U.S. patent application number 14/138527 was filed with the patent office on 2014-04-24 for [(1h-indol-5-yl) - heteroaryloxy] - (1-aza-bicyclo [3.3.1] nonanes as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenrative disorders.
This patent application is currently assigned to NOVARTIS AG. The applicant listed for this patent is NOVARTIS AG. Invention is credited to Dominik FEUERBACH, Mathias FREDERIKSEN, Konstanze HURTH, Bernard Lucien ROY, Beatrix WAGNER.
Application Number | 20140113908 14/138527 |
Document ID | / |
Family ID | 35736290 |
Filed Date | 2014-04-24 |
United States Patent
Application |
20140113908 |
Kind Code |
A1 |
FEUERBACH; Dominik ; et
al. |
April 24, 2014 |
[(1H-INDOL-5-YL) - HETEROARYLOXY] - (1-AZA-BICYCLO [3.3.1] NONANES
AS CHOLINERGIC LIGANDS OF THE N-ACHR FOR THE TREATMENT OF PSYCHOTIC
AND NEURODEGENRATIVE DISORDERS
Abstract
The present invention relates to 1-aza-bicycloalkyl derivatives
of Formula (I) wherein the substituents are as defined in the
specification and to processes for their production to
pharmaceutical compositions comprising them and to their use in the
manufacture of a medicament for the treatment and/or delay of
progression of psychotic and nemodegenerative disorders.
##STR00001##
Inventors: |
FEUERBACH; Dominik;
(Mullheim, DE) ; FREDERIKSEN; Mathias; (Basel,
CH) ; HURTH; Konstanze; (Saint Louis, FR) ;
ROY; Bernard Lucien; (Fribourg, CH) ; WAGNER;
Beatrix; (Lorrach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVARTIS AG |
Basel |
|
CH |
|
|
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
35736290 |
Appl. No.: |
14/138527 |
Filed: |
December 23, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13252608 |
Oct 4, 2011 |
8637517 |
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14138527 |
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12732646 |
Mar 26, 2010 |
8048885 |
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13252608 |
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12097681 |
Jun 16, 2008 |
7713976 |
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PCT/EP2006/012023 |
Dec 14, 2006 |
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12732646 |
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Current U.S.
Class: |
514/252.04 ;
514/274; 514/299; 544/238; 544/315; 546/183 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
25/08 20180101; A61P 1/14 20180101; A61P 31/04 20180101; A61P 25/18
20180101; A61P 27/02 20180101; A61P 9/06 20180101; A61P 25/30
20180101; A61P 25/16 20180101; A61P 25/24 20180101; C07D 471/08
20130101; A61P 15/08 20180101; A61P 19/02 20180101; A61K 45/06
20130101; A61P 1/18 20180101; A61P 25/14 20180101; A61P 9/12
20180101; A61P 25/34 20180101; A61K 31/439 20130101; A61P 21/00
20180101; A61P 29/00 20180101; A61P 3/10 20180101; A61P 25/20
20180101; A61P 25/32 20180101; A61P 43/00 20180101; A61K 31/501
20130101; A61P 25/22 20180101; A61P 15/10 20180101; A61K 31/506
20130101; A61P 25/28 20180101; A61P 1/04 20180101; A61P 25/00
20180101; A61P 25/36 20180101; A61P 1/12 20180101 |
Class at
Publication: |
514/252.04 ;
546/183; 514/299; 514/274; 544/315; 544/238 |
International
Class: |
C07D 471/08 20060101
C07D471/08; A61K 31/506 20060101 A61K031/506; A61K 45/06 20060101
A61K045/06; A61K 31/439 20060101 A61K031/439; A61K 31/501 20060101
A61K031/501 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 16, 2005 |
GB |
0525672.2 |
Claims
1. A compound of formula (I) ##STR00014## wherein X represents
hydrogen or hydroxyl and Y represents one of the following groups:
##STR00015## in free base or acid addition salt form.
2. A compound according to claim 1, wherein the compound is
(4S,5R)-4-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonan-
e.
3. A compound according to claim 1, wherein the compound is
5-{2-[(4S,5R)-(1-Aza-bicyclo[3.3.1
]non-4-yl)oxy]-pyrimidin-5-yl}-1,3-dihydro-indol-2-one.
4. A compound according to claim 1, wherein the compound is
(4S,5R)-4-[6-(1H-Indol-5-yl)-pyrimidin-3-yloxy]-1-aza-bicyclo[3.3.1]nonan-
e.
5. A compound according to claim 1, wherein the compound is
(4S,5R)-4-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonan-
e.
6. A compound according to claim 1, wherein the compound is
(4S,5R)-4-[6-(1H-Indol-5-yl)-pyrimidin-3-yloxy]-1-aza-bicyclo[3.3.1]nonan-
e.
7. A compound according to claim 1, wherein the compound is
5-{6-[(4S,5R)-(1-Aza-bicyclo[3.3.1]non-4-yl)oxy]-pyridazine-3-yl}-1,3-dih-
ydro-indol-2- one.
8. A process for preparation of a compound of formula (I) according
to claim 1 comprising the steps of i) reacting a compound of
formula (IX) ##STR00016## wherein Y is as defined above and z
represents a leaving group with a compound of formula (X)
##STR00017## where R represents H, C.sub.1-C.sub.4alkyl or both RO
represent together with the B to which they are attached a
heterocyclic moiety, X is as defined above, and ii) recovering the
so obtained compound of formula (I).
9. A process for preparation of a compound of formula (I) according
to claim 1 comprising the steps of i) reacting a compound of
formula (XI) ##STR00018## with a compound of formula (XII)
##STR00019## wherein X and Y are as defined above and PG is a
suitable protecting group, ii) subsequent deprotection of the so
obtained compound and iii) recovering the so obtained compound of
formula (I) in free base or acid addition salt form.
10. The compound of claim 1 in free base or pharmaceutically
acceptable acid addition salt form, for use as a
pharmaceutical.
11. The compound of claim 1 in free base or pharmaceutically
acceptable acid addition salt form, for use in the prevention,
treatment and/or delay of progression of psychotic and
neurodegenerative disorders.
