IE902964A1 - Use of amide complex compounds - Google Patents
Use of amide complex compoundsInfo
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- IE902964A1 IE902964A1 IE296490A IE296490A IE902964A1 IE 902964 A1 IE902964 A1 IE 902964A1 IE 296490 A IE296490 A IE 296490A IE 296490 A IE296490 A IE 296490A IE 902964 A1 IE902964 A1 IE 902964A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Complex compounds of the general formula I in which n denotes the figures 0, 1 or 2, R<1> and R<2> denotes hydrogen atoms, lower alkyl groups, phenyl groups, benzyl groups or, if n represents the figure 0, also together denote a trimethylene or a tetramethylene group, R<3> denotes a saturated, unsaturated, straight- or branched-chain or cyclic aliphatic hydrocarbon radical having up to 16 C atoms, or, if R<4> is a hydrogen atom, at least one R<3> group, a cycloalkyl group or an aryl or aralkyl group optionally substituted by one or more di-C1-C6-alkanylamino groups or by one or more C1-C6- alkoxy groups, R<4> denotes a hydrogen atom, a saturated, unsaturated, straight- or branched-chain or cyclic hydrocarbon radical having up to 16 C atoms, or R<3> and R<4> together denote a saturated or unsaturated 5-membered or 6-membered ring optionally substituted by one or more C1-C6-alkyl radicals, C1-C5-hydroxyalkyl radicals, an optionally hydroxylated or C1-C6-alkoxylated C2-C6-acyl radical, hydroxyl radical, carbamoyl radical, carbamoyl-substituted C1-C6-alkyl radical, carbamoyl radical substituted on the carbamoyl nitrogen by one or two C1-C6-alkyl radical(s) - which can also form a ring optionally containing an oxygen atom - or a C1-C6-acylamino radical or C1-C6-alkylamino radical, which optionally contains a further nitrogen, oxygen or sulphur atom or a carbonyl group, X denotes a hydrogen atom and/or a metal ion equivalent, at least one element of atomic number 21-29, 42, 44 or 58-70, and Y denotes a with the proviso that at least two of the substituents X represent a metal ion equivalent, and their salts with organic and/or inorganic bases, are useful compounds for organ-specific NMR diagnosis and in patients with renal insufficiency.
Description
COMPLETE SPECIFICATION Use of amide complex compounds Patent Application by SCHERING AKTIENGESELLSCHAFT, a German Company of Berlin and Bergkamen, Federal Republic of Germany. -laSummarv of the Invention This invention relates to physiologically compatible amide complex compounds and the use thereof in the production of agents for organ-specific NMR diagnostics and for cases involving patients with renal insufficiency, as well as NMR methods utilizing these compounds.
European Patent Application Publication Number *·*» . - 2 (I) 1C 263,059 claims compounds of·Formula I R3 Y-CH, CH.CO-N I / ''R4 N— I -CH—(CH2-N-CH2)n- -CH- I -N I I xoocch2 '1 ' R CH2COOX R2 I ch2coox wherein n is 0, 1 or 2, R1 and R2 independently are hydrogen atoms, lower alkyl groups, phenyl groups, benzyl groups or, if n is 0, jointly can also form a trimethylene or a tetramethylene group, R3 is a saturated, unsaturated, straight-chain or branched-chain or cyclic .aliphatic hydrocarbon ’’j'ji or z ' residue of up to 16 carbon atoms and-, if R is a hydrogen atom, at least one R3 is a cycloalkyl group, or an aryl or aralkyl group optionally substituted by one or several di-C,-C6alkylamino groups or by one or several C,-^alkoxy groups, R4 is a hydrogen atom, or a saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon residue of up to 16 carbon atoms, or R3 and R4 jointly form a saturated or unsaturated 5- or 6-membered ring which is optionally substituted by one or several of Ο,-^-alkyl, C1-C5-hydroxyalkyl, optionally hydroxylated or C.,-C6-alkoxylated C2-C6-acyl, hydroxy, carbamoyl, carbamoylsubstituted C1-C6-alkyl residue, carbamoyl substituted on the carbamoyl nitrogen by one or two C^C^alkyl residue(s) — which can also form a ring optionally containing an oxy-gen atom — or C.,-C6-acylamino or C1-C6-alkyl-amino; this 5- or 6-membered ring optionally containing a further nitrogen, oxygen or sulfur atom, or carbonyl group, ’ ·.* X means a hydrogen atom and/or a metal ion equivalent, R3 / Y is a COOX or f0N. group, y as well as their salts with organic and/or inorganic 5 bases.
Compounds having the anion of one of these complex-forming amides and one or several central ions of an element of atomic numbers 21-29, 31, 32, 38, 39, 42-44, 49, 57-83 and optionally one or several cations of an inorganic and/or organic base or amino acid are suited for the production of NMR, X-ray and radiology diagnostic media.
It has now been found that surprisingly an unexpected pharmacokinetic behavior is displayed by compounds of this general Formula I if these compounds contain at least one element of atomic numbers 21-29, 42, 44 or 58-70 , i.e., at least two of the substituents X must stand for a metal ion equivalent of these elements, but in particular compounds of general Formula I wherein n is the number 1, 2 R and R are hydrogen atoms, · t td R is a saturated, unsaturated, straight-chain 'λ or branched-chain or cyclic hydrocarbon residue of ud to 16 carbon atoms or . 4 3 and, if R is a hydrogen atom, at least one R is a cycloalkyl group, or an aryl or aralkyl group optionally substituted by one or several di-C^-Cgalkylamino groups or by one or several C^-Cg-alkoxy groups, R is a hydrogen atom or a saturated, unsaturated straight-chain , branched-chain or cyclic hydrocarbon residue of up to 16 carbon atoms, X is a hydrogen atom and/or a metal ion equivalent of at least one element of atomic numbers 21-29, 42, 44 or 58-70, R3 / Y is a COOX or C0N\ group, R4 with the proviso that at least two of the substituents X stand for a metal ion equivalent, as well as their salts with organic and/or inorganic bases .
Thus, for example, MAGNEVIST®, thus far the only NMR contrast medium permitted worldwide, is distributed upon intravenous injection in an extra15 cellular fashion and is excreted via the kidneys by glomerular secretion. Passage of intact cell membranes and extrarenal excretion are practically not at all observed.
MAGNEVIST^ is especially well suited for the diagnosis of pathological regions (for example, inflammations, tumors, infarctions, etc.).
Contrast media exhibiting an at least partial extrarenal excretion would be desirable, especially for patients with limited, kidney function (β) (renal insufficiency) where MAGNEVIST is excreted only very slowly and, in part, can be removed from the organism only with the aid of a dialysis device. - 5 Consequently, there is a need for NMR contrast media exhibiting a 'different pharmacokinetic behavior and thus higher organ specificity than MAGNEVIST®.
Accordingly, it is an object of this invention 5 to provide such compounds and media and methods of using same.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
It has been found that the above-mentioned compounds surprisingly show the desired' property: renal elimination as well as excretion with the feces.
Surprisingly, elimination via the gallbladder, however, is not the only extrarenal path of elimination: in NMR studies on rats, upon intravenous administration of the compounds of this invention, a contrast enhancement of the gastrointestinal tract has also been unexpectedly observed. The kidneys, as well as implanted tumors, are likewise visualized with improved contrast.
Elimination (secretion) by way of the stomach has the advantage that contrasting of abdominal structures (e.g. pancreas) from the gastrointestinal tract is made possible, with a simultaneous contrast enhancement of pathological processes (tumors, inflammations). Imaging of the renal system, of the liver and gallbladder, and the bile ducts can moreover likewise be achieved. Besides the improved visualization of ulcers and 3C stomach carcinomas, it is also possible to perform studies on gastric acid secretion with the aid of imaging procedures.
Accordingly, by making the compounds of this invention available, help can be extended to patients with renal insufficiency as well as patients suffering from gastrointestinal disorders (at least 10% of the population in the Western industrial countries) .
Most of these patients, as well as a larg£ number of patients suspected of harboring such disease, must submit to diagnostic tests. At present, two methods suitable for this purpose are utilized above all: endoscopy and X-ray diagnostics with the aid of barium contrast media.
These tests exhibit various drawbacks: they carry the risk of radiation stress, cause trauma, are connected with inconveniences, occasionally even with risks for the patient, and thus can evoke psychological stress. In most cases, these tests must be repeated; their performance is relatively complicated, require the patient’s active cooperation (e.g. assumption of a specific bodily attitude) and frequently cannot be employed in case of frail and high-risk patients.
The object of providing novel diagnostic methods for the identification and localization of gastrointestinal diseases, which methods do not exhibit these drawbacks, has thus likewise been attained by the complex compounds and agents as mentioned above.
Their pharmacokinetics permit, even without specific measures, an improvement in the diagnosis of numerous diseases. The complexes for the most part are excreted again in unchanged form and rapidly so that, especially also in case of using relatively toxic metallic ions, no damaging effects are observed even at high dosage.
