DE2426040A1 - TRICYCLIC LINKS - Google Patents

Description

The present invention relates to tricyclic ones Compounds of the general formula

in which X is oxygen or sulfur, R-, and Rp is hydrogen or lower alkyl, R_ is hydrogen or together with R _? an additional bond and R. and R ₁ - hydrogen, lower alkyl, hydroxy-lower alkyl, alkanoyloxy-lower alkyl or together a saturated, 5- or 6-membered, optionally an oxygen atom, sulfur atom or another

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Represent nitrogen atom-containing heterocycles which can be substituted by lower alkyl, hydroxy-lower alkyl or alkanoyloxy-lower alkyl, and in which furthermore Rg lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, M- (lower alkyl) sulfamoyl, hydroxy, Halogen, irifluoromethyl, nitro, amino or di- (lower alkyl) -amino and R ₇ and Ep each individually hydrogen or one under R, -

ö D

represent listed substituents,

as well as N-oxides of compounds of the formula I, in the R. and Rp- of Hydrogen are different, and acid addition salts of the mentioned Links.

The term "lower alkyl" (alone or in combinations such as "lower alkoxy", "lower alkylthio" etc.) refers to straight-chain or branched hydrocarbon radicals with preferably up to 7 carbon atoms, such as methyl, ethyl, isopropyl, n-hexyl, etc. "Alkanoyloxy" means straight-chain or branched alkanoyloxy groups with preferably up to 18, in particular up to 10 carbon atoms, such as, for example, acetoxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, iTonanoyloxy, decanoyloxy, tetradecanoyloxy, and octanoyloxy, hexanoyloxy. The heterocycle is 5- or 6-gliedri- gen heterocycles containing one or two nitrogen atoms or one nitrogen atom and one oxygen atom or sulfur atom derived; Examples of these are pyrrolidino, piperazino, piperidino, morpholino, thiomorpholines, methylpiperidino, etc. The lower alkyl, hydroxy-lower alkyl or alkanoyloxy-lower alkyl group optionally linked to the heterocycle is preferably linked to the second nitrogen atom of a piperazine radical; Examples are H-methylpiperazino, N-hydroxyethylpiperazino, N-hydroxypropylpiperazino, ET-heptanoyloxypropylpiperazino. All 4 halogen atoms come in as halogen atoms

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Consideration, i.e. fluorine, chlorine, bromine and iodine. Chlorine is preferred.

It has been found that the compounds of the formula I according to the invention and their N-oxides and the salts of these compounds, which are new compounds, are distinguished by strong neuroleptic properties. They can therefore be used, for example, for the treatment of schizophrenia and also as tranquilizers. It is particularly advantageous that no or only minor cataleptic side effects occur, so that no or only insignificant motor disorders are observed. A preferred group of the compounds according to the invention are those in which R _{1 is} hydrogen. Also preferred are those of the compounds according to the invention in which R ₂ and R- together represent an additional bond. Another preferred subgroup of the compounds according to the invention is that in which X is sulfur. Also preferred are those of the compounds according to the invention in which R. and R ₁ - both represent lower alkyl, in particular methyl. An additional preferred subgroup of the compounds according to the invention is that in which R represents methylthio or chlorine, and R ₇ and R 1 represent hydrogen. Furthermore, those compounds are preferred in which Rg is chlorine, R _{7 is} hydrogen and R _{g is} methoxythio. A preferred group of the compounds according to the invention is that in which R, hydrogen, Rp and R "together form an additional bond, R. hydrogen or lower alkyl, R ₁ - lower alkyl, hydroxy-lower alkyl or alkanoyloxy-lower alkyl or R. and R ^ - together represent a saturated, 5- or 6-membered heterocycle optionally containing an oxygen atom or another nitrogen atom, which may be substituted by hydroxy-lower alkyl or alkanoyloxy-lower alkyl, R, - lower alkyl, lower alkoxy, lower alkylthio , lower alkylsulfonyl, di- (lower alkyl!

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sulfamoyl, halogen, trifluoromethyl, nitro, amino or di- (lower alkyl) -amino and one of the substituents R1 and Rq is hydrogen and the other is lower alkyl, lower alkoxy or halogen. A preferred subgroup of these compounds is that in which R _{1 is} hydrogen, Rp and R "together are an additional bond, R. is hydrogen, methyl or ethyl, R _{5 is} methyl, ethyl, hydroxyethyl or acetoxyethyl or R. and Rf- together are piperidine-pyrrolidine -, Morpholine, N-Hydroxyäthylpiperazin- or N-Acetoxyäthylpiperazinrest, R _{6 represent} methyl, methoxy, methylthio, methylsulfonyl, dimethyl sulfamoyl, chlorine, trifluoromethyl, nitro, amino or dimethylamine, R ₇ hydrogen, methyl or chlorine and Rg hydrogen, methyl or methoxy.

Preferred compounds are N, N "-dimethyl-3- [8- (methylthio ) -dibenzo [b, f] thiepin-10-yl] -2-propynylamine, N, N-dimethyl-3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propynylamine and lT, N-dimethyl-3- (S-chloro-5-methoxy-dibenzo [b, f] thiepin-10-yl) -2-propynylamine and their acid addition salts.

The tricyclic compounds of the formula I and their N-oxides and the salts of these compounds are prepared according to the invention by a process which is characterized in that
a) a compound of the formula

409881/128?

= CH

II

in which R-, -R, and X have the meaning given above and Rg'-Rg 'have the same meaning as Rg-Rg, although any hydroxyl groups present may be protected,
with formaldehyde and a compound of the formula

III

in the R. and R ₁ - has the meaning given above,
implements, or that one

b) a compound of the formula

R _n R «R - C - C

in which Rn-iU and X have the meaning given above, T represents a leaving group and Rg'-R ₈ 'have the same meaning as Rg-Rg, although any hydroxyl groups present can be protected »

IV

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with a compound of the formula

III

in which R. and R_ have the meaning given above,
implements, or that one

c) for the preparation of a compound of the 'formula I, in the Rp and R_ together represent an additional bond, a compound of the formula

in which R ₁ , R., R ₁ - and X have the meaning given above and R / - '-Ro ^{1 have the} same meaning as R ^ -Ro, although any hydroxyl groups present may be protected,
dehydrated, or that one

d) for the preparation of a compound of the formula I in which R is hydrogen or lower alkyl and Is alkyl, a compound of the formula

lower

= C- CH2 BHR '

in the Rn-R- * and X the meaning given above 409881/1267

24260A0

have, R. ' Represents hydrogen or lower alkyl and Rg'-Rq 'has the same meaning as R ^ -Ro have, however, existing hydroxy

do

groups can be protected, alkylated, or that one

e) for the preparation of an N-oxide of a compound of the formula I in which R * and R ₅ are different from hydrogen, a compound of the general formula

R _n R_ R_ C_zr.C (

VII

_L -R, and X have the above meaning, the same meaning as R. and R ₁ .

in the

and R ₁ - ¹ 0

have, but are not hydrogen and R / -'- R ₀ ^{1 have the} same meaning as R ^ -R ₀ ,

DO DO

however, existing hydroxyl groups can be protected,
subject to oxidation or that one

f) for the preparation of a compound of the formula I in which R. is hydrogen and R _{1 is} alkanoyloxy-lower alkyl, a compound of the general formula

R-, R

.CEC- CH ₀ EH-R "·

^ z>

VIII

in the R-i

have the above meaning

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-S-

" ¹ denotes hydroxyalkyl, and Hg'-H ₈ ^{1 have the} same meaning as Rg-R ₈ , but the hydroxyl groups present may be protected, alkanoylated, or that one

g) a base of the formula I or an N-oxide thereof in a corresponding acid addition salt is transferred, '

where, after one of the "process alternatives a) -f)" has been carried out, any protected hydroxyl groups Rg'-R ₈ ^{1 which are present are converted} into hydroxyl groups.

