CA1133935A - Triio dophenyl-aminopropionic acids and x-ray contrast media comprising the same - Google Patents
Triio dophenyl-aminopropionic acids and x-ray contrast media comprising the sameInfo
- Publication number
- CA1133935A CA1133935A CA324,144A CA324144A CA1133935A CA 1133935 A CA1133935 A CA 1133935A CA 324144 A CA324144 A CA 324144A CA 1133935 A CA1133935 A CA 1133935A
- Authority
- CA
- Canada
- Prior art keywords
- acetyl
- triiodophenyl
- compound
- beta
- recovering
- 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.)
- Expired
Links
- 239000002253 acid Substances 0.000 title claims abstract description 10
- 239000002872 contrast media Substances 0.000 title abstract description 10
- 150000007513 acids Chemical class 0.000 title abstract description 5
- 229940039231 contrast media Drugs 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 2
- 239000011575 calcium Substances 0.000 claims 2
- 229910052791 calcium Inorganic materials 0.000 claims 2
- 125000004494 ethyl ester group Chemical group 0.000 claims 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000001110 calcium chloride Substances 0.000 claims 1
- 229910001628 calcium chloride Inorganic materials 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- -1 acids compounds Chemical class 0.000 abstract description 2
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 210000000013 bile duct Anatomy 0.000 description 4
- 210000000232 gallbladder Anatomy 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 241000237858 Gastropoda Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002601 radiography Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- GSVQIUGOUKJHRC-YFKPBYRVSA-N (2s)-3-(n-acetyl-3-amino-2,4,6-triiodoanilino)-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](C)CN(C(C)=O)C1=C(I)C=C(I)C(N)=C1I GSVQIUGOUKJHRC-YFKPBYRVSA-N 0.000 description 1
- BSIWIVCJKKGHQY-UHFFFAOYSA-N 2-acetamido-2-methylpropanoic acid Chemical compound CC(=O)NC(C)(C)C(O)=O BSIWIVCJKKGHQY-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N Alanine Chemical group CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 101100460716 Aspergillus sp. (strain MF297-2) notO gene Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical group CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960001943 iocetamic acid Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/48—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/12—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to hydrogen 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
NEW U.S. PATENT APPLICATION
Corresponding to: U.K. Application Serial No. 13200/78 F?: April 4,1978 F?: Triidophenyl-Aminopropionic Acids and X-Ray Contrast Media Comprising the Same CODE: 1244 TRIIODOPHENYL-AMINOPROPIONIC ACIDS AND X-RAY CONTRAST
MEDIA COMPRISING THE SAME
ABSTRACT OF THE DISCLOSURE
New triiodophenyl-aminopropionic acids compounds are pro-vided which have excellent properties as X-ray contrast media.
Corresponding to: U.K. Application Serial No. 13200/78 F?: April 4,1978 F?: Triidophenyl-Aminopropionic Acids and X-Ray Contrast Media Comprising the Same CODE: 1244 TRIIODOPHENYL-AMINOPROPIONIC ACIDS AND X-RAY CONTRAST
MEDIA COMPRISING THE SAME
ABSTRACT OF THE DISCLOSURE
New triiodophenyl-aminopropionic acids compounds are pro-vided which have excellent properties as X-ray contrast media.
Description
~L33~3~
BACKGROUND OF THE IN'JENTION
X-ray contrast agents are of considerable importance for opacification of various organs of the body, for example the gall-bladder and the bileducts. Many iodine-containing compounds have been used for such purposes. However, it is very difficult to estimate beforehand whether any projected compounds may be suitable for use as an X-ray contrast agent.
British Patent No. 1,116,586 discloses that N-acetyl-N-(3-amino-2,4,6-triiodophenyl)-~-amino- c~ -methylpropionic acid (iocetamic acid) can be used for the visualization of the gall-bladder and the bileduct.
SUMMARY OF THE INVENTION
Generally speaking, in accordance with the present invention, it has been found that certain specific derivatives of N-acetyl-N-(3-amino-2,4,6-triiodophenyl)-~-aminopropionic acids, namely such compounds in which the amino group has been substituted by a dimethylaminomethyleneamino group and wherein the aminopropionic acid group may be also an aminobutyric acid group, possess low toxicity and excellent cholecystographic properties.
It is accordingly a primary object of the present invention to provide new compounds which are useEul as X-ray contrast agents.
It is a further object of the pres~nt invention to provide new compounds and compositions for X-ray contrast media.
