US2566038A

US2566038A - Water-soluble sulfonamides

Info

Publication number: US2566038A
Application number: US82021A
Authority: US
Inventors: Jr George Madison Sieger
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1949-03-17
Filing date: 1949-03-17
Publication date: 1951-08-28
Anticipated expiration: 1968-08-28

Description

Patented Aug. 28, 1951 WATER-SOLUBLE SULFONAMIDES George Madison Sieger, Jr., Pearl River, N. Y., assignor to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application March 17, 1949,

:Serial No. 82,021 i This invention relates to certain new soluble derivatives of certain heterocyclic derivatives of sulfanilamide; more particularly to therapeutic agents containing as a nucleus the ring system of 2-sulfanilamido pyrimidine which are solubilized by having as a substituent on one of the nitrogen atoms thereof, other than the N nitrogen, a 2,3-dihydroxypropyl side chain; and certain methods of their preparation.

The new products of this invention are therapeutically useful in combating infection and have been found to be substantially as effective on a molar basis as the corresponding sulfa drugs without the side chain. Because of the particular substituent placed on this nucleus, by my invention, it has been found that these sulfa drugs which in the past have been comparatively insoluble are solubilized and are much more convenient for therapeutic use as a result of the substituent of this invention. It is to be noted that the pyrimidine ring of the nucleus may be substituted in any of the carbon positions without interfering with the solubilization. Further, the solubilizing effect does not have a deleterious effect upon the therapeutic activity of these drugs and those drugs which are therapeutically effective in the unsubstituted form are equally effective in the substituted form, in addition to being more soluble. More specifically among the most effective of these drugs-are the 2,3-dihydroxypropyl derivatives of sulfadiazine, sulfamerazine and sulfamethazine which are respectively 2-sulfanilamido-pyrimidine, 2-s'u-lfanilamido-4-methyl-pyrimidine, and 2-sulfanilamido-4,G-dimethylpyrimidine.

Because of the peculiar nature of the products formed and the labile characteristics of the products, it is not possible with certainty to say whether or not the 2,3-dihydroxypropyl side chain is attached to the nitrogen of the sulfonamide portion of the molecules or to one of the ring nitrogens in the pyrimidine nucleus.

The side chain is most conveniently attached by the reaction of an alkali metal derivative of the sulfa drug and a glycerol-alpha-mono-halohydrin. From the reaction it might be expected that by the elimination of salt, the2,3-dihydroxy-' propyl radical would be attached to the nitrogen from which the sodium was removed. By certain experimental evidence, note for example that on page 70 of the ACS monograph by E. H. Northey, it might appear that the side chain ties on to one of the ring nitrogens of the pyrimidine and in effect forms a compound which might be well named as an amido LZ-dihydro-pyrimidine. The

9 Claims. (Cl. 260239.75)

exact point of attachment or the chemistry involved does not form an essential portion of this invention because the methods of forming the compounds are simple as hereinafter shown, the products possess a structure which therapeutically is equivalent tothe compound without the side chain and possess very desirable solubility I characteristics.

In the past the sodium derivatives of these therapeutic agents, such as sodium sulfadiazine, sodium sulfamerazine and sodium sulfamethazine have been largely used. The solutions of these sulfanilamide sodium salts are strongly alkaline and have pH rangesfrom 9 to 11. When the solutions of the sodium salt are injected intravenously in the concentrations which are clinically desirable, the administration must be carried out extremely carefully because the highly alkaline solution is definitely'ir'ritating to the tissues and necrosis of the tissues may result if there is leakage outside of the vein. Similarly these particular sodium salts cannot be used subcutaneously, intramuscularly or by the intraspinal route. In contrast to this, the 2,3-dihydr'oxypropyl derivatives prepared in accordance with my invention are comparatively-soluble over a wide range of pH, and may be used in the con centrations considered therapeutically desirable at a pH which is non-"irritating, and is within the range considered therapeutically desirable. This permits the injectionof the clinically desir able dosages of these sulfa drugs without any of the deleterious side effects which in the past have been associated with their more alkalinesalts. The peculiar relationship whereby these 2,3-di 'hydroxypropylderivatives are therapeutically equivalent to the corresponding sodium sulfa drug and yet are in solubility in aclass by themselves represents a marked and surprising advance whereby the therapy of the sulfa drugs may achieve new heights in the alleviation of disease. A less highly dihydroxylated product does not have the solubility advantages of the product produced in accordance with this invention.

