NO150187B - VEHICLE TIRE WITH PROFILED ROAD - Google Patents

Abstract

1. Pneumatic vehicle tyre having a profiled tread strip which is provided laterally externally with circumferential bands (3), the outer edge of which comprises projections (5, 6) which are separated from one another by grooves (4) extending transversely to the circumferential direction of the tyre, and said projections extend at different lengths laterally towards the outside in the circumferential direction of the tyre, whereby, when viewed in the circumferential direction of the tyre, every second projection has the same transverse extension, characterised in that the lateral faces (7) of the shorter projections (6) extend into a flat recess (9) which terminates at the upper edge of the lateral wall (10) of the tyre and is defined by sharp edges both laterally and at the lower edge, the edges of said recess extending substantially radially and being identical to the lateral edges of the projections which have the greatest extension laterally towards the outside, and in that the lateral faces (7) of the shorter projections (6) extend substantially parallel to the lateral faces (8) of the longer projections (5).

Description

Process for the production of new dibenzocycloheptene derivatives.

The present invention relates to a method for the production of 5H-ditaenzo[a,d] cycloheptenes which are substituted in the 5-position with a tertiary aminopropylidene radical and in the 3-position with a sulfamoyl radical.

The compounds produced by the method according to the invention correspond to the following general formulas:

In these general formulas R and R' which may be the same or different denote unbranched or branched lower alkyl radicals with up to 4 carbon atoms, R" and R'" which may also be the same or different denote lower alkyl radicals with an unbranched or branched carbon chain and with up to 6 carbon atoms or lower alkyl radicals which are bound to each other through one carbon, nitrogen or oxygen atom so that a heterocyclic ring with from 5 to 6 atoms is formed, such as 1-piperidyl, 1-pyrrolidyl, 4-morpholinyl and 1 -lower alkyl-4-piperazinyl. The compounds may have substituents on the propylidene side chain such as lower alkyl radicals, preferably with from 1 to 4 carbon atoms. X in the general formulas denotes hydrogen or halogen, preferably bromine or chlorine.

Among representative compounds that can be prepared by the method according to the invention are the following: 5-(3-dimethylaminopropylidene)-3-dimethyl-sulfamoyl-5H-dibenzo [a,d] cycloheptene 5-(3-dimethylaminopropylidene)-3-diethyl-sulfamoyl -5H-dibenzo[a,d]cycloheptene 5-(3-dimethylaminopropylidene)-3-di-n-butyl-sulfamoyl-5H-dibenzo[a,d]cycloheptene 5- [3-(1-methyl-4-piperazinyl ) -propylidene] -3-dimethylsulfamoyl-5H-dibenzo[a,d]-cycloheptene

5- [3-(4-morpholinyl)-propylidene]-3-dimethylsulfamoyl-5H-dibenzo[a,d]cycloheptene 5-(1-piperidyl)-propylidene]-3-dimethyl-sulfamoyl-5H-dibenzo [a ,d]cycloheptene 5- [3-(1-pyrrolidyl)-propylidene]-3-dimethylsulfamoyl-5H-dibenzo[a,d]cycloheptene 5-(3-dimethylaminopropylidene)-7-bromo-3-dimethylsulfamoyl-5H- dibenzo [a,d]-cycloheptene

5-(3-dimethylaminopropylidene)-10,11-dihydro-3-dimethylsulfamoyl-5H-dibenzo-[a,d]cycloheptene

5-(3-dimethylaminopropylidene)-7-chloro-10,11-dihydro-3-dimethylsulfamoyl-5H-dibenzo-[a,d]cycloheptene

5-(3-dimethylaminopropylidene)-3-(N-ethyl-N-methyl)-sulfamoyl-5H-dibenzo [a,d]-cycloheptene

It has been found that the compounds produced according to the invention have both sedative and antidepressant effects. Consequently, they can be advantageously used in pharmaceutical preparations. In addition, some of the compounds also have an anti-histamine effect.

When used in medicine, the compounds can be used orally or parenterally in the form of aqueous solutions or suspensions, but preferably they are used orally in the form of tablets, powders, granules with delayed release of the active compounds and the like. With oral or parenteral use, satisfactory results are achieved with daily doses from approx. 25 mg to approx. 500 mg. Such doses are preferably given divided into several portions during the day, or in a form where the active ingredient is released with a delay. The compounds are preferably used in the form of their addition salts with non-toxic acids and the production of such salts as well as of other non-toxic salts is covered by the present invention.

