Procedure for the production of new Azepinderivaten and their acid addition salts

The available invention concerns a procedure for the production of new Azepinderivaten. Connections of the general formula I: in which R-S R3 (I) a low Alkygruppe, hydrogen or a low alkyl group, a low Alkygruppe, and a low alkyl group finally means or together with R a group of alkyls with (3-n) or (4-11) Kettengliedem or together with RA a group of alkyls with 4--6 Kettenlo arranged form, m 1 or 2, n 0.1 or 2 and (ra+n) 1.2 or 3 is, and their acid addition salts are so far do not admit become. i like now was found, possesses these connections and their addition salts with inorganic and organic acids valuable pharmakologische characteristics. They potemäeren among other things the effect of Catecholaminen and antagonisieren the effect of reserpine. The pharmakologischen Beftmde characterizes Azepindedvate of the general formula I and its acid addition salts, which antriebsfördemden because of its s timmung8hebenden and effect alone or in combination with other Pkarmaka for the treatment are suitable by mind depressions. In the connections of the general formula I R” R-S, RA and R can be as low alkyl groups methyl, ethyl, n-Propyl, Isopropyl, n-Butyloder Isobutylgruppe. Under itself connected Raund R - groups e.g. are as alkyl remainders. Ring members of the 2-Pyrrolidinyl, 1-Methyl-2-pyrrolidinyl, 1-Arhyl-2-pyrrolidinyl, 3-Pyrrolidinyl, 1-Methyl-3-pyrrolidinyl, l-Athyl-3-pyrrolidinyl, 2-Iäperidyl, 2 1-Methyl-2-piperidyl, 1thyl-2-piperidyl, 3-Piperidyl, l-Merhyl-3-piperidyl, 1-Ethyl-3-piperidyl, 4-Piperidyl, l-Methyl-4-piperidyl-oder 1-Ethyl-4-piperidylgruppe. Finally R-S and I as well as the lying close nitrogen atom can be connected to the 1-Pyrrolidinyl, Piperidinooder Hexahydro-lH-azepin-1-1-gruppe. Connections of the general formula I can be manufactured, by one a connection of the general-common formula: I H (ii) into which g 1 the meaning indicated by formula I has, in presence of a basic KondensaUonsmittels with a reaktionsf'ähigen more £ster an amino-alcohol of the general formula III: jRs HO--(CH2) m--CH--(CH2) n--lq ((II) in which RA, R3, R4, m and n the meaning indicated by formula I have, converts, and gewünschtenfalls into a salt with an inorganic or organic ù " acid transfers the received connection of the general formula. When Kondensaüonsmittel are suitable in particular sodium amide, lithium amide, potassium amide, sodium, potassium, lithium, Butyllithium, Phenylüthium, sodium tert. butylat, lqatriumhydrid or lo Lithhlmhydrid. The conversion, at the one reaction temperature of about 75--150 ° C is kept, can in Anoder absence of an inert organic solvent, like e.g. Benzene, toluol, xylene, Cumol, tetralin or dimethylformamide, to be accomplished. At basic materials of the general formula II one arrives for example, by one a 3-Amino-5acyl-10,11-dihydro-5H-dibeuz [b, f] azepin däazoüert and the received Diazoniumsalz transfers ii-chloride and sulfur dioxide by Kupferss in a 3-Chlorsulfonyl-5-acy1-10,11-dihydro-5H-dibenz [b, f] azepin, soft one with hydriodic acid at a until (5-acyl-10,11-dihydro-5Hdibenz [b, f] azepin-3-yl) - disulphide reduces. The received disulphide is reduced far with glucose to a 5-Acyl-10,11-dihydro-5H-dibeuz [b, f] azepin-3-rhiol, which entacyliert the latters in the same processing step with an alkyl halide to a 3-Alkylthio-5-acyl-10,11-dihydro-5H-dibenz [b, f] azepin alkylated, this ae with Perjodsäure or a Iöslichen Perjodat oxidized and the received 3-Alkylsulfinyl-verbindung with Kaliùmhydroxyd. As examples of basic materials of the general formula II the 3-Methylsul nyl, 3thylsn are mentioned] finyl, 3-Fropyisulfinylund 3-Isopropyls lfinyl-10,11-dihydro-SH-dibenz [b, f] azepin. As reaktionsf'ähige esters of Arnlnoalkoholen of the general formula III is possible in particular the 2s of halides, in detail is mentioned: 2-Dimethy mino ärhylchlorid, 2-Diärhylaminoäthylctflorid, 2-Methyläthy] srninorhylchlorid, 2-Dimethyl mino propylchlorid 3-Dimethylamino-propylchlorid, 3-Dimerhylamino-butylchlorid, 4-Dimer.hylamino-butylchlorid, 3-Dimethylamino-2-methylpropylchlorid, 2-Dipropylnm NO ethyl chloride, 2-Methyl-isopropylnmlno-ärhylchlorid, 1 (2-Chloräthyl) - pyrrolidin, 1 (3-Chlorpropyl) - pyrrolidin, 1 (2-Chloräthyl) - piperidin, 1 (3-Chlorpropyl) - piperidin, 2so (2-Chloräthyl) - l-merhyl-pyrrolidin, 2 (2-Chloräthyl) - l-merhylpiperidin, 3-Chlormethyl-l-methyl-piperidin, 1 (3-Chlorpropyl) - hexamethylenimin and 1 (5-Chlor-2-merhyl-propyl) - hexamethylenlmin as well as appropriate bromide, iodides and p-Toluolsulfonsäureester. According to invention the Azepinderivate of the general formula I received in the procedure is transferred afterwards