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Publication numberUS2365776 A
Publication typeGrant
Publication dateDec 26, 1944
Filing dateSep 15, 1943
Priority dateSep 15, 1943
Publication numberUS 2365776 A, US 2365776A, US-A-2365776, US2365776 A, US2365776A
InventorsRaymond Albert L, Schroeder Elmer F
Original AssigneeSearle & Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Iodo-sugar derivatives and method of preparing same
US 2365776 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

Patented Dec. 26, 1944 UNlTED ,sTA'rEs PATENT. OFFICE IODO-SUGAR DERIVATIVES AND METHOD 015- PREPARING SAME f Albert L. Raymond, Northfleld,-- and Elmer F.- Schroeder,- Qhicago. 11L, assiznors to G. D. Searle & 00., Skokie, IIL, a corporation of Illi- This invention relates to sugar derivatives in which at least one iodine atom is substituted for at least one primary hydroxy group, and in which no free hydroxyl group is attached to a carbon atom adjacent to the carbon atom upon which the iodine atom is substituted, and in which all carbonyl groups (that is, aldehyde or ketone groups) are blocked by a glycoside linkage, and to the process of preparing those derivatives. These iodo-sugar glycosides are in general readily soluble in water, and are characterized by a relatively high degree of stability both in the solid state and in aqueous solution. They are quite useful, among other things, as agents for causing certain structures of the kidney to become visualized under X-ray observation.

It is commonly known that compounds containing a relatively high percentage of iodine, when present in sufllcient concentration in bod tissues or cavities, cause such tissues or cavities to cast shadows under X-rays, and so to become visualized. We have found that many of the iodo-sugar glycosides of this invention are readily excreted through the kidney following intravenous administration, and, in being so excreted, cause certain structures of the kidney to become visible under X-rays.

A survey of the chemical literature discloses the previous preparation of certain iodo-sugar derivatives. With but one exception (6-iodoglucose), however, all of these previously known iodo-sugar derivatives have contained, in addition to the iodine atom, one or more substituents of such a nature that the water solubility of the compounds is impaired and that they are otherwise unsuited for therapeutic purposes. So far as we are aware, there is no record of the successful preparation of an iodo-sugar glycoside such as is the subject of this invention.

In. searching for a compound suitable for therapeutic purposes, we have prepared iodosugars representing various types of structure, and found the various structure-types to vary greatly among themselves in stability. Thus, it has been found that iodo-sugar derivatives, such as iodo-mannitol or iodo-sorbitol, which have a free hydroxyl group adjacent to the iodine atom, are relatively unstable, the compound decomposing during the process of preparation in most instances. Secondly, it has been found that iodo-derivatives of certain otherwise unsubstituted sugars, such as iodoglucose and iodogalactose are distinctly more stable than those of the previously mentioned category. The iodoglucose has been suggested as a contrast medium for kidney visualization in British Patent No. 361,437, though it seems doubtful whether the patentees ever had the compound in hand since the method which they outline for its preparation has failed utterly to produce it in our hands. We have prepared both iodoglucose and iodogalactose; in spite of the disclosure in the above-mentioned British patent, we have found that iodoglucose is not a satisfactory contrast medium for this purpose, since, among other things, it apparently is not excreted with suflicient rapidity by the kidney to produce sufiicient concentration to cast a satisfactory shadow. The iodogalactose, however, is of distinct utility and is more specifically described and claimed in our copending application, Serial No. 502,543, filed September 15, 1943.

The iodo-sugars of this category are capable of existing, theoretically at least, in two readily interconvertible tautomeric forms. In one such form (A) a free hydroxyl group will be adjacent to the iodine atom, while in the other form (B) this hydroxyl group will be blocked by the internal ring structure. We have now found that if the structure of the iodo-sugar is definitely fixed in a structure of type B by converting it into a glycoside (C) the resulting iodoglycoside is a compound of greatly increased stability:

CHO oHoH CHOR .r inon Fnon [13011 011011 0 dnon tnon HOH (anon HOH CHOH H H (21111 dim Hi1 Since, in addition, these compounds (0) are very soluble in water and are relatively non-toxic, and are sufficiently rapidly concentrated and excreted by the kidney, they are of great utility as kidney visualizing agents. 5

