HU193592B - Process for producing tetrahydro-carbazolone derivatives - Google Patents

Abstract

Compounds of formula (I). <IMAGE> [wherein R<1> is hydrogen C1-10 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, phenyl or phenyl-C1-3alkyl, and one of the groups represented by R<2>, R<3> and R<4> is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl-C1-3alkyl and each of the other two groups, which may be the same or different, is hydrogen or C1-6alkyl; and physiologically acceptable salts and solvates, e.g. hydrates, thereof] are potent selective antagonists at "neuronal" 5-hydroxytryptamine receptors and are useful in the treatment of migraine and psychotic disorders such as schizophrenia.

Description

The present invention relates to pharmaceutical compositions containing heterocyclic compounds and to novel compounds.

More particularly, the present invention relates to compounds that act on 5-hydroxytryptamine (5-HT) receptors.

5-HT, which is found in large amounts within the body in the peripheral nerves and platelets, causes pain in humans through its action on 5-HT receptors on afferent nerve endings. Compounds that antagonize the neuronal effects of 5-HT have been shown to have analgesic effects such as migraine pain.

By the same action of 5-HT receptor, 5-HT causes depolarization of isolated rat skeletal preparation; however, inhibition of this effect is related to the in vivo analgesic effect.

5-HT occurs at several sites in the central nervous system, and abnormalities in 5-HT-containing pathways alter behavioral states such as mood, psychomotor activity, appetite, and memory. Because so-called neuronal 5-HT receptors in primary afferent terminals are of the same type as those in the central nervous system, it is believed that compounds that antagonize the neuronal effects of 5-HT may be useful in other conditions such as schizophrenia, obesity, anxiety and mania. conditions.

Known treatments for these conditions are disadvantageous for a number of reasons. For example, ergotamine vasoconstrictor used to treat migraine is known to be non-selective and causes vasoconstriction throughout the body, thus ergotamine has unwanted and potentially dangerous side effects. Migraine is further treated in combination with an analgesic such as aspirin or paracetamol, usually an antiemetic such as metaclopramide, but this treatment is of limited value.

Serious side effects, such as extrapyramidal effects, are expected when using known treatments for psychotic disorders such as schizophrenia.

Thus, there is a need for a safe and effective drug for the treatment of conditions resulting from disorders of the 5-HT-containing pathways, such as migraine or psychotic conditions such as schizophrenia. It is believed that a compound which is a significant and selective antagonist of neuronal 5-HT receptors also fulfills the above requirements.

It has been found that a certain group of compounds of 3-imidazolylmethyl-tetrahydro-carbazolone derivatives are significant and selective antagonists of the neuronal 5-HT receptors.

More particularly, the present invention relates to the preparation of tetrahydro-carbazolone derivatives of general formula (I) wherein:

R ¹ is hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, phenyl or phenyl (C 1 -C 3) alkyl,

One of R ² , R ³ and R ⁴ is hydrogen or C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl or phenyl (C 1-3) alkyl; and the other two groups, which may be the same or different, represent a hydrogen atom or a C 1-6 alkyl group.

The invention also relates to the preparation of pharmaceutically acceptable salts and solvates, such as hydrates, of these compounds.

In the case where R ¹ is C 3-6 alkenyl, the double bond cannot be directly attached to the nitrogen atom.

In the formula (I), R ¹ , R ² , R ³ and R ^{4 are} linear or branched alkyl groups such as methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl. , 2-methylprop-2-yl, pentyl, pent-3-vagy or hexyl.

Alkenyl is, for example, propenyl.

Examples of phenyl (C1-C3) alkyl include benzyl, phenethyl or 3-phenylpropyl.

Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.

In the tetrahydrocarbazolone derivatives of the invention, the carbon at the 3-position is asymmetric and thus may have the R or S configuration. The present invention also relates to individual isomeric forms of the compounds of formula I as well as to various mixtures thereof, such as racemic forms.

Pharmaceutically acceptable salts of the indole derivatives of formula I include organic or inorganic acid addition salts such as hydrochlorides, hydrobromides, sulfates, phosphates, citrates, fumarates and maleate. Examples of solvates include hydrates.

Preference is given to compounds of formula I wherein R ¹ is hydrogen or C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 alkenyl.

Further preferred are compounds of formula I wherein

One of R ² , R ^3, and R ^{4 is C} 1-3 alkyl, C 3-6 cycloalkyl, or C 3-6 alkenyl, and the other two groups, which may be the same or different, are hydrogen or C 1-3 alkyl. .

-2193592

Also preferred are compounds of formula I wherein R ¹ is hydrogen or C 1-6 alkyl, C 5-6 cycloalkyl or C 3-4 alkenyl, or R ² is hydrogen and R ³ and / or R ⁴ are preferred. is C 1-3 alkyl or R ² is C 1-3 alkyl and both R ³ and R ⁴ are hydrogen.

Particularly preferred are the compounds of formula (Ia) in which

R ^1a is hydrogen, methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl;

R ² 'is methyl, ethyl, propyl or prop-2-yl and

R ^4a is hydrogen or

R ^2a is hydrogen and R ^4a is methyl or ethyl, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds.

The following compounds are preferred:

1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl / methyl] -9- (prop-2-enyl) -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- (prop-2-yl) -4H-carbazol-4-one and physiologically acceptable their salts and solvates.

Particular preference is given to 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl / methyl] -4H-carbazol-4-one of formula Ib, as well as pharmaceutically acceptable salts and solvates (e.g., hydrates), preferably in the form of the hydrochloride dihydrate.

