BENZIMIDAZOLE AND BENZIMIDAZOLIDINE DERIVATIVES WITH DIURETIC AND ANTIHYPERTENSIVE ACTIVITY

DERIVES DE BENZIMIDAZOLE ET DE BENZIMIDAZOLIDINE, AGISSANT COMME DIURETIQUE ET ANTIHYPERTENSEUR

English Abstract

ABSTRACT OF THE DISCLOSURE
Compounds having diuretic and antihypertensive properties are disclosed
which have the following structural formulae:

Image
or

Image
or pharmaceutically acceptable salts thereof, wherein:
X = halogen or trifluoromethyl
Y1 and Y2 = independently hydrogen, alkyl, acyl, azyl, substituted aryl or
heterocycle,
R1 = hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl,
aralkyl, heterocycle or substituted heterocycle,
n = 0 or an integer from 1-4
R2 = amino, substituted amino, guanidino, substituted guandino, halogen, alkyl,
substituted alkyl, aryl, substituted aryl or heterocycle, and
R3 = hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl
aralkyl, heterocycle, substituted heterocycle or acyl.
Methods of preparation are also disclosed.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a sulfamyl benzimidazole of formula

Image

and pharmaceutically acceptable acid addition salts thereof
wherein n is 0 or an integer from 1 to 4,
X is halogen or trifluoromethyl and R2 is amino, furyl,
halogen, lower alkyl, lower alkyl substituted by phenyl, phenyl,
phenyl substituted by lower alkyl, formamido, guanidino, guanidino
substituted by lower alkyl, and amino substituted by lower alkyl, by
carboxy, by carboxy-lower alkyl, by lower alkyl-carboxy, by phenyl,
by benzyl, by phenyl substituted by carboxy, by phenyl substituted by
hydroxy, by phenyl substituted by lower alkyl, by phenyl substituted
by halogen, by furfuryl, by carboxy substituted by phenoxy lower
alkyl and by carboxy substituted by dihalogeno phenoxy lower alkyl;
which comprises subjecting a compound of formula

Image






wherein X is as already defined to ring closure with a compound that will
add the substituent - (CH2)nR2 wherein n and R2 are as defined, at the
2-position of the formed sulfamyl benzimidazole and recovering the required
sulfamyl benzimidazole.
2. The process of claim 1 wherein the compound that will add a substituent -
(CH2)nR2 is a cyanide or an aldehyde.
3. A compound of the formula

Image

and pharmaceutically acceptable acid addition salts thereof
wherein n is 0 or an integer from 1 to 4,
X is halogen or trifluoromethyl and R2 is amino, furyl,
halogen, lower alkyl, lower alkyl substituted by phenyl, phenyl,
phenyl substituted by lower alkyl, formamido, guanidino, guanidino
substituted by lower alkyl, and amino substituted by lower alkyl, by
carboxy, by carboxy-lower alkyl, by lower alkyl-carboxy, by phenyl,
by benzyl, by phenyl substituted by carboxy, by phenyl substituted by
hydroxy, by phenyl substituted by lower alkyl, by phenyl substituted
by halogen, by furfuryl, by carboxy substituted by phenoxy lower
alkyl and by carboxy substituted by dihalogeno phenoxy lower alkyl;
when prepared by the process of claim I or an obvious chemical equivalent.
4. A process for the preparation of the compound 2-amino-5-chloro-6-sulf-

