U.S. patent application number 11/881438 was filed with the patent office on 2007-11-22 for benzothiadiazine compounds.
This patent application is currently assigned to LESLABORATOIRES SERVIER. Invention is credited to Alexis Cordi, Patrice Desos, Pierre Lestage.
Application Number | 20070270415 11/881438 |
Document ID | / |
Family ID | 34950935 |
Filed Date | 2007-11-22 |
United States Patent
Application |
20070270415 |
Kind Code |
A1 |
Desos; Patrice ; et
al. |
November 22, 2007 |
Benzothiadiazine compounds
Abstract
The invention relates to compounds of formula (I): ##STR1##
wherein: R.sub.1 represents alkyl substituted by one or more
halogen atoms, R.sub.2 represents hydrogen, halogen or hydroxy,
R.sub.3 represents unsubstituted or substituted aryl, their
isomers, and also addition salts thereof. and medicinal products
containing the same which are useful in treating or preventing
disorders associated with AMPA flux.
Inventors: |
Desos; Patrice;
(Bois-Colombes, FR) ; Cordi; Alexis; (Suresnes,
FR) ; Lestage; Pierre; (La Celle-St-Cloud,
FR) |
Correspondence
Address: |
THE FIRM OF HUESCHEN AND SAGE
SEVENTH FLOOR, KALAMAZOO BUILDING
107 WEST MICHIGAN AVENUE
KALAMAZOO
MI
49007
US
|
Assignee: |
LESLABORATOIRES SERVIER
COURBEVOIE CEDEX
FR
92415
|
Family ID: |
34950935 |
Appl. No.: |
11/881438 |
Filed: |
July 27, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11265011 |
Nov 2, 2005 |
7268130 |
|
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11881438 |
Jul 27, 2007 |
|
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Current U.S.
Class: |
514/223.2 |
Current CPC
Class: |
A61P 25/24 20180101;
C07D 285/24 20130101; A61P 25/14 20180101; A61P 25/18 20180101;
A61P 25/00 20180101; A61P 25/28 20180101; A61P 25/08 20180101; A61P
43/00 20180101; A61P 25/22 20180101; A61P 9/10 20180101 |
Class at
Publication: |
514/223.2 |
International
Class: |
A61K 31/5415 20060101
A61K031/5415; A61P 25/28 20060101 A61P025/28 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 3, 2004 |
FR |
04.11690 |
Claims
1. A method for treating a living animal body, including a human,
afflicted with a condition selected from Alzheimer's disease and
disorders of memory and cognition associated with age, such method
comprising administering to the living animal body, including a
human, a therapeutically effective amount of a compound selected
from those of formula (I): ##STR14## wherein: R.sub.1 represents
linear or branched (C.sub.1-C.sub.6)alkyl substituted by one or
more halogen atoms, R.sub.2 represents hydrogen, halogen or
hydroxy, R.sub.3 represents unsubstituted aryl or aryl substituted
by one or more identical or different groups selected from: linear
or branched (C.sub.1-C.sub.6)alkyl; linear or branched
(C.sub.1-C.sub.6)alkoxy; linear or branched
(C.sub.1-C.sub.6)polyhaloalkyl; halogens; linear or branched
(C.sub.1-C.sub.6)alkoxy-carbonyl; linear or branched
(C.sub.1-C.sub.6)alkylthio; carboxy; linear or branched
(C.sub.1-C.sub.6)acyl; linear or branched
(C.sub.1-C.sub.6)polyhaloalkoxy; hydroxy; cyano; nitro amidino,
optionally substituted by one or two identical or different groups
selected from linear or branched (C.sub.1-C.sub.6)alkyl, hydroxy,
linear or branched (C.sub.1-C.sub.6)alkoxy and ##STR15## amino,
optionally substituted by one or two linear or branched
(C.sub.1-C.sub.6)alkyl; aminocarbonyl, optionally substituted by
one or two linear or branched (C.sub.1-C.sub.6)alkyl; benzyloxy;
(C.sub.1-C.sub.6)alkylsulphonylamino, optionally substituted on the
nitrogen by linear or branched (C.sub.1-C.sub.6)alkyl;
trifluoromethylsulphonylamino; a heterocyclic group; and linear or
branched (C.sub.1-C.sub.6)alkyl substituted by one or more
identical or different groups selected from halogen, linear or
branched (C.sub.1-C.sub.6)alkyl, NR.sub.4R.sub.5,
S(O).sub.nR.sub.6, OR.sub.7, amidino, optionally substituted by one
or two identical or different groups selected from linear or
branched (C.sub.1-C.sub.6)alkyl, hydroxy, linear or branched
(C.sub.1-C.sub.6)alkoxy and ##STR16## and a heterocyclic group,
wherein: R.sub.4 represents hydrogen, linear or branched
(C.sub.1-C.sub.6)alkyl, S(O).sub.pR.sub.8, COR.sub.9 or
P(O)(OR.sub.10)(OR.sub.11), R.sub.5 represents hydrogen, linear or
branched (C.sub.1-C.sub.6)alkyl, or R.sub.4 and R.sub.5, together
with the nitrogen atom carrying them, form a heterocyclic group,
R.sub.6, R.sub.8, R.sub.9, R.sub.10, R.sub.11 and R.sub.12, which
may be the same or different, each represent hydrogen or linear or
branched (C.sub.1-C.sub.6)alkyl optionally substituted by one or
more halogen atoms; aryl-(C.sub.1-C.sub.6)alkyl wherein the alkyl
moiety is linear or branched; or aryl, R.sub.7 represents linear or
branched (C.sub.1-C.sub.6)alkyl or linear or branched
(C.sub.1-C.sub.6)acyl, n and p, which may be the same or different,
each represent 0, 1 or 2, its enantiomers and diastereoisomers, and
addition salts thereof with a pharmaceutically-acceptable acid or
base.
