NO811793L - 7.8.9.10-TETRAHYDROFURO (3,2-E) PYRIDO (4,3-B) INDOLES, PROCEDURES FOR THEIR PREPARATION AND THEIR USE IN PHARMACEUTICALS AND THEIR PREPARATION - Google Patents

Description

The invention relates to new 7,8,9,10 tetrahydrofuro/3»2-e_/pyrido/4-»3-b7indoles, a process for their preparation, as well as their use in pharmaceuticals, especially in pharmaceuticals that affect the central nervous system.

Methods for the production of indole derivatives with condensed heterocyclic rings have already been described in the literature. A therapeutic utility is not previously known for these compounds (cf. N.M.Sharkova et al, Khim. Geterotsikl. Soedin, 1972, 1075-1078, cited in C. A. Vol 77, 152028, t 408-409 (1 972)). Not for any of these known indole compounds with a similar chemical structure could an effect on the central nervous system be found that would have been close to their use in medicines.

The invention relates to new 7, 8, 9, 10-tetrahydrofuro/3, 2-e_7pyrido/4." 3-b7indole-der ivate with the general formula

in which

R 1 and R 2 are the same or different and each means hydrogen, linear, branched or cyclic alkyl, alkenyl, alkynyl aryl, acyl, aroyl, mono- and dialkylaminoalkyl, arylalkylaminoalkyl, heteroarylalkylaminoalkyl or acylamino, the aforementioned alkyl-alkenyl and aryl residues optionally is substituted with halogen, nitro, amino, alkyl, trifluoromethyl, alkoxy, hydroxy, acylamino, optionally substituted phenyl, heteroaryl or with a 5-, 6- or 7-membered saturated or unsaturated aliphatic ring, which may contain one or two identical or different heteroatoms from the group oxygen, sulfur or N-R', ie

R' means hydrogen, alkyl, alkenyl, aryl, aralkyl, acyl or aroyl,

R 3 and R k are the same or different, and each means hydrogen, straight or branched or cyclic alkyl, alkenyl or alkynyl, aryl, acyl or aroyl, the aforementioned alkyl, alkenyl and aryl residues being optionally substituted with halogen, alkyl, alkoxy, acylamino, optionally substituted phenyl or heteroaryl, R 3 not meaning hydrogen when R 2 and R L mean methyl and R -| means hydrogen or

R 3 and R L together mean an optionally branched alkylene residue,

which may be interrupted by oxygen or by the group S(0), where n means 0, 1 or 2,

R 5 means hydrogen, halogen, alkyl, alkoxy or phenyl,

as such, in the form of their quaternary ammonium salts, formed with alkyl halides and their pharmacologically tolerable acid addition salts.

The invention further relates to a method for the preparation of a compound of the general formula I, the method being characterized in that hydrazine compounds of the general formula II

is reacted with piperidones of the general formula III

in which

2

R has the above meaning,

respectively with salts of these piperidones with inorganic or organic acids in the presence of inert organic solvents at temperatures between 20 and 250° C, optionally in the presence of condensing agents, and the thus formed compounds of formula I are then easily transferred in a known manner in the quarters .more ammonium salts or acid addition salts,

1 2

and for the case that the nitrogen substituents R and R

means hydrogen, these are replaced according to known methods with other substituents according to the invention.

The new compounds of the general formula I

shows surprisingly pronounced and beneficial effects on the central nervous system. In particular, their use as antidepressants should be mentioned. The antidepressant effect of the compound group could not be predicted with knowledge of the state of the art. Since, according to experience, different groups of compounds are metabolised differently by the body, and thus for these compounds a new mechanism of action can also be assumed, they lead to an enrichment of the pharmacy. They can also be used in such cases where known antidepressants produce compatibility or habituation.

As an interesting pharmacological effect, mention should be made of the amphetamine-potentiating effect of the compound according to the invention. This amphetamine-potentiating effect was determined according to the method of Boksay et al, Arzneimittelforschung 29. 1 93 (1 979). It turned out that the compounds produced according to the invention by oral application already at dosages below 20 mg/kg have a significant amphetamine-potentiating effect. They can thus be used as psychopharmaceuticals, especially as antidepressants, while also having a good tolerability .

In addition to the amphetamine potentiating effect

of compound according to the invention, plus further properties that refer to a broad and versatile spectrum of pharmacological action. In detail, the following main effects should be mentioned: The compounds have an antagonistic effect towards reserpine, butyrylperazine and clopenthixol.

New compounds have analgesic and antiphlogistic effects, such as e.g. could be detected on kaolin paw edema in rats (cf. Jakobi et al, Arzneimittelforschung 27, 1 926 (177)).

Of particular importance are compounds with the general formula I, and likewise the compounds with II and III used as starting compounds, in which

R 1 and R 2 are the same or different, and each represents hydrogen, straight, branched or cyclic alkyl, alkenyl or alkynyl of up to 12 carbon atoms, aralkyl of 7 to 16 carbon atoms, phenyl, acyl with up to 8 carbon atoms, benzoyl,

mono- and dialkylaminoalkyl and phenylalkylaminoalkyl with each time up to 4 carbon atoms in the alkyl residue, or acylamino,

whose nitrogen atom can be substituted by 1 or 2 alkyl residues with 1 to 4 carbon atoms or by phenyl, the two alkyl groups possibly forming a 5- to 7-membered ring with the nitrogen atom which optionally contains a further hetero atom from the group oxygen, NH or N -alkyl with 1-4 carbon atoms, with the above-mentioned alkyl, alkenyl and phenyl residues being optionally substituted with halogen, nitro, amino, hydroxy, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, acylamino with 1 to 4 carbon atoms in the acyl group, phenyl, pyridyl or with a 5-, 6- or 7-membered saturated or unsaturated aliphatic ring, which may contain 1 or 2 identical or different heteroatoms from the group oxygen, sulfur or.NR', where R' means hydrogen, alkyl with 1 to 4 carbon atoms, phenyl, benzyl or acyl with up to 4 carbon atoms,

