NZ750121B2 - Triple combination of histamine-3 receptor inverse agonists, acetylcholinesterase inhibitors and nmda receptor antagonist - Google Patents
Triple combination of histamine-3 receptor inverse agonists, acetylcholinesterase inhibitors and nmda receptor antagonist Download PDFInfo
- Publication number
- NZ750121B2 NZ750121B2 NZ750121A NZ75012117A NZ750121B2 NZ 750121 B2 NZ750121 B2 NZ 750121B2 NZ 750121 A NZ750121 A NZ 750121A NZ 75012117 A NZ75012117 A NZ 75012117A NZ 750121 B2 NZ750121 B2 NZ 750121B2
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- NZ
- New Zealand
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- combination
- phenyl
- morpholinyl
- Prior art date
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Abstract
The present invention relates to a combination of histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA receptor antagonist. Also, the present invention provides histamine-3 receptor (H3R) inverse agonist, or the 10 pharmaceutically acceptable salt(s) thereof in combination with or as adjunct to acetylcholinesterase inhibitor and N-Methyl-D-aspartate (NMDA) receptor antagonist and their use in the treatment of cognitive disorders. The present invention further provides the pharmaceutical composition containing the said combination. ith or as adjunct to acetylcholinesterase inhibitor and N-Methyl-D-aspartate (NMDA) receptor antagonist and their use in the treatment of cognitive disorders. The present invention further provides the pharmaceutical composition containing the said combination.
Description
James & Wells Ref: 310855NZ
TRIPLE COMBINATION OF HISTAMINE-3 RECEPTOR INVERSE
AGONISTS, ACETYLCHOLINESTERASE INHIBITORS AND NMDA
RECEPTOR ANTAGONIST
FIELD OF THE INVENTION
The present invention relates to histamine-3 receptor (H R) inverse agonists
or the pharmaceutically acceptable salt(s) thereof in combination with or as adjunct
to acetylcholinesterase inhibitors (AChEIs) and N-Methyl-D-aspartate (NMDA)
receptor antagonist. The present invention further relates to the use of the
combination and the pharmaceutical composition containing the said combination
in the treatment of cognitive disorders.
BACKGROUND OF INVENTION
Alzheimer’s disease (AD) is the most common cause of dementia
worldwide. The exponential rise in the number of cases of AD in the past and the
future projection over the next few decades is anticipated to result in great pressure
on the social and health-care systems of developed and developing economies alike.
AD also imposes tremendous emotional and financial burden to the patient’s family
and community.
The current list of approved cognitive enhancing drugs for AD is not long
and historically been focused on acetylcholinesterase inhibitors (donepezil,
rivastigmine and galantamine). These drugs act by inhibiting the hydrolysis of
acetylcholine (ACh) into acetate and choline by targeting acetylcholinesterase
(AChE) enzyme. Increasing the ACh levels in the synapse can stimulate cholinergic
receptors and promote memory function. Although acetylcholinesterase inhibitors
(AChEIs) can temporarily delay the progression of cognitive decline in AD, their
effects are modest. ACh being present both in the central and peripheral nervous
system, AChEIs produce several undesirable side effects such as gastrointestinal
disturbances, bradycardia and excessive salivation that are associated with an action
on peripheral muscarinic cholinergic receptors (Expert Opinion on Drug Safety, 3,
2004, 425–440). The limitation of AChE inhibitor class of drugs is that they are
poorly tolerated, their efficacy is not sustained and they require constant dose-
James & Wells Ref: 310855NZ
titration as the disease progresses (Cochrane Database Systematic Reviews, 2006,
CD005593) which lead to significant patient noncompliance. The incidence and the
severity of these side effects increase with the dose amount and in general more
pronounced at the initiation of the treatment or after dose increase. Hence there is
an unmet need of alternate therapy for treating cognition disorders.
The H R is a G protein-coupled receptor (GPCR), mainly expressed in the
anterior part of the cortex, hippocampus and the striatum. H Rs function as both
autoreceptors and heteroreceptors. It modulates the synthesis and release of several
neurotransmitters which play an important role in cognition, mood and sensory
gating. Preliminary literature reports suggest that H R antagonists may have
promising utility for the treatment of various CNS disorders including AD,
schizophrenia, attention-deficit hyperactivity disorder (ADHD), epilepsy,
narcolepsy, neuropathic pain and metabolic disorders. Antagonism of this receptor
by several investigational compounds has been shown to improve learning and
memory in animal models.
Since blocking H R modulates histaminergic and cholinergic activity, one
might expect H R inverse agonist to complement and/or augment cognitive
function of AChEIs. This may in turn help to reduce side effects with better patient
compliance and thus can be administered over a long period.
The glutamatergic system is also involved in learning and memory and is a
target for treatment of Alzheimer’s disease. Memantine, another approved
treatment for Alzheimer’s disease, acts on the glutamatergic system by inhibiting
NMDA receptor under conditions of excess stimulation. It may act to protect
glutamate neurons from excessive glutamate stimulation, while increasing the
signal to noise ratio. It is known that glutamate neurons have synaptic connections
on cholinergic neurons in brain areas associated with learning and memory.
Since the cause and development of the dementia depend on the different
mechanisms, it may be an advantageous to use the combination of drugs working
in different mechanism for the treatment of AD. The current approved treatment for
AD includes the combination of acetylcholinesterase inhibitor, donepezil and
James & Wells Ref: 310855NZ
NMDA receptor antagonist, memantine. However, there remains the need for the
new drugs/combination to treat the patients with AD.
The compounds of the present invention are H R inverse agonists with high
affinity and very high selectivity over closely related receptor subtypes and
improves learning and memory in animals. The H R inverse agonist compounds
mentioned here are described in US9079888B2 which is incorporated by reference.
The preparation of these compounds is given in the said patent.
As the treatment of AD is chronic in nature, there is a desperate unmet
medical need for better and safer treatment options. A therapeutic strategy eagerly
sought for AD patients is to target an improvement with an adjunct to existing
therapies that would bring additional relief for patients, lower the burden on the
caregiver and allow the patient to enjoy a better quality of life without the need for
institutional care and/or hospitalization.
The instant invention provides H R inverse agonist compounds or the
pharmaceutically acceptable salt(s) thereof, which enhances the cognitive function
of patients on treatment in combination with AChEIs and NMDA receptor
antagonist. The present invention is based on the unusual finding that the
combination of compounds with H R inverse agonist activity, the compounds
which act as AChEIs (for example donepezil) and the compounds which act as
NMDA receptor antagonists (for example memantine), demonstrate synergistic
effect in their pharmacological activity. Memantine acts by blocking the
glutamatergic neurotransmissions in the brain when the levels are excessively high.
Histamine modulates the release of glutamate from corticostriatal nerve terminals.
Hence it is not anticipated that the combination of a H R inverse agonist + donepezil
+ memantine would result in synergistic pro-cognitive effects. However
surprisingly, the combination of H R inverse agonist + AChEIs + NMDA receptor
antagonist (triple combination) showed synergistic effects in animal models and
also increased the levels acetylcholine, the neurotransmitter which plays a vital role
in cognitive improvement. Based on these results one can infer that such combined
administration and/or co-treatment of H R inverse agonist + AChEIs + NMDA
receptor antagonist, may result in beneficial effect to improve the therapeutic
James & Wells Ref: 310855NZ
efficacy in humans. Further the H R inverse agonist compounds or the
pharmaceutically acceptable salt(s) thereof of the instant invention enhances the
effect of the AChEIs and NMDA receptor antagonist in the treatment of cognitive
disorders.
