IL31451A - Tetrahydrodibenzocyclootene-12-methylamines and their preparation - Google Patents

Description

. f TetrahydrodibenzQoyclo0atene-12-amines and their preparation MERCK & GO. , INC.

C.29560 31451/2 - la - This invention relates to derivatives of dibenzocycloo'ctenes. In particular, it relates to dibenzocycloo'ctenes which are substituted at the 12- position with an aminomethyl group, and to methods of preparing the same.

The invention also relates to intermediates which are useful in the preparation of the above compounds and to methods for preparing same.

The new compounds of! our invention, including the intermediate cyano-substituted and formamido- substituted compounds, as well as the pharmaceutically- active amines, are represented structurally as dibenzocyclooctenp--. of the formula: wherein A is a cyano substituent, an alkanoylaminomethyl substituent, an aminomethyl substituent, a monoalkyl- amlnbmethyi substituent or a dialkylaminomethyl substituen . 11909 31451/2 1 An especially preferred group of compounds included within the scope ofj our invention, are . represented by the formula: in which R is hydrogen or a loweralkyl substituent, said loweralkyl substituents having preferably from 1-5 carbon atoms.

Also included within the scope of the invention, are the non-toxic pharmaceutically accept-able salts of the above compounds, the preferred salts being the non-toxic acid addition salts su'ch as the hydrochloride, the maleate, and the like, and pharmaceutical compositions of the above compounds, or the salts in combination with a non-toxic pharma- ceutically acceptable diluent.

Illustrative of the compounds included within the scope of the invention are 5,6,7,12-tetra- hydrodibenzo [a,d] cyclooctene-12-methylamine, the corresponding secondary amines as, for example, the .

N-methyl, N-ethyl, N-propyl, N-isopropyl, N-butyl, N-t-butyl, N-amyl and the N-hexyl derivatives thereof, as well as the. corresponding N,N-dialkyl derivatives thereof.

The compounds represented above, in either their free base or salt form, possess useful pharma-cological properties. In particular, they have been found to possess antiarrhythmic activity. It has been found that the administration of compounds of the present invention, depicted in the above formula, results in the prevention of arrhythmia in animals under conditions which ordinarily cause the develop-ment of arrhythmia in the animal 100% of the time.

It has further been found that .administration of the compounds of the present invention will arrest an existing arrhythmia in the animal being treated and. cause a resumption of normal cardiac rhythm. As antiarrhythmic agents, these compounds may be administered orally or parenterally. The formulations for administration may be prepared in conventional manner, employing conventional pharmaceutical carriers and excipients.

The non-toxic acid addition salts useful as components in the compositions provided by the present invention, are salts formed by the reaction of an equivalent amount of the amine compound of the above formula and an acid which is pharmacologically accept-able in the intended doses. Salts of the above compound which are useful are salts of the amine with hydro-chloric acid, hydrobromic acid, sulfuric acid, phos-phoric acid, fumaric acid, acetic acid, propionic acid, lactic acid, gluconic acid, aleic acid, succinic acid, tartaric acid, and the like. Salts of these acids with the amine base are useful as the active component of the compositions in the method of this invention.

The daily doses are based on the total body -weight. of the test animal and vary between about 1.0 and 100.0 mg./kg. for mature animals. Thus, a unit dose based on four-times-a-day administration is between 2.5 mg. and 250 mg. for a 10 kg. dog, and a total daily dose for a 10 kg. dog would vary between about 10 mg. and 1,000 mg. For larger animals, up to 100 kg. and above, proportional dosages are employed, based on the weight of the animal. Suitable dosage units provided for the administration of the compositions used in the method of the invention are tablets, capsules (which may be suitably formulated for either immediate or sustained release), syrups, elixirs, parenteral solutions, and the like. These dosage forms preferably contain per unit one or more multiples of the desired dosage unit in combination with the pharmaceutically acceptable diluent or carrier required for preparing the dosage unit.

Although the pharmaceutical compositions of my invention will ordinarily be administered within the ranges indicated, it is necessary for the skilled practitioner to determine the exact dosage, based on variables encountered in treating individual subjects. These variables include the age, sex, general health, and various other factors and, in part, will all affect the determination of the exact amount of active ingredient to be administered, as well as the route of administration. * The compounds represented by the above * J . . 31451/2 - 6 - ■·. "' . ''' '■ '· ' ' wherein .is hydrogen or a 1-4 carbon alkyl; and R2 and are each hydrogen or lower alkyl. .