The compounds corresponding to the above-mentioned general formula II in which X is halogen are prepared according to the invention by treating a 10,11-dihydro-3-halo-5H-dibenzo-[a,d]cyclohepten-5-one with a halogen- sulfonic acid, whereby the corresponding 10,11-dihydro-7-halogen-3-halogensulfonyl ketone is formed, which is condensed with a mono- or dialkylamino, whereby the corresponding 3-alkyl-substituted sulfamoyl-10,11-dihydro-7-halogen ketone is obtained. The latter compound is condensed with a Grignard reagent and the resulting Grignard adduct is hydrolysed, whereby the corresponding 3-alkyl-substituted sulfamoyl-5-hydroxy-5-(3-tertiary aminopropyl) derivative is formed. This 5-hydroxy derivative is then dehydrated. This procedure in its generality can be illustrated by the following reaction nucleus:

In this reaction scheme, Hal and Y denote halogen, while R, R', R" and R'" have the above meaning.

For the preparation of compounds corresponding to the general formula I in which X is halogen, the resulting compound is subjected to

from step 2 a dehydrogenation. Conversion of the resulting 10,11-unsaturated ketone to the desired compound is then carried out by proceeding according to steps 3 and 4 as indicated above. This process can be shown by the following reaction scheme:

In this reaction scheme, Hal, R, R', R" and R'" have the above meaning.

In order to prepare compounds corresponding to the foregoing general formulas I and II in which X is hydrogen, the appropriate compound, as will be described below, obtained from step 2 or 5 is subjected to a dehalogenation step whereby the halogen is removed and is -replaced with hydrogen. The transfer of the de-halogenated ketones to the desired compound is then carried out in accordance with the previously described steps 3 and 4. This process can be shown by the following reaction scheme:

In this reaction scheme, Z denotes bromine or iodine, while R, R', R" and R'" have the above meaning.

The dashed line between the carbon atoms in the 10- and 11-positions indicates that the compounds may be saturated or unsaturated at this location. The saturated compounds are identified in this specification and in the claims by the term 10,11-dihydro.

When performing the dehalogenation (step 6), it is of significant importance that the halogen to be removed is either bromine or iodine, as it is not possible to remove fluorine or chlorine by dehalogenation under the conditions specified here for performing step 6. When it is thus desired to prepare the compounds in which X is hydrogen in the foregoing general formulas I and II, it is necessary to start from either 10,11-dihydro-3-iodo-5H-dibenzo[a,d] cyclohepten-5-one or 3-bromo-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-one, the latter compound being preferred.

When it is further desired to prepare the compounds in which X is hydrogen in the general formula I, it is not necessary to dehydrogenate (step 5) before the dehalogenation (step 6). Thus, if desired, the appropriate compound from step 2 can first be dehalogenated, thereby obtaining the corresponding 3-alkyl-substituted sulfamoyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, which is then subjected to dehydrogenation, whereby gives the corresponding 10,11-unsaturated ketone. Transfer of this ketone to the desired compound is then carried out in accordance with the above-mentioned steps 3 and 4. This embodiment can be shown by the following reaction scheme:

In this reaction scheme, Z, R, R', R" and R'" have the previously indicated meanings.

The starting materials, namely 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, with a halogen substituent in the 3-position of the benzene ring can be prepared by the method described for the preparation of 3-chloro-10, 11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-one.

3-bromo-10,11-dihydro-5H-dibenzo[a.d]-cyclohepten-5-one prepared in this way has a melting point of 79.5-80.5°C.

Step 1 of the method according to the invention comprises treatment of a 10,11-dihydro-3-halo-5H-dibenzo[a,d]cyclohepten-5-one with a halosulphonic acid, preferably fluorosulphonic acid, whereby the corresponding 10,11 is formed -dihydro-7-halo-3-halosulfonyl-5H-dibenzo[a,d]cyclohepten-5-one. It is of essential importance when carrying out this step that one starts from the 3-halogen ketone. The halogen acts as a blocking atom, thereby avoiding the formation of the undesired di-(halo-sulfonyl)-substituted ketone.

The turnover of the ketone with e.g. fluorosulfonic acid can be carried out in the presence of a suitable inert organic solvent. However, the use of a special solvent is not necessary as fluorosulfonic acid can be used as such. The reaction can be carried out at room temperature or at a higher temperature up to approx. 100°C, but is preferably carried out at approx. 80-90°C. It is preferred to use an excess of fluorosulfonic acid, particularly when this acid is also used as a solvent in the reaction. The reaction is preferably allowed to go to completion, after which the product can be isolated by adding the mixture to ice water and recovering the precipitated product by filtration. The crude product can be further purified by recrystallization from a suitable inert solvent.