SUMMARY OF THE INVENTION
The objective of the present invention is to provide an improved
combination therapy for the treatment of cognitive disorders, such as Alzheimer’s
disease, schizophrenia, Parkinson’s disease, lewy body dementia, vascular
dementia, frontotemporal dementia, Down syndrome or Tourette’s syndrome.
In the first aspect, the present invention relates to a combination of
histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist.
In yet another aspect, the present invention relates to a combination of
histamine-3 inverse agonist, acetylcholinesterase inhibitor and NMDA receptor
antagonist; wherein the histamine-3 receptor inverse agonist is selected from:
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholin
yl)acetamide;
N-[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholin
yl)acetamide; and
N-[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide;
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a combination of
histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist; wherein the histamine-3 receptor inverse agonist is N-[4-(l-
Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide or a
pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a combination of
histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist; wherein the histamine-3 receptor inverse agonist is N-[4-(1-
James & Wells Ref: 310855NZ
Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide or a
pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a combination of
histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist; wherein the histamine-3 receptor inverse agonist is N-[4-(1-
Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide or a
pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a combination of
histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist; wherein the acetylcholinesterase inhibitor is selected from
donepezil, galantamine and rivastigmine or a pharmaceutically acceptable salt
thereof.
In another aspect, the present invention relates to a combination of
histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist; wherein the NMDA receptor antagonist is memantine or a
pharmaceutically acceptable salt thereof.
In yet another aspect the present invention relates to a combination of N-[4-
(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide, donepezil
and memantine or a pharmaceutically acceptable salt thereof.
In yet another aspect the present invention relates to the combination of N-
[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide,
donepezil and memantine or a pharmaceutically acceptable salt thereof.
In yet another aspect the present invention relates to the combination of N-
[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide, donepezil
and memantine or a pharmaceutically acceptable salt thereof.
In yet another aspect, the present invention relates to the said combination
for use in the treatment of cognitive disorders.
In yet another aspect, the present invention relates to the said combination
for use in the treatment of cognitive disorders such as Alzheimer’s disease,
schizophrenia, Parkinson’s disease, lewy body dementia, vascular dementia,
frontotemporal dementia, Down syndrome or Tourette’s syndrome.
James & Wells Ref: 310855NZ
In yet another aspect, the present invention relates to a method of treatment
of cognitive disorders such as Alzheimer’s disease, schizophrenia, Parkinson’s
disease, lewy body dementia, vascular dementia, frontotemporal dementia, Down
syndrome or Tourette’s syndrome comprising administering to a patient in need
thereof a therapeutically effective amount of the said combination.
In yet another aspect, the present invention relates to histamine-3 receptor
inverse agonist for use in the adjunct treatment of cognitive disorders such as
Alzheimer’s disease, schizophrenia, Parkinson’s disease, lewy body dementia,
vascular dementia, frontotemporal dementia, Down syndrome or Tourette’s
syndrome in patients on treatment with acetylcholinesterase inhibitor and NMDA
receptor antagonist.
In yet another aspect, the present invention relates to the compound, N-[4-
(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide or a
pharmaceutically acceptable salt thereof for use in the adjunct treatment of
cognitive disorders such as Alzheimer’s disease, schizophrenia, Parkinson’s
disease, lewy body dementia, vascular dementia, frontotemporal dementia, Down
syndrome or Tourette’s syndrome in patients on treatment with donepezil and
memantine.
In yet another aspect, the present invention relates to the compound, N-[4-
(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide or a
pharmaceutically acceptable salt thereof for use in combination with or adjunct to
an acetylcholinesterase inhibitor and NMDA receptor antagonist for the treatment
of cognitive disorders such as Alzheimer’s disease, schizophrenia, Parkinson’s
disease, lewy body dementia, vascular dementia, frontotemporal dementia, Down
syndrome or Tourette’s syndrome.
In another aspect, the present invention relates to a method for treatment of
cognitive disorders comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(l-Cyclobutylpiperidinyloxy)phenyl]-
2-(morpholinyl) acetamide or a pharmaceutically acceptable salt thereof in
combination with or as an adjunct to donepezil or a pharmaceutically acceptable
salt thereof and memantine or a pharmaceutically acceptable salt thereof.
James & Wells Ref: 310855NZ
In yet another aspect, the present invention relates to use of a combination
of histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist for the treatment of cognitive disorders such as Alzheimer’s
disease, schizophrenia, Parkinson’s disease, lewy body dementia, vascular
dementia, frontotemporal dementia, Down syndrome or Tourette’s syndrome.
In yet another aspect, the present invention relates to use of a combination
of N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide,
donepezil and memantine or a pharmaceutically acceptable salt thereof for the
treatment of cognitive disorders such as Alzheimer’s disease, schizophrenia,
Parkinson’s disease, lewy body dementia, vascular dementia, frontotemporal
dementia, Down syndrome or Tourette’s syndrome.
In another aspect, the present invention relates to pharmaceutical
composition comprising the histamine-3 receptor inverse agonist,
acetylcholinesterase inhibitor and NMDA receptor antagonist and pharmaceutically
acceptable excipients or combination thereof.
In another aspect, the present invention relates to pharmaceutical
composition comprising N-[4-(l-Cyclobutylpiperidinyloxy)phenyl]
(morpholinyl)acetamide, donepezil and memantine or a pharmaceutically
acceptable salt thereof and the pharmaceutically acceptable excipients or
combination thereof.
In another aspect, the present invention relates to pharmaceutical
composition comprising the histamine-3 receptor inverse agonist,
acetylcholinesterase inhibitor and NMDA receptor antagonist or the
pharmaceutically acceptable salt thereof along with the pharmaceutically
acceptable excipients or combination thereof for use in the treatment of cognitive
disorders such as Alzheimer’s disease, schizophrenia, Parkinson’s disease, lewy
body dementia, vascular dementia, frontotemporal dementia, Down syndrome or
Tourette’s syndrome.
James & Wells Ref: 310855NZ
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS
Figure 1a depicts the results of the effect of a co-treatment of compound 1 with
donepezil and memantine on cognition enhancing properties using object
recognition task model.
Figure 1b depicts the results of the effect of a co-treatment of compound 3 with
donepezil and memantine on cognition enhancing properties using object
recognition task model.
Figure 2 depicts the effect of compound 1 in combination with donepezil and
memantine on extracellular levels of acetylcholine in medial prefrontal cortex of
male Wistar rats.
Figure 3 depicts the effect of compound 2 in combination with donepezil and
memantine on extracellular levels of acetylcholine in medial prefrontal cortex of
male Wistar rats.
Figure 4 depicts the effect of compound 3 in combination with donepezil and
memantine on extracellular levels of acetylcholine in medial prefrontal cortex of
male Wistar rats.
Figure 5 depicts the effect of compound 1 in combination with donepezil and
memantine on evoked theta levels in dorsal hippocampus of anesthetized male
Wistar rats.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the following terms used in the specification and
claims have the meanings given below:
The term, “histamine-3 receptor inverse agonist” as used herein refers to a
ligand or drug that binds with the constitutively active histamine-3 receptors,
stabilize them and thus reduce the activity (negative intrinsic activity). It blocks or
inhibits the function / binding of agonist at the H receptor and exert opposite
pharmacological effect of a receptor agonist.
