WO1994018193A1 - Novel heterocyclic aminomethyl-4 piperidine derivatives, their preparation and application in therapy - Google Patents

Novel heterocyclic aminomethyl-4 piperidine derivatives, their preparation and application in therapy Download PDF

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Publication number
WO1994018193A1
WO1994018193A1 PCT/FR1994/000152 FR9400152W WO9418193A1 WO 1994018193 A1 WO1994018193 A1 WO 1994018193A1 FR 9400152 W FR9400152 W FR 9400152W WO 9418193 A1 WO9418193 A1 WO 9418193A1
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Prior art keywords
piperidine
benzodioxan
methyl
general formula
methylamino
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PCT/FR1994/000152
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French (fr)
Inventor
Dennis Bigg
Florence Castan
Wouter Koek
Bernard Bonnaud
Original Assignee
Pierre Fabre Medicament
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Publication date
Application filed by Pierre Fabre Medicament filed Critical Pierre Fabre Medicament
Priority to EP94906261A priority Critical patent/EP0683775A1/en
Priority to AU60033/94A priority patent/AU6003394A/en
Priority to JP6517735A priority patent/JPH08506334A/en
Publication of WO1994018193A1 publication Critical patent/WO1994018193A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, ***e
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 5-HT- receptors one of the subtypes of serotoninergic receptors, play an important physiological role. Also, as the various chapters of the book “Brain 5-HT Receptors: Behaviourai and Neurochemical Pharmacology” show (Editors C.T. Dourish, S. Ahlenins, P.H. Hutson,
  • 5-HT 1A agonists may be useful for the treatment of anxiety, depression, sleep disorders, vascular and cardiovascular disorders, and the regulation of food.
  • Agonists 5-HT-. are also known as inhibitors of gastric secretion (JS Gidda, JM Schaus EP.455.510 A2, 1991).
  • the present invention carried out at the Pierre Fabre Research Center, relates to new chemical compounds endowed with agonist activity at 5-HT 1 ⁇ receptors, their preparation and their therapeutic application.
  • A represents an oxygen atom, a sulfur atom, or a methylene radical; m can take the values of 0 or 1;
  • B represents a carbonyl function (CO) or a methylene
  • n can take the values of O or 1; R represents a cycloalkyy radical, monocyclic or polycyclic, C O -C- Q .
  • the invention also relates to the salts of the compounds of general formula _ with pharmaceutically acceptable mineral or organic acids.
  • the acid employed can be, by way of nonlimiting example, p-toiuessesulfonique acid, or fumaric acid.
  • the present invention relates to both racemic mixtures and the various enantiomers of the compounds of general formula _1_ as well as their mixtures in all proportions.
  • the compounds of general formula _1_ where B represents a carbonyl radical can be prepared according to the reaction scheme:
  • - X represents a water-repellent group such as methylsulfonyloxy, benzenesulfonyloxy, or jo-toluenesulfonyloxy.
  • reaction between a compound of general formula 2 ⁇ and a compound of general formula 3 ⁇ is carried out either in the absence or in the presence of a solvent such as toluene, xylene, dimethylformamide or acetonitrile, preferably at a temperature between 50 ° C and 200 ° C, and optionally in the presence of an organic base such as a tertiary or mineral amine, such as an alkali carbonate or hydro-carbonate.
  • a solvent such as toluene, xylene, dimethylformamide or acetonitrile
  • a compound of general formula 4_ obtained according to the methods described above, is carried out by means of a simple or complex hydride of boron or aluminum, for example, 1 * double hydride of lithium and d aluminum, a diborane / ether complex, or the diborane / methyl sulfide complex, or any other equivalent means, in an inert solvent such as ethyl ether or tetrahydrofuran.
  • the reduction can be carried out at room temperature or accelerated by heating to the reflux temperature of the solvent.
  • a compound of general formula 5_ is thus obtained which corresponds to the general formula j_ when B represents a methylene.
  • R cyclohexyl
  • X p_-toluenesulfonyloxy
  • the compounds of the invention have been subjected to pharmacological tests which have demonstrated their advantage as substances with therapeutic activities.
  • rat cerebral cortices are used.
  • the brain is dissected and the cortex is homogenized in 20 volumes of Tris-HCl buffer (50 mil, pH 7.4 at 25 ° C) maintained at 4 ° C.
  • the homogenate is centrifuged at 39,000 xg for 10 minutes, the centrifugation pellet is suspended in the same volume of buffer and centrifuged again. After resuspending under the same conditions, the homogenate is incubated for 10 minutes at 37 ° C and then centrifuged again.
  • the final pellet is suspended in 80 volumes of reaction buffer containing: pargyline (10 -5 M), CaCl 2 (4 mM) and ascorbic acid (0.1%) in Tris-HCl (50 mM, pH 7 , 4 at 25 ° C).
  • the final concentration of tissue in the incubation medium is 10 mg / tube.
  • the reaction tubes contain 0.1 ml of different concentrations of ⁇ 3 H_7 ⁇ -OH-DPAT (between 0.06 and 8 nM), 0.1 ml of reaction buffer or 5-HT (10 M, to determine non-specific binding) and 0.8 ml of tissue.
  • Displacement experiments are carried out as described by Sleight and Peroutka (Naunyn-Schneideberg Arch. Pharmacol., 343, 106-116, 1991). All the dilutions of the products to be studied are made in the reaction buffer.
  • the reaction tubes contain 0.1 ml of J_H_ / 8-OH-DPAT (0.2 nM), 0.1 ml of product to be tested 6-7 concentrations (successive dilutions to 1/10) and 0.8 ml tissue. If the alleged affinity of the products is in the nanomo- laire, the lowest concentration tested is 10-11 M, if the product has an assumed low affinity, the highest concentration tested is 10 -4 M.
  • reaction tubes are incubated at 23 ° C for 30 minutes and then rapidly filtered under vacuum on hatman GF / B filters, the tubes are rinsed with 2 x 5 ml of Tris-HCl buffer (50 mM, pH 7.4 at 25 ° C).
  • the radioactivity collected on the filter is analyzed in liquid scintillation by adding 4 ml of scintillating liquid
  • the dissociation constant (K D ) and the maximum number of binding sites (Bmax) for the radio frequency are estimated from the saturation experiments using the non-linear regression program EBDA / LIGAND (Biosoft) (Munson and Rodbard, Anal. Biochem., 107, 220-239, 1980).
  • the affinity constants (Ki) of the reference products are estimated from the displacement experiments using the non-linear regression program EBDA / LIGAND. This method admits that the value of the Hiil coefficient is not different from unity.
  • the data from the displacement experiments are analyzed respectively with the one site and two site models and the calculated F makes it possible to determine whether the two site model is more representative of the data obtained than the one site model.
  • the pKi values are given as an average + SEM of 3 to 5 experiments.
  • Table 2 gives, by way of example, pKi 5-HT 1A for certain derivatives of the invention, compared with Buspirone which is used in clinical practice.
  • Table 2 Affinity for the 5-HT-A receptor
  • the central activity of the compounds of the invention has been evaluated by their capacity to cause 5-HT syndrome, which is characterized by alternating flexion and extension of the front legs (reciprocal fore-paw treading: FPT), the re ⁇ traction of the lower lip (lower-lip retraction: LLR) and by a posture where the ventral surface of the animal is in contact with the floor of the cage with the extended hind legs (flat body posture: FBP).
  • the compounds of the invention can therefore be useful for the treatment of anxiety, depression, sleep disorders, for the regulation of food intake, for the regulation of gastric secretion, and for the treatment of vascular disorders.
  • cardiovascular and cerebrovascular such as hypertension or migraine.
  • Pharmaceutical preparations containing these active ingredients can be shaped for administration by oral, rectal or parenteral route, for example in the form of capsules, tablets, granules, capsules, liquid solutions, syrups or oral suspensions, and contain the appropriate excipients.

Abstract

Heterocyclic aminomethyl-4 piperidine derivatives corresponding to general formula (1), and the therapeutically acceptable salts of these molecules. The invention also concerns the use of compounds of general formula (1) in therapy and processes for their preparation.

Description

Nouveaux dérivés hétérocycliques de i'aminométhyl-4 piperidine leur préparation et leur application en thérapeutique.New heterocyclic derivatives of 4-aminomethyl piperidine, their preparation and their therapeutic use.
