U.S. patent application number 11/725855 was filed with the patent office on 2007-08-16 for isoquinoline compounds.
This patent application is currently assigned to LES LABORATOIRES SERVIER. Invention is credited to Valerie Audinot, Caroline Bennejean, Jean Albert Boutin, Philippe Delagrange, Anne Gasnereau, Daniel Lesieur, Sophie Poissonnier-Durieux, Pierre Renard, Valerie Wallez, Said Yous.
Application Number | 20070191328 11/725855 |
Document ID | / |
Family ID | 32865399 |
Filed Date | 2007-08-16 |
United States Patent
Application |
20070191328 |
Kind Code |
A1 |
Poissonnier-Durieux; Sophie ;
et al. |
August 16, 2007 |
Isoquinoline compounds
Abstract
The invention relatests compound of formula (I): ##STR1##
wherein: n is 1, 2 or 3, A represents a group ##STR2## or a group
##STR3## X represents N or NR.sup.1, R.sup.2 represents an alkoxy,
cycloalkyloxy or cycloalkylalkyloxy group. and medicinal products
containing the same which are useful in treading or in preventing
melatoninergic disorder.
Inventors: |
Poissonnier-Durieux; Sophie;
(Rainneville, FR) ; Wallez; Valerie; (Wervicq-Sud,
FR) ; Gasnereau; Anne; (Lille, FR) ; Yous;
Said; (Loos, FR) ; Lesieur; Daniel;
(Gondecourt, FR) ; Delagrange; Philippe; (Issy les
Moulineaux, FR) ; Renard; Pierre; (Le Chesnay,
FR) ; Bennejean; Caroline; (Charenton le Pont,
FR) ; Boutin; Jean Albert; (Suresnes, FR) ;
Audinot; Valerie; (Poissy, FR) |
Correspondence
Address: |
THE FIRM OF HUESCHEN AND SAGE
SEVENTH FLOOR, KALAMAZOO BUILDING
107 WEST MICHIGAN AVENUE
KALAMAZOO
MI
49007
US
|
Assignee: |
LES LABORATOIRES SERVIER
COURBEVOIE
FR
|
Family ID: |
32865399 |
Appl. No.: |
11/725855 |
Filed: |
March 20, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10820904 |
Apr 8, 2004 |
7214689 |
|
|
11725855 |
Mar 20, 2007 |
|
|
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Current U.S.
Class: |
514/183 |
Current CPC
Class: |
A61P 25/16 20180101;
A61P 29/00 20180101; A61P 43/00 20180101; A61P 1/00 20180101; A61P
9/00 20180101; A61P 15/00 20180101; A61P 25/14 20180101; A61P 37/02
20180101; C07D 217/16 20130101; A61P 25/08 20180101; A61P 3/00
20180101; A61P 35/00 20180101; A61P 3/04 20180101; A61P 25/24
20180101; A61P 25/00 20180101; A61P 3/02 20180101; A61P 25/20
20180101; A61P 25/06 20180101; A61P 15/18 20180101; A61P 25/02
20180101; A61P 37/00 20180101; A61P 25/18 20180101; A61P 3/10
20180101; A61P 25/22 20180101; A61P 9/10 20180101; A61P 25/28
20180101 |
Class at
Publication: |
514/183 |
International
Class: |
A61K 31/33 20060101
A61K031/33 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 9, 2003 |
FR |
03/04381 |
Claims
1. A method for treating a living animal body, including a human,
afflicted with a disorder of the melatoninergic system selected
from stress, sleep disorders, anxiety, cardiovascular pathologies,
pathologies of the digestive system, insomnia and fatigue due to
jetlag, melancholia, appetite disorders, obesity, insomnia,
epilepsy, diabetes, Parkinson's disease, disorders associated with
normal or pathological aging, migraine, memory loss, Alzheimer's
disease, cerebral circulation disorders, sexual dysfunctions, and
cancer, comprising the step of administering to the living animal
body, including a human, an amount of a compound selected from
those of formula (I): ##STR19## wherein: n is 1, 2 or 3, A
represents ##STR20## wherein: Z represents sulphur or oxygen, R and
R'', which may be identical or different, each represents hydrogen
or linear or branched (C.sub.1-C.sub.6)alkyl, and R' represents
linear or branched (C.sub.1-C.sub.6)alkyl; linear or branched
(C.sub.2-C.sub.6)alkenyl; linear or branched
(C.sub.2-C.sub.6)alkynyl; (C.sub.3-C.sub.8)cycloalkyl;
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl in which the
alkyl moiety is linear or branched; aryl;
aryl-(C.sub.1-C.sub.6)alkyl in which the alkyl moiety is linear or
branched; heteroaryl; or heteroaryl(C.sub.1-C.sub.6)alkyl in which
the alkyl moiety is linear or branched, X represents nitrogen or
N--R.sup.1 wherein R.sup.1 represents hydrogen or linear or
branched (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl-(C.sub.1-C.sub.6)alkyl in which the
alkyl moiety is linear or branched, aryl, aroyl,
aryl-(C.sub.1-C.sub.6)alkyl in which the alkyl moiety is linear or
branched, heteroaryl, heteroaroyl or
heteroaryl-(C.sub.1-C.sub.6)alkyl in which the alkyl moiety is
linear or branched, R.sup.2 represents linear or branched
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyloxy or
(C.sub.3-C.sub.8)cycloalkyl-(C.sub.1-C.sub.6)alkyloxy in which the
alkyloxy moiety is linear or branched, the representation denotes
that the bond is single or double, with the proviso that the
valency of the atoms is respected, its enantiomers and
diastereoisomers, and addition salts thereof with a
pharmaceutically acceptable acid or base, which is effective for
alleviation of the disorder, it being understood that: "aryl" may
be "phenyl" or "naphthyl", each of those groups being optionally
substituted by from one to three identical or different groups
selected from linear or branched (C.sub.1-C.sub.6)alkyl, linear or
branched (C.sub.1-C.sub.6)alkoxy, OH, COOH, alkoxycarbonyl in which
the alkoxy moiety is linear or branched, formyl, nitro, cyano,
hydroxymethyl, amino (optionally substituted by one or two linear
or branched (C.sub.1-C.sub.6)alkyl) and halogen, "heteroaryl" may
be any mono- or bi-cyclic group that contains from 5 to 10 ring
members and may contain from 1 to 3 hetero atoms selected from
oxygen, sulphur and nitrogen, each of those groups being optionally
partially hydrogenated and optionally substituted by from one to
three identical or different groups selected from linear or
branched (C.sub.1-C.sub.6)alkyl, linear or branched
(C.sub.1-C.sub.6)alkoxy, OH, COOH, alkoxycarbonyl in which the
alkoxy moiety is linear or branched, formyl, nitro, cyano, amino
(optionally substituted by one or two linear or branched
(C.sub.1-C.sub.6)alkyl), hydroxymethyl and halogen.
2. The method of claim 1, wherein n is 2 and A represents
--NHCOR'.
3. The method of claim 1, wherein n is 3 and A represents
CONHR'.
4. The method of claim 1, wherein R.sup.2 represents methoxy.
5. The method of claim 1, wherein X represents nitrogen.
6. The method of claim 1, wherein X represents NPh or NBz.
7. The method of claim 1, wherein the compound of formula (I) is
selected from N-[2-(6-methoxy-4-isoquinolinyl)ethyl]acetamide, and
its addition salts with a pharmaceutically acceptable acid.
8. The method of claim 1, wherein the compound of formula (I) is
selected from N-[2-(6-methoxy-4-isoquinolinyl)ethyl]butanamide, and
its addition salts with a pharmaceutically acceptable acid.
9. The method of claim 1, wherein the compound of formula (I) is
selected from N-[2-(6-methoxy-4-isoquinolinyl)ethyl]propanamide,
and its addition salts with a pharmaceutically acceptable acid.
