NO164333B - PROCEDURE AND MEASUREMENT FOR DECOMINATING MEAT. - Google Patents

Description

Analogous method for the production of therapeutically effective 5-substituted aza-dibenzo-[a,d]-cycloheptenes.

The present invention relates to an analogous method for the production of therapeutically effective aza-dibenzo-f a,d]-cycloheptene derivatives of the general formula:

and their pharmaceutically acceptable acid addition salts, in which formula the dashed line denotes a possible double bond, A denotes hydrogen or one or more of the substituents halogen, lower alkyl, trifluoromethyl, al-

koxy, hydroxy and alkanoyloxy bound in the positions 6,7,8 and/or 9, B denotes the group of atoms required for, together with the carbon atoms to which it is bound, to form a pyridine nucleus, and Z denotes one of the groups

pretty

where Rj and independently of each other can be hydrogen, lower alkyl, lower hydroxyalkyl or a group which, together with the nitrogen atom to which they are attached, forms an optionally lower-alkyl-substituted 5- or 6-membered heterocyclic ring where one of the members can be an oxygen atom or an additional nitrogen atom.

Attention is drawn to patent applications no. 152,953 and 164,332, which likewise relate to the production of the 5-substituted aza-dibenzo-[a,d]-cycloheptenes described here, but according to other analogous methods.

The nomenclature used here is largely based on the nomenclature approved by Chemical Abstracts for dibenzo-cycloheptenes. The identification of the positions in the tricyclic system is illustrated by the following formula I for 5-(^-dimethyl-aminoethyl)-4-aza-10,11-dihydro-5H-dibenzo-[a,dj-cycloheptene, which is a of the preferred new compounds:

Included in formula I are the respective 1-aza-, 2-aza-, 3-aza- and 4-aza analogues, all of which fall within the definition given for B. By definition, the compounds according to formula I which contain a hydrogen atom at the Cg atom, in the following sometimes referred to as "saturated compounds", while the compounds which have a double-bonded ■substituent in the 5-Btil lift gene are sometimes referred to as "unsaturated compounds" or "alky liden compounds".

The substituent

includes NH 3 , lower-alkylamino (preferably methylamino), and di-lower-alkylamino (preferably dimethylamino), hydroxyalkylamino, (e.g. -hydroxyethylamino), di-(hydroxyalkyl)-amino, e.g. di-(£-hydroxyethyl)-amino, pyrrolidino, piperidino, morpholino and piperazino, including lower-alkyl-substituted analogues such as e.g. 4-methyl-piperazino.

The compounds of formula I are basic and form addition salts with acids. Some of these salts have greater solubility and are therefore better suited for the production of preparations than the free bases. Accordingly, the pharmaceutically acceptable acid addition salts of the above-mentioned free bases are included within the scope of the invention. Such salts include those derived from maleic acid, salicylic acid, succinic acid, methylsulfonic acid, tartaric acid, citric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.

The compounds of formula I and the aforementioned salts thereof are distinguished by their antihistaminic action, their antiserotonin action and their antianaphylactic action and are useful in the treatment of allergic disorders such as urticaria, coryza and sensitivity to pollen.

Among the classes of compounds encompassed by formula I (ie the "saturated compounds" pg "alkylidene compounds" of each of the 1-aza, 2-aza, 3-aza and 4-aza series), some appear to have better therapeutic properties than others. Although all the compounds have the properties described above, there is a certain connection between structure and activity as far as strength and applicability are concerned. Thus, e.g. The 4-aza compounds to be stronger as antihistamines than the isomers in the other positions. The compounds which are unsaturated in positions 10 and 11, turn out to be somewhat weaker than their saturated analogues.

The compounds of formula I can be administered in the form of pharmaceutical preparations where the active ingredient is present in admixture with a pharmaceutical carrier which is suitable for enteral or parenteral administration. Usually, a dose in the range from 0.1 mg to 15 mg of the active ingredient per kg body weight per day be appropriate.

A selection of the new compounds was tested with regard to therapeutic properties, more specifically antihistaminic action and antianaphylactic action, in comparison with related known compounds. The methods used were the following:

( X) Oral antihistamine action (AH-PD^q) in mice

A standard method was used where the two compounds were tested

know with respect to the ability to protect pertussis-sensitized mice (Kind.L.S., Bact.Rev. 22, 173, 1958) from death by intravenous injection of 25 mg/kg histamine (bas.e.equivalent), the compounds being given orally to fasting animals before being given histamine. The dose response values were used to determine the dose that protected 50% of the animals (AH-PD5Q) from death.

(2) Oral antianaphylactic effect (AA-PD^q) in mice

A standard method was used where the two compounds were tested on mice that had been sensitized 10 days earlier with pertussis vaccine and 0.05 ml horse serum, intraperitoneally. The compounds were given orally to fasted animals 1 hour before they were subjected to intravenous administration of 0.1 ml of diluted (1:4) horse serum. The dose response values were used to determine the dose that protected 50% of the animals (AA-PD^q).

(3) Oral acute toxicity (LD^q) in mice

A standard method described by Labelle, A. and Tislow, R., The Journal of Pharmacology and Experimental Therapeutics, Vol.

113 : 72, 1955.

(4) Oral antihistamine effect (AH-PD^q) on guinea pigs

A method similar to that described by Labelle, A; and Tislow, R., The Jour. of Pharm, and Exper. Therapeutics, 113:72, 1955. The compounds were tested for their ability to protect normal guinea pigs against death caused by intravenous injection of 1.1 mg/kg histamine dihydrochloride (twice the LD^^). The compound to be tested was given orally to fasting animals 1 hour before the histamine injection was made. The dose response values were used to determine the dose that protected 50% of the animals from death (AH-PD50).

The following Table I shows the oral antihistamine effect on mice (method 1), the antianaphylactic effect on mice (method 2) and the oral acute toxicity on mice (method 3) as well as therapeutic indices for a preferred compound among the new compounds, namely 4- aza-5-(N-methyl-4-piperidylidene)-10,11-dihydro-dibenzo-[a,d]-cycloheptene (compound A) in comparison with a corresponding, known des-aza compound, namely 5-( N-methyl-4-piperidylidene)-dibenzo-[a,d]-cycloheptene (compound B), which is known under the name "Cypro-heptadine".

It will be seen from the table that compound A, namely 4-aza-5-(N-methyl-4-piperidylidene)-10, 11 -dihydro-dibenzo-fa.d^-cycloheptene, has a far stronger antihistaminic effect and antianaphylactic effect than compound B, "Cypro-heptadine", and moreover, as shown by the toxicity values and the therapeutic indices, is much safer as a drug than the above-mentioned "Cyproheptadine".

