U.S. patent application number 16/090142 was filed with the patent office on 2020-01-23 for novel compositions and methods.
This patent application is currently assigned to INTRA-CELLULAR THERAPIES, INC.. The applicant listed for this patent is INTRA-CELLULAR THERAPIES, INC.. Invention is credited to Lawrence P. WENNOGLE.
Application Number | 20200022981 16/090142 |
Document ID | / |
Family ID | 59966433 |
Filed Date | 2020-01-23 |
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United States Patent
Application |
20200022981 |
Kind Code |
A9 |
WENNOGLE; Lawrence P. |
January 23, 2020 |
NOVEL COMPOSITIONS AND METHODS
Abstract
The invention provides methods for the prophylaxis or treatment
of one or more disorders associated with dementia comprising
administering to a patient in need thereof, a therapeutically
effective amount of (i) a 5-HT2A or 5-HT2A/D2 receptor ligand and
(ii) a PDE1 inhibitor, and pharmaceutical compositions comprising
(i) a 5-HT2A or 5-HT2A/D2 receptor ligand and (ii) a PDE1
inhibitor.
Inventors: |
WENNOGLE; Lawrence P.;
(Hillsborough, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INTRA-CELLULAR THERAPIES, INC. |
New York |
NY |
US |
|
|
Assignee: |
INTRA-CELLULAR THERAPIES,
INC.
New York
NY
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20190117658 A1 |
April 25, 2019 |
|
|
Family ID: |
59966433 |
Appl. No.: |
16/090142 |
Filed: |
March 28, 2017 |
PCT Filed: |
March 28, 2017 |
PCT NO: |
PCT/US17/24575 PCKC 00 |
371 Date: |
September 28, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62314314 |
Mar 28, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/519 20130101;
A61K 45/06 20130101; A61P 25/28 20180101; A61K 31/5383 20130101;
A61P 25/16 20180101; A61K 31/4985 20130101; A61P 25/18 20180101;
A61K 31/4985 20130101; A61K 2300/00 20130101; A61K 31/519 20130101;
A61K 2300/00 20130101; A61K 31/5383 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 31/4985 20060101 A61K031/4985 |
Claims
1. A method for the prophylaxis or treatment of one or more
disorders associated with dementia comprising administering to a
patient in need thereof, a therapeutically effective amount of (i)
a 5-HT2A or 5-HT2A/D2 receptor ligand and (ii) a PDE1
inhibitor.
2. The method of claim 1, wherein the 5-HT2A or 5-HT2A/D2 receptor
ligand is a compound of Formula I: ##STR00023## wherein: X is
--N(H)--, --N(CH.sub.3)-- or --O--; Y is --C(.dbd.O), --C(H)(OH) or
--C(H)(OR.sub.1); R.sub.1 is --C(O)--C.sub.1-21alkyl, optionally
saturated or unsaturated and optionally substituted with one or
more hydroxy or C.sub.1-22alkoxy, wherein such compound hydrolyzes
to form the residue of a natural or unnatural, saturated or
unsaturated fatty acid, in free, pharmaceutically acceptable salt
or prodrug form.
3. The method of claim 1 wherein the PDE1 inhibitor is a compound
according to Formula II ##STR00024## wherein R.sub.2 is H and
R.sub.3 and R.sub.4 together form a tri- or tetra-methylene bridge;
or R.sub.2 and R.sub.3 are each methyl and R.sub.4 is H; or R.sub.2
and R.sub.4 are H and R.sub.3 is isopropyl; R.sub.6 is optionally
halo-subsitututed phenylamino or optionally halo-subsitututed
benzylamino; R.sub.10 is optionally halo-subsitututed phenyl,
optionally halo-subsitututed pyridyl, or thiadiazolyl; in free or
pharmaceutically acceptable salt form.
4. The method of claim 1, wherein the Compound of Formula I is
##STR00025## in free or pharmaceutically acceptable salt form.
5. The method of claim 1, wherein the Compound of Formula II is
##STR00026## in free or pharmaceutically acceptable salt form.
6. The method of claim 1, wherein the method comprises
administration of a pharmaceutical composition comprising effective
amounts of both a Compound of Formula I and a Compound of Formula
II.
7. The method of claim 1, wherein the daily dosage of the Compound
of Formula 1 is 1 mg to 10 mg.
8. The method of claim 1 wherein the daily dosage of the Compound
of Formula 1I is 0.1 mg to 10 mg.
9. The method of claim 1 wherein the Compound of Formula I is:
##STR00027## in free or pharmaceutically acceptable salt form,
administered in a daily dose of 1 mg to 10 mg, the dosage
calculated as the free base equivalent; and the Compound of Formula
II is: ##STR00028## in free or pharmaceutically acceptable salt
form, administered in a daily dose of 0.5 mg to 10 mg, the dosage
calculated as the free base equivalent.
10. The method of claim 9, wherein the compound of Formula I is in
tosylate salt form administered in a daily dose equivalent to 1 to
5 mg of free base and the compound of Formula II is in
monophosphate salt form administered in a daily dose equivalent to
0.5 to 2 mg of free base.
11. The method of claim 10, wherein the method comprises once daily
administration of a unit dosage for oral administration, comprising
the compound of Formula I in tosylate salt form in an amount
equivalent to 1 to 5 mg of free base, the compound of Formula II in
monophosphate salt form in an amount equivalent to 0.5 to 2 mg of
free base, and a pharmaceutically acceptable diluent or
carrier.
12. The method of claim 1, wherein the one or more disorders
associated with dementia are selected from disorders associated
with mild to severe cognition impairment and dementing illnesses
including senile dementia, Alzheimer's disease, Pick's disease,
frontotemporal dementia, parasupranculear palsy, dementia with Lewy
bodies, vascular dementia, Huntington's disease, Parkinson's
disease, multiple sclerosis, amyotrophic lateral sclerosis, Down
syndrome, elderly depression, Wernicke-Korsakoff's syndrome,
corticobasal degenerations, and prion disease.
13. The method of claim 1, wherein the disorders associated with
dementia include one or more of behavioral or mood disturbances,
psychosis, depression and/or sleep disturbances.
14. The method of claim 1, comprising enhancing cognition in a
patient with dementia.
15. The method of claim 1, wherein the disorder is Alzheimer's
disease or symptoms thereof.
16. A pharmaceutical composition comprising a therapeutically
effective amount of (i) a 5-HT2A or 5-HT2A/D2 receptor ligand and
(ii) a PDE1 inhibitor.
17. The pharmaceutical composition of claim 16 wherein the 5-HT2A
or 5-HT2A/D2 receptor ligand is a compound of Formula I:
##STR00029## wherein: X is --N(H)--, --N(CH.sub.3)-- or --O--; Y is
--C(.dbd.O), --C(H)(OH) or --C(H)(OR.sub.1); R.sub.1 is
--C(O)--C.sub.1-21alkyl, optionally saturated or unsaturated and
optionally substituted with one or more hydroxy or C.sub.1-22alkoxy
groups, wherein such compound hydrolyzes to form the residue of a
natural or unnatural, saturated or unsaturated fatty acid, in free,
pharmaceutically acceptable salt or prodrug form.
18. The pharmaceutical composition of claim 16 wherein the PDE1
inhibitor is a compound according to Formula II ##STR00030##
wherein R.sub.2 is H and R.sub.3 and R.sub.4 together form a tri-
or tetra-methylene bridge; or R.sub.2 and R.sub.3 are each methyl
and R.sub.4 is H; or R.sub.2 and R.sub.4 are H and R.sub.3 is
isopropyl; R.sub.6 is optionally halo-subsitututed phenylamino or
optionally halo-subsitututed benzylamino; R.sub.10 is optionally
halo-subsitututed phenyl, optionally halo-subsitututed pyridyl, or
thiadiazolyl; in free or pharmaceutically acceptable salt form.
19. The pharmaceutical composition of claim 16 wherein the Compound
of Formula I is ##STR00031## in free or pharmaceutically acceptable
salt form.
20. The pharmaceutical composition of claim 16 wherein the Compound
of Formula II is ##STR00032## in free or pharmaceutically
acceptable salt form.
21. The pharmaceutical composition of claim 16 further comprising a
pharmaceutically acceptable diluent or carrier.
22. The pharmaceutical composition of claim 16 in the form of a
tablet, capsule, or transdermal patch.
23. The pharmaceutical composition of claim 16 comprising a
Compound of Formula I and a Compound of Formula II in a bioerodable
matrix.
