US5141740A
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Complexes and compositions for magnetic resonance imaging and usage methods
Assignee: Mallinckrodt Inc
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Filing: 1990-11-21
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Granted: 1992-08-25
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Expires: 2010-11-21
Abstract
Abstract Novel magnetic resonance imaging agents comprise complexes of paramagnetic ions with hydrazide derivatives of polyaminocarboxylic acid chelating agents. These novel imaging agents are characterized by excellent NMR image-contrasting properties and by high solubilities in physiological solutions. A novel method of performing an NMR diagnostic procedure involves administering to a warm-blooded animal an effective amount of a complex as described above and then exposing the warm-blooded animal to an NMR imaging procedure, thereby imaging at least a portion of the body of the warm-blooded animal.
Inventors
- 👤 Raghavan Rajagopalan
- 👤 Rebecca A. Wallace
- 👤 Muthunadar P. Periasamy
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 10:12
CPC Classifications
G; G01; G01R; G01R33/00; G01R33/20; G01R33/44; G01R33/48; G01R33/54; G01R33/56; G01R33/5601; A; A61; A61K; A61K49/00; A61K49/06; Y; Y10; Y10S; Y10S436/00; Y10S436/806; Y10T; Y10T436/00; Y10T436/24
Claims Analysis
Total Claims: 37
Claim 1
Independent Claim
134 words
A complex comprising the following formula: ##STR13## wherein M Z+ is a paramagnetic ion of an element with an atomic number 21-29, 42-44, or 58-70 and a valence, z, of 2+ or 3+; A is selected from the group consisting of ##STR14## the R 1 groups are selected from a group consisting of --O -- and ##STR15## wherein at least one R 1 group is ##STR16## the R 2 , R 3 , R 4 , and R 5 groups may be the same or different selected from a group consisting of alkyl, acyl, aryl, mono- or polyhydroxyalkyl, mono- or poly-alkoxyalkyl, aminoalkyl and acylaminoalkyl; the carbon-containing R groups preferably contain 1 to 6 carbon atoms; where R 2 and R 3 may be joined together to form a 5, 6 or 7 membered ring.
Claim 2
Dependent Claim
134 words
A complex comprising the following formula: ##STR13## wherein M Z+ is a paramagnetic ion of an element with an atomic number 21-29, 42-44, or 58-70 and a valence, z, of 2+ or 3+; A is selected from the group consisting of ##STR14## the R 1 groups are selected from a group consisting of --O -- and ##STR15## wherein at least one R 1 group is ##STR16## the R 2 , R 3 , R 4 , and R 5 groups may be the same or different selected from a group consisting of alkyl, acyl, aryl, mono- or polyhydroxyalkyl, mono- or poly-alkoxyalkyl, aminoalkyl and acylaminoalkyl; the carbon-containing R groups preferably contain 1 to 6 carbon atoms; where R 2 and R 3 may be joined together to form a 5, 6 or 7 membered ring.
Claim 3
Dependent Claim
9 words
The complex of claim 1, wherein A is ##STR17##
Claim 4
Dependent Claim
38 words
The complex of claim 2, wherein M Z+ is selected from a group consisting of praseodymium (III), neodymium (III), sumarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III) erbium (III), iron (III), and manganese (II).
Claim 5
Dependent Claim
27 words
The complex of claim 2, wherein R 4 and R 5 are both methyl and M Z+ is Gd 3+ , Dy 3+ or Fe 3+ .
Claim 6
Dependent Claim
23 words
The complex of claim 2, wherein R 5 is methyl and M Z+ is Gd 3+ , Dy 3+ or Fe 3+ .
Claim 7
Dependent Claim
23 words
The complex of claim 2, wherein R 5 is hydroxyethyl and M Z+ is Gd 3+ , Dy 3+ or Fe 3+ .
Claim 8
Dependent Claim
42 words
The complex of claim 1, wherein A is --CHR 2 CHR 3 -- and R 2 and R 3 are selected from a group consisting of hydrogen and alkyl, which may join together to form a 5, 6 or 7 membered ring.
Claim 9
Dependent Claim
38 words
The complex of claim 7, wherein M Z+ is selected from a group consisting of praseodymium (III), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III) erbium (III), iron (III) and manganese (II).
Claim 10
Dependent Claim
21 words
The complex of claim 7, wherein R 4 and R 5 are both methyl and M Z+ is Mn 2+ .
Claim 11
Dependent Claim
23 words
The complex of claim 7, wherein R 5 is methyl and M Z+ is Gd 3+ , Dy 3+ or Fe 3+ .
