DE2710730A1 - N-TRIIODOBENZOYLAMINOACYL DERIVATIVES OF POLYHYDROXYAMINES, THE METHOD FOR THEIR MANUFACTURING AND RADIOLOGICAL AGENTS CONTAINING THESE COMPOUNDS - Google Patents

Description

PATENT LAWYERS

DR. WALTER KRAUS DIPLOMA CHEMIST DR.-ING. ANNEKÄTE WEISERT DIPU-ING. SPECIALIZATION CHEMISTRY IRMGARDSTRASSE 15 D-8OOO MUNICH 71 TELEPHONE 089 / 797077-79 70 78 TELEX O5-212156 kpot d

TELEGRAM CRAUS PATENT

PG-0040 1468 WK / My

MALLINCKRODT, INC., St. Louis, Missouri 63147 / USA

N-triiodobenzoylaminoacyl derivatives of polyhydroxy amines, Process for their preparation and radiological agents containing these compounds

The invention relates to certain N-triiodobenzoylaminoacyl-polyhydroxyamines, which are suitable as non-ionic X-ray contrast media. The invention also relates to radiological means and the use of such means.

In US Pat. No. 3,701,771, nonionic N- (2,4,6-triiodobenzyl) sugar amines have recently been described which suitable as an X-ray contrast medium for cerebrospinal cavities meant to be. These compounds have a polyhydroxyalkyl chain coupled to an iodine aromatic group in order to give this water solubility without causing ionic compounds must be used.

Certain of the nonionic compounds described in this patent are known to be highly water-soluble

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draws, while others have a medium or low water solubility should have.

An older, well-known X-ray contrast medium is the sodium salt of 2-iodohippuric acid. This connection is in Medical Radiography and Photography, Volume 40, Amendment 1964.

There are currently no triiodohippuric acids or derivatives of which used as an X-ray contrast medium. However, several ionic compounds have been described which are based on Based on triiodohippuric acid. For example, DT-OS 2 207 950 and in European Journal of Medicinal Chemistry-Chimica Therapeutica, JK), 84, 1975, compounds of general structures 1 and 2 described

CONH-alkyl I. CO ₂ H Acyl-HN - " I.
, ^^ CO-A-OH I.
< ^ CO-A-NH-alkyl

1 2

A stands for an aminoacyl radical.

Other compounds are in GB-PS 867 880 and in the publication by H. Suter and H. Zutter in HeIv. Chim. Acta, Vol. 54, p. 2551 (1971).

In certain cases, nonionic X-ray contrast media have been used as less toxic than their ionic genes

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proven pieces. This is presumably due at least in part to the fact that nonionic compounds, which are essentially non-ionized in aqueous solution, a lower osmotic imbalance generate as ionic compounds. This can be attributed to the fact that non-ionic X-ray contrast media only add one molecular species per iodinated group, which is in contrast to ionic X-ray contrast media, the two or add several species per iodized part.

There has therefore developed an interest in the synthesis of water-soluble, non-ionic X-ray contrast media, which have a low toxicity and a high iodine content and those for the X-ray visualization of Areas of the body, such as the cardiovascular and central nervous systems, can be used where high Contrast media concentrations are required to obtain sufficient opacity.

The invention therefore relates to compounds of the general types which are suitable as nonionic X-ray contrast media formula

CX) -A-N-Z

(D

in the

X and Y. Each stand for non-ionic groups with low toxicity and / or water solubility are consistent in the 2,4,6-triood configuration,

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A for an amino-substituted lower alkanecarboxylic acid coupling group stands and

-N-Z for a monovalent radical of a polyhydroxyamine stands in which N is a nitrogen atom, R is a hydrogen atom, lower-alkyl, hydroxy-lower-alkyl or Polyhydroxy-lower alkyl and Z denotes polyhydroxy-lower alkyl or is oxopolyhydroxy-lower alkyl.

Another object of the invention is a radiological agent, which is characterized in that it at least one of the nonionic compounds described above as X-ray contrast media together with a pharmaceutical contains acceptable carrier.

Another object of the invention is a process for the preparation of this compound and the use the radiological means described above in an X-ray visualization procedure.

Certain of the above compounds are advantageous because they are 100? 6 in water of 25 ° C (W / v) are soluble. Such solutions are different Types of angiography are particularly advantageous due to the high concentrations of iodine available. The high concentration gives a solution that is satisfactory for visualization.

As used herein, the term "amino-substituted low-alkanecarboxylic acid coupling agents "or" amino-substituted low-alkanecarboxylic acid coupling group "includes straight-chain and branched alkanecarboxylic acids up to 12 carbon atoms, which are sub-

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ΊΟ

are established, as well as the corresponding groups. The substituted benzoyl part is attached to the amino part of this coupling agent or this coupling group. To the The polyhydroxyamine is attached to the acyl part. One of the amino hydrogen atoms the amino group can be further with lower-alkyl, hydroxy-lower-alkyl or polyhydroxy-lower-alkyl be substituted.

Examples of amino-substituted lower alkanecarboxylic acid coupling groups are those that differ from aliphatic amino acids such as glycine, alanine, serine, threonine, Valine, leucine, isoleucine; aromatic amino acids such as phenylalanine, tyrosine; Sulfur containing amino acids such as Cysteine, cystine, methionine; heterocyclic amino acids like tryptophan, proline, hydroxyproline and others like Histidine, lysine and arginine. Glycine is preferred because of its easy availability and usability.

As used herein, the term "lower alkyl" includes straight and branched groups of up to 8 carbon atoms. Examples are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. The here The term "hydroxy-lower-alkyl" used includes straight-chain and branched groups with up to 8 carbon atoms substituted with a hydroxyl group. Examples are hydroxyethyl, hydroxypropyl, hydroxybutyl, Hydroxypentyl, hydroxyhexyl and hydroxyoctyl. Preferably the carbon atom is the same as the nitrogen atom is not substituted with the hydroxy group. The term "polyhydroxy-lower alkyl" as used herein includes straight and branched groups of up to 8 carbon atoms substituted with 2 to 8 hydroxy groups are. However, it does not include groups that have two or more hydroxyl groups substituted on one carbon

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ΑΛ

Atom of matter. Preferably, the carbon atom connected to the nitrogen atom is not substituted by a hydroxyl group. Examples of these are 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5,6-pentahydroxyhexyl and 2,3 »4-trihydroxyoctyl. As used herein, ⁿ Oxopolyhydroxy-lower alkyl "includes straight, branched and cyclic groups containing up to 8 carbon atoms which are substituted with an oxygen atom (= 0) and 2 to 6 hydroxyl groups. However, this term does not include groups having two or more hydroxyl groups substituted on a carbon atom, those which have an oxygen atom as a substituent on the carbon atom bonded to nitrogen, and those which ionize, ie those which have a hydroxyl group and an oxygen atom on the same carbon atom the carbon atom connected to the nitrogen atom is not substituted with a hydroxy group. Examples of oxopolyhydroxy-lower-alkyl are 3 »4-dihydroxy-2-oxobutyl, 2,4,5-trihydroxy-3-oxopentyl and 3,4» 5,6- Tetrahydroxy-2-oxohexyl, etc.

The groups R and Z in the above formula I include, as stated above, such groups as lower-alkyl, Hydroxy-lower alkyl and polyhydroxy-lower alkyl as well as oxopolyhydroxy-lower alkyl a. It is preferably, but not necessary, groups with only hydrocarbon, Hydroxy hydrocarbon or oxohydroxy hydrocarbon nature.

R.
t

N-Z is preferably the monovalent radical of Aldos-

amines, N- (lower-alkyl) -aldosamines, ketosamines, N- (lower-alkyl) -ketosamines, N- (polyhydroxy-lower-alkyl) -amines, N-alkyl-N- (polyhydroxy-lower-alkyl) -amines and Deoxyaldo saminen.

