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
  • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
  • C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
• • 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

Definitions

• the present invention relates to new derivatives of 1, 2, 5, 6-tetrahydropyridine, their preparation process and their application in therapy, in particular as sedatives.
• compounds of formula have already been described:
• R is a C 2 -C 4 alkyl group and, in particular, N-isopropyl-3-phenyl-1,2,5,6-tetrahydropyridine having activities on the central nervous system, and their use in therapy as sedative agents.
• FR-2416886 derivatives of the 3- (3-trifluoromethyl phenyl) -l, 2,5,6- tetrahydropyridine type have been described as having appetite suppressing properties.
• the present invention aims to provide new derivatives of 3-phenyl-1,2,5,6-tetrahydropyridine exhibiting sedative properties with a markedly improved affinity for the ⁇ 2 receptors.
• the present invention more particularly relates to compounds of formula:
• R is chosen from a 3-chloro group, a 3- or 4-bromo group, a 4-fluoro group, a 4-trifluoromethyl group, a 2-C x -C 4 alkoxy group, a group 4-C 1 -C 4 alkoxy, 4-hydroxy group, 2- C 1 -C 4 alkyl group and 4-C 1 -C 4 alkyl group, and their addition salts with pharmaceutical acids- acceptable.
• “Addition salts with acceptable pharmaceutical acids” means the salts which give the biological properties of the free bases, without having an undesirable effect.
• These salts can be in particular those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, acid fumaric, maleic acid, citric acid, malonic acid, methane sulfonic acid, lactic acid, succinic acid, tartaric acid.
• mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid
• acidic metal salts such as disodium orthophosphate and monopotassium sulfate
• organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, acid fumaric, maleic acid, citric acid, malonic acid, methane sulfonic acid, lactic acid
• the compounds according to the present invention can be prepared by dehydration of a compound of formula
• Dehydration can be carried out in particular using paratoluene sulfonic acid.
• the salts can be obtained conventionally by reaction of a compound of formula I with a pharmaceutically acceptable acid in an appropriate solvent.
• the catalyst After the end of absorption of hydrogen, the catalyst is filtered, evaporated to dryness, recrystallizes the residue in acetone + ethanol.
• the azeotrope C 6 H 6 -H 2 0 is distilled from a solution of 18.52 g (0.095 M) of 3- (4-fluoro phenyl) -3- hydroxypiperidine, 200 ml of benzene and 40 g of acid. sulfonic paratoluene, monohydrate. Basified with 20 ml of concentrated sodium hydroxide + 60 ml H 2 0, decant the benzene, washed with water, dried over MgS0 4 , filtered, evaporated to dryness.
• the catalyst is filtered, the filtrate is evaporated to dryness and the residue is recrystallized from acetone + ethanol.
• the azeotrope C 6 H 6 -H 2 0 is distilled from a mixture of 13 g (0.053 M) of 3- (4-trifluoromethyl phenyl) -3-hydroxy piperidine, 22.8 g (0.12 M) d paratoluene sulfonic acid hydrates and 250 ml of dry benzene.
• the azeotrope C 6 H 6 -H 2 0 is distilled from a mixture of 55 g (0.26 M) of 3- (3-chloro phenyl) -3-hydroxypiperidine, 117.4 g (0.618 M) paratoluene sulfonic acid, 1 H 2 0 and 772 ml of C 6 H 6 .
• the catalyst is filtered, evaporated to dryness and the residue is recrystallized from acetone + ethanol.
• the benzene-water azeotrope is distilled from a mixture of 24.84 g (0.12 M) of 3- (2-methoxy phenyl) -3- hydroxypiperidine, 54.18 g (0.285 M) of paratoluene sulfonic acid , monohydrate and 360 ml of anhydrous benzene.
• the benzene-water azeotrope is distilled from a solution of 23.8 g (0.115 M) of 3- (4-methoxy phenyl) -3-hydroxy piperidine, 51.9 of (0.273 M) of para-toluene sulfonic acid , 1 H 2 0, 340 ml of anhydrous benzene.
• the benzene-water azeotrope is distilled from a mixture of 46.45 g (0.243 M) of 3- (4-methyl phenyl) -3- hydroxypiperidine, 100 g (0.578 M) of paratoluene sulfonic acid, monohydrate and 700 ml of anhydrous benzene.
• the mixture is brought to reflux until magnesium is dissolved.
