DE2128902C - 3-square bracket to (3-acylamino-2,4,6-triiodo-phenoxy) -alkoxy square bracket to -2-alkyl-propionic acids, their production and their use as X-ray contrast media - Google Patents

Description

i ■ <

wherein acyl is the acetyl or propiony group. / i 2.? or 4 and alkyl represents the methyl or ethyl radical, as well as their physiologically compatible Metal and amine salts.

2. A method for the preparation of the compounds no according to claim 1, characterized in that a 3-acylamiiiC-2.4.6-triiodophenol is used in a manner known per se with a reactive 3-alkoxy-2-alkyl-propionic acid derivative of the general Formula 2;

X- (CH,) - O -CH ₁ -CH-COOR '

11th

Alcvl

wherein X is the reactive radical of a strong acid and —COOR 'is a carboxylic acid ester or a Carboxyl group means, etherified in the presence of a basic condensing agent and optionally The esters obtained are saponified and the free acids, if appropriate, in metal and amine salts convicted.

3. X-ray contrast media. containing the compounds according to claim 1 as the sole active ingredient.

The invention relates to 3 - [(3-acylamino-2.4.6-triiodophenoxy) -alko \ y] -2-alk \ i-propionic acids the general formula

C!

0- (CH ₂ I _n -O-CHj-CH-COOH

Alkyl

I.
J
- acyl

wherein acyl is the acetyl or propiony group. η 2. 3 or 4 and alkyl represents the methyl or ethyl radical, or their physiologically compatible metal and amine salts and the process for their production and X-ray contrast media that they contain as the sole active ingredient.

These connections are called schailcngcngcende Components used in X-ray contrast media.

The preferred keying components are 3- [2- (3-acetylamino-2,4,6-tnjod-phcnoxylethoxy] -2-ethyl-propionic acid and their physiologically well-tolerated alkali metal, calcium. Magnesium- or alkanolamine salts.

X-ray contrast media containing compounds of general formula 1 are particularly suitable for use suitable in cholecystography. They are preferably administered orally.

These new shading components show sesien over the best used today, oral \ available bile contrast media, iodopanoic acid [3- (3-Amino-2.4.6-iriiodo-phenyl-2-iurnlpropionic acid], dem lopodate [3- (3-Dimethylaminomethy lenamino - 2.4.6 - triiodo - phenyl) - propionic acid] ur.d the structure part closest known 2- [2-13-N-Ath \ l-aeety! Arnino-2.4.6-triiodo-phenoxyethoxy] -propionic acid dodoxanic acid. Swiss Patent specification 4S3 2621 has the following advantages:

The bilitropism of the new connections is considerably stronger and the biliary transport maxima (G. Miller et Schweiz, med. Wochenschrift. ¹ W. 5 ~~ bi> 5Sl [l ^L n Ji liciien higher. Dements ^, echend the KomrasiabbiWungen the biliary organs are essential better.

The bile ducts are regularly visible for the first time

The tolerance is significantly greater, and indeed especially intravenous tolerance, '., oak a much more objective measure of the harmlessness of a Connection represents al. that of the dosage form and the individual absorption good oral toxicity.

Elimination is much quicker, and it will be no intestinal debris observed.

The nephrotoxicity is much lower than for example with iodopanoic acid, which is still most commonly used today.

By eliminating the N-alkyl group. like them you \ erbindungen of the Swiss patent specification 4S3 262, the geometrical observed there occurs cal isomerism does not arise. The isomers are separated; way: the production of pure connections is uel easier and better guaranteed.

Ci. M 111 e r et al. loc. Zit .. have shown that «for the evaluation of biliary contrast means the biluue Transport maximum (Tm). i.e. the transport capacity of the organism for the contrast medium in question is a decisive factor and an increase in the dosage beyond this capacity is pointless is. since it does not cause increased bile excretion and no improvement in shadow density. Ie the higher the transport maximum, the greater the density of shadows and the better the X-ray contrast images are achieved.

With the invention it was possible for the first time to be administered orally Ga'.lenkontrastmittel with sufficient effectiveness, which are very well tolerated containing acylamino group that is not alkylated at the N.

The new compounds can be used as free acids or in the form of their physiologically compatible metal and amine salts can be used.

