| CORP. SALE | 3,5-Bis(AcetylMethylAmino)-2,4,6-Tri-I Benzoic Acid. |
| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 04.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 18.04.00 |
| PATENT TITLE |
N,N-dimethyldiatrizoic acid and its conjugates as hepatobiliary agents for X-ray CT imaging |
| PATENT ABSTRACT |
Compounds having formulae I, II or III, or pharmaceutically acceptable salts thereof, ##STR1## wherein ##STR2## R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are the same or different and are hydrogen, alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl or carboxamido alkyl with the proviso that in formula I R.sub.2 and R.sub.3 cannot be methyl; and m, n and p are the same or different and are 0-24 with the proviso that m+n.ltoreq.24, are useful as contrast agents in x-ray imaging compositions and methods. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 22.03.99 |
| PATENT REFERENCES CITED | Haugen et al., Chemical Abstracts 60:15692(c), 1963. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS | This application is a continuation of U.S. application Ser. No. 08/856,796, filed May 15, 1997, now abandoned |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to compositions containing conjugates of N,N-dimethyldiatrizoic acid and methods for their use in diagnostic radiology. More particularly, the invention relates to compositions containing N,N-dimethyldiatrizoic acid or a conjugate thereof for use as hepatobiliary agents for x-ray CT imaging. 2. Reported Developments Roentgenographic examination utilizing X-rays and computed tomography (hereinafter CT) scans of fractures and other conditions associated with the skeletal system is routinely practiced without the use of contrast agents. X-ray visualization of organs containing soft tissues, such as the gastrointestinal tract, heart, lung, kidneys and spleen, requires the use of contrast agents which attenuate x-ray radiation. D. P. Swanson et al. in "Pharmaceuticals In Medical Imaging", 1990, MacMillan Publishing Company, provides an excellent background in medical imaging utilizing contrast agents and compositions therewith. Roentgenographic examination of the GI tract are indicated for conditions of digestive disorders, changes in bowel habit, abdominal pain, GI bleeding and the like. Prior to radiological examination, administration of a radiopaque contrast medium is necessary to permit adequate delineation of the respective lumen or mucosal surface from surrounding soft tissues. Accordingly, a contrast medium is administered orally to visualize the mouth, pharynx, esophagus, stomach, duodenum and proximal small intestine. The contrast medium is administered rectally for examination of the distal small intestine and the colon. The most widely used contrast agent for the visualization of the GI tract is barium sulfate administered as a suspension orally or rectally as an enema. (See, for example, U.S. Pat. Nos. 2,659,690; 2,680,089; 3,216,900; 3,235,462; 4,038,379; and 4,120,946.) Notwithstanding its relatively good contrast characteristics, negligible absorption from the GI tract following oral or rectal administration and speedy excretion form the body, barium sulfate has certain disadvantages. In the presence of intestinal fluids it lacks homogeneity and poorly adheres to mucus membranes which can result in poor x-ray images. In the colon, when administered as an enema, it flocculates and forms irregular clumps with fecal matter. In addition to, or in place of barium sulfate, iodinated organic compounds have also been used as GI contrast agents since the iodine atom is an effective x-ray absorber. They have the most versatility and are utilized in the widest variety of procedures. They are very absorptive of x-rays with which the iodine interacts and produce a so-called photoelectric effect which is a large magnification in contrast caused by the photons stopped in the iodine-containing medium. The magnification of contrast exceeds the level that would be expected from relative changes in density. Because of this magnification, relatively low concentrations of the contrast agents can be utilized. (For iodinated agents see, for example, U.S. Pat. Nos.: 2,786,055; 3,795,698; 2,820,814; 3,360,436; 3,574,718; 3,733,397; 4,735,795; 5,047,228; 5,308,607; 5,310,538; 5,318,769; 5,334,370; 5,336,484 and 5,344,638.) The desiderata for an ideal GI contrast agent includes: good toxicological profile; the ability to fill the entire bowel/lumen and evenly coat the gut mucosa so that the presence of the bowel is detectable when the lumen is not distended; nonirritation to the intestinal mucosa; and