Step 2 of the method according to the invention comprises the transfer of the halogensulfonyl group to the dialkylsulfamoyl group by reaction with a dialkylamine. When using dimethylamine, which is a gas at room temperature, the reaction is preferably carried out in the presence of an inert organic solvent such as dioxane and the gas is bubbled through or the dimethylamine is added in the form of an aqueous solution. When using other dialkylamines which are liquid at room temperature, the use of a solvent is not necessary as the relevant amine can be used as such. The reaction can be carried out at room temperature or at higher temperatures, but is preferably carried out at the boiling temperature of the mixture. The quantity ratio between the reaction components is not critical. Equimolecular amounts can be used, but it is preferred to use an excess of the amine, especially when this is also used as a solvent. The reaction is preferably allowed to proceed to completion, after which the crude product is recovered after evaporating the mixture to dryness, by extracting the residue with a suitable solvent which is then removed. The product can be further purified by recrystallization from a suitable solvent.

The Grignard reagent used in step 3 can be prepared using known methods, but it has been found that it can be prepared with high yields according to the following reaction scheme:

in which Hal, R" and R'" have the above meanings.

It has further been found that the use of tetrahydrofuran as a solvent in this reaction gives a rapid formation of the Grignard reagent with high yields.

The reaction with the Grignard reagent (step 3) is preferably carried out at a low temperature in the beginning, such as using an ice bath, and can finally continue at room temperature. It has been found that tetrahydrofuran is a very good solvent in carrying out this reaction. Accordingly, the ketone can be added directly to the reaction mixture in which the Grignard reagent is prepared. However, any inert solvent can be used for the reaction components. The hydrolysis of the Grignard adduct is carried out in such a way that strongly acidic conditions are avoided and the presence of water alone may be sufficient.

The dehydration, step 4 in the method according to the invention, can be carried out with the help of commonly used dehydrating agents such as acetyl chloride, acetic anhydride or trio-nyl chloride. The alcohol can be dehydrated directly or can first be transferred to a salt such as the hydrochloride, hydrobromide or sulphate. Transfer to the salt before dehydration is preferable in some cases. The reaction can be carried out in an excess of the dehydrating agent or in a solvent such as chloroform or glacial acetic acid. The desired product is recovered after the mixture has been made alkaline, by extraction with a suitable solvent with subsequent removal of this solvent.

The dehydrogenation step (step 5) used in the preparation of compounds which are unsaturated in the 10,11 position comprises treating the compound obtained from step 2 or the 10,11-saturated compound from step 6 (described more fully below) after desired, with a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, bromine, chlorine or sulfuryl chloride in the presence of a suitable inert organic solvent, whereby an intermediate is formed with the halogen in the 10- or 11-position. Conversion to the 10,11-unsaturated compound is then effected by treating the halogen-containing intermediate with a hydrogen halide acceptor. Suitable as such are tertiary amines such as e.g. triethylamine. The crude product obtained is recovered by extraction with a suitable inert solvent and can be purified by repeated recrystallizations from a suitable solvent.

The dehalogenation (step 6) is carried out by catalytic hydrogenation at atmospheric pressure. The compound to be dehalogenated is dissolved in a suitable organic solvent which contains a sufficient amount of an acceptor for hydrogen halide, such as e.g. triethylamine, to remove the hydrogen halide formed during the hydrogenation. The solution is preferably hydrogenated at atmospheric pressure and in the presence of a suitable catalyst such as a palladium-on-charcoal catalyst with 10% palladium, until the theoretical amount of hydrogen is absorbed. After removal of the catalyst and solvent, the residue is triturated with a suitable organic solvent to precipitate the hydrogen halide, which is then removed by filtration. Evaporation of the solvent gives the crude product which can be purified by recrystallization.

As mentioned above, when carrying out the dehalogenation it is of essential importance that the halogen to be removed is either bromine or iodine, as it is not possible to remove fluorine or chlorine during the dehalogenation under the above conditions.

The compounds produced by the method according to the invention can exist as geometric isomers. The separation of these isomers can be carried out by conventional techniques, as shown in the examples below. As mentioned above, the compounds produced by the method according to the invention have a calming effect and an anti-depressant effect. It has been found that of certain compounds one modification is more active than the other modification. This is particularly the case with the compound 3-dimethylsulfamoyl-5-(3-dimethylaminopropylidene)-5H-dibenzo [a,d ] -

cycloheptene, whose (5-form is the most active.

In the following, some embodiments of the method according to the invention are described as examples.

