CA2191984A1 - Alpha-(cycloalkyl, aryl and aralkyl)substituted polyiodinated aroyloxy compounds - Google Patents

Abstract

Compounds having structure (I) wherein m is 1, 2, 3 or 4; Z-(-COO-)-m is the residue of a polyiodinated aromatic mono- or polyacid; R1 is H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl or acetamidoalkyl; n is an integer from 0 to 20; R2 is cycloalkyl or aryl; and R3, R4 and R5 are independently H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, halogen, hydroxy, acylamino, acetamidoalkyl, cyano, sulfonyl, carboxamido or sulfonamido are useful as x-ray contrast agents in medical diagnostic x-ray imaging compositions and methods.

Description

WO96/00211 21 9 1 9 8 4 PCT~S9~07421 .

ALPHA-(CYCLOALKYL, ARYL AND ARALKYL)SUBSTITUTED POLYIODINATED AROYLOXY
COMPOUNDS

FIE~D OF INVENTION
S
This invention relates to polyiodinated aroyloxy esters which find particular utility as particulate x-ray contrast agents in medical diagnostic imaging.

~ACKGROUND OF THE INVENTION

X-ray imaging is a well known and extremely valuable tool for the early detection and diagnosis of various disease states in the human body. The use of contrast agents for image enhancement in medical x-ray imaging procedures is widespread. An excellent background on iodinated and other contrast agents for medical imaging is provided by D.P. Swanson et al, PhArm~ceuti~7s in Mefiic21 I~aina. l990, MacMillan Publishing Company.
U.S. Patent No. 3,097,228 describes derivatives of 2,4,6-triiodobenzoyloxyalkanoic acids having the structure ICOOR
COOC~
R
I ~ I

~ 2 R ~ NHR

wherein Rl is H or lower alkyl; R2 is H or lower alkanoyl;
R3 is H or lower alkanoylamino and R4 is lower alkyl. The agents are useful as x-ray contrast agents for visualizing the gall bladder (cholecystography) when administered orally, in the free acid form or in the form of a non-toxic 21 9f 984 W O 96/00211 PC~r~US95/07421 salt, or intravenously, in the form of water soluble, non-toxic salt.
Bacon et al, commonly assigned U.S. Patent Application Serial No. 07/990,987 filed December 16, 1992 s 5 describes iodinated aroyloxy esters which are useful as contrast agents in x-ray imaging compositions and methods.
However, all of the compounds descri~ed by sacon et al feature an ester group linked through a C2 or higher alkylene group to another ester group on an iodinated lO aromatic ring.
EP-A 498,482 describes nanoparticulate x-ray contrast compositions which have proven to be extremely useful in medical imaging. The compositions comprise particles of:an organic x-ray contrast agent and a surface 15 modifier adsorbed on the surface thereof and have an effective average particle size of less than 400 nm. The agents can be delivered to a specific tissue or fluid site, e.g., the blood pool, liver, spleen, kidney or lymph nodes.
EP-A 498,482 describes derivatives of diatrizoate, 20 iothalamate, metrizoic and iodipamide but does not suggest the a-cycloalkyl, aryl, or aralkyl substituted polyiodinated aroyloxy esters of this invention.
Moreover, it has been discovered that some of the derivatives described in EP-A 498,482 can exhibit multiple 25 crystal forms, i.e., polymorphs, e.g., when recrystallized from various solvents. The reasons for this behavior are not completely understood, but, in any event, multiple crystal forms are disadvantageous for a variety of reasons.
For example, the presence of multiple crystal forms renders 30 scale-up problematic due to the lack of repro~nc;h;l;ty of the results obtained, including, e.g., in chemical manufacturing and in the milling process. Furthermore, particulate contrast agents in certain in vivo appl;cat;onc can exhibit less than fully satisfactory solubility profiles 35 and/or enzymatic stability, e.g., in plasma and blood.
Consequently, it would be highly desirable to provide poorly soluble x-ray contrast agents having a WO96/00211 2 1 9 1 9 8 4 PCT~S95/07421 ~ -3-consistent crystal morphology and improved solubility profiles and enzymatic stability.

