Note: Descriptions are shown in the official language in which they were submitted.
l;
76~1Z
'.-. :.'
The present invention relates to benzamides. More
particularly, the invention is concerned with benzamide
derivatives, a process for the manufacture thereof and
~ pharmaceutical preparations containing same.
;1 The benzamide derivatives provided by the present ~ ~-
invention are compounds of the general formula -
,' ~',''. ':
~` I { ~ NH CH2 CH2 N ~I)
! \_=:= ( ~/ ~ ' : ,'
Y
~ wherein X represents a halogen atom or a trifluoromethyl or `~
```'~ C3 4-alkyl group and Y represents a hydrogen or halogen atom ; -
~; 10 or a nitro group, and N-oxides and pharmaceutically acceptable -
- acid addition$ salts thereof.
A halogen atom denoted by X or Y is a chlorine,
fluorine, bromine or iodine atom. A C3 4-alkyl group is a
, ~; straight-chain or branched-chain alkyl group containing 3 or
4 carbon atoms, namely n-propyl, isopropyl, n-butyl, isobutyl~
l-methylpropyl or t-butyl.
`~ The compounds of formula I form pharmaceutically
.. . . .
acceptable addition salts with organic or inorganic acids
at the nitrogen atom of the morpholino radical. Examples
; 20 of such salts are hydrohalides
. ~`1,
.' ': '. ' ~ ~:
,, ,:
:. - ' .
.,
~- ,
- 2 -
, . .
-, " , , , : -
.. . .
76~L1Z ~ ~
:
(e.g. hydrochlorides), phosphates, alkylsulphonates (e.g. --~
ethanesulphonates), monoarylsulphonates (e.g. toluene-
sulphonates), acetates, citrates, benzoates and the like.
.~ . .
Preferred benzamide derivatives provided by ~his
invention are those ln which X represents a halogen atom.
Also preferred are those benzamide derivatives in whlch Y
.:
represents a hydrogen atom or a nitro group.
~:
The following are particularly preferred benzamide
derivatives of this invention:
. . : :
.- ~ .
p-Chloro-N-(2-morpholinoethyl)-benzamide,
. i
~ ~ p-fluoro-N-(2-morpholinoethyl)-benzamide, ~ ~
.:.. ~ . ,
p-bromo-N-(2-morpholinoethyl)-benzamide,
p-iodo-N-(2-morpholinoethyl)-benzamide,
4-chloro-N-(2-morpholinoethyl)-2-nltrobenzamide.
,j ~ ,,' .
~ ~ 15 Other preferred benzamide derivatlves of this invention
. I ~ . , .
l~ are:~ -
- a,a,~-Trifluoro-N-(2-morpholinoethyI)-p-toluamide,
p-t-butyl-N-(2-morpholinoethyl)-benzamide,
2,4-dichloro-N-(2-morpholinoethyl)-benzamide,
; ~20 p-chloro-N-(2-morpholinoethyl)-benzamlde N'-oxlde.
According to the process provided by the present
invention, the aforementioned benzamide derivatives (i.e. the
. ' r~ pf~r~ ce~f~ca//~ a
~ ~ compounds of formula I and N-oxides and~acid additlon ~alts
- thereof) are manufactured by
,
. ~ - .
., ~ , ,.
; - 3 -
.
076~LZ ~ ~;
,~ ~, .
- (a) reacting N-(2-aminoethyl)-morpholine with an acid of the
general formula
X ~ COOH (II)
:' ~ '. '
,':;' \ - '
.'~ Y , .- .
;~,
. ~ .:, : ' , .
, wherein X and Y have the significance
. given earlier,
.~.,
or wlth a reactive functional derivative thereof selected from halides, ~ .
` symmetrical and mixed anhydrides, esters, azides and amides,
or
(b) reacting morpholine with a compound of the general
10 formula : :~
'; :
': :,,
X--~ CO--N--CHl--CH~ ;
, wherein X and Y have the significance
: I given earlier, Rl represents a hydrogen
atom and R2 represents a halogen atom, or
Rl and R2 together represent an additional ' ;;
bond,
! ~ I :
or
l (c) oxidislng a compound of the general formula
..;
:
~ X--~CI~=N--CH2--CH2--N ~O
y
:: :
- ' ' ~ ' ` ~ ',' ' . . . : ': ' '
. . .