24. The pharmaceutical composition of claim 16 in unit dosage form
wherein the Compound of Formula I is: ##STR00033## in free or
pharmaceutically acceptable salt form, in an amount of 1 mg to 10
mg, the dosage calculated as the free base equivalent; and the
Compound of Formula II is: ##STR00034## in free or pharmaceutically
acceptable salt form, in an amount of 0.5 mg to 10 mg, the dosage
calculated as the free base equivalent.
25. The pharmaceutical composition of claim 24 in the form of a
tablet or capsule for oral administration comprising the compound
of Formula I in tosylate salt form in an amount equivalent to 1 to
5 mg of free base, the compound of Formula II in monophosphate salt
form in an amount equivalent to 0.5 to 2 mg of free base, and a
pharmaceutically acceptable diluent or carrier.
26. The method of claim 1 comprising administration of the
composition according to claim 16.
27. (canceled)
28. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and the benefit of U.S.
Provisional Application No. 62/314,314, filed Mar. 28, 2016, the
contents of which are hereby incorporated by reference in their
entirety.
TECHNICAL FIELD
[0002] The present invention relates to use of (i) a 5-HT2A or
5-HT2A/D2 receptor ligand, for example a substituted heterocycle
fused gamma-carbolines as described herein, in free,
pharmaceutically acceptable salt or prodrug form, and (ii) a cyclic
nucleotide phosphodiesterase 1 (PDE1) inhibitor, for example a
7,8-dihydro-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-one compounds,
in combination (sequentially or simultaneously, or in the form of a
fixed dose combination for the prophylaxis or treatment of one or
more disorders associated with dementia (including behavioral or
mood disturbances (e.g., agitation/aggression), psychosis,
depression and/or sleep disturbances), or enhancing cognition, for
example in schizophrenia or dementia.
BACKGROUND OF THE INVENTION
[0003] Dementia is a disorder characterized by the loss of
cognitive abilities affecting memory, reasoning, judgment and
behavior. At an early stage of dementia, people may experience mild
cognitive impairment (MCI, also known as incipient dementia, or
isolated memory impairment) which is cognitive impairment beyond
that expected based on the age and education of the individual, but
which is not significant enough to interfere with their daily
activities. Studies suggest that these individuals tend to progress
to probable Alzheimer's disease at a rate of approximately 10% to
15% per year. Alzheimer's disease is the most common type of
dementia and is an irreversible, progressive neurodegenerative
disease that disrupts memory, perception, reasoning, judgment,
information processing, emotional behavior, personality as well as
social and occupational functions. Of date, 5.4 million of
Americans are believed to be living with Alzheimer's and nearly 36
million people worldwide are believed to be living with this
disease or other dementias.
[0004] Currently, there is no cure or standard of treatment for
dementia. Available treatments are palliative and symptomatic in
nature aiming to manage and slow the progression of the cognitive
manifestation of the disease. Drugs approved in the United States
for the treatment of Alzheimer's disease, which are also used to
treat dementia in general include acetylcholinesterase inhibitors
(e.g., Tacrine, rivastigmine (Exelon), donepezil (Aricept), and
galantamine (Razadyne, formerly called Reminyl)) and NMDA receptor
antagonist (e.g., memantine (Namenda)). While these drugs improve
mental function (such as memory, attention, social interaction,
reasoning ability, language ability, and ability to perform
activities of daily living), they often cause side effects
including stomach upset, diarrhea, nausea, vomiting, muscle cramps,
fatigue, difficulty falling or staying asleep or excess sleepiness,
depression, bradycardia and other side effects. In addition, these
drugs do not treat affective symptoms and/or other behavior
disruptions such as mood swing, agitation, aggressive/assaultive
behavior and paranoia which are common in dementias. In fact, some
studies have shown that memantine, a drug approved for Alzheimer's
disease and often used for dementias in general, may have some
adverse effects on neuropsychiatric functioning, particularly
agitation/aggression, delusions or hallucinations. These untreated
and sometimes aggravated behavioral disruptions often prevent the
patients from integrating back into society, causing further
distress to the caregivers and eventually leading to the patients'
institutionalization. To control aggression and psychosis in
dementia, particularly in Alzheimer's disease, antipsychotic drugs
are used. However, antipsychotic drugs such as haloperidol,
risperidone and quetiapine are associated with serious side effects
including extrapyramidal side effects (akinesia or akathisia), bone
marrow suppression, seizure, orthostatic hypotension, insomnia,
sedation, somnolence and weight gain. Many atypical antipsychotic
agents also have a higher risk of heart failure. Therefore, the use
of these antipsychotic agents in combination with
anticholinesterase inhibitor or NMDA receptor antagonist is
undesirable.
[0005] In addition to behavior and mood disturbances, many dementia
patients, particularly those at a more serious stage of the disease
also commonly experience sleep disturbances wherein the patients
either have difficulty falling asleep, maintaining sleep or
experience changes in their sleep-wake cycle/pattern. These
patients may also feel restless or agitated in the late afternoon
or early evening (often called "sundowning"). In fact, studies have
shown evidence that a loss in the suprachiasmatic nucleus (SCN)
neuronal population coincides with Alzheimer's patients' stage of
dementia. This loss of SCN neuronal population appears to be
causative in the observed disturbances in melantonin rhythm which
may underlie accompanying sleep disturbances. While agents such as
temazepam (Restoril), zolpidem (Ambien), or zaleplon (Sonata), or
sedating antidepressants, such as trazodone (Desyrel, Molipaxin),
may be useful in managing insomnia, failure of these drugs to
improve sleep quality in addition to the associated risk of falling
due to drowsiness and psychomotor impairment caused by these agents
render them undesirable for dementia, particularly Alzheimer's
patients.
[0006] Particularly in later stages of dementia, patients may
suffer psychosis. While psychosis is often associated with
schizophrenia in young people, people with dementia may, as the
disease progresses, exhibit a spectrum of behaviors from agitation
to positive symptoms of psychosis such as paranoia, delusions and
hallucinations. The patients may also suffer negative symptoms such
as emotional withdrawal, passive social withdrawal, and stereotyped
thinking, and symptoms of general psychopathology including active
social avoidance, anxiety, tension, and somatic concerns. These
negative symptoms are often accompanied by depression, cognitive
dysfunction and insomnia. Collectively, these residual phase
symptoms are not well-treated by many antipsychotic drugs currently
available on the market and therefore are usually most apparent
when the more dramatic positive or active phase symptoms have been
brought under control by antipsychotic medications.
[0007] There remains an urgent need for an effective therapeutic
regime for the prophylaxis or treatment of dementia and disorders
associated thereof, particularly to alleviate behavioral/mood
disturbances (e.g., agitation, aggressive/assaultive behavior) and
sleep disturbances in patients suffering from dementia or psychosis
associated with dementia.
[0008] Substituted heterocycle fused gamma-carbolines are known to
be 5-HT2A or 5-HT2A/D2 receptor ligands, useful in treating central
nervous system disorders. These compounds have been disclosed in
U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; U.S.
RE39680, and U.S. RE39679, as novel compounds useful for the
treatment of disorders associated with 5-HT2A receptor modulation
such as obesity, anxiety, depression, psychosis, schizophrenia,
sleep disorders, sexual disorders, migraine, conditions associated
with cephalic pain, and social phobias. PCT/US08/03340 and U.S.
Pat. No. 7,081,455 also disclose methods of making substituted
heterocycle fused gamma-carbolines and uses of these
gamma-carbolines as serotonin agonists and antagonists useful for
the control and prevention of central nervous system disorders such
as addictive behavior and sleep disorders. WO 2009/145900 and WO
2013/155506, each incorporated herein by reference, disclose use of
specific substituted heterocycle fused gamma-carbolines for the
treatment of a combination of psychosis and depressive disorders as
well as sleep, depressive and/or mood disorders in patients with
psychosis or Parkinson's disease and for the treatment or
prophylaxis of disorders associated with dementia, particularly
behavioral or mood disturbances such as agitation, irritation,
aggressive/assaultive behavior, anger, physical or emotional
outbursts and psychosis and sleep disorders associated with
dementia.
