Classifications

• • 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
  • 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
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/88—Carboxylic acid amides having nitrogen atoms of carboxamide groups bound to an acyclic carbon atom and to a carbon atom of a six-membered aromatic ring wherein at least one ortho-hydrogen atom has been replaced
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring

Definitions

• This invention relates to polyiodinated aroyloxy esters which find particular utility as particulate x-ray contrast agents in medical diagnostic imaging.
• X-ray imaging is a well known and extremely valuable tool for the early detection and diagnosis of various disease states in the human body.
• the use of contrast agents for image enhancement in medical x-ray- imaging procedures is widespread.
• An excellent background on iodinated and other contrast agents for medical imaging is provided by D.P. Swanson et al, Pharmaceuticals in Medi cal Ima ⁇ in ⁇ . 1990, MacMillan Publishing Company.
• U.S. Patent No. 3,097,228 describes derivatives of
• R 1 is H or lower alkyl
• R 2 is H or lower alkanoyl
• R 3 is H or lower alkanoylamino
• R 4 is lower alkyl.
• the agents are useful as x-ray contrast agents for visualizing the gall bladder (cholecystography) when administered orally, in the free acid form or in the form of a non-toxic salt, or intravenously, in the form of water soluble, non- toxic salt.
• Bacon et al commonly assigned U.S. Patent Application Serial No. 07/990,987 filed December 16, 1992 describes iodinated aroyloxy esters which are useful as contrast agents in x-ray imaging compositions and methods.
• all of the compounds described by Bacon et al feature an ester group linked through a C 2 or higher alkylene group to another ester group on an iodinated aromatic ring.
• EP-A 498,482 describes nanoparticulate x-ray contrast compositions which have proven to be extremely useful in medical imaging.
• the compositions comprise particles of an organic x-ray contrast agent and a surface modifier adsorbed on the surface thereof and have an effective average particle size of less than 400 nm.
• the agents can be delivered to a specific tissue or fluid site, e.g., the blood pool, liver, spleen, kidney or lymph nodes.
• EP-A 498,482 describes derivatives of diatrizoate, iothalamate, metrizoic and iodipamide but does not suggest the ⁇ -cycloalkyl, aryl, or aralkyl substituted polyiodinated aroyloxy esters of this invention.
• novel iodinated compounds having the structure I: I.
• n 1, 2, 3 or 4;
• Z-fCOO- n is the residue of a polyiodinated aromatic mono- or polyacid
• R 2 is cycloalkyl or aryl
• R 3 , R 4 and R 5 are independently H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, halogen, hydroxy, acylamino, acetamidoalkyl, cyano, sulfonyl, carboxamido or sulfonamido.
• novel polyiodinated aroyloxy esters are provided which find particular utility in particulate x-ray contrast compositions. It is an advantageous feature of this invention that novel polyiodinated aroyloxy esters are provided which exhibit a consistent crystal morphology.
• Still another advantageous feature of this invention is that novel polyiodinated aroyloxy esters are provided having improved solubility profiles and enzymatic stability.
• Z-CO m is the residue of a polyiodinated aromatic acid
• m can be 1, 2, 3, or 4.
• m is 1 or 2.
• the polyiodinated aromatic acid can contain two, three or more iodine atoms per molecule.
• Preferred species contain at least three iodine atoms per molecule.
• Suitable aromatic acids include diatrizoic acid, metrizoic acid, urokonic acid,
• Z-fCO -hm is the residue of a substituted triiodobenzoic acid such as an acyl, carbamyl, and/or acylamino substituted triiodobenzoic acid.
• R 2 is cycloalkyl, preferably containing from 3 to
• aryl preferably containing from 6 to 14 carbon atoms such as phenyl, naphthyl, anthracenyl and the like.
• R 5 is H, alkyl, fluoroalkyl, acetamidoalkyl, cyano, sulfonyl, carboxamido or sulfonamido. The reason for this is that when R 5 is halogen, hydroxy, or acylamino, the compounds tend to be more reactive and less useful as particulate x- ray contrast agent.
• R 6 and R 7 are independently a substituent as defined for R 3 above, or R 6 and R 7 , taken together with the nitrogen atom to which they are attached, represent a 4-7 membered saturated or unsaturated nitrogen containing ring such as piperidyl, piperizinyl, pyrrolidinyl, and the like.
• the following are specific illustrative examples of compounds of this invention that have been prepared:
• the compounds of this invention can be prepared by contacting the carboxylate of a 5-substituted-amino-2,4, 6- triiodoisophthalic acid with a functionalized ester having the formula
• X is a leaving group and n and R 1 -R 5 are as defined above, in a suitable solvent.
