US2245610A - Medicinal composition - Google Patents

Description

Patented June 17, 1941 MEDICINAL COMPOSITION Charles William Schaifer and Reinhard Beutner, Philadelphia, Pa.

No Drawing. Application January 21, 1938, Serial No. 186,086

9 Claims.

The present invention relates to a medicinal composition intended for the treatment of various diseased conditions by the provision of iodine in therapeutically active form.

Most of the therapeutically used iodine compounds have a transitory and inadequate thera-- peutic action. The inorganic iodides are rapidly excreted; and the same is true for most iodo proteins since the iodine is split off in the form of hydriodic acid or inorganic salts which are excreted. In the iodized fats, on the other hand, iodine is so tightly bound that it is not available for the body.

The present invention is concerned with a hitherto unknown class of iodo proteins and similar iodine compounds, the iodine of which is readily available in the body. The iodine made available by these compounds may become therapeutically active in two possible ways. In the first alternative, the available iodine may be transferred to tyrosine to form di-iodo-tyrosine, and related compounds which condense to form thyroxin, while in the second alternative preformed iodo-tyrosine and related products may be split off from an iodo protein and transformed into thyroxin.

Of these two alternatives mentioned above leading to the formation of thyroxin, our experience leads us to favor the first possibility as that actually occurring, since our improved composition comprises substances containing iodine, the iodine of which we have found readily passes from an aliphatic chain into an aromatic ring at a temperature as low as 35 0., preferably in the presence of oxidizing agents. Such an iodination is quite extraordinary and unexpected, since even free iodine does not enter into combination with benzene atsuch a low temperature as 35 C. We have also investigated which other iodine-containing compounds have the peculiar property of transferring iodine in such a manner, and have found that beta-iodo-propionic acid, as well as other beta-iodo fatty acids, will readily transfer their iodine to benzene at a low temperature in the presence of oxidizing agents. We have also found that tyrosine may be iodized to di-iodotyrosine by treatment with beta-iodo-propionic acid in the presence of oxidizing agents such as hydrogen peroxide at 35 0., whereas free iodine never iodizes tyrosine at such a low temperature. Alpha-iodo fatty acids, however, will not trans fer their iodine to an aromatic nucleus under the same circumstances. Hence it may, perhaps be concluded that our new iodo-proteins likewise contain iodine tied up to a beta-carbon atom, al-

though it is possible that the iodine may be attached to a delta-carbon atom.

As stated, the transfer of iodine from a beta carbon atom is facilitated by the oxidation process occurring in the tissues. It has been demonstrated that oxidation of proteins and organic acids in general always sets in at the beta carbon atom. Our experiments indicate that if iodine is attached in a beta, or possibly delta, position to an aliphatic compound it is set free by oxidation and becomes readily transferred to an aromatic nucleus, as, for example, tyrosine.

While beta-iodo-propionic acid and other betaiodo fatty acids can be used as iodizing agents for therapeutic purposes since they readily transfer their iodine leading to the formation of iodo tyrosine and then thyroxin in the tissues of the body, we have found it preferable to form proteins which probably contain iodine on a beta carbon by the method described below and to use these proteins for therapeutic purposes since iodo proteins are much easier to ingest than the iodized lower fatty acids.

Included in this application within the scope of the term protein" are peptides and peptones which function in both their chemical and therapeutic behaviors in the same fashin as proteins.

Apparently the therapeutic value of the betaiodo proteins herein described is primarily due to their beta-iodization, although not all of their iodine is bound in this fashion nor is the otherwise bound part of the iodine entirely inactive. A part of the iodine in these proteins is merely adsorbed to the protein and becomes readily available for iodization in the body. This free adsorbed iodine can be determined by extraction with othersolvents. In the proteins iodinated according to our method, the adsorbed iodine represents only a fraction of the total iodine present, whereas in proteins icdinated by Lugols solution nearly all the iodine may be extracted with alcohol.

