GB1583905A - Quaternary ammonium salts of hydantoin and broad spectrum bactericidal/fungicidal compositions thereof - Google Patents

Description

(54) QUATERNARY AMMONIUM SALTS OF HYDANTOIN AND BROAD SPECTRUM BACTERICIDAL/FUNGICIDAL COMPOSITIONS THEREOF (71) We, GLYCO CHEMICALS, INC., a Corporation organized under the Laws of the State of Pennsylvania, United States of America, of 51 Weaver Street, Greenwich, Connecticut, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to certain hydantoin derivatives, which are characterized as salts having linked to either one of the ring nitrogens a quaternary ammonium group. The quaternary ammonium salts of hydantoin, according to the present invention, are useful as anti-static agents. Certain of these quaternary ammonium hydantoin salts also exhibit bactericidal and/or fungicidal activity, and.

to that extent, this invention relates to germicidal compositions having a broad spectrum of bactericidal and fungicidal activity and containing as an active ingredient certain quaternary ammonium salts of hydantoins, and to methods for combating bacteria and fungi.

The survival of man has for a long time considerably depended upon his ability to protect both himself and the environment upon which he depends from the various agents which tend to destroy them. With an ever-increasing world population, there is an important and continuing need to improve the efficiency of both the methods and substances which provide protection from undesirable bacteria and fungi. Such improvements may take the form of more effective control of bacteria and/or fungi by using less material or labor. Certain of the compounds, compositions and methods of the present invention provide a major step forward in both of these areas.

As noted in U.S. Patent No. 3,228,829, water-containing organic mixtures such as emulsified cutting oils, latexes, latex paints, aqueous adhesives, hydraulic fluids, and pulp dispersions used in paper-making, in the absence of an effective germicide, are characteristically subject to attack by putrefactive bacteria, particularly, species of Pseudomonas and Aerobacter which cause loss of useful properties, foul odors, slime formation and the possibility of skin infections in persons handling these materials. The problems involved in preserving watercontaining systems against microbial decomposition are many and varied and a very considerable amount of work has been done in efforts to find protective substances which meet the numerous requirements. The variety of materials offered for the purpose is, to some extent, evidence that none is without disadvantage.

The first requisite of such a preservative is, of course, its activity and effectiveness against the offending organisms. Contributing to the effectiveness of a preservative are its stability and its persistence in the system. To exert its activity in these systems, the preservative must have a degree of water solubility. Where the aqueous system is subject to handling, the preservative should be non-irritating to the skin under the conditions of use. For reasons of waste disposal, it is becoming increasingly important that the toxicity of these preservative materials to humans and fish be relatively low.

Furthermore, with the significant restrictions which have been placed upon the use of such bactericides as hexachlorophene, the present invention provides a promising alternative.

Accordingly, it is the primary object of the present invention to provide new broad spectrum bactericidal and fungicidal compositions incorporating therein lower effective amounts of active ingredients than generally employed heretofore.

It is a further object of the present invention to provide a new group of hydantoin salts which exhibit anti-static properties.

Still yet another object of the present invention is to provide a new class of compounds have specialty sufactant properties.

Accordingly, this invention provides quaternary ammonium salts of hydantoin, being the compounds of the formula:

wherein: R1 and R2, which may be the same or different, are selected from hydrogen, alkyl of I to 6 carbons, -CnH2nOH, and

Xo; provided that at least one of R1 and R2 is

R3 and R4, which may be the same or different, are selected from hydrogen, alkyl of I to 6 carbons and phenyl, or R3 and R4 taken together may be a cycloaliphatic group of 4 or 5 carbon atoms; R5, R6 and R,, which may be the same or different, are selected from benzyl and + l; CpH2p X is a physiologically acceptable anion; n is an integer from I to 4, and p is an integer from I to 24.

One of the embodiments of the present invention includes those compounds (I) wherein: when Rl is CnH2OH, R2 is

when Rl is

R2 is CH2OH A further embodiment of the present invention includes those compounds (1): wherein: R, and R2, which may be the same or different, are

Still another embodiment of the present invention includes those compounds (I): wherein: one of R, and R2 is hydrogen or alkyl of I to 6 carbons and the other is

Preferred hydantoin derivatives of the present invention are the quaternary ammonium salts of 5,5-disubstituted hydantoin wherein: R3 and R4, which may be the same or different, are selected from alkyl of I to 6 carbons and phenyl, or R3 and R4 taken together may be a cycloaliphatic group of 4 or 5 carbon atoms. Especially preferred are the 5,5-dimethyl hydantoin derivatives.

Preferably, R7 is -C H2p l wherein p is an integer from 8 to 24 and most preferably 12 to 18, while Rs t R, are alkyl of I to 6 carbons, particularly methyl.

These salts exhibit anti-static properties and may be incorporated, for example, into textile materials, such as carpets, socks and undergarments, during the finishing thereof to impart anti-static and softening properties thereto. The salts also possess surfactant properties and are useful wetting agents. In those salts wherein R, or R2 is --C,H,,OH and n = 1, there is provided a useful group of formaldehyde release agents.

Also, the incorporation of these mono-quaternary ammonium salts of hydantoin in aqueous organic mixtures, cosmetic compositions, as well as application of these salts to the skin of non-human animals or of man, provides effective germicidal protection and considerably reduces or precludes damage to the compositions or skin due to microbial attack of bacteria or fungi. Bacterial and fungal infestations and infections may be destroyed or prevented from increasing to prohibitive levels by the presence of at least one active compound according to the present invention. Thus, certain of the compounds, according to the present invention, are germicidal having broad spectrum bactericidal/fungicidal activity.

Compounds, according to the present invention, which have been found to possess bactericidal and/or fungicidal properties, are those having the formula:

wherein: R8 is --C,H,,OH, Z is a physiologically acceptable anion and n is as previously defined.

Suitable physiologically acceptable anions X- and Z- include the halogens, particularly bromide, chloride or iodide, as well as sulfate. The halogens are preferred, especially bromide.

It is to be understood that when sulfate anions are present in the compounds of the present invention, only one half mole of anion is present for each mole of cation.

