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Publication numberUS3574718 A
Publication typeGrant
Publication dateApr 13, 1971
Filing dateDec 11, 1967
Priority dateDec 13, 1966
Also published asDE1643493A1
Publication numberUS 3574718 A, US 3574718A, US-A-3574718, US3574718 A, US3574718A
InventorsBjork Lars, Erikson Uno E, Ingelman Bjorn G-A, Lindberg Bernt J
Original AssigneePharmacia Ab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Method for producing x-ray contrast agents
US 3574718 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent 3,574,718 METHOD FOR PRODUCING X-RAY CONTRAST AGENTS Lars Bjiirk, Uno E. Erikson, Bjorn G.-A. Ingelman, and Bernt J. Lindberg, Uppsala, Sweden, assignors to Pharmacia AB, Uppsala, Sweden No Drawing. Filed Dec. 11, 1967, Ser. No. 689,282 Claims priority, application Sweden, Dec. 13, 1966,

Int. Cl. C07c 3101/48, 103/32 US. Cl. 260-50111 22 Claims ABSTRACT OF THE DISCLOSURE The present invention is concerned with a method for the X-ray visualization of body cavities and a preparation for carrying out the method.

The method according to the invention is mainly characterized in that there is administered to the body a contrast-producing agent consisting of or containing one or more iodine compounds of the formula:

wherein 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.

According to a suitable embodiment of the invention, each nitrogen atom in the bridge ice is located at a distance of two carbon atoms from a group O-R In this connection, 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.

Acetyl and propionyl, for instance, may come into question as the substituent R. As R is preferably chosen a hydrogen atom when hydrophilic compounds are desired. When compounds having more lipophilic properties are desired there is chosen as R a lower alkyl or acyl group such as methyl or ethyl or acetyl or propiouyl.

Examples of the bridge A in the above formulae are:

CH2.CH(OH).CH2.O.CH.CHz.CH2.O.CHz. CH(OH) CH2 or CH2.CH (OH) .CHz.O.CH2.CH2.O.CHz.CHz.O.CH2.CH (OH).CHa or -CH2.OH (OH). 0131 .0. CH2.CH (OH).CH2.O. CHz.CH(OH) CHaor any of the above bridges which have one or more hydroxyl groups alkylated or acylated with, respectively, a lower alkyl group such as methyl or ethyl, or acyl group, such as acety or propionyl, said alkyl and acyl containing each no more than 5 carbon atoms.

Examples of 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.

As examples of valuable compounds may be mentioned the following wherein 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.

One example of the various body cavities which can be visualized according to the invention is the gastrointestinal tract. In this instance 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.

The novel iodine compounds used according to the invention have a low toxicity and present good characteristics as an X-ray contrast-producing agent.

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.

If the preparation according to the invention is in the form of an aqueous solution the concentration of the iodine compounds will be chosen in accordance with the field of application. Preferably, a content is chosen which exceeds grams per 100 ml. of solution. However, generally 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.

Examples of such salts are the sodium salt or methylglucamine salt. Sodium and methylglucamine salts are satisfactorily soluble in water.

As examples of the bifunctional compounds of the type Y.A.X. or corresponding epoxide compounds obtainable from the compound Y.A.X. by splitting off hydrogen halide can be mentioned where n is an integer, in the range of from 2 to 4 inclusive, and

CHZOH.CH2.O.CH2.OHCHZ and CH2-OH.CH .O.CHz.CH(OH).CHz.O.CH2.CHCHg or corresponding halogen hydrins, and bifunctional glycerine derivatives of the formula e.g., dichlorohydrin and dibromohydrin, or corresponding e.g. epichlorohydrin and epibromohydrin, obtainable by splitting oif hydrogen halide. Another example of such a bifunctional compound is 1,2-3,4-diepoxybutane.

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. In this connection, the alkaline reacting substance can also act as an acceptor for hydrogen halide possibly liberated in the reaction.

If it is desired to convert one or more hydroxyl groups in the bridge to alkylated or acylated hydroxyl groups 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.

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.

EXAMPLE 2 0.2 mole of 3-acetylamino-2,4,6-triiodobenzoic acid was dissolved in 100 ml. of an aqueous 4 N solution of sodium hydroxide. 0.1 mole of 1,2-ethanedioldiglycide ether was slowly added to the solution in a dropwise manner at 20 C. with agitation for 4 hours. The reaction mixture was allowed to stand for 24 hours at 20 C., whereupon 311116:

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:

35 grams of substance and equivalent amounts of methyl glucamine were dissolved in water to a solution volume of 100 ml. The pH was adjusted to 7.3-7.4. The solution was filtered and filled into bottles, which were sealed and sterilized by autoclaving.

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.

After the lapse of, for instance, 30 minutes, 1 hour and 2 hours X-ray examination and photographing of the stomach region showed a sufficiency of contrast-producing agent in the gall bladdeer and bile ducts.

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.

What we claim is:

1. A compound selected from the group consisting of (A) compounds of the formula:

has each nitrogen atom thereof located at a distance of two carbon atoms from said substituent and no more than one oxygen atom is bound to one and the same carbon atom in the bridge A.

3. 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

4. A compound of the formula:

and nontoxic salts thereof.

5. A compound selected from the group consisting of (A) compounds of the formula:

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 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.

