Title of Invention

DERIVATIVES OF 1,4-DIAZABICYCLO[3.2.1]OCTANECARBOXAMIDE, PREPARATION METHOD THEREOF AND USE OF SAME IN THERAPEUTICS

Abstract The invention relates to compound, having general formula (I) and pharmaceutical composition comprising the same.
Full Text

Derivatives of 1,4-diazabicyclo[3.2.1]octanecarbox-
amide, preparation method thereof and use of same in
therapeutics
The present invention relates to compounds which are
nicotinic receptor ligands. They are useful in the
treatment or prevention of disorders associated with
dysfunction of nicotinic receptors.
The compounds of the invention conform to the general
formula (I)

in which
X represents a nitrogen atom or a group of general
formula C-R2,
P, Q, R and W represent each independently of one
another a nitrogen atom or a group of general formula
C-R3,
RX represents a hydrogen atom or a (C1-C6) alkyl group,
R2 represents a (C1-C6) alkyl group,
R3 represents a hydrogen or halogen atom or a (C1-C6)
alkyl, (C1-Cs)alkoxy, nitro, amino, trifluoromethyl or
cyano group or a group of general formula -NR4R5, -NR4C
(=O)R5, -NR4C(=O)NR5R6, -NR4C (=O) OR5, NR4S (=O) 2NR5R6, -OR5,
-OC(=O)R5, -OC(=O)OR5, -OC(=O)ONR4R5, -OC(=O)SR5, -C(=O)
OR5, C(=O)R5, -C(=O)NR4R5, SR5, -S(=O)R5, -S(=O)2R5 or -S
(=O)2NR4R6, or a phenyl group optionally substituted by
one or more groups selected from halogen atoms and
(C1-C6) alkyl, (C1-C6) alkoxy, nitro, amino,
trifluoromethyl or cyano groups or groups of general
formula -NR4R5, -NR4C(=O)R5, -NR4C (=O)NR5R6, -NR4C (=O) OR5,

NR4S(=O)2NR5R6, -OR5, -OC(=O)R5, -OC(=O)OR5, -OC (=O) ONR4R5,
-OC(=O)SR5, -C(=O)OR5, -C(=O)NR4R5, SR5, -S(=O)R5, -S (=O)
2R5 or -S (=O)2NR4R6,
or R3 represents a group selected from imidazole,
pyridine, pyridazine, pyrimidine, pyrazole, pyrazine,
triazole, quinoline, isoquinoline, tetrazole, furan,
thiophene, thiazole, isothiazole, oxazole, isoxazole,
pyrrole, tetrahydroquinoline, tetrahydroisoquinoline,
indole, benzimidazole, benzofuran, dihydrobenzofuran,
cinnoline, indazole, phthalazine, triazine, isoindole,
oxadiazole, thiadiazole, furazan, benzofurazan,
benzothiophene, dihydrobenzothiophene, benzotriazole,
benzothiazole, benzisothiazole, benzoxazole, benz-
isoxazole, quinazoline, quinoxaline, naphthyridine,
dihydroquinoline, dihydroisoquinoline, furopyridine,
dihydrofuropyridine, pyrrolopyridine, thienopyridine,
dihydrothienopyridine, imidazopyridine, pyrazolo-
pyridine, oxazolopyridine, isoxazolopyridine,
isoxazolopyridine, thiazolopyridine, isothiazolo-
pyridine, pyrrolopyrimidine, furopyrimidine, dihydro-
furopyrimidine, thienopyrimidine, dihydrothieno-
pyrimidine, imidazopyrimidine, pyrazolopyrimidine,
oxazolopyrimidine, isoxazolopyrimidine, thiazolo-
pyrimidine, isothiazolopyrimidine, furopyrazine,
dihydrofuropyrazine, pyrrolopyrazine, thienopyrazine,
dihydrothienopyrazine, imidazopyrazine, pyrazolo-
pyrazine, oxazolopyrazine, isoxazolopyrazine,
thiazolopyrazine, isothiazolopyrazine, furopyridazine,
dihydrofuropyridazine, pyrrolopyridazine, thieno-
pyridazine, dihydrothienopyridazine, imidazopyridazine,
pyrazolopyridazine, oxazolopyridazine, isoxazolo-
pyridazine, thiazolopyridazine or isothiazolopyridazine
ring systems,
R4, R5 and R6 represent each independently of one
another a halogen atom or a linear or branched (C1-C6)
alkyl, linear or branched (C2-C6)alkenyl or linear or
branched (C2-C6) alkynyl group, or a (C3-C8) cycloalkyl,
(C3-C8) cycloalkyl (Cx-C3) alkyl, (C4-C8) cycloalkenyl or
phenyl group,

