CA2229664A1 - Formyl derivatives as nonionic contrast media - Google Patents
Formyl derivatives as nonionic contrast media Download PDFInfo
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- CA2229664A1 CA2229664A1 CA002229664A CA2229664A CA2229664A1 CA 2229664 A1 CA2229664 A1 CA 2229664A1 CA 002229664 A CA002229664 A CA 002229664A CA 2229664 A CA2229664 A CA 2229664A CA 2229664 A1 CA2229664 A1 CA 2229664A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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Abstract
Carboxamide substituted N-formyl, N-alkyl or hydroxyalkyl triiodo anilides are provided. The subject composition have high iodine percentages and excellent water solubility, finding use as preferred embodiments for conventional nonionic contrast media.
Description
W O 97/0~240 PCTnJS96/10433 FORl~YL DERIVATIVES AS NONIONIC CONTRAST MEDIA
INTROl:)UCTION
Techni~l Field The field of this invention is nonionic contrast media.
R~c~l~round SThe X-ray is the most often used diagnostic tool for the çx~min~tion of various co,l,pal~",ents of the body, such as the gastrointestinal tract, vascular system, and individual solid organs. These procedures are done in conjunction with iodinated contrast agents, due to the low inherent contrast differential within the tissues. Criteria for contrast media are that they are biologically inert; that they are 10 capable of c~line~ting anatomical detail accurately and consistently, that they provide accurate radiopacity; that they should have a high iodine content; and that they should be water soluble and should have reasonable osmolality at the concentrations at which they are ~-lmini~tered. The demands on the contrast media employed varies with the nature of the e7c~min~tiQn. In addition, the media should be 15 substantially homogenous, so as to avoid im~ging artifacts and should not be affected by pH or other physiological conditions during their use.
In order to provide for water solubility, the nonionic contrast media have hydroxyalkyl con~tituents to enhance the hydrophilicity. However, the water solubility is to a great extent dependent upon the capability of the compounds to 20 form isomeric mixtures in water solutions. In the nonionic contrast media involving hydroxyalkylated ~nili~les, the isomeric mixtures are dependent upon the endo and exo isomerism of the substituted anilide group. For the most part, the acyl group bonded to the amino group is acetyl, glycolyic acid, or glyceric acid, since such acyl group is stable and of relatively low molecular weight. There is substantial interest in developing new improved non-ionic contrast media, where the iodine content can 5 be enhanced, as well as water solubility and the other factors in(lic~tt~A above.
P~levant T it~r~ture U.S Patent Nos. of interest include 4,547,357; 4,021,481; 3,701,771;
4,364,921; and 4,341,756.
SUMMARY OF THF INVFNTION
Novel nonionic contrast media are provided, which are N-formylated, N-alkylated or -hydroxyalkylated triiodo~nili(les or bis-compounds, where the rem~ining positions on each ring are substituted with at least one carboxy group or an amino group. The subject compositions have high water solubility, good stability, and high iodine content. The subject compounds find use as contrast media in a wide 15 variety of applications for X-ray and other non-invasive diagnosis.
T~F.~CRTPTION OF THF SPF.CIFIC F.l\~ROT~IMF.NTS
Novel nonionic contrast media are provided having excellent water solubility and high iodine content. The contrast media are characterized by having at least one N-formyl, N-alkyl or -hydroxyalkyl amino group bonded to a substituted 20 triiodobenzene, either symmetrical or asymmetrical, usually symmetrical, where the rem~ining two sites have from zero to one substituted amino group and from one to two non-oxocarbonyl groups, particularly amides, more particularly unsubstituted or N-alkyl or N-hydroxyalkyl amides, mono- and di-substituted, i.e. from 0 to 2 alkyl (including hydroxyalkyl) substituents. The compounds may be monomeric or bis-25 dimers, joined by a bond, or more usually an alkylene linking group.
For the most part, the monomeric compounds of this invention will havefewer than 30 carbon atoms, usually fewer than 25 carbon atoms, preferably fewer than about 20 carbon atoms, usually having at least about 12 carbon atoms, more usually at least about 14 carbon atoms. The dimers may have twice the number of 30 carbon atoms, usually up to twice the number of carbon atoms plus 5, more usually plus 3. Other than the formylated aniline nitrogen, the nitrogen atoms will be either mono- or disubstituted, usually monosubstituted when bonded to non-oxocarbonyl bonded to an annular carbon atom, while the nitrogen bonded to an annular carbonatom will be disubstituted, i.e. formylated and N-alkylated or -hydroxyalkylated.
5 When two substituents are present on arl amide nitrogen, usually one will be an oxyalkyl group and the other an alkyl group. (In referring to carbo~mide and amide nitrogen, it is intendecl that the non-oxo-carbonyl carbon is bonded to anannular carbon atom, as distinguished from the formadinyl group, where the nitrogen is bonded to an annular carbon atom.) 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:
CoNR2R3 HCONI~Z (Y)b a Wherein:
a is I or 2, and b is 0 when a is one and 1 when a is 2;
Rl 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 hydroxylgroups, having hydroxyl at other than at the a-carbon atom, generally having from 1 20 to n - 1 hydroxyl groups, where n is the number of carbon atoms present in the group, wherein alkyl is usually of from 1 to 3 carbon atoms, preferably methyl;
R2 may be the same or different from Rl, being hydrogen or coming within the definition of R';
R3, when a is 1, is hydrogen or comes within the definition of Rl, at least 25 one of R2 and R3 having an hydroxyl group;
when a is 2, either two of R3s, R's or Ws are taken together with Y to form a bridge between the two monomers;
Y is not present when a is 1, and when a is 2, is a bridge comprising a bond or linking group of from 1 to 6 carbon atoms, usually of from 2 to 3, carbon atoms, 5 normally aliphatic, usually saturated, particularly comprising one or more methylene groups, having from 0 to n-2 oxy groups, where n is the number of carbon atoms of the linking group;
Z is CONWR', NRICHO or CoNR2R3, preferably CONHR2; and W is hydrogen when a is 1 or, when a is 2, is taken together with Y to form 10 a bridge.
For the most part for the dimeric compounds, where Z is CoNR2R3, R3 of each monomer 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 0 to n-2 oxy groups, where n is the number of carbon atoms of the alkylene group. Where Z is CONWR', W is taken 15 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 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, 4-20 trihydroxybutyl.
Compounds of particular interest are triiodoisophth~l~mide~, where thenitrogens of the carboxamide groups are substituted with 2,3-dihydroxypropyl, 1,3-dihydroxypropyl or hydroxyethyl or bis-hydroxyethyl, or a combination of methyl and 2,3-dihydroxypropyl or 1,3-dihydroxypropyl. Although they may be non-25 identical, preferably, both annular substituted carboxamide nitrogen atoms areidentically substituted, and the anilide nitrogen is substituted with 2,3-dihydroxypropyl, or 2-hydroxyethyl.
Specific compounds of interest include: 5-N-(2,3-dihydroxypropyl) formylamido-2,4,6-triiodo-N,N'-bis-(2,3-dihydroxypropyl)isoph~h~l~mide (BP-257);30 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-triiodo-N-(2 ,3-dihydroxypropyl)-N'-(2-hydroxyethyl)-WO 97~a~24a PCT~US96/10433 isophth~l~mide (BP-278); 5-N-(2,3-dihydroxypropyl)formylamido-2,4,6-triiodo-3-N-(2,3-dihydroxypropyl)-carbamoyl-ben7~mide (BP-256); and 5-N-(1-hydroxyethyl)formylamido-2,4,6-triiodc-N,N'-bis-(1 ,3-dihydroxypropyl)isophth~l~mide (BP-293).
S The subject compounds may be prepared in accoldaulce with conventional ways, except that the formylation is ~lrol-,-ed prior to the alkylation of the anilide nitrogen and the alkylation is carried Ollt under conditions which avoids hydrolysis of the form~nilide. Usually, the groups on the amide nitrogens will be present prior to the final allcylation.
For formylation, activated formic acid may be employed, where the formic acid may be present as the mixed anhyclride, where the mixed anhydride may 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 0 to 15~C. Usually, the formic acid will be added in excess, generally in at least about S fold molar excess, and may be from 10 to 20 fold molar excess. Where an anhydride is added, e.g. aceticanhydride, to the mixture to form the mixed anhydride, the formic acid will be present in at least stoichiometric amount and usually about 1.5 to 3 fold excess over the anhydride. Other mixed anhydrides may include benzoyl isobutyrl, benzyl carbonate, pivaloyl, etc. The work up 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, e.g. 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 11 to 13, where the reaction will be at 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. Basic salts may be added to enhance the reactivity of the halo group. Generally, the halohydrin will be in at least stoichiometric amount,preferably in excess, usually not greater than about 3 fold excess, more usually not greater than about 2.5 fold excess. The workup is conventional, the salts filtered, the filtrate acidified, followed by neutralization and purification of the residue.
