NO800725L - POLICE SUBSTITUTED DIAZATRICYCLES. - Google Patents

Description

The invention relates to new diazatricycles of formula

in which

means hydrogen, lower alkyl, lower alkenyl, 2-propynyl,

cycloalkyl lower alkyl, hydroxyl lower alkyl or optionally. substituted benzyl,

R2 means hydrogen or lower alkyl,

R^ means hydrogen or lower alkyl,

R^ and R^- means lower alkyl and

Rg and R^, mean hydrogen, lower alkyl, lower alkoxy or halogen,

as well as salts of such compounds, methods for the preparation of these compounds, as well as their salts, pharmaceutical preparations containing such and their use as antidepressants.

Polysubstituted diazatricycles.

The invention relates to new diazatricycles and methods for their production, as well as pharmaceutical preparations containing these new compounds as well as their use.

The invention relates in particular to new diazatricycles of formula in which R^ means hydrogen, lower alkyl, lower alkenyl, 2-propynyl,

cycloalkyl lower alkyl, hydroxyl lower alkyl or optionally

substituted benzyl,

R 2 means hydrogen or lower alkyl,

Rj means hydrogen or lower alkyl,

R^ and R^ mean lower alkyl and

R 8 and R 8 are hydrogen, lower alkyl, lower alkoxy or

halogen

as well as salts of such compounds.

The residues and compounds designated in connection with "lower" preferably contain up to 7 and primarily up to 4 carbon atoms.

Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-

butyl, further n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl.

Lower alkenyl is e.g. vinyl, allyl, 2-methylallyl, 2-butenyl or 3}3-dimethylallyl.

Cycloalkyl lower alkyl preferably has 4-10, especially 4-8 carbon atoms and is e.g. cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or cycloheptylmethyl.

Hydroxyl lower alkyl where the hydroxy group is separated by at least 2 C atoms from nitrogen is e.g. 2-hydroxyethyl, further 2- or 3-hydroxypropyl.

Lower alkoxy is e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy or n-butyloxy.

Halogen means fluorine or bromine, preferably, however, chlorine.

The new compounds may exist in the form of their salts such as their acid addition salts and primarily their pharmaceutical utility, not toxic acid addition salts. Suitable salts are e.g. those with inorganic acids such as hydrohalic acid, e.g. hydrochloric acid or hydrobromic acid, sulfuric acids e.g. sulfuric or phosphoric acids or with organic acids such as aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulphonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycol, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, hydroxy-maleic acid, pyruvic acid, fumaric acid, benzoic acid, 4-aminobenzoic acid, anthranil, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, embonic acid, methanesulfonic acid , ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethylenesulfonic acid, toluenesulfonic acid, naphthalene sulfonic acid or sulfanilic acid or other acidic organic compounds such as ascorbic acid.

The new compounds according to the invention can exist in the form of mixtures of isomers such as positional isomers or their racemates or of pure racemates or optically active antipodes.

Compounds of the general formula I and their acid addition salts of valuable pharmacological, especially antidepressant, properties. As can also be seen from the results of the isotopic determination of the enzyme activity, after oral administration to rats in doses from 0.3 mg/kg monoamine oxidase, particularly selectively and without cumulation, reversibly inhibit its Abform. At the same time, the compounds of the general formula I and their pharmaceutically acceptable acid addition salts, when administered intraperitoneally to mice, antagonize the hypothermia caused by reserpine in doses from 0.3 mg/kg and the ptosis caused by reserpine, as well as the catalepsy caused by tetrabenazine in doses from each time approx. 1 mg/kg. Together with a favorable therapeutic index, the above-mentioned pharmacological properties characterize the compounds of the general formula I and their pharmaceutically acceptable monoacidic acid addition salts as antidepressants such as e.g. can1 be administered orally or parenterally, for the treatment of mental depressions.

The invention relates in particular to compounds of formula I, in which R^ means hydrogen, lower alkyl or lower alkenyl with up to 7 carbon atoms, 2-propynyl, cycloalkyl lower alkyl with 4-10 carbon atoms, hydroxyl lower alkyl with 2-7 carbon atoms or optionally with lower alkyl or lower alkoxy with up to 7 carbon atoms or halogen-substituted benzyl means hydrogen or lower alkyl with up to 7 carbon atoms, R^ means hydrogen or lower alkyl with up to 7 carbon atoms, R^ and R,- means lower alkyl with up to 7 carbon atoms and Rg and R^ mean hydrogen, lower alkyl or lower alkoxy with up to 7 carbon atoms, or • halogen and salts, especially acid addition salts primarily pharmaceutical usable, non-toxic acid addition salts thereof.

The invention relates above all to compounds of formula I, in which R^ means hydrogen, lower alkyl or lower alkenyl with up to 4 carbon atoms, e.g. methyl or allyl, 2-propynyl, cycloalkyl lower alkyl with 4-8 carbon atoms, e.g. cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, or cycloheptylmethyl, hydroxylaverealkyl with 2-4 carbon atoms, e.g. 2-hydroxyethyl, 2-or 3-hydroxypropyl or optionally with lower alkyl or alkoxy with up to 4 carbon atoms or with halogen substituted benzyl, R^ means hydrogen or lower alkyl with up to 4 carbon atoms, R^ means hydrogen or lower alkyl with up to 4 carbon atoms , R^ and R^ mean lower alkyl with up to 4 carbon atoms and Rg and R^ mean hydrogen, lower alkyl or lower alkoxy with up to 4 carbon atoms or halogen and salts, especially acid addition salts, primarily pharmaceutically usable non-toxic acid addition salts thereof.

The invention primarily relates to compounds of formula I, in which R-^ means in particular a hydrogen, but also methyl, 2-propynyl, 2-hydroxyethylbenzyl or p-fluorobenzyl, R^ means in particular hydrogen and methyl, R^ means hydrogen or especially methyl, R^ and R,- means methyl, Rg means methyl or hydrogen and R^, means hydrogen, in that the groups R^ and R,- preferably occupy the 5- and 7-positions, and salts, especially acid addition salts primarily pharmaceutically usable toxic acid addition salts thereof.

In particular, the invention relates to the new compounds and salts mentioned in the examples, especially acid addition salts, primarily pharmaceutical usable non-toxic acid addition salts thereof.

The new compounds of formula I can be prepared according to methods known per se.

Thus, they can be obtained when a compound of formula is decarboxylated and, if desired, a compound of formula I prepared according to the method is converted into another compound of formula I, and/or if desired, a salt formed according to the method is converted into the free compound or another salt or a free compound formed according to the method is converted into a salt and/or if desired, an isomer mixture formed in the method is divided into the individual isomers.

The decarboxylation of an acid compound of formula II preferably takes place by heating, preferably within a range of 40-100°C and/or treatment with an aqueous acid. as a mineral acid, e.g. hydrochloric acid or a strong organic acid such as methanesulfonic acid.

The starting materials for formula II a new. However, they can be produced in a manner known per se because in e.g. being primarily in a connection with formula

cleavage of the amide bond is carried out. This preferably takes place with an inorganic base, e.g. potassium chloride in an organic solvent, e.g. ethyl alcohol. The formed aminocarboxylic acid leads after decarboxylation with an aqueous acid such as e.g. hydrochloric acid or methanesulfonic acid to a compound of formula

The compound IV is then reacted with a compound of the formula R^-CO-COOH (V) under the influence of acid to the corresponding compound of the formula II.

The compounds of formula III are likewise new.

However, they can also be produced in a manner known per se.

A possibility for the preparation of compounds of formula III, in which R, means hydrogen, consists in a defined ring-substituted aniline being first diazotized and then coupled with a possible corresponding to the definition of R^ N-substituted 2-oxo-3-piperidine carboxylic acid ester to the corresponding 2,3-piperidinion-3-hydrazone which is then transferred by heating in formic acid into the corresponding compounds of formula III.

A further possibility for the preparation of such compounds is that a defined ring-substituted diazotized aniline is coupled with monoethyl-2-(3-chloropropyl)-malomate and the formed hydrazone is transferred by boiling in an alcohol, preferably n-butanol, in a hydrochloric acid environment to the corresponding in the aromatic ring-substituted 2-ethoxycarbonyltryptamine hydrochloride. Upon release of the base and heating, the corresponding compound with formula III is then formed.

Compounds of formula III, in which R₂ means lower alkyl, can be prepared from the corresponding N-unsubstituted compounds, e.g. by treatment with dilute alkyl sulphate in alkaline aqueous solution.

The compounds of formula III, in which R.sub.1 and R.sub.2 mean lower alkyl, can be prepared by simultaneous alkylation at the two nitrogen atoms from corresponding N-substituted compounds, e.g. by treatment with sodium hydride and lower alkyl bromide in toluene or by treatment with dilave alkyl sulphate in methylene chloride, caustic soda and tetrabutylammonium bromide.

The above-mentioned reaction according to the invention can also be carried out in such a way that the preparation of the compound of formula II is disregarded, i.e. a compound of formula IV is likewise reacted under the influence of acid with a compound of formula IV, but under energetic conditions, i.e. e.g. during heating, in that turnover and decarb-. the oxylation takes place in a work process.