• Suitable leaving groups include halogen, such as Br, I and Cl, and sulfonyloxy, such as methanesulfonyloxy and toluenesulfonyloxy.
• the carboxylates of iodinated aromatic acids and functionalized esters useful as the starting materials in the preparation of the compounds of this invention are known compounds and/or can be prepared by techniques known in the art.
• suitable esters include commercially available bromoester and chloroester derivatives as exemplified below.
• the requisite bromoesters can be prepared by the process described in J. Am. Chem. Soc. ,7_0_/ 3626 (1948) .
• a summary of this preparation of suitable bromoesters is as follows:
• the reaction can take place at various temperatures ranging between -78°C and 100°C, and preferably between -40°C and 50°C. For convenience, the reaction can take place at ambient pressure, however, higher and lower pressures are contemplated.
• the reaction can take place in any suitable solvent.
• suitable solvents include N,N-dimethylformamide (DMF) and dimethylsulfoxide (DMSO) .
• the iodinated compounds can contain substituents which do not deleteriously affect the contrast enhancing capability of the compound.
• the alkyl, cycloalkyl, aryl, aralkyl and alkoxy groups in structure I above can be unsubstituted or substituted with various substituents which do not adversely affect the stability or efficacy of -the compounds as x-ray contrast agents such as alkyl, cycloalkyl, aryl, aralkyl, alkoxy, hydroxy, acyloxy, halogen, such as chlorine, bromine and iodine, acylamino, carboalkoxy, carbamyl and the like.
• the compound of this invention When used as an x-ray contrast agent, the compound of this invention preferably comprises at least about 35%, more preferably at least 40% iodine by weight.
• the compounds of this invention can be formulated into particulate x-ray contrast compositions, preferably nanoparticulate x-ray contrast compositions, as described in commonly-owned EP-A 498,482. Preferred compounds exhibit a melting point of greater than 150°C.
• Such nanoparticulate compositions can be prepared by dispersing the compounds of the invention in a liquid dispersion medium, and wet grinding the compound in the presence of rigid grinding media and a surface modifier to form the nanoparticles. Alternatively, the surface modifier can be contacted with the compound after attrition.
• Preferred surface modifiers include nonionic surfactants.
• the surface modifier is a high molecular weight nonionic surfactant.
• Such surfactants include poloxamers such as Pluronic_ F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, poloxamines, such as Tetronic_ 908 (also known as Poloxamine 908) , which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, and dialkyl esters of sodium sulfosuccinic acid, such as dioctylsulfosuccinate sodium (DOSS) .
• the concentrations of the surface modifier can vary from about 0.1-75%, preferably 1-60%, and more preferably 10-30% by weight based on the total combined weight of the contrast agent and surface modifier.
• the x-ray contrast composition in the form of surface modified nanoparticles can contain a cloud point modifier to further enhance stability during steam heat autoclaving, i.e., the cloud point modifier can reduce particle aggregation during heat sterilization.
• Preferred cloud point modifiers include nonionic cloud point modifiers, such as polyethylene glycols such as PEG 400, propylene glycol, ethanol, hydroxypropylcyclodextrin and glycerol; ionic cloud point modifiers, such as those described in U.S. Patent No.
• 5,298,262 including dialkylesters of sodium sulfosuccinic acid such as the dioctylester of sodium sulfosuccinic acid (DOSS); and charged phospholipids, such as diacylphosphatidyl glycerol and dimyristoylphosphatidyl glycerol.
• the cloud point modifier can be present in an amount of 0.005-50%, preferably 0.01-30% and more preferably 0.05-20% by weight based on the total weight of the x-ray contrast composition.
• the x-ray contrast compositions of this invention comprise the above-described compounds, preferably in the form of particles, and a physiologically acceptable carrier therefor.
• the particles can be dispersed in an aqueous liquid which serves as the carrier for the x-ray contrast agent.
• suitable carriers include liquid carriers such as mixed aqueous and nonaqueous solvents, such as alcohol; gels; gases, such as air; and powders.
• the x-ray contrast composition can comprise from about 1-99.9, preferably 2-45 and more preferably 10-25% by weight of the above-described particles, the remainder of the composition being the carrier, additives and the like. Compositions up to about 100% by weight of the particles are contemplated when the composition is in a lyophilized form.
