SK277923B6 - 3-imidazolymethyl-1,2,3,9-tetrahydro-4h-carbazole-4-on derivatives, method of their preparation and pharmaceutical agents containing this agents - Google Patents

Abstract

1,2,3,9-Tetrahydro-3-(imidazole-1-yl-methyl)4H- -carbazole-4-on derivatives with general formula I, in which R exp.1 means hydrogen atom, alkyl with 1 to 10 carbon atoms, cycloalkyl with 3 to 7 atoms of carbon, alkenyl with 3 to 7 carbon atoms phenyl or phenylalkyl with alkyl part with 1 to 3 atoms of carbon, one from symbols R exp.2, R exp.3 and R exp.4 means atom of hydrogen, alkyl with 1 to 6 atoms of carbon, cycloalkyl with 3 to 7 atoms of carbon, alkenyl with 2 to 6 atoms of carbon or phenylalkyl with alkyl part with 1 to 3 atoms of carbon and other symbols, same or different mean atom of hydrogen or alkyl with 1 to 6 atoms of carbon. Solution is concerning also method of production of these matters and pharmaceutical compounds with antagonistic effect against 5HT-receptors.

Description

Technical field

The present invention relates to 1,2,3,9-tetrahydro-3- (imidazol-1-ylmethyl) -4H-carbolol-4-one derivatives, to a process for their preparation and to pharmaceutical compositions containing them. It has substances that act on certain 5-hydroxytryptainine receptors (5HT).

BACKGROUND OF THE INVENTION

The 5HT receptors, which are abundant in peripheral nerves and platelets, cause, as is well known, painful sensations in humans by specifically acting on these receptors, which are deposited at the terminals of the primary and inert nerves. It has also been observed that agents that antagonize the effect of 5HT on neurons have an analgesic effect, for example, ameliorate migraine pain. 5HT also causes depolarization on the rat vag isolated nerve preparation by the same mechanism, inhibiting this effect is consistent with the analgesic effect in vivo.

5HT also occurs abundantly in the central nervous system pathways and disorders of the pathways containing these receptors are known to lead to changes in behavior, for example, mood changes, psychomotor activity, appetite and memory changes. Since these receptors in the central nervous system are of the same type as 5HT in the peripheral nervous system, it is believed that those compounds that antagonize the effects at peripheral 5HT receptors will also be effective in some central nervous system conditions such as schizophrenia, anxiety, obesity and mania.

The prior treatment of these conditions is burdened with a number of disadvantages. For example, in the known treatment of migraine, ergotamine, i.e. a substance that causes nonselective contraction of blood vessels not only in the head region, but also throughout the body, is administered. Therefore, ergotamine has undesirable and potentially dangerous side effects. Migraine can also be treated by the administration of analgesics such as aspirin or paracetamol, usually in combination with an anti-emetic anti-emetic such as metaclopramide, but these compositions are of limited value.

Similarly, the prior treatment of psychotic disorders, such as schizophrenia, is carried out using drugs that have serious side effects, for example, causing extrapyramidal disorders that need to be treated again.

Thus, there is a need for safe and effective agents for the treatment of conditions caused by pathway disorders containing 5HT receptors such as migraine or psychotic disorders such as schizophrenia. Substances that are potent and selective antagonists of neuronal 5HT receptors are likely to meet these requirements.

SUMMARY OF THE INVENTION

It has now been shown that a group of 3-imidazolylmethyltetrahydrocarbazole derivatives includes potent and selective antagonists of said 5HT receptors.

The present invention provides 3-imidazolylmethyl-1,2,3,9-tetrahydro-4H-carbazol-4-one derivatives of formula I

0 R «» ’ ] -------- [ Λ J R » (I) R ¹

wherein R * is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkenyl of 3 to 6 carbon atoms, phenyl or phenylalkyl of 1 to 3 carbon atoms in the alkyl moiety, one of R ² , R ³ and R ⁴ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkenyl of 2 to 6 carbon atoms or phenylalkyl of 1 to 3 carbon atoms and the other symbols, the same or different, represent hydrogen or alkyl having 1 to 6 carbon atoms, as well as physiologically acceptable salts thereof, and solvates, for example hydrates.

It will be appreciated that in the case where R ¹ is C 3 -C 6 alkenyl, the double bond cannot be stored directed to the nitrogen atom.

The alkyl groups of formula (I) may be straight or branched chain and may be, for example, methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, 2-methyl-2-propyl, pentyl, 3-pentyl or o hexyl.

Alkenyl in the meaning of all the above symbols can be, for example, a propenyl group. Phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety may be, for example, benzyl, phenethyl or 3-phenylpropyl.

Cycloalkyl may be, for example, cyclopentyl, cyclohexyl or cycloheptyl.

It will be appreciated that the carbon atom at the 3-position of the tetrahydrocarbazolone ring is asymmetric and may exist in the R or S configuration. The invention encompasses both the individual isomeric forms of the compounds of Formula I and all mixtures of these isomers including the racemic mixture.

Suitable physiologically acceptable salts are, in particular, the addition salts of the indole derivatives of the formula I with organic or inorganic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, citrates, fumarates and maleates. The solvates may be, for example, hydrates.

A preferred group of formula (1) is that wherein R ¹ is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkenyl of 3 to 6 carbon atoms.

Another preferred group of compounds of the invention are those compounds of formula (I) wherein one of R ² , R ³ and R ⁴ is C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 alkenyl. and the other two symbols, identical or different, represent a hydrogen atom or an alkyl of 1 to 3 carbon atoms.

Another preferred group of compounds are those compounds of formula (I) wherein R ¹ is hydrogen, C 1 -C 6 alkyl, C 5 -C 6 cycloalkyl or C 3 -C 4 alkenyl and either R ² is hydrogen and R ² is hydrogen. ³ and / or R ⁴ is C 1 -C 3 alkyl or R ² is C 1 -C 3 alkyl and R ³ and R ⁴ are hydrogen atoms.

A particularly preferred class of compounds of the invention can be represented by formula Ia

SK 277923 Β6

OR * · R ^J1

wherein R < ¹ > is hydrogen, methyl, ethyl, propyl, 2-propyl, 2-propenyl or cyclopentyl; R * is hydrogen and either R ² * is methyl, ethyl, propyl or 2-propyl and R * is hydrogen or R "is hydrogen and R ⁴ * is methyl or ethyl, and salts thereof, acceptable from physiological and solvates thereof, for example hydrates.

Preferred compounds of the invention include:

122.9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9- (2-propenyl) -4H-carbazol-4-one;

9-cyclopentyl-1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one; and

1,2.3.9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9- (2-propyl) -4H-carbazol-4-one, and physiologically acceptable salts thereof , and solvates thereof.

A particularly preferred compound of the invention is

1,2.3.9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one, represented by formula 1b o

and physiologically acceptable salts thereof, and solvates thereof, for example hydrates. A preferred form of this compound is hydrochloride dihydrate.

It is to be understood that the invention also encompasses other acceptable equivalents of the compounds, i. physiologically acceptable compounds which are converted in vivo to the own compounds of formula I.

The compounds of the invention are potent and selective antagonists of the 5HT receptor-induced response to rat vagal isolated nerve preparations and are therefore potent and selective antagonists of neuronal-type 5HT receptors deposited on primary afferent nerves.

The compounds of the invention may be used, for example, as analgesics, to relieve pain associated with migraine, headache of another type and to alleviate other forms of pain for which 5HT receptors are an endogenous mediator.

Animal experiments have also shown that the compounds of the invention will also be useful in the treatment of schizophrenia and other psychotic disorders. As already mentioned, 5HT receptors are widespread in the neuronal pathways of the central nervous system, and disorders of these pathways result in a variety of disorders in the form of various syndromes, such as mood disorders, appetite and memory disorders. Since the 5HT receptors in the central nervous system are of the same type as receptors that are located on primary afferent terminals, it is anticipated that the compounds of the invention will also be useful in the treatment of anxiety, obesity and mania.

In particular, the compounds of formula (Ia) as defined above are highly selective and have a very high activity. They are well absorbed from the stomach and intestinal system and are therefore suitable for oral or rectal administration. The compounds of formula Ia do not prolong the sleep time in mice under pentobarbitone anesthesia, meaning that there is no undesirable interaction with the enzyme that metabolizes the substance. These substances have no effect on normal behavior, are non-toxic and do not cause any adverse effects when administered to mice up to 1 mg / kg intravenously.

The compounds of formula (1b) also have exceptionally good properties of the compounds of formula (Ia) and no adverse effects were observed when administered to humans.

The present invention provides pharmaceutical compositions comprising at least one compound of formula (I) or a physiologically acceptable salt or solvate thereof, for example a hydrate. These compositions are intended for both human and veterinary use and can be formulated in conventional dosage forms by conventional techniques.

One or more physiologically acceptable carriers or excipients may be used to formulate the compounds of the invention into pharmaceutical compositions.

The compounds of the invention may be formulated for oral, mucosal, parenteral or rectal administration, or may be formulated for administration by inhalation or insufflation into the mouth or nose.