Claim 12
Dependent Claim
23 words
The complex of claim 7, wherein R 5 is hydroxyethyl and M Z+ is Gd 3+ , Dy 3+ or Fe 3+ .
Claim 13
Dependent Claim
162 words
A diagnostic composition suitable for enteral or parenteral administration to a warm-blooded animal, which comprises a MRI-effective amount of a complex of a paramagnetic ion comprising the following formula: ##STR18## wherein M Z+ is a paramagnetic ion of an element with an atomic number 21-29, 42-44, or 58-70 and a valence, z, of 2+ or 3+; A is selected from the group consisting of ##STR19## the R 1 groups are selected from a group consisting of --O -- and ##STR20## wherein at least one R 1 group is ##STR21## the R 2 , R 3 , R 4 , and R 5 groups may be the same or different selected from a group consisting of alkyl, acyl, aryl, mono- or polyhydroxyalkyl, mono- or poly-alkoxyalkyl, aminoalkyl and acylaminoalkyl; the carbon-containing R groups preferably contain 1 to 6 carbon atoms; where R 2 and R 3 may be joined together to form a 5, 6 or 7 membered ring; and a pharmaceutically acceptable carrier.
Claim 14
Dependent Claim
162 words
A diagnostic composition suitable for enteral or parenteral administration to a warm-blooded animal, which comprises a MRI-effective amount of a complex of a paramagnetic ion comprising the following formula: ##STR18## wherein M Z+ is a paramagnetic ion of an element with an atomic number 21-29, 42-44, or 58-70 and a valence, z, of 2+ or 3+; A is selected from the group consisting of ##STR19## the R 1 groups are selected from a group consisting of --O -- and ##STR20## wherein at least one R 1 group is ##STR21## the R 2 , R 3 , R 4 , and R 5 groups may be the same or different selected from a group consisting of alkyl, acyl, aryl, mono- or polyhydroxyalkyl, mono- or poly-alkoxyalkyl, aminoalkyl and acylaminoalkyl; the carbon-containing R groups preferably contain 1 to 6 carbon atoms; where R 2 and R 3 may be joined together to form a 5, 6 or 7 membered ring; and a pharmaceutically acceptable carrier.
Claim 15
Dependent Claim
9 words
The composition of claim 12, wherein A is ##STR22##
Claim 16
Dependent Claim
38 words
The composition of claim 13, wherein M Z+ is selected from a group consisting of praseodymium (III), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II).
Claim 17
Dependent Claim
27 words
The composition of claim 13, wherein R 4 and R 5 are both methyl and M Z+ is Gd 3+ , Dy 3+ or Fe 3+ .
Claim 18
Dependent Claim
23 words
The composition of claim 13, wherein R 5 is methyl and M Z+ is Gd 3+ , Dy 3+ or Fe 3+ .
Claim 19
Dependent Claim
23 words
The composition of claim 13, wherein R 5 is hydroxyethyl and M Z+ is Gd + , Dy 3+ or Fe 3+ .
Claim 20
Dependent Claim
18 words
The composition of claim 12, wherein the composition contains a pharmaceutically acceptable buffer and a pharmaceutically acceptable electrolyte.
Claim 21
Dependent Claim
15 words
The composition of claim 12, wherein the composition contains an excess of a complexing agent.
Claim 22
Dependent Claim
58 words
The composition of claim 12, wherein the composition contains an excess complexing agent preferably employed in an amount ranging from 0.01 to 15 mole % excess, relative to the paramagnetic metal complex, and is complexed with a cation selected from a group consisting of sodium ions, calcium ions, magnesium ions, copper ions and zinc ions and mixtures thereof.
Claim 23
Dependent Claim
17 words
The composition of claim 12, wherein the composition contains an excess complexing agent complexed with calcium ions.
Claim 24
Dependent Claim
22 words
The composition of claim 12, wherein the composition contains an excess complexing agent complexed with one or more physicologically acceptable, non-toxic cations.
Claim 25
Dependent Claim
42 words
The composition of claim 12, wherein A is --CHR 2 CHR 3 --, and R 2 and R 3 are selected from a group consisting of hydrogen and alkyl, which may join together to form a 5, 6 or 7 membered ring.
Claim 26
Dependent Claim
24 words
The composition of claim 23, wherein R 4 is methyl; R 5 is either methyl or hydroxyethyl; and M Z+ is Mn 2+ .
