Patented Nov. 5, 1946 2,410,796 UNITED :sTATEs PATENT OFFICE SOLUBLE AMIDINE SALTS ' George _Newbery, Brentwood, and Alexander Peter Tawse Easson, HornohurchEngland, as sig’nors to May & Baker Limited, Dagenham, Essex, England, a British company ' No Drawing. Original application April 11,1942, Serial No. 438,612. Divided and this ‘applica tion‘ ‘May 11, 1945, Serial No. 593,326. In Can 'La‘da' April 77, .1942 "5 Claims. (Cl. 260-501‘) 2 ' I This application is a division of application able salt 'of either of such acids (e. g. the-ammo Serial No. 438,612, ?led April 11, 1942. nium salt). Alternatively, the required . Jsalts This invention relates to new salts of certain maybe'iformed by‘ producing‘the diamidin'e base therapeutically-active amidine derivatives and it in situ and .m the :presencev-o‘flei-ther :one ‘of fthe has for its principal object the provision of a new CH said acids or a salt of such acid. Thus,ith‘e imino class of therapeutically active compounds that ether corresponding to ‘the diamidin'e' ‘base 1may can be administered in the form of an aqueous be reacted with the amm'oniumlsalt of hydroxy solution. A further object is to provideprocesses ethane or") hydroxy-propane sulphoriic acid. for the production of such compounds. Again, the required salts may be obtained by ~It vhas already been shown that valuable thera 10 double decomposition of suitable salt pairs e. g. peutic properties are possessed 'by‘the symmetrical using the dihydrochloride of‘the diamidine base aromatic diamidines ‘possessing the general and the silver salt of the acid. formula Am. R. X. R. Am,gin 'which‘Amrepresents Examples of diamidines of the foregoinggener-al an amidine group ‘ ‘ formula are: 4:4’-diamidino-diphenoxy pentane, 15 4:4’-diamidino-dip'henoxy propane and 4:4’ diamidino-diphenyle'ther, 4 :4 ’i-diamidino-'stilbene and 4 : 4’ i~diamidino-a,u'-dimethyl-stilbene. In the following description, there are given, a linkage which may be a single bond or an alkane purely byway of illustration, examples of the manufactureof compounds Within the scope-of not very readily soluble in water. "It is an ‘ob droxyethane sulphonate (di-iseth‘ionate) crystal R represents a benzene radical; and X represents the present “invention. ' chain ,—(C>H2)n (where .n represents 1 to 10_ andjin which also one'or more of the ‘CH2 groups ‘Example I‘ may be replaced by’oxygen, sulphur ‘or the group 4:4’-diamidino-stilbene ‘(7.2 g.) was added to NH) orX represents a —-.CR1=CR2—- grouping in 6.8 cc. of ‘8N ‘aqueous solution of ,B-hydroxy which R1 and Breach represent either a'hydrogen .25 ethane-sulphonic acid; the mixture warmed vto atom or a hydrocarbon group (e. ‘g; an alkyl, about‘ 40° C. and just sufficient water added'to aryl or aralkyl group). Generally, the salts of complete solution. .Acetone was 1then slowly these diamidines, such as the hydrochlorides, are added, when ‘4:4’-diamidino-1sti1b'ene di-pehy vious therapeutic advantage to have ‘available. .30 lised in the form of prisms :(solubilityin water ‘ap stable salts possessing a high degree of solubility prox. T1 in Sat 20°C.) ' ' ' ' in water and the present invention has, for its The corresponding di-ql-hydroxy-‘propane-isuh object the production of such salts. In many in phonate is similarly prepared (using the theoret stances, therapeutically useful basic compounds ical amount of v-hydroxy-propane-sulphonic have been found to furnish extremely soluble acid) and c-rystallises in prisms (solubility .in salts with methane-sulphonates; ‘but in the case of the various therapeutically useful amidine water approx; 1 in ,4 at 20°C.) I ’ Example "II 4 :4’ -diamidinodiphenoxyepentane-di-hydroxy ane-sulphon'ates .are very little more soluble than 40 ethane-sulphonate_prepared by the method of Ex ‘the hydro chlorides. _ > ' ‘ ample I, using the theoretical amounts of the We have discovered a new class of salts of the diamidine-and the acid, crystallised as prisms symmetrical aromatic diamidines having the fore on addition of acetone to the ‘aqueous solution. going general formula, which salts are stable and It contains 21/2‘ H20 and is soluble ‘in water, ap possess a high degreeof solubility in water, such 45 proX. 1 in ‘8 at 20°C. . > salts being the salts with member-s of the group ‘ Example II] consisting of hydro-xy-ethane sulphonic acid and hydroxy-propane sulphonic acid. 3.2 grms. of .4:4"-diamidinodiphenoxy propane compounds, such as 4:-4'-.diamidino-stilbene or 4:74’édiamidinoediphenoxypentane, the dimeth In general, these new salts can be prepared by were ‘dissolved ‘in a "slight excess of 4N isethionic combining ‘the diamidine base or a salt thereof 50 acid. The solution was just acid to litmus. 