AU485000B2 - 5 (6)-benzene ring substituted benzimidazole 2-carbamate derivatives having anthelmintic activity - Google Patents

Description

70.180 /74 FIELD OF THE INVENTION

This invention relates to novel chemical compounds.

More particularly, this invention relates to novel anthel-

mintically active benzimidazole-2-carbamate derivatives

wherein the benzene ring is substituted at the 5(6)-position. BACKGROUND OF THE INVENTION

Anthelmintically active benzimidazole-2-carbamate derivatives either unsubstituted at the 5(6)-position or

substituted with different substituents than those described

and claimed herein are known in the art (for example, see United States Letters Patents Nos. 3,480,642; 3,573,321; 3,574,845; 3,578,676 and 3,595,870). Related fungicidal compounds are also shown in United States Letters Patents

Nos. 2,933,504 and 3,010,968.

SUMMARY OF THE INVENTION

The novel benzene ring substituted benzimidazole-2-

carbamate derivatives of the present invention can be represented by the following formula:

4 X--S N H N -S C2-N-COOR

Y--S Np 7 1 H where R is a lower alkyl group having 1 to 4 carbon atoms;

and X and Y are independently

or or a counterpart thereof substituted with one or more alkyl, aryl, alkoxy or hydroxy radicals; the fused bicyclic hetero ring-S-substitution being at the 5(6)-position;

and the pharmaceutically acceptable salts thereof.

The hydrogen on the nitrogen at the 1-position can be

replaced with acyl, carbalkoxy, carbamoyl, alkyl-substituted

485.500

70.180 /74 carbamoyl subst ituents.

As used in this specification and claims, the term "lower

alkyl"? refers to both straight and branched chain alkyl groups

having a total of from 1 through 4 carbon atoms, and thus

includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,

and t-butyl. Exemplary fused, bicyclic heterocyclic rings

expressed in radical form include, for example, 2,3,5,6- 2 2, 3-dihydro-thiazolo- tetrahydro-thiazolo[ ,3-blthiazol-7a-y1;

[2,3-b~thiazol-7a-yl; thfazolo[2,3-b~thiazol-7a-yl; 2,3,5,6-

tetrahydrothiazolo[2,3-b3>(1 ,3)thiazin-8a-yl; 2,3,6,7- tetrahydro-( 1,3 )thiazinoC2

3 485.500

70.1 8 0 /74 thiazin-9a-yl; and the like. The aforementioned fused,

bicyclic heterocyclic ring can be substituted with one or

more alkyl, such as methyl; aryl, such as phenyl; alkoxy,

such as methoxy; or hydroxy radicals; The term "cycloalkyl"

refers to cyclic hydrocarbon group having from 3 to 7 carbon

atoms including, for example, cyclopropyl, cyclopentyl,

cyclohexyl, and the like. The term "alkoxy" refers to the

group having the formulae RO- wherein R is a lower alkyl,

as defined above, and includes, for example, methoxy, ethoxy,

propoxy, t-butoxy, and the like. The term "halo" refers to

iodo, bromo, chloro, and fluoro radicals. The term "acyl"

refers to acyl groups derived from carboxylic acids having

from 1 to 6 carbon atoms, such as, for example, acetyl,pro-

pionyl, butyryl, valeryl, isovaleryl, hexanoyl, and the like. The compounds of the present invention, and the non-

toxic salts thereof formed with pharmaceutically acceptable

inorganic or organic acids, possess activity against parasites in mammals, including both mature and immature parasitic

forms. In particular, these compounds are found to exhibit

485.5 00

7.0,180/7 high activity against tape worm infections of the intestinal tract of economically important animals, coupled with low

systemic toxicity to the host animal. Such infections may

be due to tapeworm parasites such as Hymenolepis nana, Dipylidium

canium, Taenia saginata, Multiceps serialis, etc.

The compounds .of the present invention are also. useful

as antifungal agents, particularly as systemic fungicides for

controlling fungal diseases of plants of economic importance.

Where the compound has a basic moiety, the term "non-

toxic salts" as used herein refers to those pharmaceutically

acceptable salts of the compounds of this invention which do

not adversely affect the antifungal or anthelmintic properties

of the basic compound, such as those salts conventionally used

in the art. Such non-toxic salts include, for example, salts

of inorganic acids such as, for example, sulfuric, sulfonic,

sulfamic, nitric, phosphoric, hydrochloric acids and the like,

and salts of organic acids such as, for example, acetic,

citric, lactic, palmitic, tartaric, succinic, maleic, benzoic

acids and the like.

