US3546226A - 11-basic-substituted dibenzoxazepines - Google Patents

11-basic-substituted dibenzoxazepines Download PDF

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US3546226A
US3546226A US797281A US3546226DA US3546226A US 3546226 A US3546226 A US 3546226A US 797281 A US797281 A US 797281A US 3546226D A US3546226D A US 3546226DA US 3546226 A US3546226 A US 3546226A
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formula
acid
dibenz
oxazepine
ether
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Jean Schmutz
Fritz Hunziker
Franz Martin
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Wander AG
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Wander AG
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Priority claimed from CH1190763A external-priority patent/CH450422A/en
Priority claimed from CH676263A external-priority patent/CH436297A/en
Priority claimed from CH410367A external-priority patent/CH481133A/en
Priority claimed from CH655767A external-priority patent/CH484924A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • R is a member of the class consisting of hydrogen, lower alkyl, lower hydroxyalkyl, acetylated lower hydroxyalkyl, and alkoxyalkyl having not more than carbon atoms;
  • R represents a member of the group consisting of hydrogen, allyl, alkyl containing not more than 3 carbon atoms, hydroxyalkyl containing not more than 3 carbon atoms, alkoxyalkyl containing not more than 6 carbon atoms and alkoyloxyalkyl containing not more than 6 carbon atoms; and R is a member of the group consisting of nitro, amino, aminosulphonyl of the formula SO NR R wherein R and R are the same or ditferent members of the group consisting of hydrogen and methyl, alkyl-sulphinyl of the formula SOR wherein R denotes alkyl with not more than 3 carbon atoms, and alkylsulphonyl of the formula SO R wherein R, denotes alkyl with not more than 3 carbon atoms; and
  • These compounds have a pronounced therapeutic effect on the central nervous system and are particularly active as nenroplegics, neuroleptics, neuroleptic antidepressants, antimetics, analgesics and sedatives.
  • the object of the present invention is to provide 11- basic substituted dibenz[b,f][l,4]oxazepines having a pronounced therapeutic effect on the central nervous system.
  • a further object of the invention is to provide ll-basic substituted dibenz[b,f] [1,4]oxazepines having the abovementioned action of the general formula:
  • R denotes hydrogen, lower alkyl, lower hydroxyalkyl, acetylated lower hydroxyalkyl, or alkoxyalkyl having not more than 5 carbon atoms, and which compounds are unsubstituted in the benzene nuclei or substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthio; as well as acid addition salts of these basic compounds.
  • Substituents in the benzene nuclei are preferably in the 2-, 4-, or 8-positions.
  • the term lower alkyl etc. is intended to mean alkyl etc. having from 1 to 3 carbon atoms.
  • a further object of the invention is to provide ll-basic substituted dibenz[b,f] [1,4]oxazepines having the abovementioned action of the general formula:
  • R represents hydrogen, allyl, alkyl containing not more than 3 carbon atoms, hydroxy-alkyl containing not more than 3 carbon atoms, alkoxyalkyl containing not more than 6 carbon atoms or alkoyloxyalkyl containing not more than 6 carbon atoms.
  • R denotes nitro; amino; aminosulphonyl of the formula 4O NR R wherein R and R are the same or different and represent hydrogen or methyl; alkylsulphinyl of the formula SOR wherein R denotes alkyl with not more than 3 carbon atoms; or alkylsulphonyl of the formula -SO R in which R represents alkyl with not more than 3 carbon atoms.
  • the compounds of Formula I are obtained by reacting a reaction mixture containing nitrilium or imonium cations of the formulae:
  • Nitrilium or imonium cations of Formulae III can be regarded as dissociation products of corresponding compounds of the formula:
  • A represents a halogen atom, the sulfhydryl group, or an alkoxy or alkylthio group which is activated if required, e.g., the p-nitrobenzylthio group.
  • Such compounds V are obtained, for instance, by conversion of lactams of the formula: 30
  • lactams (VI) can be obtained, for example, by ring closure of suitable o-isocyanato-diphenyl ethers with aluminum chloride.
  • the V compounds in the reaction mixtures obtained are dissociated to a higher or lower degree into the nitrilium or imonium cations, so that the reaction mixtures can be used directly for reacting with piperazine or the piperazine derivative of Formula IV.
  • the compounds of Formula V produced in this or in another manner can be isolated in undissociated form and then yield the desired nitrilium or imonium cations (III) upon dissolution in a suitable, preferably polar solvent, if required by heating and in the presence of piperazine or the piperazine derivative of Formula IV, which can also serve as a solvent.
  • Reaction mixtures containing cations of Formula III can also be produced, for example, by intramolecular 60 Ritters reaction (action of a nitrile group on a phenyl cation) in o-cyanodiphenyloxides, by Beckmanns transformation of (if desired suitably substituted) xanthonoximes, or by Schmidts reaction of (if desired suitably substituted) xanthones with hydrazoic acid. Both the 6 last-named reactions may lead, if the starting material consists of unsymmetrically substituted oximes or ketones, to isomeric products which, if necessary, must be subsequently separated.
  • the anionoid components which may appear are-besides 70 those derived from the substituent A of Formula Vdepending upon the mode of preparation of the cations (III), for example also anions of sulphuric, toluenesulpho, phosphoric, hydrofluoric, or hydrofluoboric acids, etc. 7
  • R1 it (VIII) wherein R has the above-mentioned meaning, and Y represents an oxygen or sulphur atom, and which are unsubstituted in the benzene nuclei or substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthio.
  • a purely thermal condensation cannot usually be successfully carried out with the acid amides, which, in turn, are produced, for example, by reduction of suitable nitro compounds, but it can rather in the case of the thioamides, which are obtained, for example, by treating the acid amides with phosphorus pentasulphide and do not require to be isolated prior to the subsequent condensation.
  • condensing agents such as phosphorus pentachloride, phosphoroxychloride, phosgene, polyphosphoric acid, and the like.
  • the ring closure involved goes partly through intermediate stages, like imide chlorides, amide chlorides, imidophosphates, amidophosphates or salt-like derivatives thereof, which can not generally be isolated.
  • Condensation of the thioamides may be aided by the presence of mercury salts or by intermediate formation of (if desired activated) imido thio ethers. Heating and, if required, the use of an inert diluent are useful when Working with phosphoroxychloride and phosphorus pentachloride, as also the addition of catalytic amounts of dimethylformamide or dimethylaniline.
  • the reaction is carried out following or by simultaneous treat ment with a basic catalyst or metallization agent such as sodamide, lithium amide, sodium hydride, butyl lithium, phenyl sodium, sodium ethylate or potassium-t-butoxide.
  • a basic catalyst or metallization agent such as sodamide, lithium amide, sodium hydride, butyl lithium, phenyl sodium, sodium ethylate or potassium-t-butoxide.
  • the primary amines of Formula IV are obtained by treating a reaction mixture containing nitrilium or imonium cations of Formula III with ammonia.
  • R has the meaning defined above and X denotes a residue capable of being split off with the hydrogen of amines, is reacted with piperazine or a piperazine derivative, respectively, of the formula:
  • a residue capable of being split off with the hydrogen of amines, which can be bound ionically or covalently to the carbon atom, can most conveniently be represented by halogen, sulphydryl, or alkoxy and alkylthio which may be activated, e.g. methoxy, thiomethyl or p-nitrobenzylthio, or by tosyl.
  • Lactams of Formula XIII may also be obtained by ring closure of compounds of the formula:
  • Hal stands for halogen, or of isocyanates of the formula:
  • the ring closure proceeds by way of intermediate steps such as imidochlorides, amidochlorides, imidophosphates, amidophosphates or salt-like derivatives thereof, which, in general, are not isolatable.
  • intermediate steps such as imidochlorides, amidochlorides, imidophosphates, amidophosphates or salt-like derivatives thereof, which, in general, are not isolatable.
  • the condensation of the thioamides is favoured by the presence of mercury (-11) salts or by intermediate formation of imidothioethers which may be activated. Heating and, if required, the use of a suitable inert solvent are desirable, and when using phosphorus oxychloride and phosphorus pentachloride addition of catalytic amounts of dimethylformamide or dimethylaniline.
  • R has the above-mentioned meaning and R means R or denotes a removable group, especially a hydrolytically removable group.
  • the ring closure is preferably carried out by heating in the presence of dehydrating agents such as zinc chloride, aluminum chloride, stannic chloride, phosphoric acid, polyphosphoric acid and the like, especially phosphorus oxychloride or phosphorus oxychloride and phosphorus pentoxide, if desired in an inert solvent of suitable boiling point such as benzene or toluene etc.
  • dehydrating agents such as zinc chloride, aluminum chloride, stannic chloride, phosphoric acid, polyphosphoric acid and the like, especially phosphorus oxychloride or phosphorus oxychloride and phosphorus pentoxide, if desired in an inert solvent of suitable boiling point such as benzene or toluene etc.
  • carbalkoxy especially carbethoxy
  • carbethoxy are cyclicized directly to the 11-(1- piperazinyl) compounds by hydrolysis of the removable group.
