compounds of the present invention can be made according to the procedure known in the art using commercially available starting materials , intermediates and reagents . starting materials , reagents and solvents can be obtained from chemical suppliers such as aldrich , baker and eastman chemical companies , or they may be prepared by techniques known in the art . the following examples will further illustrate the compounds used in the present invention . a flask containing n -( 4 &# 39 ;- iodophenyl )- 2 - amino octane ( 1 . 50 g , 4 . 5 mmol ) was charged with acetic acid ( 15 ml ) and acetic anhydride ( 15 ml ). the reaction flask was immersed in an oil bath which was warmed to 70 ° c . over a period of 0 . 5 hr . after stirring for 19 hrs , the reaction was allowed to cool , diluted with ether ( 200 ml ), washed with water ( 2 × 50 ml ), saturated aqueous sodium bicarbonate ( 4 × 50 ml ), water ( 2 × 50 ml ) and brine ( 50 ml ), dried ( na 2 so 4 ), filtered , and evaporated in vacuo . flash column chromatography ( silica , 1 : 4 ; etoac : hexanes ) provided n - acetyl - n - 2 - octyl - 4 - iodoaniline ( 1 . 48 g , 70 %) as a white solid . mp 60 °- 62 ° c . title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . fab / ms mh + 374 . calculated for c 16 h 24 nio : c , 51 . 48 ; h , 6 . 48 ; n , 3 . 75 ; i , 34 . 00 . found : c , 51 . 68 , h , 6 . 46 ; n , 3 . 67 ; i , 33 . 87 . a flask containing 4 - iodoaniline ( 11 . 0 g , 50 . 2 retool ) was charged with dry dichloroethane ( 125 ml ), 2 - octanone ( 7 . 9 ml , 50 . 0 retool ) and sodium triacetexyborohydride ( 13 . 8 g , 65 retool ). after stirring for 10 minutes , acetic acid ( 2 . 9 ml , 50 . 7 retool ) was added via syringe over a 5 minute period . the reaction was stirred under an n 2 atmosphere for 16 hrs . at the end of this period the reaction was quenched by the careful addition of a solution of saturated aqueous ammonium chloride ( 100 ml ). after stirring for 0 . 5 hr , the reaction was poured over ether ( 250 ml ) and the layers were separated . the ether layer was washed with saturated aqueous ammonium chloride ( 100 ml ), dried ( na 2 so 4 ), filtered and evaporated in vacuo . flash column chromatography ( silica , 1 : 39 ; etoac : hexanes ) provided n -( 4 &# 39 ;- iodophenyl )- 2 - aminooctane ( 14 . 6 g , 88 %) as a light yellow oil . title compound : 1 h ( 300 mhz ) and 13c ( 75 mhz ) nmr spectra were consistent with the desired structure . calculated for c 14 h 22 ni : c , 50 . 97 ; h , 6 . 69 ; i , 38 . 31 . found : c , 51 . 19 , h , 6 . 72 ; i , 37 . 94 . the natural , pharmaceutically acceptable clays incorporated in the present invention comprise aluminum silicates . they are used in purified form , suitable for administration to patients . the natural , pharmaceutically acceptable clays of the present invention , generally referred to as smectities , consist of dioctohedral smectites and trioctahedral smectites . ______________________________________dioctahedral smectites include : montmorillonite , having the formulam . sup .+ al . sub . 3y ( femg ). sub . y si . sub . 4 o . sub . 10 ( oh ). sub . 2 . nh . sub . 2 o ; beidelite , having the formulam . sup .+ ( al . sub . 2 ( si . sub . 4 - x al . sub . x ) o . sub . 10 ( oh ). sub . 2 . nh . sub . 2 o ; nontronite , having the formulam . sup .+ ( fe . sub . 2 . sup . 3 + ( si . sub . 4 - x al . sub . x ) o . sub . 10 ( oh ). sub . 2 . nh . sub . 2 o ; wherein m . sup .+ is na , ca or mg . trioctahedral smectites include : saponite , having the formulam . sup .+ ( mg . sub . 3 - y ( alfe ). sub . y ) si . sub . 4 - x al . sub . x ) o . sub . 10 ( oh ). sub . 2 . nh . sub . 2 o ; andhectorite , having the formulam . sup .+ ( mg . sub . 3 - y li . sub . y ) si . sub . 4 o . sub . 10 ( oh ). sub . 2 . nh . sub . 2 o ; wherein m . sup .+ is na , ca or mg . ______________________________________ the clays are available from chemical suppliers , such as , for example , american colloid company , arlington heights , ill ., under the tradenames : other suppliers include : engelhard corp ., iselin , n . j . ; ashland chemical inc ., colombus , ohio ; rt vanderbilt co ., inc ., norwalk , conn . and whittaker clark & amp ; daniels , inc ., s . plainfield , n . j . the contrast agent and the pharmaceutically acceptable clay are formulated for administration using physiologically acceptable carriers or excipients in a manner within the skill of the art . the contrast agent with the addition of pharmaceutically acceptable aids ( such as surfactants and emulsifiers ) and excipients may be suspended or emulsified in an aqueous medium resulting in a suspension or emulsion . compositions of the present invention comprise the following pharmaceutically acceptable components based on % w / v : ______________________________________ most broad preferred preferredingredients range range range______________________________________contrast agent 5 - 45 10 - 35 15 - 25clay 0 . 