For oral administration, the pharmaceutical compositions of the invention may take the form of, for example, a tablet or capsule prepared by conventional means using pharmaceutically acceptable excipients such as binders, e.g. pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose; calcium hydrogen phosphate, glidants such as magnesium stearate, talc or silica, a disintegrating agent such as potato starch or sodium starch glycolate or wetting agents such as sodium lauryl sulphate. The tablets may be coated in the usual manner. Liquid formulations for oral administration may be, for example, solutions, syrups or suspensions, or the compounds may be presented in the form of a dry powder to be mixed with water or other vehicle before use. Such liquid compositions may be prepared in a conventional manner using additives customary in the manufacture of such compositions, such as suspending agents such as sorbitol syrup, cellulose derivatives or hydrogenated edible fats, emulsifying agents such as lecithin or acacia gum, non-aqueous vehicles. , such as almond oil, aliphatic acid esters, ethyl alcohol or fired vegetable oils, and also preservatives, for example methyl or propyl hydroxybenzoates or sorbic acid. Pharmaceutical compositions of this type may also contain buffers, flavoring agents, coloring agents or sweeteners.

Oral formulations may also be formulated so as to provide controlled release of the active ingredient after administration.

For oral administration, the compounds of the invention may be formulated in conventional manner into tablets or lozenges.

For parenteral administration, the compounds of the invention may be formulated, for example, into a suitable form

For injection. It may be in a single dose form, for example, ampoules or o (Multi-dose sachets, in which case a preservative is usually added. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain auxiliary agents. The active ingredient for parenteral administration may also be provided in the form of a powder to be mixed with a suitable vehicle, for example sterile pyrogen-free water, before use.

For rectal administration, the compounds of the invention may be formulated into, for example, suppositories or retention enemas, such dosage forms containing, for example, conventional suppository bases such as cocoa butter or other glycerides.

In addition to the aforementioned pharmaceutical compositions, the compounds of the invention may also be formulated into a depot effect. Such long acting formulations may be administered, for example, as implants, for example subcutaneously or into a muscle, or by intramuscular injection. For example, it is possible to mix the compounds of the invention with a suitable polymeric or hydrophobic material, for example to form an emulsion in a physiologically acceptable oil, or to mix with an ion exchange resin, or to make them sparingly soluble derivatives, for example sparingly soluble salts.

For administration by inhalation, the compounds of the invention may be delivered in the form of aerosol sprays in a pressurized pack or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetraluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, it is possible to release a specified single dose using a metered valve. Capsules, for example, gelatin capsules for use in an inhalation or insufflation device, may contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

A proposed dose of the compounds of the invention in a human having a body weight of about 70 kg is 0.05 to 20 mg, preferably 0.1 to 10 mg, of the active ingredient per unit dose, which may be administered, for example, 1 to 4 times daily. The dose will depend on the route of administration and the weight of the patient. Of course, it may be desirable to make routine deviations from the indicated dosage depending on the age and weight of the patient, as well as the severity of the condition being treated.

For oral administration, a single dose will preferably contain 0.5 to 10 mg of the active ingredient. For parenteral administration, a dosage of 0.1 to 10 mg of the active ingredient is preferred.

The aerosol formulations are preferably adapted so that each dose that is released by depressing the aerosol can valve measures 0.2 to 2 mg of a compound of the invention using capsules for an insufflation or inhaler device, said capsule containing 0.2 to 20 mg of the compound of the invention. The total daily inhalation dose should be in the range of 0.4 to 80 mg of active ingredient. By inhalation, the active ingredient can be administered several times a day, for example 2 to 8 times a day, each time releasing one, two or three doses.

If desired, the compounds of the invention may be administered in combination with other active agents, for example, nausea-suppressants.

The compounds of formula (I) and their physiologically acceptable salts or physiologically acceptable solvates or equivalents thereof can be obtained by a number of procedures which are set forth below.

According to the first general procedure A, a compound of the formula I, a physiologically acceptable salt thereof, a solvate thereof or a physiologically acceptable solvate thereof, can be obtained by reacting a compound of the formula Π

wherein R ¹ is as defined above and Y is a reactive group, or a protected derivative thereof, with an imidazole derivative of the general formula m

and wherein R ² , R ³ and R ⁴ are as defined above or with a salt of the derivative.

Examples of compounds of formula Π which are starting materials for carrying out process A may be those in which Y represents an alkenyl group = CH ₂ or a group of formula CH ₂ Z in which Z represents an easily cleavable atom or group such as a halogen atom, e.g. chloro or bromo, acyloxy, for example acetoxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy, further the group -bTR'RVX ', where R ⁵ , R ⁶ and R ⁷ , the same or different, denote lower alkyl, e.g. methyl, for example phenyl or arylalkyl, for example benzyl, or R ³ and R ⁶ form, with the nitrogen atom to which they are attached, a 5- to 6-membered ring, for example a pyrrolidine ring and X is an anion, for example a halide such as chloride, bromide or iodide of the formula -NR'R ⁶ , wherein R ⁵ and R ⁶ have the above meaning, for example, -N (CH3) i.

When Y is = CH 2, the process may be carried out in a suitable solvent such as water, esters such as ethyl acetate, ketones such as acetone or methyl isobutyl ketone, amides such as dimethylformamide, alcohols such as ethanol and ethers such as dioxane or tetrahydrofuran or mixtures of these solvents. The reaction temperature is, for example, between 20 and 100 ° C.

When Y is -CH 2 Z in which Z is halogen or acyloxy, the process can readily be carried out in a suitable solvent, for example an amide such as dimethylphonamide, an alcohol such as methanol or an industrial methylated alcohol or a haloalkane, e.g. dichloromethane at a temperature in the range of -10 to 150 ° C, for example 20 to 100 ° C.

The reaction of a compound of formula Π in which Y represents a group -CH 2 Z, in which Z represents a group -N ⁺ R ⁵ R ⁶ R ⁷ X 'can be easily carried out in a suitable

A solvent such as water, an amide such as dimethylformamide, a ketone such as acetone or an ether such as dioxane, the reaction temperature is in the range of 20 to 150 ° C.

The reaction using a compound of formula Π in which Y is a group -CH 2 Z, wherein Z is a group of formula -NR'R * can be easily carried out in a suitable solvent, for example water or an alcohol such as methanol or a mixture of these solvents at a temperature 20 to 150 ° C.

In another embodiment B, a compound of formula I can be obtained by oxidizing a compound of formula IV

wherein A represents a hydrogen atom or a hydroxyl group and R ¹ , R ² , R ³ and R ⁴ are as defined above, or a salt thereof or a protected derivative thereof.

The oxidation can be carried out using conventional procedures and the reagents and reaction conditions must be chosen such that the oxidation is preferably carried out using a mild oxidizing agent.

When a compound of formula IV wherein A is hydrogen is oxidized, suitable oxidizing agents include quinones in the presence of water, for example 2,3-dichloro-2,6-dicyano-1,4-benzoquinone or 2,3, 5,6-tetrachloro-1,4-benzoquinone, selenium dioxide or a tetravalent cationic oxidant such as cesium ammonium nitrate or a hexavalent chromium oxidizing agent, e.g. a solution of chromic acid in acetone, e.g. Jones reagent, or also use chromium trioxide in pyridine.

In the oxidation of a compound of formula IV in which A is a hydroxyl group, suitable oxidizing agents are, for example, quinones in the presence of water, such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3,5,6 tetrachloro-1,4-benzoquinone; ketones such as acetone, methyl ethyl ketone or cyclohexanone in the presence of a base such as aluminum tert-butoxide; a hexavalent chromium oxidizing agent such as a solution of chromic acid in acetone such as Jones reaction can be used a reagent or chromium trioxide in pyridine, further N-halosuccinimide, for example N-chlorosuccinimide or N-bromosuccinimide, dialkylsulfoxides, for example dimethylsulfoxide in the presence of an activating agent such as Ν, Ν'-dicyclohexylcarbodiimide or acyl chloride, as an allyl also a pyridine / sulfur trioxide complex or a dehydrogenation catalyst such as copper chromite, zinc oxide copper, copper or silver.

A suitable solvent is, for example, a ketone such as acetone or butanone, an ether such as tetrahydrofuran or dioxane, an amide such as dimethylformamide, an alcohol such as methanol, a hydrocarbon such as benzene or toluene, a halogenated hydrocarbon such as dichloromethane, water and mixtures of said solvents.

The procedure is usually carried out at a temperature of -70 to 50 ° C. Of course, the reaction temperature selected depends on the oxidizing agent used.

In a further process (C), a compound of formula (I), a salt thereof, or a protected derivative thereof may be converted to another compound of formula (I) using conventional procedures. Such a conventional procedure is, for example, alkylation which can be carried out at any position of a compound of formula I in which one or both of R @ 1 and R @ ² are hydrogen atoms. Another conventional procedure is hydrogenation, which can be used, for example, to convert an alkenyl substituent into an alkyl substituent. Alkylation in this case also includes the introduction of related groups, for example cycloalkyl or alkenyl. It is for example possible to convert a compound of formula I wherein R is H to the corresponding compound of formula I, wherein R ¹ is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkenyl of 3 to 6 carbon or phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety.

