Classifications

• • 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
  • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
  • A61K49/0452—Solutions, e.g. for injection

Definitions

• R is a lower acyl group having no more than carbon atoms and wherein A is an alkylene group substituted by one or more substituents of the formula -0R wherein R is a hydrogen or a lower alkyl or acyl group having no more than 5 carbon atoms, said alkylene containing from 3 to 15 inclusive carbon atoms and being optionally broken by one or more oxygen bridges, or physiologically acceptable salts thereof.
• each nitrogen atom in the bridge ice is located at a distance of two carbon atoms from a group O-R
• no more than one heteroatom is preferably bound to one and the same carbon atom in the bridge A.
• the bridge A suitably contains from 3 to 10 inclusive carbon atoms in the alkylene group.
• R is preferably chosen a hydrogen atom when hydrophilic compounds are desired.
• R a lower alkyl or acyl group such as methyl or ethyl or acetyl or propiouyl.
• salts of the above compounds are the sodium salt, methylglucamine salt or other nontoxic salts. These can be used in the form of an aqueous solution.
• A is any of the above bridges which have one or more hydroxyl groups alkylated or acylated with, respectively, a lower alkyl, such as methyl or ethyl or acyl group such as acetyl or propionyl, said alkyl and acyl containing each no more than 5 carbon atoms, or physiologically acceptable salts thereof, such as the sodium salt ortris-hydroxymethylaminomethane or methylglucamine salt.
• a preparation for carrying out the method according to the invention may suitably consist of a mixture, such as an aqueous solution, or contain a physiologically acceptable solid carrier; the preparation being, for example, in tablet form or in the form of any other suitable dosage unit, and the mixture containing one or more of the aforesaid compounds as an active contrast-producing substance.
• the method according to the invention comprises the steps of administering the contrast-producing composition or agent to the body of the test object and causing X-rays to pass through this body, photographing or direct examination on a fluorescent screen or some other conventional X-ray examination technics being carried out in a normal manner.
• the dosage of the contrast-producing agent is selected in accordance with the category of case to be investigated so that a sufficient contrast effect is attained.
• the various body cavities which can be visualized according to the invention is the gastrointestinal tract.
• the contrast-producing agent is introduced perorally either as a solid or in solution. It is also possible to make the intestines visual by introducing the contrast-producing agent in the form. of an enema.
• Another example is the visualization of blood vessels after injection of the contrast-producing agent in the form of a sterile solution. It is of particular value that, subsequent to intravenous injection of the contrastproducing agent, the latter is excreted with the bile and therefor also makes possible the visualization of the bile ducts and gall bladder in an advantageous manner.
• Further examples are the use of the iodine compounds in hysterosalipingography, cholangiography, urethrography and sialography.
• novel iodine compounds used according to the invention have a low toxicity and present good characteristics as an X-ray contrast-producing agent.
• iodine compounds As carriers for the iodine compounds can be mentioned conventional additives such as water in respect of solutions for injection purposes and extenders with regard to tablets.
• the concentration of the iodine compounds will be chosen in accordance with the field of application.
• a content is chosen which exceeds grams per 100 ml. of solution.
• a much higher content is chosen, e.g., in the order of 20, 30, 40 or 50 grams or more per 100- ml. of solution.
• the above iodine compounds are prepared by a process which comprises reacting compounds of the formula or salts thereof, wherein R has the above significance, with compounds of the Formula Y.A.X., wherein A has the above significance, R being preferably a hydrogen atom, and Y and X each represent a halogen atom, preferably chloro or bromo, or with corresponding epoxide compounds, obtainable by splitting ofi hydrogen halide from the compound Y.A.X.
• the obtained compound is either recovered as such or in the form of a physiologically acceptable salt.
• salts examples include the sodium salt or methylglucamine salt.
• Sodium and methylglucamine salts are satisfactorily soluble in water.
• n is an integer, in the range of from 2 to 4 inclusive, and
• the reaction is preferably carried out in the presence of a solvent, such as water, or an aqueous liquid, and there is usually added alkaline reacting substances, such as alkali metal hydroxides; which latter act as catalyst.
• alkaline reacting substances such as alkali metal hydroxides; which latter act as catalyst.
• the alkaline reacting substance can also act as an acceptor for hydrogen halide possibly liberated in the reaction.
