USRE31237E - 2-Benzoyl-4-nitroanilides and their use as medicaments - Google Patents

2-Benzoyl-4-nitroanilides and their use as medicaments Download PDF

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Publication number
USRE31237E
USRE31237E US06/350,233 US35023382A USRE31237E US RE31237 E USRE31237 E US RE31237E US 35023382 A US35023382 A US 35023382A US RE31237 E USRE31237 E US RE31237E
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US
United States
Prior art keywords
benzoyl
nitro
acetanilide
morpholino
methyl
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.)
Expired - Lifetime
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US06/350,233
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English (en)
Inventor
Henri Cousse
Gilbert Mouzin
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Pierre Fabre SA
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Pierre Fabre SA
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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)
US06/350,233 1979-06-25 1982-02-19 2-Benzoyl-4-nitroanilides and their use as medicaments Expired - Lifetime USRE31237E (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7916213 1979-06-25
FR7916213A FR2459793A1 (fr) 1979-06-25 1979-06-25 Nouveaux derives de benzoyl-2 nitro-4 anilides, leur preparation et leur application en tant que medicaments

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US06/159,070 Reissue US4289770A (en) 1980-06-13 1980-06-13 2-Benzoyl-4-nitroanilides and their use as medicaments

Publications (1)

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USRE31237E true USRE31237E (en) 1983-05-10

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US (1) USRE31237E (enrdf_load_stackoverflow)
EP (1) EP0022017B1 (enrdf_load_stackoverflow)
JP (1) JPS568353A (enrdf_load_stackoverflow)
AT (1) ATE960T1 (enrdf_load_stackoverflow)
AU (1) AU536228B2 (enrdf_load_stackoverflow)
CA (1) CA1141380A (enrdf_load_stackoverflow)
DE (1) DE3060367D1 (enrdf_load_stackoverflow)
ES (1) ES493256A0 (enrdf_load_stackoverflow)
FR (1) FR2459793A1 (enrdf_load_stackoverflow)
ZA (1) ZA803721B (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4476061A (en) 1978-09-25 1984-10-09 Pierre Fabre, Sa 2'-(Orthochlorobenzoyl)-4'-chloroglycylanilides

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2525214B1 (fr) * 1982-04-16 1986-02-07 Fabre Sa Pierre Nouveaux derives d'halogeno benzoyl-2 nitro-4 glycylanilides, leur procede de preparation et leur application en therapeutique
FR2528424A1 (fr) * 1982-06-11 1983-12-16 Fabre Sa Pierre Nouveaux derives d'alpha-hydroxybenzylglycylanilides, leur procede de preparation et leur application en tant que medicaments anxiolytiques
JP2711034B2 (ja) * 1991-09-25 1998-02-10 大日本スクリーン製造株式会社 感光板貯蔵・搬送装置
US6063921A (en) * 1997-11-20 2000-05-16 Pharm-Eco Laboratories, Inc. Synthesis of 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepines
EP1357892B1 (en) 2001-02-05 2007-07-25 Amcol International Corporation Multifunctional particulate additive for personal care and cosmetic compositions, and the process of making the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3772371A (en) * 1967-11-27 1973-11-13 Sankyo Co Benzodiazepine derivatives and process for preparing the same
US3906003A (en) * 1970-10-19 1975-09-16 Sumitomo Chemical Co Benzodiazepine derivatives and preparation thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1462887A (fr) * 1966-01-06 1966-12-16 Hoffmann La Roche Procédé pour la préparation de dérivés de benzodiazépine
BG17604A3 (bg) * 1968-07-01 1973-11-10 Sankyo Co Ltd Метод за получаване на бензодиазепинови производни
US3799928A (en) * 1970-09-18 1974-03-26 L Schlager 3-amino alkyl-4-phenyl-2(1h)-quinolone derivatives
LU65340A1 (enrdf_load_stackoverflow) * 1972-05-12 1973-11-22
DE2356239A1 (de) * 1973-11-10 1975-05-15 Cassella Farbwerke Mainkur Ag Benzophenon-derivate und verfahren zu ihrer herstellung
JPS52113952A (en) * 1976-03-19 1977-09-24 Shionogi & Co Ltd Aminobenzophenone derivatives
FR2403330A1 (fr) * 1977-06-16 1979-04-13 Fabre Sa Pierre Nouveaux derives de benzoyl-2-chloro-4-glycinanilides substitues, leur procede de preparation et leur application en tant que medicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3772371A (en) * 1967-11-27 1973-11-13 Sankyo Co Benzodiazepine derivatives and process for preparing the same
US3906003A (en) * 1970-10-19 1975-09-16 Sumitomo Chemical Co Benzodiazepine derivatives and preparation thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4476061A (en) 1978-09-25 1984-10-09 Pierre Fabre, Sa 2'-(Orthochlorobenzoyl)-4'-chloroglycylanilides

Also Published As

Publication number Publication date
AU536228B2 (en) 1984-05-03
EP0022017A1 (fr) 1981-01-07
FR2459793A1 (fr) 1981-01-16
EP0022017B1 (fr) 1982-05-05
ZA803721B (en) 1981-07-29
CA1141380A (fr) 1983-02-15
AU5953180A (en) 1981-01-08
ES8104199A1 (es) 1981-04-16
ES493256A0 (es) 1981-04-16
FR2459793B1 (enrdf_load_stackoverflow) 1983-09-09
DE3060367D1 (en) 1982-06-24
ATE960T1 (de) 1982-05-15
JPS568353A (en) 1981-01-28

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