U.S. patent application number 16/218186 was filed with the patent office on 2019-11-21 for combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline.
The applicant listed for this patent is Axovant Sciences GmbH. Invention is credited to Tsu Tshen CHUANG, Ann Jacqueline HUNTER, David John VIRLEY.
Application Number | 20190350927 16/218186 |
Document ID | / |
Family ID | 40427203 |
Filed Date | 2019-11-21 |
![](/patent/app/20190350927/US20190350927A1-20191121-C00001.png)
United States Patent
Application |
20190350927 |
Kind Code |
A1 |
CHUANG; Tsu Tshen ; et
al. |
November 21, 2019 |
COMBINATIONS COMPRISING
3-PHENYLSULFONYL-8-PIPERAZINYL-1YL-QUINOLINE
Abstract
The combination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline
or a pharmaceutically acceptable salt thereof with a second
therapeutic agent, and its use for the treatment of a) psychiatric
disorders with prominent cognitive deficits e.g. chronic PTSD (Post
traumatic stress disorder); b) non-degenerative disorders with
prominent cognitive deficits e.g. MS (multiple Sclerosis),
post-chemotherapy, post-CABG (Coronary artery bypass graft),
post-stroke; and/or c) paediatric disorders e.g. autism, mental
retardation and learning disabilities, in particular for the
treatment of schizophrenia.
Inventors: |
CHUANG; Tsu Tshen; (Essex,
GB) ; HUNTER; Ann Jacqueline; (Hertfordshire, GB)
; VIRLEY; David John; (Essex, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Axovant Sciences GmbH |
Basel |
|
CH |
|
|
Family ID: |
40427203 |
Appl. No.: |
16/218186 |
Filed: |
December 12, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15718803 |
Sep 28, 2017 |
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|
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16218186 |
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|
14802036 |
Jul 17, 2015 |
9808455 |
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15718803 |
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12746968 |
Jun 9, 2010 |
9084742 |
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PCT/EP2008/067225 |
Dec 10, 2008 |
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14802036 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/519 20130101;
A61K 31/4525 20130101; A61K 31/13 20130101; A61P 25/28 20180101;
A61K 2300/00 20130101; A61K 31/5513 20130101; A61K 31/00 20130101;
A61K 31/5513 20130101; A61K 31/496 20130101; A61P 25/18 20180101;
A61K 45/06 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/5513 20060101 A61K031/5513; A61K 31/00
20060101 A61K031/00; A61K 31/4525 20060101 A61K031/4525; A61K 45/06
20060101 A61K045/06; A61K 31/519 20060101 A61K031/519; A61K 31/13
20060101 A61K031/13 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 12, 2007 |
GB |
0724281.1 |
Dec 12, 2007 |
GB |
0724285.2 |
Claims
1.-6. (canceled)
7. A method of treating a cognitive memory disorder in a patient in
need thereof comprising administering to said patient more than 40
mg of 3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a
pharmaceutically acceptable salt thereof, and a therapeutically
effective amount of an acetylcholinesterase inhibitor; wherein said
cognitive memory disorder is selected from the group consisting of
Alzheimer's disease, age related cognitive decline, mild cognitive
impairment, dementia associated with mixed Alzheimer's disease,
cardiovascular disease, vascular dementia, dementia with Lewy
Bodies, and dementia associated with Huntingdon's disease.
8. The method of claim 7, wherein the cognitive memory disorder is
Alzheimer's disease.
9. The method of claim 7, wherein the acetylcholinesterase
inhibitor is selected from donepezil, galanthamine, rivastigmine,
and any combination thereof.
10. The method of claim 7, wherein the dose of
3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceutically
acceptable salt thereof, is administered once a day.
11. The method of claim 7, wherein the dose of
3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceutically
acceptable salt thereof, is administered more than once a day.
12. A method for the treatment of a cognitive memory disorder in a
patient in need thereof comprising administering to said patient a
pharmaceutical composition comprising more than 40 mg of
3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceutically
acceptable salt thereof, a therapeutically effective amount of an
acetylcholinesterase inhibitor, and a pharmaceutically acceptable
carrier; wherein said cognitive memory disorder is selected from
the group consisting of Alzheimer's disease, age related cognitive
decline, mild cognitive impairment, dementia associated with mixed
Alzheimer's disease, cardiovascular disease, vascular dementia,
dementia with Lewy Bodies, and dementia associated with
Huntingdon's disease.
13. The method of claim 12, wherein the cognitive memory disorder
is Alzheimer's disease.
14. The method of claim 12, wherein the acetylcholinesterase
inhibitor is selected from donepezil, galanthamine, rivastigmine,
and any combination thereof.
15. The method of claim 12, wherein the dose of
3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceutically
acceptable salt thereof, is administered once a day.
16. The method of claim 12, wherein the dose of
3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceutically
acceptable salt thereof, is administered more than once a day.
17. A method for improving the cognitive function of a patient
suffering from one or more of Alzheimer's disease, age related
cognitive decline, mild cognitive impairment, dementia associated
with mixed Alzheimer's disease, cardiovascular disease, vascular
dementia, dementia with Lewy Bodies, and dementia associated with
Huntingdon's disease, comprising administering to said patient more
than 40 mg of 3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a
pharmaceutically acceptable salt thereof, and a therapeutically
effective amount of an acetylcholinesterase inhibitor.
