U.S. patent application number 11/640595 was filed with the patent office on 2007-05-31 for substituted biphenyl compounds.
This patent application is currently assigned to LES LABORATOIRES SERVIER. Invention is credited to Caroline Bennejean, Herve Da-Costa, Philippe Delagrange, Carole Descamps-Francois, Gerald Guillaumet, Daniel Lesieur, Pierre Renard, Marie-Claude Viaud, Said Yous.
Application Number | 20070123529 11/640595 |
Document ID | / |
Family ID | 8854338 |
Filed Date | 2007-05-31 |
United States Patent
Application |
20070123529 |
Kind Code |
A1 |
Descamps-Francois; Carole ;
et al. |
May 31, 2007 |
Substituted biphenyl compounds
Abstract
The invention relates to compound of formula (I) ##STR1##
wherein: B represents hydrogen, COOR, CONRR', or
(C.sub.1-C.sub.6)alkyl substituted by COOR, CONRR', or OR, G.sub.1
represents --X'--(CH.sub.2).sub.n--X--(CH.sub.2).sub.m--X''-- chain
wherein X, X', X'', n and m are as defined in the description, Cy
represents a grouping of formula (II) or (III): ##STR2## G.sub.2
represents alkylene chain as defined in the description, and A
represents NRCOR', NRCSR', CONRR', CSNRR', NRCONR'R'', or
NRCSNR'R''. and medicinal products containing the same which are
useful in treating or preventing melatoninergic disorders.
Inventors: |
Descamps-Francois; Carole;
(Hellemes, FR) ; Yous; Said; (Loos, FR) ;
Lesieur; Daniel; (Gondecourt, FR) ; Guillaumet;
Gerald; (Saint Jean Le Blanc, FR) ; Viaud;
Marie-Claude; (Tours, FR) ; Da-Costa; Herve;
(Chambray Les Tours, FR) ; Bennejean; Caroline;
(Charenton Le Pont, FR) ; Delagrange; Philippe;
(Issy Les Moulineaux, FR) ; Renard; Pierre; (Le
Chesnay, 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
92415
|
Family ID: |
8854338 |
Appl. No.: |
11/640595 |
Filed: |
December 18, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10380866 |
Mar 14, 2003 |
7161035 |
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PCT/FR01/02297 |
Jul 16, 2001 |
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11640595 |
Dec 18, 2006 |
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Current U.S.
Class: |
514/232.8 ;
514/300; 544/127; 546/112 |
Current CPC
Class: |
A61P 25/20 20180101;
C07C 233/18 20130101; C07C 2601/04 20170501; A61P 25/04 20180101;
C07D 307/79 20130101; A61P 3/10 20180101; C07C 2602/10 20170501;
C07D 307/68 20130101; A61P 25/16 20180101; C07C 2602/08 20170501;
A61P 35/00 20180101; A61P 25/28 20180101; C07D 209/08 20130101;
A61P 15/00 20180101; C07D 333/54 20130101; C07D 471/04 20130101;
A61P 3/04 20180101; C07C 233/60 20130101; A61P 25/00 20180101 |
Class at
Publication: |
514/232.8 ;
514/300; 544/127; 546/112 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/4745 20060101 A61K031/4745; C07D 471/02
20060101 C07D471/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 15, 2000 |
FR |
00.11779 |
Claims
1. A compound selected from those of formula (I): ##STR7## wherein
B represents hydrogen, COOR, CONRR', or linear or branched
(C.sub.1-C.sub.6)alkyl substituted by COOR, CONRR', or OR wherein R
and R', which may be identical or different, each represents
hydrogen, or 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, aryl, aryl-(C.sub.1-C.sub.6)alkyl in
which the alkyl moiety may be linear or branched, heteroaryl,
heteroaryl-(C.sub.1-C.sub.6)alkyl in which the alkyl moiety may be
linear or branched, polyhalo-(C.sub.1-C.sub.6)alkyl in which the
alkyl moiety may be linear or branched, (C.sub.3-C.sub.8)cycloalkyl
or (C.sub.3-C.sub.8)cycloalkyl-(C.sub.1-C.sub.6)alkyl in which the
alkyl moiety may be linear or branched, it being possible in
addition for R and R' to form, together with the nitrogen carrying
them, morpholinyl, piperidyl, piperazinyl, or pyrrolidinyl, G.sub.1
represents an --X'--(CH.sub.2).sub.n--X--(CH.sub.2).sub.m--X''--
chain wherein X represents CH.sub.2, X' and X'', which may be
identical or different, each represents oxygen or sulphur, n and m,
which may be identical or different, each represents 0, 1, 2, 3, 4
or 5, it being understood that it is not possible to have two
consecutive hetero atoms in the chain and that the chain so defined
may contain one or more unsaturations, Cy represents a group of
formula (II) ##STR8## wherein D represents phenyl or pyridine, W
represents oxygen, sulphur, CH.sub.2, or NR, wherein R is as
defined hereinbefore, R.sub.1 represents halogen, R, OR, or COOR,
wherein R is as defined hereinbefore and the representation denotes
that the bond is single or double, it being understood that the
valency of the atoms is respected, G.sub.2 represents a 1 to 6
carbon atom chain containing that is optionally substituted by one
or more groups selected from R, OR, COR, COOR, wherein R is as
defined hereinbefore, and halogen, and A represents NRCOR', NRCSR',
CONRR', CSNRR', NRCONR'R'', or NRCSNR'R'', wherein R and R' are as
defined hereinbefore and R'' may have the same meanings as R and
R', wherein: "aryl" is to be understood as meaning phenyl or
naphthyl that is unsubstituted or substituted by one or more
identical or different groups selected from R, OR, COR, COOR, NRR',
wherein R and R' are as defined hereinbefore, nitro, cyano and
halogen, "heteroaryl" is to be understood as meaning any mono- or
bi-cyclic group having from 5 to 10 ring members and capable of
containing from 1 to 3 hetero atoms selected from oxygen, sulphur,
and nitrogen, that group being unsubstituted or substituted by one
or more identical or different groups selected from R, OR, COR,
COOR, NRR', wherein R and R' are as defined hereinbefore, nitro,
cyano, and halogen, its enantiomers and diastereoisomers, and also
addition salts thereof with a pharmaceutically acceptable acid or
base.
