US3446837A - 3 - (n - substituted - acylamino) - 2,4,6 - triiodophenyl fatty acid compounds - Google Patents

3 - (n - substituted - acylamino) - 2,4,6 - triiodophenyl fatty acid compounds Download PDF

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US3446837A
US3446837A US317074A US3446837DA US3446837A US 3446837 A US3446837 A US 3446837A US 317074 A US317074 A US 317074A US 3446837D A US3446837D A US 3446837DA US 3446837 A US3446837 A US 3446837A
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters

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  • RJ-COOH This invention relates to halogenated compounds and more particularly to certain novel iodinated phenyl fatty acids.
  • the present invention is directed to certain 3- (N-substituted-acylarnino)-2,4,6-triiodophenyl fatty acids and to certain salts thereof.
  • the invention also includes methods of preparing the novel compounds of the class described.
  • the present invention is directed to the novel compounds represented by the formula:
  • R C OOH RKIO-N-R
  • R is a lower divalent aliphatic radical containing not more than four carbon atoms selected from the group consisting of straight and branched chain paraffinic radicals and branched chain olefinic radicals, R is a lower alkyl radical, and R is a primary or secondary lower monovalent aliphatic radical; to the lower alkyl esters thereof; and to the salts thereof with pharmaceutically acceptable cations.
  • R and R will be straight or branched chain alkyl groups but they may contain other features such as olefinic structures, for example.
  • the pharmaceutically acceptable cations contemplated as forming salts within the scope of the invention are those inorganic and organic cations known to be useful in the contrast media art, such as sodium, calcium, N- methylglucamine and diethanolamine. Such salts are prepared from the free acids by conventional means.
  • novel acids and salts of the present invention are useful as roentgenographic contrast agents, especially in oral cholecystography.
  • Their significant properties such as toxicity, rate of excretion and concentration in the gall bladder, degree of opacification, rate of absorption from the gastrointestinal tract, and incidence of side effects, compare favorably with those of compounds previously known to the art.
  • Lower alkyl esters within the scope of the invention are useful intermediates in the preparation of the acids of the invention by one synthetic route.
  • they are useful themselves as X-ray contrast agents in selected techniques where low water solubility and substantial fat solubility may be important.
  • the compounds of the present invention may be prepared from previously known compounds by a variety of processes.
  • a 3-amino-2,4,6-triiodopheny1 fatty acid is first converted to a lower alkyl ester by any suitable method.
  • the acid may first be converted to a salt, then an alcoholic suspension of the latter esterfied by means of an alkylating agent, such as dimethyl sulfate.
  • the amino group of the resulting ester may then be acylated by treatment with a suitable acid anhydride, acyl halide or other acylating agent.
  • the resulting substituted anilides may then be alkylated by methods similar to those previously used in somewhat analogous situations. For example, the technique disclosed in the copending application of V. H. Wallingford and R. D. Rands, Jr., Ser. No.
  • N-substituted triiodophenyl fatty acids of the invention may be made by direct alkylation of 3-acylamino-2,4,6-triiodophenyl fatty acids by techniques similar to those disclosed in the Wallingford-Rands application and the French patent referred to previously.
  • EXAMPLE 5 The preparations described in Examples 3 and 4 were repeated, using a solution of sodium ethoxide prepared by dissolving metallic sodium (2.3 g.) in ethanol (75 ml.) in place of the alcoholic sodium hydroxide solution. Yield of 2,4,6 triiodo 3 (N methylacetamido) hydrocinnamic acid, 8.3 g. (33.1%). M.P. 183-1845 C. The infrared spectrum was consistent with the indicated structure. Found: carbon, 24.76%; hydrogen, 2.25%; nitrogen. 2.24%; neutral equivalent, 597.
  • the acid (61.1 g., 0.1 mole) was added to a solution of sodium ethylate prepared from sodium (4.8 g., 0.209 mole) and anhydrous ethanol (180 ml.). After a few minutes stirring to complete solution of all the acid, allyl chloride (15.0 g., 0.196 mole) was added and the mixture was stirred at reflux temperature for six and three-quarter hours to complete the alkylation.
  • the mixture was practically neutral at this point, and dilution of a small sample with water produces a turbidity, indicating that considerable esterification had occurred.
  • the solution was cooled to 60 C. and 50% sodium hydroxide solution 10 ml.) was added. After fifteen minutes, hydrolysis of the ester was complete, as indicated by the dilution test.
  • the crude product was dissolved in water (500 ml.), with the aid of sodium hydroxide, and the sodium salt was precipitated by the addition of sodium chloride (75 g.).
  • the gummy sodium salt after separation from the liquor, was redissolved in water (500 ml.) and the pure product was precipitated by the addition of acetic acid. Addition of ether at intervals (three 25 cc. portions) and stirring for three hours caused the product to become entirely crystalline.
  • EXAMPLE 7 The N-rnethylglucamine salt of the acid of Example 6 is prepared 'by conventional means.
  • the intravenous LD of this salt in mice is approximately 531 rug/kg.
  • Alpha ethyl 3 butyramido 2,4,6-triiodocinnamic acid (63.9 g., 0.1 mole) was added to a stirred solution of the sodium ethylate, prepared from sodium (48 g., 0.209 mole) and anhydrous ethanol (180 ml.). After solution was complete, methyl iodide (25 g., 0.176) was added and the mixture was heated at reflux temperature for one and three-quarter hours to complete the methylation.
  • the temperature was adjusted to 60 C. and 50% sodium hydroxide solution ml.) was added to hydrolyze any methyl ester present. After fifteen minutes, hydrolysis was complete, as indicated by dilution of a sample with water.
  • the aqueous solution was acidified with hydrochloric acid and the crude alpha-ethyl-3-(N- allylacetamido) 2,4,6 triiodohydrocinnamic acid was extracted into ether (300 ml.).
  • the ether solution was treated with decolorizing carbon, filtered, and extracted with water (300 ml.) containing excess sodium hydroxide.
  • the aqueous layer was partially neutralized with hydrochloric acid (pH 8) and heated to remove dissolved ether. The solution was then chilled in an ice bath and the amorphous product precipitated by the addition of an excess of 10% acetic acid.
  • the product was separated from the liquor and dried in a high vacuum over anhydrous calcium chloride. It weighed 44.2 g. and melted indefinitely between 85 and 100 C. Its neutral equivalent, 711, as compared with the theoretical value of 652.7, indicated that sodium salt had been occluded in the amorphous material. Trials with various solvents failed to produce crystals.
