Note: Descriptions are shown in the official language in which they were submitted.
~Lh~3'^~Pl
The present invention concerns novel substituted 2,3-
alkylene bis (oxy) benzamides having the general formula (I),
their pharmaceutically acceptable acid addition salts, their
quaternary ammonium salts, their oxides, their dextrorotatory
and levorotatory isorners, and processes for the preparation
thereof.
: The invention also concerns the medicaments whose
active principle cornprises the compounds of the invention.
The structure of the compounds of the invention can
be diagrammatically shown by the following formula:
CO-N .
I \ R'
Z ~\, 0
yl$~ 0/ ( I )
' X ;'
.`.,
- - .
in which:
A represents a Cl 3 alkylene chaini
R represents hydrogen, a Cl 4 alkyl group, or a
radical having the following general formula~
--B--N~ 1 ( I I )
,` R 2
in which~
B represents a single bond or a Cl 3 alkylene
chain; ;
Rl represents a Cl 4 alkyl group or can be connected ~:
~; 10 to B so as to form a pyrrolidinyl or piperidinyl group hetero-
cycle;
R2 represents a Cl 4 alkyl group, a C2 4 alkenyl
group, benzyl, cycloalkyl, pyrimidyl, or is linked to Rl to
form a piperidinyl or 4-alkylpiperazinyl,
'''
' ~ '
...
.
.
~.
: ~
- 2 - ~
;-C1 ~,
' :
' ~
R' represents hydrogen, a Cl 4 alkyl group, benzyl,
adamantyl, pyrimidinyl, or is linked to Rl to forrn a piper-
azinyl group, or is linked to Rl and R2 to form a diaza-
bicycloalkyl group;
X represents hydrogen, a halogen atom, a C.l 4
alkoxy group, nitro, amino or acetamino;
Y represents hydrogen, a halogen atom, nitro,
amino? acetamino, sulfamoyl, Cl 4 alkylsulfamoyl, Cl 4 alkyl-
sulfonyl, adamantylsulfamoyl, C3 8 cycloalkylsulfamoyl ? Cl 4
dialkylsulfamoyl, or is linked to X to form an azimido group,
Z represents hydrogen, a halogen atom, nitro, amino
or acetamino, or is linked to Y to form an azimido group;
and their oxides, their pharmaceutically acceptable acid
addition salts, their quaternary ammonium salts and their
dextrorotatory and levorotatory isomers.
In the defin;tions mentioned in the present specification:
~, .
. ~
~' :
,:' ~, '
"4'~
alkyl Cl 4 mainly includes methyl, ethyl, propyl, iso-
propyl, butyl, isobutyl, tertiobutyl,
alkylene Cl 3 mainly includes methylene, ethylene, propylene,
alkenyl C2 4 mainly includes vinyl, allyl,
alkinyl C2 4 mainly includes ethinyl, propargyl,
alkoxy Cl 4 mainly includes methoxy, ethoxy, propoxy, iso-
propoxy, butoxy, isobutoxy, t-butoxy,
aralkyl mainly includes benzyl, phenethyl, substituted
or unsubstituted by one or more halogen atom,
alkoxy, alkyl, halomethyl, amino group,
substituted phenyl mainly includes a phenyl ring substituted
by one or more halogen atom, alkoxy, alkyl,
halomethyl, amino group,
halogen mainly includes chlorine, bromine, iodine,
fluorine,
substituted amino mainly includes an amino group mono or
disubstituted by alkyl, acyl, aralkyl, :
; furanyl, pyranyl, alkoxycarbonyl group,
acyl mainly includes formyl, acetyl, phthaloyl group.
The preferential values of the substituents are
- for X : hydrogen atom, alkoxy group mainly methoxy, nitro,
halogen atom mainly chlorine, amino, acylamino mainly
acetamino group
- for Y : hydrogen, halogen mainly bromine and chlorine atom,
amino, acylamino mainly acetamino, alkylsulfonyl
mainly ethylsulfonyl group, a sulfonyl group substi-
tuted
- by an amino group
- by an amino group especially monosubstituted by
an alkyl mainly methyl, by an adamantyl group
- by an amino group especially disubstituted by an
, ~. , . : ~ .
alkyl mainly methyl, ethyl group
- for Z : hydrogen, halogen mainly bromine, ch10rirle atom,
nitro, acylamino mainly acetamino, amino group.
The preferential values of the substituents in the disubsti-
tuted compounds are:
~X - alkoxy mainly methoxy
- ~Y sulfonyl group substituted by an amino group
rx - acylamino mainly acetamino group
` LY - nitro group
X and Y can be joined together through a heteroatom
. mainly a nitrogen atom to form a triazole cycle
X Y - amino group
¦X halogen mainly chlorine atom
Y - amino group
. ~X = amino group
LY acylamino mainly acetamino group
X = Y - acylamino mainly acetamino group
Y = Z = nitro group
:~ Y - 7 = acylamino mainly acetamino group
Y Z halogen mainly bromine atom
Y - Z amino group
Y and Z can be joined together through a heteroatom
mainly a nitrogen atom to form a triazole cycle.
The preferential values of the substituents in the trisubsti-
tuted compounds are:
-~ {X nitro group
~ Y - Z - halogen atom mainly chlorine and bromine
IX - halogen atom mainly chlorine and bromine
Y = Z = nitro group
~X = nitro group
Y = Z - acylamino mainly acetamino.
-- 5
;
The preferential values of A are alkylene Cl 3 such as
methylene, propylene and mainly ethylene.
The preferential values of R' are:
- a hydrogen atom
- an alkyl mainly ethyl, butyl group
- an aralkyl group, mainly benzyl group which can be substi-
tuted with a halogen atom pre~erably bromine or fluorine or
with a trifluoromethyl group
- an adamantyl group, a pyrimidinyl group -
;10 - a saturated di-nitrogen heterocycle when linked to Rl, ~;
preferably a piperazine ring which can be substituted.
The preferential values of R are:
- a hydrogen atom
- an alkyl group mainly ethyl group
- a radical according to the formula II3 in which the prefer- :
ential values of B are:
- a single bond,
- an alkylene group mainly ethylene3 propylene,
- a di-nitrogen heterocycle when linked to Rl, such :
as defined hereafter.
The preferential values of Rl are:
- an alkyl group mainly ethyl group ~:~
- a saturated nitrogen heterocycle when linked to B, mainly
pyrrolidine, piperidine group
- a nitrogen heterocycle when linked to R2
- mainly a pyrrolidine, a piperidine
- or containing another hetero atom, mainly a
nitrogen atom~ preferably a piperazine substituted
with an alkyl group, mainly methyl, ethyl group
- a saturated di-nitrogen heterocycle when linked -to R', mainly
a substituted piperazine group.
When at -the same time Rl is linked to R2 such as to ~orm a
nitrogen heterocycle, mainly a pyrrolidine group, and Rl is
linked to R' such as to form a saturated di-nitrogen hetero-
cycle, mainly a piperazine group, the whole constitutes a
bicyclic radical, mainly a diazabicyclononane group.
The compounds of the invention can be prepared by the
reaction of a compound having the following general formula:
COD
Z ~ \A (111)
in which:
A, X, Y and Z are as defined above;
D represents a hydroxy group, a halogen atom or an
organic residue, on an amine having the general formula:
: R
: HN / (IV)
\~
in ~hich R and R' are as defined aboveg
or by the reaction of their reactive derivatives.
In the starting compound, the organic residue
comprises groups which are capable of forming reactive acid
derivatives. These can be lower alkyl esters such as methyl,
:~ ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, or
isopentyl; reactive acid esters such as methoxymethyl ester,
cyanomethyl ester, substituted or unsubstituted aromatic
esters, or N-hydroxyimide esters; acid azides, acid hydrazides;
symmetrical anhydrides; mixed anhydrides such as those formed
~ from carboxylic acid esters and haloformic esters, azolides
such as triazolides, tetrazolides, and especially imiclazolides;
substituted ~-trihaloacetophenones; acid isothiocyanates;
L3~7;~
substituted ~-oxo benzeneacetonitriles; benzamides which are
substituted on the ring, or other equivalents, or the compound
having the follow~ng general formula:
Y~ ;OO--~ C ~ C2~15
(formed from the acid and an isoxazol1um salt). In the above
formula, A, X, Y and Z are as defined above. However, the
invention is not limited to the reactive derivatives mentioned
above.
According to the process of this invention, the amine
10 can react in the form of one of its reactive derivatives. By ~ .
way of example, ment;on can be made of the reaction products of
the amine with phosphorus chlorides, phosphorus oxychloride,
dialkyl, diaryl, and orthophenylene chlorophosphites, alkyl or
;aryl dichlorophosphites or isothiocyanate of the amine or the
symmetrical or asymmetrical sulfamides of the amine, the corre-
- sponding symmetrical urea, the corresponding enamines, or any
other equivalent.
The above-mentioned reactive derivatives can react
with the acid 'in situ' or after preliminary isolation. How-
ever, the invention is not limited to the reactive derivativesdescribed above.
In addition, it is also possible to perform the
reaction of the free acid and the free amine in the presence of
a condensing agent, for example silicon tetrachloride, phos-
phoric anhydride or a carbodiimide such as dicyclohexyl carbo-
diimide or alkoxyacetylenes such as methoxy or ethoxyacetylene.
Among the synthesis processes described for the preparation of
-- 8 --
3'7~L
':
the compounds according to the invention:
- the use of an acid halide is particularly suitable For
- compounds which are unsubstituted on the benzene
ring
- compounds which are monosubstituted with a halogen
atom, a nitro group, an alkylsulfonyl group, an
adamantylsulfonyl group, a cycloalkylsulfonyl
group~ a sulfonyl radical substituted with:
- an amino group
- an amino group mono or di-substituted with an
alkyl group, an adamantyl group, a cycloalkyl
group
- the use of alkyl esters, activated acid esters, or aromatic
esters~ is particularly suitable for
- compounds having the benzene ring substituted with
. a hydroxy group, an amino group3 an acylamino ~ ~
group, an alkylsulfonyl group, an adamantylsulfonyl :
group, a cycloalkylsulfonyl group, a sulfonyl group
substituted with: ~
- an amino group ` . :
- an amino group mono or di-substituted with an
. alkyl group, an adamantyl group, a cycloalkyl group
- compounds having two of X and Y or Y and Z radicals
linked together so as to form a cycle,
- the use of mixed anhydrides (formed 'in situ' by reaction of
-the starting benzoic acid on haloformic esters, preferably
. chloroformic acid esters) is particularly suitable for com-
pounds substituted with a nitro group, an acylamino group, a
sulfonyl group substituted with:
- an amino group
~ 3'7
- an amino group mono or di-substitute~ with an alkyl
group, an adamantyl group, a cycloalkyl group
- the use of reactive derivatives of amines, preferably formed
with phosphorus chlorides, and particularly the phosphorus
trichloride, with alkyl and aryl chlorophosphites, is par-
ticularly suitable for primary amines and specially aliphatic
amines.
The amidification reaction of the invention can be carried out
in the presence or in the absence of a solvent. The systems
used as a solvent, which are inert with respect to the amidifi~
cation reaction, are for example alcohols, polyols, benzene,
;~ toluene, dioxane, chloroform, or diethylene glycol dimethyl
ether, xylene. It is also possible to use, as the solvent, an
excess of the amine used as the prime material. It may be
preferable to heat the reaction mixture during the amidi-fi-
cation operation, for example up to the boiling temperature o~
the above-mentioned solvents.
The compound produced by the process of the invention can react
if necessary with pharmaceutically acceptable organic or
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, oxalic acid, acetic acid,
tartric acid, citric acid, methane sulfonic acid, to give acid
addition salts.
It can also react if necessary with alkyl halides or sulFates
to give quaternary ammonium salts.
It can also be oxidized in a manner known pe~ se, for instance
by means of hydrogen peroxide and manganese bioxide, to obtain
the corresponding N-oxide.
In order to illustrate the technical features of the present
invention, some embodimen~s will be described hereina-fter, it
being understood that these are not limiting as regards the
-- 1 0 --
mode of operation and the uses to which they can be put.
EXAMPLE 1
N~ allyl-2-pyrrolidylmethyl)-7-methylsulfanloyl-1,4-benzo-
dioxane-5-carboxamide
7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid
670 9 of chlorosulfonic acid were introduced into a
balloon flask provided with a condenser and a thermometer. 173
g of 1,4-benzodioxane-5-carboxylic acid were added in portions,
with the temperature being maintained at 5-10C. The mixture
was heated at 55C then cooled and poured into ice. The pre-
cipitate was dried off, washed and dried. 250 g of 7-chloro-
sulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained.
(M.P. = 210 - 215C; yield = 93.5%).
7-methylsulfamo~1-194-benzodioxane-5-carboxylic acid
139.5 9 of a 40% methylamine aqueous solution and
139.5 cm3 of water were introduced into a balloon flask pro-
vided with an agitator and a thermometer9 then, in port;ons,
250 9 of 7-chlorosulfonyl-1,4-benzodioxane-5-carSoxylic acid
and a solution of 180 cm3 of 30% soda lye in 180 cm3 o~ water
were added. The mixture was agitated then poured into 2200 cm3
of water. The solution was filtered, then treated with 139 cm3
of concentrated hydrochloric acid. The precipitate was dried
offl washed and dried. 190.5 9 of 7-methylsulfamoyl-1,4-
benzodioxane-5-carboxylic acid were obtained. (M.P. = 208 -
209C; yield ~ 80%).
7-methylsulfamoyl-1~4-benzodioxane-5-carbonyl chloride
176.5 9 of thionyl chloride were introduced into a
balloon flask provided with a condenser, then~ in portions, 135
g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were
added under heating at 40-45C. The mixture was heated under
reflux then treated by 250 cm of chloroform. The precipitate
was dried off and washed with chloroform.
,
- 1 1 - ' ' '
. .
~ ~ ~f~'7~
N-(l-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzo
dioxane-5-carboxamide
69 9 of 1-allyl-2-aminomethyl pyrrolidine and 432 ml
of chloroform were introduced into a 1 litre balloon flask pro-
vided with a thermometer and an agitator. 144 9 of 7-methyl-
sulfamoyl-1,4-benzodioxane-5-carbonyl chloride was added in
portions, with the temperature being maintained at from 5 to
10C. Agitation of the mixture was continued for one hour, and
then the mixture was treated with 1750 ml of water. After
distillation of the chloroform, the mixture was acidified to a
pH-value of 4, by 4 ml of 20% sulfuric acid, and then filtered
on carbon black; the solution of the sulfate formed was render-
ed alkaline by 60 ml of 20% ammonia. After crystallization,
the base was dried off, washed with water and dried at 40C.
After recrystallization from acetonitrile9 134 g of N-(l-allyl-
2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-
carboxamide was produced (yield: 68.7%; Melting point: 142 -
143C).
The Nuclear Magnetic Resonance spectra are compatible
with the proposed structure.
EXAMPLE 2
N-(l-ethyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-
carboxamide
` 7-sulfamoyl-1,4-benzodioxane-5-carbox~lic acid
. .