As metal salts come into consideration: The sodium. Lithium-. Calcium and or magnesium salts.

The preferred amine salts are salts of alkanolamines !! used, for example by N-Methylg'.ukamin. N-methylxylamine (= 1-methylamino-1 -deoxy- [D] -xylitol |. 1 -Methylamino ^ J-propanediol or diethanolamine.

Mixtures of these salts can also be used.

The production of the new shading 3 - [(3 - acylamino - 2.4.6 - triiodo - phenoxy) - alkoxy] -

»Onn
gnd

fiills tissue

j ₃ lkyi-propionic acids of the general formula! is indicated by this. that one in _{per se known ^ e} j _s cein 3-acylamino-2.4.6-tri_iodo-phenol. • by Lm- nzunsi with a reactive 3-Alko \ y-2 -;! k \ l _er0 pJO "of the general [acid tert. derivative Ormel

X - (CHo, —O - CH- —CH - C (X) R-

11
Alkyl

X denotes the reactive radical of a strong acid ((X) R a carboxylic acid ester or a v - '. Iisiruppe,' etherified and, if necessary, old esters and the free acids are converted into metal and amine salts
The etherification is either carried out in the presence of a basic ": condensation medium consisting of an alkali alcoholate or alkali carbonate, or a corresponding alkali-acv! :::;" ino-2.4.6-triiodine is used for this purpose -phenolate.

Gew · ■; · iiiich becomes in the etherification as reactive - "- alkoxy-2-alkyl-propionic acid-demate a siennaalko \ y) -2-alkyl-propionic acid ester example 1

i- [Ji ^; - \ cetylamino-2.4.6-triiodophenoxy l-ethoxy j-2-ethyl-propionic acid

a) ethyl ester

Lit · .. solution of 192g Natnum-3-aceiylamino-2 4.6-.ri; od-phenolate (00:35 Moi "in" 50 ml ^{Dimethylacet:} -i; d is within stirring at 90 C 2t) to ■ " OM-Vitcn with 107.5 g of 3- (2-iodoethoxy) -2-ethyl-propion-aire-ethyl ester (0.35 minor, replaced. The mixture is stirred for 16 hours at 95 to 100 ° C., then distilled The solvent is removed in vacuo and the backwater is poured into 4000 ml of water. The precipitated solid product is washed extensively with water, dilute sodium carbonate, dilute sodium hydrogen sulfite solution and finally again with water.

3-lHai
turn;

Yield: 220 g (90% of theory).
Melting point (after recrystallization from 75% aqueous ethanol): 85 to 86 C.

C ₁ -H ₂₂ J ₃ NO ₅ :
Calculated ..
found ...

C 29.12. J 54.31%:
C 29.15. J 54.53%.

Thin-layer chromatogram (TLC) on silica gel with chloroform to give glacial acetic acid = 19: 1; R _f = 0.57.

b) Free acid

70 g of the ethyl ester (0.1 mol) are in a Boiling mixture of 250 ml of methanol and 250 ml of water with stirring in portions with 100 ml 1 η-sodium hydroxide solution added.

The methanol is distilled off, the residue is mixed with water and extracted with ethyl acetate; the aqueous phase is acidified with hydrochloric acid in the presence of sodium hydrogen sulfite.

The free acid gradually crystallizes. It melts after recrystallization from 50% ethanol and of ethyl acetate at 13O ⁰ C.

C ₁₅ H ₁ SJ, NO ₅ :

Calculated ... C 26.77. .1 56.57 "ο: found C 26.69. J 56.75%.

TLC on Riesekel with chloroform to Eisessis - 19: 1: R _f = 032.

Solubility:

Insoluble in water, soluble in chloroform.

Easily soluble in methanol and ethanol.

Sodium salt: 50 to 100 ml of water at 20 C.

N-methylslucamine salt (MGA-Salz): 100s 100 ml water at 20C.

The ethyl 3- (2-iodoethycyl-2-ethylpropionic acid used as starting material: r is made as follows:

1. 0.8 mol of ethyl malonic acid diethyl ester are in Ethyl ether with 0.84 mol nairium hydride and then with 0.8 mol (2-chloro-ethoxy I-methyl chloride implemented.

