CA1117538A - Derivatives of benzimidazoles - Google Patents

Abstract

GS90/95 ABSTRACT Derivatives of Benzimidazoles Benzimidazoles are provided having the structure wherein R is lower alkyl or phenyl-lower alkyl and A is wherein R1 is lower alkyl, R2 is hydrogen or lower alkyl, or R1 and R2 may be taken together with the carbons to which they are attached to form a cycloalkenyl ring, R3 is hydrogen or lower alkyl, and y is 0 or 1; herein R4 and R5 are the same or different and are hydrogen or lower alkyl, R6 is lower alkyl or phenyl, and R7 and R8 are the same or different and are chlorine, bromine, fluorine or iodine, m is 0 to 3, n is 0 to 3, and m + n is ? 5; or GS90/95 wherein R9, R10 and R11 may be the same or different and may be lower alkyl or lower alkoxy, z is 0, 1 or 2 and p is 1 to 5, with the proviso that when A is R is lower alkyl. The benzimidazoles have anthelmintic activity and are useful in the treatment and/or preven-tion of helminthiasis.

Description

~ 3~ G~ 5 -Derivatives o Berlzim:idazoles .____ _ The present invent~on relates to derivatives o~
benzimidazoles having the structure A_ ~ ~ ~ N
N ~HC02R
H

wherein R is lowex alkyl or phenyl-lower alkyl and A i5 R2 Rl ( O ) y 10R3~ C= C - S -wherein Rl is lower alkyl, R2 is hydrogen or lower alkyl, or Rl and R2 may be taken together with the carbons to which they are attached to give a cycloalkenyl ring containing 3 to 10 carbons, preferably 4 to 8 carbons, optimally 5 to 7 carbons, R3 is hydrogen or lower alkyl, and n is O or l;
R ~ R8 ~ R4 - (CH2) m~f~ ( CH2)n R R

wherein R4 and R5 are the same or different and are hyd-rogen or lower alkyl, R6 occupies the 1- or 3-position and is lower alkyl or phenyl, and R7 and R8 are the same or di~ferent and are chlorine, bromine, fluorine or iodine, m is O to 3, n is O to 3, and m ~ n is - 5;
or 1~7S3~
r~,sso/s5 R (O)z Rlo _ Si (CH2 ) p/~--Rll wherein Rg, Rlo and Rll may be the same or dif~erent and may be lower alkyl or lower alkoxy, z is 0, 1 or 2 and (CH2Jp represents an alkylene group having 1 to 5 carbons, with the proviso that when A is ~<9 (~) z Rl o-- Si ~CH2 ) pS
Rll~
R is lower alkyl.
The term "lower alkyl" as used herein includes straight or branched chain aliphatic hydrocarbon radicals having up to and including 7 carbon atoms, preferably 1 to 4 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, heptyl and the like. However, in the case of Rg, Rlo and Rll, only one or two lower alkyls of same m~y contain more than one branch.
The term "lower alkoxy" includes any of the above lower alkyl groups linked to an oxygen atom.
The term "phenyl lower alkyl" as used herein refers to lower alkyl groups as discussed above having a phenyl substi-tuent, such as benzyl.
The term "cycloalkenyl" includes cyclic hydro-carbon groups containing 3 to 10 carbons. Examples of suitable cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclohe~enyl, cycloheptenyl, cyclononenyl and cyclodecenyl. In the above cycloalkenyl rings, the 7~

doub].e bond is a~ the alpha position in the riny.
(CH2)m and (C~I2)n repxesen~ a single bond or straight or branched chain alkylene radicals containing 3 or less carbons in the longest normal chain.
A me-thod is also provided for treating or pre-venting whipworm, tapeworm and other helminth infestation by orally, parenterally or topically administering to a mammalian or poultry host a benzimidazole as described above.
The preferred compounds of structure 1 are those wherein R is ~ethyl, ethyl, propyl or benzyl, y îs O or 1, Rl and ~2 are taken together to form a cyclohexen-l-yl ring or a cyclopenten-l-yl ring, or Rl is methyl, ethyl or n-propyl and R2 is hydrogen, methyl or ethyl, and R3 is hydrogen.
Examples of preferred compounds falling within the present invention include the following.

R2 R ()Y
R3 i _ i _ S ~ ~

N ~HC02R

~7~3~
GS9o/95 R3 y , , ,, _ ., ,_, ~
1 . C~ 3 Cfl 3 ~l ~l

2 5 C2ll5 C~13 H O

3. C2H4C6~l5 4l~8 H

4. CH3 C3~l6 I-l O

5. CH3 C3H7 C2fl5 H O
C2 ~5 C3H6 H
7. CH3 C3H6 M

9. CH3 C3H7 C2H5 H
10. CH3 C2H4 c~3 11. CH3 C6H12 H O
12. CH3 C8H16 H
13. C2H5 C5ll11 C2H5 0 14. CH2C6H5 C2H5 CH3 CH3 ~_~ ( CH2 ) m--C - ( CH2 ) n ~

6 5 ~ J NE~C02R

~7~3~

The preferred compounds of structure 2 are those benzimidazoles wherein R7 and ~8 are chlorine and/or bromine, R6 is methyl or e~hyl in the L-position, l4 -(CH2~m-C~(CH2)n- is methylene or ethylene, and R is methyl or benzyl.
RLo_ si (CH2) ps~ \~3----The preferred compounds of structure 3 are those wherein ~ is methyl, ethyl or propyl, p is 1, z is 0 or 1 and Rg, Rlo and Rll are each methyl, or two thereof are ethoxy and the other methyl, or each are ethoxy.
The compounds of structure 1 may be prepared as follows.
The vinyl thiol II is prepared by using the methods published by Mayer [J. Praktische Chemie 34, 116 (1966);
Chem. Ber. 96, 3096 (1963); 99, 1771 (1966); Agnew.
Chemie Internat. Ed. 1, 217 (1962)~. The alkali salt of II is then reacted with 5-chloro-2-nitroaniline III
to furnish IV. The reaction can be carried out in solvents such as alcohols, acetonitrile or glyme at temperatures ranging from a~out 25 to about 100 for periods of about 30 minutes to 10 hours.

i3~
GS9Q/~5 R~
CEI-C-S
R ~' R

R2~ l. MOH \ C~

C~ 2. Cl ~ NEr2 l ~ 2 II III IV

M=K, Na The compounds of ~tructure IV where Rl and R2 form a cycloalkene may be prepared as reported by Seebach et al. [Chem. Ber. l , 847 (1964)]. Reaction of the lithilated vinyl derivative V with a disulfide VI yields 2Q IV.
- Br (CH.~2)m ~ ~ (CH3)3-C Li (CH ~ L

V

(CE2~

V VI IV

$3~

R12 - NO2 or NH2 R14 = ~ ~ R13 R13 = N~2 or NO2 Mykaiyama ~Chem. Letters 479 (1973)] describes an additional route toward IV by reacting a carbonyl compound VII with a thiol VIII in the presence of TiCl~.
\ CH HS ~ \ C

. C=O Rl3 R3 ~ ~C-S
R3 Rl ( 2 5)3 ~1 VII VIII IV

Vinyl sulfides IV are conveniently reduced to the requi-site o-phenylenediamines IX by using aqueous Na2S2O

R ~ ~C-S R Na2S2o4 R C~C S NH22 IV IX
The final step in the synthesis of 1 where n ~ 0, namely ring-closure of IX to furnish la, can be achieved in various ways. Refluxing IX with the isolated thiourea derivative X will yield la. The preferred method of preparing la is by forming X in situ and then without ~7~3~ g0/95 isol~tln~J it, addin~J IX and refluxing it for 30 minutes to 5 hours, to yield the desired product.
E~2 ~,N-C02 R R~2=~-S7 CH3S-C IX ~ ~N \ NHCO2P~

X la Compound III can be prepared by ~he se~uence depicted below:
~i' V 2 ~ ~ HCOCH3 Cl\~ `~ NHCOCH3 ~ ~ AC2O l~ ~ 2 l~ ~ O _~

Cl \ ~ ~NH2 ~ N02 III
Compound VI can be prepared by oxidizing XI with air.

2 ~ ~ ~ ~ 2 XI yI
Compound XI is prepared by the route outlined below:
NO2 NCS~ NO
~ j~ SCN ~ ~ NaBH4 ~,/\ Br2 ,~\~ ~t HS NO

NH

XI
,, . . . , ., . , . , ~ .. . . . . . . . . . . . . ... .. .. . . . . . . .