The new starting compounds of the formulas II, IV, V, VI, VII and VIII are also a subject of the invention.

The following are the various embodiments of the process according to the invention for the preparation of the tricyclic compounds and their N-oxides or acid addition salts explained in more detail.

Starting compounds of the formula II in which R ₂ and R together represent an additional bond can be prepared from the corresponding 10-ketone by reaction with an acetylene organometallic compound, for example lithium acetylide, an aoetylene magnesium halide or trimethylsilylethinyllithium. The lithium acetylide is preferably in liquid ammonia and / or an organic solvent such as tetrahydrofuran or benzene, or as a complex with ethylenediamine in an inert solvent such as dioxane, tetrahydrofuran or benzene at a temperature between about -1O ⁰ C and the boiling point of the reaction mixture implemented. The Acetylenmagnesium halide and the Trimethylsilyläthinyllithium are preferably reacted the reaction mixture in an organic solvent such as tetrahydrofuran or benzene at a temperature between about -10 ⁰ C and the boiling point. The get-

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tene addition product is then subjected to hydrolysis, for example by. Implementation with aqueous Ammonium chloride solution at room temperature. The received

10-ethynyl-10-carbinol or (if from trimethylsilyläthinyHithium is assumed) 10-Trimethylsilyläthinyl-10-carbinol, is then subjected to dehydration, for example by heating with a strong acid such as p-toluenesulfonic acid in an organic solvent such as methylene chloride, carbon tetrachloride, acetonitrile, benzene or o-, m- or p-xylene. The corresponding starting compound is obtained of the formula II, in which Rp and R- together have an additional Represents bond, or (if of Trimethylsilyläthinyllithium is assumed) the corresponding 10-trimethylsilylathynyl compound. The latter is subjected to a metal-catalyzed hydrolysis, for example in aqueous acetone or in aqueous Ethanol is treated with silver nitrate and potassium cyanide.

The trimethylsilyl group is split off under these conditions even at room temperature, and the desired starting compound of the formula II, in which R ₂ and R 1 together represent an additional bond, is obtained.

Starting compounds of the formula II in which R ₂ and R, both represent hydrogen, are prepared, for example, by reacting a corresponding tricyclic 10-halogen compound, for example the chlorine compound, with one of the abovementioned acetylene organometallic compounds. The reaction is preferably carried out in an inert organic solvent such as ether, benzene or tetrahydrofuran and at a temperature between about -1O ⁰ C and the boiling point of the reaction mixture.

The inventive implementation of the starting compounds of the formula II with formaldehyde and the compounds of the formula III takes place in the sense of a Mannich reaction, preferably in the presence of an inert organic solution

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means, for example in the presence of a lower alkanol, such as methanol or ethanol, in a cyclic! Ethers, such as dioxane, or in a lower alkanecarboxylic acid, for example acetic acid, optionally mixed with water. The temperature is preferably in the range from about 0 to 100 ^° C. The reaction is preferably catalyzed by metal salts, in particular copper (II) salts, such as copper acetate.

The symbol T of the starting compounds of the formula IV preferably represents halogen or alkyl or aryl-substituted substances Sulfonyloxy. The ones present in these substituted sulfony1 residues Alkyl or aryl groups are preferably lower groups, in particular methyl or phenyl or p-tolyl; Y is preferred in its meaning as "halogen" Are chlorine or bromine.

10,11-unsaturated starting compounds of the formula IV can be prepared, for example, by reacting the corresponding tricyclic 10-ketone with an organometallic compound of 2-propynyl-2-tetrahydropyranyl ether, for example with the corresponding lithium or magnesium halogen compound. The organometallic compound of 2-propynyl-2-tetrahydropyranyl ether carries the corresponding metal radical (eg lithium radical or magnesium halogen radical) on the carbon atom in the 3-position of the 2-propynyl radical. The lithium compound is preferably reacted the reaction mixture in liquid ammonia and / or an organic solvent, such as tetrahydrofuran, the magnesium halide compound in an organic solvent such as tetrahydrofuran, at a temperature between about -1O ⁰ C and the boiling point. The addition compound obtained is then subjected to hydrolysis, for example by treatment with aqueous ammonium chloride solution at room temperature, and the resulting tricyclic 10- [3- (2-tetrahydropyranyloxy) -1-propynyl] -10-carbinol is then dehydrated and one r

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Subjected to hydrolysis, "for example by treating with egg strong acid, e.g. p-toluenesulfonic acid, in methylene chloride, Benzene or ό-, m- or p-xylene, at the boiling point of the reaction mixture (with dehydration taking place) and an.schliessen.des Boiling with p-toluenesulfonic acid in aqueous ethanol (whereby the dehydration product is hydrolyzed). The 10,11-unsaturated tricyclic 10- (3-hydroxy-1-propynyl) compound thus obtained can now be converted into a corresponding, 10,11-unsaturated reactive ester of the formula IV be, for example by reaction with the corresponding alkyl or aryl substituted sulfonic acid halide, e.g. the chloride, or with thionyl chloride or thionyl bromide.

Another method of making the 10,11-unsaturated Starting compounds of the formula IV are described in Example 5.

10,11-G-unsaturated starting compounds of the formula IV can by reacting a corresponding tricyclic 10-halogen compound, e.g. the chlorine compound, with a of the above-mentioned organometallic compounds of 2-propynyl-2-tetrahydropyranyl ether. The 10,11-saturated tricyclic 10- [3- (2-tetrahydropyranyloxy) -l-propyny] compound obtained is then, as described above, hydrolyzed and converted into the corresponding 10,11-saturated reactive Converted ester of the formula IV.

The inventive reaction of the compounds of the formulas IV and III can in an inert organic Solvents such as benzene, toluene, dimethylformamide or the like, take place. It is preferable to work in the presence an excess of the compound of formula III to be used, which serves as an acid-binding agent. However, other acid-binding agents can also be used

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e.g. anhydrous potassium carbonate. With the use of volatile compounds of formula III, the reaction is conveniently carried out in a closed vessel at elevated temperature, for example at about 50 ° to about 175 ⁰ C. The reaction temperature is not critical otherwise they conveniently lies between about -20 ⁰ C and the boiling point of the reaction mixture, for example between room temperature and the boiling point of the reaction mixture.

The tricyclic 10-carbinols of the formula V can for example by reacting the corresponding tricyclic 10-ketone with an organometallic compound an optionally correspondingly N-substituted 2-propynylamine getting produced. For example, the corresponding lithium or magnesium halogen compound is used, where the metal radical is in the 3-position of the 2-propynylamine. Lithium compounds are preferably in liquid ammonia and / or an organic solvent such as tetrahydrofuran, reacted magnesium halogen compounds in an organic solvent such as tetrahydrofuran, at the boiling point of the Reaction mixture *. The addition compound obtained is then subjected to hydrolysis, for example by treatment with aqueous ammonium chloride solution at room temperature, after which the corresponding tricyclic 10-carbinol Formula V receives.

The inventive dehydration of the starting compounds Formula V leads to 10, !! - unsaturated end products of the formula I. The dehydration is expediently using strong acids, such as organic sulfonic acids, e.g. p-toluenesulfonic acid, methanesulfonic acid, or Mineral acids, such as hydrochloric or hydrobromic acid, carried out, it is possible to work in an anhydrous or aqueous medium. Preferably, the dehydration in an organic sulfonic acid, e.g. p-toluosulfonic acid,

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in the presence of an inert organic solvent such as methylene chloride, carbon tetrachloride, acetonitrile, benzene or o-, m-, or p-xylene. When using mineral acids, these are used, for example, in solution in a lower alkanol. Other customary dehydrating agents can also be used, for example acetic anhydride. The temperature for the dehydration is conveniently lies between about room temperature and about 200 ⁰ C, preferably between about 5O ⁰ G and about 200 ⁰ C.

Pur the inventive alkylation of the starting compounds Various methods are available for formula VI.