Les récepteurs 5-HT- , un des sous-types de ré¬ cepteur sérotoninergique, jouent un rôle physiologique impor- tant. Aussi, comme le montrent les différents chapitres du livre "Brain 5-HT Receptors : Behaviourai and Neurochemical Pharmacology" (Editeurs C.T. Dourish, S. Ahlenins, P.H. Hutson,5-HT- receptors, one of the subtypes of serotoninergic receptors, play an important physiological role. Also, as the various chapters of the book "Brain 5-HT Receptors: Behaviourai and Neurochemical Pharmacology" show (Editors C.T. Dourish, S. Ahlenins, P.H. Hutson,
Eilis Horwood Ltd., Chichester, 1987), les agonistes 5-HT 1A peuvent être utiles pour le traitement de l'anxiété, la dé- pression, les troubles du sommeil, les désordres vasculaires et cardiovasculaires, et la régularisation de la prise de nourriture. Les agonistes 5-HT-., sont également connus comme inhibiteurs de la sécrétion gastrique (J.S. Gidda, J.M. Schaus EP.455.510 A2, 1991) . La présente invention, réalisée au Centre de Re¬ cherche Pierre Fabre, a pour objet de nouveaux composés chi¬ miques dotés d'activité agoniste aux récepteurs 5-HT1Ά, leur préparation et leur application en thérapeutique.Eilis Horwood Ltd., Chichester, 1987), 5-HT 1A agonists may be useful for the treatment of anxiety, depression, sleep disorders, vascular and cardiovascular disorders, and the regulation of food. Agonists 5-HT-., Are also known as inhibitors of gastric secretion (JS Gidda, JM Schaus EP.455.510 A2, 1991). The present invention, carried out at the Pierre Fabre Research Center, relates to new chemical compounds endowed with agonist activity at 5-HT 1Ά receptors, their preparation and their therapeutic application.
Les composés de l'invention répondent à la for- mule générale 1 :The compounds of the invention correspond to general formula 1:
Figure imgf000003_0001
Figure imgf000003_0001
dans laquelle :in which :
A représente un atome d'oxygène, un atome de soufre, ou un radical méthylène; m peut prendre les valeurs de 0 ou 1 ;A represents an oxygen atom, a sulfur atom, or a methylene radical; m can take the values of 0 or 1;
B représente une fonction carbonyie (CO) ou un méthylèneB represents a carbonyl function (CO) or a methylene
(CH2) ; n peut prendre les valeurs de O ou 1 ; R représente un radical cycioalkyie, monocyclique ou poiy- cyciique, en CO-C-Q. L'invention concerne également les sels des com¬ posés de formule générale _ avec des acides minéraux ou orga¬ niques pharmaceutiquement acceptables. L'acide employé peut être, à titre d'exemple non limitatif, l'acide p_-toiuènesulfo- 5 nique, ou l'acide fumarique.(CH 2 ); n can take the values of O or 1; R represents a cycloalkyy radical, monocyclic or polycyclic, C O -C- Q . The invention also relates to the salts of the compounds of general formula _ with pharmaceutically acceptable mineral or organic acids. The acid employed can be, by way of nonlimiting example, p-toiuènesulfonique acid, or fumaric acid.
La présente invention concerne aussi bien les mélanges racémiques que les différents énantiomères des com¬ posés de formule générale _1_ ainsi que leurs mélanges en toutes proportions. Les composés de formule générale _1_ où B représente un radical carbonyle, peuvent être préparés selon le schéma de réaction :The present invention relates to both racemic mixtures and the various enantiomers of the compounds of general formula _1_ as well as their mixtures in all proportions. The compounds of general formula _1_ where B represents a carbonyl radical, can be prepared according to the reaction scheme:
Figure imgf000004_0001
2 3 4 où
Figure imgf000004_0001
2 3 4 where
- A, m, n, et R sont définis comme ci-dessus.- A, m, n, and R are defined as above.
- X représente un groupe nuciéofuge tel que méthylsulfonyloxy, benzènesulfonyloxy, ou jo-toluènesulfonyloxy. Les aminés de départ 2_ et les pipéridines de for¬ mule 3_ peuvent être obtenues selon des méthodes classiques.- X represents a water-repellent group such as methylsulfonyloxy, benzenesulfonyloxy, or jo-toluenesulfonyloxy. The starting amines 2_ and the piperidines of formula 3_ can be obtained according to conventional methods.
La réaction entre un composé de formule générale 2^ et un composé de formule générale 3^ s'effectue, soit en l'absence, soit en présence d'un solvant tel que le toluène, le xylène, le dimethylformamide ou l'acetonitrile, de préfé¬ rence à une température comprise entre 50°C et 200°C, et éventuellement en présence d'une base organique telle qu'une aminé tertiaire ou minérale, telle qu'un carbonate ou hydro- génocarbonate alcalin. On obtient ainsi un composé de formule générale 4 qui correspond à la formule générale _ lorsque B représente une fonction carbonyle.The reaction between a compound of general formula 2 ^ and a compound of general formula 3 ^ is carried out either in the absence or in the presence of a solvent such as toluene, xylene, dimethylformamide or acetonitrile, preferably at a temperature between 50 ° C and 200 ° C, and optionally in the presence of an organic base such as a tertiary or mineral amine, such as an alkali carbonate or hydro-carbonate. A compound of general formula 4 is thus obtained which corresponds to the general formula _ when B represents a carbonyl function.
Les composés de formule générale _1_ où B repré¬ sente un méthylène, peuvent être préparés selon le schéma de réaction :The compounds of general formula _1_ where B represents a methylene, can be prepared according to the reaction scheme:
Figure imgf000005_0001
Figure imgf000005_0001
où A, m, n et R sont définis comme ci-dessus.where A, m, n and R are defined as above.
La réduction d'un composé de formule générale 4_, obtenu selon les méthodes décrites ci-dessus, s'effectue au moyen d'un hydrure simple ou complexe de bore ou d'aluminium, par exemple, 1*hydrure double de lithium et d'aluminium, un complexe diborane/éther, ou le complexe diborane/sulfure de méthyle, ou tout autre moyen équivalent, au sein d'un solvant inerte tel que l'éther éthylique ou le tétrahydrofuranne .The reduction of a compound of general formula 4_, obtained according to the methods described above, is carried out by means of a simple or complex hydride of boron or aluminum, for example, 1 * double hydride of lithium and d aluminum, a diborane / ether complex, or the diborane / methyl sulfide complex, or any other equivalent means, in an inert solvent such as ethyl ether or tetrahydrofuran.
La réduction peut être effectuée à température ambiante ou accélérée par chauffage jusqu'à la température de reflux du solvant.The reduction can be carried out at room temperature or accelerated by heating to the reflux temperature of the solvent.
On obtient ainsi un composé de formule générale 5_ qui correspond à la formule générale j_ lorsque B représente un méthylène.A compound of general formula 5_ is thus obtained which corresponds to the general formula j_ when B represents a methylene.
Les exemples suivants illustrent l'invention sans toutefois en limiter la portée.The following examples illustrate the invention without, however, limiting its scope.
Les analyses élémentaires et les spectres IR et RMN confirment la structure des composés obtenus selon l'in¬ vention. ' Exemple 1 : ( 1 -Adamantanecarbonyl) -1 (1 ,4-benzodioxan-2yl méthylaminométhyl) -4 piperidine (composé n° _1_0; A = O, m = 1, B = CO, n = 0. Dans un ballon de 250 ml; surmonté d'un réfrigé-Elementary analyzes and IR and NMR spectra confirm the structure of the compounds obtained according to the invention. 'Example 1: (1 -Adamantanecarbonyl) -1 (1, 4-benzodioxan-2yl methylaminomethyl) -4 piperidine (compound n ° _1_0; A = O, m = 1, B = CO, n = 0. In a 250 ml; topped with a refrigerator
-2 rant, on introduit 2,70 g (1,63.10 mole) d'aminé 2 (A = O, m = 1) et 7,05 g (1 ,63.10~ mole) de tosylate 3_ (n = 0, R = 1-adamantyle, X = p_-toiuènesulfonyloxy) . Le mélange est porté à 150°C pendant environ 2 heures. Ce brut reactionnel est ensuite solubilisé dans 50 ml de CHC13, puis traité par 50 ml de H4OH à 10 %, et extrait. La phase aqueuse est ré¬ extraite par 50 ml de CHC1.,. Les phases organiques sont réu¬ nies et lavées avec 2x100ml de NaCl/H20. Après séchage de la phase organique sur MgSO. , filtration et purification par flash chromatographie sur gel de silice (éluant : CHC13/CH_0H = 90/10; Rf = 0,50) on récupère 2,60 g (6,12.1 O-3 mole) de-2 rant, 2.70 g (1.63.10 mol) of amine 2 are introduced (A = O, m = 1) and 7.05 g (1.63.10 ~ mole) of 3_ tosylate (n = 0, R = 1-adamantyl, X = p_-toiuènesulfonyloxy). The mixture is brought to 150 ° C. for approximately 2 hours. This crude reaction product is then dissolved in 50 ml of CHC1 3 , then treated with 50 ml of H 4 OH at 10%, and extracted. The aqueous phase is re¬ extracted with 50 ml of CHC1.,. The organic phases are reunited and washed with 2x100ml of NaCl / H 2 0. After drying the organic phase over MgSO. , filtration and purification by flash chromatography on silica gel (eluent: CHC1 3 / CH_0H = 90/10; Rf = 0.50) 2.60 g (6.12.1 O -3 mole) of
( 1-adamantanecarbonyl) -1 (1 ,4-benzodioxan-2 yl méthylamino-(1-adamantanecarbonyl) -1 (1, 4-benzodioxan-2 yl methylamino-
_3 méthyl)-4 piperidine. A 1,00 g (2,35.10 mole) de ce produit, solubilisé à chaud dans 30 ml de EtOH, on ajoute 0,27 g_3 methyl) -4 piperidine. 0.27 g is added to 1.00 g (2.35.10 mol) of this product, dissolved hot in 30 ml of EtOH
_3 (2,33.10 mole) d'acide fumarique. La solution est concentrée et le sel est précipité par addition d'AcOEt. Après filtration_3 (2.33.10 mole) of fumaric acid. The solution is concentrated and the salt is precipitated by addition of AcOEt. After filtration
2 lavages avec E 20 et séchage, on obtient 0,60 g de l'hémi- fu arate du composé J_0 sous la forme d'une poudre blanche.2 washes with E 2 0 and drying, 0.60 g of the hemifu arate of compound J_0 is obtained in the form of a white powder.
