CN1136805A - Aryl halide substituted metallic complexes, pharmaceuticals containing these complexes, their use for diagnostic purpose and complexs - Google Patents

Aryl halide substituted metallic complexes, pharmaceuticals containing these complexes, their use for diagnostic purpose and complexs Download PDF

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CN1136805A
CN1136805A CN94194372A CN94194372A CN1136805A CN 1136805 A CN1136805 A CN 1136805A CN 94194372 A CN94194372 A CN 94194372A CN 94194372 A CN94194372 A CN 94194372A CN 1136805 A CN1136805 A CN 1136805A
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group
theoretical value
formula
acid
base
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W·克劳斯
F·K·梅尔
W-R·普雷斯
G·舒曼-吉姆皮里
M·鲍尔
H·施米特-威利克
P·马里斯基
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Bayer Pharma AG
Merck Sharp and Dohme Corp
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Schering AG
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    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
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    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
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    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • 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
    • C07C237/22—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 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups

Abstract

The invention pertains to new metallic complexes containing an ion of an element of atomic number 12, 13, 20-31, 39-42, 44-50 or 57-83 and a halogenated complexing ligand of formula (I), where R1, R2, R3, Z1, Z2, Z3, U1, U2, V1, V2 or V3 have various meanings. The invention pertains as well to pharmaceuticals containing these complexes, to their use in NMR and/or X-ray diagnostics, especially in X-ray diagnosis of the liver, and to methods for preparing the complexes and pharmaceuticals.

Description

The metal complex that halogenated aryl replaces contains the pharmaceutical preparation of these complex compounds, its application in diagnosis and the preparation method of complex compound and preparation
The present invention relates to indicate in a plurality of claims a plurality of themes of feature, meaning is the metal complex of new halogenated aryl-replacement, contains the pharmaceutical preparation of these complex compounds, its application in diagnosis and the preparation method of complex compound and preparation.
Contrast medium is must obligato auxiliary agent in modern diagnosis, so many illness are if can't diagnose without contrast medium.Contrast medium is used for all diagnostic fields, for example X-X-ray diagnosis X, radiodiagnosis or Ultrasonic Diagnosis or mr X planigraphy x.
Diagnosis problem is depended in the selection of each preferred method in addition, but also is decided by the equipment that the confession medical worker selects for use.Therefore particularly nuclear spin X line body layer radiography paid wages based on technical problem and the high cost that links to each other therewith and be it would be better additive method for example X-X-ray diagnosis X method is widely-used like that.
The selection change of suitable contrast medium is also relevant with the problem that proposes separately.Therefore the suitability of the contrast medium of usefulness specific purpose is final rather than minimum by its (accumulation) distribution situation decision in organism.
Although not only make much progress, still also there is not satisfied terms of settlement available to the problem of all propositions in the plant and instrument technology but also aspect the contrast medium.
Therefore the contrast medium that different developing methods also all is not fit to all indications does not particularly have suitable x-ray contrast agent to use for liver diagnosis so far.
In the X-X-ray diagnosis X, can use contrast medium basically for a long time, because these compounds have high x-ray density and very little general local toxicity and water-soluble fine based on phenyl triiodide.
This compound for example at European patent specification EP0 105 725, was described among the EP 0 015867, but these compounds show to develop in liver and concentrate inadequately.
Because compound as the x-ray contrast agent needs, main relevant with the element mass attenuation coefficient that is contained in the compound in the diagnosing radiation scope except situation about concentrating in each organ, therefore the metal complex of high atomic number element also should be fit to except that containing iodine compound.This compounds is widespread use in the NMR-diagnostic field.At this metal complex that is usually directed to, for example existing description in European patent specification EP 0 071 564.
The metal complex that WO 93/16375 describes is to be connected on the aromatic substance of iodine replacement through amido linkage.These compounds not only can carry out NMR research but also can carry out the research of X-ray only a kind of indication of contrast medium.The combination of two kinds of developing methods is described differential in many cases and is determined that a certain illness is favourable reliably.Particularly these compounds are fit to angiography.But this compound shows as dual preparation embodiment, shows that in liver research does not have enough accumulations to the X-ray.
NMR-contrast medium existing description in European patent EP 0 405 704 that liver is specific.This contrast medium is the X-X-ray diagnosis X because the metal content in complex compound also should suit in principle.。(concentration: 1M/l, dosage 0.5mmol Gd/kg intravenously) do not have enough liver contrast gradients yet on the X-actinogram even the work of binomial trial embodiment shows high dosage administration in experimentation on animals.A kind of sufficient imaging effect only just can reach when a kind of dosage in the X-X-ray diagnosis X, and the edge of safety reduces to no longer reasonably degree when this dosage.
Therefore task of the present invention provides fine compatible and water-soluble contrast medium, and it is particularly suitable for the X-X-ray diagnosis X of liver.
This is resolved by the present invention.
Found that metal complex is particularly useful for producing the contrast medium of NMR-diagnosis and/or X-X-ray diagnosis X, preferred X-X-ray diagnosis X, be particularly suitable for preparing the contrast medium of liver X-X-ray diagnosis X, it is 12 that this complex compound contains at least one ordination number, 13,20-31,39-42, the ion of 44-50 or 57-83 element and the formula I part of a halogen-containing formation complex compound
In the formula
R 1Be hydrogen atom, carboxylic acid group, C straight chain or side chain 1-C 15Alkyl, C 6-C 15-aryl or C 7-C 15Aralkyl, this group randomly and/or at interval by 1-4 Sauerstoffatom by 1-5 hydroxyl and/or 1-2 carboxyl substituted, or R ' is the group of general formula I I or III in the formula ,-CO-NR 4R 5(II)
-CH 2-NR 6-CO-R 7 (III)
In the formula
R 4, R 5Be hydrogen atom independently of each other, straight or branched C 1-C 15-alkyl, C 6-C 15-aryl or C 7-C 15Aralkyl, this group randomly contain 1-5 hydroxyl, 1-2 carboxyl and/or 1-4 Sauerstoffatom, or R in the formula 4, R 5Be combined together to form 5 or 6 yuan of rings that randomly contain a Sauerstoffatom, other acylated nitrogen atom or alkylsulfonyl, randomly replaced with nitrogen-atoms by 1-3 hydroxyl,
R 6Be hydrogen atom, C straight chain or side chain 1-C 15-alkyl, C 6-C 15-aryl or C 7-C 15-aralkyl, this group randomly contain 1-4 hydroxyl, a 1-2 carboxyl and/or 1-2 Sauerstoffatom, or
R in the formula 6And R 7With nitrogen-atoms and carbonyl be combined together to form a nitrogen-atoms that randomly contains a Sauerstoffatom, an other acidylate or alkylsulfonyl, 5 or 6 yuan of rings that randomly replaced by 1-3 hydroxyl and
R 7Be hydrogen atom, C straight chain or side chain 1-C 15-alkyl, C 6-C 15-aryl or C 7-C 15-aralkyl, this group randomly contain 1 to 2 hydroxyl or carboxyl or
R in the formula 7And R 65 or 6 yuan of rings that are combined together to form a nitrogen-atoms that randomly contains a Sauerstoffatom, an other acidylate or alkylsulfonyl, randomly replaced with nitrogen-atoms and carbonyl by 1-3 hydroxyl,
R 2, R 3Be hydrogen atom independently of each other, C 1-C 15-alkyl, C 6-C 15-aryl or C 7-C 15-aralkyl, this group are randomly replaced by 1-5 hydroxyl and/or by 1-4 Sauerstoffatom interval, or form trimethylene or tetramethylene jointly, or have U 1(U 2) described identical implication.
Z 1, Z 2, Z 3Be independently of each other hydroxyl or-NR 17-U 1 'Group,
In the formula
R 17Be hydrogen atom, methyl or methoxy ethyl and U 1, U 1 ', U 2, V 1, V 2And V 3Be the halogenated aryl of hydrogen atom or general formula I V independently of each other,
Figure A9419437200111
In the formula
R 8, R 9Be independently of each other-NR 6-CO-R 7The base and/or have R 1The implication that illustrates does not wherein comprise C 1-C 15Alkyl, C 6-C 15Aryl or C 7-C 15Aralkyl,
R 10, R 11Be halogen atom or hydrogen atom independently of each other,
X be halogen atom or general formula V the bridge chain and
Y is R 9Or the bridge chain of general formula V
(α)-(CH 2) p-(C 6H 4) n-(L) m-R 12-(β) (V)
In the formula
M, n, p are 0 or 1 independently of each other,
L is a Sauerstoffatom, sulphur atom, C 1-C 4Alkylidene group,＞S=O base,＞SO 2Or＞NR 4, R 4Have the implication above addressed and
R 12Be a key, carbonyl, carboxyl ,-CO-NR 18-,-NR 18-CO-,-NH-CS-or-the CS-NH-base, R in the formula 18Be hydrogen atom, C straight chain or side chain 1-C 15Alkyl, C 6-C 15Aryl or C 7-C 15Aralkyl, this group randomly contain 1-4 hydroxyl, 1-2 carboxyl and/or 1-2 Sauerstoffatom,
Or R in the formula 12Be C straight chain or side chain 1-C 4Alkylidene group, this group randomly contains carbonyl and/or amino,
Be connected with the diethylene triaminepentaacetic acid(DTPA) main chain in this (α) position and (β) position be connected with halogenated aromatic compound,
Wherein when X be halogen when plain, Y is the bridge chain of formula V, and X is when being the bridge chain of formula V, Y is R 9And
At R 2, R 3, Z 1, Z 2, Z 3, U 1, U 2, V 1, V 2Or V 3At least one group is the group of general formula I V or contains this group in the base, and randomly freely, is not for carboxyl that the described metal element ion of complexing needs is that salt or amino acid whose salt as inorganic and/or organic bases exists,
And satisfy one of following condition at least,
R 8And/or R 9Contain aryl, and/or
In substituent R 2, R 3, U 1, U 2, V 1, V 2Or V 3In at least one when being not hydrogen atom, Z 1And/or Z 2Then be the base of general formula I V, and/or
If Z 3Contain the formula IV aromatic substance that replaces fully, then a Z 1And/or Z 2Do not contain the formula IV aromatic substance that replaces fully, and/or
If all substituent R 2, R 3, U 1, U 2, V 1, V 2Or V 3Be hydrogen, then at R 8, R 9, R 10Or R 11In at least one group be hydrogen atom and/or R 8And/or R 9Be a base, this base contains not direct bonded carboxylic acid.
Complex compound of the present invention preferably contains manganese (II) ion, iron (III) ion, iron (II) ion, praseodymium (III) ion, neodymium (III) ion, samarium (III) ion, dysprosium (III) ion, yttrium (III) ion or bismuth (III) ion, particularly gadolinium (III) ion are as metal ion.
Complex compound of the present invention contains (1) chlorine atom, bromine atoms or iodine atom as halogen atom, preferred (1) bromine atoms or iodine atom, but (1) iodine atom particularly.
Preferred formula IV halogenated aromatic compound is triiodinated aromatic substance, and meaning is following aromatic substance: wherein X, R 10And R 11Be iodine and R wherein 8And R 9Be hydrogen atom independently of each other, for-OH ,-COOH ,-O-CH 2-CH (OH)-CH 2-OH ,-O-CH 3,-O-CH 2-CH 3,-CO-NH-CH (CH 2OH)-(CHOH-CH 2OH) ,-CO-NR 4-CH-(CH 2OH) 2,-NR 6-CO-CH 2OH ,-CO-NR 4-CH 2-CH 2OH ,-CO-NH 2,-N (CH 3)-CO-CH 3,-NH-CO-CH 3,-CO-NH-CH 3,-N (CH 3)-CO-(CH 2) 2COOH ,-CO-N-(C 2H 5) 2,-CO-N (CH 3)-CH 2-COOH ,-CO-NH-(CH 2) 10-COOH ,-CO-NH-CH 2-C 6H 4-OEt or-CO-N (CH 3)-CH 2-CH (OH)-CH 2OH and wherein Y be the bridge chain of formula V.
Preferred formula V bridge chain is that situation is: if a group in the U base is a halogenated aryl, then the bridge chain of formula V is:
-CH 2-,-CH 2-C 6H 4-O-CH 2-,-CH 2-O-CH 2-,-CH 2-O-,-CH 2-O-CO-,-CH 2-NH-CO-,-CH 2-CO-NH ,-CH 2-C 6H 4-O-CH 2-CO-NH-,-CH 2-O-CO-NH-,-CH 2-NH-CO-NH-,-NH-CO-,-NH-CO-CH 2-, if a group in the Z base is a halogenated aryl, then the bridge chain of formula V is
-NH-CH 2-CO-NH-,-NHCH 2CH 2-CO-NH-or-NHCH 2CH 2-NH-CO-and
If a group in the V base is a halogenated aryl, then the bridge chain of formula V is
-CH 2-,-CH 2-O-,-CH 2-O-CH 2,-CH 2-O-CO-,-CH 2-NH-CO-,-CH 2-CO-NH-,-CH 2-O-CO-NH-or-CH 2-NH-CO-NH-.
Wherein particularly preferably be wherein U 1Be the complex compound of general formula I V group, meaning is these compounds: they be in the ethylene bridge of polyaminocarboxylic acid, replace with halogenated aromatic compound and wherein Z be hydroxyl.
R 1Group is alkyl straight chain or side chain, as methyl, and ethyl, propyl group, sec.-propyl, the butyl and the tertiary butyl, but preferred hydrogen, C 1-C 4Alkyl and hydroxyalkyl be methylol and alkoxyalkyl methoxyl methyl for example for example.
R 2, R 3Group and R 1Listed group is identical, but preferred hydrogen atom.
To the special preferred ion complex compound of the X-X-ray diagnosis X of liver, there be (that is to say the electric charge that does not need to come with carboxyl the metal ion of the described ordination number element of balance) in the free carboxy that wherein exists in molecule as free acid or as the salt or the amino acid whose salt of inorganic and/or organic bases.
The positively charged ion of suitable mineral alkali is a lithium ion for example, potassium ion, calcium ion, magnesium ion, particularly sodium ion.The positively charged ion of Shi Yi organic bases is a primary amine in addition, secondary amine or tertiary amine, thanomin for example, diethanolamine, morpholine, glycosamine, N, N-dimethyl glycosamine, particularly N-methylglucosamine.Suitable amino acid positively charged ion is for example Methionin ion, arginine ion and ornithine ion.
Preparing complex compound of the present invention can realize with several different methods and mode.These different methods and required for this reason starting compound are known in principle concerning the those skilled in the art.So these compounds are similar to known complex compound or complexing agent usually, can prepared in reaction in The suitable solvent come out by active halogenated aromatic compound and active complexing agent.Required juncture between halogenated aromatic compound and poly-aminopolycanboxylic acid is depended in the selection of each optimum route of synthesis.Complex compound can be divided into three groups according to this.Like this halogenated aromatic compound can be combined in poly-amino many carboxylics 1) on the alpha-carbon atom of carboxylic acid (acetate) base
II) on alkylidene group-(ethylidene) bridge or
III) on the carboxylic acid group.
The 1st group complexing agent or complex compound can prepare according to being similar to the method for describing among the EP 0 230 893.Illustrate the synthetic possibility of other general available complexing agents below.
Like this, can be by the Mono Chloro Acetic Acid derivative of general formula VI
Figure A9419437200151
R in the formula 13Be the required halogenated aryl of general formula I V or randomly be the not halogenated as yet precursor of this group, with the polyamine reaction of general formula VII
At first obtain the compound of general formula VIII,
These compounds then with methods known in the art and halogenated acetic acids ester, preferably with the bromacetate reaction, if then-relate to the precursor of desired aromatic substance-carry out halogenation with methods known in the art also to use existing ester group of method known to those skilled in the art cracking or protecting group where necessary.Can be achieved equally under two situations that are substituted in corresponding stechiometry.
The poly-aminopolycanboxylic acid's that a kind of other preparations α-C-replaces method is that polyaminocarboxylic acid from the acid protection is (for example from pentamethyl-ester) of diethylene triaminepentaacetic acid(DTPA).The lithium salts of the precursor of itself and desirable aromatic substance reacts.Corresponding lithium salts be by benzyl halide (3-nitrobenzyl chloride for example, 3,5-dinitrobenzene benzyl chloride, 3-benzyl oxygen benzyl chloride) in tetrahydrofuran (THF)/hexane by obtaining with the lithium diisopropylamine reaction.Aromatic substance is converted into the halogenated aromatic compound of desirable formula IV after the coupling, and for example by randomly the nitroreduction that exists being become amino method, amino randomly is converted into acid amides with Acetyl Chloride 98Min.; Benzyloxy for example can change into hydroxyl by shortening.Also can realize equally the iodate of aromatic substance with methods known in the art, for example in hydrochloric acid medium by transforming with the iodine monochloride solution reaction.Before introducing the iodine atom, make sour protecting group saponification in alkali lye of five-ester.
The method that a kind of preparation of other selections contains the poly-aminopolycanboxylic acid of iodine is from the alpha-amino acid derivatives of general formula X XIII,
Its primary amino also can exist with shielded form (for example as a benzyl amine) in case of necessity.This amino alkylating agent with formula XXIV
Figure A9419437200162
And after the protecting group cracking that then-where necessary exists-with the alkylating agent of formula XXV
Figure A9419437200171
Carry out two alkylations on nitrogen-atoms, wherein Nf is a for example muriate of freestone agent, bromide, iodide, mesylate or tosylate, and R 14Be sour protecting group for example low alkyl group, aryl, aralkyl or trialkylsilkl, and R 1, R 2, R 3, U 1, U 2, V 1, V 2, V 3, Z 1, Z 2And Z 3Described implication before having.
The poly-aminopolycanboxylic acid's that preparation α-C-replaces synthesis example is in this way from phenylamino acid 3-aminophenyl L-Ala for example.At first make this raw material with the methods known in the art halogenation, then acidic group is protected with the form of ester.The intermediate product that obtains like this and two normal N, two [(carbobenzoxy-(Cbz))-methyl]-2-brooethyl amine reactions of N-.Before cracking acid protecting group, randomly make the substituting group of aromatic substance be converted into desirable group.