Examples of the histamine-3 receptor inverse agonist include,
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide;
N-[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide; and
James & Wells Ref: 310855NZ
N-[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide;
or a pharmaceutically acceptable salt thereof.
Examples of pharmaceutically acceptable salt of the above identified
compounds include but not limited to,
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride; N-[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholin
yl)acetamide tartrate; and
N-[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide tartrate.
The term, “acetylcholinesterase inhibitor” as used herein is a chemical or
drug that inhibits the acetylcholinesterase enzyme from breaking down
acetylcholine, thereby increasing both the level and duration of action of the
neurotransmitter acetylcholine. Examples of acetylcholinesterase inhibitor are
donepezil, rivastigmine and galantamine. Preferably, the acetylcholinesterase
inhibitor is donepezil and rivastigmine. More preferably the acetylcholinesterase
inhibitor is donepezil.
Donepezil is a drug approved for treatment of mild, moderate and severe
dementia of Alzheimer’s disease. Donepezil is a reversible inhibitor of the enzyme
acetylcholinesterase and sold under trade name Aricept as hydrochloride salt.
Rivastigmine is a drug approved for treatment of mild, moderate and severe
dementia of Alzheimer’s disease. Rivastigmine is a reversible cholinesterase
inhibitor and sold under trade name Exelon and Exelon Patch as tartrate salt.
Galantamine is a drug approved for treatment of mild, moderate and severe
dementia of Alzheimer’s disease. Galantamine, a reversible, competitive
acetylcholinesterase inhibitor and sold under trade name Razadyne as
hydrobromide salt.
The term, “NMDA receptor antagonist” as used herein refers to class of
compounds which act on glutamatergic system by inhibiting the NMDA receptor.
Example of NMDA receptor antagonist is memantine. Memantine is a drug
approved for treatment of moderate to severe dementia of the Alzheimer’s disease.
Memantine is NMDA receptor antagonist and sold under trade name Namenda
and Namenda XR as hydrochloride salt.
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The combination of memantine and donepezil is approved for the treatment
of moderate to severe dementia of the Alzheimer's disease and sold under trade
name Namzaric as memantine hydrochloride salt and donepezil hydrochloride
salt.
The phrase, "therapeutically effective amount" is defined as an amount of a
compound of the present invention that (i) treats the particular disease, condition or
disorder, (ii) eliminates one or more symptoms of the particular disease, condition
or disorder and (iii) delays the onset of one or more symptoms of the particular
disease, condition or disorder described herein.
The term, “pharmaceutically acceptable salt” as used herein refers to salts
of the active compound and are prepared by reaction with the appropriate organic
or inorganic acid or acid derivative, depending on the particular substituents found
on the compounds described herein.
The term, “patient” as used herein refers to an animal. Preferably the term
“patient” refers to mammal. The term mammal includes animals such as mice, rats,
dogs, rabbits, pigs, monkeys, horses and human. More preferably the patient is
human.
The term, “Alzheimer’s disease” as used herein refers to a dementia that
causes problems with memory, thinking and behavior. The Alzheimer’s disease can
be mild to moderate to severe Alzheimer’s disease.
The compound 1 as used herein is N-[4-(l-Cyclobutylpiperidin
yloxy)phenyl](morpholinyl)acetamide dihydrochloride which has the
chemical structure,
. 2 HCl
.
The compound 2 as used herein is N-[4-(1-Cyclopropylpiperidin
yloxy)phenyl](morpholinyl)acetamide tartrate which has the chemical
structure,
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N N HO
. OH
O OH
The compound 3 as used herein is N-[4-(1-Isopropylpiperidin
yloxy)phenyl](morpholinyl)acetamide tartrate which has the chemical
structure,
O OH
O .
The term, "treatment' or 'treating" as used herein refers to any treatment of
a disease in a mammal, including: (a) slowing or arresting the development of
clinical symptoms; and/or (b) causing the regression of clinical symptoms.
The term, "compound for use" as used herein embrace any one or more of
the following: (1) use of a compound, (2) method of use of a compound, (3) use in
the treatment of, (4) the use for the manufacture of pharmaceutical composition /
medicament for treatment / treating or (5) method of treatment / treating /
preventing / reducing / inhibiting comprising administering an effective amount of
the active compound to a subject in need thereof.
The term, “cognitive disorder” as used herein refers to a group of mental
health disorders that principally affect learning, memory, perception and problem
solving and includes amnesia, dementia and delirium. Cognitive disorders can
result due to disease, disorder, ailment or toxicity. Example of cognitive disorders
includes but not limited to, Alzheimer’s disease, schizophrenia, Parkinson’s
disease, lewy body dementia (LBD), vascular dementia, frontotemporal dementia
(FTD), Down syndrome or Tourette’s syndrome. Preferably, the cognitive disorder
is Alzheimer’s disease.
The term, “adjunct” or “adjunctive treatment” as used herein refers to an
additional treatment to a patient who has already received at least one other therapy
for cognitive disorders. A drug used as adjunctive therapy is administered to a
patient to make that primary treatment works better.
Embodiments
James & Wells Ref: 310855NZ
The present invention encompasses all the combinations described herein
without limitation, however, preferred aspects and elements of the invention are
discussed herein in the form of the following embodiments.
In one embodiment, the present invention relates to the combination of
histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist; wherein the histamine-3 receptor inverse agonist is N-[4-(l-
Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride.
In another embodiment, the present invention relates to the combination of
histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist; wherein the histamine-3 receptor inverse agonist is N-[4-(1-
Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide tartrate.
In another embodiment, the present invention relates to the combination of
histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist; wherein the histamine-3 receptor inverse agonist is N-[4-(1-
Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide tartrate.
In another embodiment, the present invention relates to the combination of
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide,
rivastigmine and memantine or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to the combination of
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide,
galantamine and memantine or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to the combination of
N-[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide,
rivastigmine and memantine or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to the combination of
N-[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide,
galantamine and memantine or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to the combination of
N-[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide,
rivastigmine and memantine or a pharmaceutically acceptable salt thereof.
James & Wells Ref: 310855NZ
In another embodiment, the present invention relates to the combination of
N-[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide,
galantamine and memantine or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to the combination of
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride, donepezil hydrochloride and memantine hydrochloride.
In another embodiment, the present invention relates to the combination of
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride, rivastigmine tartrate and memantine hydrochloride.
In another embodiment, the present invention relates to the combination of
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride, galantamine hydrobromide and memantine hydrochloride.
In another embodiment, the present invention relates to the combination of
N-[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide
tartrate, donepezil hydrochloride and memantine hydrochloride.
In another embodiment, the present invention relates to the combination of
N-[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide
tartrate, rivastigmine tartrate and memantine hydrochloride.
In another embodiment, the present invention relates to the combination of
N-[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide
tartrate, galantamine hydrobromide and memantine hydrochloride.
In another embodiment, the present invention relates to the combination of
N-[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide tartrate,
donepezil hydrochloride and memantine hydrochloride.
In another embodiment, the present invention relates to the combination of
N-[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide tartrate,
rivastigmine tartrate and memantine hydrochloride.