C28H38N2°5 : 482'63 PF : 124 - 125°C C 28 H 38 N 2 ° 5 : 482 '63 PF: 124 - 125 ° C
IR (KBr) : 1623 cm"1 (C=0)IR (KBr): 1623 cm "1 (C = 0)
RMN 1H (CDC13) : 0,94-1,06 (m, CH2, 2H) ; 1,67-1,99 (m, CH2 et 1 H NMR (CDC1 3 ): 0.94-1.06 (m, CH 2 , 2H); 1.67-1.99 (m, CH 2 and
CH, 18H); 2,51-2,87 (m, CH2, 6H) ; 3,93-4,37 (m, CH2 et CH, 5H)CH, 18H); 2.51-2.87 (m, CH 2 , 6H); 3.93-4.37 (m, CH 2 and CH, 5H)
4,50-6,50 (large s, OH et NH, 2H) ; 6,54 (s, -CH=, 1H) ; 6,83-6,85 (m, CH arom, 4H)4.50-6.50 (broad s, OH and NH, 2H); 6.54 (s, -CH =, 1H); 6.83-6.85 (m, CH arom, 4H)
Analyse élémentaire : % Cale. C 69,68 H 7,94 N 5,80Elementary analysis:% Cale. C 69.68 H 7.94 N 5.80
% Tr. C 68 ,?3 H 8,10 N 5,68% Tr. C 68, 3 H 8.10 N 5.68
% eau 1,38% water 1.38
% Cor. C 69,18 H 8,06 N 5,76% Cor. C 69.18 H 8.06 N 5.76
Exemple 2 : Cyclohexylacétyi-1 (1 ,4-benzodioxan-2yl méthyl- aminométhyl) -4 piperidine (composé n° J_4/* = O, m = 1, B = CO, n = 1) .Example 2: Cyclohexylacétyi-1 (1, 4-benzodioxan-2yl methylaminomethyl) -4 piperidine (compound n ° J_4 / * = O, m = 1, B = CO, n = 1).
Dans un ballon de 250 ml, surmonté d'un réfrigé-In a 250 ml flask, topped with a refrigerator
-2 rant, on introduit 4,06 g (2,46.10 mole) d'aminé 2 (A = O, m = 1) et 9,70 g (2,46.10~ mole) de tosylate 3_ (n = 1 , R = cyc-xohexyie, X = p_-toluènesulfonyloxy) . Le mélange est porté à 180°C pendant environ 12 heures. Ce brut reactionnel est ensuite solubilisé dans 50 mi de CHC13, puis traité par 50 ml de NH.OH à 10 %, et extrait. La phase organique est ensuite lavée avec 2x50 ml de NH^OH à 10 %, puis avec 2x50 ml de NaCl/H20. Après séchage sur MgSO. , filtration et purifica¬ tion par flash chromatographie sur gel de silice (éluant : CHCi3/CH3OH = 90/10; Rf = 0,42) on récupère 3,40 g (8,80.10~3 mole) de cyclohexylacétyl-1 (1 ,4-benzodioxan-2yl éthylamino- méthyl)-4 piperidine. Ce produit est solubilisé à chaud dans-2 rant, 4.06 g (2.46.10 mol) of amine 2 are introduced (A = O, m = 1) and 9.70 g (2.46.10 ~ mole) of tosylate 3_ (n = 1, R = cyc-xohexyie, X = p_-toluènesulfonyloxy). The mixture is brought to 180 ° C. for approximately 12 hours. This crude reaction product is then dissolved in 50 ml of CHCl 3 , then treated with 50 ml of 10% NH.OH, and extracted. The organic phase is then washed with 2x50 ml of NH 4 OH at 10%, then with 2x50 ml of NaCl / H 2 0. After drying over MgSO. , filtration and purification by flash chromatography on silica gel (eluent: CHCi 3 / CH 3 OH = 90/10; Rf = 0.42) 3.40 g (8.80.10 ~ 3 mole) of cyclohexylacetyl- is recovered 1 (1, 4-benzodioxan-2yl ethylamino-methyl) -4 piperidine. This product is hot dissolved in
10 ml de CH->OH. On ajoute une solution méthanolique d'acide10 ml of CH- > OH. Add a methanolic acid solution
-3 paratoluènesulfonique monohydrate (1,33 g; 7,00.10 mole).-3 paratoluenesulfonic monohydrate (1.33 g; 7.00.10 mole).
La solution est concentrée et le sel est cristallisé à froid. Après filtration, 2 lavages avec Et-0 et séchage, on obtientThe solution is concentrated and the salt is crystallized when cold. After filtration, 2 washes with Et-0 and drying, we obtain
3,20 g du £-toluènesulfonate du composé _1_4 sous la forme d'une poudre blanche.3.20 g of the £ -toluenesulfonate of compound _1_4 in the form of a white powder.
C30H42N2°6S : 558'74 PF : 216 - 217°C C 30 H 42 N 2 ° 6 S: 558 '74 PF: 216 - 217 ° C
IR (KBr) : 1634 cm"1 (C=0)IR (KBr): 1634 cm "1 (C = 0)
RMN 1H (CDCi3) : 0,76-2,09 (m, CH2, 16H); 2,27 (s, CH3, 3H) ; 1 H NMR (CDCl 3 ): 0.76-2.09 (m, CH 2 , 16H); 2.27 (s, CH 3 , 3H);
2,37-4,74 (m, CH2 et CH, 13H); 6,78 (s, CH arom, 4H) ; 7,082.37-4.74 (m, CH 2 and CH, 13H); 6.78 (s, CH arom, 4H); 7.08
(d, CH arom, JHH = 8,1 Hz, 2H) ; 7,64 (d, CH arom, JHH = 8,1 Hz, 2H) ; 8,90-9,45 (large s, OH et NH, 2H)(d, CH arom, J HH = 8.1 Hz, 2H); 7.64 (d, CH arom, J HH = 8.1 Hz, 2H); 8.90-9.45 (broad s, OH and NH, 2H)
Analyse élémentaire : % Cale. C 64,49 H 7,58 N 5,01 S 5,74Elementary analysis:% Cale. C 64.49 H 7.58 N 5.01 S 5.74
% Tr. C 64,71 H 7,62 N 5,12 S 5,84% Tr. C 64.71 H 7.62 N 5.12 S 5.84
Exemple 3 = (Cyclohexyl-2 éthyl)-1 (1 ,4-benzodioxan-2yl méthyl- aminométhyl) -4 piperidine (composé n° j_5; A = O, m = 1,Example 3 = (2-Cyclohexyl ethyl) -1 (1,4-benzodioxan-2yl methylaminomethyl) -4 piperidine (compound n ° j_5; A = O, m = 1,
B = CH2, n = 1) .B = CH 2 , n = 1).
Cette réaction est effectuée sous atmosphère inerte. Dans un tricol de 100 ml, on introduit 0,29 gThis reaction is carried out under an inert atmosphere. 0.29 g is introduced into a 100 ml three-necked flask
_3 (7,63.10 mole) de LiAlH. dans 10 ml de THF anhydre. On addi-_3 (7.63.10 mole) of LiAlH. in 10 ml of anhydrous THF. We addi-
-3 tionne goutte à goutte et à 0°C 1,97 g (5,10.10 mole) du composé J_4 en solution dans 15 ml de THF anhydre. Après 48 heures à température ambiante, on traite par 50 ml d'AcOEt et 50 ml de NaOH 2N. La phase organique extraite est ensuite lavée avec 2x50 ml de NaCl/H~0. Après séchage de la phase organique sur MgSO^ , filtration et purification par flash chromatographie sur gel de silice (éluant : CHCi3/ CH3OH/NH4OH = 90/9/1; Rf = 0,26) on récupère 0,41 g (1,10.10~ mole) de (cyclohexyl-2 éthyl)-1 (1 ,4-benzodioxan- 2yl méthyiaminométhyl)-4 piperidine. Sur ce produit, solubi- lise à chaud dans 10 ml de CH-sOH, on ajoute une solution méthanolique d'acide fumarique 3 (0,20 g; 1,72.10-3 mole) . La solution est concentrée et le sel précipite à froid après addition d'AcOEt. Après filtration, 2 lavages avec Et-0 et séchage, on obtient 0,45 g du difumarate du composé _1_5 sous la forme d'une poudre blanche.-3 works dropwise and at 0 ° C 1.97 g (5.10.10 mole) of compound J_4 in solution in 15 ml of anhydrous THF. After 48 hours at room temperature, treatment is carried out with 50 ml of AcOEt and 50 ml of 2N NaOH. The extracted organic phase is then washed with 2x50 ml of NaCl / H ~ 0. After drying the organic phase over MgSO 4, filtration and purification by flash chromatography on silica gel (eluent: CHCi 3 / CH 3 OH / NH 4 OH = 90/9/1; Rf = 0.26), 0 is recovered, 41 g (1,10.10 ~ mole) of (2-cyclohexyl-ethyl) -1 (1, 4-benzodioxan- 2yl methyiaminomethyl) -4 piperidine. To this product, dissolved hot in 10 ml of CH-sOH, a methanolic solution of fumaric acid 3 (0.20 g; 1.72.10-3 mole) is added. The solution is concentrated and the salt precipitates cold after addition of AcOEt. After filtration, 2 washes with Et-0 and drying, 0.45 g of the difumarate of compound _1_5 is obtained in the form of a white powder.
