DE19740403C2 - New contrast media - Google Patents

Description

The invention relates to the ge in the claims marked object, that is, new contrast media, agents containing these compounds, their use as diagnostic agents, as well as methods of manufacturing the connections and means.

All X-ray contrast media currently available for the Urography and angiography and the computed tomography phie are connections that are either exclusively for Representation of body cavities and the extracellular space and the urinary organs ("Group I") or Representation of the bile ducts ("Group II") are suitable. Examples of the former group are amidotrizoate, Iohexol, Iopamidol, Iopromid and Iotrolan. Examples of that second group are iotroxic acid, iopodic acid and iodipa minic acid.

The next generation of X-ray contrast media should either have tissue-specific distribution patterns indicate or be able to de pathological conditions tect.

It has now surprisingly been found that the compounds of the general formula I

wherein
R ¹ and R ^{2 may be the} same or different and hydrogen, a -COOH group, a -CONR ³ R ⁴ group or -NR ⁵ COR ⁶ group, and both radicals R ¹ and R ² do not mean hydrogen at the same time , in which
R ³ and R ⁴ independently of one another represent a hydrogen atom or a straight-chain or branched C ₁ -C ₆ alkyl group optionally substituted by 1-5 hydroxy and / or 1-3 C ₁ -C ₃ alkoxy groups,
R ^{5 represents} a hydrogen atom or a straight-chain or branched C ₁ -C ₆ alkyl group optionally substituted by 1-5 hydroxyl and / or 1-3 C ₁ -C ₃ alkoxy groups and / or 1-2 phosphono groups and
R ^{6 represents} a hydrogen atom or a straight-chain or branched C ₁ -C branch which is optionally interrupted by an oxygen atom and which is optionally substituted by 1-5 hydroxyl and / or 1-3 C ₁ -C ₃ alkoxy groups and / or 1-2 phosphono groups ₆ alkyl group and
Y is a phosphono group, a (CONH) _n R ⁷ group or an NR ⁵ COR ⁶ group, where
n can be 0 or 1, and
R ^{7 represents} a C ₁ -C ₆ -alkyl group substituted by at least one phosphono group and / or one or more carboxy groups,
where the phosphono group can optionally be present as a phosphonic acid monoester,
mean,
with the proviso that at least one phosphono group must be present in the molecule,
as well as their salts with inorganic and / or organic bases, amino acids and amides, are suitable for binding metal ions and / or detecting locations of high metal ion concentrations and / or accumulating at these locations.

Preferred metal ions are calcium, magnesium and Zinc.

Locations of high calcium concentrations are e.g. B. calcifi decorated tissues, tumors, infarcted tissue, late stages of arteriosclerosis or inflammatory tissue area.

The compounds of the invention are also for ent Removal of heavy metal ions from the human Body suitable.

The rest is an example of R ¹ / R ² = CONR ³ R ⁴
CONH (CH ₂ CH (OH) CH ₂ OH),
CONH (CH (CH ₂ OH) CH ₂ OH),
CONH (CH (CH ₂ OH) CH (OH) CH ₂ OH),
CON (CH ₃ ) (CH ₂ CH (OH) CH ₂ OH),
CON (CH ₂ CH ₂ OH) (CH ₂ CH (OH) CH ₂ OH). Compounds in which a radical R ³ or R ^{4 is} hydrogen are preferred.

Preferred alkyl groups R ³ and R ⁴ are C ₁ -C ₄ -alkyl groups, which are optionally substituted by 1-3 hydroxyl groups and / or 1-2 alkoxy groups. Examples of R ³ and R ⁴ are CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₂ OH, CH (CH ₂ OH) CH ₂ OH, CH (CH ₂ OH) CH (OH) CH ₂ OH to call. The alkoxy groups in R ³ and R ⁴ can e.g. B. OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH (CH ₃ ) ₂ ; OCH ₃ is preferred.

Examples of R ¹ / R ² = NR ⁵ COR ⁶ are the residues NHCOCH ₃ , NHCOCH ₂ OH, NHCOCH ₂ OCH ₃ , N (CH ₂ CH ₂ OH) COCH ₃ , N (CH ₃ ) COCH ₂ OH, NHCOCH ₂ PO ₃ H ₂ , N (CH ₂ CH ₂ PO ₃ H ₂ ) COCH ₂ OH, N (CH ₂ CH ₂ PO ₃ H ₂ ) COCH ₂ PO ₃ H ₂ .

Preferred radicals R ⁵ are the hydrogen atom and ge-chain alkyl groups, optionally with 1-3 hydroxyl groups and / or 1-2 methoxy groups and / or 1-2 phono groups.

Examples of R ⁵ are hydrogen, CH ₃ , CH ₂ CH ₂ OH and CH ₂ CH ₂ PO ₃ H ₂ .

For the alkyl groups R ⁶ , C ₁ -C ₄ alkyl groups, which are optionally interrupted by an oxygen atom and / or are optionally substituted by 1-3 hydroxyl groups and / or a phosphono group, are preferred. Examples are CH ₃ , CH ₂ OH, CH ₂ OCH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ OH, CH (OH) CH ₂ OH, CH (OCH ₃ ) CH ₂ OCH ₃ , CH ₂ CH (OH) CH ₂ OH, CH (CH ₂ OH) CH ₂ OH, CH (CH ₂ OH) CH (OH) CH ₂ OH, and CH ₂ PO ₃ H ₂ .

Suitable ester components for the monoester of the phosphonic acid group in Y are, in particular, straight-chain or branched C ₁ -C ₄ -alkyl esters.

Preferred groups Y when R ¹ and R ² contain no phosphono groups are the phosphono group and the (CONH) _n R ⁷ group with n = 0 and 1.

Examples of R ⁷ are -CH ₂ PO ₃ H ₂ , -CH ₂ CH ₂ PO ₃ H ₂ , -CH (PO ₃ H ₂ ) ₂ , -CH ₂ CH (PO ₃ H ₂ ) ₂ , -CH (PO ₃ H ₂ ) (COOH), -CH ₂ CH (PO ₃ H ₂ ) (COOH), -CH (PO ₃ HCH ₃ ) ₂ , -CH (PO ₃ HCH ₂ CH ₃ ) ₂ , -CH (PO ₃ HCH ₃ ) (COOH), -CH (PO ₃ HCH ₂ CH ₃ ) (COOH).

