BENZHYDRYLOXY-ALKYLAMINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF

DERIVES DE BENZHYDRYLOXYALKYLAMINE

English Abstract

ABSTRACT OF THE DISCLOSURE
Benzhydryloxy-alkylamine derivatives of the general for-
mula:
<IMG> (I)
wherein X represents a halogen atom, a methyl or a methoxy group,
A represents, together with the nitrogen atom to which it is
attached, a hexamethyleneimino,heptamethyleneimino, 1, 2,
3, 4-tetrahydro-2-isoquinolyl or 1, 2, 3, 4-tetrahydro-6,7-
dimethoxy-2-isoquinolyl group,and n is an integer having the
value of 2, 3, or 4, and the pharmaceutically acceptable acid
addition salts thereof. These compounds have prolonged anti-
histaminic effect. And, a process for preparing the above
compound.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of benzhydryloxy-
alkylamine derivatives of the general formula:
(I)
<IMG>
and their pharmaceutically acceptable acid addition salts, wherein:
X represents a halogen atom, a methyl or a methoxy group;
A represents together with the nitrogen atom to which it is
attached, a hexamethyleneimino, heptamethyleneimino, 1, 2, 3, 4,
tetrahydro-2-isoquinolyl or 1, 2, 3, 4-tetrahydro-6, 7-dimethoxy-
2-isoquinolyl group, and
n is 2, 3 or 4;
which comprises:
a) reacting in the presence of a base a cyclic imino
compound of the general formula:
<IMG>
(II)
wherein A and n have the aforesaid meanings and Hal represents a
halogen atom, with a benzhydrol derivative of the general formula:
<IMG> (III)
wherein X has the aforesaid meaning; or
b) reacting in the presence of a base a cyclic imino

compound of the general formula:
<IMG> (II)
wherein A and n have the aforesaid meanings, with a benzhydryl
derivative of the general formula:
<IMG> (IV)
wherein X has the aforesaid meaning and Hal represents a halogen
atom; or
c) reacting in the presence of a base a cyclic imino
compound of the general formula:
<IMG> (II")
wherein A has the aforesaid meaning, with a benzhydryl ether of
the general formula:
(V)
<IMG>
wherein X and n have the aforesaid meanings and Z represents a
halogen atom or a tosyloxy group; and
d) when a pharmaceutically acceptable acid addition
salt of the derivative of formula (I) obtained is desired, further
reacting the benzhydryloxyalkylamine derivative thus obtained with
an acid to provide the required salt.
11

2. Process according to claim 1, wherein step d is
effected without isolation of the benzhydryloxyalkylamine deriva-
tive.
3. Process according to claim 1, wherein a cyclic imino
compound of formula (II) is reacted with a benzhydrol derivative
of formula (III) in the presence of a base.
4. Process according to claim 1, wherein a cyclic imino
compound of formula (II') is reacted with a benzhydryl derivative
of formula (IV) in the presence of a base.
5. Process according to claim 1, wherein a cyclic imino
compound of formula (II") is reacted with a benzhydryl ether of
formula (V) in the presence of a base.
6. Process according to claim 3, wherein A represents,
together with the nitrogen atom to which it is attached, a
heptamethyleneimino group, n is 2 and X is chlorine.
7. Process according to claim 4, wherein A represents,
together with the nitrogen atom to which it is attached, a
heptamethyleneimino group, n is 2 and X is chlorine.
8. Process according to claim 5, wherein A represents,
together with the nitrogen atom to which it is attached, a
heptamethyleneimino group, n is 2 and X is chlorine.
9. Process according to claim 3, wherein A represents,
together with the nitrogen atom to which it is attached, a
hexamethyleneimino group, n is 2 and X is chlorine.
10. Process according to claim 4, wherein A represents,
together with the nitrogen atom to which it is attached, a
hexamethyleneimino group, n is 2 and X is chlorine.
11. Process according to claim 5, wherein A represents,
12

together with the nitrogen atom to which it is attached, a
hexamethyleneimino group, n is 2 and X is chlorine.
12. Benzhydryloxy-alkylamine derivatives of the general
formula:
<IMG> (I)
wherein: X represents a halogen atom, a methyl or a methoxy group,
A represents together with the nitrogen atom to which it
is attached, a hexamethyleneimino, heptamethyleneimino,
1, 2, 3, 4-tetrahydro-2-isoquinolyl or 1, 2, 3, 4-
tetrahydro-6, 7-dimethoxy-2-isoquinolyl group, and
n is an integer having the value of 2, 3, or 4, and
the pharmaceutically acceptable acid addition salts there-
of, whenever obtained by a process according to claim 1,
or its obvious chemical equivalent.
13. N - [2 - (p-chloro-.alpha.- methyl -.alpha.- phenyl-benzyloxy) -
ethyl] - heptamethyleneimine, and its pharmaceutically acceptable
acid addition salts, whenever obtained by a process according to
claims 6, 7 or 8, or their obvious chemical equivalents.
14. N - [2 - (p-chloro-.alpha.-methyl -.alpha.- phenyl-benzyloxy) -
ethyl] - hexamethyleneimine, and its pharmaceutically acceptable
acid addition salts, whenever obtained by a process according to
claims 9, 10 or 11, or their obvious chemical equivalents.
13

Description

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
'`~:.,j ' ~
.~., .
.
.
.
.,~, ~ . .
.
.` '~r '
;`',~ ,
- .
. .~ .
.:j`,
''~.'
. .~
9_
~, . ~ .