  • Other removable groups can be split off after ring closure in a way known per se, e.g. by hydrogenolysis.
  • HO-CH2CH2 noorrz-oin wherein R has the above-mentioned meaning.
  • the reaction is carried out following or by simultaneous treatment with a basic catalyst or metallization agent such as sodamide, lithium amide, sodium hydride, butyl lithium, phenyl sodium, sodium ethylene or potassium-t-butoxide.
  • Suitable esters are those of inorganic or organic acids, e.g. hydrohalic acid, sulphonic acid or carbonic acid esters.
  • the required amidines XIX are in turn obtained by treating compounds or Formula XI with ammonia.
  • compounds of Formula II, wherein R is amino may be obtained by reduction of the corresponding nitro compounds.
  • the reduction is most suitably carried out by treatment with hydrogen in the presence of a catalyst such as palladium charcoal or Raney nickel or by treatment with stannous chloride and hydrochloric acid.
  • Compounds of Formula II, wherein R represents alkylsulphinyl or alkylsulphonyl, respectively, can also be obtained by mild (e.g. with periodates) or strong (e.g. with hydrogen peroxide or peracetic acid) oxidation of the corresponding alkylthio compounds. Products wherein R represents alkylsulphonyl are also obtainable by strong oxidation of the corresponding alkylsulphinyl compounds.
  • R represents hydrogen
  • R does not represent hydrogen
  • An alkyl group R can also be introduced by the method of reductive alkylation, i.e. by reaction with corresponding aldehydes either with hydrogen in the presence of a catalyst with a reducing agent such as formic acid.
  • the introduction of a hydroxyalkyl group R can also be carried out by treating with a corresponding alkylene oxide.
  • the bases I or II obtained in this manner are in most cases crystallizable or can otherwise be distilled in high vacuum without decomposition and react with inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, acetic aid, maleic acid, succinic acid, tartaric acid, toluene sulphonic acid and the like to form addition salts which are stable in water, in which form the products may also be used.
  • inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, acetic aid, maleic acid, succinic acid, tartaric acid, toluene sulphonic acid and the like to form addition salts which are stable in water, in which form the products may also be used.
  • the bases I and II as Well as their acid addition salts are new compounds which can be used as active substances in pharmaceuticals. They produce a favourable 8 effect on the central nervous system and may therefore be used, for example, as neuroplegics, neuroleptics, neuroleptic antidepressants, antiemetics, analgesics and sedatives.
  • the compounds of Formula I and their acid-addition salts are particularly of interest as neuroplegics, neuroleptics and analgesics. Some of them are suitable for the treatment of psychotic conditions.
  • Preferred specific compounds are:
  • oxazepine The utility as neuroplegic or neuroleptic, respectively, manifests pharmacologically e.g. in a supression of locomotor activity, a cataleptic and/or an apomorphine antagonising eflect in mice or rats, respectively.
  • the motility depressing action can be shown by measuring the locomotor activity in accordance with the method of Caviezel and Baillod [Pharm. Acta Helv. 33, 469 (1958)].
  • Table I the locomotor activity obtained with some compounds of Formula I, as Well as their toxicity, are compared with the corresponding data of chloropromazine. From Table I it can be seen that the 2-substituted products are the most active.
  • Pronounced antiemetic activity is shown by Z-dimethylaminosulphonyl 11 (4 methyl-l-piperazinyl)-dibenz[-b,f] [1,4]oxazepine and Z-methylsulphonyl-ll-(S-methyl 1 piperazinyl)-dibenz[b,f] [l,4]oxazepine obtained according to Examples 6 or 7, respectively, and their acid addition salts.
  • the compounds of this invention can be administered in the form of pharmaceutical preparations containing, besides the active substance, organic or inorganic solid or liquid carriers suitable for enteral or parenteral administration.
  • the pharmaceutical preparations may be, for example, in the form of tablets, dragees, or solutions for injection, one dosage unit containing from 1 to 100 mg. of active substance, depending on its nature, on the route of administration and on the physicians prescription, the effective daily dose amounting to from to 500 mg. of active substance.
  • EXAMPLE 1 3 m1. of N,N-dimethylaniline are poured over gm. of 2-chloro-l0,l1-dihydro-1l-oxo-dibenz[b,f] [1,4] oxazepine and, after adding 80 ml. of phosphoroxychloride, heated for 3 hours under reflux. The reaction mixture is evaporated in vacuo. The residue is suspended in absolute xylol. The residue obtained by re-evaporating the suspension in vacuo, is taken up in 300 ml. of ether and poured over ice/Water.
  • the ethereal phase is separated and washed 3 times with dilute hydrochloric acid, the hydrochloric Washing water being rewashed with ether.
  • the combined ether phases are successively washed with water, sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate, treated with active charcoal, filtered through alumina and largely concentrated by evaporation.
  • EXAMPLE 2 8 gm. of 8-chloro-10,1l-dihydro-l1-oxo-dibenz[b,f] [1,4]oxazepine are mixed with 8 gm. of phosphorus pentachloride and, after adding 50 ml. of phosphoroxychloride, heated for 4 hours under reflux. Excess phos phoroxychloride is removed from the reaction mixture by distillation in vacuo. The residue is mixed with xylol, which is removed by evaporation, once again taken up in xylol and poured over ice water.
  • the xylol phase is separated, dried over sodium sulphate, treated with active charcoal, evaporated in vacuo to 100 ml. and, after adding 10 ml. of N-methylpiperazine, heated for 4 hours under reflux.
  • the reaction mixture is mixed with Water and concentrated soda lye.
  • the xylol phase is separated and exhaustively extracted with dilute hydrochloric acid.
  • the hydrochloric extract is washed with ether, made alkaline with concentrated soda lye and then extracted with ether.
  • the ethereal extract is washed with water, dried over sodium sulphate, treated with active charcoal, filtered through alumina and evaporated.
  • the residue is crystallized from methanol, yielding 5.9 gm. of 8-chloro-1l-(4- 10 methyl-l-piperazinyl)-dibenz[*b,f] [1,4] oxazepine in the form of yellow prisms of melting point 165-166 C
  • EXAMPLE 3 13.4 gm. of 2-(4-methyl-l"-piperazinyl-carbonylamino)diphenyloxide are heated with 150 ml. of phosphoroxychloride for 30 hours under reflux. The reaction mixture is evaporated in vacuo to dryness. While being cooled the residue is mixed with water and made alkaline with concentrated soda lye. The ethereal extract obtained by shaking twice with ether is washed twice with water and then exhaustively extracted with dilute hydrochloric acid. The combined hydrochloric extracts are washed with ether, made alkaline with concentrated soda lye and extracted twice with ether.
  • EXAMPLE 4 8.3 gm. of 2-amino-2'-(4"-methyll-piperazinyl-carbonyl)diphenyloxide are boiled under reflux with 8.5 gm. of finely powdered mercuriacetate in ml. xylene during 24 hours. The reaction mixture is filtered and the filtrate is extracted with dilute acetic acid. The acid solution is treated With ammonia and extracted with ether. The ethereal solution is washed with water, dried over sodium sulphate, filtered through alumina and evaporated. The residue is crystallized from petroleum ether. 4.5 gm. of 11-(4-methyl 1 piperazinyl)-dibenz[b, f] [1,4] oxazepine of melting point 97-98 C. are obtained; the product is identical to that of Example 3.
  • EXAMPLE 5 4.9 g. of 2-nitro-l0,1l-dihydro-l1-oxo-dibenz[b,f] [1,4] oxazepine (M.'P. 263 C.) and 2 ml. of N,N-dimethylaniline are heated in 60 ml. of phosphorus oxychloride at reflux for 4 hours. The reaction mixture is then evaporated in vacuo to remove the excess phosphorus oxychloride and the residue is decomposed with ice/water and shaken out immediately with chloroform. The chloroform extracts are washed with dilute hydrochloric acid and Water, dried over sodium sulphate and evaporated to dryness in vacuo.
  • the crystalline residue consisting of crude 2-nitro-11-chloro-dibenz[b,f][1,4]oxazepine is heated at reflux for 6 hours with 6 m1. of N-methylpiperazine in 200 ml. of xylene. The organic phase is then shaken out with water and dilute hydrochloric acid. The acid extracts are made alkaline with concentrated soda lye and the base which separates is extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulphate and evaporated to dryness. The residue is crystallized from chloroform/ acetone/ petroleum ether and gives 4.7 g. of 2-nitro-l1-(4-methyl-1-piperazinyl)- dibenz[b,f] [1,4]oxazepine in the form of yellow needles of melting point l92l93 C.
  • EXAMPLE 6 1.8 g. of Z-dimethylaminosulphonyl-l0,1l-dihydro-l1- oxo-dibenz[b,f][ 1,4]oxazepine (M.P. 243245 C.) and 0.6 m1. of N,N-dimethylaniline are refluxed. in 20 ml. of phosphorus oxychloride for 4 hours. The excess phosphorus oxychloride in removed completely in vacuo and the residue dissolved in xylene and poured onto ice/Water.