The complexing agent for preparing the II group can be similar to the method that vapour is stated in EP 0 405 704 and DE 432289 to carry out.Therefore, this method is for example set out by the known compound (document that quote DE3710 730 and there) of general formula I X,
R in the formula 14, R 1, R 2And R 3Have the implication that has illustrated, wherein the OH-of phenol base reacts with the actives of the required halogenated aromatic compound (or its precursor, for example benzyl halide) of formula X
Figure A9419437200182
R in the formula 8 ', R 9 ', R 10 'And R 11 'Be desirable radicals R 8, R 9, R 10And R 11Or the precursor of these groups.If radicals R 8 ', R 9 ', R 10 'And R 11 'Be the precursor of desired group, just can make these groups by those precursor group.Acid protecting group R 14With known method [for example referring to E.Wunsch, Methoden der Org.Chemie[Methods ofOrg.Chemistry] (Houben Weyl), Bd.XV/I, 4 Aufl.1974, S 315 ff], the method for saponification by hydrolysis, hydrogenolysis or alkali for example, generally cracking before aromatic substance is by halogenation.Not only can select the tart reaction conditions but also can select aqueous basic reaction conditions this cracking of reacting particularly advantageous tertiary butyl ester.
In the compound of general formula I X, also can make aryl with methods known in the art for example with iodine monochloride carry out iodate, in case of necessity make phenol-the OH base with methods known in the art with alkyl halide/sodium hydride etherificate.In aforesaid method, realize the cracking of sour protecting group.
A kind of other systems of selection are set out by the halogen-containing chlorinating aromatic compounds of formula X equally, and the shielded glycerine reaction of these chlorinating aromatic compounds and part at first changes into corresponding formula XI dihydroxyl propoxylation compound,
Figure A9419437200191
Follow this compound after part is protected a hydroxyl and residue group activation with reaction of sodium azide, be converted into azido--compound of corresponding general formula X II
Figure A9419437200192
R in the formula 15Be a protecting group, for example benzyl.
At OH-protecting group R 15The hydroxyl activation back (for example as methane sulfonate) of cracking and generation at first with corresponding reacting ethylenediamine, and then for example makes azido-be reduced to formula XIII compound with triphenyl phosphine with methods known in the art
Figure A9419437200201
Back one compound generates corresponding five-ester with known method and bromacetate reaction.After sour protecting group cracking (for example by with trifluoroacetic acid reaction and by radicals R 8 ', R 9 ', R 10 'And R 11 'Generate desirable R 8, R 9, R 10And R 11Group), just obtain desirable complexing agent.
A kind of other systems of selection that prepare II group complexing agent are from the polyaminocarboxylic acid derivative of the acid protection of general formula X IV,
The isocyanato-of this compound and general formula X V-compound reaction generates corresponding urethane.
Figure A9419437200203
Perhaps can also make the hydroxyl in general formula X IV compound for example generate corresponding formula XVI muriate with the N-chloro-succinimide reaction
Figure A9419437200211
Then will back one compound react with a kind of actives of the required halogenated aromatic compound of methods known in the art and formula XVII (for example hydroxyl, or carboxylic)
Figure A9419437200212
R in the formula 8, R 9, R 10And R 11Have the implication of having addressed, and Y ' is OH or COOH group, changes into corresponding ether or ester.The cracking of acid protecting group is undertaken by the method for narrating previously.
Perhaps, the compound of general formula X VI can generate corresponding azido cpd (this azido cpd then is reduced into aminocompound with currently known methods) with dissolve compound (for example sodiumazide) reaction of nitrogen.This azido cpd then
A) or with the isocyanato-of formula XV-compound reaction generate corresponding urea derivative or
B) the halogenated aryl chlorine reaction with formula XVIII generates corresponding amide
Figure A9419437200221
A kind of other systems of selection are that the monoethanolamine from formula XIX sets out
Figure A9419437200222
R in the formula 16Be amino protecting group, be preferably carbobenzoxy-(Cbz), and R 13 'Be the precursor of halogenated desirable aromatic substance not, or in next reactions steps with required halogenated aromatic compound bonded " linking group ".Monoethanolamine at first for example generates corresponding methanesulfonates, tosylate or trifluoro-acetate with methylsulfonyl chloride, toluene sulfonyl chloride or trifluoroacetic acid anhydride reactant with methods known in the art, and follows and a reacting ethylenediamine that replaces in case of necessity.If R 13 'Relate to the precursor of the desirable aromatic substance of not halogenated general formula I V, just can for example use the iodine monochloride iodate; But if R 13 'Relate to " linking group ", this " linking group " just reacts with the actives of desirable aromatic substance (or its not halogenated precursor).
Follow the cracking amino protecting group and generate desirable amino acid (complexing agent) with the reaction of halogen acetic acid ester.
The complexing agent of III group, meaning promptly wherein halogenated aryl be combined in complexing agent on poly-aminopolycanboxylic acid's the carboxylic acid group with the amido linkage form, can be prepared according to being similar to the method for in DE 42 32 925, describing.
Like this by will be for example activated carboxyl in the desirable pentacarboxylic acid partly be converted into amide group, can prepare this complexing agent.This process is considered all synthetic possibilities well known by persons skilled in the art, and for example the halogenated aromatic combination reaction of the acid anhydrides of general formula X X or XXI and general formula X XII generates acid amides of the present invention,
Figure A9419437200231
R in the formula 8 ', R 9 ', R 10 'And R 11 'Be desirable radicals R 8, R 9, R 10And R 11Or its precursor and Q are the linking group of general formula V.The aromatic substance of preparation general formula X XII is like carries out described in the DE 25 23 567.
The H that can mention 2The N-Q base for example is H 2N-CH 2-CO-NH-, H 2N-NH-CO-NH-, H 2N-CH 2CH 2-CO-NH-, H 2N-NH-CO-CH 2CH 2-, H 2N-CH 2CH 2-NH-CO-or H 2N-CH 2CH 2-N (CO-CH 3) group.
This being reflected in the liquid phase carried out, and suitable reaction medium is a water for example, dipolar aprotic solvent such as ether, tetrahydrofuran (THF), dioxan, acetonitrile, N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE etc. or its mixture.Temperature of reaction is preferred from 20 ℃ to 80 ℃ between about-80 ℃ and 160 ℃.Reaction times is between 0.5 hour and 7 days, preferably between 1 hour and 36 hours.
The acid anhydrides of preparation general formula X X can be undertaken by currently known methods, for example by in U.S. Pat 3,660,388 or DE 1695050 described in method in pyridine, carry out with diacetyl oxide.But in some cases, the dehydration of for example carrying out appropriateness with carbodiimide in dimethyl formamide or the N,N-DIMETHYLACETAMIDE in a suitable solvent is favourable.
The monobasic acid anhydrides of preparation general formula X XI is at pharmaceutical science monthly magazine (J.Pharm.Sci), narrates in 68 (1979) 194.
The halogenated aromatic compound that uses in diverse ways is known or can be easily made by known compound.
Therefore for example described iodinating aromatic substance in the prospectus DE 29 28 417 of Germany, they generate the aromatic substance that contains the acid chloride base accordingly with for example thionyl chloride reaction easily.
Other aryl can be at M.Sovak; Radiopaque contrast medium, in practical pharmacology handbook 73 volumes (1984), Springer press, Berlin-Heidelberg-New York-Tokyo or producing described in the European patent EP 0 015 867.
Corresponding chlorinated compound or bromine compounds can be prepared as described in European patent EP 0,055 689 or DE 1,003 743, EP 0 073 715 or the EP 0 118 347 or be similar to the compound described of there.
Contain amino aromatic substance, when for example needing to produce the compound of acetic acid substituted of III group, can be similar to the compound of in DE 25 23 567, describing and be prepared like that with them.
Preparing metal complex of the present invention by the complexing agent of aforementioned I-III group is undertaken by disclosed method in the following document: EP 0,071 564, EP 0 130 934 and DE 3,401 052, making ordination number is 12,13,20-31,39-42, the metal element oxide compound of 44-50 or 57-83 or metal-salt (nitrate for example, acetate, carbonate, muriate or vitriol) in water and/or lower alcohol (as methyl alcohol, ethanol, Virahol and/or N, dinethylformamide) in dissolving or suspend and with the solution and/or the suspension reaction of the complexing agent of equivalent quantity.
If when wishing, then, the acid hydrogen atom of other acidic group can be by inorganic and/or organically alkali or amino acid whose positively charged ion replace.
The alkali that is fit to is sodium, the mineral alkali of potassium or lithium (oxyhydroxide for example, carbonate or supercarbonate) and/or organic bases, in addition as primary amine, secondary amine and tertiary amine for example thanomin, morpholine, glycosamine, N-methylglucosamine and N, N-dimethyl glycosamine reaches alkaline amino acid for example Methionin, arginine and ornithine.
In order to prepare the neutral complex compound, for example the required alkali of capacity can be added in the acid complex salts in the aqueous solution or the suspension, make to reach neutral point.The solution that obtains can be followed dry in a vacuum concentrating.Usually, by adding neutral salt that can go out to generate with the miscible solvent deposition of water and the crystallization that obtains segregative and easy purifying thus is favourable, can for example be lower alcohol (methyl alcohol, ethanol, Virahol etc.), lower ketones (acetone etc.), polar ether (tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.) with the miscible solvent of water.Confirm that it is particularly advantageous adding required alkali in reaction mixture complexing process, and saves a method steps thus.
When if the tart complex compound contains a plurality of free acidic group, then often be to be fit to the neutral mixing salt of preparation, this salt not only contains inorganic but also contains organic positively charged ion as counterion.
For example can realize this situation: the acid that forms complex compound is reacted with the oxide compound of the element that central ion is provided or salt with for half of the required organic bases quantity of neutralization in aqueous suspension or solution by following method, isolate the complex salts of generation, randomly make its purifying, mix the organic bases of aequum for neutralizing fully then.The order that adds alkali also can be put upside down.
Another one theme of the present invention is a preparation, and they contain at least a compound of the present invention.
The present invention relates to a kind of method for preparing these preparations in addition, the feature of this method is, with this in water dissolved paramagnetic complex salts make the form that is suitable for enteron aisle or parenteral medication with additive common in galenical and stablizer, therefore the concentration of complex salts is 1 to 1500mMol/l, and preferred concentration is 10-1000mMol/l.The content of halogen of solution is usually in the scope between 10-400mg/ml.The preparation that obtains is then by desirable situation sterilization.According to the problem of content of halogen and diagnosis, said preparation is generally with the dosed administration of 1-300ml.
Suitable additive for example is a damping fluid (for example tromethane) harmless on the physiology, a spot of complexing agent additive (for example diethylene triaminepentaacetic acid(DTPA)) or, (if need) electrolytic solution for example sodium-chlor or, (if needs) antioxidant is vitamins C for example.
If need through enteron aisle medicine or other purposes in water or physiological saline in the suspension or the solution of medicament of the present invention, then can with itself and one or more in galenical commonly used assistant agent (methylcellulose gum for example, lactose, N.F,USP MANNITOL) and/or tensio-active agent (lecithin for example, tween R, Myrj R) and/or flavoring substance (for example volatile oil) mixing.
In principle, can not prepare diagnostic reagent of the present invention even do not separate complex salts yet.Must carry out chelating formation by SC in a word, make salt of the present invention and salts solution in fact not have the metal ion of the toxic effect of not complexing.
This purpose can be for example orange by color indicator such as xylenol, be guaranteed by contrast titration in preparation process.Therefore the present invention also relates to the preparation method of complex compound and its salt.The issues of purification that still has isolated complex salts as last security.
Other themes of the present invention are indicated by claim.
Material of the present invention has satisfied the requirement miscellaneous that in modern diagnosis contrast medium is proposed.These compounds and have outstanding performance because of following characteristics by its preparation of making:
To the high absorption coefficient of X-ray,
Good consistency, this consistency are that to keep the Noninvasive checking feature necessary,
High efficiency, this high efficiency are to make a small amount of as far as possible foreign matter of body burden necessary,
Good water-soluble (this can make highly concentrated solution, as in particular as the essential solution of x-ray contrast agent, the circulation volumetric loading is remained in the rational boundary),
Low viscosity
Hypotonic molconcentration
Suitable drainage power.
Preparation of the present invention in addition not only has a high stability external, and surprising high stability is also arranged in vivo, therefore in for some time that this new contrast medium is discharged fully again, do not appear at release of non-covalent combination in the complex compound (this is deleterious) ionic itself or exchange.
Except highly water-soluble (when paramagnetic metal ion exists, can make in the scope of the water-soluble X-of bringing up to X-ray diagnosis X needs unexpectedly), The compounds of this invention can produce positive effect in the X-X-ray diagnosis X, be complex compound of the present invention and compare with traditional contrast medium unexpectedly and can under the X-ray shorter, check than shortwave, reduced radiation quantity thus significantly to patient, because absorbing soft radiation, well-known tissue is better than transmitted radiation (R.Felix, X-ray image greatly; Thieme Stuttgart 1980).
Because contrast medium of the present invention has suitable absorptive character in the X-ray scope that penetrates, so preparation also is particularly suitable for digital deshadowing technology (Substraktionstechniken) (using higher tube voltage work).
The interior distribution state of body that is stressed that preparation of the present invention especially is favourable.This preparation allows to use a kind of common dose (content of halogen: 50-400mg/ml of x-ray contrast agent for the first time; Dosage 0.1-1ml/kg body weight), be formed with the X-actinogram of high diagnostic value at liver area.
Complex compound of the present invention has like this drawn the optimal contrast gradient of liver when dosage is 0.5mmol/kg.The last figure of Fig. 1 shows the mouse liver before the contrast medium administration.Figure below shows that same mouse is at invention compound the liver 10 minute after of injection 0.5mmol/kg by embodiment (d) preparation.
The photo of taking under other identical conditions is being given same dose (4S) 4-(4-ethoxy benzyl)-3,6,9-three (carboxylic acid group's methyl)-3,6, the disodium salt (European patent EP 0,405 704 of the gadolinium complex of 9-three azepine undecane diacids; Embodiment 8c) shows not useful contrast gradient (referring to Fig. 2 figure below) after to liver diagnosis.Last figure is illustrated in the liver before the administration of contrast agents.
Fig. 3 shows that the density of the compound (embodiment 8c) of comparison The compounds of this invention (embodiment 1d) and European patent EP 0 405704 improves (can be considered the size of contrast medium validity) and time relation.Contrast has higher density numerical value significantly observing The compounds of this invention during the whole inspection in the mouse liver.Therefore, the maximum value of material of the present invention be about 60 floods must distinguish-unit (Houndsfield-Einheit (HU), but the contrast material only be 15HU.In female mouse (body weight=200-280g) add that VD31 (checks parameter: bed thickness=2mm, tube voltage/electric current=120KV/290mA), carried out check test behind each material of each 0.5mmol/kg of intravenous injection.
The complex compound of describing in figure border patent WO 93/16375 also shows the accumulation that is not enough to imaging in liver.
1 of international monopoly WO 93/16375 embodiment 1,13-pair-[5-(propionyl-3-base amido)-2,4,6-triiodo m-phthalic acid-two-(2-hydroxyl-1-hydroxymethyl ethyl)-diamide]-4,7,10-three-(carboxymethyl)-(2-12-dioxo)-1,4,7,10, the gadolinium complex of the isomer of 13-five or three azepine decane (embodiment 17b) is almost completely discharged through kidney.Have only 1.3% of total amount to excrete by other approach.Both made imagination, this 1.3% complex compound all accumulates in the liver, and these quantity are yet well below the needed dosage of imaging effect.
Give female mouse (90-110g body weight) intravenously administrable 0.27mmol/kg compound 17b) after carried out this test.With x-ray fluorescence-assay determination the iodine concentration in blood, urine, excrement and liver,kidney,spleen, bone.Measured gadolinium concentration with the 1CP-atomic emission spectrum in addition.Transformation period is 0.32 hour and distributes volume to show that the distribution in ECS discharged by kidney through kidney by glomerular filtration.
Preparation of the present invention (said preparation contains ordination number in complex compound be 21-29,42,44 or the paramagnetic metal ion of 57-70 element) also can be used for the NMR-diagnosis except being used for the X-X-ray diagnosis X.This dual nature has been opened up other use field.Therefore, for differential describe and measure reliably a certain illness need X-ray and NMR-diagnosis in conjunction with the time, always can advantageously use preparation of the present invention.This formulation example as the bosom is coagulated tumor operation or auxiliary also be believable when penetrating the recurrence of treatment back.In this case, by using a kind of contrast medium (this agent all is fit to two kinds of technology) to exempt the additional load that the double administration of patient is caused.
Be successful with the new diagnostic medical possibility of above-mentioned complex compound developing in a word.
Following embodiment is used for theme of the present invention is described in more detail, but theme is not limited.
Embodiment 1
3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-[4-(2,4,6-triiodo benzyloxy)-benzyl]-gadolinium complex of undecane diacid disodium salt
A) 2,4, the preparation of 6-triiodo benzyl chloride
With 41.6g (80.1mmol) 3-amino-2,4,6-triiodo benzyl chloride (CollectionCzechoslov.Chem.Commun.[Vol.41] 1976) is suspended in the 416ml Glacial acetic acid and under agitation mixes with 6.08g (88.1mmol) Sodium Nitrite suspension in the 40ml vitriol oil in batches.Temperature of reaction remains on 25 ℃ by cooling.After 30 minutes reaction mixture is added in the copper powder suspension of 12g in 416ml methyl alcohol and and finishes until putting nitrogen in stirring at room.Cooling suspension to 10 ℃ filters then, and resistates 300ml N, dinethylformamide absorb and precipitate 30 minutes and also filter this suspension.Evaporation concentration filtrate in a vacuum, the resistates water absorbs precipitation, filters and vacuum-drying.Crude product stirs with gac in hot acetonitrile, filters then and cools off filtrate to 0 ℃, generates precipitation around here, and the sucking-off throw out is also dry in a vacuum.
The light beige solid thing of output: 29.8g (73.8%)
Analyze (is base with first vehicle substance): theoretical value: C 16.67 H 0.80 C l7.03 I 75.50 measured values: C 16.82 H 0.95 C l7.14 I 75.41b) 3,6,9-three azepines-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-4-[4-(2,4,6-triiodo benzyloxy)-benzyl]-undecane diacid-two-tert-butyl ester
At 0 ℃, with 15.6g (20.0mmol) 3,6,9-three azepines-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-4-(4-hydroxyl-benzyl)-undecane diacid-di tert butyl carbonate (embodiment 9f, DE 3710730) mixes with the sodium hydride suspension in mineral oil of 660mg (22.0mmol) 80% in tetrahydrofuran (THF).Press embodiment 1a to wherein adding 12.4g (22.0mmol) again) preparation 2,4,6-triiodo benzyl chloride also stirred 3 hours.Water mixing in solution then distills out tetrahydrofuran (THF) and uses the extracted with diethyl ether aqueous emulsion.Organic phase washes with water, through Na 2SO 4Dry also evaporation concentration.
