Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
100-4767
l-AMINO-3-ARYLOXY-2-PROPANOLS
The present invention relates to l-amino-3-
aryloxy-2-propanols.
The present invention provides compounds of
formula I ~.
OH
OCH2CHCH2NH-Rl
R2
(CH2)n ~ .I
.0
wherein (i) m is 0, n is 2 and p is 1 or
(ii) m is O or 1, n is 1, and p is 1 or
(iii) m is 1, n is 1 or 2 and p is Ot -~
Rl is (i) alkyl of 3 to 7 carbon atoms or
(ii) phenylalkyl, phenoxyalkyl or phenylthio-
alkyl of 8 to 11 carbon atoms in the aggregate
thereof and wherein the phenyl ring is separated
by at least 2 carbon atoms from the nitrogen
atoms to which Rl is bound and wherein the
phenyl ring is unsubstituted, or mono-substituted
by,or inde~endently disubstituted by,a~yl or a~oxy or
1 to 4 carbon atoms, halogen of atomic number
from 9 to 35, trifluoromethyl or cyano,
R2 and R3 are either together straight chain alky-
lene of 4 to 6 carbon atoms,
- ;.,i
100-4767
or, independently, hydrogen or alkyl of 1 to 4
carbon atoms, with the proviso that when m is 1,
n is 1 and p is 0 then at least one of R2 and
- R3 is other than hydrogen, and
R4 and R5 are, independently, hydrogen or alkyl
of 1 to 4 carbon atoms; and pharmaceutically
acceptable acid addition salts thereof.
When m is 0, preferably n is 2 and p is 1. When
m is 1, preferably n is 1. Alkyl and/or alkoxy con-
- 10 tains preferably 1 or 2 carbon atoms, especially 1
carbon atom, except where otherwise stated herein- -
after. Halogen is preferably chlorine or bromine,
especially chlorine. Alkylene contains preferably 4
or 5 carbon atoms, especially 4 carbon atoms.
The alkylene moiety of the phenylalkyl, phenoxy-
alkyl or phenylthioalkyl radical has preferably 2 to
4 carbon atoms. When the alkylene moiety contains
more than 2 carbon atoms it is preferably branched,
preferably in the a-position to the nitrogen atom to
which R1 is bound.when the phenyl ring is disubsti-
tuted, the substituents are preferably in the 3 or
4 positions and are preferably identical.
When Rl is alkyl, this moiety preferably has
3 to 5 carbon atoms, especially 3 or 4 carbon atoms.
This is preferably branched, especially in the
a-position.
-- 2 --
,,,,;
~,, ..
Rl is preferably alkyl or phenylalkyl, especially
alkyl. R2 and R3 are preferably either each alkyl or
together alkylene. R4 and R5 are preferably each hydrogen.
The present invention provides a process for the
production of a compound of formula I as defined above
which comprises reacting a compound of formula II
OCH2-R ',
~ (CR4R f R3 II
O
wherein m, n, p and R2 to R5 are as defined above, and
Rx is a group capable of reacting with an amine
:to give a 2-amino-1-hydroxysthyl group,
with a compound of formula III
Rl NH2 III
wherein Rl is defined above; and where necessary or desired,
forming a pharmaceutically acceptable acid addition salt of
the resulting compound of formula I.
The present process is an amination by a primary
amlne. It may be effected in conventional manner for
the production of analogous 3-amino-2-hydroxypropoxy-
aryl compounds.FOr example R may be a group of formula
-CH-CH2 or a reactive derivative of this group, e.g.
of formula -CH(OH)-CH2Y wherein Y is halogen, preferably
chlorine or bromine/or a group Ry-SO2~O~ wherein Ry is
phenyl, tolyl or lower alkyl. Y is especially chlorlne.
~*J'
3 --
100-4767
The reaction is effected preferably in an inert
organic solvent/ e.g. in an appropriate ether such as
dioxane- Optionally an excess of a compound of formula
III may be used as solvent. Alternatively the reaction
may be effected in a fusion melt.
Suitable reaction temperatures may be from about
20 to about 200 C, conveniently the reflux tempera-
ture of the reaction mixture when a solvent is present.
Free base forms of the compounds of formula I
may be converted into acid addition salt forms in con-
ventional manner and vice versa. Suitable acids for
salt formation include maleic acid and fumaric acid.
