Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/24—Oxygen or sulfur atoms
  • C07D207/26—2-Pyrrolidones
  • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
• • 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
  • 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

Definitions

• This invention relates to novel X-ray contrast agents, methods of preparing them, radiological
• compositions containing such agents and methods for X- ray visualization utilizing such compositions.
• Nonionic contrast agents for intravascular and central nervous system visualization are complex
• the iodine in the molecule provides opacification to the X-rays, while the remainder of the molecule provides the framework for transport of the iodine atoms.
• the structural arrangement of the molecule is important in providing stability,
• nonionic contrast agents are particularly desirable compared to contemporary ionic agents due to the minimization of those pharmacological effects associated with colligative properties, e.g., osmolality.
• contrast agents are often incompatible so that all such agents represent compromises.
• the controlling factors are pharmacological inertness, i.e., in vivo safety, and high water
• the ideal intravascular or central nervous system nonionic agent represents a compromise in an attempt to obtain the following criteria: (1) maximum opacification to X-rays; (2) pharmacological inertness; (3) high water solubility; (4) stability; (5) selective excretion; (6) low viscosity; and (7) minimal osmotic effects.
• Illustrative nonionic contrast agents include N,N'- bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl) glycolamido- 2 ,4,6-triiodoisophthalamide (Lin, U.S. Patent No.
• contrast agents with improved pharmacological inertness, i.e., low toxicity, by means of the incorporation of highly hydrophilic side chains. It is a still further object of this invention to provide chemically stable nonionic X-ray contrast agents having low osmolality.
• the present invention is directed to
• R 1 is N(CH 2 CH 2 OH) CH 2 CHOHCH 2 OH
• R 2 equals R 1 , NH 2 , NHCH 3 , NHCH 2 CH 2 OH, N(CH 3 )CH 2 CH 2 OH or NHCH 2 CHOHCH 2 OH
• R 3 equals CH 3 , CH 2 CH 3 , CH 2 OH, CH(CH 3 )OH, CH(CH 3 )OCH 3 , CHOHCH 2 OH,
• R equals H, CH 3 , CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CHOHCH 2 OH, or CH 2 CHOHCH 2 OCH 3 ; or R 3 , R 4 , and the 5-N together form the group
• n 0 or 1.
• the present invention is also directed to dimers of the above compound connected at the 5-N position by means of a diamide, thus:
• R 1 and R 2 have the meanings given above;
• R 5 is H, CH 3 , CH 2 CH 2 OH, CH 2 CHOHCH 2 OH, and CH 2 OCH 3 ; and
• m equals 0-4, preferably 0-2.
• the present invention is further directed to methods for making such compounds by incorporation of an amino- alcohol, 3-(N-2-hydroxyethyl)amino-1,2-propanediol, and methods of making this amino-alcohol.
• the invention is also directed to radiological compositions containing such compounds and methods for utilizing such compounds in X-ray visualization.
• 3-(N-2- Hydroxyethyl)amino-1,2-propanediol as in the case of other amino-polyhydroxyl groups, such as 3-amino-1,2- propanediol used for N,N'-bis(2,3-dihydroxypropyl)-5-N- (2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide and 5-N-(2,3-dihydroxypropyl)acetamido-2,4, 6-triiodo- N,N'-bis(2,3-dihydroxypropyl)isophthalamide and 2-amino- 1,3-propanediol used for N,N'-bis(1,3-dihydroxypropyl)L- 5- ⁇ -hydroxypropionylamino-2,4,6-triiodoisophthalamide, provides good water solubility and in viv
• an advantage of using 3-(N- 2-hydroxyethyl)amino-1,2-propanediol is to provide even higher hydrophilicity for the contrast molecule due to the introduction of an additional hydroxyl group.
• This highly hydrophilic amino-triol can confer water- solubility and improve the safety of X-ray contrast media.
• the compounds may be used as nonionic X-ray contrast agents. These agents may be used in various radiographic procedures including those involving
• Each of the compounds of the present invention has at least one amide group derived from the amino- alcohol, 3-(N-2-hydroxyethyl)amino-1,2-propanediol.
• This starting material may be prepared by reacting glycidol with ethanolamine under epoxide-opening conditions or by reacting 3-chloro-1,2-propanediol with ethanolamine under secondary amine-forming conditions and neutralizing the hydrochloride salt thus formed.
