U.S. patent application number 14/174272 was filed with the patent office on 2014-06-05 for synthesis process, and crystalline form of 4-{3[cis-hexahydrocyclopent a[cjpyrrol-2( 1 h)-yljpropoxyj benzami de hydrochlori de and pharmaceutical compositions containing it.
This patent application is currently assigned to LES LABORATOIRES SERVIER. The applicant listed for this patent is LES LABORATOIRES SERVIER. Invention is credited to Mathieu BOIRET, Marina GAILLARD, Jean-Pierre LECOUVE, Jean-Michel LERESTIF, Philippe LETELLIER, Loic MEUNIER, Nicolas ROBERT.
Application Number | 20140155453 14/174272 |
Document ID | / |
Family ID | 46172744 |
Filed Date | 2014-06-05 |
United States Patent
Application |
20140155453 |
Kind Code |
A1 |
ROBERT; Nicolas ; et
al. |
June 5, 2014 |
SYNTHESIS PROCESS, AND CRYSTALLINE FORM OF
4-{3[CIS-HEXAHYDROCYCLOPENT A[CjPYRROL-2( 1 H)-YLjPROPOXYj BENZAMI
DE HYDROCHLORI DE AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT
Abstract
Medicinal products containing the crystalline form I of the
compound of formula (I): ##STR00001## and/or crystalline form I of
the associated free base which are useful in the treatment of
disorders of the histaminergic system.
Inventors: |
ROBERT; Nicolas; (Le Havre,
FR) ; LERESTIF; Jean-Michel; (YVETOT, FR) ;
LECOUVE; Jean-Pierre; (LE HAVRE, FR) ; GAILLARD;
Marina; (Orleans, FR) ; MEUNIER; Loic;
(Vennecy, FR) ; LETELLIER; Philippe; (ORLEANS,
FR) ; BOIRET; Mathieu; (ORLEANS, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LES LABORATOIRES SERVIER |
SURESNES CEDEX |
|
FR |
|
|
Assignee: |
LES LABORATOIRES SERVIER
SURESNES CEDEX
FR
|
Family ID: |
46172744 |
Appl. No.: |
14/174272 |
Filed: |
February 6, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13489691 |
Jun 6, 2012 |
8664408 |
|
|
14174272 |
|
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Current U.S.
Class: |
514/412 |
Current CPC
Class: |
A61P 25/24 20180101;
A61P 25/18 20180101; A61P 25/28 20180101; A61P 43/00 20180101; A61P
3/04 20180101; C07C 309/63 20130101; A61P 25/22 20180101; A61P
29/00 20180101; C07D 209/52 20130101; A61P 9/04 20180101; C07D
319/06 20130101; C07D 317/22 20130101; C07B 2200/13 20130101; A61P
9/10 20180101; C07C 235/46 20130101; A61P 25/16 20180101; A61P
25/04 20180101; A61P 37/00 20180101; A61P 25/00 20180101 |
Class at
Publication: |
514/412 |
International
Class: |
C07D 209/52 20060101
C07D209/52 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 8, 2011 |
FR |
11/01746 |
Claims
1. A method of treating disorders of the histaminergic system, in a
subject in need thereof, comprising administration of an effective
amount of a compound selected from the group consisting of a
crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride of formula (I): ##STR00010## having an X-ray powder
diffraction diagram exhibiting the following diffraction lines
(Bragg's angle 2 theta, expressed in degrees .+-.0.2.degree.):
16.97.degree., 17.84.degree., 18.90.degree., 20.32.degree.,
23.87.degree., 27.10.degree., 27.86.degree. and 30.34.degree., and
a crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide:
##STR00011## having an X-ray powder diffraction diagram exhibiting
the following diffraction lines (Bragg's angle 2 theta, expressed
in degrees .+-.0.2.degree.): 6.25.degree., 12.55.degree.,
17.74.degree., 18.19.degree., 19.43.degree., 20.72.degree.,
21.00.degree., 23.50.degree. and 27.00.degree..
2. The method of claim 1, wherein the disorder of the histaminergic
system is selected from the group consisting of cognitive and
psycho-behavioural disorders associated with cerebral aging and
with neurodegenerative diseases, mood disorders, attention-deficit
hyperactivity syndrome, obesity and pain.
3. The method of claim 2, wherein the disorder of the histaminergic
system is selected from the group consisting of cognitive and
psycho-behavioural disorders associated with Alzheimer's disease,
Parkinson's disease, Pick's disease, Korsakoffs disease, Lewy body
dementias, frontal and subcortical dementias, frontotemporal
dementias and vascular dementias.