Claim 27
Independent Claim
175 words
A method of performing a MRI diagnostic procedure, which comprises: (a) administering to a warm-blooded animal a diagnostically effective amount of a complex of the formula: ##STR23## wherein M Z+ is a paramagnetic ion of an element with an atomic number 21-29, 42-44, or 58-70 and a valence, z, of 2+ or 3+; A is selected from the group consisting of ##STR24## the R 1 groups are selected from a group consisting of --O -- and ##STR25## wherein at least one R 1 group is ##STR26## the R 2 , R 3 , R 4 , and R 5 groups may be the same or different selected from a group consisting of alkyl, acyl, aryl, mono-or poly-hydroxyalkyl, mono- or poly-alkoxyalkyl, aminoalkyl and acylaminoalkyl; the carbon-containing R groups preferably contain 1 to 6 carbon atoms; where R 2 and R 3 may be joined together to form a 5, 6 or 7 membered ring; and (b) exposing the animal to a MRI procedure, thereby imaging at least a portion of the body of the warm-blooded animal.
Claim 28
Independent Claim
175 words
A method of performing a MRI diagnostic procedure, which comprises: (a) administering to a warm-blooded animal a diagnostically effective amount of a complex of the formula: ##STR23## wherein M Z+ is a paramagnetic ion of an element with an atomic number 21-29, 42-44, or 58-70 and a valence, z, of 2+ or 3+; A is selected from the group consisting of ##STR24## the R 1 groups are selected from a group consisting of --O -- and ##STR25## wherein at least one R 1 group is ##STR26## the R 2 , R 3 , R 4 , and R 5 groups may be the same or different selected from a group consisting of alkyl, acyl, aryl, mono-or poly-hydroxyalkyl, mono- or poly-alkoxyalkyl, aminoalkyl and acylaminoalkyl; the carbon-containing R groups preferably contain 1 to 6 carbon atoms; where R 2 and R 3 may be joined together to form a 5, 6 or 7 membered ring; and (b) exposing the animal to a MRI procedure, thereby imaging at least a portion of the body of the warm-blooded animal.
Claim 29
Dependent Claim
17 words
A method of performing a MRI diagnostic procedure as defined in claim 25, wherein A is ##STR27##
Claim 30
Dependent Claim
35 words
A method of performing a MRI diagnostic procedure as defined in claim 25, wherein M Z+ is selected from a group consisting of praseodymium(III), neodymium(III), samarium(III), ytterbium(III), gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), iron(III), and manganese(II).
Claim 31
Dependent Claim
39 words
A method of performing a MRI diagnostic procedure as defined in claim 25, wherein R 4 is methyl, R 5 is either methyl or hydroxyethyl, and M Z+ is Gd 3+ , Dy 3+ , or Fe 3+ .
Claim 32
Dependent Claim
23 words
A method of performing a MRI diagnostic procedure as defined in claim 25, wherein the complex is combined with a pharmaceutically acceptable buffer.
Claim 33
Dependent Claim
28 words
A method of performing a MRI diagnostic procedure as defined in claim 25, wherein the complex is combined with a pharmaceutically acceptable buffer and a pharmaceutically acceptable electrolyte.
Claim 34
Dependent Claim
39 words
A method of performing a MRI diagnostic procedure as defined in claim 25, wherein the complex is combined with an excess of a complexing agent, said complexing agent being optionally complexed with one or more physiologically acceptable nontoxic cations.
Claim 35
Dependent Claim
67 words
A method of performing a MRI diagnostic procedure of as defined in claim 25, wherein the complex is combined with an excess complexing agent employed in an amount ranging from 0.01 to 15 mole percent excess, relative to the paramagnetic metal complex, said excess complexing agent being complexed with a cation selected from a group consisting of sodium, calcium, magnesium, copper, and zinc ions, and mixtures thereof.
Claim 36
Dependent Claim
28 words
A method of performing a MRI diagnostic procedure of as defined in claim 25, wherein the complex is combined with an excess complexing agent complexed with calcium ions.
Claim 37
Dependent Claim
50 words
A method of performing a MRI diagnostic procedure of as defined in claim 25, wherein A is --CHR 2 CHR 3 --, and R 2 and R 3 are selected from a group consisting of hydrogen and alkyl, which may join to form a 5, 6 or 7 membered ring.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1995-08-25 | 1996-02-24 | 1996-08-25 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1999-08-25 | 2000-02-24 | 2000-08-25 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2003-08-25 | 2004-02-24 | 2004-08-25 | $7700.00 | Window Closed / Lapsed |