The new compounds can likewise be obtained in that a compound of formula

is reacted with a compound of formula

and if desired, additional precautions are implemented.

The reaction of a compound of formula IV with

a compound of formula VI preferably takes place under the influence of an acid, such as a mineral acid, e.g. hydrochloric acid or an organic acid, e.g. p-toluenesulfonic acid, called in a protic solvent such as water or alcohol.

The starting substances with formula IV can be prepared in a manner known per se, e.g. as stated above.

The new compounds can also be obtained in that in a compound of formula which can additionally have a double bond in the 3,4 position, in which XV"~^>et<y>r an anion, C = N double bondin<g> is reduced one and one possibly present 354 double bond, and if desired, additional precautions are implemented.

The anion is preferably the anion of a hydrohalic acid.

The reduction of the compounds with the formula VII and VIII can take place according to methods known per se, namely either by catalytically activated hydrogen or nascent hydrogen. As a catalyst, e.g. noble metal catalysts such as palladium on charcoal. For the reduction with nascent hydrogen, it is suitable e.g. sodium and a lower alcohol, such as ethanol, butanol or amyl alcohol. Base metals, such as zinc, and acids, such as hydrochloric acid or acetic acid, are also suitable. Furthermore, sodium amalgam and a mineral acid can be used. A further reducing agent is a hydride reducing agent such as e.g. sodium boron cyanhydride in acetonitrile. In particular, sodium borohydride is suitable, possibly with water mixed with a lower alkanol, such as methanol or ethanol.

The starting substances with the formula VII and VIII are new.

They can be produced in a manner known per se, e.g. in idet a compound with formula

is reacted with a compound of formula R2COHal (Xa) or formula (R2CO)20 (Xb), in which Hal means a halogen atom, preferably chlorine. The acid amide formed is cyclized by reaction, e.g. with phosphorus trichloride in toluene or with polyphosphoric acid ester in chloroform or with polyphosphoric acid to the compound of formula which directly or after quaternization is used with a compound of formula - X (XI) in the method according to the invention. The new compounds can likewise be obtained when a compound of formula is reacted with a compound of formula

or with hydrate or a ketal resin, and if desired, extra precautions are taken.

Among ketals, for example, dimethyl or diethyl ketals and above all ethylene ketals come into consideration.

The reaction of a compound of the formula XII with a compound of the formula XIII preferably takes place in an acidic medium, such as in the presence of polyphosphoric acid or Lewis acids, especially boron trifluoride etherate in glacial acetic acid or ethanol hydrochloric acid or dilute aqueous sulfuric acid (hot) preferably at a temperature of 40 - 150°C. Under the same reaction conditions, a ketal can also be converted.

The starting materials are known or can be produced

in a manner known per se.

The new compounds can likewise be obtained in a compound of formula

in which

Z stands for -CO- or

-group and

R-j^ either means R^ or -CO-R-^ group in that

Rc^l means one with a methylene group reduced, otherwise to the above definition for R^ corresponding residue,

in that at least one of the symbols Z and R^ means respectively contains a carbonyl group,

carbonyl groups present are reduced to methylene groups, and if desired, the additional process features are carried out.

According to the invention, the compound of formula XIV, in which Z means -CO group and R^ has the meaning R^, is particularly reduced.

Complex metal hydrides, such as lithium aluminum hydride and sodium aluminum borohydride in the presence of a solvent such as e.g. tetrahydrofuran, dimethoxyethane, diethyl ether, toluene, benzene and especially dioxane. The reduction is preferably carried out under gentle heating. A further suitable reducing agent is sodium in butanol.

The starting substances of formula XIV are new. However, they can be produced in a manner known per se.

One possibility for the production of starting substances with formula XIV, especially those of these comprising formula III, in which Rj means hydrogen, consists in a defined ring-substituted aniline being first diazotized and then coupled with an optionally N-substituted 2-oxo-3-piperidinecarboxylic acid ester to the corresponding 2,3-piperidini0nT-3^hydrazone which is then transferred by heating in formic acid into the corresponding starting material with formula III.

A further possibility for the production of such starting materials consists in a defined ring-substituted diazotized aniline being coupled with monoethyl-2-(3-chloropropyl-malonate. and the hydrazone formed is transferred by boiling in an alcohol, preferably n-butanol in a hydrochloric acid environment, to the corresponding definitionally substituted 2-ethoxycarbonyl-tryptamine hydrochloride in the aromatic ring.When a base is released and heated, it is formed when the corresponding starting substance f is of formula III.

Starting materials of formula III, wherein means lower alkyl, can be prepared from the corresponding N-unsubstituted starting materials, e.g. by treatment with dilave alkyl sulfate in alkaline aqueous solution.

Starting material f is of formula III, in which R-1 and R2 mean lower alkyl, can be prepared by 2-fold alkylation from corresponding N-unsubstituted starting materials, e.g. either by treatment with sodium hydride and lower alkyl bromide in toluene or by treatment with dilave alkyl sulphate in methylene chloride, caustic soda and tetrabutylammonium bromide.

Furthermore, starting substances with formula XIV, where Z means the -CO group and Rj^ means the CO-R-j^ group according to the invention, can be reduced. Particularly suitable reducing agents are complex metal hydrides, preferably lithium aluminum hydride in the presence of tetrahydrofuran as solvent.

Starting substances of formula XIV, in which Z means the -CO group and R^ means -CO-R^ group, can e.g. is produced by acylation of corresponding starting material f is in which R^ means hydrogen.

The new compounds of formula I, in which R^ and/or R^ means hydrogen can likewise be obtained, in that a corresponding compound where instead of R-^ and/or R^ there is one by means of solvolysis or by reduction of a cleavable protecting group this is removed by solvolysis, respectively reduction.

For example, acyl groups such as acetyl groups or lower alkoxycarbonyl groups are split off by hydrolysis in an alkaline or acidic medium, or benzyl or benzyloxycarbonyl groups through reduction, especially catalytic hydrogenation.

The starting material, in which instead of R-^ there is an acyl group and R^ means lower alkyl, can for example be prepared from compounds of formula I, in which R-^ and

*R^ means hydrogen by acylation in the basic hydrogen

atom and subsequent introduction of a lower alkyl residue R^

in the manner indicated above, e.g. either by treatment with sodium hydride in toluene or by treatment with dilavereal alkyl sulphate in methylene chloride.

Starting materials which contain an optionally substituted benzyl group as a protective group in the 2-position and which

R contains lower alkyl, falls under formula I and can be prepared by one of the methods described above or in the following.

Starting materials which in the 9-position instead of R^ contain an optionally substituted benzyl residue, from which a hydrogenolytically cleavable protective group can be prepared,

in the reaction with a compound of formula XIII specified further above, instead of a phenylhydrazine of formula XII, an analogous compound is used, which instead of R^ contains a possibly substituted benzyl residue and in the reaction product, a hydrogen atom R^ is optionally substituted on the one below indicated manner, with another residue R^.

According to the method, the obtained compound of formula I can be transferred into other compounds of formula

IN.

Thus, in compounds of formula I, in which R represents hydrogen, this hydrogen can be replaced by a substituent. This replacement can take place by reacting such a compound of formula I with a compound of formula R^-Y (XV), in which Y means reactive ester hydroxy. Halogen is particularly relevant as an acid residue. This replacement can also take place by reacting such a compound of formula I with an oxo compound of formula R1 = 0, (XVI) in which R-^ means a geminal divalent residue corresponding to the residue R.^, under reducing conditions. Suitable reducing agents are sodium borohydride in acetonitrile, further sodium borohydride in an alcohol lower in water, such as methanol or catalytically activated hydrogen.

Furthermore, compounds of formula I, in which R-^ means benzyl group, which transfer formula I through reduction in the compounds in which R-^ means hydrogen. This reduction is preferably carried out catalytically.

Furthermore, compounds of formula I, in which R^ denotes hydrogen, can by alkylation be transferred in connection with formula I in which R^ denotes lower alkyl. The transfer can take place by a compound of formula I, in which R^ means hydrogen, is reacted with a compound of formula R^-Y (XVII), in which Y means reactive ester hydroxy. As acid residues, those of a hydrohalic acid or sulfuric acid are particularly relevant. This turnover can e.g. is carried out in the presence of sodium amide and liquid ammonia, n-butyllithium in tetrahydrofuran or in the presence of sodium hydride and toluene, or in the presence of methylene chloride and 50% caustic soda and tetrabutylammonium bromide, or tetrabutylammonium hydrogensulphate. If the formed compound of formula I R 1 is to mean hydrogen, then it is appropriate to protect the corresponding nitrogen atom during the alkylation with an acetyl group.

The above-mentioned reactions are usually carried out in the presence or absence of dilution, condensation and/or catalytic agents, if necessary, at reduced or elevated temperature in a closed vessel and/or in an inert gas atmosphere.