1 i3L~S~B

() The sulfides of struc-ture IV are con~erted to the corresponding sulfoxides by oxidizing aq~nts such as hydrogen peroxide, peracids (e.g., perace~ic acld, m-chloroperbenzoic acid), manyanese dioxide, sodium meta-periodate as outlined by Sandler and Caro (Organlc Functional Group r ~ , 1968, p. 493).
[O] ~ R ~ R12 Iy ---~ R -~ - C- S- ~ R13 whereln one of XII
The resulting sulfoxides XII may be purified by crystal-lization and then reduced to the corresponding o-phenyl-enediamine XIII. Chemical reduction may be used. Forthe chemical reduction, the procedure outlined by Sandler and Caro (Organic Functional ~ reparations, 1968, pp. 339-340) is preferred. The final step in the synthesis of sulEoxides of formula 1 (n=l), namely ring closure of XIII to furnish lb, can be achieved in various ways. Whereas refluxing of XIII with the isolated thiourea derivative XIV in alcohols such as methanol or ethanol will furnish lb, the preferred method of pre~
paring 1 is by forming XIV ln situ and then without isolating it adding XIII and refluxing it for 30 minutes to 5 hours to yield the desired product.
XII Fe/H0 R2 ll ~ NH2 -Ir R3-C --C- S_ ~ ~
XIII ~ NH2 SCH3 o XIV

R3-C--C~

\ W /"
lb Alternatively, sulfoxides o~ structure lb may be prepared directly from the sulfides la by oxidizing the sulfides with NaIO4.
The benzimidazole derivatives of structure 2 may be prepared by thiocyanation of 0-nitroaniline to yield 4-thiocyano-2-nitroaniline. This product is then subjected to a sodium borohydride reduction to yield the corresponding 4-mercapto-2-nitroaniline XI. The mercapto derivative may be i~olated or used directly for the next step. Thus, to the reaction mixture there is added the haloalkyl cycloalkane XV to furnish the sulfide XVI.

~ ~ NH2 Acet~c ~cid~ ~ NH2 _.~
HS ~ ~ NO2 XI

~753'~

XI ~R7~ R8 l4 ~,~,,," _ ((~12)m 1 (Cl~
~6 5 (wherein X is Cl or Br) XV

~ ~ (CH2) -C-(CH2) -s~3-- 2 Examples of haloalkyl cycloalkanes of formula XV suitable for use herein include the following:

Cl ~ Cl Br ~ ~ Cl 20 ~ CH2-Cl ~ ~ ~CH2-Cl C~3 CH3 Cl Cl Br ~ Br ~ 3 CH3 ~ _CH2-~r CH3 Cl Cl ~ ~_ CH2Cl ~) ~7~

The resultin~ sulfides XVI rnay be purified by crystallization and then reduced to the corresponding o-phenylene diamine XVII.
Either chemical or catalytic reduction may be used. For the chemical reduction the procedure outlined by Sandler and Caro (_rganic Functional Group Preparations, 1968, pp. 339-340) is preferred. The final step in the synthesis of 2, namely ring closure of XVII to ~urnish 2, can be achieved ln various ways. Whereas re~luxing of XVII with the isolated thiourea derivative XVIII in alcohols such as methanol or ethanol will furnish 2, the preferred method of preparing 2 i5 by forming XVIII
in s u and then without isolating it adding XVII and refluxing it for 30 minutes to 5 houxs to yield the desired product.

or ~ (CH2)m-C-(CH2)n ~NH

20Fe/H0 t XVII 2 O O
ll SCH3 1¦
ROC-N=C-NH -OR

XVIII
An alternative route toward the intermediate XVII
offers the reaction of III with the requisite mercapto-alkyl cycloalkane XIX, to yield XX. Here, in contrast to the alkylation step described above, (i.e., XV ~ XVI) the reaction temperature has to ~e higher and the reaction periods have to be longer. Reduction of XX yields the desired diamine XVII.

L7`~
GS9o/95 NO2 \ ~ R4 S Cl ~H2 + ~(C~12)m-1- (C~2)n III XIX

R7 R~
4~(CH2)m ¦(CH2)n 5 ~ ~ ~

XX

A great variety of haloalkyl cycloalkanes XV are commercially available. ~n some cases the requisite haloalkyl cycloalkane has to be synthesized. For example, reaction of the appropriate alkene wit.h the requisite halocarbene will yield the desired starting material.
The requisite haloalkyl cycloalkanes may also be prepared from the corresponding alcohols by standard reactions.

q~he coml~ound~ of~ ~3 tructure 3 may be prep~red acco.rdi ng to t:he following reaction ~equences ~
NCS NO2 NasH HS N0z 1 ~'S~ N2 ~(C~ nan-reaa in~ (~ ~ ~
NH2 solvent NH2 ~ NH2 e.q. DMF or acetonitxile / XXII
u~er N2 /~,^Y~

~ >

r -- oq NH2 ~ R ' S No2 R ' S ~H2 15 R' ~<~NH2 ~ NH2 ~H2 XXVI XXV XXI I I
S~
I /~
~ RD2CN=C-NHCO R ~ ~2C~C~NHc~ R
XXIV XX:[V

'~q N>_~C02R ~ ran-react ng~>-NHC02R
H
3d 3a Rl q= 1 or 2 R' = R~ Si (CH2¦p '753~3 The compounds of structure 3 wherein m is 0, that i8 ~9 Rlo _Si (C~12)p-S f `~ \\
3a Rll / 1 J r NHCO2R
~ ~ N
~1 may ~e prepared by reacting 4-thiocyanate-2 nitroaniline with sodium borohydride in the presence of a non-reacting solvent, such as dimethyl formamide or acetonitrile under nitrogen ~or a period ranging ~rom about 0.5 to about 4 hours. Thereafter, a silane derivative XXI is admixed with the mi~ture wi~h heating to form a silylalkylene-thio-2-nitroaniline derivative ~XII.
The silylalkylenethio-2-nitroaniline derivative XXII is then reduced employing conventional reduction techniques, for example, catalytically with hydrogen and platinum or chemically with dithionite, or zinc and acetic acid, to form the corresponding o-phenylenediamine XXIII
which is then reacted with an isothiourea of the structure - 20 XXrV in the presence of an alcohol solvent (~OH) or other non-reacting sol~ent, and optionally, an acid catalyst, such as acetic acid at temperatures ranging from about 50 to about 200C, and preferably from about 80 to about 130C, for one minute to 3 days, preferably for 1 to 24 hours, to form the formula 3a compounds.
The formula 3a compound may be oxidized to the corresponding sulfoxide 3b employing one equivalent o~ an oxidizing agent such as hydrogen peroxide in acetic acid, sodium meta periodate or m-chloroperbenzoic acid.

~l7~38 9 \ 16 3b Rlo Si(CH~)p~S _ " __N

Rll / l~ ~JHC02R
El The sulfone 3c R10--Si(CH2)p~5 ~ \>~ HCO2 may be prepared ~y reacking the thio compound 3a with two or more e~uivalents o any of the a~ove oxidizing agents;
alternati~ely, the sulfone 3c may be prepared by reacting the sulfoxide 3b with one equi~alent of any of the above oxidizing agents.
Compounds o~ structures 3b and 3c may also be prepared by oxidizing the ~ormula XXII silylalkylenethio-2-nitroaniline derivati~e with one or two or more equi~a-lents of oxidizing agent to ~orm a silylalkylenesulfinyl-(or sulfonyl~-2-ni~roaniline XXV which is then reduced to the o-phenylenediamine XXVI. The o-phenylenediamine XXVI is then reacted with the thiourea xxrv in the presence o~ an alcohol solvent tROH~ or other non-reacting solvent to ~orm the compound o~ structure 3d tthat is, 3b or 3c).
The sta~ting materials employed in the a~o~e reactIons are either known in the art or easily prepared according to conventional techniques.