12. A pharmaceutical composition comprising a compound of claim 1
in free base or pharmaceutically acceptable acid addition salt
form, in association with a pharmaceutical carrier or diluent.
13. The use of a compound of claim 1 in free base or
pharmaceutically acceptable acid addition salt form, as a
pharmaceutical for the prevention and the treatment of psychotic
and neurodegenerative disorders.
14. The use of a compound of claim 1 in free base or
pharmaceutically acceptable acid addition salt form, for the
manufacture of a medicament for the prevention, treatment and/or
delay of progression of psychotic and neurodegenerative
disorders.
15. A method for the prevention, treatment and/or delay of
progression of psychotic and neurodegenerative disorders, in a
subject in need of such treatment, which comprises administering to
such subject a therapeutically effective amount of a compound of
claim 1 in free base or pharmaceutically acceptable acid addition
salt form.
16. A compound of claim 1 in free base or pharmaceutically
acceptable acid addition salt form, for use in the prevention,
treatment and/or delay of progression of a disease or condition in
which nAChR .alpha.7 activation plays a role or is implicated.
17. The use of a compound of claim 1 in free base or
pharmaceutically acceptable acid addition salt form, as a
pharmaceutical for the prevention, treatment and/or delay of
progression of a disease or condition in which nAChR .alpha.7
activation plays a role or is implicated.
18. A method for treating or preventing a disease or condition in
which nAChR .alpha.7activation plays a role or is implicated, in a
subject in need of such treatment, which comprises administering to
such subject a therapeutically effective amount of compound of
claim 1 in free base or pharmaceutically acceptable acid addition
salt form.
19. A combination comprising: a compound of formula (I)
##STR00020## wherein X represents hydrogen or hydroxyl and Y
represents one of the following groups: ##STR00021## as the first
active ingredient and a second therapeutic compound as the second
active ingredient, wherein the active ingredients are present in
each case in free form or in the form of a pharmaceutically
acceptable salt.
20. The combination of claim 19, wherein the second active
ingredient is selected from the group consisting of
benzodiazepines, selective serotonin reuptake inhibitors (SSRIs),
selective serotonin and norepinephrine reuptake inhibitors (SNRIs),
conventional antipsychotics, atypical antipsychotics, buspirone,
carbamazepine, oxcarbazepine, gabapentin, and pregabalin.
Description
[0001] The present invention relates to novel 1-axa-bicyclononane
derivatives, to processes for their production, their use as
pharmaceuticals and to pharmaceutical compositions comprising
them.
[0002] More particularly the present invention provides in a first
aspect, a compound of formula (I)
##STR00002##
wherein
[0003] X represents hydrogen or hydroxyl and
[0004] Y represents one of the following groups:
##STR00003##
[0005] in free base or acid addition salt form.
[0006] A preferred compound according to the invention is
(4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonan-
e having the formula shown below.
##STR00004##
[0007] A further preferred compound according to the invention is
5-(2-[(4S,5R)-(1-aza-bicyclo[3.3.1]non-4-yl)oxy]-pyrimidin-5-yl)-1,3-dihy-
dro-indol-2-one having the formula shown below.
##STR00005##
[0008] A further preferred compound according to the invention is
(4S,5R)-4-[6-(1H-indol-5-yl)-pyridin-3-yloxy]-1-aza-bicyclo-[3.3.1]nonane
having the formula shown below.
##STR00006##
[0009] A further preferred compound according to the invention is
(4S,5R)-4-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane
having the formula shown below.
##STR00007##
[0010] A further preferred compound according to the invention is
(4S,5R)-4-[6-(1H-indol-5-yl)-pyridin-3-yloxy]-1-aza-bicyclo[3.3.1]nonane
having the formula
##STR00008##
[0011] A further preferred compound according to the invention is
5-(6-[(4S,5R)-(1-aza-bicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3yl)-1,3-dihyd-
ro-indol-2-one having the formula shown below.
##STR00009##
[0012] Compounds of formula (I) exist in free or acid addition salt
form. In this specification, unless otherwise indicated, language
such as "compounds of formula (I)" is to be understood as embracing
the compounds in any form, for example free base or acid addition
salt form. Salts which are unsuitable for pharmaceutical uses but
which can be employed, for example, for the isolation or
purification of free compounds of formula (I), such as picrates or
perchlorates, are also included. For therapeutic use, only
pharmaceutically acceptable salts or free compounds are employed
(where applicable in the form of pharmaceutical preparations), and
are therefore preferred.
[0013] Compounds of formula (I) may exist in form of various
isomers, e.g. keto-enol tautomers. In this specification, unless
otherwise indicated, language such as "compounds of formula (I)" is
to be understood as embracing the compounds in any form, for
example in the keto or in the enol form or any mixture of them
[0014] Where the plural form is used for compounds, salts, and the
like, this is taken to mean also a single compound, salt, or the
like.
[0015] In a further aspect, the present invention also provides
processes for the production of compounds of formula (I).
[0016] A first process comprises the steps of
[0017] i) reacting a compound of formula (IX)
##STR00010##
[0018] wherein Y is as defined above and Z z represents a leaving
group, such as Cl, Br, I, Tosylate
[0019] with a compound of formula (X)
##STR00011##
[0020] where R represents H, C.sub.1-C.sub.4alkyl or both RO
represent together with the B to which they are attached a
heterocyclic moiety, X is as defined above, and
[0021] ii) recovering the so obtained compound of formula (I)
[0022] A second process comprises the steps of
[0023] i) reacting a compound of formula (XI)
##STR00012##
[0024] with a compound of formula XII
##STR00013##
[0025] wherein X and Y are as defined above and PG is a suitable
protecting group,
[0026] ii) subsequent deprotection of the so obtained compound
and
[0027] iii) recovering the so obtained compound of formula (I) in
free base or acid addition salt form.
[0028] This process is particular suitable wherein Y represents the
3-pyridyl moiety.
[0029] Starting materials are known or may be obtained by well
known processes. The synthesis of the starting materials is
described e.g In GB 123456, which is hereby incorporated by
reference.