Example 1.

Preparation of 3-dimethylsulfamoyl-5-(3-dimethylaminopropylidene)-SH-dibenzola. d^ cycloheptene

A. Preparation of 7-bromo-3-fluorosulfonyl-10,ll-dihydro-5H-dibenzo[a,d~\cyclohepten-5-one 100 ml of fluorosulfonic acid is placed in a 300 ml, 3-neck round flask fitted with a polyethylene inlet tube and outlet pipes likewise made of polyethylene, with a drying pipe half-filled with anhydrous na triumf luoride. A nitrogen atmosphere is maintained there throughout the course of the reaction.

While stirring, 17.0 g (0.059 mol) of 3-bromo-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5-one are added in portions over the course of 20 minutes. After stirring for a further 10 minutes, the dark brown solution is heated on a steam bath for 6y2 hours. The reaction mixture is then cooled to room temperature, poured carefully and while stirring into 1.5 kg of crushed ice and the mixture is allowed to stand overnight at room temperature. The brown solid thus obtained is collected, washed with water, dried in a vacuum desiccator over sodium hydroxide and then extracted in a Sohxlet extraction apparatus with 700 ml of boiling cyclohexane for 16 hours. On cooling, 11.65 g of 7-bromo-3-fluorosulfonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one are separated from the cyclohexane extract in the form of dark yellow flakes with a melting point of 148-151° C. Recrystallization from ether and cyclohexane yields an analytically pure sample with a melting point of 150—

152°C.

Analysis: Calculated for C,5HinO.,FBRS:

C: 48.79 per cent, H 2.73 per cent, S 8.69 per cent.

Found: C 48.78 per cent, H 2.83 per cent, S 8.87 per cent.

B. Preparation of 7-bromo-3-dimethylsulfamoyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one 7-bromo-3-fluorosulfonyl-10,11-dihydro-5H-dibenzo[a ,d]cyclohepten-5-one (2.5 g, 0.00677 mol) together with 30 ml of 25% aqueous dimethylamine and 30 ml of p-dioxane are heated under reflux for 3 hours. The brown solution thus obtained is evaporated to dryness under reduced pressure and the residue is distributed between benzene and water. After washing with water, the benzene layer is evaporated to dryness under reduced pressure, whereby 7-bromo-3-dimethylsulfamoyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is obtained as a residue as a brown-colored solid substance, with a melting point of 142-145°C and with a yield of 2.1 g corresponding to 80 per cent of the theoretical. An analytically pure sample melts at 146-148°C after recrystallization from mixtures of benzene and hexane and from methanol.

Analysis: Calculated for C17<H>1(i<O.,>NBrS:

C 51.78 per cent, H 4.09 per cent, N 3.55 per cent.

Found: C 51.71 per cent, H 4.12 per cent, N 3.53 per cent.

C. Preparation of 3-dimethylsulfamoyl-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-one 7-bromo-3-dimethylsulfamoyl-10,ll-dihydro-5H-dibenzo[a,d]cycloheptene -5-one, 8.0 g (0.0203 mol) is dissolved in a mixture of 100 ml of absolute ethanol, 70 ml of dimethylformamide and 5 ml of triethylamine. The resulting solution is hydrogenated at atmospheric pressure and in the presence of 600 mg of palladium-on-charcoal catalyst with 10% palladium, until the absorption of hydrogen is complete. The catalyst is then removed by filtration and washed with absolute ethanol. The filtrate is evaporated to dryness under reduced pressure and the residue is triturated with benzene. The insoluble triethylamine hydrobromide thus obtained is filtered off and the benzene filtrate is evaporated to dryness under reduced pressure. By

the recrystallization of the solid, white residue from absolute ethanol yields 6.1 g of 3-dimethylsulfamoyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-one with melting point 122-124°C. The compound's melting point remains unchanged after recrystallization from absolute ethanol. Analysis: Calculated for C17<H>170.,NS:

C 64.74 per cent, H 5.44 per cent, N 4.44 per cent.

Found: C 64.20 percent, H 5.47 percent, N 4.16.