4. The method of claim 1, wherein the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride is administered.
5. The method of claim 4, wherein the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride has the following X-ray powder diffraction diagram,
measured using a PANalytical X'Pert Pro MPD diffractometer with an
X'Celerator detector, and expressed in terms of line position
(Bragg's angle 2 theta, expressed in degrees .+-.0.2.degree.) and
interplanar distance d (expressed in .ANG.): TABLE-US-00008 Angle
2-theta Interplanar Line no. (degrees) distance (.ANG.) 1 16.97
5.219 2 17.84 4.967 3 18.90 4.690 4 20.32 4.366 5 23.87 3.724 6
27.10 3.288 7 27.86 3.200 8 30.34 2.943
6. The method of claim 4, wherein the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride has a Raman spectrum exhibiting a significant peak at
the location 1606 cm.sup.-1 or 1676 cm.sup.-1.
7. The method of claim 4, wherein the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride has a Raman spectrum exhibiting significant peaks at
the locations 1676 cm.sup.-1, 1606 cm.sup.-1, 1564 cm.sup.-1, 1152
cm.sup.-1, 830 cm.sup.-1 and 296 cm.sup.-1.
8. The method of claim 1, wherein the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
is administered.
9. The method of claim 8, wherein the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
has the following X-ray powder diffraction diagram, measured using
a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator
detector, and expressed in terms of line position (Bragg's angle 2
theta, expressed in degrees .+-.0.2.degree.) and interplanar
distance d (expressed in .ANG.): TABLE-US-00009 Angle 2-theta
Interplanar Line no. (degrees) distance (.ANG.) 1 6.25 14.131 2
12.55 7.049 3 17.74 4.997 4 18.19 4.873 5 19.43 4.565 6 20.72 4.284
7 21.00 4.226 8 23.50 3.782 9 27.00 3.297
10. The method of claim 8, wherein the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
has a Raman spectrum exhibiting a significant peak at the location
1683 cm.sup.-1.
11. The method of claim 8, wherein the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
has a Raman spectrum exhibiting significant peaks at the locations
292 cm.sup.-1, 618 cm.sup.-1, 1045 cm.sup.-1, 1483 cm.sup.-1, 1568
cm.sup.-1, 1683 cm.sup.-1.
Description
[0001] The present invention relates to a process for the
industrial synthesis of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride of formula (I):
##STR00002##
[0002] The present invention relates also to crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride, to a process for its preparation and also to
pharmaceutical compositions containing it.
[0003] Crystalline form I of the free base of the compound of
formula (I) is, moreover, also obtained by the process of the
invention and forms an integral part of the invention, as do
pharmaceutical compositions containing it.
[0004]
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
has the characteristic of interacting with central histaminergic
systems in vivo. These properties provide it with activity in the
central nervous system and, more especially, in the treatment of
cognitive deficiencies associated with cerebral aging and with
neurodegenerative diseases.
[0005]
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide,
its preparation in the form of an oxalate and its therapeutic use
have been described in Patent Application WO2005/089747.
[0006] In view of the pharmaceutical value of this compound it was
important to be able to obtain it by an effective synthesis process
that is readily transferable to the industrial scale, yielding
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride in a good yield and with excellent purity.
[0007] It was also important to be able to obtain
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride in a well-defined, perfectly reproducible crystalline
form having valuable filtration characteristics and ease of
formulation.
[0008] The Patent Application WO2005/089747 describes obtaining
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
oxalate in three steps starting from 4-hydroxybenzonitrile, which
undergoes an O-alkylation reaction before being coupled to an
octahydrocyclopenta[c]pyrrole-type ring system to form
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzonitrile.
The latter compound is finally subjected to basic hydrolysis in
order to yield
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide,
which is crystallised in the form of an oxalate. The yield for
these three steps is 46.6%.
[0009] The present invention relates to a new industrial synthesis
process which yields
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride with satisfactory purity from the pharmaceutical
point of view and in an effective yield from the industrial point
of view. By virtue of this process it is possible to ensure a very
low level of genotoxic impurities, which is compatible with
regulatory requirements.
[0010] The present invention relates, more specifically, to a
process for the industrial synthesis of the compound of formula
(I):
##STR00003##
which process is characterised in that the compound of formula
(II):
##STR00004##
is reacted with ammonia at a temperature greater than 100.degree.
C. to form the compound of formula (III):
##STR00005##
which is reduced to yield the bicyclic amine of formula (IV):
##STR00006##
which latter compound is subsequently subjected:
[0011] either to a coupling reaction, under basic conditions in a
polar medium, with a compound of formula (V):
##STR00007##
wherein Y represents --CH.sub.2-Hal wherein Hal is a halogen, or a
group --CH.sub.2--OSO.sub.2--R wherein R is a
(C.sub.1-C.sub.6)alkyl group or a --C.sub.6H.sub.4--CH.sub.3
group,
[0012] or to reductive amination, in an acid medium, with a
compound of formula (V'):
##STR00008##
wherein R' and R'' represent, each independently of the other, a
(C.sub.1-C.sub.6)alkyl group, or R' and R'' together form a group
--(CH.sub.2)-- wherein n=2-3, or one of the groups R' and R''
represents a hydrogen atom and the other represents a
(C.sub.1-C.sub.6)alkyl group,
[0013] or to reductive amination with the compound of formula
(V''):
##STR00009##
to yield the free base of the compound of formula (I), which is
placed in the presence of HCl to form the compound of formula (I),
which is isolated in the form of a solid.