: ':, , . ` ` ` . .
L07~
, wherein X and Y have the significance ~ .
given earlier,
or
.~ (d) converting a thioamide of the general formula - ::
~ ~ X~--CSNH--CH~--Cll~ / \0 (v)
:'' ~' ,'"'~''
.
, wherein X and Y have the significance .
given earlier, -
. ~ into the corresponding amide, ~ - .
. .~ or ~ ~:
~10 (e) converting the grouping -CEI=~- in a nitrone of the :~
~ : general formula ~: .
'~ ; ':: '
~(~CH=hl--CH2--CH2--N~0 (VI)
Y . :.
, wherein X and Y have the significance
; ` given earlier,
into the grouping - C-NH- and, if desired, oxidising a resulting compound
of formula I to the corresponding N-oxide or converting a resulting ; ;
compound of the farmula I into an acid addition salt.
. Halides of the acids of formula II are e.g. chlorides,
'i: ,.
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;;,::' '.`, '" .
, .: '
.:~ ;, ..
:.:, ~ .. .
' :
~: r~ ~
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, . ,
esters are e.g. methyl esters, p-nitrophenyl esters or N-hydroxysuccinimide
esters, and amides are e.g. imidazolides or succinimides.
The reaction of N-(2-aminoethyl)-morpholine with an acid of
.. , ; ,
formula II or a reactive functional derivative thereof (as defined above)
according to embodiment (a) of the present process can be carried out
according to methods which are customary in peptide chemistry. Thus, for
example, a free acid of formula II can be reacted with N-(2-aminoethyl)- ~-
morpholine in the presence of a condensation agent in an inert solvent. ;~
If a carbodiimide (e.g. dicyclohexylcarbodiimide) is used as the
condensation agent, the reaction is appropriately carried out in ethyl
. . . -: .
acetate, dioxan, methylene chloride, chloroform, benzene, acetonitrile or
dimethylformamide at a temperature between about -20C and room temperature,
:
preferably at about 0C. If phosphorus trichloride is used as the
condensation agent, the reaction is appropriately carried out in a solvent
. .. :
`~ such as pyridine at a temperature between about 0 C and the reflux ~
.. ~ :
; temperature of the reaction mixture, preferably at about 90 C. In another
aspect of embodiment (a), N-(2-aminoethyl)-morpholine is reacted with one
~- of the above-mentioned reactive functional derivatives of an acid of
~: . : : .,: ~ . .... ..
formula II. Thus, for example, a halide (e.g. the chloride) of an acid
:~ 20 of formula II can be reacted with N-(2-aminoethyl)-morpholine in the
.. ' . .
~ presence of a solvent (e.g. diethyl ether, pyridine or water) at about
o
O C .
;~ The compounds of formula III in which Rirepresents a hydrogen
~ atom and R2 represents a halogen atom are N-(2-haloethyl~-benzamides
. ~ : .
; such as p-chloro-N-(2-chloroethyl)-
,
-- 6 --
' '
. .
~ 1~761~Z
` ~
-benzamide and the like. The compounds of formula III in
which Rl and R2 together represent an additional bond are
benzoylaziridines (e.g. p-chloro-benzoylaziridine and the like).
According to embodiment (b) of the present process
morpholine can be reacted in a manner known per se with a
. . .
compound of formula III at a temperature up to the reflux
temperature of the reaction mixture, if desired in the presence
of a solvent. If a benzoylazirldine of formula III is used,
;~ the~reaction is preferably carried out at the reflux temperature
of the reaction mlxture in the presénce of an inert solvent
' (e.g. toluene, acetone or benzene). ~ I a N-t2-haloethyl)- ~-
-benzamide of formula III is used, the reaction is preferably
;~ ~ carried out at a temperature of about 100C. - `~
The oxidation of a compound of formula IV according to
embodiment (c) of the present process can be carrIed out in a
,.. ., :
manner known per se using an oxidising agent such as hydrogen
peroxide, potasslum permanganate, an organlc peracid (e.g.
peracetic acid) or a compound which releases hydrogen peroxlde
on solutlon in water (e.g. an alkali metal peroxide or
; 20 persulphuric acld). The oxidation is appropriately carried
out in an inert solvent, (e.g. methanol, ethanol or acetone).
