CA2096136A1 - 1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5- (mono- or poly-hydroxyalkyl)aminocarbonyl-2,4,6- triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propanes, their methods of preparation and x-ray contrast media containing them - Google Patents

Abstract

Symmetrical or asymmetrical 1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or polyhydroxyalkyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propanes, useful to constitute the opacifying component of X-ray contrast media, are described.

Description

WO9~/08691 PCrlEP~

2~96~3`~

1,3-BIS-r3-(MONO- OR POLY-~YDROXY)ACYLAM_~o-5 ~MONO~ OR
PO~Y-~YDROXYALRYL)AMINOCARBONYL-2,4,6-TR~IODo-B~RZOYL~
AMINO]-HYDROXY- OR HYDROXYALRYL-PROPANES _ n~IR ~r~C~s OF P~:PARATION_AND X--RAY CONTR~ST M~DIA CONTAININ
~M.
__ This invention relates to symmetrical or asymme~
trlcal 1,3-bis-[3-(mono- or poly-hydroxy) acylamino~5~ :
(mono- or polyhydroxyalkyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propanes, use~
5, ful to constitute the opacifying component of X-ray contrast media, of general formula (I) 2' kyltoH)l-5 ~ Alkyl~OH~l~5 o D~ 3 73 1~ o (1) R N ~ N ~ X ~ N ~ N R ' . I
A B
15~ wherein:
R, R', which are the same or different, are a straight or branched mono- or poly-hydroxyalkyl Cl-C3 re-sidue containing from 1 to 2 OH groups, Rl, R2, R3, which are the same or dif ferent, are H or CH3~
Rl" R2 " R3 " which are the same or different, are H
or CH3 Alkyl(oH)l-s is one of the groups of formula -CH(CH20H)CH(OH)CH20H, -CH(CH20H)2, -cH2cH(oH) CH2OH, -CH2~CHOH)4CH20H, or -CH2CH20H, , .

.,. ~ ., ,, ,, ... ~ . .. , . . .. .. :

WO92/08691 PCT/EP~ 2.~5D

2 ~ 3 ~ 2 X is one of the groups -CH~OH)-, -CH(CH2O~
-C(OH)(C~2OH)- or C(C~2OH)2-, A and B, may be the same or different.
The invention also comprises the possible enan~lo--5 mers, diastereoisomers and/or rotamers of compounds (I). ;
The invention also relates to a process for ~h2preparation of these non-ionic compounds, as well as ~o the X-ray contrast media which contain them as opa-cifying components. ~ .
Preferred compounds of formula (I) are the ones inwhich R2, R2', R3, R3', are H. Particularly preferred are the ones in which X represents the -CH(OH)- group.
From the structural point of view, the non-ionic X-ray contrast agents which are more similar to the ones o this invention are the a,~-bis-[3-hydroxyacylamino~5 (dihydroxyalkyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-oxaalkanes described in patents DE 2805928 and US 4,139,605. In these compounds the two ~riiodo-ben-zcyl-amino residues are joined via an oxaalkylenic re-sidue of formula ~CnH2n ( CnH2n)0-4 n 2n ning from 4 to 12 atoms of C and from 1 to S atoms of O. They can produce oversaturated solutions and after some time, these ones may spontaneously crystallize, therefore causing a limit~tion to the use of such com-pounds. Patent US 4,062,934 describes N,N'-bis-(3-N-methyl-N-acetylamino-5-N-gluconylamino-2,4,6-triiodo-benzoyl)-diaminoalkanes. Due to an iodine content comparatively low, they show a reduced opacifying capa-city. In addition, their solutions are quite viscous.These features cause some problems when the product is , , . , : .. .- .

W092/08691 P~CT/EP91~0f215 (~ ~ .;

3 2~9G13~
..~ .
used in procedures which require administration via catheter.
N,N'-bis-(3-acylamino-5-N-methyl-carbamoyl-2ff4,ff~
triiodo-ben~oyl-amino)-carboxyalkanes are described in patent application GB 1,488,904. The preparation of so~
lutions acceptable from the pharmacological point of view requires that free carboxylic groups, where pre~
sent, are neutralized. Therefore, if compared to ~h~
non-ionic contrast agents, the solutions of the com~
pounds described in the above mentioned patent applica-tion have a high osmolality. Slmilarly, their neuroto-xicity is higher than the one of the non-ionic contrast media.
Sova~ et Al. described in application WO 8501727 among other compounds, also N,N~-bis-[3,5-bis-(N-2,3 dihydroxy-propyl-N-acetyflamino)-2,4,6-triiodo-be~zo~ffffl~
ethylendiamines and the corresponding N'-h~ffdroxyal~yl~
derivatives. The synthesis of these compounds is quite difficult. The four 2,3-dihydroxy-propyl groups are ob~
tained by treating the corresponding tetraalkenylderi-vatives with l-butyl-hydroperoxide in the presence of osmium tetroxide. The reaction occurs in a fragmented and unaccomplished way. None of the compounds descri-bed, mentioned or claimed by Sovak has as conjunction bridge of the two 2,4,6-txiiodo-benzoyl-amino residues th~ hydroxyalkylenic chain of formula -CH2-X-CH2-, with X equivalent to C~(OH)-, -CH(CH2O~)~, -C(OH)(CH2OH)-or -C(CH2OH)2-, which is characteristic of this inven-tion.
A last reference concerns the European patent ap-plications EP 74307 and EP 74309 abandoned in 1985.

: :

W0 92iO8691 P~EP9]/u2151 1~

2~13``3 4 , ~
The first one only describes aromatic bi- or tricyclic compounds where the aromatic moiety contains iodine and bromine atoms at the same t:ime and in the same molecule.
S The second one does not describe new compounds~
but a process which increases the tolerability of opa~
cifying compositions by using a mixture of iodobenzenic and bromobenzenic compounds. The general formulas de~
scribing these compounds are extremely wide, unclear and indefinite and include billions of compounds basi-cally different among them.
The compounds of formula (I) belong to the class of non-ionic contrast agents for X-ray diagnosis, which are more and more replacing the salts up to now used of the derivatives of 2,4,6-triiodo-benzoic acid, due to their better tolerability and the reduced side-effectsO
Thanks to the elimination of the ionic species, their . .
solutions, if compared to the ones of the ionic agents9 have the same content o iodine, but a lower osmotic pressurel that's to say a lower osmolality. Therefore, for instance, in angiography, they cause less pain and endothelial damage. In subarachnoidal administration for myelography and cisternography, unlike the previou-sly used contrast media, they rarely cause arachnoidi-tis or epileptic disorders. Unfortunately non-ionic contrast agents, consisting of iodinated monocyclic aromatic nu~lei, are still too hypertonic, despite their excellent physical and pharmacological proper-ties, if compared with blood, at the high dosages and high concentrations which many diagnoses require. This fact led to the development of bicyclic hexaiodinated , WO92t08691 PCT/EP91/02~5~
1 . i :
`~ 2~61~ ~

compounds, whose osmolality is reducecl in comparison with the total amount of iodine in the moleculeO
However, concentrated solutions of these compounds are frequently too much viscous. In addition, a larye number of products, even if they are expected to be promising from the theore~ical point of view, are not enough soluble.
For this reason, researchers investigated on new hexaiodinated bicyclic derivatives characterized byo high solubility, low viscosity and osmolality as well as high intravenous, intracisternal and intracerebral tolerability and minimum tendency to give side effects (pain, temperature increase, nausea, decrease of pressure and vessel damages).
In particular, ?hysicians need new contrast media characterized by a wide range of possible uses, i.e. in urography, angiography, cardioangiography, flebography~
myelography, cisternography, lymphography, isterosal~
pingography, bronchography and gastrography or the vi-sualization of articular cavities.
The products of this invention are generally cha-racterized by a good water solubility, which can exceed 100 g per 100 ml of solution at 20C, and a low toxi-city.
If compared to the known hexaiodinated dimers, they show low osmolality without causing a foreseeable corresponding rise in the viscosity.
One of the preferred compounds of the invention is for example 1,3-bis-[3-( L-2-hy~roxy-propionyl ) amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane (compound A of Table .