The following Table II shows the oral histamine effect on guinea pigs (method 4) of the new compound 5-(2'-dimethyl-aminoethyl)-4-aza-5H-dibenzo-Ja, dj-cycloheptene (compound C) in comparison with the correspondingly, known des-aza compound 5-(2'-dimethylaminoethyl)-5H-dibenzo-[a,d]-cycloheptene (compound D), and for the new compounds 5-(2'-dimethylaminoethyl)-8-chloro -4-aza-10, 11-dihydro-5H-dibenzo-[a,d^-cyclohepten-maleate (compound G) and 5-(2'-dimethylaminoethyl)-4-aza-10,11-dihydro-5H- dibenzo-α, d}-cycloheptene maleate (compound H) in comparison with the known compound 2-[p-chloro-ct(2-dimethylaminoethyl)-benzyl}-pyridine maleate (compound J).

The compound 2-[p-chloro-Ol-(2-dimethylaminoethyl)-benzyl}-pyridine, better known under the name "Chlorpheniramine", has the formula:

Table III below shows the oral anti-anaphylactic effect on mice (method 2) of a selection of the new compounds in comparison with two known compounds, namely the above-mentioned compounds D and J.

It will be seen from the above-mentioned table, among other things, that the new compound 5 - (2'-dimethylaminoethyl)-4-aza-5H-dibenzo-[a,d]-cycloheptene (compound C) has a significantly higher anti-anaphylactic effect than the corresponding, known des-aza compound (compound D).

The new compounds of the general formula I are prepared by the carbnyl group in a compound of the general formula: in which the dashed lines A and B have the meanings indicated above and Z' denotes one of the groups

where Rj and R^ have the meanings given above, is reduced, as any hydrogen on the nitrogen atom in the amino group of the Z' group can be protected by substitution with an easily cleavable radical, preferably a benzyl radical, that a 5,1'-unsaturated compound, if desired, is hydrogenated to the corresponding 5,1'-saturated compound, and that an obtained compound of formula I is, if desired, subjected to one or more of the following final steps, in any order:

(a) hydrogenation at the 10, 11 position,

(b) cleavage of a protecting group attached to the nitrogen atom

in the amino group which forms part of the group Z',

(c) transferring to a pharmaceutically acceptable acid addition salt.

If the compound of formula I" used as starting material contains either double bonds in the ring system or substituents which are easily cleaved but which must be retained, it is important that the reduction at the carbonyl group is carried out in a selective manner. This is preferably carried out using lithium aluminum hydride or the like reducing agents that lead to selective reduction of the archide group.

Any subsequent hydrogenation of products that are unsaturated

in the 5,1' and/or 10,11 positions of the respective saturated compounds is preferably carried out catalytically, e.g. using a palladium catalyst. However, such a reduction is not selective. If thus beg-

if these double bonds are present and only one of them is to be hydrogenated, or if the molecule contains other easily reducible bonds, the aforementioned hydrogenation cannot be carried out without special precautions being taken, such as protection or subsequent reintroduction of the respective bonds.

Any subsequent reductive debenzylation (which is carried out if the end product is to contain a primary or secondary amino group which has been present in the compound used as starting material and has been protected by benzylation before the compound was used in the process according to the invention), is also preferably carried out by catalytic hydrogenation using of Pd/C. However, such debenzylation can easily be carried out in a selective manner by stopping the hydrogenation as soon as the theoretical amount of hydrogen has been absorbed.

Any subsequent transfer of the product to a salt can be carried out by conventional methods.

The compounds of formula I" used as starting materials are mainly prepared according to the methods known for the synthesis of their des-aza analogues, i.e. corresponding compounds which have a benzene ring instead of the pyridine ring in the tricyclic nucleus in the compound of formula I".

A preferred method is that which first involves the condensation of a 5-keto-aza-dibenzo-cycloheptene (IIA) with a bromoacetic acid ester (preferably ethyl bromoacetate) in the presence of zinc, namely the well-known Reformatsky condensation, which leads to the formation of a carbalkoxymethyl- intermediate III as follows,

In this reaction scheme, A, B and the dashed line have the meanings indicated above. The reaction is advantageously carried out in an inert solvent such as in toluene or xylene at reflux temperature, and the product III is separated from the reaction mixture by methods well known in the art. The ester III is then subjected to dehydration, e.g. on heating with thionyl chloride, to form the exocyclic unsaturated analogue, IV, which is saponified by treatment with acid or alkali to the carboxylic acid V. Carboxylic acid V is converted to an amide VI, by first forming the acid chloride with thionyl chloride, which is then reacted with an amine HNRjR^, where Rj and have the above stated meanings, but preferably neither of them is hydrogen. These reaction steps are illustrated in the following reaction scheme, where for reasons of expediency only the 5-position in the tricyclic system is shown:

When reducing the double bond shown in formula VI by catalytic reduction in the presence of e.g. of palladium gives the corresponding saturated compound.

The compounds of formula IIA which are referred to above in connection with the preparation of the compounds used as starting materials in the process according to the invention can be prepared by many different methods, among which the intramolecular Friedel-Crafts cyclization of an ortho-styryl- or ortho-phenethyl-pyridine-carboxylic acid (VIII) according to the following reaction scheme:

In this reaction scheme, A, B and the dashed line have the meanings indicated above. The cyclization of the ortho-substituted pyridine carboxylic acid (VIII) is preferably carried out by heating it with polyphosphoric acid at a temperature in the range from 100 to 160°C, whereby the cyclization takes place with formation of the ketone, IIA. It is thus obvious that the isomer formed is determined by the choice of pyridine carboxylic acid. Starting, for example, with a compound VIIIA, such as 3-styryl-picolinic acid or 3-phenethyl-2-picolinic acid, a 4-aza-ketone (IIAd) is formed:

By starting in a similar way with the 4-styryl or 4-phenethyl-nicotinic acids (VIIIB), the corresponding 3-aza-ketones (IIAc) are obtained. From the 3-styryl or 3-phenethylisonicotinic acids (VIITC) 2-aza-ketones (iIAb) are obtained and from the 2-styryl- or 2-phenethyl-nicotinic acids (VIIID) 1-aza-ketones (IlAa) are obtained.

The cyclization illustrated above is carried out on free pyridine carboxylic acids (VIII). Alternative and equivalent methods will be apparent to one skilled in the art. Thus, instead of the acid, a functional derivative of this can be used, such as a corresponding ester, an amide, a nitrile or an isomeric lactone, or the carboxylic acid can first be transferred to an acid halide, e.g. chloride, using a chlorinating agent such as thionyl chloride, phosphorus trichloride or oxalyl chloride with subsequent treatment, e.g. with a Friedel-Crafts catalyst such as aluminum chloride, whereby cyclization takes place with consequent formation of the respective compound encompassed by the general formula IIA. The cyclization is usually carried out according to conventional methods for carrying out a Friedel-Crafts reaction, namely by heating the mixture in an inert solvent such as carbon disulphide, petroleum ether, benzene and the like and isolating the cyclized product from this.