.; ,:
. ~.;
` The converslon of a thioamide of formula V into the
corresponding amide of ormula I according to embodiment (d)
; of the present process can be carried out in a manner known per
se, for example using lead tetraacetate in an inert solvent
(e.g. water) at a temperature up to the reflux temperature of
the reaction mixture, or also using 1,2-butylene oxide, if
:., .';
. ~, .. .
.~ : .
_ 7 _ ~
. ... ...... . . . . . .. . .. . .
.. . . .,, . j , . . , ~ . ,,
, . . .. . ..
761~L2
.. . .
,, ~
appropriate in an inert solvent such a~ a lower alkanol (e.g.
methanol) at a temperature up to the reflux temperature of the
reaction mixture.
.
The conversion of a nitrone of formula VI into a
compound of formula I according to embodiment (e) of the
present process can be carried out in a manner known per se,
;` for example in the presence of acetic anhydride or acetyl
. . :
~ chloride, if appropriate in a solvent such as glacial acetic
:. .
~ acid ~at a temperature up to the reflux temperature of the
- 10 reaction mixture, preferably at about 90~C.
.,
:.,
. ,:, ; ~ , .
A compound of formula I can be converted in a manner
known per se into the correspondlng N-oxide uslng an oxidlsing
., .
`~ agent such as hydrogen peroxide or a peracid (e.g. peracetic
acid) in-a solvent such as glacial acetic acid at a temperature
between about 0C and 50C, preferably at room temperature.
:, :
. . I . ~ .
The starting materials of formulae II~, III, IV, V and VI
are known or analogues of known compounds and can be prepared
by methods known per seO
The compounds of formula 1, their N-oxides and acid
addition salts have monoamlnooxidase (MA0) inhibiting activity.
Because of this activity, the compounds of formula I, their
N-oxides and pharmaceutically acceptable acid addition salts
~ can be used for the treatment of depressive conditions.
..
;`.
The MA0 inhibiting activity of the compounds of the
present invention can be determined using standard methods.
:
,, , . . . , : . . .
07611~:
,:
:,-
` Thus the compounds to be tested were administered p.o. to rats.One hour thereafter the animals were killed and the MAO
lnhibiting activity in the liver homogenates was measured
; according to the method described in Biochem. Pharmacol. 12
(1963) 1439-1441. The activity thus determined of representative
compounds of the present invention and their toxicity can be
seen from the ED50 values (~mol/kg, p.o. ln rats) and LD50
values (mg/kg, p.o. ln mice) listed in the following Table:
- ~ Table
Compound ~ ED50 LD50 ~
p-Chloro-N-(2-morpholinoethyl)-benzamide 5 -
: I ~ a, a, ~-Trifluoro-N-(2-morpholinoethylj-p-
-toluamlde 16 1000-2000
p-t-Butyl-N-(2-morpholinoethyl)-benzamide ~ 16 1250-2500
~p-Fluoro-N-(2-morpholinoethyl)-benzamide 11 1250-2500
p-Bromo-N-(2-morpholinoethyl)-benzamide 6 1250-2500
i`~ p-Iodo-N-(2-morpholinoethyl)-benzamlde 4 1250-2500 -
~'f~ ~ ~ 2,4-Dichloro-N-(2-morpholinoethyl)-benzamide 13 1250-2500
4-Chloro-N-(2-morpholinoethyl)-2-nitro-
~ ~ 20 -benzamide 2
,.' ` . ' ~, :~._ ,,
The toxicity of p-chloro-N-(2-morpholinoethyl)-benzamide
expressed in LD50 (mg/kg, p.o. in rats) is 707 ~ 55 after 10
days.
~-~ ,. .
. .