As but a few examples of the many quaternary ammonium salts of 3 - (3' aminopropyl) hydantoin compounds (I), encompassed by the present invention, there may be mentioned: I - methylol - N,N - dimethyl - N - dodecyl quaternary ammonium bromide salt I - methylol - N,N - dimethyl - N - dodecyl quaternary ammonium chloride salt I - methylol - N,N,N - trimethyl quaternary ammonium iodide salt 1 - methylol - N,N - dimethyl - N - dodecyl quaternary ammonium iodide salt I - methylol - N,N - dimethyl - N - benzyl quaternary ammonium chloride salt 1 - methylol - N - methyl - N - ethyl - N - dodecyl quaternary ammonium bromide salt I - methylol - N - methyl - ethyl - N - dodecyl quaternary ammonium chloride salt 1 - methylol - N - methyl - N - benzyl - N - dodecyl quaternary ammonium bromide salt I - methylol - N,N - dibenzyl - N - dodecyl quaternary ammonium bromide salt 1 - methylol - N - N - dimethyl - N - octadecyl quaternary ammonium bromide salt 1 - methylol - N,N - octadecyl quaternary ammonium chloride salt 1 - methylol - N,N - dimethyl - N - hexadecyl quaternary ammonium chloride salt 1 - methylol - N,N - dimethyl - N - hexadecyl quaternary ammonium bromide salt 1 - (p - hydroxyethyl) - N,N - dimethyl - N - dodecyl quaternary ammonium chloride salt 1 - (p - hydroxyethyl) - N,N - dimethyl - N - dodecyl quaternary ammonium bromide salt 1 - ( - hydroxyethyl) - N,N - dimethyl - N - benzyl quaternary ammonium chloride salt ! - ( - hydroxyethyl) - N,N - dimethyl - N - dodecyl quaternary ammonium iodide salt - (il - hydroxyethyl) - N - methyl - N - ethyl - N - dodecyl quaternary ammonium bromide salt I - (fi- hydroxyethyl) - N - methyl - N - ethyl - N - dodecyl quaternary ammonium chloride salt 1 - (p - hydroxyethyl) - N,N - dimethyl - N - hexadecyl quaternary ammonium bromide salt.

Representative of but a few of the many mono-quaternary ammonium salts of 3 - 3' - aminopropyl) hydantoin compounds encompassed by the present invention, there may be mentioned: N,N - dimethyl - N - dodecyl quaternary ammonium bromide salt N,N - dimethyl - N - dodecyl quaternary ammonium chloride salt N,N - dimethyl - N - benzyl quaternary ammonium chloride salt N,N - dimethyl - N - dodecyl quaternary ammonium iodide salt N - methyl - N - ethyl - N - dodecyl quaternary ammonium bromide salt N - methyl - N - ethyl - N - dodecyl quaternary ammonium chloride salt N - methyl - N - benzyl - N - dodecyl quaternary ammonium bromide salt N,N - dibenzyl - N - dodecyl quaternary ammonium bromide salt N,N - dimethyl - N - octadecyl quaternary ammonium bromide salt N,N - dimethyl - N - hexadecyl quaternary ammonium chloride salt N,N - dimethyl - N - hexadecyl quaternary ammonium bromide salt One may also envision similar mono-quaternary ammonium salts derived from 1 - (3' - aminopropyl) hydantoins, and to that end, the above quaternary salts are included as representative of but a few.

These salts are but a few of the many compounds according to the present invention and are intended as representative of the hydantoin, 5 - monosubstituted - and 5,5 - disubstituted derivatives; including but not limited to hydantoin, 5 - methyl hydantoin or 5,5 - dimethyl hydantoin.

As but a few examples of the many bis-quaternary ammonium salts of 1,3di(3' - aminopropyl) hydantoin compounds, encompassed by the present invention, there may be mentioned: .N,N - dimethyl - N - dodecyl quaternary ammonium bromide salt N,N - dimethyl - N - dodecyl quaternary ammonium chloride salt N,N,N - trimethyl quaternary ammonium iodide salt N,N - dimethyl - N - dodecyl quaternary ammonium iodide salt N,N - dimethyl - N - benzyl quaternary ammonium chloride salt N - methyl - N - ethyl - N - dodecyl quaternary ammonium bromide salt N - methyl - N - ethyl - N - dodecyl quaternary ammonium chloride salt N - methyl - N - benzyl - N - dodecyl quaternary ammonium bromide salt N,N - dibenzyl - N - dodecyl quaternary ammonium bromide salt N,N - dimethyl - N - octadecyl quaternary ammonium bromide salt N,N - dimethyl - N - octadecyl quaternary ammonium chloride salt N,N - dimethyl - N - hexadecyl quaternary ammonium chloride salt N,N - dimethyl - N - hexadecyl quaternary ammonium bromide salt.

These salts are but a few of the many compounds according to the present invention and are intended as representative of the hydantoin, 5 - monosubstituted - and 5,5 - disubstituted derivatives; including but not limited to hydantoin, 5 - methyl hydantoin or 5,5 - dimethyl hydantoin.

While the 5,5 - disubstituted hydantoin compounds are preferred, particularly the 5,5 - dimethyl, other disubstituted materials may also be used to form any of the above salts. For example, 5 - methyl - 5 - ethyl hydantoin, 5,5 - diphenyl hydantoin, 5 - methyl - 5 - phenyl hydantoin and 5,5 - pentamethylene hydantoin are suitable.

As will be appreciated, this specification sets forth a considerable number of quaternary ammonium salts of hydantoin and their method of preparation. For the skilled man in the art, it is only a matter of elementary chemistry and relative ease to prepare a particular derivative differing from any compound not specifically set forth in this specification merely in the number of carbon atoms in any alkyl or aromatic moiety. All that need be done is to commence with the appropriate reactants and, if necessary, adjust the reaction conditions. Hence, it is impractical to recite herein specifically each and every simple variation possible.

