|||||||||||||| USOO5260478A United States Patent (19) 11 Patent Number: 5,260,478 Bacon et al. (45) Date of Patent: Nov. 9, 1993

(54) IODINATED AROYLOXY CARBOXAMIDES 57) ABSTRACT 75 Inventors: Edward R. Bacon, East Greenbush; Compounds having the structure Sol J. Daum, Albany, both of N.Y.; Carl R. Illig, Phoenixville, Pa. O R1 R3 O R5 / 73 Assignee: Sterling Winthrop Inc., New York, (z)-c-o-c-e-cc-N R2 R. Yr

21 Appl. No.: 986,646 wherein (Z-)-COO is the residue of an iodinated aromatic 22 Filed: Dec. 8, 1992 acid; n is an integer from 0 to 20; 51) Int. Cl...... C07C 69/76 R and R2 are independently H, alkyl, fluoroalkyl, 52 U.S. Cl...... 560/110; 424/5 cycloalkyl, aryl, aralkyl, alkoxy or aryloxy; 58 Field of Search ...... 560/110; 424/5; R3 and R4 are independently a substituent as defined 514/535, 532 for R1 and R2 above, halogen, hydroxy or acyl amino; (56) References Cited and R and R6 are independently H, alkyl, cycloalkyl, U.S. PATENT DOCUMENTS aryl, aralkyl, alkoxy, alkoxyalkyl, or acetamidoal 5,055.45. 10/1991 Krantz et al...... 560/110 kyl; or R5 and R6, taken together with the nitrogen atom FOREIGN PATENT DOCUMENTS to which they are attached, represent a 4 to 7-mem 30385.98 5/1982 Fed. Rep. of Germany . bered nitrogen containing ring, are useful as con 112915.4 6/1986 Japan . trast agents in x-ray imaging compositions and methods. Primary Examiner-Paul J. Killos Attorney. Agent, or Firm-William J. Davis 8 Claims, No Drawings 5,260,478 1. 2

IODINATED AROYLOXY CARBOXAMIDES O R. R. O. RS (I) II / FIELD OF INVENTION (zy-C-O-c-e-cc-N This invention relates to iodinated aroyloxy carbox R2 R4 Yrs amides which are particularly useful as contrast agents for x-ray imaging. wherein (Z-)-COO is the residue of an iodinated aromatic BACKGROUND OF THE INVENTION acid; O n is an integer from 0 to 20; X-ray imaging is a well known and extremely valu R1 and R2 are independently H, alkyl, fluoroalkyl, able tool for the early detection and diagnosis of various cycloalkyl, aryl, aralkyl, alkoxy or aryloxy; disease states in the human body. The use of contrast R3 and Rare independently a substituent as defined agents for image enhancement in medical x-ray imaging for R and R2 above, halogen, hydroxy or acyl procedures is widespread. An excellent background on 15 anino; iodinated and other contrast agents for medical imaging and R5 and R6 are independently H, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, alkoxyalkyl, or acetamidoal is provided by D. P. Swanson et al., Pharmaceuticals in kyl; Medical Imaging, 1990, MacMillan Publishing Com or R5 and R6, taken together with the nitrogen atom pany. 20 to which they are attached, represent a 4 to 7-mem Various soluble and water insoluble iodinated amides bered nitrogen containing ring. and esters have been used as x-ray contrast agents. For This invention further provides an x-ray contrast example, U.S. Pat. No. 3,097,228 describes derivatives of 2,4,6-triiodobenzoyloxyalkanoic acids having the composition comprising the above-described com 25 pound and a method for medical X-ray diagnostic imag Structure ing which comprises administering to the body of a mammal a contrast effective amount of the above described x-ray contrast composition. foort It is an advantageous feature of this invention that novel compounds are provided which find particular I foohRI utility as x-ray contrast agents. It is another advantageous feature of this invention that compounds are provided having appropriate solu R NHR bility profiles and improved enzymatic degradability. 