18. The method of claim 17, wherein the acetylcholinesterase
inhibitor is selected from donepezil, galanthamine, rivastigmine,
and any combination thereof.
19. The method of claim 17, wherein the dose of
3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceutically
acceptable salt thereof, is administered once a day.
20. The method of claim 17, wherein the dose of
3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceutically
acceptable salt thereof, is administered more than once a day.
21. A method for improving the cognitive function of a patient
suffering from one or more of Alzheimer's disease, age related
cognitive decline, mild cognitive impairment, dementia associated
with mixed Alzheimer's disease, cardiovascular disease, vascular
dementia, dementia with Lewy Bodies, and dementia associated with
Huntingdon's disease, comprising administering to said patient a
pharmaceutical composition comprising more than 40 mg of
3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceutically
acceptable salt thereof, a therapeutically effective amount of an
acetylcholinesterase inhibitor; and a pharmaceutically acceptable
carrier.
22. The method of claim 21, wherein the acetylcholinesterase
inhibitor is selected from donepezil, galanthamine, rivastigmine,
and any combination thereof.
23. The method of claim 21, wherein the dose of
3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceutically
acceptable salt thereof, is administered once a day.
24. The method of claim 21, wherein the dose of
3-phenylsulfonyl-8-piperazinyl-1-yl-quinoline or a pharmaceutically
acceptable salt thereof, is administered more than once a day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 15/718,803, filed on Sep. 28, 2017,
which is a continuation of U.S. patent application Ser. No.
14/802,036, filed on Jul. 17, 2015, which is a continuation
application of U.S. patent application Ser. No. 12/746,968 filed on
Jun. 9, 2010, which is a National Stage filing under 35 U.S.C.
.sctn. 371 of International Patent Application No.
PCT/EP2008/067225, filed Dec. 10, 2008, which claims the priority
of United Kingdom Application Nos. 0724281.1 and 0724285.2, both
filed on Dec. 12, 2007, the contents which are incorporated herein
by reference in their entireties.
[0002] The present application relates to new uses of 5-HT.sub.6
receptor antagonists, specifically
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline, and to the
combination of 5-HT.sub.6 receptor antagonists, specifically
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline, with a second
therapeutic agent.
[0003] WO03/080580 discloses compounds of formula (I) and
pharmaceutically acceptable salts thereof:
##STR00001##
[0004] wherein:
[0005] R.sup.1 and R.sup.2 independently represent hydrogen or
C.sub.1-6 alkyl or R.sup.1 is linked to R.sup.2 to form a group
(CH.sub.2).sub.2, (CH.sub.2).sub.3 or (CH.sub.2).sub.4;
[0006] R.sup.3, R.sup.4 and R.sup.5 independently represent
hydrogen, halogen, cyano, --CF.sub.3, --CF.sub.3O, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl or a group
--CONR.sup.6R.sup.7;
[0007] R.sup.6 and R.sup.7 independently represent hydrogen or
C.sub.1-6 alkyl or together may be fused to form a 5- to 7-membered
aromatic or non-aromatic heterocyclic ring optionally interrupted
by an O or S atom;
[0008] m represents an integer from 1 to 4, such that when m is an
integer greater than 1, two R.sup.2 groups may instead be linked to
form a group CH.sub.2, (CH.sub.2).sub.2 or (CH.sub.2).sub.3;
[0009] n represents an integer from 1 to 3;
[0010] p represents 1 or 2;
[0011] A represents a group --Ar.sup.1 or --Ar.sup.2Ar.sup.3;
[0012] Ar.sup.1, Ar.sup.2 and Ar.sup.3 independently represent an
aryl group or a heteroaryl group, both of which may be optionally
substituted by one or more (eg. 1, 2 or 3) substituents which may
be the same or different, and which are selected from the group
consisting of halogen, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6 alkyl, trifluoromethanesulfonyloxy,
pentafluoroethyl, C.sub.1-6 alkoxy, arylC.sub.1-6 alkoxy, C.sub.1-6
alkylthio, C.sub.1-6 alkoxyC.sub.1-6 alkyl, C.sub.3-7
cycloalkylC.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, C.sub.1-6
alkoxycarbonyl, C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylsulfinyl,
C.sub.1-6 alkylsulfonyloxy, C.sub.1-6 alkylsulfonyl C.sub.1-6
alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC.sub.1-6 alkyl,
C.sub.1-6 alkylsulfonamido, C.sub.1-6 alkylamido, C.sub.1-6
alkylsulfonamidoC.sub.1-5 alkyl, C.sub.1-6 alkylamidoC.sub.1-6
alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC.sub.1-6
alkyl, arylcarboxamidoC.sub.1-6 alkyl, aroyl, aroylC.sub.1-6 alkyl,
arylC.sub.1-6 alkanoyl, or a group CONR.sup.8R.sup.9 or
SO.sub.2NR.sup.8R.sup.9, wherein R.sup.8 and R.sup.9 independently
represent hydrogen or C.sub.1-6 alkyl or together may be fused to
form a 5- to 7-membered aromatic or non-aromatic heterocyclic ring
optionally interrupted by an C or S atom;
[0013] or solvates thereof.