The amount of the compound to be administered will depend

upon the actual compound utilized, and upon the weight of the

animal being treated. In general, however, the daily

dosage level will usually be between -fbee 5 mg/kg and The 100 mg/kg of body weight of the animal being treated.

active ingredient is administered to the animal by mixing it with the diet of the animal, as with a feed mix,

or formulating it with a non-toxic carrier to give anthel-

mintic compositions. The carrier may be an orally ingestible

container for the active ingredient such as, for example, a

gelatin capsule, or it may be an excipient of the kind

485,5.00

70,180 /74 normally used in medicaments of this character, including maize

starch, terra alba, lactose, sucrose, calcium phosphate, Examples, of gelatin, stearic acid, agar, pectin or the like. and water. suitable liquid carriers are peanut oil, sesame oil in A wide variety of pharmaceutical forms can be employed with the those cases wherein the medicament is not admixed can be feed. Thus, if a solid carrier is used, the compound

administered in tablet or capsule form. If a liquid carrier soft gelatin is used, the medicament may be in the form of a

capsule or in a liquid suspension. invention The 5(6)-substituted compounds of the present nitro can be prepared from benzene starting compounds having

and amino or acylamino (for example, acetamido) substituents at the 1- and 2- adjacent positions on the benzene nucleus and a displaceable moiety, for example, a chloro posiions), substituent at the 4- or 5-position of the benzene nucleus compound at what will be the 5(6)-position of the benzimidazole

to be prepared). Such a benzene starting material is reacted 4- or with a heterocyclic mercaptan to give the corresponding If bicyclic heterocyclicthio benzene derivative. amino group. applicable, the acylamino group is converted to an a benzene The nitro group is reduced to an amino group to afford The derivative having amino groups at the 1- and 2-position.

1,2-diamino compound is then reacted with a 1,3-bis(alkoxy- carbonyl)-S-alkyl-isothiourea to give the corresponding 5(6)-

fused, bicyclic heterocyclicthio-benzimidazole-2-carbamate

compound of the present invention. The hydrogen on the nitrogen

at the 1-position may of course be replaced with certain

substituents, as mentioned above. Also, the compound of the to invention may be treated with a non-toxic salt to give rise

a pharmaceutically acceptable salt thereof.

-6- 485.5 00 of the The fused, bicyclic heterocyclicthio compounds a suitable present invention can also be prepared by treating the 4- or starting material having a thiocyanato group at ,position with sodium bor-ohydride to form the corresponding fused, mercaptide, reacting the mercaptide with an appropriate resultant bicyclic heterocyclic halide salt, converting the bicyclic compound to the corresponding l,2-diamino-5(6)-fuSed, the latter corn- heterocyclicthiobenzene compound, and reacting pound with a 1,3-bis (alkoxy-carbonyl) .S-alky1-isothiourea heterocyclicthio- to give the corresponding 5(6)-fused, bicyclic benzimi. azole-2-carbmate derivative. 4 A suitable starting material is 1-acetamido-2-nitro- to the thiocyanatobenzene which can be prepared according T. Peters, J. Chem. Soc., method of F. Challenger and A.

1364 (1928). other suitable starting materials include, for

l-amino-2 -nitro-4-thiocyanatobenzene, 2 -ainino-4- example,

chloro-1-nitrobelzene, and 2-acetamido,4ch1oro-lnitro-

benzene.

Conversion of the thiocyanato group of the 1-acetamido-

2-.nitro-4-thiocyanatobenzene (or l-amino-2 -nitro-4-thio-

cyanatobenzene) starting material to a heterocyclicthio sub- of the afore- stituent can be affected by treatment of either at room mentioned 4-thiocyanatobenzene starting materials,

temperature, with sodium borohydride in dimethylformamide with for abovt- 1/4 to abettt- 2 hours, followed by treatment as, for a fused, bicyclic heterocyclic halide salt, such

example, 2,3,5, 6-tetrahydrothiazolo- r2,3-b] -thiazolium chloride, and the like, in dimethylformamide, dimethylacetamfide, as methanol quinoline, pyridine, or an alcoholic medium, such

485,500 or ethanol. This latter reaction is conducted at a tempera- ture from abaet 100 C. to-abo to 150 0 generally at about room temperature if feasible, for abob-1/2 to 12 hours using an excess of the halide reactant. The reaction is preferably conducted in dimethylformamide. Alternatively, the mercaptide intermediate can be generated with other bases instead of sodium borohydride.

