US3047466A - X-ray contrast agent - Google Patents

X-ray contrast agent Download PDF

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Publication number
US3047466A
US3047466A US779065A US77906558A US3047466A US 3047466 A US3047466 A US 3047466A US 779065 A US779065 A US 779065A US 77906558 A US77906558 A US 77906558A US 3047466 A US3047466 A US 3047466A
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compounds
carbon atoms
ray contrast
general formula
compound
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US779065A
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Priewe Hans
Poljak Alexander
Junkmann Kart
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Bayer Pharma AG
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Schering AG
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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
    • 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
    • A61K49/0495—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 intended for oral administration

Definitions

  • the present invention relates to X-ray contrast agents, and more particularly to X-ray contrast agents suit-able for peroral administration to serve as a contrast agent for the taking of X-ray pictures of the gall bladder and in general for cholecystography.
  • the present invention mainly comprises a compound selected from the group consisting of compounds of the followinggeneral formula:
  • R is a hydrocarbon radical of 1-6 carbon atoms, and non-toxic salts thereof.
  • the advantages of the compounds of the present invention are: considerably lower toxicity, a markedly excellent resorbability upon peroral administration, and a preferred deposition in the gall with a simultaneous increased degree of contrast development. Furthermore, the new compounds of the present invention have the advantage of being able to leave the body, if necessary, through the urinary tract, which in the case of occlusions of the bile duct represents a considerable advantage as compared to the above mentioned monoamino compounds which do not have this property.
  • the compounds of the present invention are primarily useful as radiopaque substances to be given orally for cholecystography, these compounds being given in the form of the free acids or in the form of their non-toxic salts.
  • the compounds may also, however, be given for the purpose of taking X-ray pictures of other organs than the gall bladder, such as body cavities in general.
  • the substituent R is a hydrocarbon radical of preferably 1-6 carbon atoms.
  • the substituent R is an alkyl or cycloalkyl radical of l-6 carbon atoms.
  • the compounds may be used in the form of the tree acids or in the form of non-toxic salts thereof with inorganic or organic bases.
  • suitable salts which may be mentioned are: the methylglucamine, ammonium, sodium, lithium, potassium, calcium, glucamine, ethylglucamine, ethanol-amine, diethanolamine and triethanolamine salts.
  • the compounds may be mixed with suitable pharmaceutical excipients and made up into a form suitable for 3,647,466 Patented July 31, 1962 ice 2 oral administration, for example in the form of capsules, dragees, and the like.
  • the compounds of the present invention are preferably produced by iodinating a compound having the following general formula:
  • the styrene resin may be produced according to the methods generally used in organic synthesis for the production of similar compounds, for example from 3,5-dinitrobenzoyl-acetic ester by introducing into the zit-position in known manner the desired aliphatic or cycloaliphatic radical. This is carried out, for exam le, by reacting the sodium enolate of the 3,S-dinitrobenzoyl-acetic ester in alcoholic solution with an alkyl or cycloalltyl halogenide, e.g. chloromethyl, isopropylbromide, hexyliodide, or the like. Upon hydrogenation the corresponding ,8-3,5-diaminophenyl- 8- hydroxy-a-alkyl. or cycloalkyl-propionic acid ester is obtained. By reaction with thionyl chloride, the ,B-position hydroxyl is replaced by chlorine, which is subsequently replaced by hydrogen by means of hydrogenation.
  • Example 1 18 g. of a-ethyl-B-(3,5-diaminophenyl)-propionic acidethyl ester are heated for saponifioation with a mixture of 150 cc. of 3 N sodium hydroxide and 250 cc. of methanol for 3 hours to boiling under reflux conditions. The reaction mixture is then acidified with dilute hydrochloric acid and the methanol is driven ofi under vacuum.
  • the distillation residue is diluted with ice water to 1200 cc. and 90 cc. of 2 N potassium iodide-dichloride solution is added dropwise under stirring.
  • the precipita ted sand colored precipitate is subjected to suction filtration, washed with water and dissolved in ether.
  • the solution which is dried over sodium sulfate is reacted with alcoholic sodium hydroxide which results in precipitation of the sodium salt of u-ethyl-B-(3,S-diarnino 2,4,6-triiodophenyl)spropionic acid.
  • the salt is filtered by suction, dissolved in water, and the free acid is precipitated from the aqueous solution by means of dilute hydrochloric acid.
  • the yield of the air-dried product is 24 g.
  • the melting point is above C., with decomposition.
  • the substance By treatment with benzene under cold conditions and subsequent recrystallization from a large amount of benzene, the substance is obtained in the form of practically colorless crystals having a melting point of 156.5- 157 C., with decomposition.
  • the salt may be obtained by neutralization of the acid in aqueous solution with the corresponding base, and then freezing-drying.
  • Example 2 10 kg. of the methyl-[H3,S-diamino-2,4,6 triiodophenyl)propionic acid produced according to Example 1 are kneaded in a kneading machine with 4 liters of starch paste containing 200 g. of corn starch. The wet mass is granulated in a normal manner in a granulation machine and then dried under vacuum. The finished granulate is then mixed with 1 kg. of corn starch and 50 g. of magnesium stcarate and pressed into tablets each containing 500 mg. of the active ingredient.
  • Example 3 The easily water soluble sodium salt of methyl-543,5- diamino-2,4,G-triiodophenyl)-propionic acid produced according to Example 1 is introduced into gelatin capsules filling the same. Each capsule contains 750 mg. of the active substance.
  • the sodium salt can be mixed with a 40% mixture of corn oil, soybean lecithin and cocoa fat to a flowing paste.
  • Example 4 The granulate produced according to Example 2 is with 20% of the weight thereof of sugar syrup formed into dragees in a dragee vessel, and subsequently waxed.
  • R is a hydrocarbon radical of 1-6 carbon atoms; and non-toxic salts thereof.
  • R is an alkyl radical of 1-6 carbon atoms.
  • R is a cycloalkyl radical of 1-6 carbon atoms.
  • R is an alkyl radical of l-6 carbon atoms.
  • Hal 1 wherein R is a cycloalkyl radical of 1-6 carbon atoms.
  • R is an alkyl radical of 1-6 carbon atoms.
  • R H N I R iN wherein R is a hydrocarbon radical of 1-6 carbon atoms, and non-toxic salts thereof; and pharmaceutical excipients adapted for pero-ral administration.

