CA1160219A

CA1160219A - Cycloheptene derivatives

Info

Publication number: CA1160219A
Application number: CA000393178A
Authority: CA
Inventors: Werner Aschwanden; Quirico Branca; Emilio Kyburz; Rudolf Pfister
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1981-01-16
Filing date: 1981-12-23
Publication date: 1984-01-10
Also published as: AU7941782A; EP0056616B1; EP0056616A2; DK18082A; ZA82138B; DE3265480D1; EP0056616A3; JPS57139022A; AU546906B2

Abstract

Abstract The novel cycloheptene derivatives of the general formula I

wherein R1 signifies lower alkyl, the dotted line signifies an optional bond and n signifies the number 1, 2 or 3, and either R2 signifies hydrogen or lower alkyl and R3 signifies lower alkyl or R2 and R3 together with the nitrogen atom signify a 5- or 6-membered heterocycle, and their pharmaceutically acceptable acid addition salts have valuable histamine-H1 antagonistic properties and are suitable for the control or prevention of allergic reactions such as urticaria, hay fever, anaphylaxis and over-sensitivity to medicaments.

These compounds can be manufactured according to various processes starting from partly novel starting materials and can be brought into galenical administration forms.

Description

RAN 4016~17 The present invention is concerned with cyclo-heptene derivatives. In particular, it is concerned with cycloheptene derivatives of the general formula ( IH2)n ~N~

wherein Rl signifies lower alkyl, the dotted line signifies an optional bond and n signifies the number 1, 2 or 3, and either R2 signifies hydrogen or lower alkyl-and R3 signifies lower alkyl or R~ and R3 together with the nitrogen atom signify a 5-or 6-membered heterocycle, and pharmaceutically acceptable acid addition salts thereof.

Nt/~.11.81

2~

These compounds are novel; they possess valuable thQra-peutic properties and, accordingly, can be used in the treat-ment or prevention of illnesses.

Objects of the present invention are compounds of general formula I and their pharmaceutically acceptable acid addition salts per se and as pharmaceutically active substances, the manufacture of these compounds, inter-mediates for the manufacture of these compounds, medicaments containing said compounds and the manufacture of said medicaments.

The term "lower alkyl" denotes straight-chain or branched-chain saturated hydrocarbon groups containing at most 7, preferably at most 4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl and the like. The term "5- or 6-membered heterocycle" includes optionally lower-alkyl substituted l-pyrrolidinyl, l-piperidinyl, 4-morpholinyl, 1--piperazinyl, 3-thiazolidinyl and the like groups.

The term "pharmaceutically acceptable acid addition salts" includes pharmaceutically acceptable salts of compounds of formula I not only with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid and the like, but also with organic

- 3 - ~ Z1 g acids such as maleic acid, citric acld, acetic acid, succinic acid, malic acid, tartaric acid, camphorsulphonic acid, mandelic acid, fumaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like. The manufacture of the pharmaceutlcally acceptable acid addition salts is carried out according to methods which are known per se and famlliar to any person skilled in the art.

The compounds of formula I contain an asymmetric carbon atom; the present invention includes not only the }O optically uniform forms but also mixtures thereo~ (espe-cially the racemates). The resolution of the racemates can be carried out according to methods known per se;
for example, by fractional crystallization of an acid addition salt o~ a compound of formula I with an optically active acid ~e.g. with tartaric acid, camphorsulphonic acid, mandelic acid and the like). The optically uniform forms can, however, also be obtained by using optically u~iform starting materials in process variants (a), (b) and (d) described hereinafter.

The term "leaving group" used hereinafter includes halogen atoms such as chlorine, bromine and iodine, sul-phonic acid groups such as methanesulphonyloxy, p-toluene-sulphonyloxy, p-bromobenzenesulphonyloxy, benzene-sulphonyl-oxy and the like, and other equivalent leaving groups.

v~g In formula I, Rl preferably signifies methyl.

The group -NR2R3 preferably signifies methylamino, dimethylamino, diethylamino, l-pyrrolidinyl or 1--piperidinyl.