  • the purified alpha ethyl 3 (N allylacetamido)- 2,4,6-triiodohydrocinnamic acid weighed 41.6 g. It was still amorphous and melted indefinitely between and C. Neutral equivalent: theory, 652.7; found, 656. Iodine: theory, 58.3%; found, 57.9%. The infrared spectrum confirmed the indicated structure.
  • the pressure was reduced and practically all of the alcohol was distilled from the mixture over a period of about one and one-half hours. At the end of the distillation, the pressure was about 0.2 mm. of mercury and the temperature of the contents of the flask was about 25 C.
  • the neutral reaction mixture was diluted with water to a volume of 900 ml. and acidified (pH 2) with hydrochloric acid, whereupon a gummy mass precipitated.
  • the liquor was decanted from the gum and extracted with ether (200 ml.).
  • the ether extract was evaporated and the residue combined with the main product and dissolved in hot ethanol (200 ml.).
  • a solution of potassium hydroxide (12 g.) in ethanol ml.) and water (10 ml.) was added and the mixture was stirred and maintained at a temperature of 5560 C. for one and onequarter hours to hydrolyze any ester present.
  • Acetic acid (8 ml.) was added to neutralize the excess alkali,'and most of the alcohol was evaporated on a steam bath. The residue was diluted to a volume of 600 ml. with warm water and the product was precipitated as a guru by the addition of acetic acid. The liquor was decanted off and discarded. The remaining gum was dissolved in water (150 ml.) with the aid of N-methylglucamine (about 14.5 g.) and the solution was extracted with three 150 ml. portions of ether to remove any non-acidic material. The aqueous layer was then stirred with ether (400 ml.) and acidified with hydrochloric acid. After separation of the layers, crystals soon began to deposit from the ether layer. The mixture was stored in a refrigerator overnight to complete crystallization.
  • the N-methylglucamine salt of the acid of Example 12 is prepared by conventional means.
  • the intravenous LD of this salt in mice is approximately 411 mg./kg.
  • Butyl iodide (45 g., 0.244 mole) was added, and the mixture was stirred and maintained at a temperature of about 90 C. for one and one-half hours to complete the alkylation. During this time a solid which had previously separated had entirely dissolved.
  • Acetic acid (15 ml.) was added to neutralize excess alkali, and most of the alcohol was evaporated on a steam bath. The residue was diluted to a volume of 800 ml. with water to form a clear, nearly colorless solution.
  • the crude product was precipitated by the addition of hydrochloric acid (pH 2) and was rendered crystalline by digesting the mixture on a steam bath for two hours. The mixture was cooled, filtered and dried at 70 C. Yield, 66.0 g.; M.P. 184.9-190.9 C.
  • EXAMPLE 15 The N-methylglucamine salt of the acid of Example 14 is prepared by conventional means.
  • the intravenous LD of this salt in mice is approximately 180 mg./kg.
  • Acetic acid (15 ml.) was added to neutralize excess alkali, and most of the alcohol was evaporated on the steam bath. The residue was dissolved in water (800 ml. total volume), and the addition of hydrochloric acid precipitated the crude product as a gum which became crystalline after a half hours stirring.
  • the crude product was filtered oil and dried at C. Yield, 59.7 g.
  • a rapidly heated sample melted at about 120 C. with bubble formation.
  • the sample was placed in a melting point apparatus which had been preheated to 110 C., and the temperature was raised slowly (2 C./ min.) the sample softened at 1l7-120 C., resolidified, and did not melt until the temperature reached 181 C. It is probable that the stable phase at low temperature is a hydrate.
  • EXAMPLE 17 The N-methylglucamine salt of the acid of Example 16 is prepared by conventional means.
  • the intravenous LD of this salt in mice is approximately 1,030 rug/kg.
  • EXAMPLE 1 8 2,4,6-triiodo-3-(N-isopropylpropionamido)-hydrocinnamic acid 2,4,6-triiodo-3-propionamidohydrocinnamic acid (59.9 g., 0.1 mole) and dimethylformarnide (150 ml.) were added to a solution of sodium ethylate, prepared from sodium (4.7 g., 0.204 mole) and anhydrous ethanol rnl.). The original solid material dissolved but new crystals formed as a thick slurry. The flask was provided with a magnetic impeller and was connected through a Dry Ice trap to a vacuum pump. Practically all of the ethanol was distilled from the mixture, the temperature of the contents of the flask finally rising to about room temperature at a pressure of about 0.2 mm. of mercury.
  • the flask was provided with a mechanically driven stirrer and a reflux condenser, isopropyl bromide (35.0 g., 0.284 mole) was added, and the mixture was stirred rapidly and heated at 6070 C. for one-half hour and then at -85" C. for one and one-half hours to complete the alkylation. During this heating, all of the caked material had dissolved, leaving a hazy suspension of sodium bromide. The pH had dropped to 7.5.
  • the mixture was diluted to a volume of 1 liter with water and acidified with hydrochloric acid.
  • the resulting precipitate was filtered off and stirred with anhydrous ethanol (200 ml.) and 50% sodium hydroxide solution (15 ml.) at 60-70 C. for twenty minutes to hydrolyze any ester present.
  • a sample dissolved to a clear solution in water, indicating complete hydrolysis.
  • the mixture was diluted to a volume of 1 liter with water, and the crude product was precipitated by the addition of, first, acetic acid, and then, hydrochloric acid.
  • the precipitation mixture was digested on a steam bath for about an hour and the crude product was filtered oil and dried at 110 C. Weight, 61.5 g.
  • the crude product was digested with benzene (300 ml.) on a steam bath for one-half hour.
  • the mixture was cooled and 29.2 g. of starting material (2,4,6-triiodo-3- propionamidohydrocinnamic acid), melting at 270.8- 271.2 C., was filtered ofi.
  • the liquor and washings were evaporated, leaving an oil which was converted to crystalline product by dissolving it in anhydrous ethanol ml.) and adding water (65 rnl.). Slow crystallization occurred while the mixture was stirred at room temperature for four hours.
  • the purified 2,4,6-triiodo 3 (N-isopropylpropion- EXAMPLE 19
  • the N-methylglu-camine salt of the acid of Example 18 is prepared by conventional means.
