NZ599633B - New association between 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide and an acetylcholinesterase inhibitor, and pharmaceutical compositions containing it - Google Patents
New association between 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide and an acetylcholinesterase inhibitor, and pharmaceutical compositions containing it Download PDFInfo
- Publication number
- NZ599633B NZ599633B NZ599633A NZ59963312A NZ599633B NZ 599633 B NZ599633 B NZ 599633B NZ 599633 A NZ599633 A NZ 599633A NZ 59963312 A NZ59963312 A NZ 59963312A NZ 599633 B NZ599633 B NZ 599633B
- Authority
- NZ
- New Zealand
- Prior art keywords
- pyrrol
- propoxy
- cis
- benzamide
- hexahydrocyclopenta
- Prior art date
Links
- MRNMYWNBLVJWKG-GASCZTMLSA-N 4-[3-[(3aR,6aS)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]propoxy]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1OCCCN1C[C@H]2CCC[C@H]2C1 MRNMYWNBLVJWKG-GASCZTMLSA-N 0.000 title claims abstract description 49
- 239000000544 cholinesterase inhibitor Substances 0.000 title claims description 32
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- 239000011780 sodium chloride Substances 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 22
- ADEBPBSSDYVVLD-UHFFFAOYSA-N Donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960003530 donepezil Drugs 0.000 claims abstract description 21
- ASUTZQLVASHGKV-JDFRZJQESA-N Galantamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims abstract description 20
- XSVMFMHYUFZWBK-NSHDSACASA-N EXELON Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims abstract description 19
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- 150000003840 hydrochlorides Chemical class 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical class OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 claims description 3
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
599633 Disclosed is a combination therapy of neurodegenerative diseases such as Parkinson’s and Alzheimer’s with 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide or a pharmaceutically acceptable addition salt with an acid or base and an acetylcholine inhibitor preferably donepezil, rivastigmine or galantamine rivastigmine or galantamine
Description
NEW ZEALAND
PATENTS ACT, 1953
COMPLETE SPECIFICATION
NEW ASSOCIATION BETWEEN 4-{3-[CIS-HEXAHYDROCYCLOPENTA[C]PYRROL-
2(1H)-YL]PROPOXY}BENZAMIDE AND AN ACETYLCHOLINESTERASE INHIBITOR,
AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT
We, LES LABORATOIRES SERVIER, a French company of 35, rue de Verdun, 92284 Suresnes
Cedex, France, do hereby declare the invention for which we pray that a patent may be granted to
us, and the method by which it is to be performed, to be particularly described in and by the
following statement:
The present invention relates to a new association between 4-{3-[cis-hexahydro-
cyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide of formula (I):
(I),
or an addition salt thereof with a pharmaceutically acceptable acid or base, and an
acetylcholinesterase inhibitor, for obtaining pharmaceutical compositions for use in the treatment
of cognitive disturbances associated with cerebral ageing and with neurodegenerative diseases.
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 ageing and with neurodegenerative diseases.
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, its preparation and its
therapeutic use have been described in Patent Application WO2005/089747.
The Applicant has now found that 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-
benzamide of formula (I), or an addition salt thereof with a pharmaceutically acceptable acid or
base, used in association with an acetylcholinesterase inhibitor has valuable properties for the
treatment of cognitive disturbances associated with cerebral ageing and with neurodegenerative
diseases.
Neurodegenerative diseases related to cerebral ageing such as Alzheimer's disease are
characterised by disturbances of memory and cognitive dysfunction. The cognitive disturbances
are usually associated with a reduction in the ability of neurons to synthesise and release certain
neurotransmitters. There is moreover observed a progressive loss of synaptic plasticity and of
neuronal processes, this neuronal loss being accelerated in certain specific regions of the brain.
Among the various neurotransmitters, central histamine and acetylcholine play a crucial part in
the control of cognitive functions (Witkin and Nelson, Pharmacol.& Therap., 2004, 103, 1-20)
and their levels have been shown to greatly diminish in patients suffering from Alzheimer's
disease compared to those observed in healthy elderly people (Panula et al., Neuroscience, 1998,
82(4), 993-997).
