US3867431A - Contrast agent for angiography and urography - Google Patents

Contrast agent for angiography and urography Download PDF

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US3867431A
US3867431A US274973A US27497372A US3867431A US 3867431 A US3867431 A US 3867431A US 274973 A US274973 A US 274973A US 27497372 A US27497372 A US 27497372A US 3867431 A US3867431 A US 3867431A
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acid
compound
urography
angiography
propanediol
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Ernst Felder
Davide Pitre
Hans Zutter
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Bracco SpA
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    • 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

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  • the aqueous solutions employed contained 300 mg iodine per milliliter and were injected at a rate of g iodine per minute per kg of test animal weight.
  • the amount of aqueous test solution was 2 ml per kg of body weight, and the concentration was varied to modify the dosage.
  • All solutions used for testing intracisternal toxicity contained 280 mg iodine per milliliter. Hyphens in the Table indicate that the test was not performed.
  • the free acid of Compound A is primarily useful as an intermediate in the preparation of the water-soluble salts with pharmaceutically acceptable alkali metals and amines.
  • Sodium is the preferred alkali metal.
  • the lithium salt may also be employed.
  • the other alkali metals contribute physiological properties of their own which are not normally desirable.
  • Small amounts of the calcium or magnesium salts may be employed jointly with the alkali metal salts.
  • the amines employed are those commonly used in galenic pharmacy as physiologically inert, cationic moieties in salts of physiologically active acids. They include, but are not limited to N-methylglucamine, N- methylxylamine l-methylamino-l dsoxy-[D1-xylite), l-methylamino-2,3-propanediol, monoethanolamine, diethanolamine, tris-(hydroxymethyl)-aminomethane, and mixtures of such alkanolamines.
  • the free acid of Compound A is prepared by alkylating 3-acetyl-amino-5-acetylaminomethyl-2,4,6- triiodobenzoic acid in strongly alkaline solution with an ester of the formulas X CH CHOH CH OH or x c21 CH ⁇ 6/CH2 wherein X is the anionic radical of a strong acid, such as a hydrogen halide (l-lCl, HB,, HI), an alkylsulfonic acid, or an arylsulfonic acid..An epoxide may replace the esters.
  • the most conveniently available alkylating agents include 3-chloro-l,2-propanediol, 3-bromo-l ,2-
  • the alkylation is preferably performed in alcoholic solution in the presence of an alkali metal alcoholate as an acid acceptor.
  • the aqueous solutions of the salts are epichlorohydrin,
  • the solutions are also employed to advantage in urography. It has been found that the two hydroxyl groups in the side chain in position 3 do not materially interfere with excretion of the compound by the kidney so that at least 60% to 70% of an intravenous dosage of 100 mg per kg body weight is discharged by the kidney. of standard laboratory test animals within three hours. A sufficient amount of the radiopaque material is thus available in the urinary system for producing X-ray pictures of good contrast. Otherwise closely related compounds having more than two hydroxyl groups in side chains of the basic triiodobenzoic acid molecule do not produce useful X-ray images of the urinary tract.
  • EXAMPLE 1 50.2 g 3-Acetylamino-5-acetylaminomethyl-2,4,6- triiodobenzoic acid (0.08 mole) was dissolved in 400 ml methanol, and the solution was mixed sequentially with 128 ml 2.5-molar sodium methylate solution (0.32 mole) in methanol and 13.4 ml 3chloro-l,2- propanediol (0.16 mole). The mixture was stirred at ambient temperature (about 20C) for 24 hours. An additional 32 ml 2.5-molar sodium methylate solution (0.08 mole) and 6.7 ml 3-chloro-1,2-propanediol were admixed, and stirring was continued for 24 hours.
  • the free acid is soluble in 40 times its own weight of boiling water, 7 weights of cold methanol, 3 weights of boiling methanol, 50 weights of cold ethanol, and 5 weights of boiling ethanol, but is insoluble in chloroform.
  • the salts with the alkali metals and amines mentioned above are readily soluble in water, the sodium and N-methylglucamine salts dissolving at C in about their own weights of water.
  • EXAMPLE 3 12.55 g 3-Acetylamino-5-acetylaminomethyl-2,4,6- triiodobenzoic acid (0.02 mole) was dissolved in ml of a 0.5 molar solution of sodium methylate in methanol, and 4 g 2,3-epoxy-1-propanol was added. The mixture was stirred for 1 hour at ambient temperature and stored thereafter for 60 hours. 1t was then worked up as in Example 1 to recover 10.5 g 3-(N-[3,ydihydroxypropyl-acetylamino)-5-acetylaminomethyl- 2,4,6-triiodobenzoic acid melting at 196 to 198C (74.7% yield).
  • EXAMPLE 4 553 g 3-(N-B,y-dihydroxypropyl-acetylamino)-5- acetylaminomethyl-Z,4,6-triiodobenzoic acid, 136.7 g N-methylglucamine, and 3.6 g sodium hydroxide were added sequentially with stirring to a solution of 0.01 g disodium edetate in a small amount of bi-distilled wa ter, and adding enoughadditional water to produce 800 ml solution. The solution was adjusted to pH 7.1i0.2, subjected to ultrafiltration, distributed in glass vials in amounts of 10 and 20 ml, and sterilized.
  • the injectable solutions so obtained contained 375 mg iodine per milliliter.
  • a compound as set forth in claim 1 which is a salt of said acid with sodium, lithium, or an alkanolamine.
  • a compound as set forth in claim 1 which is a salt of said acid with an alkanolamine selected from the group consisting of N-methylglucaminc, N- methylxylamine, 1-methylamino-2,3propanediol, monoethanolamine, diethanolamine, and tris-(hydroxymethyl )-aminomethane.
  • an alkanolamine selected from the group consisting of N-methylglucaminc, N- methylxylamine, 1-methylamino-2,3propanediol, monoethanolamine, diethanolamine, and tris-(hydroxymethyl )-aminomethane.

