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US4512967A Expired / Lapsed US ⏱️ 0.0 years remaining

Cationic technetium complexes useful as radiodiagnostic agents

Assignee: Bristol Myers Squibb Pharma Co
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Filing: 1982-08-02
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Granted: 1985-04-23
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Expires: 2002-08-02
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Abstract

Abstract A cationic lipophilic complex of technetium is disclosed wherein all of the coordination positions of the technetium atom are filled with a neutral donor atom having a pair of electrons available for forming a coordinate bond with technetium. The donor atoms are provided by target-seeking ligands or salts thereof, said ligands having the following structure of one of formulas I, II or III. Such complexes are useful for imaging heart and hepatobiliary tissues.

Inventors

  • 👤 Karen E. Linder

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-10-28 04:08
CPC Classifications
C; C07; C07F; C07F9/00; C07F9/02; C07F9/28; C07F9/54; C07F9/5449; A; A61; A61K; A61K51/00; A61K51/02; A61K51/04; C07F9/50; C07F9/5045; A61K2123/00

Claims Analysis

Total Claims: 22
Claim 1
Independent Claim 424 words
A cationic lipophilic complex of technetium wherein all of the coordination positions of the technetium atom are filled with a donor atom having a pair of electrons available for forming a coordinate bond with technetium to form said cationic complex, said donor atoms being provided by ligands or salts thereof, said ligands having the following structure: ##STR9## wherein: i is an integer from 1 to 6; R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups, and R plus R i may be taken together to form a cyclic compound or separately to form a linear compound; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each, independently, a donor atom having a free electron pair available for complexing with Tc-99m or Tc-99 to form a cationic complex; and k 1 , k 2 , k 3 , k 4 , k 5 and k 6 are each independently zero or one; ##STR10## wherein: R, R' and R" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; X and X' are saturated or unsaturated alkyl groups; A, A' and A" are independently selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; t and t' are independently 0 or 1; n is 0, 1 or 2; and n' and n" are independently the integer 1 or 2; or ##STR11## wherein R, R', R" and R'" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; A', A" and A'" are independently selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; B is an atom selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99, boron, or from the elements of Group IV A of the periodic table; m is 0 or 1; and n', n" and n'" are independently the integer 1 or 2.
Claim 2
Dependent Claim 424 words
A cationic lipophilic complex of technetium wherein all of the coordination positions of the technetium atom are filled with a donor atom having a pair of electrons available for forming a coordinate bond with technetium to form said cationic complex, said donor atoms being provided by ligands or salts thereof, said ligands having the following structure: ##STR9## wherein: i is an integer from 1 to 6; R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups, and R plus R i may be taken together to form a cyclic compound or separately to form a linear compound; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each, independently, a donor atom having a free electron pair available for complexing with Tc-99m or Tc-99 to form a cationic complex; and k 1 , k 2 , k 3 , k 4 , k 5 and k 6 are each independently zero or one; ##STR10## wherein: R, R' and R" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; X and X' are saturated or unsaturated alkyl groups; A, A' and A" are independently selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; t and t' are independently 0 or 1; n is 0, 1 or 2; and n' and n" are independently the integer 1 or 2; or ##STR11## wherein R, R', R" and R'" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; A', A" and A'" are independently selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; B is an atom selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99, boron, or from the elements of Group IV A of the periodic table; m is 0 or 1; and n', n" and n'" are independently the integer 1 or 2.
Claim 3
Dependent Claim 23 words