SUMMARY OE THE INVENTION
S
We have discovered and synthesized certain ~ polyiodinated aroyloxy esters substituted at the ~-carbon atom with a cycloalkyl, aryl or aralkyl group which exhibit improved solubility profiles and improved enzymatic stability.
More specifically, in accordance with this invention, there are provided novel iodinated compounds having the structure I:
I.

RO- f Z-~Coo ~ ~ ~_ wherein m is l, 2, 3 or 4;
ZtCOO~m is the residue of a polyiodinated aromatic mono- or polyacid;
Rl is H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl or acetamidoalkyl;
n is an integer from 0 to 20;
R2 is cycloalkyl or aryl; and R3, R4 and R5 are independently H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, halogen, hydroxy, acylamino, acetamidoalkyl, cyano, sulfonyl, carboxamido or sulfonamido.
It is an advantageous feature of this invention that novel polyiodinated aroyloxy esters are provided which find particular utility in particulate x-ray contrast compositions.

21 9~984 WOg6/00211 PCT~595/07421 It is an advantageous feature o~ this invention that novel polyiodinated aroyloxy esters are provided which exhibit a consistent crystal morphology.
Still another advantageous feature of this invention is that novel polyiodinated aroyloxy esters are provided having improved solubility profiles and enzymatic stability.

DESCRIP~ION OF PF~FERRED EMBODIMENTS
In structural Formula I above, ztcoo~m is the residue of a polyiodinated aromatic acid. m can be l, 2, 3, or 4. In preferred embodiments, m is l or 2. The polyiodinated aromatic acid can contain two, three or more iodine atoms per molecule. Preferred species contain at least three iodine atoms per molecule.
Illustrative examples of suitable aromatic acids include diatrizoic acid, metrizoic acid, urokonic acid, 5-acetylamino-2,4,6-triiodoisophthalic acid, iothalamic acid, triiodotrimesic acid, ioxaglic acid (hexabrix), ioxitalamic acid, tetraiodotersphthalic acid, iocarmic acid, io~;p~m;fle, and the like. In preferred embodiments, ZtCOO~m is the residue of a substituted tr~;o~nb~n7~;c acid such as an acyl, carbamyl, and/or acylamino substituted triiodobenzoic arid. In highly preferred embodiments Z~COO~m is the residue of a polyiodinated aromatic mono- or diacid such as diatrizoic acid, metrizoic acid, nroknn;c acid or 5-acetylamino-2,4,6-triiodoisophthalic acid.