53~

In c~rtain instances, the compounds of formulae 1, 2 and 3 foxm physiologically accep~able aci~-addition sa].ts with inor-~anic and organic acids. These sal-ts frequently provide useful means ~or isolatiny the products from reaction mi~tures by forming the salt in a medium in which it is insoluble. The free base may then by obtained by neutralization. Then any other salt may again be formed from the ~ree base and the appropriate in-organic acid. Illustrative are the hydrohalides, espec-ially the hydrochloride and hydrobromide which are pre-ferred, sul~ate, nitrate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, and the like.
The compounds of formulae 1, 2 and 3 have anthel-mintic activity and are use~ul in the treatment and/or prevention of helminthiasis, a parasitic disease which causes widespread and often serious infection in do-mesticated animals such as swine, cattle, horses, dogs~
cats and sheep. The compounds are useful in treating infections caused by Haemonchus, Ostertagia, Tricho-strongylus, Cooperia, Dictyocaulus, Nematodirus, Buno-stomum, Strongyloides, Oesophagostomum, Trichuris, Moniezia, and liver flukes (for example in sheep). In treating domesticated animals, the compounds are given orally; however, other routes such as parenterally, for example, subcutaneously, intravenously, interperitoneally and intramuscularly may be employed. The compounds of formula 2 can also be applied topically (cutaneously~, preferably directly on to exposed skin surface.
When the compounds are to be administered in unit dosage form, capsules, boluses or drenches containing the desired amount of anthelmintic distri~uted in a pharma-ceutically accepta~le ~ehicle are usually employed. These are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, sus-pending agents, fillers, disintegrating agents and/or

7~3~
GS~0/95 1~
binders such as starch, lactose, talc, magnesium, stea~ate, v~getable gums an~ -the like and are compounded by tech-niques generally known in the ar-t.
The compounds may also be administered as a cam-ponent of the feed of the animals or suspended in thedrinking water. Thus, novel feed and feed supplement compositions may be prepared in which the compounds o~
this invention are present as an active anthelmintic ingredient. A typical feed supplement comprises the anthel~intic agent intimately dispersed in or admixed with an inert carrier or diluent, i.e., one that is non-reactive with respect to the anthelmintic ayent and that may be administered with safety to the animals. The carrier or ~iluent is preferably one that is or may be an ingredient of an animal ration. This composition may be mixea with the feed to give any useful desired concen-tration, preferably about 0.1-2%. Lastly, feeds containing the active ingredient may be made directly by mixing said active ingredient in a feed which is inert to said anthel-mintic compounds so as to give feeds having concentrationsof anthelmintic agent of from 0.1-2~.
In preparing injectable compositions, the compounds are mixed with a non-toxic, physiologically acceptable non-pyrogenic carrier such as sterile water, sterile saline solution, henzyl benzoate, 1,3-butylene glycol, ethyl oleate, castor oil, glyceryl triacetate, sesame oil, and sesame oil:benzyl benzoate ~1:1). The parenteral product will usua:!ly take the form of a suspension containing from about 1 to about 10~ by weight of the compound of formulae 1, 2 or 3.

~3L7~3~

The above in~ectable compositions may also include a non-toxic phy~iologically acceptable non-pyrogenic suspending a~ent. Thus, where a non-oily carrier is em-E)lYed such as water, suspending a~ents such as carboxy-methyl cellulose, methyl cellulose, polyvinyl pyrrolidoneor non-antigenic gelatin may be employed. ~nlere the carrier employed is an oil, aluminum monostearate may be employed as a suspending agent. The suspending agent may be employed in amounts ranging from about 0.05 to about 2%, and preferably from about 0.1 to abou~ 1% ~y volume of carrier ~the above % may be based on the weight of the carrier where the carrier is ~s to 100g).
A non-toxic, non-pyrogenic wetting agent may also be included in the in~ectable compositions in amounts ranging from about 0.005 to about ~% and preferably from about 0.01 to about 0.1~ by weight of the carrier. Examples of suitable we~ting agents include non-ionic surfactants such as polyoxyethylene sorbitan monostearate, polyoxy-ethylene sorbitan monooleate Ie.g., Tweens] and fatty acid monoglycerides or diglycerides. Other surfactants suitable ~or use herein are disclosed in the published literature, for example, Kirk-Othmer, Encyclopedia of Chemical Technology, Second Edition, Volume 19, page 507 et seq.
In preparing topical or cutaneous compositions, the anthelmintic compounds are mixed with carriers which are effective in penetrating the skin, whereby the compounds are absorbed by the animal through the skin and transmitted systemically within the animal. A wide range of appropriate carriers may be employed to pass the compound through the * Trade Mark ~ 53~ GS90/95 skin. The composition employed may be a cream. A liquid composition, however, is particularly convenient to use, e . g., facilita~ing meas~lri~g out doses/ and ~acilitating absor~ance through the skin. Thus, a solution or suspension 5 of the compound in a liquid carrier is pre~erred. Solutions are especially yood for -transmittlng the compound through the skin ana are therefore most preferred. The liquid carrier preferably comprises one or more liquids selected from hydrocarbons (e.g., aromatic hydrocarbons, such as an aromatic hydrocarbon frac-tion of boiling point 130-250C, e.g., 180-220C, xylene, benzene or toluene, or paraffins, such as those of 6-20 car~on atoms~, halogenated aliphatic hydrocarbons (e.g., carbon tetrachloride), ketones (e.g., cyclohexanone or 2-butanone), esters (e.g., ethyl acetate, ethyl benzoate or triacetin~, ethers (e.g., diisopropyl ether or tetrahydrofuran), alcohols (e.~., alkanols of 2-8 carbon atoms, such as butyl alcohol, amyl alcohol or isopropyl alcohol, or qlycols, such as monopropylene glycol), amides (e.g., dimethylformamide), sulphones (e.g., dimethyl sulphone or sulpholane), and sulphoxides (e.g., dimethyl sulphoxide).
In many cases a mixture of liquids is desirable. Preferably the liquid carrier comprises ~ne or more liquids selected from hydrocarbons (e.g., aromatic hydrocarbons especially xylene), alcohols (e.g., isopropyl alcohol or amyl alcohol and sulphoxides (e.g., dimethyl sulphoxide). Water tends to be ineffective as a liquid carrier for passing the compound through the skin of the animal. Accordingly, the carrier in the liquid compositions preferably comprises an organic liquid.

5;~

The vlscosity of li~uid compositions may be increased over what it would otherwise b~ by including thickeners which increase the vi~cosity. This may ~e desirable in order to retard or prevent the composition from running off the animal.
The additives may include, for example, a surface acti~e agent, an animal fat or wax, e.g., lanolin, a mineral oil, e.g., liquid paraffin, a ~egetable oil, e.g., peanut oil, olive oil, corn oil or cA~tor oil, or a polymer, e.g., a hydrocarbon polymer such as polyiso~utene.
The surface active agents may comprise anionic compounds, for example, soaps, fatty sulphate esters, such as dodecyl sodium sulphate, fatty aromatic sulphonates, such as alkylbenzene sulphonates or butyl-naphthalene lS sulphonates, m~re complex fatty sulphonates, such as the amide condensation product of oleic acid and N-methyl taurine or the sodium sulphonate of dioctyl succinate.
The surface active agents may also comprise non-ionic sur~ace active agents such as, for example, condensation products of fatty acids, fatty alcohols or fatty polyhydric alcohols, or the products obtained from the latter by condensation with ethylene oxide, or the products known as block copolymers of ethylene oxide and propylene oxide.
The surface active agents may also comprise cationic agents such as, for example, cetyl trimethylammonium bromide.
The term "surface active agent" is used in the broad sense to cover materials variously called wetting agents, emulsifying agents and dispersing agents.
The composition may contain substances whose taste 3a ~7S3~ GS90/95 deters other animals erom lickin-J the composition of~ the animal treated. An example o~ such a substance is bitter aloes .
Generally, additives eacilitatlng the u.se in pour-on ~ormulations of other materials, e.g., systemi~ insecticides, active on animal physiolo~y may be of use also in the present composition.
In general, in carrying out the method of the invention, the oral, parenteral or topical compositions descri~ed above may be a~ministered to animals in a single dose or divided into a plurality of smaller doses gi~en over one or more days, for example, up to 14 days, to pro-vide from 1 to about 200 mg acti~e compound per kilogram of animal body weight. It is preferred to employ in the range of 2.5-75 mg per kilogram of body weight.
The compounds of formula 2 are especially useful against whipworm (Trichuris vulpis~, and when so employed, it is preferred that such compounds be administered over a 5 to 9 day period in amounts ranging from about 4 to 2~ about 10 mg per kilogram of animal body weight per day, and more prefera~ly over a 6 to about 8 day period in amounts ranging from about 4 to about 6 mg per kilogram of animal body weight per day.
If the compounds of the invention are to be employed against tapeworm, for example, Taenia ~isiformis and Dipylidium caninum, i~ is pre~erred that such c~mpounds be administered over a 2 to 10 day period, in amounts ranging from about 7 to about 20 mg per kilogram of animal body weight to provide ~rom about 75 to about 400 mg per 3Q day and moreprefera~ly from about 8 to a~out 15 mgper kilogram ~7~3~
GS9o/95 of a~nimal body weight ~o provide ~rom about lQQ to about 300 mg per day.
The follo~ing examples are provided ~or illus-trative purposes and may include particular ~eatures of khe invention~ however the examples should not Be construed as limiting the invention, many variations o~ which are possible ~ithout departing ~r~m ~he spirit or scope thereof. All temperatures are in degrees centigrade.

