Poly-iodinated compounds, process for their preparation, contrast medium containing them

The invention relates to novel poly-iodinated compounds of general formula: ##STR1## in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10, identical or different, are selected from an iodine atom, a group of formula ##STR2## provided that at least two of the R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 groups represent an iodine atom, utilizable in contrast media for radiography. The invention also relates to a process for the preparation of these compounds as well as a contrast medium containing them.

This application is a 371 of PCT/Fr 92/00172 filed Feb. 25, 1992. 
The present invention relates to novel poly-iodinated compounds utilizable 
in contrast media for radiography. 
The invention also relates to a process for the preparation of these 
compounds as well as the contrast media containing them. 
The invention thus relates to poly-iodinated compounds of formula: 
##STR3## 
in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, 
R.sub.8, R.sub.9, and R.sub.10, identical or different, are selected from 
an iodine atom, a group of formula 
##STR4## 
in which R.sub.11 and R.sub.12, identical or different, represent a 
hydrogen atom, a linear or branched C.sub.1 -C.sub.6 alkyl group, a linear 
or branched C.sub.1 -C.sub.6 hydroxy- or polyhydroxy-alkyl group, bearing 
optionally in addition one or more C.sub.1 -C.sub.6 alkoxy groups, in 
particular methoxy or ethoxy, a linear or branched C.sub.1 -C.sub.6 alkoxy 
- C.sub.1 -C.sub.6 -alkyl group or a linear or branched C.sub.1 -C.sub.6 
hydroxy- or polyhydroxy-alkoxy --C.sub.1 -C.sub.6 -alkyl group bearing two 
to five --OH groups, a group of formula 
##STR5## 
wherein R.sub.11 and R.sub.12 identical or different are as defined 
previously or represent hydroxy and n and m are integers selected so that 
the sum n+m is an integer from 3 to 6, a group COO.sup.- M.sup.+ or 
--COOH, M.sup.+ representing a mineral or organic physiologically 
acceptable cation, a group of formula 
##STR6## 
a group of formula 
##STR7## 
and a group of formula 
##STR8## 
in which R.sub.13 and R.sub.14, identical or different, represent a 
hydrogen atom, a linear or branched C.sub.1 -C.sub.6 alkyl group, a linear 
or branched C.sub.1 -C.sub.6 hydroxy- or polyhydroxy-alkyl group, bearing 
optionally in addition one or more C.sub.1 -C.sub.6 alkoxy groups, in 
particular methoxy or ethoxy, a linear or branched C.sub.1 -C.sub.6 alkoxy 
C.sub.1 -C.sub.6 -alkyl group or a linear or branched C.sub.1 -C.sub.6 
hydroxy- or polyhydroxy-alkoxy C.sub.1 -C.sub.6 -alkyl group bearing two 
to five --OH groups, or R.sub.13 and R.sub.14 form together a C.sub.4 
-C.sub.8 alkylene, a C.sub.4 -C.sub.8 hydroxy alkylene or a C.sub.4 
-C.sub.8 polyhydroxyalkylene group with a linear or branched chain, such 
that R.sub.13 and R.sub.14 form with the nitrogen atom to which they are 
attached a 5 or 6-membered nitrogenous heterocycle, optionally substituted 
by one or more hydroxy or C.sub.1 -C.sub.4 hydroxyalkyl groups, and 
R.sub.15 has the same meaning than R.sub.13 excepted an hydrogen atom, 
provided that at least two of the R.sub.1, R.sub.2, R.sub.3, R.sub.4, 
R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 groups represent 
an iodine atom. 
The invention is particularly concerned with poly-iodinated compounds of 
general formula I in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, 
R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10, identical or different, 
are selected from an iodine atom, a group of formula 
##STR9## 
in which R.sub.11 and R.sub.12, identical or different represent a 
hydrogen atom, a linear or branched C.sub.1 -C.sub.6 alkyl group, a linear 
or branched C.sub.1 -C.sub.6 hydroxy- or polyhydroxyalkyl group, 
optionally bearing in addition one or more C.sub.1 -C.sub.6 alkoxy groups, 
a linear or branched C.sub.1 -C.sub.6 alkoxyalkyl group, or linear or 
branched C.sub.1 -C.sub.6 hydroxy- or polyhydroxy- alkoxyalkyl group 
containing from two to five --OH groups, and a group of formula 
##STR10## 
in which R.sub.13 and R.sub.14, identical or different, are as R.sub.11 
and R.sub.12 defined above, provided that at least two of the R.sub.1, 
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and 
R.sub.10 groups represent an iodine atom. 
A first group of preferred compounds comprises the tetraiodinated compounds 
of general formula II: 
##STR11## 
in which R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.8 and R.sub.10 are as 
defined previously. 
A second group of preferred compounds comprises the hexaiodinated compounds 
of general formula III: 
##STR12## 
in which R.sub.1, R.sub.3, R.sub.7 and R.sub.9 are as defined previously. 
The compounds of general formula I are preferred in which R.sub.11, 
R.sub.12, R.sub.13 and R.sub.14 are selected from: --H, --CH.sub.3, 
--CH.sub.2 CH.sub.3, --CH.sub.2 OH, --CHOH --CH.sub.3, --CH(OCH.sub.3) 
CH.sub.2 OH, --CHOH--CH.sub.2 (OCH.sub.3), 
##STR13## 
Preferred 
##STR14## 
groups are those in which: --R.sub.13 represents the 
##STR15## 
group and R.sub.14 is selected from --H, --CH.sub.3, --CH.sub.2 CH.sub.2 
OH and --CH.sub.2 CHOH--CH.sub.2 OH; 
--R.sub.13 represents the 
##STR16## 
group, and R.sub.14 is selected from --H, --CH.sub.3, --CH.sub.2 CH.sub.2 
OH and --CH.sub.2 CHOHCH.sub.2 OH; 
--R.sub.13 represents the 
##STR17## 
group and R.sub.14 is selected from --H, --CH.sub.3, --CH.sub.2 CH.sub.2 
OH, --CH.sub.2 CHOHCH.sub.2 OH and --CH CH.sub.2 OH).sub.2 ; --R.sub.13 
and R.sub.14 form with the nitrogen atom to which they are attached a 
group 
##STR18## 
--R.sub.13 represents a --CH.sub.2 CHOHCHOHCH.sub.2 OH group and R.sub.14 
is selected from --H, --CH.sub.3, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 
CHOHCH.sub.2 OH and --CH(CH.sub.2 OH).sub.2 ; 
--R.sub.13 represents a 
##STR19## 
group, and R.sub.14 is selected from --H, --CH.sub.3, --CH.sub.2 CH.sub.2 
OH, --CH.sub.2 CHOHCH.sub.2 OH and --CH(CH.sub.2 OH).sub.2. 
Among the preferred 
##STR20## 
groups forming a heterocycle, the following groups may be cited: 
##STR21## 
Among the tetra-iodinated compounds of general formula II, those are 
particularly preferred in which: 
(I) R.sub.2 and R.sub.8 are identical and represent the 
##STR22## 
group and R.sub.4, R.sub.5, R.sub.6 and R.sub.10 are identical and 
represent the 
##STR23## 
group. (II) R.sub.2 and R.sub.8 are identical and represent the 
##STR24## 
group and R.sub.4, R.sub.5, R.sub.6 and R.sub.10 are identical and 
represent the 
##STR25## 
group. (III) R.sub.2, R.sub.5, R.sub.6 and R.sub.8 are identical and 
represent the 
##STR26## 
group and R.sub.4 and R.sub.10 are identical and represent the 
##STR27## 
group, (IV) R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.8 and R.sub.10 are 
identical and represent the 
##STR28## 
group; R.sub.11, R.sub.12, R.sub.13 and R.sub.14 being as defined 
previously. 
The preferred compounds of formula II are those in which: 
--R.sub.2 and R.sub.8 represent the group --CO--NH--CH.sub.2 
--CHOH--CH.sub.2 OH and R.sub.4, R.sub.5, R.sub.6 and R.sub.10 represent 
the --NH--CO--CHOH--CH.sub.3 group (compound No. 4); 
--R.sub.2 and R.sub.8 represent the group --NH--CO--CH.sub.2 OH and 
R.sub.4, R.sub.5, R.sub.6 and R.sub.10 represent the group 
--CO--NH--CH.sub.2 --CH.sub.2 OH (compound No. 2); 
--R.sub.2 and R.sub.8 represent the group 
##STR29## 
and R.sub.4, R.sub.5, R.sub.6 and R.sub.10 represent the group 
--CO--NH--CH.sub.2 --CH.sub.2 OH (compound No. 3); 
R.sub.2 and R.sub.8 represent the group --NH--CO--CH.sub.2 OH and R.sub.4, 
R.sub.5, R.sub.6 and R.sub.10 represent the group --CO--NH--CH.sub.2 
--CHOH--CH.sub.2 OH (compound No. 1); 
--R.sub.2, R.sub.5, R.sub.6 and R.sub.8 represent the group 
--CO--NH--CH.sub.2 --CHOH--CH.sub.2 OH and R.sub.4 and R.sub.10 represent 
the group --NH--CO--CH.sub.2 OH (compound No. 7); 
--R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.8 and R.sub.10 represent the 
group --NH--CO --CHOH--CH.sub.3 (compound No. 5); 
--R.sub.2, R.sub.4, R.sub.6 and R.sub.8 represent the group 
--CO--NH--CH.sub.2 --CH.sub.2 OH and R.sub.5 and R.sub.10 represent the 
group --NH--CO--CHOH--CH.sub.3 (compound No. 6). 
Among the hexa-iodinated compounds of general formula III, those are 
particularly preferred in which: 
(V) R.sub.1 and R.sub.7 are identical and represent the group 
##STR30## 
and R.sub.3 and R.sub.9 are identical and represent the group 
##STR31## 
R.sub.11, R.sub.12, R.sub.13 and R.sub.14 being as defined previously; 
(VI) R.sub.1 and R.sub.9 are identical and represent the group 
##STR32## 
and R.sub.3 and R.sub.7 are identical and represent the group 
##STR33## 
R.sub.11, R.sub.12, R.sub.13 and R.sub.14 being as defined previously; 
(VII) R.sub.1, R.sub.3, R.sub.7 and R.sub.9 are identical and represent 
the group 
##STR34## 
R.sub.11 and R.sub.12 being as defined previously; (VIII) R.sub.1, 
R.sub.3 and R.sub.7 are identical and represent the group 
##STR35## 
and R.sub.9 represents the group 
##STR36## 
R.sub.11, R.sub.12, R.sub.13 and R.sub.14 being as defined previously. 
(IX) R.sub.1, R.sub.3, R.sub.7 and R.sub.9 are identical and represent the 
group 
##STR37## 
R.sub.13 and R.sub.14 being as defined previously. 
The preferred compounds of formula III are those in which: --R.sub.1 and 
R.sub.7 represent the group --NH--CO--CH (CH.sub.2 OH).sub.2 ; and R.sub.3 
and R.sub.9 represent the group 
##STR38## 
(compound No. 8) --R.sub.1 and R.sub.7 represent the group 
--NH--CO--CH(CH.sub.2 OH).sub.2 and R.sub.3 and R.sub.9 represent the 
group --CO--N(CH.sub.2 --CHOH--CH.sub.2 OH).sub.2 (compound No. 9) 
--R.sub.1 and R.sub.7 represent the group --NH--CO--CH.sub.2 OH and R.sub.3 
and R.sub.9 represent the group 
##STR39## 
(compound No. 10), --R.sub.1 and R.sub.7 represent the group 
--NH--CO--CHOH--CH.sub.2 OH and R.sub.3 and R.sub.9 represent the group 
##STR40## 
(compound No. 11), --R.sub.1 and R.sub.7 represent the group 
--NH--CO--CH.sub.2 OH and R.sub.3 and R.sub.9 represent the group 
##STR41## 
(compound No. 12), --R.sub.1 and R.sub.7 represent the group 
##STR42## 
and R.sub.3 and R.sub.9 represent the group 
##STR43## 
(compound No. 13), --R.sub.1 and R.sub.7 represent the group 
--N--(COCH.sub.3).sub.2 and R.sub.3 and R.sub.9 represent the group 
##STR44## 
(compound No. 14) --R.sub.1 and R.sub.7 represent the group 
##STR45## 
and R.sub.3 and R.sub.9 represent the group 
##STR46## 
(compound No. 15), --R.sub.1 and R.sub.7 represent the group 
##STR47## 
and R.sub.3 and R.sub.9 represent the group 
##STR48## 
(compound No. 16). 
The compounds of general formula I may be prepared by alkylation and/or 
acylation reactions. 
The compounds of general formula I may be prepared in particular by a 
process comprising the following steps: 
a) coupling of the benzene derivatives of formula IV and V 
##STR49## 
X being selected from chlorine, bromine and iodine and R'.sub.1, 
R'.sub.2, R'.sub.3, R'.sub.4, R'.sub.5, R'.sub.6, R'.sub.7, R'.sub.8, 
R'.sub.9 and R'.sub.10, identical or different, being selected from a 
hydrogen atom and the groups --NO.sub.2 and --CO.sub.2 R with R 
representing a C.sub.1 -C.sub.6 alkyl group so as to obtain a compound of 
formula VI: 
##STR50## 
in which R'.sub.1, R'.sub.2, R'.sub.3, R'.sub.4, R'.sub.5, R'.sub.6, 
R'.sub.7, R'.sub.8, R'.sub.9, R'.sub.10 are as defined previously; 
b) amidation of the --CO.sub.2 R groups by an amine of formula 
##STR51## 
(XIII); c) reduction of the nitro groups to amino groups; 
d) iodination under standard conditions; 
e) optional protection of the --OH groups by means of the usual protecting 
groups, 
f) acylation of the aromatic amino groups by an acid chloride of formula 
R'.sub.12 --COCl; R'.sub.12 representing a R.sub.12 group as defined 
previously, the hydroxy groups of which are protected by means of a usual 
protecting group; and either 
g) optional alkylation of the amido groups by means of a reactant of 
formula Z--R.sub.11, Z being a labile group such as Cl, Br or I and 
R.sub.11 being as defined previously; and deprotection of the protected 
hydroxy groups, or 
h) deprotection of the protected hydroxy groups, and optional alkylation of 
the amino groups by a reactant of formula Z--R.sub.11, R.sub.11 being as 
defined previously. 
The reaction of step a) preferably takes place in a suitable solvent such 
as xylene, nitrobenzene, nitrotoluene, DMF or pyridine, in the presence of 
a metal catalyst such as copper according to the method of ULLMAN (E. 
FANTA, Chem. Rev. 64, 613, 1964). 
The reaction of step c) is a catalytic reduction by means of hydrogen on 
palladised charcoal or on Raney nickel or a chemical reduction. 
The iodination reaction of step d) takes place under the usual conditions 
such as by means of aqueous ICl or I.sub.2 in the presence of 
KI/ethylamine at temperatures included between 0.degree. C. and 
100.degree. C. 
The alkylation reactions of steps f) and g) are performed under standard 
conditions, in the presence of a strong base. 
