CA1094061A - 5(6)-benzene ring substituted benzimidazole-2- carbamate derivatives having anthelmintic activity - Google Patents

Abstract

Abstract of the Disclosure Benzene ring substituted benzimidazole-2-carbamate derivative represented by the formula:

(I) where R is a lower alkyl group having 1 to 4 car-bon atoms; is a 5, 6, 7 or a membered hetero-cyclic ring containing 1 or 2 hetero atoms; the substitution being at the 5(6)-position;
and the pharmaceutically acceptable salts thereof.
The compounds are useful as pesticides, particularly as anthelmintic and antifungal agents.

Description

iO'~34(~fi1 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.
8ACKGROUND OF THE rNVENTION
l-Position isomers of c~rtain of the 5(6)-substituted benzimidazole-2-carbamates described and claimed herein are sus-gested-inthis art (for example, see United States Letters ~atents Nos. 3,541,213 and 3,626,070). Related antifungal compounds are also shown in French Patent NQ. 2,054,799.

-SUMMARY OF THE INVENTION
The novel benzene ring substituted benzimidazole-2-carbamate derivati~es of the present inven~ion can be repre-sented by the following formula:

~ ~ N COOR
7 11 (I) where R is a lower alkyl group having 1 to 4 carbon atoms; ~ - is a 5,6, 7 or8 memberedheterocyclic rlng containing 1 or 2 hetero ~toms; the ~ -~-su~stitution being at the 5(6)-position; and the pharmaceutically acceptable salts thereof- ~hese benzi-midazole-2-carDomate derivatives are use~ul as anthel-mintics and antifungals and may be formulated with suitable 3Q pharmaceutical or industrial carriers. ~hes2 cor~ounds ~re very .;seful as aqueous, injectable solutions.

~. .~

lO'~ fil DETAILED DESCRIPTIO~ OF THE INVE~TION
Compounds of the Invention In the above definition of the invention, the term "heterocyclic ring" refers to both substituted and unsub-stituted heterocyclic rings having 5, 6, 7 or 8 total ring atoms and containing 1 or 2 hetero atoms, and includes both saturated and mono- or di-olefinically unsaturated hetero-cyclic rings. The heterocyclic ring canbe substitutedwith one hydroxy, phenyl, benzyl or oxo radical, or one or two alkyl ~roups. The second hetero atom, if the ring contains two hetero atoms, can be nitrogen, oxygen or sulfur, with the sulfur being in the sulfide, sulfoxide or sulfone form and the additional nitrogen atom, if present in the ring, beins substituted with phenyl, benzyl or an alkyl group. Typical heterocyclic rings, expressed in radical form, include, for example, pyrrolidinyl; piperidino; 4-hydroxypiperidino; 2-methylpiperidino; 3-methylpiperidino; 4-methylpiperidino;

2,6-dimethylpiperidino; 4-phenylpiperidino; 4-benzylpiperidino;
piperazinyl; 4-alkylpiperazinyl-tsuch as 4-methylpiperazinyl);
4-phenylpiperazinyl; 4-benzylpiperazinyl; morpholino; 2,6-dimethylmorpholino; 4-oxo-1~4-dihydropyridyl; 1,2,3,6-tetra-hydropyridyl; thiazolidin-3-yl; 1-oxo-thiazolidin-3-yl;
1,1-dioxo-thiazolidin-3-yl; thiomorpholinc; l-oxo-thio-morpholino; 1,l-dioxo-thiomorpholino; pyrrolinyl; perhydro-az~pinyl; perhydroazocinyl; imidazolinyl; oxazolidinyl;
tetrahydroazinyl;` tetrahydrothiazinyl; and the like.
A subgroup of the heterocyclic rings of the present invention, expre~sed in radical form, includes the following heterocyclic rings: 4-hydroxyPiperidino; 2-methylpiper dino;

3-methylpiperidino; 4-methylpiperidinoi 2,6-dimethvlpiper di~o;

10'~0~;~

4-phenylpiperidino; 4-~enzylpiperidino, piperazinyl; 4-methylpiperazinyl; 4-phenylpiperazinyl; 4-benzylpiperazinyl;
2,6-dimethylmorpholino; 1,2,3,6-tetrahydropyridyl; 4-oxo-1,4-dihydropyridyl; thiazolidin-3-yl; 1-oxo-thiazolidin-3-yl;
morpholino; thiomorpholino; l-oxo-thiomorpholino; and pyrrolinyl.
A further subgroup of the heterocyclic rings of the present invention includes the following heterocyclic rings, also expressed in radical form: 4-hydroxypiperidino; 4-phenylpiperidino; 4-benzylpiperi~ino; piperazinyl; 4-methyl-piperazinyl; 4-phenylpiperazinyl; 4-benzylpiperazinyl;
1,2,3,6-tetrahydropyridyl; 4-oxo-1,4-dihydropyridyl; thia-zolidin-3-yl; 1-oxo-thiazolidin-3-yl; morpholino; l-oxo-thio-morpholino; and pyrrolinyl.
The hydrogen on the nitrogen at the l-position of the benzimi-tazole ring can be replaced with one of the following substituents:
N-alkylcarbamoyl (for example, methylcarbamoyl or n-butylcar-bamoyl), N,N-dialkylcarbamoyl, N-alkoxycarbonylcarbamoyl, phenylcarbamoyl, cyano, trichloromethylthio, alkylthio, phenylthio, nitrophenylthio, alkylsulfinyl, phenylsulfinyl, alkanoyl, alkoxycarbonyl, alkoxycarbonylalkylcar~onyl, alkyl, alkenyl, benzyl, benzoyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxy and conventional esters and e~ers thereof, etc. These compounds can be prepared from the co~poun~s of ~ormula I by the appropriate substitution reaction with isocyanates as described in South African Patent 74/6665.
_ Ofil As used in this specification and claims, the term "lower alkyl" refers to both straight and branched chain alkyl groups having from 1 through 4 carbon atoms and thus includes primary, secondary and tertiary alkyi groups.
Typical lower alkyls include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. The term "alkyl" refers to both straight and branched chain alkyl groups having 1 to 6 carbon atoms and thus includes those listed above with respect to "lower alkyl" and, for example, n-pentyl, isopentyl, n-hexyl, and the like. The term "alkenyl" refers to an unsaturated hydrocarbon group having from 3 to 6 carbon atoms and a single carbon-carbon double bond, provided that the double bond cannot be on the a-carbon atom. Typical alkenyl groups include, for example, 2-propenyl, 2-butenyl, 3-butenyl, and the like. The term "alkoxy" refers to the group having the formula R30- wherein R3 isan alkyl group as defined above. Typical alkoxy groups in~lude, for example, methoxy, ethoxy, t-butoxy, hexyloxy, and the like. The terms "alkylthio" and "alkylsulfinyl"

refer to those groups having the formula R3S- and R3S-, respectively, where R3 is an alkyl group as defined above.
The term "alkanoyl" refers to alkanoyl groups derived from carboxylic acids having 1 through 6 carbon atoms such as acetyl, propionyl, butyryl, valeryl, isovaleryl, hexanoyl and the like.
Exemplary of the compounds of the present invention, as represented by Formula I above, are the following illustrative compounds:

5(6)-~pyrrolidinylcarbonyl)-2-carbomethoxyamino-benzimidazole;
5(6)-piperidinocarbonyl-2-carbometho~vaminobenzimida-ole;

10940fil 5(6)-(4-hydroxypiperidinocarbonyl)-2-carbomethoxyamino-benzim~dazole;
5(6)-(2,6-dimethylpiperidinocarbonyl)-2-carbomethoxy-aminobenzimidazole;
5(6)-(1,2,3,6-tetrahydropyridylcarbonyl)-2-carbomethoxy-aminobenzimidazole;
5(6)-(4-methylpiperazinylcarbonyl)-2-carbomethoxyamino-benzimidazole;
5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimidazole;
5(6)-(2,6-dimethylmorpholinocarbonyl)-2-carbomethoxy-aminobenzimidazole;
5(6)-thiomorpholinocarbonyl-2-carbomethoxyaminoben~i-midazole;
5(6)-(1-oxo-thiomorpholinocarbonyl)-2-carbomethoxy-aminobenzimidazole;
5(6)-(thiazolidin-3-yl)-2-carbomethoxyaminobenzimidazole;
5(6)-(,1-oxo-thiazolidin-3-yl)-2-carbomethoxyaminobenzi-midazole;
5(6)-(2-methylpiperidinocarbonyl)-2-carbomethoxyamino-benzi~idazole;
5(6)~(3-methylpiperidinocarbonyl)-2-carbomethoxyamino-benzimidazole;
5(6)-(4-methylpiperidinocarbonyl)-2-carbomethoxyamino-benzimidazole;
and the corres~onding 2-carbethoxyamino-,2-carbopropoxyamino-, or 2-carbobutoxyamino-compounds.
Of the above compounds, 5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimidazole is presently preferred because of the substantial activity thereof aqainst the helminths specifically referred to above.

