CH513806A - Tricyclic cpds antidepressive - Google Patents

Abstract

(A) Cpds. of general formula (I) Including salts, and stereoisomers of I. R' = H or Me R = Me or MeCO (B) N-oxides of I (R' = Me). Antidepressants, adrenolytics, antihistamines, and local anaesthetics, with low toxicity and slight anticholinergic activity. 1-Methyl-10,11-dihydro-(3-dimethylamino-propylidene) 5H-dibenzo(a,d)cycloheptene (39.5 g), was hydrogenated at 25 deg./1 atm., over Pt2O (3 g.) in AcOH (400 ml). The mixture was filtered, evapd. and the residue distilled, giving the 3-dimethylaminopropyl deriv., b.p.140 deg./0.01 mm. (Hydrochloride m.p.181-3 deg., from Et2O-EtOH).

Description

  

  
 



  Process for the preparation of tricyclic compounds 5H-dibenzo [a, d] cycloheptene and 10,1 1-dihydro-SH-dibenzo [a, d] cycloheptene with a basic side chain in the 5-position are already known as psychotropic drugs, e.g. B.



     10.1 1-dihydro-5- (3-dimethylaminopropylidene) - 5H-dibenzo [a, d] cycloheptene and 10.1 -dihydro-5- (3-methylaminopropylidene) -
5H-dibenzo [a, d] cycloheptene.



   It has now surprisingly been found that tricyclic compounds of the formula
EMI1.1
 or the 10,11-dihydro derivatives thereof, in which formula R denotes the methyl or acetyl group, as well as geometrical and optical isomers and acid addition salts of these compounds, which differ from the known representatives of the substance group in question by the presence of a methyl or acetyl group differ in position, characterized by a considerably increased antidepressant effect and decreased toxicity. The only slight anticholinergic effect should be mentioned as particularly advantageous. The compounds are also characterized by diverse effects on the nervous system.



  Adrenolytic, antihistamine-like and local aesthetic effects have been established.



   The products of the process are: l-methyl (or acetyl) -10, 1 1-dihydro-5- (3-dimethylaminopropyl) -5H-dibenzo [a, d] cycloheptene and l-methyl (or acetyl) -5- ( 3-dimethylaminopropyl) -
5H-dibenzo [a, d] cycloheptene
1-methyl-10,1 1-dihydro-5- (3-dimethylaminopropyl) -
SH-dibenzo [a, d] cycloheptene.



   The process according to the invention for the preparation of the tricyclic compounds mentioned is characterized in that a compound of the formula
EMI1.2
 or a 10,11-dihydro derivative thereof, in which formula R 'denotes the methyl group or a ketalized acetyl group and W denotes a halogen atom, is reacted with a dimethylaminopropylmagnesium halide, whereupon any ketal group present is split off. Then, if desired, the geometric and / or optical isomers can be isolated from a mixture of isomers obtained and, if desired, a base obtained can be converted into an acid addition salt.



   According to a preferred embodiment of the process according to the invention, a compound of the formula II in which W is chlorine is either in solid, finely powdered form or in an inert organic solvent, such as e.g. in absolute ether, benzene, tetrahydrofuran, registered in a suspension of dimethylaminopropylmagnesium chloride in one of the above-mentioned inert solvents. The reaction is expediently carried out at a temperature between room temperature and the boiling point of the reaction mixture.



   The starting halide of the formula II can be obtained by methods known per se, starting from the corresponding tricyclic 5-ketone.



  The latter can be obtained by methods known per se (cf. the examples below).



   A l-acetylated 5-ketone is prepared, for. B. in the following way:
The corresponding, tricyclic, 1-brominated 5-ketone is heated with copper cyanide in pyridine or quinoline, the bromine atom being replaced by a cyano group. The nitrile obtained is converted into the corresponding carboxylic acid by alkaline hydrolysis. This is converted with a halogenating agent such as thionyl chloride into the corresponding acid chloride, which after treatment with a methylcadmium halide, e.g. the chloride, into the corresponding l-acetyl-5H-dibenzo [a, d] cyclohepten-5-one or into the l-acetyl-10,1 l-dihydro-SH-dibenzo [a, d] cyclohepten- 5-on passes. The acetyl group can now be ketalized in a manner known per se, e.g.

  B. by treating the compound obtained with a lower alkanol or glycol, especially methyl alcohol or ethylene glycol.



   A tricyclic 5-ketone obtained in the above manner is then reduced, and the 5-hydroxy compound obtained is converted into the 5-halogenated starting compound of the formula II by halogenation. Products obtained after the halogenation and decetalized in the l-position are ketalized again as described above.



   If the compounds obtained according to the invention contain a ketalized 1-acetyl group, this should be decetalized. The decetalization is conveniently carried out by treating the product with a dilute acid, such as hydrochloric acid or sulfuric acid, at a temperature between room temperature and the boiling point of the reaction mixture. Optionally, the reaction is carried out in the presence of a lower alkanol, e.g. Methanol or ethanol.