The compounds of formula II in which R.sub.2, R.sub.4, R.sub.5, R.sub.6, 
R.sub.8 and R.sub.10 represent a group 
##STR52## 
R.sub.11 and R.sub.12 being as defined previously, may also be obtained by 
a process consisting of the following steps: 
a1) coupling of a benzene derivative of formula 
##STR53## 
R' representing a methyl or ethyl group, and X being selected from 
chlorine, bromine or iodine atom following the ULLMAN reaction as 
described above in order to obtain a compound of formula VIII, 
##STR54## 
in which R' is as defined previously; b1) after saponification of the 
esters, azide formation and rearrangement according to the SCHMIDT 
reaction to obtain a diamine of formula IX 
##STR55## 
c1) acylation of the amino groups by means of an acid chloride of formula 
R'.sub.12 --COCl, R'.sub.12 corresponding to R.sub.12 as defined 
previously the --OH groups of which may or may not be protected. 
d1) catalytic reduction or chemical reduction of the nitro groups to amino 
groups as described previously in step c). 
e1) iodination of the aromatic amino groups as described previously in step 
d). 
f1) acylation by means of an acid chloride of formula R'.sub.12 
--COC.sub.1, as described previously in f) R' being as defined previously. 
g1) optional deprotection, and 
h1) optional alkylation as described previously in g). 
The compounds of formula II may also be obtained by the HOFMANN 
rearrangement of the iodinated series, according to the method described 
in FR-A-84 15 494. 
The compounds of formula II in which R.sub.2, R.sub.4, R.sub.5, R.sub.6, 
R.sub.8 and R.sub.10 represent the group 
##STR56## 
may be obtained in addition by standard processes according to which the 
aromatic NH.sub.2 groups obtained in c) are converted into CO.sub.2 H 
groups, by example by means of the SANDMEYER reaction in the iodinated 
series as described in the patent EP-A-32387. 
The compounds of formula III in which R.sub.1, R.sub.3, R.sub.7 and R.sub.9 
represent a group 
##STR57## 
R.sub.13 and R.sub.14 being as defined previously, may be prepared by the 
following procedure: 
a2) diazotation of a compound of formula: 
##STR58## 
in order to obtain a compound of formula XI 
##STR59## 
b2) coupling of the compound of formula XI in order to obtain a compound 
of formula XII 
##STR60## 
c2) conversion of the compound of formula XII into its corresponding acid 
chloride, and 
d2) amidation of the compound obtained with an amine of formula: 
##STR61## 
in order to obtain a compound of formula III in which R.sub.1, R.sub.3, 
R.sub.7 and R.sub.9 represent the group: 
##STR62## 
Compounds of formula III wherein R.sub.1 and R.sub.7 represent 
##STR63## 
and R.sub.3 and R.sub.9 represent 
##STR64## 
may additionally be obtained by a method consisting of the following 
steps: 
coupling benzene derivatives of formula IV and V as previously defined so 
as to obtain a compound of formula VI bis: 
##STR65## 
catalytic reduction of the nitro groups to amino groups as described 
previously, 
iodination as described previously, 
conversion of the COOR groups into acide chloride groups by means of a 
compound such as SOCl.sub.2 or (COCl).sub.2 under standard conditions; 
acylation of the amino groups by means of an acid chloride of formula 
R'.sub.12 --COCl as previously defined; 
amidation of the --COCl groups by means of an amine of formula 
##STR66## 
as previously defined; deprotection of hydroxy groups which are 
protected; 
optional alkylation of the amido groups by means of a reactant of formula 
Z--R.sub.11, as previously defined. 
The amines of general formula XII are for the most part known and 
commercially available compounds or may be prepared in the following 
manner. 
The amine alcohol of formula: 
##STR67## 
is prepared as described in Tetrahedron Letters, 31, 6777 (1990), J. Org. 
Chem., 50, 891 (1985) or J. Chem. Soc. Chem. Commun. 262 (1987). 
The amine alcohol of formula XII in which R.sub.13 represent H and R.sub.14 
represents 
##STR68## 
is prepared as described in U.S. Pat. Nos. 4,341,756 and 4,439,613. 
The amine alcohol of formula XII in which R.sub.13 represents --CH.sub.3 
and R.sub.14 represents 
##STR69## 
is prepared as described in Zh. Org. Khim., 22 (2), 298, 1986. 
The amine-alcohol of formula XII in which R.sub.13 represent --CH.sub.2 
CH.sub.2 OH and R.sub.14 represents 
##STR70## 
is marketed by Eastman Kodak. 
The amine-alcohol of formula XII in which R.sub.13 represents 
##STR71## 
is prepared as described in J. Am. Chem. Soc. 66, 881, 1944. 
The amine-alcohol of formula XII in which R.sub.13 represents H, and 
R.sub.14 represents 
##STR72## 
is prepared as described in Propellants, Explos., Pyrotech. 16(1), 40-42, 
1991. 
The amine-alcohols of general formula: 
##STR73## 
are prepared in the following manner: when R.sub.14 represents --CH.sub.3, 
as described in EP-25083; 
when R.sub.14 represents --CH.sub.2 CH.sub.2 OH, as described in EP-25083 
and J. Med. Chem. 10 (3), 511, 1967; 
when R.sub.14 represents 
##STR74## 
as described in J. Med. Chem. 10 (3), 511, 1967 and EP-25083. 
The preparation of other amine-alcohols of formula XII will be described 
hereafter: 
Preparation of compound No. 1 
##STR75## 
a) Preparation of the compound of formula 
##STR76## 
2 g (13.7 mmoles) of 2,4-ethylidene D-erythrose obtained according to the 
procedure described in J. Am. Chem. Soc. 2301, 1960 Barker R. et al. are 
dissolved in 10 ml of water at 30.degree. C. 10 ml of a 40% aqueous 
solution of methylamine are added dropwise at 0.degree. C. After the 
reaction mixture has warmed to room temperature, stirring is continued for 
2 h. The solution is then reduced at room temperature in the presence of 
palladium on charcoal. The catalyst is then filtered off and the filtrate 
is concentrated to dryness. After solidification in ethyl ether, 1.7 g of 
the title compound are obtained, i.e. a yield of 77%. TLC (dioxan/H.sub.2 
O/NH.sub.3 :8/3/2) Rf: 0.74 TLC (CH.sub.2 Cl.sub.2 MeOH 8/2) Rf: 0.17. 
.sup.13 C NMR (DMSO) (.delta., ppm) 200 MHz 98.2 (C--CH.sub.3); 80.3 
(CH--O); 70.5 (CH.sub.2 --O); 63.4 (CHOH); 53.1 (CH.sub.2 --N); 36.5 
(NH--CH.sub.3); 20.7 (C--CH.sub.3). 
b) Preparation of the compound of formula: 
##STR77## 
1.5 g (9.3 mmoles) of the compound obtained in a) are dissolved in 20 ml of 
2N HCl. The solution is stirred at 50.degree. C. for 5 h. After 
concentration and purification by passage through a H.sup.+ resin, the 
solution is evaporated to dryness. The residue is taken up in ethyl ether. 
After filtration and drying, 0.8 g of the title compound are obtained 
(yield: 64%). TLC (dioxan/H.sub.2 O/NH.sub.3 :8/3/2) Rf: 0.18 
.sup.13 C NMR (DMSO) (.delta.,ppm) 200 MHz 74.5 (CH--CH.sub.2 OH); 69.6 
(CHOCH.sub.2); 63.3 (CH.sub.2 OH); 54.7 (CH.sub.2); 36.12 (NHCH.sub.3) MS 
(DCI(NH.sub.3) m/z; 153 (M+NH.sub.4.sup.+); 136 (M+H.sup.+) base peak 
Preparation of the compound No. 2 
##STR78## 
a) Preparation of the compound of formula: 
##STR79## 
The compound is prepared according to the method described previously. 
The reductive amination of 2,4-ethylidine-D-erythrose (6 g, 41 mmoles) is 
performed in the presence of aminopropanediol (1.2 equiv.) in ethanol (40 
ml). 
After chromatography on a column of silica, the title compound is obtained 
in a yield of 73%. TLC (dioxan/H.sub.2 O/NH.sub.3 :8/3/2) Rf: 0.73 
.sup.13 CNMR (DMSO) .delta., ppm (200 MHz)(98, C--CH.sub.3); (80.2-80.5, 
CH--O); (70.2-70.4, CH.sub.2 --O); (70.3, CHOH); (64.5-64.6, CH.sub.2 OH); 
62.2-63.1, CH--OH); (52.9-53, CH.sub.2); (50.8-51, CH.sub.2); (20.5, 
CH.sub.3). 
b) Preparation of the compound of formula: 
##STR80## 
6 g (29.8 mmoles) of the compound obtained in the preceding step are 
deprotected by treatment with 5N HCl (50 ml). The reaction medium is 
stirred for 4 h at 50.degree. C. After evaporation, the residue obtained 
is purified on a H.sup.+ resin. After concentration and solidification in 
ethyl ether, 2.6 g of the title compound are obtained (yield 54.7%) TLC 
(dioxan/H.sub.2 O/NH.sub.3 :8/3/2) Rf: 0.39 
.sup.13 C NMR (DMSO) (.delta.,ppm) 74.3 (CH--CH.sub.2 OH) butanetriol 
chain); 70.3 (CHCH--CH.sub.2).times.2; 64.5-64.6 (CH.sub.2 OH butanetriol 
chain); 63.3 (CH.sub.2 OH); 52.8 (CH.sub.2 N).times.2 MS (DCI/NH.sub.3) 
m/z 196 (M+H.sup.+) base peak; 178 (M+H.sup.+ --H.sub.2 O); 160 (M+H.sup.+ 
--2H.sub.2 O) 136, 122, 109, 92. 
Preparation of the compound No. 3 
##STR81## 
In the same manner as methylamine (for the preparation of the amino-alcohol 
No. 1) and aminopropanediol (for the preparation of the amino-alcohol No. 
2) ethanolamine in the presence of 2,4-ethylidene-D-erythrose leads to the 
title compound under the same conditions of reductive amination. 
a) Data of the compound of formula: 
##STR82## 
TLC (CH.sub.2 Cl.sub.2 /MeOH/NH.sub.3 : 8/2/1) Rf: 0.56 
.sup.13 C NMR (DMSO) (.delta., ppm) 97.9 (C--CH.sub.3); 80.5 (CH--O); 70.2 
(CH.sub.2 OH); 62.9 (CHOH); 60.2 (CH.sub.2 --O); 51.6 (CH.sub.2 --N); 50.7 
(CH.sub.2 --N); 20.4 (CH.sub.3). 
b) Data of the compound of formula: 
##STR83## 
TLC (CH.sub.2 Cl.sub.2 /MeOH/NH.sub.3 55/30/15) Rf: 0.25 TLC 
(dioxan/H.sub.2 O/NH.sub.3 :8/3/2) Rf: 0.48 
.sup.13 C NMR (DMSO) (.delta., ppm) 74.5 (CHOHCH.sub.2 OH); 70.2 
(CHOH--CH.sub.2); 63.5 (CHOHCH.sub.2 OH); 60.4 (CH.sub.2 --CH.sub.2 OH); 
52.5 (CH.sub.2 --CHOH); 51.8 (CH.sub.2 CH.sub.2 OH). 
By employing- the procedures described previously and by using serinol with 
2,4-ethylidene-D-erythrose, the amine-alcohol of the following formula is 
prepared in the same manner: 
##STR84## 
(compound No. 4) Preparation of the compound No. 5 
##STR85## 
3 g (18 moles) of 2,3-epoxy 1,4-butanediol prepared according to the method 
described in J. Med. Chem. 1976, vol. 9, No. 1, 153-158 are dissolved in 
10 ml of methanol. 0.9 equiv. of aminopropanediol in 10 ml of methanol are 
added dropwise at room temperature. The reaction mixture is heated at 
45.degree.-50.degree. C. for 48 h. After evaporation, the crude product is 
purified on a H.sup.+ resin and is concentrated to dryness. After being 
taken up in ether and dried, 4 g of the title compound are obtained (Yield 
72.7%). TLC (dioxan/H.sub.2 O/NH.sub.3 :8/3/2) Rf : 0.58 TLC (CH.sub.2 
Cl.sub.2 /MeOH/NH.sub.3 : 6/3/1) Rf : 0.55 
.sup.13 C NMR (DMSO) (.delta., ppm) 71-71.2 (CHOH); 64.6(--NH--CH--CH.sub.2 
OH); 63.5 (CH.sub.2 OH propanediol chain); 61.4 (--CH--); 61 (CH.sub.2 
OH); 51.3 (CH.sub.2 --N). 
The opening of the epoxide previously described may also be carried out 
using methylamine, ethanolamine and serinol so as to obtain respectively 
the compounds: 
##STR86## 
Preparation of the compound of formula: 
##STR87## 
18.1 g (1 mmole) of 3-hydroxymethyloxetane prepared according to the method 
described in Propellants, Explos., Pyrotech., 16(1) 40-42, 1991 are 
stirred in 20 ml of methanol and 76 ml (1 mole) of 40% aqueous methylamine 
at 50.degree. C. for 24 h. The mixture is evaporated to dryness and the 
residue is dissolved in 100 ml of 0.1N sulfuric acid. 
The solution is refluxed for 12 h, then passed through a resin. The title 
compound is obtained by evaporation of the eluent. 
Preparation of the compound of formula: 
##STR88## 
18.1 g (0.1mole) of 3-bromoethyl-3-hydroxymethyloxetane obtained as 
described previously are stirred in 20 ml of methanol and 60.5 ml (0.1 
mole) of ethanolamine at 50.degree. C. for 24 h. The mixture is evaporated 
to dryness and the residue is dissolved in 100 ml of 0.1N sulfuric acid. 
The solution is refluxed for 12 h then passed through a resin. The title 
compound is obtained by evaporation of the eluent. 
It will be obvious that the invention encompasses not only the compounds of 
formula I in the form of racemic mixtures but also the stereoisomers such 
as enantiomers, diastereoisomers, atropoisomers, SYN-ANTI isomers, 
ENDO-EXO isomers, E-Z isomers, associated with the presence of asymmetric 
carbon atoms and/or with restriction of rotation due to the steric 
hindrance created by the iodine atoms and/or by the substituents R.sub.1 
to R.sub.10 of the compounds of formula I. 
The present invention also relates to contrast media which contain at least 
one compound of formula I. 
These contrast media are used in man and animals for radiological purposes. 
The preferred pharmaceutical form of the contrast media according to the 
invention consists of aqueous solutions of the compounds. According to one 
embodiment of the invention, the compounds are encapsulated within 
liposomes. 
The aqueous solutions usually contain a total of 5 to 100 g of compounds 
per 100 ml and the injectable volume of such solutions may vary generally 
from 1 to 1000 ml. The solutions may also contain additives such as a 
sodium salt, in particular sodium citrate, heparin and disodium-calcium 
EDTA. 
These compositions may be administered by all of the routes commonly used 
for iodinated non-ionic contrast media. Thus, they may be administered by 
the enteral or parenteral routes (intravenous route, intraarterial route, 
opacification of the cavities) and, in particular, into the subarachnoidal 
space.

Examples of the preparation of compounds according to the invention will be 
given hereafter. 
EXAMPLE 1 
Preparation of 4,4'-di-(hydroxyacetylamino)-2,2', 
6,6'-tetrakis-(2,3-dihydroxypropylcarbamoyl) 3,3', 5,5'-tetraiodo diphenyl 
(compound No. 1). 
1) Preparation of 2-bromo isophthalic acid 
125 g (0.676 mole) of 2-bromo meta xylene are added rapidly to a solution 
of 440 g (4.1.times.0.676 mole) of potassium permanganate in 2.5 l of 
water. After being refluxed with stirring for 48 h and allowed to cool to 
room temperature, the reaction mixture is filtered through Celite; after 
the cake has been washed with hot water, the volume of the filtrate is 
reduced to 1.5 l by evaporation. After being cooled to 0.degree. C. the 
solution is acidified by means of 100 ml of 10N HCl to pH=1. The 
precipitate is filtered off, washed with water then dried for 12 h at 
70.degree. C. The product is obtained in a yield of 70.6% (117 g). 