A quite especially preferred compound of formula I
is 4,5,10!11-tetrahydro-N,N,9-trimethyl-lH-dibenzo[a,d]~
cycloheptene-5-propylamine.

Other especially preferred compounds of formula I
are:

2,3,4,5,10,11-Hexahydro-~,N~9-trimethyl-lH-dibenzo-[a,d]cycloheptene-5-propylamine and 1-[2-(4,5,10,11-tetra-hydro-9-methyl-lH-dibenzo[a,d]cyclohepten-5-yl)ethyl]~
pyrrolidine~

The compounds of formula I and their pharma-ceutically acceptable acid addition salts can be manufactured in accordance with the invention by ~a) 1,4-reducing the aromatic ring denoted by C in a compound of the general formula 5 ~

(IH2)n II

~N~ 3 wherein Rl, R2, R3 and n have the above significance, or tb) hydrogenating the 2,3-double bond in a compound of the general formula Ia ( IH2)n ~N~ 3 wherein Rl, R2, R3 and n have the above significance, or - 6 ~ alZl~

(c) reacting a compound of the general formula Rl ~ A J ~ III

wherein R1 and the dotted line have the above significance, in the presence of a strong base with a compound of the general formula / -(CH2)n-X IV

wherein R2, R3 and n have the above significance and X signifies a leaving group, or (d) reacting a compound of the general formula 7 ~

V

( IH2~n X

wherein Rl, the dotted line, n and X
have the above significance, with an amine of the general formula NH VI
R3~

wherein R~ and R3 have the above significance, and (e) isolating a resulting compound of formula I
as the free base or as a pharmaceutically acceptable acid addition salt.

According to variant (a) of the process in accordance with the invention, compound of formula I
in which the dotted line signifies an additional bond can lS be manufactured by 1,4-reducing the aromatic ring denoted .~, .

- 8 ~ J~

by C in a compound of formula II. As the reduclng agent there can be used, for example, an alkali metal such as lithium, sodium or potassium, in which case the solvent used is liquid ammonia or an amine which is suitable for such reductions ~e.g. methylamine, ethylamine, dimethylamine or the like). Conveniently, this 1,4-reduction is carried out in the presence of a solubilizer and/or a proton donator. ~Suitable solubilizers are, for example, ethers such as diethyl ether, t-butyl methyl ether, tetrahydro-furan, dioxan, ethyleneglycol dimethyl ether, diglyme andthe like. Preferred proton donators are alcohols such as methanol, ethanol, propanol, isopropanol, butanol, t--butanol, l,l-dimethylpropanol, ethyleneglyCol monomethyl ether, propyleneglycol monomethyl ether and the like.
The temperature at which this 1,4-reduction is carried out depends on the solvent used and lies in a ranse of abo~t -50C to the boiling point of the reaction mixture.

The 1,4-reduction can be carried out, for example, by pre-preparing a solution of a compound of formula II
in one of the aforementioned solvents, preferably in boiling ammonia, or, if desired, in a mixture of the solvent, the solubilizer, preferably dry tetrahydrofuran, and/or the proton donator, pxeferably dry t-butanol or ethanol, and treating this solution with the alkali metal, preferably lithium or sodium.

' The 1,4-reduction can, however, also be carxied out readily in the opposite manner, i.e. a solution of the alkali metal ln the solvent can be prepared and this solution can be treated with a compound of formula II, or, if desired, with a solution of this compound in the solubilizer and/or proton donator~

A further embodiment consists in adding the proton donator only after the 1,4-reduction has been completed. In this case, acidic ammonium salts such as ammonium chloride and the like are also suitable as proton donators.

Finally, the desired 1,4-reduction can also be carried out electrochemically. The electrochemical 1,4--reduction can be carried out in an undivided cell or in a divided cell, an undivided cell being preferred~ The cathode material is not critical and there can accordingly be used platinum, graphite, mercury, lead, nickel, aluminium and the like. Platinum is preferably used as the cathode material. Platinum is the preferred anode material~
although lead or graphite or another non-corroding material can also be used. As solvents there can be used amines, such as methylamine, propylamine and ethylenediamine, or the like. If necessary, solubilizers such as tetrahydro-furan and diethyleneglycol dimethyl ether and/or proton donators such as ethanol and ~-butanol can also be used.