[0014] In a preferred embodiment of the invention, the reaction
mixture obtained at the end of the reaction of the compound of
formula (II) with ammonia is subjected to pyrolysis. The pyrolysis
in question is carried out preferably at a temperature greater than
or equal to 200.degree. C., and even more preferably at a
temperature greater than or equal to 280.degree. C.
[0015] Conversion of the compound of formula (III) into the
compound of formula (IV) is advantageously carried out in the
presence of hydrogen and a metal or metal-containing catalyst.
[0016] Preference is given to the compound of formula (V) being
4-(3-chloropropoxy)benzamide.
[0017] The coupling reaction of the compound of formula (IV) with
the compound of formula (V) is preferably carried out in the
presence of a carbonate, an amine or a hydroxide. Among the
preferred carbonates, amines and hydroxides there may be mentioned
potassium carbonate, caesium carbonate, triethylamine, pyridine,
potassium hydroxide, sodium hydroxide and lithium hydroxide. Even
more preferably, the coupling reaction of the compound of formula
(IV) with the compound of formula (V) is carried out in the
presence of potassium carbonate or triethylamine. This reaction is
moreover advantageously performed in a polar medium composed of one
or more polar solvents selected from water, alcohols, ketones,
ethers, amides, DMSO and acetonitrile. Preferred alcohols are
methanol, ethanol, isopropanol and butanol. The preferred solvents
also include acetone and methyl ethyl ketone among the ketones,
tetrahydrofuran, methyltetrahydrofuran and cyclopentyl methyl ether
among the ethers, and also N-methyl-2-pyrrolidone among the amides.
Even more preferably, the coupling reaction of the compound of
formula (IV) with the compound of formula (V) is performed in a
water/acetonitrile mixture or a water/isopropanol mixture.
[0018] In the case of reductive amination, in an acid medium, of
the compound of formula (IV) with a compound of formula (V'), the
latter is preferably 4-(3,3-diethoxypropoxy)benzamide.
[0019] Furthermore, the step of forming a salt from the free base
of the compound of formula (I) in the presence of HCl preferably
takes place in a solvent selected from water, acetone and an
alcohol. Preferred alcohols are methanol, ethanol and isopropanol.
Acetone and isopropanol are more especially preferred for this salt
formation step.
[0020] Optionally, the compound of formula (I) isolated at the end
of the salt formation step is subjected to recrystallisation.
[0021] It is important to emphasise that this synthesis process
makes it possible to obtain the compound
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide,
exclusively, in a satisfactory yield on the industrial scale, and
not its trans homologue. Besides this advantage, it makes it
possible to keep the levels of genotoxic impurities (especially
4-(3-chloropropoxy)benzamide) present in the batches well below the
regulatory threshold.
[0022] The compounds of formula (V) wherein Y represents a group
--CH.sub.2--OSO.sub.2--R wherein R is a (C.sub.1-C.sub.6)alkyl
group or a --C.sub.6H.sub.4--CH.sub.3 group and the compounds of
formula (V') are new and useful as intermediates in the synthesis
of compound of formula (I). The compound of formula (V'') is also
useful as intermediate in the synthesis of compound of formula
(I).
[0023] The invention relates also to crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride obtained according to the process described above.
This crystalline form is well-defined, perfectly reproducible and
consequently has valuable characteristics of filtration, drying,
stability and ease of formulation.
[0024] Crystalline form I of the compound of formula (I) is
characterised by an X-ray powder diffraction diagram having the
following diffraction lines (Bragg's angle 2 theta, expressed in
degrees .+-.0.2.degree.): 16.97.degree., 17.84.degree.,
18.90.degree., 20.32.degree., 23.87.degree., 27.10.degree.,
27.86.degree. and 30.34.degree..
[0025] More specifically, crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride is characterised further by the X-ray powder
diffraction diagram below, measured using a PANalytical X'Pert Pro
MPD diffractometer with an X'Celerator detector, and expressed in
terms of line position (Bragg's angle 2 theta, expressed in degrees
.+-.0.2.degree.) and interplanar distance d (expressed in
.ANG.):
TABLE-US-00001 Angle 2-theta Interplanar Line no. (degrees)
distance (.ANG.) 1 16.97 5.219 2 17.84 4.967 3 18.90 4.690 4 20.32
4.366 5 23.87 3.724 6 27.10 3.288 7 27.86 3.200 8 30.34 2.943
[0026] Besides that, form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide
hydrochloride has been characterised by Raman spectroscopy.
Significant peaks were observed in the following locations: 1676
cm.sup.-1, 1606 cm.sup.-1, 1564 cm.sup.-1, 1152 cm.sup.-1, 830
cm.sup.-1 and 296 cm.sup.-1.