2. A compound of claim 1, wherein B represents COOR.
3. A compound of claim 2, wherein R represents hydrogen.
4. A compound of claim 2, wherein R represents linear or branched
(C.sub.1-C.sub.6)alkyl.
5. A compound of claim 1, wherein B represents linear or branched
(C.sub.1-C.sub.6)alkyl substituted by COOR.
6. A compound of claim 1, wherein B represents linear or branched
(C.sub.1-C.sub.6)alkyl substituted by OR.
7. A compound of claim 1, wherein G.sub.1 represents
--O--(CH.sub.2).sub.p--O-- in which p is an integer such that
0<p<6.
8. A compound of claim 1, wherein A represents NHCOR.
9. A compound of claim 1, which is selected from ethyl
4'-[4-({3-[2-(acetylamino)ethyl]-1-methyl-1H-pyrrolo[3,2-b]pyrid-5-yl}oxy-
)butoxy]-[1,1'-biphenyl]-4-carboxylate and addition salts thereof
with a pharmaceutically-acceptable acid or base.
10. A method for treating a living animal body, including a human,
afflicted with a disorder of the melatoninergic system, comprising
the step of administering to the living animal body, including a
human, an amount of a compound of claim 1 which is effective for
the alleviation of the disorder.
11. A pharmaceutical composition comprising as active principle an
effective amount of a compound of claim 1, together with one or
more pharmaceutically-acceptable excipients or vehicles.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new substituted biphenyl
compounds to a process for their preparation and to pharmaceutical
compositions containing them.
[0002] In view of their novel structure, the compounds of the
present invention are new and they exhibit pharmacological
properties of great interest in relation to melatoninergic
receptors.
DESCRIPTION OF THE PRIOR ART
[0003] There are known from the literature indolic biphenyl
compounds that are useful as metalloprotease inhibitors (WO 96
15096) or specific ligands of 5HT-1B and 5HT-1D receptors (WO 95
01334).
[0004] Also, benzimidazolic biphenyl compounds are described in
Patent Application EP 468 470 as angiotensin inhibitors.
BACKGROUND OF THE INVENTION
[0005] 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.
[0006] 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, for example
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). Such 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).
[0007] 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, to have specific
ligands available is of great interest. 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.
[0008] 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
[0009] More especially, the present invention relates to compounds
of formula (I): ##STR3## wherein: [0010] B represents a hydrogen
atom, a COOR group, a CONRR' group, or a linear or branched
(C.sub.1-C.sub.6)alkyl group substituted by a COOR, CONRR' or OR
group (wherein R and R', which may be identical or different, each
represents a hydrogen atom, or a group 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, aryl, aryl-(C.sub.1-C.sub.6)alkyl in
which the alkyl moiety may be linear or branched, heteroaryl,
heteroaryl-(C.sub.1-C.sub.6)alkyl in which the alkyl moiety may be
linear or branched, polyhalo-(C.sub.1-C.sub.6)alkyl in which the
alkyl moiety may be linear or branched, (C.sub.3-C.sub.8)cycloalkyl
or (C.sub.3-C.sub.8)cycloalkyl-(C.sub.1-C.sub.6)alkyl in which the
alkyl moiety may be linear or branched, it being possible in
addition for R and R' to form, together with the nitrogen atom
carrying them, a morpholinyl, piperidyl, piperazinyl or
pyrrolidinyl group), [0011] G.sub.1 represents a
--X'--(CH.sub.2).sub.n--X--(CH.sub.2).sub.m--X''-- chain wherein
[0012] X represents an oxygen or sulphur atom, or a CH.sub.2 or NR
group (wherein R is as defined hereinbefore), [0013] X' and X'',
which may be identical or different, each represents an oxygen or
sulphur atom or an NR group (wherein R is as defined hereinbefore),
[0014] n and m, which may be identical or different, each
represents 0, 1, 2, 3, 4 or 5, it being understood that it is not
possible to have two consecutive hetero atoms and that the chain so
defined may contain one or more unsaturations, [0015] Cy represents
a grouping of formula (II) ##STR4## [0016] wherein D represents a
phenyl or a pyridine, W represents an oxygen or sulphur atom, or a
CH.sub.2 or NR group (wherein R is as defined hereinbefore),
R.sub.1 represents a halogen atom or an R, OR or COOR group
(wherein R is as defined hereinbefore) and the representation
denotes that the bond is single or double, it being understood that
the valency of the atoms is respected, [0017] or a grouping of
formula (III) ##STR5## [0018] wherein R.sub.1 and the
representation are as defined hereinbefore [0019] G.sub.2
represents a chain containing from 1 to 6 carbon atoms that is
optionally substituted by one or more groups selected from R, OR,
COR, COOR (wherein R is as defined hereinbefore) and halogen atoms,
[0020] and A represents a NRCOR', NRCSR', CONRR', CSNRR',
NRCONR'R'' or NRCSNR'R'' group (wherein R and R' are as defined
hereinbefore and R'' may have the same meanings as R and R'),
wherein: [0021] "aryl" is to be understood as meaning a phenyl or
naphthyl group that is unsubstituted or substituted by one or more
identical or different groups selected from R, OR, COR, COOR, NRR'
(wherein R and R' are as defined hereinbefore), nitro, cyano and
halogen atoms, [0022] "heteroaryl" is to be understood as meaning
any mono- or bi-cyclic group having from 5 to 10 ring members and
capable of containing from 1 to 3 hetero atoms selected from
oxygen, sulphur and nitrogen, that group being unsubstituted or
substituted by one or more identical or different groups selected
from R, OR, COR, COOR, NRR' (wherein R and R' are as defined
hereinbefore), nitro, cyano and halogen atoms, to their enantiomers
and diastereoisomers and also to addition salts thereof with a
pharmaceutically acceptable acid or base.
[0023] Among the pharmaceutically acceptable acids there may be
mentioned by way of non-limiting example hydrochloric, hydrobromic,
sulphuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic,
malonic, succinic, glutaric, fumaric, tartaric, maleic, citric,
ascorbic, methanesulphonic, camphoric acid etc.