One way in which such blocking may be achieved is by making a synthetic glycoside with an alcohol of relatively low molecular weight (such as methanol) prior to iodination. The necessary blocking can, however, equally well be achieved by using a natural polysaccharide sugar (such as surcrose'or trehalose) in which all of the carbonyl groups are mutually blocked by the oi the component monosaccharides is free in the natural sugar but is blocked by the formation of a synthetic glycoside linkage prior to introducing the iodine atom. In each of the latter cases, it is most convenient and efficacious to introduce an iodine atom into each of the monosaccharide components of the polysaccharide. Such compounds, containing more than one iodine atom in the molecule, are satisfactorily stable whenever the structure of the compound conform to the two conditions previously named, i. e., no free hydroxyl group is adjacent to an iodine atom, and each reducing group in the molecule is blocked by a glycoside linkage. These compounds are included within the general formula in which n represents the integers 2 or 3, and R represents an alhl group or a 6-iodomonosaccharide group in which the carbonyl group is blocked by a glycoside linkage and in which no free hydroxyl group is attached to the carbon atom in position 5. The system of numbering above referred to is that conventionally used in sugar chemistry, in which the terminal carbon atom nearest to the carbonyl group is said to be in position 1.

The stability of the iodo-sugar derivatives, as referred to in the above discussion, can be measured in roughly quantitative fashion by heating an aqueous solution of the compound in a boiling water bath, and, after cooling, titratin with standard alkali the acidity formed from decomposition. When the concentration of the solution used, and the length of the heating, are kept constant for a series of compounds, the ratio of titration values for these compounds forms an approximate measure of the ratio of their stabilities. This ratio will vary somewhat under different conditions of conducting the test, but will normally yield results of the same order of magnitude.

Closely allied to, and in partial consequence of our invention of a series of very stable iodo-sugar derivatives, is out invention of a simplified method of preparing such iodo compounds. The prior art has taught that an iodine atom can be introduced into a sugar molecule only when most or all of the other hydroxyl groups in the molecule are blocked or substituted by some protecting group. For instance, the 6-iodoglucose described in the prior art was said to have been prepared by introducing an iodine atom into tetra-acetylated glucose and subsequently removing the acetyl groups. When such other hydroxyl groups are not thus protected, it has been the general experience that more or less profound decomposition of the molecule ensues in place of a smooth introduction of iodine. We have now found, however, that the iodo-sugar glycosides of this invention can be prepared directly from the corresponding p-toluenesulfonyl derivatives without the intervening steps of the protecting hydroxyl groups and subsequently removing the protecting groups.

The following examples, showing in detail how this process may be carried out, and how the -new iodo-sugar derivatives of this invention may be prepared, are merely illustrative and are not intended in any way to limit this invention:

Example 1.-A solution of 300 grams of a-methly glucoside in 2500 cubic centimeters of I frigerator.

dry pyridine is cooled to -5 centrigrade and 325 grams of p-toluenesuifonyl chloride are added in small portions during a period of about 30 minutes with continued stirring. After the solution has stood another 30 minutes at room temperature, most of the free pyridine is removed by distillation in a vacuum. The residue is dissolved in 500 cc. of alcohol, then 500 cc. of water are added and the solution neutralized with a 20 per cent sodium hydroxide solution, using bromthymol blue as an external indicator. The solvent is'again removed in vacuum, the residue treated with six liters of acetone, and, after standing overnight in a refrigerator, filtered to remove insoluble material. After the acetone solution is concentrated to about 1.2 liters, 200 gm.

of sodium iodide are dissolved therein, and the whole is then heated at C. for three hours in a pressure vessel. After cooling, the mixture is filtered, the solvent removed from the filtrate in a vacuum, and the residue dissolved in about 700 cc. of water. This solution is extracted twice with methylene dichloride, made neutral with dilute sodium hydroxide, and about 500 cc. of water distilled on in a vacuum. Upon adding a seed crystal of o-iodo-a-methyl glucoside to the residue, crystallization starts immediately and is complete on standing overnight in a re- The compound may be purified by recrystallization from alcohol. The purified 6- iodo-a-methyl glucoside forms long dense prisms which melt sharply at l44l45 C., is readily soluble in water, warm alcohol and warm acetone, but is insoluble in chloroform.