• the obtained compounds are treated with, respectively, an alkylating or acylating agent such as dimethylsulphate or acetic anhydride, in the usual manner for the alkylation or acylation of hydroxyl groups.
• an alkylating or acylating agent such as dimethylsulphate or acetic anhydride
• the reaction can be carried out at difierent temperatures, for example in the range of 0 to 50 C. such as 20 C. and 40 C.
• EXAMPLE 1 0.2- mole of 3-acetylamino-2,4,6-triidobenzoic acid was dissolved in ml. of an aqueous 4 N solution of sodium hydroxide. 0.1 mole of bis[2,3-epoxypropyl]ether was slowly added in a dropwise manner to the solution at 40 C. with stirring for 3 hours. The reaction mixture was then allowed to stand for 20 hours at 20 C., whereupon an aqueous 6 N solution of hydrochloride was added in an amount suflicient to cause precipitation of the discarboxylic acid formed in the reaction. The precipitated acid was removed by filtration and washed with water.
• the acid was dissolved in aqueous 1 N sodium hydroxide solution and again precipitated by adding aqueous 6 N solution of hydrochloride.
• the precipitate was thoroughly washed with water and dried under vacuum at 50 C.
• the dried precipitate was dissolved in m1. of dioxane. A small quantity of undissolved material was removed by filtration. 700 ml. of water were added to the dioxane solution.
• the obtained precipitate was isolated and dissolved in aqueous 1 N solution of sodium hydroxide; whereupon aqueous 6 N solution of hydrochloride was added to cause the acid to precipitate.
• the acid was once again dissolved in aqueous 1 N solution of sodium hydroxide and caused to precipitate by adding aqueous 6 N solution of hydrochloride.
• the precipitate was washed thoroughly with water and dried under vacuum at 50 C. Approximately 100 grams of the dicarboxylic acid formed in the reaction was obtained.
• Solutions can be prepared from the obtained acid by adding water and, for instance, equivalent amounts of sodium hydroxide or methylglucamine.
• ous 6 N solution of hydrochloride was added in an amount suflicient to precipitate the dicarboxylic acid formed in the reaction.
• the acid was removed by filtration and washed with water.
• the acid was dissolved in aqueous 1 N solution of sodium hydroxide and caused to precipitate again by adding aqueous 6 N solutions of hydrochloride.
• the precipitate was thoroughly washed with water, whereupon it was dried under vacuum at 50 C.
• the dried precipitate was dissolved in 150 ml. of dioxane. A small quantity of undissolved substance was removed by filtration. 500 ml. of water were added to the dioxane solution.
• the obtained precipitate was isolated and dissolved in aqueous l N solution of sodium hydroxide, whereupon aqueous 6 N solution of hydrochloride was added for the purpose of precipitating the acid.
• the acid was again dissolved in NaOH- solution and precipitated by adding aqueous 6 N solution of hydrochloride.
• the precipitate was thoroughly washed with water and dried under vacuum at 50 C. Approximately 100 grams of the dicarboxylic acid formed in the reaction was obtained.
• Salt solutions can be prepared from the obtained acid by adding water and, for instance, equivalent amounts of sodium hydroxide or methyl glucamine.
• EXAMPLE 3 0.2 mole of the compound 3-acetylamino-2,4,6-triiodobenzoic acid was dissolved in 110' ml. of aqueous 4 N solution of sodium hydroxide. 0.1 mole of 1,4-butane-diolediglycide ether was slowly added to the solution in a dropwise manner at 40 C. with agitation for 3 hours. The reaction mixture was allowed to stand at 20 C. for 24 hours, whereupon aqueous 6 N solution of hydrochloride was added. The precipitated acid was removed by filtration and washed with water. The acid was dissolved in solution of sodium hydroxide and again precipitated by adding aqueous 6 N solution of hydrochloride.
• the precipitate was thoroughly washed with water, whereupon it was dried under vacuum at 50 C.
• the dried precipitate was dissolved in 200 ml. of dioxane, whereupon a small amount of undissolved residue was filtered off. 700 ml. of water were added to the dioxane solution.
• the obtained precipitate was isolated and dissolved in 250 ml. of aqueous 1 N solution of sodium hydroxide whereupon aqueous 6 N solution of hydrochloride was added for the purpose of precipitating the acid.
• the acid was again dissolved in sodium hydroxide solution and precipitated by adding aqueous 6 N solution of hydrochloride.
• the precipitate was thoroughly washed wtih water and dried under vacuum at 50 C., whereupon approximately 96 grams of the dicarboxylic acid formed in the reaction was obtained.
• Salt solutions can be prepared from the obtained acid by adding water, and, for instance, equivalent amounts of sodium hydroxide or methylglucamine.
• EXAMPLE 4 In a manner similar to that described in Example 1, 0.2 mole of 3-acetylamino-Z,4,6-triiodo benzoic acid was reacted with 0.1 mole of epichlorohydrin or with 0.1 mole of epibromohydrin or with 0.1 mole of dichlorohydrin. Purification of the dicarboxylic acid formed in the reaction was effected in the manner illustrated in Example 1.
