Title of Invention

NOVEL INDOLIZINE DERIVATIVES, METHOD FOR PREPARING SAME AND THERAPEUTIC COMPOSITIONS COMPRISING SAME

Abstract The invention concerns indolizine derivatives of formula (I) wherein: X represents -(CH2)n- with n being an integer from 1 to 6, or a group of formula CH2-Z-(CH2)2-, wherein Z represents a O(CH2)m- wherein m is an integer from 0 to 3, Ri represents a linear, branched or cyclic C1-C6, alkyl radical; Am represents a NR3R4 group wherein R3 and R4 identical or different; represent independently of each other a hydrogen atom, a linear, branched or cyclic C1-C6 alkyl radical, or C1-C3 alkyl radical substituted by a C3-C6 cycloalkyl radical, or a (CH2)I-O-B, wherein B represents a hydrogen atom or a (CH2)K alkyl radical with I and k being integers 1 ≥ 2 and 1+k ≤ 6 or R3 and R4 form together with the nitrogen atom whereto they are bound a 4- to 6-membered heterocycle capable of containing one or more heteroatoms selected among N, O and optionally bearing one or more substituents selected among a linear, branched or cyclic C1-C6 alkyl radical, R2 represents a hydrogen atom, a linear, branched or cyclic C1-C6 alkyl radical, and their pharmaceutically acceptable salts.
Full Text NOVEL INDOLIZINE DERIVATIVES, METHOD FOR PREPARING SAME,
AND THERAPEUTIC COMPOSITIONS COMPRISING SAME
The present invention relates to novel indoiizine derivatives, to a method for
their preparation and to pharmaceutical compositions containing them.
French patent FR-A-2 341 578 and European patent EP-A-0 471 609
describe indoiizine derivatives which have remarkable pharmacological
properties, especially antiarrhythmic properties, since those derivatives have
been shown to be capable of suppressing or staving off ventricular and
auricular rhythm problems. The majority of the compounds described have
electrophysiological properties in classes 1, 2, 3 and 4 of the Vaughan-
Williams classification which in addition to their antiarrhythmic properties,
indicate their bradycardiac, anti-hypertensive and a and β non-competitive
anti-adrenergic properties. Such properties render the compounds in
question very useful in the treatment of certain pathological syndromes of the
cardiovascular system, in particular in the treatment of angina pectoris,
hypertension or ventricular or supraventricular arrhythmia. Similarly, such
compounds are used to treat cardiac insufficiency, myocardial infarction
complicated or otherwise by cardiac insufficiency, or to prevent post-infarction
mortality.
However, such compounds have the disadvantage of being insoluble or only
slightly soluble in water, in particular at pH =4 and especially at a
physiological pH.
Amiodarone, which is an auricular and ventricular antiarrhythmic which is
administered orally and intravenously, is a molecule which is insoluble in
water; the injectable solution thus contains solvents such as polysorbate 80
and benzyl alcohol. Such solvents induce hypotensive and negative inotropic
effects in patients. The injectable solution also causes local venous

intolerances which are prevented by recommending a central injection in a
specialized hospital environment.
Dronedarone, a derivative of benzofuran, contains no iodine in its chemical
structure, in contrast to amiodarone, and is also an auricular and ventricular
antiarrhythmic which is administered orally and intravenously. Its low
solubility (solubility in water S = 0.247 mg/ml at a pH of 3) limits the possibility
of preparing and storing it in the form of an injectable substance.
That low solubility substantially limits the possibility of preparing and storing
them in the form of an injectable substance.
In the context of the invention, novel indolizine derivatives have now been
discovered which have good solubility in water while retaining or even
improving their pharmacological properties, especially their antiarrhythmic
properties. Their good solubility in water, in particular at pH = 4, allows
injectable pharmaceutical forms to be produced.
The compounds of the present invention are molecules which are soluble in
water which can be administered intravenously in a physiological solution
(0.9% sodium chloride) or glucosated, and which have the
electrophysiological, haemodynamic and antiarrhythmic properties of
amiodarone.
Furthermore, these novel compounds also exhibit good metabolic stability.
Thus, the invention proposes indolizine derivatives comprising an
aminoalkylbenzoyl chain represented by formula (I) below.
Thus, the present invention concerns novel indolizine derivatives with general
formula (I):


in which:
X represents a -(CH2)n- radical where n is a whole number from 1 to 6, or a
group with formula CH2-Z-(CH2)2-, in which Z represents an O(CH2)m- group
in which m is a whole number from 0 to 3; Ri represents a linear, branched
or cyclic C1-C8 alkyl radical; Am represents an NR3R4 group in which R3 and
R4 are identical or different and independently of each other represent:
- a hydrogen atom;
- a linear, branched or cyclic C1-C6 alkyl radical or a C1-C3 radical substituted
with a C3-C6 cycloalkyl radical;
- or a (CH2)1-O-B radical in which B represents a hydrogen atom or a (CH2)k
alkyl radical, where I and k are whole numbers, I ≥ 2 and l+k = 6;
or R3 and R4 together with the nitrogen atom to which they are attached form
a heterocycle containing 4 to 6 links which may optionally contain one or
more heteroatoms selected from N and O and optionally carrying one or more
substituents selected from a linear, branched or cyclic C1-C6 alkyl radical;
R2 represents a hydrogen atom or a linear, branched or cyclic C1-C6 alkyl
radical;
and their pharmaceutically acceptable salts.
In a first variation, the invention concerns indolizine derivatives as defined
above in which X represents a -(CH2)n- radical where n is a whole number
from 1 to 6.

In a second variation, the invention concerns indolizine derivatives as defined
above in which X represents a group with formula CH2-Z-(CH2)2-, in which Z
represents an O(CH2)m- group in which m is a whole number from 0 to 3.
More particularly, the invention concerns indolizine derivatives as defined
above, characterized in that X represents a (CH2)n- radical where n is a whole
number from 3 to 4.
More particularly, the indolizine derivatives of the invention are characterized
in that R1 represents a C1-C4 alkyl radical.
More particularly, the indolizine derivatives of the invention are characterized
in that R3 and R4 independently of each other represent a linear C1-C4 alkyl
radical.
In particular, the indolizine derivatives of the invention are characterized in
that R3 and R4 together form a piperidinyl or piperazinyl group optionally
carrying one or more methyl radicals.
In particular, the indolizine derivatives of the invention are characterized in
that R2 represents a hydrogen atom.
The compounds of formula (I) can exist in the form of bases or in the form
salified with acids or bases, in particular phamnaceutically acceptable acids or
bases. Such addition salts form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable
acids, but the salts of other acids that are of use, for example, for the
purification or isolation of the compounds of formula (I), also form part of the
invention.

The compounds of formula (I) can also exist in the form of hydrates or of
solvates, i.e. in the form of associations or of combinations with one or more
molecules of water or with a solvent. Such hydrates and solvates also form
part of the invention.
The invention also pertains to pharmaceutically acceptable salts of
compounds with formula (I) formed from an organic or inorganic acid.
Examples of organic salts of this type which may be cited are the malonate,
dodecanoate, oxalate, maleate, fumarate, methanesulphonate, benzoate,
ascorbate, pamoate, succinate, hexamate, bis-methylenesalicylate,
ethanedisulphonate, acetate, propionate, tartrate, salicylate, citrate,
gluconate, lactate, malate, cinnamate, mandelate, citraconate, aspartate,
palmitate, stearate, itaconate, glycolate, p-aminobenzoate, glutamate,
benzenesulphonate, p-toluenesulphonate and theophylline acetate, as well as
the salts formed from an amino acid, such as the lysine or histidine salt.
Inorganic salts of this type which may be cited are hydrochlorides,
hydrobromides, sulphates, sulphamates, phosphates and nitrates.
More particularly, the invention concerns indolizine derivatives as defined
above, characterized in that the pharmaceutically acceptable salt is selected
from the oxalate and the hydrochloride.
The invention also pertains to the preparation of compounds with formula (I).
Thus, the present invention concerns a method for preparing derivatives with
formula (I) as defined above, comprising the reaction of an amine H-Am with
a compound represented by formula (II):


in which Y represents a halogen atom and the other substituents are as
defined above.

with a compound represented by formula (IV):
The invention also concerns a method comprising a method for preparing a
compound with formula (II) as defined above and comprising the reaction of a
compound represented by formula (III):

Thus, in accordance with the invention, compounds with formula (I) in which X
represents a -(CH2)n- radical as defined above are prepared in accordance
with the following reaction scheme:


in which Y represents a halogen, for example Cl or Br, and n and the R1, R2,
Am groups have the same meanings as given above.
Reference may be made to United States patent US-A-6 949 583 for the
preparation of the compounds with formula (III).
To prepare compounds with formula (IV), reference may be made to the
publication EUR J. MED. CHEM-CHEMICAL THERAPEUTICA, NOV.-DEC.
1975-10, N°6, pp 579 to 584 and to LABAZ's patent US-A-4 103 012.
Similarly, to prepare indolizine derivatives with formula (I) by condensing a
secondary amine with formula H-Am with the chlorinated derivative with
formula (II) and to prepare compounds with formula (II) by reacting
compounds with formula (III) with derivatives with formula (IV), reference
should be made to the document US-A-4 103 012.