C31H44N2°10 : 604'70 PF : 214 - 215°C C 31 H 44 N 2 ° 10 : 604 '70 PF: 214 - 215 ° C
RMN 1H (CDC13) : 0,85-1,85 (m, CH2, 18H); 2,50-4,45 (m, CH2 et CH, 13H); 6,53 (s, -CH=, 4H) ; 6,79-6,89 (m, CH arom, 4H) ; 1 H NMR (CDC1 3 ): 0.85-1.85 (m, CH 2 , 18H); 2.50-4.45 (m, CH 2 and CH, 13H); 6.53 (s, -CH =, 4H); 6.79-6.89 (m, CH arom, 4H);
7,50-10,50 (large s, H mobiles, 4H)7.50-10.50 (large s, mobile H, 4H)
Analyse élémentaire : % Cale. C 61,57 H 7,33 N 4,63Elementary analysis:% Cale. C 61.57 H 7.33 N 4.63
% Tr. C 61,91 H 7,26 N 4,73% Tr. C 61.91 H 7.26 N 4.73
Exemple 4 : Cyclohexylacétyl-1 /Tdihydro-3,4 2/H7-1-benzopyran 2yl) méthyiaminométhyl/-4 piperidine (composé n° j_8; A = CH2, m = 1, B = CO, n = 1) .Example 4: Cyclohexylacetyl-1 / Tdihydro-3,4 2 / H7-1-benzopyran 2yl) methyiaminomethyl / -4 piperidine (compound n ° j_8; A = CH 2 , m = 1, B = CO, n = 1).
Dans un ballon de 250 mi, surmonté d'un réfrigé-In a 250 mi balloon, topped with a refrigerator
-2 rant, on introduit 5,34 g (3,27. 10 mole) d'aminé 2_ (A = CH2, m = 1) et 10,15 g (2,58.10~3 mole) de tosylate 3_-2 rant, 5.34 g (3.27.10 mole) of amine 2_ (A = CH 2 , m = 1) and 10.15 g (2.58.10 ~ 3 mole) of tosylate 3_ are introduced.
(n = 1, R = cyclohexyie, X = p_-toluènesulfonyloxy) . Le mélange est porté à 170°C pendant environ 3 heures. Ce brut reactionne est ensuite solubilisé dans 100 ml de CH2C12, puis traité par 3 x 100 ml de H4OH à 10 %. La phase organique est ensuite lavée par 2 x 100 m de NaCl/H20, séchée sur MgSO. , filtrée, concentrée et puri¬ fiée par flash chromatographie sur gel de silice (éiuant : CH2Cl2/CH3OH/NH4OH ≈ 90/9/1; Rf = 0,45). On récupère 4,41 g (1 , 1.10~2mole) de composé _1_8. A 0,51 g (1,33.10"° mole) de ce produit solubilisé à chaud dans un minimum de CH-.OH, on(n = 1, R = cyclohexyia, X = p_-toluènesulfonyloxy). The mixture is brought to 170 ° C. for approximately 3 hours. This crude reaction product is then dissolved in 100 ml of CH 2 C1 2 , then treated with 3 x 100 ml of H 4 OH at 10%. The organic phase is then washed with 2 x 100 m NaCl / H 2 0, dried over MgSO. , filtered, concentrated and puri¬ fied by flash chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH ≈ 90/9/1; Rf = 0.45). 4.41 g (1.10 ~ 2 mole) of compound _1_8 are recovered. At 0.51 g (1.33.10 " ° mole) of this product dissolved hot in a minimum of CH-.OH,
-3 ajoute 0,23 g (1,21.10 mole) d'acide paratoiuèηesuifonique en solution dans le CH3OH. On évapore partiellement le sol¬ vant. Le sel précipite à froid après addition d'éther iso- propyiique. Après filtration, 2 lavages avec Et~0 et séchage,-3 adds 0.23 g (1.21.10 mole) of paratoiuèηesuifonique acid in solution in CH 3 OH. The solvent is partially evaporated. The salt precipitates cold after the addition of isopropyl ether. After filtration, 2 washes with Et ~ 0 and drying,
-4 on obtient 0,42 g (7,54.10 mole) de paratoluènesuifonate du composé _1_8_, sous la forme d'une poudre blanche.-4.42 g (7.54.10 mol) of paratoluenesulfonate of the compound _1_8_ is obtained, in the form of a white powder.
C31H44N205S : 556,77C 31 H 44 N 2 0 5 S: 556.77
PF : 160 - 162°C IR (KBr) : 1645 cm" (C = O)Mp: 160 - 162 ° C IR (KBr): 1645 cm " (C = O)
RMN1H (CDCi3) : 0,85-1,37 (m, CH2, 7H) ; 1,54-2,15 (m, CH2, 1 H NMR (CDCl 3 ): 0.85-1.37 (m, CH 2 , 7H); 1.54-2.15 (m, CH 2 ,
14H); 2,35 (s, CH3, 3H) ; 2,42-4,60 (m, CH2 et CH, 10H);14H); 2.35 (s, CH 3 , 3H); 2.42-4.60 (m, CH 2 and CH, 10H);
6,78-7,05 (m, CH arom, 4H) ; 7,13 (d, JHH = 8,0 Hz, CH arom,6.78-7.05 (m, CH arom, 4H); 7.13 (d, J HH = 8.0 Hz, CH arom,
2H) ; 7,71 (d, J„ri„ri = 8,0 Hz, CH arom. 2H) ; 8,90 (large s, H mobiles, 2H) .2H); 7.71 (d, J „ri„ ri = 8.0 Hz, CH arom. 2H); 8.90 (large s, mobile H, 2H).
Analyse élémentaire : % Cale. C 66,87 H 7,96 N 5,03 S 5,76Elementary analysis:% Cale. C 66.87 H 7.96 N 5.03 S 5.76
% Tr. C 67,21 H 8,02 N 5,07 S 5,75% Tr. C 67.21 H 8.02 N 5.07 S 5.75
Exemple 5 : Cyciohexylacétyl-1 (1 ,4-benzoxathian-2yl méthyl- aminométhyl) -4 piperidine (composé n° 2_0, A = S, m = 1,Example 5: Cyciohexylacetyl-1 (1, 4-benzoxathian-2yl methyl-aminomethyl) -4 piperidine (compound n ° 2_0, A = S, m = 1,
B = CO, n = 1 ) .B = CO, n = 1).
Dans un ballon de 250 ml, surmonté d'un réfrigé-In a 250 ml flask, topped with a refrigerator
_2 rant, on introduit 5,73 g (3,16. 10 mole) d'aminé 2_ (A = S, m = 1) et 9,3 g (2,36.10~2 mole) de tosylate 3_ (n = 1 , R = cyclohexyle, X = p_-toluènesulfonyloxy) . Le mélange est porté à 180°C pendant environ 3 heures. Ce brut reactionnel est ensuite solubilisé dans 150 ml de CH2C12, puis traité par_2 rant, 5.73 g (3.16.10 mole) of amine 2_ (A = S, m = 1) and 9.3 g (2.36.10 ~ 2 mole) of tosylate 3_ (n = 1) are introduced. , R = cyclohexyl, X = p_-toluenesulfonyloxy). The mixture is brought to 180 ° C. for approximately 3 hours. This crude reaction product is then dissolved in 150 ml of CH 2 C1 2 , then treated with
3 x 100 ml de H4OH à 10 %.3 x 100 ml of 10% H 4 OH.
