MXPA97010220A - Derivatives of formilo as means of contrast noioni - Google Patents

Abstract

Substituted carboxamides of N-formyl, N-alkyl or hydroxyalkyl triiode anilides are provided. The object composition has high iodine percentages and excellent water solubility, finding use as preferred modalities for conventional non-ionic contrast media

Description

FORMILO DERIVATIVES AS NON-IONIC CONTRAST MEDIA I NTRODUCTION TECHNICAL FIELD CO The field of this invention is in the non-ionic contrast media.

BACKGROUND X-rays are the most frequently used diagnostic tool for examining various sections of the body, such as the gastrointestinal tract, the vascular system and individual solid organs. These procedures are done in conjunction with iodinated contrast agents, due to the low contrast differential inherent with the tissues. The criteria for contrast media are that they are biologically inert; that are able to delineate anatomical details accurately and consistently, which provide accurate radiopacity; which must have a high iodine content; and that they must be water soluble and must have reasonable osmolality at the concentrations in which they are administered. The demands employed on contrast media vary with the nature of the examination. In addition, the media should be substantially homogeneous, to avoid imaginary artifacts and should not be affected by pH or other psychological conditions during its use. In order to provide solubility in water, the nonionic contrast media have hydroxyalkyl constituents to increase hydrophilicity. However, the solubility in water is to a large extent dependent on the ability of the compounds to form isomeric mixtures in water solutions. In non-ionic contrast media involving hydroxyalkylated annonates, the isomeric mixtures are dependent on the endo and exoomerism of the anuided group. For the most part, the acyl group linked to the amino group is acetyl, glycolic acid or glyceric acid, since such acyl group is stable and relatively low molecular weight. This is of substantial interest to develop new improved non-ionic contrast media, wherein the iodine content can be improved, as well as the solubility in water and the other factors indicated in the foregoing.

Related Literature Nos. Of the United States Patents of interest include 4,547,357; 4,021,481; 3,701,771; 4,364,921 and 4,341,756.

BRIEF DESCRIPTION OF THE INVENTION Novel novel non-ionic contrast media are provided, which are triiodoanilides or N-formylated, N-alkylated or -hydroxyalkylated bis-compounds, wherein the remaining positions on each ring arc substituted with at least one carboxy group or a group Not me. The subject compositions have high water solubility, good stability and high iodine content. The subject compounds find use as contrast media in a wide variety of applications for X-rays and other non-invasive diagnostics.