Type H histaminergic receptors, which are especially abundant in the central nervous system,
are mainly presynaptic modulators of neural transmission and are present in a variety of neuronal
circuits relevant to cognition (Blandina et al., Learn Mem., 2004, 11(1), 1-8). They act by
negatively regulating the release of neurotransmitters such as histamine, acetylcholine, serotonin,
noradrenaline and dopamine. Given that histaminergic neurons seem to be largely spared in
Alzheimer's disease, compounds that are antagonists or inverse agonists of H receptors could
open the way to new treatments for the cognitive disturbances related to cerebral ageing.
Conversely, progressive degeneration of cholinergic neurons is observed in the course of
Alzheimer's disease. Acetylcholinesterase inhibitors such as donepezil are commonly used in the
symptomatic treatment of Alzheimer's disease in order to limit the lowering of acetylcholine
levels in the brain by blocking the action of acetylcholinesterase. It has been shown that
acetylcholinesterase inhibitors, like antagonists/inverse agonists of H receptors, make it possible
to improve cognitive properties in various animal models of episodic memory and working
memory (Esbenshade et al., Br. J. Pharmacol., 2008, 154(6), 1166-1181; Yuede et al., Behav.
Pharmacol., 2007, 18(5-6), 347-363). Improving cognitive functions may therefore be based on
two types of strategy targeting either histamine or acetylcholine.
The present invention has shown, surprisingly, that the effects of acetylcholinesterase inhibitors
are potentiated by those of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-
benzamide or addition salts thereof with a pharmaceutically acceptable acid or base.
Accordingly, co-administration of these compounds could make it possible to improve the
cognitive performance of patients compared to the simple administration of an
acetylcholinesterase inhibitor without, however, increasing the adverse effects associated with
the treatment (especially gastrointestinal disturbances such as nausea or diarrhoea, headaches or
fatigue). In other words, treatments involving therapeutic doses of acetylcholinesterase inhibitor
that are lower than those customarily used in mono-therapy can therefore now be envisaged, with
equivalent or even superior cognitive performance and fewer adverse effects.
This unforeseeable effect makes it possible to envisage using associations between 4-{3-[cis-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof, and an
acetylcholinesterase inhibitor in the treatment of cognitive disturbances associated with cerebral
ageing and with neurodegenerative diseases. The cognitive disturbances associated with
Alzheimer's disease and with Parkinson's disease are being especially targeted.
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide is used preferably in the
form of an oxalate or hydrochloride within the context of the invention.
Among the acetylcholinesterase inhibitors according to the invention, donepezil, rivastigmine
and galantamine are especially preferred. Preferably, donepezil is used in the form of a
hydrochloride, rivastigmine in the form of a hydrogen tartrate, and galantamine in the form of a
hydrobromide.
More especially, the association of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-
benzamide and donepezil is used in the treatment of cognitive disturbances associated with
Alzheimer's disease, whereas the association of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-
yl]propoxy}benzamide and rivastigmine is preferred in the treatment of cognitive disturbances
associated with Parkinson's disease.
The invention accordingly relates to use of the association between 4-{3-[cis-hexahydro-
cyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or addition salts thereof with a
pharmaceutically acceptable acid or base, and an acetylcholinesterase inhibitor in obtaining
pharmaceutical compositions intended for the treatment of cognitive disturbances associated with
cerebral ageing and with neurodegenerative diseases.
The invention relates also to pharmaceutical compositions comprising the association between 4-
{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or addition salts thereof
with a pharmaceutically acceptable acid or base, and an acetylcholinesterase inhibitor in
combination with one or more pharmaceutically acceptable excipients.
More specifically, in one aspect, the present invention provides a pharmaceutical composition
comprising 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide of formula (I):
(I),
or an addition salt thereof with a pharmaceutically acceptable acid or base, and an
acetylcholinesterase inhibitor, in combination with one or more pharmaceutically acceptable
excipients.
In another aspect, the present invention provides a use of 4-{3-[cis-hexahydrocyclo-
penta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically
acceptable acid or base, and an acetylcholinesterase inhibitor in the manufacture of a medicament
for the treatment of cognitive disturbances associated with cerebral ageing and with
neurodegenerative diseases.