35 DESCRIPTION OF PREFERREED EMBODEMENTS wherein R is H or lower alkyl, R2 is H or alkanoyl, R3 In structural formula I above, (Z-)-COO is the resi is H or alkanoylamino, and R is lower alkyl. However, due of an iodinated aromatic acid. The iodinated aro there is no suggestion of a carboxamide group linked to 40 matic acid can comprise one, two, three or more iodine an ester group on an iodinated aromatic ring. atoms per molecule. Preferred species contain at least U.S. Pat. No. 4,328,202 describes ionic 5-C-sub two, and more preferably, at least three iodine atoms stituted 2,4,6-triiodoisophthalic acid derivatives as x-ray per molecule. The iodinated compounds can contain contrast agents, but does not suggest a carboxamide substituents which do not deleteriously effect the con group linked to an ester group on an iodinated aromatic 45 trast enhancing capability of the compound. acid. Illustrative examples of suitable aromatic acids in U.S. Pat. No. 4,364,921 describes triiodinated iso clude diatrizoic acid, phthalic acid diamides as nonionic X-ray contrast media, metrizoic acid, but does not suggest a carboxamide group linked to an 50 urokonic acid, ester group on an iodinated aromatic ring. 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. However, particulate con ioxitalamic acid, trast agents in certain in vivo applications can exhibit 55 tetraiodoterephthalic acid, less than fully satisfactory enzymatic degradation, e.g., iodipamide, and the like. in plasma and blood. In preferred embodiments, (Z-)-COO is the residue of a It would be desirable to provide compounds for use substituted triiodobenzoic acid such as an acyl, carba as x-ray contrast agents having improved enzymatic myl, and/or acylamino substituted triiodobenzoic acid. R1 and R2 independently represent H; substituted or degradability and appropriate solubility profiles. unsubstituted, linear or branched alkyl, preferably con SUMMARY OF THE INVENTION taining from 1 to 20, more preferably 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, We have discovered and prepared novel iodinated pentyl, hexyl and the like; fluoroalkyl, preferably con aroyloxy carboxamides which are useful as contrast 65 taining from 1 to 3 fluorine atoms, the alkyl portion of agents in X-ray contrast compositions. which is as described for R1 above; cycloalkyl, prefera More specifically, in accordance with this invention, bly containing from 3 to 8 carbon atoms such as cyclo there are provided compounds having the structure propyl and cyclobutyl; aryl, preferably containing from 5,260,478 3 4. 6 to 10 carbon atoms, such as phenyl and naphthyl; aralkyl, preferably containing from 7 to 12 carbon R. R. O R atoms, such as benzyl; alkoxy, the alkyl portion of / which contains from 1 to 20 carbon atoms as described X-c-e-cc-N N above; or aryloxy, the aryl portion of which preferably R2 R4 R6 contains from 6 to 10 carbon atoms as described above. R3 and R independently represent a substituent as wherein X is a leaving group and Rl-R6 are as defined defined for R above, halogen, such as chlorine or bro above. Suitable leaving groups include halogen, such as mine, hydroxy, or acylamino, i.e., a Br, I and Cl, sulfonyloxy, such as methanesulfonyloxy 10 and toluenesulfonyloxy. When X = Cl, it has been found O R7 that the addition of NaI can facilitate the reaction. The 7 carboxylates of iodinated aromatic acids and functional -C-N ized amides useful as the starting materials in the prepa Yrs ration of the compounds of this invention are known 15 compounds and/or can be prepared by techniques group wherein R7 and R8 are as defined for R5 below. known in the art. For example, suitable amides include However, reactive substituents such as halogen are not commercially available bronoacetamide and chlo preferred on the carbon atom adjacent to the amide roacetamide derivatives as exemplified below. A gen carbonyi. eral reaction scheme is as follows: Rhu 5 and R6 independently represent H, alkyl as 20 defined for R above; cycloalkyl as defined for Rl R. R3 O R5 above; aryl as defined for R above, aralkyl as defined E / for R above; alkoxy as defined for R1 above; alkoxyal (Z-COO -- X-C-C-C-N -GI kyl, the alkyl portions of which are as defined for R l, N above; acetamidoalkyl, i.e., 25 The reaction can take place between - 78° C. and O 100 C. For convenience, the reaction can take place at -NH-C-alkyl ambient temperature. 