CH521981A - Pyrrolo-dibenzazepine derivs - with cns depressant and antihistamine activity - Google Patents

Abstract

Title derivs. of formula (I) (where R is methyl, ethyl or propyl and R2 is H, unbranched 1-4C alkyl, isopropyl or allyl) and their acid addition salts, which are useful in the treatment of tension and anxiety states, are prepd. by reducing a cpd. (I; R1 = R3) (where R3 is an alkanoyl residue corresponding to R1) with diborane (e.g. generated from NaBH4 and BF3 etherate) in an ether type solvent and opt. converting the product into an acid addition salt.

Description

  

  
 



  Process for the production of new azepine derivatives
The present invention relates to a process for the preparation of new azepine derivatives of the general formula I,
EMI1.1
 in which Rt denotes the methyl, ethyl or propyl group R2 hydrogen, a lower unbranched alkyl group with 1-4 carbon atoms, an isopropyl group and the allyl group as well as their addition salts with inorganic or organic acids.



   Such compounds, in particular compounds whose radical R 2 is a lower alkyl group, and the addition salts of such compounds, have interesting pharmacological properties and a high therapeutic index. They have a central damping effect when administered perorally, rectally and parenterally, e.g. B. they reduce the motility, potentiate the effect of narcotics, antagonize the effect of amphetamine, act in the test de la traction, have an antiemetic, serotonin-antagonistic effect on the rat paw, analgesic in the stretch test and lower body temperature. They also have antihistamine effects. These effectiveness qualities, which are determined by selected standard tests [vg. R. Domenjoz and W. Theobald, Arch.Int.Pharmacodyn. 120, 450 (1959), W. Theobald et al., Arzneimittelforsch. 17, 561 (1967) and W. Theobald and R.

  Domenjoz, drug research. 8, 18 (1958)] characterize the compounds as being suitable for treating states of tension and excitement.



   In the compounds of general formula I, for example, as an alkyl group, R2 is: the methyl, ethyl, propyl or butyl group.



   Compounds of the general formula I are prepared by adding a compound of the general formula II,
EMI1.2
 in which R2 has the meaning given under formula I and R3 means a corresponding alkanoyl radical, reduced by means of diborane, in an ethereal liquid and the compound of general formula I obtained is optionally converted into an addition salt with an inorganic or organic acid.



   Tetrahydrofuran, dioxane, methylene glycol dimethyl ether or diethylene glycol dimethyl ether, for example, are used as the reaction medium. The reaction temperature is preferably between room temperature and about 100 "and the reaction time between about 30 minutes and 25 hours. The diborane is, for example, developed from boron trifluiride etherate and sodium borohydride either in a separate apparatus and introduced into the reaction mixture or in situ formed.



   Starting materials of the general formula II, in which R3 as the alkanoyl radical can be the formyl, acetyl or propionyl group, are prepared by adding 5-alkanoyl-10,1 1-bis-bromomethyl-5H-dibenz [b, - f] azepine compounds of the general formula III
EMI2.1
 with an amine of the general formula IV,
EMI2.2
 wherein R2 has the meaning given, converts.



   The 5-alkanoyl-1 0.11 -bis-bromomethyl-5H-dibenz- [b, f] azepine compound of the general formula III is z. B. obtained if the 10,11-dimethyl 5H-dibenz [b, f] azepine (cf. Geigy AG, US Pat. No. 3,130,191) with an alkanoyl chloride to give 5-alkanoyl-10,11-dimethyl-5H -dibenz [b, f] azepine acylated and the reaction product brominated with N-bromo-succinimide.



   The compounds of general formula I obtained by the process according to the invention are then, if desired, converted into their addition salts with inorganic and organic acids in the customary manner. For example, a solution of a compound of the general formula I in an organic solvent is mixed with the 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. B.



  Methanol, acetone, methyl ethyl ketone, acetone-ethanol, methanol-ether or .3ithanol-laither.



   For use as drugs, pharmaceutically acceptable acid addition salts can be used in place of free bases; H. 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 are readily crystallizable and have little or no hygroscopic properties. For salt formation with compounds of general formula I, for. B. the hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, β-hydroxyethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenyl acetic acid.



   As mentioned above, the new active ingredients are administered orally, rectally or parenterally. The dosage depends on the mode of administration, the species, the age and the individual condition.



  The daily doses of the free bases or pharmaceutically acceptable salts thereof are between 0.1 mgikg and 10.5 mg / kg for warm-blooded animals. Suitable dosage unit forms, such as dragees, tablets, suppositories or ampoules, preferably contain 5-200 mg of an active ingredient according to the invention or a pharmaceutically acceptable salt thereof.



   The following examples explain the preparation of the new compounds of general formula I and of intermediates not previously described, but are not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius.



   Example 1 a) 0.64 g of diborane, freshly prepared from 2.6 g of sodium borohydride and 13 g of boron trifluoride etherate (G.



  Doubt and G.C. Brown, Organic Reactions, vol.