M.p.=222.degree. Thin layer chromatography (TLC) (isopropanol/ethyl acetate 
(AcOEt)/NH.sub.4 OH: 25/25/30); R.sub.f =0.25 TLC 
(toluene/methyl-ethyl-ketone/HCOOH:60/25/5): R.sub.f :0.5 Determination of 
the acidity ((t-butyl).sub.4 --N--OH 103.1% (1st acid function) 100.6% 
(2nd acid function). 
2) Preparation of 2-bromo 5-nitro isophthalic acid 
To a solution of 117 g (0.477 mole) of the preceding compound in 892 ml of 
98% H.sub.2 SO.sub.4 is added dropwise a mixture of fuming HNO.sub.3 (167 
ml) and concentrated H.sub.2 SO.sub.4 (264 ml) while the temperature is 
maintained below 15.degree. C. The reaction mixture is stirred for 12 h at 
room temperature. The precipitate is filtered off, washed with 3.times.200 
ml of water, then dried at 70.degree. C. for 12 h. 
Yield 93.4% 
M.p.=214.degree. C. TLC (isopropanol 25/AcOEt 25/NH.sub.4 OH/30): R.sub.f 
=0.45 
.sup.1 H NMR (DMSO) 8.5 (s 2H arom) 13 (s, COOH 2H) 
3) Preparation of the dimethyl ester of 2-bromo 5-nitro isophthalic acid 
880 ml of methanol containing 129 g (0.445 mole) of the preceding compound 
and 90 ml of 98% H.sub.2 SO.sub.4 are refluxed for 24 h. The precipitate 
obtained is filtered off, washed with 120 ml of methanol, then 2.times.120 
ml of H.sub.2 O. After being dried at 65.degree. C., the product is 
obtained in a yield of 74%. 
M.p. 134.degree. C. TLC (toluene 60/methyl-ethyl-ketone 35/HCOOH 25): 
R.sub.f =0.8 
IR 1730 (COOCH.sub.3) 1350-1560 (NO.sub.2) 
NMR .sup.1 H DMSO 4.0 (s COOCH.sub.3 6H) 8.5 (s 2H arom) 
4)Preparation of 4,4'-dinitro-2,2', 6,6-tetra(methoxy-carbonyl) diphenyl 
To a solution of 100 g (0.314 mole) of the preceding product in 420 ml of 
p-xylene previously heated to 80.degree. C. are added portionwise 36.0 g 
(0.566 mole) of copper. After 5 h of reflux (at 140.degree. C.) a further 
18 g (0.283 mole) of copper are added to the reaction mixture. The same 
operation is repeated after 12 h of reflux. The mixture is then filtered 
through Celite after a further 12 h period of reflux. In order to remove 
the CuBr which precipitates with the desired product, an extraction with 
CH.sub.2 Cl.sub.2 is carried out; the filtrate is evaporated to dryness, 
taken up in ether, filtered then dried at 80.degree. C. to give compound 5 
in a yield of 70% 
M.p.=226.degree. C. TLC (CH.sub.2 C.sub.12): R.sub.f =0.1 
.sup.1 H NMR (CDCl.sub.3) 3.6 (s, COOCH.sub.3 12H) 9.0 (s 4H arom) 
5) Preparation of 4,4'-dinitro-2,2', 6,6'-tetrakis-(2,3-dihydroxypropyl 
carbamoyl) diphenyl 
To 89.0 g of 2,3-aminopropanediol diluted in 450 ml of MeOH heated to 
40.degree. C., 49 g (0.103 mole) of the preceding product are added 
portionwise. After vigorous stirring for 1/2 h at 40.degree. C., a 
quantity of MeONa sufficient to produce a homogeneous solution is added. 
After 12 h at room temperature, the mixture is evaporated and the residue 
is taken up in 1 l of H.sub.2 O and passed through columns of H.sup.+ and 
OH.sup.- ion exchange resins. After evaporation to dryness, the product 
is crystallized from isopropanol, filtered off, washed with 2.times.250 ml 
of ether, then dried at 70.degree. C. Yield 88.3%. TLC (Dioxan 9/H.sub.2 O 
1) R.sub.f =0.70 
.sup.1 H NMR (DMSO) 2.8-3.2 (CH aliphatic 20H) 3.9-4.5 (OH 8 H 
exchangeable) 8.2 (s 4H aromatic) 8.3-8.6 (CONH) 4H exchangeable). 
6) Preparation of 4,4'-diamino 2,2', 6,6'-tetrakis-(2,3-dihydroxypropyl 
carbamoyl) diphenyl. 
39 g (0.0550 mole) of the preceding product dissolved in 675 ml of H.sub.2 
O in the presence of 13.4 g of 10% palladised charcoal are stirred under a 
H.sub.2 pressure of about 3.10.sup.5 PA at room temperature for 6 hours. 
After filtration of the catalyst and evaporation of the water, the residue 
is suspended in ethyl ether, filtered off, washed with 2.times.100 ml of 
ether and the product is dried in a vacuum at room temperature. 
Yield=96.3% TLC (MeOH 8/CH.sub.2 Cl.sub.2 2) R.sub.f =0.5 Determination of 
acidity (HClO.sub.4) 93.5% per NH.sub.2 function 
.sup.1 H NMR (DMSO) 2.7-4 (multiplet 20H aliphatic) 4.1-6 (multiplet 8H, 
OH; 4H NH.sub.2 exchangeable) 6.7 (s 4H arom) 8.1-8.6 (m CONH4H 
exchangeable) 
Preparation of 4,4'-diamino-2,2', 6,6'-tetrakis-(2,3-dihydroxypropyl 
carbamoyl) 3,3', 5,5'-tetraiodo diphenyl 
90.5 ml of 70% ICl are added dropwise to a solution of 54.5 g (0.0826 mole) 
of the preceding product in 545 ml of water. After heating to 80.degree. 
C. for 8 h followed by stirring for 24 h at room temperature, the 
precipitate obtained is filtered of, washed with 20 ml of bisulfite and 
then with 40 ml of H.sub.2 O. 
The first crop is obtained in a yield of 23.4% and a HPLC purity of 88%. 
The recovery of a second crop is achieved by neutralization of the mother 
liquors to pH 5 with 5N sodium hydroxide. The I.sub.2 precipitate is 
filtered off, the solution is evaporated to dryness and the residue is 
taken up in ethanol. The suspension obtained is filtered, washed with 
2.times.200 ml of ethanol, followed by 200 ml of ether. After drying at 
70.degree. C., 103.5 g of product are obtained containing 50.7% by weight 
of NaCl. After purification by means of preparative HPLC on SiO.sub.2 RP 
18, the product is obtained in a purity with respect to iodine of 98.35%. 
Yield: 75% TLC (dioxan 9/H.sub.2 O 1/NH.sub.4 OH 1): R.sub.f =0.45 
.sup.1 H NMR (DMSO d.sup.6) 2.7-3.7 (m 20H aliphatic) 4-6 (multiplets 8H 
OH; 4H NH.sub.2 exchangeable) 8-8,8 (m, CONH 4H exchangeable). 
8) Preparation of 4,4'-di-(acetoxyacetylamino) 2,2', 
6,6'-tetrakis-(2,3-di-acetoacetoxypropyl carbamoyl) 3,3', 5,5'-tetraiodo 
diphenyl. 
To a solution of 40.6 g (0.0351 mole) of the preceding product in 320 ml of 
anhydrous DMAC are added 71.9 g (15.times.0.0351 mole) of acetylated 
glycolic acid chloride. The temperature of the reaction mixture is heated 
to 58.degree. C., then the solution is stirred vigorously for 12 h at 
50.degree. C. The residue is taken up in 500 ml of CH.sub.2 Cl.sub.2 and 
washed with water. The organic phase is dried over Na.sub.2 SO.sub.4, 
filtered and the volume is reduced by 3/4 to permit precipitation with 
ether. The suspension obtained is filtered and the precipitate is washed 
with 2.times.200 ml of ether. 
Yield: 100%; amine test negative. 
.sup.1 H NMR DMSO 2.0-2.3 (s OCOCH.sub.3 30H) 4.0-5.5 (m 40H aliphatic) 
8.3-9.0 (m CONH, 4H exchangeable) 10.2-10.4 (m NHCO 2H exchangeable) 
9) Preparation of 4,4'-di-(hydroxy-acetylamino) 2,2', 
6,6'-tetrakis-(2,3-dihydroxypropyl carbamoyl) 3,3', 5,5'-tetraiodo 
diphenyl (compound No. 1 
75.7 g (0.0351 mole) of the preceding product are dissolved in 1.1 l of 
NaOH. After being stirred for 1 h 30 at room temperature, the reaction 
mixture is diluted with 700 ml of H.sub.2 O for passage through H.sup.+ 
and OH.sup.- ion exchange resins. The solution obtained at pH 7.2 is 
evaporated. 
Compound No. 1 is obtained in a yield of 60.2%. TLC (dioxan 9/H.sub.2 O 
1/NH.sub.4 OH 2): R.sub.f =0.4 Purity with respect to iodine: 99.29% HPLC 
purity=99.3% in 2 isomeric peaks (C8 Hypersyl 5M.15 cm buffer NaH.sub.2 
PO.sub.4 /MeOH 92/8. 
.sup.1 H NMR (DMSO) 2.6-6 (m. complex 24H aliphatic 10H OH exchangeable) 
8-8.8 (m. CONH 4H exchangeable) 9.8-10.4 (m, NHCO, 2H exchangeable). 
EXAMPLE 2 
Preparation of 4,4'-di-(hydroxy-acetylamino)-2,2', 
6,6'-tetra-(2-hydroxyethyl carbamoyl) 3,3', 5,5'-tetraiodo diphenyl 
(compound No. 2) 
1) Preparation of 4,4'-dinitro 2,2', 6,6'-tetra (2-hydroxyethyl carbamoyl) 
diphenyl 
4,4'-dinitro-2,2', 6,6'-tetramethoxycarbonyl diphenyl is prepared as 
indicated in part 4 of the preceding example. 
35 g of the product obtained is then added portionwise to a solution of 
ethanolamine (42.6 g) in 350 ml of MeOH at 40.degree. C. After vigorous 
stirring for 1/2 h at 40.degree. C., powdered MeONa is added until a 
homogeneous solution is obtained. 
The reaction mixture is stirred for 12 h at 40.degree. C., evaporated, 
taken up in 700 ml of water then passed through H.sup.+ and OH.sup.- ion 
exchange resins. After evaporation to dryness, the product is crystallized 
from acetone. It is filtered off, washed with ether and dried at 
70.degree. C. The product is obtained is a yield of 78.2%. TLC (CH.sub.2 
Cl.sub.2 8/MeOH 2) R.sub.f =0.75 
.sup.1 H NMR (DMSO) 2.9-3.5 (m. 16H aliphatic) 3.6-4.8 (m OH 4H 
exchangeable) 8.1-8.3 (s 4H arom) 8.4-8.8 (m CONH 4H exchangeable with 
D.sub.2 O) 
2) Preparation of 4,4'-diamino-2,2', 6,6'-tetra-(2-hydroxyethyl carbamoyl) 
diphenyl 
34 g of the preceding product are dissolved in 900 ml of H.sub.2 O and in 
the presence of 10.5 g of 10% palladised charcoal are subjected to H.sub.2 
pressure of 3.10.sup.5 Pa with stirring at room temperature for 6 h. After 
filtration of the catalyst, the water is evaporated to give a final volume 
of 350 ml which is used as such in the next step. TLC (MeOH 8/CH.sub.2 
Cl.sub.2 2): R.sub.f =0.55 (product not isolated) 
3) Preparation of the 4,4'-diamino-2,2', 6,6'-tetra-(2-hydroxyethyl 
carbamoyl) 3,', 5,5'-tetraiodo diphenyl 
50 ml of 70% ICl are added dropwise to the solution of the product obtained 
in the preceding step. After heating the reaction mixture at 80.degree. C. 
for 3 h, the suspension obtained is filtered and washed with bisulfite and 
then abundantly with water. After being dried in a vacuum at 60.degree. C. 
for 24 h, the desired product is obtained in a yield of 82.3%. TLC 
(CHCl.sub.2 8/MeOH 2) R.sub.f =0.7 
.sup.1 H NMR (DMSO) 2.9-3.5 (m 16 aliphatic) 3.8-5 (m 4H, OH and 4H, 
NH.sub.2 exchangeable with D.sub.2 O) 8.2-8.7 (m 4H CONH exchangeable) 
4) Preparation of 4,4'di-(acetoxyacetylamino) 2,2', 
6,6'-tetra-(acetoxy-acetoxy carbamoyl) 3,3', 5,5'-tetraiodo diphenyl 
101.2 g (12.times.0.0618 moles) of acetylated glycolic acid chloride are 
added rapidly to a solution of 64 g (0.0618 mole) of the preceding product 
in 1.1 l of anhydrous DMAC. After being heated for 12 h at 60.degree. C., 
the mixture is evaporated, the residue is extracted with 700 ml of 
CH.sub.2 Cl.sub.2 and washed with 250 ml of H.sub.2 O. After drying of the 
organic phase over MgSO.sub.4 and filtration, the filtrate is treated with 
active charcoal. After evaporation, the residue is crystallized from 
ether. After being dried in a vacuum, the desired product is obtained in a 
yield of 88.5%. TLC (CH.sub.2 Cl.sub.2 9/MeOH 1): R.sub.f =0.95 Purity 
with respect to iodine 99.4% 
.sup.1 H NMR (DMSO) 1.8-2.2 (d OCOCH.sub.3 18H) 2.8-3.5 (m CONH CH.sub.2 
8H) 3.6-4.2 (m CH--CH.sub.2 OCO 8H) 4.3-4.7 (m CO--CH.sub.2 --OAc 12H) 
8.2-8.7 (m CONH, 4H exchangeable) 9.1-10.2 (m, NH--CO, 2H exchangeable) 
5) Preparation of 4,4'-di-(hydroxy-acetylamino) 2,2', 6,6'tetra- 
(2-hydroxyethyl carbamoyl) 3,3', 5,5'-tetraiodo diphenyl 
89 g (0.0544 mole) of the preceding product are stirred in the presence of 
740 ml of N NaOH at room temperature for 2 h. The solution is then diluted 
to a volume of 3.8 l , then passed through H.sup.+ and OH.sup.- ion 
exchange resins. The aqueous phases are then evaporated to dryness and the 
residue then crystallized from acetone. After washing with ether and 
drying in an oven at 50.degree. C., compound No. 2 is obtained in a yield 
of 78.1%. TLC (CHCl.sub.3 55/MeOH 30/NH.sub.4 OH 10): R.sub.f =0.45 Purity 
with respect to iodine: 98.30% H.sub.2 O content: 2.15% 
.sup.1 H NMR (DMSO d.sup.6) 2.6-6 (m 28H aliphatic 6 OH exchangeable) 
8.2-8.6 (m CONH 4H exchangeable) 9.9-10.1 (m NHCO 2H exchangeable with 
D.sub.2 O) 
EXAMPLE NO. 3 
Preparation of 4,4'-bis-[(N-2,3-dihydroxy) propyl-acetylamino]-2,2', 
6,6'-tetra-(2-hydroxyethyl carbamoyl) 3,3', 5,5'-tetraiodo-diphenyl 
(compound No. 3) 
1) Preparation of 4,4'-diacetylamino-2,2', 6,6'-tetra-(2-acetoxyethyl 
carbamoyl) 3,3', 5,5'-tetraiodo diphenyl. 
