US2742470A - Quaternary salts - Google Patents

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US2742470A
US2742470A US2742470DA US2742470A US 2742470 A US2742470 A US 2742470A US 2742470D A US2742470D A US 2742470DA US 2742470 A US2742470 A US 2742470A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton

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  • This invention relates to quaternary-compounds and relates more particularly to certain quaternary salts of thonzylamine, i. e., N,N-dimethyl-N"-'(p-methoxybenzyl)- N -(2-pyrimidyl)-ethylene diamine.
  • An object ofthis invention is the production of novel quaternary ammonium salts having desirable solubilizing and other surfactant properties.
  • Another object of this invention is the provision of novel solubilizing agents which are particularly valuable as solubilizing agents for antibiotics such as, for "example, gramicidin, tyrothricin, subtilin, etc.
  • a further object of this invention is, the provision of quaternary ammonium salts which are effective mucolytic agentsfor the solubilization of secretions of then'os e, throat and lungs, and which may be administered satisfactorily by aerosoliz'ation techniques.
  • novel quaternary ammonium'salt's of my invention are also highly effective as 'mucolytic agentsand exhibit. marked ability to reduce the viscosity of many thick, tenacious secretions of the nasal, pharyngeal andbron'chialpassages frequently encountered in cases of pneumonia and plumonary tuberculosis.
  • One highly eflective manner of administering these quaternary ammonium salts for maximum mucolytic activity is in the form of 'an aerosol;
  • This technique involves the nebuliz'ation ofa'p'fedeter mined amount of an aqueous solution 'containingrfrom' as little as 0.01% to 1.0% by weight of the quaternaryam' monium salt into a relatively confined space, such' a's-a tentor, preferably, a mask, and the patient under -treatmentiin I United States Patent hales the resulting mist or aerosol.
  • the mucolytic-agent is thus brought into directand intimate contact with the secretions present in the nose, throat and lungs. This therapy causes a marked loosening and liquefaction of the secretions. In many instances-the sputum flow is greatly.
  • the aerosol mayv also 'be administered concurrently With oxygen therapy-
  • a typical formulation which has' been'found to be clinically efiective in mucolytic therapy contains 0.1546 0.20 gram of N,N-di methyl-N-(p-methoxybenzyl)-N'-(2 pyrimidyl)-Ncetyl-N-bromo-ethylene diamine, or other of the novel quaternary ammonium salts of my invention, dissolved in 10.0 grams of propylene glycol, which is then brought up to a volume ofmL Withdi'stiIIed water and" buffered to a pH of 7.4 with sodiumcarbonate.
  • the iodide, bromide or chloride may be readily formed in this man her." If an iodide salt is 'fo'rmedhiuitially, itim'ayfbe readily converted to the corresponding bromideor Iclilo' ride salt by-r'eacting' said'iodide" salt with' eitherisilver bromide or" with silver chloride; forexa'mple, so as tore place the iodine in the salt by an atom" of chlorineor" bro minasthe' case mayhbe.
  • the alanine; chlbride'or iodide salt may also be converted to the cor responding sulfate salt by reacting these antigen-sans with silver sulfate or, where a phosphate salt is desired, by reacting any one of the halide salts with silver phos-
  • the novel quaternary salts of my invention may also be made by reacting an "N- (p 'methoxybe'n' Example I 1 2.86 parts by Weight of thonzylamine base are dissolved in 22 parts by weight of benzo'l and tothe solution thus obtained are added 1.42 parts-by Weight of methyl' iodide; The reaction mixture is maintained at room temperature and the quaternary ammoniunrsai-t- N,N-dimethyl-N-(pmethoxybenzyl) N' -,(2' pyrimidyDgethylehediarnine N-methyliodide percipitates from the solution.
  • Example II Example Ill 2.86 parts by weight of thonzylamine base and 2.5 parts by weight of N-decyl bromide are heated together at about 100 C. for 48 hours, the reaction mixture cooled to about 20 C. and then extracted with ether by decantation. On being allowed to stand, the ether-insoluble residue solidifies and upon recrystallization from a 3:2 mixture of ether-isopropanol by weight, white crystals of N,N-dimethy1-N'-(p-methoxybenzyl) -N- (2-pyrimidy1) ethylene diamine-N-decyl bromide are obtained. This compound has a melting point of l107 C. This novel quaternary ammonium salt is soluble in water and in the alcohols mentioned in Example II.
