ot~7
This invention rel.ates to heterocyclic compounds
and is concerned with novel indolizine derivatives and with a
method oE preparing the said novel derivatives.
The indolizine derivatives with which the present
invention is concerned are the compoun.ds represented by the
general formula :
Xl
~-C-A-O ~C~12) -~ I
O Rl
and the pharmaceutically acceptable acid addition salts thereof,
for example the oxalate or hydrochloride, wherein :
R represents a branched or straight-chain alkyl
radical having from 1 to 8 carbon atoms, or a phenyl group non-
substituted or bearing one or two substituents, which may be
the same or differentl selected from halogen atoms, for example.
fluorine, chlorine and bromine and from lower alkyl and alkoxy
groups for example methyl and methoxy,
Xl represents hydrogen, chlorine, bromine iodine,
methyl or methoxy,
A represents a group selected from :
X Cl Cl
~= ~ / and R3=~
x3
in which X2 represents hydrogen, chlorine, bromine, iodine,
methyl or methoxy and X3 represents hydrogen, chlorine, bromine,
iodine or methyl,
Rl represents a methyl, ethyl, n-propyl or n-butyl
radicall ~i~
~5;2(~7~
n represents an i~.tege~ i~ the range of 2 t~ 6
inclusive, with the proviso that ~he~ both X2 and X3 ~epresent
hydrogen or methyl, Xl is other than hydrogen.
In the aforesaid general formul.a I, R represents,
preferably, a branched- or straight-chain alkyl radical having
from 1 to 8 carbon atoms, a phenyl radical, a mono-fluoro-,
mono-chloro-, mono-bromo-, mono-methyl-, or mono-methoxy-phenyl
radical, a di-fluoro-, di-chlc,ro-, di-bromo-phenyl radical or
a methyl-phenyl radical substi.tuted in the aromatic moiety by
an atom of fluorine, chlorine or bromine.
The present invention also provides a process for
preparing indolizine derivatives corresponding to the general
formula (I):
Xl
C-A-O-(CH2)n-N \ (I)
Rl
and pharmaceutically acceptable acid addition salts thereof
wherein:
R represents a branched- or straight-chain alkyl radical
having from 1 to 8 carbon atorns, or a phenyl group non-substituted
or bearing one or two substituents, which may be the same or
different selected from halogen atoms and from lower alkyl and
alkoxy groups,
Xl represents hydrogen, chlorine, bromine, iodine,
methyl or methoxy,
A represents a group selected from:
R2 ~ Cl Cl
X3
- ~ r~
~.~ ~ 2 ~
. ,,~ . ~
;z~
in which X2 represents hydrogen, chlori~e, bromine, .iodine,
methyl or methoxy and X3 repre,ents hydrogen,chlorine, bromine,
iodine or methyl,
Rl represents a methyl, ethyl, n-propyl or n-butyl
radical,
n represents an integer in the range of 2 to 6
inclusi~e with the proviso that when both X2 and X3 represent
hydrogen or methyl, Xl is other than hydrogen, characterized in
that
(A) to obtain an indolizine derivative corresponding to
the general formula (I) as defined above and phar-
maceutically acceptable acid addition salts thereof,
a substituted bromoalkoxy-benzoyl-indolizine of the
general formula: Xl
R
-A-O-(CH2)n-Br
o
wherein Xl, R, A and n have the same meanin~ as defined
above, is condensed, with a secondary amine oE the
general formula:
/R
H-N \
Rl
in which Rl has the same meaning as defined above,
to form the required indilizine derivative which,
if desired, is reacted with an appropriate organic
or inorganic acid to provide a pharmaceutically
acceptable acid addition salt thereof,
(B) to obtain an indolizine derivative corresponding
........... .~ Oi
~ ~ - 2a -
~, "
~lS21~77
to the general formula (I) a.s defined above and
pharmaceutically acceptable acid addi-tion salts
thereof, an alkali metal salt of a substitu-ted
indolizine derivative represented by the general
formula: Xl
~/ ~ R
N l-C-A-O~
o
in which R, A and Xl have the same meaning as defined
above, is condensed with an alkylamino derivative of
the general formula:
~ Rl
Z (C 2)n
Rl
or an acid addition salt thereof, in which Z represents
a halogen atom or a p-toluenesulphonyl-oxy group and n
and Rl have the same meaning as defined above to form
the re~uired indolizine derivative which, if desired,
is reacted with an appropriate organic or inorganic
acid to provide a pharmaceutically acceptable acid
addition salt thereof,
or (C) to obtain an indoliæi.ne derivative corresponding to
the general formula (I) as defined above and pharmaceu-
tically acceptable acid addition salts thereof, wherein
Xl represents chlorine, bromine or iodine, X2 repre-
sents chlorine~ bromine or iodine, methyl or methoxy~
and X3 represents chlorine, bromine, iodine or methyl
an indolizine derivative of general formula:
3Q
- 2b -
~. .,~
` -- 1152(~77
R / ,R
C-A-O-(cH2)n-N \
Rl
in which R, A, n and Rl have the same meaning as
given above is reàcted:
a) either with N-chlorosuccinimide, between 0C and room-temperature,
to form the required indolizine derivative in which Xl repre-
sents chlorine,
b) or with bromine or iodine, th~ reaction taking place at room-
temperautre in the presence of an alkali metal acetate, to
form the required indolizine derivative in which Xl represents
bromine or iodine
the obtained indolizine derivative being reacted, if desired,
with an appropriate organic or inorganic acid to provide a
pharmaceutically acceptable acid addition salt thereof.
The indolizine derivatives of the invention have been
found to posses useful pharmacological properties capable of
rendering them of considerable value in the treatment of certain
pathological syndromes of the heart, more particularly in the
treatment of angina pectoris and auricular and ventricular
cardiac arrhythmias of various origins.
The present invention is also concerned with pharma-
ceutical and veterinary compositions containing, as active
principle, at least one indolizine derivative of formula I
or a pharmaceutically acceptable acid addition salt thereof, in
association with a pharmaceutical carrier or excipient therefor.
Another object of the present invention is to provlde
a process for preparing pharmaceutical or veterinary compositions
whereby at least on,e indolizine derivative of formula I or a
pharma~eutically acceptable acid addition salt thereof, is
; ''~
_ 2c -
. .~.~ .
1~5;~(~77
associated with a pharmaceutical carrier or excipient therefor.
Yet another object of the present inven-tion is to
provide a method of treating pathological syndromes of the heart
and particularly angina pectoris and cardiac arrythmias in a
subject needing such treatment which method comprises administer-
ing to said subject an effective dose of at least one indolizine
derivative of formula I or a pharmaceutically acceptable acid
~lSZ~77
addition salt thereo.
Daily dosages will be preferably ~rom 100 to 300 mg
of active principle by oral rollte and preferably from 1 to 3 mg
of active principle by parenteral route to a subject weighing
60 kgs.
As indicated above, the compounds of formula I may b~e prepared,
in accordance with the invention, by condensing, advantageously in an inert
solvent such as, for example benzene or toluene, a substituted bromoalkoxy-
benzoyl indolizine of the general formula (IIa):
~ _c_A_o-(cll2)n-~r (IIa)
wherein Xl, R, A and n have the same meaning as in formula I,
with a secondary amine of the general formula (IIIa):
Rl
H-N (IIIa)
Rl
in which Rl has the same meaning as in formula I, to form the
required indolizine derivative of formula I which, if desired,
is reacted with an appropriate organic or inorganic acid to
provide a pharmaceutically acceptable acid addition salt thereof.
The compounds of formula I may alternatively be
prepared by condensing, advantageously in an aprotic solvent
such as, for example, acetone, methyl ethyl ketone or toluene,
an alkali metal salt, preferably the potassium or sodium salt
or an appropriately substituted indolizine derivative represent-
ed by the general formula (II):
. - 3
l~lS~ 7
Xl
R (II)
~ -C-A-OH
in which R, A and Xl have the same meaning as in formula I,
with an alkylamino derivative of the general formula (III):
Z (C 2)n \ (III) .
Rl
or an acid addition salt thereof, in which Z represents a hologen
atom such as chlorine or bromine or a p-toluenesulphonyloxy
group and n and Rl have the same meaning as in formula I to give
the required indolizine derivative which, if desired, is reacted
with an appropriate organic or inoganic acid to provide a phar-
maceutically acceptable acid addition salt thereof.
In accordance with a further aspect of the invention,
the indolizine derivatives of formula I in which Xl represents
chlorine, bromine or iodine and A represents the group R3 or a
group R2 in which X2 represents chlorine, bromine, iodine,
methyl or methoxy and X3 represents chlorine, bromine, iodine or
methyl can also be prepared by reacting an indolizine derivative
of general form~la (IVa):
l ~ ~ -C-A-0-(C~)n~
O Rl I .
in which R, R1 and n have the same meaning as in formula I and
A represents the group R3 or a group R2 in which X2 represents
~ ~ _ 4
~i5Z(~77
chlorine, bromine, iodine, methyl or methoxy ancl X3 represents
chlorine, bromine, iodine or methyl :
a) either with N-chlorosuccinimide, the reaction a~vantageously ~aking place
in a suitable medium such as dichlorethane and between 0 C
and room-temperature, to obtain the required compound of
formula I in which Xl represents chlorine,
b) or with bromine or iodine, the reaction taking place at room-
temperature advantageously in a suitable solven-t such as dioxan and in the
presence of an alkali metal acetate, for instance sodium
acetate, to obtain the required compound of formula I in which
Xl represents bromine or iodine,
the obtained indolizine derivative being reacted,if desired, wi-~ an
appropriate organic or inorganic acid, to provide aphannaceutically
acceptable acid addition salt thereof.