60 g of the product obtained in part 3 of the preceding example are 
suspended in 300 ml of acetic acid and 60 ml of acetic anhydride, then 
heated at 60.degree. C. 2.5 ml of H.sub.2 SO.sub.4 are added dropwise 
while the temperature is maintained at 70.degree.--80.degree. for 1/2 
hour. The reaction mixture is then evaporated to dryness and the residue 
is taken up in ether, filtered off and dried. The desired product is 
obtained in a yield of 76%. The purity with respect to iodine is 102%. TLC 
(CH.sub.2 Cl.sub.2 90/MeOH 10): R.sub.f =0.55 
.sup.1 H NMR (DMSO) 2 (s. COCH.sub.3 18H) 3.3 and 3.9 (d CH.sub.2 
--CH.sub.2 16H) 8.5 (n CONH 4H exchangeable) 10 (m, NH--CO, 2H 
exchangeable) 
2) Preparation of 4,4'-diacetylamino 2,2', 6,6'-tetra-(2-hydroxy-ethyl 
carbamoyl)-3,3', 5,5'-tetraiodo diphenyl 
99 g of the preceding product in 1.3 l of methanol containing 21.7 g of 
K.sub.2 CO.sub.3 are added and the mixture is stirred for 3 h at room 
temperature. The precipitate formed is filtered off, washed with a minimal 
quantity of methanol and with ether. Yield: 100% 
.sup.1 H NMR (DMSO d.sup.6) 1.8 (s. COCH.sub.3 6H) 3.2 and 3.7 (2 m 
CH.sub.2 -CH.sub.2, 20H) 8.5 (m, CONH, 4H exchangeable) 10 (m, NHCO, 2H 
exchangeable) 
3) Preparation of 4,4'-bis [N-(2,3-dihydroxypropyl)-acetylamino]-2,2', 
6,6'-tetra-(2-hydroxyethyl carbamoyl) 3,3', 5,5'tetraiododiphenyl 
(compound No. 3) 
35 g of the preceding product are suspended in 200 ml of ethylene glycol. 
0.186 mole of MeONA dissolved in methanol is added dropwise and the 
reaction mixture is heated for 1 h 30 min at 50.degree. C. 18.2 ml of 
chloropropane diol are added at 10.degree. C. The reaction mixture is 
heated at 50.degree. C. for 44 h, while 0.062 mole of Na methylate in 
solution and 15 ml of chloropropane diol are added every 10 hours. 
After evaporation of the methanol, the residual paste is taken up in 
acetone. After filtration of the salts, the ethylene glycol is evaporated 
under reduced pressure. The residue obtained solidifies in an 
acetone/isopropanol (70:30) mixture, then is filtered off and washed with 
ether. 
The crude compound No. 3 obtained is then purified on a preparative HPLC 
column (SiO.sub.2 C.sub.18) in a yield of 70% TLC (CH.sub.2 Cl.sub.2 
89/MeOH 20): R.sub.f =0.15 TLC (Dioxan 90/H.sub.2 O 10): R.sub.f =0.7 
Purity with respect to iodine: 98% HPLC purity: 97% 
.sup.1 H NMR(DMSO).sub.2 (s, COCH.sub.3 6H) 3-3.6 (m partially exchangeable 
26H aliphatic and 8 OH) 8.4 (s, CONH, 4H exchangeable). 
EXAMPLE 4 
Preparation of 4,4'-bis-(2,3-dihydroxypropyl carbamoyl) 2,2', 
6,6'-tetra-(2-hydroxy-propionylamino) 3,3', 5,5'-tetraiodo diphenyl 
(compound No. 4) 
1) Preparation of 4-bromo 3,5-dinitro benzoic acid 
A sulfuric-nitric acid mixture composed of 346 ml of H.sub.2 SO.sub.4 and 
346 ml of fuming HNO.sub.3 is added dropwise to 100 g (0.49 mole) of 
p-bromobenzoic acid suspended in 900 ml of 98% H.sub.2 SO.sub.4. The 
mixture is heated for 8 h at 80.degree. C., then cooled and poured onto 
ice. The precipitate formed is filtered off, washed with 3.times.200 ml of 
H.sub.2 O, then suspended in 600 ml of H.sub.2 O. After the pH has been 
brought to 9-10 by means of 5N NaOH, the sodium salt is filtered off, then 
resuspended in 1 l of water and acidified to pH=1 by means of 5N HCl. The 
precipitate is then filtered off, washed with water and dried. 
Yield 79% (95 g), M.p. 188.degree. C. TLC (toluene 60/methyl ethyl ketone 
35/formic acid 25): R.sub.f =0.85 Purity with respect to bromine: 99% 
.sup.1 H NMR (DMSO d.sup.6) 8.5 ppm (s, 2H aromatic); 10.4 (s OH acid, 
exchangeable with D.sub.2 O) 
2) Preparation of the methyl ester of 4-bromo 3-5-dinitro benzoic acid 
115 g (0.398 mole) of 4-bromo 3,5-dinitro benzoic acid are dissolved in 840 
ml of methanol. After addition of 57.5 ml of 98% H.sub.2 SO.sub.4, the 
mixture is heated at reflux for 3 hours. After cooling, the product 
precipitates. The reaction product is filtered off, washed with H.sub.2 O 
(3.times.300 ml), then by 100 ml of methanol. 
Yield: 90% 
M.p.: 122.degree.-124.degree. C. (124.degree. C. in the literature) TLC 
(toluene/methyl ethyl ketone/formic acid: 60/35/25): R.sub.f =0.95 
.sup.1 H NMR (DMSO d.sup.6) 4.1 (s, COOCH.sub.3, 3H) 8.75 (s 2H arom.) 
3) Preparation of 4,4'-dimethoxycarbonyl 2,2', 6,6'-tetranitro diphenyl 
To a solution of 60 g (0.196 mole) of the preceding product in 260 ml of 
paraxylene preheated to 80.degree. C. are added 12.6 g of copper. The 
mixture is then heated at 160.degree. C. for 1 h 30 with vigorous 
stirring. 6.4 g of copper are added and the mixture is maintained at 
160.degree. C. for a further hour. The mixture is cooled, then filtered 
through Celite. After evaporation, the residue is taken up in ethyl 
acetate. 
Yield: 73% 
M.p.: 171.degree. C. TLC (toluene/methyl ethyl ketone/formic acid: 
60/35/25): R.sub.f =0.9 
.sup.1 H NMR (DMSO d.sup.6) 4.1 (s COOCH.sub.3, 6H) 9 (s 4H arom.) 
4) Preparation of 4,4'-bis-(2,3-dihydroxypropyl carbamoyl)2,2', 
6,6'-tetranitro diphenyl 
21 g (0.046 mole) of the preceding product are dissolved in 240 ml of DMAC. 
After the reaction mixture has been heated at 60.degree. C., 17.5 g of 
aminopropane diol in 50 ml of DMAC are added dropwise. After being stirred 
for 1 h 30 min., the reaction mixture is cooled, then poured into 1.5 l of 
water. The precipitate is then filtered off, washed with H.sub.2 O and 
then with ether. 
M.p. : 130.degree. C. TLC (toluene/methyl ethyl ketone/formic acid: 
60/35/25): R.sub.f =0.15 
.sup.1 H NMR (DMSO) 3.4-3.9 (m CH--CH.sub.2 12H) 4.5-5 (m OH exchangeable 
4H) 9.1 (s 4H arom) 
5) Preparation of 4,4'-bis (2,3-dihydroxypropyl carbamoyl) 
2,2'-6,6'-tetraamino diphenyl 
A suspension of 9 g of the preceding product is added to a H.sub.2 O/MeOH 
mixture (150 ml/150 ml) containing 30 g of Raney nickel and the mixture is 
stirred under H.sub.2 pressure (3.10.sup.5 Pa) for 24 h at room 
temperature. After the reaction mixture has been filtered through Celite, 
the filtrate is evaporated and the residue is crystallized from absolute 
methanol. 
Yield: 50%, M.p.=250.degree. C. TLC (dichloromethane/methanol: 80/20): 
R.sub.f =0.05 
6) Preparation of 4,4'-bis-(2,3-dihydroxypropyl carbamoyl) 2,2', 
6,6'-tetraamino 3,3', 5,5'-tetraiodo diphenyl 
A solution of 20.4 g of I.sub.2 (0.084 mole) and 13.3 g (0.0804 mole) of KI 
in 20 ml of H.sub.2 O, prepared immediately before use, is added dropwise 
to a solution of 6 g of the preceding product in 600 ml of H.sub.2 O and 
60 ml of 33% ethylamine. At the end of the addition, the mixture is heated 
for 3 h at 80.degree. C. After addition of 10 ml of a solution of 6.8 g of 
12 (0.0268 mole) and 4.4 g (0.0268 mole) of KI in water, the mixture is 
heated for 3 h at 80.degree. C., then left to stand overnight at room 
temperature. The precipitate is filtered off, washed with water, bisulfite 
and acetone, and dried. 
Yield=50% TLC (dichloromethane/methanol: 80/20): R.sub.f =0.3 Purity with 
respect to iodine: 97% 
.sup.1 H NMR (DMSO d.sup.6) 3.1 (m complex) 4.4 and 8 (multiplets 
exchangeable with D.sub.2 O 
7) Preparation of 4,4'-bis-[2,3-di-(2-acetoxy 
propionyloxy)-propyl-carbamoyl]2,2', 6,6'-tetra-(2-acetoxy-propionyl 
amino) 3,3', 5,5'-tetraiodo diphenyl. 
5 g (0.033 mole) of acetylated lactic acid chloride and 4.7 ml (0.033 mole) 
of triethylamine are added simultaneously to a solution cooled to 
5.degree. C. of 2.7 g (0.0024 mole) of the preceding product in 15 ml of 
DMAC. During the addition, the temperature is maintained below 10.degree. 
C., then the mixture is heated slowly to 40.degree. C. during 8 h. 
1.08 g (0.0072 mole) of acetylated lactic acid chloride and 1.01 ml (0.0072 
mole) of triethylamine are then added simultaneously at 10.degree. C. The 
reaction mixture is then heated at 40.degree. C. for 12 h. After removal 
of the triethylamine hydrochloride formed by filtration and evaporation of 
the DMAC, the residue is poured into water. The crystals obtained are 
washed with water, then with ether. 
Yield: 80% Purity with respect to iodine: 105% TLC (toluene 60/methyl ethyl 
ketone 35/formic acid 25): R.sub.f =0.6 (3 spots joined together) 
.sup.1 H NMR (DMSO d.sup.6) 1.3 (multiplet C--CH.sub.3, 24H) 2.1 (s. 
COCH.sub.3 24H) 3.1-5.4 (multiplet, partially exchangeable NH--CO4H; 
C--CH--C 12H, CO--CH--C 8H) 
8) Preparation of 4,4'-bis-(2,3-dihydroxypropyl carbamoyl) 2,2', 6,6'-tetra 
(2-hydroxypropionylamino)-3,3', 5,5'-tetraiodo diphenyl (compound No. 4) 
31.5 g (0.0168 mole) of the preceding product are added to a suspension of 
27.6 g of K.sub.2 CO.sub.3 in 400 ml of methanol and the mixture is 
stirred for 4 h at room temperature. The solution is then evaporated and 
passed through a H.sup.+ ion exchange resin. The product obtained after 
evaporation is washed with acetone. 
Yield: 50% Purity with respect to iodine: 96.6% Water content: 1.83% 
M.p.=220.degree. TLC (dichloromethane/methanol: 80/20): R.sub.f =0.7 TLC 
(butanol/water/acetic acid: 50/25/11): R.sub.f =0.35 
.sup.1 H NMR (DMSO) 1.2 (s. C--CH.sub.3, 12H) 3 to 6 (3 complex multiplets 
##STR89## 
10H, CO--CH--O 4H, 8 OH, exchangeable) 9-9.5 (1 multiplet exchangeable 
with D.sub.2 O, --NH--CO, CO--NH--, 5H). 
EXAMPLE 5 
Preparation of 2,2', 4,4', 6,6'-hexa-(2-hydroxy-propionyl amino) 
3,3'-5,5'-tetraiodo diphenyl (compound No. 5) 
1) Preparation of 4,4'-dicarboxy 2,2', 6,6'-tetranitro diphenyl 
55.4 g (0.123 mole) of the product obtained in part 3 of the preceding 
example is suspended in 600 ml of H.sub.2 O containing 10.6 g (0.27 mole) 
of NaOH. The mixture is heated at 80.degree. C. for 6 h, then cooled. The 
aqueous phase is washed with 2.times.200 ml of dichloromethane, then 
acidified by means of HCl. The precipitate is washed with H.sub.2 O 
(3.times.300 ml), then dried. 
Yield: 100%. M.p.&gt;300.degree. C. TLC (toluene/methyl ethyl ketone/formic 
acid: 60/35/25): R.sub.f =0.75 
.sup.1 H NMR (DMSO) 8.9 (s. 4H arom) 14 (2 2H COOH exchangeable with 
D.sub.2 O). 
2) Preparation of 4,4'-diamino 2,2', 6,6'-tetranitro diphenyl 
51 g (0.120 mole) of the preceding product is dissolved in 320 ml of 30% 
oleum, then diluted with 280 ml of 1,2-dichloroethane. The mixture is 
heated to 45.degree. C. Then, 23 g of NaN.sub.3 are added in portions, 
while the temperature is maintained below 50.degree. C. After the end of 
the addition, the reaction mixture is heated progressively to 90.degree. 
C., then stirred for 3 hours. 9 g of NaN.sub.3 are then added at a 
temperature lower than 50.degree. C. The mixture is heated at 90.degree. 
C. for 2 h. After cooling to room temperature and decantation, the lower 
phase is poured slowly into an ice-water mixture. The product precipitates 
and the suspension is stirred for 1/2 hour at 60.degree. C., then left 
overnight at room temperature. After filtration, washing with water, then 
with ether, the desired product is obtained in a yield of 90%. 
M.p.&gt;300.degree. C. TLC (toluene 60/methyl ethyl ketone 35/formic acid 25): 
R.sub.f =0.9 
.sup.1 H NMR (DMSO) 5.8 (1s NH.sub.2 4H disappears with D.sub.2 O) 7.5 (s, 
4H arom) 
3) Preparation of 4,4'-di-(2-acetoxypropionylamino) 2,2', 6,6'-tetranitro 
diphenyl 
59.5 g (0.163 moles) of the preceding product are added in portions to a 
solution of 54.3 g (0.358 mole) of acetylated lactic acid chloride in 300 
ml of anhydrous DMAC. The temperature is maintained below 10.degree. C. 
during the addition, then is allowed to rise to room temperature and the 
mixture is stirred for 2 h. After evaporation of the DMAC, the residue is 
poured into an ice/water mixture to give the desired product in the form 
of crystals. After washing with water and then with methanol, the yield is 
83%. 