  • Example IV 2.86 parts by weight of thonzylamine base and 5 parts by weight of lauryl bromide are heated together at about 100 C. for 48 hours, the reaction mixture cooled to about C. and then extracted with ether by decantation. On being allowed to stand, the ether-insoluble residue solidifies. Upon recrystallization of the ether-insoluble residue from a mixture of ether-isopropanol in a ratio of 3 :2 parts by weight, a yield of 5 parts by weight of N,N-dimethyl- N (p-methoxybenzyl) N (2 pyrimidyl) ethylene diamine-N-lauryl bromide is obtained in the form of white crystals. The product obtained has a melting point of l07.5108 C., is soluble in ethyl alcohol, and slightly soluble in water.
  • Example V By reacting 2.86 parts by weight of thonzylamine base and 10 parts by weight of n-decyl iodide in the manner described in Example III, 8.5 parts by weight of N,N- dimethyl N (p methoxybenzyl) N (2 pyrimidyl) ethylene diamine-N-decyl iodide are obtained in the form of light yellow crystals having a melting point of 9697 C. This compound is slightly soluble in water and soluble in ethyl alcohol.
  • Example VI By reacting 2.86 parts by weight of thonzylamine base and 10 parts by weight of cetyl iodide in the manner described in Example III, 8.3 parts by weight of N,N-dimethyl N (p methoxybenzyl) N (2 pyrimidyl)- ethylene diamine-N-acetyl iodide are obtained in the form of light yellow crystals which have a melting point of 92-94 C. This compound is soluble in ethyl alcohol.
  • Example VII By reacting 2.86 parts by weight of thonzylamine base and 10 parts by weight of dodecyl iodide in the manner described in Example III, 8.0 parts by weight of N,N-dimethyl N (p methoxybenzyl) N (2 pyrimidyl)- ethylene diamine-N-dodecyl iodide are obtained in the form of light yellow crystals having a melting point of 96-98 C. This compound is soluble in ethyl alcohol.
  • Example VIII 5.8 parts by weight of thonzylamine base are reacted with 10 parts by weight of cetyl bromide at about 100 C. for 48 hours and after being cooled at 20 C. the reaction mixture is extracted with ether. On cooling the ratfinate, solidification takes place and the recrystallization of the solid material from ether-isopropanol yields 5.5 parts by weight of white crystalline N,N-dimethyl-N-(p-methoxybenzyl)-N-(2-pyrimidyl)-ethylene diamine-N-acetyl bromide. This compound has a melting point of 9192 C., is soluble in alcohol and is slightly soluble in water.
  • Example IX 1.18 parts by weight of the cetyl bromide quaternary ammonium salt of thonzylamine prepared as described in Example VIII are dissolved in 75 parts by weight of water warmed to C. and a solution of 0.312 part by weight of silver sulfate in parts by weight of water at 80 C. is added thereto. The resulting mixture is warmed at about 100 C. until the precipitate of silver bromide which forms has coagulated. The silver bromide is filtered off and the filtrate evaporated. The N,N-dimethyl-N-(pmethoxybenzyl) N (2 pyrimidyl) ethylene diamine- N-cetyl sulfate obtained is a yellow oil.
  • Example X 1.1 parts by weight of the n-decyl iodide quaternary ammonium salt of thonzylamine prepared as described in Example V are dissolved in 50 parts by weight of ethanol and to this solution is added a solution of 0.34 part by weight of silver nitrate in 50 parts by weight of ethanol. The precipitate of silver iodide which forms is filtered off. The filtrate is evaporated to dryness and then recrystallized from ether-isopropanol to yield a white crystalline product.
  • N,N-dimethyl-N'-(p-methoxybenzyl)-N-(2- pyrimidyl)-ethylene diamine-N-decyl nitrate melts at l0l102 C. and is soluble in alcohol and slightly soluble in water.
