US2755279A - I-alkyl z - Google Patents

Description

United States Patent l-ALKYL 2,5-DIMETHYL PIPERAZINES Richard Baltzly and Marion B. Sherwood, Westchester County, N. Y., assignors to Burroughs Wellcome & Co. g1. A.) Inc., Tuckahoe, N. Y., a corporation of New No Drawing. Application April 20, 1953, Serial No. 349,964

Claims priority, application Great Britain May 30, 1952 6 Claims. (Cl. 260-268) This invention relates to a group of N-alkyl substituted 2,5-dimethyl piperazines the members of which have unusual antibacterial and especially antifungal activity combined with relatively moderate toxicity. In the investigation of antifungal compounds a number of substituted piperazines have been studied. The known N-n-decyl and N-lauryl piperazines are fairly good fungicides as well as moderately strong disinfectants, the former being somewhat preferable. Activity falls ofi with the lower members and also with the higher members of the series. The corresponding derivaties of 2,5-dirnethylpiperazine which are the subject of the present invention while somewhat similar are found to possess definite advantages both as compared to the previously known and mentioned N- alkyl piperazines and as compared to other known fungicides.

One of the outstanding advantages of these l-alkyl- 2,5-dimethylpiperazines, is that their fungicidal activity is only slightly diminished by the presence of protein material. For example, the concentration required to kill typical test organisms, such as Trichophyton interdigitale, Epidermatophyton floccosum and Monilia albzcans, is not much higher in the presence of blood serum than in its absence.

As compared to the corresponding l-alkylpiperazines, the compounds of this invention are consistently as active or more active as fungicides, are somewhat less toxic intraperitoneally (about 10%) and are markedly less toxic when taken orally. For example, the oral LD-50 in mice of 1-lauryl-2,S-dimethylpiperazine dihydrochloride is 1350 mg./kg. while that of l-laurylpiperazine dihydrochloride is 725 mg./kg. Such variation in oral toxicity, while of small concern for purely external application is of considerable interest if the fungicide is to be used against monilia infections of the throat and digestive tract, which infections are increasingly prominent of recent years apparently as a result of the use of antibiotics in the treatment of bacterial infections.

The compounds of this invention may be represented by the formula:

wherein R is an alkyl group of 10 to 14 carbon atoms. It will be observed that the methyl groups are in the transposition. These compounds are capable of existence as d and l stereo-isomers but a resolution has not been accomplished up to the present. The bases are viscous oils or low melting solids, distillable in vacuo. Salts, especially di-hydrochlorides, are crystallizable from alcohol-ether mixtures or the like. Mono-hydrochlorides, which give approximately neutral solutions when dissolved in water, are isolable but are not readily crystallized. On

'ice

the other hand, such neutral solutions are quite satisfactory for therapeutic application.

The bases are conveniently prepared by refluxing 2,5- dimethyl piperazine with the appropriate alkyl halide in alcoholic solution. In practice we use about alcohol but other concentrations of alcohol or other solvents of similar dielectric constants are equivalent. It is desirable that the concentration of water should be low enough to prevent formation of a separate layer by the alkyl halide and high enough to prevent excessive precipitation of salts. The proportions of reactants are not critical but better utilization of alkyl halide is obtained if an excess of dimethyl piperazine is present. It is also advantageous, though not necessary, to neutralize the dimethyl piperazine partially at the start so that mainly a monovalent cation {Ha mug /NH) is present and to add small amounts of a base (sodium bicarbonate) during the course of the reaction maintaining a pH of about 8. In this manner the formation of N,N'-dialkyl piperazine is minimized. Below pH 6.5-7.0, however, the rate of alkylation is inconveniently slow wherefore it is not feasible to suppress dialkylation completely. The complete buffering of this alkylation reaction would be desirable but is not in fact convenient. Phosphates form insoluble precipitates with the starting base; acetates tend to react with the alkyl halide which is usually the most expensive reagent. 'Probably the most economical procedure isto employ an excess (2,3-equiv.) of dimethylpiperazine. The unreacted dimethylpiperazine can be recovered on a commercial scale, While N,N- dialkylated material is of no further value.

When the reaction is largely finished (which is shown by the pH remaining constant) most of the alcohol is boiled ofl, alkali is added, and the reaction mixture is partitioned between ether and water, the ethereal layer being washed with water until the washings are nearly neutral (pH 78). The ethereal layer is then extracted with dilute hydrochloric acid (ca; 1 N), which extracts first the salts of the most soluble base. By taking the acid in portions it is possible to get the bulk of the mono-N-alkyl base into aqueous solution as the monohydrochloride accompanied by very little of the N,N'- dialkyl compound. When solid appears in the separatory funnel it is advantageous to add an excess of hydrochloric acid whereby most of the N,N-dialkyl piperazine separates as the dihydrochloride and can be filtered off, the aqueous portion of the filtrate being added to the previous aqueous extracts. These combined extracts are then basified and the base is taken into ether, dried over potassium carbonate and distilled in vacuo. Yields average between 50 and 60%.