passage through the GI tract without producing artifacts or stimulating vigorous intestinal peristalsis. We have found that the compounds of the present invention having these and other desirable characteristics in the GI tract do satisfy the requirements of an x-ray contrast agent when incorporated in suitable aqueous oral or rectal formulations for examination of the GI tract utilizing x-rays and CT scans. During extensive investigation we have also discovered that the compounds of the present invention are eminently suitable for intravenous administration for CT imaging of organs, such as the kidneys and liver. It is well known by those skilled in the art that agents for intravenous administration must meet certain requirements that are more stringent than the requirements for oral and rectal administration since the agents are directly introduced into the blood stream of the patient. The imagining of the organ or body section is accomplished by means of roentgenography commonly referred to as computed tomography (CT) or computerized axial tomography (CAT) in which the emergent x-ray beam is measured by a scintillation counter, the electronic impulses are recorded on a magnetic disk, and then processed by a computer for reconstruction display. SUMMARY OF THE INVENTION In one aspect the present invention provides hepatobiliary agents for x-ray CT imaging having the formula I, II or III, or a pharmaceutically acceptable salt thereof ##STR3## wherein ##STR4## R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are the same or different and are hydrogen, alkyl, cycloalkyl, aralkyl, aryl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl or carboxamido alkyl; and m, n and p are the same or different and are 0-24 with the proviso that m+n.ltoreq.24. The terms herein throughout the specification and the claims have the following meaning. The term "alkyl" refers to both straight, and branched, unsubstituted chains of 1 to 10 carbon atoms. Those chains having 1 to 5 carbon atoms are preferred. Methyl is the most preferred alkyl group. The term "cycloalkyl" refers to cyclic hydrocarbon groups of 3 to 7 carbon atoms. The groups may be unsubstituted or substituted by, for example, alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthiol, nitro, cyano, carboxy, carbamoyl, alkoxycarbonyl, alkylsulfonyl, sulfonamido and the like. The term "aryl" refers to phenyl, pyridyl, furanyl, thiophenyl, pyrrolyl, imidazolyl and the like, all of which may be substituted. Preferred substituted aryl groups are those substituted with 1, 2 or 3 halogen, nitroamino, maleimido, isothiocyanato, hydroxy, hydroxyalkyl, alkyl, alkoxy, carbamoyl, carboxamide, acylamino or carboxy moieties. The term "aralkyl" refers to an aryl group bonded through an alkyl group. The term "halo" refers to bromo, chloro, fluoro or iodo. The term "alkoxy" refers to a chain consisting of C and O atoms of a 2:1 ratio in the range of 4 to 10 atoms, wherein methoxy is the most preferred alkoxy group. The term "carboxy" refers to the group --C(O)OH or the group --C(O)OR wherein R is alkyl. The compounds or pharmaceutically acceptable salts thereof incorporated in a suitable pharmaceutically acceptable vehicle, such as human serum albumin, and administered to a mamnmal intravenously, provide sufficient iodine concentration in the liver and other organs for x-ray CT imaging at dose levels of 5 mmol/kg of body weight or higher. There is further provided a method for x-ray CT diagnostic imaging of the liver and/or other organs which comprises intravenously administering to the patient an effective contrast producing amount of the x-ray contrast composition comprising a compound of formula I, II or III. In another aspect the present invention provides an x-ray contrast composition for diagnostic imagining of the GI tract by x-rays or CT scans wherein the composition comprises in a pharmaceutically acceptable aqueous carrier the compounds of the formula I, II or III, or a pharmaceutically acceptable salt thereof. There is further provided a method for x-ray diagnostic imaging of the GI tract which comprises orally or rectally administering to the patient an effective contrast producing amount of the x-ray contrast composition. DETAILED DESCRIPTION OF THE INVENTION Some starting materials/reagents used in the synthesis of the compounds of the present invention are readily available, while others can be made by methods known in the art. The compounds of the present invention were synthesized as shown in the following schemes. The compound of formula I, N,N-Dimethyldiatrizoic acid (I') (hereinafter sometimes referred to as MDTA) was