• U.S. Patent No. 4,396,597 teaches that compounds with a 5-[N- ( ⁇ -hydroxyalkyl)acetylamino] group are unstable and undergo a base catalyzed cyclization and iodine
• the present invention also includes dimeric compounds. Hyperosmolality is known to cause vascular pain during the injection of an X-ray contrast agent. Furthermore, high osmolality has been shown to be an important factor in perturbation of the normal heart functions at the time of cardioangiography.
• the main advantage of the dimers of the present invention is the low osmolality with concomitant low toxicity.
• dimeric compounds having six iodine atoms per molecule.as provided by the present invention. At a fixed iodine concentration, these compounds exhibit significantly, lower osmotic effects than equivalent monomeric agents due to reduced number of solvated particles in the solution.
• the dimeric compounds of the present invention provide this advantage while maintaining acceptable solubility characteristics due to the high hydrophilicity of the amine-alcohol side chains.
• radiological compositions may be prepared containing one of the aforementioned compounds of the invention as an X-ray contrast agent together with a pharmaceutically acceptable radiological vehicle.
• pharmaceutically acceptable radiological vehicles include those that are suitable for injection such as aqueous buffer solutions; e.g.,
• the vehicles may contain a chelating amount, e.g., a small amount, of ethylenediamine tetraacetic acid, the calcium disodium salt, or other
• concentration of the X-ray contrast agents of the invention in the pharmaceutically acceptable vehicle varies with the particular field of use. A sufficient amount is present to provide satisfactory X-ray visualization.
• the concentration of iodine is generally 140-440 mg/ml and the dose is 25-300 ml.
• the radiological compositions of the invention may be used in the usual way in X-ray procedures. For example, in the case of selective coronary arteriography, a sufficient amount of the radiological composition to provide adequate visualization is injected into the coronary system and then the system is scanned with a suitable device such as a fluoroscope.
• R 1 and R 2 are the same are N,N'-bis[(2,3- dihydroxypropyl)-2-hydroxyethyl]-5-acetamido-2,4,6- triiodoisophthalamide; N,N'-bis[(2,3-dihydroxypropyl)-2- hydroxyethyl]-5-hydroxyacetamido-2,4,6-triiodo- isophthalamide; N,N'-bis[(2,3-dihydroxypropyl)-2- hydroxyethyl]-5-(2-hydroxy)propionamido-2,4,6-triiodo- isophthalamide; N,N'-bis[(2,3-dihydroxypropyl)-2- hydroxyethyl]-5-methoxyacetamido-2,4,6-triiodo- isophthalamide; N,N'-bis[(2,3-dihydroxypropyl)-2- hydroxyethyl]-5-[N-[N-bis[(2,3-
• 5- amino-2,4,6-triiodoisophthaloyl chloride which may be made from 5-amino-2,4, 6-triiodoisophthalic acid, which is disclosed in U.S. Patent No. 4,396,598, incorporated herein by reference.
• the 5-amino group may first be substituted under amide-forming conditions to form the desired amide and the resulting compound reacted with 3-(N-2-hydroxyethyl)amino-1,2-propanediol under amide-forming conditions to add the desired amide to the 1 and 3 carbonyl groups.
• Examples of the compounds that may be used to react with the 5-amine are acetyl
• acetoxy groups may later be hydrolyzed to produce a hydroxy group by various means, including acid hydrolysis or ion-exchange resins.
• Secondary substitution of the 5-amido group is generally preferred to follow addition of the amino-alcohol.
• Examples of compounds which may be used to react with the 5-amido group under basic, alkylating conditions are alkyl halides, for example, methyl halides, such as methyl iodide; 2-haloethylacetates, such as 2-bromoethylacetate; 2-haloethanols, such as 2-chloroethanol; and 2-haloethyl methyl ethers, such as 2-bromoethyl methyl ether.
• the substitution of the 5-amino group to form the cyclic butyrolactamide is also generally preferred to follow addition of the amino-alcohol.
• Substitution of the amine may be accomplished by the addition, under amide-producing conditions, of various butyryl acid halides, such as 4-chlorobutyryl chloride, 2-acetoxy-4- (methylthio) butyryl chloride, or 2,4-dibromobutyryl bromide. Use of the latter two will result in a hydroxy- substituted lactamide following hydrolysis. Cyclization of the butyramide chain is caused by exposure to
• the cyclization may be accomplished by using alkaline alcohol mixtures, such as methanol and aqueous sodium hydroxide mixtures.
• alkaline alcohol mixtures such as methanol and aqueous sodium hydroxide mixtures.
• 2-acetoxy-4- (methylthio) butyryl chloride the methyl iodide of the butyramide is preferably formed first, followed by treatment with alkaline alcohol.
