U.S. patent application number 09/772569 was filed with the patent office on 2001-10-25 for piperidine-4 sulphonamide compounds.
Invention is credited to Bourguignon, Marie-Pierre, Dessinges, Aimee, Peglion, Jean-Louis, Poitevin, Christophe, Thollon, Catherine, Vilaine, Jean-Paul, Villeneuve, Nicole.
Application Number | 20010034352 09/772569 |
Document ID | / |
Family ID | 8846469 |
Filed Date | 2001-10-25 |
United States Patent
Application |
20010034352 |
Kind Code |
A1 |
Peglion, Jean-Louis ; et
al. |
October 25, 2001 |
Piperidine-4 sulphonamide compounds
Abstract
Compound of formula (I): 1 wherein: R.sub.1 represents hydrogen
or alkyl, R.sub.2a and R.sub.2b represent a group selected from
hydrogen, halogen, alkyl, hydroxy, alkoxy, trihaloalkyl, cyano,
nitro, amino, alkylamino and dialkylamino, R.sub.3 represents
hydrogen or hydroxy, X represents oxygen or methylene, V represents
an alkylene chain that is optionally unsaturated and optionally
substituted, U represents a bond or an alkylene chain, W represents
a group selected from aryl and heteroaryl, each of those groups
being optionally substituted by one or more identical or different
groups, its isomers, its hydrates, its solvates and addition salts
thereof with a pharmaceutically acceptable acid. Medicinal products
containing the same which are useful in the treatment of diseases
or pathological conditions in which endothelial dysfunction is
known.
Inventors: |
Peglion, Jean-Louis; (Le
Vesinet, FR) ; Dessinges, Aimee; (Rueil-Malmaison,
FR) ; Poitevin, Christophe; (Paris, FR) ;
Vilaine, Jean-Paul; (Chatenay-Malabry, FR) ;
Villeneuve, Nicole; (Rueil Malmaison, FR) ; Thollon,
Catherine; (Paris, FR) ; Bourguignon,
Marie-Pierre; (Chatou, FR) |
Correspondence
Address: |
The Firm of Hueschen and Sage
715 The "H" Building
310 East Michigan Avenue
Kalamazoo
MI
49007
US
|
Family ID: |
8846469 |
Appl. No.: |
09/772569 |
Filed: |
January 30, 2001 |
Current U.S.
Class: |
514/309 ;
514/317; 514/320; 546/148; 546/196 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
9/12 20180101; A61P 43/00 20180101; C07D 405/06 20130101; C07D
417/14 20130101; C07D 405/14 20130101; C07D 495/04 20130101; C07D
471/04 20130101; A61P 9/10 20180101; A61P 9/08 20180101; A61P 9/04
20180101; C07D 413/14 20130101; C07D 491/04 20130101; C07D 401/12
20130101; A61P 7/02 20180101 |
Class at
Publication: |
514/309 ;
514/317; 514/320; 546/148; 546/196 |
International
Class: |
A61K 031/47; A61K
031/445 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 31, 2000 |
FR |
00.01171 |
Claims
We claim:
1. A compound selected from those of formula (I): 33wherein:
R.sub.1 represents hydrogen or linear or branched
(C.sub.1-C.sub.6)alkyl, R.sub.2a and R.sub.2b, which may be
identical or different, each independently of the other represents
a group selected from hydrogen, halogen, linear or branched
(C.sub.1-C.sub.6)alkyl, hydroxy, linear or branched
(C.sub.1-C.sub.6)alkoxy, linear or branched
(C.sub.1-C.sub.6)trihaloalkyl, cyano, nitro, amino, linear or
branched (C.sub.1-C.sub.6)alkylamino, and
di-(C.sub.1-C.sub.6)alkyl-amino in which each alkyl moiety is
linear or branched, R.sub.3 represents hydrogen or hydroxy, X
represents oxygen or methylene, V represents a linear or branched
(C.sub.1-C.sub.6)alkylene chain optionally containing one or more
unsaturations and being optionally substituted by one or more
identical or different groups selected from halogen, hydroxy and
linear or branched (C.sub.1-C.sub.6)alkoxy, U represents a bond or
a linear or branched (C.sub.1-C.sub.6)alkylene chain, W represents
a group selected from aryl and heteroaryl, each of those groups
being optionally substituted by one or more identical or different
groups selected from halogen, linear or branched
(C.sub.1-C.sub.6)alkyl, hydroxy, linear or branched
(C.sub.1-C.sub.6)alkoxy, linear or branched
(C.sub.1-C.sub.6)trihaloalkyl, oxo, cyano, nitro, amino, linear or
branched (C.sub.1-C.sub.6)-alkylamino,
di-(C.sub.1-C.sub.6)alkylamino in which each alkyl moiety is linear
or branched, pyridyl, linear or branched
(C.sub.1-C.sub.6)alkylcarbonyl, aminocarbonyl (the amino moiety
being optionally substituted by one or two identical or different
linear or branched (C.sub.1-C.sub.6)alkyl), linear or branched
(C.sub.1-C.sub.6)alkoxycarbonyl, linear or branched
(C.sub.1-C.sub.6)trihaloalkylcarbonyl, linear or branched
(C.sub.1-C.sub.6)alkylsulphonyl, and linear or branched
(C.sub.1-C.sub.6)-trihaloalkylsulphonyl, its isomers, its hydrates,
its solvates and addition salts thereof with a pharmaceutically
acceptable acid or base, it being understood that: "aryl group" is
understood to mean a group selected from phenyl, biphenyl,
naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl and indenyl,
"heteroaryl group" is understood to mean a monocyclic aromatic or
bicyclic system having from 5 to 12 ring members and containing
from 1 to 3 identical or different hetero atoms selected from
oxygen, nitrogen and sulphur, and in the case of a bicyclic system
one of the rings has an aromatic character, it being possible for
the other ring to be aromatic or partially hydrogenated.
2. Compound of claim 1, characterised in that X represents oxygen,
its isomers, its hydrates, its solvates and addition salts thereof
with a pharmaceutically acceptable acid.
3. Compound of claim 1, characterised in that R.sub.1 represents
hydrogen or methyl, its isomers, its hydrates, its solvates and
addition salts thereof with a pharmaceutically acceptable acid.
4. Compound of claim 1, characterised in that it represents a
compound of formula (I/A): 34wherein W, U, V, R.sub.2a and R.sub.2b
are as defined for formula (I), its isomers, its hydrates, its
solvates and addition salts thereof with a pharmaceutically
acceptable acid.
5. Compound of claim 1, characterised in that W represents
isoquinolin-5-yl, its isomers, its hydrates, its solvates and
addition salts thereof with a pharmaceutically acceptable acid.
6. Compound of claim 1, characterised in that W represents
1,2,3,4-tetrahydro-isoquinolin-5-yl optionally substituted in the
2-position by a group of formula --C(O)--A wherein A represents a
group selected from linear or branched (C.sub.1-C.sub.6)alkyl,
amino (itself optionally substituted by one or two identical or
different linear or branched (C.sub.1-C.sub.6)alkyl), linear or
branched (C.sub.1-C.sub.6)alkoxy, trifluoromethyl, linear or
branched (C.sub.1-C.sub.6)alkylsulphonyl, and
trifluoromethylsulphonyl, its isomers, its hydrates, its solvates
and addition salts thereof with a pharmaceutically acceptable
acid.
7. Compound of claim 4, characterised in that it represents a
compound of formula (I/A) as defined hereinbefore wherein U, V,
R.sub.2a and R.sub.2b are as defined for formula (I) and W
represents isoquinolin-5-yl, its isomers, its hydrates, its
solvates and addition salts thereof with a pharmaceutically
acceptable acid.
8. Compound of claim 4, characterised in that it represents a
compound of formula (I/A) as defined hereinbefore wherein U, V,
R.sub.2a and R.sub.2b are as defined for formula (I) and W
represents 1,2,3,4-tetrahydroisoquin- olin-5-yl optionally
substituted in the 2-position by a group of formula --C(O)A wherein
A is as defined hereinbefore, its isomers, its hydrates, its
solvates and addition salts thereof with a pharmaceutically
acceptable acid.
9. Compound of claim 1 which is selected from:
N-{1-[2-(benzofuran-3-yl)et-
hyl]-4-piperidyl}-(isoquinolin-5-yl)sulphonamide, ethyl
5-{[({(1-[2-(benzofuran-3-yl)ethyl]-4-piperidy}methyl)-(methyl)amino]sulp-
honyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate,
N-({2-[2-benzofuran-3-yl-
)ethyl]-4-hydroxy-4-piperidyl}ethyl)-5-isoquinolinesulphonamide,
N-({1-[2-(benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N-methyl-2-
,1,3-benzoxadiazole-4-sulphonamide, and isopropyl
5-{[({1-[2-(benzofuran-3-
-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]sulphonyl}-3,4-dihydro-2(1H)--
isoquinolinecarboxylate.
10. Method for treating a living body afflicted with a disease or
pathological condition in which endothelial dysfunction is known,
comprising the step of administering to the living body an amount
of a compound of claim 1 which is effective for alleviation of said
disease or condition.
11. Pharmaceutical composition useful for treatment of a disease or
pathological condition in which endothelial dysfunction is known,
comprising as active principle an effective amount of a compound as
claimed in claim 1, together with one or more inert, non-toxic
pharmaceutically acceptable excipients or vehicles.
12. Method for treating a living body afflicted with myocardial or
peripheral ischaemia, cardiac insufficiency or pulmonary arterial
hypertension, comprising the step of administering to the living
body an amount of a compound of claim 1 which is effective for
alleviation of said conditions.
13. Pharmaceutical composition useful for treatment of myocardial
or peripheral ischaemia, cardiac insufficiency or pulmonary
arterial hypertension, comprising as active principle an effective
amount of a compound as claimed in claim 1, together with one or
more inert, non-toxic pharmaceutically acceptable excipients or
vehicles.
14. Method for preventing a living body from the development,
extension and complications of atherosclerotic lesions, or for
preventing vascular complications after vascular bypass, vascular
dilatation, vascular repermeabilisation and heart transplantation,
comprising the step of administering to the living body an amount
of a compound of claim 1 which is effective for said
preventions.
15. Pharmaceutical composition useful for prevention of the
development, extension and complications of atherosclerotic
lesions, or for prevention of vascular complications after vascular
bypass, vascular dilatation, vascular repermeabilisation and heart
transplantation, comprising as active principle an effective amount
of a compound as claimed in claim 1, together with one or more
inert, non-toxic pharmaceutically acceptable excipients or
vehicles.
Description
BACKGROUND OF THE INVENTION
[0001] The compounds of the present invention are useful in the
treatment of diseases or pathological conditions in which
endothelial dysfunction is known to be a pathogenic and/or
aggravating mechanism. Such pathologies are: atherosclerosis, the
existence of vascular risk factors (dyslipidaemia, diabetes,
systemic arterial hypertension), the various clinical forms of
myocardial or peripheral ischaemia, cardiac insufficiency and the
various forms of pulmonary arterial hypertension. Such compounds
are also useful in the treatment of patients undergoing heart
transplantation or vascular repermeabilisation such as a bypass,
thrombolysis or arterial dilatation with or without a stent.
[0002] A reduction in the vascular availability of nitrogen
monoxide (NO) constitutes the major mechanism of endothelial
dysfunction observed in the diseases and pathological conditions
mentioned above and explains its pathogenic role (Cardiovasc. Res.,
1999, 43, 572; Coronary. Art. Dis. 1999, 10, 277; Coronary. Art.
Dis., 1999, 10, 301; Coronary. Art. Dis., 1999, 10, 287; Coronary.
Art. Dis., 1999, 10, 295).
[0003] In those pathological conditions, the endothelial
dysfunction may in fact result from two main mechanisms: 1)
inadequate production of NO associated with inhibition of
endothelial NO synthase by endogenous inhibitors such as ADMA
(asymmetric dimethylarginine), the plasma concentration of which
increases in patients exhibiting cardiovascular risk factors
(Cardiovasc. Res., 1999, 43, 542; Hypertension, 1997, 29, 242;
Circulation, 1997, 95, 2068), 2) inactivation of NO by the
superoxide anion (O.sub.2.sup.-), the production of which is
increased in pathological conditions (Cardiovasc. Res., 1999, 43,
562; Eur. J Biochem. 1997, 245, 541; J. Clin. Invest., 1993, 91
2546).
[0004] Under normal conditions, NO produces major effects such as:
1) regulation of arterial vasomotricity by means of its vasodilator
effect (N Engl. J Med., 1993, 329, 2002 ; Nature, 1980, 288, 373),
2) limitation of platelet adhesion and aggregation (Trends
Pharmacol. Sci., 1991, 12, 87), 3) control of the adhesion of
leukocytes and monocytes to endothelial cells (Proc. Natl Acad.
Sci. USA, 1991, 88, 4651), 4) inhibition of the proliferation of
vascular smooth muscle cells (Cardiovasc. Res., 1999, 43, 580,
Circulation, 1993, 87 V51), which explains why the deficiency of NO
in the arterial wall is favourable to pathological phenomena such
as vasoconstriction, thrombosis, lipid accumulation and
proliferation of vascular smooth muscle cells.
[0005] In vitro experiments have enabled it to be shown that the
compounds of the present invention enable limitation of the
endothelial dysfunction and of the reduced vascular availability of
NO induced by tests involving the two physiopathological mechanisms
already mentioned: inhibition of endothelial NO synthase and
oxidative stress due to production of O.sub.2.sup.-.
[0006] Thus, in addition to the fact that they are new, by virtue
of their specific pharmacological activity, which is capable of
limiting the development of endothelial dysfunction, the compounds
of the present invention are useful in preventing the development,
extension and complications of atherosclerotic lesions, especially
in patients exhibiting a vascular risk factor (dyslipidaemia,
diabetes, arterial hypertension), and in treating the various
clinical forms of myocardial or peripheral ischaemia, cardiac
insufficiency and the various forms of pulmonary arterial
hypertension. The compounds are also used for preventing vascular
complications (spasm, thrombosis, restenosis, accelerated
atherosclerosis) in patients undergoing a bypass, vascular
dilatation with or without a stent or other forms of vascular
repermeabilisation and also heart transplantation.
DESCRIPTION OF THE PRIOR ART
[0007] Compounds of similar structure have been described in the
literature, that being the case, more especially, for Patent
Application WO 94/13659, which claims especially
piperidinebenzofurane compounds. Such compounds are useful in the
treatment and/or prophylaxis of arrhythmia. They are distinguished
clearly from the compounds of the present invention by their
chemical structure and especially by the absence of the
sulphonamide function, and by their pharmacological properties.
[0008] Patent Specification EP 0 526 342 describes new
(isoquinolin-5-yl)sulphonamides and claims those compounds for
their usefulness in the treatment and prevention of disorders
resulting from tissue pain phenomena.