  • the combined xylene extracts are washed with dilute hydrochloric acid, water and aqueous sodium chloride solution, dried over sodium sulphate, treated with active charcoal and filtered through a small amount of aluminum oxide.
  • the filtrate is concentrated and then refluxed with 12 ml. of N-methylpiperazine for 6 hours.
  • the reaction mixture is treated with water and concentrated soda lye and shaken out twice with ether.
  • the ether extracts are washed several times with water and then shaken out with dilute hydrochloric acid.
  • the acid extracts are made alkaline and extracted twice With ether.
  • the ether phase is washed with water and aqueous sodium chloride solution, dried over sodium sulphate, treated with active charcoal and filtered through a small amount of aluminum oxide.
  • EXAMPLE 8 3 g. of 2-(4"-methyl-1"-piperazinyl-carbonylamino)-4- methylsulphonyl-diphenyloxide (M.P. 145146 C.) and a mixture of 2 g. of phosphorus pentoxide and 10 ml. of phosphorus oxychloride are refluxed for 24 hours. The excess phosphorus oxychloride is then distilled off in vacuo and the residue decomposed with ice/water. The solution obtained is made alkaline with concentrated soda lye and shaken out with ether. The ether extracts are washed with water and shaken out thoroughly with dilute hydrochloric acid.
  • the acid extracts are made alkaline with concentrated soda lye and shaken out with chloroform.
  • the chloroform extracts are washed with water, dried over sodium sulphate and evaporated to dryness in vacuo.
  • the residue is crystallized from acetone/petroleum ether and gives 1.5 g. of Z-methylsulphonyl-l1(4-methyl-1-piperazinyl)-dibenz[b,f] [l,4]oxazepine of melting point 178- 179 C. identical to the product obtained according to Example 7.
  • EXAMPLE 9 15.2 g. of 2-nitro-11-(4-methyl-1-piperazinyl)-dibenz- [b,f][1,4]oxazepine obtained according to Example 5 are hydrogenated with hydrogen in the presence of 1 g. of 5% palladium-charcoal in 450 ml. of methanol at normal pressure. After take-up of 3.05 l. of hydrogen the hydrogenation is discontinued and the reaction mixture filtered to remove the catalyst. The filtrate is evaporated in vacuo and the residue taken up in chloroform, filtered through aluminum oxide and concentrated. On addition of petroleum ether crystals are formed which are separated and recrystallized from chloroform/ ether/ petroleum ether. 14.1 g. of 2-amino-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine of melting point 153-156" C. are obtained.
  • EXAMPLE 10 The free base obtained from 6.83 g. of 2-thiomethyl-ll- (4-methyl-l-piperazinyl)-dibenz[b,f] [1,4] oxazepine maleate (M.P. 19820l C.) is dissolved in ml. of water and 10 ml. of glacial acetic acid. This solution is treated dropwise while stirring at 0 C. with a solution of 3.42 g. of sodium metaperiodate in 10 ml. of water. After the addition is complete the reaction mixture is left to stand at room temperature for 24 hours, then made alkaline with concentrated soda lye and shaken out with ether.
  • the ether extracts are washed with water and then exhaustively shaken out with dilute hydrochloric acid.
  • the acid extracts are made alkaline with concentrated soda lye and shaken out with chloroform.
  • the chloroform extracts are washed with water, dried over sodium sulphate and evaporated to dryness in vacuo.
  • the residue is dissolved in acetone and treated with 1.8 g. of maleic acid.
  • concentration and addition of ether crystals precipitate which are recrystallized from methanol/acetone/ ether to give 6.0 g. of Z-methylsulphinyl-l1-(4-methyl-1- piperazinyl)dibenz[b,f][l,4]oxazepine maleate of melting point 206-207 C.
  • EXAMPLE 1 A solution of 5.2 g. of crude 2-chlorosulphonyl-11-(4- methyl 1 piperazinyl) dibenz[b,f] [l,4]oxazepine, obtained as described below, in ml. of chloroform is treated dropwise at room temperature with 50 ml. of a 10% dimethylamine solution in toluene. The reaction mixture is stirred for a further 2 hours at room temperature, then for 1 hour at 40 C. and finally evaporated to dryness in vacuo. The residue is taken up in dilute acetic acid, treated with active charcoal and made alkaline with concentrated ammonia solution.
  • reaction mixture After the development of nitrogen subsides at room temperature the reaction mixture is warmed for 15 minutes at 40 C. The reaction mixture is then diluted to 1:1 with Water and treated with active charcoal. While stirring and cooling carefully, the basic fraction is precipitated with concentrated soda lye and taken up in chloroform. The chloroform extracts are washed once with dilute soda lye and once with Water, dried over sodium sulphate and evaporated. Crude 2- chlorosulphonyl l1 (4 rnethyl-l-piperazinyl)-dibenz [b,f][1,4]-oxazepine is obtained as residue.
  • EXAMPLE 12 5.4 g. of 2-dimethylaminosulphonyl-1l-(l-piperazinyD- dibenz[b,f] [l,4]oxazepine obtained according to Example 50 are dissolved in 50 ml. of acetone and treated with 1 g. of anhydrous potassium carbonate and 2.24 g. of ethyl iodide in 20 ml. of acetone and refluxed for 3 hours while stirring. The reaction mixture is then evaporated in vacuo and the residue distributed between dilute soda lye and ether. The ether extracts are washed with water and exhaustively shaken out with dilute aqueous hydrochloric acid.
  • the acid extracts are made alkaline with concentrated soda lye and shaken out with chloroform.
  • the chloroform extracts are washed with water, dried over 13 sodium sulphate and evaporated to dryness in vacuo.
  • the residue is crystallized from acetone/petroleum ether to give 4.9 g. of Z-dimethylaminoshlphonyl-l1-(4-ethyl-1- piperazinyl)-dibenz[b,f][1,4]oxazepine of melting point 160l61 C.
  • EXAMPLE 14 4 g. of 2-dimethylarninosulphonyl-l l-(4-fi-hydroxyethyll-piperazinyl) -dibenz [b,f] 1,4] oxazepine obtained according to Example 48 are mixed with 30 ml. of absolute EXAMPLE 13 5 pyridine and 15 ml. of acetic anhydride, left to stand for one hour at room temperature and then warmed for a 4.63 g. of the same starting material as in Example 12 short time on the steam bath. The reaction mixture is are dissolved in 80 ml. of isopropanol and treated with evaporated in vacuo and the residue diluted with water. 1.6 g.
  • the products of this invention can be mixed with lactose and granulated with 2 h i p gg g2 methyl 1 Water, 0.5% sodium alginate or 1% gelatine solution.
  • the 15 L pltperazmy 1 H 10Xazepme 70 dried granulate is compressed into tablets in the presence i 5 of about 5% of talcum, 5% of corn starch and 0.1% of s are n 5 magnesium stearate. In this way, there are obtained, e.g. 0 1 tablets of the following composition: agneslum stearate These 90 mg.
  • tablets which are provided with a crackline, can be administered orally in a dosage of one half 2 chloro 11 Y 'P P Y to two tablets one to three times per day in the treatment [EUUAl p 2 of subjects suffering from nausea and vomiting follow- Lactose 34 ing operations or ray treatment or due to stomach or corn Starch 2 metabolism disorders, intoxications, drug incompatability, Talcum 2 pressure on the brain or pregnancy.
  • These tablets may Magneslum m also be used prophylactically against post operative vomit- These 40 mg. tablets possess neuroleptic action. They are w claim: administgred orally in a dPSage of 3 6 tamets 3O 1.
  • oxazepine 30 Lactose 160 Corn starch 10 Talcum 10 Magnesium stearate 0.2 40
  • R is a member of the class consisting of hydro- (C) gen, lower alkyl, lower hydroxyalkyl, acetylated lower M hydroxyalkyl, and alkoxyalkyl having not more than 5 2 nitro 11 (4 methyl 1 piperazinyl)-dibenz carbon atoms; and (B) derivatives of (A) substituted in [b,f] [1,4]oxazepine 25 a benzene nucleus at the 2-position by a member of the Lactose 115 class consisting of halogen, trifluoromethyl, lower alkyl, Corn starch 7,5 lower alkoxy, and lower alkythio; and (C) the non-toxic Talcum 7.5 pharmaceutically acceptable acid addition salts of (A) Magnesium stearate 0.15 and (B)- 2.
  • R' is a member of the class consisting of alkyl Magnesium Steamte 15 having not more than 3 carbon atoms, hydroxyalkyl having not more than 3 carbon atoms, alkoxyalkyl having not These 155 mg.
  • tablets which are provided with a crackmore than 6 carbon atoms and alkoyloxyalkyl having not line, can be administered orally in the dosage of onemore than 6 carbon atoms, and R' is a member of the half to two tablets two to five times, in some cases up group consisting of halogen, lower alkyl, lower alkoxy, to 5 times 4 tablets per day in the treatment of subjects lower alkylthio, and trifluoromethyl; and (B) the nonsuffering from states of mental depression and especially toxic pharmaceutically acceptable acid addition salts of agitated forms of depression. (A).
