selected from the group consisting of a carboxylic acid, a carboxylic acid ester, an isothiocyanate, and a succinate.
Claim 28
Dependent Claim
73 words
The chelating agent of claim 39 in which R is: --(NH).sub.a CY(CH.sub.2).sub.e Z in which a=0-2, e=0-10, CY is C═S, C═O or CH 2 ; and Z is H, N(R') 3 + X - , SO 3 H, CO 2 H, OH, H 2 PO 3 ; in which X - is a counterion such as a halide or an acid salt and R' is a C 1 to C 4 lower alkyl.
Claim 29
Dependent Claim
31 words
The chelating agent of claim 26 in which Z is selected from the group consisting of an amine or salt thereof, an acid or a salt thereof, and a hydroxy group.
Claim 30
Dependent Claim
18 words
The chelating agent of claim 27 in which the amine-salt is trimethylammonium chloride, trimethylammonium acetate, or trimethylammonium trifluoroacetate.
Claim 31
Dependent Claim
13 words
A complex comprising the chelating agent of claim 20 and a metal ion.
Claim 32
Dependent Claim
26 words
The complex of claim 29 in which the metal ion is an isotope selected from the group consisting of technetium, rhenium, copper, mercury, lead and bismuth.
Claim 33
Dependent Claim
12 words
The complex of claim 30 in which the metal ion is technetium-99m.
Claim 34
Dependent Claim
42 words
A conjugate comprising the chelating agent of claim 20 and a targeting molecule capable of specific interaction with a target molecule, said targeting molecule selected from the group consisting of an antibody, a protein, a peptide, a nucleic acid, and a steroid.
Claim 35
Dependent Claim
27 words
The conjugate of claim 32 in which the targeting molecule is an antibody, an Fab fragment of an antibody, or an F(ab') 2 fragment of an antibody.
Claim 36
Dependent Claim
13 words
The conjugate of claim 32 in which the targeting molecule is a peptide.
Claim 37
Dependent Claim
13 words
The conjugate of claim 32 in which the targeting molecule is a protein.
Claim 38
Dependent Claim
12 words
A complex comprising the conjugate of claim 32 and a metal ion.
Claim 39
Dependent Claim
26 words
The complex of claim 36 in which the metal ion is an isotope selected from the group consisting of technetium, rhenium, copper, mercury, lead and bismuth.
Claim 40
Dependent Claim
12 words
The complex of claim 37 in which the metal ion is technetium-99m.
Claim 41
Dependent Claim
17 words
The chelating agent of claim 4 in which L is --CONH(CH 2 ) 5 CONHNH 2 .
Claim 42
Dependent Claim
17 words
The chelating agent of claim 23 in which L is --CONH(CH 2 ) 5 CONHNH 2 .
Claim 43
Dependent Claim
19 words
The chelating agent of claim 6 in which L is a carboxylic acid or a carboxylic acid methyl ester.
Claim 44
Dependent Claim
19 words
The chelating agent of claim 25 in which L is a carboxylic acid or a carboxylic acid methyl ester.
Claim 45
Dependent Claim
25 words
The chelating agent of claim 20 in which R is ##STR13## in which X - is a halide ion; and L is an acid hydrazide.
Claim 46
Dependent Claim
31 words
A conjugate comprising the chelating agent of claim 43 and a targeting molecule which is an antibody, an Fab fragment of an antibody or an F(ab') 2 fragment of an antibody.
Claim 47
Dependent Claim
19 words
A complex comprising the conjugate of claim 44 and a metal ion in which the metal ion is technetium.
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1997-07-04 | 1998-01-03 | 1998-07-05 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2001-07-04 | 2002-01-03 | 2002-07-05 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2005-07-04 | 2006-01-03 | 2006-07-05 | $7700.00 | Window Closed / Lapsed |