Classifications

• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
• • 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
• • 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
• • 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

Definitions

• the field of this invention is nonionic contrast media.
• X-ray is the most often used diagnostic tool for the examination of various compartments 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 capable of delineating 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 administered.
• the demands on the contrast media employed varies with the nature of the examination. In addition, the media should be substantially homogenous, so as to avoid imaging artifacts and should not be affected by pH or other physiological conditions during their use.
• the nonionic contrast media In order to provide for water solubility, the nonionic contrast media have hydroxyalkyl constituents to enhance the hydrophilicity.
• the water solubility is to a great extent dependent upon the capability of the compounds to form isomeric mixtures in water solutions.
• the isomeric mixtures are dependent upon the endo and exo isomerism of the substituted anilide group.
• the acyl group bonded to the amino group is acetyl, glycolyic acid, or gly ceric acid, since such acyl group is stable and of relatively low molecular weight.
• U.S Patent Nos. of interest include 4,547,357; 4,021,481; 3,701,771; 4,364,921; and 4,341,756.
• Novel nonionic contrast media are provided, which are N-formylated, N- alkylated or -hydroxyalky lated triiodoanilides or bis-compounds, where the remaining 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 variety of applications for X-ray and other non-invasive diagnosis.
• the contrast media are characterized by having at least one N-formyl, N-alkyl or -hydroxyalkyl amino group bonded to a substituted triiodobenzene, either symmetrical or asymmetrical, usually symmetrical, where the remaining 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- dimers, joined by a bond, or more usually an alkylene linking group.
• the monomeric compounds of this invention will have fewer 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 carbon atoms, usually up to twice the number of carbon atoms plus 5, more usually plus 3.
• 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 carbon atom will be disubstituted, i.e.
• 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.
• R 1 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 at other than at the ⁇ -carbon atom, generally having from 1 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;
• R 2 may be the same or different from R 1 , being hydrogen or coming within the definition of R 1 ;
• R 3 when a is 1, is hydrogen or comes within the definition of R 1 , at least one of R 2 and R 3 having an hydroxyl group; when a is 2, either two of R 3 s, 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, 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 1 , NR'CHO or CONR 2 R 3 , preferably CONHR 2 ;
• W is hydrogen when a is 1 or, when a is 2, is taken together with Y to form a bridge.
• Z is CONR 2 R 3
• R 3 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.
• Z is CONWR 1
• 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 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.
• Compounds of particular interest are triiodoisophthalamides, where the nitrogens 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.
• they may be non- identical, preferably, both annular substituted carboxamide nitrogen atoms are identically 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)isophthalamide (BP-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-triiodo-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-(l
• the subject compounds may be prepared in accordance with conventional ways, except that the formylation is performed prior to the alkylation of the anilide nitrogen and the alkylation is carried out under conditions which avoids hydrolysis of the formanilide.
• the groups on the amide nitrogens will be present prior to the final alkylation.
• activated formic acid may be employed, where the formic acid may be present as the mixed anhydride, 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.
• the formic acid will be added in excess, generally in at least about 5 fold molar excess, and may be from 10 to 20 fold molar excess.
• an anhydride e.g. acetic 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.
• hydroxyalkylation is the use of an alkylene oxide or alkylene oxide precursor, e.g. a 1 ,2-halohydroxyalkane.
• 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.
• 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.
• the subject compositions may be formulated in accordance with conventional ways, depending upon the particular application.
• solutions in water are prepared either in advance or ad hoc from a mixture of the subject compound with lactose, citric acid, methylcellulose, and a detergent, particularly a nonionic detergent, such as Tween-80.
• a detergent particularly a nonionic detergent, such as Tween-80.
• For intestinal (rectal) use only methylcellulose (or other polysaccharide) and a detergent are used.
• the detergent will be present from about 0.1 to 1 weight percent of the composition (excluding water).
• the solution concentration of iodine will 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, will be employed.
• 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 for administration will be in the range of about 5 cps to 5000 cps, with the prefened range of about 10 to 1000 cps.
• compositions may be administered by any convenient means, depending upon the particular site or compartment to be investigated.
• Nonionic contrast media as obvious from the relevant art literature, have found extensive use and the prior art compounds may be substituted with the subject compounds accordingly.
• EXPERIMENTAL 5-N-formylamido-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide.
• the filtrate was acidified to pH 1.6 with concentrated hydrochloric acid and stined 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.
• TLC Silica gel 60,F 254 , 60% n-butanol, 40% 5N HOAc.
• R f (BP- 258 isomer) 0.39 and 0.27.
• TLC Silica gel 60, F 254 , 60% n-butanol, 40% 5N HOAc.
• R f (BP- 293 isomers) 0.60 and 0.33.
• Retention times (BP-293) isomer peaks at 9.54 and 10.75 minutes.
• liver function tests show no alterations in serum SGPT and SGOT enzymes, indicating that none of the studied drug treatments causes liver damage.
• novel compositions 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.

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• Veterinary Medicine (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 1996
  • 1996-06-13 WO PCT/US1996/010433 patent/WO1997000240A1/en not_active Application Discontinuation
  • 1996-06-13 JP JP9503385A patent/JPH11502231A/ja active Pending
  • 1996-06-13 AU AU61143/96A patent/AU6114396A/en not_active Abandoned
  • 1996-06-13 EP EP96918506A patent/EP0855997A4/de not_active Withdrawn
  • 1996-06-13 KR KR1019970709413A patent/KR19990022943A/ko not_active Application Discontinuation
  • 1996-06-13 CA CA002229664A patent/CA2229664A1/en not_active Abandoned
• 1997
  • 1997-12-15 NO NO975880A patent/NO975880L/no unknown

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