The compounds of formula (I) wherein R ¹ , R ² , R ³ and R ⁴ are as defined, their physiologically acceptable salts, solvates and their optically active enantiomers are prepared as follows:

a) a compound of formula II, wherein Y is a methylene group in formula II, in which case it is double bonded to the carbazolone ring, or a group of formula -CH ₂ Z wherein Z is an easily cleaved atom or group; with an imidazole derivative of the general formula (II) or a salt thereof, or

b) oxidizing a compound of formula IV, wherein A represents a hydrogen atom or a hydroxy group, or a salt thereof, and optionally substituted R ¹ with a substituent other than hydrogen and phenyl; A compound of formula (I) wherein R ¹ is hydrogen is alkylated, alkenylated or aralkylated, or / and, if desired, R ¹ , R ² , R ³ and / or R ⁴ is C 2 -C 6 alkyl. For the preparation of compounds of formula (I), the compound of formula (I) wherein R ¹ , R ² , R ³ and / or R ⁴ is C 2 -C 6 alkenyl is obtained as above and optionally a racemic compound of formula (I) compound and / or the resulting compound (I) GENERAL free base of formula if desired, converting a physiologically acceptable salt.

The compounds of the invention are selective and potent antagonists of the 5-HT-induced response in the rat isolated cuticle preparation and thus are potent and selective antagonists of the neuronal 5-TH receptor type located in the primary afferent nerves.

Thus, the compounds of the present invention may be used as analgesics, such as those associated with migraine, headache, and other 5-HT non-endogenous mediators.

Experiments demonstrate that the compounds of the invention can be used to treat schizophrenia and other psychotic disorders.

It has been pointed out above that 5-HT is more abundant in the central nervous system, and disorders of these pathways containing 5-HT may cause a variety of behavioral states, such as altering mood, appetite and memory. Because neuronal 5-HT receptors at primary afferent terminals and central compounds may be useful in overcoming fear, obesity, and manic conditions.

In particular, the compounds of formula (Ia) as defined above are highly selective and potent. They are well absorbed from the gastrointestinal tract and are suitable for oral and rectal administration. Compounds of formula Ia do not prolong sleep in mice anesthetized with pentobarbitone, thus demonstrating that they do not interact with drug metabolizing enzymes. In fact, they have no effect on the normal condition, are non-toxic and have no undesirable side effects when administered intravenously up to 1 mg / kg.

Compounds of formula (Ia) exhibit similar properties to compounds of formula (Ib) of this class and have no adverse effects in human use.

A further important feature of the present invention is that it provides a method for treating conditions resulting from neuronal 5-HT disorders in human or veterinary medicine. For example, in human medicine it is used to treat migraine pain or a psychotic disorder such as schizophrenia.

The present invention also relates to the preparation of conventional human or veterinary formulations containing at least one 3-imidazolyl-mephyl-tetrahydrocarbazolone derivative of the formula (I), a pharmaceutically acceptable salt and / or a solvate thereof, such as a hydrate.

These compositions may be formulated with one or more pharmaceutically acceptable carriers and excipients in a conventional manner.

The compounds of the invention are formulated into compositions suitable for oral, buccal, parenteral or rectal administration, or for inhalation or insufflation (either orally or nasally).

For oral administration, for example, conventionally, pharmaceutically acceptable excipients, such as excipients (e.g., pregelatinised corn starch, polyvinylpyrrolidone or hydroxypropylcellulose), carriers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate, e.g. magnesium stearate, talc or diatomaceous earth), disintegrating agents (e.g., potato starch or sodium starch glycolate) or wetting agents (e.g., sodium lauryl sulfate) are prepared and used.

The tablet may be coated in a manner known in the art. Liquid preparations for oral use may be formulated as solutions, syrups or suspensions, and may be formulated with water or other suitable vehicle prior to use. These liquid compositions may be formulated in conventional manner with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles, e.g. alcohol or fractionated vegetable oils) and preservatives (e.g., methyl or propyl (p-hydroxybenzoates), sorbic acids). The formulations may also contain buffer salts, fragrances, colorants and sweeteners.

Formulations for oral administration may also be formulated to provide controlled release.

Formulations for buccal administration may be presented in the form of tablets or rectangular tablets in a conventional manner.

For parenteral administration, the compounds of the invention may be formulated for injection. In the case of an injection composition, the composition is provided in a unit dose form, for example, in an ampoule or in multiple dose formulations with a preservative.

These compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may also contain other excipients such as suspending, stabilizing and / or dispersing agents. 4

Alternatively, the powdered active ingredient may be formulated with a suitable vehicle prior to use. for example pyrogenated water.

Formulations for rectal administration in the form of suppositories or retention enemas, containing the usual suppository bases, such as cocoa butter or other glyceride, are used.

In addition to the compositions described above, the compounds of the present invention may be formulated into depot compositions. These sustained release formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. For example, the compounds of the present invention may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in a suitable oil) or ion exchange resins or with sparingly soluble derivatives, such as sparingly soluble salts.

For administration by inhalation, the compounds of the present invention are conveniently delivered from a pressurized container or nebulizer to a site such as an aerosol spray with a suitable carrier gas such as dichlorodifluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be measured by a valve, and the capsule and filler for an inhalation or insufflation device such as gelatin may be prepared from a mixture of a compound of the invention and a suitable powder base such as lactose or starch.

The compounds of the invention may conveniently be administered in a dosage unit containing 0.05 to 20 mg, preferably 0.1 to 10 mg of active ingredient, for example 1 to 4 times daily, for human administration (based on 70 kg body weight). The dose will depend on the route of administration and the weight of the individual being treated. Depending on the age, weight, and severity of the condition being treated, it may be necessary to use standard dose differences.

The dosage unit for oral administration is preferably from 0.5 to 10 mg, and for parenteral administration it is preferably from 0.1 to 10 mg.

