U.S. patent application number 12/784007 was filed with the patent office on 2010-09-16 for derivatives of n-phenyl(piperidine-2-yl) methyl benzamide preparation method thereof and applications of same in therapeutics.
This patent application is currently assigned to SANOFI-AVENTIS. Invention is credited to Gihad DARGAZANLI, Genevieve ESTENNE-BOUHTOU, Pascale MAGAT.
Application Number | 20100234424 12/784007 |
Document ID | / |
Family ID | 34385233 |
Filed Date | 2010-09-16 |
United States Patent
Application |
20100234424 |
Kind Code |
A1 |
DARGAZANLI; Gihad ; et
al. |
September 16, 2010 |
DERIVATIVES OF N-PHENYL(PIPERIDINE-2-YL) METHYL BENZAMIDE
PREPARATION METHOD THEREOF AND APPLICATIONS OF SAME IN
THERAPEUTICS
Abstract
Compounds of formula (I) as defined herein: ##STR00001## are
useful for treating behavioral disorders associated with dementia,
psychoses, in particular schizophrenia (deficient form and
productive form) and acute or chronic extrapyramidal symptoms
induced by neuroleptics; for the treatment of various forms of
anxiety, panic attacks, phobias, and compulsive obsessive
disorders; for treating various forms of depression, including
psychotic depression; for treating disorders caused by alcohol
abuse or weaning from alcohol, sexual behavior disorders, eating
disorders and for treating migraine. Moreover, the compounds of the
invention may be used for treating painful muscle contracture in
rheumatology and in acute spinal pathology; for treating spastic
contractures of medullary or cerebral origin; for the symptomatic
treatment of acute and subacute pain of light to moderate
intensity; for treating intense and/or chronic pain, neurogenic
pain and intractable pain; for treating Parkinson's disease and
Parkinson-like symptoms of neurodegenerative origin or induced by
neuroleptics; for treating partial primary and secondary
generalized epilepsy of simple or complex symptomology, mixed forms
and other epileptic syndromes in addition to another antiepileptic
treatment, or in monotherapy, for the treatment of sleep apnea, and
for neuroprotection.
Inventors: |
DARGAZANLI; Gihad; (Cachan,
FR) ; ESTENNE-BOUHTOU; Genevieve; (Chevilly-Larue,
FR) ; MAGAT; Pascale; (Chilly Mazarin, FR) |
Correspondence
Address: |
ANDREA Q. RYAN;SANOFI-AVENTIS U.S. LLC
1041 ROUTE 202-206, MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
SANOFI-AVENTIS
Paris
FR
|
Family ID: |
34385233 |
Appl. No.: |
12/784007 |
Filed: |
May 20, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11405169 |
Apr 17, 2006 |
7750025 |
|
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12784007 |
|
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|
|
PCT/FR2004/002640 |
Oct 15, 2004 |
|
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11405169 |
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Current U.S.
Class: |
514/314 ;
514/318; 514/319; 514/322; 514/323; 514/324; 514/326; 546/169;
546/194; 546/199; 546/201; 546/202; 546/205; 546/210; 546/213 |
Current CPC
Class: |
C07D 403/12 20130101;
A61P 25/08 20180101; A61P 25/06 20180101; A61P 1/14 20180101; A61P
25/22 20180101; C07D 409/12 20130101; A61P 25/18 20180101; A61P
25/24 20180101; A61P 25/30 20180101; A61P 25/32 20180101; A61P
25/04 20180101; C07D 401/12 20130101; A61P 25/28 20180101; A61P
25/14 20180101; A61P 25/16 20180101; A61P 25/00 20180101 |
Class at
Publication: |
514/314 ;
514/318; 514/319; 514/322; 514/323; 514/324; 514/326; 546/169;
546/194; 546/199; 546/201; 546/202; 546/205; 546/210; 546/213 |
International
Class: |
C07D 401/12 20060101
C07D401/12; A61P 25/32 20060101 A61P025/32; A61K 31/4545 20060101
A61K031/4545; A61P 25/28 20060101 A61P025/28; A61P 25/00 20060101
A61P025/00; A61K 31/445 20060101 A61K031/445; C07D 211/06 20060101
C07D211/06; A61K 31/4535 20060101 A61K031/4535; A61P 25/08 20060101
A61P025/08; A61K 31/454 20060101 A61K031/454; A61K 31/47 20060101
A61K031/47; C07D 215/14 20060101 C07D215/14; A61P 25/24 20060101
A61P025/24; A61P 25/06 20060101 A61P025/06; C07D 409/12 20060101
C07D409/12; A61P 25/18 20060101 A61P025/18 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 17, 2003 |
FR |
0312140 |
Claims
1. A compound of formula (I) ##STR00025## in which R.sub.1
represents either a hydrogen atom or a linear or branched
(C.sub.1-C.sub.7)alkyl group optionally substituted with one or
more fluorine atoms, or a (C.sub.3-C.sub.7)cycloalkyl group, or a
(C.sub.3-C.sub.7)cycloalkyl (C.sub.1-C.sub.3)alkyl group, or a
phenyl(C.sub.1-C.sub.3)alkyl group optionally substituted with one
or two methoxy groups, or a (C.sub.2-C.sub.4)alkenyl group, or a
(C.sub.2-C.sub.4)alkynyl group; X represents a hydrogen atom or one
or more substituents chosen from halogen atoms and trifluoromethyl
and linear or branched (C.sub.1-C.sub.4)alkyl and
(C.sub.1-C.sub.4)alkoxy groups; R.sub.2 represents a group chosen
from naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridyl,
triazinyl, indanyl, indenyl, quinolyl, isoquinolyl, quinazolyl,
quinoxalyl, phthalazinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl,
oxadiazolyl, triazolyl, benzofuryl, benzimidazolyl, benzothiazolyl,
indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl,
benzotriazolyl, benzisothiazolyl, dihydroindolyl, pyrrolopyridyl,
furopyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl,
thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl,
isothiazolopyridyl, tetrahydroquinolyl and tetrahydroisoquinolyl
groups, and optionally substituted with one or more substituents
chosen from halogen atoms and (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, thio(C.sub.1-C.sub.4)alkyl or phenyl
groups optionally substituted with one or more substituents chosen
from halogen atoms and trifluoromethyl, (C.sub.1-C.sub.4)alkyl and
(C.sub.1-C.sub.4)alkoxy groups; or an acid-addition salt
thereof.