• the butyryl group Prior to addition of the butyryl group it is preferred to protect the hydroxyl groups of the amides, preferably by means of acetate groups. This may be simply done by any acetate addition method under suitable protecting conditions, such as by using acetic anhydride under ester-forming conditions, such as in the presence of a base, for example, pyridine.
• These protecting acetate groups and the one from 2-acetoxy-4- (methylthio)butyryl chloride, if used, can then be removed by hydrolysis utilizing various conditions such as using an aqueous sodium hydroxide
• R 2 does not equal R 1
• R 2 substitution is preferably made first, followed by a substitution at the 5-amino group.
• the intermediate compound 5-amino- 2,4,6-triiodo-3-N-methylaminocarbonylbenzoic acid
• the intermediate compounds may be prepared from 5-nitroisophthalic acid monomethyl ester via well- established synthetic routes. See, for example, U.S. Patent No. 3,290,366, incorporated herein by reference, and European Application 0 308 364.
• R 2 does not equal R 1
• examples of such compounds, wherein R 2 does not equal R 1 are [N-(2,3-dihydroxypropyl)-N-(2- hydroxyethyl)]-DL-5- ⁇ -hydroxypropionylamino-2,4,6- triiodo-3-N-methylaminocarbonylbenzamide, [N-(2,3- dihydroxypropyl)-N-(2-hydroxyethyl)]-5-hydroxyacetyl- amino-2,4,6-triiodo-3-N-methylaminocarbonylbenzamide, [N- (2,3-dihydroxypropyl)-N-(2-hydroxyethyl)]-DL-5- ⁇ - hydroxypropionylamino-2,4,6-triiodo-3-N-(2- hydroxyethyl)aminocarbonylbenzamide, [N-(2,3- dihydroxypropyl)-N-(2-hydroxyethyl)]-3-N-(2- hydroxyethy
• R 2 equals R 1 are N,N'-bis[3,5- bis (N-2,3-dihydroxypropyl-N-2-hydroxyethylaminocarbonyl)- 2,4,6-triiodophenyl]malondiamide; N,N'-bis[3,5-bis(N-2,3- dihydroxypropyl-N-2-hydroxyethylaminocarbonyl)-2,4,6- triiodophenyl]oxamide; and N,N'-bis[3,5-bis(N-2,3- dihydroxypropyl-N-2-hydroxyethylaminocarbonyl)-2,4,6- triiodophenyl]succinamide.
• These compounds may be prepared by first forming a dimer by reacting two moles of 5-amino-2,4,6-triiodoisophthaloyl chloride under amide-forming conditions with one mole of a diacid chloride such as oxalyl chloride, malonyl chloride, or succinyl chloride. 3-(N-2-Hydroxyethyl)amino-1,2- propanediol is then reacted with the intermediate dimer to form the compounds of the present invention.
• a diacid chloride such as oxalyl chloride, malonyl chloride, or succinyl chloride.
• Examples of dimeric compounds of the present invention wherein R 2 does not equal R 1 are N,N'-bis[3-(N- 2-hydroxyethylaminocarbonyl)-5-(N-2,3-dihydroxypropyl-N- 2-hydroxyethylaminocarbonyl)-2,4,6-triiodophenyl]- malondiamide; N,N'-bis[3-(N-2-hydroxyethylaminocarbonyl)- 5-(N-2,3-dihydroxypropyl-N-2-hydroxyethylaminocarbonyl)- 2,4,6-triiodophenyl]-oxamide; N,N'-bis[3-(N-2- hydroxyethylaminocarbonyl)-5-(N-2,3-dihydroxypropyl-N-2- hydroxyethylaminocarbonyl)-2,4,6-triiodophenyl]- succinamide; N,N'-bis[3-(N-2,3-
• These compounds are prepared by first making the desired R 2 substitution and then forming the dimer by reaction with the desired diacid chloride, such as oxalyl chloride, malonyl chloride, or succinyl chloride. The amino-alcohol is then added under amide-forming
• alkyl halides for example, methyl halides, such as methyl iodide; 2-haloethylacetates, such as 2-bromoethylacetate; 2-haloethanols, such as 2-chloroethanol; and 2-haloethyl methyl ethers, such as 2-bromoethyl methyl ether.
• the reactions necessary to produce the compounds of the present invention may be carried out at any convenient temperature and pressure, such as at atmospheric pressure and ambient temperatures. It is preferred that amidation and alkylation reactions be performed at such ambient temperatures. It is preferred that hydrolysis steps be carried out at elevated temperatures
• temperatures to achieve a sufficient rate of hydrolysis such as at temperatures between 90 and 100 °C.