[0009] PDE1 is a Ca.sup.2+-calmodulin-dependent phosphodiesterase
(CaM-PDE), which can downregulate intracellular cAMP and cGMP
signaling by hydrolyzing these cyclic nucleotides to their
respective inactive 5'-monophosphates (5'AMP and 5'GMP). PDE1 plays
a critical role in mediating signal transduction in brain cells,
particularly within an area of the brain known as the basal ganglia
or striatum. For example, NMDA-type glutamate receptor activation
and/or dopamine D2 receptor activation result in increased
intracellular calcium concentrations, leading to activation of
effectors such as calmodulin-dependent kinase II (CaMKII) and
calcineurin and to activation of PDE1, resulting in reduced cAMP
and cGMP. Dopamine D1 receptor activation, on the other hand, leads
to activation of calcium dependent nucleotide cyclases, resulting
in increased cAMP and cGMP. These cyclic nucleotides in turn
activate protein kinase A (PKA; cAMP-dependent protein kinase)
and/or protein kinase G (PKG; cGMP-dependent protein kinase) that
phosphorylate downstream signal transduction pathway elements such
as DARPP-32 (dopamine and cAMP-regulated phosphoprotein) and cAMP
responsive element binding protein (CREB). Inhibition of PDE1 can
thus potentiate the effect of a dopamine D1 agonist by protecting
cGMP and cAMP from degradation, and likewise can inhibit dopamine
D2 receptor signaling pathways, by inhibiting PDE1 activity. WO
2014/145617, incorporated herein by reference, e.g., for its
disclosure of PDE1 inhibitors, describes the use of PDE1 inhibitors
as neuroprotective agents and/or neural regenerative agents, e.g.
to prevent the development of a CNS disease or disorder in an
individual at risk for the development of a CNS disease or
disorder. By facilitating increased levels of intracellular cAMP
and/or cGMP, PDE1 inhibitors can initiate the transcription of
genes that are necessary for overcoming myelin inhibition of
regeneration after nerve injury and promoting neurite outgrowth
and/or axonal regeneration in the case of a CNS disease, disorder,
or injury, thus encouraging axonal regeneration and/or
neuroprotection while simultaneously decreasing or lessening damage
associated with chronically elevated intracellular calcium levels,
which can lead to calmodulin activation of PDE 1.
[0010] New methods of treating and improving the quality of life in
patients having dementia and slowing the progression of dementia
are urgently needed.
SUMMARY OF THE INVENTION
[0011] The invention provides a method of treating dementia
(including associated disorders such as behavioral or mood
disturbances (e.g., agitation/aggression), psychosis, depression
and/or sleep disturbances), and/or enhancing cognition, for example
in patients suffering from schizophrenia or dementia, comprising
administering an effective amount of (i) a 5-HT2A or 5-HT2A/D2
receptor ligand, for example a substituted heterocycle fused
gamma-carbolines as described herein, in free, pharmaceutically
acceptable salt or prodrug form, together with (ii) a PDE1
inhibitor, as described herein. The 5-HT2A/D2 ligand promotes
quality of sleep and reduces agitation, while the PDE1 inhibitor
promotes cognitive function. The administration may be sequential
or simultaneous. The invention further provides a pharmaceutical
composition, e.g., for use in such a method, comprising (i) a
5-HT2A or 5-HT2A/D2 receptor ligand and (ii) a PDE1 inhibitor.
DETAILED DESCRIPTION
[0012] Administration of a PDE1 inhibitor as described herein will
enhance cognition and also act to increase levels of intracellular
cAMP and initiate the transcription of genes that are necessary for
overcoming the inhibition of axonal regeneration and promoting
neurite outgrowth and/or axonal regeneration thus inhibiting the
neurodegenerative process. For instance, increased intracellular
cAMP, such as would result from PDE1 inhibition, leads to increased
activity of cAMP-dependent proteins, such as protein kinase C
(PKC).
[0013] Another benefit of the administration of a PDE1 inhibitor of
the invention is an increase in intracellular cGMP. This increase
in intracellular cGMP may lead to an increase in the activity of
PKG, preventing a further rise in intracellular calcium levels.
Thus, it is believed that the administration of a PDE1 inhibitor
could have the dual benefit of, for example, playing a beneficial
role in axonal regeneration (and/or neuroprotection) while
simultaneously decreasing the deleterious effects that may be
associated with elevated intracellular calcium levels.
[0014] The 5-HT2A or 5-HT2A/D2 receptor ligand is a compound which
antagonizes serotonin-2A (5-HT2A) receptor, and/modulates dopamine
receptor signaling at the level of key intra-cellular
phosphoproteins and therefore is useful for the treatment of not
only acute symptoms, but also residual symptoms of pyschosis,
particularly schizophrenia. At dopamine D2 receptors, these
compounds have dual properties and act as both post-synaptic
antagonists and pre-synaptic partial agonists. They also stimulate
phosphorylation of glutamatergic NMDA NR2B, or GluN2B, receptors in
a mesolimbic specific manner. It is believed that this regional
selectivity in the brain areas thought to mediate the efficacy of
antipsychotic drugs, together with serotonergic, glutamatergic, and
dopaminergic interactions, may result in antipsychotic efficacy for
positive, negative, affective and cognitive symptoms associated
with schizophrenia. The compounds also exhibit serotonin reuptake
inhibition, providing antidepressant activity for the treatment of
schizoaffective disorder, co-morbid depression, and/or as a
stand-alone treatment for major depressive disorder. The 5-HT2A or
5-HT2A/D2 receptor ligands as described are also useful for the
treatment of bipolar disorder and other psychiatric and
neurodegenerative disorders, particularly behavioral disturbances
associated with dementia, autism and other CNS diseases. These
features may be able to improve the quality of life of patients
with schizophrenia and enhance social function to allow them to
more fully integrate into their families and their workplace. At a
low-dose, the Thus, the combination of the PDE1 inhibitor with a
5-HT2A or 5-HT2A/D2 receptor ligand will be particularly useful,
e.g., in the treatment of dementia or psychosis (e.g.,
schizophrenia) and disorders associated thereof. At lower doses,
they are useful in treating sleep, aggression and agitation. At a
high-dose, they can treat acute exacerbated and residual
schizophrenia, bipolar disorders, and mood disorders.
[0015] As 5-HT2A or 5-HT2A/D2 receptor ligand compounds used in the
current disclosure are effective in treating not just acute
symptoms, but also residual symptoms of psychosis, their
combination with a PDE1 inhibitor disclosed herein, which is
believed to provide a neuroprotective effect, is useful in the
treatment of a wide range of symptoms and disorders associated with
dementia or psychosis such as schizophrenia.
[0016] Therefore, in a particular embodiment, the invention
provides a method (Method I) for the prophylaxis or treatment of
one or more disorders associated with dementia (e.g., disorders
associated with mild to severe cognition impairment and dementing
illnesses including senile dementia, Alzheimer's disease, Pick's
disease, frontotemporal dementia, parasupranculear palsy, dementia
with Lewy bodies, vascular dementia, Huntington's disease,
Parkinson's disease, multiple sclerosis, amyotrophic lateral
sclerosis, Down syndrome, elderly depression, Wernicke-Korsakoff's
syndrome, corticobasal degenerations, and prion disease; and
further including behavioral or mood disturbances (e.g.,
agitation/aggression), psychosis, depression and/or sleep
disturbances, as well as enhancing cognition, for example in
schizophrenia or dementia) comprising administering to a patient in
need thereof, a therapeutically effective amount of [0017] (i) a
5-HT2A or 5-HT2A/D2 receptor ligand, for example a compound of
Formula I:
[0017] ##STR00001## [0018] wherein: [0019] X is --N(H)--,
--N(CH.sub.3)-- or --O--; [0020] Y is --C(.dbd.O)--, --C(H)(OH)--
or --C(H)(OR.sub.1)--; [0021] R.sub.1 is --C(O)--C.sub.1-21alkyl
(e.g., --C(O)--C.sub.1-5alkyl, --C(O)--C.sub.6-15alkyl or
--C(O)--C.sub.16-21alkyl), preferably said alkyl is a straight
chain, optionally saturated or unsaturated and optionally
substituted with one or more hydroxy or C.sub.1-22alkoxy (e.g.,
ethoxy) groups, for example R.sub.1 is --C(O)--C.sub.6alkyl,
--C(O)--C.sub.7alkyl, --C(O)--C.sub.9alkyl, --C(O)--C.sub.11alkyl,
--C(O)--C.sub.13alkyl or --C(O)--C.sub.15alkyl wherein such
compound hydrolyzes to form the residue of a natural or unnatural,
saturated or unsaturated fatty acid, e.g., the compound hydrolyzes
to form the hydroxy compound on the one hand and octanoic acid,
decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic
acid on the other hand), in free, pharmaceutically acceptable salt
or prodrug form; and [0022] (ii) a PDE1 inhibitor, for example a
compound according to Formula II
[0022] ##STR00002## [0023] wherein [0024] R.sub.2 is H and R.sub.3
and R.sub.4 together form a tri- or tetra-methylene bridge [pref.
with the carbons carrying R.sub.3 and R.sub.4 having the R and S
configuration respectively]; or R.sub.2 and R.sub.3 are each methyl
and R.sub.4 is H; or R.sub.2 and R.sub.4 are H and R.sub.3 is
isopropyl [pref. the carbon carrying R.sub.3 having the R
configuration]; [0025] R.sub.6 is (optionally halo-subsitututed)
phenylamino or (optionally halo-subsitututed) benzylamino; [0026]
R.sub.10 is (optionally halo-subsitututed) phenyl, (optionally
halo-subsitututed) pyridyl (for example 3-fluoropyrid-2-yl), or
thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl); in free or
pharmaceutically acceptable salt form.