If a tertiary amine of the formula I is desired, you can proceed as follows, for example:

A starting compound of the formula VI is combined with a compound of the formula R ₁ - ¹ Y _n , in which R 'is lower alkyl and Y _{1 is} a leaving group, for example halogen, such as chlorine, bromine or iodine, or lower alkanesulphonyloxy, benzenesulphonyloxy, or lower alkylbenzenesulphonyloxy , implemented. as

Alkylating agents can also be used with ethylene oxide (which in turn can be substituted by lower alkyl); thereby, a (optionally alkylated) HydroxJäthylgruppe eingeführt.Die reaction is preferably carried out eg in an inert solvent, in a lower alkanol, such as ethanol, or in dimethylformamide, and at a temperature of about 15 to 75 ⁰ C. According to another procedure for the preparation of tertiary amines of the formula I, a starting compound of the formula VI is reacted with a mixture of formaldehyde and formic acid, preferably in excess and at an elevated temperature, for example between ¹ approx. 50 ^° C. and the boiling point of the reaction mixture. Instead of

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of formic acid, sodium borohydride can also be used in this reaction.

Starting compounds of the formula VI in which R 'is hydrogen, ie primary amines of the formula VI, can be converted into secondary amines of the formula I by adding the primary amine of the formula VI with a haloformic acid ester, for example with ethyl chloroformate or bromoformate converts a carbamate and then reduces it with a complex metal hydride such as lithium aluminum hydride. Both reaction stages are preferably carried out in an inert solvent, for example ether or tetrahydrofuran, and at a temperature between about room temperature and the reflux temperature of the reaction mixture, in particular at the reflux temperature. According to another method for the preparation of secondary amines of the formula I is a primary amine of formula VI with chloral, preferably in an inert solvent such as chloroform or benzene, at elevated temperature, for example between about 5O ⁰ C and the boiling point of the reaction mixture, . The resulting formylamino compound is then reduced to the secondary amine of the formula I with a complex metal hydride, for example lithium aluminum hydride in anhydrous ether. After another

Method for the preparation of secondary amines of formula I is a primary amine of formula VI with formaldehyde, preferably in an inert solvent such as benzene or toluene and at a temperature between about room temperature and that Boiling point of the reaction mixture, implemented. The resulting Schiff's base is then converted into a secondary amine of the formula I by reduction. This reduction is conveniently done by treatment with a complex metal hydride, such as sodium borohydride or lithium aluminum hydride in anhydrous ether or dioxane.

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The oxidation according to the invention of the compounds of the formula VII yields the corresponding M-oxides. Hydrogen peroxide or an organic peracid, for example m-chloroperbenzoic acid, is preferably used as the oxidizing agent. The oxidation is advantageously carried out in an inert organic solvent, such as, for example, in a lower allcanol, such as methanol or ethanol; Ether, benzene, chloroform or methylene chloride, and at a temperature between about -5O ⁰ C and room temperature, for example between ^{0 0} C and room temperature. After working up in the usual way with removal of the excess oxidizing agent, the corresponding N-oxide is obtained. the latter is conveniently obtained in the form of an acid addition salt.

The inventive alkanoylation of compounds of formula VIII is preferably carried out by heating at about 5O ⁰ C to 150 ⁰ C with a reactive derivative of a carboxylic acid corresponding alkane, for example the corresponding acid chloride or acid anhydride. The esterification can also be carried out by reaction with an alkanecarboxylic acid in the presence of a strongly acidic catalyst, e.g. sulfuric acid oder.p-toluenesulfonic acid, or in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or carbonyldiimidazole. The esterification is preferably carried out in an organic solvent, for example benzene, toluene or pyridine.

If a compound of the formula I in which R (

if necessary also R ₇ and / or Rg) is hydroxy, or a corresponding Η-oxide is to be prepared, a starting compound of the formula II, IV, V, VI, VII "or VIII in which the corresponding hydroxy group is protected is preferably used is, for example, by lower alkyl, benzyl or trimethylsilyl

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split off this protective group, the alkyl group preferably by treatment with a pyridine salt, for example pyridine hydrochloride, optionally in the presence of water, or by treatment with a boron trihalide, for example boron tribromide or boron trichloride, the benzyl group preferably in the manner indicated for the alkyl group or by treatment with a Alkali metal, for example sodium in a lower alkanol, for example butanol, and the trimethylsilyl group preferably by acid-catalyzed hydrolysis, for example by treatment with aqueous-alkanolic mineral acid, such as aqueous-ethanolic hydrochloric acid. Preference is given to working in an inert organic solvent, for example benzene, toluene or xylene, or a halogenated hydrocarbon, such as, for example, methylene chloride, chloroform or carbon tetrachloride. The temperature is preferably between room temperature and the boiling point of the reaction mixture, except for the use of a boron halide, wherein the temperature is advantageously in the range of about -70 ⁰ C to room temperature.

Bases of the formula I obtained form salts with both inorganic and organic acids, e.g. with hydrogen halide acid, such as hydrochloric acid, hydrobromic acid or hydriodic acid, with other mineral acids, such as sulfuric acid, phosphoric acid or nitric acid, as well as with organic acids such as tartaric acid, citric acid, Camphorsulphonic acid, methanesulphonic acid, toluenesulphonic acid, Salicylic acid, ascorbic acid, maleic acid or mandelic acid, etc. Preferred salts are the hydrohalides, especially those Hydrochloride and the Maleates. The acid addition salts are preferably in a suitable solvent, such as ethanol, Acetone or acetonitrile, produced by treating the free base with the appropriate, non-aqueous acid.

The bases of the formula I are partly crystalline, 409881/1287

solid substances in dimethyl sulfoxide, dimethylformamide or in chlorinated hydrocarbons such as chloroform, methylene chloride, in alkanols such as methanol or ethanol, or in ether or benzene, are relatively soluble and relatively insoluble in water.

The acid addition salts of the bases of the formula I are crystalline, solid substances. They are in dimethyl sulfoxide and dimethylformamide and in alkanols, such as methanol or ethanol, and partly also in chloroform, methylene chloride and Well soluble in water. They are relatively insoluble in benzene, ether and petroleum ether.

As stated above, the inventive

"End products are characterized by strong neuroleptic properties as well with the additional advantage that they have no or very little cataleptic effect. A cataleptic effect ("Wakefulness", i.e. abnormally long retention of a forced body position) applies to neuroleptically effective Compounds as a bothersome side effect and testifies to motor Disruptions. Representative representatives of the Final products administered intraperitoneally to the rat. The following representatives, among others, were examined:

Product A: tf, N-dimethyl-3- [8- (methylthio) -dibenzo- [b, f] thiepin-10-yl] -2-propynylamine maleate.

Product B-: N, N-D: uiiethyl-3- (8-chloro-dibenzo [b, f] thiepin-10-yl] -2-propynylamine maleate.

Product C: N, H-dimethyl-3- (8-chloro-3-methoxydibenzo [b, f] thiepin-10-yl) -2-propynylamine methanesulfonate.

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Chlorpromazine, a recognized substance, was used as a comparison substance neuroleptic agent used.

The animals are considered cataleptic if the homolateral extremities are in for at least ten seconds crossed position remain. The number of the cataleptic Animals are noted every 30 minutes for 6 hours. the ED 50 is the dose at which $ 50 of the animals show catalepsy.

Result:

product ED 50
mg / kg A.
B.
G ^> 100
100
> 100 Chlorpromazine 6th

The table shows that there is no or very little cataleptic effect in A, B and C, im Contrasted with chlorpromazine.

To demonstrate the neuroleptic properties of the end products, representative representatives were given the following Subject to test:

of homovanillic acid

Rats are injected with the test substance 2 hours before killing.