For use as contrast media, the subject compositions may be form~ t~din accordance with conventional ways, depending upon the particular application. For oral use, solutions in water are prepared either in advance or ad hoc from a ~ uof the subject compound with lactose, citric acid, methylcellulose, and a detergent, 5 particularly a nonionic detergent, such as Tween-80. For inte~tin~l (rectal) use only methylcellulose (or other polys~çh~ride) and a detergent are used. The detergentwill be present from about 0.1 to 1 weight percent of the composition (excludingwater).
For X-ray computer tomography, the solution concentration of iodine will 10 generally be in the range of about 5 to 15 mg I/ml, preferably about 10 mg I/ml; for plain radiography, about 200 to 400 mg I/ml, preferably 300 to 350 mg I/ml, willbe employed. 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 from about 20 to 150% by weight/volume. The viscosity of the compositions 15 for arimini~tration will be in the range of about 5 cps to 5000 cps, with the plc~r~l~ed range of about 10 to 1000 cps.
The subject compositions may be ~-lmini~t~red by any convenient means, depending upon the particular site or co~ al~l"ent to be investig~t~l. Nonionic contrast media, as obvious from the relevant art literature, have found extensive use 20 and the prior art compounds may be substituted with the subject compounds accordingly.
The following examples are offered by way of illustration and not by way of limitation.
EXPERIMENTAL
25 1. S-N-formylamido-2~4~6-triiodo-N~Nl-bis(2~3-dihydroxypropyl)isophth~l~mide.A. To a stirring suspçncion 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 was added acetic anhydride (13.44 mL, 0.142 mol) and the mixture allowed to stir overnight. The yellow, homogenous solution was 30 concentrated on a rotary evaporator yielding a brownish foam. This was dissolved in EtOAc (100 mL) and extracted with 30~o brine (60 mL). The solution was dried WO 97/00240 PCTfUS96/10433 over MgSO4 and concentrated on a rotary evaporator to a white foam. The solid was dissolved in MeOH (50 mL) basified with 30% NaOMe (7 mL) to pH = 12 and concentrated to 1/2 volume. After reconstitution with methanol, neutralization to pH
= 7 with concentrated HCl, filtration, and solvent removal, a white foam was 5 obtained. (70% yield) B. Analysis:
1. TLC: Silica gel 60, F254, 50% CHC13/50% methanol, UV cletectiQn ~? 254 nm. Rf(starting material) = 0.53. Rf ~roduct) = 0.47 2. HPLC: Alltech NH2 econosphere, 4.6 x 250 mm, 5~, 85%
10 acelonillile/15% H20, 1.5 mL/min, 254 nm dete~ti~n7 30~C. Retention time (starting m~teri~l) = 5.42 min. Retention time (product) = 8.61 min.
INTROl:)UCTION
Techni~l Field The field of this invention is nonionic contrast media.
R~c~l~round SThe X-ray is the most often used diagnostic tool for the çx~min~tion of various co,l,pal~",ents of the body, such as the gastrointestinal tract, vascular system, and individual solid organs. These procedures are done in conjunction with iodinated contrast agents, due to the low inherent contrast differential within the tissues. Criteria for contrast media are that they are biologically inert; that they are 10 capable of c~line~ting anatomical detail accurately and consistently, that they provide accurate radiopacity; that they should have a high iodine content; and that they should be water soluble and should have reasonable osmolality at the concentrations at which they are ~-lmini~tered. The demands on the contrast media employed varies with the nature of the e7c~min~tiQn. In addition, the media should be 15 substantially homogenous, so as to avoid im~ging artifacts and should not be affected by pH or other physiological conditions during their use.
In order to provide for water solubility, the nonionic contrast media have hydroxyalkyl con~tituents to enhance the hydrophilicity. However, the water solubility is to a great extent dependent upon the capability of the compounds to 20 form isomeric mixtures in water solutions. In the nonionic contrast media involving hydroxyalkylated ~nili~les, the isomeric mixtures are dependent upon the endo and exo isomerism of the substituted anilide group. For the most part, the acyl group bonded to the amino group is acetyl, glycolyic acid, or glyceric acid, since such acyl group is stable and of relatively low molecular weight. There is substantial interest in developing new improved non-ionic contrast media, where the iodine content can 5 be enhanced, as well as water solubility and the other factors in(lic~tt~A above.
P~levant T it~r~ture U.S Patent Nos. of interest include 4,547,357; 4,021,481; 3,701,771;
4,364,921; and 4,341,756.
SUMMARY OF THF INVFNTION
Novel nonionic contrast media are provided, which are N-formylated, N-alkylated or -hydroxyalkylated triiodo~nili(les or bis-compounds, where the rem~ining positions on each ring are substituted with at least one carboxy group or an amino group. The subject compositions have high water solubility, good stability, and high iodine content. The subject compounds find use as contrast media in a wide 15 variety of applications for X-ray and other non-invasive diagnosis.
T~F.~CRTPTION OF THF SPF.CIFIC F.l\~ROT~IMF.NTS
Novel nonionic contrast media are provided having excellent water solubility and high iodine content. The contrast media are characterized by having at least one N-formyl, N-alkyl or -hydroxyalkyl amino group bonded to a substituted 20 triiodobenzene, either symmetrical or asymmetrical, usually symmetrical, where the rem~ining two sites have from zero to one substituted amino group and from one to two non-oxocarbonyl groups, particularly amides, more particularly unsubstituted or N-alkyl or N-hydroxyalkyl amides, mono- and di-substituted, i.e. from 0 to 2 alkyl (including hydroxyalkyl) substituents. The compounds may be monomeric or bis-25 dimers, joined by a bond, or more usually an alkylene linking group.
For the most part, the monomeric compounds of this invention will havefewer than 30 carbon atoms, usually fewer than 25 carbon atoms, preferably fewer than about 20 carbon atoms, usually having at least about 12 carbon atoms, more usually at least about 14 carbon atoms. The dimers may have twice the number of 30 carbon atoms, usually up to twice the number of carbon atoms plus 5, more usually plus 3. Other than the formylated aniline nitrogen, the nitrogen atoms will be either mono- or disubstituted, usually monosubstituted when bonded to non-oxocarbonyl bonded to an annular carbon atom, while the nitrogen bonded to an annular carbonatom will be disubstituted, i.e. formylated and N-alkylated or -hydroxyalkylated.
5 When two substituents are present on arl amide nitrogen, usually one will be an oxyalkyl group and the other an alkyl group. (In referring to carbo~mide and amide nitrogen, it is intendecl that the non-oxo-carbonyl carbon is bonded to anannular carbon atom, as distinguished from the formadinyl group, where the nitrogen is bonded to an annular carbon atom.) 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:
CoNR2R3 HCONI~Z (Y)b a Wherein:
a is I or 2, and b is 0 when a is one and 1 when a is 2;
Rl 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 hydroxylgroups, having hydroxyl at other than at the a-carbon atom, generally having from 1 20 to n - 1 hydroxyl groups, where n is the number of carbon atoms present in the group, wherein alkyl is usually of from 1 to 3 carbon atoms, preferably methyl;
R2 may be the same or different from Rl, being hydrogen or coming within the definition of R';
R3, when a is 1, is hydrogen or comes within the definition of Rl, at least 25 one of R2 and R3 having an hydroxyl group;
when a is 2, either two of R3s, R's or Ws are taken together with Y to form a bridge between the two monomers;
Y is not present when a is 1, and when a is 2, is a bridge comprising a bond or linking group of from 1 to 6 carbon atoms, usually of from 2 to 3, carbon atoms, 5 normally aliphatic, usually saturated, particularly comprising one or more methylene groups, having from 0 to n-2 oxy groups, where n is the number of carbon atoms of the linking group;
Z is CONWR', NRICHO or CoNR2R3, preferably CONHR2; and W is hydrogen when a is 1 or, when a is 2, is taken together with Y to form 10 a bridge.
For the most part for the dimeric compounds, where Z is CoNR2R3, R3 of each monomer 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 0 to n-2 oxy groups, where n is the number of carbon atoms of the alkylene group. Where Z is CONWR', W is taken 15 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 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, 4-20 trihydroxybutyl.
Compounds of particular interest are triiodoisophth~l~mide~, where thenitrogens of the carboxamide groups are substituted with 2,3-dihydroxypropyl, 1,3-dihydroxypropyl or hydroxyethyl or bis-hydroxyethyl, or a combination of methyl and 2,3-dihydroxypropyl or 1,3-dihydroxypropyl. Although they may be non-25 identical, preferably, both annular substituted carboxamide nitrogen atoms areidentically substituted, and the anilide nitrogen is substituted with 2,3-dihydroxypropyl, or 2-hydroxyethyl.