Preferred groups Y if R ¹ and / or R ² already contains phosphono groups are -COOH, -CONH (CH ₂ CH (OH) CH ₂ OH), -CON (CH ₃ ) CH ₂ CH (OH) CH ₂ OH, -CONH (CH (CH ₂ OH) CHCH (OH) CH ₂ OH).

The salt formation can be done with all acidic ones Groups of the compounds according to the invention take place.

Inorganic bases such as e.g. B. Alka lihydroxide, alkaline earth hydroxides and as organic bases are primary, secondary and tertiary amines, amino acids or to understand amides. Lithium hydro are examples xide, sodium hydroxide, potassium hydroxide, magnesium hydro xid, calcium hydroxide, ethanolamine, diethanolamine, Mor pholine, glucamine, N, N-dimethylglucamine, meglumine, Ar  called ginin, lysine, ornithine.

The invention also relates to a process for the preparation of compounds of general formula I.

wherein R ¹ , R ² and Y have the meaning given above, characterized in that either a compound of the general formula II

wherein R ^{5 is} hydrogen, CONR ³ R ⁴ or NR ⁵ and Y and R ^{5 have} the meaning given above, and the heteroatoms optionally present in R ⁸ and Y are optionally present in protected form, with one, optionally one or more than Acetate-protected hydroxy groups containing acid chloride of the general formula III,

Cl-CO-R ⁶ (III)

with R ⁶ in the meaning given above,
is implemented, and in any order the acetate groups and, if appropriate, saponified carboxylic acid esters present in Y or R ⁷ , the heteroatoms optionally present in R ⁸ and Y, if appropriate, are released again and the phosphonic esters are partially or completely saponified and
optionally salts of the acidic groups optionally present are formed, or
a compound of the general formula IV

wherein R ^{9 is} a hydrogen atom, a C ₁ -C ₄ alkyl group or a benzyl group and R ^{10 is} a hydrogen atom, a C ₁ -C ₃ alkyl group, PO ₃ (R ⁹ ) ₂ or CO ₂ R ¹¹ with R ¹¹ in the meaning a C ₁ -C ₄ alkyl group or a benzyl group, with an acid chloride of the general formula V

is implemented, in which R ¹ and R ² optionally protect existing hydroxyl groups as acetates and acid groups are present as esters, and then, in any order, the acetate groups and optionally present carboxylic acid esters are optionally saponified and the phosphonic acid esters are partially or completely saponified and, if appropriate Salts of the acidic groups which may be present are formed.

Compounds of the general formula II are obtained from for example by mono- or di-nitration of phenylp phosphonic acid, subsequent reduction to the corresponding amine and subsequent iodination.

Compounds of the general formula III are mentioned by way of example in:
DOS 2643841, DOS 2547789, WO 96/09285, EP 0501875, EP 0345163, US 4125599.

Compounds of the general formula V are mentioned by way of example in:
DE 43 44 464, DE 39 37 118, WO 94/05337, US 5075502, WO 93/10825, WO 91/09007; Invest. Rad. 29, Suppl. 1, S51 ('94).

The compounds of the general formula IV are analogous for methods known in the literature, see e.g. B. CR Acad. Sci. II 316 (2), 181-186 (1993); JOC 42, 376 (1977); Synth. 399 (1988); THL 23: 3835 (1982) Synth. Commun. 26 (10), 2037 (1996); JCS Perk. Trans I, 2879 (1996); JCS Perk. Trans I, 2885 (1996).

Another object of the invention are pharmaceutical cal agents containing at least one of the invention Connections included.

The invention further relates to a method for the manufacture position of this means, which is characterized in that one or more of the compounds of the general For mel I with the additives and stabilizers common in galenics in one for enteral or parenteral application appropriate form.

The pharmaceutical preparation can in general to the specific needs of the user be fitted. The concentration of new compounds when used as an X-ray contrast medium in aqueous Medium depends entirely on the X-ray diagnostic Method. The usual concentrations are in ranges from 2 to 250 mmol / l, preferably 5 to 150 mmol / l. The iodine content of the solutions is more common as in the range between 50 to 450 mg / ml, preferably 100 to 350 mg / ml.

The resulting funds are then ge if desired, heat sterilized. You become addicted the iodine content and the X-ray diagnostic used Method or question usually in a dose of 30 mg iodine / kg body weight up to 2000 mg iodine / kg body weight important applied.

The application of the aqueous X-ray contrast medium solution can be enteral or parenteral, e.g. B. oral, rectal, intrave nasal, intraarterial, intravascular, intracutaneous, subcutaneous (Lympho graphie), subarachnoidal (myelography).

Suitable additives are, for example, physiologically un questionable buffers (such as tromethamine, bicarbonate,  Phosphate, citrate), stabilizers (such as DTPA, natriu medetat, calcium disodium edetate), or - if necessary - Electrolytes (such as sodium chloride) or - if required derlich - antioxidants (such as ascorbic acid) or also substances to adjust the osmolality (such as Mannitol, glucose). Are for enteral administration or other purposes suspensions or solutions of the inventions agents according to the invention in water or physiological salt solutions are desired, they are combined with one or more auxiliaries customary in galenics (e.g. methyl cellulose, Lactose, mannitol) and / or surfactants (e.g. lecithins, Tweens®, Myrj®) and / or flavorings for taste correction (e.g. essential oils) mixed.

The compounds of the invention can - also in the form of radioactive iodine-labeled derivatives, for. B. the ¹²³ I or ¹²⁵ I derivatives in in vivo nuclear medicine to find application. Starting from an average body weight of 70 kg, the radioactivity required for diagnostic applications of the agents according to the invention is between 10 MBq and 5 GBq per application. The preferred dosage is in the range of 37 MBq and 1.85 GBq per application. The dosage range from 185 MBq to 1.11 GBq is particularly preferred. The application is usually carried out by intravenous, in traarterial, peritoneal or intratumoral injection of 0.1 to 2 ml of a solution of the agent according to the invention. Intravenous administration is preferred.