La phase organique est ensuite lavée par 2 x 100 ml de NaCl/H20, séchée sur MgS04, filtrée, concentrée et purifiée par flash chromatographie sur gel de silice (éluant : CH2C12/CH30H/ H40H = 90/9/1; Rf = 0,45) . On récu¬ père 3,04 g de composé 2_0. A 0,96 g (2,33.10~3 mole) de ce produit solubilisé à chaud dans un minimum de CH-^OH, onThe organic phase is then washed with 2 x 100 ml of NaCl / H 2 0, dried over MgS0 4 , filtered, concentrated and purified by flash chromatography on silica gel (eluent: CH 2 C1 2 / CH 3 0H / H 4 0H = 90/9/1; Rf = 0.45). 3.04 g of compound 2_0 are collected. At 0.96 g (2.33 × 10 −3 mole) of this product, dissolved hot in a minimum of CH- ^ OH,
-3 ajoute 0,40 g (2,10.10 mole) d'acide paratoluènesulfonique en solution dans le CH-OH. On évapore partiellement le sol¬ vant. Le sel précipite à froid après addition d'éther iso- propylique. Après filtration, 2 lavages avec Et-0 et séchage, on obtient 1,10 g (1,91.10 -3 mole) de paratoluènesulfonate de composé 2_0, sous la forme d'une poudre blanche.-3 adds 0.40 g (2.10.10 mol) of paratoluenesulfonic acid in solution in CH-OH. The solvent is partially evaporated. The salt precipitates cold after addition of isopropyl ether. After filtration, 2 washes with Et-0 and drying, 1.10 g (1.91.10 -3 mole) of paratoluenesulfonate of compound 2_0 are obtained in the form of a white powder.
C30H42N2°5S2 : 574'81 PF : 149 - 151 °C C 30 H 42 N 2 ° 5 S 2 : 574 '81 PF: 149 - 151 ° C
IR (KBr) : 1642 cm"1 (C = O) RMN1H (CDC13) : 0,45-1,36 (m, CH2, 8H) ; 1,68-2,23 (m, CH2,IR (KBr): 1642 cm "1 (C = O) 1 H NMR (CDC1 3 ): 0.45-1.36 (m, CH 2 , 8H); 1.68-2.23 (m, CH 2 ,
12H); 2,36 (s, CH3, 3H) ; 2,77-4,83 (m, CH2 et CH, 9H) ;12H); 2.36 (s, CH 3, 3H); 2.77-4.83 (m, CH 2 and CH, 9H);
6,84-7,06 (m, CH arom, 4H) ; 7,16 (d, JHH = 8,0 Hz, CH arom,6.84-7.06 (m, CH arom, 4H); 7.16 (d, J HH = 8.0 Hz, CH arom,
2H) ; 7,70 (d, J„„n = 8,0 Hz, CH arom, 2H) ; 9,04 (s, H mobiles), 2H) . Analyse élémentaire : % Cale. C 62,69 H 7,36 N 4,87 S 11,12H); 7.70 (d, J „„ n = 8.0 Hz, CH arom, 2H); 9.04 (s, mobile H), 2H). Elementary analysis:% Cale. C 62.69 H 7.36 N 4.87 S 11.1
% Tr. C 62,66 H 7,42 N 4,91 S 11,2% Tr. C 62.66 H 7.42 N 4.91 S 11.2
Exemple 6 : Cyclohexylacétyl-1 Tdihydro-2,3 benzofuran-2yl) méthylaminométhyl7-4 piperidine (composé n° 2 _; A = CH2, m = 0, B = CO, n = 1) .Example 6: Cyclohexylacetyl-1 Tdihydro-2,3 benzofuran-2yl) methylaminomethyl7-4 piperidine (compound n ° 2 _; A = CH 2 , m = 0, B = CO, n = 1).
Dans un ballon de 250 ml, surmonté d'un réfrigé-In a 250 ml flask, topped with a refrigerator
-3 rant, on introduit 1,24 g (8,31.10 mole) d'aminé 2 (A =-3 rant, 1.24 g (8.31.10 mol) of amine 2 are introduced (A =
CH2, m = 0) et 3,26 g (8,28.10~3 mole) de tosylate 3_ (n = 1,CH 2 , m = 0) and 3.26 g (8.28.10 ~ 3 mole) of tosylate 3_ (n = 1,
R = cyclohexyle, X = p_-toluènesulfonyloxy) . Le mélange est solubilisé dans 10 mi de 1 ,2-dichloroéthane, puis porté à 90°-100°C pendant 5 heures. Ce brut reactionnel est ensuite solubilisé dans 100 ml de CH2C12, puis traité par 3 x 100 ml de NH4OH à 10 %. La phase organique est ensuite lavée par 2 x 100 ml de NaCl/H20, séchée sur MgS04, filtrée, concentrée et purifiée par flash chromatographie sur gel de silice (éluant : CH2Cl2/CH3OH/NH4OH = 90/9/1; Rf = 0,35) . On récu¬ père 0,89 g (2,40. 10~ mole) de composé 2_4. Ce produit est solubilisé à chaud dans un minimum de CH OH, on ajoute 0,41 g (2,15.10 —3 mole) d'acide paratoiuènesulfonique en solution dans CH--.OH. On évapore partiellement le solvant. Le sel pré- cipite à froid après addition d'éther isopropylique. Après filtration, 2 lavages avec Et 0 et séchage, on obtient 0,71 g (1,31.10 -3 mole) du paratoiuènesulfonate du composé 2Λ_ sous la forme d'une poudre blanche.R = cyclohexyl, X = p_-toluenesulfonyloxy). The mixture is dissolved in 10 ml of 1,2-dichloroethane, then brought to 90 ° -100 ° C for 5 hours. This crude reaction product is then dissolved in 100 ml of CH 2 C1 2 , then treated with 3 x 100 ml of NH 4 OH at 10%. The organic phase is then washed with 2 x 100 ml of NaCl / H 2 0, dried over MgS0 4 , filtered, concentrated and purified by flash chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH = 90/9/1; Rf = 0.35). Father 0.89 g (2.40. 10 ~ mole) of compound 2_4 is collected. This product is dissolved hot in a minimum of CH OH, 0.41 g (2.15 × 10 -3 mole) of paratoiuenesulfonic acid in solution in CH -. OH is added. The solvent is partially evaporated. The salt precipitates cold after addition of isopropyl ether. After filtration, 2 washes with Et 0 and drying, 0.71 g (1.31.10 -3 mole) of the paratoiuenesulfonate of the compound 2Λ_ is obtained in the form of a white powder.
C3QH42 205S ; 0,28 H20 : 547,78C 3Q H 42 2 0 5 S; 0.28 H 2 0: 547.78
PF : 158-160°CMp: 158-160 ° C
IR (KBr) : 1645 cm"1 (C = 0)IR (KBr): 1645 cm "1 (C = 0)
RMN1H (CDC13) : 0,90-2,14 (m, CH2, 18H); 2,37 (s, CH3, 3H) ; 1 H NMR (CDC1 3 ): 0.90-2.14 (m, CH 2 , 18H); 2.37 (s, CH 3, 3H);
2,40-5,31 (m, CH2 et CH, 9H) ; 6,77-6,91 (m, CH arom., 2H) ; 7,08-7,27 (m, CH arom., 4H) ; 7,19 (d, CH arom. JHH = 8,06 Hz,2.40-5.31 (m, CH 2 and CH, 9H); 6.77-6.91 (m, CH arom., 2H); 7.08-7.27 (m, CH arom., 4H); 7.19 (d, CH arom. J HH = 8.06 Hz,
2H) ; 7,75 (d, CH arom., JRH = 8,06 Hz, 2H) ; 9,01 (large s,2H); 7.75 (d, CH arom., J RH = 8.06 Hz, 2H); 9.01 (large s,
NH et OH, 2H) .NH and OH, 2H).
Analyse élémentaire : % Cale. C 66,39 H 7,80 N 5,16 S 5,91Elementary analysis:% Cale. C 66.39 H 7.80 N 5.16 S 5.91
% Tr. C 65,75 H 7,84 N 5,12 S 5,99 % eau 0,93% Tr. C 65.75 H 7.84 N 5.12 S 5.99% water 0.93
% Cor. C 66,37 H 7,81 N 5,17 S 6,05% Cor. C 66.37 H 7.81 N 5.17 S 6.05
Le tableau 1 ci-après résume les principaux pro¬ duits synthétisés qui illustrent l'invention sans toutefois en limiter la portée. Table 1 below summarizes the main synthesized products which illustrate the invention without, however, limiting its scope.
Figure imgf000012_0001
Les composés de l'invention ont été soumis à des essais pharmacoiogiques qui ont mis en évidence leur intérêt comme substances à activités thérapeutiques.
Figure imgf000012_0001
The compounds of the invention have been subjected to pharmacological tests which have demonstrated their advantage as substances with therapeutic activities.
Ainsi, ils ont fait l'objet d'une étude portant sur leur affinité pour les récepteurs sérotoninergiques du type 5-HT1A.Thus, they were the subject of a study on their affinity for serotonergic receptors of the 5-HT 1A type .