  • Example XI 1.16 parts by weight of the n-dodecyl iodide quaternary ammonium salt of thonzylamine obtained in accordance with the process of Example VII are stirred in 1000 parts by weight of water at 80 C. and 1.14 parts by weight of silver chloride are then added. The mixture is then heated to about 100 C. and maintained at this temperature for about 48 hours with stirring. The precipitate of silver iodide formed is filtered off and, after the filtrate is evaporated to dryness, the residue is recrystallized from ether-isopropanol to yield white crystals.
  • N,N-dimethyl N (p methoxybenzyl) N (2 pyrimidyl)- ethylene diamine-Nm-dodecyl chloride obtained has a melting point of 75-78 C. and is soluble in water and alcohol.
  • novel quaternary ammonium salts of thonzylamine of my invention are as stated, effective disinfecting agents against various bacteria.
  • In vitro tests against Staph. aureus demonstrate that the n-decyl bromide, lauryl bromide, cetyl bromide and n-decyl iodide quaternary salts of thonzylamine, for example, show effective bacteriostasis in concentrations of less than 0.25 mg.%. The test is carried out as follows:
  • these compounds In addition to the antibacterial activity exhibited by the quaternary ammonium salts of thonzylamine, these compounds also exhibit marked antifungal activity and are particularly active against Tricophyton melztagrophytes, Trichophyton rubrum, Sporotrichum schenkii and Penicillium digitatum.
  • the cetyl bromide quaternary of thonzylamine is fungistatic in a concentration of 0.2 mg.%
  • Tricophyton rubrum in a concentration of 0.04 mg.%
  • Sporotrichum schenkii in a concentration of 0.2 mg.%
  • Penicillium digiiatum in a concentration of 1 mg.%.
  • This compound is also fungistatic in a concentration of 5 mg.% against Candida albicans.
  • a particularly valuable property of my novel quaternary ammonium salts of thonzylamine is their ability to disperse or solubilize antibacterial agents, such as gramicidin.
  • I have been able to prepare a clear aqueous dispersion containing 1% by weight of thonzylamine-hydrochloride, 0.25% by weightof -1-phenylephrine hydrochloride, 0.005% by Weight of gramicidin, 2% by weight of a mixture of monobasic sodium phosphate and dibasic sodium phosphate and .001% by Weight of Paraben preservative (mixed methyl and propyl esters of p-hydroxybenzoic acid).with the aid of 0.1% by weight of my novel thonzylamine quaternary ammonium salts such as, for example, the cetyl bromide or lauryl bromide quaternary ammonium salt.
  • the solution remains clear
  • This application is a continuation-in-part of my copending application S.
  • Process for the production of quaternary ammo nium salts of N,N-dimethyl-N-( n-methoxybenzyl)-N'- (2-pyrimidyl)ethylene diamine which comprises reacting said amine compound with an alkyl halide in which the halogen is a member of the group consisting of chlorine, bromine and iodine and said alkyl group contains up .to 20 carbon atoms, said reaction being carried out at a temperature of 40 to C. for 8 to 72 hours.
  • a mucolytic agent comprising an aqueous solution of a quaternary ammonium salt of the formula oorr, I
  • Bovet et al. Medicaments au System Nerveux Vegetative, pp. 772 and 775 (1948),. published by S. Karger S. A., Basle, Switzerland.

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Description

No Drawing. Application June 9, 1954, Serial No. 435,617
16 Claims (Cl. 260--256.4) This invention relates to quaternary-compounds and relates more particularly to certain quaternary salts of thonzylamine, i. e., N,N-dimethyl-N"-'(p-methoxybenzyl)- N -(2-pyrimidyl)-ethylene diamine.
An object ofthis invention is the production of novel quaternary ammonium salts having desirable solubilizing and other surfactant properties.
Another object of this invention is the provision of novel solubilizing agents which are particularly valuable as solubilizing agents for antibiotics such as, for "example, gramicidin, tyrothricin, subtilin, etc.
A further object of this invention is, the provision of quaternary ammonium salts which are effective mucolytic agentsfor the solubilization of secretions of then'os e, throat and lungs, and which may be administered satisfactorily by aerosoliz'ation techniques.
Other objects of this invention will appear from the followingdetailed'description.