' 2:~9 Suitable conducting salts for the present process aspect are, for example, lithium chloride, sodium chloride, tetrabutylammonium chloride and the like. The temperatuxe at which this 1,4-reduction is carried out is not critical and it can accordingly be carried out in a temperature range of about -20C to about 100C depending on the solvent used.

In an especially preferred embodiment, methyl-amine is used as the solvent, lithium chloride i5 used as the conducting salt and platinum is used as the anode and cathode material and the 1,4-reduction is carried out at a temperature of about -10C.

According to variant tb) of the process in accordance with the invention, compounds of formula I in which the dotted line does not signify an additional bond can be manufactured by hydrogenating the 2,3-double bond in a compound of formula Ia. This hydrogenation can be carried out according to methods which are known per se and familiar to any person skilled in the art. In a preferred embodiment the hydrogenation is carried out using elemental hydrogen in the presence of a catalyst which is usual in such cases such as palladium/carbon, Raney-nickel, platinum oxide, palladium/aluminium oxide and the like in an organic solvent which is inert under the hydrogenation conditions, for example, an alcohol such as methanol, ethanol etc, an ether such as diethyl ether, tetrahydrofuran, dioxan etc, ethyl acetate, acetic acid and the like. Depending on the reactivity of the catalyst the hydrogenation is carried out at pressures of about normal pressure to about 300 bar and at temperatures of about room temperature to about 300C.

According to variant (c) of the process in accordance with the invention, a compound of ~ormula I
can be manufactured by reacting a compound of formula III
in the pxesence of a strong base with a compound of formula IV. Conveniently, the compound of formula III in an inert organic solvent, for example in an ether such as tetrahydrofuran, dioxan, diethyl ether, dimethoxyethane, diglyme, t-butyl methyl ether or the like or in a mixture thereof with alkanes such as, for example, pentane, hexane and heptane, is converted with a strong base, for example with an alkyl lithium or aryl lithium compound such as n-butyl lithium, methyl lithium and phenyl lithium or with an alkali metal amide such as lithium diisopropyl-amide and sodium amide or with sodium hydride or the like into the corresponding anion and this is reacted with a compound of formula IV. Depending on the base used the reaction san be carried out at a temperature of about -70C
to about room temperature~

According to variant (d) of the process in accordance with the invention, a compound of formula I can be manufactured by reacting a compound of formula V with an amine of formula VI. This reaction is conveniently carried out in an iner~ organic solvent in the presence of an acid-binding agent. Suitable solvents or the present process aspect are, for example, ethers such as diethyi ether, t-butyl methyl ether, tetrahydrofuran, ethyleneglycol dimethyl ether and the like, alcohols such as ethanol, ethyleneglycol and the li]ce, or excess amine of formula VI. As acid binding agents there can be used inorganic bases such as potassium and sodium carbonate or ~le like or organic bases such as triethylamine, quinuclidine or the like, or excess amine of general formula VI. In a preferred embodiment, excess amine of formula VI is used as the solvent and simultaneously as the acid-binding agent. The temperature at which the reaction is carried out can vary in a range from about 0C to the boiling point of the reaction mixture and depends, of course, on the reactivity of the l~aving group denoted by X. The p-toluenesulphonylo~y group is an especially preferred leaving group.

In accordance with the invention, a resulting compound o~ ~ormula I is isolated as the free base or as a pharmaceutically acceptable acid addition salt. The isolation of a free base or a pharmaceutically acceptable acid addition salt thereof is carried out according to methods which are known per se and familiar to any person skilled in the art; for example, by extraction or filtration techniques, by optional fractional crystallization, by chromatographic methods such as gas chromatography and high pressure-liquid chromatography, by distilla~ion or by suitable combination o~ several of these methods known per se~

The compounds of formula II used as starting materials in process variant (a) belons to a class of compound known per se; specific members of this class of compound which have not previously been described can be prepared in analogy to the known members. Example 3 hereinafter contains detailed information concerning the manufacture of a compound of formula II.