., ~ , W092/08691 PCT/EP91/0215~ ¦

~ 6 2). It gives stable aqueous solutions which ContaiRO at 2QC, more than 100 g of product in 100 ml of solutionO
As far as the physiological characteristics are concerned, the study of plasma kinetics revealed half life for the distribution and elimination phases of 2~9 and 22.9 min, after intravenous administration in rats (200 mgI/kg).
The apparent volume of distribution is 12305 ml/kg showing that the produot is distributed in plasma and the extracellular spaces. The total clearance is 709 ml min-l.. kg~l, Elimination occurs mainly through urinary pathway and in less extent through the bile. After 7 hours from the administration, 76.7% of the administered dose was found in the urine and 3 . 5% in the bile.
Its tolerability is very good as reported in Table lo In Table 2, there are reported the values of some characteristic properties of preferred products of this invention in comparison with IODIXANOL (Nycomed), which is an hexaiodinated non-ionic dimer in advanced phase o. development (EP 108538; CLINICA 413~ p 7~ 08.08.90)o The process for the preparation of the 1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or poly-hy-droxyalkyl~aminocarbonyl-2,4,6-triiodo-benzoyl-aminol~
hydroxy- or hydroxyalkyl-propanes of general formula (I) is characterized in tha~ a 1,3-diamino-hydroxy- or hydroxyalkyl-propane of general formula (II~
R3-HN-cH2-x-c~2-NH-R3l (II) wherein R3 and R3' are H or CH3, X represents the groups -CH(OH)-, -CHICH20H)-~ -C(OH)(CH20H)- or WO92/08691 PCT/EP911021~ .
-( 2~9~ 3~

-C(CH2OH~2- and one of the amino groups may be protec~
ted by a suitable protective group, is reacted, direc tly or by a multi-step process, with a reactive deriva~-tive of a 3-(mono- or poly-acyloxy)aclyamino-5-(mono~
or poly-hydroxyalkyl)aminocarbonyl-2,4,6-triiodo-ben~
zoic acid of general formula (III) ~ ~AIkYltOH)l S

R J~ N~ ( 111 ), Rl I

wherein:
lS Rl, R2, are H or CH3, R4, is a straight or branched mono- or poly-acy~
loxyalkyl Cl-Cl3 residue containing from 3 to l3 atoms of C and from l to 2 lower acyloxy groups C2-C5, Alkyl(OH~l 5, is one of the groups of formula -CH2CH(OH)cH2oH, -cH2cH2oH, -CH(CH2OH)2' -CH(CH2OH)CH(OH)CH2OH or -CH2(CHOH)4CH2OH, where the hydroxy groups may be preferably protected by acetalic or Ketalic groups, CO-Y, is the residue of a mixed anhydride or, pre-ferably, a halocarbonyl group, to give a compound of general formula (IV) :
. ~ ... . .. .
., : , .. - .... , .: . . . . .

WO92/08691 PCT/P91~02D51 ?.
2 ~ 3 ~ ` `

~ ~iukyl(oH)l 5 q~ ,Alkyl(OH)1-5 \~ 13 R . 1~ o ~IV).
R 1 N /~ N ~ X ~ N ~

wherein Rl, R2, R3, Rl , R2 ' 3 4 and X have the meaning as previously defined and R5 may be R or R4, preferably according to one of the two following procedures: ;
a) a compound of formula (II) is reacted with a compound of formula (III) in a molar ratio of 1-2 in a solvent and in the presence of a basic condensation agent in order to obtain the corresponding compound of formula (IV) where R5 corresponds to R~, b) a compound of formula (II), where one of the two ~ .
amino groups is protected by a suitable protective group, is reacted with a compound of formula (III) in a molar ratio of 1:1 in a solvent and in the presence of a basic condensation agent in order to obtain, after hydrolysis of the protective groups, the corresponding 1-[3-(mono- or poly-hydroxy~-2S acylamino-5-(mono- or poly-hydroxyalkyl)aminocar~
bonyl-2,4,6-triiodo-benzoyl-amino]-3-aminohydroxy_ alkyl derivative of general formula (V) AlkYltOH))~5 (V)'.

~ N ~ X ~ N H

Rl I `.

, WO92~08691 PCT/EP91/02151 f :'-'?
9 ~ 1 3 ~ ` `

wherein R~ Rl, R2~ R3~ R3'~ Alkyl(oH)l-5 and X ha meaning as previously deined, and this compound (V) is subsequently reacted with a derivative of formula (III) in the presence of a basic condensation agent to obtain ¦
compound (IV) where R5 is R, then, the compound of formula (IV), obtained by synthetic methods a) or b);
is txansformed by hydrolysis of the protective groups, into the corresponding compound of formula (I)o Finally, in case that Rl, Rl' are H, this last one rnay, if desidered, be methylated in alkaline medium.
Methylation occurs through reaction with suitable methylating agents, for instance methyl halides;
dimethylsulphate, methylsulphonate, dimethylcarbonate.
For instance, the di-sodium derivative of general formula (VI) 72 72 ~ :
~ Alkyl~OH)1 5 q~ ~AIkYl(OH)l ~; , No O ~ N~

is prepared in a basic environment, preferably in the presence of alcoholate or alkaline hydroxide, and is then transformed into the corresponding dimethyl de-rivative of general formula (VII) qf Alkyl(oH)l-5 q~ Alkyl(oH)l-5 30 l ~ 73 73 ~ I ~ (Vll).
R J~ N ~ ~ ~\ C H 3 ,` : , ::: ::' : ,.. . , , ,, , .. ~. :

WO92/08691 PCT/EP91/02~
~,'. `
~Q~13~ lo by treatment with methyl halides, d:Lmethylsulphate~
dimethyl carbonate, methyl methanesulphonate, methyl benzenesulphonate, methyl toluenesulphonate.
In case of direct reaction of the product of gene~
ral formula (II) with a compound of general formula (III), according to synthesis a), symmetrical products are obtained, where both residues A and B of general formula (I) are identical.
Following the multistep reaction according to synthesis b), asymmetrical products may be obtained, in which the residues A and B of general formula (I) are different. In fact, during the second step of the reac-tion, a compound of formula (III), which is different from the one used during the first step of the reac-tion, may be used.
Anhydrous tertiary amines, potassium hydroxide;
sodium hydroxide, sodium bicarbonate, calcium caxbo~
nate, magnesium carbonate may be used as basic conden sation agents.
In both a) and b) synthesis, anhydrldes with orga-nic or inorganic acids~ azides, derivatives of phospho-ric acids, alkylcarbonic acids may be used as compounds of formula (III).
Therefore, the reactive residue Y in compounds of formula (III) represents the residue of an inorganic or organic acid such as: chlorine, bromine, iodine, pho-sphite, azide, acyloxy or alkoxycarbonyloxy.
The preferred group C0-Y is the residue CO-Cl.
The hydroxy functions in the Alkyl(OH)l 5 group of formula (III) may be preferably protected by tran-sformation into the corresponding acetales or ketals.

: , . .............. ,.,., ,. , , : : . ~ .. :; : - .... '; ' . . ..

, -~
! ` - 2096~3 ~
11 :

Examples of such protective groups may be for instance methylidene, ethylidene, l-methyl-ethylidene, l-ethyl~

ethylidene., l-t-butyl-ethylidene, l-ph~enyl-ethylidene, 2,2,2-trichloro-ethylidene, l-ethyl-propylidene. These groups may be easily and fully submitted to hydrolysis through a short treatment with a strong acid, for instance diluted hydrochloric acid, aqueous trifluoroacetic acid or through a strongly acidic ion exchange resin, realeasing the corresponding ketonic compounds, usually acetone, methylethylketone or diethylketone.

The lower acyloxy protective C2-C5 groups, inclu- .

ded in the R4 residue of formula (III), may.be for in-stance acetoxy, propionyloxy, butiroyloxy and may be easily submitted to hydrolysis by treatment with alka-line aqueous solutions, in order to obtain the desired mono- or poly-hydroxyalkyl R groups of formula (I).

The reaction of a compound of general formula (II) with one of formula (III) to give a compound (IV) takes place preferably in an aprotic solvent, such as, for instance, dimethylacetamlde (DMAC), dimethylformamide (DMF), hexamethylphosphoramide (HMPT) or dioxane, but also in acetone, ethyl alcohol and isopropyl alcohol.

The te~perature is not critical. The reaction takes place when temperature ranges from -10C to + lS0aC~

preferably within 0C and 100C.

l,3-Diamino-hydroxy- or hydroxyalkyl-propanes of general formula (II) are described in literature, for instance in "Beilsteins Handbuch der Organischen Che-mie":

l,3-diamino-2-hydroxy-propane, Beil.4 H 290, E II

.: ~: ......... . . .,. . :

.. ,: "
,;; ,': : : . : :' WO92/08691 PCT/EP91/02151 ~
.

2 ~ 12 739, E III 766, E IV 1694;
1,3-bis-(me~hylamino)-2-hydroxy-propane, Beil. 4 IV 1695;
1,3-diamino-2,2-bis-hydroxymethyl-propane, BeilO 4 E III 850;
1,3-bis-(methylamino)-2,2-bis-hydroxymethyl-pro- ' pane, Beil. 4 E III 851. :~:
When a compound of formula (II) is reacted with one of formula (III) in a molar ratio of 1:1 according to synthesis b), then the 1,3-diaminoderivative of for-mula (II) is monoprotected on one of the two amino groups in order to avoid side-reactions. Protective groups which meet this purpose may be for instance acetyl, dichloroacetyl, trifluoroacetyl groups. Tri-fluoroacetyl is particularly preferred. Afterwards~these groups may be easily and completely hydrolysed through treatment with alkaline aqueous solutions~
The reactive derivatives of the 3-(mono- or poly~
acyloxy)acylamino-5-(mono- or poly-hydroxyalkyl)amino~
2,4,6-triiodo-benzoic acids of general formula (III) are obtained by reaction of a reactive derivative of a 3-(mono- or poly-acyloxy)acylamino-2,4,6-triiodo-iso-phthalic acid of general formula (VIII~
o~Y

2 5 ~ ~ (V l l l ~ .