Resistates is gone up at silica gel 60 (Merck) and is carried out chromatographic separation with hexane/methyl acetate/triethylamine, and product cut carries out evaporation concentration and dry in a vacuum.Output: 22.8g (theoretical value 91.2%) yellow oil analysis (is base with solvent-free material): theoretical value: C 46.20 H 5.82 I 30.51 N 3.37 O 14.10 measured values: C 46.37 H 5.93 I 30.44 N 3.35
C) 3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-[4-(2,4,6-triiodo benzyloxy)-benzyl]-undecane diacid is 22.8g (18.3mmol) embodiment 1b) butyl ester described dissolves in the 250ml trifluoroacetic acid and stirring at room 1 hour.Then mix t-butyl methyl ether to solution, the sucking-off throw out, with t-butyl methyl ether washing, at 40 ℃ in a vacuum through the Vanadium Pentoxide in FLAKES drying.Crude product absorbs precipitation in water, filter and vacuum-drying.The light beige solid analysis of output: 15.4g (theoretical value 86.8%) (is base with the anhydrous substances): theoretical value: C 34.77 H 3.33 I 39.36 N 4.34 O 18.19 measured values: C 34.63 H 3.56 I 39.28 N 4.38d) 3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-[4-(2,4,6-triiodo benzyloxy)-benzyl]-gadolinium complex of undecane diacid disodium salt
With 11.8g (12^2mmol) by embodiment 1c) suspension and 2.21g (6.1mmol) the gadolinium oxide compound of five acid in 118ml water of preparation mix and be incorporated in 80 ℃ of stirrings 2 hours.Add the sodium hydroxide solution of 24.4ml monovalent with a droplet fixed tube then and stirred 1 hour.Then after adding the 0.5g gac, stirred 2 hours and filtered at 80 ℃.Filtrate draws colorless solid after lyophilize.Output: 13.1g (theoretical value 91.8%) analyzes (being base with the anhydrous substances): theoretical value: C 28.86 H 2.34 I 32.67 N 3.61 O 15.10 Gd13.49 Na 3.95 measured values: C 28.66 H 2.43 I 32.70 N 3.49 Gd 13.28 Na 4.16
Embodiment 23,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-[4-(N-ethanoyl-3-methylamino--2,4,6-triiodo benzyloxy)-benzyl]-a) N-ethanoyl-3-methylamino--2,4 of the gadolinium complex of undecane diacid disodium salt, 6-triiodo benzyl chloride
With 42.5g (79.7mmol) 3-methylamino--2,4,6-triiodo benzyl chloride (Collec-tion Czechoslov.Commun.[vol.41] 1976) dissolves in the 180ml N,N-dimethylacetamide and drip 13.7ml (191.3mmol) Acetyl Chloride 98Min. under ice-cooled situation.About 0 ℃ stir 30 minutes after, stirring at room 12 hours and under stirring state, this deep brown solution is added in the water.Be settled out throw out, the sucking-off throw out is also dry in a vacuum.The light beige solid of output: 44.6g (theoretical value 99.6%).Analyze (being base with the anhydrous substances): theoretical value: C 20.88 H 1.58 Cl 6.16 I 66.17 N 2.43 O 2.78 measured values: C 20.98 H 1.69 Cl 6.04 I 66.18 N 2.52b) 3; 6; 9-three azepines-3; 6; 9-three-(tertiary butyloxycarbonyl ylmethyl)-4-[4-(N-ethanoyl-3-methylamino--2; 4,6-triiodo benzyloxy)-benzyl]-undecane diacid-two-tertiary butyl diester
With 15.6g (20.0mmol) 3,6,9-three azepines-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-4-(4-hydroxybenzyl)-undecane diacid-two-tert-butyl ester (DE3710730 embodiment 9f) mixes with the suspension of 660mg (22.0mmol) 80% sodium hydride in mineral oil at 0 ℃ in tetrahydrofuran (THF).Again to wherein adding 12.66g (22.0mmol) by the compound of embodiment 2a preparation and stirred 3 hours.In solution, mix water then, distill out tetrahydrofuran (THF) and use the extracted with diethyl ether water miscible liquid.Organic phase washes with water, through Na 2SO 4Dry also evaporation concentration.Resistates is gone up at silicagel column 60 (Merck) and is carried out chromatographic separation with hexane/methyl acetate/triethylamine, evaporation concentration product cut and vacuum-drying.Output: 23.5g (theoretical value 89.2%) yellow oil analysis (is base with solvent-free material): theoretical value: C 46.45 H 5.89 I 28.87 N 4.25 O 18.49 measured values: C 46.63 H 5.96 I 28.72 N 4.18C) 3; 6; 9-three azepines-3; 6; 9-three-(carboxymethyl)-4-[4-(N-ethanoyl-3-methylamino--2; 4,6-triiodo benzyloxy)-benzyl]-undecane diacid
With 21.9 (16.6mmol) at embodiment 2b) in the tert-butyl ester described dissolve in the 250ml trifluoroacetic acid and stirring at room 1 hour.Then in this solution, mix ether; The sucking-off throw out, with ether washing and 40 ℃ in vacuum through the Vanadium Pentoxide in FLAKES drying.Crude product is absorbed precipitation in water, filter also dry in a vacuum.The light beige solid of output: 16.2g (theoretical value 94.1%).Analyze (being base with the anhydrous substances): theoretical value: C 35.86 H 3.59 I 36.67 N 5.40 O 18.49 measured values: C 35.73 H 3.75 I 36.81 N 5.41d) 3; 6; 9-three azepines-3; 6; 9-three-(carboxymethyl) 4-[4-(N-ethanoyl-3-methylamino--2; 4,6-triiodo benzyloxy)-benzyl]-undecane diacid
With five acid suspension and 2.58g (7.13mmol) gadolinium sesquioxide mixed be incorporated in 80 ℃ stirrings 2 hour in 150ml water of 14.8g (14.3mmol) by embodiment 2c preparation.Then add the normal sodium hydroxide solution of 28.5ml and continue and stirred 1 hour with micro pipette.After adding the 0.8g gac, stirred this solution 2 hours and filtration then at 80 ℃.Filtrate draws colorless solid after evaporation concentration.Output: 16.4g (theoretical value 93.3%) analyzes (being base with the anhydrous substances): theoretical value: C 30.11 H 2.61 I 30.79 N 4.53 O 15.53 Gd 12.72Na 3.72 measured values: C 30.00 H 2.82 I 30.58 N 4.67 Gd 12.79 Na 3.82
Embodiment 33,6,9-three azepines-3,6; the gadolinium complex of 9-three-(carboxymethyl)-{ 4-[N-(3-carboxypropanoyl)-3-methylamino--2,4,6-triiodo benzyloxy]-benzyl }-undecane diacid trisodium salt is N-(5-oxa--1 a); 4-dioxo heptyl)-and 3-methylamino--2,4,6-triiodo benzyl chloride
In room temperature, to the 53.3g that under the dehumidifying situation, is stirring (100mmol) 3-methylamino--2,4, add 24.7g (150mmol) succinic chloride-ethyl ester in the suspension of 6-triiodo benzyl chloride (Collection Czechoslov.Chem.Commun.[vol.41] 1976) in the no Shui diox of 200ml.This reactant refluxes several hours, until there is not raw material to show by thin-layer chromatography; Evaporation concentration then, resistates is dissolved in the methylene dichloride and with the saturated sodium bicarbonate aqueous solution jolting and separates.Organic phase is evaporation concentration behind anhydrous magnesium sulfate drying, resistates ethyl acetate/t-butyl methyl ether recrystallization.Output: 58.4g (theoretical value 88.3%) colorless solid.Analyze (is base with solvent-free material) theoretical value: C 25.42 H 2.29 Cl 5.36 I 57.56 N 2.12 O 7.26 measured values: C 25.31 H 2.49 Cl 5.43 I 57.50 N 2.17b) 3,6,9-three azepines-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-4-{4-[N-(5-oxa--1,4-dioxo-heptyl)-and 3-methylamino--2,4,6-triiodo benzyloxy]-benzyl }-undecane diacid
With 15.6g (20.0mmol) 3,6,9-three azepines-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-4-(4-hydroxybenzyl)-undecane diacid-two-tert-butyl ester (DE3710730 embodiment 9f) mixes with the sodium hydride suspension of 660ml (22.0mmol) 80% in mineral oil at 0 ℃ in tetrahydrofuran (THF).Again to wherein adding 14.55g (22.0mmol) by embodiment 3a) preparation compound and stirred 3 hours.In solution, mix water then, distill out tetrahydrofuran (THF) and use the extracted with diethyl ether aqueous emulsion.Wash organic phase with water, through dried over sodium sulfate and evaporation concentration.Resistates is gone up at silica gel 60 (Merck) and is carried out chromatographic separation with hexane/ethyl acetate/triethylamine, with product cut evaporation concentration and vacuum-drying.Output: 22.9g (theoretical value 81.6%) yellow oil analysis (is base with solvent-free material): theoretical value: C 47.02 H 5.95 I 27.10 N 3.99 O 15.94 measured values: C 46.86 H 6.13 I 26.98 N 3.84c) 3; 6; 9-three azepines-3; 6; 9-three-(carboxymethyl)-{ 4-[N-(3-carboxypropanoyl)-3-methylamino--2; 4,6-triiodo benzyloxy]-benzyl }-undecane diacid
Six esters that 20.4g (14.5mmol) has been addressed at embodiment 3b dissolve in the 100ml methyl alcohol and add 87ml 2n sodium hydroxide solution to it and mix.It was refluxed about 2 hours, under vacuum, extract methyl alcohol out and after adding 100ml water, continue stirring 2 hours at 60 ℃.By transferring PH with half concentrated hydrochloric acid is that 1-2 produces a kind of colourless precipitation, sucking-off precipitation and vacuum-drying.Output: 15.3g (theoretical value 96.0%) colorless solid.Analyze (being base with the anhydrous substances): theoretical value: C 36.15 H 3.59 I 34.72 N 5.11 O 20.43 measured values: C 36.23 H 3.65 I 34.58 N 5.05d) 3; 6; 9-three azepines-3; 6; 9-three-(carboxymethyl)-{ 4-[N-(3-carboxypropanoyl)-3-methylamino--2; 4,6-triiodo benzyloxy]-benzyl }-gadolinium complex of undecane diacid trisodium salt
With six acid suspension and 2.33g (6.43mmol) gadolinium sesquioxide mixed be incorporated in 80 ℃ stirrings 2 hour in 150ml water of 14.1g (12.9mmol) by embodiment 3c preparation.Then add the sodium hydroxide solution of 38.6ml monovalent and continue stirring 1 hour with micro pipette.After adding the 0.8g gac, stirred this solution 2 hours and filtration then at 80 ℃.Filtrate draws colorless solid after lyophilize.Output: 16.3g (theoretical value 96.4%) analyzes (being base with the anhydrous substances): theoretical value: C 30.11 H 2.53 I 28.92 N 4.26 O 17.01 Gd 11.94Na 5.24 measured values: C 30.01 H 2.64 I 28.88 N 4.34 Gd 11.86 Na 5.02
Embodiment 43,6,9-three azepines-3,6, the gadolinium complex of 9-three-(carboxymethyl)-4-(3,5-two iodo-4-ethoxy benzyls)-undecane diacid disodium salt a) 3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-(4-hydroxybenzyl)-undecane diacid
With 7.8g (10mmol) 3,6,9-three azepines-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl) 4-(4-acrinyl)-undecane diacid-two-tert-butyl ester (DE 3710730 embodiment 9f) dissolve in the 100ml trifluoroacetic acid and stirring at room 1.5 hours.Then with ether dilution and sucking-off precipitation.With the ether washing and 50 ℃ of vacuum-dryings.Crude product dissolves in the water and uses activated carbon treatment.Remaining trifluoroacetic acid is removed in the filtrate freeze-drying for several times.The colourless lyophilized products of output: 4.0g (theoretical value 80.1%).Ultimate analysis (considering under the solvent situation): theoretical value: C 50.50 H 5.85 N 8.41 O 35.24 measured values: C 50.68 H 5.99 N 8.25b) 3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-(3,5-two iodo-4-hydroxybenzyls)-undecane diacid
The phenol that 3.2g (6.4mmol) is obtained by embodiment 4a suspends in the 50ml water and is mixed to neutral point with solid sodium hydroxide.50 ℃ of reaction stirred and splash into the iodine monochloride solution of 5.7ml (14.1mmol) 40% hydrochloric acid.50 ℃ after 20 hours with the superfluous iodine of bisulfite sodium reduction, the sucking-off precipitation also washes with water.Output: 4.15g (theoretical value 86%) faint yellow solid ultimate analysis (considering under the solvent situation): theoretical value: C 33.57 H 3.62 I 33.78 N 5.59 O 23.43 measured values: C 33.71 H 3.86 I 33.41 N 5.65c) 3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-(3,5-two iodo-4-ethoxy benzyls)-undecane diacid
With 3.0g (4mmol) by embodiment 4b) phenol diiodide that obtains mixes with 0.792g (26.4mmol) 80% sodium hydride suspension in mineral oil in the 25ml tetrahydrofuran (THF).In this suspension, add 4.1g (26.4mmol) iodoethane and stirring at room reaction mixture 6 hours.Then mix 30ml 2N sodium hydroxide solution, be evaporated to dry doubling and make resistates soluble in water.Aqueous solution concentrated hydrochloric acid acidifying, the sucking-off throw out also washes with water.Be purifying ethyl alcohol recrystallization crude product.Output: 2.35g (theoretical value 75.4%) colourless crystallization ultimate analysis (considering under the solvent situation): theoretical value: C 35.45 H 4.01 I 32.57 N 5.39 O 22.58 measured values: C 35.59 H 3.94 I 32.39 N 5.23d) 3,6,9-three azepines-3,6, the gadolinium complex of 9-three-(carboxymethyl)-4-(3,5-two iodo-4-ethoxy benzyls)-undecane diacid
Five acid that 1.75g (2.2mmol) is made by embodiment 4c suspend in the 55ml water and at 60 ℃ to wherein mixing 407mg (1.1mmol) gadolinium oxide compound.After 4 hours, use the activated carbon treatment clear solution.Then through a cellulose membrane strainer (0.2mm, Sartorius) finly filtration and lyophilize.The colourless lyophilized products ultimate analysis of output: 1.95g (theoretical value 94.9%) (considering under the solvent situation): theoretical value: C 29.59 H 3.02 Gd 16.84 I 27.19 O 18.85 measured values: C 29.64 H 3.25 Gd 16.66 I 26.93e) 3,6,9-three azepines-3,6, the gadolinium complex of 9-three-(carboxymethyl)-4-(3,5-two iodo-4-ethoxy benzyls)-undecane diacid disodium salt
The complex compound that 1.5g (1.6mmol) is described at preceding embodiment dissolve in the 120ml water and with micro pipette to the sodium hydroxide solution that wherein mixes the 3.2ml monovalent.After lyophilize, obtain disodium salt, be colourless lyophilized products.The colourless lyophilized products ultimate analysis of output: 1.55g (theoretical value 99%) (considering under the solvent situation): theoretical value: C 28.26 H 2.68 Gd 16.09 I 25.96 N 4.30 Na 4.70O 18.00 measured values: C 28.03 H 2.91 Gd 15.86 I 25.72 N 4.09 Na4.45
Embodiment 54-(N-ethanoyl-3-methylamino--2; 4; 6-triiodo benzyloxymethyl)-3,6,9-three azepines-3; 6; the gadolinium complex of 9-three-(carboxymethyl)-undecane diacid disodium salt is N-ethanoyl-N-methyl-3-[(2 a), 2-dimethyl-1,3-dioxolane-4-yl)-methoxymethyl]-2; 4,6-triiodo aniline
With 20.0g (36.3mmol) embodiment 2a) compound, the 5.8g (43.6mmol) 2 that make, 3-O-isopropylidene glycerol, 0.41g (1.8mmol) chlorination N-benzyl-N, N, N-triethyl ammonium and 4.1g (72.7mmol) ground potassium hydroxide was 35ml reflux in toluene 6 hours.Tell organic phase then, separate and through dried over mgso with the full common salt aqueous solution shake that closes.Obtain the oily resistates after filtration and evaporation concentration filtrate, this resistates carries out chromatographic separation with toluene/acetic ester on silica gel.Evaporation concentration product cut obtains water white oil, makes it dry in a vacuum.Output: 21.3g (theoretical value 87.2%) analyzes (is base with solvent-free material): theoretical value: C 28.64 H 3.00 I 56.73 N 2.09 O 9.54 measured values: N-ethanoyl-N-methyl-3-[(2 C 28.60 H 3.09 I 56.72 N 2.11b); 3-dihydroxyl propoxy-)-and methyl]-2; 4,6-triiodo aniline
With 20.2g (30.1mmol) by implementing your 5a) compound of preparation adds in the mixture of being made up of the 60ml ethanol and the 10ml vitriol oil.30 ℃ stir 12 hours after, this reactant is dissolved in the methylene dichloride and with organic phase with the concentrated sodium chloride solution jolting once with dense sodium hydrogen carbonate solution shake separated secondary.Make organic phase through anhydrous magnesium sulfate drying, filter and evaporation concentration, resistates is gone up at silica gel 60 (Merck) and is carried out chromatographic separation with methylene chloride.Behind evaporation concentration product cut, get a water white oil, make it dry in a vacuum.Productive rate: 16.9g (theoretical value 89.2%) analyzes (is base with solvent-free material): theoretical value: C 24.25 H 2.56 I 60.34 N 2.22 O 10.14 measured values: N-ethanoyl-methyl-3-[(3-benzoyloxy-2-hydroxyl propoxy-C 24.86 H 2.69 I 60.12 N2.34c))-methyl]-2; 4,6-triiodo aniline