DESCRIPTION OF THE SPECIFIC MODALITIES Novel novel non-ionic contrast media having excellent water solubility and high iodine content are provided. The contrast media are characterized in that they have at least one N-formyl, N-alkyl or -hydroxyalkyl amino group linked to a substituted triiodobenzene, either symmetrical or asymmetric, usually symmetrical, where the two remaining sites have zero to a substituted amino group and one to two non-oxocarbonyl groups, particularly amides, more particularly unsubstituted or N-alkyl or N-hydroxyalkylamides, mono- and di-substituted, ie from 10 to 2 hydroxyalkyl substituents (including hydroxyalkyl. compounds can be monomeric or bis-monomeric dimers, linked by a bond, or more usually an alkylene linker group For the most part, the monomeric compounds of this invention will have less than 30 carbon atoms, usually less than 25 carbon atoms , preferably less than about 20 carbon atoms, usually have at least about 12 carbon atoms, more usually at least less about 14 carbon atoms. The dimers can have twice the number of carbon atoms, usually up to twice the number of carbon atoms plus 5, more usually plus 3. Except for the formyl aniline nitrogen, the nitrogen atoms will be either mono- or disubstituted, usually monosubstituted when they are linked to the non-oxocarbonyl linked to an annular carbon atom, while the nitrogen bonded to an annular carbon atom will be disubstituted, i.e. formylated and N-alkylated or -hydroalkylated. When two substituents are present on an amide nitrogen, usually one will be an oxyalkyl group and the other an alkyl group. (With reference to the carboxamide and the nitrogen amide, it is intended that the non-oxo-carbonyl carbon be bonded to an annular carbon atom, as distinguished from the formadinyl group, in which the nitrogen is bonded to a carbon atom. ring carbon.) One or both of the carboxamide nitrogens may have from 1 to 2 hydroxyalkyl groups of from 2 to 4 carbon atoms and from 0 to 1 alkyl group of from 1 to 3 carbon atoms, preferably methyl. For the most part, the compounds of this invention will have the following formula: Where: a is 1 or 2, and b is 0 when a is one and 1 when a is 2; R1 is alkyl of from 1 or 2 to 4 carbon atoms usually, more usually 1 to 3 carbon atoms, and 0 to 3, usually 0 or 1 to 3, more usually 0 or 1 to 2 hydroxyl groups having hydroxyl except that the α-carbon atom, generally has 1 to 1 hydroxyl groups, where n is the number of carbon atoms present in the group, wherein the alkyl is usually from 1 to 3 carbon atoms, preferably methyl; R ^ can be the same or different from R1, being hydrogen or falling within the definition of R1; R3, when a is 1, is hydrogen or falls within the definition of R ^, in at least one of R2 and R3 have a hydroxyl group; when a is 2, either of R3s, R1S or Ws are taken together with Y to form a bridge between the two monomers; And it is not present when a is 1, and when a is 2, it is a bridge comprising a bond or linking group of from 1 to 6 carbon atoms, usually from 2 to 3 carbon atoms, usually aliphatic, usually saturated , particularly comprises one or more methylene groups, having 0 to n-2 oxy groups, wherein n is the number of carbon atoms of the linking group; Z is CONWR1, NR1CHO or CONR2R3, preferably CONHR2; and W is hydrogen when a is 1 or, when a is 2, they are taken together with Y to form a bridge. For the most part for the dimeric compounds, where Z is CONR2R3t R3, each of the monomers is taken together with Y to form a bond or an alkylene group of from 1 to 6, usually 2 to 3 carbon atoms, and to n-2 oxy groups, where n is the number of carbon atoms of the alkylene group. Where Z is CONWR1, W is taken together with Y to form a bridge of an alkylene group of from 1 to 6, usually 2 to 3 carbon atoms, and 0 to n-2 oxy groups, where n is the number of carbon atoms. carbon of the alkylene group. Hydroxyalkyl groups of interest include: hydroxyethyl; 2-hydroxypropyl; 1,3-dihydroxypropyl; 2,3-dihydroxypropyl; 1,3,4-trihydroxybutyl; and 2, 3, 4-trihydroxybutyl. The compounds of particular interest are triiodoisophthalamides, where the nitrogens of the carboxamide groups are substituted with 2,3-dihydroxypropyl, 1,3-dihydroxypropyl or dihydroxyethyl or bis-hydroxyethyl, or a combination of methyl and 2,3-dihydroxypropyl or 1, 3-dihydroxypropyl. Although they can not be identical, preferably, both substituted carboxamide nitrogen atoms are substituted identically, and the annulated nitrogen is substituted with 2,3-dihydroxypropyl, or 2-hydroxyethyl. Specific compounds of interest include: 5-N- (2,3-dihydroxy propyl) f orm Mam-2,4,6-triy odo-N, N'-bi s- (2,3-dihydroxypropyl) ) isophthalamide (RP-257); 5-N- (2-hydroxyethyl) -formylamido-2,4,6-triiodo-N, N'-bis- (2,3-dihydroxypropyl) isophthalamide (BP-258); 5-N- (2,3-dihydroxypropyl) formylamido-2,4,6-t-pyodo-N- (2,3-dihydroxypropyl) -N '- (2-hydroxyethyl) -isophthalamide (BP-278); 5-N- (2,3-dihydroxypropyl) formylamido-2,4,6-triiodo-3-N- (2,3-dihydroxypropyl) -carbamoyl-benzamide (BP-256); and 5-N- (1-hydroxyethyl) formylamido-2,4,6-triiodo-N, N'-bis- (1,3-dihydroxypropyl) isophthalamide (BP-293). The subject compounds can be prepared according to conventional forms, except that the formylation is carried out prior to the alkylation of the anuted nitrogen and the alkylation is carried out under conditions which prevent the hydrolysis of the formanilide. Usually, the groups on the amide nitrogens will be present prior to the final alkylation. For formylation activated formic acid can be used, where formic acid can be present as the mixed anhydride, where the mixed anhydride can be prepared in situ. Temperatures will generally be kept below about 30 ° C, preferably below about 25 ° C, and may be in the range of about 1 to 1 5 ° C. Usually, the formic acid will be added in excess, usually in at least about 5 molar excess binding, and may be 10 to 20 molar excess binding. Where an anhydride is added, for example, acetic anhydride, to the mixture to form the mixed anhydride, the formic acid will be present in at least a stoichiometric amount and usually about 1.5 to 3 molar excess of linkage on the anhydride. Other mixed anhydrides may include isobutyryl benzoyl, benzyl carbonate, pivaloyl, etc. The preparation of the product is conventional as described in the experimental section. Of particular interest for hydroxyalkylation is the use of an alkylene oxide or alkylene oxide precursor, for example, a 1,2-halohydroxyalkane. For the alkylation, the halohydrin is of particular interest, where the reaction is carried out in solution in a polar organic solvent at a basic pH, generally in excess of 10, preferably from about 1 to 13, where the reaction will be an elevated temperature, generally at least 30 ° C, and less than about 60 ° C, usually less than about 50 ° C, preferably in the range of about 35 to 50 ° C, preferably in the range of about 35 ° C 50 ° C. The basic salts can be added to increase the reactivity of the halo group. Generally, the halohydrin will be in at least a stoichiometric amount, preferably in excess, usually not greater than about 3 excess bond, more usually not greater than about 2.5 excess bond. The preparation is conventional, the salts are filtered, the filtrate is acidified, followed by neutralization and purification of the residue. To be used as contrast media, the subject compositions may be formulated in accordance with conventional forms, depending on the particular solitude. For oral use, the solutions in water are prepared either in the process or ad hoc from a mixture of the subject compound with Jactose, citric acid, methylcellulose and detergent, particularly a non-ionic detergent.; such as Tween-80. For intestinal (rectal) use, only methylcellulose (or another polysaccharide) and a detergent are used. The detergent will be present from about 0.1 to 1 percent by weight of the composition (excluding water). For x-ray computer tomography, iodine solution concentration will generally be in the range of about 5 to 15 mg L / ml, preferably about 10 mg L / ml; for flat radiography, approximately 200 to 400 mg L / ml, preferably 300 to 350 mg L / ml will be used. Generally, the fractions of the subject compounds in water will be from about 0.5 to 150% by weight / volume; for standard radiography, the fraction will be about 20 to 150% w / v%. The viscosity of the compositions for administration will be in the range of about 5 cps to 5000 cps, with the preferred range being about 10 to 1000 cps. The subject compositions may be administered by any convenient means, depending on the particular site or section to be investigated. Non-ionic contrast media, as is obvious from the literature of the relevant art, has found extensive use and therefore the prior art compounds can be substituted with the subject compounds. The following examples are offered by way of illustration and not by way of limitation.

