CH498123A - Anorexigenic chloro-2,3,4,5-tetrahydro-1h-3-benzazepine - derivatives - Google Patents

Abstract

Benzazepine derivatives with the general formula (I) and their addition salts with organic and inorganic acids are new compounds prepared from the corresponding dinitriles (II) by hydrogenation until 4 mol of hydrogen are absorbed, using a suitable catalyst. (in which one of the groups X is chlorine and the other H). Hydrogenation is pref. carried out in methanol in the presence of a rhodium-aluminium oxide as a catalyst at temperatures between 20 and 60 degrees C at 3-10 atm. pressure. Alternatively Raney nickel may be used as catalyst at 80-100 degrees C and a pressure of 50-100 atm. The catalyst is removed by filtration and the product isolated by removal of solvent, or alternatively converted directly to the corresponding acid addition salt by addition of acid. Used perorally, rectally or parenterally in doses from 25 to 200 mg for adults for treating anorexia.

Description

  

  
 



  Process for the preparation of new tetrahydrobenzazepine derivatives
The present invention relates to a process for the preparation of new tetrahydrobenzazepine derivatives and their acid addition salts.



   The ar-chloro-2,3,4,5-tetrahydro-iH-3-benzazepines of the general formula I.
EMI1.1
 in which one X is chlorine and the other X is hydrogen, and their addition salts with inorganic and organic acids have not yet become known.



   As has now been found, these new substances have valuable pharmacological properties, e.g. anorexigenic effects.



   For the inventive preparation of the above-defined ar-chloro-2,3,4,5-tetrahydro-1H-3-benzazepme and their acid addition salts, a dinitrile of the general formula II
EMI1.2
 in which X has the meaning given under formula I, catalytically activated hydrogen act until the essentially four-fold molar amount is absorbed and, if desired, converts the resulting tetrahydrobenzazepine derivative of general formula 1 into an addition salt with an inorganic or organic acid. For example, a nitrile of the general formula II is hydrogenated in a lower alkanol, e.g.



  Methanol, in the presence of a rhodium-alumina catalyst at room temperature or moderately elevated temperatures and pressures, e.g. at 20-600 and 3-10 atmospheres. According to another process variant, a dinitrile of the general formula I is hydrogenated in a lower alkanol or in a lower alkanol saturated with ammonia, e.g. Ethanol, in the presence of Raney nickel or Raney cobalt at medium temperatures and pressures between approx. 800 and 1000 and approx. 50-100 atmospheres. The crude bases that remain after filtration and evaporation of the solvent are, for example, first distilled or converted directly into acid addition salts which can be purified by recrystallization.

  To convert to an addition salt, for example, a solution of an ar-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine in an organic solvent is mixed with the inorganic or organic acid desired as the salt component or with a solution thereof. For the reaction, preference is given to choosing organic solvents in which the salt formed is sparingly soluble so that it can be separated off by filtration. Such solvents are e.g. Acetonitrile, acetone, methyl ethyl ketone, acetone-ethanol, methanol-ether or ethanol-ether.



   For use as drugs, a pharmaceutically acceptable acid addition salt thereof can be used in place of the free bases, i.e. Salts with acids whose anions are not toxic at the dosages in question. It is also advantageous if the salts to be used as medicinal substances can be crystallized easily and are not or only slightly hygroscopic. For salt formation with the ar-chloro-2,3,4,5-tetrahydro-1H-3-benzazepines e.g. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, -hydroxyethanesulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, mandeliacetic acid are used.



   The dinitriles of the general formula 11 required as starting materials are in turn, e.g. starting from 4-chloro- or 3-chloro-o-xylene, can be prepared. These ar-chloro-xylenes are brominated in a manner known per se to their ^ c'-dibromo derivatives and the latter is treated with a suitable cyanide, e.g. Potassium or sodium cyanide, to the desired dinitriles.