16



amyl-1H-benzimidazole hydrobromide, which comprises reacting 2-amino-4-chloro-
5-sulfamylaniline with cyanogen bromide in suspension and recovering the
required compound.
5. 2-amino-5-chloro-6-sulfamyl-1H-benzimidazole hydrobromide when prepared
by the process of claim 4 or an obvious chemical equivalent.
6. A process for the preparation of the compound 5-chloro-2-guanidino-6-
sulfamyl-1H-benzimidazole hydrochloride which comprises reacting 2-amino-4-
chloro-5-sulfamylaniline with cyanoguanidine in the presence of HCl and water
and recovering the required compound.
7. 5-chloro-2-guanidino-6-sulfamyl-1H-benzimidazole hydrochloride when
prepared by the process of claim 6 or an obvious chemical equivalent.
8. A process for the preparation of the compound 5-chloro-2-phenyl-6-sulf-
amyl-1H-benzimidazole which comprises reacting 2-amino-4-chloro-5-sulfamylan-
iline with benzaldehyde in glacial acetic acid and recovering the required
compound.
9. 5-chloro-2-phenyl-6-sulfamyl-1H-benzimidazole when prepared by the
process of claim 8 or an obvious chemical equivalent.
10. A process for the preparation of the compound 5-chloro-2-N3-methyl-
guanidino-6-sulfamyl-1H-benzimidazole hydrochloride which comprises reacting
2-amino-4-chloro-5-sulfamylaniline with N-methyl cyanoguanidine in the presence
of HCl in solution and recovering the required compound.
11. 5-chloro-2-N3-methylguanidino-6-sulfamyl-1H-benzimidazole hydrochloride
when prepared by the process of claim 10 or an obvious chemical equivalent.

17

Description

~ 1126~80


The inventlon generally relates to compounds having diuretlc and anti-

hypertensive properties and which have the following structural formulaq:



Y~




; or
R1 3
X ~ N H


Yl ,, ~\ ~ N ~ ( 2)n 2

Y2Rl

or pharmaceutically acceptable salts thereof, wherein:
X - halogen or trifluoromethyl
Yl and Y2 ~ independently hydrogen, alkyl, acyl, aryl, substituted aryl or
heterocycle,
Rl ~ hydrogen, lower alkyl, aryl, substituted aryl, benzyl, ~ubstltuted benzyl,
aralkyl, heterocycle or substituted heterocycle,
n ~ O or an lnteger from 1-4
R2 ~ amino, substltuted amino, guanidino, substituted guanidino, halogen, alkyl,
substituted alkyl, aryl, sub9titutet aryl or heterocycle, and

R3 ~ hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl,
aralkyl, heterocycle, substituted heterocycle or acyl.
, - 1 - ~ i

, '' ' ~ ~
:
'''''

:: ;

1126~8~

It 19 a primary ob~ect to provide for new compounds of the above
structure.
It i9 a further ob~ect of the present invention to provlde for methods
of produclng the above compounds.
It 19 yet a further ob~ect of the present invention to provite a new
class of compounds whlch exhlblt dluretlc and antlhypertenslve activity.
Other ob~ects and advantages of the present lnvention will be apparent
from a further reading of the ~pecificatlon and of the~appended claims.
The productlon of the compoundæ of the present inventlon may be effect-
" 10 ed by varlous methods whlch are known ln prlnciple. The following illustrates
two different convenient syntheses which may be used ln the production~of the
compounds of the lnventlon:




~ ..
. .


- ~'

',.'' , ' ', , :
.. , . . ~
, :.... . ..

, .

, . :
. , . . - : -
.

--`` 112ti28~

PREPARATION OF 2 - AMINO - 5 - CHLORO - 6 -
SULFAM~L - lH - BENZIMIDAZOLE HYDROBROMIDE (VII)

. O
Cl ~ NH2 Cl ~ NHIC~CH3
(CH3CO)20 ~

I II HN03


1. ClSO3H ¢1 ~ NH2 Cl ~ NHIOC-CH
2. NH40H l ll NaOCH3 ¦ 1 3
: ~--N02 ~ N02

IV III




V ~ 2

.BrCN


C~ 3r
; ~ ~ VII H


/
;: - 3 -
'~



; ~
,. . . .
'. . ' : ~ . :
.''-' ~
, ~ .

6~8~

PREPARATION OF 5 - CHLORO - 2 - GUANIDINO - 6 -
SULFAMYL - lH - BENZIMIDAZOLE HYDROCHLORIDE ~VIII?
'.~


I (CH3CO~20 II

/ ~N03


IV NaOCH3 III
~ 1. ClS03H
Z. NH40H
LH]




V ) VI




Cl ~ N / HCl 2



VIII




- 4 -



.