For aerosol formulations, the metered dose or pressure will contain from 0.2 to 2 mg of the compound of the invention from an aerosol, while the capsule or cartridge of the inhalation or insufflation device will contain from 0.2 to 20 mg of the compound of the invention. The total daily dose for inhalation is between 0.4 and 80 mg. The dosage is given several times a day, for example 2 to 8 times a day, 1, 2 or 3 dosage units.

The compounds of the invention may, if desired, be combined with one or more other non-synergistic therapeutic agents, such as anti-emetic agents.

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The present invention relates to compounds of the formula I, their physiologically acceptable salts and their solvates, as described below.

The physiologically acceptable salts and solvates of the compounds of formula (I) according to process (a) of the invention are prepared by reacting a compound of formula (II) wherein R 'is as defined above and Y is methylene or CH ₂ A group of formula Z wherein Z is an easily cleaved atom or group is reacted with an imidazole derivative of formula III wherein R ² , R ³ and R ⁴ are as defined above or a salt thereof. In the process (a), compounds of formula (II) may be used, for example, in which Y is methylene or -CH ₂ Z wherein Z is, for example, a halogen atom such as chlorine or bromine, acyloxy such as e.g., acetoxy, trifluoromethane-sulfonyloxy, p-toluene-sulfonyloxy or methane sulfonyloxy group -, a group -N ⁺ R ⁵ R ⁶ R'a formula wherein R ^5, R ⁶ and R ⁷ may be the same or different and each represents a lower alkyl such as methyl, aryl such as phenyl or aralkyl such as benzyl or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached. bonded to form a five- or six-membered ring, such as a pyrrolidine ring, and X is an anion, such as a halide ion such as chloride, bromide or iodide, or -NR ⁵ R ⁶ R ⁵ l and R ⁶ are as defined above, e.g., dimethylamino group.

When Y is methylene, the reaction may conveniently be carried out in a suitable solvent. Examples of the solvent include water, esters such as ethyl acetate, ketones such as acetone, methyl isobutyl ketone, amides such as dimethylformamide, alcohols such as ethanol and ethers such as dioxane or tetrahydrofuran, or mixtures thereof. The reaction may be carried out, for example, at a temperature between 20 and 100 ° C.

When Y is -CH ₂ Z, wherein Z is halogen or an acyloxy group, the reaction may conveniently be carried out in a suitable solvent. Suitable solvents are amides such as dimethylformamide, alcohols such as methanol or industrial methylated ethyl alcohol, or halogenated alkanes such as dichloromethane. The reaction may be carried out at a temperature of -10 to 150 ° C, for example +20 to 100 ° C.

In the case where Y represents the group -CH ₂ Z, wherein Z is -N ⁺ R ⁵ R ⁶ R ⁷ X ^_ is a group of formula, the reaction is conveniently effected in a suitable solvent végez8 hetjük. Suitable solvents include water, amides such as dimethylformamide, ketones such as acetone, or ethers such as dioxane. The reaction can be carried out at temperatures between +20 and 150 ° C.

In the case where Y is -CH ₂ Z wherein Z is -NR ⁵ R ⁶ , the reaction may conveniently be carried out in a solvent. Suitable solvents are water, alcohols such as methanol, or mixtures thereof. The reaction can be carried out at temperatures between +20 and 150 ° C.

According to process (b) of the invention, compounds of formula (I) may be prepared by reacting a compound of formula (IV) wherein A is hydrogen or hydroxy, R ¹ , R ² , R ³ and R ⁴ are as defined above. or oxidation of its salt.

The oxidation may be carried out in the usual manner, but the reagent (s) and reaction conditions must be selected so that oxidation of the indole group does not occur. Thus, a mild oxidizing agent is preferably used in the oxidation reaction.

In the case where A is hydrogen in formula IV, a suitable oxidizing agent is, for example, quinones such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3,5, 6-tetrachloro-1,4-benzoquinone in the presence of water, ketones such as acetone, methyl ethyl ketone or cyclohexanone in the presence of a base such as aluminum t-butoxide, chromium (VI) oxidizing agents such as chromic acid in acetone a solution of a solution of chromium trioxide in pyridine, N-halosuccinimides such as N-chlorosuccinimide or N-bromosuccinimide, dialkylsiloxides such as dimethylsulfoxide, an activating agent In the presence of, for example, Ν, Ν-dicyclohexylcarbodiimide or an acyl halide such as oxalyl chloride or tosyl chloride, in the presence of a pyridine-sulfur trioxide complex or dehydrogenation catalysts such as copper chromite, zinc oxide, copper or silver -.

Suitable solvents are, for example, ketones such as acetone or butanone, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide, alcohols such as methanol, hydrocarbons such as benzene or toluene, halogenated solvents. hydrocarbons such as dichloromethane and water or mixtures thereof,

The reaction is conveniently carried out at a temperature of -70 to + 50 ° C. The reaction temperature used depends on the oxidizing agent chosen.

According to the desired conversion procedures, the compound of formula (I) is present

-5193592, their salts or their hydrates, by converting a compound of formula (I) into another compound of formula (I) by conventional methods. Such conventional techniques include alkylation, which occur in any position in a compound of formula (I) wherein R ¹ and R ² is hydrogen, by hydrogenation, for example, in which the alkyl substituent is prepared an alkenyl szubsztituensből. Alkylation also refers to the reaction of introducing another group such as cycloalkyl or alkenyl. For example, compounds of formula I wherein R ¹ is hydrogen may be converted to the corresponding compounds of formula I wherein R ¹ is C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, 3- C 6 -C 6 alkenyl or phenyl (C 1 -C 3) alkyl.

