AP424A - Piperidine derivatives, their preparation and their application in therapy. - Google Patents

Piperidine derivatives, their preparation and their application in therapy. Download PDF

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Publication number
AP424A
AP424A APAP/P/1993/000575A AP9300575A AP424A AP 424 A AP424 A AP 424A AP 9300575 A AP9300575 A AP 9300575A AP 424 A AP424 A AP 424A
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group
compound
compounds
alkyl
hydrogen atom
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APAP/P/1993/000575A
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AP9300575A0 (en
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Samir Jegham
Itzchak Angel
Johannes Schoemaker
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Synthelabo
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Compounds corresponding to the formula in which r represents either a hydrogen atom or an unbranched or branched (c1-c6)alkyl group, and ar represents either a phenyl group optionally substituted with one or more radicals chosen from halogen atoms and amino, (c1-c2)alkoxy and (c3-c6)cycloalkyl(c1-c2)alkoxy groups, or a heteroaryl group, excepting the compounds in which r is a hydrogen atom and ar is a phenyl group or a 4-chlorophenyl group, as well as their addition salts with pharmaceutically acceptable acids. Therapeutic application.

Description

PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR
APPLICATION IN THERAPY
SYNTHELABO
An invention of: Samir JEGHAM, Itzchak ANGEL, Thomas PURCELL, Johannes SCHOEMAKER
Abstract
Compounds corresponding to the formula
Ar in which
R represents either a hydrogen atom or an unbranched or branched (C1-C6) alkyl group, and Ar represents either a phenyl group optionally substituted with one or more radicals chosen from halogen atoms and amino, (C,-C2) alkoxy and (Cj-C6)cycloalkyl(Ct-C2)alkoxy groups, or a heteroaryl
BAD ORIGINAL ft
AP Ο Ο Ο 4 2 4
- lb group, excepting the compounds in which R is a hydrogen atom and Ar is a phenyl group or a 4-chlorophenyl group, as well aa their addition salts with pharmaceutically acceptable acids.
Therapeutic application.
BAD ORIGINAL ft
AP Ο Ο Ο 4 2 4
- Ic —
The present invention relates to piperidine derivatives, to their preparation and their application in therapy.
The compounds of the invention correspond to 5 the formula (I)
in which
R represents either a hydrogen atom or an unbranched or branched (C,-C6) alkyl group, and Ar represents either a phenyl group optionally substituted with one or more radicals chosen from halogen atoms and amino, (C,-^) alkoxy and (Cj-C6) cycloalkyl (C,—C2) alkoxy groups, or a heteroaryl ( group, excepting the compounds for which R is a hydrogen atom and Ar is a phenyl group or a 4-chlorophenyl group.
Among the compounds according to the invention, preferred compounds are the compounds corresponding to the formula (I) in which R represents either a hydrogen atom or an unbranched or branched (C,—C6)alkyl group, and
Ar represents either a phenyl group optionally substituted with one or more radicals chosen from the
BAD ORIGINAL
AP 0 0 0 4 2 4 chlorine atom and amino, methoxy and cyclopropylmethoxy groups, or an imidazo[l,2-a]pyridin-2-yl group, or a
3-indolyl group, or a 3-indazolyl group optionally substituted at position 1 with a radical chosen from (C1-CJ) alkyl and aryl (Cj-Cj) alkyl groups and at position 5 with a radical chosen from hydrogen and halogen atoms and the (Cj-Cj) alkyl group.
Among these, there may be mentioned the compounds corresponding to the formula (I) in which R represents either a hydrogen atom or an unbranched or branched (Cj-CJ alkyl group, and
Ar represents a 3-indazolyl group optionally substituted at position 1 with a radical chosen from (Cj-Cj)alkyl and aryl (Cj-Ca) alkyl groups and at position 5 with a radical chosen from hydrogen and halogen atoms and the (Cj-Cj)alkyl group.
The compounds according to the invention can be in the state of free bases or of addition salts with pharmaceutically acceptable acids. The compounds whose formula is a mesomeric form of the formula (I) form part of the invention.
