Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• ABSTRACT The invention relates to compounds of theformula:
• the present invention relates to novel biologically active imidazolidine derivatives. More particularly it relates to tetra-hydro-imidazo-dibenzo-oxazepines, -thiazepines and -diazepines.
• R, and R hydrogen, hydroxy, halogen, alkyl or alkoxy with 1-6 carbon atoms, acyloxy with l-8 carbon atoms, or a trifluoromethyl group
• 7 R hydrogen, an alkyl group with 1-6 carbon atoms, or an aralkyl group with 7-10 carbon atoms
• the compounds according to this invention show, fully contrary to the compounds described in the said British patent, a positive effect in the reserpine antagonism test, which means that they possess antidepressant activity, whereas the antihistamine and antiserotonine activity of the present compounds may, in general, be disregarded in comparison with the strong antihistamine and/or antiserotonine activity of the compounds described in the British patent.
• the compounds according to the invention can be prepared by any method commonly used for this type of compounds. They are, however, prepared most conveniently starting from a substance with the general formula:
• R, and R each represent hydrogen, halogen, hydroxyl, acyloxy, lower alkyl, lower alkoxy, or trifluoromethyl
• R represents hydrogen, lower alkyl, lower aralkyl, aminoethyl or aminopropyl
• X represents oxygen, sulfur or NR in which R, is lower alkyl.
• the groups Z, and Z may represent halogen, a substituted or unsubstituted amino group, the group CR or SR in which R represents hydrogen, a hydrocarbon radical that may be substituted by hetero atoms or halogen, a R -sulfonyl group, in which R represents a hydrocarbon radical, or Z, and Z together may represent sulphur or oxygen.
• Reagents III belonging to this type of compounds are, for example, methylenechloride, methylenebromide or methylene diol formaldehyde solution in water or a water containing solvent).
• Y represents oxygen or sulphur
• the most suitable moieties for Z and Z are halogen, substituted or unsubstituted amino groups, R or SR in which R represents a hydrocarbon radical that may be substituted by hetero atoms or halogen, or Z and Z together are sulphur (in combination with Y sulphur).
• Suitable reagents III belonging to this type of compounds are, for example, phosgene, thiophosgene, haloformic esters, such as ethylchloroformate, esters of carbonic acid such as diethylcarbonate, urea and urea derivatives such as thiourea or N,N'-carbonyl-diimidazole, and carbondisulphide.
• methylene halide or formaldehyde in water is used as the reagent III in the present condensation reaction because they yield the desired final product according to the invention in a direct way.
• a reagent according to the formula III, in which Y represents oxygen or sulphur is used, the resulting compound must be reduced additionally to obtain the desired final product.
• any suitable reducing agent can be used, for example, metal hydrides such as sodium hydride, lithium aluminium hydride or diborane. Said reduction can also be performed catalytically by hydrogenation in the presence of a metal or a metal compound.
• Z and/or Z represent halogen
• an agent capable of binding the hydrohalide released in the condensation reaction such as pyridine, triethylamine, etc., is usually added to the reaction mixture.
• the condensation reaction can be performed in any suitable solvent.
• methylene halide is used as the reagent III
• an aprotic polar solvent such as dimethylsulfoxide, sulfolane or acetonitril. It is also possible, however, to perform the condensation exclusively in the reagent, for example, methylenechloride or a formaldehyde solution, so in the absence of an (additional) solvent.
• the condensation can be carried out in a melt.
• the acid addition salts of the compounds according to the invention are prepared in the conventional manner by reacting the free base with a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycollic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or benzoic acid.
• a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycollic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or benzoic acid.
• the pharmaceutically acceptable quaternary ammonium compounds in particular the lower (1-4 C) alkyl quaternary ammonium compounds, are obtained by reacting the compounds of the general formula I with an alkyl halide, for example methyl iodide or methyl bromide.
• optical antipodes are possible, also forming part of this invention. Said optical antipodes can be isolated from the racemic mixture in a conventional manner. It is also possible to resolve the racemic starting product II into its optical antipodes and to perform the condensation reaction after that, or to resolve an intermediate product obtained in the synthesis into its optical antipodes.
• a hydroxy group present can be acylated or converted into an alkoxy group, an amino group into a halogen group, a methoxy group into a hydroxy group, etc.
• the substituent (R at the N nitrogen atom can be obtained by alkylating or aralkylating the unsubstituted nitrogen atom (R H) or by acylating the unsubstituted nitrogen atom followed by a reduction of the carbonyl moiety of the N-acyl compound thus obtained.
• the compounds according to the present invention exert as said before, an antidepressant activity. They can be administered both orally and parenterally, preferably in a dosage of between 0.01 and 1 mg per kg body weight.
• suitable auxiliaries the compounds can be compressed into solid dosage units, such as pills, tablets and coated tablets. They can also be processed into capsules, mixed with auxiliaries, if desired.
• suitable liquids the compounds can be applied as injection preparations in the form of solutions, emulsions or suspensions.
• EXAMPLE II Preparation methyliodide salts (quat. ammonium compounds) A.
• 2-methyl- 1,2,3 ,13b-tetrahydro-imida2o[3 ,4d]- dibenzo[b,f](1,4) oxazepine 300 mg is boiled for 5 minutes in 10 ml of ether and 2 ml of methyl iodide. The mixture is cooled down, after which the precipitate obtained is filtered off and recrystallised from ethanol. Melting point of the CH salt 192l94C.
• the 'ether extracts are washed with water, dried on anhydrous sodium-sulphate and evaporated.
• the resulting yellow oil is chromatographed over silicagel.
• the methanol eluate yields, after evaporation, 5.6 g of the crystalline substance, that melts at l02C after recrystallisation from ethanol.
• X is oxygen, sulfur or NR in which R, is hydrogen or alkyl of 1-6 carbon atoms; R and R are 20 each hydrogen, halogen, hydroxy, alkyl of l-6 carbon atoms, alkoxy of 1-6 carbon atoms or trifluoromethyl; R is hydrogen, alkyl of l-6 carbon atoms or phenylalkyl of 7-10 carbon atoms; or a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable quaternary ammonium compound thereof.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (1)