• Purification of the compounds of the present invention is desired for their use as X-ray contrast agents. Purification may be by standard isolation methods, such as crystallization, or by preparative HPLC, such as by reverse-phase HPLC, or combinations of these.
• N-(2,3-Dihydroxypropyl)-N-(2-hydroxyethyl)-3-N-(2 , 3- dihydroxypropylaminocarbonyl)-5-(acetoxyacetylamino)- 2,4,6-triiodobenzamide To 3-N-(2,3-dihydroxypropyl- aminocarbonyl)-5-acetoxyacetylamino-2,4,6-triiodobenzoyl chloride (60 g, 0.0817 moles) was added DMAc (150mL) and the mixture stirred until dissolution was complete.
• N-(2,3-Dihydroxypropyl)-N-(2-hydroxyethyl)-3-N-(2 ,3- dihydroxypropylaminocarbonyl)-5-(hydroxyacetylamino)- 2,4,6-triiodobenzamide N-(2,3-Dihydroxypropyl)-N-(2- hydroxyethyl)-3-N(2,3dihydroxypropylaminocarbonyl)-5- (acetoxyacetylamino)-2,4,6-triiodobenzamide was added deionized water (200mL) and the mixture was stirred until all the oil dissolved.
• the pH was adjusted to pH ⁇ 1 by the addition of concentrated H 2 SO 4 (9.8g, 0.1005 moles) (initial pH 8.54; final pH 0.945).
• the reaction mixture was steam distilled and the distillate collected while maintaining the original volume of the reaction mixture by periodic addition of additional deionized water.
• the progress of the reaction was monitored by HPLC [employing a C18 reverse phase 10 ⁇ m silica gel column employing a mobile phase of water-acetonitrile (70:30 v/v) at a flow rate of 2 mL/min, and detection at 254 nm]. After 6 hours of steam distillation, HPLC analysis indicated an 84.5 area % for the desired product.
• the product was further purified by repeating the above preparative chromatography procedure.
• the above purified sample 41 g was dissolved in deionized water (50 mL) and injected onto the above M-70 reverse phase HPLC column which had been preequilibrated with deionized water.
• the column was eluted with deionized water at a flow of 150 mL/min.
• Fractions containing the purified product were combined and concentrated under reduced pressure to a volume of ⁇ 250mL. This solution was stirred for 1 hour with 1.2g of activated charcoal and then filtered through a Millipore 0.22 ⁇ m membrane filter. The filtered solution was completely
• A. 5-Amino-3-(N-2-acetoxyethyl-N-methylaminocarbonyl)- 2,4,6-triiodobenzoic Acid To a stirred solution of 5- amino-3-(N-2-acetoxyethyl-N-methylaminocarbonyl)-2,4,6- triiodobenzoic acid (203g, 0.33 g-mole) in DMAc (385 ml) containing 4-dimethylaminopyridine (8.1g, 0.066 g-mole) is added acetic anhydride (135g, 1.32 g-mole) at 25-35°C. Stirring is continued at room temperature for 16 hours to complete the reaction.
• the solution is then evaporated under vacuum to distill off 350 ml of the solvent to provide a thin oil.
• the oil is dissolved in 150 ml of DMAc and the solution is added slowly into 2L of water with stirring to precipitate yellow solid.
• the resulting slurry is acidified with 150 ml of 6N HCl to pH 1.
• the solid is collected, reslurried in 500 ml of water, treated with NaHSO 3 (20g), collected, washed three times each with 50 ml of water and dried to obtain 180g of the desired product (83% yield).
• Step B 5-Amino-3-(N-2-acetoxyethyl-N-methylaminocarbonyl)- 2,4,6-triiodobenzoyl Chloride.
• the product of Step A 49g, 0.075 g-mole
• thionyl chloride 89g, 0.75 g- mole
• the excess thionyl chloride is evaporated to give a thick oil.
• a mixture of THF (150 ml) and EtOAc (50 ml) is added to dissolve the oil and the resulting solution is washed twice with 10% NaCl (200 and 100 ml).
• Step C 5-Acetoxyacetylamino-3-(N-2-acetoxyethyl-N- methylaminocarbonyl)-N-2,3-dihydroxypropyl-N-2- hydroxyethyl-2,4,6-triiodobenzemide.