  • R" is a member of the class consisting of alkyl having not more than 3 carbon atoms and hydroxyalkyl having not more than 3 carbon atoms, and R" is a member of the group consisting of halogen, and methyl; and (B) the non-toxic pharmaceutically acceptable acid addition salts of (A).

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Description

United States Patent Olfice 3,546,226 Patented Dec. 8, 1970 Int. Cl. C07d 51/70 US. Cl. 260-268 9 Claims ABSTRACT OF THE DISCLOSURE (A) ll-basic substituted dibenzoxazepines having the general Formula A:
wherein R is a member of the class consisting of hydrogen, lower alkyl, lower hydroxyalkyl, acetylated lower hydroxyalkyl, and alkoxyalkyl having not more than carbon atoms; and
(B) Derivatives of A substituted in the benzene nuclei by at least one member of the class consisting of halogen, trifluoromethyl, lower alkyl, lower alkoxy, and lower alkylthio; and
(C) ll-basic substituted dibenzoxazepines having the general Formula C:
wherein R represents a member of the group consisting of hydrogen, allyl, alkyl containing not more than 3 carbon atoms, hydroxyalkyl containing not more than 3 carbon atoms, alkoxyalkyl containing not more than 6 carbon atoms and alkoyloxyalkyl containing not more than 6 carbon atoms; and R is a member of the group consisting of nitro, amino, aminosulphonyl of the formula SO NR R wherein R and R are the same or ditferent members of the group consisting of hydrogen and methyl, alkyl-sulphinyl of the formula SOR wherein R denotes alkyl with not more than 3 carbon atoms, and alkylsulphonyl of the formula SO R wherein R, denotes alkyl with not more than 3 carbon atoms; and
(D) The non-toxic pharmaceutically acceptable acidaddition salts of A, B and C.
These compounds have a pronounced therapeutic effect on the central nervous system and are particularly active as nenroplegics, neuroleptics, neuroleptic antidepressants, antimetics, analgesics and sedatives.
This is a continuation-in-part application of our copending patent application Ser. No. 371,123, filed May 28, 1964, and Ser. No. 712,956, filed Mar. 14, 1968 both now abandoned.
The object of the present invention is to provide 11- basic substituted dibenz[b,f][l,4]oxazepines having a pronounced therapeutic effect on the central nervous system.
A further object of the invention is to provide ll-basic substituted dibenz[b,f] [1,4]oxazepines having the abovementioned action of the general formula:
1' 1 i =0 8 9 1o 11 1 l wherein R denotes hydrogen, lower alkyl, lower hydroxyalkyl, acetylated lower hydroxyalkyl, or alkoxyalkyl having not more than 5 carbon atoms, and which compounds are unsubstituted in the benzene nuclei or substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthio; as well as acid addition salts of these basic compounds. Substituents in the benzene nuclei are preferably in the 2-, 4-, or 8-positions. The term lower alkyl etc. is intended to mean alkyl etc. having from 1 to 3 carbon atoms.
A further object of the invention is to provide ll-basic substituted dibenz[b,f] [1,4]oxazepines having the abovementioned action of the general formula:
R2 ii: [N] n=6 {T10 11 1 -R, i7 I l 3 and acid addition salts thereof. In Formula II R: represents hydrogen, allyl, alkyl containing not more than 3 carbon atoms, hydroxy-alkyl containing not more than 3 carbon atoms, alkoxyalkyl containing not more than 6 carbon atoms or alkoyloxyalkyl containing not more than 6 carbon atoms. R denotes nitro; amino; aminosulphonyl of the formula 4O NR R wherein R and R are the same or different and represent hydrogen or methyl; alkylsulphinyl of the formula SOR wherein R denotes alkyl with not more than 3 carbon atoms; or alkylsulphonyl of the formula -SO R in which R represents alkyl with not more than 3 carbon atoms.
The compounds of Formula I are obtained by reacting a reaction mixture containing nitrilium or imonium cations of the formulae:
3 which are unsubstituted in the benzene nuclei or substituted by halogen, trifiuoromethyl, lower alkyl, lower alkoxy or lower alkylthio with piperazine or a piperazine derivative, respectively, of the formula:
Nitrilium or imonium cations of Formulae III can be regarded as dissociation products of corresponding compounds of the formula:
wherein A represents a halogen atom, the sulfhydryl group, or an alkoxy or alkylthio group which is activated if required, e.g., the p-nitrobenzylthio group. Such compounds V are obtained, for instance, by conversion of lactams of the formula: 30
into the thiolactams, if required with subsequent alkylation of the latter, or by reacting the lactams (V1) with a halogenating agent like phosphoroxychloride or phosphorus pentachloride, preferably in the presence of catalytic amounts of dimethylaniline or dimethylformamide. The lactams (VI) can be obtained, for example, by ring closure of suitable o-isocyanato-diphenyl ethers with aluminum chloride. Depending upon the chemical nature 0 of the residue A and also of eventual nuclear substituents, the V compounds in the reaction mixtures obtained are dissociated to a higher or lower degree into the nitrilium or imonium cations, so that the reaction mixtures can be used directly for reacting with piperazine or the piperazine derivative of Formula IV. In part the compounds of Formula V produced in this or in another manner can be isolated in undissociated form and then yield the desired nitrilium or imonium cations (III) upon dissolution in a suitable, preferably polar solvent, if required by heating and in the presence of piperazine or the piperazine derivative of Formula IV, which can also serve as a solvent. Reaction mixtures containing cations of Formula III can also be produced, for example, by intramolecular 60 Ritters reaction (action of a nitrile group on a phenyl cation) in o-cyanodiphenyloxides, by Beckmanns transformation of (if desired suitably substituted) xanthonoximes, or by Schmidts reaction of (if desired suitably substituted) xanthones with hydrazoic acid. Both the 6 last-named reactions may lead, if the starting material consists of unsymmetrically substituted oximes or ketones, to isomeric products which, if necessary, must be subsequently separated. In the said reaction mixtures the anionoid components which may appear are-besides 70 those derived from the substituent A of Formula Vdepending upon the mode of preparation of the cations (III), for example also anions of sulphuric, toluenesulpho, phosphoric, hydrofluoric, or hydrofluoboric acids, etc. 7
4 Compounds of Formula I are also obtained by dehydration of urea derivatives of the formula:
(VII) wherein R has the meaning indicated above, and which are unsubstituted in the benzene nuclei or substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthio, for instance through several hours action by dehydrating agents like Zinc dichloride, aluminum chloride, tin tetrachloride, phosphoric acid and the like, but preferably phosphoroxychloride, if required in the presence of an inert solvent 'with a suitable boiling point, such as benzene, toluene, etc.
Compounds of Formula I are also obtained by ring closure, through intramolecular condensation, of acid amides or thioamides of the formula:
R1 it (VIII) wherein R has the above-mentioned meaning, and Y represents an oxygen or sulphur atom, and which are unsubstituted in the benzene nuclei or substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthio. A purely thermal condensation cannot usually be successfully carried out with the acid amides, which, in turn, are produced, for example, by reduction of suitable nitro compounds, but it can rather in the case of the thioamides, which are obtained, for example, by treating the acid amides with phosphorus pentasulphide and do not require to be isolated prior to the subsequent condensation. Especially in the case of the acid amides it is useful to work in the presence of condensing agents, such as phosphorus pentachloride, phosphoroxychloride, phosgene, polyphosphoric acid, and the like. It is to be supposed that the ring closure involved goes partly through intermediate stages, like imide chlorides, amide chlorides, imidophosphates, amidophosphates or salt-like derivatives thereof, which can not generally be isolated. Condensation of the thioamides may be aided by the presence of mercury salts or by intermediate formation of (if desired activated) imido thio ethers. Heating and, if required, the use of an inert diluent are useful when Working with phosphoroxychloride and phosphorus pentachloride, as also the addition of catalytic amounts of dimethylformamide or dimethylaniline.
Finally, compounds of Formula I can be prepared by reacting primary amines of the formula:
or derivatives thereof substituted in the benzene nuclei, with reactive esters of alcohols having the formula:
OH-GHz-CHz OH-CHZCHZ (2;) wherein R has the meaning identified above. The reaction is carried out following or by simultaneous treat ment with a basic catalyst or metallization agent such as sodamide, lithium amide, sodium hydride, butyl lithium, phenyl sodium, sodium ethylate or potassium-t-butoxide. The primary amines of Formula IV are obtained by treating a reaction mixture containing nitrilium or imonium cations of Formula III with ammonia.
Compounds of Formula I, obtained according to one of the above methods, wherein R represents hydrogen, can be converted to such compounds, wherein R does not represent hydrogen, e.g., by treatment with reactive esters of alcohols of formula R -OH. Hydrohalic acid or toluene sulphonic acid esters are suitable for this purpose.
Compounds of Formula H are obtained when a compound of the formula:
wherein R has the meaning defined above and X denotes a residue capable of being split off with the hydrogen of amines, is reacted with piperazine or a piperazine derivative, respectively, of the formula:
wherein R has the above-mentioned meaning.