M.p.=264.degree. C. TLC (toluene/methyl ethyl ketone/formic acid: 
60/35/25): R.sub.f =0.7 
.sup.1 H NMR (DMSO d.sup.6) 1.5 (d C--CH.sub.3 6H) 2.1 (s, COCH.sub.3 6H) 
5.1 (d CO--CH--C 2H) 8.7 (s 4H arom) 14 (s CO--NH-phenyl 2H exchangeable) 
4) Preparation of 4,4'-di-(2-hydroxypropionyl amino) 2,2'-6,6'-tetraamino 
diphenyl 
10 g (0.0167 mole) of the preceding product are added to a mixture of MeOH 
(460 ml) and water (160 ml) containing 40 g of Raney nickel and the 
mixture is stirred under H.sub.2 pressure (3.10.sup.5 Pa) for 24 h at room 
temperature. After removal of the catalyst by filtration and evaporation 
of the filtrate, the residue is crystallized from ethanol. The final 
product is obtained after filtration in a yield of 60%. TLC 
(dichloromethane/methanol: 80/20): Rf 0.45 
.sup.1 H NMR (DMSO d.sup.6) 1.3-1.5(C--CH.sub.3 6H) 4.1 (s NH.sub.2 8H 
exchangeable) 5 (m C--CH--CO, 2H) 5.5 (s. C--OH 2H, exchangeable) 6.4 (s 
4H arom) 8.8 (s CO--NH-phenyl 2H) 
5) Preparation of 4,4'-di-(2-hydroxypropionyl amino) 2,2', 6,6'-tetraamino 
3,3', 5,5'-tetraiodo diphenyl 
To a solution of 6 g (0.129 mole) of the preceding product in a mixture of 
water (800 ml) and 33% ethylamine (80 ml) is added dropwise a solution of 
100 ml of H.sub.2 O containing 41.7 g of I.sub.2 and 31 g of KI. As soon 
as the addition is complete, the mixture is heated for 6 h at 80.degree. 
C., then stirred overnight at room temperature. The precipitate which 
forms is filtered off, washed with H.sub.2 O, then with a solution of 
bisulfite and, finally, dried. The final product is obtained in a yield of 
80%. Purity with respect to iodine: 97% TLC (toluene/methyl ethyl 
ketone/formic acid: 60/35/25): R.sub.f =0.2 
.sup.1 H NMR (DMSO) 1.3-1.5 
##STR90## 
3.7-4.4 
##STR91## 
4H, HN.sub.2 8H, partially exchangeable with D.sub.2 O) 9.1 (s, 
CO-NH-phenyl, 2H exchangeable) 
6) Preparation of 4,4-di[(2-acetoxy 2-propionyloxy)-propionyl amino]2,2', 
6,6'-tetra-(2-acetoxypropionyl amino) 3,3', 5,5'-tetraiodo diphenyl 
To a solution of 9.5 g (0.01065 mole) of the preceding product and 20 ml of 
triethylamine in 100 ml of anhydrous DMAC are added dropwise 21.3 g of 
acetylated lactic acid chloride. The reaction mixture is heated for 10 h 
at 50.degree. C., then it is left to stand for 12 h at room temperature; 
the DMAC is evaporated in a vacuum and the residue is poured into water. 
The precipitate obtained is taken up in CHCl.sub.3. The chloroform phase 
is washed with water, dried over MgSO.sub.4 and evaporated. The residue 
obtained crystallizes from isopropyl ether and gives the final product in 
a yield of 73%. Purity with respect to iodine: 105% TLC (toluene/methyl 
ethyl ketone/formic acid: 60/35/25): R.sub.f =0.6 (3 spots joined 
together) 
.sup.1 H NMR (DMSO) 0.8 to 1.6 (multiplet CH--CH.sub.3 24H) 2 (s 
OCOCH.sub.3 18H) 4.4 to 5.4 (m --CH8H) 7.8 to 12 (multiplet - NH- 6H 
exchangeable) 
7) Preparation of 2,2', 4,4', 6,6'-hexa-(2-hydroxy propionyl amino) 3,3', 
5,5'-tetraiodo diphenyl (compound No. 5) 
3 g of K.sub.2 CO.sub.3 are added to a solution of 6 g (0.0038 mole) of the 
preceding product in 120 ml of MeOH. After being stirred overnight at room 
temperature, the solution is evaporated to dryness, then diluted with 
H.sub.2 O. This solution is passed through a H.sup.+ ion exchange resin, 
then evaporated. The residue is crystallized from acetone and the crystals 
are washed with petroleum ether. 
Yield: 35% Purity with respect to iodine: 93% TLC 
(dichloromethane/methanol: 60/40): R.sub.f =0.9 TLC (butanol/water/acetic 
acid: 50/25/11): R.sub.f =0.5=0.6 
.sup.1 H NMR (DMSO) 0.6-1.6 (multiplet CH--CH.sub.3 18H) 3.6-4.8 (multiplet 
-CH--OH 12H, partially exchangeable) 8.5-9.8 (multiplet-NH, 6H 
exchangeable) 
EXAMPLE 6 
Preparation of 2,2'-di-(2-hydroxypropionyl amino) 4,4', 6,6'-tetra 
(2-hydroxyethyl carbamoyl) 3,3', 5,5'-tetraiodo diphenyl (compound No. 6) 
1) Preparation of 4-bromo isophthalic acid 
10 g (54 mmoles) of 5-bromo xylene are dissolved in 200 ml of water 
containing 49 g (0.22 mole) of potassium permanganate. The reaction 
mixture is refluxed for 48 hours. 
The manganese dioxide formed is filtered onto Celite and the filtrate is 
acidified by a 2N solution of HCl. The white precipitate obtained is 
filtered off, washed with water and dried in an oven. 
Yield: 43% TLC (isopropanol/ethyl acetate/ammonia: 25/35/40) R.sub.f =0.67 
M.p.&gt;260.degree. C. Purity with respect to bromine: 106% 
IR (KBr): 3000 cm.sup.-1 (.nu.OH), 1680 (.nu.CO) 
.sup.1 H NMR (DMSO): disappearance of the methyl protons 
2) Preparation of 4-bromo 5-nitro isophthalic acid 
235 ml of a sulfuric-nitric acid mixture (HNO.sub.3 :3.5 ml+H.sub.2 
SO.sub.4 : 20 ml) are added dropwise at 0.degree. C. to a solution of 
4-bromo isophthalic acid (10 g) in 100 ml of sulfuric acid. The reaction 
mixture is heated at 50.degree. C. overnight until the starting compound 
has disappeared. The reaction product obtained is then precipitated on 
crushed ice. After filtration, washing with water and drying, 10.8 g of 
product are recovered in a yield of 91%. TLC (toluene/methyl ethyl 
ketone/formic acid 60/25/25): R.sub.f :0.68 TLC (isopropanol/ethyl 
acetate/ammonia 25/35/40): R.sub.f :0.4 
M.p.&gt;260.degree. C. Purity with respect to bromine: 99.3% 
IR (KBr): 3000 cm.sup.-1 (.nu.OH); 1700 (.nu.CO), 1590 (.nu.C=C arom.); 
1540 (.nu.NO.sub.2) 
.sup.1 H NMR (DMSO): .delta.8.4-8.5 ppm (2 split doublets, 2H aromatic) 
3 Preparation of dimethyl 4-bromo 5-nitro isophthalate 
16 ml of concentrated sulfuric acid are added to a solution of 105 g (0.23 
mole) of 4-bromo 5-nitro isophthalic acid in 60 ml of methanol. The 
reaction mixture is refluxed for 15 hours. After being left overnight at 
room temperature, the crystallized product is filtered off, washed with 
water, then dried in an oven. 
Yield: 91% TLC (toluene/methyl ethyl ketone/formic acid 60/25/25): R.sub.f 
=0.82 TLC (dichloromethane): R.sub.f :0.7 
M.p.=90.degree. C. Purity with respect to bromine: 100% 
IR (KBr): 1735 cm.sup.=1 (.nu.CO), 1600 (.nu.C=C); 1540 (.nu.NO.sub.2) 
.sup.1 H NMR (CDCl.sub.3): .delta.4 ppm (singlet, 6H, 2CH.sub.3 of the 
esters) 8 ppm (2 multiplets, 2H aromatic) 
4) Preparation of 2,2'-dinitro 4,4', 6,6'-tetra-methoxycarbonyl diphenyl 
40.5 g of copper are added to a solution of dimethyl 4-bromo 5-nitro 
isophthalate (71 g, 0.22 mole) in 240 ml of p-xylene. The mixture is 
heated at reflux for 24 hours. After being allowed to cool to room 
temperature, the reaction mixture is filtered and the filtrate is 
evaporated under reduced pressure. The residue obtained is crystallized 
from isopropyl ether. 42.5 g of product are obtained. 
Yield: 80% TLC (hexane/ethyl acetate v/v) R.sub.f :0.6 TLC (CH.sub.2 
Cl.sub.2) R.sub.f :0.4 
M.p. : 116.degree.-119.degree. C. 
IR (KBr): 1720 (.nu.CO), 1530 (.nu.NO.sub.2) 
.sup.1 H NMR (CDCl.sub.3): .delta.8.8 ppm (multiplet, 4H aromatic), 
.delta.4 ppm (singlet, 6H, 2 methyl at 4,4'); .delta.3.6 ppm (singlet, 6H, 
2 methyl at 6,6'). 
5) Preparation of 2,2'-dinitro 4,4', 6,6'-tetra-(2-hydroxyethyl carbamoyl) 
diphenyl 
58.8 g of ethanolamine are added to a suspension of the preceding product 
(48.3 g; 0.1 mole) in 360 ml of methanol. After being refluxed for 48 
hours, the reaction mixture is left to stand at room temperature for 24 
hours. The precipitate formed is filtered off, then taken up in acetone. 
After drying, 50.5 g of the product are obtained in a yield of 84%. TLC 
(dioxane/water: 9/1): R.sub.f 0.75 TLC (dichloromethane/methanol: 8/2): 
R.sub.f 0.23 
IR (KBr): 3430 cm.sup.-1 (.nu.N--H), 3200-3500 (.nu.OH), 3090 (.nu.H 
aromatic) 2900 (.nu.H aliphatic), 1640 (.nu.CO--NH), 1000 (.nu.C=C arom.), 
1545 (.nu.NO.sub.2) 
.sup.1 H NMR (DMSO, H.sub.2 O): .delta.8.4 and 8.9 ppm (2 doublets, 4H 
aromatic) .delta.3.25 and 3.6 ppm (2 multiplets, 16H CH.sub.2 aliphatic ) 
6) Preparation of 2,2'-diamino 4,4', 6,6'-tetra-(2-hydroxyethyl carbamoyl) 
diphenyl 
A methanolic solution (250 ml) of 15 g of the preceding product is stirred 
under an atmosphere of hydrogen (pressure of 3.10.sup.5 Pa) for 1 h30 in 
the presence of 10% palladised charcoal (2.5 g). The catalyst is then 
removed by filtration. After evaporation of the solvent under reduced 
pressure, the residue is recrystallized from ether and 12.9 g of product 
are obtained in a yield of 90.6%. TLC (dichloromethane/methanol: v/v): 
R.sub.f 0.45 
.sup.1 H NMR (DMSO): .delta.8.1 and 8.35 ppm (2 multiplets, 2H exchangeable 
with D.sub.2 O, NH); .delta.7.05 ppm (multiplet 4H, aromatic), .delta.4.4 
ppm (multiplet, 8H exchangeable with D.sub.2 O, NH.sub.2, OH); .delta.3.05 
and ppm (2 multiplets, 16H, CH.sub.2 aliphatic). 
7) preparation of 2,2'-diamino 4,4', 6,6'-tetra-(2-hydroxyethyl carbamoyl) 
3,3', 5,5'-tetraiodo diphenyl 
35 ml of iodine chloride (70% in iodine) are added dropwise with vigorous 
stirring and at room temperature to a solution of the preceding product 
(23.6 g) in 470 ml of water. The reaction medium is heated at 40.degree. 
C. for 2 hours. After being left to stand for half an hour at room 
temperature, the excess iodine is destroyed by sodium hydrosulfite and the 
precipitate is filtered off, washed with water and then with ethanol. It 
is dried in an oven at 60.degree. C. to give 40.2 g of product in a yield 
of 87.5% TLC (methylene chloride/methanol v/v): R.sub.f 0.87 TLC 
(butanol/water/acetic acid 50/25/11): R.sub.f 0.45 Purity with respect to 
iodine: 103% 
.sup.1 H NMR (DMSO): .delta.7.8-8.5 ppm (2 m, 4H, NH), .delta.4.15 ppm 
(singlet, 4 exchangeable, OH); .delta.2.6-3.8 ppm (2 multiplets, 16H, 
CH.sub.2 aliphatic) HPLC Lichrospher 100 rp 8.5.mu.; 12.5 cm MeOH 65/water 
35: l ml/min., purity 99% 
8) Preparation of 2,2'-di-(2-acetoxypropionyl amino) 4,4', 
6,6'-tetra-(2-acetoxyethyl carbamoyl) 3,3', 5,5'-tetraiodo diphenyl 
5.3 g of O-acetylated lactic acid (34.7 moles) are added dropwise at 
0.degree. C. to a solution containing 3 g of the preceding product in 35 
ml of anhydrous DMAC. The suspension is then heated at 60.degree. C. for 
21 hours. The DMAC is evaporated under reduced pressure. The oil obtained 
is retreated with dichloromethane, washed with water then dried over 
sodium sulfate. After evaporation in a vacuum, the residue is precipitated 
with a mixture of methylene chloride and isopropyl ether, then filtered 
off to give 3.6 g of product in a yield of 78.3%. TLC (methylene 
chloride/methanol 8/2): R.sub.f 0.88 TLC (butanol/water/acetic acid 
50/25/11): R.sub.f :0.82 TLC (isopropanol/ethyl acetate/ammonia: 
25/35/40): R.sub.f :0.86 Purity with respect to iodine: 98.2% 
IR (KBr): 3340 (.nu.N--H), 1730 cm.sup.-1 (.nu.CO ester); 1650 (.nu.CO--NH) 
.sup.1 H NMR (CDCl.sub.3): .delta.5 ppm (multiplet, 1H, CH lactic); 4.3 ppm 
(m, 2H, CH.sub.2 --CO); 3.7 ppm (multiplet, 2H, N--CH.sub.2); 2.1 ppm 
(singlet, 18H, O--CO--CH.sub.3); 1.5 ppm (d, 18H, CH.sub.3 lactic). 
9) Preparation of 2,6-di-(2-hydroxypropionyl amino)-2,4,4', 
6,'-tetra-(2-hydroxyethyl carbamoyl) 3,3', 5,5'-tetraiodo diphenyl 
(compound No. 6) 
The O-acylated compound obtained in the preceding step (49 g) dissolved in 
600 ml of ethanol is treated with an ethanolic solution (200 ml) of sodium 
hydroxide (16 g). The reaction mixture is stirred for 3 hours. The residue 
after evaporation of the solvent is washed with acetone, then precipitated 
with ether. The product is filtered off and desalted by being passed 
through H.sup.+ (IRN77) and OH.sup.- (IRN 78) resins. The water is 
evaporated under reduced pressure and the residue is precipitated with 
acetone, then washed with ether to give 23 g of crude product. 
EXAMPLE 7 
Preparation of 2,2'-di-(2-hydroxy-acetylamino)-4,4', 
6,6'-tetrakis-(2,3-dihydroxypropyl carbamoyl) 3,3', 5,5'-tetraiodo 
diphenyl (compound No. 7). 
