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Publication numberUS2820814 A
Publication typeGrant
Publication dateJan 21, 1958
Filing dateMar 21, 1955
Priority dateMar 21, 1955
Publication numberUS 2820814 A, US 2820814A, US-A-2820814, US2820814 A, US2820814A
InventorsGinsberg Helen F
Original AssigneeSchering Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Polyiodinated 5-aminoisophthalic acids, salts, and esters
US 2820814 A
Abstract  available in
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Description  (OCR text may contain errors)

United States Patent POLYIODINATED S-AMINOISOPHTHALIC ACIDS, SALTS, AND ESTERS No Drawing. Application March 21, 1955 Serial No. 495,763

9 Claims. (Cl. 260471) This invention relates to a new group of halogenated compounds which have important X-ray contrast properties. More particularly, this invention relates to new acylaminopolyiodoisophthalic acids, their salts and esters and to'methods for preparing same.

It is an object of this invention to provide derivatives of isophthalic acid containing a plurality of iodine atoms and possessing a relatively low toxicity as well as a substantial solubility in water in the form of their salts. It is a further object of this invention to provide for improved contrast media in X-ray diagnosis and to further provide improved X-ray contrast agents which are relatively stable under normal conditions of storage and use in the presence of body fluids.

According to the present invention, it has been found that aliphatic-acylated-S-amino-polyiodoisophthalie acids, specifically, 5-acetylamino-2,4,G-triiodo-isophthalic acid, possess many valuable properties. These compounds consist of the acids of the general formula:

H -COOH (1) l COOH wherein R is a member of the group consisting of H and lower acyl and n is an integer from 2-3, together with their non-toxic salts and esters.

pression techniques whereby the diffusion rate of the injected compound throughout the blood stream is reduced, visualization of the calyx and ureters is made possible within 5 to minutes after injection. These aforementioned urographic properties appear to be peculiar to those compounds of the general formula which contain three iodine atoms, a lower acyl group on the amino-nitrogen atom and a free carboxylic acid group preferably in the form of its salt. For example; the formyl, acetyl and propionyl derivatives of the triiodinated acids of the general formula are excellent urographic agents, with the acetyl compound exhibiting the most desirable properties.

As the number of carbon atoms in the acyl group is increased, there is an observable transitional change in the properties of the compounds, Specifically, the urographic utility decreases and the compounds become better suited as cholecystographic agents.

Esters of the acids of the general formula, especially those compounds containing three iodine atoms provide for X-ray contrast agents useful in bronchography and hysterosalpingography. For these diagnostic methods the esters are used preferably in oil solution or suspension. It is possible, however, to employ salts of the acids for use in bronchography and hysterosalpingography provided thickening agents such as methyl cellulose, gelatin, dextran, and other acceptable agents are employed whereby proper concentration of the radiopaque material is obtained with concomitant reduction in difiusion rate away from the site under examination.

Thus it is seen that the compounds of this invention may be administered parentally, orally or deposited at the site to be visualized. Depending upon the, mode of administration, the compounds therefore are useful in urogenital, gynecological and gastro-intestinal diagnoses.

The compounds of the invention possess a favorable therapeutic ratio in that the dose: toxicity value is very small. It has been found that the intravenous toxicity of many of the compounds of this invention lie between 5 and 10 grams of substance per kilogram of body weight as compared with a maximum of 400 mg. per kilogram as an effective dose. Thus, these compounds can be utilized effectively at about one-twentieth of the LD/SO dose.

With S-acetylamino-2,4,6-triiodo-isophthalic acid, as the preferred compound in the form of a pharmacologically acceptable soluble salt, excellent X-ray visualization is obtainable at a dose which is comparable to other diagnostic agents in use. At the dose employed, there is a marked absence of side effects including venous spasm which is sometimes noted with iodinated acids of this type.

Excretion urography is based upon parenteral administration, usually by intravenous injection, of a contrast agent which is then excreted by the kidneys in such concentration that the kidneys and urinary tract are clearly outlined in a roentgenogram. As stated heretofore, a urogram may generally be taken within about five to twenty minutes after injection. It is generally known, however, that if normal renal function is impaired, suflicient medium may not concentrate in the kidneys until about one to twenty-four hours afterinjection.