In the compounds of formula I, the carbon atom
to which the hydroxy group is bound is asymmetrically
substituted. The compounds may thus exist in the ra-
cemic form or in individual optical isomer form. If
either R2 and R3 or R4 and R5 are not identical, then the
compounds may exist in individual diastereoisomeric
forms. In certain conditions these diastereoisomeric
,forms may be interconverted,e.g. when there is a hydrogen
atom attached to a carbon atom adjacent to a carbonyl
group,epimerisation may occur in the presence of a base.
Preferred ccmpounds are,however, the compounds wherein
R2 and R3 are identical and R4 and R5 are identical.The
; preferred optical isomer has the S co~figuration at
the asymmetrically substituted carbon atom of the hy-
droxypropoxy side chain.
~J ~
~i 4 _
~3. ~
100-4767
Individual optical isomer forms and diastereo-
isomeric forms may be obtained in conventional manner.
For example the S isomers may be produced by using
optically active starting materials or by fractional
crystallisation using optically active acids. Indi-
vidual diastereoisomeric forms may be similarly obtained `
using fractional crystallisation, or chromatography, of
a mixture of salt forms or using optically active
starting materials.
The starting materials may be obtained as
follows: - ;
Compounds of formula II may be obtained by
demethylating or debenzylating a compound of formula IV
(CR4R5~ ~ IV
wherein m, n, p and R2 to R5 are as defined above, and
R is methyl or benzyl, and
replacing the hydroxy group by a group -O-CH2-R in
the resulting phenol in kno~n manner.
-
~
100-4767
A compound of formula IV a
RO
~ ~ ~ R2
I IVa
wherein n is 1 or 2,
R is as defined above, and
either R2I and R3I together are straight chain alkylene
of 4 to 6 carbon atoms, or R2 and R3 are,
independently, hydrogen or alkyl (Cl 4) with the
proviso that, when n is 2, R2 and R3 are not
both hydrogen, may be obtained by
a) reacting a compound of formula V
RO
~ (CH2)nI V
wherein n and R are as defined above, and
Z is chlorine or bromine,
with a compound of formula VI
2 ~_ " ,R
1 . VI
R~OOC CN
100-4767
wherein R2I and R3I are as defined above and
R6 is alkyl (Cl_43,
to produce a compound of formula VII
R~ I
( 2)n ~ I VII
R OOC ~
6 ~N
b) hydrolysing the compound of formula VII and splitting
off carbon dioxide from the reaction product to pro-
duce a compound of formula VIII
R0
( 2) ~ 2 VIII
and,
c) cyclizing the resulting compound of formula VIII with
e.g. poly-phosphoric acid.
For the production of a compound of formula VIII when n
is 1 and R2 and R3 are both hydrogen, it is preferred to
react cyanoethylene with a compound of formula V and to
hydrolyse the resulting compound~
Compounds of formula IVaa
R0
~,
IVaa
- ~.9 ~
100-4767
may be produced by oxidizing the corresponding benzo-
5-suberol with, for example, chromium dioxide or
manganese dioxide.
Compounds of formula IVb
R0 II
wherein either m is 0 or 1 and n is 1,
or m is 0 and n is 2,
R is as defined above, and
either R2 I and R3 I together are straight-chain
alkylene (C4_6)~
or R2 and R3 are, independently, hydrogen
or alkyl (Cl_4),
R4I and R5I are, independently, alkyl
(Cl_4 ),
may be obtained by alkylating the corresponding 5-non-
alkylated compounds.
Compounds of formula IVc
R,0 II
II IVc
-- 8 --
100-4767
wherein m , n I, Rl, R2 I, R3 and R4 are as defined
above, may be obtained by
a) effecting a wittig reaction between a compound of
formula IVd
~ ( ~)mI Vd
with a compound of formula IX
~ f - CH - R4 IX
~ ' ' .~ ~
to obtain a compound of formula X
R0
2)nII R~
~ 2 ~nI
and,
b) reacting the resulta~t compound of formula X with
thallium trinitrate in the presence of a lower alkanol.
100-4767
~ hen m is 0 and R2 and R3 are both other
than hydrogen in the compound of formula X, this may
alternatively be produced by (a) reacting the appropriate
compound of formula IVd with a Grignard reagent of an
alkyl bromide to produce a carbinol and (b) splitting off
water from the resulting carbinol.
Compounds of formula IVda
R0
1 o ~ lII IV da
h i III is 1 or 2
R is defined above, and
either R2 and R3 together are straight chain
alkylene (C4_6), or
R2 is hydrogen or alkyl (Cl 4), and
R3 is alkyl (Cl_4),
may be produced by mono-or di-alkylating 'the
corresponding compound wnerein the 6 position is un-
substituted.