  • the intravenous LD of this salt in mice is approximately 422 mg./ kg.
  • EXAMPLE 20 The sodium, calcium, and diethanolamine salts of the acids of Examples 4-12 are prepared by conventional methods.
  • m-Aminohydrocinnamamide hydrochloride is iodinated, using a solution of iodine monochloride in hydrochloric acid as the iodina-ting agent, to form 3-amino- 2,4,6-triiodohydrocinnamamide (B), which is then acetylated, using acetyl chloride as the acetylating agent and dimethylformamide as the reaction medium, to form 3- acetamido-2,4,6-triiodohydrocinnamamide (C), which is then methylated by means of sodium ethylate and methyl iodide in an anhydrous alcoholic medium to form 2,4,6- triiodo-3-(N-methylacetamido) hydrocinnamamide (D) which is then hydrolyzed in an acidic nitrite medium (H SO /NaNO to the desired 2,4,6-triiodo-3-(N-methylacetamido)
  • reaction conditions maintained in the iodination, acylation and alkylation steps are similar to those maintained in the corresponding steps in the alternative synthetic routes of the previous examples.

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Description

3,446,837 3 (N SUBSTITUTED ACYLAMINO) 2,4,6 TRI- IODOPHENYL FATTY ACID COMPOUNDS Vernon H. Wallingford, Ferguson, Mo., assignor to Mallinckrodt Chemical Works, St. Louis, M0., a corporation of Missouri No Drawing. Filed Oct. 17, 1963, Ser. No. 317,074
Int. Cl. C07c 101/44, /04
US. Cl. 260-471 18 Claims ABSTRACT OF THE DISCLOSURE 3-(N-substituted-acylamino)-2,4,6 triiodophenyl fatty acid compounds of the general formula:
RJ-COOH This invention relates to halogenated compounds and more particularly to certain novel iodinated phenyl fatty acids.
Briefly, the present invention is directed to certain 3- (N-substituted-acylarnino)-2,4,6-triiodophenyl fatty acids and to certain salts thereof. The invention also includes methods of preparing the novel compounds of the class described.
Among the objects of the invention may be mentioned the provision of new halogenated compounds; the provision of new iodinated phenyl fatty acids; the provision of new 3-(N-substituted-acylamino)-2,4,6-triiodophenyl fatty acids; the provision of compounds of the type indicated which are useful as roentgenographic contrast agents; and the provision of methods of preparing the novel compounds of the class mentioned. Other objects and features will be in part apparent and in part pointed out hereinafter.
The invention accordingly comprises the products and methods hereinafter described, the scope of the invention being indicated in the following claims.
The present invention is directed to the novel compounds represented by the formula:
R C OOH RKIO-N-R where R is a lower divalent aliphatic radical containing not more than four carbon atoms selected from the group consisting of straight and branched chain paraffinic radicals and branched chain olefinic radicals, R is a lower alkyl radical, and R is a primary or secondary lower monovalent aliphatic radical; to the lower alkyl esters thereof; and to the salts thereof with pharmaceutically acceptable cations.
nited States Patent 3,446,837 Patented May .27, 1969 In most instances R and R will be straight or branched chain alkyl groups but they may contain other features such as olefinic structures, for example.
The pharmaceutically acceptable cations contemplated as forming salts within the scope of the invention are those inorganic and organic cations known to be useful in the contrast media art, such as sodium, calcium, N- methylglucamine and diethanolamine. Such salts are prepared from the free acids by conventional means.
The novel acids and salts of the present invention are useful as roentgenographic contrast agents, especially in oral cholecystography. Their significant properties, such as toxicity, rate of excretion and concentration in the gall bladder, degree of opacification, rate of absorption from the gastrointestinal tract, and incidence of side effects, compare favorably with those of compounds previously known to the art.
Lower alkyl esters within the scope of the invention are useful intermediates in the preparation of the acids of the invention by one synthetic route. In addition, they are useful themselves as X-ray contrast agents in selected techniques where low water solubility and substantial fat solubility may be important.
The compounds of the present invention may be prepared from previously known compounds by a variety of processes.
In one reaction sequence a 3-amino-2,4,6-triiodopheny1 fatty acid is first converted to a lower alkyl ester by any suitable method. For example, the acid may first be converted to a salt, then an alcoholic suspension of the latter esterfied by means of an alkylating agent, such as dimethyl sulfate. The amino group of the resulting ester may then be acylated by treatment with a suitable acid anhydride, acyl halide or other acylating agent. The resulting substituted anilides may then be alkylated by methods similar to those previously used in somewhat analogous situations. For example, the technique disclosed in the copending application of V. H. Wallingford and R. D. Rands, Jr., Ser. No. 75,916, filed Dec. 15, 1960, for the alkylation of a 3-amino-5-alkanamido-2,4,6-triiodobenzoic acid, may be used. This utilizes an alkyl halide as the alkylating agent, in the presence of an equivalent quantity of an alkali metal alkoXide. As an alternative, a method similar to that disclosed in French BSM M820, utilizing a dialkyl sulfate as the alkylating agent, may be used. After completion of the alkylation the ester is hydrolyzed and the desired substituted triiodophenyl fatty acid is isolated by conventional methods.
If desired, the N-substituted triiodophenyl fatty acids of the invention may be made by direct alkylation of 3-acylamino-2,4,6-triiodophenyl fatty acids by techniques similar to those disclosed in the Wallingford-Rands application and the French patent referred to previously.
The following examples illustrate the invention.
EXAMPLE 1 Methyl 3-amino-2,4,6-triiodohydrocinnamate 3-amino-2,4,6-triiodohydrocinnamic acid (200 g.) was dissolved in a solution of sodium hydroxide (50 ml. of 50% sodium hydroxide solution in 3 l. of water) with the aid of heat. The solution was filtered and then chilled in an ice water bath for three hours. The precipitated sodium 3-amino-2,4,6-triiodohydrocinnamate was filtered off and dried at 110 C. Yield, 197.4 g.
A suspension of sodium 3-amino-2,4,6-triiodohydrocinnamate (112.8 g., 0.2 mole) in methanol (500 ml.) was heated to reflux temperature. Most of the salt dissolved. Dimethyl sulfate (22.2 ml., 0.235 mole) was neutralized (pH 6-7) with sodium carbonate and the neutralized material was added during a period of five minutes to the methanol solution of sodium 3-amino-2, 4,6-triiodohydrocinnamate. The resulting slurry was heated for an hour after which it was cooled to room temperature and the precipitated methyl 3-amino-2,4,6-triiodohydrocinnamate was filtered ofi and dried at 80 C. Yield, 107 g. (96%). M. P. 120.7-122.7 C.