For the preparation of iodo proteins having the desirable properties indicated herein we preferably react a sodium proteinate with or without an excess of alkali, or a solution of such a proteinate, with an organic or other weak acid in which free iodine has been dissolved. The quantity of iodine used should amount to 5%-50% of the weight of the protein. Preferably the quantity of the acid employed should substantially exactly neutralize the alkali combined with or added to the protein, though neutralization is no indispensable requisite of our process. The acids used may be, for example, lactic, acetic, propionic,

phosphoric or butyric used alone or in admixture with alcohols or other iodine solvents, or in aqueous solution. If the alkali bound to the protein is not entirely neutralized by the addition of an acid, some of the added iodine will interact with it to form alkali iodate.

The proteins which are preferably used in this process include serum protein, vegetable protein, albumins of various origins, casein, or other proteins in the form of their sodium salts. The iodizing reaction is carried on at 25 to 45 C. with agitation to facilitate the reactions at definite dilution, depending on the solubility of the sodium proteinates used. As an example of a specific preparation there may be cited the treatment of sodium caseinate, or another sodium proteinate, to form the corresponding beta-iodo protein. The sodium proteinate is dissolved in water to form a solution or emulsion containing from 5% to 30% thereof. This is warmed to 35 to 45 C. and mixed with lactic acid or another acid in which 20% to 30% by weight of iodine is dissolved. Under these circumstances neutralization is effected and the protein is precipitated. After and during precipitation and coagulation the protein is gradually iodized by the iodine present. It is theniiltered, washed and dried, preferably in vacuo, at a temperature desirably not exceeding 60 C. The temperature is so limited so as not to completely dehydrate the iodo protein, which might thus be rendered undigestable in the body. It may be here noted that the yield in the case of sodium caseinate is about 90%. Proteins of the conjugated type are generally broken down into simpler protein constituents in the process. In conjugated proteins such as casein the amino groups are protected by a type of peptide structure already existing therein. In the case of some proteins, for example, albumins, it may be necessary to preliminarily peptize the protein in order to protect the amino groups against substitution of iodine for their hydrogen atoms. 7

If proteins iodinated by this method are treated with hydrogen peroxide in an acidic medium, they readily liberate iodine; and in contact with tyrosine they form di-iodo tyrosine. These reactions prove that the iodine in these proteins is readily transferable, in a fashion similar to the exchange of iodine in iodo-propionic acid and in the body. Hence it is very probable that the iodine in the proteins is also attached in a beta position, though because of the complexity of the protein it is rather diflicult to be certain that this is the case. We have discovered that the transfer of iodine to tyrosine to form di-iodo-tyrosine in the presence of hydrogen peroxide in an acid medium at low temperatures of the order of 35 C. may be used as a test of the emcacy of the iodo proteins for their intended therapeutic use. Consequently, where we herein refer to beta-iodo proteins (which our compounds appear to be), we wish to be understood as meaning such iodo proteins as will transfer their io he to tyrosine when treated with hydrogen per de in an acid medium or in the presence of acidic ions at 35 C.

In addition to the iodine which is chemically bound, our iodo proteins contain free adsorbed iodine which may be extracted by alcohol or other solvents for iodine, though it is not extracted by dilute hydrochloric acid or by the gastric juice. This adsorbed iodine appears to be of importance, since our experiments indicate that it acts catalytically in conjunction with the iodine apparently bound in the beta position.

Of the compounds heretofore investigated, beta-iodo-casein has been found most satisfactory, although it appears that substantially any protein may be used in the iodinated form of the type described.

As contrasted with our iodo proteins, the iodized proteins heretofore produced will not iodinate tyrosine under the action of hydrogen peroxide at 35 0. Our iodo proteins are also differentiated from those heretofore produced by the extractibility of a much lower percentage of the total iodine content by alcohol or water, the former removing adsorbed iodine which has been the primary type of iodine present in previous compounds, and the latter removing salts of iodine.

