|||||||||||||| 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.