it being possible for the groups of general formulae
NR4R5 and NR5R6 to form, with the nitrogen atom which
carries them, a group selected from aziridinyl,
azetidinyl, pyrrolidinyl, piperidinyl, azepinyl,
piperazinyl, morpholinyl, thiomorpholinyl, pyrrolinyl,
indolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,
3H-indolyl, quinuclidinyl and quinolizinyl groups.
The compounds of the invention may exist in the form of
bases or of addition salts with acids, of hydrates or
of solvates.
Since the diazabicyclooctane ring systems contain an
asymmetric carbon atom, the compounds of the invention
may exist in the form of pure enantiomers or of
mixtures of enantiomers. The enantiomers may be
separated by methods known to the skilled person, such
as separation by fractional crystallization of
diastereoisomeric salts of chiral acids, or separation
by chromatography on a chiral support.
In accordance with the invention the compounds of
general formula (I) may be prepared by a process which
is illustrated by scheme 1 below.
1,4-Diazabicyclo[3.2.1]octane of formula (II) is
reacted with a compound of general formula (III) in
which X, P, Q, R, W and Ri are as defined above in the
presence of a coupling agent such as, for example,
N/W-carbonyldiimidazole in a solvent such as
dimethylformamide. The carboxylic acid function present
on the compound of general formula (III) may also be
converted, in a prior step, into an acid chloride
function, in order to react with the 1,4-diazabicyclo
[3.2.1]octane in a solvent such as dichloroethane.


Alternatively the compounds of general formula (I) may
be prepared by a process which is illustrated by scheme
2 below.
1,4-Diazabicyclo[3.2.1]octane of formula (II) is
reacted with a compound of general formula (IV) in
which X, P, Q, R, W and Ri are as defined above and Z
represents a bromine or iodine atom in the presence of
carbon monoxide and a palladium catalyst such as, for
example, bis(triphenylphosphino)dichloropalladium and
of a base such as, for example, triethylamine in a
solvent such as, for example, dimethylformamide.


The compounds of general formula (III) are available
commercially or are accessible by methods described in
the literature, as for example in Can. J. Chem. 1988,
66, 420-8.
The compounds of general formula (IV) are available
commercially or are accessible by methods described in
the literature, as for example in J. Het. Chem. 1983,
475.
The preparation of 1,4-diazabicyclo[3.2.1]octane is
described in J. Med. Chem. 1977, 20, 1333.

The examples below illustrate in detail the preparation
of a number of compounds according to the invention.
The elemental microanalyses and the IR and NMR spectra
confirm the structures of the compounds obtained. The
numbers of the compounds indicated between parentheses
in the titles correspond to those of the table given
later on. In the names of the compounds, the hyphen "-"
forms part of the word, and the underscore mark "_"
serves merely to indicate the line break; it should be
deleted in the absence of a break, and should not be
replaced with either a normal hyphen or a space.