Other derivatives of the pyridine-carboxylic acids (VIII), such as certain lactones of which examples are given below, can likewise be used as starting materials in the cyclization process leading to the intermediate products

IIA.

The phenethyl-pyridine-carboxylic acid starting materials with the general formula can be easily prepared from the corresponding styryl-pyridine-carboxylic acids by known methods such as by catalytic hydrogenation or by independent syntheses, which will be described further on. As will be noted, the cyclic ketones (IIA) with an unsaturation between the stillin-,-genes 10 and II are produced, occasionally preferentially from the 10,11-dihydro-analogues of dehydro-Benzene cannot strictly speaking be called "inert" in a Friedel-Crafts reaction.

However, it can be considered here as practically inert..

genation with selenium dioxide or by other methods that give the same result, such as by treatment with N-bromosuccinimide or by bromination under the influence of sunlight, with subsequent dehydrohalogenation using triethylamine, alcoholic potassium hydroxide or other known dehydrohalogenation agents .

In particular, the 1-aza-ketones (IIAa) are preferably prepared in one of the possible ways shown in the following reaction scheme:

</> In the preceding reaction scheme, the turnover is carried out between X

and a 2-methyl-nicotinic acid ester (IX) such as ethyl-2-methyl-nicotinate by heating with reflux in acetic anhydride, whereby a lactone (XI) is obtained. The lactone (XI) can be transferred directly to the corresponding cyclic ketone (HAaa) by heating with polyphosphoric acid. As shown, it can also be transferred indirectly to the cyclic ketone via a 2-styryl-nicotinic acid VIIIDa. By treating the lactone (XI) with phosphorus and iodine in water (or with 57% aqueous iodic acid and phosphorus) or by reducing the 2-styryl-nicotinic acid (VIIIDa), the corresponding 2-phenethyl-nicotinic acid (VIIlDb) is obtained. This latter is transferred by heating with polyphosphoric acid to the 10, 11-dihydro analogue (IIAad) and IIAaOL

In the reaction described above, it is a chemical transformation

of IX to XI known in the field for A ff H, but it is shown here to provide a basis for the preparation of the cyclic ketones (IIAa ) and their 10,11-dihydro analogues (IIAaa) where A has meanings other than hydrogen .

The 2-aza-ketones (IIAb) are preferably prepared in the following steps:

In this series of reactions, a 4-methyl-nicotinic acid ester (XII) such as ethyl-4-methyl-nicotinate is condensed with a phenylacetonitrile (XIII), whereby the respective ketonitrile (XIV) is formed. Preferably, a basic catalyst such as an alkali metal alkoxide, e.g. sodium ethoxide in ethanol. However, other condensing agents can also be used, such as sodium amide or sodium hydroxide in a solvent such as benzene or toluene. The conversion to the ketone, XV, is carried out by heating XIV with a strong mineral acid, preferably concentrated hydrobromic acid. (Alternatively, this step can be performed by heating XIV with concentrated sulfuric acid, whereby the compound is converted to the corresponding acid amide. This can be hydrolyzed, and the product can be decarboxylated by adding water to the reaction mixture with continued heating). Reduction of the ketone (XV) is preferably carried out by the well-known Wolff-Kishner reaction which comprises heating XV with hydrazine hydrate in a high-boiling polar solvent such as trimethylene glycol in the presence of an alkali such as sodium hydroxide or potassium hydroxide. Instead of the Wolff-Kishner reduction, one can also use copper chromite in dioxane at a temperature of approx. 160°C and a hydrogen pressure of approx. 100 atmospheres. This reduction gives a 3-phenethyl-4-methyl-pyridine, XVI. This latter connection is transferred, e.g. by oxidation with selenium dioxyde in pyridine, to the corresponding 3-phenethyl-isonicotinic acid (VHICb), which, on heating with polyphosphoric acid, undergoes cyclization to the cyclic ketone IIAbp.

It will be seen that by using a para-substituted phenylacetonitrile (XIII) a cyclic ketone (UAbp) with the aforementioned substituent in the 7-position will be obtained. With a meta-substituted phenylacetonitrile (CIIl) a mixture of ketones (IIAbp) is obtained, one having the substituent in the 6-position and the other having the substituent in the 8-position. These can be separated either in this final step, or the isomeric intermediates can be separated in any step in the series of reactions according to known methods, such as by fractional distillation, fractional crystallization, column chromatography and the like.

The 10, 11 -dehydro-analog (iIAbtt) of IIAbfi is preferably prepared from the latter by dehydrogenation, either with the help of selenium dioxide in pyridine or by treating IIAbpm with N-bromosuccinimide with subsequent dehydro-bromination of the bromine intermediate thus obtained .

In the preparation of the 3-aza-ketones (IIAc), the following series of reactions is preferred:

In this series of reactions, a 4-methyl-nicotinic acid ester (XII) such as the ethyl-4-methyl-nicotinate, namely the same starting material that was used in the preferred method described above for the preparation of compounds of the 2-aza series, is reacted with X by heating in acetic anhydride with reflux, thereby obtaining a 4-styryl-nicotinic acid ester (VIIIBa<1>). By reacting the ester (VIIIBa<1>), preferably catalytically such as with palladium and hydrogen, with subsequent hydrolysis of the ester group, obtain

es a 4-phenethyl-nicotinic acid (VIIIBb) which, when heated with polyphosphoric acid, is cyclized to the corresponding 3-aza-ketone (iIAcj*). The 10, 11-dehydro analogues (iIAcd) of IIAcp are produced either by dehydrogenation of the ketone itself (IIAcp.) as previously described, or by hydrolysis of VIIIBa' to the corresponding free carboxylic acid (VIIIBa) with subsequent heating of the latter with polyphosphoric acid. If the cyclization is carried out at elevated temperatures in the region of around 190°C, IIAcO is mainly obtained. At lower temperatures, a lactone, namely the 4-aralkyl isomer of XI, is formed as a by-product. When this lactone is heated with polyphosphoric acid according to the procedure described for the 1-aza series, it is in turn converted to the cyclic ketone (IIAca). ;For the production of the 4-aza-ketones (iIAd), the following series of reactions is preferably used: ;In this reaction scheme, a nicotinic acid ester (XVII), preferably ethyl nicotinate, is transferred to a 3-phenethyl-pyridine (XX) following the same series of reactions as described for the respective homo-compounds in the preparation of the 2-aza series, The condensation of XVII with a phenylacetonitrile (XIII) is preferably carried out in ethanol in the presence of sodium ethoxyde or other condensing agents such as those used in the above described condensation "XII + XIII —*XIV". Instead of the Wolff-Kishner reduction, copper chromite in dioxane can also be used at approx. 160°C under a hydrogen pressure of approx.