The above alkylation reaction may be carried out using an appropriate alkylating agent selected from compounds of formula R * X * wherein R * is C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 alkenyl. And X * represents a readily cleavable group such as a halide or acyloxy group as defined above for Y or may be a sulfate of formula (R'isO *).

The alkylation reaction can readily be carried out in an inert organic solvent, for example in an amide such as dimethylformane, in an ether such as tetrahydrofuran or in an aromatic hydrocarbon such as toluene, preferably in the presence of a base. Suitable bases include, for example, alkali metal hydrides such as sodium hydride, alkali metal amides such as sodium amide, alkali metal carbonates such as sodium carbonate or alkali metal alkoxides such as sodium or potassium methoxide or tert-butoxide. The reaction may be carried out at a temperature in the range of -20 to 100, preferably 0 to 50 ° C.

The hydrogenation of process C can be carried out using conventional procedures, for example by treatment with hydrogen in the presence of a noble metal catalyst such as palladium, Raney nickel, platinum, platinum oxide or rhodium. The catalyst can be used on a support, for example activated carbon, or a homogeneous catalyst, for example tris (triphenylphosphine) rhodium chloride, can be used. Hydrogenation is generally carried out in a solvent such as an alcohol such as ethanol, an amide such as dimethylformamide, an ether such as dioxane or an ester such as ethyl acetate at a temperature in the range of -20 to 100 ° C. preferably 0 to 50 ’C.

It will be appreciated that in carrying out the above transformations, it may be necessary or desirable to protect sensitive groups in the compound so as to avoid undesired side reactions. The protecting groups used in the preparation of the compounds of the formula I are preferably those which are readily cleavable at a suitable stage in the reaction system, usually in the last step. For example, it may be shown that during the reaction sequence it may be desirable to protect the keto group, for example in the form of a ketal or thioketal.

Thus, the compounds of formula (I) may be prepared by a further process (D) by removing any protecting groups from the protected form of the compound of formula (I). Removal of the protecting groups may be accomplished using conventional procedures as described, for example, in: Protective Groups in Organic Chemists, Ed. J. F. W. McOmie, Plenum Presa, 1973. For example, a ketal group such as an alkylene ketal group can be removed by treatment with an inorganic acid such as hydrochloric acid. The thioketal group can be cleaved by treatment with a mercuric salt, for example mercuric chloride, in a suitable solvent, for example ethanol.

The compounds of formula (I) may be converted into physiologically acceptable salts in a conventional manner. For example, it is possible to treat the free base of formula I with an appropriate acid, preferably an equivalent amount of the acid in a suitable solvent, for example aqueous ethanol.

Physiologically acceptable compounds of formula (I) may be prepared by conventional methods.

The individual enantiomers of the compounds of the invention may be obtained by resolving a mixture of enantiomers, for example a racemic mixture, in a conventional manner, for example using an optically active acid as described, for example, in Stereochemistry of Carbon Compounds, EL Eliel, McGraw Hill 1962 and Tables of Resolving Agents, SH Wilen.

Examples of optically active acids which can be used for such separation by forming a salt of these compounds with racemic compounds are the R and S forms of organic carboxylic and sulfonic acids such as tartaric acid, di-p-toluoyltartaric acid, acid camphorsulfonic acid and lactic acid. The mixture of isomeric salts thus obtained can then be separated from one another, for example, by traction crystallization to give the diastereoisomers, and then optionally converting the desired optical active isomer to the corresponding base.

The above processes for the preparation of the compounds of the invention can be used as a major final step in the preparation of these compounds. The same general procedures can be used to introduce the desired groups into the intermediate at any stage of the production of the desired substance, and it is understood that these general procedures can be combined in various ways in the form of a multi-stage process. However, the sequence of the reaction steps in the multistage process must be selected so that the reaction conditions used do not affect those groups in the molecule that are desired in the final product.

The starting materials of formula Π in which Y is = CH = may be prepared from compounds of formula Π in which Y is a group of the formula CHiN'R'R''R '' X ', wherein each symbol is as defined above, by reaction with a base in a suitable solvent. Examples of a suitable base are alkali metal hydroxides such as potassium hydroxide or alkali metal carbonates or bicarbonates such as sodium bicarbonate.

Quaternary salts can be formed from the corresponding tertiary amine by reaction with an alkylating agent, for example methyl iodide or dimethyl sulfate, preferably in a suitable solvent, for example dimethylformamide. The tertiary amine can be prepared by reacting the tetrahydrocarbazolone of formula V

wherein R ¹ is as defined above, with formaldehyde and the corresponding secondary amine, optionally in a suitable solvent, for example in an alcohol such as ethanol.

Compounds of formula V may be prepared, for example, by the method of H. Iida et al., J. Org. Chem., 1980, Vol. 45, no. 15, p. 2938 to 2942.

The starting materials of formula Π in which Y represents a -CH 2 Z group in which a halogen atom or an acyloxy group may be prepared from the corresponding hydroxymethyl derivative of formula VI

wherein R * is as defined above.

Said derivative may be obtained by reacting the tetrahydrocarbazolone of formula V with formaldehyde, preferably in a suitable solvent such as an alcohol, for example ethanol, and preferably in the presence of a base.

Compounds in which Z represents a halogen atom can be obtained by reacting a compound of formula VI with a halogenating agent, for example a phosphorus trihalide such as phosphorus trichloride.

Compounds in which Z is acyloxy may be prepared by reacting a compound of formula VI with an appropriate acylating agent, for example an acid anhydride or a sulfonyl halide, for example a sulfonyl chloride.

Compounds of formula H in which Y represents a group of formula -CH 2 Z where Z represents a halide atom may also be prepared by reacting a compound of formula Π in which Y represents = CH 3 with an appropriate halide, for example hydrogen chloride, usually in a suitable solvent, in ether, such as diethyl ethers.

Compounds of formula (IV) may be prepared by reacting a compound of formula (VII)

wherein R ¹ and A are as defined above and Z ¹ represents a readily displaceable atom or group such as halogen, acyloxy, or R ⁴ -N ^{5 EXAMPLE 7} R X ', in the meaning that has been previously defined for Z ^1, with an imidazole of the general formula H1 according to the method of the above procedure A.

Compounds of formula VH may be prepared by reacting compounds of formula Π, for example by treatment with lithium aluminum hydride or sodium borohydride.

Compounds of formula VH in which A is hydrogen may also be prepared by formation of a compound of formula VH

Reacts a compound of formula VII wherein A is a hydroxyl group and the other symbols are as defined above with tosyllialogenidoin, for example tosyl chloride, and the resulting tosylate is reduced with Utiumaluminium hydride.

The invention will be explained by the following examples in which temperatures are given in ´C. Where indicated, the solutions were dried with sodium sulfate, the solids were dried under vacuum with phosphorus pentoxide overnight at 50 ° C. Chromatography was performed by W. C. Still et al., J. Org. Chem., 1978, 43, 2923-2925, using Kieselgel 9385.

DETAILED DESCRIPTION OF THE INVENTION

Preparation 1

4-Oxo-N, 4, N-trimethyl-2,3,4,9-tetrahydro-1H-carbazol-3-ylmethylammonium iodide.

A solution of 0.53 g of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one in 15 ml of iodomethane was heated at reflux for 5 hours and then the mixture was evaporated. to dryness to give 0.84 g of the product as a white solid, mp 202-205 ° C.

Preparation 2 4-Oxo-N, 4 ' -N-tetramethyl-2,3,4,9-tetrahydrocarbazole-3-methylammonium iodide.

A suspension of 3.80 g of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one in 100 ml of iodomethane is heated at reflux for 57 hours. The resulting suspension was evaporated in vacuo to give 5.72 g of the resulting methylammonium iodide as a solid, mp 192-195 ° C.

Preparation

1.2.3.9-Tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one.

A solution of 5.0 g of the product of Preparation 2 in 20 ml of water is mixed with 6.55 ml of 2 N sodium carbonate solution and the mixture is heated at 35 ° C for 45 minutes. The resulting suspension is cooled to 0 ° C, the solid is filtered off, washed with water and then dried to give 2.8 g of the title product as a solid, mp 127-129 ° C.

Preparation 4

2.3.4.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazole maleate.

mg of sodium borohydride are added under stirring to a solution of 500 mg of the product of Example 7 in a mixture of 3 ml of methanol and 3 ml of chloroform under nitrogen. After stirring for 48 hours, 250 mg of sodium borohydride are added after 17.75 hours and 42 hours, then the suspension is partitioned between 15 ml of a 2 M hydrochloric acid solution and 3 x 10 ml of chloroform. The aqueous layer was basified by addition of solid sodium carbonate, extracted with 3 x 10 mL chloroform, the extracts were combined and washed with 2 x 10 mL water and 10 mL saturated aqueous sodium chloride solution, dried and evaporated in vacuo. 557 mg of a foam are obtained, which is chromatographed, eluting with dichloromethane / ethanol / 0.88% aqueous ammonia (300: 10: 1 by volume) to give a solid (200 mg). This material was dissolved in 3 ml of absolute ethanol under reflux and a solution of 80 mg of maleic acid in 1 ml of absolute ethanol was added under reflux. The hot solution is filtered, mixed and simultaneously diluted with 40 ml of anhydrous ether to give 240 mg of the product as a solid, m.p. 138.5-140 ° C.

