Note: Descriptions are shown in the official language in which they were submitted.
Case loo-4851
. . :
,
INDOYLOXY - AMINOPPOPANOL DERIVATIVES
The present invention relates to l-~indol 4-yloxy)-
3-amino-2-propanol derivatives.
In accoxdance with the invention there are pro-
vided compounds of formula I
R ' . . .
H
wherein ; R
~ 3
R is a group A-X- ~ R4~ W-~-erein
is alkylene of 2 to 5 carbon atoms,
X is a bond, oxygen or sulfur,
.,
',' ~ ' :`.
i`, :
.,,~ .
:: : , .: . , .:,:.,~ , : :
2 - 100-~851
~ R3 is hydrogen, hydroxy, al~oxy of 1 to ~ carbon
atoms, halogen of atomic member of from 9 to 35,
cyano, carbamoyl or a group NHCORd, wherein Rd
is alkyl of 1 to 4 carbon atoms, and
R4 is hydrogcn and, when R3 is alkoxy of 1 to 4
carbon atoms, R4 addLt~onally may be alkoxy of
1 to 4 carbon atoms or, when R3 is halogen o
atomic n~mber o from 9 to 35, R~ additionally
may be halogen of atomic number of from 9 to 35
~-- 10 either ;~
i) Rl is hydro~en or methyl and
R2 i5 cyano, CONRa ~ , COORC or CH20Re, wherein
Ra, ~ ~Rc and Re independently are hydrogen or
alkyl of 1 to 4 carbon atoms,
or
ii) either Rl is met~yl and R2 is halogen of atomic
number of from 17 to 35
or Rl is halogen of atomic number of from 17 to
`' 35 and R2 is hydrogen or methyl,
with the provisos that
a) X is separated from the nitrogen atom of the 3-
amino-2-hydroxypropoxy chain by at least 2 carbon
atoms,
; b) when X is a bond, R3 is other than hydrogen and
c) when R2 is cyano, R additionally may be alkyl of
3 to 7 carbon atoms; and pharmaceutically
acceptable acid addition salts thereof.
~: .
- ~
.
- : : . - -', i
. :. .
98S~i~3~ ~
- 3 ~ 100-4851
R preferably is a group A-X ~ . X pre-
ferab~y is a bond or oxygen. R3 preferably is hydrogen,
hydroxy or alkoxy. R4 preferably is hydrogen or alkoxy.
Rl preferably is hydrogen or halogen. R2 preerably is
methyl, cyano or CONR ~ . Ra, ~ and Re preferably are
hydrogen. Rc preferably is alk~l.
Alkyl (except as lndicated hereunder for R and Rc)
and/or alkoxy preferably are of 1 or 2, especially of
1 carbon atom. When R is alkyl, it preferably is of 3 to
- lo 5 carbon atoms and preferably is branched, especially in
the position ~ to the nitrogen atom to which it is bound.
Interesting alkyl groups R are e.g. isopropyl, ter~-
butyl and 3 pentyl, especially tert-butyl. When R~ is
alkylrit preferably is of 1 to 3 carbon ato~s; when it
is of more than 2 carbon atoms, it preferably is branched,
~ as e.g. in isopropyl.
Halogen preferably is bromine or chlorine, es-
pecially chlorine. A pre~erably is branched alXylene,
especially in the position ~ to the nitrogen atom to which
it is bound, e.gO the group -CH(CH3)-CH2-, -C(CH3)2-CH2-
a
or -C(CH3)2-(CH2)2-, or it is ethylene.
". c~
When R3 and R4 are hydrogen, X preferably is
oxygen. When R3 is not hydrogen, X prefera~ly is a bond.
'- '
- ~s~
.
,
, ' .,; .,. ! ~ , ; ~ . i
- 4 - 100~4851
When R3 is not hydrogen, it preferably is in the para
position. When R4 is not hydrogen, it preferably is
in the meta position. When R4 is alkoxy or halogen, it
preferably is identical to R3.
A yroup of compounds of formula I are the com-
pounds of formula Ix
-- OCH2CHCH;~NH--R
1 Ix
H ::
wherein x
Rx is a group A XX- ~ R4 , wherein A is as
: 10 defined above, ~ .
either
i) XX ls oxygen or sulfur and
Rl to RX4 have the significances lndicated above for
.
: Rl to R4
:~ 15 or
ii)XX is a bond and
either j) R3 is alkoxy of 1 to 4 carbon atoms or
halogen of atomic number of from 9
to 35,
R4 is hydrogen and, when R3 is alkoxy of 1
: ~' .