The practical use of the novel complexes is also facilitated by their favorable chemical stability. > · Compounds of formula I, wherein X is hydrogen, are called complexing agents, and those wherein at least two of the substituents X are a metal ion equivalent are called metal complexes.
For use in NMR diagnostics, the central ion of the complex salt will be paramagnetic. These are, in particular, the divalent and trivalent ions of the elements of atomic numbers 21-29, 42, 44 and 58-70. Suitable ions include, for example, the chromium(III), manganese(II), iron(II), cobalt(II), nicksl(II), copper(II), praseodymium(III), neodymium(III), samarium(III) and ytterbium(III) ions. On account of their very strong magnetic moment, the gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III) and iron(III) ions are especially preferred.
Suitable alkyl substituents R1 and R2 are hydrocarbons of 1-8, preferably 1-4 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, η-, sec- or tert.-butyl, isobutyl, and all isomers of pentyl, hexyl>t heptyl and octyl.
Suitable aliphatic* substituents R3 and R4 are saturated (e.g., alkyl), unsaturated (e.g., alkenyl), straight-chain or branched-chain or cyclic hydrocarbons of up to 16 carbon atoms, preferably 1-10 C atoms, most preferably saturated hydrocarbons of 1-10 carbon atoms, especially saturated hydrocarbons of 1-5 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, cyclohexyl, propenyl, etc.
Other suitable groups are the other alkyl groups mentioned above for R1 and R2 and isomers containing 9-16 C atoms as well as their alkenyl counterparts.
When R4 is a hydrogen atom, at Z.east one R3 is preferably C6-C10-aryl or C^qQ-Ar-q-C^alkyl group, e.g., phenyl or benzyl group, optionally substituted by one or several (e.g., up to three) di-C,- to C6-alkylamino groups - 8 or by one or several (e.g., up to three) C.,- to C6-alkoxy groups.
In addition, when R4 is a hydrogen atom, R3 can also preferably be a cycloalkyl group, as mentioned above. The cycloalkyl group generally contains 3-16 carbon atoms, preferably 4-7 carbon atoms.
The heterocyclic 5- or 6-membered ring formed by R3 and R4 with inclusion of the amide nitrogen can be saturated, unsaturated and/or substituted and can optionally contain a nitrogen, oxygen or sulfur atom or carbonyl group.
The heterocycle can be substituted by hydroxy, C.,-C6-alkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl, C^-Cj-hydroxyalkyl, e.g., hydroxymethyl, hydroxyethyl, or by C2-C6-acyl (e.g., alkanoyl), for example acetyl, propionyl, which can, if desired, be substituted by hydroxy or C^-C^-alkoxy, e.g., methoxy, ethoxy, etc.
A further substituent that can be mentioned is carbamoyl, linked to the heterocycle directly or separated by a C1-C6-alkylene group, for example methylene, ethylene, propylene, and which can also be substituted at the nitrogen, if desired, by one or two ^C6-alkyl residue(s), e.g., methyl, ethyl, propyl, isopropyl, etc. The alkyl groups can, optionally, form a ring, such as, for example, a pyrrolidine or piperidine ring. The carbamoyl nitrogen can also be part of a morpholine ring, i.e., the latter ring can have an O atom.
Another possible substituent on the heterocycle that can be mentioned is an optionally C^-C^-alkylated or (^-C^-acylated (e.g., alkanoylated) primary or secondary amino group, such as, for example, the methyl-, ethyl-, acetyl-, propionyl-, amino-, etc., group.
If the heterocycle is substituted, the total number of substituents is 1 to 3. - 9 Suitable heterocycles are, for example: the pyrrolidinyl, piperidyl, pyrazolidinyl, pyrrolinyl, pyrazolinyl, piperazinyl, morpholinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl rings.
If not all of the acidic hydrogen atoms are substituted by the central ion, then one, several, or all remaining hydrogen atom(s) can be replaced by cations of inorganic and/or organic bases or amino acids. Suitable inorganic cations include, for example, the lithium ion, the potassium ion, the calcium ion and, in particular, the sodium ion. Suitable cations of organic bases include, inter alia, those of primary, secondary or tertiary amines, e.g., ethanolamine, diethanolamine, morpholine, glucamine, Ν,Ν-dimethylglucamine and especially N-methylglucamine. Suitable cations of amino acids include, for example, those of lysine, of arginine, and of ornithine.
Introduction of amide groups for the production of the complexing agents, i.e., of compounds of general Formula I wherein X means hydrogen, takes place by conventional partial conversion of activated carboxyl groups into amide groups of the respectively suited tetra-, penta- and hexacarboxylic acids — in correspondence with the desired final product. All of the synthesis pathways known to a person skilled in the art are suitable for this procedure.
One example is the reaction of the anhydrides or esters of general Formulae II, IV, V and VI: voc-ch2 ^ch2-cov \ n-ch-(ch9-n-ch9) -CH-N 20C-CH2 r CH2C0'0H rz ch2-C0Z HOOC-CH? CH2-COV N-CH-(CH2-N-CH2)n-CH-N^ r5ooc-ch^ r1 ch2cooh r2 xch2-coz (II) (IV) HOOC-CH •N-CH-(CH2-N-CH2)η-ζΗ-Ν R5OOC-CH^ r1 CH„COOH -CH-N Π Ϊ2 \ )h r x ^/CH2C00H CH2C00H (V) HOOC-CH2· χ ΓΛ N-CH-(CH2-N-CH2)n-CH-N 0 (VI) c Z M ‘2 v R 00C-CH2z CH2COOH r wherein 1 2 R , R and n have the above-mentioned meanings, V and Z jointly mean an oxygen atom, or V is a 5 hydroxy group and Z is the grouping OR , wherein is a c-C,-alkyl residue, lb \ ♦ with amines of general Formula III HN ( III ) , 4 wherein R and R have the meanings given above.
Examples of suitable amines include: dimethyl5 amine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, di-sec-butylamine, N-methyl-n-propylamine, dioctylamine, dicyclohexylamine, N-ethylcyclohexylamine, diisopropenylamine, benzylamine, aniline, 4-methoxyaniline, 4-dimethyl10 aminoaniline, 3,5-dimethoxyaniline, 4-methoxybenzylamine, morpholine, pyrrolidine, piperidine, N-methylpiperazine, N-ethylpiperazine, N-(2-hydroxyethyl)piperazine, N-(hydroxymethyl)piperazine , piperazinoacetic acid isopropylamide, N-(piperazinomethyl15 carbonyl)morpholine, N-(piperazinomethylcarbonyl)pyrrolidine, 2-(2-hydroxymethyl)piperidine , 4-(2-hydroxyethyl) piperidine, 2-hydroxymethyIpiperidine, 4-hvdroxymethyIpiperidine, 2-hydroxymethylpyrrolidine, 3-hvdroxypiperidine, 4-hydroxypiperidine, 3-hydroxy20 pyrrolidine, 4-piperidone, 3-pyrroline, piperidine-3carboxylic acid amide, piperidine-4-carboxylic acid amide, piperidine-3-carboxylie acid diethylamide, piperidine-4-carboxylic acid dimethylamide, 2,6dimethylpiperidine, 2,6-dimethylmorpholine, N-acetyl25 piperazine, N-(2-hydroxypropionyl)piperazine , N-(3-hydroxypropionyl)piperazine, N-(methoxyacetyl)piperazine, 4-(N-acetyl-N-methylamino)piperidine, piperidine-4-carboxylic acid (3-oxapentamethylene)amide, piperidine-3-carboxylic acid (3-oxapentamethylene)amide, Ν-(Ν',N*-dimethylcarbamoyl)piperazine, pyrazoline, pyrazolidine, imidazoline, oxazolidine, thiazolidine, etc.
The saponification of any ester groups that may still be present takes place according to methods known to one skilled in the art, for example, by alkaline hydrolysis.
The acid anhydrides of general Formula II 10 can be prepared conventionally, for example in accordance with the mode of operation disclosed in U.S.
Patent 3,660,388 or DOS 1,695,050, with acetic anhydride in pyridine. However, in certain instances, it is especially advantageous to conduct the step of splitting off water in a gentle fashion with carbodiimides in a suitable solvent, such as, for example dimethylformamide or dimethylacetamide.
The preparation of the monoanhydrides of general Formula VI will be described by using as the example the monoanhydride of diethylenetriaminepentaacetic acid ethyl ester starting with the monoethyl ester of DTPA (J. Pharm. Sci. 68 : 194, 1979): 6 N - (2,6-Dioxomorpholinoethyl)-N -(ethoxycarbonylmethyl) -3,6-diazaoctanedioic Acid A suspension of 21.1 g (50 millimoles) of 6 9 N ,N -bis(carboxymethyl)-N -(ethoxycarbonylmethyl)3,6,9-triazaundecanedioic acid in 250 ml of acetic anhydride is agitated for 3 days at room temperature after adding 42.2 ml of pyridine. Then the precip30 itate is suctioned off, washed three times with respectively 50 ml of acetic anhydride and subsequently stirred for several hours with absolute diethyl ether. After suctioning off the product, washing same with absolute diethyl ether and drying under vacuum at 40° C, 18.0 g (= 89% of theory) of a white powder is obtained, mp 195-196° C.