R 3 and R 4 are the same or different and each means hydrogen, straight, branched or cyclic alkyl, alkenyl or alkynyl with up to ..12 carbon atoms, aryl with 6 to 12 carbon atoms, acyl with up to 4 carbon atoms, or benzoyl where the above-mentioned alkyl- , alkenyl and aryl residues optionally substituted with halogen, trifluoromethyl, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, acylamino with up to 4 carbon atoms, phenyl or pyridyl, the phenyl residue optionally being substituted with 1 or 2 identical or different substituents from the group halogen, trifluoromethyl, alkyl or .alkoxy with each time 1 to 2 carbon atoms,

wherein RJ 3 does not mean hydrogen when R 2 and R 4 1 mean methyl and R<1> means hydrogen, or

RJ 3 and R^ 4 together mean an optionally branched alkylene residue with up to 10 carbon atoms which may be interrupted by oxygen, sulfur or the group S09, and

R 5 means hydrogen, halogen, phenyl, alkyl or alkoxy with each

1 to 4 carbon atoms.

Of particular importance is the compound of the general formula I, wherein

R 1 and R 2 are the same or different, and each means hydrogen, linear, branched or cyclic alkyl or alkenyl with up to 8 carbon atoms, phenyl, acyl with up to 4 carbon atoms, benzoyl or acylamino, the nitrogen of the amino residue being optionally substituted with 1 or 2 alkyl groups, or means a ring member of a morpholine, piperidine or piperazine residue, the rings of which are optionally substituted with methyl or ethyl, the aforementioned alkyl, alkenyl, phenyl and acyl residues being optionally substituted with alkyl with 1 to 4 carbon atoms, mono- or dialkylamino with each time 1 to 4 carbon atoms in the alkyl residue, halogen, nitro, amino, trifluoromethyl, trifluoromethoxy, alkoxy with 1 to 2 carbon atoms in the aldehyde st©.n, phenyl, piperidine, acetylamino, morph o-lino or cyano,

R 3 and R 4 are the same or different, and each means hydrogen, alkyl with 1 to 4 carbon atoms, phenyl or -trifluoromethyl, the aforementioned phenyl and alkyl residues being optionally substituted with halogen, alkyl or alkoxy with each time 1 to 2 carbon atoms, where R^ 3 does not mean hydrogen, and R 2 and R^ L means methyl and R -i means hydrogen, or

R 3 and R 4 together mean an optionally branched alkylene residue with up to 6 carbon atoms which may be interrupted by oxygen or sulfur in the chain, and

R 5 means hydrogen, halogen or methyl.

In the preparation of the compounds according to the invention with the general formula I from hydrazine compounds with the general formula II and piperidines with the general formula III, depending on the reactivity of the reaction participants,

This is done according to two different variants:

a) For the acid-sensitive reaction participants (II and III), their salts are used, preferably hydrochloride with a

suitable diluent.

b) In the case of reaction participants (II and III), which preferably convert in the form of their bases into a compound of formula I, or which are characterized by acid insensitivity, one preferably works at higher temperatures in the presence of a high-boiling solvent or without a solvent.

Both reaction variants are advantageous, and carry out the reaction under an inert gas atmosphere such as e.g. nitrogen or argon.

Suitable solvents for method variant a) are all solvents which are common for the Fischer-Indo synthesis (cf. E. Enders, Houben-Weyl, vol. 10/2, p. 54-6-586 (1967 ), A. Weissberger, The Chemistry and Heterocyclic Compounds, Indole, Part I, p 232-'370 (f 972) ).

Examples include: Water, methanol, ethanol, propyl, isopropyl alcohol. benzene, toluene, xylene, dioxane, glacial acetic acid, propionic acid, polyphosphoric acid ethyl ester or high-boiling hydrocarbons.

The usual catalysts for indole ring closure are also used as condensation agents. Examples include: Zinc chloride, boron trifluoride, boron trifluoride etherate, chlorine/hydrogen, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, polyphosphoric acid ethyl ester, formic acid, trifluoroacetic acid, acidic ion exchangers such as e.g. amberlite or a mixture of glacial acetic acid-hydrogen chloride.

The reaction temperatures can be varied over a large range. Usually one works between 4-0° and 150°C, preferably between 60 and 120 C. The reaction times vary between 0.5 and 20 hours depending on the reaction temperature.

Turnovers are normally carried out at atmospheric pressure.

When carrying out method a) according to the invention, an excess of from 0.1 to 0.5 mol is preferably used per mol of hydrazine compound II piperidone III.

Usually, the turnover can also be carried out under inert gas such as e.g. nitrogen or apgon. Ketones with the general formula III can in some cases preferably also be used corresponding ketals such as e.g. ethylene ketal or propylene ketal.

Reaction variant b) is carried out preferably

at temperatures between 150 and 250°C, especially in a range between 180 and 210°C. The use of an inert gas atmosphere is advantageous. As a solubilizing agent for this reaction variant, the following are mentioned as examples: Tetralin, dichlorobenzene, acetamide, ethylene glycol, diethylene glycol, diethylene glycol monomethyl ether, triethylene glycol, glycerol, N-methyl-pyrrolidone, ethylene glycol dimethyl ether, diethylene glycol dibutyl ether, ethylene glycol being mentioned as particularly preferred.

