EP0230893A2
Expired / Lapsed
EP
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Paramagnetic chelates
Assignee: Bracco International BV
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Filing: 1987-01-12
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Granted: —
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Expires: 2007-01-12
Abstract
Abstract Compounds suitable for NMR imaging having the formula: wherein a is 2 or 3; b is an integer from 0 to 4; Me (a+) is Fe (2+) , Fe (3+) , Gd (3+) , or Mn (2+) ; E (b+) is an ion of an alkali metal, alkaline earth metal, alkyl ammonium, alkanol ammonium, polyhydroxyalkyl ammonium, or basic protonated amino acid, said ions representing a total charge of b; m is an integer from I to 5; R is H, alkyl with from I to 8 carbon atoms, alkyl with from I to 8 carbon atoms wherein from I to 5 carbons are substituted with OH; aralkyl with I to 4 aliphatic carbon atoms; phenyl or phenyl substituted by halogen, hydroxyl, carboxyl, carboxamide, ester, SO 3 H, sulfonamide, lower alkyl, lower hydroxy alkyl, amino, acylamino; (poly)oxa-alkyl with I to 50 oxygen atoms and from 3 to i50 carbon atoms, wherein I to 5 hydrogen atoms may be substituted by OH; R, is -CH 2 COOZ, -CH(CH 3 )COOZ, CH 2 CH 2 -N(CH 2 COOZ) 2 , a hydroxy arylalkyl, hydroxy pyridylalkyl, hydroxy aryl(carboxy)alkyl or hydroxy pyridyl-(carboxy)-alkyl radical, where the aryl or pyridyl radical may be substituted by hydroxyl, hydroxy alkyl, alkyl, halogen, carboxyl or SO 3 H; R 2 is the same as R, or is wherein R 3 is -CH 2 COOZ, -CH(CH 3 )COOZ or a monovalent radical having the structure R-O-(CH 2 ) m - CH-COOZ; X is a direct chemical bond, -O-, -S-, -NH-, -N -CH 2 COOZ or - N -CH(CH 3 )COOZ; n is the integer 2 or 3, with the proviso that when X represents a direct bond, n is I, 2 or 3; Z. is hydrogen or a unit of negative charge, and -(CH2) m -may also be -CH 2 -C(CH 3 ) 2 -. The compounds are relatively simple, well tolerated, partially endowed with organ specificity and are suitable for application in nuclear spin tomography. The compounds may be prepared by reacting inventive free polyamino-polycarboxylic acids having the formula where R, R, R 2 and m have the same meaning as in formula I, or alkali metal, alkaline earth metal and/or amino salts of said acids, with salts, oxides, or hydroxides of iron (2+) , iron (3+) , gadolinium (3+) , or manganese (2+) , or with the basic salts of these metal ions. Imaging compositions and methods of use are also disclosed.
Inventors
- 👤 Ernst Prof. Dr. Felder
- 👤 Luciano Prof. Dr. Fumagalli
- 👤 Fulvio Dr. Uggeri
- 👤 Giorgio Dr. Vittadini
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-23 16:45
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/28
Claims Analysis
Total Claims: 26
Claim 1
Independent Claim
280 words
I. A compound having the formula wherein a is 2 or 3; b is an integer from 0 to 4; Me (a+) is Fe (2+) , Fe (3+) , Gd (3+) , or Mn (2+) ; E (b+) is an ion of an alkali metal, alkaline earth metal, alkyl ammonium, alkanol ammonium, polyhydroxyalkyl ammonium, or basic protonated amino acid, said ions representing a total charge of b; m is an integer from I to 5; R is H, alkyl with from I to 8 carbon atoms, alkyl with from I to 8 carbon atoms wherein from I to 5 carbons are substituted with OH; aralkyl with I to 4 aliphatic carbon atoms; phenyl or phenyl substituted by halogen, hydroxyl, carboxyl, carboxamide, ester, S0 3 H, sulfonamide, lower alkyl, lower hydroxy alkyl, amino, acylamino; (poly)oxa-alkyl with I to 50 oxygen atoms and from 3 to 150 carbon atoms, wherein I to 