[0030] The following considerations apply to the individual
reaction steps described above;
[0031] a) One or more functional groups, for example carboxy,
hydroxy, amino, or-mercapto, may need to be protected in the
starting materials by protecting groups. The protecting groups
employed may already be present in precursors and -should protect
the functional groups concerned against unwanted secondary
reactions, such as acylations, etherifications, esterifications,
oxidations, solvoiysis, end similar reactions. It Is a
characteristic of protecting groups that they lend themselves
readily, i.e. without undeslred secondary reactions, to removal,
typically by soivotysis, reduction, photolysis or also by ensyme
activity, for example under conditions analogous to physiological
conditions, and that they are not present in the end-products. The
specialist knows, or can easily establish, which protecting groups
are suitable with the reactions mentioned hereinabove and
hereinafter. The protection of such functional groups by such
protecting groups, the protecting groups themselves, and their
removal reactions are described for example in standard reference
worfcs, such as J. F. W. McOmie, "Protective Groups in Organic
Chemistry", Plenum Press, London and New York 1973, in T. W.
Greene, "Protective Groups in Organic-Synthesis", Wiley, Hew York
1981, in "The Peptides"; Volume 3 (editors: E, Gross and J.
Meienhofex), Academic Press, London and New York 1981, In "Methoden
der orgariischea Chemie" (Methods of organic chemistry), Hoyben
Weyl, 4th edition, Volume 15/i, Georg Thieme Vertag, Stuttgart
1974, in H.-D, Jakufeke and H. Jescheit, "Aminosauren, Peptide,
Proteine" (Amino acids, peptides, proteins), Verlag Chemie,
Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehrnann,
"Chemie der Kohlenhydrate: Monosaccharide urid Derivate" (Chemistry
of carbohydrates; monosaccharides and derivatives), Georg Thieme
Verlag, Stuttgart 1974.
[0032] b) Acid addition salts may be produced from the free bases
in known manner, and vice-versa. Alternatively, optically pure
starting materials can be used. Suitable acid addition salts for
use in accordance with the present invention Include for example
the hydrochloride.
[0033] c) Stereoisomeric mixtures, e.g. mixtures of diastereomers,
can be separated into their corresponding isomers in a manner known
per se by means of suitable separation methods. Diastereomeric
mixtures for example may be separated into their individual
diastereomers by means of fractionated crystallization,
chromatography, solvent distribution, and similar procedures. This
separation may take place either at the level of a starting
compound or in a compound of formula I itself. Enantiomers may be
separated through the formation of diastereomeric salts, for
example by salt formation with an enantiomer-pure chirai acid, or
by means of chromatography, for example by HPLC, using
chromatographic substrates with chirai ligands. Alternatively,
optically pure starting material can be used.
[0034] d) Suitable diluents for carrying out the above-described
are especially inert organic Solvents. These include, in
particular, aliphatic, alicyclic or aromatic, optionally
halogenated hydrocarbons, such as, for example, benzine, benzene,
toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether,
hexane, cyclohexane, dichloromethene, chloroform, carbon
tetrachloride; ethers, such as diethyl ether, diisopropyl ether,
dioxane, tetrahydrofuran or ethylene glycol dimethyl ether or
ethylene glycol diethyl ether; ketones, such as acetone, butanone
or methyl isobutyl ketone; nitrites, such as acetonitrile
propionitrile or butyronitrile; amides, such as
N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide,
N-methyl-pyrrolidone or hexamethylphosphoric triamide; esters, such
as methyl acetate or ethyl acetate, sulphoxides, such as dimethyl
sulphoxide, alcohols, such as methanol, ethanol, n- or i-propanol,
ethylene glycol monomethyl ether, ethylene glycol monoethyl ether,
diethyelene glycol monomethyl ether, diethylene glycol monoethyl
ether. Further, mixtures of diluents may be employed. Depending on
the starting materials, reaction conditions and auxiliaries, water
or diluents constaining wafer may be suitable. It is also possible
to use one a starting material as diluent simultaneously.
[0035] e) Reaction temperatures can be varied within a relatively
wide range. In general, the processes are carried out at
temperatures between 0.degree. C. and 150.degree. C.,, preferably
between 10.degree. C. and 120.degree. C. Deprotonation reactions
can be varied within a relatively wide range. In general, the
processes are carried out at temperatures between -150.degree. C.
and +50.degree. C., preferably between -75.degree. C. and 0.degree.
C.
[0036] f) The reactions are generally carried out under atmospheric
pressure. However, it is also possible to carry out the processes
according to the invention under elevated or reduced pressure--in
general between 0.1 bar and 10 bar.
[0037] g) Starting materials are generally employed in
approximately equimolar amounts. However, it is also possible to
use a relatively large excess of one of the components. The
reaction Is generally carried out in a suitable diluent in the
presence of a reaction auxiliary, and the reaction mixture is
generally stirred at the required temperature for a number of
hours.
[0038] h) Working up the reaction mixtures according to the above
processes and purification of the compounds thus obtained may be
carried out in accordance to known procedures (cf. the Preparation
Examples).
[0039] The compounds of the invention, exhibit valuable
pharmacological properties when tested in vitro and in animals, and
are therefore useful as pharmaceuticals.
[0040] Thus, the compound of the invention are found to be
cholinergic ligands of the nAChR. In addition preferred compound of
the invention show selective .alpha.7-ACrhR activity. The compounds
of the present invention may in particular be found to be agonists,
partial agonists, antagonists or allosteric modulators of the
receptor.
[0041] Due to their pharmacological profiles, compound of the
invention are anticipated to be useful for the treatment of
diseases or conditions as diverse as CMS related diseases, PMS
related diseases, diseases related to inflammation, pain and
withdrawal symptoms caused by an abuse of chemical substances.