L'étude de la liaison au récepteur 5-HT-. est réalisée comme décrit par Sleight et Peroutka (Naunyn- Schneideberg Arch. Pharmacol., 343, 106-116, 1991). Pour ces expérimentations, des cortex cérébraux de rat sont utilisés. Le cerveau est disséqué et le cortex est homogénéisé dans 20 volumes de tampon Tris-HCl (50 mil, pH 7,4 à 25°C) maintenu à 4°C. L'homogénat est centrifugé à 39000 x g pendant 10 mi¬ nutes, le culot de centrifugation est mis en suspension dans le même volume de tampon et centrifugé à nouveau. Après une nouvelle mise en suspension dans les mêmes conditions, l'homo¬ génat est incubé pendant 10 minutes à 37°C puis centrifugé à nouveau. Le culot final est mis en suspension dans 80 volumes de tampon de réaction contenant : pargyline (10 -5 M), CaCl2 (4 mM) et acide ascorbique (0,1 %) dans du Tris-HCl (50 mM, pH 7,4 à 25°C) . La concentration finale de tissu dans le mi¬ lieu d'incubation est 10 mg/tube.Study of binding to the 5-HT- receptor. is carried out as described by Sleight and Peroutka (Naunyn-Schneideberg Arch. Pharmacol., 343, 106-116, 1991). For these experiments, rat cerebral cortices are used. The brain is dissected and the cortex is homogenized in 20 volumes of Tris-HCl buffer (50 mil, pH 7.4 at 25 ° C) maintained at 4 ° C. The homogenate is centrifuged at 39,000 xg for 10 minutes, the centrifugation pellet is suspended in the same volume of buffer and centrifuged again. After resuspending under the same conditions, the homogenate is incubated for 10 minutes at 37 ° C and then centrifuged again. The final pellet is suspended in 80 volumes of reaction buffer containing: pargyline (10 -5 M), CaCl 2 (4 mM) and ascorbic acid (0.1%) in Tris-HCl (50 mM, pH 7 , 4 at 25 ° C). The final concentration of tissue in the incubation medium is 10 mg / tube.
Dans les expériences de saturation, les tubes de réaction contiennent 0,1 ml de différentes concentrations de ~3H_7β-OH-DPAT (comprises entre 0,06 et 8 nM) , 0,1 ml de tampon de réaction ou de 5-HT (10 M, pour déterminer la liaison non-spécifique) et 0,8 ml de tissu.In saturation experiments, the reaction tubes contain 0.1 ml of different concentrations of ~ 3 H_7β-OH-DPAT (between 0.06 and 8 nM), 0.1 ml of reaction buffer or 5-HT (10 M, to determine non-specific binding) and 0.8 ml of tissue.
Les expériences de déplacement sont réalisées comme décrit par Sleight et Peroutka (Naunyn-Schneideberg Arch. Pharmacol., 343 , 106-116, 1991) . Toutes les dilutions des produits à étudier sont réalisées dans le tampon de réac- tion. Les tubes de réaction contiennent 0,1 ml de J_ H_/8-OH- DPAT (0,2 nM) , 0,1 mi de produit à tester 6-7 concentrations (dilutions successives au 1/10) et 0,8 mi de tissu. Si l'affi- nité présumée des produits se situe dans le domaine nanomo- laire, la plus faible concentration testée est 10-11 M, si le produit a une affinité présumée faible, la plus forte concentration testée est 10 -4 M. Les tubes de réaction sont incubés à 23°C pendant 30 minutes puis rapidement filtrés sous vide sur filtres hatman GF/B, les tubes sont rincés avec 2 x 5 ml de tampon Tris-HCl (50 mM, pH 7,4 à 25°C).Displacement experiments are carried out as described by Sleight and Peroutka (Naunyn-Schneideberg Arch. Pharmacol., 343, 106-116, 1991). All the dilutions of the products to be studied are made in the reaction buffer. The reaction tubes contain 0.1 ml of J_H_ / 8-OH-DPAT (0.2 nM), 0.1 ml of product to be tested 6-7 concentrations (successive dilutions to 1/10) and 0.8 ml tissue. If the alleged affinity of the products is in the nanomo- laire, the lowest concentration tested is 10-11 M, if the product has an assumed low affinity, the highest concentration tested is 10 -4 M. The reaction tubes are incubated at 23 ° C for 30 minutes and then rapidly filtered under vacuum on hatman GF / B filters, the tubes are rinsed with 2 x 5 ml of Tris-HCl buffer (50 mM, pH 7.4 at 25 ° C).
La radioactivité recueillie sur le filtre est analysée en scintillation liquide en ajoutant 4 ml de liquide scintillantThe radioactivity collected on the filter is analyzed in liquid scintillation by adding 4 ml of scintillating liquid
(Emulsifier Safe, Packard). Toutes les expériences sont réa- Usées en triple et répétées au moins 3 fois.(Safe, Packard emulsifier). All the experiments are carried out in triplicate and repeated at least 3 times.
La constante de dissociation (KD) et le nombre maximum de sites de liaison (Bmax) pour le radioiigand sont estimés à partir des expériences de saturation en utilisant le programme de régression non-linéaire EBDA/LIGAND (Biosoft) (Munson et Rodbard, Anal. Biochem. , 107, 220-239, 1980). Les constantes d'affinité (Ki) des produits de référence sont estimées à partir des expériences de déplacement en utilisant le programme de régression non-linéaire EBDA/LIGAND. Cette méthode admet que la valeur du coefficient de Hiil n'est pas différente de l'unité. Les données des expériences de déplace¬ ment sont analysées respectivement avec les modèles un site et deux sites et le F calculé permet de déterminer si le mo¬ dèle deux sites est plus représentatif des données obtenues que le modèle un site. Les valeurs de pKi sont données sous forme de moyenne + SEM de 3 à 5 expériences.The dissociation constant (K D ) and the maximum number of binding sites (Bmax) for the radio frequency are estimated from the saturation experiments using the non-linear regression program EBDA / LIGAND (Biosoft) (Munson and Rodbard, Anal. Biochem., 107, 220-239, 1980). The affinity constants (Ki) of the reference products are estimated from the displacement experiments using the non-linear regression program EBDA / LIGAND. This method admits that the value of the Hiil coefficient is not different from unity. The data from the displacement experiments are analyzed respectively with the one site and two site models and the calculated F makes it possible to determine whether the two site model is more representative of the data obtained than the one site model. The pKi values are given as an average + SEM of 3 to 5 experiments.
Le tableau 2 donne, à titre d'exemple, les pKi 5-HT1A pour certains dérivés de l'invention, par rapport à la Buspirone qui est utilisée en clinique. Tableau 2 : Affinité pour le récepteur 5-HT-ATable 2 gives, by way of example, pKi 5-HT 1A for certain derivatives of the invention, compared with Buspirone which is used in clinical practice. Table 2: Affinity for the 5-HT-A receptor
Composé n° pKiCompound no pKi
3 8,643 8.64
7 8,677 8.67
8 9,268 9.26
11 8,4911 8.49
14 9,2514 9.25
18 8,9318 8.93
20 8,9420 8.94
Buspirone 7,95Buspirone 7.95
Les résultats des essais montrent que les composés de formule générale J_ possèdent une haute affinité pour les récepteurs sérotoninergiques de type 5-HT-..The results of the tests show that the compounds of general formula J_ have a high affinity for serotonergic receptors of the 5-HT- type.
L'activité centrale des composés de l'invention a été évaluée par leur capacité de provoquer le syndrome 5-HT, qui est caractérisé par une flexion et une extension alternées des pattes avant (reciprocal fore-paw treading : FPT) , la ré¬ traction de la lèvre inférieure (lower-lip retraction : LLR) et par une posture où la surface ventrale de l'animal est en contact avec le sol de la cage avec les pattes arrières éten- dues (flat body posture : FBP) .The central activity of the compounds of the invention has been evaluated by their capacity to cause 5-HT syndrome, which is characterized by alternating flexion and extension of the front legs (reciprocal fore-paw treading: FPT), the re¬ traction of the lower lip (lower-lip retraction: LLR) and by a posture where the ventral surface of the animal is in contact with the floor of the cage with the extended hind legs (flat body posture: FBP).
Les expériences de l'évaluation du syndrome 5-HT sont réalisées chez le rat mâle (sprague Dawley) selon la méthode décrite par F.C. Colpaert et al. (Drug Dev. Res., 26, 21-48; 1992). Le tableau 3 donne, à titre d'exemple, les doses actives (EDr-s) pour certains dérivés de l'invention par rap¬ port à un produit de référence, la Buspirone. Tableau 3 S ndrome 5-HTThe experiments for the evaluation of the 5-HT syndrome are carried out in the male rat (Dawley sprague) according to the method described by FC Colpaert et al. (Drug Dev. Res., 26, 21-48; 1992). Table 3 gives, by way of example, the active doses (ED r -s) for certain derivatives of the invention relative to a reference product, Buspirone. Table 3 S ndrome 5-HT
Figure imgf000016_0001
Figure imgf000016_0001
Les résultats des essais montrent que les composés de formule générale 1 possèdent, in vitro, une haute affinité pour les récepteurs sérotoninergiques de type 5-HT-.,. I_n vivo, ils montrent une activité agoniste au niveau de ces récepteurs,The results of the tests show that the compounds of general formula 1 have, in vitro, a high affinity for serotonergic receptors of the 5-HT type. In vivo, they show an agonist activity at the level of these receptors,
Les composés de l'invention peuvent donc être utiles pour le traitement de l'anxiété, la dépression, les troubles du sommeil, pour la régularisation de la prise de nourriture, pour la régulation de la sécrétion gastrique, et pour le traitement des désordres vasculaires, cardiovascu- laires et cérébrovasculaires tels que l'hypertension ou la migraine. Les préparations pharmaceutiques contenant ces principes actifs peuvent être mises en forme pour l'adminis¬ tration par voie orale, rectale ou parentérale, par exemple sous la forme de capsules, comprimés, granulés, gélules, solutés liquides, sirops ou suspensions buvables, et contenir les excipients appropriés.The compounds of the invention can therefore be useful for the treatment of anxiety, depression, sleep disorders, for the regulation of food intake, for the regulation of gastric secretion, and for the treatment of vascular disorders. , cardiovascular and cerebrovascular such as hypertension or migraine. Pharmaceutical preparations containing these active ingredients can be shaped for administration by oral, rectal or parenteral route, for example in the form of capsules, tablets, granules, capsules, liquid solutions, syrups or oral suspensions, and contain the appropriate excipients.