Analysis (based on anhydrous substance): Calculated: C 47.64 H 6.25 N 10.42 Found: C 47.54 H 6.30 N 10.22 The reaction of the acid anhydrides to the amides can be performed in the liquid phase. Suitable reaction media include, for example, water, dipolar aprotic solvents, such as acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethylacetamide, and the like, or mixtures thereof. The reaction temperatures range between about 0° C and 100° C, temperatures of -80° C being preferred. The reaction periods range between 0.5 hour and 2 days, preferably between 1 hour and 36 hours.
The esters of general Formula V are produced conventionally, for example according to the processes described in R.A. Guilmette et al., J. Pharm. Sci. : 194 (1979) .
Aminolysis of the esters takes place in the liquid phase, for example in a suitable higher-boiling solvent, such as dimethylformamide, dimethylacetamide or dimethyl sulfoxide. The reaction temperatures are around 20° C to 200° C, temperatures of 100-180° C being preferred. The reaction times range between 2 hours and 2 days, reaction periods of between 4 hours and .36 hours being the preferred ones.
T Moreover, all methods known .to a person skilled in the art for converting carboxyl groups into amide groups can be employed for the synthesis of the complexing agents of Formula I according to this invention, for example, the method by Krejcarek and Tucker, Biochm. Biophys. Res. Commun. 77 : 581 (1977) via mixed anhydrides.
The resultant compounds of Formula I wherein X is a hydrogen atom represent complex-forming media. They can be isolated and purified, or they can be converted without isolation into metal complexes of general Formula I wherein at least two of the substituent X mean a metal ion equivalent.
The metal complexes are prepared conventional ly by the methods disclosed in Patents EP 71564, EP 130934 and DOS 3,401,052, by dissolving or suspending the metal oxide or a metal salt (e.g., the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 21-29, 42, 44 or 58-70 in water and/or a lower alcohol (such as methanol, ethanol or isopropanol) and reacting with a solution or suspension of the equivalent amount of the complex-forming acid of Formula I wherein X means a hydrogen atom and subsequently, if desired, substituting any acidic hydrogen atoms of acid groups present by cations of inorganic and/or organic bases or amino acids.
Neutralization is herein effected with the air of inorganic bases (for example, hydroxides, carbonates or bicarbonates) of, for example, sodium potassium, lithium and/or organic bases such as, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N,N-dimethylglucamine, as well as basic amino acids, such as, for example, lysine, arginine and ornithine.
In order to prepare the neutral complex compounds, it is possible, for example, to add to the acidic complex salts in an aqueous solution or suspension such an amount of the desired bases that the neutral point is reached. The resultant solution can subsequently be evaporated to dryness under vacuum.
It is frequently advantageous to precipitate the thusformed neutral salts by adding water-miscible solvents, such as, for example, lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.), and to obtain in this way crystallized products which can be readily isolated and easily purified. It has proven to be especially advantageous to add the desired base to the reaction mixture as early as during the complexing reaction, thereby saving a process step.
If the acidic complex compounds contain several free acidic groups, then it is frequently ex20 pedient to prepare neutral mixed salts containing inorganic as well as organic cations as the counterions.
This can be done, for example, by reacting the complexing acid in an aqueous suspension or solution with the oxide or salt of the element yielding the central ion and with half the amount of an organic base needed for neutralization, isolating the thusformed complex salt, purifying same if desired, and then combining same for complete neutralization with the required amount of inorganic base. The sequence of adding the bases can also be reversed.
The diagnostic media are likewise produced in a manner known per se by suspending or dissolving the complex compounds of this invention — optionally after adding the additives customary in galenic pharmacy — in an aqueous medium and subsequently sterilizing the suspension or solution, if desired. Suitable additives are, for example, physiologically acceptable buffers (such as, e.g., tromethamine), small additions of complexing agents (such as, e.g., diethylene triaminepentaacetic acid) or, if necessary, electrolytes such as, for example, sodium chloride or, if needed antioxidants, such as ascorbic acid, for example.
If, for enteral administration or other purposes, suspensions or solutions of the media of this invention in water or a physiological saline solution are desirable, they can be mixed with one or several auxiliary agents customary in galenic pharmacy (for example methylcellulose, lactose, mannitol) and/or tensides (e.g., lecithins, TWEENS®, MYRJ ®) and/or flavoring substances for taste improvement (e.g. ethereal oils).
In principle, it is also possible to prepare the diagnostic media of this invention even without isolation of the complex salts. In any event, special care must be directed toward effecting the chelate formation so that the salts and salt solutions according to this invention are practically devoid of toxically active metal ions that are not complexed.
This can be ensured, for example, with the aid of color indicators, such as xylenol orange, by control titrations during the manufacturing process. Consequently, the invention also relates to processes for preparing the complex compounds and their salts.
The final safety feature resides in purification of the isolated complex salt. \ · - 17 For nuclear spin tomography diagnostics in accordance with this invention, the diagnostic media are administered in a dosage of 1 /imol/kg to 5 mmol/kg, preferably 10 jxmol to 0.5 mmol/kg of the complex salt according to the invention. In case of intravenous injection, agueous formulations are used with a concentration of 50 /mol/1 to 2 mol/1, preferably 100 mmol/1 to 1 mol/1. Rectal as well as oral administration is preferably performed with solutions of a concentration of 0.1 mmol to 100 mmol/1. The volumes administered range from about ml to 2 1, in dependence on the diagnostic problem. Thus, the diagnostic media are intended for enteral and parenteral administration to mammals, including humans.
The diagnostic media fulfill the variegated requirements for suitability as contrast media for nuclear spin tomography. Thus, they are excellently suited, upon oral or parenteral administration, for improving the information content of the image obtained with the aid of the nuclear spin tomograph, by increasing the signal intensity. They show furthermore the high efficacy necessary for burdening the body with minimal amounts of foreign substances, and the good compatibility required for maintaining the noninvasive character of the tests.
The high water solubility of the diagnostic media permits production of highly concentrated solutions so that the volume load on the circulation is maintained within tolerable limits and dilution by body fluids is compensated, i.e., NMR diagnostic agents must show 100 to 1000 times the water solubility of that for in vitro NMR spectroscopy. Furthermore, the agents of this invention display not only high stability so that release or exchange of the -- toxic per se — ions not covalently bound to the complexes takes place only extremely gra35 dually within the time wherein the contrast media are again entirely eliminated. - 18 10 The agents of this invention can also be utilized for radiation therapy. Thus, complexes of gadolinium are excellently suited for neutron capture therapy due to the large capture cross section. If the medium of this invention is intended for use in the version of radiation therapy proposed by R.L. Mills et al. [Nature 336 : 787 (1988)], then the central ion must be derived from a Mossbauer isotope, such as, for example, 57Fe or 151Eu.
In their administration, the agents of this invention can also be given together with a suitable vehicle, such as, for example, serum or physiological saline solution and/or together with a protein, such as, for example, human serum albumin. The dosage herein is dependent on the type of cellular disorder and on the properties of the metal complex utilized.
Consequently, the objective has been achieved over-all of opening up novel possibilities in diagnostic medicine by means of the recited complex compounds.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
The entire disclosures of all applications, patents and publications, cited above and below, and of corresponding application Federal Republic of Germany P 39 27 444.6, filed August 16, 1989, are hereby incorporated by reference. v · Example 1 (a) 6-Carboxymethy1-3-ethoxycarbonylmethy1-9-pheny1aminocarbonylmethyl-3,6,9-triazaundecanedioic Acid At 0° C, 2.42 g (6 mmol) of N^-(2,6-dioxo5 morpholinoethyl)-Νθ-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid is combined in DMF with 4.16 ml (3.04 g, 30 mmol) of triethylamine and 559 mg (6 mmol) of aniline and stirred overnight at room temperature. Then the clear solution is concentrated under vacuum and the residue chromatographed on silica gel with dichloromethane/methanol/acetic acid/water (5:3:1:1) as the mobile phase. The combined fractions are passed over approximately 10 ml of Amberlite IR 120 (H+ form) and the acidic eluate is concentrated.
Yield: 2.35 g (79%) Calculated: C 53.21 H 6.50 N 11.29 Found: C 53.01 H 6.55 N 11.26 I (b) 3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioic Acid Phenyl Monoamide 1.5 g (3 mmol) of the ethyl ester described in Example 1(a) is dissolved in 2N NaOH and stirred for 2 hours at room temperature. A pH of 7 is set by adding Amberlite IR 120 (H+ form), the mixture is filtered off, and the neutral solution is passed over about 16 ml of Amberlite IR 120 (H+). The acidic eluate is concentrated and additionally dried under vacuum at 50° C.
Yield: 1.3 g (92.5%) Calculated: Found: C 51.27 C 51.19 H 6.03 N 11. H 5.99 N 11. (c) Gadolinium Complex of 3,6,9-Tris(carboxymethyl)3,6,9-triazaundecanedioic Acid Phenyl Monoamide 936 mg (2 mmol) of the complexing acid obtained according to Example 1(b) is dissolved in about 40 ml of water and combined at 80° C with 362 mg (1 mmol) of Gd2O3· After 30 minutes, the almost clear solution is filtered off and the filtrate is freezedried.