10. The method of claim 1, wherein the compound of formula (I) is
selected from
N-[2-(6-methoxy-4-isoquinolinyl)ethyl]cyclopropanecarboxamide, and
its addition salts with a pharmaceutically acceptable acid.
11. The method of claim 1, wherein the compound of formula (I) is
selected from 4-(6-methoxy-4-isoquinolinyl)-N-methylbutanamide, and
its addition salts with a pharmaceutically acceptable acid.
12. The method of claim 1, wherein the compound of formula (I) is
selected from
N-[2-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]acetami-
de, and its addition salts with a pharmaceutically acceptable
acid.
13. The method of claim 1, wherein the compound of formula (I) is
selected from
N-[2-(2-benzyl-6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]acetami-
de, and its addition salts with a pharmaceutically acceptable
acid.
14. The method of claim 1, wherein the compound of formula (I) is
selected from
N-{2-[2-(cyclopropylmethyl)-6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl]-
-ethyl}acetamide, and its addition salts with a pharmaceutically
acceptable acid.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new isoquinoline compounds,
to a process for their preparation and to pharmaceutical
compositions containing them.
[0002] The compounds of the present invention are, in view of their
original structure, new and have pharmacological properties that
are of great interest in relation to melatoninergic receptors.
[0003] 1. Description of the Prior Art
[0004] There are known from the literature isoquinoline compounds
that are useful as vasodilators (U.S. Pat. No. 4,880,817, U.S. Pat.
No. 4,843,071, U.S. Pat. No. 4,822,800), or useful in the growth of
plants (Czasopismo Techniezne (Krakow), 1992, 89 (1), 7-12), as
tyrosine phosphatase modulators (WO 99 46268), or also useful in
synthesis (Tetrahedron Letters, 2002, 43 (19), 3557-3560;
Heterocycles, 2000, 52 (3), 1371-1383).
[0005] 2. Background of the Invention
[0006] In the last ten years, numerous studies have demonstrated
the major role played by melatonin (N-acetyl-5-methoxytryptamine)
in a large number of physiopathological phenomena and in the
control of the circadian rhythm, but melatonin has a rather short
half-life owing to the fact that it is rapidly metabolised. Great
interest therefore lies in the possibility of making available to
the clinician melatonin analogues that are metabolically more
stable and have an agonist or antagonist character and of which the
therapeutic effect may be expected to be superior to that of the
hormone itself.
[0007] In addition to their beneficial action in respect of
circadian rhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341)
and sleep disorders (Psychopharmacology, 1990, 100, pp. 222-226),
ligands of the melatoninergic system have valuable pharmacological
properties in respect of the central nervous system, especially
anxiolytic and antipsychotic properties (Neuropharmacology of
Pineal Secretions, 1990, 8 (3-4), pp. 264-272), and analgesic
properties (Pharmacopsychiat., 1987, 20, pp. 222-223), and also for
the treatment of Parkinson's disease (J. Neurosurg. 1985, 63, pp.
321-341) and Alzheimer's disease (Brain Research, 1990, 528, pp.
170-174). The compounds have also demonstrated activity in relation
to certain cancers (Melatonin--Clinical Perspectives, Oxford
University Press, 1988, pp. 164-165), ovulation (Science 1987, 227,
pp. 714-720), diabetes (Clinical Endocrinology, 1986, 24, pp.
359-364), and in the treatment of obesity (International Journal of
Eating Disorders, 1996, 20 (4), pp. 443-446).
[0008] Those various effects are exerted via the intermediary of
specific melatonin receptors. Molecular biology studies have
demonstrated the existence of a number of receptor sub-types that
are capable of binding that hormone (Trends Pharmacol. Sci., 1995,
16, p. 50; WO 97.04094). It has been possible for some of those
receptors to be located and characterised for different species,
including mammals. In order to be able to understand the
physiological functions of those receptors better, it is of great
advantage to have available selective ligands. Moreover such
compounds, by interacting selectively with one or another of those
receptors, may be excellent medicaments for the clinician in the
treatment of pathologies associated with the melatoninergic system,
some of which have been mentioned above.
[0009] In addition to being new, the compounds of the present
invention exhibit a very strong affinity for melatonin receptors
and/or a selectivity for one or another of the melatoninergic
receptor sub-types.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The present invention relates, more especially, to the
compounds of formula ##STR4## wherein: [0011] n is 1, 2 or 3,
[0012] A represents a group ##STR5## or a group ##STR6## wherein
[0013] Z represents a sulphur atom or an oxygen atom, [0014] R and
R'', which may be identical or different, each represents a
hydrogen atom or a linear or branched (C.sub.1-C.sub.6)alkyl group,
[0015] and R' represents a linear or branched
(C.sub.1-C.sub.6)alkyl group, a linear or branched
(C.sub.2-C.sub.6)alkenyl group, a linear or branched
(C.sub.2-C.sub.6)alkynyl group, a (C.sub.3-C.sub.8)-cycloalkyl
group, a (C.sub.3-C.sub.8)cycloalkyl-(C.sub.1-C.sub.6)alkyl group
in which the alkyl moiety is linear or branched, an aryl group, an
aryl-(C.sub.1-C.sub.6)alkyl group in which the alkyl moiety is
linear or branched, a heteroaryl group or a
heteroaryl-(C.sub.1-C.sub.6)alkyl group in which the alkyl moiety
is linear or branched, [0016] X represents a nitrogen atom or a
group N--R.sup.1 wherein R.sup.1 represents a hydrogen atom or a
linear or branched (C.sub.1-C.sub.6)alkyl group, a
(C.sub.3-C.sub.8)cycloalkyl group, a
(C.sub.3-C.sub.8)cyclo-alkyl-(C.sub.1-C.sub.6)alkyl group in which
the alkyl moiety is linear or branched, an aryl group, an aroyl
group, an aryl-(C.sub.1-C.sub.6)alkyl group in which the alkyl
moiety is linear or branched, a heteroaryl group, a heteroaroyl
group or a heteroaryl-(C.sub.1-C.sub.6)alkyl group in which the
alkyl moiety is linear or branched, [0017] R.sup.2 represents a
linear or branched (C.sub.1-C.sub.6)alkoxy group, a
(C.sub.3-C.sub.8)cycloalkyloxy or
(C.sub.3-C.sub.8)cycloalkyl-(C.sub.1-C.sub.6)alkyloxy group in
which the alkyloxy moiety is linear or branched, [0018] the
representation denotes that the bond is single or double, with the
proviso that the valency of the atoms is respected, wherein: [0019]
"aryl" is to be understood as meaning a phenyl or naphthyl group,
those groups being unsubstituted or substituted by from one to
three identical or different groups selected from linear or
branched (C.sub.1-C.sub.6)alkyl, linear or branched
(C.sub.1-C.sub.6)alkoxy, OH, COOH, alkoxycarbonyl in which the
alkoxy moiety is linear or branched, formyl, nitro, cyano,
hydroxymethyl, amino (optionally substituted by one or two linear
or branched (C.sub.1-C.sub.6)alkyl groups) and halogen atoms,
[0020] "heteroaryl" is to be understood as meaning any mono- or
bi-cyclic group that contains from 5 to 10 ring members and may
contain from 1 to 3 hetero atoms selected from oxygen, sulphur and
nitrogen, such as the groups furan, thiophene, pyrrole,
imidazoline, pyridine, quinoline, isoquinoline, chroman, indole,
benzothiophene or benzofuran, it being possible for those groups to
be partially hydrogenated, unsubstituted or substituted by from one
to three identical or different groups selected from linear or
branched (C.sub.1-C.sub.6)alkyl, linear or branched
(C.sub.1-C.sub.6)alkoxy, OH, COOH, alkoxycarbonyl in which the
alkoxy moiety is linear or branched, formyl, nitro, cyano, amino
(optionally substituted by one or two linear or branched
(C.sub.1-C.sub.6)alkyl groups), hydroxymethyl and halogen atoms, to
their enantiomers and diastereoisomers, and also to addition salts
thereof with a pharmaceutically acceptable acid or base.