D. Preparation of 3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-one A mixture of 3-dimethylsulfamoyl-10,11-dihydro-5H-dibenzo[a.d]cyclohepten-5-one

(6.1 g, 0.0194 mol), N-bromosuccinimide (3.6 g, 0.029 mol), benzoyl peroxide (50 mg) and 50 ml of benzene are heated under reflux and stirring for 3 hours. The thus precipitated succinimid is filtered off and washed with hot benzene. The benzene filtrate is washed with 5% aqueous sodium hydroxide solution and then with water, after which it is evaporated to dryness under reduced pressure. The oily, solid substance obtained as a residue is suspended in 75 ml of triethylamine and the mixture is heated with stirring and refluxed for 16 hours. The triethylamine is then evaporated under reduced pressure and the solid obtained as a residue is distributed between benzene and water. The benzene layer is separated, washed with 3N hydrochloric acid and then with water after which

it is evaporated to dryness under reduced pressure. By recrystallization of the solid obtained as a residue from 95 percent ethanol, 2.83 g of 3-dimethylsulfamoyl-5H-dibenzo-[a,d]cyclohepten-5-one is obtained, m.p. 129.5-135.5°C. An analytically pure sample of this compound melts at 138.5-139.5°C after repeated recrystallizations from 95 percent ethanol. Analysis: Calculated for C^-O.jNS:

C 65.16 per cent, H 4.83 per cent, N4.47 per cent.

Found: C 64.88 percent, H 4.85 percent, N 4.1 percent.

E. Preparation of 3-dimethylsulfamoyl-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo\_ a,d1cycloheptene The Grignard reagent is prepared from 4.86 g (0.2 g atom) of magnesium and 24.34 g (0.2 mol) 3-dimethylaminopropyl chloride in 100 ml tetrahydrofuran, as described in the literature.

In a nitrogen atmosphere which is maintained throughout the reaction, 7.0 ml of a 1.7 M solution of the Grignard reagent in tetrahydrofuran is added dropwise over 15 minutes to a stirred solution of 2.0 g (0.0064 mol) of 3-dimethylsulfamoyl- 5H-dibenzo[a,d]cyclohepten-5-one in 25 ml tetrahydrofuran which is cooled in an ice bath. After a further 15 minutes of stirring at low temperature and 1y2 hours of stirring at room temperature, the main amount of the solvent is distilled off under reduced pressure and at a temperature below 40°C. The residue thus obtained is dissolved in 25 ml of benzene, cooled in an ice bath and the Grignard adduct is then hydrolysed by the dropwise addition of 8 ml of water. The solution in benzene is decanted from the gelatinous precipitate which is further extracted with three 20 ml portions of boiling benzene. The benzene extracts are mixed, washed with water and extracted with two 20 ml portions of 0.1 M citric acid. The acidic extract is made alkaline with sodium hydroxide and the base is extracted in benzene. The benzene extract is washed and evaporated under reduced pressure. The white solid residue thus obtained is recrystallized from 75 percent ethanol, whereby 1.68 g of 3-dimethylsulfamoyl-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene, sm. p. 148-149.5°C. This corresponds to a yield of 65.5 percent. The compound's melting point remains unchanged upon recrystallization from cyclohexane.

Analysis: Calculated for C^H^O^NgS:

C 65.97 percent, H 7.05 percent, "N 7.0 percent.

Found: C 65.93 per cent, H 7.18 per cent, N 6.90 per cent.

F. Preparation of 3-dimethylsulfamoyl-5-(3-dimethylaminopropylidene)-

5H-dibenzo[a,d~\cycloheptene A solution of 2.72 g (0.00175 mol) 3-dimethylsulfamoyl-5-(3-dimethylaminopropyl-5-hydroxy-5H-dibenzo[a,d]cycloheptene in 20 ml Trifluoroacetic acid and 12 ml of trifluoroacetic anhydride are heated to boiling for 1 hour. After a further 1 hour's standing at room temperature, the solvents are evaporated under reduced pressure. As a residue, a syrupy substance is obtained which is treated with water, cooled in an ice bath, made alkaline with sodium hydroxide and extracted in benzene. The benzene extract is washed and evaporated to give 2.7 g of the base as an oily substance. The hydrogen oxalate is prepared by treating a solution of the base in isopropanol with an oxalic acid in isopropanol containing a small excess of the oxalic acid. The yield of 3-dimethylsulfamoyl- 5-(3-dimethylaminopropylidene)-5H-dibenzo [a,d]cycloheptene hydrogen oxalate is 2.9 g corresponding to 90.5 percent of the theoretical. The compound's melting point is 192—■

20'0°C (decomposition). This material is a mixture of geometrical isomers. It is triturated with 300 ml of boiling isopropanol. The insoluble α-isomer (1.45 g) is collected and recrystallized;

repeatedly from absolute methanol until a constant melting point of 222-223°C (decomposition) is obtained.

Analysis: Calculated for CgH^OoNgS.CgHgO.,:

C 61.00 percent, H 5.97 percent,~N~5.93 percent.