30 For convenience, the reaction can take place at ambi wherein alkyl is as defined for R above; or R5 and R6, ent pressure, however, higher and lower pressures are taken together with the nitrogen atom to which they are contemplated. attached, represent a 4 to 7 membered saturated or The following are specific illustrative examples of unsaturated nitrogen containing ring such as piperidyl, preferred compounds of this invention that have been piperizinyl, pyrrolidinyl and the like. 35 prepared: The alkyl, cycloalkyl, aryl, aralkyl and alkoxy groups 2-amino-2-oxoethyl 3,5-bis(acetylamino)-2,4,6-trii and the nitrogen containing ring in structure I above odobenzoate (WIN 65,540), can be unsubstituted or substituted with various substit 2-ethylamino-2-oxoethyl 3,5-bis(acetylamino)-2,4,6-trii uents which do not adversely affect the stability or odobenzoate (WIN 65,312), efficacy of the compounds as x-ray contrast agents such 40 2-diethylamino-2-oxoethyl 3,5-bis(acetylamino)-2,4,6- as alkyl, cycloalkyl, aryl, aralkyl, alkoxy, hydroxy, triiodobenzoate (WIN 67,499), acyloxy, halogen, such as chlorine, bromine and iodine, 2-dibutylamino-2-oxoethyl 3,5-bis(acetylamino)-2,4,6- acylamino, carboalkoxy, carbamyl and the like. How triiodobenzoate (WIN 67,774), ever, reactive substituents such as halogen, hydroxy and 2-diisopropylamino-2-oxoethyl 3,5-bis(acetylamino)- acylamino are not preferred on the carbon atoms, if 45 2,4,6-triiodobenzoate (WIN 67,901), present in R5 and R6 adjacent to the amide nitrogen. 2-bis(2-hydroxyethyl)amino-2-oxethyl 3,5-bis The compounds of this invention can be prepared by (acetylamino)-2,4,6-triiodobenzoate (WIN 67,862), reacting the carboxylate of an iodinated aromatic acid 2-diethylamino-2-oxoethyl 3,5-bis(diacetylamino)-2,4,6- triiodobenzoate (WIN 68,187), and with a functionalized amide having the formula 2-bis(2-acetoxyethyl)amino-2-oxoethyl 3,5-bis(- 50 diacetylamino)-2,4,6-triiodobenzoate (WIN 67,888). These preferred compounds of this invention con form to structure I above, wherein R1-R2 = H and n=0 as indicated below:

WN Z R5 R6 65,540 H H

CH3CONH NHCOCHs I

65.32 H C2H5 67,499 C2Hs CHs 67,774 CHg C4H9 67,90) CH(CH3) CH(CH3) 67,862 CHCHOH CHCH-OH 5,260,478 5 6 -continued WIN Z RS R6

67,888 CH2CH2OCOCH3 CH2CH2OCOCH3 I I

(CH3CO)2N N(COCH3) I 68,187 C2H5 C2H5 When used as an x-ray contrast agent, the compound of this invention preferably comprises at least about 35%, more preferably 40% iodine by weight. 5 in preferred embodiments, the compounds of this above-described x-ray contrast composition. In addition invention can be formulated into particulate x-ray con to human patients, the test subject can include mamma trast compositions, preferably nanoparticulate x-ray lian species such as rabbits, dogs, cats, monkeys, sheep, contrast compositions, as described in commonly pigs, horses, bovine animals and the like. Thereafter, at owned EPO 498, 482, the disclosure of which is hereby least a portion of the body containing the administered incorporated by reference in its entirety. Such nanopar contrast agent is exposed to x-rays to produce an x-ray ticulate compositions can be prepared by dispersing the image pattern corresponding to the presence of the compounds of the invention in a liquid dispersion me contrast agent. The image pattern can then be visual dium, and wet grinding the compound in the presence ized. For example, any x-ray visualization technique, of rigid grinding media and a surface modifier to form 25 preferably, a high contrast technique such as computed the nanoparticles. Alternatively, the surface modifier tomography, can be applied in a conventional manner. can be contacted with the compound after attrition. Alternatively, the image pattern can be observed di The x-ray contrast compositions of this invention rectly on an x-ray sensitive phosphor screen-silver hal comprise the above-described compounds, preferably in ide photographic film combination. the form of particles, and a physiologically acceptable 30 The compositions of this invention can be adminis carrier therefor. For