IL27537A - Basically substituted oximes of 6,11-dihydrodibenzo-(b,e)-oxepinor-thiepin-11-ones and their production - Google Patents

Description

Basically substituted of or and their the invention consists in new basically substituted of or or salts thereof with pharmaceutically acceptable organic and organic acids o the formula in which is oxygen or is lower or lower A is a straight or branched chain of 2 6 carbon and and are each individually hydrogen or or and form together with the nitrogen atom to they are attached a saturated heterocyclic ring optionally interrupted by a nitrogen It is known that the reaction of or with magnesium halides leads to or which yield the corresponding compounds by elimination of water Stach and is also known that the basic alkylation of of yields compounds having psychotropic action patents It has now been found that compounds of formula I above can be produced by reacting oxepinones and with or their or converting and thieplnones with into and the reactive esters of Typical compounds are and process according to the invention an or thiepinone of the la is reacted with an of the formula 0 A in which and X have the same meaning as in I above or with a salt of the formula another process according to the invention an oxepinone or thiepinone of formula II above is reacted with to form an of the and the latter is treated with a reactive ester of a t A in which formulae and 1 have the above meanings 1 is radical of a reactive a halogen atom radical of a sulphuric acid or sulphonic acid It must regarded as surprising that the processes described above should because a cation in the journal states that and cannot be reacted with ketone The reaction of the oxepinones or thiepinones of the formula II with the of the formula or their salts is carried out at an acid Suitable solvents for reaction inter alcohols such as ethanol or aliphatic or aliphatic ethers such as diethyl or and mixtures of these In the operation lis carried out at the boiling temperature of these The pH value can be for by gaseous hydrochloric acid or by adding a solution of hydrogen chloride in the solvent The or of formula are preferably prepared by reacting the oxepinones or thiepin ones of formula II with an excess of hydrox hydrochloride in For this the reaction mixture is heated at boiling temperature for several but it is also possibl to work at higher temperatures in a pressure The basic alkylation of the oximes of the formula IV with the reactive esters of of the formula V can be carried inter in in alcohols such as ethanol or in aliphatic ketones such as acetone or methyl ethyl in aliphatic or aromatic in aliphatic or cycloaliphatic and in mixtures of these For this the oximes of the formula IV are previously converted into their alkali metal salts by means of an alkali metal alkali metal alkali metal alkali metal alcoholate or alkali metal In the reaction is carried out at the boiling temperature of the The process according to the invention also comprises the production of pharmacologically compatible salts of the basically substituted oximes of or of the formula I with inorganic such as hydrochloric hydrobromic sulphuric acid and phosphoric and with organic acids such as lactic maleic tartaric acid and citric The compounds which can be produced according to the invention have remarkable pharmacodynamic properties and are useful as therapeutical agents for the treatment of as They can be applied in the treatment of all kinds of manic depressive neurotic depressed conditions and stages of The can be administered orally and parenterally and The dosage in a single oral and shall not exceed 25 to and the daily dosage shall not exceed 400 mg orally and 0 mg EXAMPLE 1 21 of and g of amine are dissolved in 400 ml of the solution is acidified with ethanolic hydrochloric acid until the pH is 3 and subsequently boiled under reflux Another g of are then the reaction mixture is again adjusted to pH 3 with ethanolic hydrochloric acid and boiled under reflux for a further 24 hours The alcohol is subsequently distilled off in a vacuum and the residue is stirred with water for several hours The undissolved matter is then filtered off with suction g of the filtrate is rendered alkaline with a sodium hydroxide solution and the precipitated base is taken up with The ether phase is dried with sodium evaporated and the residue is distilled in a g of of oxepine of C H N C H N The hydrochloride is prepared in methyl ethyl ketone with ethereal hydrochloric Melting point indistinct at 176 to The following compounds are also prepared according to Example By reacting one with Melting point 114 to yield of theory The in acetone with ethereal hydrochloric is comparatively sparingly soluble in water and crystallizes from water as the Melting point 186 