• the product of Step C (14.9g, 0.02 g-mole) is dissolved in dioxane (40 ml) and a solution of DMAc (14.5 ml) containing 6g (0.044 g- mole) of 3-(N-2-hydroxyethyl)amino-1,2-propanediol is added. The solution is stirred at room temperature overnight to complete the reaction. The solvent is then evaporated to provide the crude desired product. The material is used directly in the following reaction without further purification.
• the solution is passed through ion-exchange resins (50 ml of IRA-68, 40 ml of IRA-458 and 50 ml of IR-120 H) and the resins washed four times with 50 ml of a 1:1 mixture of methanol-water.
• the solutions are combined and evaporated to provide a yellow glassy solid (13.7g, 80% pure by HPLC).
• the crude product is then purified by reverse-phase preparative HPLC to provide the purified desired product.
• 5-Amino-2,4,6-triiodoisophthalic acid (234.5 g, 0.42 g- mole) is slurried in 200 ml of ethylacetate at 50°C.
• A. 5-Acetamido-2,4,6-triiodoisophthaloyl chloride 5- Amino-2,4,6-triiodoisophthaloyl chloride (190 g,0.32 g- mole) prepared as in Example 1 is dissolved in 475 ml of N,N-dimethylacetamide (DMAc) (dried over molecular sieves), and the solution is stirred and cooled to 0-3°C. Acetyl chloride (75.1 g, 68 ml, 0.96 g-mole) is added dropwise over a period of 100 minutes, keeping the temperature between 0°C and 3°C. The ice bath is removed and the solution is stirred overnight at room temperature (20-25°C).
• DMAc N,N-dimethylacetamide
• the white solid is filtered, washed with cold water and dried, giving 69 g (99% yield) of the desired product.
• the product shows one spot by TLC analysis (EtOAc/CH 2 Cl 2 ; 30/20).
• the 13 C nmr data are consistent with the
• the solution is then concentrated and the crude product is purified by preparative liquid chromatography to provide the purified desired product (51 g; 0.06 g- mole, 70% yield).
• the 13 C nmr spectra are consistent with the structure.
• the HPLC purity is 99.1% (C 18 , H 2 O/MeOH; 95/5).
• the water solubility (w/v) is 100%; the iv LD 50 in mice is 5 g I/kg (based on iodine content) .
• Osmolality 676 mOsm/kg (32% I); viscosity: 8.2 cps (37°), 10.0 cps (25°) (32% I).
• This compound is prepared in the same manner as described in Example 3 starting from 5-amino-2,4,6- triiodoisophthaloyl chloride and ( ⁇ )-2-acetoxypropionyl chloride.
• the D- and L- individual optical isomer of the title compound is prepared in the same manner as described in Example 4 from 5-amino-2,4,6-triiodoisophthaloyl chloride and the D- and L- optical isomer of 2-acetoxypropionyl chloride.
• the white solid is filtered, washed with cold water and dried to provide the desired product.
• Methoxyacetamido-2,4,6-triiodoisophthaloyl chloride (56.7 g, 0.085 g-mole) and anhydrous Na 2 CO 3 (18 g, 0.17 g-mole) are mixed in DMAc (70 ml).
• DMAc a solution of DMAc (57 ml) containing 3-(N-2-hydroxyethyl) amino-l, 2-propanediol (34.5 g, 0.255 g-mole) is added.
• the mixture is allowed to stir at 35-40°C until the reaction is complete.
• the mixture is then filtered to remove the inorganic salts and the filtrate containing the desired product is evaporated to give a gum.
• the material is triturated with isopropyl alcohol to dissolve the excess amino- alcohol.
• the clear supernatant is decanted and the residual solid is evaporated to dryness to give the crude product.
• the crude product is dissolved in water and purified by reverse-phase preparative HPLC to provide the purified product.
• the mixture is stirred at 35-40°C until the reaction is complete (approximately 8-12 hours).
• the solution is then cooled to room temperature and the inorganic salts are filtered.
• the filtrate is then evaporated under vacuum at 70°C to yield a thick, oil.
• the oil is
• Step C (85.1 g, 0.1 g-mole) is dissolved in 200 ml of water and 110 ml of 1N NaOH (0.11 g-mole) is added. The solution is stirred at room temperature for 1 hour and evaporated to dryness under vacuum. The residue is then dissolved in 100 ml of DMAc and the solution is warmed to 35oC.
• Methyl iodide (17 g, 0.12 g-mole) is added dropwise and the solution is stirred at 35°C for 12- 16 hours until the reaction is complete as monitored by HPLC.
• the solution is evaporated and the residue is dissolved in water.
• the solution is then treated with a cationic ion-exchange resin, e.g., Amberlite® IR-120H (Rohm & Haas Co.) to remove the salts.
