EP0687252A1 - 2-phenoxyethylaminderivate, ihre herstellung und ihre therapeutische anwendung - Google Patents

2-phenoxyethylaminderivate, ihre herstellung und ihre therapeutische anwendung

Info

Publication number
EP0687252A1
EP0687252A1 EP94908368A EP94908368A EP0687252A1 EP 0687252 A1 EP0687252 A1 EP 0687252A1 EP 94908368 A EP94908368 A EP 94908368A EP 94908368 A EP94908368 A EP 94908368A EP 0687252 A1 EP0687252 A1 EP 0687252A1
Authority
EP
European Patent Office
Prior art keywords
piperidine
ethylaminomethyl
phenoxy
general formula
phenoxyethylaminomethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94908368A
Other languages
English (en)
French (fr)
Inventor
Bernard Bonnaud
Florence Castan
Dennis Bigg
Wouter Koek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pierre Fabre Medicament SA
Original Assignee
Pierre Fabre Medicament SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pierre Fabre Medicament SA filed Critical Pierre Fabre Medicament SA
Publication of EP0687252A1 publication Critical patent/EP0687252A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • 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, cocaine
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • 5-HT] ⁇ a subtypes of serotoninergic receptor, play an important physiological role. Also, as the various chapters of the book “Brain 5-HTJA Receptors: Behavioral and Neurochemical Pharmacology" show (Editors CT Dourish, S. Ahlenius, PH Hutson; Ellis Horwood Ltd., Chichester, 1987) 5-HTj ⁇ may be useful for the treatment of anxiety, depression, sleep disturbances, vascular and cardiovascular disorders, and the regulation of food intake. The 5-HTJ receptors also play a role in the regulation 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 which show a high affinity for the 5-HTIA receptors, their preparation and their therapeutic application.
  • - X represents one or more substituents chosen from a halogen atom, a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 alkoxy group:
  • - A represents a carbonyl function (CO), or a methylene:
  • - n can take the values of 0 or 1:
  • - R represents a C3-C10 cycloalkyl, monocyclic or polycyclic radical . or a phenyl group substituted or not by one or more substituents chosen from a halogen atom, a C-- -C4 alkyl group, or a C1-C4 alkoxy group.
  • the invention also relates to the salts of the compounds of general formula 1 with pharmaceutically acceptable mineral or organic acids.
  • the acid used can be, by way of nonlimiting example, hydrochloric acid, maleic acid, fumaric acid, or p-toluenesulfonic acid.
  • the present invention relates more particularly to the compounds of general formula 1, chosen from: Benzoyl-1 (2-phenoxy-ethylaminomethyl) -4 piperidine Benzyl-1 (2-phenoxy-ethylaminomethyl) -4 piperidine (3-methyl benzoyl) - 1 (phenoxy -2 ethylaminomethyl) -4 piperidine (3-methyl benzyl) -l (2-phenoxy ethylaminomethyl) -4 piperidine (3-methoxy benzoyl) - 1 (2-phenoxy ethylaminomethyl) -4 piperidine (3-methoxy benzyl) -l ( 2-phenoxyethylaminomethyl) -4 piperidine (3-Chloro benzoyl) - 1 (2-phenoxy ethylaminomethyl) -4 piperidine (3-Chloro benzyl) -l (2-phenoxy ethylaminomethyl) -4 piperidine (3-Chloro benzy
  • - Y represents a nucleofuge group such as methylsulfonyloxy, benzenesulfonyloxy, or p-toluenesulfonyloxy.
  • the starting amines 2 and the piperidines of formula 3 can be obtained according to conventional methods.
  • 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, of 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 hydrogen carbonate.
  • a compound of general formula 4 is thus obtained which corresponds to general formula 1 when A represents a carbonyl function.
  • n and R are defined as above.
  • 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, the 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.
  • a simple or complex hydride of boron or aluminum for example, the 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.
  • centesimal analyzes as well as the IR and NMR spectra confirm the structure of the products obtained.
  • the compounds of the invention have been subjected to pharmacological tests which have demonstrated their interest as substances with therapeutic activity.
  • rat cerebral cortices are used.
  • the brain is dissected and the cortex is homogenized in 20 volumes of Tris-HCl buffer (50 mM, pH 7, 4 at 25 ° C) maintained at 4 ° C.
  • the homogenate is centrifuged at 39,000 xg for 10 minutes, the centrifuge pellet is suspended in the same volume of buffer and centrifuged again. After resuspension 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 (4 mM) and ascorbic acid (0.1%) in Tris-HCl (50
  • the reaction tubes contain 0J ml of different concentrations of [ 3 H] 8-OH-DPAT (between 0.06 and 8 nM), 0J ml of reaction buffer or 5-HT (ÎO " - * 5 M, to determine non-specific binding) and 0.8 ml of tissue.
  • the displacement experiments are carried out as described by Sleight and Peroutka fNauvn-Schmiedebere Arch. Pharmaco 343. 106-116, 1991). All the dilutions of the products to be studied are made in the reaction buffer.
  • the reaction tubes contain 0J ml of [ 3 H] 8-OH-DPAT (0.2 nM), 0J ml of product to be tested 6-7 concentrations (successive dilutions to 1/10) and 0.8 ml of tissue. If the alleged affinity of the products is in the nanomolar range, the lowest concentration tested is 10 " * M, if the product has a presumed low affinity, the highest concentration tested is ÎO " ⁇ M.
  • reaction tubes are incubated at 23 ° C for 30 minutes then quickly filtered under vacuum on Whatman 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 (Emulsifier Safe, Packard). All the experiments are carried out in triplicate and repeated at least 3 times.
  • the dissociation constant (K - ) ) and the maximum number of binding sites (Bmax) for the radioligand 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 Hill coefficient is not different from unity.
  • the data from the displacement experiences are analyzed with the one site and two site models, respectively, 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 of 3 to 5 experiments.
  • Table 2 gives, by way of example, certain derivatives of the invention, compared to Buspirone which is used in cn that.
  • SUBSTITUTE SHEET (RULE 26) The results of the tests show that the compounds of the invention have a high affinity for serotonergic receptors of the 5-HTJA type. Also, the compounds of the invention can be useful for the treatment of anxiety, depression, disorders. sleep, for the regulation of food intake, for the regulation of gastric secretion, and for the treatment of vascular, cardiovascular and cerebrovascular disorders such as hypertention or migraine.
  • Pharmaceutical preparations containing these active ingredients can be shaped for oral, rectal or parenteral administration, for example in the form of capsules, tablets, granules, capsules, liquid solutions, syrups or oral suspensions, and contain the suitable excipients. It is also possible to combine it with other active pharmaceutical and therapeutically acceptable ingredients.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
EP94908368A 1993-03-04 1994-02-24 2-phenoxyethylaminderivate, ihre herstellung und ihre therapeutische anwendung Withdrawn EP0687252A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9302502 1993-03-04
FR9302502A FR2702211B1 (fr) 1993-03-04 1993-03-04 Nouveaux dérivés de la phénoxy-2 éthylamine, leur préparation et leur application en thérapeutique.
PCT/FR1994/000202 WO1994020466A1 (fr) 1993-03-04 1994-02-24 Nouveaux derives de la phenoxy-2 ethylamine, leur preparation et leur application en therapeutique