-
1126~8~

As indicated above, in the structural formulas of the compounds of the

inventlon which were lllustrated X i9 a halogen or trlfluoromethyl.
i
Yl and Y2 are each hydrogen, alkyl, acyl, aryl, substltuted aryl or
heterocycle. Most pre~erably Yl and ~2 are each either hydrogen and/or lower
alkyl.
The substltutent Rl may be hydrogen~ lower alkyl, aryl, substituted
aryl, benzyl, substituted benzyl, aralkyl, heterocycle or substituted hetero-
cycle. Most preferably Rl is hydrogen, lower alkyl, aryl or substituted aryl,
preferably substituted by lower alkyl, alkoxy, or halogen.
As lndicated "n" may be 0 or an integer from 1-4.
Most preferably "n" = 0.
R2 may be amino, substituted amino, guanidino, substituted guanidino,
halogen, alkyl, substituted alkyl, aryl, shbstltuted aryl or heterocycle. Most
preferably R2 i9 amino, substituted amino substit~ted by lower alkyl or guani-
dino.
The substituent R3 may be hydrogen, lower alkyl, aryl, substituted aryl,
benzyl, substituted benzyl, aralkyl, heterocycle, su~s~ituted heterocyle or acyl.
Most preferably R3 is hydrogen or lower alkyl.
In addition to compounds (VII) and (VIII) shown above, other specific
; suitable compounds of the above Pormula lnclude:
5-- chloro - 2 - formamido - 6 - sulfamyl - lH - benzlmldazole
2-- carbethoxyamino - 5 - chloro - 6 - ~ulfamyl - lH - benzimidazole
2 - benzylamino - 5 - chloro - 6 sulfamyl - lH - benzimidazUe
S - chloro - 6 - N,N - dimethylsulfonamido - 2 - guanidino - 1~ - benzimidazole
5 - chloro - 2 - guanidino - 6 - N - methylsulfonamido - lH - benzimidazole
2 - amino ~ 5 - chloro - 6 - sulfamyl - 1 - (o-tolyl) - lH - benzimidazole
2 - amino - 5 - chloro - 1 - (o-methylbenzyl) - 6 - sulfamyl - lH - benzimidazole
- 5 -
~, ,,




,
' ' ~ . , '

~` 11;~280

5 - chloro - 2 - dlmethylamlno - 6 - sulfamyl - lH - benzlmldazole
2 - dimethylamino - 6 - sulfamyl - 5 - trifluoromethyl - lH - benzlmidazole
2 - acetamido - 5 - chloro - 6 - sulfamyl - lH - benzimidazole
5 - chloro - 2 - guanldlno - 1 - methyl - 6 - sulfa~yl - lH - benzimidazole
2 - acetamido - 5 - chloro - 6 - sulfamyl - lH - benzimldazole
- 2 - acetamido - 5 - chloro - 6 - sulfamyl - lH - benzlmidazole
2 - carbethoxyamlno - 5 - chloro - 6 - sulfamyl - lH - benzimidazole
2 - formamido - 6 - sulfamyl - 5 - trlfluoromethyl - lH benzimidazole
2 - carbethoxyamlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzimldazole
, 10 2 - benzylamlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzimidazole
: 2 - benzylamlno - 5 - bromo - 6 - sulfa~yl - lH - benzlmidazole
5 - chloro - 2 - (2,6-- dichloro) anilino - 6 - sulfamyl - lH - benzimidazole
2 - (2,6 - dichloro) anllino - 6 - sulfamyl - 5 - trlfluoromethyl - lH -
: benzlmldazole
5 - bromo - 2 - (2.6 - dlchloro) anillno - 6 - sulfamyl - lH - benzimidazole
5 - chloro - 2 - (2,6 - dimethyl) anilino - 6 - sulfamyl - lH - benzimldazole
2 - (2,6 - dimethyl) anlllno - 6 - sulfamyl - S - trlfluoromethyl - lH -
benzlmldazole
5 - bromo - 2 - (2,6 - dlmethyl) anllino - 6 - sulfamyl - lH - benzimidazole
2 - amino - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzlmidazole
2 - amlno - 5 - bromo - 6 - sulfamyl - lH - benzimldazole
2 - guanldlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzlmldazole
5 - bromo - 2 - guanldino - 6 - sulfamyl - lH - benzimidazole
5 - chloro - 2 - guanldlno - 6 - N - methylsulfonamldo - lH - benzlmldazole
2 - amino - 5 - chloro - 6 - N - methylsulfonamldo - lH - benzlmidazole
2 - amlno - 6 - N - methylsulfonamido - S - trlfluoromethyl - lH - benzimidazole
,, 2 - amino - 5 - chloro - 6 - N,N - dlmethylsulfonamido - lH - benzimldazole
.;,
; 2 - guanldino - 6 - N - methylsulfonamido - 5 - ~rlfluoromethyl - lH -
benzlmidazole
; 30 5 - bromo - 2 - guanldlno - 6 - N-methylsulfonamido - lH - benzlmidazole
- 6 -


