2-Chloro-4-(4-lower alkyl-1-piperazinyl)benzenemethanol, N.sup..omega. -oxides and methods for their preparation

2-Chloro-4-(4-lower alkyl-1-piperazinyl)benzenemethanol, N.sup..omega. -oxides and their acid addition salts. These compounds are prepared by oxidizing the corresponding 2-chloro-4-(4-lower alkyl-1-piperazinyl)benzenemethanol. In addition, pharmaceutical compositions comprising said N-oxides and methods for treating schistosomiasis are disclosed.

SUMMARY AND DETAILED DESCRIPTION 
The present invention relates to new organic piperazine-N-oxides useful in 
the treatment of schistosomiasis. More particularly, the invention relates 
to compounds of the formula 
##STR1## 
and acid addition salts thereof wherein R is methyl, ethyl, propyl or 
isopropyl; preferably where R is methyl. 
In accordance with the invention, the compounds of formula I and acid 
addition salts thereof, are prepared by oxidizing a compound of the 
formula 
##STR2## 
wherein R is as previously defined for formula I, and adjusting the pH to 
give the N-oxide or a salt thereof, as desired. The oxidation is generally 
carried out employing a peroxy acid, such as 3-chloroperbenzoic acid, 
perbenzoic acid, peracetic acid, etc. or hydrogen peroxide. Generally, 
about equimolar amounts of oxidizing agent and substrate are employed. 
The reaction is carried out at from about -20.degree. C. to about 
40.degree. C. for from about a couple of minutes to about 24 hours, 
preferably about 0.degree. C. to 25.degree. C. for about one hour. 
Advantageously, the oxidation is effected in an inert solvent such as 
hydrocarbons, chlorinated hydrocarbons, alkanols, aliphatic ketones, 
water, etc. 
The starting materials of the formula II are prepared according to the 
procedures described in U.S. Pat. No. 3,714,167. 
The term acid addition salt is intended to mean salts formed by the 
addition of an acid, such as hydrochloric acid, sulfuric acid, benzoic 
acid, acetic acid, etc. The preferred salts are relatively non-toxic salts 
which are generally termed pharmaceutically acceptable salts. 
The compounds of this invention may exist in anhydrous form as well as 
solvated, including hydrated, forms. In general, the solvated forms are 
equivalent to the anhydrous or unsolvated form for the purposes of this 
invention. 
The compounds of this invention have the specific advantage over the 
corresponding des-N-oxide compounds in that the compounds are 
non-mutagenic in a test designed to determine mutagenicity which is 
described in J. Pharm. Exp. Therap., 200, 1 (1977). 
In addition, the compounds of the invention are significantly less toxic 
when administered via the intramuscular route than the corresponding 
des-N-oxide. 
In accordance with the invention, oral pharmaceutical compositions are 
produced by formulating a compound of the invention, optionally with other 
active ingredients, in dosage unit form with a pharmaceutical carrier. 
Some examples of dosage unit forms are tablets, capsules, lozenges, and 
pills; as well as powders and aqueous and non-aqueous solutions and 
suspensions packaged in containers containing either one or some larger 
number of dosage units and capable of being sub-divided into individual 
doses by such means as measurement into a teaspoon or other standard 
container. Some examples of suitable pharmaceutical carriers, including 
pharmaceutical diluents, are gelatin capsules; sugars such as lactose and 
sucrose; starches such as corn starch and potato starch, cellulose 
derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, 
methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic 
acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed 
oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene 
glycol; glycerine, sorbitol; polyethylene glycol; water; agar; alginic 
acid; as well as other compatible substances normally used in 
pharmaceutical formulations. The compositions of the invention can also 
contain other components such as coloring agents, flavoring agents, and/or 
preservatives. These materials, if present, are usually used in relatively 
small amounts. The compositions can, if desired, also contain other 
therapeutic agents. 
The percentage of the active ingredient in the foregoing compositions can 
be varied within wide limits but for practical purposes it is preferably 
present in a concentration of at least 10% in a solid composition and at 
least 2% in a primarily liquid composition. The most satisfactory 
compositions are those in which a much higher proportion of the active 
ingredient is present. The compositions of the invention preferably 
contain from 1 to 500 mg., preferably 5 to 100 mg., of the active 
ingredient per dosage unit so that the entire amount to be administered 
during a day can be made up from a reasonable number of dosage units. 
The compounds of the invention may be administered parenterally, especially 
intramuscularly, in a suitable vehicle, such as isotonic saline solution, 
which may contain other active ingredients, buffering agents, 
preservatives, etc. 