[0021] Among the pharmaceutically acceptable acids there may be
mentioned, without implying any limitation, hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid,
trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid,
succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic
acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric
acid etc.
[0022] Among the pharmaceutically acceptable bases there may be
mentioned, without implying any limitation, sodium hydroxide,
potassium hydroxide, triethylamine, tert-butylamine etc.
[0023] The preferred values for n are 2 and 3.
[0024] Preferred compounds of the invention are compounds of
formula (I) wherein: [0025] n is 2 and A represents an --NHCOR'
group and more especially an --NHCOR' group wherein R' represents a
linear or branched (C.sub.1-C.sub.6)alkyl group, such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl for
example, or a (C.sub.3-C.sub.8)cycloalkyl group, such as
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl for example,
[0026] n is 3 and A represents a --CONHR' group and more especially
a --CONHR' group wherein R' represents a linear or branched
(C.sub.1-C.sub.6)alkyl group, such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, pentyl or hexyl for example, or a
(C.sub.3-C.sub.8)cycloalkyl group, such as cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl for example.
[0027] The preferred R.sup.2 group is the alkoxy group and more
especially the methoxy group.
[0028] X represents preferably a nitrogen atom or an NR.sup.1 group
wherein R.sup.1 represents a cycloalkylalkyl group, an
unsubstituted or substituted phenyl group, or a benzyl group in
which the phenyl moiety is substituted or unsubstituted.
[0029] Even more preferably, the invention relates to the following
compounds of formula (I): [0030]
N-[2-(6-methoxy-4-isoquinolinyl)ethyl]acetamide, [0031]
N-[2-(6-methoxy-4-isoquinolinyl)ethyl]butanamide, [0032]
N-[2-(6-methoxy-4-isoquinolinyl)ethyl]propanamide, [0033]
N-[2-(6-methoxy-4-isoquinolinyl)ethyl]cyclopropanecarboxamide,
[0034] 4-(6-methoxy-4-isoquinolinyl)-N-methylbutanamide, [0035]
N-[2-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]acetami-
de, [0036]
N-[2-(2-benzyl-6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)]ethyl]acetam-
ide, [0037]
N-{2-[2-(cyclopropylmethyl)-6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl]-
-ethyl}acetamide.
[0038] The enantiomers, diastereoisomers and also addition salts
with a pharmaceutically acceptable acid or base of the preferred
compounds of the invention form an integral part of the
invention.
[0039] The present invention relates also to a process for the
preparation of compounds of formula (I), which process is
characterised in that there is used as starting material a compound
of formula (II): ##STR7## wherein R.sup.2 and n are as defined for
formula (I) and R.sub.a represents a linear or branched
(C.sub.1-C.sub.6)alkyl group, which is subjected to the action of
POCl.sub.3 to obtain a compound of formula (III): ##STR8## wherein
R.sup.2, n and R.sub.a are as defined hereinabove, which is placed:
[0040] in the presence of palladium-on-carbon to obtain a compound
of formula (IV): ##STR9## wherein R.sup.2, n and R.sub.a are as
defined hereinabove, [0041] or which is hydrogenated in the
presence of palladium-on-carbon to yield a compound of formula (V):
##STR10## wherein R.sup.2, n and R.sub.a are as defined
hereinabove, which compound of formula (V) is condensed with a
compound of formula G-R'.sup.1 wherein G represents a leaving
group, such as a halogen atom, or a tert-butoxycarbonyl group, and
R'.sup.1 may have any of the meanings given for R' with the
exception of a hydrogen atom, to yield a compound of formula (VI):
##STR11## wherein R.sup.2, R'.sup.1, n and R.sub.a are as defined
hereinabove, the compounds of formulae (III) to (VI) constituting
the compounds of formula (VII): ##STR12## wherein R.sup.2, n and
R.sub.a are as defined hereinabove and X and the representation are
as defined for formula (I), which is condensed with an amine of
formula HNRR' wherein R and R' are as defined for formula (I) to
obtain a compound of formula (I/a), a particular case of the
compounds of formula (I): ##STR13## wherein R.sup.2, R, R', X, n
and the representation are as defined hereinabove, or which
compound of formula (VII) is subjected to a sequence of reactions
conventional in organic chemistry to yield a compound of formula
(VIII): ##STR14## wherein R.sup.2, X, n and the representation are
as defined hereinabove, which is [0042] either reacted with an acyl
chloride ClCOR' or the corresponding mixed or symmetric anhydride
wherein R' is as defined hereinabove to yield a compound of formula
(I/b), a particular case of the compound of formula (I): ##STR15##
wherein R.sup.2, R', X, n and the representation are as defined
hereinabove, optionally followed by the action of a compound of
formula R'.sub.a-J wherein R'.sub.a may have any of the meanings of
R' and J represents a leaving group, such as a halogen atom or a
tosyl group, to obtain a compound of formula (I/c), a particular
case of the compounds of formula (I): ##STR16## wherein R.sup.2,
R', R.sub.a', X, n and the representation are as defined
hereinabove, [0043] or subjected to the action of a compound of
formula (IX): O.dbd.C.dbd.N--R' (IX) wherein R' is as defined
hereinabove, optionally followed by the action of a compound of
formula R'.sub.a-J as defined hereinabove, to yield a compound of
formula (I/d), a particular case of the compounds of formula (I):
##STR17## wherein R.sup.2, R, R', n, X and the representation are
as defined hereinabove and R'' is as defined for formula (I), it
being possible for the compounds of formulae (I/a) to (I/d) to be
subjected to the action of a thionisation agent, such as Lawesson's
reagent for example, to yield a compound of formula (I/e), a
particular case of the compounds of formula (I): ##STR18## wherein
R.sup.2, n and the representation are as defined hereinabove and B
represents a C(S)NRR', N(R)C(S)R' or N(R)C(S)NR'R'' group wherein
R, R' and R'' are as defined hereinabove, the compounds (I/a) to
(I/e) constituting the totality of the compounds of formula (I),
which compounds may be purified according to a conventional
separation technique, are converted, if desired, into addition
salts with a pharmaceutically acceptable acid or base, and are
optionally separated into the isomers according to a conventional
separation technique.
[0044] The starting compounds (II) are either commercially
available or are easily obtainable by the person skilled in the art
by conventional chemical reactions or by chemical reactions
described in the literature.
[0045] The compounds of the invention and pharmaceutical
compositions containing them prove to be useful in the treatment of
disorders of the melatoninergic system.
[0046] A pharmacological study of the compounds of the invention
has in fact demonstrated that they are non-toxic, have a high
affinity for melatonin receptors and have substantial activity in
respect of the central nervous system and in respect of
microcirculation, enabling it to be established that the products
of the invention are useful in the treatment of stress, sleep
disorders, anxiety, severe depression, seasonal affective
disorders, cardiovascular pathologies, pathologies of the digestive
system, insomnia and fatigue due to jetlag, schizophrenia, panic
attacks, melancholia, appetite disorders, obesity, insomnia, pain,
psychotic disorders, epilepsy, diabetes, Parkinson's disease,
senile dementia, various disorders associated with normal or
pathological ageing, migraine, memory loss, Alzheimer's disease,
and in cerebral circulation disorders. In another field of
activity, it appears that the products of the invention can be used
in the treatment of sexual dysfunction, that they have
ovulation-inhibiting and immunomodulating properties and that they
lend themselves to use in the treatment of cancers.
[0047] The compounds will preferably be used in the treatment of
severe depression, seasonal affective disorders, sleep disorders,
cardiovascular pathologies, insomnia and fatigue due to jetlag,
appetite disorders and obesity.
[0048] For example, the compounds will be used in the treatment of
seasonal affective disorders and sleep disorders.