The compounds of (I), (III) and (IV) can be readily prepared by the addition of I mole of acrylonitrile to the applicable hydantoin (which may be unsubstituted or mono- or disubstituted at the 5-position, e.g., 5,5 - dimethyl hydantoin) so as to produce the corresponding mono-nitrile. The reaction is carried out in a confined reaction zone (e.g., a stirred autoclave) in an aqueous solvent and in the presence of a catalytically effective amount (e.g., from 0.5 to 1.5%, by weight, of starting hydantoin) of a 4550% aqueous solution of KOH or NaOH at a temperature ranging from 70 to 101 0C, represented schematically as follows:

R3 R3 I I R1 C = O 6 j F I I I I H-N N-H cat. , H NH-N NCll2CH2CN ; (H2=(HCN '1/ O o (V) The nitrile (V) produced is reduced with hydrogen under a pressure of 400 600 p.s.i. at a temperature of from 100 to 1250C in the presence of a suitable catalyst (e.g., Raney Nickel) to produce the corresponding mono-amine (VI) represented schematically as follows:

R3 R3 2 H2 ,0 H N(H2(H2CN Ni cat. H 11 NCH2CH2 CH2 NH2 (VI) (V) The mono-amine VI is then methylated using formaldehyde and formic acid to produce the corresponding mono-tertiary amine VII represented schematically as follows:

Other useful mono-tertiary amines may be prepared by stepwise alkylation of the mono-amine (VI). For example, the N - methyl - N - benzyl - tertiary amine (VIla) may be prepared by stepwise addition of methyl chloride followed by benzyl chloride to the amine (VI) represented schematically as follows:

Compounds wherein R5 and/or R6 are CpH2 + 1 may be prepared in similar fashion by stepwise addition of the appropriate alkyl halide CpH2p + ,X (where X and p are defined as above).

Reaction of the tertiary amine (VII) or (VIIa) with an appropriate alkyl halide (e.g., dodecyl bromide) of the formula CpH2pX (X and p being defined above) preferably in the presence of an effective amount (e.g., less than 1%) of alkali metal hydroxide catalyst and solvent yields the desired quaternary ammonium salt (VIII) represented schematically as follows:

R3 CpH2p+1 X R4 > cPH2p+1 H sH2(H2(H2N-(H3 o HN NCH2CH2CH2N-CH3 X H NaOH cat. 4' NCFaOH ci"1' x 0 CH3 toluene or (H3 solve nt (VII) (VIII) The bis quaternary ammonium compounds of (I) and (II) can be readily prepared by the addition of 2 moles of acrylonitrile to the applicable hydantoin (which may be unsubstituted, mono- or disubstituted at the 5-position, e.g., 5,5dimethyl hydantoin) so as to produce the corresponding dinitrile (IX). The reaction is carried out in a confined reaction zone (e.g., a stirred autoclave) in the presence of a catalytically effective amount (e.g., from 0.5 to 1.5%, by weight, of starting hydantoin) of a 45-50% aqueous solution of KOH or NaOH at a temperature ranging from 70 to 1350C, represented schematically as follows:

R13 '(3 R-( (=0 C=O C=O cat. I I I I NCCH2CH2N \rf " H N N-H 2 CH2=(HCN 0 O (IX) The dinitrile (IX) produced is reduced with hydrogen under a pressure of 500--600 p.s.i. at a temperature of from 100 to 1250C in the presence of a suitable catalyst (e.g., Raney Nickel) to produce the corresponding diamine (X) represented schematically as follows:

R3 R3 RL0 LH2 Rq-H21NH2 NCCH2CH2N CHCHZCN NCH2CH2CN Ni cat H2N(H2(H2CH2N t (IX) (X) The diamine (X) is then methylated using formaldehyde and formic acid to produce the corresponding di-tertiary amine XI represented schematically as follows:

Other useful di-tertiary amines may be prepared by stepwise alklyation of the diamine (IX). For example, the N-methyl-N-benzyl-di-tertiary amine may be prepared by stepwise addition of methyl chloride followed by benzyl chloride to the diamine (IX) represented schematically as follows:

Compounds wherein R5 and/or R6 areCpH2p +, may be prepared in similar fashion by stepwise addition of the appropriate alkyl halide CpH2p + ,X (where X and p are defined as above).

Reaction of the di-tertiary amine (X) or (Xa) with an appropriate alkyl halide (e.g., lauryl bromide) of the formula CpH2pX (X and p being defined above) preferably in the presence of an effective amount (e.g., less than 1%) of alkali metal hydroxide catalyst and solvent yields the desired bis-quaternary ammonium salt (XI) represented schematically as follows:

'(3 R3 2(pH2p+1X CH3-N(H2CH2(N NCH2C(H2N1-(H3 --- CH3 CH3 benzene or toluene IX) solvent '(3 X ClpH2pvl e CPH2p+1 CH3 NCH2CH2CH2N NCH2CH2(H2N1-CH3 CH3 0 CH3 (XI) It is recognized that commercially available alkyl halides of the formula CpH2p + 1X may be mixtures which vary, for example, according to chain length, and as such these mixtures are as suitable for the present invention as the alkyl halide in its purified state. For example, a suitable alkyl halide would include a mixture of predominantly octadecyl halide together with hexadecyl halide and/or tetradecyl halide. Compounds prepared from such mixtures, of course, may contain alkyl chain lengths which vary within the desired range.

Reaction of the mono-quaternary ammonium salt (VIII) in an aqueous alkaline solution with formaldehyde yields the desired monomethylol mono-quaternary ammonium salt (XII) represented schematically as follows:

The compounds of (I) and (IV) wherein R, is p-hydroxyethyl may be prepared in like manner by simply adding ethylene oxide to the applicable mono-quaternary ammonium compounds.