The aforementioned compounds are administered in dosage unit form, with the 
dose adjusted to the needs and tolerances of the individual patient. The 
usual mammalian dosage range for a 70 kg. subject is from 10 to 1000 mg. 
per day (0.1 mg. to 14 mg. per kg. of weight per day), preferably 50 to 
250 mg. per day (0.7 mg to 3.6 mg. per kg. of weight per day), optionally 
in divided portions.

Preparation of the novel compounds is shown in the following illustrative 
examples: 
EXAMPLE 1 
A solution of 5.0 g of 3-chloroperoxybenzoic acid in 50 ml of chloroform is 
added slowly with stirring to a solution of 5.0 g of 
2-chloro-4-(4-methyl-1-piperazinyl)benzenemethanol in 50 ml of chloroform. 
After stirring 0.5 hr the solution is extracted with 5% potassium 
carbonate. The aqueous extracts are then placed on a column of Amberlite 
XAD-2 resin. The column is washed with water, and then with methanol. 
Concentration of the methanol eluate gives a clear, colorless oil. Upon 
standing, crystallization occurs, yielding 3.0 g of the desired 
2-chloro-4-(4-methyl-1-piperazinyl)benzenemethanol, N.sup..omega. -oxide, 
mp 224.degree.-226.degree. C. (decomposition). 
The hydrochloride salt may be prepared as follows: A solution of 0.43 g of 
hydrogen chloride in 2 ml of 2-propanol is added dropwise with stirring to 
3.0 g of 2-chloro-4-(4-methyl-1-piperazinyl)benzenemethanol, N.sup..omega. 
-oxide dissolved in 25 ml of 2-propanol. Upon dilution with ether and 
cooling the desired 2-chloro-4-(4-methyl-1-piperazinyl)benzenemethanol, 
N.sup..omega. -oxide, monohydrochloride precipitates. 
EXAMPLE 2 
A solution of 1.36 g of 3-chloroperoxybenzoic acid in 15 ml of chloroform 
is added dropwise with stirring to a solution of 2.0 g of 
2-chloro-4-(4-ethyl-1-piperazinyl)benzenemethanol in 35 ml of chloroform. 
After stirring 1 hr at room temperature, an additional 0.43 g of 
3-chloroperoxybenzoic acid is added. The solution is then extracted with 
aqueous sodium carbonate. The aqueous layers are placed in a column of 
Amberlite XAD-2 resin. The column is washed with water and then methanol. 
Concentration of the methanol eluate yields the desired 
2-chloro-4-(4-ethyl-1-piperazinyl)benzenemethanol, N.sup..omega. -oxide. 
Crystallization from ether gives 0.82 g of the hemihydrate, mp 
183.degree.-185.degree. C. (decomposition). 
EXAMPLE 3 
A solution of 3.1 g of 3-chloroperoxybenzoic acid in 30 ml of chloroform is 
added dropwise at 0.degree. C. to a solution of 4.04 g of 
2-chloro-4-[4-(1-methylethyl)-1-piperazinyl]benzenemethanol in 90 ml of 
chloroform. After stirring 0.5 hr the solution is washed with 20 ml of 
saturated aqueous potassium carbonate. The chloroform layer is then dried 
over solid potassium carbonate and concentrated to dryness. 
Recrystallization from 2-propanol gives 0.7 g of 
2-chloro-4-[4-(1-methylethyl)-1-piperazinyl]-benzenemethanol, 
N.sup..omega. -oxide, mp 167.degree. C. (decomposition), as colorless 
crystals. 
Alternatively, purification can be achieved through chromatography. A 
methanol solution of 3 g of crude 
2-chloro-4-[4-(1-methylethyl)-1-piperazinyl]benzenemethanol, N.sup..omega. 
-oxide is placed in a column of 300 g of silica gel and eluted with 
methanol. The appropriate fractions are combined on the basis of thin 
layer chromatography, and concentrated to dryness. There is obtained 2 g 
of 2-chloro-4-[4-(1-methylethyl)-1-piperazinyl]benzenemethanol, 
N.sup..omega. -oxide, essentially identical with that obtained above. 