,~, .
.. ~ ~ ... .
'
", ~ ~:
,' . . , ` '
;.,:., :

- `` 11~6Z8~
'
6 - N,N - dimethylsulfonamldo - 2 - guanidino - 5 - trifluoromethyl - lH -
benzimidazole
5 - bromo - 6 - N,N - dimethylsulfonamldo - 2 - guanidino - lH - benzlmidazole
5 - fluoro - 2 - guanldino - 6 - sulfamyl - lH - benzlmidazole
2 - amlno - 5 - fluoro - 6 - sulfamyl - lH - benzimldazole
5 - chloro - 2 - [4 - (2,3~- dlchlorophenoxymethylcarboxyl)] amino - 6 - sulfamyl
- lH - benzlmidazole
2 - [4 - 2,3 - dlchlorophenoxymethylcarboxy)] amino - 6 - sulfamyl - 5 - tri-
fluoromethyl - lH - benzlmldazole
5 - bromo - 2 - [4 - (2,3 - dlchlorophenoxymethylcarboxy)~ amino - 6 - sulfamyl
- 1 H - benzlmltazole
2 - amino - 5 - chloro - 6 - sulfamylbenzimidazolidine
: 2 - amino - 6 - sulfamyl - 5 - trifluoromethylbenzlmldazolldlne
2 - amino - 5 - bromo - 6 - sulfamylbenzimidazolidine
5 - chloro - 2 - guanidino - 6 - sulfamylbenzlmidazolldine
2 - guanidlno - 6 - sulfamyl - 5 - trlfluoromethylbenzimidazolidine
5 - bromo - 2 - guanitino - 6 - ~ulfamylbenzlmidazolidlne
2 - amino - 5 - chloro - 6 - sulfamyl - 1 - (3-tolyl) - lH - benzimldazole
: 2 - amino - 6 - sulfamyl - 1 - (3-tolyl) - 5 - trifluoromethyl - lH - benzl-
: 20 mitazole
2 - amlno - 5 - bromo - 6 - sulfamyl - 1 - (3-tolyl) - lH - benzimldazole
2 - amino - 5 - chloro - 6 - sulfamyl - 1 - (4-tolyl~ - lH - benzimidazole
2 - amino - 6 - sulfamyl - 1 - (4-tolyl) - 5 - trifluoromethyl - lH benzimida-
zole
2 - amlno - 5 - bro - 6 - sulfamyl - 1 - (4-tolyl) - lH - benzlmldazole
2 - amlno - 5 - chloro - 1 - (2,6 - dimethylphenyl) - 6 - sulfamyl - lH -
benzlmidazole
2 - amino - 1 - (2,6 - dlmethylphenyl) - 6 - sulfamyl - 5 - trifluoromethyl -
: lH - benzimldazole
~; 30 2 - amlno - 5 - bromo - 1 - (2,6 - dimethylphenyl) - 6 - sulfamyl - lH -
benzimidazole
2 - amino - 5 - chloro - 6 - culfamyl - 1 - (2-tolyl) benzimidazolldlne

S 7


, ~...... .,

~ . .

