GB2157283A - Esters of 3,5-diacetylamino-2,4,6-triiodobenzoic acid as X-ray contrast agents - Google Patents
Esters of 3,5-diacetylamino-2,4,6-triiodobenzoic acid as X-ray contrast agents Download PDFInfo
- Publication number
- GB2157283A GB2157283A GB08408251A GB8408251A GB2157283A GB 2157283 A GB2157283 A GB 2157283A GB 08408251 A GB08408251 A GB 08408251A GB 8408251 A GB8408251 A GB 8408251A GB 2157283 A GB2157283 A GB 2157283A
- Authority
- GB
- United Kingdom
- Prior art keywords
- ray contrast
- diatrizoate
- ray
- contrast medium
- carbons
- 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.)
- Granted
Links
- 239000002872 contrast media Substances 0.000 title claims abstract description 55
- YVPYQUNUQOZFHG-UHFFFAOYSA-N amidotrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 title abstract description 14
- 150000002148 esters Chemical class 0.000 title abstract description 5
- 239000002502 liposome Substances 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- -1 octadecyl diatrizoate Chemical compound 0.000 claims description 30
- 229960005423 diatrizoate Drugs 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 23
- 210000000056 organ Anatomy 0.000 claims description 4
- 210000000952 spleen Anatomy 0.000 claims description 4
- 238000012800 visualization Methods 0.000 claims description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 210000000232 gallbladder Anatomy 0.000 claims 1
- 230000001926 lymphatic effect Effects 0.000 claims 1
- 210000000278 spinal cord Anatomy 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 229960005223 diatrizoic acid Drugs 0.000 abstract description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- WSULSMOGMLRGKU-UHFFFAOYSA-N 1-bromooctadecane Chemical compound CCCCCCCCCCCCCCCCCCBr WSULSMOGMLRGKU-UHFFFAOYSA-N 0.000 description 7
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229940039231 contrast media Drugs 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000002591 computed tomography Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- MIKKOBKEXMRYFQ-WZTVWXICSA-N meglumine amidotrizoate Chemical compound C[NH2+]C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I MIKKOBKEXMRYFQ-WZTVWXICSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000003904 phospholipids Chemical group 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- VJGNLOIQCWLBJR-UHFFFAOYSA-M benzyl(tributyl)azanium;chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 VJGNLOIQCWLBJR-UHFFFAOYSA-M 0.000 description 2
- 239000008366 buffered solution Substances 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- QYOXLKAKUAASNA-UHFFFAOYSA-N 1-bromodocosane Chemical group CCCCCCCCCCCCCCCCCCCCCCBr QYOXLKAKUAASNA-UHFFFAOYSA-N 0.000 description 1
- PBLNBZIONSLZBU-HNHCFKFXSA-N 1-bromododecane Chemical group CCCCCCCCCCC[13CH2]Br PBLNBZIONSLZBU-HNHCFKFXSA-N 0.000 description 1
- CZASMUMJSKOHFJ-UHFFFAOYSA-N 1-bromoicosane Chemical group CCCCCCCCCCCCCCCCCCCCBr CZASMUMJSKOHFJ-UHFFFAOYSA-N 0.000 description 1
- GWESGLGUMMNXDU-UHFFFAOYSA-N 1-bromononadecane Chemical group CCCCCCCCCCCCCCCCCCCBr GWESGLGUMMNXDU-UHFFFAOYSA-N 0.000 description 1
- JKOTZBXSNOGCIF-UHFFFAOYSA-N 1-bromopentadecane Chemical group CCCCCCCCCCCCCCCBr JKOTZBXSNOGCIF-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- ZMZGFLUUZLELNE-UHFFFAOYSA-N 2,3,5-triiodobenzoic acid Chemical class OC(=O)C1=CC(I)=CC(I)=C1I ZMZGFLUUZLELNE-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 125000005236 alkanoylamino group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- UXAJBSZQOZOHEI-UHFFFAOYSA-N chloromethyl decanoate Chemical group CCCCCCCCCC(=O)OCCl UXAJBSZQOZOHEI-UHFFFAOYSA-N 0.000 description 1