[0049] The present invention relates also to pharmaceutical
compositions comprising at least one compound of formula (I) on its
own or in combination with one or more pharmaceutically acceptable
excipients.
[0050] Amongst the pharmaceutical compositions according to the
invention there may be mentioned more especially those which are
suitable for oral, parenteral, nasal, per- or trans-cutaneous,
rectal, perlingual, ocular or respiratory administration,
especially tablets or dragees, sublingual tablets, sachets,
paquets, gelatin capsules, glossettes, lozenges, suppositories,
creams, ointments, dermal gels and drinkable or injectable
ampoules.
[0051] The dosage varies according to the sex, age and weight of
the patient, the administration route, the nature of the
therapeutic indication or any associated treatments, and ranges
from 0.01 mg to 1 g per 24 hours in one or more
administrations.
[0052] The following Examples illustrate the invention and do not
limit it in any way. The following Preparations result in compounds
of the invention or in synthesis intermediates for use in the
preparation of compounds of the invention.
Preparation 1: Ethyl
4-(6-methoxy-3,4-dihydro-4-isoquinolinyl)butanoate
hydrochloride
Step A: Ethyl 5-cyano-5-(3-methoxyphenyl)pentanoate
[0053] Two grams of (3-methoxyphenyl)acetonitrile and 1.5 ml of
ethyl 4-bromobutyrate are dissolved in 50 ml of dimethylformamide
at 0.degree. C. Six hundred milligrams of 60% sodium hydride (600
mg; 15 mmol) are progressively added to the solution. The reaction
mixture is stirred at ambient temperature for 4 hours, taken up in
100 ml of acidic water and extracted with ether. The organic phase
is then dried over magnesium sulphate, filtered and evaporated
under reduced pressure. The oil obtained is purified on a column
(eluant:ether/cyclohexane 4/6) to yield the title product in the
form of a yellow oil.
Step B: Ethyl 6-amino-5-(3-methoxyphenyl)hexanoate
hydrochloride
[0054] The compound obtained in Step A (11.2 g; 43 mmol), dissolved
beforehand in 150 ml of ethanol, is poured into an autoclave, and
then Raney nickel is added (10% by weight). The mixture is then
placed under hydrogen pressure (10 bars) and heated at 50.degree.
C. for 48 hours with stirring. After removing the Raney nickel by
filtration, the organic phase is evaporated under reduced pressure.
The residue obtained is taken up in ether, HCl.sub.(g) is bubbled
into the solution, which is then stirred until precipitation
occurs. The precipitate obtained is then suction-filtered off and
recrystallised from toluene, and the title product is obtained in
the form of a white solid.
[0055] Melting point: 104-106.degree. C.
Step C: Ethyl 6-(formylamino)-5-(3-methoxyphenyl)hexanoate
[0056] The amine obtained in Step B, in the form of a base (6.4 g;
27 mmol), is dissolved in 60 ml of ethyl formate. The reaction
mixture is heated at reflux for 6 hours with stirring and then
evaporated under reduced pressure. The residue obtained is taken up
in ether. The organic phase is then washed in succession with
acidic water (1N HCl), water, and a 10% hydrogen carbonate
solution, subsequently dried over magnesium sulphate, filtered and
evaporated under reduced pressure to yield the title product in the
form of a yellow oil.
Step D: Ethyl 4-(6-methoxy-3,4-dihydro-4-isoquinolinyl)butanoate
hydrochloride
[0057] The formaldehyde obtained in Step C (6.8 g; 23 mmol) is
dissolved in 100 ml of acetonitrile, then the reaction mixture is
heated to approximately 60.degree. C. Phosphorus oxychloride (7 ml)
is added to the solution, which is heated at reflux for 6 hours
with stirring and then evaporated under reduced pressure. The
residue obtained is taken up twice in ethanol and evaporated under
reduced pressure, and is then taken up in water. The aqueous phase
is washed with dichloromethane and then rendered alkaline with a
saturated sodium hydrogen carbonate solution and extracted with
dichloromethane. The organic phase is dried over magnesium
sulphate, filtered and evaporated under reduced pressure. The oil
obtained is taken un in ether saturated with HCl.sub.(g) and then
evaporated under reduced pressure. The residue is taken up in
toluene in the heated state and is stirred until precipitation
occurs. The precipitate obtained is then suction-filtered off and
the title product is obtained in the form of a white solid.
[0058] Melting point: 97-99.degree. C.
Preparation 2: tert-Butyl
4-(2-aminoethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate
Step A: Methyl cyano(3-methoxyphenyl)acetate
[0059] Twenty five grams of (3-methoxyphenyl)acetonitrile are
dissolved in 200 ml of anhydrous THF in an Erlermeyer ground-necked
flask. 60% sodium hydride (8.88 g; 0.37 mol) is added to the
solution and the reaction mixture is heated at reflux for 30
minutes with stirring. Dimethyl carbonate (58 ml; 0.6814 mol) is
then added dropwise in the course of half an hour and the reaction
mixture is subsequently heated at reflux for 2 hours with stirring.
The reaction mixture is poured into cold and slightly acidic water.
The aqueous phase is extracted with ether, and then the ethereal
phase is washed with water before being evaporated. A solution of
potassium carbonate (47.15 g; 0.34 mol) is added to the oil
obtained above. After stirring, the mixture is washed with ether.
The ethereal phase obtained is rewashed with a solution of
potassium carbonate (12.02 g; 0.08 mol). The two aqueous phases are
combined, immediately acidified, and extracted with ether. The
organic phase so obtained is washed with a 10% sodium hydrogen
carbonate solution, dried over magnesium sulphate and evaporated
under reduced pressure to yield the title product in the form of an
orangey yellow oil.
Step B: Methyl 3-amino-2-(3-methoxyphenyl)propanoate
hydrochloride
[0060] The compound obtained in Step A (34.32 g; 0.1672 mol) is
dissolved in 150 ml of methanol. The solution is poured into an
autoclave and then 50 ml of chloroform and platinium oxide (10% by
weight) are added to the solution. The autoclave is placed under
hydrogen pressure (60 bars) at ambient temperature and stirred
magnetically for 24 hours. After removal of the catalyst by
filtration, the solution is evaporated under reduced pressure. The
oil obtained is taken up in ether. The precipitate formed is
suction-filtered off and recrystallised from acetonitrile to yield
the title product in the form of a white solid.
[0061] Melting point: 170-172.degree. C.
Step C: Methyl 3-(formylamino)-2-(3-methoxyphenyl)propanoate
[0062] The compound obtained in Step B (20.25 g; 0.08 mol), in the
form of a base, is dissolved in 130 ml of ethyl formate (1.81 mol).
The reaction mixture is heated at reflux for 6 hours and then
evaporated under reduced pressure. The oil obtained is taken up in
ethyl acetate. The organic phase is washed with basic water
(NaHCO.sub.3), dried over magnesium sulphate, filtered and
evaporated to yield the title product in the form of a yellow
oil.
Step D: Methyl 6-methoxy-3,4-dihydro-4-isoquinolinecarboxylate
hydrochloride
[0063] The compound obtained in Step C (8.03 g; 0.03 mol) is
dissolved in 100 ml of acetonitrile, and then the reaction mixture
is heated to approximately 60.degree. C. Phosphorus oxychloride (16
ml; 0.17 mol) is added to the solution, which is then heated at
reflux for 6 hours with stirring and subsequently evaporated under
reduced pressure. The residue obtained is taken up twice with
methanol and evaporated under reduced pressure, and then taken up
in a minimum of acetone. The precipitate formed is then
suction-filtered off to yield the title product in the form of a
white solid.
[0064] Melting point: 212-215.degree. C.