In another embodiment, the present invention relates to the combination of
N-[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide tartrate,
galantamine hydrobromide and memantine hydrochloride.
James & Wells Ref: 310855NZ
In another embodiment, the present invention provides the combination of
histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist which is more effective than the combination of histamine-3
receptor inverse agonist and acetylcholinesterase inhibitor, acetylcholinesterase
inhibitor and NMDA receptor antagonist or histamine-3 receptor inverse agonist
and NMDA receptor antagonist.
In another embodiment, the present invention provides the combination of
the histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor and NMDA
receptor antagonist which is more effective than the histamine-3 receptor inverse
agonist, acetylcholinesterase inhibitor and NMDA receptor antagonist alone.
In another embodiment, the present invention provides the combination of
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride, donepezil hydrochloride and memantine hydrochloride which is
more effective than the combination of N-[4-(l-Cyclobutylpiperidin
yloxy)phenyl](morpholinyl)acetamide dihydrochloride and donepezil
hydrochloride, donepezil hydrochloride and memantine hydrochloride or N-[4-(l-
Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride and memantine hydrochloride.
In another embodiment, the present invention provides the combination of
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride, donepezil hydrochloride and memantine hydrochloride which is
more effective than N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholin
yl)acetamide dihydrochloride, donepezil hydrochloride and memantine
hydrochloride alone.
In another embodiment the pharmaceutically acceptable salt of histamine-3
receptor inverse agonist includes but not limited to, dihydrochloride salt, oxalate
salt, succinate, tartrate salt and the like. Preferably, the pharmaceutically acceptable
salt is dihydrochloride salt and tartrate salts. More preferably, the pharmaceutically
acceptable salt is dihydrochloride salt.
James & Wells Ref: 310855NZ
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of the said combination.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(l-Cyclobutylpiperidinyloxy)phenyl]-
2-(morpholinyl)acetamide or a pharmaceutically acceptable salt thereof,
acetylcholinesterase inhibitor and NMDA receptor antagonist.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(1-Cyclopropylpiperidin
yloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt
thereof, acetylcholinesterase inhibitor and NMDA receptor antagonist.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(1-Isopropylpiperidinyloxy)phenyl]
(morpholinyl)acetamide or a pharmaceutically acceptable salt thereof,
acetylcholinesterase inhibitor and NMDA receptor antagonist.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(l-Cyclobutylpiperidinyloxy)phenyl]-
2-(morpholinyl)acetamide or a pharmaceutically acceptable salt thereof in
combination with acetylcholinesterase inhibitor and NMDA receptor antagonist.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(1-Cyclopropylpiperidin
yloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt
thereof in combination with acetylcholinesterase inhibitor and NMDA receptor
antagonist.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
James & Wells Ref: 310855NZ
therapeutically effective amount of N-[4-(1-Isopropylpiperidinyloxy)phenyl]
(morpholinyl)acetamide or a pharmaceutically acceptable salt thereof in
combination with acetylcholinesterase inhibitor and NMDA receptor antagonist.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(l-Cyclobutylpiperidinyloxy)phenyl]-
2-(morpholinyl)acetamide dihydrochloride in combination with
acetylcholinesterase inhibitor and NMDA receptor antagonist.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(1-Cyclopropylpiperidin
yloxy)phenyl](morpholinyl)acetamide tartrate in combination with
acetylcholinesterase inhibitor and NMDA receptor antagonist.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(1-Isopropylpiperidinyloxy)phenyl]
(morpholinyl)acetamide tartrate in combination with acetylcholinesterase
inhibitor and NMDA receptor antagonist.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(l-Cyclobutylpiperidinyloxy)phenyl]-
2-(morpholinyl)acetamide dihydrochloride in combination with donepezil or a
pharmaceutically acceptable salt thereof and memantine or a pharmaceutically
acceptable salt thereof.
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of N-[4-(l-Cyclobutylpiperidinyloxy)phenyl]-
2-(morpholinyl)acetamide dihydrochloride in combination with donepezil
hydrochloride and memantine hydrochloride.
In another embodiment, the present invention relates to the combination of
N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
James & Wells Ref: 310855NZ
dihydrochloride, acetylcholinesterase inhibitor and NMDA receptor antagonist for
use in the treatment of Alzheimer’s disease.
In yet another aspect, the present invention relates to N-[4-(l-
Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide or a
pharmaceutically acceptable salt thereof for use in the adjunct treatment of
Alzheimer’s disease in a patient on treatment with acetylcholinesterase inhibitor
and NMDA receptor antagonist.
In yet another aspect, the present invention relates to N-[4-(1-
Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide or a
pharmaceutically acceptable salt thereof for use in the adjunct treatment of
Alzheimer’s disease in a patient on treatment with acetylcholinesterase inhibitor
and NMDA receptor antagonist.
In yet another aspect, the present invention relates to N-[4-(1-
Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide or a
pharmaceutically acceptable salt thereof for use in the adjunct treatment of
Alzheimer’s disease in a patient on treatment with acetylcholinesterase inhibitor
and NMDA receptor antagonist.
In another embodiment, the present invention relates to N-[4-(l-
Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride for use in the adjunct treatment of Alzheimer’s disease in a patient
on treatment with donepezil and memantine or a pharmaceutically acceptable salt
thereof.
In another embodiment, the present invention relates to N-[4-(1-
Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide tartrate for
use in the adjunct treatment of Alzheimer’s disease in a patient on treatment with
donepezil and memantine or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to N-[4-(1-Isopropyl
piperidinyloxy)phenyl](morpholinyl)acetamide tartrate for use in the
adjunct treatment of Alzheimer’s disease in a patient on treatment with donepezil
and memantine or a pharmaceutically acceptable salt thereof.
James & Wells Ref: 310855NZ
In another embodiment, the present invention relates to use of the
combination of histamine-3 receptor inverse agonist, acetylcholinesterase inhibitor
and NMDA receptor antagonist in the manufacture of a medicament for treatment
of Alzheimer’s disease.
In another embodiment, the present invention relates to use of histamine-3
receptor inverse agonist in the manufacture of a medicament for treatment of
Alzheimer’s disease in combination with acetylcholinesterase inhibitor and NMDA
receptor antagonist.
In another embodiment, the present invention relates to use of histamine-3
receptor inverse agonist in the manufacture of a medicament for treatment of
Alzheimer’s disease as adjunct to acetylcholinesterase inhibitor and NMDA
receptor antagonist.
In another embodiment, the present invention relates to use of the N-[4-(l-
Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for
the treatment of Alzheimer’s disease in combination with donepezil or a
pharmaceutically acceptable salt thereof and memantine or a pharmaceutically
acceptable salt thereof.
In another embodiment, the present invention relates to use of the N-[4-(l-
Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride in the manufacture of a medicament for treatment of Alzheimer’s
disease in combination with donepezil or a pharmaceutically acceptable salt thereof
and memantine or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to use of N-[4-(l-
Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide
dihydrochloride in the manufacture of a medicament for treatment of Alzheimer’s
disease in combination with donepezil hydrochloride and memantine
hydrochloride.
In another embodiment, the present invention relates to histamine-3 receptor
inverse agonist for use in the treatment of Alzheimer’s disease in combination with
Namzaric .
James & Wells Ref: 310855NZ
In another embodiment, the present invention relates to a method of treating
Alzheimer’s disease comprising administering to a patient in need thereof a
therapeutically effective amount of histamine-3 receptor inverse agonist in
combination with Namzaric .