2. The method of claim 1, wherein R.sub.1 represents haloethyl.
3. The method of claim 1, wherein R.sub.2 represents hydrogen.
4. The method of claim 1, wherein R.sub.3 represents unsubstituted
phenyl.
5. The method of claim 1, wherein R.sub.3 represents phenyl
substituted by amidino, hydroxyamidino, alkoxy,
alkylsulphonylamino, optionally substituted on the nitrogen by
alkyl, or alkyl substituted by amidino, hydroxyamidino, OR.sub.7,
NH(SO).sub.pR.sub.8 or NHCOR.sub.9.
6. The method of claim 1, wherein the compound of formula (I) is
selected from:
N-(4-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothi-
adiazin-7-yl]oxy}benzyl)methanesulphonamide and
N-(4-{[4-(2-chloroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-
-7-yl]oxy}benzyl)methanesulphonamide, and addition salts thereof
with a pharmaceutically-acceptable acid or base.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new benzothiadiazine
compounds. The compounds of the present invention are new and have
very valuable pharmacologic characteristics as AMPA modulators.
BACKGROUND OF THE INVENTION
[0002] It has now been recognised that the excitatory amino acids,
very especially glutamate, play a crucial role in the physiological
processes of neuronal plasticity and in the mechanisms underlying
learning and memory. Pathophysiological studies have clearly shown
that a deficit in glutamatergic neurotransmission is closely linked
to the development of Alzheimer's disease (Neuroscience and
Biobehavioral Reviews, 1992, 16, 13-24; Progress in Neurobiology,
1992, 39, 517-545).
[0003] In addition, innumerable works have in recent years
demonstrated the existence of sub-types of excitatory amino acid
receptors and their functional interactions (Molecular
Neuropharmacology, 1992, 2, 15-31).
[0004] Among those receptors, the AMPA
(.alpha.-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid)
receptor appears to be involved to the greatest extent in the
phenomena of physiological neuronal excitability and, especially,
in those phenomena involved in memorisation processes. For example,
it has been shown that learning is associated with an increase in
the binding of AMPA to its receptor in the hippocampus, one of the
areas of the brain essential to processes of memory and cognition.
Likewise, nootropic agents such as aniracetam have very recently
been described as modulating the AMPA receptors of neuronal cells
in a positive manner (Journal of Neurochemistry, 1992, 58,
1199-1204).
DESCRIPTION OF THE PRIOR ART
[0005] In the literature, compounds having a benzamide structure
have been described as possessing this same mechanism of action and
as improving memory performance (Synapse, 1993, 15, 326-329).
Compound BA 74, in particular, is the most active of those new
pharmacological agents.
[0006] Finally, the patent specification EP 692 484 describes a
benzothiadiazine compound having facilitating activity on the AMPA
current, and the patent application WO 99/42456 describes, inter
alia, certain benzothiadiazine compounds as modulators of AMPA
receptors.
[0007] The benzothiadiazine compounds to which the present
invention relates, besides being new, surprisingly exhibit
especially valuable pharmacological activity on the AMPA current.
They are useful as AMPA modulators for the treatment or prevention
of disorders of memory and cognition that are associated with age,
with syndromes of anxiety or depression, with progressive
neurodegenerative diseases, with Alzheimer's disease, with Pick's
disease, with Huntington's chorea, with schizophrenia, with the
sequelae of acute neurodegenerative diseases, with the sequelae of
ischaemia and with the sequelae of epilepsy.