With the compounds of the invention it is, for. B. possible to localize inflammatory tissue areas.

The following examples serve to explain in more detail tion of the subject matter of the invention, without being on it want to restrict.

The starting materials for the individual examples are either for sale or can, as in DE 43 44 464 open beard to be synthesized.

example 1 3-acetamido-2,4,6-triiodophenylphosphonic acid a) 3-nitrophenylphosphonic acid

30 g (188 mmol) phenylphosphonic acid are added in portions to 168 ml nitric acid (100%) with ice cooling. The temperature must not rise above 10 ° C during the addition. The reaction mixture is then left to stir at 120 ° C. for 4 hours. After the end of the reaction, the mixture is evaporated to dryness and the brownish oil is taken up in ethyl acetate, mixed with 3 g of active carbon at room temperature, filtered and evaporated. The oil is mixed with 130 ml of toluene and 20 ml of diethyl ether. The resulting crystal slurry is filtered off and washed with toluene / diethyl ether.
Yield: 34.2 g (89.5% of theory) of yellowish crystals.

Elemental analysis (taking into account the solvent content):
calculated: C 35.49; H; 2.98 N; 6.90 P; 15.25; O 39.39;
found: C 35.54; H 2.79; N 6.81; P 15.07.

b) 3-aminophenylphosphonic acid

28.4 g (140 mmol) of 3-nitrophenylphosphonic acid are suspended in 284 ml of water and adjusted to pH 8 with aqueous ammonia solution. This solution is mixed with 2.84 g of palladium on carbon (10%) and hydrogenated at room temperature under normal pressure. After 28 hours, the batch is flushed with nitrogen, the catalyst is filtered off and the product is precipitated with concentrated hydrochloric acid. The suctioned solid is washed with water and dried at 50 ° C in a vacuum.
Yield: 19.1 g (79% of theory) of a colorless solid.

Elemental analysis (taking into account the solvent content):
calculated: C; 41.63 H; 4.66 N; 8.09 P; 17.89 O; 27.73;
found: C 41.49; H 4.75; N 8.13; P 17.71.

c) 3-amino-2,4,6-triiodophenylphosphonic acid

53.5 ml (132.7 mmol) of a 40% iodine monochloride solution in 48.1 ml of water, 16.8 ml of concentrated hydrochloric acid and 100 ml of glacial acetic acid are mixed at room temperature with a solution of 7.27 g (42 mmol) 3-aminophenylphosphonic acid in 727 ml of water and 12.6 ml of concentrated hydrochloric acid. The reaction mixture is heated to 85 ° C and stirred for 30 hours. The precipitate which has precipitated out during the reaction is filtered off with suction and washed with a lot of water. The solid obtained in this way is stirred with acetone, filtered and rinsed with dichloromethane.
Yield: 15.9 g (69% of theory) of a pale yellow powder.

Elemental analysis (taking into account the solvent content):
calculated: C 13.08; H 0.92; I 69.12; N 2.54; P 5.62; O 8.71;
found: C 13.22; H 1.09; I 68.97; N 2.43; P 5.51.

d) 3-acetamido-2,4,6-triiodophenylphosphonic acid

14.65 g (34.5 mmol) of 3-amino-2,4,6-triiodophenylphosphonic acid (Example 1c) are suspended in 30 ml of N, N-dimethylacetamide and at 0 ° C with 5.9 ml (82, 8 mmol) of acetyl chloride was added dropwise. After the train has ended, the mixture is allowed to come to room temperature and the reaction mixture is stirred further overnight at this temperature. The suspension is introduced into 500 ml of acidified ice water and the precipitate is filtered off with suction. The solid is dissolved in 300 ml of water and stirred with 3 g of activated carbon at 60 ° C for 30 minutes. After filtration, the aqueous solution is freeze-dried.
Yield: 16.7 g (81.7% of theory) of colorless lyophilisate.

Elemental analysis (taking into account the solvent content):
calculated: C 16.21; H 1.19; I 64.22; N 2.36; P 5.22; O 10.80;
found: C 16.34; H 1.23; I 63.98; N 2.27; P 5.15.

Example 2 Bis-3,5- (hydroxyacetamido) -2,4,6-triiodophenylphosphon acid a) 3,5-dinitrophenylphosphonic acid

40 ml (920 mmol) of nitric acid (100%) are mixed in portions at 5 ° C with 56 ml of concentrated sulfuric acid and 20 ml of oleum, the temperature not to rise above 10 ° C. The cooled nitric acid is then added dropwise to 31.6 g (200 mmol) of phenylphosphonic acid, the temperature here also not being allowed to rise above 10 ° C. After the addition has ended, the solution is stirred for one hour at room temperature. To complete the reaction of the starting material, the reaction mixture is stirred for 5 days at a bath temperature of 110 ° C. The product solution is introduced into 1.2 l of ice-cooled, saturated sodium chloride solution and isolated by repeated extraction with diethyl ether. After evaporation, an orange oil is obtained which slowly crystallizes through. The raw product is used in the next stage without further purification.
Yield: 37.8 g (76% of theory) of orange crystals.

b) 3,5-diaminophenylphosphonic acid

28.3 g (114 mmol) of 3,5-dinitrophenylphosphonic acid (Example 2a) are suspended in 280 ml of water and adjusted to pH 8 with 18 ml of concentrated ammonia solution, the starting material going into solution. After adding 5.64 g of palladium on carbon (10%), the dinitro compound is hydrogenated at room temperature under normal pressure. After 9 hours the hydrogen uptake has ended and the catalyst is filtered off. The reddish-colored filtrate is treated with 3.2 g of activated carbon for one hour and, after filtration, acidified with concentrated hydrochloric acid. The precipitate is filtered off and washed with water.
Yield: 15.1 g (70.4% of theory) of a yellowish solid.