The compounds of general formula III used as starting materials in process variant (c) can be prepaxed, for example, by l,~-reducing the aromatic ring denoted by C in a compound of the general formula ~ VII

wherein Rl has the above significance, in analogy to process variant (a) and, if desired~
hydrogenating the 2~3-double bond in a re~ulting compound of the general formula S p IIIa wherein Rl has the above significance, in analogy to process variant (b).

The compounds of formula VII are known or can be prepared according to methods which are known per se and familiar to any person skilled in the art.

The compounds of formula V used as starting materials in process variant (d) can be prepared starting from compounds of the general forrnula ¦ VIII

~CH2)n OH

)Z1~33 wherein R1 and n have the above signi~icance, which belong ko a class of substance known per se and which can be prepared according to methods which are known and familiar to any person skilled in the art, by 1~4-reduction of the aromatic ring denoted by C in analogy to process variant (a) and, if desired, hydro-genation of the 2,3-doublP bond in the product obtained in analogy to process variant (b).

A thus-obtained compound of the general formula ¦ ¦ ~ IX

( IH2~n OH

wherein Rl, the dotted line and n have the above significance, can now be converted according to methods which are known per se and familiar to any person skilled in the art into a compound of formula V. For example, th~ hydroxy group in a compound of formula IX can be esterified with an - 16 ~ 2~

organic sulphonic acid by treatment with a reactive sulphonic acid derivative such as methanesulphonic acid chloride, benzenesulphonic acid chloride, p-toluene-sulphonic acid chloride, p-bromobenzenesulphonic acid chloride or the like and, when a halogen atom is desired as the leaving groupl the sulphonic acid group can be replaced in a manner known per se by a halogen atom such as chlorine, bromine or iodine~ The halides can, however, also be obtained directly from the corresponding alcohols of formula IX, for example by reaction with a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, carbon tetrabromide/triphenyl-phosphine, iodine/red phosphorus or the like.

The compounds of formulae III and V are novel;
they are likewise objects of the present invention.

Suprisingly, it has been found that the compounds of formula I and their pharmaceutically acceptable acid addition salts ar~ capable of inhibiting the Hl-action of histamine. They are accordinaly valuable histamine-H
antagonistic active substances and are suitable~ in particular, for the control or prevention of allergic reactions such as, for example, urticaria, hay fever, anaphylaxis and over-sensitivity to medicaments Thes~
histamine-Hl antagonistic properties can be detennined as - - 17 ~ 9 described hereinafter on male and female guinea pigs weighing 240 - 300 g (SPF, Fullinsdorf):

The feed is withdrawn from the experimental animals (lO per dosage) 24 hours before ~he beginning of S the experiment, althoug~ water is obtainable ad libitum.
l hour after oral administration of a solution of the test substance (10 ml/kg~ the experimental animals receive a lethal dosage of histamine dihydrochloride (10 mg~kg s.c.).
Unprotected animals, i.e. animals treated only with histamine dihydrochloride, die within 1 hour. After counting the surviving, protected animals, the ED50 is determined ~ccording to the Probit methodO The ED50 is that dosage which is required to protect from death 50~ of the animals treated with the test substance.

The following Table contains, for two representative compounds of formula I, the ED50 values as well as data concerning their acute toxicity in the case of single oral administration to mice (LD50 in mg/kg).

Table _ _D50 in LD50 in Test compound mg/kg p.o. mg!kg P-A 0.4 600-1200 B 0.9 250- 500 A: 4,5,10,11~Tetrahydro-N,N,9-trimethyl~ dibenzo~
[a,d]cycloheptene-5-propylamlne;

~: 2,3,4,5,10,11 Hexahydro-N,N,9-t~imethyl-lH-dibenzo-[a,d]cycloheptene-5-propylami~e.

The compounds of formula I and their pharma ceutically acceptable acid salts can be used as medicaments, for example, in the form of pharmaceutical preparations.
The pharmaceutical preparations can be administered orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions). The administration can, however, also be carried out rectally (e.g. in the form of suppo itories) or parenterally (e.g. in the ~orm of injection solutions).

