Patented May 16, 1956 UNITED STATES PATENT OFFICE ARSENIC SULFATHIALZOLE CHEL COMPLEX IbertMellan, Chicago, IlL, assignor to Chicago Pharmacal Company, Chicago, .1114, as vcorporate.
tion of Illinois No Drawing. Application Janua 5,; 5.." Serial No. 57259. I
.0 m It The invention relatesato improvements in msdicinal compounds and methods of preparingihe same and has for itsjpitimary object the production oinew and novel, medicinal compounds or coinplexswhicli are highly efficient in use.
Another, object of the invention, is; to provide new, i and novel. compounds or complexes of the salts of inorganic kmentssuchassilyer, copper, arsenic, bismuth, mercury, gold" or antimony,
combined with one or.) more of the sulfa drugs,v
. new andnovel methodsof v procedure for; producing such compounds or complexes.
Other objects will appear" hereinafter.
The invention consists'of the compounds or complexes and the methods of; procedure ihereinafter described andrclaimed.
Example I In preparing, the .silver-su1fathiazolecomplex,
a,.1,0 normal solution"ofrsulfathiaaole; is obtained by, adding 255.31 gramsoi sulfathiazolei and43 grams of sodium; hydroxide to 80 0; cc. of water. When all the sulfathiazole has dissolved, the
solution is diluted tolOOO co. and filtered. The. v 1 nature ofzsolution, its concentration and the -.hy-
drogen ion concentration heforev and aiter; the reaction play;an, important ,rolein the character ofithelresulting complex formed. Therefore; the type of complex desired will determine'the conditionof manufacture. A solutionofsilver nitrate is obtainednby dissolving, 1 619.9; ramsaof silver:nitratesinenouglr distilledwwater to-make 1000.'cc.' 500 vcc. of thesuliathiazole so11 1 tion-,is then di1utedto:500;0 ,cc.,/ and ;to.this is added, with constant stirring, ,500 cc;.of;the:silvernitrate isolution afterithelatter has been diluted to 590,0cc.
Immediately, at colloidal precipitate .;is, formed which darkens color on standing, butsuch darkening in color may; bBnOVBICOIIlQ by; adding Z a little .ammonialwater; The originalr-suliathiazole solution has a -pI-I' of' 1-1.4; .the silver nitrate solution a pH- of 6.7 and; the resultingzmixtune has a-pH'of '65: The-chemical iormulaiionchelate ring of the complex thus-xproduced-may be expressed as follows:
a le oi; the-ssul a hi zq i q utiomm used so that; the resulting reaction mixture is ico loi all; milk complexsis ipneventedaand cipitatea is ffOLIIlQd-u wh ch ma ramme washed,vconcentratedgandmsedyas a pastewor as .a 1d ysnow erifor-v:ma treatm nt:-o mingw rm mfections, such as athletes foot, with good results.
Example 2 In preparing the silver sulfanilamide complex, a solution of sulfanilamide is obtained by adding 172.14 grams oi,sulfanilamide andJAO grams of sodium hydroxide to 800 cc. of distilled water. Ordinarily, a clear solution will result, but a small, additional amountofsodium hydroxide may have to be added to dissolve the sulfanilamide completely. The resulting solution is diluted to 1000 cc. and filtered. 10 litersioi ithe aqueous solution containing 2500 cc. 0f, 1'.0. Nsulfanilamide sodium is added, with constantstirring, .to 10j1iter oj an aque us ol on ma as-250 mmoil-answe trate A i e o lo al-, r mit e ilire u in mi iatur -h la PIT Q 1 nd ma beremovedswashed nd onc tr t dnss s d ei The trated as before. 1 complex is to mix 10 liters of an aqueous solution containing 5000 cc. of 1.0 N sulfadiazine sodium with 10 liters of an aqueous solution, containing} 3 chemical formula or chelate ring of the complex thus produced may be expressed as follows:
no H Ag O= NH Example 3 In preparing the silver-sulfapyridine complex, a solution of sulfapyridine is obtained by adding 289.18 grams of sulfapyridine sodium,
to enough water to make 1000 cc. and then filtering the same. 10 liters of an aqueous solution containing 2500 cc. of 1.0 silver nitrate solution added, with constant stirring, to 10 liters of an aqueous solution containing 2500 cc. of 1.0 N sulfapyridine sodium produces a gelatinous precipitate which transforms the reaction mixture into pasty nearly solid mass, the mixture having -a pH of 8.9, and may be removed, washed and concentrated as before. The chemical formula .or chelate ring of the complex thus produced may be expressed as follows:
Example 4 2500 cc. of 1.0 N silver nitrate. This mixture has "a pH of 7.7. The chemical formula or chelate ring complex thus produced may be expressed as follows Example 5 complex are formed. The chemical formula or chelate ring of the complex thus produced may be expressed as follows:
0 Ag NH: 0=l N 6H Solutions containing the corresponding compounds of the metals mentioned, may be prepared as follows:
Example 6 Copper sulfate solution.A 1.0 molar copper sulfate solution is prepared by adding 249.71 grams of CuSO4.5I-I2O to enough water to make 1000 cc. Then filtered.