In accordance with the process of the invention, the dibenzocyclooctene-12-methylamine compound.is readily prepared from the corresponding 12-chloro compound in stepwise fashion by first reacting the 12-chloro-5 ,6,7, 12-tetrahydro-dibenzo [a, d] Ciolooctene with a metal cyanide such as cuprous cyanide or silver cyanide in a suitable anhydrous non-hydroxylic solvent such as benzene, toluene, chloroform or acetonitrile to produce the corresponding 12-cyano tetrahydrodibenzo [a,d] cyclooctene.

The temperature at which the reaction is carried out is not critical, but it is preferred to employ elevated temperatures in the range of about 50-100°C. The desired product is readily recovered employing conventional techniques to remove the metal salts which precipitate from the reaction mixture, followed by filtration and evaporation of the solvent and crystallization of the product from solvents.

The thus-obtained 12-cyano-substituted dibenzocyclooctene is then reduced to produce the corresponding 12-methylamine. The reduction is readily effected by contacting the 12-cyano compound with lithium aluminum hydride in the presence of a suitable inert organic solvent such as tetrahydrofuran, ether, or other solvent conventionally employed with lithium aluminum hydride. Preferably, this reduction is. carried out in the presence of aluminum chloride and an ether compatible with aluminum chloride as a solvent. The temperature at which the reduction is carried out is not critical, but it is preferred to employ elevated temperatures up to about 50eC. The resulting amino-methyl derivative is readily recovered employing conventional techniques. The 12-formamidomethyl derivative (II) is prepared by formylation of the aminomethyl compound (I) employing conventional con-ditions and reagents, such as formic acid or esters thereof, for this purpose. The resulting formamido-methyl derivative can be recovered in the conventional manner. .The dimethylaminomethyl derivative (III) is readily j. epared by the treatment of the primary amine compound (I with formaldehyde and formic acid in accordance with the known Eschweiler-Clarke modifica-tion of the Leuckart Reaction. Recovery of the dimethylaminomethyl derivative is accomplished in con-ventional manner. The methylaminomethyl compound^ (IV) may be prepared by either reduction of the formamido-methyl derivative (II) or by mono-dealkylation of the dimethylaminomethyl derivative (III) . Reduction of the formamidomethyl derivative is effected under the first-described conditions set forth above for carrying out the reduction of the 12-cyano derivative. Similarly, dealkylation of (III) can be effected in known manner such as. by treatment with cyanogen bromide followed by hydrolysis of the intermediate cyanamide or by treat-ment with a haloformate followed by hydrolysis of the urethane intermediate. In each instance, the desired compound can be recovered employing conventional techniques.

The N-loweralkylamines and the N,N-diiower-alkylamines corresponding to compounds IV and III, respectively, are likewise prepared from the corres-ponding primary amine I by analogous reactions.

Thus, the primary amine I is treated with a lower aliphatic acid halide or anhydride of from 2-5 carbon atoms, e.g., acetyl chloride, acetic anhydride, propionyi chloride, butyryl chloride or valeryl chloride to produce the N-alkanoyl amide corresponding to II as, for example, the N-acetyl, N-propionyl, N-butyryl or N-valeryl amine. The thus-obtained amide is reduced to the corresponding 12-N-loweralkylamino-methyl compound by reduction in the manner described for the corresponding 12-cyano compound, i.e., reduction with lithium aluminum hydride. The secondary amine compounds produced in this manner are the 12- (loweralkyl) derivatives of 5, 6, 7, 12-tetrahydro-dibenzo [a,d] cyclo ctene-12-methylamine as, for example, the 12- (ethyl), 12- (propyl) , 12- (butyl) and the 12-(amyl) derivatives. The corresponding tertiary amines, the Ν,Ν-diloweralkyl derivatives, are prepared from the secondary amines by repeating the process employed in the preparation of the secondary amines. Thus, the amides of the secondary amines are prepared and reduced with lithium aluminum hydride to produce the corresponding tertiary amines as, for example, the corresponding 12- (diethyl) , 12- (ethylmethyl) , 12- (di ro l) , 12-(dibutyl) and the 12-(diamyl) derivatives of BUbsfeifeufecd and unoubot-ltu ed 5, 6 , 7, 12-tetrahydro-dibenzo [a,d] cyclooctene-12-methylamine.