Elemental analysis (taking into account the solvent content):
calculated: C 38.31; H 4.82; N 14.89; P 16.46; O 25.51;
found: C 38.56; H 4.98; N 14.57; P 16.59.

c) 3,5-diamino-2,4,6-triiodophenylphosphonic acid

63.5 ml (157.5 mmol) iodine monochloride solution (40%) in 57 ml water and 20 ml concentrated hydrochloric acid are placed at room temperature and mixed with 9.41 g (50 mmol) 3,5-diaminophenylphosphonic acid (example 2b ) in 94 ml of water and 10 ml of concentrated hydrochloric acid. After 4 hours at room temperature, the reaction mixture is diluted with 250 ml of ice water. The precipitate is filtered off and washed with plenty of water. The solid obtained is used in the next reaction without further purification.
Yield: 18.8 g (66.5% of theory) of a yellowish solid.

d) bis-3,5-acetoxyacetamido-2,4,6-triiodophenylphosphon acid

10.13 g (17.9 mmol) of 3,5-diamino-2,4,6-triiodophenylphosphonic acid (Example 2c) are suspended in 16 ml of N, N-dimethylacetamide and cooled to 0.degree. Then 5.9 g (43 mmol) of acetoxyacetyl chloride (Aldrich) are added dropwise to the stirred suspension. When the addition is complete, the mixture is allowed to come to room temperature and is stirred further overnight. When the reaction is complete, the mixture is poured into hydrochloric ice water and the precipitate is filtered off with suction. The solid is washed with water and dried at 50 ° C in a vacuum.
Yield: 9.35 g (68% of theory) of a yellowish solid.

Elemental analysis (taking into account the solvent content):
calculated: C 21.95; H 1.84; I 49.70; N 3.66; P 4.04; O 18.80;
found: C 21.76; H 1.95; I 49.54; N 3.49; P 3.91.

e) Bis-3,5-hydroxyacetamido-2,4,6-triiodophenylphosphon acid

8.9 g (11.6 mmol) bis-3,5-acetoxyacetamido-2,4,6-tri iodophenylphosphonic acid (Example 2d) in 55 ml of 2 n Dissolved sodium hydroxide solution and stirred at 50 ° C for 3 hours. After the implementation is neutralized, mixed with 1.1 g of activated carbon and after filtration with concentrated hydrochloric acid until complete precipitation acidified of the product. The precipitation is suctioned off with washed plenty of water and ge at 50 ° C in a vacuum dries. Yield: 7.45 g (94% of theory) of a colorless solid.

Elemental analysis (taking into account the solvent content):
calculated: C 17.61; H 1.48; I 55.83; N 4.11; P 4.54; O 16.42;
found: C 17.84; H 1.52; I 55.69; N 4.02; P 4.38.

Example 3 2- (3-acetamido-2,4,6-triiodophenyl) -1,1-ethanediphosphone acid a) 2- (3-Nitrophenyl) -1,1-ethylenediphosphonic acid tetraethyl ester

A solution of 35.2 ml (320 mmol) of titanium tetrachloride in 77.44 ml of carbon tetrachloride is introduced into 641 ml of anhydrous tetrahydrofuran at 0 ° C. with exclusion of moisture with vigorous stirring. After 30 minutes, 24.1 g (160 mmol) of 3-nitrobenzaldehyde and 47.0 g (160 mmol) of tetraethylmethylene diphosphonate are added. After a further 15 minutes, a solution of 70.4 ml (640 mmol) of N-methylmorpholine in 112.6 ml of water-free tetrahydrofuran is added dropwise. The reaction mixture is then allowed to slowly come to room temperature. After two hours at room temperature, the mixture is hydrolyzed with water while cooling with ice, and 160 ml of diethyl ether are added. After the organic phase has been separated off, the aqueous phase is extracted with 150 ml of diethyl ether and the combined organic phases are washed with dilute hydrochloric acid. It is washed neutral with half-concentrated sodium chloride solution and dried over sodium sulfate. To purify the substance, it is filtered through silica gel.
Yield: 54.1 g (80.3%; Th.) Colorless oil.

Elemental analysis (taking into account the solvent content):
calculated: C 45.61; H 5.98; N 3.32; P 14.70; O 30.38;
found: C 45.68; H 6.05; N 3.54; P 14.53.

b) 2- (3-aminophenyl) -1,1-ethanediphosphonic acid tetra ethyl ester

27.4 g (65 mmol) of 2- (3-nitrophenyl) -1,1-ethendiphosphonic acid tetraethyl ester (Example 3a) are dissolved in 548 ml of methanol and using 1.37 g of palladium on carbon (10% - ig) hydrogenated at room temperature. When the hydrogenation has ended, the catalyst is filtered off and the filtrate is evaporated.
Yield: 25.2 g (100% of theory) of colorless oil.

Elemental analysis (taking into account the solvent content):
calculated: C 48.85; H 7.43; N 3.56; P 15.75; O 24.40;
found: C 48.87; H 7.66; N 3.38; P 15.61.

c) 2- (3-Amino-2,4,6-tiiodophenyl) -1,1-ethanediphosphone acid tetraethyl ester

24.86 g (63 mmol) of 2- (3-aminophenyl) -1,1-ethanediphosphonic acid tetraethyl ester are dissolved in 248 ml of water / methanol (1: 1) and added dropwise at room temperature with 83.8 ml (208 mmol ) Iodine monochloride solution added. The reaction mixture is heated to 60 ° C. and stirred for 7 hours. The precipitated oil is isolated, taken up in ethyl acetate and washed with sodium bisulfite solution, saturated sodium bicarbonate solution and water. It is dried over sodium sulfate and the solution is somewhat concentrated. The resulting crystals are filtered off and dried in vacuo.
Yield: 35.1 g (72.3% of theory) of a yellowish solid.