Publications (1)

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ID=19815531

Family Applications (1)

Country Status (16)

Cited By (7)

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Citations (1)

• 1972
  • 1972-03-07 NL NL7202963A patent/NL7202963A/xx unknown
• 1973
  • 1973-02-15 ZA ZA731086A patent/ZA731086B/xx unknown
  • 1973-02-19 AU AU52303/73A patent/AU471800B2/en not_active Expired
  • 1973-02-26 IE IE297/73A patent/IE37322B1/xx unknown
  • 1973-03-01 AR AR246878A patent/AR202388A1/es active
  • 1973-03-01 GB GB1006173A patent/GB1421006A/en not_active Expired
  • 1973-03-02 US US337323A patent/US3860606A/en not_active Expired - Lifetime
  • 1973-03-06 BE BE128428A patent/BE796341A/xx unknown
  • 1973-03-06 CH CH328773A patent/CH589083A5/xx not_active IP Right Cessation
  • 1973-03-06 HU HUAO353A patent/HU166348B/hu unknown
  • 1973-03-06 CA CA165,357A patent/CA1010032A/en not_active Expired
  • 1973-03-06 ES ES412372A patent/ES412372A1/es not_active Expired
  • 1973-03-06 JP JP48026503A patent/JPS4899198A/ja active Pending
  • 1973-03-06 DE DE19732311019 patent/DE2311019A1/de active Pending
  • 1973-03-07 AT AT203073A patent/AT326667B/de not_active IP Right Cessation
  • 1973-03-07 FR FR7308169A patent/FR2181796B1/fr not_active Expired
• 1974
  • 1974-11-08 AR AR256461A patent/AR202429A1/es active
  • 1974-11-08 AR AR256460A patent/AR203866A1/es active

Patent Citations (1)

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