Depending on process conditions and starting materials, any salt-forming final material is obtained in free form or in the form of their salts, which in the usual way can be transferred into each other or into other salts. Compounds of formula I with basic character can optionally be obtained in the form of their acid addition salts. The latter can be converted into salts by reaction of a free basic compound of formula I with an organic or inorganic acid, especially those which are suitable for the formation of pharmaceutically usable salts. Formed acid addition salts of basic compound of formula I,

can in a manner known per se, e.g. when treating alkaline agents, e.g. alkali metal hydroxides or basic ion exchangers, are transferred in the free bases.

These and other salts can be used for cleaning

the new connections e.g. in transferring the free compounds into their salts, isolating these and again transferring them into the free compounds. Due to the narrow relationship between the new compounds in free form and in the form of their salt, they are in the preceding and subsequent also to understand the corresponding salts.

Depending on the choice of starting materials and working methods, the new compounds can exist as optical antipodes or racemates, or if they contain at least two asymmetric carbon atoms, also as racemate mixtures or possibly also as mixtures of positional isomers.

Formed racemate mixtures can, due to the physical chemical differences of diastereoisomers, be divided in a known manner into two larger stereoisomers (diastereoisomers) racemates, e.g. by chromatography and/or fractional crystallization. Similarly, preferably by fractional crystallization, mixtures and positional isomers can be separated.

Formed racemates can be divided into the antipodes according to methods known per se, e.g. by recrystallization of an optically active solvent, by treatment with suitable microorganisms or by reaction with a salt-forming optically active substance with the racemic compound, especially acid, and separation of the salt mixture formed in this way, e.g. due to different solubility in the diastereomeric salts from which the free antipodes can be released by the action of suitable agents. Particularly common optically active acids are e.g. The D and L form of tartaric acid, di-o-toluyl tartaric acid, malic acid, mandelic acid, champersulfonic acid, glutamic acid, aspartic acid or quinic acid. Preferably, the most effective of the two antipodes is isolated.

The invention also relates to the embodiments of the method according to which one starts from a compound formed as an intermediate in one or another step of the method and carries out the missing method step, or interrupts the method at one or another step or where a starting substance is formed under the reaction conditions or where a reaction component possibly present in the form of a derivative, e.g. a salt.

Expediently, for carrying out the reaction according to the invention, such starting substances are used, which lead to the groups of final substances specifically mentioned at the outset and especially in the specially mentioned or emphasized final substances.

The compounds of the general formula I as well as their pharmaceutically acceptable acid addition salts are preferably administered orally or rectally, however, in the form of an aqueous solution, their acid addition salts can also be administered parenterally.

The daily doses for warm-blooded animals range between 0.03 and 3 mg/kg and for warm-blooded animals are approx. 70 kg body weight preferably between 3 and 30 mg. Suitable dosage unit forms such as dragee tablets or suppositories preferably contain 1 to 30 mg of an active substance according to the invention, i.e. of a compound of the general formula I, or a pharmaceutically acceptable acid addition salt thereof. In their manufacture, the active substance is combined with solid powdery carriers, such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, further laminaria powder or citrus powder, cellulose derivatives or gelatins, possibly with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, for tablets or for dragee cores. The latter is coated, for example, with concentrated sugar solutions such as des-suten may contain gum arabic, talc and/or titanium dioxide, or with a volatile organic solvent or solvent mixtures of dissolved varnish. Dyes can be added to these covers, e.g. for characterizing different active drug doses. As additional oral dosage unit forms, injectable capsules made of gelatin as well as soft, closed capsules made of gelatin and a plasticizer such as glycerin are suitable. The first contain the active substance, preferably as granules, in a mixture with lubricants such as talc or magnesium stearate and possibly stabilizers such as sodium metabisulphide or ascorbic acid.

The following regulations shall explain in more detail the production of tablets, dragées, suppositories and ampoules: a) 100.0 g 1,557,9-tetramethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b )indole maleate is mixed with 450 g of lactose and 292 g of potato starch, the mixture is moistened with an alcoholic solution of 8 g of gelatin and granulated using a sieve. After drying, 60 g of potato starch, 60 g of talc, 10 g of magnesium stearate and 20 g of highly dispersed silicon dioxide are mixed and the mixture is pressed into 10,000 tablets, each with 100 mg weight and 10 mg active substance content, which, if desired, can be equipped with breaking instructions for finer adjustment of the dosage. b) 12.5 g of 537J9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)_indole~methanesulfonate are mixed well with 16 g of corn starch and 6 g of highly dispersed silicon dioxide. The mixture is moistened with a solution of approx. 70 ml of isopropyl alcohol and granulated through a sieve with a mesh size of 1.2 mm. The fir-wood is dried approx. 14 hours and then passed through a sieve with a mesh size of 1.2 to 1.5 mm. It is then mixed with 16 g of corn starch, 16 g of talc and 2 g of magnesium stearate and pressed to 1,000 dragon kernels. These are coated with a concentrated syrup of 2 g of lacca, 755 g of gum arabic, 0.15 g of dye, 2 g of highly dispersed silicon dioxide, 25 g of talc and 53335 g of sugar and dried. The formed dragees each weigh 172.5 mg and each contain 12.5 mg of active substance. c) 25.0 g 1,5,7J9-tetramethyl-2,3,4,9-tetrahydro-9H-pyrido(3,4-b)indole maleate and 1975 g finely grated suppository base mass (e.g. cocoa butter) mix well and then melt. 1,000 suppositories of 2 g are cast from the melt, which has been kept homogeneous by stirring. They each contain 172.5 mg of active substance. d) Dissolve 12.5 g of 5,7J9-trimethyl-2,3,4,9-tetrahydro-9H-pyrido(3s4-b)indole methanesulfonate in 1 liter

double-distilled pyrogen-free water and the solution is filled into 1000 ampoules and sterilized. One ampoule contains a 2.5% solution of 12.5 mg of active substance.

The following non-limiting examples explain the preparation of the new compounds with the general formula I and previously unknown starting materials in more detail.

Example 1

14.6 g of 6,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3j^-b)indole-1-carboxylic acid are introduced at reflux temperature in portions into 350 ml of water and 50 ml of concentrated hydrochloric acid. The reaction mixture is kept for 2 hours at reflux temperature and after casting, the clear solution is made alkaline with approx. 70 ml 2-n. baking soda. The precipitated product is shaken off with chloroform, washed with water and the organic phase is dried over magnesium sulphate. After removal of solvent in vacuo, a crystalline residue remains which after recrystallization from 90% alcohol in pure 6,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,^-b)indole of melting point 252 - 256°C.

20.0 g 6,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido •

(3j4-b)indole is dissolved in 200 mg of absolute alcohol and mixed dropwise with 9.6 g of methanesulfonic acid. The precipitated product is filtered off and recrystallized from 96% alcohol. The pure 6,7-dimethyl-2,3,4,5-tetrahydro-1H-pyrido(3,4-b)indole methanesulfonate melts at 304-306°C.

The starting material can be prepared as follows: a) 25.5 g of 2-oxo-3-piperidinecarboxylic acid ethyl ester is stirred with a solution of 9a0 g of potassium hydroxide in 300 ml of water for 12 hours at 30°C. The resulting solution is cooled with an ice-sodium chloride mixture to 0°C and adjusted with 1.0 normal hydrochloric acid to pH 4.5. A freshly prepared diazo solution is then prepared from 18.8 g of 3,4-dimethylaniline, 11.25 g of sodium nitrite and 350 ml of normal hydrochloric acid, which was adjusted to pH 6.0 with a 10% sodium carbonate solution, in the course of about. 10 minutes introduced at 0°C. The reaction mixture is stirred for 1 hour at 5 - 10°C, and buffered with a 45% sodium acetate solution to pH 5S5. The mixture is stirred for 12 hours at room temperature, cooled again to 0°C, and the precipitated product is filtered off. After washing with ice water, the raw product is dried in a vacuum at 60°C. It melts at 214-219°C. A sample recrystallized from alcohol gives the pure 2,3-piperidinion-3~ [(3,4-dimethylphenyl)-hydazone] of melting point 237 - 239°C. b) 29.2 g of 2,3-piperidinedione-3-j(_3,4-dimethylphenyl]~ hydrazone is boiled in 200 ml of 70% formic acid for 1 hour under reflux. The reaction mixture is diluted with 500 ml of water and cooled with ice to 5° C. The precipitated product is filtered off. After washing with ice water and drying in vacuum at 50° C, the crude product is recrystallized from absolute ethanol and gives a mixture of 5,6- and 6,7-dimethyl-2,334,9-tetrahydro- 1H-pyrido(3,4-b)indol-1-one of melting point 220 - 250° C. c) 21.4 g of the mixture formed according to point b is boiled with 46 g of potassium hydroxide in 190 ml of water and 190 ml of ethanol for 12 hours under reflux. 200 ml of water is then added and the alcohol is distilled off as best as possible. Into the warm, clear reaction mixture, 100 ml of concentrated hydrochloric acid are slowly dripped over the course of 40 minutes. The clear yellow solution slowly turns brownish and foams strongly. After the acid addition has been completed, the mixture is kept under reflux for 2 hours, cooled and made alkaline with caustic soda and the resulting milky suspension is shaken off with chloroform. The organic phase is washed with water, dried over magnesium sulphate and evaporated to dryness under vacuum.