1~40~1 Where the compound has a basic moiety, the term "pharmaceutically acceptable salts" refers to those salts prepared from non-toxic inorganic or organic acids, such as those salts conventionally used in the art. Such salts include, for example, salts of inorganic acids such as, for example, sulfuric, sulfonic, sulfamic, nitric, phosphoric, hydro-chloric 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.
Utility and Administration The compounds of the present invention, and the pharma-ceutically acceptable salts thereof, possess broad spectrum activity against parasites of mammals (human or animal), including both mature and immature parasitic forms, as repre-sented for example, by the genera Trichostronglylus, Haemonchus, Ostertagia, Cooperia, i~ematodirus, and Stronglyoides, and specifically, for example against ~ematospiroides dubius, HYmenolepis Nana, Syphacia obvelata, and/or Aspiculuris tetraptera. In particular, these compounds are found to exhibit high activity against vaxious helminthic infections of the intestinal tract of economically important animals, coupled with low systemic toxicity to the host animal.
The compounds of the present invention are also useful as antifungal agents, particularly as sytemic fungicides for controlling fungal diseases of plants of economic impor-tance.

>1 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 d~sage level will usually be between about 0.~ mg/kg and S 100 mg/kg of body weight of the animal being treated. The active ingredient is adapted to be 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 gi~e anthelmintic compositions. The carrier may be an orally ingestible car-rie~ for the active ingredient such as, for example, a gelatin capsule, or it may be an excipient of the kind nor-mally used in medicaments o~ this characterr including maize starch, terra alba, lactose, sucrose, calcium phosphate, gelatin, stearic acid, agar, pectin or the like. Examples of suitable li~uid carri~ers are peanut oil, sesame oil and water.
A wide v2riety of pharmaceutical forms can be employed ih those cases wherein the medicament is not a~mixed with the feed. Thus, if a solid carrier is used, the compound 2~ can be administered in tablet or capsule form. I~ a liquid carrier is used, the medicament may be in the form of a soft gelatin capsule, a liquid suspension, or a solution suitable for injection. Because the salts o the compounds of this invention are very water solu~le, aqueous solutions or sus-pensions are preferred.
Process for Pre~aration In general, ~he compounds o~ the present invention car.
be pxepaxed by six basic routes. (A) In the fi-st out~, the 4-heterocyclic carbonyl-1,2-phenylenediamine compound 3~ is reacted witn a suitable reactant to for~ the ~rocucts o-10940~>1 this invention directly. ~B) In a second process the 4-heterocyclic carbonyl-1,2-phenylenediamine is reacted with a suita~le reactànt to form an intermediate thioureido com-pound which is then cyclized to form the compounds of the invention represented by formula I. (C) A third process of preparing the compounds of this invention comprises reacting the 4-heterocyclic carbonyl-1,2-phenylenediamine with a suit-able reagent to form a 2-amino-5(6)-heterocyclic carbonyl-benzLmidazole and reacting that intermediate with a carboxylatins agentbo give the products of this invention. (D) In a fourth process, 3,4-diaminobenzoic acid is reacted with a suitable reagent to form the benzimidazole carbamate substituted at the 5(6) position with a carboxylic acid, then reacting that compound with a heterocyclic compound to form the desired product of this invention represented by formula I. (E) In a fifth process 2-nitro-4-heterocyclic carbonyl~aniline is converted to the corresponding 2-nitro-4-heterocyclic car-bonyl-carbalkoxythioureidobenzene which is then reduced to the corresponding 2-amino compound which in turn is cyclized to form a compound of this invention. The cyclization may either be a one step procedure or a two step proce~ure wherein an inter-mediate dithioureido compound is first formed which in turn is cyclized. (F) In the cixth process l-acylamino-2~nitro-4-heterocycliccarbonylbenzene is reduced to form l-acylamino-2-amino-4-heterocycliccarbonylbenzene which is then reacted to form l-acylamino-2-carbalkoxythioureido-4-heterocycliccar-bonylbenzene which may then be treated with acid or base to form the corresponding l-amino-2-carboalkoxythioureido com-pound, which in turn is cyclized to form a compound of this ~O.'~ ~Ofil invention or may be reacted to form the bis-carbalkoxythio-ureido compound.
Once the desired compound of this invention is obtained, if it has a sulfur atom in the heterocyclic ring, the sulfur atom may be converted to a sulfoxide and the sul-foxide to a sulfone by treating with a suitable oxidizing agent such as a peracid, e.g., peracetic acid, in a suitable solvent at temperatures of about -30C to 25C as discussed hereafter.
It will be appreciated that the compounds of this invention exist as a free base or as a salt. The free base is readily converted to a salt by reacting equimolar portions of the free base and a suitable organic or inorganic acid, as discussed hereinbefore. Conversely, the salt is converted into the free base by treating the salt with at least a molar equivalent of an appropriate organic or inorganic base.
The intermediate mono- and bis-carbalkoxythioureido compounds are also useful as anthelmintics since these com-pounds show anthelmintic acitivty.
The starting materials for these six basic processes can be prepared by methods discussed hereafter.
An overall reaction scheme setting forth the process for making the compounds OL this invention is set for~ as follows:

10~40fil ~ (3) 1 ~ NHAC

HOOC NO2 (4) NHAC, (F) ~ NHAc ~ NHCNHCOOR

10r~-~N ~ UHZ~_~N ,Co N2 ~ -~ ~2 5) / (E) ~ N02 ~ N2 ~ ~H ~ COOR

o ~2 ~ ~ NO2 3~ -,C--~2 --1(1) 1(6, ~ 2 ~ ~ . ~ Z~-C ~ c~H2 Z~-~N-~ N2 Z N-o 2 N

~ I(C') (E ) ¦
NC(S)NHCOOR
~ Z~ -C~&-~COOR

~ ~(D) ~ 2 _~ ~ C-~COOR
HOOC ~ N~2 (D) HOOC

1C~940~;1 (A) The first process for making the compounds of this invention is set forth in the followins reaction scheme.

S ~ ~ ~ + X-COOR ~ ~O ~ ~ ~N~OR

(III) (I) wherein R and Z ~ have the value set forth hereinbefore, X
is chosen from the group consisting of R1S Hal~
~C=N- C=N- ;
H2N ~ Hal ~

C=N- ;
'~t:--N- ; Hal~
ROC-N~
. R S
~C=N- ;
NCNH-; IIal COOR R O ~
1 1 C=N-NC-N- ; R O ~

~'C=N- ; and RO- CS~ RlS
C=~~;
H 2N~
R S

ROCS~
C=N-;
RO~N~

wherein Hal is chloro, bromo or iodo, ] 2 iO~l and Rl is lower alkyl, aralkyl of 7 or 8 carbon atoms (espe-cially benzyl) or alkylene sulfonic acid of 2-4 carbons or the alkali metal salt thereof such as proovlene sulfonic acid and the salts such as sodium, potassium and the like.
In general, the diamino compounds are converted to the corresponding benzimidazole 2-carbamate compounds by reacting the diamino group with the XCOOR reagent in a suitable protic solvent such as water or an alcohol such as methanol or ethanol at temperatures of a~out 20 to 100C, preferably under re-flux conditions for about from 1/2 to six hours.
Preferably, the diamino compounds are converted to the corresponding benzimidazole 2-carbamate compounds directly, as exemplified by steps (A) and (C) above, by reacting the diamino compound with (i) a reagent believed to be a l-mono- or 1,3-bis(alkoxycarbonyl)-S-alkyl isothiourea, for example 1,3-bis(methoxycarbonyl)-S-methyl isothiourea or 1,3-bis-(ethoxycarbonyl)-S-methyl isothiourea, or (il~ a mono- or bis(alkoxycarbonyl)cyanamide, e.g., bis (methoxycarbonyl) cyanamide, in an aqueous alcoholic medium, for example, aq.
methanol or aq. ethanol, at from about room temperature to the reflux temperature of the reaction medium for about 1/2 to about 6 hours. The reaction medium is preferably made acidic to a pH of about 4-6 with, for example, a sufficient amount (e.g., 1-2 moles~ of acetic acid. About 1-2 moles, generally about 1.1 moles, of the XCOOR reagent are utilized per mole of the diamino compound.
The preferred reagent believed to be the l-mono- or 1,3-bis(alkoxycarbonyl)~ kyl isothiourea is prep~rea .~ reactlng 10~40fil thiourea with about equimolar amounts alkyl sulfate or alkylc~loroformate at elevated temperatures, e.g. about 20 to 100C to form S-alkyl isothiourea (or the H2SO~ or HCl salt thereof) which is then reacted with a molar excess of alkyl chloroformate (more than 1 mole of the alkylchloro-formate per mole of the S-alkyl isothiourea and preferably about 1.9-2.5 moles of the former per mole of the latter) in the presence of a suitable aqueous base, such as sodium hydroxide, potassium hydroxide and the like, at low tempera-tures of about 0 to 50C for about 3 hours. The resulting reagent is substantially insoluble in water and so may be filtered off and used in the process of this invention.
Alternatively the desired reagent (II) may be extracted with a suitable organic solvent such as a chlorinated hydrocarbon such as methylene chloride and the like, benzene, toluene, or other hydrocarbon solvents and isolated by evaporating the solvent. The reagent is preferably utilized ir. sit~ to carry out the process of this invention.
(B) The second process for making the compounds of this invention may be represented by the following reaction scheme:

., ~ 2 ~ ~ NH CNE~ COO R
Z~-C~NH2+ r~ cooR2 N-C~NHY

(III) ~ ( L~i) ~.;
Z~-c~~ coo~
O (, ~

1094()~1 wherein Y is hydrogen, COR, COOR or CSNHCOOR and W is -NCS, i.e. WCOOR is an alkoxycarbonyl isothiocyanate.
In this reaction scheme, the diamine is reacted with a suit-able reagent to form the corresponding thioureido compound indicated as formula IV wherein Y is preferably H or C(S)NHCOOR. In this step the diamine and the reagent are reacted in a suitable inert solvent such as acetone, tetra-hydrofuran, dioxane, or dim~thylformamide at temperature of about 0C to 100C until the thioureido compound is obtained.
Preferably, the conversion of the diamino compound pre-pared in step (2)or(6)to the corresponding bis(carbalkoxy-thioureido)- compound, as exemplified by step (~) above, is achieved by reacting the diamino compound with an alkoxy carbonyl isothiocyanate, such as methoxy carbonyl isothio-cyanate or ethoxy carbonyl isothiocyanate, in an inert reaction medium, such as acetone, tetrahydrofuran, dioxane, or dimethylformamide. This reaction is typically conducted at a temperature from about 0C. to about 60C., generally about room temperature, for about 1/4 hour to about 120 hours using an excess of the isothiocyanate reactant, generally about a two-fold molar excess.
Cyclization of the bis~carbalkoxythioureido) compound may be conducted in the presence of a suitable metal ion catalyst such as Cu , Hg , Pb and the like, prefexably cupric acetate in a mixture of acetic acid and water. This treatment, which m~y also be conducted on the mono(carbal-koxythioureido)-mono-amino compound, is generally conducted at about 45C to about 120C for about l/2 to ~4 hours.
Alternatively, the carbalkoxythioureido compound may first be alkylated witn an alkyl halide or a dialkyl sulfate, lO'~ fil e.g., methyl chloride or dimetnyl sulfate, to form the S
alkyl carbalkoxythioureido compound which is then cyclized by heating to about 60 to 120C, preferably about 70C, at a pH of about 3-7. In still another alternative cyclization, the carbalkoxythioureido compound is oxidized using a peracid such as peracetic acid to form a compound represented by the formula H

~ -~ ~ N~ - NHCOOR

which in turn is heated to about 60 to 100C under acidic conditions to give a compound of this invention. See German Offenlegungshrift 2,246,605 to I.C.I.