The complex of claim 1 wherein A is selected from the group consisting of P, As, N, O, S, Sb, Se and Te.
Claim 4
Dependent Claim 79 words
The complex of claim 1 wherein at least one of the donor atoms are provided by a ligand having the formula: ##STR12## or salts thereof wherein M and M' are arsenic, phosphorus, nitrogen, sulfur, oxygen, selenium, tellurium, or any combination of them, n and n' are independently 1 or 2 depending upon the particular M and M', and R and R' are independently hydrogen, an alkyl group having from 1 to about 6 carbon atoms, or an aryl group.
Claim 5
Dependent Claim 105 words
The complex of claim 1 wherein at least one of the donor atoms are provided by a ligand having the formula: R'.sub.n' M'--CX'.sub.2 CX.sub.2 --MR.sub.n or salts thereof wherein M and M' are arsenic, phosphorus, nitrogen, sulfur, oxygen, selenium, tellurium, or any combination of them, n and n' are independently 1 or 2 depending on the particualr M and M', R and R' are independently hydrogen, an alkyl group having from 1 to about 6 carbon atoms, or an aryl group, and X and X' are independently selected from hydrogen, halide, or substituted or unsubstituted lower alkyl groups having 1 to about 6 carbon atoms.
Claim 6
Dependent Claim 91 words
The complex of claim 1 wherein at least one of the donor atoms are provided by a ligand having the formula: ##STR13## or salts thereof wherein M, M' and M" are independently selected from arsenic, phosphorous, nitrogen, sulfur, oxygen, selenium, and tellurium, n is 0 or 1 and n' and n" are independently 0, 1 or 2 depending upon the particular M, M' and M" used, and R, R' and R" are independently selected from hydrogen, halide, an alkyl group having 1 to about 6 carbon atoms, or an aryl group.
Claim 7
Dependent Claim 46 words
The complex of claim 1 consisting of a technetium atom and three ligands, each having the formula: ##STR14## wherein each A is independently P or As; and each R is independently H, a lower alkyl group having from 1 to about 6 carbon atoms, or phenyl.
Claim 8
Dependent Claim 18 words
The complex of claim 1 consisting of a technetium atom and three ligands each having the formula: ##STR15##
Claim 9
Dependent Claim 34 words
The complex of claim 1 consisting of a technetium atom and three ligands each having the formula: ##STR16## wherein R is H or a lower alkyl group having 1 to about 6 carbon atoms.
Claim 10
Independent Claim 411 words
A method for making a cationic complex comprising Tc-99m for radioscintigraphic imaging, said method comprising admixing, in a suitable solvent at a basic pH, 99m Tc pertechnetate and a ligand or a salt thereof, said ligand having the formula: ##STR17## wherein: i is an integer from 1 to 6; R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups, and R plus R i may be taken together to form a cyclic compound or separately to form a linear compound; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each, independently a donor atoms having a free-electron pair available for complexing with Tc-99m or Tc-99 to form a cationic complex; and k 1 , k 2 , k 3 , k 4 , k 5 and k 6 are each independently zero or one; ##STR18## wherein: R, R' and R" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; X and X' are saturated or unsaturated alkyl groups; A, A' and A" are independently selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; t and t' are independently 0 or 1; n is 0, 1 or 2; and n' and n" are independently the integer 1 or 2; or ##STR19## wherein R, R', R" and R'" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; A', A" and A'" are independently selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; B is an atom selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99, boron, or from the elements of Group IV A of the periodic table; m is 0 or 1; and n', n" and n'" are independently the integer 1 or 1; thus forming the cationic complex.
Claim 11
Independent Claim 411 words
