DE1076894B - X-ray contrast media - Google Patents

X-ray contrast media

Info

Publication number
DE1076894B
DE1076894B DESCH24255A DESC024255A DE1076894B DE 1076894 B DE1076894 B DE 1076894B DE SCH24255 A DESCH24255 A DE SCH24255A DE SC024255 A DESC024255 A DE SC024255A DE 1076894 B DE1076894 B DE 1076894B
Authority
DE
Germany
Prior art keywords
contrast media
ray contrast
acids
propionic acid
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
DESCH24255A
Other languages
German (de)
Inventor
Dr Hans Priewe
Dr Alexander Poljak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to DESCH24255A priority Critical patent/DE1076894B/en
Priority to DESCH24639A priority patent/DE1080266B/en
Priority to GB7421/59A priority patent/GB884623A/en
Priority to CH7064459A priority patent/CH381806A/en
Priority to AT238759A priority patent/AT210991B/en
Priority to BE577346A priority patent/BE577346A/en
Priority to NL237800A priority patent/NL121190C/xx
Priority to NL237800D priority patent/NL237800A/xx
Priority to DESCH26697A priority patent/DE1094931B/en
Priority to DESCH26696A priority patent/DE1097085B/en
Priority to DESCH26755A priority patent/DE1099696B/en
Priority to DESCH26802A priority patent/DE1102345B/en
Publication of DE1076894B publication Critical patent/DE1076894B/en
Priority to GB2248860A priority patent/GB950321A/en
Priority to FR835872A priority patent/FR195M/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/69—Benzenesulfonamido-pyrimidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/195—Radicals derived from nitrogen analogues of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/16—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing hetero atoms
    • C09B23/162—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing hetero atoms only nitrogen atoms
    • C09B23/166—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing hetero atoms only nitrogen atoms containing two or more nitrogen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Description

Röntgenkontrastmittel Die Verwendung der a-Äthyl-ß-(3-amino-2,4,6-trijodphenyl)-propionsäure in Röntgenkontrastmitteln zur Abbildung der Gallenwege ist bereits bekannt (vgl. deutsches Patent 907 529). Weiterhin ist eine große Anzahl von Röntgenkontrastmitteln bekanntgeworden, in denen die Aminogruppe nachträglich, z. B. durch die Acetylgruppe, substituiert wurde.X-ray contrast medium The use of a-ethyl-ß- (3-amino-2,4,6-triiodophenyl) propionic acid in X-ray contrast media for imaging the biliary tract is already known (cf. German patent 907 529). Furthermore, a large number of X-ray contrast media become known, in which the amino group subsequently, z. B. by the acetyl group, has been substituted.

Es wurde nun gefunden, daß durch Ersatz der Aminogruppe durch die Dimethylaminomethylenaminogruppe in den oben beschriebenen kernjodierten a-AHr-yl-ß-(aminophenyl)-propionsäuren Verbindungen erhalten werden, die als freie Säuren oder in Form ihrer Salze mit nichttoxischen anorganischen oder organischen Basen bei ihrer Verwendung in Röntgenkontrastmitteln gegenüber den eingangs erwähnten bekannten Verbindungen erhebliche Vorteile bieten.It has now been found that by replacing the amino group by the Dimethylaminomethyleneamino group in the nuclear iodinated a-AHr-yl-ß- (aminophenyl) propionic acids described above Compounds are obtained as free acids or in the form of their salts with non-toxic inorganic or organic bases when used in X-ray contrast media offer considerable advantages over the known compounds mentioned at the outset.

Diese Vorteile bestehen vor allem in einer vergleichsweise sehr niedrigen Toxizität, einer ausgezeichneten Resorbierbarkeit bei peroraler Applikation und einer wesentlich besseren Gallenverteilung bei gleichzeitig kräftiger Kontrastgebung. Dadurch eignen sich die neuen Verbindungen vor allem als schattengebende Substanzen in Röntgenkontrastmitteln für die perorale Cholecystographie. Sie sind daneben nach entsprechender Verarbeitung aber auch zur röntgenographischen Abbildung anderer Körperhöhlen bzw. Organe geeignet. Man wird sie hierbei je nach dem speziellen Verwendungszweck als freie Säuren oder als deren nichttoxische Salze mit anorganischen und/oder organischen Basen nach bekannten Methoden in eine zweckentsprechende Applikationsform, für die perorale Cholecystographie beispielsweise in Dragees, überführen.These advantages consist primarily in a comparatively very low one Toxicity, excellent absorbability when administered orally and a much better bile distribution with strong contrast at the same time. This makes the new compounds particularly suitable as shading substances in X-ray contrast media for peroral cholecystography. You are next to it appropriate processing but also for radiographic imaging of others Body cavities or organs suitable. They are used here depending on the specific purpose as free acids or as their non-toxic salts with inorganic and / or organic Bases according to known methods in an appropriate application form for the peroral cholecystography, for example in coated tablets.