2. A pharmaceutical composition which comprises a compound
according to claim 1, or a pharmaceutically acceptable salt
thereof, combined with an excipient.
3. A method for treating a behavioral disorder selected from the
group consisting of dementia, psychoses, various forms of anxiety,
panic attacks, phobias, compulsive obsessive disorders, various
forms of depression, disorders caused by alcohol abuse or weaning
from alcohol, sexual behavior disorders, eating disorders and
migraine, which comprises administering to a patient with said
disorder an effective amount of a compound according to claim 1, or
a pharmaceutically acceptable salt thereof.
4. A method for treating a condition selected from the group
consisting of contracture, pain, Parkinson's disease and
Parkinson-like symptoms, epilepsy, mixed forms and other epileptic
syndromes in addition to another antiepileptic treatment, or in
monotherapy, sleep apnea, and neuroprotection migraine, which
comprises administering to a patient in need thereof an effective
amount of a compound according to claim 1, or a pharmaceutically
acceptable salt thereof.
5. The compound according to claim 1, which is
threo-4-[2-chloro-3-(trifluoromethyl)phenyl]-N-[(1-methyl-2-piperidyl)(ph-
enyl)methyl]-1H-imidazole-2-carboxamide.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/405,169, filed Apr. 17, 2006, now allowed, which is a
continuation of PCT/FR2004/002640, filed Oct. 15, 2004, which
claims the benefit of priority of French Patent Application No.
0312140, filed Oct. 17, 2003.
SUMMARY OF THE INVENTION
[0002] The compounds of the invention correspond to the general
formula (I)
##STR00002##
in which R.sub.1 represents either a hydrogen atom or a linear or
branched (C.sub.1-C.sub.7)alkyl group optionally substituted with
one or more fluorine atoms, or a (C.sub.3-C.sub.7)cycloalkyl group,
or a (C.sub.3-C.sub.7)cycloalkyl (C.sub.1-C.sub.3)alkyl group, or a
phenyl(C.sub.1-C.sub.3)alkyl group optionally substituted with one
or two methoxy groups, or a (C.sub.2-C.sub.4)alkenyl or
(C.sub.2-C.sub.4)alkynyl group, X represents a hydrogen atom or one
or more substituents chosen from halogen atoms and trifluoromethyl
and linear or branched (C.sub.1-C.sub.4)alkyl and
(C.sub.1-C.sub.4)alkoxy groups, R.sub.2 represents a group chosen
from naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridyl,
triazinyl, indanyl, indenyl, quinolyl, isoquinolyl, quinazolyl,
quinoxalyl, phthalazinyl, thienyl, furyl, pyrrolyl, imidazolyl,
pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,
thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuryl,
benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, indazolyl,
benzoxazolyl, benzisoxazolyl, benzotriazolyl, benzisothiazolyl,
dihydroindolyl, pyrrolopyridyl, furopyridyl, thienopyridyl,
imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl,
isoxazolopyridyl, isothiazolopyridyl, tetrahydroquinolyl and
tetrahydroisoquinolyl groups, and optionally substituted with one
or more substituents chosen from halogen atoms and
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
thio(C.sub.1-C.sub.4)alkyl or phenyl groups optionally substituted
with one or more substituents chosen from halogen atoms and
trifluoromethyl, (C.sub.1-C.sub.4)alkyl and (C.sub.1-C.sub.4)alkoxy
groups.
[0003] The compounds of general formula (I) may exist in the form
of the threo racemate (1R,2R;1S,2S) or in the form of enantiomers
(1R,2R) or (1S,2S); they may exist in the form of free bases or of
acid-addition salts.