The formed crude residue of melting point 75 - 85°C consists of

a mixture of 4,5-dimethyl- and 5,6-dimethyl-tryptamine.

d) 188 g of the crude mixture formed according to point c is distilled in a ball tube under high vacuum (boiling point 0.01 mm Hg=

145 - 155°C). The resulting distillate is recrystallized for further purification from benzene. This results in a purified mixture of 4,5-dimethyl- and 5,6-dimethyltryptamine, melting point 92-106°C. 150 g of the purified mixture are dissolved in 750 ml of absolute ethanol and a solution of 200 g of (+)-camphor-10-sulfonic acid monohydrate in 750 ml of absolute ethanol is added. After cooling, 1000 ml of ethyl ether is added to complete the crystallization. The mixture is left for 12 hours in a refrigerator, the crystals are filtered off and washed with a little ethyl acetate and the residue is dried in a vacuum. 310 g of the mixing camphor sulphonic acid salts are dissolved hot in 4 liters of 90% ethanol and allowed to cool completely at room temperature. The precipitated product is filtered off and stored for recovery of 4,5-dimethyltryptamine.

The formed mother liquor is evaporated in 2000 ml and left for 12 hours in an icebox. The again precipitated product (70 g) is filtered off, recrystallized twice from 96% ethanol, and gives the pure 5,6-dimethyl-tryptamine-(+)-camphor-10-sulfonate of melting point 254 - 256°C.i shape of fine little needles. 58.8 g of this salt is shaken with 100 ml of 2-normal caustic soda in 200

ml of methylene chloride. The organic phase is separated, washed with water and dried over magnesium sulphate. After removal of the solvent, the crystalline residue is recrystallized from ether-pentane and gives pure 5,6-dimethyltryptamine of melting point 108 - 109°C.

The crystalline mixture of camphor sulphonic acid salts (250 g) formed during the first recrystallization is again dissolved hot in 3 liters of 90% ethanol, and cooled slowly to approx. 1/3 of the amount of substance has crystallized. The crystallisate is then filtered off at once and the formed crystal mass is recrystallized 3 times in the same way. Pure 4,5-dimethyl-tryptamine-(+)-camphor-10-sulfonate of melting point 275 - 277°C is obtained in the form of small leaves. The camphor sulphonate is shaken with 100 ml of 2-normal caustic soda in 200 ml of methylene chloride, the organic phase is separated, washed with water and dried over magnesium sulphate. After removal of the solvent, the crystalline residue is recrystallized from ligroin and gives pure 4,5-dimethyltryptamine of melting point 136 - 137°C.

e) 11.28 g of 5,6-dimethyltryptamine is dissolved in 60 ml of 1-normal hydrochloric acid and 250 ml of water and "it" is instilled during

15 minutes at room temperature, a resolution of 6.07

g glyoxylic acid monohydrate in 25 ml water. The mixture is then stirred for 30 minutes at room temperature and then treated with 10% caustic soda to pH 3.8-4.0. The resulting suspension is stirred for 30 minutes at room temperature and then cooled with ice to 5 C. The precipitated product is filtered off, washed with a little ice water and dried in a vacuum at 50°C. The crude product formed is slurried in ethanol, filtered off and dried again. The pure 6,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(354-b)indole-1-cariboxylic acid formed melts at 243-245°C.

Example 2

14.6 g of 5,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido (3,4-b)indole-1-carboxylic acid is suspended in 350 ml of water, and at reflux temperature is added dropwise over approx. 30 minutes 50 ml concentrated hydrochloric acid. After the addition is complete, the mixture is heated for a further 3 hours under reflux. After cooling, the mixture is made alkaline with concentrated caustic soda and shaken out with chloroform:. The organic phase is separated, washed with water and dried over magnesium sulphate. After removal of the solvent, the crystalline residue formed is recrystallized from a benzene-petroleum ether mixture and gives pure 5,6'-dimethyl-2,3,^,9-tetrahydro-1H-pyrido(3j)indole of melting point 203 - 205°C.

From the base formed, methanesulfonate is prepared analogously to example 1 with methanesulfonic acid. 12.5 g of the pure 5,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole methanesulfonate of melting point 308-310°C were obtained. The starting material can be prepared in the following way:* a) Analogous to example 1 e) 5,6-dimethyl-2 j 3 j 4,9,-tetrahydro-1H-pyrido( 3 5 4-b)indole-1-carboxylic acid with melting point 223 - 224°C.

Example 5

9.1 g of 4,6-dimethyltryptamine methanesulfonate is dissolved

in 250 ml of water and at room temperature a solution of 3512 g of glyoxylic acid monohydrate in 20 ml of water is added dropwise over the course of 15 minutes. The reaction mixture is then adjusted to pH 4.0 with 2-normal caustic soda, stirred for 30 minutes at room temperature, and during this time the pH is rechecked or adjusted constantly. Then add 7.25

g of methanesulfonic acid and the mixture is slowly brought to reflux temperature. After 5 hours of boiling at reflux temperature, the contents of the distillation flask are brought to room temperature, made alkaline with concentrated caustic soda and shaken out with chloroform. The organic phase is separated and washed with water, dried over magnesium sulfate. The formed crystalline residue is recrystallized from a benzene-petroleum ether mixture and gives pure 5,7_dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 230 - 232°C.

Analogous to example 1, pure 5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido (3,1-b)indole methanesulfonate of melting point 280 - 282°C will be obtained from the base and the methanesulfonic acid.

The starting material can be prepared as follows: a) 171.0 g of 2-oxo-3-piperidinecarboxylic acid ethyl ester is introduced into a solution of 60 g of potassium hydroxide in 1.8 liters

water and stirred for 12 hours at 30°C. The resulting solution is cooled with an ice-sodium chloride mixture to 0°C and adjusted with 1.0 normal hydrochloric acid to pH 4.5. A freshly prepared diazonium salt solution of 3,5-dimethylaniline is then introduced, which had been debuffered with 2-normal sodium carbonate solution to pH 6.0 within 10 minutes at 0°C.

The diazonium salt solution is prepared as follows: 125.5 g of 335-dimethylaniline is dissolved in 500 ml of water and 1.2 liters of 1-normal hydrochloric acid and the mixture is cooled with an ice-sodium chloride mixture to +10°C. At the same time, a solution of 74.8 g of sodium nitrite in 200 ml of water and 650 • ml of 2-normal hydrochloric acid is introduced and the reduction mixture is continuously cooled to 5°C. The resulting solution is then stirred for 1 hour at 5°C and any excess nitrite is neutralized with sulfamic acid. The reaction mixture is then buffered as mentioned above with sodium carbonate solution to pH 6.0.

After the diazo solution has been added, the reaction mixture is stirred for 2 hours at 5°C, buffered with a 40% sodium acetate solution to pH 5.5 and allowed to stand for 12 hours at room temperature. After cooling again to 0°C, the precipitated product is filtered off, washed with ice water and dried in a vacuum at 50°C. The crude 2,3-piperidinion-3-[(3,5-dimethylphenyl)hydrazone] formed melts at 235-240°C. A substance sample is recrystallized with alcohol-petroleum ether and gives the pure 2,3-piperidinedione-3-[N'(3,5-dimethylphenyl)-hydrazone] of melting point 239 - 241°C as pale yellow crystals. b) Analogous to example 1 b), pure 5,7-dimethyl-2,3,^,9-tetrahydro is obtained from 2,3-piperidine-dione-3-|_N'-(3,5-dimethylphenyl)-hydrazone -1H-pyrido(3,4-b)indol-1-one of melting point 261 - 263°C (after dmcrystallization from absolute ethyl alcohol). c) 182.5 g of 5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyridone(3,4-b)indol-1-one are introduced into a solution of 360 g of potassium hydroxide in 2000 ml of water and 2000 ml of alcohol and boil for 12 hours under reflux. The alcohol is then distilled off as best as possible with a descending cooler and 2000 ml..water is added. The reaction mixture is cooled to room temperature and adjusted with acetic acid to pH 6. The resulting suspension is cooled with stirring to 0°C, the precipitated product is filtered off and washed with a little ice water. A sample of the crude product is dried, recrystallized from dimethylformamide ethyl ether and gives pure 4,6-dimethyltryptamine-2-carboxylic acid hemihydrate of melting point 263 - 265°C. The moist crude product formed above is introduced without purification into a mixture of 4,000 ml of water and 400 ml of concentrated hydrochloric acid, and is slowly heated to reflux. The mixture is boiled for 5 hours under reflux, cooled to room temperature and made alkaline with a concentration of caustic soda. The precipitated product is shaken off with chloroform, the organic phase is washed with water and dried over magnesium sulphate. After removal of the solvent, the crystalline residue is recrystallized from a toluene-petroleum ether mixture and gives pure 4,6-dimethyltryptamine of melting point 115 - 116°C.