[0024] Among the pharmaceutically acceptable bases there may be
mentioned by way of non-limiting example sodium hydroxide,
potassium hydroxide, triethylamine, tert-butylamine etc.
[0025] Preferred compounds of the invention are compounds of
formula (I) wherein B represents: [0026] a COOR group wherein R is
preferably a hydrogen atom or a linear or branched
(C.sub.1-C.sub.6)alkyl group, such as, for example, methyl, [0027]
or a linear or branched (C.sub.1-C.sub.6)alkyl group substituted by
a COOR or OR group, more especially COOH, alkyloxycarbonyl, OH or
alkoxy.
[0028] The preferred G.sub.1 group of the compounds of the
invention is the group --O--(CH.sub.2).sub.p--O-- wherein p is an
integer such that 0<p<6, such as, for example,
--O--(CH.sub.2).sub.4--O--.
[0029] The invention relates more especially to compounds of
formula (I) wherein Cy represents a naphthalene,
tetrahydronaphthalene, benzothiophene, benzofuran, indole, indene
or azaindole group.
[0030] G.sub.2 prefereably represents a --(CH.sub.2).sub.2-- or
--(CH.sub.2).sub.3-- group.
[0031] Preferred meanings for A are the groups NRCOR' and CONRR',
more especially the groups NHCOR' and CONHR.
[0032] Even more especially, the invention relates to the following
compounds of formula (I): [0033] methyl
4'-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1'-biphenyl]-4-
-carboxylate, [0034]
4'-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1'-biphenyl]-4-
-carboxylic acid, [0035]
N-{2-[7-(4-{[4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl]oxy}butoxy)-1-naphth-
yl]ethyl}-acetamide, [0036]
N-(2-{7-[4-([1,1'-biphenyl]-4-yloxy)butoxy]-1-naphthyl}ethyl)acetamide,
[0037]
N-(2-{7-[4-([1,1'-biphenyl]-3-yloxy)butoxy]-1-naphthyl}ethyl)acet-
amide.
[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 the compounds of formula (I), which process is
characterised in that there is used as starting material a compound
of formula: MeO-Cy-G.sub.2-A (IV) wherein A, G.sub.2 and Cy are as
defined for formula (I), which is subjected to demethylation using
conventional agents, such as HBr, AlCl.sub.3, AlBr.sub.3, BBr.sub.3
or Lewis acid/nucleophile binary systems such as
AlCl.sub.3/PhCH.sub.2SH or BBr.sub.3/Me.sub.2S, for example, to
obtain a compound of formula (V): HO-Cy-G.sub.2-A (V) wherein A,
G.sub.2 and Cy are as defined hereinbefore, which is converted in
conventional manner [0040] by the action of sodium
N,N-dimethylthiocarbamate for example, to the corresponding thiol
of formula (VI): HS-Cy-G.sub.2-A (VI) [0041] wherein A, G.sub.2 and
Cy are as defined hereinbefore, [0042] or to the corresponding
amine compound of formula (VII): RNH-Cy-G.sub.2-A (VII) [0043]
wherein A, G.sub.2, Cy and R are as defined hereinbefore, the
compounds of formula (V), (VI) and (VII) representing the compound
of formula (VIII): HX''-Cy-G.sub.2-A (VIII) wherein Cy, G.sub.2,
X'' and A are as defined hereinbefore, which compound of formula
(VIII) is condensed with a compound of formula (IX): ##STR6##
wherein Hal represents a bromine, chlorine or iodine atom, and X, n
and m are as defined for formula (I), (it being understood that it
is not possible to have two consecutive hetero atoms and that the
chain so defined may contain one or more unsaturations), to yield a
compound of formula (X):
HO--(CH.sub.2).sub.n--X--(CH.sub.2).sub.n--X''-Cy-G.sub.2-A (X)
wherein A, G.sub.2, Cy, X, X'', n and m are as defined hereinbefore
(it being understood that it is not possible to have two
consecutive hetero atoms in the
HO--(CH.sub.2).sub.n--X--(CH.sub.2).sub.m--X''--chain and that the
chain so defined may contain one or more unsaturations), the
hydroxy function of which is converted in conventional manner into
a leaving group; such as, for example, a mesylate, a tosylate, or a
halogenated compound, to yield a compound of formula (X'):
E-(CH.sub.2).sub.n--X--(CH.sub.2).sub.m--X''-Cy-G.sub.2-A (X')
wherein A, G.sub.2, Cy, X, X'', n and m are as defined hereinbefore
and E represents a mesyl or tosyl group or a halogen atom, which is
reacted in basic medium with a compound of formula (XI):
B'-Ph-Ph-X'H (XI) wherein X' is as defined for formula (I), and B'
may have the same meanings as B as defined for formula (I) with the
exception of the groups COOH and alkyl substituted by a COOH group,
to yield a compound of formula (I/a), a particular case of the
compounds of formula (I): B'-Ph-Ph-G.sub.1-Cy-G.sub.2-A (I/a)
wherein A, G.sub.2, G.sub.1, Cy and B' are as defined hereinbefore,
the compound of formula (I/a) being subjected, when B' represents a
COOR.sub.1' group or alkyl substituted by a COOR.sub.1' group
(wherein R.sub.1' may have any of the meanings of R defined
hereinbefore with the exception of a hydrogen atom), to hydrolysis
to yield a compound of formula (I/b), a particular case of the
compounds of formula (I): B''-Ph-Ph-G.sub.1-Cy-G.sub.2-A (I/b)
wherein A, G.sub.2, G.sub.1 and Cy are as defined hereinbefore, and
B'' represents a COOH group or alkyl substituted by a COOH group,
the totality of the compounds (I/a) and (I/b) constituting the
compounds of formula (I) which may, if desired, be purified by a
conventional purification technique, are optionally separated into
their isomers according to a conventional separation technique and,
if desired, are converted into addition salts with a
pharmaceutically acceptable acid or base.
[0044] The compounds of formula (IV) are readily obtainable by the
person skilled in the art according to methods described in the
literature.