Description

3,047,466 X-RAY CONTRAST AGENT Hans Priewe, Berlin-Steglitz, Alexander Poljak, Berlin- Frohnan, and Karl Junkmann, Berlin, Germany, assignors to Firma Schering A.G., Berlin, Germany No Drawing. Filed Dec. 9, 1958, Ser. No. 779,065 Claims priority, application Germany Dec. 18, 1957 12 Claims. (Cl. 167-95) The present invention relates to X-ray contrast agents, and more particularly to X-ray contrast agents suit-able for peroral administration to serve as a contrast agent for the taking of X-ray pictures of the gall bladder and in general for cholecystography.
It is a primary object of the present invention to provide new X-ray contrast agents for peroral administration which are suitable for cholecystography.
It is another object of the present invention to provide for the production of the new compounds of the present invention.
*Other objects and advantages of the present invention will be apparent from a further reading of the -specification and of the appended claims.
With the above objects in view, the present invention mainly comprises a compound selected from the group consisting of compounds of the followinggeneral formula:
1 R HzN I wherein R is a hydrocarbon radical of 1-6 carbon atoms, and non-toxic salts thereof.
It has been discovered that while a-alkyl-fl-(B-amino- 2,4,6-triiodophenyl) -propionic acids are suitable as X-ray contrast agents for the taking of X-ray pictures of the gall bladder, the diamino compounds of the present invention have many advantages over the above mentioned monoamino compounds.
Among the advantages of the compounds of the present invention are: considerably lower toxicity, a markedly excellent resorbability upon peroral administration, and a preferred deposition in the gall with a simultaneous increased degree of contrast development. Furthermore, the new compounds of the present invention have the advantage of being able to leave the body, if necessary, through the urinary tract, which in the case of occlusions of the bile duct represents a considerable advantage as compared to the above mentioned monoamino compounds which do not have this property.
The compounds of the present invention are primarily useful as radiopaque substances to be given orally for cholecystography, these compounds being given in the form of the free acids or in the form of their non-toxic salts. The compounds may also, however, be given for the purpose of taking X-ray pictures of other organs than the gall bladder, such as body cavities in general.
As indicated above, the substituent R is a hydrocarbon radical of preferably 1-6 carbon atoms. Preferably, the substituent R is an alkyl or cycloalkyl radical of l-6 carbon atoms.
The compounds may be used in the form of the tree acids or in the form of non-toxic salts thereof with inorganic or organic bases. Among the suitable salts which may be mentioned are: the methylglucamine, ammonium, sodium, lithium, potassium, calcium, glucamine, ethylglucamine, ethanol-amine, diethanolamine and triethanolamine salts.
The compounds may be mixed with suitable pharmaceutical excipients and made up into a form suitable for 3,647,466 Patented July 31, 1962 ice 2 oral administration, for example in the form of capsules, dragees, and the like.
The compounds of the present invention are preferably produced by iodinating a compound having the following general formula:
may be produced according to the methods generally used in organic synthesis for the production of similar compounds, for example from 3,5-dinitrobenzoyl-acetic ester by introducing into the zit-position in known manner the desired aliphatic or cycloaliphatic radical. This is carried out, for exam le, by reacting the sodium enolate of the 3,S-dinitrobenzoyl-acetic ester in alcoholic solution with an alkyl or cycloalltyl halogenide, e.g. chloromethyl, isopropylbromide, hexyliodide, or the like. Upon hydrogenation the corresponding ,8-3,5-diaminophenyl- 8- hydroxy-a-alkyl. or cycloalkyl-propionic acid ester is obtained. By reaction with thionyl chloride, the ,B-position hydroxyl is replaced by chlorine, which is subsequently replaced by hydrogen by means of hydrogenation.
The following examples are given to further illustrate the present invention. The scope of the invention is not, however, meant to be limited to the specific details of the examples.