.
- - . ,. , - . - . :. - ~ , ,
.. . . . . .
- S - 100-~851
to 4 carbon atoms, R3x additionally
may be al]coxy of 1 to 4 carbon atoms :~
or, when R3x is halogen of atomic num~er
of from 9 to 35, R4 additionally may
be halogen of atomic number of from
9 to 35,
Rl is hydrogen or methyl and
R2 is CONRaRb, wherein Ra and Rb are as
defined above,
or jj) R3 is hydroxy, cyano, carbamoyl or NHCORd,
whexein Rd is as defined a~ove,
RX4 is hydrogen and
RXl and RX2 have the signiicances indicated
above for Rl and ~2~
`l 15 with the proviso, that X is separated by at least 2
carbon atoms from the nitrogen atom of the 3-amino-2-
hydroxypropoxy chain.
~`~
A group of compounds of formula Ix axe the
;,!` compounds of formula Ix'
,.
H-Pr~ ~ R3
~ ~ xl R~ Ix'
H :
:~ .
,~ '
:~
,: ,, :, :; ~ ,.~ '
- 6 - 100-4851
wherein
A is as defined above,
.~
X.X. is oxygen or sulfur and
. ,
Rl to R4 have ~he significances indicated above for
Rl to R4,
with the proviso, that X~ i5 separated by at least
2 carbon atoms from the nitrogen atom of the 3-amino-
(........... 2~hydroxypropoxy chain.
In accordance with the invention, a compound of
formula I may be obtained by a process comprising re-
acting a corresponding compound or formula II
~' . .
ICH2--Ro
II
H ::
(_.
-~ wherein
Rl and R2 are as defined above and Ro is a group capable
:~ 15 Of reacting with an amine to give a 2-amino-1-hydroxy-
ethyl group,
with a corresponding compound of formula III
R - NH~ III
wherein R is as defined above; and where des~ed, converting
~. ... .. .. ..... .
~ t~e resulting compound of fon~a I into a p~maceutically acceptable
~ - ,... ~
acid addition salt thereof.
~, . . , ~: . . .
": . " .. ,, . , . :
- ., . ~
- 7 ~ 100-~851
The present process is an amination by a primary
amine. It may be effected in conventional manner for
the production of analogous 3- ~lino-2-hydroxypropoxy-
aryl comp~unds. ~or example ~0 may be a group of~0~
formula -CH-CH2 or a reactive derivative of this group,
e.g. of formula -CH(OH)-CH2Y, wherein Y is halogen, pre-
ferably chlorine or brornine, or a group Ry~S02-:0 t wherein
( Ry is phenyl, tolyl or lower alkyl. Y is especially
chlorine. The reaction is effected preferabJy 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 ~ffected in a fusion melt. Suitable reaction
temperatures may be from about 20 to about 200C,
conveniently the reflux temperature of the reaction
mixture ~Jhen a solvent is present.
; ~ Free base forms o~ the compounds of formula I
may be converted into salt forms, e.g. into acid addi-
tion salt forms, in conventional manner and vice versa.
Suitable acids for salt formation include maleic, malonic
and fumaric acid. When R3 is hydroxy or Rc is hydrogen,
.: ,
salts may be formed with strong bases, e.g. sodium
hydroxide.
In the compounds of formula I, the carbon atom
to which the hydroxy group is bound is asymmetrically
.,
:: , :: :. ,:............ :: - - . ,,~: . . . : . : -
, ; ; , , :, :: . ,: ~:.
- 8 - 100-4851
substituted. The compounds may thus exist in the racemic
form or in individual optical isomer form.The preferred
optical isomer has the~ S configuration at the asymmetri-
cally substituted carbon atom of the hydroxypropoxy
side chain.
Individual optical isomer ~orms may be obtained
in conventional manner, ~or example by using optically
active starting materials or by fractional crystalli-
`-~ sation usi~g optically active acids. ~r
~ Insofar as the preparation of any particular
starting material is not particularly described, this
may be effected in conventional manner. 4-Hydroxyindol-
2-carbonitrile and 4-E~ydroxy-3-methylindol-2-carbonitrile
may be obtained by splitting off of a water molecule
from the corresponding 2-Carboxamide derivative, e.g.
using titanium tetrachloride.
In the following examples all temperatures are
Ln degrees Centigrade and are uncorrected.
,
,.
, .
- ~ , .
. : .