DETAILED DESCRIPTION OF THE INVENTION
[0009] More especially, the present invention relates to compounds
of formula (I): 2
[0010] wherein:
[0011] R.sub.1 represents a hydrogen atom or a linear or branched
(C.sub.1-C.sub.6)alkyl group,
[0012] R.sub.2a and R.sub.2b, which may be identical or different,
each independently of the other represents a group selected from a
hydrogen atom, a halogen atom, a linear or branched
(C.sub.1-C.sub.6)alkyl group, a hydroxy group, a linear or branched
(C.sub.1-C.sub.6)alkoxy group, a linear or branched
(C.sub.1-C.sub.6)trihaloalkyl group, a cyano group, a nitro group,
an amino group, a linear or branched (C.sub.1-C.sub.6)alkyla- mino
group, and a di-(C.sub.1-C.sub.6)-alkylamino group in which each
alkyl moiety is linear or branched,
[0013] R.sub.3 represents a hydrogen atom or a hydroxy group,
[0014] X represents an oxygen atom or a methylene group,
[0015] V represents a linear or branched (C.sub.1-C.sub.6)alkylene
chain optionally containing one or more unsaturations and being
optionally substituted by one or more identical or different groups
selected from halogen atoms, hydroxy groups and linear or branched
(C.sub.1-C.sub.6)alkoxy groups,
[0016] U represents a bond or a linear or branched
(C.sub.1-C.sub.6)alkyle- ne chain,
[0017] W represents a group selected from aryl and heteroaryl, each
of those groups being optionally substituted by one or more
identical or different groups selected from halogen atoms, linear
or branched (C.sub.1-C.sub.6)alkyl groups, hydroxy groups, linear
or branched (C.sub.1-C.sub.6)alkoxy groups, linear or branched
(C.sub.1-C.sub.6)trihaloalkyl groups, oxo groups, cyano groups,
nitro groups, amino groups, linear or branched
(C.sub.1-C.sub.6)-alkylamino groups, di-(C.sub.1-C.sub.6)alkylamino
groups in which each alkyl moiety is linear or branched, pyridyl
groups, linear or branched (C.sub.1-C.sub.6)alkylcarbonyl groups,
aminocarbonyl groups (the amino moiety being optionally substituted
by one or two identical or different linear or branched
(C.sub.1-C.sub.6)alkyl groups), linear or branched
(C.sub.1-C.sub.6)alkoxycarbonyl groups, linear or branched
(C.sub.1-C.sub.6)trihaloalkylcarbonyl groups, linear or branched
(C.sub.1-C.sub.6)alkylsulphonyl groups, and linear or branched
(C.sub.1-C.sub.6)-trihaloalkylsulphonyl groups,
[0018] their isomers, their hydrates, their solvates and addition
salts thereof with a pharmaceutically acceptable acid or base,
[0019] it being understood that:
[0020] "aryl group" is understood to mean a group selected from
phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl,
indanyl and indenyl,
[0021] "heteroaryl group" is understood to mean a monocyclic
aromatic or bicyclic system having from 5 to 12 ring members and
containing from 1 to 3 identical or different hetero atoms selected
from oxygen, nitrogen and sulphur, and in the case of a bicyclic
system one of the rings has an aromatic character, it being
possible for the other ring to be aromatic or partially
hydrogenated.
[0022] Among the heteroaryl groups there may be mentioned by way of
non-limiting example the groups pyridyl, pyrazolyl, isoxazolyl,
dihydroisoxazolyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl,
benzofurazanyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,
2,1,3-benzoxodiazolyl, 2,1,3-benzothiadiazolyl,
thieno[2,3-c]pyridyl, furo[2,3-c]pyridyl, etc.
[0023] Among the pharmaceutically acceptable bases there may be
mentioned by way of non-limiting example sodium hydroxide,
potassium hydroxide, triethylamine, tert-butylamine, etc.
[0024] Among the pharmaceutically acceptable acids there may be
mentioned by way of non-limiting example hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid,
trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid,
succinic acid, glutamic acid, fumaric acid, tartaric acid,
dibenzoyltartaric acid, maleic acid, citric acid, ascorbic acid,
oxalic acid, methanesulphonic acid, camphoric acid, etc.
[0025] The preferred substituent X according to the invention is
the oxygen atom.
[0026] The preferred substituents R.sub.1 according to the
invention are the hydrogen atom and the methyl group.
[0027] According to an advantageous embodiment, the preferred
compounds of the invention are compounds of formula (I/A): 3
[0028] wherein W, U, V, R.sub.2a and R.sub.2b are as defined for
formula (I).
[0029] Advantageously, the preferred substituent W according to the
invention is the isoquinolin-5-yl group. According to another
embodiment of the invention, the preferred substituent W is the
group 1,2,3,4-tetrahydro-isoquinolin-5-yl optionally substituted in
the 2-position by a group of formula --C(O)--A wherein A represents
a group selected from linear or branched (C.sub.1-C.sub.6)alkyl,
amino (itself optionally substituted by one or two identical or
different linear or branched (C.sub.1-C.sub.6)alkyl groups), linear
or branched (C.sub.1-C.sub.6)alkoxy, trifluoromethyl, linear or
branched (C.sub.1-C.sub.6)alkylsulphonyl, and
trifluoromethylsulphonyl.
[0030] Especially advantageously, the preferred compounds of the
invention are the compounds of formula (I/A) as defined
hereinbefore wherein U, V, R.sub.2a and R.sub.2b are as defined for
formula (I) and W represents an isoquinolin-5-yl group.
[0031] According to another especially advantageous embodiment, the
preferred compounds of the invention are the compounds of formula
(I/A) as defined hereinbefore wherein U, V, R.sub.2a and R.sub.2b
are as defined for formula (I) and W represents a
1,2,3,4-tetrahydroisoquinolin-- 5-yl group optionally substituted
in the 2-position by a group of formula --C(O)A wherein A is as
defined hereinbefore.
[0032] The preferred compounds of the invention are:
[0033]
N-{1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-(isoquinolin-5-yl)sulp-
honamide,
[0034] ethyl
5-{[({(1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(meth-
yl)amino]-sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate,
[0035]
N-({2-[2-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}ethyl)-5-isoq-
uinolinesulphonamide,
[0036]
N-({1-[2-(benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N-me-
thyl-2,1,3-benzoxadiazole-4-sulphonamide, and
[0037] isopropyl
5-{[({1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(m-
ethyl)amino]-sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate.
[0038] The isomers, hydrates, solvates and addition salts thereof
with a pharmaceutically acceptable acid or base of the preferred
compounds form an integral part of the invention.
[0039] The invention relates also to a process for the preparation
of compounds of formula (I), characterised in that there is used as
starting material a compound of formula (II): 4
[0040] wherein X, R.sub.2a and R.sub.2b are as defined for formula
(I), V.sub.1 represents a bond or a linear or branched
(C.sub.1-C.sub.5)alkyle- ne chain optionally containing one or more
unsaturations, R.sub.5 represents a hydrogen atom, a chlorine atom,
a hydroxy group or a linear or branched (C.sub.1-C.sub.6)alkoxy
group,
[0041] which compounds of formula (II) are reacted:
[0042] either with a compound of formula (III/A): 5
[0043] to yield compounds of formula (IV): 6
[0044] wherein R.sub.2a, R.sub.2b, X and V.sub.1 are as defined
hereinbefore, the ketal function of which compounds of formula (IV)
is deprotected in accordance with conventional techniques of
organic synthesis, and which are then reacted under conditions of
reductive amination with a compound of formula (V):
R'.sub.1--NH.sub.2 (V)
[0045] wherein R'.sub.1 represents a linear or branched
(C.sub.1-C.sub.6)alkyl group, to yield compounds of formula (VI/A):
7
[0046] wherein R'.sub.1, R.sub.2a, R.sub.2b, X and V.sub.1 are as
defined hereinbefore,
[0047] or with a compound of formula (III/B): 8
[0048] wherein Boc represents a tert-butoxycarbonyl group, to yield
compounds of formula (VII): 9
[0049] wherein Boc, R.sub.2a, R.sub.2b, X and V.sub.1 are as
defined hereinbefore, the terminal amine function of which
compounds of formula (VII) is deprotected to yield compounds of
formula (VI/B): 10
[0050] wherein R.sub.2a, R.sub.2b, V.sub.1 and X are as defined
hereinbefore, the totality of the compounds of formulae (VI/A) and
(VI/B) constituting the compounds of formula (VI): 11
[0051] wherein R.sub.1 is as defined for formula (I) and R.sub.2a,
R.sub.2b, X and V.sub.1 are as defined hereinbefore, which
compounds of formula (VI) are treated with one of the reducing
agents currently used in organic synthesis to reduce amide
functions, to yield compounds of formula (VIII): 12
[0052] wherein R.sub.1, V.sub.1, X, R.sub.2a and R.sub.2b are as
defined hereinbefore, which compounds of formula (VIII) are treated
with a compound of formula (IX):
W--SO.sub.2Cl (IX)
[0053] wherein W is as defined for formula (I), to yield compounds
of formula (I/a), a particular case of the compounds of formula
(I): 13
[0054] wherein W, R.sub.1, V.sub.1, X, R.sub.2a and R.sub.2b are as
defined hereinbefore,
[0055] or with a compound of formula (III/C): 14
[0056] wherein U.sub.1 represents a bond or a linear or branched
(C.sub.1-C.sub.5)alkylene chain, to yield compounds of formula (X):
15
[0057] wherein U.sub.1, V.sub.1, X, R.sub.2a and R.sub.2b are as
defined hereinbefore, which compounds of formula (X) are treated
with ammonium hydroxide or with a compound of formula (V) as
defined hereinbefore in the presence of a coupling agent, such as
dicyclohexylcarbodiimide, carbonyldiimidazole or
1,1,1,3,3,3-hexamethyldisylazane, to yield compounds of formula
(XI): 16
[0058] wherein R.sub.1 is as defined for formula (I), and U.sub.1,
V.sub.1, X, R.sub.2a and R.sub.2b are as defined hereinbefore,
[0059] which compounds of formula (XI) are reduced in accordance
with conventional conditions of organic synthesis, to yield
compounds of formula (XII): 17
[0060] wherein U.sub.2 represents a linear or branched
(C.sub.1-C.sub.6)alkylene chain, and R.sub.1, V.sub.1, X, R.sub.2a
and R.sub.2b are as defined hereinbefore,
[0061] which compounds of formula (XII) are reacted with a compound
of formula (IX), as defined hereinbefore, to yield compounds of
formula (I/b), a particular case of the compounds of formula (I):
18
[0062] wherein W, R.sub.1, U.sub.2, V.sub.1, X, R.sub.2a and
R.sub.2b are as defined hereinbefore,
[0063] or the terminal carbonyl group of which compounds of formula
(II), which group is substituted by a group R'.sub.5 having the
meanings of R.sub.5 as defined hereinbefore with the exception of
the meaning "chlorine atom", is reduced, the resulting hydroxy
group of which is then replaced by a halogen atom, such as Cl, Br
or I, using customary techniques of organic chemistry, to yield
compounds of formula (II/B): 19
[0064] wherein X and V are as defined for formula (I) and Hal
represents a halogen atom, which compound of formula (II/B) is
added to a compound of formula (III/D): 20
[0065] wherein U.sub.2 is as defined hereinbefore, to yield
compounds of formula (XIII): 21
[0066] wherein U.sub.2, V, X, R.sub.2a and R.sub.2b are as defined
hereinbefore, which compounds of formula (XIII) are treated with a
reducing agent or with a strong alkaline base, to yield compounds
of formula (XIV): 22
[0067] wherein R.sub.1a represents a hydrogen atom or a methyl
group, and U.sub.2, V, X, R.sub.2a and R.sub.2b are as defined
hereinbefore,
[0068] which compounds of formula (XIV) are treated with a compound
of formula (IX), to yield compounds of formula (I/c), a particular
case of the compounds of formula (I): 23
[0069] wherein W, R.sub.1a, U.sub.2, V, X, R.sub.2a and R.sub.2b
are as defined hereinbefore,
[0070] or which compound of formula (II), in the particular case
when R.sub.5 represents a hydrogen atom and V.sub.1 has the meaning
V'.sub.1 representing a linear or branched
(C.sub.1-C.sub.4)alkylene chain, is treated with
trimethylsulphoxonium iodide in the presence of sodium hydride in
dimethyl sulphoxide, to yield compounds of formula (II/C): 24
[0071] wherein R.sub.2a, R.sub.2b, X and V'.sub.1 are as defined
hereinbefore, which compounds of formula (II/C) are reacted with
any one of the compounds of formulae (III/A), (III/B) and (III/C),
the resulting intermediates then being deprotected and
functionalised in accordance with the respective methods described
hereinbefore, to yield compounds of formula (XV): 25
[0072] wherein R.sub.1, U, X, R.sub.2a and R.sub.2b are as defined
hereinbefore and V'.sub.1 is as defined hereinbefore,
[0073] or which compound of formula (II), in the particular case
when it represents a compound of formula (II/D): 26
[0074] wherein R.sub.2a, R.sub.2b and X are as defined for formula
(I), is reacted with any one of the compounds of formulae (III/A),
(III/B) and (III/C), the resulting intermediates then being
deprotected and functionalised in accordance with the respective
methods hereinbefore, to yield compounds of formula (XVI): 27
[0075] wherein R.sub.1, U, X, R.sub.2a and R.sub.2b are as defined
hereinbefore, which compounds of formula (XVI) are reduced in
conventional manner to yield compounds of formula (XVII): 28
[0076] the totality of the compounds of formulae (XV) and (XVII)
constituting the compounds of formula (XVIII): 29
[0077] wherein R.sub.1, U, X, R.sub.2a and R.sub.2b are as defined
hereinbefore, and V'.sub.1a represents a bond or a linear or
branched (C.sub.1-C.sub.4)alkylene chain,
[0078] the hydroxy function of which compounds of formula (XVIII)
is replaced, if desired, by a halogen atom, in accordance with
conventional conditions of organic synthesis, to yield compounds of
formula (XIX): 30
[0079] wherein Hal represents a halogen atom, and R.sub.1, U,
V'.sub.1a, X, R.sub.2a and R.sub.2b are as defined
hereinbefore,
[0080] the totality of the compounds of formulae (XVIII) and (XIX)
being reacted with a compound of formula (IX) as described
hereinbefore, to yield compounds of formula (I/d), a particular
case of the compounds of formula (I): 31
[0081] wherein W, R.sub.1, U, X, R.sub.2a and R.sub.2b are as
defined for formula (I), V'.sub.1a is as defined hereinbefore and
R.sub.6 represents a hydroxy group or a halogen atom,
[0082] which compounds of formula (I/d), in the particular case
when R.sub.6 represents a hydroxy group, are subjected to the
action of an alkylating agent in accordance with conventional
conditions of organic chemistry, to yield compounds of formula
(I/e), a particular case of the compounds of formula (I): 32
[0083] wherein W, R.sub.1, U, V'.sub.1a, X, R.sub.2a and R.sub.2b
are as defined hereinbefore and R.sub.7 represents a linear or
branched (C.sub.1-C.sub.6)alkyl group,
[0084] which compounds of formulae (I/a) to (I/e) constitute the
totality of the compounds of the invention, which are purified, if
necessary, in accordance with conventional purification techniques,
which may be separated, if desired, into their different isomers in
accordance with a conventional separation technique, the
substituents R.sub.2a and R.sub.2b of which and those of the group
W being transformed in accordance with conventional methods of
organic synthesis used in the field of aromatic chemistry, the W
group of which, when it is a bicyclic system, is reduced, if
desired, to yield bicyclic W groups, one of whose rings is
partially hydrogenated and which may then be substituted in
accordance with conventional conditions of organic chemistry, and
which are converted, if desired, into their addition salts with a
pharmaceutically acceptable acid or base, and which may be in the
form of hydrates or solvates.