~Z6Z8~

2 - amino - 6 - sulfamyl - 1 - (2-tolyl) - 5 - trifluoromethylbenzimidazolidine
2 - amino - 5 - bromo - 6 - sulfamyl - 1 - (2-tolyl) benzimidazolidine
5 - chloro - 2 - guanidino - 6 - sulfamyl - 1 - (2-tolyl) benzimidazolidine
2 - guanidino - 6 - sulfamyl - 1 - (2-tolyl)- 5 - trifluoromethylbenzimidazolidine
, 5 - bromo - 2 - guanidlno - 6 - sulfamyl - 1 - (2-tolyl) benzimidazolidine
2 - amlno - 5 - chloro - 1 - (2-methoxyphenyl)- 6 - sulfamyl-lH- benzlmidazole
~4 2 - amino - 1 - (2-methoxyphenyl) - 6 - sulfamyl - 5 - trifluoromethyl - lH -
benzimldazole
2 - amino - 5 - bromo - 1 - (2-methoxyphenyl) - 6 - sulfamyl - lH - benzimidazole
?,
2 - amlno - 5-chloro -1 - (2-methoxyphenyl) - 6 - sulfamyl - lH - benzimidazole
; 2 - amino - 1 - (2-chlorophenyl) - 6 - sulfamyl - 5 - trifluoromethyl - lH -
benzlmidazole
; 2 - amino - 5 - bromo - 1 - (2-chlorophenyl) - 6 - sulfamyl - lH - benzimidazole
; 5 - chloro - 1 - (2-chlorophenyl) - 2 - guanidlno - 6 - sulfamyl - lH - benzi-
midazole
1 - (2-chlorophenyl) - 2 - guanldlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH -.~ benzlmidazole
5 - bromo - 1 - (2-chlorophenyl) - 2- guanidlno - 6 - sulfamyl-lH- benzimidazole
2 - amino - 5 - chloro - 1 - (2-chlorophenyl) - 6 - sulfamylbenzimidazolidine
2 - amlno - 1 - (2-chlorophenyl) - 6 - sulfamyl - 5 - trifluoromethylbenzi-
midazolldlne
2 - amlno - 5 - bromo - 1 - (2-chlorophenyl) - 6 - sulfamylbenzlmldazolldine
:'' ,
, 5 - chloro - 1 - (2-chlorophenyl) - 2 - guanldino - 6 - sulfamylbenzimazolidine
1 - (2-chlorophenyl) - 2 - guanidlno - 6 - sulfamyl - 5 - trlfluoromethyl
;, benzlmldazolitlne
, I
;, 5 - bro - 1 - (2-chlorophenyl) - 2 - guanidlno - 6 - sulfamylbenzimidazolidine
., 5 - chloro - 2 - (furfurylamino) - 6 - sulfamyl - lH - benzlmldazole
2 - (furfurylamlno) - 6 - sulfamyl - 5 - trifluoromethyl - lH - benzlmidazole
,. 5 - chloro - 2 - (furfurylamino) - 6 - sulfamylbenzimidazolidine
2 - (furfurylamino) - 6 - sulfamyl - 5 - trlfluoromethylbenzlmldazolidine
5 - chloro - 6 - sulfamyl - 2 - (2-tolyl) - lH - benzimldazole
.~ 2 - (2-tolyl) - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzimldazole
: - 8 -