With 15.2g (24.1mmol) at embodiment 5b) in the compound of preparation in the 150ml methylene dichloride, stirring under the argon atmospher and at first mixing 4.0ml (28.9mmol) triethylamine, mix 3.47g (26.5mmol) benzoyl cyanide 0 ℃ of dropping then.0 ℃ stir 12 hours after with methylene dichloride diluting reaction thing and carry out jolting again with saturated sodium bicarbonate solution and separate.Organic phase is filtered and evaporation concentration through dried over mgso, and resistates is gone up at silica gel 60 (Mderck) and carried out chromatographic separation with methylene chloride.The product cut gets a water white oil after concentrating.Productive rate: 13.9g (theoretical value 78.4%) analyzes (is base with solvent-free material): theoretical value: C 32.68 H 2.74 I 51.79 N 1.91 O 10.88 measured values: methyl N-ethanoyl-N-methyl-3-[(3-benzoyloxy-2-mesyloxy propoxy-C 32.54 H 2.88 I 51.83 N 1.74d))]-2; 4,6-triiodo aniline
With 13.4g (18.2mmol) embodiment 5c) compound of preparation stirs in the methylene dichloride at 80ml under the argon atmospher and also at first mixes 3.0ml (21.9mmol) triethylamine, mixes 1.56ml (20.1mmol) methylsulfonyl chloride 0 ℃ of dropping then.Making temperature of reaction rise to room temperature in 3 hours also separates with the saturated sodium bicarbonate solution jolting then.Organic phase is filtered and evaporation concentration through dried over mgso.The oily resistates is gone up at silica gel 60 (Merck) and is carried out chromatographic separation with methylene dichloride, enriched product cut and dried residue in a vacuum.Productive rate: 12.8g (theoretical value 86.2%) yellow foam analysis (is base with solvent-free material) theoretical value: C 31.02 H 2.73 I 46.82 N 1.72 O 13.77 S3.94 measured value: C 31.20 H 2.89 I 46.67 N 1.83 S 4.02e) N-ethanoyl-N-methyl-3-[(3-benzoyloxy-2-azido-propoxy-)-and methyl]-2; 4,6-triiodo aniline
With 11.8g (14.5mmol) at embodiment 5d) in the compound of preparation at 50ml N, stirred 1 hour under 85 ℃ and argon atmospher with 2.83g (43.5mmol) sodium trinitride in the dinethylformamide.Evaporation concentration and resistates separated with methylene dichloride/saturated sodium bicarbonate solution jolting in a vacuum then.Organic phase is filtered also evaporation concentration in a vacuum through dried over mgso.Output: 10.2g (theoretical value 92.1%) yellow foam analysis (is base with solvent-free material) theoretical value: C 31.60 H 2.52 I 50.09 N 7.37 O 8.42 measured values: methyl N-ethanoyl-N-methyl-3-[(2-azido--3-hydroxyl propoxy-C 31.59 H 2.63 I 49.87 N 7.49f))]-2; 4,6-triiodo aniline
With 9.58g (12.6mmol) by embodiment 5e) preparation compound dissolve in the 60ml methyl alcohol.After adding 40ml 2N sodium hydroxide solution, bathed the temperature stirring 1 hour and after cooling, used the neutralization of 2N hydrochloric acid at 50 ℃.Extract methyl alcohol out in vacuum, and resistates is distributed between methylene dichloride and the saturated sodium bicarbonate solution.Organic phase is through dried over mgso, filters, and evaporation concentration, resistates separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel 60 (Merck), and with product cut evaporation concentration in a vacuum.Output: 7.47g (theoretical value 90.3%) analyzes (is base with solvent-free material) theoretical value: C 23.80 H 2.31 I 58.04 N 8.54 O 7.32 measured values: N-ethanoyl-N-methyl-3-[(2-azido--3-mesyloxy propoxy-C 23.92 H 2.50 I 57.85 N 8.6g))-methyl]-2; 4,6-triiodo aniline
7.22g (11.0mmol) is being implemented 5f) oxy-compound of preparation is at embodiment 5d) change into corresponding methylsulfonyl thing under the condition described.Output: 7.46g (theoretical value 92.4%) analyzes (is base with solvent-free material) theoretical value: C22.91 H2.33 I5.86 N7.63 O10.90 S4.37 measured value: N-ethanoyl-N-methyl-3-(6 C23.01 H2.58 I51.63 N7.75 S4.49h); 9-diaza-4-azido--2-oxa-nonyl)-2; 4,6-triiodo aniline dihydrochloride
With 7.21g (9.82mmol) at embodiment 5g) in the methylsulfonyl thing described dissolve in the 50ml methyl alcohol, and after adding the 150ml 1 stirring at room 15 hours.Then evaporation concentration reactant and between methylene dichloride and saturated sodium bicarbonate solution, distributing.Water with dichloromethane extraction for several times.The organic phase that merges is filtered and evaporation concentration through dried over sodium sulfate.Resistates is dissolved in t-butyl methyl ether/methyl alcohol and transfers PH with concentrated hydrochloric acid is 2, is settled out colourless throw out thus.Isolate throw out and dry in a vacuum.Output: 7.33g (theoretical value 96.8%) analyzes (is base with solvent-free material) theoretical value: C 23.37 H 3.01 I 49.38 N 10.90 O 4.15 Cl 9.20 measured values: N-ethanoyl-N-methyl-3-(4-amino-6 C 23.28 H 3.22 I 49.39 N 11.02 Cl 9.37i); 9-diaza-2-oxa-nonyl)-2; 4,6-triiodo aniline tri hydrochloride
With 7.04g (9.13mmol) embodiment 5h) preparation dihydrochloride be dissolved in 70ml in 4: 1 the mixture that diox/water is formed, and to wherein mixing 12.0g (45.7mmol) triphenyl phosphine, reaction stirred is three days under room temperature and argon atmospher, boil off organic solvent and filter out throw out, with 2N hydrochloric acid washing precipitate; The filtrate that evaporation concentration merges also makes the resistates recrystallization with methyl alcohol/t-butyl methyl ether.Output: 6.12g (theoretical value 85.8%) analyzes (is base with solvent-free material): 4-(N-ethanoyl-3-methylamino--2 theoretical value: C 23.05 H 3.35 I 48.72 N 7.17 O 4.10 Cl13.61 measured value: C 23.28 H 3.60 I 48.49 N 7.43 Cl13.88j); 4; 6-triiodo benzyloxymethyl)-3; 6; 9-three-(tertiary butyloxycarbonyl ylmethyl)-3; 6,9-three azepine undecane diacid-two-tert-butyl esters
With 5.98g (7.65mmol) at embodiment 5i) tri hydrochloride of preparation at 60ml N, stirs in the dinethylformamide and to wherein mixing 10.6g (76.5mmol) salt of wormwood and 7.46g (38.3mmol) bromoacetic acid-tert-butyl ester under room temperature and argon atmospher.Stirring 12 hours after-filtration, in a vacuum evaporation concentration and resistates is distributed between ethyl acetate and the saturated sodium bicarbonate solution.Organic phase is through dried over sodium sulfate.Filter, evaporation concentration, and resistates gone up at silica gel 60 (Merck) carry out chromatographic separation with hexane/ethyl acetate.After product cut evaporation concentration, obtain a yellow oil.Output: 8.94g (theoretical value 98.5%) analyzes (is base with solvent-free material): theoretical value: 41.50 H, 5.52 I, 32.08 N, 4.74 O, 16.18 measured values: 4-(N-ethanoyl-3-methylamino--2 C 41.52 H 5.73 I 31.96 N 4.68k); 4; 6-triiodo benzyloxymethyl)-3; 6; 9-three azepines-3; 6,9-three-(carboxymethyl)-undecane diacid
With 8.50g (7.16mmol) at embodiment 5j) preparation five-ester at embodiment 1c) in the description condition under change into corresponding five acid.The light beige solid of output 5.80g (theoretical value 84.1%).Analyze (being base with the anhydrous substances): theoretical value: C 31.20 H 3.46 I 39.56 N 5.82 O 19.95 measured values: 4-(ethanoyl-3-methylamino--2 C 31.25 H 3.66 I 39.42 N 5.83l); 4; 6-triiodo benzyloxymethyl)-3; 6; 9-three-azepine-3; 6, the gadolinium complex of 9-three-(carboxymethyl)-undecane diacid disodium salt
With 5.69g (6.19mmol) at embodiment 5k) in five acid of preparation at embodiment 1d) under the condition of description with the gadolinium sesquioxide complexing and change into corresponding disodium salt.
The colourless lyophilized products analysis of output: 6.81g (theoretical value 94.8%) (is base with the anhydrous substances): theoretical value: C 25.88 H 2.43 I 32.81 N 4.83 O 16.55 Gd 13.55Na 3.96 measured values: C25.94 H 2.61 I 32.78 N 4.85 Gd 13.44 Na 4.00
Two (3-carboxyl-2,4, the 6-triiodophenyl)-7,10 of embodiment 61.19-, 13-three-(carboxymethyl)-2,5,15,18-four oxos-1,4,7,10,13,16,19-seven azepine nonadecanes, gadolinium complex, disodium salt is 1.19-pair-(3-carboxyl-2,4,6-triiodophenyl)-7,10 a), 13-three-(carboxymethyl)-2,5,15,18-four oxos-1,4,7,10,13,16,19-seven azepine nonadecanes
With 11.42g (20mmol) 3-glycyl amino-2,4,6-Triiodobenzoic acid (DE2523567) dissolves in 60ml N under heating state, in the dinethylformamide.To wherein mixing 6.9ml triethylamine and 3.6g (10mmol) N, N-is two-[2,6-dioxo morpholine generation) ethyl]-glycine and stirring at room reaction mixture 15 hours in room temperature.Then be evaporated to dried, resistates is soluble in water and use the concentrated hydrochloric acid acidifying.The throw out that sucking-off settles out also washes with water.Crude product on silica gel RP18 through chromatogram purification.Output: 9.5g (theoretical value 63%) colorless solid.Ultimate analysis (considering under the solvent situation): theoretical value: C 25.60 H 2.22 I 50.73 N 6.53 O 13.18 measured values: 1.19-pair-(3-carboxyl-2,4,6-triiodophenyl)-7 C 25.53 H 2.35 I 50.52 N 6.29b), 10,13-three-(carboxymethyl)-2,5,15,18-four oxos-1,4,7,10,13,16,19-seven azepine nonadecanes, gadolinium complex, disodium salt
With 7.2g (48mmol) by embodiment 6a) part that obtains suspend in the 50ml water and at 50-60 ℃ in batches to wherein mixing 17.4g (4.8mmol) gadolinium oxide compound.Transferring the PH value with the 1N sodium hydroxide solution after complete complexing is 7, filters and the lyophilize aqueous solution.The colourless lyophilized products ultimate analysis of output: 7.6g (theoretical value 93%) (considering under the solvent situation): theoretical value: C 22.62 H 1.66 Gd 9.25 I 44.81 N 5.77 Na 2.71O 13.18 measured values: C 22.43 H 1.85 Gd 9.07 I 44.71 N 5.63 Na 2.49
Embodiment 71.19-pair-the 3-[(10-carboxy decyl)-formamyl]-2,4, the 6-triiodophenyl }-7,10; 13 ,-three-(carboxymethyl)-2,5; 15,18-four oxos-1,4; 7,10,13; 16,19-seven azepine nonadecanes, gadolinium complex; disodium salt is (3-glycyl amino)-N-(10-carboxy decyl)-2,4 a), 6-phenyl triiodide methane amide
With 10.9g (15mmol) 3-phthalimido kharophen)-2,4,6-phenyl triiodide formyl chloride (DE 2523567) dissolves in 60mlN, reacts with the amino undecanoic acid of 1.98g (16mmol) 11-in the N-N,N-DIMETHYLACETAMIDE and at 80 ℃.This temperature stirred reaction mixture 32 hours, and then filter salts hydrochlorate.To doing, resistates suspends in the 40ml water and reacts with 4.5g (90mmol) hydrazine hydrate with the filtrate evaporation concentration.Stir the throw out that 3 hours postcoolingization answer mixture and sucking-off to settle out at 65 ℃.With well-to-do water flushing product and at vacuum and 50 ℃ of these solids of drying.The faint yellow crystallization ultimate analysis of output: 9.8g (theoretical value 87%) (considering under the solvent situation): theoretical value: C 34.73 H 4.05 I 40.77 N 6.75 O 13.71 measured values: 34.90 H, 3.92 I, 40.68 N 6.51b) 1.19-two-the 3-[(10-carboxy decyl)-formamyl]-2,4, the 6-triiodophenyl }-7; 10,13-three-(carboxymethyl)-2,5; 15; 18-four oxos-1,4,7; 10; 13,16,19-seven azepine nonadecanes
With 8.75g (11.6mmol) by embodiment 7a) amine that obtains is by being similar to embodiment 6a) and method and 2.14g (6mmol) N, N-two [2-(2,6-dioxo morpholine generation) ethyl] glycine react and in a similar manner on silica gel RP18 through the column chromatography purifying.The solid of the little Huang of output: 17.4g (theoretical value 80%).Ultimate analysis (considering under the solvent situation): theoretical value: 34.73 H, 4.05 I, 40.77 N, 6.75 O, 13.71 measured values: C 34.90 H 3.92 I 40.68 N 6.51c) 1.19-pair-the 3-[(10-carboxy decyl)-formamyl]-2,4, the 6-triiodophenyl }-7; 10,13-three-(carboxymethyl)-2,5; 15,18-four oxos-1,4; 7,10,13; 16; 19-seven azepine nonadecanes, gadolinium complex, disodium salt
With 15g (8mmol) by embodiment 7b) part that obtains is according to embodiment 6b) carry out complexing and change into disodium salt with 2.9g (8mmol) gadolinium sesquioxide with the 1N sodium hydroxide solution.The colourless lyophilized products ultimate analysis of output: 15.6g (theoretical value 95%) (considering under the solvent situation): theoretical value: C 31.40 H 3.42 Gd 7.61 I 36.86 N 6.10 Na 2.23O 12.39 measured values: C 31.28 H 3.63 Gd 7.56 I 36.61 N 5.89 Na 1.97
Embodiment 84-(3-acetylamino-2,4,6-phenyl triiodide formyl radical-amino methyl)-3,6,9-three azepines 3,6,9-three-(carboxymethyl)-4-methyl undecane diacid disodium salt gadolinium complex a) 2,4-dimethyl-4-mesyloxy methyl-2-oxazoline
With 40.8g (316mmol) 2,4-dimethyl-4-hydroxymethyl-2-oxazoline (J.Nys and J.Libeer, Bull.Soc.Chin.Belg., 65,377 (1956)) under 0 ℃ and nitrogen atmosphere, in 400ml methylene dichloride and 52.5ml (379mmol) triethylamine, stir and mix 39.8g (347mmol) methylsulfonyl chloride to it in the dropping mode.Make temperature of reaction be increased to room temperature in 3 hours, reactant is with the saturated sodium bicarbonate solution jolting.Organic phase is filtered and evaporation concentration through dried over sodium sulfate.Output: 58.5g (theoretical value 89.4%) yellow oil analysis (is base with solvent-free material): theoretical value: C 40.57 H 6.32 N 6.76 O 30.88 S 15.47 measured values: 4-(2 C 40.49 H 6.48 N 6.83 S15.30b), 5-diaza amyl group)-2,4-dimethyl-2-oxazoline, dihydrochloride
With 36.7g (177mmol) by embodiment 8a) preparation the solution of compound in 100ml methyl alcohol be added in 291ml (4427mmol) 1 in the dropping mode.Reaction mixture stirred 3 hours and stirred 12 hours in the room temperature continuation at 50 ℃.Complete in a vacuum then evaporation concentration reactant.It is 1.5 that the solution of resistates in methyl alcohol is transferred PH at 0 ℃ with concentrated hydrochloric acid.At this quadrol-dihydrochloride that is settled out is passed through filtering separation.In filtrate, splash into t-butyl methyl ether and produce a kind of colourless throw out, sucking-off precipitation and in vacuum-drying.Output: 38.2g (theoretical value 88.4%) analyzes (is base with solvent-free material): theoretical value: C 39.35 H 7.84 N 17.21 O 6.55 Cl 29.04 measured values: 2-amino-4 C 39.40 H 7.78 N 17.09 Cl 29.11c), 7-diaza-2-methyl heptan-1-alcohol, tri hydrochloride
With 30.8g (126mmol) at embodiment 8b) preparation dihydrochloride be dissolved in the 150ml ethanol.After adding the 31ml concentrated hydrochloric acid, refluxed 4 hours.Stir with the reaction mixture vacuum concentration and in the 300ml Virahol after the cooling.Sucking-off precipitation is with Virahol and ether washing and in vacuum-drying.Output: 29.6g (theoretical value 91.4%) analyzes (is base there not to be molten material): theoretical value: C 28.08 H 7.86 N 16.38 O 6.24 Cl 41.45 measured values: C 28.23 H 7.95 N 16.46 Cl 41.19d) 3,6,9-three azepines-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-4-hydroxymethyl-4-methyl undecane diacid-two-tert-butyl ester.
In the solution of 51.2g (369mmol) salt of wormwood in 60ml water, add 18.9g (73.7mmol) embodiment 8c) preparation tri hydrochloride.Under vigorous stirring, add 60.0ml (369mmol) bromo-acetic acid tert-butyl be dissolved in the 60ml tetrahydrofuran (THF) and stirred 6 hours at 60 ℃.Adding ethyl acetate after cooling separates with water and jolting; Water with ethyl acetate extraction for several times.The organic phase that merges is filtered and the vacuum-evaporation concentrated filtrate through dried over sodium sulfate.
Output: 52.2g (theoretical value 98.8%) analyzes (is base with solvent-free material): theoretical value: C 60.23 H 9.41 N 5.85 O 24.51 measured values: 4-chloromethyl-4-methyl-3 C 60.11 H 9.62 N 5.67e), 6,9-three-(tertiary butyloxycarbonyl ylmethyl)-3,6,9-three azepines-undecane diacid-two-tert-butyl ester
To 22.3g (31.0mmol) embodiment 8d) in mix 8.91g (34.0mmol) triphenyl phosphine in the solution of alcohol in the 100ml methylene dichloride of preparation, and after being cooled to 0 ℃, mix 4.54g (34.0mmol) N-neoprene imide., stir in the 200ml ether after 2 hours 0 ℃ of stirring, separating solid substances also discards.Evaporation concentration ether upward carries out chromatographic separation with hexane/ethyl acetate (2: 1) to resistates mutually and at silica gel 60 (Merck).