Diseases or disorders related to the CMS include general anxiety
disorders, cognitive disorders, learning and memory deficits and
dysfunctions, Alzheimer's disease (AD), prodromal AD, mild
cognitive impairment in the elderly (MCI), amnestic MCI, age
associated memory impairment, attention deficit and hyperactivity
disorder (ADHD), Parkinson's disease, Huntington's disease, ALS,
prionic neuro-degenerative disorders such as Creutzfeld-Jacob
disease and kuru disease, Gilles de la Tourette's syndrome,
psychosis, depression and depressive disorders, mania, manic
depression, schizophrenia, the cognitive deficits in schizophrenia,
obsessive compulsive disorders, panic disorders, eating disorders,
narcolepsy, nociception, AIDS-dementia, senile dementia, mild
cognitive dysfunctions related to age, autism, dyslexia, tardive
dyskinesia, epilepsy, and convulsive disorders, post-traumatic
stress disorders, transient anoxia, pseu-dodementia, pre-menstrual
syndrome, late luteal phase syndrome, chronic fatigue syndrome and
jet lag. Furthermore, compound of the invention may be useful for
the treatment of endocrine disorders, such as thyrotoxicosis,
pheochromocytoma, hypertension and arrhythmias as well as angina
pectoris, hyperkinesia, premature ejaculation and erectile
difficulty. Still further, compound of the invention may be useful
in the treatment of inflammatory disorders (Wang et al., Nature
2003, 421, 384; de Jonge et al., Nature Immunology 2005, 6, 844;
Saeed et al., JEM 2005, 7, 1113), disorders or conditions including
inflammatory skin disorders, rheumatoid arthritis, post-operative
ileus, Crohn's disease, inflammatory bowel disease, ulcerative
colitis, sepsis, fibromyalgia, pancreatitis and diarrhoea. Compound
of the invention may further be useful for the treatment of
withdrawal symptoms caused by termination of the use of addictive
substances, like heroin, cocaine, tobacco, nicotine, opioids,
benzodiazepines and alcohol. Finally, compound of the invention may
be useful for the treatment of pain, e.g. caused by migraine,
postoperative pain, phantom limb pain or pain associated with
cancer. The pain may comprise inflammatory or neuropathic pain,
central pain, chronic headache, pain related to diabetic
neuropathy, to post therapeutic neuralgia or to peripheral nerve
injury.
[0042] Furthermore, degenerative ocular disorders which may be
treated include ocular diseases which may directly or indirectly
involve the degeneration of retinal cells, Including ischemic
retinopathies in general, anterior ischemic optic neuropathy, all
forms of optic neuritis, age-related macular degenerationl (AMD),
in its dry forms (dry AMD) and wet forms (wet AMD), diabetic
retinopathy, cystoid macular edema (CME), retinal detachment,
retinitis pigmentosa, Stargardt's disease, Best's vitelliform
retinal degeneration, Leber's congenital amaurosis and other
hereditary retinal degenerations, pathologic myopia, retinopathy of
prematurity, and Leber's hereditary optic neuropathy.
[0043] It has been found that the effect of a combination which
comprises at least one nicotinic-alpha 7 receptor agonist and at
least one compound selected from the group consisting of (a)
conventional antipsychotics and (b) atypical antipsychotics is
greater than the additive effect of the combined drugs in the
treatment of psychiatric disorders. In particular, the combinations
disclosed herein can be used to treat schizophrenia which is
refractory to monotherapy employing one of the combination partners
alone.
[0044] Hence, the invention relates to a combination, such as a
combined preparation or pharmaceutical composition, which comprises
at least one nicotinic-alpha-7 receptor agonist and at least one
compound selected from the group consisting of (a) conventional
antipsychotics and (b) atypical antipsychotics, in which the active
ingredients are present in each case in free form or in the form of
a pharmaceutical acceptable salt and optionally at least one
pharmaceutically acceptable carrier; for simultaneous, separate or
sequential use.
[0045] The term "psychiatric disorders" as used herein includes,
but is not limited to schizophrenia, anxiety disorders, depression
and bipolar disorders. Preferably, the psychiatric disorder to be
treated with the combination disclosed herein is schizophrenia,
more preferably schizophrenia which is refractory to monotherapy
employing one of the combination partners alone. The term
"conventional antipsychotics" as used herein includes, but is not
limited to haloperidol, fluphenazine, thiotixene and
flupentixol.
[0046] The term "atypical antipsychotics" as used herein includes,
but is not limited to clozaril, risperidone, olanzapine,
quetiapine, ziprasidone and aripiprazol.
[0047] In another aspect, the compound of the invention are used as
diagnostic agents and/or PET ligands, e.g. for the identification
and localization of nicotine receptors in various tissues. Properly
isotope-labeled agents of the invention exhibit valuable properties
as histopathological labeling agents, imaging agents and/or
biomarkers, hereinafter "markers", for the selective labeling of
the nAChR. More particularly the agents of the invention are useful
as markers for labeling the alpha7 nAChR receptors in vitro or in
vivo. In particular, compound of the invention which are properly
isotopically labeled are useful as PET markers. Such PET markers
are labeled with one or more atoms selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F.
[0048] The agents of the invention are therefore useful, for
instance, for determining the levels of receptor occupancy of a
drug acting at the nAChR, or diagnostic purposes for diseases
resulting from an imbalance or dysfunction of nAChR and for
monitoring the effectiveness of pharmacotherapies of such
diseases.
[0049] In accordance with the above, the present invention provides
an agent of the invention for use as a marker for neuroimaging.
[0050] In a further aspect, the present invention provides a
composition for labeling brain and peripheral nervous system
structures Involving nAChR in vivo and in vitro comprising an agent
of the invention.
[0051] In still a further aspect, the present invention provides a
method for labeling brain and peripheral nervous system structures
involving nAChR in vitro or in vivo, which comprises contacting
brain tissue with an agent of the invention.
[0052] The method of the invention may comprise a further step
aimed at determining whether the agent of the invention labeled the
target structure. Said further step may be effected by observing
the target structure using positron emission tomography (PET) or
single photon emission computed tomography (SPECT), or any device
allowing detection of radioactive radiations.
[0053] In particular,, the agents of the invention are .alpha.7
nicotinic acetylcholine receptor (.alpha.nAChR .alpha.7)
agonists.