[0027] Alternatively, form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide
hydrochloride may be characterised by the X-ray powder diffraction
diagram having the 8 significant lines given above and also by a
Raman spectrum having a significant peak at the location 1606
cm.sup.-1 or 1676 cm.sup.-1.
[0028] Obtaining this crystalline form has the advantage of
allowing especially rapid and efficient filtration and also the
preparation of pharmaceutical formulations having a consistent and
reproducible composition, which is especially advantageous when
those formulations are intended for oral administration.
Furthermore, form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride has noteworthy properties of immediate
dissolution.
[0029] The form thereby obtained is sufficiently stable to allow
its storage for an extended period without particular conditions
for temperature, light, humidity or oxygen levels. More
specifically, form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide
hydrochloride has been found to be very stable over periods of up
to 18 months under the following conditions: [0030] at 25.degree.
C. with a humidity level of 60% in a double bag of polyethylene,
[0031] at 30.degree. C. with a humidity level of 65% in a double
bag of polyethylene, [0032] at 30.degree. C. with a humidity level
of 85% in a double bag of polyethylene.
[0033] Another aspect of the invention relates to crystalline form
I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
obtained according to the process described above. This crystalline
form is well-defined and perfectly reproducible. Obtaining this
form and isolating it in the course of the synthesis process for
the hydrochloride of formula (I) described above make it possible
to eliminate a large proportion of the genotoxic impurities present
in the batches.
[0034] Crystalline form I of the free base of the compound of
formula (I) is characterised by its X-ray powder diffraction
diagram having the following diffraction lines (Bragg's angle 2
theta, expressed in degrees .+-.0.2.degree.): 6.25.degree.,
12.55.degree., 17.74.degree., 18.19.degree., 19.43.degree.,
20.72.degree., 21.00.degree., 23.50.degree. and 27.00.degree..
[0035] More specifically, crystalline form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
is characterised further by the X-ray powder diffraction diagram
below, measured using a PANalytical X'Pert Pro MPD diffractometer
with an X'Celerator detector, and expressed in terms of line
position (Bragg's angle 2 theta, expressed in degrees
.+-.0.2.degree.) and interplanar distance d (expressed in
.ANG.):
TABLE-US-00002 Angle 2-theta Interplanar Line no. (degrees)
distance (.ANG.) 1 6.25 14.131 2 12.55 7.049 3 17.74 4.997 4 18.19
4.873 5 19.43 4.565 6 20.72 4.284 7 21.00 4.226 8 23.50 3.782 9
27.00 3.297
[0036] In addition, form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
has been characterised by Raman spectroscopy. Significant peaks
were observed in the following locations: 292 cm.sup.-1, 618
cm.sup.-1, 1045 cm.sup.-1, 1483 cm.sup.-1, 1568 cm.sup.-1, 1683
cm.sup.-1.
[0037] Alternatively, form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
may be characterised by the X-ray powder diffraction diagram having
the 9 significant lines given above and also by a Raman spectrum
having a significant peak at the location 1683 cm.sup.-1.
[0038] Finally, form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
has also been characterised by solid-state NMR spectroscopy.
Significant peaks were observed at 112.2 ppm, 119.2 ppm, 127.2 ppm,
128.6 ppm, 132.4 ppm, 162.2 ppm and 173.2 ppm. More precisely, the
.sup.13C CP/MAS (Cross Polarization Magic Angle Spinning) spectra
have the following peaks (expressed in ppm.+-.0.2 ppm):
TABLE-US-00003 Peak no. Chemical shift (ppm) 1 173.2 2 162.2 3
132.4 4 128.6 5 127.2 6 119.2 7 112.2 8 67.1 9 64.0 10 59.7 11 52.1
12 44.5 13 42.8 14 31.5 15 30.8 16 30.2 17 26.2
[0039] Pharmacological study of form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride and also that of form I of its free base have shown
substantial activity on the central nervous system which makes it
possible to establish its usefulness in the treatment of cognitive
and psycho-behavioural disorders associated with cerebral aging and
with neurodegenerative diseases, and also in the treatment of mood
disorders, attention-deficit hyperactivity syndrome, obesity and
pain. Neurodegenerative diseases more especially targeted are
Alzheimer's disease, Parkinson's disease, Pick's disease,
Korsakoffs disease, Lewy body dementias, frontal and subcortical
dementias, frontotemporal dementias and vascular dementias.
[0040] The invention relates also to pharmaceutical compositions
comprising as active ingredient crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide
hydrochloride, or crystalline form I of its free base, together
with one or more appropriate, non-toxic, inert excipients. Among
the pharmaceutical compositions according to the invention there
may be more especially mentioned those that are suitable for oral,
parenteral (intravenous or subcutaneous) or nasal administration,
tablets or dragees, granules, sublingual tablets, capsules,
lozenges, suppositories, creams, ointments, dermal gels, injectable
preparations, drinkable suspensions and chewing gums.