In another embodiment, the present invention relates to the combination for
treatment of Alzheimer’s disease, wherein Alzheimer’s disease is mild Alzheimer’s
disease.
In another embodiment, the present invention relates to the combination for
treatment of Alzheimer’s disease, wherein the Alzheimer’s disease is moderate
Alzheimer’s disease.
In another embodiment, the present invention relates to the combination for
treatment of Alzheimer’s disease, wherein the Alzheimer’s disease is severe
Alzheimer’s disease.
In another embodiment, the present invention relates to the combination
wherein the active ingredients can be administered to a patient concurrently or
separately.
In yet another aspect, the active ingredients of the combination of the
present invention are normally administered by formulating the active ingredients
into a pharmaceutical composition in accordance with standard pharmaceutical
practice.
In yet another aspect, the active ingredients of the combination of the
present invention may be administered by oral, nasal, local, dermal or parenteral
routes.
In yet another aspect, the active ingredients of the combination of the
present invention can be administered by the same or different route of
administration. For instance, the histamine-3 receptor inverse agonist of the instant
invention can be administered orally, the acetylcholinesterase inhibitor can be
administered transdermally and the NMDA receptor antagonist can be administered
locally.
The pharmaceutical compositions of the present invention may be
formulated in a conventional manner using one or more pharmaceutically
James & Wells Ref: 310855NZ
acceptable excipients. The pharmaceutically acceptable excipients are diluents,
disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, co-
solvents, preservatives, wetting agents, thickening agents, antifoaming agents,
sweetening agents, flavouring agents, antioxidants, colorants, solubilizers,
plasticizer, dispersing agents and the like. Excipients are selected from
microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sodium starch
glycolate, corn starch or derivatives thereof, povidone, crospovidone, calcium
stearate, glyceryl monostearate, glyceryl palmitostearate, talc, colloidal silicone
dioxide, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc
stearate, stearic acid or hydrogenated vegetable oil, gum arabica, magnesia,
glucose, fats, waxes, natural or hardened oils, water, physiological sodium chloride
solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions,
such as glucose solutions or mannitol solutions and the like or a mixture of the
various excipients.
In yet another aspect, the active compounds of the invention may be
formulated in the form of pills, tablets, coated tablets, capsules, powder, granules,
pellets, patches, implants, films, liquids, semi-solids, gels, aerosols, emulsions,
elixirs and the like. Such pharmaceutical compositions and processes for preparing
same are well known in the art.
In yet another aspect, the pharmaceutical composition of the instant
invention contains 1 to 90 %, 5 to 75 % and 10 to 60 % by weight of the compounds
of the instant invention or pharmaceutically acceptable salt thereof. The amount of
the active compounds or its pharmaceutically acceptable salt in the pharmaceutical
composition(s) can range from about 0.1 mg to about 100 mg or from about 0.1 mg
to about 60 mg or from about 0.1 mg to about 30 mg or in any range falling within
the broader range of 0.1 mg to 100 mg.
In yet another aspect, the pharmaceutical composition of the combination of
the instant invention can be conventional formulations such as immediate release
formulations, modified release formulations such as sustained release formulations,
delayed release formulations and extended release formulations or new delivery
systems such as oral disintegrating formulations and transdermal patches.
James & Wells Ref: 310855NZ
The dose of the active compounds can vary depending on factors such as
age and weight of patient, nature, route of administration and severity of the disease
to be treated and such other factors. Therefore, any reference regarding
pharmacologically effective amount of the compounds 1, 2 and 3 refers to the
aforementioned factors.
In yet another aspect, the histamine-3 receptor inverse agonist can be co-
administered with acetylcholinesterase inhibitor and NMDA receptor antagonist at
a daily dose of 0.1 mg to 100 mg; such as 0.1, 0.5, 0.75, 1, 1.5, 3, 5, 6, 10, 20, 25,
, 50, 75 and 100 mg, preferably at a daily dose of 0.1, 3, 5, 6, 10, 20, 25, 30 or 50
mg and most preferably at a daily dose of 0.5, 3, 5, 10 or 20 mg.
In yet another aspect, the acetylcholinesterase inhibitor can be co-
administered with histamine-3 receptor inverse agonist and NMDA receptor
antagonist at a daily dose of 1 mg to 30 mg; such as 1, 1.5, 2, 3, 4, 4.5, 5, 6, 8,
9.5,10, 12, 13, 13.3, 15, 16, 23, 24, 25 or 30 mg, preferably at a daily dose of 1, 1.5,
2, 3, 4, 4.5, 5, 6, 8, 9.5, 10, 12, 13, 13.3, 16, 23, 24, or 25 mg and most preferably
at a daily dose of 1.5, 3, 4, 4.5, 5, 6, 8, 9.5, 10, 12, 13.3, 16, 23 or 24 mg.
In yet another aspect, the NMDA receptor antagonist, memantine can be co-
administered with histamine-3 receptor inverse agonist and acetylcholinesterase
inhibitor at a daily dose of 1 mg to 40 mg; such as 5, 7, 10, 14, 20, 28 or 40 mg,
preferably at a daily dose of 5, 7, 10, 14, 20 or 28 mg and most preferably at a daily
dose of 5, 10, 14, 20 or 28 mg.
In yet another aspect, the acetylcholinesterase inhibitor, donepezil can be
co-administered with histamine-3 receptor inverse agonist and NMDA receptor
antagonist at a daily dose of 2 mg to 30 mg; such as 2, 5, 10, 15, 23, 25 or 30 mg,
preferably at a daily dose of 2, 5, 10, 23 or 25 mg and most preferably at a daily
dose of 5, 10 or 23 mg.
In yet another aspect, the acetylcholinesterase inhibitor, rivastigmine can be
co-administered with histamine-3 receptor inverse agonist and NMDA receptor
antagonist at a daily dose of 0.5 mg to 15 mg; such as 1, 1.5, 3, 4.5, 5, 6, 9.5, 10 or
13.3 mg, preferably at a daily dose of 1, 1.5, 3, 4.5, 5, 6, 9.5 or 13.3 mg and most
preferably at a daily dose of 1.5, 3, 4.5, 6, 9.5 and 13.3 mg.
James & Wells Ref: 310855NZ
In yet another aspect, the acetylcholinesterase inhibitor, galantamine can be
co-administered with histamine-3 receptor inverse agonist and NMDA receptor
antagonist at a daily dose of 1 mg to 30 mg; such as 1, 2, 4, 6, 8, 12, 16, 24 and 30
mg, preferably at a daily dose of 2, 4, 6, 8, 12, 16 and 24 mg and most preferably at
a daily dose of 4, 8, 12, 16 and 24 mg.
In yet another aspect, the treatment comprises administering to the patient
0.1 mg to 100 mg of N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholin
yl)acetamide or a pharmaceutically acceptable salt thereof, per day.
In yet another aspect, the treatment comprises administering to the patient
0.1 mg to 60 mg of N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholin
yl)acetamide or a pharmaceutically acceptable salt thereof, per day.
In yet another aspect, the treatment comprises administering to the patient
0.1 mg to 30 mg of N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholin
yl)acetamide or a pharmaceutically acceptable salt thereof, per day.
In yet another aspect, the treatment comprises administering to the patient 1
mg to 25 mg of donepezil or a pharmaceutically acceptable salt thereof, per day.