Yield: 1.23 g (98.8%), based on anhydrous substance. 10 Calculated: C 38.57 H 4.05 N 9.00 Gd 25.25 Found: C 38.33 H 4.10 N 9.03 Gd 24.99 Example 2 Preparation of a Solution of the N-Methylglucamine Salt of the Gadolinium Complex of 3,6,9-Tris(carboxymethyl)15 3,6,9-triazaundecanedioic Acid Phenyl Monoamide 1.87 g (3 mmol) of the gadolinium complex of ♦ 3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioic acid phenyl monoamide (Example 1) is suspended in 5 ml of water pro injectione and combined with 0.586 g (3 mmol) of N-methylglucamine, thus dissolving the complex. The mixture is filled up with water to 10 ml, the solution is introduced into a vial and subjected to heat sterilization. Τχ relaxation (1/mmol sec) is: in water: in plasma: 3.79 + 0.16 5.45 ± 0.68 Example 3 Preparation of a Solution of the Sodium Salt of the Gadolinium(III) Complex of 3,6,9-Tris(carboxymethyl)3,6,9-triazaundecanedioic Acid Phenyl Monoamide 62.27 g (0.1 mol) of the gadolinium complex obtained according to Example 1(c) is suspended in 800 ml of water pro injectione (p.i.) and dissolved at pH 7.2 by dropwise addition of normal sodium hydroxide solution. After adding 0.2 g of tromethamine, the mixture is filled up with water p.i. to 1000 ml, the solution is dispensed into bottles and heat-sterilized.
Example 4 (a) 3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioic Acid (N,N1-Diphenyl)diamide 42.88 g (120 mmol) of DTPA bis-anhydride is suspended in 330 ml of dimethylformamde and cooled inan ice bath under agitation to about 5° C. Within 50 minutes, a solution of 32.9 ml (360 mmol) of aniline in 30 ml of dimethylformamide is added dropwise. The mixture is stirred for another hour in an ice bath, then overnight at room temperature. After this time, a slightly turbid solution has formed. The solvent is removed under vacuum, and the smeary residue is triturated with diethyl ether to remove traces of sol25 vent. The residue is combined with 500 ml of water and dissolved by adding 20 ml of UN sodium hydroxide solution. The solution is combined with 3.5 g of active carbon, filtered, and freeze-dried, thus obtaining 73.9 g of the sodium salt of the title compound as a powder. (b) Gadolinium Complex of 3,6,9-Tris(carboxymethyl)3,6,9-triazaundecanedioic Acid (N,N1-Diphenyl)diamide .9 g of gadolinium oxide (30 mmol) is 5 heated under reflux with 10.6 ml of glacial acetic acid and 150 ml of water for 20 minutes. The solution is filtered through a 0.1 pm membrane filter, combined with 35.3 g (60 mmol) of the ligand obtained according to 4(a), and heated for 90 minutes to 80° C. The solution is stirred with 2.1 g of active carbon for 30 minutes, filtered, and then passed in succession over an anion exchange column (200 ml IRA-410) and 100 ml of cation exchanger (IRC-50). The eluates from the columns a filtered through a 0.1 ym membrane filter and freeze-dried, thus obtaining 17.6 g of the title compound as a white powder.
Analysis : Calculated: C 44.75 H 4.33 Gd 22.54 N 10.04 Found: C 44.60 H 4.44 Gd 22.42 N 9.89 Example 5 (a) 3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioic Acid (Ν,N'-Dibenzyl)diamide 42.88 g (120 mmol) of DTPA bis-anhydride is suspended in 330 ml of dimethylformamide and cooled in an ice bath under agitation to 5° C. Within one hour, a solution of 39.3 ml (360 mmol) of benzylamine in 30 ml of dimethylformamide is added dropwise. The mixture is stirred for another hour in the ice bath, then overnight at room temperature. After removal of the solvent under vacuum, the residue is triturated with % diethyl ether, combined with 500 ml of water, and dissolved by adding 20 ml of UN sodium hydroxide solution. After freeze-drying, 71 g of the sodium salt of the title compound is obtained as a light-yellow powder. (b) Gadolinium Complex of 3,6,9-Tris(carboxymethyl)3,6,9-triazaundecanedioic Acid (Ν,Ν’-Dibenzyl)diamide .9 g of gadolinium oxide (30 mmol) is heated under reflux with 10.6 ml of glacial acetic acid and 150 ml of water for 20 minutes. The solution is filtered over a 0.1 pm membrane filter, combined with 37 g (60 mmol) of the ligand obtained according to 5(a), and heated for 90 minutes to 80° C. The solution is stirred with 3 g of active carbon for minutes, filtered, and then passed in succession over an anion exchange column (200 ml IRA-410) and 100 ml cation exchange column (100 ml IRC-50). The eluates are filtered through a 0.1 pm membrane filter and freeze-dried, thus obtaining 18 g of the title com- pound as a white powder. Analysis : Calculated: C 46.33 H 4.72 Gd 21.66 N 9.65 Found: C 46.46 H 4.49 Gd 21.50 N 9.81 \ · Example 6 (a, 6-Carboxymethy1-3-ethoxycarbonylmethyl-9-benzylaminocarbonylmethyl-3,6,9-triazaundecanedioic Acid .04 g (12.5 mmol) of N - (2,6-dioxomorpholino6 ethyl)-N -(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid is suspended in 65 ml of dimethylformamide, stirred in an ice bath and combined, in succession, with 8.7 ml (62.5 mmol) of triethylamine and 1.34 g (12.5 mmol) of benzylamine. The mixture is then 10 stirred for another 2 hours in the ice bath, then overnight at room temperature. The solvent is removed by vacuum distillation, the residue is agitated with diisopropyl ether, suctioned off, and dried. For further purification, the residue is dissolved in such a quantity of 11N sodium hydroxide solution that a pH of 7 is just attained. To this mixture is added 5 g of silica gel, the suspension is dried under vacuum, and the residue is introduced into a column of 350 g of'silica gel charged with a mixture of chloroform/meth20 anol/glacial acetic acid/water (1750/1050/350/350).
The product is eluted with the same solvent and, after evaporation of the solvent, 4.98 g of a colorless, smeary substance is obtained which is dissolved in 35 ml of water and passed over a column with 35 ml of the cation exchangerIR 120. The column is washed with 70 ml of water, the combined eluates are evaporated under vacuum, and the residue is triturated with diethyl ether, thus obtaining 2.65 g of the title compound as a white powder.
Analysis: Calculated: Found: C 54.11 C 53.95 H 6.71 H 6.88 N 10.97 N 11.23 % (b) 3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioic Acid Benzyl Monoamide A solution of 2.26 g of the compound prepared according to Example 6(a) in 46 ml of IN sodium hydroxide solution is allowed to stand for 2.5 hours at room temperature, and the solution is then passed over a column of 110 ml of cation exchanger IR 120. Elution is first carried out with 200 ml of water, and this fraction is discarded. Then, 600 ml of 0.5N ammonia is used for elution; this eluate is adjusted to pH 2.3 by adding IR 120, and the solution is subjected to freeze-drying, thus obtaining 1.50 g of the title compound as a white powder Analysis : 15 Calculated: C 52.28 H 6.27 N 11 .61 Found: C 52.44 H 6.32 N 11 .80 (c) Gadolinium Complex of 3,6,9-Tris(carboxymethyl)3,6,9-triazaundecanedioic Acid Benzyl Monoamide 965 mg (2 mmol) of the compound produced in 20 accordance with Example 6(b) is heated with 40 ml of water and 362 mg (1 mmol) of gadolinium oxide for one hour to 80° C. The mixture is cooled to room temperature, the solution is filtered through a 0.1 ym membrane filter, and the compound is yielding 1.15 g of the title isolated by freeze-drying, compound as a white powder. Analysis : Calculated: C 39.61 H 4.27 Gd 24.70 N 8.80 Found: C 39.50 H 4.48 Gd 24.61 N 8.97 Example 7 Dysprosium(III) Complex of 3,6,9-Tris(carboxymethyl)3,6,9-triazaundecanedioic Acid Benzyl Monoamide 965 mg (2 mmol) of 3,6,9-tris(carboxymethyl)5 3,6,9-triazaundecanedioic acid benzyl monoamide (Example 6b) is heated with 40 ml of water and 373 mg (1 mmol) of dysprosium(III) oxide for one hour to 80° C. The mixture is cooled to room temperature, the solution is filtered through a 0.1 um membrane filter, and the compound is isolated by freeze-drying, thus obtaining 1.22 g of the title compound as a white powder. Analysis : Calculated: C 39.29 H 4.24 Dy 25.31 N 8.73 Found: C 39.41 Η 4.-51 Dy 25.19 N 8.70 Example 8 (a) 6-Carboxymethyl-3-ethoxycarbonylmethyl-9-tert♦ butylaminocarbonylmethy1-3,6,9-triazaundecanedioic Acid At 0° C, 2.42 g (6 mmol) of N^-(2,6-dioxo20 morpholinoethyl)-N^-(ethoxycarbonylmethyl)-3,6-diazaoctaneaioic acid is combined in DMF with 4.16 ml (3.04 g, 30 mmol) of triethylamine and 0.64 g (6 mmol) of tert-butylamine and stirred overnight at room temperature. The clear solution is then concentrated under vacuum and the residue chromatographed on silica gel with dichloromethane/methanol/acetic acid/water (5:3:1:1) as eluent. The combined fractions are passed over about 10 ml of Amberlite IR 120 (H+ form), and the acidic eluate is concentrated.