Die Vorteile der neuen Verbindungen ergeben sich deutlich beim Vergleich mit schon bekannten Kontrastmitteln im Tierversuch. Bei Gegenüberstellung z. B. der a-Äthyl-ß-(3-dimethylaminomethylenamino-2,4,6-trij odphenyl)-propionsäure (I) mit der entsprechenden bekannten a-Äthyl-ß-(3-aminophenyl-2,4;6-trijodphenyl),-propionsäure (11) wurden folgende Werte erhalten: Verteilung in 0% LD5°' -g/kg nach 24 Stunden nach 200 ing/kg i. d. am Kaninchen i. v. I p. o. Galle I Harn (1) 490 2500 86,3 0,2 (11) 320 2450 26,0 16,0 Die Herstellung der neuen kernjodierten a-Alkyl ß - (dimethylaminomethylenaminophenyl) - propionsäuren geschieht z. B. über die bekannten jodierten Aminoverbindungen, indem man diese bzw. ihre Säureadditionssalze mit N-Dimethyl-formamid in Gegenwart eines sauren Reaktionsvermittlers, wie Phosphoroxychlorid, bei mäßig erhöhten Temperaturen reagieren läßt. Selbstverständlich sind auch andere allgemeine Methoden verwendbar. Die Verfahren zur Herstellung der Verbindungen sind nicht Gegenstand des Schutzrechts.The advantages of the new compounds clearly emerge when compared with known contrast media in animal experiments. When comparing z. B. the a-ethyl-ß- (3-dimethylaminomethyleneamino-2,4,6-trij odphenyl) propionic acid (I) with the corresponding known a-ethyl-ß- (3-aminophenyl-2,4; 6-triiodophenyl ), - propionic acid (11) the following values were obtained: Distribution in 0% LD 5 ° -g / kg after 24 hours after 200 ing / kg id on the rabbit iv I po bile I urine (1) 490 2500 86.3 0.2 ( 11 ) 320 2450 26.0 16.0 The production of the new nuclear iodinated α-alkyl ß - (dimethylaminomethyleneaminophenyl) - propionic acids is done, for. B. via the known iodinated amino compounds by allowing them or their acid addition salts to react with N-dimethylformamide in the presence of an acidic reaction mediator, such as phosphorus oxychloride, at moderately elevated temperatures. Of course, other general methods can also be used. The processes for making the connections are not part of the property right.

Beispiele 1. 5 kg a-Äthyl-ß-(3-dimethylaminomethylenamino-2,4,6-trijodphenyl)-propionsäure werden mit 21 Stärkekleister, der 100g Maisstärke enthält, in einer Knetmaschine angeteigt. Die feuchte Masse wird wie üblich in einer Granuliermaschine granuliert und im Vakuum getrocknet. Das fertige Granulat wird. dann mit 0,5 kg Maisstärke und 25 g Magnesiumstearat vermischt und zu Tabletten mit einem Wirkstoffgehalt von 500 mg verpreßt.Examples 1. 5 kg of α-ethyl-β- (3-dimethylaminomethyleneamino-2,4,6-triiodophenyl) propionic acid are mixed with 21 starch paste containing 100g corn starch in a kneading machine made into a paste. The moist mass is granulated as usual in a granulating machine and dried in vacuo. The finished granules will. then with 0.5 kg of corn starch and 25 g of magnesium stearate and mixed into tablets with an active ingredient content of 500 mg pressed.

2. Das gut wasserlösliche Natriumsalz der a-Äthylß- (3-dimethylaminomethylenamino-2, 4, 6-trij odphenyl)-propionsäure wird in Gelatinekapseln abgefüllt. Jede Kapsel enthält 750 mg Wirkstoff. Zur maschinellen Kapselherstellung kann das Natriumsalz mit 40 % Paraffinöl zu einer fließfähigen Paste verarbeitet werden.2. The readily water-soluble sodium salt of a-Ethylß- (3-dimethylaminomethyleneamino-2, 4,6-trijodphenyl) propionic acid is filled into gelatin capsules. Any capsule contains 750 mg of active ingredient. The sodium salt can be used for mechanical capsule production can be processed into a flowable paste with 40% paraffin oil.