100 atmospheres. The phenethyl pyridine (XX) is transferred to its N-oxide (XXI) by means of a peroxyacid, such as hydrogen peroxide and acetic acid. By reacting XXI with dimethylsulphate and then with aqueous sodium cyanide solution, a 2-cyano-3-phenthyl-pyridine (XXII) is obtained. The nitrile (XXII) can be cyclized directly to the corresponding 4-aza-ketone (Hadp) by heating with polyphosphoric acid, or it can first be hydrolyzed to the corresponding carboxylic acid (VIIIAb) which is then cyclized. The 10, 11 -dehydro analogues (iIAdtt) of IIAdJS can be prepared by direct dehydrogenation of the latter, e.g. with selenium dioxide in pyridine, or by any of the methods indicated in the following examples,

The N-oxides XXI are particularly valuable in the production of the 4-aza-ketones (IIAd) because further other conversions can also be carried out which ultimately lead to such ketones (IIAd). In particular, by reacting an N-oxide (XXI) with acetic anhydride, the corresponding 2-acetoxy-3»phenethyl-pyridine is obtained, which can be hydrolysed to its 2-free-hydroxy analogue using aqueous mineral acid, e.g. . hydrochloric acid. The hydroxy group can then be replaced by bromine (using phosphorus oxybromide), whereby the respective 2-bromo-3-phenethyl-pyridine is obtained. By reacting this latter intermediate with butyl lithium and then with carbon dioxide, the carboxylic acid (VIIIAb) is obtained which can then be cyclized to IIAd£.

It will be obvious to the person skilled in the art that there are countless

variants of the reactions described above which will lead to the formation of phenethyl and styrylpyridine carboxylic acids. All these reactions are considered chemically equivalent to those illustrated above. For example, the reaction scheme for the production of a 2-aza-ketone (IIAb) can be adapted for the production of a 4-aza-ketone (IIAd) simply by using a 2-methyl-nicotinic acid ester such as ethyl-2 -methylnicotinate as starting material. The close analogy between the methods for the preparation of the 1-aza-ketones (HAa) and the 3-aza-ketones (iIAc) will also be readily seen.

Below is illustrated the preparation of compounds of formula IIA, (Procedure 1-4) and the preparation of those used as starting materials

L

compounds of the general formula I" from said compounds IIa (Method 5).

I. MANUFACTURING OF PREFERRED OUTPUT GSM A T ERIALS

Method 1 1-aza-10, 11-dihydro-5H-dibenzo-[a,dj-cyclohepten-5-one and

1-aza-5H-dibenzo-{a,dj-cyclohepten-5-one

A. 2-( ft- hydroxy- tf- phenyl) - ethyl- nicotinic acid - lactone- hydrochloride

Stir and reflux a mixture of 65 g of ethyl-2-methyl-nicotinate, 57 g of benzaldehyde and 37 ml of acetic anhydride for 20 hours. Then cool and pour the mixture into 2.0 N hydrochloric acid. Filter off the solid after crystallization and recrystallize it from ethanol. 13.5 g of 2-(<1-hydroxy-ft-phenyl)-ethyl-nicotinic acid lactone hydrochloride are obtained, m.p. 183 - 185°C.

B. 2-styryl-nicotinic acid

Mix 60 g of red phosphorus, 20 g of iodine in 1.5 liters of glacial acetic acid and add in portions to the mixture thus obtained 176 g of 2-((&-hydroxy-£-phenyl)-ethyl-nicotinic acid lactone hydrochloride). Heat for 20 hours and filter the hot solution through a sintered glass funnel. Pour the filtrate into water and filter the precipitate after the time required for its formation and coagulation. Dissolve the filtered precipitate in 2 liters of hot, diluted (10 - 15 %) aqueous ammonia, filter again, and neutralize the filtrate with acetic acid. Cool and separate the precipitated 2-styryl-nicotinic acid by filtration and recrystallize from ethanol. M.p.: 219 - 221°C; yield: 130 g.

C. 2-phenethyl-nicotinic acid

(1) Mix 22 g of 2-sty-yl-nicotinic acid, 200 ml of ethanol and 20 ml of a 25% aqueous solution of sodium hydroxide in a (Parr) shaker-type hydrogenation apparatus. The mixture is hydrogenated at a hydrogen pressure of approx. 3.6 atmospheres using a freshly prepared Raney nickel catalyst. After the theoretical amount of hydrogen has been absorbed (1 mole per mole of acid), usually after about 30 - 60 minutes, the mixture is filtered, and the filtrate is concentrated by heating on a steam bath. The residue dissolves in water. After acidification, the impure phenethyl-nicotinic acid is filtered off. After recrystallization from benzene-hexane, the melting point is 162 - 163°C. (2) Alternatively, 2-phenethyl-nicotinic acid can be prepared in the following way: 100 g of the lactone from part A of this example is heated with 1 liter of 57% iodic acid with the addition of 60 g of red phosphorus over a period of 2 hours. The mixture is heated under reflux for 18 hours and filtered hot. Most of the excess iodic acid is removed by concentration, and the remaining solution is neutralized with aqueous ammonia, whereby 2-phenethyl-nicotinic acid precipitates.

D. 1-aza-10,11-dihydro-5H-dibenzo-[a,d)-cyclohepten-5-one

50 g of 2phenethyl-nicotinic acid and 500 g of polyphosphoric acid are mixed and heated at 160 - 165°C for 5 - 6 hours with stirring. The mixture is then cooled, poured into ice water, neutralized with aqueous ammonia and extracted with ether. The ether extract is washed with 10% sodium hydroxide solution. The ether layer is dried and concentrated to a residue which, upon crystallization from hexane, gives the desired ketone. Sm.p. 62 - 64°C.