In accordance with the invention, to prepare compounds with formula (I) when
X represents a group with formula CH2-Z-(CH2)2-, in which Z represents an
O(CH2)m- group as defined above, reference should be made to
US-A-6 949 583 and to Monatsh Chem: 129;3; 1998; 309-318 and to the
following reaction scheme:

in which the groups R1, R2, Am have the same meanings as given above.
The invention also pertains to a pharmaceutical or veterinary composition,
characterized in that it contains, as the active principle, at least one indolizine
derivative with formula (I) as defined above or a pharmaceutically acceptable
salt thereof, in association with a pharmaceutically acceptable vehicle or an
appropriate excipient.
As an example, the pharmaceutical compositions of the present invention
may be formulated for oral, sublingual, subcutaneous, intramuscular,
intravenous, transdermal or rectal administration. Preferably, the
compositions are present in an injectable form, exploiting the good solubility
characteristics of the derivatives of the invention.

Regarding the administration unit, this may take the shape, for example, of a
tablet, a dragee, a capsule, a gellule, a powder, a suspension, a syrup or
granules for oral administration, a suppository for rectal administration or a
solution or suspension for parenteral administration.
The pharmaceutical compositions of the invention may, for example,
comprise, per administration unit, 50 to 500 mg by weight of active ingredient
for oral administration, 50 to 200 mg of active ingredient for rectal
administration and 50 to 150 mg of active ingredient for parenteral
administration.
Depending on the administration route selected, the pharmaceutical or
veterinary compositions of the invention are prepared by associating at least
one of the compounds with formula (I) or a pharmaceutically acceptable salt
of that compound with a suitable excipient, the latter possibly being
constituted, for example, by at least one ingredient selected from the following
substances: lactose, starches, talc, magnesium stearate, polyvinyl
pyrrolidone, alginic acid, colloidal silica, distilled water, benzyl alcohol or
sweetening agents.
When they are in tablet form, they may be treated so that they have an
extended or delayed action and so that they continuously release a
predetermined quantity of active principle.
The invention also concerns indolizine derivatives with general formula (I) as
defined above for their use as a drug. The present invention thus concerns
drugs comprising indolizine derivatives with general formula (I) as defined
above.
The indolizine derivatives with general formula (I) of the present invention as
defined above may be used to prepare a drug for the treatment of

pathological syndromes of the cardiovascular system. More particularly, the
indolizine derivatives with general formula (I) of the present invention as
defined above may be used to prepare a drug for the treatment of angina
pectoris, hypertension, ventricular arrhythmia, supraventricular arrhythmia, in
particular auricular fibrillation, cardiac insufficiency, myocardial infarction
which may or may not be complicated by cardiac insufficiency or for the
prevention of post-infarction mortality.
The results of pharmacological tests carried out to determine the properties of
the compounds of the invention as regards the cardiovascular system are
recorded below.
1. Ventricular arrhythmias
This test aims to determine the capacity of the compounds of the invention to
protect against arrhythmias caused by re-perfusion of a previously
ischaemiated coronary artery. To this end, we used the method set out by
MANNING A. S. et al. in Circ. Res. 1984, 55: 545-548 modified as follows:
Firstly, rats sorted into batches were anaesthetized with sodium pentobarbital
(60 mg/kg intraperitoneally) then they were intubated to assist respiration.
A cannula was then placed in a jugular vein for intravenous administration, a
catheter was placed in a carotid artery to measure the arterial pressure, and
cutaneous electrodes were placed to measure the ECG. After equilibrating
the parameters, an intravenous dose of the compound to be studied was
administered and 5 minutes later, after carrying out a thoracotomy, a loop of
ligature was placed around the left anterior descending coronary artery in the
immediate proximity of its origin. Thus, that artery was occluded for 5
minutes by tension on the ends of the ligature. Re-perfusion was obtained by
releasing the tension.

The arrhythmias induced by that re-perfusion were then evaluated.
An analogous test was carried out after oral administration of the compound.
In this case, the study compound was administered 60 to 120 minutes before
ligating the left anterior descending coronary artery.
The results of these tests showed that the compounds of the invention,
administered in doses in the range 0.3 to 10 mg/kg intravenously and 30 to
100 mg/kg orally, significantly or completely protected the treated animals
from ventricular arrhythmia.
II. Antiadrenergic properties
This test aims to determine the capacity of the compounds of the invention to
reduce the increase in blood pressure induced by phenylephrin (anti-a effect)
and the acceleration in cardiac frequency induced by isoprenaline (anti-p
effect) in a dog which had been anaesthetized beforehand with pentobarbital
and chloralose.
Initially, for each dog the dose of phenylephrin (5 µg/kg was determined which
provoked an increase in the arterial pressure in the range 25 to 40 mmHg and
the dose of isoprenaline (0.5 or 1 µglkg) which should cause an increase in
cardiac frequency in the range 40 to 110 beats/minute.
Every 10 minutes, the doses of phenylephrin and isoprenaline determined in
this way were injected alternately and after obtaining two successive
reference responses, a dose of the compound to be studied was administered
intravenously.
• Anti-a effect

The percentage reduction by the compound of the invention in the
hypertension caused compared with the reference hypertension obtained
before injecting that compound was recorded.
• Anti-3 effect
The percentage reduction in the study compound of the acceleration caused
in the cardiac frequency was recorded.
The results of these tests showed that in doses of 3 to 10 mg/kg, the
compounds of the invention exhibited anti-a and/or anti-p effects, resulting in
reductions in the provoked hypertension and/or the provoked increase in
cardiac frequency, of up to 50%.
III. Auricular arrhythmias
This test aims to evaluate the efficacy of the compounds of the invention as
regards auricular arrhythmia (left auricular vulnerability) induced by extra
stimuli in the anaesthetized pig using the method described in Naunyn-
Schmiedeberg's Arch Pharmacol 2001, 363: 166-174.
The study compounds were administered in a dose of 3 mg/kg in slow 5-
minute intravenous perfusions. The haemodynamic and electrocardiographic
parameters and the right and left auricular refractory periods were determined
before and after administering the study compound.
In a dose of 3 mg/kg, the compounds of the invention generally abolished
100% of non-sustained fibrillation or auricular flutter episodes induced by
early extra stimuli. In this dose, significant increases in the effective auricular
refractory periods were observed for different basal values of the cardiac
period.
IV. Effects of cardiac ion channels

This test aims to determine the effects of the compounds of the invention on
cardiac ion channels.
The compounds of the invention (1 to 5//M) inhibited the permeability of
human hERG (IKr) and hKv1.5 (IKur) gene channels expressed in the CHO
(Chinese hamster ovary) cell line. They also inhibited native sodium (Ina),
calcium (ICaL) and potassium channel currents, acetylcholine (IK(Ach))-
activated and ATP-dependent (IKATP), in guinea pig cardiomyocytes, and
potassium channels (Ito and Isus) in rat cardiomyocytes.
Thus, the compounds of the invention are inhibitors of multiple cardiac ion
channels.
V. Toxicity
The toxicity of the compounds of the invention proved to be compatible with
their therapeutic use.
VI. Solubility
The solubility tests for the compounds of the invention were carried out at pH
= 4 (starting from a phosphate buffer, pH = 6, 0.1M) by HPLC (high
performance liquid chromatography) using an H2O/CH3CN/CH3SO3H gradient
and compared with a reference sample (a dilute solution of test product which
acts as an internal reference).
The results for solubility, S, and pH are shown in the table below and are
expressed in mg/ml.
In general, compounds with formula (I) of the present invention have a
solubility of 1 mg/ml or more at pH= 4; some of them had a solubility of more
than 8 mg/ml or even more than 10 mg/ml.

TABLE OF EXAMPLES






The following non-limiting examples illustrate the preparation of the
compounds and compositions of the invention:
The proton magnetic resonance spectra (1H NMR) described below were
recorded at 200 MHz in DMSO-d6 using the DMSO-d6 peak as the reference.
The chemical displacements 5 are expressed in parts per million (ppm). The
signals observed are expressed as follows: s: singlet; bs: broad singlet; d:
doublet; dd: double doublet; t: triplet; dt: double triplet; q: quadruplet; qui:
quintuplet; m: mass; mt: multiplet; sxt: sextuple!
Example 1 (2-butyl-6-ethylindolizin-3-yl){4-[3-
(dipropylamino)propyl]phenyl}methanone hydrochloride (compound
44)
a) 1 -bromohexane-2-one
60 g (0.599 mole) of 2-hexanone was slowly added to a solution of 58.6 g
(0.976 mole) of urea in 210 ml of acetic acid at ambient temperature. The
medium was cooled to 0°C in an ice bath then 33 ml of bromine (0.640 mole)
was added and it was stirred for 18 hours at ambient temperature. It was
poured onto water (1500 ml) and extracted with methylene chloride, the
organic phase was washed with a sodium bicarbonate solution, then dried
over sodium sulphate and the solution was concentrated.
The residue was distilled under reduced pressure. 76 g of the expected
compound was recovered (boiling point: 80-90°C/18 mmHg), contaminated
with a little of its isomer, 3-bromohexanone (6%).
b) N-(hexanone-2-yl)-2-methyl-5-ethylpyridinium bromide
21.6 g (0.178 mole) of 5-ethyl-2-methylpyridine was added slowly to 40 g of 1-
bromo-2-hexanone (0.223 mole) and stirred for 3 hours at ambient