1 - 10 0 . 5 - 5 1 - 2surfactant 1 - 20 2 - 10 3 - 5excipients 0 - 15 0 . 5 - 5 1 - 2water - q . s . to 100 % by volume______________________________________ excipients contemplated by the present invention include antifoaming agents , such as simethicone , siloxyalkylene polymers and polyoxyalkylated natural oils ; preservatives , such as methyl paraben , propyl paraben , benzoic acid and sorbic acid ; flavoring / sweetening agents , such as sodium saccharine ; and coloring agents , such as lakes and dyes . while the iodoaniline derivatives of the present invention in formulations with a pharmaceutically acceptable vehicle provide good quality x - ray images , the addition of a pharmaceutically acceptable clay to the formulations greatly increases the quality of the x - ray images . at the low extreme of the concentration range there is little or no benefit gained , while above the higher extreme of the concentration range the formulations are too viscous for administration . ______________________________________components______________________________________n - acetyl - n - 2 - octyl - 4 - iodoaniline 18 . 00 ghectabrite ® dp 1 . 5 gsorbitan monostearate 0 . 5 gpolysorbate 60 ( tween 60 ) 1 . 2 gpoloxamer 338 4 . 0 gsodium saccharine 0 . 3 gbenzoic acid 0 . 1 gsorbic acid 0 . 05 gwater q . s . to make 100 ml______________________________________ ______________________________________components______________________________________n -( 4 &# 39 ;- iodophenyl )- 2 - amino octane 25 . 00polargel ® nf 2 . 0 gsorbitan mono - oleate 0 . 4 gpolysorbate 20 ( tween 20 ) 1 . 2 gpolvinylalcohol 4 . 5 gsodium saccharine 0 . 2 gsimethicone ( food - grade ) 0 . 1 gwater q . s . to make 100 ml______________________________________ the formulations are prepared using standard formulation techniques which are well - known in the pharmaceutical industry . the surface active agents used in the present invention may be cationic , anionic , nonionic or zwittefionic . suitable cationic surfactants include cetyl trimethyl ammonium bromide , cetyl pyridinium chloride , myristyl gamma picolinium chloride and benzalkonium chloride . suitable anionic agents include sodium lauryl sulphate , sodium heptadecyl sulphate , alkyl benzenesulphonic acids and salts thereof , sodium butylnapthalene sulfonate , and sulphosuccinates . zwitterionic surface active agents are substances that when dissolved in water they behave as diprotic acids and , as they ionize , they behave both as a weak base and a weak acid . since the two charges on the molecule balance each other out they act as neutral molecules . the ph at which the zwitterion concentration is maximum is known as the isoelectric point . compounds , such as certain amino acids having an isoelectric point at the desired ph of the formulations of the present invention are useful in practicing the present invention . in preparing the formulations of the present invention we prefer to use nonionic emulsifiers or surface active agents which , similarly to the nonionic contrast agents , possess a superior toxicological profile to that of anionic , cationic or zwitterionic agents . in the nonionic emulsifying agents the proportions of hydrophilic and hydrophobic groups are about evenly balanced . they differ from anionic and cationic surfactants by the absence of charge on the molecule and , for that reason , are generally less irritating than the cationic or anionic surfactants . nonionic surfactants include carboxylic esters , carboxylic amides , ethoxylated alkylphenols , ethoxylated aliphatic alcohols , ethylene oxide polymer or ethylene oxide / propylene oxide co - polymers polyvinylpyrrolidone and polyvinylalcohol . one particular type of carboxylic ester nonionic surface active agents are the partial , for example mono -, esters formed by the reaction of fatty and resin acids , for example of about 8 to about 18 carbon atoms , with polyalcohols , for example glycerol , glycols such as mono -, di -, tetra - and hexaethylene