It should be noted that addition of the first mole of acrylonitrile in alkaline media to hydantoins having unsubstituted ring nitrogens takes place at the 3position ring nitrogen. Thus, when preparing compounds of the present invention having the mono-quaternary ammonium substituent attached to the I-position ring nitrogen and aCnH2nOH (n = 2A) substituent attached to the 3-position ring nitrogen, it is necessary to add the appropriate alkylene oxide to the 3-position prior to addition of acrylonitrile. In such instances when R2 is methylol (i.e. n = 1) it is necessary to add a protective grouping to the 3-position nitrogen, which is inert to acrylonitrile, prior to the addition of acrylonitrile and then remove the protective group after acrylonitrile addition. One may envision, for example, addition of a -CH2Cl substituent to the 3-position nitrogen by reacting the desired 1,3-unsubstituted hydantoin with formaldehyde and thionyl chloride. Then, subsequent to addition of acrylonitrile to the I-position nitrogen the -CH2Cl substituent is removed by hydrolysis to yield the corresponding I - mono quaternary hydantoin salt which upon further treatment with formaldehyde in an aqueous solution provides the l-mono-quaternary ammonium - 3 - methylol hydantoin salt.

The starting hydantoins used in the preparation of (I), (II), (III) and (IV) are known compounds.

It is also to be noted that the addition of the first mole of acrylonitrile in alkaline media to hydantoins which possess unsubstituted nitrogen atoms at the 1and 3-position takes place at the 3-position. Therefore, in preparation of the compounds having a mono-quaternary ammonium substituent at the I-position nitrogen and hydrogen on the 3-position nitrogen, it is necessary to add a protecting group, inert to acrylonitrile, to the 3-position prior to the addition of acrylonitrile, which group is subsequently removed. One may envision, for example, the addition of a -CH2Cl substituent to the 3-position nitrogen (via treatment with formaldehyde and thionyl chloride) which may be removed by hydrolysis subsequent to the addition of the acrylonitrile.

In a further aspect of the present invention, there is provided a bactericidal composition comprising as an active ingredient, a bactericidally effective amount of a quaternary ammonium salt of hydantoin as represented in formulae (II), (III) or (IV) above.

A yet further aspect of the present invention provides a fungicidal composition comprising as an active ingredient a fungicidally effective amount of a quaternary ammonium salt of hydantoin as represented by formulae (II), (III) or (IV) above.

Thus, the invention provides for germicidal compositions having broad spectrum bactericidal/fungicidal activity and containing a hydantoin of the above formulae (II), (III) or (IV) in an effective amount as an active ingredient to combat bacteria and fungi. simultaneously in cases of dual infestation.

While the compounds of the present invention are useful as anti-static agents, surfactants or wetting agents, certain of these are particularly suited for use with an incorporated in deodorants, soaps, cosmetics and antiseptic lotions to combat, destroy and/or prevent the infestation of undesired bacteria, fungi, or both. The compounds may be used to combat and prevent undesired bactericidal and fungicidal infections in the skin wounds of non-human animals and of man, by applying to the locus of the skin wound a bactericidally and/or fungicidally effective amount of the active compound as a wound cleanser.

The active compounds are well suited for addition to such aqueous organic mixtures as emulsified cutting oils, latexes, and paints to combat and prevent infestation of putrefactive bacteria as described in the U.S. Patent No. 3,228,829, which is incorporated herein by reference.

The broad spectrum bactericidal and/or fungicidal compositions, according to the present invention, in addition to an effective amount of the active compound (II), (III) or (IV) comprise an inert solid or liquid diluent or carrier. Generally, the active compound (III) or (IV) is effective when present in an amount of from 0.0025 to 10% and preferably from 0.0025 to 0.1% by weight, and may be effectively incorporated into such aqueous-organic mixtures as described in the abovementioned U.S. Patent No. 3,228,829. The active compound (II) is effective when present in an amount of from 0.00007 to 10% and preferably from 0.00007 to 0.1%.

Thus, the bactericidal and/or fungicidal compositions may be prepared in the form of liquids or solids. The active compounds may, for example, be incorporated directly into cosmetic compositions to combat and prevent infestation of undesirable bacteria and/or fungi. The active compound may be present in solution suspension or antiseptic formulation.

The compounds (II), (III), and (IV) may be incorporated in an effective amount in formulations in the nature of gels, creams, lotions or powders.

The compositions, when in the form of a liquid, preferably contains a surfaceactive agent so as to effect dispersion of the active compound in aqueous solutions.

These solutions may be used, for example, as sprays.

The bactericidal and/or fungicidal compositions, when used as an antiseptic to combat, destroy or prevent infestation of undesirable bacteria, fungi, or both, necessitate that the inert carrier be non-toxic. Such compositions may be in the form of gels, creams, lotions, suspensions, and powder which may be prepared in a conventional manner by incorporation of the active compound therein as described in U.S. Patent No. 2,886,487, which is incorporated herein by reference.

As noted, the bactericidal and/or fungicidal compositions of the invention may be used as sprays in the form of aerosols wherein the formulation is held in a container under pressure in the presence of a propellant, such as fluorotrichloromethane or dichlorodifluoromethane.

The compositions which are to be used inthe form of aqueous dispersions or emulsions are generally supplied in the form of a concentrate containing a high proportion of the active ingredient or ingredients, the said concentrate to be diluted with water before use. These concentrates are often required to withstand storage for prolonged periods and after such storage, to be capable of dilution with water in order to form aqueous preparations which remain homogeneous for a relatively long period of time.

It is to be understood that the fungicidal compositions of this invention may comprise, in addition to the hydantoin salt, one or more other compounds having biological activity.

The following examples are provided to more fully illustrate the invention, but are not to be construed as limiting the scope thereof.

EXAMPLE 1.

Preparation of Mono-Quaternar! Ammonium Salt liter To a 2i liter flask fitted with mechanical stirrer, thermometer and reflux condenser is added 3203 g (25 mol) 5,5-dimethyl hydantoin (DMH) and 5000 ml water. Upon heating to 730C, complete solution of the DMH results. Then 664 g (12.5 mol) acrylonitrile and 24 g of 50% aq. NaOH catalyst is added to it. Refluxing is begun and is continued until the temperature reaches 100"C. Heating is stopped and when the temperature falls to N 730C, the final 663 g (12.5-mol) acrylonitrile is added. When the temperature reaches 100--101"C, all heating is stopped, external cooling is applied until the temperature reaches 31"C, and a seed crystal of mononitrile is added to the cooled reaction solution. The mononitrile crystallizes out of solution and is collected via filtration, air dried and found to have a mp of 97.5--99.5"C (lit. 98--101"C) and a yield of 3,245 g (71.6%).

