Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
23~
~his invention relates to new benzhydryloxy-alkyl-
amine derivatives of the general formula I
CH
C_ O_ (C~-12)n--I~C~ ( )
,,;
; wherein: X represents a haloyen atom, a methyl or a methoxy
group
A represents, together with the nitrogen atom to
which it is attached, a hexamethyleneimiro,
heptamethyleneimino, 1, 2, 3, 4-tetrahydro-2-
. isoquinolyl or 1, 2, 3, 4-tetrahydro-6,7-dimethoxy-
`~ 2-isoquinolyl group, and
~r n is an integer having the value of 2, 3, or 4, and
a the pharmaceutically acceptable acid addition salts
' thereof.
`' According to the present invention, the process
for preparing the above compound comprises:
a) reacting in the presence of a base a cyclic
: imino compound of the general formula:
:~`
A ~ i -( clr2 )n ~ Hal (II)
: wherein A and n have the aforesaid meanings and Hal represents a
halogen atom, with a benzhydrol derivative of the general formula:
' L:
`` c~r
A 1 3
x ~ c _ o~r ( III)
'~ 30 ~ J
2 -
j/,',' ~7
"',"A, ~ S~,"i
wherei.n X has the aforesalcl meaning; or
b) reacting in the presence of a base a cyclic
imino compound o:f the general formula:
:`
~' N _ (cll2) - Oll
,
- wherein A and n have the aforesaid meanings, with a benzhydryl
. , .
~ derivative of the general fo~mula:
.
~ I 3
X ~ C- ~a~. (IV)
-:. . .-
Wherein X has the aforesaid meaning and Hal represents a halogen ~:-
,9$ atom; or
~ c) reacting in the presence of a base a cyclic
; ~i
.,.~
:-~3 imino compound of the general ormular ~.
. s,
T H (II")
... .
`, 20 wherein A has the aforesaid meaning, with a benzhydryl either of
;`. the general formula: .
c~ :
` 7 X _ ~ _ C _ 0 _ (C~I2)n-_ 2 (V) ::
:?
~:
~ wherein X and n have the aforesaid meanings and Z represents a
.1 halogen atom or a tosyloxy group; and
.
~ d) when a pharmaceutically acceptable acid addition
.~ 30 salt of the derivative of formula (I) obtained is desired, further
. ~
`~: reacting the benzhydryloxy~lkylamine derivative thus obtained with
,:, .
.. 1 an acid to provide the required salt.
. . .
.''9
~ 2a -
. ~
,.~ . .
The new compound of general formula I have prolonged
antihis~aminic effect.
It is known from the literature that some benz-
hydryloxy alkylamlnes show antihistaminic effect (British patent
. speci.fica-tion No. 942,152; C.A. 60, 9250h).
s Now it has been found that if the alkyl chain o~
the benzhydryloxy alkylamines is bonded to a voluminous~ partly
: or fully saturatea heterocyclic imine, the obtained compounds have
~ an increased antihistaminic effect which is A 789-62/172 alt.
/
:~ /
/
. "
:, '
., . /
~,, / :
,.: /
.. ~ / , ~
:1 / ~ :
:.
~ - 2b ~
., .
.',,, ~'~' ' .
.~ ,.~ :
: .. , .. ,... - . . . .. . .. . . .
LZ36~
exerted during a con~iderably longer time, whereby the
compounas hav~ higher therapeutical value. These compound~
~how a selective antihi~taminic effect both in vivo and ~n vitro
te~ts. When administered perorally and ~ubcutaneou~l~ to guinea-
pig9, they inhibit bronchu~ ~pam3 induced by hi~-tamin more 3~rongly
and for a oon~iderably lo~ger longer time than the ~ecla~tine
methyl~2-(2~ methyl-p-chlorodiphenyl-methoxy/~ethyl)
-pyrolidine hydrogenfumarate_7. ~he therapeutical broadn~s of
u~ability of th~ compound~ is ad~antageously influenced
. ~ .
by the low toxicity value~.
The inhibition of bronchus spasm~ induced b~ hi~-
~i~` tamine on guinea-pig~ wa~ te~tad in vivo in the following ~ay:
~ he animal~ were put into a glas~ ve~sel, and a
0.2 ~ hi3tamine ~olution wa~ ~prayed into the ves~el with con~-
tant pressure. ~efore admini~tering the te~ted compound~ the
control time nece~ar~ for inducing bronchu~ ~pa8m~ wa~ measu~
red with each animal, and the inhibiting effect induced by
the compound~ was compared -to thi~ contro~, this compound being
i otherwi~e generall~ used in the clinical practice and u~ed a~
20 . control ~ubstance.
he tim~-inhibition wa~ t~ken a~ 100 % if the typical
~ "a~phy~y" reaction did not appegr during the threefold ralua of
-~. the oontrol time.
, ~ .
Some typical result~ together with toxicity value~ ~ ~
are summarized in Table I. _ _
.,,~, ~ .
," ~ ,.