The 2 - (2 - chlorathoxy - methyl i-2-ethyl-malonic acid diethyl ester obtained is isolated: Rp. 136 to 144 C 4 mm Hs. "

2. 0.47 mol of 2 ·· (2 - chloroethoxy - methyl) - 2 - ethylmalonic acid diethyl ester are in 500 ml of 60% aqueous methanol with 0.5 mol of sodium hydroxide partially soaped by heating at 60 to 65 C for 2 hours. The one after Evaporation of the methanol by acidification and extraction with ethyl ether obtained 2- (2-chloroethoxy - methyl! - 2 - ethyl - malonic acid - monoethyl ester is increased by increasing it to 140 to 150 ° C decarboxylated.

The resulting 3- (2-chloroethoxy) -2-ethylpropionic acid ethyl ester wire, isolated. Kp 119 to 124 C 14 mm hg.

3. 0.325 mol of 3- (2-chloroetho.vy) -2-ethyl-propionic acid ethyl ester are reacted with 0.65 mol of sodium iodide in 300 ml of ethanol by refluxing for 16 hours. The 3-t2-iodoethoxy> 2-ethyl-propionic acid ether formed is isolated, boiling point 125 to 128, C 3 to 4 mm Hg; η : 1.482.

Example 2

3- [2- (3-Acetyiamino-2.4.6-trijcd-phenoxy) -ethoxy ~ j-2-methyl-propicic acid

a) ethyl ester

A solution of 165 g of the sodium salt of 3-acetylamino-2.4.6-triiodophenol (0.3 mol) in 350 ml of dimethylacetamide is mixed with 85.5 g of ethyl 3- (2-iodoethoxy) -2-methylpropionate (0.3 mol) implemented according to the method described in Example 1 a).

Yield: 192 g (93% of theory). Melting point (after recrystallization from ethyl acetate): 125 ^C C.

C ₁₆ H ₂₀ J ₃ NO ₅ :

Calculated ... C 27.97, J 55.42%; found .... C 27.77, J 55.85%.

TLC on silica gel with chloroform to Eisessie = 19: 1; R _f = 0.54.

b) Free acid

134.4 g of the ethyl ester (0.2 mol) are dissolved in boiling 35% aqueous methanol with 52 ml of 4N sodium hydroxide solution saponified. The free acid is from theirs

2 1

902

Nairium salt solution according to that described in example I b) Method isolated.

Yield: 119 g (90% of theory).
Melting point (after recrystallization from ethyl acetate): 151 C.

C ₁₁ H ₁₆ JjNO ₅ :

Calculated ... C 25.5 !. J 57.77 ° ,,:
found C 25.48. J 57.72 "o.

D.C. on silica gel with chloroform to form glacial acetic acid = 19: I: R, - = 0J4.

Solubility:

Insoluble in water, soluble in chloroform, ! Easily soluble in methanol and ethanol. , _

Sodium salt: 3On 100 ml of water at 20 C. ^

MGA-SaIz: 60 g HX) ml water at 20 C.

The 3- (2-Jodäthoxv \ -2-meih \ l-propionic acid-ethylsier used as starting material is analogous to the ethyl 3- (2-iodoethoxy-2-eth \! - propionate described in Example 1 manufactured:

b) Free acid

26 9 g of the ethyl ester are i 50 ml of ethain 60 ml of water by 3- to iv-.iindiges boiling: Presence of 4! ml of 1 η sodium hydroxide solution stranded.

The crude product up to St) C isolated analogously to Example 1 b1 is dissolved in 50 his K) O ml of boiling AtIv. \:>, added: steady dissolution and then crystallization of the stable high-temperature crystal modification occurs.

Mp. 135 to 137 C.

Yield: ¹⁷ g (64 "of theory !.

l and n in

In. 77

1. By reacting 140 g of diethyl methjimalonate with 20 g of sodium hyuride and 103.2 g of 2-chloroethoxymethyl chloride IIS. ⁷ g of 2 - (2 - chloroethoxy -'methyl) - 2 - methylma ionic acid diethyl ester were obtained.

Bp. 132 to 139 C 4 mm Hg.