to H20 C H N H20 C H N By reacting with Boiling 202 to mm yield of N 0CH3 N salt Melting point of the to C By reacting with Boiling point 201 to mm yield 61X of C H N C N salt The prepared in acetone with ethereal hydrochloric Melting point 176 to By reacting with salt The prepared in acetone with ethereal hydrochloric Melting point 189 to of N total N total By reacting with salt Melting point of the at 226 to N N EXAMPLE 2 Grams of 6 are reacted in analogy with Example 1 in ethanol at pH 3 first with g after boiling with a further g of The reaction mixture is worked up as described in Example 1 and g of thiepinone of are first The residue of the ether phase is distilled in a 198 mm g of of C N S C H N S salt The prepared in methyl ethyl ketone with ethereal hydrochloric Melting point indistinct at 136 to The following compounds are also prepared according to Example By reacting one with Boiling point 190 to mm of C H N S C H N S salt The hydrochloride prepared in acetone with ethereal hydrochloric Melting point 208 to By reacting one with Boiling point 196 to mm of C H N S C H N The hydrochloride is prepared in methyl ethyl ketone with ethereal hydrochloric Melting point 199 to C By reacting with The crude base could be divided by fractional crystallization from petroleum ether into the a more sparingly soluble fraction of melting point 118 to about of r N S CI N S CI and a more readily soluble fraction of melting point 70 to about of N S CI By reacting with Boiling point 219 to mm of N S N S salt The prepared in methyl ethyl ketone with ethereal hydrochloric Melting point ethyl 174 to By reacting with dihydr salt Melting point of the 214 to C 2OS N S N S By reacting with salt Melting point of the 251 to C N S CI total N S total EXAMPLE 3 Grams of and g of hydroxylamine hydrochlorid are boiled under in 100 ml of pyridine or 3 days The pyridine is subsequently distilled off in a the residue is triturated with dried crystallized from g of of melting point 201 to C H C H N Grams of this oxime are added with stirring to a solution of g gram of sodium in of chloride are added and the mixture is boiled under reflux for 5 hours The solvent is then distilled off in a the residue stirred with the water and the ether phase is dried and The residue is dissolved in acetone and the salt chloride precipitated with ethereal hydrochloric It can be recrystallized from g of According to the spectrum and the melting the substance is identical with the hydrochloride obtained in Example By preparing one in analogy with Example 3 and this with there is obtained salt Melting point of the 170 to C H N C H N EXAMPLE 4 Grams of and g of hydrochloride are boiled under reflux in 100 ml of pyridine for 24 The pyridine is subsequently distilled off in a the residue is triturated with dried and crystallized from Melting point 223 to g of of C H S C H N S Grams of this oxime are added with stirring to a solution of g gram of sodium in 200 ml of When a clear solution has g of chloride are added and the mixture is boiled under reflux for 5 hours The ethanol ia subsequently distilled off in a the residue stirred with water and the ether phase is dried and The residue is twice distilled in a Boiling point 196 to mm g of According to the spectrum of the base and salt the melting point of the hydrochloride the substance is identical with the described in Example insufficientOCRQuality

Claims (1)

1. Basically substituted of or and their pharmacologic cally acceptable salts inorganic or organic of the formulas o A in which X oxygen or is lowe or lower A is a straight or branched chain of 2 to 6 carbon and and are or or form together wi the nitrogen to which they are attached a heterocyclic optionally by a nitrogen 17 di hydrochloride A process for production of basically aubstit of or ones of formula I in Claim reacting an or of V 0 an of the formula A which formulae and X have the same meaning as in Claim or with a salt of the of formula and if converting a free into an aeid addition A process for the production of basically substituted of or of formula I in Claim which reacting an oxepinone or thiepinone o the formula in 17 to form an of the and reacting the latter with a reaetive ester of a of the formula Z A in formulae the meaning as in Claim 1 and is the radical of a reactive including a halogen atom or the radical of a acid or 19 acid if converting a into an acid addition Processes for the preparation of basically substituted oxiraes of or and their pharmacologically acceptable salts with inorganic or organic substantially as described herein with reference to the Pharmaceutical compositions for the treatment of containing as an active ingredient a compound of formula I in Claim 1 or a pharmaceutically acceptable acid addition salt For insufficientOCRQuality