The solubilization of many therapeutic organic compounds frequently presents a serious problem in the practical application of such compounds, especially Where the use of organic solvents, such as alcohol, is"undesirable. Thus; for example, gramicidin isquite insoluble in water, and where the use of an aqueous medium is'of importance, the only manner in which the gramicidin can be employed is in the form of a suspension. Not only does this limit'the practical concentrationof the antibiotic which can be made available for action, butthe'preparw tion of stable suspensions is'also' a matter of-no little difliculty. I
I have'now found that quaternaryaminoniuin'salts of I the" general formula where R is an alkyl group up. to about 20 carbon atoms and X is the anion of an acid; comprisehighly-effective" solubilizing agents which are particularly valuable for solubilizing ditficultly soluble antibiotics In addition; these salts exhibit bacteriostatic action against various organisms, especially Staphylococcus au'reusa'nd as such, comprise highly. elfective disinfectant materials.
The novel quaternary ammonium'salt's of my inventionare also highly effective as 'mucolytic agentsand exhibit. marked ability to reduce the viscosity of many thick, tenacious secretions of the nasal, pharyngeal andbron'chialpassages frequently encountered in cases of pneumonia and plumonary tuberculosis. One highly eflective manner of administering these quaternary ammonium salts for maximum mucolytic activity is in the form of 'an aerosol; This technique involves the nebuliz'ation ofa'p'fedeter mined amount of an aqueous solution 'containingrfrom' as little as 0.01% to 1.0% by weight of the quaternaryam' monium salt into a relatively confined space, such' a's-a tentor, preferably, a mask, and the patient under -treatmentiin I United States Patent hales the resulting mist or aerosol. The mucolytic-agent is thus brought into directand intimate contact with the secretions present in the nose, throat and lungs. This therapy causes a marked loosening and liquefaction of the secretions. In many instances-the sputum flow is greatly.
increased. The application of the novel quaternary; atnmonium salts of my invention to the treatment'of the premature new-born by this aerosolization technique is particularly effective in those instances Where the infants are born with or develop atelectasis. The nebulization of an'aqueous solution of 'said quaternary ammonium salt'into an isolette, incubator or croup tent to produce an aerosol has been associated with a definite decrease in mortality of such premature infants. The aerosol mayv also 'be administered concurrently With oxygen therapy- A typical formulation which has' been'found to be clinically efiective in mucolytic therapy contains 0.1546 0.20 gram of N,N-di methyl-N-(p-methoxybenzyl)-N'-(2 pyrimidyl)-Ncetyl-N-bromo-ethylene diamine, or other of the novel quaternary ammonium salts of my invention, dissolved in 10.0 grams of propylene glycol, which is then brought up to a volume ofmL Withdi'stiIIed water and" buffered to a pH of 7.4 with sodiumcarbonate.
As examp'les-of acid anions which may constitute that portion of the above general formula representedby the substituent X, there may bementioned'the anions of such inorganic acids as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid and the several phosphoric acids. Those compounds containing halogen asthe inorganic anion in the quaternary ammonium salt structure are preferable since they are-most conveniently andccO- nomically obtained. 7 The novelsalts of iny invention may be produced, for example, by dissolving the 'thonzylamine base in a suit;-
able organic solvent such as benzol, toluene or-xylene,
and 'then adding an alkyljhalide 'to the solution. Uponstanding or upon-moderate heating, the desired alkyl'halide quaternary ammonium salt of thonzylamineisformed," The amine base 'may also 'be 'rea c'tedlwith analkyl halide directly and without the use'of'a solvent'by mixingithe reactants and Warming at 40 to 100 C., for about 8to'72 hours. Mol ratios are preferablyr'employed. The iodide, bromide or chloride may be readily formed in this man her." If an iodide salt is 'fo'rmedhiuitially, itim'ayfbe readily converted to the corresponding bromideor Iclilo' ride salt by-r'eacting' said'iodide" salt with' eitherisilver bromide or" with silver chloride; forexa'mple, so as tore place the iodine in the salt by an atom" of chlorineor" bro minasthe' case mayhbe. Furthermore, the alanine; chlbride'or iodide salt may also be converted to the cor responding sulfate salt by reacting these antigen-sans with silver sulfate or, where a phosphate salt is desired, by reacting any one of the halide salts with silver phos- In' addition, the novel quaternary salts of my invention may also be made by reacting an "N- (p 'methoxybe'n' Example I 1 2.86 parts by Weight of thonzylamine base are dissolved in 22 parts by weight of benzo'l and tothe solution thus obtained are added 1.42 parts-by Weight of methyl' iodide; The reaction mixture is maintained at room temperature and the quaternary ammoniunrsai-t- N,N-dimethyl-N-(pmethoxybenzyl) N' -,(2' pyrimidyDgethylehediarnine N-methyliodide percipitates from the solution. This novel compound has a melting point of 168-l69 C.