gewiinschtenfalls in usual way into its Additiomsalze with inorganic and organic acids. BeispieIsweise shifts one a solution of a Azepinderivates of the general formula I in an organic solvent with the acid wished as salt component or with a solution the same. Preferably one selects organic solvents for the conversion, in which the developing salt is with difficulty soluble, so that it can be separated by filtration. Such solvents e.g. are. Methanol, methanol Ärher or ethanol ether. For use as active substances of drugs non-toxic acid addition salts can be inserted, i.e. salts with such acids to steep ones of free bases, whose anions are pharmaceutical acceptable with the which are applicable dosages. Furthermore it is of advantage, if aIs the active substances are a little hygroscopic salts which can be used well crystallizable and not or. For the seeing formation with Azepinderivaten of the general formula I can be e.g. used the hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfone acid, 1,2-Ärhandisulfonsäure, 2-Hydroxyäthansulfonsäure, acetic acid, ÄpfeIsäure, tartaric acid, Citronensäure, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, Salicylsäure, Phenylessigsäure, almond acid and t] mbonsäure. The new Wkkstoffe is parenterally given by-orally, rektal and. The daily doses of the free o bases or of non-toxic salts derseIben move between 10 and 800 mg for adult patient. Suitable dose unit forms, like dragees it, TabIetten, Suppositorian or ampuls, preferably contain 5--50 mg available of a according to invention Azepinderivates or a non-toxic salt of the same. Furthermore also the application of appropriate quantities of non-singleproportioned Applikaüonsformen, like syrup, in consideration comes. The following example describes the production of the new connections of the general Formei I and from so far descriptive intermediate products more near, is not however the range of the invention in no way to limit. The temperatures are indicated in centigrades. i example: 3-Äthylsulfinyl-5 (3-dimethylamino-2-methyl-propyl) - 10,11-dihydro-5H-dibenz [b, f] azepin oxalate. To a solution of i, 3 g 3-Äthylsulfinyl-10,11-dihydro-5H-dibenz [b, f] azepin in 100 ml exp. toluol with 70° under nitrogen atmosphere and agitating a suspension of 0,15 g sodium amide in 5 ml s exp. toluol is admitted and the mixture 30 min under return flow is cooked. Then one drips 0.75 g 2-Methyl3-dimethylamino-propylchlorid in I0 ml exp. toluol to and cooks the reaction mixture 15 h under return flow. It is cooled down on that on 20 ° and extracted with 2n hydrochloric acid. One places the salt-sour excerpt with konz. Caustic soda solution alkalinely and extracts the set free basic Autele with ether. The Atherlösung is washed with water, dried and evaporated over sodium sulfate. One solves the arrears in acetone and gives to 0.3 g water-free oxalic acid in 5 mi ethanol in addition. The 3-Athylsnlfinyl-5 (2-methyl-3-dimethylamino-propyl) - 10,11-dihydro-5tI-dibenz [b, f] azepin oxalate fäilt crystals out; it melts after Umkristailisieren from acetone ether with 128--130°. In similar way are manufactured: 3-Methylsulfinyl-5 (3-dimethylamino-propyl) - 10,11-dihydro-5H-dibenz [b, f] azepin oxalate, stop. 157 o, 3-Isopropylsulfmyl-5 (3-dimethylamino-propyl) - I 0,11-di_hydro-5H-dibenz azepin oxalate, stop. 169 o. The basic material for the 3thylsulfinyl-5 (3-dimethylamlno-2-methyl-propyl), described above - 10,11-dihydro-5H-dibenz [b, f] azepin oxalate is manufactured e.g. as follows: a) To a ice-cooled solution of 3,8 g Natriummetaperjodat in 56 ml water and 28 ml ethanol is course-dripped within 30 min a solution by 5,0 g 3thylthio-5-acety1-10,11-dihydro-5H-dibenz [b, f] azepin in 56 ml ethanol under agitating, whereby the temperature of the Reaksionslösung between 0 and 5 is held °. After terminated Zutropfen one agitates 3 h under ice cooling and afterwards 12 h at ambient temperature. Ethanol is mostly abdestilliert under reduced pressure, the remaining reaction mixture with 200 is shifted ml water and extracted three times with ether. The united therlösnngen is evaporated and the 3othylsulfiayl-5-acetyl-10,11-dähydro-5 staying! Idibenz azepin from benzene ether recrystallizes, stop. 135. b) 3.5 g 3-Äthylsulfinyl-5-acetyl-10,11-dihydro-5tt-dibenz [b, f] azepin, 3.2 g potassium hydroxide and 100 ml ÄthanoI are cooked 10 h under return flow. Subsequently, one evaporates ethanol under water jet vacuum, shifts the arrears with 100 ml water and extracts him with chloroform. The Chloroformlösnng is washed and evaporated with water. From the oily arrears one receives by crystallization from benzene ether the pure 3thylsulfinyl-10,11-dihydro-5H-dibenz [b, f] to a0 azepin, Smp. 128 °.