[0027] For example, Method 1 may be as follows: [0028] 1.1. Method
I, wherein X in the compound of Formula I is --N(H)--,
--N(CH.sub.3)-- or --O--; [0029] 1.2. Method I or 1.1, wherein X in
the compound of Formula I is --N(H); [0030] 1.3. Method I or 1.1,
wherein X in the compound of Formula I is --N(CH.sub.3)--; [0031]
1.4. Method I or 1.1, wherein X in the compound of Formula I is
--O--; [0032] 1.5. Method I or any of formulae 1.1-1.4, wherein Y
in the compound of Formula I is --C(.dbd.O)--, --C(H)(OH)-- or
--C(H)(OR.sub.1)--; [0033] 1.6. Method I or any of formulae
1.1-1.4, wherein Y in the compound of Formula I is --C(.dbd.O)--;
[0034] 1.7. Method I or any of formulae 1.1-1.4, wherein Y in the
compound of Formula I is --C(H)(OH)--; [0035] 1.8. Method I or any
of formulae 1.1-1.4, wherein Y in the compound of Formula I is
--C(H)(OR.sub.1)--; [0036] 1.9. Method I or 1.8, wherein R.sub.1 in
the compound of Formula I is --C(O)--C.sub.1-21alkyl (e.g.,
--C(O)--C.sub.1-5alkyl, --C(O)--C.sub.6-15alkyl or
--C(O)--C.sub.16-21alkyl), preferably said alkyl is a straight
chain, optionally saturated or unsaturated and optionally
substituted with one or more hydroxy or C.sub.1-22alkoxy (e.g.,
ethoxy) groups, for example R.sub.1 is --C(O)--C.sub.6alkyl,
--C(O)--C.sub.7alkyl, --C(O)--C.sub.9alkyl, --C(O)--C.sub.11alkyl,
--C(O)--C.sub.13alkyl or --C(O)--C.sub.15alkyl wherein such
compound hydrolyzes to form the residue of a natural or unnatural,
saturated or unsaturated fatty acid, e.g., the compound hydrolyzes
to form the hydroxy compound on the one hand and octanoic acid,
decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic
acid on the other hand); e.g., wherein R.sub.1 in the compound of
Formula I is --C(O)--C.sub.6-15alkyl, e.g., --C(O)--C.sub.9alkyl;
or wherein R.sub.1 in the compound of Formula I is
--C(O)--C.sub.1-5alkyl, e.g., --C(O)--C.sub.3alkyl. [0037] 1.10.
Method I or any of 1.1-1.5 or 1.7, wherein the Compound of Formula
I is:
[0037] ##STR00003## [0038] 1.11. Method I or any of 1.1-1.5 or 1.7,
wherein the Compound of Formula I is:
##STR00004##
[0039] 1.12. Any foregoing Method 1, or 1.1-1.3, 1.5, or 1.9
wherein the Compound of Formula I is
##STR00005## [0040] 1.13. Method 1.12 wherein the Compound of
Formula 1 is in the form of the tosylate salt. [0041] 1.14. Method
1.12 wherein the Compound of Formula 1 is in the form of the free
base. [0042] 1.15. Any foregoing Method wherein, in the Compound of
Formula II, R.sub.6 is phenylamino or 4-fluorophenylamino. [0043]
1.16. Any foregoing Method wherein, in the Compound of Formula II,
R.sub.10 is 3-fluoropyrid-2-yl or methylcarbonyl. [0044] 1.17. Any
foregoing Method wherein, in the Compound of Formula II, R.sub.6 is
phenylamino or 4-fluorophenylamino and R.sub.10 is
3-fluoropyrid-2-yl or methylcarbonyl. [0045] 1.18. Any foregoing
Method wherein the Compound of Formula II is
[0045] ##STR00006## [0046] in free or pharmaceutically acceptable
salt form. [0047] 1.19. Method 1.16 wherein the Compound of Formula
II is in the form of the monophosphate salt. [0048] 1.20. Any
foregoing Method, wherein the Compound of Formula I is:
[0048] ##STR00007## [0049] in free of pharmaceutically acceptable
salt form, e.g., tosylate salt form; and the Compound of Formula II
is:
[0049] ##STR00008## [0050] in free of pharmaceutically acceptable
salt form, e.g., monophosphate salt form. [0051] 1.21. Any
foregoing Method comprising administration of a pharmaceutical
composition comprising effective amounts of both a Compound of
Formula I and a Compound of Formula II. [0052] 1.22. Any foregoing
method wherein the daily dosage of the Compound of Formula 1 is 1
mg to 10 mg. [0053] 1.23. Any foregoing method wherein the daily
dosage of the Compound of Formula 1I is 0.1 mg to 10 mg. [0054]
1.24. Any foregoing method wherein the Compound of Formula I
is:
[0054] ##STR00009## [0055] in free or pharmaceutically acceptable
salt form, administered in a daily dose of 1 mg to 10 mg, e.g., 2
mg to 7 mg, the dosage calculated as the free base equivalent;
[0056] and the Compound of Formula II is:
[0056] ##STR00010## [0057] in free or pharmaceutically acceptable
salt form, administered in a daily dose of 0.5 mg to 10 mg, e.g.
0.5 to 2 mg, or 1 to 5 mg, the dosage calculated as the free base
equivalent. [0058] 1.25. Method 1.21 wherein the compound of
Formula 1 is in tosylate salt form administered in a daily dose
equivalent to 1 to 5 mg of free base, the compound of Formula II is
in monophosphate salt form administered in a daily dose equivalent
to 0.5 to 2 mg of free base. [0059] 1.26. Any foregoing Method
wherein the compound of Formula I and/or of Formula II is
deuterated, e.g., wherein the deuterium:protium ratio at a
specified position in the molecule is significantly higher, e.g.,
at least 2.times., for example at least 10.times. higher, than the
natural isotope ratios. [0060] 1.27. Any foregoing Method wherein
the Compound of Formula I is a Compound of Formula 1 as described
in WO 2015/154025, the contents of which are incorporated herein by
reference, e.g., wherein the --CH.sub.2- adjacent to X and/or Y is
--CHD- or --CD2-. [0061] 1.28. Method 1.22 wherein the method
comprises once daily administration of a unit dosage for oral
administration, for example a tablet or capsule, comprising the
compound of Formula I in tosylate salt form in an amount equivalent
to 1 to 5 mg of free base, the compound of Formula II in
monophosphate salt form in an amount equivalent to 0.5 to 2 mg of
free base, and a pharmaceutically acceptable diluent or carrier.
[0062] 1.29. Any foregoing method wherein the disorders associated
with dementia are disorders associated with Huntington's disease,
Parkinson's disease, Mulitple sclerosis, Amyotrophic lateral
sclerosis, Down syndrome, Eldery depression, Wernicke-Korsakoff's
syndrome, corticobasal degenerations, and prion disease. [0063]
1.30. Any foregoing method wherein the disorders associated with
dementia are disorders associated with mild cognition impairment
and dementing illnesses including senile dementia, Alzheimer's
disease, Pick's disease, frontotemporal dementia, parasupranculear
palsy, dementia with Lewy bodies and vascular dementia. [0064]
1.31. Any foregoing method wherein the disorders associated with
dementia are disorders associated with senile dementia, Alzheimer's
disease, Pick's disease, frontotemporal dementia, parasupranculear
palsy, dementia with Lewy bodies and vascular dementia. [0065]
1.32. Any foregoing method wherein the disorders associated with
dementia are disorders associated with Alzheimer's disease. [0066]
1.33. Any foregoing method wherein the disorders associated with
dementia are disorders associated with mild cognition impairment.