E. 1-aza-5H-dibenzo-(a,d]-cyclohepten-5-one

(1) Dissolve 20 g of the ketone from part D of this example in 150 ml of acetic acid, after which 40 ml of 30% hydrogen peroxide is added. The mixture is heated for 24 hours in a water bath maintained at 65 - 70°C and then poured into ice water. The mixture is neutralized with concentrated sodium hydroxide solution and allowed to crystallize. After filtration, recrystallization from dilute ethanol and air drying, the N-oxide of the ketone from part D is obtained. (2) To 100 ml of acetic anhydride which is heated with reflux cooling, 15 g of the N-oxide produced under point (l) is added. The mixture is heated with reflux cooling for 10 hours and then poured into water. The mixture is allowed to stand for several hours (to hydrolyse any excess of anhydride) and is then neutralized with sodium bicarbonate. The mixture is extracted with chloroform, and the chloroform extract is evaporated to dryness. The residue is processed

with 100 ml of 48% bromic acid, after which 100 ml of acetic acid is added and the mixture is heated with reflux for 6 hours. After concentration in vacuum, the residue is dissolved in water. The solution is made alkaline with aqueous ammonia. The mixture is extracted with ether. The ether extract is concentrated to a residue, which on crystallization from petroleum ether gives 1-aza-5H-dibenzo-[a,d]-cyclohepten-5-one with m.p. 95 - 9b°C.

Procedure 2

2-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-one and 2-aza-5H-dibenzo-[a,d}-cyclohepten-5-one

A. 3-phenethyl-isonicotinic acid via (t-(4-methyl-nicotinyl)-phenylacetonitrile; benzyl-(4-methyl-3-pyridyl)-ketone and 3-phenethyl-4-methyl-pyridine

Preferably, 3-phenethyl-isonicotinic acid is prepared in the following way: (1) 3-phenethyl-4-methylpyridine is first prepared analogously to the method described in method 4, part A (1-3), starting with -

point in ethyl-4-methyl-nicotinate, via tt.-(4-methyl-nicotinoyl)-phenylacetonit-

ryl and benzyl-(4-methyl-3-pyridyl) ketone.

(2) A mixture of 8.6 g of the 3-phenethyl-4-methyl-pyridine thus obtained, 50 ml of dry pyridine and 12 g of powdered selenium dioxide is then heated with reflux for 3 hours, diluted with CHCl^ and filtered. The filtrate is evaporated, the residue is dissolved in dilute aqueous ammonia, and the solution is extracted with ether. The remaining aqueous layer is then acidified with acetic acid, and the precipitate is filtered and recrystallized from isopropyl ether. 3.9 g of the desired product is obtained. Sm.p. : 99 - 101°C.

B. Alternative method for the production of 3-phenethyl-isonicotinic acid

Alternatively, 3-phenephyl-isonicotinic acid can be prepared according to the following stepwise procedure: (1) A solution of 24.2 g of 3-styryl-4-nitro-pyridine-N-oxide in 250 ml of glacial acetic acid is reduced in a Par r hydrogenation apparatus in the presence of 10 g of 5% palladium on carbon as catalyst, at 55 - 60° and approximately 3.6 atmospheres of pressure. The reduction usually takes about 6 hours. The mixture is then filtered, the filtrate is concentrated in vacuo on a steam bath, and the residue is dissolved in 150 ml of 20% hydrochloric acid. The acidic solution is concentrated to dryness, and the impure 3-phenethyl-4-amino-pyridine chloride which is thereby obtained as a residue is used directly in the method described in point (2) below. (2) (a) The product obtained under point (1) is dissolved in 100 ml of 10% hydrochloric acid, and the solution is cooled to 0 - 5°C. A solution containing 6.9 g of sodium nitrite in 50 ml of water is then added slowly, while the temperature is kept at 0 - 5°C. The diazonium salt solution thus formed is stirred for a further <j>hour. Meanwhile, a solution of 0.3 mol of cuprocyanide is prepared according to the guidelines given in "Organic Synthesis" Vo. 1, p. 500. The solution is cooled slowly to 0°C, after which it is added to the above, cooled diazonium salt solution. The mixture is allowed to warm to room temperature and stirred for a further 1 hour. The solution is then made alkaline by the careful addition of 50% aqueous sodium hydroxide solution, while it is cooled thoroughly in a bath of ice and salt. The 3-phenethyl-4-cyano-pyridine obtained is extracted with chloroform. The chloroform extract is washed, and the chloroform is evaporated.

(b) Alternatively, the diazonium salt solution from the one under point (a) can first be transferred to 3-phenethyl-4-hydroxy-pyridine by heating with 25% aqueous sulfuric acid with reflux, after which the latter over-

is led to its 4-bromo analog by heating in a glass-lined autoclave for 6: hours at 160 - l65°C with three times its weight of phosphorus oxybromide. 4 - the bromine analogue is isolated by pouring the reaction mixture into ice water, neutralizing with sodium carbonate, extracting with chloroform and distilling off the solvent from the extract. The 4-bromo compound thus obtained is further converted by dissolving it in four times its weight of anhydrous pyridine, adding an equivalent amount of cuprocyanide, heating gently to 110 - 111°C until the first exothermic reaction is over and finally heating under vacuum using a bath temperature of 200 - 220°C, the 3-phenethyl-4-cyano-pyridine being distilled off as it is formed. (c) Another alternative method for the preparation of 3-phenethyl-4-cyano-pyridine is described in subsection (a) of part A (5) of Method 4. (3) A solution containing 20.8 g of 3-phenethyl- 4-cyano-pyridine, 40 g of potassium hydroxide, 60 ml of water and 150 ml of ethanol are heated under reflux and with stirring for 24 hours or until the evolution of ammonia has ceased. The mixture is evaporated to half the volume, and the remaining part is poured into water. The resulting solution is cooled and extracted with ether. The aqueous solution is carefully neutralized with acetic acid to crystallize the 3-phenethyl-isonicotinic acid, which is then filtered and recrystallized from ethanol.

C. 2-aza-10,11-dihydro-5H-dibenzo-ja,d]-cyclohepten-5-one

(1) Preferably, 2-aza-10,11-dihydro-5H-dibenzo-J,d]-cyclohepten-5-one is prepared by heating 3-phenethyl-isonicotinic acid with polyphosphoric acid analogously to the method described in part D of Procedure 1. (2) Alternatively, 50 ml of purified thionyl chloride are added to 20.8 g of 3-phenethyl-isonicotinic acid. The mixture is heated on a steam bath for j hour. The excess of thionyl chloride is removed under vacuum, and the residue is suspended in 2.0 liters of anhydrous petroleum ether (boiling range 60 - 90°C). With vigorous stirring, slowly add 26 g of anhydrous aluminum chloride granules. The resulting solution is stirred for 4 hours at room temperature, after which the solution is poured into a mixture of 2 kg of ice and 25 ml of concentrated hydrochloric acid. The petroleum ether is separated and lifted. The aqueous solution is made alkaline with 50% aqueous sodium hydroxide solution, while it is kept chilled to 5 - 10°C. The product, 2-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-one, is extracted with chloroform, and the chloroform is removed. After trituration with ice-cold petroleum ether omkrystal-L

the residue is lysed from a mixture of benzene and hexane.