[0041] The useful dosage can be varied according to the nature and
severity of the disorder, the administration route and also the age
and weight of the patient. The useful dosage varies from 1 mg to
100 mg per day, in one or more administrations. Preferably,
crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride is administered at daily doses (expressed as free
base equivalent) of 2 mg, 5 mg and 20 mg (or, that is to say, 2.25
mg, 5.63 mg and 22.52 mg of the hydrochloride).
[0042] The Examples hereinbelow illustrate the invention.
Preparation 1: 4-(3-Chloropropoxy)benzamide
[0043] 10.5 kg of 4-hydroxybenzamide, 10.58 kg of potassium
carbonate and 83 kg of acetonitrile are introduced into a reactor.
The mixture is stirred and then there are added 24.14 kg of a
solution of 1-bromo-3-chloropropane. The reaction mixture is heated
at reflux for 4 hours. Water (105 L) is added in the hot state, the
mixture is then cooled to 5.degree. C. and filtered. The filter
cake is washed with water and then with acetonitrile. The title
product is obtained in the form of a powder in a yield of 82%.
[0044] Melting point: 144.degree. C.
Preparation 2: 4-(3-Oxopropoxy)benzamide
Step A: 4-(3,3-Diethoxypropoxy)benzamide
[0045] 500 mg of 4-hydroxybenzamide, 1.51 g of potassium carbonate,
10 mL of DMF and 730 mg of 3-chloro-1,1-diethoxypropane are added
to a flask. The reaction mixture is stirred at 100.degree. C. for
18 hours and then 5 mL of water are added. The aqueous phase is
extracted with ethyl acetate, and then the organic phases are
collected, washed with water and concentrated under reduced
pressure. The product is obtained in the form of a powder in a
yield of 89% and with a chemical purity of 95%.
[0046] Melting point: 108.degree. C.
Step B: 4-(3-Oxopropoxy)benzamide
[0047] 5 g of the product obtained in Step A, 100 ml of THF and 94
mL of 1N hydrochloric acid solution are added to a flask. The
mixture is stirred at ambient temperature for 1 hour. The aqueous
phase is extracted with dichloromethane, and then the organic
phases are concentrated under reduced pressure. The product is
obtained in the form of a solid in a yield of 96% and with a
chemical purity of 93%.
EXAMPLE 1
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride
Step A: Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione
[0048] Load 1 kg of diethyl 1,2-cyclopentanedicarboxylate and 1.02
kg of 27% ammonia into an autoclave. The reaction mixture is heated
in the autoclave at a temperature of 130.degree. C. for a minimum
of 4 hours. After cooling to 60.degree. C. and depressurisation,
evaporation of the solvent is carried out. The residue is then
subjected to pyrolysis at 280.degree. C. for 1 hour. The imide is
purified by distillation in vacuo (4-12 mbars) at a temperature of
200.degree. C. After isolation, the title product is obtained in a
yield of 96%.
[0049] Melting point: 89.degree. C.
Step B: cis-Octahydrocyclopenta[c]pyrrole
[0050] 1 kg of the imide of Step A, 250 g of copper chromite and 2
L of dioxane are loaded into a reactor. The reaction mixture is
stirred at a temperature of 265.degree. C. and under a hydrogen
pressure of 205 bars until the absorption of hydrogen is complete.
After cooling of the reactor, the catalyst is filtered off.
[0051] The hydrogenation liquors are loaded into a separator and
then 0.37 L of water is added. The pH is adjusted to a pH of less
than 3 by adding sulphuric acid 96%. The lower, aqueous phase is
drawn off. After adding 2.5 L of water, the residual dioxane is
removed by azeotropic distillation with monitoring of the
refractive index. The pH is then brought to 13 by adding 30% sodium
hydroxide solution. The title product is purified by azeotropic
distillation with water to obtain a 30% solution by weight in a
yield of 83%.
Step C:
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
[0052] 13.35 kg of 4-(3-chloropropoxy)benzamide obtained according
to Preparation 1, 10.33 kg of potassium carbonate and 168 kg of
acetonitrile are introduced into a reactor. The mixture is stirred.
There are then loaded 34.74 kg of cis-octahydrocyclopenta[c]pyrrole
in a 30% aqueous solution, 26.7 L of water. The reaction mixture is
heated at reflux until all the starting material has been consumed.
Then water (13.3 L) is added. The mixture is cooled to 5.degree.
C., before being filtered and washed with water. The title product
is obtained in the form of a solid in a yield of 81% and with a
chemical purity of 96%.