In another aspect, the present invention provides a use of 4-{3-[cis-hexahydrocyclo-
penta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically
acceptable acid or base, and an acetylcholinesterase inhibitor in the manufacture of a medicament
for the treatment of cognitive disturbances associated with Alzheimer's disease and with
Parkinson's disease.
In another aspect, the present invention provides a use of 4-{3-[cis-hexahydrocyclo-
penta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically
acceptable acid or base, and donepezil in the manufacture of a medicament for the treatment of
cognitive disturbances associated with Alzheimer's disease.
In another aspect, the present invention provides a use of 4-{3-[cis-hexahydrocyclo-
penta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically
acceptable acid or base, and rivastigmine in the manufacture of a medicament for the treatment of
cognitive disturbances associated with Parkinson's disease.
In another aspect, the present invention provides a use of 4-{3-[cis-hexahydrocyclo-
penta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically
acceptable acid or base, in the manufacture of a medicament for the treatment of cognitive
disturbances associated with cerebral ageing and with neurodegenerative diseases wherein the
medicament is to be administered sequentially or simultaneously with an acetylcholinesterase
inhibitor.
In another aspect, the present invention provides a use of 4-{3-[cis-hexahydrocyclo-
penta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically
acceptable acid or base, in the manufacture of a medicament for the treatment of cognitive
disturbances associated with Alzheimer's disease and Parkinson's disease wherein the
medicament is to be administered sequentially or simultaneously with an acetylcholinesterase
inhibitor.
In another aspect, the present invention provides a combination of 4-{3-[cis-hexahydrocyclo-
penta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically
acceptable acid or base and an acetylcholinesterase inhibitor.
In the pharmaceutical compositions according to the invention, the proportion of active
ingredients by weight (weight of active ingredients over the total weight of the composition) is
preferably from 5 to 50 %.
Among the pharmaceutical compositions according to the invention there will be more especially
used those which are suitable for administration by the oral, parenteral and especially
intravenous, per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory route, more
specifically tablets, dragées, sublingual tablets, hard gelatin capsules, glossettes, capsules,
lozenges, injectable preparations, aerosols, eye or nose drops, suppositories, creams, ointments,
dermal gels etc..
Besides 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and the acetyl-
cholinesterase inhibitor compound, the pharmaceutical compositions according to the invention
comprise one or more excipients or carriers selected from diluents, lubricants, binders,
disintegration agents, stabilisers, preservatives, absorbents, colourants, sweeteners, flavourings
etc..
By way of non-limiting example there may be mentioned:
as diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol,
as lubricants: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene
glycol,
as binders: magnesium aluminium silicate, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose and polyvinylpyrrolidone,
as disintegrants: agar, alginic acid and its sodium salt, effervescent mixtures.
The compounds of the association may be administered simultaneously or sequentially. The
administration route is preferably the oral route, and the corresponding pharmaceutical
compositions may allow the instantaneous or delayed release of the active ingredients. The
compounds of the association may moreover be administered in the form of two separate
pharmaceutical compositions, each containing one of the active ingredients, or in the form of a
single pharmaceutical composition, in which the active ingredients are in admixture.
Preference is given to the pharmaceutical compositions being tablets.
The useful dosage regimen varies according to the sex, age and weight of the patient, the
administration route, the nature of the disorder and of any associated treatments and ranges from
0.5 mg to 100 mg of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide per
24 hours, more preferably 5 mg per day. The dose of the acetylcholinesterase inhibitor will be the
same as or less than that used when it is administered on its own. In the case of donepezil, the
dosage regimen is from 0.5 mg to 30 mg per day, preferred daily doses being 5 and 10 mg for the
donepezil hydrochloride. For rivastigmine, the dosage regimen is from 1 mg to 20 mg per day.
Preferred daily doses are 3 and 6 mg twice per day when rivastigmine is administered in the form
of a tablet, whereas they are 4.6 mg and 9.5 mg per day when the product is presented in the form
of a patch. In the case of galantamine, the dosage regimen is from 1 to 30 mg per day, preferred
daily doses being 16 and 24 mg.