, '
':, , ' , ~,

, ~ - -
. ~ ' ' ,

~ 628~

S - chloro - 6 - sulfamyl - 2 - (2-tolyl) benzlmldazolidine
- 6 - sulfamyl - 2 - (2-tolyl) - 5 - trlfluoromethylbenzimidazolidlne
5 - chloro - 6 - sulfamyl - 2 - (3-tolyl) - lH - benzimldazole
~; 6 - sulfamyl - 2 - (3-tolyl) - 5 - trifluoromethyl - lH - benzimidazole
5 - chloro - 2 - phenyl - 6 - sulfamyl - lH - benzimidazole
2 - phenyl - 6 - sulfamyl - S - trlfluoromethyl - lH - benzimidazole
5 - chloro - 6 - sulfamyl - 2 - (3-tolyl) benzimidazolldine
6 - sulfamyl - 2 - (3-tolyl) - 5 - trlfluoromethylbenzimidazolidine
5 - chloro - 2 - phenyl - 6 - sulfamylbenzimidazolidine
2 - phenyl - 6 - sulfamyl - 5 - trlfluoromethylbenzimidazolidine
2 - (3-carboxy-4-hydroxy) anilino - 6 - sulfamyl - 5 - trifluoromethyl - lH -
benzimitazole
2 - (3-carboxy-4-hydroxy) anlllno - 5 - chloro - 6 - sulfamyl - lH - benzimida-
zole
5 - bromo - 2 - (3-carboxy-4-hydroxy) anllino - 6 - sulfamyl - lH - benzimida-
~: zole
': 2 - (4-carboxy-3-hydroxy) anlllno - 5 - chloro - 6 - sulfamyl - lH - benzimida-
,~ zole
; 2 - (4-carboxy-3-hydroxy) anilino - 6 - sulfam~l - 5 - trifluoromethyl - lH -
benzlmidazole
i: 5 - bromo - 2 - (4-carboxy-3-hydroxy) anilino - 6 - sulfamyl - lH -~benzimida-
; zole
, 5 - chloro - 2 - (N -methylguanidino) - 6 - sulfamyl - lH - benzimidazole
5 - bromo - 2 - (N3-methylguanldino) - 6 - sulfamyl - lH - benzimidazole
2 - (N -methylguanidino) - 6 - sulfamyl - 5 - trifluoromethyl - lH - benzimida-
zole
, 5 - chloro - 2 - (N3-methylguanidino) - 6 - sulfamyl - 1 - (2-tolyl) - lH -
benzimidazole
' 5 - bromo - 2 - (N3-methylguanidino) - 6 - sulfamyl - 1 - (2-tolyl) - lH -
benzlmldazole
: 2 - (N3-methylguanidino) - 6 - sulfamy~l - 1 - (2-tolyl) - S - trlfluoromethyl -
; lH - benzimidazole
. S - bromo - 2 - (N3-methylguanidino) - 6 - sulfamylbenzimidazolidine
, ,;
_ 9 _

',';

... . .


. ~.
,~

6Z8~

5 - chloro - 2 - (N3-methylguanidino) - 6 - sulfamyl - 1 - (2-tolyl) ben~imida-
zolidine
5(6)-chloro-2-methyl-6(5)-sulfamyl-1(3)H-benzimidazole hydrochloride
5(6)-chloro-benzlmldazole-6(5)-sulfonamide
5(6)-chloro-2-(2-furyl)-6(5)-~ulfamyl-1(3)H-benzim~da~ole
2-acetylamlno-5(6)-chloro-benzlmldazole-6(5)-sulfonamide
2,5(6)-dlchloro-6(5)-sulfamyl-1(3)H-benzimidazole HCl ~onohydrate
5(6)-chloro-2-propyl-6(5)-sulfam~l -1(3)H-benzimldazole
2-benzyl-5(6)-chloro-6(5)-sulfamyl-1-(3)H-benzlmldazole HCl monohydrate
10The following examples are given to illustrate the production of
compounds according to the lnventlon. The scope of the invention is not,
however, meant to be llmlted to the speclflc details of the examples
EXAMPLE 1
Preparatlon of 3 - Chloroacetanillde (II)
To 500 g. of 3 - chloroanlllne ~I) suspended ln 4.5 1. of water heated
to 35 was added stream wlse 690 g. of acetic anhydride over a 40 minute period.
After the addltion, the reactlon was stlrred for 4 hours, filtered, and the
; product washed wlth 12 1. of water and drled to provide 620.2 g. of 3-chloro-
acetanlllde (II) as whlte crystals, m.p. 72.5 - 73C.
! 20 Preparatlon of 5 - Chloro - 2 - ~ltroacetanillde_(III)
; To 100 g. of 3 - chloroacetanlllde ~II) ln 110 ml. of acetlc acld and
120 ml. of acetlc snhydrlde was added dropwlse at -10 to -5C 44 ml. of 90%
fumlng nltrlc acld ln 50 ml. of glacial acetlc acld. After completlon of the
addltlon, the yellow solutlon was stirred for one hour at 0 to +5C and then
; decanted into lce water. The yellow solld was collected by fll~ratlon, stirred
30 mlnutes wlth water, flltered, and then stlrred 20 mlnutes wlth 1 1. of ether
and flltered. Drylng of the solld provlded 110 g. of 5 - chloro - 2 - nltro-