In yet another aspect, the treatment comprises administering to the patient 5
mg to 25 mg of donepezil or a pharmaceutically acceptable salt thereof, per day.
In yet another aspect, the treatment comprises administering to the patient,
5, 10 or 23 mg of donepezil or a pharmaceutically acceptable salt thereof, per day.
In yet another aspect, the treatment comprises administering to the patient 1
mg to 40 mg of memantine or a pharmaceutically acceptable salt thereof, per day.
In yet another aspect, the treatment comprises administering to the patient 5
mg to 30 mg of memantine or a pharmaceutically acceptable salt thereof, per day.
In yet another aspect, the treatment comprises administering to the patient
, 10, 14, 20 or 28 mg of memantine or a pharmaceutically acceptable salt thereof,
per day.
In yet another aspect, the treatment comprises administering the active
compounds to the patient one to three times per day, one to three times per week or
one to three times per month. Preferably, the treatment comprises administering the
James & Wells Ref: 310855NZ
compound to a patient once a day, twice a day, or thrice a day. More preferably, the
treatment comprises administering the compound to a patient once a day.
Examples
The examples given below are provided by the way of illustration only and
therefore should not be construed to limit the scope of the invention.
Abbreviations:
ANOVA : Analysis of variance
AP : Anterior Posterior
aCSF : Artificial Cerebrospinal fluid
CaCl . 2H O : Calcium chloride dihydrate
DV : Dorsal Ventral
DTT : Dithiothreitol
EC : Half maximal effective concentration
EDTA : Ethylenediaminetetraacetic acid
EEG : Electroencephalogram
GDP : Guanosine diphosphate
GPCR : G-Protein Coupled Receptor
HCl : Hydrochloric acid
h : Hour (s)
HEPES : 4-(2-Hydroxyethyl)piperazineethanesulfonic acid
i.p. : Intraperitoneal
i.v. : Intravenous
KCl : Potassium chloride
K : Binding constant
K : Inhibitory constant
LC-MS/MS : Liquid chromatography-Mass spectrometry/ Mass
spectrometry
mg : Milligram
MgCl : Magnesium chloride
min : Minute (s)
James & Wells Ref: 310855NZ
ML : Medial Lateral
mM : Millimolar
nmol/L : Nanomoles per litre
NaCl : Sodium chloride
NaH PO .2H O : Sodium dihydrogen phosphate dihydrate
2 4 2
Na HPO .7H O : Sodium monohydrogen phosphate heptahydrate
2 4 2
NPO : Nucleus Pontis Oralis
nM : Nanomolar
p.o. : Per oral
s.c. : Subcutaneous
S.E.M. : Standard error of the mean
µM : Micromolar
? : Theta
Example 1: Determination of K value at human and rat histamine-3 receptor
Test compounds were evaluated according to the following procedures to
determine the K value at human and rat histamine-3 receptor.
Materials and Methods:
Receptor source: Rat brain frontal cortex or recombinant human cDNA expressed
in CHO cells
Radioligand: [3H] R-a-methylhistamine
Final ligand concentration: [3.0 nM]
Non-specific determinant: R-a-methylhistamine (100 µM)
Reference compound: R-a-methylhistamine
Positive control: R-a-methylhistamine
Incubation conditions:
Increasing concentrations of test compounds or standard were incubated
with membrane receptors and radioligand in 5 mM MgCl and 50 mM TRIS-HCl
(pH 7.4) for 60 minutes at room temperature. The reaction was terminated by rapid
vacuum filtration onto the glass fiber filters. Radioactivity trapped onto the filters
was determined and compared to the control values in order to ascertain any
James & Wells Ref: 310855NZ
interactions of the test compound(s) with either cloned human or rat receptor
binding site.
Results:
Human histamine-3 Rat histamine-3
S. No Example receptor receptor
K (nM) K (nM)
1 Compound 1 8.7 9.8
2 Compound 2 19.9 ND
3 Compound 3 8.3 ND
ND-Not done
Reference:
Br J Pharmacol., 2008, 154(6): 1166–1181.
Example 2: Determination of IC50 values at histamine-3 receptor
Test compounds were evaluated according to the following procedures to
determine the IC values.
Materials and Methods:
Receptor source: Human recombinant (CHO-K1 cells)
Radioligand: [35S]-GTP?S
Final ligand concentration: [0.3 nM]
Reference compound: Thioperamide
Positive control: Thioperamide
Incubation conditions:
Increasing concentrations of test compounds and/or vehicle is pre-incubated
with the membranes (0.09 mg/mL) and 10 µM GDP in modified HEPES pH 7.4
buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl , 1 mM DTT, 1 mM
EDTA) for 20 minutes and SPA beads are then added for another 60 minutes at
°C. The reaction is initiated by 0.3 nM [ S]GTP?S for an additional 30 minutes
incubation period. Test compound-induced increase of [ S]GTP?S binding by 50
percent or more (=50 %) relative to the 3 µM R(-)-a-methylhistamine response
indicates possible histamine-3 receptor agonist activity. Test compound induced
inhibition of 0.03 µM R(-)-a-methylhistamine-induced increase of [ S]GTP?S
binding response by 50 percent or more (=50 %) indicates receptor antagonist
James & Wells Ref: 310855NZ
activity. These studies were conducted and the data were analyzed at Eurofins
Panlabs Taiwan Ltd, Taiwan using standard radioligand binding techniques as
described above.
Results:
Compound 1 exhibits inverse agonist like properties in GTP?S assay on
human recombinant histamine-3 receptor with IC value of 20 nM.
Reference:
J. Neurochem., 1998, 71(2): 808-816.
Example 3: Object Recognition Task Model
The cognition enhancing properties of compounds of this invention were
estimated by using this model.
Male Wistar rats (8-10 weeks old) were used as experimental animals. Four
animals were housed in each cage. Animals were kept on 20 % food deprivation
from a day prior to experimentation. Water was provided ad libitum throughout the
experiment. Animals were maintained on a 12 hours light/dark cycle in temperature
and humidity controlled room. The experiment was carried out in an open field
made up of acrylic. Rats were habituated to individual arenas (open field) in the
absence of any objects on day 1.
Rats received vehicle, donepezil and memantine or test compound,
donepezil and memantine on the day of habituation, before familiar (T ) and choice
(T ) trials. During the familiarization phase (T ), the rats were placed individually
in the arena for 3 minutes, in which two identical objects (a and a ) were positioned
cm from the wall. 24 hours after T , trial for long-term memory test was assessed.
The same rats were placed in the same arena as they were placed in T trial. During
the choice phase (T ) rats were allowed to explore the arena for 3 minutes in
presence of a copy of familiar object (a ) and one novel object (b). During the T
and T trial, explorations of each object (defined as sniffing, licking, chewing or
having moving vibrissae whilst directing the nose towards the object at a distance
of less than 1 cm) were recorded using stopwatch.
T is the total time spent exploring the familiar objects (a + a ).
1 1 2
James & Wells Ref: 310855NZ
T is the total time spent exploring the familiar object and novel object (a
+b).
Discriminative index is ratio of time spent exploring the novel object
divided by sum of time spent exploring the novel object and familiar object in
choice trial (T ).
The object recognition test was performed as described in Behavioural
Brain Research, 1988, 31, 47-59.