In preferred embodiments of the invention, the association between 4-{3-[cis-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide (compound S) and donepezil is
administered at the following daily doses:
Composition 1 Composition 2 Composition 3
Hydrochloride of compound S
2 mg 5 mg 20 mg
(expressed as base)
Donepezil hydrochloride 10 mg 10 mg 10 mg
Pharmaceutical composition:
Pharmaceutical composition:
Formula for the preparation of 1000 tablets each containing 5 mg (expressed as base) of 4-
{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride and 10
mg of donepezil hydrochloride:
4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride (expressed as base) .............................................................................................. 5 g
Donepezil hydrochloride ................................................................................................... 10 g
Maize starch ...................................................................................................................... 20 g
Maltodextrin .................................................................................................................... 7.5 g
Colloidal silica ................................................................................................................. 0.2 g
Sodium starch glycolate...................................................................................................... 3 g
Magnesium stearate ........................................................................................................... 1 g
Lactose .............................................................................................................................. 55 g
The term “comprising” as used in this specification and claims means “consisting at least in part
of”. When interpreting statements in this specification and claims which include the term
“comprising”, other features besides the features prefaced by this term in each statement can also
be present. Related terms such as “comprise” and “comprised” are to be interpreted in similar
manner.
In this specification where reference has been made to patent specifications, other external
documents, or other sources of information, this is generally for the purpose of providing a
context for discussing the features of the invention. Unless specifically stated otherwise,
reference to such external documents is not to be construed as an admission that such documents,
or such sources of information, in any jurisdiction, are prior art, or form part of the common
general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not within
the scope of the claims of the current application. That subject matter should be readily
identifiable by a person skilled in the art and may assist in putting into practice the invention as
defined in the claims of this application.
EXAMPLE A:
EXAMPLE A:
E Ex xp pe er riim me en nt t iin n a a m mo od de ell o of f e ep piis so od diic c m me em mo or ry y,, t th he e c co on nt te ex xt tu ua all s se er riia all d diis sc cr riim miin na at tiio on n t te es st t: :
The effects of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and
donepezil (both in the form of a hydrochloride), administered on their own or in combination,
were studied using a contextual serial discrimination test in the middle-aged (14-15 months old)
C57B16 mouse (n=12 per group) (Célérier et al., Learn Mem., 2004, 11(2), 196-204; Tronche et
al., Behav. Brain Res., 2010, 215(2): 255-60). In this model, the middle-aged mice have a
specific dysfunction of contextual memory compared to young mice, without a deficiency in
spatial memory. This model is relevant for evaluating the effects of products in Alzheimer's
disease because patients suffering from that form of dementia also have disturbances of
contextual episodic memory, this being the case from a very early stage (Gold and Budson,
Expert Rev Neurother., 2008, 8(12): 1879-1891).
The mice, placed in a box with raised edges, learn two types of consecutive spatial discrimination
(D1: white floor, then D2: black floor) on a floor with four holes, in which just one of the holes is
baited, the arrangement being opposite in D1 and in D2 (see Figure 1). Each discrimination is
performed on a specific floor (black or white), which constitutes the internal context specific to
each discrimination. 24 hours after the learning step, the mice are returned to the white
contextual floor, and the following are measured:
- the percentage of correct responses (i.e. % of lowering the head into the hole that was
baited during the learning exercise on the white floor),
- the percentage of interfering responses (i.e. % of lowering the head into the hole that was
baited during the learning exercise on the black floor, the last context presented to the
mice),
- and the percentage of errors (i.e. % of lowering the head into the two holes that were not
baited during learning, whether on the white floor or on the black floor (see Figure 1).
The results show that the middle-aged mice treated with the carrier have a percentage of correct
responses which is close to the level of chance in this test on 4-hole boards (≈ 25%). Following
chronic treatment for 9 days with donepezil hydrochloride (0.1 mg/kg of base per os), no
significant improvement in the percentage of correct responses is observed compared to the
carrier (see Figure 2). In contrast, the level of correct responses increases by more than 60%
compared to the carrier following chronic treatment for 9 days with 4-{3-[cis-hexahydro-
cyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride at doses of 0.3 and 1 mg/kg of
base per os (compound referred to as "S" in Figure 2). Finally, administration of the association
of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide (0.3 and 1 mg/kg of
base per os) with donepezil (0.1 mg/kg of base per os) results in an increase in the level of
correct responses of more than 100% compared to the carrier on its own. These results show
clear potentiation of the effects of donepezil in the presence of 4-{3-[cis-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide.