Alkylation reactions described above, an appropriate alkylating agent - for example, ^the compound X ^U R, wherein R ^represents C 1 -C 10 alkyl, C3-7 cycloalkyl, C3-6 alkenyl or phenyl- (Cl-C3 alkyl ), X ^a is a leaving group such as a halide or acyloxy group (as defined for Y) or (R ^a ) ₂ SO ₄ .

The alkylation reaction is conveniently carried out in an inert organic solvent. Suitable solvents are, for example, amides such as dimethylformamide ethers such as tetrahydrofuran aromatic hydrocarbons such as toluene, preferably in the presence of a base. Suitable bases are, 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, ethoxide or tert - butoxide. The reaction is conveniently carried out at a temperature of -20 to + 100 ° C, preferably 0 to 50 ° C.

The hydrogenation reaction can be carried out in conventional manner. For example, hydrogenation is carried out in the presence of a noble metal catalyst such as palladium, Raney nickel, platinum, platinum oxide or rhodium. The catalyst may be used on a support such as charcoal or a homogeneous catalyst such as tris (triphenylphosphine) rhodium chloride may be used. The hydrogenation reaction is carried out in a solvent. Suitable solvents are alcohols such as ethanol, amides such as dimethylformamide, ethers such as dioxane, or esters such as ethyl acetate at -20 to 100 ° C, preferably 0 to 50 ° C. Temperature.

The compounds of formula (I) may be converted into their physiologically acceptable salts in conventional manner. For example, a free base of formula (I) is treated with a suitable acid, preferably in an equivalent amount, in a suitable solvent such as ethanol.

The physiologically acceptable equivalents of the compounds of formula (I) may be prepared by conventional methods.

The enantiomers of the compounds of the present invention may be prepared by resolution of a mixture of enantiomers, such as a racemic mixture. Resolution is carried out by conventional methods, such as optically active resolving acid, see also E. L. Eliel, Stereochemical of Carbon Compounds (S.G. Wilen, Tables of Resolving Agents).

Examples of optically active resolving acids are those which form salts with racemic compounds. For example, organic (R) and (S) forms of organic carboxylic and sulfonic acids, such as tartaric acid, di-p-toluoyl tartaric acid, camphorsulfonic acid and lactic acid. The mixture of isomeric salts is then separated, for example by fractional crystallization, and the diastereomers thus obtained are optionally converted to the optically active free base.

The methods described above for the preparation of the compounds of the invention may also be used as a last step in the preparative order. The same general methods can be used to introduce the desired moiety into an interstitial preparation of the target compound. It should be noted that these general methods may be combined in various ways during such multi-step syntheses. Obviously a multi-step synthesizer! order must be chosen so that the reaction conditions do not affect those portions of the molecule which are not required in the final product.

The starting compounds of formula II wherein Y is a methylene group may be prepared from compounds of formula II wherein Y is -CH ₂ N ⁺ R ⁵ R ⁶ R ⁷ X by reaction in a suitable solvent. a base is used as the reaction partner. Suitable bases include, for example, base metal hydroxides such as potassium carbonates such as sodium bicarbonate.

The quaternary salts can be prepared from the corresponding tertiary amine with an alkylating agent such as methyl iodide or dimethyl sulfate, optionally in a suitable solvent such as dimethylformamide. The tertiary amino compound is a tetrahydrocarbazolone of formula (V)

-6193592 by the reaction of formaldehyde with the corresponding secondary amine. The reaction may be carried out, if desired, in a suitable solvent such as alcohols such as ethanol.

The compounds of formula (V) are described in H.Iida et al. (J. Org. Chem. (1980) Vol 45, No. 15, 2938-2942).

Compounds of formula (II) wherein Y is -CH ₂ Z wherein Z is halogen or acyloxy may be prepared from the corresponding hydroxymethyl derivative of formula (VI). The compounds of formula (VI) may be prepared by reacting the tetrahydro-carbazolones of formula (V) with formaldehyde, preferably in a suitable solvent such as alcohols such as ethanol, preferably in the presence of a base.

Compounds wherein Z is halogen can be prepared by reacting a compound of formula VI with a halogenating agent such as phosphorus trihalide, phosphorus trichloride.

Compounds wherein Z is acyloxy may be prepared by reacting a compound of formula VI with a suitable acylating agent such as anhydride or a sulfonyl halide such as sulfonyl chloride.

Compounds of formula (II) wherein Y is -CH ₂ Z wherein Z is halogen may also be prepared by reacting a compound of formula (II) wherein Y is methylene with the corresponding hydrogen halide, e.g. hydrogen chloride, suitably in a suitable solvent such as ethers such as diethyl ether.

Compounds of formula (IV) may be prepared by reacting a compound of formula (VII) wherein R ¹ and A are as defined above, Z ¹ is an easily substituted atom or group such as halogen, acyloxy or N ⁺ R ⁵ R ⁶ R ⁷ X 'where R ⁵ , R ⁶ , R ⁷ and X are as defined above, is reacted with an imidazole of formula III according to the method described in process (a).

The compound of formula (VII) may be prepared by reducing the compound of formula (II), such as lithium aluminum hydride or sodium borohydride.

Compounds of formula (VII) wherein A is hydrogen may also be prepared by reacting a compound of formula (VII) wherein A is hydroxy with a tosyl-ha 12 logenide such as tosyl chloride to give the tosylate. and reduced with lithium aluminum hydride.

The compounds of formula IV are novel. The invention is further illustrated by the following examples, without limiting the scope thereof.

Temperature data is expressed in ° C. Unless otherwise noted, the solutions are dried over sodium sulfate while the solids are vacuum dried over 50 ° C overnight over phosphorus pentoxide. The chromatographic method used was as described in the literature (W.C. Still et al., J. Org.Chem. 43, 2923-2925 (1978)) (kieselgel 9385).