BACKGROUND OF THE INVENTION
[0004] Compounds of structure similar to that of the compounds of
the invention are described in U.S. Pat. No. 5,254,569 as
analgesics, diuretics, anticonvulsivants, anesthetics, sedatives
and cerebroprotective agents, via a mechanism of action on the
opiate receptors. Other compounds of similar structure are
described in patent application EP-0 499 995 as 5-HT.sub.3
antagonists that are useful in the treatment of psychotic
disorders, neurological diseases, gastric symptoms, nausea and
vomiting.
DETAILED DESCRIPTION OF THE INVENTION
[0005] The preferred compounds of the invention lack activity on
the opiate or 5-HT.sub.3 receptors and show particular activity as
specific inhibitors of the glycine transporters glyt1 and/or
glyt2.
[0006] The compounds of general formula (I) in which R.sub.1 is
other than a hydrogen atom may be prepared via a process
illustrated by Scheme 1 below.
[0007] Coupling of a diamine of general formula (II), in which
R.sub.1 and X are as defined above (with R.sub.1 other than a
hydrogen atom) with an activated acid or an acid chloride of
general formula (III) in which Y represents an activated OH group
or a chlorine atom and R.sub.2 is as defined above, is performed
using the methods known to those skilled in the art.
##STR00003##
[0008] The diamine of general formula (II) may be prepared via a
process illustrated by Scheme 2 below.
##STR00004##
[0009] The Weinreb amide of formula (IV) is reacted with the
phenyllithium derivative of general formula (V), in which X is as
defined above, in an ether solvent such as diethyl ether, between
-30.degree. C. and room temperature; a ketone of general formula
(VI) is obtained, which is reduced to the alcohol of threo
configuration of general formula (VII) with a reducing agent such
as K-Selectride.RTM. or L-Selectride.RTM. (potassium or lithium
tri-sec-butylborohydride), in an ether solvent such as
tetrahydrofuran, between -78.degree. C. and room temperature. The
carbamate of general formula (VII) may then be reduced to threo
N-methylamino alcohol of general formula (VIII) via the action of a
mixed hydride such as lithium aluminum hydride, in an ether solvent
such as tetrahydrofuran, between room temperature and the reflux
temperature.
[0010] The threo alcohol of general formula (VIII) is then
converted into the threo intermediate of general formula (II) in
which R.sub.1 represents a methyl group, in two steps: the alcohol
function is first converted into an electrophilic group, for
example a methanesulfonate group, via the action of methanesulfonyl
chloride, in a chlorinated solvent such as dichloromethane, and in
the presence of a base such as triethylamine, between 0.degree. C.
and room temperature, and the electrophilic group is then reacted
with liquefied ammonia at -50.degree. C., in an alcohol such as
ethanol, in a closed medium such as an autoclave, between
-50.degree. C. and room temperature.
[0011] The carbamate of general formula (VII) may also be
deprotected using a strong base such as aqueous potassium
hydroxide, in an alcohol such as methanol, to give the threo amino
alcohol of general formula (IX), followed by an N-alkylation using
a halogenated derivative of formula R.sub.1Z, in which R.sub.1 is
as defined above, but other than a hydrogen atom, and Z represents
a halogen atom, in the presence of a base such as potassium
carbonate, in a polar solvent such as N,N-dimethylformamide,
between room temperature and 100.degree. C. The alcohol of general
formula (X) thus obtained is then treated as described with respect
to the alcohol of general formula (VIII).
[0012] Another process variant, illustrated by Scheme 3 below, may
be used when R.sub.1 represents a methyl group and X represents a
hydrogen atom. The pyridine oxime of formula (XI) is quaternized,
for example via the action of methyl trifluoromethanesulfonate, in
an ether solvent such as diethyl ether, at room temperature. The
pyridinium salt thus obtained, of formula (XII), is then subjected
to a hydrogenation under a hydrogen atmosphere, in the presence of
a catalyst such as platinum oxide, in a mixture of alcohol and of
aqueous acid such as ethanol and 1N hydrochloric acid. The diamine
of general formula (II) in which R.sub.1 represents a methyl group
and X represents a hydrogen atom is obtained in the form of a 9/1
threo/erythro mixture of the two diastereoisomers. It can be
salified, for example with oxalic acid, and then purified by
recrystallization of the oxalate formed from a mixture of alcohol
and of an ether solvent such as methanol and diethyl ether, to give
the pure threo diastereoisomer (1R,2R;1S,2S).
##STR00005##
[0013] The compounds of general formula (II) in which R.sub.1
represents a hydrogen atom may be prepared according to Scheme 2,
with use of a compound of general formula (I) in which R.sub.1
represents an optionally substituted phenylmethyl group, followed
by deprotection of the nitrogen of the piperidine ring, for example
with an oxidizing agent or with a Lewis acid, such as boron
tribromide, or via hydrogenolysis, i.e. an alkenyl group,
preferably an allyl group, and in deprotecting the nitrogen with a
Pd.sup.0 complex, to obtain a compound of general formula (I) in
which R.sub.1 represents a hydrogen atom.