EXPERIMENTS 1. 5-N-formylamido-2,4,6-tr yiodo-N, N'-bis (2, 3-d i hydroxy pro-pyl) isophthalamide. A. To an active solution of 5-amino-2,4,6-triiodo-N, N'-bis (2,3-dihydroxypropyl) isophthalamide (10.0 g, 0.0158 mol) and formic acid (10.68 mL, 0.283 mol) in an ice bath, acetic anhydride (13.44 mL, 0.142 mol) is added and the mixture is allowed to stir overnight. The yellow homogeneous solution is concentrated in a rotary evaporator to produce a brownish foam. This is dissolved in EtOAc (100 mL) and extracted with 30% brine (60 mL). The solution is dried over MgSO 4 and concentrated on a rotary evaporator to a white foam. The solid is dissolved in MeOH (50 mL), basified with 30% NaOMe (7 mL) pair pH = 12 and concentrated to 1/2 volume. After reconstitution with methanol, neutralization to pH = 7 with concentrated CHI, filtration and removal of the solvent, a white foam is obtained (70% yield).

B. Analysis: 1. TLC: Silica gel 60, F254, 50% CHCl3 / 50% methanol, UV detection @ 254 nm. Rf (start material) = 0.53. Rf (product) = 0.47 2. CLAP: NH2 Alltech Econosphere, 4.6 x 250 mm, 5μ, 85% acetonitrile / 15% H2O, 1.5 mL / min, detection 254 nm, 30 ° C. Retention time (starting material) = 5.42 min. Retention time (product) = 8.61 min. 3. 1 H NMR, DMSOdβ product; 10.3-10.0 ppm (m, 1H), 8.5 ppm (m, 2H), 8.3 ppm (m, 1H), 5.2-4.4 ppm (m, 4H), 3.7-3.1 (m, 10H). 2. 5-N- (2,3-dihydroxypropyl) -formylamido-2,4,6-triiodo-N, N'-bis- (2,3-dihydroxypropyl) isophthalamide. To a suspension of 5-N-formylamido-2,4,6-triode-N, N-b '(2,3-dihydroxypropyl (isophthalamide (1.0 g, 1.17 mmol) and 5 Ml of MeOH were add Na3P? 4.12 H2O (1.30 g, 3.41 mmol) followed by 3-chloro-1,2-propanediol (0.23 mL, 2.73 mmol) in an individual portion.The reaction mixture is maintained at pH 12 and 45 ° C for 4 hours. The precipitated salt is filtered off and washed with dry MeOH The filtrate is acidified to pH = 1.6 with concentrated HCl and stirred overnight on a rotary evaporator, 2 mL of isopropane is added to the residue. they are filtered and dried (75% yield), taken to recrystallization from aqueous ethanol, BP-257> 99% pure.

