Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • 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 developed at the Pierre FABRE Research Center, concerns new chemical compounds derived from 2-benzoyl-4-nitroanilides, their method of preparation and their use in therapy.
• R represents a linear or branched alkyl group or an alkenyl, cycloalkyl or benzyl group
• R 1 represents a hydrogen atom or an alkyl or hydroxyalkyl group
• R 2 represents a hydroxyalkyl, alkenyl, or alkynyl group, possibly substituted one or more times by an alkyl radical, or a cycloalkyl group having 3 to 6 carbom atoms;
• R 1 and R 2 may furthermore form, with the nitrogen atom to which they are bound, a nitrogen heterocycle, possibly including a second heteroatom selected from among oxygen and nitrogen.
• the present invention also applies to salts of compounds of formula I obtained with therapeutically acceptable inorganic or organic acids.
• the present invention also relates to a method of preparing compounds of formula I which are characterized by condensing a compound of general formula II: ##STR3## in which
• X represents a halogen atom; with an amine of general formula III ##STR4## in which
• R 1 and R 2 have the meaning given in connection with general formula I.
• the products of general formula II may be prepared by one of the two following methods:
• the present invention finally relates to the use of the compounds of general formula I as medicaments which are active on the central nervous system and in particular as hypnotics.
• a suspension of 11.07 g (0.031 mol) of 2-benzamido-5-nitro benzophenone and 724 mg (0.003 mol) of benzyltriethyl ammonium chloride is heated to 60° C. in 450 cc of toluene.
• 16 cc of 10 N caustic soda (0.16 mol) and 10 cc of methyl sulfate (0.1 mol) in 50 cc of toluene are added simultaneously drop by drop.
• the reaction mixture is maintained under strong agitation at 60° C. for 8 hours. After return to room temperature, it is diluted and allowed to settle.
• the organic phase is evaporated and the residue absorbed by 200 cc of ethanol and 60 cc of 6 N caustic soda (0.36 mol). After heating for two hours at 70° C., the ethanol is evaporated, the residue is absorbed by ethyl acetate, washed with water and dried over sodium sulfate. Upon recrystallization from a mixture of ethyl acetate and hexane (75:25), there are recovered 7.22 g of yellow crystals. Melting point 168° C. Yield 88%.
• Empirical formula C 20 H 22 ClN 3 O 5 ; Molecular weight: 419.87; Crystals: Slightly colored white; Melting point: 170° C.; IR spectrum (KBr) ⁇ cm -1 : 1679-1655 and 1612.
• Solubilities Insoluble in water. 2.5% soluble in DMSO and 10% soluble in methylpyrrolidone.
• N-ethyl-2'-benzoyl-4'-nitro-2-bromo acetanilide is recovered in a yield of 95%.
• Empirical formula C 25 H 27 N 3 O 9 ; Molecular weight: 513.49; White crystals; Melting point: 165° C.
• Empirical formula C 26 H 29 N 3 O 9 ;
• Empirical formula C 26 H 29 N 3 O 9 ; Molecular weight: 527.54; White crystals; Melting point: 183° C.
• Empirical formula C 26 H 27 N 3 O 9 ; Molecular weight: 525.52; White crystals; Melting point: 165° C.
• Empirical formula C 26 H 25 N 3 O 5 ; Molecular weight: 459.58; Crystals of a slightly colored white; Melting point: 110° C.
• Aqueous phases are combined and treated with sodium carbonate and extracted with ethyl acetate. They are settled, washed with water and dried over sodium sulfate.
• Empirical formula C 22 H 26 ClN 3 O 4 ; Molecular weight: 431.9; Crystals: white; Melting point: 204° C.
• Empirical formula C 27 H 31 N 3 O 8 : Molecular weight: 525.56; Crystals: white; Melting point: 173° C.
• the compounds of the present invention which have a remarkable action on the central nervous system, are therefore capable of being administered to man or animal orally or by injection, in the form of a free base or else in the form of one of their therapeutically acceptable salts.
• the compounds of the present invention were subjected to toxicity controls.
• the LD 50 is between 500 and 3000 mg/kg for all the derivatives tested. It was determined orally and calculated in accordance with the method of Miller and Tainter (Proc. Soc. exper. Biol. Med., 1944, 57, 261).
• mice of Swiss strain were placed on a wooden rod of a diameter of 3 cm rotating at the rate of 5 revolutions per minute.
• the mice who are able to remain on the rod for at least three minutes during the course of successive tests are selected and assembled in groups of 10 for the testing of each dose. If the mouse falls from the rod in less than two minutes, the compound tested is considered effective.
• the results of the compounds are expressed as ED 50 in accordance with N. W. Dunham and T. S. Miva--J. Amer. Pharm. Assoc., 1957, 46, 208.
• the ED 50 values of the compounds of greatest interest vary from 0.2 to 20 mg/kg.
• mice were Swiss strains. Within a period of 15 minutes after the subcutaneous injection of 125 mg/kg of penetrazol, the mice have tonic convulsions the outcome of which is fatal.
• the compounds are administered orally 60 minutes before the injection of pentetrazol. The animals are observed for two hours after administration of the pentetrazol.
• the results are expressed by the effective dose ED 50 in accordance with Goodmann et al. J. Pharmacol. 108,1953.
• the ED 50 values of the most interesting compunds vary from 0.1 to 3 mg/kg.
• these chemical compounds can be used in therapy and, more particularly, for the treatment of insomnia.
• These compounds and their therapeutically compatible acid addition salts can be used as drugs, for instance in the form of pharmaceutical preparations suitable for enteral or parenteral administration with, for instance, water, lactose, gelatin, starches, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, petroleum jelly, etc.
• preparations may be in solid form, for instance in the form of tablets, pills, capsules, etc., or else in liquid form, for instance solutions, suspensions or emulsions.
• compositions in a form suitable for injection are preferred. These preparations can be subjected to conventional pharmaceutical operations such as sterilization and/or may contain adjuvants, for instance preservatives, stabilizers, wetting or emulsifying agents, buffer compounds, etc.
• adjuvants for instance preservatives, stabilizers, wetting or emulsifying agents, buffer compounds, etc.
• the doses in which the active compounds and their therapeutically compatible acid addition salts can be administered may vary within large proportions depending on the condition of the patient.
• a daily dose of about 0.01 mg to 1 mg per kg of body weight is, however, preferred.
• compositions of the invention can be used in medicine, for instance in the treatment of insomnia.
• Such compositions may furthermore contain other active principles which supplement or reinforce the therapeutic action of the derivatives of general formula I of the present invention.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Anesthesiology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Biomedical Technology (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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• 1979
  • 1979-06-25 FR FR7916213A patent/FR2459793A1/fr active Granted
• 1980
  • 1980-06-23 ZA ZA00803721A patent/ZA803721B/xx unknown
  • 1980-06-23 AU AU59531/80A patent/AU536228B2/en not_active Ceased
  • 1980-06-23 ES ES493256A patent/ES8104199A1/es not_active Expired
  • 1980-06-24 AT AT80400942T patent/ATE960T1/de not_active IP Right Cessation
  • 1980-06-24 DE DE8080400942T patent/DE3060367D1/de not_active Expired
  • 1980-06-24 EP EP80400942A patent/EP0022017B1/fr not_active Expired
  • 1980-06-25 JP JP8639980A patent/JPS568353A/ja active Pending
  • 1980-06-25 CA CA000354714A patent/CA1141380A/fr not_active Expired
• 1982
  • 1982-02-19 US US06/350,233 patent/USRE31237E/en not_active Expired - Lifetime

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