BACKGROUND OF THE IN'JENTION
X-ray contrast agents are of considerable importance for opacification of various organs of the body, for example the gall-bladder and the bileducts. Many iodine-containing compounds have been used for such purposes. However, it is very difficult to estimate beforehand whether any projected compounds may be suitable for use as an X-ray contrast agent.
British Patent No. 1,116,586 discloses that N-acetyl-N-(3-amino-2,4,6-triiodophenyl)-~-amino- c~ -methylpropionic acid (iocetamic acid) can be used for the visualization of the gall-bladder and the bileduct.
SUMMARY OF THE INVENTION
Generally speaking, in accordance with the present invention, it has been found that certain specific derivatives of N-acetyl-N-(3-amino-2,4,6-triiodophenyl)-~-aminopropionic acids, namely such compounds in which the amino group has been substituted by a dimethylaminomethyleneamino group and wherein the aminopropionic acid group may be also an aminobutyric acid group, possess low toxicity and excellent cholecystographic properties.
It is accordingly a primary object of the present invention to provide new compounds which are useEul as X-ray contrast agents.
It is a further object of the pres~nt invention to provide new compounds and compositions for X-ray contrast media.
-2-1~33~3335 It is yet another object of the present invention to provide for the visualization of the gallbladder and bileduct by the use of the new compounds of the invention.
Other objects and advantages of the present invention wiLl be apparent from a further readiny of the specificat~ion and of the appended claims With the above and other objects in view, the present invention mainly comprises compounds of the formula:
H- N, C ~1 ~ Ci ~ c tl~ t f~ - C ~
in which R is hydrogen or methyl, as well as non-toxic salts thereof with inorganic or organic bases.
The above compounds of the invention may be used for X-ray radiography by the preparation of compositions of the compound together with a non-toxic or physiologically compatible carrier or diluent. The non-toxic adjuvant may be any of those commonly used in the art. The preparation of compositions with the X-ray contrast agent dcscribed above and the adjuvant can be made by any commonly used method in the art.
~33~3~i The administration of the compositions of the present invention results in excellent opacificdtion of the gallbladder and the bileducts and thus, after administration of such com-position to a patient, the patient may be subjected to X-ray radiography in normal manner.
The high degree of suitability of the X-ray contrast agents of the present invention for these purposes was confirmed from investigations on dogs, 12 hours after oral administration of quantities equivalent to 93 mg of iodine per kg of bodyweight, wherein the compounds of the present invention were compared with a number of known chol.ecystographic agents of great practical importance, such as c~ -e.thyl-~-(3-amino-2,4,6-triiodophenyl-propionic acid (I), ~-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl)-propionic acid (II) and N-acetyl-N-(3-amino-2,4,G-triiodophenyl)- ~-amino- ~ -methyl-propionic acid (III).
The compound of the present invention (A) in which R- CH3 occurs in two diastereoisomeric forms, as does the parent compound (III) from which it is derived. This type of stereoisomerism is caused by a hindered rotation of the acetylaminoisobutyric acid grouping, combined with the asymmetric carbon atom, resulting in two racemic mixtures, L,L + D,D
and L,D + D,L. These can be obtained separately by taking the separate isomers of the parent compound as the starting material.
. .
~33~
The isomers are distinguished by their meltiny points, one racemic pair having a melting point of 185C (derived from the parent compound (III) with melting point 201 C) and the other racemic pair having a melting point of 234C (derived from the parent compound (III) with melting point 231C). No significant difference in toxicity was found between each pair of isomers whereas the isomers of the parent compound III exhibit a very distinct difference.
The toxicities of the compounds of the present invention are comparatively low. Intravenous injection of the methyl-glucamine salts in mice gave LD 50 values as follows:
Compound LD50 mg/kg I 300 (270-335) II 355 (330-380) III m.p. 231 C 390 (356-~27) III m.p. 201 C 780 (701-868) III 1/1 isomer mixture 450 (421-481) A wherein R - CH3 m.p. 234 C 510 (479-543) A wherein R - CH3 m.p. 185C 530 (498-564) A wherein R c CIl3 1/1 isomer mixture 630 (517-768) A wherein R - H 275 (250-330) On oral administration of suspensions of the compounds of the invention to mice it was found that the new compound A
in which R=CH3 showed a LD50 of about 3000 mg/kg in a normal 1~3~33S
dOSe-mortality response, whereas compounds I/III gave in the same range a constant and limited mortality. This indicates a More rapid absorption of tile compound of the invention.