5;~

2~

[5~ Cyclohexen- 1~Y1thiO1 l~r-ben ~ l~c-arbamic acia, methyl estex A. 5~ Cyclohexen~l-ylthio)-2 nitro~enzen~amine To a solutio~ o~ 6.9 g (0.04 mole) of 5-chloro-2-nitroaniline in 50 ml oY absolute ethanol there is added 6.0 g o~ the potassium salt of l-cyclohexene-l-thiol IJ. Praktische Chemie 34, 116 ~1966~]. The mi~ture is heated on the steam bath ~or 0.5 hour, ~iltered and the filtrate is reduced in volume ln vacuo. ~he resulting solia is filtered off and crystallized from absolute ethanol to yield 5.3 g, m.p. 100-102.
B. 5-(1-C~clohexen~ lthio)~o-phenylenediamine To a suspension of 3.5 g (0.014 mole~ of 5~
cyclohexen-1-ylthio)-2-nitrohenzene-amine in 125 ml of absolute ethanol under N2 there is added a solution of

8.4 g of Na2S2O4, 8.4 ml o~ concentrated aqueous ammonia and 52.5 ml of water. The mixture is refluxed for 15 minutes and an additional 0.8 g of Na2S2O4 is added.
~fter an additional 15 minutes reflux period TLC (silica, Et2O~ shows no starting material present. The ethanol is removed ln vacuo; the aqueous residue is taken to pH 12 with 50% aqueous NaOH and then extracted with CH2C12.
The organic extracts are combined, dried ~MgS04) and evaporated to give an oil which is used immediately in the following reaction.
C. ~5~ Cyclohexen~ -lthlo-lH-benzimidazol-2-yl]
~ar~mic acid, me*hyl ester To a solution of the above diamine in 50 ml o methanol there is added 1 ml of acetic acid and 2.8 g (0.014 mole~

11~753'd ~1S~0~95 of 1,3-bis(methoxycarbonyl)-5-methylisothiowrea and the resulting mixture is re~luxed for 2 hours. The methanol is removed ln vacuo and water is ~dded. The resulting solid is filtered o~, dried and crystallized from glyme-acetonitrile (l:l)to yield 2.9 g o~ the title compound, m.p. 224~226C (dec.).

Exa~ple 2 I5~cl-c-yclopenten~l~ylthio)~ Een~imodazol~2-yl]ca-~amic acld, m t_yl ester Following the procedure of Example 1, but substituting for cyclohexanone, cyclopentanone, the title c~mpound is outlined.

~xample 3 I5 (:l-cyclohepten-l-ylthiol-lH~benzimidazol~2-yl]carbamic acid, methyl ester Following the procedure of Example 1 but substituting ~or cyclohexanone, cycloheptanone, the title compound is obtained.
Example 4 ~5~C4-Hepten-l-ylthio~ benzlmidazol~2-yl]carbamic acid, methyl ester Following the procedure of Mayer LBer. 99, 1771 (1966)] for preparing heptan-4~thione and substituting it ~or the l-cyclohexene-l-thiol used in Example 1, the title compound is ohtained.
.

3~
GS~0/9S

E,xample 5 Is~ cyclo-exen-~ lH-benzimidazol~2-yl~-carbamic Hcid, methyl ester A~ 4~fl-Cyclohexen-l-ylthio~-2-ni'~ro~enzen~-amin'e To 500 ml of ary tetra~ydrofuran under N2 there i~
a~ded 5.0 g o~ cyclohexanone and then 5.5 ml of TiCl~.
T~en there is added a mixt~re of 11. 0 ml of ~rie~hylamine and 8.5 g o~ 3-amino-4-ni~robenzenethiol in 105 ml of dry tetrahydrofuran and the mixture is stirred overnight at room temperature. Then there is added 300 ml of H2O and the mi~ture is extracted with aichloromethane. The organic layers are com~ined, dried (MyS04) and evaporated in vacuo.
The residue is chromatographed on silica gel. Elution with 1:1 PE-Et2O yields 2.8 g of 4~ cyclohexen-1-ylthio)-2-lS nitro~enzene-amine, m.p. 93-95~C.
B. 4~ Cyclohexen~l~ylsulfinyl'~-2-nitrobenzene-amine To a solution of 2.5 g (0.01 mole) of the benzeneamine obtained from part A in 50 ml of methanol under N2 there is added a solu~ion of 2.2 g NalO4 in 20 ml of H2O at 0-5~C
~or 30 hours. The mixture is then extracted with dlchloro-methane. The organic layers are combined, dried and evaporated. The re~idue is crystallized from acetonitrile to give 2.2 g, m.p. 1'39-1~0C of the sulfoxide.' C. ~5~ C~clohexen-l-ylsulfinyl)-o-phenylenediamine To a suspension of 2.Q g ~0.0075 mole~ of 4~
cyclohex-l-ylsulfinyl~-2-nitrobenzeneamine in 75 ml of absolute ethanol under N2 there is added a solution of 4~9 g o~ Na2S204, 4.9 ml o~ concentrated ammonia and 30 ml o~ H20. The mixture is refluxed for 15 minutes and an ., ~

,;:
,, _., ,,~
.

~7~3~
~S90/95 addition~l a. ~ ~ of Na2S20~ i.s adde~. After an additional 15 minutes reflux pexiod th~ ethanol is remo~ed ln vacuo The aqueous residue is taken to pH 12 Wi~h 50~ aqueous NaOH and then extracted with ~ichloromethane. The organic extracts are dried (MgSO4] and evaporated to gi~e an oil which is used immediatel~ in the following reaction.
D. I5~ C~clohexen~ sulfin~ H-~enzimidaZol-2-yl]carbamic acid, meth~l ester To a solution of the a~o~e diamine in 25 ml of ~ethanol there is added 0.5 ml o~ acetic acid and 1.5 g o~ 1,3-bis(methoxy carbonyl)-5-methylisothiourea and the resultin~ mixture is refluxed for 3 hours. The methanol is remo~ed in ~acuo ana water is added. The resulting solid is ~iltered off and crystallized from acetonitrile to yield 1.05 g of the title compound, m.p. 228-230C Cdec.~.

Exa_~le 6 ~5~ Cyclopenten-l-ylsulfinyll-lH-benzimidazol-2~yl~--carbamic acid, methyl ester 2Q Following the procedure of Example 5, but substituting for cyclohexanone, cyclopentanone, the title compound is obtained.

Exam~ple 7 ~5-(1-Cyclohepten-l-ylsul~inyl)-lH-ben ~idazo1~2-yl]~
carbamic acid, methxl ester Following the procedure of Example 5, but substituting for cyclohexanone, cycloheptanone, the title compound is o~tained.
Example 8 7~3~

~8 [5-(4 ~y~ sulfinyl~-lH~benzimidazol--2-yl~carbamic acid, methy~
The sulfide of Example 4 is oxidized with Na~04 to gi~e the title sulfox~de.
s Fxample 9 15-C3-Penten-l-ylthio~-lH-benzimidazol~2-ylJc,arbamic aeid, m thyl estër ~~
Following the proeedure set out in Example 5A, C
and D except substituting 3-pentanone ~or cyclohex~none, the title compound is o~tained.

Example 10 I5-(5-Nonen-l-ylt-hio?-lH--benzimia-a-zol-2-yl]carbamic acid, methyl ester Following the proeedure set out in Example 5A, C
and D except substituting 5-nonanone for eyelohexanone, the title eompound is obtained.

2~ Examples ll_to 21 Following the proeedure of Example 1 but substituting for l-cyelohexene-l thiol the eompound shown in Column I
of Table I below, and substituting for 1,3-bis~methoxy-earbonyl)-5-methylisothiourea the eompound shown in Col-umn II, the sulfide deri~atiYes of benzimidazoles asshown in Column III are obtained.

1~1753B
GS90/g5 ~, 29 H r V~ U~
C~
~ U
8 / \ ~ ¦ ) H

~1) U

~; P;
O O

z 3 ~ mn ~ ~ ~n ~ul U
~ ~1 N ~ t~
W C.) ~ C~ U U U O C) C~ ~ U U U

In In U~ U ~
In ~n P; I ~ U I I U I ~

H U~ ~ ~ ~ N tr~
~ 11 P; V U I I ~ ~ I C,) ~,) I I
t) t~

co ~1 p; l ~ u o ~ c~ u l i c) o o ,~ n ~ co ~ o ~1 ~; ~

~3 ~753~

Rxamples 22 to 32 Followin~ the procedure of Ex~mple 8, the sulfides o~ Examples 11 to 21 shbw~ in Column I o:~ Table II ~elow are oxidi zed to ~ive the corresponding sul~o~ides .