Preparation

2.3.4.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazol-4-ol.

30.0 g of the product of Example 7 was added under nitrogen to a stirred suspension of 7.75 g of lithium aluminum hydride in 750 ml of anhydrous tetrahydrofuran. The mixture was refluxed for 1 hour and then cooled in ice. The resulting suspension was carefully diluted with 100 mL of 15% aqueous tetrahydrofuran solution and 100 mL of water, evaporated in vacuo and the resulting solid extracted with 2 x 500 mL of dichloromethane. The organic extracts were evaporated in vacuo to give a solid (16.4 g) which was chromatographed on a short silica column (500 g Kieselgel 60, Merck RTM 7747), eluting with dichloromethane / ethanol / 0.88%. aqueous ammonia (150: 10: 1 by volume) to give the title compound (13.4 g) as a foam. T.l.c. using silica and dichloromethane / ethanol / 0.88% ammonia (150: 10: 1). Rf = 0.34 and 0.36 (two pairs of diastereoisomers), detection with ultraviolet light and iodoplatinic acid.

NMR (CDCl 3 + CD 3 OD (1 drop)): 1.6-2.3 and 2.6 3.0 (5H, m), 2.32 and 2.40 (3H, s + s, Me in two different isomers ), 3.32 (3H, s, NMe), 3.65-4.3 (2H, m, CHCHiN), 4.75-4.85 (1H, m CH-OH), 6.8-7, Δ (CH, m, aromatic).

Example 1a

1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride.

A solution of 2.0 g of the product of Preparation 2 and 5.0 g of 2-methylimidazole in 30 ml of anhydrous dimethylformamide was stirred under nitrogen at 95 ° C for 16.75 hours and then allowed to cool. The crystallized solid was filtered, washed with ice-cold anhydrous dimethylphonamide (3 x 2 mL) and then 2 x 10 mL of anhydrous ether, then dried. 0.60 g of the resulting solid is obtained, which is suspended in a mixture of 30 ml of absolute ethanol and 1 ml of ethanolic hydrochloric acid solution and the mixture is gently warmed to obtain a solution which is then filtered while hot. The filtrate was then diluted with anhydrous ether to give 0.6 g of a solid which was recrystallized from absolute ethanol to give 0.27 g of the title compound as a solid, mp 186-187 ° C.

Analysis for C 18 H 19 N 3 O. HC1. H2O calculated C 62.3 H 6.1 N 12.1% found C 61.9 H 6.4 N 11.8%

In a manner similar to that of Example 1a, the resulting products can be obtained. Details of the composition of these products and their basic parameters are given in Table I below.

In Examples 1e, 1f and 1g, 2,3,4,9-tetrahydro-9-N, N, N-tetramethyl-4-oxo-1H-carbazole-3-methylammonium methanesulfate was used as starting material. C 'represents cyclohexyl.

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Table 1

Pr. no. vacrec X hnot: nness V. B. g intidazalu 9 Having> M roipáiťtd. D vol tWDt ”well pEcduk. g beat temperature molecular V30T6C analýza t R> R ^J R ³ R find C Measured H M calculating C H N lb C1I. II II II 2-00 4.in 50 IICL 0.70 1W.5- 200.5 ' ιι ε ,, ,, Ν, η. IICL. 0,011.0 62.05 5.5 12.7 61.n 5.9 12.7 lc II αι. CH, OJI 5 llaleutv 0.XI 151 * 152 ιι ε ,, ,, Ν, η. 11 ,, 11, 0, .0,211.0 64 .6 6.0 9.0 64.7 6.0 **. C ld CH, 1 l * y II II J.z 2.9 oo IICL 1.0 170- 162 ° ιι ε ,, ,, Ν, η. IICl.0.511,0 64.9 6.9 11.z 45.5 6.9 11:45 « 1 · II · It AIJN · II l.z J I, (C 1 -C 00:25 150-135 ' cn ii ₂₁ n _{j (} > IICl. 0.511.0) 69.1 6.1 9.9 69.5 6.1 10.1 • tr ite II II αι, ΐΊ> - 00:05 170-174 ° Ε ^ ΙΙ ,, Ν, η. 1.5 11, (1 7! .R 6.2 111.5 72.7 4.4 in.4 • 19 him C II J .11 1.6 M IICL 0.5 150-155® Ιι Γ ,,, ,, Η, η. IICL. 0,511.0 411.5 i.K 10.4 «0.4 7.15 W. «

Compounds 1e and 1f were prepared in the same experiment and their isomers separated on a short chromatography column according to the method of D. F. Taber, J. Org. Chem., 1982, 47, 1351, eluting with dichloromethane / ethanol / 0.88% 5 ammonia (30: 10: 1 by volume). The 1 H NMR values obtained for the compound of Example 1e, If and 1g are shown in the following table

R ³ d = doublet dd = doublet of doublets s = singlet solvent 1 H NMR spectrum - 250 MHz Selected proton shifts and multiple signals

Carbazolone protons imidazolyl imiduzolové aromatic aliphatic methylene protons H-5,6,7,8 CH ₂ -1 and protons H-2 'H-4'ale- CH ₂ -2, H-3 bo H-5 · lc d ₆ -DMSO 7.2 to 8.05 2.91-3.25 4.47 (dd) 1.75-2.3 4.64 (dd) and 9,20s 7,55s lf CDCl 3 + 7.15 to 8.05 2.6-3.05 4.02 (dd) and 8,17s 6,93s DMSO 1.75-2.1 4.63 (dd) 18 d ₆ -DMSO 7.2 to 8.05 among others- 4.42 (dd) and 7,61d ho 2.9-3.3 4.73 (dd) and 1.6-2,2 7,78d

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Example 2 »2,3,9-Tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4-6n-maleate.

300 g of 2,3,9-tetrahydro-9-methyl-3 - [(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one are suspended in 5 ml of hot ethanol and 116 ml of ethanol are added. mg of maleic acid. The solution was cooled and the crystallized white solid was filtered and dried to give 300 mg of the title compound, mp 132.3 ° C.

Example 3a

12,3,9-Tetrahydro-3- (1H-imidazol-1-ylmethyl) -4H-carbazol-4-one.

A solution of 0.84 g of the product of Preparation 1 and 0.90 g of imidazole in 25 ml of DMF is heated for 6 hours at room temperature.

105 ° C, then the mixture is cooled, poured into 200 ml of water and extracted six times with ethyl acetate. The extracts were combined, washed, dried and evaporated to give a solid, which was purified on a silica column 5 (Merck 7734), eluting with ethyl acetate / methanol (4: 1). After recrystallization twice from the mixture of ethyl acetate and methanol gave 0.095 g of the title compound as a crystalline solid, m.p. 220-222 ° C. T.l.c .: silica, dichloromethane / ethanol / 0.88% ammonia (100: 8: 1 by volume). Rf = 0.33, detection with ultraviolet light and iodoplatinic acid.

In a similar manner, the compounds 15 shown in Table Π can be prepared, the reaction conditions and the parameters of the resulting compounds are shown in the table. The salt formation was carried out as in Example 2.

Table 2

EX formula I wt. hmntn. volume reaction The weight. room R ¹ R ² R ³ R * in m wished. ruzp. Time / T shot productivity mp (B) imlda- (1) h / ’C • c anisole (g)

3b H ch ₃ H H 6.60 17,00 75 17.25 / 10U maleate 00:40 155-156 3c H ch ₂ ch ₃ H H 7.00 10.50 75 18/85 na 1eát 00:48 154.5 to 156 3d H CH ₂ Ph H H 3:00 3.10 25 24/100 zero 0.61 100.5 to 102 3e H 11 ch ₃ H 1.00 2.2 5 18/95 maleate 0.16 144-145.5 3f H H H ch ₃ 1.00 2.2 5 18/95 maleate 0 .09 143-144 3 g H r H H 1.80 1.0 20 20/100 HCl 0.11 142-146

NtlR spectrum, obtained at 250 MHz in D _Ŕ -DMSO Selected proton shifts and counting signals

Art. Aromatic carbazolones H-5,6,7,8 aliphatic CI1 _2-1 and _CH2 -2 H-3 inidazolylaetylén i zm dazu1 H2 ' H-4 ’and / or H-5’ 3b 7.1 to 8.05 3.0-3,25 4.29 (dd) a 7.57d and 7.67 1.9-2.2 4.69 (dd) 3c 7.15-8,05 3.0-3.25 4.32 (dd) a - 7.61d for 7.69d 1.9-2.2 4.72 (dd) 3d 7.15-8,05 2,85-3.1 4.28 (dd) a 7.59d and 7.71d 1.8-2.05 4.71 (dd) 3c 7,15-8.05 3.0-3.20 4.48 (dd) a 8,97s 7,46s 1.75-2.25 4.62 (dd) 3f 7.15 to 8.05 3.0 to 3.20 4.29 (dd) a 8,93s 7.41s 1.90-2.20 4.74 (dd) 38 7,1-8.0 2.9-3.2 6.32 (dd) a 7.75J at 7.83d 1.75 to 2.1 6.70 (dd)

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Notes on table Π:

Compounds 3e and 3f were prepared in the same experiment and the isomers were separated by preparative high pressure liquid chromatography using a Zorbax-Sil column, eluting with hexane: ethyl acetate / ethanol / 0.88% ammonia (400: 100): 100: 0.6.