The Bratton-Marshalltest shows that the active N amino group is intact and bacteriological tests show the activity of the substituted sulfa drug to be approximately that which would be expected on 'a molar basis. Therefore, the solubility of these substituted sulfadiazines over a wide range of pH permits the ready introduction of the slightly soluble parent compound into the body at an optimum pH. The; advantages of my invention appear to extend with equal merit to an unsubstituted sulfadiazineor to a sulfadiazine sunin which there are substituents on the pyrimidine ring. Therapeutically among the more useful of these derivatives are sulfamerazine in which there is a d-methyl group and sulfamethazine in which there are 4,6-methyl groups on the pyrimidine ring. In the formation of my new watersoluble com-pounds either the alkali metal salt may be used or the alkali metal salt may be formed in solution by treatment of the unsubstituted compound with sodium hydroxide. To the solution may then be added the glycerol-alphamono-halo-hydrin. Because of the elimination of the thus produced salt, it is immaterial from the standpoint of the finishedproduct which alkali metal is used or which of the halogens. From the standpoint of cost considerations, normally sodium is used as the alkali metal, and chlorine is used as the halogen. The invention may be illustrated by, but is not restricted to the following examples in which certain aspects of my invention are set forth.

Example 1 300 grams of sodium sulfamethazine were suspended in 2500 cc. of anhydrous alcohol. The mixture was heated with vigorous agitation for about 30 minutes in a large round bottom flask on a steam bath under an efficient reflux condenser so as much as possible of the sodium sulfamethazine was dissolved. There was then added 110.5 grams of glycerol-alpha-mono-chloro-hydrin dissolved in 500 cc. of anhydrous alcohol. After stirring and refluxing for about to minutes, almost a complete solution was obtained. The refluxing was continued for five hours during the course of which an insoluble inorganic salt was precipitated together with certain minor impurities. At the end of the reflux period, the inpropyl derivative of sulfamethazine in which a 2,3-dihydroxypropyl chain. was either tied on to the N1 portion or to one of the pyrimidine nitro-. gens, in which by migration of the hydrogen, there was produced a 1(2,3-dihydroxypropyl) -2-= sulfanilamido-1,2-dihydro-pyrimidine. It is to be clearly understood that the structure is speculative and is not necessarily to be considered as soluble material was filtered ofi and the volume of the clear filtrate reduced by distillation under reduced pressure. The concentrated alcohol solution was then diluted into an excess of ether with stirring whereby the desired product was precipitated out as a pink colored precipitate which was filtered off, washed with dry ether and allowed to dry. The material as thus produced is hygroscopic and accordingly must be protected from moisture to prevent caking. It is found to be freely soluble in neutral, alkaline and acid aqueous solutions. The material was treated with decolorized carbon in anhydrous alcohol, reprecipitated with ether and recrystallized from isopropyl alcohol, giving a melting point of around 136 to 140 C. as contrasted with sulfamethazine itself which melts at 198 to 200 C. and the sodium salt which does not melt but which decomposes somewhat above 300 C.

Example 2 43 grams of sodium hydroxide were dissolved in 2500 cc. of anhydrous alcohol and thereto were added 278 grams of sulfamethazine with vigorous stirring. After refluxing at the boiling point for approximately 30 minutes, there was added thereto 110.5 grams of glycerol-alphamonc-chloro-hydrin dissolved in 500 cc. of anhydrous alcohol. The mixture was refluxed for five hours, the precipitate filtered off and the clear liquid treated in accordance with the preceding example. A compound which appeared to be identical with that described in Example 1 was obtained. The recrystallized product was found to have49.7% carbon, 5.7% hydrogen, 16.4% nitrogen and 6.9% ash. These results appear to indicate that there was formed a 2,3-dihydroxythe only possible structure for the product.

Example 3 To 1 mole of potassium sulfamerazine suspended in 2500 cc. of anhydrous alcohol there may be added one mole of glycerol-alpha-monopromo-hydrin dissolved in 500 cc. of anhydrous alcohol. Upon refluxing with stirring, filtering ofi of any residual solids and concentrations of the product in accordance with the procedure of Example 1, there is obtained thereby a corresponding 2,3-dihydroxypropyl derivative of sulfamerazine which is found to be comparatively soluble in water over a large range of pH and which exhibits therapeutically, on a molar basis, the desired therapeutic characteristics of sulfamerazine itself.