Il est également possible d'y associer d'autres principes actifs pharmaceutiquement et thérapeutiquement acceptables. It is also possible to combine it with other pharmaceutically and therapeutically acceptable active ingredients.

Claims

- REVENDICATIONS - 1 - Dérivés hétérocyciiques de 1'aminométhyl-4 piperidine correspondant à la formule générale 1 : - CLAIMS - 1 - Heterocyte derivatives of 4-aminomethyl piperidine corresponding to the general formula 1:
Figure imgf000017_0001
Figure imgf000017_0001
dans laquelle :in which :
A représente un atome d'oxygène, un atome de soufre, ou un radical méthylène; m peut prendre les valeurs de 0 ou 1 ; B représente une fonction carbonyle (CO) ou un méthylèneA represents an oxygen atom, a sulfur atom, or a methylene radical; m can take the values of 0 or 1; B represents a carbonyl function (CO) or a methylene
(CH2) ; n peut prendre les valeurs de 0 ou 1 ; R représente un radical cycloalkyle, monocyclique ou poly- cyclique, en CO-C-Q. ainsi que leurs sels avec des acides minéraux ou organiques thérapeutiquement acceptables et les mélanges racémiques, aussi bien que les différents énantiomères des composés et leurs mélanges en toutes proportions.(CH 2 ); n can take the values of 0 or 1; R represents a cycloalkyl radical, monocyclic or polycyclic, C O -C- Q . as well as their salts with therapeutically acceptable mineral or organic acids and racemic mixtures, as well as the various enantiomers of the compounds and their mixtures in all proportions.
2 - Composés de formule générale J_ selon la reven- dication 1, caractérisés par le fait qu'ils sont choisis par¬ mi :2 - Compounds of general formula J_ according to claim 1, characterized in that they are chosen from:
- Cyclopropanecarbonyl-1 (1 ,4-benzodioxan-2 yl méthylamino- méthyl)-4 piperidine- Cyclopropanecarbonyl-1 (1, 4-benzodioxan-2 yl methylamino-methyl) -4 piperidine
- Cyclopropylméthyl-1 (1 ,4-benzodioxan-2 yl méthylaminométhyl) - 4 piperidine- Cyclopropylmethyl-1 (1, 4-benzodioxan-2 yl methylaminomethyl) - 4 piperidine
- Cyciobutanecarbonyl-1 (1 ,4-benzodioxan-2 yl méthylamino¬ méthyl) -4 piperidine- Cyciobutanecarbonyl-1 (1,4-benzodioxan-2 yl methylamino¬ methyl) -4 piperidine
- Cyclopentanecarbonyl-1 (1 ,4-benzodioxan-2 yl méthylamino¬ méthyl) -4 piperidine - Cyclopentyiméthyi-1 (1 ,4-benzodioxan-2 yl méthylaminométhyl) - 4 piperidine - Cyclohexanecarbonyl-1 (1 ,4-benzodioxan-2 yl méthylamino¬ méthyl)-4 piperidine- Cyclopentanecarbonyl-1 (1, 4-benzodioxan-2 yl methylamino¬ methyl) -4 piperidine - Cyclopentyimethyi-1 (1, 4-benzodioxan-2 yl methylaminomethyl) - 4 piperidine - Cyclohexanecarbonyl-1 (1, 4-benzodioxan-2 yl methylamino¬ methyl) -4 piperidine
- Cyclohexylméthyl-1 (1 ,4-benzodioxan-2 yl méthylamino¬ méthyl)-4 piperidine - Cycloheptanecarbonyl-1 (1 ,4-benzodioxan-2 yl méthylamino¬ méthyl)-4 piperidine- Cyclohexylmethyl-1 (1, 4-benzodioxan-2 yl methylamino¬ methyl) -4 piperidine - Cycloheptanecarbonyl-1 (1, 4-benzodioxan-2 yl methylamino¬ methyl) -4 piperidine
- Cycloheptylméthyl-1 (1 ,4-benzodioxan-2 yl méthylaminométhyl) 4 piperidine- Cycloheptylmethyl-1 (1, 4-benzodioxan-2 yl methylaminomethyl) 4 piperidine
- (1-Adamantanecarbonyl)-1 (1 ,4-benzodioxan-2-yl méthylamino- méthyl)-4 piperidine- (1-Adamantanecarbonyl) -1 (1, 4-benzodioxan-2-yl methylamino-methyl) -4 piperidine
- (1-Adamantylméthyl) -1 (1 ,4-benzodioxan-2-yl méthylamino¬ méthyl)-4 piperidine- (1-Adamantylmethyl) -1 (1, 4-benzodioxan-2-yl methylamino¬ methyl) -4 piperidine
- Cyclopentyiacétyi-1 (1 ,4-benzodioxan-2 yl méthylaminométhyl) 4 piperidine - (Cyclopentyl-2 éthyl)-1 (1 ,4-benzodioxan-2 yl méthylamino¬ méthyl)-4 piperidine- Cyclopentyiacétyi-1 (1,4-benzodioxan-2 yl methylaminomethyl) 4 piperidine - (Cyclopentyl-2 ethyl) -1 (1,4-benzodioxan-2 yl methylamino¬ methyl) -4 piperidine
- Cyclohexylacétyl-1 (1 ,4-benzodioxan-2 yl méthylaminométhyl)- 4 piperidine- Cyclohexylacetyl-1 (1, 4-benzodioxan-2 yl methylaminomethyl) - 4 piperidine
- (Cyclohexyl-2 éthyl)-1 (1 ,4-benzodioxan-2-yl méthyiamino- méthyl)-4 piperidine- (2-Cyclohexyl ethyl) -1 (1, 4-benzodioxan-2-yl methyiamino-methyl) -4 piperidine
- (1-Adamantylacétyl)-1 (1 ,4-benzodioxan-2 yl méthylamino¬ méthyl)-4 piperidine- (1-Adamantylacetyl) -1 (1, 4-benzodioxan-2 yl methylamino¬ methyl) -4 piperidine
- /Tl-Adamantyl)-2 éthyl7-1 (1 ,4-benzodioxan-2 yl méthylamino¬ méthyl)-4 piperidine - Cyclohexylacétyl-1 Tdihydro-3,4 2/57-1-benzopyran-2 yl) méthylaminométhyl7-4 piperidine.- / Tl-Adamantyl) -2 ethyl7-1 (1, 4-benzodioxan-2 yl methylamino¬ methyl) -4 piperidine - Cyclohexylacetyl-1 Tdihydro-3,4 2 / 57-1-benzopyran-2 yl) methylaminomethyl7-4 piperidine.
- (Cyclohexyl-2 éthyl)-1 /Tdihydro-3,4 2/57-1-benzopyran-2 yl) méthylaminométhyl7-4 piperidine.- (2-Cyclohexyl ethyl) -1 / Tdihydro-3,4 2 / 57-1-benzopyran-2 yl) methylaminomethyl7-4 piperidine.
- Cyclohexylacétyl-1 (1 ,4-benzoxathian-2 yl méthylaminométhyl) 4 piperidine- Cyclohexylacetyl-1 (1, 4-benzoxathian-2 yl methylaminomethyl) 4 piperidine
- (Cyclohexyl-2 éthyl)-1 (1 ,4-benzoxathian-2 yl méthylamino¬ méthyl)-4 piperidine- (2-Cyclohexyl ethyl) -1 (1, 4-benzoxathian-2 yl methylamino¬ methyl) -4 piperidine
- (3-Noradamantanecarbonyl)-1 (1 ,4-benzodioxan-2 yl méthyl¬ aminométhyl)-4 piperidine - (3-Noradamantylméthyl)-1 (1 ,4-benzodioxan-2 yl méthylamino¬ méthyl)-4 piperidine - CyclohexylacétyI-1 /(dihydro-2,3 benzofuran-2-yl)méthyl- aminométhyl7-4 piperidine.- (3-Noradamantanecarbonyl) -1 (1, 4-benzodioxan-2 yl methyl¬ aminomethyl) -4 piperidine - (3-Noradamantylmethyl) -1 (1, 4-benzodioxan-2 yl methylamino¬ methyl) -4 piperidine - CyclohexylacetyI-1 / (2,3-dihydro-benzofuran-2-yl) methylaminomethyl7-4 piperidine.