In Table O, the positions of the protons are numbered along the positions indicated in the following general formula:

The symbols in the table Π have the following meanings: d = doublet dd = doublet of doublets s = singlet γ = means a group of formula 'Λ

Example 4 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl} methyl) -4H-carbazol-4-one.

A solution of 1.0 gl, 2,3,9-tetrahydro-3 - ((2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in 10 mL of anhydrous dimethylformamide was added dropwise under to a stirred, ice-cooled suspension of 0.11 g of sodium hydride in oil, the suspension is 80% and mixed with 5 ml of anhydrous dimethylformamide. After 0.5 10 hours, 0.34 ml of dimethyl sulphate is added and the solution is stirred for 4 hours. The resulting solid was filtered, washed with 2 x 5 ml of ice-cold anhydrous dimethylformamide and 3 x 15 ml of anhydrous ether and then dried to give 0.25 g of the title compound as a solid, m.p. 223 DEG-224 DEG C. with decomposition of Tlc: silica and a 93: 7 mixture of chloroform and methanol, Rf = 0.27 as detected by ultraviolet light and iodoplatinic acid, identical to that of Example 1a.

In a similar manner, the compounds listed in the following Table ΠΙ may be prepared using the appropriate alkylating agent together with the basic reaction conditions and product parameters.

Table 3

steep. alkylating agent R ² R ¹ R reaction time n sol product 9 melting point molecular formula analysis% found C H N calculated C B N 4b nn _and 5a " HIjCIIj II II II. 5 ILCI 0.1) 2) 1212 · „ ₂ , Ν _{> 0} . HCI .O.bMjtl 64.7 A.5 U ·· M.7 <.. «u. 4 ' □ i / **> N 11 4 IIaIoaI. n. n 14 5I3> · ^ "ΙΙ, / Ι / ΙCJW 69.15 5.5 ».5 69.) 5.6 n.6> U tl.SI. 1) 1, II II ¢ .5 Itolelll 0.67 15 »ITN · Γ ,, ΙΙ ,, Ν, ΙΙ.Γ .11,11, G. 5.) 5 G.l 9 65.25 5.95 9. » 4e HÄljUr Cllj H II 57) lial, i l i.uo 150- 15) .5 * ¢ ,, 0, / 1 /). 4:, 11, n. 0.1 5-45 0.55 «») if αι, (αι,), ι i. II II 7-25 ilsle.t 1-16 lili »· ¢ ,, 11,, 44,0.4:, 11.14, 67 0.7 6.9 67.6 6. »O.Q rhíoijJjiir ° ') II 11 5.75 llnlofct Π.Β4 95- 96.5 ' ^{H, O} , 11.211 / 1 69.5 5.9 0.I | 6.1 9.7 6.1 fl.l 4h 01, (01,), 11541, - / Yo 1, Cll, II II 4 5O · ^- CImoI * 11-14 > 0 -> 2 · .11.) 11 /) 66.7 7.Y 7.Y 66.6 7.0 II.H you x EijCiwídj -. ^ □ 1, II II μη. 40 »Γ. HCl 00:12 m in · C "II" clay / I.IIĽI. 1. IIIjH 65.B 7.v] «.) 6 '· .4 7.5 111.4

Note to table ΙΠ: d = doublet The proton positions in the table are numbered according to the following general formula: dd = doublet of doublets s = singlet

6 H NMR spectra at 250 MHz solvent Selected proton shifts and multiple signals

Carbazolone protons imidazolyl methylene protons and imidazole protons H-2'H-4'or H-5 ’ aromatic H-5.6.7.8 or fatal CH ₂ -1 and CH ₂ -2, H-3 4g d ₆ -DMS0 7,15-8.1 2.9- 3,2 1.9- 2,2 6.29 (dd) 6.68 (dd) 7,55d a 7,65d 4h d _Ŕ -DMSO 7.2-8 l 2.9-3.3 1.8-2.2 6.26 (dd) 6.65 (dd) 7.42d a 7,57d

Example 5

9-Cyclopentyl-1,2,3,9-tetrahydro-3- (2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one maleate.

A solution of 1.20 g, 2,3,9-tetrahydro-3 - [(2-methyl-1H-5-imidazol-1-yl) methyl] -4H-carbazol-4-one in 9 ml of anhydrous dimethylformamide is added to of a stirred, ice-cooled suspension of 0.14 g of 80% sodium hydride in oil in 2 ml of anhydrous dimethylformamide under nitrogen and the mixture is stirred for a further 1/4 hours. 0.51 ml of bromocyclopentane is then added and the stirred solution is heated to 100 ° C for 18.5 hours. The solution was then allowed to cool and partitioned between 100 mL of water and 3 x 70 mL of ethyl acetate. The organic extracts were combined, washed with 2 x 50 ml 2 N sodium carbonate, 2 x 50 ml water and 50 ml 15 saturated aqueous sodium chloride solution, then dried, evaporated to dryness and purified by chromatography, eluting with dichloromethane / ethanol. and 0.88% ammonia in a 150: 10: 1 by volume ratio to give 0.27 g of an oil. This oil is dissolved in 7 ml of ethanol at reflux and a solution of 0.10 g of maleic acid in 0.5 ml of boiling absolute ethanol is added at the same temperature at reflux. The hot solution is filtered and diluted with 20 ml of anhydrous ethyl ether with stirring. The resulting yellow gum was washed with 7 x 25 with 25 mL of anhydrous ether and the mother liquors and wash was allowed to stand. The crystallized solid is filtered, washed with 3 x 5 ml of anhydrous ether and then dried to give 0.058 g of the product as a white crystalline solid, m.p. 104.5-306 ° C.

Analysis for C22H25N3O. C4H4O4. 0.6 H2O calculated C 65.8 H 6.4 N 8.9% found C 65.95 H 6.4 N 8.6%

Example 6 1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9- (2-propenyl) -4H-carbazol-4-one maleate.

A solution of 1.0 g of 12,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazolin-1-one in 6 ml of anhydrous 40-dimethylformamide was added to a stirred, ice-cooled mixture. a suspension of 0.12 g of sodium hydride as an 80% suspension in oil in 2 ml of anhydrous dimethylformamide. After 1/4 hour allyl bromide was added, the solution was stirred at 0 ° C for a further 1/4 hour and then for 20 hours at room temperature, then partitioned between 75 mL water and 3 x 50 mL ethyl acetate. The organic extracts were combined, washed with 2 x 50 mL water, 50 mL saturated aqueous sodium chloride solution, then dried and evaporated in vacuo and the residue purified by chromatography using a mixture of dichloromethane, ethanol and 0.88% aqueous ammonia in elution. 200: 10: 1 by volume to give 0.43 g of a solid. This solid is dissolved in 2 ml of absolute ethanol at reflux and a solution of 0.18 g of maleic acid in 1 ml of absolute ethanol is added at the same temperature under reflux. The hot solution is filtered, diluted with 4 ml of anhydrous ether and the crystallized solid is filtered, washed with 3 x 5 ml of anhydrous ether and then dried to give 0.48 g of the title product as a white solid, m.p. 150.5. up to 151 ° C.

Analysis for C20H21N3O. C4H4O4 calculated C 662 H 5.8 N 9.65% found C 66.3 H 5.75 N 9.6%

Example 7

12.3.9- Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazole-

yl) methyl) -4H-carbazol-4-one

A solution of 1.7 g of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride in 17 ml of water is mixed with 1.4 g of 2-methylimidazole and the mixture was heated under reflux for 20 hours. After cooling, the mixture was filtered and the solid was washed with water (3 x 15 mL) to give 1.7 g of crude product, mp 221-221.5 ° C. This material was recrystallized from methanol to give 1.4 g of the title compound, m.p. 231-232 ° C, according to t.l.c. the product is identical to the product of Example 4.

Example

1.2.3.9-Tetrahydro-9-methyl - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one.

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A suspension of 0.5 g of the product of Preparation 3 and 0.4 g of 2-methylimidazole in 5 ml of water was heated at reflux for 20 hours. The cooled reaction mixture is filtered and the solid is washed with 3 x 10 ml of water, dried and recrystallized from 18 ml of methanol to give 0.3 g of the product, m.p. 232-234 ° C dec. the product is identical to the product of Example 4.