209 9 of 34% ammonia and 97 g of 7-chlorosulfonyl-
ly4-benzodioxane-5-carboxylic acid were introduced into a
balloon flask provided with an agitator and a thermometera at a
temperature of 5-10C. The mixture was agitated at ambient
temperature, then the precipitate was dissolved in 415 cm3 of
water. The solution was filtered and treated with 140 cm3 of
concentrated hydrochloric acid. The crystals were dried off,
washed with water and dried. 7~ g of 7-sulfamoyl-1,4-benzo-
.~
- 12 -
dioxane-5-carboxylic acid were obtained. (M.P. - 272 - 274C;
yield - 87%).
Methyl 7-sulfamoyl--1,4-benzodioxane-5-carboxylate
429 g of methanol were introduced into a balloon
flask provided with a condenser, then, under cooling, 54 g o-f
93% sulfuric acid and 111 g of 7-sulfamoyl l,4-benzodioxane-5-
carboxylic acid were added. The mixture was heated under
reflux then cooled. The crystals were dried off~ washed with
methanol then treated with 500 cm3 of water and 5 9 o-f sodium
carbonate. The precipitate was dried off, washed with water
and dried. 95 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-
carboxylate were obtained. (M.P. ~ 225 - 226C; yield - 81%).
N-(l-ethyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-
carboxamide
.. ..
145 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-
carboxylate, 4~ g of water and 81.5 g of l-ethyl-2-aminomethyl
pyrrolidine were introduced into a balloon flask provided with
a reflux condenser and an agitator. The resulting suspension
was heated on a water bath until a test sample is soluble in
dilute acids. The reaction mixture was then treated with 1
litre of water and acidified by 70 ml of acetic acid. The
acetate solution formed was filtered on carbon black and the
base was precipitated by 20% ammonia. The crystals were dried
off, washed with water and dried. The ben~amide was purified
by passage over hydrochloride (melting point: 238 - 240C).
The base was reprecipitated by the addition of 20% ammonia.
120 g of N-(l-ethyl-2-pyrrolidylmethyl)-7 sulfamoyl-1,4-benzo-
dioxane-~-carboxamide was produced (yield: 61.5%, melting point
160 - 161C).
The NMR spectra are compatible with the proposed
structure.
- 13 -
3 ~
EXAMPLE 3
N~ methyl-2~pyrrolidylmethyl)~7-ethylsulfonyl-1,4-benzo-
dioxane-5-carboxamide
_
7-mercapto-1,~-benzodioxane~5~carboxy1ic acid
243 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carbox-
y1ic acid and 654 cm3 of acetic acid were introduced into a
balloon flask provided with an agitator and a condenser. The
mixture was heated at 9~C then cooled at 45C. 389 ~ of tin
and 1744 cm3 of hydrochloric acid were then added. The mixture
was heated at 55-60C, cooled and poured into water. The pre-
cipitate was dried off, washed and dried. 166 9 of 7-mercapto-
1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. ~
191 - 192C; yield - 90%).
7-ethylthio-1,4-benzodioxane-5-carboxylic acid
166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic
acid, 242 cm3 of water, 216 cm3 of soda lye and 181 g of ethyl-
sulfate were introduced into a balloon flask provided with a
condenser. The mixture was heated under reflux, then cooled.
The solution was poured into 1.3 1 of water, filtered and
treated with 110 cm of hydrochloric acid. The precipitate was
dried off, washed with water and dried. 152 9 of 7-ethylthio-
1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. ~
153 - 154C; yield = 81%).
7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid
152 9 of 7-ethylthio-1,4-benzodioxane-5-carboxylic
acid and 958 cm3 of acetic acid were introduced into a balloon
flask provided with a condenser. 398 cm3 of hydrogen peroxide
were then added and the mixture was heated. The crystals
formed by cooling were dried off, washed and dried. 139 g of
7-ethylsulfonyl-1,4~benzodioxane-5-carboxylic acid were obtain-
- ed. (M.P. - 217 - 218C; yield - 81%).
,
- 14 -
7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride
243 y of thionyl chloride, some drops oF dimethyl-
formamide and 139 g of 7-ethylsulfonyl-1~4-benzodioxane-5-
car~oxylic acid were introduced into a balloon flask provided
with a condenser. The mixture was heated~ then the thionyl
chloride in excess was distilled off under vacuum. 148 g of 7-
ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride were obtain-
ed. (M.P. - 146 - 147C; yield - 100%).
N-(l-methyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzo-
dioxane-5-carboxamide
. . . ~
59 g of 1-methyl-2-arninomethyl pyrrolidine, 450 ml of
chloroform and then, in portions, 150 g of 7-ethylsulfonyl-1,4-
benzodioxane-5-carbonyl chloride, were introduced, at a temper-
ature of from S to 10C, into a balloon flask provided with an
agitator and a thermometer. The mixture was then agitated for
one hour at ambient temperature, and then 1850 ml of water was
added. After distillation of the chloroform, the solution was
filtered over carbon black and benzamide was precipitated by
the addition of 65 ml of soda lye. The solid was dried off,
washed with water and dried at 40C. After recrystallization
from absolute alcohol, 151 g of N-(l-methyl-2-pyrrolidyl-
methyl)-7-ethylsulfonyl-1~4-benzodioxane-5-carboxamide was
obtained. (Yield: 80.5%; melting point: 140 - 141C). ;~
The structure was confirmed by NMR.
EXAMPLE 4
1-(2,3-ethylenedioxy-5-sulfamoyl benzoyl)-4-(2-pyrimidinyl)-
piperazine
146 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic
acid, 300 ml of dioxane and then 57 g of triethylamine were
introduced into a 1 litre 3-neck flask provided with an agi-
tator, a thermometer and an introduction funnel. The mixture
was heated at 40 to 50C and ~30 ml of water was added. The
- 15 -
solution was cooled to a temperature of from 5 to 10C and
61.5 g of ethyl chloroformiate was added. Agitation of the
mixture was maintained for 1 hour at 10C and 93 g of 1-(2-
pyrimidinyl)piperazine was added, without the temperature
rising above 15C. Agitation of the mixture was continued for
1 hour at ambient temperature and then, after the addition of
1500 ml of water, the mixture was rendered alkal~ne to a pH-
value of 10, by ammonia. The crystals produced after distil-
lation under vacuum of the solvents and cooling, were dried
off, washed with water, dried in a drying oYen at 50C and then
purified by treatment with 120 ml of chloroform. After fil-
tration and drying, 92 g of 1-(2,3-ethylenedioxy-5-sulfamoyl-
benzoyl)-4-(2-pyrimidinyl)piperazine was produced. (Yield
40.2%; melting point: 239C).
The structure was confirmed by NMR analysis.
EXAMPLE 5
N-(l-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide
7-dimethylsulfamoyl-1,~-benzodioxane-5-carbox~lic acid
500 cm3 of acetone and a solution of 99 9 of
dimethylamine in 250 cm3 of acetone were introduced into a
balloon flask provided with an agitator and a thermometer. The
mixture was cooled at 0C, then, 139 g of 7-chlorosulfonyl-1,4-
benzodioxane-5-carboxylic acid were added. The mixture was
agitated at ambient temperature, the acetone distilled off and
the residue dissolved in 1 1 of water. The solution was
rendered alkaline, filtered and treated with 70 cm3 of hydro-
chioric acid. The precipitate was dried off, washed and dried.
128 g of 7-dimethylsulfamoyl~ -benzodioxane-5-carboxylic acid
were obtained. ~M.P. - 220 - 221C; yield - 89~).
- 16 -
7-dimethylsulfamoyl-l,4-benzodioxane-5-carbonyl chloride
190 g of thionyl chloride and 153 g of 7-dimethyl-
sulfamoyl-1,4-benzodioxane-5-carboxylic acid were introduced
into a balloon flask provided with a condenser. The mixture
was heated, then the thionyl chloride in excess was distilled
off. 163 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl
chloride were obtained. (M.P. - 160 - 162C, yield = 100%).
N-(l-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide _ _
61 g of 1-methyl-2-aminomethyl pyrrolidine and 560 ml
of chloroform were introduced into a balloon flask provided
with an agitator and a thermometer, and then, with the temper-
ature being kept at from 0 to 5C, 163 g of 7-dimethyl-
sulfamoyl-1,4-benzodioxane-5-carbonyl chloride was introduced.
The mixture was agitated for 1 hour, allowing the temperature
to rise, and then 1 litre of water was added. After distil-
lation of the chloroform the solution was filtered and the
carboxamide was precipitated by the addition of 30% of soda
lye. The crystals produced were filtered, washed with water
and dried.
After recrystallization from absolute alcohol, 157 9
of N-(l-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-
benzodioxane-5-carboxamide was obtained. (Yield: 76.9%,
~; melting point: 165 - 166C).
The NMR spectra are compatible with the proposed
structure.
EXAMPLE 6
N-(l-benzyl-2-pyrrolidylmethyl)-1,~-benzodioxane-5-carboxamide,
440 ml of chloroform and 110 g of 1-benzyl-2-amino-
methyl pyrrolidine were introduced into a balloon flask pro-
vided with an agitator and a thermometer, and then, at a
. - ~
temperature of from 5 to 10C, 110 g of 1,4-benzodioxane-5-
carbonyl chloride was added. After agitation of the mixture
and addition of 3 litres of water, chloroform was removed.
The solution was treated with ammonia and then the
precipitate was extracted by means of methylene chloride. The
organic solution was dried and then the solvent was removed.
The resulting compound, dissolved in absolute ethanol, was
treated with 30 ml of 85% phosphoric acid. The precipitate
formed was dried off, washed with ethanol and dried. 153 g of
N-(l-benzyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-oarboxamide
phosphate was produced. (Yield: 61%; melting point: 165C).
EXAMPLE 7
N-(l-allyl-2~pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-
carboxamide
145 g of methyl 7-sulfamoyl-1,4 benzodioxane-5-
- carboxylate, 48 g of water and 89 g of 1-allyl-2-aminomethyl
pyrrolidine were introduced into a balloon flask provided with
a condenser. The mixture was heated on a water bath until a
test sample was soluble in dilute acids, and then 1 litre of
water was added. The precipitated carboxamide was redissolved,
by acetate formation. The solution formed was filtered on
carbon black and then the base was precipitated by the addition
of 20% ammonia. The resulting crystals were dried off, washed
with water, dried and purified by passing over hydrochloride
(melting point: 228 - 230~C), followed by transformation into a
base by treatment with 20% ammonia. 131 g of N-(l-allyl-2-
pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide
was produced. (Yield: 64.8%; melting point: 143 - 144C).
The structure was confirmed by NMR analysis.
EXAMPLE 8
N-(l-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide
- 18 -
i
Methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate
750 ml of methanol were introduced into a balloon
flask provided with a condenser, then, under cooling, 273 g of
concentrated sulfuric acid and 160 g of 7-methylsulfamoyl-1,4-
benzodioxane-5-carboxylic acid were added. The mixture was
heated under reflux, cooled and poured into water and sodium
carbonate. The precipitate was dried off, washed and dried.
143 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxyl-
ate were obtained. (M.P. - 159 - 160C; yield - 85%).
N-(l-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide
137 9 of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-
carboxylate, 43 g of water and 73 g of 1-ethyl-2-aminomethyl ;~
pyrrolidine, were introduced into a balloon flask provided with
an agitator and a reflux condenser. The mixture was heated on
a water bath until a test sample was totally soluble in dilute
acids. The carboxamide produced by cooling was purified by
passing it over acetate, and then treatment with 100 ml of
acetic acid in 950 ml of water. After the resulting solution
was filtered on carbon black, the base was precipitated by the
addition of 20% ammonia. The resulting crystals were dried
off, washed with water, dried and purified by recrystalli~ation
from boiling isopropyl alcohol. 121 g of N-(l-ethyl-2-pyrrol-
idylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide
was produced. (Yield: 66.2%; melting point: 139 - 140C).
The structure was confirmed by NMR analysis. The
corresponding hydrochloride was produced by treatment of the
carboxamide with hydrochloric acid ~specific gravity: 1.18)
(melting point: 186 - 188C).
EXAMPLE 9
; N-(l-ethyl-2-pyrrolidylmethyl)-2,3-methylenedioxy benzamide
In a similar manner, 34.9 9 of ethyl 2,3-methylene-
19
3~ L
dioxy benzoate was reacted with 24.2 g of 1-ethyl-2-aminomethyl
pyrrolidine, to give, after treatment and purification, 28.3 g
of N-(l-ethyl-2-pyrrolidylmethyl)-2,3-methylenedioxy benzamide.
The NMR spectra are compatible with the expected
structure.
EXAMPLE 10
Levorotatory N-(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-
1,4-benzodioxane-5-carboxamide
65 9 of levorotatory 1-ethyl-2-aminomethyl pyrroli-
dine9 was dissolved in 430 ml of chloroformg in a balloon flask
provided with an agitator and a thermometer. The resulting
solution was cooled to 5C and then 148 g of finely pulverised
7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride was added,
with the temperature being maintained at from 5 to 10C. At
the end oF the operation of introducing this substance, the
-,
mixture was agitated for 1 hour and then treated with 1 litre
: .
of water. After distillation of the chloroform, the solution
was filtered on carbon black and the base was precipitated by
an excess o~ 30% soda. The resulting crystals were dried off,
washed with water, dried and recrystallized from isopropyl
alcohol.
151.5 g of levorotatory N-~l-ethyl-2-pyrrolidyl-
methyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide was
produced. ~Yield: 77.7%; melting point: 111 - 112C), ~D0
-54.2 (in 5% sGlution in dimethylformamide).
EXAMPLE 11
Dextrorotatory N~ ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl~
1,4-benzodioxane-5-carboxamide
.~
In a similar manner, 64.5 g of dextrorotatory 1-
ethyl-2-aminomethyl pyrrolidine was reacted on 146 g of 7-
ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride to give,
a~ter treatment and purification, 133.5 g of dextrorotatory N-
- 20 -
~;
3~7:~
(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-
5-carboxamide. (Yield: 69.8%; melting point: 111 - 112C);
- 55.5 (in 5% solution in dimethylformamide).
EXAMPLE 1?
N-(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzo-
dioxane-5-carboxamide
,
In a similar manner, 58 9 of 1-ethyl-2-aminomethyl
pyrrolidine was reacted on 131 g of 7-ethylsulfonyl-1,4-benzo-
dioxane-5-carbonyl chloride to give, after treatment and puri-
fication, 103.5 9 of N-(l-ethyl-2-pyrrolidylmethyl)-7-ethyl- -
sulfonyl-1,4-benzodioxane-5-carboxamide. (Yield: 60.2%;
melting point: 118 - 119C). 100 9 of the base prodwced was
dissolved in 220 ml of acetone, then the solution was filtered
on carbon black, and a solution of 9.5 9 of hydrochloric acid
in acetone was added. The resulting hydrochloride crystals
were dried off, washed with acetone and then dried. 96 9 of N-
(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-
5-carboxamide hydrochloride was produced. (Yield: 88.2%i
melting point: 148 - 150C).