Example II Example Ill 2.86 parts by weight of thonzylamine base and 2.5 parts by weight of N-decyl bromide are heated together at about 100 C. for 48 hours, the reaction mixture cooled to about 20 C. and then extracted with ether by decantation. On being allowed to stand, the ether-insoluble residue solidifies and upon recrystallization from a 3:2 mixture of ether-isopropanol by weight, white crystals of N,N-dimethy1-N'-(p-methoxybenzyl) -N- (2-pyrimidy1) ethylene diamine-N-decyl bromide are obtained. This compound has a melting point of l107 C. This novel quaternary ammonium salt is soluble in water and in the alcohols mentioned in Example II.
Example IV 2.86 parts by weight of thonzylamine base and 5 parts by weight of lauryl bromide are heated together at about 100 C. for 48 hours, the reaction mixture cooled to about C. and then extracted with ether by decantation. On being allowed to stand, the ether-insoluble residue solidifies. Upon recrystallization of the ether-insoluble residue from a mixture of ether-isopropanol in a ratio of 3 :2 parts by weight, a yield of 5 parts by weight of N,N-dimethyl- N (p-methoxybenzyl) N (2 pyrimidyl) ethylene diamine-N-lauryl bromide is obtained in the form of white crystals. The product obtained has a melting point of l07.5108 C., is soluble in ethyl alcohol, and slightly soluble in water.
Example V By reacting 2.86 parts by weight of thonzylamine base and 10 parts by weight of n-decyl iodide in the manner described in Example III, 8.5 parts by weight of N,N- dimethyl N (p methoxybenzyl) N (2 pyrimidyl) ethylene diamine-N-decyl iodide are obtained in the form of light yellow crystals having a melting point of 9697 C. This compound is slightly soluble in water and soluble in ethyl alcohol.
Example VI By reacting 2.86 parts by weight of thonzylamine base and 10 parts by weight of cetyl iodide in the manner described in Example III, 8.3 parts by weight of N,N-dimethyl N (p methoxybenzyl) N (2 pyrimidyl)- ethylene diamine-N-acetyl iodide are obtained in the form of light yellow crystals which have a melting point of 92-94 C. This compound is soluble in ethyl alcohol.
Example VII By reacting 2.86 parts by weight of thonzylamine base and 10 parts by weight of dodecyl iodide in the manner described in Example III, 8.0 parts by weight of N,N-dimethyl N (p methoxybenzyl) N (2 pyrimidyl)- ethylene diamine-N-dodecyl iodide are obtained in the form of light yellow crystals having a melting point of 96-98 C. This compound is soluble in ethyl alcohol.
Example VIII 5.8 parts by weight of thonzylamine base are reacted with 10 parts by weight of cetyl bromide at about 100 C. for 48 hours and after being cooled at 20 C. the reaction mixture is extracted with ether. On cooling the ratfinate, solidification takes place and the recrystallization of the solid material from ether-isopropanol yields 5.5 parts by weight of white crystalline N,N-dimethyl-N-(p-methoxybenzyl)-N-(2-pyrimidyl)-ethylene diamine-N-acetyl bromide. This compound has a melting point of 9192 C., is soluble in alcohol and is slightly soluble in water.
Example IX 1.18 parts by weight of the cetyl bromide quaternary ammonium salt of thonzylamine prepared as described in Example VIII are dissolved in 75 parts by weight of water warmed to C. and a solution of 0.312 part by weight of silver sulfate in parts by weight of water at 80 C. is added thereto. The resulting mixture is warmed at about 100 C. until the precipitate of silver bromide which forms has coagulated. The silver bromide is filtered off and the filtrate evaporated. The N,N-dimethyl-N-(pmethoxybenzyl) N (2 pyrimidyl) ethylene diamine- N-cetyl sulfate obtained is a yellow oil.