   Compounds obtained with a double bond in the 10,11-position and their salts can be converted into their geometric isomers, i.e. H. a- and ss-isomers, respectively. The separation methods are known per se. Preferably, the geometric isomers are separated by fractional crystallization of the acid addition salts from a solvent, e.g. Acetone, or from a mixed solvent, e.g. Methanol / diethyl ether.



   Process products obtained and their salts are present as racemates. A racemate can be converted into its optical isomers in a manner known per se, e.g. B. by reaction with optically active acids, such as tartaric acid or camphor sulfonic acid, and subsequent crystallization, separated.



   The compounds obtained according to the invention have a basic character and can be converted into their acid addition salts. Such salts are, for example, those with organic acids such as oxalic acid, citric acid, acetic acid, lactic acid, maleic acid and tartaric acid, or with inorganic acids such as hydrochloric acid, hydrobromic acid or sulfuric acid. The acid addition salts are crystalline, solid substances which are soluble in water, somewhat less soluble in polar solvents such as methanol, ethanol, etc., and relatively insoluble in non-polar solvents such as benzene, ether and petroleum ether.



   As mentioned above, the compounds mentioned have an outstanding antidepressant effect. To prove this, groups of 5 rats each were given the preparation 1-methyl-1 0.1 1-dilwdro-5- (3-dimethylaminoprnpy-
5H-dibenzo [a, d] cycloheptene hydrochloride in three doses of 50 mg / kg p. o. (applied twice the day before, once on the day of the experiment). The animals received six hours after the last administration
20 mg / kg of 2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-1,2,3, 4,6,7-hexahydro-l l-bH-benzo [a] quinolizine hydrochloride injected subcutaneously . The same dose was given to a group of 5 treatment-naïve rats. The assessment includes central and peripheral symptoms as they are characteristic of tricyclic antidepressants (cf. Ann. N. Y. Acad.

  Sci. 96, 279 [1962]). In particular, the motility (climbing), sensitivity to stimuli, searching behavior and the elimination of ptosis were observed. These changes were expressed in numbers according to a rating scheme.



   In this test, the preparation showed a strong antidepressant effect, which was expressed in greatly increased, characteristic motility, sensitivity to stimuli, searching behavior and complete elimination of ptosis. The effectiveness was 180% of the effectiveness of the same amount of amitriptyline.



   The low toxicity of the compounds of the formula I can be caused by the acute toxicity of 1-methyl-10,1 1-dihydro-5- (3-dimethylaminopropyl) -
SH-dibenzo [a, d] cycloheptene hydrochloride in mice (24 hour values) are illustrated: DLÏo i. v. = 25-50 mg / kg DLÏo p. o. = 300-600 mg / kg
Amitriptyline has a less favorable acute toxicity.



   The low anticholinergic effect can be determined by the lack of salivation inhibition in rabbits: In rabbits under mild urethane anesthesia, pilocarpine injection (5 mg / kg s. C.) Increased salivation and the amount of saliva was measured at 5-minute intervals. The inhibition of salivation was expressed as% of the salivation of animals that received only pilocarpine. The salivation inhibition of I-methyl-10, l-dihydro-5- (3-dimethylaminopropyl) SH-dibenzo [a, d] cycloheptene hydrochloride after administration of 3 mg / kg i. v. was only 50%, while an inhibition of salivation of 96% was observed for the same amount of amitriptyline.

 

   The products of the process can be used as medicaments in the form of pharmaceutical preparations which contain them or their salts in admixture with an enteral, e.g. Oral or parenteral administration suitable pharmaceutical, organic or inorganic inert carrier material. The pharmaceutical preparations can be in solid form or in liquid form. They may contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.



   -vvr P
1.4 g of Gilman alloy are covered with 10 ml of dry ether and mixed with three drops of methyl iodide. After the lively reaction has subsided somewhat, 5.5 ml of 1-chloro-3-dimethylaminopropane in 25 ml of dry ether are added dropwise in such a way that the reaction mixture is kept boiling.



  The mixture is heated for a further 3 hours under reflux conditions at 450 ° C., then cooled with ice water and treated dropwise over the course of one hour with a solution of 3.3 g of 1-methyl-10,11-dihydro-5-chloro-5H-dibenzo a, d] cyclohepten in 40 ml of dry ether and 25 ml of dry benzene were added. The mixture is then stirred for another hour and a half under reflux conditions at 450 ° C., then cooled with ice water and decomposed with a cold saturated ammonium chloride solution. The ethereal layer is separated and shaken with dilute hydrochloric acid. The aqueous, acidic solution is made alkaline with potassium carbonate, the precipitating oil is shaken out with ether, the ethereal solution is washed with water, dried over sodium sulfate and evaporated.

  The 1-methyl-10,11-dihydro-5- (3-dimethylaminopropyl) - obtained
SH-dibenzo [a, d] cycloheptene is isolated as the hydrochloride, which melts at 181-1830 ° C. after recrystallization from ethanol / sither.