Specific compounds of interest include: 5-N-(2,3-dihydroxypropyl) formylamido-2,4,6-triiodo-N,N'-bis-(2,3-dihydroxypropyl)isoph~h~l~mide (BP-257);30 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-triiodo-N-(2 ,3-dihydroxypropyl)-N'-(2-hydroxyethyl)-WO 97~a~24a PCT~US96/10433 isophth~l~mide (BP-278); 5-N-(2,3-dihydroxypropyl)formylamido-2,4,6-triiodo-3-N-(2,3-dihydroxypropyl)-carbamoyl-ben7~mide (BP-256); and 5-N-(1-hydroxyethyl)formylamido-2,4,6-triiodc-N,N'-bis-(1 ,3-dihydroxypropyl)isophth~l~mide (BP-293).
S The subject compounds may be prepared in accoldaulce with conventional ways, except that the formylation is ~lrol-,-ed prior to the alkylation of the anilide nitrogen and the alkylation is carried Ollt under conditions which avoids hydrolysis of the form~nilide. Usually, the groups on the amide nitrogens will be present prior to the final allcylation.
For formylation, activated formic acid may be employed, where the formic acid may be present as the mixed anhyclride, where the mixed anhydride may 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 0 to 15~C. Usually, the formic acid will be added in excess, generally in at least about S fold molar excess, and may be from 10 to 20 fold molar excess. Where an anhydride is added, e.g. aceticanhydride, to the mixture to form the mixed anhydride, the formic acid will be present in at least stoichiometric amount and usually about 1.5 to 3 fold excess over the anhydride. Other mixed anhydrides may include benzoyl isobutyrl, benzyl carbonate, pivaloyl, etc. The work up 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, e.g. 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 11 to 13, where the reaction will be at 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. Basic salts may be added to enhance the reactivity of the halo group. Generally, the halohydrin will be in at least stoichiometric amount,preferably in excess, usually not greater than about 3 fold excess, more usually not greater than about 2.5 fold excess. The workup is conventional, the salts filtered, the filtrate acidified, followed by neutralization and purification of the residue.
For use as contrast media, the subject compositions may be form~ t~din accordance with conventional ways, depending upon the particular application. For oral use, solutions in water are prepared either in advance or ad hoc from a ~ uof the subject compound with lactose, citric acid, methylcellulose, and a detergent, 5 particularly a nonionic detergent, such as Tween-80. For inte~tin~l (rectal) use only methylcellulose (or other polys~çh~ride) and a detergent are used. The detergentwill be present from about 0.1 to 1 weight percent of the composition (excludingwater).
For X-ray computer tomography, the solution concentration of iodine will 10 generally be in the range of about 5 to 15 mg I/ml, preferably about 10 mg I/ml; for plain radiography, about 200 to 400 mg I/ml, preferably 300 to 350 mg I/ml, willbe employed. 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 from about 20 to 150% by weight/volume. The viscosity of the compositions 15 for arimini~tration will be in the range of about 5 cps to 5000 cps, with the plc~r~l~ed range of about 10 to 1000 cps.
The subject compositions may be ~-lmini~t~red by any convenient means, depending upon the particular site or co~ al~l"ent to be investig~t~l. Nonionic contrast media, as obvious from the relevant art literature, have found extensive use 20 and the prior art compounds may be substituted with the subject compounds accordingly.
The following examples are offered by way of illustration and not by way of limitation.
EXPERIMENTAL
25 1. S-N-formylamido-2~4~6-triiodo-N~Nl-bis(2~3-dihydroxypropyl)isophth~l~mide.A. To a stirring suspçncion 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 was added acetic anhydride (13.44 mL, 0.142 mol) and the mixture allowed to stir overnight. The yellow, homogenous solution was 30 concentrated on a rotary evaporator yielding a brownish foam. This was dissolved in EtOAc (100 mL) and extracted with 30~o brine (60 mL). The solution was dried WO 97/00240 PCTfUS96/10433 over MgSO4 and concentrated on a rotary evaporator to a white foam. The solid was dissolved in MeOH (50 mL) basified with 30% NaOMe (7 mL) to pH = 12 and concentrated to 1/2 volume. After reconstitution with methanol, neutralization to pH
= 7 with concentrated HCl, filtration, and solvent removal, a white foam was 5 obtained. (70% yield) B. Analysis:
1. TLC: Silica gel 60, F254, 50% CHC13/50% methanol, UV cletectiQn ~? 254 nm. Rf(starting material) = 0.53. Rf ~roduct) = 0.47 2. HPLC: Alltech NH2 econosphere, 4.6 x 250 mm, 5~, 85%
10 acelonillile/15% H20, 1.5 mL/min, 254 nm dete~ti~n7 30~C. Retention time (starting m~teri~l) = 5.42 min. Retention time (product) = 8.61 min.
3. IH NMR, product: DMSOd6; 10.3-10.0 ppm (m,lH), 8.5 ppm (m, 2H), 8.3 ppm (m,lH),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(2,3-15 dihydroxypropyl)isophth~l~micle (BP-257) To a suspension of 5-N-formylamido-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophth~l~mide (1.0 g, 1.17 mmol) and 5 mL MeOH was added Na3PO4.12 H2O (1.30 g, 3.41 mmol) followed by 3-chloro-1,2-propandiol ( 0.23 mL, 2.73 mmol) in a single portion. Tlhe reaction mixture was maintained at pH 12 20 and 45~C for 4 hours. The precipitated salts were filtered off and washed with dry MeOH. The filtrate was acidified to pH = 1.6 with concentrated HCl and stirred overnight. The reaction was neutralized with sodium methoxide in methanol, filtered and concentrated on a rotary evaporator. 2 mL of isoplopallol was added to the residue. The solids were filtered and dlied. (75% yield). Following recryst~lli7~tion 25 from aqueous ethanol, BP-257 was >99% pure.
B. Analysis 1. TLC: Silica gel 60, F254, 50% CHCl3/50% methanol, UV cletectinn ~ 254 nm. Rf (starting material) = 0.47. Rf(product) = 0.39 2. HPLC: Alltech NH2 econosphere, 4.6 x 250 mm, 5,u, 85%
30 acetonitrile/15% H20, 1.5 mL/min, 254 nm dete~tion, 30~C. Retention time ~0 97/00240 PCTAUS96/10433 (starting material) = 8.10 min. Reten~ion times (product) = 12.13 min and l4.45 min.
3. lH NMR (BP-257): 8.6-8-4 ppm (m,2H), 8.4-7.9 ppm (d,lH), 4.9-4.5 ppm (m,4H), 4.0-3.1 ppm (m,lSH).
3. 5-[N-(2,3-dihydroxypropyl)]formylamido-2,4,6-triiodo- N'-(2-hydroxyethyl)-N'-(2,3-dihydroxypropyl)-isophth~l~mkie [BP-278]
A 2 liter flask was charged with 5-[N-(2,3-diacetoxypropyl)]formylamido-2,4,6-triiodo-3-[N-(2,3- ~ etnxypropyl)]carbamoyl benzoyl çhlonde (74.29 g, 0.0807 moles), acetonitrile (296 mL) and ethannl~mine (11.69 ml, 0.1937 moles).
This mixture was stirred for 2 hours at 25~C and then neutralized to pH 8 with concentrated hydrochloric acid (2.69 mL, 0.0323 moles). After fil~ering salts, the filtrate was evaporated and vacuum dried to a yellow foam. It was partitioned between ethyl acetate (460 mL) and saturated sodium chloride (200 mL) and the aqueous layer was back extracted with ethyl acetate (100 mL), the ethyl acetate extracts were combined, dried over m~necium sulfate, and filtered. After solventremoval and drying, 73.97 g (97%) of the title compound was obtained. The reaction was repeated and the combined lots charged into a 1 liter flask (144.8 g, 0.1532 moles) with methanol (580 mL). 30% mçth~nolic sodium methoxide (1.84 mL, 10.21 mmoles) was added dropwise at 25~C. After 30 minutes the solution was concentrated to half-volume and then neutralized with Dowex 50 H+ resin.
The resin was filtered off and the solvent removed to give 117.2 g (95.4%) of the title compound [BP-278].
Analysis:
1. TLC: Silica gel 60, F254, 40% methanol/60% CHCl3, UV detection at 254 nm. Rf (BP-278) = 0.40 2. HPLC: Alltech C8 Absorbosphere, 4.6x 250mm, 5 ~u, 5%
acetonitrile/95% 0.02 M KH2PO4, pH 3, 1.0 ml/min., 246 nm detection, 30~C.
Retention times (BP-278) = isomer peaks at 8.95 min, 9.44 min., and 11.97 minutes.