A very good correlation was moreover observed between the increase in the level of correct
responses and the reduction in the level of interfering responses, thereby confirming the specific
effect of each compound and of their association on contextual memory. Accordingly, the
administration of the association of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-
benzamide (0.3 and 1 mg/kg of base per os) with donepezil (0.1 mg/kg of base per os)
significantly increases the power of contextual memory (correct responses - interfering
responses) compared to that observed with the compounds on their own. This increase that is
observed for the association cannot be explained by simply adding together the effects of the
compounds administered on their own and shows synergistic activity of the two compounds
when they are co-administered (see Figure 3).
The results clearly demonstrate that the administration of these two compounds in association
makes it possible to obtain a large synergistic effect which was entirely unexpected.
Pharmacokinetic analyses have moreover shown that there was no pharmacokinetic-type
interaction between the two treatments which might justify or interfere with the synergistic effect
described above.
EXAMPLE B:
EXAMPLE B:
E Ex xp pe er riim me en nt t w wiit th h r riiv va as st tiig gm miin ne e iin n t th he e s sa am me e c co on nt te ex xt tu ua all s se er riia all d diis sc cr riim miin na at tiio on n t te es st t: :
The effects of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and
rivastigmine (used in the form of a hydrogen tartrate), administered on their own or in
combination, were studied using the contextual serial discrimination test in the middle-aged
C57B16 mouse described in the Example above.
In this model it has been shown that, compared to young mice, the middle-aged mice have a
contextual memory deficit due to the fact that the last context in which they learnt the location of
the baited hole (i.e. the black floor) substantially interferes with memory of the baited hole in the
first context presented during learning (i.e. the white floor). Because of this fact, the elderly mice
have negative values for the power of contextual memory (correct responses - interfering
responses) because the percentage of interfering responses is higher than the percentage of
correct responses. In contrast, the young mice have a positive power of contextual memory
(Tronche et al., Behav. Brain Res., 2010, 215(2): 255-60).
As in the Example above, the results of this study confirm the contextual memory deficit in
middle-aged mice, the mice treated with the carrier showing a negative contextual memory
power of -28% (see Figure 4). Following chronic treatment for 9 days with rivastigmine at a dose
of 0.1 mg/kg of base per os, a slight increase in the power of contextual memory compared to the
carrier is observed (-9% versus -28%), but it still remains negative, the percentage of interfering
responses still being greater than the percentage of correct responses, giving rise to the
conclusion that the 0.1 mg/kg dose of rivastigmine is a sub-active dose.
Similarly, the power of contextual memory increases only slightly compared to the carrier
following chronic treatment for 9 days with 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-
yl]propoxy}benzamide hydrochloride at doses of 0.3 and 1 mg/kg of base per os (+6% and
+10%, respectively, versus -28%). In contrast, administration of the association of rivastigmine
(sub-active dose of 0.1 mg/kg of base per os) with 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-
2(1H)-yl]propoxy}benzamide (0.3 or 1 mg/kg of base per os) results in a substantial increase in
the power of contextual memory, which then becomes significantly superior (% of correct
responses > % of interfering responses), on the one hand relative to the value obtained with the
carrier and on the other hand relative to that obtained for rivastigmine on its own (+28% and
+28% versus -9%, respectively). These results show clear potentiation of the effects of
rivastigmine at a sub-active dose in the presence of active doses of 4-{3-[cis-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, which is reflected by an increase in
the memory performance of the mice treated with the association.
In this second example too, the increase in the power of contextual memory observed for the two
associations cannot be explained by simply adding together the effects of the compounds
administered on their own and shows entirely unexpected synergistic activity for the two
compounds when they are co-administered.