(C) In a third process for making the compounds of this invention, the 4-heterocyclic carbonyl-1,2-phenylene-diamine is ~onverted to the 2-amino-5(6)-heterocyclic car-bonyl benzimidazole which in turn is converted to the compound of this invention according to the following reaction scheme Z N-C ~ + HalC~ ~ N-~ ~ ~ 2 C

~~~ (III) 2 ¦ (V) ~_, ( I ) ~

wherein X and ~.al are defined as set forth above and U iS ohloro, alkoxy of 1-6 carbon atoms (RO-) or alkylthio of 1-6 carbon atoms (RS-).

1~94~fil In the formation of the 2-amino-benzimidazole, the XH
or HalCN compound is reacted with the diamine in a suitable solvent such as toluene, methylene chloride, methanol, ethanol, tetrahydrofuran, water at temperatures of about 0 to 100C
for about one to ten hours. The resulting 2-aminobenzimidazole is reacted at temperaturPs of about -20 to 100C with a suitable haloformate ester, a carbonate or a thiocarbonate in a suitable organic or inorganic solvent such as toluene, methylene chloride, alcohols (e.g. methanol, ethanol, isoprop-anol), tetrahydrofuran, pyridine, and the like alone or, pre-ferably, in the presence of an organic or inorganic base such as tertiary amines (trimethylamine, triethylamine, etc.) pyridine, morpholine, alkali metal alkoxides such as sodium methoxide, and the like, carbonate, alkali metal hydroxide such as sodium hydroxide, and the like.
(~) In a fourthprocess for making compounds of this invention, the 5(6)-carboxy-2-alkoxycarbonylaminobenzimidazole is conver~ed to the compounds of this inventiOon by converting the carboxy to the heterocyclic carbonyl Z~_,N~. First the carboxy group is co~verted into an acid chloride or mixed anhydride wnich in turn is reacted with the appropriate heterocyclic compound.
Generally, one equivalent of the heterocyclic base ( ~ -H) and an additional equivalent of an organic base ~which may be the heterocyclic base or triethylamine) is reacted with the acid 2~ chloride or anhydride in an inert solvent such as, for example, tetrahydrofuran, benzene or methylene chloride, at about 0C
to about 80C for about 1/4 to about 2~ hours to yield the desired compound of this invention. The acid chloride or mixed anhydride is readily prepared by conventional methods well known in the art for example from the corresponding acid 10~40~>1 and thionyl chloride or from trifluoroacetic anhydride, respectively.
(E) A fifth alternative method of making the compounds of this invention is set forth in the following reaction shceme NH2 ~ CNHCOOR

N - C ~
(VIII) (VII) NH\ HCNHCOOR
~ HCOOR< ~ l~ ~
Z N----C/--~_~'\N Z N----C H2 (I) (VI) In this case the 2-nitro-4-heterocyclic carbonyl aniline compound is reacted with a reagent such as one set forth in process (B) to give the 2-nitro-4-heterocyclic carbonyl phenyl thioureido compound. Thereafter, the nitro group of that com-pound is then reduced using a suitable reducing agent such as ~ ous sulfate and iron in aqueous methanol to form the cor-responding amino compound which in turn is cyclized according to the procedure set forth in Part (B) to give the product of this invention.
Alternatively the monothioureeido compound (VI) may be further reacted with an alkoxycarbonyl isothiocyanate to form the bis thioureido compound which is then cyclized according to the procedure of step (B).
(F) The sixth alternative process may be represented by the following reaction scheme:

1o~o6l ~NHAc ~NHAc ~NHAc S z ~ ~N02 Z N-~J~H2 ~ oC, ~HCNHCOR
(VIII) (VII) (VI) z~-~ -NH~OR
~ Z--~N~ H~,-NH~OR
(I) ~ (IVa) ~-NH~OR

Z '~- ,C,~-NHC-OR

( It~n~) Thus in this process the nitrobenzene compound, repre-sented by formula VIII,is reduced to form the aminobenzene compound, represented by formula VII. This reduction may be performed using any of the processes discussed hereinbe-fore or hereafter. The resulting aminobenzene compound is converted to the corresponding carbalkoxy thioureido com-pound VI by reacting the aminobezene compound VII with a suitable reagent such as that used in step A for the first process for m~king the compounds of this invention, herein-Defore described. Once the carbalkoxy thioureido compound VI is obtained, it is treated with a suitable strong acid or base under conditions suitable to hydrolyze the acyl (Ac in the formulae) and form the monocarbalkoxythioureido compound 109406~

indicated as IVa. This product in turn can be cyclized by heating as discussed in the discussion of step B for making the compounds of this invention or may be further reacted with a reagent to form the bis thioureido compound indicated as IVb which in turn may be cyclized to form the compound of this in~ention. Both the mono and bis carbalkoxy thio-ureido compounds show anthelmintic activity and thus are useful as anthelmintics themselves. The intermediate mono-carboalkoxy isothioureido compound is the position isomer of the monocarbalkoxyisothioureido compound formed as dis-cussed in part E, i.e. the fifth process for making the products of this invention.
Preparation of Starting Materlals .

The reaction of 3,4-dinitrobenzoyl chloride,or 4-acetamido-3-nitrobenzoylchloride with the appropriate heterocyclic compound, as exemplified by steps (1) and (4) above, respec-tively, can be effected by reacting the benzoylchloride starting material with two equivalents of the heterocyclic base ( ~ -H ) or one equivalent of the heterocyclic base plus one equivalent of triethylamine in an inert solvent, such as, for example, tetrahydrofuran, benzene or methylene chloride, at about 0C to about 80C for about l/4 to about 24 hours. In a similar manner, the 5(6)-carboxy-2-carbalkoxyaminobenzimidazolç can be reacted, as exemplified by step (Dl) abo~e, with the heterocyclic base to afford the desired compound of Formula I. In this later procedure, the 5~6)-carboxy-2-carbalkoxyaminobenzimida701e ls first converted to an activated intermediate thereof, as by treat-ment with trifluoroacetic acid, an alkyl chloroformate or thionyl chloride, and then reacted with the heterocyclic base as set forth above.

10~40~;1 Reduction of a nitro group to amino group, as exempli-fied by steps (2), (6) and (E') above, can be effected bv a varietY
of techniques, for example, the nitro group can be catalytically reduced utilizing hydrogen over a palladium/charcoal catalyst.
This reaction is conducted in an inert solvent, such as methanol, at a temperature from about 0C to 35C, generally about room temperature, for about 1/2 to about 2 hours.
Other suitable inert solvents include ethyl acetate, acetic acld, and ethanol.
Anothcr suitable reducing technique is to treat the ~itro group-containinc3 compound with stannous chloride in concentrated hydrochloric acid at a temperature in a rang~
from about -20C to about 100C, generally about room temperature, for about 1/2 to about 6 hours. An excess of the stannous chloride reactant should be utilized, generally about 5 parts (by weiqht) per unit weight of the starting compound.
The reduction can also be conducted using sodium dithio-nit~ ~sodium hvdrosulfite) in basic aqueous methanol or other alkanols such as ethanol or propanol) with hydrazire in the presence of a "boride" catalyst [for example, generated from ferrous sulfate, cobalt chloride or nickel sulfate and sodium borohydride] at lower temperatures such as about 2~C to the reflux temperature for about 1/2 to 24 hours;
or by treating the nitro-containing compound with iron powder and a ferrous salt, such as ferrous sulfate or ferrous chloride, in aqueous methanol at reflux under neutral conditions ^or about 1 to 6 hours, with other suitable reac'ion media nclucing ~cetic acid or concentrated hydrochloric ccid, and other su table :netais including zinc.

4-Acetamido-3-nitrobenzoic acid is converted to the corresponding benzoyl chloride, as exemplified by step (3) above, by treatment with thionyl chloride with or without an inert diluent (e.g., benzene, methylene chloride, chloro-form, etc.) at about 20-80C.
Conversion of an acylamino group, for example, an acetamido group, to an amino group, as exemplified by step (5) above, can be effected by treating the acylamino group-containing compound with a strong acid, such as hydrochloric acid, or strong base, such as sodium hydroxide, potassium hydroxide, potassium carbonate, or sodium carbonate in aqueous methanol at about 20~C to about 100C for about 1/4 hour to about 24 hours, The l-amino-2-nitro-4-heterocyclic-carbonylbenzene resulting from step (5) can also be prepared by treating the corresponding 5-carbo~y compound to form the acid anhydride or acid halide thereof,- and then reacting the latter compound with a heterocyclic base, for e~ample as set forth above with regard to steps (1) and (4).

Conversion of a hetero sulfur atom in the heterocyclic ring (2 ~ -) to the sulfoxide or sulfone form, or conversion of a hetero sulfur atom already in the sulfoxide form to the sul-fone form, is conveniently effected by treat~ent with hydrogen per-oxide in glacial acetic acid, nitric acid or chromic acid with glacial acetic acid or a peracid, such as peracetic acid, perbenzoic acid, metachloroperbenzoic acid, perphthalic acid, or pertrifluroracetic acid in an inert solvent for the compound being treated. Suitable solvent materials include, for example, methylene chloride or chloroform.