The compounds of the invention can be prepared by reacting tlle corresponding amino compounds with dimethylformamide in the presence of an acid reaction promotor such as phosphorus oxychloride in the manner of the process described in the British Patent Nos. 884,623 and 1,097,720.
The compounds of the present invention may be used in the form of free acids or as salts thereof with any of the commonly used non-toxic or physiologically compatible inorganic or organic basis, e.g. sodium salts, calcium salts, etc.
_SCRIPTION ~ ~ '`I;i rLI; ~L-- '~lD~ lENTS
The following examples are given to further illustrate the present invention. The scope of the invention is notO how-ever, meant to be limited to the specific details of the examples:
_.~MP E_l Acetyl-N-(3-dimethylam nomethyleneamino-2,4,6-triiodoE~enyl)-~-aminoisobutyric acid 61.4 g (0.1 mole) of N-acetyl-N-(3-amino-2,4,6-triiodophenyl)-~-aminoisobutyric acid is dissolved in 125 ml of dimethylformamide.
., _ . .. ... .
~3~3~
15.35 g (0.1 mole) of phosphorus oxychloride is added dropwise with stirring and cooling, maintaining the temperature at 15-20 C.
After standing overnight the solution is di~lted with 250 ml of water, the precipitate is dissolved in water with the aid of hydrochloric acid and reprecipltated by adding sodium hydroxide solution to pH = 6. The precipitate is filtered, washed with water and dried. Yield 48 gO Melting range: 180 - 220 C.
As the starting material consists of a mixture of diastereoisomers with a melting range of 191 - 217 C, as described in British Patent No. 1,116,586, the reaction product is also a mixture of diastereoisomers and does not have a sharp melting point.
N-acetyl-N-(3-dimethylaminometh leneamino-2,4,6-triiodo~enyl)-y mino ro ionic acid P P
62.8 g (0.1 mole) of N-acetyl-N-(3-amino-2,4,6-triiodophenyl)-p-aminopropionic acid ethyl ester is suspended in a mixture of 200 ml of chloroform and 35 ml of dimethylformamide. A solution of 15.35 g (0.1 mole) of phosphorus oxychloride in 12 ml of chloroform is added dropwise at room temperature. The initial suspension dissolves. After five minutes a precipitate gradually forms as a rather thick suspension. After stirring for three hours the solid is filtered and washed with chloroform. Yield: 63 g.
~gL33~3S
The ester is saponified by refluxing ]5 minutes in 400 ml of ethanol and 60 m] of 4N sodium hydroxide solution.
The solution is acidified with 40 ml of acetic acid, treated with charcoal and slowly diluted with 500 ml of water. A
white crystalline product separates. It is filtered and washed with 50~/O ethanol/water. Yield 48 g. Melting point: 211 C.
Cal_ium N-acetyl-N-(3-dime_hylaminomethylene_mino-2,4,6 triiodophenyl)-~-aminoisobutyrate 67 g (0.1 mole) of N-acetyl-N-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl-~-aminoisobutyric acid is dissolved in 150 ml of water, with the aid of 4 g of sodium hydroxide. A
solution of 7.35 g (0.05 mole) of CaC12.2 H2O in 50 ml of water is added with stirring. The precipitate thus obtained is filtered, stirred in lS0 ml of hot water, filtered again and finally dried. Yield: 65 g.
500 g of N-acetyl-N-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl)-~-aminoisobutyric acid is mixed with 360 g of corn starch 37 g of talcum and 3 g of magnesium stearate.
The mixture is compressed into 'slugs'. The slugs are milled into a granulate, which is then passed through a fine (1 mm) sieve. The granulate is compressed into tablets which contain 500 mg of active substance.
~L33935 While the invention has been illustrated in particular with respect to specific s~lts, it is apparent that variations and modifications thereof can be made without cleparting from th~ spirit or scope of the invention.
, .. . , . _
Other objects and advantages of the present invention wiLl be apparent from a further readiny of the specificat~ion and of the appended claims With the above and other objects in view, the present invention mainly comprises compounds of the formula:
H- N, C ~1 ~ Ci ~ c tl~ t f~ - C ~
in which R is hydrogen or methyl, as well as non-toxic salts thereof with inorganic or organic bases.
The above compounds of the invention may be used for X-ray radiography by the preparation of compositions of the compound together with a non-toxic or physiologically compatible carrier or diluent. The non-toxic adjuvant may be any of those commonly used in the art. The preparation of compositions with the X-ray contrast agent dcscribed above and the adjuvant can be made by any commonly used method in the art.