The compounds of the general formula I, in which the substituents R 1 and/or R 2 at the nitrogen mean hydro-

gene, can be subsequently transferred by known methods into correspondingly substituted:.:f orbindel ser. Such a subsequent substitution preferably takes place by e.g. converts the NH compound with sodium, potassium, sodium amide, potassium amide, potassium hydroxide, lithium hydroxide, sodium hydroxide or alkali alcoholate, such as for example sodium ethylate or potassium ethylate, preferably sodium hydride, in the alkali salt (I, R 1 = Na, K or Li) and reacts this on ° in a manner known per se with the corresponding substituted halides, such as e.g. acid halides of aliphatic, alicyclic or aromatic carboxylic acids, or with the corresponding substituted aliphatic, alicyclic or aromatic halogen compounds, which in their residues may have unsubstituted or with alkyl, aralkyl, cycloalkyl or aryl mono- or disubstituted NH^ groups.

The aroylation and alkylation of the NH groups in the pyrrole and tetrahydropyridine part of I with R 1 and/or R<2>

for H can possibly be carried out with sufficient basicity of these groups, also directly in the presence of suitable proton acceptors, such as trimethylamine, triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-dimethylaniline, N,N-diethylaniline, heterocyclic bases such as pyridine, picolines, collidines, quinolines or isoquinoline.

The turnover can be carried out without solvents or also in the presence of suitable solvent mediators. Solvent mediators are all organic solvents that are inert to the possible reaction participants. These preferably include aromatic hydrocarbons such as benzene, toluene, xylene or tetralin,

ethers such as diethyl ether, diisopropyl ether, tetrahydofuran, dioxane, ethylene glycol diethyl ether, nitriles, such as acetonitrile, propionitrile, carboxylic acid amides, such as dimethylformamide, dimethylacetamide, hexamethylphosphoric acid triamide, N-methylpyrrolidone, dimethylsulfoxide, heterocyclic bases, such as pyridine, quinoline or picolines, further commercially available technical mixtures of these solvents.

The reaction can be carried out at normal pressure, but also at elevated pressure, especially with low-boiling alkyl halides as reaction participants, elevated pressure may be necessary for the reaction.

The reaction temperatures can be varied within a certain range. Usually one works at temperatures between 0 and 200°C, preferably between 20 and 150°C, especially between 4-0 and 80°C in some cases room temperature is sufficient.

Processing of the ideal tendon then takes place again analogously as mentioned above.

The hydrazines of formula II which can be used as starting materials are known or can be prepared according to known methods, for example according to the following scheme:

sml (a) T. Sheradsky, Tetrah. Letters 1966, 5225, (b) A. Mustafa in "The Chemistry of Heterocyclic Compounds", Vol 29»Benzofurans (Ed:A Weissberger and E.C. Taylor) pp 1 - 77, Wiley -Interscience, New York, 1974,

(c) P. Cagniant and D. Cagniant in "Advances in Heterocyclic Chemistry" Vol. 18: Recent Advances in the Chemistry of Benzo /b_7furan and its Derivates, Part I, (Ed. A. R. Katritzky and

A.J. Boulton), pp. 337-4-82. Academic Press, New York, 1 975. (d) E. Enders in Houben-Weyl, vol. 10/2: Methoden zur Herstellubg und Umwandlung von Arylhydraziner und Aryl-hydrazonen, p 177-4-09 (1 967).

As new active substances, the following should be mentioned in detail: 9-methyl-6-(4--acetylaminophenyl)-6H-7, 8, 9, 10-tetra-hydr of uro/3» 2 -ejfpyrido/T -, 3-b7indole, 1 -methyl-6H-7, 8, 9, 10-tetrahydrofuro/3,2-e7pyrido/7, 3-b_7-indole, 1 -methyl-9-ethyl-6H-7, 8, 9 . pyrido A, 3-b/indole, 2-methyl-6H-7, 8, 9, 10-tetrahydrofluoro/J» 2-e/pyr id o/_7, 3-pJ/-indole, 2-methyl- 9-Acetyl-6H-7, 8, 9, 10-tetrahydrofuro/3" 2-ε_7pyrido/7, 3-p7indole, 2-methyl-9-benzoyl-6H-7, 8, 9, 10-tetrahydrofuro/ 3,2-e/-pyrido /4. 3-b/indole, 2-methyl-9-diethylaminocarbonyl-6H-7,8,9»10-tetrahydrofuro /3. 2-e_7pyridoZ.4-. ( 4-methylpiperazinocarbonyl)-6H-7, 8, 9, 10-tetrahydjDO - furo/3, 2-e/pyrido/4-» 3-b_/indole,

2, 9-Dimethyl-6-ethyl-6H-7, 8, 9-10-tetrahydrofluoro[3] 2-ε_7-pyridojj, 3-b7indole,

2, 9-Dimethyl-6-allyl-6H-7, 8, 9, 10-tetrahydrofuro/3, 2-e7~pyrido / J, 3-b7indole,

2,9-Dimethyl-6-(3,4-»5-trimethoxybenzyl)-6H-7,8,9,10-tetrahydrofluoro[3,2-e]pyrido[4],3-b-7indole,

2,9-dimethyl-6-(4-(4-fluorophenyl)-4-oxybutyl)-6H-7,8,9,10-tetrahydrofluoro[3,2-e]pyrido[4-[3-b] indole,

2-trifluoromethyl-9-methyl-6H-7, 8, 9» 10-tetrahydrofluoro/J, 2-e7 pyrido/4-» 3-b_7indole,

2-trifluoromethyl-9-ethyl-6H-7,8,9,10-tetrahydrofluoro/3. 2-e_/pyrido/4-» 3-b/indole,

2-trifluoromethyl-6-ethyl-9-methyl-6H-7,8,9,10-tetrahydrofuro

/3, 2-e/pyrido /7, 3-b_7indole,

2-trifluoromethyl-6, 9-dimethyl -gH-7, 8, 9, 10-tetrahydrofluoro-/j, 2-e_7 pyrido/4-, 3-b/indole,