Example 4 To 5 moles of sodium sulfadiazine suspended in 15 liters of anhydrous alcohol, there may be added 5 moles of glycerol-alpha-mono-chlorohydrin dissolved in 2 liters of anhydrous alcohol. Upon refluxing for 10 hours followed by filtration, vacuum concentration, and recrystallization as set forth in Example 1, there may be obtained thereby a 2,3-dihydroxypropyl derivative sulfadiazine which product is freely water soluble over an extended pH range, which possesses the therapeutic characteristics of sulfadiazine and which is much more satisfactory for therapeutic use because of its remarkable solubility.

Having thus described certain embodiments thereof as my invention 1 claim:

1. As a new compound, the 2,3-dihydroxypropyl derivative of a compound of the group consisting of sulfadiazine, sulfamerazine and sulfamethazine, in which the 2,3-dihydroxypropyl group is attached to a nitrogen atom adjacent to the carbon atom in the 2-position in the pyrimidine ring.

2. As a new compound, the 2,3-dihydroxypropyl derivative of sulfadiazine in which the 2,3-dihydroxypropyl group is attached to a nitrogen atom adjacent to the carbon atom in the 2-position in the pyrimidine ring.

3. As a new compound, the 2,3-dihydroxypropyl derivative of a sulfamerazine in which the 2,3-dihydroxypropyl group is attached to a nitrogen atom adjacent to the carbon atom in the 2-position in the pyrimidine ring.

4. As a new compound, the 2,3-dihydroxypropyl derivative of sulfamethazine in which the 2,3-dihydroxypropyl group is attached to a nitrogen atom adjacent to the carbon atom in the 2-position in the pyrimidine ring.

5. The method of preparing a 2,3-dihydroxypropyl derivative of a compound of the group consisting of sulfadiazine, sulfamerazine and sulfamethazine in which the 2,3-dihydroxypropyl chain is attached to a nitrogen atom adjacent to the carbon atom in the 2-position in the pyrimidine ring which comprises reacting by heating in an inert solvent the alkali metal salt of said com pound with glyceryl-alpha-mono-halo-hydrin.

6. The method of preparing a 2,3-dihydroxypropyl derivative of a compound of the group consisting of sulfadiazine, sulfamerazine and sulfamethazine in which the 2,3-dihydroxypropyl chain is attached to a nitrogen atom adjacent to the carbon atom in the 2-position in the pyrimidine ring which comprises reacting by heating in an inert solvent the sodium salt of the said. compound with glyceryl-alphamono-ch1oro-hydrin.

7. A method of preparing the 2,3-dihydroxypropyl derivative of sulfamethazine in which the 2,3-dihydroxypropyl chainis attached to a nitrogen atom adjacent to the carbon atom in the 2- position in the pyrimidine ring, which comprises refluxing sodium sulfamethazine and glycerylalpha-mono-chloro-hydrin in an inert solvent and recovering the said 2,3-dihydroxypropy1 derivative of sulfamethazine.

8. A method of preparing the 2,3-dihydroxypropyl derivative of sulfamerazine in which the 2,3-dihydroxypropy1 chain is attached to a nitrogen atom adjacent to the carbon atom in the 2- position in the pyrimidine ring, which comprises refluxing sodium sulfamerazine and glycerylalpha-mono-chloro-hydrin in an inert solvent and recovering the said 2,3-dihydroxypropy1 derivative of sulfamerazine.

9. A method of preparing the 2,3-dihydroxypropyl derivative of sulfadiazine in which the 2,3- dihydroxypropyl chain is attached to a nitrogen atom adjacent to the carbon atom in the 2-position in the pyrimidine ring, which comprises refluxing sodium sulfadiazine and glyceryl-alphamono-chloro-hydrin in an inert solvent and recovering the said 2,3-dihydroxypropyl derivative of sulfadiazine.

GEORGE MADISON SIEGER, JR.

REFERENCES CITED The following references are of record in the file oithis patent:

UNITED STATES PATENTS OTHER REFERENCES Adams et a1., Jour. Amer. Chem. Soc, vol. 61 (1939), pp. 2342-2346.

Van Dyke et at, J. Pharm.

and Expte. Therap., vol. 83 (1945), D1 203-212.

Claims

1. AS A NEW COMPOUND, THE 2,3-DIHYDROXYPROPLY DERIVATIVE OF A COMPOUND OF THE GROUP CONSISTING OF SULFADIAZINE, SULFAMERAZINE AND SULFAMETHAZINE, IN WHICH THE 2-3-DIHYDROXYPROPYL GROUP IS ATTACHED TO A NITROGEN ATOM ADJACENT TO THE CARBON ATOM IN THE 2-POSITION IN THE PYRIMIDINE RING.