[0067] 1.34. Any foregoing method wherein the disorder associated
with dementia to be treated is selected from the group consisting
of (1) behavioral or mood disorders such as agitation/irritation,
aggressive/assaultive behavior, anger, physical or emotional
outbursts; (2) psychosis; (3) depression; and (4) sleep disorders
in patients suffering from dementia, particularly Alzheimer's
disease. [0068] 1.35. Any foregoing method wherein the disorder to
be treated is psychosis in a patient with dementia, particularly
Alzheimer's disease. [0069] 1.36. Any foregoing method wherein the
disorder to be treated is depression in a patient with dementia,
particularly Alzheimer's disease. [0070] 1.37. Any foregoing method
wherein the disorder to be treated is behavioral or mood disorders
such as agitation/irritation, aggressive/assaultive behavior,
anger, physical or emotional outbursts in a patient with dementia,
particularly Alzheimer's disease. [0071] 1.38. Any foregoing method
wherein the disorder to be treated is sleep disorders in a patient
with dementia, particularly Alzheimer's disease. [0072] 1.39. Any
of Method I et seq. wherein the disorder to be treated is sleep
maintenance insomnia, frequent awakenings, and waking up feeling
unrefreshed in a patient with dementia, particularly Alzheimer's
disease. [0073] 1.40. Any foregoing method wherein the disorder to
be treated is sleep maintenance insomnia in a patient with
dementia, particularly Alzheimer's disease. [0074] 1.41. Any of
Method I et seq. wherein the disorder to be treated is advanced
sleep-phase syndrome in a patient with dementia, particularly
Alzheimer's disease. [0075] 1.42. Any foregoing method wherein the
disorder to be treated is delayed sleep-phase syndrome in a patient
with dementia, particularly Alzheimer's disease. [0076] 1.43. Any
foregoing method wherein the disorder associated with dementia is
selected from behavioral or mood disturbances (e.g.,
agitation/aggression), psychosis, depression and/or sleep
disturbances. [0077] 1.44. Any foregoing method comprising
enhancing cognition, for example in schizophrenia or dementia.
[0078] 1.45. Any foregoing method further comprising administering
one or more additional therapeutic agents useful for the
prophylaxis or treatment of dementia, particularly Alzheimer's
disease. [0079] 1.46. The foregoing method wherein the therapeutic
agent useful for the prophylaxis or treatment of dementia,
particularly Alzheimer's disease is a cholinesterase inhibitor
(e.g., acetylcholinesterase inhibitor) or an N-Methyl D-Asparate
(NMDA) receptor antagonist, in free or pharmaceutically acceptable
salt form; [0080] 1.47. The foregoing method wherein the
cholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) is
selected from the group consisting of Tacrine, rivastigmine
(Exelon), donepezil (Aricept), and galantamine (Razadyne, formerly
called Reminyl)) in free or pharmaceutically acceptable salt form;
[0081] 1.48. The foregoing method wherein the cholinesterase
inhibitor (e.g., acetylcholinesterase inhibitor) is donepezil in
free or pharmaceutically acceptable salt form; [0082] 1.49. Any
foregoing method wherein the patient additionally receives a NMDA
receptor antagonist, e.g., memantine in free or pharmaceutically
acceptable salt form; [0083] 1.50. Any foregoing method further
comprising administering one or more additional therapeutic agents
useful for the prophylaxis or treatment of dementia, particularly
Alzheimer's disease, wherein the therapeutic agent useful for the
prophylaxis or treatment of dementia, particularly Alzheimer's
disease is a combination of a cholinesterase inhibitor (e.g.,
acetylcholinesterase inhibitor) and an N-Methyl D-Asparate (NMDA)
receptor antagonist, in free or pharmaceutically acceptable salt
form. [0084] 1.51. The foregoing method wherein the one or more
therapeutic agent(s) useful for the prophylaxis or treatment of
dementia, particularly Alzheimer's disease or symptoms thereof is a
combination of donepezil and memantine in free or pharmaceutically
acceptable salt form. [0085] 1.52. Any foregoing method further
comprising administering one or more therapeutic agents useful for
the prophylaxis or treatment of dementia, particularly Alzheimer's
disease further comprises administering one or more therapeutic
agents selected from antidepressant compounds, compounds that
modulate GABA activity (e.g., enhances the activity and facilitates
GABA transmission), a GABA-B agonist, a serotonin-2
antagonist/reuptake inhibitor (SARIs), an orexin receptor
antagonist, an H3 agonist, a noradrenergic antagonist, a galanin
agonist, a CRH antagonist, human growth hormone, a growth hormone
agonist, estrogen, an estrogen agonist, a neurokinin-1 drug, and an
antipsychotic agent, e.g., an atypical antipsychotic agent, in free
or pharmaceutically acceptable salt form.
[0086] In another aspect, the invention provides a pharmaceutical
composition (Composition 1) [e.g., for the prophylaxis or treatment
of one or more disorders associated with dementia (e.g., disorders
associated with mild to severe cognition impairment and dementing
illnesses including senile dementia, Alzheimer's disease, Pick's
disease, frontotemporal dementia, parasupranculear palsy, dementia
with Lewy bodies, vascular dementia, Huntington's disease,
Parkinson's disease, multiple sclerosis, amyotrophic lateral
sclerosis, Down syndrome, elderly depression, Wernicke-Korsakoff's
syndrome, corticobasal degenerations, and prion disease, e.g., for
use in any of Methods 1 et seq.], comprising [0087] (i) a 5-HT2A or
5-HT2A/D2 receptor ligand, for example a compound of Formula I:
[0087] ##STR00011## [0088] wherein: [0089] X is --N(H)--,
--N(CH.sub.3)-- or --O--; [0090] Y is --C(.dbd.O), --C(H)(OH) or
--C(H)(OR.sub.1); [0091] R.sub.1 is --C(O)--C.sub.1-21alkyl (e.g.,
--C(O)--C.sub.1-5alkyl, --C(O)--C.sub.6-15alkyl or
--C(O)--C.sub.16-21alkyl), preferably said alkyl is a straight
chain, optionally saturated or unsaturated and optionally
substituted with one or more hydroxy or C.sub.1-22alkoxy (e.g.,
ethoxy) groups, for example R.sub.1 is --C(O)--C.sub.6alkyl,
--C(O)--C.sub.7alkyl, --C(O)--C.sub.9alkyl, --C(O)-C.sub.11alkyl,
--C(O)--C.sub.13alkyl or --C(O)--C.sub.15alkyl wherein such
compound hydrolyzes to form the residue of a natural or unnatural,
saturated or unsaturated fatty acid, e.g., the compound hydrolyzes
to form the hydroxy compound on the one hand and octanoic acid,
decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic
acid on the other hand), [0092] in free, pharmaceutically
acceptable salt or prodrug form; and [0093] (ii) a PDE1 inhibitor,
for example a compound according to Formula II
[0093] ##STR00012## [0094] wherein [0095] R.sub.2 is H and R.sub.3
and R.sub.4 together form a tri- or tetra-methylene bridge [pref.
with the carbons carrying R.sub.3 and R.sub.4 having the R and S
configuration respectively]; or R.sub.2 and R.sub.3 are each methyl
and R.sub.4 is H; or R.sub.2 and R.sub.4 are H and R.sub.3 is
isopropyl [pref. the carbon carrying R.sub.3 having the R
configuration]; [0096] R.sub.6 is (optionally halo-subsitututed)
phenylamino or (optionally halo-subsitututed) benzylamino; for
example, phenylamino or 4-fluorophenylamino; [0097] R.sub.10 is
methylcarbonyl, (optionally halo-subsitututed) phenyl, (optionally
halo-subsitututed) pyridyl (for example 3-fluoropyrid-2-yl), or
thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl); [0098] in free or
pharmaceutically acceptable salt form.