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Aldosamines include those with the formula

CHO

(CHOH) "ι ⁿ CHNH ₂

(CHOH) _m CH ₂ OH

in which m = 0 to 4, η = 0 to 4 and the sum of m + η = 0 to 4, a. Examples are amines such as D-erythrosamine, D-glucosamine (2-amino-2-deoxy-D-glucose), D-galactosamine and various other tetrosamines, pentosamines, hexosamines, and heptosamines. Other amines of this type are e.g. Z-Amino-Z-deoxy-D-galactose, 2-Amino-2-deoxy-D-mannose, 2-amino-2-deoxy-D-talose, 2-amino-2-deoxy-D-glucose, etc. Lower alkyl aldosamines include those of the formula

HC = 0 (CHOH) _n

CHNHR (CHOH) _m

CH ₂ OH

in which m = 0 to 4, η = 0 to 4 and the sum of m + η = 0 to 4, it also being possible to use compounds in which R is lower-alkyl. Examples such! imines are N-methyl-D-glucosamine (2-methylamino-2-deoxy-D-glucose), N-methyl-D-galactosamine, 3-methylamino-3-deoxy-D-xylose, 4-ethylamino-4-deoxy-D-galactose, etc.

Ketosamines include those with the formula

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Al

CH ₂ OH (CHOH) _a

CHNH ₂ (CHOH) _m

C = O
(CHOH) _n

CH ₂ OH

in which a = 0 to 4, m = 0 to 4, η = 0 to 4 and the Sum of a + m + η = 0 to 4, a. Examples of this are amines such as D-ribulosamine, D-sorbosamine, D-fructosamine, D-gluco-heptulosamine and various other pentulosamine, Hexulosamine and Heptulosamine. Likewise, N- (lower-alkyl) -ketosamines include those of the formula

CH ₂ OH (CH0H) _a

CHNHR (CHOH) _m

C = O
(CHOH) _n

CH ₂ OH

in which a = 0 to 4, m = 0 to 4, η = 0 to 4 and the sum of a + m + η = 0 to 4 and R is lower-alkyl, a. Examples are amines such as N-methyl-D-sorbosamine, N-methyl-D-fructosamine, etc.

Ketosamines include those of the formula

CH ₂ NH ₂ (CHOH) _n C = O

CH ₂ O

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AH

in which η = 0 to 4, m = 0 to 4 and the sum of η + m = O to 4 is a. Examples are 1-amino-1-deoxy-D-fructose.

Likewise include N- (lower-alkyl) -ketosamines those of the formula

CH ₂ NHR (CHOH) _n

C = O (CHOH) _m

CH ₂ OH

in which η = 0 to 4, m = 0 to 4, R for lower alkyl stands in and the sum of η + m = 0 to 4 is a. An example this is 1-hydroxy-3-methylamino-2-propanone.

N- (polyhydroxy-lower alkyl) amines include those of the formula

(CHOH) _n

CHNH ₂

(CHOH) _m

CH ₂ OH

in which η = 0 to 5, m = 0 to 5 and the sum of η + m = 0 to 5, a. Examples include such amines as 2-amino-2-deoxyglucitol and 1-amino-1-deoxysorbitol, etc. Others Amines of this type are e.g. 1-amino-1-deoxy-D-glycero-D-guloheptit, 1-amino-1-deoxy-glycero-D-galacto-heptit, 1-amino-1-deoxy-D-glycero-1-manno-heptit, 1-Amino-1-deoxy-D-arablte and 1-Amino-deoxy-D-glucitol.

N-lower alkyl-N- (polyhydroxy-lower alkyl) amines include those of the formula

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AS

H (CHOH) _n

CHNHR (CHOH) _m

CH ₂ OH

in which η = O to 2, m = 1 to 5 and the sum of m + η = Is 1 to 5 and R is lower alkyl or hydroxy lower alkyl stands, a. Specific examples are 1-deoxy-1-methylamino-sorbitol, 1-deoxy-i-ethylamino-sorbitol, 1-ethylamino-1-deoxy-D-arabitol, 1-methylamino-2,3-propanediol, 2-methylamino-1,3-propanediol, 3-ethylamino-3-deoxy-D-arabitol and 1-Deoxy-i-methylamino-D-glucitol (N-MethyIglucamin) as well secondary amines such as diethanolamine and dipropanolamine.

Deoxy-aldosamine, which is the source of the monovalent Radicals of a polyhydroxyamine include the 2-deoxy compounds of the formula

HC =

CH ₂ HCNH ₂ (CHOH) _n CH ₂ O

in which η = 1 to 3, and the corresponding 3-deoxyaldosamines and 4-deoxyaldosamines.

Lower alkyl glycosidoamines can also be used will. These include those of the formula

ROCH RCNH ₂ (CHOH) _n

HC

CH ₂ OH

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in which η = 1 to 3 and R is lower-alkyl. Examples are compounds such as Hethyl-glucosidoamine, Methylgulosidoamine, etc.

Polyhydroxycarbocyclic amines are suitable for practicing the invention. Examples are compounds like i-amino ^^^^ e-pentahydroxy-cyclohexane, 1-amino-2,3,4,5-tetrahydroxy-cyclopentane, etc. Likewise the lower-alkyl- (polyhydroxy-carbocyclic) -amines e.g. i-N-methylamino-Z ^^ fSje-pentahydroxy-cyclohexane, 1-N-methylamino-2,314,5-tetrahydroxy-cyclopentane, etc.

The substituents in the 3- and 5-positions of the ring, namely X and Y, are non-ionizing groups or Features consistent with low toxicity and / or solubility in the 2,4,6-triiodophenyl configuration stand. As is well known, the term "detoxifying and / or solubilizing groups" became generic Term used for a considerable number of functional groups whose presence in the meta position (s) in a 2,4,6-triiodinated part has resulted in compounds that have a relatively low toxicity and / or a relatively have high solubility in water [cf. G.B. Hoey, P.E.Wiegert and R.D. Rands Jr., "Organic Iodine Compounds as X-Ray Contrast Media "in International Encyclopedia of Pharmacology and Therapeutics, Section 76," Radiocontrast Agents ", P.K. Knoefel, Section Editor, Pergamon Press, Volume 1, pp. 23 to 40, 54 to 73 (1971)]. Although using this Terminology related to 2,4,6-triiodobenzoic acid derivatives which have a relatively low toxicity and / or a relatively high water solubility yet the results obtained herein are consistent with the view that practically the same, nonionizing groups also with a low toxicity and / or a

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Water solubility in the triiodinated part of the invention go hand in hand with non-ionic compounds.

The following groups can be mentioned among the non-ionizing groups or functions which X and Y represent are: lower alkoxy, e.g. methoxy and ethoxy; Hydroxy (lower alkoxy), e.g., 2-hydroxyethoxy; lower alkoxy (lower alkoxy), e.g., methoxyethoxy and ethoxypropoxy; low acylamino, e.g., acetamido and propionamido; lower acylamino (lower alkyl), e.g., acetamidomethyl and acetamidoethyl; lower acylamino (lower acylamino), e.g., aceturamido; Hydroxy-lower acylamino, e.g., hydroxyacetamido and hydroxypropionamido; N- (lower alkyl) lower acylamino, e.g., N-methylacetamido and N-methylpropionamido; lower-alkylsulfonamido, e.g., methylsulfonamido and ethylsulfonamido; N- (lower-alkyl) -lower-alkylsulfonamido, e.g., N-methylethylsulfonamido and N-ethyl-methylsulfonamido; 3,3-bis (lower alkyl) ureido, e.g. 3,3-dimethylureido and 3-methyl-3-ethylureido; lower perfluoroacylamino, e.g., perfluoroacetamido and perfluoropropionamido; Carbamyl; N- (lower alkyl) carbamyl, e.g., N-methylcarbamyl and N-ethylcarbamyl; N- (hydroxy-lower alkyl) -carbamyl, e.g., N- (2-hydroxyethyl) carbamyl and N- (3-hydroxypropyl) carbamyl; N- (polyhydroxy-lower-alkyl) -carbamyl, e.g., K- (2,3-dihydroxypropyl) carbamyl and N- (2,3,4-trihydroxybutyl) carbamyl; N, N-di (lower alkyl) carbamyl, e.g. N, N, dimethylcarbamyl and N, N-diethylcarbamyl; N, N-bis (hydroxy-lower alkyl) -carbamyl, e.g., N, N-bis (2-hydroxyethyl) carbamyl; N, N-bis (polyhydroxy-lower alkyl) carbamyl, e.g., N, N-bis (2,3-dihydroxypropyl) carbamyl; lower alkoxy (lower acylamino), e.g., methoxy acetamido and ethoxy acetamido; lower-alkoxy-alkoxy- (lower-acylamino), e.g. methoxyethoxy-acetamido; Hydroxy and hydroxy-lower alkyl, e.g. hydroxymethyl and hydroxyethyl. The designation used above

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term "low" (e.g. "lower-alkyl" and "lower-alkoxy") means that the group contains 1 to 8 carbon atoms. Groups of a different type, as specifically mentioned above, can of course also form the substituents X and Y.