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Homovanillic acid is obtained from the supernatant of the brain homogenate 'Extracted in butyl acetate and later in an aqueous solution and combined with potassium ferricyanide to one fluorescent dimer oxidized. From the increased concentration of homovanillic acid (HVS) one can conclude that that the test substance acts like chlorpromazine, i.e. it increases the turnover of dopamine in the basal ganglia. The homovanillic acid titer in untreated rats is arbitrarily set at $ 100.

A comparison between A, B, C and chlorpromazine gives:

product dose
mg / kg po Increase of
HVS, i-> A.
B.
C. 50
5
50
30th 330
300
370
320 Chlorpromazine 20th 321

In this test, A, B and C show an effect of the same order of magnitude as that of chlorpromazine.

The products according to the invention can be used as remedies, e.g. in the form of pharmaceutical preparations, which they or their salts in a mixture with an enteral, e.g. pharmaceutical, organic or inorganic inert substances suitable for oral or parenteral administration Carrier material, such as water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, gum arabic, Contains polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets,

4 0 9 8 81/12 6 7

DrageOs, suppositories, capsules or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contained Auxiliaries, such as preservatives, stabilizers, wetting agents or Emulsifiers, salts to change the osmotic pressure or buffers. You can also do others therapeutically contain valuable substances.

Appropriate pharmaceutical dosage forms contain approx. 1 to 200 mg of a compound of the formula I or one of their salts. Useful organic dosage ranges are from about 0.1 mg / kg per day to about 15.0 mg / kg per day, especially at about 0.1 mg / kg per day to about 7.5 mg / kg per day. Appropriate parenteral dosage ranges are from about 0.01 mg / kg per day to about 0.75 mg / kg per day. It can, however, the ranges mentioned above or can be extended downwards, depending on the individual needs and instructions of the specialist.

The following examples illustrate the invention. All temperatures are in ⁰ C.

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example 1

63 g of p-toluenesulfonic acid and 1800 ml of o-xylene will be heated to boiling and the water present is distilled off. This solution is mixed with 90 g of 10- [3- (dimethylamino) -1-propynyl] -8-chloro-10, ll-dihydro-dibenzo [b, f] thiepin-10-ol offset. The reaction mixture is 45 minutes "at the boiling point held, the resulting water being distilled off. The whole thing is cooled and poured onto 90 ml of 2 η aqueous sodium hydroxide solution poured. DiB-aqueous phase is extracted with ether. The combined organic extracts are washed three times with water and then three times with about 3 η aqueous methanesulfonic acid extracted. The aqueous phase is washed with ether and made alkaline with concentrated sodium hydroxide solution. The whole thing is extracted with ether and the ether extract washed with water, dried and evaporated. Crude N, N-dimethyl-3- (8-chlorodibenzo {b, f] thiepin-10-yl) -2-propynylamine is obtained, which melts after recrystallization from hexane at 118-120 °. The maleate precipitated from ethanol melts at 178-180 °.

The 10- [3- (dimethylamino) -1-propynyl] -8-chloro-10, 11-dihydro-dibenzo [b, f] thiepin10-ol used as the starting compound can be made as follows:

2100 ml of liquid ammonia become ferric nitrate with a few crystals and then within about 2 hours with, -10.4 g lithium wire (0 approx. 2 mm) offset. After stirring for 30 minutes, 369 ml of dimethylamino-1-propyne are added within 40 minutes added, after which the reaction mixture is stirred for a further 45 minutes. Within 105 minutes a Solution of 300 g of 8-chloro-10, ll-dihydro-5H-dibenzo [b, f] thiepin-10-one in 1500 ml of tetrahydrofuran added dropwise. The reaction mixture is left to stand overnight. At the the following morning the reaction mixture with 228 g of ammonium

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ohlorid is added to 600 ml of water, the ammonia is evaporated, 900 ml of tetrahydrofuran are added and the whole is heated under reflux conditions for 2 hours. That The reaction mixture is evaporated, diluted with water and extracted with ether. The essential extracts will be washed with water and extracted with 3 η aqueous methanesulfonic acid. Unreacted starting ketone can come from the essential Phase to be recovered. The aqueous phase is made alkaline with concentrated sodium hydroxide solution, whereby one crude 10- [3- (dimethylamino) -1-propynyl] -8-chloro-10, III-dihydro-dibenzo [b, f] thiepin-10-ol obtained, which is taken up in chloroform. The chloroform phase is washed with water, dried and evaporated. The compound obtained melts after recrystallization from acetone at 150-152 °.

Example 2

In the same manner as indicated in Example 1, 10- [3- (dimethylamine) -l-propynyl] -10,11-dihydro-8- (methylthio) -dibenzo [b, f] thiepin-10-ol is obtained N, F-Dimethyl-3- [8- (methylthio) -dibenzo [b, f] thiepin-10-yl] -2-propynylamine. The maleate melts at 145-146 °.

The starting material is obtained in analogy to Example 2 from 10, ll-dihydro-8- (methylthio) -5H-dibenzo [b, f] thiepin-10-one obtained and melts after recrystallization from benzene / hexane at 142-144 °.

Example 3

In the same way as in Example 1, 10- [3- (dimethylamine) -l-propynyl] -10,11-dihydro-8-methyl-dibenzo [b, fthiepin-10 is obtained -Oil IT, 2J-Dimethyl-3- (8-methyl-dibenzo [b, f] thiepin-10-yl) -2-propynylamine. The latter compound is by chromatography on silica gel using

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Purified chloroform as the eluent. The corresponding Maleate melts at 121-123 °.

The starting material used is made in analogy to Example 1 from 10, ll-dihydro-8-methyl-5H-dibenzo [b, f] thiepin-10-one produced and melts after recrystallization from ether at 145-147.5 °.

Example 4

A solution of 5.1 g of 10-ethynyl-8-chloro-dibenzo [b, f] thiepin in 40 ml of absolute dioxane is mixed with 630 mg of paraformaldehyde, 4.5 ml of a 6 molar solution of dimethylamine in Dioxane and 200 mg of copper (II) acetate are added. The reaction mixture is poured into a well-closed flask during 2 Heated to 100 ° for hours. After cooling, the mixture is poured onto ice and then acidified with 3N methanesulfonic acid. The neutral products are removed by extracting with ether. The aqueous phase becomes alkaline with ammonia posed. Extraction with ether gives N, N-dimethyl-3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propynylamine obtained, which melts after recrystallization from hexane at 118-120 °. The maleate melts at 178-180 °.

The following connections are established in an analogous manner:

-N, F-Dimethyl-3- [8- (methylthio) -dibenzo [b, f] thiepinlO-yl] -2-propynylamine, Pp. 78-80 °. The hydrochloride melts at 182-184 °.

-F, H-Dimeth? L-3- (8-methyl-dibenzo [b, f] thiepin-10-yl) -2-propynylamine, Pp. 70-72 ° ν The hydrochloride melts at 214-216 °. . _.

409881/1267

-F, N-dimethyl-3- (8-fluoro-dibenzo [b , f] thiepin-10-yl) 2-propynylamine, mp 59-61 °. The hydrochloride melts at 234-236 °.

-N, IT-Diethyl-3- (8-chloro-dit> enzo [>, f] thiepin-10-yl) -2-propynylamine. The maleate melts at 146-148 °.

-N, N-dimethyl-3- (8-chloro-2-methyl-dibenzo [b, f] thiepin-10-yl) -2-propynylamine, Pp. 96-97 °. The hydrochloride melts at 174-176 °.

1- [3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propynyl] piperidine, mp 59-61 °. The methanesulfonate melts at 179-181 °.

4- [3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propynyl] morpholine, Mp. 109 °. The methanesulfonate melts at 164-166 °.

1- [3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propynyl] pyrrolidine, pp. 76-77 °. The methanesulfonate melts at 152-154 °.

-F, N-dimethyl-3- (8-fluoro-2-methyl-dibenzo [b, f] thiepin-10-yl) propynylamine, M.p. 74-76 °. The hydrochloride melts at 231-234 °.