Pharmacokinetic analyses have moreover shown that there was no pharmacokinetic-type
interaction between the two treatments which might justify or interfere with the synergistic effect
described above.
In conclusion, the results presented above demonstrate synergistic activity between 4-{3-[cis-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and rivastigmine in terms of
cognitive performance, this being the case without any pharmacokinetic interaction.
E EX XA AM MP PL LE E C C: :
E Ex xp pe er riim me en nt t w wiit th h g ga alla an nt ta am miin ne e iin n t th he e s sa am me e c co on nt te ex xt tu ua all s se er riia all d diis sc cr riim miin na at tiio on n t te es st t: :
The effects of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and
galantamine (used in the form of a hydrobromide), administered on their own or in combination,
were also studied using the contextual serial discrimination test in the middle-aged C57B16
mouse.
As in the Examples above, the results of this study confirm the contextual memory deficit of
middle-aged mice, the mice treated with the carrier showing a negative contextual memory
power of -28% (see Figure 5).
Following chronic treatment for 9 days with galantamine at a dose of 0.3 mg/kg of base per os,
there is observed no significant improvement in the power of contextual memory compared to the
carrier (-18% versus - 28%), the power remaining markedly negative (% interfering responses >
% correct responses); the 0.3 mg/kg dose of galantamine is therefore sub-active. Neither, after
chronic treatment for 9 days with 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-
yl]propoxy}benzamide hydrochloride at a dose of 0.3 mg/kg of base per os, does contextual
memory power increase significantly compared to the carrier (-3% versus -28%, respectively).
Moreover, after chronic treatment for 9 days with 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-
2(1H)-yl]propoxy}benzamide hydrochloride at a dose of 1 mg/kg of base per os, it increases only
slightly compared to the carrier (+9% versus -28%). In contrast, administration of the association
of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide (0.3 and 1 mg/kg of
base per os) with galantamine (sub-active dose of 0.3 mg/kg of base per os) results in a
substantial increase in contextual memory power, which becomes significantly superior
compared to the value obtained with the carrier on its own (+31% and +24% versus -28%,
respectively). These results show clear potentiation of the effects of galantamine at a sub-active
dose in the presence of a sub-active or slightly active dose of 4-{3-[cis-hexahydrocyclo-
penta[c]pyrrol-2(1H)-yl]propoxy}benzamide, which is reflected by an increase in the memory
performance of the mice treated with the association.
Here too, in this third Example of association with an acetylcholinesterase inhibitor, the increase
in the power of contextual memory observed cannot be explained by simply adding together the
effects of the compounds administered on their own.
In conclusion, the results presented above show synergistic activity between 4-{3-[cis-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and galantamine in terms of
cognitive performance.
E EX XA AM MP PL LE E D D: :
Irwin's primary observation test:
Irwin's primary observation test:
The effects, in terms of safety, of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-
benzamide and donepezil (both in the form of a hydrochloride), administered on their own or in
association, were studied using Irwin's primary observation test in the C57B16 mouse (n=4
individuals per group).
Behavioural changes, physiological and neurotoxic symptoms, rectal temperature and pupil
diameter were recorded using a standardised observation grid derived from that of Irwin.
It was observed that 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide (0.3
and 1 mg/kg of base per os) and donepezil (0.1 and 0.3 mg/kg of base per os), administered on
their own or in co-administration, brought about no observable changes in Irwin's test in the
mouse. At the strongest dose (1 mg/kg of base per os), donepezil administered on its own reduces
reactivity to touch and causes slight sedation. No potentiation of the adverse effects of donepezil
at 1 mg/kg is observed when it is co-administered with 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-
2(1H)-yl]propoxy}benzamide (0.3 and 1 mg/kg of base per os). On the contrary, when 4-{3-[cis-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide at the strongest dose (1 mg/kg of
base per os) is co-administered with donepezil at 1 mg/kg p.o., no sedation is observed, which
suggests that 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide antagonises
the sedation caused by donepezil at 1 mg/kg p.o..
In conclusion, the results presented above demonstrate synergistic activity between 4-{3-[cis-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and donepezil in terms of cognitive
performance, this being the case with a good safety profile and without pharmacokinetic
interaction.