~33~3~i The administration of the compositions of the present invention results in excellent opacificdtion of the gallbladder and the bileducts and thus, after administration of such com-position to a patient, the patient may be subjected to X-ray radiography in normal manner.
The high degree of suitability of the X-ray contrast agents of the present invention for these purposes was confirmed from investigations on dogs, 12 hours after oral administration of quantities equivalent to 93 mg of iodine per kg of bodyweight, wherein the compounds of the present invention were compared with a number of known chol.ecystographic agents of great practical importance, such as c~ -e.thyl-~-(3-amino-2,4,6-triiodophenyl-propionic acid (I), ~-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl)-propionic acid (II) and N-acetyl-N-(3-amino-2,4,G-triiodophenyl)- ~-amino- ~ -methyl-propionic acid (III).
The compound of the present invention (A) in which R- CH3 occurs in two diastereoisomeric forms, as does the parent compound (III) from which it is derived. This type of stereoisomerism is caused by a hindered rotation of the acetylaminoisobutyric acid grouping, combined with the asymmetric carbon atom, resulting in two racemic mixtures, L,L + D,D
and L,D + D,L. These can be obtained separately by taking the separate isomers of the parent compound as the starting material.
. .
~33~
The isomers are distinguished by their meltiny points, one racemic pair having a melting point of 185C (derived from the parent compound (III) with melting point 201 C) and the other racemic pair having a melting point of 234C (derived from the parent compound (III) with melting point 231C). No significant difference in toxicity was found between each pair of isomers whereas the isomers of the parent compound III exhibit a very distinct difference.
The toxicities of the compounds of the present invention are comparatively low. Intravenous injection of the methyl-glucamine salts in mice gave LD 50 values as follows:
Compound LD50 mg/kg I 300 (270-335) II 355 (330-380) III m.p. 231 C 390 (356-~27) III m.p. 201 C 780 (701-868) III 1/1 isomer mixture 450 (421-481) A wherein R - CH3 m.p. 234 C 510 (479-543) A wherein R - CH3 m.p. 185C 530 (498-564) A wherein R c CIl3 1/1 isomer mixture 630 (517-768) A wherein R - H 275 (250-330) On oral administration of suspensions of the compounds of the invention to mice it was found that the new compound A
in which R=CH3 showed a LD50 of about 3000 mg/kg in a normal 1~3~33S
dOSe-mortality response, whereas compounds I/III gave in the same range a constant and limited mortality. This indicates a More rapid absorption of tile compound of the invention.
The compounds of the invention can be prepared by reacting tlle corresponding amino compounds with dimethylformamide in the presence of an acid reaction promotor such as phosphorus oxychloride in the manner of the process described in the British Patent Nos. 884,623 and 1,097,720.
The compounds of the present invention may be used in the form of free acids or as salts thereof with any of the commonly used non-toxic or physiologically compatible inorganic or organic basis, e.g. sodium salts, calcium salts, etc.
_SCRIPTION ~ ~ '`I;i rLI; ~L-- '~lD~ lENTS
The following examples are given to further illustrate the present invention. The scope of the invention is notO how-ever, meant to be limited to the specific details of the examples:
_.~MP E_l Acetyl-N-(3-dimethylam nomethyleneamino-2,4,6-triiodoE~enyl)-~-aminoisobutyric acid 61.4 g (0.1 mole) of N-acetyl-N-(3-amino-2,4,6-triiodophenyl)-~-aminoisobutyric acid is dissolved in 125 ml of dimethylformamide.
., _ . .. ... .
~3~3~
15.35 g (0.1 mole) of phosphorus oxychloride is added dropwise with stirring and cooling, maintaining the temperature at 15-20 C.
After standing overnight the solution is di~lted with 250 ml of water, the precipitate is dissolved in water with the aid of hydrochloric acid and reprecipltated by adding sodium hydroxide solution to pH = 6. The precipitate is filtered, washed with water and dried. Yield 48 gO Melting range: 180 - 220 C.
As the starting material consists of a mixture of diastereoisomers with a melting range of 191 - 217 C, as described in British Patent No. 1,116,586, the reaction product is also a mixture of diastereoisomers and does not have a sharp melting point.