3. Das gemäß Beispiel 1 erhaltene Granulat wird durch Auftragen von 20 % des Eigengewichtes Zuckersirup im Dragierkessel dragiert und anschließend gewachst.3. The granulate obtained according to Example 1 is coated in a coating pan by applying 20% of its own weight sugar syrup and then waxed.

Claims (3)

PATENTANSPRÜCHE: 1. Röntgenkontrastmittel, insbesondere zur perralen Applikation für die Cholecystrographie, entaltend als schattengebende Substanz kernjodierte -All-,yl-ß-(dimethylaminomethylenaminophenyl)-propionsäuren der allgemeinen Formel worin R ein niederes Alkyl oder Cycloalkyl mit 1 bis 6 Kohlenstoffatomen und n die Zahlen 2 und 3 bedeutet. PATENT CLAIMS: 1. X-ray contrast media, especially for perral application for cholecystrography, containing -all-, yl-ß- (dimethylaminomethyleneaminophenyl) propionic acids of the general formula in which R is a lower alkyl or cycloalkyl as a shadow-giving substance 1 to 6 carbon atoms and n denotes the numbers 2 and 3. 2. Röntgenkontrastmittel gemäß Anspruch 1, dadurch gekennzeichnet, daß es die nichttoxischen Salze der Säuren mit anorganischen und/oder organischen Basen enthält. 2. X-ray contrast media according to claim 1, characterized in that it is the non-toxic salts of the acids with inorganic and / or organic bases. 3. Röntgenkontrastmittel gemäß Anspruch 1 und 2, dadurch gekennzeichnet, daß es als schattengebende Substanz a-Äthyl-ß-(3-dirnethylaminomethylenamino-2,4,6-trijodphenyl)-propionsäure enthält.3. X-ray contrast media according to Claims 1 and 2, characterized in that the shading substance is α-ethyl-β- (3-dirnethylaminomethyleneamino-2,4,6-triiodophenyl) propionic acid contains.
DESCH24255A 1958-04-05 1958-06-20 X-ray contrast media Pending DE1076894B (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
DESCH24255A DE1076894B (en) 1958-06-20 1958-06-20 X-ray contrast media
DESCH24639A DE1080266B (en) 1958-06-20 1958-08-29 X-ray contrast media
GB7421/59A GB884623A (en) 1958-04-05 1959-03-03 New triiodophenyl-propionic acids and x-ray contrast media comprising the same
CH7064459A CH381806A (en) 1958-04-05 1959-03-11 X-ray contrast media
AT238759A AT210991B (en) 1958-06-20 1959-03-26 X-ray contrast media
BE577346A BE577346A (en) 1958-04-05 1959-04-03 Process for the preparation of N, N'-trisubstituted formamidines.
NL237800D NL237800A (en) 1958-04-05 1959-04-04
NL237800A NL121190C (en) 1958-06-20 1959-04-04
DESCH26697A DE1094931B (en) 1958-06-20 1959-09-16 X-ray contrast media
DESCH26696A DE1097085B (en) 1958-06-20 1959-09-16 X-ray contrast media
DESCH26755A DE1099696B (en) 1958-06-20 1959-09-30 X-ray contrast media
DESCH26802A DE1102345B (en) 1958-06-20 1959-10-06 X-ray contrast media
GB2248860A GB950321A (en) 1958-04-05 1960-06-27 Derivatives of iodophenyl-propionic acids and improvements in and relating to x-ray contrast media
FR835872A FR195M (en) 1958-04-05 1960-08-12 X-ray contrast agent.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DESCH24255A DE1076894B (en) 1958-06-20 1958-06-20 X-ray contrast media

Publications (1)

Publication Number Publication Date
DE1076894B true DE1076894B (en) 1960-03-03

Family

ID=7429841

Family Applications (1)

Application Number Title Priority Date Filing Date
DESCH24255A Pending DE1076894B (en) 1958-04-05 1958-06-20 X-ray contrast media

Country Status (1)

Country Link
DE (1) DE1076894B (en)

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