1) Preparation of 2,2'-dinitro 4,4', 6,6'-tetrakis-(2,3-dihydroxypropyl 
carbamoyl) diphenyl 
74 g of aminopropane diol are added dropwise to a preheated solution of a 
product (38.7 g; 81.3 moles) in part 4 of the preceding example in 255 ml 
of methanol. The mixture is heated at reflux for 12 h. After being allowed 
to cool to room temperature, the reaction mixture is filtered and the 
filtrate is evaporated under reduced pressure. The residue is dissolved in 
750 ml of water, then purified by passage through a column of a H.sup.+ 
resin (IRN 77). The water is eliminated by distillation and the residue is 
taken up in isopropyl ether. The product obtained is filtered off and 
dried to give 55.3 g in a yield of 95.5%. TLC (dioxan/water: 9/1) R.sub.f 
:0.65 
.sup.1 H NMR (DMSO): .delta.3.6 and 3.3 ppm (2 m, 20H, CH.sub.2 and CH 
aliphatics) .delta.4.55 ppm (1 m, 8H exchangeable with D.sub.2 O, OH) 
.delta.8.95 and 8.5 ppm (2 m, 4H aromatic) 
IR (KBr) 3300 cm.sup.-1 (.nu.OH) 1630 (.nu.CO--NH); 1520 and 1310 
(.nu.NO.sub.2) 
2) Preparation of 2,2'-diamino 4,4', 6,6'-tetrakis-(2,3-dihydroxy-propyl 
carbamoyl) diphenyl 
An aqueous solution (600 ml) of the preceding compound (28.9 g; 40.6 mmole) 
is stirred under an atmosphere of hydrogen (pressure of 4.10.sup.5 Pa) for 
5 hours in the presence of 10% palladised charcoal (6 g). The catalyst is 
then removed by filtration. After evaporation of the solvent under reduced 
pressure, the residue is taken up in methanol, concentrated then 
neutralized with isopropyl ether. 
24.7 g of product are obtained in a yield of 93.3% TLC (dioxan/water: 9/1): 
R.sub.f 0.6 
.sup.1 H NMR (DMSO) .delta.3.3 and 3.1 ppm (1 multiplet, 20 H, CH.sub.2 and 
CH aliphatic) .delta.4.45 ppm (1 multiplet, 12H exchangeable with D.sub.2 
O, 8 OH+2 NH.sub.2); .delta.7.1 ppm (1 multiplet, 4H aromatic); .delta.8.4 
and 8.1 ppm (2 multiplets, 4H exchangeable with D.sub.2 O, 4 NH) 
IR (KBr) 3100-3500 cm.sup.-1 (.nu.OH, NH.sub.2) 1620(.nu.CONH) 
3) Preparation of 2,2'-diamino 4,4', 6,6'-tetrakis-(2,3-dihydroxypropyl 
carbamoyl) 3,3', 5,5'-tetraiodo diphenyl 
126 ml of iodine chloride (70% in iodine) are added dropwise with vigorous 
stirring and at room temperature to a solution of the compound obtained in 
the previous step (63.9 g; 98 moles) in 300 ml of water. The reaction 
mixture is maintained at 45.degree. C. for 7 hours and then for 16 hours 
at room temperature. After evaporation, the residue is taken up in 
absolute ethanol. The solid collected by filtration is then purified after 
being dissolved in 1 l of water by successive passages through H.sup.+ 
(IRN 77) and OH.sup.- (IRN 78) resins. The resulting solution is 
evaporated to dryness. After washing with ether and drying, 73.7 g of 
product are isolated in a yield of 65%. TLC (dioxan/water: 9/1) R.sub.f 
:0.86 Purity with respect to iodine: 98.1% 
.sup.1 H NMR (DMSO) .delta.3.95 ppm (1 multiplet, 20H CH.sub.2 and CH 
aliphatic); 4.6 ppm (1 multiplet, 12H exchangeable with D.sub.2 O, 8 OH 
and 2 NH.sub.2); 8.2 ppm (1 multiplet, 4H exchangeable, NH) 
4) Preparation of 2,2'-di-(2-acetoxyacetylamino) 4,4', 
6,6'-tetrakis-/2,2-di(2-acetoxy-acetoxy)propyl carbamoyl/3,3', 
5,5'-tetraiodo diphenyl 
100.4 g of O-acetylated glycolic acid chloride (0.735 mole) are added 
dropwise to a solution of 42.5 g (36.7 moles) of the preceding compound in 
300 ml of anhydrous DMAC. The reaction mixture is stirred at room 
temperature for 22 hours until the starting amine has disappeared (checked 
by the thiocol test). The DMAC is evaporated under reduced pressure, the 
residue obtained is extracted with dichloromethane, washed with water then 
dried over Na.sub.2 SO.sub.4. After being concentrated and taken up in 
ethyl ether 72.1 g of product are obtained in a yield of 91%. TLC 
(dioxan/water: 9/1): R.sub.f 0.9. Purity with respect to iodine: 99.2% 
5) Preparation of 2,2'-di-(2-hydroxy acetylamino) 4,4', 
6,6'-tetrakis-(2,2-dihydroxypropyl carbamoyl) 3,3', 5,5'-tetraiodo 
diphenyl (compound No. 7) 
69 g (0.032 mole) of the product described in the preceding step are 
deprotected by dissolution in 100 ml of absolute ethanol to which 1.3 l of 
a 0.5N solution of ethanolic sodium hydroxide is added. The reaction 
mixture is stirred for 3/4 hour. The precipitate formed is filtered off, 
dried and then desalted by passages through H.sup.+ (IRN 77) and OH.sup.- 
(IRN 78) resins. The water is removed by distillation and the residue is 
taken up in ethyl ether. 28.7 g of product are recovered and purified by 
HPLC (RP 18). Overall yield: 56.4% TLC (dioxan/water: 9/1): R.sub.f :0.55 
HPLC purity: 98.3% 
.sup.1 H NMR (DMSO) .delta.8.95 ppm (multiplet, 2H exchangeable with 
D.sub.2 O, --NH--CO); .delta.8.35 ppm (multiplet, 4H exchangeable with 
D.sub.2 O, --CO--NH); .delta.5.2 ppm (multiplet, 2H exchangeable with 
D.sub.2 O, --NHCOCH.sub.2 OH); .delta.4.7 ppm (multiplet, 8H exchangeable 
with D.sub.2 O, --CONHCH.sub.2 --CHOH--CH.sub.2 OH); .delta.63.4 ppm 
(multiplet, 24H exchangeable with aliphatic protons) 
EXAMPLE 8 
Preparation of 3,3'-bis-/(3-hydroxy 2-hydroxy-methyl)propionyl/ amino 
5,5'-bis/N-methyl-N-(2,3-dihydroxy-propyl)/carbamoyl 2,2', 4,4', 
6,6'-hexaiodo diphenyl (compound No. 8). 
1) Preparation of 3-iodo 5-nitro benzoic acid 
To 122 g (0.53 mole) of H.sub.5 IO.sub.6 and 400 g (1.57 mole of iodine 
dissolved in 2750 ml of 20% oleum at 10.degree. C. by stirring for 30 
minutes are added 120 g (0.72 mole) of 3-nitro benzoic acid. After being 
stirred at room temperature for 12 hours, this solution is poured slowly 
onto ice. The precipitate formed is filtered off, then washed with a 20% 
solution of sodium bisulfite before being dissolved in a solution of 
sodium hydroxide, followed by filtration through paper. After 
acidification with HCl, 170 g of white crystals are obtained which are 
filtered off and dried. 
Yield=81% 
M.p.=172.degree. C. TLC (toluene 60/methyl ethyl ketone 25/HCOOH 5) R.sub.f 
=0.75 Purity with respect to iodine=99% 
.sup.1 H NMR (DMSO) .delta.8.5 ppm (s, 2H aromatic); .delta.8.7 ppm (s, 1H 
aromatic); 13 ppm (m, COOH 1H exchangeable with D.sub.2 O) 
2) Preparation of the methyl ester of 3-iodo 5-nitro benzoic acid 
180 g (0.614 mole) of the compound obtained in 1 dissolved in 1800 ml of 
methanol and 10 ml of 98% H.sub.2 SO.sub.4 are heated at reflux for 24 
hours. After evaporation of two-thirds of the methanol, the solution 
obtained is cooled and the ester which precipitates is filtered off. After 
dissolution of the product in 2000 ml of ether, the etheral phase is 
washed with 1000 ml of water, then dried over MgSO.sub.4 and evaporated to 
dryness. 181 g of white crystals are obtained. 
Yield: 90% 
M.p.=88.degree. C. Purity with respect to iodine 99% TLC (CH.sub.2 Cl.sub.2 
70-MeOH 30): R.sub.f =0.95 
IR 1720 (COOCH.sub.3); 1520 (NO.sub.2). 
.sup.1 H NMR (DMSO) .delta.3.9 ppm (s, COOCH.sub.3, 3H); .delta.8.5 ppm (s, 
2H aromatics); .delta.8.7 ppm (s, 1H aromatic). 
3) Preparation of 5,5'-dimethoxycarbonyl 3,3'-dinitro diphenyl 
86 g (0.28 mole) of the compound obtained in step 2) are heated to 
220.degree. C. After addition of 86 g of copper, the temperature is raised 
gradually to 270.degree. C. and a further 20 g of copper are added. The 
mixture is maintained at this temperature for 1 hour before being cooled. 
After extraction with CH.sub.2 Cl.sub.2 and filtration through Celite, the 
organic phase is evaporated to dryness. 
The residual paste is washed with 2.times.500 ml of petroleum ether, then 
taken up in ether. The brown precipitate formed is filtered off, then 
purified by means of chromatography on silica. After evaporation, 20 g of 
brown crystals are obtained. 
Yield=40% 
M.p.=159.degree. TLC (CH.sub.2 Cl.sub.2): R.sub.f =0.6 
.sup.1 H NMR (DMSO): .delta.3.9 ppm (s, COOCH.sub.3, 6H); .delta.8.5 ppm 
(2s, 4H aromatic); .delta.8.7 ppm (1s, 2H aromatic) 
4) Preparation of 5,5'-dicarboxy 3,3'-dinitro diphenyl 
14 g (0.038 mole) of the compound obtained in 3) are heated at reflux for 
18 h in 100 ml of a 25% aqueous solution of NaOH. 
The solution obtained is cooled; after acidification, the precipitate 
formed is extracted with ethyl acetate and washed with water. After 
evaporation and washing with ether, 12 g of white crystals are obtained. 
Yield =95% 
M.p.&gt;300.degree. C. TLC (toluene 60/methyl ethyl ketone 25/HCOOH 25): 
R.sub.f =0.8 
.sup.1 H NMR (DMSO): .delta.5.3 ppm (m, COOH, 2H exchangeable with D.sub.2 
O); .delta.8.65 to 8.8 ppm (3s, 6H aromatic). 
5) Preparation of 3,3'-dinitro 5,5'-bis-(N-methyl N-2,3-dihydroxy propyl) 
carbamoyl diphenyl 
1.66 g (0.005 mole) of the compound obtained in 4) are added to a solution 
of 60 ml of SOCl.sub.2 and 0.1 ml of dimethylformamide. The solution is 
heated at reflux for 5 hours. After distillation of the SOCl.sub.2, the 
paste obtained is dissolved in CH.sub.2 Cl.sub.2 and poured dropwise at 
5.degree. C. into a solution containing 2.1 g (0.02 mole) of N-methyl 
amino 2,3-propanediol and 2.8 ml (0.02 mole) of triethylamine dissolved in 
20 ml of dimethylacetamide. After addition, the mixture is stirred at room 
temperature for 12 h. After filtration of the triethylamine hydrochloride, 
the solvent is evaporated. The paste obtained is purified by passage 
through a H.sup.+ /OH.sup.- resin, then by chromatography on silica. After 
evaporation of the solvents 1.9 g of white crystals are obtained. 
Yield=70% TLC (CH.sub.2 Cl.sub.2 85/MeOH 15) R.sub.f =0.35 
IR: 3300-3500 (OH); 1600 
##STR92## 
1520 (NO.sub.2) 
.sup.1 H NMR (DMSO): .delta.3 ppm 
##STR93## 
.delta.3.2 ppm to 4 ppm (m, CH.sub.2 --CH--CH.sub.2, 10H) ; .delta.4.4 ppm 
to 5.5 ppm 
##STR94## 
exchangeable with D.sub.2 O); .delta.8.3 ppm (s, 4H arom); 8.7 ppm (s, 2H 
arom) 
b 6) Preparation of 3,3'-diamino 5,5'-bis-[N-methyl N-(2,3-dihydroxypropyl) 
carbamoyl]2,2', 4,4', 6,6'-hexaiodo diphenyl 
a) Reduction of the nitro groups: 
1.6 g (0.0031 mole) of the compound obtained in 5) dissolved in 200 ml of 
methanol in the presence of 1 g of 10% Pd/C are shaken in a 500 ml 
autoclave for 2 h30 at 40.degree. C. under a hydrogen pressure of 
6.10.sup.5 Pa. After removal of the catalyst by filtration and evaporation 
of the solvent, a paste is obtained. TLC (CH.sub.2 Cl.sub.2 80/MeOH 20): 
R.sub.f =0.1 
b) Iodination by ICl 
To the paste obtained in a) dissolved in 100 ml of a mixture MeOH/H.sub.2 
O:50/50 are added dropwise 2.1 ml (0.027 mole) of a 70% solution of ICl. 
When the addition is complete, the reaction mixture is heated at 
60.degree. C. for 4 h, then left to stand at room temperature for 12 h. 
The brown solution obtained is poured with stirring into 200 ml of water. 
The precipitate formed is filtered off, then washed with a 20% solution of 
sodium bisulfite and H.sub.2 O. The product is taken up in ether, then 
dried. 3 g of white crystals are obtained. 
Yield=80% Purity with respect to iodine=99% TLC (CH.sub.2 Cl.sub.2) 85/MeOH 
15): R.sub.f =0.4 
.sup.1 H NMR (DMSO) .delta.2.9 and 3.1 ppm (s, N--CH.sub.3 Z) (s, 
N--CH.sub.3 E) 6H; .delta.3.2 to 4 ppm (m, CH.sub.2 --CH--CH.sub.2, 10H); 
.delta.4.4 to 4.8 ppm 
##STR95## 
exchangeable with D.sub.2 O) .delta.5.5 ppm (s, NH.sub.3, 4H exchangeable 
with D.sub.2 O) 
7) Preparation of 3,3'-diamino 5,5'-bis/N-methyl N-(2,3-diacetoxypropyl) 
carbamoyl/ 2,2, 4,4', 6,6'-hexaiodo diphenyl 
To 1.2 g (0.001 mole) of the compound obtained in 6) dissolved in 12 ml of 
pyridine 1.5 ml of acetic anhydride are added dropwise at 5.degree. C. 
After the reaction mixture has been stirred at room temperature for 18 h, 
the crude product is poured into ice-cold water, acidified with 30 ml of 
5N HCl. The precipitate formed is filtered off, then taken up in CH.sub.2 
Cl.sub.2. The organic phase is washed with water, then dried over 
MgSO.sub.4. After evaporation, 1 g of white crystals are obtained which 
are washed with ether and dried. 