For the manufacture of pharmaceutical preparations, the compounds of formula I and their pharmaceutically acceptable acid addition salts can be processed with pharmaceutical inert, inorganic or organic carriers.
Examples of such carriers which can be used for tablets, coated tablets, dragées and hard gelatine capsules are lactose, maize starch or derivatives thereof, talc, stearic acid or its salts and the like. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like;

- 19 ~

depending on the nature of the active substance no carriers are, however generally necessary in the case of soft gelatine capsules. Suitable carriers for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like. Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerine, vegetable oils and the like. Suitable carriers fox suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabili~ing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants.
They can also contain still other therapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formul~ I or a pharmaceutically acceptable acid addition salt ~hereof are also an object of the present invention, as is a process for the manufacture of such medicaments which comprises bringing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and, if desired, one or more other thera~
peutically valuable substances into a galenical }6~:L5 administration form. As mentioned earlier, the compounds of formula I and their pharmaceutically acceptable acid addition salts can be used in the control or prevention of allergic reactions such as urticaria, hay fever, anaphylaxis and over-sensitivity to medicaments. The dosage can thereby vary within wide limits and is, of course, fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 mg to 150 mg should be appropriate.

The following Examples illustrate the present invention in more detail, but are not intended to limit its extent. In these Examples, all temperatures are given in degrees Centigrade.

Example 1 A solution of 10.2 g of 10,11-dihydro-N,N,9-tri-methyl-5H-dibenzo[a,d]cycloheptene-5-propylamine in 150 ml of dry tetrahydrofuran and 50 ml of t-butanol is treated with 300 ml of dry liquid ammonia. 1.4 g of lithium pieces are added thereto at the boiling point over a period of 30 minutes. After the dark blue colour changes to colourless, the mixture is treated dropwise with 20 ml of ethanol and the ammonia is removed. The resiude is evaporated in vacuo and partitioned between diethyl ether and saturated sodium chloride solution. The oxganic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. 4,5,10,11--Tetrahydro-N,N,9-trimethyl-1~1-dibenzo[a,d]cycloheptene--5-propylamine is obtained as a yellowish oil.

The corresponding maleic acid salt crystallizes from acetone/diethyl ether and has a melting point of 103--105.

Example 2 A solution of 2~4 g of 4,5,10,11-tetrahydro~N,N,9--trimethyl-lH-dibenzo[a,d]cycloheptene-5-propylamine in 100 ml of ethanol is hydrogenated over 0.25 g of 5 percent palladium-carbon at normal pressure. After filtering off the catalyst, the mixture is evaporated and ~he crude base remaining is taken up in 15 ml of acetone. The solution is treated firstly with a solution of 0.975 g of maleic acid in 10 ml of acetone and then with 125 ml of ether. The mixture is left to stand in a refrigerator overnight and the crystallized-out material is filtered off~
After recrystallization from acetone/ether, there is obtained 2,3,4,5,10,11-hexahydro-N,N,9-trimethyl lH-di~enzo[a,d]-cycloheptene-5-propylamine maleate of melting point 114--117.5.

Example 3 (a) A solution of 72.5 g of sodium borohydride in 150 ml of water and 300 ml of dioxan is added to 212 g of 10,11-dihydro-1-methyl-5H-dibenzo[a,d]cyclohepten-5-one and 700 ml of dioxan and the mixture ohtained is stirred at 60 for 16 hours. After evaporation of the mixture, the residue is partitioned between 1000 ml of toluene and three 500 ml portions of water. The organic phase is washed with water, dried o~er magnesium sulphate and - 23 ~ 2-~

evaporated. After recrystallization from diethyl ether/
petroleum ether (low boiling), there is obtained 10,11--dihydro-l-methyl-5H-dibenzo[a,d]cyclohepten-~-ol of melting point 102-105.

(b) A solution of 207 g of 10,11-dihydro-1-methyl-5H--dibenzo[a,d~cyclohepten-5-ol in 700 ml of benzene is treated over a period of 40 minutes with 344 ml of thionyl chloride, subsequently stirred for 90 minutes and evaporated. Toluene is added to ~he residue and the mixture is evaporated. After recrystallization from methylene chloride/cyclohexane, there is obtained 5-chloro--10,11-dihydro-1-methyl-5~-dibenzo[a,d]cycloheptene of melting point 126-128.