Example 9, 2,3,9-Tetrahydro-9- (1-methylethyl) -3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride.

0.208 g of sodium hydride as an 80% dispersion in oil is added to a stirred solution of 1.93 g of 1,2,3,9-tetrahydro-3 - ((2-methyl-1H-imidazol-1-yl) methyl] - 4H-carbazol-4-one at 0 ° C in 35 ml of dimethylformamide and the resulting suspension is stirred for an additional 14 hours at 0 ° C. Then 0.78 ml of 2-bromopropane is added and the mixture is stirred at room temperature overnight. then 4 hours at 40 ° C.

The reaction mixture was then partitioned between 200 mL of 2 N sodium carbonate and 2 x 150 mL of ethyl acetate. The organic extracts were combined, washed with water (3 x 75 mL), dried and evaporated in vacuo and the product purified by chromatography eluting with dichloromethane: ethanol: ammonia (100: 8: 1) to give an oil. This oil was dissolved in 3 mL of ethanol, acidified with ethereal HCl and diluted with anhydrous ether to give the title product as a white solid (0.13 g), mp 230-232 ° C. Analysis for C 10 H 11 N 3 O. Calculated for C 65.3 H 6.6 N 11.1%

Example 10

1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate.

18.3 gl, 2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in a hot mixture of 90 ml of isopropanol and 18.3 ml of water are mixed with 6.25 ml of concentrated hydrochloric acid. The hot mixture is filtered, the filtrate is diluted with 90 ml of isopropanol and then stirred at room temperature for 17 hours, then cooled to 2 ° C and the solid is filtered. 21.6 g of crude product are obtained. A sample of 6 g was recrystallized from a mixture of 6 ml of water and 10 ml of isopropanol to give 6 g of the title product as a white crystalline solid, m.p. 178.5-179.5 ° C. Analysis for C19H18N2O. Calculated for C 59.45 H 6.45 N 11.5%

Water content: calculated 9.85%, found 10.23%.

Example 11

1,2.3.9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9-phenyl-4H-carbazol-4-one maleate.

i) 3- | (Dimethylamino) methyl | -1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one hydrochloride

A solution of 3.90 g, 2,3.9-tetrahydio-9-phenyl-4H-carbazol-4-one, 1.50 g of dimethylamine hydrochloride and 0.60 g of paraformaldehyde in glacial acetic acid was stirred at reflux for 42 hours. The mixture was allowed to cool and evaporated in vacuo. The brown gum obtained is mixed with 50 ml of water, then with 50 ml of ethyl acetate and finally stirred for 1/4 hour with 20 ml of saturated sodium chloride solution, the resulting mixture is filtered, washed with 4 x 30 ml of anhydrous ethyl ether and dried. 4.2 g of the title compound. 1.0 g of this product is recrystallized twice from 10 ml of absolute ethanol to give 0.39 g of the product as an off-colored solid, mp 193-194 ° C with decomposition.

ii) 1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9-phenyl-4H-carbazol-4-one maleate

1.4 g of 2-methyl-1H-imidazole was added to a stirred suspension of 2.0 g of 3 - [(dimethylamino) methyl] -1,3,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one hydrochloride in 20 ml of water. The mixture is heated at 90 ° C for 43 hours and then the solvent is decanted. The mixture is filtered and the suspension is filtered through Hyflo (RTM), the filtrate is dried and then evaporated in vacuo. 2.04 g of an off-colored foamed product is obtained which is purified by chromatography, eluting with dichloromethane: ethanol: 0.88% aqueous ammonia (200: 10: 1 by volume) to give 1.1 g of a white foam. . To a solution of this foam in 3 mL of ethanol was added a solution of 0.4 g of maleic acid in 1 mL of ethanol and then 40 mL of anhydrous ethyl acetate, and the resulting gummy product was triturated with 2 x 40 mL of anhydrous ethyl ether to give 1.37 g of product. 165-166 ° C with decomposition.

Analysis for C23H21N3O. C4H4O4 calculated C 68.8 H 5.3 N 8.9% found C 68.65 H 5.5 N 8.7%

Example 12

1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one phosphate (1: 1).

Dissolve 0,61 gl, 2,3,9-tetrahydro-9-methyl-3- | (2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in a hot mixture of 0,13 ml 90% phosphoric acid and 10 ml of water, the mixture is filtered through Hyflo and allowed to crystallize to give 0.5 g of the title product, mp 225 ° C.

Analysis for C 18 H 19 N 3 O. H3PO4 calculated C 55.2 H 5.7 N 10.7% found C 55.1 H 5.6 N 10.55%

Example 13

1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one citrate (2: 1).

0,89 gl, 2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one is dissolved in hot solution 0, 58 g of citric acid in 20 ml of ethanol are allowed to crystallize. The resulting crystalline solid was recrystallized by dissolving in 2 mL of 2: 1 acetone / water followed by dilution with 20 mL of acetone to give 0.6 g of the product as a solid, mp 162 ° C.

Example 14

1.2.3.9-Tetrahydro-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride.

0.75 ml of iodomethane is added to a stirred solution of 2.9 g of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one in 30 ml of anhydrous dimethylformamide and the solution is stirred for 30 minutes. minutes at room temperature. A solution of 2 g of 2-propyl-1H-imidazole in 5 ml of dimethylformamide is then added and the solution is stirred at 100 ° C for 2 days, then cooled and partitioned between 150 ml of 2 N sodium carbonate and 2 x 100 ml of ethyl acetate. The organic extracts are combined, washed with 100 ml of water, dried and dried

2776 evaporate in vacuo. The residue was purified by column chromatography eluting with dichloromethane: ethanol: ammonia (400: 30: 3, v / v) to give 1 g of the first free base. Dissolve 0.2 g of this base in 5 ml of absolute ethanol, acidify with ethereal hydrochloric acid and then dilute with approximately 200 ml of anhydrous ether to obtain an oil which crystallizes to give 0.15 g of a solid. The salt was crystallized from a mixture of methanol and isopropyl acetate to give 0.08 g of product, m.p. 206-208 ° C.

Analysis for C 11 H 11 N 10 O. HC1.0,2 _H2O Requires C 65.7 H 6.5 N 12.1% Found C 65.6 H 6.8 N 12.0% NMR (CD3SOCF3): 0.94 (3H, t, CH ₃ ), 1.77 (2H, sextet, CH2CH3CH3), 1.9-2.15 and 2.95-3.2 (7H, m), 4.32 and 4.71 (2H, ABX, CHCH2N), 7.1-8.0 (6H, aromatic).

Example 15

1.2.3.9-Tetrahydro-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride.

A solution of 0.03 g of the product of Example 3g in 15 ml of ethanol is hydrogenated at room temperature at atmospheric pressure using 0.3 g of 10% palladium on charcoal as a 50% water paste for 4 hours for a total hydrogen uptake of 5 ml. . Then the catalyst is filtered and the filtrate is evaporated in vacuo to an oil. Trituration with ether gave the title compound as a white solid (0.03 g), m.p. 199-203 ° C.

Pri t.l.c. and NMR spectra are identical to those of Example 14.

Example 16

1,2.3.9-Tetrahydro-9-propyl-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-ol hydrochloride.

An 80% sodium hydride dispersion in oil was added to a stirred solution of 1.0 g of the product of Example 14 in 20 mL of anhydrous dimethylformamide under nitrogen, and the resulting suspension was stirred at room temperature for 30 minutes. 0.35 ml of 1-bromopropane is then added and the solution is stirred at 40 ° C for 20 hours. The solution was then partitioned between 150 mL 2 N sodium carbonate and 2 x 100 mL ethyl acetate. The organic extracts are combined, washed with 100 ml of water, dried and evaporated in vacuo to an oil which is purified by chromatography using a 10: 8: 1 mixture of dichloromethane, ethanol and ammonia to give the pure free base. in the form of an oil. This oil was dissolved in 5 mL of absolute ethanol, acidified with ethereal hydrogen chloride solution and then diluted with 200 mL of anhydrous ethyl ether. The ether was decanted from the remaining oil and replaced with an additional portion of 200 mL of ether. The mixture was allowed to stand overnight at 0 ° C to crystallize the oil to give 0.53 g of product, mp 144-147 ° C.

NMR (CDCl 3 SOCD 3): 0.90 and 0.93 (6H, t + t, 2 × Me), 1.65-2a and 2.9-3.25 (10H, m), 4.19 (2H, t CH ₂ CH ₂ N), 4.32 and 4.71 (2H, ABX, CH ₂ CH ₂ N), 7.15-8.1 (6H, m, aromatic).

Analysis for C22H27N3O. HCI. 0.7 H2O calculated C 66.3 H 7.4 N 10.5% found C 66.6 H 7.7 N 10.0%

Example 17 ia, 3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9-propyl-4H-carbazol-4-one maleate.