[0085] The compounds of formulae (II), (III/A), (III/B), (III/C),
(III/D), (V) and (IX) are either commercial products or are
obtained according to known conventional methods of organic
synthesis.
[0086] The compounds of the present invention are useful in the
treatment of diseases or pathological conditions in which
endothelial dysfunction is known. Owing to their specific
pharmacological activity, the compounds of the invention are
accordingly useful in preventing the development, extension and
complications of atherosclerotic lesions, in the treatment of
myocardial or peripheral ischaemia, cardiac insufficiency,
pulmonary arterial hypertension, in the prevention of vascular
complications after vascular bypass, vascular dilatation, vascular
repermeabilisation and heart transplantation.
[0087] The present invention relates also to pharmaceutical
compositions comprising as active ingredient at least one compound
of formula (I), its optical isomers, its hydrates, its solvates,
and addition salts thereof with a pharmaceutically acceptable acid
or base, alone or in combination with one or more inert, non-toxic,
pharmaceutically acceptable excipients or carriers.
[0088] Among the pharmaceutical compositions according to the
invention, there may be mentioned more especially those that are
suitable for oral, parenteral (intravenous, intramuscular or
subcutaneous), per- or trans-cutaneous, nasal, rectal, perlingual,
ocular or respiratory administration, and especially tablets or
dragees, sublingual tablets, gelatin capsules, capsules,
suppositories, creams, ointments, dermal gels, injectable or
drinkable preparations, aerosols, eye or nose drops, etc.
[0089] The useful dosage varies according to the age and weight of
the patient, the route of administration, the nature and severity
of the disorder, and whether any associated treatments are being
taken, and ranges from 1 mg to 200 mg in one or more
administrations per day.
[0090] The following Examples illustrate the invention but do not
limit it in any way. The starting materials used are known products
or are prepared according to known procedures. The various
Preparations yield synthesis intermediates for use in the
preparation of the compounds of the invention.
[0091] The structures of the compounds described in the Examples
were determined according to the usual spectrophotometric
techniques (infrared, nuclear magnetic resonance, mass
spectrometry, etc.).
[0092] The melting points were determined using a Kofler hotplate
(K.), or using a hotplate under a microscope (M.K.). When the
compound exists in the form of a salt, the melting point given
corresponds to that of the salt.
PREPARATION 1
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-methylamine
[0093] Step A: Ethyl
1-(benzofuran-3-ylacetyl)-4-piperidinecarboxylate
[0094] 22 g of carbonyldiimidazole are added in portions to 23.9 g
of benzofuran-3-ylacetic acid in 250 ml of dichloromethane. When
the evolution of gas has stopped, the reaction mixture is stirred
for 1 hour and then 21 ml of ethyl piperid-4-ylcarboxylate are
added dropwise. After 12 hours' stirring at room temperature, the
reaction mixture is washed with 1N sodium hydroxide solution and
then with 1N hydrochloric acid. After decanting and drying,
concentration under reduced pressure enables the expected product
to be isolated.
[0095] Step B: 1-(Benzofuran-3-ylacetyl)-4-piperidinecarboxylic
Acid
[0096] 200 ml of 1N sodium hydroxide solution are added to a
solution of 42.1 g of the product obtained in Step A in 200 ml of
ethanol. After 8 hours' stirring at room temperature, the ethanol
is removed by evaporation, the mixture is washed with ether, and
the aqueous phase is rendered acidic with 1N hydrochloric acid.
After extraction with dichloromethane, decanting and drying,
concentration under reduced pressure enables the expected product
to be isolated.
[0097] Step C:
1-(Benzofuran-3-ylacetyl)-N-methyl-4-piperidinecarboxamide
[0098] 19 g of carbonyldiimidazole are added in portions to 33 g of
the product obtained in Step B in 350 ml of dichloromethane. When
the evolution of gas has stopped, the reaction mixture is stirred
for 1 hour at room temperature and then a stream of methylamine is
circulated through it. After 12 hours' stirring, the mixture is
diluted with water, decanted, washed with 1N sodium hydroxide
solution and then with 1N hydrochloric acid, decanted, dried and
evaporated, enabling the expected product to be isolated.
[0099] Step D:
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-meth-
ylamine
[0100] 7.6 g of lithium aluminium hydride are added in portions to
a solution of 28.7 g of the product obtained in Step C in 1.5
liters of tetrahydrofuran heated at 60.degree. C. After 18 hours at
reflux, the reaction mixture is hydrolysed by the addition of 5.24
ml of water, 4.2 ml of 20% sodium hydroxide solution and then 19.2
ml of water. After filtration, drying and concentration under
reduced pressure, the expected product is isolated. The
hydrochloride thereof recrystallises from methanol.
[0101] Melting point (M.K.): 270-280.degree. C. (decomposition)
PREPARATION 2
N-({1-[2-(Benzofuran-2-yl)ethyl]-4-piperidyl}methyl)-N-methylamine
[0102] The product is obtained according to the process of
Preparation 1, using benzofuran-2-ylacetic acid as substrate in
Step A.
PREPARATION 3
{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-methylamine
[0103] The product is obtained according to the process of
Preparation 1, using a stream of ammonia instead of a stream of
methylamine in Step C.
PREPARATION 4
N-({1-[2-(1-H-Inden-3-yl)ethyl]-4-piperidyl}methyl)-N-methylamine
[0104] The product is obtained according to the process of
Preparation 1, using 1H-inden-3-ylacetic acid as substrate in Step
A.
PREPARATION 5
N-({-[(2E)-3-(Benzofuran-2-yl)-2-propenyl]-4-piperidyllmethyl}-N-methylami-
ne
[0105] Step A: 3-(Benzofuran-2-yl)acrylic Acid
[0106] A mixture of 20 g of benzofuran-2-ylcarbaldehyde and 14.25 g
of malonic acid in 13.8 ml of pyridine is heated at 100.degree. C.
until the evolution of gas has stopped. After cooling, the expected
product is precipitated with 1N hydrochloric acid. The expected
product is isolated by filtration, washing with hydrochloric acid
and then with water, and drying.
[0107] Step B: Ethyl
1-[(2E)-3-(benzofuran-2-yl)-2-propenoyl]-4-piperidine-
carboxylate
[0108] 25 g of the acid chloride of the product obtained in Step A
(obtained by the action of thionyl chloride) are slowly added at
room temperature to a solution of 19 g of ethyl
piperid-4-ylcarboxylate and 9.75 ml of pyridine in 250 ml of
acetonitrile. After stirring for 1 hour, the reaction mixture is
concentrated, taken up in ethyl acetate, washed with 1N
hydrochloric acid and then with 0.1N sodium hydroxide solution,
dried and filtered. Concentration under reduced pressure enables
the expected product to be isolated.
[0109] Step C:
N-({-[(2E)-3-(Benzofuran-2-yl)-2-propenyl]-4-piperidyl}meth- yl)-N
Methylamine
[0110] The product is obtained according to the process of
Preparation 1, Steps B to D, using the product isolated in the
preceding Step B as substrate in Step B.
PREPARATION 6
1-[2-(Benzofuran-3-yl)ethyl]-N-methyl-4-piperidinamine
[0111] Step A:
8-(Benzofuran-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane
[0112] The product is obtained according to Step A of Preparation 1
using 1,4-dioxa-8-azaspiro[4.5]decane as reagent.
[0113] Step B: 1-(Benzofuran-3-ylacetyl)-piperidin-4-one
[0114] 50 ml of 1N hydrochloric acid are added to a solution of 5 g
of the product obtained in Step A in 200 ml of acetone. After
stirring for 1 hour 30 at room temperature, 50 ml of 1N
hydrochloric acid are again added and the mixture is heated for 2
hours at 50.degree. C. After cooling, the reaction mixture is
neutralised by the addition of 100 ml of a 10% sodium hydrogen
carbonate solution and then concentrated, taken up in
dichloromethane, washed with water, decanted and dried.
Concentration under reduced pressure enables the expected product
to be isolated.
[0115] Step C:
1-(Benzofuran-3-ylacetyl)-N-methyl-4-piperidinamine
[0116] A 33% solution of methylamine in ethanol is added dropwise
to a solution of 13.7 g of the product obtained in Step B in 130 ml
of isopropanol. After 2 hours at 10.degree. C., 3.5 g of sodium
hydroxide are added and stirring is maintained for 1 hour at room
temperature. The reaction mixture is then cooled to 10.degree. C.
and 2.8 g of sodium borohydride are added. After 12 hours' stirring
at room temperature, the reaction mixture is concentrated, taken up
in water and dichloromethane, decanted, dried and evaporated.
Chromatography over silica gel (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH:
95/5/0.5) enables the expected product to be isolated.
[0117] Step D:
1-[2-(Benzofuran-3-yl)ethyl]-N-methyl-4-piperidinamine
[0118] 7.2 g of the product obtained in Step C are added to a
suspension of 2 g of LiAlH.sub.4 in 210 ml of tetrahydrofuran.
After 48 hours at room temperature, the reaction mixture is
hydrolysed with 1.4 ml of water, 1.1 ml of 20% sodium hydroxide
solution and 5 ml of water. After filtration and concentration,
chromatography over silica gel enables the expected product to be
isolated.
[0119] Melting point (M.K): <50.degree. C.
PREPARATION 7
1-[2-(Benzofuran-3-yl)ethyl]-4-piperidinamine
[0120] Step A: Tert-butyl
1-[2-(benzofuran-3-yl)ethyl]-4-piperidylcarbamat- e
[0121] 13 ml of acetic acid and 61 g of sodium
triacetoxyborohydride are added in succession to a solution of 33 g
of 2-(benzofuran-3-yl)acetaldeh- yde and 41.3 g of tert-butyl
4-piperidylcarbamate in 1.4 liters of dichloromethane. After 24
hours' stirring at room temperature, a 20% sodium hydroxide
solution is added. After 10 minutes, the reaction mixture is
decanted and the organic phase is washed, dried and concentrated.
Chromatography over silica gel (cyclohexane/ethyl acetate: 30/70)
enables the expected product to be isolated.
[0122] Step B: 1-[2-(Benzofuran-3-yl)ethyl]-4-piperidinamine
[0123] 235 ml of a 2.9N ethanolic hydrogen chloride solution are
added to a solution of 21 g of the product obtained in Step A in
786 ml of ethanol. After 3 hours at 70.degree. C. and then 16 hours
at room temperature, the reaction mixture is concentrated under
reduced pressure. The residue is taken up in 150 ml of water. The
expected product is precipitated by the addition of 20% sodium
hydroxide solution.
[0124] Melting point (K.): 64-66.degree. C.
PREPARATION 8
1-[2-(1H-Inden-3-yl)ethyl]-4-piperidinamine
[0125] Step A: 1-(1H-Inden-3-ylacetyl)piperidin-4-one
[0126] The product is obtained according to the process of
Preparation 6, Steps A to B, using 1H-inden-3-ylacetic acid as
substrate in Step A.
[0127] Step B: 1-(1H-Inden-3-ylacetyl)-4-piperidinone Oxime
[0128] A mixture of 11.5 g of the product obtained in Step A, 12.5
g of hydroxylamine hydrochloride, 13.3 g of sodium acetate and 100
ml of ethanol is heated at reflux for 1 hour. The reaction mixture
is then filtered, concentrated, taken up in water and extracted
with dichloromethane. The organic phase is then dried and
evaporated, enabling the expected product to be isolated.
[0129] Melting point: 190-192.degree. C.
[0130] Step C: 1-[2-(1H-Inden-3-yl)ethyl]-4-piperidinamine
[0131] A solution of 6.8 g of the product obtained in Step B in 123
ml of tetrahydrofuran is added at room temperature to a suspension
of 4 g of lithium aluminium hydride in 12 ml of tetrahydrofuran.
After 12 hours' stirring at room temperature, hydrolysis is carried
out with 2.8 ml of water, 2.2 ml of 20% sodium hydroxide solution
and 10.1 ml of water, and then the reaction mixture is filtered and
concentrated under reduced pressure, enabling the expected product
to be isolated.
PREPARATION 9
1-[2-(5-Methoxy-1H-inden-3-yl)ethyl]-4-piperidinamine
[0132] The product is obtained according to the process of
Preparation 8, using (5-methoxy-1H-inden-3-yl)acetic acid as
substrate in Step A.
PREPARATION 10
1-[2-(6-Fluoro-1H-inden-3-yl)ethyl]-4-piperidinamine
[0133] The product is obtained according to the process of
Preparation 8, using (6-fluoro-1H-inden-3-yl)acetic acid as
substrate in Step A.
PREPARATION 11
1-[3-(Benzofuran-2-yl)propyl]-N-methyl-4-piperidinamine
[0134] Step A:
8-[3-(Benzofuran-2-yl)propyl]-1,4-dioxa-8-azaspiro[4.5]deca- ne
[0135] A solution of 5 g of 3-(benzofuran-2-yl)-1-bromopropane, 3 g
of 1,4-dioxa-8-azaspiro[4.5]decane and 5.8 g of potassium carbonate
in 200 ml of acetone is refluxed for 24 hours, and then evaporated
to dryness. The residue is taken up in ethyl acetate, washed with
water, dried and evaporated to yield the expected product.
[0136] Step B: 1-[3-(Benzofuran-2-yl)propyl]-4-piperidinone
[0137] A solution of 6 g of the product of Step A, 60 ml of 10%
sulphuric acid and 30 ml of tetrahydrofuran is heated at 50.degree.
C. for 12 hours, and then evaporated. The residue is taken up in
ether, rendered basic with 20% sodium hydroxide solution, extracted
with ethyl acetate, dried and evaporated, enabling the expected
product to be isolated.
[0138] Step C:
1-[3-(Benzofuran-2-yl)propyl]-N-methyl-4-piperidinamine
[0139] The product is obtained according to the process of Step C
of Preparation 6, using the product obtained in the preceding Step
B as substrate.
PREPARATION 12
1-[3-(Benzofuran-3-yl)propyl]-4-piperidinamine
[0140] The product is obtained in four steps using, in the first
step, the process of Step A of Preparation 11 with 3-(benzofuran-3
-yl)-1-bromopropane as substrate, then the process of Step B of
Preparation 6, and then the process of Steps C and D of Preparation
8.
PREPARATION 13
1-[(4-Methoxybenzofuran-3-yl)methyl]-4-piperidinamine
[0141] Step A: Tert-butyl
1-(4-methoxybenzofuran-3-carbonyl)-4-piperidylca- rbamate
[0142] A solution of 2.9 g of 4-methoxybenzofuran-3-ylcarboxylic
acid chloride in 4 ml of dichloromethane is added, at 0.degree. C.,
to a solution of 4.3 ml of diisopropylethylamine and 2.75 g of
tert-butyl N-(4-piperidyl)carbamate in 43 ml of dichloromethane.