(c) A mixture of 20.9 g of magnesium shavings and 400 ml of ether is treated with a small amount of iodine, warmed to the boiling point and treated dropwise over a period of 30 minutes with a mixture of 138 g of diethyl malonate and 200 ml of dry ethanol. The mixture is heated to boiling under reflux for a further 2 houxs and the suspension obtained is subsequently evaporated. 400 ml of benzene are added to the resiude, the mlxture is evaporated and the residue is dissolved in 500 ml of dry tetrahydrofuran. This solution is treated at 40 over a period of 20 minutes with a solution of 190 g of 5-chloro-- 24 ~

-10,11-dihydro-1-methyl-5H-dibenzo[a,d]c~cloheptene in 600 ml of dry tetrahydrofuran, heated to boiling under reflux for 18 hours and the mixture obtained is concentrated. The residue is partitioned between ether and ice-water; the organic phase is washed with lN
hydrochloric acid, twice with ice-water, once with saturated sodium bicarbonate solution and with water, dried over magnesium sulphate and evaporated. There is obtained crude, crystalline diethyl 10,11-dihydro-1-methyl-5H--dibenzo[a,d]cycloheptene-5-malonate which i5 used in the next step without further purification. After two-fold recrystallization from diethyl ethex, there is obtained pure material of melting point 79-80.

~d) A mixture of 2~4 g of crude diethyl 10,11-dihydro -1-methyl-5H-dibenzo[a,d]cycloheptene-5-malonate and 1.5 1 of ethanol is treated with 128 g of potassium hydroxide in 400 ml of water. The mixture obtained is heated to boiling for 90 minutes while stirring and subsequently evaporated. The residue is partitioned between 2 1 of ice-water and two 500 ml portions of chloroform each time.
The aqueous phase is washed with 500 ml of chloroform and adjusted to pH 2 with concentrated hydrochloric acid.
The precipitated solid material is filtered off, washed neutral with water and dried in vacuo at 60 over phosphorus pentoxide. There is obtained 10,11-dihydro-1-methyl-5H--dibenzo[a,d]cycloheptene-5-malonic acid as beige crystals of melting point 195-198.

(e) 176 g of 10,11-dihydro-1-methyl-5H-dibenzo[a,d]-cycloheptene-5-malonic acid are heated to 170-175 for 50 minutes while stirring. Subsequently, the residue ~s treated with 300 ml of benzene and heated to boiling under reflux. The mixture is filtered in order to remove insoluble constituents and the filtrate is treated with 660 ml of cyclohexane at the boiling point. After cooling to 10, the precipitated material ls filtered off. 10,11--Dihydro-l-methyl-5H-dibenzo[a,d]cycloheptene-5-acetic acid of melting point 162-164~ is obtained.

(f) A mixture of 138 g of 10,11-dihydro-1-methyl-5H-~dibenzo[a,d]cycloheptene-5-acetic acid, 100 ml of benzene and 308 g of thionyl chloride is heated to boiling under reflux for 150 minutes and subsequently evaporated. The residue is treated twice with benzene and in each case again evaporated. There is obtained lO,ll~dihydro-l--methyl-5H-dibenzo~a,d]cycloheptene-5-acetic acid chloride as a red-brown oil which is use~ in the next step without further purification.

(g) A mixture of 215 ml of pyrrolidine and 400 ml of ~enzene is treated dropwise at 0 to 20 over a period of 45 minutes with a solution of 147 g of 10,11-dihydro-1--methyl-5H-dibenzo[a,d~cyclohepteneo5-acetic acid chloride ~r in 400 ml of benzene. The mixture is stirred at 40 for 120 minutes and poured into ice-water. The aqueous phase is extracted with benzene. The combined organic extracts are washed successively twice with 250 ml of 2N sodium hydroxide each time, with 250 ml of water, with 250 ml of 2N hydrochloric acid and with saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and evaporated. The residue is dissolved in 700 ml of petroleum ether (boiling range 80-105). The solution obtained is cooled to 4 and the crystallized--out material is filtered off. l-[~10,11-Dihydro-l-methyl--5H-dibenzo[a,d]cyclohepten-5-yl)acetyl]pyrrolidine of melting point 106-109 is obtained.