1, 2-dimethyl-9-acetyl-6H-7, 8, 9, 10-tetrahydrofluoro/1, 2-e/-pyrido/7, 3-b/indole,

1,2-dimethyl-9-ethyl-6H-7,8,9,10-tetrahydrofluoro[3,2-e]pyrido[7,3-b]indole,

1,2-dimethyl-9-(2,2,2-trifluoroethyl)-6H-7, 8, 9, 1O-tetrahydrofluoro/3, 2-e/pyrido/4-, 3-b/indole,

1, 2-Dimethyl -9-isopropyl-6H-7, 8, 9, 10-tetrahydrofluoro £}, 2-eJ pyrido/4-» 3-b/indole,

1,2,6-trimethyl-6H-7,8,9,10-tetrahydrofluoro/3,2-e/pyrido/Z,3-b/indol,

1,2,6-trimethyl-9-trifluoroacetyl-6H-7,8,9,10-tetrahydrofluoro/3,2-e/pyrido/4.,3-b/indole,

1, 2, 6, 9-tetramethyl-6H-7, 8, 9, 10-tetrahydrofluoro/3, 2- ej-pyrido/7~, 3-b/indole,

1,2, 9-trimethyl-6-acetyl-6H-7, 8, 9, 10-tetrahydrofluoro-/l, 2-e/pyrido/4-, 3-b/indole,

1,2,9-trimethyl-6-(4-chlorobenzoyl)-6H-7,8,9,10-tetrahydrofuro/3,2-e_/pyrido/4-,3-b/indole ,

1,2,9-trimethyl-6-phenyl-6H-7,8,9,10-tetrahydrofluoro/3,2-§/pyrido/4-,3-b/indole,

1,2,9-trimethyl-6-(4-nitrophenyl)-6H-7,8,9,10-tetrahydrofluoro[3,12-e]pyrido[4-,3-b]indole,

1,2,9-trimethyl-6-(4-aminophenyl)-6H-7,8,9,10-tetrahydrofluoro[3,2-e]pyrido[4],3-[b]indole,

1,2, 9-trimethyl-6-(4-.acetylaminophenyl)-6H - 7, 8, 9, 10 - te trahydr o - f uro/3, 2 -e_/pyrido_/4-> 3-_b /indole,

1,2,9-trimethyl-6-(3-dimethylaminopropyl)-6H-7,8,9,10-tetrahydrofur0/3, 2-e/pyrido_/4-, 3-b/indole,

1,2,9-trimethyl-6-(3-piperidinopropyl)-6H-7,8,9,10-tetrahydrofluoro/3,2-e/pyrido/4-,3-b/indole,

2-phenyl-6H-7, 8, 9, 10-tetrahydrofluoro/3, 2-e/pyrido -//, 3-b/indole, 2-phenyl-9-ethyl-6H-7, 8, 9. 10-tetrahydrofluoro/3, 2-e/-pyrido/7, 3-b/indole,

2-phenyl-9-(4--methylpiperazinocarbonyl )-6H-7, 8, 9, 1 O-tetrahydro-

f uro/3» 2e/pyrido/4, 3-b/T.ndol,

2-phenyl-9-methyl-6H-7, 8, 9, 1 O-tetrahydrofuro/I, 2-e_7-pyrido/T, 3-b/indole,

2-phenyl-9-methyl-6-(3-diethylaminopropyl)-6H-7, 8, 9, 10-tetrahydrofluoro[3] 2-e[pyrido][4t] 3-b[indole,

1-methyl-2-phenyl-6H-7, 8, 9, 10-tetrahydrofur o/J, 2-e/-pyrido &, 3-b/indole,

1, 9-dimethyl-2-phenyl-6H-7, 8, 9, 10-tetrahydrofuro/T, 2-e/-pyrido //, 3-b/indole,

The invention includes pharmaceutical preparations which, in addition to non-toxic inert pharmaceutical suitable carriers, contain one or more of the compounds produced according to the invention or their salts, or which consist of one or more of the compounds according to the invention, or their salts, as well as methods for producing these preparations.

The invention also covers pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual parts, e.g. tablets, dragees, capsules, pills, suppositories and ampoules, the active substance content of which contains a fraction or a multiple of a single dose. The dosing unit can e.g. contain 1,2,3 or 4 single doses or 1/2, 1/3 or 1/4. of a single dose. A single dose preferably contains the amount of active substance that is administered by application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

By non-toxic inert pharmaceutical suitable carriers are meant solid, semi-solid or liquid diluents, fillers or formulation aids of any type.

As preferred pharmaceutical preparations

mention should be made of tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions, emulsions.

Tablets, dragees, capsules, pills and granules may contain part of it. active substances in addition to the usual carriers such as (a) fillers and thickeners, e.g. starches, milk sugar, cane sugar, glucose, mannitol and silicic acid (b) binders, e.g. carboxyl methyl cellulose, alginates, gelatins, polyvinylpyrrolidone, (c) humectants,

e.g. glycerol (d) explosives, e.g. agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarders, e.g., paraffins (f) resorption accelerator, e.g. quaternary ammonium compounds (g) wetting agents, e.g. cetyl alcohol, glycerol monostearate, (fr) adsorbent, e.g. kaolin and bentonite, and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

Tablets, dragees, capsules, pills and granules can be equipped with the usual, possibly opacifying agent-containing coatings and sleeves, and also be composed in such a way that they release the active substance(s) only preferably in a specific part of the digestive tract, possibly delayed, as the embedding mass, e.g. polymer substances and waxes can be used.

Or the active substances may possibly be present with one or more of the above-mentioned carriers as well

in microencapsulated form.

Suppositories can contain the usual water-soluble or water-insoluble carriers, e.g. polyethylene glycols, fats, e.g. cocoa butter and higher esters (e.g. C114 alcohol with C14-acetic acid) or mixtures of these substances.