370.4 g (2 mol) the mononitrile is then added to a 2 liter Parr pressure reaction vessel with 41.2 g Raney Nickel catalyst and 500 ml toluene. The system is flushed with H2 and then a partial pressure of 70 p.s.i. NH, is added. The system is then pressurized with H2 to 500 p.s.i. The temperature Is raised to 1170C and the H2 uptake is recorded, while continually maintaining the pressure at 400-600 p.s.i.

Once the H2 uptake is complete, the reactor is cooled and the toluene solution is filtered to remove nickel catalyst. Upon standing, the toluene filtrate yields white or very pale blue crystalline pure monoamine: mp = 79--81"C (lit. N 70"C), yield - 90-95%.

A modified Eschweiler-Clarke reaction is used to prepare the mono-tertam

N,N - dimethyl - N - dodecyl quaternary ammonium bromide salt of 3 - (3' aminopropyl) - 5,5 - dimethyl hydantoin (VIII a) Physical Properties: 1. MP=90--93"C 2. Appearance = waxy-white solid 3. C, H, N, Br analysis: Found: C 57.02 H 9.56 N 9.02 Br 17.44 Theory: C57.13 H9.59 N9.09 Br 17.28 EXAMPLE 2.

Preparation of Monomethylol-Mono-Quaternary Ammonium Salt (Xlla) To a small flask is added 14.8 g (0.032 mol) mono-quaternary bromide salt of Example 1 and 25 ml H2O. Upori stirring, all the salt dissolves and then the pH is adjusted to 8.2 with aq. NaOH. To the adjusted solution is added 2.85 g (0.033 mol) 37% aq. formaldehyde. After mixing thoroughly, the solution is allowed to stand for 24 hours. Concentration on the roto-evaporator followed by high vacuum drying yields the solid white methylol quaternary salt having the structure and properties set forth below:

C, H, N, Br analysis: Found: C 56.02 H 9.22 N 8.40 Br 15.97 Theory: C 56.09 H 9.41 N 8.53 Br 16.22 mp= 135--138"C, yield=9.5 g (60%).

EXAMPLE 3.

Preparation of Monomethylolmonobenzyl Quaternary Salt (Xlll) To a 500 ml flask fitted with condenser, stirrer and thermometer is added 43.3 g (0.20 mol) mono-tert-amine from Example 1, 36.2 g (0.28 mol) benzyl chloride and 250 ml benzene. The mixture is stirred vigorously and heated at reflux for 3 hours. A white precipitate forms, which is collected via filtration, washed with solvent and dried in a vacuum oven. If desired, the monobenzyl chloride quaternary salt may be recrystallized from an i-PrOH/Et2O/H2O mixture to yield 50 g (73.5 %) of a white solid having mp 243--244"C and the following structure and properties:

C, H, N, Cl analysis: Found: C 59.95 H 7.63 N 12.46 Cl 10.28 Theory: C 60.08 H 7.71 N 12.36 Cl 10.43 To a 250 ml flask is added 40.11 g (0.118 mcl) monobenzyl chloride quaternary and 150 ml distilled H2O. The pH of the solution is adjusted to 8.1 with aq. NaOH.

To the adjusted solution is added 9.5 g 37% aq. formaldehyde and the resulting homogeneous mixture is stirred for 3 hours. The solution is then concentrated on the roto-evaporator, yielding a product having the structure and properties set forth below:

C, H, N, Cl analysis: Found: C 55.87 H 7.89 N 11.02 Cl 9.36 Theory: C 58.45 H 7.63 N 11.36 Cl 9.58 Each of the quaternary ammonium salts produced in Examples 1--3 are water soluble.

EXAMPLE 4.

Preparation of Di-Quaternary Ammonium Salt (XIa) To a 12 liter flask fitted with mechanical stirrer, thermometer and reflux condenser is added 5253 g (41 mol) 5,5 - dimethyl hydantoin (DMH) and 2176 g (41 mol) acrylonitrile. The stirred slurry is heated to 55"C, and 82 g of 50% aq. NaOH catalyst is added to it. Heating is continued until the temperature reaches 70"C. An exotherm ensues, which becomes so strong that external cooling is required. Once the exotherm has subsided, the now homogeneous amber viscous solution is cooled to N 680C and 1114 g (21 mol) additional acrylonitrile is added. Another strong exotherm is observed which once again requires external cooling. When the temperature falls to N 700C, the final 1060 g (20 mol) acrylonitrile is added. The final strong exotherm raises the temperature to N 1240C. No external cooling is applied. The temperature slowly falls back to N 800 C, when the viscous green amber crude dinitrile is poured into 8 liter stirred warm water. Crystallization gradually takes place. The purified dinitrile is collected via filtration and air dried: mp 98-1000C (lit. 98--99"C), appearance -- white powder, yield = 94.1%.

To a liter Parr pressure reaction vessel is added 468.5 g (2 mol) dinitrile, 40 g Raney Nickel catalyst and 500 ml toluene. After flushing the system with H2, a partial pressure of 95 p.s.i. NH3 is added. The system is then pressurized with H2 to 500 p.s.i. The temperature is raised to 1170C, and then H2 uptake is recorded. The pressure is maintained at 400-600 p.s.i. by adding H2 as needed. Once H2 uptake ceases, the reactor is cooled and the toluene solution, which now contains crude diamine and catalyst, is filtered to remove nickel catalyst. The resulting light blue solution is concentrated on the roto-evaporator, yielding high purity crude diamine: yield - 450 g (93%), Total Amine Value (TAV) = 433/463 = 93.4%, glc (BSA derivative)= 94.6%.

The crude diamine is distilled under reduced pressure, yielding water white, somewhat viscous pure diamine: BP= 161"C/35 , TAV=458.3/463=98.9%, glc (BSA derivative)= 99%.