[0054] In functional assays, the agents of the invention display
high affinity at the nAChR .alpha.7 as shown in the following
tests:
[0055] a) A functional assay for affinity at the nAChR .alpha.7 is
earned out with a rat pituitary cell line stably expressing the
nAChR .alpha.7. Briefly, GH3 cells recombinanfiy expressing the
nAChR .alpha.7 were seeded 72 h prior to the experiment on black
96-well plates and incubated at 37.degree. C. in a humidified
atmosphere (5% CO.sub.2/95% air). On the day of the experiment
medium was removed by flicking the plates and replaced with 100
.mu.l growth medium containing af fluorescent calcium sensitve dye,
in the presence of 2.5 mM probenecid (Sigma). The cells were
Incubated at 37.degree. C. in a humidified atmosphere (5%
CO.sub.2/95% air) for 1 h. Plates were flicked to remove excess of
Fluo-4, washed twice with Hepes-buffered salt solution (in mM: NaCl
130, KCL 5.4, CaCl.sub.2,2, MgSO.sub.4 0.8, NaH.sub.2PO.sub.4 0.9,
glucose 25, Hepes 20, pH 7.4, HBS) and refilled with 100 .mu.l of
HBS containing antagonists when appropriate. The incubation in the
presence of the antagonist lasted between 3 and 5 minutes. Plates
were then placed into an imaging plate reader and fluorescence
signal recorded. In this assay, compound of the invention exhibit
pEC.sub.50 values of about 5 to about 9. Partial and potent
agonists in this test are preferred.
[0056] b) To assess the antagonist activity of the compound of the
invention on the human neuronal nAChR .alpha.4.beta.2, a similar
functional assay is carried out using a human epithelial cell line
stably expressing the human .alpha.4.beta.2 subtype (Michelmore et
al., Naunyn-Schmiedeberg's Arch. Pharmacol. (2002) 366, 235). In
this assay, the preferred compounds of the invention show
selectivity for the nAChR.alpha.7 subtype.
[0057] c) To assess the antagonist activity of the compound of the
invention on the "ganglionic subtype" (.alpha.3.beta.4), the muscle
type of nicotinic receptor (.alpha.1.beta.1.gamma..delta.) and the
5-HT.sub.3 receptor, similar functional tests as just described
under a) are carried out with a human epithelial cell line stably
expressing the human ganglionic subtype, a cell line endogenousty
expressing the human muscle type of nicotinic receptors or a cell
line endogenously expressing the murine 5-HT.sub.3 receptor
(Michelmore et at., Naunyn-Schmiedeberg's Arch. Pharmacol. (2002)
368, 235). Compounds which display little or no activity on the
.alpha.3.beta.4 nAChR, the muscle subtype of nicotinic receptor as
well as the 5-HT.sub.3 receptor are especially preferred.
[0058] In the model of mice showing sensory gating deficit
(DBA/2-mice) described by S. Leonard et al. in Schizophrenia
Bulletin 22, 431-445 (1996), the compound of the invention induce
significant sensory gating at concentrations of about 10 to about
40 .mu.M.
[0059] The compound of the invention may be shown to increase
attention in a test of attention for rodents (Robbins, J.
Neuropsychiatry Clin. Neurosci. (2001) 13, 328-35), namely the
5-choice serial reaction time test (5-CSRTT). In this test, the rat
must observe a wall containing 5 holes. When a light flash appears
in one of them, the rat must respond with a nose-poke into the
correct hole within 5 sec. in order to receive a food pellet
reward, delivered to a feeder in the opposite wall.
[0060] Compound of the Invention may also show learning/memory
enhancing effects in the social recognition and in the object
recognition test in mice and rats (Ennaceur and Delacour, Behav.
Brain Res. (1986) 31, 47-59).
[0061] The compound of the invention are therefore useful for the
prevention and treatment (including mitigation and prevention) of
various disorders, especially those mentioned above. The usefulness
of nAChR .alpha.7 agonists in neurodegeneraiion is documented in
the literature, e.g. in Wang et al., J. Biol. Chem. 275, 5826-5632
(2000),
[0062] For the treatment of the above and other disorders, the
appropriate dosage of a compound (active ingredient) of the
invention will, of course, vary depending upon, for example, the
host, the mode of administration and the nature and severity of the
condition being treated as well as the relative potency of the
particular agent of the invention employed. For example, the amount
of active agent required may be determined on the basis of known in
vitro and in vivo techniques, determining how long a particular
active agent concentration in the blood plasma remains at an
acceptable level for a therapeutic effect. In general, satisfactory
results in animals are indicated to be obtained at dally dosages of
from about 0.01 to about 30.0 mg/kg p.o. in humans, an indicated
daily dosage is in the range of from about 0.7 to about 1400 mg/day
p.o., e.g. from about 50 to 200 mg (70 kg man), conveniently
administered once or in divided doses up to 4 .times. per day or in
sustained release form. Oral dosage forms accordingly suitably
comprise from about 1.75 or 2.0 to about 700 or 1400 mg of a
compound of the invention admixed with an appropriate
pharmaceutically acceptable diluent or carrier therefore.
[0063] Pharmaceutical compositions contain, for example, from about
0.1% to about 99.9%, preferably from about 20% to about 60%, of the
active ingredient(s).
[0064] Examples for compositions comprising a compound of the
invention include, for example, a solid dispersion, an aqueous
solution, e.g. containing a solubilising agent, a microemulsion and
a suspension of, e.g. a salt of a compound of formula I or a free
compound of the formula I in the range of from 0.1 to 1%, e.g.
0.5%. The composition may be buffered to a pH in the range of, e.g.
from 3.5 to 9.5, e.g. to pH 4.5, by a suitable buffer.
[0065] The compound of the invention are also commercially useful
as research chemicals.
