This invention relates to novel guanidine derivatives of the general ormula

their isomers at the guanidine groups and pharmaceu ical ly acceptable salts of such compounds, wherein

.R is C, to O r- alkyl or C, -to C- alkyl substituted 1 0 1 0

R or

R drogen, N-alkyl-piperidyl (wherein the alkyl gr,oup has 1 to 4 carbon atoms), tetrah dropyranyl, morphol inyl, piperidyl and C. to C alkyl substituted by one or mlo<re substi utents selected from OH, SCH-,

0S0 H, SO H,

"B UKi

'.T?; '

COR9, COOR10 , piperazinyl, pyridyl and

, with the proviso that R2 and R3 cannot both be hydrogen;

4 5 one of R and R is selected from hydrogen, C, to C _g

alkyl and C. to C_ alkoxy and the other from hydrogen,

14 14

C. to C. alkyl and R Z wherein. R is C ₁ to C _g alkyl

or phenyl and Z represents O, S, SO or SO-NR with

n being 1, 2 or 3 and R 15 being hydrogen or C, to C _g

alkyl; whereby, in the above definitions,

- •' 8 R is C, to m. alkyl, C. to C _fi alkyl substituted with phenyl or halogen, phenyl or phenyl substituted with C, to C _g alkyl or with halogen;

9 R is C-.L to Cb. alkyl, C-.L to C. acyl or a peptide

residue having up to three amino acids;

R is hydrogen or C, to C _g alkyl;

_12 ■ , „13

R and R are independently selected from hydrogen,

C being C. to C. alkyl . -L o

The C_ to C,. alkyl and alkoxy groups referred to above 1 o may be straight or branched chains and include, when the groups have 3 or more C-atoms, cycloalkyl and, when the grou have 4 to 6 C-atoms, also cycloalkylalkyl groups. The tetrahydropyranyl, morpholinyl, piperidyl, piperazinyl, and pyridyl groups include all possible configurations (e.g.2-.

3- and 4- pyridyl) . Halogen includes fluorine, chlorine,

4 bromine and iodine. The SO -group in the definition of R

5 and/or R includes all possible variations, e.g.

-OSO - and -SO.O-. Equally the S0 ₂ NR - ^' group

may be -SO NR -, -NR SO.- , etc.

2

The preferred definition of R is hydrogen and it is equall preferred that only one of R 4 and R 5 represents hydrogen and the other is as defined above (except hydrogen) . A

4 more important group of compounds is the one wherein R

is hydrogen , X is CR (with R being other than hydrogen) and Y is N or CH . preferably CH . The preferred meaning of

R 1 is NO_ , NHCOR8 or NH_ , and of R 3 is a substituted C., to

10 C, alkyl group wherein the preferred substituents are COOR ,

12 13 piperazinyl , pyridyl , NR R , S0.- H and 0S0 „ H

(R , R and R being as defined above). The preferred

definition of R 4 and R 5 is R 14 Z with R~ ^" ■ 4 being C ±, to C b,

alkyl or phenyl , particularly C _χ to C _g alkyl and Z being as defined above , but preferably S.

.6

The preferred meaning of R is CH_

The most preferred group of compounds of this invention may be illustrated by the following formula

wherein

1 ^* 8

R is NO-, NH or NHCOR ;

12

R is C to C alkyl substituted by N ,

10 ^R piperazinyl, COOR , SO-H or 0S0-H _j

R is -S•CH- λ ( m being 0,1,2 or 3,

preferably 1) ;

8 R is Cm to C- alkyl, preferably CH ;

R is hydrogen or C- to C_ alkyl, preferably hydrogen and

,-12 ₃ 13

R and R are either both C. to C alkyl,

preferably ethyl, or one is hydrogen and the

N-C - other is -C-NHCH .

The compounds of this invention may be prepared according to processes generally known in the art for the prepa¬ rations of similar compounds. Preferably the compounds are obtained according to the reaction illustrated in the following reaction scheme:

(III) (IV)

(R to R , X and Y are as defined above).

The reaction is preferably carried out by dissolving the reactants III and IV in an inert solvent, if necessary by heating, and to stir the resulting solution, prefer¬ ably at ambient temperature, until the reaction is completed

The starting compounds of formula III are either known or may be obtained by standard reactions well known in the art. The compounds of formula III, for example, may be obtained by following the procedure outlined in Belgian Patent No. 654.306 for the preparation of closely related compounds, i.e. :

1 4 6 (R , R , R X and Y are as defined above and X ¹ represents halogen (Cl, Br, or I) or sulfonate) .