If the compound being treated is not soluble in the partic-ular reaction media desired to be utilized, then a co-solvent material, such as acetic acid or methanol, should be utilized in an amount sufficient to dissolve the compouna being treated. Typically, the reaction is conduc.ed at a temperature from about -30C to about room temperature for about l/2 hour to about 6 hours. When it is desired to convert the hetero sulfur atom to the sulfoxide form, molar quantities are utilized, and reaction conditions are carefully monitored to insure that the reaction does not proceed further than desired. When it is desired to convert the hetero su~fur atom to the sulfone form, or it is desired to convert the sulfoxide to the sulfone, an excess of the oxidizing material, for example, 2 moles of a pe~acid per mole of the compound being treated, is utilized and the reaction conditions do not have to be as carefully monitored.
Optionally, such conversions can aiso be effected by treatment with periodate in aqueous methanol or aqueous acetonitrile at a temperature in the range of about -20C. to about 50C. for about 1~2 to about 12 hours.

iO'~'~Ofi~

In each of the process steps, described herein above and below, unless otherwise indicated,-the respective intermediate products are not separated from the reaction mixtures. If desired, however, they can be separated and purified prior to their use as starting materials for the next step in the process. Such separation and purification 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 chroma-tography. 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 beprepared 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. In view of thi~ disclosure, the preparation of particular com-pounds, including compounds falling within the scope of the present invention but not particularly described in this specification, will be apparent to those skilled in this art.

10~40~

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 S as a l~mitation upon the scope of the in~ention but merely ~s being illustrati~e and representative thereof.
P~EPARATION 1 175 G. of S-methyl isothiouronium $ulfate in one liter of water is cooled to 0~C and 162.5 ~. of methylchloroformate added, followed by the addition of a solution of 250 g.
potassium hydroxide in 750 ml. water at 0 to 5C. The crude prvduct is extracted into benzene, the benzene dried and ovaporated, and the residue recrystallized from methanol.
1,3-~is(methoxycarbonyl)-S-methyL isothiourea is thus obt~ined.
In a similar manner, substituting ethylchloroformate, propylchloroformate and butylchloroformate for the methyl-chloroformate, 1,3-bis(ethoxycarbonyl)-S-methyl isothiourea, 1,3-bis(propoxycar~onyl)-S-methyl isothiourea, and 1,3-bis(butoxycar~onyl)-S-methyl isothiourea are, respecti~ ly, prepared.
PREPA~ATION 2 7.6 G (0.1 mol) of thiourea and 10 ml of water are mixed inside a 4-neck flask of 200 ml capacity equipped with an agitator, condenser, pipet and a thermometer and the mixture is agitated. 10.4 G. (0.11 mol~ of methyl chloroformate is added dropwise using the pipet 2t room temperature and the mixture is left standing for about 20 minutes until the crystals of thiourea are completely dissolved. The mixture is heated then left sta~ding for 30 minutes at temperatures ~0~340fil in the range of 90 ~ 100C. It is cooled with ice water and 12.3 g (O.13 mol) of methyl chloroformate is added while the temperature is maintained at 5C. ~herea.ter about 45 g of a 25%-water solution of caustic soda is gradually added dropwise through the pipet to adjust the pH value to approximately 7. This requires about 30 minutes.
The temperature was further maintained in the ran~e of 10 15C for 2 hours. The crude product is extracted into benzene, the benzene dried and evaporated, and the residue is recrystallized from methanol to give what is believed to be l,3-bis(methoxycarbonyl)-S-methyl isothiourea.
In a slmilar 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. The resulting reagents are then reacted with suitable phenylenediamines as set forth in the Examples hereafter.
- EXAMP~ES I-XII
A solution of 17.4 g. (0.075 mol.) of 3,4 dinitrobenzoyl-chloride in 250 ml of methylene chloride is treated at 0-20C
with a solution of t3 ~. (0.15 mol.) of morpholine in 10~ ml.
of methylene chlori~e. The solution is kept at 20-25C for 2 hrs., the solvent is e~aporated and the residue ~riturated wi~h water. Recrystallization from meth?nol affords 4-~orpholinocarbonyl-1,2-dinitrobenzene lm.p. 136-137C).

-~6-0fil 17.0 G. of 4-morpholinocarbonyl-1,2-dinitrobenzene in 340 ml. of methanol is hydrogenated for 3 hrs. at 45-50 psi ~n the presence of 1.7 g. of 5% palladized charcoal. The re~ulting solutiqn of 1,2-diamino-4-morpholinocarbonylbenzene S ~s filtered and concentrated to ~ 170 ml. 14.0 G. of 1,3-bis-methoxycarbonyl-S-methyl isothiourea, 170 ml. of water and 4 ml. of acetic acid are added to the diamine solution and the mixture is refluxed for 3 hrs. The solution is concen-trated and cooled. Filtration and recrystallization from methanol-chloroform affords 5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimidazole (m.p. 224C dec.).
In cimilar manner, substituting:
4-methylpiperazine;
piperidine;
thiomorpholine;
pyrrolidine;
thiazolidine;
2,6-dimethylpiperidine;
2,6-dimethylmorpholine;
4-hydroxypiperidine; __ -2-methylpiperidin~;
3-methylpiperidine; or ~-methylpiperidine;
for the morpholine,the following com~ounds are prepared:
2S 5(6)-(4-methylpiperazinylcarbonyl)-2-carbomethoxyamino-benzimadazole ~m.p. 217-220C dec.);
5~6)-piperi~inocarbonyl-2-carbomethoxyaminobenzimidazole (m.p. 203-207qC dec~);

10~40fil 5(6)-thiomorpholinocarbonyl-2-carbomethoxyaminobenzi-midazole (m.p. 242-243C dec.);
5(6~p~rolidinylcarbonyl-2-carbomethoxyaminobenzimidazole (m.p. 221-222C dec.);
5(6)-thiazolidin-3-ylcarbonyl-2-carbomethoxyamino-benzimidazole (m.p. 244C dec.);
5(6)-(2-6-dimethylpiperidinocarbonyl)-2-carbomethoxy-a~inobenzimidazole (m.p. 206-214C);
5(6)-(2,6-dimethylmorpholinocarbonyl)-2-carbomethoxy-aminobenzimidazole (m.p. ~ 245C dec.);
5(6)-(4-hydroxypiperidinocarbonyl)-2-carbomethoxy-aminobenzimidazole (m.p. ~ 270C dec.);
5(6)-~2-methylpiperidinocarbonyl)-2-carbomethoxyamino-benzimidazole;
5(6)-(3-methylpiperidinocarbonyl)-2-carbomethoxyamino-benzimidazole; and 5(6)-(4-methylpiperidinocarbonyl)-2-carbomethoxyamino-benzimidazole; respectively.
In a similar manner, substituting 1,3-bis(ethoxycarbonyl)-S-methyl isothiourea, 1,3-bis(propoxycarbonyl)~S-methyl isothiourea, l,3-bis(butoxycarbonyl)-S-methyl isothiourea for the l,3-bis(methoxycarbonyl)-S-methyl isothiourea, the corresponding compounds are prepared where R is ethyl, propyl or butyl, including, for example, 5(6)-morpholino-carbonyl-2-carbethoxyaminobenzimidazole, 5(6)-morpholino-carbonyl-2-carbopropoxyaminobenzimidazole, and 5(6)-morpholinocarbonyl-2-carbobutoxyaminobenzimidazole.

-2~-0f~

EXAMPLE XIII
1.52 G. of 5t6)-morpholinocarbonyl-2-carbomethoxyamino-benzimidazole is dissolved in a mixture of 2 ml. of water and 0.5 ml. of concentrated hydrochloric acid, and the resulting solution is diluted with 100 ml. of acetone. After 6 hrs.
at ~ 20C, the product is filtered off to afford the hydro-chloride salt of 5(6)-morpholinocarbonyl-2-carbomethoxyamino-benzimidazole (m.p. 180-182C dec.).
EXAMPLE XIV
5 G. of 3,4 dinitrobenzoic acid is hydrogenated in 100 ml. of methanol in the presence of 1 g. of 5% palladized charcoal at 40-50 psi. The catalyst is filtered off and the filtrate concentrated to ~ 40 ml. To this solution there is added 5 g. of 1,3 bismethoxycar~onyl-S-methyl isothiourea, 40 ml. of water and 2 ml. of acetic acid. The mixture is refluxed for 3 hrs., cooled, filtered and washed well with water and methanol to afford 5(6)-carboxy-2-carbo-methoxyaminobenzimidazole (m.p. > 310C).
0.6 G. of 5(6)-carboxy-2-carbomethoxyaminobenzimidazole is suspended in 30 ml of tetrahydrofuran and 1 ml. of trifluoroaceticanhydride is added. The mixture is stirred at 20-25C for ~ 6-10 hrs. until homogeneous. Then 2 ml. of 1,2,3,6 tetrahydropyridine i5 added with cooling at 15-20C.
The mixture is stirred for 3 hrs. at 20-25C., concentrated under vacuum and the residue diluted with water and extracted with chloroform. The chloroform extracts are washed with water, dried (MgSO4) and evaporated. The residue is rec ys-tallized for methanol to afford 5(6)-(1,2,3,6-tetrahydropyridyl)-2-carbomethoxyaminobenzimidazole (m.p. ~ 243C dec.).

--2g--10'340fil EXAMPLES XV-XVI
0.64 G.of 5(6)-thiomorpholinocarbonyl-2-carbomethoxy-aminobenzimidazole is dissolved in a mixture of 3 ml.
of acetic acid and 30 ml. of chloroform. A solution of 0.42 g. of meta-chloroperbenzoic acid in 20 ml. of chloroform is added at -15 to -10C, then the mixture is allowed to warm slowly to ~ 20-25C. After ~ 6 hours, the solvent is removed under vacuum at 20-30C and the residue treated with sodium bicar~onate solution. The product is filtered off and recrystallized from methanol-chloroform to afford 5(6)-(1-oxo-thiomorpholinocarbonyl)-2-carbomethoxy-aminobenzimidazole (m.p. 249-250~5C dec.).
