United States Patent 19 11 Patent Number: 5,346,688 Bacon Et Al

USOO534.6688A United States Patent 19 11 Patent Number: 5,346,688 Bacon et al. 45 Date of Patent: Sep. 13, 1994 54) IODINATED WETTINGAGENTS OTHER PUBLICATIONS 75 Inventors: Edward R. Bacon, East Greenbush, Chemical Abstract 57: 4604a Search Report (STN); N.Y.; Gregory L. McIntire, West 1962. Chester, Pa. Primary Examiner-José G. Dees Assistant Examiner-Samuel Barts 73 Assignee: Sterling Winthrop Inc., New York, Attorney, Agent, or Firm-William J. Davis N.Y. 57 ABSTRACT 21 Appl. No.: 991,640 Compounds having the structure 22) Fied: Dec. 16, 1992 (Z--COO-L-CO2M 51 Int. Cl............................................... A61K 49/04 : - 424/5; 560/47 wherein (Z)-COO is the residue of an iodinated aro 58 Field of Search ............................. 560/25, 47,77; matic acid; 58 Fi 514/533, 424/5 M is H, a cation, -e-CH2CH2O)-H, and G-CH2C s H(OH)OH; 56) References Cited m is an integer from 1 to 150; p is an integer from 1 to 50; and U.S. PATENT DOCUMENTS L is one or more divalent linking groups selected 3,144,479 8/1964 Obendorf. from alkylene, cycloalkylene, arylene, arylenealky lene, and alkylenearylene are particularly useful as FOREIGN PATENT DOCUMENTS wetting agents in X-ray imaging compositions. 1082368 5/1960 Fed. Rep. of Germany . 866184 4/1958 United Kingdom . 5 Claims, No Drawings 5,346,688 1. 2 as wetting agents for therapeutic agents and in various ODINATED WETTING AGENTS other applications. In structural formula I above, (Z)-COO is the resi FIELD OF THE INVENTION due of an iodinated aromatic acid. The iodinated aro This invention relates to iodinated aromatic com matic acid can comprise one, two, three or more iodine pounds which are particularly useful as wetting agents. atoms per molecule. Preferred species contain at least two, and more preferably, at least three iodine atoms BACKGROUND OF THE INVENTION per molecule. The iodinated compounds can contain X-ray imaging is a well known and extremely valu substituents which do not deleteriously effect the con able tool for the early detection and diagnosis of various O trast enhancing capability of the compound. disease states in the human body. The use of contrast Illustrative examples of suitable aromatic acids in agents for image enhancement in medical X-ray imaging clude procedures is widespread. An excellent background on iodinated and other contrast agents for medical imaging diatrizoic acid, is provided by D. P. Swanson et al, Pharmaceuticals in 15 metrizoic acid, Medical Imaging, 1990, MacMillan Publishing Com urokonic acid, pany. iothalamic acid, EP-A 498,482 describes nanoparticulate x-ray con trimesic acid, trast compositions which have proven to be extremely ioxaglic acid (hexabrix), useful in medical imaging. The particles consist of a 20 ioxitalamic acid, poorly soluble diagnostic agent having adsorbed tetraiodoterephthalic acid, thereon a non-crosslinked surface modifier, the particles iodipamide, and the like. having a mean particle size of less than about 400 (nm). The present invention is directed to novel iodinated 25 In preferred embodiments, (Z)-COO is the residue of surfactants which are particularly useful as surface a substituted triiodobenzoic acid such as an acyl, carba modifiers in nanoparticle formulations. myl, and/or acylamino substituted triiodobenzoic acid. SUMMARY OF THE INVENTION In a particularly preferred embodiment, Z represents We have discovered and prepared novel iodinated aromatic compounds which are particularly useful as wetting agents in x-ray contrast compositions. More specifically, in accordance with this invention, there are provided novel compounds having the struc In ture 35 R-OCN co-r (Z--COO-L-CO2M (I) k R2 wherein (Z)-COO is the residue of an iodinated aro wherein n = 1, 2 or 3, matic acid; each R independently is H, C1-C18 alkyl, or C1-C18 M is H, a cation -6-CH2CH2OS-mH, or -6-CH2C fluoroalkyl, and H(OH) O-e-H; R and R2 are independently H or C1-C1s alkyl. m is an integer from 1 to 150; M is H; a cation, such as an alkaline or alkaline earth p is an integer from 1 to 50; and cation such as Na+, K+, Li, Cat, Ba, or an L is one or more divalent linking groups selected 45 ammonium cation such as NH4, tetramethylam from alkylene, cycloalkylene, arylene, arylenealky monium, and the like; G-CH2CH2OG-H, or lene, and alkylenearylene. -G-CH2CH(OH)O-pH; wherein m=an integer It is an advantageous feature of this invention that from 1 to 150, and p=an integer from 1 to 50. iodinated wetting agents are provided for x-ray contrast L represents a divalent linking group preferably se compositions which agents contribute to contrast en lected from alkylene containing from 1 to 20, prefera hancement bly 1 to 8 carbon atoms such as methylene, ethylene, It is another advantageous feature that the wetting propylene, butylene, pentylene, hexylene, heptylene agents of this invention can be used in vivo