B. Analysis 1. TLC: Silica gel 60, F254, 50% CHCl3 / 50% methanol, UV detection @ 254 nm. Rf (start material) = 0.47. Rf (product) = 0.39 2. CLAP: NH2 Alltech Econosphere, 4.6 x 250 mm, 5μ, 85% acetonitrile / 15% H2O, 1.5 mL / min, detection 254 nm, 30 ° C. Retention time (start material) = 8.10 min. Retention time (product) = 12.13 min and 14.45 min. 3. 1 H NMR, (BP-257); 8.6-8.4 ppm (m, 2H), 8.4-7.9 ppm (d, 1H), 4.9-4.5 ppm (m, 4H), 4.0-3.1 (m, 15H). 3. 5- [N- (2,3-dihydroxypropyl)] formylamido-2,4,6, -triyodo-N, - (2-hydroxyethyl) -N '(2,3-dihydroxypropyl) -isophthalamide [BP-278] A 2-liter flask is charged with 5- [N- (2,3-diacetoxypropyl)] formylamido-2,4,6-triiodo-3- [N- (2,3-diacetoxypropyl) chloride. ] carbamoyl benzoyl (74.29 g, 0.0807 moles), acetonitrile (296 L) and ethanolamine (11.69 ml, 0.1937 moles). The mixture is stirred for 2 hours at 25 ° C and then neutralized to pH 8 with concentrated hydrochloric acid (2.69 mL, 0.0323 mol). After the salts are filtered, the filtrate is evaporated and dried under vacuum to a yellow foam. It is partitioned between ethyl acetate (469 mL) and saturated sodium chloride (200 mL) and the aqueous layer is subsequently extracted with ethyl acetate (100 mL), the ethyl acetate extracts are combined, dried over magnesium sulfate. , and they filter. After the solvent is removed and dried, 73.97 g (97%) of the title compound are obtained. The reaction is repeated and the combined portions are loaded into a 1 liter flask (144.8 g, 0.1532 moles with methanol (580 mL). 30% methanolic sodium methoxide (1.84 mL, 10.21 mmol) is added per drop at 25 °. C. After 30 minutes the solution is concentrated to medium volume and then neutralized with Dowex 50 H + resin The resin is filtered off and the solvent is removed to give 117.2 g (95.4%) of the title compound [BP- 278].