W O 96/00211 P~rrUS95/07421 ~ -5-In structure I above n represents an integer from 0 to 20 inclusive. In preferred embodiments, n is 0, 1, 2, 3 or 4.
R1 represents H; linear or branched alkyl, S preferably containing from 1 to 20, more preferably from 1 to 14, and most preferably from 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like; fluoroalkyl, the alkyl portion of which is as defined above and containing from 1 to (2m t 1) fluorine atoms (where m = the number of carbon atoms in the alkyl group), such as trifluoromethyl; cycloalkyl, preferably containing from 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; aryl, preferably containing from 6 to 10 carbon atoms, such as phenyl and naphthyl; aralkyl, preferably c~t~;n~ng from 7 to 12 carbon atoms, such as ben~yl; alkoxyalkyl, the alkyl portions of which preferably contain from 1 to 20 carbon atoms as defined for alkyl above; or acetamidoalkyl, i.e., Y wherein alkyl is as defined above.
R2 is cycloalkyl, preferably containing from 3 to 12, more preferably 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like; or aryl, preferably containing from 6 to 14 carbon atoms such as phenyl, naphthyl, anthracenyl and the like.
R3, R4 and R5 are independently H; linear or branched alkyl, preferably containing from 1 to 20, more preferably 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like;
fluoroalkyl, the alkyl portion of which is as described above and containing from l to (2m+1) fluorine atoms (where m = the number of carbon atoms in the alkyl group~, such as trifluoromethyl; cycloalkyl, preferably ~ont~;nin~
from 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; aryl, preferably containing WO96100211 ~ /421 from 6 to 10 carbon atoms, such as phenyl and naphthyl;
aralkyl, preferably containing from 7 to 12 carbon atoms, such as benzyl; halogen, such as chlorine, bromine or iodine; hydroxy; acylamino, i.e , ~ R
Il ~
--~ N~ 6 O
S a group; acetamidoalkyl, i.e., - NH ~ -alkyl wherein alkyl is as defined above; cyano; sulfonyl;
carboxamido; sulfonamido and the like. However, reactive substituents such as halogen, hydroxy, and acylamino are not preferred on the carbon atoms closest to the ester groups. Thus, in particularly preferred embodiments, R5 is H, alkyl, fluoroalkyl, acetamidoalkyl, cyano, sulfonyl, c~rhnY~;do or sulfonamido. The reason for this is that when R5 is halogen, hydroxy, or acylamino, the compounds tend to be more reactive and less useful as particulate x-ray contrast agent.
R6 and R7 are independently a substituent asdefined for R3 above, or R6 and R7, taken together with the nitrogen atom to which they are attached, represent a 4-7 membered saturated or unsaturated nitrogen c~nt~in;ng ring such as piperidyl, piperizinyl, pyrrolidinyl, and the like.
The following are specific illustrative examples of compounds of this invention that have been prepared:
(l-Ethoxy-l-oxo-2-phenylethan-2-yl)-3,5-bis(acetylamino)-2,4,6-triiodobenzoate;
(1-Ethoxy-1-oxo-2-cyclopentylethan-2-yl)-3,5-bis(acetylamino)-2,4,6-triiodobenzoate;
(l-Ethoxy-l-oxo-2-cyclohexylethan-2-yl)-3,5-bis(acetylamino)-2,4,6-triiodobenzoate;
(1-Ethoxy-1-oxo-2-cyclohexylpropan-2-yl)-3,5-bis(acetylamino)-2,4,6-triiodobenzoate;
(1-EthoYy-1-oxo-2-phenylethan-2-yl)-3-acetylamino-5-N-methylacetylamino-2,4,6-triiodobenzoate;

WO96/00211 ~ PCT~595107421 ~ _7_ 2191984 (l-Ethoxy-l-oxo-2-phenylethan-2-yl)-3-acetylamino-2,4,6-triiodobenzoate;
Bis(l-ethoxy-l-oxo-2-cyclohexylethan-2-yl)-5-acetylamino-2,4,6-triiodoisophthalate; and sis(l-ethoxy-l-oxo-2-cyclopentylethan-2-yl)-s-acetylamino-2,4,6-triiodoisophthalate.

Preferred compounds of this invention conform to structure I above, wherein R3 and R4,if present, are H, as indicated in the Table set forth below:

Compound Z Rl R2 n R5 1 ¦ -C2H5 -C6H5 ~ H
I ~ I

NH ~ HCOCX

2 n -C2HS ~ 0 H

3 " ~ -C2H5 ~ 0 H

4 " -C2H5 ~ 1 H

¦ -C2H5 -C6H5 ~ H
I ~ I

CH3CONH ~ N(CH3)COCH3 6 ¦ -C2Hs -c6Hs o H

2~ 91 9P4 WO 96/00211 J PCT/IJS9~/07421 7 ¦ -C2H5 --O O H
I~I

8 " -C2Hs --a ~ H

The compounds of this invention can be prepared by contacting the carboxylate of a 5-substituted-amino-2,4,6-triiodoisophthalic acid with a functionalized ester havingthe formula RO--f X-C-~C~-R
Rs 1 4n R

wherein X is-a leaving group and n and R1-R5 are as defined above, in a suitable solvent. Suitable leaving groups include halogen, such as sr, I and Cl, and sulfonyloxy, such as methanesulfonyloxy and toluenesulfonyloxy. The carboxylates of iodinated aromatic acids and f~nctionalized esters useful as the starting materials in the preparation of the compounds of this invention are known compounds and/or can be prepared by techniques known in the art. ~or example, suitable esters include commercially available bromoester and chloroester derivatives as exemplified below.
Alternatively, the requisite bromoesters can be prepared by the process described in J. Am. Chem. Soc. 70, 3626 (1948).
A summary of this preparation of suitable bromoesters is as follows:

WO96/00211 P~ 421 ~ _g_ R (C ~ CH(R5)Co2H l) SOC12 14 2) Br2 sr-R 3) RlOH Rs R4 A general reaction scheme is as follows: Z~COOtm +
o 3 RO- 1I Rl , I
X- ~ R
Rs 14 R

The reaction can take place at various temperatures ranging between -78~C and 100~C, and preferably between -40~C and 50~C. For convenience, the reaction can take place at ambient pressure, however, higher and lower pressures are contemplated.
The reaction can take place in any suitable solvent. Suitable solvents include N,N-dimethylformamide (DMF) and dimethylsulfoxide ~DMSO~.
The iodinated compounds can contain substituents which do not deleteriously affect the contrast ~nhAn~ing capability of the compound. For example, the alkyl, cycloalkyl, aryl, aralkyl and alkoxy groups in structure above can be unsubstituted or substituted with various substituents which do not adversely affect the stability or efficacy of the compounds as x-ray contrast agents such as alkyl, cycloalkyl, aryl, aralkyl, alkoxy, hydroxy, acyloxy, halogen, such as chlorine, bromine and iodine, acylamino, nArhnAl kn~y, carbamyl and the like.
When used as an x-ray contrast agent, the compound of this invention preferably comprises at least about 35%, more preferably at least 40% iodine by weight.
In preferred embodiments, the compounds of this invention can be formulated into particulate x-ray contrast compositions, preferably nanoparticulate x-ray contrast compositions, as described in commonly-owned EP-A 498,482.

WO96/00211 PCT~S95/07421 Preferred compounds exhibit a meltîng point of greater than 150~C. Such nanoparticulate compositions can be prepared ~r dispersing the compounds of the invention in a li~uid dispersion medium, and wet grinding the compound in the presence of rigid grinding media and a surface modifier to form the nanoparticles. Alternatively, the surface modifier can be contacted with the compound after attrition.
Preferred surface modifiers include nonionic surfactants.
In preferred embodiments, the surface modifier is a high molecular weight nonionic surfactant. Such surfactants include poloxamers such as Pluronic_ F68 and Fl08, which are block copolymers of ethylene oxide and propylene oxide, polnY~mine~ such as Tetronic_ 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from se~uential addition of propylene oxide and ethylene oxide to ethylrnr~iam;ne, and dialkyl esters of sodium sulfosuccinic acid, such as dioctylsulfosuccinate sodium (DOSS). The concentrations of the surface modifier can vary from about 0.1-75%, preferably 1-60%, and more preferably 10-30% by weight based on the total nnmhiner3 weight of the contrast agent and surface modifier.
In preferred rmhQ,~;mr~ntc, the x-ray contrast composition in the form of surface modified nanoparticles can contain a cloud point modifier to further enhance stability during steam heat autoclaving, i.e., the cloud point modifier can reduce particle aggregation during heat sterilization Preferred cloud point modifiers include nonionic cloud point modifiers, such as polyethylene glycols such as PEG 400, propylene glycol, ethanol, hydroxypropylcyclodextrin and glycerol; ionic cloud point modifiers, such as those described in U.S. Patent No.