Example 1 (Compound No. 2).
3-(1,4-Diazabicyclo[3.2.1]oct-4-ylcarbonyl)-ltf-indazole
hydrochloride 1:1.
A 50 ml reactor is charged with 0.165 g (1.02 mmol) of
1H-indazole-3-carboxylic acid and 1 ml of thionyl
chloride and the mixture is heated at reflux for 1 h
min and concentrated under reduced pressure. Then
1.2 ml of pyridine and 0.30 g (2.67 mmol) of 1,4-
diazabicyclo[3.2.1]octane are added and the mixture is
heated at reflux for 1 h 30 min.
The solvent is evaporated off under reduced pressure
and the residue is taken up in 1 ml of chloroform and
purified by chromatography on a silica gel column,
eluting with a 70/30/3 mixture of ethyl acetate,
methanol and aqueous ammonia.
This gives 0.16 g of product, which is dissolved in
10 ml of acetone before addition of 0.47 ml of a 5N
solution of hydrochloric acid in isopropyl alcohol. The
crystals obtained (0.17 g) are collected by filtration
and dried under reduced pressure.
Melting point: 286-287°C.
Example 2 (Compound No. 3)
6-Chloro-3-(1,4-diazabicyclo[3.2.1]oct-4-ylcarbonyl)-
1H-indazole hydrobromide 1:1.
A 10 ml reactor is charged in succession with 0.25 g
(0.9 mmol) of 3-iodo-6-chloro-lff-indazole, 0.09 g
(0.13 mmol) of bis(triphenylphosphino)-dichloro-
palladium, 0.25 g (2.24 mmol) of 1,4-diazabicyclo
[3.2.1]octane and 0.31 ml (2.24 mmol) of triethylamine
in solution in 1 ml of dimethylformamide. The mixture
is subsequently purged with carbon monoxide and heated
at 70°C for 8 h. The reaction mixture is poured into
10 ml of saturated aqueous ammonium chloride solution
and the aqueous phase is extracted with chloroform. The
organic phases are dried, filtered and concentrated
inder reduced pressure. The residue is purified by

chromatography on a silica gel column, eluting with a
90/10/1 mixture of chloroform, methanol and aqueous
ammonia.
This gives 0.2 g of product, which is dissolved in 1 ml
of isopropyl alcohol before addition of 0.13 ml of a 5N
solution of hydrochloric acid in isopropyl alcohol.
The crystals obtained (0.076 g) are collected by
filtration and dried under reduced pressure.
Melting point: 285-286°C.


Example 3 (Compound No. 1).
3-(1,4-Diazabicyclo[3.2.1]oct-4-ylcarbonyl)-6-methyl-
1H-pyrazolo [3, 4-b] pyridine hydrobromide 2:1.
By analogy with Example 2, 0.7 g (3.3 mmol) of 3-bromo-
6-methyl-lH-pyrazolo [3,4-jb]pyridine is reacted with
1.1 g (9.9 mmol) of 1,4-diazabicyclo[3.2.1]octane in
the presence of 0.35 g (0.5 mmol) of bis
(triphenylphosphino)dichloropalladium and 2.3 ml of
triethylamine in 10 ml of dimethylformamide under the
conditions described for Example 1, giving 0.21 g of
product, which is dissolved in 20 ml of acetone before
addition of 0.27 ml of a 5.7 N solution of hydrobromic
acid in acetic acid. The dihydrobromide crystals are
collected by filtration and dried under vacuum,
Melting point: 290-291°C.
Example 4 (Compound No. 4).
3— (1, 4-Diazabicyclo [3.2.1] oct-4-ylcarbonyl) -5-fluoro-
lH-indazole hydrobromide 2:1.
By analogy with Example 2, 0.23 g (0.88 mmol) of 3-
iodo-5-fluoro-lfl-indazole is reacted with 0.25 g
(2.19 mmol) of 1, 4-diazabicyclo [3. 2 .1] octane in the
presence of 0.092 g (0.13 mmol) of bis(triphenylphos-
phino)dichloropalladium and 0.3 ml of triethylamine in
1 ml of dimethylformamide under the conditions
described for Example 2. This gives 0.136 g of product,


which is dissolved in 20 ml of acetone before addition
of 0.18 ml of a 5.7 N solution of hydrobromic acid in
acetic acid. The hydrobromide crystals are collected by
filtration and dried under vacuum.
Melting point: 283-284°C.
The table below illustrates the chemical structures and
the physical properties of a number of compounds of the
invention.
In the column "Q", "Me" denotes a methyl group and "Ms"
denotes a methanesulfonyl group.
In the column "St.", "(+/-)" denotes a racemate, and
"(+)" and "(-)" denote the dextrogyratory and
levogyratory enantiomers, respectively,
In the "Salt" column, "-" denotes a compound in base
form, "HBr" denotes a hydrobromide, "HCl" denotes a
hydrochloride and "ox." denotes an oxalate, or
ethanedioate.