Example 7 Mercurz'c chloride solution.--A 0.5 normal mercuric chloride solution is prepared by dissolving 135.8 grams of mercuric chloride in enough water to make 2000 cc. When all of the salt dissolves filter.
Example 8 Bismuth chloride solution.A 0.5 molar solution is prepared by dissolving 259.5 grams of basic bismuth carbonate ((BiO)2COa. H2O) in 425 cc. of concentrated hydrochloric acid and diluting to 1000 cc. with water.
Example 9 Arsenic trichloride solution.A 1.0 N arsenic trlchloride solution is prepared by dissolving with the aid of heat, 66 grams of arsenic trioxide U. S. P. X1 in 400 cc. of concentrated hydrochloric acid and suilicient water to make 1000 cc.
Example 10 Gold tribromide solution.-A 1.0 N gold tribromide solution is prepared by dissolving 145.65 grams of gold tribromide in suflicient water to make 1000 cc. The addition of hydrochloric acid may be needed to aid in getting the salt in solution.
Example 11 Antimony solution.A 1.0 N solution is prepared by dissolving 111.3 grams of antimony and potassium tartrate in sufiicient water to yield a volume of 1000 cc.
From these, by replacing the silver atom in the foregoing formulae with the elements, Cu/z, Bi/a, Hg/z, As/s, Au/a. Sb/s, the various other complexes may be formed as follows:
Example 12 Copper sulfanilamide complea:.This complex is made by mixing 1500 cc. of an aqueous solution containing 500 cc. of a 1.0 N sulfanilamide sodium with 1500 cc. of an aqueous solution containing 250 cc. 1.0 molar copper sulfate. A thick gelatinous green precipitate is formed which turns blue-green in color. The color varies with the method of making and the pH of the resulting mixture. In this bath the resulting mixture has a pH of 9.7. The quantities of each solution can be so varied as to use up all of the sulfanilamide and the copper sulfate or to have an excess of either the sulfanilamide or the copper sulfate. A light green colored complex of copper sulfanilamide is made by mixing 1500 cc. of an aqueous solution containing 500 cc. 1.0 N-'sulfanilamide' with=l500 cc. of an aqueous solution containing-- The resulting 500 cc. 1.0 molar copper sulfate. mixture has a pH of 4.7.
Ea'ample13 Copper salfapym'dine complex.500 cc. of. 1.0
sulfapyridine sodium diluted to 1000.00. isadded 110-1000 cc. of an aqueous solution containing250.
cc. of 1.0. molar copper sulfate. Alightv green precipitate is. formed which turns olive-greenand,
finally purple incolor. The mixture. has a pH 01-7.4;
Example 14 Copper sulfadiazine compleax-One. liter of solution containing 500Tcc. .1.0 N sulfadiazine is mixed with one liter of solution containing 250 cce 1.0: m01ar' copper sulfate. A light green precipitateis formed which changes'toa dark green andfinally to a purple colored precipitate. The resulting-mixture before filtrate and purification hasa pH 8.4.
Example 15 Copper sulfathiaeole comple:c.-One liter of solution containing. 500 cc. of 1.0 N. sulfathiazole sodium isadded to 1000 cc. of a solution containing-250 cc. 1.0 molar copper sulfate. A thick gelatinous precipitate is formed which goes thru a change of fieetingcolors and finally turns purple.
Whenthe reactionis completethe pH is 5.6.
Copper sulfaguanidine compZer.-192' grams of sulfaguanidine are dissolved. in 1000 cc. of hot water. and to this is added 500 cc. of 1.0 molar copper..sulfate.. Thesolution turns green in color and-.aprecipitate beginsto form, so 200 cc. of concentrated hydrochloric acid is added. Upon standing'crystals of coppersulfaguanidine begin toLform.
Example 17 Mercurysulfathiazole comple:c.-Two liters of;
solution containing 500 cc. of 1.0 Nsulfathiazolez sodium-are mixed. with two liters of. solution .containing 1000..cc; of- 0.5 mercuric chloride. white thick precipitate isformed and the mixture has a pH of 6.5.
Example 18 'M'erc'ury :sulfadz'azine comple:r.-One liter" of. ani'aqueousv solution containing 500 cc. of 1.0 N
sulfadiazine: sodium is mixed with 2000.00. of an aqueous solution containing 1000 .cc; of 0.5 N mercuric chloride. A White precipitateiis formed andjthemixture has a pH of 9.4. Another. way of making this complex is. tomix 100000. of 0.5 N sulfadiazine sodium with 2000 cc. of 0.5 N mercuric .1chloride. formed. The resulting mixture has a pH of 7.8.