example, the particles can be dis tered by a variety of routes depending on the type of persed in an aqueous liquid which serves as the carrier procedure and the anatomical orientation of this tissue for the x-ray contrast agent. Other suitable carriers being examined. Suitable administration routes include include liquid carriers such as mixed aqueous and nona intravascular (arterial or venous) administration by queous solvents, such as alcohol; gels; gases, such as air; 35 catheter, intravenous injection, rectal administration, and powders. subcutaneous administration, intranuscular administra The x-ray contrast composition can comprise from tion, intralesional administration, intrathecal adminis about 1-99.9, preferably 2-45 and more preferably tration, intracisternal administration, oral administra 10-25% by weight of the above-described particles, the tion, administration via inhalation, administration di remainder of the composition being the carrier, addi 40 rectly into a body cavity, e.g., arthrography, and the tives and the like. Compositions up to about 100% by like. weight of the particles are contemplated when the com In addition to preferred applications, i.e., for blood position is in a lyophilized form. pool, liver, spleen and lymph node imaging, the x-ray The dose of the contrast agent to be administered can contrast compositions of this invention are also ex be selected according to techniques known to those 45 pected to be useful as contrast agents for any organ or skilled in the art such that a sufficient contrast enhanc body cavity. For example, the compositions of this ing effect is obtained. Typical doses can range from 50 invention are expected to be useful as angiographic to 350 mg of iodine per kilogram of body weight of the contrast media, urographic contrast media, myelo subject for many imaging applications. For some appli graphic contrast media, gastrointestinal contrast media, cations, e.g., lymphography, lower doses, e.g., 0.5-20 SO cholecystographic and cholangiographic contrast me mg I/kg, can be effective. dia, arthrographic contrast media, hysterosalpingo The x-ray contrast composition can contain one or graphic contrast media, oral contrast media and bron more conventional additives used to control and/or chographic contrast media. enhance the properties of the x-ray contrast agent. For The following examples further illustrate the inven example, thickening agents such as dextran or human 55 tlOn. serum albumin, buffers, viscosity regulating agents, suspending agents, peptizing agents, anti-clotting EXAMPLE 1 agents, mixing agents, and other drugs and the like can Preparation of WIN 65, 540 be added. A partial listing of certain specific additives Bromoacetamide (21 76 g, 157.8 mmol) was added to includes gums, sugars such as dextran, human serum 60 a solution of sodium diatrizoate (100.3 g, 157.8 mmol) in albumin, gelatin, sodium alginate, agar, dextrin, pectin 1000 ml of dry dimethylformamide and the solution was and sodium carboxymethyl cellulose. Such additives, stirred at ambient temperature under an argon atmo surface active agents, preservatives and the like can be sphere for approximately 12 hr. The reaction mixture incorporated into the compositions of the invention. was then concentrated under vacuum to give a residue A rhethod for diagnostic imaging for use in medical 65 which was taken up in cold water. The solid product procedures in accordance with this invention comprises was collected, washed with water, and air dried to give administering to the body of a test subject in need of an a white solid. This crude product was taken up in 350 ml x-ray an effective contrast producing amount of the of Saturated aqueous sodium bicarbonate and the mix 5,260,478 7 8 ture was stirred for 15 min. The product was collected, washed successively with water, methanol and ether O R1 R O R5 and dried to give 92.4 g (88%) of the desired product. / (Z-C-O-C-C-C-N Recrystallization from DMF-H2O gave analytically N pure