Abstract

3-(N- Beta , gamma -dihydroxypropyl-acetyl-amino)-5acetylaminomethyl-2,4,6-triiodobenzoic acid and its non-toxic, water-soluble salts with alkali metals and amines are better tolerated by the central nervous system for intracerebral and intracisternal application than X-ray contrast agents available heretofore for cerebral angiography. They are preferentially excreted from the blood by the kidney in a manner to make them useful for urography.

Description

United States Patent [1 1 Felder et a1.
[ Feb. 18, 1975 CONTRAST AGENT FOR ANGIOGRAPHY AND UROGRAPHY [75] Inventors: Ernst'Felder; Davide Pitre, both of Milan, ltaly; Hans Zutter, Schaffhausen, Switzerland [73] Assignee: Bracco Industria Chimica Societa per Azioni, Milan, Italy [22] Filed: July 25, 1972 [21] Appl. No.: 274,973
[30] Foreign Application Priority Data Aug. 26, 1971 Switzerland 12569/71 [52] US. Cl 260/50l.l1, 260/519, 424/5 [51] Int. Cl. C07c 103/32 [58] Field of Search 260/501.l1, 519
[56] References Cited UNITED STATES PATENTS 3,360,436 12/1967 Felder et al 260/50l.ll
3,702 866 11/1972 Salvesen et al. 260/50lil1 Primary Examiner--Leon Zitver Assistant Examiner-Michael W. Glynn Attorney, Agent, or Firm-1-1ans Berman; Kurt Kelman [57] ABSTRACT 4 Claims, N0 Drawings CONTRAST AGENT FOR ANGIOGRAPHY AND UROGRAPHY This invention relates to X-ray contrast agents, and particularly to contrast agents suitable for angiography and urography which are derivatives of 2,4,6- triiodobenzoic acid.
It has been found that 3-(N-B,y-dihydroxypropylacetyl)-amino)--acetylaminomethyl-2,4,6- triiodobenzoic acid of the formula cooa on I ca -cn-ca -oa CH3-CO-NH-CH2 n 2 2 co-ca I 3 and its non-toxic, water-soluble salts with alkali metals and amines are better tolerated by the central nervous system than contrast agents available heretofore, being particularly superior to the known compounds in their low intracerebral and intracisternal toxicities. They are generally suitable for vasography, and particularly for cerebral angiography.
The following Table shows toxicity values for the compound of the invention (Compounds A and A), for the structurally closely related 3-(N-B- hydroxyethyl-acetylamino)-5-acetylaminomethyl- 2,4,6-triiodobenzoic acid (Compound B, German published patent application No. 1,928,838, Example 5), and for lodamide (Compound C, 3-acetylamino-5- acetylaminomethyl2,4,6-triiodobenzoic acid, U.S. Pat. No. 3,360,436) which is representative of the best contrast agents available heretofore for cerebral angiography.
Compounds A, B, and C were employed in the form of their N-methylglucamine salts, and Compound A as the corresponding sodium salt of the invention. All listed toxicity values are expressed as LD in mg iodine per kg of test animal, the intravenous and intracerebral toxicity being determined in mice, and the intracisternal toxicity in rabbits. ldentical standardized test conditions were maintained for each tested compound in each group of tests, and the tests of each group were performed at the same time so that the test results for the several compounds are directly comparable.
In testing toxicity after intravenous injection, the aqueous solutions employed contained 300 mg iodine per milliliter and were injected at a rate of g iodine per minute per kg of test animal weight. In all tests for intracerebral toxicity, the amount of aqueous test solution was 2 ml per kg of body weight, and the concentration was varied to modify the dosage. All solutions used for testing intracisternal toxicity contained 280 mg iodine per milliliter. Hyphens in the Table indicate that the test was not performed.