A method for making a cationic complex comprising Tc-99m for radioscintigraphic imaging, said method comprising admixing, in a suitable solvent at a basic pH, 99m Tc pertechnetate and a ligand or a salt thereof, said ligand having the formula: ##STR17## wherein: i is an integer from 1 to 6; R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups, and R plus R i may be taken together to form a cyclic compound or separately to form a linear compound; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each, independently a donor atoms having a free-electron pair available for complexing with Tc-99m or Tc-99 to form a cationic complex; and k 1 , k 2 , k 3 , k 4 , k 5 and k 6 are each independently zero or one; ##STR18## wherein: R, R' and R" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; X and X' are saturated or unsaturated alkyl groups; A, A' and A" are independently selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; t and t' are independently 0 or 1; n is 0, 1 or 2; and n' and n" are independently the integer 1 or 2; or ##STR19## wherein R, R', R" and R'" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; A', A" and A'" are independently selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; B is an atom selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99, boron, or from the elements of Group IV A of the periodic table; m is 0 or 1; and n', n" and n'" are independently the integer 1 or 1; thus forming the cationic complex.
Claim 12
Dependent Claim 21 words
The method of claim 9 wherein the pH of the solution is maintained at 9 or more during the complexing reaction.
Claim 13
Dependent Claim 23 words
The method of claim 9 where A is selected from the group consisting of P, As, N, O, S, Sb, Se and Te.
Claim 14
Dependent Claim 79 words
The method of claim 9 wherein at least one of the donor atoms are provided by a ligand having the formula: ##STR20## or salts thereof wherein M and M' are arsenic, phosphorus, nitrogen, sulfur, oxygen, selenium, tellurium, or any combination of them, n and n' are independently 1 or 2 depending upon the particular M and M', and R and R' are independently hydrogen, an alkyl group having from 1 to about 6 carbon atoms, or an aryl group.
Claim 15
Dependent Claim 105 words
The method of claim 9 wherein at least one of the donor atoms are provided by a ligand having the formula: R'.sub.n' M'--CX'.sub.2 CX.sub.2 --MR.sub.n or salts thereof wherein M and M' are arsenic, phosphorus, nitrogen, sulfur, oxygen, selenium, tellurium, or any combination of them, n and n' are independently 1 or 2 depending on the particular M and M', R and R' are independently hydrogen, an alkyl group having from 1 to about 6 carbon atoms, or an aryl group, and X and X' are independently selected from hydrogen, halide, or substituted or unsubstituted lower alkyl groups having 1 to about 6 carbon atoms.
Claim 16
Dependent Claim 90 words
The method of claim 9 wherein at least one of the donor atoms are provided by a ligand having the formula: ##STR21## or salts thereof wherein M, M' and M" are independently selected from arsenic, phosphorous, nitrogen, sulfur, oxygen, selenium, and tellurium, n is 0 or 1 and n' and n" are independently 1 or 2 depending upon the particular M, M' and M" used, and R, R' and R" are independently selected from hydrogen, halide, an alkyl group having 1 to about 6 carbon atoms, or an aryl group.
Claim 17
Dependent Claim 49 words
The method of claim 9 wherein a technetium atom and three ligands or salts thereof, each ligand having the formula: ##STR22## wherein each A is independently P or As; and each R is independently H a lower alkyl group having from 1 to about 6 carbon atoms, or phenyl.
Claim 18
Dependent Claim 23 words
The method of claim 9 wherein said complex a technetium atom and three ligands or salts thereof, each ligand having the formula: ##STR23##
Claim 19
Dependent Claim 40 words
The method of claim 9 wherein said complex comprises a technetium atom and three ligands or salts thereof, each ligand having the formula: ##STR24## wherein R is H or a lower alkyl group having 1 to about 6 carbon atoms.
Claim 20
Dependent Claim 15 words
The method of claim 9 further comprising heating the admixture to at least 80° C.
Claim 21
Dependent Claim 23 words
The method of claim 9 wherein the pH is maintained in the range of from about 10 to about 12 during the reaction.
Claim 22
Independent Claim 40 words
A method for visualizing the heart or the hepatobiliary system of a mammal by radioscintigraphy, said method comprising injecting into the mammal the cationic complex of any of claims 1 through 8, and scanning the mammal using radioscintigraphic imaging apparatus.

USPTO Annuity & Maintenance Windows

Annuity Stage Window Opens Payment Deadline Surcharge Period Until Estimated Fee Status
3.5 Years (Year 4) 1988-04-22 1988-10-22 1989-04-23 $2000.00 Window Closed / Lapsed
7.5 Years (Year 8) 1992-04-22 1992-10-22 1993-04-23 $3760.00 Window Closed / Lapsed
11.5 Years (Year 12) 1996-04-22 1996-10-22 1997-04-23 $7700.00 Window Closed / Lapsed

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