Example 19 Mercury sulfapyricline complem.500 cc. of 1.0
A thick White precipitate is N :sulfapyridine sodium diluted to a liter is added.
to 2000 cc. of 0.5. N'mercuric chloride solution.
A thick white gelatinous precipitate iszformed. Th'emixture has a pH 6.4:.
Erample 20 Mercury sulfam'lamicle complex-500 cc. of
1.0:N'sulfanilamide sodium diluted-to a liter is added, with constant stirring, to 2000. cc. of 0.5;
N mercuricv chloride. A white precipitate is formed and after the reaction is complete the mixture has a pH "of 6.7.
Ea'c ample 21 Bismuth sulfathiazole cOmpZexF To 500 cc: of
Upon cooling the solution crystals of the complex begin to form.
Example 22 Bismuth"salfaguanidine complex.-500- "cc? of 0:5 'molarbismuth chloride -are used to dissolve" grams ofsuIfag-uanidine. At times it is *n'e essary to use --heat-andtheaddition'of a 'little' concentrated hydrochloric acid (60 cc.). cooling the complex is formed.
Bismuth sulfaguam'cl'ine completc;'-To cc'xof- 0.5 molar bismuth chloride isadded 192* grams of sulfaguanidine- The 'mixture is heated and 200 cc. of hydrochloric acid added. The addition of'acid and the application of heatre'sults.
in'a clearsolution; Upon"coolingithe"solution" crystals of bismuth sulfaguanidine complex'are formed."
EZ'cample"24"' Bismuth sulfadz'azz'ne complem.This complex is. formed: by; adding .500 cc.- of. 0.5 molar bismuth chloride; solution to. .17 50; cc; of 11.0. N t sulfadiazine sodium. A...thick.-precipitateis formed which -is dissolved. by .the. addition of 200-cc. concentrated a hydrochloric .acid andi heat. Upon .standing and cooling yellow crystals are formed. Theseare removed and are purifiedabyleither working or recrystallization. Another method of preparing this complex isto dissolve "grams ofsulfadiazine in 500cc. of 015 molarbismuthchloride;' T6 1 aid solution it may be necessary to apply heat" and to add'mo're hydrochloric acid (60 c'c'.) Up: on. standing or by cooling. yellow crystals of bismuth 'sulfadia'zine are formed.
Bismuth sulfapyrzdz'ne: complex-To 500 cc. of 0.5 molarbismuth chloride is added 750 cc. of 1.0 N' sulfa'pyridlne sodium solution. A'precipitate is formed which' is dissolved by heatlrig' andiaddin'g 100cc. of hydrochloric acid. Upon 7 standing or cooling translucent crystals are formed which could -be-purified by recrystallization, Anotherv way. .to prepare thiscomplex is to dissolve. 186.9 grams of sulfapyridine in 50000. of e 0.5 molar bismuth chloride solution. At times it'- may be necessary to apply-heat to aid inthe solution or it may require the addition of hydro chloric acid. Upon standing a crystalline complex is formed.
Emample26 Bismuth sulfamlamide comp'letc;"To 500 cc." of 0.5m'ol'ar bismuth 'Chlbri'dEISOlutiOil "is added 129 grams of sulfanilainide; Toaid solution heat is applied and 30 cc. ofr hyd rochloric acid is added. Upon dilution with water, the bismuth sulfanil'amide complex separatesou't and is re- 75 moved and" washe'dby "filtration? Example 27 Arsenic sulfathiazole complex.To make this complex add 255 grams of sulfathiazole to 1000 cc. of 1.0 N arsenic chloride solution and stir. In a few minutes the whole mass solidifies. The solid complex is then broken up and washed. Another method of making this complex is to add 2000 cc. of boiling water to a liter of 1.0 N arsenic chloride and then dissolve in this solution 255 grams of sulfathiazole. Upon standing an arsenic sulfathiazole complex crystallizes out of solution. In place of the two liters of boiling water we can use one liter of water containing 50 cc. of concentrated hydrochloric acid.
Example 28 Arsenic sulfaguanidine complex.This complex is formed by adding 232 grams of sulfaguanidine to 1000 cc. of 1.0 N arsenic chloride solution. The mixture is heated to aid in the solution of sulfaguanidine. Upon standing the complex crystallizes out of solution.
Example 29 Arsenic sulfadiazine complex.250 grams of sulfadiazine is dissolved in 1000 cc. of 1.0 N arsenic chloride solution with the aid of heat. Upon standing or cooling the complex is formed.