Results:
Vehicle treated animals spent almost equal time exploring the novel and the
familiar objects. The groups treated with combination of test compound, donepezil
and memantine spent significantly more time exploring the novel object. No
significant increase in discriminative index was observed in the group treated with
donepezil and memantine when compared to the vehicle treatment. However the
group co-treated with test compounds, donepezil and memantine showed
significant improvement in the memory end point (discriminative index). This
procognitive effect suggests a potentiating effect of test compounds over the
procognitive effect of donepezil and memantine. The results of this study are
provided in figure 1a and 1b.
Example 4: Evaluation of acetylcholine modulation in medial prefrontal cortex
of male Wistar rats
Neurotransmitter modulating effects of triple combination were evaluated
by this model.
Male Wistar rats (240-300 g body weight) were stereotaxically implanted
with a microdialysis guide cannula in medial prefrontal cortex (mPFC; AP: +3.2
mm, ML: -0.5 mm, DV: -3.0 mm) under isoflurane anesthesia. Co-ordinates were
taken according to atlas for the rat brain (Paxinos and Watson, 2004) with reference
points taken from bregma and vertical from the skull. The rats were allowed to
recover individually for four days in a round bottom Plexiglas bowl with free access
to feed and water.
James & Wells Ref: 310855NZ
After surgical recovery of 4 days, male Wistar rats were connected to dual
quartz lined two-channel liquid swivel (Instech, UK) on a counter balance lever
arm, which allowed unrestricted movements of the animal. Sixteen hours before
start of the study, a pre-equilibrated microdialysis probe (2 mm dialysis membrane)
was inserted into mPFC through the guide cannula. On the day of study, probe was
perfused with artificial cerebrospinal fluid (aCSF; NaCl 147 mM, KCl 2.7 mM,
MgCl 1 mM, CaCl . 2H O 1.2 mM, pH 7.4) at a flow rate of 1.5 µL/min and a
2 2 2
stabilization period of 2 hours was maintained. Five basal samples were collected
at 20 min intervals prior to the treatment of test compounds (3 or 10 mg/kg, p.o.) or
vehicle. Donepezil (1 mg/kg, s.c.) and memantine (1 mg/kg, s.c.) were administered
min after administration of test compounds. Dialysate samples were collected
for an additional period of 4 h post treatment of test compounds. Dialysates were
stored below -50°C prior to analysis.
Quantitation of acetylcholine:
Acetylcholine concentrations in dialysates were quantified using LC-
MS/MS based method.
Statistical analysis:
All microdialysis data for acetylcholine was plotted as percent change from
mean dialysate basal concentrations with 100 % defined as the average of five pre-
dose values. The percent change in acetylcholine levels were compared with
donepezil and memantine combination using two-way analysis of variance (time
and treatment), followed by Bonferroni’s posttest. Area under the curve (AUC)
values for percent change in acetylcholine levels was calculated and the statistical
significance between the mean AUC values was compared against donepezil and
memantine treatment using unpaired “t” test. Statistical significance was considered
at a p value less than 0.05. Incorrect probe placement was considered as criteria to
reject the data from animal.
Reference:
1. Paxinos G. and Watson C. (2004) Rat brain in stereotaxic coordinates.
Academic Press, New York.
Results:
James & Wells Ref: 310855NZ
Compound 1
Treatment with donepezil and memantine produced increase in
acetylcholine levels to the maximum of 1726 ± 297 % of basal levels. The increase
in acetylcholine after combination of compound 1, donepezil and memantine was
significantly higher compared to donepezil and memantine combination. Mean
maximum increase in acetylcholine was observed to be 2968 ± 585 of pre-dose
levels after triple combination (Figure 2(a)).
Mean area under the curve values (AUC) calculated after the treatment of
compound 1, donepezil and memantine were significantly higher compared to
donepezil and memantine combination (Figure 2(b)).
Compound 2
Treatment with donepezil and memantine produced increase in
acetylcholine levels to the maximum of 1365 ± 249 % of basal levels. The increase
in acetylcholine after combination of compound 2, donepezil and memantine was
significantly higher compared to donepezil and memantine combination. Mean
maximum increase in acetylcholine was observed to be 2696 ± 504 % of pre-dose
levels after triple combination (Figure 3(a)).
Mean area under the curve values (AUC) calculated after treatment of
compound 2, donepezil and memantine were significantly higher compared to
donepezil and memantine combination (Figure 3(b)).
Compound 3
Treatment with donepezil and memantine produced increase in
acetylcholine levels to the maximum of 1375 ± 461 % of basal levels. The increase
in acetylcholine after combination of compound 3, donepezil and memantine was
significantly higher compared to donepezil and memantine combination. Mean
maximum increase in acetylcholine was observed to be 2674 ± 271 of pre-dose
levels after triple combination (Figure 4(a)).
Mean area under the curve values (AUC) calculated after treatment of
compound 3, donepezil and memantine were significantly higher compared to
donepezil and memantine combination (Figure 4(b)).
James & Wells Ref: 310855NZ
Example 5: Evaluation of theta modulation in dorsal hippocampus of
anesthetized male Wistar rats
Effect of triple combination on brain activity as a pharmacodynamic
endpoint is evaluated using this model.
Male Wistar rats (240-320 g) were anesthetized by intraperitoneal
administration of urethane (1.2 to 1.5 g/kg) for implantation of a catheter in the left
femoral vein. The animal was placed in a stereotaxic frame for implanting an
electrode (stainless steel wire, Plastics One) into the dorsal hippocampus (AP: –3.8
mm; ML: +2.2 mm; DV: –2.5 mm; Paxinos and Watson, 2004). Bipolar stimulating
electrode (untwisted stainless steel wires, separated by 0.75–1.0 mm at their tips,
Plastics One) was implanted in the Nucleus Pontis Oralis (NPO; AP: –7.8 mm; ML:
1.8 mm; DV: –6.0 mm; Paxinos and Watson, 2004). Additionally one electrode was
implanted into the cerebellum which served as a reference. Hippocampal ? rhythm
was evoked via a 6-s electrical stimulation train (20-160 µA, 0.3-ms pulse duration,
250 Hz) delivered to the NPO at a rate of 0.01 trains/s with a Grass S88 stimulator
and PSIU6 stimulus isolation unit (Grass Medical Instruments, Quincy, MA). EEG
was recorded at a rate of 1000 Hz using Ponemah (Version 5.2) software and stored
for off-line analysis using NeuroScore (Version 3.0). Baseline amplitude level was
achieved by using the current required to elicit ? rhythm to 50% of the maximal
amplitude under control conditions. After the stabilization period of one hour,
baseline recording was done for 30 min followed by the treatment of vehicle or
compound 1 (1 mg/kg, i.v.). Donepezil (0.3 mg/kg, i.v.) and memantine (0.3 mg/kg,
i.v.) was administered 30 min after compound 1 treatment and recording was
continued for additional 1 hour.
Statistical analysis:
Power in the ? rhythm frequency in the stimulation period during the 30-
min baseline period was calculated and the % changes in these measures post
treatment were calculated. The percent change in relative theta power after triple
combination of Compound 1, donepezil and memantine was compared with
donepezil and memantine using two-way analysis of variance (time and treatment),
James & Wells Ref: 310855NZ
followed by Bonferroni’s posttest. Statistical significance was considered at a p
value less than 0.05.
