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. 35 about 1-99.9, preferably 2-45 and more preferably 14, 1992, the disclosures of which are hereby incorpo 10-25% by weight of the above-described particles, the rated by reference in their entirety. Thereafter, the ester remainder of the composition being the carrier, addi can be converted into the corresponding acid by hydro tives and the like. Compositions up to about 100% by lysis using techniques well known in the art. weight of the particles are contemplated when the com The following are specific specific illustrative exam position is in a lyophilized form. ples of preferred compounds of this invention that have The dose of the contrast agent to be administered can been prepared: be selected according to techniques known to those 5-(3',5'-bis(acetylamino)-2',4',6'-triiodophenyl)car skilled in the art such that a sufficient contrast enhanc bonyloxypentanoic acid (WIN 68040), ing effect is obtained. Typical doses can range from 50 6-(3',5'-bis(acetylamino)-2',4',6'-triiodophenyl)car 45 to 350 mg of iodine per kilogram of body weight of the bonyloxylhexanoic acid (WIN 68056), subject for many imaging applications. For some appli 7-C3',5'-bis(acetylamino) -2',4',6'-triiodophenyl)car cations, e.g., lymphography, lower doses, e.g., 0.5-20 bonyloxyheptanoic acid (WIN 68167), mg I/kg, can be effective. 8-(3',5'-bis(acetylamino)-2',4',6'-triiodophenyl)car The X-ray contrast composition can contain one or bonyloxyoctanoic acid (WIN 68237), and 50 more conventional additives used to control and/or 4-(3',5'-bis(acetylamino)-2',4',6'-triiodophenyl)car enhance the properties of the x-ray contrast agent. For bonyloxymethylbenzoic acid (WIN 68016). example, thickening agents such as dextran or human Preferred compounds of this invention having Struc serum albumin, buffers, viscosity regulating agents, ture I above, wherein Z is the residue of diatrizoic acid suspending agents, peptizing agents, anti-clotting and M=H, are set forth below: 55 agents, mixing agents, and other drugs and the like can be added. A partial listing of certain specific additives WN L includes gums, sugars such as dextran, human serum 68040 (CH2)4 albumin, gelatin, sodium alginate, agar, dextrin, pectin 68.056 (CH2)5 and sodium carboxymethyl cellulose. Such additives, 68167 (CH2)6 surface active agents, preservatives and the like can be 68273 (CH2)7 incorporated into the compositions of the invention. A method for diagnostic imaging for use in medical procedures in accordance with this invention comprises When used as a wetting agent in an x-ray contrast administering to the body of a test subject in need of an composition, the compound of this invention can com 65 X-ray an effective contrast producing amount of the prise up to about 40% or higher iodine by weight. above-described x-ray contrast composition. In addition In preferred embodiments, the compounds of this to human patients, the test subject can include mamma invention can be formulated as wetting agents into par lian species such as rabbits, dogs, cats, monkeys, sheep, 5,346,688 5 6 pigs, horses, bovine animals and the like. Thereafter, at was filtered and acidified with glacial acetic acid. The least a portion of the body containing the administered precipitate that formed was collected, washed with a contrast agent is exposed to X-rays to produce an x-ray solution (1:1) of ethanol-ethyl ether and dried to give image pattern corresponding to the presence of the the crude product (93%). Recrystallization from DMF contrast agent. The image pattern can then be visual gave analytically pure material, mp 251-255 C.; CI ized. For example, any X-ray visualization technique, MS: MH+ 729. The H-NMR (300 MHz) spectral date preferably, a high contrast technique such as computed was consistent with the desired material. Calculated for tomography, can be applied in a conventional manner. C17H193N2O6: C 28.05, H2.63, I 52.29, N 3.85; Found: Alternatively, the image pattern can be observed di C 28.05, H2.63, I 52.39, N 3.78. rectly on an x-ray sensitive