[0014] Specifically disclosed is
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline (Example 16) and its
hydrochloride salt (Example 2).
[0015] 3-Phenylsulfonyl-8-piperazinyl-1yl-quinoline can be prepared
as described in WO03/080580 or by the further process described in
WO07/039238. WO05/040124 discloses a further polymorphic form of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline as Form III. These
International Patent Applications are incorporated herein in their
entirety.
[0016] Compounds of formula (I) and their pharmaceutically
acceptable salts are disclosed in WO03/080580 as having affinity
for the 5-HT.sub.6 receptor and are believed to be of potential use
in the treatment of certain CNS disorders such as anxiety,
depression, epilepsy, obsessive compulsive disorders, migraine,
cognitive memory disorders (e.g. Alzheimers disease, age related
cognitive decline and mild cognitive impairment), Parkinsons
Disease, ADHD (Attention Deficit Disorder/Hyperactivity Syndrome),
sleep disorders (including disturbances of Circadian rhythm),
feeding disorders such as anorexia and bulimia, panic attacks,
withdrawal from drug abuse such as cocaine, ethanol, nicotine and
benzodiazepines, schizophrenia (in particular cognitive deficits of
schizophrenia), stroke and also disorders associated with spinal
trauma and/or head injury such as hydrocephalus. WO03/080580 also
discloses that Compounds of formula (I) and their pharmaceutically
acceptable salts are expected to be of use in the treatment of
certain GI (gastrointestinal) disorders such as IBS (Irritable
Bowel Syndrome) and in the treatment of obesity.
[0017] It will be appreciated by those skilled in the art that the
term cognitive memory disorders includes other neurodegenerative
disorders associated with dementia, e.g. VaD (Vascular Dementia),
DLB (dementia with Lewy Bodies), Mixed AD+CVD (Alzheimer's Disease
and Cardiovascular Disease) and HD (Huntingdon's Disease).
[0018] US2007/0167431 and WO07/087151 (both Wyeth) disclose a
method for the treatment of a cognitive disorder such as
Alzheimer's disease in a patient in need thereof which comprises
providing to said patient a therapeutically effective amount of a
combination of an acetylcholinesterase inhibitor and a 5-HT.sub.6
receptor antagonist.
[0019] US2007/0167431 discloses that the acetylcholinesterase
inhibitors suitable for use are donepezil (i.e. Aricept.TM.
manufactured by Pfizer), galanthamine (i.e. Razadyne.TM.,
manufactured by Johnson and Johnson), rivastigmine (i.e.
Exelon.TM., manufactured by Novartis) or any other compounds known
to inhibit acetylcholinesterase. A number of patent applications
were cited therein which disclosed 5-HT6 antagonists suitable for
use. Furthermore the following 5HT6 compounds were listed by name,
3-(1-naphthylsulfonyl)-5-piperazin-1yl-1H-indazole,
N,N-dimethyl-3-{3-(1-naphthylsulphonyl)-1H-indazol-5-yl]oxy}propan-1-amin-
e, (2-{[3-(1-naphthylsulphonyl)-1H-indazol-7-yl]oxy}ethyl)amine,
1-(phenylsulphonyl)-4-(1-piperazinyl)-1H-indazole,
5-chloro-N-[4-methoxy-3-(1-piperazinyl)phenyl]-3-methylbenzo(b)thiophene--
2-sulfonamide (SB-271046),
4-amino-N-[2,6-bis(methylamino)pyrimidin-4-yl]benzenesulfonamide
(Ro 04-6790,
4-amino-N-[2,6-bis(methylamino)pyridin-4-yl]benzenesulfonamide (Ro
63-0563), SB357134, SB399885, GSK-742457, LY4833518/SGS-518,
Ro43-68554 and PRX-07034.
[0020] The present invention provides the combination of a
5-HT.sub.6 receptor antagonist, specifically
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically
acceptable salt thereof, with a second therapeutic agent. In one
embodiment the present invention provides a combination of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically
acceptable salt thereof with a therapeutic agent known to modify
cholinergic transmission such as M1 muscarinic receptor agonists or
allosteric modulators, M2 muscarinic antagonists,
acetylcholinesterase inhibitors, nicotinic receptor agonists or
allosteric modulators, 5-HT4 receptor partial agonists or 5HT1A
receptor antagonists and NMDA receptor antagonists or modulators,
glutamate antagonists, GABA-ergic antagonists, H3 antagonists,
putative metabolic/mitochondrial modulators, or disease modifying
agents such as .beta. or .gamma.-secretase inhibitors, Tau-targeted
therapeutics, .beta.-amyloid aggregation inhibitors and
.beta.-amyloid immunotherapies.
[0021] Examples of putative metabolic/mitochondrial modulators are
Ketasyn.TM., RSG-XR, intranasal insulin and Dimebon.
[0022] Examples of .beta.-amyloid aggregation inhibitors and
.beta.-amyloid immunotherapies include PBT2 (Prana Biotechnology),
ELND005/AZD-103 (Elan and Transition Therapeutics), Gammagard/IGIV
(Baxter International), monoclonal antibody LY2062430 (Eli Lilly),
and bapineuzumab (Wyeth/Elan).