The product cut obtains a kind of xanchromatic oil in a vacuum after evaporation concentration.Output: 18.7g (theoretical value 81.7%) analyzes (is base there not to be molten material): theoretical value: C 58.72 H 9.03 Cl 4.81 N 5.71 O 21.73 measured values: C 58.68 H 9.23 Cl 4.98 N 5.64f) 3,6,9-three azepines-4-azido methyl-3,6,9-three-tertiary butyloxycarbonyl ylmethyl)-4-methyl undecane diacid-two-tert-butyl ester
To 18.6g (25.3mmol) embodiment 8e) in the muriate of preparation at 70ml N, mix 4.92g (75.8mmol) sodiumazide in the solution in the dinethylformamide and stirred 6 hours at 50 ℃.Evaporation concentration in a vacuum then, and resistates distributed between ethyl acetate and saturated sodium bicarbonate solution.Organic phase gets a yellow oil after dried over mgso, filtration and evaporation concentration.Output: 18.2g (theoretical value 97.0%) analyzes (is base with solvent-free material): theoretical value: C 58.20 H 8.95 N 11.31 O 21.73 measured values: 4-amino methyl 3 C 58.15 H 8.72 N 11.18G), 6,9-three azepines-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-4-methyl undecane diacid-two-tert-butyl ester
With 18.0g (24.2mmol) embodiment 8f) in the solution of trinitride in 180ml ethanol of preparation be stated from the palladium (palladium of 10% weight percentage on the gac adding 0.90g, producer Degussa) back violent jolting under nitrogen atmosphere, until do not observe hydrogen be absorbed as to.Filter out catalyzer then and at the vacuum-evaporation concentrated filtrate.Output: 17.4g (theoretical value 99.9%) yellow oil analysis (is base with solvent-free material): theoretical value: C 60.31 H 9.56 N 7.82 O 22.32 measured values: 4-(3-acetylaminohydroxyphenylarsonic acid 2 C 60.22 H 9.78 N 8.03h), 4,6-phenyl triiodide formamido group methyl)-3,6,9-three azepines-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-4-methyl undecane diacid-two-tert-butyl ester
To 17.2g (24.0mmol) embodiment 8g) preparation amine be dissolved in 70ml N, mix 3.99g (28^8mmol) triethylamine and 15.2g (26.4mmol) 3-acetylaminohydroxyphenylarsonic acid 2 in the solution in the N-N,N-DIMETHYLACETAMIDE, 4,6-phenyl triiodide formyl chloride (H.Priewe etal., Chem.Ber.87 651 (1954)), and stirring at room 6 hours.Evaporation concentration in a vacuum then, resistates distributes between ethyl acetate and saturated sodium bicarbonate solution, and organic phase is through dried over sodium sulfate.Filter back evaporation concentration filtrate, and resistates is upward carried out chromatographic separation with hexane/ethyl acetate at silica gel 60 (Merck).Behind the enriched product cut, obtain yellow oil.
Output: 27.9g (theoretical value 92.6%) analyzes (is base with solvent-free material): theoretical value: C 43.04 H 5.78 I 30.32 N 5.58 O 15.29 measured values: 4-(3-acetylaminohydroxyphenylarsonic acid 2 C 43.21 H 5.86 I 30.19 N 5.63i), 4,6-phenyl triiodide formamido group methyl)-3,6,9-three-(carboxymethyl)-4-methyl undecane diacid
With 26.6g (21.2mmol) embodiment 8h) five-ester described is at embodiment 1c) in be converted into corresponding five acid under the condition of description.Output: 19.5g (94.4% light beige solid.Analyze (being base with the anhydrous substances) theoretical value: C 30.79 H 2.23 I 39.04 N 7.18 Na 3.92 O 19.69 measured values: 4-(3-acetylaminohydroxyphenylarsonic acid 2 C 30.98 H 2.40 I 38.84 N 7.24 Na 4.04j); 4; 6-phenyl triiodide formyl radical-amino methyl)-3; 6; 9-three azepines-3; 6, the gadolinium complex of 9-three-(carboxymethyl)-4-methyl-undecane diacid disodium salt
With 18.8g (19.3mmol) embodiment 8i) in five acid described at embodiment 1c) in change into title compound under the condition of description.Output: 20.7g (theoretical value 91.5%) colorless solid analysis (is base with the anhydrous substances): theoretical value: C 25.59 H 2.32 Gd 13.50 I 32.44 N 5.97 Na 3.92O 16.36 measured values: C 25.64 H 2.40 Gd 13.29 I 32.27 N 6.08 Na 4.04 embodiment 94-(3-acetylaminohydroxyphenylarsonic acids 2,4,6-Triiodobenzoic acid base-methyl-3,6,9-three azepines-3,6, the gadolinium complex of 9-three-(carboxymethyl)-4-methyl undecane diacid disodium salt is 4-(3-acetylaminohydroxyphenylarsonic acid 2 a), 4,6-Triiodobenzoic acid ylmethyl)-4-methyl-3,6,9-three (tert.-butoxy-carboxymethyl)-3,6,9-three azepine undecane diacid-two-tert-butyl esters are with 14.7g (20.0mmol) embodiment 8e) in the chlorine compound described at 30ml N, solution in the N-N,N-DIMETHYLACETAMIDE is added to by 16.9g (29.9mmol) 3-acetylaminohydroxyphenylarsonic acid 2 in room temperature, 4, the sodium salt of 6-Triiodobenzoic acid (Wallingford etal., J.Am.Chem.Soc.74.4365 (d1952)) in the solution in the 50ml N,N-dimethylacetamide.80 ℃ of stirred reaction mixtures 6 hours, evaporation concentration in a vacuum then, and separate with the saturated sodium bicarbonate solution shake with ethyl acetate.Organic phase is filtered and evaporation concentration through dried over sodium sulfate, and resistates is gone up at silica gel 60 (Merck) and carried out chromatographic separation with hexane/ethyl acetate (3: 1), a remaining light cream-coloured oil after product cut evaporation concentration.Output: 18.0g (theoretical value 71.9%) analyzes (is base with solvent-free material): theoretical value: C 43.01 H 5.59 I 30.29 N 4.46 O 16.55 measured values: 4-(3-acetylamino-2 C 43.11 H 5.84 I 30.42 N 4.48b); 4; 6-Triiodobenzoic acid ylmethyl)-4-methyl-3; 6; 9-three azepines 3; 6,9-three-(tert.-butoxy-carboxymethyl)-undecane diacid
With 17.7g (14.1mmol) embodiment 9a) five-ester described is at embodiment 1d) change into corresponding five acid under the condition described.Output: 12.7g (theoretical value 92.7%), light beige solid analysis (is base with the anhydrous substances): theoretical value: C 30.76 H 3.20 I 39.00 N 5.74 O 21.30 measured values: 4-(3-acetylaminohydroxyphenylarsonic acid 2 C 30.81 H 3.48 I 38.90 N 5.77c), 4,6-Triiodobenzoic acid ylmethyl)-3,6,9-three azepines-3,6, the gadolinium complex of 9-three-(carboxymethyl)-4-methyl undecane diacid disodium salt
With 9.26g (9.48mmol) embodiment 9b) five acid described to be to be similar to embodiment 1d) in the condition described change into title compound.Output: 9.88g (theoretical value 88.7%) colorless solid analysis (is base with the anhydrous substances): theoretical value: C 25.14 H 2.29 I 33.21 N 4.89 O 16.75 Gd 13.72Na 4.01 measured values: C 25.13 H 2.38 I 33.11 N 4.93 Gd 13.67 Na 4.11
Embodiment 103,6,9-three azepines-3; 6; the gadolinium complex of 9-three-(carboxymethyl)-4-methyl-4-(3-methylamino formyl radical-2,4,6-phenyl triiodide yloxymethyl)-undecane diacid disodium salt a) 3; 6; 9-three azepines-3,6,9-three-tertiary butyloxycarbonyl ylmethyl)-4-methyl-4-(3-methyl-formamyl-2; 4,6-phenyl triiodide yloxymethyl)-undecane diacid-two-tert-butyl ester
With 18.9g (25.7mmol) embodiment 8e) muriate described is at 35ml N, solution in the N-N,N-DIMETHYLACETAMIDE is added to 16.3g (30.8mmol) 3-hydroxyl-2 in room temperature, 4,6-Triiodobenzoic acid-methane amide (P.L.Conturior, Ann.Chim II 10 (f1938) 559) and 1.72g (30.8mmol) potassium hydroxide at 30ml N, in the solution in the dinethylformamide.60 ℃ of stirred reaction mixtures 8 hours, evaporation concentration in a vacuum then, and resistates is carried out jolting with ethyl acetate and saturated sodium bicarbonate solution separate.Organic phase is through dried over sodium sulfate, filters and evaporation concentration, and resistates is gone up with hexane/ethyl acetate 3: 1 at silica gel 60 (Merck)) carry out chromatographic separation.Remaining light cream-coloured oil after the product cut evaporation concentration.Output: 21.9g (theoretical value 69.4%) analyzes (is base with solvent-free material): theoretical value: C 43.01 H 5.82 I 30.98 N 4.56 O 15.63 measured values: C 43.20 H 5.97 I 30.72 N 4.60b) 3; 6; 9-three azepines-3; 6; 9-three-(carboxymethyl)-4-methyl-4-(3-methylamino formyl radical-2; 4,6-phenyl triiodide yloxymethyl)-undecane diacid
With 20.6g (17.0mmol) embodiment 10a) in the five-ester described at embodiment 1c) in change into corresponding five acid under the condition of description; the light beige solid analysis of output: 13.9g (theoretical value 86.3%) (is base with the anhydrous substances): theoretical value: C 30.40 H 3.30 I 40.15 N 5.91 O 20.25 measured values: C 30.64 H 3.52 I 39.94 N 6.04c) 3; 6; 9-three azepines-3; 6; 9-three-(carboxymethyl)-4-methyl-4-(3-methylamino formyl radical-2; 4; 6-phenyl triiodide yloxymethyl)-gadolinium complex of undecane diacid disodium salt with 13.2g (13.9mmol) at embodiment 10b) five acid described, be similar to 1d at embodiment) in the condition of description be converted into title compound.The colourless lyophilized products analysis of output: 15.0g (theoretical value 94.1%) (is base with the anhydrous substances): theoretical value: C 25.14 H 2.29 I 33.21 N 4.89 O 16.75 Gd 13.72Na 4.01 measured values: C 25.13 H 2.38 I 33.11 N 4.93 Gd 13.67 Na 4.11
Embodiment 11N, N-pair-[2-[N ', N '-two-(carboxymethyl)-amino]-ethyl]-3-acetylaminohydroxyphenylarsonic acid 2,4, the gadolinium complex of 6-triiodophenyl L-Ala disodium salt is 3-amino-2,4 a), 6-triiodophenyl L-Ala hydrochloride
With 32.5g (150mmol) 3-aminophenyl L-Ala hydrochloride (Jen-nings, J.Chem.Soc., 1957,1512) solution in 300ml water 50 ℃ and stir under slowly be added drop-wise in the mixture of in 6.01l water, forming by 300ml concentrated hydrochloric acid and 240ml 2N potassiumiodide dichloride solution.After having spent 3.5 hours, filter this hot turbid solution and be concentrated into beginning crystalline volume in vacuum-evaporation.Then also will fully cool off in ice, the sucking-off crystallization is with the water absorbability precipitation and through the Vanadium Pentoxide in FLAKES drying.Output: 50.7g (theoretical value 67.0%) analyzes (being base with the anhydrous substances): theoretical value: C 18.19 H 1.70 I 64.06 N 4.71 O 5.38 Cl 5.97 measured values: 3-amino-2 C 18.38 H 1.94 I 63.82 N 4.83 Cl 6.11b), 4,6-triiodophenyl alanine ethyl ester hydrochloride
30.8g (51.8mmol) is pressed embodiment 11a) amino acid of preparation refluxed 10 minutes in the mixture of being made up of 150ml ethanol and 4.1ml (57mmol) thionyl chloride, then stirring at room 12 hours.Then evaporation concentration reaction mixture and dried residue in a vacuum.The light beige solid analysis of output: 32.3g (theoretical value 00%) (is base with the anhydrous substances): theoretical value: C 21.23 H 2.27 I 61.17 N 4.50 O 5.14 Cl 5.70 measured values: N C 21.44 H 2.38 I 60.93 N 4.62 Cl 5.89c), N-pair-[2-[N ', N '-two [(benzyloxycarbonyl)-methyl]-amino]-ethyl]-3-amino-2,4,6-triiodophenyl alanine ethyl ester
20.4g (32.7mmol) is pressed embodiment 11b) preparation amine and 31.0g (73.7mmol) N, two [(benzyloxycarbonyl)-methyl]-2-bromine methylamine (the M.Williamsund H.Rapoport of N-, J.Org.Chem.58,1151 (1993)) add in the 50ml acetonitrile, and mix 20ml 2N phosphate buffered saline buffer (PH8.0) to it.Room temperature vigorous stirring reaction mixture 24 hours, around here 2 hours with 8 hours after replace aqueous phosphate buffered mutually with fresh buffer.Concentrate organic phase in vacuum-evaporation then, and on silica gel with hexane/ethyl acetate/triethylamine (3:: 0.01) resistates is carried out chromatographic separation.Evaporation concentration contains the cut of product in a vacuum.Output: 25.8g (theoretical value 62.3%) yellow oil.Analyze (is base with solvent-free material): theoretical value: C 48.43 H 4.38 I 30.10 N 4.43 measured values: N C 48.50 H 4.45 I 30.01 N 4.44d), N-pair-[2-[N ', N '-two [(carbobenzoxy-(Cbz))-methyl]-amino]-ethyl]-3-acetylaminohydroxyphenylarsonic acid 2,4,6-triiodophenyl alanine ethyl ester
With 13.7g (10.8mmol) embodiment 11c) in the compound described dissolve in the 30ml N,N-dimethylacetamide, and after adding 1.80ml (13.0mmol) triethylamine and 0.85ml (11.9mmol) Acetyl Chloride 98Min., under room temperature and dehumidifying situation, stirred 12 hours.Concentrate in vacuum-evaporation then, and in ethyl acetate and sodium hydrogen carbonate solution, distribute resistates.Organic phase is filtered and evaporation concentration through dried over sodium sulfate. Output: 13.8g (theoretical value 97.6%) yellow oil analysis (is base with solvent-free material): theoretical value: C 48.71 H 4.40 I 29.13 N 4.29 O 13.47 measured values: C 48.83 H 4.67 I 29.02 N 4.38e) N-N-two-[2-[N ', N '-two-(carboxymethyl)-amino]-ethyl]-3-acetylaminohydroxyphenylarsonic acid 2,4,6-triiodophenyl L-Ala
With 12.8g (9.80mmol) embodiment 11d) in the five-ester described dissolve in the 75ml methyl alcohol and to wherein mixing 49ml 2N sodium hydroxide solution.Reflux and also took out methyl alcohol in about 2 hours in a vacuum.Transferring PH with half dense hydrochloric acid is 1-2, produces a kind of colourless throw out, and the sucking-off throw out is also dry in a vacuum.Output: 7.80g (theoretical value 86.7%) analyzes (being base with the anhydrous substances): theoretical value: C 30.09 H 3.18 I 41.46 N 6.10 O 19.17 measured values: N C 30.22 H 3.31 I 41.39 N 6.17f), N-pair-[2-[N ', N '-two-(carboxymethyl)-amino]-ethyl]-3-acetylaminohydroxyphenylarsonic acid 2,4, the gadolinium complex of 6-triiodophenyl L-Ala disodium salt
With 7.42g (8.08mmol) embodiment 11e) in five acid described be similar to 1d at embodiment) described in condition under be converted into title compound.Output: 8.72g (theoretical value 96.7%) analyzes (being base with the anhydrous substances) theoretical value: C 24.75 H 2.17 Gd 14.07 I 34.10 N 5.02 Na 4.12O 15.76 measured values: C 24.64 H 2.38 Gd 13.83 I 33.94 N 5.08 Na 3.89
Embodiment 122-(3-acetylaminohydroxyphenylarsonic acid 2,4,6-triiodo benzyl)-3,6,9-three azepines-3,6,9-three-(carboxymethyl)-undecane diacid, gadolinium complex, disodium salt a) 3,6,9-three azepines-3,6,9-three (methoxycarbonyl methyl)-undecane diacid methyl esters (JC 55,2868,1990)
Will the 20.6g in the 618ml methyl alcohol (52.4mmol) diethylene triaminepentaacetic acid(DTPA) be placed at 0 ℃ and in 30 minutes to wherein dripping 38.2ml (0.524mol) thionyl chloride.Then stirring at room reaction mixture 16 hours.After reaction finishes, in rotatory evaporator, carry out evaporation concentration and white solid is suspended in the 300ml ether.Mix the saturated hydrocarbon sodium solution of 200ml at 0 ℃ to suspension, isolate organic phase, and each uses 100ml extracted with diethyl ether water three times.Extract is through the salt of wormwood drying and be evaporated to dried after filtration.Product is in a vacuum through the Vanadium Pentoxide in FLAKES dried overnight.Output: 19.7g (theoretical 81%) water white oil ultimate analysis (considering under the solvent situation): theoretical value: C 49.24 H 7.18 N 9.07 O 34.52 measured values: C 49.37 H 7.26 N 8.85b) 3,6,9-three azepines-3,6,9-three-(methoxycarbonyl methyl)-2-(3-nitrobenzyl)-undecane diacid dimethyl ester
In light argon gas stream, will the 6.64ml in the 200ml anhydrous tetrahydro furan (47.3mmol) Diisopropylamine place 0 ℃ and in 15 minutes to wherein dripping 22.2ml (52mmol) butyllithium (15%, in hexane).Then be cooled to-78 ℃, and to wherein add 18.4g (40mmol) five-ester (embodiment 12a) that is dissolved in the 300ml anhydrous tetrahydro furan in batches.After this temperature stirs 30 minutes, in 30 minutes, add 8.11g (47.3mmol) 3-nitrobenzyl chloride and 1.38ml (11.44mmol) 1.3-dimethyl-3,4,5,6 ,-tetrahydrochysene-2 (the 1H)-solution of pyrimidone in the 180ml anhydrous tetrahydro furan.Make reaction mixture in ambient temperature overnight, and in rotatory evaporator this solution of evaporation concentration.Be dissolved in the oily resistates in the 150ml ethyl acetate and mix the 50ml frozen water.Separate organic phase and three each 75ml ethyl ester aqueous phase extracted.The organic phase that merges filters and is evaporated to dried through the salt of wormwood drying.For the purifying crude product upward carries out chromatographic separation to this material at silica gel 60 (Merck).Output: 13.2g (theoretical value 55%) light yellow oil
Ultimate analysis (considering under the solvent situation): theoretical value: C 52.17 H 6.40 N 9.36 O 32.07 measured values: 2-(3-aminobenzyl)-3 C 52.01 H 6.23 N 9.48c), 6,9-three-(methoxycarbonyl methyl)-undecane diacid dimethyl ester
With 12.7g (21.2mmol) by embodiment 12b) methanol solution of the nitro-compound that obtains is loaded in adding in room temperature under the situation of the palladium 1.35g (10%) on the gac and carries out hydrogenation under 4 bar pressure.Hydrogenation finishes to leach catalyzer after 5 hours.Filtrate is evaporated to dried, and need not further purification and promptly be used for next step.Output: 11.35g (theoretical value 94%) water white oil d) 2-(3-aminobenzyl)-3,6,9-three azepines-3,6,9-three-(carboxymethyl)-undecane diacid
With 10.8g (fd19mmol) by embodiment 12c) five-ester that obtains at 40 ℃ with the saponification of 60ml2N sodium hydroxide solution.Mixing concentrated hydrochloric acid after reaction finishes in solution all precipitates until acid.The sucking-off throw out also is washed with water to neutrality.Product is in a vacuum 50 ℃ of dried overnight.Output: 9.25g (theoretical value 96%) colorless solid ultimate analysis (considering under the solvent situation): theoretical value: C 47.15 H 5.84 Cl 6.63 N 10.47 O 29.91 measured values: 2-(3-amino-2 C 47.04 H 6.12 Cl 6.35 N 10.59e), 4,6-triiodo benzyl)-3,6,9-three azepines-3,6,9-three-(carboxymethyl)-undecane diacid
Be suspended in 9.55g (18mmol) five formic acid (embodiment 12d) in the 50ml water and splash into 40% iodine monochloride solution of 22.8ml (56.4mmol) hydrochloric acid.Reduce superfluous iodine 65 stirred reaction mixtures 16 hours and with rare sodium sulfite solution.The throw out that sucking-off is settled out also washes with water, and the exsiccant solid is dissolved in the strong aqua, filters and precipitates with concentrated hydrochloric acid.Washing precipitate is neutral until washing water.Product is dried to constant weight in 50 ℃ of vacuum.Output: 13.1g (83% (faint yellow solid of theoretical value.Ultimate analysis (considering under the solvent situation): theoretical value: C 28.79 H 3.11 I 43.45 N 6.39 O 18.26 measured values: 2-(3-acetylaminohydroxyphenylarsonic acid 2 C 28.93 H 3.37 I 43.32 N 6.48f), 4,6-triiodo benzyl)-3,6,9-three-(carboxymethyl)-3,6,9-three azepine undecane diacids
With 12.7g (d14.5mmol) by embodiment 12e) the triiodo aniline that obtains is dissolved in 30mlN, in the N-N,N-DIMETHYLACETAMIDE, and ice-cooled down to wherein mixing 2.465ml (34.8mmol) Acetyl Chloride 98Min..It is in ambient temperature overnight, and reaction mixture is stirred in frozen water.The sucking-off throw out washes with water and drying in 50 ℃ of vacuum.Output: 11.55g (theoretical 87%) colorless solid.Ultimate analysis (considering under the solvent situation): theoretical value: C 30.09 H 3.18 I 41.46 N 6.10 O 19.17 measured values: 2-(3-acetylaminohydroxyphenylarsonic acid 2 29.88 H, 3.26 I, 41.29 N 6.02g), 4,6-triiodo benzyl)-3,6,9-three azepines-3,6,9-three-(carboxymethyl)-undecane diacid, gadolinium complex, disodium salt.