Elemental analysis (taking into account the solvent content):
calculated: C 24.92; H 3.40; I 49.38; N 1.82; P 8.03; O 12.45;
found: C 24.76; H 3.48; I 49.22; N 1.70; P 8.14.

d) 2- (3-acetamido-2,4,6-triiodophenyl) -1,1-ethanediphos phonic acid tetraethyl ester

30.84 g (40 mmol) of 2- (3-amino-2,4,6-triiodophenyl) -1,1-ethanediphosphonic acid tetraethyl ester are dissolved in 308 ml of dioxane and added dropwise at room temperature with 7.13 ml (100 mmol) of acetyl chloride transferred. The mixture is stirred at room temperature overnight and the mixture is then evaporated to dryness. The crude product is filtered over silica gel for cleaning.
Yield: 32.2 g (99% of theory)

Elemental analysis (taking into account the solvent content):
calculated: C 26.59; H 3.47; I 46.82; N 1.72; P 7.62; O 13.77;
found: C 26.67; H 3.55; I 46.65; N 1.68; P 7.46.

e) 2- (3-acetamido-2,4,6-triiodophenyl) -1,1-ethanediphos phonic acid

29.1 g (35.8 mmol) of 2- (3-acetamido-2,4,6-triiodophenyl) -1,1-ethanediphosphonic acid tetraethyl ester are mixed with 49.4 ml (387 mmol) of bromotri-methylsilane and excluded from Room temperature stirred. After 20 minutes, a solution is formed from which a precipitate precipitates after a further 60 minutes. The solidified reaction mixture is added dropwise with water and stirred for 5 hours. Then evaporated to dryness and distilled several times with water. The residue is foamed on the oil pump and then recrystallized from isopropanol.
Yield: 22.4 g (89.3% of theory) of colorless crystals.

Elemental analysis (taking into account the solvent content):
calculated: C 17.14; H 1.73; I 54.32; N 2.00; P 8.84; O 15.98;
found: C 17.22; H 1.98; I 54.19; N 1.86; P 8.63.

Example 4 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3-di hydroxypropyl) - (1,1-diphosphonomethyl)] diamide a) Diazomethane diphosphonic acid tetraethyl ester

6.8 g (55.2 mmol) of potassium tert-butoxide are suspended in 472 ml of toluene and cooled to 0 ° C. 13.3 g (46 mmol) of tetraethylmethylene diphosphonate in 66.3 ml of toluene are added dropwise. After 45 minutes a clear solution is formed and 10.7 g (46 mmol) of naphthalene-2-sulfonic acid azide in 75.1 ml of toluene are added. The reaction mixture is allowed to come to room temperature and is stirred overnight. The precipitate is suctioned off and the filtrate evaporated to an oil. The crude product is purified on a silica gel column.
Yield: 10.9 g (75.4% of theory) of a pale yellow oil.

Elemental analysis (taking into account the solvent content):
calculated: C 34.40; H 6.42; N 8.91; P 19.72; O 30.55;
found: C 34.27; H 6.55; N 8.76; P 19.58.

b) Aminomethane diphosphonic acid tetraethyl ester

9.7 g (31 mmol) of diazomethane diphosphonic acid tetraethyl ester are dissolved in 97 ml of water, mixed with 0.97 g of palladium on carbon (10%) and hydrogenated at normal pressure. When the reaction has ended, the catalyst is filtered off and the solution is evaporated. The residue is chromatographed for purification.
Yield: 3.8 g (40.4% of theory) of a colorless oil.

Elemental analysis (taking into account the solvent content):
calculated: C 35.65; H 7.64; N 4.62; P 20.43; O 31.66;
found: C 35.48; H 7.71; N 4.58; P 20.33.

c) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3- diacetoxypropyl) - (1,1-tetraethoxydiphosphorylmethyl)] - diamid

8.06 g (10 mmol) of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-diacetoxypropyl) amide chloride are dissolved in 8 ml of N, N-dimethylformamide and at room temperature with 1.52 ml (11 mmol) of triethylamine and 3.64 g (12 mmol) of aminomethane diphosphonic acid tetraethyl ester were added. The reaction mixture is stirred for two hours at room temperature and then warmed to 50.degree. After a further three hours at this temperature, the batch is precipitated in ice water. The precipitate is filtered off, washed with water and dried in vacuo. The crude product is chromatographed using silica gel.
Yield: 8.26 g (77% of theory) of a colorless solid.

Elemental analysis (taking into account the solvent content):
calculated: C 30.22; H 3.76; I 35.47; N 3.92; P 5.77; O 20.87;
found: C 30.04; H 3.83; I 35.29; N 3.77; P 5.72.

d) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3- dihydroxypropyl) - (1,1-tetraethoxydiphosphorylmethyl)] - diamid

8.15 g (7.6 mmol) of 5-methoxyacetylamino-2,4,6-tri iodoisophthalic acid - [(2,3-diacetoxypropyl) - (1,1-tetraethoxy diphosphorylmethyl)] - diamide are suspended in 81 ml of water and saponified with 1N sodium hydroxide solution until, according to the DC, the starting material is completely converted. It is neutralized with 1N hydrochloric acid, evaporated in vacuo and purified chromatographically.
Yield: 6.98 g (92.8% of theory) of a pale yellow solid.

Elemental analysis (taking into account the solvent content):
calculated: C 27.93; H 3.67; I 38.49; N 4.25; P 6.26; O 19.41;
found: C 27.71; H 3.73; I 38.23; N 4.09; P 6.17.

e) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3- dihydroxypropyl) - (1,1-diphosphonomethyl)] diamide

6.75 g (6.8 mmol) of 5-methoxyacetylamino-2,4,6-tri iodoisophthalic acid - [(2,3-dihydroxypropyl) - (1,1-tetraethoxy diphosphorylmethyl)] - diamide are excluded with 10 5 ml (82 mmol) bromotrimethylsilane ver and stirred at room temperature. After 30 minutes, a solution is formed from which a precipitate precipitates after a further 120 minutes. The solidified reaction mixture is added dropwise with water and stirred overnight at room temperature. Then evaporated to dryness and distilled several times with 30 ml of water each. The residue is foamed on the oil pump and then recrystallized from isopropanol.
Yield: 4.2 g (70.4% of theory) of colorless crystals.