D. 2-aza-5H-dibenzo-α,d-cyclohepten-5-one

(1) 2-aza-5H-dibenzo-[a, d)-cycloheptene-5 is preferably prepared -

on by dehydrogenation of its 10,11-dihydro analogue (can be prepared as described in Part C above) analogously to the method described in Part C, section (1) of Method 4. (2) Alternatively, the aforementioned dehydrogenation can be carried out as follows method: A solution of 19.7 g of 2-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-one in 150 ml of dry carbon tetrachloride is added slowly with vigorous stirring to a suspension of 17.8 g of N-bromosuccinimide in 500 ml of carbon tetrachloride containing 0.1 g of benzoyl peroxide. After the first exothermic reaction is over, the mixture is heated under reflux and with stirring for a further 3 hours. The succinimide thus formed is removed by filtration, and the carbon tetrachloride solution is concentrated to dryness. 30 ml of triethylamine is added to the residue, and the mixture is heated on a steam bath for 18 - 20 hours. After filtration, the filtrate is concentrated to a residue, which is poured into water. The resulting mixture is then extracted with chloroform, and 2-aza-5H-dibenzo-[a,dj-cyclohepten-5-one is isolated from the extract and purified by recrystallization from dilute ethanol.

Procedure 3

3-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-one and 3-aza-5H-dibenzo-[a,d]-cyclohepten-5-one

A. Ethyl-4-styryl-nicotinate

A mixture of 165 g ethyl-4-methyl-nicotinate, 106 g benzaldehyde

and 1 liter of acetic anhydride is heated with reflux for 4 hours. The mixture is poured onto ice, filtered and recrystallized from benzene, whereby the ester is obtained.

B. 4-phenethyl-nicotinic acid

(l) A mixture of 50 g of the ester from part A of this example, 50 g of potassium hydroxide, 50 ml of water and 200 ml of ethanol is heated under reflux for 6 hours. The mixture is concentrated to remove the solvents, and the residue is dissolved in 200 ml of water. After neutralization with acetic acid, the mixture is allowed to crystallize. After filtration and drying, 22 g of the 4-styryl-nicotinic acid thus obtained is hydrogenated in a similar manner as described in part C of Method 1.

(2) Alternatively, dissolve 20.2 g of the ester from part A of this example

in 200 ml of ethanol with subsequent hydrogenation under approximately 3.6 atmospheres of hydrogen pressure at room temperature in the presence of a catalyst consisting of 5 g of 5% palladium on carbon. The ethyl-4-phenethyl-nicotinate thus obtained is soaped in a known manner.

C. 3 - aza - 10, 11 - dihydro - 5H- dibenzo - {a, d) - cyclohepten- 5 - one

80 g of 4-phenethyl-nicotinic acid and 1 kg of polyphosphoric acid are mixed, after which a procedure analogous to that described in part D of Method 1 is followed. By recrystallization from benzene-petroleum ether, get-

es a melting point of 66 - 67°C.

D. 3-aza-5H-dibenzo-ja,d]-cyclohepten-5-one

(l) 50 g of 4-styryl-nicotinic acid (the compound mentioned under point (1) in part B above) is mixed with 1 kg of polyphosphoric acid, after which the procedure described in part A of Method 1 is followed. By recrystallization from benzene -hexane, a melting point of 157 - 158°C is obtained. (2) Alternatively, 3-aza-5H-dibenzo-[a,dj-cyclohepten-5-one can be prepared by dehydrogenation of the corresponding 10,11-dihydro compound (the product from part C of this example) in a similar manner as described in section (2) of part D of Procedure 2.

Procedure 4

4-aza-10,11-dihydro-5-dibenzo-[a,d]-cyclohepten-5-one and 4-aza-5H-dibenzo-[a,d]-cyclohepten-5-one

A. 2- Cyano- 3- phenethyl- pyridine via ot- nicotinoyl- phenyl- acetonitrile, benzyl-(3-pyridyl)- ketone, 3- phenethyl- pyridine and 3- phenethyl- pyridine- N-oxide (1) To a solution of 34 g of metallic sodium in 500 ml of absolute ethanol which is heated with reflux, a mixture of 260 g of ethyl nicotinate and 133 g of phenylacetonitrile is added dropwise. After 4 hours, the mixture is poured onto ice and extracted with ether. The aqueous phase is neutralized with acetic acid, and the product is allowed to crystallize. The crystallized product is filtered off, washed with water and dried in air. The lft-nicotinoyl-phenylacetonitrile thus obtained (m.p. 137 - 141°C) is used in the next step (2) without further purification.

(2) The nitrile obtained under point (l) is heated with reflux cooling for 16 hours with 1.4 liters of concentrated bromic acid. The mixture is poured over ice and allowed to crystallize. The hydrobromide is filtered off, suspended in water and neutralized with sodium carbonate solution. After crystallization, filtration and drying in air, 1 26 g of benzyl-(3-pyridyl) ketone with melting point 53 - 56°C are obtained.

(3) 26 g of the ketone obtained under point (2) are mixed with 11 g of sodium hydroxide, 11 ml of 85% hydrazine hydrate and 175 ml of diethylene glycol. Mixture-

one is placed in a distillation apparatus and heated at 235 - 240°C for 3 - 4 hours, so that the distillation is complete. After cooling, the mixture and the distillate are extracted with benzene. The combined benzene extracts are washed with water and distilled in vacuo. The fraction that boils at 120 - 128°C

is taken care of. Yield: 21 g.

(4) A mixture of 183 g of 3-phenethylpyridine (the product obtained under point (3)), 120 ml of 30% hydrogen peroxide and 300 ml of glacial acetic acid is heated for 20 - 24 hours at 60 - 65°C. The mixture is then poured into ice water, and the pH value is adjusted to 8-9 with aqueous ammonia. The precipitate is filtered off and dissolved in hexane. 150 - 158 g of 3-phenethyl-pyridine-N-oxide with m.p. 82 - 89°C (5) (a) 2-cyano-3-phenethyl-pyridine is preferably prepared from the N-oxide obtained under point (4) in the following way: 75.6 g of dimethylsulphate is added dropwise while stirring to 118, 8 g of 3-phenethyl-pyridine-N-oxide. The mixture is heated at 85°C

for 3 hours, cool and dissolve in 1 80 ml of water. The aqueous solution is added dropwise to a stirred solution of 88.2 g of sodium cyanide in 250 ml of water. This is carried out under a nitrogen atmosphere, while the reaction temperature is kept in the range 0 - 5°C. After stirring for 6 hours at 0°C, the mixture is allowed to warm to room temperature by standing overnight. The mixture is extracted with chloroform and distilled in vacuo after washing with water. The fraction that boils at 160 - 167°C at 0.8 Torr is collected. (A higher-boiling fraction, which boils at 190 - 195°C/l.5 Torr, is made up of the 4-cyano-isomer, which can be used as an intermediate in the preparation of the 2-aza-ketone, see part B of Method 2) .