[0066] For use according to the invention, a compound of the
formula I and/or a pharmaceutically acceptable salt thereof may be
administered as single active agent or in combination with one or
more other active agents of the formula I and/or a pharmaceutically
acceptable salt thereof or especially other active agents commonly
employed especially for the treatment of the disorders mentioned
herein or further other disorders, in any customary manner; e.g.
orally, for example in the form of tablets, capsules, or as nasal
spray, or parenterally, for example in the form of injection
solutions or suspensions. The other active agents employed in such
combinations are preferably selected from the group consisting of
benzodiazepines, selective serotonin reuptake inhibitors (SSRIs),
selective serotonin and norepinephrine reuptake inhibitors (SNRIs),
conventional antipsychotics, atypical antipsychotics, buspirone,
carbamazepine, oxcarbazepine, gabapentin and pregabalin.
[0067] An SSRI suitable for the present invention is especially
selected from fluoxetine, fuvoxamlne, sertraline, paroxetine,
citalopram and escitalopram. An SNRI suitable for the present
invention is especially selected from veniafaxine and duloxetine.
The term "benzodiazepines" as used herein includes, but is not
limited to clonazepam, diazepam and lorazepam. The term
"conventional antipsychotics" as used herein includes, but is not
limited to haloperidol, fluphenazine, thiotixene and flupentixol.
The term "atypical antipsychotics" as used herein relates to
clozaril, risperidone, olanzapine, quetiapine, ziprasidone and
aripiprazol.
[0068] Buspirone can be administered in free form or as a salt,
e.g. as its hydrochloride, e.g., in the form as marketed, e.g.
under the trademark Buspar.TM. or Bespar.TM.. It can be prepared
and administered, e.g., as described in U.S. Pat. No. 3,717,834.
Fluoxetine can be administered, e.g., in the form of its
hydrochloride as marketed, e.g. under the trademark Proza.TM.. It
can be prepared and administered, e.g., as described In CA 2002182.
Paroxetine
((3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine-
) can be administered, e.g., in the form as marketed, e.g. under
the trademark Paxil.TM.. It can be prepared and administered, e.g.,
as described in U.S. Pat. No. 3,912,743. Sertraline can be
administered, e.g., in the form as marketed, e.g. under the
trademark Zoloft.TM.. It can be prepared and administered, e.g., as
described in U.S. Pat. No. 4,838,518. Clonazepam can be
administered, e.g., in the form as marketed, e.g. under the
trademark Antelepsin.TM.. Diazepam can be administered, e.g., in
the form as marketed, e.g. under the trademark Diazepam
Desitin.TM.. Lorazepam can be administered, e.g., in the form as
marketed, e.g. under the trademark Tavor.TM.. Citalopram can be
administered in free form or as a salt, e.g. as its hydrobromide,
e.g., in the form as marketed, e.g. under the trademark
Cipramil.TM.. Escitalopram can be administered, e.g., in the form
as marketed, e.g. under the trademark Cipralex.TM.. It can be
prepared and administered, e.g., as described in AU623144.
Veniafaxine can be administered, e.g., in the form as marketed,
e.g. under the trademark Treviler.TM.. Duloxetine can be
administered, e.g., in the form as marketed, e.g. under the
trademark Cymbalta.TM.. It may be prepared and administered, e.g.,
as described in CA 1302421, Carbamazepine can foe administered,
e.g., in the form as marketed, e.g. under the trademark
Tegretal.TM. or Tegretol.TM.. Oxcarbazepine can be administered,
e.g., in the form as marketed, e.g. under the trademark
Trileptal.TM.. Oxcarbazepine is well known from the literature [see
for example Schuetz H. et al., Xenobiotica (GB), 16(8), 789-778
(1986)]. Gabapentin can be administered, e.g., in the form as
marketed, e.g. under the trademark Neurontin.TM.. Haloperidol can
be administered, e.g., in the form as marketed, e.g. under the
trademark Haloperidol STADA.TM.. Fluphenazine can be administered,
e.g., in the form of its dihydrochloride as marketed, e.g. under
the trademark Prolixin. Thiothixene can be administered, e.g., in
the form as marketed, e.g. under the trademark Navane.TM.. It can
be prepared, e.g., as described in U.S. Pat. No. 3,310,553.
Flupentixol can be administered for instance in the form of its
dihydrochloride, e.g., in the form as marketed, e.g. under the
trademark Emergil.TM. or in the form of its decanoate, e.g., in the
form as marketed, e.g. under the trademark Depixol.TM.. It can be
prepared, e.g., as described in BP 925,538. Clozaril can be
administered, e.g., in the form as marketed, e.g. under the
trademark Leponex.TM.. It can be prepared, e.g., as described in
U.S. Pat. No. 3,539,573. Risperidone can be administered, e.g., in
the form as marketed, e.g. under the trademark Risperdal.TM..
Olanzapine can be administered, e.g., in the form as marketed, e.g.
under the trademark Zyprexa.TM.. Ouetiapine can be administered,
e.g., in the form as marketed, e.g. under the trademark
Seroquel.TM.. Ziprasidone can be administered, e.g., in the form as
marketed, e.g. under the trademark Geodon.TM.. It can be prepared,
e.g., as described in GB 281,309. Aripiprazole can be administered,
e.g., in the form as marketed, e.g. under the trademark
Abilify.TM.. It can be prepared, e.g., as described in U.S. Pat.
No. 8,008,828.
[0069] The structure of the active ingredients identified by code
nos., generic or trade names may be taken from the actual edition
of the standard compendium "The Merck Index" or from databases,
e.g. Patents International (e.g. IMS World Publications). The
corresponding content thereof is hereby incorporated by reference.
Any person skilled in the art is fully enabled to identify the
active ingredients and, based on these references, likewise enabled
to manufacture and test the pharmaceutical indications and
properties in standard test models, both in vitro and in vivo.
[0070] In the case of a combination, the pharmaceutical
compositions for separate administration of the combination
partners and/or those for administration in a fixed combination,
i.e. a single galenical composition comprising at least two
combination partners, according to the invention can be prepared in
a manner known per se and are those suitable for enteral, such as
oral or rectal, and parenteral administration to mammals, including
man, comprising a therapeutically effective amount of at least one
pharmacologically active combination partner alone or in
combination with one or more pharmaceutically acceptable carriers,
especially suitable for enteral or parenteral application. When the
combination partners employed are applied in the form as marketed
as single drugs, their dosage and mode of administration can take
place in accordance with the information provided on the packet
leaflet of the respective marketed drug in order to result in the
beneficial effect described herein, if not mentioned herein
otherwise.