After 12 hours' stirring at room temperature, the reaction mixture
is washed with water, decanted, dried and then evaporated, enabling
the expected product to be isolated.
[0143] Step B:
1-(4-Methoxybenzofuran-3-carbonyl)-4-piperidinamine
[0144] The product is obtained according to the process of Step B
of Preparation 7, using the product obtained in the preceding Step
A as substrate.
[0145] Step C 1-[3-(Benzofuran-3-yl)propyl]-4-piperidinamine
[0146] The product is obtained according to the process of Step D
of Preparation 8, using the product obtained in the preceding Step
B as substrate.
PREPARATION 14
1-[(Benzofuran-3-yl)methyl]-4-piperidinamine
[0147] The product is obtained according to the process of
Preparation 13, Steps A to C, using benzofuran-3-ylcarboxylic acid
chloride as substrate in Step A.
PREPARATION 15
1-[2-(6-Methoxy-benzofuran-3-yl)ethyl]-4-piperidinamine
[0148] The product is obtained according to the process of
Preparation 13, Steps A to C, using
(6-methoxybenzofuran-3-yl)acetic acid as substrate in Step A.
PREPARATION 16
1-[2-(Benzofuran-3-yl)ethyl]-4-[(methylamino)methyl]-4-piperidinol
[0149] Step A: Ethyl
N-(1-benzyl-4-hydroxy-4-piperidyl)methylcarbamate
[0150] A solution of 14.75 g of ethyl chloroformate in 125 ml of
dichloromethane is added, at 0.degree. C., to a solution of 30 g of
1-benzyl-4-aminomethyl-piperidin-4-ol and 13.8 g of triethylamine
in 250 ml of dichloromethane. After 10 minutes' contact, the
reaction mixture is washed with 0.1N sodium hydroxide solution and
then dried over MgSO.sub.4. Concentration under reduced pressure
enables the expected product to be isolated.
[0151] Step B: Ethyl N-(4-hydroxy-4-piperidyl)methylcarbamate
[0152] A solution of 47.7 g of the product obtained in Step A, 51.4
g of ammonium formate, 9.5 g of 10% palladium-on-carbon and 1600 ml
of methanol is refluxed for 1 hour. After cooling and filtration,
concentration under reduced pressure enables the expected product
to be isolated.
[0153] Step C: Ethyl
N-({1-[2-(benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidy-
l}-methyl)-carbamate
[0154] A mixture of 15 g of 2-(benzofuran-3-yl)-1-bromoethane, 13.5
g of the product obtained in Step B, 73.5 g of potassium carbamate,
21.5 g of tetrabutylammonium bromide and 150 ml of acetonitrile is
stirred vigorously for 4 days at room temperature. The reaction
mixture is then concentrated, taken up in ethyl acetate, washed
with water, dried over MgSO.sub.4 and then evaporated.
Chromatography of the residue over silica gel
(CH.sub.2Cl.sub.2/EtOH/NH.sub.4OH: 95/5/0.5) enables the expected
product to be isolated.
[0155] Step D:
1-[2-(Benzofuran-3-yl)ethyl]-4-[(methylamino)methyl]-4-pipe-
ridinol
[0156] A solution of 13.4 g of the product obtained in Step C in
130 ml of tetrahydrofuran is added, at a reaction mixture
temperature of 20.degree. C., to a suspension of 3.63 g of lithium
aluminium hydride in 20 ml of tetrahydrofuran. After 9 hours'
reflux and then 12 hours at room temperature, the reaction mixture
is hydrolysed, filtered and then concentrated under reduced
pressure, enabling the expected product to be isolated.
PREPARATION 17
4-(Aminomethyl)-1-[2-(benzofuran-3-yl)ethyl]-4-piperidinol
[0157] A solution of 2 g of the product obtained in Step C of
Preparation 16, 0.65 g of potassium hydroxide, 23 ml of ethanol and
17 ml of water is brought to reflux. After 24 hours, 0.65 g of
potassium hydroxide is added and refluxing is maintained for 3
days. The reaction mixture is then concentrated, and subsequently
diluted with dichloromethane, washed with water, neutralised, dried
and then concentrated under reduced pressure, enabling the expected
product to be isolated.
[0158] Melting point: 78.degree. C.
PREPARATION 18
1-[2-(5-Fluoro-benzofuran-3-yl)ethyl]-4-[(methylamino)methyl]-4-piperidino-
l
[0159] The product is obtained according to the process of
Preparation 16, Steps A to D, using
2-(5-fluoro-benzofuran-3-yl)-1-bromoethane in Step C.
PREPARATION 19
4-(Aminomethyl)-1-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-piperidinol
[0160] The product is obtained according to the process of
Preparation 17, using ethyl
N-{1-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidy-
lmethyl}carbamate as substrate, which is prepared as for the
product of Step C of Preparation 16 starting from
2-(5-fluoro-benzofuran-3-yl)-1-bro- moethane.
PREPARATION 20
1-[2-(7-Methoxy-benzofuran-3-yl)ethyl]-4-[(methylamino)methyl]-4-piperidin-
ol
[0161] The product is obtained according to the process of
Preparation 16, Steps A to D, using
2-(7-methoxy-benzofuran-3-yl)-1-bromoethane in Step C.
PREPARATION 21
4-(Aminomethyl)-1-[2-(5-methoxy-benzofuran-3-yl)ethyl]-4-piperidinol
[0162] The product is obtained according to the process of
Preparation 17, using ethyl
N-({1-[2-(5-methoxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperi-
dyl}methyl)carbamate as substrate, which is prepared according to
the process of Preparation 16, Steps A to C, using
2-(5-methyloxy-benzofuran-- 3-yl)-1-bromoethane in Step C.
PREPARATION 22
4-(Aminomethyl)-1-[2-(1H-inden-3-yl)ethyl]-4-piperidinol
[0163] The product is obtained according to the process of
Preparation 17, using ethyl
N-({1-[2-(1H-inden-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)c-
arbamate as substrate, which is prepared according to the process
of Preparation 16, Steps A to C, using
2-(1H-inden-3-yl)-1-bromoethane in Step C.
PREPARATION 23
1-[2-(5-Methoxy-benzofuran-3-yl)ethyl]-4-[(methylamino)methyl]-4-piperidin-
ol
[0164] The product is obtained according to the process of
Preparation 16, Steps A to D, using
2-(5-methoxy-benzofuran-3-yl)-1-bromoethane as substrate in Step
C.
PREPARATION 24
4-(Aminomethyl)-1-[2-(7-methoxy-benzofuran-3-yl)ethyl]-4-piperidinol
[0165] The product is obtained according to the process of
Preparation 17, using the product obtained in Step C of Preparation
20 as substrate.
PREPARATION 25
1-[2-(1H-Inden-3-yl)ethyl]-4-[(methylamino)methyl]-4-piperidinol
[0166] The product is obtained according to the process of
Preparation 16, Steps A to D, using 2-(1H-inden-3-yl)-1-bromoethane
as substrate in Step C.
PREPARATION 26
4-(2-Aminoethyl)-1-[2-(benzofuran-3-yl)ethyl]-4-piperidinol
[0167] The product is obtained according to the process of
Preparation 16, Steps A to D, using
4-(2-aminoethyl)-1-benzyl-4-piperidinol as substrate in Step A, and
then subjecting the product to the process of Preparation 17.
PREPARATION 27
1-[2-(5-Hydroxy-benzofuran-3yl)ethyl]-4-[(methylamino)methyl]-4-piperidino-
l
[0168] 6.46 ml of a 1M solution of boron tribromide in
dichloromethane are added, at a temperature of from -5 to
-10.degree. C., to a solution of 3.23 mmol of the product of
Preparation 23 in 14.3 ml of chloroform. After 12 hours' reaction
at room temperature, the reaction mixture is hydrolysed and
rendered basic with powdered sodium hydrogen carbonate. The
expected product is isolated by extraction and purification.
PREPARATION 28
2-(4-Amino-1-piperidyl)-1-(benzofuran-3-yl)-ethanol
[0169] Step A: Tert-butyl
1-[2-(benzofuran-3-yl)-2-oxoethyl]-4-piperidylca- rbamate
[0170] 10 g of 1-(benzofuran-3-yl)-2-bromoethanone are added to a
suspension of 8.4 g of tert-butyl N-(piperid-4-yl)carbamate, 17.3 g
of potassium carbonate and 80 ml of acetonitrile. After 1 hour 45
minutes' reaction at room temperature, the reaction mixture is
diluted with water, extracted with ethyl acetate, and then dried
over MgSO.sub.4 and concentrated under reduced pressure, enabling
the expected product to be obtained.
[0171] Step B: Tert-butyl
1-[2-(benzofuran-3-yl)-2-hydroxyethyl]-4-piperid- ylcarbamate
[0172] 1.2 g of sodium borohydride are added in portions to a
solution of 7.7 g of the product obtained in Step A in 100 ml of
ethanol. After 1 hour's reaction, the solution is evaporated, taken
up in water, extracted with ethyl acetate, dried and then
concentrated under reduced pressure. Chromatography over silica gel
(dichloromethane/ethanol: 95/5) enables the expected product to be
isolated.
[0173] Step C:
2-(4-Amino-1-piperidyl)-1-(benzofuran-3-yl)-ethanol
[0174] The product is obtained according to the process of
Preparation 7, using the product obtained in the preceding Step B
as substrate.
PREPARATION 29
1-(4-Amino-1-piperidyl)-3-(benzofuran-3-yl)-2-propanol
[0175] Step A: Tert-butyl
1-[3-(benzofuran-3-yl)-2-hydroxypropyl]-4-piperi- dylcarbamate
[0176] A solution of 2.9 g of 3-(2-oxiranylmethyl)benzofuran, 4 g
of tert-butyl 4-piperidylcarbamate and 35 ml of isopropanol is
heated at 80.degree. C. for 5 hours. After evaporation to dryness,
chromatography over silica gel enables the expected product to be
isolated.
[0177] Melting point (K.): 118-120.degree. C.
[0178] Step B:
1-(4-Amino-1-piperidyl)-3-(benzofuran-3-yl)-2-propanol
[0179] The product is obtained according to Step B of Preparation
7, using the product of the preceding Step A as substrate.
PREPARATION 30
1-[3-(Benzofuran-3-yl)-2-fluoropropyl]-4-piperidinamine
[0180] Step A: Tert-butyl
1-[3-(benzofuran-3-yl)-2-fluoropropyl]-4-piperid- ylcarbamate
[0181] A solution of 0.85 ml of diethylaminosulphur trifluoride in
10 ml of dichloromethane is added dropwise, under argon and at
0.degree. C., to a solution of 2 g of the product obtained in Step
A of Preparation 29 in 25 ml of dichloromethane. After 2 hours'
reaction at 0.degree. C. and 1 hour at room temperature, the
reaction mixture is hydrolysed at 0.degree. C. with an aqueous 10%
NaHCO.sub.3 solution. After decanting, drying and evaporation,
chromatography over silica gel (dichloromethane/ethanol: 95/5)
enables the expected product to be isolated.
[0182] Melting point: 118-120.degree. C.
[0183] Step B:
1-[3-(Benzofuran-3-yl)-2-fluoropropyl]-4-piperidinamine
[0184] A stream of hydrogen chloride gas is circulated through a
solution of 3.64 g of the product obtained in Step A in 70 ml of
ethanol. After 2 hours' stirring at 50.degree. C., the reaction
mixture is concentrated under reduced pressure. The residue is
taken up in water and in 20% sodium hydroxide solution, extracted
with dichloromethane, dried and then evaporated, enabling the
expected product to be isolated.
PREPARATION 31
1-[2-(Benzofuran-3-yl)-1-(fluoromethyl)ethyl]-4-piperidinamine
[0185] The product is obtained according to the process of Step B
of Preparation 30 using as substrate the first product isolated in
the course of the chromatography over silica gel carried out in
Step A of Preparation 30.
PREPARATION 32
7-Methoxy-1H-pyrrolo[2,3-c]pyridine-3-sulphonyl Chloride
[0186] Step A: (2-Methoxy-3-nitro-4-pyridyl)acetonitrile
[0187] A solution, cooled to -30.degree. C., of 68.8 g of potassium
tert-butylate in 250 ml of dimethylformamide is added, at a
temperature less then -15.degree. C. and over a period of 45
minutes, to a solution of 40 g of 2-methoxy-3-nitropyridine and
48.8 g of 4-chlorophenoxyacetonitrile in 350 ml of
dimethylformamide. After 1 hour 30 minutes' reaction at a
temperature of from -20 to -10.degree. C., the reaction mixture is
poured into 2 liters of 1N hydrochloric acid and then the solution
is stirred for 30 minutes at -10.degree. C. The resulting
precipitate is filtered off, dried and recrystallised from
anhydrous ethanol, enabling the expected product to be
isolated.
[0188] Melting point (K.): 110-114.degree. C.
[0189] Step B: 7-Methoxy-1H-pyrrolo[2,3-c]pyridine
[0190] 3.1 g of 10% Pd/C are added to a solution of 30.8 g of the
product obtained in Step A in 600 ml of anhydrous ethanol and 150
ml of acetic acid. The mixture is hydrogenated at room temperature,
under 4 bars, for 6 hours and is then filtered and concentrated
under reduced pressure. The residue is taken up in 50 ml of a
saturated sodium hydrogen carbonate solution, diluted with ethyl
acetate, brought to pH=8 by the addition of sodium hydrogen
carbonate, decanted, washed with water, dried and then concentrated
under reduced pressure, enabling the expected product to be
obtained.
[0191] Melting point (K.): 129-132.degree. C.
[0192] Step C: 3-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine
[0193] 19.7 g of N-bromosuccinimide are added, over the course of 5
minutes, to a solution of 16.5 g of the product obtained in Step B
in 340 ml of anhydrous ethanol. After 12 hours' stirring at room
temperature, the reaction mixture is concentrated in vacuo, taken
up in water and in ether, washed, dried and concentrated.
Chromatography over silica gel (dichloromethane/cyclohexane: 80/20
to 100/0) enables the expected product to be isolated.
[0194] Melting point (K.): 130-134.degree. C.
[0195] Step D:
3-Bromo-1-(tert-butyldimethyl)silyl-7-methoxy-1H-pyrrolo[2,-
3-c]-pyridine
[0196] 22.7 ml of a 1.6M n-butyllithium solution in tetrahydrofuran
are added to a solution, cooled to -76.degree. C., of 7.5 g of the
product obtained in Step C in 200 ml of tetrahydrofuran. After 20
minutes' stirring at that temperature, 5.5 g of
tert-butyldimethylsilyl chloride in 50 ml of tetrahydrofuran are
added, and stirring is maintained for 3 hours at -76.degree. C.
After returning to room temperature, 15 ml of water, 200 ml of a
saturated sodium chloride solution and 600 ml of ether are added.
The solution is decanted, dried and then concentrated under reduced
pressure. Chromatography over silica gel (dichloromethane 100%)
enables the expected product to be isolated.
