Method and composition for treating helminths containing O,O-dialkyl-N-(substituted phenyl)aminothiocarbonyl phosphoramidates

Phosphoramidates and salts and salt complexes useful as anthelmintics are disclosed. The products are prepared by treating an aminobenzene with an appropriately substituted isothiocyanatoate.

FIELD OF THE INVENTION 
This invention relates to phosphoramidates and salts and salt complexes, to 
processes for making such compounds, to methods of treating helminth 
infections and to anthelmintic compositions containing them. 
DESCRIPTION OF THE PRIOR ART 
There are numerous patents describing phosphoramidates and salts thereof 
including U.S. Pat. Nos. 4,139,614; 3,957,924; 3,393,253; 3,384,683; 
3,476,837; 3,887,657; and 3,975,522; German Pat. Nos. 1,139,494; 
2,114,885; 957,712 and 2,260,719. However none of these patents disclose 
or suggest the compounds of this invention. 
An object of this invention is to provide a new class of phosphoramidates 
(I, infra), methods for preparing these compounds, compositions containing 
said compounds and to their use as anthelmintic agents. 
The novel phosphoramidates (I, infra) of this invention have the following 
structural formula: 
##STR1## 
R.sup.1 and R.sup.2 is the same or different group selected from alkyl for 
example lower alkyl of from 1 to 6 carbon atoms such as methyl, ethyl, 
n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl and 
the like; and X is phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxy or 
styryl and the agronomically acceptable metal salts and metal salt 
complexes thereof. 
When compounds of General Formula I can exist in various isomer and 
stereoisomer forms all such isomers and their mixtuures and racemates are 
includes within the scope of this present invention. 
PREFERRED EMBODIMENT 
A preferred embodiment of this invention relates to the 2-substituted 
phosphoramidates (Ia, supra) of the following structural formula: 
##STR2## 
X is as defined above; R.sup.3 and R.sup.4 are lower alkyl of from 1 to 4 
carbon atoms and zinc salts and zinc metal complexes thereof. These 
compounds exhibit particularly good anthelmintic activity. 
The phosphoramidates (I, supra) of this invention are prepared by treating 
the corresponding 2-amino-substituted benzene deriv. (II, infra) with an 
appropriately substituted isothiocyanatoate. The reaction may be conducted 
at a temperature in the range of from 0.degree. C. to 60.degree. C. for a 
period of time from a few minutes to about three hours. Any solvent in 
which the reactants are reasonably soluble and substantially inert may be 
employed. Suitable solvents include dimethyl formamide (DMF), acetone, 
diethyl ether, 1,2-dimethoxy ethane and the like. The following equation 
illustrates this process: 
##STR3## 
wherein R.sup.1, R.sup.2 and X are as defined above. 
The metal salts of this invention are the alkali metal, alkaline earth 
metal and transition metal salts of the compounds of Formula I. The 
preferred metal salt is the zinc salt. 
The metal salt complexes of this invention can be represented by the 
following formula which is presented for illustrative purposes only: 
##STR4## 
wherein R.sup.1, R.sup.2, and X are as defined above, M is a metal cation 
which can be selected from Groups IIA, IIIA, IB, IIB, VIIB and VIII of the 
Periodic Table; W is an anion such as chloride, bromide, iodide, sulfate, 
bisulfate, phosphate, nitrate, perchlorate, carbonate, bicarbonate, 
hydroxide, acetate, oxalate, malate, citrate and the like; m is an integer 
of 1-2; n is an integer of 1 to 3; and n' is an integer of 0-4. 
Among the compounds depicted by Formula III above, the preferred compounds 
are those wherein the metal cation is a transition metal such as copper, 
zinc, nickel, cobalt, tin, cadmium, or manganese; or an alkaline earth 
metal such as calcium or magnesium and wherein the anion is chloride, 
bromide, nitrate, sulfate or hydroxide. The most preferred salts are those 
wherein the metal cation is copper, zinc, nickel, cobalt, tin, cadmium or 
manganese, and the anion is hydroxide. 
The alkali and alkaline earth metal salts of this invention are prepared by 
(1) adding an alkali or alkaline earth metal hydroxide or hydride to a 
suspension of the phosphoramidate in a suitable solvent, (2) stirring the 
mixture until a solution forms, and (3) freeze drying the solution, or in 
the alternative, (4) concentrating the solution in vacuo at room 
temperature and drying the residue in a vacuum oven at room temperature. 