-N, F-Dimethyl-3- (8-chloro-3-methoxydibenzo [b, f] thiepin-10-yl) -2-propynylamine, Pp. 102-104 °. The methanesulfonate melts at 211-214 °.

-IT, li-dimethyl-3- (8-methoxy-dibenzo [b, f] thiepin-10-yl) 2-propynylamine, M.p. 68-71 °. The methanesulfonate melts at 132-135 °.

-Ii, N-dimethyl-3- (8-chloro-dibenzo [b, f] oxepin-yl) -2-

409881/1267

propynylamine, m.p. 62-64 °. The methanesulfonate melts at 127-129 °.

-N, N-dimethyl-3- (8-isopropyl-dibenzol.b, f] thiepin-10-yl) -2-propynylamine, Boiling point 170 ° / 0.02 mm Hg. The Hydrochloric! melts at 194-197 °.

-N, N-dimethyl-3- (2,8-dichloro-dibenzoLb, f] thiepin-10-yl) -2-propynylamine, Pp. 83-85 °. The hydrochloride melts at 224-227 °.

2- ^ [3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propynyl] -methylamino ^ -ethanol, M.p. 87-90 °. The maleate melts at 149-151 °.

2_J4- [3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propynyl] -1-piperazinyl ^ -ethanol, 111-113 °. The dihydrochloride melts at 253-257 °.

-N, N-Dimethyl-3- [2-chloro-8- (methylthio) -dibenzo [b, f J thiepin-10-yl] -2-propynylamine, m.p. 100-103 °. The hydrochloride melts at 206-208 °.

-N, N-Dimethyl-3- [2-methy1-8- (methylthio) -dibenzo [b, f]. thiepin-10-yl] -2-propynylamine, m.p. 80-82 °. The hydrochloride melts at 185-187 °.

-N, N-dimethyl-3- (8-nitro-dibenzo Lb, f] thiepin-10-yl] -2-propynylamine, 113-115 °. The maleate melts at 179-182 °.

-N, N-dimethyl-3- (8-chloro-ll-methyl-dibenzo [b, f] thiepin-10-yl) -2-propynylamine, bp 210 ° / 0.2 mm Hg. The hydrochloride melts at 240-243 °.

-N, N-3-L 3-methyl-8- (methylthio) -dibenzo [b, f] thiepin-10-yl] ■

409881/1267

2-propynylamine, m.p. 69-72 °. The maleate melts at 161-163 °

-Η ", If-dimethyl-3- (8-amino-dib enzo [b, f] thiepin-10-yl) 2-pr opinionylamine.

-E, N-Dimethyl-3- [8- (dimethylamino) -diben »o [b, f] thiepin-10-yl] -2-propynylamine.

-N, N-dimethyl-3- [8- (methylsulfonyl) dibenzo [b, f] th.iepin-10-yl] -2-propynylamine, M.p. 151-1330. The hydrochloride melts at 247-250 °.

-N, N-dimethyl-3- [8- (dime thy lsulf amoyl) -dibenzo [b, f] th.iepin-10-yl] -2-propynylamine, m.p. 112-114 °. The hydrochloride melts at 217-220 °.

-K, N-dimethyl-3- [8- (trifluoromethyl) -dibenzo [b, f] th.iepin-10-yl] -2-propynylamine, m.p. 88-91 °. The hydrochloride melts at 196-198 °.

The 10-ethynyl-8-chloro-dibenzo [b, f] thiepin used as starting material can be made as follows:

59 g of a trimethylethinylsilane / tetrahydrofuran mixture (corresponding to 0.44 mol of trimethylethinylsilane) in 300 ml of benzene are mixed with 235 ml of n-butyllithium solution in hexane (corresponding to O.4 mol) slowly added dropwise at 0 °. After stirring for a further half an hour at this temperature, a Solution of 52.8 g of 8-chloro-10, ll-dihydro-5H-dibenzo [b, f] thiepin -10-one in 250 ml of benzene was slowly added dropwise. The solution is left in the refrigerator overnight. The following morning will the reaction mixture to a solution of 250 g of ammonium chloride

409881/1267

- ■ 27 -

poured into 1.5 l of water. By extracting with benzene a mixture of unreacted starting ketone and 8-chloro-10, II-dihydro-10- [(trimethylsilyl) -ethinyl] -dibenzo [b, f] thiepin-10-ol obtained, which is directly subjected to dehydration.

For this purpose, the mixture is taken up in 500 ml of benzene and, after adding 1.2 g of p-toluenesulfonic acid, for 2 hours boiled under reflux, the resulting water being distilled off. By diluting with benzene and washing neutral with water, a mixture of unreacted starting ketone and [(8-chloro-dibenzo [b, f] thiepin-10-yl) ethinyl] trimethylsilane is obtained, which is immediately subjected to the cleavage of trimethylsilyl groups.

A solution of 64 g of silver nitrate is added dropwise to the mixture, which is dissolved in 660 ml of acetone / water (10: 1) 150 ml of water are added over the course of 30 minutes and another is stirred Hour. Then a solution of 120 g of potassium cyanide in 500 ml Water and 500 ml of benzene are added and the mixture is stirred until two clear phases are formed. By extracting with benzene a mixture of unreacted ketone and 10-ethynyl-8-chloro-dibenzo is obtained [b, f] thiepin, which is separated by chromatography on silica gel. The connection obtained melts after recrystallization from ether / n-pentane at 105-108 °. "

The following starting compounds are produced in an analogous manner:

10-ethynyl-8- (methylthio) -dibenzo [b, f] thiepin, m.p. 99-101 °.

10-ethynyl-8-methyl-dibenzo [b, f] thiepin, mp 94-96 °. 409881/1267

10-ethynyl-8-fluoro-dibenzo [b, f] thiepin. The connection represents a pure oil according to the thin-layer chromatogram.

10-ethynyl-8-chloro-2-methyl-dibenzo L b, f] thiepin. Fp. 127-129 °.

10-ethynyl-8-fluoro-2-methyl-dibenzo [b, f] thiepin, pp. 74-76 °.

10-ethynyl-8-chloro-3-methoxy-dibenzoLb, f] thiepin, pp. 103-105 °.

10-ethynyl-8-methoxy-dibenzoLb * f] thiepin, pp. 131-136 °. 10-ethynyl-8-chloro-dibenz [b, f] oxepin, pp. 118-120 °.

10-ethynyl-8-isopropyl-dibenzo [b, fjthiftpin. The connection represents a pure OeI according to the thin-layer eromatogram represent.

10-ethynyl-2,8-dichloro-dibenz [b, f] oxepin, pp. 134-137 °.

10-ethynyl-2-chloro-8- (methy1thio) -dibenzo [b, f] thiepin, 100-103 °.

10-ethynyl-2-methyl-8 - (methylthio) -dibenzo [b, f] thiepin, Pp. 124-126 °.

10-ethynyl-8-nitro-dibenzoib, f] thiepin, mp 175-177 °.

10-ethynyl-e-chloro-II-methyl-dibenzoLb, fJthiepin. the According to the thin-layer chromatogram, the compound represents a pure one OeI represents.

10-ethynyl-3-methyl-8- (methylthio) dibenzo [b, f] thiepin.

According to the thin-layer chromatogram, the compound is a pure oil.

409881/1267

10-ethiny1-8- (methylsulfonyl) -dibenzo [b, f] thiepin, 140-143 °.

■ 10-ethynyl-8-aminodibenzo [b, f] thiepin.

10-ethynyl-8- (dimethylamine) - dibenzo [b, f] thiepin.

10-Aethiny1-8- (dimethylsulf amoyl) -dibenzo [b, f] thiepin, 133-135 °.

10-ethynyl-8- (trifluoromethyl) -dibenzo [b, f] thiepin, M.p. 63-65 °.