A small amount of the methyl 3-amino-2,4,6-triiodohydrocinnamate was recrystallized from methanol (M. P. 1205-1225 C.). The infrared spectrum was consistent with the indicated structure. Calculated for C H l NO z carbon, 21.5%; hydrogen, 1.8%; nitrogen, 2.5%. Found: carbon 21.82%; hydrogen 1.93%; nitrogen 2.36%.
EXAMPLE 2 Methyl 3-acetamido-2,4,6-triiodohydrocinnamate Acetic anhydride (200 ml.) and a small amount of concentrated sulfuric acid (25 drops) were added dropwise with vigorous stirring to a suspension of methyl B-amino- 2,4,fi-triiodohydrocinnamate (100 g.) in glacial acetic acid (200 ml.). During the ten minute period of addition, the temperature rose to about 50 C. and most of the original ester went into solution and was replaced by a new insoluble substance. The reaction mixture was heated at 50-60" C. for an hour, during which the crystal form of the solid material appeared to change. The mixture was then poured into a solution of sodium acetate (20 g. CH COONa-3H O) in 1.5 l. of water. The resulting suspension was cooled to room temperature and the precipitate of methyl 3-acetamido-2,4,6-triiodohydrocinnamate was removed by filtration and dried at 110 C. Yield, 101 g. (94%); M. P. l98200.5 C.
A small amount of the methyl 3-acetamido-2,4,6-triiodohydrocinnamate was recrystallized from ethanol (M. P. 202-2035 C.). The infrared spectrum was consistent with the indicated structure. Calculated for C H I NO carbon, 24.0%; hydrogen, 2.0%; nitrogen, 2.3%. Found: carbon, 24.55%; hydrogen, 2.15%; nitrogen, 2.13%.
EXAMPLE 3 Methyl 2,4,6-triiodo-3-(N-methylacetamido)- hydrocinnamate Dimethyl sulfate (7.5 ml.) was added at room temperature during a period of minutes to a solution of methyl 3-acetamido-2,4,6-triiodohydrocinnamate (25 g.) and sodium hydroxide (4 g.) in ethanol (75 ml.). The mixture was stirred an additional five minutes at room temperature and was then heated under reflux to complete the formation of the desired intermediate. This solution of methyl 2,4,6-triiodo-3-(N-methylacetamido)- hydrocinnamate was submitted to hydrolysis in the next example without isolation of the intermediate product.
EXAMPLE 4 2,4,6-triiodo-3-'(N-methylacetamido) -hydrocinnamic acid Sodium hydroxide (7 .5 ml. of 50% solution) was added to the solution of methyl 2,4,6-triiodo-3-(N-methylacetamido)-hydrocinnamate from the preceding example. The resulting solution was heated until hydrolysis of the ester was complete, as indicated by the absence of the formation of a White precipitate of unhydrolyzed ester when a drop of the solution was mixed with a few ml. of water. The resulting solution of sodium 2,4,6-triiodo- 3-(N-methylacetamido)-hydrocinnamate was diluted with water (100 ml.), filtered, and added dropwise to an excess of dilute hydrochloric acid ml. of 37% acid in 500 ml. of water). The resulting precipitate was filtered off. Yield, 24.3 g. M.P. 180-183 C. (softened at 108 C.).
The crude product was dissolved in ethanol {125 ml.), the solution was treated with activated carbon and filtered, and the filtrate was diluted with water (500 ml.). The precipitate was filtered otf and the process repeated. Yield of 2,4,6-triiodo-3 (N-methylacetami-do)-hydrocinnamic acid, 18.3 g. (73%). M.P. 18.3-185 C. The infrared spectrum was consistent with the indicated structure. Calculated for C ;H; I NO carbon, 2 4.0%;
4 drogen, 2.0%; neutral equivalent, 599. Found: carbon, 24.54%; hydrogen, 2.2%; neutral equivalent, 599.5.
EXAMPLE 5 The preparations described in Examples 3 and 4 were repeated, using a solution of sodium ethoxide prepared by dissolving metallic sodium (2.3 g.) in ethanol (75 ml.) in place of the alcoholic sodium hydroxide solution. Yield of 2,4,6 triiodo 3 (N methylacetamido) hydrocinnamic acid, 8.3 g. (33.1%). M.P. 183-1845 C. The infrared spectrum was consistent with the indicated structure. Found: carbon, 24.76%; hydrogen, 2.25%; nitrogen. 2.24%; neutral equivalent, 597.
EXAMPLE 6 Alpha-ethyl-3-(N-allylacetamid-o) -2,4,6-triiodocinnamic acid Alpha ethyl 3 acetamido 2,4,6 triiodocinnamio acid was prepared by the method of Mien Chao and Ping-Cheng Hu, Hua Hsueh Hsueh Pao, 23, 361-6 (1957); Chemical Abstracts, 52, 15467 1958). The product melted at 2l9.1220.7 0., whereas the Chinese authors reported a melting point of 205-207 C.
The acid (61.1 g., 0.1 mole) Was added to a solution of sodium ethylate prepared from sodium (4.8 g., 0.209 mole) and anhydrous ethanol (180 ml.). After a few minutes stirring to complete solution of all the acid, allyl chloride (15.0 g., 0.196 mole) was added and the mixture was stirred at reflux temperature for six and three-quarter hours to complete the alkylation.
The mixture was practically neutral at this point, and dilution of a small sample with water produces a turbidity, indicating that considerable esterification had occurred. The solution was cooled to 60 C. and 50% sodium hydroxide solution 10 ml.) was added. After fifteen minutes, hydrolysis of the ester was complete, as indicated by the dilution test.
The excess alkali was neutralized with acetic acid (10 ml.) and most of the alcohol was evaporated on a steam bath. The salts were then dissolved in water (800 ml.), and the solution was treated with decolorizing carbon and filtered. The crude product was precipitated as a somewhat sticky, amorphous solid by the addition of diluted acetic acid (15 ml. of glacial acid in 75 ml. of Water). The addition of 25 m1. of ether and continued stirring caused the precipitate to become partly crystalline. The mixture was filtered and the crude product washed and dried at C. Yield, 61.8 g. M.P. 1750- 183.0 C.