Elemental analysis (taking into account the solvent content):
calculated: C 20.54; H 2.30; I 43.41; N 4.79; P 7.06; O 21.89;
found: C 20.40; H 2.46; I 43.28; N 4.69; P 7.02

Example 5 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3-di hydroxypropyl) - (1-phosphono-1-carboxymethyl)] - diamide a) Ethyl diethylphosphonodiazoacetate

12.5 g (102 mmol) of potassium tert-butoxide are suspended in 625 ml of toluene and cooled to 2 ° C. 19.8 g (85 mmol) of triethyl phosphonoacetate in 57.3 ml of toluene are added dropwise. After 20 minutes, a clear solution is formed and 19.8 g (85 mmol) of naphthalene-2-sulfonic acid azide in 49.5 ml of toluene are added. The reaction mixture is allowed to come to room temperature and is stirred overnight. The precipitate is suctioned off and the filtrate evaporated to an oil. The crude product is distilled in a high vacuum.
Yield: 10.6 g (49.8% of theory) of colorless oil.

Elemental analysis (taking into account the solvent content):
calculated: C 38.41; H 6.04; N 11.20; P 12.38; O 31.97;
found: C 38.28; H 6.11; N 11.07; P 12.22.

b) Ethyl diethylphosphonoaminoacetate

16.1 g (64 mmol) of diethylphosphonodiazoacetic acid, ethyl ester, are dissolved in 320 ml of methanol, 12.2 g (64 mmol) of p-toluenesulfonic acid decahydrate are added and, after adding 8.0 g of palladium on carbon (10%) four bar hydrogenated. After 70 minutes at room temperature, the hydrogenation is complete and the catalyst is suctioned off. The filtrate is evaporated, the residue is dissolved in water and the aqueous solution is adjusted to pH 1 with 5N hydrochloric acid. The mixture is extracted with ethyl acetate and the aqueous phase is adjusted to pH 8 with sodium hydrogen carbonate. It is shaken out three times with chloroform and the organic phase is washed with saturated sodium chloride solution. After drying over sodium sulfate, the solvent is evaporated off.
Yield: 13.8 g (90.1% of theory) of a colorless oil.

Elemental analysis (taking into account the solvent content):
calculated: C 40.17; H 7.59; N 5.86; P 12.95; O 33.44;
found: C 40.26; H 7.71; N 5.68; P 12.83.

c) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3- diacetoxypropyl) - (1-diethoxyphosphoryl-1-ethoxycarbo nyl-methyl)] - diamide

13.6 g (16.85 mmol) of 5-methoxyacetylamino-2,4,6-triio disophthalic acid (2,3-diacetoxypropyl) amide chloride are dissolved in 135 ml of dioxane at 40 ° C. and then with 3. 5 ml (25.3 mmol) of triethylamine, 6.05 g (25.3 mmol) of diethylphosphono-aminoacetic acid ethyl ester in 18.2 ml of dioxane were added at room temperature. Then stirred for seven hours at 80 ° C and overnight at room temperature.
Yield: 8.26 g (77% of theory) of a colorless solid.

Elemental analysis (taking into account the solvent content):
calculated: C 30.22; H 3.76; I 35.47; N 3.92; P 5.77; O 20.87;
found: C 30.04; H 3.83; I 35.29; N 3.77; P 5.72.

d) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3- dihydroxypropyl) - (1-diethoxyphosphoryl-1-carboxy-me thyl)] - diamide

7.67 g (7.6 mmol) of 5-methoxyacetylamino-2,4,6-triiod isophthalic acid - [(2,3-diacetoxypropyl) - (1-diethoxyphospho ryl-1-ethoxycarbonyl-methyl)] - diamide in 77 ml Suspended water and saponified with 1N sodium hydroxide solution until loud DC the educt is completely implemented. You neutralize with 1N hydrochloric acid, evaporate in vacuo and clean chro matographically.

Yield: 6.35 g (93.1% of theory) of a yellowish solid.

Elemental analysis (taking into account the solvent content):
calculated: C 26.78; H 3.03; I 42.44; N 4.68; P 3.45; O 19.62;
found: C 26.64; H 3.21; I 42.17; N 4.55; P 3.29.

e) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3- dihydroxypropyl) - (1-phosphono-1-carboxymethyl)] - diamide

5.49 g (6.1 mmol) of 5-methoxyacetylamino-2,4,6-tri iodoisophthalic acid - [(2,3-dihydroxypropyl) - (1-diethoxyphos phoryl-1-carboxy-methyl)] - diamide are moistened with moisture exclusion with 9.45 ml (74 mmol) of bromotrimethylsilane and stirred at room temperature. After 30 minutes, a solution is formed from which a precipitate precipitates after a further 120 minutes. The solidified reaction mixture is added dropwise with water and stirred overnight at room temperature. Then evaporated to dryness and distilled several times with 25 ml of water each. The residue is foamed on the oil pump and then recrystallized from isopropanol.
Yield: 4.4 g (85.8% of theory) of colorless crystals.

Elemental analysis (taking into account the solvent content):
calculated: C 22.85; H 2.28; I 45.27; N 5.00; P 3.68; O 20.93;
found: C 22.68; H 2.33; I 45.05; N 4.86; P 3.52.

Example 6 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3-di hydroxypropyl) - (phosphonomethyl)] - diamide a) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3- diacetoxypropyl) - (phosphonomethyl)] - diamide

1.61 g (2 mmol) of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-diacetoxypropyl) amide chloride are dissolved in 3.2 ml (23 mmol) of triethylamine and 1 ml of N, N- Dimethyl formamide suspended and mixed with 0.27 g (2.4 mmol) of aminomethanephosphonic acid. The reaction mixture is stirred at 60 ° C. for 55 hours and then poured into 50 ml of water. The pH is adjusted to 1 with 1N hydrochloric acid, the precipitate is filtered off with suction and dried in vacuo.
Yield: 1.35 g (72.0% of theory) of a beige solid.