The compounds of formula (IIa)can be obtained by
condensing, advantageously in an inert medium such as for
example acetone or methyl ethyl ketone, an alkali metal salt,
preferably the potassium or sodium salt, of a compound of formu-
la ~II)hereabove, with a dibromoall<ane of the general formula (VI):
Br-(CH2)n-Br
in which n has the same meaning as in formula I to obtain the
required compound of formula (IIa).
The compounds of formula(II)in which A represents the
group R2 are either compounds described in copending British
patent application N 80 21924 filed on the 4th July, 1980 or
compounds which can be prepared in accordance with methods
described in the aforesaid British patent application.
The other compouncls of formula (II), i.e.those in
which A represents the group R3 can be obtained by reacting
the appropriate 2-substituted-indolizine with 2,3-dichloro-4-
acetyloxy or 4-tosyloxy-benzoyl chloride. This benzoyl chloride
.,.;. ~
~ - 5
77
derivative is itsel preparedl by aeetylating 1,2-dichloro-
anisole in aceordance with the eonditions of the FRIEDEI, and
CRAF~S reaetion oxydating the acetyl derivative so obtained with
sodium hypoehlorite to form the corresponding benzoic aeid
derivative, demethylating with hydriodic aeid in aeetic acid to
obtain 2,3-dichloro-4-hydroxy-benzoic acid~ This last-cited
compound is then reacted with acetyl chloride or tosyl ehloride
to form the required 2,3-dichloro-4-acetyloxy or 4-tosyloxy-
benzoie aeid and the eorresponding aeyl chloride is subsequently
formed in aeeordance with known procedures, for instance by
reaetion with thionyl ehloride.
With respeet to the eompounds of formula IVa, these
are eompounds falling within the seope of formula I above.
Indolizine derivatives are already known whieh have
pharmaeologieal effeets eapable of rendering them useful in the
treatment of angina peetoris and eardiac arrhythmias.
In this eonneetion, British patent N l,518,443 can
be eited whieh more partieularly deseribes 2-ethyl-3-~4-(3-di-
n-butylaminopropyl)-oxy-benzoyl~-indolizine known under the
non-proprietary name of butoprozine. In the British patent in
question, antianginal propert;ies are attributed to eompounds
deseribed therein sinee they produee the following eardiovaseular
effeets :
- bradyeardia
- deerease in arterial pressure
- ~-antiadrenergic effect
- ~-antiadrenergic effect
- eoronarodilating effeet.
The inerease of the blood-flow to the myocardium provoked by
30 these compound is, in faet, only slight beeause their aetion
does not last long : it is e~erted for only a few minutes after
an intravenous injeetion.
-- 6 --
P7'7
Furthermore, the compounds described in the aforesaid
British patend only possess a weak ~-adrenergic antagonist
action. This action is only slight at the minimum dose at which
the other four cardiovascular effects cited above manifest
themselves to a significat degree~
It has now been found quite surprisingly that by
substituring in an appropriate manner with one or more methyl
or methoxy groups or halogen atoms for example chlorine, bromine
or iodine, dialkylaminoalkyloxybenzoyl indolizine derivatives,
compounds are obtained which present a much broader spectrum of
cardiovascular properties then the derivatives of British patent
N 1,518,443 while showing less toxicity.
Thus, it has been possible to demonstrate that the
indolizine derivatives of the invention can be regarded as
powerful coronarodilators since they are capable of increasing
the blood-flow to the myocardium to a marked degree and for a
longer period oE time than butoprozine. Compounds of the
invention were also found to reduce cardiac frequency and arterial
pressure in the animal.
Furthermore, the indolizine derivatives present a ~-
antiadrenergic effect which iS much more powerful than that of
the derivatives of the aforesaid British patent. At the minimum
dose required to produce bradycardia, a reduction in arterial
pressure, ~-antiadrenergic and coronarodilatory effects to a
significat degree, the ~-antiadrenergic effect is, in fact,
only slight in the case of the derivatives of the British patent
in question whereas it is much stronger with the indolizine
derivatives of the invention.
Moreover, the compounds of the invention reduce the
consumption of oxygen by the myocardium calculated by multiplying
the difference between the artirial and venous blood in oxygen
by the coronary blood-flow. Thus the compounds of the invention
~lS2(~77
cause a consi~erable reduction in the arterio-venous difference
which induces a decrease in t:he consumption of oxygen in spite
of the increase of the coronary bloo-Elow.
Furthermore, unlike butoprozine, these beneficial
effects on the consumption of oxygen are obtained with the
compounds of the invention without any decrease in the con-
tractility of the myocardium.
It has been further demonstrated that the derivatives of
the invention are less toxic than the compounds of British
10 patent N 1,518,443. Acute toxicity tests carried out by intra-
venous and oral routes in the animal have shown that the lethal
doses are higher in the case of compounds of the invention than
in the case of derivatives of the British patent in question.
Furthermore, higher blood levels can be obtained with
compounds of the invention than with butoprozine.
Thus, it has been shown that the same oral dose of
l-bromo-2-methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-
benzoyl~-indolizine and of butoprozine administered to the
dog induces a blood level which is three times higher with the
compound of the invention than with butoprozine. Likewise,
the compounds of the invention, when administered in long-term
treatment per os in the dog have shown no cardiac toxicity as
represented by ventricular arrhythmia which is not the case with
butoprozine.
Finally, the indolizine derivatives of the invention
exert a milder depressant action on the contractility of the
myocardium than does butoprozine.
In man, an attack of angina pectoris is the painful
consequence of a deficiency between the supply and the requirement
in oxygen of the myocardium.
A compound can thus be active in the treatment of
angina pectoris either by increasing the supply of oxygen or by
-
1~5iZ~7~7
devreasing the need for oxygen. Amongst the products commonly
used in humans for treating angina pectoris, can be cited
dipyridamole amongst the coronarodilators and amiodarone amongst
the compounds which decrease the consumption of oxygen by the
myocardium.
Comparative tests have~ however, shown that the
compounds of the invention are very superior to dipyridamole
and amiodarone from several points of view.
In particular, it has been shown that dipyridamole
does not decrease the consumption of oxygen by the myocardium
and that amiodarone cannot be regarded as a coronarodilator.
The derivatives of the present invention exert their
effect through both of these factors~ Thus, they decrease the
consumption of oxygen by the myocardium through their metabolic
effects and also increase the coronaty blood-flow in a long-
lasting manner. Moreover, they are capable of preventing or
curing nct only arrhythmias induced by ischemia of the myocardium
but also the auticular and ventricular arrhythmias of widely
varying origins.
Thus, it appears that the halogenating, methoxylating
or methylating o indolizine derivatives of British patent N
1,518,443 gives rise to compounds possessing a novel spectrum
of pharmacological properties valuable in the treatment of
cardiac deficiencies.
For instance :
- thesites of the myocardium which are insufficiently irrigated
can be nourished by means of the coronarodilating effect which
can induce the development of an additional collateral circu-
lation . This effect is valuable for the treatment of both
anginal pain and the disturbances of rhythm consequent upon
ischemia of the myocardium.
- the antiadrenergic effect is also valuable for the treatment of
_ 9 _
~l~ZC~7~'7
both angina pectoris and cardiac arrhythmia in view of the
important role played by hyperacti,vity of the sympathetic
system in the etiology of these two cardiac diseases.
Since the physiological mediator of the sympathetic
system is epinephrine, a compound which inhibits all the effects
of epinephrine will probably be moxe active than a compound
which only inhibits a part of these effects.
For this reason, the compounds of the present invention
which inhibit both ~and ~effects,of epinephrine present an
advantage over the derivatives of the British patent N 1,518,443
which practically only inhibit the ~effects at the minimum dose
at which the other pharmacological cardiovascular effects occur.
Amongst the compounds of the invention which have
shown the most outstanding anti-anginal potentialities, the
following may be cited :
1-Bromo-2-methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-
benzoyl~-indolizine
2-n-Butyl-3-C4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-
indolizine
2-Ethyl-3-~4-,(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoyl~-indolizine
2-n-Butyl-3-f4-(3-di-n-butylaminopropyl)-oxy-3-chloro-benzoy~J-indolizine
2-Isopropyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3,5-dichloro-
benzoyll-indol,izine
l-Bromo-2-phenyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-chloro-
bensoyl~- indolizine
l-Chloro-2-ethyl-3- ~4-(3-di-n-butylaminopropyl)-oxy-3-chloro-
benzoyl'l-indolizine
l-Chloro-2-n-butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-benzoyl]-
indolizine
1-Bromo-2-(4-chloro-phenyl3-3-~4-(3-di-n-butylaminopropyl)-oxy-
3-chloro-benzoyl]-indolizine
these compounds being in the form of the free base or of a
-- 10 --
llS~ 77
pharmaceutically acceptable acid addition salt such as, for
example, the hydrochloride or acid oxalate.
The results of pharmacological tests carried out
in order to determine the cardiovascular properties of the
compounds of the invention are given hereunder.
I, Antianginal proPerties
1) Effect on blood-flow to the myocardium.
This test was carried out in accordance with the technique
described by R. CHARLIER & J.BAUTEIIER in Arzneimittel - Forschung
"Drug Research" 23, n 19, 1305-1311 (1973).
It was undertaken on anaesthetized dogs which received the
substance under study by intravenous route. The intensity of
the maximum effect on blood-fLow to the myocardium was expressed
in percentage of the corresponding value before injection. The
time required for the maximum effect to decrease by 50% repre-
sented the duration of the effect. This time was measured in
minutes.