Rl l O

wherein Rl, R4, and Y are as previously defined, or by reaction of a derivative belonging to the ones already W092/0869] PCT/EP91fO295~ ~
~- 2~?~1 3f;) described in patents ~S 4,001,323 and EP 26281 with the hydroxyalkyamines 2-hydroxy-ethylamine, 1,3-dihydroxy~
lsopropylamine (serinol), 2,3-dihydroxy-propylam.ine (isoserinol), 3-amino-1,2,4-butantriol, or with the corresponding N-methylamines, or with N-methyl~
glucamine or with a corresponding derivative thereof wherein the hydroxy sroups are preferably protected by chelatization, for instance with 5-amino-2,2-dimethyl-1,3-dioxane, 5-~mino-2-methyl-2-ethyl-1,3-dioxane, 5 amino-1,3-dioxane, 5-amino-2,2-diethyl-1,3-dioxane, 4-aminomethyl-2,2-dimethyl-1,3-dioxolane, 4-aminomethyl-2,2-diethyl-1,3-dioxolane, 5-amino-6-hydroxy-2,2-di-methyl-1,3-dioxepane or 5-amino-6-hydroxy-2-ethyl-2-methyl-1,3-dioxepane.
lS The reactive derivatives of 3-(mono- or poly-acy loxy)acylamino-2,4,6-triiodo-isophthalic acid (VII~
are generally reacted with one of the above mentioned amines in a molar ratio of about 1:2 without using a basic condensation agent, or in a ratio of 1:1 by using a basic condensation agent in an inert organic solvent.
For instance, dioxane or tetrahydrofuran (THF) are pre ~erred solvents. The HY acid, released during the reac-tion of (VIII) with the amine, is.neutralized by the second mole of the amine, giving the corresponding am-monium salt, or by the basic condensation agent used.
Some of t~e preferred reactive derivatives of the 3-(mono- or poly-acyloxy)acylamino~5-(mono- or poly-hy-droxyalkyl)aminocarbonyl-2,4,6-triiodo-ben7.oic acids of general formula ~III) have already been des~ribed in patents DE 2805928 or US 4,139,605.
The compounds of this invention may be used as W092/08691 PCT/EP91/02~51 3 ~
1~

opacifying agents in non-ionic contrast me!dia for X~ray diagnosis.
They may be formulated in a suitable carrier agent which is acceptable from the pharmacological point of view. Suitable carrier agents include, for instanceO
the ones which can be used for enteral or parenteral administration, such as buffered sterile aqueous solutions containing tromethamine, phosphate, ci~ra~e and/or bicarbonate ions, ionically balanced solutions containing physiologically acceptable anions and cations such as: Cl( ), HC03( ), Ca(2~), Na(+), K(+) and Mg(2~. Solutions of the contrast agents of this invention may also contain a small amount of a physiologically tolerable chelating agent, such as the sodium and calcium salts of EDTA, in concentrations from 0,05 to 2 mM/l, or even heparin, at a dosage ranging from 5 to 500 units per 100 ml of solution, vr another suitable anticoagulant agent.
~ypotonic solutions of the contrast media of this invention may be isotonically balanced by adding the correct amount of Merlis liquid (The Am. J. of Phy~
Vol. 131, 1940 p. 67-72). Useful concentrations of io-dine for such contrast media vary from 140 to 500 m~I/ml at a dosage of 10-300 ml, according to the desi~
red diagnostic use.
The following experimen~al examples show the basic principles of this invention.
EXA~PLE 1 1,3-bis-~3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihyclro-xy-isopropyl)-aminocarbonyl-2,4,6-triiodo-benzoyl~
no]-2-hydroxy propane.

WO92/08691 PCT/EP91/02l5~
~.`' .
2~6~3~

a) 124 g of 3-(L-2-acetoxy-propionyl)amino-5~ 3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo~
benzoyl-chloride (0.162 mol), obtained according to the procedure described in DE 2805928/Example 1, are solubilized in 490 ml of dimethylformamide (DMF). The resulting solution is cooled to 0-S~C~
added of 32.4 g of anhydrous tributylamine (0O175 mol) and then dropwise mixed under stirring with a solution of 7.66 g of 1,3-diamino-2-hydroxy-propane (0.085 mol) in 200 ml of D~iF. The reaction mixture is kept under stirring at 0-5C fcr 1 h, then is left at room temperature for about 20 ho Hence the solvent is evaporated under vacuum. The residue is crystallized with ethyl acetate. The crystalline precipitate is filtered and dried~
then suspendend in 500 ml of water at 50C. pR is adjusted at l0.3 with NaOH 2N and the mixture is stirred until the acetoxy groups of the propionyl residues are totally hydrolysed. The resulting solution is made free from salts by passage through ion exchange resins t360 ml of AmberliteR
IR 120 and 400 ml of DuoliteR A 30B). The eluate is evaporated to dryness and crystallized from 600 ml of ethyl alcohol. After filtration and drying 75.8 g of 1,3-bis-[3-(L-2-hydroxy-propionyl)amino~
5- ( 1, 3-dihydroxy-isopropyl )aminocarbonyl-2,4,6-triiodo-benzoyl-amlno~-2-hydroxy-propane are obtained.
Yield: ~4~ m.p.: 280C (dec.) Elemental Analysis (%) , -......... . ~: , .:
,......... . . .
:,: ;,, . ,. . , .. ~, , - ~: ;: . , i. . . , ., . :
:, .' ' :," : ' ' . , ::
.. ;: :.~

WO92/08691 PCT/EP91/02~5D
~;
2 0 ~

C H I N
Calculated: 25.47 2.48 52.08 5.76 Found: 25.47 2.35 52012 5O53 [~]20 = ~6.03 (c = 9-6% H2O) S Solubility in H2O at 20C : > 100% w/v.
TLC: (Silica Gel 60 F254, Merck) Eluent: CHC13/CH30H/NH40H 25% = 6/3/1 v/v/v. Rf = 0.14~
HPLC: Rt = 12.4 min. Titre = 98.5% (on the area) Chromatographic conditions:
10 Column: LICHROSORB RP 18 (Merck), 5 ~ (250 x 4 mm) Eluent: A) H2O B) CH3CN
Gradient (flow 1 ml/min; Detector UV 254 nm):
time (min) = 0 - 3; 3 - 25; 25 - 30 %B = 0; 0 - 40; 40 15 b) the above disclosed compound can be obtained also by reacting, according to the procedure of the previous Example la), 65.2 g of 3-(L-2-acetox~
propionyl)amino-5-(4,4-dimethyl-3,5-dioxa-cyclo-hexyl)aminocarbonyl-2,4,6-triiodo-benzoylchloride (0.081 mol); described in DE 2805928/Example lB(b), with 3.83 g of 1,3-diamino-2-hydroxy-propane (0.042 mol) in 350 ml of DMF in the presence of 16.2 g o tributylamine (0.087 mol).
The obtained product is transformed into 1,3-bis~
[3-(L-2-acetoxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-ami-no]-2-hy~roxy-propane by treatment with HCl 2N and corresponding elimination of acetone. This product i~ suspended in water at 50C, the pH is adjusted to 10.3 with ~aOH 2N and the basic treatment continues until the acetoxy groups are completely ., ~ , ,, . .
: . . :: . . : .

WO~2/0B691 PCT/EP9~/02~1 ~, ;:i .
17 ~ ~ 3 6~3 1~

hydrolysed. After elimination of the ionic species, due to the passage through ion exchange resins,. 41.4 g of 1,3-bis-[3--(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isop:ropyl)amino~
carbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane are obtained with a yield of 70%.
c) This reaction may also be performed in ethyl alcohol (EtOH) instead of DMF: 588 g of 3-(L-2--acetoxy-propionyl)-amino-S-(1,3-dihydroxy-isopro-pyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.67 mol) in 5.8 1 of EtOH are reacted at room temperature with 36.4 g of 1,3-diamino-2-hydroxy-propane (0.404 mol) dissolved in 2.9 1 of ~tOH, in the presence of 144 g of tributylamine (0.777 mol). The obtained precipitate is filtered, suspended in water and treated with NaOH 2N up to pH 10.3 as previously described in a). 350 g of 1,3-bis-[3-(L-2-hydroxy-propionyl)-amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane are obtained with a yield of 6~.2~.
EXAMPL~ 2 1,3-bis-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopro-pyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane.
a) 144 g of 3-ace~oxyacetylamino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride ~0.192 mol), described in DE
2805928/Example 10, dissolved in 600 ml of DMF, are dropwise added under stirring and between 5 to 10C to a solution of 13.4 g of 1,3-diamino 2,2-WO92/08691 PCT/EP9~02~5D
~ - . .
~ 18 bis-hydroxymethyl-propane (0.10 mol) and 39 g o tributylamine ~0.21 mol~ in 80 ml of D~F. The reaction mixture is kept under stirring for some hours at 10-20C. Hence it is poured under heavy stirring into 5.5 1 of ethyl acetate from which the final product crystallizes. After filtration and drying, 140 g of raw 1,3-bis [3-acetoxyacetyl-amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl~
2,4,6-triiodo-benzoyl-amino]-2,2-bis hydroxymethyl-propane are obtained.
A sample crystallized from methyl alcohol has the following characteristics:
m.p.: 284-287C ;~
Elemental Analysis (%) C H
Calculated: 26.91 2.58 48.74 5O37 Found: 26.82 2.70 48.45 5O37 b) 105 g of raw 1,3-bis-[3-acetoxyacetylamino-5~ 3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane are diluted in 1. 9 1 of water and 0.8 1 of methyl alcohol tCH3OH) and slowly mixed with 170 ml of ~:
~aOH lN until a constant pH value of 10.3 is o~tained. The mixture is kept under stirring for about 10 h at 20C. Then, the methyl alcohol is evaporated under vacuum. The resulting aqueous solution is made free from salts by passage through ion exchange resins (160 ml of AmberliteR
IR 120 and 150 ml of DuoliteR A 30B). The eluate is evaporated to dryness under vacuum, diluted again in 1.2 1 of water, bleached on active carbon . .: . , . .: , . ., " , - . .:: .
:. , , . :: .. . . . : ::. ... :