EXAMPLE 13
N-(l-methyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-
5-carboxamide
131 g of methyl-7-sulfamoyl-1,4-benzodioxane-5-
carboxylate, 43 g of water and 66 g of 1-methyl-2-aminomethyl
pyrrolidine were introduced into a balloon flask provided with
a reflux condenser. The mixture was heated on a water bath
until a test sample was totally soluble in dilute acids. The
carboxamide produced by cooling was purified by treatment with
; a solution of 50 ml of acetic acid in 1250 ml of water. After
the resulting solution was filtered on carbon black, the base
was precipitated by the addition of 2~% ammonia. The resulting
crystals were dried off, washed with water, dried and purified
- 21 -
~$~
by recrystallization from boiling methyl alcohol. 119.5 g of
N~ methyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-
5-carboxamide was produced. (Yield: 70.1%; melting point:
187 - 188C).
EXAMPLE 14
N-(l-allyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzo-
dioxane-5-carboxamide
58 g of 1-allyl-2-aminomethyl pyrrolidine and 360 ml
of chloroform were introduced into a balloon flask provided
with an agitator and a thermometer and then, with the tempera-
ture being maintained at 5 to 10C, 120 g of 7-ethylsulfonyl-
1,4-benzodioxane-5-carbonyl chloride was added. After agi-
tation of the mixture and the addition of a litre of water,
chloroform was distil.led. The resulting solution was filtered
on carbon black and then the base was precipitated by the
addition of 40 ml of 30~ soda lye. The resulting crystals
were dried off, washed with water and then dried~ 152 g of N-
(l-allyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-
5-carboxamide was produced. (Yield: 93.4%; melting point:
78 - 80C). 146 g of the resulting base was dissolved hot in
290 ml of absolute alcohol and then the solution was filtered
on carbon black and acidified by the addition of a solution of
13.5 g of hydrochloric acid in 100 ml of absolute alcohol.
After cooling, the crystals formed were dried off, washed with
absolute alcohol and dried, and then purified by recrystalli-
zation from absolute alcohol. 119.5 g of N~ allyl 2-pyrrol-
idylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide
hydrochloride was produced. tYield: 75%; melting point:
138 - 140C).
:
EXAMPLE 15
N-(l-ethyl-2-pyrrolidylme~hyl)-2~-3,4-dihydro-1,5-benzo-
dioxepine-6-carboxamide __
Methyl 2~I-3,4-dihydro-1,5~benzodioxepine-6-carboxylate
- ~2 -
, - .
~ 7
111 9 of methyl 2,3-dihydroxy benzoate, 660 cm3 of
methyl ethyl ketone, 167 y of 1,3-dibromopropane and 10 9 of
sodium iodide were introduced into a balloon flask provided
with an agitator and a therrnometer. The mixture was heated at
40C then 182 9 of potassium carbonate were added. The mixture ~-
was heated under reflux and 2 1 of water were added. The oily
phase was decanted, extracted by ether and the solution was
washed with 10% soda and dried. The ether was removed. By
distillation under vacuum, 86.5 9 of methyl 2H-3,~-dihydro-1,5-
benzodioxepine-6-carboxylate were obtained. (Boiling point =
166 - 176C under 8 mm/Hg; yield ~ 63%).
2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid
_
160 9 of methyl 2H-3,4-dihydro-1,5-benzodioxepine-6-
carboxylate and 388 cm3 of soda were introduced into a balloon
flask provided with a condenser. The mixture was heated under
reflux then poured into 1 1 of water and treated with 5 g of
~ sodium metabisulfite. The solution was filtered and treated
; with 77 cm3 of concentrated hydrochloric acid. The precipitate
was drained off, washed with water and dried. 120 9 of 2H-3,4-
dihydro-1,5-benzodioxepine-6-carboxylic acid were obtained.
(M.P. - 65 - 67C; yield - ~0.5%).
2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride
246 9 of thionyl chloride and 134 9 of 2H-3,4-
dihydro-1,5-benzodioxepine-6-carboxylic acid were introduced
into a balloon flask provided with a condenser. The mixture
was heated under reflux, then the thionyl chloride in excess
was distilled off under vacuum. 147 9 of 2H-3,4-dihydro-1,5-
benzodioxepine-6-carbonyl chloride were obtained. (M.P. - 35 -
37C; yield = 100~).
N-(l-ethyl-2-pyrrolidylmethyl)-2H-3,4-dihydro-1,5-benzodioxe-
pine-6-carboxamide
- 23 -
92 g of 1-ethyl-2-aminomethyl pyrrolidine and 458 ml
of chloroform were introduced into a balloon flask provided
with an agitator and a thermometer, and then, with the temper-
ature being kept at from 5 to 10C, 152 g of 2H-3,4-dihydro-
1,5-benzodioxepine-6-carbonyl chloride was added. After agi-
tation for 1 hour, with the temperature being allowed to rise,
1450 ml of water was added, then chloroform was distilled. The
solution was filtered over carbon black and the base was
precipitated by the addition of 75 ml of 20% ammonia. The
crystals formed were dried o-Ff, washed with water and dried.
191 g of N-(l-ethyl-2-pyrrolidylmethyl)-2H-3,4-dihydro-1,5-
benzodioxepine-6-carboxamide monohydrate was produced. (Yield:
82.4%; melting point: 51 to 52C). 173.5 g oF the compound
produced was dissolved in 750 ml of absolute alcohol. The
solution was filtered over carbon black and then a solution of
62 g of 85% phosphoric acid in 100 ml of absolute alcohol was
added. The crystals formed were dried oFf, washed with abso-
- lute alcohol and dried, and then recrystallized from alcohol.
198 g of N-(l-ethyl-2-pyrrolidylmethyl)-2H-3,4-dihydro-1,5-
benzodioxepine-6-carboxamide phosphate was produced. (Yield:
92%; melting point 189 - 190C).
EXAMPLE 16
N-(l-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide
169 9 of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-
carboxylate, 53 ml of water and 81 g of l~methyl-2-aminomethyl
pyrrolidine were introduced into a balloon flask provided with
a reflux condenser.
The mixture was heated on a water bath until a test
sample was totally soluble in dilute acids. The resulting
crystals were dissolved in a solution of 50 ml of acetic acid
in 1250 ml of water, then the solution was filtered over carbon
- 2~ -
,
black and the base was reprecipitated by the addition of 100 ml
of 20~ ammonia. The crystals were dried off, washed with water
and dried. 182 g of N~ methyl-2-pyrrolidylmethyl)-7-methyl-
sulfamoyl-1,4-benzodioxane-5-carboxamide was produced. (Yield:
83.6%; melting point 189 - 190C).
EXAMPLE 17
N-(diethylaminoethyl)-1,4-benzodioxane-5-carboxamide,hydro-
chloride
21 9 of die~hylaminoethylamine and 85 ml of acetone
10 were introduced into a balloon flask provided with an agitator
and a thermometer. The mixture was cooled to 0C, then 36 9 of
1,4-benzodioxane-5-carbonyl chloride were added. The crystals
formed at ambient temperature were dried off, washed with
acetone, dried and purified by recrystalli~ation from isopropyl
alcohol. 36.5 9 of N-(diethylaminoethyl)-1,4-benzodioxane-5-
carboxamide hydrochloride were obtained. (M.P. - 120C~
yield _ 64%).
EXAMPLE 18
~::
N-(l-ethyl-2~pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzo-
20 dioxane-5-carboxamide
13 9 of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic
acid, 3ao ml of tetrahydrofuran and 13 9 of carbonyldiimidazole
were introduced into a balloon flask provided with an agitator,
- a thermometer and a condenser. The mixture was agitated at
ambient temperature and then 9.5 9 of 1-ethyl-2-aminometh~l
pyrrolidine was added. Agitation was maintained at ambient
temperature and then the solvent was evaporated under vacuum. d
The crystals produced were washed with water and then dried.
14 9 of N-(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-
- 30 benzodioxane-5-carboxamide was produced. (Yield: 73.8%;
mPlting poin~ 118 - 119C).
;~
- ~5 -
.. . .
: , : '
EXAMPLE 19
N~ methyl-2-pyrrolidylmethyl)-7 dimeth~ylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide
A solution of 6 9 of 1-methyl-2-aminomethyl pyrroli-
dine in pyridine, and then, dropwise, with agitation and with
the temperature being kept at from 0 to 5C, a solution of 3.5
g of phosphorus trichloride in 20 ml of pyridine~ were intro-
duced into a balloon flask provided with an agitator, a thermo-
meter and a condenser. Agitation was maintained at a temper-
ature of from 0 to 5C and then at ambient temperature. 14.5 g
of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid was
then added. The mixture was heated with agitation. After the
mixture had been cooled and the solvent removed, the residue
was dissolved in chloroform, then the solution was washed with
aqueous sodium carbonate and dried on anhydrous magnesium
sulfate. After concentration under reduced pressure, 12.5 g of
N-~l-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide was produced. (Yield: 64.5%; melting
point: 165 - 166C).
EXAMPLE 20
N-(l-cyclohexy1-3-pyrrolidyl)-7-methylsulfamoyl-1,4-ben~o-
dioxane-5-carboxamide
84 9 of 1-cyclohexyl-3-aminopyrrolidine, 430 ml of
chloroForm and 146 g of 7-methylsulfamoyl-1,4-benzodioxane-5-
carbonyl chloride were introduced into a balloon flask provided
with an agitator and a thermometer. After agitation of the
mixture, the base was extracted with methylene chloride and
then the solvent was evaporated. The crystals formed were
dissolved in boiling absolute alcohol and the resulting
solution was filtered on carbon black. The crystals produced
after cooling were dissolved in a solution of acetic acid in
water, then the solution was filtered over carbon black and the
- 26 -
3'~
base was reprecipitated by the addition of 20% ammonia. 129.5
g of N-(l-cyclohexyl-3-pyrrolidyl)-7-me~hylsulfa~oyl-1,4-benzo-
dioxane-5-carboxamide was produced. (Yield: 61.2%; melting
point: 160 - 161C).
EXAMPLE 21
N-(l-ethyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide
64 g of 1-ethyl-2-aminomethyl pyrrolidine and 530 ml
of chloroform were introduced into a balloon flask provided
with an agitator and a thermometer, and then, with the temper-
ature being maintained at from 0 to 5C, 153 9 of 7-dimethyl-
sulfamoyl-1,4-benzodioxane-5-carbonyl chloride was added. The
mixture was a~itated for an hour, allowing the temperature to
rise, and then 1 litre of water was added. After distillation
~; of the chloroform, the solution was filtered and the carbox-
amide was precipitated by the addition of 30% soda lye. The `
crystals produced were filtered, washed with water and dried.
After recrystallization from absolute alcohol, 144.5 9 of N-
(l-ethyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzo-
20 dioxane-5-carboxamide was obtained. (Yield: 72.8%; melting -
point 146 - 1~8C).
EXAMPLE 22
Dextrorotatory N-(l-ethyl-2-pyrrolidylmethyl)-7-methyl-
sulfamoyl-1,4-benzodioxane-5-carboxamide
82 9 of dextrorotatory 1-ethyl-2-aminomethyl pyrroli-
dine, 600 ccm of chloroform and, gradually, at a temperature nf
from 5 to 10C, 200 g of 7-methylsulfamoyl-1,4-benzodioxane-5-
carbonyl chloride, were introduced into a balloon flask with an
agitator and a thermometer.
After the addition of a litre of water, chloroform
was distilled, then the remaining solution was filtered. The
base was precipitated by the addition of 60 ccm of 20% ammonia.
- 27 ~
The crystals formed were dried off, washed with water and then
dried. 162 9 of dextrorotatory N~ ethyl-2-pyrrolidylmethyl)-
7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced.
. (Yield: 66%; melting point: 136 - 137C).
EXAMPLE 23
Levorotatory N-(l-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-
194-benzodioxane-5-carboxamide
In a similar manner to that of the above example, 82
g of levorotatory l-ethyl-2-aminomethyl pyrrolidine was reacted
with 195 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl
chloride, to give 151 g of levorotatory N-(l-ethyl-2-pyrrol-
idylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide.
(Yield: 62%, melting point: 136 - 137C).
EXAMPLE 24
Levorotatory N-(l-allyl-2-pyrrolidylmethyl)-7-methylsul~amoyl-
1,4-benzodioxane-5-carboxamide
85 g of levorotatory 1-allyl-2-aminomethyl pyrrol-
idine, 610 ccm of chloroform, and gradually, 178 9 of 7-methyl-
sulfamoyl-1,4-benzodioxane-5-carbonyl chloride, at a temper-
ature of from 5 - 10C, were introduced into a balloon flask
provided with an agitator and a thermometer.
After agitation oF the mixture, 1.2 litres of water
was added, then chloroform was distilled.
The remaining solution was filtered and then the base
was precipitated by 70 ccm of 20% ammonia. The crystals formed
were dried off ~nd washed with water.
After recrystallization from ethyl acetate, 117 9 of
levorotatory N-(l-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-
1,4-benzodioxane-5-carboxamide was produced. (Yield: 49%;
melting point: 101 - 102C).
EXAMPLE 25
Dextrorotatory N-(l-allyl-2-pyrrolidylmethyl)-7-methyl-
sulfamovl-1,4-benzodioxane-5-carboxamide
~,
- 28 -
In a similar manner to the above example, 84 9 of
dextrorotatory l-allyl-2-aminomethyl pyrrolidine was reacted
with 175 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl
chloride, to give, after purification, 125 g of dextrorotatory
N-(l-allyl-2-pyrrolidylmethyl)-7-methylsulFamoyl-1,4-benzo-
dioxane-5-carboxamide. (Yield: 52.6%; melting point 104 -
105C)
EXAMPLE 26
Dextrorotatory N-(l-methyl-2-pyrrolidylmethyl)-7~methyl-
sulfamoyl-1,4-benzodioxane-5-carboxamide
61 g oF dextrorotatory l-methyl-2-aminomethyl pyrrol-
idine, 465 ccm of chloroform, and, in portions, 155 g of 7-
methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, with the
; temperature being maintained at 5 to 10C, were introduced into
, a balloon flask provided with an agitator and a thermometer.
After agitation of the mixture and the addition of 1850 ccm of
water, chloroform was distilled and the remaining solution was
filtered. The base was precipitated by the addition of 65 ccm
of 20% ammonia. The crystals formed were dried off, washed and
dried. 154 g oF dextrorotatory N-(l-methyl-2-pyrrolidyl-
methyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was
produced. (Yield: 78.5%; melting point: 187 - 188C).
;~ EXAMPLE 27
Levorotatory N-(l-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-
1,4-benzodioxane-5-carboxamide
In a similar manner to that of the above example, 71
g of levorotatory l-methyl-2-aminomethyl pyrrolidine was
reacted with 180.5 9 of 7-methylsulfamoyl-1,4-benzodioxane-5-
carbonyl chloride, to give 175 9 of levorotatory N-~l-methyl-2-
30 pyrrolidylmethyl)-7-methylsulfamoyl-174-benzodioxane-5-carbox-
amide. (Yield: 77%; melting point: 187 - 187.5C).
