DE1077218B - Process for the preparation of N, N-disubstituted piperazines effective against hookworm infections - Google Patents

Description

Process for the preparation of N, N-disubstituted piperazines effective against hookworm infections The invention relates to a process for the preparation of N, N-disubstituted piperazines of the general formula in which R is a phenyl radical or the pyridyl radical, optionally substituted by chlorine or methyl groups, R1 is hydrogen or an alkyl radical, Hal is a chlorine or bromine atom and X is hydrogen or a chlorine atom, which are particularly useful in the treatment of ankylostomiasis.

The disease ankylostomiasis, commonly known as hookworm, is common in warm countries, especially where there is a lot of shade and rain and a constant moist soil is present. The four main species of hookworm are nematodes, those belonging to the family Ancylostomadidae, such as Ancylostoma duodenale, Ancylostoma canium, Ancylostoma brasiliensis and Necator americanus, include. The hookworms invade usually through the skin of the animal, reach the capillaries, rise the Bronchial tree and migrate down the digestive system. The disease is in that southern part of the United States very common and often poses a problem of health care. It spreads especially where there is poverty and one-sided Diet predominate.

Until now it has been treated with compounds such as tetrachlorethylene. Tetrachloroethane, although quite effective, causes nausea and drowsiness.

Another commonly used compound is hexylresorcinol. These Compound is also effective to some extent, but it is irritating to the mucous membranes and is expensive.

Up until now, the treatment of hookworm infections has been in humans and animals introduced to starvation, the administration of an anti-helmintic, such as 2-naphthylthymol, Chenopodium oil, hexylresorcinol, tetrachlorethylene, etc., followed. DietoxiscllenAnthelmintica must get along with the hookworms from the body through the use of laxatives are excreted, whereas the N-haloacetylpiperazines prepared according to the process Can and always be given orally without starvation or the use of laxatives cause virtually complete disappearance of the hookworm infection.

The new substances are produced in a manner known per se by reacting an N-substituted piperazine of the general formula with a mono- or dihaloacetyl chloride of the general formula where the substituents R, R1, Hal and X have the meaning given.

The reaction is carried out at a low temperature, between -5 and +400 C, preferably between 0 and 100 ° C. in the generally one works in the presence of a solvent such as water, ether, petroleum ether, Acetone, benzene or ethyl acetate. If you work anhydrous, then you can Reaction product can be absorbed with water and, if desired, with alkali, around the relatively water-insoluble haloacetylpiperazine of the resulting Separate hydrochloride.

These compounds are generally crystalline solids, which are slightly soluble in the usual organic solvents and proportionally in water are insoluble.

The activity of the compounds prepared according to the invention against Hookworm is arguably more on the 1,4-substituents than on the piperazine structure in itself, since N, N-disubstituted piperazines with other substituents, such as 1-diethylcarbamyl-4-methylpiperazine, the thiocarbamyl analogs of these compounds and i-carbethoxy-4-methylpiperazine have no activity against hookworms.

The following examples illustrate the preparation of the substituted Haloacetylpiperazines.

Example 1 A solution of 1.5 g of 1-phenylpiperazine in about 50 ml dry ether were slowly stirred with 2g dichloroacetyl chloride, dissolved in 25 ml of dry ether added. A white product precipitated out.

Upon complete addition of the dichloroacetyl chloride, the white became Filtered off product, washed with dry ether and dried. The yield of 4-dichloroacetyl-1-phenylpiperazine was 2.7 g. After two recrystallization from dry ether, the compound melted at 129 to 1300 C.

Example 2 A solution of 39.2 g (0.2 mol) 1- (4-chlorophenyl) piperazine in 500 ml of dry benzene were added dropwise 16.2 g (0.1 mol) of dichloroacetyl chloride with stirring added. A white precipitate formed. When the addition was complete stirring continued for about 15 minutes. The precipitate was collected by filtration separated, washed with benzene and finally slurried in 300 ml of warm acetone, around the end product of the 1- (4-chlorophenyl) piperazine hydrochloride formed at the same time to separate. This acetone extraction was repeated several times, which combined Acetone solution dried, concentrated, cooled and the white precipitate formed filtered off. There was thus a yield of 27 g of 1- (4-chlorophenyl) -4-dichloroacetylpiperazine obtained from F. = 148 to 1500 C.

After purification by recrystallization from acetone and then from hot alcohol, the compound melted at 152 to 1530 C.