- HNUBMUSOXKDQIN-UHFFFAOYSA-N chloromethyl hexanoate Chemical group CCCCCC(=O)OCCl HNUBMUSOXKDQIN-UHFFFAOYSA-N 0.000 description 1
- JRCUJOMLYAQHDP-UHFFFAOYSA-N chloromethyl octanoate Chemical group CCCCCCCC(=O)OCCl JRCUJOMLYAQHDP-UHFFFAOYSA-N 0.000 description 1
- FOSRCBUBSTZSGY-UHFFFAOYSA-N chloromethyl pentadecanoate Chemical group CCCCCCCCCCCCCCC(=O)OCCl FOSRCBUBSTZSGY-UHFFFAOYSA-N 0.000 description 1
- ZYDSTVMBNBPPLQ-UHFFFAOYSA-N chloromethyl pentanoate Chemical group CCCCC(=O)OCCl ZYDSTVMBNBPPLQ-UHFFFAOYSA-N 0.000 description 1
- BTBBPNVBJSIADI-UHFFFAOYSA-N chloromethyl propanoate Chemical group CCC(=O)OCCl BTBBPNVBJSIADI-UHFFFAOYSA-N 0.000 description 1
- 238000013189 cholangiography Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 description 1
- 229940093541 dicetylphosphate Drugs 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000008344 egg yolk phospholipid Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000000244 kidney pelvis Anatomy 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000009608 myelography Methods 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005506 phthalide group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- ZEYOIOAKZLALAP-UHFFFAOYSA-M sodium amidotrizoate Chemical compound [Na+].CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I ZEYOIOAKZLALAP-UHFFFAOYSA-M 0.000 description 1
- XZNXVSDNACTASG-RZNNTOFGSA-M sodium;3,5-diacetamido-2,4,6-triiodobenzoate;3,5-diacetamido-2,4,6-triiodobenzoic acid;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound [Na+].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I.CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I XZNXVSDNACTASG-RZNNTOFGSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Emergency Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
New X-ray contrast agents are provided which are esters of diatrizoic acid having the structure <IMAGE> wherein R is an alkyl group of 10 to 22 carbons or a group of the structure <IMAGE> wherein R<1> is an alkyl group of 2 to 15 carbons. X-ray contrast medium containing the above X-ray contrast agent and a carrier therefor such as a liposome carrier.
Description
SPECIFICATION
X-ray contrast agents
Field of the invention
The present invention relates to esters of diatrizoic acid which are useful as contrast agents, to X-ray contrast media containing such contrast agents, which may include a liposome carrier, and to a method of using the above X-ray contrast media in the X-ray visualization of body cavities and organs.
Background of the invention
The use of certain iodine-containing benzoic acid derivatives as X-ray contrast agents is well known. For example, U.S. Patent No. 4,018,783 to Soulal discloses X-ray contrast agents which are of the structure
wherein A is -CONHCH3 or -N(CH3)COCH3 and R is a phthalide group or lower alkyl optionally substituted with an aryl or dialkylamino group, or with a group of the formula
-OCOR1 wherein R1 is lower alkyl, except that when A is -CONHCH3, then R is not acetoxymethyl or pivaloyloxymethyl.
British Patent 866,184 discloses triiodobenzoic acid derivatives of the structure
wherein R1is H or lower alkyl; R2 is H or lower alkanoyl; R3 is H or lower alkanoylamino.
U. S. Patent No. 3,128,301 discloses 3,5-diacylamino-2, 4, 6,-triiodobenzoic acid esters of the structure
wherein R is lower alkyl, and R1 and R2 are lower alkanoyl.
U. S. Patent No. 4,192,859 to Mackaness et al discloses the use of liposomes as carriers for contrast agents such as diatrizoic acid, sodium diatrizoate and other iodinated contrast agents.