5 hydrogen atoms may be substituted by OH; R 1 is -CH 2 COOZ, -CH(CH 3 )COOZ, CH 2 CH 2 -N(CH 2 COOZ) 2 , a hydroxy arylalkyl, hydroxy pyridylalkyl, hydroxy aryl(carboxy)alkyl or hydroxy pyridyl-(carboxy)-alkyl radical, where the aryl or pyridyl radical may be substituted by hydroxyl, hydroxy alkyl, alkyl, halogen, carboxyl or SO 3 H; R 2 is the same as R, or is where R 3 is -CH 2 COOZ, -CH(CH 3 )COOZ or a monovalent radical having the structure R-O-(CH 2 ) m C H-COOZ; X is a direct chemical bond, -0-, -S-, -NH-, - N -CH 2 COOZ or - N -CH(CH3)COOZ; n is the integer 2 or 3, with the proviso that when X represents a direct bond, n is I, 2 or 3;
Claim 2
Dependent Claim
32 words
Z is hydrogen or a unit of negative charge, and -(CH 2 ) m -may also be -CH 2 -C(CH 3 ) 2 -2. The compound of claim I having the formula
Claim 3
Dependent Claim
8 words
The compound of claim I having the formula:
Claim 4
Dependent Claim
45 words
The compound of claim I having the formula wherein T is -(CH 2 ) 1-2 -, -CH(COOH)-or -CH(COOH)CH 2 -, Q is = CH-or = N-, A is hydrogen, hydroxyl or lower hydroxyalkyl and B is hydrogen, lower alkyl, halogen, carboxyl or -SO 3 H.
Claim 5
Dependent Claim
12 words
The compound of claim 4 wherein Me (a+) is Fe (3+) .
Claim 6
Dependent Claim
8 words
The compound of claim I having the formula
Claim 7
Dependent Claim
56 words
The compound of claim I wherein is selected from the group consisting of 3-hydroxy-2-N-[2'-N'-[2"-N",N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)aminoethyl]-N-(carboxymethyl)-amino-propionic acid, 3-phenylmethoxy-2-N-[2'-N'-[2"-N",N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid, 3-methoxy-2-N,N-bis-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-aminopropionic acid, 3-phenylmethoxy-2-N,N-bis-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-aminopropionic acid, 4-(3,6,9,I2,I5-pentaoxahexadecyloxy)-3,3-dimethyl-2-N-[2'-N'-[2"-N",N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxy methyl)-aminoethyl]-N-(carboxymethyl)-amino-butyric acid, 4-(4'-amino-phenylmethoxy)-3,3-dimethyl-2-N,N-bis-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-amino-butyric acid, 4-(3,6,9,I2,I5-pentaoxahexadecyloxy)-3,3-dimethyl-2-N,N-bis-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-amino-butyric acid, 3-hydroxy-2-N-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-amino-propionic acid, 3-phenylmethoxy-2-N-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-amino-propionic acid, 3-octyloxy-2-N-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-amino-propionic acid, N,N'-bis-(2-hydroxy-I-carboxy-I-ethyl)-N,N'-bis-(carboxymethyl) ethylene diamine, 4-methoxy-3,3-dimethyt-2-N-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-amino-butyric acid, 3-phenylmethoxy-2-N-[I',2'-dimethyl-2-N',N'-bis-(carboxymethyl)-aminosthyl]-N-(carboxymethyl)-aminopropionic acid, N,N'-bis-(4,7,I0,I3-tetraoxa-2,2-dimethyl-I-carboxy-I-tetra decyl)-N,N'-bis-(carboxymethyl)-ethylene diamine, N,N'-bis-(4,7,10,I3-tetraoxa-2,2-dimethyl-I-carboxy-I-tetra decyl)-N,N'-bis-(carboxymethyl)-(,2-dimethyl-ethylene diamine, 4-(3,6,9,I2,I5-pentaoxahexadecyloxy)-3,3-dimethyl-2-N-[2'-N',N'-bis-(carboxymethyl)-aminocyclohexyl(trans)-]-N-(carboxymethyl)-amino-butyric acid, N,N'-bis-(3-methoxy-2,2-dimethyl-I-carboxy-I-propyl)-N,N'-bis-(carboxymethyl)-I,2-(trans)-cyclohexane diamine, 3-phenylmethoxy-2-N-[2-[2-N',N'-bis-(carboxymethyl)-aminoethoxy]-ethyl]-N-(carboxymethyl)-aminopropionic acid, and N,N'-bis-(24-hydroxy-4,7,I0,I3,I6,I9,22-heptaoxa-2,2-dimethyl-I-carboxy-I-tetracontyl-N,N'-bis-(carboxymethyl)-diaminediethyl ether.