Insofar as the preparation of any particular
starting material is not particularly described, this
may be effected in conventional manner.
In the following examples all temperatures are
in degrees Centigrade and are uncorrected.
~ - 10 -
~ 100-4767
EXAMPLE 1 1-(3-tert-butYlamlno-2-hydroxypropoxy)-6,7,
'8,9- rahy'dro'-'7','7-dimethYl-5H-benzocYclo-
'hepten-6-one
2,2 g crude 1~(3-chloro-2-hydroxypropoxy)-6,7,
8,9-tetrahydro-7,7-dimethyl-5~-benzocyclohepten-6-one
in 20 ml dioxane and 10 ml tert~butylamine are heated
at 130 for 20 hours in an autoclave. The reaction
mixture is divided between 10~ (w/w) aqueous tartaric
- acid solution and ether. The aqueous phase is made
alkaline and extracted with ether. Evaporation of the
ether phase yields the title compound (M.pt of hydrogen
maleate 186-188after crystallization from ethanol).
The starting material may be obtained as follows: -
a) 44.0 g 5-methoxy-1-tetralone in tetrahydrofuran are
added dropwise to a suspension of 21 g sodium hydride in
tetrahydrofuran. 142 g methyl iodide in tetrahydro-
furan is added to the resulting mixture. 5-methoxy-2,2-
dimethyl-l-tetralone ~M.pt 162-170/12 mm) is obtained
ater working up.
b) A solution of methyl magnesium iodide ~producea from
69.7 g methyl iodide and 11.9 g magnesium turnings in
ether) is treated with a solution of 66.5 g 5-methoxy-
2,2-dimethyl-1-tetralor.e in ether~The reaction mixture
is treated with a solution of 62 g ammonium chloride
-- 11 --
-
.
- . . ~
1~0-4767
in water. The resultant carbinol is extracted with
ether and is treated, dissolved in benzene, with 0.5 g
para~toluene-sulphonic acid. After chromatographic
purification on basic aluminium oxide usin~ petroleum
ether as eluant, methyl 1-(5,6,7,8-tetrahydro-6,6-
dimethyl-5-methylene-naphthyl) ether is obtained as
an oil which is worked up further directly.
c) 125 g thallium trinitrate trihydrate in methanol are
treated with 55 g methyl 1-(5,6,7,8-tetrahy~ro-6,6-dime-
thyl-5-methylene-naphthyl~ ether in benzene-.~he--precipi-
tated thallium nitrate is filtered off and the solution
is extracted with methylene chloride. The resultant
6,7,8,9-tetrahydro-1-methoxy-7,7-dimethyl-5H-~
benzocyclohepten-6-one melts at 58-59 (from hexane).
d) 4.0 g 6,7,8,9-tetrahydro-1-methoxy-7,7-dimethyl-5H-
benzocyclohepten-6-one are refluxed with 45 ml aeetic
acid and 5 ml 48% hydrobromic acid for 20 hours. The
solutlon is concentrated, diluted with water and extracted
with ether. After removal of the e~her~6,7,8,9-tetra-
hydro-7,7-dimethyl-6-oxo-5~-benzocyclohepten-1-ol melts
at 152-154 (from toluene).
e) Two drops of piperidine are added to 1.8 ~ 6,7,8,9-
tetrahydro-7,7-dimethyl-6-oxo-5H-benzocycloheptQn-l-ol
in 8 ml epichlorhydrin. The mixture is stirred at 100
: for 4 hours. The solution is evaporated, taken up in
ether, filtered and concentrated to -
- 12 -
100-4767
give crude 1-(3-ChlOrO-2-hydroxypropoxy)-6~7~8~9~tetra-
hydro-7,7-dimethyl-5H-benzocyclohepten-6-one.
EXAMP~E 2 8'-(3-tert-butYlamino-2-hydroxy~ropoxy)sPiro
[cyclopentane-1,2'(1~ na~hthalen]-4'~3'H)-one
The title compound is obtained in analogous
manner to Example 1 starting from 8'-(3-chloro-2-
hydroxypropoxy)spiro[cyclopentane-1,2'(1'H)~naphthalen]
-4'(3'E~)-one. M.pt.(hydrogen maleate) 18a-190 (from
ethanol).