Conversion of an acylamino group, for example, an

acetamido group, to an amino group can be effected by treating

the acylamino group-containing compound with a strong base,

such as sodium hydroxide, potassium hydroxide, potassium carbonate

or sodium carbonate in aqueous methanol at -abeo 200C. to-about 0 100 C. for about 1/4 hour to -abett 24 hours.

Reduction of the nitro group to an amino group can be

effected by treating a nitro-group containing compound with

iron and a ferrous salt, such as ferrous sulfate or ferrous

chloride, or zinc powder, in aqueous methanol or acetic acid

at reflux under neutral conditions for abeot 1 to-about

hours. It is desirable to add the metal powder in distinct

portions, as opposed to all at one time.

The diamino compounds resulting from reduction of the

nitro group in the starting compound to an amino group, and,

if necessary, conversion of the acylamino group to an amino

group, are converted to the corresponding benzimidazole-2-

carbamate compounds by reacting the diamino compound with a

1,3-bis(alkoxy-carbonyl)-S-alkyl-isothiourea, for example,

1,3-bis(methoxycarbonyl)-S-methyl-isothiourea or 1,3-bis-

485.5 00

(ethoxycarbonyl)-S-methyl-isothiourea, in an aqueous alcoholic

medium, for example, aqueous methanol or aqueous ethanol, at

from about room temperature to the reflux temperature of the

reaction medium for eabout 1/2 to about 6 hours. The reaction medium is preferably made acidic to a pH of -abtej 4-6 with,

for example, a sufficient amount moles) of acetic

acid. About 1-2 moles, generally aobe 1.1 moles, of the

isothiourea reactant are utilized per mole of the diamino com-

pound.

When 2-amino-4-chloro-l-nitrobenzene or 2-acetamido-4-

chloro-l-nitrobenzene is utilized as a starting material, it

can be converted to the corresponding heterocyclicthio compound,

by the reaction thereof with an appropriate heterocyclic mercaptan, such as 4,5-dihydro-2-mercaptothiazole, and the

like, in an inert solvent, such as dimethylformamide, ethanol,

or methanol, in the presence of a suitable inorganic base,

such as potassium hydroxide, potassium carbonate, sodium carbo-

nate, sodium hydroxide or sodium hydride. Typically, this 0 reaction is conducted at a temperature from about 20 C. to

about-150°C. to about the reflux temperature of the

solvent material) for -abe 1/2 to-about. 6 hours, using

an excess (2-3 moles) of the mercaptan reactant. If 2-

acetamido-4-chloro-l-nitrobenzene is utilized as the starting

material, the acetamido group can be converted to an amino

group as described above. With either case, the nitro group

is reduced to an amino group. The resultant 1,2-diamino

compound is treated, as described above, to give the corres-

ponding 5(6)-fused, bicyclic heterocyclicthio-benzimidazole- 2-carbamate compounds of this invention.

485.5 Oo

In each of the process steps, described herein above inter- and below, unless otherwise indicated, the respective

mediate products are preferably separated from the reaction

mixture and purified prior to their use.as starting materials

for the next step in the process. Such separation and puri-

fication can be effected by any suitable procedure. For

example, typical separation procedures include filtration,

extraction, evaporation, and typical purification procedures

include crystallization, and both thin-layer and column

chromatography. Optimum separation and isolation procedures

can be obtained for any given step by routine experimentation

as will be apparent to those skilled in this art.

Particular compounds falling within the scope of the

present invention can be prepared by selecting an appropriate starting material, for example, from those referred to above,

and then selecting particular reaction step or steps, as

for example described above, to give the compound desired.