Claim 8
Dependent Claim
33 words
The compound of claim I wherein Me (a+) is is selected from the group consisting of N,N'-bis-(2-methoxy-I-carboxyl-I-ethyl)-N,N'-bis-(2-hydroxyphenylmethyl)-ethylene diamine, N,N'-bis-(3,6,9,I2-tetraoxa-I-carboxy-I-tridecyl)-N,N'-bis-(2-hydroxy-phenylmethyl)-ethylene diamine, N,N'-bis-(3,6,9,I2-tetraoxa-I-carboxy-I-tridecyl)-N,N'-bis-(2-hydroxy-5-methoxy-phenylmethyl)-ethylene diamine, N,N'-bis-(3-methoxy-2,2-dimethyl-I-carboxy-I-propyl)-N,N'-bis-(2-hydroxy-phenylmethyl)-ethylene diamine, N,N'-bis-21-hydroxy-4,7,10,13,16,19-hexaoxa-2,2-dimethyl-I-carboxy-I-uncontyl-N,N'-bis-(2-hydroxyphenylmethyl)-ethylene-diamine, N,N'-bis-3-(2,3-dihydroxypropoxy)-2,2-dimethyl-1-carboxy-lpropyl)-N,N'-bis-(2-hydroxy-phenylmethyl)-ethylene diamine, N,N'-bis-(3-methoxy-2,2-dimethyl-I-carboxy-I-propyl)-N,N'-bis-(2-hydroxy-5-methoxy-phenylmethyl)-ethylene diamine, N,N'-bis-(3-hydroxy-2,2-dimethyl-I-carboxy-I-propyl)-N,N'-bis-(pyridoxyl)-ethylene diamine, and N,N'-bis-(3-phenylmethoxy-2,2-dimethyl-I-carboxy-I-propyl)-N,N'-bis-(pyridoxyl)-ethylene-diamine.
Claim 9
Dependent Claim
319 words
In a media for NMR contrast imaging which contains an agent for influencing relaxation time, the improvement which comprises said agent being a compound having the formula wherein a is 2 or 3; b is an integer from 0 to 4; Me (a+) is Fe (2+) , Fe (3+) , Gd (3+) , or Mn (2+) ; E (b+) is an ion of an alkali metal, alkaline earth metal, alkyl ammonium, alkanol ammonium, polyhydroxyalkyl ammonium, or basic protonated amino acid, said ions representing a total charge of b; m is an integer from I to 5; R is H, alkyl with from I to 8 carbon atoms, alkyl with from I to 8 carbon atoms wherein from I to 5 carbons are substituted with OH; aralkyl with I to 4 aliphatic carbon atoms; phenyl or phenyl substituted by halogen, hydroxyl, carboxyl, carboxamide, ester, SO 3 H, sulfonamide; lower alkyl; lower hydroxy alkyl, amino, acylamino; (poly)oxa-alkyl with I to 50 oxygen atoms and from 3 to 150 carbon atoms, wherein I to 5 hydrogen atoms may be substituted by OH; R, is-CH 2 COOZ, -CH(CH 3 )COOZ,-CH 2 CH 2 -N(CH 2 COOZ) 2 , a hydroxy arylalkyl, hydroxy pyridylalkyl, hydroxy aryl(carboxy)-alkyl or hydroxy pyridyl-(carboxy)-alkyl radical, where the aryl or pyridyl radical may be substituted by hydroxyl, hydroxy alkyl, alkyl, halogen, carboxyl or SO 3 H; R 2 is the same as R, or is where R 3 is -CH 2 COOZ, -CH(CH3)COOZ or a monovalent radical having the structure R-O-(CH 2 ) m H-COOZ; X is a direct chemical bond, -O-, -S-, -NH-, - -CH 2 COOZ or - -CH(CH 3 )COOZ; n is the integer 2 or 3, with the proviso that when X represents a direct bond, n is I, 2 or 3; Z is hydrogen or a unit of negative charge, and -(CH 2 ) m -may also be -CH 2 -C(CH 3 ) 2 -.