3. 'H NMR, (BP-278; DMSOd6): 7.9 and 8.35 ppm (m, lH), 8.5 ppm (m, 2H), 4.5 - 4.9 ppm (m, SH), 3.3-3.9 ppm (m, 14H) wo 97/00240 Pcr/uss6/l0433 4. [N-(2,3-diacetoxypropyl)]formylamido-2,4,6-triiodo-3-[N-(2,3-dia cetoxypropyl)] carbamoyl benzoic acid [BP-256]
In a S L flask 5-amino-2,4,6-triiodo-3-[N-(2,3-dihydroxypropyl)] carbamoyl benzoic acid (g47.8 g, 1.50 moles) and 95-97% formic acid (1.85 L) were stirred at 5 -1 to 10~C while acetic anhydride (1133 mL, 12.0 moles) was added dropwise over 6 hours, followed by stirring for 6 hours 20~C and a partial solvent removal. To the residue butyl acetate (1.5 L) was added. A white plccipi~te was filtered off, and vacuum dried to yield 970.7 g (91 %) of 5-formylamido-2,4,6-triiodo-3-[N-(2,3-diformyloxypropyl)] carbamoyl benzoic acid. In a 10 L flask charged with this 10 compound (950 g, 1.33 moles), methanol (2.85 L) and a 30% m~th~nolic sodium methoxide solution (478 mL, 2.65 moles), after stirring for 10 mim1tes at 25~C, acetic acid (76 mL, 1.33 moles) was added. The solution was reduced to half.
Adding anhydrous ethanol (1.5 L) gave a white pre~irit~te which was filtered, washed with ethanol, and vacuum dried, yielding 982.4 g of the sodium salt of 5-15 formylamido-2,4,6-triiodo-3-[N-(2,3-dihydroxypropyl)] carbamoyl benzoic acid and some salts. A 12 L flask was charged trisodium phosphate dodecahydrate (1366 g, 3.59 moles), 1,2-propanediol (1 L), and 3-chloro-l~2-prop~n~liol (240 mL, 2.87 moles). After stirring at 40-45~C for 3ID minutes, a solution of the sodium salt of 5-formylamido-2,4,6-triiodo-3-[N-(2,3-dihydroxypropyl)] carbamoyl benzoic acid 20 (980 g, 1.44 moles) in 1,2-prop~ne~liol (3 L), was added over 5 hours and thesuspension stirred 1.5 hours at 40-45~C, and filtered to remove salts. The filtrate was brought to pH 1.5 with concentrated hydrochloric acid (250 mL) arld stirred for 16 hours at 25~C to destroy residual glycidol. The solvent was removed and the product precipitated with isoplopanol (2 L), filtered, washed with isop~ allol, and 25 vacuum dried, 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 was charged with this solid, ethyl acetate (0.8 L), pyridine (19.7 mL, 0.24 moles) and acetic anhydride (1.285 L, 13.6 moles).
This mixture was stirred for 4.5 hours at 50-60~C. The solvent was removed 30 yielding an orange oil which was dissolved in butyl acetate (1.5 L) and treated with a solution of MaHCO3 (102.5 g, 1.22 moles) in H2O (2 L). The layers were separated and the aqueous layer extracted with butyl acetate (3 X 0.5 L). To the aqueous layer was added chloroform (1.5 L) followed by concentrated hydrochloricacid (22 mL, 0.26 moles). The organic layer was separated and the aqueous layer extracted with chloroform (1 L). The combined chloroform extracts were dried over magnesium sulfate, filtered and the solvent removed, yielding 845.7 g (77%). of 5-[N-(2,3-diacetoxypropyl)]formylamido-2,4,6-triiodo-3-[N-(2,3-diacetoxypropyl)]carbamoyl benzoic acid.
To a 1 L flask charged with 5-tN-(2,3-diacetoxypropyl)] formylamido-2,4,6-triiodo-3-[N-(2,3-diacetoxypropyl)] carbamoyl benzoic acid (102 g, 0.11 moles) and ethyl acetate (300 mL) was added thionyl chloride (41.2 mL, 0.57 moles) dropwiseover 1.5 hours at 70~C. The solution was stirred for 2.5 hours and the solvent removed yielding 106.6 g of 5-[N-(2,3-diacetoxypropyl)]formylamido-2,4,6-triiodo-3-[N-(2,3-diacetoxypropyl)] carbamoyl benzoyl chloride. This compound was dissolved in acetonitrile (250 mL), and liquid ammonia added dropwise using a dry ice condenser. After 3 hours at 40~C the suspension was purged with nitrogen andfiltered, dissolved in dichlorometh~ne (250 mL) and the solution washed with 0.1 N
hydrochloric acid (250 mL). The organic layer was dried over m~gnecium sulfate, filtered and the solvent removed, yielding 89.4 g (86%) of 5-[N-(2,3-diacetoxypropyl)]formylamido-2,4,6-triiodo-3-[N-(2,3-diacetoxypropyl)] carbamoylbenzamide. To a 1 L flask charged with this compound and meth~nol (500 mL) was added a 30% methanolic sodium methoxide solution (5.5 mL) to pH 13-14. When deacetylation was judged complete by TLC, the mixture was neutralized with Dowex 50 H+ to pH 5-6. The solvent was removed and the residue dissolved in H20, treated with resin, charcoal, and cryst~lli7ed from boiling alcohol. The resultant BP-256 (80% cryst~lli7~tiQn yield) was ~ 99% pure by HPLC.
Analysis:
1. TLC: Silica gel 60, F254, 60% chloroform/30% meth~nol/10% acetic acid, UV detection @~ 254 nm. Rf (BP-256) = 0.40 2. HPLC: Alltech C18 Absorbosphere, 4.6 x250 mm, 5 ~L, 98% 0.02 M KH2PO4 pH 3, 2% acetonitrile, 1.0 mL/min, 246 nm detection, 30~C.
Retention times (BP-256) = isomer peaks at 5.69, 6.11, 7.26, 7.71, 9.54, and 10.00 minutes.
W O 97/00240 PCT~US96/10433 3. IH NMR (BP-256; DMSO-d6): 7.90 and 8.35 ppm (d, lH); 8.50 (m, lH); 7.99 and 7.72 ppm (m, 2H); 4.49-4.89 ppm (m, 4H); 3.20-3.96 ppm (m, 10H) .
5. 5-[N-(2-hydroxyethyl)]formylamido-2,4,6-triiodo-N,N'-bis-(2,3-di hydroxypropyl)-isophth~l~mide [BP-258]
To a s~spen~inn of trisodium phosphate dode~hydrate (196.3 g, 0.52 moles) in 1,2-propanediol (800 mL) was adde~ 2-chloroethanol (28.9 mL, 0.43 moles) in asingle portion. After stirring for 30 minutes at 40~C, solid 5-N-formylamido-2,4,6-triiodo-N,N'-bis-(2,3-dihydroxypropyl)-is ophth~l~mide (152 g, 0.21 moles) was added over 2 hours. The pH was m~ ined at 11-12 and the mixture was heated at 40-45~C for 4 hours. The precipitated salts were filtered off and washed with dry methanol. The filtrate was acidified to pH 1.6 with concentrated hydrochloric acid and stirred for 3 hours to destroy the excess alkylating agent. The reaction mixture was neutralized with 30% methanolic sodium methoxide, and concentrated. Propyl alcohol (650 mL) was added, precipitating a solid which was filtered, washed with propanol, dissolved in water, and deionized with resins. After boiling with 5%
charcoal, the product was dried and cryst~lli7ed 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)-isophth~l~mide [BP-258].
Analysis:
1. TLC: Silica gel 60,F254, 60% n-butanol, 40% SN HOAc. Rf (BP-258 isomer) = 0.39 and 0.27.
2. HPLC: Alltech (C-18 Adsorbosphere, 4.6 X 250 mm, 5~, 2%
acetonitrile, 98%, 0.02 M KH2PO4, pH = 3, 1.0 mL/min, 246 nm detection, 30~C.
Retention times (BP-258) = isomer peaks at 14.33 and 17.10 minutes.
3. 'H NMR (BP-258; DMSOd6): 7.86 and 8.4 ppm (m, lH), 8.5 ppm (m, 2H), 4.5 - 4.9 ppm (m, SH), 3.0 - 3.9 (m, 14H).
6. 5-[N-(2-hydroxyethyl)]formylamido-2,4,6-triiodo-N,N'-bis-(1,3-di hydroxy-prop-2-yl)-isophthalamide [BP-293]
A 2 L flask was charged with 5-amino-2,4,6-triiodo-N,N'-bis-(1,3-dihydroxy-prop-2-yl) isophthalamide (250.0 g, 0.355 moles) and formic acid (341 mL), stirred at 0-10~C while acetic anhydride (233.6 g, 2.29 moles) was added dropwise over 1.6 hours. After stirring at RT for six hours, the solution was reduced and a solid precipitated with butyl acetate (800 mL), filtered and washed with butyl acetate. The solid was vacuum dried, yielding 299.1 g (99.8%) 5-N-formylamido-2,4,6-triiodo-N,N'-bis-(1,3-diformyloxy-prop-2- yl)- isophth~l~mide.This compound was charged into a 2 L flask with methanol (1200 mL), and 30%
methanolic sodium methoxide (89.3 mL). After stirring for 20 minl-tes at 0-10~C,the solution was reduced to half volume and acetic acid (29.8 g, 0.496 moles) was added. A white solid was precipitated with isoplop~lol (500 mL), filtered, washed with isopropanol, and vacuum dried. The product was re-suspended in methanol (1000 mL), heated at 60~C for 30 minutes, cooled to 20~C, filtered, washed with methanol, and vacuum dried to yield 216.4 g (83.4%) of 5-formylamido-2,4,6-triiodo-N,N'-bis-(1,3-dihydroxy-prop-2-yl)- isophth~l~mi~le.