Yield: 73% Purity with respect to iodine: 98% TLC (CH.sub.2 Cl.sub.2 
85/MeOH 15): R.sub.f =0.8 
IR 3300-3450:--NH.sub.2 ; 1720: 
##STR96## 
1580: NH.sub.2 
.sup.1 H NMR (DMSO) .delta.2.1 ppm (s, OCOCH.sub.3, 12H); .delta.2.9 ppm 
and 3 ppm 
##STR97## 
.delta.3.5 ppm to 4,5 ppm (m, --N--CH.sub.2, CH.sub.2 --O--, 8); 
.delta.5.3 ppm (s, --CH--2H); .delta.5.6 ppm (s, NH.sub.2, 4H exchangeable 
with D.sub.2 O) 
8) Preparation of 3,3'-bis-[5-(2-isopropyl) dioxan-1,3-yl]carbonylamino 
5,5'-bis-[(N-methyl N-(2,3-diacetoxy propyl)carbamoyl]2,2', 4,4', 
6,6'-hexaiodo diphenyl a) preparation of 5-(2-isopropyl 
dioxan-1,3-yl)carboxylic acid chloride 0.28 ml of SOCl.sub.2 are added 
slowly to 0.6 g (0.0035 mole) of 5-(2-isopropyl dioxan-1,3-yl) carboxylic 
acid dissolved in 5.5 ml of dimethylacetamide. When the addition is 
complete, the solution is stirred for 5 h at room temperature b) After a 
portionwise addition of 0.68 g (0.0005 mole) of the compound obtained in 
7) to the solution prepared in a), the crude reaction product is heated 
for 12 h at 45.degree. C., then poured onto ice. The precipitate formed is 
filtered off, taken up in CH.sub.2 Cl, and washed with water. After being 
evaporated and taken up in ether, 0.7 g of beige crystals are obtained. 
Yield: 83% TLC (CH.sub.2 Cl.sub.2 80/MeOH 20): RF=0.7 
IR 1730 (OCO--CH.sub.3); 1620 (CO--NH+CO--NCH.sub.3) 
.sup.1 H NMR (DMSO) .delta.0.8 ppm 
##STR98## 
.delta.1.7 ppm 
##STR99## 
2H); .delta.2.1 ppm (s, OCOCH.sub.3, 12H); .delta.2.9 ppm to 3.2 ppm (m, 
CO--CH, N--CH.sub.3, 8H), .delta.3.4 ppm to 4.6 ppm (m, N--CH.sub.2 
--CH--CH.sub.2, 
##STR100## 
Preparation of 3,3'-bis-[5-(2-isopropyl) dioxan-1,3-yl]carbonylamino 
5,5'-bis-[N-methyl N-(2,3-dihydroxypropyl)]carbamoyl 2,2', 4,4', 
6,6'-hexaiodo diphenyl 
0.5 g (0.3 mmole) of the compound obtained in 8) dissolved in 10 ml of MeOH 
containing 80 mg of K.sub.2 CO.sub.3 in suspension are stirred for 24 
hours at room temperature. After filtration, evaporation of the methanol 
and solidification in ether, 0.6 g of white crystals are obtained. 
Yield&gt;100% (presence of K.sub.2 CO.sub.3) 
IR 1620 (CO--N--CH.sub.3 +CO--NH); 
##STR101## 
TLC (CH.sub.2 Cl.sub.2 85/MeOH 15): R.sub.f =0.3 
.sup.1 H NMR (DMSO) .delta.0.8 ppm 
##STR102## 
.delta.1.5 ppm to 1.8 ppm (m, --CH, 2H); .delta.2.9 ppm to 4.9 ppm (m, 
partially exchangeable with D.sub.2 O) 
##STR103## 
Preparation of 3.3'-bis-[(3-hydroxy 2-hydroxymethyl) propionyl]amino 
5,5'-bis-[N-methyl N-(2,3-dihydroxy-propyl)]carbamoyl 2,2', 4,4', 
6,6'-hexaiodo diphenyl 
0.5 mg (0.33 mmole) of the compound obtained in 9) are stirred in the 
presence of 13 ml of 5N hydrochloric acid for 6 h at room temperature. 
After evaporation, the residue obtained is purified by passage through 
H.sup.+ /OH.sup.- resins, then by chromatography on silica. 
After concentration and solidification in ether 0.3 g of white crystals are 
obtained. 
Yield: 60% TLC (CH.sub.2 Cl.sub.2 60/MeOH 40): R.sub.f =0.3 Purity with 
respect to iodine=99.5% 
IR: 3200-3500 
##STR104## 
1620 (CO--N--+CO--NH). 
.sup.1 H NMR (DMSO): .delta.2.6 ppm to 4 ppm (m, partially exchangeable 
with D.sub.2 O) 
##STR105## 
.delta.4.4 ppm to 4.9 ppm 
##STR106## 
4H exchangeable with D.sub.2 O); 10 ppm (s, H N--CO) 
.sup.13 C NMR: 38.35 ppm, s, N--CH.sub.3, 50.57 ppm, s, N--CH.sub.2 59.99 
ppm, s, 
##STR107## 
64.2 ppm, s, --CH.sub.2 --OH 69.92 ppm, s, CH--OH 94 to 105 ppm, m, C--I, 
128 ppm, 
##STR108## 
143 to 156 ppm, m, ring C 173 ppm C=0 
EXAMPLE 9 
Preparation of 3,3'-bis-[(3-hydroxy 2-hydroxymethyl)propionyl]amino 
5,5'-bis-[N-bis-(2,3-dihydroxy)propyl]carbamoyl 2,2', 4,4', 6,6'-hexaiodo 
diphenyl 
1) Preparation of 3,3'-dinitro 5,5'-bis (2,3-dihydroxy propyl) carbamoyl 
diphenyl 
0.9 g (2.7 mmoles) of the compound obtained in part 4) of Example 8 are 
added to a solution of 50 ml of SOCl.sub.2 and 0.05 ml of 
dimethylformamide. The solution is heated at reflux for 6 h, then the 
SOCl.sub.2 is distilled in a vacuum. The residual paste obtained is 
dissolved in 5 ml of CH.sub.2 Cl.sub.2 and added dropwise at 5.degree. C. 
to a solution of 1.8 g (0.011 mole) of 2,3-(N-2,3-dihydroxy propyl amino) 
propanediol and 1.53 ml (0.011 mole) of triethylamine dissolved in 10 ml 
of dimethylacetamide. When the addition is complete, the mixture is 
stirred for 12 h at room temperature. The triethylamine hydrochloride is 
removed by filtration and the solvents are evaporated. The residue is 
purified by chromatography on silica. After evaporation, 0.9 g of white 
crystals are obtained. 
Yield=55% TLC (CH.sub.2 Cl.sub.2 60/MeOH 40): R.sub.f =0.3 
IR 3300-3500 (OH); 
##STR109## 
1520 NO.sub.2 
.sup.1 H NMR (DMSO) .delta.3 to 4 ppm (m, CH.sub.2 --CH--CH.sub.2, 20H); 
.delta.4.4 ppm to 5.2 ppm 
##STR110## 
8H exchangeable with D.sub.2 O); .delta.8.3 ppm (s, 4H arom); .delta.8.6 
ppm (s, 2H arom) 
2) Preparation of 3,3'-diamino 5,5'-bis-/N-bis-(2,3-dihydroxy) 
propyl/carbamoyl diphenyl 
a) Reduction of the nitro groups: 
0.8 g (1.27 mmole) of the compound obtained in 2) dissolved in 100 ml of 
MeOH are shaken in a 500 ml autoclave for 2 h30 at 40.degree. C. under a 
hydrogen pressure of 6.10.sup.5 Pa in the presence of 1 g of 10% aqueous 
Pd/C. 
After removal of the catalyst by filtration and evaporation of the solvent 
a paste is obtained. TLC (CH.sub.2 Cl.sub.2 50/MeOH 50): R.sub.f =0.05 
b) Iodination by ICl: 
0.84 ml (11 mmoles)of a 70% solution of ICl are added dropwise to the paste 
obtained in a) dissolved in 60 ml of a mixture MeOH/H.sub.2 O (50/50). 
When the addition is complete, the reaction mixture is heated at 
60.degree. C. for 4 h then left to stand at room temperature for 12 h. 
After evaporation of the brown solution to dryness, the residue solidifies 
in ethyl acetate. The dark beige crystals are filtered off, washed with 
carbon tetrachloride and petroleum ether. After drying, 0.7 g of beige 
crystals are obtained. 
Yield=43% TLC (CH.sub.2 Cl.sub.2 65/MeOH 35): R.sub.f =0.2 Purity with 
respect to iodine: 96% 
.sup.1 H NMR (DMSO) .delta.3 to 4.2 ppm (m, partially exchangeable with 
D.sub.2 O) 
##STR111## 
3) Preparation of 3,3'-diamino 5,5'-bis-[N-bis-(2,3-diacetoxy) 
propyl]carbamoyl 2,2', 4,4', 6,6'-hexaiodo diphenyl 
0.7 ml of acetic anhydride are added dropwise to 0.3 g (0.23 mmole) of the 
compound contained in 2) dissolved in 5 ml of pyridine at 5.degree. C. 
After being stirred for 18 h at room temperature, the reaction mixture is 
poured into ice-cold water acidified with 15 ml of 5N HCl. The precipitate 
formed is filtered off, then taken up in CH.sub.2 Cl.sub.2. The organic 
phase is washed with water, then dried over MgSO.sub.4. After evaporation 
and solidification in ether, 0.3 g of white crystals are obtained. 
Yield: 80% Purity with respect to iodine=95% TLC (CH.sub.2 Cl.sub.2 85/MeOH 
15): R.sub.f =0.8 
IR: 3300-3450: NH.sub.2 1720: --O--CO--CH.sub.3 
##STR112## 
1580: --NH.sub.2 4) Preparation of 3.3'-bis-[5-(2-isopropyl) 
dioxan-1,3-yl]carbonylamino 
5,5'-bis-[N-bis-(2,3-diacetoxy)propyl]carbamoyl 2,2', 4,4', 6,6'-hexaiodo 
diphenyl) 
a) Preparation of 5-(2-isopropyl dioxan-1,3-yl)carboxylic acid chloride: 
0.112 ml of SOCl.sub.2 are added slowly to 0.24 g (1.38 mmoles) of 
5-(2-isopropyl dioxan-1,3-yl) carboxylic acid dissolved in 2.3 ml of 
dimethylacetamide at 0.degree. C. When the addition is complete, the 
solution is stirred for 5 hours at room temperature. 
b) After 0.3 g (0.2 mmole) of the compound obtained in 3) have been added 
portionwise to the solution obtained in a), the reaction mixture is heated 
for 12 h at 45.degree. C., then poured onto ice. 
The precipitate formed is filtered off, taken up in CH.sub.2 Cl.sub.2 and 
washed with water. After being evaporated and taken up in ether, 0.2 g of 
beige crystals are obtained. 
Yield: 52% 
IR: 1730 (OCOCH.sub.3); 
##STR113## 
TLC (CH.sub.2 Cl.sub.2 95/MeOH 5); R.sub.f =0.45 5) Preparation of 
3,3'-bis-[5-(2-isopropyl) dioxan-1,3-yl]carbonylamino 
5,5'-bis-[N-bis-(2,3-dihydroxy) propyl]carbamoyl 2,2', 4,4', 6,6'-hexaiodo 
diphenyl 
0.2 g (0.1 mole) of the compound obtained in 4) and 50 mg of K.sub.2 
CO.sub.3 are dissolved in 5 ml of MeOH and stirred for 18 h at room 
temperature. After filtration and evaporation of the methanol, 200 mg of 
white crystals are obtained. 
6) Preparation of 3,3'-bis-[(3-hydroxy 2-hydroxymethyl)propionyl]amino 
5,5'-bis-[N-bis(2,3-dihydroxy)-propyl]carbamoyl 2,2', 4,4', 6,6'- hexaiodo 
diphenyl 
0.2 g of the compound obtained in 5) are stirred in the presence of 5 ml of 
5N HCl for 6 h at room temperature. After evaporation, the residue 
obtained is purified by passage through H.sup.+ /OH.sup.- resins and by 
crystallization from ether. 100 mg of white crystals are obtained. 
Yield=50% (overall for the steps 5) and 6) Purity with respect to 
iodine=93% TLC (CH.sub.2 Cl.sub.2 20/MeOH 80): 2 spots joined together: 
R.sub.f =0.8 
IR: 3200-3500 
##STR114## 
1600 
##STR115## 
.sup.1 H NMR (DMSO) .delta.3 to 5.1 ppm (m, partially exchangeable with 
D.sub.2 O ) 
##STR116## 
EXAMPLE 10 
Preparation of the compound of formula: 
##STR117## 
1 - Preparation of the compound of formula: 
##STR118## 
1.4 g (0.01 mole) of Cl--CO--CH.sub.2 OCOCH.sub.3 are added dropwise to 5.5 
g (0.0040 mole) of the compound obtained in example 8-7 dissolved in 15 ml 
of DMAC. The solution obtained is stirred at 50.degree. C. for 16 h, then 
poured onto ice. The precipitate obtained is filtered off, washed with 
H.sub.2 O then dried. 3.4 g of white crystals are obtained. 
Yield: 55% TLC (ethyl acetate): R.sub.f :0.3 
I.R.: 1730 (OCO--CH.sub.3) 1620 (CO--NH+CO--N--CH.sub.3) 
.sup.1 H NMR (DMSO) .delta.1.9 ppm - 2.1 ppm (2s, OCOCH.sub.3, 18H); 
.delta.2.8 ppm 
##STR119## 
.delta.3.5 ppm to 4.5 ppm (m, CH.sub.2 --CH--CH.sub.2, 8H) .delta.4.7 ppm 
(s, CO--CH.sub.2 --O, 4H) .delta.5.3 ppm (m, CH.sub.2 --CH--CH.sub.2, 2H) 
.delta.10.3 ppm (s, NH--CO, 2H exchangeable with D.sub.2 O) 
2-Preparation of the compound of formula: 
##STR120## 
2.5 g (0.00153 mole) of the compound obtained in 1) dissolved in 100 ml of 
MeOH and 1.3 g (0.01 mole) of K.sub.2 CO.sub.3 are stirred for 48 h at 
room temperature. After filtration and evaporation of the methanol, the 
residue is dissolved in 100 ml of water, then passed through a H.sup.+ 
resin. After evaporation, the product obtained is purified by 
chromatography on silica. After evaporation and solidification in ether, 
1.6 g of white crystals are obtained. 
Yield: 76% TLC: silica; CH.sub.2 Cl.sub.2 /MeOH: 70/30; R.sub.f :0.4 Purity 
with respect to iodine=99.5% 
I.R. (cm.sup.-1) 1600 (CO--NH+CO--N--CH.sub.3); 3200-3500 
##STR121## 
.sup.1 H NMR (DMSO): .delta.2.8 ppm (1s, --N--CH.sub.3), 6H); .delta.3 ppm 
to 3.9 ppm (m, CH.sub.2 --CH--CH.sub.2, 10H); .delta.4 ppm (1s, 
--CO--CH.sub.2 --OH, 4H); .delta.5.8 ppm to 4.1 ppm 
##STR122## 
CO--CH.sub.2 --OH, 6H exchangeable with D.sub.2 O); .delta.9.8 ppm (1s, 
NH--CO--, 2H exchangeable with D.sub.2 O). 
.sup.13 C NMR: 38.35 ppm s, --N--CH.sub.3 50 ppm s, --N--CH.sub.2 61 ppm s, 
--CO--CH.sub.2 --OH 63 ppm s, --CH.sub.2 --CH.sub.2 --OH 69.5 ppm s, 
##STR123## 
98 to 105 ppm, C--I (ring) 144 ppm s, C--NH (ring) 148.5 ppm s, C--C 
(diphenyl) 155 ppm s, C--CO(ring) 170 ppm s, NH--CO--CH.sub.2 +C--CO--N 
EXAMPLE 11 
Preparation of the compound of formula: 
##STR124## 
I - Preparation of the compound of formula: 
##STR125## 
a) Preparation of the compound of formula: 
##STR126## 
An aqueous solution of 294 g (1.75 mole) of KMnO.sub.4 is added dropwise to 
an aqueous solution of 150 g (1.14 mole) of Solketal.RTM. (commercially 
available from the Janssen company (Pantin)) and 69.4 g (1.23 mole) of 
potassium, the temperature being maintained at 4.degree.-9.degree. C. 