With, S-acetylamino:2,4,6-triiodo-isophthalic acid in solution as its sodium, or othertherepeutically acceptable salt, generally about twenty milliliters of a 50% solution is sufficient for intravenous urography in adults. For children half the adult dose is'generally sutficient. Obviously the restriction of fluid for several hours prior to examination permits greater urinary concentration of the salt allowing for more clearly defined roentgenograms.

It is not intended that the compounds of this invention be limited solely to urographic, cholecystographic and similar media since the properties of these compounds make them useful for many other purposes. As heretofore stated, visualization of the gastra-intestinal tract is made possible by the proper administration of some of the compounds of this invention. In such an indication the compounds may for example be administered orally in the form of solutions, suspensions, tablets, capsules, and the like. It is not even essential that soluble salts be employed. Furthermore, the utility of these compounds is not necessarily restricted to visualization of human organs since they are equally adaptable for X-ray visualization of other structures which can not be visua1- ized directly.

2,820,814 I r J The con'ipo'ufidsof' this invention may be prepared from -amino is'ophtha'lic acid "according 'to "the following scheme:

coon coon 101 v y HzN- 00011 HO] NH coon Hell/Q01 (The preparation "of the requisite starting material 5- amino-isophthalic acid and its precursor 5-nitr0-isophthalic acidhas been reported in theliterature.) In addition to the i above scheme, aminodsophthalic acid in glacial acetic 'acid is iodinate'd'with iodine moriochloride in acetic acid giving rise to a mixture of both monoiodo and diiodo-5-amino-isophthalic acid which are easily separable byfractionalrecrystallization. "It is possible to carry out the' reaction in'sucha manner was to Obtain a preponderance of the 'diiodoacid over monohalogenated substances. By employing an excess of iodine monochloride in hy'drochloric acid it is possible-to triiodinate the amino-isophthalic acid although' one can stepwise 'iodinate whereby the ir'ite'rmediatemono-- or dihalo'genated substance" is isolated and*siibjected to further iodination.

The iodinated amino'ac'ids areacylated -with"a' suitable agent such as a carboxylicfacid; carb'oxylic acid chloride 'or anhy'clride preferablydn the presenceof afltraceiof= a strong mineralacid'such as sulfur'iciacid. 'FSpecific'exam- 'ples of acy'lafing a'g'ents' which" are envisiond'tasco'ming withinthe scope of this invention are for'mic acid; acetic acid, acetyl chloride, acetic?anhydride, l propionic anhydride, "butyricf anhydride' and" the like. Thus, although acetic anhydrideis preferred becauseof its'rel'ativeeconomy "and availability, otl'ler'lower aliphatic acylating agents may be employed.

The saltsafid esters 'ofthese compounds are prepared by the-usual methods employed in preparing salts and esters of organic acids.

The following examples further illustrate the'invention but in no way limit the said-invention except as defined in the appended claims.

-of--acetic acid --ov'er 1 a: one-hour. period. After stirring for-an additionalhour, -200zml.-of".water is added dropwise and thelmixture IlS'LflllOWfidwtO standat room item- 'perature for about 30 minutes. The mixture is heated on a steam bath-at-about 70- forabout '40 minutes and then allowed to stand at room temperature overnight. Excess iodine monochloride is destroyed by the addition of sodium bisulfite solution and the acetic-acid is 'rernoved'by steam distillation. 'Upon'the addition 6f concentrated hydrochloric acid to the residue from the steam distillation there is obtained 10 g. of a mixture of iodinated acids melting at 270-285 (dec.). The crude iodinated acid is recrystallized from 500 m1. of water yielding mono-i0dO-S-amino-isophthalic acid, M. P. 293 (dec.).

Upon the addition of concentrated hydrochloric acid to the recrystallization liquor, there --is obtained-about 5 g. of diiodo-5-an'1i-no-isophthalic acid-as a white microcrystalline solid, M. P. SOS-309 dec.).