Claim 10
Dependent Claim
11 words
The media of claim 9 wherein the agent has the formula
Claim 11
Dependent Claim
12 words
II. The media of claim 9 wherein the agent has the formula
Claim 12
Dependent Claim
49 words
The media of claim 9 wherein the agent has the formula wherein T is -(CH 2 ) 1-2 -, -CH(COOH)-, or -CH(COOH)CH 2- , Q is = CH-or = N-, A is hydrogen, hydroxyl or lower hydroxyalkyl, and B is hydrogen, lower alkyl, halogen, carboxyl or -SO 3 H.
Claim 13
Dependent Claim
12 words
The media of claim 12 wherein Me (a+) is Fe (3+) .
Claim 14
Dependent Claim
11 words
The media of claim 9 wherein the agent has the formula
Claim 15
Dependent Claim
337 words
I5. In a method for NMR diagnosis of tissue wherein an effective amount of a media for diagnosis is administered, the improvement which comprises said media containing a relaxation time influencing effective amount of a compound having the formula wherein a is 2 or 3; b is an integer from 0 to 4; Me (a+) is Fe (2+) , Fe (3+) , Gd (3+) , or Mn (2+) ; E (b+) is an ion of an alkali metal, alkaline earth metal, alkyl ammonium, alkanol ammonium, polyhydroxyal- kyi ammonium, or basic protonated amino acid, said ions representing a total charge of b; m is an integer from I to 5; R is H, alkyl with from I to 8 carbon atoms, alkyl with from I to 8 carbon atoms wherein from I to 5 carbons are substituted with OH; aralkyl with I to 4 aliphatic carbon atoms; phenyl or phenyl substituted by halogen, hydroxyl, carboxyl, carboxamide, ester, S0 3 H, sulfonamide; lower alkyl, lower hydroxy alkyl, amino, acylamino; (poly)oxa-alkyl with I to 50 oxygen atoms and from 3 to 150 carbon atoms, wherein I to 5 hydrogen atoms may be substituted by OH; R 1 is -CH 2 COOZ, -CH(CH 3 )COOZ, CH 2 CH 2 -N(CH 2 COOZ) 2 , a hydroxy arylalkyl, hydroxy pyridylalkyl, hydroxy aryl(carboxy)alkyl or hydroxy pyridyl-(carboxy)-alkyl radical, where the aryl or pyridyl radical may be substituted by hydroxyl, hydroxy alkyl, alkyl, halogen, carboxyl or SO 3 H; R 2 is the same as R, or is wherein R 3 is -CH 2 COOZ, -CH(CH 3 )COOZ or a monovalent radical having the structure R-O-(CH 2 ) m - C H-COOZ; X is a direct chemical bond, -0-, -S-, -NH-, - N -CH 2 COOZ.or - N -CH(CH 3 )COOZ; n is the integer 2 or 3, with the proviso that when X represents a direct bond, n is I, 2 or 3; is hydrogen or a unit of negative charge, and -(CH2) m -may also be -CH 2 -C(CH 3 ) 2 -.
Claim 16
Dependent Claim
11 words
The method of claim 15 wherein the compound has the formula
Claim 17
Dependent Claim
11 words
The method of claim 15 wherein the compound has the formula:
Claim 18
Independent Claim
47 words
The method of claim I5 wherein the compound has the formula: wherein T is -(CH 2 ) I-2 -, -CH(COOH)-, or -CH(COOH)CH 2 -, Q is =CH-or =N-, A is hydrogen, hydroxyl or lower hydroxyalkyl, and B is hydrogen, lower alkyl, halogen, carboxyl or -SO 3 H.
Claim 19
Dependent Claim
12 words
The method of claim 18 wherein M (a+) is Fe (3+) .