(b) Alternatively, add 98 g of 3-phenethyl-pyridine-N-oxide to 1 liter of vinegar -

acid anhydride, and the mixture is heated under reflux for 20 hours. The excess of solvents is distilled off, and the residue is poured into water. The mixture is neutralized with base, and the product is extracted with chloroform. The chloroform is distilled off, 200 ml of 20% sodium hydroxide solution is added to

the residue, and the resulting solution is heated at reflux for 6 hours. The mixture is cooled and neutralized with acetic acid and left to precipitate. The 2-hydroxy-3-phenethyl-pyridine thus obtained is transferred to its 2-bromo analogue in a similar manner as in the second and third steps of the forward

procedure described in subsection (b) of part B (2) of Procedure

tea 2.

B. 4-aza-10,11-dihydro-5H-dibenzo-| a, d]-cyclohepten-5-one

(1) 99 g of 2-cyano-3-phenethyl-pyridine and 5 kg of polyphosphoric acid are stirred and heated at 180°C for 20 - 24 hours. The mixture is poured onto ice, neutralized with 50% aqueous sodium hydroxide and extracted with chloroform. After concentration in a residue, with subsequent trituration with hexane and filtration, the desired ketone is obtained. Sm.p. 68 - 73°C.

(2) Alternatively, cyclization can be carried out in two steps as follows:

(o) A mixture containing 25 g of 2-cyano-3-phenethyl-pyridine, 25 g of potassium hydroxide (dissolved in 50 ml of water) and 100 ml of ethanol is heated for 24 hours at reflux temperature. You then proceed analogously to the method described in part B (3) of Method 2, whereby 3-phenethyl-picolinate is obtained. (b) A mixture of 20 g of 3-phenethyl-picolinic acid and 200 g of polyphosphoric acid is heated for 6 hours at 105 - 110°C. You then proceed in a similar way as described in part D of Procedure 1.

C. 4-aza-5H-dibenzo-[a,d]-cyclohepten-5-one

(1) A mixture of 15 g of the ketone obtained as described in part B of this example, 15 g of selenium dioxide and 60 ml of pyridine is heated with reflux cooling for 4 hours under a nitrogen atmosphere. The mixture is cooled and the precipitate is filtered off and washed with ethanol. The filtrate and washing liquid are combined and concentrated in vacuo to a residue. Water is added to the residue, and the resulting mixture is made alkaline with aqueous ammonia, after which it is extracted with chloroform. The chloroform solution is washed with water and concentrated to a residue. Crystallization from isopropyl ether or benzene-hexane yields the desired product, with a melting point of 118 - 119°C. (2) Alternatively, dehydrogenation can be carried out in the following way: To a solution of 50 g of 4-aza-10, 11-dihydro-5H-dibenzo-ja.d]-cyclohepten-5-one in 150 ml of anhydrous cymene is added 30 g of a catalyst consisting of 5% palladium on the kitli, and the mixture is heated under reflux for 24 hours. The resulting mixture is cooled, and the palladium and carbon are filtered off. The filtrate is poured

into 250 ml of 10% hydrochloric acid. The cymen layer is separated and lifted. The remaining acidic solution is neutralized with aqueous ammonia, and the resulting oil is extracted with chloroform. The chloroform is removed, and the product is recrystallized from dilute ethanol.

L

The preceding Procedures indicate the preparation of ketones of formula IIA. All these procedures lead to aza-dibenzo-cycloheptenones which are unsubstituted in the benzenoid ring. To prepare ketones with a substituent L in one or more of the 6-, 7-, 8- and 9-positions, as mentioned above, it is only necessary to use the suitably substituted reactant. In Methods 1 and 3, benzaldehyde is used as reactant, while in Methods 2 and 4 phenylacetonitrile is used. If these reactants are substituted, the substituent will be carried to the respective aza-dibenzo-cycloheptenone, in which position will depend on the position in the original reactant. For example, a para-substituent in the original reactant leads to a 7-substituted aza-dibenzo-cycloheptenone, while an ortho-substituent appears in the 19-position and a meta-substituent leads to a mixture consisting of a 6-substituted and an 8-substituted aza-dibenzo-cycloheptenone. (For the separation of a mixture of 6- and 8-substituted aza-dibenzo-cycloheptenones, column chromatography is preferably used, where the mixture is adsorbed on aluminum oxide and eluted with mixtures of benzene and hexane in varying proportions. Combining eluates that have been detected by analysis in the infrared or the ultraviolet range or by thin-layer chromatography, give the respective isomers separated from each other). The original reactant, namely the benzaldehyde or the phenylacetonitrile, may thus have an o-, m- or p-substituent, such as methyl, chlorine, bromine, trifluoromethyl, methoxy and the like, and such a substituent will be present in the corresponding position in the obtained aza-dibenzo-cycloheptanone. The substituted, original reactants, such as p-chloro-phenylacetonitrile or p-trifluoromethylbenzaldehyde, are either known compounds or can be easily prepared according to methods that will be known to a person skilled in the field. Method 5 5 - dimethylcarboxamidomethylidene-4 - aza - 10 , 11 - dihydro - 5H - dibenzo- [ a , dj - cycloheptene A. To a stirred mixture of 13 g of zinc (20 mesh) and 33.4 g of ethyl bromoacetate in 400 ml of benzene -toluene (1:1) is added dropwise to a solution of 41.4 g of 4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-one. • The mixture is heated for 2 hours in a steam bath, after which 13 g of zinc is added and the heating is continued for 4 hours. After cooling, 10% acetic acid is added, and the layers are separated. The aqueous phase is extracted with benzene, and the benzene fractions are combined and concentrated to a residue. Vacuum distillation yields 5-hydroxy-5-carbethoxymethyl-4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclo-heptene.