A residue capable of being split off with the hydrogen of amines, which can be bound ionically or covalently to the carbon atom, can most conveniently be represented by halogen, sulphydryl, or alkoxy and alkylthio which may be activated, e.g. methoxy, thiomethyl or p-nitrobenzylthio, or by tosyl.
Starting materials of the Formula XI are obtained by converting lactams of the formula:
(XII) (XIV) wherein R has the above-mentioned meaning and R denotes hydrogen or lower alkyl. Lactams of Formula XIII may also be obtained by ring closure of compounds of the formula:
wherein Hal stands for halogen, or of isocyanates of the formula:
NCO
(XVI) (XVII) wherein R and R have the ab0ve-mentioned meaning and Y represents oxygen or sulphur. A purely thermal condensation rarely succeeds with the acid amides but rather with the thioamides which are, for example, obtained from the acid amides by treatment with phosphorus pentasulphide and need not be isolated before the following condensation. Especially in the case of the acid amides it is desirable to perform the ring closure in the presence of condensing agents, such as phosphorus pentachloride, phosphorus oxychloride, phosgene, polyphosphoric acid, and the like. It is assumed that the ring closure proceeds by way of intermediate steps such as imidochlorides, amidochlorides, imidophosphates, amidophosphates or salt-like derivatives thereof, which, in general, are not isolatable. The condensation of the thioamides is favoured by the presence of mercury (-11) salts or by intermediate formation of imidothioethers which may be activated. Heating and, if required, the use of a suitable inert solvent are desirable, and when using phosphorus oxychloride and phosphorus pentachloride addition of catalytic amounts of dimethylformamide or dimethylaniline.
Compounds of Formula II can also be obtained by dehydration of urea derivatives of the formula:
l a /N (XVIII) wherein R has the above-mentioned meaning and R means R or denotes a removable group, especially a hydrolytically removable group. The ring closure is preferably carried out by heating in the presence of dehydrating agents such as zinc chloride, aluminum chloride, stannic chloride, phosphoric acid, polyphosphoric acid and the like, especially phosphorus oxychloride or phosphorus oxychloride and phosphorus pentoxide, if desired in an inert solvent of suitable boiling point such as benzene or toluene etc. According to the chosen reaction conditions the starting materials of Formula XVIH with a hydrolytically removable group R e.g. carbalkoxy, especially carbethoxy, are cyclicized directly to the 11-(1- piperazinyl) compounds by hydrolysis of the removable group. Other removable groups can be split off after ring closure in a way known per se, e.g. by hydrogenolysis.
As long as R does not denote amino, the compounds of Formula H can also be obtained when amidines of the formula:
(XIX) wherein R' represents R with exclusion of amino, are treated with a reactive ester of an alcohol of the formula:
HO-CH2CH2 noorrz-oin wherein R has the above-mentioned meaning. The reaction is carried out following or by simultaneous treatment with a basic catalyst or metallization agent such as sodamide, lithium amide, sodium hydride, butyl lithium, phenyl sodium, sodium ethylene or potassium-t-butoxide. Suitable esters are those of inorganic or organic acids, e.g. hydrohalic acid, sulphonic acid or carbonic acid esters. The required amidines XIX are in turn obtained by treating compounds or Formula XI with ammonia.
On the other hand, compounds of Formula II, wherein R is amino, may be obtained by reduction of the corresponding nitro compounds. The reduction is most suitably carried out by treatment with hydrogen in the presence of a catalyst such as palladium charcoal or Raney nickel or by treatment with stannous chloride and hydrochloric acid.
Compounds of Formula II, wherein R represents alkylsulphinyl or alkylsulphonyl, respectively, can also be obtained by mild (e.g. with periodates) or strong (e.g. with hydrogen peroxide or peracetic acid) oxidation of the corresponding alkylthio compounds. Products wherein R represents alkylsulphonyl are also obtainable by strong oxidation of the corresponding alkylsulphinyl compounds.
Finally, compounds of Formula II, wherein R denotes aminosulphonyl of the formula SO NR R are obtained when the corresponding compounds containing the group --SO X instead of aminosulphonyl, wherein X denotes a residue which is removable with the hydrogen of amines, especially halogen, are reacted with ammonia or an amine of the formula HNR R wherein R and R have the above defined meaning. Starting materials containing a sulphochloride group (-SOgCl) are obtained by diazotization of the corresponding amino compounds followed by the Meerwein reaction.
Compounds of Formula II, obtained according to one of the above methods, wherein R represents hydrogen can be converted to such compounds wherein R does not represent hydrogen, e.g. by treatment with reactive esters of alcohols of the formula R OH. Hydrohalic acid or toluenesulphonic acid esters are suitable for this purpose. An alkyl group R can also be introduced by the method of reductive alkylation, i.e. by reaction with corresponding aldehydes either with hydrogen in the presence of a catalyst with a reducing agent such as formic acid. The introduction of a hydroxyalkyl group R can also be carried out by treating with a corresponding alkylene oxide.
Compounds of Formula II in which R denotes a hydroxy-alkyl group can be subsequently treated with an acylating agent to obtain products wherein R represents an alkoyloxyalkyl group. Acid chlorides and acid anhydrides are especially suitable as acylating agents.
Subsequent introduction of a group R other than hydrogen, and also subsequent acylation of a hydroxyalkyl group R can lead to additional substitution in products in which R denotes an amino group; this amino group being additionally substituted.
The bases I or II obtained in this manner are in most cases crystallizable or can otherwise be distilled in high vacuum without decomposition and react with inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, acetic aid, maleic acid, succinic acid, tartaric acid, toluene sulphonic acid and the like to form addition salts which are stable in water, in which form the products may also be used.
The bases I and II as Well as their acid addition salts are new compounds which can be used as active substances in pharmaceuticals. They produce a favourable 8 effect on the central nervous system and may therefore be used, for example, as neuroplegics, neuroleptics, neuroleptic antidepressants, antiemetics, analgesics and sedatives.
The compounds of Formula I and their acid-addition salts are particularly of interest as neuroplegics, neuroleptics and analgesics. Some of them are suitable for the treatment of psychotic conditions.
Preferred specific compounds are:
l l-(4-methyl-1-piperazinyl) -dibenz [b,f] [1,4] oxazepine, 2-chloro-l l-(4-methyl-1-piperazinyl)-dibenz[b,f] [1,4]
ozazepine, 2-bromo-11-(4-methyl-1-piperazinyl)-dibenz[b,f] [1,4]
oxazepine, 4-chloro-1 1- (4-methyl-1-piperazinyl) )-dibenz [b,f] [1,4]
oxazepine, 2-fiuoro-11-(4-methyl-1-piperazinyl)-dibenz[b,f] [1,4]
oxazepine and 8-chloro-11-(4-methyl-l-piperazinyl)-dibenz[b,f] [1,4] as Well as their acid-addition salts.
oxazepine The utility as neuroplegic or neuroleptic, respectively, manifests pharmacologically e.g. in a supression of locomotor activity, a cataleptic and/or an apomorphine antagonising eflect in mice or rats, respectively. The motility depressing action can be shown by measuring the locomotor activity in accordance with the method of Caviezel and Baillod [Pharm. Acta Helv. 33, 469 (1958)]. In the following Table I, the locomotor activity obtained with some compounds of Formula I, as Well as their toxicity, are compared with the corresponding data of chloropromazine. From Table I it can be seen that the 2-substituted products are the most active.
Compounds of Formula II in which R denotes nitro show also the typical behaviour pattern for neuroleptics. The most effective compounds in this respect are 2-nitro- 11-(4-methyl-1-piperazinyl) dibenz[b,f][1,4]oxazepine, obtained according to Example 5, as well as its acid addition salts.
Other compounds, especially those with ll-(l-piperazinyl) residue show simultaneously the behaviour pattern for neuroleptics and antidepressants whereby the antidepressant action is shown pharmacologically by a tetrabenazine antagonism observed in rats. Especially active in this respect are the compounds 2-nitro-11-(1-piperazinyl)-dibenz[b,f] [1,4]oxazepine obtained according to Example 41 and its acid addition salts.
Compounds of Formula II in which R represents aminosulphonyl or alkylsulphonyl exhibit a marked antiemetic activity. This is shown pharmacologically by a strong apomorphine antagonising elfect in dogs and rats as well as a comparatively weak cataleptic and locomotor activity suppressing eifect. Pronounced antiemetic activity is shown by Z-dimethylaminosulphonyl 11 (4 methyl-l-piperazinyl)-dibenz[-b,f] [1,4]oxazepine and Z-methylsulphonyl-ll-(S-methyl 1 piperazinyl)-dibenz[b,f] [l,4]oxazepine obtained according to Examples 6 or 7, respectively, and their acid addition salts.
The compounds of this invention can be administered in the form of pharmaceutical preparations containing, besides the active substance, organic or inorganic solid or liquid carriers suitable for enteral or parenteral administration. The pharmaceutical preparations may be, for example, in the form of tablets, dragees, or solutions for injection, one dosage unit containing from 1 to 100 mg. of active substance, depending on its nature, on the route of administration and on the physicians prescription, the effective daily dose amounting to from to 500 mg. of active substance.