,
- 29 -
'XAMPLE 28
N~ ethyl-2-pyrrolidylmethyl)-8-methylsulfamoyl-2H-3,4-
dihydro-1,5-benzodioxepine-6-carboxamide
8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic
acid
1092 cm3 of chlorosulfonic acid were introduced into
a balloon flask provided with an agitator, a condenser and a
thermometer, then, in portions, 106 9 of 2H-3,4-dihydro-1,5-
benzodioxepine~6-carboxylic acid were added, with the temper-
ature being maintained at from 5 to 10C. The mixture was agi-
tated at ambient temperature then poured on ice. The crystals
were dried off, washed with water and dried. 146 9 of 8-
chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic
acid were obtained. (M.P. 114 - 115C; yield - 91%).
8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbox-
ylic acid
.
233 g of a methylamine aqueous solution were intro-
duced into a balloon flask provided with an agitator and a
thermometer, then, in portions, 146 9 of 8-chlorosulfonyl-2-H-
- 20 3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were added,
with the temperature being maintained at from 5 to 10C. The
mixture was agitated and the precipitate was then dissolved in
water. The solution was filtered and treated with 150 cm3 oF
concentrated hydrochloric acid. The crystals were dried oFf,
washed and dried. 112 9 of 8-methylsulfamoyl-2H-3,4-dihydro-
1,5-benzodioxepine-6-carboxylic acid were obtained. (M.~. -
145 - 146C; yield - 78%).
8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl
chloride
220 y of thionyl chloride and 177 9 of 8-methyl-
sulfamoyl-2~1-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid
were introduced into a balloon flask provided with a condenser.
The mixture was heated, then the thionyl chloride in excess was
- 30 -
distilled off under vacuum. 188 9 of 8-methylsulfamoyl-2H-3,4-
dihydro-1,5-benzod;oxepine-6-carbonyl chloride were obtained.
~M.P. - 93 - 94C; yield ~ lOOX).
N-(1-ethyl-2-pyrrolidylmethyl )-8-methylsul famoyl -2H-3,4-
dihydro-1,5-benzodioxepine-6-carboxamide
79 9 of l-ethyl-2-aminomethyl pyrrolidine, 750 ccm of
methyl ethyl ketone and, gradually, 188 9 of 8-methylsul famoyl-
2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride, with the
temperature being maintained at from 5 to 10C, were introduced
into a balloon flask provided with an agitator and a thermo-
meter.
The hydrochloride precipitate was dried off, washed
with methyl ethyl ketone and then dried.
After recrystallization from methyl alcohol, the '!"~
hydrochloride was dissolved in 850 ccm of water. The solution , ;~
was filtered and then the base was precip; tated by the addition
of 60 ccm of 20X ammonia. The crystals formed were dried o'F'F9
washed with water and then dried. 180 9 of N-(l-ethyl-2-
pyrrolidylmethyl )-8-methylsulfamoyl-2H-3,4-dihydro-lj5-benzo- , ~5
dioxepine 6-carboxamide was produced. (Yield: 63.8%; melting
point: 144 - 145C). '
EXAMPLE 29
N-(l-ethyl-2-pyrrolidylmethyl)-2,3-methylene dioxy benzamide
hYdrochloride _ _
134 9 of l-ethyl-2-aminomethyl pyrrolidine, 950 ccm
of chloroform and, gradually, 183 9 of 293-methylenedioxy
benzoyl chloride, with the temperature being maintained at-from
5 to 10C5 were introduced into a balloon flask provided with
an agitator and a thermome~er.
After the addition of 1 litre of water, chloroform
was distilled and then the remaining solution was filtered.
After the addition of 120 ccm o~ 20% ammonia and
extraction with ether, the ethereal solution was dried on
potassium carbonate and thesl the ether was distilled.
31 -
37 ~
The base produced was dissolved in 300 ccm of acetone
and then a solution of 34 g of hydrochloric ac;d in 330 ccm o~
ace~one was added. The hydrochloridè precipita~e was dr;ed,
washed with acetone and then dried.
After recrystallization from isopropyl alcohol, 154 9
of N-(l-ethyl-2-pyrrolidylmethyl)-2,3-methylenedioxy benzamide
hydrochloride was produced. (Yield: 49.7%; melting point:
127.5 - 128.~C).
EXAMPLE 30
4-(1,4-benzodioxane-7-ethylsulfonyl-5-carbonyl)-1,4-diaza- -
bicyclo (4-3-0) nonane
41.5 9 of 1,4-diazabicyclo (4-3-0) nonane and 300 ml
of chloroform were introduced into a 1 litre balloon flask.
The mixture was cooled to 5, then 87 9 of 7-ethyl-
sulfonyl-1,4-benzodioxane-5-carbonyl chloride was added in
~- small amounts. After agitation of ~he mixture at ambient
temperature 5 g of acticarbon was added. ~;
After filtration and removal of the chloroform, the
oily residue was dissolved in 200 ml of water and then 30 ml of
20% ammonia was added. The resulting residue was dried and
then recrystallized from acetone. 40 g of 4-(1,4-benzodioxane-
7-ethylsulfonyl-5-carbonyl)-1,4-diazabicyclo (4-3-0) nonane was
; produced. (Yield: 35Xi melting point: 147C).
Example 31
~ . .
5- ~ 4-methyl-1-1-piperazinyl)carbony ~-7-nitro-1,4-benzodioxane,
hydrochloride _
7-nitro-1,4-ben2Odioxane-5-carboxylic acid
16~ ml of acetic acid, 160 ml of acetic anhydride and
100 9 of 1,4-benzodioxane-5-carboxylic acid were introduced
into a balloon flask provided with an agitator and a thermo-
meter. The mixture was heated and a solution Df 40 ml of
~ nitric acid in 40 ml of acetic acid was added. The mixture was
:~
~ - 32 -
. . . . ~ . . .
~ '7 ~
dgitated at 40 - 45C, then cooled. The crystals were dr;ed
off, washed and dried. 34 9 of 7-nitro-1l4-benzodioxane-5-
carboxylic acid were ob~ained. (M.P. - 246C; yield - 27%).
5- ~ 4-methyl-1-piperazinyl)carbony ~-7-nitro-1,4-benzodioxane,
hydrochloride _ -
22 ml of water, 22.5 9 of 7-nitro-1,4-benzodioxane-5-
carboxylic acid, 65 ml of acetone and 10.5 9 of triethylamine
were introduced into a 250 ml balloon flask provided with an
agitator and a thermometer.
lD The mixture was cooled to 10C and then 14 9 of
isobutyl chloroformiate was added. The mixture was agitated,
the temperature being allowed to rise. The oily compound
formed was cooled to 10, 11 9 of N-methyl piperazine was
added, and then the mixture was agitated, allowing the temper-
ature to rise.
The crystals formed were washed with water. 20.5 9
of 5- ~ 4-methyl-1-piperazinyl)carbony ~-7-nitro-1,4-benzo-
dioxane was produced. (Yield: 66.7%; melting point: 218C).
The 20.5 9 o~ base produced was treated by a solution
20 of 7 ml of hydrochloric acid (specific gravity - 1.18) in 100
ml of water. The crystals formed by cooling were washed with
water and then dried. 20.5 9 of 5- ~4-methyl-1-piperazinyl)-
carbony ~-7-nitro-1,4-benzodioxane hydrochlor;de was ~roduced.
(Yield: 89.4%; melting point: 250C~.
EXAMPLE 32
5- ~ 4-methyl-1-piperazinyl)carbony ~-7- ~l-adamantyl)-
sulfamoy~7-1,4-benzodioxane, hydrochloride_
7-(1-adamantyl)sulfamoyl-1,4-benzodioxane-5-carboxylic acid
187.5 9 of adamantylamine hydrochloride, 500 ml of
soda and 1000 ml of triethylamine were introduced into a
balloon f1ask provided with an agitator and a thermometer. 280
g of 7-chlorosulfonyl-1,4-benzodioxane-5~carboxylic acid were
~; ~ - 33 -
,v
~ '7 ~
then added at a temperature below 15C. The mixture was agi-
tated at ambient temperature and treated with 1.5 1 of methyl-
ene chloride. The organic phase was separated and the solvent
removed. The residue was treated with 1200 ml of water and
lS0 ml of hydrochloric acid, then the precipitate was dis-
solved in 1200 ml of water and 120 ml of soda. The solution
was filtered and treated with 150 ml of hydrochloric acid. The
crystals were dried off, washed and dried. 200 9 of 7-(1-
adamantyl)sulfamoyl-1,4-benzodioxane-5-carboxylic acid were
obtained. (M.P. 205C; yield ~ 51%).
5- ~4-methyl-1-piperazinyl)carbony ~-7- ~l-adamantyl)-
sulfamoy~/-1,4-benzodioxane, hydrochloride
500 ml of dioxane and 49 g of 7-(1-adamantyl)-
sulfamoyl-1,4-benzodioxane-5-carboxylic acid were introduced
into a 1 litre balloon flask provided with an agitator and a
thermometer. After agitation of the mixture, 12.5 9 of tri-
ethylamine was addedg then, in small amounts, 17 9 of isobutyl-
chloroformiate.
After agitation of the mixture at a temperature of
20C, a solution of 14 9 of N-methyl piperazine in 50 ml of
dioxane was introduced. The mixture was agitated and then
cooled. The triethylamine hydrochloride formed was removed by
filtrationg the filtrate was concentrated under vacuum, and
then dissolved in 300 ml of water. 15 ml of hydrochloric acid
was added, then the solution was treated with 20 ml of ammonia.
The product formed was dissolved in 150 ml of boiling ethanol
and the solution was filtered hot.
A solution of hydrochloric acid in absolute ethanol
was added to the filtrate, until the pH-value was 1.
The crystals formed were dried off, washed with
ethanol and dried. 37 9 of 5- ~4-methyl-1-piperazinyl)-
carbony ~-7- ~l-adamantyljsulfamoy ~-1,4~benzodioxane hydro-
- 34 -
\
7~
chloride was produced. (Yield: 58%; melting point: 260C).
EXAMPLE 33
N-(piperidinoethyl)-7-chloro-1,4-benzodioxane-5-carboxamide,
hydrochloride
_______
7-amino-1,4-benzodioxane-5- arboxylic acid
56 9 of 7-nitro-1,4-benzodioxane-5-carboxylic acid,
560 ml of absolute ethanol and Raney nickel were introduced
into an autoclave, then hydrogen under a pressure of 65 kg/cm
was introduced while heating. The mixture was then agitated at
60C, and treated with a solution of 50 ml of soda lye in 450
ml of water. The solution was filtered and treated with 50 ml
; of hydrochloric acid. The precipitate was dried off, washed
with water and dried. 36.5 9 of 7-amino-1,4-benzodioxane-5-
carboxylic acid were obtained. (M.P. = 220C; yield - 75%).
7-chloro-1,4-benzodioxane-5-carboxylic acid
49 9 of 7-amino-1,4-benzodioxane-5-carboxylic acid,
200 ml of water and 50 ml of hydrochloric acid were introduced
into a balloon flask provided with an agitator and a thermo-
meter. The mixture was cooled to 5C, then a solution of 17.5
9 of sodium nitrite in 38 ml of water was added.
The suspension was then poured into a solution of 20
g of cuprous chloride in 75 ml of hydrochloric acid. The pre-
cipitate was dried off, washed and dissolved in a solution of
42 9 of sodium bicarbonate in 420 ml of water. The solution
was filtered and treated with 100 ml of hydrochloric acid: 50
g of 7-chloro-1,4-benzodioxane-5-carboxylic acid were obtained.
(M.P. = 180C; yield = 92.7%).
` 7-chloro-1,4-benzodioxane-5-carbonyl chloride
32.2 g of 7-chloro-1,4-benzodioxane-5-carboxy1ic acid
3~ and 64 ml of thiony~ chloride were introduced into a balloon
flask provided with an agitator, a thermometer and a condenser.
The mixture was heated under reflux, then the thionyl chloride
~ 35 -
in excess was distilled off under vacuum. 35 9 of 7-chloro~
1,4-benzodioxane-5-carbonyl chloride were obtained. (M.P. -
140C; yield 100%).
N-(piperidinoethyl)-7-chloro-1,4-benzodioxane-5-carboxamide,
hydrochloride
150 ml of methyl ethyl ketone and 22 9 of N-(amino-
ethyl)piperidine were introduced into a 500 ml balloon flask
provided with an agitator and a thermometer. The mixture was
cooled, then a suspension of 35 g of 7-chloro-1,4-benzodioxane-
5-carbonyl chloride in 200 ml of methyl ethyl ketone was added
at a temperature of from 15 to 20C.
After agitation, the crystals formed were dried off,
then washed with methyl ethyl ketone. 35 9 of N- ~iperidino
ethy ~-7-chloro-1,4-benzodioxane-5-carboxamide hydrochloride
was produced. (Yield: 64.5%, melting point: 192C).
EXAMPLE 34
N-(butyl)-7- ~l-adamantyl)sulfamoy ~-1,~-benzodioxane-5-
carboxamide
500 ml of dioxane, 50 ml of water, 49 9 of 7- ~1-
adamantyl)sulfamoy ~-1,4-benzodioxane-5-carboxylic acid and
12.5 9 of triethylamine were introduced into a 2 litre balloon
flask provided with an agitator and a thermometer. The
solution was agitated at ambient temperature, then 17 9 of
isobutyl chloroformiate was added.
The mixture was agitated and then 10 9 of butylamine
was introduced. After agitation of the mixture, dioxane was
removed.
The residue was dissolved in 200 ml of water in a hot
condition. The crystals formed by cooling were washed with
water, dried and redissolved in 250 ml of acetone at boiling
temperature. The solution was filtered hot. The crystals
formed by cooling were dr~ed off, washed and dried. 26 g of
- 36 -
N-(butyl)~7- ~l-adamantyl)sulfamoy ~-1,4-benzodioxane-5-carbox-
amide was produced. (M.P. - 147C; yield - 46.4%)~
EXAMPLE 35
~ N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-
-~ carboxamide oxalate
'.:;
8-methoxy-1,4-benzodioxane-5-carboxylic acid
171.5 g of 2,3-dihydroxy-4-methoxybenzoic acid, 515
cm3 of alcohol, 280 cm3 of soda lye and 175 9 of ethylene
bromide were introduced into a balloon flask provided with an
agitator, a thermometer and an inlet pipe for nitrogen. The
mixture was heated under reflux, then cooled and poured into
2.8 1 of water. The solution was filtered and treated with 85
cm of concentrated hydrochloric acid. The precipitate was
dried off, washed and dried. After recrystallization in
dimethylformamide, 110 9 of 8-methoxy-1,4-benzodioxane-5-
carboxylic acid were obtained. (M.P. - 224 - 226C; yield
57%)-
8-methoxy-1,4-benzodioxane-5-carbonyl chloride
391 g of thionyl chloride and 138 g of 8-methoxy-1,4-
benzodioxane-5-carboxylic acid were introduced into a balloon
flask provided with a condenser. The mixture was heated at
50 - 55C and the thionyl chloridé in excess was distilled off
under vacuum. 151 9 of 8-methoxy-1,4-benzodioxane-5-carbonyl
~` chloride were obtained ~yield 100%).