DETAILED DESCRIPTION OF THE INVENTION
[0008] More specifically, the present invention relates to
compounds of formula (I): ##STR2##
[0009] wherein:
[0010] R.sub.1 represents a linear or branched
(C.sub.1-C.sub.6)alkyl group substituted by one or more halogen
atoms,
[0011] R.sub.2 represents a hydrogen atom, a halogen atom or a
hydroxy group,
[0012] R.sub.3 represents an unsubstituted aryl group or an aryl
group substituted by one or more identical or different groups
selected from: linear or branched (C.sub.1-C.sub.6)alkyl; linear or
branched (C.sub.1-C.sub.6)alkoxy; linear or branched
(C.sub.1-C.sub.6)polyhaloalkyl; halogen atoms; linear or branched
(C.sub.1-C.sub.6)alkoxy-carbonyl linear or branched
(C.sub.1-C.sub.6)alkylthio; carboxy; linear or branched
(C.sub.1-C.sub.6)acyl; linear or branched
(C.sub.1-C.sub.6)polyhaloalkoxy; hydroxy; cyano; nitro; amidino
(optionally substituted by one or two identical or different groups
selected from linear or branched (C.sub.1-C.sub.6)alkyl, hydroxy,
linear or branched (C.sub.1-C.sub.6)alkoxy and ##STR3## amino
(optionally substituted by one or two linear or branched
(C.sub.1-C.sub.6)alkyl groups); aminocarbonyl (optionally
substituted by one or two linear or branched (C.sub.1-C.sub.6)alkyl
groups); benzyloxy; (C.sub.1-C.sub.6)alkylsulphonylamino
(optionally substituted on the nitrogen by a linear or branched
(C.sub.1-C.sub.6)alkyl group); (trifluoromethylsulphonyl)amino; a
heterocyclic group; and linear or branched (C.sub.1-C.sub.6)alkyl
on the one hand substituted by one or more identical or different
groups selected from hydrogen and halogen atoms and linear or
branched (C.sub.1-C.sub.6)alkyl groups and on the other hand
substituted by a group selected from NR.sub.4R.sub.5,
S(O).sub.nR.sub.6, OR.sub.7, amidino (optionally substituted by one
or two identical or different groups selected from linear or
branched (C.sub.1-C.sub.6)alkyl, hydroxy, linear or branched
(C.sub.1-C.sub.6)alkoxy and ##STR4## and a heterocyclic group,
wherein:
[0013] R.sub.4 represents a hydrogen atom or a linear or branched
(C.sub.1-C.sub.6)alkyl, S(O).sub.pR.sub.8, COR.sub.9 or
P(O)(OR.sub.10)(OR.sub.11) group,
[0014] R.sub.5 represents a hydrogen atom or a linear or branched
(C.sub.1-C.sub.6)alkyl group,
[0015] or R.sub.4 and R.sub.5, together with the nitrogen atom
carrying them, form a heterocyclic group,
[0016] R.sub.6, R.sub.8, R.sub.9, R.sub.10, R.sub.11 and R.sub.12,
which may be the same or different, each represent a hydrogen atom
or a linear or branched (C.sub.1-C.sub.6)alkyl group optionally
substituted by one or more halogen atoms; an
aryl-(C.sub.1-C.sub.6)alkyl group in which the alkyl moiety is
linear or branched; or an aryl group,
[0017] R.sub.7 represents a linear or branched
(C.sub.1-C.sub.6)alkyl group or a linear or branched
(C.sub.1-C.sub.6)acyl group,
[0018] n and p, which may be the same or different, each represent
0, 1 or 2,
[0019] to their enantiomers and diastereoisomers, and also to
addition salts thereof with a pharmaceutically acceptable acid or
base,
[0020] it being understood that: [0021] a heterocyclic group means
a monocyclic or bicyclic, aromatic or non-aromatic group containing
from one to four identical or different hetero atoms selected from
nitrogen, oxygen and sulphur, optionally substituted by one or more
identical or different groups selected from halogen, linear or
branched (C.sub.1-C.sub.6)alkyl, linear or branched
(C.sub.1-C.sub.6)alkoxy, linear or branched
(C.sub.1-C.sub.6)polyhaloalkyl, linear or branched
(C.sub.1-C.sub.6)alkoxy-carbonyl, oxo, thioxo, carboxy, linear or
branched (C.sub.1-C.sub.6)acyl, linear or branched
(C.sub.1-C.sub.6)polyhaloalkoxy, hydroxy, cyano, nitro, amino
(optionally substituted by one or more linear or branched
(C.sub.1-C.sub.6)alkyl groups), aminosulphonyl (optionally
substituted by one or more linear or branched
(C.sub.1-C.sub.6)alkyl groups) and
(C.sub.1-C.sub.6)alkylsulphonylamino, [0022] an aryl group means a
monocyclic aromatic group or a bicyclic group in which at least one
of the rings is aromatic, optionally substituted by one or more
identical or different groups selected from halogen, linear or
branched (C.sub.1-C.sub.6)alkyl (optionally substituted by one or
more hydroxy groups), linear or branched (C.sub.1-C.sub.6)alkoxy,
linear or branched (C.sub.1-C.sub.6)polyhaloalkyl, linear or
branched (C.sub.1-C.sub.6)alkoxy-carbonyl, oxo, thioxo, linear or
branched (C.sub.1-C.sub.6)alkylthio, carboxy, linear or branched
(C.sub.1-C.sub.6)acyl, linear or branched
(C.sub.1-C.sub.6)polyhaloalkoxy, hydroxy, cyano, nitro, amino
(optionally substituted by one or more linear or branched
(C.sub.1-C.sub.6)alkyl or linear or branched (C.sub.1-C.sub.6)acyl
groups), aminocarbonyl (optionally substituted by one or more
linear or branched (C.sub.1-C.sub.6)alkyl groups), aminosulphonyl
(optionally substituted by one or more linear or branched
(C.sub.1-C.sub.6)alkyl groups), mono- or
di-((C.sub.1-C.sub.6)alkylsulphonyl)amino, mono- or
di-(trifluoromethylsulphonyl)amino, PO(OR.sub.a)(OR.sub.b) (wherein
R.sub.a and R.sub.b, which may be the same or different, each
represent a hydrogen atom or a linear or branched
(C.sub.1-C.sub.6)alkyl group), benzyloxy and phenyl (optionally
substituted by one or more identical or different groups selected
from halogen, linear or branched (C.sub.1-C.sub.6)alkyl, linear or
branched (C.sub.1-C.sub.6)perhaloalkyl, hydroxy and linear or
branched (C.sub.1-C.sub.6)alkoxy).