With 11.2g (12.2mmol) by embodiment 12f) complexing agent that obtains is by embodiment 4d) and method react with gadolinium sesquioxide at 50 ℃.After the networkization intermediate product is being changed into disodium salt with the 1N sodium hydroxide solution fully.The solution 1.2g activated carbon purification that produces filters and then lyophilize through-0.2 μ m-cellulose membrane strainer.The colourless lyophilized products ultimate analysis of output: 12.6g (theoretical value 92.5%) (considering under the solvent situation): theoretical value: C 24.75 H 2.17 Cd 14.09 I 34.10 N5.02 Na 4612O 15.76 measured values: C 24.89 H 2.23 Gd 13.88 I 34.02 N 4.87 Na 4.03
Embodiment 133; 6,9-three azepines-3,6; 9-three-(carboxymethyl)-4-(3-[N; N '-dimethyl-N, N '-two (2, the 3-dihydroxypropyl)-3; 5-diamino formyl radical-2; 4,6-triiodophenyl carbamyl ylmethoxy]-benzyl]-a) N of the gadolinium complex of undecane diacid disodium salt, O-is two-(carbobenzoxy-(Cbz))-3-hydroxy phenyl L-Ala-N-[2-(benzyloxycarbonyl amino)-ethyl]-acid amides
With 168.54g (375mmol) N, O-pair-(carbobenzoxy-(Cbz))-3-hydroxy phenyl L-Ala (de castiglione, Bosisio, Gazz.Chim.Ital., 97,1858 (1967)) is dissolved in 3.0 liters of tetrahydrofuran (THF)s and is cooled to 0 ℃.After adding 72.8ml (525mmol) triethylamine, splash into 36.7ml (383mmol) chloro ethyl formate.Be added in 75.8g (390mmol) carbobenzoxy-(Cbz)-(2-the amino-ethyl)-acid amides (G.Atwell, W.Denny, Synthesis, 1032-33 (1948)) in the 500ml tetrahydrofuran (THF) after 20 minutes.At the stirring throw out that the back sucking-off generates that spends the night, evaporation concentration filtrate and in vacuum-drying.
Productive rate: 183.7g (theoretical value 78.3%) colorless solid
Analyze (is base with solvent-free material): theoretical value: C67.19 H5.64 N6.72 O 20.46 measured values: C67.07 H5.78 N6.84
B) 3-hydroxy phenyl L-Ala-(2-amino-ethyl)-acid amides
With 62.57g (100mmol) embodiment 13a) in the compound described be suspended in 1.5 liters of methyl alcohol, and add 6.3g be loaded in palladium on the gac (10% weight palladium, Degussa) after, under normal pressure, use hydrogen hydrogenation.Filter evaporation concentration filtrate and absorptivity precipitation resistates in diisopropyl ether then.Get colorless solid at suction strainer with after vacuum-drying.
Output: 21.4g (theoretical value 95.8%)
Analyze (is base with solvent-free material): theoretical value: C59.17 H7.67 N18.82 O14.33 measured value: C59.28 H7.73 N18.74
C) 1,5-diamino-3-azepine-2-(3-ethoxy benzyl)-pentane, tri hydrochloride
With 20.1g (90mmol) at embodiment 13b) in the compound described be dissolved in the 135ml tetrahydrofuran (THF) and in 0 ℃ and argon atmospher, drip the hydroborons solution of 180ml 1m in tetrahydrofuran (THF)., continue to stir 120 hours after 30 minutes 0 ℃ of stirring at 60 ℃.After cooling, drip 100ml methyl alcohol, make reaction mixture saturated, and stirred the acidic suspension that generates 6 hours with hydrogenchloride.Sucking-off throw out and dry in a vacuum then at 50 ℃.
Output: 25.0g (theoretical value 87.2%) colorless solid
Analyze (is base with solvent-free material): theoretical value: C41.46 H6.96 Cl 33.38 N13.19 O5.02 measured values: C41.40 H7.04 Cl 33.47 N13.08
D) 3,6,9-three azepines-4-(3-hydroxybenzyl)-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-undecane diacid-two-tert-butyl ester
With 15.1g (47.4mmol) embodiment 13c) in the compound described be suspended in the 500ml tetrahydrofuran (THF), and to wherein mixing 25m water and 34.5g (249mmol) salt of wormwood.Behind Dropwise 5 2.3ml (356mmol) bromoacetic acid-tert-butyl ester, stirred 3 days at 60 ℃.In cooled and filtered, evaporation concentration in a vacuum, and resistates carried out chromatographic separation with ether/hexane/triethylamine (70: 20: 5) on silica gel.
The product cut is evaporation concentration in a vacuum
Output: 27.2g (theoretical value 73.3%) water white oil
Analyze (is base with solvent-free material): theoretical value: C63.13 H8.92 N5.39 O22.56 measured value: C63.24 H8.88 N5.43
E) 5-chloro acetylamino-2,4,6-triiodo m-phthalic acid-(N, N '-dimethyl-N, N '-two-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl))-diamide
With 81.0g (100mmol) 5-chloro acetylamino-2,4,6-triiodo m-phthalic acid-N, N '-dimethyl-N, N '-two-(2, the 3-dihydroxypropyl)-diamide (DE 2928417) adds in the 500ml tetrahydrofuran (THF), and mix 0.95g (5.0mmol) right-toluenesulphonic acids-hydrate and 22.9g (220mmol) 2, the 2-Propanal dimethyl acetal.Refluxed then 12 hours, and concentrated in vacuum-evaporation, and between ethyl acetate and sodium hydrogen carbonate solution, distribute resistates.Organic phase is through dried over mgso and filter, evaporation concentration, and precipitate resistates with tertiary butyl methyl esters absorptivity.Dried residue in a vacuum after the filtration.
Output: 79.7g (theoretical value 89.6%) colorless solid
Analyze (is base with solvent-free material): theoretical value: C32.40 H3.51 Cl 3.99 I 42.79 N4.72 O12.59 measured values: C32.38 H3.62 Cl 4.04 I 42.70 N4.63
F) 3; 6,9-three azepines-3,6; 9-three-(tertiary butyloxycarbonyl ylmethyl)-4-(3-(N; N '-dimethyl-N, N '-two-(2,2-dimethyl-1; 3-dioxolane-4-ylmethyl)-3; 5-diamino formyl radical-2,4,6-triiodophenyl-formamyl-methoxyl group)-benzyl)-undecane diacid-two-tert-butyl ester
With 12.8g (16.4mmol) at embodiment 13d) in the oxy-compound described under argon atmospher, be dissolved in 50ml N, in the dinethylformamide, and mix the 80% sodium hydride suspension of 0.59g (19.7mmol) in mineral oil.In stirring at room after 30 minutes, add 19.0g (21.3mmol) embodiment 13e) in the compound described, and 50 ℃ of reaction stirred 12 hours.Evaporation concentration in a vacuum then, and go up at silica gel 60 (Merck) and with ether/hexane/triethylamine (70: 20: 5) resistates to be carried out chromatographic separation.The product cut is evaporation concentration in a vacuum.
Output: 16.8g (theoretical value 62.6%) heavy-gravity oil
Analyze (is base with solvent-free material): theoretical value: C47.80 H6.11 I 23.31 N5.15 O17.63 measured values: C47.63 H6.05 I 23.24 N5.24
G) 3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-(3-(N, N '-dimethyl-N, N '-two-(2, the 3-dihydroxypropyl)-3,5-diamino formyl radical-2,4,6-triiodophenyl carbamyl ylmethoxy)-benzyl)-undecane diacid
With 16.1g (9.86mmol) embodiment 13f) in the compound described at embodiment 1c) slough whole protecting groups under the condition described, and change into title compound.
The light beige solid of output: 12.4g (theoretical value 98.7%)
Analyze (being base with the anhydrous substances):
Theoretical value: C36.81 H4.04 I 29.92 N6.60 O 22.63 measured values: C36.94 H4.05 I 29.86 N6.53
H) 3,6,9-three azepines-3,6; 9-three-(carboxymethyl)-4-(3-(N, N '-dimethyl-N, N '-two-(2, the 3-dihydroxypropyl)-3; 5-diamino formyl radical-2,4,6-triiodophenyl-carbamyl ylmethoxy)-benzyl)-gadolinium complex of undecane diacid disodium salt
With 11.9g (9.35mmol) embodiment 13g) five acid described are at similar embodiment 1d) in be converted into title compound under the condition of description.
The colourless lyophilized products of output: 13.1g (theoretical value 95.5%)
Analyze (being base with the anhydrous substances): theoretical value: C31.85 H3.15 I 25.88 N5.57 O 19.58 Gd10.69 Na 3.13 measured values: C31.92 H3.20 I 25.76 N5.73 Gd 10.58 Na 3.20
Embodiment 14
3,6,9-three azepines-3,6, the gadolinium complex of 9-three-(carboxymethyl)-4-(3-methoxyl group-2,4,6-triiodo benzyl)-undecane diacid disodium salt
A) 3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-(3-hydroxybenzyl)-undecane diacid
With 13.2g (16.9mmol) embodiment 13d) in the compound described at embodiment 1c) in change into corresponding five acid under the condition of description.
Output: 8.20g (theoretical value 97.0%)
Analyze (being base with the anhydrous substances): theoretical value: C50.50 H5.85 N8.41 O 35.24 measured values: C50.41 H5.93 N8.49
B) 3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-(3-hydroxyl-2,4,6-triiodo benzyl)-undecane diacid
With 8.11g (16.2mmol) embodiment 14a) compound described is dissolved in the 80ml 5N ammoniacal liquor.Under agitation slowly to wherein dripping 26.8ml 2N potassiumiodide dichloride solution, and continue to stir 12 hours.Transferring pH value with concentrated hydrochloric acid is 1.5, and the adding sodium bisulfite occurs until light suspension; It was stirred 6 hours and filtered.Resistates is also dry in a vacuum with 2N salt acid elution.
Output: 12.1g (theoretical value 84.8%)
Analyze (anhydrous substances is a base): theoretical value: C28.75 H2.99 I 43.40 N4.79 O 20.06 measured values: C28.81 H2.83 I 43.43 N4.62
C) 3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-(3-methoxyl group-2,4,6-triiodo benzyl)-undecane diacid
With 11.6g (13.2mmol) embodiment 14b) in the compound described in the 60ml tetrahydrofuran (THF), mix with the 80% sodium hydride suspension of 2.77g (92.6mmol) in mineral oil at 0 ℃.Adding 13.1g (92.6mmol) methyl iodide also stirred 30 minutes.In this solution, mix 60ml 2N sodium hydroxide solution then and refluxed 30 minutes.Taking out organic solvent after the cooling in a vacuum and the remaining aqueous solution is transferred PH with concentrated hydrochloric acid is 1.5.Be settled out throw out, sucking-off is also dry under vacuum.
Output: 10.7g (theoretical value 91.4%)
Analyze (anhydrous substances is a base): theoretical value: C29.65 H3.17 I42.72 N4.72 O 19.75 measured values: C29.74 H3.23 I42.65 N4.63
D) 3,6,9-three azepines-3,6, the gadolinium complex of 9-three-(carboxymethyl)-4-(3-methoxyl group-2,4,6-triiodo benzyl)-undecane diacid disodium salt
With 10.2g (11.4mmol) embodiment 14c) in five acid described as at embodiment 1d) described in change into title compound.
The colourless lyophilized products of output: 11.7g (theoretical value 94.0%).
Analyze (being base with the anhydrous substances): theoretical value: C24.26 H2.13 I34.95 N3.86 O16.15 Gd14.43 Na4.22 measured value: C24.30 H2.10 I34.91 N3.90 Gd14.50 Na4.28
Embodiment 15
3,6,9-three azepines-4-(3-diethylamino formyl radical-2,4,6-triiodophenyl carbamyl yloxymethyl)-3,6, the gadolinium complex of 9-three-(carboxymethyl)-undecane diacid disodium salt
A) 3-isocyanide acyl-2,4,6-Triiodobenzoic acid diethylamide
With 57.00 (100.0mmol) 3-amino-2,4,6-Triiodobenzoic acid diethylamide (CA 54, P20987i (1960)) under nitrogen atmosphere at the toluene solution of room temperature and 250ml2N carbonyl chloride.Add 0.5ml N, behind the dinethylformamide, 60 ℃ of reaction stirred 5 hours, and then evaporation concentration to doing.
Productive rate: 59.60g (theoretical value 100%) yellow solid
Analyze (is base with solvent-free material): theoretical value: C24.18 H1.86 I63.88 N4.70 O5.37 measured value: C24.07 H1.92 I63.80 N4.66
B) 4-(3-diethylamino formyl radical-2,4,6-triiodophenyl formamyl oxygen base)-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-3,6,9-three azepine undecane diacid-two-tert-butyl esters
With 14.68g (20.85mmol) 3,6,9-three azepines-3,6,9-three-the solution of (tertiary butyloxycarbonyl ylmethyl)-4-hydroxymethyl-undecane diacid-two-tert-butyl ester (DE 3806795) in the 100ml anhydrous pyridine under the dehumidifying situation with 12.42g (20.85mmol) embodiment 15a) in the isocyanic ester described mix, and in stirred overnight at room temperature.Follow complete evaporation concentration, and on silica gel chromatographic separation resistates (eluent: hexane/ethyl acetate).Evaporation concentration contain behind the cut of product a yellow oily resistates.
Output: 24.29g (theoretical value 89.6%)
Analyze (solvent-free material is a base): theoretical value: C43.43 H5.98 I 29.29 N5.39 O 16.00 measured values: C43.42 H6.11 I 29.25 N 5.44
C) 3,6,9-three azepines-4-(3-diethylamino formyl radical-2,4,6-triiodophenyl carbamyl yloxymethyl)-3,6,9-three-(carboxymethyl)-undecane diacid
With 21.62g (16.63mmol) embodiment 15b) in the five-ester described at embodiment 1c) in be converted into five acid under the condition of description.
Output: 16.17g (theoretical 95.4%) colorless solid
Analyze (is base with solvent-free material):
Theoretical value: C31.81 H3.56 I37.56 N6.87 O20.40
Measured value: C31.73 H3.64 I37.25 N6.72
D) 3,6,9-three azepines-4-(3-diethylamino formyl radical-2,4,6-triiodophenyl carbamyl yloxymethyl)-3,6, the gadolinium complex of 9-three-(carboxymethyl)-undecane diacid disodium salt
With 15.52g (15.22mmol) embodiment 15c) in five acid described as at embodiment 1d) described in change into title compound.