[0099] For example, Composition 1 includes, inter alia, the
following embodiments: [0100] 1.1. Composition I, wherein X in the
compound of Formula I is --N(H)--, --N(CH.sub.3)-- or --O--; [0101]
1.2. Composition I or 1.1, wherein X in the compound of Formula I
is --N(H); [0102] 1.3. Composition I or 1.1, wherein X in the
compound of Formula I is --N(CH.sub.3)--; [0103] 1.4. Composition I
or 1.1, wherein X in the compound of Formula I is --O--; [0104]
1.5. Composition I or any of formulae 1.1-1.4, wherein Y in the
compound of Formula I is --C(.dbd.O), --C(H)(OH) or
--C(H)(OR.sub.1); [0105] 1.6. Composition I or any of formulae
1.1-1.4, wherein Y in the compound of Formula I is --C(.dbd.O);
[0106] 1.7. Composition I or any of formulae 1.1-1.4, wherein Y in
the compound of Formula I is --C(H)(OH); [0107] 1.8. Composition I
or any of formulae 1.1-1.4, wherein Y in the compound of Formula I
is --C(H)(OR.sub.1); [0108] 1.9. Composition I or 1.8, wherein
R.sub.1 in the compound of Formula I is --C(O)--C.sub.1-21alkyl
(e.g., --C(O)--C.sub.1-5alkyl, --C(O)--C.sub.6-15alkyl or
--C(O)--C.sub.16-21alkyl), preferably said alkyl is a straight
chain, optionally saturated or unsaturated and optionally
substituted with one or more hydroxy or C.sub.1-22alkoxy (e.g.,
ethoxy) groups, for example R.sub.1 is --C(O)--C.sub.6alkyl,
--C(O)--C.sub.7alkyl, --C(O)--C.sub.9alkyl, --C(O)--C.sub.11alkyl,
--C(O)-C.sub.13alkyl or --C(O)--C.sub.15alkyl wherein such compound
hydrolyzes to form the residue of a natural or unnatural, saturated
or unsaturated fatty acid, e.g., the compound hydrolyzes to form
the hydroxy compound on the one hand and octanoic acid, decanoic
acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on
the other hand); e.g., wherein R.sub.1 in the compound of Formula I
is --C(O)--C.sub.6-15alkyl, e.g., --C(O)--C.sub.9alkyl; or wherein
R.sub.1 in the compound of Formula I is --C(O)--C.sub.1-5alkyl,
e.g., --C(O)--C.sub.3alkyl. [0109] 1.10. Composition I or any of
1.1-1.5 or 1.7, wherein the Compound of Formula I is:
[0109] ##STR00013## [0110] 1.11. Composition I or any of 1.1-1.5 or
1.7, wherein the Compound of Formula I is:
[0110] ##STR00014## [0111] 1.12. Composition I or any of 1.1-1.5 or
1.7, wherein the Compound of Formula I is:
[0111] ##STR00015## [0112] 1.13. Composition I or any of 1.1, 1.3,
1.5 or 1.7, wherein the Compound of Formula I is:
[0112] ##STR00016## [0113] 1.14. Composition I or any of 1.1, 1.3,
1.5 or 1.6, wherein the Compound of Formula I is:
[0113] ##STR00017## [0114] 1.15. Composition 1.14 wherein the
Compound of Formula I is in the form of the tosylate salt. [0115]
1.16. Any foregoing Composition wherein, in the Compound of Formula
II, R.sub.6 is phenylamino or 4-fluorophenylamino. [0116] 1.17. Any
foregoing Composition wherein, in the Compound of Formula II,
R.sub.10 is 3-fluoropyrid-2-yl or methylcarbonyl. [0117] 1.18. Any
foregoing Composition wherein, in the Compound of Formula II,
R.sub.6 is phenylamino or 4-fluorophenylamino and R.sub.10 is
3-fluoropyrid-2-yl or methylcarbonyl. [0118] 1.19. Any foregoing
Composition wherein the Compound of Formula II is
[0118] ##STR00018## [0119] in free or pharmaceutically acceptable
salt form. [0120] 1.20. Any foregoing Composition wherein the
Compound of Formula II is in the form of the monophosphate salt.
[0121] 1.21. Any foregoing Composition, wherein the Compound of
Formula I is:
[0121] ##STR00019## [0122] in free of pharmaceutically acceptable
salt form, e.g., tosylate salt form; and the Compound of Formula II
is:
[0122] ##STR00020## [0123] in free of pharmaceutically acceptable
salt form, e.g., monophosphate salt form. [0124] 1.22. Any
foregoing Composition comprising effective amounts of both a
Compound of Formula I and a Compound of Formula II. [0125] 1.23.
Any foregoing Composition in unit daily dosage form comprising 1 mg
to 60 mg, e.g. 1 mg to 10 mg, e.g. 2 mg to 7 mg of the Compound of
Formula 1. [0126] 1.24. Any foregoing Composition in unit daily
dosage form comprising 0.1 mg to 10 mg e.g., lmg to 5 mg, of the
Compound of Formula II, [0127] 1.25. Any foregoing Composition
further comprising a pharmaceutically acceptable diluent or
carrier. [0128] 1.26. Any foregoing Composition in the form of a
tablet. [0129] 1.27. Any foregoing Composition in the form of a
capsule. [0130] 1.28. Any foregoing Composition in the form of a
transdermal patch. [0131] 1.29. Any foregoing composition wherein
the Compound of Formula I and the Compound of Formula II are in a
bioerodable matrix, e.g., a bioerodable copolymer, for example
poly(lactic-co-glycolic acid), e.g., for administration by
injection to form a depot. [0132] 1.30. Any foregoing Composition
in unit dosage form wherein the Compound of Formula I is:
[0132] ##STR00021## [0133] in free or pharmaceutically acceptable
salt form, in an amount of 1 mg to 10 mg, e.g., 2 mg to 7 mg, the
dosage calculated as the free base equivalent; [0134] and the
Compound of Formula II is:
[0134] ##STR00022## [0135] in free or pharmaceutically acceptable
salt form, in an amount of 0.5 mg to 10 mg, e.g. 1 to 5 mg, the
dosage calculated as the free base equivalent. [0136] 1.31.
Composition 1.30 in the form of a tablet or capsule for oral
administration comprising the compound of Formula I in tosylate
salt form in an amount equivalent to 1 to 5 mg of free base, the
compound of Formula II in monophosphate salt form in an amount
equivalent to 0.5 to 2 mg of free base, and a pharmaceutically
acceptable diluent or carrier. [0137] 1.32. Any foregoing
Composition wherein the compound of Formula I and/or of Formula II
is deuterated, e.g., wherein the deuterium:protium ratio at a
specified position in the molecule is significantly higher, e.g.,
at least 2.times., for example at least 10.times. higher, than
above the natural isotope ratios. [0138] 1.33. Any foregoing
Composition wherein the Compound of Formula I is a Compound of
Formula 1 as described in WO 2015/154025, the contents of which are
incorporated herein by reference, e.g., wherein the --CH.sub.2-
adjacent to X and or Y is --CHD- or --CD2-, wherein D signifies a
deuterium hydrogen.
[0139] Any foregoing Composition for use in any of Methods 1, et
seq. The disclosure further provides the use of a compound of
Formula I as hereinbefore described in combination with a compound
of Formula II as hereinbefore described, for use in the manufacture
of a medicament, e.g., according to any of Composition 1, et seq.,
for use in any of Methods 1 et seq.
[0140] The 5-HT2A or 5-HT2A/D2 receptor ligand for use in the
foregoing Methods and Compositions may for example be a 5-HT2A or
5-HT2A/D2 receptor ligand compound as disclosed in any of the
following: U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017;
6,713,471; U.S. RE39680, U.S. RE39679; for example as disclosed in
U.S. Pat. No. 8,598,119, or WO 2011/133224 or WO 2015/154025, for
example, a Compound of Formula I as described above. The compounds
of Formula I and their pharmaceutically acceptable salts and salt
crystals may be made using the methods as described and exemplified
in any of the following patents or applications: U.S. Pat. Nos.
6,548,493; 7,238,690; 6,552,017; 6,713,471; U.S. RE39680; U.S.
RE39679; PCT/US08/03340; U.S. application Ser. No. 10/786,935; WO
2009/114181 and WO 2011/133224, the contents of each of which are
incorporated by reference in their entirety.
[0141] The Compounds of Formula I as hereinbefore described have a
selective receptor profile wherein at low doses, e.g., 5-10 mg,
they fully saturate the 5-HT2A receptors and only partially occupy
(e.g. 5%-15% occupancy) the dopamine D2 receptors, and also bind to
dopamine D2 receptors more extensively and to serotonin reuptake
transporter (SERT) at a higher dose. Therefore the Compounds of the
Invention are effective in treating one or more disorders
associated with dementia, e.g., one or more disorders associated
with mild cognition impairment and dementing illnesses including
senile dementia, Alzheimer's disease, Pick's disease,
frontotemporal dementia, parasupranculear palsy, dementia with Lewy
bodies, vascular dementia, Huntington's disease, Parkinson's
disease, multiple sclerosis, amyotrophic lateral sclerosis, Down
syndrome, elderly depression, Wernicke-Korsakoff's syndrome,
corticobasal degenerations, and prion disease, particularly
behavioral/mood disturbances (e.g., agitation,
aggressive/assaultive behavior) and sleep disorders, which are
inadequately treated by the current marketed drugs for dementia and
Alzheimer's disease, as well as treating psychosis and depressive
disorders in patients suffering from dementia.