According to a further aspect of the invention, one of the substituents X and Y can be hydrogen or a of the above groups and the other of the substituents

X and Y are the group -CO-A-N-Z, where A, R and Z are as above have given meanings.

Representative compounds according to the present invention are the following:

2- (3-acetamido-2,4,6-triiodo-5-N-methylacetamidobenzoylglycylamino) -2-deoxy-D-glucitol,

2- (3-acetamido-2,4,6-triiodo-5-N-methylcarbamylbenzoylglycylamino) -2-deoxy-D-glucitol,

1 - (3-Acetamido-2,4, ö-triood-S-N-methylacetamidobenzoylglycylamino) -1-deoxy-D-glucitol,

2- (3-Acetamido-2,4,6-triiodo-5-N-methy Iac etamidobenzoyl-L-alanylamino) -2-deoxy-D-mannitol,

3- (3,5-diacetamido-2,4,6-triiodobenzoyl-L-phenylalanylamino) -3-deoxy-D-galactitol,

2- (3-Acetamido-2,4,6-triiodo-5-N-methylacetamidobenzoylglycylamino) -2-deoxy-D-glucose,

2- (3-butyrylamino-2,4,6-triiodo-5-N-ethylacetamidobenzoyl-L-valinyl) -2-deoxy-D-galactose,

6- (3-acetamido-2,4,6-triiodo-5-N-propylacetamidobenzoyl-L-leucinyl) -6-deoxy-D-fructose,

(5-acetamido-2,4,6-triiodisophthaloyl) -N, N ¹ -bis-2,3-dihydroxypropyl-N, N -dimethyl-bis-glycine amide,

(5-Acetamido-2,4,6-triiodisophthaloyl) -N, N -bis-2-hydroxyethyl-N, N -dimethyl-bis-glycine amide,

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A3

5-propionylamino-N, N'-bis-2,3-dihydroxypropyl-2,4,6-triiodoisophthaloyl-bis-alanine amide.

The new compounds according to the invention and mixtures of these can be used as X-ray contrast media for various radiographic work methods, e.g. for cardiovascular Visualization, coronary arteriography, aortography, cerebral and peripheral angiography, myelography, ventriculography, Arthrography, cholangiography, intravenous pyelography, urography, and bronchography, can be used. Certain Compounds according to the invention show high water solubility and relatively low toxicity, while others have limited water solubility and relatively low toxicity, such as those for orally administered Radiographs than are necessary for powdered preparations for bronchography. 2- (3-Acetamido-2,4,6-tri ^ od-5-N-methylacetamidobenzoylglycylamino) -2-deoxy-D-glucitol is particularly suitable for angiography as this compound to IOO96 is soluble. It can therefore be used in small volumes while still providing enough iodine for imaging.

Isomeric mixtures of the compounds according to the invention can also be used as X-ray correlation agents. In general, the amount of each isomer contained in the mixture can vary within a wide range, provided that the mixture acts as a satisfactory radiographic contrast agent.

Another object of the invention is therefore a radiological agent, which is characterized in that there is at least one non-ionic compound according to the invention

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dung as an X-ray contrast medium together with a pharmaceutical contains acceptable carrier.

Suitable carriers are, for example, those which are suitable for injection purposes, e.g. aqueous buffer solutions, sterile Water for injection, physiological saline solutions and balanced ion solutions, the chloride and / or bicarbonate salts of normal blood plasma cations, e.g. of Ca, Na, K and Mg.

The concentration of the compounds of the invention in the pharmaceutically acceptable carrier, e.g., an aqueous Medium, varies according to the application. There must be an amount sufficient to provide satisfactory radiographic visualization. Using of aqueous solutions are e.g. lower concentrations for ventriculography, myelography or radiculography required than is the case with angiocardiography. The preferred concentration and dosage ranges the compounds in aqueous solutions for these three uses are as follows:

concentration
mg J / ml 300 dose
ml until 12th Myelography 150 to 580 5 until 100 cardiovascular Visualization 300 to 400 VJl until 300 Urography 140 to 25th

The radiological agent is administered so that the contrast agent is in the system for about 2 to 3 hours remains, although shorter and longer residence times are usually acceptable. The compounds according to the invention can thus be used, e.g. for cerebrospinal visualization, in vials or ampoules with 5 to

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JM

15 ml of their aqueous solution can be formulated. For the vascular Larger amounts, e.g. 10 to 500 ml, are given for visualization. The preparations can also be formulated and lyophilized to a powder.

The radiological means can be used in the usual way with X-ray methods. For example, the cardiovascular visualization a sufficient amount of radiological agent that adequate visualization is injected into the cardiovascular system. The cardiovascular agent is then applied with a suitable device, e.g. a fluorescope.

The new compounds according to the invention can be prepared in any desired manner.

Compounds of the formula I can be prepared, for example, by the following method.

CO-N-CH-CO ₀ H

k * ²

II

CO-N-CH-CO ^ H

III

Ri is H or lower-alkyl; IT stands for H, lower-alkyl,

_ Hydroxy-lower alkyl; R ^ or R « stands for nitro, while

■ z the other of the substituents R ^ or R ^ is any group X or Y, as defined above, or the group -CO-N (R ¹ ) -C (R ² ) H-C0 ₂ H.

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CO-N-CH-CO ₀ H ι I ² Ro

IV

CO-N-CH-CO ₀ R-

ir stands for methyl, ethyl or propyl

The compounds of the formula II in which one of the groups R ³ or R ^{4 is} -CON (R ¹ ) CH (R ² ) C0 ₂ H can be prepared by the method described in "Practical Organic Chemistry ;, AIVogel, Pp.436-437, John Wiley & Sons Inc.,

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New York, N.Y. (1966). You will be in connections of formula III by catalytic reduction, e.g. with a noble metal catalyst such as palladium or platinum, in a suitable solvent such as methanol, ethanol or Water, converted. When using water as a solvent, the compounds of the formula II are treated with an alkali metal hydroxide converted into an alkali metal salt. Typically the ratio of solvent to compound is of formula II or the alkali metal salt thereof about 1: 1 to 500: 1. The reaction proceeds at room temperature. she is finished after about 2 hours. However, the temperature can range from 10 to 150 ° C and the reduction time can 1 to 4 hours. Any suitable pressure can be used, e.g. 1.05 to 7.03 at. In general, enough catalyst is used to reduce the compound of Formula II or its alkali metal salt will. Typically about 0.01 to 1 part by weight of catalyst for each part by weight of the compound of formula II or their salt used. After the completion of the reaction, the reaction mixture is filtered to remove the catalyst and then used to prepare the compounds of Formula IV.

The compounds of the formula IV are prepared in such a way that compounds of the formula III are iodinated. First, the solution containing the compound of formula III is acidified to pH 1 with a suitable acid such as hydrochloric acid. The temperature is kept at 40 to 50 ^° C. at the beginning. After the iodination agent has been added, it is allowed to rise to 50 to 80 ° C. and heating is continued until the iodination is complete, usually 3 to 6 hours. In general, 3 to 4 molar equivalents of the iodinating agent, for example iodine monochloride, are used for each mole of the compounds of the formula III. The iodized compounds are recovered and purified by filtration.

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Alternatively, the compounds of the formula IV can also be prepared from 5-nitroisophthalic acid by the method according to DT-OS 2 207 950 can be produced.

Alternatively, the compounds of the formula IV which are derived from 3> 5-dinitrobenzoic acid can be prepared using the same general reduction and iodination conditions as described above in connection with compounds of the formula II in which one of the substituents R ³ or R ⁴ -CO N (R ¹ ) CH (R ² ) C0 ₂ H.