Analysis: 1. TLC: Silica gel 60, F254, 40% methanol / 60% CHCI3, UV detection at 254 nm. Rf (BP-278) = 0. 40. 2. CLAP: Ce Alltech absorber, 4.6 x 250 mm, 5μ, 5% acetonitrile / 95% 0.02M KH2PO4 > pH 3, 1.0 ml / min, detection 246 nm, 30 ° C. Retention time (start material) = 8.10 min. Retention times (BP-278) = isomer peaks at 8.95 min, 9.44 min and 11.97 min. 3. 1 H NMR, (BP-278; DMSOdβ); 7.9 and 8.35 ppm (m, 1H), 8.5 ppm (m, 2H), 4.5-4.9 ppm (m, 5H), 3.3-3.9 ppm (m, 4. 5- [N- (2,3-dihydroxypropyl )] formylamido-2,4,6, -triyodo-3- [N- (2-3-diacetoxypropyl)] carbamoyl benzoic acid [BP-256] 5-amino-3 acid is stirred in a 5 L flask, 4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoyl benzoic acid (947.8 g, 1.50 mol) and 95-97% formic acid (1.8 g) at -1 to 1 0 ° C while acetic anhydride is added (1 1 33 m L, 1 2.0 mols by dripping for 6 hours, followed by stirring for 6 hours at 20 ° C and a partial solvent is removed) Butyl acetate (1.5 L) is added. ) to the residue A white precipitate is filtered off and dried under vacuum to give 970.7 g (91%) of 5-formylamido-2,3,6-triiodo-3- [N- (2,3-diformyloxypropyl) acid. )] carbamoyl benzoic acid A 1 0 L flask is charged with this compound (950 g, 1.33 moles, methanol (2.85 L) and 30% methanolic sodium methoxide solution (478 mL, 2.65 moles), then Stir for 10 minutes at 25 ° C, add acid or acetic (76 mL, 1.33 moles). The solution is reduced by half. The addition of anhydrous ethanol (1.5 L) gives a white precipitate, which is filtered, washed with ethanol, and dried under vacuum, yielding 982.4 g of sodium salt of 5-formylamido-2,4,6- triiodo-3- [N- (2, 3, -dihydropropyl)] carbamoyl benzoic acid and some salts. A 12 L flask is charged with trisodium phosphate dodecahydrate (240 mL, 2.87 mol), 1,2-propanediol (1 L), and 3-chloro-1,2-propanediol (240 mL, 2.87 mol): After of stirring at 40-45 ° C for 30 minutes, a solution of 5-f-ormilamido-2,4,6-triiodo-3- [N- (2,3-dihydroxy-propyl)] carbamoyl-benzoic acid salt (980 g) , 1.44 moles) in 1,2-propanediol (3 L), added for 5 hours and the suspension stirred for 1.5 hours at 40-45 ° C, and filtered to remove salts. The filtrate is brought to pH 1.5 with concentrated hydrochloric acid (250 mL) and stirred for 16 hours at 25 ° C to destroy residual glycidol. The solvent is removed in the product precipitated with isopropanol (2 L), filtered, washed with isopropanol and dried in vacuo, yielding 895.7 g (85% corrected for salt content) of 5- [N- (2, 3-dihydroxypropyl)] formylamido-2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoyl benzoic acid. A 5 L flask is charged with this solid, ethyl acetate (0.8 L), pyridine (19.7 mL, 0.24 mol) and acetic anhydride (1285 L, 13.6 mol). The mixture is stirred for 4.5 hours at 50-60 ° C. The solvent is removed by producing an orange oil, which is dissolved in butyl acetate (1.5 L) and tart with a solution of NaHC 3 (102.5 g, 1.22 mol) in H O (2 L). The layers are separated and the aqueous layer is extracted with butyl acetate (3 X 0.5 L). Chloroform (1.5 L) is added to the aqueous layer followed by concentrated hydrochloric acid (22 mL, 0.26 mol). The organic layer is separated and the aqueous layer is extracted with chloroform (1 L). The combined chloroform extracts are dried over magnesium sulfate, filtered and the solvent is removed, yielding 845.7 g (77%) of 5- [N- (2,3-diacetoxypropyl)] formylamido-2,4 acid, 6-triiodo-3- [N- (2,3-diacetoxypropyl)] carbamoyl benzoic acid. To a 1 L flask charged with 5- [N- (2, 3-di-ac-ethoxy-propyl)] formyl-2,4,6-tr and odo-3- [N- (2, 3- diacetoxypropyl)] carbamoyl benzoic acid (102 g, 0.1 1 mole) and ethyl acetate (300 mL) is added thionyl chloride (42.2 mL, 0.57 mole) by dropping for 1.5 hours at 70 ° C. The solution is stirred for 2.5 hours and the solvent is removed yielding 106.6 g of 5- [N- (2, 3-diacetoxypropyl)] formylamido-2,4,6-triiodo-3- [N- (2, 3) chloride. -day-toxopropyl)] carbamoyl benzoyl. This compound is dissolved in acetonitrile (250 mL), and liquid ammonia is added by dripping using a dry ice condenser. After 3 hours at 40 ° C the suspension is purged with nitrogen and filtered, dissolved in dichloromethane (250 mL) and the solution washed with 0.1 N hydrochloric acid (250 μL). The organic layer is dried over magnesium sulfate, filtered and the solvent is removed, yielding 89.4 g (86%) of 5- [N- (2,3-diacetoxypropyl)] formylamido-2,4,6-triiodo-3. - [N- (2, 3-diace-toxipropyl)] carbamoyl benzamide. To a 1 L flask loaded with this compound and methanol (500 μL) is added a solution of 30% methanolic sodium methoxide (5.5 mL) at pH 13-14. When deacetylation is judged complete by TLC, the mixture is neutralized with Dowex 50 H + at pH 5-6.

The solvent is removed and the residue is dissolved in H2O, treated with resin, charcoal, and crystallized from boiling alcohol. The resulting BP-256 (80% crystallization yield) is > 99% pure by CLAP.