Preparation 1

2.3.4.9- Preparation of Tetrahydro-N, N, N-trimethyl-4-oxo-1H-carbazole-3-methanaminium iodide

A solution of 0.53 g of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one in 15 ml of methyl iodide is refluxed for 5 hours and then evaporated to dryness. 0.84 g of the title compound is obtained, m.p. 202-205 ° C (white solid).

Preparation 2

2.3.4.9- Preparation of Tetrahydro-N, N, N-9-tetramethyl-4-oxo-1H-carbazole-3-methanaminium 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 methyl iodide was stirred for 57 hours. reflux. Subsequently, the suspension was concentrated in vacuo to give 5.72 g of the title compound, m.p. 192-195 °.

Preparation 3

1.2.3.9- Preparation of tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one

To a solution of 5.0 g of the compound of Preparation 2 in 20 ml of water was added 6.55 ml of 2N sodium carbonate solution and kept at 35 ° for 45 minutes. The resulting slurry was cooled to 0 °, the solid was collected by filtration, washed with water and dried. 2.8 g of the title compound are obtained, m.p. 127-129 °.

Preparation 4

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

To a solution of the compound of Example 7 (500 mg) in methanol (3 mL) and chloroform (3 mL) was added sodium borohydride (90 mg) under nitrogen. Stirring was continued for 48 hours (17.75 hours and after 42 hours additional sodium borohydride (250 mg) was added). To the resulting suspension was added 15 ml of 2N hydrochloric acid and extracted three times with 10 ml of chloroform. The aqueous '' phase was separated and made basic with solid sodium carbonate, extracted three times with 10 ml of chloroform, and the combined extracts were washed twice with 10 ml of water each time.

The mixture was washed with brine (7193592 ml), then dried and concentrated in vacuo. The resulting foam, weighing 557 mg, was purified by column chromatography. The solvent was eluted with dichloromethane-ethanol-aqueous 0.88 ammonia solution (300: 10: 1) to give 200 mg of a solid which was dissolved in hot ethanol (3 ml) and 80 mg of maleic acid in 1 ml of hot abs. ethanol solution. The hot solution was filtered, stirred and diluted with 40 mL of dry ether. 240 mg of the title compound are obtained, m.p. 138.5-140 °.

Preparation 5

Preparation of 2,3,4,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazol-4-ol

To a suspension of 7.75 g of lithium aluminum hydride in 750 ml of dry tetrahydrofuran was added 30.0 g of the compound of Example 7 with stirring under a nitrogen atmosphere. The reaction mixture was refluxed for 1 hour with stirring and then cooled in ice. To the resulting slurry was carefully added 100 ml of aqueous tetrahydrofuran containing 15% water, then 100 ml of water, the mixture was concentrated in vacuo and the residue was extracted with dichloromethane (2 x 500 ml). The combined organic extracts were concentrated in vacuo and the solid residue (16.4 g) chromatographed on a silica gel short column (Kieselgel 60, Merck 7747, 500 g) eluting with dichloromethane-ethanol-0.88 aqueous ammonia (150: 10: 1). using a solvent mixture. as a foam

13.4 g of the title compound are obtained. TLC: silica gel plate, dichloromethane - ethanol - 0.88

Table 1 Ammonia 150: 10: 1, Rf = 0.34 and 0.366 (two pairs of diastereomers), UV and iodine-platinum acid detection.

1 H-NMR (CDCl ₃ + 1 drop CD ₃ OD): δ: 1.6-

2.3 and 2.6-3.0 (5H, m), 2.32 and 2.40 (3H, s + s,

Me in the two different isomers), 3.32 (3H, s, NMe), 3.65-4.3 (2H, m, CHCH ₂ N), 4.75-4.85 (1H, m, CH-OH 6, 8-7.8 (CH, m, aromatic).

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

2.0 g of the compound of Preparation 2 and 5.0 g

A solution of 2-methylimidazole in 30 ml of dry dimethylformamide was stirred under nitrogen and stirred at 95 ° C for 16.75 hours under nitrogen and allowed to cool. The precipitated crystals were collected by filtration washed three times with 2 ml of ice-cooled in advance of dimethylformamide and twice with 10 ml dry ether and ²⁵ dried. The resulting solid (0.60 g) was dissolved in 30 ml of abs. slurry in ethanol and 1 ml of ethanolic hydrogen chloride solution and heat gently until a solution is obtained. The resulting solution is filtered while still warm. The filtrate is diluted with dry ether to give 0.6 g of a solid which is abs. recrystallized from ethanol. 0.27 g of the title compound is obtained, m.p.

186-187 °.

Analysis: Found: C 6 H 9 N 6.4 N 11.8 Theory: 62.3 6.1 12.1% (calculated for C ₈ H ₁₉ N ₃ OHCl.H ₂ O)

Similarly, the compounds described in Table 140 were prepared.

Example Formula (I)

tb le td le '

If

1s'

CH ₃

CH ₃

Cll ₃

Cil ₃

CH ₃ ch ₃

pr

H

H

H

Imidazole is alkali,

Wt weight

Solvent- Rel. Products O.p. salt weight ° C (ml) tip. (G)

Molecular formula

Analysis / 2 /

received:

Theoretical:

H H

CH ₃ ch ₃

Η H

-CH ₂ PhH

H € H ₂ Ph

Η H

S. M cg) (G) C H N C H N 2.00 4.10 30 IIC1 0.78 199.5 ^β Ci7H17N3O. 62.05 5.5 12.7 61.8 5.9 12.7 200.5 ₂ 0 ° HC1.0.8H 0.8 0.6 5 Malek 0.50 1 51 ^e - Ci9H21N3O. 64.6 6.0 9.8 64.7 6.0 9.8 152 ° CuHuOu.0.2H ₂ 0 3.2 2.9 40 HC1 1.0 173 ° - C20H23N3O. 64.9 6.9 11.2 65.5 6.9 11.4! 182 ° HC1,0.5H ₂ 0 0.8 1.2 5 HC1 0.25 130 to 135 ° C ₂ j, H ₂₃ N ₃ O. HCl. 0.5H _t 0 69.1 6.1 9.9 69.5 6.1 10.1 - 0.05 170- C ₂ uH ₂₃ N ₃ O « 72.8 6.2 10.5 72.7 6.6 10.6 74 ° , 1.5 H ₂ U 1.0 1, '6 30 HC1 0.30 150- c ₂₃ h ₂₇ n ₃ o. 68.5 7.55 10.4 68.4 7.15 10.4 155 ° HC1. O ₃ H ₂ O

'2,3,4,9-Tetrahydro-9, N, N, N-tetramethyl-4-oxo-1 H -carbazole-3-ylmethanamine methosulfate is used as starting material. Λ in Table »h is phenyl,

ΓΙ is cyclohexyl Wt S.M. * weight of parent compound

Note to Table 1

Le and lf were prepared in the same experiment and isolated by short column chromatography (D.F. Taber, J. Org. Chem. 1982, 47, 1351), eluting with dichloromethane-ethanol-0.88.

-8193592

16: Density ammonia 300: 10: 1 is summarized in Table 2 below using a solvent mixture. The Ή-NMR is a compound of formula (I)

Table 2

Example Solvent ¹ H NMR Spectrum (at 250 MHz measurement frequency) Number ----------------------------------- ----------------------------- *

Chemical shift (§, ppm) and multiplicita's (spectrum details)

Carbazolone Proto- Imidazolyl Imidazole Protons Female Methylene ------------------

aromatic H-5,6,7,8 Aliphatic CH ₂ and CH ₂ -2 H-3 protons H2 ' H-4 ' H-5 ' 1 e d ₆ -DMS0 7.2 to 8.05 2.91 to 3.25 4.47 / dd / and 9,20s 7,55s 1.75 to 2.3 4.64 / dd / 1f ₃ CDC1 7.15 to 8.05 2.6 to 3.05 4.02 / dd / and 8.1 7s 6, S3s + DMSO 1.75-2.1 4.63 / dd / lg DMSO-d 7.2 to 8.05 2.9-3.3 4.42 / dd / and - 7.61 d 1.6-2.2 4.73 / dd / and

7.70d d = doublet dd = double doublet s = singlet

Example 2

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

300 mg of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one compound were suspended in 5 ml of hot ethanol and 116 mg maleic acid is added. The resulting solution was cooled and the precipitated crystals were collected by filtration and dried. This gave 300 mg of the title compound, m.p. 132.3 °.

Example 3a

1.2.3.9- Preparation of tetrahydro-3- (1H-imidazol-1-ylmethyl) -4H-carbazol-4-one

A solution of 0.84 g of the compound of Preparation 1 and 0.90 g of imidazole in 25 ml of dimethylformamide is heated at 105 ° for 6 hours, cooled and 200 ml of water are added. It was then extracted six times with ethyl acetate, and the combined organic phases were washed, dried and evaporated. The resulting solid residue was chromatographed on a silica gel column (Merck 7734) with ethyl acetate-methanol (4: 1) and recrystallized twice from ethyl acetate-methanol. 0.095 g of the title compound is obtained, m.p. 220-222 °. TLC: silica gel plate, dichloromethane: ethanol - 0.88 ammonia = 100: 8: 1, Rf = 0.33 UV and iodine-platinum acid detection. Similarly, we prepared the

Table 3. The salt formation was carried out as in Example 2.

-910

H NMR. spectrum (250 MHz, DMSO-d6) δ

N tn ví -rt - <y 'd ®

CL 4J tO Cl 'rt

-SHE

Μ I ex i

44 I r- / Ο I

O C l Ν O t rt w i 73

I 73 I r-. I \ O

I r- * I l 73 i

I cm

I 'rl | • 3 P • Η H C tí

Β · Η’Φ o

-rt

S

I ffi

I 73 l 73

I <r -rt <r <r - <u <j- -rt <r I m

I 04 CM o l i I cn

Li t X * r-1

I U W 3 I Φ 50 bű o

CM I i Oí Oí Stí M CJ Q <33 l Eo pj o to; o \

Φ -rl Ό 43 'O

Cd O -r \

I

Ό Ρ Ψΐ z- * x

X) QJ μ r— (r-1 bJ Ο »B

Ο M U V • I

M-l 73 —I GO Ή O r-t GO Ο β M '3' -z s n-í rt 05

I tí rt> »x-s ί -H Oű l» rl ti -3

I fcd rt «{CL í I -rt I I 44 t

I Cd l -rt rt N I {X, Ό W

I 33

0 73 44 ti

U -r4 rt N

Λ o

O CM o o

I 0 cn <r rt a

rt a

o oo

I

B o

>.

ti rt rt

I

I cn

O: 3 0? S 73 sin * M rt »—i O> rt &

U-í 44 rH 44 cn: a -H C • r-j cn 3

W U r-l rt -η χ -rt ti rt ti rt í0 33 N e- | h L {Λ íti o rt <44 N 43

-10193592

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

A solution of 1.0 g of 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in 10 ml of dry dimethylformamide under nitrogen, stirring and adding dropwise, under ice-cooling, a suspension of 0.11 g of sodium hydride (80% mineral oil suspension) in 5 ml of dry dimethylformamide. After 0.5 h, 0.34 mL of dimethyl sulfate was added and the resulting solution was poured at room temperature for 4 h. The resulting solid was collected by filtration, washed twice with ice-cold dry dimethylformamide (5 mL) and dry with ether (3 x 15 mL) and dried. 0.25 g of the title compound is obtained, m.p. 223-224 ° (dec.).