Particular reaction step or steps may be conducted in a

different order from that specified above since, in certain

instances, the particular sequence of steps may not be

critical. For example, the acetamido group of a 1-acetamido-

2-nitro-4-thiocyanatobenzene can be converted to an amino

group before the reaction of such compound with a heterocyclic

halide salt or the starting material can be reacted with the

485,500 j7,801 hcterocyclic halide salt and hen the aLcetaxnido group con- verted to the corresponding amino group. In view of this disclosure, the preparation of particular compounds, including compounds falling within the scope of the present invention but not particularly described in the specification, and the' various sequences of reaction steps which can be utilized to prepare such compounds, will be apparent to those skilled in this art. Exemplary of the compounds of the present invention, as' represented by the structural formula above, are the following illustrative compounds: 5(6) 6-tetrahydrothiazolo thiazol-7a-ylthio) 2-carbomethoxyaminobenzimidazole; 5(6) ,3-dihydrothiazolo[2, 3-b] thiazol-7a-yltbio) -2- carbomethoxyaminoberzimidazole; 5(6) -(thiazolo 3-b] thiazol-7a-ylthio) -2 -carbomethoxy- aminobenzimidazole; 6 2 ,3,5,6-tetrahydrotiazolo2,3-b-(l,3)thiazin- 8a-ylthio) -2-carbometboxyaminobenzimidazo le; 5(6)-(5,6-dihydrothiazolo[2,3-bJ-(1,3) -thiazin-8a-ylthio) 2-carbomnethoxyaminobenzimidazole; thiazin-9a-ylth io) -2-carbomethoxyamninobenzimidazole; 5(6) 6-tetrahydrothiazolo(2, 3-b]thiazol-7a-ylthio) 2-carboethoxyaxninobenzimidazole; carboethoxyazninobenzimidazole; 5(6) -(thiazolo[2, 3-b] thiazol-7a-ylthio) -2-carboethoxy- aminbnimzo

_11- 485,500

70,180 /74 3, hia a6.tzo .hdro 3-bj-13)tIain-

8a-ylthio) -2-carboethoxyaninobenzirnidazole;

5(6) -(5,6-dihydrothiazolo[2,3-b]-(1,3) -thiazin-8a-ylthio)

2 -carboethoxyaminobenzimidazole;

5(6)-(2,3,6,7-tetrahydro(1,3)thiazino[2,3-b]-(1,3)-

thiazin-9a-ylthio )-2-carboethoxyaminobenzimidazole;

5(6)-(2,3,5,6-tetrahydrothiazolo[2,3-b]thiazol-7a-ylthio)-

2 -carbopropoxyaminobenzimidazole;

5(6) -(2,3-dihydrothiazolo[2,3-blthiazol-7a-ylthio) -2-

carbopropoxyaminobenzimidazole;

-(thiazolo 3-b] thiazol-7a-ylthio) -2-carbopropoxy-

axninobe.!izimidazole;

5(6)-(2,3,5,6-tetrahydrothiazolo[2,3-b]-(1,3)-thiazin-

8a-ylthio) -2-carbopropoxyaminobenzimidazole;

5(6) 6-dihydrothiazolo[2 -thiazin--8a-yltbio)

2 -carbopropoxyaminobenzimidazole;

5(6)-(2,3,6,7-tetrahydro(1,3)thiazino[2,3-b--(1,3)-

thiazin-9a-ylthio) -2 -carbopropoxyaininobenzimidazole;

5(6) -(2,3,5,6-tetrahydrothiazolo[2,3-b]thiazol-7a-ylthio)

2 -carbobutoxyaaninobenzimidazole;

5(6) ,3-dihydrothiazolo[2,3-b]thiazol-7a-ylthio)-2-

carbobutoxyaminobeinzimidazole;

5(6) -(thiazolo thiazol-7a-ylthio) -2-carbobutoxy-

aiinobenzimidazole;

5(6)-(2,3,5,6-tetrahydrothiazolo(2,3-b]-(1,3)-thiazin-

8a-ylthio) -2-carbobutoxyaminobenzimidazole;

5(6) -(5,6-dihydrothiazolo[2,3-b]-(1,3) -thiazin-8a-ylthio)

2 -carbobutoxyaxninobcnzimidazole; and

-12- 485,5 -12- 00 y /74 5(6)-(2,3,6,7-tetrahydro(l,3)thiazino[2,3-b]-(1,3)- thiazin-9a-ylthio)-2-carbobutoxyaminobenzimidazole.

Of the compounds listed above, 5(6)-(2,3,5,6-tetrahydro-

thiazolo[2,3-b]thiazol-7a-ylthio-2-carbomethoxyaminobenzimid-

azole is presently preferred because it has shown substantial

and quite specific activity against Hymenolepis nana at

extremely low concentrations. The compound is, thusly, an

anthelmintic agent specifically adapted for treatment of

tapeworn infections of the intestinal tract of economically

important animals.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The following specific description is given to enable

those skilled in this art to more clearly understand and

practice the present invention. It should not be considered

as a limitation upon the scope of the invention but merely

as being illustrative and representative thereof.