The starting compound^, namely, the 12-cyano-5, 6, 7, 12-tetrahydrodibenzo [a,d] cycloo'ctene or a oubotitutod dor-ivatlvo thoiroof, ac dof-Lnod abovo, may be prepared from the known 12-keto compound by reduction with sodium borohydride to the corresponding 12-hydroxy-5, 6, 7, 12-tetrahydrodibenzo [a,d] cyclooctene, as des-cribed by S. 0* Winthrop, M. A. Davis, F. Herr, J.

Stewart and R. Gaudry, J. Med. Chem. 6, 130-132 (1963), followed by treatment with hydrogen chloride to produce the corresponding 12-chloro-5, 6, 7, 12-tetrahydrodibenzo-[a, d] cycloo'ctene. The thus-obtained 12-chloro compound is then treated with silver cyanide in a suitable anhydrous non-hydroxylic solvent and at a suitable temperature, preferably in the range of 50-150eC.

The following examples are illustrative but not limitative of the invention.

Example 1 12-Cyano-5 , 6,7, 12-tetrahydrodibenzo [a, d] cyclooctene ,6,7,12-Tetrahydrodibenzo[a,d]cycloocten-12-ol, 5.95 g. (0.0266 mole), is dissolved in 210 ml. of dry benzene and the ice-cold solution saturated with hydrogen chloride. The mixture is allowed to stand for 3-1/2 hours, with additional passage of hydrogen chloride through the solution for 5 minutes at the end of the first hour. The excess hydrogen chloride and the bulk of the solvent are evaporated under reduced pressure at 30-35°C, leaving 12-chloro-5, 6, 7, 12-tetrahydro-dibenzo [a,d] cyclooctene as the residual oil.

The crude chloride is dissolved in 150 ml. of dry acetonitrile and stirred at reflux with 5.35 g. (0.04 mole) of silver cyanide. After about 18 hours, 50 ml. of dry benzene is added and refluxing is continued for another 24 hours. Silver salts are removed by filtration and washed with boiling benzene. Evaporation of the solvents under reduced pressure and crystallization of the residue from cyclohexane yields product, m.p. 188-192°C. A purified sample melts at 193-194°C. after repeated crystallizations from cyclo-hexane.

Anal. Calcd. for C17H15N: C, 87.50; H, 6.48.

Found: C, 86.81; H, 5.68.

Example 2 ,6,7, 12-Tetrahydrodibenzo [a, d] cyclooctene-12-methylamlne Lithium aluminum hydride, 0.304 g. (0.008 mole) is weighed under nitrogen, transferred to a dry, nitrogen-flushed reaction flask, and suspended in 10 ml. of absolute ether. A solution of 1.05 g. (0.008 mole) of aluminum chloride in 20 ml. of absolute ether is added dropwise and the mixture is stirred for 5 minutes at room temperature. A solution of 0.90 g. (0.00386 mole) of 12-cyano-5, 6, 7, 12-tetrahydrodibenzo [a, d] cyclooctene in 100 ml. of absolute ether then is added dropwise and the mixture is stirred at room temperature for about 17 hours under a slow stream of nitrogen. The adduct is hydrolyzed by the dropwise addition of 8 ml. of water.

The ethereal solution is decanted and the gelatinous precipitate washed with ether. The precipitate is shaken with 20 ml. of 10 N aqueous sodium hydroxide and 50 ml. of water, and the mixture extracted with three portions of benzene. Evaporation of the combined extracts under reduced pressure leaves the product as the oily base.

The base is converted to the hydrogen oxalate salt by treating an ethanolic solution of the base with a slight excess of oxalic acid in ethanol. The hydrogen oxalate separates in white crystals, m. p. 216-218°C. dec. An analytical sample melts at 219-220°C. dec, after repeated crystallizations from methanol.

Anal. Calcd. for C, 7H. QN . C,H 0. : C, 69.70; H, 6.47; A/ Ay Δ * ■ N, 4.28.

Found: C, 69.36; H, 6.25; N, 4.25.