[0014] Moreover, the chiral compounds of general formula (I)
corresponding to the (1R,2R) or (1S,2S) enantiomers of the threo
diastereoisomer may also be obtained by separation of the racemic
compounds by high-performance liquid chromatography (HPLC) on a
chiral column, or by resolution of the racemic amine of general
formula (II) by using a chiral acid such as tartaric acid,
camphorsulfonic acid, dibenzoyltartaric acid or N-acetyl leucine,
by fractional and preferential recrystallization of a
diastereoisomeric salt, in a solvent of alcohol type, or
alternatively via enantioselective synthesis according to Scheme 2
with use of a chiral Weinreb amide of formula (IV).
[0015] The racemic or chiral Weinreb amide of formula (IV), and
also the ketone of general formula (VI), may be prepared according
to a method similar to that described in Eur. J. Med. Chem., 35,
(2000), 979-988 and J. Med. Chem., 41, (1998), 591-601. The
phenyllithium compound of general formula (V), in which X
represents a hydrogen atom, is commercially available. Its
substituted derivatives may be prepared according to a method
similar to that described in Tetrahedron Lett., 57, 33, (1996),
5905-5908. The pyridine oxime of general formula (XI) may be
prepared according to a method similar to that described in patent
application EP-0 366 006. The amine of general formula (IX) in
which X represents a hydrogen atom may be prepared in the chiral
series according to a method described in U.S. Pat. No. 2,928,835.
Finally, the amine of general formula (XIII) may be prepared
according to a method similar to that described in Chem. Pharm.
Bull., 32, 12, (1984), 4893-4906 and Synthesis, (1976),
593-595.
[0016] The acids and acid chlorides of general formula (III) are
commercially available, except for
4-[2-chloro-3-(trifluoromethyl)phenyl]-1H-imidazole-2-carboxylic
acid, which may be prepared under conditions comparable to those
described in patent application EP-0 365 030 and in U.S. Pat. No.
3,336,300.
[0017] The examples that follow illustrate the preparation of a
number of compounds of the invention. The elemental microanalyses,
the IR and NMR spectra and the HPLC on a chiral column confirm the
structures and the enantiomeric purities of the compounds
obtained.
[0018] The numbers given in parentheses in the titles of the
examples correspond to those in the first column of the table given
later.
Example 1
Compound 4
Threo-2,5-dichloro-N-[(1-methyl-2-piperidyl)(phenyl)methyl]-3-thiophenecar-
boxamide Hydrochloride 1:1
1.1. 2-(Benzyloxyiminophenylmethyl)-1-methylpyridinium
Trifluoromethanesulfonate
[0019] To a suspension of 35 g (120 mmol) of
phenyl(2-pyridyl)methanone O-benzyl oxime in 200 ml of diethyl
ether are added dropwise, at 0.degree. C., 17.4 ml (120 mmol) of
methyl trifluoromethanesulfonate and the mixture is stirred at room
temperature for 3 hours. The precipitate formed is collected by
filtration and dried under reduced pressure.
[0020] 49 g of product are obtained, which product is used without
further purification in the following step.
1.2. Threo-(1-methylpiperidin-2-yl)phenylmethanamine ethanedioate
1:2
[0021] 14.8 g (31.89 mmol) of
2-(benzyloxyiminophenylmethyl)-1-methylpyridinium
trifluoromethanesulfonate and 0.74 g of platinum oxide are placed
in 50 ml of ethanol and 50 ml of 1N hydrochloric acid in a Parr
flask, and hydrogenation is performed for 5 hours.
[0022] The ethanol is evaporated off under reduced pressure, the
residue is extracted with dichloromethane, the aqueous phase is
separated out, aqueous ammonia solution is added thereto and the
mixture is extracted with dichloromethane. After washing the
combined organic phases, drying over sodium sulfate, filtering and
evaporating off the solvent under reduced pressure, 6.7 g of oily
product comprising 10% of erythro diastereoisomer are obtained.
[0023] The ethanedioate is prepared by dissolving these 6.7 g of
base in methanol, via the action of two equivalents of ethanedioic
acid dissolved in a minimum amount of methanol.
[0024] The salt obtained is purified by recrystallization from a
mixture of methanol and diethyl ether.
[0025] 4.7 g of ethanedioate of the pure threo diastereoisomer are
finally isolated.
[0026] Melting point: 156-159.degree. C.
1.3. Threo-2,5-dichloro-N-(1-methyl-2-piperidyl)
(phenyl)methyl]thiophene-3-carboxamide Hydrochloride 1:1
[0027] 0.768 g (4 mmol) of 2,5-dichlorothiophene-3-carboxylic acid
dissolved in 15 ml of dichloromethane is introduced into a 100 ml
round-bottomed flask, 0.651 ml (4.7 mmol) of triethylamine and
0.447 ml (4.7 mmol) of ethyl chloroformate are then added and the
reaction mixture is stirred at room temperature for 2 hours.
