5(6)-BENZENE RING SUBSTITUTED BENZIMIDAZOLE-2- CARBAMATE DERIVATIVES HAVING ANTHELMINTIC ACTIVITY

TRADUCTION NON-DISPONIBLE

English Abstract

Abstract of the Disclosure
Benzene ring substituted benzimidazole-2-
carbamate derivative represented by the formula:
<IMG> (I)
where R is a lower alkyl group having 1 to 4 car-
bon atoms; <IMG> is a 5, 6, 7 or a membered hetero-
cyclic ring containing 1 or 2 hetero atoms; the
<IMG> 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.

Claims

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:
<IMG> (I)
wherein R is a lower alkyl group having 1 to 4 carbon atoms,
<IMG> 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 <IMG> 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:
<IMG>
wherein <IMG> is previously defined, with a compound represented
by X-COOR, wherein R is previously defined and X is
<IMG>,,,
42

<IMG>,,,
NCCH- ,
<IMG>,,, or
<IMG> ,,
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:
<IMG> , wherein
(IV)
<IMG> and R are previously defined and Y is H or <IMG>,
with a metal ion catalyst suitable to effect cyclization;
c) reacting a 2-aminobenzimidazole compound represented
by the formula:
<IMG> , wherein
(V)
<IMG> is previously defined, with a compound represented by
<IMG> wherein U is chloro, alkoxy or 1-6 carbon atoms or alkylthio
of 1-6 carbon atoms;
43

d) reacting a compound represented by the formula:
<IMG> , 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 <IMG> wherein <IMG> 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.
44

3. A process according to claim 1, wherein steps a through
g <IMG> is a 5- or 6-membered heterocyclic ring.
4. A process according to claim 1, wherein steps a through
g <IMG> is a 5-membered heterocyclic ring having 1 hetero atom.
5. A process according to claim 1, wherein wherein steps a
through a <IMG> is a 5-membered heterocylic ring having 2 hetero
atoms.
6. A process according to claim 1, wherein steps a through
g <IMG> is a 6-membered heterocyclic ring having 1 hetero atom.
7. A process according to claim 1, wherein steps a through
g <IMG> 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.
46

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.
47

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:
<IMG>
wherein R is a lower alkyl group having 1 to 4 carbon aroms,
<IMG> 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 <IMG> 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.
48

28. The compound of claim 26, wherein <IMG> is a 5- or 6-
membered heterocyclic ring, when prepared by the process of
claim 3.
29. The compound of claim 26, wherein <IMG> 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 <IMG> 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 <IMG> 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 <IMG> 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.
49

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.
51

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.
52

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.
53

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.
54

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;
--3--

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--

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
3Q

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
2 5 O R10
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,
-15-

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-).
-16-

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
-17-

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:
- 18 -

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
--19--

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.
-20-

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.
-21-

1094061
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).
-22-

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.
-24-

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
-25-

~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~);
-27-

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
-30-

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
62 0 0 100100
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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
62 0 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.
-32-

~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.
-34-

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
36

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~-

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.
- 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.