PREPARATION 1

175 G. of S-methyl isothiouronium sulfate in one liter

of water is cooled to OOC. and 162.5 g. of methylchloroformate

added, followed by the addition of a solution of 250 g. of

potassium hydroxide in 750 ml. water at 00 to 50 C. The crude

product is extracted into benzene, the benzene dried and

evaporated, and the residue recrystallized from methanol.

1,3-bis(methoxycarbonyl)-S-methyl isothiourea is thus obtained.

In a similar manner, substituting ethylchloroformate,

propylchloroformate and butylchloroformate for the methyl-

chloroformate, 1,3-bis(ethoxycarbonyl)-S-methyl isothiourea,

1,3-bis(propoxycarbonyl)-S-methyl isothiourea, and 1,3-bis-

(butoxycarbonyl)-S-methyl isothiourea are, respectively,

prepared.

-13- 485.5 00

PREPARATION 2

A mixture of 12 g. of thiazolidine-2-thiofle, and 16 g.

of 1-bromo-3-chloro propane in 100 ml. of acetonitrile is ref luxed for 12 hours, cooled and the product jemoved by filtration. Recrystallization from ethanol gives 2,3,5,6- tetrahydrothiazolo[2, 3-b] -thiazinium bromide. PREPARATION 3

A mixture of 66.5 g. of tetrah-ydro-1,3-thiazin-2-thione

and 83 g. of l-bromo-3-chloropropale in 200 ml. of ethanol is ref luxed for 24 hours. The solvent is removed under

vacuum and the residue triturated with ether, then acetone. The product is recrystallized from ethanol yielding 2,3,6.7- tetrahydro-(l, 3)-thiazino- 3-b] -thiazinium bromide. PREPARATION 4

Thiazolo[2, 3-b] -tbiazoliun chloride and thiazolo[2, 3-b]- thiazolium bromide are prepared according to the procedure of Bradsher et al, Tetrahedron Letters No. 22, pp. 1723-1725 (1965).using chloroacetaldehyde or bromoacetaldehyde acetal, respect ively, in place of the haloacetone or the phenacyl halide. PREPARATIONS 5 AND 6

2-Mercapto-thiazole is reacted with l-bromo-2-chloro-

ethane or 1-bromo-3-chloropropane to afford, respectively,

2, 3-dihydrothiazolo 3-b] thiazolium halide and 5, 6-dihydro-

thiazolo[2, 3-b] -thiazinium halide. Alternatively,

these compounds can be prepared according to Bradsher et al, supra, using chloroacetaldehyde or bromoacetaldehyde acetal and the requisite heterocyclic starting-material.

-14- 485.5 -14- 00

EXAMPLE I

A mixture of 121 g. of 2-amino-4-chloro-l-nitrobenzene, carbonate 208 g. of thiazolidine-2-thione, 242 g. of potassium 0 and 1 liter of dimethylformamide is stirred at 900 to 100 C.

for 8 hours, cooled and drowned into water. The insoluble

material is washed with water and a little methanol, and

then treated with boiling chloroform, cooled, and the product

filtered off. Re-treatment with boiling chloroform and a

similar treatment with boiling methanol gives 2-amino-4-

[2,3,5,6-tetrahydrothiazolo[2,3-b]-thiazol-7a-yl]-1-nitro- benzene. Recrystallization may be effected from acetic acid

if desired. 2 3 G. of 2-amino-4-(2,3,5,6-tetrahydrothiazolo[

thiazol-7a-yl]-l-nitrobenzene is suspended in 3 liters of meth-

anol. 60 G. of iron powder and a solution of 30 g. of ferrous

sulfate in 600 ml. of water are added. The mixture is stirred

under gentle reflux for approximately 15 hours,during which

period three further 60 g. portions of iron are added, and after which essentially no starting material remains. The

mixture is filtered and the filtrate is concentrated under

vacuum, the residue is dissolved in a warm mixture of 1

liter of ethanol and 1 liter of water, and re-filtered. 40 G.

of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea and 15 ml.

of acetic acid are added. The mixture is refluxed gently

for 4 hours, cooled and the product filtered off and washed

with aqueous ethanol, then methanol to afford

tetrahydrothiazolo[2,3-b]thiazol-7a-ylthio)-2-carbomethoxy-

amino-benzimidazole. Recrystallization may be effected from

485.500 aqueous acetic acid if desired.