Yield: 2.14 g (75%) Calculated: C 50.41 H 7.62 N 11.76 Found: C 50.26 H 7.66 N 11.80 (b) 3,6,9-Tris(Carboxymethyl)-3,6,9-triazaundecanedioic Acid tert-Butyl Monoamide 1.43 g (3 mmol) of the ethyl ester described in Example 8(a) is dissolved in 2N NaOH and stirred for 2 hours at room temperature. By addition of Amberlite 120 (H+ form), the mixture is adjusted to pH 7, filtered off, and the neutral solution passed over about 16 ml of Amberlite IR 120 (H+). The acidic eluate is concentrated and further dried at 50° C under vacuum. Yield: 1.20 g (89%). Calculated: C 48.21 H 7. 19 N 12.49 Found : c 48.13 H 7. 24 N 12.41 15 (c) Gadolinium Complex of 3 ,6 , 9-Tris (carboxymethyl)- 3,6,9-triazaundecanedioic Acid tert-Butyl Monoamide 897 mg (2 mmol) of the complex-forming acid obtained according to Example 8(b) is dissolved in about 40 ml of water and combined at 80° C with 362 mg (1 mmol) of Gd2O3- After 30 minutes, the almost clear solution is filtered and the filtrate freeze-dried. Yield: 1.19 g (99%), based on anhydrous substance.
Calculated: C 35.87 H 4.85 N 9.30 Gd 26.09 Found: C 35.97 H 4.79 N 9.28 Gd 25.83 - 28 Example 9 (a) 6-Carboxymethyl-3-ethoxycarbonyImethy1-9(4-methoxybenzylcarbamoyImethyl)-3,6,9triazaundecanedioic Acid 14.10 g (35 mmol) of N - (2,6-dioxomorpholinoethyl)-N -(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid is combined in 175 ml of dimethylformamide at 0° C with 24.4 ml (175 mmol) of triethylamine and 4.67 ml (35 mmol) of 4-methoxybenzylamine and stirred overnight at room temperature. The solvent is extensively removed by vacuum distillation and the residue is heated to boiling with 600 ml of diisopropyl ether. After cooling to room temperature, the mixture is decanted off from the solvent. The residue is dissolved in 185 ml of water and passed over a column with 140 ml of cation exchanger IR 120 (H+ form), and the column is washed with 200 ml of water. The combined eluates are concentrated to one-third under vacuum and then freezedried, yielding 16.33 g of the title compound as a white powder which still contains 1.2% water and 1% dimethylformamide .
Analysis (after correction of solvent proportions): Calculated: C 53.33 H 6.71 N 10.36 Found: C 53.51 H 6.78 N 10.18 (b) 3,6-Bis(carboxymethyl)-9-(4-methoxybenzylcarbamoylmethyl)-3,6,9-triazaundecanedioic Acid 12.34 g (22 mmol) of the ethyl ester described in Example 9(a) is dissolved in 200 ml of water and 20 ml of UN sodium hydroxide solution and stirred for 2 hours at room temperature. A pH of 2.3 is reached by addition of 140 ml of Amberlite IR 120 (H+ form). The mixture is filtered and the solution subjected to freeze-drying.
Yield: 9.61 g (85% of theory), water content 2.18%.
Analysis (after correction of water content): Calculated: C 51.56 H 6.29 N 10.93 Found: C 51.37 H 6.44 N 10.89 (c) Gadolinium Complex of 3,6-Bis(carboxymethyl)-915 (4-methoxybenzylcarbamoylmethyl)-3,6,9triazaundecanedioic Acid .24 g (10 mmol) of the complexing acid obtained according to Example 9(b) is stirred in 200 ml of water with 1.81 g (5 mmol) of gadolinium oxide for one hour at 80° C, producing an almost clear solution. The latter is filtered and the filtrate subjected to freeze-drying.
Yield: 6.31 g, water content 3.7%.
Analysis (after correction of water content): Calculated: C 39.63 H 4.38 N 8.40 Gd 23.99 Found: C 39.88 H 4.53 N 8.51 Gd 23.70 (d) N-Methylglucamine Salt of the Gadolinium Complex of 3,6-Bis(carboxymethyl)-9-(4-methoxybenzylcarbamoyImethy1)-3, 6,9-triazaundecanedioic Acid g of the gadolinium complex obtained according to Example 9(c) is dissolved in 30 ml of water, combined with 1 equivalent of N-methylglucamine, and the solution is concentrated by evaporation under vacuum.
Yield: 2.30 g, water content 4%.
Analysis (after correction of water content): Calculated: C 40.41 H 5.38 N 8.12 Gd 18.24 Found : C 40.52 H 5.11 N 8.27 Gd 18.39 (e) Sodium Salt of the Gadolinium Complex of 3,6-Bis(carboxymethyl)-9-(4-methoxybenzylcarbamoylmethyl)-3,6,9-triazaundecanedioic Acid 0.5 g of the gadolinium complex obtained in accordance with Example 9(c) is dissolved in 10 ml of water, combined with 1 equivalent of sodium hydroxide dissolved in 5 ml of water, and the solution of the title compound is subjected to freeze-drying, producing 0.55 g of the title compound as a white powder with a water content of 4.5%.
Analysis (after correction of water content): Calculated: C 38.37 H 4.10 Gd 22.83 N 8.13 Na 3.34 Found: C 38.40 H 4.45 Gd 22.43 N 8.10 Na 3.57 Example 10 (a) 6-Carboxymethyl-3-ethoxycarbonylmethy1-9(N-undecylcarbamoylmethyl)-3,6,9-triazaundecanedioic Acid Under a nitrogen atmosphere, 12.10 g 6 (30 mmol) of N-{2,6-dioxomorpholinoethyl)-N (ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid in 1 liter of absolute dimethylformamide is combined at 0° C with 12.6 ml (91 mmol) of triethylamine and .14 g (30 mmol) of 1-undecylamine and stirred for hours at 20-25° C. After the reaction is completed, the solvent is evaporated under vacuum and the remaining oily residue is stirred with 1 liter of diethyl ether. The thus-separated white powder is suctioned off, rinsed with 1 liter of diethyl ether in portions, and the product is dried at 40° C under vacuum.
Yield: 14.31 g (83%), white powder.
Water content: .1.41 % Dimethylformamide content: 0.8% Analysis (after correction of solvent proportions): Calculated: C 56.43 H 8.77 N 9.75 Found: C 56.25 H 8.89 N 9.48 (b) 3,6-Bis(carboxymethyl)-9-(N-undecylcarbamoylmethyl)-3,6,9-triazaundecanedioic Acid g (17.4 mmol) of the ethyl ester described in Example 10(a) is dissolved in 200 ml of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. After the reaction is finished, the mixture is cooled to 5° C and concentrated hydro30 chloric acid is added until a pH value of 2.15 has been \ · - 32 attained. The thus-separated white powder is suctioned off and washed five times with 50 ml of ice water, five times with diethyl ether/ethanol (8:2), five times with 50 ml of diethyl ether, and five times with 50 ml of n-pentane.
Yield: 8.25 g (86.7%), white powder.
Water content: 2.12% Dimethylformamide content: < 0.05% Analysis (after correction of water content): Calculated: C 54.93 H 8.48 N 10.25 Found: C 54.78 H 8.67 N 9.98 (c) Gadolinium Complex of 3,6-Bis(carboxymethyl)-9(N-undecylcarbamoylmethyl)-3,6,9-triazaundecanedioic Acid At 80° C, 5.47 g (10 mmol) of the complexforming acid obtained according to Example 10(b) is stirred in 500 ml of water with 1.81 g (5 mmol) of gadolinium oxide for 4 hours, thus producing an almost clear solution. The latter is filtered and the filtrate subjected to freeze-drying.
Yield: 6.35 g (90.6%), white powder.
Water content: 4.2% Analysis (after correction of water content): Calculated: Found: C 42.84 C 42.91 H 6.18 H 6.25 N 7. N 7.
Gd 22.44 87 Gd 22.40 - 33 (d) Mono-N-methylglucamine Salt of the Gadolinium Complex of 3,6-Bis(carboxymethyl)-9-(N-undecylcarbamoylmethyl)-3,6,9-triazaundecanedioic Acid g of the gadolinium complex obtained in 5 accordance with Example 10(c) is dissolved in 35 ml of water, combined with one equivalent of N-methylglucamine, filtered, and the solution is evaporated under vacuum.