[0023] Among the pharmaceutically acceptable acids there may be
mentioned, without implying any limitation, hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid,
trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid,
succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic
acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric
acid etc.
[0024] Among the pharmaceutically acceptable bases there may be
mentioned, without implying any limitation, sodium hydroxide,
potassium hydroxide, triethylamine, tert-butylamine etc.
[0025] Preference is given to the group R.sub.1 being haloethyl
such as fluoroethyl, chloroethyl or bromoethyl, more preferably
fluoro- or chloro-ethyl.
[0026] R.sub.2 preferably represents a hydrogen atom.
[0027] Preference is given to the group R.sub.3 being a phenyl or
substituted phenyl group, more specially substituted by: [0028] an
amidino group, [0029] a hydroxyamidino group, [0030] an alkoxy
group, [0031] an alkylsulphonylamino group optionally substituted
on the nitrogen by an alkyl group, [0032] or an alkyl group
substituted by an amidino, hydroxyamidino, OR.sub.7,
NHS(O).sub.pR.sub.8 or NHCOR.sub.9 group.
[0033] Even more especially, the invention relates to compounds of
formula (I) which are: [0034]
N-(4-{[4-(2-bromoethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin--
7-yl]oxy}benzyl)methanesulphonamide, [0035]
N-(4-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-
-7-yl]oxy}benzyl)methanesulphonamide, [0036]
N-(4-{[4-(2-chloroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-
-7-yl]oxy}benzyl)methanesulphonamide, [0037]
N-(3-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-
-7-yl]oxy}phenyl)methanesulphonamide, [0038]
N-(4-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-
-7-yl]oxy}phenyl)methanesulphonamide, [0039]
4-(2-fluoroethyl)-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiaz-
ine 1,1-dioxide, [0040]
N-(3-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-
-7-yl]oxy}-benzyl)acetamide, [0041]
N-(3-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-
-7-yl]oxy}-benzyl)methanesulphonamide, [0042]
N-(4-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-
-7-yl]oxy}-benzyl)-N-ethylmethanesulphonamide, [0043]
4-(2-fluoroethyl)-7-phenoxy-3,4-dihydro-2H-1,2,4-benzothiadiazine
1,1-dioxide, [0044]
3-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7--
yl]oxy}-N'-hydroxybenzenecarboximidamide, [0045] and
3-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7--
yl]oxy}-N-methylbenzamide.
[0046] The invention relates also to a process for the preparation
of compounds of formula (I), which process is characterised in that
there is used as starting material the compound of formula (II):
##STR5##
[0047] wherein R.sub.2 is as defined in formula (I),
[0048] with which there is condensed, in a basic medium, a linear
or branched (C.sub.1-C.sub.6)haloalkyl bearing an hydroxy
group,
[0049] which is then converted into a corresponding halogenated
compound to yield compound of formula (III): ##STR6##
[0050] wherein R.sub.1 and R.sub.2 are as defined for formula (I),
[0051] which is subjected to a demethylation reaction, in the
presence of BBr.sub.3 or BF.sub.3, for example, to yield the
compound of formula (IV): ##STR7##
[0052] wherein R.sub.1 and R.sub.2 are as defined hereinbefore,
[0053] with which there is condensed, in the presence of
Cu(OAc).sub.2, the boronic acid compound of formula (V):
R.sub.3--B(OH).sub.2 (V),
[0054] wherein R.sub.3 is as defined for formula (I),
[0055] to yield the compound of formula (VI): ##STR8##
[0056] wherein R.sub.1, R.sub.2 and R.sub.3 are as defined
hereinbefore,
[0057] which is subjected to reduction with NaBH.sub.4, for
example, to yield the compound of formula (I): ##STR9##
[0058] wherein R.sub.1, R.sub.2 and R.sub.3 are as defined
hereinbefore, [0059] or which compound of formula (III) is
subjected to reduction, in the presence of NaBH.sub.4, for example,
to obtain the compound of formula (VII): ##STR10##
[0060] wherein R.sub.1 and R.sub.2 are as defined hereinbefore,
[0061] which is subjected to a demethylation reaction, in the
presence of BBr.sub.3 or BF.sub.3, for example, to yield the
compound of formula (VIII): ##STR11##
[0062] wherein R.sub.1 and R.sub.2 are as defined hereinbefore,
[0063] with which there is condensed, in the presence of
Cu(OAc).sub.2, the boronic acid compound of formula (V) as defined
hereinbefore to yield the compound of formula (I),
[0064] which compound of formula (I) is purified, if necessary,
according to a conventional purification technique, is separated,
where appropriate, into its isomers according to a conventional
separation technique and is converted, if desired, into its
addition salts with a pharmaceutically acceptable acid or base.