The compounds of the invention were subjected to
pharmacological tests, which demonstrated their
advantage as active substances of medicaments.
For instance, they were studied with regard to their
affinity for nicotinic receptors containing the α 4β 2
subunit in accordance with the methods described by
Anderson and Arneric in Eur. J. Pharmacol. 1994, 253,
261 and by Hall et al. in Brain Res. 1993, 600, 127.
Male Sprague Dawley rats weighing 150 to 200 g are
decapitated and the whole brain is removed rapidly,
homogenized in 15 volumes of 0.32 M sucrose solution at
4 °C and then centrifuged at 1000 G for 10 min. The
pellet is discarded and the supernatant is centrifuged
at 20 000 G at 4°C for 20 min. The pellet is recovered
and homogenized using a Polytron™ mill in 15 volumes of
double-distilled water at 4°C, then centrifuged at
8000 G for 20 min. The pellet is discarded and the
supernatant and the layer of skin (buffy coat) are
centrifuged at 40 000 G for 20 min, and the pellet is
recovered, resuspended in 15 ml of double-distilled
water and centrifuged again at 40 000 G, before being

stored at -80°C.
On the day of the experiment the tissue is slowly-
thawed and is suspended in 3 volumes of buffer. 150 p. 1
of this membrane suspension are incubated at 4°C for
120 min in the presence of 100 \i 1 of 1 nM [3H] -cytisine
in a final volume of 500 |l 1 of buffer, in the presence
or absence of test compound. The reaction is stopped by
filtration on Whatman GF/B™ filters pretreated with
polyethyleneimine, the filters are rinsed with twice
5 ml of buffer at 4°C and the radioactivity retained on
the filter is measured by liquid scintigraphy. The non-
specific binding is determined in the presence of 10 n M
(-)-nicotine; the nonspecific binding represents 75% to
85% of the total binding recovered on the filter. For
each concentration of compound studied, the percentage
inhibition of the specific binding of [3H]-cytisine is
determined, after which the IC50 is calculated, which is
the concentration of compound that inhibits 50% of the
specific binding.
The IC50 values of the compounds of the invention having
the greatest affinity are situated between 1 and 10 µ M.
The compounds of the invention were also studied with
regard to their affinity for nicotinic receptors
containing the α7 subunit, in accordance with the
methods described by Mark and Collins in J. Pharmacol.
Exp. Ther. 1982, 22, 564 and by Marks et al. in Mol.
Pharmacol. 1986, 30, 427.
Male OFA rats weighing 150 to 200 g are decapitated,
the whole brain is removed rapidly and is homogenized
using a Polytron™ mill in 15 volumes of 0.32 M sucrose
solution at 4°C, then centrifuged at 1000 G for 10 min.
The pellet is discarded and the supernatant is
centrifuged at 8000 G at 4°C for 20 min. The pellet is
recovered and is homogenized using a Polytron™ mill in
15 volumes of double-distilled water at 4°C, then
centrifuged at 8000 G for 20 min. The pellet is
discarded and the supernatant and layer of skin (buffy
coat) are centrifuged at 40 000 G for 20 min. The


pellet is recovered and resuspended in 15 volumes of
double-distilled water at 4°C and is centrifuged again
at 40 000 G for 20 min, before being stored at -80°C.
On the day of the experiment, the tissue is slowly
thawed and is suspended in 5 volumes of buffer. 150 µ 1
of this membrane suspension are preincubated at 37°C
for 30 min, in the dark, in the presence or absence of
the test compound. The membranes are then incubated at
37°C for 60 min, in the dark, in the presence of 50 µ 1
of 1 nM [3H]-α -bungarotoxin in a final volume of
250 µ 1 of 20 mM HEPES, 0.05% polyethyleneimine buffer.
The reaction is stopped by filtration on Whatman GF/C™
filters pretreated for 3 h with 0.05% polyethylene-
imine. The filters are rinsed with two times 5 ml of
buffer at 4°C and the radioactivity retained on each
filter is measured by liquid scintigraphy. The
nonspecific binding in the presence of a -bungarotoxin
at 1 µ M final is measured; the nonspecific binding
represents approximately 60% of the total binding
recovered on the filter. For each concentration of
compound studied, the percentage inhibition of the
specific binding of [3H]-a -bungarotoxin is measured and
then the IC50 is calculated, the concentration of
compound that inhibits 50% of the specific binding.
The IC50 values of the compounds of the invention which
have the greatest affinity are situated between 0.010
and 0.10 |iM.
The IC50 values of some specific compounds are indicated
in the table below.