A 2 L flask was charged with trisodium phosphate dodecahydrate (194.8 g, 0.513 moles), propylene glycol (850 mL), and (33.0 g, 0.409 moles) 2-chloro ethanol (33.0 g, 0.409 moles). After stirring at 40-45~C for 1 hour, solid 5-N-formylamido-2,4,6-triiodo-N,N'-bis-(1,3-dihydroxy-2-prop-2-yl)- isophth~l~mide (150 g) was added over 30 minutes. The sl-spencion was stirred for 4 hours at 40-45~C, allowed to cool, filtered, and the salts washed with propylene glycol. Thefiltrate was acidified to pH 1.5-2.0 with 12 M hydrochloric acid to destroy residual ethylene oxide. After neutrali_ation to pH 7 with 30% methanolic sodium methoxide, the solution was concentrated, and a solid precipitated with propyl alcohol, filtered, washed with propyl alcohol, and vacuum dried. After dissolving in water, deioni_ation with resins and boiling with 5% charcoal, the product wascryst~lli7tod 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)-is ophthalamide [BP-293].
Analysis: ,.
1. TLC: Silica gel 60, F2s4, 60% n-butanol, 40% SN HOAc. Rf (BP-293 isomers) = 0.60 and 0.33.
2. HPLC: Alltech Cl8 Adsorbosphere, 4.6 X 250 mm, S,u, 5%
methanol/95% 0.02 M KH2PO4, pH = 3, 1.0 mL/min., 246 nm detection, 30~C.
Retention times (BP-293) = isomer pe~llcs at 9.54 and 10.75 minutes.
3. 'H NMR (BP-293; DMSOd6): 7.85 and 8.4 ppm (m, 14), 8.25 ppm 5 (m, 2H), 4.4 - 5.0 ppm (m, SH), 3.3-4.0 (m, 14H).
2. 5-N-(2,3 dihydroxypropyl)-formylamido-2, 4,6-triiodo-N,N'-bis(2,3-15 dihydroxypropyl)isophth~l~micle (BP-257) To a suspension of 5-N-formylamido-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophth~l~mide (1.0 g, 1.17 mmol) and 5 mL MeOH was added Na3PO4.12 H2O (1.30 g, 3.41 mmol) followed by 3-chloro-1,2-propandiol ( 0.23 mL, 2.73 mmol) in a single portion. Tlhe reaction mixture was maintained at pH 12 20 and 45~C for 4 hours. The precipitated salts were filtered off and washed with dry MeOH. The filtrate was acidified to pH = 1.6 with concentrated HCl and stirred overnight. The reaction was neutralized with sodium methoxide in methanol, filtered and concentrated on a rotary evaporator. 2 mL of isoplopallol was added to the residue. The solids were filtered and dlied. (75% yield). Following recryst~lli7~tion 25 from aqueous ethanol, BP-257 was >99% pure.
B. Analysis 1. TLC: Silica gel 60, F254, 50% CHCl3/50% methanol, UV cletectinn ~ 254 nm. Rf (starting material) = 0.47. Rf(product) = 0.39 2. HPLC: Alltech NH2 econosphere, 4.6 x 250 mm, 5,u, 85%
30 acetonitrile/15% H20, 1.5 mL/min, 254 nm dete~tion, 30~C. Retention time ~0 97/00240 PCTAUS96/10433 (starting material) = 8.10 min. Reten~ion times (product) = 12.13 min and l4.45 min.
3. lH NMR (BP-257): 8.6-8-4 ppm (m,2H), 8.4-7.9 ppm (d,lH), 4.9-4.5 ppm (m,4H), 4.0-3.1 ppm (m,lSH).
3. 5-[N-(2,3-dihydroxypropyl)]formylamido-2,4,6-triiodo- N'-(2-hydroxyethyl)-N'-(2,3-dihydroxypropyl)-isophth~l~mkie [BP-278]
A 2 liter flask was charged with 5-[N-(2,3-diacetoxypropyl)]formylamido-2,4,6-triiodo-3-[N-(2,3- ~ etnxypropyl)]carbamoyl benzoyl çhlonde (74.29 g, 0.0807 moles), acetonitrile (296 mL) and ethannl~mine (11.69 ml, 0.1937 moles).
This mixture was stirred for 2 hours at 25~C and then neutralized to pH 8 with concentrated hydrochloric acid (2.69 mL, 0.0323 moles). After fil~ering salts, the filtrate was evaporated and vacuum dried to a yellow foam. It was partitioned between ethyl acetate (460 mL) and saturated sodium chloride (200 mL) and the aqueous layer was back extracted with ethyl acetate (100 mL), the ethyl acetate extracts were combined, dried over m~necium sulfate, and filtered. After solventremoval and drying, 73.97 g (97%) of the title compound was obtained. The reaction was repeated and the combined lots charged into a 1 liter flask (144.8 g, 0.1532 moles) with methanol (580 mL). 30% mçth~nolic sodium methoxide (1.84 mL, 10.21 mmoles) was added dropwise at 25~C. After 30 minutes the solution was concentrated to half-volume and then neutralized with Dowex 50 H+ resin.
The resin was filtered off and the solvent removed to give 117.2 g (95.4%) of the title compound [BP-278].
Analysis:
1. TLC: Silica gel 60, F254, 40% methanol/60% CHCl3, UV detection at 254 nm. Rf (BP-278) = 0.40 2. HPLC: Alltech C8 Absorbosphere, 4.6x 250mm, 5 ~u, 5%
acetonitrile/95% 0.02 M KH2PO4, pH 3, 1.0 ml/min., 246 nm detection, 30~C.
Retention times (BP-278) = isomer peaks at 8.95 min, 9.44 min., and 11.97 minutes.
3. 'H NMR, (BP-278; DMSOd6): 7.9 and 8.35 ppm (m, lH), 8.5 ppm (m, 2H), 4.5 - 4.9 ppm (m, SH), 3.3-3.9 ppm (m, 14H) wo 97/00240 Pcr/uss6/l0433 4. [N-(2,3-diacetoxypropyl)]formylamido-2,4,6-triiodo-3-[N-(2,3-dia cetoxypropyl)] carbamoyl benzoic acid [BP-256]
In a S L flask 5-amino-2,4,6-triiodo-3-[N-(2,3-dihydroxypropyl)] carbamoyl benzoic acid (g47.8 g, 1.50 moles) and 95-97% formic acid (1.85 L) were stirred at 5 -1 to 10~C while acetic anhydride (1133 mL, 12.0 moles) was added dropwise over 6 hours, followed by stirring for 6 hours 20~C and a partial solvent removal. To the residue butyl acetate (1.5 L) was added. A white plccipi~te was filtered off, and vacuum dried to yield 970.7 g (91 %) of 5-formylamido-2,4,6-triiodo-3-[N-(2,3-diformyloxypropyl)] carbamoyl benzoic acid. In a 10 L flask charged with this 10 compound (950 g, 1.33 moles), methanol (2.85 L) and a 30% m~th~nolic sodium methoxide solution (478 mL, 2.65 moles), after stirring for 10 mim1tes at 25~C, acetic acid (76 mL, 1.33 moles) was added. The solution was reduced to half.
Adding anhydrous ethanol (1.5 L) gave a white pre~irit~te which was filtered, washed with ethanol, and vacuum dried, yielding 982.4 g of the sodium salt of 5-15 formylamido-2,4,6-triiodo-3-[N-(2,3-dihydroxypropyl)] carbamoyl benzoic acid and some salts. A 12 L flask was charged trisodium phosphate dodecahydrate (1366 g, 3.59 moles), 1,2-propanediol (1 L), and 3-chloro-l~2-prop~n~liol (240 mL, 2.87 moles). After stirring at 40-45~C for 3ID minutes, a solution of the sodium salt of 5-formylamido-2,4,6-triiodo-3-[N-(2,3-dihydroxypropyl)] carbamoyl benzoic acid 20 (980 g, 1.44 moles) in 1,2-prop~ne~liol (3 L), was added over 5 hours and thesuspension stirred 1.5 hours at 40-45~C, and filtered to remove salts. The filtrate was brought to pH 1.5 with concentrated hydrochloric acid (250 mL) arld stirred for 16 hours at 25~C to destroy residual glycidol. The solvent was removed and the product precipitated with isoplopanol (2 L), filtered, washed with isop~ allol, and 25 vacuum dried, 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 was charged with this solid, ethyl acetate (0.8 L), pyridine (19.7 mL, 0.24 moles) and acetic anhydride (1.285 L, 13.6 moles).