temperature. A viscous medium was obtained which was used as is for the
next step.
c) 2-butyl-6-ethvyl-indolizine
A solution of 65 g of triethylamine in 370 ml of ethanol was added dropwise to
a solution of the product described above in 300 ml of ethanol then it was
heated under reflux for 18 hours. It was vacuum concentrated, taken up in
ethyl acetate, washed with water then the organic phase was dried over
sodium sulphate and concentrated to dryness. Next, it was purified by flash
chromatography over silica (eluent: heptane/methylene chloride, 50/50). In
this manner, 15 g of the desired compound was obtained in the form of a
yellow oil.
Yield: 34%.
d) (2-butyl-6-ethylindolizin-3-yl)[4-(3-chloropropyl)phenyl]methanone
A mixture of 5 g (27 mmoles) of the compound obtained in the preceding step
and 5.9 g (27 mmoles) of 4-(3-chloropropyl)benzoyl chloride was heated to
50°C for 18 hours. It was taken up in water, extracted with dichloromethane,
the organic phase was washed with a sodium carbonate solution, then dried
over sodium sulphate and concentrated to dryness. It was then purified by
flash chromatography over alumina (eluent: heptane/methylene chloride,
50/50). In this manner, 8 g of the desired compound was obtained in the form
of an oil.
Yield: 76%..
e) (2-butyl-6-ethylindolizin-3-yl){4-[(3-
(dipropylamino)propyl]phenyl}methanone
4 g (10.4 mmoles) of the compound obtained in the preceding step was
dissolved in 50 ml of methylisobutyl-ketone in a reactor and 2.7 g
(27 mmoles) of dipropylamine and 0.31 g (2 mmoles) sodium iodide were
added to this reaction medium and then heated to 110°C for 48 hours. It was
poured into water, extracted with dichloromethane, washed with a sodium
bicarbonate solution, dried over sodium sulphate and concentrated to
dryness. It was then purified by flash chromatography over alumina (eluent:

methylene chloride-ethyl acetate, 80/20). In this manner, 3.9 g of the desired
compound was obtained.
Yield: 84%.
f) (2-butyl-6-ethylindolizin-3-yl){4-[3-(dipropylamino)propyl]phenyl}methanone
hydrochloride
6.5 ml of a solution of hydrochloric ether (2M in ether) was added to a solution
of the product described above (3.9 g) in ether (400 ml), stirred for 30 minutes
and the salt which precipitated out was filtered. In this manner, 3.7 g of the
desired compound was obtained.
Yield: 88%, MP=140.7°C.
1H NMR spectrum (200 MHz, (DMSO), δ in ppm);
0.65 (t: 3H); 0.79 - 1.10 (m : 8H); 1.11 - 1.44 (m : 5H); 1.66 (mt: 4H); 2.03
(mt: 2H) ; 2.17 (t: 2H); 2.62 (q : 2H); 2.74 (t: 2H); 2.87 - 3.16 (m : 6H);
6.45 (s : 1H); 7.15 (d : 1H); 7.29 - 7.65 (m : 5H); 9.36 (s : 1H); 10.49 (bs :
1H)
The following compounds were prepared using the method described above
in Example 1, but using appropriate starting substances:
• (2-butyl-6-methylindolizin-3-yl){4-[3-
(dipropylamino)propyl]phenyl}methanone hydrochloride
MP = 14O°C
1H NMR spectrum (200 MHz, (DMSO), 5 in ppm); 0.65 (t: 3H); 0.79 - 1.10
(m : 8H); 1.32 (qui : 2H); 1.66 (m : 4H); 2.03 (mt: 2H); 2.17 (t: 2H); 2.30
(s : 3H); 2.74 (t: 2H); 2.87 - 3.16 (m : 6H); 6.45 (s : 1H); 7.09 (d : 1H);
7.31 - 7.61 (m : 5H); 9.34 (s : 1H); 10.60 (bs : 1H)
• (2-butyl-6-methylindolizin-3-yl)(4-{3-
[ethyl(propyl)amino]propyl}phenyl)methanone hydrochloride
MP = 132°C

1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.64 (t: 3H); 0.79 - 1.09
(m:5H); 1.09 - 1.43 (m : 5H); 1.65 (mt: 2H); 2.01 (mt: 2H); 2.15 (t: 2H);
2.29 (s : 3H); 2.74 (t: 2H); 2.85 - 3.21 (m : 6H); 6.44 (s : 1H); 7.08 (d :
1H); 7.25-7.65 (m : 5H); 9.33 (s : 1H); 10.57 (bs : 1H)
• (2-butyl-6-ethylindolizin-3-yl)(4-{3-
[ethyl(propyl)amino]propyl}phenyl)methanone hydrochloride
MP = 148.7°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.64 (t: 3H); 0.79 - 1.10
(m:5H); 1.10 - 1.44 (m : 8H); 1.65 (mt: 2H); 2.01 (mt: 2H); 2.17 (t: 2H);
2.62 (q : 2H); 2.75 (t: 2H) ; 2.85 - 3.23 (m : 6H); 6.45 (s : 1H); 7.15 (d :
1H); 7.29 - 7.65 (m:5H); 9.36 (s: 1H); 10.53 (bs:1H)
Example 2 (2-ethylindolizin-3-yl){4-[3-
(diethylamino)propyl]phenyl}methanone oxalate (compound 2)
a) (2-ethylindolizin-3-yl)[4-(3-chloropropyl)phenynmethanone
A mixture of 8 g (55 mmoles) of 2-ethyl-indolizine and 13.1 g (60 mmoles) of
4-(3-chloropropyl)benzoyl chloride was heated to 50°C for 18 hours. It was
taken up in water, extracted with dichloromethane, washed with a sodium
carbonate solution; the organic phase was then dried over sodium sulphate
and concentrated to dryness. It was purified by flash chromatography over
alumina (eluent: cyclohexane/methylene chloride, 50/50). In this manner,
17 g of the desired compound was obtained in the form of an oil. Yield: 94%.
b) (2-ethylindolizin-3-yl){4-[3-(diethvlamino)propy]phenyl)methanone
4 g (12 mmoles) of the compound obtained in the preceding step was
dissolved in 50 ml of methyl isobutylketone in a reactor then 2.3 g (31
mmoles) of diethylamine and 0.36 g (2.4 mmoles) of sodium iodide were
added to that medium and heated to 110°C for 48 hours. It was poured into
water, extracted with dichloromethane, washed with a solution of sodium
bicarbonate, dried over sodium sulphate and concentrated to dryness. It was
then purified by flash chromatography over silica (eluent: methanol –

methylene chloride, 10/90). In this manner, 2.9 g of the desired compound
was obtained.
Yield: 65%.
c) (2-ethylindolizin-3-yl)(4-[3-(diethylamino)propynphenyl]methanone oxalate
2.9 g of the product described above was dissolved in 40 ml of ethyl acetate
and 0.719 g (1 equivalent) of oxalic acid was added. Next, the salt which
crystallized out was filtered. In this manner, 2.9 g of the desired compound
was obtained.
Yield: 80% MP = 160 °C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.98 (t: 3H) ; 1.15 (t:
6H); 1.96 (m : 2H); 2.20 (q : 2H); 2.74 (t: 2H); 2.90 - 3.19 (m : 6H); 6.54 (s
: 1H); 6.93 (t : 1H); 7.21 (t : 1H); 7.31 - 7.58 (AA'-BB' system : 4H); 7.64
(d : 1H); 9.47 (d : 1H); 8.39 (bs : 2H).
Example 3: (2-butylindolizin-3-yl){4-[3-
(dipropylamino)propyl]phenyl}methanone hydrochloride (compound 7)
a) 2-methyl-1-(2-oxo-hexyl)-pyridinium bromide
30.21 g of 2-picoline (0.32 mole) was slowly added to 83 g of 1-bromo-2-
hexanone (0.46 mole) and stirred for 4 hours at ambient temperature. A
viscous medium was obtained which was used as is for the next step.
b) 2-butylindolizine
The N-(hexanone-2-yl)methyl-pyridinium bromide obtained above was
dissolved in 100 ml of ethanol and 84 g of sodium bicarbonate in solution in
630 ml of water was added. The reaction medium was heated for 3 h at
110°C. It was vacuum concentrated, taken up in water, extracted with
dichloromethane, the organic phase was washed with a sodium chloride
solution, dried over sodium sulphate and evaporated to dryness. The product
obtained was purified on a silica column under pressure (eluent: methylene
chloride/heptane, 20/80). In this manner, 33 g of 2-butylindolizine was
obtained.
Yield : 30 %

c)2-butylindolizin-3-yl)r4-(3-chloropropyl)phenynmethanone
A mixture of 9 g (56 mmoles) of 2-butyl-indolizine and 12.4 g (57 mmoles) of
4-(3-chloropropyl)benzoyl chloride was heated to 50°C for 18 hours. It was
taken up in water, extracted with dichloromethane, washed with sodium
carbonate solution, the organic phase was dried over sodium sulphate and
concentrated to dryness. Next, it was purified by flash chromatography over
silica (eluent: methylene chloride-heptane, 80/20). In this manner, 14 g of the
desired compound was obtained in the form of an oil.
Yield : 77 %
d) (2-butylindolizin-3-yl)(4-f3-(dipropylamino)propyl]phenyl}methanone
6 g (17 mmoles) of the compound obtained in the preceding step was
dissolved in a reactor in 60 ml of methylisobutylketone and 4.4 g (44 mmoles)
of dipropylamine and 0.5 g (3.4 mmoles) of sodium iodide were added, then
the medium was heated to 110°C for 48 hours. It was poured into water,
extracted with dichloromethane, washed with a sodium bicarbonate solution,
dried over sodium sulphate and concentrated to dryness.
It was then purified by flash chromatography over alumina (eluent: methylene
chloride/methanol, 98/2).
In this manner, 6.2 g of the desired compound was obtained.
Yield : 88 %
e) (2-butylindolizin-3-yl)(4-[3-(dipropylamino)propyl]phenvl}methanone
hydrochloride
11 ml of a solution of hydrochloric ether (2M in ether) was added to a solution
of the product described above (6.2 g) in ether (100 ml) and stirred for 30
minutes. It was vacuum concentrated, taken up in the ethyl acetate (60ml)
and the product which crystallized out was filtered. In this manner, 6.3 g of the
desired compound was obtained.
Yield: 95% MP = 115°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.64 (t: 3H) ; 0.78 - 1.12