Yield: 2.25 g (88%), white powder.
Water content: 3.75% Analysis (after correction of water content): Calculated: C 42.89 H 6.75 N 7.82 Gd 17.55 Found: C 42.73 H 6.89 N 7.69 Gd 17.48 Example 11 (a) 6-Carboxymethyl-3-ethoxycarbonylmethyl-9-(1-hexadecylcarbamoylmethyl)-3,6,9-triazaundecanedioic Acid 28.20 g (70 mmol) of N^-(2,6-dioxomorpholinoethyl) -N^-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid is combined in 320 ml of dimethylformamide at 0° C with 28.8 ml (350 mmol) of triethylamine and 16.90 g (70 mmol) of 1-hexadecylamine and then stirred for 24 hours at 20-25° C. The mixture is thereafter concentrated under vacuum and the residue stirred under boiling heat with 1 liter of methyl tert-butyl ether. After cooling to +10° C, the mixture is suctioned off, the residue dried at 45° C under vacuum, taken up in 400 ml of water, and the solution is passed over a column with 300 ml of ion exchanger IR 120 (H+ form), the column is washed with 0.5 liter of water, and the combined eluates are concentrated under vacuum to about 300 ml, and the title compound is isolated by freezedrying, thus obtaining 36.5 g as a white powder.
Water content: 1.70% Dimethylformamide content: 0.7% Analysis (after correction of solvent proportions): Calculated: C 59.60 H 9.38 N 8.69 Found: C 59.42 H 9.49 N 8.85 (b) 3,6-Bis(carboxymethyl)-9-(1-hexadecylcarbamoylmethyl)-3,6,9-triazaundecanedioic Acid 6.45 g (10 mmol) of the ethyl ester disclosed in Example 11(a) is dissolved in 100 ml of water and 9.1 ml of 11N sodium hydroxide solution and left for 2 hours at room temperature. Under agitation, the mixture is combined with 65 ml of ion exchanger Amberlite IR 120 (H+ form), thus setting a pH of 2.5. The mixture is filtered and the solution is subjected to freeze-drying, thus obtaining 5.30 g of the title compound as a white powder.
Water content: 3.2% Dimethylformamide content: < 0.05% Analysis (after correction of water content): Calculated: C 58.42 H 9.15 N 9.08 Found: C 58.59 H 9.44 N 8.95 (c) Monomeglumine Salt of the Gadolinium Complex of 3,6-Bis(carboxymethyl)-9-(1-hexadecylcarbamoylmethyl)-3,6,9-triazaundecanedioic Acid At 80-85° C, 4.93 g (8 mmol) of the complex5 forming acid obtained according to Example 11(b) is stirred in 170 ml of water for 2 hours with 1.45 g (4 mmol) of gadolinium oxide and 1.56 g (8 mmol) of N-methylglucamine. The almost clear solution is filtered and freeze-dried.
Yield: 7.49 g of a white powder.
Water content: 2.8% Analysis (after correction of water content): Calculated: c 45.99 H 7. 30 N 7.25 Gd 16.27 Found: c 46.21 H 7. 55 N 7.08 Gd 16.18 15 By the same route as described· in Example 11, the monomeglumine salt of the europium complex of 3,6bis(carboxymethyl)-9-(1-hexadecylcarbamoylmethyl)3,6,9-triazaundecanedioic acid can be prepared as well.
Example 12 Preparation of a Solution of the Meglumine Salt of the Gadolinium Complex of 3,6,9-Tris(carboxymethyl)-3,6,9triazaundecanedioic Acid Undecyl Monoamide 448.57 g (0.5 mol) of the compound described in Example 10(d) is dissolved under heating in 600 ml of water pro injectione (p.i.). After addition of 4.92 g (10 mmol) of the monohydrate of the calciumtrisodium salt of DTPA, CaNa^DTPA, the solution is filled up with water p.i. to 1000 ml. The solution is subjected to ultrafiltration, dispensed into bottles, and heatsterilized, and is ready for use for parenteral administration. . > ♦ - 36 Example 13 Production of a Powder Form of Administration 89.61 g (0.1 mol) of the meglumine salt disclosed in Example 10(d) is finely ground up with 25 g of sucrose 5 and 5 g of Pluronic F 68 and 10 mg of raspberry flavoring. The powder is filled into bags and is ready for oral administration.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Claims (28)
1. In a method of NMR imaging, the improvement comprising administering an organ-specific contrast agent wherein said agent comprises a compound of the formula R 3 / Y-CH 2 CH.CO-N' I / ''E 1 N-CH— (CH ? -N-CH-,) n -CH-N II, I I 2 I (I) xoocch 2 r 1 ch2coox r z ch2coox wherein n is 0, 1 or 2; R 1 and R 2 are each independent H, C^g-alkvl, phenyl, benzyl, or, if n is 0, can also jointly form trimethylene or tetramethylene; 3 . ,a saturated,, unsaturated, straight-chain or branched-chain or R is /apx>a^Pfe«axexowixffl)cam®n&xex»teams cyclic hydrocarbon or up to 16 C atoms nr arKJ, when R is H, at least one R 0 is C 3 . 16 -cycloalkyl, C 6 . 10 -aryl, C 6 . l0 -aryl-C 1 . 6 -alkyl, i r ’ or C 6 . 10 -aryl or C 6 . 10 -aryl-C l . 6 -all:yl substituted by one or more di-C 1 . 6 -alkylamino or one or more C.^-alkoxy; / , saturated, unsaturated, straight-chain or branchedR* is chain or cyclic hydrocarbon of up to 16 C atoms aWftSiX or R 3 and R 4 jointly form a saturated or unsaturated 5- or 6-membered ring, optionally containing a N, 0 or S atom and/or optionally substituted by oxo, C 1 . 6 -alkyl, C^j-hydroxyalkyl, C 2 . ( -alkanoyl, C 2 . 6 -alkanoyl substituted by OH, C 2 . 6 -alkanoyl substituted by C V6 -alkyl, hydroxy, carbamoyl', C^-alkyl substituted - by carbamoyl, carbamoyl' - 38 substituted on the carbamoyl nitrogen by one or two C 1 . 6 -alkyl group(s) — the latter optionally together fora a ring which optionally contains an 0 atom, or a C.,-C 6 -acylamino or alkylamino; is H and/or a metal ion equivalent of at least one element of atomic numbers 21-29, 42, 44 or 58-70, with the proviso that at least two of the X groups represent a metal ion equivalent; and is a COOX- or CON ; or physiologically acceptable salt and/or inorganic base. thereof with organic R 1 R 3
2. and R 2 EC A method according to claim 1, wherein is 1 ; are each H; , . , □ L a saturated, unsaturated, straight-chain or branched-chain is/ an, xa 1 iphat ic< >hy dr oca rbonxof< >up x t ex xl 6x XI xa toms or cyclic hydrocarbon of up to lb C atoms or and, when R is H, at least one R 5 is C 3 . 16 -cycloalkyl, C 6 . 10 -aryl, C^-aryl-C^-alkyl, or C 6 . 1Q -aryl or C 6 . 10 -aryl-C 1 . 6 -all;yl substituted by one or more di-C 1 . 6 -alkylamino or one or more C. .-alkoxy; and , saturated, unsaturated, straight-chain or branched-chain is H/ atoms 7 . or cyclic hydrocarbon of up to 16C atoms.
3. A method according to claim 1, wherein Y is COOX-.
4. A method according to claim 1, wherein Y is ,R CON R - 39 - 5. A method according to claim 2, wherein Y is COOX-. 6. A ^ R3 method according to claim 2, wherein Y is GON • 7. A method according to claim 1, wherein R 4 is H and R 3 is C 3 . 16 -cycloalkyl, C 6 . 10 -aryl, C^Q-.iryl-C^-alkyl, or C 6 . 10 -aryl or C 6 . 10 -aryl-C 1 . 6 -alkyl substituted by one or more di-C^-C^-alkylamino or one or more C, 6 -alkoxy.
5. 8. A method according to claim 2, wherein R 4 is H and R 3 is C 3 . 16 -cycloalkyl, C 6 . 10 -aryl, C 6 . 10 -aryl-C, . 6 -alkyl, or C 6 . 10 -aryl or C 6 . 10 -aryl-C 1 . 6 -alkyl substituted by one or more di-C,-C 6 -alkylamino or one or more C 1 . 6 -alkoxy.