[0065] The invention relates also to the compound of formula
(VIII): ##STR12##
[0066] as defined hereinbefore, which is useful as a synthesis
intermediate for the synthesis of compounds of formula (I) and is
useful as an AMPA receptor modulating agent, and more especially to
the compound of formula (IX), a particular case of compounds of
formula (VIII): ##STR13## [0067] wherein X represents a fluorine,
chlorine, bromine or iodine atom, which is useful as a synthesis
intermediate for the synthesis of compounds of formula (I) and is
useful as an AMPA receptor modulating agent.
[0068] The invention relates also to pharmaceutical compositions
comprising, as active ingredient, a compound of formula (I) or (IX)
with one or more appropriate, inert, non-toxic excipients. Among
the pharmaceutical compositions according to the invention there
may be mentioned more especially those that are suitable for oral,
parenteral (intravenous or subcutaneous) or nasal administration,
tablets or dragees, sublingual tablets, gelatin capsules, lozenges,
suppositories, creams, ointments, dermal gels, injectable
preparations, drinkable suspensions etc.
[0069] The useful dosage can be varied according to the nature and
severity of the disorder, the administration route and the age and
weight of the patient and ranges from 1 to 500 mg per day in one or
more administrations.
[0070] The Preparations and Examples that follow illustrate the
invention but do not limit it in any way.
[0071] The starting materials used are products that are known or
that are prepared according to known operating procedures.
[0072] The structures of the compounds described in the Examples
were determined according to the usual spectrophotometric
techniques (infrared, NMR, mass spectrometry, . . . ).
Preparation 1
4-(2-Bromoethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-ol
1,1-dioxide
[0073] Step A:
2-(7-Methoxy-1,1-dioxido-4H-1,2,4-benzothiadiazin-4-yl)ethanol
[0074] To a solution of 7-methoxy-4H-1,2,4-benzothiadiazine
1,1-dioxide (4.0 g, 18.8 mmol) in a mixture of 30 ml of DMF and 30
ml of CH.sub.3CN there are added 8.6 g (56.6 mmol) of CsF and 1.47
ml (18.8 mmol) of 2-bromoethanol. Stirring is carried out for 2
hours at 75.degree. C. and 1.47 ml (18.8 mmol) of 2-bromoethanol
are added. After 6 more hours at 75.degree. C., a further 1.47 ml
(18.8 mmol) of 2-bromoethanol and then 2.8 g (18.8 mmol) of CsF are
added and stirring is continued at 75.degree. C. overnight. The
salts are filtered off at ambient temperature and rinsed with
CH.sub.3CN; the filtrate is evaporated to dryness. The residue is
taken up in CH.sub.2Cl.sub.2, and the organic phase is washed with
saturated NaCl solution and dried (MgSO.sub.4). After evaporation,
the sticky residue is taken up in a mixture of ethyl
ether/CH.sub.2Cl.sub.2. The gum is triturated until a solid is
obtained, which is filtered off to obtain the title compound.
[0075] Melting point: 160-162.degree. C.
[0076] Elemental microanalysis: TABLE-US-00001 C H N S theoretical
% 46.87 4.72 10.93 12.51 experimental % 46.99 4.96 10.34 12.51
[0077] Step B:
4-(2-Fluoroethyl)-7-methoxy-4H-1,2,4-benzothiadiazine
1,1-dioxide
[0078] To a solution of 3.85 g (15.02 mmol) of the compound of the
previous Step in 100 ml of CH.sub.2Cl.sub.2, cooled in an ice bath,
there are added, dropwise, 3.97 ml (30.0 mmol) of DAST diluted with
20 ml of CH.sub.2Cl.sub.2. The reaction solution is then allowed to
return to ambient temperature in about 1 hour; 100 ml of saturated
NaCl solution are then poured in and the organic phase is decanted
off, dried (MgSO.sub.4) and evaporated in vacuo. The residue is
triturated in a mixture of ethyl ether/CH.sub.2Cl.sub.2 until a
solid is obtained which is filtered off to obtain the title
compound.
[0079] Melting point: 123-128.degree. C.
[0080] Elemental microanalysis: TABLE-US-00002 C H N S theoretical
% 46.50 4.29 10.85 12.42 experimental % 45.88 4.41 10.46 12.61
[0081] Step C:
4-(2-Fluoroethyl)-7-methoxy-3,4-dihydro-2H-1,2,4-benzothiadiazine
1,1-dioxide
[0082] 454 mg (12.0 mmol) of NaBH.sub.4, in small portions, are
added to a suspension of 2.77 g (10.7 mmol) of the compound of the
previous Step in 25 ml of ethanol. After stirring for 2 hours at
ambient temperature, 1N HCl is added dropwise until a white
precipitate forms which is filtered off in order to recover the
title compound.
[0083] Melting point: 91-93.degree. C.