(m : 8H); 1.33 (qui: 2H); 1.66 (mt: 4H); 2.02 (mt: 2H); 2.20 (t: 2H); 2.74 (t
: 2H); 2.85-3.15 (m : 6H); 6.50 (s : 1H);6.92(t: 1H);7.20(t: 1H);7.30-
7.57 (AA'-BB1 system: 4H); 7.62 (d : 1H), 9.45 (d : 1H); 10.60 (bs : 1H)
(2-Butylindolizin-3-yl)(4-[3-(dipropylamino)propyl]phenyl)methanone
hydrochloride hemihydrate
11 ml of water were added to a solution of (2-butylindolizin-3-yl){4-[3-
(dipropylamino)propyl]phenyl}methanone (500 g) in ethyl acetate (796 ml). A
solution of hydrochloric ether (2M in ether) was added to this coloured
solution, cooled to 10°C. The medium was seeded and then maintained for
three hours under isothermal conditions. The product obtained was filtered,
washed with methyl isobutyl ketone and dried.
In this manner, 478.5 g of the desired compound was obtained.
Yield : 86.3%
The NMR analysis confirmed the structure of the compound.
DSC ("Differential Scanning Calorimetry"): Endotherm at 95.2°C
corresponding to the loss of water, followed by an endotherm at 117.1°C
corresponding to melting.
(2-Butylindolizin-3-yl)4-[3-(dipropylamino)propvnphenyl}methanone sulphate
A solution of sulfuric acid in ethyl acetate was added to a solution of
(2-butylindolizin-3-yl){4-[3-(dipropylamino)propyl]phenyl}methanone (4.19 g)
in ethyl acetate (30 ml) which have then been heated to 70°C. The medium
was cooled to 20°C and then, after an isothermal period at this temperature,
the compound obtained was filtered, washed and dried.
In this manner, 4.4 g of the desired compound was obtained.
Yield: 85%
The NMR analysis confirmed the structure of the compound.
DSC: endotherm at 92°C corresponding to melting.

(2-Butylindolizin-3-yl){4-[3-(dipropylamino)propynphenyl}methanone fumarate
A solution of fumaric acid in ethyl acetate was added to a solution of
(2-butylindolizin-3-yl){4-[3-(dipropylamino)propyl]phenyl}methanone (9.5 g) in
ethyl acetate (39 ml) which have then been heated to 50°C. The medium was
cooled to 30°C, seeded, and then cooled to 5°C. After an isothermal period at
this temperature, the compound obtained was filtered and dried.
In this manner, 9.2 g of the desired compound were obtained.
Yield: 75.8%
The NMR analysis confirmed the structure of the compound.
DSC: melting endotherm at 83.9°C.
The following compounds were prepared using the methods described above
in Examples 2 or 3, but using the appropriate starting products:
(2-butylindolizin-3-yl){4-[3-(diethylamino)propyl]phenyl}methanone
hydrochloride
MP = 145°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.65 (t: 3H) ; 0.99 (sxt:
2H); 1.18 (t : 6H); 1.34 (qui: 2H); 1.99 (mt: 2H); 2.20 (t: 2H); 2.75 (t:
2H); 2 .93 - 3.22 (m : 6H); 6.50 (s : 1H); 6.92 (t: 1H); 7.20 (t: 1H); 7.32-
7.57 (AA'-BB1 system: 4H); 7.62 (d : 1H); 9.45 (d : 1H); 10.10 (bs : 1H)
{4-[3-(diethylamino)propyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride
MP = 152°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.60 (t: 3H) ; 1.19 - (t:
6H); 1.38 (sxt : 2H); 2.01 (mt : 2H); 2.17 (t: 2H) ; 2.75 (t : 2H); 2.89 - 3.21
(m : 6H); 6.51 (s : 1H); 6.92 (t : 1H); 7.20 (t : 1H); 7.32 - 7.57 (AA'-BB1
system: 4H); 7.62 (d : 1H); 9.45 (d : 1H) -10.52 (bs : 1H)

(2-butylindolizin-3-yl){4-[4-(diethylamino)butyl]phenyl}methanoneoxalate
MP = 102°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.64 (t: 3H) ; 0.98 (sxt:
2H); 1.17 (t:6H); 1.33 (qui: 2H); 1.65 (t: 4H); 2.20 (t: 2H); 2.70 (t: 2H);
2.93 - 3.21 (m : 6H); 6.50 (s : 1H); 6.92 (t: 1H); 7.20 (t: 1H); 7.29 - 7.56
(AA'-BB' system : 4H); 7.62 (d : 1H), 9.45 (d : 1H)
{4-[4-(diethylamino)butyl]phenyl}(2-ethylindolizin-3-yl)methanone oxalate
MP = 143°C
NMR spectrum 1H (200 MHz, (DMSO), δ in ppm); 0.98 (t: 3H); 1.15 (t: 6H);
1.64 mt : 4H); 2.20 (q : 2H); 2.72 (t: 2H); 2.89 - 3.19 (m : 6H); 6.53 (s :
1H); 6.92 (t : 1H); 7.20 (t : 1H); 7.29 -7.57 (AA'-BB1 system: 4H); 7.63 (d :
1H);9.45(d:1H)
{4-[4-(diethy!amino)butyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride
MP = 133°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.60 (t: 3H); 1.20 (t: 6H)
; 1.37 (sxt: 2H) ;1.68 (mt: 4H) ; 2.17 (t: 2H); 2.71 (t : 2H); 2.90 - 3.18 (m
: 6H); 6.50 (s : 1H); 6.93 (t: 1H); 7.20 (t: 1H); 7.29 - 7.57 (AA'-BB1 system
: 4H); 7.62 (d : 1H); 9.46 (d : 1H) - 10.37 (bs : 1H)
{4-[3-(dipropylamino)propyl]phenyl}(2-ethylindolizin-3-yl)methanone
hydrochloride
MP = 152°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.89 (t: 6H) ; 0.98 (t:
3H); 1.65 (mt : 4H); 2.03 (mt: 2H); 2.20 (q: 2H); 2.74 (t : 2H) ; 2.86 - 3.14
(m : 6H); 6.54 (s : 1H); 6.93 (t : 1H); 7.21 (t : 1H); 7.32 - 7.58 (AA'-
BB1 system: 4H); 7.63 (d : 1H); 9.47 (d : 1H); 10.46 (bs : 1H)

{4-[3-(dipropylamino)propyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride
MP = 122.6°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.60 (t: 3H) ; 0.89 - (t:
6H); 1.3 (sx : 2H); 1.65 (m : 4H); 1.89 - 2.26 (m : 4H); 2.75 (t: 2H); 2.85 -
3.14 (m : 6H); 6.50 (s : 1H); 6.92 (t: 1H) ;7.20 (t: 1H); 7.32 - 7.57 (AA-BB
system : 4H); 7.62 (d : 1H); 9.45 (d : 1H) -10.47 (broad singlet: 1H)
(2-butylindolizin-3-yl){4-[4-(dipropylamino)butyl]phenyl}methanone
hydrochloride
MP = 117°C
1H NMR spectrum (250 MHz, (DMSO), δ in ppm); 0.64 (t: 3H) ; 0.79 - 1.08
(superimposed multiplets : 8H) ; 1.31 (qui : 2H) ; 1.48 - 1.89 (superimposed
multiplets :8H) ; 2.18 (mt : 2H); 2.70 (mt : 2H) ; 2.78 - 3.17 (superimposed
multiplets : 6H); 6.48 (s : 1H); 6.92 (t: 1H); 7.21 (t: 1H); 7.35 (d : 2H) ; 7.48
(d : 2H); 7.60 (d : 1H); 9.45 (d : 1H); 10.56 (broad signal: 1H)
{4-[4-(dipropylamino)butyl]phenyl}(2-ethylindolizin-3-yl)methanone
hydrochloride
MP = 130°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.89 (t: 6H) ; 0.98 (t:
3H); 1.67 (mt : 8H); 2.21 (q: 2H); 2.71 (t: 2H); 2.81 - 3.19 (m : 6H) ; 6.53
(s : 1H); 6.93 (t : 1H); 7.20 (t : 1H); 7.29 - 7.57 (AA'-BB' system: 4H);
7.63 (d : 1H); 9.45 (d : 1H); 10.32 (bs : 1H)
4-[3-(dipropylamino)propyl]phenyl}(2-isopropylindolizin-3-yl)methanone
hydrochloride
MP = 154°C
1H NMR spectrum (200 MHz, (DMSO-D6), δ in ppm); 0.89 (t: 6H) ; 1.03 (d :
6H); 1.64 (mt: 4H); 2.03 (mt: 2H); 2.54 (mt: 1H); 2.75 (t: 2H); 2.84 - 3.17