B. 20 g of the product from step A is dehydrated by heating with

90 - 100°C. with 100 ml of acetic anhydride containing 1 -2% sulfuric acid. After 3 hours, the mixture is concentrated in vacuo, diluted with water, neutralized and extracted with ether. Concentration of the mixture to a residue and vacuum de-scaffolding gives 5-carbethoxy-methylidene-4-aza-10, 11-dihydro-5H-dibenzo-(a,dj-cycloheptene. C. 15 g of the product from step B heated on a steam bath for 6 hours under reflux with a mixture of 15 g of potassium hydroxide, 50 ml of water and 150 ml of ethanol. The mixture was concentrated to a residue, after which water was added and extracted with ether. The aqueous layer was neutralized with acetic acid and allowed to stand for crystallization. The precipitate is filtered and recrystallized from aqueous methanol, whereby 5-carboxymethylidene-4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene is obtained. D. 12 g of the acid obtained in step C is heated by refluxing with 50 ml of thionyl chloride. After concentration in vacuum, with the subsequent addition of 50 ml of benzene, the mixture is evaporated to a residue. The residue is taken up in 150 ml of benzene, and a solution of 9 g of dimethylamine in benzene is added while stirring. Stir the mixture es and heated with reflux i5. hours, after which it is poured into water. The mixture is made alkaline with sodium carbonate, and extracted with benzene. After concentration in vacuum, 5-dimethylcarboxamido-methylidene-4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene is obtained, which is purified by recrystallization from methanol.

In the examples below, the preparation of a selection of the new 5-substituted aza-dibenzo-[a,d]-cycloheptene derivatives of formula I is illustrated.

Example 1

5 -flS-dimethylaminoethylidene)-4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclo-heptene

An ether solution of 10 g of the amide from Method 5 is added to a suspension of 3 g of lithium aluminum hydride in 250 ml of ether. It is stirred for 2 hours. Water is added to separate the two layers. By concentrating the ether layer to a residue, 5-dimethylamino-ethylidene-4-aza-10, 11-dihydro-5.H-dibenzo-[a, dj-cycloheptene is obtained. Purification is carried out by vacuum distillation. The free base m.p. 75 - 77°C. Maleate's m.p. 155 - 158°C.

Example 2

5 - (^- dimethylaminoethyl) - 4- aza- 10, II - dihydro - 5H- dibenzo - a, d - cycloheptene A solution of 6.8 g of the compound prepared according to Example 1 in 100 ml of ethanol is hydrogenated in a Parr - shake in the presence of 0.5 g of platinum oxide under approx. 3.6 atmospheres of hydrogen pressure, until an equivalent amount of hydrogen has been absorbed, i.e. usually for approx. 1 hour. The mixture is filtered and the filtrate is concentrated to a residue. The product is purified by vacuum distillation. The free base m.p. 85 - 86.5°C.

Example 3

5-((^-dimethylaminoethyl)-4-aza-10, 11-dihydro-5H-dibenzo-[a,d]-cycloheptene-dimaleate

To a solution containing 4.2 g of 5-(^-dimethylaminoethyl)-4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene in 55 ml of ethyl acetate is added a solution of 3.45 g of maleic acid dissolved in ethyl acetate. The resulting precipitate is filtered off, and the desired product is recrystallized from a mixture of ethyl acetate and methanol, whereby 5-((^-dimethylaminoethyl)-4-aza-10,11-dihydro-5H-dibenzo-Ja,d]-cycloheptene is obtained -dimaleate, mp 117 - 120°C.

Example 4

5- dimethylaminoethyl- 4- aza- 10, 11 - dihydro- 5H- dibenzo - fa, d]- cycloheptene

13.1 g of 5-dimethylaminoethylidene-4-aza-dibenzo-Ja,d]-cycloheptene is dissolved in 250 ml of ethanol, and 10 g of 5% palladium-on-charcoal is added as a catalyst. The compound is reduced at room temperature in a Parr hydrogenator at 3.5 kg/cm 2 . After an equivalent amount of hydrogen has been absorbed, the temperature is raised to approx. 80°C, after which this temperature is maintained until a further equivalent amount of hydrogen has been absorbed. The mixture is filtered, after which the ethanol is removed and the residue is vacuum distilled. This gives 4-aza-5-dimethylaminoethyl-10, 11-dihydro-5H-dibenzo-[a, d]-cycloheptene with a melting point of 85 - 86.5°C.

When proceeding as described in the above examples, using the corresponding starting materials, the following compounds are obtained: 1. 5-(1-dimethylaminoethyl)-8-chloro-4-aza-10,11-dihydro-5H-dibenzo -yes, dj-cycloheptene. Acetylglycinate's m.p. 137 - 139°C 2. 5-(^-1-pyrrolidylethyl)-4-aza-10,11-dihydro-5H-dibenzo-[a,dj-cycloheptene maleate. Sm.p. 139 - 141°C. 3. 5 -((V-1 -piper idinoethyl) -4-aza-10, 11 -dihydr o-5H-dibenzo-fa, d] - cycloheptene maleate. M.p. 172 - 176°C. 4. 5 -Qj - (N-morpholino)-ethyl]-4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene maleate.M.p.148-150°C.5.5-{fr- dimethylaminoethyl) - 8-chloro-4-aza - 10 , 11 -dihydro-5H-dibenzo - ja,dj -cycloheptene maleate. Sm.p. 114 - 116°C. 6. 5 - (^-dimethylaminoethyl) -4 - aza -5H-dibenzo - Yes, dj - cyclohepten-dima-leate. Sm.p. 143 - 144°C. 5-((b-dimethylaminoethylidene)-4-aza-10, 11-dihydro-5H-dibenzo-[a,d]-cycloheptene. M.p. 75 - 77°C.

Claims (1)

Analogous method for the production of therapeutically effective 5-substituted aza-dibenzo-[a,d]-cycloheptenes of the general formula: and their pharmaceutically acceptable acid addition salts, in which formula the dashed line denotes a possible double bond, A denotes hydrogen or one or more of the substituents halogen, lower alkyl, trifluoromethyl, alkoxy, hydroxy, and alkarioyloxy bonded in positions 6, 7, 8 and/or 9; B denotes the group of atoms which, together with the carbon atoms to which it is bound, forms a pyridine nucleus, and Z denotes one of the groups where Rj and R, independently of each other, can be hydrogen, lower alkyl, lower hydroxyalkyl or a group which, together with the nitrogen atom to which it is bound, forms an optionally lower-alkyl-substituted 5- or 6-membered heterocyclic ring where one of the members can be an oxygen atom or a further nitrogen atom, characterized in that the carbonyl group in the group Z ' in a connection of the general formula: in which the dashed line A and B have the above meanings and Z' denotes one of the groups where and R^ have the meanings given above, is reduced, as any hydrogen on the nitrogen atom in the amino group of the Z' group can be protected by substitution with an easily cleavable radical, preferably a benzyl radical, that a 5, 1'-unsaturated compound is obtained if desired hydrogenated to the corresponding 5,1'-saturated compound, and that an obtained compound of formula I is optionally subjected to one or more of the following final steps, in any order: (a) hydrogenation in the 10, 11-position, (b) cleavage of a protecting group attached to the nitrogen atom of the amino group forming part of the group Z', (c) transfer to a pharmaceutically acceptable acid addition salt.