[0023] Examples of Tau-targeted therapeutics include
tetramethylthionine chloride (REMBER.TM., TauRX) and AL-108
(Allon).
[0024] This combination may be useful in the treatment of cognitive
memory disorders, for example Alzheimer's disease, age related
cognitive decline and mild cognitive impairment, neurodegenerative
disorders for example dementia including vascular dementia (VaD),
dementia with Lewy Bodies (DLB), Alzheimer's Disease and
Cardiovascular Disease (Mixed AD+CVD) and Huntingdon's Disease
(HD).
[0025] Accordingly the present invention also provides a method for
the treatment of cognitive memory disorders, for example
Alzheimer's disease, age related cognitive decline and mild
cognitive impairment, neurodegenerative disorders for example
dementia including vascular dementia (VaD), dementia with Lewy
Bodies (DLB), Alzheimer's Disease and Cardiovascular Disease (Mixed
AD+CVD) and Huntingdon's Disease (HD) in a patient in need thereof
which comprises providing to said patient a therapeutically
effective amount of a combination of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically
acceptable salt thereof, with a therapeutic agent known to modify
cholinergic transmission such as M1 muscarinic receptor agonists or
allosteric modulators, M2 muscarinic antagonists,
acetylcholinesterase inhibitors, nicotinic receptor agonists or
allosteric modulators, 5-HT4 receptor partial agonists or 5HT1A
receptor antagonists and NMDA receptor antagonists or modulators,
glutamate antagonists, GABA-ergic antagonists, H3 antagonists,
putative metabolic/mitochondrial modulators, or disease modifying
agents such as .beta. or .gamma.-secretase inhibitors, Tau-targeted
therapeutics, .beta.-amyloid aggregation inhibitors and
.beta.-amyloid immunotherapies.
[0026] One embodiment is directed to combinations of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically
acceptable salt thereof and a second therapeutic agent selected
from donepezil, rivastigmine, tetrahydroaminoacridine, memantine,
galantamine,
6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3--
pyridinecarboxamide hydrochloride or
1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridi-
nyl}-2-pyrrolidinone.
[0027] At a mechanistic level, pharmacodynamic interactions between
an acetylcholinesterase inhibitor and a 5HT.sub.6 receptor
antagonist are feasible. In preclinical studies in rats
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline induces a small
increase in the extra cellular levels of acetylcholine in the
prefrontal cortex. Although the underlying mechanism is still
unknown, it is likely due to increases in the release of
acetylcholine from cholinergic neurons. On the other hand,
donepezil increases the extracellular levels of acetylcholine by
inhibiting the acetylcholinesterase to reduce the degradation of
acetylcholine. Therefore this action may prevent the degradation of
acetylcholine induced by
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline resulting in a net
increased level of acetylcholine that may influence cognitive
functions.
[0028] In another embodiment the present invention provides a
combination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a
pharmaceutically acceptable salt thereof with an antidepressant,
for example a tricyclic, a MAOI (Monoamine oxidase inhibitor) a
SSRI (Selective Serotonin Reuptake Inhibitor), a SNRI (Serotonin
and Noradrenaline Reuptake Inhibitor) or a NaSSA (noradrenergeric
and specific serotonergic antidepressant). Examples of specific
antidepressant compounds are described below.
TABLE-US-00001 Medication Trade name Group Amitriptyline Tryptizol
Tricyclic Clomipramine Anafranil Tricyclic Citalopram Cipramil SSRI
Dosulepin Prothiaden Tricyclic Doxepin Sinequan Tricyclic
Fluoxetine Prozac SSRI Imipramine Tofranil Tricyclic Lofepramine
Gamanil Tricyclic Mirtazapine Zispin NaSSA Moclobemide Manerix MAOI
Nortriptyline Allegron Tricyclic Paroxetine Seroxat SSRI Phenelzine
NardiI MAOI Reboxetine Edronax SNRI Sertraline Lustral SSRI
Tranylcypromine Parnate MAOI Trazodone Molipaxin Tricyclic-related
Venlafaxine Efexor SNRI
[0029] In a further embodiment the present invention provides a
combination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a
pharmaceutically acceptable salt thereof and an atypical
antipsychotic, for example olanzapine, clozapine, prisperidone,
quentiapine, aripriprazole or paliperiden.
[0030] This combination may be useful in the treatment of
schizophrenia. Accordingly, in yet another aspect the present
invention provides a method for the treatment of schizophrenia in a
patient in need thereof which comprises providing to said patient a
therapeutically effective amount of a combination of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically
acceptable salt thereof, with an atypical antipsychotic, for
example olanzapine, clozapine, prisperidone, quentiapine,
aripriprazole or paliperiden.
[0031] In a further embodiment the present invention provides a
combination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a
pharmaceutically acceptable salt thereof and a second therapeutic
agent suitable for use in Attention Deficit Disorders/Hyperactivity
Syndrome, e.g. methylphenidate (Ritalin) or dexamfetamine
(Dexedrine).
[0032] In a further aspect the present invention also provides the
use of a combination of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically
acceptable salt thereof and a second therapeutic agent in the
manufacture of a medicament for use in the treatment of the above
disorders.