• the mixture is cooled by an ice + salt bath and a solution of 20.79 g (0.11 M) of 1-benzyl-3-piperidone is poured into 500 ml of anhydrous ether. After the end of casting, the temperature is allowed to rise to 25 ° C., the reaction mixture is poured into 500 ml of ice, the ether is decanted, which is washed with water and dried over MgS0 4 . Filtered, the hydrochloride precipitates with hydrochloric ethanol and recrystallizes the crystals from acetone + ethanol.
• the benzene-water azeotrope is distilled from a mixture of 39.5 g (0.207 M) of 3- (2-methyl phenyl) - 3-hydroxy piperidine, 93.5 g (0.49 M) of paratoluene acid sulfonic, monohydrate and 500 ml of anhydrous benzene. It is cooled, basified with 45 ml of sodium hydroxide solution + 135 ml H 2 0, the benzene is decanted which is washed with water, dried over MgSO 4 , filtered, evaporated to dryness. The residue is taken up in ether, acidified with hydrochloric ethanol, filtered crystals and recrystallized from acetone + ethanol.
• mice Half an hour after having received the test compound intraperitoneally, the mice are placed on an actimeter where their motility is recorded for 30 minutes.
• the compound of Example 3 decreases the number of fights.
• the rats males, CD lf Sprague Dawley, 200-250 g are sacrificed by decapitation.
• the cerebral cortex is immediately removed.
• the cerebral cortices of 4 rats are homogenized in 40 ml of buffer. Homogenates are centrifuged at 20,000 rpm for 15 minutes.
• the pellet resuspended in 40 ml of buffer is subjected to a second centrifugation (20,000 rpm for 15 minutes).
• the pellet thus obtained is suspended in 8 ml of buffer, then stored at -80 ° C until use.
• a membrane suspension is prepared from the frozen suspension.
• Specific binding is defined as the difference between total binding and non-specific binding (displaced by an excess of non-radioactive ligand).
• the values obtained in counts per minute (cpm) are then transformed into disintegrations per minute (dpm) according to the efficiency of the counter.
• the IC 50 is defined as the concentration of the studied substance, necessary to displace 50% of the specifically linked radioactive marker.
• the present invention also relates to therapeutic compositions comprising, as active principle, a compound of formula I or one of its addition salts with pharmaceutically acceptable acids.
• compositions according to the invention can be administered to humans or to animals by oral or parenteral route.
• They can be in the form of solid, semi-solid or liquid preparations.
• the active principle is generally mixed with one or more usual pharmaceutically acceptable excipients well known to those skilled in the art.
• the amount of active ingredient administered obviously depends on the patient being treated, the route of administration and the severity of the disease.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Biomedical Technology (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Chemical & Material Sciences (AREA)
• Anesthesiology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Hydrogenated Pyridines (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 1993
  • 1993-03-31 FR FR9303783A patent/FR2703354B1/fr not_active Expired - Fee Related
• 1994
  • 1994-03-22 US US08/215,782 patent/US5439920A/en not_active Expired - Fee Related
  • 1994-03-24 CZ CZ94691A patent/CZ69194A3/cs unknown
  • 1994-03-25 AU AU59035/94A patent/AU5903594A/en not_active Abandoned
  • 1994-03-28 NO NO941134A patent/NO941134L/no unknown
  • 1994-03-28 SK SK372-94A patent/SK37294A3/sk unknown
  • 1994-03-29 KR KR1019940006328A patent/KR940021524A/ko not_active Application Discontinuation
  • 1994-03-29 CA CA002120203A patent/CA2120203A1/en not_active Abandoned
  • 1994-03-29 NZ NZ260212A patent/NZ260212A/xx unknown
  • 1994-03-30 AU AU65065/94A patent/AU6506594A/en not_active Abandoned
  • 1994-03-30 HU HU9400909A patent/HUT70847A/hu unknown
  • 1994-03-30 JP JP6521756A patent/JPH08509707A/ja active Pending
  • 1994-03-30 FI FI941480A patent/FI941480L/sv not_active Application Discontinuation
  • 1994-03-30 JP JP6061320A patent/JPH06321899A/ja active Pending
  • 1994-03-30 CN CN94104072A patent/CN1099386A/zh active Pending
  • 1994-03-30 WO PCT/FR1994/000362 patent/WO1994022827A1/fr not_active Application Discontinuation
  • 1994-03-30 EP EP94912574A patent/EP0691956A1/fr not_active Withdrawn
  • 1994-03-30 EP EP94400691A patent/EP0618194A1/fr not_active Withdrawn
  • 1994-03-30 ZA ZA942256A patent/ZA942256B/xx unknown

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