[0053] .sup.1H NMR: 8 (600.13 MHz; DMSO-d6; 300K): 7.82 (d, 2H,
J=9.0 Hz); 7.79 (bs, 1H); 7.14 (bs, 1H); 6.95 (d, 2H, J=9.0 Hz);
4.06 (t, 2H, J=6.5 Hz); 2.57 (m, 2H); 2.48 (m, 2H); 2.44 (bt, 2H,
J=6.5 Hz); 2.14 (bd, 2H, J=7.5 Hz); 1.86 (qt, 2H, J=6.5 Hz);
1.65-1.55 (m, 3H); 1.45-1.38 (m, 1H); 1.37-1.30 (m, 2H)
[0054] where bs: broad singlet; bd: broad doublet; bt: broad
triplet
[0055] Characterisation of the product thereby formed, using the
techniques given in Examples 6 to 8, demonstrated that the
crystalline form I of the free base was obtained.
Step D:
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride
[0056] 14.69 kg of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
and 122 L of water are introduced into a reactor. A solution of
6.81 kg of 37% hydrochloric acid in 11.54 L of water is also
prepared. 13.75 kg of this acid solution are added to the reactor.
The mixture is stirred for 1 hour at ambient temperature, and then
for 1 hour 30 minutes at 60.degree. C. The suspension is filtered
in the hot state and the filter is then rinsed with water. A
solvent change is then carried out on the filtrate, keeping the
volume constant, in order to obtain an isopropanol/water ratio of
9/1. The product is isolated at 0.degree. C. and the precipitate
obtained is washed with isopropanol. The title product is finally
obtained in a yield of 89% and with a chemical purity greater than
99%.
[0057] Characterisation of the product thereby formed, using the
techniques given in Examples 4 to 5, demonstrated that the
crystalline form I of the hydrochloride was obtained.
Step E:
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride
[0058] The hydrochloride salt obtained in Step D is recrystallised
from a mixture of isopropanol (264 kg) and water (37.4 L). The
mixture is heated at reflux for 45 minutes. The solution is
filtered in the hot state and then rinsed with isopropanol.
Crystallisation is then initiated at 55.degree. C. The mixture is
maintained at that temperature for 40 minutes before being cooled
to 0.degree. C. After several hours, the product is isolated by
filtration. After washing with isopropanol, the title product is
obtained in the form of a powder in a yield of 93% and with a
chemical purity greater than 99%.
[0059] Melting point: 213-215.degree. C.
[0060] Characterisation of the product thereby formed, using the
techniques given in Examples 4 to 5, demonstrated that the
crystalline form I of the hydrochloride was obtained.
EXAMPLE 2
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride
Step A: Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione
[0061] The procedure is the same as that described in Step A of
Example 1.
Step B: cis-Octahydrocyclopenta[c]pyrrole
[0062] The procedure is the same as that described in Step B of
Example 1.
Step C:
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
[0063] 15.2 kg of 4-(3-chloropropoxy)benzamide, 40.28 kg of
cis-octahydrocyclopenta[c]pyrrole in 30% aqueous solution, 63.84 kg
of water, 21.48 kg of isopropanol and 14.39 kg of triethylamine are
introduced into a reactor. The reaction mixture is stirred and
heated at reflux until all the starting material has been consumed.
The reaction mixture is then cooled to 20.degree. C., before being
filtered and washed with a mixture of isopropanol and water. The
product is obtained in the form of a powder in a yield of 83% and
with a chemical purity of 97%.
[0064] .sup.1H NMR: 8 (600.13 MHz; DMSO-d6; 300K): 7.82 (d, 2H,
J=9.0 Hz); 7.79 (bs, 1H); 7.14 (bs, 1H); 6.95 (d, 2H, J=9.0 Hz);
4.06 (t, 2H, J=6.5 Hz); 2.57 (m, 2H); 2.48 (m, 2H); 2.44 (bt, 2H,
J=6.5 Hz); 2.14 (bd, 2H, J=7.5 Hz); 1.86 (qt, 2H, J=6.5 Hz);
1.65-1.55 (m, 3H); 1.45-1.38 (m, 1H); 1.37-1.30 (m, 2H)
[0065] where bs: broad singlet; bd: broad doublet; bt: broad
triplet
[0066] Characterisation of the product thereby formed, using the
techniques given in Examples 6 to 8, demonstrated that the
crystalline form I of the free base was obtained.
Step D:
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride
[0067] 16.49 kg of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide,
16.36 kg of acetone, 6.76 kg of concentrated aqueous hydrochloric
acid and 18.96 kg of water are introduced into a reactor. The
mixture is stirred and heated at 50.degree. C. for 1 hour. The
mixture is then filtered in the hot state into a second reactor
containing 57.67 kg of acetone and 1.65 kg of water. The mixture is
then brought to reflux and 73.32 kg of acetone are added. Reflux is
maintained for 10 minutes and then cooling to 0.degree. C. is
carried out. The product is filtered off and the solid obtained is
washed with acetone. The product is obtained in the form of a
powder in a yield of 85% and with a chemical purity greater than
99%.
[0068] Characterisation of the product thereby formed, using the
techniques given in Examples 4 to 5, demonstrated that the
crystalline form I of the hydrochloride was obtained.