-- 11 --
il5~2~77
The following results were registered :
RX2 _o / R
i C~ (CH2) n N~
3 . Rl
Xl x2 X3 R R1n Dose Max. Time
(mg/ lnCrea requi-
. kg) se~(%) decdrea-
~ _ se
Br Br H C2H5 n-C4Hg 310 60 90
Br Br H CH3 n-C4Hg 310125 40
Br Br EI n-C4Hg n~C3H7 3 lo 100 20
Br Br H 3 7 n~C3H7 3 10 90 20
Br Br H ~ n~C3H7 3 10 100 20
,Br
Br Br H ~ n-C4Hg 3 10 150 100
H Br H ~ ~ -Br N-C4~Ig 310 90 25
Br Br H CH3 n-C4Hg 310 77 45
H Br H 3 7 n-C4Hg 32 120 25
H Br H n-C4Hg n-C4Hg 3 5 70 60
Br Cl H iso-C H n-C4Hg 3 5 133 20
Cl H H n-C4Hg n-C4~Ig 3 10 60 30
H Cl C1 iso-C3H n-C4Hg 3 10 30 75
H Cl Cl - ~ > -Br n-C4Hg 3 10 45 15
H C1 ¦ Cl iso-C3H7 n-C4H9 3 10 30 75
. - 12 -
~15Z~
H C 1 H n-C 4H 9~ ~ 1 0 3 0 ; 4 S
H -.. Cl H ~~ n~C3H7 38 45 25
El Cl H i so-C H7 n- C3117 35 8 0 9 0
Br Cl H ~ n-C4Hg 310 90 90
Br Cl H n-C4Hg n~C3H7 310 40 90
Br Cl H ~ ~ -Br n~C3H7 310 50 50
H Cl H n-C4Hg n-C4Hg 35 75 30
H Cl H C2H5 n-C4EIg 36 70 45
Br Cl H -~-Cl n~C3H7 310 63 45
H Cl H ~ ~ -Br n-C4Hg 310 60 2 5
Br Cl H n-C l-I n-C~EIg 32 . 5 50 60
Cl Cl H ~~ n-C3I~7 38 70 90
Cl Cl H C2H5 n-C4Hg 31 40 15
Cl Cl H C2H5 n~C3H7 33, 3 60 25
Cl , ~ _~_ Cl n-C3117 35 50 40
Butoprozine 10 120 4
Amiodarone 10 36 7
30 These results clearly show that the compounds of the invention
are more valuable than butoprozine and amiodarone as regards the
effects on blood-flow to the mycardium.
- 13 -
2) Atladrenerqlc ef~ects
The purpose of this test was to determine the
capacity oE the compounds under study to reduce epinephrine-
increased blood-pressure (anti-~effect) and epinephrine-
accelerated heart rate (anti ~ effect) in the do~ previously
anaesthetized with pentobarbital and atropinized.
- Ant~ ==e=_=ct
For each dog, the dose of epinephrine was first
determined which provoked a reproductible increase by about
100 mm. Hg in the arterial pressure (between 5 and 10 ~g/kg).
After that/ the dose of epinephrine so determined
was administered followed by a dose by intravenous route of the
compound to be studied~ The percentage of reduction of the
hypertension provoked by the compound under study in comparison
with the hypertension previously obtained (about 100 mm.Hg)
was then registered.
- Aati~~==8=f==Ct
During the same test as that described above, the
epinephrine provoked a reprocluctible increase in the heart-
rate of about 70 beats/min. The percentage of reduction of theepinephrine-induced accelerat:ion of heart-rate produced by the
compound under study in comparison with the tachycardia previ-
ously measured (about 70 beats) was then registered.
In both cases, the results were expressed as follows:
+ for a <50%-reduction of the increase in pressure or cardiac
frequency
++ for a ~50~-reduction of t:he increase in pressure or cardiac
frequency
+++ for a subtotal reduction of the increase in pressure or cardiac
frequency
- - 14 -
1~52(~77
The foLlowing results were registered:
Xl x2 X3 R Rl Dose Anef~ ~nef~
Kg) ~ect fect
, _. .... _ ~ - .
Br Br H C2H5 n~C4H9 3 lO +++ +++
. Br H H C2H,5_ n-c4H9 36 +++ +++
Br E3 r H _ </.=,9-F n-C 4Hg 3 l 0 +++ ++
Br Br Br 3 7 n-C3H7 3 lO +++ +++
H Br H _ ~ ~ n-c4H9 3 10 +++ ++
H Br EI C2H5 n-C4Hg 3 7.5 +++ ++
H Br H n-c4H9 n-c4H9 35 +++ ++
H Br H n-C4Hg n~C3H7 35 +++ ++
Br Br H CH3 n-c4H9 3~105 +++ +++
H Br H n-C4Hg n-C4Hg 3( 5 +++ ++
~10 +++ +++
H Br H i So-C H n-C4Hg 36 +++ ++
Cl E~ H n-C4Hg n~C4H9 3 lO +++ ++
Cl H H n~C3H7 n~C4H9 3 7.5 +++ +++
H Cl H n-C4Hg n~C4H9 3 10 +++ ++
H Cl H C2H5 n~C3H7 3 lO++ ++
H Cl H C2H5 n-C4Hg 3 6+++ ++
H Cl Cl iso C3~E7 n-c4H9 3 10 ++ ++
H Cl H ~ ~ n-c4H9 3 lO ++ ++
H Cl H iso-C3E~7 n-C3H7 3 lO ++ ++
Br Cl H ~~ n-C4Hg 3 lO ++ +++
Br Cl H c2 5 n-C3H7 3 7 . 8 ++ ++
Br Cl H -~-Br n-C3H7 3 lO ++ ++
-- :15 --
2(~77
Br Cl H n~C4H9 n~C3H7 3 10 ++ +
Br Cl H - ~ Cl n~C4H9 3 10 ++ ++
Br Cl II ~ ~_Br n~C3H7 3 10 ++ ++
. Br Cl H C2H5 n~C4H9 3 10 +++ +++
Br Cl H~ ~_Cl n~C3H7 3 10 +~+ ++
H Cl H~ Br n-C4Hg 3 10 ++ +
~B:r
Br Cl H ~ ~ n~C3H7 3 10 +++ +++
3r Cl ~ ~ 3H~n-C4~19~ ~ 10 ~ +++ +++
Cl Cl h ~n~C3H7 3 8 -~++ ++
Cl Cl H C2H5n-C4Hg 3 0.5 +++ +
Cl Cl H C2H5_n~C3H7 3 3.3. +++ +++
Cl H H - ~ ~ Cl n~C4E19 3 10 +++ ++
Cl 11 M - ~ ~-Cl n-C3117 3 5 +-~ +
Cl H H ~ n-C4119 3 5 ~ +++
H Br H iso-C3H7 n-C3117 3 7.5 +++ +-~
Br OCH3 11 CH3 n~C3H7 3 7.5 ++ ++
Cl Cl Cl C~H5 n~C3H7 3 10 ++ ++
Cl Cl Cl ~ n-C4Hg 3 10 +++ ++
Cl Br H C2H5 n-C4Hg 3 10 +-~+ -~++
Cl Br Br ~ ~ ~ n~C3H7 3 10 + +
.
- ]-6 -
~5~(~77
Br Cl Cl ~ n~C3H7 3 10 ++ ++
Br Cl Cl ~ ' n-c4H9 3 10 ++ ++
Br CH3 CH3 CH3 n-C4Hg 3 10 +++ ++
H Br Br - ~ -Br n~C3H7 3 10 +++ +++
H Br Br _ ~ n-C4Hg 3 10 ++ ++
OCH3 Cl H _ ~ ,n-C3ll7 3 l0 +++ +++
OCH3 OCH3 H _ ~n~C3H7 310 ++ ++
H OCH3 H C2II5 n-C4Hg 310 +++ ++
Br OCH3 H C2H5 n-C4ll9 3 5 ++ ++
Br OCH3 H CH3 n~C4H9 3 7 ++ ++
Br OCH3 H 3 n-C3B7 37 5
Butoprozine 5 +++ +
Amiodatone 10 ++ ++
These results again show that the compounds of the invention
are more valuable than those of the prior art.
II. Anti-arrhythmic properties.
These properties were demonstrated after administration
of the compound under study by intragastric route to mice using
the LAWSON test (J. Pharmac. Exp. Therap. 1968, 160 (l) p. 22-31).
The arrhythmia was provoked by making the animals
inhale chloroform to total asphyxia and by later observing the
ventricular rhythm.
The dose of compound protecting 50% of the animals
against ventricular fibrillation i.e. the AD50 was then recorded.
The following results were reg:istered :
- 17 --
l~Ci~77
Xl X2 X3 R Rl n AD50
(my/kg)
, ._ . . _ . .
Br Br H CH3 n-C4Hg 3 180
Br H n~C4H9 4 9 3 170
Butoprozine 270
III Toxicity
Acute toxicity
_____________
Acute toxicity tests were carried out on rats and mice.
The following results were registered in comparison
with butoprozine.