• the solution is evaporated and the material is purified by reverse-phase HPLC to yield the purified desired material.
• This compound is prepared from 5-acetamido-N, N' -bis[2,3- dihydroxypropyl)-2-hydroxyethyl]-2,4,6- triiodoisophthalamide in the same manner as described in Example 10.
• 5-Amino- 2,4, 6-triiodoisophthaloyl chloride prepared as in Example 1 (59.6 g, 0.1 g-mole), and anhydrous Na 2 CO 3 (31.8 g, 0.3 g-mole) are mixed in DMAc (200 ml).
• a solution of DMAc (100 ml) containing 3-(N-2-hydroxyethyl)amino-1,2- propanediol (40.5 g, 0.3 g-mole) is added slowly and the mixture is allowed to stir at 35-40°C overnight.
• the mixture is then filtered to remove the inorganic salts.
• the filtrate is evaporated under vacuum and the gummy residue is triturated with isopropyl alcohol to effect the precipitation of the product.
• the solid is collected and dried to provide 5-amino-N,N'-bis[(2,3-dihydroxy- propyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide.
• This compound (79 g, 0.1 g-mole) is slurried in pyridine, and acetic anhydride (71.4 g, 0.7 g-mole) is added dropwise with stirring and cooling so that the reaction temperature is maintained at ⁇ 30°C. After the addition, the mixture is allowed to stir at room temperature overnight to complete the reaction.
• the reaction solution is diluted with EtOAc (350 ml); ice water (350 ml) is added and the mixture is stirred for 30 minutes. A mixture of cold water (350 ml) and cone. HCl (70 ml) is added and the mixture is stirred for 30 minutes.
• butyrolactone The system is connected to a gas trap through the condenser.
• the reaction mixture is cooled with an ice bath.
• Bromine (188.4 mL, 584 g) is added over 35 minutes.
• the reaction mixture reaches a maximum temperature of 54°C.
• the reaction mixture is warmed to 70°C with a steam bath.
• the remaining bromine (188.4 mL, 584 g) is added while the reaction is cooled with an ice bath to keep its temperature between 70-80°C.
• the reaction mixture is heated with a steam bath to 80°C for 3 hours.
• the steam bath is turned off and nitrogen is bubbled through the reaction mixture for 3.5 hours to drive out hydrogen bromide and excess bromine. A slow stream of nitrogen is bubbled through the reaction mixture over night.
• reaction mixture is filtered through glass wool to remove the gummy residue. It is distilled at 155-170°C under vacuum (1.5 to 0.7 mm) to give 958.17 g (89% yield) of light yellow 2,4- dibromobutyryl bromide. Its NMR spectrum is consistent with its structure.
• 2,4-Dibromobutyryl bromide (92 g, 0.3 g-mole) is placed into a flask equipped with a mechanical stirrer, a
• Step A The compound prepared in Step A (78.5 g, 0.075 g-mole) in DMAc (200 ml) is added while the reaction mixture is cooled to room temperature with an ice bath. The mixture is stirred at room temperature
• distilled ethanol (500 ml) and potassium acetate (11.8 g, 0.12 g-mole) are mixed in a 2 L flask equipped with a mechanical stirrer, a reflux condenser and a thermometer. The mixture is refluxed until the reaction is complete. The solvent is removed under vacuum and a solid is obtained. The solid is dissolved in water (200 ml) and the solution is treated with 150 g of pre-washed mixed- bed ion-exchange resins. After stirring for 15 minutes, the resins are filtered off and the solution is
• the extract is washed with water, three times 300 ml, dried over anhydrous sodium sulfate, evaporated to
• the brucine salt is prepared by dissolving 1.1 g (0.0057 ml) of the above material L-2-acetoxy-4-(methylthio)- butyric acid, in 10 ml EtOH and treatment with a hot filtered solution of brucine (0.0057 mol, 2.26 g in ethanol, 20 ml).
• the salt obtained is filtered and recrystallized from ethanol (40 ml) three times to obtain pure salt, m.p. 184-186°C [ ⁇ ] -31° (1% H 2 O), identical in m.p., mixed m.p. (undepressed), and optical rotation to compound prepared in Steps A and B.
• the mixture is stirred at room temperature overnight and then treated with 65 ml of AcOH. Methanol is removed under reduced pressure and the solution is treated with mixedbed ion-exchange resins. The solution is filtered and concentrated to provide the crude product.
• the crude product is dissolved in water and purified by preparative HPLC (C 18 , water as the mobile phase) to provide the purified material.