, .-` ~ ,' : ~
- 9 100-4851
Example 1: 1-(3-chloro-2-methylindol~a ylox~)-3-
______~______.____ ___~_____ ___ ____
(2-~henoxyethylamino~-2-~ro~anol
5 y 3-chloro-4-(2,3-epoxypropoxy)-2~methylindole, 473 g
phenoxyethylamine and 75 ml dioxane are heated at 130
for 15 hours in an autoclave. The reaction mixture is
allowed to cool do~n, the excess dioxane is evaporated
in a vacuum produced by a water~ump and the excess amine
is distilled off under hiyh vacuum at 80. The reaction
mixture is partitioned between aqueous tartaric acid ~ -
',r'lo solution and methylene chloride. The aqueous phase is made
alkaline with conc. ammonia and extracted with methylene
-~chloride. Evaporation of the organic phase yields the
-title compound (M.P. of the hydrogen malonate 135-137
after crystallization from methanol).
; 15 From the appropriate compound of formula II,
.
wherein Rx is-CH(OH~-CH2C1, and the appropriate compound
- of formula III the following compounds of formula I may
be obtained in analogous manner to Example 1:
.
:
., : .; , .: :::, .. , .. . . : . ;, ~
~ lO - 100-~8Sl :~
Examplel R R I I~ Y r
_ _ _~. ~:
2 -C (CH3) 3 ~ H CN f 259-261
3 CH 2CH 2-~ H CN hmi 16 6 - l 6 9
5 4 - CH 2CH 2~ OCH 3 H CN ( f oam )
Cl 3 .
¦ S I -C-CH2~ ~ OH ~H ~ CN If 172-17S
6 3 El CONH 2 b 19 8 - 200
Cl EI 3
7 --C--CH2-0~ CONH2 H CONH2 f 209-212
¦ 8 ¦ -CH2CH2 ~ ¦ ¦ CONH2 jhcl 111-113~ ¦
9 -C-CH2~ OH H CONH2 f 170-173
OCH 3 .
-CH2CH2~ OCH3 H CONH2 hcl 94
11 -f-CH2~0H H CN~cH f 157-l60
: .- ~ ~ ~ ~
: , . ~
~9~
- 11 - 100-4851
¦ Example¦ R ¦ 1 ¦ R2 ~ M.P. -~
No. . ~ `
.
. CH3
12 --C-CH2 ~ -OH CH3 CONH2 ~ 236-238
CH3
13 -CH2CH2-0 ~ H COOCH~CH3)2 b 121-124
. . CH
14 -C CH2 ~ OH H COOCH(CH3)2 h 203-205
~" ': '
. CH3
~CI-CH2 ~ OH CH3 COOCH2CH3 f 241-243
- ,i
~OCH3
16 -C~I2C~2 ~ OC 3 CH3 Cl b 129-131
CH .
: 17 -CH2CH2 ~ OCH Cl CH3 hf 99
: :~ 3 ~(-sïnters)
. OCH3
. 18 -CH2CH2 ~ OCH3 CH3 Br b 126-128
. CH3
19 -C-CH2 ~ OH Cl CH3 f 141~143
CH3
: :
OCH3 ~
20 -CH2C12- ~ OCH3 H COnUCE~ ~ 4~ .
.
:
.
,, .! ..
~ . ~
- 12 - 100-4851 ::
_~ _ ._
Example R R1 R2 M.P.
OCH3 _ _ _ _ _
21 -CH2CH2 ~ OCH3 H C~2CH3 f 103-106
22 ¦ I-CE2 ~ OH H CH20CH9~ ~ 149-iSI ¦
b = free form
= bisEbase]fumarate
hcl = hydrochloride .
hf = hydrogen fumarate
hmi = hydrogen maleinate
~. ~ ~:'
.
- 13 - ~00-4851
','~
The compounds of formula I exhibit pharmacological
activity.
In particular, the compounds possess cardiovascu~-
lar adrenergic ~- and ~-blocking activity, as indicated :~
by standard tests. For example, the inhibition of
ci-a~renoceptors may be observed in isolated spiral strips ~;
; of the Vena femoxalis of dogs ~E. ~uller-Schweinitzer and
~ ~. Sturme.r, Br. J. Pharmacol. [1974~ 51, 441-446) and
.; ~ - . .
the inhibition of ~-adrenoceptors in isolated spiral
strips of the Arteria coronaria of dogs (T.J. Bucher et
alO, Naunyn-schmiedebergl-s-Arch. Pharmacol. 280 [1973]
153--160). These actions take place at a bath concentra~
tion of from about 10 9 to about 10 6 M. In the spon-
taneously beating guinea pig atrium (K. Saameli, Helv. ~;
Physiol. Aeta 25 [1967] CR 219- CR 221) they inhibit the
positive inotropic adrenaline effect at bath concentra-
tions of from 0.005 to 2.S mg/l.