Example 3 A solution of 38 g (0.2 mol) of t- (2,6-dimethylphenyl) piperazine in 500 ml of dry ether, with stirring between 5 and 100 ° C., 16.2 g (0.1 mol) Dichloroacetyl chloride. dissolved in 100 ml of dry ether, added dropwise. A white precipitate formed. When the addition was complete, stirring was stopped continued for about 15 minutes. The precipitate was filtered off and washed with dry Ether washed. It was then slurried several times in 300 ml portions of warm acetone. the Acetone and ether solutions were combined, dried, to a small volume concentrated, mixed with hot ethanol, cooled and then filtered. It a crude yield of 26 g of a light colored product was obtained. For cleaning about 21 g of 4-dichloroacetyl-1- (2,6-dimethylphenyl) were recrystallized from hot alcohol -piperazine obtained. A small sample recrystallized for analysis had one Melting point from 96 to 970 C.

Example 4 A solution of 15 g (0.1 mol) of dichloroacetyl chloride in 300 ml of dry ether were added dropwise to 32.6 g (0.2 Mol) 1- (2-pyridyl) -piperazine, dissolved in 100 ml of dry ether, added, whereby a white precipitate formed. After the addition was complete, about 15 minutes were left stirred further, the precipitate filtered off and washed with ether. The ethereal solution (Filtrate) was saved. The white crude product was well slurried in water, filtered and washed with water, the 1- (2-pyridyl) piperazine hydrochloride was released. The insoluble residue became after air drying dissolved in ether. The combined ethereal solution was poured over anhydrous magnesium sulfate dried, concentrated to about a third of its volume, cooled in ice water and then filtered. 20.5 g of 4-dichloroacetyl-1- (2-pyridyl) piperazine were obtained from F. = 90 to 910 C. The mother liquor was converted into another 5 g of F. = 88 to 900 C received.

Example 5 A solution of 27 g of 1-phenylpiperazine in 400 ml of dry Ether was added dropwise at 5 to 100 C while stirring 20 g of dibromoacetyl chloride, dissolved in 100 ml of dry ether, added. The addition took about 0.5 hours Claim. A white precipitate separated out. Stirring was continued for 15 minutes continued after the addition was complete. The resulting precipitate was filtered off, washed with dry ether and then dried. Then he got in Slurried water and filtered off the water-insoluble portion and dried. Crude yield 29 g, m.p. = 1230 C (not spicy). After purifying the crude product recrystallization from acetone gave 18.5 g of 4-dibromoacetyl-1-phenylpiperazine from F. = 128 to 1290 C (with evolution of gas).

The 4-dibromoacetyl-1-phenylpiperazine is soluble in acetone, alcohol, Ether and chloroform, but insoluble in petroleum ether with a boiling range of 20 up to 400 C and water.

Example 6 To a solution of 32.4 g of 1-phenylpiperazine in 500 ml dry ether was added dropwise between 0 and +50 C with stirring 11.3 g of chloroacetyl chloride, dissolved in 50 ml of dry ether, added.

A white precipitate formed. After the addition is complete stirring was continued for a further 15 minutes. The resulting precipitate was filtered off and washed with dry ether. This crude product was 1-phenylpiperazine hydrochloride.

The filtrate (ether solution) was with a 10 / above sodium hydroxide solution washed to rid it of hydrochlorides. The ethereal solution was then concentrated, cooled, and the precipitated 4-chloroacetyl-1-phenylpiperazine was filtered off and washed with cold, dry ether. The yield was 10 g; F. = 80 to 810 C. The 4-chloroacetyl-1-phenylpiperazine is very soluble in acetone, in alcohol and chloroform soluble, in petroleum ether boiling from 20 to 400 C and Insoluble in water and partially soluble in ether.

Example 7 A solution of 1.9 g of N-phenyl-2,6-dimethylpiperazine in 25 ml of dry benzene were 0.6 g of dichloroacetyl chloride dissolved in 15 ml of dry Benzene, added. Then it was heated on the steam bath for about 10 minutes. The solution was cooled and then distilled, leaving a gummy residue. The latter was slurried in dry acetone, leaving a white, insoluble Precipitation developed. This acetone-insoluble fraction was suspended in water, filtered and dried; F. = 259 to 2620 C (with decomposition). After cleaning recrystallization from hot alcohol gave a yield of about 0.3 g of 4-dichloroacetyl - 1 - phenyl - 2,6 - dimethylpiperazine hydrochloride from F. = 262 to 2640 C (below Decomposition).