[0045] The compounds of the invention and pharmaceutical
compositions containing them have proved 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 the microcirculation,
enabling it to be established that the products of the invention
are useful in the treatment of stress, sleep disorders, anxiety,
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 aging, migraine, memory
losses, 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 dysfunctions, that
they have ovulation-inhibiting and immunomodulating properties and
that they are capable of being used in the treatment of
cancers.
[0047] The compounds will preferably be used in the treatment of
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 route of administration, the nature of the
therapeutic indication or possibly 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 but do not
limit it in any way. The following Preparations result in compounds
of the invention or in synthesis intermediates useful in the
preparation of the invention.
Preparation 1: N-[2-(7-Hydroxy-1-naphthyl)ethyl]acetamide
[0053] Under an inert atmosphere, 27.5 mmol of boron
tribromide/dimethyl sulphide complex are dissolved in 100 ml of
dichloromethane and stirred for 15 minutes at ambient temperature.
A solution of 13.7 mmol of
N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of
dichloromethane is added, and the reaction mixture is heated at
reflux for 30 hours. After cooling, the reaction mixture is
cautiously hydrolysed and the dichloromethane is evaporated off.
The mixture is then extracted with ethyl acetate and the combined
organic phases are washed with an aqueous 1M potassium hydrogen
carbonate solution. The organic phase is dried over magnesium
sulphate and concentrated to yield the title compound. White
solid.
[0054] Melting point: 125-126.degree. C.
[0055] By proceeding as in Preparation 1, using as starting
material the appropriate substrate, Preparations 2 to 14 are
obtained:
Preparation 2:
N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]acetamide
Preparation 3:
N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide
Preparation 4:
N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]-2-furamide
Preparation 5: N-[2-(7-Hydroxy-1-naphthyl)ethyl]butanamide
Preparation 6:
N-[2-(5-Hydroxy-1-benzothien-3-yl)ethyl]acetamide
Preparation 7:
N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyrid-3-yl)ethyl]cyclopropane-carboxamid-
e
Preparation 8: N-[2-(5-Hydroxy-1H-indol-3-yl)ethyl]acetamide
Preparation 9:
N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyrid-3-yl)ethyl]acetamide
Preparation 10:
N-[2-(7-Hydroxy-1-naphthyl)ethyl]cyclobutanecarboxamide
Preparation 11:
2,2,2-Trifluoro-N-[2-(7-hydroxy-1-naphthyl)ethyl]acetamide
Preparation 12: N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-furamide
Preparation 13:
N-[2-(2-Benzyl-5-hydroxy-1H-pyrrolo[2,3-b]pyrid-3-yl)ethyl]-acetamide
Preparation 14: N-[2-(5-Hydroxy-1H-inden-3-yl)ethyl]pentanamide
Preparation 15:
N-[2-(5-Mercapto-1-benzofuran-3-yl)ethyl]acetamide
[0056] The product obtained in Preparation 2 (9 mmol) is added,
with stirring, to a solution of potassium hydroxide (10 mmol)
dissolved in 15 ml of water and 16 ml of tetrahydrofuran. The
solution is cooled using an ice/salt bath, and
dimethylthiocarbamoyl chloride (9 mmol) dissolved in
tetrahydrofuran (15 ml) is added dropwise with stirring. After
stirring for half an hour while keeping cold, the reaction mixture
is extracted with chloroform. The organic phases are combined,
dried over magnesium sulphate, filtered and then concentrated under
reduced pressure. The residue is taken up in diphenyl ether (10 ml)
and heated at reflux for one hour under a nitrogen atmosphere. The
diphenyl ether is evaporated off under reduced pressure until a
solution of approximately 2 ml is obtained. The 2 ml of distillate
are cautiously poured, while still hot, into 50 ml of hexane to
yield, after cooling, a solid isolated by filtration. The solid so
obtained is added to a solution of potassium hydroxide (380 mg)
dissolved in a water/methanol (1 ml/10 ml) mixture. The solution is
heated at reflux for 12 hours and then cooled and concentrated
under reduced pressure. The residue is taken up in 20 ml of
chloroform and extracted 3 times with water. The organic phase is
dried over magnesium sulphate, filtered and concentrated under
reduced pressure. The residue is chromatographed on silica gel to
yield the title product.
Preparation 16: N-[2-(5-Amino-1-benzofuran-3-yl)ethyl]acetamide
Step A: N-[2-(5-Bromo-1-benzofuran-3-yl)ethyl]acetamide
[0057] Triphenylphosphine (10 mmol) and acetonitrile (70 ml) are
poured into a 150 ml three-necked flask equipped with a dropping
funnel, a condenser on top of which is mounted a tube filled with
calcium chloride, and a mechanical stirrer. The solution is cooled
using an ice-bath while maintaining stirring, and bromine (10 mmol)
is added. When the addition is complete, the ice-bath is removed
and then the product obtained in Preparation 2 (8 mmol) is added.
The reaction mixture is stirred at 60-70.degree. C. until the
starting material has disappeared. At the end of the reaction, the
mixture is filtered, and then the filtrate is concentrated under
reduced pressure. The residue is taken up in ethyl acetate, washed
with water and then with a saturated potassium hydrogen carbonate
solution, and once again with water, and then dried over magnesium
sulphate and concentrated under reduced pressure. The residue is
filtered over silica gel to yield the title product.
Step B: N-[2-(5-Iodo-1-benzofuran-3-yl)ethyl]acetamide
[0058] A mixture of the product obtained in Step A (2 mmol),
potassium iodide (30 mmol) and copper(I) iodide (10 mmol) in
hexamethylphosphoramide (6 ml) is heated at 150-160.degree. C. with
stirring, under a nitrogen atmosphere, until a 90% conversion rate
has been reached. Dilute hydrochloric acid is then added, followed
by ether, and the mixture is then filtered to remove the insoluble
copper(I) salts. The organic phase is separated off, washed with a
solution of sodium sulphite and with water, dried over magnesium
sulphate and evaporated to yield a residue which is chromatographed
on silica gel to yield the title product.