A modified Eschweiler-Clarke reaction is used to prepare the di-tert-amine.

To a 1 liter flask fitted with mechanical stirrer, condenser and thermometer is added 97.1 g (0.4 mol) diamine and 169.34 g 37% aq. formaldehyde. An exotherm is noted, and the resulting solution becomes noticeably gelatinous. Once the solution cools down to 400C, 241.5 g 90% formic acid is carefully added. Gas evolution is observed. The stirred reaction solution is heated to gentle reflux, which is maintained for 6-8 hours. After cooling, the crude reaction product is placed on the roto-evaporator and concentrated to 1/2 its original volume. Then 200 ml 25% aq. NaOH is added. Further concentration on the roto-evaporator yields a greenish viscous liquid, which is the desired crude di-tert-amine, together with precipitated sodium formate. The sodium formate is collected via filtration, washed with isopropyl alcohol and discarded. The i-PrOH wash is combined with the filtrate and concentrated on the roto-evaporator. The resulting crude di-tert-amine is distilled under reduced pressure yielding clear, colorless, somewhat viscous pure di-tertamine: BP = 137 C/90y, TAV = 364/376 = 96.8%, yield = 80 ml (67%).

To a 500 ml flask fitted with mechanical stirrer, thermometer and condenser is added 27.5 g (0.092 mol) di-tert-amine, 64.8 g (0.26 mol) bromododecane and 250 ml benzene. Refluxing is started, and after several hours, 1 drop 50% aq. NaOH is added as a catalyst. Additional refluxing yields a voluminous white precipitate. The di-quaternary salt is collected via filtration, washed with solvent and dried in a vacuum oven: white, slightly waxy, very hygroscopic solid having the properties and structure set forth below:

bis - N,N - dimethyl - N - dodecyl quaternary ammonium bromide salt of 1,3 di(3'-aminopropyl)-5,5-dimethyl hydantoin (XIa) Physical Properties: 1. MW = 796.92 2. MP=174--76"C 3. Appearance = cream-white solid 4. IR Spectrum = (KBr) = 3.4, 3.49, 5.65, 5.85, 6.8, 6.98, 7.27, 7.4, 12.9 y 5. C, H, N, Br analysis: Found: C 58.49 H 9.96 N7.31 Cr 20.41 Theory: C58.78 H 10.12 N7.03 Br 20.05 If desired, the quaternary salt can be recrystallized from a mixture of isopropyl alcohol and ether, mp 176--177.5"C.

EXAMPLE 5.

Preparation o+Dioctadecyl Bromide Quaternary Salt (Xlh) To a 500 ml flask fitted with condenser, thermometer and mechanical stirrer is added 29.80 g (0.1 mol) di-tert-amine, as prepared in Example 4, 66.7 g (0.2 mol) bromooctadecane. 100 ml benzene and I drop 50Y aq. NaOH catalvst. The mixture is refluxed for 8 hours. The solvent is removed on the roto-evaporator, yielding a viscous mass. To the viscous mass is added 100 ml toluene, and refluxing is continued for an additional 4 hours. Upon standing for several days, the reaction mixture becomes gelatinous. Addition of Et2O to the mixture yields a white tacky solid, which is collected via filtration, washed with solvent and dried in a vacuum oven. The dioctadecyl quaternary salt should be of acceptable quality at this stage, but, if necessary, additional bromooctadecane is reacted with the salt to insure complete quaternization providing a white waxy solid compound having a mp = 1500 C, structure and properties set forth below:

C, H, N, Br analysis: Found: C62.43 H 10.27 N6.45 Br 16.92 Theory: C 63.46 H 10.86 N 5.80 Br 16.59 EXAMPLE 6.

Preparation of Dimethyl iodide Quaternary Salt (XlcJ To a flask is added 14.95 g (0.05 mol) of the di-tert-amine of Example 4 and a total of 25 ml (0.39 mol) methyl iodide. A strong exotherm rapidly ensues yielding a white solid. A slurry of the solid with ethyl alcohol is made. The solid is collected via filtration, washed with ethyl alcohol and dried in a vacuum oven, yielding essentially pure dimethyl iodide quaternary salt: cream white solid, mp 256.5--259"C dec., yield = 22.5 g (77.2%) having the following structure and properties:

C, H, N, I analysis: Found: C 34.84 H 6.02 N 9.88 143.62 Theory: C 35.06 H 6.23 N9.61 143.58 EXAMPLE 7.

Preparation of Dibenzyl Chloride Quaternarv Salt (XIV) To a 500 ml flask fitted with mechanical stirrer and condenser is added 27.5 g (0.092 mol) of the di-tert-amine of Example 1, 34.85 g (0.26 mol) benzyl chloride and 250 ml benzene. After thorough mixing, the solution is allowed to stand, yielding a white precipitate. Refluxing for 15 minutes yields considerably more precipitate. The di-quaternary salt is collected via filtration, washed with solvent and air dried to give a compound having the following structure and properties:

mp = 129 -- 132"C appearance -- white solid: C, H, N, Cl analysis: Found: C 62.80 H 7.91 N 9.89 Cl 12.81 Theory: C 63.15 H 8.04 N 10.16 Cl 12.85 The salts prepared in Examples 5, 6 and 7 do not possess bactericidal and/or fungicidal activity when used in amounts as high as 1,000 p.p.m. Each of the quaternary ammonium salts produced in Examples 4-7 are water soluble and give a positive test for halogen with AgNO3.

EXAMPLE 8 Preparation of Mono-Quaternary Ammonium Salt (XV) To a 22 liter flask fitted with stirrer, condenser and thermometer is added 3203 g (25 mol) DMH and 5000 ml H2O. Upon heating to 730C, complete solution of the DMH results. Then 664 g (12.5 mol) acrylonitrile and 24 g of 50% aq. NaOH catalyst is added. Refluxing is begun, and the solution is maintained at reflux until the temperature reaches N 1000C. All heating is now stopped, and when the temperature falls to 730C, the remaining 663 g (12.5 mol) acrylonitrile is charged.