[0071] Pharmaceutical preparations for the combination therapy for
enteral or parenteral administration are, for example, those in
unit dosage forms, such as sugar-coated tablets, tablets, capsules
or suppositories, or furthermore ampoules. If not indicated
otherwise, these are prepared in a manner known per se, for example
by means of conventional mixing, granulating, sugar-coating,
dissolving or lyophilizng processes. It will be appreciated that
the unit content of a combination partner contained in an
individual dose of each dosage form need not in itself constitute
an effective amount since the necessary effective amount can
instead with a single dosage unit also be reached by administration
of a two or more dosage units.
[0072] In particular, a therapeutically effective amount of each of
the combination partners may be administered simultaneously or
sequentially and in any order, and the components may be
administered separately (e.g. sequentially after fixed or variable
periods of time), or as a fixed combination. For example, the
method of treatment (including mitigation) of a disorder according
to the invention may comprise (i) administration of the combination
partner (a) (a compound of the present invention) in free or
pharmaceutically acceptable salt form and (ii) administration of a
combination partner (b) (e.g. a different compound of the present
invention or an active Ingredient of a different formula) in free
or pharmaceutically acceptable salt form, simultaneously or
sequentially in any order, in jointly therapeutically effective
amounts, preferably in synergistically effective amounts, e.g. in
daily dosages corresponding to the amounts described herein. The
individual combination partners can be administered separately at
different times during the course of therapy or concurrently in
divided or single combination forms. Furthermore, the term
"administering" also encompasses the use of a prodrug of a
combination partner that convert in vivo to the combination partner
as such. The instant invention is therefore to be understood as
embracing all such regimes of simultaneous and/ or alternating
treatment and the term "administering" is to be interpreted
accordingly.
[0073] The effective dosage of the combination partners employed
may vary, for example depending on the particular compound or
pharmaceutical composition employed, the mode of administration,
the disorder being treated, and/or the severity of the disorder
being treated. Thus, the dosage regimen is selected in accordance
with a variety of factors including the route of administration,
metabolism by and the renal and hepatic function of the patient. A
physician, clinician or veterinarian of ordinary skill can readily
determine and prescribe the effective amount of the single active
ingredients required to prevent, mitigate, counter or arrest the
disorder. Optimal precision in achieving concentration of the
active ingredients within the range that yields efficacy without
toxicity requires a regimen based on the kinetics of the active
ingredients' availability to target sites.
[0074] In accordance with the foregoing, the present invention also
provides;
[0075] (1) A compound of the formula I, and/or a salt thereof, for
use in the diagnostic or therapeutic treatment of a mammal,
especially a human; especially for use as an alpha-7 receptor
agonist, for example for use in the treatment (including
mitigation) of any one or more disorders, especially of any one or
more of the particular disorders set forth hereinbefore and
hereinafter.
[0076] (2) A pharmaceutical composition comprising a compound of
the formula I, and/or a pharmaceutically acceptable salt thereof,
as active ingredient together with a pharmaceutical acceptable
diluent or carrier.
[0077] (2') A pharmaceutical composition for the treatment or
prevention of a disorder in the treatment of which alpha-7 receptor
activation plays a role or is involved and/or in which alpha-7
receptor activity is involved, especially any one or more of the
disorders mentioned hereinbefore or hereinafter, comprising a
compound of the formula I, and/or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable diluent or
carrier.
[0078] (3) A method for the treatment of a disorder, especially any
one or more of the particular disorders set forth hereinbefore, in
a subject in need of such treatment, comprising administering a
phamiaceutically effective amount of a compound of the formula I,
or a pharmaceutically acceptable salt thereof.
[0079] (3') A method for treating or preventing a disorder in the
treatment of which alpha-7 receptor activation plays a role or is
involved and/or in which alpha-7 receptor activity is involved,
comprising administering to a mammal in need thereof a
therapeutically effective amount of a compound of the formula I,
and/or a pharmacaoticaity acceptable salt thereof.
[0080] (4) The use of a compound of the formula I, and/or a
pharmaceutically acceptable salt thereof, for the manufacture of a
medicament for the treatment or prevention of a disease or
condition in the treatment of which alpha-7 receptor activation
plays a role or is involved and/or in which alpha-7 receptor
activity is involved, especially one or more of the disorders
mentioned above.
[0081] (5) A method as defined above comprising co-administration,
e.g. concomitantly or in sequence, of a therapeutically effective
amount of an alpha-7 agonist of the formula I, and/or a
pharmaceutically acceptable salt thereof, and a second
pharmaceutically active compound and/or a pharmaceutically
acceptable salt thereof, said second pharmaceutically active
compound and/or salt thereof being especially for use in the
treatment of any one or more of the disorders set forth
hereinbefore or hereinafter.
[0082] (6) A combination comprising a therapeutically effective
amount of an alpha-7 agonist of the formula I, and/or a
pharmaceutically acceptable salt thereof, and a second
pharmaceutically active compound and/or a pharmaceutically
acceptable salt thereof, said second pharmaceutically active
compound being especially for use or of use in the treatment of any
one or more of the particular disorders set forth hereinbefore.
[0083] The Examples which follow serve to illustrate the invention
without limiting the scope thereof.
[0084] The following abbreviations are used: [0085] AcOEt ethyl
acetate [0086] aq. aqueous [0087] EtOH ethanoi [0088] FC flash
chromatography [0089] HV high vacuum [0090] MeOH MeOH [0091] m.p.
melting point [0092] MTBE methyl tert-butyl ether [0093] NHMDS
sodium hexamethyi disilazane [0094] rt room temperature [0095] soln
solution [0096] THF tetrahydrofuran
[0097] Temperatures are measured in degrees Celsius. Unless
indicated otherwise, reactions are carried out at room temperature.