N-acetyl-N-(3-dimethylaminometh leneamino-2,4,6-triiodo~enyl)-y mino ro ionic acid P P
62.8 g (0.1 mole) of N-acetyl-N-(3-amino-2,4,6-triiodophenyl)-p-aminopropionic acid ethyl ester is suspended in a mixture of 200 ml of chloroform and 35 ml of dimethylformamide. A solution of 15.35 g (0.1 mole) of phosphorus oxychloride in 12 ml of chloroform is added dropwise at room temperature. The initial suspension dissolves. After five minutes a precipitate gradually forms as a rather thick suspension. After stirring for three hours the solid is filtered and washed with chloroform. Yield: 63 g.
~gL33~3S
The ester is saponified by refluxing ]5 minutes in 400 ml of ethanol and 60 m] of 4N sodium hydroxide solution.
The solution is acidified with 40 ml of acetic acid, treated with charcoal and slowly diluted with 500 ml of water. A
white crystalline product separates. It is filtered and washed with 50~/O ethanol/water. Yield 48 g. Melting point: 211 C.
Cal_ium N-acetyl-N-(3-dime_hylaminomethylene_mino-2,4,6 triiodophenyl)-~-aminoisobutyrate 67 g (0.1 mole) of N-acetyl-N-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl-~-aminoisobutyric acid is dissolved in 150 ml of water, with the aid of 4 g of sodium hydroxide. A
solution of 7.35 g (0.05 mole) of CaC12.2 H2O in 50 ml of water is added with stirring. The precipitate thus obtained is filtered, stirred in lS0 ml of hot water, filtered again and finally dried. Yield: 65 g.
500 g of N-acetyl-N-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl)-~-aminoisobutyric acid is mixed with 360 g of corn starch 37 g of talcum and 3 g of magnesium stearate.
The mixture is compressed into 'slugs'. The slugs are milled into a granulate, which is then passed through a fine (1 mm) sieve. The granulate is compressed into tablets which contain 500 mg of active substance.
~L33935 While the invention has been illustrated in particular with respect to specific s~lts, it is apparent that variations and modifications thereof can be made without cleparting from th~ spirit or scope of the invention.
, .. . , . _
Claims (9)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of formula (I) (A) wherein R is hydrogen or methyl, and pharmaceutically acceptable salts thereof which comprises reacting a compound of formula (B) with dimethylformamide in the presence of an acid reaction promoter, recovering the required compound and where required converting it to a pharmaceutically acceptable salt thereof and recovering said salt.
2. A compound of formula (A) wherein R is hydrogen or methyl and pharmaceutically acceptable salts thereof when prepared by the process of claim 1 or in obvious chemical equivalent.
3. The process of claim 1 wherein R in formulae (A) and (B) is methyl and (A) is in the form of a diastereoisomeric mixture.
4. A compound of the formula as a diastereoisomeric mixture when prepared by the process of claim 3 or an obvious chemical equivalent.
5. The process of claim 1 wherein R in formulae (A) and (B) is hydrogen.
6. A process for the preparation of the mixture of diastereoisomers of the compound N-acetyl-N-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl)-.beta.-aminoisobutyric acid which comprises reacting N-acetyl-N-(3-amino-2,4,6-tri-iodophenyl)-.beta.-aminoisobutyric acid with dimethyl formamide in which it is dissolved in the presence of phosphorus oxychloride and recovering the said mixture of diastereoisomers.
7. A mixture of diasterioisomers of N-acetyl-N-(3-dimethylaminomethylene-amino-2,4,6-triiodophenyl)-.beta.-aminoisobutyric acid when prepared by the process of claim 6 or an obvious chemical equivalent.
8. A process for the preparation of the compound N-acetyl-N-(3-dimethylamino-methyleneamino-2,4,6-triiodophenyl)-.beta.-aminopropionic acid which comprises reacting N-acetyl-N-(3-amino-2,4,6-triiodophenyl)-.beta.-aminophopionic acid ethyl ester suspended in chloroform and dimethyl formamide with said dimethyl formamide in the presence of phosphorus oxychloride, recovering the ethyl ester of the required compound, saponifying it with sodium hydroxide; neutralizing and recovering the required compound.