Found: C 60.74 per cent, H 5.91 per cent, N 5.89 per cent.

The isopropanol filtrate obtained as described above is evaporated to half its volume and cooled. The (3-isomer is then crystallized with a yield of 1.18 g, with a melting point of 194-196°C (decomposition). A constant melting point of 198-199°C (decomposition) is obtained after repeated recrystallizations from a mixture of absolute ethanol and absolute ether and from isopropyl alcohol.

Analysis: Calculated for C22H2(102N2S.C„H30,:

C 61.00 per cent., H 5.97 per cent., N 5~.93" per cent. Found: C 60.92 per cent., H 6.09 per cent., N 5.87 per cent.

Example 2.

Preparation of 7-chloro-5-(3-dimethylaminopropylidene)-3-dimethylsulfamoyl-5H-dibenzo\_ a, d~\

cycloheptene

A. Preparation of 7-chloro-3-fluorosulfonyl-10,11-dihydro-5H-dibenzo[a,d~]cyclohepten-5-one By proceeding as described in example 1, step A, using 300 ml of fluorosulfonic acid and 50.00 g (0.206 mol) of 3-chloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, a gray solid is obtained when the reaction mixture is poured onto crushed ice. This solid is collected and extracted with five 250 mL portions of boiling benzene. The extracts are mixed and evaporated under reduced pressure. The black solid obtained as a residue is boiled with 450 ml of cyclohexane and the resulting mixture is filtered. On cooling, 19.10 g of product melting at 132.5-136.5°C are separated from the brown filtrate. Recrystallization from cyclohexane yields 17.02 g of product, m.p. 138.5—140°C.

Analysis: Calculated for C15HlnO:3ClFS:

C 55.47 per cent, H 3.10 per cent, S 9.87 per cent.

Found: C 55.30 per cent, H 3.23 per cent, S 10.01 per cent.

B. Preparation of 7-chloro-3-dimethylsulfamoyl-10,ll-dihydro-5H-dibenzo[a,d1cyclohepten-5-one Starting from 7-chloro-3-fluorosulfonyl-10,ll-dihydro-5H- dibenzo[a,d]cyclohepten-5-one (22.64 g, 0.070 mol), 120 ml of p-dioxane and 120 ml of 25% aqueous dimethylamine and proceeding essentially as described in Example 1, step B, obtain the product is obtained as a brown-yellow solid with a melting point of 154.5-155.5°C and with a yield of 18.44 g corresponding to 75 per cent of the theoretical. An analytically pure sample melts at 154.5-155°C after recrystallization from a mixture of benzene and hexane.

- Analysis: Calculated for C)7HUiClN03S:

3 C 58.36 per cent, H 4.61 per cent, N 4.00 per cent.

s Found: C 58.37 per cent, H 4.65 per cent, N 3.91 per cent.

pp

- C. Preparation of 7-chloro-3-dimethylsulfamoyl-5H-dibenzo[a,d~\ cyclohepten-5-one A mixture of 7-chloro-3-dimethylsulfamoyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-r 5-one (2.74 g, 0.0078 mol), N -bromosuccinimide

■ (2.12 g, 0.012 mol), benzoyl peroxide (30 mg), and in 20 ml benzene (which has previously been dried over: calcium hydride) are heated under reflux; cooling and stirring for S^hour. The succinimide is then filtered off and washed with hot benzene. The solution in benzene is washed with 5 per cent aqueous; sodium hydroxide solution and then with water, after which it is evaporated to dryness under reduced pressure. The oily solid obtained as a residue is suspended in 60 ml of triethylamine and heated under reflux and stirring for 16 hours. The reaction mixture is then distributed between benzene and water. The benzene layer is separated and evaporated under reduced pressure. The residue thus obtained, which is a solid substance, is dissolved in benzene and the solution is washed with 3N hydrochloric acid and then with water, after which it is evaporated to dryness under reduced pressure. The solid obtained as a residue is dissolved in benzene and boiled with decolorizing charcoal for 20 minutes. The filtrate is diluted with hexane until it becomes cloudy and after cooling to room temperature, 1.79 g of a yellowish-brown solid with a melting point of 165-168°C is obtained. Recrystallization of this from a mixture of benzene and hexane yields 1.67 g of product (corresponding to a yield of 62 per cent) with a melting point of 167.5-168.5°C. An analytically pure sample of the product melts at 170-171 °C after recrystallization from a mixture of benzene and hexane with subsequent recrystallization from a mixture of ethanol and water.