The compounds of formula I, their N-oxides and their
pharmaceutically acceptable acid addition salts can be used as
medicaments in the form of pharmaceutical preparations which
contain them in association with a compatible pharmaceutical
'; :
_ 9 _
:
' ;- ' . ,',- ' ~.:: ', i , . , . . . , . , ,, , :
:,. ,'., '' ,,' : ;" ' ', ' ~" '
)76~12
. ~ . . .
i~
carrler material. This carrier material can be an organic or
inorganic inert carrier material which is suitable for enteral
` (e.g. oral) or parenteral administration such as water, gelatine,
gum arabic, lactose, starch, magnesium stearate, talc, vegetablè
oils, polyalkylene glycols etc. The pharmaceutical preparations
can be made up in a solid form (e.g. as tablets, dragées,
suppositories or capsules) or in a llquid form (e.g. as
so1utions, suspenslons or emulsions). They may be sterilised
and/or may contain compatible adjuvants such as preservativos,
stabilislng agents, wettlng agents, emulsifylng agents, salts
for modifying the o~motic pressure or buffering agents. They
;~ ~ can also contain other therapeutic substances.
. , .
Appropriate pharmaceutical dosage forms contain ca l to
~; lOO mg of a compound of formula I, a N-oxide thereof or a
lS~ pharmaceutically acceptable acid addition salt thereof.
Appropriate oral dosage ranges are from about O.l mg/kg per day
to about 5 mg/kg per day. Approprlate parenteral dosage
;
ranges are from about O.Ol mg/kg per day to about 0.5 mg/kg
per day. ~hese ranges can be extended upwards or downward ,
~ 20 depending on the individual requirement and the directions
- ~ of the attendlng physician. Oral administratlon is preferred.
:: .
. ,~ '
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., .
',`'` . .
. .-
~
:: .
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~ -- 10 -- ,
,,
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:
:' ~07611Z
.,` : .
The following Examples illustrate the process provided
by the present invention:
.~ .
Example 1
35 g of p-chlorobenzoyl chloride are added dropwise to
!
a solution of 26 g of N-(2-aminoethyl)-morphollne in 200 ml of
pyridine, whilst stirring and cooling with ice-water. There-
.. ~ : .
after the mixtura is stirred overnight at room temperature and
subsequently evaporated to dryness~. The residue ls then
evaporated twice more with 200 ml of toluene each time. The
~ solid residue is taken up in 300 ml of ice-water and 300 ml of
methylene chloride and rendered basic with 3-N sodium hydroxlde
solution~ The phases are separated and the methylene chloride
extract is wa~hed~with water, dried over sodium~sulphate and
evaporated to dryness. The residue is recrystaLlised from
15~ ~isopropanol.~ 41.5 g of p-chloro-N-(2-morpholinoethyl)-
bénz~mLde,~meltlng point 137C, are obt~ined.
The following compsunds were manufactured in an analogous
manner:
a,a,a-Trifluoro-N-~2-morpholinoethyl)-p-toluamide,
melting point 120C to 121C;
,
p-t-butyl-N-(2-morpholinoethyl)-benzamid~, melting point
94C;
. ., . ' ..
p-fluoro-N-(2-morpholinoethyl)-benzamide, melting point
136C to 137C;
~; 25 p-bromo-N-(2-morpholinoethyl)-benzamlde, melting point
140C to 141C;
.''`'` '
.' .
-: , , ~ 11- '
.: . ' " ." ' ' . . . . , ' i,'.,
~1076~
.':,"
p-iodo-N-(2-morpholinoethyl)-benzamide, melting point
160C-
2,4-dichloro-N-(2-morpholinoethyl)-benzamide, melting
point 120C.
"~ :
~xam~
"
,'~d', 13 g of N-(2-aminoethyl)-morphollne are added dropwise
to a solution of 17.5 g of p-chlorobenzoyl chloride in 100 ml
of diethyl ether, whilst stirring and cooling wlth ice-water.
After complete addition the mixture is stirred for 2 hours at
~; 10 room temperature. The crystaIline product is filtered off
and washed with diethyl ether. 9.1 g of p-chloro-N-(2-
morpholinoethyl)-benzamide hydrochloride, melting point 207C
to 208C, are obtained after recryctallisation from isopropanol.
:
~: ,
-: : :
4-Chloro-N-t2-morpholinoethyl) 2-nitrobenzamide hydro-
lS chloride, melting polnt 208C, was manufactured in an analogous
manner.
Exam le 3
.
. ~
10.5 g of p-chlorobenzolc acid anhydride are added porti~nwise
to a solution of 4.55 g of N-(2-aminoethyl)-morpholine in
~; 20 100 ml of pyridine, whilst stirring and cooling with ice-water.
After complete addition the mixture is stirred overnight at
; room temperature and subsequently evaporated to dryness.