A solution of 0.86 g of the product of Example 6 from a mixture of 20 ml of absolute ethanol and 5 ml of anhydrous dimethylformate was hydrogenated at room temperature at atmospheric pressure using 0.1 g of pre-reduced 5% platinum on activated carbon in 10% absolute ethanol. hour, hydrogen uptake is 70 ml. The catalyst is filtered, washed with ethanol and the filtrate evaporated in vacuo to a volume of approximately 15 ml. The solution obtained is diluted with stirring with 50 ml of water, the precipitate formed is filtered, washed with 3 x 15 ml of water and then dried to give 0.73 g of a powdered material.

This material was dissolved at reflux in 7 ml of absolute ethanol, filtered and a solution of 0.25 g of maleic acid in 1 ml of boiling absolute ethanol was added to the filtrate. The stirred solution is diluted with 50 ml of anhydrous ether to give 0.84 g of product, m.p. 150-151 ° C.

Analysis for C20H23N3O. C4H4O4 calculated C 65.9 H 6.2 N 9.6% found C 65.8 H 6.1 N 9.3%

Example 18 ia.3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one.

i) 3- (Chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one

3.0 ml of ethereal hydrogen chloride solution is added to a stirred, ice-cooled solution of 1.90 g of the product of Preparation 3 in 15 ml of chloroform, and the resulting suspension is stirred in a sealed vessel at room temperature for 16.5 hours, then evaporated in vacuo. 2.27 g of the solid obtained are purified by column chromatography using chloroform as eluent to give 1.75 g of the product, m.p. 109-110.5 ° C. An attempt to crystallize part of this material from ethyl acetate resulted in its decomposition.

ii) 1α, 3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

A solution of 0.50 g of 5- (chloromethyl) -ia, 3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 1.60 g of 2-methyl-1H-imidazole in anhydrous dimethylformamide is stirred with 3.75 The mixture is poured into 25 ml of water. The suspension is stirred for 1 hour, then the solid is filtered off, washed with 3 x 20 ml of water and dried under vacuum at 50 ° C. 0.53 g of the obtained solid is chromatographed on a column using dichloromethane / ethanol / 0.88% aqueous ammonia (150: 10: 1) to give 0.45 g of the product, m.p. 228-229 ° C. pri tl.c. and NMR spectra are identical to the product of Example 7.

Example 19 a> 3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one.

A solution of 170 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 1.5 ml of anhydrous tetrahydrofuran was added dropwise under nitrogen in a stirred, ice-cooled suspension of 100 mg of the product of Preparation 4 in a mixture of 3.5. ml of tetrahydrofuran and 0.4 ml of water. The resulting blue solution was stirred for a further 1.5 hours, then evaporated in vacuo. The solid obtained is chromatographed on a column using dichloromethane / ethanol / 0.88% aqueous ammonia (150: 10: 1) to give 45 mg of the product, m.p. 227-228.5 ° C. According t.l.c. and NMR spectra are identical to those of Example 7.

SK 277923 Β6

Example 20

1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one.

A solution of 80 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 1.5 ml of anhydrous tetrahydrofuran was added dropwise under nitrogen to a stirred, ice-cooled suspension of the product of Preparation 5 (100 mg) in mixture 3. , 5 ml of tetrahydrofuran and 0.4 ml of water. The resulting blue solution was stirred for 1.5 hours and then the red suspension was evaporated in vacuo.

The solid thus obtained is chromatographed on a column using dichloromethane / ethanol / 0.88% ammonia (150: 10: 1 by volume) to give 0.47 g of the product as a white solid, m.p. 5 to 229 ° C. According t.l.c. and NMR spectra are identical to those of Example 7.

Example 21 3S-1,2,3,9-Tetrahydro-3- [(2-methylimidazol-1-yl) methyl] -9-methyl-4H-carbazol-4-oleateeate.

A solution of 0.5 g of the product of Example 7 in 30 ml of hot methanol is treated with a hot solution of 0.7 g of (+) - di-p-toluoyl-D-tartaric acid monohydrate in 10 ml of methanol and the resulting solution is left to crystallize overnight. 0.68 g of the desired salt is obtained. This salt is dissolved in 20 ml of hot dimethylformamide, the solution is diluted with 10 ml of hot water and the product is left to crystallize overnight. The product is then filtered and dried under vacuum to give 0.23 g of (+) - di-p-toluoyl-D-tartrate, mp 231-233 ° C. As can be shown by NMR, it is an enantiomer, the purity is about 90%. A 0.15 g sample of this salt was partitioned between 25 mL of 8% sodium bicarbonate and 2 x 25 mL of chloroform. The organic extracts were combined and evaporated in vacuo to give 0.07 g of pure free base. This base was dissolved in 5 mL of methanol, acidified with 0.03 g of maleic acid, and the addition of an excess of 80 mL of anhydrous ethyl ether precipitated the salt to give 0.062 g of the title maleate, m.p. 142-145 ° C.

Tlc using silica and dichloromethane / ethanol / 0.88% ammonia (100: 8: 1 by volume). Rf = 0.3, detected with iodoplatinic acid and ultraviolet light to demonstrate that the product is identical to the product of Example 7. The ratio of enantiomers determined by Ή-NMR was 93: 7 (S: R). The maleate sample had no significant optical rotation in methanol. The free base, regenerated from the maleate salt, had an optical rotation of [alpha] _D- 14 (R), c = 0.19, methanol.

Example 22

3R-1,2,3,9-Tetrahydro-3 - [(2-methylimidazol-1-yl) methyl] -9-methyl-4H-carbazol-4-one maleate

A solution of 0.5 g of the product of Example 7 in 30 ml of hot methanol is treated with a hot solution of 0.7 g of (-) - di-p-toluoyl-1-tartaric acid monohydrate in 10 ml of methanol and the resulting solution is left to crystallize. overnight to give 0.8 g of the desired salt. This salt is dissolved in 20 ml of hot dimethylformamide, the solution is diluted with 10 ml of hot water and the product is left to crystallize for 3 days. The product is then filtered off and dried under vacuum to show 0.26 g of (-) - di-p-toluoyl-D-tartrate, m.p. 170-172 ° C, and a purity of approximately 95 g. 15%. A 0.2 g sample of this salt was partitioned between 25 mL of 8% sodium bicarbonate and 2 x 25 mL of chloroform. The organic extracts were combined and evaporated in vacuo to give 0.12 g of pure free base. This base was dissolved in 5 mL of methanol, acidified with 0.045 g of 20 maleic acid, and the addition of an excess of 80 mL of anhydrous ethyl ether precipitated the salt to give 0.08 g of the title product, m.p. 142-145 ° C.

Tlc using silica and dichloromethane / ethanol / 0.88% ammonia (25: 100: 8: 1, Rf = 0.3). Detection with iodoplatinic acid and ultraviolet light showed that the product was identical to the product of Example 7. The ratio of enantiomers determined by 1 H-NMR was 95: 5. The maleate sample had no significant optical rotation in methanol. The free base, regenerated from the maleate salt, had an optical rotation [alpha _D + 16 ®, c = 0.34, methanol.

The following examples describe pharmaceutical pros35 formulations according to the invention containing 1,2,3,9-tetrahydro-9-methyl-3 - [(2-ethylimidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate as active ingredient 1.25 g of dichloride dihydrate contains 1.00 g of the free base. Other compounds of the invention may be formulated in a similar manner to form pharmaceutical compositions.

Tablets for oral administration

Tablets may be prepared by conventional methods, for example by direct compression or wet granulation.

The tablets may be coated with a suitable material, for example hydroxypropylmethylcellulose, using conventional methods. Otherwise, the tablets may also be sugar coated.

Direct pressing.

* In a form suitable for direct compression.

ingredient active ingredient mg / tablet

4.688 28.125 calcium hydrngene phosphate BP ^X

83.06 87.75 Croscarmeilose NF sodium salt

1,8 magnesium stearate BP

0.45 0.45 compression weight

90.0 118.0

SK 277923 Β6

The active ingredient is passed through a 60 mesh sieve, mixed with calcium hydrogen phosphate, Croscarmellose sodium and magnesium stearate. The resulting mixture is compressed into tablets using a conventional tabletting machine (Manesty, RTM F3), the machine has a punch with a diameter of 5.5 mm, being flat tablets.

Sublingual tablets.

component mg / tablet active ingredient

2.5

pressed sugar NF magnesium stearate BP weight on pressing 62.5 0.5 65.0

The active ingredient is passed through a suitable screen, mixed with the auxiliary components and pressed using a suitable device. Tablets with a different content of active ingredient may be obtained by varying the ratio of active ingredient and excipients or by changing the compression weight and using a suitable device.

Wet granulation.

Ordinary tablet.

mg / tablet component

active ingredient 2.5 lactose BP 151.5 starch BP 30.0 pregelatinized corn starch BP magnesium stearate BP weight on compression 15.0 1.5 200.0

The active ingredient is passed through a suitable screen and mixed with lactose, starch and pregelatinized corn starch. A suitable volume of purified water is added and the powder mixture is granulated. After drying, the granulate aiova is sieved and mixed with magnesium stearate. The resulting granulate is compressed into tablets having a diameter of 7 mm.