Havron et al in "Radiopaque Liposomes: A Promising New Contrast Material for Computed Tomography of the Spleen", Radiology 140:507-511, August, 1981, disclose radiopaque positively charged liposomes as carriers for diatrizoate meglumine and diatrizoate sodium (Renografin) for use in computed tomography of the spleen.
Ryan et al in "The Preparation and Characterization of Liposomes Containing X-Ray Contrast Agents,"
Biochemica et Biophysica Acta. 756(1983), 106-110 (Elsevier Biomedical Press) disclose use of Renografin and Hypaque (RTM) in liposomes in X-ray computed tomography.
Description ofthe invention
In accordance with the present invention, new X-ray contrast agents are provided having the formula I
wherein R is an alkyl contains 10 to 22 carbons, and preferably 14 to 20 carbons, or a group of the structure
wherein R1 is an alkyl group of 2 to 15 carbons, and preferably 4 to 12 carbons.
Thus, the compounds of formula I of the invention cover compounds of the following structures
Further in accordance with the present invention, there is provided an X-ray contrast media composition which includes a compound of formula I together with a suitable pharmaceutically acceptable carrier therefor.
The term "alkyl" as employed herein includes both straight and branched chain radicals of 10 to 22 carbons, preferably 14 to 20 carbons in the case of R, and 2 to 15 carbons, preferably 4 to 12 carbons, in the case of R1. Examples of suitable R and R1 alkyl groups include, but are not limited to decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, septadecyl, octadecyl, nonadecyl, eicosanyl, heneicosanyl, and docosanyl, and including the various branched chain-isomers thereof.
The esters of diatrizoic acid of the invention may be prepared by using conventional esterification techniques. For example, in preparing the long chain esters of formula IA, diatrizoic acid of structure A
TAKE IN HERE
is reacted with an appropriate alcohol of structure B
ROH B
In a preferred process, diatrizoic acid is reacted with an alkali metal hydroxide such as KOH or NaOH to form the corresponding alkali metal diatrizoate which in turn, is reacted with an alkyl halide of the structure C
RX C wherein X is Br, Cl or I, in the presence of an inert organic solvent such as acetone, dimethyl formamide and an alkali metal iodide such as KI.
Compounds of formula IB may be prepared by reacting diatrizoic acid with an aqueous alkali metal hydroxide such as KOH or NaOH to form the corresponding salt. A solution of the diatrizoate salt in water is then treated with a tetraalkylammonium halide, for example, benzyltributylammonium chloride, in the presence of a water immiscible organic solvent, such as chloroform, dichloromethane ortoluene. A halomethyl ester of the structure D is added
(where X is Cl or Br) D and the mixture is allowed to react for 1 to 16 days to form IB.
The X-ray contrast medium of the invention which includes an X-ray contrast agent of the invention and a pharmaceutically acceptable carrier therefor, may be used in X-raying and scanning body cavities and organs.
In a more preferred embodiment of the invention, the X-ray contrast agent of formula I is incorporated in a liposome carrier employing procedures as described in U.S. Patent No.4,192,859 and as such is especially useful in lymphographictechniques.
The X-ray contrast agent of the invention will be present in the liposome contrast medium in an amount within the range of from about 20 to about 60% by weight of the contrast medium, and preferably from about 30 to about 50% by weight of the contrast medium, depending upon the desired concentration of iodine.
The liposomes and preparations for same suitable for use herein include those disclosed in U. S. Patent
No.3,957,971 to Oleniacz; G Sessa et al, J. Lipid Res., Vol.9,310 (1968), as well as in the various references discussed hereinbefore, and other liposomes known in the art.
Liposomes employed in the present invention generally comprise lipid materials, predominantly of the phospholiped type (for example, a sterol), lecithin, dicetyl phosphate, or stearylamine, in an organic solvent.