[0033] Accordingly, in one embodiment the present invention
provides the use of a combination of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically
acceptable salt thereof with a therapeutic agent known to modify
cholinergic transmission such as M1 muscarinic receptor agonists or
allosteric modulators, M2 muscarinic antagonists,
acetylcholinesterase inhibitors, nicotinic receptor agonists or
allosteric modulators, 5-HT4 receptor partial agonists or 5HT1A
receptor antagonists and NMDA receptor antagonists or modulators,
glutamate antagonists, GABA-ergic antagonists, H3 antagonists,
putative metabolic/mitochondrial modulators, or disease modifying
agents such as .beta. or .gamma.-secretase inhibitors, Tau-targeted
therapeutics, .beta.-amyloid aggregation inhibitors and
.beta.-amyloid immunotherapies, in the manufacture of a medicament
for use in the treatment of cognitive memory disorders, for example
Alzheimer's disease, age related cognitive decline and mild
cognitive impairment, neurodegenerative disorders for example
dementia including vascular dementia (VaD), dementia with Lewy
Bodies (DLB), Alzheimer's Disease and Cardiovascular Disease (Mixed
AD+CVD) and Huntingdon's Disease (HD).
[0034] In another embodiment the present invention provides the use
of a combination of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or
a pharmaceutically acceptable salt thereof and an atypical
antipsychotic, for example olanzapine, clozapine, prisperidone,
quentiapine, aripriprazole or paliperiden in the manufacture of a
medicament for use in the treatment of schizophrenia.
[0035] The present invention is also directed to new uses of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically
acceptable salt thereof; specifically [0036] a) further psychiatric
disorders with prominent cognitive deficits e.g. chronic PTSD (Post
traumatic stress disorder); [0037] b) non-degenerative disorders
with prominent cognitive deficits: MS (multiple Sclerosis),
post-chemotherapy, post-CABG (Coronary artery bypass graft),
post-stroke; and [0038] c) paediatric disorders: autism, mental
retardation and learning disabilities.
[0039] The invention further provides a method of treatment or
prophylaxis of these disorders, in mammals including humans, which
comprises administering to the sufferer a therapeutically effective
amount of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a
pharmaceutically acceptable salt thereof.
[0040] The invention also provides the use of a
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically
acceptable salt thereof in the manufacture of a medicament for use
in the treatment or prophylaxis of these disorders.
[0041] The invention also provides combinations of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline and a second
therapeutic agent for use in these disorders.
[0042] In respect of the treatment of PTSD, the second therapeutic
agent may be selected from: serotonergic antidepressants (SSRIs),
e.g. fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil),
trazodone (Desyrel); medicines that help decrease the physical
symptoms associated with PTSD, e.g. clonidine (Catapres),
guaneficine (Tenex), and propranolol; mood stabilizers such as
lamotrigine (Lamictal), tiagabine (Gabitril), divalproex sodium
(Depakote); monoamine oxadazine inhibitors, phenelzine (Nardil);
antiadrenergic agents, e.g. clonidine (Catapres), propanolol
(Inderal) and guanfacine (Tenex), mood stabilizers that are also
antipsychotics, like risperidone (Risperdal), olanzapine (Zyprexa),
and quetiapine (Seroquel).
[0043] In respect of the treatment of MS, the second therapeutic
agent may be selected from: steroids, e.g. methylprednisolone (eg
Depo-Medrone), prednisone, dexamethasone disease-modifying agents
e.g. interferon beta-1a (Avonex or Rebif), interferon beta-1b
(Betaferon), glatiramer acetate (Copaxone) injections or
mitoxantrone (Novantrone); symptomatic agents e.g. Muscle Relaxants
(Baclofen, Dantrolene, Tizanidine, Cyclobenzaprine, Clonazepam,
Diazepam); Anticholinergics (Propantheline, Tolterodine
Dicyclomine); Urinary Tract Antispasmodics (Oxybutynin); Tricyclic
Antidepressants (Amitriptyline, Imipramine); Antidiuretic Hormone
(desmopressin and desmopressin acetate); Anticonvulsants
(carbamazepine, phenytoin, acetazolamide, lamotrigine); Central
Nervous System Stimulants (pemoline); Selective Serotonin Reuptake
Inhibitors (SSRIs) (citalopram, fluoxetine, paroxetine,
sertraline); Non-Steroidal Anti-Inflammatory Drugs (NSAIDS)
(ibuprofen, naproxen, ketoprofen); and Phosphodiesterase-5
Inhibitors (sildenafil, tadalafil, vardenafil).
[0044] Additionally the second therapeutic agent for use in the
treatment of MS or its associated symptoms may be selected from an
H3 receptor antagonist,
6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3--
pyridinecarboxamide hydrochloride or
1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridi-
nyl}-2-pyrrolidinone; S1P1 agonists; anti-CD20 monoclonal antibody
therapies such as rituximab, ofatumumab; anti-CD3 monoclonal
antibody therapies such as otelixizumab; rosiglitazone
(Avandia.TM.), alpha 4 integrin antagonist e.g firategrast,
natalizumab (TYSABRI.TM.).
[0045] Additionally the second therapeutic agent for use in the
treatment of MS or its associated symptoms may be selected from
BG12 (Biogen Idec), an S1P agonist e.g. Fingolimod, an
immunosuppressant e.g. Laquinimod, Teriflunomide; an estrogen
agonist e.g. Trimesta.