Elemental analysis (taking into account the solvent content):
calculated: C 29.48; H 3.33; I 40.62; N 4.48; P 3.31; O 18.78;
found: C 29.59; H 3.30; I 40.48; N 4.32; P 3.09.

b) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3- dihydroxypropyl) - (phosphonomethyl)] - diamide

1.25 g (1.3 mmol) of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3-diacetoxypropyl) - (phosphonomethyl)] - diamide are suspended in 15 ml of water and saponified with 1N sodium hydroxide solution until, according to the DC, the educt has been completely implemented. It is acidified with 1N hydrochloric acid, evaporated in vacuo, stirred with hot ethanol, filtered and the evaporated filtrate is purified by chromatography.
Yield: 0.9 g (86.9% of theory) of a colorless solid.

Elemental analysis (taking into account the solvent content):
calculated: C 22.60; H 2.40; I 47.77; N 5.27; P 3.89; O 18.07;
found: C 22.51; H 2.66; I 47.53; N 5.34; P 3.70.

Example 7 2- (3-hydroxyacetamido-2,4,6-triiodophenal) -1-phosphono ethane-1-carboxylic acid a) 2- (3-Nitrophenyl) -1-diethoxyphosphoryl-ethene-1-car bonic acid ethyl ester

A solution of 7.05 ml (64 mmol) of titanium tetrachloride in 15.5 ml of carbon tetrachloride is introduced into 128 ml of anhydrous tetrahydrofuran at 5 ° C. with exclusion of moisture with vigorous stirring. After 20 minutes, who added 4.8 g (32 mmol) of 3-nitrobenzaldehyde and 7.4 g (32 mmol) of triethyl phosphonoacetate. After a further 10 minutes, a solution of 14.1 ml (128 mmol) of N-methylmorpholine in 25 ml of anhydrous tetrahydrofuran is added dropwise. Then the reaction mixture is allowed to slowly come to room temperature. After three hours at room temperature, the mixture is hydrolyzed under ice cooling with 30 ml of water and mixed with 35 ml of diethyl ether. After the organic phase has been separated off, the aqueous phase is extracted with 35 ml of diethyl ether and the combined organic phases are washed with dilute hydrochloric acid. It is washed neutral with half-concentrated sodium chloride solution and dried over sodium sulfate. To purify the substance, filter through a silica gel column.
Yield: 8.3 g (72.6% of theory) of a colorless oil.

Elemental analysis (taking into account the solvent content):
calculated: C 50.42; H 5.64; N 3.92; P 8.67; O 31.34;
found: C 50.30; H 5.88; N 3.95; P 8.54.

b) 2- (3-aminophenyl) -1-diethoxyphosphoryl-ethane-1-car bonic acid ethyl ester

30 7.8 g (22 mmol) of 2- (3-nitrophenyl) -1-diethoxyphos phoryl-ethene-1-carboxylic acid ethyl ester are dissolved in 200 ml of methanol and using 0.27 g of palladium on carbon (10% ) hydrogenated at room temperature. When the hydrogenation has ended, the catalyst is filtered off and the filtrate is evaporated.
Yield: 7.15 g (98.7% of theory) of a colorless oil.

Elemental analysis (taking into account the solvent content):
calculated: C 54.71; H 7.35; N 4.25; P 9.40; O 24.29;
found: C 54.84; H 7.29; N 4.11; P 9.37.

c) 2- (3-Amino-2,4,6-triiodophenyl) -1-diethoxyphosphoryl ethane-1-carboxylic acid ethyl ester

6.9 g (21 mmol) of 2- (3-aminophenyl) -1-diethoxyphosphoryl-ethane-1-carboxylic acid ethyl ester are dissolved in 85 ml of water / methanol (2: 1) and dropwise at room temperature with 28 min (69, 3 mmol) ver iodine monochloride solution. The reaction mixture is heated to 50 ° C. and stirred for six hours. The precipitated oil is isolated, taken up in ethyl acetate and washed with sodium bisulfite solution, saturated sodium bicarbonate solution and water. It is dried over sodium sulfate and the solution is somewhat concentrated. The resulting crystals are filtered off and dried in vacuo.
Yield: 11.4 g (76.8% of theory) of a beige solid.

Elemental analysis (taking into account the solvent content):
calculated: C 25.48; H 2.99; I 53.85; N 1.98; P 4.38; O 11.32;
found: C 25.22; H 3.14; I 53.67; N 1.81; P 4.30.

d) 2- (3-acetoxyacetamido-2,4,6-triiodophenyl) -1-diethoxy phosphoryl-ethane-1-carboxylic acid ethyl ester

10.60 g (15 mmol) of 2- (3-amino-2,4,6-triiodophenyl) -1-diethoxyphosphoryl-ethane-1-carboxylic acid ethyl ester are dissolved in 100 ml of dioxane and added dropwise at 0 ° C. with 4.1 g (30 mmol) acetoxyacetyl chloride was added. The mixture is stirred at room temperature overnight and the mixture is then evaporated to dryness. The crude product is chromatographed over silica gel for purification.
Yield: 9.7 g (80% of theory)

Elemental analysis (taking into account the solvent content):
calculated: C 28.27; H 3.12; I 47.17; N 1.74; P 3.84; O 15.86;
found: C 28.14; H 3.21; I 47.02; N 1.55; P 3.64.

e) 2- (3-Hydroxyacetamido-2,4,6-triiodophenyl) -1-diethoxy phosphoryl-ethane-1-carboxylic acid

8.88 g (11 mmol) of 2- (3-acetoxyacetamido-2,4,6-triiodophenyl) -1-diethoxyphosphoryl-ethane-1-carboxylic acid ethyl ester are suspended in 90 ml of water and saponified with 1N sodium hydroxide solution until, according to the DC Educt is completely implemented. It is adjusted to pH 2 with 1N hydrochloric acid, evaporated in vacuo and the residue is stirred with ethanol. The salts are filtered off and the filtrate is evaporated to dryness.
Yield: 7.7 g (95% of theory) of a yellowish solid.