Example 5

A mixture of 20 ml of dimethylformamide and 10 ml Methylamine is mixed at about 0 ° with a solution of 4.7 g of 3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propyn ^ l-ol-mesylate in 30 ml of dimethylformamide are slowly added dropwise. After about The mixture is poured onto water for a reaction time of one hour. Extraction with ether gives N-methyl- [3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propynyl.amine which, after recrystallization from ether, melts at 92-94 °. The maleate melts at 104-106 °.

The following can be produced in an analogous manner:

3- (8-chloro-dibenzo [b, f] thiepin-10-y.l) -2-propynylamine, Pp of the maleate 170-172 °.

The 3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propyn-1-ol mesylate used as the starting compound can be made as follows:

409881/1287

A solution of 13.5 g of 10-ethynyl-8-chloro-dibenzo [b, f] thiepin in 150 ml of absolute tetrahydrofuran is treated dropwise at room temperature with 52 ml of a 1 molar ethylinagnesium bromide solution in tetrahydrofuran. After stirring for a further hour, 1.85 g of paraformaldehyde is pyrolyzed and passed into the reaction mixture as a gas. The solution, which has now been heated to approx. 50 °, is stirred for a further 30 minutes and then poured into a saturated aqueous ammonium chloride solution. Extraction with benzene and subsequent chromatography on silica gel with benzene / methanol (20: 1) as the eluent gives 3- (8-chloro-dibenzo [b, f] -thiepin-10-yl) -2-propyn-1-ol , which melts at 12JJ-TLy ⁰ after recrystallization from ethyl acetate / petroleum ether.

A solution of 6 g of 3- (8-chloro-dibenzo [b, f] thiepin-10-yl} -2-propyn-1-ol in 50 ml of pyridine is mixed with 1.7 ml of methanesulfonyl chloride in 10 ml of pyridine at -10 added dropwise to O ⁰ and then stirred for 2 hours at this temperature. Pouring onto ice, followed by acidification with hydrochloric acid and extraction with ether gives 3- (8-chloro-dibenzo [_b, f] thiepin-10-yl) - 2-propyn-l-ol-mesylate, which melts at 100-102 ° after recrystallization from ether.

Example 6

A solution of 2 ml of ethylene oxide in 10 ml of ethanol is with a solution of 0.6 g of N-Methy1-3- (8-chloro-dibenzo- [b, f] thiepin-10-yl) -2-propynylamine added in 5 ml of ethanol and stirred for about 4 hours at room temperature. The solvent is evaporated and the residue is partitioned between water and ether. The ether phase is diluted with aqueous Washed ammonia solution, dried over sodium sulfate and evaporated. 2- | [3- (8-Chlordibenzo [b, f] thiepin-10-yl) -2-propynyl] methylamino] ethanol is obtained, which after recrystallization from ether / n-pentane melts at 86-88 °.

409881/1267

Example 7

A solution of 5.0 g of 2- [4-L3- (8-chloro-dibenzene, b, f] -thiepin-10-yl) -2-propynyl] -l-piperazinyl} -ethanol in 50 ml of acetic anhydride is heated on the steam bath for 15 minutes. To After evaporation of the excess acetic anhydride under greatly reduced pressure, the oil obtained is taken up in ether and washed with saturated potassium bicarbonate solution. Concentration of the ether phase gives / 2-14- [3- (8-chlorodibenzo [b, f] thiepin-10-yl) -2-propynyl] -l-piperazinyl $ ethyj £ acetate, which melts after recrystallization from ethyl acetate / hexane at 96-99 °.

In an analogous manner one obtains / 2-j [3- (8-Chlox-dibenzo- [b, f] thiepin-10-yl) -2-propynyl] -methylamino ^ -äthyj £ acetate, which melts after recrystallization from petroleum ether at 48-51 °.

Example 8

A solution of 2 g of N, N-dimethyl-3- (8-chloro-dibenzo- [b, f] thiepin-10-yl) -2-propynylamine in 100 ml of chloroform, 1.2 g of m-chloroperbenzoic acid are added at -50 °. The reaction solution is stirred for 15 minutes at this temperature, warmed to room temperature and on basic aluminum oxide chromatographed. Chloroform / methanol is used as the eluent (9: 1) is used. The obtained N, N-dimethyl-3- (8-chloro-dibenzo- [b, f] thiepin-10-yl) -2-propynylamine-N-oxide melts after recrystallization from ethyl acetate / petroleum ether at 68-69 ° C

409881/1267

Pharmaceutical preparation forms containing representative representatives of the products according to the invention can be produced with the aid of customary methods. Examples of such pharmaceutical preparation forms are
following:

Example 9 Manufacture of tablets;

N, N-dimethyl-3- [8- (methylthio) -dibenzo-

[b, f] thiepin-10-yl] -2-propynylamine-ma

leat 25.00 g

Lactose 110.00 g

Corn starch 61.00 g

Talc 3.40 g

Magnesium stearate 0 _t 60 g

200.00 g

The ingredients are intimately mixed with one another and pressed into tables of 200 mg each. Then be they covered with ethyl cellulose and carbowax.

Example 10 Manufacture of tablets:

N, F-Dimethyl-3- [8- (methylthio) -dibenzo- [b, f] thiepin-10-yl] -2-propynylamine

Lactose
Cornstarch

Hydrolyzed corn starch calcium stearate

409881/1267

The active ingredient, the lactose, the corn starch and the hydrolyzed corn starch are mixed and added with water a tough paste granulated. This paste is passed through a sieve and then dried at 45 ° over fold. The dried granulate is passed through a sieve and then mixed with the calcium stearate. The received Mixture is compressed into tablets with a weight of 41Θ mg and a diameter of about 10 mm.

Example 11 Preparation of tablets

JT _f N ~ dimethyl-3- [8- (methylthio) -dibenzo-

■ [b, f] thiepin-10-yl] -2-propynylamine 25, above

Lactose 114.0 g

Corn starch 50.0 g

Gelatinized corn starch 8.0 g

Calcium stearate 3 * 0 g

200.0 g

The active ingredient, lactose, corn starch and gelatinized corn starch are intimately mixed with one another. The mixture is passed through a crushing machine and then moistened with water to form a thick paste. The moist mass is passed through a sieve. The moist granules are dried at 45 °. The dried granules is thoroughly mixed with the calcium stearate. The granules now become tablets weighing 200 mg and one Pressed about 8 mm in diameter.

409 881/1267

Example 12 Manufacture of tablets:

K, F-Dimethyl-3- [8- (methylthio) -dibenzo- [b, f] thiepin-10-yl] -2-propynylamine maleate 14.5 g

Lactose 124.5 g

Corn starch 50, above

Gelatinized corn starch 8.0 g

Calcium stearate 3.0 g

200.0 g

The active ingredient, lactose, corn starch and gelatinized corn starch are intimately mixed with one another. The mixture is passed through a crushing machine and then moistened with water to form a thick paste, The moist mass is passed through a sieve. The moist granules are dried at 45 °. The dried granules is thoroughly mixed with the calcium stearate. The granules now become tablets weighing 200 mg and one Pressed about 8 mm in diameter.

Example 13 Manufacture of capsules:

IT, ir-dimethyl-3- [8- (methylthio) -dibenzo- [b, f] thiepin-10-yl] -2-propynylamine maleate 29.0 g

Lactose 156.0 g

Corn starch 30.0 g

5.0 g 220.0 g

The active ingredient, the lactose and the corn starch are 409881/1267

intimately mixed with each other and passed through a shredding machine. The mixture is now with the talc thoroughly mixed and filled into hard gelatin capsules.

Example 14 Manufacture of capsules;

Ή, N-dimethyl-3- [8- (methylthio) -dibenzo-

[b, f] thiepin-10-yl] -2-propynylamine 25.5 g

Lactose 159.5 g

Corn starch 30.0 g

Talc 5.0 g

220.0 g

The active ingredient, the lactose and the corn starch are intimately mixed with one another and passed through a grinder happened. The mixture is then mixed thoroughly with the talc and filled into hard gelatin capsules.