   The new active ingredients are administered orally, rectally or parenterally. The daily doses of the free bases or pharmaceutically acceptable salts thereof range between 25 and 200 mg for adult patients. Suitable dosage unit forms, such as dragees, tablets, suppositories or ampoules, preferably contain 5-50 mg of the active ingredient according to the invention or a pharmaceutically acceptable salt thereof.



   The following example is intended to explain the implementation of the method according to the invention in more detail. The temperatures are given in degrees Celsius.



   example
7.6 g (0.04 mol) of 4-chloro-o-benzodiacetonitrile (4-chloro -j,: '? - dicyano-xylene) are dissolved in 100 ml of methanol and poured over 2.5 g of rhodium aluminum oxide (5% Rh content) at initially 300 and gradually heating to 500 in hydrogen from 3-4 atm. hydrogenated until the theoretical amount (0.16 mol) has been absorbed. After filtering off the catalyst, the hydrogenation solution is evaporated. The crude base that remains, e.g. 7-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride prepared with ethereal hydrogen chloride solution, melts after repeated recrystallization from acetonitrile at 1711730. The free base distills under 0.1 torr at 110-1150, and = 1.5765.



   The 6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride with a melting point of 214-2150 (after repeated recrystallization from absolute ethanol) is obtained in an analogous manner.



     B.p. of the free base around 75-850 / 0.05 torr, and 20 = 1.5779.



   The dinitriles required as starting materials are prepared as follows: a) 492 g (3.5 mol) of 4-C: chloro-o-xylene are heated to 150-1600 using an immersion lamp. While stirring, 1150 g (7.2 mol) of bromine are added dropwise at the same temperature over the course of 2 hours and the mixture is stirred for a further 16 hours at 150-1600 (immersion lamp).



  After cooling, the dissolved hydrogen bromide is sucked off by means of a water jet vacuum and the dark brown liquid is distilled in vacuo over a Vigreux column of 20 cm, a, a "-dibromo-4-chloro-o-xylene of bp 171-1790 / Receives 14 torr.



   b) 299 g (1 mol) of a.sc'-dibromo-4-chloro-o-xylene are cooled in 1000 ml of ethanol with stirring to 3-40 and at this temperature within 5 hours a solution of 250 g (2.1 Mol) potassium cyanide in 1000 ml of water was added dropwise. The reaction mixture becomes cloudy and pale brown, and towards the end of the dropping in, a slimy, white precipitate can be observed. The reaction mixture is then stirred for a further 18 hours at room temperature. Then you separate the dark brown
Solution of the dark brown ones located on the bottom
Lump and evaporate the solution in a rotary evaporator under vacuum at 600 to dryness. The residue is dissolved in 500 ml of ethyl acetate.

  The above-mentioned lumps in the reaction vessel are dissolved in 600 ml of ethyl acetate, the two solutions are combined, dried with sodium sulfate and evaporated to dryness in a rotary evaporator under vacuum at 400. The remaining resin is slurried with 100 ml of ethanol, the undissolved crystals of crude 4-chloro-o-benzene diacetonitrile are suction filtered and rewashed with ethanol. For cleaning, the raw product is first made
900 ml of ethanol left to crystallize in the refrigerator.



   The crystals obtained are dissolved in 250 ml of hot ethanol and after decolorization with 1 g of activated charcoal
Allowed to crystallize with stirring, the 4-chloro-benzene diacetonitrile having a melting point of 127-1290.



   The sc, Gc'-dibromo-3-chloro-o-xylene and from this analog b) the 3-chloro-o-benzene diacetonitrile can be obtained analogously to a).

 

Claims (1)

PATENT CLAIM Process for the preparation of new tetrahydro azepine derivatives of the general formula I. EMI2.1 in which one X is chlorine and the other X is hydrogen, and its acid addition salts, characterized in that a dinitrile of the general formula It EMI2.2 in which X has the meaning given under formula I, catalytically activated hydrogen is allowed to act until the substantially four-fold molar amount is absorbed, and if desired, the resulting tetrahydrobenzazepine derivative of general formula I is converted into an addition salt with an inorganic or organic acid.