6. 9. A method according to claim 1, wherein said compound is: (a) gadolinium complex of 3,6,9-tris(carboxymethyl)3,6,9-triazaundecanedioic acid phenyl monoamide; (b) gadolinium complex of 3,6,9-tris(carboxymethyl)3,6,9-triazaundecanedioic acid (N,N'diphenyl) diamide; (c) gadolinium complex of 3,6,9-tris(carboxymethyl)3,6,9-triazaundecanedioic acid (N,N'~ dibenzyl) diamide; (d) gadolinium complex of 3,6,9-tris(carboxymethyl)3,6,9-triazaundecanedioic acid benzyl monoamide; (e) dysprosium(III) complex of 3,6,9tris(carboxymethyl)-3,6,9-triazaundecanedioic acid benzyl monoamide; (f) gadolinium complex of 3,6,9-tris(carboxymethyl)3,6,9-triazaundecanedioic acid tert-butyl monoamide - 40 (g) gadolinium complex of 3,6,9-bis(carboxymethyl)-9(4-methoxybenzylcarbamoylmethyl)-3,6,9triazaundecanedioic acid; (h) gadolinium complex of 3,6-bis(carboxymethyl)-9-(Nundecylcarbamoylmethyl) -3,6,9-triazaundecanedioic acid; (i) gadolinium complex of 3,6-bis(carboxymethyl)-9-(1hexadecylcarbamoylmethyl )-3,6,9-triazaundecanedioic acid; or a physiologically acceptable salt of anyone of (a)-(h) with organic and/or inorganic base.
7. 10. A method according to any preceding claim, wherein said agent further comprises a pharmaceutically acceptable carrier. A method according to any preceding claim, wherein said agent is sterile. 12 A method according to any preceding claim, wherein said agent further comprises additional separate complexing agent. 13 A method according to any preceding claim, wherein said agent further comprises a physiologically acceptable buffer, an electrolyte, and/or an antioxidant. 14 A method according to any preceding claim, wherein said agent is administered orally.
8. 15. A method according to claim 14, wherein said complex is administered at a concentration of 0.1 mmol/1-100 mmol/1.
9. 16. A method according to any of claims 1 to 13, wherein said agent is administered intravenously. .·... - 41
10. 17. A method according to claim 16, wherein said complex is administered at a concentration of 50 /imol/1-2 mol/1.
11. 18. A method according to any preceding claim, wherein said complex is administered at a dosage of 1 umol-5 m-mni per kg of body weight.
12. 19. agent is A method according to any preceding administered to a human. claim, wherein said
13. 20. A method according to any preceding claim, wherein the renal system is imaged.
14. 21. A method according to any of claims 1 to 19, wherein the liver is imaged.
15. 22. A method according to any of claims 1 to 19, wherein the gall bladder is imaged.
16. 23. A method according to any of claims 1 to 19, wherein bile duct(s) are imaged.
17. 24. A method according to any of claims 1 to 19, wherein stomach ulcer(s) are imaged. 25 A method according to any of claims 1 to 19, wherein stomach carcinoma(s) are imaged.
18. 26. In a method of organ-specific NMR imaging, the improvement comprises administering a contrast agent wherein said agent comprises a physiologically compatible complex compound of the formula - 42 R 3 / Y-CH, CH,CO-N I / 2 X R 4 N-CH— (CH 2 -N-CH 2 ) n -CH-N XOOCCH 2 R 1 CH 2 COOX R CH 2 COOX wherein n is 0, 1 or 2; R 1 and R 2 are each independent H, C^g-alkyl, phenyl, benzyl, or, if n is 0, can also jointly form trimethylene or tetramethylene; , a saturated, unsaturated, straight-chair, or branched-chain R is /^n X»p< xtox i&xCx stOTasx or cyclic hydrocarbon of up to 16 C atoms or andy when R is H, at least one R is C 6 . 10 -aryl, Cg^-aryl-C^-alkyl, ! Z* \ or C 6 . 10 -aryl or Cg.^-aryl-C^-alkyl substituted by one or more di-C 1 . 6 -alkylamino or one or more C. 6 -alkoxy; , saturated, unsaturated, straight-chain or branched-chain r is or cyclic hydrocarbon of up to 16 C atoms atoms? or R 3 and R 4 jointly form a saturated or unsaturated 5- or 6-membered ring, optionally containing a N, 0 or S atom and/or optionally substituted by oxo, C 1 . 6 -alkyl, C^-hydroxyalkyl, C 2 . 6 -alkanoyl, C 2 . 6 -alkanoyl substituted by OH, C 2 . 6 -alkanoyl substituted by C 1 . 6 -alkyl, hydroxy, carbamoyl, C 1 . 6 -alkyl substituted by carbamoyl, carbamoyl substituted on the carbamoyl nitrogen by one or two C 1 . 6 -alkyl group(s) — the latter optionally together form a ring which optionally contains an O atom, or a C^g-acylamino or C 1 . 6 alkylamino; X is H and/or a metal ion equivalent of at least one element of atomic numbers 21-29, 42, 44 or 58-70, with the proviso that at least two of - 43 the X groups represent a metal ion equivalent; ,3 or is a COOX- or CON or physiologically acceptable salt thereof with organic and/or inorganic base.
19. 27. n R 1 and R 2 A method according to claim 26, wherein is 1; are each H; a saturated, unsaturated, straiqht-chain or branched-chain i s /anx a/kiphtafcicx hydrccaoKboEK xxfx xipc xtoxxt<6 x or cyclic hydrocarbon of up to 16 C atora% ana/ when R is H, at least one R or is 2H C 3 . 16 -cycloalkyl, C 6 . 10 -aryl, C< or C 6 . 10 -aryl or C 6 . 10 -aryl-C 1 . 6 -al];yl substituted by one or more di-C 1 . 6 -alkylamino or one or more νλ ω -γϊΛ C^-alko and '' ,, saturated, unsaturated, straight-chain or branched-chain is h /nr atoms.
20. 28. In a method of NMR imaging, the improvement comprises administering to a patient with renal insufficiency a contrast agent wherein said agent comprises a physiologically compatible complex compound of the formula R 3 / Y-CH-, CH,CO-N I / N-CH— (CH,-N-CH,) n -CH-N IL III (i) xoocch 2 r ch 2 coox r ch 2 coox wherein n R 1 and R 2 is 0, 1 or 2; are each independent H, C^g-alkyl, phenyl, benzyl, or, if n is 0, can also jointly form C./' 1 trimethylene or tetramethylene; a saturated v unsaturated, straight-chain„q. is ^x»iasphwb05a:xtaya3iac»«»3ianxxxKXMixXR«x: or cyclic hydrocarbon of up to 16 C atojns. or arack, when R* is H, at· least one R is ranched-chain R J - 44 C 3 . 16 -cycloalkyl, C 6 . 10 -aryl, C 6 . 10 -aryl-C,. 6 -alkyl, or or c 6-io _ar yl“ c i-6~alkyl substituted by one or more di-C^-alkylamino or one or more C, 6 -alkoxy; saturated, unsaturated, straight-chain or branched-chain is H/ai%>«li£it^£i&X)hydxxH3arbxxxx8&}upxfco(xigx;C; or cyclic hydrocarbon of up to 16 C atoms R 3 and R 4 is or jointly form a saturated or unsaturated 5- or 6-membered ring, optionally containing a N, 0 or S atom and/or optionally substituted by oxo, C 1 . 6 -alkyl, C^j-hydroxyalkyl, C 2 . 6 -alkanoyl, C 2 . 6 -alkanoyl substituted by OH, C 2 . 6 -alkanoyl substituted by C V6 -alkyl, hydroxy, carbamoyl, C 1 . 6 -alkyl substituted by carbamoyl, carbamoyl substituted on the carbamoyl nitrogen by one or two C 1 . 6 -alkyl group(s) — the latter optionally together form a ring which optionally contains an 0 atom, or a C 1 . 6 -acylamino or C v6 alkylamino; is H and/or a metal ion equivalent of at least one element of atomic numbers 21-29, 42, 44 or 58-70, with the proviso that at least two of the X groups represent a metal ion equivalent; or R 3 is a COOX- or CON or physiologically acceptable salt thereof with organic and/or inorganic base.