The compounds of the invention were used in oxalate
acid form except those marked (x) which were tested in
hydrochloride form.
a) B=y=i~tr==ven==o===_o======to==r===
Xl X2 X3 R Rl n(mg/kg
(x) Br Br H CH3 n~C4M9 3 70
H Br H 4 9 n-C4Hg 3 60
(x) H Cl H C2H5 n~C4E~9 3 65
H Cl Cl iso-C H n-C4Hg 3>100
(x) Br Cl H~ ~ ~ n-C4Hg 3>lO0
(x) H Cl EE n~C4H9 n-C4H9 3 > 50
, (LD ~50 mg/kg
Cl Cl HC2H5 n~C4H9 3 50
Cl H E~4 9 ~-C4H9 3 50
Br Cl H- ~ ~-Cl n-C4Hg 3>lO0
(Ld~ lO0 mg/kg
Botoprozine 22
- 18 -
77
b) By _nt=a=venous=ro=t=e==t=o=m=_ce=
(x) Br¦ Br ¦ El ¦ CH3 ¦ n~C4ll9 ¦ 31 50
Butoprozine 25
c) By=i=n=t==g=s=__=c=_o===t==t=o=l=ni=c=
(x) Br ¦Br ¦ H ~ CH3 ~ n~C4Hg ~ 3 ~>5000
Butoprozine 1600
These results show that the compounds of the invention are far
less toxic than butoprozine.
- C===dl==c==to=l=_=a=c=e====d=a==n==a_=t=o=xl=cl=ty=l=n=_o==n~-=t=e==m=t=oxi=city
====t=
l-Bromo-2-methyl-3-~4-(3-di-n--butylaminopropyl)-oxy-3-bromo-
benzoyl~-indolizine hydrochloride, 2-n-butyl-3-~4-(3-di-n-
butylaminopropyl)-oxy-3-bromo--benzoyl~-indolizine hydrochloride
and 2-n-butyl-3-~4-(3-di-n-but:ylaminopropyl)-oxy-3-chloro-
benzoyl~-indolizine hydrochloride provoked neither venticular
arrhythmia nor mortality at the dose of 200 mg/kg/day by oral
route in the dog.
As against this, butoprozine was found to provok
ventricular arrhythmia.with a close as low as 50 mg/kg/day by oral
route in the dog, the lethal close of this compound being between
50 and 100 mg/kg/day.
It will be appreciated that for therapeutic use the
compounds of the invention wil.l normally be administered in the
form of a pharmaceutical or veterinaty composition, which may
be in a dosage unit form appropriate to the desired mode of
administration.
Thus the pharmaceutical or veterinaty composition may
be in a dosage unit form suitable for oral administration, for
example a coated or uncoated tablet, a hard- or soft-gelatin
capsule, a packaged powder, or a discrete amount of a suspension,
-- 19 --
~15Z(~
or a syrup. The composition may alternatively take the form
of a suppository Eor rectal administration, or of a solution
or suspension for parenteral administration.
When in dosage unit form, the composition may contain
for example from 15~ to 50~ by weight of the active ingredient
per dosage unit for oral administration, from 3% to 15% of the
active ingredient per dosage unit for rectal administration
and from 3% to 5~ of the active ingredient per dosage unit
parenteral administration.
Irrespective of the form which the composition takes,
the pharmaceutical or veterinary composition of the invention
will normally be prepared by associating at least one of the
compounds of formula I or a pharmaceutically acceptable acid
addition salt thereof with an appropriate pharmaceutical carrier
or excipient therefor, for example one or more of the following
substances : milk sugar, starches, talc, magnesium stearate,
polyvinylpyrrolidone, alginic acid, colloidal silica, distilled
water, benzyl alcohol or flavouring agents.
The following Examples illustrate the invention :
EXAMPLE 1
l-Bromo-2-ethyl-3-[4-(3-di-n-propylaminopropyl)-oxy-3-bromo-
benzoyl~-indolizine and its acid oxalate.
a) l-bromo-2-ethyl-3-/ 4-(3-bromoeropyl)-oxy-3-bromo-benzoy~_-mdollzlne
A mixture of 7.7. g (0.018 mol) of 1-bromo-3-~3-bromo-
4-hydroxy-benzoyl)-indolizine, 5 g (0.036 mol) of anhydrous
potassiuM carbonate and 50 ml of methyl ethyl ketone was stirred
in a fla9k for 30 minutes. To this reaction medium 14.4 g
(0.072 mol) of 1,3-dibromo-propane were then added and the
mixture was refluxed for 20 hours. After cooling, the mineral
30 salts were filtered out and wasked with acetone. The solvents
were evaporated off together with the 1,3-dibromo-propane in L
excess. In this manner, 13.2 g of a product were obtained which
- 20 -
~152077
were purified by elution chrc~matography on silica using benzene
as elution agent. A first fraction of an unknown product was
obtained and then a second fraction vf ~ g of the desired
product.
In this manner, 1-bromo-2-ethyl-3- L4- (3-bromopropyl)-
oxy-3-bn~o-benzoyl7-indolizine was obtained in a yield of 83.6%.
M.P. : 105-106 C.
b) l_Bromo-2-ethyl-3-C4-(3-di-n-~ro~ylamlno~ro~yl)-oxy-3-bromo-
benzoylZ-indollzine
A mixture of 2.2. g (0.004 mol) of 1-bromo-2-ethyl-
3-r4-(3-bromopropyl)-oxy-3-bromo-~enzoyl7-1ndolizlne, 1.2 g (0.012 mol)
of N,N-di-n-propylamine and 25 ml of toluene were refluxed in a
flask for 20 hours. After cooling, the reaction medium was
washed twice with 10 ml of water and the solvent was evaporated
off under vacuum. Thus, 2.5 g of a residue were obtained which
were purified by elution chromatography on silica using ethyl
acetate as eluent. By this method, 2.4 g of 1-bromo-2-ethyl-
3-L4-(3-di-n-propylaminopropyl )-oxy-3-bromo-benzoylJ-indolizine
in free base form were obtained.
c) 1 Bromo-2-ethyl-3-~4-(3-di-n-propylamino~ropyl)-oxy-3-brom
_____________ ____..__ ____.___ __ ______ __ _ ___ _________
benzoyl]- indolizine acid oxalate.
__.__ ____~_______________.________
The base previously obtained was dissolved in 30 ml
of ethyl ether and then react~d with 0.55 g of oxalic acid
in 7Q ml of ethyl ether to give 2.4 g of the desired salt in
crude form. From this quantil:y, 2.0 g of pure 1-bromo-2-ethyl-
3-~4-(3-di-n-propylaminopropy])-oxy-3-bromo-benzoyl~- indolizine
acid oxalate were obtained by recristallization from 75 ml of
isopropanol.
Yield : 75%
M.P. : 139-140C
- 21 -
77
EX~MPLE 2
l-Bromo-2-methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-
benzoyl¦-indolizine and salt, thereof.
_ .. _ . . . ..
Into a 1-1 flask, a mixture of 130 ml of water, 180 ml
of toluene, 73 g (0.178 mol) of 1-bromo-2-methyl-3-(3-bromo-
~ 4-hydroxy-benzoyl)-indolizine, 42.7 g (0.21 mol) of l-di-n
butylamino-3-chloro-propane and 34.5 g of potassium carbonate
was introduced while stirring. The reaction medium was heated
under reflux for 20 hours. ~fter cooling to room-temperature,
the aqueous phase was decanted and the toluene layer was washed
three times, each time with 200 ml of water. The toluene
solution was transferred to a flask and, under atmospheric
pressure, toluene was distilled off to dryness and the residue
so obtained was cooled.
In this manner, crucle l-bromo-2-methyl-3-[4-(3-di-n-
butylaminopropyl)-oxy-3-bromo-benzoyl]-indolizine was obtained
in free base form.
The following salts of this compound were then prepared :
a) hydrochlorlde
To the free base previously obtained, a solution of
8 g of hydrochloric acid in 61 ml of ethyl acetate was added.
The precipitate so formed, i.e. 104 g, was suction-filtered,
washed with ethyl acetate and recrystallized from 500 rnl of
isopropanol. In this manner, 93 g of 1-bromo-2-methyl-3-
~4-(3-di-n-butylaminopropyl)-oxy-3-bromo-benzoyl~-indolizine
hydrochloride were obtained.
~ield : ~4.7% M.P. : 172 C.
b) acid oxalate
_____________
To an ethereal solution of the base previously obtained,
an equimolecular solution of oxalic acid in ethyl ether was
added. The salt so obtained was recrystallized from isopropanol.
- 22 -
l~S;~(~77
In this manner, l-bromo-2-meth~L-3-~4-(3~di-n~
bytylaminopropyl)-oxy-3-bromo-benzoyl]-indolizine acid oxalate
was obtained. M P. :89-90 C.
EXAMPLE 3
2-Methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3,5-dibromo-
benzoylJ-indo;lizine acid oxa:Late.
Into a 250 ml-flask, a mixture of 4 g (0.01 mol) of
2-methyl-3-(3,5-dibromo-4-hydroxy-benzoyl)-indolizine and 150
ml of acetone was introduced After the indolizine dissolved,
there were added 4 g of anhyclrous potassium carbonate and 2.2 g
of di-n-butylaminopropyl chloride~
While stirring, the reaction mixture was refluxed
for 16 hours. After cooling to room-temperature, the mineral
salts were filtered out and washed with acetone on the filter.
The acetone was then distilled off under reduced pressure using
a rotatory evaporator and the oily residue was dissolved in
about 100 ml of ethyl acetate. The medium was filtered on a
filter and 1.5 g of anhydrous oxalic acid was added to the
filtrate. The reaction medium was allowed to stand and the
oxalate which crystalIized was filtered out, washed on the
filter with ethyl acetate and dried under vacuum.
In this manner, 6.2 g of 2-methyl-3-[4-(3-di-n-
butylaminopropyl)-oxy-3,5-dibromo-benzoyl~-indolizine acid
oxalate were obtained.