Step E: Methyl
6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinecarboxylate
hydrochloride
[0065] The compound obtained in Step D (9.21 g), in the form of a
base, is dissolved in 150 ml of methanol and then
palladium-on-carbon (900 mg) is added to the solution. The reaction
mixture is stirred at ambient temperature under hydrogen for 4
hours. After removal of the palladium-on-carbon by filtration, the
organic phase is evaporated under reduced pressure. The oil
obtained is taken up in ether saturated with HCl. The precipitate
formed is suction-filtered off and recrystallised from acetonitrile
to yield the title product in the form of a white solid.
[0066] Melting point: 191-193.degree. C.
Step F: tert-Butyl 4-methyl
6-methoxy-3,4-dihydro-2,4(1H)-isoquinoline-dicarboxylate
[0067] The compound obtained in Step E (4.02 g; 15 mmol) is
suspended in 100 ml of dichloromethane and then triethylamine (6.6
ml) is added. When dissolution is complete, di-tert-butyl
dicarbonate (4 g; 18 mmol) is added and the reaction mixture is
stirred at ambient temperature for 30 minutes. The solution is
poured into 100 ml of water and the excess of triethylamine is
neutralised with acidic water (0.1N HCl). After separation, the
aqueous phase is extracted with dichloromethane and the combined
organic solutions are dried over magnesium sulphate, filtered and
evaporated under reduced pressure. The title product is purified by
chromatography on silica gel.
[0068] Colourless oil.
Step G: tert-Butyl
4-(hydroxymethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinoline-carboxylate
[0069] Lithium aluminium hydride (5.62 g; 148 mmol) is suspended in
50 ml of anhydrous tetrahydrofuran. A solution of the compound
obtained in Step F (11.9 g; 37 mmol), dissolved beforehand in 50 ml
of anhydrous tetrahydrofuran, is then added dropwise. The reaction
mixture is then stirred at ambient temperature for 2 hours. A
minimum of sodium hydroxide solution (2N NaOH) is added to the
reaction mixture until the evolution of gas has ceased in order to
form the precipitates of lithium and aluminium hydroxides. The
precipitates are then filtered off and washed with tetrahydrofuran.
The organic phase is evaporated under reduced pressure. The title
compound is purified by chromatography on silica gel.
[0070] Clear yellow oil.
Step H: tert-Butyl
6-methoxy-4-{[(methylsulphonyl)oxy]methyl}-3,4-dihydro-2(1H)-isoquinoline-
carboxylate
[0071] The compound obtained in Step G (10.5 g; 36 mmol) is
dissolved in 150 ml of dichloromethane and then triethylamine (8.5
ml) is added. The solution is cooled to 0.degree. C. and
methanesulphonyl chloride (4.8 ml; 62 mmol) is added dropwise. The
reaction mixture is stirred at ambient temperature for 2 hours and
then poured into 150 ml of water. The solution is extracted with
dichloromethane, dried over magnesium sulphate, filtered and
evaporated under reduced pressure. The title compound is purified
by chromatography on silica gel.
[0072] Yellow oil.
Step I: tert-Butyl
4-(cyanomethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinoline-carboxylate
[0073] Potassium cyanide (5.52 g; 85 mmol) is suspended in 50 ml of
DMSO and the solution is heated to 80.degree. C. The compound
obtained in Step H (6.3 g; 17 mmol), dissolved beforehand in 50 ml
of DMSO, is progressively added to the preceding solution, and then
the reaction mixture is heated again at 80.degree. C. for 30
minutes. The solution is poured into 150 ml of water and extracted
three times with dichloromethane. The organic phase is then dried
over magnesium sulphate, filtered and evaporated. The dark red oil
obtained is purified by chromatography on silica gel
(eluant:cyclohexane with the progressive addition of ethyl acetate
until the proportions 8/2 are reached) and the solid obtained is
recrystallised from cyclohexane to yield the title product in the
form of a white solid.
[0074] Melting point: 75-77.degree. C.
Step J: tert-Butyl
4-(2-aminoethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinoline-carboxylate
[0075] The compound obtained in Step 1 (6.3 g; 21 mmol) is
dissolved in 150 ml of methanol saturated with NH.sub.3(g). The
solution is poured into an autoclave and Raney nickel (600 mg) is
added. The reaction mixture is then stirred at 60.degree. C. and
under a hydrogen pressure of 50 bars for 6 hours. After removal of
the catalyst by filtration, the solution is evaporated under
reduced pressure and the title compound is obtained in the form of
a colourless oil.
Preparation 3: (6-Methoxy-4-isoquinolinyl)acetonitrile
hydrochloride
Step A: Methyl 6-methoxy-4-isoquinolinecarboxylate
hydrochloride
[0076] The compound obtained in Step D of Preparation 2 (1.56 g;
0.006 mol), in the form of a base, is dissolved in 10 ml of
decahydronaphthalene and then activated palladium-on-carbon is
added (10% by weight). The reaction mixture is heated at
130.degree. C. for 24 hours with stirring. The catalyst is filtered
off in the heated state and washed with ethyl acetate. After
evaporation under reduced pressure, the oil obtained is taken up in
an ethereal solution saturated with HCl.sub.(g). The precipitate
formed is suction-filtered off and recrystallised from acetonitrile
to yield the title product in the form of a white solid.
[0077] Melting point: 178-180.degree. C.
Step B: (6-Methoxy-4-isoquinolinyl)methanol hydrochloride
[0078] The compound obtained in Step A (0.395 g; 0.0015 mol), in
the form of a base, is dissolved in 200 ml of ether. Lithium
aluminium hydride (0.14 g; 0.004 mol) is then progressively added
while cooling the flask in ice. The reaction mixture is stirred at
ambient temperature for one week. A minimum of 30% sodium hydroxide
solution (a few drops) is added to the reaction mixture to form the
precipitates of lithium and aluminium hydroxides. The precipitates
are then filtered off and washed with ethyl acetate. The organic
phase is dried over magnesium sulphate, filtered and evaporated
under reduced pressure. The oil obtained is taken up in ether
saturated with HCl.sub.(g). The precipitate formed is
suction-filtered off and recrystallised from acetonitrile to yield
the title product in the form of a white solid.
[0079] Melting point: 250-252.degree. C.
Step C: 4-(Chloromethyl)-6-methoxyisoquinoline
[0080] The hydrochloride of the compound obtained in Step B (1.09
g; 0.005 mol) is suspended in 50 ml of chloroform. Thionyl chloride
(2.80 ml; 0.04 mol) is added and then the reaction mixture is
heated at reflux for 24 hours with stirring. After evaporation
under reduced pressure, the residue obtained is taken up in ethyl
ether. The precipitate formed is suction-filtered off and
recrystallised from acetonitrile to yield the title compound in the
form of a white solid.
[0081] Melting point: 256-257.degree. C.
Step D: (6-Methoxy-4-isoquinolinyl)acetonitrile hydrochloride
[0082] The hydrochloride of the compound obtained in Step C (0.60
g; 0.0024 mol) is dissolved in 10 ml of a saturated aqueous
potassium carbonate solution and 40 ml of dichloromethane.
Tetrabutylammonium bromide (2 g; 0.006 mol) and potassium cyanide
(0.80 g; 0.012 mol) are then added to the preceding solution. The
reaction mixture is stirred at ambient temperature for 24 hours.
The solution is extracted with dichloromethane, and the organic
phase is washed with water, dried over magnesium sulphate, filtered
and evaporated. The oil obtained is taken up in acetone and in
ether saturated with HCl.sub.(g). The precipitate formed is
suction-filtered off and recrystallised from toluene/cyclohexane,
5/5, to yield the title compound in the form of a yellow solid.
[0083] Melting point: 114-115.degree. C.
Preparation 4: tert-Butyl
4-(aminomethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate
Step A: tert-Butyl
6-methoxy-4-{[(methylsulphonyl)oxy]methyl}-3,4-dihydro-2(1H)-isoquinoline-
carboxylate
[0084] The procedure is as in Steps A to H of Preparation 2.