(h) 18.6 g of lithium aluminium hydride are placed in 250 ml of dry dioxan. Then there is added dropwise thereto at the boiling point over a period of 60 minutes a solution of 156 g of l-[(10,11-dihydro-1-methyl-SH-dibenzo[a,d]-cyclohepten-5-yl)acetyl]pyrrolidine in 600 ml of dry dioxan.
After 20 minutes at the boiling point, the mixture ls treated slowly at 10 to 40 with 250 ml of ethyl acetate and subsequently at 10 with 150 ml of water. After filtration over kieselguhr, the mixture is evaporated and the residue is partitioned between ether and cold lN
hydrochloric acid. The organic phase is extracted ~urther with 2N hydrochloric acid. ~he combined aqueous extracts are adjusted to pH 10-12 with concentrated sodium hydroxide while cooling with ice and extracted - ~7 ~

with methylene chLoride. The methylene chloride phase ls washed neutral with water, dried over magnesium sulphate and evaporated. 1-[2-(10,11-Dihydro-l-methyl~5H-dibenzo-[a,d]cyclohepten-5-yl)ethyl]pyrrolidine of meltin~ point 58~61 is obtained.

(i) A mixture of 170 ml of liquid ammonia, 6.1 g of 1-[2-(10,11-dihydro-1-methyl-5H-dibenzo[a,d]cyclohepten--5-yl~ethyl]pyrrolidine, 180 ml of dry tetrahydrofuran and 50 ml of dry t-butanol is treated at the boiling point and over a period of 30 minutes with 0.69 g of lithium wire. After the daxk blue colour has changed to colourless, 20 ml of ethanol are added dropwise and the ammonia is distilled off. The residueis diluted with diethyl ether and washed three times with saturated sodium chloride solution, dried over magnesium sulphate and evaporated.
1-[2-(4,5,10,11-Tetrahydro-9-methyl-lH-dibenzo[a,d]-cyclohepten-5-yl)ethyl]pyrrolidine is obtained as a light yellow oil. The corresponding maleic acid salt has a melting point of 118-120 after two-fold recrystalli~ation from acetone/n-hexane.

Example A

4,5,10,11-Tetrahydro-N,N,9 trimethyl-lH-dibenzo-~a,d~cycloheptene-5-propylamine can be used as follows as the active substance for the production of pharmaceutical preparations:

Capsules mg/capsule Active substance 6.98 Maize starch 20.00 Lactose (powdered) 40.00 Lactose (crystallina) 68.0~
Talc 4.50 Magnesium stearate 0.50 Capsule fill weight 140.00 The active substance is mixed with the adjuvants and the mixture is sieved. After renewed mixing, the capsule fill mass obtained is filled into interlocking gelatine capsules of suitable size on a fully automatic filling machine.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the manufacture of cycloheptene deriva-tives of the general formula I
wherein R1 signifies lower alkyl, the dotted line signifies an optional bond and n signifies the number 1, 2 or 3, and either R signifies hydrogen or lower alkyl and R3 signifies lower alkyl or R2 and R3 together with the nitrogen atom signify a 5-or 6-membered heterocycle, and of pharmaceutically acceptable acid addition salts thereof, which process comprises (a) 1,4-reducing the aromatic ring denoted by C in a compound of the general formula II
wherein R1, R2, R3 and n have the above significance, or (b) hydrogenating the 2,3-double bond in a compound of the general formula Ia wherein R1, R2, R3 and n have the above significance, or (c) reacting a compound of the general formula III

wherein R1 and the dotted line have the above significance, in the presence of a strong base with a compound of the general formula IV

wherein R2, R3 and n have the above significance and X signifies a leaving group, or (d) reacting a compound of the general formula V

wherein R1, the dotted line , n and X have the above significance, with an amine of the general formula VI

wherein R2 and R3 have the above significance, and (e) isolating a resulting compound of general formula I as the free base or as a pharmaceutically acceptable acid addition salt.