'It with hydroxy ethane 'sulphonic acid or hydroxy was'?ltered with charcoalythe solids washed with propane sulphonic acid ‘or with a salt (of either of a little’methanol and the amidine isethionate pre such acids. Speci?cally, the diamidine base can cipitated'from the ?ltrate and washings by adding be directly combined with hydroxy-ethane or acetone. The yield of the required 4:4'-diamidi hydroxy-propane sulph‘onicxacid or with a suit 55 nodip'henoxy propane di-isethionatewas 5.2grms. 2,410,796 3 4 Example I til precipitation was complete. The yield ob tained was 49 grms. of 95% of theory. 67.2 grms. of 4:4'-diamidinodiphenylether were dissolved in a slight excess of 8N isethionic acid We claim: ‘ c 1“.- 4:4'—diamidino-diphenylether-di -.-' beta - hy with su?icient water‘to give complete solution in 5 droxyethane-sulphonate. 2. Process for the production of a symmetrical the cold. The solution was just acid to litmus, and to it was added about quarter of its volume aromatic diamidine salt having the formula of alcohol. Acetone was then added slowly and with stirring, so that the amidine isethionate separated in crystalline form. Addition was con tinued until precipitation was almost complete. The mixture was allowed to stand for some time and the crystals ?ltered o?, washed with acetone and dried. The yield of the required 4:4'-di amidinodiphenylether (ii-isethionate was 130 grmS. - ' in which X is selected from the group consisting Example V of ,hydroxy-ethyl and hydroxy-propyl radicals, 9.0 grins. of 4:4'-diamidino-a,a'-dimethylstil- , _ which comprises reacting a compound of the for bene dihydrochloride were dissolved in a little warm water‘ and slight excess of caustic soda so 20 lutionadded. The diamidine base was precipi tated as an oil which solidi?ed on cooling in ice. The base was ?ltered off, washed with water: and then while damp dissolved in a slight excess of 8N isethionic acid. A little alcohol was added and 25 the vrequired 4:4'-diamidino-m,u'-dimethyl-stil bene di-isethionate precipitated‘ in the form of buff yellow micro crystals. Yield 9.8 grms. <I3=NH NHQ ('3=NH NH: _ with a member selected from the group consist Example VI 26 grms. of 4:4'-diamidino stilbene were added 30 ing of beta-hydroxyethane-sulphonic acid, gam ma-hydroxy-propane-sulphonic acid, and the am in small portions to a gently boiling mixture of 28 grms. (2 mole.) of ammonium isethionate and monium salt of a said acid. 3. A symmetrical compound of the formula 250‘ cos. of 50% alcohol. Ammonia was immedi ately evolved with the formation of the amidine 35 base which'dissolved completely in a few min utes. The reaction was completed by boiling off the ammonia, whereafter the solution was ?ltered with charcoal. The required 4:4'-diamiclinostil bene di-isethionate was precipitated by slowly 40 adding acetone. Yield. aboutv 90% . in which X is selected from the group consist ing of hydroXy-ethyl and hydroxy-propyl radi Example VII cals. ‘ A mixture of stilbene 4:4’-di-iminoethyl-ether (1.6 g.)‘ and ?nely powdered ammonium e-hy . . 4. Process for the production of 4:4'-diami 45 dino-diphenylether-di-beta-hydroxy-ethane- sul droxy-ethane-sulphonate was suspended in 5 cc. of absolute alcohol to which was added a few drops of concentrated alcoholic ammonia and the mixture brought to the boil. Most of the ammo nium salt dissolved and separation of the amidine 50 phonate, which comprises reacting 4:4'-diami dino-diphenylether with beta-hydroxy-ethane sulphonic acid. ' . 5. Process for the production of a symmetrical aromatic diamidine salt having the formula isethionate followed in a few minutes. _ The tem perature was maintained at 40° C. for approx. 20 hours with occasional shaking, acetone was then added and the precipitated solid ?ltered o? and dissolved in a little Water. The somewhat turbid solution was charcoaled, ?ltered and again treated with acetone. The required 4:4'-diami dino-stilbene-di-c- hydroxy - ethane - sulphonate crystallised out as in Example I. Example VIII ‘in which X is selected from the group consist ing of hydroxy-ethyl and hydroXy-propyl radi-' 60 cals, which comprises reacting a symmetrical compound of the formula ‘ 37.3 grins. of pure 4:4'-diamidinostilbene .dihy drochloride dihydrate (33.7 grms. of anhydrous salt) were dissolved in 400 cos. of a solution of 46.8 grms. of silver 100 cos. of water was added with mixture was heated on the steam ©—0_Q hot water and _> isethionate in stirring. The bath for some (I3=NH NH: time to coagulate the silver ‘chloride which pre cipitated. The precipitate was ?ltered olT (char: 7 .. NHz with a member selected from the group consist coal can be used if necessary to clarify), and the 70 ing of beta-hydroxy-ethane-sulphonic acid, gam ma-hydroxy-propane-sulphonic acid, and the am solids washed with water. The ?ltrate and wash monium salt of a said acid. ings. were concentrated by evaporation and the required diamidine di-isethionate precipitated in GEORGE NEWBERY. crystalline form by adding a little alcohol, followed , by the slow addition of acetone with shaking, un-' 7s ' ALEXANDER PETER TAWSE EAssoN; '