[0197] Step E: 7-Methoxy-1H-pyrrolo[2,3-c]pyridine-3-sulphonyl
Chloride
[0198] 11 ml of tert-butyllithium are added to a solution, cooled
to -80.degree. C., of 3 g of the product obtained in Step D in 80
ml of ether. After 30 minutes' stirring at that temperature, a
stream of sulphur dioxide is passed through the reaction mixture
for 10 minutes, and then 2.3 g of N-chlorosuccinimide in 40 ml of
tetrahydrofuran are added, and the reaction mixture is returned to
room temperature. The expected product is isolated by concentration
under reduced pressure and purification of the residue.
PREPARATION 33
4-Bromo-5-isoquinolinesulphonyl Chloride Hydrochloride
[0199] Step 1: 4-Bromo-5-nitro-isoquinoline
[0200] Add 11 g of 4-bromoisoquinoline to 45 ml of sulphuric acid,
followed, dropwise, by a solution of 9.1 g of potassium nitrate in
45 ml of sulphuric acid whilst cooling in an ice-bath. The reaction
mixture is stirred at room temperature for 2 hours 30, before being
poured onto ice. After the resulting solution has been rendered
basic with ammonium hydroxide, the crystals are filtered off,
washed and dried to yield the expected product.
[0201] Melting point (K): 176-178.degree. C.
[0202] Step 2: 5-Amino-4-bromoisoquinoline
[0203] 100 ml of concentrated hydrochloric acid are added to a
suspension of 16 g of the compound obtained in Step 1 in 55 ml of
ethanol. The mixture is cooled with ice and stirred whilst a
solution of 62.6 g of SnCl.sub.2.2H.sub.2O in 100 ml of ethanol is
being introduced and then for a further 3 hours. After removal of
the solvent by evaporation, the residue is diluted with 140 ml of
ice-cold water and rendered basic with 2N sodium hydroxide
solution. The resulting aqueous phase is extracted 3 times with 350
ml of methylene chloride each time. The combined organic phases are
dried over MgSO.sub.4 and evaporated. The residue is purified by
flash chromatography (CH.sub.2Cl.sub.2/MeOH: 98/2) to yield the
expected product.
[0204] Melting point (K): 151-153.degree. C.
[0205] Step 3: 4-Bromo-5-isoquinolinesulphonyl Chloride
[0206] A solution of 3.45 g of sodium nitrite in 14 ml of water is
added dropwise, at -5.degree. C., to a suspension of 5.4 g of the
product obtained in Step 2 in 66 ml of concentrated hydrochloric
acid, and the solution is stirred for 30 minutes at room
temperature (solution A). There is prepared, separately, an aqueous
solution (8.5 ml) of 1.95 g of CuCl.sub.2.2H.sub.2O, which is
introduced into 42 ml of a solution of acetic acid saturated with
sulphurous anhydride. The resulting solution is poured dropwise
into solution A, and then the reaction mixture is stirred for one
hour at room temperature before being warmed at 30.degree. C. for
30 minutes in a water bath. The expected product is isolated by
extraction with chloroform, decanting, washing with a saturated
solution of sodium hydrogen carbonate and customary treatment.
[0207] Melting point (K): 84-86.degree. C.
PREPARATION 34
4-Fluoro-5-isoquinolinesulphonyl Chloride
[0208] The product is obtained according to the process of
Preparation 33, Steps 1 to 3, but in Step 1 of that Preparation
using 4-fluoroisoquinoline, the preparation of which is described
in J. Am. Chem. Soc., 1951, pp. 687-688, instead of
4-bromoisoquinoline.
[0209] Melting point (K): 88-89.degree. C.
EXAMPLE 1
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-methyl-5-isoquinoli-
nesulphonamide and its Dihydrochloride
[0210] 5.1 g of 5-isoquinolinesulphonyl chloride hydrochloride is
added in fractions to a solution, cooled to 0.degree. C., of 5.26 g
of the product of Preparation 1 and 5.5 g of diisopropylethylamine
in 750 ml of dichloromethane. After 6 hours' reaction at room
temperature, the mixture is concentrated under reduced pressure,
taken up in ethyl acetate, washed with water, dried and evaporated.
Chromatography over silica gel (dichloromethane/methanol: 95/5)
enables the expected product to be isolated, which is converted to
the dihydrochloride with a solution of ethereal hydrogen
chloride.
[0211] Melting Point: 237-239.degree. C.
1 Elemental microanalysis: C H N Cl S % found 57.77 5.79 7.99 13.68
5.65 % calculated 58.21 5.82 7.83 13.22 5.98
EXAMPLE 2
2-Acetyl-8-chloro-N-({1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-m-
ethyl-1,2,3,4-tetrahydro-5-isoquinolinesulphonamide and its
Fumarate
[0212] The product is obtained according to the process of Example
1, using
2-acetyl-8-chloro-1,2,3,4-tetrahydro-5-isoquinolinesulphonyl
chloride as reagent. The resulting product is converted to its
fumarate with a solution of 0.172M fumaric acid in ethanol.
[0213] Melting point (M.K.): 168-170.degree. C.
2 Elemental microanalysis: C H N Cl S % found 57.77 5.86 6.21 5.35
4.36 % calculated 58.22 5.80 6.36 5.37 4.86
EXAMPLE 3
N-({1-[2-(Benzofuran-2-yl)ethyl]-4-piperidyl}methyl)-N-methyl-5-isoquinoli-
nesulphonamide
[0214] The product is obtained according to the process of Example
1 using the compound of Preparation 2 as substrate instead of the
compound of Preparation 1.
[0215] Melting point (M.K.): 105-108.degree. C.
3 Elemental microanalysis: C H N S % found 67.48 6.47 9.14 6.68 %
calculated 67.36 6.30 9.06 6.92
EXAMPLE 4
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-5-isoquinolinesulphon-
amide and its Fumarate
[0216] The product is obtained according to the process of Example
1 using the compound of Preparation 3 as substrate instead of the
compound of Preparation 1. The resulting product is converted to
its fumarate.
[0217] Melting point (M.K.): 140-155.degree. C.
4 Elemental microanalysis: C H N S % found 61.29 5.63 7.27 5.31 %
calculated 61.58 5.52 7.43 5.67
EXAMPLE 5
N-({1-[2-(1H-Inden-3-yl)ethyl]-4-piperidyl}methyl)-N-methyl-5-isoquinoline-
sulphonamide
[0218] The product is obtained according to the process of Example
1 using the compound of Preparation 4 as substrate instead of the
compound of Preparation 1. The product is crystallised from
isopropyl ether.
[0219] Melting point (M.K.): 92-95.degree. C.
5 Elemental microanalysis: C H N S % found 70.30 6.70 9.17 6.45 %
calculated 70.25 6.77 9.10 6.95
EXAMPLE 6
N-({1-[(2
E-3-(Benzofuran-2-yl)-2-propenyl]-4-piperidyl}methyl)-N-methyl-5-
-isoquinolinesulphonamide
[0220] The product is obtained according to the process of Example
1 using the compound of Preparation 5 as substrate instead of the
compound of Preparation 1. The product recrystallises from
acetonitrile.
[0221] Melting point (K.): 109.degree. C.
6 Elemental microanalysis: C H N S % found 68.57 6.23 8.95 6.57 %
calculated 68.19 6.15 8.83 6.74
EXAMPLE 7
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-N-methyl-5-isoquinolinesuipho-
namide and its Hemifumarate
[0222] The product is obtained according to the process of Example
1 using the compound of Preparation 6 as substrate instead of the
compound of Preparation 1. The product is converted to its
hemiflimarate, which recrystallises from ethyl acetate.
[0223] Melting point (M.K.): 122-124.degree. C.
7 Elemental microanalysis: C H N S % found 63.30 5.71 8.00 6.43 %
calculated 63.88 5.77 8.29 6.32
EXAMPLE 8
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulphonamide
and its Fumarate
[0224] The product is obtained according to the process of Example
1 using the compound of Preparation 7 as substrate instead of the
compound of Preparation 1. The product is converted to its
fumarate.
[0225] Melting point (M.K.): 230-235.degree. C.
8 Elemental microanalysis: C H N S % found 60.90 5.17 7.50 6.08 %
calculated 60.97 5.30 7.62 5.81
EXAMPLE 9
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-2,1,3-benzoxadiazole-4-sulpho-
namide and its Fumarate
[0226] 3.13 g of benzo[2,1,3]oxadiazole-4-sulphonic acid chloride
are added to a solution, at 0.degree. C., of 3.5 g of the product
of Preparation 7 and 1.85 g of diisopropylethylamine in 35 ml of
dichloromethane. After 3 hours at room temperature, the reaction
mixture is washed with water, dried and evaporated. The residue is
taken up in a 0.172M solution of fumaric acid in ethanol. The
resulting precipitate is filtered off. It recrystallises from
ethanol to yield the expected product.
[0227] Melting point (M.K.): 200-210.degree. C.
9 Elemental microanalysis: C H N S % found 55.00 4.96 10.15 6.19 %
calculated 55.34 4.83 10.33 5.91
EXAMPLE 10
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-1-naphthylsulphonamide
and its Fumarate
[0228] The product is obtained according to the process of Example
8 using naphthalene-1-sulphonyl chloride as reagent instead of
5-isoquinolinesulphonyl chloride. The product is converted to its
fumarate.
[0229] Melting point (M.K.): 226-230.degree. C.
10 Elemental microanalysis: C H N S % found 63.04 5.50 5.10 5.67 %
calculated 63.26 5.49 5.09 5.82
EXAMPLE 11
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-5-chloronaphthyl-1-sulphonami-
de
[0230] The product is obtained according to the process of Example
8 using 5-chloro-naphthalene-1-sulphonyl chloride as reagent
instead of 5-isoquinolinesulphonyl chloride.
[0231] Melting Point (M.K.): 107-110.degree. C.
11 Elemental microanalysis: C H N S Cl % found 64.16 5.38 6.15 6.72
7.49 % calculated 64.02 5.37 5.97 6.84 7.48
EXAMPLE 12
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-7-methoxynaphthyl-1-sulphonam-
ide
[0232] The product is obtained according to the process of Example
8 using 7-methoxynaphthalene-1-sulphonyl chloride as reagent
instead of 5-isoquinolinesulphonyl chloride. The product
crystallises from a mixture of ether/heptane.
[0233] Melting point (M.K.): 140-145.degree. C.
12 Elemental microanalysis: C H N S % found 66.99 6.24 5.92 6.73 %
calculated 67.22 6.07 6.03 6.90
EXAMPLE 13
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-7-chlorofuro[2,3-c]pyridine-3-
-sulphonamide and its Fumarate
[0234] The product is obtained according to the process of Example
8 using 7-chlorofuro[2,3-c]pyridine-3-sulphonyl chloride as reagent
instead of 5-isoquinolinesulphonyl chloride. The product is
converted to its fumarate.
[0235] Melting point (M.K.): 185-195.degree. C.
13 Elemental microanalysis: C H N Cl S % found 54.94 4.82 7.70 6.52
5.90 % calculated 55.04 4.62 7.76 6.55 5.92
EXAMPLE 14
1-Chloro-N-{1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulpho-
namide
[0236] The product is obtained according to the process of Example
8 using 1-chloroisoquinoline-5-sulphonyl chloride as reagent
instead of 5-isoquinolinesulphonyl chloride.
[0237] Melting point (M.K.): 130-132.degree. C.
14 Elemental microanalysis: C H N Cl S % found 61.44 5.19 9.00 7.57
6.69 % calculated 61.33 5.15 8.94 7.54 6.82
EXAMPLE 15
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-7-chlorothieno[2,3-c]pyridine-
-3-sulphonamide and its Fumarate
[0238] The product is obtained according to the process of Example
8 using 7-chlorothieno[2,3-c]pyridine-3-sulphonyl chloride as
reagent instead of 5-isoquinolinesulphonyl chloride.
[0239] Melting point (M.K.): 170-173.degree. C.
15 Elemental microanalysis: C H N Cl S % found 52.58 4.41 6.97 6.21
11.13 % calculated 52.74 4.43 7.10 5.99 10.83
EXAMPLE 16
1-Ethoxy-N-{1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulpho-
namide
[0240] The product is obtained according to the process of Example
8 using 1-ethoxy-5-isoquinolinesulphonyl chloride as reagent
instead of 5-isoquinolinesulphonyl chloride.
[0241] Melting point (M.K.): 109-114.degree. C.
16 Elemental microanalysis: C H N S % found 65.10 6.35 8.66 6.72 %
calculated 65.11 6.09 8.76 6.69
EXAMPLE 17
1-Methoxy-N-{1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulph-
onamide
[0242] The product is obtained according to the process of Example
8 using 1-methoxy-5-isoquinolinesulphonyl chloride as reagent
instead of 5-isoquinolinesulphonyl chloride.
[0243] Melting point (M.K.): 124-128.degree. C.
17 Elemental microanalysis: C H N S % found 64.43 6.03 9.07 6.99 %
calculated 64.50 5.85 9.03 6.89
EXAMPLE 18
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-5-chloro-1,3-dimethyl-1-H-pyr-
azole-4-sulphonamide and its Hydrochloride
[0244] The product is obtained according to the process of Example
8 using 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulphonyl chloride as
reagent instead of 5-isoquinolinesulphonyl chloride.
[0245] Melting Point (M.K.): 205-210.degree. C.
18 Elemental microanalysis: C H N Cl S % found 50.57 5.61 11.50
15.40 6.95 % calculated 50.74 5.54 11.83 14.98 6.77
EXAMPLE 19
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-3,5-dimethyl-4-isoxazolesulph-
onamide and its Hydrochloride
[0246] The product is obtained according to the process of Example
8 using 3,5-dimethyl-4-isoxazolesulphonyl chloride as reagent
instead of 5-isoquinolinesulphonyl chloride.
[0247] Melting Point (M.K.): 266-268.degree. C.
19 Elemental microanalysis: C H N Cl S % found 54.59 6.06 9.31 8.28
7.55 % calculated 54.60 5.96 9.55 8.06 7.29
EXAMPLE 20
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-7-oxo6,7-dihydro-1H-pyrrolo[2-
,3-c]pyridine-3-sulphonamide
[0248] The product is obtained according to the process of Example
8 using the product of Preparation 32 as reagent instead of
5-isoquinolinesulphonyl chloride.
[0249] Melting point (M.K.): 251-255.degree. C.
20 Elemental microanalysis: C H N S % found 59.70 5.44 12.41 7.18 %
calculated 59.98 5.49 12.72 7.28
EXAMPLE 21
N-{1-[2-(1H-Inden-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulphonamide
[0250] The product is obtained according to the process of Example
1 using the compound of Preparation 8 as substrate instead of the
compound of Preparation 1.
[0251] Melting point (M.K.): 170-172.degree. C.
21 Elemental microanalysis: C H N S % found 69.28 6.32 9.68 7.45 %
calculated 69.26 6.28 9.69 7.40
EXAMPLE 22
N-{1-[2-(5-Methoxy-1H-inden-3yl)ethyl]-4-piperidyl}-5-isoquinolinesulphona-
mide and its Fumarate
[0252] The product is obtained according to the process of Example
1 using the compound of Preparation 9 as substrate instead of the
compound of Preparation 1.
[0253] Melting point (M.K.): 165-170.degree. C.