The crude product was dissolved in water (500 ml.), with the aid of sodium hydroxide, and the sodium salt was precipitated by the addition of sodium chloride (75 g.). The gummy sodium salt, after separation from the liquor, was redissolved in water (500 ml.) and the pure product was precipitated by the addition of acetic acid. Addition of ether at intervals (three 25 cc. portions) and stirring for three hours caused the product to become entirely crystalline.
The pure alpha ethyl-3-(N-allylacetamido)-2,4,6-triiodocinnamic acid was separated from the liquor and dried at 110 C. Yield, 59.5 g.; M.P. 179.2-181.2 C. Neutral equivalent: theory, 650.7; found, 649. Iodine: theory, 58.51%; found, 57.8%. The infrared spectrum confirmed the indicated structure.
EXAMPLE 7 The N-rnethylglucamine salt of the acid of Example 6 is prepared 'by conventional means. The intravenous LD of this salt in mice is approximately 531 rug/kg.
EXAMPLE 8 Alpha-ethyl-2,4,6-triiodo-3- (N-methylbutyramido)- cinnamic acid Alpha ethyl 3 butyramido 2,4,6 triiodocinnamic acid was prepared by essentially the method of Mien Chao and Ping-Cheng Hu, referred to in Example 6. The product melted at 14l-l43 C., whereas the Chinese authors reported a melting point of 128-129 C. Chemical abstracts erroneously refer to the substance as the propionyl compound.
Alpha ethyl 3 butyramido 2,4,6-triiodocinnamic acid (63.9 g., 0.1 mole) was added to a stirred solution of the sodium ethylate, prepared from sodium (48 g., 0.209 mole) and anhydrous ethanol (180 ml.). After solution was complete, methyl iodide (25 g., 0.176) was added and the mixture was heated at reflux temperature for one and three-quarter hours to complete the methylation.
The temperature was adjusted to 60 C. and 50% sodium hydroxide solution ml.) was added to hydrolyze any methyl ester present. After fifteen minutes, hydrolysis was complete, as indicated by dilution of a sample with water.
The excess alkali was neutralized with acetic acid (10 ml.) and most of the alcohol was evaporated on a steam bath. The residue was dissolved in water (800 ml.), the solution was extracted with ether (250 m1.) and the crude product was precipitated by the addition of acetic acid. The precipitation mixture was heated to drive 01f dissolved ether, then colled, and the product was filtered off, washed and dried at 110 C. Yield, 63.9 g.; M.P. 198.8- 200.9 C.
After crystallization from anhydrous ethanol, the pure alpha-ethyl-2,4,6-triiodo-3-(N methylbutyramido) cinnamic acid melted at 202.9-204.5 C. Neutral equivalent: theory, 652.7; found, 659. Iodine: theory, 58.3% found, 58.06%. The infrared spectrum confirmed the indicated structure.
EXAMPLE 9 The N-methylglucamine salt of the acid of Example 8 is prepared by conventional means. The intravenous LD of this salt in mice is approximately 556 mg./kg.
EXAMPLE l0 Alpha-ethyl-3- (N-allylacetamido)-2,4,6-tri-iodohydrocinnamic acid Alpha ethyl-beta (2,4,6 triiodo 3 acetamidophenyl) propionic acid (46.0 g., 0.075 mole) was dissolved in a solution of sodium ethylate prepared from sodium (3.6 g., 0.156 mole) and anhydrous ethanol (100 ml.). Allyl chloride chloride g., 0.266 mole) was added and the mixture :was stirred and maintained at reflux temperature for six and one-half hours. The temperature was adjusted to 65 C. and 50% sodium hydroxide solution (12 ml.) was added to hydrolyze any ester present. After ten minutes a sample dissolved to a clear solution in water.
The excess alkali was neutralized with acetic acid (10 ml.) and the alcohol was evaporated on a steam bath. The residue was diluted with water to a volume of 600 ml. and an excess of hydrochloric acid was added. The amorphous crude product was separated from the liquor and redissolved in water (100 ml.) with the aid of N- methylglucamine (15 g.). The solution was extracted with two 150 ml. portions of ether.
Since the remaining aqueous solution of the N- methlylucamine salt of the product tended to peptize decolorizing carbon, the aqueous solution was acidified with hydrochloric acid and the crude alpha-ethyl-3-(N- allylacetamido) 2,4,6 triiodohydrocinnamic acid was extracted into ether (300 ml.). The ether solution was treated with decolorizing carbon, filtered, and extracted with water (300 ml.) containing excess sodium hydroxide. The aqueous layer was partially neutralized with hydrochloric acid (pH 8) and heated to remove dissolved ether. The solution was then chilled in an ice bath and the amorphous product precipitated by the addition of an excess of 10% acetic acid.
The product was separated from the liquor and dried in a high vacuum over anhydrous calcium chloride. It weighed 44.2 g. and melted indefinitely between 85 and 100 C. Its neutral equivalent, 711, as compared with the theoretical value of 652.7, indicated that sodium salt had been occluded in the amorphous material. Trials with various solvents failed to produce crystals.
The crude material was dissolved in water (1,800 ml.) with the aid of sodium hydroxide, and the solution Was cooled to 8 C. and added during ten minutes to a similarly chilled dilute hydrochloric acid solution (125 ml. of concentrated acid in 1,800 ml. of water). The product was filtered off, washed thoroughly and dried to constant weight over anhydrous calcium chloride under a vacuum maintained at about 0.2 mm. of mercury.
The purified alpha ethyl 3 (N allylacetamido)- 2,4,6-triiodohydrocinnamic acid weighed 41.6 g. It was still amorphous and melted indefinitely between and C. Neutral equivalent: theory, 652.7; found, 656. Iodine: theory, 58.3%; found, 57.9%. The infrared spectrum confirmed the indicated structure.
The N-methylglucamine salt of the acid of Example 10 is prepared by conventional means. The intravenous LD of this salt in mice is approximately 519 mg./kg.