Claims (19)
1- A pharmaceutical composition comprising 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)- yl]propoxy}benzamide of formula (I): (I), or an addition salt thereof with a pharmaceutically acceptable acid or base, and an 5 acetylcholinesterase inhibitor, in combination with one or more pharmaceutically acceptable excipients.
2- A pharmaceutical composition according to claim 1, wherein the 4-{3-[cis-hexahydrocyclo- penta[c]pyrrol-2(1H)-yl]propoxy}benzamide is used in the form of an oxalate or hydrochloride. 10
3- A pharmaceutical composition according to either claim 1 or claim 2, wherein the acetylcholinesterase inhibitor is donepezil, rivastigmine or galantamine.
4- A pharmaceutical composition according to any one of claims 1 to 3, wherein donepezil is in the form of a hydrochloride, rivastigmine in the form of a hydrogen tartrate, and galantamine in the form of a hydrobromide. 15
5- A pharmaceutical composition according to any one of claims 1-4 for use in the treatment of cognitive disturbances associated with cerebral ageing and with neurodegenerative diseases.
6- A pharmaceutical composition according to any one of claims 1-4 for use in the treatment of cognitive disturbances associated with Alzheimer's disease and with Parkinson's disease.
7- A pharmaceutical composition according to any one of claims 1-4, wherein the 4-{3-[cis- 20 hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide is to be administered in the form of a hydrochloride at a daily dose of 2 mg, 5 mg or 20 mg (expressed as base), and the acetylcholinesterase inhibitor is donepezil hydrochloride, to be administered at a daily dose of 10 mg.
8- A pharmaceutical composition according to any one of claims 1-4 wherein the 5 acetylcholinesterase inhibitor is donepezil for use in the treatment of cognitive disturbances associated with Alzheimer's disease.
9- A pharmaceutical composition according to any one of claims 1-4 wherein the acetylcholinesterase inhibitor is rivastigmine for use in the treatment of cognitive disturbances associated with Parkinson's disease.
10 10- A use of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically acceptable acid or base, and an acetylcholinesterase inhibitor in the manufacture of a medicament for the treatment of cognitive disturbances associated with cerebral ageing and with neurodegenerative diseases.
11- A use of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an 15 addition salt thereof with a pharmaceutically acceptable acid or base, and an acetylcholinesterase inhibitor in the manufacture of a medicament for the treatment of cognitive disturbances associated with Alzheimer's disease and with Parkinson's disease.
12- A use of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically acceptable acid or base, and donepezil in the 20 manufacture of a medicament for the treatment of cognitive disturbances associated with Alzheimer's disease.
13- A use of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically acceptable acid or base, and rivastigmine in the manufacture of a medicament for the treatment of cognitive disturbances associated with 25 Parkinson's disease.
14- A use of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of a medicament for the treatment of cognitive disturbances associated with cerebral ageing and with neurodegenerative diseases wherein the medicament is to be administered sequentially 5 or simultaneously with an acetylcholinesterase inhibitor.
15- A use of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of a medicament for the treatment of cognitive disturbances associated with Alzheimer's disease and Parkinson's disease wherein the medicament is to be administered sequentially or 10 simultaneously with an acetylcholinesterase inhibitor.
16- A combination of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, or an addition salt thereof with a pharmaceutically acceptable acid or base and an acetylcholinesterase inhibitor.
17- A pharmaceutical composition according to any one of claims 1-9, substantially as herein 15 described with reference to any example thereof.
18- A use according to any one of claims 10-15, substantially as herein described with reference to any example thereof.
19- A combination according to claim 16, substantially as herein described with reference to any example thereof. -
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR11/01347 | 2011-05-02 | ||
FR1101347A FR2974729B1 (en) | 2011-05-02 | 2011-05-02 | NOVEL ASSOCIATION BETWEEN 4- {3- [CIS-HEXAHYDROCYCLOPENTA [C] PYRROL-2 (1H) -YL] PROPOXY} BENZAMIDE AND AN ACETYLCHOLINESTERASE INHIBITOR AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ599633A NZ599633A (en) | 2014-02-28 |
NZ599633B true NZ599633B (en) | 2014-06-04 |
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