5,298,262 including dialkylesters of sodium sulfosuccinic acid such as the dioctylester of sodium sulfosuccinic acid (DOSS); and charged phospholipids, such as diacylphosphatidyl glycerol and dimyristoylphosphatidyl glycerol. The cloud point modifier can be present in an amount of 0.005-50%, preferably 0.01-30% and more preferably W O 96/00211 ~ 1 9 1 9 8 4 PC~rrUS95/07421 0.05-20~ by weight based on the total weight of the x-ray contrast composition.
The x-ray contrast compositions of this invention comprise the above-described compounds, preferably in the S form of particles, and a physiologically acceptable carrier -:
therefor. For example, the particles can be dispersed in an aqueous liquid which serves as the carrier for the x-ray contrast agent. Other suitable carriers include liquid carriers such as mixed aqueous and nonaqueous solvents, such l0 as alcohol; gels; gases, such as air; and powders.
The x-ray contrast composition can comprise from about 1-99.9, preferably 2-45 and more preferably 10-25~ by weight of the above-described particles, the r in ~l~r of the composition being the carrier, additives and the like.
15 Compositions up to about 100~ by weight of the particles are contemplated when the composition is in a lyophilized form.
The dose of the contrast agent to be administered can be selected according to techniques known to those skilled in the art such that a sufficient contrast ~nh~ncing effect is obtained. Typical doses can range from 20 to 350 mg of iodine per kilogram of body weight of the subject for a many imaging applications. For some applications, e.g., lymphography, lower doses, e.g., 0.5-20 mg I/kg, can be effective. For blood pool imaging, the dose can range from 50 to 350 mg of iodine per kilogram of body weight and preferably from 100 to 250 mg of iodine per kilogram of body weight.
The x-ray contrast composition can contain one or more conventional additives used to control and/or enhance the properties of the x-ray contrast agent. For example, thickening agents such as dextran or human serum albumin, buffers, viscosity regulating agents, suspending agents, peptizing agents, anti-clotting agents, mixing agents, and other drugs and the like can be added. A partial listing of certain specific additives includes gums, sugars such as dextran, human serum albumin, gelatin, sodium alginate, agar, dextrin, pectin and sodium carboxymethyl cellulose.

2 ~ 9 ~ 984 W O 96/00211 PC~r~US95/07421 Such additives, surface active a~ents, preservativeS and the like can be incorporated into the compositions of the invention.
A method for diagnostic imaging for use in medical procedures in accordance with this invention comprises administering to the body of a test subject in need of an x-ray an effective contrast producing amount of the above-described x~-ray contrast composition. In addition to human patients, the test subject can include mammalian species such as rabbits, dogs, cats, monkeys, sheep, pigs, horses, bovine animals and the like. Thereafter, at least a portion of the body containing the administered contrast agent is exposed to x-rays to produce an x-ray image pattern corresponding to the presence of the contrast agent. The image pattern can then be visualized. For example, any x-ray visualization technique, preferably, a high contrast technique such as computed tomography, can be applied in a convention manner. Alternatively, the image pattern can be observed directly on an x-ray sensitive phosphor screen-silver halide photographic film combination.
The compositions of this invention can beadministered by a variety of routes depending on the type of procedure and the anatomical orientation of this tissue being ~m; n~d . Suitable administration routes include intravascular (arterial or venous) administration by catheter, intravenous injection, rectal administration, subcutaneous administration, intramuscular administration, intralesional administration, intrathecal administration, intracisternal administration, oral administration, administration via inhalation, administration directly into a body cavity, e.g., arthrography, and the like.
In addition to preferred applications, i.e., for blood pool and lymph node imaging, the x-ray contrast compositions of this invention are also expected to be useful as contrast agents for any organ or body cavity. For example, the compositions of this invention are expected to be useful as angiographic contrast media, urographic 21 9 1 9~
WO96/00211 PCT~S95107421 ~ -13-contrast media, myelographic~contrast media, gastrointestinal contrast media, cholecystographic and cholangiographic contrast media, arthrographic contrast media, hysterosalpingographic contrast media, oral contrast S media and bronchographic contrast media.
The following examples further illustrate the invention.