When employing an X-ray contrast medium containing an X-ray contrast agent and a liposome carrier therefor, according to the invention, the X-ray contrast medium is administered to the body of the test object wherafterthe body is exposed to X-rays and photographs may be taken or the image observed directly on a fluorescent screen, or other X-ray techniques may be applied in a conventional manner. The dose of contrast medium administered is selected according to the category of the investigation, so that a sufficient contrast effect is obtained.
The test object may include mammalian species, such as humans, dogs, cats, monkeys, sheep, pigs, horses, bovine animals and the like.
As indicated, the X-ray contrast medium of the invention is particularly suitable for use in lymphography.
However, the X-ray contrast medium may be employed for visualizing many different body cavities and organs, such as the chest cavity including the bronchial tree, and the gastrointestinal tract. In the latter instance, the contrast medium is administered perorally as a thick liposomal formulation. The intestines can also be visualized by administering the X-ray contrast medium rectally in the form of a liposomal enema.
Another example is the visualization of blood vessels subsequent to the X-ray contrast medium being injected in the form of a sterile liposomal preparation. When injected intraveneously the X-ray contrast medium is excreted with the urine and enables visibilization of the renal pelvis, ureters and bladders. Further examples are the use of the X-ray contrast media in imaging the biliary system, hysterosalpingography, cholangiography, myelography, angiography, sialography, and liver and spleen imaging.
As indicated, the X-ray contrast agent of the invention may be combined with a pharmaceutically acceptable carrier (other than liposomes) depending upon the particular use of the final composition which may be employed for diagnostic purposes in bronchography, the delineation of tissue planes, salpinography and transumbilical heptography. In such applications, the X-ray contrast agents of the invention may be administered as an aqueous dispersion, an aerosol, in microencapsulated form or in an oily solution. Thus, for bronchography, the X-ray contrast agent of the invention may be combined with a non-toxic water-insoluble or metabolizable solid carrier, such as lactose, for purpose of insufflation.
The following Examples represent preferred embodiments of the present invention.
EXAMPLE 1
Octadecyl diatrizoate
A solution of potassium hydroxide (5.36 g of 85% purity) in water (17 ml) was added to diatrizoic acid (50 9), followed by acetone (300 mi), 1-bromooctadecane (30 g) and potassium iodide (5 g). The suspension was stirred and heated at 56"C (under reflux) for 10 days. The insoluble material was collected by filtration and washed with ethyl acetate. The solid was then extracted with hot (600C) methanol-chloroform (1:1) and the solution obtained was filtered and concentrated to give octadecyl diatrizoate, which was recrystallized from 1:1 methanol :chloroform. The white solid had a m.p. 248-250"C(d).
EXAMPLE 2
Pivaloyloxymethyl diatrizoate
Aqueous N sodium hydroxide (33 ml) was added to a stirred suspension of diatrizoic acid (20 g) in water (20 ml), followed by benzyltributylammonium chloride (10.2 g), chloroform (55 ml) and chloromethyl pivalate (5 ml). The reaction mixture was stirred vigorously at room temperature for 2 weeks. The precipitated solid was collected by filtration and recrystallized from methanolchloroform, affording the pivaloyloxymethyl diatrizoate as white crystals, m.p. 253-254.5"C(d).
EXAMPLE 3
Nonadecyl diatrizoate
Following the procedure of Example 1 except substituting 1-bromononadecane for 1-bromooctadecane, the title compound is obtained.
EXAMPLE 4
Septadecyl diatrizoate
Following the procedure of Example 1 except substituting 1-bromoseptadecane for 1-bromooctadecane, the title compound is obtained.
EXAMPLE 5
Pentadecyl diatrizoate
Following the procedure of Example 1 except substituting 1-bromopentadecane for 1 -bromooctadecane, the title compound is obtained.
EXAMPLE 6 Dodecyl diatrizoate Following the procedure of Example 1 except substituting 1-bromododecane for 1-bromooctadecane, the title compound is obtained.