Example 8 To a solution of 1578 g cooled to 0 to + 100 ° C N-phenylpiperazine in 10 1 of water were added dropwise with simultaneous stirring 1578 g of dichloroacetyl chloride and 550 g of an 850 / above sodium hydroxide solution, dissolved in 1.5 l of water. The rate of addition was set so that that the solution always remained slightly alkaline. During the addition of the dichloroacetyl chloride a white precipitate formed. After the addition was complete, about Stirred for 15 minutes. The white precipitate was filtered off and washed free of alkali and dried. This crude product was recrystallized from 5.5 liters of alcohol and so on 620 g of 4-dichloroacetyl -1-phenylpiperazine with a melting point of 128 to 1300 ° C. were obtained. By another recrystallization from alcohol melted the compound at 129-1300 C.

Experimental results of 29 street dogs of various kinds Age, weight and breed were orally bred with a thousand hookworm larvae (Ancylostoma canium).

5 days later these dogs were divided into three groups of seven and split a group of eight. A group of 8 to 9 kg dogs were used 100 mg daily 4-dichloroacetyl-1-phenylpiperazine, which is hand mixed with 0.453 kg canned dog food had been mixed, administered. A group of 7 kg dogs were taken 200 mg daily and a group of 6 kg heavier 300 mg daily. The approximate daily doses were therefore 10, 25 and 50 mg / kg. The remaining eight dogs were fed with canned dog food without the addition of the active ingredient. All administrations were performed daily with the exception of the 6th, 7th, 34th and 35th day.

All dogs were taken for three consecutive days The 3rd, 4th, 5th and 6th week of treatment collected fecal samples and the number of eggs determined quantitatively using the Stoll dilution technique. This technique is a standard method of measuring the number of hookworm eggs per unit weight Feces that are a qualitative Approximation of the number of adults present in the intestine Worms.

For all three groups of dogs treated, the total number was the hookworm eggs compared with the untreated controls during one 6 weeks of continued feeding markedly reduced. Individual Differences were more noticeable at doses of 10 mg / kg, suggesting this allows this value to come close to the minimum effective dose.

After 6 weeks there were no hookworm eggs in those at 25 and 50 mg / kg treated groups found more.

In the case of the dogs, who daily use all of the active ingredient Had eaten food, there were no unpleasant symptoms associated with the active ingredient could be attributed. They also accepted the food without hesitation. The following The table contains an overview of the results.

Effect of 4-dichloroacetyl-1-phenylpiperazine on experimental hookworm infections in dogs when administered daily in the diet at doses of 10, 25 and 50 mg / kg Daily hookworm eggs per g of feces Dog dose treatment vodien 4649 L. No. mg / kg 1 3. 1 4. 1 5. 1 6. 25 10 6200 6700 3800 3500 53 10 0 100 0 100 46 10 200 300 0 0 67 10 0 0 0 0 61 10 3700 2800 700 600 52 25 1600 1900 100 0 50 25 800 900 300 0 44 25 400 100 100 0 66 25 1700 300 900 0 42 50 0 0 0 0 41 50 0 0 0 0 60 50 300 0 0 0 39 50 0 0 0 0 (Kon- 49 trolls) 1000 5100 4800 7100 45 - 10200 35400 7900 32700 68 - 5700 7000 4900 14800 40 - 5200 4100 7900 5900 63 - 2000 9300 3800 18500 58 - 6600 16500 26200 21100

Claims (1)

PATENT CLAIM: Process for the preparation of N, N-disubstituted piperazines of the general formula that are effective against hookworm infections in which R is a phenyl radical or the pyridyl radical, optionally substituted by chlorine or methyl groups, R1 is hydrogen or a methyl radical, Hal is a chlorine or bromine atom and X is hydrogen or a chlorine atom, characterized in that piperazines of the general formula are used in a manner known per se with a mono- or dihaloacetyl chloride of the general formula where the substituents R and Rl, Hal and X have the meanings given above. Considered publications: German Patent Specifications No. 887 043, 844 744, 833 962, 825 840; »J. of org. Chemistry ", Vol. 13 (1948), pp. 134ff .; »J. of Am. chem. Soc. ”, Vol. 76 (1954), p.4991ff.