Fx~m~le l - PreD~ration of (l-Ethoxv-l-oxo-2-cvcloDentvlet~n-2-vl)-3,5-his(acetvlAm;no)-2,4,6-triiodobenzoate To a stirred solution of sodium diatrizoate (60 g, 94.3 mmole) in 400 ml of dry DMF was added the ethyl 2-bromocyclopentyl acetate (24.4 g, 95.4 mmole). After stirring at ambient temperature for 2 hrs, a solid began to precipitate and the mixture was heated at 80~C overnight whereupon it became homogenous. On cooling, the solution was slowly poured into 6 L of water and the resulting precipitate was collected by filtration and dried under vacuum over P2O5 at 60~C to give 57.9g (80~) of product.
The crude product was then recrystallized from DMF/H2O to give analytically pure material, mp 245-246~C. The lH-NMR(300 MHz) and mass spectral (CI-MS) data were consistent with the desired product.
Calculated for C2oH23I3N2O6: C 31.27, H 3.02, I 49.56, N
3.64;
Found: C 30.99, H 2.85, I 49.28, N 3.57.

Ex~m~le 2 - PreDaration of (l-Ethoxv-l-oxo-2-cvcloh~xvlethAn-2-vl)-3.5-bis(acetvlam; n~ ) -2,4 6-triiodob~nzoate In a manner similar to the procedure described in Example l above, analytically pure compound was obtained in 72~ yield, mo 267-268~C. The MS and lH-NMR(300 ~Hz) spectral data were consistent with the desired product.
Calculated for C2lH2sI3N2o6: C 32.25, H 3.22, I 48.67, N
3.58;

W O 96/00211 PC~rAUS95/07421 Found: C 32.49, H 3.09, I 48 35, N 3.57.

~xAmnle 3 - Pre~aration of (1-Ethoxv-1-oxo-2-cvclohr~xvl~ro~An-2-vl~-3,5-bislacetvlAmino)-2.4.6-triiodobenzoate In a manner similar to the procedure described in Example 1 above, analytically pure compound was obtained in 71~ yield, mp 247-246~C. The MS and 1H-NMR(300 MHz) spectral data were consistent with the desired product.
I0 Calculated for C22H27I3N2~6: C 33.19, H 3.42, I 47.82, N
3.52;
Found: C 33.21, H 3.39, I 47.68, N 3.48.

~xAmnle 4 - Pre~aration of (l-Ethoxv-l-oxo-2-~henvlethAn-2 vl)-3.5-bis(acetvlAminr-)-2,4.6-triiodoben7oate In a manner similar to the procedure described in Example 1 above, analytically pure compound was prepared, mp > 180~C. The MS and 1H-NMR(300 MHz) spectral data were consistent with the desired product.
Calculated for C2lH1gI3N04: C 32.50, H 2.47, N 3.61, I 49.05;
Eound: C 32.41, H 2.36, N 3.49, I 48.86.

E~mnle 5 - Pre~aration of (1-Ethoxv-1-oxo-2-nh~nvleth~n-2-vl~-3-acetvlAmino-5-N-methvlacetvlAmin~-2.4.6-triiodoben70ate In a manner similar to the procedure described in Example 1 above, analytically pure compound was prepared, mp 249~C (dec.). The purification solvent was ethanol. The MS
and 1H-NMR(300 MHz) spectral data were consistent with the desired product.
Calculated for C22H21I3N206 C 33.44, H 2.68, N 3.55, I 48.18;
Found: C 33.41, H 2.59, N 3.48, I 48.39.

~Amnle 6 -= (l-Ethoxv-l-oxo-2-~henvleth~n-2-vl)-3 acetvlAmino-2.4.6-triiodobr~nzoate In a manner similar to the procedure described in Example 1 above, analytically pure com.pound was obtained, mp 21 9~ 984 WO96/00211 PCT~Ss~l0742l 175-176~C. The ~S and 1H-N~R(300 MHz~ spectral data were consistent with the desired product.
Calculated for C19H16I3NOs C 31.74, H 2.24, N 1.95, I 52.95;
Found: C 31.52, H 2.15, N 1.89, I 53.09.
s Ex~mnle 7 - Pre~aration of sis (l-ethoxv-1-oxo-2- - =
cvcloh~xvleth~n-2-vl)-5-acetvl~min~-2,4.6-triiodoiso~hth~late In a manner similar to the procedure described in Example 1 above, analytically pure compound, mp 205-207~C
was prepared. The MS and 1H-NMR(300 MHz) spectral data were consistent with the desired product.
Calculated for C2gH3gI3NOg C 38.44, H 4.08, N 1.49, I 40.61;
Found: C 38.60, H 4.01, N 1.38, I 40.48.
ExAm~le 8 - Pre~aration of Bis rl-ethoxv-1-oxo-2-cvclo~entvleth~n-2-vl)-5-acetvl~m;n~-2.4.6-triiodoiso~hth~late In a manner similar to the procedure described in Example 1 above, analytically pure compound was prepared, mp 198-200~C. The MS and lH-NMR(300 MHz) spectral data were consistent with the desired product.
Calculated for C3gH34I3Nog C 36.98, H 3.77, N 1.54, I 41.86;
Found: C 36.53, H 3.74, N 1.74, I 41.72.
The corresponding acids of the above-described esters, i.e., wherein R1=H, can be prepared by conventional techniques known in the art. Such acids and salts thereof are useful as wetting agents and/or as surface modifiers in x-ray contrast compositions, particularly in nanoparticulate x-ray contrast compositions.
The invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.