The compounds are therefore indicated for use
as a- and ~-blocking agents, e.g. for the prophylaxis
and therapy of diseases related to an adrenergic vaso-
constriction, and of coronary diseases, especially of
Angina pectoris. They are also useful for the treatment
of diseases related to an inhibition of howel motility,
especially of paralytic ileus. In view of their ant.-
arxhythmic actlvity they are also useful as antiarrhyth-
~ 100-4~51
mics.
The compounds of Example 1 and 19 exhibit parti-
cularly interesting activity as a- and ~-blockers. The
Example 10 com~pound exhibits particularly interesting
activity as a ~-blocker.
For these uses an indicated daily dose is rom
about 20 to about 100 my,conveniently given in divided `~
doses 2 to 4 times a day in unit dosage form containing
from about 5 to about 50 mg, or in sustained release
form .
The compounds of formula I also exhibit anti-
hypertensive activity, as indicated in standard tests.
For example, this activity may be observed in
the Grollman rat test [A. Grollman, Proc.Soc. Exp. Biol.
and Med. 57 (1944)~ 102] on s.c. administration of from
0.1 to 10 mg/kg animal body weight of the compounds,
and on p.o. administration of from 10 to 100 mg/kg.
The compounds are therefore useful as antihyper-
tensive agents. Especially interesting in this indica-
tion is the compound of E.;ample 1.
For this use an indicated daily dose 1s from
about 1 to about 50 mg, conveniently given in divided
doses 2 to 4 times a day in unit dosage form containing
from about 0.25 to about 25 my, or in sustained release
form.
..:
~ 15 ~ 100~4851
: ,:
The compounds of formula I also possess ~:
interesting metabolic activity. In particular, hey ~:
inhibit glycerol release and hyperglycemia stimulated
by isoproterenol in standard tests~
For example, inhibition of glycerol release
stimulatecl by isoproterenol is observed in vitro in
isolated at cells of epidiclymal fa~ tissue of rats,
the cells having been isolated in accordance with the
: :
method of M. Rodbell [J,Bicl. Chem 239, 375~380 (1964)], ~:
at a concentration of from about 0.1 to about 10 mg/
litre, and in vivo in rats at a dose of from about 0.1
:
to about 10 mg/kg body weight s.c.
: Inhibition of hyperglycemia is e.~. observed in
rats in vivo~at a dose of ron! about 0.1 to about 10
mg/kg animal body weight s.c.
The~compounds are tberefore lndicated for use
in the treatment: of lipolysis:in the blood and hyper-
glycemia induced by emotional stress, and are useful
therefore ior the treatment of, or prophylaxis of,
myocardlal infarction and appetite induced by er.~otional
stress.
: E~pecially interesting in this indication are
the compounds of Examples 2,5 and 19, especially the
compound of Example 5.
For these uses as metabolic inhibitors an indi-
., .
- 16 - 100-~851
cated daily dose ls from about 0.1 to about 200 mg,
conveniently given in divided ~oses 2 to 4 times a day
in unit dosage form containing from about 0.025 to
about 100 mg, or in sustained release form.
Vne gro~p ofcompounds of formula I, i.e. the
compounds of formula Iu
OH
OCH2C~ICH2NH-R
~ ~ Rl Iu
wherein RU
Ru is a group A- ~ R4 ,wherein
10 A is as defined above,
Rl, R2 and R4 have the significances indicated above ~ ~
for Rl, R2 and R~ and :
R3 with the exception of hydrogen has the significance
- indlcated above for R3,
with the ~rovisos, that
. a) the phenyl ring is separated by at Ieast two carbon
; atoms from the nitrogen atom of the 3-amino-2-hydroxy-
propoxy chain and ~ .
b) when ~2 is cyano, Ru addi~ionally may be alkyl of 3 ~
'' '
~ , , ,,, . ........................ ., ~ . ....... .
~: : ~:::, .. ., , :
~9~
- 17 - 100~4~51
.
to / carbcr. ator:s, .
exhibit activities that are unexpectedly more interesting
than those exhibited by known compounds o similar struc-
ture.