22 Elemental microanalysis: C H N S % found 61.93 5.75 7.10 5.53 %
calculated 62.16 5.74 7.25 5.53
EXAMPLE 23
N-{1-[2-(7-Fluoro-1H-inden-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulphona-
mide and its Fumarate
[0254] The product is obtained according to the process of Example
1 using the compound of Preparation 10 as substrate instead of the
compound of Preparation 1.
[0255] Melting Point (M.K.): 215-222.degree. C.
23 Elemental microanalysis: C H N S % found 61.36 5.43 7.18 5.61 %
calculated 61.36 5.33 7.40 5.65
EXAMPLE 24
N-{1-[3-(Benzofuran-2-yl)propyl]-4-piperidyl}-N-methyl-5-isoquinolinesulph-
onamide and its Fumarate
[0256] The product is obtained according to the process of Example
1 using the compound of Preparation 11 as substrate instead of the
compound of Preparation 1.
[0257] Melting point (M.K.): 146-148.degree. C.
24 Elemental microanalysis: C H N S % found 62.23 5.86 6.99 5.23 %
calculated 62.16 5.74 7.25 5.53
EXAMPLE 25
N-{1-[3-(Benzofuran-3-yl)propyl]-4-piperidyl}-5-isoquinolinesulphonamide
[0258] The product is obtained according to the process of Example
1 using the compound of Preparation 12 as substrate instead of the
compound of Preparation 1.
[0259] Melting point (M.K.): 115-118.degree. C.
25 Elemental microanalysis: C H N S % found 66.79 6.05 9.35 7.13 %
calculated 66.20 6.27 9.28 6.91
EXAMPLE 26
N-{1-[(4-Methoxy-benzofuran-3-yl)methyl]-4-piperidyl}-5-isoquinolinesulpho-
namide and its Hemifumarate
[0260] The product is obtained according to the process of Example
1 using the compound of Preparation 13 as substrate instead of the
compound of Preparation 1.
[0261] Melting point (M.K.): 204-219.degree. C.
26 Elemental microanalysis: C H N S % found 60.82 5.44 7.95 6.00 %
calculated 61.28 5.35 8.25 6.29
EXAMPLE 27
N-{1-[(Benzofuran-3-yl)methyl]-4-piperidyl}-5-isoquinolinesulphonamide
and its Fumarate
[0262] The product is obtained according to the process of Example
1 using the compound of Preparation 14 as substrate instead of the
compound of Preparation 1.
[0263] Melting point M.K.): 203-208.degree. C.
27 Elemental microanalysis: C H N S % found 59.40 5.12 7.80 5.48 %
calculated 59.54 5.10 7.49 5.72
EXAMPLE 28
N-{1-[2-(6-Methoxy-benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquinolinesulph-
onamide and its Fumarate
[0264] The product is obtained according to the process of Example
1 using the compound of Preparation 15 as substrate instead of the
compound of Preparation 1.
[0265] Melting point (M.K.): 174-178.degree. C.
28 Elemental microanalysis: C H N S % found 59.64 5.55 7.16 5.32 %
calculated 59.89 5.37 7.22 5.51
EXAMPLE 29
1-Methoxy-N-{1-[2-(6-methoxy-benzofuran-3-yl)ethyl]-4-piperidyl}-5-isoquin-
olinesulphonamide and its Fumarate
[0266] The product is obtained according to the process of Example
1 using the compound of Preparation 15 as substrate instead of the
compound of Preparation 1, and using
1-chloroisoquinoline-5-sulphonyl chloride as reagent. The product,
obtained by chromatography over silica gel, is treated with
methanolic potassium hydroxide to yield the expected product.
[0267] Melting point (M.K.): 194-196.degree. C.
29 Elemental microanalysis: C H N S % found 58.99 5.54 6.95 5.08 %
calculated 58.91 5.44 6.87 5.24
EXAMPLE 30
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N-methyl-5--
isoquinolinesulphonamide
[0268] The product is obtained according to the process of Example
1 using the compound of Preparation 16 as substrate instead of the
compound of Preparation 1.
[0269] Melting point (M.K.): 115-120.degree. C.
30 Elemental microanalysis: C H N S % found 64.76 6.03 8.60 6.85 %
calculated 65.11 6.09 8.76 6.69
EXAMPLE 31
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N-methyl-2,-
1,3-benzothiadiazole-4-sulphonamide and its Hydrochloride
[0270] The product is obtained according to the process of Example
1 using the compound of Preparation 16 as substrate instead of the
compound of Preparation 1, and using
2,1,3-benzothiadiazole-4-sulphonyl chloride as reagent.
[0271] Melting point (M.K.): 217-220.degree. C.
31 Elemental microanalysis: C H N Cl S % found 53.10 5.41 10.64
6.80 12.37 % calculated 52.81 5.20 10.71 6.78 12.26
EXAMPLE 32
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N-methyl-2,-
1,3-benzoxadiazole-4-sulphonamide and its Fumarate
[0272] The product is obtained according to the process of Example
1 using the compound of Preparation 16 as substrate instead of the
compound of Preparation 1, and using
2,1,3-benzoxadiazole-4-sulphonyl chloride as reagent.
[0273] Melting point (M.): 216-223.degree. C.
32 Elemental microanalysis: C H N S % found 55.38 5.31 9.60 5.30 %
calculated 55.28 5.15 9.55 5.47
EXAMPLE 33
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-5-isoquinol-
inesulphonamide
[0274] The product is obtained according to the process of Example
1 using the compound of Preparation 17 as substrate instead of the
compound of Preparation 1.
[0275] Melting point (M.K.): 120-130.degree. C.
33 Elemental microanalysis: C H N S % found 64.68 5.82 9.00 6.47 %
calculated 64.50 5.85 9.03 6.89
EXAMPLE 34
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-2,1,3-benzo-
xadiazole-4-sulphonamide
[0276] The product is obtained according to the process of Example
1 using the compound of Preparation 17 as substrate instead of the
compound of Preparation 1, and using
2,1,3-benzoxadiazole-4-sulphonyl chloride as reagent.
[0277] Melting point (M.K.): 140-142.degree. C.
34 Elemental microanalysis: C H N S % found 58.11 5.36 12.09 6.87 %
calculated 57.88 5.30 12.27 7.02
EXAMPLE 35
N-({1-[2-(5-Fluoro-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N--
methyl-5-isoquinolinesulphonamide and its Dihydrochloride
[0278] The product is obtained according to the process of Example
1 using the compound of Preparation 18 as substrate instead of the
compound of Preparation 1.
[0279] Melting point (M.K.): 195-200.degree. C.
35 Elemental microanalysis: C H N Cl S % found 55.12 5.34 7.31
12.42 5.61 % calculated 54.74 5.30 7.37 12.43 5.62
EXAMPLE 36
N-({1-[2-(5-Fluoro-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-5--
isoquinolinesulphonamide and its Dihydrochloride
[0280] The process is obtained according to the process of Example
1 using the compound of Preparation 19 as substrate instead of the
compound of Preparation 1.
[0281] Melting point (M.K.): 220-230.degree. C.
36 Elemental microanalysis: C H N Cl S % found 53.50 5.14 7.49
12.79 5.92 % calculated 53.96 5.07 7.55 12.74 5.76
EXAMPLE 37
N-({1-[2-(7-Methoxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N-
-methyl-5-isoquinolinesulphonamide
[0282] The product is obtained according to the process of Example
1 using the compound of Preparation 20 as substrate instead of the
compound of Preparation 1.
[0283] Melting point (M.K.): 125-135.degree. C.
37 Elemental microanalysis: C H N S % found 63.63 6.36 8.00 6.69 %
calculated 63.63 6.13 8.25 6.29
EXAMPLE 38
N-({1-[2-(7-Methoxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N-
-methyl-2,1,3-benzoxadiazole-4-sulphonamide and its
Hemifumarate
[0284] The product is obtained according to the process of Example
1 using the compound of Preparation 20 as substrate instead of the
compound of Preparation 1, and using
2,1,3-benzoxadiazole-4-sulphonyl chloride as reagent.
[0285] Melting point (M.K.): 175-178.degree. C.
38 Elemental microanalysis: C H N S % found 55.73 5.43 9.96 5.79 %
calculated 55.90 5.41 10.03 5.74
EXAMPLE 39
N-({1-[2-(5-Methoxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-5-
-isoquinolinesulphonamide
[0286] The product is obtained according to the process of Example
1 using the compound of Preparation 21 as substrate instead of the
compound of Preparation 1.
[0287] Melting point (M.K.): 95-105.degree. C.
EXAMPLE 40
N-({1-[2-(5-Methoxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-2-
,1,3-benzoxadiazole-4-sulphonamide and its Fumarate
[0288] The product is obtained according to the process of Example
9 using the compound of Preparation 21 as substrate instead of the
compound of Preparation 1.
[0289] Melting point (M.K.): 204-208.degree. C.
39 Elemental microanalysis: C H N S % found 54.04 5.15 9.02 5.14 %
calculated 53.81 5.02 9.30 5.32
EXAMPLE 41
N-({1-[2-(1H-Inden-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-5-isoquinolin-
esulphonamide and its Sesquifumarate
[0290] The product is obtained according to the process of Example
1 using the compound of Preparation 22 as substrate instead of the
compound of Preparation 1.
[0291] Melting point (M.K.): 200-210.degree. C.
40 Elemental microanalysis: C H N S % found 59.92 5.74 6.53 4.81 %
calculated 60.27 5.53 6.59 5.03
EXAMPLE 42
N-({1-[2-(5-Methoxy-benzofuran-3-ylethyl]-4-hydroxy-4-piperidyl}methyl)-N--
methyl-5-isoquinolinesulphonamide and its Fumarate
[0292] The product is obtained according to the process of Example
1 using the compound of Preparation 23 as substrate instead of the
compound of Preparation 1.
[0293] Melting point (M.K.): 160-165.degree. C.
41 Elemental microanalysis: C H N S % found 59.23 5.67 6.65 4.86 %
calculated 59.51 5.64 6.72 5.12
EXAMPLE 43
N-({1-[2-(7-Methoxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-5-
-isoquinolinesulphonamide and its Hemifumarate
[0294] The product is obtained according to the process of Example
1 using the compound of Preparation 24 as substrate instead of the
compound of Preparation 1.
[0295] Melting point (M.K.): 160-165.degree. C.
42 Elemental microanalysis: C H N S % found 60.97 5.68 7.54 5.79 %
calculated 60.75 5.64 7.59 5.79
EXAMPLE 44
N-({1-[2-(1H-Inden-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N-methyl-5-is-
oquinolinesulphonamide
[0296] The product is obtained according to the process of Example
1 using the compound of Preparation 25 as substrate instead of the
compound of Preparation 1.
[0297] Melting point (M.K.): 160-162.degree. C.
43 Elemental microanalysis: C H N S % found 67.99 6.61 8.70 6.68 %
calculated 67.90 6.54 8.80 6.71
EXAMPLE 45
N-({2-[2-(Benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}ethyl)-5-isoquinoli-
nesulphonamide
[0298] The product is obtained according to the process of Example
1 using the compound of Preparation 26 as substrate instead of the
compound of Preparation 1.
[0299] Melting point (M.K.): 174-176.degree. C.
44 Elemental microanalysis: C H N S % found 65.09 6.19 8.81 6.55 %
calculated 65.11 6.10 8.76 6.49
EXAMPLE 46
N-({1-[2-(5-Hydroxy-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N-
-methyl-5-isoquinolinesulphonamide and its Potassium Salt
[0300] 6.46 ml of a molar solution of boron tribromide in
dichloromethane are added dropwise at -15.degree. C. to a solution
of 1.65 g of the product of Example 42 in 14 ml of chloroform.
After 12 hours at room temperature, the reaction mixture is
hydrolysed and rendered basic with sodium hydrogen carbonate. The
precipitate that forms is filtered off and then chromatographed
over silica gel (dichloromethane/EtOH/NH.sub.4OH: 90/10/1). The
expected product is thus isolated and converted to its potassium
salt with methanolic potassium hydroxide.
[0301] Melting point (M.K.): 185-190.degree. C.
45 Elemental microanalysis: C H N S % found 58.03 5.20 7.06 5.52 %
calculated 58.51 5.29 7.87 6.01
EXAMPLE 47
N-{1-[2-(Benzofuran-3-yl)-2-hydroxyethyl]-4-piperidyl}-5-isoquinolinesulph-
onamide
[0302] The product is obtained according to the process of Example
I using the compound of Preparation 28 as substrate instead of the
compound of Preparation 1.
[0303] Melting Point (M.K.): 160-165.degree. C.
46 Elemental microanalysis: C H N S % found 63.46 5.65 9.20 7.21 %
calculated 63.84 5.58 9.31 7.10
EXAMPLE 48
N-{1-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-5-isoquinolinesulp-
honamide and its Fumarate
[0304] The product is obtained according to the process of Example
1 using the compound of Preparation 29 as substrate instead of the
compound of Preparation 1.
[0305] Melting Point (M.K.): 102-109.degree. C.
47 Elemental microanalysis: C H N S % found 58.94 5.42 6.62 5.06 %
calculated 59.24 5.32 6.98 5.32
EXAMPLE 49
N-{1-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-2-(3-pyridyl)-benz-
enesulphonamide and its Fumarate
[0306] Step A:
N-{1-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-2-b-
romobenzenesulphonamide
[0307] The product is obtained according to the process of Example
1 using the compound of Preparation 29 as substrate instead of the
compound of Preparation 1, and using 2-bromobenzenesulphonic acid
chloride as reagent.
[0308] Melting point (M.K.): 108-110.degree. C.
[0309] Step B:
N-{1-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-2-(-
3-pyridyl)benzenesulphonamide and its Fumarate
[0310] 20.3 ml of a 2M sodium carbonate solution are added at room
temperature over the course of 2 hours to a solution of 3 g of the
product obtained in Step A and 280 mg of
tetrakis-(triphenylphosphine)pal- ladium in 50 ml of toluene, and
then, under argon, 1.3 g of diethylboran-3-ylpyridine in 25 ml of
ethanol are added thereto. The reaction mixture is then refluxed
for 2 days, and subsequently diluted with water, extracted with
ethyl acetate, dried over MgSO.sub.4 and concentrated under reduced
pressure. Chromatography of the residue over silica gel enables the
expected product to be isolated.
[0311] Melting point (M.K.): 94-103.degree. C.
48 Elemental microanalysis: C H N S % found 61.27 5.58 6.79 5.06 %
calculated 61.27 5.47 6.91 5.28
EXAMPLE 50
N-{1-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-2-[3-aminophenyl]--
benzenesulphonamide
[0312] The product is obtained according to the process of Example
49 using 3-aminophenylboronic acid as reagent in Step B.
[0313] Melting point (M.K.): 68-70.degree. C.
49 Elemental microanalysis: C H N S % found 66.39 6.31 8.07 5.99 %
calculated 66.51 6.18 8.11 6.34
EXAMPLE 51
N-{1-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-3-[3-aminophenyl]--
benzenesulphonamide
[0314] The product is obtained according to the process of Example
49 using 3-bromobenzenesulphonic acid as reagent in Step A and
using 3-aminophenylboronic acid as reagent in Step B.
[0315] Melting point (M.K.): 68-78.degree. C.