130.5 g of 4,6-dimethyltryptamine is dissolved in 500 ml of alcohol and mixed with 66.5 g of methanesulfonic acid. After adding 200 ml of ether, the precipitated product is filtered off and recrystallized from alcohol-ethyl ether. Pure 4,6-dimethyltryptamine methanesulfonate of melting point 204 - 205°C is obtained.

Example 4

14.92 g of 4,5,7-trimethyl-tryptamine-methanesulfonate and 5.06 g of glyoxylic acid monohydrate are reacted analogously to example 2. Crude 5,6,8-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole is obtained Analogously to example 2, methanesulfonate is prepared: 8.4 g of base and 3, 76 g of methanesulfonic acid gives, after recrystallization from a 90% alcohol-ethyl ether mixture, pure 5,6,8-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole methanesulfonate of melting temperature 290 - 292°C.

The starting material can be prepared in the following way: a) Analogously to example 3a), 25.5 g of 2-oxo-3-piperidinecarboxylic acid ethyl ester and 21.0 g of 2,4,5-trimethylaniline form 20.8 g 2 , 3-piperidinedione-3-1_N,-(2,4,5-trimethylphenyl)-hydazone J of melting temperature 198 - 200°C. b) Analogously to example 1 b), pure 5,6,8-trimethyl-2,3, ,9-tetrahydro-1H-pyrido(3,4-b)indol-1-one of melting point 213 - 215°C. c) Analogy: example 3c) from 5,6,8-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indol-1-one is formed 4,5,7- trimethyl-tryptamine of melting point 169 - 171°C. The free base is prepared analogously to example 3c) with methanesulfonic acid 4,5,7-trimethyltryptamine methanesulfonate of melting point 274-276°C.

Example 5

Analogously to example 3), 6,8-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 270 is formed from 5,7-dimethyltryptamine methanesulfonate and glyoxylic acid monohydrate - 272°C. Analogous to example 3, 6,8-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole methanesulfonate of -melting temperature 286-288°C is obtained from the free base.

The starting material can be prepared in the following way: a) Analogously to example 3a), 2,3-piperidinedione-3-(2,4-dimethylphenyl)-hydrazone is formed from 2,4-dimethylaniline and 2-oxo-3-piperidinecarboxylic acid ester of melting point 187 - 189°C. b) Analogous to example 1 b), 6,8-dimethyl-2j3j4,9-tetrahydro-1H-pyrido(3, 4-b)indol-1-one of melting point 217 - 221°C. c) Analogous to example 3c), 5,7-dimethyltryptamine of melting point 112 is formed from 6,8-dimethyl-2j3,4,9-tetrahydro-1H-pyrido-(3,4-b)indol-1-one 114°C. The methanesulfonate melts at 228-230°C.

Example 6

Analogously to example 3, 5,7-dimethyl-6-methoxy-2,3,4,9-tetrahydro-1H-pyrido (3 ,4-b)indole of melting point 236 - 240°C.

Analogous to example 3, 5,7-dimethyl-6-methoxy-2,3,4,9-tetrahydro-1H-pyrido(3,4-b) indole methanesulfonate of melting point 262 - 265°C is formed from the free base .

The starting material can be prepared in the following way: a) Analogously to example 3a), from 3,5_dimethyl-4-methoxyaniline (Baldwin and Robinson J.chem.Soc. 193^ 1264, 1266) and 2-oxo-3-piperidinecarboxylic acid ethyl ester will be obtained 2, 3-piperidinedione-3-[n'-(3,5-dimethyl-4-methoxy-phenyl)-hydrazori] of melting point "236 - 238°C. b) Analogous to example 1 b) it will from 2,3- piperidine-dione-3 3 , 5_dimethyl-4-methoxy-phenyl)-hydrazone"} is obtained 5 5 7-dimethyl-4-methoxy-2,3,4,9-tetrahydro-1H-pyrido(3 > 4-b) indol-1-one of melting point 235 - 237°C. c) Analogous to example 3c), 4,6-dimethyl will be obtained from 5,7-dimethyl-6-methoxy-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indol-1-one -5-methoxy-tryptamine in the form of an oil.

Analogous to example 3c) 4,6-dimethyl-5-methoxy-tryptamine-methanesulfonate of melting point 251-253°C is prepared from the free base.

Example 7

21.4 g of 5 3 7-dimethyl-2',3 34 ,9-tetrahydro-1H-pyrido (3>4-b)indol-1-one are filled into the upper part of an extractor (soxhlet apparatus with glass frit). In the reflux flask, 7.56 g of lithium aluminum hydride are placed in 1000 ml of ethyl ether. The ether is kept under a nitrogen gas atmosphere for approx. 74 hours until complete dissolution of the introduced substances under reflux. The flask is then cooled with ice and excess lithium aluminum hydride is decomposed by the addition of

1.) 7.5 ml water, 2.) 735 ml 15% caustic soda and

3.) 22.5 ml of water.

The precipitate formed is filtered off and boiled 4 times with 500 ml of toluene. The toluene extracts are combined with the ether solution formed as a filtrate and extracted with 1-molar methanesulfonic acid. The acidic aqueous solution is made alkaline with concentrated caustic soda and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and the solvent is removed under vacuum. The crystalline residue formed is recrystallized from a benzene-petroleum ether mixture and gives pure 5,7-dimethyl-233,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 230-232°C.

13.0 g of 5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido-(334-b)indole are dissolved in 100 ml of absolute ethanol and mixed with 6.25 g of methanesulfonic acid. After adding 50 ml of ethyl ether, the precipitated product is filtered and recrystallized from 96% ethanol. Pure 5,7-dimethyl-2,334,9-tetrahydro-1H-pyrido(334-b)indole methanesulfonate of melting point 280 - 282°C is obtained.

Example 8

Analogous to example 7, it will off

6,8-dimethyl-2,3,4,9-tetrahydro-1H-pyrido( 3 3 4-b) indol-1-one is obtained 6,8-dimethyl-2,33^,9-tetrahydro-1H-pyrido

(3,4-b)indole of melting point 270 - 272°C and its methanesulfonate • of melting point 286 - 288°C, and

of 5,6,8-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indol-1-one gives 5,6,8-trimethyl-2,3,^,9 -tetrahydro-1H-pyrido(3,4-b)indole methanesulfonate of melting point 290 - 292°C.

Example 9

2 > 0<;g of 5 , 7-dimethyl-2 , 3,4, 9-tetrahydro-1H-pyrido (3,4-b)indole and 1.81 g of 1 bromohexane are introduced with 1.42 g of potassium carbonate in 50 ml acetone and boil with stirring and reflux for 36 hours. The reaction mixture is cooled slightly, filtered through diatomaceous earth and the residue is extracted with hot acetone. The combined filtrates are evaporated under vacuum and the remaining residue is shaken with toluene and water. The organic phase is washed with water and dried under magnesium sulfate. After the removal of the solvent, the crystalline residue is recrystallized once from a toluene-petroleum ether mixture and gives pure 2-n — hexy;I3:5,7_dimethyl-2 ,3 ,4 ,9-tetrahydro-1H-pyrido(3j4-b)indole of melting point 124 - 126°C.

Example 10

Analogously to example 9, from 5,7-dimethyl-2,3,4,9~ tetrahydro-1H-pyrido(3j4-b)indole and p-fluoro-benzyl bromide will be obtained 2-(p-fluorobenzyl)-5,7 -dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 168 - 170°C.

Example 11

Analogous to example 9, with benzyl bromide 2-benzyl-5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b) indole of melting point 157 - 159°C will be obtained

Example 12

2.0 g of 5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido (3,4-b)indole are kept with 1.2 g of benzaldehyde in 50 ml of benzene for 4 hours under reflux. The benzene is then distilled off as best as possible and the residue is taken up in 50 ml of methanol and at reflux temperature a solution of 0.57 g of sodium borohydride in 10 ml of ice water is added dropwise. The mixture is kept under reflux for 3 hours, cooled, mixed with 50 ml of water and in-

made acidic with 2-normal hydrochloric acid. Methanol is then distilled off and the resulting solution is made alkaline with 2-normal caustic soda and extracted with methylene chloride. The organic phases are washed with water, dried over magnesium sulphate and the solvent is removed in vacuo. The residue is crystallized from an ethyl ether-pentane mixture and gives 2-benzyl-5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 158 - 160°C.

Example 13

12.8 g of 2-acetyl-5,7,9-tetrahydro-1H-pyrido(3,4-b)indole are boiled with 250 ml of 1.5 normal caustic soda and 250 ml of ethanol for 5 hours under reflux. The ethanol is then removed under vacuum and the resulting suspension is shaken with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and the solvent is removed under vacuum. The residue formed is recrystallized from ethyl acetate and gives pure 5,7s9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 140 - 142°C.

The obtained base is dissolved in 30 ml of absolute ethanol, mixed with 3.8 g of methanesulfonic acid and 30 ml of ethyl ether is added. The precipitated product is filtered off and recrystallized from an absolute ethanol-ethyl ether mixture. Pure 557, 9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-methane-sulfonate is obtained. of melting point 263 - 264°C.