Step C: N-[2-(5-Vinyl-1-benzofuran-3-yl)ethyl]acetamide
[0059] 15 mmol of the product obtained in Step B, 16 mmol of
vinyltributyltin and 0.43 mmol of
tetrakis(triphenylphosphine)palladium are heated for 3 hours at
110.degree. C., with stirring, in 30 ml of N-methylpyrrolidinone.
After removal of the solvent by evaporation, the residue is taken
up in 20 ml of dichloromethane and treated with an aqueous 10%
potassium fluoride solution. Extraction, concentration under
reduced pressure and chromatography on silica gel yield the pure
title product.
Step D: N-[2-(5-Formyl-1-benzofuran-3-yl)ethyl]acetamide
[0060] 1.10 g of osmium tetroxide in 2-methyl-2-propanol and then
8.70 g of sodium periodate are added at ambient temperature to a
solution of 10 mmol of the product obtained in Step C in a mixture
of 50 ml of dioxane and 25 ml of water. After stirring overnight at
ambient temperature, the suspension is filtered and the filtrate is
concentrated under reduced pressure. The resulting residue is taken
up in dichloromethane. The organic phase is washed with water,
dried and evaporated. The residue is purified by chromatography on
silica gel to yield the title product.
Step E: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxylic acid
[0061] 2.7 g of potassium permanganate in 50 ml of an acetone/water
mixture (50/50) are added at ambient temperature to a solution of
6.88 mmol of the product obtained in Step D in 30 ml of acetone.
The solution is stirred for 2 hours at ambient temperature and then
filtered. The filtrate is concentrated under reduced pressure and
chromatographed on silica gel to yield the title product.
Step F: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxylic acid
chloride
[0062] 5 mmol of the product obtained in Step E are dissolved in 40
ml of thionyl chloride. After stirring under an inert atmosphere
for 1 hour, the thionyl chloride is removed by evaporation under
reduced pressure to yield the title product.
Step G: N-[2-(5-Amino-1-benzofuran-3-yl)ethyl]acetamide
[0063] A solution of the product obtained in Step F (20 mmol) in
dichloromethane (30 ml) containing tetrabutylammonium bromide (20
mg) is cooled in an ice-bath. After the addition of sodium azide
(25 mmol) dissolved in 5 ml of water, the solution is stirred
vigorously at 0.degree. C. for 2 hours. The organic phase is
separated off, washed with water (2.times.5 ml) and dried over
magnesium sulphate. After filtration, trifluoroacetic acid (30
mmol) is added and the solution is stirred under reflux for 60
hours. After cooling, the organic phase is washed with a saturated
sodium hydrogen carbonate solution (2.times.5 ml) and concentrated
under reduced pressure. The residue is then taken up in methanol
(20 ml), and water (80 ml) and then potassium carbonate (30 mmol)
are added. After stirring at ambient temperature for 20 hours, the
reaction mixture is concentrated under reduced pressure to a volume
of about 60 ml, and is then extracted 3 times with ether
(3.times.50 ml). After drying over sodium sulphate, the organic
phase is filtered and then evaporated under reduced pressure. The
residue is chromatographed on silica gel to yield the title
product.
Preparation 17:
N-[2-(5-Amino-1-benzofuran-3-yl)ethyl]-2-furamide
[0064] The procedure is as in Preparation 16 starting from the
compound obtained in Preparation 4.
Preparation 18:
N-[2-(5-Hydroxy-1-methyl-1H-pyrrolo[2,3-b]pyrid-3-yl)ethyl]-acetamide
[0065] The procedure is as in Preparation 1.
Preparation 19:
N-[2-(7-Hydroxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide
[0066] The procedure is as in Preparation 1.
Preparation 20:
N-[2-(5-Hydroxy-1-methyl-1H-pyrrolo[3,2-b]pyrid-3-yl)ethyl]-acetamide
[0067] The procedure is as in Preparation 1.
EXAMPLE 1
Methyl
4'-[2-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)ethoxy]-[1,1'-biphe-
nyl]-4-carboxylate
Step A: N-{2-[7-(2-Bromoethoxy)naphth-1-yl]ethyl}cetamide
[0068] The compound obtained in Preparation 1 (0.009 mol) is
dissolved in 20 ml of a mixture of dimethyl sulphoxide (6 ml) and
butanone (14 ml). 0.027 mol of potassium carbonate and 0.036 mol of
dibromoethane are added, and the mixture is heated at reflux for 48
hours. The reaction mixture is then cooled and poured into water.
The aqueous phase is extracted with Et.sub.2O, and then the organic
phase is washed with water until the washing waters are neutral,
and subsequently dried over magnesium sulphate and evaporated under
reduced pressure. The resulting residue is purified by
chromatography on silica gel (eluant: acetone/cyclohexane (2/8))
and recrystallized. White solid.
[0069] Melting point: 1110-111.degree. C.
[0070] Elemental microanalysis: TABLE-US-00001 % C H N Calculated:
57.15 5.40 4.17 Found: 57.28 5.38 3.91
Step B: Methyl
4'-[2-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)ethoxy]-[1,1'-biphenyl]-4-
-carboxylate
[0071] In a 100 ml round-bottomed flask, 0.003 mol of methyl
4'-hydroxy[1,1'-biphenyl]-4-carboxylate and 0.003 mol of the
compound obtained in Step A are dissolved in a mixture of 3 ml of
dimethyl sulphoxide and 20 ml of butanone. 0.009 mol of potassium
carbonate and one potassium iodide crystal are added and then the
mixture is heated at reflux for 12 hours. The reaction mixture is
then cooled and poured into 100 ml of water. The precipitate that
forms is suctioned off and recrystallized to yield the title
product.
EXAMPLE 2
4'-[2-({8-[2-(Acetylamino)ethyl]-2-naphthyl}oxy)ethoxy]-[1,1'-biphenyl]-4--
carboxylic acid
[0072] In a 100 ml round-bottomed flask, 19 mmol of the compound
obtained in Example 1 are suspended in 25 ml of THF, and then 15 ml
of methanol, 15 ml of water and 38 mmol of sodium hydroxide are
added. The reaction mixture is maintained at ambient temperature
with stirring for 10 hours. The solution is subsequently
concentrated, poured into water and then acidified with 12M HCl.