- The residue is then evaporated twice more with 100 ml of toluene
,
each time. The solid residue ls taken up in 200 ml of
methylene chloride and 200 ml of water and rendered basic with
'
~ - 12 -
"; - - ,, . , . , . .. .: , , ' -
'
1~17~2
. ~ ` ,. ....
3-N sodium hydroxide solution. The phases are separated and
.
the methylene chloride extract is washed with water, dried
over sodium sulphate and evaporated. The residue is
recrystallised from isopropanol. 4.5 g of p-chloro-N (2-
; 5 -morpholinoethyl)-benzamide are obtained, which is identical
to the product obtained in Example 1.
Ex mPle_4
. ~ , .
~'~. . ,
5.3 ml of chloroformic acid ethyl ester are added dropwise
to a solution of 8.6 g of p-chlorobenzoic acid and 7.6 ml of
triethylamine in 150 ml of acetone, whilst stirring and cooling
with ice-water. After one hour at~0C, a solution of 6.5 g of
N-(2-aminoethyl)-morpholine in S0 ml of acetone is added
.. . . .
dropwise~to the mixture and the mixture is then stirred over- -
night at room temperature. Thereafter it is concentrated,
lS allowed to stand for 2 hours in the refrigerator and then
filtered. The filtrate is evaporated to dryness and the
residue is taken up in 250 ml of water and 250 ml of methylene
chloride. The phases are separated and the methylene chloride
extract is dried over sodium sulphate and evaporated. The
-i . .
residue is recrystallised from isopropanol. 7.8 g of p-chloro-
-N-(2-morpholinoethyl)-benzamide are obtained, whlch is
identical to the product obtained ln Example 1.
~,.;' '
i .
.:,
Example S
,. .
,,'' ,
8.2 g of p-chlorobenzoic acid methyl ester and 6.25 g of
N-(2-aminoethyl)-morpholine are stirred together for 6 hours
,:
-~ at 120C. The mixture is then cooled to room temperature and
,'~ .
- 13 -
.
~,, ,., ' ~' , . , ', ~ ' ',' ;
" ,ii ~ s,,,~,, , "" ,,.,, ,,",, "",,",, ,~, ,., .,, ,.,,, :,,, ,,." ~, , ,
1761~2
,',':.' ,:
40 ml of diethyl ether are added. The mixture is then left to
stand overnight in the refrigerator. The crys~alline product
, . . .
is filtered off, washed with diethyl ether and recrystallised
from isopropanol. 2.6 g of p-chloro-N-(2-morpholinoethyl)-
-benzamide are obtained, which is identical to the product
obtained in Example 1.
Example 6
~`
~ 5.55 g of p-chlorobenzoic acid p-nitrophenyl ester are
- added to a solution of 2.6 g of N~2-aminoethyl)-morpholine in
100 ml of tetrahydrofuran and the mixture is allowed to stand
overnight at room temperature. It is then evaporated to
: ~ :
`~ drynegs and the residue is taken up in 200 ml of methylene
;~ chloride. The methylene chloride solution is washed three
; ~ times with 50 ml of a 1~ sodium hydroxide solution each time `
and twice with 50 ml of water each time untll neutral, dried
over sodium sulphate and evaporated to dryness. The residue
is recrystalllsed from lsopropanol. 3.1 g of p-chloro-N-(2-
-morphollnoethyl)-benzamide are obtained, which ls ldentical
.. , ~
~ ko the product obtained in Example 1.
. . .
Example 7
. 1 '
~, 2.4 g of N-(p-chlorobenzoyl)-succinimide are added to a
solution of 1.3 g of N-(2-aminoethyl)-morpholine in 100 ml of
. ~..
dloxan and the mixture is stirred overnight at room temperature.
It is then evaporated to dryness. 50 ml of ice-water are
added to the oily residue and the crystallising mixture is
allowed to stand overnight in khe refrigerator. The product
is filtéred off, washed with cold water, dried and recrystal-
'' ' ',.':
- 14 -
76~12
lised from isopropanol. 0.65 g of p-chloro-N-(2-morpholino-
.
- ethyl)-benzamide is obtained, which is identical to the product
obtained in Example 1.
.: ...