Yield : 92.7%
M.P. : 96 C.
EXAMPLE 4
_
l-Bromo-2-ethYl-3-~4~3-di-n-Propylaminopropyl)-oxy-
3,5-dichlorobenzoyl~-indolizine acid oxalate.
.
Into a 250 ml-flask were introduced 2.8 g (0.005 mol)
of 2-ethyl-3-l4-(3-di-n-propylaminopropyl)-oxy-3,5-dichloro-
benzoyl]-indolizine acid oxalate and 80 ml of dioxan. The
- 23 -
liS2(~77
reaction mixture was stirred and after the indolizine had
di.ssolved, 0.8 g of anhydrous sodium acetate was added,
dropwise and under vigorous stirring, a solution of 0.8 g of
bromine in 20 ml of dioxan. The temperature was mainteined
at about 20C during the introduction of the bromine.
After the medium had been stirred for 2 hours at room-
temperature, the dioxan was distilled off under vacuum with a
rotatory evaporator. The sol:id residue was disso~.ved in water,
made alkaline with a sodium hydroxide solution and extracted
with chloroform. The chloroformic solution was washed three
times with water and the chloroform was distilled off under
reduced pressure. The oily residue so obtained was taken up
in dry ethyl ether and after f.iltration on a filter the acid
oxalate was formed.
In this manner, 1.8 g of 1-bromo-2-ethyl-3-[4-(3-di-
n-propylaminopropyl)-oxy-3,5-dichloro-benzoyl~ indolizine acid
oxalate was obtained after recristallization from ethyl acetate.
Yield : 55.8%
M.P. : 135C.
Using the appropriate starting-products, the following
compounds were prepared by uti.lizing the various processes
described in the foregoing Examples.
Compounds M.P._ C
l-Bromo-2-ethyl-3-L4-(3-di-n-butylaminopropyl)-
oxy-benzoyl~-indolizine acid oxalate 107-108
(isopropanol)
l-Bromo-2-(4-bromo-phenyl)-3- ~-(3-di-n-
butylaminopropyl)-oxy-benzoyl]-indolizine92-94
acid oxalate (isopropanol)
l-Chloro-2-methy].-3-~4-(3-di-n-butylaminopropyl)-
oxy-benzoyl~-indolizine acid oxalate 92-93
(isopropanol)
- 2~ _
11512~77
l-Chlor~-2-ethyl-3-[4-(3-di-n-propylaminopropyL)-
oxy-benzoyl~-indolizine acid oxalate 162
(isopropanol)
l-Chloro-2-n-propyl-3- L4- (3-di-n-butylaminopropyl)-
oxy-benzoyl~-indolizine acid oxalate 111-112
(isopropanol)
l-Chloro-2-n-buty-3-~4-(3-di-n-butylaminopropyl)-
oxy-benzoyl~-indolizine acid oxalate 106-108
(isopropanol)
l-Chloro-2-phenyl-3-C4-(3-di-n-propylaminopropyl)-
oxy-benzoyl~-indolizine acid oxalate 161-162
(isopropanol)
l-Chloro-2-(4-chloro-phenyl)-:3-L4-(3-di-n-
butylaminopropyl)-oxy-benzoyl~-indolizine
acid oxalate 158-159
(methanol)
l-Chloro-2-phenyl-3-[4-(3-di-n-butylaminopropyl)-
oxy-benzoyll-indolizine acid oxalate 160-161
(methanol)
l-Chloro-2-n-butyl-3-L4-(6-di-n-butylaminohexyl)-
oxy-benzoyl~-indolizine acid oxalate 80-82
(benzene)
20 2-Methyl-3-l4-(3-di-n-butylam.inopropyl)-oxy-3-
bromo-benzoyl]-indolizine acid oxalate 141-143
(10/1 ethyl acetate/
isopropanol)
2-Ethyl-3-L4-(3-di-n-propylam:inopropyl)-
oxy-3-bromo-benzoyl~-indolizine acid oxalate 163
(isopropanol)
2-Ethyl-3-~4-(3-di-n-butylaminopropyl)-oxy-
3-bromo-benzoyl~-indolizine acid oxalate 98-99
(isopropanol)
2-n-Propyl-3-r4-(3-di-n-propylaminopropyl)-
oxy-3-bromo-benzoyl~-indolizine acid oxalate 145
(isopropanol)
2-n-Propyl-3-[4-(3-di-n-butylaminopropyl)-oxy
3-bromo-benzoyl~-indolizine acid oxalate 113-115
(isopropanol)
- 25 -
~152,~77
2-Isopropyl-3-~4-(3-di-n-butylaminopropyl)-oxy-
3-bromo-benzoyl~-indolizine acid oxalate105-107
(benzene)
2-n-Butyl-3-~4-(3-di-n-propylaminoprop~l)-
oxy-3-bromo-benzoyl¦-indolizine acid oxalate 136-137
(isopropanol)
2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-
3-bromo-benzoyl~-indolizine acid oxalate86-87
(isopropanol)
2-Phenyl-3-~4-(3-di-n-propylaminopropyl) oxy-
3-bromo-benzoyl~-indolizine acid oxalate148-149
(isopropanol)
2-Phenyl-3-~4-(3-di-n-butylaminopropyl)-oxy-
3-bromo-benzoyl~-indolizine acid oxalate129-130
(isopropanol)
2-(4-Fluoro-phenyl)-3-[4-(3-di-n-butylamino-
propyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 110
(isopropanol)
2-(4-Chloro-phenyl)-3-~4-(3-di-n-propylamino-
propyl-oxy-3-bromo-benzoylJ-indolizine acid
oxalate 163-164
. (methanol)
2-(4-Chloro-phenyl)-3-~4-(3-di-n-butylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 139-140
(isopro~anol)
2-(3-Bromo-phenyl)-3-[4-(3-di-n-propylaminopro-
pyl)-oxy-3-bromo-benzoyl~-ind.olizine acid
oxalate 142-143
(isopropanol)
2-(4-Bromo-phenyl)-3-[4-(3-di-n-butylaminopro-
pyl)-oxy-3-bromo-benzoylJ-indolizine acid
oxalate 147-148.5
(methanol)
2-(4-Methoxy-phenyl)-3-~4-(3-di-n-butylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid oxalate 169
(isopropanol)
- 26 -
1~52(~77
2-Isopropyl-3-~4--(5-di-n-butylaminopentyl)-oxy
3-bromo-benzoyl~-indolizine acid oxalate 80-82
(benzene)
2-Isopropyl-3-~4-(3-di-n-propylaminopropyl)-oxy-3
-bromo-benzoyl~-indolizine acid oxalate 179
(isopropanol)
2-Methyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-
chloro-benzoyl~-indolizine acid oxalate 141-143
(isopropanol)
2-Ethyl-3-C4-(3-di-n-propylaminopropyl)-oxy-
3-chloro-benzoyl~-indolizine acid oxalate 161-162
(methanol)
2-Ethyl-3-t4-(3-di-n-butylami:nopropyl)-oxy-3-
chloro-benzoyl~-indolizine acid oxalate 116-117
. (isopropanol)
2-Isopropyl-3-~4-(3-di-n-butylaminopropyl)-oxy-
3-chloro-benzoyl~-indolizine acid oxalate 115-117
(isopropanol)
2-Isopropyl-3-L4-(3-di-n-propylaminopropyl)-
oxy-3-chloro-benzoyl~-indolizine acid oxalate 168-169
(methanol)
2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-
3-chloro-benzoyl~-indolizine acid oxalate 84-85
and
107-109
(isopropanol)
2-n-Butyl.-3-~4-(3-di-n-propylaminopropyl)-oxy-
3-chloro-benzoyl~-indoLizine acid oxalate 130-131
(isopropanol)
2-Phenyl-3-L4-(3-di-n-butylaminopropyl)oxy-3
-chloro-benzoyl]-indolizine acid oxalate 121-122
(isopropanol)
2-Phenyl-3-[4-(3-di-n-propyla:minopropyl)oxy-
3-chloro-benzoyl~-indolizine acid oxalate 157-159
(methanol)
2-(4-Methyl-phenyl)-3-L4-(3-di-n-propylaminopro-
pyl)-oxy-3-chloro-benzoylJ-indolizine acid
oxalate 134-135
(isopropanol)
- 27 -
~lSZ~77
2-(4-Bromo-phenyl)-3-L4-(3-di-n-propylaminopro-
pyl)-oxy-3-chloro-benzoyl~-indolizine acid
oxalate 154-155
(methanol)
2-(4-Bromo-phenyl)-3-C4-(-di-n-butylaminipro-
pyl)-oxy-3-chloro-benzoyl~-indolizine acid
oxalate . 134-135
(isopropanol)
2-(3-Bromo-phenyl)-3-~4-(3-di-n-butylaminopro-
pyl)oxy-3-chloro-benzoyl~-indolizine acid
10 oxalate 92-93
(isopropanol)
2-(3-Bromo-phenyl)-3-C4-(3-di-n-propylaminopro-
pyl)-oxy-3-chloro-benxoyl~-indolizine acid
oxalate 148-150
(isopropanol)
2-(4-Chloro-phenyl)-3-C4-(3-di-n-butylaminopro-
pyl)-oxy-3-chloro-benzoyl~-indolizine acid
oxalate 116-118
(isopropanol)
2-(4-Chloro-phenyl)-3-L4-(3-di-n-propylamino-
propyl)oxy-3-chloro-benzoyl~-indolizine acid
oxalate 159-160
(methanol)
l-Bromo-2-methyl-3 ~4-(3-di-n-butylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 89-90
(isopropanol)
l-Bromo-2-methyl-3-L4-(3-di-n-propylaminopro-
pyl~-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 164-165
(isopropanol/
methanol)
l-Bromo-2-ethyl-3-[4-(2-dimethylaminoethyl)-
oxy-3-bromo-benzoyl~-indolizine acid oxalate 164-165