The solution and emulsions may contain, in addition to the active substance(s), the usual carrier substances such as solvents, solubilizers and emulsifiers,

e.g. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral application, the solution and emulsion can also be available in sterile and blood isotonic form.

In addition to the active substance(s), the suspensions may contain the usual carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

The aforementioned formulations may also contain coloring agents, preservatives, as well as odor and taste-improving additives, e.g. peppermint oil, eucalyptus oil and sweeteners, e.g. saccharin.

The therapeutically active compounds must be present in the above-mentioned pharmaceutical preparations, preferably in a concentration from approx. 0.1 to 99.5, preferably from approx. 0.5 to 95% by weight of the total mixture.

The pharmaceutical preparations listed above may, without a compound of formula I and/or their salts, also contain other pharmaceutical active substances.

The production of the above-mentioned pharmaceutical preparations takes place in the usual way according to known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.

The invention also includes the use of compounds of formula I and/or their salts as well as pharmaceutical preparations containing one or more compounds of formula I and/or their salts in human medicine for the prevention, improvement and/or healing of the above-mentioned diseases .

The active substances in pharmaceutical preparations can/preferably be applied orally, parenterally and/or rectally, preferably orally and parenterally, especially orally and intravenously.

Generally, it has proven advantageous to administer the active substance(s) by parenteral (i.v. or i.m.) application in amounts from approx. 0.01 to about 10, preferably from 0.1 to 1 mg/kg body weight per 24 hours, and by oral application in amounts from approx. 0.05 to about 100, preferably 0.1 to 10 mg/kg body weight per 24 hours, possibly in the form of several individual submissions to achieve the desired results. A single administration contains the active substance(s), preferably in amounts from approx.

0.01 to approx. 30, especially 0.03 to 3 mg/kg body weight.

However, it may be necessary to deviate from

the mentioned dosages, namely depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and application of the drug, as well as the time period or the interval within which the administration takes place. Thus, in some cases it may be sufficient to come out with less than the above-mentioned amount of active substance, while in other cases the above-mentioned amounts of active substance must be exceeded. The determination of the optimal dosage and type of application of the active substances required in each case can be carried out by any professional due to his professional knowledge.

The invention also covers such medicines as

in addition to the compound of formula I also contains additional active substances. The following should preferably be mentioned:

6-rezeptor blockers, parasympatholytics, anxiolytics, neuroleptics, hypnotics and tranquilizers. Example 1

6H-7,8,9»10-tetrahydrofuro/3,2-e7pyrido/4,3-b7indole.

0.022 mol of 5-hydroazinobenzofuran hydrochloride is suspended with stirring in 200 ml of isopropanol, mixed with 0.026 mol of 4-piperidone hydrochloride monohydrate and heated to boiling for 2 hours. Evaporate to dryness, alkalize with 2N caustic soda and extract with dichloromethane.. For purification

recrystallized from isopropanol.

Yield: 70% of the theoretical, m.p. 183°C.

Example 2

9-methyl-6H-7,8,9,10-tetrahydrofuro[3,2-e]pyrido[7,3-b]indole.

0.1 mol of 5-hydrazinobenzofuran hydrochloride is mixed in 300 ml of isopropanol with 0.11 mol of 1-methyl-4-piperidone and heated to boiling. 100 ml of HC1-saturated isopropanol is added and boiled for 1/2 to 1 hour. After the solvent has evaporated, the residue is treated with aqueous caustic soda and the free base is extracted with ethyl acetate. Recrystallization from isopropanol gives the pure product.

Yield: 67% of the theoretical, m.p. 236-238°C.

Lactate: m.p. 196°C.

Example 3

9-Methyl-6-ethyl-6H-7, 8, 9, 10-tetrahydrofuro[3,2-e7 pyrido-[7»3-b]indole hydrochloride.

0.02 mol of 9-methyl-6H-7,8,9,10-tetrahydrofuro/3,2-e/pyrido/7,3-b_7indole is dissolved in 100 ml of absolute dimethylsulphate oxide, 0.02 mol sodium hydride and in4 drops after 1 hour of stirring 0.022 mol ethyl bromide at 20°C. After a further hour, pour into ice water, extract with ethyl acetate and chromatograph the crude product on silica gel or eluent: dichloromethane/methanol (95:5).

The oily base is converted with isopropanol HCl into the crystalline hydrochloride.

The yield: 4-5% of the theoretical, m.p. 239°C.

Example 4-

9-methyl-6-cyclohexyl methyl-6H-7, 8, 9, 1O-tetrahydrofluoro -/3> 2 -e_/pyrido/_4., 3-b/indole.

0.1 mol of 9-methyl-6H-7, 8, 9, 10-tetrahydrofuro/3, 2-e7 pyrido/4-, 3-b/indole is mixed in 500 ml of absolute dimethylformamide with 0.1 mol of sodium hydr.dd and after 2 hours, react by adding 0.1 mol of cyclohexylmethylbromide at 20°C. After 16 hours, you work up in the usual way, and about mkry st.all i - sers raw base from the isopropanol.

Yield: 50% of the theoretical, m.p. 160°C.

Example 5

9-methyl-6-(1-fluoro-2-iodethenyl)-6H-7,8,9,10-tetrahydrofluoro[3,2-e]pyrido[4-,3-b]indole,

One dissolves 0.05 mol of 9-methyl-6H-7, 8, 9, 10-tetrahydrofuro/3, 2-e/pyrido/4., 3-b/indole in 250 ml of absolute dimethyl formamide, adds 0 .05 mol of sodium hydride and stir for 2 hours at 20°C. 0.05 mol of 2-iodo-1,1,1-trifluoroethane is then added, it is left to react for 24 hours at 20°C,

and then pour on water. The precipitated product is taken up in ethyl acetate and, after distilling off the solvent, recalcitrate from diethyl ether.