phosphor screen-silver hal 10 ide photographic film combination. EXAMPLE 3 The compositions of this invention can be adminis tered by a variety of routes depending on the type of Wetting Agent for X-Ray Nanoparticle procedure and the anatomical orientation of this tissue WIN 68056 was mixed at concentrations of 0.5 to 3% being examined. Suitable administration routes include 15 with WIN 67722 together with water sufficient to pre intravascular (arterial or venous) administration by pare a 10% suspension of WIN 67722. After milling for catheter, intravenous injection, rectal administration, 7 days, the particle size was reduced to approximately subcutaneous administration, intramuscular administra 110 to 130 nm, as determined by standard light scatter tion, intralesional administration, intrathecal adminis ing techniques. tration, intracisternal administration, oral administra 20 tion, administration via inhalation, administration di EXAMPLE 4 rectly into a body cavity, e.g., arthrography, and the Wetting Agent for X-Ray Nanoparticle like. In addition to preferred applications, i.e., for blood WIN 68016 was treated as described above together pool, liver, spleen and lymph node imaging, the X-ray 25 with WIN 67722 and resulted in particles with an aver contrast compositions of this invention are also ex age size of less than 110 nm as determined by standard pected to be useful as contrast agents for any organ or light scattering techniques. body cavity. For example, the compositions of this The foregoing specification, including the specific invention are expected to be useful as anglographic embodiments and examples is intended to be illustrative contrast media, urographic contrast media, myelo 30 of the present invention and is not to be taken as limit graphic contrast media, gastrointestinal contrast media, ing. Numerous other variations and modifications can cholecystographic and cholangiographic contrast me be effected without departing from the true spirit and dia, arthrographic contrast media, hysterosalpingo scope of the present invention. graphic contrast media, oral contrast media and bron We claim: chographic contrast media. 35 1. A compound having the structure The following examples further illustrate the inven tion. O O EXAMPLE 1 C-O-CH2 C-OM Preparation of WIN 68016 I A mixture of WIN 67923, i.e., 4-(ethoxycarbonyl)- phenyl3, 5-bis(acetylamino) 2,4,6-triiodobenzoate, (11.8 g, 15.2 mmol) prepared by reacting sodium diatrizoate CH3CONH NHCOCH3 and ethyl 4-bronomethylbenzoate, as described by Singh et al, cited above, and sodium hydroxide (0.8 g., 45 I 20.0 mmol) in 100 ml of water and 50 ml of methanol wherein M is H or a cation. was stirred and heated under reflux for 5 hrs. The meth 2. A compound having the structure anol was removed under reduced pressure and the re maining solution was filtered to remove some insoluble 50 solids. The filtrate was acidified with concentrated HCl O O whereupon a white solid precipitated. The precipitate I was collected, washed with water and dried under vac C-O-CH2 C-OH. uum at 80-85 C. to give 9.8g of a white granular solid, mp 289°-292 C. (dec.); CI-MS: MH+749. The 1H NMR (300 MHz) spectral data was consistent with the 55 desired product. Calculated for C19H15I3N2O6: C30.51, CH3CONH NHCOCH3 H 2.02, I 50.89, N 3.74; Found: C30.35, H 1.91, 51.05, I N 3.62. 3. An X-ray contrast composition comprising the EXAMPLE 2 compound of claim 1. Preparation of WIN 68056 4. The X-ray contrast composition of claim 3 further A mixture of the ester, WIN 67722, i.e., 6-ethoxy-6- including a pharmaceutically acceptable carrier. oxohexyl-3,5-bis(acetamide)2,4,6-triiodobenzoate, pre 5. A method of medical x-ray diagnostic imaging pared as described by Bacon et al, cited above, (5.6 g, 65 which comprises administering to the body of a man 7.3 mmol) and powdered 95% potassium hydroxide (1.6 mal a contrast effective amount of the x-ray contrast g, 24.1 mmol) in 25 ml of water was heated on a steam composition of claim 3. bath for 15 minutes. After cooling, the resulting solution k is : k is