Analysis: Calculated for CnHHClN03S:

C 58.70 per cent, H 4.06 per cent, N 4.03 per cent.

Found: C 58.50 percent, H 4.02 percent, N 4.00 percent.

D. Preparation of 7-chloro-5-(3-dimethylaminopropyl)-3-dimethylsulfamoyl-5-hydroxy-5H-dibenzo[a,d]cycloheptene

A solution in tetrahydrofuran of 3-dimethylaminopropyl magnesium chloride is prepared from 0.78 g (0.032 g atom) magnesium and 3.87 g (0.032 mol) 3-dimethylaminopropyl chloride in 21 ml tetrahydrofuran, thus as described in example 1, step E The Grignard reagent solution is stirred and cooled in an ice bath while 7-chloro-3-dimethylsulfamoyl-5H-dibenzo[a,d]-cyclohepten-5-one (5.60 g, 0.016 moles). After stirring for a further 30 minutes at ice bath temperature and for 12 hours at room temperature, the main amount of the solvent is distilled off

at a temperature below 45°C during the reduction

Print. The residue is dissolved in 50 ml of benzene and the Grignard adduct is hydrolysed by dropwise addition of

ning of 14 ml of water while cooling in an ice bath. The benzene solution is decanted from and the gelatinous precipitate is extracted three times with 80

ml portions of boiling benzene. The benzene extracts are mixed and washed with water, after which they are evaporated under reduced pressure. By recrystallization of the solid obtained as a residue from a mixture of ethanol and water, 5.19 g of product with a melting point of 173-174.5°C is obtained. This corresponds to a yield of 75 percent. An analytically pure sample of the compound melts at 175-176°C after recrystallization from a mixture of ethanol and water.

Analysis: Calculated for C2:,H27C1N203S:

C 60.74 per cent, H 6.26 per cent, N 6.44 per cent.

Found: C 60.42 per cent, H 6.18 per cent, N 6.40 per cent.

E. Preparation of 7-chloro-5-(3-dimethylaminopropylidene)-3-dimethylsulfamoyl-5H-dibenzo[_ a, d'] cycloheptene

(mixture of geometric isomers)

A solution of 7-chloro-5-(3-dimethylaminopropyl)-3-dimethylsulfamoyl-5-hydroxy-5H-dibenzo[a,d]cycloheptene (1.72 g, 0.0040 mol)

in 12 ml of glacial acetic acid, cool in an ice bath and saturate with anhydrous hydrogen chloride for 5 minutes. Acetic anhydride (1.63 g, 0.016 mol) is then added and the solution is heated on a steam bath for 2y2 hours. It is then cooled to room temperature

tur and dilute with 17 ml of water, cover with 50 ml of benzene, cool in an ice bath and make alkaline with a 10 N sodium hydroxide solution. The benzene sieve is separated and the aqueous layer is extracted with two 35 ml portions of benzene. The extracts are mixed and the mixture is boiled with decolorizing charcoal, after which it is filtered. The filtrate is washed with water and freed from water with sodium sulphate. The benzene is then evaporated under reduced pressure. The mixture of geometric isomers of 7-chloro-5-(3-dimethylaminopropylidene-3-dimethylsulfamoyl-5H-dibenzo[a,d] cycloheptene is obtained as a yellow, oily substance in quantitative yield (1.67 g).

F. Preparation of α-isomers of 7-chloro-5-(3-dimethylaminopropylidene)-3-dimethylsulfamoyl-5H-dibenzo[α,d'\-cycloheptene

The mixture of geometric isomers obtained from step E above is dissolved in 3 ml absolute ethanol and the solution is treated with a solution of 0.49 g (0.0042 mol) maleic acid in 1 ml absolute ethanol. 16 ml of water is then added

free ether until incipient cloudiness and a yellow-brown precipitate of the mixed geometric isomers with melting point 147-156°C is obtained with a yield of 91.5 percent (1.95 g). Recrystallization of this material yields 1.21 g of the hydrogen maleate of the α-isomer with a melting point of 166-170°C. The mother liquor from the crystallization of this yellow solid is used to prepare the p-isomer as indicated under step G below. The hydrogen maleate is recrystallized from absolute ethanol until a constant melting point of 174-175.5°C is obtained.

Analysis: Calculated for C^H^ClNPaS.C^Oj:

C 58.58 per cent, H 5.48 per cent, N 5.26 per cent.

Found: C 58.82 percent, H 5.73 percent, N 5.13 percent.