The reaction mixture is stirred overnight at room temperature. After 
filtration, adjustment of the pH of the solution to 9 and concentration to 
dryness, the residue is taken up in ethanol. The mineral salts are 
filtered off and the ethanolic phase is concentrated to dryness. 
Yield: 75% (potassium salt) b) Preparation of the compound of formula: 
##STR127## 
1.15 ml of oxalyl chloride are added dropwise to 2.2 g (0.012 mole) of the 
product obtained in a) above suspended in 12 ml of anhydrous ether at a 
temperature of 0.degree. C. The mixture is stirred for two hours at 
0.degree. C., then for 18 hours at room temperature. 
After removal of the KCl by filtration, the solution is evaporated at 
20.degree. C. in a vacuum. 
c) The solution prepared in b) above is added dropwise to 2.7 g (0.002 
mole) of the compound obtained in example 8-7) dissolved in 10 ml of DMAC. 
The mixture obtained is stirred for 17 hours at room temperature, then 
poured into ether. The crystals formed are filtered off and dried. 3 g of 
beige crystals are obtained in a yield of 90%. TLC (ethyl acetate): 
R.sub.f =0.75 
2 - Preparation of the compound of formula: 
##STR128## 
3 g (0.0018 mole) of the compound obtained in the preceding step in 150 ml 
of methanol and 1.8 g (0.015 mole) of K.sub.2 CO.sub.3 are stirred for 48 
hours at room temperature. After filtration and evaporation of the 
methanol, the residue is dissolved in an aqueous solution at pH3. The 
solution is stirred for one hour, passed through H.sup.+ and OH.sup.- 
resins, then purified by chromatography on silica. After evaporation and 
solidification in ether, 1.2 g of white crystals are obtained (Yield=46%) 
TLC (CH.sub.2 Cl/MeOH:50/50) R.sub.f :0.6 Purity with respect to iodine: 
99% 
IR: 1600 (CO--N--CH.sub.3 +CO--NH--); 3200-3500 
##STR129## 
.sup.1 H NMR (DMSO) .delta.2.8 ppm (1s, --N--CH.sub.3, 6H); .delta.3 to 4.1 
ppm (m, CH.sub.2 --CH--CH.sub.2, CH--CH.sub.2 16H); .delta.4.55 to 4.75 
ppm 
##STR130## 
.delta.5.65 ppm, 
##STR131## 
.delta.9.7 ppm (m, NH--CO, 2H) 
.sub.13 C NMR (DMSO) 38.35 ppm (s, --N--CH.sub.3); 50 ppm (s, 
--N--CH.sub.2) 64 ppm (s, --CH.sub.2 --OH) 70 and 73.5 ppm (2s, CH--OH) 95 
to 105 ppm (m, C--I) 143 to 155 ppm (3s, C--C diphenyl; C--N of the ring; 
C--C.dbd.O) 170 ppm 
##STR132## 
EXAMPLE 12 
Preparation of the compound of formula: 
##STR133## 
1 -Preparation of the compound of formula: 
##STR134## 
a) Synthesis of the compound of formula: 
##STR135## 
9.9 g (0.03 mole) of the compound obtained in example 8-4) are added to a 
solution of 100 ml of SOCl.sub.2 and 0.1 ml of dimethyl-formamide. The 
solution is heated at reflux for 5 h. After evaporation of the SOCl.sub.2, 
the paste obtained is dissolved in dioxan. 
b) amidation 
##STR136## 
obtained according to the procedure described in WO-9109007 and 21.4 ml 
(0.09 mole) of tributylamine dissolved by heating in 100 ml of dioxan is 
added dropwise at 80.degree. C. to the product obtained in a). The mixture 
is stirred overnight at room temperature. The supernatant is decanted and 
the viscous residue is washed with CH.sub.2 Cl.sub.2, then with ether. 20 
g of the title compound are obtained. TLC (CH.sub.2 Cl.sub.2 /MeOH:75/25) 
R.sub.f =0.7 
IR: 3100-3500 (OH); 1610, 
##STR137## 
1520, NO.sub.2 
.sup.1 H NMR (DMSO) .delta.3 to 3.5 ppm 
##STR138## 
.delta.3.9 ppm 
##STR139## 
.delta.4.5 to 5 ppm 
##STR140## 
6H exchangeable with D.sub.2 O); .delta.8.3 ppm 1d .delta.8.6 ppm 1s CH 
aromatic, 6H 
.sup.13 C NMR (DMSO) 48 ppm (2s, N--CH.sub.2 --CH.sub.2 OH) 52 ppm 
##STR141## 
58 ppm (2s, CH.sub.2 --CH.sub.2 OH) 63 ppm (2s, CH--CH.sub.2 OH) 69 ppm 
##STR142## 
______________________________________ 
122 ppm (1s 
133 ppm (1s 
140 ppm (2s C-C aromatic) 
149 ppm (1s 
______________________________________ 
168 ppm 1s, --CO-- 
2 - Preparation of the compound of formula: 
##STR143## 
a) Reduction of the nitro groups: 
0.03 mole of the compound obtained in 1) dissolved in 300 ml of methanol 
are shaken in a 500 ml autoclave in the presence of 1 g of 10% Pd/C for 5 
h at 50.degree. C. under a hydrogen pressure of 6.10.sup.5 Pa. After 
removal of the catalyst by filtration and evaporation of the solvent a 
paste is obtained. TLC (CH.sub.2 Cl.sub.2 /MeOH 50/50) R.sub.f =0.2 
b) Iodination by ICl: 
53 ml (0.3 mole) of a 70% solution of ICl are added dropwise to the paste 
obtained in a) dissolved in 500 ml of methanol. The reaction mixture is 
heated at 60.degree. C. for 12 h. After being cooled, the solution is 
poured into a mixture of ice and water. The precipitate obtained is 
filtered off and washed with a dilute aqueous bisulfite solution. 
The product thus obtained is redissolved in methanol (V-300 ml) and 10.6 ml 
(0.06 mole) of a 70% solution of ICl are added dropwise. The mixture is 
stirred for 12 h at 60.degree. C., then poured onto ice, and the 
precipitate formed is washed by a dilute aqueous bisulfite solution. The 
product is taken up in ether, then dried. 23 g of beige crystals are 
obtained. 
Yield: 63% Purity with respect to iodine: 98% TLC (CH.sub.2 Cl.sub.2 /MeOH: 
75/25): R.sub.f =0.4 
IR: 3100-3500 (OH); 1580 NH.sub.2, 
##STR144## 
.sup.1 H NMR (DMSO) .delta.3.1 ppm to 4 ppm: (m, CH.sub.2 --CH.sub.2 --, 
8H, CH.sub.2 --CH--CH.sub.2, 10H); .delta.4.4 ppm to 4.9 ppm: 
##STR145## 
6H exchangeable with D.sub.2 O .delta.5.5 ppm (s, NH.sub.2 4H exchangeable 
with D.sub.2 O) 
3 - Preparation of the compound of formula: 
##STR146## 
30 ml of acetic anhydride are added dropwise to 23 g (0.0182 mole) of the 
compound obtained in 2) dissolved in 280 ml of pyridine at 5.degree. C. 
After the reaction mixture has been stirred for 18 h at room temperature, 
the reaction medium is poured into acidified, ice-cold water. The 
precipitate water is filtered off, then taken up in CH.sub.2 Cl.sub.2. The 
organic phase is washed with water, dried over MgSO.sub.4 and purified by 
chromatography on silica. 
After evaporation, 11 g of white crystals are obtained. 
Yield: 50% TLC (ethyl acetate/heptane: 9/1) R.sub.f =0.6 Purity with 
respect to iodine: 97% 
.sup.1 H NMR (DMSO) .delta.2 ppm (m, O--CO--CH.sub.3, 18H); .delta.3.1 ppm 
to 4.1 ppm (m, CH.sub.2 --CH.sub.2, 8H, CH.sub.2 --CH--CH.sub.2, 8H); 
.delta.5.1 ppm to 5.4 ppm (s, NH.sub.2, 4H) (m, CH.sub.2 --CH--CH.sub.2, 
2H). 
4 - Preparation of the compound of formula: 
##STR147## 
a) Preparation of Cl--CO--CH.sub.2 --OCOCH.sub.3 : 88 g (0.745 mole)of 
COOH--CH.sub.2 OCOCH.sub.3 are added to a solution of 200 ml of 
SOCl.sub.2, then heated at reflux for 5 hours. 
After evaporation of the SOCl.sub.2, 70 g of product are recovered by 
distillation. 
Yield: 70% 
b) Acylation: 
10 g (0.073 mole) of the acid chloride obtained in 4a) are added dropwise 
to 22 g (0.0145 mole) of the compound obtained in 3) dissolved in 150 ml 
of anhydrous DMAC. The mixture is heated at 60.degree. C. for 5 h, then 
poured onto ice. The precipitate formed is taken up in CH.sub.2 Cl.sub.2 
and washed with water, purified by chromatography on silica then 
solidified on trituration with isopropyl ether. 14 g of white crystals are 
obtained. 
Yield: 60% Purity with respect to iodine: 99% TLC (ethyl acetate) R.sub.f 
:0.8 
.sup.1 H NMR (DMSO): .delta.1.9 ppm to 2.2 ppm (m, O--CO--CH.sub.3, 18H); 
.delta.6 3.3 ppm to 4.5 ppm (m, CH.sub.2 --CH.sub.2, 16H) CH.sub.2 
--CH--CH.sub.2 .delta.4.7 ppm (s, CO--CH.sub.2 --O--, 4H); .delta.5.4 ppm 
(s, CH.sub.2 --CH--CH.sub.2, 2H); .delta.10.3 ppm (s, NH--CO--, 2H 
exchangeable with D.sub.2 O) 
5 - Preparation of the compound of formula: 
##STR148## 
14 g (0.00816 mole) of the compound obtained in 4b) and 1.4 g of K.sub.2 
CO.sub.3 suspended in 140 ml of methanol are stirred for 18 h at room 
temperature. After filtration and evaporation white crystals are obtained, 
which are then purified on a H.sup.+ resin and by chromatography on 
silica. 8 g of product are obtained. 
Yield: 80% TLC (CH.sub.2 Cl.sub.2 /MeOH 60/40): R.sub.f =0.4 
IR: 3100-3500--R--OH; 1590--NH--CO--+--CO--N-- 
.sup.1 H NMR (DMSO) 3.1 ppm to 3.9 ppm (m, CH.sub.2 --CH.sub.2, CH.sub.2 
--CH--CH.sub.2, 18H) 4 ppm (1s, --CO--CH.sub.2 --OH, 4H); 4.5 to 4.9 ppm 
##STR149## 
CH.sub.2 --CH.sub.2 --OH, 6H exchangeable with D.sub.2 O); 5.5 ppm (ppm 
(1s, COCH.sub.2 OH, 2H); 9.8 ppm (1s, --NH--CO, 2H exchangeable with 
D.sub.2 O) 
##STR150## 
EXAMPLE 13 
Preparation of the compound of formula: 
##STR151## 
1 g (0.000725 mole) of the compound obtained in example 12-5) is dissolved 
in 6 ml of anhydrous methanol containing 0.0015 mole of sodium methylate. 
The reaction mixture is stirred for 1 hour, then 0.17 ml (0.002 mole) of 
methyl iodide are added dropwise and the solution is heated at 
35.degree.-40.degree. C. for 3 hours. After evaporation of the solvent, 
the residue solidifies in ether, is washed with acetone and purified by 
chromatography on silica. 600 mg of white crystals are obtained. 
Yield: 70% Purity with respect to iodine: 99% TLC (CH.sub.2 Cl.sub.2 
/MeOH/NH.sub.4 OH: 60/30/10): R.sub.f :0.3 
EXAMPLE 14 
Preparation of the compound of formula: 
##STR152## 
7.1 g (4.7 mmoles) of the compound obtained in example 12-2b) are added to 
a solution of acetyl chloride (1.2 ml) (0.0165 mole) in 80 ml of DMAC. The 
reaction mixture is heated at 60.degree. C. for 72 h. After being allowed 
to cool to room temperature, the reaction mixture is precipitated by means 
of an ice+water mixture. 
The crude product (7.2 g; yield 96%) obtained after filtration and 
solidification in heptane is purified on a column of silica. 5.8 g of 
product are obtained. 
Yield: 77% TLC (CH.sub.2 Cl.sub.2 /MeOH 90/10) R.sub.f :0.7 Purity with 
respect to iodine: 98.4% HPLC purity: 97% Lichrosphere C.sub.18, 5.mu., 25 
cm CH.sub.3 CN 80,50 H.sub.2 O 20,50 
.sup.1 H NMR (DMSO): 200 MHz; .delta.5.2 to 5.4 ppm (m, CH 2H); .delta.4 to 
4.4 ppm (m, CH.sub.2 --OAc 8H); .delta.3.7 to 4 ppm (m, CONCH.sub.2 CHhd 
2OAc 8H); .delta.2.15 to 2.4 ppm 
##STR153## 
.delta.1.8 to 2.2 ppm (s, --OCOCH.sub.3 18H). 
EXAMPLE 15 
Preparation of the compound of formula: 
##STR154## 
7.5 g (4.45 mmoles) of the compound obtained in example 14 are added to a 
5N solution of sodium hydroxide (5 ml) in a methanol-water mixture 
(30/15). The reaction mixture is stirred at 50.degree. C. for 2 h and at 
room temperature overnight. 
After concentration and purification of the reaction medium on SiO.sub.2, 
desalting is performed by passages through H.sup.+ and OH.sup.- resins. 
After concentration of the aqueous phase, 3.2 g of a white solid are 
obtained (yield 54%) Purity with respect to iodine: 98.5% HPLC purity: 
99.9% Lichrosphere C.sub.18, 25 cm, 5.mu. H.sub.2 O 50 CH.sub.3 CN 50 
.sup.1 H NMR (DMSO) .delta.20 ppm, s,--NH--,2H; .delta.4,6-4.9 ppm, m,--OH, 
6H; .delta.4 ppm, s, --CH--, 2H ; .delta.3.2 to 3.8 ppm, m, 
##STR155## 
.delta.2 ppm, s,NHCOCH.sub.3, 6H 
EXAMPLE 16 
Preparation of the compound of formula: 
##STR156## 
404 mg (3 mmoles) of the product prepared in example 15 are dissolved in 3 
ml of methanol. 
1.7 ml (8.4 mmoles) of a 5N solution of sodium methylate and 1.25 ml (15 
mmoles) of 3-chloro-1,2-propanediol are simultaneously added dropwise. 
The reaction mixture is stirred for 7 days at 35.degree. C. 
After neutralization with 1N HCl and desalting on H.sup.+ and OH.sup.- 
resins, the title product is obtained. TLC (CH.sub.2 Cl.sub.2 /MeOH 
40/60): R.sub.f :0.3 HPLC purity: 97.7% Column R sil NH.sub.2 25F, 5 
.mu.m, 25 cm; CH.sub.3 CN: 75; H.sub.2 O: 25.