The starting material can be obtained in the following way:

a) 30 g of 5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido (3,4-b)indole are heated with 12.3 g of sodium acetate in 500 ml of acetic anhydride for 4 hours at 70°C. The acetic anhydride is then removed as best as possible under vacuum and the solid residue is poured into water and heated for 30 minutes at 50°C. The resulting suspension is shaken with methylene chloride, the organic phase is washed with 1-normal sodium bicarbonate solution and with water, and dried over magnesium sulfate. After removal of the solvent under vacuum, the crystalline residue formed is recrystallized from an ethyl acetate-petroleum ether mixture. Pure 2-acetyl-5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 190 - 192°C is obtained. b) 24.2 g of 2-acetyl-5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(334-b)indole are dissolved in 500 ml of methylene chloride and mixed at room temperature with a solution of 16, 9 g of tetrabutylammonium hydrogen sulphate in 250 ml of 50% caustic soda. The mixture is vigorously vibrated in a vibratory mixer for approx. 3 minutes, so that a thick liquid emulsion is formed. Then, with further thorough mixing, 13.8 g of dimethylsulphate in 50 ml of methylene chloride are added dropwise at a maximum of 25°C (cooling with an ice bath), and the mixture is vibrated for 1 hour at room temperature. The contents of the flask are then poured onto ice, the methylene chloride is rinsed off and the aqueous phase is shaken twice with 200 ml of methylene chloride. The combined aqueous phases are washed with water and dried over magnesium sulfate. After removal of the solvent under vacuum, the residue is recrystallized from an ethyl acetate-petroleum ether mixture. Pure 2-acetate-5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido (3,4-b)indole of melting point 150 - 151°C is obtained.

Example 14

Analogous to example 13, from 2-acetyl-6,8,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole 6,8-9-trimethyl-2 ,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 186 - 188°C.

The starting material can be prepared in the following way: a) Analogous to example 13a), from 6,8-dimethyl-2, 3,4,9-tetrahydro-1H-pyrido(3,4-b)indole, 2-acetyl-6, 8-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 192 - 195°C. b) Analogously to example 13b), 2-acetyl-6,8-dimethyl-2,3J4,9-tetrahydro-1H-pyrido(3J^-b)indole will yield 2-acetyl-6,8,9-trimethyl- 2,3,4,9-tetrahydro-1H-pyrido(3,4-b) indole of melting point 129 - 130°C.

Example 15

Analogous to example 9), from 5,7,9_trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole and 2-propynyl bromide, 2-(2-propynyl)-5,7 ,9~trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 160 - 161°C. The hydrochloride, prepared with hydrochloric acid in ethanol, melts at 233 - 234°C.

Example 16

Analogous to example 9), 5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole and benzyl bromide give 2-benzyl-5,7,9 -trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole, melting point 135 - 137°C. The maleate melts at 178 - 180°C (from absolute ethanol-ether).

Example 17

Analogous to example 9), 5,7,9-trimethyl-2j3j4,9-tetrahydro-1H-pyrido(3j4-b)indole and p-fluorobenzyl bromide will yield 2-(p-fluorobenzyl)-5,7,9 -trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole, melting point 152 - 154°C.

Dissolve 16.1 g of base in 50 ml of acetone and mix with 5.8 g of maleic acid. After adding 50 ml of ethyl acetate, the precipitated product is filtered off and recrystallized from a 90% ethanol-ether mixture. Pure 2-(p-fluorobenzyl)-5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole maleate of melting point 185 - 187°C is obtained.

Example 18

Analogous to example 9), from 5,7,9~trimethyl-2, 3,4,9-tetrahydro-1H-pyrido(3,4-b)indole and 2-bromoethanol, 2-(2-hydroxyethyl)-5 ,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole; melting point 140 - 141°C.

From the free base and ethanolic hydrochloric acid, pure 2-(2-hydroxyethyl)-5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido (3,4 -b) indole hydrochloride of melting point 253 - 255°C.

Example 19

24.2 g of 2-formyl-5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole are added in small portions to a boiling solution of 3.8 g of lithium aluminum hydride in 500 ml of ethyl ether. The reaction mixture is kept under reflux for 12 hours and then excess lithium aluminum hydride is decomposed under ice cooling by adding 4 ml of water, 4 ml of 15% caustic soda and 11 ml of water. The ether is filtered from the precipitated granular precipitate and this is boiled three times with hot toluene. The organic filtrate >purified,~ dried over magnesium

sulfate, and the solvent is removed under vacuum. The crystalline crude product formed is recrystallized from an ethyl ether-pentane mixture and gives pure 2,5,7,9-tetramethyl-2,354,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 144 - 145°C.

The starting material can be prepared as follows:

21.4 g of 5,7,9-trimethyl-2,3J4,9-tetrahydro-1H-pyrido(3,4-b)indole are dissolved in 500 ml ethyl formic acid and boiled for 12 hours under reflux. The excess ethyl formic acid is removed under vacuum and the crystalline residue is recrystallized from an ethyl alcohol-petroleum ether mixture. Pure 2-formyl-5,7,9~trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 158 - 160°C is obtained.

Example 20

6.4 g of 5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido (3,4-b)indol-1-one are placed in a glass frit extractor and extracted in a boiling solution of 2, 4 g of lithium aluminum hydride in 400 ml of absolute ether. The contents of the flask are stirred vigorously with a vibro-mixer. After approx. After 30 hours, the extra-healing is finished, the flask is cooled with ice, and 2.2 ml of water, 2.2 ml of 15% caustic soda and 6.6 ml of water are dropped in each time in sequence. The granular precipitate formed is filtered off over diatomaceous earth, boiled 3 times, each time with 100 ml of methylene chloride and filtered off again. The combined filtrates are dried over magnesium sulfate and evaporated to dryness under vacuum. The residue formed is recrystallized from toluene-petroleum ether and gives 5.0 g of 5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4~b)indole of melting point 142 - 143°C .

The starting material can be prepared as follows:

a) 87 g of 3,5-dimethylaniline is dissolved in 1570 ml of 1-normal hydrochloric acid, cooled to -3°C, and at this temperature a solution of 49.6 g of sodium nitrite in 142 ml of water is added dropwise over the course of 15 minutes. The clear pale yellow solution is stirred for 5 minutes at -2°C, and an accidental excess of nitrite is neutralized with a 1-molar sulfamic acid solution (test with potassium iodide-starch paper). A solution of 102 g of 2-oxo-3-piperidine carboxylic acid ethyl ester in 300 ml of water is then quickly added at -2°C to 0°C, and mixed over the course of 50 minutes approx. 800 ml of a half-saturated potassium carbonate solution so that the pH reaches 9. After the addition of approx. 30 ml of this solution, a brown, tough precipitate begins to fall out. It is obtained by adding 100 ml of toluene-hexane 3:7 in crystalline form. The reaction mixture is stirred for one hour at 0°C, the precipitate formed is filtered off, washed neutrally with cold water and dried overnight in a vacuum desiccator. Yellow crystals of melting point 91 - 96°C are obtained as crude product (still somewhat moist). The pure 4-ethoxycarbonyl-2,3~piperidinion-3-[n'-(3,5-dimethylphenyl)hydrazone J melts after recrystallization from toluene-petroleum ether at 106-109°C.

b) Dissolve 204.5 g of the crude product formed above in 1200 ml of methanol, filter over diatomaceous earth and the

the resulting clear solution is cooled to 8°C. Then 600 ml of 1-normal caustic soda is added and the mixture is stirred for 2 hours at room temperature. The mixture is then cooled to 0°C, adjusted with 2-normal hydrochloric acid to pH 6-7, and after stirring for 1 hour the precipitated crystals are filtered off in an ice bath. The residue is first washed with 200 ml of an ice-cold methanol-water mixture 1:1, and then with water. The formed crystals are dried in vacuum and then washed out with ether.

The crude product formed melts at 217°C. A sample of the crude product is recrystallized from alcohol-ether to give pure 2,3-piperidinion-3-[n'-(3,5-dimethylphenyl)hydrazone] of melting point 239 - 240°C as pale yellow crystals. c) 5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyridone (3j4-b)indol-1-one can be prepared according to example 3b).

d) In a three-necked reaction flask, add 80 ml of 50%

1 g of caustic soda and 6.76 g of tetrabutylammonium hydrogen sulfate.

then a solution of 8.56 g of 5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyridone(3,4-b)indol-1-one in 200 ml of methylene chloride is added. The reaction mixture is mixed well with a vibratory mixer and at 20°C a solution of 5.52 g of dimethylsulphate in 20 ml of methylene chloride is added dropwise over the course of 20 minutes. After the addition is complete, the reaction mixture is vibrated for a further 30 minutes. 100 ml of water are then added, the methyl chloride phase is separated and the water is extracted each

times 3 times with 100 ml of methylene chloride. The organic expression is washed out each time 3 times with 100 ml of water and combined. The organic phases are dried over magnesium sulfate and evaporated to dryness in vacuo. The residue formed is boiled off with ethyl acetate and the dissolved part is crystallized from a little ethyl acetate-petroleum ether. Pure 5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indol-1-one of melting point 237 - 238°C is obtained.