• the dose of the contrast agent to be administered can be selected according to techniques known to those skilled in the art such that a sufficient contrast enhancing effect is obtained. Typical doses can range from 20 to 350 mg of iodine per kilogram of body weight of the subject for many imaging applications. For some applications, e.g., lymphography, lower doses, e.g., 0.5-20 mg I/kg, can be effective. For blood pool imaging, the dose can range from 50 to 350 mg of iodine per kilogram of body weight and preferably from 100 to 250 mg of iodine per kilogram of body weight.
• the x-ray contrast composition can contain one or more conventional additives used to control and/or enhance the properties of the x-ray contrast agent.
• thickening agents such as dextran or human serum albumin, buffers, viscosity regulating agents, suspending agents, peptizing agents, anti-clotting agents, mixing agents, and other drugs and the like can be added.
• a partial listing of certain specific additives includes gums, sugars such as dextran, human serum albumin, gelatin, sodium alginate, agar, dextrin, pectin and sodium carboxymethyl cellulose.
• Such additives, surface active agents, preservatives and the like can be incorporated into the compositions of the invention.
• a method for diagnostic imaging for use in medical procedures in accordance with this invention comprises administering to the body of a test subject in need of an x- ray an effective contrast producing amount of the above- described x-ray contrast composition.
• the test subject can include mammalian species such as rabbits, dogs, cats, monkeys, sheep, pigs, horses, bovine animals and the like.
• the body containing the administered contrast agent is exposed to x-rays to produce an x-ray image pattern corresponding to the presence of the contrast agen .
• the image pattern can then be visualized.
• any x- ray visualization technique preferably, a high contrast technique such as computed tomography, can be applied in a convention manner.
• the image pattern can be observed directly on an x-ray sensitive phosphor screen- silver halide photographic film combination.
• compositions of this invention can be administered by a variety of routes depending on the type of procedure and the anatomical orientation of this tissue being examined. Suitable administration routes include intravascular (arterial or venous) administration by catheter, intravenous injection, rectal administration, subcutaneous administration, intramuscular administration, intralesional administration, intrathecal administration, intracisternal administration, oral administration, administration via inhalation, administration directly into a body cavity, e.g., arthrography, and the like.
• intravascular arterial or venous
• rectal administration subcutaneous administration
• intramuscular administration intralesional administration
• intrathecal administration intracisternal administration
• oral administration administration via inhalation
• administration directly into a body cavity e.g., arthrography, and the like.
• the x-ray contrast compositions of this invention are also expected to be useful as contrast agents for any organ or body cavity.
• the compositions of this invention are expected to be useful as angiographic contrast media, urographic contra ⁇ t media, myelographic contrast media, gastrointestinal contrast media, cholecystographic and cholangiographic contrast media, arthrographic contrast media, hysterosalpingographic contrast media, oral contrast media and bronchographic contrast media.
• Example 2 Preparation of (l-Ethoxv-l-oxo-2- cvclohexylethan-2-yl) -3.5-bis (acetylamino) -2.4.6- triiodobenzoate
• analytically pure compound was obtained in 72% yield, mp 267-268°C.
• MS and iH-NMROOO MHz) spectral data were consistent with the desired product. Calculated for C 21 H 25 I 3 2 O 6 : C 32.25, H 3.22, I 48.67, N 3.58; Found : C 32 . 49 , H 3 . 09 , I 48 . 35 , N 3 . 57 .
• Example 8 Preparation of Bis (l-ethoxy-l-oxo-2- cvclopentylethan-2-yl)-5-acetylamino-2.4.6- triiodoisophthalate
• analytically pure compound was prepared, mp 198-200°C.
• MS and ⁇ -NMRPOO MHz) spectral data were consistent with the desired product.
• Such acids and salts thereof are useful as wetting agents and/or as surface modifiers in x-ray contrast compositions, particularly in nanoparticulate x-ray contrast compositions.

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• 1995
  • 1995-06-09 JP JP8503207A patent/JPH10502084A/ja active Pending
  • 1995-06-09 EP EP95922300A patent/EP0767779A1/de not_active Withdrawn
  • 1995-06-09 CA CA002191984A patent/CA2191984A1/en not_active Abandoned
  • 1995-06-09 WO PCT/US1995/007421 patent/WO1996000211A1/en not_active Application Discontinuation
  • 1995-06-09 AU AU27035/95A patent/AU2703595A/en not_active Abandoned
  • 1995-06-23 IL IL11430695A patent/IL114306A0/xx unknown
• 1996
  • 1996-12-11 NO NO965302A patent/NO965302D0/no unknown
  • 1996-12-18 FI FI965096A patent/FI965096A/fi not_active Application Discontinuation

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