The precipitate obtained is filtered off, washed with water and
recrystallized to yield the title product.
EXAMPLE 3
Methyl
4'-[2-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}oxy)ethoxy]-[1,1-
'-biphenyl]-4-carboxylate
[0073] The procedure is as in Example 1, with the replacement in
Step A of the compound obtained in Preparation 1 by the compound
obtained in Preparation 2.
EXAMPLE 4
Methyl
4'-{2-[(3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl)o-
xy]ethoxy}-[1,1'-biphenyl]-4-carboxylate
[0074] The procedure is as in Example 1, with the replacement in
Step A of the compound obtained in Preparation 1 by the compound
obtained in Preparation 3.
EXAMPLE 5
Methyl
4'-[2-({3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl}oxy)ethoxy]-[1-
,1'-biphenyl]-4-carboxylate
[0075] The procedure is as in Example 1, with the replacement in
Step A of the compound obtained in Preparation 1 by the compound
obtained in Preparation 4.
EXAMPLE 6
Methyl
4'-[2-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}amino)-ethoxy]-[-
1,1'-biphenyl]-4-carboxylate
[0076] The procedure is as in Example 1, with the replacement in
Step A of the compound obtained in Preparation 1 by the compound
obtained in Preparation 16.
EXAMPLE 7
Methyl
4'-[2-({8-[2-(butyrylamino)ethyl]-2-naphthyl}oxy)ethoxy]-[1,1'-biph-
enyl]-4-carboxylate
[0077] The procedure is as in Example 1, with the replacement in
Step A of the compound obtained in Preparation 1 by the compound
obtained in Preparation 5.
EXAMPLE 8
Methyl
4'-[2-({3-[2-(acetylamino)ethyl]-1-benzothien-5-yl}oxy)ethoxy]-[1,1-
'-biphenyl]-4-carboxylate
[0078] The procedure is as in Example 1, with the replacement in
Step A of the compound obtained in Preparation 1 by the compound
obtained in Preparation 6.
EXAMPLE 9
Methyl
4'-{2-[(3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo-[2,3-b]p-
yrid-5-yl)oxy]ethoxy}-[1,1'-biphenyl]-4-carboxylate
[0079] The procedure is as in Example 1, with the replacement in
Step A of the product obtained in Preparation 1 by the compound
obtained in Preparation 7.
EXAMPLE 10
N-{2-[7-(2-{[4'-(Hydroxymethyl)-[1,1'-biphenyl]-4-yl]oxy}ethoxy)-1-naphthy-
l]ethyl}acetamide
[0080] The procedure is as in Example 1, with the replacement in
Step B of methyl 4'-hydroxy[1,1'-biphenyl]-4-carboxylate by
4'-(hydroxymethyl)-[1,1'-biphenyl]-4-ol.
EXAMPLE 11
Methyl
4'-[2-({3-[2-(acetylamino)ethyl]-1H-indol-5-yl}oxy)ethoxy]-[1,1'-bi-
phenyl]-4-carboxylate
[0081] The procedure is as in Example 1, with the replacement in
Step A of the compound obtained in Preparation 1 by the compound
obtained in Preparation 8.
EXAMPLE 12
4'-[2-({3-[2-(Acetylamino)ethyl]-1H-indol-5-yl}oxy)ethoxy-]-[1,1'-biphenyl-
]-4-carboxylic acid
[0082] The procedure is as in Example 2, starting from the compound
obtained in Example 11.
EXAMPLE 13
Methyl
4'-[3-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)propoxy]-[1,1'-biph-
enyl]-4-carboxylate
Step A: N-{2-[7-(3-Hydroxypropyloxy)naphth-1-yl]ethyl}acetamide
[0083] In a 100 ml round-bottomed flask, 0.022 mol of the compound
obtained in Preparation 1 is dissolved in 30 ml of
dimethylformamide. 0.066 mol of potassium carbonate and 0.033 mol
of 3-bromopropan-1-ol are added, and then the mixture is heated at
80.degree. C. for 4 hours. The reaction mixture is cooled and
poured into 100 ml of a 1M HCl solution. The aqueous phase is
extracted 3 times with Et.sub.2O and then the organic phase is
dried over MgSO.sub.4 and evaporated under reduced pressure. The
title product is obtained by recrystallization. White solid.
[0084] Melting point: 141-142.degree. C.
Step B: 3-({8-[2-(Acetylamino)ethyl]-2-naphthyl}oxy)propyl
methanesulphonate
[0085] In a 250 ml round-bottomed flask, the alcohol obtained in
Step A is dissolved in 50 ml of dichloromethane, and 0.012 mol of
triethylamine is added. The mixture is cooled in an ice/salt bath
at -10.degree. C., and then 0.012 mol of mesyl chloride is added
dropwise with magnetic stirring. The reaction mixture is stirred at
ambient temperature for 4 hours. 100 ml of water are then added,
followed by extraction with CH.sub.2Cl.sub.2. The organic phase is
washed with water, dried over MgSO.sub.4 and evaporated under
reduced pressure. The resulting oil is purified by chromatography
on silica gel (eluant: acetone/cyclohexane (2/8)).
Step C: Methyl
4'-[3-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)propoxy]-[1,1'-biphenyl]--
4-carboxylate
[0086] In a 100 ml round-bottomed flask containing 30 ml of
methanol, 0.06 g of sodium is added in small portions. When the
sodium has been completely used up, 0.0033 mol of methyl
4'-hydroxy[1,1'-biphenyl]-4-carboxylate is added and the mixture is
stirred for 20 minutes. The methanol is removed by evaporation
under reduced pressure, the residue is taken up in 15 ml of DMF,
and then 0.0027 mol of the compound obtained in Step B is added.
The reaction mixture is then heated at reflux for 12 hours and
subsequently cooled and poured into 100 ml of water and 10 ml of 3M
HCl. After extraction with ethyl acetate, the organic phase is
washed with a 10% sodium hydroxide solution and then with water.
After drying over MgSO.sub.4 and removal of the solvent by
evaporation under reduced pressure, the title compound is purified
by chromatography on silica gel.