Compounds of the formula IV in which one of the groups is an acylamino group can be mixed with an alkylating agent in a suitable solvent, such as water, methanol or ethanol, and with sufficient base, generally 4 to 6 molar equivalents / mol of the compound of the formula IV, be alkylated. Any bases, for example sodium hydroxide, sodium ethoxide or sodium methoxide, can be used for this purpose. Suitable alkylating agents are, for example, alkyl halides, such as methyl iodide, ethyl chloride, propyl bromide, etc., or dialkyl sulfates, such as dimethyl sulfate or diethyl sulfate. The alkylation takes place at 50 ^° C. and is normally complete after about 1 to 5 hours. However, the temperature range can extend from 40 to 60 ° C. The product is isolated in a customary manner, for example by dissolving it in aqueous sodium hydroxide solution and precipitating it with hydrochloric acid.

Compounds of the formula IV in which X stands for an amino group can also be acylated with an acyl anhydride. Typically, about 4 to 6 parts by weight of acyl anhydride and 0.01 to 1 part by weight of sulfuric acid are used for each part by weight of the compound of the formula IV. The reaction temperature can be 20 to 60 ° C and is usually 30 ⁰ C. The reaction takes 5 to 20 hours,

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comfortably about 8 hours, finished. The product is in common Way obtained by filtration.

Compounds of the formula V are prepared by adding compounds of the formula IV with the corresponding alcohol be esterified. Usually a mineral acid, e.g. sulfuric acid, is used as a catalyst in catalytic amounts, e.g. 1 weight per liter, based on the compound of the formula IV, is used. Typically about 10 parts by weight of alcohol are used for each part by weight of the compound of Formula IV. The compounds of the formula V are in the usual way, i.e. by cooling and collecting the crystallized solids, isolated.

Compounds of formula I are then prepared by converting the compound of formula V, if necessary, in a suitable solvent, e.g., methanol, with a polyhydroxy amine heated to reflux. Typically 1 to 3 parts by weight of polyhydroxyamine and 5 to 7 parts by weight of solvent are used for each part by weight of the compound of formula V used. The polyhydroxyamine can also be used as a solvent will. In this case, a larger proportion of it is used. Typically 6 to 10 parts by weight / part by weight will be used the compound of formula V is used. The compounds of formula I can be obtained in any suitable manner will.

Alternatively, compounds of the formula I can also be prepared using the following method:

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VI

R ⁵ NC (R ⁵ ) HCON (R ⁵ )
polyhydroxy

VIIj

7.1 *

X and Y have the above definition and can also be -N (COCH,) ρ or -N (COR ⁶ ) ₂ , in which R ^{6 is} lower-alkyl

R ^p stands for hydrogen, lower-alkyl or lower-hydroxy-alkyl, which can be identical or different

-N-polyhydroxy stands for the remainder of one as described above polyhydroxyamine

Compounds of the formula VI are prepared according to DT-PS 2,031,724. Compounds of the formula VII are prepared according to Lieflander, Hoppe-Seyler's Z.Physicol Chem., 348 , 363-70 (1967). The reaction of VI with VII to form compounds of the formula I is carried out according to the general method of DT-PS 2,031,724.

The invention is illustrated in the examples. All temperatures are in ⁰ C.

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example

Preparation of 2- (3-acetamido-2,4,6-triiodo-5-N-methylacetamidobenzoylglycylamino) -2-deoxy-D-glucitol

(A) Preparation of 2-acetamido-2-deoxy-D-glucitol

CHO

NHCOCH.

CH ₂ OH - NHCOCH,

CH ₂ OH

CH ₂ OH

A solution of 100 g (0.45 mol) of N-acetyl-D-glucosamine in 300 ml of water was cooled to 15 ° and a solution of 16 g of sodium borohydride in 300 ml of v / water was added dropwise. During the addition, the temperature was kept below 50 ° by adding ice. After the addition, the mixture was stirred for 40 min, cooled to 10 ° and excess hydride was decomposed by adding 102 ml (0.58 mol) of acetic acid. The solution was poured into 550 ml of pre-washed Amberlite 120 resin (H ⁺ form) (0.96 mol, approx 1.75 meq / ml) and stirred for 15 minutes. The resin was filtered off and washed with water. The filtrate and washing water were combined and the whole was evaporated to dryness. The residue was dissolved in 1 l of hot 2 [beta] ethanol and the mixture was evaporated to 700 ml and stirred overnight. 90 g (90%) of product were isolated. The melting point of the product was 153 to 154 ° (lit. 153 °). Thin-layer chromatography (silica gel plate - ethanol / conc. Ammonia 50:50 - spraying with methanolic sulfuric acid and evolution of heat) showed that the product was pure.

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Xt

(B) Preparation of 2-amino-2-deoxy-D-glucitol hydrochloride

CH ₂ OH
_ NHCOCH-

CH ₂ OH

CH ₂ OH

A solution of 90 g (0.40 mol) of 2-acetamido-2-deoxy-D-glucitol in 1.4 1 of water and 0.6 1 of concentrated hydrochloric acid was 6 h heated to 90 °. The mixture was left to stand at room temperature overnight. The solution was drawn up under suction pressure about 1 1 evaporated. Ethanol was added in 100 ml portions to the solution given and it was further evaporated. The addition and evaporation were repeated until crystals appeared. The solution was allowed to stand at room temperature for 3 hours and filtered to give 68 g of product. One second portion, 10 g, was isolated from the mother liquor. The melting point of the first and second portions were 161 and 160 ° (Ref. 160-161). Thin-layer chromatography (silica gel plate-ethanol / conc. Ammonia 50:50, development with ninhydrin and methanolic sulfuric acid) showed that both products obtained were pure.

The free 2-amino-2-deoxy-D-glucitol was prepared by adding 78 g of the hydrochloride in a mixture of 400 ml Stirring ethanol and 83 ml of diethylamine for 2 days. The solid was filtered off and washed with ethanol, whereby 62 g (95%) of product with a melting point of 129 to 130 ° (literature melting point. 131) were obtained.

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(C) Preparation of 2- (N-carbobenzyloxyglycylamino) -2-deoxy- D-glucitol

CH ₂ OH _. NH,

CH ₂ OH

CH ₂ OH

CH ₂ OH

A mixture of 275 ml of dry tetrahydrofuran and 275 ml of dry dioxane was cooled to -5 ° and 12.88 ml (9.35 g, 0.092 mol) triethylamine, 3.74 ml (9.96 g, 0.092 mol) ethyl chloroformate and 19.23 g (0.092 mol) N-carbobenzyloxyglycine were admitted. The mixture was stirred for 15 min at -5 ° and then in one portion with a cold one (0-5 °) solution of 16.65 g (0.092 mol) of 2-amino-2-deoxy-D-glucitol in AO ml of water. The cooling bath was removed, and the mixture was stirred at ambient temperature for 4 hours. The solvent was evaporated in vacuo at 30 to 40 ° and the residue was stirred with 500 ml of ethanol overnight. Filtering gave 30 g of a solid. Of the Solid was recrystallized from 700 ml of methanol to give 21 g of product. Thin layer chromatography showed the product to be pure (silica gel plate - benzene / methyl ketone / 88 # formic acid 60:25:25, development with methanolic sulfuric acid).

(D) Preparation of 2-deoxy-2-glycylamino-D-glucitol hydrochloride

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CH ₂ OH _ NHC0CH-NHC0_CH_C, H _c

CH ₂ OH

CH ₂ OH µ- NHCOCh ₂ NH ₂ -HCI

CH ₂ OH

500 mg of 5% palladium-on-charcoal were added to a solution of 5 g (0.013 mol) of 2- (N-carbobenzyloxyglycylamino) -2-deoxy-D-glucitol in 90 ml of water and 10 ml of acetic acid. The mixture was shaken under hydrogen at a pressure of 3.52 atm for 16 hours. The catalyst was filtered off and the filtrate was admixed with 14 ml of 1N hydrochloric acid. The solution was evaporated in vacuo to a gummy residue. This was recrystallized from 2 ml of water and 100 ml of ethanol. The crystals, 3.4 g (0.0125 mol, 92%) had a pp of 122-123 °. Thin-layer chromatography (cellulose plate-acetonitrile / O, 1N ammonium acetate 60:40, development with silver nitrate / ammonia or ninhydrin spray) showed that the material was homogeneous.

Analysis calculated for

calculated: C 32.82% H 7.23% N 9.57% found: 33.61 7.37 9.59.