EXAMPLE H Diiodo-S-amz'no-isaphthalic ,acid

To a suspension'of 9=;g.- of:fiamino-isophthalic acid in 1 liter of water thereisadded sufficient concentrated hydrochloric acid (about"1'5"rr1l;)"to'fiect complete solution. To the solution is then added 26.7 g. of iodine monochloride and- .the reactionrmixture. is=stirred 1- atroom temperature -for three days. After 1 removing 1 3. :small amount of insolubles byhfiltration thefiltrateis treated with sodium-;hydrosulfite-nntil the color indicativeof-cxcess iodine monochloride disappears. 'Thesolutionnis then saturated with sodium chloride rand extractedt thoroughly with ether. .The ether solution is 'fdrie'd' with anhydrous sodium: sulfate and .evaporatedto afi-residue, yielding -l4 :g. of crude diiodo-5-amino isophthalic:acid. The crude acid is purified by recrystallization from water using decolorizing charcoal "and reprecipitated --from'- the cooled filtratebythe addition of-concentrated'hydrochloric acid.

EXAMPLE III p t 2;4,6-trif0d0 5-amino-isophthalic acid To a ,solution of 4.5 g. of 5-amino-isophtha1ic acid in 250ml. of water-and 8.5 ml. of concentrated hydrochloric acid there is added 14 g. of iodine mono'chlor'ide and the reaction mixture is allowed to stand for two days. After filtration of the'insoluble"material, the filtrate is treated with sodium hydrosulfite, saturated with sodium chloride and extracted thoroughly with ether. The ether extracts are dried over anhydrous sodium sulfate and evaporated to a residue yielding 7.5 g. of the crude acid of ;this.exarnple',-1\ l.,P. 2.704749. Purification is effectediby ztrleatinggahot aqueous ssolutionuof; theiodinatedacidcwith charcoal and reprecipitating;ihelrpnoduct :fromatheucold :filtrate by :theaddition of concentrated hydrochloric acid, 1M; P. '27'8"280' (deer).

"EXAMPLE 'IV- a DiiodwS-acetylamino-isqphthiilic acid suspension of1'-4.3 g. of diiodo 5eamino-isophth'alic drops of concentrated sulfuric acid and "theLmiXture-iS refluxed for=30 minutes. 'After cooling, the-mixture-is poured into' ml. -of-' water, neutralized" with .-5-'*-1 gfi'of 60 sodium acetate and evaporated to a'residue in wacuo.

hated hydrochloric acid yields 3- got the acetylamino compound of this exainple;-M;"P. ever'340.

.; EXAMPLE V '2,4;6-triiodo-5-acetylamino-isophthalic :acid I A: suspension of 55. gH- of 2A;6 triiodo-5-amino-isophthaliclacid in 15 mlt ofi -acetic anhydride in the-presence of: 1-'-2 drops of sulfuric acid :is refluxed for: 30minutes. The: crude: acetylated. acid: is :obtainedaccoi'ding.1o .-.the procedure :in :the precedingexample. Purification aiszieffected by solutionuin dilute ammonium; hydroxide and treatment withdecolorizing charcoal; followed by;.-filtration, cooling and reprecipitation with. concentratedhydrochloric acid. Recrystallization from water as described Recrystallization from-water andthe addition-of-concenasaaare in the preceding example yields the iodinated acid of this example, 3 g., M. P. above 340".

I EXAMPLE VI 2,4,6-triid0-5-formylamino-isophthalic acid To a mixture of 50 g. of 2,4,6-triiodo-5-amino-isophthalic acid and 500 ml. of 8790% formic acid is added about six drops of concentrated sulfuric acid and the resultant reaction mixture is heated and stirred on a steam bath for two hours. After cooling, the sulfuric acid is neutralized by the addition of a small amount of sodium acetate and the mixture is evaporated to a residue in vacuo. Upon recrystallization of the residue from water to which has been added concentrated hydrochloric acid, the formyl derivative of this example is obtained.