::. -:::: :~: .: ; : :. :

, " ~ . , ,., ', , . , . ' : ' , :

W092/08691 PCr/EP91/02151 19 2$~3~

and percolated on 1200 ml of AmberliteR XAD-2. The fractions containing the product are gathered and dried. 66 g of 1,3-bls-[3 hydroxyacetylamino-5 (1,3-dihydroxy-isopropyl~aminocarbonyl-2,4,6-tri- !
iodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane are obtained.
The last impurities are eliminated by dissolving the product in aqueous ethyl alcohol 80% and filtering the turbid solution.
Yield: 62% m.p.: 285C
~lemental Analysis ~%) C H I N
Calculated: 25.19 2.45 51.51 5.68 Found: 25.26 2.60 51.36 5.57 TLC: (Silica Gel 60 F254, Merck) Eluent: CHC13/CH30H/NH40H 25% = 3/2/1 v/v/v. Rf = 0.230 HPLC Rt - 9.6 min. Titre = 99% ~on the area) Chromatographic conditions:
Column: as reported in Example 1 Eluent: A) KH2PO4 0.01 M B) H20 75%, CH3CN 25%
Gradient (flow 1 ml/min; Detector UV 254 nm):
time (min) = 0 - 5; 5 - 15; 15 - 25 %B = 20; 20 - 80; 80 In the same way the following compounds are obtained:
- 1,3-bis-[3-hydroxyacetylamino-5-(2,3-dihydroxypro~
pyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane.
- 1,3-bis-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoylamino]-2,2-bis-hydroxymethyl-propane.

W092/OB691 PCT/EPgl/02~51 ~ 20 1,3-bis-l3-(L-2-hydroxy-propionyl)amino-5-(2,3-di hydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl~ .
amino]-2-hydroxy-propane.
197 g of 3-(L-2-acetoxy-propionyl)amino-5~(2~3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl~
chloride (0.25 mol), described in DE 2805928/Example 6, are reacted in 500 ml of DMF and in the presence o 55.6 g of tributyl.amine (0.30 mol) with 11.3 g of 1,3-diamino-2-hydroxy-propane ~0.125 mol) according to the procedure described in the Example 2a). The condensa-tion product is submitted to hydrolysis, as described in the Example 2b). Similarly, the isolation and the purification of the final product are performed.
94.2 g of 1,3-bis-~3-tL-2-hydroxy-propionyl)amino-5~
(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-ben~
zoyl-amino]-2-hydroxy-propane are obtained.
Yield: 50% m.p.: 278-.282C
Elemental Analysis (%) C H I N
Calculated: 25.47 2.48 52.09 5~75 Found: 25.21 2.53 51.89 5059 TLC: (Silica Gel 60 F254, Merck) Eluent: CHC13/CH30H/NH40H 25% = 6/3/1 v/v/v. Rf = 0~24, HPLC: Rt = 15.4 min. Titre = 99.4% (on the area~
Chromatographic conditionso Column: LICHROSPHERRRP18 (Merck), 5 ~ (250 x 4 mm) Eluent: A) H3P04 0.1 M B) H20 50%, CH3CN 50 ~
Gradient (flow 1 ml/min; Detector UV 254 nm):
time (min) = O - 5;5 - 20; 20 - 30; 30 - 35 hB = 10;10 - 28; 28 - 70; 70 ,.. . .
,; ! `,'. . " ', ; ~ , : , ,, " ' ` ' `"' '' i ' ''` "' " ' ' : ' ` .

WO92/OB69l PCT/EI91/02i5~ ¦
~ !
21 2Q3~

EXAMPL~ 4 1,3-bis [3-(L-2-hydroxy-propionyl)amino-5-(1,3,4-tri~ 3 hydro~y-2-butyl)zminocarbonyl-2,4,6-triiodo-benzoyl- ¦
amino]-2-hydroxy-propane~
24 g of 3-(L-2-acetoxy-propionyl)amino-5-(1,3~4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl~
chloride (0.03 mol), obtained by known methods descri--bed in DE 2805928, in 30 ml of DMF and in presence of 3.8 g of triethylamine (O.037 mol1 are reacted with ,a solution of 1.45 g of 1,3-diamino-2-hydroxy-propane (0.016 mol) in 30 ml of DMF at 5 to 8C, according to the procedure described in Example 3.
7.2 g of the title compound are obtained.
~ield: 30% m.p.: 250-256C
Elemental Analysis (~) C ~ I N
Calculated: 26.05 2.65 50.02 SO52 Found: 26~04 2.95 49.15 5~33 [~]20 = _5.01 (c = 10.13% H2O) Solubility in H20 at 20C: 100% w/v TLC: (Silica Gel 60 F254, Merck) Eluent: CHC13¦CH3OH/NH4OH 25% = 5/4/1 v/v/v- Rf = 00240 lH-and 13C-NMR spectra are in accordance with the proposed structure~
EXAMoeLE 5 1,3-bis-[3-(h-2-hydroxy-propionyl)amino-5-[N-methyl-N-(D-l-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-ben-zoyl-amino]-2-hydroxy-propane.
20.6 g of 3-(L-2-acetoxy-propionyl~amino-5-[N-me-thyl-N-(D-l-deoxy-glucitol)]aminocarbonyl-2,4,6-tri-iodo-benzoyl-chloride (0.024 mol), obtained by known -~ , ~.,: -. : . . , . ~.. .: : . :. ~

W092iO8691 PCT/EP9~dO~5~ ~
~"
2~ 22 methods described in DE 2805928, in 100 ml of DMF are reacted with a solution of 1.124 g of 1,3-diamino-2-hy~
droxy-propane (O.012 mol) and 2.53 g of triethylamine ~0~025 mol) in 30 ml of DMF, according to the procedure described in Example 3.
9.26 g of the title compound are obtained.
Yield: 47% m.p.: 266C (decO) El2mental Analysis (%) C H
Calculated: 28.04 3.14 45.58 5003 Found: 28.19 3.29 45.48 5.03 ~] 436 = -19 (c = 7.04% H20) 13C-NMR spectrum is in accordance with the proposed structure.
In the same way the following compounds are obtainedo - 1,3-bis-[3-tL-2-hydroxy-propionyl)amino-5- E N-me-~hyl-N-(1,3-dihydroxy-isopropyl)3aminocarbonyl 2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propaneO
- 1,3-bis-[3~(L-2-hydroxy-propionyl)amino-5-[N-me~
thyl-~-(2,3-dihydroxy-propyl)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
~XAMPLE 6 1,3-bis-[N-methyl-N-[3-(L-2-hydroxy-propionyl)amino-5-(2-hydroxy-ethyl)aminocarbonyl-2,4,6-triiodo-benzoyl]-amino]-2-hydroxy-propane.
20.85 g of 3-(L-2-acetoxy-propionyl)amino-5-(2-hy- ;;~
droxy~ethyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chlori-de (0.025 mol), obtained by known methods described in DE 2805928, in 80 ml of DMF are reacted with a solution of 1.47 g of 1,3-bis-(methylamino1-2-hydroxy-propane (0~012 mol) and 2.63 g of triethylamine (0.026 mol~ in W092iO8691 PCTtEP91/02~5D
.._ 23 2 ~

30 ml of DMF at 5C to room temperature, according to ~he procedure described in Example 3.
9.6 g of the title compound are obtained.
Yield: 56% m.p.: 285C (decO) 5 Elemental Analysis (%) C H
Calculated: 26.03 2.54 53.24 5088 Found: 25.86 2.43 52.81 5~78 ~X]20 _3.85 (c = 9.95% H20) lH-and 13C-NMR spectra are in accordance with the proposed structure.

1,3-bis-[N-methyl-N-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane.
21.4 g of 3-(L-2-acetoxy-propionyl)amino-5-(103~-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-ben-zoylchloride (0.025 mol), obtained by known methods described in DE 2805928, in 85 ml of DMF are reacted with a solution of 1.~7 g of 1,3 bis-(methylamino)-2-hydroxy-propane (00012 mol) and 2.63 g of triethylamine (0.026 mol~ in 30 ml of DMF at 5C to room temperature, according to the procedure described in Example 3.
11.1 g of ~he title compound are o~tained.
Yield: 62% m.p.: 295C (dec El~mental Analysis (%) C H I N
Calculated: 26.60 2.70 51 09 5.64 Found: 26.31 2.95 50.68 5.48 ~] 436 = -3.540 (c = 10-44% H20) Solubility in H20 at 22DC: > 100% w/v ,, ,, . : . .