The above results show that the compounds of the
invention are selective ligands for the α 7 subunits of
the nicotinic receptor.

The results of the various tests suggest the use of the
compounds in the treatment or prevention of disorders
associated with dysfunction of the nicotinic receptors,
particularly within the central nervous system.
These disorders include cognitive impairment, more
specifically memory impairment, but also attention
impairment, which are associated with Alzheimer's
disease, pathological aging (Age Associated Memory
Impairment, AAMI), Parkinson's disease, trisomy 21
(Down's syndrome), Korsakoff's alcoholic syndrome, and
vascular dementia (multi-infarct dementia, MDI).
The compounds of the invention might also be useful in
the treatment of motor disorders observed in
Parkinson's disease or other neurological diseases,
such as Huntington's chorea, Tourette's syndrome,
tardive dyskinesia, and hyperkinesias.
The compounds of the invention may also constitute a
curative or symptomatic treatment for cerebrovascular
accidents and cerebral hypoxic episodes. They may be
used in cases of psychiatric pathologies:
schizophrenia, depression, anxiety, panic attacks, and
obsessive compulsive behaviors.
They may prevent the symptoms caused by withdrawal from
tobacco, from alcohol, and from various substances that
induce a dependency, such as cocaine, LSD, cannabis and
benzodiazepines.
furthermore, the compounds of the invention may also be
used for the treatment of lower limb ischemia,
obliterative arteritis of the lower limbs (PAD:
peripheral arterial disease) , cardiac ischemia (stable
angina), myocardial infarction, cardiac insufficiency,
5cutaneous cicatrization deficiency in diabetic
patients, and varicose ulcers of venous insufficiency.
For each of the aforementioned pathologies, treatment
may be performed with the nicotinic agent alone and/or

in combination with the reference medicaments indicated
in the pathology.
Consequently the present invention additionally
provides pharmaceutical compositions containing an
effective dose of at least one compound according to
the invention, in base form or in the form of a salt or
solvate which is pharmaceutically acceptable, and in a
mixture, where appropriate, with suitable excipients.

The said excipients are selected according to the
pharmaceutical form and mode of administration desired.
The pharmaceutical compositions according to the
invention may thus be intended for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical,
intratracheal, intranasal, transdermal, rectal or
intraocular administration.
The unit forms of administration may be, for example,
tablets, gel capsules, granules, powders, oral or
injectable solutions or suspensions, transdermal
patches, or suppositories. For topical administration
consideration may be given to ointments, lotions, and
eyedrops.
The said unit forms are dosed to allow a daily
administration of 0.01 to 20 mg of active principle per
kg of bodyweight, depending on the pharmaceutical form.

To prepare tablets, the active principle, in micronized
form or otherwise, is admixed with a pharmaceutical
vehicle, which may be composed of diluents, such as,
for example, lactose, microcrystalline cellulose,
starch, and formulation adjuvants such as binders
(polyvinylpyrrolidone, hydroxypropylmethylcellulose,
etc.), glidants, such as silica, lubricants, such as
magnesium stearate, stearic acid, glycerol tribehenate,
and sodium stearylfumarate. Wetting agents or

surfactants such as sodium lauryl sulfate may also be
added.
The production techniques may be direct tableting, dry
granulation, wet granulation or hot melting.
The tablets may be plain, coated, for example with
sucrose, or enveloped with various polymers or other
appropriate materials. They may be designed in order to
allow rapid, delayed or sustained release of the active
principle by virtue of polymeric matrices or of
specific polymers used in the covering.
To prepare gel capsules, the active principle is mixed
with dry pharmaceutical vehicles (simple mixing, dry or
wet granulation, or hot melting) , or with liquid or
semisolid pharmaceutical vehicles.
The gel capsules may be hard or soft, and may be film-
coated or not, so as to exhibit rapid, sustained or
delayed activity (for an enteric form, for example).