Step B: tert-Butyl
4-(azidomethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinoline-carboxylate
[0085] Sodium azide (1.12 g) is suspended in 40 ml of DMF and the
solution is heated to 80.degree. C.
[0086] The compound obtained in Step A (1.6 g), dissolved
beforehand in 10 ml of DMF, is progressively added to the preceding
solution, and then the reaction mixture is heated again at
80.degree. C. for from 2 to 3 hours.
[0087] The solution is poured into 150 ml of water and extracted
three times with ethyl acetate. The organic phase is then dried
over magnesium sulphate, filtered and evaporated. The dark red oil
obtained is purified by chromatography on silica gel
(eluant:cyclohexane with the progressive addition of ethyl acetate
until the proportions 5/5 are reached) to yield the title product
in the form of a colourless oil.
Step C: tert-Butyl
4-(aminomethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinoline-carboxylate
[0088] The compound obtained in Step B (1.14 g) is dissolved in 100
ml of methanol and then palladium-on-carbon (120 mg) is added to
the solution. The reaction mixture is stirred at ambient
temperature and under hydrogen for 3 hours.
[0089] After removal of the palladium-on-carbon by filtration, the
organic phase is evaporated under reduced pressure. The residue
obtained is purified by chromatography on silica gel
(eluant:cyclohexane with the progressive addition of ethyl acetate
until the proportions 5/5 are reached) to yield the title product
in the form of a colourless oil.
EXAMPLE 1
4-(6-methoxy-3,4-dihydro-4-isoquinolinyl)-N-methylbutanamide
[0090] The compound obtained in Preparation 1 (41 mmol), in the
form of a base, is dissolved in 10 ml of ethanol. 60 ml of aqueous
methylamine are added and the reaction mixture is stirred at
ambient temperature for 12 hours. After evaporation under reduced
pressure, the filtrate is taken up in 50 ml of water and extracted
with dichloromethane. The organic phase is washed with water, dried
over magnesium sulphate, filtered and evaporated under reduced
pressure. The title product is obtained after chromatography of the
resulting oil on silica gel.
[0091] Yellow oil.
EXAMPLE 2
4-(6-Methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)-N-methylbutanamide
[0092] The compound obtained in Example 1 (54 mmol), in the form of
a base, is dissolved in 50 ml of methanol and then
palladium-on-carbon (150 mg) is added to the solution. The reaction
mixture is stirred at ambient temperature and under hydrogen for 4
hours. After removal of the palladium-on-carbon by filtration, the
organic phase is evaporated under reduced pressure. The oil
obtained is purified by chromatography on silica gel to yield the
title product in the form of a yellow oil.
EXAMPLE 3
4-(6-methoxy-4-isoquinolinyl)-N-methylbutanamide
Step A: Ethyl 4-(6-methoxy-4-isoquinolinyl)butanoate
hydrochloride
[0093] The compound obtained in Preparation 1 (1.6 g; 5 mmol) is
dissolved, with the application of heat, in 20 ml of toluene
containing triethylamine (0.9 ml) and absolute ethanol (2 ml).
Palladium-on-carbon (300 mg) is added to the reaction mixture,
which is then heated at reflux for 24 hours with stirring. After
removal of the palladium-on-carbon by filtration, the organic phase
is evaporated under reduced pressure. The residue obtained is
purified by chromatography on silica gel (eluant:dichloromethane
with the progressive addition of methanol). The oil obtained is
converted to hydrochloride form and then the precipitate formed is
recrystallised from acetonitrile.
[0094] Melting point: 190-192.degree. C.
Step B: 4-(6-methoxy-4-isoquinolinyl)-N-methylbutanamide
[0095] The compound obtained in Step A (2.2 g; 7 mmol) is dissolved
in 30 ml of methylamine (40% in water) and the mixture is heated at
reflux for 3 hours with stirring. The reaction mixture is taken up
in 50 ml of water and extracted with ether. The organic phase is
washed with water, dried over magnesium sulphate, filtered and
evaporated under reduced pressure. The oil obtained is purified by
chromatography on silica gel (eluant:dichloromethane with the
progressive addition of methanol). The oil obtained is evaporated
under reduced pressure and the precipitate so formed is
recrystallised from toluene to yield the title product in the form
of a white solid.
[0096] Melting point: 117-119.degree. C.
[0097] Elemental Microanalysis TABLE-US-00001 C % H % N %
calculated 69.74 7.02 10.84 found 69.64 7.22 10.83
EXAMPLE 4
N-[2-(6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]acetamide
hydrochloride
[0098] The compound obtained in Step I of Preparation 2 (6 g; 20
mmol) is dissolved in 100 ml of acetic anhydride and then the
solution is poured into an autoclave. Raney nickel (600 mg) is then
added to the solution and the reaction mixture is stirred at
60.degree. C. and under a hydrogen pressure of 50 bars for 6 hours.
After removal of the catalyst by filtration, the solution is
evaporated under reduced pressure. The orange residue obtained is
taken up in a 10% sodium hydroxide solution and stirred for 15
minutes, and then extracted with ethyl acetate (3 times). The
organic phase is washed once with water, dried over magnesium
sulphate, filtered and evaporated under reduced pressure. The oil
obtained is taken up in 50 ml of methanol. Hydrogen chloride gas is
bubbled into the solution, which is then stirred for 24 hours with
a CaCl.sub.2 guard. The solution is evaporated under reduced
pressure and the precipitate so obtained is recrystallised from
acetonitrile to yield the title product in the form of a white
solid.
[0099] Melting point: 182-184.degree. C.
EXAMPLE 5
N-[2-(6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]propanamide
hydrochloride
[0100] The compound obtained in Preparation 2 and 2 equivalents of
potassium carbonate are dissolved in a 3/2 ethyl acetate/water
mixture. Propanoyl chloride (2 equivalents) is then added dropwise
to the solution. The reaction mixture is stirred at ambient
temperature for one hour. After separation of the phases, the
organic phase is washed with water, dried over magnesium sulphate,
filtered and evaporated under reduced pressure. The oil obtained is
purified by chromatography on silica gel (eluant ethyl
acetate/cyclohexane 5/5). The oil obtained is taken up in methanol.
Hydrogen chloride gas is bubbled into the solution, which is then
stirred for 24 hours with a CaCl.sub.2 guard. The solution is
evaporated under reduced pressure and the title compound is
obtained in the form of a white solid.
[0101] Melting point: 161-163.degree. C.
EXAMPLE 6
N-[2-(6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]butanamide
hydrochloride
[0102] The title compound is obtained by the same procedure as in
Example 5, with the replacement of propanoyl chloride by butanoyl
chloride.
[0103] Very hygroscopic white solid.
EXAMPLE 7
N-[2-(6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]cyclopropane
carboxamide hydrochloride
[0104] The title compound is obtained by the same procedure as in
Example 5, with the replacement of propanoyl chloride by
cyclopropylcarboxylic acid chloride.
[0105] White solid.
[0106] Melting point: 215-217.degree. C.
EXAMPLE 8
N-[2-(6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]cyclobutane-carbo-
xamide hydrochloride
[0107] The title compound is obtained by the same procedure as in
Example 5, with the replacement of propanoyl chloride by
cyclobutylcarboxylic acid chloride.
[0108] White solid.
[0109] Melting point: 130-132.degree. C.
EXAMPLE 9
N-[2-(6-methoxy-4-isoquinolinyl)ethyl]acetamide hydrochloride
[0110] The compound obtained in Preparation 3 (0.30 g; 0.0015 mol),
in the form of a base, dissolved beforehand in 10 ml of acetic
anhydride, is poured into an autoclave and then Raney nickel is
added (10% by weight). The mixture is then placed under hydrogen
pressure (60 bars) and heated at 60.degree. C. for 6 hours with
stirring. After removal of the Raney nickel by filtration, the
organic phase is taken up in 10% sodium hydroxide solution at
ambient temperature and stirred magnetically for 15 minutes. The
solution is extracted with ethyl acetate, the organic phase is
washed with brine, dried over magnesium sulphate, filtered and
evaporated under reduced pressure. The oil obtained is purified on
a column (eluant dichloromethane with the progressive addition of
methanol until the proportions 9/1 are reached). The purified oil
is taken up in ether saturated with HCl.sub.(g). The precipitate
formed is suction-filtered off and recrystallised from ethanol to
yield the title product in the form of a white solid.