Tablets with a different content of active ingredient can be prepared by varying the ratio of active ingredient to lacquer weight or compression weight and using the appropriate equipment.

Tablet to be placed under the tongue.

ingredient mg / tablet active ingredient 2.5 mannitol BP 56.5 hydroxypropylmethylcellulose 5.0 magnesium stearate BP 1.5 compression weight 65.5

The active ingredient is passed through a suitable sieve and mixed with mannitol and hydroxypropyl methylcellulose. A suitable volume of purified water is added and the powder mixture is granulated. After drying, the granulate is passed through a sieve and processed into tablets of suitable diameter.

Tablets with a different content of active ingredient may be prepared by varying the ratio of active ingredient 15 to mannitol, or by adjusting the compression weight and the tablet diameter.

SK 277923 Β6

Capsule.

* In the form of directly compressible starch.

ingredient mg / capsfa active ingredient 2,5 starch 1500 * 97,0 magnesium stearate BP 1,0 weight at compression 100,0

The active ingredient is passed through a sieve and mixed with excipients. The mixture is filled into hard gelatin capsules *. 2 using a suitable device. Capsules, obSirup.

The syrup may be made with or without sucrose. A. A sucrose syrup containing a different dose of the active ingredient may be prepared by varying the weight of the filling and, if necessary, using a different capsule size.

z Iožka mg / 5 ml active ingredient sucrose BP glycerol BP buffer flavoring coloring agent preservative purified water BP

2.5 2750.0 500.0 «

up to 5.0 ml as needed

The active ingredient, buffer, flavoring, coloring and preservative are dissolved in a small amount of water 5 and glycerol is added. The remainder of the water is heated to dissolve the sucrose and then the solution is cooled. Combine both solutions, adjust volume and mix. The syrup is then filtered.

B. Sucrose-free syrup ingredient mg / 5 ml active ingredient

2,5 hydroxypropyl methylcellulose Iose viscosity type 4000 buffer flavor coloring agent preservative sweetener purified water BP

USP

22.5 as needed to 5.0 ml

The hydroxypropylcellulose is dispersed in hot water, the dispersion is cooled, and then the active ingredient as well as the other ingredients of the formulation are added. The volume is then made up, the mixture is stirred and the resulting syrup is filtered.

SK 277923 Β6

Solution for injection

Injectable solutions may be administered by intravenous or subcutaneous routes.

component gg / ml active ingredient

800 dilute hydrochloric acid BP to pH 3,5 sodium chloride solution BP to 1 m

The active substance is dissolved in a suitable volume of sodium chloride BP solution for injection, then the pH of the solution is adjusted to 3.5 with dilute hydrochloric acid BP, the solution is made up to volume with sodium chloride solution BP and thoroughly

Aerosol in a pressure vessel with a volumetric valve.

mixed. The solution is then filled into 5 ml clear glass type 1 ampoules and the ampoules are sealed while leaving some air above the solution, and then the ampoules are autoclaved for at least 15 minutes at 5 ° C 120.

ingredient mg / dose content in the package

micronized active substance 0,250 66 mg oleic acid BP 0,020 5.28 mg Trichlorofluoromethane BP 23.64 5.67 8 dichlorodifluoromethane BP 61,25 14.70 8

The active ingredient is micronized into a very small particle in a high energy mill. The oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 and the micronized active ingredient is mixed into the resulting solution in a high shear mixer. The suspension is then metered into aluminum aerosol cans and fitted with suitable metering valves to release 85 mg of the suspension per actuation. Dichlorodifluoromethane is then filled into the vessels under pressure.

Aerosol in the form of a solution.

z Beds mg / dose content in the package

active substance 0,250 30.0 mg ethanol BP 7,500 1,80 g Trichlorofluoromethane BP 18,875 4,35 g dichlorodifluoromethane BP 48,525 11,65 g

It is also possible to add oleic acid BP together with a suitable wetting agent, for example sorbitan trioleate, Span 85 (RTM).

The active ingredient is dissolved in ethanol together with oleic acid and a wetting agent when oleic acid is also used. The resulting alcohol solution is then metered into suitable containers, then trichlorofluoromethane is added. Appropriate metering valves are then fitted to the vessels and dichlorodifluoromethane is pressurized into the vessels under pressure.

Packaging for inhalation.

ingredient tng / package active substance (micronized)

0.5 lactose BP up to 25.00

SK 277923 Β6

The active ingredient is micronized in a high energy mill to very fine particles and then mixed in a high energy mixer with a conventional type of lactose to make tablets. The powder mixture obtained is then filled into a capsule no. 3 of hard gelatin. The contents of these packages are then administered using a powder inhaler device.

Claims (16)

1. 3-ylmethyl-l, 2,3,9-tetrahydro-4H-carbazol-4-one derivatives of the formula I, wherein R ¹ is H, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkenyl of 3 to 6 carbon atoms, phenyl or phenylalkyl of 1 to 3 carbon atoms in the alkyl moiety, one of R ² , R ³ and R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 atoms carbon, alkenyl of 2 to 6 carbon atoms or phenylalkyl of 1 to 3 carbon atoms and the other symbols, the same or different, mean a hydrogen atom or a alkyl of 1 to 6 carbon atoms, as well as physiologically acceptable salts thereof and solvates Derivatives according to claim 1, in which R ¹ represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, a cycloalkyl or an alkenyl of 3 to 6 carbon atoms. Compounds of formula I according to claim 1 or 2, in which one of R ² , R ³ and R ⁴ is alkyl of 1 to 3 carbon atoms or cycloalkyl or alkenyl of 3 to 6 carbon atoms and the other of these, which may be the same or different represent a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms. 4. A compound of formula I according to claim 1, wherein R is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 5-6 carbon atoms or alkenyl having 3 to 4 carbon atoms and either R ² is H, and R ³ and / or R ⁴ are alkyl of 1 to 3 carbon atoms or R ² is alkyl of 1 to 3 carbon atoms and R ³ and R ⁴ are hydrogen atoms. 5. Compounds of formula (Ia) according to claim 1 wherein R @ 1 is hydrogen, methyl, ethyl, propyl, 2-propyl, 2-propenyl or cyclopentyl. R ⁴ represents a hydrogen atom and either R ²¹ represents methyl, ethyl, propyl or 2-propyl and R ⁴ * represents a hydrogen atom or R ² * represents a hydrogen atom and R * represents methyl or ethyl, and salts thereof, acceptable from physiological and solvates thereof. 6. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one and its salts, acceptable from physiologically and solvates. 7. N, 3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in the form of its hydrochloride. 8. 1, 3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate. 9. 1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9- (2-propenyl) -4H-carbazol-4-one, 9- cyclopentyl-1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one α1,3,9-tetrahydro-3- [(2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazol-4-one, as well as physiologically acceptable salts thereof, and solvates thereof. A process for the preparation of 3-imidazolylmethyl-1,2,3,9-tetrahydro-4H-carbazol-4-one derivatives of the general formula I according to claim 1 or a physiologically acceptable salt thereof or solvates thereof, characterized in that the binders are: A) reacting a compound of formula Π wherein R ¹ is as defined in claim 1 and Y is a reactive group, or a protected derivative thereof, with an imidazole of formula m wherein R ² , R ³ and R ⁴ are as defined in of claim 1 or a salt thereof; B) oxidizes a compound of formula IV wherein A is a hydrogen atom or a hydroxyl group and R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 or a salt thereof or a protected derivative thereof; C) converting a compound of formula I or a salt thereof or a protected derivative thereof into another compound of formula I, or D) removes the protecting group or groups from the protected form of a compound of formula I, and if the compound of formula I is obtained in the form of a mixture of enantiomers, this mixture is optionally separated into the desired enantiomers and / or is obtained in the form of the free base, which base is optionally converted into a salt. 11. A process according to claim 10, wherein the starting material is a compound of formula Π in which Y is alkenyl = Cl12 or of formula -CH2Z wherein Z is an easily cleavable atom Or a group and R ¹ is as defined in claim 10. 12. A process according to claim 10C, wherein the compound of formula I or a salt thereof or a protected derivative thereof is converted to another compound of formula I by alkylation or hydrogenation. 13. A pharmaceutical composition having 5HT-receptor antagonist activity, which comprises at least one physiologically acceptable derivative of the formula I according to claim 1 or a salt thereof, or a solvate thereof together with at least one physiologically acceptable carrier. or at least one excipient. 14. A pharmaceutical composition according to claim 13 which comprises, as an active ingredient, 2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazole-1-yl) -benzylamine]. yl) methyl] -4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof together with at least one physiologically acceptable carrier or excipient. 20 Pharmaceutical composition according to claim 13, characterized in that it contains 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl hydrochloride as the active ingredient. 1 H-carbazol-4-one together with at least one physiologically acceptable carrier 25 or excipient. Pharmaceutical composition according to claim 13, characterized in that 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] - hydrochloride dihydrate is used as the active ingredient. 4H-carbazol-4-one together with at least one physiologically acceptable carrier or excipient.