A composition in the form of a syrup or elixir or for
administration in the form of drops may contain the
active principle together with a sweetener, preferably
a calorie-free sweetener, methylparaben or
propylparaben as an antiseptic, a flavor enhancer, and
a dye.
Water-dispersible granules and powders may contain the
active principle mixed with dispersants or wetting
agents, or with dispersants such as
polyvinylpyrrolidone, and also with sweeteners and
taste corrigents.
For rectal administration, suppositories are employed
which are prepared with binders that melt at the rectal
temperature, such as cocoabutter or polyethylene
glycols, for example.

For parenteral administration, use is made of aqueous

suspensions, isotonic saline solutions or sterile
injectable solutions containing pharmacologically
compatible dispersants and/or wetting agents, such as
propylene glycol or butylene glycol, for example.

The active principle may also be formulated in the form
of microcapsules, where appropriate with one or more
vehicles or additives, or else with a polymeric matrix
or with a cyclodextrin (transdermal patches, sustained-
release forms).
The topical compositions according to the invention
comprise a medium which is compatible with the skin.
They may in particular be in the form of aqueous,
alcoholic or aqueous-alcoholic solutions, gels, water-
in-oil or oil-in-water emulsions having the appearance
of a cream or gel, microemulsions or aerosols, or else
in the form of vesicular dispersions containing ionic
and/or nonionic lipids. These pharmaceutical forms are
prepared according to the usual methods in the fields
under consideration.
Finally, the pharmaceutical compositions according to
the invention may contain, in addition to a compound of
general formula (I), other active principles which may
be useful in the treatment of the disorders and
diseases indicated above.

WE CLAIM :
1. A compound, in the form of a pure enantiomer or
enantiomer mixture, conforming to the general
formula (I)

in which
X represents a nitrogen atom or a group of general
formula C-R2,
P, Q, R and W represent each independently of one
another a nitrogen atom or a group of general
formula C-R3,
R1 represents a hydrogen atom or a (C1-C6) alkyl
group,
R2 represents a (C1-C6) alkyl group,
R3 represents a hydrogen or halogen atom or a
(C1-C6) alkyl, (C1-C6)alkoxy, nitro, amino,
trifluoromethyl or cyano group . or a group of
general formula -NR4R5, -NR4C(=O)R5, -NR4C (=O)NR5R6,
-NR4C(=O)OR5, NR4S(=O)2NR5R6, -OR5, -OC(=O)R5, -OC
(=O)OR5, -OC(=O)ONR4R5, -OC(=O)SR5, -C(=O)OR5, C(=O)
R5, -C(=O)NR4R5, SR5, -S(=O)R5, -S(=O)2R5 or -S (=O)
2NR4R6, or a phenyl group optionally substituted by
one or more groups selected from halogen atoms and
(C1-C6) alkyl, (C1-Cs)alkoxy, nitro, amino,
trifluoromethyl or cyano groups or groups of
general formula -NR4R5, -NR4C(=O)R5, -NR4C (=O) NR5R6,
-NR4C(=O)OR5, NR4S(=O)2NR5R6, -OR5, -OC(=O)R5, -OC
(=O)OR5, -OC(=O)ONR4R5, -OC(=O)SR5, -C(=O)OR5, -C
(=O)NR4R5, SR5, -S(=O)R5, -S(=O)2R5 or -S (=O) 2NR4R6,