[0046] In respect of the treatment post chemotherapy, the second
therapeutic agent may be selected from: Aldesleukin or IL-2
(Proleukin), Alemtuzumab (MabCampath), Amsacrine (acridinyl
anisidide; m-AMSA), Anastrozole (Arimidex), Asparaginase
(Crisantaspase), Bevacizumab (Avastin), Bicalutamide (Casodex),
Bleomycin, Bortezomib (Velcade), Busulfan, (Campto) Irinotecan,
Capecitabine (Xeloda) Carboplatin (Paraplatin), Carmustine (BCNU),
Cetuximab, Chlorambucil, Cisplatin, Cladribine (2-CdA, Leustatin),
Co-codamol, Cyclophosphamide, Cyproterone acetate (Cyprostat),
Cytarabine (Ara C, cytosine arabinoside), Dacarbazine (DTIC),
Dactinomycin (Actinomycin D), Daunorubicin, Disodium pamidronate
(Aredia), Docetaxel (Taxotere), Doxorubicin, Epirubicin, Erlotinib
(Tarceva), Estramustine (Emcyt, Estracyte), Etoposide (VP16,
Etopophos), Exemestane (Aromasin), Fentanyl (Durogesic),
Fludarabine, Fluorouracil (5FU), Flutamide (Drogenil), Gemcitabine
(Gemzar), (Herceptin) Trastuzumab, Goserelin (Zoladex) for breast
cancer, Goserelin (Zoladex) for prostate cancer, Hydroxycarbamide
(used to be called hydroxyurea), Ibandronic acid (Bondronat),
Ibritumomab (Zevalin), Ibuprofen, Idarubicin (Zavedos) Ifosfamide,
Imatinib (Glivec), Interferon (Roferon, Intron A), Irinotecan
(Campto), Interleukin, Iapatinib (Tykerb), Letrozole (Femara),
Liposomal Doxorubicin (Caelyx, Myocet, Doxcil), Lomustine (CCNU),
Melphalan, Mercaptopurine (6-MP, Purinethol), Methotrexate,
Mitomycin C, Mitoxantrone, Morphine, Oxaliplatin, Paclitaxel
(Taxol), Pentostatin, Procarbazine, Raltitrexed (Tomudex),
Rituximab (Mabthera), Sodium clodronate (Bonefos, Loron),
Streptozocin (Zanosar), Steroids, Tamoxifen, (Taxol) Paclitaxel,
(Taxotere) Docetaxel, Tegafur with uracil (Uftoral), Temozolomide
(Temodal), Tioguanine (Lanvis, 6-TG, 6-tioguanine, Tabloid),
Thiotepa (Thioplex, Triethylenethiophosphoramide), (Tomudex)
Raltitrexed, Topotecan (Hycamtin), Tretinoin (Vesanoid, ATRA),
Treosulfan, Vinblastine (Velban), Vincristine (Oncovin) Vindesine
(Eldisine), Vinorelbine (Navelbine), Zevalin (90Y Ibritumomab
tiuxetan) and Zoledronic acid (Zometa).
[0047] Specifically the second therapeutic agent may be lapatinib,
which may also be used in conjunction with capecitabine.
[0048] In respect of treatment after a stroke, the second
therapeutic agent may be selected from alteplase (Actilyse),
aspirin, dipyridamole, fluvastatin sodium (Lescol), clopidogrel
hydrogen sulphate (Plavix), ramipril (Tritace) and simvastatin
(Simvador, Zocor).
[0049] It will be appreciated that reference to treatment is
intended to include prophylaxis as well as the alleviation of
established symptoms.
[0050] The two therapeutic agents may be administered
simultaneously or sequentially and, when administration is
sequential, either may be administered first. When administration
is simultaneous, the combination may be administered either in the
same or different pharmaceutical composition.
[0051] The two therapeutic agents may be used either as separate
formulations or as a single combined formulation. When combined in
the same formulation it will be appreciated that the two compounds
must be stable and compatible with each other and the other
components of the formulation.
[0052] Therefore, in further aspect the present invention also
provides pharmaceutical compositions comprising an effective amount
of a combination of a 5-HT.sub.6 receptor antagonist, specifically
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or a pharmaceutically
acceptable salt thereof and a second therapeutic agent, and a
pharmaceutically acceptable carrier.
[0053] In one embodiment the second therapeutic agent is an agent
known to modify cholinergic transmission such as M1 muscarinic
receptor agonists or allosteric modulators, M2 muscarinic
antagonists, acetylcholinesterase inhibitors, nicotinic receptor
agonists or allosteric modulators, 5-HT4 receptor partial agonists
or 5HT1A receptor antagonists and NMDA receptor antagonists or
modulators, glutamate antagonists GABA-ergic antagonists, H3
antagonists or disease modifying agents such as .beta. or
.gamma.-secretase inhibitors.
[0054] In another embodiment the second therapeutic agent is an
antidepressant, for example a tricyclic, a MAOI (Monoamine oxidase
inhibitor) a SSRI (Selective Serotonin Reuptake Inhibitor), a SNRI
(Serotonin and Noradrenaline Reuptake Inhibitor) or a NaSSA
(noradrenergeric and specific serotonergic antidepressant).