• Step B 5-N-Butyrolactamido-N,N'-bis[ (2,3-dihydroxypropyl)- 2,4,6-triiodoisophthalamide.
• the crude compound prepared in Step A (18.4 g, 0.016 g-mole) is suspended in MeOH (100 ml) in a flask equipped with a mechanical stirrer, an addition funnel and a thermometer.
• the suspension is cooled to 10°C and NaOH solution (98 ml of 1 N solution) is added slowly so the temperature is maintained at 10- 20°C.
• NaOH solution 98 ml of 1 N solution
• A. DL-5- ⁇ -Acetoxypropionylamino-2,4,6-triiodo-3-N- methylaminocarbonylbenzoyl chloride 5-Amino-2,4,6- triiodo-3-N-methylaminocarbonylbenzoyl chloride (59 g, 0.1 g-mole) is slurried in DMAc (110 ml) at 35-40°C.
• DL- 2-Acetoxypropionyl chloride (30.2 g, 0.2 g-mole) is added dropwise keeping the temperature at 40-48°C. The slurry is stirred at 40°C for 30 minutes, turning into a clear brown solution. After stirring overnight at 40°C, HPLC analysis indicates complete reaction.
• Step A DL-5- ⁇ -Aceto ⁇ ypropionylamino-[N-(2,3-dihydroxypropyl)-N-(2-hydroxyethyl)]-2,4,6-triiodo-3-N- methylaminocarbonylbenzamide.
• the compound prepared in Step A (60 g, 0.085 g-mole) is added to a mixture of 3- (N-2-hydroxyethyl)amino-1,2-propanediol dissolved in DMAc (23 g, 0.17 g-mole, in 56.4 ml solution, 40.87% w/v), additional DMAc (70 ml) and sodium carbonate (18 g, 0.17 g-mole) at 40°C.
• DMAc 3- (N-2-hydroxyethyl)amino-1,2-propanediol dissolved in DMAc (23 g, 0.17 g-mole, in 56.4 ml solution, 40.87% w/v),
• Step B [N-(2,3-dihydroxypropyl)-N-(2-hydroxyethyl)-DL-5- ⁇ - hydroxypropionylamino-2,4,6-triiodo-3-N-methylamino- carbonyl]benzamide.
• the crude product prepared in Step B (theoretically 0.085 g-mole) is dissolved in 300 ml water (pH 9.2). Cone. H 2 SO 4 (5 ml) is added to adjust the pH to 1. The solution is refluxed for 7 hours and then
• mice 13.1 g I/kg. Osmolality: 506
• Step A The crude product of Step A (theoretically 0.1033 g-mole) is added to a mixture of 3-(N-2- hydroxyethyl)amino-1,2-propanediol (28 g dissolved in 110 ml DMAc) and sodium bicarbonate (17.7 g, 0.21 g-mole) with stirring and heating to 55°C.
• Carbon dioxide is added to a mixture of 3-(N-2- hydroxyethyl)amino-1,2-propanediol (28 g dissolved in 110 ml DMAc) and sodium bicarbonate (17.7 g, 0.21 g-mole) with stirring and heating to 55°C.
• Step B [N-(2,3-dihydroxypropyl)-N-(2-hydroxyethyl)]-5- hydroxyacetylamino-2,4,6-triiodo-3-N-methylaminocar- bonylbenzamide.
• the product of Step B is hydrolyzed and purified as in Example 15, Step C, yielding 10.8 g, 99.8% pure. However, the solubility in water (w/v) was found to be less than 25%.
• Step B 3-[N-(2-Acetoxyethyl)aminocarbonyl]-5-amino-2,4,6- triiodobenzoyl chloride.
• thionyl chloride 207.9 g, 1.75 g-mole, 15 equiv.
• the resulting solution is heated to reflux with stirring for 3 hours.
• Excess thionyl chloride is removed by distillation under reduced pressure, partly as an
• Step B 5-Acetoxyacetylamino-3-N-(2-acetoxyethyl)amino- carbonyl-2,4,6-triiodobenzoyl chloride.
• DMAc 60 ml
• acetoxyacetyl chloride 24.73 g, 0.18 g- mole, 2 equiv.
• Step D [N-(2,3-Dihydroxypropyl)-N-(2-hydroxyethyl]-5-(2- hydroxyacetyl)amino-2,4,6-triiodo-3-N-(2- hydroxyethyl)aminocarbonylbenzamide.
• the crude diacetate product of Step D is dissolved in methanol (90 ml) and water (90 ml) is added.