(dichlorethane)
- 28 -
~s2~7
l-Bromo-2-ethyl-3- L4- ( 3-dimet:hylaminopropyl)-
oxy-3-bromo-benzoyl~-indolizi.ne acid oxalate 150-151
(dichlorethane)
l-Bromo-2-eth~1-3-~4-(2-diethylaminoethyl)-
oxy-3-bromo-benzoyl~-indolizi.ne acid oxalate 16~-169
(dichlorethane)
l-Bromo-2-ethy-3-L4-(3-diethylaminopropyl)-
oxy-3-bromo-benzoyl¦-indolizine acid oxalate 140-141.5
(isopropanol)
l-Bromo-2-ethyl-3-[4-(2-di-n-propylaminoethyl)-
oxy-3-bromo-benzoyl~-indolizine acid oxalate 163-164
(isopropanol)
l-Bromo-2-ethyl-3-r4-(3-di-n-propylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 1.39-140
(isopropanol)
l-Bromo-2-ethyl-3 L4-(2-di-n-butylaminoethyl)-
oxy-3-bromo-benzoyl~-indolizine acid oxalate 164-165
(isopropanol)
l-Bromo-2-ethy-3-~4-(3-di-n-butylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 101-101.5
(isopropanol)
l-Bromo-2-n-propyl-3-r4-(3-di-n-butylamillopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 92
(benzene)
l-Bromo-2-n-propyl-3-~4-(3-di--n-propylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 132-136
(isopropanol)
l-Bromo-2-n-butyl-3-C4-(3-di-n-propylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 151-152
(2/1 isopropanol/
methanol)
- 29 -
7~
l-Bromo-2-n-butyl-3-[4-(3-di-n-butylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 101-103
. (isopropanol)
l-Bromo-2-phenyl-3- [4-(3-di-n-propylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 169-170
(1/1 metyanol/iso-
propanol)
l-Bromo-2-phenyl-3-L4-(3-di-n-butylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 167-169
(isopropanol)
l-Bromo-2-(4-methoxy-phenyl)-3-[4-(3-di-n-buty-
laminopropyl)-oxy-3-bromo-benzoyl~-indolizine
acid oxalate 17~-179
(methanol)
l-Bromo-2-(4-methyl-phenyl)-3-l4-(3-di-n-buty-
laminopropyl -oxy-3-bromo-benzoyl~-indolizine
acid oxalate 169-170.5
(1/1 isopropanol/
methanol)
l-Bromo-2-(4-fluoro-phenyl)-3-l4-(3-di-n-buty-
laminopropyl)-oxy-3-bromo-benzoyl~-indolizine
acid oxalate 170-171
(methanol)
l-Bromo-2-(3-bromo-phenyl)-3-l4-(3-di-n-buty-
laminopropyl)-oxy-3-bromo-berlzoyl~-indolizine
acid oxalate . 172-173
(methanol)
l-Bromo-2-n-butyl-3-~4-(4-di-n-butylamino-
butyl)-oxy-3-bromo-l)cnzoyl~ dolizillc acid
oxalate 11~-120
(isopropanol)
30 1-Chloro-2-ethyl-3-~4-(3-di-n-butylaminopropyl)-
oxy-3-chloro-benzoyl~-indolizine acid oxalate 115-117
(isopropanol)
.".,~ - 30 -
:115~(~77
l-Chloro-2-ethyl-3- L4- ( 3-di-n-propylamirlopro
pyl)-oxy-3-chloro-benzoyl~-indolizine acid
oxalate 137-133
(isopropanol)
1-Chloro-2-(3-bromo-phenyl)-3- [4- ( 3-di-n-buty-
laminopropyl)-oxy-3-chloro-benzoyl~-indolizine
acid oxalate 171-172
(methanol)
l-Chloro-2-(3-bromo-phenyl) 3-~4- (3-di-n-propyl-
aminopropyl)-oxy-3-chloro-benzoylJ-indolizine
acid oxalate 194-195
(methanol)
l-Chloro-2-ethyl-3-L4-(3-di-n-propylaminopro-
pyl)-oxy-3,5-dichloro-benzoy~ -indolizine 141
(ethyl acetate )
acid oxalate
l-Chloro-2-ethyl-3-[4-(3-di-n-butylaminopro-
pyl)-oxy-3,5-dichloro-benzoy~]-indolizine 129
(acid acetate )
acid oxalate
l-Chloro-2-phenyl-3-~4-(3-di-n-propylaminopro-
pyl)-oxy-3,5-dichloro-benzoyl~-indolizine
acid oxalate 156
(isopropanol)
l-Chloro-2-phenyl-3- L4- ( 3-di-:n-butylaminopro-
pyl)oxy-3,5-dichloro-benzoyl~-indolizine 136
(isopropanol/
acid oxalate heptane)
l-Bromo-2-methyl-3-~4-(3-di-n-propylaminopro-
pyl)-oxy-3-chloro-benzoyl~-indolizine acid
oxalate 110-112
(isopropanol)
l-Bromo-2-methyl-3-[4-(3-di-n-butylaminopro-
pyl)-oxy-3-chloro-benzoylJ-indolizine acid
oxalate 103-110
(isopropanol)
l-Bromo-2-ethyl-3-C4-(3-di-n-propylaminopro-
pyl)-oxy-3-chloro-benzoyl~-indolizine acid
l~ SZ~77
oxalate 136.5-138
(isopropanol)
l-Bromo-2-ethyl-3-~4-(3-di-n-butylaminopro-
pyl)~oxy-3-chloro-benzoyl]-indolizine acid
oxalate 103-105
(isopropanol)
l-Bromo-2-n-propyl-3-~4-(3-di-n-butylaminopro-
pyl)-oxy-3-chloro-benzoyl~-indolizine acid
oxalate 95-96
(isopropanol)
l-Bromo-2-isopropyl-3- ~4-(3-di-n-butylamino-
propyl) oxy-3-chloro-benzoyl~-indolizine
acid oxalate 116
(isopropanol)
l-Bromo-2-n-buty-3- L4- (3-di-n-propylamino-
propyl)-oxy-3-chloro-benzoyl~-indolizine
acid oxalate 159-160
(methanol)
l-Bromo-2-n-butyl-3- ~4- (3-di-rl-butylamino-
propyl)-oxy-3-chloro-benzoyl~-indolizine
acid oxalate 101-103
(isopropanol)
20 1-Bromo-2-phenyl-3- ~4-(3-di-n--butylaminopro-
pyl)-oxy-3-chloro-benzoyl~-inclolizine acid
oxalate 167.5-169
(methanol)
l-Bromo-2-phenyl-3- ~4- (3-di-n-propylaminopro-
pyl)-oxy-3-chloro-benzoyl]-indolizine acid
oxalate 169-170
(methanol)
l-Bromo-2-(4-chloro-phenyl)-3-~4-di-n-
butylaminopropyl)-oxy-3-chloro-benzoyl~-
indolizine acid oxalate 160-161
(isopropanol)
l-Bromo-2-(4-chloro-phenyl)-3-[4-(3-di-n-
propylaminopropyl)-oxy-3-chloro-benzoyl~-
indolizine acid oxalate 184-185
(methanol)
- 32 -
~lSZ~77
l-Bromo-2-(4-bromo-phenyl)-3-L4-(3-di-n-
propylaminopropyl)-oxy-3-chloro-benzoyll-
indolizine acid oxalate 176-177
(methanol)
l-Bromo-2-(4-bromo-phenyl)-3- ~4-(3-di-n-
butylaminopropyl)-oxy-3-chloro-benzoyl~-
indolizine acid oxalate 168-169
(isopropanol)
l-Bromo-2-(3-bromo-phenyl)-3-L4-(3-di-n-
propylaminopropyl)-oxy-3-chloro-benzoyl~-
indolizine acid oxalate 200-201
(methanol)
l-Bromo-2-(3-bromo-phenyl)-3-~4-(3-di-n-
butylaminopropyl)-oxy-3-chloro-benzoyl~-
indolizine acid oxalate 170.5-172
(methanol)
l-Chloro-2-ethyl-3-[4-(3-di-npbutylaminopro-
pyl)-oxy-3-bromo-benzoyl~-indolizine acid
oxalate 104-105
(isopropanol)
l-Chloro-2-ethyl-3- L4-(3-di-n-propylaminopro-
pyl)-oxy-3,5-dibromo-benzoyl~-indolizine
acid oxalate 157
(isopropanol)
l-Chloro-2-ethyl-3-[4-(3-di-n7butylaminopro-
pyl)-oxy-3,5-dibromo-benzoy~-indolizine 140
(isopropanol)
acid oxalate
1-Chloro-2-phenyl-3-~4-(3-di-n-propylamino-
propyl)-oxy-3,5-dibromo-benzoyl~-indo-
lizine acid oxalate 172
(isopropanol)
l-Chloro-2-phenyl-3-~4-(3-di-n-butylamino-
propyl)-oxy-3,5-dibromo-benzoy~ -indolizine
acid oxalate 146
(isopropanol)
- 33 -
.~ls2a~7
2-Methyl-3-L4-(3-di-n-propylaminopropyl)-
oxy-3,5-dibromo-benzoyl~-indolizine sesqui-
oxalate 136
(ethyl acetate)
2-Ethyl-3-[4-(3-dimethylaminopropyl)-oxy-
.3,5-dibromo-benzoyl~-indolizine acid oxalate 148
(ethyl acétate)
2-Ethyl-3-[4-(2-diethylaminoethyl)-oxy-3,5-
dibromo-benzoyl~-indolizine ac:id oxalate 171
(ethanol)
2-Ethyl-3- ~-(3-diethylaminopropyl)-oxy-3,5-
dibromo-benzoyl~-indolizine hydrochloride 191
(50/50 ethyl ace-
tate/acetone)
2-Ethyl-3- ~4-(3-di-n-propylamlnopropyl)-
oxy-3,5-dibromo-benzoyl]-indolizine
hydrochloride 166
(ethyl acetate)
2-Ethyl-3-[4-(3-di-n-butylaminopropyl)-
oxy-3,5-dibromo-benzoyl~-indolizine
hydrochloride 157
(ethyl acetate)
2-n-Propyl-3-~4-(3-di-n-propylaminopropyl)-
oxy-3,5-dibromo-benzoyl~-indolizine
hydrochloride 145
(ethyl-acetate)
2-n-Propyl-3-L4-t3-di-n-butylaminopropyl)-
oxy-3,5-dibromo-benzoyl~_indolizine acid
oxalate 107
(ethyl acetate)
2-Isopropyl-3-~4-(3-di-n-propylaminopropyl)-
oxy-3,5-dibromo-benzoy~ -indolizine acid
oxalate 126
(ethyl acetate/
ethanol)
2-Isopropyl-3-~4-(3-di-n-butylaminopropyl)-
oxy-3,5-dibromo-benzoy~ -indolizine acid
.