50 Elemental microanalysis: C H N S % found 66.27 6.43 7.98 6.38 %
calculated 66.51 6.18 8.31 6.34
EXAMPLE 52
N-{1-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-3-(3-pyridyl)-benz-
enesulphonamide
[0316] The product is obtained according to the process of Example
49, Steps A to B, using 3-bromobenzenesulphonic acid as reagent in
Step A.
[0317] Melting point (M.K.): 55-63.degree. C.
51 Elemental microanalysis: C H N S % found 66.02 6.03 8.41 6.19 %
calculated 65.97 5.95 8.55 6.52
EXAMPLE 53
N-{1-[3-(Benzofuran-3-yl)-2-fuoropropyl]-4-piperidyl}-5-isoquinolinesulpho-
namide and its Difumarate
[0318] The product is obtained according to the process of Example
1 using the product of Preparation 30 as substrate instead of the
product of Preparation 1.
[0319] Melting point (M.K.): 197-204.degree. C.
52 Elemental microanalysis: C H N S % found 56.76 4.86 6.00 4.50 %
calculated 56.15 4.86 5.81 4.43
EXAMPLE 54
N-{1-[2-(Benzofuran-3-yl)-1-(fluoromethyl)ethyl]-4-piperidyl}-5-isoquinoli-
nesulphonamide and its Fumarate
[0320] The product is obtained according to the process of Example
1 using the product of Preparation 31 as substrate instead of the
product of Preparation 1.
[0321] Melting point (M.K.): 143-153.degree. C.
53 Elemental microanalysis: C H N S % found 59.72 5.48 6.82 5.00 %
calculated 59.68 5.18 7.20 5.49
EXAMPLE 55
N-{1-[2-(Benzofuran-3-yl)-ethyl]-4-piperidyl}-2-(3-pyridyl)benzenesulphona-
mide and its Fumarate
[0322] Step A:
N-{(1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-2-bromobenzen-
esulphonamide
[0323] The product is obtained according to the process of Step A
of Example 49 using the product of Preparation 7 as substrate.
[0324] Melting point (K): 105-108.degree. C.
[0325] Step B:
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-2-bromo-N-[(2--
methoxyethoxy)methyl]benzenesulphonamide
[0326] 1.9 g of 60% sodium hydride in oil are added, at room
temperature and under argon, to a solution of 15.8 g of the product
obtained in Step A in 180 ml of tetrahydrofuran. After 30 minutes'
stirring, 5 ml of 2-methoxyethoxymethane chloride are added. After
5 hours at room temperature, the reaction mixture is concentrated
under reduced pressure, taken up in dichloromethane, washed with
water, dried and concentrated under reduced pressure to enable the
expected product to be obtained.
[0327] Step C:
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-N-[(2-methoxye-
thoxy)-methyl]-2-(3-pyridyl)benzenesulphonamide
[0328] The product is obtained according to the process of Step B
of Example 49 using the product obtained in the preceding Step B as
substrate.
[0329] Step D:
N-{1-[2-(Benzofuran-3-yl)-ethyl]-4-piperidyl}-2-(3-pyridyl)-
benzenesulphonamide and its Fumarate
[0330] A solution of 1.7 g of the product obtained in Step C in 50
ml of ethanol and 50 ml of 6N hydrochloric acid is refluxed for 2
hours and then left for 12 hours at room temperature. The reaction
mixture is then evaporated, diluted with water, adjusted to pH=7 by
the addition of an aqueous 10% sodium hydrogen carbonate solution,
extracted with ethyl acetate, dried and evaporated to yield the
expected product, which is converted to its fumarate.
[0331] Melting point (M.K.): 189-191.degree. C.
54 Elemental microanalysis: C H N S % found 62.34 5.52 7.26 5.46 %
calculated 62.38 5.41 7.27 5.55
EXAMPLE 56
N-{1-[2-(Benzofuran-3-yl)-ethyl]-4-piperidyl}-2-[3-aminophenyl]benzenesulp-
honamide and its Fumarate
[0332] Step A:
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-N-[(2-methoxye-
thoxy)-methyl]-2-(3-aminophenyl)benzenesulphonamide
[0333] The product is obtained according to the process of Example
50 using the product obtained in Step B of Example 55 as
substrate.
[0334] Step B:
N-{1-[2-(Benzofuran-3-yl)-ethyl]-4-piperidyl}-2-[3-aminophe-
nyl]benzenesulphonamide and its Fumarate
[0335] The product is obtained according to the process of Step D
of Example 55 using the product obtained in the preceding Step A as
substrate.
[0336] Melting point (M.K.): 97-102.degree. C.
55 Elemental microanalysis: C H N S % found 62.71 5.89 6.71 5.02 %
calculated 62.93 5.62 7.10 5.42
EXAMPLE 57
N-{1-[2-(Benzofuran-3-yl)-ethyl]-4-piperidyl}-3-(3-pyridyl)benzenesulphona-
mide and its Fumarate
[0337] The product is obtained according to, in succession, the
process of Step A of Example 49 using the product of Preparation 7
as substrate and 3-bromobenzenesulphonyl chloride as reagent, then
according to the process of Step B of Example 55, then according to
the process of Step B of Example 49 and finally according to the
process of Step D of Example 55.
[0338] Melting point (M.K.): 191-194.degree. C.
56 Elemental microanalysis: C H N S % found 62.15 5.51 7.13 5.31 %
calculated 62.38 5.41 7.27 5.55
EXAMPLE 58
N-{1-[2-(Benzofuran-3-yl)-ethyl]-4-piperidyl}-3-[3-aminophenyl]-benzenesul-
phonamide and its Dihydrochloride
[0339] The product is obtained, in succession, according to the
process of Example 50 using the product obtained in the second
synthesis Step of Example 57 as substrate, and then according to
the process of Step D of Example 55. The resulting product is
converted into its dihydrochloride with a 2.5N solution of ethereal
hydrogen chloride.
[0340] Melting point (M.K.): 155-167.degree. C.
57 Elemental microanalysis: C H N S Cl % found 59.18 5.82 7.37 5.64
12.35 % calculated 59.12 5.70 7.66 5.85 12.93
EXAMPLE 59
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-methyl-1,2,3,4-tetr-
ahydro-5-isoquinolinesulphonamide and its Dihydrochloride
[0341] 13.3 g of the product of Example 1 and 1.3 g of platinum
oxide in 500 ml of acetic acid are hydrogenated under 5 bars at
room temperature for 4 hours. The reaction mixture is then
evaporated, taken up in water and ethyl acetate, rendered basic
with 1N sodium hydroxide solution, decanted, washed, dried and
concentrated under reduced pressure. Chromatography over silica gel
enables the expected product to be isolated.
[0342] Melting point (M.K.): 162-174.degree. C.
58 Elemental microanalysis: C H N S Cl % found 57.77 6.85 7.77 5.29
13.26 % calculated 57.77 6.53 7.77 5.93 13.12
EXAMPLE 60
2-Acetyl-N-({1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-methyl-1,2-
,3,4-tetrahydro-5-isoquinolinesulphonamide and its
Hydrochloride
[0343] 2.2 g of the product obtained in Example 1 and 0.1 g of
platinum oxide in 120 ml of acetic acid and 10 ml of acetic
anhydride are hydrogenated under 5 bars, at room temperature, for
12 hours. The expected product is isolated by chromatography over
silica gel (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/210.2).
[0344] Melting point (M.K.): 108-110.degree. C.
59 Elemental microanalysis: C H N S Cl % found 61.48 6.72 7.71 5.82
6.49 % calculated 61.58 6.64 7.69 5.87 6.49
EXAMPLE 61
5-{[({1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]sulph-
onyl}-N-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide and its
Fumarate
[0345] 2 g of the product of Example 59 in 4 ml of dichloromethane
are added, at 10.degree. C., to a solution of 0.25 g of methyl
isocyanate in 1 ml of dichloromethane. After 45 minutes, the
reaction mixture is washed, decanted, dried and evaporated.
Chromatography over silica gel (dichloromethane/methanol: 95/5)
enables the expected product to be isolated.
[0346] Melting point (M.K.): 107-116.degree. C.
60 Elemental microanalysis: C H N S % found 59.82 6.40 8.57 4.95 %
calculated 59.98 6.29 8.74 5.00
EXAMPLE 62
Ethyl
5-{[({1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino-
]-sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate and its
Fumarate
[0347] 0.41 ml of ethyl chloroformate is added to a solution,
cooled to 0.degree. C., of 2 g of the product of Example 59 and
0.43 g of triethylamine in 7 ml of dichloromethane. After 2 hours
at room temperature, the reaction mixture is diluted with water,
decanted, dried and evaporated. Chromatography over silica gel
(dichloromethane/methanol: 98/2) enables the expected product to be
isolated.
[0348] Melting point (M.K.): 109-113.degree. C.
61 Elemental microanalysis: C H N S % found 60.11 6.43 6.28 4.92 %
calculated 60.44 6.30 6.41 4.89
EXAMPLE 63
5-{[({1-[2-(Benzofuran-3-yl)ethyl]-4-piperdyl}methyl)-(methyl)amino]sulpho-
nyl}-3,4-dihydro-2(1H)-isoquinolinecarboxamide and its Fumarate
[0349] A solution of 1 g of the product of Example 59 in 10 ml of
1N hydrochloric acid and 40 ml of water is adjusted to pH=3 by the
addition of 20% sodium hydroxide solution, and then a solution of
0.187 g of potassium isocyanate in 0.5 ml of water is added at room
temperature. After 20 minutes, the pH of the mixture has increased
to pH=6 and is returned to pH=3 by the addition of 1N hydrochloric
acid. After 3 hours' reaction, the preceding operation is repeated.
The reaction mixture is then heated for 3 hours at 50.degree. C.,
and then 0.187 g of potassium isocyanate in 0.5 ml of water is
added again, and the pH of the mixture is maintained at pH=3. After
2 hours, the reaction mixture is rendered basic with sodium
hydroxide solution and extracted with dichloromethane. The expected
product is isolated by customary treatment.
[0350] Melting point: 105-113.degree. C.
62 Elemental microanalysis: C H N S % found 59.41 6.11 8.94 5.12 %
calculated 59.16 5.95 8.36 4.91
EXAMPLE 64
5-{[({1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]sulph-
onyl}-N,N-dimethyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide and
its Fumarate
[0351] 0.22 ml of N,N-diethylcarbamoyl chloride is added to a
solution, cooled to 0.degree. C., of 1 g of the product of Example
59, 0.24 g of triethylamine and 15 ml of dichloromethane. After 5
hours' reaction at room temperature, followed by 3 hours at reflux,
0.33 ml of triethylamine and 0.22 ml of N,N-diethylcarbamoyl
chloride are added, and refluxing is maintained for 1 hour. After
conventional treatment, the evaporation residue is chromatographed
over silica gel (dichloromethane/methanol) enabling the expected
product to be isolated.
[0352] Melting point (M.K.): 115-120.degree. C.
EXAMPLE 65
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-methyl-2-(methylsul-
phonyl)-1,2,3,4-tetrahydro-5-isoquinolinesulphonamide and its
Hydrochloride
[0353] 0.27 ml of methanesulphonic acid chloride is added to a
solution, cooled to 0.degree. C., of 1.5 g of the product of
Example 59 and 0.36 g of triethylamine in 15 ml of dichloromethane.
After 10 minutes' reaction, the reaction mixture is treated in
conventional manner, enabling the expected product to be obtained,
which is converted to its hydrochloride with an ethereal hydrogen
chloride solution.
[0354] Melting point (M.K.): 223-233.degree. C.
EXAMPLE 66
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-methyl-2-[(trifluor-
omethyl)sulphonyl]-1,2,3,4-tetrahydro-5-isoquinolinesulphonamide
and its Fumarate
[0355] 0.36 ml of trifluoromethanesulphonic acid anhydride is added
to a solution, cooled to -5.degree. C., of 1 g of the product of
Example 59 in 20 ml of dichloromethane, followed, after 1 hour, by
0.36 g of triethylamine and 0.36 ml of trifluoromethanesulphonic
acid anhydride. After 12 hours' reaction at room temperature and
customary treatment, chromatography over silica gel
(dichloromethane/methanol: 98/2) enables the expected product to be
isolated.
[0356] Melting point (M.K.): 198-200.degree. C.
63 Elemental microanalysis: C H N S % found 52.77 5.16 5.82 8.99 %
calculated 52.02 5.07 5.87 8.96
EXAMPLE 67
Methyl
5-{[({1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amin-
o]-sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate and its
Fumarate
[0357] The product is obtained according to the process of Example
62 using methyl chloroformate as reagent.
[0358] Melting point (M.K.): 110-115.degree. C.
64 Elemental microanalysis: C H N S % found 59.39 5.96 6.46 4.73 %
calculated 59.89 6.13 6.55 5.00
EXAMPLE 68
Isopropyl
5-{[({1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)a-
mino]-sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate and its
Fumarate
[0359] The product is obtained according to the process of Example
62 using isopropyl chloroformate as reagent.
[0360] Melting point (M.K.): 175-180.degree. C.
65 Elemental microanalysis: C H N S % found 61.17 6.51 6.36 4.49 %
calculated 60.97 6.47 6.27 4.79
EXAMPLE 69
Tert-butyl
5-{[({1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)-
amino]-sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate and its
Fumarate
[0361] The product is obtained according to the process of Example
62 using tert-butyl chloroformate as reagent.
[0362] Melting point (M.K.): 71-175.degree. C.
66 Elemental microanalysis: C H N S % found 61.40 6.75 6.10 4.54 %
calculated 61.48 6.63 6.14 4.69
EXAMPLE 70
N-({1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-1,2,3,4-tetrahydro-5--
isoquinolinesulphonamide and its Dihydrochloride
[0363] A solution of 6.6 g of the compound of Example 4, 150 ml of
methanol, 3 ml of concentrated hydrochloric acid and 0.7 g of
PtO.sub.2 is hydrogenated under 5 bars for 5 hours. After
conventional treatment, the resulting residue is taken up in
methanol and the dihydrochloride is precipitated from a solution of
methanolic hydrogen chloride.
[0364] Melting point (M.K.): 125-135.degree. C.
67 Elemental microanalysis: C H N S Cl % found 57.01 6.39 7.78 5.78
13.39 % calculated 57.03 6.32 7.98 6.09 13.47
EXAMPLE 71
2-Acetyl-N-({1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-1,2,3,4-tetr-
ahydro-5-isoquinolinesulphonamide and its Fumarate
[0365] 0.32 ml of acetic acid chloride is added to a solution,
cooled to 0.degree. C., of 2 g of the product of Example 70 and 2.8
ml of diisopropylethylamine. After 10 minutes' stirring at room
temperature, the reaction mixture is treated in conventional
manner. Chromatography over silica gel (dichloromethane/methanol:
95/5) enables the expected product to be isolated.
[0366] Melting point (M.K.): 136-140.degree. C.
68 Elemental microanalysis: C H N S % found 60.96 6.15 6.86 5.02 %
calculated 60.87 6.10 6.87 5.24
EXAMPLE 72
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-N-methyl-1,2,3,4-tetrahydro-5-
-isoquinolinesulphonamide
[0367] The product is obtained according to the process of Example
70 using the product of Example 7 as substrate.