[0084] Step D:
4-(2-Bromoethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-ol
1,1-dioxide 17.6 ml (17.6 mmol) of a 1M solution of BBr.sub.3 in
CH.sub.2Cl.sub.2 are added, dropwise, to a solution of 1.53 g (5.88
mmol) of the compound of the previous Step in 70 ml of
CH.sub.2Cl.sub.2, cooled in an ice bath. The mixture is stirred
overnight while being allowed to return to ambient temperature. The
reaction suspension is cooled in an ice bath and 50 ml of water are
added dropwise. After stirring for 30 minutes, the precipitate is
filtered off, rinsed with water and dried in vacuo. The expected
compound is accordingly obtained in the form of a light brown
powder.
[0085] Melting point: 144-148.degree. C.
Preparation 2
4-(2-Fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-ol
1,1-dioxide
[0086] Step A: 4-(2-Fluoroethyl)-4H-1,2,4-benzothiadiazin-7-ol
1,1-dioxide
[0087] 100 ml (950 mmol) of the complex BF.sub.3.Me.sub.3S are
introduced into a two-necked flask purged with nitrogen and
connected to a trap containing sodium hypochlorite, by means of a
cannula and under nitrogen pressure. Whilst stirring and under a
gentle current of nitrogen there is then quickly added, in small
portions, a suspension of 5.63 g (21.8 mmol) of the compound of
Step B of Preparation 1 in 75 ml of CH.sub.2Cl.sub.2. The current
of nitrogen is stopped and the reaction suspension is stirred
overnight at ambient temperature. The reaction mixture is cooled in
an ice bath, and ice and water are added. The suspension is stirred
for 30 minutes, and the precipitate is filtered off and rinsed with
water and with heptane. The solid is dried and recrystallised from
water to yield the title compound.
[0088] Melting point: 230-235.degree. C.
[0089] Elemental microanalysis: TABLE-US-00003 C H N S theoretical
% 44.26 3.71 11.47 13.13 experimental % 44.55 4.18 11.34 13.59
[0090] Step B:
4-(2-Fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-ol
1,1-dioxide
[0091] The procedure is as in Step C of Preparation 1, starting
from the compound obtained in Step A above, except that the title
compound is not precipitated after addition of 1N HCl but is
extracted with CH.sub.2Cl.sub.2.
[0092] Melting point: 178-180.degree. C.
[0093] Elemental microanalysis: TABLE-US-00004 C H N S theoretical
% 43.90 4.50 11.38 13.02 experimental % 43.73 4.37 11.10 12.80
Preparation 3
4-(2-Chloroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-ol
1,1-dioxide
[0094] Step A:
4-(2-Chloroethyl)-7-methoxy-4H-1,2,4-benzothiadiazine
1,1-dioxide
[0095] To a suspension of 1.0 g (3.90 mmol) of the compound of Step
A of Preparation 1 in 20 ml of CH.sub.2Cl.sub.2 there are added, at
ambient temperature, 0.1 ml of DMF and then, dropwise, a solution
containing 1.42 ml (19.5 mmol) of SOCl.sub.2 in 5 ml of
CH.sub.2Cl.sub.2. At the end of the addition, a solution is
obtained which is stirred at the reflux of CH.sub.2Cl.sub.2 for 2
hours. The CH.sub.2Cl.sub.2 is evaporated off in vacuo and the
residue is taken up in a 5% solution of NaHCO.sub.3. After
trituration of the residue, a solid is obtained which is filtered
off, rinsed with water and dried to yield the title compound.
[0096] Melting point: 126-130.degree. C.
[0097] Elemental microanalysis: TABLE-US-00005 C H N S theoretical
% 43.72 4.04 10.20 11.67 experimental % 43.79 4.06 9.84 12.01
[0098] Step B:
4-(2-Chloroethyl)-7-methoxy-3,4-dihydro-2H-1,2,4-benzothiadiazine
1,1-dioxide
[0099] Conditions and treatment identical to Step C of Preparation
1.
[0100] Melting point: 139-143.degree. C.
[0101] Elemental microanalysis: TABLE-US-00006 C H N S Cl
theoretical % 43.40 4.73 10.12 11.59 12.81 experimental % 43.73
5.05 9.89 11.07 13.30
[0102] Step C:
4-(2-Chloroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-ol
1,1-dioxide
[0103] Conditions and treatment identical to Step D of Preparation
1.
[0104] Melting point: 171-173.degree. C.
[0105] The compounds of Examples 1-12 are obtained by an
O-arylation reaction carried out on the intermediates described in
Preparations 1, 2 or 3 using the appropriate boronic acid and under
the reaction and treatment conditions described in Example 1
hereinbelow.