;, -3--
T ~V4 4~ f2;30
Compound toxicity Dose Inhibition in % of bron~hus
according LD mg/kg mg~/kg. spasms indllced by histamine
Example on mice ~ Y' ''~Z=C~,- fter _ _ _ __
No. gusly 3h 6h l~h 24h 48h
_ . ..... _ ~
~ ~2100 50 20
1 500
100 100 80 - 60
_ . _, . _ . ,., . . _ ~
~ 550 0 . 285 90 20
~ 1 100 100 90 '
100 100 - 90
_ ...
~ 7 ~1600 10 80 75 - 50
_ _ . ..
8 lZ30 10 60 70 - 80 40
. - . .
Meclas-280 0.5 go 45 o
. tine
2 100 60 0
100 - - - ` O
. . _ .
~. The benzhydryloxy alkylamines of the general formula
:~ I can be prepared according to the invention from the cyclic
-imino compounds of the general formula II
~ 20 ~____,,N - (CH2)m _ y (II)
;.;, wherein A has the same meaning as above,
Y stands for a halogen atom or a hydroxyl group
~,,'j
:~ and then
~; m stands for an integer having the value of 2, 3
or 4, or
;:
.~, Y stands for a hydrogen atom and then
`~ m stands for zero.~- - ------- . ---- -~_ :~
,, . - / '~'''`
~, ~ .
- `: ! . , -- _ _ _
,,~ -- 4
'i`' ~5!1
. . j . .
by the following mathod~:
a) a compound of the general ~crmula II, wherein
Y ~tands ~or a halogen atom, m i~ 2, 3 or 4~ ha~
the ~ame meaning a~ above, i8 reacted with a
b~n~hydrol derivatlve of the general formula III
X ~,= C - OH ~III)
,:' l
13
:~` wherein X ha~ the same mea~ing a~ abore7 or
: b) a compouna of the general formula II, wherein Y
~tand~ for a hydroxyl group9 m i5 2, 3 or 4p ~nd
.. A has the same meanlng as above, i~ reaeted with
~ 2;,~
: a ben~hyd~yl derivative of the generPl formula IV
'
~ ~ C -~al (I~)
i wherein X has the same meaning as above and.1 Hal ~tands ~or a halogen atom, or
`~ c) a compound of general formula II, wherein Y i8
.~i . a hydrogen atom, m i~ ~ero and A haæ the ~ame
~;~ meaning a~ abo~e, i~ reacted with a benzhydryl -
3~ ether of the general formula V
~ i
~j, ~ C -O t~H2)n (V) ~ ~
'' ~3 :,
', :
....
f
; ~5-
: .
., . ` .
. . .
, .. .
3~
wherein X and n have the ~ me~ing a~ above,
and æ ~tands for a halogen atom or a to~ylsxy groupO
In all th~ thr~e ~rari~t~ of the proce~ aocording
to th~ in~ention the cycli~ imino compound OI ge~ral :~ormula
II i~ prefer~bly reacted wlth th~ compound of gcneral ieormula
III, IV or V in th0 presence OI a base a~d the obtained compound
of the general formula I can be tr~3Iormed7 if d~ired, into
acid addition ~alt by reacting it ~ith a pharmaceutically
acceptable inorgan~ c or orga~ic acid. ~he acid addit~ on ~alt
call be preferably prepared without i~olation o:~ the compound.
The obtained compolmd~ OI general formula I aIld their
acid addition ~alt~ can be tr~formed into pharmaceutical
compo~ition~ by adju~ting them alone or together with other
ph~rmaceutically active compound~ with carrier~ and/or auxilia-
r~ agents u~ed in the pharmaceutical indu~try into pill9,
coated pillY, cap3ule~, 3u~pen~ions5 emul~ions, solutions~ .
dilution~ etc. into pharmaceutical product~. :
~he proce~s according to the invention i~ further
illustrated by t~e aid of the following E~ample~,
. .
~
,: ~o a mixture o~ 4~2 g. of ~odium amide and 80 ml.
j
o~ dry ben~ene 27.9 ~. ~0.12 mole~) of ~-methyl~pchlorobenzhydrol
and thereafter 17.6 g. (0.1 mole~) of N~ ~~chloroethyl~-hepta-
meth~leneimine are added. ~he mixture i~ ~tirred ~or 20 hour~
at its boiling point. Aft~r cooling the mixture i8 wa~hed with
2 x 20 ml. of water and then with 4 :c 50 ml. of 2N h~drochloric
acid ~olution. ~he acidic extract~ are combined th~ pH o~ the
combined extract~
==--
. ~
. ' ' .
.,
~ 4 ~'~ 3~
i~ set to a value of 9 with a concentrated aqueous ~odium
hydro~ide ~olution. The organic pha~e being ~eparated i8
e~tracted With 3 ~ ~0 ml. of ben~ene, The ~olution i~ di~tilled
~ off and the r~sidue i~ purifi~d by di~till~tion. ~he th~
-:: obtained N-F ~-(p-chloro-~-methyl-~ -phenyl-ben~yl-oxy)-ethyl
-heptamethyleneimine boils at 158-162C under a pre~ure of
0.005 mmHg. Yield: 55 ~.
nD : 1.5574,
~he hydrogen fumarate ~alt of the compound can be
rec~y~tallized fxom ethanol; m.p.: 144~145 C.