European Patent Application 0,494,010 describes compounds of formula (I) in which R is a hydrogen atom and Ar is a phenyl group optionally substituted at the para-position with a chlorine atom.
According to the invention, the compounds of formula (I) may be prepared according to the process illustrated in Scheme 1 below:
ΘΑΟ ORIGINAL &
Scheme 1
A compound of formula (II), in which Ar ie as defined above and X represents either a halogen atom, for example a chlorine atom, or a hydroxyl group, is reacted with a piperidine derivative of formula (III) in which R is as defined above.
The starting compounds are commercially available or are described in the literature, or may be prepared according to methods which are described therein or which are known to a person skilled in the art.
ltf-Indazole-3-carboxylic acid is described in J. Aater. Cheat. Soc., 1952, 2009.
4-Amino-5-chloro-2-(cyclopropylmethoxy)15 benzoic acid is described in British Patents
GB 1,507,462, GB 1,088,581 and GB 101,978.
4-(Lff-Imidazol-4-yl)piperidine is described in Arch. Pharmaz., (Weinheim. Ger.) 1973, 306(12), 93442 and in European Patent Application 0,197,840.
4-(5-Methyl-lff-imidazol-4-yl)pyridine ie described in J. Med. Cheat., 1986, 29, 2154-63.
BAD ORIGINAL
AP Ο Ο Ο 4 2 4
The examples which follow illustrate in detail the preparation of the compounds according to the invention.
The microanalyses and the IR and NMR spectra 5 confirm the structure of the compounds obtained.
1-(3,5-Dichlorobenzoyl)-4-( IK-imidazol-4-yl) piperidine fumarate f~ 0.469 g (2.5 mmol) of 4-(IK-imidazol-4-yl)10 piperidine monohydrochloride is dissolved in 5 ml of
N sodium hydroxide at 0»C. 0.524 g (2.5 mmol) of 3,5-dichlorobenzoyl chloride is then added and the mixture is stirred at 0*C for 15 minutes. The precipitate obtained is filtered off, washed with 1 N sodium hydroxide and then with water and dried. The residue is recrystallized in ethanol.
0.4 g of product are obtained.
Melting point « 240-242*C ( The fumarate is prepared by dissolving the base in ethanol and then adding one equivalent of fumaric acid. The fumarate is recrystallized in a mixture of isopropanol and ethanol.
Melting point 178-183*C
Example,2
4 - (IK- Imidazol-4 -yl )-1-(( lK-indol-3-yl) carbonyl ] piperidine fumarate
0.81 ml (5.82 mmol) of triethylamine is added to a suspension of 0.48 g (3 mmol) of
AP 0 0 0 4 2 4
ΙΗ-indole-3-carboxylic acid and 0.453 g (3 mmol) of 4-(lH-imida2ol-4-yl)piperidine in 10 ml of dichloromethane, at room temperature and under argon. 1.29 ml (6 mol) of diphenylphosphoryl azide are added and the mixture is stirred for 20 hours. The reaction medium is extracted with ethyl acetate in an acid medium. The aqueous phase is recovered, alkalinized with potassium carbonate solution and extracted with ethyl acetate. The organic phase is recovered and washed with water and then with saturated sodium chloride solution. It is dried over magnesium sulphate. The residue obtained is purified by chromatography on a column of silica gel, eluting with a dichloromethane/ methanol (90:10) mixture. The pure fractions are evaporated and 0.27 g of product is collected.
To prepare the fumarate, the base is taken up with ethanol and one equivalent of fumaric acid is added. After recrystallization in a mixture of ethanol and isopropyl ether, the product obtained in the form of a hemifumarate is filtered off and dried.
0.3 g of product is obtained.
Melting point - 250°C (dec) Yield » 28 %
Example 3
1- ((lH-Indazol-3-yl) carbonyl ] -4- (5-methyl-lff-imidazol4-yl)piperidine fumarate
In a 100-ml round-bottomed flask, 1.35 g (8.15 mmol) of 4-(5-methyl-lH-imidazol-4-yl)piperidine are placed in 15 ml of dichloromethane and 4 ml of
AP 0 0 0 4 2 4 diemthylforsuunj.de. 1.32 g (8.15 mmol) of LH-indazole-3carboxylic acid and 2.2 ml of triethylamine are added. The mixture ie left stirring for 5 minutes. 3.5 ml of diphenylphosphoryl azide are added and the mixture is left stirring for 72 hours. Ethyl acetate is added and the mixture is extracted 3 times with 2 N hydrochloric acid. The aqueous phase is recovered and alkalinized with sodium carbonate solution. It is extracted 3 times with ethyl acetate and the organic phase is collected, dried and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane/methanol/ammonia solution (90:10:1) mixture.