.HC1.H ₂ O

(E) Preparation of 2-deoxy-2- (3-diacetylamino-2,4,6-triiodo- 5-N-methylacetamido-benzoylglycylamino) -D-glucitol

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coci

V »

CH ₂ OH
_ NHCOCH ₂ NH ₂

HCl

CH ₂ OH

CH ₂ OH
_ NHCOCh ₂ NHCO

CH ₃ OH

(CH ₃ CO) ₂ N

N (CH ₃ ) COCH ₃

To 90 ml of dry dimethylformamide at -5 were 13/77 g (0.020 mol) of 3-diacetylamino-5-N-methylacetamido-2,4,6-triiodobenzoyl chloride, 6.0 g (0.022 mole) of 2-deoxy-2-glycylamino-D-glucitol hydrochloride and 6.08 g (0.044 mole) potassium carbonate. The reaction mixture was 3 h at 0 ° and Stirred for 4 days at room temperature. The mixture was filtered and the filtrate turned gummy like at 55 ° in vacuo Product evaporated. The residue was dissolved in 100 ml of water and brought to a pH of 4 with hydrochloric acid and stirred overnight with 1 g of charcoal. The filtered solution was made with five 30 ml portions of 90 oigem extracted aqueous phenol. The combined phenolic extracts were washed with three 25 ml portions of v / water, diluted with 650 ml of ether and extracted with six 30 ml portions of water. The combined aqueous extract was with

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- vT -

washed five 50 ml portions of ether and evaporated to dryness, whereby 17 g (95%) of the crude product were obtained.

The crude product was used directly in the next stage.

(F) Preparation of 2- (3-acetamido-2,4,6-triiodo-5-N-methylacetamido -benzoylglycylamino) -2-deoxy-D-glucitol.

CH ₂ OH

—NHCOCH-NH — CO ^-

CH ₂ OH

N (CHjCOCH,

N (COCH)

3 2

CH OH

- NHCOCH ₀ NH O CH ₂ OH

N (CH

A solution of 17 g (0.019 mol) of 2-deoxy-2- (3-diacetylamino-2,4,6-triiodo-5-N-methylacetamido-benzoylglycylamino) -D-glucitol in 150 ml of water the pH was adjusted to 7 with 1N sodium hydroxide. The solution was on Heated to 45 ° and treated dropwise with 1N sodium hydroxide solution, until the pH reached 11. Heating continued and the pH dropped to 10. The addition of 1N sodium hydroxide solution was continued, with the pH remaining around 11. When the pH remained at 10.8 for 5 minutes, became Ice added to cool the solution and the pH was adjusted to 2 with 10% hydrochloric acid. The solution was extracted with six 25 ml portions of 90% aqueous phenol. The combined phenolic extract was washed with three 15 ml portions of water, diluted with 800 ml of ether and washed with extracted six 25 ml servings of water. The combined aqueous extract was washed with six 25 ml portions of ether

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and evaporated to 100 ml. The solution is stirred overnight with 1 g of charcoal and filtered. The filtrate was extracted with fifteen 20 ml portions of chloroform / isopropanol - 3/1. The aqueous layer was evaporated to remove traces of chloroform and isopropanol and diluted to 150 ml of water. The solution was continuously extracted with ether for 3 days. The aqueous layer was evaporated to 100 ml and filtered through an ultrafilter (0.22 / u). On evaporation 10.5 g of product (m.p .: softens at 180 ⁰ C, decomposes at about 204 ° C). Thin layer chromatography (silica gel plate - ethyl acetate / methanol / acetic acid 70/30/2) showed the product to be pure. The NMR and IR spectra indicated that the product was consistent with the proposed structure.

Analysis for

Calculated: C, 28.32 # H , found: 28.17, 3.20

J 44.89 # N 6.61% 45.68 6.47

This compound is about 100 μl soluble in water (w / v ).

Example 2

Preparation of 2-Deoxy ~ 2- (3-acetamido-2,4,6-triiodo-5-N-methylcarbamyl-benzoylglycylamino) -D-glucitol

CH ₂ OH -HCl
_ NHCOCH ₂ NH ₂

- NHCOCH ₂ NH CO

CH OH

CH ₃ MHCO "N ^, ^" ^ NHCOCH

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To 300 ml of dry dimethylformamide at -10 ° were 34.85 g (0.055 mol) of 3-acetamido-5-N-methylcarbamyl-2,4,6-triiodobenzoyl chloride, 16.72 g (0.121 mol) anhydrous potassium carbonate and 15 g (0.061 mol) 2-deoxy-2-glycylamino-D-glucite hydrochloride, prepared according to Example 1B, given. The mixture was left at -10 to 0 ° for 3 h and at room temperature for 4 days touched. The reaction mixture was filtered and the filtrate was evaporated at 50 ° in vacuo, leaving a gummy Residue remained. The residue was stirred with 200 ml of water and 20 ml of 1N hydrochloric acid and filtered, to remove undissolved material. The filtrate was extracted with six 35 ml portions of 90 # aqueous phenol. the combined phenol extracts were washed with three 25 ml portions of water, diluted with 750 ml of ether and with six 50 ml portions of water extracted. The combined aqueous extracts were washed with eight 50 ml portions of ether and then stirred overnight with 2 g of charcoal. The charcoal was filtered off and the filtrate turned out to be twenty 50 ml portions of chloroform / isopropanol - 3/1 - extracted. The aqueous layer was evaporated to give 20.56 g of a solid material were obtained. A 7 g portion of this material was added to a mixture of 21 ml of methanol and 0.5 ml Concentrated ammonia slurried, stirred for 30 min and filtered. The solids were washed with 13 ml of methanol and dried to give 5.94 g of product. This was dissolved in 180 ml of water and stirred overnight with 0.6 g of charcoal. The solution was filtered, first through a paper filter and then through a 0.22 / u filter. When evaporating 5.52 g of product ($ 36 £) were obtained. Thin layer chromatography (silica plate - ethyl acetate / methanol / acetic acid 60: 40: 2) shows that the product is pure v / ar. The IR and NMR spectra showed that the product with the proposed Structure (m.p .: 245 ° dark color; 252 to 255 ° decomposition) was consistent.

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Analysis for C ₁₉ H ₂₅ J ₃ N ₄ O ₉

Calculated: C 27.36% H 3, O2? S J 45.645 $ N 6.72? $ found: 27.16 3.00 46.33 6.59

The solubility of this compound in water is about 596 (wt. AoI.).

Example 3

Preparation of (5-acetamido-2,4,6-triiodisophthaloyl) -N, N ^f bis-2,3-dihydroxypropyl-N, N'-dimethyl-bis-glycine amide

(A) Production of 5-amino-2,4 _t 6-tri.iodisophthaloyl chloride

ClOC

OCl

A slurry of 195.2 g (0.35 mole) 5-amino-2,4,6-tri;} odisophthalic acid in 300 ml of thionyl chloride was refluxed for 24 h. Dissolved during the reflux period the solids on. The solution was cooled to 40 ° and the solvent was evaporated to dryness in vacuo. The gummy residue was dissolved in 250 ml of tetrahydrofuran and evaporated to dryness. The residue was dissolved in 500 ml of tetrahydrofuran and washed with a mixture of saturated sodium chloride solution and saturated sodium carbonate solution washed. The tetrahydrofuran solution was washed twice with saturated sodium chloride solution and dried over anhydrous calcium chloride. The solution was filtered, diluted with 5OO ml of benzene and diluted to 450 ml -3inge-

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steams. 450 ml of petroleum ether (30 to 60 °) added dropwise with stirring. After standing for 2 hours, the solids were isolated and dried, whereby 100.5 g of product (43%) were obtained. Thin layer chromatography (Silica plate - benzene / acetone 80/20) showed the material was pure.

(B) Preparation of 5-acetamido-2,4,6-triiodoisophthaloyl chloride

ClO

COCl

ClOC

NHCOCH-

COCl

A mixture of 50 ml of acetic anhydride and 0.1 ml of conc. Sulfuric acid was stirred for 5 minutes at room temperature. To this mixture was added 15 g (0.025 mol) of 5-amino-2,4,6-triiodoisophthaloyl chloride added in one portion and stirring was continued for 1 h at room temperature. The mixture was stored overnight at 0 °. Filtration gave 16 g of solid material. The product was recrystallized from ethyl acetate, whereby 10 g (6390 pure product were obtained. Thin-layer chromatography (silica plate - benzene / acetone 80/20) showed that the connection was pure.