Example 15

Manufacture of a parenteral preparation form; Each 1 ml ampoule contains;

N, N-dimethyl-3- [8- (methylthio) -dibenzo-10.20 mg

[b, f] thiepin-10-yl] -2-propynylamine (2 $ excess) Methanesulfonic acid for injections 2.22 glucose for injections 40.0 mg

Water for injections q.s. ad 1 ml

In a glass vessel, while stirring at room temperature, the following are dissolved in 8000 ml of water for injections one after the other:

409881/1267

22.2 g methanesulfonic acid for injections, 102 g active ingredient and 400 g glucose. Subsequently, water for injections "up to a total volume of 10 ¹ OOO ml was added. The solution is either sterile filtered, transferred into colorless ampules, sparged with nitrogen and sealed or filled into colorless ampules purged with nitrogen, sealed, and followed by 30 minutes Sterilized with flowing steam or autoclaved at 120 °.

Instead of the active ingredients used according to Examples 9-15, the preparation forms described there of course, other active ingredients according to the invention can also be used, for example

-N, IT-Dimethyl-3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propynylamine or its maleate or methanesulfonate.

-N, N-dimethyl-3- [8-chloro-3- (methoxy) - dibenzo [b, f] thiepin-10-yl] -2-propynylamine or its methanesulfonate.

409881/1267

Claims (32)