Included within the scope of this invention are the isomers

at the guanidine ,and -the salts

This includes acid addition salts -and Cmetai)salts-o "those

2 3 compounds wherein R and/or R represent C. to C _fi alkyl

substituted by COOR with R being hydrogen^ or by OSO-H or SO-H. Preferred metal salts are alkali metal :. salts, in particular sodium salts. The salts are obtained according to standard proceudres. Typical acids to be used for forming acid addition salts are hydrochloric, hydro- bromic, sulfuric, phosphoric, acetic, propionic, succinic, pamoic, caproic, palmitic and stearic acid.

The following example illustrates the process of this invention .

Example

N- ethoxy carbonyl-N ' - [ 2- ( ' -cy ano- "-me h l quanidino ) ^■ ethyl ]-N"-*42-nitro-4-propylthiophenyl) guanidine.

Dissolve ^β .7g of ^" N-methoxycarbonyl-N ^• •- (2-nitro-4- . propylthiophenyl)-3-methyl-isothiourea and 3.7g of N'- (2-aminoethγl)-N ^, -cyano-N"-methyl-guanidine in 50 ml of acetonitrile by heating. Stir the resulting solution for 24 hours at ambient temperature. Remove the solvent by evaporation and chromatograph the residue on 350 g of silica gel, eluting with 1% methanol in laethylene chloride to give, after evaporation of the solvent, the title product (m.p.72-73°C).

By following the process exemplified above, using the appropriate starting compounds, the compounds listed and tabulated below may be prepared:

N-methoxycarbonyl-N ^« - (2-nitxo-5-propylthiophenyl ) - "- ^[ 2- (.N-piperazinyl) ethyl] guanidine (m.p. 101-104°C); N-methoxycarbonyl-N' -[2 (N*-cyano- "-methylguanidino)ethyl]- N"-[2-nitro-5-propylthiophenyl] guanidine (m.p. 124°C, dec);

OMPI

N-methoxycarbonyl-N'- (2-nitro-5-propylthiophenyl)-N"-(2- diethylaminoethyl)guanidine(amber gum).; N-methoxycarbohyl-

N'-(2-nitro-5-propylthiophenyl)-N"-(2-carboxyethy1)guanid ine (m.p. 116-118°C, dec); N-methoxycarbonyl- '-[2-( *-cyano-N"-methylguanidino) .ethyl]

-N"-(2-aminό-5-propylthipphenyl)guanidine(m.p. 116-119 C, dec.) ;

N-methoxycarbonyl- ^€ -[2-(N-s-cyano-N"-methylguanidino) .ethyl]

-N"-[2-acetamido—5-propylthiophenyl]guanidine (m.p. > 160 C, dec.) ;

N-methoxycarbonyl-N*-(3-carbσxypropyl)-N—(2-nitro-5- propylthiophenyl)guanidine (m.p. 112-114 C, dec);

N-methoxycarbonyl—N'-carbox methyl—N"-(2-nitro-5- propylthiophenyl)guanidine sodium salt (m.p. 195-198 C _. dec.) _' N-methoxycarbonyl-N'-(2-diethylaminoethyl)-N"-(2-nitro-5- propoxyphenyl) uanidine (m.p. 60-63 C) ;

N-methoxycarbonyl-N'-[2-(N'~cyano-N"-methylguanidino) ethyl]

-N"-(2-nitro-5-propoxyphenyl)guanidine (m.p. 149-152 C, dec. ) ; N-methoxycarbonyl-N'—(2-diethylaminoethyl)-N"-(2-nitro-4- propylthiophenyl)guanidine (orange viscous oil);

N-methoxycarbonyl- '-(2-diethylaminoethyl)-N"-(2-nitro-5- propylthiophenyl)guanidine;

N-methoxycarbonyl-N'-[2-(N'-cyano-N-methylguanidino) ethyl]- N"-(2-nitro-5-phenylthiophenyl)guanidine (m.p. 181-183 c, de ) ;

N-methoxycarbonyl-N'-(2-nitro-4-propyloxyphenyl-N"-(2- o diethylaminoethyl)guanidine (m.p. 91-93 C) ;