TLC: silica gel plate, developing solvent: chloroform: methanol - 93: 1, Rf = 0.27, UV and iodine-platinum acid detection. According to this test, the chemical ¹ θ let is the same. la. The compounds described in Table 4 were prepared in a similar manner using the corresponding alkylating agents listed in the Table.

Table 4 for the preparation of compounds of formula I from compounds of formula IV *

examples da song alkylating R ¹ R ² _ R ³ R ^k Reac. address salt time __ £ h) ._________ - —— - · - 4b Me ₂ SOj, ch ₃ - -CH2CH3 H H 0.5 HCl 4c MeaSOu ch ₃ - -CH ₂ Ph H H 4 Malay 4d Et ₂ SO _n CHjClh- ch ₃ - H H 6.5 Malea

4e PhCH ₂ Br PhCll ₂ - CH3 H H 5.75 maleate 4f CH a (CH ₂ ) ₅ I CH ₃ (CH ₂ ) ₅ - ch ₃ - H H 7.25 maleate 4q Ph (CH ₂ ) ₃ Br Ph (CII _{2) 3} - ch ₃ - H II 5.75 maleate

Product op Molecular Formula Analysis (%) ^S “ ^l2 · ⁽ ° ^C) 'found theoretical

C Η N C Η N

0.13 211- 212 ' C19H2 _A N ₃ 0. HC1.O.5H ₂ O 64.7 6 5 11.8 64.7 6.6 11.9 0.32 143 145 ' C 21 H _{2 3} N ₃ O. CulluOu 69.35 5.5 8.5 69.3 5.6 8.65 0.67 159- 160 ' Ci9H2iN ₃ O.Cí Hi, O ₍₄ 65.15 6.1 9.85 65.25 5.95 9.9 1.00 150151 .5 ° 69.1 5.65 8.55 b9.3 5.6 8.65 1.16 1 181 19 ° C _{2 3} H ₂ 9N ₃ O.Ci, H ^ O _I , 67.4 6.9 8.7 67.6 6.9 8.8 0.84 95 96.5 ' C26H27N9O. CulUO *, .0.2H ₂ 0 69.5 5.9 8.0 69.7 6.1 8.1

4h

Η H (50C-Oxalate at 0.14)

50- C ₂₇ H ₃ 7N ₃ O.C2H ₂ O ₄ ,.

51 ', O.3lI ₂ O

7.8 66.6 7.8 8.0

4i decil-tozilat

CH ₃ (CH ₂ ) ₉ OSO ₂ CH ₃ (CH ₂ )> - ch ₃ ch ₃

3-pentyl tosylate

Et ₂ CHOSO ₂ β - CH ₃ CII ₂ ) ₂ C _{11 -} CII _{3 I} 4h

Η H (at 40 ° C-1Cl)

0.12 131133 °

C ₂₂ H ₂ ? N ₃ O.HCl 1. 1ll ₂ 0

65.8

7.9 10.3

65.4 7.5 10.4

Note to Table 4

The relevant ¹ H NMR spectroscopic data are summarized in Table 5.

Formula (I) Formula ^I

Table 5

Example Solvent 1 H-NMR Spectrum (250 MHz Measurement; Frequency) Number ---------------------------------- Chemical shift (5> ppra) &; multiplicity (spectral gap; leaks)

Carbazolone-pro- Imidazolyl - Imidazole Protons Tons of Methylene- --------------

--------- protons H-2 'H-4' and /

You're an aromatic Aliphat

H-5,6,7,8 CH ₂ -1 and H-5 '

CH ₂ -2 B-3

-DMSO 7.15 to 8.1 2.9-3.2 1.9-2.2 6.29 / dd / es 6.68 / dd / 7.55 and 7.65 4h -DMSO 7.2-8.1 2.9 to 3 ,: 1.8-2.2 6.26 / dd and 6.55 / dd / 7.42 and 7.57

d »doublet dd - double doublet s - singlet

-11193592

Example 5

Preparation of 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 of 2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] 4H-carbazol-4-one in 9 ml of dry dimethylformamide was stirred under nitrogen and while cooling with ice, to a suspension of 0.14 g of sodium hydride (80% mineral oil suspension) in 2 ml of dry dimethylformamide and stirring was continued for 0.25 hours. 0.51 ml of bromocyclopentane are then added with stirring and the mixture is heated at 100 ° for 18.5 hours. The resulting solution was allowed to cool, water (100 mL) was added and the mixture was extracted with ethyl acetate (3 x 70 mL). The combined organic layers were washed with 2N sodium carbonate solution (2 x 50 mL), water (2 x 50 mL) and brine (50 mL), eluting with dichloromethane-ethanol-0.88 ammonia solution 150:

Using a 10: 1 mixture of solvents, 0.27 g of oil was obtained. The resulting oil was dissolved in 7 mL of ethanol while hot and 0.1 g of maleic acid in 0.5 mL of hot abs. ethanol solution was added, the hot solution was filtered, stirred and diluted with 20 ml of dry ether. The resulting yellow gum was washed with ether (7 x 25 mL), and the combined mother liquors and washings were allowed to stand at room temperature. The precipitated crystals were collected by filtration, washed three times with 5 ml of dry ether and dried. 0.058 g of the title salt is obtained, m.p. 104.5-106 °.