~l~L753~:3 GSgO/95 PS K 1`
~ I ~/
Z ~< ~

H ~ ,1 ~ ~ 3-- ~ j .. . . .. ... ..
.

H K
H 5~ N ~) ~ ~ ~'1 ~I

g H
~ I ~

C~ ~ 00 U~
; ~ ~ ~ ~ ~ ~

. . . , . I , . . . , ~
O N l`t ~ It~ O _I
~:1 Z ~ ~ ~J ~ ~a ~ ~ ~`I M ~1 ~7~i3'~

_x~ e 33 L5-~(2~2-Dic~lloro-l-me-h~ xclopropyl)methyl~thioJ-lH
benzimidazol-2-yl]carbamic ac ~ 1 ester _ _ w A. 1,1-Dichloro-2-chloromet~yl-2-m _hylc~clo-pro~__e ~Makosza and Fedorynski Synthesis, 1974, p.2 Robinson, ~ . ChemO 34, 2518 (1969)) To a vigorously stirred mixture of 45.3 g (0.5 mole) of 3-chloro-2-methylpropene, 120 g of chloroform (precursor of dichlorocarbene) and 1.5 g of benzyl-triethylammonium chloride tTEBA) there is added dropwise 120 ml of 50% NaOH not allowing the temperature to rise above 40C. The mixture i 5 kept at 35 to 40C for 3 hours then diluted with 250 ml of H2O and extracted with chloro-~orm. The organic layer is dried (MgSO4) and the CHC13 removed in vacuo. Distillation of the residue under house vacuum yields a fraction, b.p. 89-90C, 45.7 g.
B. [5-[[(2~-2-Dichloro----l--methylcyclopropyl?methyl]-thio-lH-benæimida~ol-2-yl]carbamic acid, me_hyl ester To a stirred mixture o 9.75 g (0.05 mole) of 2-nitro-4-thiocyanoaniline in 500 ml of absolute ethanol under N2, there is added 2.1 g of sodium boroh~dride in portionsO The mixture is stirred at room temperature for 15 minutes and then refluxed for 15 minutes. The heating mantle is removed and 3~25 g (0.05 mole) of KOH in 30 ml of absolute ethanol is added. The mixture is stirred for 1 minute. A solution of 8.7 g (0.05 mole) of 1,1-dichloro-2-chloromethyl-2 methylcyclopropane in 15 ml of absolute ethanol is added and the mixture is re~luxed for 3 hours. Equal amounts of H2O and CHC13 are added until two layers are formed. The organic layex is separated, dried (MgSO4), and the solvent removed ln vacuo to give ~753'~

a red oil which is tri~urated with 10 Inl of absolute eth~nol to yield 9.6 g o~ solid, ~.p. 76-78aC.
A mixture o~ 9.Q g (0.03 mole~ of 2-nitro-4-~2,2-dichloro-l-methylcyclopropyl~methyl]thioaniline and 0.9 g of PtO2 in 200 ml of absolute ethanol i9 reduced on the Parr hydrogenator at 50 psi until the theoretical amount of H2 is absorbed. The mixture is filtered and the solvent is removed ln vacuo to give a dark oil which is used immediately in the following reaction.
~rO a mixture of 6 g of 2~methyl-2-thiopseudourea sulfate in 6 ml of ~2~ there is added 5.7 ml of methyl-chloroformate at 0C and the mixture is stirred for 15 minutes. Then there is added 14 ml of 25% NaOH dropwise and the mixture is stirred for 15 minutes. Then there is added 6 ml of acetic acid dropwise and the mixture is stirred for 15 minutes. Then the entire amount of the phenylenediamine from the preceding reaction in 20 ml of MeOH is added and the mixture is refluxed for 3 hours.
The alcohol is removed in vacuo and H2O is added. The resulting solid is filtered off and crystallized from MeCN to yield 4.9 g, m.p. 175-178.
Examples 34 to 40 Following the procedure of Example 33A except substituting for 3-chloro-2-methylpropene, the compound shown in Column I of Table I Below, and substituting for chloroform, the compound shown in Column II, the cyclopropane starting material shown in Column III is obtained.

3~ GS g O/ g 5 H C ) u _a N~ ,~m m ~ u ~q~

. _ . _ _ . ... .
H~ p$~ U \ m H

N
u ) m ,~

x ~7~3~3 GS9o/95 .. . . . .

~ _,,, ~ ., H
H
~ P~
o _~ ~ ,, m ~ Ul` ><L

H o~) r~l 1^~ h t~ ~1 \ U ~ \ m ~ o H

~ .

~_~
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U
H ~ n ~ I~;-V-P~

o ~ m C~ O
c~ ~ r---~ U

. .
~ ~; ~ ~

~3L7~i;3~
GS9o/95 X

_~ `~.

H

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,~ ~

, _ _ ,~
_1 `_, . .. _ ._ __ X

H e~ l ~ p~
C~ ~ C~
~, ~ 1 m C~
--~ o-~
P~

X~l o 7~
GS9o/95 Following the procedure of Example 33B except substituting for l,l-dichloro-2-chloromethyl-2-methyl-cyclopropane the compound shown in Column III of Table I (Column I of Table II) below and substituting or S methyl chloroformate the compound shown in Column II, the product shown in Column III is obtained.

~; GS90/95 ~ 38 ,~ 0 o ~ _ H C) U
~ _ _, ~r I ~ ~r I Ir) ~i -1 _ _. I 1_ O ~ ~
~>
a U~
/ ,a w~ ~1 ~1 U~ a~

~i ~i .
~ p:
H
~ 1 ~ 1 ,1 _ _ O ~ C`l ~U>d ~

x~l ~39 o ) 'u~

H ~N

O N ~
U $ O
e~ C~
~ ~ r ~ H
U ~

H ¦ o p~

-N

m P~ ~ N
N m N N

U~
~c ~1 , ~L753~3 .,, H 1:~
u ~ !
, ~ , o V ~ ~ U
.

~ ~ u I ~Yi I 3 xl ~.

N
U- ~;U

t CO I ~ ~
~,X _W

~ ol o ~1753B
GSgO/~5 _al~
f5-~[(2,2-Dichloro-3~ y_c~ oE~r~ thyl]thio]-lH-benzimidazol-~y~ _aid, me_~l ester A mixture o~ 21.6 g (0.3 molel of crotyl alcohol, 600 ml of 50% aqueous sodium hydroxide and 1.2 g of triethylbenzylammonium chloride (T~sA) is s-tirred vigorously a-t 40C -to ernulsify. Then 480 ml of chloro-orm is added dropwise over 2 hours and the mixture is stirred for a ~urther 2 hours. The mixture is poured into water and extracted with chloroform. The organic layers are combined, dried (MgSO4), and the solvent is removed in vacuo. Distillation of -the residue yields 18.3 g of 1-chloromethyl-2,2-dichloro-3-methylcyclopropane.
To a stirred mixture of 9.75 g (0 05 mole) o 2~nitro-4-thiocyanoaniline in 200 ml of dry acetonitrile under nitrogen there is added 2.1 g (0.05 mole) of sodium borohydride in portions. The mixture is stirred at room temperature for 15 minutes and then refluxed for 15 minutes. The heating mantle is removed and 3.5 g (0.05 mole) of KQH is added. The mixture is stirred for 15 minutes. Then a solution of 8.7 g (0.05 mole) of l-chloro-methyl~2,2-dichloro-3-methylcyclopropane in 10 ml of acetonitrile is added and the mixture is refluxed for 2 hours. The reaction mixture is cooled, filtered, and the solvent is removed in vacuo. Water and chloroform are added to the residue. The organic layer is separated, dried (MgSO4), and the solvent is removed in ~acuo to give 12.4 g of red orange oil.
A mixture of 12 g (0.04 mole~ of the above nitro-aniline and 1.2 g PtO2 in 200 ml of absolute ethanol is reduced on the Parr hydrogenator at 50 psi. The mixture is filtered and the solution is used immediately in the following reaction.

l7~i3~
GS9o/g5 To the above solution there is added 8.1 g o~
1,3-bis~methoxycarbonyl)-5-methylisothiourea and 0.5 ml of acetic acid and the mixture i5 refluxed for 3 hours.
The solvent is removed ln vacuo and water is added.
The resulting solid is filtered off and crys~allized from ethanol to yield 6.2 g o~ the title compound.
~ le 42 Oral Formulation of [5-~(2,2-Dichloro-l-meth~yclopr _ . . .
meth~l]thio]-lH-benzimi~azol-2-yl]carbamic acid, methyl ester Medication suitable ~or oral administration is prepared by filling gelatin capsules with suitable amounts of ~5-~ r ( 2,2-dichloro-l~methylcyclopropyl)methyl~-thio-lH-benzimidazol-2-yl]carbamic acid, methyl ester.
Example 43 Testing of Oral Formulation of [5-~[(2,2-Dichloro-l-methyl-cyclopropyl)methyl]thio]-lH-benzimidazol-2-yl]carbamic acid, methyl ester The following test -is carried out to determine the effectiveness of treating dogs naturally infected with whipworm (Trichuris vulpis) and tapeworms (Taenia pisifor-mls and Dipylidium caninum~ by orally administering capsules containing ~5-~[(2,2-dichloro-1-methyl-cyclo-propyl~methyl~thio]-1~-benzimidazol-2-yl]carbamic acid, methyl ester prepared in Example 33.
The dogs are fasted overnight and receive medication the following morning.
Total fecal collections are made from each dog daily ~or seven days ~ollowing treatment. Daily fecal material is soaked in water and washed through a 40-mesh sieve using a water spray and all scolices, strobilae, proglottids and nematodes, immatures and adults are recovered.