., .
N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-
carboxamide oxalate
-- - ,
87 9 of 1-ethy1-2-aminomethyl pyrrolidine and 775
ccm of methyl ethyl ketone were introduced into a balloon flask
provided with an agitator and a thermometer, and then, in
30 portions, 155 9 of 8-methoxy-1~4-benzodioxane-5-carbonyl
chloride was added, with the temperature being maintained at
from 5 to 10C. After agitation, the mixture was dissolved
:
- 37 -
~$~ 3'7~
with 1500 ccm of water -then the methyl ethyl ke-tone was dis-
tilled. The remaining solution was filt:ered then treated with
sodium hydroxide. The oil was decanted, then extracted with
methylene chloride. The solution was dried on potassium
carbonate and then methylene chloride was distilled under
vacuum.
224.5 g of N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxy-
1,4-benzodioxane-5-carboxamide was produced.
197.5 g of the base produced was dissolved in 760 ccm
of absolute alcohol, then 67 g of oxalic acid in solution in
195 ccm of absolute alcohol was added. The crystals formed
were dried off, washed with absolute alcohol and then dried.
208.5 g of N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxy-
1,4-benzodioxane-5-carboxamide oxalate was produced. (Yield:
82%; melting point: 129 - 130C).
EXAMPLE 36
N-(l-ethyl-2-pyrrolidylmethyl~-8-methoxy-7-sulfamoyl-1,4-
` benzodioxane-5-carboxamide
8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid
1045 cm3 of chlorosulfonic acid were introduced into
a balloon flask provided with an agitator, a thermometer and a
condenser, then, in portions, 110 g of 8-methoxy-1,4-benzo-
dioxane-5-carboxylic acid were added with the temperature being
maintained at from 5 to lQC. The mixture was agitated at
ambient temperature then poured on ice. The precipitate was
dried off, washed and dried. 159 g of 8-methoxy-7-chloro-
sulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained
(yield 98%).
8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid
300 g of 34% ammonia were introduced into a balloon
flask provided with an agitator and a thermometer, theng 159 g
of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-c:arboxylic
- 38 -
~, :
acid were added in portions, the temperature being maintained
at from 0 to 5C. The mixture was agitated~ then the precipi-
tate was dissolved in water. The solution was filtered and
treated with 280 cm3 of concentrated hydrochloric acid. The
precipitate was dried off, washed and dried. 118 g of 8-
methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were
obtained. (M.P. 247 - 248C; yield 82%).
Methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate
396 g of methanol were introduced ;nto a balloon
flask provided with a condenser, then 51 g of sulfuric acid and
114.5 g oF 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic
acid were added while cooling. The mixture was heated under -
reflux then poured into 485 cm3 of water and 40 g of sodium
carbonate. The precipitate was dried off, washed and dried.
110.5 g of methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-
carboxylate were obtained. (M.P. - 202 - 203C; yield - 92%).
N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxy-7-sulfamoyl-1,4-
benzodioxane-5-carboxamide _ _
150 g of methyl 8-methoxy-7-sulfamoyl-1,4-benzo-
dioxane-5-carboxylate and 750 ccm of ethylene glycol were
introduced into a balloon flask. After dissolution, 127 9 of
l-ethyl-2-aminomethyl pyrrolidine was added and the mixture was
heated at 50C. The resulting solution was dissolved with 2
litres of water and acidified by means of 120 ccm of acetic
acid. The precipitate formed was dried off, washed with water
and then dried.
The precipitate was then redissolved in 915 ccm of
hot water. The solution was filtered and then the base was pre-
cipitated with ammonia. The precipitate was dried ofF, washed
with water and then dried. 144 g of N-(l-ethyl-2-pyrrolidyl-
methyl)-8-methoxy-7-sulFamoyl-1,4-benzodioxane-5-carboxamide
was produced. (Yield: 73%; melting point: 110 115C).
- 39 -
-. ~ - .
EXAMPLE 37
4-(1,4-benzodioxane-5-carbonyl)-1,4-diazabicyclo (4-3-0) nonane
63 9 of 1,4-diazabicyclo (4-3-0) nonane and 400 ml of
chloroform were introduced into a 1 litre balloon flask pro-
vided with an agitator and a thermometer and then, in portions,
50 9 of 1,4-benzodioxane-5-carbonyl chloride was added, with
the temperature being maintained at 10C.
The mixture was then agitated at ambient temperature,
and then 1 litre of water was added. ;~
After the addition of acetic acid to give a pH-value
of 4, the addition of carbon black and filtration, the product
was precipitated with ammonia.
After extraction by methylene chloride, the solution
was dried and then filtered. The solvent was removed under
vacuum and the resulting product was purified by recrystalli-
zation from ethanol. 50 g of 4-(1,4-benzodioxane-5-carbonyl~-
,; 1,4-diazabicyclo (4-3-0) nonane was produced. (Yield: 69%;
, melting point: 128C).
EXAMPLE 38
N-(benzyl)-7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide
7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid
200 ml of water~ 100 ml of diethylamine and 200 ml of
triethylamine were introduced into a balloon flask provided
with an agitator and a thermometer, then, 140 9 of 7-chloro-
sulfonyl-1,4-benzodioxane-5-carboxylic acid were added in
portions, the temperature being maintained at from 20 to 30C.
The mixture was agitated at ambient temperature then 500 ml of
water were added. The solution was filtered and treated with
300 ml of hydrochloric acid. The precipitate was dried off~
washed and dried. 117 9 of 7-diethylsulfamoyl-1,4-benzo-
dioxane-5-carboxylic acid were obtained. (M.P. - 149C; yield
- 74%).
- 40 -
.
. .
,,
't~
N- ~benzyl)-7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide
37.8 g of 7-diethylsulfamoyl-1,4-benzodioxane-5-
carboxylic acid, 40 ml of water, 12.5 g of triethylamine and
120 ml of acetone were introduced into a balloon flask provided
with an agitator and a thermometer.
The mixture was cooled to about 10 to 15C and then
17.2 g of isobutyl chloroformiate was added.
After the addition, at a temperature of from 15 to
20C, of 14.1 g of benzylamine and agitation of the mixture,
the crystals formed were dried off9 washed with water and then
purified by recrystallization from ethanol.
33 g of N-(benzyl)-7-diethylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide was produced. (Yield: 68%; melting
point: 125C).
EXAMPLE 39
N-(l-benzyl-4-piperidyl)-7-methylsulfamoyl-1,4-benzodioxane-
5-carboxamide
70 ml of water, 68.5 g of 7-methylsulfamoyl-1,4-
benzodioxane-5-carboxylic acid, 25.5 g of triethylamine and 200
ml of acetone were introduced into a balloon flask provided
with an agitator and a thermometer and then 34.5 g of isobutyl
chloroformiate was added, with the temperature being kept at
from 15 to 20C.
After the addition, at a temperature of from 15 to
` 20C, of 52 g of 1-benzyl 4-aminopiperidine and agitation of
the mixture, the crystals formed were dried o-Ff, washed with
water and then dried.
The product formed was purified by treatment with a
solution of hydrochloric acid then precipitation by means of
sodium hydroxide. The precipitate was then dried off, washed
with water and dried.
76 g of N-(l-benzyl-4-piperidyl)-7-methylsulfamoyl-
- 41 -
~ 3'7~
1,4-benzodioxane-5~carboxamide was produced. (Yield: 68%;
melting point: 228C).
EXAMPLE ~0
N-(l-adamantyl)-l,~-benzodioxane-5-carboxamide
200 ml of chloroform and 37.5 9 of adamantamine were
introduced into a balloon flask provided with an agitator and a
thermometer~ and then 50 g of 1,4-ben7Odioxane-5-carbonyl
chloride was added in portions, at a temperature oF From 5 to
10C. After agitation at ambient temperature, 1500 ml of water
was added and then chloroform was removed under vacuum. The
base which was precipitated by ammonia was extracted by means
of methylene chloride. AFter removal of the solvent, the
residue was dissolved in hydrochloric ethanol. The crystals
formed by cooling were dried off, washed and then dried. 20 g
of N-(l-adamantyl)-1,4-benzodioxane-5-carboxamide was produced.
(Yield: 25%; melting point: 137C).
EXAMPLE 41
N-(l-benzyl-2-pyrrolidylmethyl)-7-diethylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide phosphate
~0 ml of water, 37.8 9 of 7-diethylsulfamoyl-1,4-
benzodioxane-5-carboxylic acid, 12.5 g of triethylamine and 120
ml of methyl ethyl ketone were introduced into a balloon flask
provided with an agitator and a thermometer, and then 17.2 g of
isobutyl chloroformiate was added at a temperature of From 15
to 20 C.
After agitation of the mixture 25 g of 1-benzyl-2-
aminomethyl pyrrolidine was added, with the temperature being
maintained at from 15 to 2~C.
The mixture was agitated at ambient temperature and
then the solvents were removed. The residue was dissolved in
200 ml of methylene chloride and 300 ml oF water. After agi-
tation, the solvent was decanted and then dried on magnesium
., . . ~ .
3\7~
sulfate. The solution was filtered and then the solvent
removed. The resulting compound was dissolved in ethanol at
boiling temperature and 18 g of 85% phosphoric acid was added.
The crystals formed by cooling were dried off, washed with ice-
cold ethanol and then dried. 56 g of N~ benzyl-2-pyrrolidyl-
methyl)-7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide
phosphate was produced. (Yield: 79.6%; melting point 180C).
EXAMPLE 42
N-~l-benzyl-4-piperidyl)-1,4-benzodioxane-5-carboxamide,
hydrochloride
200 ml of chloroform and 50 9 of 1-benzyl-4-amino-
piperidine were introduced into a balloon flask provided with
an agitator and a thermometer, and then 50 g of 1,4-benzo-
dioxane-5-carbonyl chloride was added in portions, at a temper-
ature of from 5 to 10C.
After agitation of the mixture at ambient tempera-
ture, the solvent was removed under vacuum and the residue was
dissolved in 300 ml of water. After precipitation of the base
by addition of ammonia, the water was removed and the resulting
product was treated with a solution of hydrochloric acid. 75 g
of N-(l-benzyl-4-piperidyl)-1,4-benzodioxane-5-carboxamide
hydrochloride was produced. (Yield: 77%; meltiny point:
205C).
EXAMPLE 43
N-(l-ethyl-2-pyrrolidylmethyl)-8 ethylsulfonyl-2H-3,4-dihydro-
1,5-benzodioxepine-6-carboxamide, hydrochloride
8-mercapto-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid
A solution of 106 g of 8-chlorosulfonyl-2H-3,4-
dihydro-1,5-benzodioxepine-6-carboxylic acid in 273 ml of
acetic acid and 159.5 g of tin were introduced into a balloon
flask provided with an agitator and a thermometerO The mixture
was agitated under heatin~ at 40 - 45C, then 705 ml of concen-
- 43
3'7~ ::
trated hydrochloric acid were added. After hea ~iIng at 55 -
60C, the solution was cooled. The precipitate was dried off,
washed and dried. 65 9 of 8-mercapto-2H-3,4-dil~dro-1,5-benzo-
dioxepine-6-carboxylic acid were obtained. (M.IP.. = 99 5 -
100C; yield - 80%).
8-ethylthio-2H-3,4-dih~dro-1,5-benzodioxepine-6-- rboxylic acid
8~ 9 of 8-mercapto-2H-3,4-dihydro-1,5- ~nzodioxepine-
6-carboxylic acid, 152 ml of water, 76 ml of sod~a and 58.5 9 of
ethylsulfate were introduced into a balloon flas;k provided with
a condenser. The mixture was heated under refl~x then cooled.
150 ml of water were added, then the solution wal~ filtered and
treated with 60 ml of hydrochloric acid. The pre~ipitate was
dried off, washed and dried. 88 9 of 8-ethylthio-2H-3,4-
dihydro-1,5-benzodioxepine-6-carboxylic acid wert~ obtained.
(M.P. - 66 - 670; yield = 91%~.
8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepin~e-6-carboxyl;c
; acid
- 88 9 of 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine- ~-6-carboxylic acid in 528 ml of acetic acid were hntroduced into
a balloon flask provided with a condenser, then ~10 ml of
hydrogen peroxide were added in portions. The s~lution was ~ ;
heated and the a~etic acid removed under vacuum. The residue
was dissolved in 180 ml of water and cooled. Th~ precipitate
was dried off, washed and dried. 90 9 of 8-ethylsulfony7-2H-
3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were obta-ined.
(M.P. = 142 - 1430; yield = gl%).
~ 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl
-~ chloride
- -
75 9 of thionyl chloride and 90 9 of 8-ethylsulfonyl-
2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were intro-
duced into a balloon flask provided with a condenser. The
mixture was heated at 45 - 50C and ~he thionyl chloride in
44 -
.
, ,. : : .
3~7~
excess was removed under vacuum. The residue was treated with
petrolic ether, then dried off, washed and dried. 94 g of 8-
ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl
chloride were obtained. (M.P. - 10~ - 110C; yield - 98%).
N-(l-ethyl-2-pyrrolidylmethyl)-8-ethylsulfonyl-2H-3,4-dihydro-
1,5-benzodioxepine 6-carboxamide, hydrochloride
39.5 g of 1-ethyl-2-aminomethyl pyrrolidine in 282 ml
of chloroform were introduced into a balloon flask provided
with an agitator and a thermometer, then, 94 g of 8 ethyl-
10 sulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride
were added in portions, the temperature being maintained at
from 5 to 10C. The mixture was heated then poured into water.
The aqueous phase was cooled, filtered and treated with 30 ml
of soda. The precipitate was extracted by methylene chloride
and the organic phase was dried on potassium carbonate. The
solvent was distilled off, the residue dissolved in isopropyl
alcohol and treated with a solution of hydrochloric acid in
isopropyl alcohol. The precipitate was dried off, washed with
alcohol and dried. 98 g of N-(l-ethyl-2-pyrrolidylmethyl)-8-
20 ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide
were obtained. (M.P. - 141 - 142C; yield = 73~
EXAMPLE 44
5- ~4-methyl-1-piperazinyl)carbony ~-6~7-dibromo-8-nitro-1,4-
benzodioxane
6,7-dibromo-1,4-benzodioxane-5-carboxylic acid
: 1440 ml of acetic acid and 360 g of 1,4-benzodioxane-
5-carboxylic acid were introduced into a balloon flask provided
with an agitator, an introduction funnel and a condenser. The
mixture was heated to 55C, then a solution of 700 y of bromine
in 360 ml o~ acetic acid was added in portions. The mixture
was heated to 120C, then cooled to 15C. The precipitate was
dried off, washed with acetic acid and dried. 332 g of 6,7-
- 45 -
: . .
dibromo-1,4-benzodioxane-5-carboxylic acid were obtained.
(M.P. ~ 212C). The structure was confirmed by NMR analysis.