Analysis 1. TLC: Silica gel 60, F254, 60% chloroform / 30% methanol / 10% acetic acid, UV detection @ 254 nm. Rf (BP-256) = 0.40 2. CLAP: Absorbosphere C18 Alltech, 4.6 x 250 mm, 5μ, 98% 0.02M KH PO4 pH 3, 2% acetonitrile, 1.0 mL / min, detection 246 nm, 30 ° C. Retention times (BP-256) = isomer peaks in 5.69, 6.11, 7.26, 7.71, 9.54 and 10.00 minutes. 3. 1 H NMR, (BP-256; DMSO-d 6); 7.90 and 8.35 ppm (d, 1H); 8.50 (m, 1H); 7.99 and 7.72 ppm (m, 2H); 4.49-4.89 ppm (m, 4H); 3.20-3.96 ppm (m, 10H). . 5- [N- (2-hydroxyethyl)] formylamido-2,4,6-triiodo-N, N'-bis- (2,3-dihydroxypropyl) isophthalamide [BP-258] is added to a suspension of phosphate dodecahydrate of trisodium (196.3 g, 0.52 mol) in 1,2-propandiol (800 mL) 2-chloroethanol (28.9 mL, 0.43 mol) in an individual portion. After stirring for 30 minutes at 40 ° C, the solid is added 5-N-formylamido-2,4,6-triiodo-N, N'-bis- (2,3-dihydrixipropyl) isophthalamide (152 g, 0.21 moles ) for 2 hours. The pH is maintained at 11-12 and the mixture is heated at 40-45 ° C for 4 hours. The precipitated salts are removed by filtration and washed with dry methanol. The filtrate is acidified to pH 1.6 with concentrated hydrochloric acid and stirred for 3 hours to destroy excess alkylating agent. The reaction mixture is neutralized with 30% methanolic sodium methoxide and concentrated. Propyl alcohol (650 mL) is added, precipitating a solid which is filtered, washed with propanol, dissolved in water, and deionized with resins. After boiling with 5% charcoal, the product is dried and crystallized from isobutanol to yield 116.5 g (72.1%) of 5- [N- (2-hydroxyethyl)] formylamido-2,4,6- triiodo-N, N, -bis- (2,3-dihydroxypropyl) isophthalamide [BP-258].

Analysis 1. TLC: Silica gel 60, F254, 60% n-butanol, 40% HOAc 5N, Rf (isomer BP-258) = 0.39 and 0.27. 2. CLAP: Alltech (Absorbosphere C-18), 4.6 x 250 mm, 5μ, 2% acetonitrile, 98%, 0.2M KH2PO4, pH = 3, 1.0 mL / min, detection 246 nm, 30 ° C. Retention times (BP-258) = isomer peaks at 14.33 and 17.10 minutes. 3. 1H NMR, (BP-258, DMSO-d6): 7.86 and 8.4 ppm (m, 1H), 8.5 ppm (m, 2H), 4.5-4.9 ppm (m, 5H), 3.0-3.9 (m, 14H ). 6. 5- [N- (2-hydroxyethyl)] formylamido-2,4,6-tr yiodo-N, N, -bis- (1,3-dihydroxy-prop-2-yl) isophthalamide [BP-293] A 2L flask is charged with 5-amino-2,3,6-triiodo-N, N, -bis- (1,3-dihydroxy-prop-2-yl) isophthalamide (250.0 g, 0.355 moles and formic acid (341 mL), is stirred at 0-10 ° C while acetic anhydride (233.6 g, 2.29 moles) is added dropwise for 1.6 hours.After stirring at RT for six hours, the solution is reduced and a solid precipitated with butyl acetate (800 mL), filtered and washed with butyl acetate The solid is dried under vacuum, yielding 299.1 g (99.8%) of 5-N-formylamido-3,4,6-triiodo-N, N'bis- ( 1,3-diformyloxy-prop-2-yl) -isophthalide amide This compound is charged to a 2 L flask with methanol (1200 mL) and 30% methanolic sodium methoxide (89.3 mL). 20 minutes at 0-10 ° C, the solution is reduced to medium volume and acetic acid (29.8 g, 0.496 moles) is added.A white solid is precipitated with isopropanol (500 mL), filtered, filtered, vacuum with isopropanol and dried under vacuum. The product is resuspended in methanol (1000 mL), heated at 60 ° C for 30 minutes, cooled to 20 ° C, filtered, washed with methanol, dried under vacuum to yield 216.4 g (83.4%) of -formylamido-3,4,6-triiodo-N, N'bis- (1,3-dihydroxy-prop-2-yl) -isophthalamide. A 2 L flask is charged with trisodium phosphate dodecahydrate (194.8 g, 0.513 mole), propylene glycol (850 mL) and (33.0 g, 0.409 mole) 2-chloro ethanol (33.0 g, 0.409 mole) After stirring at 40 -45 ° C for 1 hour, the solid is added 5-N-formylamido-2,4,6-triiodo-N, N'-bis- (1, 3-dihydro-2-prop-2-yl) -isophthalamide (150 g) for 30 minutes. The suspension is stirred for 4 hours at 40-45 ° C, allowed to cool, filtered and the salts washed with propylene glycol. The filtrate is acidified to pH 1.5-2.0 with 12 M hydrochloric acid to destroy the residual ethylene oxide. After neutralization to pH 7 with 30% methanolic sodium methoxide, the solution is concentrated, and the solid precipitated with propyl alcohol is filtered, washed with resins and boiled with 5% charcoal, the product crystallize from n-butanol to yield 115.3 g (72.49%) of 5- [N- (2-hydroxyethyl)] formylamido-2,4,6-triiodo-N, N'-bis- (1, 3-dihydroxy-prop-2-yl) isophthalamide [BP-293].