(C) Preparation of 1-amino-N-glycyl-N-methyl- »2,3-propanediol

f 3

^C 6 ^H 5 ^CH 2 ^0C0NHCH 2 ^C0 2 ^{H + CH} 3 ^NH CH ₂ CHOHCH ₂ OH

f 3

CO-NCH CHOHCH OH

CH ₃

709838/0812 nh ₂ ch ^ conch ₂ chohch oh

0.5 ml (10.8 g, 0.1 mol) of ethyl chloroformate, 14.2 ml (10.1 g, 0.1 mol) of triethylamine and 20.9 g (0.1 mol) of N-carbobenzyloxyglycine were at - 5 ° added to a stirred mixture of 150 ml of dry tetrahydrofuran and 150 ml of dry dioxane . The mixture was stirred at -5 ° for 15 min. A solution of 10.8 g of 1-methylamino-2,3-propanediol in 50 ml of dioxane was then added. The cooling bath was removed and the mixture was stirred at ambient temperature for 16 hours. The white solid in the mixture was filtered off and the filtrate was evaporated to a gummy product. The gummy product was dissolved in 150 ml of water and the resulting solution was extracted with eight 40 ml portions of methylene chloride. The combined methylene chloride extracts were washed with 40 ml of saturated sodium chloride solution and evaporated to a sticky white solid. The solid was dissolved in 200 ml of ethanol and evaporated to dryness. The residue was dissolved in 200 ml of ethanol. 4 g of 5% palladium-on-charcoal was added and the mixture was shaken under a hydrogen atmosphere for 20 h at 3.52. The catalyst was filtered off and the solvent was evaporated to give 12 g (74%) of a nearly pure material . The material was checked by thin layer chromatography (silica plate - ethanol / conc. Ammonium hydroxide 1/1) and used further without further purification .

(D) Preparation of (5-acetamido-2,4,6-trioodisophthaloyl) -N, N'-bis-2,3-dihydroxypropyl-N, N'-dlmethyl-bis-glycine amld

NHCOCH _n

ClOC

CH, N-COCH.NH_ 3; 2 2

CHOH>

CH ₂ OH HN

ίο ι

I CH ₃

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CONHCH CON ¹ CH CHOHCH OH % jL & Z

>> COn ¹ HCH ₂ CONCH CHOHCH OH CH,

To 12 g of i-Amino-N-glycyl-N-nethyl-N-methyl ^^ - propanediol, slurried in 150 ml of dry dimethylformamide of 5 °, 15.9 g (0.025 mol) of 5-acetamido-2,4,6-triiodoisophthaloyl chloride and 6.9 g (0.05 mol) of anhydrous potassium carbonate. The mixture was at 5 bis for 2 h and stirred for 5 days at room temperature. The solution was filtered and evaporated at 60 to 70 ° under reduced pressure, whereby a rubbery product was obtained. The gummy product was dissolved in 150 ml of water with Hydrochloric acid adjusted to a pH of 1.4 and with five 30 ml portions of 90% v / aqueous phenol extracted. The combined phenolic extracts were made in three 20 ml servings Washed water, diluted with 800 ml of ether and extracted with five 40 ml portions of water. The combined aqueous Extracts were washed with seven 50 ml portions of ether and evaporated to give 20 g of a crude solid became. The solid was deposited on 150 g of silica gel using chloroform / methanol as the eluting solvent chromatographed. The combination of the almost pure fractions yielded 9 g of product. Renewed chromatography on silica gel with isobutanol / isopropanol / water as the eluting solvent provided 5 g of material. These 5 g were dissolved in water and covered with 200 mg of charcoal overnight treated. Then through paper and through a 0.22 / U Filter filtered. Concentration of the filtrate provided 5 g of pure material as shown by thin layer chromatography (Silica gel plate - isobutanol / isopropanol / concentrated ammonia - 10/4/6), m.p. 171 to 175 ° C.

Elemental analysis for C ₂₂ H 1 ₀ J, Nc0q.H ₂ O calculated: C 29.15% H 3.34% N 7.88% J 42.05% found: 28.84 3.39 7.68 42.67 .

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The solubility of this compound in water is about 10056 (w / v).

Example 4

Production of S-acetamido ^^ e-triiodisophthaloyl-NiN'-bis-2,3-dihydroxypropyl-N, N · -dimethyl-bis-glycine amide

(A) Preparation of N, N '- (5-Acetamido-2,4 | 6-trioodisophthaloyl) diglycine dlraethyl ester

CH COHN

CONHCH ₀ CO ₀ H

CONHCH CO H

CONHCH ,,

CH COHN

CONHCH ₂ CO ₂ CH ₃

A slurry of 43 g (60 mmol) N, N ^! - (5-Acetamido-2,4,6-triiodisophthaloyl) diglycine in 400 ml of methanol and 2 ml of conc. Sulfuric acid was refluxed for 20 hours. The material dissolved after about 30 minutes of the reflux period and progressively precipitated into the reaction solution during the remainder of the reaction tent. The reaction mixture was cooled to 10 ° and filtered. The solids were slurried with 200 ml of boiling methanol, stirred for 30 minutes, cooled to 10 ° and filtered. There was thus obtained 38.5 g (51.8 mmol, 8656) of the diester. Thin layer chromatography (silica gel plate - ethyl acetate / acetic acid 49/1) showed the compound to be pure.

(B) Preparation of (S-acetamido-I ^ N'-bis ^^ - dihydroxypropyl- N. N '-dimethyl-2,4,6-tri.-iodisophthaloyl) -bis-giveinamide

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MO

+ CH NHCH ₂ CHOHCh ₂ OH

CONHCH ₂ CO ₂ CH ₃

CONHCH CONCh ₂ CHOHCH ₂ OH

C0 :: HCH_C0NCH _o CHOHCH-OH 2.2 2

To a solution of 44.9 g (0.43 Hol) of 1-methylamino-2,3-propanediol in 450 ml of methanol, 60.0 g (0.084 mol) of N.N'-iS-acetamido - ^^ o-triiodisophthaloylJ-diglycine dimethyl ester admitted. The slurry was stirred under reflux for 2 days. The reaction mixture was at the reflux period after 36 hours a clear solution. The reaction mixture was filtered and the filtrate was evaporated to a syrup. Of the Syrup was stirred with 500 ml of isopropanol overnight and the solids were isolated by filtration. The solids were dissolved in 250 ml of water and stirred with 5 g of charcoal for 20 minutes. The charcoal was filtered off and the water was evaporated to give 72.5 g of crude product. The crude product was redissolved in water and over Treated overnight one after the other with 5 g and 10 g charcoal. After filtering off, the solution was evaporated to dryness. The dry solid was slurried with 400 ml of isopropyl alcohol with stirring for several hours and then filtered. The solids were dissolved in water and evaporated to dryness. 43.5 g were obtained, which is a yield of 58? 6. Thin layer chromatography (silica gel plate - Isobutanol / isopropanol / concentrated ammonia 10/4/6 and

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Chloroform / isopropanol / water 10/25/5) shows that the product was pure. Two spots appeared on the thin-film plates. They were separated by column chromatography. the Infrared and NMR spectra indicated that they were isomers. The solubility of these compounds in water is about 10OJi (w / v).

Example 5

Preparation of N- (3-acetamido-2,4,6-triiodo-5-N-methylacetamidobenzoylglycyl) -1- (methylamino) -1-deoxy-D-glucitol

(A) Preparation of 3-acetamido-5-amino-2,4,6-triiodobenzoyl glycine

CONHCH ₀ CO ₉ H

CONHCH ₂ CO ₂ H

NHCOCH.