~ Analy~i~ data for C27H34CINOs
-v calculat~d C 66.31 H 7.03 Cl 7.26 ~ 2.86
t
~j found C 66~36 H 7.18 Cl 7.35 ~ 2.78.
,, ~ ` .
:- ~o ~i~ture of 4.2 g~ o~ sodium amide and 80 ml.
of dr~ ben~ene 27.9 g. (0.12 moles) of ~-methyl~p-chloro-
ben~hydrol and ther2after 16.2 g. (0.1 mole~) of N~ chloro-
~; ethyl)-hexamethylen~imine are add~d. ~he mixture iB ~tirred
~or 20 hour~ at its boiling point and after cooling it i~ washe~
~ith 2 x 20 ml of water. ~he benzenic solution i~ dried over.
magnesium sulphate until free from water and then clarified with
. charcoal, ~h~n dry hydrochloric acid gas i~ introdu¢ed into
:' the solution. ~he ~eparated cr~stal.line.product i~ filtered
.:
through a glas~ filter and then recry~tall~:zed frDm acetone. ~ -~
this w~y N-~ 2-~C-methyl-p-chloro- ~ -phenyl-ben~ylo~y)-ethyl~
. " .
.`., -he~amsthyleneimin~ hydrochloride i8 obtained with~a ~leld o~
:`~ 65 %; m~p. 170-171C.
~ .,
Analy~i~ date for C22H29C1 ~ 0
calculat~d - a 67.12 H 7.41 ~1 18.07 N 4.06
found C 67.03 H 7.47 Cl 17.95 N 4.12
".?
.i
, - `
; -7-
~,
23~
Exampl ~ 3
~ o a ~olutio~ of 27.9 g. (0.12 mol~) of ~L m~thyl-
p chlorobenzh~drol in 100 ml. of pet~oleum ether 20 g. of
powderad calcium chloride fre~ from water ar~ added,. Dr~ hydr~-
chloric acid ga~ i~ led through the ~olution for two hour~ at
a temperature of 0 to 5 C~ The mi~ture i~ filtered and the
f$1trate i~ evaporat~d. 16.2 g. (0.1 mole~) of N~ hydroXy-
ethyl)-~h~xamethylenQimin~ and 10.6 g. (0.1 mole~ of sQdium
car~onate are added to the formed ~ -methyl~p chlorob~n~hydryl
10 chloride, ~he mixture i~ med to 125 C a~d is held at thi~
: temperature for 8 hours. After cooling 100 ml. of benzane are
ad~ed to the mixture. After filtering and clari~ying dry
I hydrochloric acid gas i~ led through the solution. ~h~ thus-
formed cry~talline product i~ filetered on ~ filter glas~ and
recrystallized from acetone. The thu~-obtained ~-~p-chloro-
methyl~-phenyl-ben~yloxy-ethyl J-hexamethylen~lmine hydro
chloriae melt~ at a temperature of 170 to 171 C, yield: 355~,
;. (~hi~ product i~ identical with that of Example 2
E:~amp~e 4
,~; .
.'. ~o ~o ~ solution of 22.6 g. (0.2 moles) of heptam~thy-
li~
:, lene imine in 100 ml. of ac~tone 43.1 g. (0.1 mole~ of
(p-chloro- ~ -methyl-~ -phenyl-benzyloxy)-ethyl-~p-toluene)-
.~ulphonate are added. ~he mixture i~ boiled for 16 hour~, then
the ~ol~ent i~ avaporated. ~he re~idu~ i~ di~olved in 80 ml.
. .
~4, of water a~d the p~ o~ the æolution i8 æet to a value o~ 9 by
...
adding aqueou~ ~odium h~droxide ~olution. The organic pha~e i8
xtracted with 3 x 30 ml. of b~n~ene. After drying the ben~enic
....
~- ~olution iB e~aporated
",.
.,
`''.~"
....
,. ~
,.
.,
.. . _
,...
3~
and the obtained produot i~ di~tilled under reduced pre~ure;
b;p~: 158-162 C/0.005 m~Ig, Yield: 42 ~ (The product i9
- identical wlth that of Exi~nple 1. )
By corre~pondingly modifyirlg the m~thods a~ de~cribe~
in Exampl~ 1 to 4 the ~ompou~ds ~ummari~d in ~able 2 have been
; prepared:
: . Table 2
~ .,
,
No . of X n ~A Salt M . p ., C
Examiple
.,
~: 6 Cl 3_~ ~) HCl 165 167
7 :Br 2 ~ umarate 149-150
,,
~, 8 F 2 - " HCl 117~;120
CH3 0 2 ~ HC1 111~
_aH3 2 ~ HCl 139-141
. .11 Cl 4 - " - HCl 147-149
12 Cl -N~ Cl 148-150
13 C1 2-~CH HC1 104 108
' -,'1
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