The metal salt complexes and transition metal salts are prepared in 
substantially the same manner varying the molar ratios of the metal salt 
employed by (1) reacting, in an aqueoous or alcoholic medium an alkali 
metal salt of a phosphoramidates of this invention, with a metal salt 
selected from Group IIA, IIIA, IB, IIB, VIIB, or VIII of the Periodic 
Table, (2) filtering off the precipitate which forms, and (3) washing and 
drying the precipitate to give the product. This method is more fully 
described in U.S. Pat. No. 4,139,614. 
The phosphoramidates of Formula I are anthelmintics and have broad spectrum 
activity against parasites of animals especially warm blooded animals, 
including both mature and immature parasitic forms. In particular, these 
compounds exhibit high activity against various helmintic infections of 
the intestinal tract of economically important animals, coupled with low 
systemic toxicity to the host animal. 
For example, the disclosed compounds are generally effective in clearing 
mice of worm infections for laboratory purposes, among others: Syphacia 
obvelata and 
Aspilcularis tetraptera (mouse pinworm), the migratory stages of Ascaris 
suum, Hymenolepsis nana and Nematospiroides dubius. 
Animals of low weight are treated with unit doses ranging no higher than a 
few milligrams; whereas, animals of higher body weight, require 
proportionately larger unit doses ranging up to several grams. Preferably, 
a single dose is administered for each animal species based on the weight 
of that species. 
The amount of ingredient administered will depend on the weight of the 
host, but will usually be a unit dosage between about 1 mg./kg. and 125 
mg./kg. of body weight. It is contemplated that dosage units containing 
the compounds of Formula I of this invention as the essentially active 
ingredient will be administered, orally or by injection, in the treatment 
and control of helmintic infections in domestic animals such as sheep, 
cattle, horses, dogs, cats, fish, swine and goats and also in man. 
When used as an anthelmintic agent for the treatment and/or prevention of 
helminthiasis, the novel compounds of Formula I of this invention may be 
administered orally in a unit dosage form such as a paste, gel, capsule, 
bolus, tablet or as a liquid drench. They may also be administered orally 
by intimately dispersing them in an animal feedstuff or by using them as a 
top dressing or in the form of pellets which are added to a finished feed. 
Alternatively, they may be administered to animals in a liquid carrier 
vehicle by intraruminal, intramuscular and intratracheal injection. The 
quantity of active material required to give best anthelmintic response 
will depend upon the particular compound employed, the species of animal 
to be treated and the type and severity of helminth infection. Good 
results are usually obtained when there is administered a total dose of 
from about 1 to about 125 mg. of active ingredient per kg. of animal body 
weight. Such total dose may be given at one time or in divided doses over 
a short period of time such as 1 to 2 days.

The following examples illustrate the compounds of this invention and the 
methods by which they are prepared. However, the examples are illustrative 
only and it will be apparent to those having ordinary skill in the art 
that all of the products embraced by Formula I, supra, may also be 
prepared in an analogous manner by substituting the appropriate starting 
materials for those set forth in the examples. 
EXAMPLE 1 
O,O-Diethyl-N-(2-phenoxyphenyl)aminothiocarbonyl phosphoramidate 
To a solution of 1.3 g. (0.007 mol) 2-phenoxyaniline in 10 ml. of acetone 
there is added 1.4 g. (0.007 mol) of O,O-diethyl 
phosphoroisothiocyanatoate. The solution is diluted with water, made basic 
with 50% aqueous sodium hydroxide, and extracted with ether. The aqueous 
layer is acidified with concentrated hydrochloric acid and extracted with 
methylene dichloride. The methylene dichloride solution is concentrated in 
vacuo to afford 1.8 g. (66.7% yield) of product that crystallizes upon 
standing, mp. 100.degree.-103.degree. C. 
Elemental analysis for C.sub.17 H.sub.21 N.sub.2 O.sub.4 PS: Calc. C 53.67 
H 5.56 N 8.14 P 8.43; Found C 54.11 H 5.64 N 8.12 P 9.05; 53.90, 5.64 
EXAMPLE 2 
Zinc salt of O,O-Diethyl-N-(2-phenoxyphenyl)aminothiocarbonyl 
phosphoramidate 
Step A--Sodium salt of 
O,O-Diethyl-N-(2-phenoxyphenyl)aminothiocarbonylphosphoramidate 
To a slurry of 2.9 g. (0.0076 mol) 
O,O-diethyl-N-(2-phenoxyphenyl)aminothiocarbonyl phosphoramidate in 50 ml 
of deionized water there is added 0.6 g. (0.0076 mol) of 50% aqueous 
sodium hydroxide to afford sodium salt of 
O,O-diethyl-N-(2-phenoxyphenyl)aminothiocarbonyl-phosphoramidate. 