The structure of final products, intermediates and starting
materials is confirmed by standard analytical methods, e.g.
microanalysis and spectroscopic characteristics (e.g. MB, IR,
NMR)
EXAMPLE 1
[0098]
(4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1-
]nonane 1-Aza-bicyclo[3.3.1]nonan-4-one (11.92 g, 85.6 mmol) is
dissolved in 160 ml MeOH and cooled to -10.degree. C. NaBH.sub.4
(1.69 g, 42.9 mmol)) is added portionwise so that the inner
temperature does not exceed 0.degree. C., The reaction mixture is
stirred at -10.degree. C. for 1 h. Water is added and the solvents
are evaporated. The remaining solid is dissolved in MTBE/MeOH,
filtered over hyflo and the filtrate is evaporated to give 19.28 g
of crude product which is purified by chromatography over aluminum
oxide (400 g, eluent: MTBE/MeOH 95:5 to 80:20) to give 10.98 g
(91%) (4SR,5RS)-1-aza-bicyclo[3.3.1]nonan-4-ol.
[0099] To acetic anhydride (150 ml)
(4SR,5RS)-(1-aza-bicyclo[3.3.1]nonan-4-ol (21.34 g, 151 mmol) is
added portionwise under cooling. The reaction mixture is heated to
120.degree. C. for 2.5 h, is evaporated and extracted with THF/sat.
K.sub.2CO.sub.3 soln. The aq. layer is reextracted with THF. The
combined organic layers are washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated. The crude product is
purified by bulb-to-bulb distillation (HV. 90.degree. C.) to give
24.07 g (87%) of (4SR,5RS)-acetic acid 1-aza-bicyclo[3.3.1]non-4-yl
ester.
[0100] Acetic acid 1-aza-bicyclo[3.3.1]non-4-yl ester (120.0 g, 655
mmol) is dissolved in 200 ml EtOH abs, and 50 ml water,
L(+)-tartaric acid (98.3 g, 655 mmol) is added and the mixture is
heated to reflux for 1 minute. The mixture is cooled to rt, then to
4.degree. C. The precipitate is filtered off, washed with EfOH, and
3.times. recrystallized from EtOH/H.sub.2O 4:1 to give 41.16 g of
the tartrate salt ([a].sub.D=-14.72.degree. (c=0.265, MeOH)) which
gives after treatment with sat. Na.sub.2CO.sub.3 soln. 22.6 g (123
mmol, 19%) (4S,5R)-acetic acid 1-aza-bicyclo[3.3.1]non-4-yl ester
as the free base. Another 10.7 g (32.1 mmol, 5%) of tartrate can be
obtained from the mother liquors by another 3 recrystallizations
from EtOH/H.sub.2O 4:1.
[0101] (4S,5R)-acetic acid 1-aza-bicyclo[3.3.1]non-4-yl ester (5.45
g, 29.7 mmol) is dissolved in 10% aq. NaOH soln. and stirred for 1
h at 50.degree. C. After cooling to rt, the mixture is extracted
with THF/brine. The organic layer is dried over Na.sub.2SO.sub.4,
filtered and the filtrate is evaporated to give 3.83 g (91%) of
(4S, 5R)-1-aza-bicyclo [3.3.1]nonan-4-ol, which is dissolved in 50
ml THF and cooled to 0.degree. C. NHMDS (35 ml of 1 M THF soln.) is
added dropwise, the reaction mixture is stirred at rt for 0.5 h and
then added to a precooled soln. (-15.degree. C.) of
5-bromo-2-chloro-pyrimidine (5.89 g, 30.5 mmol) in THF. The mixture
is stirred for 15 h at rt, then diluted with THF and extracted with
1M aq. NaOH soln. and brine. The aq. layers are 2.times.
reextracted with THF, the combined organic layers are dried over
Na.sub.2SO.sub.4, filtered and the filtrate is evaporated. The
resulting crude product (10.15 g) is recrystallized from
CH.sub.3CN/MeOH to give 5.21 g (65%) of
(4S,5R)-4-(5-bromo-pyrimidin-2-yloxy)-1-aza-bicyclo[3.3.1]nonane.
[0102] 5.19 g (17.4 mmol) of
(4S,5R)-4-(5-bromo-pyrimidin-2-yloxy)-1-axa-bicyclo[3.3.1]nonane is
dissolved in 200 ml toluene/EtOH 9:1. 5-indolyl boronic acid (3.47
g, 21.6 mmol), Pd(PPh.sub.3).sub.4 (1.04 g, 0.873 mmol) and a soln.
of Na.sub.2CO.sub.3 (7.38 g, 69.6 mmol) in 35 ml H.sub.2O is added.
The reaction mixture is stirred at 90.degree. C. for 15 h. After
cooling to rt the mixture is filtered over hyflo, the filtrate is
extracted with water and brine. The aq. layers are reextracted with
AcOEt and the combined organic layers are dried over
Na.sub.2SO.sub.4, filtered and the filtrate is evaporated. The
resulting crude product is purified by FC (255 g silica gel, eluent
AcOEt/MeOH/Et.sub.3N 70:27:3) and recrystallization from EtOH to
give 3.87 g (67%)
(4S,5R)-4-[5-(1H-indol-5yl)-pyrimidn-2-yloxy]-1-aza-bicyclo[3.3.1]nonane.
MS (ES*): m/e=335 (MH*), m.p. 195-199.degree. C.
[0103] Preparation of the precursor 1-aza-bicyclo[3.3.1]nonan-4-one
is done according to M. G. Kim et al., J. Med. Chem. (2003) 46,
2216.
EXAMPLE 2
(Manufacture of Soft Capsules)
[0104] 5000 soft gelatin capsules, each comprising as active
ingredient 0.05 g of one of the compounds of formula (I) mentioned
in the preceding Examples, are prepared as follows: 250 g of the
pulverized active ingredient is suspended in 2 litres
Lauroglykol.RTM. (propylene glycol iaurate, Gattefosse S.A., Saint
Priest, France) and ground in a wet pulverizer to produce a
particle size of about 1 to 3 .mu.m, 0.419 g portions of the
mixture are then introduced into soft gelatin capsules using a
capsule-filling machine.
* * * * *