Analysis: 1. TLC: Silica gel 60, F254, 60% n-butanol, 40% HOAc 5N, Rf (isomer BP-293) = 0.60 and 0.33. 2. CLAP: Alltech Absorbosphere C < | 8 > 4.6 x 250 mm, 5μ, 5% methanol / 95% 0.2 M KH2PO4, pH = 3, 1.0 mL / min, detection 246 nm, 30 ° C. Retention times (BP-293) = isomer peaks in 9.54 and 10.75 minutes. 3. 1 H NMR, (BP-293; DMSOdβ): 7.85 and 8.4 ppm (m, 4), 8.25 ppm (m, 2H), 4.4-5.0 ppm (m, 5H), 3.3-4.0 (m, 14H). a = 289.6 mg l / mL f = 346.1 mg l / mL k = 349.3 mg l / mL b = 357.4 mg l / mL g = 394.6 mg l / mL l = 300.1 mg l / mL c = 288.5 mg l / mL h = 353.5 mg l / mL m 373.1 mg l / mL d = 351.1 mg / mL i = published value e = 300.0 mg l / mL j = 308.9 mg l / mL 8. Contrast Media Toxicity in Balb / C Mice 9. Renal and Hepatic Effects of BP-257 and BP-258 Means of Control in Younger Rabbits The effects of kidney and liver from a single bolus injection of BP-257 or BP-258 in 5g of Iodine / kg were evaluated in rabbits and they were compared to those of lohexol in the same dose. The young female rabbits were injected into the posterior vein using 350 mg of iodine / ml narcotic solutions. Blood samples were collected within 15 minutes prior to the narcotic injections, two hours, 24 hours and six days after the treatment. Serum levels of creatinine, BUN, SGPT / ALT and SGOT / AST were estimated in these periods of time. The study showed that BP-257 and lohexol treatments resulted in normal creatinine serum and BUN levels, indicating that none of those narcotic treatments have toxic renal effects at any of the time periods examined. Furthermore, they show that while BP-258 does not have effects of renal deterioration until 24 hours after the treatment, six days after the injections, all animals treated with BP-258 have elevated levels of serum creatinine and BU N. The liver function tests of the animals show no alterations in the SGPT serum and the SGOT enzymes, indicating that none of the narcotic treatments causes liver damage. In accordance with the subject invention, novel compositions are provided which find use as non-ionic contrast media. The subject compositions have a high iodine content while having excellent water solubility and low osmolality to provide excellent properties for general use as non-ionic contrast media. All publications and patent applications cited in this specification are incorporated herein by reference as if each individual publication or patent application were specially and individually indicated to be incorporated for reference. Although the foregoing invention has been described in some details by way of illustration and example for purposes of clarity and understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention, that certain changes and modifications may be made to it without departing from the spirit and scope of the appended claims.