~7S3~

~3 Sev~n days a~ter medication, the dogs are eu~hanitized and in~estine~ and ceclLm are remoYed and examined ~r tapeworms and whipworms. The intestinal contents and mucosal scrapings are washed through a 40-mesh sieve prior to examina~ion for tapeworms (.scolices)and whipworm under the dissection microscope.
A first group o~ dogs receiving 5 mg/kg for 7 days of fS-~(2,2-dicllloro-1-methylcyclopropyl~methyl]
thio]~ benzimidazol-2-yl]carbamic acid, methyl ester is found to have a 93~ reduction in whipworms.
In a Control A experiment, one group of dogs receiving 5 mg/kg for 7 days of [5-~[(2,2~dichlorocyclo-propyl)methyl]-thio]-lH-benzimidazol-2-yl]carbamic acid, methyl ester is found to have a 16% reduction in whip-worms.
A second group of dogs receiving 100 mg twicedaily for 5 days o~ [5-[~(2/2-dichloro-l-methylcyclopr methyl]-thio]-lH-benzimidazol-2-yl]carbamic acid, methyl ester is found to have a 100~ reduction in Taenia pisiformis and a 50% reduction in Di~ylidium caninum.
In a Control B experiment, one group of dogs receiving 100 mg twice daily for 5 days of ~5 ~(2,2-dichlorocyclopropyl)methyl]thio]-lH-benzimidazol-2-yl]
carbamic acid, methyl ester is found to have a 0% reduction in the tapeworms Taenia plsi~ormis and Dipylidium caninum.
A third group o~ dogs receiving 25 mg/kg for 5 days of l5-~(2~2-dichloro-1-methylcyclopropyl)methyl]thio]-lH-benzimidazol-2~yl]carbamic acid, methyl ester is found to have a 100~ reduction in whipworms, a 100% reduction in Taenia pisiformis and a 100~ reduction in Dipylidium caninum.

S3~3 GSgO/g5 ~4 In a Control C experiment, one g~oup of dogs receiviny 25 m~/kg for 5 days of [5-~r(2,2-dichlorocyclo-propyl)methyl~thio]~ benzimidazol-2-yl]carb~mic acid~
methyl ester is found to have only a 34~ reduction in whipworms and a 0~ reduction in -the tapeworrns Taenia pisiformis and Dip~lidlum caninum.
The above test results clearly show the suprising superiority of L5-l~(2~2-dichloro-l-methylcyclopropyl)-methyl]thio~-lH-benzimidazol-2-yl]carbamic acid, methyl ester over ~5-~[(2,2-dichlorocyclopropyl)methyl]thio~-lH-benzimidazol-2-yl]carbamic acid, methyl ester in the treatment or prevention of whipworm and tapeworm.

Exampl_ 44 [5-[(Diethox~methylsilylmethyl)thio]-lH-benzimidazol-2-yl carbamic acid, methyl ester A. 4-(DiethoxymethylsilylmethJyl)thio-2-nitr aniline To a stirring solution of 25.3 g (0.13 mol~ 4-thio-cyanato-2-nitroaniline in 500 ml of acetonitrile under nitrogen is added 4.94 g (0.13 mol) of sodium borohydride in portions over 45 minutes at room temperature. The mixture is stirred for 2 hours and 25.0 g (0.137 mol) of chloromethylmethyldi~thoxysilane is added and the mixture is refluxed overnight. The reaction mixture is cooled, filtered and the filtrate evaporated to dryness. The residue is extracted repeatedly with hot hexane to yield, on evaporation, 31 g of the title compound as a red oil.
This is used without further purification.
B. 1,3-Bis(methoxycarbonyl)-S-methylisothiourea To a solution of 11.2 g of 2-methyl-2-thiopseud-ourea sulfate in 200 ml of water at 0C there is added concurrently 260 ml of 25% NaOH and 160 ml of methylchloro-formate at such a rate that the pH remains between 7 and 8 as monitored by a pH meter. After the addition is ~.1753~ GS9o/95 ~5 complete the mix-twre is ~tirred ~or an additional 2 hours at room -temperature. Then ~00 ml of water is added and the mixture is ex-tracted with dichloromethane. The organic layers are combined, dried over magnesium sulfate, and evaporated in vacuo to qive a white solid. Crystal-lization from methanol yields 60.4 g of the title B
compound, m.p. 99-101C.
C. ~5-~(Diethox~methylsilylmethyl)thio~-lH-ben~imidazol-2-yl3carbamic acid, methy~ ester 7.9 g (0.028 mol) of the nitroaniline obtained in part A is hydrogenated at 60 psi in 225 ml of methanol with 0.8 g of platinum oxide catalys-t~ After 24 hours, the color is largely gone and thin layer chroma~ography shows the absence of starting material. The mixture is filtered and 5.7 g (0.028 mol) of 1,3-bis(methoxycarbonyl)-S-methylisothiourea (prepared in part ~), and 0.1 ml of acetic acid added to the filtrate. The mixture is refluxed for 36 hours, cooled and allowed to stand in the freezer.
The resulting crystals are filtered off and recrystallized (hot filtration) from cyclohexane to give 4.0 g of the title compound.

~ 45 [5-~(Diethoxymethylsil~lm~ ___yl]-ld'b-~-i~id--AI-2-yl]carbamic acid, methyl ester To an ice-cold solution of 40 mmol o~ [5-[(diethoxy-methylsilylmethyl~thio]-lH-benzimidazol-2-yl]carbamic acid, methyl ester prepared as described in Example 44, in 150 ml methanol is added 8.98 g (42 mmol) sodium metaperiodate in 150 ml water. The resulting suspension is stirred at 5C

7S~3~3 ~6 Eor 42 hollrs, then partitioned between water and dichloro-methane. The layers axe separated and the aqueous làyer re-extracted. The or~anic layers are combined and washed with saturated NaCl, dried, fiLtered and e~aporated to yield a residue which is cxystallized three times from acetonitrile to yield the title sulfinyl compound.

Example 45 ~5-~(Diet~ methylsilylmethyl)sulfonyl]-lH-benzlmida 2-yl]carhamic acid, meth~l ester 0.00625 mole of ~5-~(diethoxymethylsilylmethyl)-thio]-lH-benzimidazol-2-yl]carbamic acid, methyl ester prepared as described in Example 44, is dissolved in 40 ml acetic acid and 40 ml chloroform, and cooled to -10C with an ice-methanol bath. To this is added 2 equivalents of ~-chloroperbenzoic acid in 10 ml chloroform, all at once. Stirring is continued for three hours, allowing temperature to rise to room temperature. ~he solvent is removed _ vacuo yielding an oil, which is digested with aqueous NaHCO3. Solids are collected, washed with water, dried and crystallized from 1,2-dimethoxyethane to give the title sulfone.