Yield: 15% of the theoretical, m.p. 14-7°C.

Example 6

9-methyl-6-(4-nitroenyl)-6H-7, 8, 9, 10-te trahydr o-

f uro /~3, 2 -e7pyrido / 4» 3 -b7indole.

— —• * ■— ;0.05 mol of 9-methyl-6H-7, 8, 9, 10-tetrahydrofuro,/3, 2-e7 pyrido/4-» 3-b/indole is dissolved in 250 ml absolute dimethylformamide, add 0.05 mole of sodium hydride, and allow to stir for 2 hours at 20°C. Now drop in 0.055 mol of 4-fluoronitrobenzene, allow it to react for 1 hour, and pour it into ice water. The reaction product is extracted with ethyl acetate, and finally recrystallized from isopropanol. ;Yield: 74-% of the theoretical, m.p. 189°C. ;Lactate: Sm.p. 177°C. ;Example 7 ; ; 9-methyl-6-acetyl-6H-7, uro/3, 2-e/- pyrido/4., 3-b/indole. ;0.1<:>mol of 9-methyl-6H-7, 8, 9, 10-tetrahydrofuro/3, 2-e_/- pyrido/_4-, 3-b7indole is allowed to react in 500 ml of absolute dimethylformamide with 0.1 ml of sodium hydride, add 0.11 mol of acetyl chloride, and stir for 2 hours at 20°C. ;The column chromatographic purification on silica gel (eluent: acetone) yields an approximately pure product which is recrystallized from isopropanol. ;Yield: 20% of the theoretical, m.p. 14.8°C. ;b) 0.1 mol of 9-methyl-6H-7, 8, 9, 10-tetrahydrofuro/3, 2-eJpyrido/7, 3-b_/indole is allowed to react in 500 ml of absolute i.di- methylformamide in the presence of 0.1 mol of N,N-dimethylaniline with 0.1 mol of acetic anhydride for 2 hours at 20°C. After pouring in ice water, extraction is carried out. the product with ethyl acetate and purify by recrystallization from isopropanol. ;Yield: 25% of the theoretical, m.p. 14.8°C. ;Example 8 ; ; 1, 9-dimethyl-6H-7, 8, 9, 1 0-te trahydrof uro/3, 2- ej pyrido-//., 3-b/indole. ;0.3 mol of 3-methyl-5-hydrazinobenzofuran and 0.32 mol of 1-methyl-4-piperidone are heated in 250 ml of ethylene glycol for 2 hours at 180 to 190°C. It is allowed to cool, preferably in ice water, and no crystal precipitate is filtered off. The dried product is dissolved in toluene and chromatographed on aluminum oxide (neutral). After elution with toluene/methanol (10:1), the compound recrystallizes from isopropanol. ;Yield: 35% of the theoretical, m.p. 183-184°C. Lactate: m.p. 205°C. ;Example 9 ; ; 1,2,'-9-trimethyl. 6H-7,8,9,1O-tetrahydrofuro/3,2-e_7-pyrido/4-,3-b/indole. ; 0.23 mol of 2,3-dimethyl-5-hydrazinobenzofuran and 0.25 mol of 1*methyl-4--piperidone are heated in 350 ml of ethylene glycol under an inert gas atmosphere for 1 hour at 180 to 190°C The crystals formed during cooling are filtered off and washed with a little water and isopropanol and dried. For further purification, it is dissolved in acetone and chromatographed on neutral aluminum oxide with acetone. Combined eluates are evaporated, the residue is recrystallized from ethyl acetate.

Yield: 51% of theory, pale yellow crystals, m.p. 223-224°C during decomposition.

Lactate: Colorless crystals of m.p. 216-217°C.

9-Benzyl-1,'2-dimethyl-6H-7,8,9,10-tetrahydrofluoro[3,2-e]-pyrido[7,3-b]indole.

a) 0.3 mol. 2,3-dimethyl-5-hydrazinobenzofuran and 0.33 mol of 1-benzyl-4-piperidone are suspended with stirring and N^'

protective gas atmosphere in 100 ml ethylene glycol, slowly heated to 180°C. After 1 hour, it is allowed to cool to 20°C, as the product separates out oily. The oil is decanted, taken up in toluene and purified by column chromatography

on neutral aluminum oxide (eluent: toluene/isopropanol (100:2)). A yellow-brown product is obtained from the evaporated eluates, which is recrystallized from isopropanol.

Yield: 4-2% of the theoretical, m.p. 178°C.

b) 0.2 mol 2,3-dimethyl-5-hydrazinobenzofuran hydrochloride and 0.25 mol 1-benzyl-4.-piperidone are dissolved cold

in 500 ml of ethanol. The solution is brought to the boil and mixed with 150 ml of HCl-saturated isopropanol while warm. After 3 hours of boiling, the solvent is distilled off, the residue is treated with sodium hydroxide and taken up in methylene chloride. The dried methylene chloride solution is applied to a neutral aluminum oxide column and eluted with toluene/methanol (100:1).

Yield: 36% of the theoretical, m.p. 178°C after recrystallization from isopropanol.

Lactate: Sm.p. 165°C.

Example 11

1, 2-dimethyl-6H-7, 8, 9, 1 0-te trahydrof uro/3, 2 - £/ pyrido/4-, 3-b/indole.

0.1 mol of 9-benzyl-1,2-dimethyl-6H-7, 8, 9, 10-tetrahydrofuro/3, 2-e/pyrido3-b_/indole is hydrogenated in 600 ml of methanol in the presence of 3»0 g palladium charcoal ($5-ig). at 4-0°C until uptake of 0.1 mol of hydrogen.