EXAMPLE 1 3 m1. of N,N-dimethylaniline are poured over gm. of 2-chloro-l0,l1-dihydro-1l-oxo-dibenz[b,f] [1,4] oxazepine and, after adding 80 ml. of phosphoroxychloride, heated for 3 hours under reflux. The reaction mixture is evaporated in vacuo. The residue is suspended in absolute xylol. The residue obtained by re-evaporating the suspension in vacuo, is taken up in 300 ml. of ether and poured over ice/Water. The ethereal phase is separated and washed 3 times with dilute hydrochloric acid, the hydrochloric Washing water being rewashed with ether. The combined ether phases are successively washed with water, sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate, treated with active charcoal, filtered through alumina and largely concentrated by evaporation. Upon adding petroleum ether there are obtained 9.3 gm. (86.5% of the theory) of 2,1l-dichloro-dibenz[b,f] [1,4]oxazepine in the form of yellow needles of melting point 131- 134 C.
9.3 gm. of the 2,11-dichloro-dibenz[b,f] l,4] oxazepine thus obtained are heated in 100 ml. of absolute xylol with 10 ml. of N-methylpiperazine for 4 hours under reflux. The reaction mixture is mixed with water and concen trated soda lye. The aqueous phase is separated and washed with ether, and the ether used for washing is combined with the xylol phase. The organic phase is exhaustively extracted with dilute acetic acid and then with dilute hydrochloric acid. The combined acid extracts are washed with ether, made alkaline with concentrated soda lye and then extracted with ether. The ethereal extract is washed with water and saturated sodium chloride solution, dried over sodium sulphate, treated with active charcoal and evaporated. The residue is taken up in petroleum ether. The solution is filtered through alumina and largely concentrated by evaporation. When the concentrated solution cools down pale yellowish, grainy crystals are formed. There are obtained 8.9 gm. of 2-chloro-ll-(4-methyl-lpiperazinyl)-dibenz[b,f][l,4]oxazepine of melting point 109-110" C.
EXAMPLE 2 8 gm. of 8-chloro-10,1l-dihydro-l1-oxo-dibenz[b,f] [1,4]oxazepine are mixed with 8 gm. of phosphorus pentachloride and, after adding 50 ml. of phosphoroxychloride, heated for 4 hours under reflux. Excess phos phoroxychloride is removed from the reaction mixture by distillation in vacuo. The residue is mixed with xylol, which is removed by evaporation, once again taken up in xylol and poured over ice water. The xylol phase is separated, dried over sodium sulphate, treated with active charcoal, evaporated in vacuo to 100 ml. and, after adding 10 ml. of N-methylpiperazine, heated for 4 hours under reflux. The reaction mixture is mixed with Water and concentrated soda lye. The xylol phase is separated and exhaustively extracted with dilute hydrochloric acid. The hydrochloric extract is washed with ether, made alkaline with concentrated soda lye and then extracted with ether. The ethereal extract is washed with water, dried over sodium sulphate, treated with active charcoal, filtered through alumina and evaporated. The residue is crystallized from methanol, yielding 5.9 gm. of 8-chloro-1l-(4- 10 methyl-l-piperazinyl)-dibenz[*b,f] [1,4] oxazepine in the form of yellow prisms of melting point 165-166 C.
EXAMPLE 3 13.4 gm. of 2-(4-methyl-l"-piperazinyl-carbonylamino)diphenyloxide are heated with 150 ml. of phosphoroxychloride for 30 hours under reflux. The reaction mixture is evaporated in vacuo to dryness. While being cooled the residue is mixed with water and made alkaline with concentrated soda lye. The ethereal extract obtained by shaking twice with ether is washed twice with water and then exhaustively extracted with dilute hydrochloric acid. The combined hydrochloric extracts are washed with ether, made alkaline with concentrated soda lye and extracted twice with ether. The ethereal extract is washed with Water and saturated sodium chloride solution, dried over sodium sulphate, filtered through alumina and evaporated. The residue is crystallized from petroleum ether. 6.2 gm. of 1l-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4] oxazepine of melting point 102-104 C. are obtained.
EXAMPLE 4 8.3 gm. of 2-amino-2'-(4"-methyll-piperazinyl-carbonyl)diphenyloxide are boiled under reflux with 8.5 gm. of finely powdered mercuriacetate in ml. xylene during 24 hours. The reaction mixture is filtered and the filtrate is extracted with dilute acetic acid. The acid solution is treated With ammonia and extracted with ether. The ethereal solution is washed with water, dried over sodium sulphate, filtered through alumina and evaporated. The residue is crystallized from petroleum ether. 4.5 gm. of 11-(4-methyl 1 piperazinyl)-dibenz[b, f] [1,4] oxazepine of melting point 97-98 C. are obtained; the product is identical to that of Example 3.
EXAMPLE 5 4.9 g. of 2-nitro-l0,1l-dihydro-l1-oxo-dibenz[b,f] [1,4] oxazepine (M.'P. 263 C.) and 2 ml. of N,N-dimethylaniline are heated in 60 ml. of phosphorus oxychloride at reflux for 4 hours. The reaction mixture is then evaporated in vacuo to remove the excess phosphorus oxychloride and the residue is decomposed with ice/water and shaken out immediately with chloroform. The chloroform extracts are washed with dilute hydrochloric acid and Water, dried over sodium sulphate and evaporated to dryness in vacuo. The crystalline residue consisting of crude 2-nitro-11-chloro-dibenz[b,f][1,4]oxazepine is heated at reflux for 6 hours with 6 m1. of N-methylpiperazine in 200 ml. of xylene. The organic phase is then shaken out with water and dilute hydrochloric acid. The acid extracts are made alkaline with concentrated soda lye and the base which separates is extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulphate and evaporated to dryness. The residue is crystallized from chloroform/ acetone/ petroleum ether and gives 4.7 g. of 2-nitro-l1-(4-methyl-1-piperazinyl)- dibenz[b,f] [1,4]oxazepine in the form of yellow needles of melting point l92l93 C.
EXAMPLE 6 1.8 g. of Z-dimethylaminosulphonyl-l0,1l-dihydro-l1- oxo-dibenz[b,f][ 1,4]oxazepine (M.P. 243245 C.) and 0.6 m1. of N,N-dimethylaniline are refluxed. in 20 ml. of phosphorus oxychloride for 4 hours. The excess phosphorus oxychloride in removed completely in vacuo and the residue dissolved in xylene and poured onto ice/Water.
form extracts are dried over sodium sulphate and evaporated in vacuo. The residue is crystallized from ether/ petroleum ether whereby 1.8 g. of 2-dimethylaminosulphonyl-l1-(4-Inethyl-1-piperazinyl) dibenzyl[b,f] [1,4] oxazepine of melting point 149150 C. are obtained.
EXAMPLE 7 g. of 2-methylsulphonyl-10,1l-dihydro-1l-oxo-dibenz- [b,f][l,4]oxazepine (M.P. 242-244" C.) and 1.8 ml. of N,N-dimethylaniline are refluxed in 50 -ml. of phosphorus oxychloride for 5 hours after which the reaction mixture is evaporated to dryness in vacuo. The residue is treated with xylene, once again evaporated and then dissolved in xylene and poured onto ice. The aqueous phase is shaken out three times with xylene. The combined xylene extracts are washed with dilute hydrochloric acid, water and aqueous sodium chloride solution, dried over sodium sulphate, treated with active charcoal and filtered through a small amount of aluminum oxide. The filtrate is concentrated and then refluxed with 12 ml. of N-methylpiperazine for 6 hours. The reaction mixture is treated with water and concentrated soda lye and shaken out twice with ether. The ether extracts are washed several times with water and then shaken out with dilute hydrochloric acid. The acid extracts are made alkaline and extracted twice With ether. The ether phase is washed with water and aqueous sodium chloride solution, dried over sodium sulphate, treated with active charcoal and filtered through a small amount of aluminum oxide. The filtrate is concentrated and treated with petroleum ether. The crystals which precipitate are dissolved in acetone and, after concentrating, recrystallized by addition of ether/petroleum ether. 5.8 g. of 2 methylsulphonyl-l1-(4-methyl-l-piperazinyl)-dibenz[b,f][1,4]oxazepine in the form of slightly yellow needles of melting point 178179 C. are obtained.
EXAMPLE 8 3 g. of 2-(4"-methyl-1"-piperazinyl-carbonylamino)-4- methylsulphonyl-diphenyloxide (M.P. 145146 C.) and a mixture of 2 g. of phosphorus pentoxide and 10 ml. of phosphorus oxychloride are refluxed for 24 hours. The excess phosphorus oxychloride is then distilled off in vacuo and the residue decomposed with ice/water. The solution obtained is made alkaline with concentrated soda lye and shaken out with ether. The ether extracts are washed with water and shaken out thoroughly with dilute hydrochloric acid. The acid extracts are made alkaline with concentrated soda lye and shaken out with chloroform. The chloroform extracts are washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The residue is crystallized from acetone/petroleum ether and gives 1.5 g. of Z-methylsulphonyl-l1(4-methyl-1-piperazinyl)-dibenz[b,f] [l,4]oxazepine of melting point 178- 179 C. identical to the product obtained according to Example 7.