The compounds of the invention are useful in the treatment of 
schistosomiasis. Compounds of this invention, when placed in the primary 
screen in mice described in Am. J. Trop. Med. Hyg., 21, 302 (1972) yielded 
the following data which is reported in Table I: 
TABLE 1 
__________________________________________________________________________ 
Effects of Single Oral Doses (Aqueous Solutions ) of 2-Chloro- 
4-(4-alkyl-1-piperazinyl)benzenemethanol, N.sup..omega. -oxides Against 
Mature S. mansoni Infections in Mice 
##STR3## 
% % 
Dose 
Reduction 
Mice 
No. of 
R Schistosome Strain 
mg/kg 
Live Worms 
Cured 
Tests 
__________________________________________________________________________ 
CH.sub.3 
Puerto Rican/Michigan 
300 99 87 1 
CH.sub.3 
Puerto Rican/Michigan 
75 90 52 5 
CH.sub.3 
Puerto Rican/Michigan 
40 79 43 11 
CH.sub.3 
Puerto Rican/Sterling Winthrop 
75 69 60 5 
CH.sub.3 
Puerto Rican/Sterling Winthrop 
40 56 33 3 
CH.sub.3 
Puerto Rican/Walter Reed 
100 100 100 2 
CH.sub.3 
St. Lucian 150 16 0 2 
CH.sub.3 
Brazilian 40 88 51 3 
CH.sub.3 
Brazilian 20 73 0 1 
CH.sub.3 
Liberian 50 25 0 2 
C.sub.2 H.sub.5 
Puerto Rican/Michigan 
75 92 71 1 
CH(CH.sub.3).sub.2 
Puerto Rican/Michigan 
125 90 57 1 
CH(CH.sub.3).sub.2 
Puerto Rican/Michigan 
75 100 100 1 
CH(CH.sub.3 (.sub.2 
Puerto Rican/Michigan 
40 57 19 5 
CH(CH.sub.3).sub.2 
Puerto Rican/Sterling Winthrop 
75 25 0 1 
CH(CH.sub.3).sub.2 
Puerto Rican/Walter Reed 
75 85 72 1 
CH(CH.sub.3).sub.2 
Puerto Rican/Walter Reed 
40 96 75 1 
CH(CH.sub.3).sub.2 
St. Lucian 75 75 57 1 
CH(CH.sub.3).sub.2 
St. Lucian 40 50 0 1 
CH(CH.sub.3).sub.2 
Brazilian 40 32 0 1 
CH(CH.sub.3).sub.2 
Liberian 125 100 100 1 
CH(CH.sub.3).sub.2 
Liberian 75 42 0 2 
__________________________________________________________________________ 
The preferred compound of the invention, when placed in a secondary test in 
monkeys described in Am. J. Trop. Med. Hyg. 15, 705 (1966) gave the 
following data: 
TABLE II 
______________________________________ 
Effects of 2-chloro-4-(4-methyl-1-piperazinyl)benzenemethanol, 
N.sup..omega. -oxide Against Mature S. mansoni (Puerto Rican/Walter Reed 
Strain) Infections in Monkeys (Cebus apella) 
##STR4## 
% Final 
Dose Reduction Egg 
mg/kg Live Worms Count 
______________________________________ 
50 .times. 4 92 0 
50 .times. 4 91 0 
______________________________________ 
The absence of mutagenic activity is shown in the trials reported in the 
following table: 
TABLE III 
__________________________________________________________________________ 
Mutagenic Activity Using Salmonella typhimurium (TA-98 and TA-100) 
##STR5## 
Revertants per n mole 
In Vitro Mouse Urine Host 
TA-98 TA-100 TA-98 TA-100 
Mediated 
R N-oxide 
-S.sub.9 
+S.sub.9 
-S.sub.9 
+S.sub.9 
-S.sub.9 
+S.sub.9 
-S.sub.9 
+S.sub.9 
TA-98 
TA-100 
__________________________________________________________________________ 
CH.sub.3 
Yes -- -- -- -- -- -- -- -- -- -- 
CH.sub.3 
No -- -- -- 0.1 
CH(CH.sub.3).sub.2 
Yes -- -- -- 0.007 
__________________________________________________________________________ 
" --" indicates result not significantly different than control 
In addition, the compounds of the invention are significantly less toxic 
when administered via the intramuscular route than the corresponding 
des-N-oxide. 
The reduced toxicities of the N-oxides are shown in the following table: 
TABLE IV 
______________________________________ 
Approximate Acute Intramuscular LD.sub.50 
Values in Uninfected Mice 
##STR6## 
des 
R N-oxide N-oxide 
______________________________________ 
CH.sub.3 1500 200 
C.sub.2 H.sub.5 
&gt; 250 150 
CH(CH.sub.3).sub.2 
&gt;1500 100 
______________________________________ 
It will be appreciated that the instant specification and examples are set 
forth by way of illustration and not limitation, and that various 
modifications and changes may be made without departing from the spirit 
and scope of the present invention.