Reference:
1. Paxinos G. and Watson C. (2004) Rat brain in stereotaxic coordinates. Academic
Press, New York.
Results:
Treatment with donepezil and memantine combination produced moderate
increase in hippocampal ? power. Compound 1 in combination with donepezil and
memantine produced significant increase in ? power levels and peak levels reached
up to 167 ± 11 % of pre-dose levels. The effect in triple combination was observed
to be significantly higher than the combination of donepezil and memantine (Figure
(a)).
Mean area under the curve values (AUC) calculated after the treatment of
compound 1, donepezil and memantine were significantly higher compared to
donepezil and memantine combination (Figure 5(b)).
Claims (34)
1. A combination consisting of a histamine-3 receptor inverse agonists, an acetylcholinesterase inhibitor and a NMDA receptor antagonist; wherein the histamine-3 receptor inverse agonist is selected from N-[4-(l-Cyclobutylpiperidin yloxy)phenyl](morpholinyl)acetamide; N-[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide; and N-[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide; or a pharmaceutically acceptable salt thereof.
2. The combination as claimed in claim 1, wherein the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine and galantamine or a pharmaceutically acceptable salt thereof.
3. The combination as claimed in claim 1, wherein the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt thereof.
4. The combination as claimed in claim 1, wherein the histamine-3 receptor inverse agonist is N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt thereof.
5. The combination as claimed in claim 1 or claim 4, wherein the pharmaceutically acceptable salt of the histamine-3 receptorinverse agonist is, N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholin yl)acetamidedihydrochloride; N-[4-(1-Cyclopropylpiperidinyloxy)phenyl](morpholinyl)acetamide tartrate; N-[4-(1-Isopropylpiperidinyloxy)phenyl](morpholinyl)acetamide tartrate.
6. The combination as claimed in claim 1, 4 or 5, wherein the histamine-3 receptor inverse agonist is N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholin yl)acetamide dihydrochloride.
7. The combination as claimed in claim 1 or claim 2, wherein the acetylcholinesterase inhibitor is donepezil or a pharmaceutically acceptable salt thereof.
8. The combination as claimed in claim 1, 2or 7, wherein the acetylcholinesterase inhibitor is donepezil hydrochloride.
9. The combination as claimed in claim 1 or claim 3, wherein the NMDA receptor antagonist is memantine hydrochloride.
10. A combination comprising N-[4-(l-Cyclobutylpiperidinyloxy)phenyl] (morpholinyl)acetamide dihydrochloride, donepezil hydrochloride and memantine hydrochloride.
11. The combination as claimed in any one of claims 1 to 10, for use in the treatment of cognitive disorders in a patient.
12. The combination for use as claimed in claim 11, wherein the cognitive disorder is selected from Alzheimer’s disease, schizophrenia, Parkinson’s disease, Lewy body dementia, vascular dementia, frontotemporal dementia, Down syndrome and Tourette’s syndrome.
13. Use of a therapeutically effective amount of the combination as claimed in any one of claims 1 to 10, in the manufacture of a medicament for treating cognitive disorder in a patient.
14. The use as claimed in 13, wherein the cognitive disorder is selected from Alzheimer’s disease, schizophrenia, Parkinson’s disease, Lewy body dementia, vascular dementia, frontotemporal dementia, Down syndrome andTourette’s syndrome.
15. Use of a therapeutically effective amount of compound, N-[4-(l- Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamideor a pharmaceutically acceptable salt thereof in combination with acetylcholinesterase inhibitor and NMDA receptor antagonist, in the manufacture of a medicament for the treatment of Alzheimer’s disease in a patient.
16. The use as claimed in the claim 15, wherein the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine and galantamine or a pharmaceutically acceptable salt thereof.
17. The use as claimed in the claim 15, wherein the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt thereof.
18. Use of a therapeutically effective amount of N-[4-(l-Cyclobutylpiperidin yloxy)phenyl](morpholinyl)acetamideor or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating Alzheimer’s disease in a patient on stable treatment with acetylcholinesterase inhibitor and NMDA receptor antagonist.
19. The use as claimed in claim 18, wherein the acetylcholinesterase inhibitor is donepezil, rivastigmine and galantamine or a pharmaceutically acceptable salt thereof.
20. The use as claimed in claim 18, wherein the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt thereof.
21. The use as claimed in claim 18, wherein the medicament is formulated for administration to a patient at a dose of 0.1 mg to 100 mg of N-[4-(l- Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt thereof per day.
22. The use as claimed in claim 18, wherein the medicament is formulated for administration to a patient at a dose of 0.1 mg to 60 mg of N-[4-(l-Cyclobutylpiperidin- 4-yloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt thereof per day.
23. The use as claimed in claim 18, wherein the medicament is formulated for administration to a patient at a dose of 0.1 mg to 30 mg of N-[4-(l-Cyclobutylpiperidin- 4-yloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt thereof per day.
24. The use as claimed in claim 18, wherein the medicament is formulated for administration to a patient at a dose of 1 mg to 30 mg of donepezil or a pharmaceutically acceptable salt thereof per day.
25. The use as claimed in claim 18, wherein the medicament is formulated for administration to a patient at a dose of 1 mg to 40 mg of memantine or a pharmaceutically acceptable salt thereof per day.
26. A pharmaceutical composition comprising the combination as claimed in any one of claims 1 to 10, and pharmaceutically acceptable excipients or combination thereof.
27. The pharmaceutical composition as claimed in claim 26, for use in the treatment of cognitive disorders selected from Alzheimer’s disease, schizophrenia, Parkinson’s disease, Lewy body dementia, vascular dementia and frontotemporal dementia.
28. The pharmaceutical composition as claimed in claim 26 or claim 27, wherein the N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt thereof is present in an amount of 0.1 mg to 100 mg.
29. The pharmaceutical composition as claimed in claim 26 or claim 27, wherein the N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt thereof is present in an amount of 0.1 mg to 60 mg.
30. The pharmaceutical composition as claimed in claim 26 or claim 27, wherein the N-[4-(l-Cyclobutylpiperidinyloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt thereof is present in an amount of 0.1 mg to 30 mg.
31. The pharmaceutical composition as claimed in claim 26 or claim 27, wherein the donepezil or a pharmaceutically acceptable salt thereof is present in an amount of 2 mg to 30 mg.
32. The pharmaceutical composition as claimed in claim 26 or claim 27, wherein the memantine or a pharmaceutically acceptable salt thereof is present in an amount of 1 mg to 40 mg.
33. The use as claimed in claim 18, wherein the N-[4-(l-Cyclobutylpiperidin yloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt thereof is formulated for administration to the patient by oral, nasal, local, dermal or parenteral routes.
34. The use as claimed in claim 18, wherein the N-[4-(l-Cyclobutylpiperidin yloxy)phenyl](morpholinyl)acetamide or a pharmaceutically acceptable salt thereof is formulated for administration to the patient one to three times per day, one to three times per week or one to three times per month.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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IN201641028165 | 2016-08-18 | ||
IN201641028165 | 2016-08-18 | ||
PCT/IB2017/054939 WO2018033848A1 (en) | 2016-08-18 | 2017-08-14 | Triple combination of histamine-3 receptor inverse agonists, acetylcholinesterase inhibitors and nmda receptor antagonist |
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NZ750121A NZ750121A (en) | 2020-09-25 |
NZ750121B2 true NZ750121B2 (en) | 2021-01-06 |
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