material, mp 288-300° C. (decomp.) after drying R2 R4 R6 at 120° C. under high vacuum; CI-MS: MH+ 672. The H-NMR (300 MH) spectral data was consistent with wherein the desired product. Calculated for C13H1213N3Os: C (Z--COO is the residue of an iodinated aromatic acid; 23.27, H 1.80, I 56.74, N 6.26, Found: C 23.34, H 1.64, I 10 n is an integer from 0 to 20; 56.78, N 6.27. R1 and R2 are independently H, alkyl, fluoroalkyl, EXAMPLES 2-5 cycloalkyl, aryl, aralkyl, alkoxy or aryloxy; R3 and R4 are independently a substituent as defined The following compounds were synthesized using a for R and R2 above, halogen, hydroxy or acyl procedure similar to that described in Example 1 above 5 amino; for preparing WIN 65,540, except that in these prepara and R5 and R6 are independently H, alkyl, cycloalkyl, tions, the following chloroacetamide derivatives were aryl, aralkyl, alkoxy, alkoxyalkyl, or acetamidoal used in place of bronoacetamide, sodium iodide was kyl; added as a catalyst, and the reactions were heated on a or R3 and R6, taken together with the nitrogen atom steam bath for 2 hours after stirring for 12 hours over 20 to which they are attached, represent a 4 to 7-mem night at room temperature. bered nitrogen containing ring. 2. The compound of claim 1 wherein (Z-)-COO is the residue of an iodinated aromatic acid selected from: Chloroacetamide diatrizoic acid, Example WIN Derivative % Yield 25 metrizoic acid, 2 67,774. CCHCON(C4H9) 92. urokonic acid, 3 67,499 CCHCON(CHS) 83 iothalamic acid, 4. 67,901 CCH3CON(CH(CH3)2) 92 trimesic acid, 5 67.862 CCHCON(CH2CH2OH) 94 ioxagalic acid. 30 ioxitalamic acid, tetraiodoterephthalic acid and EXAMPLE 6 iodipamide. Preparation of WIN 67,888 3. The compound of claim 1 wherein (Z-)-COO is the residue of diatrizoic acid. Acetic anhydride (100 ml) was added to a solution of 35 4. The compound of claim 1 wherein n=0, R = H WIN 67,862 (20.3 g. 26.7 mmol) prepared as described and R2=H. above in dry pyridine (200 ml) and the mixture was 5. The compound of claim 1 selected from the group stirred for 12 hr at ambient temperature. The solution consisting of was then added to excess ice-water and the precipitated 2-amino-2-oxoethyl 3,5-bis(acetylamino)-2,4,6-trii solid was collected and washed with water. The crude 40 Odobenzoate, product (20.5 g, 88%) was recrystallized from ethyl 2-ethylamino-2-oxoethyl 3,5-bis(acetylamino)-2,4,6-trii acetate to give analytically pure material, mp 178°-180 odobenzoate, C., after drying under vacuum; CI-MS: MH 928. The 2-diethylamino-2-oxoethyl 3,5-bis(acetylamino)-2,4,6- triiodobenzoate, H-NMR (300 MH) spectral data was consistent with 2-dibutylamino-2-oxoethyl 3,5-bis(acetylamino)-2,4,6- the proposed structure. Calculated for C25H28Isn3O11: triiodobenzoate, C 32.38, H 3.04, I 41.06, N 4.53; Found: C 32.41, H 2.95, 2-diisopropylamino-2-oxoethyl 3,5-bis(acetylamino)- I 41.25, N 4.39. 2,4,6-triiodobenzoate, EXAMPLE 7 2-bis(2-hydroxyethyl)amino-2-oxethyl 3,5-bis 50 (acetylamino)-2,4,6-triiodobenzoate, Preparation of WIN 68,187 2-diethylamino-2-oxoethyl 3,5-bis(diacetylamino)-2,4,6- WIN 68,187 was synthesized using a procedure simi triiodobenzoate, and 2-bis(2-acetoxyethyl)amino-2-oxoethyl 3,5-bis(- lar to that described in Example 6 for preparing WIN diacetylamino)-2,4,6-triiodobenzoate. 67,888, except that acetic anhydride was added to a 55 6. An x-ray contrast composition comprising the solution of WIN 67,499. compound of claim 1. The invention has been described in detail with par 7. The x-ray contrast composition of claim 6 further ticular reference to certain preferred embodiments including a pharmaceutically acceptable carrier. thereof, but it will be understood that variations and 8. A method for medical x-ray diagnostic imaging modifications can be effected within the spirit and scope 60 which comprises administering to the body of a mam of the invention. mal a contrast effective amount of the x-ray contrast We claim: composition of claim 6. 1. A compound having the structure sk k k sk k 65