In addition to valuable activity against microorganisms the mono-N-alkyl compounds of this family are of value as intermediates since they can be converted to urethanes, ureas, guanidines and the like.

EXAMPLE 1 2,5-dimethyl-1-n-decylpiperazine Thirty-four and one-half g. (0.3 mole) of 2,5-dimethyl piperazine was dissolved in 200 cc. of ethanol and 9 cc. (0.15 mole) of acetic acid was added. To this was added 60 g. (0.22 mole) of n-decyl iodide and the solution was refluxed twenty-five hours. At the start the pH was about 9 and this had fallen to 7 after 35 minutes. Sodium bicarbonate (12.5 g.=0.15 mole) was added in portions over the next half-hour. At the end of the reflux period most of the alcohol Was boiled ofi. Water and sodium hydroxide solution was added to give a volume of about 200 cc. and the mixture was thoroughly extracted with ether. The ethereal layer was washed with water until the washings were neutral and extracted first with 80 cc. of N hydrochloric acid, then with 40 cc. In this second extraction some solid appeared. The ethereal layer was then shaken with 200 cc. of N hydrochloric acid. The resultant suspension was filtered and washed with water and ether. The solid (2,5-dimethyl-1,4-didecyl piperazine dihydrochloride) when dried weighed 20.5 g. (0.043 mole The ethereal layer on evaporation left 7.5 g. of neutral residue (in the main, decyl acetate). The aqueous layers containing water-soluble salts of the bases were united and basified. The oily base was taken into ether, dried on potassium carbonate and distilled in vacuo. The 2,5-dirnethyl-l-n-decyl piperazine base boils at 115-122 at 1 mm. and forms a dihydrochloride (fiattish needles) that melts at 233-233.5 C. The yield was 27 g. (0.11 mole) or 55% calculated on the decyl iodide used.

EXAMPLE 2 2,5-dimethyl-1-n-Imdecylpiperazine The procedure of Example 1 was followed in the reaction of 47 g. (0.2 mole) of n-undecyl bromide with 0.25 mole of 2,5-dimethylpiperazine. The 2,5-dimethyll-n-undecylpiperazine obtained weighed 28.5 g. (0.105 mole or 52.5%), boiled at 135-136" C. at 1 mm. and formed a dihydrochloride melting at 228. The yield of N,N'-diundecyl base was 0.03 mole and the neutral fraction weighed 11 g.

EXAMPLE 3 2,5-dimethyl-I-laurylpiperazine Thirty g. (0.26 mole) of 2,5-dimethylpiperazine was reacted by the method of Example 1 with 3.5 g. (0.014 mole) of lauryl bromide 26 g. (0.13 mole of lauryl chloride and g. of sodium iodide). No acetic acid or sodium bicarbonate was added. The neutral fraction on working up weighed only 1 g. The insoluble dihydrochloride fraction (2,5-dimethyl-1,4-dilaurylpiperazine dihydrochloride) weighed 10.5 g. (0.02 mole) and the mono-N-alkyl product, which boiled at 142-143 C. (at 1 mm.) weighed 24 g. (60%) based on the alkyl halide used. The dihydrochloride forms platelets and melts at 229-231 C.

EXAMPLE 4 1-tetradecyl-2,5-dimethylpiperazine Thirty-nine grams of 2,5-dimethylpiperazine was disthe pH to 7).

solved in 300 cc. of ethanol and partly neutralized with 25 cc. of concentrated hydrochloric acid (bringing The solution was heated to reflux with stirring and g. of crude tetradecyliodide was admitted gradually through a dropping funnel at such a rate as to minimize separation of layers. Sodium bicarbonate was added at intervals to keep the pH 7 to 7.5. The reaction time was about 20 hours after which the bulk of the alcohol was boiled off and the residual material was worked up as described in Example 1. There was ob tained 7 g. of neutral material, 43 g. of 1,4-ditetradecyl- 2,5-dimethylpiperazine dihydrochloride and 42 g. of 1- tetradecyl-2,5 dimethylpiperazine base which boils at about at 1 mm. pressure. It forms a dihydrochloride that melts with decomposition at 234 C.

We claim:

1. Compounds of the formula wherein R is an alkyl group of from 10 to 14 carbon atoms, which comprises reacting an appropriate alkyl halide with trans 2,5-dimethyl piperazine.

References Cited in the file of this patent UNITED STATES PATENTS Stoehr July 17, 1894 Buck et al. Feb. 11, 1947 Hultquist et al. July 24, l95l

Claims (2)

1. COMPOUNDS OF THE FORMULA

6. A METHOD OF FORMING COMPOUNDS OF THE FORMULA