EXAMPLE VII 2,4,6-trz'z'odo-5-propionylamino-isophthalic acid EXAMPLE VIII 2,4,6-trii0d0-5-butyrylamirzo-isophthalic acid A mixture of g. of 2,4,6-triiodo-5-amino-isophthalic acid, 100 ml. of butyric anhydride and about six drops of concentrated sulfuric acid is stirred and heated at 150 to 160 for about two hours. The excess anhydride is destroyed by the addition of 600 ml. of water as described in the preceding example and the sulfuric acid is neutralized with sodium acetate. Upon evaporation of the resultant mixture in vacuo there is obtained a semisolid residue which is dissolved in warm, dilute ammonium hydroxide. The alkaline solution is treated with decolorizing charcoal and the butyrylamino acid is reprecipitated by the addition of concentrated sulfuric acid and recrystallized from water as heretofore described.

EXAMPLE IX 2,4,6-triiod0-5-caproylamirzo-isophthalic acid A mixture of 55.9 g. of 2,4,6-triiodo-5-amino-isophthalic acid, 500 ml. of anhydrous toluene and 20 grams of caproyl chloride is stirred and refluxed for one hour. After cooling, the crude product is removed by filtration and triturated with ether to remove unacylated material. After decanting the ether layer, the remaining solid'is recrystallized from aqueous ethanol afiording the caproylamino acid of this example.

EXAMPLE X Diethyl 2,4,6-triiodo-5-acetylamino-isophthalate To a mixture of grams of 2,4,6-triiodo-5-acetylamino-isophthalic acid and 200 ml. of anhydrous ethanol is added 15 ml. of acetyl chloride. The reaction mixture is allowed to stand at room temperature overnight with occasional shaking whereupon it is diluted with one liter of water and the precipitate so formed is removed by filtration or decantation. The crude ester is dissolved in ether and the ether solution is washed, in turn, with sodium bicarbonate solution and water. After drying the ether solution with anhydrous sodium sulfate, the solvent is removed in vacuo. There is obtained the diethyl ester of this example which is purified by recrystallization from aqueous alcohol.

Alternatively the diethyl ester is prepared by treating a solution ofj2,4,6-triiodo-S-acetylamino-isophthalic acidin absolute ethanol containing a catalytic amount of sodium ethoxide with diethyl sulfate and isolating the ester in a known manner.

In addition to the foregoing procedures the diethyl ester of this example is prepared by distilling an ethanolbenzene solution of the amino acid in the presence of 0.5 g. of p-toluene sulfonic acid (or 0.5 ml. of concentrated sulfuric acid) and azeotropically removing the water so formed.

EXAMPLE XI Disoaium salt of 2,4,6-trii0zi0-5-acetylamino-isophthalic acid I A suspension of 5.58 grams of purified 2,4,6-triiodo- 5- acetylamino isophthalic acid (obtained in Example V): in 15 ml. of distilled water is neutralized with 30% aqueous sodium hydroxide until the pH rises to 7 to 7.5. The alkaline solution is filtered and the filtrate is evaporated in vacuo. Upon recrystallization of the residue from alchol-ether, using decolorizing charcoal, six grams of the sodium salt of this example is obtained as a white crystalline solid.

It is generally not necessary to isolate the sodium salt per se if the appropriate quantities of amino acid, water,

- and alkali are used to yield a solution containing the desired concentration of sodium salt.

EXAMPLE XII Di-N-methylglucamine salt of 2,4,6-triiodo-5-acetylamina isophthalic acid To an intimate mixture of 4.67 grams of 2,4,6-triiodo- 5-acetylamino-isophthalic acid and 3.03 grams of N- methylglucamine is added 4.0 ml. of distilled water and.

the mixture is stirred until complete solution is etfected. The solution is then diluted to 10 ml. with distilled water affording a 77% w./v. solution which is comparable in iodine content to a 50% w./v. solution of the sodium salt.

Alternatively the di-N-methylglucamine salt is isolated by evaporation of the aqueous solution in vacuo.