Example 1 18 g. of a-ethyl-B-(3,5-diaminophenyl)-propionic acidethyl ester are heated for saponifioation with a mixture of 150 cc. of 3 N sodium hydroxide and 250 cc. of methanol for 3 hours to boiling under reflux conditions. The reaction mixture is then acidified with dilute hydrochloric acid and the methanol is driven ofi under vacuum.
The distillation residue is diluted with ice water to 1200 cc. and 90 cc. of 2 N potassium iodide-dichloride solution is added dropwise under stirring. The precipita ted sand colored precipitate is subjected to suction filtration, washed with water and dissolved in ether.
The solution which is dried over sodium sulfate is reacted with alcoholic sodium hydroxide which results in precipitation of the sodium salt of u-ethyl-B-(3,S-diarnino 2,4,6-triiodophenyl)spropionic acid. The salt is filtered by suction, dissolved in water, and the free acid is precipitated from the aqueous solution by means of dilute hydrochloric acid. The yield of the air-dried product is 24 g. The melting point is above C., with decomposition.
By treatment with benzene under cold conditions and subsequent recrystallization from a large amount of benzene, the substance is obtained in the form of practically colorless crystals having a melting point of 156.5- 157 C., with decomposition. The salt may be obtained by neutralization of the acid in aqueous solution with the corresponding base, and then freezing-drying.
Example 2 10 kg. of the methyl-[H3,S-diamino-2,4,6 triiodophenyl)propionic acid produced according to Example 1 are kneaded in a kneading machine with 4 liters of starch paste containing 200 g. of corn starch. The wet mass is granulated in a normal manner in a granulation machine and then dried under vacuum. The finished granulate is then mixed with 1 kg. of corn starch and 50 g. of magnesium stcarate and pressed into tablets each containing 500 mg. of the active ingredient.
Example 3 The easily water soluble sodium salt of methyl-543,5- diamino-2,4,G-triiodophenyl)-propionic acid produced according to Example 1 is introduced into gelatin capsules filling the same. Each capsule contains 750 mg. of the active substance. For machine production of capsules the sodium salt can be mixed with a 40% mixture of corn oil, soybean lecithin and cocoa fat to a flowing paste.
Example 4 The granulate produced according to Example 2 is with 20% of the weight thereof of sugar syrup formed into dragees in a dragee vessel, and subsequently waxed.
Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can by applying current knowledge readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention and, therefore, such adaptations should and are intended to be comprehended within the meaning and range of equivalence of the following claims.
What is claimed as new and desired to be secured by Letters Patent is:
'1. A compound selected from the group consisting of compounds of thefollowing general formula:
HZN I wherein R is a hydrocarbon radical of 1-6 carbon atoms; and non-toxic salts thereof.
2. A compound having the following general formula:
rnN r r-Q-om-cn-ooon 1 1i H2N I wherein R is an alkyl radical of =1-6 carbon atoms.
3. A compound having the following general formula:
' HQN I- -CH2-(I3H-COOH 1 R HnN I wherein R is a cycloalkyl radical of 1-6 carbon atoms. 4. A non-toxic salt of a compound having the following general formula:
wherein R is an alkyl radical of 1-6 carbon atoms.
5. A nontoxic salt of a compound having the following general formula:
wherein R is a cycloalkyl radical of 1-6 carbon atoms.
6. The sodium salt of a compound having the following general formula:
wherein R is an alkyl radical of l-6 carbon atoms.
7. The sodium salt of a compound having the following general formula:
Hal 1 wherein R is a cycloalkyl radical of 1-6 carbon atoms.
8. The methylglucamine salt of a compound having the'foll-owing general formula:
wherein R is an alkyl radical of 1-6 carbon atoms.
9. The methylglucamine salt of a compound having the following general formula:
R H N I R iN wherein R is a hydrocarbon radical of 1-6 carbon atoms, and non-toxic salts thereof; and pharmaceutical excipients adapted for pero-ral administration.
References Cited in the file of this patent UNITED STATES PATENTS 2,705,726 Archer Apr. 5, 1955 2,820,814 Grinsberg Jan. 21, 1958 2,921,884 Nachod Jan. 19, 1960 FOREIGN PATENTS 782,313 Great Britain Sept. 4, 1957