Example 3 N- (5,6,7, 12-Tetrahydrodibenzo [a,d] cyclooctene-12-methyl) -formamlde , 6,7, 12-Tetrahydrodibenzo [a, d] cyclooctene-12-methylamine, 0.245 g.. (0.001 mole), is heated to refluxing in 15 ml. of ethyl formate for 5-1/2 hours. Evaporation of the solution under reduced pressure leaves the product as the crystalline residue, m. p. 195-196°C. A purified sample melts at 196-197.5°C. after recrystallization from benzene - hexane.

Anal. Calcd. for C18H19 0: C, 81.47; H, 7.22; N, 5.28.

Found: C, 81.32; H, 6.97; N, 5.24.

Example 4 N-Methyl-5, 6, 7, 12-tetrahydrodibenzo [a, d] cyclooctene-12-methylamine Lithium aluminum hydride, 0.33 g. (0.0087 mole) is weig-i d under nitrogen, transferred to a dry, nitrogen-flushed reaction flask, and suspended in 20 ml. of. absolute ether. A solution of 1.1 g. (0.00415 mole) of N- (5, 6, 7, 12-tetrahydrodibenzo [a, d] cyclooctene-12-methyl) -formamide in 950 ml. of absolute ether is added rapidly dropwise and the mixture is stirred at reflux for about 18 hours. After cooling in an ice-bath, the complex is hydrolyzed by the successive dropwise addition of 0.5 ml. of water, 0.5 ml. of 15% aqueous sodium hydroxide, and 1.0 ml. of water. The precipitate is removed by filtration and the ethereal filtrate evaporated under reduced pressure, leaving the product as the residual oily base.

The hydrochloride is prepared from the base by treating an ethanolic solution with a slight excess of ethanolic hydrogen chloride. Dilution with absolute ether precipitates the crystalline salt. A purified sample melts at 269°C. dec, after recrystallizations from ethanol - ether.

Anal. Caled. for C18H21 · HC1: C, 75.11; H, 7.71.

Found: C, 74.86; H, 7.83.

Example 5 N,N-Dimethy1-5, 6, 7, 12-tetrahydrodibenzo [a,d] cyclooctene-12-methylamine _^ , 6, 7, 12-Tetrahydrodibenzo [a,d] cyclooctene-12-methylamine, 1.2 g. (0.005 mole), and 0.9 g. (0.011 mole) 3.1451/2 of 36-38% aqueous formaldehyde in 3 ml. of 88% formic acid are heated on the steam-bath for about 18 hours. After the addition of 2 ml. of concentrated hydro-chloric acid, the mixture is evaporated to dryness v under reduc l pressure. The residual syrup is dissolved in 25 ml. of water, the ice-cold solution made strongly basic with 40% aqueous sodium hydroxide and the mixture extracted with several .portions of benzene. Evaporation of the combined, washed, and dried extracts under reduced pressure leaves the product as the oily base.

Prevention or Modification of Ventricular Arrhythmia Beagle dogs of either sex, and weighing from 6 to 10 kg. are anesthetized by the administration of vinbarbital employing a dose of 50 mg./kg. of body weight, and the mean arterial pressure and the electro-cardiogram (Lead II) are recorded. The animals are artificially respired and the thorax opened at the fourth or fifth interspace. The pericardium is opened and a portion of the anterior descending coronary artery just distal to the origin is freed from the surrounding tissue. Mecamy1amine is administered to slow the heart rate and 10 minutes later the compound to be tested for antiarrhythmic effect is administered intravenously. Ten minutes after administration of the test compound 0.0035 ml. /kg. of tetrafluorohexachloro-butane (TFHCB) , a sclerosing agent which produced myocardial infarction and arrhythmia in dogs, ie in-jected into the coronary artery. Following injection of the sclerosing agent, the electrocardiogram is re-corded at two-minute intervals for one hour, and the average number of electrical (ECG) complexes per minute and the precent normal complexes calculated.

In control animals, the dose of sclerosing agent used produces a ventricular arrhythmia in 100% of the animals tested, and death in 33% as a result of ventricular fibrillation. In control animals, on the average, fewer than 20% of all recorded ECG complexes are normal.