Example 21

4.2 g of 5,7,9-trimethyl-334-dihydro-9H-pyrido(354-b) indole are dissolved in 200 ml of absolute methanol and a solution of 1.92 g of methanesulfonic acid in 20 ml of methanol is added. Then, at room temperature, 1.24 g of sodium cyanoborohydride dissolved in 20 ml of absolute methanol is added and during approx. After 8 hours, a solution of 1.92 g of methanesulfonic acid dissolved in 30 ml of absolute methanol is added dropwise, so that the pH of the reaction mixture is always between 5-6. The mixture is allowed to stand for 48 hours at room temperature, acidified with 1 mol of methanesulfonic acid (pH around 1) and methanol is removed under vacuum. The resulting residue is evaporated twice, each time with 50 ml of methanol, dissolved in 100 ml of water and then made basic with 2-normal caustic soda. The mixture is shaken 3 times, each time with 50 ml of methylene chloride, the organic phases are separated and dried over magnesium sulphate. After removal of the solvent, the residue formed is recrystallized from toluene-petroleum ether. Pure 5,7,9~trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3j4-b)indole of melting point 140°C is obtained.

The starting material can be prepared in the following way: a) 11.45 g of 5,7J9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indol-1-one are suspended to the solution of 21 .7 g of potassium hydroxide in 150 ml of water and 150 ml of alcohol (7% solution) and the mixture is kept under reflux for 48 hours. The approximately clear solution is cooled, filtered over diatomaceous earth and the filtrate acidified with acetic acid to pH=6. After cooling with ice, the precipitated product is filtered off, washed with water and dried in a vacuum at 60°C. The formed 1,4,6-trimethyl-tryptamine-2-carboxylic acid (melting point 233-235°C) is further processed crude. b) 758 g of 1,4,6-trimethyltryptamine-2-carboxylic acid are suspended in 300 ml of 5% hydrochloric acid and heated under reflux. After 5 hours a clear solution is obtained. The solution is cooled, made alkaline with concentrated caustic soda and shaken out with methylene chloride. The organic phase is washed with water, dried over magnesium sulfate, and the solvent is removed in vacuo. The formed crystalline residue is recrystallized from pentane and gives pure 1,4,6-trimethyltryptamine of melting point 50-51°C.

c) 5.45 g of 1,4,6-trimethyltryptamine are suspended in

40 ml ethyl formic acid ester and heated in a bomb tube for a further 2 hours

100°C. The clear solution formed is evaporated in vacuo to dryness and the residue is recrystallized from toluene-petroleum ether. Pure N-formyl-1,4,6-trimethyltryptamine of melting point 125 -126°C is obtained. d) 4.2 g of N-formyl-1,4,6-trimethyltryptamine are dissolved in 600 ml of toluene and, with good stirring, 47 g of phosphorus pentoxide are introduced in small portions over the course of 30 minutes. The mixture is heated for 15 minutes under reflux, cooled and poured into approx. 1 liter of ice water. The resulting mixture is mixed with approx. 50 ml of 2-normal hydrochloric acid, brought to room temperature and stirred for 1 hour at room temperature. The aqueous, yellow solution is separated, made alkaline with concentrated caustic soda and shaken out with methylene chloride. The organic extracts are washed with water, dried over magnesium sulphate and the solvent is removed in vacuo. The residue formed is expelled with ether, the crystalline parts are filtered off and dried in a vacuum at 40°C. Pure 5,7,9-trimethyl-3,4-dihydro-9H-pyrido(3j4-b)indole of melting point 181 - 185°C is obtained.

Example 22

2.1 g of 5,7,9-trimethyl-9H-pyrido(3,4-b)indole are dissolved in 100 ml of absolute ethanol and hydrogenated while adding 0.96 g of methanesulfonic acid and 1g of 5% pallasium charcoal catalytic, at 40 - 50°C and 5 bar pressure. After completion of hydrogen uptake, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in water, made alkaline with 2-normal caustic soda and shaken out with methylene chloride. The organic phase is washed with water, dried

above the magnesium sulfate solvent is removed in vacuo. • The formed crystalline residue is recrystallized from toluene-petroleum ether. Pure 5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 140 - 142°C is obtained.

The starting material can be prepared as follows:

3.44 g ■ 5(7)9-trimethyl-2(3)4,9-tetrahydro-1H-pyrido(3,4-b)indol-1-one are dissolved in 40 ml of phosphorus oxychloride and kept under reflux for 4 hours. The mixture is then evaporated to dryness in vacuo, and the crystalline residue is dissolved in water and made alkaline with caustic soda. The resulting mixture is shaken with methylene chloride, and the organic phase is washed with water. The formed methylene chloride extracts are shaken with 1 mol of citric acid, the acidic, aqueous phase is separated and made alkaline with 2-normal caustic soda. The alkaline, aqueous phase is expressed again with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and the solvent is removed under vacuum. The crystalline residue formed is recrystallized from toluene-petroleum ether. Pure crystalline 5,7,9-trimethyl-9H-pyrido(3,4-b)indole of melting point 151 - 152°C is obtained.

Example 23

21.4 g of 5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3j4-b)indole is boiled with 12.9 g of diisopropylamine and 14.4

g of chloromethylcyclopropane in 200 ml of alcohol for 24 hours under reflux. After processing, the alcohol is removed under vacuum,

and the residue formed is shaken with methylene chloride and 2-normal ammonia. The organic phases are washed with water, separated and dried over magnesium sulphate. After removal of methylene chloride in vacuo, the oily residue formed is filtered over a column with 100 g of basic alumina.

(Eluent: Toluene + 5% methanol). The eluates are evaporated to dryness in vacuum, and the oily residue formed is mixed in ethyl acetic acid with ethereal hydrochloric acid until an acidic reaction occurs. The precipitated hydrochloride is recrystallized from 80% alcohol and ether, giving pure 2-cyclopropyl-methyl-5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b )indole hydrochloride of melting point 275 - 278°C.

Example 24

29.8 g of 1,4,6-trimethyl-tryptamine-methanesulfonate are dissolved in 300 ml of water and at room temperature a solution of 957 g of pyruvic acid in 60 ml of water is instilled. Then slowly instill approx. 120 ml of 1-normal potassium hydroxide likewise at room temperature, so that a final pH value of 3.8-4.0 is obtained. The resulting mixture is stirred for 5 hours at room temperature and, if necessary, adjusted

read the pH value. The resulting suspension is added slowly and in small portions to a mixture heated to 100°C of 300 ml of water and 29 g of methanolsulfuric acid. The reaction mixture is stirred

es strongly and strong foaming takes place. After the addition has been completed, the suspension is kept under reflux for 4 hours until a clear, yellow solution appears. For processing, introduce into the hot solution approx. 40 ml of concentrated caustic soda (strong alkaline reaction) and shaken after cooling with methylene chloride. The organic phases are washed three times with water, dried over magnesium sulphate and evaporated to dryness in vacuo. The oily residue formed is filtered through a column with 50 g of basic silica gel (toluene + 2% methanol) and the eluate is evaporated to dryness. The resulting residue is crystallized from petroleum ether/pentane and gives the pure 1,5,7,9-tetramethyl-2,3,4,9-tetrahydro-1H-pyrido (3,4-b)indole of melting point 86 - 87°C .

11.0 g of 1,5,7N-tetramethyl-2,3N4,9-tetrahydro-1H-pyrido(3,4-b)indole is dissolved in 30 ml of acetone and mixed with a solution of 75l4 g of maleic acid in 30 ml of acetone. After adding ether until cloudy, the mixture is cooled to 0°C and the precipitated product is filtered off. After recrystallization from absolute alcohol-ethyl ether, pure 1,5,7,9-tetramethyl 1-2 , 3,4,9-tetrahydro-1H-pyrido(3,4-b)indole maleate of melting point 194 - 196 is obtained °C.

Analogously, pure 1,5,7_trimethyl-2,3}4,9-tetrahydro-1H-pyrido(3,4-b)indole is obtained from 29 g of 4,6-dimethyl-tryptamine-methanesulfonate and 10 g of pyruvic acid.

Analogously, from 2.3 g of 1,4,6-trimethyl-tryptamine-methanesulfonate and 1.02 g of 2-oxobutyric acid, l-ethyl-5*7,9-trimethyl-2,3,4,9-tetrahydro- 1H-pyrido(3,4-b)indole.

Example 25

6.5 g of 1,4,6-trimethyltryptamine methanesulfonate is dissolved in 50 ml of water and 50 ml of alcohol and at 5°C 1.8 g of isobutyraldehyde is added dropwise. The mixture is adjusted with 1-normal caustic soda to pH 4.5 and stirred for 5 hours at 35°C. The mixture is then made alkaline with caustic soda and shaken out with methylene chloride. The organic extracts are shaken out with 1 molar (50 ml) methanesulfonic acid, the acidic aqueous phases are made alkaline again with caustic soda and extracted with methylene chloride. The organic phases are washed out with water, dried over magnesium sulphate and the solvent is removed under vacuum. The residue is recrystallized from ether-pentane to give 1-isopropyl-5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido (3,4-b)indole.