The starting material may be obtained as
follows: -
a) A solution of 39.9 g cyclopentylidene cyanoacetic
acid ethyl ester in 350 ml tetrahydrofuran is added
dropwise to a solution of 2-methoxybenzyl magnesium
chloride (produced from 5.3 g magnesium and 31.2 g
2-methoxybenzyl chloride in 400 ml ether). The mixture
is stirred for 2 hours at room temperature. The mixture
is treated with a 300 ml 15% ammonium chloride solution.
The product is extracted with ether and the ethereal
solution concentrated to yield~crude a-cyano-tl-~2-
methoxybenzyl)cyclopentane]-acetic acid ethyl ester
which distilled at 140-180/0.002 mm Hg.
b) 33.6 g potassium hydroxide are added to a solution
of 32.4 g a-cyano-[1-(2-methoxybenzyl)cyclopentane)-
acetlc acid ethyl ester in 300 ml ethylene glycol.
- 13 -
100-4767
The mlxt~re is stirred at 180 for 40 hours. The solution
is cooled,poured onto ioehYater and the neutral side products
removed by extraction with ether. The aqueous phase is
made acid with hydrochlor' acid and extracted with
ether. After removal of the solvent 1-~2-methoxybenzyl~
cyclopentane acetic acid (M,pt 85-87 from hexane) is
obtained.
c) 5,7 g 1-(2-methoxybenzyl)cyclopentane-acetic acid
is added with stirring to 30 g polyphosphoric acid at
110. The mixture is cooled and treated with 250 ml
water, After extraction with ether and concentration
of the ether extract 8'-methoxy-spiro[cyclopentane-1,2'
(l'~)-naphthalen}4'(3'H)-one (M.pt 62-66~- is ob-
tained,
d) In analogous manner to Example 1 step d)/ 8'-hydroxy-
spiro[cyclopentane-1,2'(1'H)-naphthalenl-4~(3'H)-one
(M,pt 163-165 from toluene) is obtained from the
8-methoxy derivative, and is converted into crude
8'-(3-chloro-2-hydroxypropoxy)-spiro [cyclopentane-1,2'
(llH)-naphthalen]-4l ~3'H)-one in analogous manner to
Example 1 step e).
From the appropriate compound of formula II
wherein Rx is CH(OH).CH2Cl and the appropriate compound
of formula III the following compounds of formula I may
be obtained in analogous manner to Examples 1 and 2: -
j~ i
~i - 14 -
100-4767
, rY T~
r~ ~ ~ N N ,_~ ~N N
,_ ~
~ ~ ~ ,~
.
. O 0'0 o O O o O ~ ~ ,
~ -1 N ~ 1 N ,~ I
E~ ~
p~m I I I r ~ m m
P~ I, I , ,m m
........ -- ..
. In' ' '
p~ m~ mN ~ ~ m
:~:
~n
m~ m~ :~
-- 1 - .
z I ,,,,,,. .~
': ~ . ~ '`
~ _ _ o -- -- o ~ --
~ ~ ~ ~ ~ N ~) ~ ~ ~ ~ ~7
P; m ~ m
- ~ ~ - -- -
:
- 15 -
.` ` - ~ ` .
100-4767
- ~ o ~ ~ .
CO Ln ~ ~
O O ~ ~t
~ o o O O
I I N
~ r~ 1
.
,,
~J ~ O O
. ,~
U ~D
) O
. ~1
~ 51
~;~ m ~ m ~ .
.' ~ . h~
~ ~ ~ ~a 0
~ ,_ ~ ~ ~ d
K m m :~ m o
~_ _ _ _ .
l l l l ~ ~ ~ rl
_ I '
,~
~' ,
-- 16 --
.
100-4767
The compoun~sof formula I exhibit pharma-
cological activity in animals. In particular, the com-
pounds of formula I inhibit glycerol release stimulated
by isoproterenol in standard tests, e.g. as follows: -
i) In vitro
Isolated fat cells are obtained from dog sub-
cutaneous tisue, and from rat and guinea pig epididymal
fat pads, in accordance with the method of M.Rodbell
[J. Biol. Chem. 239, 375-380 (1964)]. Cells from one of ~;
the animals are dispersed in Krebs phosphate buffer
containing 4% bovine serum albumin. 1 ml aliquots of the
cell suspension in plastic incubation flasks are treated
with the test substance at from about 0.01 to about
10 mg/litre and isoproterenol at 10 Molar. The glycerol
release is determined in conventional manner, e.g.
according to the method of S. Laurell et al, Helv. Chim.
Acta 13, 317-322 (1966).