EXAMPLE 12 Alpha-ethyl-2,4,6-triiodo-3-(N-methylbutyramido)- hydrocinnamic acid Alpha ethyl 3 butyramido 2,4,6 triiodohydrocinnamic acid (57.5 g., 0.09 mole) and dimethylformamide (50 ml.) were added to a solution of sodium ethylate prepared from sodium (4.3 g., 0.187 mole) and anhydrous alcohol (70 ml.). The flask was provided with a magnetic Impeller, suspended over an electric hot plate and connected to a vacuum pump through a trap cooled by Dry Ice and acetone. The pressure was reduced and practically all of the alcohol was distilled from the mixture over a period of about one and one-half hours. At the end of the distillation, the pressure was about 0.2 mm. of mercury and the temperature of the contents of the flask was about 25 C.
The flask was then provided with a mechanically driven stirrer and a reflux condenser. Methyl iodide (30 g., 0.212 mole) was added to the clear viscous solution, and the mixture was stirred and heated at 7080 C. for threequarters hour to complete the methylation.
The neutral reaction mixture was diluted with water to a volume of 900 ml. and acidified (pH 2) with hydrochloric acid, whereupon a gummy mass precipitated. The liquor was decanted from the gum and extracted with ether (200 ml.). The ether extract was evaporated and the residue combined with the main product and dissolved in hot ethanol (200 ml.). A solution of potassium hydroxide (12 g.) in ethanol ml.) and water (10 ml.) was added and the mixture was stirred and maintained at a temperature of 5560 C. for one and onequarter hours to hydrolyze any ester present.
Acetic acid (8 ml.) was added to neutralize the excess alkali,'and most of the alcohol was evaporated on a steam bath. The residue was diluted to a volume of 600 ml. with warm water and the product was precipitated as a guru by the addition of acetic acid. The liquor was decanted off and discarded. The remaining gum was dissolved in water (150 ml.) with the aid of N-methylglucamine (about 14.5 g.) and the solution was extracted with three 150 ml. portions of ether to remove any non-acidic material. The aqueous layer was then stirred with ether (400 ml.) and acidified with hydrochloric acid. After separation of the layers, crystals soon began to deposit from the ether layer. The mixture was stored in a refrigerator overnight to complete crystallization.
The pure alpha ethyl 2,4,6 triiodo 3 N methylbutyramido)-hydrocinnamic acid was filtered off, washed with ether and dried at C. Yield, 36.0 g.; M.P. 167.2- 170.2 C. Water content, 0.35% (Karl Fischer method).
7 Neutral equivalent: theory, 654.7; found, 658 (anhydrous basis). Iodine: theory, 58.1%; found, 57.5%. The indicated structure was confirmed by infrared analysis.
EXAMPLE 1?:
The N-methylglucamine salt of the acid of Example 12 is prepared by conventional means. The intravenous LD of this salt in mice is approximately 411 mg./kg.
EXAMPLE l4 3-(N-butylbutyramido)-2,4,6-triiodohydrocinnamic acid 3-butyramido-2,4,6-triiodohydrocinnarnic acid (61.3 g., 0.1 mole) and dimethylforrnamide (150 ml.) were added to a solution of sodium ethylate, prepared from sodium (4.7 g., 0.204 mole) and anhydrous ethanol (75 rnl.). The flask was provided with a magnetic impeller, suspended over an electric hot plate and connected through a Dry Ice trap to a vacuum pump. Practically all of the alcohol was distilled off during one and one-half hours. Toward the end of the distillation the temperature of the contents of the flask had risen to about 25 C. and the pressure was about 0.2 mm. of mercury.
Butyl iodide (45 g., 0.244 mole) was added, and the mixture was stirred and maintained at a temperature of about 90 C. for one and one-half hours to complete the alkylation. During this time a solid which had previously separated had entirely dissolved.
With the temperature at 70 C., 50% sodium hydroxide solution ml.) was added to hydrolyze any ester present. After five minutes a sample remained clear on dilution with water, indicating complete hydrolysis.
Acetic acid (15 ml.) was added to neutralize excess alkali, and most of the alcohol was evaporated on a steam bath. The residue was diluted to a volume of 800 ml. with water to form a clear, nearly colorless solution. The crude product was precipitated by the addition of hydrochloric acid (pH 2) and was rendered crystalline by digesting the mixture on a steam bath for two hours. The mixture was cooled, filtered and dried at 70 C. Yield, 66.0 g.; M.P. 184.9-190.9 C.
The crude product was dissolved in anhydrous ethanol (255 ml.), and the solution was treated with decolorizing carbon, filtered and diluted with water (50 m1.) until a slight turbidity was produced. Crystals soon began to form, and the amount increased when the solution was cooled in an ice bath. The purified 3-(N-butylbutyramido) -2,4,6- triiodohydrocinnamic acid was filtered off, washed with 80% ethanol, and dried at 110 C. Yield, 50.8 g., M.P. 192.0l94.0 C. Neutral equivalent: theory, 668.7; found, 664. Iodine: theory, 56.93%; found 56.4%. The infrared spectrum agreed with the indicated structure.
EXAMPLE 15 The N-methylglucamine salt of the acid of Example 14 is prepared by conventional means. The intravenous LD of this salt in mice is approximately 180 mg./kg.
EXAMPLE 16 2,4,6-triiodo-3-(N-methylacetamido)-hydrocinnamic acid 3-acetamido-2,4,6-triiodohydrocinnamic acid (58.5 g., 0.1 mole) was added to a solution of sodium ethylate prepared from sodium (4.7 g., 0.204 mole) and anhydrous ethanol (150 rnl.). The mixture was stirred at 50 C. for three-quarters hour to complete solution of the acid. Methyl iodide (20 g., 0.141 mole) was added, and the mixture was stirred at reflux temperature for one and onehalf hours, at which point the pH was about 7.5.
A small sample of the reaction solution diluted with water deposited crystals (M.P. 130.7-132.7 C.) of the methyl ester of 2,4,6-triiodo-3-(N-methylacetamido)- hydrocinnamic acid. Sodium hydroxide (15 ml. of 50% solution) was added to the reaction mixture and its temperature was maintained at 65-70 C. for five minutes. A sample remained clear on dilution with water, indicating that all the ester had been hydrolyzed.
Acetic acid (15 ml.) was added to neutralize excess alkali, and most of the alcohol was evaporated on the steam bath. The residue was dissolved in water (800 ml. total volume), and the addition of hydrochloric acid precipitated the crude product as a gum which became crystalline after a half hours stirring.