  XIII, p.32) with nitrogen in a solution of 13.5 g of 2-ethyl-8-acetyl-1,2,3,8-tetrahydrodibenzo [b, f] - pyrrolo [3,4-d] azepine in 70 ml abs. Tetrahydrofuran is passed in, the temperature being kept between 0 and 5 "by cooling with ice. The mixture is then stirred for a further hour at 0-5" and a further hour at 20-25. 30 ml of 100% sodium phosphate solution are then added dropwise with ice cooling and the tetrahydrofuran is then evaporated off in a rotary evaporator. The residue is now heated to boiling with 300 ml of 4N hydrochloric acid under reflux for one hour and, after cooling to 20O, with conc. Sodium hydroxide solution made phenolphthalein-alkaline and the precipitated base extracted with ether.

  The ethereal solution is washed with water, dried over potassium carbonate and concentrated to a small volume, the 2,8-diethyl-1,2,3,8-tetrahydrodibenzo [b, f] pyrrolo [3,4 -d] azepine crystallized out. The crude product is recrystallized from ethanol, melting point 100 102O. 5.8 g of the base obtained are dissolved in 40 ml of abs.



  Acetone and gives 4 mol of 5n abs. Ethanolic hydrochloric acid, whereupon the hydrochloride crystallizes out; After recrystallization from isopropanol 267-271 (decomp.).



   The starting material, the 5-acetyl-10,11-bis-bromo methyl-5H-dibenz [b, f] azepine, is prepared as follows: b) To a solution of 98 g 10,11-dimethyl-SHdibenz [b, f] azepine (cf. Geigy AG, USA Patent No. 3 130 191) with a melting point of 131-132 in 295 ml of toluene is allowed to add 39.5 g of acetyl chloride dropwise over 30 minutes with stirring. The reaction mixture is then refluxed for 5 hours, evaporated in vacuo and the residue is dissolved in ether.



  The ethereal solution is washed with water, dried over sodium sulfate and evaporated. The residue, which is recrystallized from petroleum ether, gives 5-acetyl-10,1-1-dimethyl-5H-dibenz [b, f] azepine with a melting point of 109-111; c) 101 g of 5-acetyl-10,11-dimethyl-5H-dibenz [b, f] azepine are dissolved in one liter of carbon tetrachloride, and 138 g of N-bromosuccinimide are added. The mixture is heated to the boil with stirring and exposure to two 200 watt lamps or a UV lamp. The mixture is kept at the boil until all the N-bromosuccinimide has been converted. The reaction mixture is then cooled to 0 and 200 ml of water are run in.

  The precipitated crystalline 5-acetyl-10, l-bis-bromomethyl-SH-dibenz [b, f] azepine with a melting point of 175-176 is filtered off with suction;
Analogously to example la) the following are obtained: a) 2,8-dimethyl-1,2,3,8-tetrahydrodibenzo [b, f] pyrrolo [3,4-d] azepm, SmP. 120-121, oxalate, m.p. 230-232; b) 2, -Athyl-8-methyll, 2,3,8-tetrahydrodibenzo [b, f] pyrrolo [3,4-d] azepine, oxalate, m.p. 208-210 (from methanol), c) 2-allyl-8-methyl-1,2,3,8-tetrahydrodibenzo [b, f] pyrrolo [3,4-d] azepm, m.p. 137-139 "(from absolute ethanol), methanesulfonate, Mp 194-296 (from absolute ethanol);

  ;
Example 2 a) The following is produced analogously to Example 1a):
From 8 g of 2-sithyl-8-formyl-1,2,3,8-tetrahydrodibenzo [b, f] pyrrolo [3,4-d] azepine; M.p. 107-109 (from ethyl acetate); Hydrochloride: m.p. 239-2430 (from isopropanol); Yield 6 g (78% of theory).



   The 2-ethyl-8-formyl-1, 2,3,8-tetrahydrodibenzo [b, f] pyrroloi3,4-d] azepine required as the starting product is prepared as follows: b) 10 g of 2-ethyl-1, 2,3,8-tetrahydro dibenzo [b, f] pyrrolo [3,4-d] azepine and 100 ml of 990% formic acid are refluxed with stirring for 2 hours. The excess formic acid is then distilled off from the reaction mixture in vacuo. The residue is dissolved in water and precipitated with conc. Ammonia is the base that is absorbed in ether. The ether solution is washed with water, dried over potassium carbonate and evaporated.

  The residue, the 2-ethyl-8-formyl-1, 2,3,8-tetrahydrodibenzo [b, f] pyrrolo [3,4-d] azepine, is a viscous oil, crude product, 10 g of the crude base obtained are in 30ml abs. Dissolved acetone and with 6.9 mol of 5n abs. Ethanol-safe hydrochloric acid is added, whereupon the hadrochloride crystallizes out. After recrystallization from methanol, the substance melts at 245-250 (decomposition).

 

Claims (1)

PATENT CLAIM Process for the preparation of new azepine derivatives of the general formula I, EMI3.1 in which Rt denotes the methyl, ethyl or propyl group, R2 denotes hydrogen, a lower unbranched alkyl group with 1-4 carbon atoms, an isopropyl group and the allyl group and their addition salts with inorganic or organic acids, characterized in that one a compound of the general formula II, EMI3.2 in which R2 is the meaning given under formula I and R3 is a corresponding alkanoyl radical, reduced by means of diborane in an ethereal liquid and the compounds of general formula I obtained are optionally converted into an addition salt with an inorganic or organic acid.