G. Preparation of the p-isomer of 7-chloro-5-(3-dimethylaminopropylidene)-3-dimethylsulfamoyl-5H-dibenzo[a,d~\-cycloheptene The mother liquor from the first crystallization of the maleate of the mixed geometric isomers, i.e. from step F, evaporated to dryness under reduced pressure. The brown, oily residue you get here is dissolved in 10 ml of water. The resulting solution is made alkaline and extracted with three 20 ml portions of benzene. The extracts are mixed, washed and evaporated to dryness under reduced pressure. The p-isomer is obtained in the form of the base as a yellow, oily substance in an amount of 0.56 g. The base is transferred to the oxalate by treatment with a five-fold molar excess of the oxalic acid in the form of a solution in absolute ethanol. The oxalate, which melts at 184.5°C, is dissolved in water and treated with a 5% molar excess of picric acid dissolved in an equal volume of ethanol. The yellow picrate thus obtained melts at 238.5-239°C during decomposition. Recrystallization from a mixture of n-propanol and water yields a material that melts at 240-240.5°C during decomposition.

Analysis: Calculated for C!>2H2,ClN202S.C(iH.,Ns07:

C 52.05 per cent, H 4.37 per cent, N 10.84 per cent."

Found: C 52.13 per cent, H 4.61 per cent, N 10.59 per cent.

H. Preparation of p-isomers of 7-chloro-5-(3-dimethylaminopropylidene)-3-dimethylsulfamoyl-5H-dibenzo[a,d~l-cycloheptene in the form of the base 250 mg of the picrate of the p-isomer is suspended in 5 N lithium hydroxide solution (20 ml) and 150 ml of benzene. The suspension is shaken for 6 hours. The benzene layer is then separated and washed with 5 N lithium hydroxide solution followed by washing with water. After evaporation of the benzene under reduced pressure, a brown, oily residue weighing 330 mg is obtained. This residue is distributed between 5 ml of 0.1 N hydrochloric acid and 8 ml of benzene. The aqueous layer is separated, made alkaline with 5% sodium hydroxide solution and extracted with two 10 ml portions of benzene. The extracts are mixed, washed with water, freed from water with anhydrous sodium sulfate and evaporated under reduced pressure. The yellow, oily residue obtained in this way consists of the p-isomer in the form of the base and weighs 140 mg, which corresponds to a yield of 88 per cent.

Claims (1)

Process for the preparation of dibenzo-cycloheptene compounds with therapeutic activity, in particular both sedative and antidepressant effects and corresponding to the general formula: (in which Z denotes halogen or hydrogen, and the dashed line in the 10,11 position means that the compounds here can be either saturated or olefinically unsaturated, R and R' denote lower alkyl radicals, while R" and R'" denote lower alkyl radicals or lower alkylene radicals, which are bound to each other through a carbon, nitrogen or oxygen atom so that a heterocyclic ring is formed, namely 1-piperidyl, 4-morpholinyl, 1-pyrrolidyl or 1-lower alkyl-4-piperazinyl), characterized by that one (1) reacts a 3-halogen (especially 3-bromo or 3-iodo)-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-one with a halosulfonic acid, whereby it is formed corresponding to 10,11-dihydro-7-halo-3-halogensulfonyl ketone, and (2) reacts this ketone with a compound corresponding to R\ of the general formula NH, in which R and R'/R' have the meanings given above, whereby a compound with the general formula is formed: in which Hal denotes halogen, while R and R' have the previously stated meanings, whereupon one — for the preparation of compounds saturated in the 10,11 position, halogenated in the 7 position (Z = halogen) reacts the formed in step (2) connection with a Grignard reagent which corresponds to the eenerellfi fnrmftl R'" has the meanings indicated above in the presence of an inert organic solvent, hydrolyzes the Grignard adduct thus formed, whereby the corresponding 5-hydroxy-5-(3-tertiary amino -propyl) derivative which is de-hydrated, or — for the preparation of corresponding compounds unsaturated in the 10,11 position — dehydrogenates the compound formed in step (2), with subsequent reaction of the obtained 10,-11-unsaturated compound with a Grignard reagent as indicated above, hydrolysis of the formed Grignard adduct and dehydration of this adduct, or for the production of corresponding non-halogenated compounds (Z = hydrogen) dehalogenate the compound obtained in step (2) where Hal means bromine or iodine — with subsequent or prior dehydrogenation in cases where it is desired to produce in the 10,11 position unsaturated compounds — and, after the dehalogenation and possible dehydrogenation, reacts the resulting compound with a Grignard reagent as stated above, hydrolyzes the Grignard adduct thus formed and dehydrates this adduct.