Example 30 Arsenic sulfapyridine complex.2492 grams of sulfapyridine are dissolved in 1000 cc. of 1.0 N arsenic chloride solution with or without the aid of heat. Upon standing and cooling the complex crystallizes out of solution.
Example 31 Arsenic sulfanilamide complex.To form this complex dissolve 172 grams of sulfanilamide in 1000 cc. of arsenic chloride solution with or without the aid of heat. Upon cooling the complex of arsenic sulianilamide will crystallize out of solution.
Example 32 Gold sulfathiazole complex.This complex is formed by adding 102 grams of sulfathiazole to 400 cc. of 1.0 N gold chloride. When all of the sulfathiazole dissolves, a red precipitate begins to form. The formation of this red complex is hastened when the solution is heated. The complex can be purified by dissolving it in a dilute solution of hydrochloric acid and recrystallizing.
Example 33 Gold sulfaguanidine complex.92 grams of sulfaguanidine are dissolved in 400 cc. of 1.0 N gold chloride solution and 100 cc. of water. A light brown colored complex is formed upon standing.
Example 34 Gold sulfanilamide complex-69 grams of sulfanilamide are dissolved in 400 cc. of 1.0 N gold chloride and 100 cc. of water. In one hour or so a brown to red colored complex of gold sulfanilamide is formed.
Example 35 Gold suljadiazine complex.lco grams of sulfadiazine are dissolved in 400 cc. of 1.0 N gold chloride and 100 cc. of water. Upon standing a red colored complex is formed.
Example 36 Gold sulfapyridine complex.lOO grams of suliapyridine are dissolved in 400 cc. of 1.0 N gold 8. chloride and 300 cc. of 10% hydrochloric acid. Upon standing or cooling a red colored complex is formed.
Example 37 Antimony sulfathiazole complex.This complex is formed by mixing 500 cc. of antimony and potassium tartrate with 500 cc. of 1.0 N sulfathiazole sodium. In the course of a minute the complex is formed. Another method of making this white antimony sulfathiazole complex is to add 250 grams of sulfathiazole to cc. of 1.0 N antimony and potassium tartrate. To aid in the solution of the sulfathiazole 250 cc. of concentrated hydrochloric acid is added. Upon standing the complex is formed.
Example 38 Antimony sulfaguanidine complex-232 grams of sulfaguanidine are added to 10 cc. of 1.0 N antimony and potassium tartrate. From 100 to 300 cc. of concentrated hydrochloric acid are added to completely dissolve the sulfaguam'dine. Upon standing the complex separates out of the solution.
Example 39 Antimony sulfadz'azine complex.This complex is formed by adding 500 cc. of 1.0 N antimony and potassium tartrate to 500 cc. of 1.0 N sulfadiazine. Another method is to dissolve 250 grams of sulfadiazine in 1000 cc. of antimony and potassium tartrate containing 450 cc. of concentrated hydrochloric acid. Upon standing over night the complex precipitates out.
Example 40 Antimony suljapyridine complex.This complex is formed by adding 500 cc. of 1.0 N antimony and potassium tartrate to 500 cc. of 1.0 N sulfapyridine sodium. More rapid and complete precipitation is brought about by cooling the solution once the reaction has taken place. Another method is to dissolve 249 grams of sulfapyridine in 1000 cc. of 1.0 N antimony and potassium tartrate containing 300 cc. of concentrated hydrochloric acid. Upon standing over night or cooling the crystalline complex is formed.
Example 41 Antimony sulfanilamide complex.This complex is formed upon mixing 500 cc. of 1.0 N antimony and potassium tartrate with 500 cc. of 1.0 N sulfanilamide sodium. Another way of making this complex is to dissolve 172 grams of sulfanilamide in 1000 cc. of 1.0 N antimony and potassium tartrate containing 300 cc. of concentrated hydrochloric acid. From the clear solution a precipitate is formed upon standing.
While I have set forth in detail the preferred compounds and methods of procedure, these are capable of variation and modification without departing from the spirit of the invention. I therefore do not wish to be limited to the precise details disclosed, but desire to avail myself of such variations and modifications as fall within the scope of the appended claim.
As a new chemical compound of therapeutic value an arsenic sulfathiazole complex in which the arsenic has at least one bond with the N1 atom of a sulfathiazole structure, and at least one chelate bond with one of the strongly polar atoms of the thiazole ring.
(References on following page) 9 10 REFERENCES CITED OTHER REFERENCES The following references are of record in the Scudi: Jour. Ind. &Eng. Chem. (Analytical EdJ. file O t Patent: vol. 10, No. 6 (June 15, 1938).
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1939), pp. 2950-2955. Number N Dame Jour. Am. Chem. Soc. (Dec. 1939), page 3593.
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