In a similar manner substituting 1,3-bis(cethoxycarbonyl)-

S-methyl isothiourea, 1, 3-bis (propoxycarbonyl) -S-methyl isothiourea, and 1, 3-bis (butoxycarbonyl) -S-methyl isothiourea

for the l,3-bis(iethoxycarbonyl)-S-methyl isothiourea, the corresponding 5(6) 56-tetrahydrothiiazolo-[2,3-b]- thiazol -7a-ylthio] -2-carbalkoxyamino-benzimidazole compounds are prepared, where R is ethyl, propyl and butyl, respectively.

EXAMPLE II

A crolution of 2.37 g. of l-acetamido-2-nitro-4-thio- cyanato~benzene in 15 ml. dimethylformaiiide is treated under

nitrogen with 0.38 g. of sodium borohydride at 20 0 -30*C. After 1 hour, 5 ml. of acetone is added followed, 1 hour later, by 6 g. of 2,3,5, 6-tetrahydrothiazolo- -thiazolium- chloride [see Seto et al, Bull. Chem Soc. Japan 36(6),730-4 (1963); Chemical Abstracts 59, 7509(b)]. The mixture is stirred overnight at 200-300 (under nitrogen) then treated

with water. The crude product is filtered off and purified

by recrystallization from methanol-chloroform with charcoal

treatment, yielding I-acetamnido-2-nitro-4-( 2,3,5, 6-tetrahydro-

thiazole- thiazol-7a-ylthio) benzene.

0.55 G. of the above product is treated with a mixture

of 2 ml. of 5 N aqueous sodium hydroxide and 20 ml. of

methanol on the steam bath for 15-20 minutes. The mixture is diluted with water and filtered, yielding l-amino-2-nitro -4- 2 3 6 ,5, -tetrahydrothiazolo-(2,3-bj-t1iiazol..7a..yltbio)benzefle.Tis

is treated with 0.6 g. of iron powder and 0.3 g. of ferrous

-16- 485.,5 00

70180J14... sulfate in 25 ml. water, and 100 ml. mcthanol. The mixture

is refluxcd for 5 hours, during which time an additional

0.6 g. of iron powder is added, filtered and the filtrate

concentrated under vacuum. The residue is dissolved in a

mixture of 10 ml. ethanol and 10 ml. water, filtered from

traces of iron residues and treated with 0.32 g. of 1,3-

bis-methoxycarbonyi-S-methyl isothiourea and 0.1 ml. acetic

acid at reflux for 3 hours to afford 5(6)-(2,3,5,6-tetra-

hydrothiazolo[2,3-b]thiazol-7a-ylthio)-2-carbomethoxyamino-

benzimidazole which is filtered off.

Using-the reactants set forth in the last paragraph

of Example I according to the procedure of this Example,

the corresponding 5(6)-(2,3,5,6-tetrahydrothiazolo[2,3-b]-

thiazol-7a-ylthio]-2-carbalkoxyaminobenzimidazole compounds

are prepared where R is ethyl, propyl or.butyl.

EXAMPLE III

In a similar manner to the procedure of Example II,

using 2,3-diydrothiazolo[2,3-blthiazolium bromide in place

of the 2,3,5,6-tetrahydrothiazolo2,3-b]-thiazolium chloride,

the. corresponding 5(6)-(2,3-diydrothiazolo[2,3-b]thiazol-

7a-ylthio)-2-carbalkoxyaminobenzimidazole compounds are

prepared, where R is methyl, ethyl, propyl or butyl.

EXAMPLE IV

In a similar manner to the procedure of Example II,

using thiazolo[2,3-b]thiazolium chloride in place of the

2,3,5,6-tetrahydro-thiazolo[2,3-b]thiazolium chloride, the

-17- 485,5 00

5 (thiazolo 3-b] thiazol-7a-ylth io) -2- corresponding compounds are prepared, where carbalkoxy aminobenzimidazole butyl. R is methyl, ethyl, propyl or

.EXAMPLE V of'Example II* in a similar manner to the procedure

using 2,3,5,6-tetrahydrothiazolo[2,3-b]-(1,3)-thiazinium

bromide in place of the 2,3,5,6-tetrahydrothiazolo[2,3-bl- 5(6)-(2,3,5,6-tetra- thiazolium chloride, the corresponding

hydrothiazolo[2,3-b]-(1,3)-thiazinium-8a-yltl-iio)-2-carb- are prepared, where, alkoxyatninobenzimidazole compounds

R is me'.hyl, ethyl, propyl or butyl.