~ Example 8
`` . ':' ~,
7.8 g of p-chlorobenzoic acid and 6.5 g of N-(2-amino-
.. ~ . - .
ethyl)-morpholine are dissolved in 150 ml of pyridine. 10.5 g
~` ~ of dicyclohexylcarbodiimide are added at 4C and the mixture -
is stirred for 4 hours at 4C and overnight at room temperature.
The mixture is then poured into 1 litre of water and the
dicyclohexylurea formed is filtered off. The filtrate i5 :
~; extract:ed twice with 200 ml of methylene chloride each time.
The methylene chloride extract is dried over sodium sulphate,
evaporated to dryness~and the residue recrystallised from
isopropanol. 0.6 g of p-chloro-N-(2-morpholinoethyl)-
-benzamide~is obtained, which is identical to the product
obtained in Example 1.
Exam~le 9
2.8 g of phosphorus trichlorlde in 20 ml of pyridine are
added to 5.2 g of N-(2-aminoethyl)-morpholine in 80 ml of
pyridine at -5C over a period of 15 minutes, whilst stirring.
~; The mixture is stirred for 30 minutes at -5C and 90 minutes
at room temperature. 3.1 g of p-chlorobenzoic acid are then
,
added and the mixture is heated for 3 hours at 90C. It i9
then evaporated to dryness and the residue is evaporated twice
- 25 more with 100 ml of toluene each time. The solid residue is
. ,
taken up in 100 ml of methylene chloride and 100 ml of ice-
':
:~ .' .
.:
- ;, . . ., . .. . - . . . .. .. . .. .. . . . ...
\
~ 1~761~2
-water and the mixture is rendered basic with 3-N sodium
-~ hydroxide solution. The phases are separated and the methylene
chloride extract is washed with water, dried over sodium sulphate
and evaporated. The residue is recrystallised from isopropanol.
1.3 g of p-chloro-N-(2~morpholinoethyl)-benzamide are obtained,
which is identical ~o the product obtained in Example l.
',
`~ ExamPle 10
5504 g of p-chlorobenzoylaziridine and 26.5 g of
morpholine are boiled in 250 ml of toluene for 2 hours under
reflux. The solution is then cooled to room temperature,
whereupon crystals separate out. The crystallising solution
is allowed to stand overnight in the refrigerator. Thereafter
`~ the product is fil~ered off, washed with toluene and recrystal-
~ lised from isopropanol. 75.9 g of p-chloro-N-(2-morpholino- i
,~ 15 ethyl)-benzamide are obtained, which is identical to the
~ product obtained in Example l.
~ .
.~,,
` Example 11
'..- ~:
~- 5.45 g of p-chloro-N-(2-chloroethyl)-benzamide and 8.7 g
' ~ o morpholine are stirred together for 2 hours at 100C. The ~`
`~ 20 mixture is then cooled to room temperature and 50 ml of water
.:
- are added. The mixture is then rendered basic with 10%
ammonia solution and extracted three times with S0 ml of
.'.i ~ .
l methylene chloride each tlme. The methylene chloride extract
`I is dried over sodium sulphate and evaporated. The residue is
chromatographed over a silica gel column with a mixture of
~- chloroform and ethanol. The product is recrystallised from ~
. .:
: .
- 16 ~
.. ~ ,:
:. ." :
- f~ 76112
;.. ; .. ` .
. ,~. ~ .
isopropanol. 2.2 g of p-chloro-N-(2-morpholinoethyl)-
-benzamide are obtained, which is identical to the product
obtained in Example 1.
, . .
Example 12
., ' "~ '' ' '
26 g of p-chlorobenzaldehyde and 24 g of N-(2-amino-
ethyl)-morpholine are boiled in 150 ml of benzene for 3 hours
under reflux with water being separated.The mixture is then
evaporated to dryness and the residue is distilled at 165C/
~ .
0.01 mm Hg. 5 g of the resulting 4- r 2-[(p-chlorobenzylidene)- `
-amino]-ethyl 7-morpholine, 2.3 g of sodium acetate and 3 ml of
30% hydrogen peroxide are stirred in 60 ml of methanol overnight
~ at room temperature. Thereafter the mixture is evaporated to
""z~ dxyness and the residue is taken up in 50 ml of methylene
~ chloride and 50 ml of water. The phases are separated and
, ~
~15 the aqueous phase extracted with 50 ml of methylene chlorlde.