21. 29. n R 1 and R 2 R 3 A method according to claim 28, wherein is 1 ; are each H; a saturated, unsaturated, straight-chain or branched-chain i s x iiydrooarborx xxf x χκχ xfcox Xfe8 xCoat ®ms< or cyclic hydrocarbon of up to 16 C atoms.or and, when R is H, at least one R is Cj^-cycloalkyl, C 6 . 10 -aryl, C 6 . 10 -aryl-C 1 . 6 -alkyl, or C 6 . ]0 -aryl or C 6 . 10 -aryl-C V6 -all;yl substituted - 45 by one or more di-C^-alkylamino or one or more C^-alko and saturated, unsaturated, straight-chain or branched-chain « CWUUlWk/C.'-ij UII'JUUUIUUC'U) O Ul Cl I y ll U ό IIU I II VI V I O I IV is H /qrx;e«xala^atix2cxhyda?Q^axi>onxBi&xapx>feiaxi£ atoms:/
22. 30. In a method of NMR imaging, the improvement comprises administering to a patient with a gastrointestinal disorder a contrast agent wherein said agent comprises a physiologically compatible complex compound of the formula R 3 Y-CH, ch 2 co-n N-CH— (CH 2 -N-CH 2 ) n -CH-N xoocch 2 R 1 ch 2 coox R 2 CH 2 COOX (I) wherein n R 1 and R 2 is 0, 1 or 2; are each independent Η, C 1 . 8 -alkvl, phenyl, benzyl, or, if n is 0, can also jointly form trimethylene or tetramethylene; a saturated, unsaturated, straight-chain or branched-chain or C and, when R is Η, at least one R is - 3 -i 6 -cycloalkyl, C 6 . 10 aryl, C^Q-aryl-C^-alkyl, C 3 _ or C6.10-aryl or c 6 by one or more di-C1. 6 -alkylamino or one or more c i-6 a l^°Xfurated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon ot up to To C atoms: or ui '- 6 - l0 - aryl-C 1 , 6 -alkyl substituted R and R jointly form a saturated or unsaturated 5- or 6-membered ring, optionally containing a N, O or S atom and/or optionally substituted by oxo, C 1 . 6 -alkyl, C V5 -hydr oxy alkyl, C 2 . (i -alkanoyl, C 2 . 6 -alkanoyl substituted by OH, C 2 . 6 -alkanoyl substituted by C v6 -alkyl, hydro: 1 . 6 -alkyl substituted by carbamoyl, carbamoyl substituted on the carbamoyl nitrogen by one or two C v6 -alkyl group(s) — the latter optionally - 46 . _ together form a ring which optionally contains an O atom, or C^-acylamino or C 1 . 6 -alkylamino; X is H and/or a metal ion equivalent of at least one element of atomic numbers 21-29, 42, 44 or 58-70, with the proviso that at least two of the X groups represent a metal ion equivalent ,Ε 3 Y is a COOX- or CON ; or ^R 4 physiologically acceptable salt thereof with organic and/or inorganic base.
23. 31. A method according to claim 30, wherein R 1 and R 2 R 3 is 1; are each H; ,a saturated., unsaturated, straight-ch is /an<;^liphat;iEX 3 . 16 -cycloalkyl, C 6 . 10 -aryl, C 6 . 10 -aryl-C,. 6 -alkyl, or C 6 . 10 -aryl or C^g-aryl-C^-alkyl substituted by one or more di-C V6 -alkylamino or one or more am or branched-chain r o- xl 6 x €< >at eras C 1 _ 6 -alkoxy; and 4 ,, saturated, unsaturated, straight-chain or branched-chain R is H/xnxxahx)aidpixeofxxip;xtx>;xi6xC< 1C hydrocarbon of up to 16 C atoms.
24. 32. A contrast agent for use in NMR imaging when said agent comprises a compound as laid out in any preceding claim.
25. 33. Use of a compound as claid out in any preceding claim for the production of agents for organ-specific NMR diagnostics. -46aIE 902964
26. 34. A method substantially as hereinbefore described with reference to the Examples.
27. 35. A contrast agent substantially as hereinbefore described with reference to the Examples.
28. 36. A use substantially as hereinbefore described with reference to the Examples.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3927444A DE3927444A1 (en) | 1989-08-16 | 1989-08-16 | USE OF AMID COMPLEX COMPOUNDS |
Publications (1)
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IE902964A1 true IE902964A1 (en) | 1991-02-27 |
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ID=6387458
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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IE296490A IE902964A1 (en) | 1989-08-16 | 1990-08-15 | Use of amide complex compounds |
Country Status (10)
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EP (1) | EP0413405A3 (en) |
JP (1) | JPH03173856A (en) |
AU (1) | AU6107390A (en) |
DE (1) | DE3927444A1 (en) |
FI (1) | FI904060A0 (en) |
IE (1) | IE902964A1 (en) |
IL (1) | IL95394A0 (en) |
NO (1) | NO903597L (en) |
PT (1) | PT95008A (en) |
ZA (1) | ZA906511B (en) |
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US5077037A (en) * | 1990-08-03 | 1991-12-31 | Mallinckrodt Medical, Inc. | Novel compositions for magnetic resonance imaging |
GB9024208D0 (en) * | 1990-11-07 | 1990-12-19 | Salutar Inc | Compounds |
GB9027922D0 (en) * | 1990-12-21 | 1991-02-13 | Nycomed As | Compounds |
US5463030A (en) * | 1991-05-03 | 1995-10-31 | Research Foundation Of The State Of New York | Metal chelating agents for medical application |
AU660033B2 (en) * | 1991-05-23 | 1995-06-08 | Imarx Pharmaceutical Corp. | Liposoluble compounds for magnetic resonance imaging |
WO1994001393A1 (en) * | 1992-07-03 | 1994-01-20 | The Green Cross Corporation | Novel chelating agent, complex compound composed of said agent and metallic atom, and diagnostic agent containing said compound |
US6875864B2 (en) | 1991-08-01 | 2005-04-05 | Bracco International B.V. | Aminocarboxylate ligands having substituted aromatic amide moieties |
US5562894A (en) * | 1991-08-09 | 1996-10-08 | Regents Of The University Of California | Amino-acyl-type and catecholamine-type contrast agents for MRI |
EP0598837A4 (en) * | 1991-08-09 | 1994-07-13 | Univ California | Amino acid, ester and/or catechol contrast agents for mri. |
GB9208908D0 (en) * | 1992-04-24 | 1992-06-10 | Nycomed As | Contrast agents |
DE4317588C2 (en) * | 1993-05-24 | 1998-04-16 | Schering Ag | Macrocyclic metal complexes containing fluorine, process for their preparation and their use |
DE4318369C1 (en) * | 1993-05-28 | 1995-02-09 | Schering Ag | Use of macrocyclic metal complexes as temperature probes |
JPH09505819A (en) * | 1993-12-03 | 1997-06-10 | ブラッコ エッセ.ピ.ア. | Paramagnetic chelate for nuclear magnetic resonance diagnostics |
WO1995027705A1 (en) * | 1994-04-08 | 1995-10-19 | Bracco International B.V. | Aromatic amide compounds and metal chelates thereof |
IL117200A0 (en) * | 1995-02-21 | 1996-06-18 | Schering Ag | Diethylenetriamine-pentaacetic acid monoamide derivatives pharmaceutical compostions containing the same and processes for the preparation thereof |
DE19507822B4 (en) * | 1995-02-21 | 2006-07-20 | Schering Ag | Substituted DTPA monoamides of the central carboxylic acid and its metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics and therapy, and methods for the preparation of the complexes and agents |
DE19507820A1 (en) * | 1995-02-21 | 1996-08-22 | Schering Ag | Novel substituted DTPA derivatives, their metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics, and methods for producing the complexes and compositions |
DE19507819A1 (en) * | 1995-02-21 | 1996-08-22 | Schering Ag | New di:ethylene-tri:amine penta:acetic acid amide complexes |
DE19646762B4 (en) * | 1996-11-04 | 2004-05-13 | Schering Ag | Use of metal compounds for the production of agents for radiotherapy of tumors |
JP5406459B2 (en) * | 2008-02-20 | 2014-02-05 | 光司 山下 | Gadolinium compound and contrast medium for MRI |
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CH474533A (en) * | 1966-12-14 | 1969-06-30 | Geigy Ag J R | Process for the preparation of bis-carboxylic acid anhydrides |
DE3129906C3 (en) * | 1981-07-24 | 1996-12-19 | Schering Ag | Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics |
NL194579C (en) * | 1983-01-21 | 2002-08-05 | Schering Ag | Diagnostic. |
US4687659A (en) * | 1984-11-13 | 1987-08-18 | Salutar, Inc. | Diamide-DTPA-paramagnetic contrast agents for MR imaging |
IL83966A (en) * | 1986-09-26 | 1992-03-29 | Schering Ag | Amides of aminopolycarboxylic acids and pharmaceutical compositions containing them |
-
1989
- 1989-08-16 DE DE3927444A patent/DE3927444A1/en not_active Withdrawn
-
1990
- 1990-08-14 EP EP19900250206 patent/EP0413405A3/en not_active Withdrawn
- 1990-08-15 NO NO90903597A patent/NO903597L/en unknown
- 1990-08-15 IE IE296490A patent/IE902964A1/en unknown
- 1990-08-15 AU AU61073/90A patent/AU6107390A/en not_active Abandoned
- 1990-08-16 PT PT95008A patent/PT95008A/en not_active Application Discontinuation
- 1990-08-16 ZA ZA906511A patent/ZA906511B/en unknown
- 1990-08-16 JP JP2215096A patent/JPH03173856A/en active Pending
- 1990-08-16 IL IL95394A patent/IL95394A0/en unknown
- 1990-08-16 FI FI904060A patent/FI904060A0/en not_active IP Right Cessation
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Publication number | Publication date |
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PT95008A (en) | 1991-04-18 |
AU6107390A (en) | 1991-02-21 |
NO903597L (en) | 1991-02-18 |
IL95394A0 (en) | 1991-06-30 |
ZA906511B (en) | 1991-09-25 |
EP0413405A3 (en) | 1991-10-16 |
NO903597D0 (en) | 1990-08-15 |
FI904060A0 (en) | 1990-08-16 |
DE3927444A1 (en) | 1991-02-28 |
EP0413405A2 (en) | 1991-02-20 |
JPH03173856A (en) | 1991-07-29 |
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