Example 26

Analogously to example 21, 2.26 g of 1,5,7,9-tetramethyl-3,4-dihydro-9H-pyrido(3,4-b)indole will yield 1*5,7,9-tetramethyl-2, 3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 86 - 87°C.

The starting material can be obtained as follows:

a) 10.1 g of 1,4,6-trimethyl-tryptamine is heated with 4 l g of sodium acetate in 150 ml of acetic anhydride for 4 hours at 70°C.

The excess of acetic anhydride is best removed in a vacuum and the residue is poured into 200 ml of water. After complete hydrolysis of the acetic anhydride, the resulting suspension is extracted with methylene chloride. The organic phases are dried with magnesium sulphate and evaporated to dryness in vacuo.

b) The crude N-acetyl-1,4,6-trimethyl-tryptamine thus formed is heated with 80 g of polyphosphoric acid ethyl ester (in

according to Piesen and Piesen, Org.Reagents, Vol I, p. 892) with stirring for 15 minutes at 80°C. The reaction mixture is then poured into 2 liters of ice water and stirred for 3 hours at room temperature. The resulting suspension is filtered, the filtrates are made alkaline with concentrated caustic soda and shaken out with methylene chloride. The organic extracts are washed with water, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is recrystallized from 10% alcohol and gives pure 1,5,7,9-tetramethyl-3,4-dihydro-9H-pyrido(3,4-b)

indole.

Example 27

2.7 g of 2-acetyl-1,5,7,9-tetramethyl-2,3,4,9-tetrahydro-1H-pyrido(3j4-b)indole are boiled analogously to example 13 with 50 ml of 1,5-normal caustic soda and 50 ml of ethanol for 5 hours under reflux. Pure 1,5,7,9-tetramethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole of melting point 86 - 87°C is obtained analogously to the preparation regulations according to example 13.

The necessary starting material is obtained as follows:

a) Analogous to example 13a), pure 2-acetyl-1,5 ,7-trimethyl-2,3,4,9-tetrahydro-1H-pyrido-(3,4-b)indole. b) Analogous to example 13c), pure 11.5 g of 2-acetyl-1,5,7-trimethyl-2,3,4,9~tetrahydro-1H-pyrido(3,4-b)indole will be obtained 2-acetyl-1,5,7,9-tetramethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole.

Example 28

27.2 g of 3,5-dimethyl-phenylhydrazine is boiled with 38.0 g of N-benzyl-3-piperidone in 200 ml of absolute alcohol for 6 hours under reflux. The mixture is evaporated to dryness and the residue is crystallized from ether-pentane, in which pure N-benzyl-piperidinone-3-[~N'-(3,5-dimethyl-phenyl)-hydrazone is obtained. 30 g of N-benzyl-piperidinone-3-[n'-(3,5-dimethyl- " - phenyl)-hydrazone are dissolved in 750 ml of absolute alcohol and the solution is saturated with hydrochloric acid gas. After boiling under reflux for 3 hours, the mixture is evaporated to dryness and the residue is dissolved in water and shaken out with ether. The acidic aqueous phase is then made basic with caustic soda and shaken out with methylene chloride. The organic phases formed are washed with water and dried over magnesium sulfate. The residue formed is chrome-autographed on a column with 200 g of basic silica gel (eluent toluene + 2% methanol). This gives, after recrystallization from ether-petroleum ether, 2-benzyl-5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b) indole of melting point 157 - 159°C

Example 29

2.9 g of 2-benzyl-5,7-dimethyl-2,3,4,9-tetrahydro-1H-pyrido(3j4-b)indole are dissolved in 50 ml of tetrahydrofuran and, while stirring, 6 ml of butyllithium are added dropwise at -78°C in hexane. The mixture is stirred for 30 minutes at -78°C and then at the same temperature a solution of 1.42 g of methyl iodide in 10 ml of tetrahydrofuran is added dropwise over the course of 10 minutes. The mixture is slowly brought to room temperature and allowed to stand for 2 hours. The mixture is then mixed with ice water and evaporated to dryness in vacuo. The residue is made alkaline with 2-normal caustic soda and shaken with water and methylene chloride. The organic phases are washed with water, dried over magnesium sulphate and the solvent is removed under vacuum. The residue is crystallized from ether-pentane and gives pure 2-benzyl-5,7,9-tetrahydro-1H-pyrido(334-b)indole of melting point 135 - 136°C.

Example 50

3.04 g of 2-benzyl-5,7,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3}4-b)indole are dissolved while adding 1.0 g of concentrated sulfuric acid in 100 ml absolute alcohol and hydrogenated after adding 1 g of 5% palladium charcoal at room temperature and 5 bar hydrogen pressure. After completion of hydrogen uptake, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in water, made alkaline with 2-normal caustic soda and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and the solvent is removed under vacuum. The residue is crystallized from ether-pentane and gives pure 5,7,9-trimethyl-2,3}4,9-tetrahydro-1H-pyrido(3}4-b)indole of melting point 142 - 143°C.

Claims (7)

1. Process for the preparation of diazatricycles of formula in which R 1 means hydrogen, lower alkyl, lower alkenyl, 2-propynyl, cycloalkyl lower alkyl, hydroxyl lower alkyl or optionally substituted benzyl, R2 means hydrogen or lower alkyl, R^ means hydrogen or lower alkyl, R4 and 5 means lower alkyl, and, R6 and R^ means hydrogen, lower alkyl, lower alkoxy or halogen as well as salts of such compounds characterized by a) a compound with formula is decarboxylated, or b) a compound of formula is reacted with a compound of formula R2 -CHO (VI)c) in a compound of formula or which can additionally have a double bond in the 3,4-position where X CE) means an anion, the C = N-double bond and any present 3,4-double bond are reduced, ord) a compound of formula is reacted with a compound of formula or with the hydrate or a ketal, or) in a compound of formula in which Z stands for -CO- or -group and means either R^ or -CO-R-^ -group <e> in it Rc^1 means one, with a methylene group reduced, otherwise however, to the above definition for R-^ corresponding re st, in that at least one of the symbols Z and R^ respectively contains a carbonyl group, carbonyl groups present are reduced to methylene groups or f) for the preparation of compounds of formula I, in which R1 and/or R^ means hydrogen, becomes in a corresponding compound where instead of R^ and/or there is a protective group that can be removed by solvolysis or reduction, this removes by solvolysis the respective reduction and if desired, a compound of formula I formed according to the method is converted into another compound of formula I, and/or if desired, a salt formed according to the method is converted into the free compound or into another salt or a free compound formed according to the method is converted in a salt and/or if desired, an isomer mixture formed according to the method is divided into the individual isomers. 2. Method according to claim 1, characterized in that one starts from one or another step of the method as an intermediate formed compound, carries out the missing method step or interrupts the method at one or other step or forms a starting material under the reaction conditions or uses a reaction component possibly in the form of its derivatives. 3. Procedure according to claim 1, character-. characterized by being prepared in connection with formula I, in which R^ means hydrogen, lower alkyl or lower alkenyl with up to 7 carbon atoms, 2-propynyl, cycloalkyl-lower-alkyl with 4-10 carbon atoms, hydroxy-lower-alkyl with 2- 7 carbon atoms or optionally with lower alkyl or lower alkoxy with up to 7 carbon atoms or halogen-substituted benzyl, R2 means hydrogen or lower alkyl with up to 7 carbon atoms, R^ means hydrogen or lower alkyl with up to 7 carbon atoms, R^ and R^ mean lower alkyl with up to 7 carbon atoms and Rg and R^ mean hydrogen, lower alkyl or lower alkoxy with up to 7 carbon atoms or halogen and their salts. 4. Process according to claim 1, characterized in that a compound of formula I is prepared, in which R^ means hydrogen, lower alkyl, or lower alkenyl with up to 4 carbon atoms, 2-propynepl, cycloalkyl-lower-alkyl with 4-8 carbon atoms, hydroxy-lower alkyl with 2-4 carbon atoms or optionally with lower alkyl or lower alkoxy with up to 4 carbon atoms or with halogen substituted benzyl, R^ means hydrogen or lower alkyl with up to 4 carbon atoms, R^ means hydrogen or lower alkyl with up to 4 carbon atoms, R^ and R^ mean lower alkyl with up to 4 carbon atoms, Rg and R^ mean hydrogen, lower alkyl or lower alkoxy with up to 4 carbon atoms or halogen and salts thereof. 5. Method according to claim 1, characterized in that a compound of formula I is prepared, in which R-L means hydrogen or methyl, 2-propynyl, 2-hydroxyethyl, benzyl or p-fluorobenzyl, R2 means hydrogenic or methyl, R^ means hydrogen or! methyl, R^ and R^ mean methyl, Rg means methyl or hydrogen and R^ means hydrogen and their salts. 6. Method according to claim 1, characterized in that 5,7,9_trimethyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole and salts of this compound are produced. 7. Process according to claim 1, characterized in that 1,5,7,9-tetramethyl-2j3j 4j9 -tetrahydro-1H-pyrido(3j 4-b)indole and salts of this compound are prepared.