• the pH is adjusted to 1 with sulfuric acid, and the mixture is stirred and heated to reflux for 2 hours.
• the mixture is then concentrated by distillation and purified by passing it through ion- exchange resins and by preparative HPLC, yielding 25.77 g of 98% pure product as confirmed by HPLC, tic, and nmr.
• the product is 100% w/v water-soluble. Osmolality: 597 mOsm/kg (32% I); viscosity: 5.3 cps (37°), 7.4 cps (25o) (32% I); the i.v. LD50 in mice is 20.6 gl/kg.
• Example 12 the title compound is prepared stepwise by first reacting 5-amino-2,4,6-triiodo-3-N- methylaminocarbonylbenzoyl chloride with 3-(N-2- hydroxyethyl)amino-1, 2-propanediol dissolved in DMAc in the presence of sodium carbonate.
• Step A N,N'-Bis[3,5-bis(N-2,3-dihydroxypropyl-N-2- hydroxyethylaminocarbonyl)-2,4,6-triiodophenyl]- malondiamide.
• the product of Step A (50 g, 0.04 g-mole) is added slowly to a mixture of 3-(N-2- hydroxyethyl)amino-1,2-propanediol (32.4 g, 0.24 g-mole) dissolved in DMAc (115 ml) and sodium carbonate (17 g, 0.16 g-mole), with stirring. After 7 hours stirring at room temperature, the reaction is complete as determined by HPLC. The reaction mixture is diluted with 200 ml DMAc and filtered to remove the salts. The clear
• Osmolality 213 mOsm/kg (32% I), 191 mOsm/kg (28% I); viscosity: 18.8 cps (37°, 32% I), 11.4 cps (37°, 28% I); the i.v. LD 50 in mice: 17.5 gl/kg.
• This compound is prepared as in Example 22 using succinyl chloride in place of malonyl chloride.
• the title compound is prepared by reacting 3-N-(2- acetoxyethyl) aminocarbonyl-5-amino-2,4,6-triiodobenzoyl chloride, prepared as in Example 18, Step B, with oxalyl chloride in dioxane; reacting that product with 3-(N-2- hydroxyethyl)amino-1,2-propanediol in DMAc; and
• Example 28 hydrolyzing the acetate groups with aqueous sulfuric acid (as in Example 18, Step E).
• Example 25 The title compound is prepared as in Example 25 using malonyl chloride instead of oxalyl chloride.
• Example 30 The title compound is prepared as in Example 25 using succinyl chloride instead of oxalyl chloride.
• Example 30 The title compound is prepared as in Example 25 using succinyl chloride instead of oxalyl chloride.
• This compound is prepared by reacting two equivalents of 5-amino-3-(N-2,3-diacetoxypropionaminocarbonyl)-2,4,6- triiodobenzoyl chloride with malonyl chloride, then reacting the dimer with two equivalents of 3-(N-2- hydroxyethyl)amino-1,2-propanediol, and finally removing the acetate groups by hydrolysis.
• Example 28 The title compound is prepared as in Example 28 using succinyl chloride instead of malonyl chloride .
• the title compound is prepared by reacting the product of Example 22 with methyl iodide under basic, alkylating conditions.
• the title compound is prepared by reacting the product of Example 24 with methyl iodide under basic, alkylating conditions.
• the title compound is prepared by reacting the product of Example 25 with methyl iodide under basic, alkylating conditions.
• the title compound is prepared by reacting the product of Example 27 with methyl iodide under basic, alkylating conditions.
• the title compound is prepared by reacting the product of Example 28 with methyl iodide under basic, alkylating conditions.
• Example 41 The title compound is prepared by reacting the product of Example 29 with methyl iodide under basic, alkylating conditions.
• Example 41 The title compound is prepared by reacting the product of Example 29 with methyl iodide under basic, alkylating conditions.
• ethanolamine is removed by Kugelrohr distillation to yield 145 g of a thick oil, the hydrochloride salt of the desired product.
• the oil is dissolved in 160 ml water.
• 50% w/w NaOH solution 44.21 ml, 33.8 g, 0.85 g-mole
• the solution is stirred overnight at room temperature.
• Water is removed by rotary evaporation (80 °C, under vacuum) to yield an orange oil.
• the oil is dissolved in 125 ml of methanol to precipitate sodium chloride.
• the salt is filtered off and the filtrate is evaporated to yield 98.3 g of an orange oil.

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  • 1992-12-02 EP EP93901365A patent/EP0619744A4/de not_active Withdrawn
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