Table Com- Toxicity, LD mg l per kg pound Intravenous lntraccrcbral intracisternal 24 12 48 I2 48 12 hrs. days hrs. days hrs. days A 6600 6600 285 39 29.4 A 7400 285 38 B 5800 5700 21 C 6600 6600 97 Z0 As is evident from the values for intravenous toxicity, the compounds of the invention are at least aswell tolerated generally as lodamide (Compound C) which has been in extensive clinical use. In their most important property, the tolerance by the central nervous system, the compounds of the invention are superior by a wide margin to Compounds B and C, both in intracerebral application to mice and in intracisternal application to rabbits.
The free acid of Compound A is primarily useful as an intermediate in the preparation of the water-soluble salts with pharmaceutically acceptable alkali metals and amines. Sodium is the preferred alkali metal. The lithium salt may also be employed. The other alkali metals contribute physiological properties of their own which are not normally desirable. Small amounts of the calcium or magnesium salts may be employed jointly with the alkali metal salts.
The amines employed are those commonly used in galenic pharmacy as physiologically inert, cationic moieties in salts of physiologically active acids. They include, but are not limited to N-methylglucamine, N- methylxylamine l-methylamino-l dsoxy-[D1-xylite), l-methylamino-2,3-propanediol, monoethanolamine, diethanolamine, tris-(hydroxymethyl)-aminomethane, and mixtures of such alkanolamines.
The free acid of Compound A is prepared by alkylating 3-acetyl-amino-5-acetylaminomethyl-2,4,6- triiodobenzoic acid in strongly alkaline solution with an ester of the formulas X CH CHOH CH OH or x c21 CH\6/CH2 wherein X is the anionic radical of a strong acid, such as a hydrogen halide (l-lCl, HB,, HI), an alkylsulfonic acid, or an arylsulfonic acid..An epoxide may replace the esters. The most conveniently available alkylating agents include 3-chloro-l,2-propanediol, 3-bromo-l ,2-
propanediol, 3-iodo-l,2-propanediol, 3-benzenesulfonyloxy-l ,2-propanediol, 3-toluenesulfonyloxy-l ,2- propanediol, 3-methanesulfonyloxy-l ,2-propanediol,
2,3-epoxyl -propanol, 1- benzenesulfonyloxy-2,3-epoxypropane, methanesulfonyloxy-2,3-epoxypropane.
The alkylation is preferably performed in alcoholic solution in the presence of an alkali metal alcoholate as an acid acceptor. The aqueous solutions of the salts are epichlorohydrin,
and
prepared by dissolving the free acid in aqueous soluprecautions well established by the use of lodamide when it is desired to make blood vessels, particularly those of the. brain, visible in X-ray images.
The solutions are also employed to advantage in urography. It has been found that the two hydroxyl groups in the side chain in position 3 do not materially interfere with excretion of the compound by the kidney so that at least 60% to 70% of an intravenous dosage of 100 mg per kg body weight is discharged by the kidney. of standard laboratory test animals within three hours. A sufficient amount of the radiopaque material is thus available in the urinary system for producing X-ray pictures of good contrast. Otherwise closely related compounds having more than two hydroxyl groups in side chains of the basic triiodobenzoic acid molecule do not produce useful X-ray images of the urinary tract.
The following Examples are further illustrative of the invention.