2. By partial saponification of 267 g of this substituted Malonic acid diäthvles'.ers with 42 g sodium hydroxide and decarboxylating the substituted monoethyl malonate obtained 103 g of 3- (2-chlorathoxy) -2-methy1-propionic acid ethyl ester obtained from bp 102 to 105 C 14 mm Hg.

3. 93 g of this chlorine derivative are converted into 98 g of 3- (2 -.! Odätho.xy) -2-methyl-propionic acid-ethy-ester by reaction with 144 g of sodium iodide obtained from bp 119 C 3 to 5 mm Hg.

B e i s ρ i e 1 3

3- [3- (3-Acetylamino-2.4.6-triiodo-phenoxy) -propoxy] -2-ethy! -Propionic acid

a) ethyl ester

38.5 g of 3 - acetylamino - 2.4.6 - triiodophenolate sodium [3-AcNH-2,4,6-triiodophenyl - O-Na] in ml of dimethylformamide are only 24.1 g of 3- (3-iodopropoxy - 2 - ethyl - propionic acid - ethyl 16stündiges implemented by stirring at 70 ⁰ C.

The analog example! a) isolated crude product is in Ethyl acetate dissolved; the solution is made with nairium carbonate solution. Water, sodium hydrogen sulfite solution and water, dried with sodium sulfate and evaporated.

The amorphous residue is recrystallized from 70% ethanol.

Yield: 37.5 g (75% of theory).
Melting point: 81 to 82 ° C.

C ₁₈ H ₂₄ J ₃ NO ,:

Calculated ... C 30.23. J 53.24%:
found .... C 30.10, J 53.53%.

TLC on silica gel with benzene to chloroform to glacial acetic acid = 7: 3: ^. R _f = 0.53.

'Calculated ... C 2 ~ .9 ⁷ . J 55.42 "": found .... C 28.09. J 55.64 ", ·.

D C. on silica gel with benzene to chloroform. j

Fishy = -; 3 ^r 2: K _; = 0.46.

Solubility:

Little soluble in W ^ -er. Soluble in 2.5 liters of methanol. 7 files of ethanol and about 10 Iil · .. ··: boiling chinp'f.irm
Nitrium salt: 50 g 100 ml water at 20 C MClA-SaI /: 100 g 100 ml! Water at 20 C

The .ils source material! used 3- (3-.K '.. propoxs ι - 2 - ethyl - propionic acid - ethereal ester w :: analogous to the 3-i2-Jodätho \> ι- 2 -ath \ l-propi.m-.u: ' äthyk'Ster from Äth \! - maionsäüre-diäih \! ester he: ^ .. represents. The following new weekly products have been added receive:

1. 2 - (3 - ('hlorpropoxv - inetnv !, - 2 - at Iv. 1 - ma lon acid-di.uhs! ester: b.p.! 42 bi * -! 4s C 2 mm I Il ii: 1,443.

2. 3 - (3 - Chiorpropo \\) - 2 -; i; h \ i - propioris.tureäthylestet. Bp 103 to 10 "C 2 mm Hl '.

η: "1.438.

3. 3-l3-Jodpropo \\) - 2-eth>'- propionic acid-.: Ih \ iester: bp. 125 to 12 "C '. Mm Hg. Η : 1.47S.

Example 4 3- [4-l3-acetylamino-2.4.6-triiodo-phtiHix \ l-butox \] -

2-ether propionic acid

27.5 g of 3 - AEET>;. imino - 2.4.6 - triiodo - phenolate Natnum be 1 ⁷ .3 g of 3- (4-.lodbutoxy) -2-eth \ lpropionsäure acid ethyl ester in 60ml Dimeth \ lfnrmamid analogously to Example 3al implemented.

The amorphous 3- [4-i3-Acet \ lamino-2.4. 6-triiodo-phenoxy) -butoxy] -2-eth1-propi.insiiureäthylester is analogous to example! 3b) saponified and converted into the ireie crystalline acid.

Melting point: - 120 C.

Calculated ... C 29.12. J 54.> l "": found .... C 29.16. j 53.si9 "".

TLC on silica gel with benzene to chloroform to glacial acetic acid = 7: 3: 2: R _f = 0.43.

Solubilities:

Practically insoluble even in boiling water.

soluble in about 40 parts of cold chloroform.

10 parts of hot chloroform, about 7 parts of cold ethanol, very easily soluble in methanol and boiling ethanol.