6. A compound as claimed in claim 5, wherein the 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.

7. A compound as claimed in claim 5, wherein the 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

C'Ha

(f)OHz-CH(OH).CH2.O.CHzCHz.O.CHz.CHz.O.CH:.OH(OH).OH1

8. A compoundof the formula:

wherein A is a member selected from the group consisting of (a) CH .CH(OH).CH .O.(CH .O.

CH .CH( OH) .CH

(b) CH .CH(OH) .CH .0. (CH .0.

and (c) -CH .CH(OH) .CH .0.CH .CH(OH) .CH and nontoxic salts thereof.

9. A compound selected from the group consisting of (A) compounds of the formula:

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.

10. A compound as claimed in claim 9, wherein the bridge has each nitrogen atom thereof located at a distance of two carbon atoms from a group OH and no more than one oxygen atom is bound to one and the same carbon atom in the bridge A.

11. compound selected from the group consisting of (A) compounds of the formula:

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 15 inclusive carbon atoms and being broken by at least one oxygen bridge of the formula O, and (B) physiologically acceptable salts thereof.

12. A compound as claimed in claim 11, wherein the bridge ALA-la has each nitrogen atom located at a distance of two carbon atoms from a group OH, and that no more than one oxygen atom is bound to one and the same carbon atom in the bridge A.

13. A method for the preparation of compounds of the following formula:

wherein 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:

and nontoxic salts thereof, wherein R has the above significance, with 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.

14. A method as claimed in claim 13 wherein said 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,

(b) CHzCH-OHz-O-CH2-CH-CHz wherein 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 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:

I COOH and nontoxic salts thereof wherein R has the above significance, with an alkylene group containing compound selected from the group consisting of compounds of the formula Y.A.X. wherein Y and X are each halogen and A has the above significance, and the corresponding epoxidle compounds obtainable from the compound Y.A.X. by spltitting 01f hydrogen halide, and wherein the mole ratio of said iodine compound to said alkylene group containing compound is about 2:1.

19. A method as calimed in claim 18 wherein said 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.

20. A method as claimed in claim 18, wherein the compound is recovered as a member selected from the group consisting of sodium salt; methyl glucamine salt and tris-hydroxy-methylaminomethane salt.

21. A method as claimed in claim 18, wherein the compound is recovered as its acid.

22. A method as calimed in claim 18, which is carried out in the presence of an alkaline reacting substance.

References Cited UNITED STATES PATENTS 3,178,473 4/1965 Holtermann et a1. 260-519 LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON, Assistant Examiner U.S. Cl. X.R.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3852341 *Apr 26, 1971Dec 3, 1974Pharmacia AbNovel iodine containing polymers useful as x-ray contrast agents
US4021481 *Dec 2, 1974May 3, 1977Nyegaard & Co. A/SX-ray contrast agents
US5310538 *Mar 11, 1993May 10, 1994Sterling Winthrop Inc.Contrast agents
US5316755 *Feb 2, 1993May 31, 1994Sterling Winthrop Inc.Compositions of iodophenoxy alkanes and iodophenyl ethers for visualization of the gastrointestinal tract
US5318769 *Mar 31, 1993Jun 7, 1994Sterling Winthrop Inc.Compositions of iodophenyl esters for X-ray visualization of the gastrointestinal tract
US5326553 *Feb 2, 1993Jul 5, 1994Sterling Winthrop Inc.Compositions of iodophenoxy alkanes and iodophenyl ethers in film-forming materials for visualization of the gastrointestinal tract
US5336484 *Mar 31, 1993Aug 9, 1994Sterling Winthrop Inc.Compositions of iodophenyl esters and iodophenyl sulfonates in film-forming materials for visualization of the gastronintestinal tract
US5348727 *Mar 11, 1993Sep 20, 1994Sterling Winthrop Inc.Compositions of iodophenoxy alkylene ethers for visualization of the gastrointestinal tract
US5372800 *Feb 4, 1994Dec 13, 1994Sterling Winthrop Inc.X-ray contrast coating
US5385722 *Apr 18, 1994Jan 31, 1995Sterling Winthrop Inc.Compositions of iodophenyl esters and iodophenyl sulfonates and cellulose derivatives for visualization of the gastrointestinal tract
US5466435 *Apr 4, 1994Nov 14, 1995Sterling Winthrop Inc.Compositions of iodophenoxy alkylene ethers and cellulose derivatives for visualization of the gastrointestinal tract
US5468466 *Feb 1, 1994Nov 21, 1995Sterling Winthrop, Inc.Compositions of iodophenyl sulfonates for X-ray visualization of the gastrointestinal tract
US5472682 *May 26, 1994Dec 5, 1995Sterling Winthrop Inc.Compositions of iodophenyl esters and iodophenyl sulfonates and pharmaceutically acceptable clays for visualization of the gastrointestinal tract
US5492687 *May 3, 1994Feb 20, 1996Sterling Winthrop Inc.X-ray contrast agents
US5531979 *May 23, 1994Jul 2, 1996Sterling Winthrop Inc.X-ray contrast composition
US5607660 *May 20, 1994Mar 4, 1997Sterling Winthrop Inc.X-ray contrast agents for intestines
US5620677 *Feb 1, 1994Apr 15, 1997Sterling Winthrop Inc.Compositions of iodophenoxy alkanes and iodophenyl ethers for visualization of the gastrointestinal tract
Classifications
U.S. Classification562/455, 424/9.453, 560/251, 562/579
International ClassificationA61K49/04
Cooperative ClassificationA61K49/0452
European ClassificationA61K49/04H8B