This mixture was stirred for 4.5 hours at 50-60~C. The solvent was removed 30 yielding an orange oil which was dissolved in butyl acetate (1.5 L) and treated with a solution of MaHCO3 (102.5 g, 1.22 moles) in H2O (2 L). The layers were separated and the aqueous layer extracted with butyl acetate (3 X 0.5 L). To the aqueous layer was added chloroform (1.5 L) followed by concentrated hydrochloricacid (22 mL, 0.26 moles). The organic layer was separated and the aqueous layer extracted with chloroform (1 L). The combined chloroform extracts were dried over magnesium sulfate, filtered and the solvent removed, yielding 845.7 g (77%). of 5-[N-(2,3-diacetoxypropyl)]formylamido-2,4,6-triiodo-3-[N-(2,3-diacetoxypropyl)]carbamoyl benzoic acid.
To a 1 L flask charged with 5-tN-(2,3-diacetoxypropyl)] formylamido-2,4,6-triiodo-3-[N-(2,3-diacetoxypropyl)] carbamoyl benzoic acid (102 g, 0.11 moles) and ethyl acetate (300 mL) was added thionyl chloride (41.2 mL, 0.57 moles) dropwiseover 1.5 hours at 70~C. The solution was stirred for 2.5 hours and the solvent removed yielding 106.6 g of 5-[N-(2,3-diacetoxypropyl)]formylamido-2,4,6-triiodo-3-[N-(2,3-diacetoxypropyl)] carbamoyl benzoyl chloride. This compound was dissolved in acetonitrile (250 mL), and liquid ammonia added dropwise using a dry ice condenser. After 3 hours at 40~C the suspension was purged with nitrogen andfiltered, dissolved in dichlorometh~ne (250 mL) and the solution washed with 0.1 N
hydrochloric acid (250 mL). The organic layer was dried over m~gnecium sulfate, filtered and the solvent removed, yielding 89.4 g (86%) of 5-[N-(2,3-diacetoxypropyl)]formylamido-2,4,6-triiodo-3-[N-(2,3-diacetoxypropyl)] carbamoylbenzamide. To a 1 L flask charged with this compound and meth~nol (500 mL) was added a 30% methanolic sodium methoxide solution (5.5 mL) to pH 13-14. When deacetylation was judged complete by TLC, the mixture was neutralized with Dowex 50 H+ to pH 5-6. The solvent was removed and the residue dissolved in H20, treated with resin, charcoal, and cryst~lli7ed from boiling alcohol. The resultant BP-256 (80% cryst~lli7~tiQn yield) was ~ 99% pure by HPLC.
Analysis:
1. TLC: Silica gel 60, F254, 60% chloroform/30% meth~nol/10% acetic acid, UV detection @~ 254 nm. Rf (BP-256) = 0.40 2. HPLC: Alltech C18 Absorbosphere, 4.6 x250 mm, 5 ~L, 98% 0.02 M KH2PO4 pH 3, 2% acetonitrile, 1.0 mL/min, 246 nm detection, 30~C.
Retention times (BP-256) = isomer peaks at 5.69, 6.11, 7.26, 7.71, 9.54, and 10.00 minutes.
W O 97/00240 PCT~US96/10433 3. IH NMR (BP-256; DMSO-d6): 7.90 and 8.35 ppm (d, lH); 8.50 (m, lH); 7.99 and 7.72 ppm (m, 2H); 4.49-4.89 ppm (m, 4H); 3.20-3.96 ppm (m, 10H) .
5. 5-[N-(2-hydroxyethyl)]formylamido-2,4,6-triiodo-N,N'-bis-(2,3-di hydroxypropyl)-isophth~l~mide [BP-258]
To a s~spen~inn of trisodium phosphate dode~hydrate (196.3 g, 0.52 moles) in 1,2-propanediol (800 mL) was adde~ 2-chloroethanol (28.9 mL, 0.43 moles) in asingle portion. After stirring for 30 minutes at 40~C, solid 5-N-formylamido-2,4,6-triiodo-N,N'-bis-(2,3-dihydroxypropyl)-is ophth~l~mide (152 g, 0.21 moles) was added over 2 hours. The pH was m~ ined at 11-12 and the mixture was heated at 40-45~C for 4 hours. The precipitated salts were filtered off and washed with dry methanol. The filtrate was acidified to pH 1.6 with concentrated hydrochloric acid and stirred for 3 hours to destroy the excess alkylating agent. The reaction mixture was neutralized with 30% methanolic sodium methoxide, and concentrated. Propyl alcohol (650 mL) was added, precipitating a solid which was filtered, washed with propanol, dissolved in water, and deionized with resins. After boiling with 5%
charcoal, the product was dried and cryst~lli7ed 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)-isophth~l~mide [BP-258].
Analysis:
1. TLC: Silica gel 60,F254, 60% n-butanol, 40% SN HOAc. Rf (BP-258 isomer) = 0.39 and 0.27.
2. HPLC: Alltech (C-18 Adsorbosphere, 4.6 X 250 mm, 5~, 2%
acetonitrile, 98%, 0.02 M KH2PO4, pH = 3, 1.0 mL/min, 246 nm detection, 30~C.
Retention times (BP-258) = isomer peaks at 14.33 and 17.10 minutes.
3. 'H NMR (BP-258; DMSOd6): 7.86 and 8.4 ppm (m, lH), 8.5 ppm (m, 2H), 4.5 - 4.9 ppm (m, SH), 3.0 - 3.9 (m, 14H).
6. 5-[N-(2-hydroxyethyl)]formylamido-2,4,6-triiodo-N,N'-bis-(1,3-di hydroxy-prop-2-yl)-isophthalamide [BP-293]
A 2 L flask was charged with 5-amino-2,4,6-triiodo-N,N'-bis-(1,3-dihydroxy-prop-2-yl) isophthalamide (250.0 g, 0.355 moles) and formic acid (341 mL), stirred at 0-10~C while acetic anhydride (233.6 g, 2.29 moles) was added dropwise over 1.6 hours. After stirring at RT for six hours, the solution was reduced and a solid precipitated with butyl acetate (800 mL), filtered and washed with butyl acetate. The solid was vacuum dried, yielding 299.1 g (99.8%) 5-N-formylamido-2,4,6-triiodo-N,N'-bis-(1,3-diformyloxy-prop-2- yl)- isophth~l~mide.This compound was charged into a 2 L flask with methanol (1200 mL), and 30%
methanolic sodium methoxide (89.3 mL). After stirring for 20 minl-tes at 0-10~C,the solution was reduced to half volume and acetic acid (29.8 g, 0.496 moles) was added. A white solid was precipitated with isoplop~lol (500 mL), filtered, washed with isopropanol, and vacuum dried. The product was re-suspended in methanol (1000 mL), heated at 60~C for 30 minutes, cooled to 20~C, filtered, washed with methanol, and vacuum dried to yield 216.4 g (83.4%) of 5-formylamido-2,4,6-triiodo-N,N'-bis-(1,3-dihydroxy-prop-2-yl)- isophth~l~mi~le.
A 2 L flask was charged with trisodium phosphate dodecahydrate (194.8 g, 0.513 moles), propylene glycol (850 mL), and (33.0 g, 0.409 moles) 2-chloro ethanol (33.0 g, 0.409 moles). After stirring at 40-45~C for 1 hour, solid 5-N-formylamido-2,4,6-triiodo-N,N'-bis-(1,3-dihydroxy-2-prop-2-yl)- isophth~l~mide (150 g) was added over 30 minutes. The sl-spencion was stirred for 4 hours at 40-45~C, allowed to cool, filtered, and the salts washed with propylene glycol. Thefiltrate was acidified to pH 1.5-2.0 with 12 M hydrochloric acid to destroy residual ethylene oxide. After neutrali_ation to pH 7 with 30% methanolic sodium methoxide, the solution was concentrated, and a solid precipitated with propyl alcohol, filtered, washed with propyl alcohol, and vacuum dried. After dissolving in water, deioni_ation with resins and boiling with 5% charcoal, the product wascryst~lli7tod 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)-is ophthalamide [BP-293].
Analysis: ,.
1. TLC: Silica gel 60, F2s4, 60% n-butanol, 40% SN HOAc. Rf (BP-293 isomers) = 0.60 and 0.33.
2. HPLC: Alltech Cl8 Adsorbosphere, 4.6 X 250 mm, S,u, 5%
methanol/95% 0.02 M KH2PO4, pH = 3, 1.0 mL/min., 246 nm detection, 30~C.
Retention times (BP-293) = isomer pe~llcs at 9.54 and 10.75 minutes.