FYAM ILE VI of Example II, In a similar manner to the procedure

using 2,3,6,7-tetrahydro-(1,3)-thiazino[2,3-b]-(1,3)- the 2,3,5,6-tetrahydroth iazolo thiazinium bromide in place of

(2,3-b]thiazolium chloride, the corresponding tetrahydro-(1,3)thiazino[2,3-bl-(1,3)-thiazin-9a-ylthio) are prepared, where 2-carbalkoxyaminobenzimidazole compounds R is methyl, ethyl, propyl, or butyl.

.&XAMPLE VII Example II, In a similar manner to the procedure of bromide using 5(6)-dihydrotliiazolo[2,3-b)-(1,3)-thiazinium in place of the 2,3,5,6-tetrahydrothiazolo[2,3-b]thiazolium chloride the corresponding 5(6)-(5,6-dihydrothiazolo[2,3-b]- (1,3)-thiazin-Ba-ylthio)-2-carbalkoxyaminobenzimidazole ethyl, propyl compounds are prepa:ed, where R is metbyl, or butyl. -Is- 485.5 00

70,180 /s

In certain of the Examples above, specific reaction

sequences have been extended, in a general sense, to the

preparation of other similar and related compounds. It

should be understood, however, that with respect to any

compound which has been prepared by the extension of a

specific reaction sequence, it may be necessary or desirable

to utilize solvents, reaction media, recrystallization

media, reaction times or temperatures, etc., other than

the ones given in the specific reaction sequence upon which

such extension is based. Additionally, the specific reaction be sequence or manner in which particular compounds are to

prepared will depend, inter alia, upon the availability of the necessary starting materials, or the ease in which

the desired starting materials can be prepared, and the

reactivity thereof. These variations are deemed to be

within the skill of those working in this art and will be

apparent from a consideration of the particular reactants

utilized and/or particular compound.desired to be produced.

19 485,500

Claims (1)

1. 7 0,180 /74 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:-

   1. A compound represented by the formula:

   4 N3 H

   N S (D C -N-COOR

   Y--S N 7 1 H

   where R is a lower alkyl group having 1 to 4 carbon atoms;

   and X and Y are independently

   or or a counterpart thereof substituted with one or

   more alkyl, aryl, alkoxy or hydroxy radicals; the fused

   bicyclic hetero ring-S-substitution being at the 5(6)-position;

   and the pharmaceutically acceptable salts thereof.

   2. The compound of-Claim 1 wherein R is methyl.

   3. The compound of Claim 1 wherein the hydrogen on the

   nitrogen atom at the 1-position is replaced with a substituent

   selected from acyl, carbalkoxy, carbamoyl, alkyl-substituted

   carbamoyl substituents.

   4. The compound of Claim 1 wherein at least one of the

   member rings of said fused, bicyclic heterocyclic ring moiety

   is unsaturated.

   The compound of Claim 1 wherein at least one of the

   member rings of said fused, bicyclic heterocyclic ring moiety

   is substituted with one or more alkyl, aryl, alkoxy, or hydroxy

   radicals.

   6. The compound of Claim 1 wherein said fused, bicyclic

   485.5 00

   '74 70,180 heterocyclic ring moiety is selected from the group consisting of 2 3 6 -tetrahydrothiazolo[23blthiazol a-yl; 2,3- 7 dihydrothiazolo[2, 3-blthiazol-7a-yl; thiazolot2 ,3-blthiazol- 7a-yl; 2 ,3,5,6-tetr-ahydrothiazolo[2,3.b.( 1,3)-thiazin-8a-yl; and 2 6 ,3, ,7-tetrahydro-( 1,3)thiazino2,.3-b..(1 ,3)-thiazin-9a-yl.

   AIL ~ge~vdL 4cJe IIZA' "le 7. The compound of Claim 1 wherein *1is 2,3,5,6- tetrahydrothiazolo[2, 3-.b]thiazol-7a-yl.

   J- 4 _ZUL'&Y_ r_ .L -&V 8. The compound of Claim 1 wherein2R't is 2,3-dihydro- thiazolo[2, 3-b] thiazol-7a-yl.