N-methoxycarbonyl-N'-[2- (N*-c ano-N"-methylguanidino)eth l] ^■

N"-(2-acetamido-4-methyl-5-propoxyphenyl)guanidine (m.p.225°C, dec);

N-methoxycarbonyl-N'-(2-pyridylmethyl)-N"- (2-nitro-4- propoxyphenyl)guanidine (m.p. 83-85 C) ;

N-methoxycarbonyl-N'-(ethoxycarbonylmethyl)-N"-(2-nitro-5 - propoxyphenyl)guanidine (m.p. ^120 C, dec); N-methoxycarbonyl-N'- (2-(1-piperazinyl)ethyl)-N"-(2-nitro- 5-propylthiophenyl)guanidine (m.p. 101-104 C)^ N-methoxycarbonyl-N' -(2-hydrogensulfate-ethyl) -N"-(2-nitro- 5-propylthiophenyl)guanidine sodium salt (m.p.ftl50 C,dec.) ; and . N-methoxycarbonyl-N'-(2-.sulfonic acid ethyl)_-_N"-(2-nitro-

5-propylthiopheny )guanidine sodium sal (m.p.*-»l50 C„ dec).

TABLE I

(V)

TABLE II

(C ₂ H ₅ ) ₂

(VI)

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TABLE III

TABLE III (Cont)

TABLE IV

S*CH ₂ CH ₂ CH ₃ (VIII)

OMPI

The compounds of the present invention are useful in combatting helminths, i.e. in treating humans and animals suffering from an infestation of parasitic worms, for example, roundwor s, hookworms, whipworms or tapeworms, by administering to the host animal a therapeutic amount of a compound of the present invention.

The compounds of this invention exhibit significant anthel- mintic effects when administered to a host (e.g. swine, dogs or ruminants) at doses as low as about one milligram per kilogram of body weight per day in dosing over several days, or at about fifty milligrams per kilograms in a single day dosing, according to techniques well known in the art.

The. optimum dose for each species of animal and for each type of parasite can readily be determined by one skilled in the art by using standard techniques such as the Modified McMaster Egg Counting Technique as described by H.B. Whitloc and H. ÷ cL. Gordon, J. Council Scientific Industrial Research (Australia) 12 , p. 50, 1939 and H.B. Whitlock J. Council Scientific Research (Australia) 21, p.177, 1948.

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From these, and similar tests, anthelmintic efficacy is assessed by determining the number of eggs- in faeces passed on the days following treatment with the compound compared with pre-treatment days. In addition, autopsy of animals 5 after treatment will indicate whether the infection has been eradicated. Based on experimentation, proper dosages for curing various infections can be determined.

The compounds of this invention may be administered in 10 suspensions, capsules, feed additive preparations, tablets, etc as is well known to those skilled in -the human and veterinary :medical arts. In addition., the compounds may also be used as injectible anthelmintic preparations. For this purpose, the active ingredient is admixed with suitable 15 sterile carriers such as sterile water and isotonic saline solution.

Suitable clinical formulations containing the compounds of this invention can be administered orally in the form of tablets, capsules, elixirs and the like. The active 20. compound is compounded with inert carriers such as, for example , gums, starches and sugars or it..may be incorp¬ orated into gelatine capsules or formulated into elixirs which have the advantage of being susceptible to manipu¬ lations in flavour by the addition of standard, natural 5 or synthetic flavouring agents. -^ΩRE

OMPI

^ y °-

Particularly useful anthelmintic formulations comprising the compounds of this invention for treatment of helminthiasis are either liquid suspensions ready to use or wettable or water-dispersible powders which are mixed with water prior to use.

A liquid—suspension formulation may contain from 50 to 55% w./v. (kg/liter) • of the active compound together with a dispersing agent and stabilizing agent. A typical formulation is as follows:

N-methoxycarbonyl-N'-(.2-diethylaminoethyl)-N"-(2-nitro-

5-propylthiophenyl) guanidine 50 to 55 parts by weight

Dispersing agent. 1/2 to 2 parts by weight

Stabilizing agent 1 to 3 parts by weight

Preservative as required Water -Suf icient to make

100 volumes.