In a simllar manner, substituting thiazolidine for the thiamorpholine, there is prepared 5(6)-(1-oxo-thiazolidin-3-ylcarbonyl)-2-carbomethoxyaminobenzimidazole (m.p. ~ 270C
dec.).
In similar manner to the last paragraph of Example I, compounds corresponding to the compounds of these Examples XV and XVI are prepared where R is ethyl, propyl and butyl.
EXAMPLES XVII-XVIII
In similar manner to the first two paragraphs of Examp~es XV and XVI above, using an extra equivalent of metachloroperbenzoic acid, 5(63-(1,1-dioxo-thiomorpholino-carbonyl)-2-carbomethoxyaminobenzimidazole and 5(6)-~1,1-dioxothiazolidin-3-ylcarbonyl)-2-carbomethoxyaminobenzimidazole are prepared, respectively.
In similar manner to the last paragraph of Example I, compounds corresponding to the compounds of these Examples 10~4~

XVII and XVIII are prepared where R is ethyl, propyl, and butyl.
EXAMPLE XIX
- Fouryoung Swiss-Webster male mice (16-20 g.) are artifically infected with 200 larvae of the species Nema-tospiroides dubius (roundworm) and Hymenolepis nana (tape-worm) and naturally infected with 15-40 larvae of Syphacia obvelata and Aspiculuris tetraptera (pinworms). The drug is administered in a commercial rat/mouse diet at the stated dose(s) from day 1 through day 18, the infection being introduced at day 0. The animals are sacrificed at day 18 and the parasites remaining in the entire small intestine, cecum and large bowel are counted and differen-tiated. The average number of each parasite remaining in each medicated group is compared to the average number lS remaining in the control. This comparison is expressed as percent reduction over the parasites in the control group.
The data for illustrative compounds of this invention is tabulated in the Table below.
5(6)- ~ -~-2-carbomethoxyaminobenzimidazoles Test species dose, (% reduction) ppm Nd Hn So At morpholino 125 lO0 78 lO0lO0 62.5 lO0 0 lO0lO0 31~2) 100 0 100 70 16 87 0 lO0 37 _ 8 0 0 lO0 0 piperidino 125 66 29 100lO0 62 0 0 100lO0 thiamorpholino 125 69 0 lO0lO0 lO~Ofil . Test species dose, (% reduction) _ ppm Nd ¦ 50 A~
pyrrolidinyl 125 100 0 100 100 _62 64 0 100 100 thiazolidin-3-yl 125 59 0 100 100 1,2,3,6-tetra- 62 84 0 100 100 hydropyridyl 31 0 0 100 100 l-oxo-thiomorpho- 62 0 0 100 100 lino 31 0 0 100 100 l-oxo-thiazolidin- 62 0 0 100 100 Nd = Nematospiroides dubius ~n = ~ymenolepis nana So = Syphacia obvelata At = Aspiculuris tetraptera * The number ir. parentheses refers to the number of runs from which percent reductions are calculated and averaged to give the data set forth for that particular dose in this Table.
EXAMPLE XX

A formulation is prepared having the following composition:
5(6)-morpholinocar.bonyl-2-carbo-methoxyaminobenzimidazole 30%
polyethylene glycol 6000 40%
Myrj 52 [polyoxy(40) stearate;
a product of Atlas Chemical Co.~ 30%

This formulation is prepared by heating the polyethylene glycol 6000 and Myrj 52 to 55-60C and, when completely melted, the 5(6)-morpholinocarbonyl-2-carbomethoxyamino-benzimidazole is added with stirring until homogeneous.
The formulation is solidified by cooling and ground, without remelting of the polyethylene glycol, to a fine powder.

~0!~40fil EXAMPLE XXI
A drench powder is prepared having the following composition:
The formulation of Example XX15.1 g.

Cabosil M-5*(colloidal silica;
Cabot corp.) 6.0 g.
Carboxymethyl cellulose (7M8-SXF) 6.0 g.
The comelt formulation and carboxymethyl cellulose are blended together until uniform, then the Cabosil is added, the mixture blended until once a~ain uniform, and then finely powdered.
E ~ ~LE XXII
A suspension is prepared having the following formulation:
The formulation of Example XX7.550 g.

Citric acid, hydrous 0.431 g.
sodium citrate 0.86~ g.
carboxymethyl cellulose (7M8-SXF) 1.Q51 S-Cabosil M-5 1.000 g.
sorbic acid .300 g.

purified water to 100.00 ml.
The sorbic acid, citric acid and sodium citrate are added to 90 ml. of water wh-ch has been heated to 80~C. The Cabosil and carboxymethyl cellulose are then added, with stirring, until uniformly dispersed and fully hydrated. The mixture is cooled to 45~C, and the formulation of ExamDle XX is added, with stirrins, until it is uniformly dispersed. The suspension is cooled to room temperature and the balance of the watex is added.

* trademark $p`
,, EXAMPLE XXIII-A top dressing for horses is prepared having the following composition:
The formulation of Example XX8.550 g granular sucrose 17.450 g 25.000 g water l.Q0 ml EXAMPLE XXIV
A top dressing for cattle is prepared having the following composition:
The formulation of Example XX 75.52 g.
Soybean meal 2196.30 g.
If desired, the soybean meal can be replaced with alfalfa meal or corn gluten meal.
EXAMP~E XXV
A cattle feed addit1ve is prepared having the following compositlon:
The formulation of Example XX22.24 g.
feed excipient (Soybean meal, or corn gluten meal 77.76 g.
lOo.oo g, EXAMPLE XXVI
A cattle bolus is prepared having the following composition:
The formulation of Example XX1.89 g.
Starch 0.5-2.0 g.
Talc 0.05-2.0 g.
Magnesium stearate 0~05-2.0 g.
sodium chloride 0.5-5.0 g.
lactose 3.0_3.0 g.

10~0~1 EXAMPLE XXVII
A cattle paste is prepared having the following composition:
The formulation of Example XX 6%
Corn oil 85-90%
Antioxidant (e.g., a mixture of butylated hydroxy anisole and butylated hydroxy toluene) 0.1-0.5%
Benzoic acid 0.3%
Thickener (e.g., Cabosil M-5) 6-10%
EXAMPLE XXVIII
An equine paste is prepared having the following composition:
The formulation of Example XX 48%
Vegetable oil (e.g., corn oil) 40-60%
Other fatty acid glycerides 10-20%
Antioxidant (e.g., a mixture of butylated hydroxy anisole and butylated hydroxy toluene) 0.1-0.5%
Benzoic acid 0.3%
Thickener (e.g., Cabosil .~-5) 1-5%
100%

.
/

10940fi~
.
E~PLE ~
An oral suspension for human use is prepared having the following composition:

5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimidazole 2.5 Benzoic acid 0.3 Veegum R* (Colloidal magnesium aluminum 3.0 silicate) Citric acid 0.4%
Sodium citrate 0.8%

Sodium saccharin 0.01 Magnasweet 100 Flavor 0.03%
Color 0.0025~
Water Q.S. to 100%

Benzoic acid, citric acid and ~odium citrate are dissolved in 90 ml of water which has been heated to 95-100C.
Veegum K is added slowlv and allowed to fully hydrate. The resultant supension is cooled to room temperature and ~agnasweet 100 and saccharin are added. The active drug is stirred in, color and flavor are added and the additional water added as necessary. The suspension is milled throush a colloid mill to assure uniform dispension.

* trademark 40fil EXAMPLE XXX
A tablet for human use is prepared having the following composition:
5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimidazole 40% 100 mg Starch 15% 37.5 mg Magnesium stearate 1~ 2.5 mg Talc 2% 5.0 mg Color ~lake) 0,24% 0.6 mg Lactose 41.76%104.4 mg - 250.0 mg Water .08 ml Half of the lactose is blended with the color lake, then the balance of lactose is added and blended. The active drug is added to the lactose blend and mixed until uniform.
The starch past is prepared, granulated, screened and dried to the desired moisture content. The dried granulation is screened, lubricants are added and mixed~ Tablets are then prepared on a suitable tablet press.
EX~LE Y.~XI
A solution of 2.31 g of 3,4-dinitrobenzoylchloride in 50 ml of methylene chloride is heated at 20-25 DC with 1.3 g of 3-pyrroline. After 1 to 2 hours the solution is washed with 5% hydrochloric acid, water and dried over magnesium sulfate. The solvent is e~aporated and residual 1,2-dinitro-4-(3-pyrrolinylcarbonyl)benzene recrystallized from methanol.

lO!~ )fil 1.2 G. of the above-described dinitrocompound is dissolved in 10 ml of methanol and 10 ml of water containing 1.2 g of iron powder and 0.25 ml of conc. hydrochloric acid. The mixture is refluxed until reduction is complete (~4 hours), charcoal is added and the solution filtered. 1 G. of 1,3-bis-methoxycarbonyl-2-methylisothiourea and 0.3 ml acetic acid are added and the solution refluxed for 4-5 hours.
The cooled reaction mixture is filtered and the crude product recrystallized from methanol-chloro~orm to afford 5(6)-(3-pyrrolinylcarbonyl)-2-carbomethoxyaminobenzimidazole.
EXAMPLES XXXII-XXXIII
Ih a similar manner to the procedure to Example I, substituting perhydroazepine and perhydroazocine for morpholine, 5(6)-(perhydroazepinylcarbonyl)-2-carbomethoxy-aminobenzimidazole (m.p. 221-5C) and 5(6)-(perhydroazocinyl-- carbonyl~-2-carbomethoxyaminobenzimidazole, and the corre-sponding compounds where R is ethyl, propyl or butyl, are prepared.
EXAMPLES XXXIV-XXXV
Also in similar manner to the procedure of Example I, substituting 4-phenylpiperazine and 4-benzylpiperazine for the morpholine, there are prepared 5(6)-(4-phenyl-piperazinylcarbonyl)-2-carbomethoxyaminobenzimidazole and 5(6)-(4-benzylpiperazinylcarbonyl)-2-carbomethoxyamino-benzimidazole. In this Example XXXV, the iron reduction technique of Example XXXI is utilized in place of the catalytic hydrogenation of Example I.