The colourless lyophilized products analysis of output: 17.44g (theoretical value 94.1%) (is base with the anhydrous substances): theoretical value: C24.26 H2.13 I34.95 N3.86 O16.15 Gd14.43 Na4.22 measured value: C24.30 H2.10 I34.91 N3.90 Gd14.50 Na4.28
Embodiment 16
3,6,9-three azepines-3,6, the gadolinium complex of 9-three-(carboxymethyl)-4-(N-carboxymethyl-3-methylamino--2,4,6-triiodophenyl ureylene methyl)-4-methyl undecane diacid disodium salt
A) 3-isocyanide acyl-2,4,6-Triiodobenzoic acid-N-(ethoxycarbonylmethyl group)-methane amide
With 61.40g (100.0mmol) 3-amino-2,4,6-Triiodobenzoic acid-N-(ethoxycarbonylmethyl group)-methane amide (CA 54P 20987:(1960)) under room temperature and nitrogen atmosphere with the toluene solution of 250ml 2N carbonyl chloride.Add 0.5ml N, behind the dinethylformamide,, and then be evaporated to dried 60 ℃ of reaction stirred 5 hours.
Output: 64.00g (theoretical value 100.0%) yellow solid
Analyze (solvent-free material is a base):
Theoretical value: C24.40 H1.73 I59.49 N4.38 O10.00
Measured value: C24.37 H1.82 I59.53 N4.26
B) 3,6,9-three azepines-3,6,9-three-(tertiary butyloxycarbonyl ylmethyl)-4-(N-ethoxycarbonylmethyl group-3-methylamino--2,4,6-triiodophenyl ureylene methyl)-4-methyl undecane diacid-two-tert-butyl ester
With 16.41g (22.89mmol) embodiment 8g) in the solution of five-ester in the 100ml anhydrous pyridine described under removing the tender feeling condition with 14.65g (22.89mmol) embodiment 16a) in the isocyanic ester of description mix, in stirred overnight at room temperature.Then with the complete evaporation concentration of reaction mixture and on silica gel chromatographic separation resistates (eluent: hexane/ethyl acetate).Evaporation concentration contain behind the cut of product the yellow oily resistates.
Output: 27.39g (theoretical value 88.2%)
Analyze (is base with solvent-free material)
Theoretical value: C43.37 H5.87 I28.06 N6.19 O16.51
Measured value: C43.49 H6.01 I28.22 N6.14
C) 3,6,9-three azepines-three-(carboxymethyl)-4-(N-carboxymethyl-3-methylamino--2,4,6-triiodophenyl ureylene methyl)-4-methyl undecane diacid
With 26.68g (19.66mmol) embodiment 16b) in six esters described at embodiment 3c) in change into corresponding six acid under the condition of description.
Output: 19.19g (theoretical value 93.1%) colorless solid
Analyze (is base with solvent-free material):
Theoretical value: C30.90 H3.37 I36.32 N8.02 O21.37
Measured value: C31.03 H3.48 I36.21 N8.14
D) 3,6,9-three azepines-3,6, the gadolinium complex of 9-three-(carboxymethyl)-4-(N-carboxymethyl-3-methylamino--2,4,6-triiodophenyl ureylene methyl)-4-methyl undecane diacid disodium salt
With 24.32g (23.19mmol) at embodiment 16c) in five acid described as at embodiment 1d) described in transfer title compound to.
The colourless lyophilized products of output: 27.84g (theoretical value 94.6%)
Analyze (being base with the anhydrous substances): theoretical value: C25.57 H2.30 I30.01 N6.63 O17.66 Gd12.40 Na 5.44
Measured value: C25.62 H2.34 I29.94 N6.58 Gd 12.35 Na5.38
Embodiment 17
The isomer of simultaneous test: WO 93/16375 embodiment 1
1,13-pair-(5-(propionyl-3-base amido)-2,4,6-triiodo m-phthalic acid-two (2-hydroxyl-1-hydroxymethyl ethyl)-diamide)-4,7,10-three (carboxymethyl)-2,12-dioxo)-1,4,7,10,13-pentaaza three decane, gadolinium-complex compound
A) 1,13-pair-(5-(propionyl-3-base amido)-2,4,6-triiodo m-phthalic acid-two (2-hydroxyl-1-hydroxymethyl ethyl)-diamide)-4,7,10-three (carboxymethyl)-2,12-dioxo)-1,4,7,10,13-pentaaza three decane
With 16.5g (21.2mmol) 5-(the amino propionamido of 3-)-2,4,6-triiodo m-phthalic acid-two (2-hydroxyl-1-hydroxymethyl ethyl)-diamide is dissolved in the 82.5ml dimethyl formamide for 120 ℃ in the bath temperature.In room temperature to wherein mixing 7.38ml (53.25mmol) triethylamine and then mix 3.8g (10.64mmol) N, N '-two (2-(2,6-dioxo morpholine generation) ethyl) glycerol.Spend the night at the stirring at room reaction mixture.Boil off solvent in a vacuum, and resistates is spumed with oil pump.Solids stirred 2 hours with 200ml ethanol in room temperature, and suction strainer is also dry in 50 ℃ of vacuum.Then make resistates be dissolved in the less water and (eluent: water/methyl alcohol) carry out chromatographic separation on silica gel RP.After product cut evaporation concentration, get the colorless solid title compound.
Output: 17.24g (theoretical value 42%)
Analyze (being base with the anhydrous substances):
Theoretical value: C30.19 H3.43 I39.88 N8.07 O18.43
Measured value: C29.88 H3.30 I40.21 N7.95
B) 1, two (5-(propionyl-3-base amido)-2,4, the 6-triiodo m-phthalic acids-two (2-hydroxyl-1-hydroxymethyl ethyl)-diamide) 4,7 of 13-, 10-three (carboxymethyl)-2,12-dioxo)-1,4,7,10,13-pentaaza three decane, gadolinium complex
With 400mg at embodiment 17a) in compound and the 17.8ml 0.01 mole of acetic acid gadolinium solution batch mixing described.Transfer pH value to neutral range with triethylamine, and stirred this aqueous solution 1 hour with gac in room temperature.Obtain the colorless solid gadolinium complex after filtration and the lyophilize.
Output: 145mg (theoretical value 30.5%)
Analyze (being base with the anhydrous substances):
Theoretical value: C27.91 H3,03 I36.90 N7.47 O17.06 Gd7.62
Measured value: C27.77 H2.99 I36.72 N7.15 Gd7.38
Embodiment 18
3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-(3-iodo-4-ethoxy benzyl)-undecane diacid gadolinium complex, disodium salt
A) N-benzyloxycarbonyl-3-(4-ethoxyl phenenyl)-2-aminopropanol
In 221.41g (605.9mmol) N-carbobenzoxy-(Cbz)-solution of O-ethyl L-Tyrosine methyl ester in 1.5 liters of tetrahydrofuran (THF)s, add 31.8g (848.4mmol) sodium borohydride in room temperature.Under agitation in 2 hours to wherein dripping 279ml methyl alcohol.Then steam tetrahydrofuran (THF) in a vacuum, resistates is dissolved in 1 premium on currency and uses 700ml ethyl acetate extraction three times.The organic phase that merges washes with water, with dried over sodium sulfate and concentrated, uses the ethyl acetate/hexane recrystallization.
Output: 187.0g (theoretical value 93.7%)
Analyze (is base with solvent-free material):
Theoretical value: C69.28 H7.04 N4.25 O19.43
Measured value: C69.11 H7.20 N4.13
B) 1-acetoxyl-N-benzyloxycarbonyl-3-(3-iodo-4-ethoxyl phenenyl)-2-aminopropane
29.4g (89.3mmol) N-carbobenzoxy-(Cbz)-3-(4-ethoxyl phenenyl)-2-aminopropanol is dissolved in the 88ml Glacial acetic acid and drips 22.2g (134mmol) iodine monochloride in the 35.5ml Glacial acetic acid in room temperature.Spend the night at the stirring at room reaction mixture, and pour in 1.1 liters of frozen water for processing treatment.Water with ethyl acetate extraction for several times, organic phase water, sodium hydrogen carbonate solution and sodium sulfite solution washing, and then through dried over sodium sulfate.Obtain yellow oil after steaming solvent, this oil is slowly formed crystal.
Output: 34.5g (theoretical value 77.7%)
Analyze (is base with solvent-free material):
Theoretical value: C50.72 H4.86 I25.52 N2.82 O16.08
Measured value: C50.53 H4.98 I25.38 N2.74
C) N-benzyloxycarbonyl-3-(3-iodo-4-ethoxyl phenenyl)-2-aminopropanol
29.8g (60mmol) 1-acetoxyl-N-carbobenzoxy-(Cbz)-3-(3-iodo-4-ethoxyl phenenyl)-2-aminopropane is suspended in the 150ml methyl alcohol, and mixes 4.94g (60mmol) anhydrous sodium acetate in room temperature.0 ℃ of reaction stirred 6 hours, be evaporated to driedly, and resistates is dissolved in the ethyl acetate.The salt that sucking-off settles out is with ethyl acetate washing and evaporation concentration filtrate.The heavy-gravity oil that obtains is not further purified and promptly is used for next step to answer.
Output: 27.3g (theoretical value 100%)
D) 1-mesyloxy-N-carbobenzoxy-(Cbz)-3-(3-iodo-4-ethoxyl phenenyl)-2-aminopropane
26.5g (58mmol) N-carbobenzoxy-(Cbz)-3-(3-iodo-4-ethoxyl phenenyl)-2-aminopropanol is dissolved in the 130ml methylene dichloride, and mixes the 24.1ml triethylamine, make and react with 6.78ml (87mmol) methylsulfonyl chloride at 0 ℃.After 30 minutes, no longer include raw material in room temperature through the thin-layer chromatography check.Mixture dilutes with methylene dichloride, with sodium bicarbonate and washing with water.After dry organic phase, boil off solvent, get faint yellow oily product.
Output: 30.4g (theoretical value 98%)
Analyze (is base with solvent-free material):
Theoretical value: C 45.04 H4.54 I23.79 N2.63 O18.00 S6.01
Measured value: C 45.13 H4.72 I23.58 N2.74 S5.88
E) N-carbobenzoxy-(Cbz)-1-(3-iodo-4-ethoxy benzyl)-N-(2-amino-ethyl)-quadrol
28.2g (53mmol) 1-mesyloxy-N-carbobenzoxy-(Cbz)-3-(3-iodo-4-ethoxyl phenenyl)-2-aminopropane is dissolved in the 140ml tetrahydrofuran (THF) in room temperature, and mixes 143ml (2.12mmol) quadrol.Stir after 22 hours the reaction mixture evaporation concentration is become oil, and resistates is dissolved in the ethyl acetate, wash with water, use the dried over sodium sulfate organic phase to neutrality.After evaporation concentration, obtain yellow oil.
Output: 25.9g (theoretical value 98%)
Analyze (is base with solvent-free material):
Theoretical value: C50.71 H5.67 I25.51 N8.45 O9.65
Measured value: C50.87 H5.78 I25.40 N8.74
F) 1-(3-iodo-4-ethoxy benzyl)-N '-(2-amino-ethyl) quadrol, three hydrobromates
25g (50mmol) N-carbobenzoxy-(Cbz)-1-(3-iodo-4-ethoxy benzyl)-N '-(2-amino-ethyl)-quadrol is suspended in the 20ml Glacial acetic acid in room temperature, and mixes 33% Hydrogen bromide of 61.1ml (250mmol) in Glacial acetic acid.In room temperature after 40 hours, completely consumed raw material.Reaction mixture vacuum-evaporation in oil pump concentrates, with resistates toluene distillation three times.Water mixing is dried to being concentrated in solids.For removing remaining minor amount of water, with resistates methylene dichloride evaporation concentration three times.The crude product ethyl alcohol recrystallization.
Output: 24.6g (theoretical value 81.2%) clear crystal
Analyze (is base with solvent-free material)
Theoretical value: C25.77 H4.16 I20.94 N6.93 O2.64 Br39.56
Measured value: C25.89 H4.41 I20.73 N6.74 Br39.29
G) 4-(3-iodo-4-ethoxy benzyl)-3,6,9-three (tertiary butyloxycarbonyl ylmethyl)-3,6,9-three azepine undecanes-1,11-diacid, two-(tertiary butyl)-ester
23.2g (38.3mmol) 1-(3-iodo-4-ethoxy benzyl)-N '-(2-amino-ethyl) quadrol three hydrobromates are suspended in the 450ml tetrahydrofuran (THF), and drip 43.6g (316mmol) salt of wormwood and 18ml water, and 42.13ml (287.2mmol) bromoacetic acid-tert-butyl ester.Stirred 10 hours and followed at 60 ℃ in ambient temperature overnight.Sucking-off salt, with the tetrahydrofuran (THF) washing, and evaporation concentration filtrate.Crude product silicagel column (eluent: methylene chloride) purifying.
Output: 34.6g (theoretical value 96.7%)
Analyze (is base with solvent-free material):
Theoretical value: C55.30 H7.77 I 13.59 N4.50 O 18.84
Measured value: C55.37 H7.95 I13.44 N4.43
H) 4-(3-iodo-4-ethoxy benzyl)-3,6,9-three (carboxylic acid group's methyl (carboxylatomethyl))-3,6,9-three azepine undecanes-1,11-diacid, gadolinium-complex compound, disodium salt
With 17.6g (18.8mmol) 4-(3-iodo-4-ethoxy benzyl)-3,6,9-three (tert-butoxycarbonyl methyl)-3,6,9-three azepine undecanes-1, the 11-diacid, two-(tertiary butyl)-ester is dissolved in the 130ml methyl alcohol in room temperature, and is incorporated in 6.03g (150.4mmol) sodium hydroxide in the 10ml water.60 ℃ of reaction stirred 5 days, be evaporated to dried, and twice of water distillation.Resistates is dissolved in the 180ml water, and to transfer PH with acid ion exchangers be 2.9.Add 3.41g (9.4mmol) gadolinium sesquioxide and reaction mixture is heated to 80 ℃.Fully after the complexing, be 7.2 and make the clear soln lyophilize with cationite (Na+-type) accent PH.
Output: 14.75g (theoretical value 92%)
Analyze (being base with the anhydrous substances):
Theoretical value: C32.44 H3.20 I14.90 N4.93 O20.67 Gd18.46 Na5.40
Measured value: C32.23 H3.47 I14.76 N4.88 Gd18.36 Na5.17
Embodiment 19
3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-(3-bromo-4-ethoxy benzyl)-undecane diacid gadolinium complex, disodium salt
A) 1-acetoxyl-N-carbobenzoxy-(Cbz)-3-(3-bromo-4-ethoxyl phenenyl)-2-aminopropane
The title compound that 20.0g (61mmol) is obtained by embodiment 18a is dissolved in the 200ml Glacial acetic acid, and mixes the 0.2g iron powder.After reaction soln is cooled to 10 ℃, splash into 12.48g (78mmol) bromine in this temperature.Spend the night at the stirring at room reaction mixture, and be poured in the 750ml frozen water for further handling.Water with ethyl acetate extraction several times, organic phase water, sodium hydrogen carbonate solution and sodium sulfite solution washing, and then through dried over sodium sulfate.After steaming solvent, get the xanchromatic crystal.
Output: 19.5g (theoretical value 71.0%)
Analyze (is base with solvent-free material):
Theoretical value: C56.01 H5.37 Br17.74 N3.11
Measured value: C56.13 H5.42 Br17.84 N3.16
B) N-carbobenzoxy-(Cbz)-3-(3-bromo-4-ethoxyl phenenyl)-2-aminopropanol
18.0g (39.8mmol) 1-acetoxyl-N-carbobenzoxy-(Cbz)-3-(3-bromo-4-ethoxyl phenenyl)-2-aminopropane is suspended in the 100ml methyl alcohol, and mixes 3.30g (40mmol) anhydrous sodium acetate in room temperature.60 ℃ of reaction stirred 6 hours, be evaporated to driedly, and resistates is dissolved in the ethyl acetate.The sucking-off salt that settles out is with ethyl acetate washing and evaporation concentration filtrate.The heavy-gravity oil that obtains is not further purified and promptly is used for next reactions steps.
Output: 16.0g (theoretical value 98.2%)
C) 1-methylsulfonyl oxygen-N-carbobenzoxy-(Cbz)-3-(3-bromo-4-ethoxyl phenenyl)-2-aminopropane
15.5g (38mmol) N-carbobenzoxy-(Cbz)-3-(3-bromo-4-ethoxyl phenenyl)-2-aminopropanol is dissolved in the 100ml methylene dichloride, mixes 6.3ml (45mmol) triethylamine and react with 5.04ml (52mmol) methylsulfonyl chloride at 0 ℃.After 30 minutes, no longer include raw material in room temperature through the TLC detection.Use the methylene dichloride diluted reaction mixture, with sodium bicarbonate and washing with water.After the organic phase drying, boil off solvent and obtain faint yellow oily product.
Output: 18.1g (theoretical value 98%)
Analyze (is base with solvent-free material):
Theoretical value: C49.39 H4.97 Br16.43 N2.88 S6.59
Measured value: C49.21 H4.92 Br16.40 N2.79 S6.54
D) N-carbobenzoxy-(Cbz)-1-(3-bromo-4-ethoxy benzyl)-N '-(2-amino-ethyl) quadrol
17.0g (34.9mmol) 1-methylsulfonyl oxygen-N-carbobenzoxy-(Cbz)-3-(3-bromo-4-ethoxyl phenenyl)-2-aminopropane is dissolved in the 100ml tetrahydrofuran (THF) in room temperature, and mixes 100ml (1.48mmol) quadrol.Stir after 36 hours, the reactant evaporation concentration is become oil, and resistates is dissolved in the ethyl acetate, be washed with water to neutrality, and use the dried over sodium sulfate organic phase.After evaporation concentration, obtain yellow oil.