[0055] In another embodiment the second therapeutic agent is an
atypical antipsychotic, for example olanzapine, clozapine,
prisperidone, quentiapine, aripriprazole or paliperiden.
[0056] In another embodiment the second therapeutic agent is a
therapeutic agent suitable for use in Attention Deficit
Disorders/Hyperactivity Syndrome, e.g. methylphenidate (Ritalin) or
dexamfetamine (Dexedrine).
[0057] When formulated separately they may be provided in any
convenient formulation, conveniently in such manner as are known
for such compounds in the art.
[0058] A pharmaceutical composition may be prepared by admixture,
suitably at ambient temperature and atmospheric pressure, and is
usually adapted for oral, parenteral or rectal administration and,
as such, may be in the form of tablets, capsules, oral liquid
preparations, powders, granules, lozenges, reconstitutable powders,
injectable or infusable solutions or suspensions or suppositories.
Orally administrable compositions are generally preferred.
[0059] Tablets and capsules for oral administration may be in unit
dose form, and may contain conventional excipients, such as binding
agents, fillers, tabletting lubricants, disintegrants and
acceptable wetting agents. The tablets may be coated according to
methods well known in normal pharmaceutical practice.
[0060] Oral liquid preparations may be in the form of, for example,
aqueous or oily suspension, solutions, emulsions, syrups or
elixirs, or may be in the form of a dry product for reconstitution
with water or other suitable vehicle before use. Such liquid
preparations may contain conventional additives such as suspending
agents, emulsifying agents, non-aqueous vehicles (which may include
edible oils), preservatives, and, if desired, conventional
flavourings or colourants.
[0061] For parenteral administration, fluid unit dosage forms are
prepared utilising a compound and a sterile vehicle. The compound,
depending on the vehicle and concentration used, can be either
suspended or dissolved in the vehicle. In preparing solutions, the
compound can be dissolved for injection and filter sterilised
before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaesthetic,
preservatives and buffering agents are dissolved in the vehicle. To
enhance the stability, the composition can be frozen after filling
into the vial and the water removed under vacuum. Parenteral
suspensions are prepared in substantially the same manner, except
that the compound is suspended in the vehicle instead of being
dissolved, and sterilization cannot be accomplished by filtration.
The compound can be sterilised by exposure to ethylene oxide before
suspension in a sterile vehicle. Advantageously, a surfactant or
wetting agent is included in the composition to facilitate uniform
distribution of the compound.
[0062] The composition may contain from 0.1% to 99% by weight,
preferably from 10 to 60% by weight, of the active material,
depending on the method of administration.
[0063] Compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredients. The pack may, for example,
comprise metal or plastic foil, such as a blister pack. Where the
compounds are intended for administration as two separate
compositions these may be presented, for example, in the form of a
twin pack.
[0064] Pharmaceutical compositions may also be prescribed to the
patient in "patient packs" containing the whole course of treatment
in a single package, usually a blister pack. Patient packs have an
advantage over traditional prescriptions, where a pharmacists
divides a patients supply of a pharmaceutical from a bulk supply,
in that the patient always has access to the package insert
contained in the patient pack, normally missing in traditional
prescriptions. The inclusion of a package insert has been shown to
improve patient compliance with the physicians instructions.
[0065] It will be understood that the administration of the
combination by means of a single patient pack, or patient packs of
each composition, including a package insert directing the patient
to the correct use of the combination is a desirable additional
embodiment.
[0066] According to a further embodiment there is provided a
patient pack comprising at least one active ingredient, of the
combination and an information insert containing directions on the
use of the combination.
[0067] According to another embodiment there is provided a double
pack comprising in association for separate administration of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline and the second
therapeutic agent.
[0068] The dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline
used in the treatment of the aforementioned disorders will vary in
the usual way with the seriousness of the disorders, the weight of
the sufferer, and other similar factors. However, as a general
guide suitable unit doses may be 0.05 to 1000 mg, more suitably
0.05 to 200 mg, for example 20 to 40 mg; and such unit doses will
preferably be administered once a day, although administration more
than once a day may be required; and such therapy may extend for a
number of weeks or months.
[0069] The dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline
used in combination with a second therapeutic agent may be same as
when it is used on its own or may be different. It may be possible
that the dose of either drug used may be lower when used in
combination than when used separately.
[0070] Suitable behavioural models of cognition known to the person
of ordinary skill in the art, for example object recognition memory
in young Sprague-Dawley and aged Fisher rats, Water Maze model to
investigate spatial learning and memory in young and aged Fisher
rats.
[0071] A suitable animal model for studying therapeutic drugs
against post-traumatic stress disorder is described by Aharon Levy,
in Military Medicine, December 2001.
[0072] A suitable animal model for studing multiple sclerosis is
the experimental autoimmunal encephalomyelitis (EAE) model.
Patient Study for Schizophrenia
[0073] The study may be performed as a multicenter, double-blind,
placebo controlled randomised, parallel group determination of
efficacy of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline in
combination with an atypical antipsychotic agent approved for the
treatment of schizophrenia vs an atypical antipsychotic agent
approved for the treatment of schizophrenia with placebo.