EXAMPLE XIII Di-diethanolamine salt of 2,4,6 triiodo 5 acetylamino isophlhalic acid One mole of 2,4,6-triiodo-5-acetylamino isophthalic acid and two moles of diethanolamine are mixed and dissolved in water according to the procedure described in Example XII, giving rise to a similar w./v. concentration.

Isolation of the salt is accomplished by evaporation of its aqueous solution in vacuo.

I claim:

1. A compound selected from the group consisting of a S-amino-polyiodo-isophthalic acid of the general formula cooH

1(a) R-JFI GO0H eral formula:

(IJOOH R-N COOH

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2247880 *Jan 21, 1938Jul 1, 1941Jules Guerbet Andre GastonIodine organic compounds for use as chi-ray contrast compositions
US2611786 *May 31, 1950Sep 23, 1952Mallinckrodt Chemical Works3-carboxylic acylamino-2, 4, 6-triiodo benzoic acids and the ethyl ester and nontoxic salts
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US2963474 *Jul 23, 1958Dec 6, 1960Mallinckrodt Chemical WorksOrganic compounds
US3004964 *Jul 23, 1958Oct 17, 1961Mallinckrodt Chemical Works3-amino-2, 4, 6-triiodo-5-ureidobenzoic acid compounds
US3026351 *Sep 19, 1958Mar 20, 1962Mallinckrodt Chemical WorksIodo-benzoic acid compounds
US3047466 *Dec 9, 1958Jul 31, 1962Schering A G FaX-ray contrast agent
US3145197 *Jun 26, 1961Aug 18, 1964Mallinckrodt Chemical Works5-acetamido-nu-alkyl-2, 4, 6-trhodoiso-phthalamic acid compounds
US3210412 *Feb 6, 1962Oct 5, 1965Mallinckrodt Chemical Worksm-(alkanamidoalkanamido)-2, 4, 6-triiodobenzoic acid compounds
US3213065 *Nov 6, 1959Oct 19, 1965Bayer AgPolyesters and polyurethanes from 5-amino-benzene-1, 3-dicarboxylic acid
US3278582 *Jul 27, 1962Oct 11, 1966Velsicol Chemical CorpN-alkyl-n-alkoxy-amides of 2, 3, 5, 6-tetrachloroterephthalic acid esters
US3282987 *Jun 29, 1962Nov 1, 1966Du Pontalpha-ureidooxycarboxylic acids and their derivatives
US3347746 *Oct 12, 1964Oct 17, 1967Nyegaard & Co AsInjectable solution of an amine salt of a radiopaque iodinated organic acid containing calcium ions
US4021481 *Dec 2, 1974May 3, 1977Nyegaard & Co. A/SX-ray contrast agents
US4078142 *Jun 28, 1976Mar 7, 1978Standard Oil CompanyAmino substituted-4-t-butylphthalic acid esters
US5310537 *Mar 1, 1993May 10, 1994Sterling Winthrop Inc.Contrast agents
US5330740 *Mar 1, 1993Jul 19, 1994Sterling Winthrop Inc.Iodoaniline x-ray contrast compositions
US5422114 *Feb 25, 1994Jun 6, 1995Sterling Winthrop Inc.Compositions of iodoaniline derivatives and cellulose derivatives for visualization of the gastrointestinal tract
US5424056 *Apr 29, 1994Jun 13, 1995Sterling Wintrhop Inc.For diagnostic radiology of gastrointestinal tract
US5670136 *Jan 16, 1996Sep 23, 1997Nahosystems L.L.C.2,4,6-triiodo-5-substituted-amino-isophthalate esters useful as x-ray contrast agents for medical diagnostics imaging
WO1996037458A1 *May 17, 1996Nov 28, 1996Fructamine SpaProcess for the preparation of a halosubstituted aromatic acid
Classifications
U.S. Classification560/47, 562/456, 424/9.455
International ClassificationA61K49/04
Cooperative ClassificationA61K49/0433
European ClassificationA61K49/04H