The test compound, 5 , 6 , 7 , 12-tetrahydrodibenzo- [a,d] cyclooctene-12-methylamine, was demonstrated to have antiarrhythmic activity and in these experiments at 5.0 mg./kg. on the average 70% of all ECG complexes were normal and none of the animals succumbed to ventricular fibrillation. 7 Example ^ Tablets; Tablets for oral administration are prepared by mixing, the active ingredient with appropriate amounts of excipients and binding agents, formed into tablets by a conventional tableting machine and coated so that each tablet will have the following composition, Per Tablet N-methyl-5,6,7,12-tetrahydro-dibenzo [a,d] cyclooctene-12- ethylamine hydrochloride 10 mg.

Cellulose filter aid 11 mg.

Lactose 9 mg.

Calcium Phosphate Dibasic 143 mg.

Guar Gum 6.1 mg.

Corn Starch 4 mg.

Magnesium Stearate 0.9 mg.

Opaque yellow film coating 3 mg. 8 Example ^.

Capsules ; Capsules for oral administration are prepared by dispersing the active ingredient in lactose and magnesium stearate and encapsulating the mixture in standard soft gelatin capsules so that each capsule will have the following composition.

Per Capsule N-methyl-5, 6,7,12-tetrahydro-dibenzo [a,d] cyClooctene-12-methylamine hydrochloride 5 mg.

Lactose 430 mg.

Magnesium Stearate 5 mg. 9 Example jj Parenteral Solution; A solution suitable for administration for injection is' prepared by mixing the active ingredients, Dextrose, methylparaben, propylparaben and distilled water, so that each one will have the following composition, and sterilized.

Per ml.

N-methyl-5,6,7,l'2-tetrahydro-dibenzo [a, d] cyclooctene-12-methylamine hydrochloride 5 mg.

Dextrose 44 mg.

Methylparaben 1.5 mg.

Propylparaben ^ 0.2 mg.

Water for Injection q.s. 7 The preceding three examples, Examples ^, treatment or prevention of arrhythmia are prepared by substituting any of the compounds specifically illus-trated above in place of the 5,6,7,12-tetrahydro-dibenzo [a, d] cyclooctene as one of the active compounds useful in my · invention .

Claims (1)

1. - # - 31451/2 : 10. NtN-Dimethyl-5,6,7,12-tetrahydrodibenzo a,d7cyclo bctene-12-methylamine. 11. A process for the preparation of pound of the structural formula which comprises the steps of reducing the compound of the formula with lithium aluminum hydride in the presence of an inert organic solvent to form the corresponding methylamine, treating said methylamine with formaldehyde and formic- acid to form the corresponding dimethyl derivative, and demethylating said dimethyl derivative. · ■ ' " -119 12. A process for the preparation of the compound of the structural formula . the which comprises the steps of reducing k compound of the formula with lithium aluminum hydride in the presence inert organic solvent. 13· A process for the preparation of a general compound of the afcifucfcural formula wherein R2 is lower alkyl, which comprises acylating the & compound of the formula to form the corresponding alkanoyl derivative, and reducing said alkanoyl derivative with lithium aluminum hydride in the presence of an inert organic solvent. 11 a 1 -* A process for the preparation of a general compound of the bLrucLural formula atoms wherein R, is lower alkyl of from 1-4 carbons/which 1 the . . comprises acylating & compound of the formula 3- · A process for the preparation of a general compound o the gfrmrH-nrai formula each independently a wherein R2 and R^ are/lower alkyl substituentji, which comprises the steps of acylating a compound of the formula lower wherein Rj is/alky1, to form the corresponding N-alkanoyl-N-alkyl derivative and reducing said N-alkanoyl-N-alkyl derivative with lithium aluminum hydride in the presence of an inert organic solvent to form the corresponding N,N-dialkylmethylamine. 31451/2 16. A pharmaceutical composition comprising a compound of t he general -¾rmula in w hich R2 and R^ are independently hydrogen or a lower alkyl substituent in combination with a non-toxic phar¬ maceutically acceptable diluent. 17. A method for treating or preventing arrhythmia in animals which ©mprisee administering to an afflicted animal, an effective and non-toxic dose of an active compound having the general formula in w hich 2 and R^ are independently hydrogen or a lower alkyl substituent. For the Applicants DR. REINHOHPpOHlf AND PARTNERS By