2. A process according to Claim 1 for the manufacture of formula I, wherein either R2 signifies hydrogen or lower alkyl and R3 signifies lower alkyl or R2 and R3 together with the nitrogen atom signify 1-pyrrolidinyl or 1-piperidinyl, which comprises 1,4-reducing the aromatic ring denoted by C in a corresponding compound of formula II, or hydrogenating the 2,3-double bond in a corresponding compound of formula Ia and isolating a resulting compound of formula I as the free base or as a pharmaceutically acceptable acid addition salt.

3. A process according to claim 2, wherein signifies methyl.

4. A process according to claim 3, wherein the group -NR2R3 signifies methylamino, dimethylamino, diethylamino, 1-pyrrolidinyl or 1-piperidinyl.

5. A process according to claim 1, wherein 4,5,10,11-tetrahydro-N,N,9-trimethyl-1H-dibenzo[a,d]cycloheptene-5-propylamine is prepared by 1,4-reducing 10,11-dihydro-N,N,9-trimethyl-5H-dibenzo[a,d]cycloheptene-5-propylamine with lithium in the presence of liquid ammonia and t-butanol.

6. A process according to claim 1, wherein 2,3,4,5, 10,11-hexahydro-N,N,9-trimethyl-1H-dibenzo[a,d]cycloheptene-5-propylamine is prepared by hydrogenating the 2,3 double bond in 4,5,10,11-tetrahydro-N,N,9-trimethyl-5H-dibenzo[a,d]
cycloheptene-5-propylamine at normal pressure in the presence of palladium-carbon.

7. A process according to claim 1, wherein 1-[2-(4,5, 10,11-tetrahydro-9-methyl-1H-dibenzo[a,d]cyclohepten-5-yl)ethyl]
pyrrolidine is prepared by 1,4-reducing 1-[2-(10,11-dihydro-1-methyl-5H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine with lithium in the presence of liquid ammonia and t-butanol.

8. Cycloheptene derivatives of the general formula I

wherein R1 signifies lower alkyl, the dotted line signifies an optional bond and n signifies the number l, 2 or 3, and either R signifies hydrogen or lower alkyl and R3 signifies lower alkyl or R2 and R3 together with the nitrogen atom signify a 5-or 6-membered heterocycle, and pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 1 or by an obvious chemical equivalent thereof.

9. Compounds according to claim 8, wherein either R2 signifies hydrogen or lower alkyl and R3 signifies lower alkyl, or R2 and R3 together with the nitrogen atom signify 1-pyrrolidinyl or 1-piperidinyl; whenever prepared according to the process claimed in claim 2 or by an obvious chemical equivalent thereof.

10. Compounds according to claim 8, wherein R1 signi-fies methyl, and either R2 signifies hydrogen or lower alkyl and R3 signifies lower alkyl, or R2 and R3 together with the nitrogen atom signify 1-pyrrolidinyl or 1-piperidinyl; when-ever prepared according to the process claimed in claim 3 or by an obvious chemical equivalent thereof.

11, Compounds according to claim 8, wherein R1 signifies methyl, and the group -NR2R3 signifies methylamino, dimethyl-amino, diethylamino, 1-pyrrolidinyl or 1-piperidinyl, whenever prepared according to the process claimed in claim 4 or by an obvious chemical equivalent thereof.

12. 4,5,10,11-Tetrahydro-N,N,9-trimethyl-1H-dibenzo-[a,d]cycloheptene-5-propylamine, whenever prepared according to the process claimed in claim 5 or by an obvious chemical equivalent thereof.

13. 2,3,4,5,10,11-Hexahydro-N,N,9-trimethyl-1H-dibenzo-[a,d]cycloheptene-5-propylamine, whenever prepared according to the process claimed in claim 6 or by an obvious chemical equivalent thereof.

14. 1-[2-(4,5,10,11-Tetrahydro-9-methyl-1H-dibenzo-[a,d]cycloheptene-5-yl)ethyl]pyrrolidine, whenever prepared according to the process claimed in claim 7 or by an obvious chemical equivalent thereof.