[0028] 0.80 g (3.9 mmol) of
threo-(1-methyl-2-piperidyl)phenylmethanamine dissolved in 15 ml of
dichloromethane is added and stirring is continued at room
temperature for 12 hours.
[0029] The mixture is treated with water and extracted several
times with dichloromethane. After washing the organic phases with
water and then with aqueous 1N sodium hydroxide solution, drying
over sodium sulfate, filtering and evaporating off the solvent
under reduced pressure, the residue is purified by column
chromatography on silica gel, eluting with a 97/3 to 95/5 mixture
of dichloromethane and methanol.
[0030] 0.6 g of oily product is obtained, the hydrochloride of
which is prepared by adding a 0.1N solution of hydrogen chloride in
2-propanol.
[0031] After evaporating off the solvents under reduced pressure,
the white solid obtained is recrystallized from a mixture of
isopropyl ether and 2-propanol.
[0032] 0.474 g of hydrochloride is finally isolated in the form of
a white solid.
[0033] Melting point: 216-217.degree. C.
Example 2
Compound 5
2,5-Dichloro-N--[(S)-[(2S)-1-methyl-2-piperidyl](phenyl)methyl]thiophene-3-
-carboxamide Hydrochloride 1:1
2.1. 1,1-dimethylethyl (2S)-2-benzoylpiperidine-1-carboxylate
[0034] 11.8 g (43.3 mmol) of 1,1-dimethylethyl
(2S)-2-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate are
introduced into 100 ml of anhydrous diethyl ether in a 500 ml
round-bottomed flask, under a nitrogen atmosphere, the medium is
cooled to -23.degree. C., 21.6 ml (43.2 mmol) of a 1.8M solution of
phenyllithium in a 70/30 mixture of cyclohexane and diethyl ether
are added dropwise and the mixture is stirred at room temperature
for 3 hours. After hydrolysis with saturated aqueous sodium
chloride solution, the aqueous phase is separated out and extracted
with ethyl acetate. The organic phase is dried over sodium sulfate,
filtered and concentrated under reduced pressure, and the residue
is purified by column chromatography on silica gel, eluting with a
mixture of ethyl acetate and cyclohexane.
[0035] 4.55 g of solid product are obtained.
[0036] Melting point: 123-125.degree. C.
[0037] [.alpha.].sup.25.sub.D=-25.4.degree. (c=2.22;
CH.sub.2Cl.sub.2) ee=97.2%.
2.2. 1,1-Dimethylethyl
(1S)-2-[(2S)-hydroxy(phenyl)methyl]piperidine-1-carboxylate
[0038] 4.68 g (16.2 mmol) of 1,1-dimethylethyl
(2S)-2-benzoylpiperidine-1-carboxylate are introduced into 170 ml
of anhydrous tetrahydrofuran in a 500 ml round-bottomed flask,
under a nitrogen atmosphere, the solution is cooled to -78.degree.
C., 48.5 ml (48.5 mmol) of a 1M solution of L-Selectride.RTM.
(lithium tri-sec-butylborohydride) in tetrahydrofuran are added
dropwise and the mixture is stirred at room temperature for 5
hours.
[0039] The resulting mixture is hydrolyzed slowly under cold
conditions with 34 ml of water and 34 ml of aqueous 35% hydrogen
peroxide solution, and the mixture is allowed to warm to room
temperature while stirring over 2 hours.
[0040] The resulting mixture is diluted with water and ethyl
acetate, and the aqueous phase is separated out and extracted with
ethyl acetate. After washing the combined organic phases, drying
over sodium sulfate, filtering and evaporating, the residue is
purified by column chromatography on silica gel, eluting with a
mixture of ethyl acetate and cyclohexane.
[0041] 4.49 g of a pale yellow oil are obtained.
[0042] [.alpha.].sup.25.sub.D=+63.75.degree. (c=0.8;
CH.sub.2Cl.sub.2) ee=97.8%.
2.3. (1S)-[(2S)-(1-methyl-2-piperidyl)]phenylmethanol
[0043] 2.96 g (78.1 mmol) of lithium aluminum hydride are
introduced into 50 ml of anhydrous tetrahydrofuran in a 200 ml
two-necked flask, under a nitrogen atmosphere, the mixture is
refluxed, 4.49 g (15.4 mmol) of a solution of 1,1-dimethylethyl
(1S)-2-[(2S)-hydroxy (phenyl)methyl]piperidine-1-carboxylate in 35
ml of tetrahydrofuran are added and the mixture is maintained at
reflux for 3.5 hours.
[0044] The mixture is cooled, hydrolyzed slowly with 0.1M potassium
sodium tartrate solution and stirred overnight. The resulting
mixture is filtered, the precipitate is rinsed with tetrahydrofuran
and the filtrate is then concentrated under reduced pressure.
[0045] 2.95 g of a colorless oily product are obtained.