Exam~le 47 N- L5- ~ ~ (Trimethylsilyl)meth~l~thio]-2-benzimiaa carbamic acid, meth~l ester A. 4-[(Trimeth~lsilyl)meth~lthio]-~=nitroanilihe To a stirred solution o~ 1,95 g of 4-thiocyanato-2-nitroaniline in 40 ml o~ CH3CN blanketed by nitrogen there is added in portions 0.5 g of NaBH4. The stirring is continued for one hour. ~t this time the color of the reac-tion mixture changes from yellow to dark purple.
1.4 ml of chloromethyltrimethylsilane is added with a syringe and the mixture is refluxed overnight. The solvent is evaporated and the residue is exhaustively extracted with petroleum ether. Evaporation of the solvent 7~i3~
~S90/~5 ~7 yields 1.9 g of the -title A compound as a red solid.
B. 4-[(Trimethylsil~)methy__hio~-o-phenylenediamine A solution of 1.9 g Oe the above nitroaniline in 200 ml of methanol is cataly-tically reduced (60 psi)using 0.4 g PtO2 as catalyst. Upon completion, the catalyst is fil-tered off and the Eiltrate is used at once for the next step.
C. N-[5-[[(Trimethylsilyl)methx-l]thio]-2-benzimida zolyl]-carbamic ~ methyl ester To the above filtrate (part B) there is added 2 g of 1,3-bis[methoxycarbonyl]-S-methylisothiourea (prepared as described in Example 44, part ~), 7 drops of acetic acid and the mixture is refluxed for two hours. The solvent is evaporated and the residue extracted with ether. The ether insoluble part is crystallized from ethanol. The ether soluble material and the ethanol purified fraction are combined and recrystallized from ethanol to yield 0.7 g of the title compound, m.p. 189-191.
Example 48 N-[5-[[Trimethylsilyl)methyl]su finyl~-2- benzimidazolyl]-carbamic acid, methyl ester To an ice-cold solution of 40 mmol of r5-[[(trimethyl]-silyl)methyl~thio]-2-benzimidazolyl]carbamic acid, methyl ester prepared as described in Example 47, in 150 ml 25 methanol is added 8.98 g (42 mmol) sodium metaperiodate in 150 ml water. The resulting suspension is stirred at 5C for 42 hours, then partitioned between water and di-chloromethane. The layers are separated and the aqueous layer re-extracted. The organic layers are combined and washed with saturated NaCl, dried, filtered and evaporated to yield a residue which is crystallized -three times from acetonitrile to yield the title sulfinyl compound.

~, 75;~3 GS90/~5 x~ e 4 N-~5-[~('rrimeth~_silyl~methy-l ~ nyl]-carbamic acid ~ 1 ester .
0.00625 mole of N-~5-[[(trimethylsilyl)methyl]-thio]-2-benzimidazolyl]carbamic acid, methyl ester prepared as described in Example ~7, is dissolved in 40 ml acetic acid and 40 ml chloroform, and cooled to -10C with an ice-methanol bath. To this is add~d 2 equi~alents o~
_-chloroperbenzoic acid in 10 ml chloroform, all at once.
Stirring is continue~ ~or three hours, allowing temperature to rise to room temperature. The solvent is removed ln ~acuo yielding an oil, which is digested with aqueous NaHCO3. Solids are collected, washed with water, dried and crystallized from l,2-dimethoxyethane to give the title sulfone.

Examples 50 to 59 Following the procedure o Example 44 except substi-tuting for chloromethylmethyldiethoxysilane r the compound shown in Table I, Column I below, and substituting for 1,3-bis-(methoxycarbonyl)-S-methylisothiourea, the com-pound shown in Column II, the compound shown in Column III
is obtained.

--~ o ~ ~117 53~3 GS 9 ~/ 9 5 Z ~;

H
~C) ' ~''1 /1 \ c~
/ O \,~

~1 P; ~
o o HH Z Z
H ~ t~ J ~ ~ N
~ ~ \\ / ~ ~ V C~ O U
~q ~l ~ o U~
E~ ~
o U~ U- o ~ U~ o eq m ~ C~ U C~ U ~

~ o ~ O ~u~ O
o ~ ~ ~ N
~ V C~ V ~ U C~ U
H
~ ~ o u~ o _/
O ~ cr~
U ~ C~ C~ U C) U U U U U
C~
P~ ~ ~ ~ ~ ~
,1 ,~ ~ ~
UJ N N N N N N
/ I \ U P~ U U U t~ C.) U ~ Pl:l 1 \-~ -- C,~ u . .
O --~ ~ ~ ~' U'~ U~ I` CO CS~ :
i Z Lr) L~ Ul IS~ It~ 1~ 111 U) It~ It~

~ e_es 60 to 69 Following the procedure o~ Example 45, the sulfides of Examples 50 to 59 shown i.n Colu~n ~ o~ Table II below are oxldized *o gi~e the corresponding sul~oxides.

~7~ii3~
, GS9q/95 o H (~ }
~ o~
,~
U P~ U H
U ~, O
~1 \ u / lo \ ~1 ~
~d _ --m N ~ I m P; V U U U U U U C~ U C~

H
H

In o u~ u- o ~ ~ ~ ~ ~ 5: ~ ~ ~ ~ :q m ~ ~ ~ c $ ~
F~ N l:Y; C) U O U C~ C) O t~ O C.) ~C
/Z O O
Z~ ~ O ~ ~7 0 U) U~ o o r-l N l~ S~
)~( ~ CJ ~_) C.) U U O ~ U C ~ C,) H ~
u~ O
m ~ m O ._ a~ ~ q ~ ~ $
U ~ P U U U U C~ U U U U
m P~ N t~
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/ I \ 1 ~ m m ~ u ~; ~
. .
~C O O ~I M ~ ~ ~
W Z ~D ~ ~ ~D ~ ~D ~ D ~ ~O

7~3 n ~
Following the procedure o~ Example 46, the sul~ideY
o~ Examples 50 to 59 shown in Column I o~ Ta~le III below are oxidized to giye the corresponding ~ulfones.

753~
GS9o/g5 o ~c 5 3 Z. ~

H ~ O
~ 0~~ ~ C~
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1 ~;''1 o / lo\ ~ \ v ~ $~ m~
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H ~ ) O L~ O

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o n ~ o ~ Lr) o P~ ~ ~ ~ ~ ~ ~ ~C
~ ~ C~ O V ~ V C~
H ~
~ u~ In o Lr~o ,, ~ ~ ~ ~ m ~
O ~ a~ $ ~ ~ ~ ~ ~ ~ ~ rl :C
C~

~ ---- -- --m~ ~N
o\~ ~ t: ~ V U
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. .. . , ~ . . . ~ . .
x o o ~1 Z I~

Claims (27)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for preparing a compound of the structure wherein R is lower alkyl of 1 to 7 carbons or phenyl-lower alkyl of 1 to 7 carbons in the alkyl group and A
is wherein R1 is lower alkyl of 1 to 7 carbons; R2 is hydrogen or lower alkyl of 1 to 7 carbons, or R1 and R2 may be taken together with the carbons to which they are attached to form a cycloalkene ring containing from 3 to 10 carbons; R3 is hydrogen or lower alkyl of 1 to 7 carbons, and y is 0 or 1;

wherein R4 and R5 are the same or different and are hydrogen or lower alkyl of 1 to 7 carbons; R6 is lower alkyl of 1 to 7 carbons or phenyl; R7 and R8 are the same or different and are chlorine, bromine, fluorine or iodine; m is 0 to 3; n is 0 to 3 and m + n ? 5; or wherein R9, R10 and R11 may be the same or different and are selected from the group consisting of lower alkyl of 1 to 7 carbons or lower alkoxy of 1 to 7 carbons, z is 0, 1 or 2, and p is 1 to 5; with the proviso that when A is R is lower alkyl of 1 to 7 carbons and physiologically acceptable salts thereof, comprising when A is to be reacting a compound of the formula with a compound of the formula optionally when y is to be 1, reacting the sulfide of formula with an oxidizing agent; when A is to be reacting a compound of the formula with a compound of the formula ; and when A is to be reacting a compound of the formula with a compound of the formula optionally when Z is to be 1 or 2, reacting the sulfide of formula with one or more equivalents of an oxidizing agent.

2. A process according to claim 1 wherein A is and R is lower alkyl of 1 to 7 carbons or phenyl-lower alkyl of 1 to 7 carbons in the alkyl group, R1 is lower alkyl of 1 to 7 carbons, R2 is hydrogen or lower alkyl of 1 to 7 carbons, or R1 and R2 may be taken together with the carbons to which they are attached to form a cycloalkene ring containing from 3 to 10 carbons, R3 is hydrogen or lower alkyl of 1 to 7 carbons, and y is 0 or 1, and physiologically acceptable salts thereof.

3. A process according to claim 2 wherein y is 0.

4. The process according to claim 2 wherein y is 1.

5. The process as defined in claim 2 wherein R
is lower alkyl or benzyl.

6. The process as defined in claim 2 wherein R1 is lower alkyl and R2 is hydrogen or lower alkyl.

7. The process as defined in claim 2 wherein R1 and R2 are taken together with the carbons to which they are attached to form a cycloalkene ring.

8. The process as defined in claim 2 wherein R1 and R2 are taken together with the carbons to which they are attached to form a cycloalkene ring of 6 carbon atoms, R3 is hydrogen, y is zero and R is methyl.