EXAMPLE 9 15.2 g. of 2-nitro-11-(4-methyl-1-piperazinyl)-dibenz- [b,f][1,4]oxazepine obtained according to Example 5 are hydrogenated with hydrogen in the presence of 1 g. of 5% palladium-charcoal in 450 ml. of methanol at normal pressure. After take-up of 3.05 l. of hydrogen the hydrogenation is discontinued and the reaction mixture filtered to remove the catalyst. The filtrate is evaporated in vacuo and the residue taken up in chloroform, filtered through aluminum oxide and concentrated. On addition of petroleum ether crystals are formed which are separated and recrystallized from chloroform/ ether/ petroleum ether. 14.1 g. of 2-amino-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine of melting point 153-156" C. are obtained.
EXAMPLE 10 The free base obtained from 6.83 g. of 2-thiomethyl-ll- (4-methyl-l-piperazinyl)-dibenz[b,f] [1,4] oxazepine maleate (M.P. 19820l C.) is dissolved in ml. of water and 10 ml. of glacial acetic acid. This solution is treated dropwise while stirring at 0 C. with a solution of 3.42 g. of sodium metaperiodate in 10 ml. of water. After the addition is complete the reaction mixture is left to stand at room temperature for 24 hours, then made alkaline with concentrated soda lye and shaken out with ether. The ether extracts are washed with water and then exhaustively shaken out with dilute hydrochloric acid. The acid extracts are made alkaline with concentrated soda lye and shaken out with chloroform. The chloroform extracts are washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The residue is dissolved in acetone and treated with 1.8 g. of maleic acid. After concentration and addition of ether crystals precipitate which are recrystallized from methanol/acetone/ ether to give 6.0 g. of Z-methylsulphinyl-l1-(4-methyl-1- piperazinyl)dibenz[b,f][l,4]oxazepine maleate of melting point 206-207 C.
EXAMPLE 1 1 A solution of 5.2 g. of crude 2-chlorosulphonyl-11-(4- methyl 1 piperazinyl) dibenz[b,f] [l,4]oxazepine, obtained as described below, in ml. of chloroform is treated dropwise at room temperature with 50 ml. of a 10% dimethylamine solution in toluene. The reaction mixture is stirred for a further 2 hours at room temperature, then for 1 hour at 40 C. and finally evaporated to dryness in vacuo. The residue is taken up in dilute acetic acid, treated with active charcoal and made alkaline with concentrated ammonia solution. The base which separates is taken up in benzene, the benzene solution washed three times with water, dried over sodium sulphate and evaporated. The residue is taken up in benzene and filtered through basic aluminium oxide. The residue obtained after evaporation of the solvent is crystallized from acetone/ petroleum ether to give 3.2 g. of Z-dimethylaminosulphonyl-11-(4 methyl-l-piperazinyl) dibenz[b,f][1,4] oxazepine of melting point 148150 C. which is identical to the product obtained according to Example 6.
2-chlorosulphonyl-l l- (4 methyl-l-piperazinyl)-dibenz- [b,f][1,4]oxazepine used as starting material is obtained as follows:
15.4 g. of 2-amino-l1-(4-methyl-l-piperazinyl)-dibenz-[b,f] [l,4]oxazepine (M.P. 153l56 C.) are dissolved in 50 ml. of glacial acetic acid and 15 ml. of 38% hydrochloric acid and diazotized in the usual manner at 0-5 C. with a solution of 3.6 g. of sodium nitrite in 6 ml. of water. The diazonium solution obtained is added within a few minutes while stirring at 10 C. to 40 ml. of a 30% solution of sulphur dioxide in glacial acetic acid containing 2 g. of cuprous chloride. After the development of nitrogen subsides at room temperature the reaction mixture is warmed for 15 minutes at 40 C. The reaction mixture is then diluted to 1:1 with Water and treated with active charcoal. While stirring and cooling carefully, the basic fraction is precipitated with concentrated soda lye and taken up in chloroform. The chloroform extracts are washed once with dilute soda lye and once with Water, dried over sodium sulphate and evaporated. Crude 2- chlorosulphonyl l1 (4 rnethyl-l-piperazinyl)-dibenz [b,f][1,4]-oxazepine is obtained as residue.
EXAMPLE 12 5.4 g. of 2-dimethylaminosulphonyl-1l-(l-piperazinyD- dibenz[b,f] [l,4]oxazepine obtained according to Example 50 are dissolved in 50 ml. of acetone and treated with 1 g. of anhydrous potassium carbonate and 2.24 g. of ethyl iodide in 20 ml. of acetone and refluxed for 3 hours while stirring. The reaction mixture is then evaporated in vacuo and the residue distributed between dilute soda lye and ether. The ether extracts are washed with water and exhaustively shaken out with dilute aqueous hydrochloric acid. The acid extracts are made alkaline with concentrated soda lye and shaken out with chloroform. The chloroform extracts are washed with water, dried over 13 sodium sulphate and evaporated to dryness in vacuo. The residue is crystallized from acetone/petroleum ether to give 4.9 g. of Z-dimethylaminoshlphonyl-l1-(4-ethyl-1- piperazinyl)-dibenz[b,f][1,4]oxazepine of melting point 160l61 C.
14 EXAMPLE 14 4 g. of 2-dimethylarninosulphonyl-l l-(4-fi-hydroxyethyll-piperazinyl) -dibenz [b,f] 1,4] oxazepine obtained according to Example 48 are mixed with 30 ml. of absolute EXAMPLE 13 5 pyridine and 15 ml. of acetic anhydride, left to stand for one hour at room temperature and then warmed for a 4.63 g. of the same starting material as in Example 12 short time on the steam bath. The reaction mixture is are dissolved in 80 ml. of isopropanol and treated with evaporated in vacuo and the residue diluted with water. 1.6 g. of anhydrous potassium carbonate, then, While The basic fraction is precipitated in the cold with constirring and heating, treated dropwise with 3 g. of [3- centrated soda lye and exhaustively extracted with ether. methoxyethyl-p-toluene snlphonic acid ester in 10 ml. of The ether phase is washed with water, dried over sodium isopropanol. After the addition is complete the mixture sulphate and evaporated. The residue is dissolved in aceis refluxed for 1.5 hours, then evaporated in vacuo. The tone and treated with 1.8 g. of maleic acid. After concenresidue is partitioned between dilute soda lye and ether tration of the solution and addition of ether crystals and the ether extracts exhaustively shaken out with dilute 15 precipitate Which are recrystallized from acetone/ ether to hydrochloric acid. The acid extracts are made alkaline give 3 g. of Z-dimethylaminosulphonyl-ll-(fi-acetoxy- With-concentrated soda lye and shaken out with ether. The ethyl-l-piperazinyl)-dibenz[b,f] [1,4] oxazepine maleate of ether extracts are washed with water, dried over sodium melting point 155158 C. sulphate and evaporated in vacuo. The oily residue is dis- In a like manner as in the examples previously mensolved in warn acetone together with 1.2 g. of maleic acid tioned there are obtained from the corresponding starting and crystallized by addition of ether. 4.9 g. of 2-dimethylmaterials the products listed in the following Table II. R aminosulphonyl-ll-(4-fi-meth0xyethyl l piperazinyl)- or R respectively, has the same meaning as mentioned dibenz[b,f] [1,4]oxazepine maleate of melting point 124- above. In the last column a means acetone, e ether, ch 140 C. (decomposition) are obtained. chloroform, m methanol and p petroleum ether.
TABLE II Substltuents in the hen- R1 or R2 respectively zene nuclei Physical constants --CHs 7-01 M.P. of the base: 147l48 C.
(from 1)). CH; 2,8-dich1oro M.P. of the base: -131 0.
(rom e/p). CH3 4,841ichloro M.P. of the base: 134-135 G.
(from e/p). OH3 4-OH3 M.P. of the base: 179-182 C.
(from a p CH3 2-CH3 M.P. of the base: ISO-131 C.
(from e/p). -CH3 4-01 M.P. of the base: 173-174 c.
(from a/p). CH3 6-01 of the base: 8387 0.
rom CH3 3-CH3 M.P. of the base: 103105 C.
(from e p -OH3 2-Br of the base: 95-99 C tom -CH3 3,4-dlmethyl M.P. of the base: 167168 C.
. (from a/p). CH3 2-F M.P. of the base: 8l86 C.
(from 1)). -CH3 1, -dimethy1 M.P. of the base: 143-144D C.
(from 2/11). CH [3-01 M.P. er the base: 122-124. 0.
(frome (CH2)201 [2-01 M.P. of the dlhydrochlorlde:
197-237 o. (from m/e). OH 4-03 8-01 M.P. or the base: 151-152 C (from 6/1 H 2-C1 M.P. of the base: 178180 C.
(from a/p CE; 2-0011; M.P. of the base: 107-108" C.
(from 2/1)). CH3 4-0 11 M.P. of the base: 128-130 C.
(from e/p). CH3 2, 4-dichloro M.P. of the base: 138 C.