EXAMPLE 14
Methyl
4'-{3-[(8-{2-[(cyclobutylcarbonyl)amino]ethyl}-2-naphthyl)oxy]-prop-
oxy}-[1,1'-biphenyl]-4-carboxylate
[0087] The procedure is as in Example 13, starting from the
compound obtained in Preparation 10.
EXAMPLE 15
Methyl
4'-[3-({3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl}amino)-propoxy-
]-[1,1'-biphenyl]-4-carboxylate
[0088] The procedure is as in Example 13, starting from the
compound obtained in Preparation 17.
EXAMPLE 16
4'-[3-({3-[2-(2-Furoylamino)ethyl]-1-benzofuran-5-yl}aminopropoxy]-1,1'-bi-
phenyl]-4-carboxylic acid
[0089] The procedure is as in Example 2, starting from the compound
obtained in Example 15.
EXAMPLE 17
Methyl
4'-{3-[(8-{2-[(trifluoroacetyl)amino]ethyl}-2-naphthyl)oxy]-propoxy-
}-[1,1'-biphenyl]-4-carboxylate
[0090] The procedure is as in Example 13, with the replacement of
the compound of Preparation 1 by the compound of Preparation
11.
EXAMPLE 18
4'-{3-[(8-{2-[(Trifluoroacetyl)amino]ethyl}-2-naphthyl)oxy]propoxy}-[1,1'--
biphenyl]-4-carboxylic acid
[0091] The procedure is as in Example 2, starting from the compound
obtained in Example 17.
EXAMPLE 19
Methyl
4'-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1'-biphe-
nyl]-4-carboxylate
Step A: N-{2-[7-(4-Bromobutoxy)-1-naphthyl]ethyl}acetamide
[0092] The procedure is as in Step A of Example 1, with the
replacement of dibromoethane by 1,4-dibromobutane.
Step B: Methyl
4'-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1'-biphenyl]-4-
-carboxylate
[0093] The procedure is as in Step B of Example 1.
[0094] White solid.
[0095] Melting point: 166-168.degree. C.
[0096] Elemental microanalysis: TABLE-US-00002 % C H N Calculated:
74.61 6.45 2.72 Found: 74.62 6.48 2.81
EXAMPLE 20
4'-[4-({8-[2-(Acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1'-biphenyl]-4--
carboxylic acid
[0097] The procedure is as in Example 2, starting from the compound
obtained in Example 19.
[0098] White solid.
[0099] Melting point: 223-225.degree. C.
[0100] Elemental microanalysis: TABLE-US-00003 % C H N Calculated:
70.83 5.94 2.66 Found: 71.16 6.05 2.69
EXAMPLE 21
N-{2-[7-(4-{[4'-(Hydroxymethyl)-[1,1'-biphenyl]-4-yl]oxy}butoxy)-1-naphthy-
l]ethyl}acetamide
[0101] The procedure is as in Example 19, with the replacement in
Step B of methyl 4'-hydroxy[1,1'-biphenyl]-4-carboxylate by
4'-(hydroxymethyl)-[1,1'-biphenyl]-4-ol.
[0102] Beige solid.
[0103] Melting point: 172-173.degree. C.
[0104] Elemental microanalysis: TABLE-US-00004 % C H N Calculated:
76.99 6.88 2.90 Found: 76.74 6.70 3.12
EXAMPLE 22
N-(2-{7-[4-([1,1'-Biphenyl]-4-yloxy)butoxy]-1-naphthyl}ethyl)-acetamide
[0105] The procedure is as in Example 19, with the replacement in
Step B of methyl 4'-hydroxy[1,1'-biphenyl]-4-carboxylate by
(1,1'-biphenyl)-4-ol.
[0106] White solid.
[0107] Melting point: 138-140.degree. C.
[0108] Elemental microanalysis: TABLE-US-00005 % C H N Calculated:
79.44 6.89 3.10 Found: 79.19 6.93 3.24
EXAMPLE 23
N-(2-{7-[4-([1,1'-Biphenyl]-3-yloxy)butoxy]-1-naphthyl}ethyl)-acetamide
[0109] The procedure is as in Example 19, with the replacement in
Step B of methyl 4'-hydroxy[1,1'-biphenyl]-4-carboxylate by
(1,1'-biphenyl)-3-ol.
[0110] White solid.
[0111] Melting point: 111-112.degree. C.
[0112] Elemental microanalysis: TABLE-US-00006 % C H N Calculated:
79.44 6.89 3.10 Found: 79.23 6.79 3.21
EXAMPLE 24
Methyl
4'-[4-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}oxy)-butoxy]-[1,-
1'-biphenyl]-4-carboxylate
[0113] The procedure is as in Example 19, starting from the
compound obtained in Preparation 2.
EXAMPLE 25
Methyl
4'-[4-({3-[2-(acetylamino)ethyl]-1-benzothien-5-yl}oxy)-butoxy]-[1,-
1'-biphenyl]-4-carboxylate
[0114] The procedure is as in Example 19, starting from the
compound obtained in Preparation 6.
EXAMPLE 26
Methyl
4'-[4-({3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyrid-5-yl}-oxy)b-
utoxy]-[1,1'-biphenyl]-4-carboxylate
[0115] The procedure is as in Example 19, starting from the
compound obtained in Preparation 9.
EXAMPLE 27
4'-[4-({3-[2-(Acetylamino)ethyl]-1-benzofuran-5-yl}oxy)butoxy]-[1,1'-biphe-
nyl]-4-carboxylic acid
[0116] The procedure is as in Example 2, starting from the compound
obtained in Example 24.
EXAMPLE 28
4'-[4-({3-[2-(Acetylamino)ethyl]-1-benzothien-5-yl}oxy)butoxy[1,1'-bipheny-
l]-4-carboxylic acid
[0117] The procedure is as in Example 2, starting from the compound
obtained in Example 25.
EXAMPLE 29
4'-[4-({3-[2-(Acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyrid-5-yl}oxy)-butoxy]--
[1,1'-biphenyl]-4-carboxylic acid
[0118] The procedure is as in Example 2, starting from the compound
obtained in Example 26.