-3~-lO!~Ofil .

- EXAMPLES XXXVI-XXXVIII
_ 1.24 G. of 5(6)-(morpholinocarbonyl)-2-carbomethoxy-aminobenzimidazole is suspended in 25 ml of tetrahydropyran.
1 Ml of n-butylisocyanate is added and the mixture stirred overnight (~15 hours). The solution is evaporated to dryness under vacuum and the residue triturated with methanol to afford l-(n-butylcarbamoyl)-5(6)-(morpholinocarbonyl)-2-carbomethoxyaminobenzimidazole (m.p. 220-2C).
In similar manner to the above, substituting methyl-isocyanate and phenylisocyanate for the n-butylisocyanate, and triturated with acetone in place of methanol, l-methyl-carbamoyl-5(6)-(morpholinocarbonyl)-2-car~omethoxyamino-benzimidazole and l-phenylcarbamoyl-5(6~-(morpholinocarbonyl)-2-carbomethoxyaminobenzimidazole are prepared, respectively.
EXAMPLE XXXIX
11.2 G. of 3-nitro-4-acetamidobenzoic acid ~prepared as described in Helv. Chem. Acta 36, ~06 (1953)] is suspended in 50 ml of methylene chloride and treated with 5 ml of thionyl chloride and 5 drops of dimethylformamide. The mixture is refluxed until the reaction is complete (~3 hours). The solution is cooled and treated at 10-20C with 18 ml of morpholine and left overnight. 25 Ml of water and 10 ml of conc. hydrochloric acid are added. The lower layer is separated and washed with water, and a 5 ml wash of methylene chloride is combined with the main solution. 50 Ml of methanol and 10 ml of 5 N sodium hydroxide solution is added at 20-25C. After 1 hour, the mixture is neutralized with ~lmlof acetic acid and concentrated under vacuum to a volume -3~-10~40fil of ~50-60 ml. Water is added until the total volume is about ~200 ml and 2-nitro-4-morpholinocarbonylaniline filtered off and dried.
The preparation of 2-acetamido-5-morpholinocarbonyl-aniline, an unisolated intermediate in the above procedure, is also described in Chem. Absts.58:45416 (1963).
2.5 G. of 2-nitro-4-morpholinocarbonylaniline, 2.5 g ofironpowder, 10 ml of methanol, 10 ml of water and 0.5 ml of conc. hydrochloric acid are heated under nitrogen at reflux until reduction is complete (~30 minutes). The mixture is cooled and filtered through charcoal. 2.1 G
of l,3-bismethoxycarbonyl-S-methyl isothiourea and 0.6 ml of acetic acid are added and the mixture heated for 3 hours at reflux. The pH is adjusted to 7 with ammonium hydroxide and the methanol distilled off under vacuum. The solution is cooled, the product filtered off after a suitable aging period, recrystallized from methanol-chloroform with charcoal treatment to afford 5(6)-morpholinocarbonyl-2-carbomethoxy-aminobenzimidazole.
2 0 EY;~PLE XL
A solution of 0.14 g of ferrous sulfate heptahydrate in 15 ml of methanol is treated under nitrogen with 0.02 g of sodium borohydride. After 5 minutes, 2.5 g of 2-nitro-4-morpholinocarbonylaniline ~as prepared in Example ~XXIX) and 1 ml 64~ hydrazine are added. The mixture is refluxed until reduction is complete (~4-6 hours) to afford 1,2-diamino-4-morpholinocarbonylbenzene.

--~' O--lO!~Ofi~

\

4 G. of calcium cyanamide is suspended in 15 ml of water and 3.7 ml of ethanol. 2.7 Ml of methylchloroformate is added dropwise at 30-40C. After 1 hour more at 30-40C the mixture is filtered.
The mixture is of 1,2-diamino-4-morpholinocarbonylbenzene is cooled, filtered and treated with 2S ml of the reagent prepared in the preceeding paragraph, and the pH adjusted to 3byaddition of hydrochloric acid. The mixture is heated and kept at pH 3-4 tby addition ofadditionalhydrochloric acid as necessary) for 3 hours, cooled and pH adjusted to 7.0 with ammonia hydroxide. After 24 hours, 5(6)-morpholino-carbonyl-2-carbomethoxyaminobenzimidazole is filtered off.
While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in this art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifica~ions may be made to adapt a particular situation, material or composi~ion of ~atter, process, process step or steps, or then-present objective to the spirit of this invention without departing from its essential teachings.

Claims (67)

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 selected from the group of compounds represented by the formula:
(I) wherein R is a lower alkyl group having 1 to 4 carbon atoms, is a 5, 6 or 7 membered saturated or mono-olefinically unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and the being at the 5(6)-position, said heterocycle being optionally substituted with lower alkyl or hydroxy, or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting a phenylenediamine compound represented by the formula:
wherein is previously defined, with a compound represented by X-COOR, wherein R is previously defined and X is ,,, ,,, NCCH- , ,,, or ,, Hal is chloro, bromo or iodo, and R1 is lower alkyl, aralkyl or 7 or 8 carbon atoms, or alkylene sulfonic acid of 2-4 carbon atoms or the alkali metal salt thereof;
b) reacting a thioureido compound represented by the formula:
, wherein (IV) and R are previously defined and Y is H or , with a metal ion catalyst suitable to effect cyclization;
c) reacting a 2-aminobenzimidazole compound represented by the formula:
, wherein (V) is previously defined, with a compound represented by wherein U is chloro, alkoxy or 1-6 carbon atoms or alkylthio of 1-6 carbon atoms;

d) reacting a compound represented by the formula:
, wherein (VI) R is previously defined, with a reagent to form a 5(6)-acid chloride or mixed anhydride and reacting said 5(6)-acid chloride or mixed anhydride with at least a molar amount of a heterocyclic base of the formula wherein is previously defined, and an additional molar amount of an organic base;
e) reacting a compound represented by formula I which is a free base with a suitable inorganic or organic acid to form a pharmaceutically acceptable salt of a compound of formula I;
f) reacting a pharmaceutically acceptable salt of the compound represented by formula I with a suitable organic or inorganic base to give a compound represented by formula I which is a free base; and g) reacting a compound represented by formula I, wherein Z N- contains a sulfur atom or a sulfoxide group in the ring with an oxidizing agent to convert said sulfur to sulfoxide or said sulfoxide to sulfone.

2. A process according to claim 1, wherein steps a through g, R is methyl.

3. A process according to claim 1, wherein steps a through g is a 5- or 6-membered heterocyclic ring.

4. A process according to claim 1, wherein steps a through g is a 5-membered heterocyclic ring having 1 hetero atom.

5. A process according to claim 1, wherein wherein steps a through a is a 5-membered heterocylic ring having 2 hetero atoms.

6. A process according to claim 1, wherein steps a through g is a 6-membered heterocyclic ring having 1 hetero atom.

7. A process according to claim 1, wherein steps a through g is a 6-membered heterocyclic ring having 2 hetero atoms.

8. A process according to claim 1, wherein steps a through g said heterocylic ring is saturated and is optionally substituted with hydroxy or lower alkyl.

9. A process according to claim 1, wherein steps a through f said heterocyclic ring contains two nitrogen atoms, the nitrogen not bonded to the carbonyl group being substituted with phenyl, benzyl or an alkyl group.

10. A process according to claim 1, wherein steps a through g said heterocyclic ring contains two hetero atoms.

11. A process according to claim 1, wherein steps a through f the second hetero atom is oxygen.

12. A process according to claim 1, wherein steps a through g the second hetero atom is sulfur, said sulfur atom being either in the sulfide, sulfoxide or sulfone form.

13. A process according to claim 1, wherein steps a through g the sulfur hetero atom is in the sulfide form.

14. A process according to claim 1, wherein steps a through g the sulfur hetero atom is in the sulfoxide form.

15. A process according to claim 1, wherein steps a through f the sulfur hetero atom is in the sulfone form.

16. A process according to claim 1, wherein said heterocyclic ring, expressed in radical form, is selected from the group consisting of: pyrrolidinyl; piperidino, 4-hydroxypiperidino; 2-methylpiperidino; 3-methylpiperidino;
4-methylpiperidino; 2,6-dimethylpiperidino; 4-phenylpiperidino;
4-benzylpiperidino; piperazinyl; 4-methylpiperazinyl;
4-benzylpiperazinyl; morpholino, 2,6-dimethylmorpholino;
1,2,3,6-tetrahydropyridyl; 4-oxo-1,4-dihydropyridyl;
thiazolidin-3-yl; 1-oxo-thiazolidin-3-yl;
1,1-dioxo-thiazolidin-3-yl; thiomorpholino;
l-oxo-thiomorpholino; 1,1-dioxo-thiomorpholino; pyrrolinyl;
perhydroazepinyl; perhydroazocinyl; imidazolinyl; oxazolidinyl;
tetrahydroxazinyl; and tetrahydrothiazinyl.

17. A process according to claim 1, wherein steps a through f said heterocyclic ring is morpholino.

18. A process according to claim 1, wherein steps a through f for preparing the compound 5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimidazole, wherein said hetetocyclic ring is morpholino and R is methyl.