Sodium salt: 30 g 100 ml water of 20 C.

MCiA-SaIz: 25 ί · 100 ml W: essentially of "> 0 C

The 3 - (4 - iodobutoxy) -2-ethyl-propionic acid-ethyl ester used as a reagent is prepared analogously to the homologues from ethylmalonic acid diethyl ester. The following intermediate products were obtained:

1. 2- (4-chlorobutoxy-methyl) -2-ethyl-malonic "acid" diethyl ester; bp 145 to 155 C, 2 mm Hu;

ir: 1 '446.

2. 3 - (4-chlorobutoxy) -2-ethyl-propionic acid-ethy-ester; Bp 117-124 C 2 mm Hg; η: 1.43 «. "

3. Ethyl 3- (4-iodobutoxy) -2-ethyl-propionate; Bp. 137 to 142 C 2mm Hg; «: 1.475.

Example 5

3- [2- (3-Acetylamino-2.4.6-iriiodo-phenoxy) -ethoxy] - _ls 2-ethyl-propionic acid

22 g of 3-acetylamino-2,4,6-triiodophenolate sodium in 40 ml of dimethylformamide with 9.2g of 3- (2-chloroethoxy) -2-ethyl-propionic acid ethyl ester within 10 minutes added and by stirring for 20 hours at 110 C to 3- | 2- (3-Acetylamino-2.4.6-triiodo-phenoxy) -ethoxy] -2-ethyl-propionic acid-ethyester implemented. This is, as described in Example 1, isolated and saponified to acid.

Yield: 15.2 g (56.3% of theory).

The etherification can be accelerated by adding 5 to 7 g of sodium iodide.

Instead of ethyl 3- (2-chlorathoxy) -2-ethyl-propionate, the corresponding methyl-estc propyl- yo ester, isopropyl-estcr can also be used for the reaction described above. Butyl cster or another readily available alkyl ester can be used.

Example 6

3-f2- (3-Acctylamino-2.4.6-triiodo-phenoxy) -ethoxy] -2-ethyl-propionic acid

al 14.7 g of 3-acetylamino-2.4.6-triiodophenol become with 6 g of 3 - (2 - .lodethoxy! - 2 - ethylpropionic acid ethyl ester in the presence of 0.037 mol of sodium ethylate in 35 ml of ethanol 40 hours of cooking implemented.

b) 14.7 g of 3 - acetylamino - 2.4.6 - triiodo - phenol and 8.6 g of 3 - 12 - iodoethoxes) - 2 - ethyl - propionic acid ethyl ester in 160 ml of methyl ethyl ketone in the presence of 9 g of anhydrous potassium carbonate ^{4; i} with stirring by 30- up to 40 hours of boiling on the reflux condenser implemented.

The isolation and saponification of the according to al and b) obtained 3- [2- (3-acetylamino-2,4,6-triiodo-phenoxy) -ethoxy] -2-ethyl-propionic acid-ethyl ester takes place in the manner described in Example 1.

Yields: a) 10.2 e (54.5 ° ο of theory),
b) 9.6 g (51.3% of theory).

The following are produced analogously to the examples above:

Example 7

3- [2- (3-propionylamino-2,4,6-triiodo-phenoxy) ethoxy ] -2-ethy! -Propionic acid

a) ethyl ester

16.95 g sodium - 3 - propionylamino - 2.4,6 - triiodophenolate (0.03 mol) in 30 ml of dimethylacetamide with 10 g of 3- (2-iodoethoxy) -2-ethyl-propionic acid ethyl ester (0.033 mol) at 90 C analogous to example Ib) implemented.

Yield:.. 15.2 g (71 "" of theory) melting point (according to ( '!!! crystallization from ethylacetate): 86C.

Calculated ... C 30.23. J 53.24 ",,; found .... C 30.3«. J 52.94 ".,

D.C on silica gel with benzene to chloroform liisessig - 7: 3: 2: R (= 0.65.

b) Free acid

Obtained by saponifying the ethyl ester analogously to Example 1 b).

Melting point (after recrystallization from ethyl acetate): 114 C.

C _{1 (} , H, "J, N () _S :

Calculated ... C 27. <> 7. .1 ^ 5.42 ",,; found C 12/28. .1 55.39 ",,.