6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid
166 9 of 6,7-dibromo-1,4-benzodioxane-5-carboxylic
acid and 500 ml of acetic acid were introduced into a balloon
flask. The mixture was heated to 37C then a solutior of 60 ml
of nitric acid (d - 1.49) in 60 ml of acetic acid and sulfuric
acid, as catalyst, were added. After heating at 50C, the
mixture was poured in cold water, under agitation. The pre-
cipitate was dried off, washed with water and dried. 107 9 oF6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid were
obtained. (M.P. - 237C). The acid was purified by treatment
with a solution oF 50 9 of sodium bicarbonate in 500 ml of
water and precipitation by hydrochloric acid. The precipitate
was dried off, washed and dried. Crystals were obtained.
. . .
(M.P. - 238C; yield = 61%). The structure was confirmed by
NMR analysis.
6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride
96 9 of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-
carboxylic acid and 2Q0 ml of thionyl chloride were introduced
into a balloon Flask provided with an agitator and a thermo-
meter. The mixture was heated under reflux, then the thionyl
chloride in excess was removed under vacuum. The residue was
dissolved in 100 ml of isopropyl ether, then the solvent
removed and the product air-dried. 91 9 of 6,7-dibromo-8-
nitro-1,4-benzodioxane-5-carbonyl chloride were obtalned.
(M.P~ ~ 215C; yield - 91%).
5- ~4 methyl-1-piperazinyl)carbony ~-6,7-dibromo-8-nitro-1,4-
benzodioxane
400 ml of methyl ethyl ketone and 11 9 of methyl-
piperazine were introduced into a balloon flask provided with
an agitator and a thermometer. The mixture was coolecl to 10C,
- 46 -
then, ~1 9 of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl
chloride were added in portions with the temperature being
maintained below 20C. After agitation of the mixture, the
crystals were dried o~f~ washed with methyl ethyl ketone and
dried, then dissolved in water and reprecipitated by addition
of 50 ml of 20% ammonia. The crystals were dried off~ washed
with water and dried. 33 9 of 5- ~4-methyl-1-piperazinyl)-
carbony ~-6,7-dibromo-8-nitro-1,4-benzodioxane were obtained.
(M.P. 1&4C; yield 69.6%). The structure was con~irmed by
I.R. and NMR analysis.
EXAMPLE 45
N-(l ethyl-2-pyrrolidylmethyl)-6,7-dibromo-8-nitro-1,4-benzo-
dioxane-5-carboxamide
.
In a similar manner, by substituting l-ethyl-2-amino-
methyl pyrrolidine for methylpiperazine, N-(l-ethyl-2-pyrrol-
idylmethyl)-6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxamide
was obtained. (M.P. - 213C; yield 65%). The structure was
confirmed by NMR analysis.
EXAMPLE 46
20 N-(l-ethyl-2-pyrrolidylmethyl)-8-amino-1,4-benzodioxane-5-
carboxamide _
8-amino-1,4-benzodioxane-5-carboxylic acid
400 ml of water, 98.5 g of 6,7-dibromo-8-nitro-194-
benzodioxane-5-carboxylic acid, 100 ml of soda and 10 9 of Pd/C
were introduced into an autoclave, then hydrogen under a
pressure of 40 kg/cm2 was introduced while heating at 50C.
The mixture was ~iltered then treated with 95 ml of hydro-
chloric acid. The precipitate was dried off, washed and dried.
42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid were
. .
30 obtained. (M.P. 186C, yield 83.7%).
N-(l-ethyl-2-pyrrolidylmethyl)-8-amino-1,4~benzodioxane-5-
carboxamide
__
According to the method described in Example 2, 42 g
- 47 -
-
3'~
of 8-amino-1,4-benzodioxane-5-carboxylic acid were treated with
methanol and the resulting compound treated with 33 9 of 1-
ethyl-2-aminomethyl pyrrolidine and then with a solution of 13
g of hydroch1Oric acid in absolute alcnhol. 49 9 of N-(l-
ethyl-2-pyrrolidylmethyl)-8-amino-1,4~benzodioxane-S-carbox- ~
- amide dihydrochloride were obtained. (M.P. - 173C; yield - -
60%).
EXAMPLE 47
5- ~4-methyl-1-piperazinyl)carbony ~-8-chloro-1,4-benzodioxane
8-chloro-1,4-benzodioxane-5-carboxylic acid
29.3 9 of 8-amino-1~4-benzodioxane-5-carboxylic acid,
120 ml of water and 30 ml oF hydrochloric acid were introduced
into a balloon flask provided with an agitator and a thermo-
meter. The mixture was heated to 40C, then cooled to 5C and
a solution of 10.5 9 of sodium nitrite in 20 ml of water was
added in portions, with the temperature being maintained at
from 5 to 10C. The mixture was agitated then poured into a
solution of 12 9 of cuprous chloride in 45 ml of hydrochloric
acid (d 1.18), with the temperature being maintained below
30C. The precipitate was dried off, washed with hydrochloric
acid and water, then dissolved in 300 ml of water and 25 9 of
sod;um bicarbonate. The solution was filtered and treated with
hydrochloric acid. The precipitate was dried off, washed with
water and dried. 20 g of 8-chloro-1,4-benzodioxane-5-carbox-
ylic acid were obtained. (M.P. - 195C, yield - 62~).
5- ~4-methyl-1-piperazinyl)carbony ~-8-chloro-1,4-benzodioxane
According to the method described in Example 33, 20 g
of 8-chloro-1,4-benzodioxane-5-carboxylic acid were treated
with thionyl chloride and the resulting 8-chloro-1,4-benzo-
dioxane-5-carbonyl chloride. (M.P. - 830) was treated with
10.5 g of methylpiperazine. 14 g of 5- ~4-methyl-1-pipera-
- 48 -
. :
zinyl)carbony ~-8-chloro-1,4-benzodioxane were obtained. (M.P.
= 260C with decomposition, yield 50.5%).
EXAMPLE 48
N-(l-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-
carboxamide
8-acetamino-1,4-benzodioxane-5-carboxylic acid
43 9 of 8-amino-1,4-benzodioxane-5-carboxylic acid
and 72 ml of acetic acid were introduced into a balloon flask,
then 24.5 ml of acetic anhydride were added in portions. The
mixture was heated at 60 - 70C, then cooled. The precipitate
was dried off, washed with acetic acid and water and dried. 44
g of ~-acetamino-1,4-benzodioxane-5-carboxylic acid were ob-
tained. (M.P. = 233C; yield - 84%).
N-(l-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-5-
carboxamide _ `
According to the method described in Example 31, the
8-acetamino-1,4-benzodioxane-5-carboxylic acid was treated with
isobutyl chloroformate and l-ethyl-2-aminomethyl pyrrolidine.
N-(l-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-5-
carboxamide was obtained. The structure was confirmed by NMRanalysis.
EXAMPLE 49
N-(diethylaminoethyl)-7-nitro-8-acetamino-1,4-benzodioxane-5-
carboxamide
42 g of 8-acetamino-1,4-benzodioxane-5-carboxylic
acid, 75 ml of acetic acid and 74 ml oF acetic anhydride were
introduced into a balloon flask, then a solution of 17.5 ml of
nitric acid (d - 1.49) in 17 ml of acetic acid was added, with
the temperature being left rising. After dissolution and
; 30 crystallization, 50 ml of acetic acid were added. The mixture
was agitated at 40 - 45C then cooled to 20C. The precipitate
was dried off, washed with acetic acid and water and dried.
13.5 g of a 50% mixture of 7-nitro-8-acetamino-1,4-benzo-
- 49 -
~h~
dioxane-5-carboxylic acid and 6-nitro-8-acetamino-1,4-benzo-
dioxane-5-carboxylic acid were obtained. The 7-nitro-8-acet-
amino-1,4-benzodioxane-5-carboxylic acid was separated and then
treated according to the process of Example 31, with isobutyl
chloroformate and diethylaminoethylamine. N-(diethylamino-
ethyl)-7-nitro-8-acetamino-1,4-benzodioxane-5-carboxamide was
obtained. The structure was confirmed by NMR analysis.
EX~MPLE 50
N-(l-allyl-2-pyrrolidylmethyl)-7,8-azimido-1,4-benzodioxane-5-
carboxamide
7,8-azimido-1,4-benzodioxane-5-carboxylic acid
13 g of a 50% mixture of 7-nitro-8-acetamino-1,4-
benzodioxane-5-carboxylic acid and 6-nitro-8-acetamino-1,4-
benzodioxane-5-carboxylic acid, 90 ml of water, 4.5 ml of
sodium hydroxide, some Raney nickel and hydrogen under a 50
kg/cm2 press~re were introduced into an autoclave. At the end
of the hydrogen absorption, the nickel was filtered off and the
solution was treated with 12 ml of hydrochloric acid then with
a solution of 3.5 g of sodium nitrite in 10 ml of water, at a
temperature of from 20 to 25C. The obtained precipitate was
dried off, washed then treated with an aqueous sodium hydroxide
solution. The mixture was acidified, then the precipitate was
dried off, washed and dried. 3 g of 7,8-azimido-1,4-benzo-
dioxane-5-carboxylic acid were obtained. (M.P. : 260C with
decomposition - yield 59%).
N-(l-allyl-2-pyrrolidylmethyl)-7,8-azimido-1~4-benzodioxane-5-
carboxamide
The 7,8-azimido-1,4-benzodioxane-5-carboxylic acid
was treated with the N-hydroxyphthalimide together with the
dicyclohexylcarbodiimide. The obtained phthalimide carboxylate
was treated with the l-allyl-2-aminomethyl pyrrolidine. The N-
(l-allyl-2-pyrrolidylmethyl)-7,8-azimido-1,4-benzod-ioxane-5-
- 50 -
~ 37~
carboxamide was obtained~ the structure oF which was confirmed
by NMR.
EXAMPLE 51
N-(2-pyrimidyl)-6-chloro-1,4-benzodioxane-5-carboxamide
6-nitro-1,4-benzodioxane-5-carboxylic ac _
1600 ml of acetic acid~ 1600 ml of acetic anhydride,
100~ 9 of 1,4-benzodioxane-S-carboxylic acid were introduced in
a 6 liter bal100n flask provided with an agitator and a thermo-
meter. The mixture was heated to 40C and a solution of 400 ml
o~ nitric acid in 400 ml of acetic acid was added. AFter the
introduction, the mixture was stirred at 40 - 45C for 2 hours,
then cooled to 5C. The precipitate was dried off, washed with
600 ml of acetic acid, then with water and dried at 40C. 700
g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were collected~
the structure of which was confirmed by NMR (M.P. : 246C).
The mother-liquors were diluted with 25 liters of water~ and ;~
the obtained precipi~ate w~s dried o~f, washed with water and
dried. The S-ni~ro-194-ben70dioxane-5-carboxylic acid was
obtained. (M.P. : 188C).
6-amino-1,4-benz dioxane-5-carboxylic acid, hydrochloride
195 9 of 6-nitro-1,4-benzodioxane-5-carboxylic acid,
~ 1950 ml of ethanol, some Raney nickel were introduced into an
-~ ~utoclave. The mixture was hydrogenated under a hydrogen
-~ pressure o~ 35 kg/cm~ at 60C for one hour, then cooled. -The
nickel was filtered and the solution was acidi~ied with 160 ml
of an ethanolic solution of hydrochloric acid ~23 9/lOO ml~.
The precipitate was filtered, dried. 115 9 of 6-am;no-1,4-
benzodioxane-5-carboxylic aoid hydrochloride were obtainedO
(M.P. : 160C - yield 57.5X).
6-chloro-1,4-benzodioxane-5-carboxylic acid
58 9 of 6-amino-1~4-benzodioxane-5-carboxylic aeid
- 51 -
~ '7
hydrochloride, 116 ml of water were introduced in a 500 ml
balloon flask provided with a stirrer, a thermometer and a
dropping funnel. 28 ml of hydrochloric acid (d _ 1.18) were
added and the mixture was cooled to a temperature of from 0 to
5C.
A solution of 17.5 g of sodium nitrite in 38 ml of
water was added at a temperature within the 0 - 5C range. The
mixture was stirred for one hour. 20 g of cuprous chloride
and 75 ~1 of hydrochloric acid were added. The mixture wa~
allowed to stand overnight, ~hen filtered.
The solid was washed with water, dried at 50C and
purified by treatment with carbon black in alkaline solution
(200 ml of water and 25 ml of 36 Bé caust;c soda lye), then
addition of 25 ml of hydrochloric acid. 40 9 of 6-chloro-1,4-
; benzodioxane-5-carboxylic asid were obtained. (M.P. : 162C -
yield 74%).
; 6-chloro-1,4-benzodioxane-5-carbonyl chloride
- 56 ml of thionyl chlorideg 28 9 of 6-chloro-1,4-
benzodioxane-5-carboxylic acid were introduced into a 250 ml
balloon flask provided with a stirrer7 a condenser and a
thermometer . The mixture was heated at the reflux temperature
for 30 minutes. The excess of thionyl chloride was removed by
distillation under reduced pressure. 28.5 9 of 6-chloro-1,4-
.. . .
benzodioxane-5-carbonyl chloride were obtained; (M.P. : 50C - `
yield 93X~.
N-(2-pyrimidyl~-6-chloro-1,4-benzodioxane-5-carboxamide
280 ml o~ methyl ethyl ketone,13 9 of 2-aminopyrimi-
dine were put into a 500 ml balloon flask provided with a stirrer
:.
and a thermometer. The mixture was cooled to 10C and 28 9 of
ground 6-chloro-1,4-benzod;Qxane-5-carbonyl chloride was added
and stirred for 2 hours, the temperature being allowed to rise
52 -
.
-
to 20C. The obtained solid was filtered off, washed with 30
ml of methyl ethyl ketone~ then dissolved in 250 ml of boiling
water. The solution was treated wi~h 10 ml of 35 Be caustic
soda lye. After filtra~ion 12 9 of product were obtained and
crystallized again from 150 ml o~ ethanoll. 9.5 9 of N-(2-
pyrimidyl)-6-chloro-1,4-benzodioxane-5-carboxamide were obtained.
(M.P. = 223C with decomposition). The structure was confirmed
by NMR analysis.
XAMPLE 52
5- ~ 4-methyl~l-piperazinyl )carbony~-6-nitro-1 ,4-benzodioxane
hYdrochloride
.
360 m~ of methyl ethyl ketone and 16 9 of N-methyl
piperazine were introduced into a 500 ml balloon flask provided
with a stirrer and a thermometer. The mixture was cooled to
10C then~ 36.5 9 of 6-nitro-1,4-benzodioxane-5-carbonyl
~; chloride were added in portions. The mixture was maintained
under stirring at ambient temperature for one hour. The pre~
eipitate was dried oFf, washed with 150 ml of methyl ethyl
ketone, dried and then dissolved in 210 ml of cold water. The
solu~ion was acidified ~o pH-l by addition of hydrochloric
acid, treated with carbon black and filtered. The base was
precipitated by addition of lS ml of soda lye. The precipitate
was washed with water and dried. 24 9 were obtained. (M.P. -
221C).