Elemental analysis (our consideration of the solvent content):
calculated: C 24.45; H 2.60; I 51.66; N 1.90; P 4.20; O 15.20;
found: C 24.26; H 2.81; I 51.54; N 1.97; P 4.13.

f) 2- (3-hydroxyacetamido-2,4,6-triiodophenyl) -1-phos phono-ethane-1-carboxylic acid

7.55 g (10.2 mmol) of 2- (3-hydroxyacetamido-2,4,6-triiodophenyl) -1-diethoxyphosphoryl-ethane-1-carboxylic acid are mixed with 15.75 ml (123 mmol) of bromotrimethylsilane with exclusion of moisture and stirred at room temperature. After 40 minutes, a solution is formed from which a precipitate precipitates after a further 70 minutes. The solidified reaction mixture is added dropwise with water and stirred overnight at room temperature. Then evaporated to dryness and distilled several times with 50 ml of water each. The residue is foamed on the oil pump and then recrystallized from n-propanol.
Yield: 5.7 g (82.1% of theory) of colorless crystals.

Elemental analysis (taking into account the solvent content):
calculated: C 19.40; H 1.63; I 55.91; N 2.06; P 4.55; O 16.45;
found: C 19.26; H 1.80; I 55.84; N 1.93; P 4.29.

Example 8

With the help of Mezerein® (0.0015% ethanol / isopropyl myristat, 50: 50 v / v, Sigma), rats (Han Wist, SPF, Schering, m, 160-170 g, n = 4) by application to an outer ear side set an inflammation.

24 hours after treatment, the rats were 0.43 ml of the test (according to Example 3) - or reference (Angiogra fin®) formulation (250 mg iodine / ml) at one speed speed of 0.8 ml / min. administered intravenously.

Two hours p. a. the rats were narcotized with ether siert, killed by bleeding and the corresponding Or taken from gane. The iodine content of the Or gane was determined on the X-ray fluorescence analyzer.

In contrast to the reference substance, angiographer was after administration of a compound according to example three, two Hours after application, an accumulation in the ignite ear found.

Example 9 [ ¹²⁵ I] -2- (3-acetamido-2,4,6-triiodophenyl) -1,1-ethanediphosphonic acid

The title compound is prepared in analogy to an exchange process with Na [ ¹²⁵ I] (described in J. Lab. Comp. Rad., 36, 235 (1995)). The radioactive substance is obtained in a radiochemical yield of approximately 65%. The purity of the product is determined by HPLC.

Claims (9)

1. Compounds of the general formula I
wherein
R ¹ and R ^{2 may be the} same or different and are hydrogen, a -COOH group, a -CONR ³ R ⁴ group or -NR ⁵ COR ⁶ group, and both radicals R ¹ and R ^{2 are} not hydrogen at the same time, where R ³ and R ⁴ independently of one another represent a hydrogen atom or an optionally rad-chain or branched C ₁ -C ₆ alkyl group which is optionally substituted by 1-5 hydroxy and / or 1-3 C ₁ -C ₃ alkoxy groups,
R ^{5 represents} a hydrogen atom or a straight-chain or branched C ₁ -C ₆ alkyl group optionally substituted by 1-5 hydroxy and / or 1-3 C ₁ -C ₃ alkoxy groups and / or 1-2 phosphono groups and
R ^{6 represents} a hydrogen atom or a radical which may be interrupted by an oxygen atom and which may be substituted by 1-5 hydroxyl and / or 1-3 C ₁ -C ₃ -alkoxy groups and / or phosphono groups, and may be C ₁ -C ₆ -radigated or branched Alkyl group, and
Y is a phosphono group, a (CONH) _n R ⁷ group or an NR ⁵ COR ⁶ group, where
n can be 0 or 1 and
R ^{7 represents} a C ₁ -C ₆ alkyl group substituted by at least one phosphono group and / or one or more carboxy groups,
where the phosphono group can optionally be present as a phosphonic acid monoester,
mean,
with the proviso that at least one phosphono group must be present in the molecule,
and their salts with inorganic and / or organic bases, amino acids and amides. 2. Process for the preparation of compounds of general formula I.
wherein R ¹ , R ² and Y have the meaning given in claim 1, characterized in that
either a compound of general formula II
wherein R ^{8 is} hydrogen, CONR ³ R ⁴ or NR ⁵ H.
and Y and R ^{5 have} the meaning given in claim 1, and the heteroatoms optionally present in R ⁸ and Y are optionally present in protected form with an acid chloride of the general formula III, optionally containing one or more hydroxy groups protected as acetate ,
Cl-CO-R ⁶ (III)
is reacted with R ⁶ in the meaning given in claim 1, and in any sequence the acetate groups and, if appropriate, saponified in Y or R ⁷ , optionally saponified, the heteroatoms optionally present in R ⁸ and Y, if appropriate, released again and the phosphonic acids are partially or completely saponified and, if appropriate, salts of the acidic groups which may be present are formed, or
a compound of the general formula IV
wherein
R ^{9 represents} a hydrogen atom, a C ₁ -C ₄ alkyl group or a benzyl group and
R ^{10 is} a hydrogen atom, a C ₁ -C ₃ alkyl group, PO ₃ (R ⁹ ) ₂ or CO ₂ R ¹¹
with R ¹¹ as a C ₁ -C ₄ alkyl group or a benzyl group,
mean,
with an acid chloride of the general formula V
is implemented, in R ¹ and R ² any hydroxyl groups present as acetates are protected and acid groups are present as esters, and then, in any order, the acetate groups and any carboxylic acid esters that may be present are saponified and the phosphonic acid esters are partially or completely saponified and
optionally salts of the acidic groups which may be present are formed. 3. Use of compounds according to claim 1 for the production of pharmaceutical agents.   4. Use of compounds according to claim 1 for the preparation of Diagnostics. 5. Use of compounds according to claim 1 in the X-ray or Nuclear diagnostics. 6. Use of compounds according to claim 1 in radiotherapy. 7. Use of compounds according to claim 1 for the representation of Areas of increased calcium concentration. 8. Use of the compounds according to claim 1 or this verbin means containing agents for the representation of calcified tissue, tumors, in diseased tissue, later stages of arteriosclerosis and inflammatory Ge weaving areas. 9. Use of compounds according to claim 1 for the removal of Heavy metal ions from the human body.