Refluxing is started once again. When the temperature reaches 100--101"C, all heating is stopped, external cooling is applied until the temperature reaches 31 C, and a seed crystal is mononitrile is added to the cooled reaction solution. The mononitrile crystallizes out of solution and is collected via filtration and air dried: mp 97.5--99.5"C (lit. 98--101"C), glc (TMS derivative)=99%, yield=3,245 g (71.6%).

To a 2 liter Parr pressure reaction vessel is added 370.4 g (2 mol) mononitrile, 41.2 g Raney Nickel catalyst and 500 ml toluene. The system is flushed with H2, and then a partial pressure of 70 p.s.i. NH3 is added. The system is then pressurized with H2 to 500 p.s.i. The temperature is raised to 1 170C and the H2 uptake is recorded, while continually maintaining the pressure at 400--600 p.s.i. Once the H2 uptake is complete, the reactor is cooled and the toluene solution is filtered to remove nickel catalyst. UpoR^tst nding, the toluene filtrate yields white or very pale blue crystalline pure monoamine: mp=79-810C (lit. - 70 C), total amine value (TAV) = 297.9/300 = 98.4%, yield = 90-95%.

A modified Eschweiler-Clarke reaction is used to prepare the mono-tertamine. To a I liter flask fitted with condenser, stirrer and thermometer is added 175.6 g (0.943 mol) monoamine and 153.9 g 37% aq. formaldehyde. After cooling to 25"C, 109.5 g. 90% formic acid is added, resulting in vigorous gas evolution. After 5 minutes, a final 109.5 g 90% formic acid is added. The mixture is heated to 1050C and refluxed for 6 hours. After cooling, the pH of the solution is adjusted to 7.21 with 50% aq. NaOH. The now neutralized solution is concentrated on the rotoevaporator, yielding a gummy solid. Isopropyl alcohol is added to the solid, which dissolves the desired mono-tert-amine leaving the sodium formate by-product for collection via filtration and subsequent discarding. The filtrate is concentrated on the roto-evaporator, yielding greenish crude mono-tert-amine. Distillation of the crude amine under reduced pressure yields pure light yellow, clear, slightly viscous mono-tert-amine: BP l43-l480C/250 ,u, glc (BSA derivative) = 99+%, yield = 100 ml (52.6%).

To a 500 ml flask fitted with stirrer, condenser and thermometer is added 43.0 g (0.2 mol) mono-tert-amine. 71.4 g (0.28 mol) bromododecane and 250 ml benzene. Some quaternary salt precipitates out of solution almost immediately.

The stirred mixture is heated to 85"C, when 1 drop 50% aq. NaOH is added as a catalyst. The mixture is then refluxed for 8 hours, yielding a hazy viscous solution.

Upon cooling and standing, a viscous semi-solid precipitates from solution. By treating the mixture with Et2O, distinct waxy white solid monododecyl bromide quaternary salt is obtained, which is collected via filtration, washed with solvent and dried in the vacuum oven: mp 85-880C, positive halogen test with AgNO2, very hygroscopic, yield = 50 g (54%), as represented by the formula:

C, H, N, Br analysis: Found: C 57.02 H 9.56 N 9.02 Br 17.44 Theory: C57.l3 H 9.59 N9.09 Br 17.28 IR Spectrum (solid film)= 3.17,3.42,3.5,5.67. 5.85, 6.81, 6.92, 7.04, 7.35, 7.87, 9.39, 12.99 EXAMPLE 9.

Preparation of Monobenzyl Quaternary Salt (XVI) To a 500 ml flask fitted with condenser, stirrer and thermometer is added 43.3 g (0.20 mol) mono-tert-amine from Example 8, 36.2 g (0.28 mol) benzyl chloride and 250 ml benzene. The mixture is stirred vigorously and heated at reflux for 3 hours. A white precipitate forms, which is collected via filtration, washed with solvent and dried in a vacuum oven. If desired, the monobenzyl chloride quaternary salt may be recrystallized from a mixture of isopropanol, ethyl ether and water to yield 50 g (73.5%) of a white solid having mp 243--244"C and the following structure and properties:

C, H, N, Cl analysis: Found: C 59.95 H 7.63 N 12.46 Cl 10.28 Theory: C 60.08 H 7.71 N 12.36 Cl 10.43 The product compounds of Examples 2 and 4 through 8 were tested for antibacterial and anti-fungal activity and compared to a known commercial broad spectrum bactericide/fungicide, according to the following procedure.

Samples of the compounds were prepared for testing by making a stock solution in sterile distilled water containing 10,000 parts per million. Serial dilutions of each sample were prepared in appropriate culture media which were then innoculated with the test cultures and incubated. The tests employing bacteria were performed in BBL Trypticase Soy Broth incubated for 48 hours at 350C. The tests employing A. niger were performcd in Difco Sabouraud Dextrose Broth incubated for five days at 260 C.

The test cultures were Staphylococcus aureus #6538, Pseudomonas aeruginosa # 9027 and Aspergillus niger #16404. The compounds of Examples 5 through 7 were found to be inactive at concentrations as high as 1,000 ppm. The results were set forth in Table I below.

TABLE I Test Culture and Results Active Concentration Staphylo- Pseudomonas Aspergillis Compound in parts per coccus aureus aeruginosa niger Example million #6538 #9027 16404 Compound 1000 0 0 0 XIIa 900 0 0 0 (Example 2) 800 0 0 0 700 0 0 0 600 0 0 0 500 0 0 0 400 0 + 0 300 0 + 0 200 0 + 0 100 0 + 0 50 0 - + 25 0 - + 12.5 + - + 6.25 + + 3.12 + - + Compound 100 0 0 0 XIa 50 0 0 0 (Example 8) 25 0 0 0 12.5 0 0 0 6.25 0 + 0 3.12 0 + 0 1.56 0 + + 0.78 0 + + 0.39 + + + 0.19 + + + Compound 1000 0 0 0 XV 900 0 0 0 (Example 8) 800 0 0 0 700 0 0 0 600 0 0 0 500 0 + 0 400 0 + 0 300 0 + 0 200 0 + 100 0 + + 50 0 - - 25 0 12.5 + + 6.25 + 3.12 + 1.56 + Comparative 1000 0 0 0 Sample* 900 0 0 0 800 0 + 0 700 0 + + 600 0 + + 500 0 + + 400 0 + + 300 :0 + + 200 0 + + 100 + + + - Denotes no test.