   9. The compound of Claim.1 vwherein)R" is thiazolo- 3-b]-thiazol-7a-yl.

   The compound of Claim 1 wherein)R is 2,3,5,6- tetrahydrothiazolo2,3b-( 1,3)-thiazin-8a-yl.

   11.1 The copudof Claim 1 whereirq K' is 2,3,6,7- tetrahydro-Ci ,3)-thiazino[2,3-b]>(1 ,3)-thiazin-9a-yl.

   12. The compound of Claim 1 wherein said compound is 5(6 3,5,6 -tetrahydrothiazoloC2,3-b]thiazol-7a-ylthio carbomethoxyaminobenzimidazole.

   13. The compound of Claim 1 in combination with a pharmaceutically acceptable, non-toxic carrier.

   14. A method for controlling helminths in mammals which comprises administering to a mammal an anthelmintically effectiv~e

   21 1 -485,5 00

   70.180 /74 amount of a compound represented by the formula:

   4 H X--S N/ N S C -N-COOR 6 Y--S N H

   where R is a lower alkyl group having 1 to 4 carbon atoms;

   and X and Y are independently

   or or a counterpart thereof substituted with one or

   more alkyl, aryl, alkoxy or hydroxy radicals; the fused

   bicyclic hetero ring-S-substitution being at the 5(6)-position;

   or a pharmaceutically acceptable salt thereof.

   The method of Claim 14 wherein the hydrogen on the nitrogen atom at the 1-position of said compound is replaced

   with a substituent selected from acyl, carbalkoxy, carbamoyl,

   alkyl-substituted carbamoyl substituents.

   16. The method of Claim 14 wherein at least one of the

   member rings of said fused, bicyclic heterocyclic ring moiety

   of said compound is unsaturated.

   17. The method of Claim 14 wherein at least one of the member rings of said fused, bicyclic heterocyclic ring moiety

   of said compound is substituted with one or more alkyl, aryl,

   alkoxy or hydroxy radicals.

   18. The method of Claim 14 wherein said fused, bicyclic

   heterocyclic ring moiety of said compound is selected from the

   group consisting of 2,3,5,6-tetrahydrothiazolo[2,3-b]thiazol-

   7a-yl; 2,3-dihydrothiazolo[2,3-b]thiazol-7a-yl; thiazolo[2,3-b]- thiazol-7a-yl; 2,3,5,6-tetrahydrothiazolo[2,3-b]-(1,3)-thiazin-

   22 485,500

   70.180 74 8a-yl; and ,3,6 ,7-tetrahydro-(1,3)thiazino[2,3-b]-(1,3)- thiazin-9a-yl.

   19. The method of Claim 14 wherein said compound is 6 )-(2,3,5,6-tetrahydrothiazolo[2,3-b]thiazol-7a-ylthio)-2- carbomethoxyaminobenzimidazole.

   The method of preparing a compound represented by the formula:

   X- S N3 H N S 2-N-COOR \6 N 7 i1 H where R is a lower alkyl group having 1 to 4 carbon atoms;

   and X and Y are independently or or a counterpar thereof substituted with one or more alkyl, aryl, alkoxy or hydroxy radicals; the fused

   bicyclic hetero ring-S-substitution being at the'5( 6 )-position;

   derivatives thereof wherein the hydrogen atom at the 1-position

   is replaced with a substituent selected from acyl, carbalkoxy,

   carbamoyl, alkyl-substituted carbamoyl substituents; or the

   pharmaceutically acceptable salts thereof; said method

   comprising:

   reacting a 1,2-diamino-4(5)-) Z -tilutitd bono ne with a 1,3-bis(alkoxycarbonyl)-S-alkylisothiourea to afford the compound of Formula I; and optionally replacing the N 1-hydrogen on said compound of Formula I with a substituent selected from acyl,

   carbalkoxy, carbamoyl, alkyl-substituted carbamoyl

   substituents; and/or treating said compound of Formula I

   23 485,500

   70.180 'n4 with a non-toxic salt when it is desired to prepare a

   pharmaceutically acceptable salt thereof.

   21. The method of Claim 20 wherein

   tetrahydrothiazolo[2, 3-bjthiazol-7a-ylthio]-2-carbomethoxy-

   aminobenzimidazole is prepared.

   Dated this 9th day of May, 1977.

   SYNTEX INC.

   EDWD. WATERS SONS, Patent Attorneys,. Queen Street, Melbourne, Vie., 3000, Australia.

   24 485,5 00