DE1618695A1 - Dibenzocyclooctene derivatives and a process for their preparation - Google Patents

Description

P 16 18 695. 1-42
New documents

MBHCK & CO. , INCORPORATBO 126 Lincoln Avenue, Rahway, New Jersey 07065, V. St. A.

Dibenzoeyclooctene derivatives and a process for their preparation

The invention relates to new derivatives of dibenzocycloootenes, in particular 5,6,7,12-tetrahydrodibeiizo _i ^, d7oyclooctenes, which carry secondary or tertiary aroinopylidene substituents on the 12-carbon atom, and a process for their preparation.

The invention relates to compounds of the general formula

in which R is hydrogen or alkyl with 1-6 carbon atoms, B 'alkyl with 1-6 carbon atoms or R and R * together with the nitrogen atom to which they are attached, 1-piperi-

BAD ORlGiNAL

10982 * 87176 0

HeUe documents (Art 7 § Τ Paragraph 2 No. I Clause 3 dos Anderureegee. Ν. 4. S

10 915

dyl «4-morpholinyl« 1-pyrrolidyl or 1-lower-alkyl-4-piperazinyl mean «as well as a process for the preparation of these compounds« which is characterized by «that one a compound of the general formula

CH ₂ CH ₂ C

R *

in which each of the radicals R * is alkyl with 1-6 carbon atoms or both radicals R * together with the nitrogen atom to which they are bonded are 1-piperidyl, 4-morpholinyl, 1-pyrrolidyl or 1-low-alkyl-4-piperazinyl means «dehydrated and optionally dealkylated.

109 8 28/1760

The elimination of water can easily be carried out in a suitable one Carry out solvent and can be done by known methods using known dehydrating agents. Dehydrating agents that have proven to be particularly valuable «are aoetylochloride, thionyl chloride, acetic anhydride and trifluoroacetic anhydride «Also other dehydrating agents, such as potassium bisulfate, concentrated hydrochloric acid and the like can be used. Solvents that work well for this stage of the process when acetyl chloride or a similar dehydrating agent is used are chlorofprm, methylene chloride and trifluoroacetic acid. The desired olefin compound is obtained in known catfish.

The .12- (2-substlt * - / minopropyl) -12-hydroxy-5 # 6,7,12-tetrahydrodibenzq ^, d7cyolooetene used as starting material for the process according to the invention can be produced in the following ways:

6,7-Oihydrodibeßzo _< ^ a, d7cyoloocten-12- (5H) -one is prepared according to the method of K. Stach and H. Spingier ,months. Chenu, Jg (1962), pages 889-895 *, the same compound is also from CD. Outache et al in Journal of the Arnerioan Chemical Society, 80 (1958), pp. 5756-5767.

10 9 8 2 8/1760 bad ORIGINAL

The 6,7-Dihydrodibenzo ^ id7cyolooeten-12- (5H) -one is with a Grignard's reagent reacted and. the resulting Grignard adduct hydrolyzed to a tertiary alcohol.

The Grignard's reagent is prepared in a known manner from the corresponding jJ-tert-aminopropyl halide prepared in tetrahydrofuran. The reaction with the Grignard's reagent is preferably carried out initially at a low temperature, like them is achieved by cooling in an ice bath, and can be at room temperature be terminated. Tetrahydrofuran has been found to be an excellent solvent for carrying out the reaction «and the ketone can therefore be added directly to the reaction mixture are manufactured in which the Grignard's reagent has been. However, any inert solvent can also be used for the reactants. When the addition reaction is complete, the majority of the solvent is in vacuo distilled off and the hydrolysis of the Grignard adduct carried out while avoiding strongly acidic conditions. The Grignard adduct can for example be dissolved in a suitable solvent, such as benzene, and by adding an aqueous ammonium chloride solution hydrolyzed with cooling, although water alone may be sufficient for this purpose. The carbine oil will obtained by evaporation of the solvent after separating insoluble inorganic substances by filtration.

1 0 98 ^ * 2 8/1760

10 915-

The making of the sec. Aminopropylidene derivatives (those Compounds of the formula I in which R-H) takes place by dealkylation of the corresponding tertiary amino compounds. The one attached to the nitrogen atom of the tertiary aminopropylidene compound bonded alkyl substituents are, preferably the same. This is easily done by appropriate Choice of Grignard's reagent with which the Carbinol is produced, from which the tertiary amino compounds are derived. When secondary aminopropylidene derivatives are to be produced in which a methyl or ethyl radical is bonded to the nitrogen atom dealkylation by condensing the tertiary amino compound with a haloformic acid alkyl, aralkyl or -aryl ester to the corresponding urethane and hydrolysis of the urethane to convert the substituted carbamyl group of the urethane are made into a hydrogen atom.