While the complicated structures of protein type are preferably used to form the basis for the therapeutic beta-iodo compounds, it is possible to utilize simpler compounds, though their use is not so desirable. For example, alpha-amino-propionic acid may be treated with iodine in a fashion similar to that indicated above to form betaiodo-alpha-amino-propionic acid, which may be used in a fashion similar to the beta-iodo proteins. which, it may be noted, are in general beta-iodoalpha-amino acids combined in the protein molecule. In the case of iodization of saturated a1- pha-amino acids hydriodic acid is formed, which should be taken care of by the provision of the proper amount of alkali.

In general it may be said that the improved medicinal compositions comprise the class of beta-iodo compounds in which there is attached to the alpha carbon atom a carboxyl, hydroxyl, amino, or sulphonic acid group. These compounds may contain various substituents, primarily amino groups in the alpha position, as well as aliphatic or aromatic groups. The compounds containing alpha amino groups are exemplified by the beta-iodo proteins and by the beta-iodo-alpha-amino-propionic acid mentioned above.

The useful compounds may be structurally indicated as comprising the grouping R2CI.CR2'.R" in which R" is a COOH, OH or SOeH group, both or either R may be almost any group of non-toxic character, and both or either R may be almost any group of non-toxic character provided it does not inhibit liberation of the I by physiological oxidat ion, as is the case if either R is 9. 0001-! or SOsI-I group.

More specifically, the more desirable compounds are carboxylic acids (or their derivative) which may be structurally indicated by RACI.CR2'.COOH

in which R and B may be as indicated above.

The most desirable compounds contain the structure RBCI-CR/(NH2) .0001! in which R and R may be as indicated above. The proteins, peptides and peptones are complicated examples of this group of compounds. Allrvl substituents may replace the hydrogen of the amino group or groups.

It will be understood that where references are made to these compounds in the appended claims, their salts, homologues and derivatives are included. It will also be understood that by reference to iodo proteins it is intended to include iodo peptides and iodo peptones which are closely :flated thereto and may be regarded as derivaves. The iodinated iodinated) prepared in accordance with the above processes have been extensively applied in clinical compounds (apparently betaresearch, particularly in the conditions in which iodides are customarily given, for example, arthritis, rheumatism, syphilis, hypertension, thy- -roid disfunction and obesity. The new compounds have invariably been found to have a low toxicity and a much greater effectiveness in the above named conditions than the hitherto used iodo proteinate compounds. The improved compounds may be administered orally. In the case of the proteins they may be administered as such or in the form of salts. Even insoluble conjugated proteins are dissolved in the digestive tract into simpler fractions available for therapeutic action.

What we claim and desire to protect by Letters Patent is:

1. A composition for the treatment of pathological conditions comprising an iodo carboxylic acid capable of transferring its iodine to an arcmatic compound in the presence of hydrogen peroxide at 35 C.

2. A composition for the treatment of pathological conditions comprising an iodo-alphaamino carboxylic acid capable of transferring its iodine to an aromatic compound in the presence of hydrogen peroxide at 35 C.

3. A composition for the treatment of pathological conditions comprising an iodo-protein capable of transferring its iodine to an aromatic compound in the presence of hydrogen peroxide at C.

4. A composition for the treatment of pathological conditions comprising an iodo conjugated protein capable of transferring its iodine to an aromatic compound in the presence of hydrogen peroxide at 35 C.

5. A composition for the treatment of pathological conditions comprising an iodo casein capable of transferring its iodine to an aromatic compound in the presence of hydrogen peroxide at 35 C.

6. The method of forming an iodo protein comprising reacting iodine in solution in an organic acid with an alkali proteinate.

'7. The method of forming an iodo protein comprising reacting iodine in acid solution with an alkali proteinate.

8. The method of forming an iodo protein comprising reacting iodine in acid solution with an alkali caseinate.

9. The method of forming an iodo protein comprising reacting iodine in an acid and an iodine solvent with an alkali proteinate.