[0111] Melting point: 212-214.degree. C.
EXAMPLE 10
N-[2-(6-methoxy-4-isoquinolinyl)ethyl]propanamide hydrochloride
[0112] The compound of Example 5 is dissolved in a minimum of
methanol with the application of heat and then diluted with
toluene. 1.5 equivalents of triethylamine are then added to the
solution, and the reaction mixture is subsequently heated at reflux
in the presence of palladium-on-carbon (10% by weight) for 3 hours.
After removal of the catalyst by filtration, the solution is
evaporated under reduced pressure. The oil obtained is purified by
chromatography on silica gel (eluant dichlormethane/methanol 9/1).
The purified oil is taken up in ether saturated with HCl.sub.(g)
and stirred until a precipitate is obtained. The precipitate so
formed is suction-filtered off and placed under vacuum in a
dessicator. The title product is obtained in the form of a white
solid.
[0113] Melting point: 233-235.degree. C.
EXAMPLE 11
N-[2-(6-methoxy-4-isoquinolinyl)ethyl]butanamide hydrochloride
[0114] The title compound is obtained according to the same
procedure as in Example 10 starting from the compound obtained in
Example 6.
[0115] Melting point: 195-197.degree. C.
EXAMPLE 12
N-[2-(6-methoxy-4-isoquinolinyl)ethyl]cyclopropanecarboxamide
hydrochloride
[0116] The title compound is obtained according to the same
procedure as in Example 10 starting from the compound obtained in
Example 7.
[0117] Melting point: 226-228.degree. C.
EXAMPLE 13
N-[2-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]-acetami-
de hydrochloride
[0118] The compound obtained in Example 4 (460 mg; 1.8 mmol), in
the form of a base, is suspended in 30 ml of dichloromethane.
Triphenylbismuth (900 mg; 2 mmol) and copper acetate Cu(OAc).sub.2
(190 mg; 0.95 mmol) are then added. The reaction mixture is placed
under argon and stirred magnetically for 18 hours at ambient
temperature. The mixture is filtered, taken up in water and
extracted with ethyl acetate. The organic phase is dried over
magnesium sulphate, filtered and evaporated under reduced pressure.
The residue obtained is purified by chromatography on silica gel
(eluant ethyl acetate/cyclohexane 2/8). The purified oil is taken
up in ether saturated with HCl.sub.(g) and stirred until a
precipitate is obtained, which precipitate is then suction-filtered
off and placed under a vacuum in a dessicator to yield the title
product in the form of a white solid.
[0119] Melting point: 83-85.degree. C.
EXAMPLE 14
N-[2-(2-benzyl-6-methoxy-1,2,3,4-tetrahydro-4-isoquinoinyl)ethyl]-acetamid-
e
[0120] The compound obtained in Example 4 (740 mg; 2.5 mmol) and
potassium carbonate (720 mg; 5 mmol) are suspended in 20 ml of DMF,
and then benzyl bromide (0.37 ml; 3 mmol) is added to the solution.
The reaction mixture is heated at 125.degree. C. for 4 hours with
stirring. The solution is poured into 50 ml of water, acidified
with 6N HCl and washed with ethyl acetate. The aqueous phase is
then rendered alkaline with potassium carbonate and extracted with
dichloromethane. The organic phase is dried over magnesium
sulphate, filtered and evaporated under reduced pressure. The
residue so obtained is purified by chromatography on silica gel
(eluant:dichloromethane with the progressive addition of methanol
until the proportions 9/1 are reached). The purified oil
precipitates. The precipitate so formed is recrystallised from a
7/3 toluene/cyclohexane mixture to yield the title product in the
form of a white solid.
[0121] Melting point: 123-125.degree. C.
EXAMPLE 15
N-{2-[2-(3-formylphenyl)-6-methoxy-1,2,3,4-tetrahydro-4-iso-quinolinyl]eth-
yl}acetamide
[0122] Copper acetate Cu(OAc).sub.2 (960 mg; 5 mmol) and
triethylamine (1.5 ml; 10.5 mmol) are suspended in 60 ml of
dichloromethane. The compound of Example 4 (1 g; 3.5 mmol),
3-formylphenylboronic acid (1.05 g; 7 mmol) and molecular sieve are
then added in succession and progressively to the solution. The
reaction mixture is stirred at ambient temperature for 2 hours. The
mixture is filtered, washed with water, dried over magnesium
sulphate, filtered and evaporated under reduced pressure. The
residue obtained is purified by chromatography on silica gel
(eluant:dichloromethane with the progressive addition of methanol
until the proportions 9/1 are reached) to yield the title product
in the form of a yellow oil.
EXAMPLE 16
N-[2-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]-acetami-
de hydrochloride
[0123] Formic acid (0.55 ml) and 37% formaldehyde (0.6 ml) are
added at 0.degree. C. to the compound obtained in Example 4 (1.8 g;
7.2 mmol) in the form of a base. The reaction mixture is heated at
80.degree. C. for 24 hours with stirring. After having cooled the
reaction mixture to 0.degree. C., 10 ml of 6N HCl are added. The
mixture is then washed with ether, rendered alkaline with 2N NaOH
and extracted with ether. The organic phase is dried over magnesium
sulphate, filtered and evaporated under reduced pressure. The
yellow oil so obtained is purified by chromatography on silica gel
(eluant:dichloromethane with the progressive addition of methanol
until the proportions 9/1 are reached). The purified oil is taken
up in ether saturated with HCl.sub.(g) and stirred until a
precipitate is obtained, which precipitate is then suction-filtered
off and placed under a vacuum in a dessicator to yield the title
product in the form of a very hygroscopic white solid.
[0124] Melting point: 59-61.degree. C.
EXAMPLE 17
N-{2-[2-(Cyclopropylmethyl)-6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl]e-
thyl}acetamide hydrochloride
[0125] The compound obtained in Example 4 (1.03 g) and potassium
carbonate (1.25 g) are suspended in 50 ml of acetone. The solution
is stirred at ambient temperature for 10 minutes, and then
methylcyclopropane bromide (0.36 ml) is added to the solution. The
reaction mixture is stirred at ambient temperature for 12
hours.
[0126] The potassium carbonate is filtered off and the recovered
solution is evaporated. The residue is taken up in water and the
aqueous phase is extracted with ether. The organic phase is dried
over magnesium sulphate, filtered and evaporated under reduced
pressure. The residue so obtained is purified by chromatography on
silica gel (eluant:dichloromethane with the progressive addition of
methanol until the proportions 9/1 are reached).
[0127] The purified oil is taken up in ether saturated with
HCl.sub.(g) and stirred until a precipitate is obtained, which
precipitate is then suction-filtered off and placed under a vacuum
in a dessicator to yield the title product in the form of a
hygroscopic white solid.
[0128] Melting point: <50.degree. C.
EXAMPLE 18
N-[(6-Methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)methyl]acetamide
hydrochloride
[0129] The compound obtained in Preparation 4 (0.77 g) and
potassium carbonate (1.8 g) are dissolved in 50 ml of a 1/1
dichloromethane/water mixture. Acetyl chloride (0.47 ml) is then
added dropwise to the solution. The reaction mixture is stirred at
ambient temperature for 2 hours.
[0130] After separation of the phases, the organic phase is washed
with water, dried over magnesium sulphate, filtered and evaporated
under reduced pressure.