EXAMPLE 7
Eicosanyl diatrizoate
Following the procedure of Example 1 except substituting 1-bromoeicosane for 1 -bromooctadecane, the title compound is obtained.
EXAMPLE 8
Docosanyl diatrizoate
Following the procedure of Example 1 except substituting 1-bromodocosane for 1-bromooctadecane, the title compound is obtained.
EXAMPLE 9
Hexanoyloxymethyl diatrizoate
Following the procedure of Example 2 except substituting chloromethyl hexanoate for chloromethyl pivalate, the title compound is obtained.
EXAMPLE 10 Valero yloxymeth yl diatrizoate
Following the procedure of Example 2 except substituting chloromethyl valerate for chloromethyl pivalate, the title compound is obtained.
EXAMPLE 11
Octanoyloxymethyl diatrizoate
Following the procedure of Example 2 except substituting chloromethyl octanoate for chloromethyl pivalate, the title compound is obtained.
EXAMPLE 12
Decanoyloxymethyl diatrizoate
Following the procedure of Example 2 except substituting chloromethyl decanoate for chloromethyl pivalate, the title compound is obtained.
EXAMPLE 13
Propanoyloxymethyl diatrizoate
Following the procedure of Example 2 except substituting chloromethyl propanoate for chloromethyl pivalate, the title compound is obtained.
EXAMPLE 14 Pentadecanoyloxymethyl diatrizoate
Following the procedure of Example 2 except substituting chloromethyl pentadecanoate for chloromethyl pivalate, the title compound is obtained.
EXAMPLE 15
A quantity of each of 1.4 g egg lecithin (egg phosphotidyl choline) and 0.6 g cholesterol are dissolved in 20 ml of chloroform. The chloroform is evaporated leaving a film of neutral phospholipid residue. Two grams of the phospholipid is then added to 7 ml of neutral buffered solution containing 4 g of the X-ray contrast agent octadecyl diatrizoate prepared as described in Example 1. The mixture is stirred with a magnetic stirrer until a final homogeneous liposomal mixture is obtained. Ten milliliters of the final liposome preparation contains 4 g of the X-ray contrast agent.
The so-formed X-ray contrast medium may be employed as described in U. S. Patent No. 4,192,859.
EXAMPLE 16
Two grams of neutral phospholipid residue, prepared as described in Example 15, is added to 6.7 ml of neutral buffered solution containing 4 g of pivaloyloxymethyl diatrizoate. The mixture is stirred with a magnetic stirrer until a homogeneous liposomal mixture is obtained. Ten milliliters of the final liposome preparation contains 4 g of pivaloyloxymethyl diatrizoate.
The so-formed contrast medium may be employed as described in U. S. Patent No. 182,859.
EXAMPLE 17
An X-ray contrast composition is prepared by admixing octadecyl diatrizoate acid (10 g) and lactose (0.5 g).
EXAMPLE 18
An X-ray contrast composition is prepared by admixing pivaloyloxymethyl diatrizoate (10 g) and lactose (0.5 9).
Claims (21)
1. An X-ray contrast agent having the structure
TAKE IN HERE
wherein R is an alkyl group of from 10 to 22 carbons or a group of the structure
0 -CH20CR wherein R1 is an alkyl group of 2 to 15 carbons.
2. The compound as defined in Claim 1 wherein R is an alkyl group of 10 to 22 carbons.
3. The compound as defined in Claim 2 wherein R is an alkyl group of 14to 20 carbons.
4. The compound as defined in Claim 3 wherein R is octadecyl.
5. The compound as defined in Claim 1 wherein R is
6. The compound as defined in Claim 5 wherein R1 is an alkyl group of 4 to 12 carbons.
7. The compound as defined in Claim 6 wherein R1 is -C(CH3)3.
8. An X-ray contrast medium comprising an X-ray contrast agent as defined in Claim 1, 2,3,5 or 6 and a carrier therefor.
9. The X-ray contrast medium as defined in Claim 8 wherein said carrier is a liposome.
10. The X-ray contrast medium as defined in Claim 8 wherein said contrast agent is octadecyl diatrizoate.
11. The X-ray contrast medium as defined in Claim 8 wherein said contrast agent is pivaloyloxymethyl diatrizoate.
12. A method for the X-ray visualization of body cavities and organs, which comprises administering to the body of the test object an effective contrast producing amount of an X-ray contrast medium as defined in
Claim 8 or 9.