WO 92/08691 PCI/EP91/02~5~

2 a ~ 24 '.
lH and 13C-NMR spectra are in accordance with the proposed structure.

l,3-bis-[N-methyl-N-[3-(L-2-hydroxy-propionyl)amino~5 5 (2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodoben-zoyl]aminoJ-2-hydroxy-propane.
Title compound is obtained by reacting the desired reagents in the same quantities disclosed in Example 7 and following the same procedure. 7.9 g of final com-pound are obtained.
Yield: 44% m.p.: 280~C (dec.) Elemental Analysis (%) C H I N
Calc.: 26.60 2.70 51.09 5.64 Found: 26.32 2.81 50.24 5.44 (H2O=1OS4~
[o~J2~36 = -3.2 (c= 9-8% H2O~ ;
Solubility in H20 at 20C: >100% w/v 13C-NMR spectrum is in accordance with the proposed structure.
~ XA~E?LE
1,3-bis-[N-methyl-N-[3-(L-2-hydroxy-propionyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo- ~`?
benzoyl]amino]-2-hydroxy-propane.
19.9 g of 3-(L-2-acetoxy-propionyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-be~zoyl~
chloride (0.025 mol), obtained by known methods dPscri-bed in DE 2805928, in 30 ml of DMF are mixed with 3.8 g of triethylamine (0.037 mol), then are reacted with a solution of 1.5 g of 1,3-bis-(methylarnino)-2-hydroxy-propane (O.013 mol) in 25 ml of DMF at 5 C to room temperature, according to the procedure described in - , . . , . ~ .:

, . : . ~ , -. . ., ' . , , , , , ... : :

WO92/08691 PCT/EP9l/02151 . .
, . .. .
2 0 9 ~

Example 3.
5.68 g of the title compound are obtained.
Yield: 29.5~ m.pO 256C
Elemental Analysis (%) C H I N
Calculated: 27.12 2.86 49~12 50~2 Found: 27.46 3.15 48.55 So24 [~]20 _3.16 (c = 9.93% H2O) lH-and 13C-NMR spectra are in accordance with the proposed structure.

1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxyiso propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino] 3-[3-hydroxyacetylamino-5-(2,3-dihydroxy-propyl)aminocarbo~
15 nyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
a) 125 g of 3-(L-2~acetoxy-propionyl)amino-5-(1,3~di~
hydroxy-isopropyl)aminocarbonyl-2,4,6-triiodoben~-zoyl-chloride (0.163 mol), diluted in 150 ml of DM~, are dropwise added, while keeping ~he temperature between 0 and 10C, to a solution of 45.6 g of 1-trifluoroacetylamino-2-hydroxy-3-ami-nopropane trifluoroacetate (0.152 mol) and 3508 g of triethylamine (0.35 mol) in 280 ml of DMF. The resulting mixture is stirred at 10C for 8 hG
~fter filtration, the solution is evaporated to dryness, then is diluted with 3 1 of methylene chloride (CH2C12). The condensation product preci-pitates, then, after filtration, the protective groups are removed by hydrolysis, according to the procedure described in Example 2b). The resulting product is purified by means of fixation on a ,, ,,;. :-, - ., ;; , - :.

` l ~

WO92/08691 PCT/EWl/0~15~ I
~' ''.
9 ~ 26 strongly acidic resin ~950 ml of AmberliteR XR
120) and subsequent elution with about 6 1 o~
NH40H 2M. After evaporation of the solvent, 76~5 g of l-[3-(L-2-hydroxy-propionyl)amillO- 5- ( 1, 3-dihy~-droxyisopropyl)aminocarbonyl-2,4,6-t:riiodo-ben-zoylamino]-2-hydroxy-3-amino-propane are obtained with a yield of 65%.
Acidimetric titre = 99.4~ m.p.: 211C
b) 73.5 g of 3-acetoxyacetylamino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chlori-de (0.098 mol) in 500 ml of DMF are slowly added dropwise, at a temperature between 5 and 10C, to a solution of 76 g of the product obtained at point a) (0.098 mol) and 11.1 g of triethylamine (0.11 mol) in 500 ml of DMF. The mixture is kep~
under stirring for 20 hl then filtered and driedO
The residue is dissolved in 1.9 1 of water and 0~8 1 of methyl alcohol, then it is submitted to hydrolysis and purification according to the procedure described in Example 2b). 92 g of 1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-iso-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3-~3-hydroxyacetylamino-5-(2,3-dihydroxypropyl)~
aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hy-droxypropane are obtainedO
Yield: 64.8% m.p.: 300C
Elemental Analysis (%) C H I N
Calculated: 24.88 2.37 52.58 5.80 Found: 24.70 2.29 52.15 5.74 [~]2~36 = -2.9 (c = 10% ~I~O) .... .
r ,',: . ; ; ` ' : `' WO92/08691 PCT/EP9lJ021~D
!,'"`~
27 2~

TLC: (Silica Gel 60 F254, Merck) Eluent: CHC13/CH30H/NH40H 25% = 6/3/1 v/v/v- Rf = 00180 HPLC: Rt - 13.6 min. Titre = 97.5% (on the a~ea) Chromatographic conditions:
Column: as reported in Example 1 Eluents: A) K2P04 0.01 M B) KH2P04 0.01M 50%, CH3CN 50 Gradient (flow 1 ml/min; Detector UV 254 nm):
time (min) = 0 - 6; 6 - 25; 25 - 30 %B = 2; 2 - 80; 80 1-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-butyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)ami-nocarbonyl-2,4,6-triiodo-ben2Oyl-amino]-2-hydroxypropa-ne.
Title compound is obtained following the procedure described in Example 10.
So 8.58 g of 3-acetoxyacetylamino-5-tl,3,4-trihy-droxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl~chlo~
ride (0.011 mol) in 60 ml of DMF are reacted with a so-lution of 8.54 g 1-[3-(L-2-hydroxy-propionyl)amino~5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-ben~oyl-amino]-2-hydroxy-3-amino-propane (0.011 mol), obtained according to Example 10 a)~ and 2.22 g of triethylamine (0.022 mol) in 50 ml of DMF to give the de~ired compound.
8.75 g of the title compound are obtained.
Yield: 51% m.p.: 283~C (dec.) ~lemental Analysis (%) C H I N
CalcO: 25.19 2.45 51.51 5.68 .. : . . :: . .

, ~ , :: .. . .: : , . :
. ~, : :, .,: ... , , . :. ..
.~ ~ .. .
, .: : : ~

r~
2~ 3~ 28 Found: 24.13 2.72 48.88 5.32 (H2O = 2071%) [~]2436 = -2.6 (c = 10.44% H2O) Solubility in H20 at 25DC: >100% w/v 13C-NMR spectrum is in accordance with the proposed structure.

1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxyiso-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3-[3-(L-2-hydroxy-propionyl)amino-5-(2,3-dihydroxypropyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
Following the procedure described in Example 10, 8.75 g of 3-(L-2-acetoxy-propion~l)amino-5-(2,3-dihy-droxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chlo-ride (0.01 mol) in 60 ml of D~F are reacted with a so~
lution of 7.76 g 1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydro~y-3-amino-propane (0.01 mol), obtained according to Example 10 a)j and 2.02 g of triethylamine (0.02 mol) in 60 ml of DMF to give the desired compound. 8.15 g of the title compound are ob~-taine~.
Yield: 55% m.p.: 287C (dec.) Elemental Analysis (%) C H I N
Calculated: 25.46 2.48 52.08 5O75 Found: 25.49 2.34 51.67 5.73 [&~ 436 = -5.67 (c = 10.01% H20) Solubility in H20 at 20C: >100% w/v 3C-NMR spectrum is in accordance with the proposed struc~ure.

.
. . , -- . . . ~:
, :, , : .. , . . :. ., : .. : , :

WO 92/08691 PCI`/EP9~1/02151 . --. .
! ;
29 2~

1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxyiso~
propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3~3-(L-2-hydroxy-propionyl)amino-5-[N-methyl-N-(D-l-deoxy~
S glucitol)]aminocarbonyl~2,4,6-triiodo-benzoyl-amino~-2 hydroxy-propane.
Following the procedure described in Example 10, 6.9 g of 3-(L-2-acetoxy-propionyl)-5-[N-methyl-N-(D 1-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.008 mol) in 50 ml of DMF are reacted with a solution of 6.13 g 1-[(L-2-hydroxy-propionyl)-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-ben-zoyl-æmino]-2-hydroxy-3-amino-propane (0.008 mol), ob-tained according to E:xample 10 a), and 1.6 g of 15 triethylamine (0.016 mol) in 50 ml of DMF to give the desired compound.

4.2 g of the title compound are obtained.
Yield: 34% m.p.: 285C (deeO 3 Elemental Analysis (%) C H I N
Calculated: 26O84 2.83 48.62 5O37 Found: 27.29 2.92 48.62 5022 [o~]20 = -11.9 (c =5.0% H20) Solubility in H20 at 20C: >100,~ w/v 25 13C-NMR spectrum is in accordance with the proposed structure.