Output: 14.9g (theoretical value 95%)
Analyze (is base with solvent-free material):
Theoretical value: C56.00 H6.27 Br17.74 N9.33
Measured value: C56.21 H6.32 Br17.81 N9.38
E) 1-(3-bromo-4-ethoxy benzyl)-N '-(2-amino-ethyl) quadrol, three hydrobromates
14g (31mmol) N-carbobenzoxy-(Cbz)-1-(3-bromo-4-ethoxy benzyl)-N '-(2-amino-ethyl) quadrol is suspended in 39.1ml (160mmol) Glacial acetic acid in room temperature, and mixes 33% Hydrogen bromide of 39.1ml (160mmol) in Glacial acetic acid.After 24 hours, raw material exhausts fully in room temperature.Reaction mixture vacuum-evaporation in oil pump concentrates, and with toluene distillation three times.Water mixing and be evaporated to dried in solids.For removing methylene dichloride evaporation concentration resistates three times of remaining minor amount of water.The crude product ethyl alcohol recrystallization.
Output: 16.0g (theoretical value 92.4%) clear crystal
Analyze (is base with solvent-free material):
Theoretical value: C27.93 H4.51 Br39.56 N7.52
Measured value: C27.90 H4.48 Br39.29 N7.49
F) 4-(3-bromo-4-ethoxy benzyl)-3,6,9-three (tert-butoxycarbonyl methyl)-3,6,9-three azepine undecanes-1,11-diacid, two-(tertiary butyl)-ester
15.0g (26.8mmol) 1-(3-bromo-4-ethoxy benzyl)-N '-(2-amino-ethyl) quadrol three hydrobromates are suspended in the 400ml tetrahydrofuran (THF), and drip 29.6g (215mmol) salt of wormwood and 15ml water, and 36.67ml (250mmol) bromoacetic acid-tert-butyl ester.Stirred 12 hours and followed at 60 ℃ in ambient temperature overnight.Sucking-off salt is with tetrahydrofuran (THF) washing and evaporation concentration filtrate.Crude product silicagel column (eluent: methylene chloride) purifying.
Output: 22.4g (theoretical value 94.2%)
Analyze (is base with solvent-free material):
Theoretical value: C58.23 H8.18 Br9.01 N4.74
Measured value: C58.19 H8.12 Br8.96 N4.70
G) 4-(3-bromo-4-ethoxy benzyl)-3,6,9-three (carboxylic acid group's methyl (carboxylatomethyl))-3,6,9-three azepine undecanes-1,11-diacid
With 20.0g (22.5mmol) 4-(3-bromo-4-ethoxy benzyl)-3,6,9-three (tertiary butyloxycarbonyl ylmethyl)-3,6,9-three azepine undecanes-1, the 11-diacid, two-(tertiary butyl)-ester is dissolved in the mixture of being made up of 400ml tetrahydrofuran (THF) and 40ml water, and drips the solution of 6.4g (160.8mmol) sodium hydroxide in 20ml water in room temperature.After 48 hours, concentrated reaction mixture water distillation residue are twice in a vacuum at room temperature reaction.Remaining resistates is dissolved in the 300ml water and transfers PH with cationite (H+-type) is 2.0.The filtrate that obtains behind the sucking-off ion-exchanger produces pentacarboxylic acid after lyophilize, be colourless powder.
Output: 11.3g (theoretical value 83%)
Analyze (being base with the anhydrous substances):
Theoretical value: C45.55 H5.31 Br13.17 N6.93
Measured value: C45.62 H5.38 Br13.41 N7.02
H) 4-(3-bromo-4-ethoxy benzyl)-3,6,9-three (carboxylic acid group's methyl (carboxylatomethyl))-3,6,9-three azepine undecanes-1,11-diacid, gadolinium complex, disodium salt
With 10.0g (16.5mmol (4-) 3-bromo-4-ethoxy benzyl (and 3,6,9-three (carboxylic acid group's methyl (carboxylatomethyl))-3,6,9-three azepine undecanes-1, the 11-diacid is dissolved in the 200ml water, and mixes 3.0g (8.25mmol) gadolinium sesquioxide at 80 ℃.After 1 hour, make almost transparent reaction soln reach room temperature 80 ℃ of reactions, and to transfer pH value be 7.2 by dripping 0.2 molar sodium hydroxide solution.Filtering the postlyophilization reaction mixture.
Output: 12.7g (theoretical value 96%)
Analyze (being base with the anhydrous substances):
Theoretical value: C34.33 H3.38 Br9.93 N5.22 Gd19.54 Na5.71
Measured value: C34.26 H3.34 Br9.90 N5.21 Gd19.50 Na5.68
Embodiment 20
N, N-two (2-(N ', N '-two (carboxymethyl)-amino)-ethyl)-to the gadolinium complex of iodophenyl L-Ala disodium salt
A) to iodophenyl L-Ala isopropyl ester, hydrochloride
The 50ml Virahol is stirred and drips 3.21ml (41.6mmol) thionyl chloride under 0 ℃ and argon atmospher.Add 10.0g (34.4mmol) after 30 minutes to the iodophenyl L-Ala in batches,, and then reactant was refluxed 2 hours stirring at room 1 hour.Reaction mixture is spent the night, then the colourless throw out that settles out of sucking-off 0 ℃ of placement.
Output: 12.4g (theoretical value 97.8%)
Analyze:
Theoretical value: C38.99 H4.64 I34.33 N3.79 O8.66 Cl9.59
Measured value: C38.85 H4.70 I34.29 N3.78 Cl9.66
B) N, N-pair-(2-(N ', N '-two ((tertbutyloxycarbonyl)-methyl) amino)-ethyl)-to iodine benzyl L-Ala isopropyl ester
12.1g (32.7mmol) is pressed embodiment 20a) preparation amine and 25.4g (72.0mmol) N, N-pair-((tertbutyloxycarbonyl)-methyl)-2-bromine ethamine (M.Williams and H.Rapoport, J.Org.Chem.58,1151 (1993)) add in the 50ml acetonitrile, and mix 20ml 2N phosphate buffered saline buffer (PH8.0).Room temperature vigorous stirring 24 hours, around here 2 with 8 hours after replace aqueous phosphate buffered mutually with fresh buffer.Evaporation concentration organic phase in a vacuum then, and resistates carried out chromatographic separation with hexane/ethyl acetate/triethylamine (3: 1: 0.01) on silica gel.Evaporation concentration contains the product cut in a vacuum.
Output: 17.9g (theoretical value 62.3%)
Analyze (is base with solvent-free material):
Theoretical value: C54.85 H7.60 I14.49 N4.80 O18.28
Measured value: C54.80 H7.65 I14.41 N4.74
C) N, N-pair-(2-(N ', N '-two-(carboxymethyl)-amino)-ethyl)-to the iodophenyl L-Ala
With 17.1g (19.5mmol) at embodiment 20b) in the tert-butyl ester described be dissolved in the 250ml trifluoroacetic acid, and stirring at room 1 hour.Then evaporation concentration solution, resistates is the absorptivity precipitation in water, filters and in vacuum-drying.
The light beige solid of output: 11.5g (theoretical value 96.8%)
Analyze (being base with the anhydrous substances):
Theoretical value: C41.39 H4.63 I20.82 N6.90 O26.26
Measured value: C41.33 H4.56 I20.78 N6.93
D) N, N-is two-(2-(N ', N '-two-(carboxymethyl)-amino)-ethyl)-to the gadolinium complex of iodophenyl L-Ala disodium salt
With 7.43g (12.2mmol) by embodiment 20c) suspension and 2.21g (6.1mmol) gadolinium sesquioxide of five acid in 118ml water of preparation mix and be incorporated in 80 ℃ of stirrings 2 hours.Add 24.4ml 1N sodium hydroxide solution with a micro pipette then, and continue to stir 1 hour.Then after adding the 0.5g gac, stirred 2 hours and filtered at 80 ℃.Filtrate gets a colorless solid after lyophilize.
Output: 9.12g (theoretical value 92.6%)
Analyze (being base with the anhydrous substances):
Theoretical value: C31.23 H2.87 I15.72 N5.20 O19.81 Gd19.47 Na5.67
Measured value: C31.26 H2.95 I15.70 N5.13 Gd19.36 Na5.74
Embodiment 21
N, N-pair-(2-(N ', N '-two-(carboxymethyl)-amino)-ethyl)-glycine-N " (3,5-pair-(gadolinium complex of N -(2-hydroxyethyl)-formamyl (2,4,6-triiodophenyl-carbamyl ylmethyl)-acid amides one sodium salt
A) N, N-pair-(2-(N ', N '-two-((tertbutyloxycarbonyl)-methyl)-amino)-ethyl)-glycine-N " (3,5-pair-(N -(2-hydroxyethyl)-formamyl)-2,4,6-triiodophenyl carbamyl ylmethyl)-acid amides
With 22.1g (31.5mmol) 5-glycyl amino-2; 4; 6-triiodo m-phthalic acid-N; N '-two-(2-hydroxyethyl)-diamide and 24.4g (69.3mmol) N; N-pair-((tertbutyloxycarbonyl)-methyl)-2-bromine ethamine (M.Williams and H.Rapoport; J.Org, Chem.58 1151 (1993)) add in the 50ml acetonitrile, and mix 20ml 2N phosphate buffered saline buffer (PH8.0).Room temperature vigorous stirring reactant 24 hours, around here 2 with 8 hours after with fresh damping fluid displacement water-bearing phosphate salt buffer mutually.Concentrate organic phase and on silica gel, use methylene chloride (95: 5) chromatographic separation resistates in vacuum-evaporation then.Evaporation concentration contains the cut of product in a vacuum.
Output: 21.9g (theoretical value 55.8%), yellow oil.
Analyze (is base with solvent-free material):
Theoretical value: C40.53 H5.43 I30.59 N6.75 O16.71
Measured value: C40.50 H5.44 I30.52 N6.79
B) N, N-pair-(2-(N ', N '-two-(carboxymethyl)-amino)-ethyl)-glycine-N " (3,5-pair-(N -(2-hydroxyethyl)-formamyl (2,4,6-triiodophenyl carbamyl ylmethyl)-acid amides
With 20.8g (16.7mmol) at embodiment 21a) in the tert-butyl ester described be dissolved in the 250ml trifluoroacetic acid and stirring at room 1 hour.Then mix t-butyl methyl ether to this solution, sediment separate out is with t-butyl methyl ether washing and dry in a vacuum.
Output: 16.9g (theoretical value 98.9%)
Analyze:
Theoretical value: C30.61 H3.46 I37.31 N8.24 O20.38
Measured value: C30.77 H3.58 I37.25 N8.28
C) N, N-is two-(2-(N ', N '-two-(carboxymethyl)-amino)-ethyl)-glycine-N " gadolinium complex of (3,5-is two-(N -(2-hydroxyethyl)-formamyl)-2,4,6-triiodophenyl carbamyl ylmethyl)-acid amides one sodium salt
16.9g (16.6mmol) is pressed embodiment 21b) preparation the suspension of five acid in 130ml water mix with 3.00g (8.28mmol) gadolinium sesquioxide, and 80 ℃ stirrings 2 hours.Add 16.6ml 1N sodium hydroxide solution and continue with a micro pipette then and stirred 1 hour.Stirred 2 hours and filtered at 80 ℃ after then adding the 0.5g gac.Filtrate gets a colorless solid after lyophilize.
Output: 18.4g (theoretical value 93.0%)
Analyze (being base with the anhydrous substances):
Theoretical value: C26.10 H2.61 I31.82 N7.02 O17.38 Gd13.14 Na1.92
Measured value: C26.11 H2.74 I31.84 N7.06 Gd13.10 Na1.93

Claims (11)

1. metal complex, it is 12,13 that this complex compound contains at least one ordination number, 20-31,39-42, the ion of 44-50 or 57-83 element and the formula I part of a halogen-containing formation complex compound
In the formula
R 1Be hydrogen atom, carboxylic acid group, C straight chain or side chain 1-C 15Alkyl, C 6-C 15-aryl or C 7-C 15Aralkyl, this base randomly and/or at interval by 1-4 Sauerstoffatom by 1-5 hydroxyl and/or 1-2 carboxyl substituted, or R ' is the group of general formula I I or III in the formula,
-CO-NR 4R 5 (II)
-CH 2-NR 6-CO-R 7In the formula (III)
R 4, R 5Be hydrogen atom independently of each other, straight or branched C 1-C 15-alkyl, C 6-C 15-aryl or C 7-C 15Aralkyl, this group randomly contain 1-5 hydroxyl, a 1-2 carboxyl and/or 1-4 Sauerstoffatom, or R in the formula 4, R 5Form 5 or 6 yuan of rings that randomly contain a Sauerstoffatom, other acylated nitrogen atom or alkylsulfonyl, randomly replaced with nitrogen-atoms by 1-3 hydroxyl,
R 6Be hydrogen atom, C straight chain or side chain 1-C 15Alkyl, C 6-C 15Aryl or C 7-C 15Aralkyl, this group randomly contain 1-4 hydroxyl, a 1-2 carboxyl and/or 1-2 Sauerstoffatom, or
R in the formula 6And R 7With nitrogen-atoms and carbonyl form a nitrogen-atoms that randomly contains a Sauerstoffatom, an other acidylate or alkylsulfonyl, 5 or 6 yuan of rings that randomly replaced by 1-3 hydroxyl and
R 7Be hydrogen atom, C straight chain or side chain 1-C 15Alkyl, C 6-C 15Aryl or C 7-C 15Aralkyl, this group randomly contain 1 to 2 hydroxyl or a carboxyl, or R in the formula 7And R 65 or 6 yuan of rings that form a nitrogen-atoms that randomly contains a Sauerstoffatom, an other acidylate or alkylsulfonyl, randomly replaced with nitrogen-atoms and carbonyl by 1-3 hydroxyl,
R 2, R 3Be hydrogen atom independently of each other, C 1-C 15Alkyl, C 6-C 15Aryl or C 7-C 15Aralkyl, this group are randomly by 1-5 hydroxyl replacement and/or by 1-4 Sauerstoffatom interval, or R 2With R 3Common formation trimethylene or tetramethylene, or have U 1(U 2) implication that illustrated.
Z 1, Z 2, Z 3Be independently of each other hydroxyl or-NR 17-U 1' group,
In the formula
R 17Be hydrogen atom, the methyl or methoxy ethyl and
U 1, U 1 ', U 2, V 1, V 2And V 3Be the halogenated aryl of hydrogen atom or general formula I V independently of each other,
Figure A9419437200041
In the formula
R 8, R 9Be independently of each other-NR 6-CO-R 7The base and/or have R 1The implication that has illustrated does not just comprise C 1-C 15Alkyl, C 6-C 15Aryl or C 7-C 15Aralkyl,
R 10, R 11Be halogen atom or hydrogen atom independently of each other,
X be halogen atom or general formula V the bridge chain and
Y is R 9Or the bridge chain of general formula V
(α)-(CH 2) p-(C 6H 4) n-(L) m-R 12-(β) (V)
In the formula
M, n, p are 0 or 1 independently of each other,
L is Sauerstoffatom, sulphur atom, C 1-C 4Alkylidene group,＞the S=O base,＞SO 2Or＞NR 4, wherein, R 4Have the implication above addressed and
R 12Be a key, carbonyl, carboxyl ,-CO-NR 18-,-NR 18-CO-,-NH-CS-,-CS-NH-base, R in the formula 18Be C hydrogen atom, straight chain or side chain 1-C 15Alkyl, C 6-C 15Aryl or C 7-C 15Aralkyl, this group randomly contain 1-4 hydroxyl, a 1-2 carboxyl and/or 1-2 Sauerstoffatom,
Or R in the formula 12Be C straight chain or side chain 1-C 4Alkylidene group, this group randomly contains carbonyl and/or amino,
Be connected with the diethylene triaminepentaacetic acid(DTPA) main chain in this (α) position and (β) be connected with halogenated aromatic compound,
When X was halogen, Y was the bridge chain of formula V at this, and when X was the bridge chain of formula V, Y was R 9And
R 2, R 3, Z 1, Z 2, Z 3, U 1, U 2, V 1, V 2Or V 3At least one group in the group is the group of general formula I V or contains this group and randomly freely, be not that carboxyl for described metal element ion needs is that salt or amino acid whose salt as inorganic and/or organic bases exists,
At least satisfy one of following condition,
R 8And/or R 9Contain aryl, and/or
In substituent R 2, R 3, U 1, U 2, V 1, V 2Or V 3In at least one when being not hydrogen, Z 1And/or Z 2Then be the group of general formula I V, and/or
If Z 3Contain the formula IV aromatic substance that replaces fully, then a Z 1And/or Z 2Then do not contain the formula IV aromatic substance that replaces fully, and/or
If all substituent R 2, R 3, U 1, U 2, V 1, V 2Or V 3Be hydrogen, then at R 8, R 9, R 10Or R 11In at least one group be hydrogen atom and/or R 8And/or R 9Be one and contain the direct group of bonded carboxylic acid not.
2. by the halogen-containing metal complex of claim 1, it is characterized in that Z 1, Z 2, Z 3Base is a hydroxyl.
3. by the halogen-containing metal complex of claim 1 and 2, it is characterized in that R 8, R 9, R 10Or R 11In at least one group be a hydrogen atom.
4. by the halogen-containing metal complex of claim 1,2 and 3, it is characterized in that U 1Group for formula VI
5. by the halogen-containing metal complex of claim 1-4, this complex compound contains gadolinium ion as metal ion.
6. by the halogen-containing metal complex of claim 1-4, contain iodine as halogen atom.
7. by the compound of claim 1, promptly 3,6,9-three azepines-3,6,9-three-(carboxymethyl)-4-[4-(2,4,6-triiodo benzyloxy)-benzyl]-gadolinium complex of undecane diacid disodium salt.
8. diagnostic reagent contains the complex compound of at least a claim 1, contains additive commonly used in the galenical in case of necessity.
9. the application of at least a metal complex in preparation NMR diagnostic reagent and the agent of X-X-ray diagnosis X.
10. at least a metal complex is used for the application of the X-X-ray diagnosis X agent of liver in preparation.
11. the method for the preparation of preparation claim 1 to 6, it is characterized in that, will be in water dissolved complex salts and additive commonly used in galenical and stablizer make and a kind ofly be suitable in the intestines or the dosage forms of administered parenterally so that complex salts concentration is 1 to 1500mMol/l.
CN94194372A 1993-12-03 1994-11-26 Aryl halide substituted metallic complexes, pharmaceuticals containing these complexes, their use for diagnostic purpose and complexs Pending CN1136805A (en)

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