A hydration shake flask was charged with 220 ml of methanol, a slurry of 2 g of 5% palladium on charcoal, and 20 ml of water and 26.9 g (0.1 mole) of 3,5-dinitrohippuric acid. The mixture was shaken under a hydrogen atmosphere for 90 minutes and filtered. 200 ml of 1N hydrochloric acid were added to the filtrate. The solution was evaporated to near dryness. The residue was dissolved in 200 ml of water and 35 ml of acetic anhydride was added over 30 minutes. The solution was warmed to 50 ° and stirred for 30 min. A solution of iodine monochloride, ie 136 ml of a 2.42N solution, was added to the reaction mixture over 30 minutes. The mixture was at 75 °

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heated and stirred for 8 h at this temperature. The mixture was cooled to room temperature and the solids became isolated. The solids were slurried in water with Treated 10 g of sodium bisulfite and isolated again. The solids were in 300 ml of water with the addition of 50% sodium hydroxide solution dissolved. The pH was adjusted to 8 and the solution was stirred with 1 g of charcoal. the Slurry was filtered and the filtrate was acidified with 10% hydrochloric acid. The solids were removed by filtration isolated to give 32 g (50? 0. The product was purified by thin layer chromatography (silica gel plate - chloroform / methanol / acetic acid 25/2 / 0.5) checked and used without further purification.

(B) Preparation of 3-amino-2,4,6-triiodo-5-N-methylacet amidobenzoylglycin

CONHCH ₂ CO ₂ H

CONHCH ₂ CO ₂ H

NCOCH. 3

I ^CH 3

A solution of 32.8 g (0.052 mol) of 3-acetamido-5-amino-2,4,6-tri; iodobenzoylglycine in 208 ml of 0.5N sodium hydroxide in ethanol was heated to 50 ° and 13 ml (29.5 g, 0.208 mol) of methyl iodide were added. The mixture was left on for 3 h Heated 50 °, cooled to room temperature and by adding 1N aqueous sodium hydroxide solution to a pH of 9 brought. The material in the solution was decanted from an insoluble, black, tarry product. The solution was evaporated to a red, rubbery product.

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The gummy product was dissolved in 200 ml of water and stirred overnight. The solution was acidified to pH 1 with hydrochloric acid, stirred for 1 hour and filtered to isolate the solids. The solid material was washed with water adjusted to pH 1 with hydrochloric acid. There were obtained 26.2 g (7890) product. Thin layer chromatography (chloroform / methanol / acetic acid 25/2 / 0.5) showed that the product was pure. The NMR spectrum showed it to be consistent with the proposed structure .

(C) Preparation of 3-acetamido-2,4,6-triiodo-5-N-methylacet- amidobenzoylglycin

CONHCH ₂ CO ₂ H

CH ₃ COHN

CONHCH ₂ CO ₂ H

A mixture of 370 ml of acetic anhydride, 0.5 ml of conc. Sulfuric acid and 73.9 g (0.115 mol) of 3-amino-2,4,6-triiodo-5-N-methylacetamido-benzoylglycine were stirred at room temperature. All solids dissolved within 30 minutes . After the precipitated solids were stirred overnight, 65 g was isolated and dissolved in 600 ml of water, the pH being adjusted to 9 with 50% aqueous sodium hydroxide solution. The solution was stirred at room temperature overnight and acidified to pH 1 with 6N hydrochloric acid. The mixture was cooled to 10 ° and stirred for 10 minutes and then filtered. The collected solids were washed with water.

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Thin layer chromatography (silica gel plate - chloroform / methanol / acetic acid 25/2 / 0.5) showed that the getrock Neten solids were pure. The yield was 52.4 g (6790, melting point> 260 ^° C.

(D) Preparation of 3-acetamido-2,4,6-triiodo-5-N-methylacetamidobenzoylglycine methyl ester

CONHCH ₂ CO ₂ HI \ J ^ I

CH-CON 3 ι

NCOCH ₃

CH-CON 3 ι

CCNHCH ₂ CO ₂ CH ₃

NCOCH ₃

A slurry of 45 g (0.066 mol) of 3-acetamido-2,4,6-triiodo-5-N-methylacetainidobenzoylglycine in 225 ml of methanol and 0.2 ml of conc. Sulfuric acid was refluxed for 4 hours. The solids dissolved during the reflux period. The reaction mixture was cooled to room temperature and added dropwise to 2.5 liters of cold ether. The mixture was stirred for 15 minutes and the solids were isolated by filtration. The solids were washed with four 200 ml portions of ether and dried; Yield 38g (8396). Thin layer chromatography (silica gel plate - chloroform / methanol / acetic acid 25/2 / 0.5) showed the product to be pure; Mp. 248 to 250 ⁰ C.

(E) Preparation of N- (3-acetamido-2,4,6-triiodo-5-N-methyl acetamidobenzoylglycyl) -N-methyl-1-amino-1-deoxy-D- glucitol

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-AO-

CONHCH ₀ CO ₀ CH, HNCH, ι 2 2 3 ι 3

CONHCH ₀ COn-CH, 2.1 3

CH-CON 3 ι

CH ₂ OH

CH ₂ OH

A slurry of 35 g (0.05 mol) of the methyl ester of S-acetamido ^^ ö-triiodo-SN-methylacetamidobenzoylglycine and 29 _f 25 g (0.15 mol) 1-deoxy-i-methylamino-D-glucitol in 500 ml of methanol was refluxed for 3 days. A clear solution was obtained during the reflux period. The solvent was evaporated to give a gummy product. The gummy product was dissolved in 200 ml of water and the mixture was evaporated to about 175 ml. The solution was diluted with 150 ml v / water and extracted with four 50 ml portions of chloroform. The aqueous solution was adjusted to pH 1 with 10 hydrochloric acid and extracted with six 40 ml portions of 90% aqueous phenol. The combined phenolic extracts were washed with three 20 ml portions of water, diluted with 100 ml of ether and extracted with six 40 ml portions of water. The combined aqueous extracts were washed with six 50 ml portions of ether and evaporated to remove traces of ether. The solution was stirred with 3 g of charcoal overnight, filtered and evaporated to about 150 ml. The solution was extracted with sixteen 50 ml portions of chloroform / isopropanol - 3/1 -, evaporated to approximately 100 ml and filtered through a 0.22 / U filter pad. Evaporation provided 29 g (6755) of the pure material.

Thin-layer chromatography (silica gel plate isobutanol / isopropanol / concentrated ammonia 10/4/6) showed that the

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Product was pure. The structure was confirmed by NHR, IR and elemental analysis.

Calculated for C ₂₁ H ₂ QJ-N ^ O ₀ : mp .: softens at 155 °, melts

at 170 to 190 ° (decomp.)

Calculated: C 28.9096 H 3.48% J 43.62 # N 6.42? $ found: 29.40 3.54 42.88 6.64

This compound is about 100% soluble in water (W / v).

Example 6

The intravenous, intracerebral and intracisternal acute toxicities of the Compounds of Examples 1 to 5 determined. The results obtained are shown in the table below.

Determination of intravenous toxicity at Hausen

Swiss albino mice weighing 18-25 g were used for this test. Three to four groups of mice, the sexes being equally represented in each group, received measured single doses (mg contrast medium / kg Body weight) injected into the lateral tail vein at a rate of 1 ml / min.

After the injection, the animals were examined for immediate pharmacological and toxicological findings. the Mortalities were determined during the first 4 hours and then daily for a period of 7 days. To The surviving animals were sacrificed for 7 days and necropsies were carried out.

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The calculation of the LDcQ value for 7 days was made according to the method of Litchfield and Wilcoxon (J.Pharmacol. Exp. Ther. j3> 6, 99-113 »1949).

Determination of intracerebral toxicity in mice

Swiss albino mice of any sex and weighing 18 to 23 g were tested in this test according to the Method investigated by Haley (Brit. J. Pharmacol. _ ^ 2, 12-15, 1957). At each dose level, the contrast medium was injected as follows. The mouse was on the loose skin behind the Head held. After pulling the skin taut, a size 27 needle, 9.5 mm, attached to a 0.25 ml syringe was perpendicular through the skull into the brain at a point 2 mm from each side of the midline on one Line introduced that had been drawn through the front base on the ears. A dose of 0.05 ml (0.1 ml Maximum) of the contrast medium is injected with different concentrations.

After the injection, the animals were examined for pharmacological and toxic findings. The mortalities were up determined during the first 4 hours and then daily over a period of 2 days. The surviving animals were killed 48 hours after injection and the LDcn value was calculated according to the method of Litchfield and Wilcoxon (J.Pharmacol.Exp.Ther. <? 6, 99-113, 1949).