Example 2. -Three hundred grams of fi-methyl glucoside are treated with p-toluenesulfonyl chloride, followed by heating with sodium iodide in an acetone solution, exactly in accordance with the directions given in Example 1. On cooling, crystals separate spontaneously. These contain the desired product, but in an impure form, and are best purified in the following manner. This material is filtered (the filtrate being discarded), suspended in about 600 cc. of dry pyridine,'300 cc. of acetic anhydride are then added, and the whole is heated at 65-75 C. for a half hour. After standing for several hours at room temperature, the solution is filtered, and the pyridine removed from the filtrate by vacuum distillation. When the residue is treated with a large amount of water, 6-iodo-2,3,4-triacetyl-fl-methyl glucoside crystallizes at once. This is purified by recrystallization from 3 volumes of alcohol. This acetyl derivative is then suspended in 600 cc. of dry methyl alcohol, and 57 cc. of a one-tenth normal solution of sodium methylate in methyl alcohol are added. After standing sever-a1 hours, the clear solution is evaporated to dryness in a vacuum, crystallization of 6-iodo-p-methyl glucoside taking place towards the end of the evaporation. This compound may be purified by recrystallization irom absolute alcohol and, when so purified, melts at l56 C., with decomposition. It is readily soluble in water, warm alcohol or warm acetone, but insoluble in chloroform. The 6-iodo derivatives of both aand ,B-methyl glucoside can be stored under normal conditions for prolonged periods, either in the solid form or in dilute or concentrated aqueous solution, without any appreciable evidence of decomposition.

Emample 3.Sixty grams of sucrose, 1100 cc. of pyridine, and 60 gm. of methanesulfonyl chloride are processed in a manner analogous to Example l to yield an acetone solution of tri-(methanesulfonyl) -sucrose. This solution is heated with 58 gm. of sodium iodide at 100 C. for 3 hours. The

assure KL O CH OSOgCHe noon soda HOiIH E ii Ziiii and I 43311 This compound mayb further purified by reprecipitation from acetone solution by means of chloroform. It has an indefinite melting point: its specific rotation is [a]n=+34.8 in 24 per cent aqueous solution; it is readily soluble in water and acetone, and is somewhat hygroscopic.

By using an amount oi-p-toluenesulfonyl chloride equivalent to the methanesulfony1 chloride in Example 3, the corresponding diiodo-toluenesultonyl sucrose is obtained. This compound also is an amorphous powder, which differs from the methanesulfonyl derivative mainly in that it is but sparingly soluble in water. The residual sulionic acid group in these compounds, being situ= ated adjacent to one of the blocked reducing groups of the sucrose, is much more firmly bound and cannot readily be replaced by iodine atoms. This does not in any way interfere with the utility of these compounds in casting a shadow under K-ray observation.

In the above examples, the acid chlorides of other sulionic acids, such as ethane-sulionic or henzenesulionic acid, may be substituted in equivalent amounts for the methane or toluenesulionyl chlorides specified, with only such minor changes in amounts of solvent or other details of operation as would be readily apparent to one skilled in this field of chemistry. Similarly, by us the same general procedure outlined above, the methyl (or other) glycosides of such monosaccharide sugars as xylose or arabinose (which are pentoses) or galactose or mannose (which are heiroses), or such polysaccharide compounds as trehalose or the methyl (or other) glycosides of maltose or lactose, may be converted into stable lode-derivatives which display the same desirable characteristics as those more completely described above. Further, while methyl glycosides have been used to achieve the blocking of the reducing groups in the above examples, other glycosides such as ethyl, propyl, etc., may be used and will be emcacious in leading to stable iodo-derivatives. The water-solubilities of some of these variants of this invention will naturally difier, the less soluble derivatives being less desirable for those purposes (as for instance, kidney visualization) which require the use of concentrated aqueous solutions, though they are nonetheless useful and desirable in other forms of iodine therapy.