The base was then treated with 168 ml of ethanoi
containing ~ ml of water and 8 ml of hydrochloric acid
(d _ 1.18). After crystalliza~ion~ the solid was filtered off,
washed, dried. 19.5 g of 5- ~ 4-me~hyl-1-piperazinyl)carbony ~-
6-nitro-1,4-benzodioxane hydrochloride was obtained. (M.P. :
205C with decomposition~ The structure was confirmecl by NMR
analysis.
~ 53 ~
~ 3'~
EXAMPLE 53
N-diethyl-7-cyclohe~ moyl-1,4-benzodioxane-5-carboxamide
.
7-cyclohexylsulfamcyl-1_,4-benzodioxane-5-carbo~ylic acid
250 ml of water and 300 m1 of cyclohexylamine were
put into a 1 liter balloon flask. 13g 9 of moist 7-chloro-
sulfonyl-1,4-benzodioxane-~-carboxylic acid were added by -~
fractions, the temperature being maintained at from 20 to 30C.
- The mixture was stirred at room temperature for 3 hours then
the solution was treated with 30 9 of carbon black 35. After
filtratio~, 300 ml of hydrDchloric acid (d = 1.18) were added.
The precipitate was recrystalli~ed, washed with water, dried.
92 9 of 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxylic
acid were obtained. (M.P. ; 150C).
N-diethyl-7-cyclohexylsulfamoyl-194-benzodioxane-5-carboxam;de
34.1 9 of 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-
carboxylic acid, 35 ml of water and 10.5 9 of triethylamine
were introduced into a 250 ml balloon ~lask provided with a
stirrer and a thermometer. 100 ml of acetone were added and
the mixture was cooled to 10C. 14 g of isobutyl chloro-
formiate were added and the mixture was maintained under
stirring for 30 m~nutes at room temperature. 8 9 of diethyl-
amine were introduced at a temperature of from 15 to 20C.
After stirring during 3 hours, the solvent was removed under
vacuum. The residue was washed with water, dr~ied, dissolYed in:
180 ml of absolute ethanol and treated with 3 g of black`
carbQn. After filtration3 crystallizationp 23 9 of N-diethyl-
7-cyclohexylsulfamoyl-1~4-benzodioxane-5-carboxamide were
obtained. (M.P. : 201C). The structure was con~irmed by IR
and NMR analyses.
~ 30 EXAMPLE 54
- N-(4-methyl-1-piperazinyl)~7-nitro 1,4-benzodioxane-5-
carboxamide, hydrochloride __
:
- 54 -
~ 3'~
7-nitro-1,4-benzodioxane-5-carbonyl chlori~e
112 ml of thionyl chloride, 56 9 of J-nitro-l 94-
ben~odioxane-5-carboxylic acid were introduced into a 250 ml
balloon flask provided with a stirrer, a thermometer and a
reflux condenser. The mixture was stirred and 1 ml of
dimethylformamide was added with heating. After stirring for
1 hour at ~he reflux temperature, the excess o~ thionyl
chloride was removed by distillation under vacuum. 61 9 of 7-
nitro-1,4-benzodioxane-5-carbonyl chloride were obtained.
(M.P. : 108C, yield near 100%).
N-(4-methyl-l~piperazinyl)-7-nitro-1,4-benzodioxane-5-
carboxamide
33 9 of 1-amino-4-methylpiperazine were dissolved in
630 ml of methyl ethyl ketone. The mixture was cooled to 10C
and 61 g of 7-nitro-1~4-benzodioxane-5-carbonyl chloride were
introduced by portions. The mix~ure was stirred for 2 hours
then the solid was filtered off, washed wi~h 150 ml of methyl
ethyl ketone~ The obtained product was purified by transfor-
mation in~o the base (M.P. : 212C) and crystallization by
~- 20 treatment with hydrochloric ethanol.
45 9 of N-(4-methy~ piperazinyl)-7-nitro-~,4-benzo-
dioxane-5-carboxamide were obtained. ~M.P~ = 210~ with one
mole of water~. The structure was confirmed by NMR and IR
analyses.
EXA~PLE 55
N-(l-allyl-2-pyrrolidylmethyl) 6,7-az;mido-1,4-benzodioxane-5-
carboxamide, h~drochloride
1,4-benzodioxane-6,7-dinitro-5-carboxylic acid
165 ml of nitric acid ~d - 1.49) were put into a 500
ml b~lloon flask provided with a mechanical stirrer and a
thermometer. 90 g of 1,4-benzodioxane-5-carboxylic acid ~ere
added a~ -10C. The mixture was maintained for 2 hours at room
- 55 -
~ t_......
` .
temperature, then 1 liter iced water was added. The precipi-
tate was filtered ofF, washed with water, dried at 50C, ~hen
" purified by recrystallization in the acetic acid. 87 g oF 1,4-
benzodioxane-6,7-dinitro-5-carboxylic acid were collected.
(M.P. : 211C).
1,4-benzodioxane-6,7-diamino-5-carboxylic acid
135 g of 1,4-benzodioxane-6,7-dinitro-5-carboxylic
acid, 500 ml of water, 50 ml o~ soda lye were introduced into a
1 liter autoclave and hydrogenated under a 80 kg pressure in
presence of Raney nickel. The mixture was heated to 100C for
2 hours then cooled, filtered; the nickel was washed on the
filter with 200 ml of water and the filtrates were kept all
together. A sample was acidified with the hydrochloric acid to
form the 1,4-benzodioxane-6,7-diamino-5-carboxylic acid di-
hydrochloride which was filtered, washed and dried. (M.P. -
153C).
1,4-benzodioxane-6,7-azimido-5-carboxylic acid
The above obtained filtrate was introduced in a 2
liter balloon flask provided with a mechanical stirrer and a
thermometer. A solution of 35 g of sndium nitrite in 70 ml of
water was added dropwise at a temperature from 20 to 25C. The
crystallized product was filtered off, washed with water, dried
at 50C. 96 g of 1,4-benzodioxane-6,7-azimido-5-carboxylic
acid was obtained (yield 87%). The structure was confirmed by
NMR analysis.
1,4-benzodioxane-6,7-azimido-5-N-phthalimide carboxylate
74 g of the 1,4-benzodioxane-6,7-azimido-5-carboxylic
acid, 1 liter of dimethylformamide, 57 g of N-hydroxyphthal-
imide, 74.5 g of dicyclohexylcarbodiimide were heated at a
temperature of 9~C for 30 minutes. After cooling to 20C, the
crystals were filtered off, washed with 150 ml of dimethyl-
; - 56 -
t
~ 3'7~
formamide. The filtrates were evaporated under vacuum and the
residue was treated with 400 ml of methanol. The solid was
filtered, washed and dried. 80 g oF 1,4-benzodioxane-6,7-
azimido-5-N-phthalimide carboxylate were obtained. (M.P. :
above 250C - yield 65.6%).
N-(l-allyl-2-pyrrolidylmethyl)-6,7 azimido-1,4-benzodioxane-5-
carboxamide, hydrochloride
92 9 of 1,4-benzodioxane-6,7-azimido-5-N-phthalimide
carboxylate, 500 ml of dimethylformamide were introduced into a
1 liter balloon flask provided wi~ha mechanical stirrer and a
thermometer. 45 9 of 1-allyl-2-aminomethyl pyrrolidine were
added under stirring which was maintained at room temperature
for 2 hours. After evaporating of the solvent, the residue was
treated with 500 ml of hot acetone. After filtration, 50 ml of
an ethanolic solution of hydrochloric acid were added to the ;
filtrate. The product was filtered, washed, recrystallized.
50 9 of N-(l-allyl-2-pyrrolidylmethyl-6,7-azimido-1,4-benzo-
dioxane-5-carboxamide hydrochloride were obtained. (M.P. :
255C). The structure was confirmed by IR and NMR analyses.
EXAMPL~ 56
5- ~4-methyl-1-piperazinyl)carbony ~-6,7-dinitro-1,4-benzo-
dioxane
1,4-benzodioxane-6,7-dinitro-5-N-phthalimide carboxylate
54 g of 1,4-benzodioxane-6,7-dinitro-5-carboxylic
acid, 400 ml of dimethylformamide were introduced in a 1 liter
balloon flask provided wit;h a mechanical stirrer, a thermo-
meter. 34.2 9 of N-hydroxyphthalimide, 44.4 9 of dicyclohexyl-
carbodiimide were added under stirring. The mixture was heated
to 90C for 30 minutes, then cooled to 10C. After filtration,
the filtrate was reduced under vacuum and the residue re-
crystallized in the methanol. 67.5 9 of 1,4-benzodioxane-6,7-
dinitro-5-N-phthalimide carboxylate were obtained. (M.P.
; 225C - yield : 81.3%).
- 57 -
~ 3~ ~
5- ~4-methyl-1-piperazinyl)carbony ~-6,7-dinitro-1,4-benzo-
dioxane
-
67 9 of 1,4-benzodioxane-6,7 dinitro-5-N-phthalimide
carboxylate were dissolved in 400 ml of dimethylformamide. 20
9 of N-methylpiperazine were added and the mixture was stirred
for 2 hours. After evaporating of the solvent under vacuum,
1 liter of water was added to the residue. The solid was
filtered, recrystallized in the dimethylformamide. 40 g of 5~
~4-methyl-1-piperazinyl)carbony ~-6,7-dinitro-1,4-benzodioxane
were obtained. (M.P. 254C). The structure was confirmed by
NMR analysis.
EXAMPLE 57
N-(l-piperidinopropyl)-6,7-diacetamino-1,4-benzodioxane-5-
carboxamide
In a same manner as described in the Example 53, the
6,7-diacetamino-1,4-benzodioxane-5-carboxylic acid ~prepared by
acetylation of the 6,7-diamino-1,4-benzodioxane-5-carboxylic
acid) was condensated with the l-piperidinopropylamine in the
presence of the isobutyl chloroformiate. The N-(l-piperidino-
propyl)-6,7-diacetamino-1,4-benzodioxane-5-carboxamide was
obtained. (M.P. - above 260C with decomposition). The
structure was confirmed by NMR analysis.
EXAMPLE 58
5- ~4-methyl-1-piperazinyl)carbony ~-7-amino-1,4-benzodioxane
- - .
In a same manner as described in the Example 2, the
7-amino-1,4-benzodioxane-5-carboxylic acid was treated with the
methanol, then the obtained carboxylic ester had reacted with
;~ the N-methylpiperazine. The 5- ~4-methyl-1-piperazinyl)-
carbony ~-7-amino-1,4-benzodioxane was obtained. (M.P. :
170C).
EXAMPLE 59
N-(l-ethyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide,
hvdrochloride
- 58 -
~ 3~
In a same manner as described in the Example 17, by
reaction of the l,4-benzodioxane-5-carbonyl chloride with the
l-ethyl-2-aminomethyl pyrrolidine, the N~ ethyl-2-pyrrolidyl-
methyl)-1,4-benzodioxane-5-carboxamide hydrochloride was
obtained. (M.P. : 149 - 150C).
The structure of the compounds prepared according to
Examples 1-59 is illustrated in Table I.
. ~ ~
- - - - - -
I 1~ I
N ~) I ~) 1~~) \~ ~_) I
I N I :~: Z I I :~ N
C~ ~ ~) ~)~ t_) ~) ~ ~ .,
_ .__ ___
r\ r~ r\ r~ I~ r\ r
.~ 2 4z- ~ 4z- 4 1~- 42- 4
. ~ I ~ I I I I N
':' ~ ~ ~ l ~ ~ ~ ~
:~ ~ ~Z~
:~ _ _
_ I I I I Z I I
. _
.-.
LLI C~l ~1 N N C~l C~l C`~ C~l
_l ~ ~ ~ ~ ~ __ _~ ~
~:1 N N N N N N C~l N
c~ ~: I I I I T I I I
i- ~ ~ ~ ~ ~ ~ ~ ~
l l l l l l l l
~1 I I: I I I I I
''
``~ _ _ .
. C`~ .
I IS) I
>_ I I I I V I I I
t~l C~l C~.l C~.l N N C`.l
O O O O O O O
V~ ~ V') ~ t~) ~rl 1~)
;~ _ _ __
: ~ :
X I I I I I I I
` , _ _ . I
X
,; ~ __ ~I ~ _ ~D W _____
- 60 - .
r - -
- rT~ r~
N I: I ~) C~l I ~) I I
C~l C~l ~ I C~l T
C_~ C~ C_) C_~ C~ C_~ C_~ C~
~ ~- ~z [~z- [~z- ~ ~ 4\- ~ ~z
I I I I I I l I
C~ i C~ C~ C_) I C~
I
_ l
'." _
~ I I I I I I I I
_
~ l l l l l l l '
l C~l C~J C~ ~ C~l C~l C~l ~ .~
C~ C~l C~l C~l C~l C~ C~l C~i
~: I ~: I I I I I I
C~ ~ C~ C~ C~ C~ C~ C~
~ _~ _~ ~_ ~ _ ~_ _~
_ _ _
., . ~':
1~1 I I I I I I I I
.
I C~ ~: C~ l I Z I C~
' C~ C~ C~l C~ C~
cn cn cn cr~ co
:~ __ _ _ _ .
X I I I I I I I I : ~
,' X ~ __ ___ . :.
L~.l _ O ~y
:, C~ ~ ~ ~1 1~) U:) r~ cx~
.. O C~ ~--N __ _'
`,:
6 1 -- !
., :
3~
~NT ~ T-~I
r ~ ,~ I _c C~l ~) I
I C~l N I I C~J C~
~, `r' ~, ~, ~, ~, ~ ~)
__ , _
~< ~:~ C ~ ~Z- ~2:- ~-_ ~_ L~;Z- C~-
I 2 - I I I _c I
'~ '-' I -1' '-' '~ '~ ~ ~ ~ ..
___ ._
_ .,
C~ _c _c _c I I I _C I
Z 2 ;i~: Z~ 2: :~Z 2 Z 2
__ __ _ ''--I
l l l l l l l
N ~ ~ N ._
C~l C~J N C~l C~J N C~l l
~: I _c I I I I ~ C`~l
. ~ (-~ ~) ~ ~ C_~ ~ C~
':, _, _ _ _ _ _ ~_ ~)
.'
:.'
,: _ _ __ _
.
..
1~1 I I _c _c I I I I
_ _ _ _ _ ._
_. N
I I _c _c I I I
. C~ ~ ~ ~ t~ C_~ ~
>- _ I _ I _c I I
Z Z 2 2 2 Z 2:
N C~J N C~J C~J C`J C`~l
O O O O O O O
'~ ~ U~ ~ V~ U~ Ln ~
.~ _ __ _ ____._
" ~ ~ ~ __ _ _
. ' .
X I I I I I_c I I
'~ ___
.~ . _ _ _ _ ~ _I ____ . .
X ,_~
LL~
c~ O ~ _,_ _~_~_~, a~ ~
O r~ C~l C~l C~l C~l
~ C~l ~ ~
l C~J N C~ .l
~_ ~ _ _ . _. ___ _~ . .