3. 'H NMR (BP-293; DMSOd6): 7.85 and 8.4 ppm (m, 14), 8.25 ppm 5 (m, 2H), 4.4 - 5.0 ppm (m, SH), 3.3-4.0 (m, 14H).
7. Physicochemical Properties of Contrast Media Compound % lodine Centipoise @ Cenli~.ois6 @ Centipoise @
~300 mg l/mL ~350 mg l/mL ~370 mg l/mL
@ 37 ~C @ 37 ~C . @ 37 ~C
BP-257 47.20 5.11 (a) 8.48~b) 10.46(m) BP-278 49.00 4.23(c) 6.89(d) 9.9 10 BP-256 51.90 4.84(j) 5.95(k) ~~~
BP-258 49.00 4.82(e) 7.23(f) ~~~
BP-293 49.00 4.72(s~) 7.68(h~
lohexol 46.40 6.10 (i) 10.60 (i) 13.5 (i) lopamidol 49.00 4.50 (i~ ---15 Compound % lodine Osmolality @ Osmolality @ Osmolality @
300 mg l/mL ~350 mç~ I/mL ~370 mçl l/mL
BP-257 47.20 589(a) 790 (b) 880 BP-278 49.00 562(c~ 683(d) 740 BP-256 51.90 386(1~ 423 (k~ ---BP-258 49.00 550 (e~ 744 (fl ---20 BP-293 49.00 527 (~ 629 (h~ ---lohexol 46.40 690 (i) 880 (i) 920 (i) lopamidol 49.00 700 (i~ 800 (i) ---a= 289.6 mg I/mL f= 346.1 mg l/mL k= 349.3 mg l/mL
b= 357.4 mg I/mL ~= 294.6 mçl l/mL l= 300.1 mg l/mL
25 c= 288.5 mg l/mL h= 353.5 m~ l/mL m= 373.1 m~ l/mL
d = 351.1 m~ l/mL i = published value e = 300.0 mg I/mL j - 308.9 m~ l/mL
~300 mg l/mL ~350 mg l/mL ~370 mg l/mL
@ 37 ~C @ 37 ~C . @ 37 ~C
BP-257 47.20 5.11 (a) 8.48~b) 10.46(m) BP-278 49.00 4.23(c) 6.89(d) 9.9 10 BP-256 51.90 4.84(j) 5.95(k) ~~~
BP-258 49.00 4.82(e) 7.23(f) ~~~
BP-293 49.00 4.72(s~) 7.68(h~
lohexol 46.40 6.10 (i) 10.60 (i) 13.5 (i) lopamidol 49.00 4.50 (i~ ---15 Compound % lodine Osmolality @ Osmolality @ Osmolality @
300 mg l/mL ~350 mç~ I/mL ~370 mçl l/mL
BP-257 47.20 589(a) 790 (b) 880 BP-278 49.00 562(c~ 683(d) 740 BP-256 51.90 386(1~ 423 (k~ ---BP-258 49.00 550 (e~ 744 (fl ---20 BP-293 49.00 527 (~ 629 (h~ ---lohexol 46.40 690 (i) 880 (i) 920 (i) lopamidol 49.00 700 (i~ 800 (i) ---a= 289.6 mg I/mL f= 346.1 mg l/mL k= 349.3 mg l/mL
b= 357.4 mg I/mL ~= 294.6 mçl l/mL l= 300.1 mg l/mL
25 c= 288.5 mg l/mL h= 353.5 m~ l/mL m= 373.1 m~ l/mL
d = 351.1 m~ l/mL i = published value e = 300.0 mg I/mL j - 308.9 m~ l/mL
8. Toxicity of Contrast Media in Balb/C Mice Compound LD50 Control (@350 m~ l/ml) BP-257 18 ~ I/k~lohexol: 17 ~ I/k~
BP-278 18-19 ~ I/k~loxilan: 16-17 ~a l/kç
S BP-256 14-15 ~ I/k~lohexol: 16-17 ~ I/kç~
BP-258 17-18 ~ I/k~lohexol: 16-17 g l/k~ f BP-293 16 ~ I/k~lohexol: 15-16 ~ I/k~
BP-258: 16-17 ~ I/k~
BP-278 18-19 ~ I/k~loxilan: 16-17 ~a l/kç
S BP-256 14-15 ~ I/k~lohexol: 16-17 ~ I/kç~
BP-258 17-18 ~ I/k~lohexol: 16-17 g l/k~ f BP-293 16 ~ I/k~lohexol: 15-16 ~ I/k~
BP-258: 16-17 ~ I/k~
9. Renal and Hepatic Effects of BP-257 and BP-258 Iorlin~ted Contrast Media in Rabbits The kidney and liver effects of a single iv bolus injection of BP-257 or BP-258 at 5g Iodine/kg were evaluated in rabbits and compared to those of Iohexol at the same dose. Young female rabbits were injected in the ear vein using 350 mg Iodine/ml drug solutions. Blood samples were collected within 15 minutes prior to drug injections, two hours, 24 hours and six days after tre~tment Serum crç~tinin~, 15 BUN, SGPT/ALT and SGOT/AST levels were estim~ted at these time periods.
The study showed that BP-257 and Iohexol treatments resulted in normal serum creatinine and BUN levels, in-lic~ting that neither of these drug tre~tmçnhave toxic renal effects at any of the e~mined time periods. In addition, they showed that while BP-258 tre~tmçnt has no renal deleterious effects up to 24 hours 20 post-treatment, six days after injections, all ~nim~ls treated with BP-258 had elevated serum creatinine and BUN levels.
The animals liver function tests show no alterations in serum SGPT and SGOT enzymes, indicating that none of the studied drug tre~tment~ causes liver damage.
In accordance with the subject invention, novel compositions are provided which find use as nonionic contrast media. The subject compositions have a high iodine content while having excellent high water solubility and low osmolality to provide excellent properties for general use as non-ionic contrast media.
.. .
w ~ 97~W24~ PCTAUS96/10433 All publications and patent applications cited in this spec-ific~ti~ln are herein incorporated by referen~ as if each indlividual publication or patent application were sl)ecifically and individually indicated to be incorporated by reference.
Although the foregoing invention has been described in some detail by way S of illustration and example for purposes of clarity of underst~n~lin~ it will be readily al)~alc~ilt to those of ordinary skill in the art in light of the tP~-hing~ of this invention that certain changes and mo~lific~tiQnc may be made thereto without departing from the spirit or scope of the appended claims.
The study showed that BP-257 and Iohexol treatments resulted in normal serum creatinine and BUN levels, in-lic~ting that neither of these drug tre~tmçnhave toxic renal effects at any of the e~mined time periods. In addition, they showed that while BP-258 tre~tmçnt has no renal deleterious effects up to 24 hours 20 post-treatment, six days after injections, all ~nim~ls treated with BP-258 had elevated serum creatinine and BUN levels.
The animals liver function tests show no alterations in serum SGPT and SGOT enzymes, indicating that none of the studied drug tre~tment~ causes liver damage.
In accordance with the subject invention, novel compositions are provided which find use as nonionic contrast media. The subject compositions have a high iodine content while having excellent high water solubility and low osmolality to provide excellent properties for general use as non-ionic contrast media.
.. .
w ~ 97~W24~ PCTAUS96/10433 All publications and patent applications cited in this spec-ific~ti~ln are herein incorporated by referen~ as if each indlividual publication or patent application were sl)ecifically and individually indicated to be incorporated by reference.
Although the foregoing invention has been described in some detail by way S of illustration and example for purposes of clarity of underst~n~lin~ it will be readily al)~alc~ilt to those of ordinary skill in the art in light of the tP~-hing~ of this invention that certain changes and mo~lific~tiQnc may be made thereto without departing from the spirit or scope of the appended claims.
Claims (12)
1. A nonionic contrast media N-formyl, N-alkyl or -hydroxyalkyl symmetrically triiodo substituted anilide of from about 12 to 30 carbon atoms, wherein the remaining two sites are substituted with up to 2 carboxamides and up to 1 formamidyl, wherein each carboxamide nitrogen has from 0 to 2 N-alkyl or N-hydroxyalkyl substituents, and each formamidyl nitrogen has 0 to 1 N-alkyl or hydroalkyl groups, said alkyl groups are of from 1 to 3 carbon atoms and said hydroalkyl groups are of from 2 to 4 carbon atoms and 1 to 3 hydroxyl groups, orthe dimer thereof, wherein a nitrogen from each formamide or carboxamide is joined by a bond or linking group.
2. An anilide according to Claim 1, wherein said remaining two sites are substituted with N-hydroxyalkyl annular carbon substituted carboxamides, and said hydroalkyl groups are of from 2 to 3 carbon atoms.