~l

Claims (14)

Claims:

1. A compound having the structure wherein m is 1, 2, 3 or 4;
is the residue of a polyiodinated aromatic mono- or polyacid;
R1 is H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl or acetamidoalkyl;
n is an integer from 0 to 20;
R2 is cycloalkyl or aryl; and R3, R4 and R5 are independently H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, halogen, hydroxy, acylamino, acetamidoalkyl, cyano, sulfonyl, carboxamido or sulfonamido.

2. The compound of claim 1 wherein is the residue of a polyiodinated aromatic acid selected from::
diatrizoic acid, metrizoic acid, urokonic acid, 5-acetylamino-2,4,6-triiodoisophthalic acid, iothalamic acid, triiodotrimesic acid, ioxagalic acid, ioxitalamic acid, tetraiodoterephthalic acid, iocarmic acid and iodipamide.

3. The compound of claim 1 wherein is the residue of diatrizoic acid.

4. The compound of claim 1 wherein is the residue of metrizoic acid.

5. The compound of claim 1 wherein is the residue of urokonic acid.

6. The compound of claim 1 wherein is the residue of 5-acetylamino-2,4,6-triiodoisophthalic acid.

7. The compound of claim 1 wherein R2 is cycloalkyl.

8. The compound of claim 1 wherein R2 is phenyl.

9. The compound of claim 1 wherein n is 0 or 1.

10. The compound of claim 1 wherein R1 is alkyl.

11. The compound of claim 1 selected from the group consisting of:
(1-Ethoxy-1-oxo-2-phenylethan-2-yl)-3,5-bis(acetylamino)-2,4,6-triiodobenzoate;
(1-Ethoxy-1-oxo-2-cyclopentylethan-2-yl)-3,5-bis(acetylamino)-2,4,6-triiodobenzoate;
(1-Ethoxy-1-oxo-2-cyclohexylethan-2-yl)-3,5-bis(acetylamino)-2,4,6-triiodobenzoate;
(1-Ethoxy-1-oxo-2-cyclohexylpropan-2-yl)-3,5-bis(acetylamino)-2,4,6-triiodobenzoate;
(1-Ethoxy-1-oxo-2-phenylethan-2-yl)-3-acetylamino-5-N-methylacetylamino-2,4,6-triiodobenzoate;
(1-Ethoxy-1-oxo-2-phenylethan-2-yl)-3-acetylamino-2,4,6-triiodobenzoate;
Bis (1-ethoxy-1-oxo-2-cyclohexylethan-2-yl) 5-acetylamino-2,4,6-triiodoisophthalate; and Bis (1-ethoxy-1-oxo-2-cyclopentylethan-2-yl) 5-acetylamino-2,4,6-triiodoisophthalate.

12. An x-ray contrast composition comprising the compound of claim 1.

13. The x-ray contrast composition of claim 12 further including a pharmaceutically acceptable carrier.

14. A method of medical x-ray diagnostic imaging which comprises administering to the body of a mammal a contrast enhancing effective amount of the x-ray contrast composition of claim 11.