2.4. (1S)-[(2S)-(1-methyl-2-piperidyl)]phenylmethanamine
[0046] 2.95 g (14.4 mmol) of
(1S)-[(2S)-(1-methyl-2-piperidyl)]phenylmethanol and 2 ml (14.4
mmol) of triethylamine are introduced into 70 ml of anhydrous
dichloromethane in a 250 ml round-bottomed flask, under a nitrogen
atmosphere, the medium is cooled to 0.degree. C., 1.1 ml (14.4
mmol) of methanesulfonyl chloride are added and the mixture is
allowed to return slowly to room temperature over 2 hours and is
concentrated under reduced pressure.
[0047] Liquefied ammonia is introduced into an autoclave equipped
with a magnetic stirrer and cooled to -50.degree. C., a solution of
the methanesulfonate prepared above in 30 ml of absolute ethanol is
added, and the autoclave is closed and stirred for 48 hours.
[0048] The mixture is transferred into a round-bottomed flask, the
solvents are evaporated off under reduced pressure and the amine is
isolated in the form of an oily product, which is used without
further purification in the following step.
2.5.
2,5-Dichloro-N-[(1S)-[(2S)-1-methyl-2-piperidyl](phenyl)methyl]thioph-
ene-3-carboxamide Hydrochloride 1:1
[0049] 0.37 g (1.88 mmol) of 2,5-dichlorothiophene-3-carboxylic
acid is introduced into 15 ml of dichloromethane in a 250 ml
round-bottomed flask, 0.31 ml (2.25 mmol) of triethylamine and 0.21
ml (2.25 mmol) of ethyl chloroformate are successively added and
the mixture is stirred at room temperature for 1 hour.
[0050] 0.38 g (1.88 mmol) of
(1S)-[(2S)-(1-methyl-2-piperidyl)]phenylmethanamine dissolved in 10
ml of dichloromethane is added and stirring is continued at room
temperature for 12 hours.
[0051] The mixture is treated with water and extracted several
times with dichloromethane, the organic phases are combined, washed
with aqueous 1N sodium hydroxide solution, dried over sodium
sulfate and filtered, and the filtrate is concentrated under
reduced pressure.
[0052] The crude residue is purified by column chromatography on
silica gel, eluting with a 98/2 mixture of dichloromethane and
methanol containing 0.1% aqueous ammonia. 0.368 g of oily product
is obtained, the hydrochloride of which is prepared by addition of
a 0.1N solution of hydrogen chloride in 2-propanol.
[0053] After evaporating off the solvent under reduced pressure,
the solid is recrystallized from a mixture of 2-propanol and
isopropyl ether.
[0054] 0.36 g of hydrochloride is finally isolated in the form of a
pale yellow solid.
[0055] Melting point: 134-136.degree. C.
[0056] [.alpha.].sup.25.sub.D=+45.6 (c=0.99); CH.sub.3OH.
Example 3
Compound 18
Threo-4-[2-chloro-3-(trifluoromethyl)phenyl]-N-[(1-methyl-2-piperidyl)(phe-
nyl)methyl]-1H-imidazole-2-carboxamide Hydrochloride 1:1
[0057] 0.1 g (0.344 mmol) of
4-(2-chloro-3-(trifluoromethyl)phenyl]-1H-imidazole-2-carboxylic
acid, 0.066 g (0.344 mmol) of
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, and 0.047 g (0.344
mmol) of 1-hydroxybenzotriazole dissolved in 10 ml of
dichloromethane are introduced into a 50 ml round-bottomed flask
and the mixture is stirred at room temperature for 5 minutes.
[0058] 0.072 g (0.344 mmol) of
threo-(1-methyl-2-piperidyl)phenylmethanamine (prepared according
to Example 1.2) is added to a few ml of dichloromethane and
stirring is continued for 6 hours.
[0059] The mixture is treated with water and extracted several
times with dichloromethane, the organic phases are washed with
water and then with aqueous 1N sodium hydroxide solution, then with
saturated aqueous sodium chloride solution and dried over sodium
sulfate, and the solvent is evaporated off under reduced pressure.
The residue is purified by column chromatography on silica gel,
eluting with a mixture of dichloromethane and methanol.
[0060] 91 mg of product is obtained, the hydrochloride of which is
prepared by adding a 0.1N solution of hydrogen chloride in
2-propanol. The solvent is partially evaporated off under reduced
pressure to obtain, after crystallization, 104 mg of solid white
compound.
[0061] Melting point: 188-195.degree. C.
[0062] The table on the following page illustrates the chemical
structures and the physical properties of a number of compounds
according to the invention.
[0063] In the "Salt" column, "-" denotes a compound in base form
and "HCl" denotes a hydrochloride.
[0064] The optical rotation of compound 5 is
[.alpha.].sup.25.sub.D=+ 45.6.degree. (c=0.99); CH.sub.3OH.