9. The process as defined in claim 2 wherein R1 and R2 are taken together with the carbons to which they are attached to form a cycloalkene ring of 6 carbon atoms, R3 is hydrogen, y is one and R is methyl.

10. The process according to claim 1 wherein A is and R is lower alkyl of 1 to 7 carbons, or phenyl-lower alkyl of 1 to 7 carbons in the alkyl group; R4 and R5 are the same or different and are hydrogen or lower alkyl of 1 to 7 carbons, R6 is lower alkyl of 1 to 7 carbons or phenyl, and R7 and R8 are the same or different and are chlorine, bromine, fluorine or iodine; m is 0 to 3; n is 0 to 3; and m + N ? 5, and physiologically acceptable salts thereof.

11. The process as defined in claim 10 wherein R is lower alkyl or benzyl.

12. The process as defined in claim 10 wherein R4 and R5 are the same or different and are hydrogen or methyl.

13. The process as defined in claim 10 wherein m is 0, n is 0 and R4 and R5 are hydrogen and R6 is in the 1-position.

14. The process as defined in claim 10 wherein R7 and R8 are chlorine or bromine and R6 is lower alkyl in the 1-position.

15. The process as defined in claim 10 wherein m is 0, n is 0, R4 and R5 are hydrogen, R6 is in the 1-position and R is CH3.

16. The process according to claim 1 wherein A
is and R is lower alkyl containing 1 to 7 carbons, R9, R10 and R11 may be the same or different and are selected from the group consisting of lower alkyl of 1 to 7 carbons or lower alkoxy of 1 to 7 carbons; z is 0, 1 or 2 and p is 1 to 5.

17. The process according to claim 16 wherein z is zero.

18. The process according to claim 16 wherein z is one.

19. The process according to claim 16 wherein z is two.

20. The process as defined in claim 16 wherein R9, R10 and R11 are lower alkyl.

21. The process as defined in claim 16 wherein R9 and R10 are lower alkyl and R11 is lower alkoxy.

22. The process as defined in claim 16 wherein R9 and R10 are ethoxy, R11 is methyl, p is one, z is zero and R is methyl.

23. The process as defined in claim 16 wherein R9 and R10 are ethoxy, R11 is methyl, p is one, z is one and R is methyl.

24. The process as defined in claim 16 wherein R9 and R10 are ethoxy, R11 is methyl, p is one, z is two and R is methyl.
25. The process as defined in claim 16 wherein R9, R10, R11 are methyl, p is one, z is zero and R
is methyl.
26. The process as defined in claim 16 wherein R9, R10, R11 are methyl, p is one, z is one and R is methyl.
27. The process as defined in claim 16 wherein R9, R10, R11 are methyl, p is one, z is two and R
is methyl.
28. A compound of the structure wherein R is lower alkyl of 1 to 7 carbons or phenyl-lower alkyl of 1 to 7 carbons and A is wherein R1 is lower alkyl of 1 to 7 carbons, R2 is hydrogen or lower alkyl of 1 to 7 carbons, or R1 and R2 may be taken together with the carbons to which they are attached to form a cycloalkene ring containing from 3 to 10 carbons, R3 is hydrogen or lower alkyl of 1 to 7 carbons, and y is 0 or 1;

wherein R4 and R5 are the same or different and are hydrogen or lower alkyl of 1 to 7 carbons, R6 is lower alkyl of 1 to 7 carbons or phenyl; R7 and R8 are the same or different and are chlorine, bromine, fluorine or iodine, m is 0 to 3; n is 0 to 3 and m + N =5; or wherein R9, R10 and R11 may be the same or different and are selected from the group consisting of lower alkyl of 1 to 7 carbons or lower alkoxy of 1 to 7 carbons, z is 0, 1 or 2, and p is 1 to 5; with the proviso that when A is R is lower alkyl of 1 to 7 carbons and physiologically acceptable salts thereof when prepared by the process of claim 1.
29. A compound of the structure wherein R is lower alkyl of 1 to 7 carbons or phenyl-lower alkyl of 1 to 7 carbons in the alkyl group, R1 is lower alkyl of 1 to 7 carbons, R2 is hydrogen or lower alkyl of 1 to 7 carbons, or R1 and R2 may be taken together with the carbons to which they are attached to form a cycloalkene ring containing from 3 to 10 carbons, and R3 is hydrogen or lower alkyl of 1 to 7 carbons; y is 0 or 1, and physiologically acceptable salts thereof when prepared by the process of claim 2.
30. The compound as defined in claim 29 having the structure when prepared by the process of claim 3.
31. The compound as defined in claim 29 having the structure when prepared by the process of claim 4.
32. The compound as defined in claim 29 wherein R is lower alkyl or benzyl when prepared by the process of claim 5.
33. The compound as defined in claim 29 wherein R1 is lower alkyl and R2 is hydrogen or lower alkyl when prepared by the process of claim 6.
34. The compound as defined in claim 29 wherein R1 and R2 are taken together with the carbons to which they are attached to form a cycloalkene ring when prepared by the process of claim 7.
35. The compound having the name [5-(1-cyclo-hexen-1-ylthio)-1H-benzimidazol-2-yl]-carbamic acid, methyl ester when prepared by the process of claim 8.
36. The compound having the name [5-(1-cyclohexen-1-ylsulfinyl)-1H-benzimidazol-2-yl]-carbamic acid, methyl ester when prepared by the process of claim 9.
37. A compound of the structure wherein R is lower alkyl of 1 to 7 carbons, or phenyl-lower alkyl of 1 to 7 carbons in the alkyl group; R4 and R5 are the same or different and are hydrogen or lower alkyl of 1 to 7 carbons, R6 is lower alkyl of 1 to 7 carbons or phenyl, and R7 and R8 are the same or different and are chlorine, bromine, fluorine or iodine; m is 0 to 3; n is 0 to 3; and m + n is ? 5, and physiologically acceptable salts thereof when prepared by the process of claim 10.
38. The compound as defined in claim 37 wherein R is lower alkyl or benzyl when prepared by the process of claim 11.
39. The compound as defined in claim 37 wherein R4 and R5 are the same or different and are hydrogen or methyl when prepared by the process of claim 12.
40. The compound as defined in claim 37 wherein m is 0, n is 0 and R4 and R5 are hydrogen and R6 is in the 1-position when prepared by the process of claim 13.
41. The compound as defined in claim 37 wherein R7 and R8 are chlorine or bromine and R6 is lower alkyl in the 1-position when prepared by the process of claim 14.
42. The compound having the name [5-[((2,2-dichloro-1-methylcyclopropyl)-methyl]thio]-1H-benzimidazol-2-yl]carbamic acid, methyl ester when prepared by the process of claim 15.

43. A compound of the structure wherein R is lower alkyl containing 1 to 7 carbons, R9, R10 and R11 may be the same or different and are selected from the group consisting of lower alkyl of 1 to 7 carbons or lower alkoxy of 1 to 7 carbons;
z is 0, 1 or 2 and p is 1 to 5 when prepared by the process of claim 16.
44. The compound as defined in claim 43 having the structure when prepared by the process of claim 17.
45. The compound as defined in claim 43 having the structure when prepared by the process of claim 18.
46. The compound as defined in claim 43 having the structure when prepared by the process of claim 19.
47. The compound as defined in claim 43 wherein R9, R10 and R11 are lower alkyl when prepared by the process of claim 20.
48. The compound as defined in claim 43 wherein R9 and R10 are lower alkyl and R11 is lower alkoxy when prepared by the process of claim 21.
49. The compound having the name [5-[(diethoxy-methylsilylmethyl)thio]-1H-benzimidazol-2-yl]carbamic acid, methyl ester when prepared by the process of claim 22.
50. The compound having the name [5-[(diethoxy-methylsilylmethyl)sulfinyl]-1H-benzimidazol-2-yl]
carbamic acid, methyl ester when prepared by the process of claim 23.
51. The compound having the name [5-[(diethoxy-methylsilylmethyl)sulfonyl]1H-benzimidazol-2-yl]
carbamic acid, methyl ester when prepared by the process of claim 24.
52. The compound having the name N-[5-[[(tri-methylsilyl)methyl]thio]-2-benzimidazolyl]-carbamic acid, methyl ester when prepared by the process of

claim 25.

53. The compound having the name N-[5-[[(tri-methylsilyl)methyl]sulfinyl]-2-benzimidazolyl]carbamic acid, methyl ester when prepared by the process of

claim 26.
54. The compound having the name N-[5-[[(tri-methylsilyl)methyl]sulfonyl]-2-benzimidazolyl]carbamic acid, methyl ester when prepared by the process of

claim 27.