EXAMPLE 3
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride
Step A: Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione
[0069] The procedure is the same as that described in Step A of
Example 1.
Step B: cis-Octahydrocyclopenta[c]pyrrole
[0070] The procedure is the same as that described in Step B of
Example 1.
Step C: cis-Octahydrocyclopenta[c]pyrrole hydrochloride
[0071] 2 g of cis-octahydrocyclopenta[c]pyrrole are dissolved in 10
mL of ethanol in a flask. The solution is cooled to 0.degree. C.,
and there are then added 1.64 mL of concentrated hydrochloric acid
solution (11M). The reaction mixture is stirred at 20.degree. C.
for 30 minutes before being concentrated under reduced pressure.
The reaction mixture is stirred in methyl tert-butyl ether at
0.degree. C. The product is isolated by filtration in the form of a
solid in a yield of 83% and with a chemical purity of 99%.
[0072] Melting point: 126.degree. C.
Step D: 4-{3-[cis
-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride
[0073] 915 mg of the product obtained in Step C, 1.65 g of sodium
triacetoxyborohydride, 45 mL of THF and 7.5 mL of trimethyl
orthoformate are added into a reactor. There are then added 1 g of
the compound obtained in Preparation 2. The reaction mixture is
heated at 40.degree. C. for 50 minutes and then cooled to ambient
temperature. There are then added a saturated NaHCO.sub.3 solution.
The aqueous phase is extracted with ethyl acetate, and then the
organic phases are combined and washed with water. The organic
phase is dried over MgSO.sub.4, filtered and concentrated under
reduced pressure. The residue is suspended in an isopropanol/water
mixture in the presence of hydrochloric acid. The reaction mixture
is heated at 40.degree. C. then cooled to 5.degree. C. The product
is isolated by filtration in the form of a solid in a yield of 33%
and with a chemical purity of 98%.
[0074] Characterisation of the product thereby formed, using the
techniques given in Examples 4 to 5, demonstrated that the
crystalline form I of the hydrochloride was obtained.
EXAMPLE 4
Crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride
[0075] Prior to recording the X-ray diffraction diagram, the
samples obtained according to the procedure described in one of
Examples 1 to 3 were milled for 30 seconds at 30 Hz in the presence
of 100 .mu.L of anhydrous ethanol per 200 mg of active ingredient
in a 25-ml stainless-steel jar containing 2 stainless-steel
balls.
[0076] Recording of the data was carried out using a PANalytical
X'Pert Pro MPD diffractometer with an X'Celerator detector under
the following conditions: [0077] Voltage 45 kV, current 40 mA,
[0078] Mounting: theta/theta, [0079] Anode: copper, [0080] K
alpha-1 wavelength: 1.54060 .ANG., [0081] K alpha-2 wavelength:
1.54443 .ANG., [0082] K alpha-2/K alpha-1 ratio: 0.5 [0083]
Measurement mode: continuous from 3.degree. to 55.degree. (Bragg's
angle 2 theta) in increments of 0.017.degree., [0084] Measurement
time per step: 35.53 s.
[0085] The X-ray powder diffraction diagram of form I of the
4-{3-[cis-hexahydrocyclopenta-[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride thereby obtained is expressed in terms of line
position (Bragg's angle 2 theta, expressed in degrees
.+-.0.2.degree.), interplanar distance (expressed in .ANG.) and
relative intensity (expressed as a percentage relative to the most
intense line). The significant lines are collated in the following
table:
TABLE-US-00004 Angle 2-theta Interplanar Relative Line no.
(degrees) distance (.ANG.) intensity (%) 1 16.97 5.219 9.7 2 17.84
4.967 21.6 3 18.90 4.690 100 4 20.32 4.366 41.8 5 23.87 3.724 15.4
6 27.10 3.288 44.7 7 27.86 3.200 6.6 8 30.34 2.943 21.7
[0086] The following parameters were thereby determined: [0087]
monoclinic crystalline unit cell, [0088] unit cell parameters:
a=10.6621 .ANG., b=10.4945 .ANG., c=15.6542 .ANG.,
.beta.=101.949.degree. [0089] space group: P 1 2.sub.1/c 1 (14)
[0090] number of molecules in the unit cell: 4 [0091] volume of the
unit cell: V.sub.unit cell=1713.637 .ANG..sup.3 [0092] density:
d=1.2590 g/cm.sup.3.
EXAMPLE 5
Crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride
[0093] Form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride was characterised by Raman spectroscopy. The spectra
were recorded in reflection mode (PerkinElmer) and transmission
mode (Cobalt) with laser focalisation of 785 nm and 830 nm
respectively, using a CCD detector. The wavelength shift depends on
the material and is characteristic of that material, which allows
analysis of the chemical composition and of the molecular
arrangement of the sample studied. The spectra are acquired:
[0094] in reflection mode with a laser power of 400 mW, a spot size
of 100 five exposures of five seconds and a spectral resolution of
2 cm.sup.-1,
[0095] in transmission mode with a laser power of 650 mW, a spot
size of 4 mm, twenty exposures of 3 seconds and a spectral
resolution of 2 cm.sup.-1.