g of product is recovered in the form of the pure base.
The fumarate is prepared as described in
Example 1.
Melting point 213-215*0 Yield 32 %
The table which follows illustrates the chemical structures and physical properties of a few compounds according to the invention.
Legend to the table in the M.p, (°C) column of the table (dec) denotes decomposition in the Salt column of the table (x:y) denotes x mol of acid for y mol of base, the absence of any comment means that the compound is in the state of the base,
BAD ORIGINAL
AP Ο Ο Ο 4 2 4 chlor. represents the hydrochloride fum. represents the fumarate methanesulph. represents the methanesulphonate
No. R Ar M.p.(*C) Salt
1 -H V 178-183 fum. (1:2)
2 -H 140-145 -
3 -CH, A 135-145 -
BAD ORIGINAL
AP Ο Ο Ο 4 2 4
No. R Ar M.p.(*C) Salt
4 -H χς 135 (dec) -
5 -H > 220 (dec) fum. (1:1)
6 -H 220 (dec) fum. (1:2)
7 -CHj 175-180 fum. (1:1)
8 -H ΓΠΗ* 210 (dec) fum. (1:2)
BAD ORIGINAL
AP Ο Ο Ο 4 2 4
No. R Ar M.p.(*C) Salt
9 -CH, aX wit 202 -
10 -CH, aK* 213-215 fum. (1:2)
11 -CH, Zr( 235-237 methanesulph. (1:1)
12 -(CH, ),CH, A 217-222 fum. (1:1)
13 -CH(CH,), aK* 239-241 fum. (1:1)
bad original
AP Ο Ο Ο 4 2 4
No. R Ar M.p.(*C) Salt
14 -(CH,),CH, NH 220-224 fun. (1:1)
15 -H cd 185-192 fum. (1:1)
16 -CH, Td- 186-192 fum. (1:1)
17 -H °τχί 188-195 fum. (1:1)
18 -CH, °rX 206-212 fum. (1:1)
19 -(CH,),CH, °o5 130-135 chlor. (1:1)
bad original $
A.P Ο Ο Ο 4 2 4
Νο. R Ar M.p.(*C) Salt
20 -CHj Ιη3 181-182
21 -CHjCHj 1 ch3 182-184
22 -XL 172-175 fum. (1:1)
23 -(CHJjCH, ύΕ 0¾ 217-220 -
AP Ο Ο Ο 4 2 4
No. R Ar M.p.(*C) Salt
24 -H 186-192 fum. (1:1)
25 -CHj XX? 218-225 fum. (1:1)
26 -(CHJjCH, XX> CH, > 250 -
27 -H L· LI__/ & 165-167 fum. (1:1)
BAD ORIGINAL
AP 0 0 0 4 2 4
The compounds of the invention were subjected to pharmacological tests which showed their value as therapeutically active substances.
Thus, they were tested for their effects on the accummulation of cAMP in a primary culture preparation of neurons of mouse embryo colliculi according to the technique described by Dumuie et al., Mol. Pharmacol., 34, 880-887, 1988. This accummulation reflects adenylcyclaee activity to which the type 5-HT4 serotoninergic receptors are coupled positively.
Colliculi are removed from 14- to 15-day-old mouse embryos. The neurons are separated mechanically and cultured, in 12-well Costar91 dishes on the basis of 10* cells per well, in a DMEM/F12™ nutrient medium with supplements but without serum. The cultures are maintained at 37*C in a humidified atmosphere (5 % CO,/ 95 % air).
Six days after culturing is started, the cells are incubated for 2 hours in the culture medium described above in the presence of 0.1 nmol of tritiated adenine (specific activity 20 Ci/mmol) per well. The cells are washed with the culture medium and a second incubation is carried out in the culture medium in the presence of isobutylmethylxanthine (0.75 mM), forskolin (0.1 μΜ) and test products at different concentrations, in a final volume of 1 ml per well. After 10 minutes of incubation, the reaction is stopped by aspirating the medium and adding 1 ml of 5 *
AP 0 0 0 4 2 4 trichloroacetic acid. The neurone are detached, homogenized using ultrasound and centrifuged at 8000 g for 2.5 minutes. The supernatant is collected and 100 μΐ of a solution containing cAMP (5 mM) and ATP (5 mM) are added. The tritiated ATP and cAMP formed are separated by passage through DOWEX™ AG50WX8 resin and then through alumina.
The results were expressed as % [JH)-cAMP/ [3H]-ATP
The ECj0 and 1CSO values represent, respectively, the concentrations which produce one half of the maximal stimulation and of the maximal inhibition.
The compounds of the invention which are most active in this test are characterized by IC,0 values of between 1 and 10 μΜ.
The compounds of the invention were also tested in vivo for their effect on 5-HTP-induced diarrhoea in mice according to the technique described by Warrick et al., «7. Pharm. Pharmacol., 33, 675-676, 1981. Male CDX mice weighing 25-30 g and fasted for 18 hours are used. The compounds or the vehicle is/are administered 20 minutes (intraperitoneal route) or 60 minutes (oral route) before the intraperitoneal injection of 5-HTP at a dose of 25 mg/kg. The animals are placed in individual cages and are observed for 3 hours, noting the number of animals having diarrhoea 30 minutes, 1 hour, 2 hours and 3 hours after the