13. The method as defined in Claim 12 wherein the liver is visualized.
14. The method as defined in Claim 12 wherein the spleen is visualized.
15. The method as defined in Claim 12 wherein the gall bladder is visualized.
16. The method as defined in Claim 12 wherein the spinal cord is visualized.
17. The method as defined in Claim 12 wherein the X-ray contrast agent employed is the octadecyl diatrizoate or pivaloyloxymethyl diatrizoate.
18. The method for X-ray visualization of lymphatic channels, which comprises administering to the body of the test object an efective contrast producing amount of an X-ray contrast medium as defined in
Claim 9.
19. A method for the radiographic examination of the gastrointestinal tract, which comprises administering to the body of the test object an effective contrast producing amount of an X-ray contrast medium as defined in Claim 8.
20. A compound according to Claim 1, as named in any one of Examples 3 - 14.
21. An X-ray contrast medium according to Claim 8 substantially as described in any one of Examples 15-18.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08408251A GB2157283B (en) | 1984-03-30 | 1984-03-30 | Esters of 3,5-diacetylamino-2,4,6-triiodobenzoic acid as x-ray contrast agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08408251A GB2157283B (en) | 1984-03-30 | 1984-03-30 | Esters of 3,5-diacetylamino-2,4,6-triiodobenzoic acid as x-ray contrast agents |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8408251D0 GB8408251D0 (en) | 1984-05-10 |
| GB2157283A true GB2157283A (en) | 1985-10-23 |
| GB2157283B GB2157283B (en) | 1987-07-08 |
Family
ID=10558923
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08408251A Expired GB2157283B (en) | 1984-03-30 | 1984-03-30 | Esters of 3,5-diacetylamino-2,4,6-triiodobenzoic acid as x-ray contrast agents |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2157283B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0300828A1 (en) * | 1987-07-24 | 1989-01-25 | Nycomed As | Iodinated esters |
| WO1990007491A1 (en) * | 1989-01-09 | 1990-07-12 | Nycomed As | Iodinated esters |
| US5354549A (en) * | 1987-07-24 | 1994-10-11 | Nycomed Imaging As | Iodinated esters |
| WO1995024378A1 (en) * | 1994-03-10 | 1995-09-14 | Nanosystems, L.L.C. | Iodinated aroyloxy ketones |
| US5593687A (en) * | 1989-10-13 | 1997-01-14 | Schering Aktiengesellschaft | Aqueous dispersion containing liposomes |
| EP1287833A3 (en) * | 2001-08-20 | 2003-04-23 | Fuji Photo Film Co., Ltd. | Liposome containing hydrophobic iodine compound and X-ray contrast medium comprising said liposome |
| US7101532B2 (en) * | 2000-04-28 | 2006-09-05 | Fuji Photo Film Co., Ltd. | Liposome containing hydrophobic iodine compound |
-
1984
- 1984-03-30 GB GB08408251A patent/GB2157283B/en not_active Expired
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0300828A1 (en) * | 1987-07-24 | 1989-01-25 | Nycomed As | Iodinated esters |
| WO1989000988A1 (en) * | 1987-07-24 | 1989-02-09 | Nycomed As | Iodinated esters |
| US5354549A (en) * | 1987-07-24 | 1994-10-11 | Nycomed Imaging As | Iodinated esters |
| WO1990007491A1 (en) * | 1989-01-09 | 1990-07-12 | Nycomed As | Iodinated esters |
| US5370861A (en) * | 1989-01-09 | 1994-12-06 | Nycomed Imaging As | Iodinated esters contrast medium and use |
| US5416223A (en) * | 1989-01-09 | 1995-05-16 | Nycomed Imaging As | Iodinated esters |
| US5593687A (en) * | 1989-10-13 | 1997-01-14 | Schering Aktiengesellschaft | Aqueous dispersion containing liposomes |