Patent claims 1. Process for the preparation of tricyclic compounds of the general formula R ₁ ^U 8 in which X is oxygen or sulfur, R ₁ and R_ hydrogen or lower alkyl, R ~ hydrogen or together with Rp an additional bond and R ^ and Rf- hydrogen, lower alkyl, hydroxy-lower alkyl, alkanoyloxy-lower alkyl or together a saturated one , 5- • or 6-membered, optionally an oxygen atom, sulfur atom or a further nitrogen atom containing heterocycle which can be substituted by lower alkyl ·, hydroxy-lower alkyl or alkanoyloxy-lower alkyl, and in which furthermore Rg lower alkyl, lower alkoxy , lower alkylthio, lower alkylsulfonyl, £ i- (lower alkyl) -sulfamoyl, hydroxy, halogen, trifluoromethyl, nitro, amino or di- (lower alkyl) -amino and R ₇ and Rq each individually represent hydrogen or a substituent listed under Rg , of N-oxides of compounds of the formula I in which R ₄ and R ₅ are different from hydrogen, and of acid addition salts of the compounds mentioned, characterized in that the s man
a) a compound of the formula 409881/1267 24260A0 II in which RiR * and X have the meaning given above and Rg'-Rq 'have the same meaning as R ^ -Ro, although any hydroxyl groups present can be protected,
with formaldehyde and a compound of the formula \ l III in the R. and R ^ the meaning given above Has, implements, or that one
b) a compound of the formula in which RiR * u ^ cl X have the meaning given above, Y an exiting
Represents group and "R ^ - '-R ^' have the same meaning as R ^ -Ro, where each- 409881/1267 but existing hydroxyl groups can be protected,
with a compound of the formula III in which R - and R ₁ - have the meaning given above _t implements, or that one c) for the preparation of a compound of the formula I in which R ₂ and R together represent an additional bond, a compound of the formula in which R ^, R., R ₁ - and X have the meaning given above and Rg'-R ₈ ^{1 have the} same meaning as Rg-Ro, although any hydroxyl groups present may be protected, dehydrated, or that one d) for the preparation of a compound of the formula I in which R. is hydrogen or lower alkyl and R ₁ - lower alkyl, a compound of the formula 40 9 881/1267 ^ C-CH2- NHR. ' I T- VI in which RiR * and X have the meaning given above, R. ^{1 is} hydrogen or lower alkyl and R ^ '- Rq' have the same meaning as Rg-Rg, but with hydroxyl groups present can be protected,
alkylated, or that one, e) for the production of an N-oxide of a compound of Formula I, in which R. and Rj- are different from hydrogen, a connection of the general formula VII in which R ₁ -Ra and X have the above meaning, R "and R ₁ -" have the same meaning as R. and R, - but are not hydrogen, and R, - '-Rg ^{1 have the} same meaning as Rg- Rg have, but existing hydroxyl groups can be slotted, subject to oxidation or that one f) for the preparation of a compound of the formula I in which R, represents hydrogen and Rj- alkanoyloxy-lower alkyl, a compound of the general formula 409881/1267 VIII in which RfRz and X have the above meaning, Rj- ¹ "denotes hydroxyalkyl, and Rg'-Rg ^{1 have the} same meaning as Rg-Ro, although the hydroxyl groups present may be protected, alkanoylated, or" g) a base of the formula I or an N-oxide thereof in a corresponding acid addition salt transferred, wherein, after one of the process alternatives a) -f) has been carried out, any protected hydroxyl groups present are obtained Rg'-Rg 'converted into hydroxyl groups. 2. The method according to claim 1, characterized in that a compound of the formula II, IV, V, VI, VII, VIII, or I or an N-oxide of a compound of the formula I is used, where IL-- ', R _n ¹ and R _n ¹ or Rr ₇ and R _Q meanings other than f O have lower alkylsulfonyl and optionally protected hylroxy. 3 · Process according to claim 2 for the preparation of compounds of the formula I, ih the R, represents hydrogen, and of N-oxides thereof, or of acid addition salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 409881/1267 4 · Method according to claim 2 or 3 for production of compounds of the formula I, in which Rp and R, together represent an additional bond and of ίΓ-oxides thereof or of acid addition salts of these compounds, characterized in that they are substituted accordingly Starting connections. 5. The method according to any one of claims 2-4 for the preparation of compounds of formula I in which X is sulfur represents and of N-oxides thereof or of acid addition salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 6. The method according to any one of claims 2-5 for the preparation of compounds of the formula I in which R. and R _{1 represent} -lower alkyl and IT oxides thereof or acid addition salts of these compounds, characterized in that correspondingly substituted starting compounds begins. 7. The method according to claim 6 for the preparation of compounds of formula I in which R. and R ^ represent methyl and of IT oxides thereof or of acid addition salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 8. The method according to any one of claims 2-7 for the preparation of compounds of formula I in which Rg methylthio and R_ and R "represent hydrogen and of N-oxides of these or of acid addition salts of these compounds, characterized in that they are substituted accordingly Starting connections. 409881/1267 9. The method according to any one of claims 2-7 for production of compounds of formula I, in the IL-chlorine and R “and R _{0 represent} hydrogen and N-oxides thereof or ι ο of acid addition salts of these compounds, characterized in that that one uses correspondingly substituted starting compounds. 10. The method according to any one of claims 1-7 for the preparation of compounds of the formula I in which R _{fi is} chlorine, R "is hydrogen and R _{Q is} methoxy and of N-oxides thereof or of acid addition salts of these compounds, characterized in that one correspondingly substituted starting compounds are used. 11. The method according to claim 1 for the preparation of compounds of formula I in which R, hydrogen, R ~ and R ^ together an additional bond, R. hydrogen or lower alkyl, Rj- lower alkyl, hydroxy-lower alkyl or alkanoyloxy-lower Alkyl or R. and R ^ together represent a saturated, 5- or 6-membered heterocycle which may contain an oxygen atom or a further nitrogen atom and which may be substituted by hydroxy-lower alkyl or alkanoyloxy-lower alkyl, R _fi lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, di- (lower alkyl) sulfamoyl, halogen, trifluoromethyl, nitro, amino or di (lower alkyl) amino and one of the substituents R "and R _Q is hydrogen and the other / ö represents lower alkyl, lower alkoxy or halogen and of N-oxides thereof or of acid addition salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 409881/1267 12. The method according to claim 1 for the preparation of compounds of formula I, in which R, hydrogen, R "and R., together an additional bond, R. hydrogen, methyl or ethyl, R ^ methyl, ethyl, hydroxyethyl or acetoxyethyl or R . and Rj- together represent the piperidine, pyrrolidine, morpholine, N-hydroxyethylpiperazine or N-acetoxyethylpiperazine radical, R, - methyl, methoxy, methylthio, methylsulfonyl, dimethylsulfamoyl, chlorine, trifluoromethyl, nitro, amino or dimethylamino, R _{7 represents} hydrogen, methyl or chlorine and R _{ß represents} hydrogen, methyl or methoxy and of N-oxides thereof or of acid addition salts of these compounds, characterized in that correspondingly substituted starting compounds are used. 13. The method according to claim 8 for the preparation of N, N-dimethyl-3- [8- (methylthio) -dibenzo [b, f] thiepin-10-yl] -2-propynylamine and of acid addition salts of this compound, characterized in that they are substituted accordingly Starting connections. 14. The method according to claim 9 for the preparation of N, N-dimethyl-3- (8-chloro-dibenzo [b, f] thiepin-10-yl) -2-propynylamine and of acid addition salts of this compound, characterized in that correspondingly substituted starting compounds sets in, 15. The method according to claim 10 for the production of N, N-Dimethyl-3- (8-chloro-3-methoxy) -dibenzo [b, f] thiepin-10-yl) -2-propynylamine and of acid addition salts of this compound, characterized in that they are substituted accordingly Outgoing connections e ins e t ζ t. 16. Process for the production of preparations having an effect on the nervous system, characterized in that _dass_man.eine 409881/1267 tricyclic compound of the general formula in the X oxygen or sulfur, R-. and R _{2 is} hydrogen or lower alkyl, R, hydrogen or together with R _? an additional bond and R. and Rf- represent hydrogen, lower alkyl, hydroxy-lower alkyl, alkanoyloxy-lower alkyl or together a saturated, 5- or 6-membered heterocycle optionally containing an oxygen atom, sulfur atom or another nitrogen atom, the can be substituted by lower alkyl ₉ hydroxy-lower alkyl or alkanoyloxy-lower alkyl, and in which furthermore R _fi lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, di (lower alkyl) sulfamoyl, hydroxy, halogen, trifluoromethyl, nitro , Amino or di- (lower alkyl) -amino and R "and R _Q each individually represent hydrogen or a substituent listed under Rg, or an N-oxide of a compound of the formula. I ₁ ^ in tier R. and _{-R 1} - are different from hydrogen or an acid addition salt of one of the compounds mentioned as an active ingredient with non-toxic, inert, normal in such preparations suitable for therapeutic administration, Fe_sten_u.nd_ - liquid 'carriers and / or excipients mixed. 409881/1267 17. Preparation with an effect on the nervous system, characterized by a content of a tricyclic compound the general formula R, ^V 8 in which X is oxygen or sulfur, R and Rp are hydrogen or lower alkyl, R_ is hydrogen or together with R _? an additional bond and R. and R ^ represent hydrogen, lower alkyl, hydroxy-lower alkyl, alkanoyloxy-lower alkyl or together a saturated, 5- or 6-membered heterocycle optionally containing an oxygen atom, sulfur atom or another nitrogen atom, which by lower alkyl, hydroxy-lower alkyl or alkanoyloxy-lower alkyl can be substituted, and in which furthermore R 1 - lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, di- (lower alkyl) -sulfamoyl, hydroxy, halogen, trifluoromethyl, nitro , Amino or di- (lower Alkyl)? - amino and R „and R ₀ each individually Aqueous σ represent substance or a substituent listed _{under R g,}
or on an N-oxide of a compound of the formula I in which R. and R ₁ - are different from hydrogen or a 5 Acid addition salt of one of the compounds mentioned. 409881/1267 18.'Tricyclic compounds of the general formula in which X is oxygen or sulfur, R and R _{2 are} hydrogen or lower alkyl, R, hydrogen or together with R _? an additional bond and R. and R ₁ . Represent hydrogen, lower alkyl, hydroxy-lower alkyl, alkanoyloxy-lower alkyl or together a saturated, 5- or 6-membered heterocycle, optionally containing an oxygen atom, sulfur atom or another nitrogen atom, which is represented by lower alkyl, hydroxy-lower alkyl or alkanoyloxy -Lower alkyl can be substituted, and in which R _fi lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, di- (lower alkyl) sulfamoyl, hydroxy, halogen, trifluoromethyl, nitro, amino or di- (lower alkyl) - amino and R " and R ₀ ie individually hydrogen or one of R ^ ο ο represent listed substituents, and N-oxides of compounds of the formula I in which R. and R _{1 are} different from hydrogen, and acid addition salts of the compounds mentioned. 19. Compounds according to claim 18, characterized in that Rg, R ₇ and R _{ß have} other meanings than lower alkylsulfonyl and hydroxy. 0 9 8 8 1/12 6? 20th Tricyclic compounds according to claim 19,
characterized in that IL represents hydrogen. 21. Tricyclic compounds according to claim 19 or 2O _t, characterized in that Rp and IL. together represent an additional bond. 22nd Tricyclic compounds according to any one of claims 19-21, characterized in that X represents sulfur. ²³ Tricyclic compounds according to any one of claims 19-22 »characterized in that R- and. R ₁ - lower alkyl
represent. 24. Tricyclic compounds according to claim 23,
characterized in that R. and R ₁ - represent methyl. 25> Tricyclic compounds according to any one of claims 19-24, characterized in that R 1 - methylthio and R ₇ and R "represent hydrogen. 26th Tricyclic compounds according to any one of claims 19-24 ^ characterized in that R _{fi is} chlorine and R ₇ and R _R Represent hydrogen. 27 “Tricyclic compounds according to any one of claims 18-24, characterized in that R 1 - chlorine, R ₇ hydrogen and R _{0 represent} methoxy.
ο £ 09881/1267 _ 49 _ 28. Tricyclic compounds according to claim 18, characterized in that IL is hydrogen, Rp and R, together an additional bond, R. is hydrogen or lower alkyl, Rj- lower alkyl, hydroxy-lower alkyl or alkanoyloxy-lower alkyl or R. and Rj- together represent a saturated, 5- or 6-membered heterocycle which optionally contains an oxygen atom or a further nitrogen atom, which may be substituted by hydroxy-lower alkyl or alkanoyloxy-lower alkyl, R ^ - lower alkyl, lower alkoxy, lower alkylthio , lower alkylsulphonyl, di (lower alkyl) sulphamoyl, halogen, trifluoromethyl, nitro, amino or di (lower alkyl) amino and one of the substituents R _{1 and R 0 is} hydrogen and the other is lower ( ο Represents alkyl, lower alkoxy or halogen. 29. Tricyclic compounds according to Claiml8, characterized in that R- is hydrogen, R ~ and R_ together represent an additional bond, R. is hydrogen, methyl or ethyl, R ₁ - methyl, ethyl, hydroxyethyl or acetoxyethyl or R. together represent and Rf the piperidine, pyrrolidine, morpholine, N-Hydroxyäthylpiperazin- or N-Acetoxyäthylpiperazinrest, R _ß methyl, methoxy, methylthio, methylsulfonyl, whore thylsulfamoyl, Ghlor, trifluoromethyl, nitro, amino or methylamino Dime, Rr ₇ Hydrogen, methyl or chlorine and R ₀ water- I ο represents substance, methyl or methoxy. 30. N, N-Dimethyl-3- [8- (methylthio) -dibenzo [b, f] thiepin-10-yl] -2-propynylamine and acid addition salts of this compound. 31. NjN-Dimethyl ^ -CS-chloro-dibenzoEbjfJthiepin-10-yl) -2-propynylamine and acid addition salts of this compound. 32. N, N-Dimethyl-3- (8-chloro-3-methoxy-dibenzo [b, f] -thiepin-10-yl) -2-propynylamine and acid addition salts of this compound. 409881/1267