[0096] The spectral range explored ranges from 0 to 3278 cm.sup.-1
in reflection mode and from 37 to 2400 cm.sup.-1 in transmission
mode.
[0097] Significant peaks were observed at the following locations:
1676 cm.sup.-1, 1606 cm.sup.-1, 1564 cm.sup.-1, 1152 cm.sup.-1, 830
cm.sup.-1 and 296 cm.sup.-1.
EXAMPLE 6
Crystalline form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]-pyrrol-2(1H)-yl]propoxy}benzamide
[0098] Recording of the data was carried out using a PANalytical
X'Pert Pro MPD diffractometer with an X'Celerator detector under
the following conditions: [0099] Voltage 45 kV, current 40 mA,
[0100] Mounting: theta/theta, [0101] Anode: copper, [0102] K
alpha-1 wavelength: 1.54060 .ANG., [0103] K alpha-2 wavelength:
1.54443 .ANG., [0104] K alpha-2/K alpha-1 ratio: 0.5 [0105]
Measurement mode: continuous from 3.degree. to 55.degree. (Bragg's
angle 2 theta) in increments of 0.017.degree., [0106] Measurement
time per step: 35.53 s.
[0107] The X-ray powder diffraction diagram of form I of the free
base of
4-{3-[cis-hexahydro-cyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
obtained according to the process of one of Examples 1 to 3 is
expressed in terms of line position (Bragg's angle 2 theta,
expressed in degrees .+-.0.2.degree.), interplanar distance
(expressed in .ANG.) and relative intensity (expressed as a
percentage relative to the most intense line). The significant
lines are collated in the following table:
TABLE-US-00005 Angle 2-theta Interplanar Relative Line no.
(degrees) distance (.ANG.) intensity (%) 1 6.25 14.131 6.6 2 12.55
7.049 16.3 3 17.74 4.997 100 4 18.19 4.873 7.3 5 19.43 4.565 13.3 6
20.72 4.284 32.2 7 21.00 4.226 7.7 8 23.50 3.782 51.4 9 27.00 3.297
5.9
EXAMPLE 7
Crystalline form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]-pyrrol-2(1H)-yl]propoxy}benzamide
[0108] Form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide
was characterised by Raman spectroscopy. The spectra were recorded
in transmission mode (Cobalt) with laser focalisation of 830 nm
using a CCD detector. The wavelength shift depends on the material
and is characteristic of that material, which allows analysis of
the chemical composition and of the molecular arrangement of the
sample studied. The spectra are acquired with a laser power of 650
mW, a spot size of 4 mm, twenty exposures of 0.9 second and a
spectral resolution of 2 cm.sup.-1. The spectral range explored
ranges from 37 to 2400 cm.sup.-1.
[0109] Significant peaks were observed at the following locations:
292 cm.sup.-1, 618 cm.sup.-1, 1045 cm.sup.-1, 1483 cm.sup.-1, 1568
cm.sup.-1, 1683 cm.sup.-1.
EXAMPLE 8
Crystalline form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]-pyrrol-2(1H)-yl]propoxy}benzamide
[0110] Form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide
was also characterised by solid-state NMR spectroscopy. The
solid-state .sup.13C NMR spectra were recorded at ambient
temperature using a Bruker SB Avance spectrometer with a 4-mm
CP/MAS SB VTN type probe under the following conditions: [0111]
Frequency: 125.76 MHz, [0112] Spectral width: 40 kHz, [0113] Magic
angle spinning rate: 13 kHz, [0114] Pulse program: Cross
Polarization with SPINAL64 decoupling (decoupling power of 80 kHz),
[0115] Recycle delay: 10 s, [0116] Acquisition time: 47 ms, [0117]
Contact time: 4 ms, [0118] Number of scans: 4096.
[0119] The spectra thereby obtained were referenced relative to a
sample of adamantane.
[0120] The peaks observed are collated in the following table
(expressed in ppm.+-.0.2 ppm):
TABLE-US-00006 Peak no. Chemical shift (ppm) 1 173.2 2 162.2 3
132.4 4 128.6 5 127.2 6 119.2 7 112.2 8 67.1 9 64.0 10 59.7 11 52.1
12 44.5 13 42.8 14 31.5 15 30.8 16 30.2 17 26.2
EXAMPLE 9
Pharmaceutical Composition
[0121] Formula for the Preparation of 1000 Tablets Each Containing
5 mg of Active Ingredient (Expressed as Equivalent to the
Base):
TABLE-US-00007 Compound of Example 1 (expressed as equivalent to
the base) 5 g Maize starch 20 g Maltodextrin 7.5 g Colloidal silica
0.2 g Sodium starch glycolate 3 g Magnesium stearate 1 g Lactose 65
g
* * * * *