1,3-bis-~3-hydroxyacetylamino-5-(1,3-dihydroxy-isopro-pyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-30 hydroxy-propane.
llZ.5 g of 3-acetoxyacetylar~ino-5-(1,3-dihydroxy-;.: . ,: . , , ;:
: . . . :
~,: . : :

W092~08691 PCT/EPg1/0~5~
~ ,. ~.,, 2 0 ~ a ~ 3 ~ 30 isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.15 mol), described in DE 2805928/Example 10, in 400 ml of DMF are reacted with 16.7 g of triethylamine (0.165 mol) and with 7.13 g of 1,3-diamino-2-hydroxy~
propane (0.075 mol), according to the procedure descri-bed in Exam?le 2.
63 g of 1,3-bis-~3~hydroxyacetylamino-5-(1,3-dihy-droxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy propane are obtained.
Yield: 56% m.p.: > 280C ;~
Elemental Analysis (%) C H I N
Calculated: 24.49 2.25 53.10 5086 Found: 24.19 2.28 53.26 5083 TLC: (Silica Gel 60 F254, Merck) Eluent: CHC13/C~30H/NH40H 25% = 3/2/1 v/v. Rf = 0060o HPLC: Rt - 7.1 min. Titre = 99% (on the area) Chromatographic conditions: as reported in Example 20 1,3-bis-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-bu-tyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydro-xy-propane.
23.4 g of 3-acetoxyacetylamino-5-(1,3,4-trihydro-xy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.03 mol), obtained by known methods described in DE
2805928, in 25 ml of DMF are re~cted with 3.8 g of triethylamine (0.037 mol) and with 1.45 g of 1,3-dia-mino-2-hydroxy-propane (0.016 mol~, according to the procedure described in Example 2.
4.7 g of the title compound are obtained.
Yield: 21% m.p~: 275C

, . , . : , ~

WO92/08691 PCT/EP91/02~51 r, . .
t ~
31 2~ 3~

Elemental Analysis (%) C H ]:
Calculated:. 24.92 2.43 50~96 5O62 Found: 24.g3 2.50 49~,98 5~53 Solubility in H20 at 20C: 100% w/v In the same way the following compounds are obtainedn - 1,3-bis-[3-hydroxyacetylamino-5-(2,3-dihydroxypro--pyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino~2 hydroxy-propane.
- 1,3-bis-[3-hydroxyacetylamino-5-~N-methyl-N~ 3-dihydroxy-isopropyl)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-hydroxyacetylamino-5-[N-methyl-N-(2,3- .`
dihydroxy-propyl)~aminocarbonyl-2~4~6-triiodo-ben-zoyl-amino]-2-hydroxy-propane.

1,3-bis-~N-methyl-N-[3-hydroxyacetylamino-5-(1,3j4~tr.i~
hydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl~
amino]-2~hydroxy-propane.
23.4 g of 3-acetoxyacetylamino-5-(1,3,4-trihydro-xy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.03 mol), in 25 ml of DMF are reacted with 3.8 g o triethyl~mine (0.037 mol) and with l.9 g of 1,3-bis-(methylamino)-2-hydroxy-propane (0.016 mol), according to the procedure described in Example 2 7 g of the title compound are obtained.
Yield: 30% mOp. 263C
Elemental Analysis (%) C H I N
Calculated: 26.042.65 50.02 S~52 Found: 26~1~ 2.69 50.86 S.57 ~ . ., .', ; ' ~ " :

WO92/08691 PCT/EP91/02l51 29~3~ 32 Solubility in H20 at 20C: 100% w/v EXAMPL~ 17 1,3-bis-[N-methyl-N-[3-hydroxyacetylamino-5-[N-methyl-N-(D-l-deoxy-glucitol)]aminocarbonyl-2,4,6~triiodo~
benzoyl]amino]-2-hydroxy-propane.
24 g of 3-acetoxyacetylamino-5-[N-methyl-N~(D~
deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.028 mol), obtained by known methods descri bed in DE 2805928, in 100 ml of DMF are reacted with a 10 solution of 1.65 g of 1,3-bis-(methylamino)-2-hydroxy-propane (0.014 mol) and 2.93 g of triethylamine (0~029 mol) in 30 ml of DMF, according to the procedure de-scribed in Example 2.
10.14 g of the title compound are ob~ained.
15 Yield: 41~ m.p.: 276~C (decO) Elemental Analysis (~) C H
Calculated: 28.04 3.14 45.58 5O03 Found: 27.95 3.21 45.48 4O97 20 ~20 = -12.6 (c = 10.6% H2O) Solubility in H20 at 25~C: >100~ w/v 13C-NMR spectxum is in accordance with the propo~ed structure.
In the same way the following compounds are obtained 25 _ 1,3-bis-~N-methyl-N-[3-hydroxyacetylamino-5~ 3 dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo~
benzoyl~amino]-2-hydroxypropane.
- 1,3-bis-~N-methyl-N-[3-hydroxyacetylamino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-ben-zoyl]amino]-2-hydroxy-propane.

'' ~ :

WO92/08691 PCT/~P9~0~2~

33 209~3~

~XAMPLE 18 1,3-bis-[N-methyl-N-[3-hydroxyaCetylamino-5-[N-methyl~
N-(1,3-dihydroxy-isopropyl)]aminocarbonyl-2,4,6-triio~
do-benzoyl]amino]-2-hydroxy-propane.
21.31 g of 3-acetoxyacetylamino-5-[N-methyl-N~
(1,3-dihydroxy-isopropyl)]aminocarbonyl-2,4,6-triiodo~
benzoyl-chloride (0.025 mol), obtained by known methods described in DE 2805928, in 95 ml o~ DMF are reacted with a solution of 1.47 g of 1,3-bis-(methylamino)-2~
hydroxy-propane (0.12 mol) and 2.63 g of triethylamine (0.026 mol) in 30 ml of DMF, according to the procedure described in Example 2.
8.1 g of the title compound are obtained.
Yield: ~5% m.pO: 290C
Elemental ~nalysis (%) C H I N
Calc.: 26~98 2.86 50.33 5.55 Found: 26.29 3.01 50.21 5.24(H2O = 1~02~3 Solubility in H20 at 25C: 100% w/v 13C-NMR spectrum is in accordance with the proposed structure.

1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(1,3-dihy-droxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
a) 46 g of 3-(N-methyl-N-acetoxyacetyl)amino-2,4,6 triiodo-isophthaloyl-dichloride (0.065 mol), de scribed in EP 26281/Example 11, in 250 ml of anhydrous tetrahydro'uran (THF) are added dropwise to 12.6 g of 1,3-dihydroxy-isopropylamine (0.138 mol ) in 100 ml of THF. The mixture is kept for 3 h , , ,. , ~ .... . . . . , , ~ .
, . . . ,,, ~ , WO9~/0869] PCT/EP9t/0215D
x~ , :
~;,, ~ Q ~ 34 at room temperature under stirring. Then it is filtered and evaporated to dryness under vac-uumO
The residue is constituted by 50,4 g of 3-(N~
methyl-N-acetoxyacetyl)amino-5-(1,3-dihydroxy-iso-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chlori~
de.
b) 50 g of 3-(N-methyl-N-acetoxyacetyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo~
benzoyl-chloride (about 0.065 mol), obtained accordi~g to a), diluted in 200 ml of DMF, are reacted with 3 g of 1,3-diamino-2-hydroxy-propane (0.034 mol) in 100 ml of DMF, according to the procedure described in Example 1.
21 g of 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)ami~
no-5-(1,3 dihydroxy-isopropyl)aminocarbonyl-2,4,6-tri-iodo-benzoyl-amino]-2-hydroxy-propane are obtainedO
Yield: 44.2% m.p.~ ~ 250~C
Elemental Analysis ~%) C H
Calculated: 25.47 2.48 52.08 5u75 Found: 25.82 2.60 52.37 5o62 TLC: (Silica Gel 60 F254, Merck) Eluent: CHC13/CH30H/NH40H 25% = 6/3/1 v/v/v. Rf = 0.23 HPLC: Rt = 14.6 min. Titre = 96.7% (on the area) Chromatographic conditions: as reported in Example 2O
c) This product may be also obtain d by N-methylation of the compound already described in Example 14.
14.3 g of 1,3-bis-[3-hydroxyacetylamino-5-(1,3-di-hydroxy-isopropyl)aminocarbonyl;~2,4,6-triiodo-ben-~oyl-amino]-2-hydroxy-propane (0.01 mol) in 500 ml of anhydrous DMF 2re mixed under stirring with a : .
.. . ~ .'': .

W092/0869t PCTtEP91/0215~

2 0 ~ ~ A ~ O

solution of 1.08 g of sodium methylate (0.02 mol) in 30 ml of methyl alcohol. After 3 h, methyl alcohol is removed by distillation. An excess o methyl iodide is added and the solution is stirred for one day at room temperature. Then the reaction mixture is poured under stirring in 600 ml of ethyl acetate and the raw product precipitatesO
This one is filtered, diluted in water and made free from salts by passage through ion exchange resins (Amberlite IR 120 and IRA 400). The eluate is tréa,ed with active carbon and evaporated to dryness.
7 g of 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane are obtained with a yield of 47.9%. This compound is identical to the one obtained through ~rocess b).
In the same way the following compound is obtai~
ned:
20 - 1,3-bis-[3-~N-methyl-N-(L-2-hydroxy-propionyl)]-amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.