A preferred group of compoundq of formula Iu
are the compounds of forr~ula Iu'
OH
OCH2CHCH2NH-RU
~O ~ u' Iu'
wherein R3
R 1s a group a ~U ~ , wherein
A is as defined above,
is alkoxy of 1 to 4 carbon a~oms or halogen of
~ atomic number of from 9 to 35,
R4 is hydrogen and, when R3 is alkoY~y of 1 to 4
carbon.atoms, R4 additionally may be allcoxv
of 1 to 4 carbon atoms or, when R3 is halogen
of atomic number of from 9 to 35, R4 addi-
tionally may be halogen of atomic number of
from 9 to 35,
either
~ .
:'
`' ~ , . , ::,: : .: ' ' .: .' . ! `
', : : ,. , : ,. ',:: . ::.'' :: ::;: :', ', ' : ::
- 18 - 100-4851
i) RUl is h~drogen or methyl and
R2 is cyarlo, COORc or CH20Re, wherein ~c and Re are -
as defined above,
ox
s ii) ~ither ~1 ls me~hyl and RU2 is halogen of atomic
- nun~er of from 17 to 35
or Rl ls ~alogen of atomic number of fxom 17
to 35 and RU2 is hydrogen or methyl,
with th~ provisos, that
a) the phenyl ring is separated by at least 2 carbon
atoms from the nitrogen atom of the 3~amino ~-
hydroxypropoxy chaln and
b) when RU2 is cyano, Ru additionally may be alkyl
of 3 to 7 carbon atoms.
In general, the 2(S) optical isomers are more
active than the 2(R) optical isomers in ~he cardiovas-
cular ~ block~ng, metabolic and blood pressure lowering
tests.
The compounds of formula I may be administered
20 in pharmacsutically acceptable salt form. Such salt
~orms exhibit the same order of activity as the free
forms and are readilly prepared ln conventional manner.
The present invention also provides a pharmaceutical
.. composition co~,prising a compound of formula X, in free
:. .: , : . ":: . , :.
- :: . - ; , . ~
39~
. - ~.9 - 100-4851
form or in pharmaceutically acceptable salt form, in
association with a pharmaceutical carrier or diluent.
Such compositions may be in the orm of, for example,
a solution or a tablet.
Fuxther groups of compounds of formula I are
the following:
a~ Compounds of formula Ipa
1O~ '
OCHzCHCH2NH~RP
CN Ipa
H :~
wherein
10 RP is alkyl of 3 to 7 carbon atoms and
RP is hydrogen or methyl; :
b) compounds of formula Ipb~
OC~I 2CHCH 2NH-A~ RP
~I Ipb
N CN
Il
- wherein
~B9~9
: - 20 - 100-4851
RP and A are as defined above
R3 is hydroxy, alkoxy of 1 to 4 carbon atoms, halogen of
~tomic number o~ from 9 to 35, cyano, carbamoyl or
acetamido and
~ is hydro~en and, when RP is alkoxy of 1 to 4 carbon
atoms, RP additionally may be alkoxy of 1 to 4 carbon
atoms, or when RP is halogen of atomic number of from
9 to 35, RP additionally may be halogen of atomic
. nu~ber o~ from 9 to 35,
with the proviso that the phenyl ring is separated by
at least 2 carbon atoms from the nitrogen atom of the
3 amino-2-hydroxypropoxy moiety;
c) compounds of formula Ipc
OCH2CHCH2NH-A~RP ~:.
¦ Rl q Ipc
N ~ONR
H
wherein
Al ~ , RP, RP, Ra and Rb are as defined above
,, , ~ , . . . . .. .. . . .. . . .
with the proviso that the phenyl ring is separated by at
least ~ carbon atoms from the nitrogen atom of the 3-
. amino-2-hydroxypropoxy moiety;
:: , . . . .. ~ .
.: :: ~ : :,:: :: : : ::: : ~ .: :
~ 2l ~ 1~o-485
d) compounds of formula Ipd
OCH2C~ICH2NH A-XP~Rpd
~ ? ~ pd Rpd
wherein
A is as defined above,
; 5 elther i.) R1d is h~logen of atomic num~er of from
17 to 35 and
RP2d is methyl
or ii) RPd is hydrogen or methyl and
~ ~ is halogen of atomic number of from 17 to
.~ 10 35,
pd is hydrogen~or has the significances indicated above
for ~ :
R4pd has the si~nificances indicated above ~or RPand
XP i5 oxygen or sulfur,
15 ~Yith the proviso that XP is separated by at least 2
carbon atoms Erom the nitrogen atom of the 3-amino-2-
.
hydroxypropoxy moiety..