Suitable dispersing agents are those containing sulphonate groups , for example ^' sodium lignin sulphonate , or the sulphonated phenol or naphthol formaldehyde polyiαers . Bentonite may be employed as the stabilizing agent, although it is possible to use such protective colloids as carboxy- ethyl cellulose , sodium alginate and the like . The formulations can be prepared by mixing the active compound

and water containing dissolved dispersing agents very vigourously by means of suitable mechanical mixing equip¬ ment. -

A wettable or water-dispersible powder formulation may contain about 90 to 95% w./w. of the active compound together with a wetting agent and dispersing agent. A diluent such as kaolin can also be added if a concentration below 98% w./w. is required. An anti-foaming agent and, in some cases, a stabilizing agent may be present. A typical formulation is as follows:

N-methoxycarbonyl-N'-(2-diethylaminoethyl)-N"-(2-nitro-5- propylthiophenyl)guanidine 90 to 95 parts by weigh

Wetting agent. 1/2 to 4 parts by weigh

Stabilizing agent. 0 to 2 parts by weight Anti-foaming agent... 0.01 to 1 part by weigh

Water.. . ..........0 to 5 parts by weight

Suitable wetting agents are the non-ionic alkylphenolethy- lene oxide adducts, such as an octvlphenol or nonylphenol condensed with ten .moles of ethylene oxide, or anionic materials, such as the synthetic aryl alkyl sulphonates, or sodium dibutyl napthalene sulphonate. In general, about 1% w./w. wetting agent is required. The anti-foaming agent employed _may be either a silicone or such .materials as

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ethyl hexanol octanol and the like ; and the stabilizing agent may again be chosen from bentonite or the water- soluble gums . Wettable or water-dispersible powder formulations are prepared by careful and adequate mixing of the .active compound with other ingredients with or without the * addition of some water using typical powder blending equipment -such as a ribbon blender . The powder is stirred into water by the user before application in the field .

The following examples show particularly useful formu¬ lations :

A. Tablet formulation Grams oer 1000 tablets

N- Jfethoxycarbonyl-N ' - (2-diethylaminoethyl)-

N"- (2-nitro-5-propylthiophenyl ) guandine 200 .0

Lactose 90 , .0 Dicalcium phosphate , hydrous 122 , .5

Po ly viny lpyrro lidone 25 .0

Polyethyleneglycol 1500 7 .5

Corn Starch 50 , .0

.Magnesium Stearate 5 , .0 500.0

Mix the active compound, the lactose and the dicalcium phosphate. Dissolve the polyethyleneglycol 1500 and the polyvinylpyrrolidone in approximately 20 ml of water. Granulate the powder blend with the water solution, adding additional water if necessary, to produce a damp mass.

Pass the wet granulation through a 12 mesh screen; spread on trays and air dry at 35 C. Blend the dry granulates with the starch and the magnesium stearate. Compress into 500 g tablets.

B. Capsule formulation Grams per 1000 capsules

N-Methoxycarbonyl-N'-(2-diethylaminoethyl)- N"-(2-nitro-5-propylthiophenyl)guanidine 200.0 Lactose 198.0 Magnesium Stearate 2.0

400.0 Blend the ingredients and fill into hard gelatine capsules.

^c * Elixir formulation per 1000 ml

N-Methoxycarbonyl-N*- (2-diethylaminoethyl)-

N"- (2-nitro-5-propylthiophenyl)guanidine 40.0 g

Sodium citrate 10.0 g

Sugar 500.0 g

Glycerin 200.0 g Compound orange spirit 10.0 ml

Alcohol 100.0 ml "

Amaranth 0.1 ml

Water to total 1000.0 ml

Combine the above ingredients using standard techniques.

D.- Injectible formulation mg/ml

N-Mathoxycarbonyl-N.'-(2-diethylaminoethyl)-

N"-(2-nitro-5-propylthiophenyl)guanidine 50.0

Polyethylene Glycol 400 500.0 Dimethyl Acetamide . , 300.0

Benzyl Alcohol - ^' . 20.0

Water for Injection to q.s. 1.0 ml

Combine the above ingredients using standard techniques.

Ξ. Injectible fo ulation mg/ml

(2-diethylaminoethyl)-

N"-(2-nitro-5-propylthiophenyl)guanidine 100.0

Diemethyl Acetamide 300.0

Benzyl Alcohol 20.0

Polyethylene Glycol 400 to q.s. 1.0 ml Combine the above ingredients using standard techniques.

Similarly, prepare formulations using other compounds of the present invention, e.g. N-methoxycarbonyl-N'- [2-(N ^t -cyano-N"-methylguaniαino_)ethyl-N- 2-nitco-5- propylthiopheny]J guanidine.