Yield: 95% of the theoretical, m.p. 215°C during decomposition, Lactate: m.p. 206-207°C.

Example 12

4, 11 -dimethyl -8H-9, 10, 11, 12-tetrahydropyrido/3, k-b/ -cyclohexane/4-, 5_/f uro /~3> 2 -e /indole.

0.18 mol of 2-hydrazine-6-methyl-6,7,8,9-tetrahydro-dibenzofuran is heated in 300 ml of ethylene glycol with 0.20 mol of 1-methyl-4-piperidone with stirring for 1 hour at 180 to 190° C. After completion of NH^ evolution, allow to cool to room temperature, suck off the crystal slurry and wash with a little isopropanol. For purification, recrystallize from ethyl acetate.

Yield: 62% of the theoretical, m.p. 191 to 192°C.

Lactate: m.p. 202 - 203°C.

Example 13

12-methyl-1, 2, 3, U, 5, 10, 11, 12, 1 3-nonahydro-9H-pyrido-/3» 4-b_/cycloheptane/4> 5_/f uro/3» 2- eJindol .

0.12 mol of 2-hydrazino-7, 8, 9, 10-tetrahydro-6H-benzo/b_7-cyclohepta/d_/furan and 0.13 mol of 1^methyl-/.-piperidone are heated in 250 ml of ethylene glycol in 2 hours at 180 to 185°C. It is allowed to cool to 80°C, 100 ml of water is added dropwise while stirring and the crystal slurry that separates is sucked off. The product's purification takes place by chromatography on ■ silica gel with methylene chloride/methanol (6:4-) with subsequent recrystallization from

ethyl acetate.

Yield: 55% of the theoretical, m.p. 206 to 207°C. Lactate: m.p. 209 - 211°C.

Example 14-(

12-ethyl-1, 2, 3, A, 5 -1 0, 11, 12, 1 3-nonahydro - 9H-pyride o Z.3» 4--b7cycloheptane/4-, 5_7f uro/_3, 2-e_ /indole.

0.12 mol of 2-hydrazino-7, 8, 9, 1 O-tetrahydro-6H-b:enao/<b7>cyclohe<p>ta/d_7furan and 0.13 mol of 1-ethyl-4.-piperidone are reacted as discussed in example 13 and processed.

Yield: 4-0% of the theoretical, m.p. 180 to 181°C. Lactate: 200 to 201°C.

Ex. empel 15

4., 11-dimethyl-8-ethyl-8H-9, 10, 11, 12-tetrahydropyrido/3, 4--b_/-cyclohexane/7, 5_7f uro/3, 2-e/indole.

The compound occurs analogously to that indicated in example 3 from 0.02 mol of 4-, 11-dimethyl-8H-9, 10, 11, 12-tetrahydropyrido /3, 4--b7cyclohexane/7, 5_/furo/3, 2 -e_7indole, 0.02 mol sodium hydride and 0.022 mol ethyl bromide in dimethylformamide at 20°C.

Yield: 4-8% of the theoretical, m.p. 14.6°C (from ethanol).

k, 11-dimethyl-8-(4.-nitrophenyl J-8H-9, 10, 11, 12-tetrahydropyrido/3, 4--b_/-cyclohexane/4.» 5_/furo/3,2-e__/ indole.

The compound arises analogously to example 6 from 0.1 mol U,11-dimethyl-8H-9,10,11,12-tetrahydropyrido[3,4.-b_7cyclohexane/4-»5_/furo/3,2 -e7indole, 0.1 mol of sodium hydride and 0.1 mol of 4-fluoronitrobenzene in dimethylforoamide at 20°C.

Yield: 53% of the theoretical, m.p. 196-197°C (from ethanol). Hydrochloride: m.p. 291-293°C during cleavage.

Example 17

9-(2,2,2-trifluoroethyl)-6H-7,8,9,10-tetrahydrofuro[3,2-e]pyrido-[%,3-b]indole.

0.02 mol of 5-hydrazinobenzofuran and 0.022 mol of 1-(2,2,2-trifluoroethyl)-L,-piperidone are suspended with stirring in 20 ml of ethylene glycol, and heated for 30 minutes at 190°C. After cooling, it is mixed with water and extracted with diisopropyl ether, purified by column chromatography on neutral aluminum oxide (eluent: dichloromethane.) and recrystallized from diisopropyl ether/petroleum (4-0-60°C).

Yield: 38% of the theoretical, m.p. 110-112°C.

Example 18

9-methyl-6H-7,8,9.1O-tetrahydrofuro[3,2-e]pyrido A,3-b_[indole-N^-methoide.

0.1 mole of 9-methyl-6H-7. 8, 9, 10-tetrahydrofuro/3,2-e/pyrido/4'3-b/indole is dissolved in 1200 ml of methanol, mixed with 50 ml of iodomethane, and allowed to stand for 24 hours at room temperature. After evaporation to half the volume, ■ metho-iodide crystallizes in pure form.

Yield: 84% of the theoretical, m.p. 257°C during decomposition.