to change and the like; cycloalkylene, preferably containing from the interaction of particles with the reticuloendothelial 3 to 12 carbon atoms such as cyclopropylene, cyclobu system, thus enabling the particles to be retained in the 55 tylene, cyclopentylene, cyclohexylene and the like; blood pool or targeted to specific organs. arylene, preferably containing from 6 to 10 carbon Still another advantageous feature is that the use of atoms such as phenylene and naphthylene; arylenealky the wetting agents of this invention can result in very lene, the alkylene and arylene portions of which are as small particles, e.g., less than about 100 nm in size, ex described above; and alkylenearylene, the alkylene and hibiting both unique biological distribution, i.e., passive arylene portions of which are as describe above. tumor targeting, and enhanced pharmaceutical stability. The alkylene, cycloalkylene, arylene, alkyleneary lene and arylenealkylene groups in Structure I above DESCRIPTION OF PREFERRED can be unsubstituted or substituted with various substit EMBODIMENTS uents which do not adversely affect the stability or The compounds of this invention are described herein 65 efficacy of the compounds. Suitable substituents include primarily in connection with their preferred utility, i.e., alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy, hy as wetting agents for particulate x-ray contrast agents. droxy, aryloxy, acyloxy, halogen, acylamino, carboalk However, the compounds are also expected to be useful oxy, carbamyl and the like. However, reactive substitu 5,346,688 3 4 ents are not preferred on the carbon atom adjacent to ticulate x-ray contrast compositions, preferably as sur the ester group. face modifiers in nanoparticulate X-ray contrast compo The compounds of this invention can be prepared by sitions, as described in commonly-owned EPO 498,482, reacting the carboxylate of an iodinated aromatic acid the disclosure of which is hereby incorporated by refer with a functionalized acid having the formula 5 ence in its entirety. Such nanoparticulate compositions X-L-CO2M wherein X is a leaving group and L and can be prepared by dispersing a poorly soluble x-ray Mare as defined above, in a suitable solvent. Suitable contrast agent in a liquid dispersion medium, and wet leaving groups include halogen, such as Br, I, and Cl grinding the agent in the presence of rigid grinding sulfonyloxy, such as methanesulfonyloxy and toluene media and a wetting agent of this invention to form the sulfonyloxy. The carboxylates of iodinated aromatic O nanoparticles. Alternatively, the wetting agent can be acids and functionalized acids useful as the starting contacted with the contrast agent after attrition. materials in the preparation of the compounds of this The relative amount of the particulate x-ray contrast invention are known compounds and/or can be pre agent and wetting agent can vary widely and the opti pared by techniques known in the art. For example, mal amount of the wetting agent can depend, for exam suitable acids include commercially available bromoa 15 ple, upon the particular contrast agent and wetting cids and chloroacids. A general reaction scheme is as agent selected, the hydrophilic lipophilic balance of the follows: wetting agent, its water solubility, the surface tension of water solutions of the wetting agent, etc. The wetting Z-COO-X-L-CO2M-I agent can be present in an amount of 0.1-90%, prefera The reaction can take place at various temperatures bly 1-75%, more preferably 2-50% and most preferably ranging between -78° C. and 100° C., and preferably 2-25% by weight based on the total combined dry -40 C. to 50 C. weight of the particulate contrast agent and wetting For convenience, the reaction can take place at ambi agent. ent pressure, however, higher and lower pressures are The x-ray contrast compositions of this invention contemplated. 25 comprise the above-described compounds, preferably Alternatively, the compounds of this invention, when as a wetting agent for a particulate contrast agent, and M=H or a cation, can be prepared in a two-step synthe a physiologically acceptable carrier therefor. For exam sis. First, the carboxylate of an iodinated aromatic acid ple, the particles can be dispersed in an aqueous liquid can be reacted with a functionalized ester as described which serves as the carrier for the x-ray contrast agent. by Bacon et al in commonly owned U.S. Pat. applica Other suitable carriers include liquid carriers such as tion Ser. No. 07/990,987, entitled Iodinated Aroyloxy mixed aqueous and nonaqueous solvents, such as alco Esters, filed on Dec. 16, 1992, or by Singh et al in com hol; gels; gases, such as air; and powders. monly owned U.S. Pat, application Ser. No. 07/990,306, The X-ray contrast composition can comprise from entitled Iodinated Aromatic Compounds, filed on Dec.

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