D.C ". On silica gel with benzene to chloroform

l-acetic acid - 7: 3'2: R _f ^ 0.70. Solubilities:

Insoluble in VVasser. Easily soluble in chloroform. Methanol and ethanol. Sodium salt: 10 g HX) ml water \ on 20 C MGA-SaIz: 50g 100ml water \ on 20 C.

Example p

3-l2- (3-propionylamino-2.4.f> -iriiod-pheiKi \\ I-ätho \\ ] -2-meth \! -Propionic acid

a) Athylesians

Melting point (after recrystallization from \ th.inol to water 2: 1): 79 (. ".

Calculated ... C 29.12. .1 54.31 ".,: Found .... C 29.40. .1 54.1 ¹ )".,.

D.C. to K.cseluel with benzene / u chloroform Glacial acetic acid = 7: 3- "2: R, = 0.56.

b) Free acid

Melting point (after recrystallization from AUnI acetate): 145 C.

C ₁₅ H ₁₈ J ₁ NO ,:

Calculated ... C 26.77. j 56.57 ".,; found .... C 27.00. J 56.19%.

D.C ". On silica gel with benzene to chloroform to glacial acetic acid ■ = 7; 3: 2; R (= 0.6S.

The novel compounds described above may be used in conjunction with any suitable Carriers can be used, in particular, as a cape. Granules. Tablets. Coated tablets. Globules. Khsma Suspensions or solutions. Oral preparations are preferred, especially microni sized forms, which are absorbed more quickly to create better shadows without disturbing intestinal recoil cause booths.

Both the free acids and the leren metal and amine salts can be used ".

In the following examples ii: e production of some characteristic forms of administration described.

Example 9
Capsules

3 (K) μ to eiικ · particle size smaller than 4 μ mikronisii.-rte 3 - [2 - (3 - acetylamino - 2.4.6 - triiodophenoxylethoxy] - 2 - ethyl - propionic acid becomes with 20.4 μ a surface - active substance (surfactant). best '·: nd from a condensation product of ethylene oxide and' polypropylene glycol. that at room temperature is solid and which prevents the formation of particle aggregates (e.g.! '! uronic I- <SS). intimately mixed, through a stainless sieve, the 324 Malchen has per square centimeter, driven and mixed with 20.4 g of microcrystalline starch.

The mixture is then moistened with distilled water and then granulated by driving the mass through a sieve with 5ό meshes per square centimeter and kneading it at 40 ° C. in a stream of air. Now 7.2 g of a lubricant are added and the granules are filled into 600 soft Gclatinckapseln lib.

Example 10
Tablets

5 kg of 3- [2- (3-acelylamino-2,4,6-triiodo-phenoxy) -jitho. \ Y] -2-ethyl-propionic acid are made with 2 1 Slärke paste. each contains 100 g of corn starch in one Kneading machine made into a paste. When the wet mass is sticky. it is mixed with a little dry starch. It is then granulated in a granulating machine and dried in vacuo. The finished one Granules are then mixed with 0.5 kg of corn starch and 25 g of magnesium learate and made into tablets mil an active ingredient content of 500 mg missed.

Example 11
ίο tablets

5 kg sodium salt of 3- [2- (3-acctylamino-2.4.6-triiodo-phenoxy) -ethoxy] - 2-ethyl-propionic acid uiu: 0 75 kg of semolina sugar (sucrose) are mixed with 0.75 kg of corn starch and mixed. The mix will moistened with 1000 ml of 50% aqueous alcohol and then granulated in the machine. The granules is dried, sieved, with 0.65 kg of corn starch. 0.05 kg of talc and 0.05 kg of magnesium stearate are added and compressed into 10,000 tablets.

Example 12
Coated tablets

The granulate obtained according to Example 1 is made by applying 25% of its own weight to sugar syrup coated in dragicrkcsscl and then waxed.

Claims (1)

Patent claims: 1. 3 - [(3-acylamino- 2.4.6-iriiodine-phenoxy I-alkoxy] - 2 - alk \ '. - General propionsites formula 0- (CH _: i "-0-CH _: -CH-C" OOH O '. Alkyl ■ ι J J HN-acyl