~1) In vivo
_______ :
Rats are fasted for 16 hours. A sub-cutaneous
injection of 400 ~g/kg of isoproterenol results in a
glycerol concentration in the blood plasma of 400~ the
original value. This increased glycerol concentration
remains constant for ca. 60 minutes and acts as a control
value. The test substance is administered s.c. at a do~e of
~ - 17 -
. 'l'
. ~ ~
100-4767
from about 0.01 to about 0.5 mg/kg 10 minutes before
the isoproterenol
injection, and the animals are decapitated 40 minutes
after the isoproterenol injection. The glycerol
concentration in the blood is ca~culated in conventional
manner, e.g. using the~ conventional glycero-3-phosphate-
dehydrogenase method ~according S. Laurell et al;
reference as mentioned above].
The compounds are therefore indicated for use in
the treatment of the increase of free fatty acid
concentration in the blood induced by emotional stress,
and also inhibit lipolysis induced by emotional stress,
and myocardial infarction induced by emotional stress.
/
The compounds of formula I additionally inhibit
hyperglycemia induced by emotional stress, as indicated
by an inhibition of glycogenolysis in standard tests, as
follows:-
In the above-mentioned rat in vivo test the
glucose concentration in the blood is determined in
conventional manner, e.g. using the ferricyanide method.
In the control animals the glucose concentration doubles
after 40 minutes after isoproterenol administration. The
compounds are administered parenterally at a dose of from
about 0.01 to about 5 mg/kg animal body weiqht.
- 18 -
100-4767
The compounds are therefore indicated for use in
the treatment of hyperglycemia induced by emotional
stress, e.g. for suppressing of appetite induced by
emotional stress.
Additionally, the compounds exhibit a cardio-
vascular adrenergic ~-blocking effect as indicated in
standard tests, e.g. by an inhibition of the positive
inotropic adrenaline effect in the spontaneously beating
guinea pig atrium at bath concentrations of from 0.005
to 2.5 mg/litre in accordance with the method of K.Sam~eli,
Helv. Physiol.Acta 25, CR 215-221 tl967); and in the
infusion test in narcotized cats at doses of approximately
0.02 to 0.6 mg/kg i.v., where they induce a strong, long `~
lasting inhibition of the tachycardia and blood pressure
lowering caused by isoproterenol.
The compounds are therefore indicated for use as
cardio-vascular adrenergic ~-blockina asents, e.g. for
the prophylaxis and therapy of Angina pectoris, and also
as arrhythmics.
In general, the 2(S) optical isomers are more
active than the 2(R) optical isomers in the cardiovas-
cular ~-blocking tests.
For all these indications an indicated daily
dose is from about 1 to about 200 mg, conveniently
- lg -
s~
100-4767
administered in divided doses 2 to 4 times a day in unit
dosage form containing from about 0.25 to about 100 mg of
the compound or in sustained release form.
The compounds of formula I also exhibit a sali-
diuretic effect ~s indicated in standard tests, e.g. in
the diuretic rat test in accordance with the principles
of E. Fluckiger et al, Schweiz.med. Wschr. 1963, 93,
1232, on administration p.o. of from about 0.1 to about
- ~0 mg/kg animal body weight of the comPounds.
The compoundsare therefore indicated for use as
salidiuretic agents, e.g. for thP treatment of odema and
hypertension.
An indicated daily dose is from abol~t 1 to
about 100 mg, conveniently administered in divided do-
ses 2 to 4 times a day in unit dosage form con-
taining from abQut 0.25 to about 50 mg of the compaunds,
or in sustained release form.
The example 1 and 2 compounds exhibit particu-
larly interesting properties.
The compounds may be administered in pharmaceuti-
cally acceptable acid addition salt form. Such forms
- 20 -
100-4767
exhiblt the same order of activity as the free base forms,
The present invention also provides a pharmaceutical
composition comprising a compound of formula I in free
base form or in pharmaceutically acceptable acid addition
salt form, in association with a pharmaceutical carrier
or diluent. Such compositions may be formulated in
conventional manner so as to be, for example, a solution
or f ablet.
,, In a group of compounds p is 0, m is 1 and
n is 1 or 2. Preferably Rl is alkyl and R2 and R3 are
each alkyl or together alkylene of 4 or 5 carbon
atoms. In a sub-group R2 and R3 are together alkylene.
In another s,ub-group R2 is a]kyl of 3 or 4 carbon atoms.
In another group of compounds p is 1, m is 1 and n is
isl,In another group p is 1, m is 0 and n is 1.
In another group p is l, m is 0 and n is 2.
- 21 ~