- 62 -
__ - __ __ .__ ,__ _ _
I I, ~ C`J C~l
~ ~ ~ C~ ( ~ J J ~ ~
_ 2 ;Z 2 ~ . _ _ l : '
I
_ 2 I I I
l ~ l l
___ ____ ~ __~ ~
_ ~ ~ ~ ~ ~ N
C~l C~l C~J C~l N C~J C~l N
ct I I I I I I I }:
C_) ~ C~ ~ (~ ~ ~ ~ ~'
~ ~ ~ ~ _,~ _ _ _~ _~ ; ~
~, ___ _ _ _ ~'
I~J I I I I I I I I : ~
r~r~ r~
. ~ O N O O O
'~` V~ 2: ~ U~ V~ - ~'
'.', __ ~ _ __ _ ' '
X I I I I I O O I
1~ _ . . .................. ., '
O ~ C~J ~ ~ ~ ~ I~
: aC ~ _ _ __ ~ ~ __ _ _ __
_
- 63 -
,. . , ;
~ . . . .
~ ~ ~ ~: ---- ~ ------- -- --
~ T _ T ~ ~ r
:'` ~ __ I
2 T I~3 I I ~: I
. I Z ... .. ~ _
l I l l l l _
:: ~ N N ~ ~ . _. ~ ~
~: t~l C~J C~J C~l C`J N C~l C~l
I I I I I I I I
''' ~ ~ ~ ~ ~ ~~~ V ~
~`J I I I I I I ~
___ _ .__ . ___ _ ___
I (~ I
:~- ~_ I I Z I I CCI
N O O O
_ _ _ _~ ~
.` X I I I I I I 2 O
1~1 _ ___ _ _
0~ O~ O ~ ~ ~t ~
0~ ~ ~ __ ~ ~ ~__~
- 64 -
.
,
3~71
~r I ~ T ~A
~ C~J T C~l C~l I I
.) ~ ~ t~ ~ t_~ .,
_ U~
~:: ~ ~ ~: _~ ~: I
Z l _ z _ 1~ N . V
. I 1 ~ ~J I
. ~z~ N ~2~
_ l ~ ~q T
Z I I 2 T ~ N .
C~l C~ C~l C~l . ~ C`.l C~l N
C~ _~ ,_ _ ~ ~ ~ ~_ _~
:~C I X 3: ~ I I T
L:l <_~ ~ ~ <~ 1~ 1_~ ~7 '
C~l
1~1 I I _, I 3: 2 I
': _ . __ ,i':''',':
C~l . ~ .''~
~ :~ I I Cl I I ~ ; I _ ~ 1 ~
~ 'F o
_ N T I _ _ ::
X I _ T T 2 ~ I
1-~ _ __ Z 2 ~ __
~D ~ C~ O~ O - C~ ~r7
C .:r ~ C` t U~ U~ ~ _~ ~.~
, . ~
- 65
lZ ~ ~- ~
(~
.
a:: I I I I
____ _ .
~ N ~ ,_ _
cl I T I I I I
, ~ ___ _ _
N I
. I 2 I I I
~ _ .... _ I ' .
I
\ ~ ¦ I
O Z--Z N 2 I I
~ '.'-
__ __ __ _
'''
X I I I I I I
~ Lfl ~ I~ 00 ~
0~ ~ D ~ 0 10 ___. .,
'
- 66 -
3`7:~
Compounds according to the invention are used under
various forms such as capsules, tablets, pills, granules,
injectable solutions, the preparation of which are known per
se. Substances that do not react with ~he compounds may be
used, e.g. lactose, magnesium stearate, starch, talc, cellu-
loses, levilite, alkali metal lauryl su-l~ates, saccharose and
other vehicles used in medicinal preparations.
Compounds according to the in~/ention may be adminis-
tered at dosages of 50 to 900 mg per day. It is advantageous
to use 50 to 300 mg per day and preferably about lO0 to 150 mg
per day.
The following examples concern pharmaceutical compo-
sitions prepared by a method known per se ~ wi th the compounds
. .. .
of the invention.
EXAMPLE 60
Tablets of the following composition are prepared:
form l form 2 form 3
N-(l-ethyl-2-pyrrolidylmethyl)-7-
methylsulfamoyl-1,4-benzodioxane-
5-carboxamide...........................50 mg 50 mg 50 mg
Dried starch............................ 30 mg 30 mg 20 mg
Lactose................................. 80 mg 80 mg 120 mg
Methylcellulose 1500 cps...............1,3 mgl,2 mg li2 mg
Magnesium stearate..................... 3 mg 2,5 mg 3 mg
Levilite................................................. 8 mg 6,3 mg 5,8 mg
EXAMPLE 61
; Tablets ~f the following composition are prepared:
N-(l-methyl-2-pyrrolidylmethyl)-7-methyl-
sulfamoyl-1,4-benzodioxane-5-carboxamide............................. 50 mg
Dried starch......................................................... 2G mg
Lactose.............................................................. 80 mg
Methylcellulose 1500 cps............................................ 1,3 mg
Levilite.............................................................. 6 mg
; Magnesium stearate.................................................... 3 mg
- 67 -
- - ~
~L~ 3'7 ~
EXAMPLE 62
Tablets of the following composition are prepared:
Form 1 form 2
N~ allyl-2-pyrrolidylmethyl)-7-methyl-
sulfamoyl-1,4-benzodioxane-5-carboxamide.... 50 mg S0 mg
Dried starch........ ~............................ 15 mg 10 mg
Lactose.......................................... 50 mg 62 mg
Methylcellulose 1500 cps.................... .1 mg 1 mg
Levilite.................................... .5 mg 5 mg
10 Magnesium stearate............................ .2 mg 2 mg
EXAMPLE 63
Tablets of the following composition are prepared:
N-(l-methyl-2-pyrrolidylmethyl)-7-
sulfamoyl-1,4-benzodioxane-5-carboxamide................... 50 mg
Dried starch............................................... 10 mg
Lactose.................................................... 50 mg
Methylcellulose.......................................... 0,94 mg
Levilite.................................................... 6 mg
~agnesium stearate.......................................... 2 mg
EXAMPLE 64
Tablets of the following composition are prepared:
N-(l-methyl-2-pyrrolidylmethyl)-7-ethyl-
sulfonyl-1,4-benzodioxane-5-carboxamide.................... 50 mg
Dried starch............................................... 10 mg
Lactose Codex.............................................. 50 mg
Methylcellulose 1500 cps................................. 0,55 mg
Levilite.................................................... 4 mg
Magnesium stearate.......................................... 2 mg
EXAMPLE 65
Capsules of the following composition are prepared:
N-(l-ethyl-2-pyrrolidylmethyl)-7-ethyl-
sulfonyl-1~4-benzodioxane-5-carboxamide...~................ 50 mg
Dried starch............................................. .. 15 mg
Lactose.................................................. .. 50 mg
- 6~ -
' ' ,
3'~L
Methylcellulose 1500 cps................................... 1 mg
Levilite................................................... 5 mg
Magnesium stearate....................................... 2,5 mg
Tablets are prepared by mixing the elected compound
with starch and lactose by successive dilutions method.
Granules are prepared from the mixture and methylcellulose.
; Levilite, magnesium stearate and talc are added to granules
before compressing. Methylcellulose may be replaced by any
suitable granulating agent such as ethylcellulose, polyvinyl-
pyrrolidone,starch paste, gum-arabic...
Starch may also be replaced by another partition
agent such as maize-starch, carboxymethylic amyloids, algi- i
nates, microcrystalline cellulose
Injectable solutions may be prepared by dissolving a
compound according to the invention in the following acids:
hydrochloric, levulinic, gluconic or glucoheptonic acids.
The solution pr~pared under sterile conditions is
made isotonic by an alkali metal chloride such as sodium
chloride, then preservatives are added.
The same solution may be prepared without preserva-
tives: the ampulla is filled under nitrogen atmosphere, then
sterilized half an hour at 100C.
The compounds of the invention have attractive anxio-
lytic, psychostimulant, disinhibiting and indeed thymoanaleptic
effects giving rise to properties suitable for therapeutic uses
in the psychofunctional sphere and in particular in gastro-
enterology, cardiology, urology, rheumatology and gynecology
Their low level of toxicity is compatible with use in
human therapy, without the danger of secondary effects.
Ihe acute toxicity of the compounds of the invention
was determined in Swiss mice by parenteral (intravenous, intra-
- 69 -
3'7~
peritoneal and subcutaneous) and by oral administration.
.: Lethal doses 50 are shown in Table II.
The numbering of the compounds in the following
tables corresponds to the numbers of the examples.
.' :
:~ TABLE II - TOXICITY
. _
pound IV LD 50 - MI( SC ~
1 171,5-172 522-540 1344-1440 _
2 48-49,6 312-320 594-624 0% at 3000 mg/kg
3 120-120,4
5220,8-225,6 ~:~
7 96,6-100 _ _
: 8 84,6-90 322-328 1450-1485 35% at 2Q00 mg/kg
10 150-157,5 350-363 1260-1360 :
.
-.~ 11 168-184 442-450
12 147-154 480 1225-1230 1400-1470
13 64-67,5 234-240 430-437 0% at 3000 mg/kg . :
14 146-157 325-338 420-442 2900-3491
.:
. 15 79,7-86,2 224-227 572-613 756
16 88-96 380-396 925-1014 2760-2900
17 49,1 241 575 544-679
72,5-76 180-184,5 476-499,5 1190-~2Q0
21 196-208 .
_
~: 22 83,6-86
. ,~, _
. 23_ 115,5-126 _
.~ 24 216-232
. 25 160-168
26 lQ5-116
27 80-83,6
_ _
28 141-154 387,5-418 ~620-~850 2~00-2400
29 ~64-~75 896-957 960 ~560-1600
- 70 -
~ 3''~
The compounds of the invention are moreover virtually
devoid of cataleptic activity. They were administered subcu- ;
taneously to rats. The criterion in respect of the cataleptic
state was immobility of the animal for 30 seconds, the front
limbs of ~he animal being spread apart an~ arranged carefully
on wood cubes which were 4 cm in height, thus putting the
animal into an unusual and uncomfortable position. Cataleptic
activity was measured at the maximum of the effect. The -~
results are given in table III.
TABLE III - CATALEPTIC ACTIVITY
. . .
; Compound ED 50 SC - Rat - mg/kg
.
1 Effect of 40% at 200 mg/kg
2 Inactive...... at 200 mg/kg
3 325
Effect of 30% at 200 mg/kg
; 7 Inactive...... at 200 mg/kg
8 Effect of 10% at 200 mg/kg
Inactive...... at 200 mg/kg
11 Inactive...... at 200 mg/kg
12 Inactive...... at 200 mg/kg
; 13 Inactive...... at 200 mg/kg
14 Effect of 10% at 200 mg/kg
Inactive...... at 200 mg/kg
1~ Inactive...... at 200 mg/kg
17 38g
Inactive...... at 200 mg/kg
21 Inactive...... at 200 mg/kg
24 Effect of 30% at 200 mg/kg
Inactive...... at 200 mg/kg
28 Inactive...... at 200 mg/kg
39 Inactive...... at 200 mg/kg
- 71 -
,
3'7~
From these results it will be seen that the compounds
of the invention are virtually devoid o~ ca~eleptic activity in
a rat. This property permits clinical usage of the compounds
of the inventionS with a high degree of tolerance in respect of
the extrapyramidal system. The compounds of the invention are
also found to be particularly ac~ive in a dog in respect of the
central emetic agents such as apomorphine. The experimental
procedure followed was that of CHEN and ENSOR. The compounds
,
of the invention were administered subcutaneously 30 minutes
before apomorphine (100 ~n/kg/SCJ, the animal was observed half
an hour after the injection of the alkaloid. The results are
given in table IY. ;;
',, . .:
TABLE IY - ANTIEMETIC ACTIYITY
_ _ ~.:
Compound ED 50 ~g/kg/SC - Dog
,, i:"
1 Effect of 81%at 5 ~g/kg/SC
3 5,~
~: ~ 12 3,5
14 3,9 ``
3~
16 2,3
~0 3,5
21 4 .
~ .? - 72 -
:' ' ,' ~' '~ ,, . '
~ '7~
The interest aroused by the experiments carried out
on laboratory animals has been found to be very largely justi-
fied when carrying out human clinical tests of ~he compounds of
the invention.
The following can be quoted by way of example:
- the case of a 38 year old pat;ient suffering from
Hodgkins disease; subjected to repeated chemotherapy as an out-
pa~ient, once a week; each session was accompanied by fits of
nausea and then very substantia1 vomiting, persisting for 24
hours in spite of the usual treatments.
Treatment, 24 hours before the beginning of the
per~usion and 4 hours afterwards9 with 50 mg of N~ ethyl-Z-
pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carbox-
amide totally suppressed the nausea and vomiting att~cks.
The product was perfectly well tolerated, and no
secondary ef~ect was observed.
- a 28 year old da~a proce~sing engineer suffered
from a charac~erial neurosis with bouts of anxiety culminating
in three attempts at suicide. Analytical treatment for 18
months made it possible to achieve social reintegration but had
little effect on the anxiety aspect.
The administration of 50 mg of N-(1-methyl-2-
pyrrolidylmethyl~-7-methylsulfamoyl-1,4-benzodioxane-5-
carboxamide three times per day~ caused in a few days the
complete disappearance of any anxiety, without any troublesome
sedative action.
The product was perfec~ly well ~olerated~ and no
secondary effect was observed.
a 7~ year old subject had been su~fering for 8
mon~hs from seYere reactional depression ~close bereavement).
The existen~e Df a prostatic adenoma contraindicated the use of
yc7ics.
73 -
,
~ 3~
He was treated three times a day with 50 mg of
N~ methyl-2-pyrrolidylmethy1)-7-methylsulfamoyl-1,4-benzo-
dioxane-5-carboxamide, and in three weeksl as his condition had
substantially improved, he was able to leave hospital. The
treatment, which has been continued at home ~or 3 months, makes
it possible to maintain an excellen~ psychic balance, with the
resumption of normal act;vity ;n a retired person of this age. ~
The product was perfectly well tolerated, and no ~ ~ ;
secondary effect was observed.
- a 42 year old subject underwent a hysterectomy for
a fibroma 6 months ago. Some days after the operation, hot
flushes (10 to 20 a day) appeared with attacks o~ sweating
which awoke the patient during the night and caused her to be
embarrassed during her work.
She was treated with the N~(l-ethyl-2-pyrrolidyl-
methyl)-7-methylsulfamoyl-1,4-benzodioxane-~-carboxamide at a
single dose of 100 mg a day, the symptoms disappeared within 4
- days. Only one hot flush still persisted during the day
occurring every 2 or 3 days.
The product was perfectly well tolerated, and no
side-effects were observed.
- a 47 year old patient suffered, after the meno-
pause, from repeated attacks of cystitis with frequency and
severe urgency such that no social life was possible. Thë
patien~ consulted general practitioners and specialists~ All
the tests were negative and all treatments were without effect
în this classical case of cystitls.
She was treated for some days wi~h the N-(l-methyl-2-
pyrrolidylmethyl)-7-methylsulfamoyl-1~4-benzodioxane-5-carbox-
amide at a dose of 150 mg a day and the symptoms completely
disappeared and her psychological st~te became normal~
74
.;.. .. .