TABLE-US-00001 TABLE ##STR00006## No. Stereochemistry R.sub.1 X
R.sub.2 Salt F (.degree. C.) 1 threo (1R,2R; 1S,2S) CH.sub.3 H
##STR00007## -- M + H = 315 2 threo (1R,2R; 1S,2S) CH.sub.3 H
##STR00008## HCl 211-212 3 threo (1R,2R; 1S,2S) CH.sub.3 H
##STR00009## -- 122-125 4 threo (1R,2R; 1S,2S) CH.sub.3 H
##STR00010## HCl 216-217 5 threo (1S,2S) CH.sub.3 H ##STR00011##
HCl 134-136 6 threo (1R,2R; 1S,2S) CH.sub.3 H ##STR00012## --
134-136 7 threo (1R,2R; 1S,2S) CH.sub.3 H ##STR00013## -- 154-156 8
threo (1R,2R; 1S,2S) CH.sub.3 H ##STR00014## -- 152-155 9 threo
(1R,2R; 1S,2S) CH.sub.3 H ##STR00015## HCl 219-221 10 threo (1R,2R;
1S,2S) CH.sub.3 H ##STR00016## -- 66-74 11 threo (1R,2R; 1S,2S)
CH.sub.3 H ##STR00017## -- 99-100 12 threo (1R,2R; 1S,2S) CH.sub.3
H ##STR00018## HCl 214-215 13 threo (1R,2R; 1S,2S) CH.sub.3 H
##STR00019## HCl M + H = 363 14 threo (1R,2R; 1S,2S) CH.sub.3 H
##STR00020## -- 60-61 15 threo (1R,2R; 1S,2S) CH.sub.3 H
##STR00021## HCl 273-274 16 threo (1R,2R; 1S,2S) CH.sub.3 H
##STR00022## -- 236-237 17 threo (1R,2R; 1S,2S) CH.sub.3 H
##STR00023## -- 268-269 18 threo (1R,2R; 1S,2S) CH.sub.3 H
##STR00024## HCl 188-195
[0065] The compounds of the invention were subjected to a series of
pharmacological tests that demonstrated their value as
therapeutically active substances.
Study of Glycine Transportation in SK-N-MC Cells Expressing the
Native Human Transporter glyt1
[0066] The uptake of [.sup.14C]glycine is studied in SK-N-MC cells
(human neuroepithelial cells) expressing the native human
transporter glyt1 by measuring the radioactivity incorporated in
the presence or absence of the test compound. The cells are
cultured as a monolayer for 48 hours in plates pretreated with
0.02% fibronectin. On the day of the experiment, the culture medium
is removed and the cells are washed with Krebs-HEPES buffer
([4-(2-hydroxyethyl)-1-piperazine]ethanesulfonic acid) at pH 7.4.
After preincubation for 10 minutes at 37.degree. C. in the presence
either of buffer (control batch) or of test compound at various
concentrations or of 10 mM of glycine (determination of the
nonspecific uptake), 10 .mu.M of [.sup.14C]glycine (specific
activity 112 mCi/mmol) are then added. Incubation is continued for
10 minutes at 37.degree. C., and the reaction is quenched by
washing twice with pH 7.4 Krebs-HEPES buffer. The radioactivity
incorporated by the cells is then estimated after adding 100 .mu.A
of liquid scintillant and stirring for 1 hour. Counting is
performed on a Microbeta Tri-Lux.TM. counter. The efficacy of the
compound is determined by means of the IC.sub.50, which is the
concentration of compound that reduces by 50% the specific uptake
of glycine, defined by the difference in radioactivity incorporated
by the control batch and the batch that received 10 mM of
glycine.
[0067] The compounds of the invention have an IC.sub.50 in this
test of about from 0.01 to 10 .mu.M.
Study of the Glycine Transportation in Mouse Spinal Cord
Homogenate
[0068] The uptake of [.sup.14C]glycine by the transporter glyt2 is
studied in mouse spinal cord homogenate by measuring the
radioactivity incorporated in the presence or absence of test
compound.
[0069] After euthanizing the animals (male OF1 Iffa Credo mice
weighing 20 to 25 g on the day of the experiment), the spinal cord
of each animal is rapidly removed, weighed and stored on ice. The
samples are homogenized in pH 7.4 Krebs-HEPES buffer
([4-(2-hydroxyethyl)-1-piperazine]ethanesulfonic acid), in a
proportion of 25 ml/g of tissue.
[0070] 50 .mu.l of homogenate are preincubated for 10 minutes at
25.degree. C. in the presence of pH 7.4 Krebs-HEPES buffer and of
test compound at various concentrations, or of 10 mM of glycine to
determine the nonspecific uptake. [.sup.14C]glycine (specific
activity=112 mCi/mmol) is then added over 10 minutes at 25.degree.
C. to a final concentration of 10 .mu.M. The reaction is quenched
by vacuum filtration and the radioactivity is estimated by solid
scintillation by counting on a Microbeta Tri-Lux.TM. counter. The
efficacy of the compound is determined by means of the IC.sub.50,
the concentration capable of reducing by 50% the specific uptake of
glycine, defined by the difference in radioactivity incorporated by
the control batch and the batch that received 10 mM of glycine.