1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
80.4 g of 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane ~0.055 mol), described in Example 1, are dissolved in 900 ml of DMF and mixed under stirring with 132 ml of sodium methylate 1 M in 209~ 3'o methyl alcohol (0.132 mol). Methyl alcohol is removed by distillation. Hence, 23.7 g of dimethylsulphate (0.188 mol)iare dropwise added at a temperature of 5Co Stirring is maintained for about 1 h, then the solvent is removed by vacuum distillation. The raw material is diluted with ethyl acetate and forms a solid powder~
which is filtered, diluted in water and made free from salts bv percolation on ion exchange resins (AmberliteR
IR 120 and Duolite~ A 30B). ~rhe solution is evaporated to dryness and then dissolved in boiling ethyl alcoholO
After some days, 62 g cf 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]amino-5-(1,3-dihydroxy-isopropyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane crystallize.
Yield: 75.6% m.p.: > 300C (dec Elemental Analysis (%) C H I N
Calculated: 26.60 2.70 51.10 5o64 Found: 26.58 2.75 50.95 5.60 ] 436 = +29-7 (c = 10% H20) TLC: (Silica Gel 60 F254, Merck) Eluent: CHC13/CH30H/NH40H 25% = 6/3/1 v/v/v. Rf = 0.16.
~XaMPLE 21 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodoben-zoyl-amino]-2-hydroxy-propane.
In 250 ml of DMF, 102 g of the product described in Example 3 (0.07 mol) are reacted with 150 ml of so-dium methylate lM in methyl alcohol (0~15 mol) and with 30 g of metansulphonate methyl ester (0.27 mol), accor-ding to the procedure described in Example 20.

.:. ,, ~, ., " : , .: ,:. :

.: . :, , , , , . , : ,,.

W092/08691 PCT/EP91/0215~
, . .
I;, ,, ' 37 2~

42~6 g of l,3-bis-[3-[N-methyl-N-(L-2-hydroxy-pro-pionyl)]amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane are ob~
tained.
Yield: 41% m.p.: 284C
Elemental Analysis (%) C H I N
Calculated: 26.50 2.70 5l.lO 5064 Found: 26.24 2.80 50.88 5.47 EXAMPL~ 22 ~
1,3-bis-[3-tN-methyl-N-hydroxyacetyl)amino-5-(2 ,3-dihy ~ ~ .
droxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-ami-no]-2-hydroxy-propane.
23 g of 3-(N-methyl-N-acetoxyacetyl)amino-2,4,6-triiodo-isophthaloyl-dichloride (0.032 mol), described in EP 2628l!Example ll, are reacted with 5.8 g of 2,3-dihydroxy-propylamine (0.064 mol) in THF according to the procedure descxibed in Example l9a). The resulting product is 3-(N-methyl-N-acetoxyacetyl)amino-5-(2,3-di~
hydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride, which is reacted in DMF with 1.5 g of l,3-diamino-2-hydroxy-propane tO.016 mol). The resulting product is isolated and purified according to the pro-cedure of Example l. ll g of 1,3-bis-[3-(N-methyl-N-hy-droxyacetyl)amino-5-(2,3-dihydroxy-propyl)aminocarbo-nyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane are obtained.
Yield: 47% m.p.: 295C (dec.) Elemental Analysis (%) C H I N
Calculated: 25.47 2.~8 52.08 5 75 ~o~3$ 38 ;

Found: 25.97 2.50 51 71 5077 In the same wa~ the following compound is obtained~
- 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(1,3,4-trihydroxy-2-butyl)]a~inocarbonyl-2,4,6 triiodo-benzoyl-amino]-2-hydroxy-propane~
EXAMPL~ 23 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydro-xyisopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-aminoJ
2,2-bis-hydroxymethyl-propane.
Following the procedure described in Example 2, the 3-(L-2-acetoxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride is reacted in DMF with 1,3-diamino-2,2-bis-hydroxyme thyl-propane to give the desired product.
Yield: 65% m.p.: 285DC (dec Elemental Analysis (%) C H I N
Calculated: 26.32 2.68 50.55 5058 Found: 26.21 2.72 50.31 5053 TLC: (Silica Gel 60 F2S4, Merck) Eluent: CHC13/CH30H/NH40~ 25% = 6/3/1 v/v/v. Rf = Onl2 HPLC: Rt = 17.7 min. Titre = 98% (on the area) Chromatographic conditions: as reported in Example 3.
EXA~P~E 24 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-~N-methyl-N~
(D-l-deoxy-glucitol)~aminocarbonyl-2,4,6-triiodo-ben-zoyl-amino]-2,2-bis-hydroxymethyl-propane.
Following the procedure described in ~xampl~ 2, 10 g of 3-(L-2-acetoxy-propionyl)amino-5-[N-methyl-N-(D-l-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.011 mol) in 50 ml of D~5F are reacted wi~h .. . . , . .. :

WO92/08691 PCT/EP91~02~5D
~' .' 39 ~ 3~

1.19 g of 1,3-diamino-2,2-bis-hydroxymethyl-propane (0.006 mol) and 4.94 g of tributylamine (0.027 mol~ in 20 ml o DMF.
11.5 g of the title compound are obtained,.
Yield: 58%
Elemental Analysis (%) C H I N
Calculated: 28.72 3.29 44.41 4 90 Found: 28.60 3.33 44.37 4085 13C-NMR spectrum is in accordance wlth the proposed structure.
In the same way the following compounds are obtainedo - 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(2,3~dl-hydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzo~
yl-amino]-2,2-bis-hydroxymethyl-propane.
- 1,3-bis[3-(L-2-hydroxy-propionyl1amino-5-(1,3,4 trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo~
benzoyl-amino]-2,2-~is-hydroxymethyl-propaneO

1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)Jamino 5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane.
The product described in Example 23 is submitted to N-methylation with sodium methylate and CH3I foI
lowing the procedure of Example l9c).
Yield: 65.5~ m.p.: > 300C
Elemental Analysis (%) C H I N
Calculated: 27.40 2.89 49.63 5.48 Found: 27.38 2.91 49.47 5.45 436 +26.7 (c - 10% H2O) ", , "" " , , ,, ~ ~ " : ~,, ", ,.,, , " ", W092/08691 PCT/EP9~/02~5~ ~

3~ 40 In the same way the following compounds are o~tainedD
- 1,3-bis-[3-~N-methyl-N-(L-2-hydroxy-E)ropionyl)3 amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2~4~6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-pro-pane.
- 1,3-bis-[3-~N-methyl-N-~L-2~hydroxy-propionyl)~-amino-5-(1,3,4-trihydroxy-propyl)aminocarbonyl 2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxyme-thyl-propane.

1,3-bis-[N-methyl-N-[3-[N-methyl-N-(L-2-hydroxy-propio-nyl)]amino-5-(2-hydroxy-ethyl)aminocarbonyl-2,4,6-tri-iodo-benzoyl]amino]-2-hydroxy-propane.
The product described in Example 6 is submitted ko N-methylation with sodium methylate and CH3I following the procedure of Example 19 c).
Yield: 58% mOpoo 28~e Elemental ~nalysis (%) C H I N
Calculated: 27.18 2.76 52.22 5076 Found: 27025 2.77 52.14 5D9 3C NMR spectrum is in accordance with the proposed structure.
EX~KPLE 27 1,3-bis-[N-methyl-N-[3-[N-methyl-N-(L-2-hydroxy-propio~
nyl)]amino-5-tl,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl3amino]-2-hydroxy-propane.
The product described in Example 7 is submitted to N-methylation with sodium methylate and CH3I following the procedure of Example 19 c).
Yield: 5~% m.p.: 285C (dec.) W092~08691 PCT/EPgl/02l~8 ~l 2~9~13~

Elemental Analysis ~%) C H I N
Calc.: 27.69 2.92 50.15 5.53 Found: 25.25 3.23 48.7~ 5.27 (~20 = 207%) Solubility in H20 at 20C: 100% w/v 13C-NMR spectrum is in accordance with the proposed structure.

1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(1,3-dihy~
droxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane.
The product described in Example 2 is reacted with 2 equivalent of NaOH, hence with an excess of CH3Br in DMF for one day under stirring in a sealed system. The subsequent work follows the procedure described in ~xample 19 c).
Yield: 54% m.p~: > 285-288C
Elemental Analysis (%) C H I N
Calculated: 26.32 2.68 50.55 5.53 Found: 25.90 2.80 50.12 5.53 TLC: (Silica Gel 60 F254, Merck) Eluent: CHC13/CH30H/NH40H 25% = 3/2/1 v/v/v. Rf = 0.26 HPLC: Rt = 15.5 min. Titre = 97.7% (on the area) Chromatographic conditions: as reported in Example 2 In the same way the following compounds are obtainedo - 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(2,3-dihydroxy-propyl)aminocarbonyI 2,4,6-triiodo-ben-zoyl-amino3-2,2-bis-hydroxymethyl-propane.
~ 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-,: . ; . .,. ~ . ;~,, ., ,. ., ,.. ,.. , . , - , . . , .: .

.

WO92/08691 PCT/EF91/OZ~SI

2 ~ 3 triiodo-benzoyl-amino~-2,2-bis-hydroxymethylp~o~
pane.

:: : , .. .. : . ,.; . .. .. : .: .. :. , ~ .

WO92/08691 PCTtEP91/0215n .,.~ . . .
. . . ~
2 ~ 3 :3 ~

Table 1 - Acute toxicity of an aqueous solution of 1,3- ' ~
__ !
bis[3-(L-2-hydroxy-propionyl)amino-5-~1,3-dihydro~
xyisopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl~
amino]-2-hydroxy-propane.

Toxici~yDoses ConcentTation ¦ Administered I DeadlTreated LDSo mgl/kg mgVml Volume Ra~o C.L. 95~G
mV3;g ~
900 300 30.0 ~ 0/10 .
a) 1 1600 300 38.7 0/10 ~15000 15000 _ 300 50.0 0/10 _ b) 900 300 _~3.0 l0/10 _ > 900_ a): Intravenous administration (14 days of observation) in mice.
b): Intracisternal administration (7 days of observa~
tion) in rats.