9. N-acetyl-N-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl)-.beta.-amino-propionic acid when prepared by the process of claim 8 or an obvious chemical equivalent.
lO. A process for the preparation of the salt calcium N-acetyl-N-(3-dimethyl-aminomethyleneamino-2,4,6-triiodophenyl)-.beta.-aminoisobutyrate which comprises the process of claim 6 wherein the product is converted to the calcium salt by reaction with calcium chloride after solution in water with sodium hydroxide, and recovering said calcium salt.
ll. Calcium N-acetyl-N-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl)-.beta.-aminoisobutyrate when prepared by the process of claim lO or an obvious chemical equivalent.
lO. A process for the preparation of the salt calcium N-acetyl-N-(3-dimethyl-aminomethyleneamino-2,4,6-triiodophenyl)-.beta.-aminoisobutyrate which comprises the process of claim 6 wherein the product is converted to the calcium salt by reaction with calcium chloride after solution in water with sodium hydroxide, and recovering said calcium salt.
ll. Calcium N-acetyl-N-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl)-.beta.-aminoisobutyrate when prepared by the process of claim lO or an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB13200/78A GB1583613A (en) | 1978-04-04 | 1978-04-04 | Triiodophenylaminopropionic acids and x-ray contrast media comprising the same |
| GB13200/78 | 1978-04-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1133935A true CA1133935A (en) | 1982-10-19 |
Family
ID=10018663
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA324,144A Expired CA1133935A (en) | 1978-04-04 | 1979-03-26 | Triio dophenyl-aminopropionic acids and x-ray contrast media comprising the same |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS54148733A (en) |
| AU (1) | AU519875B2 (en) |
| BE (1) | BE874998A (en) |
| CA (1) | CA1133935A (en) |
| DE (1) | DE2913299A1 (en) |
| DK (1) | DK135979A (en) |
| FI (1) | FI791082A (en) |
| FR (1) | FR2421877A1 (en) |
| GB (1) | GB1583613A (en) |
| GR (1) | GR71192B (en) |
| IL (1) | IL56927A (en) |
| IT (1) | IT1164113B (en) |
| NL (1) | NL7902104A (en) |
| PT (1) | PT69400A (en) |
| SE (1) | SE7902783L (en) |
| ZA (1) | ZA791500B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3073814A (en) * | 1960-07-25 | 1963-01-15 | Mallinckrodt Chemical Works | Triiodobenzoic acid derivatives |
-
1978
- 1978-04-04 GB GB13200/78A patent/GB1583613A/en not_active Expired
-
1979
- 1979-03-16 NL NL7902104A patent/NL7902104A/en not_active Application Discontinuation
- 1979-03-21 BE BE0/194139A patent/BE874998A/en not_active IP Right Cessation
- 1979-03-22 IL IL56927A patent/IL56927A/en unknown
- 1979-03-26 CA CA324,144A patent/CA1133935A/en not_active Expired
- 1979-03-27 GR GR58698A patent/GR71192B/el unknown
- 1979-03-28 PT PT69400A patent/PT69400A/en unknown
- 1979-03-28 SE SE7902783A patent/SE7902783L/en unknown
- 1979-03-29 ZA ZA791500A patent/ZA791500B/en unknown
- 1979-03-30 JP JP3713679A patent/JPS54148733A/en active Pending
- 1979-03-30 AU AU45567/79A patent/AU519875B2/en not_active Ceased
- 1979-04-02 FI FI791082A patent/FI791082A/en not_active Application Discontinuation
- 1979-04-03 DE DE19792913299 patent/DE2913299A1/en not_active Withdrawn
- 1979-04-03 DK DK135979A patent/DK135979A/en not_active Application Discontinuation
- 1979-04-03 IT IT48595/79A patent/IT1164113B/en active
- 1979-04-03 FR FR7908340A patent/FR2421877A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| NL7902104A (en) | 1979-10-08 |
| IL56927A (en) | 1982-01-31 |
| IT7948595A0 (en) | 1979-04-03 |
| FR2421877A1 (en) | 1979-11-02 |
| AU4556779A (en) | 1979-10-18 |
| ZA791500B (en) | 1980-08-27 |
| DK135979A (en) | 1979-10-05 |
| PT69400A (en) | 1979-04-01 |
| FI791082A (en) | 1979-10-05 |
| SE7902783L (en) | 1979-10-05 |
| BE874998A (en) | 1979-07-16 |
| FR2421877B1 (en) | 1981-11-20 |
| GR71192B (en) | 1983-04-11 |
| JPS54148733A (en) | 1979-11-21 |
| AU519875B2 (en) | 1981-12-24 |
| IL56927A0 (en) | 1979-05-31 |
| IT1164113B (en) | 1987-04-08 |
| DE2913299A1 (en) | 1979-10-18 |
| GB1583613A (en) | 1981-01-28 |
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