(m : 6H); 6.58 (s : 1H); 6.89 (t : 1H); 7.17 (t: 1H); 7.39 (d : 2H); 7.55 (d :
2H); 7.62 (d : 1H); 9.32 (d : 1H); 10.54 (s : 1H)
{4-[3-(dipropylamino)propyl]phenyl}(2-methylindolizin-3-yl)methanone
hydrochloride
MP = 146°C
1H NMR spectrum (200 MHz, (DMSO-D6), δ in ppm); 0.87 (t: 6H); 1.62 (mt:
4H); 1.83 (s : 3H); 2.01 (mt: 2H); 2.17 (t: 2H); 2.84 - 3.12 (m : 6H); 6.46
(s : 1H); 6.94 (t :1H); 7.22 (t : 1H); 7.38 (d : 2H); 7.49 (d : 2H) ; 7.61 (d :
1H); 9.55 (d:1H); 10.42 (s : 1H)
{4-[4-(dipropylamino)butyl]phenyl}(2-isopropylindolizin-3-yl)methanone
oxalate
MP = 64°C
1H NMR spectrum (200 MHz, (DMSO-D6), δ in ppm); 0.86 (t: 6H) ; 1.00 (d :
6H) ; 1.40 - 1.78 (m : 8H) ; 2.53 (mt: 1H); 2.69 (t: 2H); 2.81 - 3.15 (m :
6H); 6.58 (s : 1H); 6.87 (t: 1H); 7.16 (t: 1H); 7.34 (d : 2H); 7.54 (d : 2H);
7.60 (d: 1H);9.30(d: 1H)
{4-[4-(dipropylamino)butyl]phenyl}(2-methylindoiizin-3-yl)methanone
hydrochloride
MP = 141.1°C
NMR spectrum 1H (200 MHz, (DMSO-D6), 5 in ppm); 0.89 (t: 6H); 1.48 -
1.79 (m : 8H); 1.85 (s : 3H); 2.71 (t: 2H); 2.82 - 3.18 (m : 6H); 6.46 (s :
1H); 6.95 (t : 1H); 7.22 (t: 1H); 7.35 (d : 2H); 7.48 (d : 2H); 7.62 (d : 1H);
9.54 (d :1H); 10.26 (s:1H)
(2-butylindolizin-3-yl){4-[3-(dibutylamino)propyl]phenyl}methanone
hydrochloride
MP = 83°C

1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.65 (t: 3H) ; 0.80- 1.11
(m : 8H) ; 1.17 - 1.73 (m : 10H) ; 2.01 (mt :2H) ; 2.20 (t: 2H); 2.74 (t: 2H) ;
2.90-3.16 (m : 6H) ; 6.50 (s : 1H);6.92(t: 1H); 7.20 (t: 1H); 7.32-7.57
(AA'BB1 system: 4H) ;7.62 (d : 1H); 9.45 (d : 1H); 10.25 (bs : 1H)
{4-[3-(dibutylamino)propyl]phenyl}(2-ethylindolizin-3-yl)methanone
hydrochloride
MP = 94.5°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.90 (t: 6H); 0.99 (t: 3H)
; 1.30 (sxt: 4H); 1.61 (mt: 4H) ; 2.02 (mt: 2H); 2.21 (q : 2H) ; 2.75 (t : 2H) ;
2.87 - 3.18 (m : 6H) ; 6.55 (s : 1H); 6.94 (t : 1H); 7.22 (t: 1H) - 7.31 - 7.59
(AA'-BBT system : 4H); 7.64 (d : 1H); 9.45 (d : 1H); 10.48 (bs : 1H)
{4-[3-(dibutylamino)propyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride
MP = 120.6°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.60 (t: 3H) ; 0.89 (t: 6H)
; 1.13 — 1.75 (m : 10H) ; 1.87- 1.25 (m : 4H); 2.74 (t: 2H); 2.88 - 3.15 (m
: 6H); 6.50 (s : 1H); 6.93 (t : 1H); 7.20 (t: 1H) ;7.31 -7.57 (AA'-BB1 system
: 4H); 7.62 (d : 1H); 9.45 (d : 1H); 10.44 (bs : 1H)
(2-butylindolizin-3-yl){4-[4-(dibutylamino)butyl]phenyl}methanoneoxalate
MP = 101°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.64 (t: 3H) ; 0.79 - 1.14
(superimposed multiplets : 8H) ; 1.14 - 1.45 (multiple superimposed
multiplets : 6H) ; 1.45 - 1.85 (multiple superimposed multiplets : 8H) ; 2.20
(mt: 2H); 2.70 (mt: 2H); 2.87 - 3.20 (superimposed multiplets : 6H); 6.50 (s
: 1H); 6.92 (t: 1H); 7.18 (t: 1H); 7.34 (d : 2H) ;7.49 (d : 2H) ; 7.61 (d : 1H) ;
9.44 (d:1H)
{4-[4-(dibutylamino)butyl]phenyl}(2-ethylindolizin-3-yl)methanone oxalate

MP = 96-101°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.89 (t: 6H) ; 0.98 (t:
3H); 1.30 (sxt : 4H); 1.43 - 1.79 (m : 8H); 2.21 (q : 2H) ; 2.72 (t: 2H); 2.82
- 3.14 (m : 6H); 6.53 (s : 1H); 6.92 (t : 1H); 7.20 (t: 1H); 7.29 - 7.57 (AA1-
BB' system : 4H); 7.63 (d :1 H); 9.45 (d : 1H)
{4-[4-(dibutylamino)butyl]phenyl}(2-propylindolizin-3-yl)methanoneoxalate
MP = 154.6°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.60 (t: 3H) ; 0.90 (t: 6H)
; 1.12-1.82 (m: 14H); 2.17 (t: 2H); 2.71 (t: 2H) 2.84-3.18 (m : 6H); 6.50
(s : 1H); 6.93 (t: 1H); 7.20 (t: 1H); 7.29 - 7.57 (AA'-BB' system : 4H); 7.62
(d: 1H)-9.45(d:1H)
(2-butylindolizin-3-yl)(4-{3-[ethyl(propyl)amino]propyl}phenyl)methanone
hydrochloride
MP = 120°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.65 (t: 3H) ; 0.81 - 1.10
(m : 5H); 1.11 - 1.45 (m : 5H); 1.65 (mt: 2H); 2.01 (mt: 2H); 2.20 (t: 2H);
2.74 (t: 2H); 2.86 - 3.21 (m : 6H); 6.50 (s : 1H); 6.92 (t: 1H); 7.20 (t: 1H);
7.31 - 7.57 (AA'-BB1 system :4H) ; 7.62 (d : 1H), 9.45 (d : 1H); 10.53 (bs :
1H)
(2-ethylindolizin-3-yl)(4-{3-[ethyl(propyl)amino]propyl}phenyl)methanone
oxalate
MP = 160°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.89 (t: 3H) ; 0.98 (t:
3H); 1.15 (t : 3H); 1.56 (mt : 2H); 1.97 (mt : 2H); 2.20 (q : 2H); 2.73 (t :
2H); 2.86 - 3.19 (m : 6H); 6.54 (s : 1H); 6.93 (t: 4H); 7.21 (t: 1H); 7.30 -
7.58 (AA'-BB' system : 4H); 7.63 (d : 1H) 9.47 (d : 1H); 5.40 - 7.31 (bs : 2H)

(4-{3-[ethyl(propyl)amino]propyl}phenyl)(2-isopropylindolizin-3-yl)methanone
hydrochloride
MP = 130°C
1H NMR spectrum (200 MHz, (DMSO-D6), δ in ppm); 0.87 (t: 3H); 1.00 (d :
6H); 1.16 (t : 3H); 1.62 (mt: 2H); 2.00 (mt: 2H); 2.53 (mt: 1H); 2.73 (t :
2H); 2.84 - 3.17 (m : 6H); 6.57 (s : 1H); 6.88 (t: 1H); 7.16 (t: 1H); 7.38 (d :
2H); 7.55 (d : 2H); 7.61 (d : 1H) ; 9.32 (d : 1H); 10.48 (s : 1H)
(4-{3-[ethyl(propyl)amino]propyl}phenyl)(2-methylindolizin-3-yl)methanone
hydrochloride
MP = 147.9°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm) ; 0.89 (t: 3H) ; 0.98 (t:
3H); 1.15 (t: 3H); 1.56 (m : 2H); 1.97 (m : 2H) ; 2.20 (q : 2H); 2.73 (t: 2H);
2.86-3.19 (m : 6H); 6.54 (s : 1H); 6.93 (t : 4H); 7.21 (t: 1H); 7.30-7.58
(AA'-BB' system : 4H) ; 7.63 (d : 1H) 9.47 (d : 1H); 5.40 - 7.31 (broad
signal: 2H)
(4-{4-[ethyl(propyl)amino]butyl}phenyl)(2-isopropylindolizin-3-yl)methanone
oxalate
MP = 136°C
1H NMR spectrum (200 MHz, (DMSO-D6), δ in ppm); 0.89 (t: 3H) ; 1.03 (d :
6H); 1.17 (t: 3H); 1.47 - 1.80 (m : 6H); 2.55 (mt: 1H); 2.72 (t: 2H); 2.84 -
3.19 (m : 6H); 6.58 (s : 1H); 6.88 (t : 1H); 7.17 (t: 1H); 7.35 (d : 2H); 7.54
(d : 2H); 7.62 (d : 1H); 9.31 (d : 1H); 5.50 - 8.00 (bs : 2H)
(4-{4-[ethyl(propyl)amino]butyl}phenyl)(2-methylindolizin-3-yl)methanone
hydrochloride
MP = 141.1°C
1H NMR spectrum (200 MHz, (DMSO-D6), δ in ppm); 0.89 (t: 3H) ; 1.20 (t:
3H); 1.43 - 1.79 (m : 6H); 1.86 (s : 3H); 2.71 (t: 2H); 2.82 - 3.22 (m : 6H);