EXAMPLE 30
Methyl
4'-[4-({3-[2-(acetylamino)ethyl]-2-benzyl-1H-pyrrolo[2,3-b]pyrid-5--
yl}oxy)butoxy]-[1,1'-biphenyl]-4-carboxylate
[0119] The procedure is as in Example 19, starting from the
compound obtained in Preparation 13.
EXAMPLE 31
Methyl
4'-[4-({8-[2-(2-furoylamino)ethyl]-2-naphthyl}oxy)butoxy]-[1,1'-bip-
henyl]-4-carboxylate
[0120] The procedure is as in Example 19, starting from the
compound obtained in Preparation 12.
EXAMPLE 32
Methyl
4'-[4-({3-[2-(pentanoylamino)ethyl]-1H-inden-5-yl}oxy)-butoxy]-[1,1-
'-biphenyl]-4-carboxylate
[0121] The procedure is as in Example 19, starting from the
compound obtained in Preparation 14.
EXAMPLE 33
Methyl
4'-[4-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}thio)-butoxy]-[1-
,1'-biphenyl]-4-carboxylate
[0122] The procedure is as in Example 19, starting from the
compound obtained in Preparation 15.
EXAMPLE 34
Methyl
4'-[4-({3-[2-(acetylamino)ethyl]-1-methyl-1H-pyrrolo[2,3-b]pyrid-5--
yl}oxy)butoxy]-[1,1'-biphenyl]-4-carboxylate
[0123] The procedure is as in Example 19, starting from the
compound obtained in Preparation 18.
EXAMPLE 35
Methyl
3'-[4-({8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}oxy)-
butoxy]-[1,1'-biphenyl]-3-carboxylate
[0124] The procedure is as in Example 19, starting from the
compound obtained in Preparation 19.
EXAMPLE 36
3'-[4-({8-[2-(Acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}-oxy)butoxy-
]-[1,1'-biphenyl]-3-carboxylic acid
[0125] The procedure is as in Example 2, starting from the compound
obtained in Example 35.
EXAMPLE 37
Ethyl 4'-[4-({3-[2-(acetylamino)ethyl]-1-methyl-1H-pyrrolo[3,2
b]pyrid-5-yl}oxy)butoxy]-[1,1'-biphenyl]-4-carboxylate
[0126] The procedure is as in Example 19, starting from the
compound obtained in Preparation 20 and ethyl
4'-hydroxy[1,1'-biphenyl]-4-carboxylate.
[0127] Melting point: 145-146.degree. C.
[0128] Elemental microanalysis: TABLE-US-00007 % C H N Calculated:
70.30 6.66 7.93 Found 69.84 6.67 7.94
Pharmacological Study
EXAMPLE A
Acute toxicity study
[0129] 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
Melatonin Receptor Binding Study on Pars tuberalis Cells of
Sheep
[0130] Melatonin receptor binding studies of the compounds of the
invention were carried out according to conventional techniques on
Pars tuberalis cells of sheep. The Pars tuberalis of the
adenohypophysis is in fact characterised in mammals by a high
density of melatonin receptors (Journal of Neuroendocrinology, 1,
pp. 1-4, 1989).
Protocol
[0131] 1) Sheep Pars tuberalis membranes are prepared and used as
target tissue in saturation experiments to determine the binding
capacities and affinities for 2-[.sup.125I]-iodomelatonin. [0132]
2) Sheep Pars tuberalis membranes are used as target tissue in
competitive binding experiments using the various test compounds in
comparison with melatonin.
[0133] Each experiment is carried out in triplicate and a range of
different concentrations is tested for each compound. The results,
after statistical processing, enable the binding affinities of the
compound tested to be determined.
Results
[0134] The compounds of the invention appear to have a strong
affinity for melatonin receptors.
EXAMPLE C
Melatonin MT.sub.1 and MT.sub.2 Receptor Binding Study
[0135] 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.
[0136] 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 of the compounds tested (IC.sub.50) to be
determined.
[0137] Thus, the IC.sub.50 values found for the compounds of the
invention show binding for one or other of the MT.sub.1 and
MT.sub.2 receptor sub-types, those values being .ltoreq.10
.mu.M.
EXAMPLE D
Action of the Compounds of the Invention on the Circadian Rhythms
of Locomotive Activity of the Rat
[0138] The involvement 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.
[0139] 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.
[0140] 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
[0141] 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).
[0142] 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.
[0143] 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).
[0144] 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.
[0145] The observations are made by means of visualization of the
rhythms of activity: [0146] influence of the light rhythm on the
rhythms of activity, [0147] disappearance of the influence on the
rhythms in permanent darkness, [0148] influence by the daily
administration of the compound transitory or durable effect.
[0149] A software package makes it possible: [0150] to measure the
duration and intensity of the activity, the period of the rhythm of
the animals during free course and during treatment, [0151]
optionally to demonstrate by spectral analysis the existence of
circadian and non-circadian (for example ultradian) components.
Results
[0152] The compounds of the invention clearly appear to have a
powerful action on the circadian rhythm via the melatoninergic
system.
EXAMPLE E
Light/Dark Cage Test
[0153] The compounds of the invention are tested on a behavioural
model, the light/dark cage test, which enables the anxiolytic
activity of the compounds to be revealed.
[0154] 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 plastic 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.
[0155] 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
[0156] 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
[0157] One-month-old rats are habituated to a light/darkness cycle
of 12 h/12 h for a period of 2 to 3 weeks.
[0158] 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.
[0159] 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
[0160] The compounds of the invention significantly modify the
diameter of caudal arteries pre-constricted by phenylephrine.
EXAMPLE G
Pharmaceutical Composition: Tablets
[0161] TABLE-US-00008 1000 tablets each containing a dose of 5 g 5
mg of 4'-[4-({8-[2-(acetylamino)ethyl]-2-
naphthyl}oxy)butoxy]-[1,1'-biphenyl]-4- carboxylic acid (Example
20) Wheat starch 20 g Maize starch 20 g Lactose 30 g Magnesium
stearate 2 g Silica 1 g Hydroxypropyl cellulose 2 g
* * * * *