[0071] The compounds of the invention have an IC.sub.50 in this
test of about from 0.1 to 10 .mu.M.
[0072] These results suggest that the compounds of the invention
may be used for treating behavioral disorders associated with
dementia, psychoses, in particular schizophrenia (deficient form
and productive form) and acute or chronic extrapyramidal symptoms
induced by neuroleptics, for the treatment of various forms of
anxiety, panic attacks, phobias, compulsive obsessive disorders,
for treating various forms of depression, including psychotic
depression, for treating disorders caused by alcohol abuse or
weaning from alcohol, sexual behavior disorders, eating disorders
and for treating migraine.
[0073] Moreover, the compounds of the invention may be used for
treating painful muscle contracture in rheumatology and in acute
spinal pathology, for treating spastic contractures of medullary or
cerebral origin, for the symptomatic treatment of acute and
subacute pain of light to moderate intensity, for treating intense
and/or chronic pain, neurogenic pain and intractable pain, for
treating Parkinson's disease and Parkinson-like symptoms of
neurodegenerative origin or induced by neuroleptics, for treating
partial primary and secondary generalized epilepsy of simple or
complex symptomology, mixed forms and other epileptic syndromes in
addition to another antiepileptic treatment, or in monotherapy, for
the treatment of sleep apnea, and for neuroprotection.
[0074] Accordingly, a subject of the present invention is also
pharmaceutical compositions containing an effective dose of at
least one compound according to the invention, in the form of base
or of pharmaceutically acceptable salt or solvate, and as a
mixture, where appropriate, with suitable excipients.
[0075] Said excipients are chosen according to the pharmaceutical
form and the desired mode of administration.
[0076] The pharmaceutical compositions according to the invention
may thus be intended for oral, sublingual, subcutaneous,
intramuscular, intravenous, topical, intratracheal, intranasal,
transdermal, rectal or intraocular administration.
[0077] The unit administration forms may be, for example, tablets,
gel capsules, granules, powders, oral or injectable solutions or
suspensions, transdermal patches or suppositories. Pomades, lotions
and eyedrops may be envisioned for topical administration.
[0078] Said unit forms are dosed to allow a daily administration of
from 0.01 to 20 mg of active principle per kg of body weight,
according to the galenical form.
[0079] To prepare tablets, a pharmaceutical vehicle, which may be
composed of diluents, for instance lactose, microcrystalline
cellulose or starch, and formulating adjuvants, for instance
binders (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.),
glidants, for instance silica, and lubricants, for instance
magnesium stearate, stearic acid, glyceryl tribehenate or sodium
stearyl fumarate, are added to the micronized or nonmicronized
active principle. Wetting agents or surfactants such as sodium
lauryl sulfate may also be added.
[0080] The preparation techniques may be direct tableting, dry
granulation, wet granulation or hot melting.
[0081] The tablets may be plain, sugar-coated, for example coated
with sucrose, or coated with various polymers or other suitable
materials. They may be designed to allow rapid, delayed or
sustained release of the active principle by means of polymer
matrices or specific polymers used in the coating.
[0082] To prepare gel capsules, the active principle is mixed with
dry pharmaceutical vehicles (simple mixing, dry or wet granulation,
or hot melting), or liquid or semisolid pharmaceutical
vehicles.
[0083] The gel capsules may be hard or soft, with or without a film
coating, so as to have rapid, sustained or delayed activity (for
example for an enteric form).
[0084] A composition in the form of a syrup or elixir or for
administration in the form of drops may contain the active
principle together with a sweetener, preferably a calorie-free
sweetener, methylparaben or propylparaben as antiseptic, a
flavoring and a dye.
[0085] The water-dispersible powders and granules may contain the
active principle as a mixture with dispersants or wetting agents,
or dispersants such as polyvinylpyrrolidone, and also with
sweeteners and flavor enhancers.
[0086] For rectal administration, use is made of suppositories
prepared with binders that melt at the rectal temperature, for
example cocoa butter or polyethylene glycols.
[0087] Aqueous suspensions, isotonic saline solutions or injectable
sterile solutions containing pharmacologically compatible
dispersants and/or wetting agents, for example propylene glycol or
butylene glycol, are used for parenteral administration.
[0088] The active principle may also be formulated in the form of
microcapsules, optionally with one or more supports or additives,
or alternatively with a polymer matrix or with a cyclodextrin
(transdermal patches, sustained-released forms).
[0089] The topical compositions according to the invention comprise
a medium that is compatible with the skin. They may especially be
in the form of aqueous, alcoholic or aqueous-alcoholic solutions,
gels, water-in-oil or oil-in-water emulsions having the appearance
of a cream or a gel, microemulsions or aerosols, or alternatively
in the form of vesicular dispersions containing ionic and/or
nonionic lipids. These galenical forms are prepared according to
the usual methods of the fields under consideration.
[0090] Finally, the pharmaceutical compositions according to the
invention may contain, along with a compound of general formula
(I), other active principles that may be useful in the treatment of
the disorders and diseases indicated above.
* * * * *