6.46 (s : 1H); 6.95 (t : 1H); 7.22 (t : 1H); 7.35 (d : 2H); 7.48 (d : 2H) ; 7.62
(d: 1H); 9.55 (d:1H); 10.30 (s:1H)
(4-{3-[ethyl(propyl)amino]propyl}phenyl)(2-propylindolizin-3-yl)methanone
hydrochloride
MP = 108.7°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.60 (t: 3H) ; 0.89 - (t:
3H); 1.19 (t : 3H); 1.38 (sxt: 2H); 1.64 (mt: 2H); 1.89-2.26 (m : 4H);
2.75 (t : 2H); 2.85 - 3.21 (m : 6H) ; 6.51 (s : 1H); 6.93 (t : 1H); 7.20 (t :
4H); 7.31 - 7.58 (AA'-BB1 system : 4H) ; 7.62 (d : 1H) -9.45 (d : 1H) - 10.38
(bs: 1H)
(2-butylindolizin-3-yl)(4-{4-[ethyl(propyl)amino]butyl}phenyl)methanone
hydrochloride
MP = 125°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.63 (t: 3H) ; 0.77 - 1.10
(m: 5H); 1.11 -1.45 (m : 5H); 1.67 (mt : 6H); 2.19 (t: 2H); 2.70 (t : 2H);
2.82 - 3.21 (m : 6H); 6.50 (s : 1H); 6.91 (t: 1H); 7.19 (t: 1H); 7.29 - 7.55
(AA'-BB' system : 4H); 7.61 (d : 1H); 9.45 (d : 1H) -10.55 (bs : 1H)
(2-ethylindolizin-3-yl)(4-{4-[ethyl(propyl)amino]butyl}phenyl)methanone
oxalate
MP = 132°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.72 - 1.35 (m : 9H) ; 1.65
- (bs : 6H); 2.20 (q : 2H); 2.70 (bs : 2H); 2.82 - 3.21 (m : 6H); 6.54 (s : 1H);
6.93 (t : 1H); 7.20 (t : 1H); 7.27 - 7.57 (AA'-BB' system : 4H); 7.63 (d :
1H); 7.63 (d : 1H); 9.45 (d : 1H); 8.20 -10 (bs : 1H)
(4-{4-[ethyl(propyl)amino]butyl}phenyl)(2-propylindolizin-3-yl)methanone
hydrochloride
MP = 133°C

1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.57 (t: 3H) ; 0.87 (t:
3H); 1.18 (t: 3H); 1.35 (sxt: 2H); 1.65 (m : 6H); 2.14 (t: 2H); 2.69 (t: 2H);
2.80 - 3.18 (m : 6H); 6.49 (s : 1H); 6.91 (t: 1H); 7.19 (t: 1H); 7.27- 7.56
(AA'-BB1 system :4H); 7.61 (d : 1H); 9.45 (d : 1H); 10.28 (bs : 1H)
(2-butylindolizin-3-yl)(4-{3-[butyl(propyl)amino]propyl}phenyl)methanone
oxalate
MP = 142°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.64 (t : 3H) ; 0.79 - 1.13
(superimposed multiplets : 8H) ; 1.14 - 1.45 (superimposed multiplets : 4H) ;
1.45 - 1.75 (superimposed multiplets : 4H) ; 1.96 (mt : 2H) ; 2.20 (mt : 2H) ;
2.73 (mt : 2H) ; 2.86 - 3.17 (superimposed multiplets : 6H) ; 6.51 (s : 1H);
6.92 (t : 1H); 7.20 (t : 1H); 7.38 (d : 2H); 7.52 (d : 2H); 7.62 (d : 1H); 9.46
(d:1H)
(4-{3-[butyl(ethyl)amino]propyi}phenyl)(2-butylindolizin-3-yl)methanone
oxalate
MP = 112°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.64 (t : 3H); 0.79 - 1.08
(superimposed multiplets : 5H) ; 1.15 (t : 3H) ; 1.23-1.44 (superimposed
multiplets : 4H); 1.55 (mt: 2H); 1.97 (mt: 2H); 2.20 (mt: 2H); 2.74 (t: 2H);
2.90-3.20 (superimposed multiplets : 6H); 6.51 (s : 1H); 6.92 (t: 1H); 7.21 (t
: 1H); 7.39 (d : 2H); 7.52 (d : 2H); 7.62 (d : 1H); 9.46 (d : 1H)
(2-butylindolizin-3-yl)(4-{3-
[(cyclopropylmethyl)(propyl)amino]propyl}phenyl)methanone hydrochloride
MP = 101°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.34 (mt : 2H) ; 0.50 -
0.80 (superimposed multiplets : 5H) ; 0.80 - 1.17 (superimposed multiplets :
6H); 1.33 (qui : 2H); 1.63 (mt: 2H); 2.00 (mt: 2H); 2.20 (mt: 2H); 2.73 (t:
2H); 2.86 - 3.40 (superimposed multiplets : 6H); 6.51 (s : 1H); 6.95 (t: 1H);

7.19 (t: 1H); 7.38 (d : 2H); 7.52 (d : 2H); 7.60 (d : 1H); 9.45 (d : 1H)
{4-[4-(propylamino)butyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride
MP = 135.3°C
1H NMR spectrum (200 MHz, (DMSO-D6), δ in ppm); 0.59 (t: 3H); 0.90 (t:
3H); 1.37 (sxt: 2H); 1.50 - 1.80 (m : 6H); 2.16 (t: 2H); 2.57 - 3.04 (m :
6H); 6.50 (s : 1H); 6.92 (t: 1H); 7.20 (t: 1H); 7.35 (d : 2H); 7.50 (d : 2H);
7.62 (d : 1H); 8.92 (s : 2H); 9.45 (d : 1H)
(2-butylindolizin-3-yl){4-[3-(propylamino)propyl]phenyl}methanone
hydrochloride
MP = 178.2°C
1H NMR spectrum (200 MHz, (DMSO-D6), δ in ppm); 0.62 (t: 3H) ; 0.78 -
1.07 (m:5H); 1.31 (qui : 2H); 1.62 (sxt: 2H); 1.96 (qui: 2H); 2.17 (t: 2H);
2.61 - 2.99 (m : 6H); 6.49 (s :1 H); 6.91 (t: 1H); 7.20 (t: 1H); 7.36 (d : 2H);
7.51 (d : 2H); 7.61 (d : 1H); 8.99 (s : 2H); 9.46 (d : 1H)
(2-butylindolizin-3-yl){4-[3-(dimethylamino)propyl]phenyl}methanone
hydrochloride
MP = 133.6°C
1H NMR spectrum (200 MHz, (DMSO-D6), δ in ppm); 0.64 (t: 3H) ; 0.99
(sxt: 2H); 1.34 (qui: 2H); 2.02 (m : 2H); 2.20 (t: 2H); 2.59 - 2.87 (m : 8H);
3.04 (m : 2H); 6.50 (s : 1H); 6.92 (t : 1H); 7.20 (t: 1H); 7.37 (d : 2H) ; 7.51
(d : 2H); 7.62 (d : 1H); 9.46 (d : 1H); 10.78 (s : 1H)
(2-butylindolizin-3-yl)(4-{3-[(3R,5S)-3,5-dimethylpiperazin-1-
yl]propyl}phenyl)methanone hydrochloride
MH+=432.3
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.65 (t : 3H) ; 0.98 (mt:
2H) ; 1.17 - 1.48 (superimposed multiplets : 8H) ; 1.93 - 2.32 (superimposed

multiplets :4H); 2.75 (t : 2H) ; 3.13 (mt: 4H); 3.73 (mt: 4H) ; 6.51 (s : 1H) ;
6.92 (t: 1H); 7.21 (t: 1H); 7.39 (d : 2H) ;7.53 (d : 2H); 7.63 (d : 1H); 9.45 (d
: 1H); 9.96 (broad signal: 2H); 12.06 (broad signal: 1H)
(2-butylindolizin-3-yl)(4-{3-[(3R,5S)-3,4,5-trimethylpiperazin-1-
yl]propyl}phenyl)methanone hydrochloride
MP = 191-201 °C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.65 (t : 3H) ; 0.98 (mt:
2H) ; 1.15- 1.58 (superimposed multiplets : 8H) ; 1.93-2.38 (superimposed
multiplets : 4H) ; 2.50 - 2.90 (superimposed multiplets : 5H) ; 2.95 - 4.50
(superimposed multiplets : 8H) ; 6.55 (s : 1H) ; 6.92 (t : 1H) ; 7.21 (t : 1H);
7.39 (d : 2H); 7.53 (d : 2H); 7.63 (d : 1H); 9.45 (d : 1H); 11.95 (broad signal
:2H)
(4-{3-[bis(2-methoxyethyl)amino]propyl}phenyl)(2-butylindolizin-3-
yl)methanone oxalate
MP = 137-139°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.65 (t : 3H) ; 0.98 (mt:
2H); 1.33 (mt: 2H); 1.90 (mt: 2H); 2.19 (mt: 2H); 2.69 (mt: 2H); 2.95 (mt:
2H) ; 3.12 (mt : 4H) ; 3.26 (s : 6H); 3.55 (mt : 4H); 6.51 (s : 1H); 6.92 (t:
1H); 7.20 (t: 1H); 7.34 (d : 2H); 7.51 (d : 2H); 7.63 (d : 1H); 9.46 (d : 1H).
(2-butylindolizin-3-yl)[4-(3-piperidin-1-ylpropyl)phenyl]methanone oxalate
MP = 191-192°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm) ; 0.65 (t : 3H) ; 0.98 (mt:
2H) ; 1.33 (mt : 2H) ; 1.53 (mt :2H) ; 1.71 (superimposed multiplets : 4H);
2.00 (mt : 2H) ; 2.20 (mt : 2H) ; 2.70 (t : 2H) ; 2.88 - 3.30 (superimposed
multiplets : 6H); 6.52 (s : 1H); 6.92 (t: 1H); 7.28 (t: 1H); 7.37 (d : 2H); 7.52
(d : 2H); 7.63 (d : 1H);9.45(d: 1H).