EXAMPLE 1
N-(4-{[4-(2-Bromoethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-
-yl]oxy}benzyl)methanesulphonamide
[0106] 80 ml of CH.sub.2Cl.sub.2, 548 .mu.l (6.79 mmol) of
pyridine, 700 mg (2.29 mmol) of the compound of Preparation 1, 8 g
of 4 .ANG. molecular sieve, 786 mg (3.43 mmol) of
4-{[(methylsulphonyl)-amino]methylphenyl)boronic acid and 623 mg
(3.43 mmol) of Cu(OAc).sub.2 are introduced into a 100 ml
Erlenmeyer flask. The suspension is stirred vigorously at ambient
temperature, the Erlenmeyer flask being left open to the air. After
4 hours 30 minutes, the reaction mixture is diluted with an
additional 50 ml of CH.sub.2Cl.sub.2 and the suspension is
filtered. The filtrate is evaporated to dryness and the residue is
chromatographed twice on a silica column, eluting successively with
CH.sub.2Cl.sub.2/MeOH (98/2) in the first chromatographic procedure
and with CH.sub.2Cl.sub.2/acetone (95/5) in the second to yield the
title compound.
[0107] Melting point: 182-184.degree. C.
[0108] Elemental microanalysis: TABLE-US-00007 C H N S theoretical
% 41.64 4.11 8.57 13.08 experimental % 42.05 3.76 8.29 13.09
EXAMPLE 2
N-(4-{[4-(2-Fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothia-diazin-
-7-yl]oxy}benzyl)methanesulphonamide
[0109] The procedure is as in Example 1, starting from the compound
obtained in Preparation 2 and
4-{[(methylsulphonyl)amino]methyl}phenylboronic acid.
[0110] Melting point: 100-102.degree. C.
[0111] Elemental microanalysis: TABLE-US-00008 C H N S theoretical
% 47.54 4.69 9.78 14.93 experimental % 47.14 4.97 9.56 14.99
EXAMPLE 3
N-(4-{[4-(2-Chloroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothia-diazin-
-7-yl]oxy}benzyl)methanesulphonamide
[0112] The procedure is as in Example 1, starting from the compound
obtained in Preparation 3 and
4-{[(methylsulphonyl)amino]methyl}phenylboronic acid.
[0113] Melting point: 172-175.degree. C.
[0114] Elemental microanalysis: TABLE-US-00009 C H N S Cl
theoretical % 45.79 4.52 9.42 14.38 7.95 experimental % 45.55 4.84
9.24 14.69 8.41
EXAMPLE 4
N-(3-{[4-(2-Fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothia-diazin-
-7-yl]oxy}phenyl)methanesulphonamide
[0115] The procedure is as in Example 1, starting from the compound
obtained in Preparation 2 and
3-{[(methylsulphonyl)amino]phenylboronic acid.
[0116] Melting point: 131-134.degree. C.
[0117] Elemental microanalysis: TABLE-US-00010 C H N S theoretical
% 46.26 4.37 10.11 15.44 experimental % 46.09 4.35 9.91 15.85
EXAMPLE 5
N-(4-{[4-(2-Fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothia-diazin-
-7-yl]oxy}phenyl)methanesulphonamide
[0118] The procedure is as in Example 1, starting from the compound
obtained in Preparation 2 and
4-{[(methylsulphonyl)amino]phenylboronic acid.
[0119] Melting point: 151-152.degree. C.
[0120] Elemental microanalysis: TABLE-US-00011 C H N S theoretical
% 46.26 4.37 10.11 15.44 experimental % 45.71 4.78 9.90 15.65
EXAMPLE 6
4-(2-Fluoroethyl)-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzo-thiadiaz-
ine 1,1-dioxide
[0121] The procedure is as in Example 1, starting from the compound
obtained in Preparation 2 and 3-methoxyphenylboronic acid.
[0122] Melting point: 101-102.degree. C.
[0123] Elemental microanalysis: TABLE-US-00012 C H N S theoretical
% 54.54 4.86 7.95 9.10 experimental % 54.50 4.85 7.77 8.91
EXAMPLE 7
N-(3-{[4-(2-Fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothia-diazin-
-7-yl]oxy}benzyl)acetamide
[0124] The procedure is as in Example 1, starting from the compound
obtained in Preparation 2 and 3-[(acetylamino)methyl]phenylboronic
acid.
[0125] Melting point: 129-131.degree. C.
[0126] Elemental microanalysis: TABLE-US-00013 C H N S theoretical
% 54.95 5.12 10.68 8.15 experimental % 55.03 5.18 10.35 8.22
EXAMPLE 8
N-(3-{[4-(2-Fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothia-diazin-
-7-yl]oxy}benzyl)methanesulphonamide
[0127] The procedure is as in Example 1, starting from the compound
obtained in Preparation 2 and
3-{[(methylsulphonyl)amino]methyl}phenylboronic acid.
[0128] Melting point: 110-112.degree. C.
[0129] Elemental microanalysis: TABLE-US-00014 C H N S theoretical
% 45.54 4.69 9.78 14.93 experimental % 47.26 4.86 9.45 15.01
EXAMPLE 9
N-(4-{[4-(2-Fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzo-thiadiazin-
-7-yl]oxy}benzyl)-N-methylmethanesulphonamide
[0130] The procedure is as in Example 1, starting from the compound
obtained in Preparation 2 and
4-{[methyl(methylsulphonyl)amino]methyl}phenyl)boronic acid.
[0131] Melting point: 59.degree. C.