3 - Procédé de préparation de composés selon les revendications 1 et 2, où B représente une fonction carbonyie, caractérisée en ce que l'on fait réagir une aminé de formule générale 2 avec un composé de formule générale 3 :3 - Process for the preparation of compounds according to claims 1 and 2, where B represents a carbonyl function, characterized in that an amine of general formula 2 is reacted with a compound of general formula 3:
Figure imgf000019_0001
Figure imgf000019_0001
OÙOR
- A, m, n et R sont définis comme ci-dessus.- A, m, n and R are defined as above.
- X représente un groupe nucléofuge tel que méthyisulfonyloxy, benzènesulfonyloxy, ou p_-toluènesulfonyloxy. - les composés de formule générale 4_ correspondent aux composé de formule générale _1_ lorsque B représente une fonction carbo¬ nyie.- X represents a nucleofuge group such as methyisulfonyloxy, benzenesulfonyloxy, or p_-toluenesulfonyloxy. - The compounds of general formula 4_ correspond to the compounds of general formula _1_ when B represents a carbon function.
4 - Procédé de préparation de composés selon la revendication 3, caractérisé en ce que la réaction d'une aminé de formule générale 2_ avec un composé de formule géné¬ rale 3_ s'effectue, soit en l'absence, soit en présence d'un solvant tel que le toluène, le xylène, le dimethylformamide ou 1*acetonitrile, de préférence a une température comprise entre 50 et 200°C, et éventuellement en présence d'une base organique telle qu'une a iné tertiaire, ou minérale, telle qu'un carbonate ou hydrogénocarbonate alcalin.4 - Process for the preparation of compounds according to claim 3, characterized in that the reaction of an amine of general formula 2_ with a compound of general formula 3_ takes place either in the absence or in the presence of a solvent such as toluene, xylene, dimethylformamide or acetonitrile, preferably at a temperature of between 50 and 200 ° C., and optionally in the presence of an organic base such as a tertiary or inorganic acid, such as an alkali carbonate or hydrogen carbonate.
5 - Procédé de préparation de composés selon les revendications 1 et 2, où B représente un méthylène, caracté¬ risé en ce que l'on réduit un composé de formule générale 4_ selon le schéma :
Figure imgf000020_0001
5 - Process for the preparation of compounds according to Claims 1 and 2, in which B represents a methylene, characterized in that a compound of general formula 4_ is reduced according to the scheme:
Figure imgf000020_0001
où :or :
- A, m, n et R sont définis comme ci-dessus. - Les composés de formule générale 5_ correspondent aux compo¬ sés de formule générale J_ lorsque B représente un méthylène.- A, m, n and R are defined as above. - The compounds of general formula 5_ correspond to the compounds of general formula J_ when B represents methylene.
6 - Procédé de préparation de composés selon la revendication 5, caractérisé en ce que la réduction d'un composé de formule générale 4_ s'effectue au moyen d'un hydrure simple ou complexe de bore ou d'aluminium, par exemple, l'hy¬ drure double de lithium et d'aluminium, un complexe diborane/ éther ou le complexe diborane/sulfure de méthyle, ou tout autre moyen équivalent, au sein d'un solvant inerte tel que 1'éther éthylique ou le tétrahydrofuranne à une température comprise entre la température ambiante et celle de reflux du solvant.6 - Process for preparing compounds according to claim 5, characterized in that the reduction of a compound of general formula 4_ is carried out by means of a simple or complex hydride of boron or aluminum, for example, Double lithium aluminum hydride, a diborane / ether complex or the diborane / methyl sulfide complex, or any other equivalent means, in an inert solvent such as ethyl ether or tetrahydrofuran at a temperature between room temperature and that of reflux of the solvent.
7 - A titre de médicaments nouveaux utiles, par exemple, pour le traitement de l'anxiété, la dépression, les troubles du sommeil, pour la régularisation de la prise de nourriture, pour la régularisation de la sécrétion gastrique, et pour le traitement des désordres vasculaires, cardiovascu- iaires et cérébrovasculaixes tels que l'hypertension ou la migraine, les composés définis selon l'une des revendications 1 et 2. 8 - Composition pharmaceutique caractérisée en ce qu'elle contient un composé défini selon l'une des re¬ vendications 1 et 2. 7 - As new drugs useful, for example, for the treatment of anxiety, depression, sleep disorders, for the regulation of food intake, for the regulation of gastric secretion, and for the treatment of 8 Vascular, cardiovascular and cerebrovascular disorders such as hypertension or migraine, the compounds defined according to one of claims 1 and 2. 8 - Pharmaceutical composition characterized in that it contains a compound defined according to one of the re ¬ vendications 1 and 2.
PCT/FR1994/000152 1993-02-11 1994-02-10 Novel heterocyclic aminomethyl-4 piperidine derivatives, their preparation and application in therapy WO1994018193A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2725989A1 (en) * 1994-10-20 1996-04-26 Pf Medicament NOVEL SUBSTITUTED 2- (1- (OMEGA-PHENOXYALCOYLPIPERIDIN-4-YL) AMINOMETHYLENE) -2H-BENZOFURAN-3-ONES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
WO1998029411A1 (en) * 1996-12-27 1998-07-09 Knoll Aktiengesellschaft Sulfonamide compounds having 5-ht receptor activity
WO1999062902A1 (en) * 1998-06-03 1999-12-09 Knoll Aktiengesellschaft N-benzodioxanylmethyl-1-piperidyl-methylamine compounds having affinity for 5-ht receptors
US7045629B2 (en) 2001-04-26 2006-05-16 Merck Patent Gmbh Method for producing-2[-5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane
WO2008052078A2 (en) * 2006-10-24 2008-05-02 Wyeth Benzoxathiine and benzoxathiole derivatives and uses thereof
US7728155B2 (en) 2003-10-24 2010-06-01 Wyeth Llc Dihydrobenzofuranyl alkanamines and methods for using same as cns agents

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4910302A (en) * 1988-12-19 1990-03-20 American Home Products Corporation Psychotropic polycyclic imides
EP0445026A1 (en) * 1990-02-27 1991-09-04 Adir Et Compagnie Aminomethylpiperidine derivatives, their process for preparation and the pharmaceutical compositions containing them
EP0447292A1 (en) * 1990-03-07 1991-09-18 Synthelabo 4-Aminomethyl-piperidine derivatives, their preparation and therapeutic application
EP0452204A1 (en) * 1990-04-09 1991-10-16 Adir Et Compagnie 3-Aminochromane derivatives, procedure for their preparation and pharmaceutical compositions containing them

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4910302A (en) * 1988-12-19 1990-03-20 American Home Products Corporation Psychotropic polycyclic imides
EP0445026A1 (en) * 1990-02-27 1991-09-04 Adir Et Compagnie Aminomethylpiperidine derivatives, their process for preparation and the pharmaceutical compositions containing them
EP0447292A1 (en) * 1990-03-07 1991-09-18 Synthelabo 4-Aminomethyl-piperidine derivatives, their preparation and therapeutic application
EP0452204A1 (en) * 1990-04-09 1991-10-16 Adir Et Compagnie 3-Aminochromane derivatives, procedure for their preparation and pharmaceutical compositions containing them

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R.A. GLENNON: "Central Serotonin Receptors as Targets for Drug Research", JOURNAL OF MEDICINAL CHEMISTRY, vol. 30, no. 1, January 1987 (1987-01-01), WASHINGTON US, pages 1 - 12 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2725989A1 (en) * 1994-10-20 1996-04-26 Pf Medicament NOVEL SUBSTITUTED 2- (1- (OMEGA-PHENOXYALCOYLPIPERIDIN-4-YL) AMINOMETHYLENE) -2H-BENZOFURAN-3-ONES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
WO1996012718A1 (en) * 1994-10-20 1996-05-02 Pierre Fabre Medicament NOUVELLES 2-[1-(φ-PHENOXYALCOYLPIPERIDIN-4-YL)AMINOMETHYLENE]-2H-BENZOFURAN-3-ONES SUBSTITUEES, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE
WO1998029411A1 (en) * 1996-12-27 1998-07-09 Knoll Aktiengesellschaft Sulfonamide compounds having 5-ht receptor activity
US6136825A (en) * 1996-12-27 2000-10-24 Knoll Aktiengesellschaft Sulfonamide compounds having 5-HT receptor activity
WO1999062902A1 (en) * 1998-06-03 1999-12-09 Knoll Aktiengesellschaft N-benzodioxanylmethyl-1-piperidyl-methylamine compounds having affinity for 5-ht receptors
US7045629B2 (en) 2001-04-26 2006-05-16 Merck Patent Gmbh Method for producing-2[-5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane
US7728155B2 (en) 2003-10-24 2010-06-01 Wyeth Llc Dihydrobenzofuranyl alkanamines and methods for using same as cns agents
WO2008052078A2 (en) * 2006-10-24 2008-05-02 Wyeth Benzoxathiine and benzoxathiole derivatives and uses thereof
WO2008052078A3 (en) * 2006-10-24 2008-06-19 Wyeth Corp Benzoxathiine and benzoxathiole derivatives and uses thereof

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FR2701479B1 (en) 1995-05-12
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