Example 4: {4-[4-(dipropylamino)butyl]phenyl}(2-propylindolizin-3-
yl)methanone hydrochloride (compound 16)
a)(2-propylindolizin-3-vl)r4-(4-chlorobutyl)phenyl] methanone
A mixture of 11 g (69 mmoles) of 2-propyl indolizine and 15.9 g (69 mmoles)
of 4-(4-chlorobutyl) benzoyl chloride was heated to 50°C for 18 hours. It was
taken up in water, extracted with dichloromethane, washed with a sodium
carbonate solution, the organic phase was dried over sodium sulphate and
concentrated to dryness. It was purified by flash chromatography over
alumina (eluent: heptane/methylene chloride, 50/50).
In this manner, 23 g of the desired compound was obtained in the form of an
oil.
Yield : 94.2 %
b) (2-propylindolizin-3-yl){4-[4-(dipropylamino)butyl]phenyl}methanone
4 g (11.3 mmoles) of the compound obtained in the preceding step was
dissolved in a reactor in 50 ml of methyl isobutylketone and 2.9 g (29.3
mmoles) of dipropylamine and 0.33 g (2 26 mmoles) of sodium iodide were
added to this reaction medium and heated to 110°C for 72 hours.
It was poured into water, extracted with dichloromethane, washed with a
sodium bicarbonate solution and concentrated to dryness. It was then
purified by flash chromatography on silica (eluent: methylene
chloride/methanol, 95/5).
In this manner, 3.9 g of the desired compound was obtained.
Yield : 82.9%
c) (2-propylindolizin-3-yl){4-[4-(dipropylamino)butyl]phenyl} methanone
hydrochloride

7 ml of a solution of hydrochloric ether (2M in ether) was added to a solution
of the product described above, 3.9 g in ether (50 ml), stirred for 30 minutes
and the salt which crystallized out was filtered.
In this manner, 3.1 g of the desired compound was obtained.
Yield: 73%
MP = 93°C
1H NMR spectrum (200 MHz, (DMSO), δ in ppm); 0.60 (t: 3H); 0.90 (t: 6H);
1.38 (sxt: 2H) ; 1.52-1.85 (m : 8H) ; 2.17 (t: 2H) 2.71 (t : 2H) ; 2.84 -3.18
(m : 6H) ; 6.50 (s : 1H) ; 6.93 (t: 1H) ; 7.20 (t : 1H); 7.29 - 7.57 (AA'-BB'
system : 4H); 7.62 (d : 1H); 9.45 (d : 1H) - 10.23 (bs : 1H)
The solubility tests were carried out at pH = 4 as follows :
A phosphate buffer, pH6, 0.1 M, was prepared by adding 6.15 ml of 0.1 M
Na2HPO4 to 43.85 ml of 0.1 M NaH2PO4. The solution was made up to
100 ml with filtered water using a Millipore system (trade mark).
Reference (test product in a concentration in which the latter is soluble and
which acts as an internal reference)
About 0.2 mg (in a boat) was weighed out exactly and diluted in 1 ml of
H2O/CH3CN: (50:50), i.e. 0.2 mg/ml, then the sample was subjected to
ultrasound for 5 minutes.
Test product sample:
About 4 mg (in a boat) was weighed out exactly and diluted in 400 µl (i.e. 10
mg/ml) of pH6 phosphate buffer (0.1 M), then the sample was subjected to
ultrasound for 5 minutes.
The pH was noted and if the pH was below 4, 1 µl of NaOH 1N was added
(from 1 µl in 1 µI) until the pH was more than 4, then the pH was noted again.
The solution (0.45 µm) was filtered then if necessary diluted with the
phosphate buffer pH6. (If the product re-precipitated after diluting, the diluted

sample was ignored, the mother solution was used and the solubility was
determined at a wavelength other than λmax, to avoid saturating the signal.
The solubility of the compound was then determined by HPLC under the
following conditions:
Experimental conditions
Instrument: Agilent 1100 chromatograph
Software : Chemstation
Column : XTERRAC18 (150 x4.6 mm ; 3.5 µm)
Eluent A : H2O / CH3CN / CH3SO3H : 1000 / 25 /1
Eluent B : H2O / CH3CN / CH3SO3H : 25 /1000 /1
Gradient:

Column temperature : 30°C
Flow rate : 0.8 ml/min
Detection : A= 230 nm
Injection volume : 5µl

38
CLAIMS.
1. Indolizine derivatives with general formula (I):

in which:
X represents a -(CH2)n- radical where n is a whole number from 1 to 6,
or a group with formula CH2-Z-(CH2)2-, in which Z represents an
O(CH2)m- group in which m is a whole number from 0 to 3; R1
represents a linear, branched or cyclic C1-C8 alkyl radical; Am
represents an NR3R4 group in which R3 and R4 are identical or different
and independently of each other represent:
- a hydrogen atom;
- a linear, branched or cyclic C1-C6 alkyl radical or a C1-C3 radical substituted
with a C3-C6 cycloalkyl radical;
- or a (CH2)1-O-B radical in which B represents a hydrogen atom or a (CH2)k
alkyl radical, where I and k are whole numbers, I ≥ 2 and l+k = 6;
or R3 and R4 together with the nitrogen atom to which they are
attached form a heterocycle containing 4 to 6 links which may
optionally contain one or more heteroatoms selected from N and O and
optionally carrying one or more substituents selected from a linear,
branched or cyclic C1-C6 alkyl radical;
R2 represents a hydrogen atom or a linear, branched or cyclic C1-C6
alkyl radical;
and their pharmaceutically acceptable salts.
2. Indolizine derivatives according to claim 1, characterized in that X
represents a -(CH2)n- radical where n is a whole number from 1 to 6.

Indolizine derivatives according to claim 1, characterized in that X
represents a (CH2)n- radical where n is a whole number from 3 to 4.
Indolizine derivatives according to claim 1, characterized in that X
represents a group with formula CH2-Z-(CH2)2-, in which Z represents
an O(CH2)m- group in which m is a whole number from 0 to 3.
Indolizine derivatives according to claim 1, 2, 3 or 4, characterized in
that R1 represents a C1-C4 alkyl radical.
Indolizine derivatives according to any one of claims 1 to 5,
characterized in that R3 and R4 independently of each other represent
a linear C1-C4 alkyl radical.
Indolizine derivatives according to any one of claims 1 to 6,
characterized in that R3 and R4 together form a piperidinyl or
piperazinyl group optionally carrying one or more methyl radicals.
Indolizine derivatives according to any one of claims 1 to 7,
characterized in that R2 represents a hydrogen atom.
Indoiizine derivatives according to any one of claims 1 to 8,
characterized in that the pharmaceutically acceptable salt is selected
from the oxalate and the hydrochloride.
Indolizine derivatives with formula (I) with the following names:
(2-butylindolizin-3-yl){4-[3-(diethylamino)propyl]phenyl}methanone
hydrochloride;
(2-ethylindolizin-3-yl){4-[3-(diethylamino)propyl]phenyl}methanone
oxalate;
{4-[3-(diethylamino)propyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride;
(2-butylindolizin-3-yl){4-[4-(diethylamino)butyl]phenyl}methanone
oxalate;

{4-[4-(diethylamino)butyl]phenyl}(2-ethylindolizin-3-yl)methanone
oxalate;
{4-[4-(diethylamino)butyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride;
(2-butylindolizin-3-yl){4-[3-(dipropylamino)propyl]phenyl}methanone
hydrochloride;
(2-butylindolizin-3-yl){4-[3-(dipropylamino)propyl]phenyl}methanone
hydrochloride hemihydrate;
(2-butylindolizin-3-yl){4-[3-(dipropylamino)propyl]phenyl}methanone
sulphate;
(2-butylindolizin-3-yl){4-[3-(dipropylamino)propyl]phenyl}methanone
fumarate;
{4-[3-(dipropylamino)propyl]phenyl}(2-ethylindolizin-3-yl)methanone
hydrochloride;
{4-[3-(dipropylamino)propyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride;
(2-butylindolizin-3-yl){4-[4-(dipropylamino)butyl]phenyl}methanone
hydrochloride;
{4-[4-(dipropylamino)butyl]phenyl}(2-ethylindolizin-3-yl)methanone
hydrochloride;

4-[3-(dipropylamino)propyl]phenyl}(2-isopropylindolizin-3-yl)methanone
hydrochloride;
{4-[3-(dipropylamino)propyl]phenyl}(2-methylindolizin-3-yl)methanone
hydrochloride;
{4-[4-(dipropylamino)butyl]phenyl}(2-isopropylindolizin-3-yl)methanone
oxalate;
{4-[4-(dipropylamino)butyl]phenyl}(2-methylindolizin-3-yl)methanone
hydrochloride;
{4-[4-(dipropylamino)butyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride;
(2-butylindolizin-3-yl){4-[3-(dibutylamino)propyl]phenyl}methanone
hydrochloride;
Hydrochloride {4-[3-(dibutylamino)propyl]phenyl}(2-ethylindolizin-3-
yl)methanone;
{4-[3-(dibutylamino)propyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride;
(2-butylindolizin-3-yl){4-[4-(dibutylamino)butyl]phenyl}methanone
oxalate;
{4-[4-(dibutylamino)butyl]phenyl}(2-ethylindolizin-3-yl)methanone
oxalate;