Publications (1)

Publication Number Publication Date
EP0687252A1 true EP0687252A1 (de) 1995-12-20

Family

ID=9444650

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94908368A Withdrawn EP0687252A1 (de) 1993-03-04 1994-02-24 2-phenoxyethylaminderivate, ihre herstellung und ihre therapeutische anwendung

Country Status (7)

Country Link
EP (1) EP0687252A1 (de)
JP (1) JPH08507302A (de)
AU (1) AU6143594A (de)
CA (1) CA2152400A1 (de)
FR (1) FR2702211B1 (de)
WO (1) WO1994020466A1 (de)
ZA (1) ZA941532B (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA58476C2 (uk) * 1997-10-09 2003-08-15 Санофі-Сентелябо Похідні 8-азабіцикло[3.2.1]октан-3-метанаміну, фармацевтична композиція та лікарський засіб
FR2769629B1 (fr) * 1997-10-09 1999-11-12 Synthelabo Derives de 8-azabicyclo[3.2.1]octane-3-methanamine, leur preparation et leur application en therapeutique
US7189753B1 (en) 1997-11-06 2007-03-13 Cady Roger K Preemptive prophylaxis of migraine
FR2786767B1 (fr) * 1998-12-02 2001-02-23 Pf Medicament Nouveaux derives de 3-alkoxybenzylamines et leur utilisation a titre de medicaments pour le traitement de la schizophrenie
FR2791676B1 (fr) * 1999-03-29 2001-06-22 Pf Medicament Nouveaux derives de [(2-substitue-5-[thienyl])-benzyl]- [2-([isopropoxy-5-fluoro]-phenoxy) ethyl]-amine, leur procede de preparation et leur utilisation a titre de medicaments
EP3260452A1 (de) * 2016-06-24 2017-12-27 Neurolixis Verbindungen zur behandlung von serotoninsensitiven erkrankungen gesteuert durch 5-ht1a rezeptoren

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2658823B1 (fr) * 1990-02-27 1992-04-30 Adir Nouveaux derives d'aminomethylpiperidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent .
EP0522914A1 (de) * 1991-06-27 1993-01-13 Synthelabo 2-Piperidinylpyrimidin-4-Carboxamidderivate, deren Herstellung und deren Verwendung als Heilmittel

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
blocking properties' *
EUR. J. PHARMACOL., vol.203, no.2, 15 Octobre 1991, (EJPHAZ,00142999); FAC. MED. BROUSSAIS HOTEL-DIEU, PARIS; 75270 FR. pages 323 - 324 H. DABIRE ET AL. 'S14063: a new potent 5-HT1a receptor antagonist devoid of beta-adrenoceptor *
See also references of WO9420466A1 *

Also Published As

Publication number Publication date
CA2152400A1 (fr) 1994-09-15
AU6143594A (en) 1994-09-26
WO1994020466A1 (fr) 1994-09-15
FR2702211A1 (fr) 1994-09-09
JPH08507302A (ja) 1996-08-06
ZA941532B (en) 1994-10-06
FR2702211B1 (fr) 1995-06-02

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