Claims (10)

1. 7, 8, 9, t'0-tetrahydrofuro/3, 2-eJpyrido/4~, 3-b7~ indole derivatives of the general formula I wherein R 1 and R 2 are the same or different, and each represents hydrogen, straight, branched or cyclic alkyl, alkenyl, alkynyl, aryl, acyl, aroyl, mono- and dialkylaminoalkyl, arylalkylaminoalkyl, heteroarylalkylaminoalkyl or acylamino, wherein said alkyl-, alkenyl and aryl residues are optionally substituted with halogen, nitro, amino, alkyl, trifluoromethyl, alkoxy, hydroxy, acylamino, optionally substituted phenyl, heteroaryl or with a 5-, 6- or 7-membered saturated or unsaturated aliphatic ring, which may contain 1 or 2 identical or different heteroatoms from the group oxygen, sulfur or N-R', where R' means hydrogen, alkyl, alkenyl, aryl, aralkyl, acyl or aroyl, R 3 and R 3 L are the same or different and each means hydrogen, linear, branched or cyclic alkyl, alkenyl or alkynyl, aryl, acyl or aroyl, the aforementioned alkyl, alkenyl and aryl residues being optionally substituted with halogen, alkyl, alkoxy, acylamino, optionally substituted phenyl or heteroaryl, wherein R 3 does not mean hydrogen, when R 2 and R 4 L means methyl and R 1 means hydrogen, or R 3 and R L together mean any branched alkylene residue which may be interrupted by oxygen or by the group S(0), where n means 0, 1 or 2, R 5 means hydrogen, halogen, alkyl, alkoxy or phenyl, as such in the form of their quaternary ammonium salts, formed with alkyl halides and their pharmacologically tolerable acid addition salts. 2. Compounds of the general formula I according to claim 1, wherein R 1 and R 2 are the same or different and each means hydrogen, straight, branched or cyclic alkyl, alkenyl or alkynyl with up to 12 carbon atoms, aralkyl with 7 to 16 carbon atoms, phenyl, acyl with up to 8 carbon atoms, benzoyl, mono- and dialkylaminoalkyl and phenylalkylaminoalkyl each time with up to 4 carbon atoms in the alkyl residue, or acylamino, whose nitrogen atom can be substituted with 1 or 2 alkyl residues with 1 to 4 carbon atoms, or with phenyl, with the two alkyl groups possibly forming a 5 - to a 7-membered ring which optionally contains further heteroatoms from the group oxygen, NH or N-alkyl with 1-4 carbon atoms, the above-mentioned alkyl, alkenyl and phenyl residues being optionally substituted with halogen, nitro, amino, hydroxy, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, acylamino with 1 to 4 carbon atoms in the acyl group, phenyl, pyridyl or with a 5-, 6- or 7-membered saturated or unsaturated aliphatic ring, which ca n contain 1 or 2 identical or different heteroatoms from the group oxygen, sulfur or NR<1>, where R' means hydrogen, alkyl with 1 to 4 carbon atoms, phenyl, benzyl or acyl with up to 4 carbon atoms, R 3 and R 4 are the same or different and each means hydrogen straight-line, branched or cyclic alkyl, alkenyl or alkynyl with up to 12 carbon atoms, ethyl with 6 to 12 carbon atoms, acyl with up to 4 carbon atoms or benzoyl, the aforementioned alkyl -, alkenyl and aryl residues are optionally substituted with halogen, trifluoromethyl, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, acylamino with up to 4 carbon atoms, phenyl or pyridyl, the phenyl residue possibly containing 1 or 2 equal or different substituents from the group halogen, trifluoromethyl, alkyl or alkoxy each time with up to 2 carbon atoms, where R 3 means hydrogen when R^ and R<4> means methyl and R means hydrogen, or RJ and R together means an optionally branched alkylene residue with up to 10 carbon atoms, which may be interrupted by oxygen, sulfur or the group S09, and R 5 means hydrogen, halogen, phenyl, alkyl or alkoxy with each 1 to 4 carbon atoms. 3. Compounds of the general formula I according to claim 1, wherein R 1 and R 2 are the same or different and each means hydrogen, straight, branched or cyclic alkyl or alkenyl with up to 8 carbon atoms, phenyl, acyl with up to 4 carbon atoms, benzoyl or acylamino, the nitrogen of the amino residues being optionally substituted. with 1.1 - or 2 alkyl groups, or means a ring member of a morpholine, piperidine or piperazine residue whose rings on their side are optionally substituted with methyl or ethyl, the aforementioned alkyl, alkenyl, phenyl and acyl residues on their side optionally substituted with alkyl with 1 to 4 carbon atoms, mono- or dialkylamino with each time 1 to U carbon atoms in the alkyl residue, halogen,, nitro, amino, trifluoromethyl, trifluoromethoxy, alkoxy with 1 to 2 carbon atoms in the alkoxy residue, phenyl, piperidine , acetylamino, morpholino or cyano, R 3 and R L are the same or different and each represents hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or trifluoromethyl, the aforementioned phenyl and alkyl residues are, in turn, optionally substituted with halogen, alkyl or alkoxy with 1 to 2 carbon atoms in each case, R 3 not meaning hydrogen nor R 2 and R<4> meaning methyl and R meaning hydrogen, or R 3 and R^ 4. together mean an optionally branched alkylene residue with up to 6 carbon atoms, which may be interrupted by oxygen or sulfur in the chain, and R 5 means hydrogen, halogen or methyl. 4-. Process for the preparation of a compound of the general formula I according to claim 1, characterized in that the hydrazine compound of the general formula II wherein 13 4 5 R , R , R and R have the above meaning are reacted with piperidones of the general formula III in which p R has the above meaning respectively with salts of these piperidones with inorganic or organic acids in the presence of inert organic solvents at temperatures between 20 and 250°C, optionally in the presence of condensation agents, and the thus formed compounds of formula I are optionally then transferred in a known manner into the quaternary ammonium salts or acid addition salts, and in the event that nitrogen-1 2 the substituents R and R mean hydrogen, this is replaced according to known methods with other substituents according to the invention. 5. Compound with the general formula I according to claim 1 for use in combating diseases. 6. Compound with the general formula I according to claim 1 for combating diseases of the central nervous system. 7. Medicines containing at least one compound of the general formula I according to claim 1. 8. Process for the production of medicinal products characterized in that the flor binder is transferred into a suitable application form with the general formula I according to claim 1, possibly under-use of usual excipients and carriers. 9. Compounds of the general formula I according to claim 1 in combating diseases. 10. Use according to claim 9 in combating diseases of the central nervous system.