Claim 20
Dependent Claim
11 words
The method of claim 15 wherein the compound has the formula
Claim 21
Independent Claim
268 words
A method for the preparation of the compound of claim I comprising reacting a salt, oxide, hydroxide, or basic salt of Me (a+) ion with a polyamino-polycarboxylic acid having the formula m is an integer from I to 5; R is H, alkyl with from I to 8 carbon atoms, alkyl with from I to 8 carbon atoms wherein from I to 5 carbons are substituted with OH; aralkyl with I to 4 aliphatic carbon atoms; phenyl or phenyl substituted by halogen, hydroxyl, carboxyl, carboxamide, ester, SO 3 H, sulfonamide; lower alkyl, lower hydroxy alkyl, amino, acylamino; (poly)oxa-alkyl with I to 50 oxygen atoms and from 3 to 150 carbon atoms, wherein I to 5 hydrogen atoms may be substituted by OH; R 1 is-CH 2 COOZ, -CH(CH 3 )COOZ,-CH 2 CH 2 -N(CH 2 COOZ) 2 , a hydroxy arylalkyl, hydroxy pyridylalkyl, hydroxy aryl(carboxy)-alkyl or hydroxy pyridyl-(carboxy)-alkyl radical, where the aryl or pyridyl radical may be substituted by hydroxyl, hydroxy alkyl, alkyl, halogen, carboxyl or SO 3 H; R 2 is the same as R, or is where R 3 is -CH2COOZ, -CH(CH3)COOZ or a monovalent radical having the structure R-O-(CH 2 ) m -CH-COOZ; X is a direct chemical bond, -0-, -S-, -NH-, -N-CH2COOZ or -N-CH(CH 3 )COOZ; n is the integer 2 or 3, with the proviso that when X represents a direct bond, n is I, 2 or 3; Z is hydrogen or a unit of negative charge and -(CH 2 ) m- may also be -CH 2 -C(CH 3 ) 2 -; or alkali metal salts, alkali-earth metal salts or amine salts thereof.
Claim 22
Dependent Claim
244 words
A polyamino-polycarboxylic acid having the formula wherein m is an integer from I to 5; R is H, alkyl with from I to 8 carbon atoms, alkyl with from I to 8 carbon atoms wherein from I to 5 carbons ar substituted with OH; aralkyl with I to 4 aliphatic carb atoms; phenyl or phenyl substituted by halogen, hydroxyl, carboxyl, carboxamide, ester, SO 3 H, sulfonamide; lower alkyl, lower hydroxy alkyl, amino, acylamino; (poly)oxa-alkyl with I to 50 oxygen atoms an from 3 to 150 carbon atoms, wherein I to 5 hydrogen ato may be substituted by OH; R, is -CH 2 COOZ, -CH(CH 3 )COOZ, CH 2 CH 2 -N(CH 2 COOZ) 2 , a hydro arylalkyl, hydroxy pyridylalkyl, hydroxy aryl(carboxy)-alkyl or hydroxy pyridyl-(carboxy)-alkyl radical, where the aryl or pyridyl radical may be substituted by hydroxyl, hydroxy alkyl, alkyl, halogen, carboxyl or SO 3 H; R2 is the same as R, or is wherein R3 is -CH 2 COOZ, -CH(CH 3 )COOZ or a monovalent radic having the structure R-O-(CH 2 ) m - C H-COOZ; X is a direct chemical bond, -0-, -S-, -NH-, - N -CH 2 COOZ or - N -CH(CH 3 )COOZ; n is the integer 2 or 3, with the proviso that when X represents a direct bond, n is I, 2 or 3; Z is hydrogen or a unit of negative charge and -(CH 2 ) m -may also be -CH 2 -C(CH 3 ) 2 -;
Claim 23
Dependent Claim
9 words
The polyamino-carboxylic acid of claim 22 having the formula
Claim 24
Dependent Claim
9 words
The polyamino-carboxylic acid of claim 22 having the formula
Claim 25
Dependent Claim
45 words
The polyamino-carboxylic acid of claim 22 having the formula wherein T is -(CH 2 ) I-2 -, -CH(COOH)-or -CH(COOH)CH 2 -, Q is = CH-or = N-, A is hydrogen, hydroxyl, lower hydroxyalkyl and B is hydrogen lower alkyl, halogen, carboxy or SO 3 H.
Claim 26
Dependent Claim
9 words
The polyamino-carboxylic acid of claim 22 having the formula
References Cited (Backward Citations)
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