[0131] The oil obtained is taken up in methanol. Hydrogen chloride
gas is bubbled into the solution, which is then stirred with a
CaCl.sub.2 guard for 24 hours, the deprotection time. The solution
is evaporated under reduced pressure and the precipitate obtained
is recrystallised from acetonitrile to yield the title product in
the form of a white solid.
[0132] Melting point: 246-248.degree. C.
Pharmacological Study
EXAMPLE A
Acute Toxicity Study
[0133] Acute toxicity was evaluated after oral administration to
groups each comprising 8 mice (26.+-.2 grams). The animals were
observed at regular intervals during the course of the first day,
and daily for the two weeks following treatment. The LD.sub.50 (the
dose that causes the death of 50% of the animals) was evaluated and
demonstrated the low toxicity of the compounds of the
invention.
EXAMPLE B
Forced Swimming Test
[0134] The compounds of the invention are tested in a behavioural
model, the forced swimming test.
[0135] The apparatus is a Plexiglas cylinder filled with water. The
animals are tested individually for a session of 6 minutes. At the
beginning of each test, the animal is placed in the centre of the
cylinder. The period of immobility is recorded. Each animal is
judged to be immobile when it ceases to struggle and remains
immobile on the surface of the water only making movements that
allow it to keep its head out of the water.
[0136] After administration 40 minutes before the beginning of the
test, the compounds of the invention significantly reduce the
period of immobility, demonstrating the anti-depressant activity of
the compounds of the invention. In particular, the compound of
Example 9, administered at 2.5 mg/kg per os, causes the duration of
immobility to be reduced from 102 seconds (control) to 57 seconds.
The compound of Example 3, administered at 25 mg/kg per os, causes
the duration of immobilisation to be reduced from 129 seconds
(control) to 60 seconds.
EXAMPLE C
Study of Binding to Melatonin Receptors MT.sub.1 and MT.sub.2
[0137] The MT.sub.1 or MT.sub.2 receptor binding experiments are
carried out using 2-[.sup.125I]-iodomelatonin as reference
radioligand. The radioactivity retained is determined using a
liquid scintillation counter.
[0138] Competitive binding experiments are then carried out in
triplicate using the various test compounds. A range of different
concentrations is tested for each compound. The results enable the
binding affinities (K.sub.i) of the compounds tested to be
determined.
[0139] Thus, the K.sub.i values found for the compounds of the
invention show binding for one or the other of the receptor
sub-types MT.sub.1 or MT.sub.2, those values being .ltoreq.10
.mu.M.
[0140] In particular, the compound of Example 9 has a K.sub.i
(MT.sub.1) of 9.12.times.10.sup.-9M and a K.sub.i (MT.sub.2) of
2.16.times.10.sup.-9M; the compound of Example 3 has a K.sub.i
(MT.sub.1) of 3.8.times.10.sup.-9M and a K.sub.i (MT.sub.2) of
2.6.times.10.sup.-9M; the compound of Example 10 has a K.sub.i
(MT.sub.1) of 4.26.times.10.sup.-9M and a K.sub.i (MT.sub.2) of
1.14.times.10.sup.-9M.
EXAMPLE D
Action of the Compounds of the Invention on the Circadian Rhythms
of Locomotive Activity of the Rat
[0141] The implication of melatonin in influencing the majority of
physiological, biochemical and behavioural circadian rhythms by
day/night alternation has made it possible to establish a
pharmacological model for research into melatoninergic ligands.
[0142] The effects of the compounds are tested in relation to
numerous parameters and, in particular, in relation to the
circadian rhythms of locomotive activity, which are a reliable
indicator of the activity of the endogenous circadian clock.
[0143] In this study, the effects of such compounds on a particular
experimental model, namely the rat placed in temporal isolation
(permanent darkness), are evaluated.
Experimental Protocol
[0144] One-month-old male rats are subjected, as soon as they
arrive at the laboratory, to a light cycle of 12 hours of light per
24 hours (LD 12:12).
[0145] After 2 to 3 weeks' adaptation, they are placed in cages
fitted with a wheel connected to a recording system in order to
detect the phases of locomotive activity and thus monitor the
nychthemeral (LD) or circadian (DD) rhythms.
[0146] As soon as the rhythms recorded show a stable pattern in the
light cycle LD 12:12, the rats are placed in permanent darkness
(DD).
[0147] Two to three weeks later, when the free course (rhythm
reflecting that of the endogenous clock) is clearly established,
the rats are given a daily administration of the compound to be
tested.
[0148] The observations are made by means of visualisation of the
rhythms of activity: [0149] influence of the light rhythm on the
rhythms of activity, [0150] disappearance of the influence on the
rhythms in permanent darkness, [0151] influence by the daily
administration of the compound; transitory or durable effect.
[0152] A software package makes it possible: [0153] to measure the
duration and intensity of the activity, the period of the rhythm of
the animals during free course and during treatment, [0154] to
demonstrate by spectral analysis the existence of circadian and
non-circadian (for example ultradian) components, where present.
Results
[0155] The compounds of the invention clearly appear to have a
powerful action on the circadian rhythm via the melatoninergic
system.
EXAMPLE E
Light/Dark Cages Test
[0156] The compounds of the invention are tested in a behavioural
model, the light/dark cages test, which enables the anxiolytic
activity of the compounds to be revealed.
[0157] The equipment comprises two polyvinyl boxes covered with
Plexiglas. One of the boxes is in darkness. A lamp is placed above
the other box, yielding a light intensity of approximately 4000 lux
at the centre of the box. An opaque plastics tunnel separates the
light box from the dark box. The animals are tested individually
for a session of 5 minutes. The floor of each box is cleaned
between each session. At the start of each test, the mouse is
placed in the tunnel, facing the dark box. The time spent by the
mouse in the illuminated box and the number of passages through the
tunnel are recorded after the first entry into the dark box.
[0158] After administration of the compounds 30 minutes before the
start of the test, the compounds of the invention significantly
increase the time spent in the illuminated cage and the number of
passages through the tunnel, which demonstrates the anxiolytic
activity of the compounds of the invention.
EXAMPLE F
Activity of the Compounds of the Invention on the Caudal Artery of
the Rat
[0159] The compounds of the invention were tested in vitro on the
caudal artery of the rat. Melatoninergic receptors are present in
those vessels, thus providing a relevant pharmacological model for
studying melatoninergic ligand activity. The stimulation of the
receptors can induce either vasoconstriction or dilation depending
upon the arterial segment studied.
Protocol
[0160] One-month-old rats are accustomed to a light/dark cycle of
12 h/12 h during a period of 2 to 3 weeks.
[0161] After sacrifice, the caudal artery is isolated and
maintained in a highly oxygenated medium. The arteries are then
cannulated at both ends, suspended vertically in an organ chamber
in a suitable medium and perfused via their proximal end. The
pressure changes in the perfusion flow enable evaluation of the
vasoconstrictive or vasodilatory effect of the compounds.
[0162] The activity of the compounds is evaluated on segments that
have been pre-contracted by phenylephrine (1 .mu.M). A
concentration/response curve is determined non-cumulatively by the
addition of a concentration of the test compound to the
pre-contracted segment. When the effect observed reaches
equilibrium, the medium is changed and the preparation is left for
20 minutes before the addition of the same concentration of
phenylephrine and a further concentration of the test compound.
Results
[0163] The compounds of the invention significantly modify the
diameter of caudal arteries pre-constricted by phenylephrine.
EXAMPLE G
Pharmaceutical Composition: Tablets
[0164] TABLE-US-00002 1000 tablets each containing a dose of 5 mg
of 5 g N-[2-(6-methoxy-4-isoquinolinyl)- ethyl]acetamide
hydrochloride (Example 9) wheat starch 20 g maize starch 20 g
lactose 30 g magnesium stearate 2 g silica 1 g hydroxypropyl
cellulose 2 g
* * * * *