- 34 -
~ 152(~77
oxalate 86
(ethyl acetate/ethyl
ether)
2-n-Butyl-3-[4-(3-di-n-propylaminopropyl)-
oxy-3,5-dibromo-benzoyl~-indoLizine acid
oxalate 146
(ethyl acetate)
2-n-Butyl-3-L4-(3-di-n-butylaminopropyl)-
oxy-3,5-dibromo-benzoyl~-indolizine 110
(ethyl acetate)
acid oxalate
2-Phenyl-3-~4-(3-di-n-propylaminopropyl)-
oxy-3,5-dibromo-benzoyl~-indo:Lizine acid
oxalate 142
(ethyl acetate/
ethanol)
2-Phenyl-3-~4-(3-di-n-butylaminopropyl)-
oxy-3,5-dibromo-benzoyl~-indol.izine acid
oxalate 86
(ethyl acetate)
2-(4-Fluoro-phenyl)-3-[4-(3-di-n-propylamino-
propyl)-oxy-3,5-dibromo-benzoyl~-indolizine
acid oxalate 166
(ethyl acetate/
ethanol)
2-(4-Fluro-phenyl)-3-~4-(3-di-~-butylami-
nopropyl)-oxy-3,5-dibromo-benzoyl]-indoli-
zine acid oxalate 152
(isopropanol)
2-(4-Chloro-phenyl)-3-~4-(3-di-n-propyla-
minopropyl)-oxy-3,5-dibromo-benzoyl~-indo-
lizine acid oxalate 190
(ethyl acetate)
2-(4-Chloro-phenyl)- 3-[4-(3-d:i-n-butylamino-
propyl)-oxy-3~5-dibromo-benzoyl~-indolizine
acid oxalate 88
(ethyl acetate)
- 35 -
9L~5~(~77
2-(3,4-Dichloro-phenyl)-3-~4-(3-di-n-propyla-
minopropyl)-oxy-3,5-dibromo-benzoyl~~indolizine
sesquioxalate 114
(ethyl acetate/iso-
~ propanol)
2-(3,4-Dichloro-phenyl)-3- [4-(3-di-n-butyl-
aminopropyl)-oxy-3,5-dibromo-benzoyl~-indo-
lizine acid oxalate 95
(ethyl acetate/iso-
propanol)
2-(3-Bromo-phenyl)-3-[4-(3-di-n-propylami-
nopropyl)-oxy-3,5-dibromo-benzoyl~-indoli-
zine acid oxalate 136
(ethanol)
2-(3-Bromo-phenyl)-3-[4-(3-di--n-butylaminopro-
pyl)-oxy-3,5-dibromo-benzoyl~--indolizine acid
fumarate 122
(ethyl acetate)
2-(4-Methyl-phenyl)-3- ~4-(3-di-n-propylamino-
propyl)-oxy-3,5-dibromo-benzoyl~-indolizine
acid oxalate 126
(ethyl acetate/
isopropanol)
2-(4-Methyl-phenyl)-3-[4-(3-di-n-butylamino-
propyl)-oxy-3,5-dibromo-benzoyl~-indolizine
acid oxalate 90
(ethyl acetate)
2-(4-Methoxy-phenyl)-3-[4-(3-di-n-propylamino-
propyl)-oxy-3,5-dibromo-benzoyl~-indolizine
acid oxalate 167
(acetone)
2-(4-Methoxy-phenyl)-3-r4-(3-di-n-
butylaminopropyl)-oxy-3,5-dibromo-benzoyl~-
indolizine acid oxalate pasty at about 70C
(ethanol/ethyl ether)
2-Methyl-3-C4-(3-di-n-propylaminopropyl)-
oxy-3,5-dichloro-benzoyl~-indolizine
~L~SZU7t7
acid oxalate 145
tethyl acetate/ethanol)
2-Methyl-3-L4-(3-di-n-butylaminopropyl)-
oxy-3,5-dichloro-benzoyl~-indolizine 95
(ethyl acetate/ethyl
acid oxalate ether)
.2-Ethyl-3- L4-(3-di-n-propylami.nQpropyl,-
oxy-3,5-dichloro-benzoyl~-indolizine
acid oxalate 100
(pasty)(ethyl acetate)
2-Ethyl-3-~4-(3-di-n-butylaminopropyl)-
10 oxy-3,5-dichloro-benzoyl~-indolizine 95
(ethyl acetate)
acid oxalate
2-n-Propyl-3-~4-(3-di-n-propylaminopro-
pyl)-oxy-3,5-dichloro-benzoyl~-indolizine
acid oxalate 142
(isopropanol)
2-n-Propyl-3-[4-(3-di-n-butylaminopropyl)-
oxy-3,5-dichloro-benzoyl]-indolizine 114
(isopropanol)
acid oxalate
2-Isopropyl-3-~4-(3-di-n-propylaminopropyl)-
oxy-3,5-dichloro-benxoyl~-indolizine
acid oxalate 36
(ethyl acetate)
2-Isopropyl-3- [4-(3--di-n-butylaminopropyl)-
oxy-3,5-dichloro-benzoyl~-indolizine acid
oxalate 90
(ethyl acetate)
2-Phenyl-3-~4-(3-di-n-propylaminopropyl)-
oxy-3,5-dichloro-benzoy].~-indolizine
acid oxalate 146
(ethanol)
2-Phenyl-3-C4-(3-di-n-butylaminopropyl)-
oxy-3,5-dichloro-benzoyl~-indolizine
acid oxalate (pasty at about 90C
. (ethyl acetate)
- 37 -
1152077
2-(4-Bromo-phenyl)-3-[4-(3-di-n-propyl-
aminopropyl)-oxy-3 t 5-dichloro-benzoyl]-
indolizine acid oxalate 174
(ethyl acetate)
2-(4-Bromo-phenyl)-3- ~4-(3-di-n-butyla-
.minopropyl)-oxy-3,5-dichloro-benzoyl~-
indolizine acid oxalate . 133
(ethyl acetate)
l-Bromo-2-methyl-3- ~4-(3-di-n-butyla-
minopropyl)-oxy-3,5-dibromo-benzoyl]-
indolizine acid oxalate 141-143
(isopropanol)
l-Bromo-2-n-propyl-3-[4-~3-di-n-propyla-
minopropyl)-oxy-3,5-dibromo-benzoyl]-
indolizine acid oxalate 138-139
(isopropanol)
l-Bromo-2-ethyl-3- ~4-(3-di-n-butylamino-
propyl)-oxy-3,5-dibromo-benzoyl~-indoli-
zine acid oxalate 131-132.5
(isopropanol)
l-Bromo-2-phenyl-3- ~4-(3-di-n-butylamino-
propyl)-oxy-3,5-dibromo-benzoyl~-indoli-
zine acid oxalate 160-161
(isopropanol)
l-Bromo-2-(4-methyl-phenyl)-3-~4-(3-di-n-
butylaminopropyl)-oxy-3,5-dibromo-benzoyl~-
indolizine acid oxalate 105-106
(isopropanol)
l-Bromo-2-(4-bromo-phenyl)-3-[4-(3-di-n-
butylaminopropyl)-oxy-3,5-dibromo-benzoyl]-
indolizine acid oxalate 148-149
(isopropanol) :
l-Bromo-2-(3,4-dichloro-phenyl)-3-[4-(3-
di-n-butylaminopropyl)-oxy-3,5-dibromo-ben-
zoyl]-indolizine acid oxalate 196-197
(isopropanol)
- 3~ -
~:152{~7
1-Bromo~2-(3-chloro-4-methyl-phenyl)-3- L4-
(3-di-n-butylaminopropyl)-oxy--3,5-dibromo-
benzoyl~-indolizine acid oxalate168-169
(isopropanol)
l-Bromo-2-ethyl-3- ~4-(3-di-n-butylaminopro-
pyl)-oxy-3,5-dichloro-benzoyl~-indolizine
acid oxalate 134
(isopropanol
l-Bromo-2-phenyl-3-~4-(3-di-n-propylamino-
propyl)-oxy-3,5-dichloro-benzoyl~-indolizine
10 acid oxalate 145
(ethyl acetate)
l-Bromo-2-phenyl-3-~4-(3-di-n-butylamino-
propyl?-oxy-3,5-dichloro-benzoyl~-indolizine
acid oxalate 106
(ethyl acetate)
2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-
3-bromo-benzoyl~-indolizine hydrochloride 113-113.5
(ethyl acetate)
2-n-Propyl-3-~4-(3-diethyl-aminopropyl)-oxy-
3,5-dibromo-benzoy~ -indolizine hydrochloride 154
(80/20 ethyl ace-
tate/acetone)
2-Ethyl-3-t4-(3-di-n-butylaminopropyl)-oxy-
3-chloro-benzoyl~-indolizine hydrochloride 132-133
(ethyl acetate/
isopropanol)
2-n-Butyl-3-~4-(3-di-n-butyl.aminopropyl)-oxy-
3-chloro-benzoy].~-indolizine hydrochloride 104
(ethyl acetate)
l-Bromo-2-phenyl-3-[4-(3-di-n butylaminopropyl)-
oxy-3-chloro-benzoyl~-indolizine hydrochloride 156-157
l-Chloro--2-(4-chloro-phenyl)-3-~4-(3-di-n-propyl-
aminopropyl)-oxy-benzoyl~-indolizine acid oxalate 168-169
(methanol)
l-Methoxy-2-phenyl-3- ~4-(3-di-n-propylaminopropyl)-
oxy-benzoyl~-indolizine acid oxalate117
(ethyl acetate~
- 39 -
~,,.