| WO1995024378A1 (en) * | 1994-03-10 | 1995-09-14 | Nanosystems, L.L.C. | Iodinated aroyloxy ketones |
| US7101532B2 (en) * | 2000-04-28 | 2006-09-05 | Fuji Photo Film Co., Ltd. | Liposome containing hydrophobic iodine compound |
| EP1287833A3 (en) * | 2001-08-20 | 2003-04-23 | Fuji Photo Film Co., Ltd. | Liposome containing hydrophobic iodine compound and X-ray contrast medium comprising said liposome |
| US7008614B2 (en) | 2001-08-20 | 2006-03-07 | Fuji Photo Film Co., Ltd. | Liposome containing hydrophobic iodine compound and X-ray contrast medium for radiograph comprising the liposome |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8408251D0 (en) | 1984-05-10 |
| GB2157283B (en) | 1987-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4567034A (en) | Esters of diatrizoic acid as X-ray contrast agents | |
| EP0603922B1 (en) | Iodinated aroyloxy esters and their use as contrast agents in X-ray imaging | |
| US4192859A (en) | Contrast media containing liposomes as carriers | |
| US5521218A (en) | Nanoparticulate iodipamide derivatives for use as x-ray contrast agents | |
| US5550263A (en) | X-ray contrast agent | |
| US6039931A (en) | Derivatized DTPA complexes, pharmaceutical agents containing these compounds, their use, and processes for their production | |
| US5846515A (en) | Calixarene conjugate diagnostic agents for computerized tomography and method for using same | |
| EP0071564B1 (en) | Paramagnetic complex salts, their preparation and their use in nmr diagnostics | |
| DE69424424T2 (en) | PERFLUORO-1H-1H-NEOPENTYL CONTRASTING AGENT AND METHOD FOR ITS USE | |
| IL94818A (en) | Derivatized diethylene triaminepentaacetic acid complexes and pharmaceutical and diagnostic compositions containing the same | |
| US5453264A (en) | Chelating agent, complex compound of said chelating agent and metallic atom, and diagnostic agent comprising same | |
| US5798092A (en) | Derivatized DTPA complexes pharmaceutical agents containing these compounds, their use, and processes for their production | |
| US4735795A (en) | Alkylammonium complexes of diatrizoic acid as X-ray contrast agents | |
| US4873075A (en) | Polyiodinated triglyceride analogs as radiologic agents | |
| GB2157283A (en) | Esters of 3,5-diacetylamino-2,4,6-triiodobenzoic acid as X-ray contrast agents | |
| US5318769A (en) | Compositions of iodophenyl esters for X-ray visualization of the gastrointestinal tract | |
| WO2013121284A1 (en) | Iodinated products intended for a use for the medical imaging and their methods of preparation | |
| US4957729A (en) | Polyiodinated triglyceride analogs as radiologic agents | |
| US5308607A (en) | Compositions of alkylbenzenes for visualization of the gastrointestinal tract using X-ray contrast | |
| US5093042A (en) | Polyiodinated triglyceride analogs as radiologic agents | |
| US5344638A (en) | Compositions of iodobenzoic acid derivatives for visualization of the gastrointestinal tract | |
| US4395391A (en) | Unsymmetrically substituted dicarboxylic-acid-bis-(2,4,6-triiodo-anilides), their preparation, and x-ray contrast media containing same | |
| US5346688A (en) | Iodinated wetting agents | |
| US5385720A (en) | Compositions of iodobenzoic acid derivatives and cellulose derivatives for visualization of the gastrointestinal tract | |
| EP0613690A2 (en) | Compositions of iodoaniline derivatives for visualization of the gastrointestinal tract |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20000330 |