3. A compound of the formula:
wherein:
a is 1 or 2, and b is D when a is one and 1 when a is 2;
R1 is alkyl of from 1 to 4 carbon atoms and 0 to 3 hydroxyl groups, having hydroxyl at other than at the .alpha.-carbon atom;
R2 may be the same or different from R1, being hydrogen or coming within the definition of R1;
R3, when a is 1, is hydrogen or comes within the definition of R1, at least one of R2 and R3 having an hydroxyl group;
when a is 2, either two R3s, R1s or Ws are taken together with Y to form a bridge between the two monomers;
Y is not present when a is 1, and when a is 2, is a bridge comprising a bond or linking group of from 1 to 6 carbon atoms, having from 0 to n-2 oxy groups, where n is the number of carbon atoms of the linking group;
Z is CONWR1, NR1CHO or CONR2R3; and W is hydrogen when a is 1 or, when a is 2, is taken together with Y to form a bridge.
wherein:
a is 1 or 2, and b is D when a is one and 1 when a is 2;
R1 is alkyl of from 1 to 4 carbon atoms and 0 to 3 hydroxyl groups, having hydroxyl at other than at the .alpha.-carbon atom;
R2 may be the same or different from R1, being hydrogen or coming within the definition of R1;
R3, when a is 1, is hydrogen or comes within the definition of R1, at least one of R2 and R3 having an hydroxyl group;
when a is 2, either two R3s, R1s or Ws are taken together with Y to form a bridge between the two monomers;
Y is not present when a is 1, and when a is 2, is a bridge comprising a bond or linking group of from 1 to 6 carbon atoms, having from 0 to n-2 oxy groups, where n is the number of carbon atoms of the linking group;
Z is CONWR1, NR1CHO or CONR2R3; and W is hydrogen when a is 1 or, when a is 2, is taken together with Y to form a bridge.
4. A compound according to Claim 3, wherein a is 1 and R2 is hydrogen or 1,3- or 2,3-dihydroxypropyl, R1 is 1,3- or 2,3-dihydroxypropyl or 2-hydroxyethyl, and R3 is hydrogen.
5. A compound according to Claim 3, wherein a is 1 and R2 is hydrogen or 1,3- or 2,3-dihydroxypropyl, R1 is 1,3- or 2,3-dihydroxypropyl or 2-hydroxyethyl, and R3 is methyl.
6. A compound of the formula:
wherein:
R1 is of 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 is 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 said alkylene group; and Z is CONWR1 or CONHR2;
when not taken together with Y, R3 is hydrogen or methyl or W is hydrogen.
wherein:
R1 is of 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 is 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 said alkylene group; and Z is CONWR1 or CONHR2;
when not taken together with Y, R3 is hydrogen or methyl or W is hydrogen.
7. A compound according to Claim 6, wherein Z is CONHR2, wherein R2 is 1,3- or 2,3-dihyroxypropyl, 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-dihydroxypropyl)isophthalamide; 5-N-(2,3-dihydroxypropyl)formylamido-2,4,6-triiodo-N-(2,3-dihydroxypropyl)-N'-(2-hydroxyethyl)-isophthalamide; 5-N-(2,3-dihydroxypropyl)formylamido-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.
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-dihydroxypropyl)isophthalamide; 5-N-(2,3-dihydroxypropyl)formylamido-2,4,6-triiodo-N-(2,3-dihydroxypropyl)-N'-(2-hydroxyethyl)-isophthalamide; 5-N-(2,3-dihydroxypropyl)formylamido-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 non-ionic contrast media formulation comprising a compound according to Claim 1, in an amount to provide for x-ray contrast when administered to a mammalian host, and a physiologically acceptable carrier.
10. A non-ionic contrast media formulation comprising a compound according to Claim 3, in an amount to provide for x-ray contrast when administered to a mammalian host, and a physiologically acceptable carrier.
11. A non-ionic contrast media formulation comprising a compound according to Claim 6, in an amount to provide for 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 employing a contrast medium to provide contrast, the improvement which comprises:
using a compound according to Claim 1 as said contrast medium.
using a compound according to Claim 1 as said contrast medium.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49113595A | 1995-06-16 | 1995-06-16 | |
| US08/491,135 | 1995-06-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2229664A1 true CA2229664A1 (en) | 1997-01-03 |
Family
ID=23950938
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002229664A Abandoned CA2229664A1 (en) | 1995-06-16 | 1996-06-13 | Formyl derivatives as nonionic contrast media |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0855997A4 (en) |
| JP (1) | JPH11502231A (en) |
| KR (1) | KR19990022943A (en) |
| AU (1) | AU6114396A (en) |
| CA (1) | CA2229664A1 (en) |
| NO (1) | NO975880L (en) |
| WO (1) | WO1997000240A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6072069A (en) * | 1998-11-04 | 2000-06-06 | Biophysica, Inc. | Biodegradable nonionic contrast media |
| US7250153B2 (en) * | 2002-12-12 | 2007-07-31 | Biophysica Research, Inc. | Contrast media formulations having improved biological tolerance |
| NZ581765A (en) * | 2007-07-12 | 2012-03-30 | Ge Healthcare As | Triiodinated compounds used in diagnostic compositions as contrast agents in diagnostic imaging |
| ES2413160T3 (en) | 2007-10-12 | 2013-07-15 | Ge Healthcare As | Contrast agents |
| WO2009047315A1 (en) | 2007-10-12 | 2009-04-16 | Ge Healthcare As | Contrast agents |
| EP2200656B1 (en) | 2007-10-12 | 2012-12-05 | GE Healthcare AS | Contrast agents |
| US20100221192A1 (en) | 2007-10-12 | 2010-09-02 | Duncan George Wynn | Contrast agents |
| JP2012514622A (en) * | 2009-01-09 | 2012-06-28 | ジーイー・ヘルスケア・アクスイェ・セルスカプ | Contrast preparation composition |
| BR112012033776A2 (en) | 2010-07-12 | 2016-11-01 | Ge Healthcare As | composition and method of x-ray examination. |
| EP2655318B1 (en) | 2010-12-21 | 2018-06-20 | GE Healthcare AS | Desalination of a composition comprising a contrast agent |
| CN103998349B (en) | 2011-09-21 | 2020-01-14 | 通用电气医疗集团股份有限公司 | Contrast media packaging |
| US9884808B2 (en) * | 2012-09-27 | 2018-02-06 | Ge Healthcare As | Preparation of an intermediate compound of ioforminol |
| WO2016079330A1 (en) | 2014-11-21 | 2016-05-26 | Technical University Of Denmark | Gel formulations for local drug release |
| BR112018073493A2 (en) | 2016-05-20 | 2019-03-26 | Technical University Of Denmark | palpable marker composition, method and part kit for identifying and / or locating a non-palpable tumor, a more precisely palpable tumor and / or target tissue, and use of a palpable marker composition. |
| US20220339285A1 (en) | 2019-06-12 | 2022-10-27 | Technical University Of Denmark | Dissacharide formulations for controlled drug release |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4021481A (en) * | 1969-06-27 | 1977-05-03 | Nyegaard & Co. A/S | Amido derivatives of 2,4,6-triiodobenzoic acids containing at least one N-hydroxyalkyl and at least two hydroxyl groups |
| DE2909439A1 (en) * | 1979-03-08 | 1980-09-18 | Schering Ag | NEW NON-ionic x-ray contrast agents |
| DE3001292A1 (en) * | 1980-01-11 | 1981-07-16 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | NON-ionic 5-C SUBSTITUTED 2,4,6-TRIJOD ISOPHTHALIC ACID DERIVATIVES |
| US4341756A (en) * | 1980-01-31 | 1982-07-27 | The Regents Of The University Of California | Novel amino-dioxepane intermediates for the synthesis of new non-ionic contrast media |
| IT1256248B (en) * | 1992-12-24 | 1995-11-29 | Bracco Spa | WATER INJECTABLE FORMULATIONS FOR RADIODIAGNOSTICS INCLUDING MIXTURES OF IODURATED AROMATIC COMPOUNDS USEFUL AS X-RAY MATTING AGENTS |
-
1996
- 1996-06-13 WO PCT/US1996/010433 patent/WO1997000240A1/en not_active Application Discontinuation
- 1996-06-13 AU AU61143/96A patent/AU6114396A/en not_active Abandoned
- 1996-06-13 KR KR1019970709413A patent/KR19990022943A/en not_active Application Discontinuation
- 1996-06-13 JP JP9503385A patent/JPH11502231A/en active Pending
- 1996-06-13 CA CA002229664A patent/CA2229664A1/en not_active Abandoned
- 1996-06-13 EP EP96918506A patent/EP0855997A4/en not_active Withdrawn
-
1997
- 1997-12-15 NO NO975880A patent/NO975880L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX9710220A (en) | 1998-10-31 |
| WO1997000240A1 (en) | 1997-01-03 |
| AU6114396A (en) | 1997-01-15 |
| JPH11502231A (en) | 1999-02-23 |
| EP0855997A4 (en) | 1998-10-07 |
| KR19990022943A (en) | 1999-03-25 |
| EP0855997A1 (en) | 1998-08-05 |
| NO975880L (en) | 1998-02-13 |
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