(from 0/1) CH 4-011 7-61 M.P. oi the base:167168 C.
(from a/e). CH2CH2OCOCH3 2-01 M.P. of the dihydrochloride:
15/53l60" G. (from ethyl acetate m e M.P. of the maleate: 180181 C.
CH 2-SGH M.P. of the maleate: 198-201 C.
(from ethanol/a/e).
H Z-SCH M.P. of the base: 114-116" C.
(from a/p).
CH 2-SC H M.P. of the base: 117119 C.
(from e/p).
H 2-SC2H M.P. of the maleate: 161162 C.
(from m e H 2-NO; M.P. of the base: 192 C.
(from a/p).
OH2CHz 0H 2-NO M.P. of the maleate: 155156 C.
(from m/a) H Z-SOzCHa M.P. of the base: 189-191 C.
(from ale/p).
H 2-NH M.P. of the base: 181-183 C.
(from ethyl acetate/e) OH 28020111 M.P. of the base: 196197 C.
(from c/p) 46 H 2-SO2C2H M.P. of the base: Bil-133 C.
(from a/p) '16 TABLE II.Co'ntin ued Substituents in the ben- Example R1 or R2 respectively zone nuclei Physical constants 47 OH2OH2o0H 2-N02 MP. of the base: 102-104 C.
(from e/p). 4s -OH2CH2-OH 2-sOzN(CHa)z M.P. of the basez164-166" C.
(from ale/p). 49 CH2CH=CH 2-SO N(CI-Ia)z M.P. oftho base: 150151 0.
(from a/p). 50 H 2-SO;N(OH MP. of the base:181182 0.
(from a/p) Production of tablets (E) M For the manufacture of tablets, the products of this invention can be mixed with lactose and granulated with 2 h i p gg g2 methyl 1 Water, 0.5% sodium alginate or 1% gelatine solution. The 15 L pltperazmy 1 H 10Xazepme 70 dried granulate is compressed into tablets in the presence i 5 of about 5% of talcum, 5% of corn starch and 0.1% of s are n 5 magnesium stearate. In this way, there are obtained, e.g. 0 1 tablets of the following composition: agneslum stearate These 90 mg. tablets, which are provided with a crackline, can be administered orally in a dosage of one half 2 chloro 11 Y 'P P Y to two tablets one to three times per day in the treatment [EUUAl p 2 of subjects suffering from nausea and vomiting follow- Lactose 34 ing operations or ray treatment or due to stomach or corn Starch 2 metabolism disorders, intoxications, drug incompatability, Talcum 2 pressure on the brain or pregnancy. These tablets may Magneslum m also be used prophylactically against post operative vomit- These 40 mg. tablets possess neuroleptic action. They are w claim: administgred orally in a dPSage of 3 6 tamets 3O 1. A compound selected from the class consisting of for the treatment of agitated conditions in psychotic (A): 11 basic Substituted dibenznoi] [1,410XaZePines Patlents' having the general Formula A:
Mg. R1 11 (4 methyl 1 piperazinyl)-dibenz-[b,f][1,4] I
oxazepine 30 Lactose 160 Corn starch 10 Talcum 10 Magnesium stearate 0.2 40
These 210 mg. tablets possess neuroleptic action. They are administered orally in a dosage of 5 to 10 tablets per day for the treatment of agitated conditions in psychotic patients. wherein R is a member of the class consisting of hydro- (C) gen, lower alkyl, lower hydroxyalkyl, acetylated lower M hydroxyalkyl, and alkoxyalkyl having not more than 5 2 nitro 11 (4 methyl 1 piperazinyl)-dibenz carbon atoms; and (B) derivatives of (A) substituted in [b,f] [1,4]oxazepine 25 a benzene nucleus at the 2-position by a member of the Lactose 115 class consisting of halogen, trifluoromethyl, lower alkyl, Corn starch 7,5 lower alkoxy, and lower alkythio; and (C) the non-toxic Talcum 7.5 pharmaceutically acceptable acid addition salts of (A) Magnesium stearate 0.15 and (B)- 2. A compound selected from the consisting of (A): These 155 mg. tablets, which are provided with a crack- 11 basic substituted dibenz[b,f][1,4]oxazepines having line, can be administered orally in a dosage of one half the general Formula A: to two tablets two to four times per day in the treatment R5 of subjects suffering from any form of schizophrenia, any I form of mania, severe psychotic and non-psychotic states N of excitement, chorea, athetosis, and extrapyramidal movement disorders.
(D) N 2 2 nitro 11 (1 piperazmyl) d1benz[b,f][1,4]
oxazepine 2O Lactose 120 Corn starch 7.5 T l 75 wherein R' is a member of the class consisting of alkyl Magnesium Steamte 15 having not more than 3 carbon atoms, hydroxyalkyl having not more than 3 carbon atoms, alkoxyalkyl having not These 155 mg. tablets, which are provided with a crackmore than 6 carbon atoms and alkoyloxyalkyl having not line, can be administered orally in the dosage of onemore than 6 carbon atoms, and R' is a member of the half to two tablets two to five times, in some cases up group consisting of halogen, lower alkyl, lower alkoxy, to 5 times 4 tablets per day in the treatment of subjects lower alkylthio, and trifluoromethyl; and (B) the nonsuffering from states of mental depression and especially toxic pharmaceutically acceptable acid addition salts of agitated forms of depression. (A).
17 3. A compound selected from the class consisting of (A): ll-basic substituted dibenz[b,f][1,4]oxazepines of the Formula A:
wherein R" is a member of the class consisting of alkyl having not more than 3 carbon atoms and hydroxyalkyl having not more than 3 carbon atoms, and R" is a member of the group consisting of halogen, and methyl; and (B) the non-toxic pharmaceutically acceptable acid addition salts of (A).
4. 11 4 methyl 1 piperazinyl) dibenz[b,f] [1,4] oxazepine and its non-toxic pharmaceutically acceptable acid addition salts.
5. 2 chloro 11 (4 methyl 1 piperazinyl)-dibenz [b,f] [1,4]oxazepine and its non-toxic pharmaceutically acceptable acid addition salts.
18 6. 2 bromo 11 (4 methyl 1 piperazinyl)-dibenz [b,f] [1,4]oxazepine and its non-toxic pharmaceutically acceptable acid addition salts.
7. 4 chloro 11 (4 methyl 1 piperazinyD-dibenz [b,f] [1,4] oxazepine and its non-toxic pharmaceutically acceptable acid addition salts.
8. 8 chloro 11 (4 methyl l piperazinyl)-dibenz [b,f] [1,4]oxazepine and its non-toxic pharmaceutically acceptable acid addition salts.
9. 2 fluoro 11 (4 methyl 1 piperazinyD-dibenz [b,f] [1,4]oxazepine and its non-toxic pharmaceutically acceptable acid addition salts.
References Cited UNITED STATES PATENTS 3,107,261 10/1963 Gerber et al. 260153 3,347,849 10/1967 Schmutz 260239 3,412,193 11/1968 Coppola 260268X 3,444,169 5/1969 Howell 260268 DONALD G. DAVIS, Primary Examiner US. Cl. X.R.
US797281A 1963-03-01 1969-02-06 11-basic-substituted dibenzoxazepines Expired - Lifetime US3546226A (en)

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CH1190763A CH450422A (en) 1963-09-27 1963-09-27 Process for the preparation of 11-basic substituted dibenz (b, f) (1,4) oxazepine
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CH676263A CH436297A (en) 1964-05-27 1964-05-27 Process for the preparation of 11-basic substituted dibenz (b, f) - (1,4) oxazepine
CH358267 1967-03-13
CH410367A CH481133A (en) 1967-03-22 1967-03-22 Process for the preparation of basic substituted heterocycles
CH655767A CH484924A (en) 1967-05-09 1967-05-09 Process for the preparation of basic substituted heterocycles
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US3697523A (en) * 1968-08-23 1972-10-10 Sandoz Ltd 2-substituted-11-(4-methyl-1-piperizinyl)-dibenzo {8 b,f{9 -1,4-oxazepin-(4-oxide)
US3717637A (en) * 1969-08-06 1973-02-20 Sandoz Ag TRIFLUOROMETHYLTHIO SUBSTITUTED DIBENZ [b,f] [1,4] OXAZEPINES
US3723466A (en) * 1969-06-20 1973-03-27 En Nom Collectif Science Union Tricyclic compounds
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US3697523A (en) * 1968-08-23 1972-10-10 Sandoz Ltd 2-substituted-11-(4-methyl-1-piperizinyl)-dibenzo {8 b,f{9 -1,4-oxazepin-(4-oxide)
US3723466A (en) * 1969-06-20 1973-03-27 En Nom Collectif Science Union Tricyclic compounds
US3761481A (en) * 1969-07-31 1973-09-25 Yoshitomi Pharmaceutical 11-(4-heterocyclic alkyl substituted-1-piperazinyl) dibenzooxazepines
US3717637A (en) * 1969-08-06 1973-02-20 Sandoz Ag TRIFLUOROMETHYLTHIO SUBSTITUTED DIBENZ [b,f] [1,4] OXAZEPINES
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