+ Denotes growth.

0 Denotes no growth.

* Dowcil 200 is a 1-(3-chloroallyl)-3,5,7-triaza-1-azonia adamantane chloride available from Dow Chemical Company (see U.S. Patent No. 3,228,829).

Dowicil is a Registered Trade Mark.

The minimum inhibitory concentrations are set forth in Table II below.

TABLE II Minimum Inhibitory Concentration (ppm) Example Example Example Dowicil Test Culture 2 4 8 200* Staph. Aureus 25 0.78 25 200 116538 Pseudo.aerugin 500 12.5 600 900 119027 Asperg. niger 100 3.12 300 800 1116404 *Dowicil 200 is a 143 chloroally1)-3,5,7-triaza-1-azonia adamantane chloride available from Dow Chemical Company (see U.S. Patent No. 3,228,829).

The invention in its broader aspects is not limited to the specific details shown and described, but departures may be made from such details within the scope of the accompanying claims without departing from the principles of the invention.

The invention may furthermore comprise, consist or consist essentially of the hereinbefore recited materials and steps.

WHAT WE CLAIM IS: 1. A hydantoin derivative having the formula:

wherein: R1 and R2, which may be the same or different, are selected from hydrogen, alkyl of l to-6 carbons, -Cn,H2n,OH, and

XC; provided that at least one of R, and R2 is

R3 and R4, which may be the same or different, are selected from hydrogen, alkyl of 1 to 6 carbons and phenyl or R3 and R4 taken together may be a cycloaliphatic group of 4 or 5 carbon atoms; R5, R6 and R7, which may be the same or different, are selected from benzyl and Cp H2p+1; X is a physiologically acceptable anion;

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (23)

**WARNING** start of CLMS field may overlap end of DESC **. The minimum inhibitory concentrations are set forth in Table II below. TABLE II Minimum Inhibitory Concentration (ppm) Example Example Example Dowicil Test Culture 2 4 8 200* Staph. Aureus 25 0.78 25 200 116538 Pseudo.aerugin 500 12.5 600 900 119027 Asperg. niger 100 3.12 300 800 1116404 *Dowicil 200 is a 143 chloroally1)-3,5,7-triaza-1-azonia adamantane chloride available from Dow Chemical Company (see U.S. Patent No. 3,228,829). The invention in its broader aspects is not limited to the specific details shown and described, but departures may be made from such details within the scope of the accompanying claims without departing from the principles of the invention. The invention may furthermore comprise, consist or consist essentially of the hereinbefore recited materials and steps. WHAT WE CLAIM IS:

1. A hydantoin derivative having the formula:

wherein: R1 and R2, which may be the same or different, are selected from hydrogen, alkyl of l to-6 carbons, -Cn,H2n,OH, and

XC; provided that at least one of R, and R2 is

R3 and R4, which may be the same or different, are selected from hydrogen, alkyl of 1 to 6 carbons and phenyl or R3 and R4 taken together may be a cycloaliphatic group of 4 or 5 carbon atoms; R5, R6 and R7, which may be the same or different, are selected from benzyl and Cp H2p+1; X is a physiologically acceptable anion;

n is an integer from 1 to 4; and p is an integer from l to 24.

2. A compound according to claim l wherein R, and R2, which may be the same or different, are

3. A compound according to claim l wherein: when R1 isCnH2nOH, R2 is

when R, is

R2 is -CnH2nOH

4. A compound according to claim l wherein: one of R, and R2 is hydrogen or alkyl of l to 6 carbon atoms and the other is

5. A compound according to Claim l wherein R3 and R4 are both methyl.

6. A compound according to Claim 1 wherein R5 and R6, which may be the same or different, are alkyl of l to 6 carbon atoms and R7 isCpH2p+, wherein p is an integer from 8 to 24.

7. A compound according to Claim 6 wherein X is bromine, R6 and R6 are methyl and p is from 12 to 18.

8. A compound according to Claim 3 having the formula:

wherein: R8 is-CnH2nOH, Z is a physiologically acceptable anion and n is as defined in claim l.

9. A compound according to Claim 8 having the general formula:

10. A compound according to Claim 8 having the formula:

11. A compound according to claim 2 having the formula:

12. A compound according to claim 2 having the formula:

13. A compound according to claim 2 having the formula:

14. A compound according to Claim 2 having the formula:

wherein Z is a physiologically acceptable anion.

15. A compound according to Claim 14 having the formula:

16. A compound according to Claim 4 having the formula:

wherein Z is a physiologically acceptable anion.

17. A compound according to Claim 16 having the formula:

18. A broad spectrum fungicidal and bactericidal composition containing as an active ingredient a fungicidally and bactericidally effective amount of a compound according to claims 8, 14 or 16, and a carrier for the active ingredient cmprising an inert solid diluent or an inert liquid diluent.

19. A cosmetic composition containing therein the compound of Claim 8, 14 or 16 in an amount sufficient to preserve the composition from prohibitive levels of fungal and bacterial infestations.

20. A soap bar containing a composition according to claim 19.

21. A method of combating undesired bactericidal and fungicidal infestations in cosmetic compositions which comprises incorporating therein a fungicidally and bactericidally effective amount of a compound according to Claims 8, 14 or 16.

22. A method of protecting the skin of non-human animals from bacteria and fungi which comprises applying to the skin a bactericidally and fungicidally effective amount of a compound according to Claims 8, 14 or 16.

23. A method of combating undesired fungicidal and bactericidal infestation in skin wounds in non-human animals which comprises applying to the locus of the skin wound a fungicidally and bactericidally effective amount of a compound as defined in Claims 8, 14 or 16.