The crude product was filtered oil and dried at C. Yield, 59.7 g. A rapidly heated sample melted at about 120 C. with bubble formation. When a sample was placed in a melting point apparatus which had been preheated to 110 C., and the temperature was raised slowly (2 C./ min.) the sample softened at 1l7-120 C., resolidified, and did not melt until the temperature reached 181 C. It is probable that the stable phase at low temperature is a hydrate.
Recrystallization from anhydrous ethanol (250 ml.) after treatment of the solution with decolorizing carbon, yielded a first crop of crystals of 2,4,6-triiodo-3-(N-methylacetamido)-hydrocinnarnic acid weighing 39.0 g. after a preliminary drying at 70 C. and a final drying at 110 C. to constant weight. M.P., 184.l-184.8 C. Neutral equivalent: theory, 598.7; found, 600. Iodine: theory, 63.59%; found, 63.20%. The indicated structure was confirmed by infrared analysis.
EXAMPLE 17 The N-methylglucamine salt of the acid of Example 16 is prepared by conventional means. The intravenous LD of this salt in mice is approximately 1,030 rug/kg.
EXAMPLE 1 8 2,4,6-triiodo-3-(N-isopropylpropionamido)-hydrocinnamic acid 2,4,6-triiodo-3-propionamidohydrocinnamic acid (59.9 g., 0.1 mole) and dimethylformarnide (150 ml.) were added to a solution of sodium ethylate, prepared from sodium (4.7 g., 0.204 mole) and anhydrous ethanol rnl.). The original solid material dissolved but new crystals formed as a thick slurry. The flask was provided with a magnetic impeller and was connected through a Dry Ice trap to a vacuum pump. Practically all of the ethanol was distilled from the mixture, the temperature of the contents of the flask finally rising to about room temperature at a pressure of about 0.2 mm. of mercury.
The flask was provided with a mechanically driven stirrer and a reflux condenser, isopropyl bromide (35.0 g., 0.284 mole) was added, and the mixture was stirred rapidly and heated at 6070 C. for one-half hour and then at -85" C. for one and one-half hours to complete the alkylation. During this heating, all of the caked material had dissolved, leaving a hazy suspension of sodium bromide. The pH had dropped to 7.5.
The mixture was diluted to a volume of 1 liter with water and acidified with hydrochloric acid. The resulting precipitate was filtered off and stirred with anhydrous ethanol (200 ml.) and 50% sodium hydroxide solution (15 ml.) at 60-70 C. for twenty minutes to hydrolyze any ester present. A sample dissolved to a clear solution in water, indicating complete hydrolysis.
The mixture was diluted to a volume of 1 liter with water, and the crude product was precipitated by the addition of, first, acetic acid, and then, hydrochloric acid. The precipitation mixture was digested on a steam bath for about an hour and the crude product was filtered oil and dried at 110 C. Weight, 61.5 g.
The crude product was digested with benzene (300 ml.) on a steam bath for one-half hour. The mixture was cooled and 29.2 g. of starting material (2,4,6-triiodo-3- propionamidohydrocinnamic acid), melting at 270.8- 271.2 C., was filtered ofi. The liquor and washings were evaporated, leaving an oil which was converted to crystalline product by dissolving it in anhydrous ethanol ml.) and adding water (65 rnl.). Slow crystallization occurred while the mixture was stirred at room temperature for four hours.
The purified 2,4,6-triiodo 3 (N-isopropylpropion- EXAMPLE 19 The N-methylglu-camine salt of the acid of Example 18 is prepared by conventional means. The intravenous LD of this salt in mice is approximately 422 mg./ kg.
EXAMPLE 20 The sodium, calcium, and diethanolamine salts of the acids of Examples 4-12 are prepared by conventional methods.
The acid compounds of the invention may also be prepared through substituted cinnamides as intermediates, the following example being illustrative.
EXAMPLE 21 2,4,6-triiodo-3-(N-methylacetamido)-hydrocinnamic acid m-Nitrocinnamamide is hydrogenated in the presence of a palladium-on-charcoal catalyst to form m-aminohydrocinnamamide, which is isolated as its hydrochloride (A). m-Aminohydrocinnamamide hydrochloride is iodinated, using a solution of iodine monochloride in hydrochloric acid as the iodina-ting agent, to form 3-amino- 2,4,6-triiodohydrocinnamamide (B), which is then acetylated, using acetyl chloride as the acetylating agent and dimethylformamide as the reaction medium, to form 3- acetamido-2,4,6-triiodohydrocinnamamide (C), which is then methylated by means of sodium ethylate and methyl iodide in an anhydrous alcoholic medium to form 2,4,6- triiodo-3-(N-methylacetamido) hydrocinnamamide (D) which is then hydrolyzed in an acidic nitrite medium (H SO /NaNO to the desired 2,4,6-triiodo-3-(N-methylacetamido)-hydrocinnamic acid (E).
The reaction conditions maintained in the iodination, acylation and alkylation steps are similar to those maintained in the corresponding steps in the alternative synthetic routes of the previous examples.
The infrared spectra of intermediates B, C and D are consistent with those expected for compounds of the indicated structures. Other identifying characteristics of the novel intermediates and the final product are indicated in the following table:
Compound: Characteristics A Neutral equivalent, 202.5 vs. 200.5
calculated.
B Loses iodine at 244 C. decomposes 247.5248.5 C. Iodine, 69.5% vs. 70.3% calculated.
C Decomposes 25726l C.
D 1 Melts 207-212" C.
E Melts 177.5-18l C.
1 Compound D is also prepared by treating 2,4,6-triiodo3- (N-methylacetamido)-hydrocinnamic acid with -.thionyl chloride to form 2,4,6triiodo 3 (N-methylacetamido)hydrocinnamoyl chloride which is then ammonolyzed to form 2,4,6- triiodo 3 (N-methylacetamido)-hydrocinnamamide D (M.P. 215217 0.). A mixture of the two preparations of D melts at 209-213 C.
It will be obvious to those skilled in the art that many other compounds within the scope of the invention may be prepared. For example, many 3-amino-2,4,6-triiodophenyl fatty acids of the type disclosed in US. Patent 2,705,726 may be acylated and alkylated by methods disclosed herein to form additional compounds within the scope of the present invention.
Following oral administration to cats, the compounds disclosed in Examples 7, 9, 11, 13, 15, 17 and 19 produced radiographic visualization of the gall bladder equivalent or superior to that produced by bunamiodyl. Substantial visualization of the bile duct also occurred. No si ns of toxicity were observed in the cats.