The methylene chlorlde extract is dried over sodium sul ~ate
and evaporated. The residue is chromatographed over a ~ilica
gel column wlth a mlxture of chloroform and ethanol. The
pure fractions are combined and evapoxated, and the resldue
! ~
, 20 recrystalllsed from isopropanol. 0.7 g of p-chloro-N-(2-
morpholinoethyl)-benzamlde is obtained, which ls identical to
the product obtained ln Example 1.
`` ! :
., ~:
r',''~,~ ' .
Example 13
. . .,, '
900 mg of p-chloro-N-(2-morphol~noethyl)-th~obenzamide
hydrochloride are boiled in 100 ml of water with 2 g of lead
tetraacetate for 10 hours under reflux. The mixture is then
.~ ,,: .
, . - .
- - 17 -
.. ,- - : . , , , , " .. ..
", ~ :'. ,; .'.. ,', ' ,, ':' ,' ', ,',,' . ,,.' , '' , , '.', " '. ' ,: " '. . .
, , ' .' , ', :' ' , '' " '; : . ' ~ . " ' ' '
10761~2 `:
- filtered and the filtrate is evaporated to dryness. The
residue is chromatographed over a silica gel column with a
mixture of chloroform and ethanol. The product is recrystal-
lised from isopropanol. 0.3 g of p-chloro-N-(2-morpholino-
ethYl)-b~nzamide is obtained, which is identical to the
product obtained in Example l.
' ~ .
Exi~mple 14
, ~ . , .
; 1.0 g of p-chloro-N-(2-morpholinoethyl)-thiobenzamide
;~ hydrochlorlde is boiled in 100 ml of methanol with 35 ml of
1,2-butylene oxlde for 14 hours under reflux. The mixture is
evaporated to dryness and the residue recrystallised from
,
isopropanol. 0.6 g of p-chloro-N-(2-morpholinoethyl)-benzamide
is obtained, which is identlcal to the product obtained in
Example l.
. .:
s `~
~ 15 Example 15
. 1 .
, ,
~ 4.0 g o~ a-(p-chlorophenyl)-N-(2-morpholinoethyl)-nitrone
`ii~ ; are heated to 90C in 15 ml of glacial acetic acid and 15 ml
~ of acetic anhydride for 24 hours. The mixture is then cooled
... .. .
; ~ to room temperature, poured into 200 ml of ice-water and ~ ~
rendered basic with 20% sodium hydroxide solution. There- `
after the mixture is extracted twice with 100 ml of methylene
` chloride each time. The methylene chloride extract is
~- washed with water, dried over sodium sulphate and evaporated.
. :;
The residue is chromatographed over a silica gel column with a
mixture of chloroform and ethanol. The product is recrystal-
lised from isopropanol. 0.13 g of p-chloro-N-(2-morpholino-
- 18 -
.. ~ .
~ 761~2
.' . :.
.
ethyl)-benzamide is obtained, which is identical to the product
~ obtained in Example 1.
:,; ' :'-.,
Example 16
. , .
25 ml of 30% hydrogen peroxide are added to a solution -
of 10 g of p-chloro-N-(2-morpholinoethyl)-benzamide in 50 ml
of glacial acetic acLd and the mixture is allowed to stand for
48 hours at room temperature. The mixture is then evaporated
to dryness and the residue chromatographed over a silica gel
; column with a mixture of chloroform and ethanol. The pure
fractions are evaporated and the residue recrystallised from
an ethyl acetate/isopropyl ether mixture. 6.8 g of p-chloro-
-N-(2-morpholinoethyl)-benzf~mide N'-oxide, melting point 201C
(decomposltion), are obtained.
: . . .
The following Bxample illustrates a typical pharmaceutical
preparation provided by this lnvention:
Example A
Tablets o~ the following composition are mf~nufactured in
:;f
a manner known per se:
p-Chloro-N-(2-morpholinoethyl)-benzamide 50 mg
, f ~
Lactose 95 mg
Maize starch100 mg
Talc 4.5 mg
I Magnesium stearate O.S mg
-; Weight of one tablet 250.0 mg
~,of
f ' :,
., ~ '
., - 19 - .
' ,, , ' , : '