acetanlllde (III) as a llght tan solid, m.p. 114 - 116C.
'
-- 10 --
'., ~

1~ 28~
,
Preparation of 5 - Chloro - 2 - Nltroanillne (IV)
To 3 1. of absolute methanol was slowly added 2.4 g, of sodium. When
all the sodlum had dissolved, 68 g. of 5 - chloro - 2 - nltroacetanillde was
added with stlrring and the solution refluxed for 7 hours. The solution was
allowed to sit overnight and then concentrated in vacuo until crystals formed.
Piltration of the precipitate provlded 51 g. of 5 - chloro - 2 - nitoraniline
(IV) as yellow needles, m.p. 124 - 126C.
Pre~aratlon of 5 - Chloro - 2 - Nitro - 4 - Sulfamylanilane (U)
To 235 ml. of chlorosulfonic acid at 2 at 10 was added portion wise
83.0 g. of 5 - chloro - 2 - nitroaniline (I~). After the addition, the dark
brown solution was stirred at 96 - 98C~for one hour, cooled, and carefully
decanted into 2 1. of lce. The precipitate was collected by filtretion, washed
with 1 1. of water, and air dried. To 365 ml. of 30~ ammonium hydroxlde was
added in 4 portions the crude sulfamyl chloride. The su~pension was stirred
for two hours at ambient temperature, heated at 100 for one hour, cooled and
set overnight. Filtration of the precipitate followed by recrystallization
from ethanol provided 30 g. of 5 - chloro - 2 - nitro - 4 - sulfamylanilane (V3
,
as light yellow crystals, m.p. 249 - 251C.
Preparation of 2 - Amino - 5 - Chloro - 4 - Sulfamylanillne (VI)
i 20 To 300 ml. of absolute methanol was added 19.25 g. of 5 - chloro - 2 -
,. . .
nitro - 4 - sulfamylanilane (V). After flushing with nitrogen, 5.5 g. of 5~
; pallsdium on carbon was added and the mixture hydrogenated for two hours after
; which time no more hydrogen was taken up. The reaction was filtered, the
charcoal washed with 100 ml. of absolute methanol, and the filtrate concentrated
to yield 10.4 g. of crude product. Recrystallization from ethanol treated with
~; activated carbon provided 10.4 g. of 2 - amino - 5 - chloro - 4 - sulfamylanilane
(VI) as brown needles, m.p. 216C.

-- 11 ---



.. . :
.
-, -.
- . : .
- . - .. : -.
: ,.- :: .
:, ' '-; ':

~l12628~

Preparation o 2 ~ Amino - 5 - Chloro - 6 - Sulfamyl - lH - Benzimidazole
` Hydrobromlde (VII?
To 19.38 g. of cyanogen bromlde ln 408 ml. of water at 5 to 10 C was
added portion wlse 15 g. of 2 - amino - 4 - chloro - 5 - sulfamylanillne (VI).
The suspenslon was stlrred at amblent temperature for two hours and then set
overnight. After concentratlng the reactlon mlxture ln vacuo, the residue was
dlssolved in bolllng ethanol and flltered to remove some insoluble material.
The ethanol solutlon was treated wlth charcoal, boiled, flltered, concentrated
tq 200 ml. and cooled. Dllutlon wlth ether followed by lce coollng preclpltat-

ed the product as off~white cry~tals which upon drying provided 7.30 g. of
2 - amlno - 5 - chloro - 6 - sulfamylbenzimadazole hydrobromide (YII), m.p.
317C,
Analy~is: Calculated for C7H8Br CI N4 02S~
25.66% C; 2.46%H; 17.10%N; 9.79%S
Found: 25.78% C; 2,52ZH; 17.25%N; 9,60%S,

? nmr: (DMS0-d6 - CDC13): 7.55 (bd, 4H), 7.78 (S,lH),
8.18 (S,lH), and 8.959 (bd, 2 H)
ir (K Br) 1680 cm (NH2)
4, Tlc (Silica gel): Rf ~ 0.60, methanol as eluant.