[0074] For example, the study may be performed using a therapeutic
dose within the prescribed guidelines of Risperidone.
[0075] The patients may receive an appropriate dose of the atypical
antipsychotic agent (defined antipsychotic agent or antipsychotic)
,and, depending on which group they belonged, a therapeutically
effective amount 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline once
daily or placebo over 12 weeks after a brief wash-out period of
earlier antipsychotic medication.
[0076] During the wash-out period, a benzodiazepine preparation
(mostly lorazepam) may be prescribed, if necessary. Patients with
agitation, anxiety, or sleeping problems may be also medicated with
lorazepam during the study.
[0077] Efficacy and tolerability of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline/antipsychotic agent vs
placebo/antipsychotic agent will be assessed using the following
endpoints--positive and negative syndrome scale (PANSS), Clinical
Global Impression score (CGI), AIMS, Simpson and Angus, Barnes
Akathisia, Calgary Depression Scale and cognition endpoints.
[0078] The use of biperiden may be monitored as a possible
indicator for side effects of the antipsychotic medication.
[0079] In order to exclude the chance that possible differences in
the therapeutic effectiveness between the two groups might be due
to non-compliance during the antipsychotic therapy or to
differences in the antipsychotic agent metabolism, the plasma
levels of this drug may be monitored during the study.
[0080] The statistics may be performed according to the criterion
of "last observation carried forward" (LOCF), i. e., the last PANSS
scores of the patients who dropped out before the end of the study
were carried forward to all subsequent observation days.
[0081] For the comparison of the main efficacy parameter, the mean
change in the PANSS between the two treatment groups, t-tests for
independent samples may be employed. With reference to the
underlying hypothesis of a better outcome of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline/antipsychotic agent
group, a significance of p<0.05 may be calculated in the
one-tailed t-test and used as the basis for the estimation of the
sample size (statistical power) and for the comparison of the
groups. For all other comparisons, two-tailed t-tests may be
used.
[0082] The improved effectiveness of the combination therapy with
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline/antipsychotic agent in
comparison to antipsychotic monotherapy may be clearly shown by the
significantly lower PANS S global scores after the 2.sup.nd to 12
weeks of treatment.
[0083] Therefore, it could be excluded that the observed
differences in the therapeutic effectiveness between the two groups
may be due to incompatibility during the antipsychotic agent
therapy or differences in antipsychotic metabolism.
[0084] The combination of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline and an atypical
antipsychotic agent according to the present invention thus may
show improved results compared to the monopreparation of the
atypical antipsychotic agent with regard to effectiveness in the
treatment of schizophrenia.
Depression/Anxiety Study
[0085] Activity of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline in
combination with SSRI inhibitors, vs. depression/anxiety may be
evaluated according to the following models: [0086] Porsolt test in
mouse for SSRPTCA (tricyclic antidepressants) (Porsolt et al 1977,
Arch Int Pharmacodyn Ther,: 229, 327-336); [0087] Chronic mild
stress in rat for SSRPTCA (Willner, 1991, TiPS,: 12, 131-136);
[0088] Maternal deprivation in rat pups for SSRI (or modulator of
serotonin receptors)/TCA (Gardner, 1985, J. Pharmacol. Methods 14:
181-187); [0089] Rat social interaction after chronic treatment
with SSRPTCA (File, 1980 J. Neurosci Methods, 2:219-238; Lightowler
et al., 1994, Pharmacol., Biochem. Behaviour,: 49, 281-285); [0090]
Gerbil social interaction after chronic treatment with SSRI (or
modulator of serotonin receptors)/TCA (File, 1997, Pharmacol.
Biochem. Behay. 58: 747-752).
Clinical Trials
[0091] The usefulness of the compound for treating a Depressive
Disorder can be supported by the following studies as
described.
Clinical Observations
[0092] A double-blind multicenter clinical trial may be designed to
assess the safety and efficacy of
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline of the present
invention in combination with an SSRI such as paroxetine for
treatment of Bipolar Disorder, Bipolar Depression or Unipolar
Depression. Patients are randomized to
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline, an SSRI such as
paroxetine or 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline plus an
SSRI.
[0093] In one such study, an 8-week, double blind trial, 28
patients diagnosed with treatment-resistant major depression would
be randomized to one of three treatment arms: (1) paroxetine and
placebo; (2) 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline and
placebo; or (3) paroxetine plus
3-phenylsulfonyl-8-piperazinyl-1yl-quinoline. The efficacy of the
treatment may be monitored using the HAMD-21 (Hamilton M. Journal
of Neurology, Neurosurgery & Psychiatry, 1960. 23: 56-62, and
Hamilton M. Development of a rating scale for primary depressive
illness. British Journal of Social and Clinical Psychology. 1967;
6:278-296), Montgomery-Asberg Depression Rating Scale (MADRS)
(Montgomery S A, Asberg M. A new depression scale designed to be
sensitive to change. British Journal of Psychiatry. 1979;
134:382-389), and the Clinical Global Impression (CGI)--Severity of
Depression rating scale (Guy, W. ECDEU Assessment Manual for
Psychopharmacology. Revised ed. US Dept of Health, Education and
Welfare, Bethesda, Md. 1976).
[0094] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
* * * * *