Table 2 - Comparison among some preferred compounds of the inven~ion and IODIXANOL.

Compound Osmolality Viscoslty 37C. 300 mgI/ml37C. 300 mgUml mosmlkg H20 mPa-s . .
A _ _14l _ 85 A:1,3-bis-[3-(L-2-hydroxy-propionyl~amino-5-(1,3-di-hydroxy-isopropyl)aminocarbonyl-2,4,6~triiodoben-zoyl-amino]-2-hydroxy-propane.
B:1-[3-~L-2-hydroxy-propionyl)amino-5-(1,3-dihydro-xyisopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl- ;~

. . :..... ,. . .. . :................. ~

:: ~ . :- : : : : :, :: ~ " ;.,.,: :, : :, : , :

W092/08691 PCT/EP91/0215a ~ ~. .
2~6~ 4 amino]-3-[3-hydroxyacetylamino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-aminGJ-2-hydroxy-propane.
C: 1,3-bis-[N-[3,5-bis-(2,3-dihydroxy-propyl)amino~
S carbonyl-2,4,6-triiodo-phenyl]-acetylamino]-2-hy-droxy-propane [IODIXAN01: EP 108638, Example 3J

i

Claims (8)

1. Symmetrical and asymmetrical 1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or poly-hydroxyalkyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propanes of general formula (I) (I).

wherein:
R, R', which are the same or different, are a straight or branched mono- or poly-hydroxyalkyl C1-C3 re-sidue containing from 1 to 2 OH groups, R1, R2, R3, which are the same or different, are H or CH3, R1', R2', R3', which are the same or different, are H
or CH3 Alxyl(OH)1-5 is one of the groups of formula -CH(CH2OH)CH(OH)CH2OH, -CH(CH2OH)2, -CH2CH(OH)-CH2OH, -CH2(CHOH)4CH2OH, or -CH2CH2OH, X is one of the groups -CH(OH)-, -CH(CH2OH)-, -C(OH)(CH2OH)- or -C(CH2OH)2-, A and B, may be the same or different, possible enan-tiomers, diastereoisomers and/or rotamers thereof.

2. Compounds according to claim 1, where R2, R2', R3, R3' represent hydrogen and the two residues A and B are equal.

3. Compounds according to claim 1, where R1, R1',R2, R2', R3, R3', represent hydrogen and the two residues A
and B are equal.

4. Compounds according to claim 1, where R2, R2', R3, R3' represent hydrogen, Alkyl(OH)1- 5 represents the groups 1,3-dihydroxy-isopropyl or 2,3-dihydroxy-propyl, X represents the group -CH(OH)- and the two residues and B are equal.

5. A compound according to claims 1-4, selected in the group constituted by:
- 1,3-bis-[3-(2-hydroxy-propionyl)amino-5-(1,3-di-hydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane.
- 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-ben-zoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydro-xy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3-[3-hydroxyacetylamino-5-t2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-hydroxyacetylamino-5-(2,3 dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis hydroxymethyl-propane.
1,3-bis-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane.
- 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-me-thyl-N-(1,3-dihydroxy-isopropyl)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-me-thyl-N-(2,3-dihydroxy-propyl)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[N-methyl-N-[3-(L-2 hydroxy-propionyl)-amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane.
- 1,3-bis-[N-methyl-N-[3-(L-2-hydroxy-propionyl)-amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6 triiodo-benzoyl]amino]-2-hydroxy-propane.
- 1,3-bis-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-hydroxyacetylamino-5 (2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-hydroxyacetylamino-S-[N-methyl-N-(1,3-dihydroxy-isopropyl)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-hydroxyacetylamino-5-[N-methyl-N-(2,3-dihydroxy-propyl)]aminocarbonyl-2,4,6-triiodoben-zoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[N-methyl-N-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane.
1,3-bis-[N-methyl-N-[3-hydroxyacetylamino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodoben-zoyl]amino]-2-hydroxy-propane.
- 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]-amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]-amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]-amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6 triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(2,3-dihydroxy-propyl3aminocarbonyl-2,4,6-triiodo-ben-zoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-(N-methyl-N hydroxyacetyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-aminol-2-hydroxy-propane.
- 1, 3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane.
- 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-ben-zoyl-amino]-2,2-bis-hydroxymethyl-propane.

- 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane.
- 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]-amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxy-methyl-propane.
- 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]-amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-pro-pane.
- 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]-amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxyme-thyl-propane.
- 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(1,3 dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane.
- 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-ben-zoyl-amino]-2,2-bis-hydroxymethyl-propane.
- 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane.
- 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-methyl-N-(D-1-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-me-thyl-N-(D-1-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-pro-pane.
- 1-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-bu-tyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiocio-benzoyl-amino]-2-hydroxy-propane.
- 1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydro-xy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3-[3-(L-2-hydroxy-propionyl)amino-5-(2,3 dihydroxy-propyl)aminocarbonyl-2,4,6-triiodoben-zoyl-amino]-2-hydroxy-propane.
- 1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydro-xy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3-[3-(L-2-hydroxy-propionyl)amino-5-[N-me-thyl-N-(D-1-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane.
- 1,3-bis-[N-methyl-N-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane.
- 1,3-bis-[N-methyl-N-[3-hydroxyacetylamino-5-[N-methyl-N-(1,3-dihydroxy-isopropyl)]aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane.
- 1,3-bis-[N-methyl-N-[3-hydroxyacetylamino-5-[N-methyl-N-(D-1-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane.
- 1,3-bis-[N-methyl-N-[3-(L-2-hydroxy-propionyl)-amino-5-(2-hydroxy-ethyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane.
- 1,3-bis-[N-methyl-N-[3-(L-2-hydroxy-propionyl)-amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane.

- 1,3-bis-[N-methyl-N-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]amino-5-(2-hydroxy-ethyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane.
- 1,3-bis-[N-methyl-N-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]amino-5-(1,3-dihydroxy-ispropyl)ami-nocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane.

6. Process for the preparation of the 1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or poly-hydroxyalkyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propane of general for-mula (I), characterized in that a 1,3-diamino-hydroxy-or hydroxyalkyl-propane of general formula (II) R3-HN-CH2-X-CH2-NH-R3' (II) wherein R3 and R3' are H ox CH3, X represents the groups -CH(OH)-, -CH(CH2OH)-, -C(OH)(CH2OH)- or -C(CH2OH)2- and one of the amino groups may be protec-ted by a suitable protective group, is reacted, direc-tly or by a multi-step process, with a reactive deriva-tive of a 3-(mono- or poly-acyloxy)acylamino-5-(mono-or poly-hydroxyalkyl)aminocarbonyl-2,4,6-triiodobenzoic acid of general formula (III) (III).

wherein:
R1, R2 represent H or CH3, R4 is a straight or branched mono- or poly-acy-loxyalkyl C1-C13 residue containing from 3 to 13 atoms of C and from 1 to 2 lower acyloxy groups C2-C5, Alkyl(OH)1-5 is one of the groups of formula -CH2(CHOH)4CH2OH, -CH2CH(OH)CH2OH, -CH(CH2OH)CH-(OH)CH2OH, -CH2CH2OH, -CH(CH2OH)2, or in which the hydroxy groups may be protected preferably by acetalic or ketalic groups, CO-Y is the residue of a mixed anhydride or, pre-ferably, a halogenocarbonyl group, to give the product of general formula (IV) (IV).

wherein R1, R2, R3, R1', R2', R3', R4, Alkyl(OH)1-5 and X have the previously described meaning and R5 may be R
or R4, according to one of the following procedures:
a) a compound of general formula (II) is reacted with a compound of general formula (III) in a molar ra-tio of 1:2 in a solvent and in the presence of a basic condensation agent to directly obtain a compound of formula (IV) where R5 corresponds to R4, b) a compound of formula (II), in which one of the two amino groups is protected by a suitable protective group, is reacted with a compound of formula (III) in a molar ratio of 1:1 in a solvent and in the presence of a basic condensation agent to obtain, after hydrolysis of the protective groups, the corresponding 1-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or poly-hydroxyalkyl)-aminocarbonyl-2,4,6-triiiodo-benzoyl-amino]-3-amino-hydroxyalkyl derivative of formula (V) (V) .

wherein R, R1, R2, R3, R3', Alkyl(OH)1-5 and X have been previously defined, and this compound (V) is subsequently reacted with a derivative of formula (III) in the presence of a basic condensation agent to obtain the desired compound (IV) where R5 corresponds to R, then, the compound (IV) obtained through one of the synthetic methods a) or b) is transformed, by hy-drolysis of the protective groups, into the correspon-ding compound of formula (I) and this last one, if the two R1 and R1' are H, may be, if desired, N-methylated in an alkaline medium.

7. Process for the preparation of compounds of general formula (I), where R1 and R1' are CH3, charac-terized in that a compound of general formula (I), in which R1 and R1' are hydrogen, is methylated in an alkaline solution by means of treatment with methyl halide, dimethylsulphate, methylsulphonate, dimethyl-carbonate.

8. Non-ionic X-ray contrast agents containing as an opacifying component at least one 1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or poly-hy droxyalkyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy or hydroxyalkyl-propane according to claims 1 to 5.