[0132] Elemental microanalysis: TABLE-US-00015 C H N S theoretical
% 48.75 5.00 9.47 14.46 experimental % 48.53 5.16 9.06 14.41
EXAMPLE 10
4-(2-Fluoroethyl)-7-phenoxy-3,4-dihydro-2H-1,2,4-benzothiadiazine
1,1-dioxide
[0133] The procedure is as in Example 1, starting from the compound
obtained in Preparation 2 and phenylboronic acid.
[0134] Melting point: 145.degree. C.
[0135] Elemental microanalysis: TABLE-US-00016 C H N S theoretical
% 55.89 4.69 8.69 9.95 experimental % 55.70 4.81 8.48 9.89
EXAMPLE 11
3-{[4-(2-Fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-y-
l]oxy}-N'-hydroxybenzenecarboximidamide
[0136] Step A
3-{[4-(2-Fluoroethyl)-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl]oxy}benzo-
nitrile
[0137] The procedure is as in Example 1, starting from the compound
obtained in Step A of Preparation 2 and 3-cyanophenylboronic acid
and extending the reaction time to 48 hours.
[0138] Melting point: 202-208.degree. C.
[0139] Step B:
3-{[4-(2-Fluoroethyl)-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl]oxy}-N'-h-
ydroxybenzenecarboximidamide
[0140] 770 .mu.L (5.52 mmol) of triethylamine are added to a
solution of hydroxylamine hydrochloride (384 mg, 5.52 mmol) in 1.8
ml of DMSO, and the suspension is stirred for 20 minutes at ambient
temperature. The precipitate is filtered off and the filtrate is
concentrated in vacuo. To the resulting filtrate there are added
225 mg (0.921 mmol) of the compound of Step A above and the
solution is stirred at 75.degree. C. for 4 hours. The reaction
mixture is cooled to ambient temperature and the reaction mixture
is precipitated from water. A white, non-filterable, gummy paste is
obtained which is separated from the aqueous phase by simple
decanting. The gum is triturated in ethanol until crystallisation
occurs. The solid is filtered off to yield the title compound.
[0141] Melting point: 181-183.degree. C.
[0142] Step
C:3-{[4-(2-Fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin--
7-yl]oxy}-N'-hydroxybenzenecarboximidamide
[0143] 10 mg (0.258 mmol) of NaBH.sub.4 are added to a suspension
of the compound obtained in Step B (75 mg, 0.198 mmol) in 1 ml of
ethanol. The suspension is stirred for 30 minutes at ambient
temperature and is then cooled in an ice bath. The reaction mixture
is neutralised by adding 1N HCl and extracted with ethyl acetate.
The organic phase is washed with saturated NaCl solution, dried
(MgSO.sub.4) and evaporated in vacuo. The evaporation residue is
crystallised from CH.sub.2Cl.sub.2. The expected compound is
recovered by filtration.
[0144] Melting point: 160-163.degree. C.
EXAMPLE 12
3-{[4-(2-Fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-y-
l]oxy}-N-methylbenzamide
[0145] The procedure is as in Example 1, starting from the compound
obtained in Preparation 2 and
3-[(methylamino)carbonyl]phenylboronic acid.
[0146] Melting point: 194-196.degree. C.
[0147] Elemental microanalysis: TABLE-US-00017 C H N S theoretical
% 53.82 4.78 11.08 8.45 experimental % 53.53 4.98 10.87 8.42
PHARMACOLOGICAL STUDY OF COMPOUNDS OF THE INVENTION
[0148] Study of the Excitatory Currents Induced by AMPA in Xenopus
oocytes
[0149] a--Method:
[0150] mRNA's are prepared from cerebral cortex of male Wistar rats
by the guanidinium thiocyanate/phenol/chloroform method. The poly
(A.sup.+) mRNA's are isolated by chromatography on oligo-dT
cellulose and injected at a level of 50 ng per oocyte. The oocytes
are incubated for 2 to 3 days at 18.degree. C. to permit expression
of the receptors and are then stored at 8-10.degree. C.
[0151] Electrophysiological recording is carried out in a
Plexiglass.RTM. chamber at 20-24.degree. C. in OR2 medium (J. Exp.
Zool., 1973, 184, 321-334) by the "voltage-clamp" method using two
electrodes, with a third electrode placed in the bath serving as
reference.
[0152] All the compounds are applied via the incubation medium and
the electric current is measured at the end of the application
period. AMPA is used in a concentration of 10 .mu.M. For each
compound studied, the concentration that doubles (EC2X) or
quintuples (EC5X) the intensity of the current induced by AMPA
alone (5 to 50 nA) is determined.
[0153] b--Results:
[0154] The compounds of the invention potentiate the excitatory
effects of AMPA to a very considerable degree and their activity is
very clearly superior to that of compounds of reference.
[0155] By way of example, the compound of Example 1 has an EC2X of
0.04 .mu.M. TABLE-US-00018 PHARMACEUTICAL COMPOSITION Formula for
the preparation of 1000 tablets each containing 100 g 100 mg of
N-(4-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-
dihydro-2H-1,2,4-benzothiadiazin-7-
yl]oxy}benzyl)methanesulphonamide (Example 2)
Hydroxypropylcellulose 2 g Wheat starch 10 g Lactose 100 g
Magnesium stearate 3 g Talc 3 g
* * * * *