glycol , sorbitan , and the like ; and similar compounds formed by the direct addition of varying molar ratios of ethylene oxide to the hydroxy group of fatty acids . another type of carboxylic esters are the condensation products of fatty and resin partial acids , for example mono -, esters ethylene oxide , such as fatty or resin acid esters of polyoxyethylene sorbitan and sorbitol , for example polyoxyethylene sorbitan , mono - tall oil esters . these may contain , for example , from about 3 to about 80 oxyethylene units per molecule and fatty or resin acid groups of from about 8 to about 18 carbon atoms . examples of naturally occurring fatty acid mixtures which may be used are those from coconut oil and tallow while examples of single fatty acids are dodecanoic acid and oleic acid . carboxylic amide nonionic surface active agents are the ammonia , monoethylamine and diethylamine amides of fatty acids having an acyl chain of from about 8 to about 18 carbon atoms . the ethoxylated alkylphenol nonionic surface active agents include various polyethylene oxide condensates of alkylphenols , especially the condensation products of mono - alkylphenols or dialkylphenols wherein the alkyl group contains about 6 to about 12 carbon atoms in either branched chain or particularly straight chain configuration , for example , octyl cresol , octyl phenol or nonyl phenol , with ethylene oxide , said ethylene oxide being present in amounts equal to from about 5 to about 25 moles of ethylene oxide per mole of alkylphenol . ethoxylated aliphatic alcohol nonionic surface active agents include the condensation products of aliphatic alcohols having from about 8 to 18 carbon atoms in either straight chain or branched chain configuration , for example oleyl or cetyl alcohol , with ethylene oxide , said ethylene oxide being present in equal amounts from about 30 to about 60 moles of ethylene oxide per mole of alcohol . ( a ) sorbitan esters ( sold under the trade name span ) having the formula : ## str4 ## wherein r 1 = r 2 = oh , r 3 = r for sorbitan monoesters , where ( x + 1 ) is the number of carbon atoms in the alkyl chain , typically : and y is the number of ethylene oxide groups in the hydrophilic chain , typically 10 - 60 ; ( c ) polyethylene sorbitan fatty acid esters , sold under the trade names of tween or polysorbates 20 , 40 , 60 , 65 , 80 & amp ; 85 , having the formulas ( 1 ) and ( 2 ) ## str5 ## wherein w + x + y + z = 20 ( polysorbate 20 , 40 , 60 , 65 , 80 and 85 ) ( e ) polyethylene oxide / polypropylene oxide block co - polymers , sold under the name pluronic ™, which include poloxamer 407 ( pluronic ™ f127 ), poloxamer 188 ( pluronic ™ f68 ), poloxamer 237 ( pluronic ™ f87 ) and poloxamer 338 ( pluronic ™ f108 ); the dosages of the contrast agent used according to the method of the present invention will vary according to the precise nature of the contrast agent used . preferably , however , the dosage should be kept as low as is consistent with achieving contrast enhanced imaging . by employing as small amount of contrast agent as possible , toxicity potential is minimized . for most contrast agents of the present invention dosages will be in the range of from about 0 . 1 to about 16 . 0 g iodine / kg body weight , preferably in the range of from about 0 . 5 to about 6 . 0 g iodine / kg of body weight , and most preferably , in the range of from about 1 . 2 to about 2 . 0 g iodine / kg body weight for regular x - ray visualization of the gi tract . for ct scanning the contrast agents of the present invention will be in the range of from about 1 to about 600 mg iodine / kg body weight , preferably in the range of from about 20 to about 200 mg iodine / kg body weight , and most preferably in the range of from about 40 to about 80 mg iodine / kg body weight . when administered to mammals , the compositions of the present invention produce excellent x - ray and ct images . the invention , having been fully described , it will be apparent to one skilled in the art that changes and modifications can be made thereto without departing from the spirit and scope thereof .
disclosed are x - ray contrast compositions for oral or retrograde examination of the gastrointestinal tract comprising an iodoaniline derivative as the x - ray producing agent in combination with a pharmaceutically acceptable clay in a pharmaceutically acceptable carrier ; and methods for their use in diagnostic radiology of the gastrointestinal tract .