Determination of intracisternal toxicity in rats

The method of intracisternal administration of the contrast medium to rats was based on the method of Melartin et al (Investigative Radiology, Jan.-Feb. IjJ, 12, 1970) Sprague Dawley rats were anesthetized with ether and placed on an incline. After cutting the

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A small amount of hair in the neck and cervical region developed Midline incision made in the skin in the occipital area to introduce a # 27 needle into the cisterna to facilitate magna. The aspiration of cerebrospinal fluid showed that the cisterna magna was precisely localized had been. Then, measured single doses of the contrast medium were injected.

After the injection, the animals were housed individually and checked for pharmacological and toxicological findings examined. Mortalities were recorded for the first 4 hours and then daily for a period of 7 days. The LD ^ Q value was calculated using the method of Litchfield and Wilcoxon (J.Phannacol.Exp.Ther. 96, 99-113, 1949).

Tabel

1
2 Intravenously 10
> 7 S / Toxicities Intrac i s ternal ^ 50.
mg J /
kg middle V ₁ Conc.
J weight /
Vol. > 15 00O ⁺
500 Intracerebral Conc.
J weight /
Vol. 525 ⁺
<200 5 26.3
11.25 8th 000 Conc. LD5Q
J weight / mg d /
Vol. Kg 35.0
11.25 100 Ex.
Il 28.2 00O ⁺ 26.3 155O ⁺
11.25> 543 14.1 400 ti
Il 28.0 28.2 1425 ⁺ 35.0 ti 28.2 110O ⁺

approximately

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Claims (12)

Claims Triiodobenzoylaminoacyl derivatives of polyhydroxyamines r formula in the X and Y (each stand for non-ionic groups, those with a low toxicity and / or a water solubility are consistent in the 2,4,6-triiodine configuration, A for an amino-substituted lower alkanecarboxylic acid coupling group stands and R.
t -N-Z for a monovalent radical of a polyhydroxy amines, in which N is a nitrogen atom, R is a hydrogen atom, lower-alkyl, hydroxy-lower-alkyl or Polyhydroxy-lower alkyl and Z denotes polyhydroxy-lower alkyl or is oxopolyhydroxy-lower alkyl. 2. Derivatives according to claim 1, characterized in that R is hydrogen or lower-alkyl. 3. Derivatives according to claim 1, characterized in that that X and Y each from the group low-alkoxy, hydroxy- (low-alkoxy), lower-alkoxy- (lower-alkoxy), lower-acylamino, lower acylamino-C lower alkyl), lower acylamino- (lower acylamino), Hydroxy-lower-acylamino, N- (lower-alkyl) -low-acylamino, lower-alkylsulfone- 709838/0812 ORIG / NAL INSPECTED amido, N- (lower-alkyl) -lower-alkylsulfonamido, 3,3-bis- (lower-alkyl) -ureido, low-perfluoroacylamino, carbamyl, N- (lower-alkyl) -carbamyl, N- (hydroxy-lower-alkyl) -carbamyl , N- (polyhydroxy-lower-alkyl) -carbamyl, N, N-bis- (hydroxy-lower-alkyl) -carbamyl, N, N-bis (polyhydroxy-lower alkyl) -carbamyl, N, N-di- (lower-alkyl) -carbamyl, lower-alkoxy- (lower-acylamino), lower alkoxy alkoxy (lower acylamino), hydroxy and hydroxy lower alkyl are selected. 4. Derivatives according to claim 2, characterized in that one of the substituents X and Y represents hydrogen or a in claim 3 specified group and that the other of the Substituents X and Y are -CO-A-N-Z, in which A, R and Z have the meanings given in claim 1. 5. Derivatives according to claim 3 »characterized in that X and Y from the group low-acylamino, N- (lower-alkyl) -low-acylamino, Carbamyl, N- (lower-alkyl) -carb- 'amyl and N, N-di- (lower-alkyl) -carbamyl. 6. Derivatives according to claim 1, characterized in that A represents glycyl, R represents hydrogen, Z represents 2- (1,3,4,5,6-pentahydroxy-D-gluco-hexyl), X for acetamido and Y is N-methylacetamido. 7. Derivatives according to claim 1, characterized in that that A is glycyl, R is hydrogen, Z is 2- (1 ^ t ^^ te-pentahydroxy-D-gluco-hexyl), X is acetamido and Y is methylcarbamyl. 8. derivatives according to claim 1, characterized in that that A stands for glycyl, R for methyl, Z for 2,3-di- 709838/0812 is hydroxypropyl, X is acetamido and Y is R.
-CO-AN (where A is glycyl, R is methyl and Z is 2,3-di- Z
mean hydroxypropyl. 9. derivatives according to claim 1, characterized in that that A stands for glycyl, R stands for methyl, Z stands for 1- (2,3,4, 5,6-pentahydroxy-D-gluco-hexyl), X stands for acetamido and Y is N-methylacetamido. 10. Derivatives according to claim 3, characterized in that that X stands for low-acylamino, low-acylamino- (low acylamino), Hydroxy-lower-acylamino, N- (lower-alkyl) -low-acylamino, lower-alkoxy- (lower-acylamino) or lower-alkoxy-alkoxy- (lower-acylamino) and Y is lower acylamino, lower acylamino (lower acylamino), hydroxy lower acylamino, N- (lower alkyl) lower acylamino , lower-alkoxy- (lower-acylamino), lower-alkoxyalkoxy- (lower-acylamino), Carbamyl, N- (lower-alkyl) -carbamyl, N- (hydroxy-lower-alkyl) -carbainyl, N- (polyhydroxy-lower-alkyl) -carbamyl, N, N-bis- (hydroxy-lower-alkyl) -carbamyl, N, N-bis (hydroxy-lower-alkyl) -carbamyl), N, N-bis- (polyhydroxy-lower-alkyl) -carbamyl or N, N-di- (lower-alkyl) -carbamyl. 11. Process for the preparation of compounds of general formula 709838/0812 in the X iand Y independently of one another from the group lower-alkoxy, lower-acylamino, lower-acylamino- (lower alkyl), Hydroxy-lower-acylamino, N- (lower-alkyl) -lower acylamino, Carbamyl, N- (lower-alkyl) -carbainyl, N- (hydroxy-lower-alkyl) -carbamyl, N- (polyhydroxy-lower-alkyl) -carbamyl, N, N-di- (lower-alkyl) -carbamyl, N, N-bis- (hydroxy-lower-alkyl) -carbamyl, N, N-bis (polyhydroxy-lower alkyl) carbamyl and lower-alkoxy- (lower-acylamino) are selected, A for an amino-substituted lower alkanecarboxylic acid coupling group stands, R for hydrogen, lower-alkyl, hydroxy-lower- alkyl or polyhydroxy-lower alkyl, R. -NZ for a monovalent radical of a polyhydroxyamine from the group of aldosamines of the formula CH0- (CH0H) _n -CH (NHR) - (CH0H) _m -CH ₂ 0H, in which m is 0 to 4, η is 0 to 4 and the sum from m + η is 0 to 4 and R has the meaning given above; Ketosamines of the formula NHRCH ₂ - (CHOH) _n -C0- (CHOH) _m -CH ₂ 0H, where η is 0 to 4, m is 0 to 4, the sum of m + η is 0 to 4, and R is the above has given meaning; N- (polyhydroxy-lower alkylamines) having the formula H- (CHOH) _n -CH (NHR) - (CHOH) _m -CH ₂ OH, where η is 0 to 2, m is 0 to 5, the sum of η + m is 0 to 5 and R has the meaning given above; and amines of the formula (CH ₂ OH) ₂ CR-NHR, in which R has the meaning given above, characterized in that one of a compound which has a sterically unhindered alkoxy group contains and that of the general formula 709838/0812 CO-A-O-R corresponds, in which X, Y and A have the meanings given above and R ^ is lower-alkyl, selectively the alkoxy group removed and replaced by the monovalent radical mentioned by taking the compound mentioned with the amine Reacts alkoxy removing conditions. 12. Radiological agent, characterized in that it is at least one compound according to claim 1 together with a pharmaceutically acceptable radiological carrier. 13 · X-ray visualization method, thereby characterized in that a radiological agent according to claim 12 is injected and then an X-ray beam is made visible performs. 709838/0812