• EXAMPLE 5 Solutions were prepared from the dicarboxylic acids obtained from each of the Examples 1, 2, 3 and 4, in the following manner:
• EXAMPLE 6 The solutions from Example 5 were injected into the blood vessels of rabbits, enabling visualization of the vessels by X-rays and photographs.
• EXAMPLE 7 Solutions from Example 5 were given orally to rabbits, whereupon the gastro-intestinal tract could be observed by X-rays and photographs, with good results.
• EXAMPLE 8 Solutions of sodium salts of the compounds, prepared in a manner similar to that of Example 5 and containing 20 grams of the dicarboxylic acids per ml. solution were administered as an enema via the rectum to rabbits; whereupon the intestines were made visible by means of X-rays and photographs, with good results.
• a compound as claimed in claim 1, wherein the bridge A of the compound is a member selected from the group consisting of --CH .CH(OH).CH and -CH .CH (OH) .CH( OH) .CH
• R is a member selected from the group consisting of acetyl and propionyl and wherein A is an alkylene group substituted by at least one substituent of the formula OR wherein R is selected from the group consisting of hydrogen, methyl, ethyl, acetyl, and propionyl; said alkylene group containing from 3 to 15 inclusive carbon atoms and being broken by at least one oxygen bridge of the formula O, and (B) physiologically acceptable salts thereof.
• bridge Jar-la has each nitrogen atom located at a distance of two carbon atoms from said at least one substituent, and that no more than one oxygen atom is bound to one and the same carbon atom in the bridge A.
• bridge A is a member selected from the group consisting of (a)OH2.cH(oH).0H2.o. oH2)4.o.CH2.0H(0H).OH2; (b)-CEIz.CH(OH).CHz.O.(CH2)2.O.CH2.CH(OH).CH (c)CHz.OH(OH).CHz.O.CH2.CH(OH),CH2; (d)CH2.CH(OH).CHz.O.CH2.CH(OH).CHz.O.CHz.CH(OH).CH1
• A is a member selected from the group consisting of (a) CH .CH(OH).CH .O.(CH .O.
• A a IELC C.NA-N.C 0.11 I I L l C (50011 JOOH wherein R is a member selected from the group consisting of acetyl and propionyl and wherein A is an alkylene group substituted by at least one substituent of the formula OH; said alkylene group containing from 3 to inclusive carbon atoms, and (B) physilogically acceptable salts thereof.
• R is a member selected from the group consisting of acetyl and propionyl and wherein A is an alkylene group substituted by at least one substituent of the formula OH; said alkylene group containing from 3 to 15 inclusive carbon atoms and being broken by at least one oxygen bridge of the formula O, and (B) physiologically acceptable salts thereof.
• R is a member selected from the group consisting of acetyl and propionyl and wherein A is alkylene substituted by at least one substituent of the formula OR wherein R is a member selected from the group consisting of hydrogen, methyl, ethyl, acetyl, and propionyl; said alkylene group containing from 3 to 15 inclusive carbon atoms and being broken by at least one oxygen bridge of the formula O, and physiologically acceptable salts thereof, which consists essentially of reacting at a temperature in the range of 0 to 50 C., an iodine compound of the formula:
• R has the above significance
• an alkylene group containing compound selected from the group consisting of compounds of the formula Y.A.X. wherein Y and X are each a halogen atom and A has the above significance and the corresponding epoxide compound obtainable from the compound Y.A.X. by splitting off hydrogen halide, and wherein the mole ratio of said iodine compound to said alkylene group containing compound is about 2:1.
• alkylene group containing compound is selected from the group consisting of (a) CH2-CH'CH2'0'(CH2)n'O-CHZCH-CHZ wherein n is an integer from 2 to 4 inclusive,
• R is a member selected from the group consisting of acetyl and propionyl
• A is alkylene substituted by at least one substituent of the formula OR wherein R is a member selected from the group consisting of hydrogen, methyl, ethyl, acetyl, and propionyl, said alkylene group containing from 3 to inclusive carbon atoms, and physiologically acceptable salts thereof, which consists essentially of reacting at a temperature in the range of 0 to 50 C., an iodine compound of the formula:
• alkylene group containing compound is selected from the group consisting of bifunctional glycerine derivatives of the formula X.CH .CH(OH).CH .Y, wherein X and Y are each a member selected from the group consisting of chloro and bromo, and corresponding epoxy compounds of the formula obtainable by splitting off hydrogen halide.

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Cited By (11)

• 1966
  • 1966-12-13 SE SE17052/66A patent/SE345198B/xx unknown
• 1967
  • 1967-12-11 US US689282A patent/US3574718A/en not_active Expired - Lifetime
  • 1967-12-12 GB GB56368/67A patent/GB1207975A/en not_active Expired
  • 1967-12-12 FR FR131890A patent/FR7250M/fr not_active Expired
  • 1967-12-12 NO NO170937A patent/NO121666B/no unknown
  • 1967-12-12 DE DE19671643493 patent/DE1643493A1/de active Pending

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