synthesized, as in reference H. Holtermann et al., U.S. Pat. No. 3,178,673, Apr. 13, 1965, by the N-methylation of diatrizoic acid (IV) using either methyl iodide or dimethyl sulfate in aqueous media at alkaline pH to obtain pure MDTA (>99.9% purity) as a white crystalline solid (m.p. 185.degree. C.). Water solubility of the sodium salt was .about.0.35 M. The solubility of the N-methyl-glucamine (NMG) salt was .about.1.3 M. ##STR5## Compounds of formula II (A), (hereinafter sometimes referred to as fatty acid conjugates or analogs of P-MDTA or FA-PMDTA). ##STR6## wherein ##STR7## R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6 and n are as defined above, and the compounds were made as shown in Scheme 1. MDTA-chloride (X) was made by treating MDTA (I') with thionyl chloride under reflux for 24 h. The compounds of formula II were prepared by reaction of (4-aminophenyl) alkanoic esters (IX) with MDTA-chloride (X) in dimethylacetamide (hereinafter sometimes referred to as DMA). In Scheme 1 specific values are denoted for n and x relating to the compounds of the illustrative working examples; however, it is to be understood that the values of n and x include the range of 0 to 24 and the alkanoic esters are attached to the ortho, meta or para positions of the amino phenyl moiety. In Scheme 1 and in working examples the abbreviation "h" denotes hour or hours, and "RT" denotes room temperature. Scheme 1: Synthesis of Fatty Acid Analogs of Diatrizoates (FA-PMDTA) ##STR8## Referring to Scheme 1, .omega.-Bromoalkanoic acids V were converted to the corresponding phosphonium salts which when subjected to Wittig reaction with p-nitrocinnamaldehyde VI in presence of potassium t-butoxide gave the Wittig products VII. No attempts were made to separate the diene mixture. The carboxylic acid group in VII was protected as its t-butyl ester by treating with dicyclohexylcarbodiimide/tBuOH or Oxalyl chloride/t-BuOH. Catalytic hydrogenation of the diene ester VIII with 10% pd/C furnished the desired synthons, 4-aminophenylalkanoic ester IX. t-Butyl 4-(4-aminophenyl)-butyrate IX b was made in 64% yield from 4-(p-nitrophenyl)-butyric acid by esterification followed by catalytic hydrogenation. Treatment of the fatty acid synthons IX with X in DMA at 80-100.degree. C. followed by deprotection of the resulting coupled product XI with trifluoroacetic acid (hereinafter referred to as TFA) containing anisole furnished the PMDTA fatty acid analogs of formula XII. Compounds of formula II (B) (hereinafter sometimes referred to as DP-MDTA analogs) wherein ##STR9## and R.sub.6 and n are as defined above are prepared as shown in Scheme 2 by reacting the MDTA-chloride X with .omega.-aminoalkanoic acids or their 1,1-dimethylethyl esters in DMA to obtain the anides of formula XIII or formula XIII'. Scheme II: Synthesis of DP-MDTA Analogs ##STR10## wherein n and R.sub.6 are as defined above. The compounds of formula III ##STR11## wherein ##STR12## wherein n, m, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.8 are as defined above, were prepared as shown in Scheme 3. Scheme 3: Synthesis of PMDTA Analogs Linked in the Middle of the Alkanoic Acid Chain ##STR13## As an example, methyl oleate XIV was subjected to the Ritter reaction with p-nitrobenzonitrile XIV in the presence of SnCl.sub.4 at 50.degree. C. to obtain the phenylamido adduct XVI. Catalytic hydrogenation of XVI (10% Pd/C in MeOH--EtOAc) provided the key aniline XVII. Treatment of XVII with MDTA-chloride X followed by basic hydrolysis furnished a desired compound of formula XVIII. Similarly, starting from appropriate unsaturated fatty acids of various chain lengths, other compounds of formula XVIII could be prepared. The compounds of formula III wherein ##STR14## wherein m, n, p and R.sub.7 are as defined above, were prepared as shown in Scheme 4. Scheme 4: Synthesis of DPMDTA Analogs Linked in the Middle of the Alkanoic Acid Chain ##STR15## As an example, methyl oleate XIV was reacted with 7-bromoheptanenitrile in the presence of SnCl.sub.4 and water at 50.degree. C. for 40 h to obtain the amide XIX. Further treatment of XIX with NaN.sub.3 in DMF gave the corresponding azide XXa, which upon catalytic hydrogenation provided the amine XXb. Coupling of XXb with MDTA-chloride X in DMA followed by basic hydrolysis furnished the desired compound of formula XXI. The following working examples will further illustrate the compounds of the present invention. The highlighted numerals in the Examples refer to compounds and moieties used in the Schemes. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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