19. A process according to claim 1 wherein steps a through g for preparing the compound 5(6)-thiomorpholinocarbonyl-2-carbomethoxyaminobenzimidazole, wherein said heterocyclic ring is thiomorpholino and R is methyl.

20. A process according to claim 1 wherein steps a through a for preparing the compound 5(6)-(1-oxo-thiomorpholinocarbonyl-2-carbomethoxyaminobenzimidazole, wherein said heterocyclic ring is 1-oxo-thiomorpholino and R is methyl.

21. A process according to claim 1 wherein steps a through g for preparing the compound 5(6)-piperidinocarbonyl-2-carbomethoxyaminobenzimidazole, wherein said heterocyclic ring is piperidino and R is methyl.

22. A process according to claim 1 wherein steps a through g for preparing the compound 5(6)-pyrrolidinylcarbonyl-2-carbomethoxyaminobenzimidazole, wherein said heterocyclic ring is pyrrolidinyl and X is methyl.

23. A process according to claim 1 wherein steps a through g for preparing the compound 5(6)-(thiazolidin-3-ylcarbonyl)-2-carbomethoxyaminobenzimidazole, wherein said heterocyclic ring is thiazolidin-3-yl and R is methyl.

24. A process according to claim 1, wherein steps a through g, for preparing the compound 5(6)-(oxo-thiazolidin-3-yl)-2-carbomethoxyaminobenzimidazole, said heterocyclic ring is 1-oxo-thiazolidin-3-yl and R is methyl.

25. A process according to claim 1, wherein steps a through g, for preparing the compound 5(6)-(1,2,3,6-tetrahydropyridyl-carbonyl)-2-carbomethoxyaminobenzimidazole, said heterocyclic ring is 1,2,3,6-tetrahydropyridyl and R is methyl.

26. A compound selected from the group of compounds repre-sented by the formula:
wherein R is a lower alkyl group having 1 to 4 carbon aroms, is a 5, 6, or 7 membered saturated or mono-olefinically unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and the being at the 5(6)-position, said heterocyclic being optionally substituted with lower alkyl or hydroxy, or a pharmaceutically acceptable salt thereof, when prepared by the process of claim 1.

27. The compound of claim 26, wherein R is methyl, when prepared by the process of claim 2.

28. The compound of claim 26, wherein is a 5- or 6-membered heterocyclic ring, when prepared by the process of claim 3.

29. The compound of claim 26, wherein is a 5-membered heterocyclic ring having 1 hetero atom, when prepared by the process of claim 4.

30. The compound of claim 26, wherein is a 5-membered heterocyclic ring having 2 hetero atoms, when prepared by the process of claim 5.

31. The compound of claim 26, wherein is a 6-membered heterocyclic ring having 1 hetero atom, when prepared by the process of claim 6.

32. The compound of claim 26, wherein is a 6-membered heretocyclic ring having 2 hetero atoms, when prepared by the process of claim 7.

33. The compound of claim 26, wherein said heterocyclic ring is saturated and is optionally substituted with hydroxy or lower alkyl, when prepared by the process of claim 8.

34. The compound of claim 26, wherein said heterocyclic ring contains two nitrogen atoms, the nitrogen not bonded to the carbonyl group being substituted with phenyl, benzyl or an alkyl group, when prepared by the process of claim 9.

35. The compound of claim 26, wherein said heterocyclic ring contains two hetero atoms, when prepared by the process of claim 10.

36. The compound of claim 26, wherein the second hetero atom is oxygen, when prepared by the process of claim 11.

37. The compound of claim 26, wherein the second hetero atom is sulfur, said sulfur atom being either in the sulfide, sulfoxide or sulfone form, when prepared by the process of claim 12.

38. The compound of claim 26, wherein the sulfur hetero atom is in the sulfide form, when prepared by the process of claim 13.

39. The compound of claim 26, wherein the sulfur hetero atom is in the sulfoxide form, when prepared by the process of claim 14.

40. The compound of claim 26, wherein the sulfur hetero atom is in the sulfone form, when prepared by the process of claim 15.

41. The compound of claim 26, wherein said heterocyclic ring, expressed in radical form, is selected from the group consisting of: pyrrolidinyl; piperidino; 4-hydroxypiperidino; 2-methyl-piperidino; 3-methylpiperidino; 4-methylpiperidino; 2,6-dimethyl-piperidino; 4-phenylpiperidino; 4-benzylpiperidino; piperazinyl;
4-methylpiperazinyl; 4-phenylpiperazinyl; 4-benzylpiperazinyl;

morpholino; 2,6-dimethylmorpholino; 1,2,3,6-tetrahydropyridyl;
4-oxo-1,4-dihydropyridyl; thiazolidin-3-yl; 1-oxo-thiazolidin-3-yl; 1,1-dioxo-thiazolidin-3-yl; thiomorpholino; 1-oxo-thiomor-pholino; 1,1-dioxo-thiomorpholino; pyrrolinyl; perhydroazepinyl;
perhydroazocinyl; imidazolinyl; oxazolidinyl; tetrahydroxazinyl;
and tetrahydrothiazinyl, when prepared by the process of claim 16.

42. The compound of claim 26, wherein said heterocyclic ring is morpholino, when prepared by the process of claim 17.

43. The compound of claim 26, wherein said compound of Formula I is 5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimi-dazole, when prepared by the process of claim 18.

44. The compound of claim 26, wherein said compound of Formula I is 5(6)-thiomorpholinocarbonyl-2-carbomethoxyamino-benzimidazole, when prepared by the process of claim 19.

45. The compound of claim 26, wherein said compound of Formula I is 5(6)-(1-oxo-thiomorpholinocarbonyl-2-carbomethoxy-aminobenzimidazole, when prepared by the process of claim 20.

46. The compound of claim 26, wherein said compound of Formula I is 5(6)-piperidinocarbonyl-2-carbomethoxyaminobenzimi-dazole, when prepared by the process of claim 21.

47. The compound of claim 26, wherein said compound of Formula I is 5(6)-pyrrolidinylcarbonyl-2-carbomethoxyaminobenzi-midazole, when prepared by the process of claim 22.

48. The compound of claim 26,wherein said compound of Formula I is 5(6)-(thiazolidin-3-ylcarbonyl)-2-carbomethoxy-aminobenzimidazole, when prepared by the process of claim 23.

49. The compound of claim 26,wherein said compound of Formula I is 5(6)-(1-oxo-thiazolidin-3-yl)-2-carbomethoxyamino-benzimidazole, when prepared by the process of claim 24.

50. The compound of claim 26, wherein said compound of Formula I is 5(6)-(1,2,3,6-tetrahydropyridylcarbonyl)-2-carbo-methoxyaminobenzimidazole, when prepared by the process of claim 25.

51. A process according to claim 1, wherein a compound prepared by selected steps a through g is mixed with a pharma-ceutically acceptable carrier.

52. A process according to claim 2, wherein a compound prepared by selected steps a through g is mixed with a pharma-ceutically acceptable carrier.

53. A process according to claim 8, wherein a compound prepared by selected steps a through g is mixed with a pharma-ceutically acceptable carrier.

54. A process according to claim 9, wherein a compound prepared by selected steps a through g is mixed with a pharma-ceutically acceptable carrier.

55. A process according to claim 10, wherein a compound prepared by selected steps a through g is mixed with a pharma-ceutically acceptable carrier.

56. A process according to claim 11, wherein a compound prepared by selected steps a through g is mixed with a pharma-ceutically acceptable carrier.

57. A process according to claim 12, wherein a compound prepared by selected steps a through g is mixed with a pharma-ceutically acceptable carrier.

58. A process according to claim 16, wherein a compound prepared by selected steps a through g is mixed with a pharma-ceutically acceptable carrier.

59. A process according to claim 17, wherein a compound prepared by selected steps a through g is mixed with a pharma-ceutically acceptable carrier.

60. A process according to claim 18, wherein the prepared compound 5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimidazole is mixed with a pharmaceutically acceptable carrier.

61. A process according to claim 19, wherein the prepared compound 5(6)-thiomorpholinocarbonyl-2-carbomethoxyaminobenzimi-dazole is mixed with a pharmaceutically acceptable carrier.

62. A process according to claim 20, wherein the prepared compound 5(6)-(1-oxo-thiomorpholinocarbonyl-2-carbomethoxy-aminobenzimidazole is mixed with a pharmaceutically acceptable carrier.

63. A process according to claim 21, wherein the prepared compound 5(6)-piperidinocarbonyl-2-carbomethoxyaminobenzimida-zole is mixed with a pharmaceutically acceptable carrier.

64. A process according to claim 22, wherein the prepared compound 5(6)-pyrrolidinylcarbonyl-2-carbomethoxyaminobenzimi-dazole is mixed with a pharmaceutically acceptable carrier.

65. A process according to claim 23, wherein the prepared compound 5(6)-thiazolidin-3-ylcarbonyl)-2-carbomethoxyaminobenzi-midazole is mixed with pharmaceutically acceptable carrier.

66. A process according to claim 24, wherein the prepared compound 5(6)-(1-oxo-thiazolidin-3-yl)-2-carbomethoxyaminobenzi-midazole is mixed with a pharmaceutically acceptable carrier.

67. A process according to claim 25, wherein the prepared compound 5(6)-(1,2,3,6-tetrahydropyridylcarbonyl)-2-carbomethoxy-aminobenzimidazole is mixed with a pharmaceutically acceptable carrier.