Step B--Zinc salt of O,O-diethyl-N-(2-phenoxyphenyl)aminothiocarbonyl 
phosphoramidate 
The mixture is stirred until a clear solution is formed and to it there is 
added a solution of 0.5 g. (0.0038 mol) zinc chloride in 10 ml of 
deionized water. The "gummy" suspension formed is stirred at room 
temperature for 18 hrs. and to it there is added 0.5 g. (0.0038 mol) of 
zinc chloride dissolved in 10 ml of deionized water. The water is decanted 
and the "gummy precipitate" is slurried in methanol. The slurry is vacuum 
filtered and the filter cake dried to afford 1.6 g. (26% yield) of 
product, mp. 90.degree.-92.degree. C. 
Elemental analysis for C.sub.34 H.sub.40 N.sub.4 O.sub.8 P.sub.2 S.sub.2 
Zn: Calc. C 49.55 H 4.89 N 6.80 P 7.78 Zn 7.93; Found C 48.38 H 4.86 N 
7.09 P 7.88 Zn 7.48 
EXAMPLE 3 
O,O-Diethyl-N-(2-thiophenoxyphenyl)aminothiocarbonyl phosphoramidate 
To a solution of 2.0 g. (0.01 mol) 2-thiophenoxyaniline in 50 ml. of 
diethyl ether there is added 2.0 g. (0.01 mol) of O,O-diethyl 
phosphoroisothiocyanatoate. The mixture is allowed to stand at room 
temperature for 2 hrs. and the diethyl ether is allowed to evaporate. The 
residue is dissolved in diethyl ether and to it there is added hexane. The 
oil that separates is isolated, washed with several portions of hexane and 
allowed to stir in hexane for 18 hrs. The crystalline precipitate that is 
formed is isolated by vacuum filtration and dried to afford 1.6 g. (40.4% 
yield) of product, mp. 97.degree.-100.degree. C. 
Elemental analysis for C.sub.17 H.sub.21 N.sub.2 O.sub.3 PS.sub.2 : Calc.: 
C 51.50 H 5.34 N 7.07 P 7.81 S 16.17; Found: C 51.44 H 5.39 N 7.22 P 7.56 
S 15.94 
By substituting 2-phenylsulfinylaniline and 2-phenylsulfonylaniline for the 
2-thiophenoxy aniline in Example 3 and by following substantially the same 
procedure there is obtained 
O,O-diethyl-N-(2-phenylsulfinylphenyl)aminothiocarbonyl phosphoramidate, 
and O,O-diethyl-N-(2-phenylsulfonylphenyl)aminothiocarbonyl 
phosphoramidate, respectively. 
EXAMPLE 4 
O,O-Diethyl-N-(2-styrylphenyl)aminothiocarbonyl phosphoramidate 
To a stirred solution of 3.4 g. (0.01 mol) 2-aminostilbene in 20 ml of 
acetone there is added 2.0 g. (0.01 mole) of O,O-diethyl 
phosphoroisothiocyanatoate. The mixture is stirred at room temperature for 
2 hrs. and is concentrated in vacuo. The concentrate is crystallized with 
ethyl acetate and the crystals are isolated to afford 0.4 g. (5% yield) of 
product, mp. 124.degree.-126.degree. C. The ethyl acetate filtrate is 
concentrated in vacuo and the concentrate is treated with diethyl ether to 
afford an additional 1.2 g. of product (38% overall yield). 
Elemental analysis for C.sub.19 H.sub.23 N.sub.2 O.sub.3 PS.sub.2 : Calc.: 
C 58.45 H 5.94 N 7.18 P 7.93 S 8.21; Found: C 58.60 H 5.85 N 6.99 P 5.63 S 
9.38 
The compositions of this invention can be utilized as the sole anthelmintic 
or they can be employed in conjunction with other anthelmintics. 
Many variations of this invention are possible without departing from the 
spirit or scope thereof.