While the utility of these compounds as therapeutic agents has been stressed in this specification, it is obvious that their utility is not limited to such application, and that the compounds 0! this invention will be useful wherever there is desired a stable lode-sugar derivative which is more or less water-soluble, and which has most or all of its hydroxyl groups unsubstituted, save for the iodine atom or atoms. It is therefore to be understood that the invention is not limited except as defined by the appended claims.

We claim:

1. Anew composition of matter consisting of a sugar in which at least one iodine atom is substituted for at least one primary hydroxyl group, and in which no tree hydroxyl group is attached to a carbon atom which is adjacent to a carbon atom to which an iodine atom is attached, and all of whose carbonyl groups are blocked by glycosidic linkages, and in which there is no constituent other than said iodine atom and said glycoside group hereinbeiore mentioned.

2. A new composition 01 water consisting 01 an iodo-sugar glycoside oi the formula:

0 BO.H.(CHOH).. H.011)! in which n is an integer between 1 and 4, and in which All: represents an alkyl group.

4. A new composition of matter consisting of fi-iodo-methylglucoside of the formula:


5. The process of preparing an iodo-sugar glycoside of the formula:

in which n is an integer between 1 and 4, and in which R. is chosen from the group comprising alkyl groups and B-iodo-monosaccharide groups whose carbonyl group is blocked by a glycoside linkage and in which no free hydroxyl group is attached to the carbon atom in position 5, which process comprises the replacement of a sulfonic acid group by iodine without the intermediate step of protecting the free hydroxyl groups in the molecule. substantially as described.

6. The process of preparing an iodo-sugar glycoside oi the formula:

0 Alk 0,015.03OH.OHOH.GHOH.lI-I.CH:I

0 CHiO EOHOHBHOlLOHOHlIIELCHzI which process comprises the replacement of a sultonic acid group by iodine without the intermediate step of protecting the free hydroxyl groups in the molecule, substantially as described.




Patent no, 2,565,776; December 26, 19th.


.It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: Page 5, second column, line 16, claim 2, for the word "water" read --matter--; and

that the said Letters Patent should .be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 27th day of March, A. D. l9l 5.

Leslie Frazer (Seal) Acting Commissioner of Patents.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US2492704 *Sep 4, 1944Dec 27, 1949Lawrence R LentzFilter
US2811516 *Sep 21, 1955Oct 29, 1957Ohio Commw Eng CoIodo carboxymethyl dextran and methods of making it
US2811517 *Sep 21, 1955Oct 29, 1957Ohio Commw Eng CoIodo-dextran and methods for producing the same
US3127361 *Nov 21, 1960Mar 31, 1964 Process for producing polymers of tri-o-
US3158493 *Oct 9, 1961Nov 24, 1964Erik VisAdhesive composition and method
US4228150 *Apr 23, 1979Oct 14, 1980Iowa State University Research Foundation, Inc.Method of inhibiting dextransucrase and oral compositions for use therein
US4335100 *Aug 6, 1980Jun 15, 1982Iowa State University Research Foundation, Inc.Method of inhibiting dextransucrase and oral compositions for use therein
US4415731 *Mar 30, 1981Nov 15, 1983Merck & Co., Inc.Process for the preparation of methyl 2,6-dideoxy-α-D-arabino-hexopyranoside
US4716225 *Sep 30, 1985Dec 29, 1987Georgetown UniversityRadioopaque sugar derivatives and a method of metabolic mapping using the same
EP0206551A2 *May 28, 1986Dec 30, 1986Nippon Universal Pharmaceutical Co., Ltd.,6-Iodoethylated starch and process for preparing the same
U.S. Classification536/18.4, 424/9.43, 536/122
International ClassificationC07H15/04, A61K49/04, C07H5/10
Cooperative ClassificationC07H15/04, A61K49/0438, C07H5/10
European ClassificationC07H5/10, C07H15/04, A61K49/04H2