[0142] The PDE1 inhibitor may for example be a PDE1 inhibitor
compound as disclosed in any of the following: WO 2006/133261, WO
2007/025103, WO 2007/143705, WO 2009/075784, WO 2009/073210, WO
2010/065153, WO 2010/065148, WO 2010/065151, WO 2010/065149, WO
2010/065147, WO 2010/065152, WO 2011/043816, WO 2011/153129, WO
2011/153135, WO 2011/153136, WO 2011/153138, WO 2012/171016, WO
2013/192556, WO 2014/151409, WO 2014/205354, or WO 2014/145617, for
example as disclosed in WO 2009/075784, the contents of each of
which are incorporated by reference herein in their entireties. For
example, the PDE1 inhibitor may be a compound of Formula II as
hereinbefore described.
[0143] The combinations as disclosed (i.e., of Compounds of Formula
I and Formula II as hereinbefore described) may be administered
simultaneously, separately or sequentially with one or more other
active agents to treat dementia or dementing illnesses as
hereinbefore described, particularly Alzheimer's disease or
symptoms thereof.
[0144] The second or further therapeutic agents useful for the
prophylaxis or treatment of dementia as hereinbefore described,
particularly Alzheimer's disease, e.g., as described in Method 1
and 2 above, include but are not limited to a cholinesterase
inhibitor and/or N-Methyl D-Asparate (NMDA) receptor
antagonist.
[0145] Cholinesterase inhibitors, e.g., acetylcholinesterase
inhibitors, are known in the art and/or are described e.g., in U.S.
Pat Nos. 4,895,841; and 4,948,807, the contents of each of which
are incorporated by reference in their entirety. Preferred
cholinesterase inhibitors to be used with the compound of the
present invention include donepezil, rivastignmine, galantamine and
tacrine.
[0146] NMDA receptor antagonists are also known in the art and are
described in U.S. Pat. No. 5,061,703, the contents of which are
incorporated by reference in their entirety. Preferred NMDA
receptor antagonist to be used with the compound of the present
invention is memantine.
[0147] Unlike dopamine receptor antagonists, Compounds of Formula I
normalize brain dopamine activity, particularly in the prefrontal
cortex. The Compounds of Formula I bind to 5-HT2A and dopamine
D.sub.2 receptors. Compounds of Formula I also exhibit nanomolar
binding affinity for SERT compared to known antidepressants.
Therefore, the compounds of Formula I are useful for the treatment
of (1) behavioral or mood disorders such as agitation/irritation,
aggressive/assaultive behavior, anger, physical or emotional
outbursts; (2) psychosis; (3) depression; and (4) sleep disorders
in patients suffering from dementia, particularly Alzheimer's
disease. Therefore, in addition to the therapeutic agents useful
for the treatment of dementia, the methods of the invention as
hereinbefore described may optionally further comprises one or more
therapeutic agents selected from antidepressant compounds,
compounds that modulate GABA activity (e.g., enhances the activity
and facilitates GABA transmission), a GABA-B agonist, a 5-HT
modulator (e.g., a 5 -HT.sub.1A agonist, a 5-HT2A antagonist, a
5-HT2A inverse agonist, etc.), a melatonin agonist, an ion channel
modulator (e.g., blocker) , a serotonin-2 antagonist/reuptake
inhibitor (SARIs), an orexin receptor antagonist, an H3 antagonist,
a noradrenergic antagonist, a galanin agonist, a CRH antagonist,
human growth hormone, a growth hormone agonist, estrogen, an
estrogen agonist, a neurokinin-1 drug, and an antipsychotic agent,
e.g., an atypical antipsychotic agent, in free or pharmaceutically
acceptable salt form. In such methods, the therapeutic agents may
be adjunctive to the compounds of the invention. As used herein the
term "adjunctive" refers to any treatment that is used in
conjunction with another to increase the chance of cure, or to
increase the first treatment's efficacy. In other words, adjunctive
therapy acts as an aid to the primary treatment. The combinations
of the invention can include mixtures of the combined drugs, as
well as two or more separate compositions of the drugs, which
individual compositions can be, for example, co-administered
together to a patient at the same of different times.
[0148] The antidepressant useful for the invention may be selected
from amitriptyline, amoxapine, bupropion, citalopram, clomipramine,
desipramine, doxepin, duloxetine, escitaloprame, fluoxetine,
fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine,
nefazodone, nortriptyline, paroxetine, phenelzine sulfate,
protiptyline, sertraline, tranylcypromine, trazodone, trimipramine,
and velafaxine, in free or pharmaceutically acceptable salt form.
In certain embodiment, the antidepressant(s) is a selective
serotonin reuptake inhibitor (SSRI). In a further embodiment, the
SSRI compound is selected from the group consisting of citalopram ,
escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine,
sertraline, and dapoxetine, in free or pharmaceutically acceptable
salt form.
[0149] The dosages for combined therapy with a compound of Formula
I, a compound of Formula II, and a further therapeutic agent can be
the same as or lower than the approved dosage for the drug, the
clinical or literature test dosage or the dosage used for the drug
as a monotherapy. In a specific embodiment, the dosages of a
compound of Formula I of Formula II, and/or the additional
therapeutic agents are lower than when used in a monotherapy.
[0150] The term "GABA" refers to gamma-aminobutyric acid. The GABA
compounds are compounds which bind to the GABA receptor, and
include, but are not limited to one or more of doxepin, alprazolam,
bromazepam, clobazam, clonazepam, clorazepate, diazepam,
flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,
oxazepam, temazapam, triazolam, indiplon, zopiclone, eszopiclone,
zaleplon, Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT 201
(Evotec Pharmaceuticals) or estazolam.
[0151] 5HT.sub.2A antagonists include ketanserin, risperidone,
eplivanserin, volinanserin (Sanofi-Aventis, France), pruvanserin,
pimavanserin (ACP-103), MDL 100907 (Sanofi-Aventis, France),
HY10275 (Eli Lilly), APD125 (Arena Pharmaceuticals, San Diego,
Calif.), AVE8488 (Sanofi-Aventis, France) and pizotifen.
[0152] 5HT.sub.1A agonists include repinotan, sarizotan,
eptapirone, buspirone and MN-305 (MediciNova, San Diego,
Calif.).
[0153] Melatonin agonists include melatonin, ramelteon
(ROZEREM.RTM., Takeda Pharmaceuticals, Japan), VEC-162 (Vanda
Pharmaceuticals, Rockville, Md.), PD-6735 (Phase II Discovery) and
agomelatine.
[0154] Ion channel blockers such as lamotrigine, gabapentin or
pregabalin.
[0155] Orexin receptor antagonists include orexin, a
1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868
(GlaxoSmithKline) and a benzamide derivative, for example.
[0156] Serotonin-2 antagonist/reuptake inhibitors (SARI) include
Org 50081 (Organon--Netherlands), ritanserin, nefazodone, serzone
and trazodone.
[0157] Neurokinin-1 drugs include Casopitant (GlaxoSmithKline).
[0158] Specific examples of additional therapeutic agents useful
for the current invention include modafinil, armodafinil, doxepin,
alprazolam, bromazepam, clobazam, clonazepam, clorazepate,
diazepam, flunitrazepam, flurazepam, lorazepam, midazolam,
nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone,
eszopiclone, zaleplon, zolpidem, gabaxadol, vigabatrin, tiagabine,
EVT 201 (Evotec Pharmaceuticals), estazolam, ketanserin,
risperidone, eplivanserin, volinanserin (Sanofi-Aventis, France),
pruvanserin, pimavanserin (ACP-103), pizotifen, MDL 100907
(Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (Arena
Pharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis,
France), repinotan, sarizotan, eptapirone, buspirone, MN-305
(MediciNova, San Diego, Calif.), melatonin, ramelteon
(ROZEREM.RTM., Takeda Pharmaceuticals, Japan), VEC-162 (Vanda
Pharmaceuticals, Rockville, Md.), PD-6735 (Phase II Discovery),
agomelatine, lamotrigine, gabapentin, pregabalin, orexin, a
1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868
(GlaxoSmithKline), a benzamide derivative, Org 50081
(Organon--Netherlands), ritanserin, nefazodone, serzone, trazodone,
Casopitant (GlaxoSmithKline), amitriptyline, amoxapine, bupropion,
citalopram, clomipramine, desipramine, doxepin, duloxetine,
escitaloprame, fluoxetine, fluvoxamine, imipramine, isocarboxazid,
maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine,
phenlzine sulfate, protiptyline, sertraline, tranylcypromine,
trazodone, trimipramine, velafaxine, chlorpromazine, haloperidol,
droperidol, fluphenazine, loxapine, mesoridazine molidone,
perphenazine, pimozide, prochlorperazine promazine, thioridazine,
thiothixene, trifluoperazine, clozapine, aripiparazole, olanzapine,
quetiapine, risperidone, ziprasidone and paliperidone, asenapine,
lurasidone, iloperidone and cariprazine, in free or
pharmaceutically acceptable salt form.