ΑΡ ϋ Ο Ο 4 2 4 administration of 5-ΗΤΡ.
The results are expressed as a percentage of animals protected by the pretreatment in comparison to the control animals which have received the vehicle as a pretreatment.
The compounds of the invention which are most active in this test inhibit 5-HTP-Induced diarrhoea after a dose of 0.002 mg/kg administered (~ intraperitoneally or 0.1 mg/kg administered orally.
The compounds according to the invention were also tested for their inhibitory effects on the binding of [’BJquipazine to the type 5-HT, serotoninergic receptors present in the rat cerebral cortex, according to a variant of the method described by Milburn and
Peroutka (J. Neurochem., 52, 1787-1792, 1989).
Male Sprague-Dawley rats weighing 150 to 200 g are used in all the tests. Their cerebral cortex is removed and homogenized in 20 volumes ' (weight/volume) of 25 mM Hepes buffer or of 25 mM Hepes buffer containing sodium chloride (180 mM), calcium chloride (2.5 mM), potassium chloride (5 mM) and magnesium chloride (1.2 mM) (pH 7.4) using a Polytron1* mill. After centrifugation of the suspension for 10 minutes at 45,000 x g, the pellet is resuspended in the initial volume of buffer, where appropriate containing 0.05% of Triton X-lOO**, and a first incubation is performed for 30 minutes at 37°C. Two further
AP Ο Ο Ο 4 2 4 and the final pellet is taken up in 11.7 volumes of 25 mM Hopes buffer, pH 7.4.
The binding of [’HJquipazine (51.6-69.8 Ci/ mmol, Hew England Huclear, Boston, Ma, USA) is determined by incubating 150 μΐ of the membrane suspension with the radioligand (0.8 nM) in a final volume of 1 ml for 30 minutes at 25*C, in the absence or presence of the compound under study. Incubation takes place in the presence of 0.1 μΜ paroxetine and
I μΜ ketanserin. Non-specific binding is determined in the presence of 1 μΜ ondansetron. After incubation, the test mixture is diluted with 5 ml of ice-cold 50 mM Trie-HCl buffer (pH 7.4 at 0*C). The membranes are collected by filtration on Whatman GF/B™ filters pretreated with 0.05% of polyethylenimine, and washed with three volumes of 5 ml of ice-cold 50 mM Tris-HCl buffer.
The radioactivity retained on the filters is measured by liquid scintillation spectrometry at an efficiency of 50 to 60%.
The results are expressed as the concentration (IC50) of the compound under study which inhibits 50% of the binding of [’HJquipazine, determined by a graphic or mathematical method. The compounds of the invention which are most active in this test are characterized by ICS0 values below 1 nM (10~*M).
The results of the biological tests show that the compounds of the invention are ligands for types
AP 0 0 0 4 2 4
5-HT, and 5-HT, eerotoninergic receptor·.
They may hence be used for the treatment and prevention of disorders in which 5-HT, and 5-HT* receptors are involved, such as nausea and vomiting, for example following antitumour treatment or the administration of an anaesthetic; disorders of the central nervous system such as schizophrenia, mania, anxiety and depression; disorders of cognition such as senile dementia or Alzheimer's presenile dementia; dyskinesia, pain, migraine and headache; disorders associated with alcohol or drug dependence or withdrawal; disorders of gastro intestinal function such as dyspepsia, peptic ulcer, heartburn, flatulence; disorders of the cardiovascular system and respiratory disorders.
They may also be used for the treatment and prevention of disorders such as diarrhoea, irritable colon, oesophageal reflux, intestinal motor disorders, disorders of intestinal secretion, cystic fibrosis of the pancreas, carcinoid syndrome and incontinence.
For this purpose, they may be presented in all forms suitable for oral or parenteral administration, such as tablets, drag£es, capsules including hard gelatin capsules, suspensions or solutions to be swallowed or injected, and the like, in combination with suitable excipients, and in doses that enable 0.005 to 10 mg to be administered 1 to 4 times a day.