{4-[4-(dibutylamino)butyl]phenyl}(2-propylindolizin-3-yl)methanone
oxalate;
(2-butylindolizin-3-yl)(4-{3-
[ethyl(propyl)amino]propyl}phenyl)methanone hydrochloride;
(2-ethylindolizin-3-yl)(4-{3-
[ethyl(propyl)amino]propyl}phenyl)methanone oxalate;
(4-{3-[ethyl(propyl)amino]propyl}phenyl)(2-isopropylindolizin-3-
yl)methanone hydrochloride;
(4-{3-[ethyl(propyl)amino]propyl}phenyl)(2-methylindolizin-3-
yl)methanone hydrochloride;
(4-{4-[ethyl(propyl)amino]butyl}phenyl)(2-isopropylindolizin-3-
yl)methanone oxalate;
(4-{4-[ethyl(propyl)amino]butyl}phenyl)(2-methylindolizin-3-
yl)methanone hydrochloride;
(4-{3-[ethyl(propyl)amino]propyl}phenyl)(2-propylindolizin-3-
yl)methanone hydrochloride;
(2-butylindolizin-3-yl)(4-{4-[ethyl(propyl)amino]butyl}phenyl)methanone
hydrochloride;
(2-ethylindolizin-3-yl)(4-{4-[ethyl(propyi)amino]butyl}phenyl)methanone
oxalate;

(4-{4-[ethyl(propyl)amino]butyl}phenyl)(2-propylindolizin-3-
yl)methanone hydrochloride;
(2-butylindolizin-3-yl)(4-{3-
[butyl(propyl)amino]propyl}phenyl)methanone oxalate;
(4-{3-[butyl(ethyl)amino]propyl}phenyl)(2-butylindolizin-3-yl)methanone
oxalate;
(2-butylindolizin-3-yl)(4-{3-
[(cyclopropylmethyl)(propyl)amino]propyl}phenyl)methanone
hydrochloride;
{4-[4-(propylamino)butyl]phenyl}(2-propylindolizin-3-yl)methanone
hydrochloride;
(2-butylindolizin-3-yl){4-[3-(propylamino)propyl]phenyl}methanone
hydrochloride;
(2-butylindolizin-3-yl){4-[3-(dimethylamino)propyl]phenyl}methanone
hydrochloride;
(2-butylindolizin-3-yl)(4-{3-[(3R,5S)-3,5-dimethylpiperazin-1-
yl]propyl}phenyl)methanone hydrochloride;
(2-butylindolizin-3-yl)(4-{3-[(3R,5S)-3,4,5-trimethylpiperazin-1-
yl]propyl}phenyl)methanone hydrochloride;
(4-{3-[bis(2-methoxyethyl)amino]propyl}phenyl)(2-butylindolizin-3-
yl)methanone oxalate;

(2-butylindolizin-3-yl)[4-(3-piperidin-1-ylpropyl)phenyl]methanone
oxalate;
(2-butyl-6-methylindolizin-3-yl){4-[3-
(dipropylamino)propyl]phenyl}methanone hydrochloride;
(2-butyl-6-ethylindolizin-3-yl){4-[3-
(dipropylamino)propyl]phenyl}methanone hydrochloride;
(2-butyl-6-methylindolizin-3-yl)(4-{3-
[ethyl(propyl)amino]propyl}phenyl)methanone hydrochloride;
(2-butyl-6-ethylindolizin-3-yl)(4-{3-
[ethyl(propyl)amino]propyl}phenyl)methanone hydrochloride;
Method for preparing derivatives with formula (I) as defined in any one
of claims 1 to 6, comprising the reaction of an amine H-Am with a
compound represented by formula (II):

in which Y represents a halogen atom and the other substituents are
as defined in the preceding claims.
Method comprising a method for preparing a compound with formula
(II) according to claim 11 and comprising the reaction of a compound
represented by formula (III):


Indolizine derivatives with general formula (I) as defined in any one of
claims 1 to 10, for use as a drug.
Drugs comprising indolizine derivatives with general formula (I) as
defined in any one of claims 1 to 10.
Pharmaceutical or veterinary composition, characterized in that it
contains, as the active principle, at least one indolizine derivative with
formula (I) according to any one of claims 1 to 10, or a
pharmaceutically acceptable salt thereof, in association with a
pharmaceutical vehicle or an appropriate excipient.
Use of an indolizine derivative with general formula (I) as defined in
any one of claims 1 to 10, to prepare a drug intended for the treatment
of pathological syndromes of the cardiovascular system, in particular in
the treatment of angina pectoris, hypertension, ventricular or
supraventricular arrhythmia, the treatment of cardiac insufficiency,
myocardial infarction complicated or otherwise by cardiac insufficiency
or for the prevention of post-infarction mortality.
Use of an indolizine derivative according to claim 16 to prepare a drug
for the treatment of angina pectoris, hypertension, ventricular or
supraventricular arrhythmia, the treatment of cardiac insufficiency,
myocardial infarction complicated or otherwise by cardiac insufficiency
or for the prevention of post-infarction mortality.

(54) Title: NOVEL INDOLIZINE DERIVATIVES, METHOD FOR PREPARING SAME AND THERAPEUTIC COMPOSITIONS
COMPRISING SAME


(57) Abstract- The invention concerns indolizine derivatives of formula
(I) wherein: X represents -(CH2)n-with n being an integer from
1 to 6, or a group of formula CH2-Z-(CH2)2-, wherein Z represents a
O(CH2)m- wherein m is an integer from 0 to 3, Ri represents a linear,
branched or cyclic C1-C6, alkyl radical; Am represents a NR3R4 group
wherein R1 end R4 identical or different; represent independently of
each other a hydrogen atom, & linear, branched or cyclic C1-C6 alkyl
radical, or C1-C3 alkyl radical substituted by a C3-C6 cycloalkyl radical,
or a (CH2)I-O-B, wherein B represents a hydrogen atom or a (CH2)K alkyl radical with I and k being integers 1 ≥ 2 and 1+k ≤ 6
or R3 and R4 form together with the nitrogen atom whereto they are bound a 4- to 6-membered heterocycle capable of containing
one or more heteroatoms selected among N, O and optionally bearing one or more substituents selected among a linear, branched or
cyclic C1-C6 alkyl radical, R2 represents a hydrogen atom, a linear, branched or cyclic C1-C6 alkyl radical, and their pharmaceutically
acceptable salts.

The invention concerns indolizine derivatives of formula (I) wherein: X represents -(CH2)n- with n being an integer from 1 to 6, or a group of formula CH2-Z-(CH2)2-, wherein Z represents a
O(CH2)m- wherein m is an integer from 0 to 3, Ri represents a linear, branched or cyclic C1-C6, alkyl radical; Am represents a NR3R4 group
wherein R3 and R4 identical or different; represent independently of each other a hydrogen atom, a linear, branched or cyclic C1-C6 alkyl
radical, or C1-C3 alkyl radical substituted by a C3-C6 cycloalkyl radical, or a (CH2)I-O-B, wherein B represents a hydrogen atom or a (CH2)K alkyl radical with I and k being integers 1 ≥ 2 and 1+k ≤ 6 or R3 and R4 form together with the nitrogen atom whereto they are bound a 4- to 6-membered heterocycle capable of containing
one or more heteroatoms selected among N, O and optionally bearing one or more substituents selected among a linear, branched or cyclic C1-C6 alkyl radical, R2 represents a hydrogen atom, a linear, branched or cyclic C1-C6 alkyl radical, and their pharmaceutically
acceptable salts.

Documents:

01538-kolnp-2008-abstract.pdf

01538-kolnp-2008-claims.pdf

01538-kolnp-2008-correspondence others.pdf

01538-kolnp-2008-description complete.pdf

01538-kolnp-2008-form 1.pdf

01538-kolnp-2008-form 3.pdf

01538-kolnp-2008-form 5.pdf

01538-kolnp-2008-gpa.pdf

01538-kolnp-2008-international publication.pdf

01538-kolnp-2008-international search report.pdf

01538-kolnp-2008-others pct form.pdf

1538-KOLNP-2008-(18-06-2013)-ABSTRACT.pdf

1538-KOLNP-2008-(18-06-2013)-AMANDED CLAIMS.pdf

1538-KOLNP-2008-(18-06-2013)-ANNEXURE TO FORM 3.pdf

1538-KOLNP-2008-(18-06-2013)-CORRESPONDENCE.pdf

1538-KOLNP-2008-(18-06-2013)-FORM-2.pdf

1538-KOLNP-2008-(18-06-2013)-OTHERS.pdf

1538-KOLNP-2008-(18-06-2013)-PA.pdf

1538-KOLNP-2008-FORM 18.pdf

abstract-1538-kolnp-2008.jpg


Patent Number 257969
Indian Patent Application Number 1538/KOLNP/2008
PG Journal Number 48/2013
Publication Date 29-Nov-2013
Grant Date 25-Nov-2013
Date of Filing 16-Apr-2008
Name of Patentee SANOFI-AVENTIS
Applicant Address 174, AVENUE DE FRANCE F-75013, PARIS
Inventors:
# Inventor's Name Inventor's Address
1 GAUTIER PATRICK C/O SANOFI-AVENTIS DEPARTMENT BREVETS - TRI E2/300 20 RAYMOND ARON, F-92160 ANTONY
2 ROCCON ALAIN C/O SANOFI-AVENTIS DEPARTMENT BREVETS - TRI E2/300 20 RAYMOND ARON, F-92160 ANTONY
3 TONNERRE BERNARD C/O SANOFI-AVENTIS DEPARTMENT BREVETS - TRI E2/300 20 RAYMOND ARON, F-92160 ANTONY
4 WAGNON JEAN C/O SANOFI-AVENTIS DEPARTMENT BREVETS - TRI E2/300 20 RAYMOND ARON, F-92160 ANTONY
5 MARCHIONNI DAVID C/O SANOFI-AVENTIS DEPARTMENT BREVETS - TRI E2/300 20 RAYMOND ARON, F-92160 ANTONY
PCT International Classification Number C07D 471/04
PCT International Application Number PCT/FR2006/002551
PCT International Filing date 2006-11-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 05/11849 2005-11-23 France