As the carbalkoxy, carbaralkoxy or carbaryloxy group is split off during dealkylation, the choice of the respective haloformic acid ester can only be obtained through its availability and limits the ease of subsequent hydrolysis of the intermediate urethane.

The reaction with the haloformic acid ester can be carried out without solvents; however, a solvent is preferably used. Suitable solution

109 ^ 28/17 60

BATH

10 915

medium are aromatic hydrocarbons such as benzene and Toluene, aliphatic hydrocarbons such as heptane and hexane, and halogenated hydrocarbons such as chloroform and Carbon tetrachloride. The reaction can be carried out at room temperature, but is preferably carried out at higher temperatures. At the end of the reaction, after the impurities have been removed, the urethane will pass through Evaporation of the solvent obtained.

The urethane thus obtained is subjected to hydrolysis. The hydrolysis can be acidic or, preferably, alkaline Conditions are carried out. After the hydrolysis has ended, the product becomes known per se Manner, for example by extracting with a suitable solvent and evaporating the solvent.

The dealkylation is preferably carried out by reaction the tertiary amino compound with a cyanide halide to give the corresponding cyanamide and hydrolysis of this intermediate to the corresponding secondary amine.

The tertiary amine is in a hydroxyl group-free Solvent, such as benzene or '4ther, dissolved and the Solution slowly added to a solution of the cyanide halide in the same solvent while stirring the alkyl halide is allowed to escape. After completion

- 6 - ^BATHROOM

109828/1760

the reaction becomes the alkaline material by washing with it The dilute acid is separated off and the cyanamide is removed by evaporation of the solvent obtained. The cyanamide is in acid or alkaline medium »preferably in acidic medium, hydrolyzed to the secondary amine and the product per se known way won. ,

The compounds obtainable according to the invention have valuable ones pharmacological properties, particular sedative and antidepressant activity. In pharmaceutical The compounds can be used in the form of their free Bases or their non-toxic acid salts are used, the latter being generally preferred. the Compounds can be taken orally or parenterally as aqueous solutions or suspensions, but are preferably given orally in the form of tablets, powders, pills, from which the Active ingredient is released into the body over a long period of time, and the like administered. The one to be administered Sosis can be within a relatively wide range vary and depends on the activity of the compound used in each case and the intended application. In most cases, satisfactory results will be achieved with daily doses of around 15 to 500 mg

BATH ORIGINAL 109828/176 0

preferably in single doses spread over the day or in one Dosage form are given from which the active ingredient in the course Longer tent is handed over to the body.

example

12- O-Dimethylaminopropylidene) -5-6,7,12-tetrahydrodibenzoj ^ a, d7-cyclooctene ■

4.0 g (0.015 mol) of 12- (5-dimethylaminopropyl) -12-hydroxy-5,6,7,12-tetrahydrodibenzo-α, α-cyclooctene are dissolved in 57 ml of trifluoroacetic acid. The solution is mixed with 22 ml of trifluoroacetic anhydride and heated to reflux temperature for 1 hour. The bulk of the liquid is then distilled off on the steam bath under reduced pressure, the residue is taken up in water and the mixture is made alkaline with sodium hydroxide solution. The base is extracted with benzene and the extract is washed with water and dried over sodium sulfate. After most of the benzene has been distilled off, 5.4 ml of a 4.15 normal solution of hydrogen chloride in benzene are added and the solution is evaporated to dryness. After adding a further portion of benzene and again evaporating to dryness, the residue is recrystallized from acetone. The product melts at I76 to 179 ⁰ C. Analysis

Calculated for C ₂₁ H ₂₅ N-HCl: C "76i95 * \ H - 7.99 % \ N" 4.27 * J Found: C - 76.76 <f> \ H - 7.69 % \ N * 4.21 ft,

109828/1760

SAD ORIGINAL

Claims (2)

Merck 4 Co., Inc * 10 915 / M 75 972 New claims 1. Compounds of the general formula in which R is hydrogen or alkyl with 1-6 carbon atoms, R "alkyl with 1-6 carbon atoms * or R and R 'together with the nitrogen atom to which they are attached, 1-piperidyl, 4-morpholinyl, 1-pyrrolidyl or 1-lower-alkyl-4-pipiperazinyl mean. 2. Process for the preparation of the compounds according to claim 1 »characterized in that a compound of the general formula 'HpCHpN ^ N * ie documents {Art. 7 n as * 2 Mr. 1 sentence 3 * » ******* * 109828/1760 BATH ORIGINAL in which each of the radicals R ^{1 is} alkyl with 1-6 carbon atoms or both radicals R ¹ together with the nitrogen atom to which they are attached «1-piperidyl, 4-morpholinyl, 1-pyrrolidyl or 1-lower-alkyl-4-piperazinyl mean «dehydrated and optionally dealkylated. 3 · Medicines, characterized by a content of one compound according to claim 1. 109828/1760