Claims (10)

  1. Claims
    1. Compounds corresponding to the formula (I) \ NH (I) in which
    5 R represents either a hydrogen atom or an unbranched or branched (Cj-C^alkyl group, and Ar represents either a phenyl group optionally substituted with one or more radicals chosen from halogen atoms and amino, (C^Cj)alkoxy and
    10 (Cj-C6)cycloalkyl (C^CJ alkoxy groups, or a heteroaryl group, excepting the compounds in which R is a hydrogen atom and Ar is a phenyl group or a 4-chlorophenyl group, as well as their addition salts with pharmaceutically
    15 acceptable acids.
  2. 2. Compounds according to Claim 1 characterized in that
    R represents either a hydrogen atom or an unbranched or branched (C,-C6) alkyl group, and
    20 Ar represents either a phenyl group optionally substituted with one or more radicals chosen from the chlorine atom and amino, methoxy and cyclopropylmethoxy
    BAD ORIGINAL
    AP Ο Ο Ο 4 2 4 groups, or an imidazofl,2-a]pyridin-2-yl group, or a
  3. 3-indolyl group, or a 3-indazolyl group optionally substituted at position 1 with a radical chosen from (C1—Ca) alkyl and aryl (Ca-Ca) alkyl groups and at position 5 with a radical chosen from hydrogen and halogen atoms and the (Cx-Ca) alkyl group.
    3. Compounds according to Claim 2, characterized in that
    R represents either a hydrogen atom or an unbranched or branched (Cj-C,)alkyl group, and Ar represents a 3-indazolyl group optionally substituted at position 1 with a radical chosen from (Ci-Cj) alkyl and aryl (Ca-Ca) alkyl groups and at position 5 with a radical chosen from hydrogen and halogen atoms and the (Ca-Ca) alkyl group.
  4. 4. Process for preparing the compounds according to Claim 1, which process is characterized in that a compound of formula (II) in which Ar is as defined in Claim 1, and X represents either a halogen atom or a hydroxyl group, is reacted with a piperidine derivative of formula (III)
    BAD ORIGINAL
    AP Ο Ο Ο 4 2 4 (III) in which R is as defined in Claim 1.
  5. 5. Medicinal product, characterized in that it contains a compound according to any one of Claims 1 to 3.
    5
  6. 6. Pharmaceutical composition, characterized in that it contains a compound according to any one of Claims 1 to 3, in combination with any suitable excipient.
  7. 7. A compound of the general formula (I) or an addition salt thereof with pharmaceutically acceptable acids substantially as herein described with reference to the accompanying examples.
  8. 8. A process for preparing a compound of the general formula (I) or an addition salt thereof with pharmaceutically acceptable acids substantially as herein described with reference to the accompanying examples.
  9. 9. A medicinal product, characterized in that it contains a compound of claim 7.
  10. 10. A pharmaceutical composition, characterized in that it contains a compound of claim 7 in combination with any suitable excipient. z'i
APAP/P/1993/000575A 1992-09-28 1993-09-27 Piperidine derivatives, their preparation and their application in therapy. AP424A (en)

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FR9211551A FR2696177B1 (en) 1992-09-28 1992-09-28 Piperidine derivatives, their preparation and their therapeutic application.

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EP0197840A1 (en) * 1985-03-26 1986-10-15 Institut National De La Sante Et De La Recherche Medicale (Inserm) (Imidazolyl-4) piperidines, their preparation and their therapeutical use

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CZ282080B6 (en) 1997-05-14
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AU4860693A (en) 1994-04-14
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IL107133A (en) 1998-03-10
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