or R3 represents a group selected from imidazole,
pyridine, pyridazine, pyrimidine, pyrazole,
pyrazine, triazole, quinoline, isoquinoline,
tetrazole, furan, thiophene, thiazole,
isothiazole, oxazole, isoxazole, pyrrole,
tetrahydroquinoline, tetrahydroisoquinoline,
indole, benzimidazole, benzofuran, dihydrobenzo-
furan, cinnoline, indazole, phthalazine, triazine,
isoindole, oxadiazole, thiadiazole, furazan,
benzofurazan, benzothiophene, dihydrobenzo-
thiophene, benzotriazole, benzothiazole,
benzisothiazole, benzoxazole, benzisoxazole,
quinazoline, quinoxaline, naphthyridine,
dihydroquinoline, dihydroisoquinoline, furo-
pyridine, dihydrofuropyridine, pyrrolopyridine,
thienopyridine, dihydrothienopyridine, imidazo-
pyridine, pyrazolopyridine, oxazolopyridine,
isoxazolopyridine, isoxazolopyridine, thiazolo-
pyridine, isothiazolopyridine, pyrrolopyrimidine,
furopyrimidine, dihydrofuropyrimidine, thieno-
pyrimidine, dihydrothienopyrimidine, imidazo-
pyrimidine, pyrazolopyrimidine, oxazolopyrimidine,
isoxazolopyrimidine, thiazolopyrimidine,
isothiazolopyrimidine, furopyrazine, dihydrofuro-
pyrazine, pyrrolopyrazine, thienopyrazine,
dihydrothienopyrazine, imidazopyrazine, pyrazolo-
pyrazine, oxazolopyrazine, isoxazolopyrazine,
thiazolopyrazine, isothiazolopyrazine, furo-
pyridazine, dihydrofuropyridazine, pyrrolo-
pyridazine, thienopyridazine, dihydrothieno-
pyridazine, imidazopyridazine, pyrazolopyridazine,
oxazolopyridazine, isoxazolopyridazine, thiazolo-
pyridazine or isothiazolopyridazine ring systems,
R4, R5 and R6 represent each independently of one
another a halogen atom or a linear or branched
(C1-C6) alkyl, linear or branched (C2-C6) alkenyl or
linear or branched (C2-C6) alkynyl group, or a
(C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C3) alkyl,
(C4-C8) cycloalkenyl or phenyl group,

it being possible for the groups of general
formulae NR4R5 and NR5R6 to form, with the nitrogen
atom which carries them, a group selected from
aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
azepinyl, piperazinyl, morpholinyl, thiomorpho
linyl, pyrrolinyl, indolinyl, pyrazolinyl,
pyrazolidinyl, imidazolinyl, 3H-indolyl, quinu-
clidinyl and quinolizinyl groups,
in the form of a base, a solvate or an addition
salt with an acid.
2. A medicament comprising a compound as claimed in
claim 1.
3. A pharmaceutical composition comprising a compound
as claimed in claim 1 in combination with an
excipient.
4. A compound as claimed in claim 1 in the
preparation of a medicament intended for the
treatment of disorders caused by cognitive and
attention impairment or motor disorders,
neurological or psychiatric disorders, or intended
for preventing the symptoms caused by withdrawal
from substances which induce dependency, or
intended for the treatment of cardiac, vascular,
arterial, and venous pathologies.



ABSTRACT


DERIVATIVES OF, 1,4-DIAZABICYCLO[3.2.1.] OCTANECARBOXAMIDE,
PREPARATION METHOD THEREOF AND USE OF SAME IN THERAPEUTICS
The invention relates to compound, having general
formula (I) and pharmaceutical composition comprising
the same.

Documents:


Patent Number 259493
Indian Patent Application Number 1850/KOLNP/2006
PG Journal Number 12/2014
Publication Date 21-Mar-2014
Grant Date 14-Mar-2014
Date of Filing 03-Jul-2006
Name of Patentee SANOFI AVENTIS
Applicant Address 174, AVENUE DE FRANCE, F-75013, PARIS
Inventors:
# Inventor's Name Inventor's Address
1 LOCHEAD, ALISTAIR 95, RUE DE PARIS, F-94220 CHARENTON LE PONT,
2 GALLI, FREDERICK 6, AVENUE, DE RUEIL, F-92420 VAUCRESSON
3 LECLERC, ODILE 11, RUE WINSTON CHURCHILL, F-91300 MASSY
PCT International Classification Number C07D 487/08
PCT International Application Number PCT/FR2005/000027
PCT International Filing date 2005-01-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0400390 2004-01-16 France