Claims (12)

1. A nonionic N-formyl, N-alkyl or symmetrically triiodo substituted hydroxyalkyl contrast medium of from about 12 to 30 carbon atoms, wherein the two remaining sites are substituted with up to 2 carboxamides and up to 1 formamidyl, wherein each carboxamide nitrogen has 1 to 2 N-alkyl or N-hydroxyalkyl substituents, and each formamidyl nitrogen has 0 to 1 N-alkyl and the hydroxyalkyl groups are 2 to 4 carbon atoms and 1 to 3 hydroxyl groups, or the dimer thereof, wherein a nitrogen of each formamide or carboxamide is linked by a bond or linking group.

2. An annuity, according to claim 1, characterized in that the two remaining sites are substituted with substituted carboxamides of N-hydroxyalkyl ring carbon, and the hydroxyalkyl groups are of from 2 to 3 carbon atoms.

3. A compound of the formula: Where: a is 1 or 2, and b is 0 when a is one and 1 when a is 2; R1 is alkyl of from 1 or 2 to 4 carbon atoms and 0 to 3 hydroxyl groups having hydroxyl with the exception of the α-carbon atom; R2 can be the same or different from R1, being hydrogen or falling within the definition of R ^; R3, when a is 1, is hydrogen or falls within the definition of R ^, in at least one of R2 and R3 have a hydroxyl group; when a is 2, either R3s, R1S or Ws are taken together with Y to form a bridge between the two monomers; And it is not present when a is 1, and when a is 2, it is a bridge comprising a bond or a linking group of from 1 to 6 carbon atoms having 0 to n-2 oxy groups, wherein n is the number of carbon atoms of the linking group; Z is CONWR1, NR1CHO or CONR R3; and W is hydrogen when a is 1 or, when a is 2, they are taken together with Y to form a bridge.

4. The compound according to claim 3, characterized in that a is 1 and R2 is hydrogen or 1,3- or 2,3-dihydroxypropyl, R ^ is 1,3- or 2,3-dihydroxypropyl or 2-hydroxypropyl, and R3 is hydrogen.

5. The compound according to claim 3, characterized in that a is 1 and R2 is hydrogen or 1,3- or 2,3-dihydroxypropyl, R "is 1,3- or 2,3-dihydroxypropyl or 2-hydroxypropyl, and R3 is methyl.

6. A compound of the formula: wherein: R1 is from 2 to 4 carbon atoms and 1 to 3 hydroxyl groups; R2 is hydrogen or alkyl of from 1 to 3 carbon atoms and 0 to 2 hydroxyl groups; R3 or W are taken together with Y; Y is a bond or alkylene group of from 1 to 6 carbon atoms and n-2 oxy groups, wherein n is the number of carbon atoms of the alkylene group; and Z is CONWR1 or CONHR2; when they are not taken together with Y, R3 is hydrogen or methyl or W is hydrogen.

7. A compound, according to claim 6, characterized in that Z is CONHR2, wherein R2 is 1,3- or 2,3-dihydroxypropyl, R1 is 1,3- or 2,3-dihydroxypropyl or 2-hydroxyethyl.

8. A compound selected from the group consisting of 5-N- (2,3-dihydroxypropyl) formylamido-2,4,6-triiodo-N, N'-bis- (2,3-dihydroxypropyl) isophthalamide, 5-N- ( 2-hydroxyethyl) formylamido-2,4,6-triiodo-N, N'-bis- (2,3-dihydroxy-propyl) isophthalamide, 5-N- (2,3-dihydroxypropyl) formylamido- 2,4,6 -triyodo-N- (2,3-dihydroxypropyl) -N '- (2-hydroxyethyl) -isophthalamide, 5- N - (2,3-dihydroxypropyl) formy I amido-2,4,6-triiodo-3 -N- (2,3-dihydroxypropyl) -carbamoyl-benzamide, and 5-N- (2-hydroxyethyl) -formylamido-2,4,6-triiodo-N, N'-bis- (1,3-dihydroxypropyl) isophthalamide .

9. A formulation of non-ionic contrast media characterized in that it comprises a compound, according to claim 1, in an amount to provide X-ray contrast when administered to a mammalian host and a physiologically acceptable carrier.

10. A formulation of non-ionic contrast media characterized in that it comprises a compound, according to claim 3, in an amount to provide X-ray contrast when administered to a mammalian host and a physiologically acceptable carrier. eleven .

A formulation of non-ionic contrast agents characterized in that it comprises a compound, according to claim 6, in an amount to provide X-ray contrast when administered to a mammalian host and a physiologically acceptable carrier.

12. In a method for obtaining an X-ray of an organ using a contrast medium to provide contrast, the improvement is characterized in that it comprises: using a compound, according to claim 1, as the contrast medium.