The compound referred to by the coined name, bunamiodyl, in the preceding paragraph has the structure I NHG OCHzCHaCHa and is also known by the name, alpha-ethyl-3-butyramido- 2,4,6-triiodocinnamic acid, sodium salt. It is marketed under the trademark Orabilex.
In view of the. above it will be seen that the several objects of the invention are achieved and other advantageous results obtained.
As various changes could be made in the above products and processes without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
What is claimed is:
1. A compound selected from the group consisting of acids of the general formula Ii -CO OH wherein R is a lower divalent aliphatic radical containing not more than four carbon atoms selected from the group consisting of straight and branched chain parafiinic radicals and branched chain olefinic radicals, R is a lower alkyl radical, and R is selected from the group consisting of primary and secondary lower alkyl and the allyl radicals, lower alkyl esters thereof and salts thereof with pharmaceutically acceptable cations.
2. 2,4,6 triiodo 3 (N methylacetamido) hydrocinnamic acid.
3. 2,4,6 triiodo 3 (N methylacetamido) hydrocinnamic acid, N-methylglucamine salt.
4. Alpha ethyl 3 (N allylacetamido) 2,4,6 triiodocinnamic acid.
5. Alpha ethyl 3 (N allylacetamido) 2,4,6 triiodocinnamic acid, N-methylglucamine salt.
6. Alpha ethyl 2,4,6 triiodo 3 (N methylbutyramido)-cinnamic acid.
7. Alpha ethyl 2,4,6 triiodo 3 (N methylbutyramido)-cinnamic acid, N-methylglucamine salt.
8. Alpha ethyl 3 (N allylacetamido) 2,4,6 triiodohydrocinnamic acid.
9. Alpha ethyl 3 (N allylacetamido) 2,4,6 triiodohydrocinnamic acid, N-methylglucamine salt.
10. Alpha ethyl 2,4,6 triiodo 3 (N methylbutyramido)-hydrocinnamic acid.
11. Alpha ethyl 2,4,6 triiodo 3 (N methylbutyramido)-hydrocinnamic acid, N-methylglucamine salt.
12. 3 (N butylbutyramido) 2,4,6 triiodohydrocinnamic acid.
13. 3 (N butylbutyramido) 2,4,6 triiodohydrocinnamic acid, N-methylglucamine salt.
14. 2,4,6 triiodo 3 (N isopropylpropionamido)- hydrocinnamic acid.
15. 2,4,6 triiodo 3 (N isopropylpropionamido)- hydrocinnamic acid, N-methylglucamine salt.
16. Methyl 3-amino-2,4,6-triiodohydrocinnamate.
17. Methyl 3-acetamido-2,4,6-triiodohydrocinnamate.
18. Methyl 2,4,6 triiodo 3 (N methylacetamido)- hydrocinnamate.
(References on following page) 11 12 References Cited LORRAINE A. WEINBERGER, Primary Examiner.
UNITED STATES PATENTS L. A. THAXTON, Assistant Examiner. 2,895,988 7/1959 Archer et a1 260-518 3,128,301 4/1964 Larsen et a1 260-471 US. 01. X.R.
FOREIGN PATENTS 5 260-501.11, 518, 544, 558,999
632,880 12/1961 Canada.
Notice of Adverse Decision in Interference In Interference N 0. 97,664 involving Patent No. 3,446,837, V. H. Vvallingford, 3-(N-SUBSTITUTED ACYLAMINO) 2,4,6 TRIIODOPHENYL FATTY ACID COMPOUNDS, final judgment adverse to the patentee was rendered May 26, 1972, as to claim 10.
[Ofioz'al Gazette July 4, 1972.]
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3666760A (en) * 1970-04-02 1972-05-30 Sterling Drug Inc Iodinated 3-aminobenzamides
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
US4314055A (en) * 1975-09-29 1982-02-02 Mallinckrodt, Inc. 3,5-Disubstituted-2,4,6-triiodoanilides of polyhydroxy-monobasic acids
US4873075A (en) * 1985-09-10 1989-10-10 The University Of Michigan Polyiodinated triglyceride analogs as radiologic agents
US5250283A (en) * 1990-03-28 1993-10-05 Molecular Biosystems, Inc. Organic contrast agent analog and method of making same
US5866100A (en) * 1995-12-19 1999-02-02 Bracco Research S.A. Compositions for imaging of the gastrointestinal tract

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2895988A (en) * 1957-09-05 1959-07-21 Sterling Drug Inc Acylated trhodoaminophenylalkanoic acids and preparation thereof
CA632880A (en) * 1961-12-19 E. Kwartler Charles Alpha-alkyl-2,4,6-triiodo-3-amino-cinnamic acids and process of preparing them
US3128301A (en) * 1953-12-17 1964-04-07 Sterling Drug Inc Alkyl esters of acylated 3,5-diamino- 2, 4, 6-triiodobenzoic acids and their preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA632880A (en) * 1961-12-19 E. Kwartler Charles Alpha-alkyl-2,4,6-triiodo-3-amino-cinnamic acids and process of preparing them
US3128301A (en) * 1953-12-17 1964-04-07 Sterling Drug Inc Alkyl esters of acylated 3,5-diamino- 2, 4, 6-triiodobenzoic acids and their preparation
US2895988A (en) * 1957-09-05 1959-07-21 Sterling Drug Inc Acylated trhodoaminophenylalkanoic acids and preparation thereof

Cited By (7)

* Cited by examiner, † Cited by third party
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
US3666760A (en) * 1970-04-02 1972-05-30 Sterling Drug Inc Iodinated 3-aminobenzamides
US4314055A (en) * 1975-09-29 1982-02-02 Mallinckrodt, Inc. 3,5-Disubstituted-2,4,6-triiodoanilides of polyhydroxy-monobasic acids
US4873075A (en) * 1985-09-10 1989-10-10 The University Of Michigan Polyiodinated triglyceride analogs as radiologic agents
US5250283A (en) * 1990-03-28 1993-10-05 Molecular Biosystems, Inc. Organic contrast agent analog and method of making same
WO1994005335A1 (en) * 1990-03-28 1994-03-17 Molecular Biosystems, Inc. New organic contrast agent analog and method of making same
US5866100A (en) * 1995-12-19 1999-02-02 Bracco Research S.A. Compositions for imaging of the gastrointestinal tract

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