EXAMPLE 2

Preparatlon of 5 - Chloro - 2 - Guanidino - 6 - Sulfamyl - lH - Benzimidazole
Hydrochlorlde (VIII)
The procedure for maklng compound (VI) ls the same as glven ln Example
1. A mlxture of 2.22 g. of 2 - amlno - 4 - chloro - 5 - sulfamylanillne (VI)
0.84 g. of cyanoguanldlne, 2 ml. of concentrated hydrochlorlc acld, and 8 ml.
of water was refluxed for four hours. The reaction was concentrated in vacuo
to a dar~ blue solid whlch was dlssolved ln methanol, treated wlth charcoal,
bolled 5 mlnutes, flltered, cooled, and then filtered through celite. Dllutlon




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with ether followed by ice cooling provided 0.2 g. of 5 - chloro - 2 - guanidino
- 6 - sulfamyl - lH - benzimidazole hydrochloride (VIII) as off-white crystals,
m p 291 292C
Analysis: Calculated for C8HloC12N602S:
; 29.55~C;3.10%H; 21.81%Cl; 25.85~N; 9.86%S
~- Found: 29.42%C; 3.17%H; 21.97%Cl; 25.67%N; 9.70%S
lr (K Br) 1630, 168$ cm (NCNH2)
, Tlc (Silica gel): R5 ~ 0.55, methanol as eluant
Therapeutically effective salts of the compounds of the invention may
be made by methods which are per se known in the art and the resulting salts
- are also useful as dluretlcs and antihypertensive agents. The most suitable
salts are the acid addition salts of the compounds with physiologically compat-
ible aclds to produce, for example, the sulfates, hydrochlorides, hydrobromides,
phosphates, cyclohexyl sulfamates, maleates, cltrates, tartrates, succinates,
ethane dlsulfonates, etc. The dluretic effectlveness of the compounds of the
lnventlon was conflrmed by pharmacologlcal tests run on selected compounds.
For example, lntravenous admlnistration of compound (VIII) to male Sprague
Dawley rats, compared to rats receivlng equal volumes of sallne lndicated great-
; er urlne volume, greater sodium excretion and greater chloride excretion in the
; case of the animals to which the compound of the invention was administered.
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EXAMPLE 3
.
Preparation of 5-Chloro-2-Phenyl-6-Sulfamyl-lH-Benzimidazole
A mixture of 2.21 g. of 2-amlno-4-chloro-5-sulfamylanllane (VI), 50 ml
of glacial acetic acid, and 1.06 g of benzaldehyde was refluxed for 16 hours
and then decanted lnto water. The precipitate was collected by filtration,
dlssolved ln ethanol, treated with Darco, filtered through fllter paper and
then through celite. Concentration in vacuo provided a solid which was dissolved
in ethanol, ~lltered, and forced out wlth water. Treatment of thls beige solid
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with bolling acetronlle provided an off-white solld, mp 314-316. --
Analysls: Calculated for C13HlOClN302S
50.73% C; 3.28~H 13.65~N
Found: 50.61% C; 3.54%H; 13.40%N



Preparation of 5-chloro-2-N -methylguanidlno-6-sulfamyl-lH-benzimidazole
hydrochloride
To 2.22 g of 2-amino-4-chloro-5-sul~amylaniline tYI) in 12 ml of water
was adted 2 ml of concentrated hydrochloric acid and 2 ml of methanol. After
addlng 1.23 g. of N-methyl-cyanoguanidine, the dark solution was refluxed for
45 mlnutes, cooled, and the resultant solld collected by filtratlon. The solid
was dlssolved ln methanol and flltered. Darco was added to the flltrate and
the suspenslon bolled 10 minutes, filtered through filter; paper, cooled and
flltered through cellne. Dllutlon wlth ether provlded a pink solid which, upon
drying, ylelded 0.5 g of light plnk solld, m.p. 284-286.
Analysis: Calculated for CgH12C12N602S
' 31.86~C; 3.57%H; 24.78~N; 9.45%S
Found: 31.44%C; 3.58%H; 24.58%N; 9.62%S
; ln (KBr) 1680 cm (NH2)
Tlc (Slllca gel): R - 0.10, ethyl acetate as eluant.
The new compounds of the present lnventlon can be mlxed with any suitable
pharmaceutlcal csrrler, solld or liqult to provlde diuretic and antlhypertensive
q compositions. These compositions can be made for oral administration or for
admlnlstration by lnJection. The active ingredlent can be in the form of the
ba~e compound or the pharmaceutlcally acceptable salt thereof.




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