*
~i.5~0~
l-Methoxy-2-phenyl-3-[4-(3-di-n-butylaminopropyl)-
oxy-benzoll-indolizine acid oxalate 80
~ (ethyl acetate)
l-Methoxy-2-phenyl-3- l4- ( 3-di-n-propylaminopropyl)-
oxy-3-chloro-benzoyl~-indolizine acid oxalate 172
(ethyl acetate)
l-Methoxy-2-phenyl-3- [4- (3-di-n-butylaminopropyl)-
oxy-3-chloro-benzoyl~-indolizine acid oxalate 120
. (ethyl acetate)
l-Methoxy-2-phenyl-3-[4-(3-di-n-propylaminopropyl)-
oxy-3-bromo-benzoyl~-indolizine acid oxalate 160
(ethyl acetate)
l-Methoxy-2-phenyl-3-~4-(3-di-n-butylaminopropyl)-
oxy-3-bromo-benzoyl~-indolizine acid oxalate 78
(ethyl acetate)
l-Methoxy-2-phenyl-3- L4- ( 3-di-n-propylaminopropyl)-
oxy-3-methoxy-benzoyl~-indolizine acid oxalate 148
(ethyl acetate)
l-Methoxy-2-phenyl-3- [4-(3-di-:n-butylaminopropyl)-
oxy-3-methoxy-benzoy~ -indolizine acid oxalate 78
(ethyl acetate)
l-Methoxy-2-(4-fluoro-phenyl)-:3-l4-(3-di-n-
propylaminopropyl)-oxy-3-methoxy-benzoyl~-
indolizine acid oxalate 79
(ethyl acetate)
2-Methyl-3-L4-(3-di-n-butylaminopropyl)-oxy-
3-methoxy-benzoyl~-indolizine acid oxalate 159
(isopropanol)
2-Methyl-3-L4-(3-di-n-propylami.nopropyl)-oxy-
3-methoxy-benzoyl~-indolizine acid oxalate 171
(methanol)
2-Ethyl-3-C4-(3-di-n-butylaminopropyl)-oxy-
3-methoxy-benzoyl~-indolizine acid oxalate 88
. (ethyl acetate)
2-Ethyl-3-C4-(3-di-n-propylaminopropyl)-oxy-
3-methoxy-benzoyl~-indolizine acid oxalate 121-122
(ethyl acetate)
- 40 -
~15~077
1-Bromo-2-methyl-3-f4-(3-di-n-butylaminopropyl)-
oxy-3-methoxy-benzoyl~-indolizine acid oxalate 87-90
(benzene)
l-Bromo-2-methyl-3-~4-(3-di-n-propylaminopropyl)-
oxy-3-methoxy-benzoyl~ indolizine acid oxalate 139-141
(isopropanol)
l-Bromo-2-ethyl-3-~4-(3-di-n-butylaminopropyl)-
oxy-3-methoxy benzoyl~-indolizine acid oxalate 111
(benzene)
l-Bromo-2-ethyl-3-~4-(3-di-n-propylaminopropyl-
oxy-3-methoxy-ben`zoyl~--indolizine acid oxalate 149
(isopropanol)
2-(4-Fluoro-phenyl)-3-~4-(3-di-n-butylaminopropyl)-
oxy-3-methoxy-benzoyl~-indolizine acid oxalate 85
(ethyl acetate)
2-Methyl-3-~4-(3-di-n-butylaminopropyl)-oxy- 149
(isopropanol)
3-methyl-benzoyl~-indolizine acid oxalate
2-Ethyl-3-~4-(3-di-n-butylami.nopropyl)-oxy- 133
(ethyl acetate)
3-methyl-benzoyl~-indolizine acid oxalate
l-Methyl-2-n-propyl-3-~4-(3-d:i-n-butylaminopropyl)-
oxy-3-bromo-benzoyl~-indolizine acid oxalate127
(ethyl acetate)
2-Isopropyl-3-~4-(3-di-n-buty.laminopropyl)-
91
oxy-3-methyl-benzoyl~-indolizine acid oxalate (isopropanol)
2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy 89
(isopropanol)
3-methyl-benzoyl~-indolizine acid oxalate
l-Methyl-2-n-butyl-3-f4-(3-di-n-butylaminopropyl)-
99
oxy-3-bromo-benzoyl~-indolizine acid oxalate(ethyl acetate)
l-Methyl-2-ethyl-3-~4-(3-di-n--butylaminopropyl)-
oxy-3-bromo-benzoyl~-indolizine acid oxalate117
(ethyl acetate)
l-Bromo-2-methyl-3-~4-(3-di-n--butylaminopropyl)-
oxy-3,5-dimethyl-benzoyl~-indolizine acid oxalate 120-122
(isopropanol)
- 41 --
~.~52077
l-Ido-2-ethyl-3-~4-(3-di-n--butylaminopropyl)-
oxy-3,5-dimethyl-benzoyl~-inclolizine acid oxalate 115
(ethyl acetate)
2-Ethyl-3-~,3-dichloro-4-(3-di-n-propylamino-
propyl)-oxy-benzoyl~-indolizine 117
(heptane)
2-Ethyl-3-~2,3-dichloro-4-(3-di-n-butylamino-
propyl)-oxy-benzoyl~-indolizine 95
(heptane)
2-Phenyl-3-~2,3-dichloro-4-(3-di-n-propylamino-
propyl)-oxy-benzoyl~-indolizine 99
(heptane)
2-Phenyl-3-~2,3-dichloro-4-(3-di-n-butylamino-
propyl)-oxy-benzoyl~-indolizine 87
(heptane)
2-(4-Fluoro-phenyl)-3-~2,3-dichloro-4-(3-di-n-
propylaminopropyl)-oxy-benzoylJ'-indolizine 119
(heptane)
2-(4-Fluoro-phenyl)-3-~2,3-dichloro-4-(3-di-n-
butylaminopropyl)-oxy-benzoyl~-indolizine95-96
(heptane)
l-Bromo-2-ethyl-3-~2,3-dichloro-4-(3-di-n-
butylaminopropyl)-oxy-benzoyl~-indolizine acid
oxalate 164
(isopropanol)
l-Bromo-2-phenyl-3-~2,3-dichloro-4-(3-di-n-
propylaminopropyl)-oxy-benzoyl~-indolizine acid
oxalate 171
(isopropanol)
l-Chloro-2-phenyl-3- ~ ,3-dichloro-4-(3-di-n-
propylaminopropyl)-oxy-benzoyl~'-indolizine 136
(heptane)
2-n-Butyl-3-~4-(3-di-n-butylclminopropyl)-oxy-
3-iodo-benzoyl~-indolizine acid oxalate90-92
(ethyl acetate)
- 42 --
077
EXAMPLE 5
.. _. . .
In accordance with known pharmaceutical techniques
soft-gelatin capsules containing the following ingredients,
were prepared:
Inqr_dient mq
2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-
3-bromo/or 3-chloro-benzoyl~-indolizine
Hydrochloride 100
Starches 99. 5
10 Colloidal silica 0.5
200.0
BXAMPL:E 6
In accordance with known pharmaceutical techniques,
injectable solutions containing the following ingredients,
were prepared:
Inqredient mg
2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-3-
bromo/or 3-chloro-benzoyl~-indolizine
hydrochloride 150
Polysorbate 80 150
Benzyl alcohol 75
Water to 3 ml
EXAMPLE_7
In accordance with known pharmaceutical techniques,
suppositories containinq the following ingredients, were prepared:
Inqredient
2-n-Butyl-3-~4-(3-di-n-butylaminopropyl)-oxy-
3-bromo/or 3-chloro-benzoyl~-indolizine
hydrochloride 100
Mixture of mono- and di-glycerides of saturated
c (C12 toC18) 1400
1500
- 43 -