Example X 1.1 parts by weight of the n-decyl iodide quaternary ammonium salt of thonzylamine prepared as described in Example V are dissolved in 50 parts by weight of ethanol and to this solution is added a solution of 0.34 part by weight of silver nitrate in 50 parts by weight of ethanol. The precipitate of silver iodide which forms is filtered off. The filtrate is evaporated to dryness and then recrystallized from ether-isopropanol to yield a white crystalline product. The N,N-dimethyl-N'-(p-methoxybenzyl)-N-(2- pyrimidyl)-ethylene diamine-N-decyl nitrate obtained melts at l0l102 C. and is soluble in alcohol and slightly soluble in water.
Example XI 1.16 parts by weight of the n-dodecyl iodide quaternary ammonium salt of thonzylamine obtained in accordance with the process of Example VII are stirred in 1000 parts by weight of water at 80 C. and 1.14 parts by weight of silver chloride are then added. The mixture is then heated to about 100 C. and maintained at this temperature for about 48 hours with stirring. The precipitate of silver iodide formed is filtered off and, after the filtrate is evaporated to dryness, the residue is recrystallized from ether-isopropanol to yield white crystals. The N,N-dimethyl N (p methoxybenzyl) N (2 pyrimidyl)- ethylene diamine-Nm-dodecyl chloride obtained has a melting point of 75-78 C. and is soluble in water and alcohol.
The novel quaternary ammonium salts of thonzylamine of my invention are as stated, effective disinfecting agents against various bacteria. In vitro tests against Staph. aureus demonstrate that the n-decyl bromide, lauryl bromide, cetyl bromide and n-decyl iodide quaternary salts of thonzylamine, for example, show effective bacteriostasis in concentrations of less than 0.25 mg.%. The test is carried out as follows:
10 ml. of a suitable nutrient medium is added to each of ten test tubes and the compound to be tested is dis solved or suspended in some of the nutrient medium in a concentration of 128 mg.%. 10 ml. of the resulting solution is added to the second tube and the mixture thoroughly mixed. 10 ml. of the mixture is removed from the second tube, added to the third tube. mixed and the dilution method continued down through the tenth tube. The 10 ml. removed from the last tube are discarded. The first tube, to which nothing is added, serves as a control. The concentration of the test compound in the tubes varies in'amount from 64 mg.% down to 0.25 mg.%. Each tube is then inoculated with an inoculum of 0.1 ml. of a 1-500 dilution of an 18 hour culture of Staph. aareus. and the tubes incubated for 72 hours. The bacteriostatic and stable.
is also quite active against Streptococcus hemolytz'cus and,
Klebsiella pneumoniae.
In addition to the antibacterial activity exhibited by the quaternary ammonium salts of thonzylamine, these compounds also exhibit marked antifungal activity and are particularly active against Tricophyton melztagrophytes, Trichophyton rubrum, Sporotrichum schenkii and Penicillium digitatum. For example, against T richophyton mentagrophytes the cetyl bromide quaternary of thonzylamine is fungistatic in a concentration of 0.2 mg.%, against Tricophyton rubrum in a concentration of 0.04 mg.%, against Sporotrichum schenkii in a concentration of 0.2 mg.% and Penicillium digiiatum in a concentration of 1 mg.%. This compound is also fungistatic in a concentration of 5 mg.% against Candida albicans.
A particularly valuable property of my novel quaternary ammonium salts of thonzylamine is their ability to disperse or solubilize antibacterial agents, such as gramicidin. I have been able to prepare a clear aqueous dispersion containing 1% by weight of thonzylamine-hydrochloride, 0.25% by weightof -1-phenylephrine hydrochloride, 0.005% by Weight of gramicidin, 2% by weight of a mixture of monobasic sodium phosphate and dibasic sodium phosphate and .001% by Weight of Paraben preservative (mixed methyl and propyl esters of p-hydroxybenzoic acid).with the aid of 0.1% by weight of my novel thonzylamine quaternary ammonium salts such as, for example, the cetyl bromide or lauryl bromide quaternary ammonium salt. The solution remains clear This application is a continuation-in-part of my copending application S. No. 276,671, filed on March 14,
1952, and now abandoned. I
It is to be understood that the foregoing detailed description is given lgerely by way of illustration and that many variations ay be made therein without departing from the spirit of my invention.