EXAMPLE 1 50.2 g 3-Acetylamino-5-acetylaminomethyl-2,4,6- triiodobenzoic acid (0.08 mole) was dissolved in 400 ml methanol, and the solution was mixed sequentially with 128 ml 2.5-molar sodium methylate solution (0.32 mole) in methanol and 13.4 ml 3chloro-l,2- propanediol (0.16 mole). The mixture was stirred at ambient temperature (about 20C) for 24 hours. An additional 32 ml 2.5-molar sodium methylate solution (0.08 mole) and 6.7 ml 3-chloro-1,2-propanediol were admixed, and stirring was continued for 24 hours.
The reaction solution was diluted with 400 ml water, neutralized with acetic acid, evaporated to one half of its original volume, and acidified with hydrochloric acid. It was then stirred overnight at ambient temperature, and the precipitate formed was recovered by suction filtration. The almost pure 3-(N-B,'ydihydroxypropyl-acetylamino)--acetylaminomethyl- 2,4,6-triiodobenzoic acid so obtained weighed 49.5 g (88% yield). When recrystallized from aqueous, approximately 40% ethanol, it melted at 195 197C and had an equivalent weight of 709 (calculated: 702). It was further identified by elementary analysis:
Calculated for C|5H11|:N2OG Found A thin layer chromatogram on silica gel with butanollwater/glacial acetic acid 3/2/1 gave a R, value of 0.57.
The free acid is soluble in 40 times its own weight of boiling water, 7 weights of cold methanol, 3 weights of boiling methanol, 50 weights of cold ethanol, and 5 weights of boiling ethanol, but is insoluble in chloroform. The salts with the alkali metals and amines mentioned above are readily soluble in water, the sodium and N-methylglucamine salts dissolving at C in about their own weights of water.
EXAMPLE 2 benzenesulfonyloxy-l,2-propanediol respectively and stirred with a turbine type agitator for 60 hours.
3-(N-B,y-dihydroxypropyl-acetylamino)-5- acetylaminomethyl-2,4,6-triiodobenzoic acid was recovered from each reaction mixture in the manner described in Example 1. The products had melting points between 194 and 198C, and the yields varied between and 90%.
EXAMPLE 3 12.55 g 3-Acetylamino-5-acetylaminomethyl-2,4,6- triiodobenzoic acid (0.02 mole) was dissolved in ml of a 0.5 molar solution of sodium methylate in methanol, and 4 g 2,3-epoxy-1-propanol was added. The mixture was stirred for 1 hour at ambient temperature and stored thereafter for 60 hours. 1t was then worked up as in Example 1 to recover 10.5 g 3-(N-[3,ydihydroxypropyl-acetylamino)-5-acetylaminomethyl- 2,4,6-triiodobenzoic acid melting at 196 to 198C (74.7% yield).
EXAMPLE 4 553 g 3-(N-B,y-dihydroxypropyl-acetylamino)-5- acetylaminomethyl-Z,4,6-triiodobenzoic acid, 136.7 g N-methylglucamine, and 3.6 g sodium hydroxide were added sequentially with stirring to a solution of 0.01 g disodium edetate in a small amount of bi-distilled wa ter, and adding enoughadditional water to produce 800 ml solution. The solution was adjusted to pH 7.1i0.2, subjected to ultrafiltration, distributed in glass vials in amounts of 10 and 20 ml, and sterilized.
The injectable solutions so obtained contained 375 mg iodine per milliliter.
EXAMPLE 5 coon I. I OH 1 ca -CH-CH -OH CH3-CONH-CH2 N 2 2 co-cr-r I 3 or a water-soluble salt of said acid with a pharmaceutically acceptable alkali metal or amine.
2. A compound as set forth in claim 1 which is said acid.
3. A compound as set forth in claim 1 which is a salt of said acid with sodium, lithium, or an alkanolamine.
4..A compound as set forth in claim 1 which is a salt of said acid with an alkanolamine selected from the group consisting of N-methylglucaminc, N- methylxylamine, 1-methylamino-2,3propanediol, monoethanolamine, diethanolamine, and tris-(hydroxymethyl )-aminomethane.