Claims (1)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FOLLOWING GENERAL FORMULA:
US779065A 1957-12-18 1958-12-09 X-ray contrast agent Expired - Lifetime US3047466A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3419657A (en) * 1964-06-23 1968-12-31 Dagra Nv Iodopanoic acid in a hydrogel
US3542861A (en) * 1967-05-08 1970-11-24 Sterling Drug Inc 3-amino-5-cycloalkylcarbonylamino-2,4,6-triiodobenzoic acids

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2705726A (en) * 1949-07-23 1955-04-05 Sterling Drug Inc Iodinated aminophenyl-carboxylic acids
GB782313A (en) * 1954-07-26 1957-09-04 Mallinckrodt Chemical Works Manufacture of new 2:4:6-triiodobenzoic acid compounds
US2820814A (en) * 1955-03-21 1958-01-21 Schering Corp Polyiodinated 5-aminoisophthalic acids, salts, and esters
US2921884A (en) * 1957-09-30 1960-01-19 Sterling Drug Inc Pharmaceutical compositions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US705726A (en) * 1902-05-05 1902-07-29 James C Wallace Filter-bed.
DE970133C (en) * 1953-02-06 1958-08-21 Schering Ag Process for the preparation of N-acyl derivatives of 3, 5-diamino-2, 4, 6-triiodo-benzoic acid

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2705726A (en) * 1949-07-23 1955-04-05 Sterling Drug Inc Iodinated aminophenyl-carboxylic acids
GB782313A (en) * 1954-07-26 1957-09-04 Mallinckrodt Chemical Works Manufacture of new 2:4:6-triiodobenzoic acid compounds
US2820814A (en) * 1955-03-21 1958-01-21 Schering Corp Polyiodinated 5-aminoisophthalic acids, salts, and esters
US2921884A (en) * 1957-09-30 1960-01-19 Sterling Drug Inc Pharmaceutical compositions

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3419657A (en) * 1964-06-23 1968-12-31 Dagra Nv Iodopanoic acid in a hydrogel
US3542861A (en) * 1967-05-08 1970-11-24 Sterling Drug Inc 3-amino-5-cycloalkylcarbonylamino-2,4,6-triiodobenzoic acids

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BE573412A (en) 1959-03-16
NL234265A (en) 1963-03-15
DE1125589B (en) 1962-03-15
FR1280566A (en) 1962-01-08
NL105700C (en) 1963-08-15
GB898781A (en) 1962-06-14

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