   The 1-methyl-10, 11-dihydro-5-chloro-5H-dibenzo [a, djcycloheptene used as the starting compound can be prepared as follows:
10.7 g of 1-methyl-1 0.1 1-dihydro-5H-dibenzo [a, d] cyclohepten-5-one are dissolved in 200 ml of methanol and added dropwise with stirring with a solution of 4 g of sodium borohydride and a piece of potassium hydroxide added in 50 ml of water. The whole is refluxed for 2 hours. The methanol is then distilled off under reduced pressure and the residue is recrystallized from high-boiling petroleum ether, the 1-methyl-10,11-dihydro-5-hydroxy-5H-dibenzo [a, d] cycloheptene being colorless at 108-1090.degree melting crystals is obtained.



   Dry hydrochloric acid is passed into a solution of 7 g of 1-methyl-10,1 1-dihydro-5-hydroxy-5H-dibenzo [a, d] cycloheptene in 150 ml of dry benzene for 30 minutes. The solution is briefly dried over calcium chloride, filtered and evaporated. The remaining 1-methyl-10, 11-dihydro-5-chloro-5H-dibenzo [a, d] cycloheptene melts after recrystallization from high-boiling petroleum ether at 128-1300 C.



   Example 2
The corresponding Grignard compound is prepared in the usual way from 7 g of Gilman alloy in 20 ml of absolute ether and 33.6 g of 3-dimethylaminopropyl chloride in 50 ml of absolute tetrahydrofuran. The solvents are distilled off in an argon atmosphere and replaced with 150 ml of absolute benzene. At room temperature, a solution of 20 g of 5-chloro-1-methyl-5H-dibenzo [a, d] cycloheptene in 250 ml of abs. Benzene too. Then heat for 15 min.



  under reflux conditions, hydrolyzed with 50 ml of water, filtered, washed three times with chloroform and the filtrate concentrated under reduced pressure. Customary work-up gives oily 1-methyl-5- (3-dimethylaminopropyl) -5H-dibenzo [a, d] cycloheptene (mixture of diastereomers in a ratio of about 1: 1). The corresponding maleate is a crystalline compound that melts at 130-1310 C (mixture of diastereomers about 2: 1).



   The 5-chloro-1-methyl-5H-dibenzo [a, d] cycloheptene used above can be prepared as follows:
22.2 g of 1-methyl-1 0.1 1-dihydro-5H-dibenzoa, d] cyclohepten-5-one are dissolved in 200 ml of carbon tetrachloride, 17.8 g of bromosuccinimide are added and the mixture is refluxed for 2 hours. After cooling, the solution is filtered from the succinimide formed and evaporated. 36.7 g of a thick oil remain, which is dissolved in 100 ml of ethanol, mixed with a solution of 20 g of potassium carbonate in 30 ml of water and heated for 2 hours on the reflux condenser. The clear solution is evaporated to dryness, the residue is dissolved in 200 ml of methylene chloride, the methylene chloride solution is washed with water, dried over sodium sulfate and evaporated.

  The remaining 1-methyl-5H-dibenzo [a, d] cyclohepten-5-one melts at 84 to 850 after recrystallization from ethanol.



   26 g of 1 - methyl - 5H - dibenzo [a, d] cyclohepten-5-one is dissolved in 200 ml of dioxane, a solution of 9 g of sodium borohydride in 35 ml of water is added and the mixture is stirred at room temperature for 4 hours. It is then concentrated under reduced pressure. The residue is partitioned between ether and water, the ethereal phase is washed with water, dried over sodium sulfate, filtered and evaporated. The 5-hydroxy-1-methyl-SH-dibenzo [a, d] cycloheptene obtained is recrystallized from petroleum ether. 114-116 C.

 

   23 g of 5-hydroxy-1-methyl-5H-dibenzo [a, d] cycloheptene in 200 ml of absolute benzene are refluxed with 45 ml of thionyl chloride for 2 hours. It is then concentrated under reduced pressure. The white, crystalline residue obtained is recrystallized from carbon tetrachloride. 5-Chloro-1-methyl-5Hdibenzo [a, d] cycloheptene, which melts at 156-1600 ° C., is obtained.

 

Claims (1)

PATENT CLAIM Process for the preparation of tricyclic compounds of the formula EMI3.1 or of 10,11-dihydro derivatives thereof, in which formula R denotes the methyl or acetyl group, characterized in that a compound of the formula EMI4.1 or a 10,11-dihydro derivative thereof, in which formula R 'denotes the methyl group or a ketalized acetyl group and W denotes a halogen atom, is reacted with a dimethylaminopropylmagnesium halide, whereupon an existing ketal group is split off. SUBCLAIMS 1. The method according to claim, characterized in that the geometric and / or optical isomers are isolated from a mixture of isomers obtained. 2. The method according to claim, characterized in that a base obtained is converted into an acid addition salt. 3. The method according to claim, characterized in that the starting compound used is a 10,11-dihydro derivative of a compound of the formula II in which R 'is methyl. F. Hoffmann-La Roche & Co. Aktiengesellschaft