[0368] Melting point (M.K.): 134-136.degree. C.
69 Elemental microanalysis: C H N S % found 66.16 6.84 9.31 6.83 %
calculated 66.20 6.89 9.26 7.07
EXAMPLE 73
2-Acetyl-N-{1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-N-methyl-1,2,3,4-tet-
rahydro-5-isoquinolinesulphonamide
[0369] The product is obtained according to the process of Example
71 using the product of Example 72 as substrate.
[0370] Melting point (M.K.): 118-120.degree. C.
70 Elemental microanalysis: C H N S % found 65.31 6.70 8.31 6.14 %
calculated 65.43 6.71 8.48 6.47
EXAMPLE 74
2-Trifluoroacetyl-N-({1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-m-
ethyl-1,2,3,4-tetrahydro-5-isoquinolinesulphonamide and its
Fumarate
[0371] The product is obtained according to the process of Example
66 using the product of Example 72 as substrate, and using
trifluoromethylacetic acid anhydride as reagent.
[0372] Melting point (M.K.): 102-106.degree. C.
71 Elemental microanalysis: C H N S % found 56.71 5.32 6.27 4.59 %
calculated 56.55 5.34 6.18 4.72
EXAMPLE 75
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-1,2,3,4-tetrahydro-5-isoquino-
linesulphonamide and its Hemifumarate
[0373] The product is obtained according to the process of Example
70 using the product of Example 8 as substrate.
[0374] Melting point (M.K.): 286-288.degree. C.
72 Elemental microanalysis: C H N S % found 62.73 6.36 8.28 6.33 %
calculated 62.76 6.28 8.44 6.44
EXAMPLE 76
2-Acetyl-N-{1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-1,2,3,4-tetrahydro-5-
-isoquinolinesulphonamide
[0375] The product is obtained according to the process of Example
71 using the product of Example 75 as substrate.
[0376] Melting point (M.K.): 70-80.degree. C.
73 Elemental microanalysis: C H N S % found 64.87 6.20 8.65 6.40 %
calculated 64.84 6.49 8.72 6.66
EXAMPLE 77
2-Ethyl-N-({1-[2-benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-N-methyl-1,2,3-
,4-tetrahydro-5-isoquinolinesulphonamide and its
Camphosulphonate
[0377] A solution of 1 g of the product of Example 60 in 60 ml of
tetrahydrofuran is added to a suspension of 0.15 g of lithium
aluminium hydride in 25 ml of tetrahydrofuran at reflux. After 1
hour at reflux followed by cooling, the reaction mixture is
hydrolysed with 0.1 ml of water, 0.08 ml of 20% sodium hydroxide
solution and 0.37 ml of water. After conventional treatment,
chromatography over silica gel (dichloromethane/methanol 90/10)
enables the expected product to be isolated.
[0378] Melting point (M.K.): 70-80.degree. C.
EXAMPLE 78
Methyl
5-{[({1-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(me-
thyl)amino]sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate and
its Fumarate
[0379] Step A:
N-[(1-Benzyl-4-piperidyl)methyl]-N-methyl-5-isoquinolinesul-
phonamide
[0380] The product is obtained according to the process of Example
1 using N-[(1-benzyl-4-piperidyl)methyl]-N-methylamine instead of
the product of Preparation 1.
[0381] Step B:
N-[(1-Benzyl-4-piperidyl)methyl]-N-methyl-1,2,3,4-tetrahydr-
o-5-isoquinolinesulphonamide
[0382] The product is obtained according to the process of Example
70 using the product obtained in the preceding Step A.
[0383] Step C: Methyl
5-{[[(1-benzyl-4-piperidyl)methyl](methyl)amino]sulp-
honyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate
[0384] The product is obtained according to the process of Example
60 using the product obtained in the preceding Step B, and using
methyl chloroformate as reagent.
[0385] Step D: Methyl
5-{[[(4-piperidyl)methyl](methyl)amino]sulphonyl}-3,-
4-dihydro-2(1H)-isoquinolinecarboxylate
[0386] A mixture of 5.6 g of the product obtained in Step C, 3.7 g
of ammonium formate and 0.56 g of 10% Pd/C in 120 ml of methanol is
refluxed for 3 hours, then filtered over Celite and evaporated to
dryness, enabling the expected product to be isolated.
[0387] Step E: Methyl
5-{[({1-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-piperi-
dyl}-methyl)-(methyl)amino]sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarbox-
ylate and its Fumarate
[0388] A mixture of 2 g of the product obtained in Step D, 1.26 g
of 2-(5-fluorobenzofuran-3-yl)-1-bromoethane, 1.4 g of potassium
carbonate and 30 ml of acetonitrile is heated at 50.degree. C. for
2 hours. After evaporation to dryness, the residue is taken up in
water and ethyl acetate and subjected to customary treatment.
Chromatography over silica gel (ethyl acetate) enables the expected
product to be isolated, which is converted into its fumarate.
[0389] Melting point (M.K.): 110-115.degree. C.
74 Elemental microanalysis: C H N S % found 58.31 5.65 6.35 4.58 %
calculated 58.26 5.81 6.37 4.86
EXAMPLE 79
Ethyl
5-{[({1-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(met-
hyl)-amino]sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate and
its Fumarate
[0390] The product is obtained according to the process of Example
78 in Steps A to E, using ethyl chloroformate as reagent in Step
C.
[0391] Melting point (M.K.): 115-120.degree. C.
75 Elemental microanalysis: C H N S % found 58.79 6.13 6.12 4.51 %
calculated 58.82 6.00 6.24 4.76
EXAMPLE 80
Isopropyl
5-{[({1-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-piperidyl}methyl)--
(methyl)amino]sulphonyl}-3,4-dihydro-2-(R)-isoquinolinecarboxylate
and its Fumarate
[0392] The product is obtained according to the process of Example
78, Steps A to E, using isopropyl chloroformate as reagent in Step
C.
[0393] Melting point (M.K.): 135-145.degree. C.
76 Elemental microanalysis: C H N S % found 59.30 6.06 6.14 4.47 %
calculated 59.38 6.15 6.11 4.66
EXAMPLE 81
Ethyl
5-{[({1-[2-(benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}ethyl)amino-
]-sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate and its
Fumarate
[0394] The product is obtained according to the process of Example
78, Steps A to E, using 4-aminomethyl-1-benzylpiperidin-4-ol as
substrate in Step A, ethyl chloroformate in Step C, and
2-(benzofuran-3-yl)ethanol mesylate in Step E.
[0395] Melting point (M.K.): 180-185.degree. C.
77 Elemental microanalysis: C H N S % found 58.17 5.99 6.30 4.56 %
calculated 58.44 5.98 6.39 4.87
EXAMPLE 82
Ethyl
5-{[({1-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}-m-
ethyl)amino]sulphonyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate
and its Fumarate
[0396] The product is obtained according to the process of Example
81, using 2-(5-fluorobenzofuran-3-yl)ethanol mesylate as reagent in
Step E.
[0397] Melting point (M.K.): 165-175.degree. C.
78 Elemental microanalysis: C H N S % found 56.82 5.69 6.13 4.40 %
calculated 56.88 5.67 6.22 4.75
EXAMPLE 83
2-Acetyl-N-{(1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl-4-hydroxy)methyl}-1,-
2,3,4-tetrahydro-5-isoquinolinesulphonamide and its Mesylate
[0398] The product is obtained according to the process of Example
81, using acetyl chloride instead of ethyl chloroformate as reagent
in Step C.
[0399] Melting point (M.K.): 201-206.degree. C.
79 Elemental microanalysis: C H N S % found 55.20 6.17 6.73 10.91 %
calculated 55.34 6.14 6.91 10.55
EXAMPLE 84
Ethyl
5-{[({1-[2-(benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-(me-
thyl)amino]sulphonyl}-3,4-dihydro-2-(1H)-isoquinolinecarboxylate
[0400] The product is obtained according to the process of Example
83, using 1-benzyl-4-(methylamino)methyl-piperidin-4-ol as
substrate in Step A.
[0401] Melting point (M.K.): 125-130.degree. C.
80 Elemental microanalysis: C H N S % found 62.76 6.76 7.56 5.90 %
calculated 62.68 6.71 8.56 5.77
EXAMPLE 85
5-{[{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}amino]sulphonyl}-3,4-dihydro-
-2(1H)-isoquinolinecarboxamide
[0402] The product is obtained according to the process of Example
63 using the compound of Example 75 as substrate.
[0403] Melting point (M.K.): 198-201.degree. C.
EXAMPLE 86
N-{1-[2-(1H-Inden-3-yl)ethyl]-4-piperidyl}-N-methyl-1,2,3,4-tetrahydro-5-i-
soquinolinesulphonamide
[0404] The product is obtained according to the process of Example
59 using the compound of Example 5 as substrate.
[0405] Melting point (M.K.): 210-214.degree. C.
EXAMPLE 87
N-{1-[3-(Benzofuran-3-yl)-2-hydroxypropyl]-4-piperidyl}-3-[2-aminophenyl]--
benzenesulphonamide and its Dihydrochloride
[0406] The product is obtained according to the process of Example
49 using 3-bromobenzenesulphonic acid in Step A and using
2-aminophenylboronic acid in Step B. The dihydrochloride is
obtained by the action of a solution of ethereal hydrogen
chloride.
[0407] Melting point (M.K.): 145-148.degree. C.
EXAMPLE 88
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-4-bromo-5-isoquinolinesulphon-
amide and its Fumarate
[0408] The product is obtained according to the process of Example
1 using the compound of Preparation 7 as substrate instead of the
compound of Preparation 1, and using the compound of Preparation 33
instead of 5-isoquinolinesulphonyl chloride hydrochloride. The
resulting product is converted to its fumarate.
[0409] Melting Point (M.K.): 243-236.degree. C.
EXAMPLE 89
N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-4fluoro-5-isoquinolinesulphon-
amide and its Fumarate
[0410] The product is obtained according to the process of Example
1 using the compound of Preparation 7 as substrate instead of the
compound of Preparation 1, and using the compound of Preparation 34
instead of 5-isoquinolinesulphonyl chloride hydrochloride. The
resulting product is converted to its fumarate.
[0411] Melting point (M.K.): 219-221.degree. C.
Pharmacological Studies of the Compounds of the Invention
[0412] Under standard in vitro conditions, relaxation of aortic
rings caused by acetylcholine (ACh), which relaxation is totally
dependent upon the presence of endothelium, reflects the production
of NO (stimulated by ACh), which by diffusing to smooth muscle
cells brings about arterial relaxation (Nature, 1980, 288,
373).
[0413] The compounds of the invention were tested in respect of two
models involving two different mechanisms implicated in the
endothelial dysfunction observed in pathology:
[0414] the first model consists of inducing inhibition of the
relaxation due to ACh by blocking the enzymatic activity
(endothelial NOS) responsible for the production of NO.
[0415] the second model consists of inducing oxidative stress in
vitro using an enzymatic system that generates O.sub.2.sup.-
(xanthine oxidase --XO and hypoxanthine--Hypo).
EXAMPLE 90
[0416] Vascular Protective Effects with Respect to Endothelial
Dysfunction Induced by an Inhibitor of NOS
[0417] The thoracic aorta of a Wistar rat (325-375 g),
anaesthetised by the intraperitoneal route using sodium
pentobarbital (30 mg/kg), is removed and dissected into rings of 3
mm in length. Each ring is suspended from an isometric tension
sensor connected to a recording system and the initial tension
applied is 2.5 g. The physiological solution used, which is
thermostatically maintained at 37.degree. C., and oxygenated (95%
O.sub.2+5% CO.sub.2), comprises (in mM): NaCl 112.0, KCl 5.0,
CaCl.sub.2 2.5, KH.sub.2PO.sub.4 1.0, MgSO.sub.4 1.2, NaHCO.sub.3
25.0, glucose 11.5, Ca-EDTA 0.016.
[0418] After a 90-minute stabilisation period, the preparations are
contracted using phenylephrine (PHE 10.sup.-6 M) and relaxed by
adding 10.sup.-5 M of acetylcholine in order to verify the 10
integrity of the endothelial layer. If that is confirmed, the
preparations are rinsed and a concentration of the test product (or
its solvent) is added to the medium, followed by 3.10.sup.-7 M of
N.sup.G-nitro-L-arginine (LNA). The preparations are again
contracted using phenylephrine and, after 30 minutes, the
relaxations due to acetylcholine (ACh--10.sup.-8M to 10.sup.-5 M)
are assessed in the presence of indomethacin (10.sup.-5M).
[0419] The relaxation values are expressed as a percentage relative
to the maximum contraction caused by PHE. The protective effects of
the compounds with respect to the endothelial dysfunction
correspond to the difference between the percentages of maximum
relaxation observed in the presence or absence of product.
[0420] By way of example, the compound of Example 8 at
3.times.10.sup.-9 M inhibits the endothelial dysfunction induced by
LNA by 23%.
EXAMPLE 91
[0421] Vascular Protective Effects with Respect to Endothelial
Dysfunction Induced by a System Generating O.sub.2.sup.-
[0422] This protocol, carried out on aortic rings of New Zealand
rabbits (2.5-3 kg) is comparable to the previous protocol except
for the following points: the initial tension applied is 5 g and
the combination XO (3 mU/ml)--Hypo (10.sup.-4 M) is used instead of
the LNA.
[0423] By way of example, the compound of Example 8 at
3.times.10.sup.-9 M inhibits the endothelial dysfunction induced by
the XO-Hypo combination by 28.3%.
EXAMPLE 92
[0424] Involvement of the NO Route in the Vascular Protective
Effects Detected: Assessment of Aortic Production of cGMP
[0425] By diffusing to the smooth muscle cells, the NO produced by
the endothelial cells activates soluble guanylate cyclase, which
brings about an increase in cyclic GMP which is responsible for
relaxation.
[0426] The level of that mediator in rat aortic rings was therefore
determined in order to demonstrate that the protective effects of
the compounds with respect to endothelial dysfunction are mediated
by an increase in the availability of NO.
[0427] The rat aortic rings are prepared as previously. Assessment
is made of the effects of a 30-minute incubation of the compounds
of the invention at different concentrations on the production of
cGMP stimulated by ACh (10.sup.-5 M--1 minute) in the presence of
LNA (3.times.10.sup.-6 M). The experiments are carried out in the
presence of isobutylmethylxanthine (10.sup.-5 M) in order to avoid
degradation of the cGMP by phosphodiesterases. The rings are frozen
in liquid nitrogen and maintained at -80.degree. C. until the assay
is carried out. The cGMP content is assessed by radioimmunoassay
and expressed in relation to the amount of protein contained in the
tissue (assay by the Bradford method).
[0428] By way of example, the compound of Example 8 at
3.times.10.sup.-9 M increases the production of cGMP stimulated by
ACh in the presence of LNA by 142.7%
EXAMPLE 93
[0429] Pharmaceutical composition--tablet
[0430] Formulation for the preparation of 1000 tablets containing a
dose of 10 mg
81 Compound of Example 8 10 g Hydroxypropylcellulose 2 g
Polyvinylpyrrolidone 2 g Wheat starch 10 g Lactose 100 g Magnesium
stearate 3 g
* * * * *