Claims (4)

1. A COMPOUND WHICH IS THE 3-(N--B,$DIHYDROXYPROPYLACETYLAMINO)-5ACETYLAMINOMETHYL-2,4,6TRIIODOBENZOIC ACID OF THE FORMULA
2. A compound as set forth in claim 1 which is said acid.
3. A compound as set forth in claim 1 which is a salt of said acid with sodium, lithium, or an alkanolamine.
4. A compound as set forth in claim 1 which is a salt of said acid with an alkanolamine selected from the group consisting of N-methylglucamine, N-methylxylamine, 1-methylamino-2,3-propanediol, monoethanolamine, diethanolamine, and tris-(hydroxymethyl)-aminomethane.
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4001323A (en) * 1974-12-13 1977-01-04 Savac Ag Water-soluble, non-ionizing hydroxy-containing amide derivatives of 2,4,6-triiodo-isophthalic acid
JPS5321137A (en) * 1976-06-11 1978-02-27 Serukapeto Xxray contrast medium
US4138589A (en) * 1974-06-17 1979-02-06 Mallinckrodt, Inc. Substituted isophthalamic acids
US4285928A (en) * 1979-01-25 1981-08-25 Juro Wada Contrast composition for angiography
WO1987000757A1 (en) * 1985-08-09 1987-02-12 Cook Imaging, Inc. Non-ionic polyol contrast media from ionic contrast media
US4954348A (en) * 1985-08-09 1990-09-04 Cook Imaging Corporation Non-ionic polyol contrast media from ionic contrast media
US5035877A (en) * 1985-08-09 1991-07-30 Cook Imaging Corporation Non-ionic contrast media from ionic contrast media
US5705692A (en) * 1996-09-27 1998-01-06 Abbott Laboratories Process for the preparation of iohexol
US20080206862A1 (en) * 2007-02-28 2008-08-28 Cinvention Ag High surface cultivation system bag
US20080213742A1 (en) * 2007-02-28 2008-09-04 Cinvention Ag High surface cultivation system

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2014728A1 (en) 2005-01-13 2009-01-14 Cinvention Ag Composite material coatings

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3360436A (en) * 1962-11-23 1967-12-26 Eprova Ltd Radioopaque compounds and methods of preparing the same
US3702866A (en) * 1968-06-10 1972-11-14 Nyegaard & Co As Novel 3,5 - bis-acylamido - 2,4,6-triiodobenzoic acids and 5-acylamido-2,4,6-triiodoisophthalamic acids

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3360436A (en) * 1962-11-23 1967-12-26 Eprova Ltd Radioopaque compounds and methods of preparing the same
US3702866A (en) * 1968-06-10 1972-11-14 Nyegaard & Co As Novel 3,5 - bis-acylamido - 2,4,6-triiodobenzoic acids and 5-acylamido-2,4,6-triiodoisophthalamic acids

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4138589A (en) * 1974-06-17 1979-02-06 Mallinckrodt, Inc. Substituted isophthalamic acids
US4001323A (en) * 1974-12-13 1977-01-04 Savac Ag Water-soluble, non-ionizing hydroxy-containing amide derivatives of 2,4,6-triiodo-isophthalic acid
JPS5321137A (en) * 1976-06-11 1978-02-27 Serukapeto Xxray contrast medium
JPS5654310B2 (en) * 1976-06-11 1981-12-24
US4285928A (en) * 1979-01-25 1981-08-25 Juro Wada Contrast composition for angiography
WO1987000757A1 (en) * 1985-08-09 1987-02-12 Cook Imaging, Inc. Non-ionic polyol contrast media from ionic contrast media
US4954348A (en) * 1985-08-09 1990-09-04 Cook Imaging Corporation Non-ionic polyol contrast media from ionic contrast media
US5035877A (en) * 1985-08-09 1991-07-30 Cook Imaging Corporation Non-ionic contrast media from ionic contrast media
AU650432B2 (en) * 1985-08-09 1994-06-23 Guerbet Llc Intermediates useful in the preparation of contrast medium and methods for their preparation
US5705692A (en) * 1996-09-27 1998-01-06 Abbott Laboratories Process for the preparation of iohexol
US20080206862A1 (en) * 2007-02-28 2008-08-28 Cinvention Ag High surface cultivation system bag
US20080213742A1 (en) * 2007-02-28 2008-09-04 Cinvention Ag High surface cultivation system

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AR192959A1 (en) 1973-03-21
FR2150805B1 (en) 1975-11-28
DE2229360A1 (en) 1974-07-11
AU4485072A (en) 1974-01-24
CH551790A (en) 1974-07-31
BE788054A (en) 1973-02-26
FR2150805A1 (en) 1973-04-13
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AT313470B (en) 1974-02-25
AU461619B2 (en) 1975-05-29
CA976184A (en) 1975-10-14
BR7205741D0 (en) 1973-11-01

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