[0159] If not commercially available, starting materials for these
processes may be made using techniques similar or analogous to the
synthesis of known compounds. All references cited herein are
hereby incorporated in their entirety by reference.
[0160] The words "treatment" and "treating" are to be understood
accordingly as embracing prophylaxis and treatment or amelioration
of symptoms of disease and/or treatment of the cause of the
disease. In particular embodiment, the word "treatment" and
"treating" refers to prophylaxis or amelioration of symptoms of the
disease.
[0161] The term "patient" may include a human or non-human
patient.
[0162] The term "dementia" is intended to refer to a condition or
disorder characterized by the loss of cognitive ability affecting
memory, thinking, language, judgment and behavior. Early symptoms
of dementia may include difficulty performing tasks that require
some thought (balancing a checkbook, playing games (such as
bridge); learning new information; getting lost on familiar routes;
having language difficulties (difficulties in finding name of
familiar objects); losing interest in things previously enjoy;
losing social skills. More severe symptoms of dementia include
change in sleep patterns, often waking up at night; difficulty
performing basic tasks such as brushing teeth or preparing a meal;
forgetting details about current events; having hallucinations,
violent behavior, delusions, depression, agitation; difficulty
reading or writing; having poor judgment or loss of ability to
recognize danger; losing the ability to recognize family members or
understand language. The term "dementia" refers to any of the
dementing illnesses as described herein regardless of etiology and
therefore shall include but not limited to mild or severe cognition
impairment and dementing illnesses such as senile dementia,
Alzheimer's disease, Pick's disease, frontotemporal dementia,
parasupranculear palsy, dementia with Lewy bodies, vascular
dementia, Huntington's disease, Parkinson's disease, multiple
sclerosis, amyotrophic lateral sclerosis, Down syndrome, elderly
depression, Wernicke-Korsakoff's syndrome, corticobasal
degenerations, and prion disease. In a particular embodiment,
dementia refers to mild cognitive impairment. In another
embodiment, dementia refers to Alzheimer's disease.
[0163] The term "disorder associated with dementia" means common
co-morbid psychiatric disorders or conditions associated with
dementia, which include but not limited to (1) behavioral or mood
disorders such as agitation/irritation, aggressive/assaultive
behavior, anger, physical or emotional outbursts; (2) psychosis;
(3) depression; and (4) sleep disorders. In particular embodiment
of the invention, the disorders associated with dementia are
disorders associated Alzheimer's disease.
[0164] The term "mild cognitive impairment" or "mild cognition
impairment" (MCI, also known as incipient dementia, or isolated
memory impairment) is cognitive impairment beyond that expected
based on the age and education of the individual, but which is not
significant enough to interfere with their daily activities.
Symptoms of MCI include difficulty performing more than one task at
a time, solving problems or making decisions, forgetting recent
events or conversations and taking longer to perform more difficult
mental activities.
[0165] If not otherwise specified or clear from context, the
following terms herein have the following meanings:
[0166] "Alkyl" as used herein is a saturated or unsaturated
hydrocarbon moiety, e.g., one to twenty-one carbon atoms in length,
which may be linear or branched (e.g., n-butyl or tert-butyl),
preferably linear, unless otherwise specified. For example,
"C.sub.1-21 alkyl" denotes alkyl having 1 to 21 carbon atoms. In
one embodiment, alkyl is optionally substituted with one or more
hydroxy or C.sub.1-22alkoxy (e.g., ethoxy) groups. In another
embodiment, alkyl contains 1 to 21 carbon atoms, preferably
straight chain and optionally saturated or unsaturated, for example
R.sub.1 is an alkyl chain containing 1 to 21 carbon atoms,
preferably 6-15 carbon atoms, 16-21 carbon atoms, e.g., so that
together with the --C(O)-- to which it attaches, e.g., when cleaved
from the compound of Formula I, forms the residue of a natural or
unnatural, saturated or unsaturated fatty acid.
[0167] The 5-HT2A or 5-HT2A/D2 receptor ligand, for example a
substituted heterocycle fused gamma-carbolines as described herein
and/or the PDE1 inhibitor for use in the Methods and Compositions
of the disclosure may be in free, pharmaceutically acceptable salt
or prodrug form. Pharmaceutically acceptable salts include, for
example, the tosylate salts in the case of Compounds of Formula 1,
the phosphate salts in the case of Compounds of Formula II, and
other salts as described above. Where dosages or amounts of a salt
are given by weight, e.g., milligrams per day or milligrams per
unit dose, the dosage amount of the salt is given as the weight of
the corresponding free base, unless otherwise indicated.
[0168] The 5-HT2A or 5-HT2A/D2 receptor ligand and/or the PDE1
inhibitor may in some cases also exist in prodrug form. A prodrug
form is compound which converts in the body to the active compound.
For example compounds which contain hydroxy or carboxy substituents
may form physiologically hydrolysable and acceptable esters. As
used herein, "physiologically hydrolysable and acceptable ester"
means esters which are hydrolysable under physiological conditions
to yield acids (in the case of compounds which have hydroxy
substituents) or alcohols (in the case of compounds which have
carboxy substituents) which are themselves physiologically
tolerable at doses to be administered. For example, wherein Y of
the compound of Formula I is --C(H)(OR.sub.1), and R.sub.1 is
--C(O)--C.sub.1-21alkyl, e.g., --C(O)--C.sub.3alkyl or
--C(O)--C.sub.9alkyl, these compounds may hydrolyze under
physiological condition to yield a compound of Formula I wherein Y
is --C(H)(OH) on the one hand and C.sub.1-21alkyl-C(O)OH, e.g.,
C.sub.3alkyl--C(O)OH or C.sub.9alkyl-C(O)OH on the other hand. As
will be appreciated the term thus embraces conventional
pharmaceutical prodrug forms. Wherein a prodrug (e.g., the compound
of formula (I) wherein R.sub.1 is --C(O)--C.sub.1-21alkyl) is used,
the dosage amount is calculated based on the amount of the compound
of formula (I) wherein Y is --C(.dbd.O)-- or --CH(OH)--, in free
base form.
[0169] The term "simultaneously" when referring to a therapeutic
use means administration of two or more active ingredients at or
about the same time by the same route of administration.
[0170] The term "separately" when referring to a therapeutic use
means administration of two or more active ingredients at or about
the same time by different route of administration.
[0171] The phrase "disorder(s) associated with Alzheimer's disease"
includes, but is not limited to (1) behavioral or mood disorders
such as agitation/irritation, aggressive/assaultive behavior,
anger, physical or emotional outbursts; (2) psychosis; (3)
depression; and (4) sleep disorders in patients suffering from
Alzheimer's disease.
[0172] Dosages employed in practicing the present invention will of
course vary depending, e.g. on the particular disease or condition
to be treated, the particular active compounds used, the mode of
administration, and the therapy desired. Unless otherwise
indicated, an amount of an active compound for administration
(whether administered as a free base or as a salt form) refers to
or is based on the amount of the compound in free form (i.e., the
calculation of the amount is based on the amount of active moiety
in free form, not taking into account the weight of the counter ion
in the case of a salt). Wherein a prodrug (e.g., the compound of
formula (I) wherein R.sub.1 is --C(O)--C.sub.1-21alkyl) is used,
the dosage amount is calculated based on the amount of the compound
of formula (I) wherein Y is C(.dbd.O) in free base form. Compounds
of the Invention may be administered by any suitable route,
including orally, intra-muscularly, subcutaneously, parenterally or
transdermally, but are preferably administered orally. Compounds of
the Invention may be administered by any suitable route, including
orally, parenterally or transdermally, but are preferably
administered orally.
[0173] For the avoidance of doubt, any disclosure of a numerical
range, e.g., "up to X" amount is intended to include the upper
numerical limit X. Therefore, a disclosure of "up to 60 mg" is
intended to include 60 mg.
[0174] Pharmaceutical compositions comprising compounds of the
Invention may be prepared using conventional diluents or excipients
and techniques known in the galenic art. Thus oral dosage forms may
include tablets, capsules, solutions, suspensions and the like.
* * * * *