Having described by invention, what I desire to secure by Letters Patent is:
What I claim is: I
1. Quaternary ammonium salts of the formula OCH where R is an alkyl group and X is an anion of the group having up to 20 carbon atoms consisting of sulfate, phosphate, nitrate chloride, bromide and iodide.
2. N,N dimethyl-N'-(p-methoxybenzyl)-N-(2-pyrimidyl) -ethylene diamine-N-cetyl bromide.
3. N,N dimethyl-N'-(p-methoxybenzyl)-N-(2-pyrimidyl) -ethylene diamine-N-lauryl bromide.
4. N,N dimethyl-N'-(p-methoxybenzyl)-N'-(2-pyrimidyl) -ethylene diamine-N-n-decyl iodide.
5. N,N dimethyl-N'-(p-methoxybenzyl)-N-(2-pyrimidyl)-ethylene diamine-N-n-decyl bromide.
6. N,N dimethyl-r '-(p-methoxybenzyl)-N'-(2-pyrimidyl)-ethylene diamine-N-n-dodecyl chloride. 7
7. Process for the production of quaternary ammonium salts of N,N-dimethyl-N'-(p-methoxybenzyl)-Ijl'- (2-pyrimidyl)-ethylene diamine which comprises reacting said amine compound with an alkyl halide in Which the halogen is a member of the group consisting of chlorine, bromine and iodine wherein said alkyl group has up to 20 carbon atoms;
8. Process for the production of quaternary ammonium salts of N,N-dimethyl-N-(p-methoxybenzyl)-N- (Z-pyrimidyD-ethylene diamine which comprises reacting said amine compound with an alkyl halide in which the halogen is a member of the group consisting of chlorine, bromine and iodine and said alkyl group contains up to 20 carbon atoms, and then replacing said halogen atom with the anion of another acid by'reacting the quaternary ammonium alkyl halide thus obtained with the silver salt N (p-rnethoxybenzyl)-N-(2-pyrimidyl)ethylene diamine-N-dodecyl iodide with silver chloride.
12. Process for the production of quaternary ammo nium salts of N,N-dimethyl-N-( n-methoxybenzyl)-N'- (2-pyrimidyl)ethylene diamine which comprises reacting said amine compound with an alkyl halide in which the halogen is a member of the group consisting of chlorine, bromine and iodine and said alkyl group contains up .to 20 carbon atoms, said reaction being carried out at a temperature of 40 to C. for 8 to 72 hours.
- 13. Process for the production of N,N-dimethyl-N-(pmethoxybenzyl) N'-(2-pyrimidyl)-ethylene diamine-N- cetyl bromidewhich comprises reacting N,N-dimethyl- N- (p-methoxybenzyl -N- Z-pyrimidyl) -ethylene diamine with cetyl bromide. I
14. A mucolytic agent comprising an aqueous solution of a quaternary ammonium salt of the formula oorr, I
References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Jensen et al.: Acta Chemica Scandinavica 2, 381384 (1948).
Wright et al.: JACS 70, 3098-3102 (1948).
Bovet et al.: Medicaments au System Nerveux Vegetative, pp. 772 and 775 (1948),. published by S. Karger S. A., Basle, Switzerland.
. Rieveschl, Jr. Mar. 7, 1950

Claims (2)

1. QUATERNARY AMMONIUM SALTS OF THE FORMULA
11. PROCESS FOR THE PRODUCTION OF N,N-DIMETHYL-N''-(PMETHOXYBENZYL)-N''-(2-PYRIMIDYL)-ETHYLENE DIMINE-N-NDODECYL CHLORIDE WHICH COMPRISES REACTING N,N-DIMETHYLN''- (P-METHOXYBENZYL)-N''-(2-PYRIMIDYL)-ETHYLENE DIAMINE-N-DODECYL IODIDE WITH SILVER CHLORIDE.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
US2499417A (en) * 1946-07-15 1950-03-07 Parke Davis & Co Trialkyl ammonium halides of benzhydryl-aminoethyl ether

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2499417A (en) * 1946-07-15 1950-03-07 Parke Davis & Co Trialkyl ammonium halides of benzhydryl-aminoethyl ether

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