Analysis: Found: C, 65.95 Η 6, 4 N, 8.6; Theory, 65.8, 6.4, 8.9% (calculated for C ₂₂ H ₂₅ N ₃ OC ₄ H ₄ O ₄ .0.6H ₂ O) )

Example 6

Preparation of 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 2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in 6 ml of dry dimethylformamide was stirred under nitrogen. and to a suspension of 0.12 g of sodium hydride (80% mineral oil suspension) in 2 ml of dry dimethylformamide under ice-cooling, and stirring was continued for 0.25 hours. Allyl bromide was added and the resulting solution was stirred at 0 ° for 0.25 hours and then at room temperature for 20 hours and water (75 ml) was added. The mixture was extracted with ethyl acetate (3 x 50 mL), and the combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried and concentrated in vacuo. The residue was purified by chromatography using dichloromethane-ethanol-0.88 aqueous ammonia (200: 10: 1) as eluant to give 0.43 g of a solid. dissolved in ethanol and 0.18 g of maleic acid in 1 ml of hot abs. ethanol solution was added, the hot solution was filtered, diluted with 4 mL of dry ether and the precipitated crystals were filtered, washed three times with 5 mL of dry ether and dried. 0.48 g of white title compound is obtained, m.p. 150.5-151 °.

Analysis Found: C 66.3 H 5.75 N 9.6 Calculated: 66.2 5.8 9.65% (C ₂₀ H ₂₁ N ₃ O ₄ H _{4 4} OG to 'calculated)

Example 7

1.2.3.9- Preparation of tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

To 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 was added 1.4 g of 2-methyl- imidazole was added and refluxed for 20 hours. The reaction mixture was cooled, filtered and the residue was washed with water (3 x 15 mL) to give 1.7 g of crude product, m.p. 221-221.5 °. so

1.4 g of the title compound are obtained, m.p. 231-232 °, and the same as in TLC.

Example 4.

Example 8

1.2.3.9- Preparation of tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

A suspension of 0.5 g of the compound of Preparation 3 and 0.4 g of 2-methylimidazole in 5 ml of water is heated under reflux for 20 hours. The reaction mixture was cooled and filtered, and the residue was washed with water (3 x 10 mL), dried and recrystallized from methanol (18). 0.3 g of the title compound is obtained, m.p. 232-234 ° (dec.). The compound was identical to the compound of Example 4 by TLC.

Example 9

1.2.3.9- Preparation of tetrahydro-9- (1-methylethyl) -3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

To a solution of 1.93 g of 2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in 35 ml of dimethylformamide, 0.208 g of sodium hydride (80% mineral oil slurry) was added with stirring and the resulting slurry was stirred at 0 ° for an additional 0.25 hours. At this time, 0.78 ml of 2-bromopropane was added and the reaction mixture was stirred at room temperature overnight and then at 40 ° C for 4 hours. Thereafter, 200 ml of 2N sodium carbonate solution were added and the mixture was extracted with ethyl acetate (2 x 150 ml), and the combined organic phases were washed with water (3 x 75 ml), dried and evaporated in vacuo. The resulting residue was purified by chromatography using dichloromethane-ethanol-ammonia 100: 8: 1 as eluent. The resulting oil was dissolved in ethanol (3 mL) and acidified with ethereal hydrogen chloride solution and diluted with dry ether to give 0.13 g of white title compound, 12193592, m.p. 230-232 °. -

Analysis: Found: C 65.3 H 6.6 N 11.1 Theory: 65.4 6.9 N 11.45% (C ₂₀ H ₂₃ N ₃ O · HCl · 0.5H ₂ O)

Example 10

1.2.3.9- Preparation of tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate

18.3 g of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one with 90 ml of isopropanol and To a solution of 3 ml of water was added hot 6.25 ml of concentrated hydrochloric acid. The hot reaction mixture was filtered and the filtrate was quenched with 90 ml of isopropanol and stirred for 17 hours at room temperature, then cooled to 2 ° and the precipitated solid was filtered. 6 g of 21.6 g of solid are recrystallized from 6 ml of water and 10 ml of isopropanol to give 6 g of the title compound as a white crystalline solid, m.p. 178.5-179.5 °. Analysis: Found: C, 59.45; H, 6.45; N, 11.5; theoretical: 59.1, 6.6; 11.5% (calculated for C ₁₂ H ₁₉ N ₃ O · HCl · 2H ₂ O). 10.23 theoretical: 9.85% _(Ig C H ₁₉ N ₂ O ₃ O.HC1.2H to számivá)

Example 11

1.2.3.9- Preparation of 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 of 1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one, 1.50 g of dimethylamine hydrochloride and 0.60 g of paraformaldehyde in glacial acetic acid under nitrogen and stirring for 42 hours. bring to a boil and allow to cool. The reaction mixture was concentrated in vacuo and the resulting brown gum was stirred in water (50 mL), ethyl acetate (50 mL) and brine (20 mL), and the resulting solid was filtered, washed with dry ether (4 x 30 mL) and dried. 1.0 g of the title compound are obtained in 10 ml of abs. Recrystallization twice from ethanol gave 0.39 g of the title compound as a fine powder, m.p. 193-194 ° (dec.).

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

2.0 g of a suspension of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one hydrochloride in 20 ml of water under stirring under nitrogen atmosphere 2-Methyl-1H-imidazole was added and the reaction mixture was heated at 90 ° for 43 hours. The solvent was decanted from the solid and chloroform was added to the solid residue. The resulting slurry was filtered through hyflon, the filtrate was dried and evaporated in vacuo. The resulting 2.04 g foam was purified by chromatography using dichloromethane-ethanol - 0.88 aqueous ammonia 24 - 200: 10: 1 as the eluent. 1.1 g of a white foam are obtained, which is dissolved in 3 ml of ethanol and a solution of 0.4 g of maleic acid in 1 ml of ethanol is added, followed by 40 ml of dry ether. The resulting gum was triturated with twice 40 mL of dry ether to give 1.37 g of the cream-colored title compound, m.p. 165-166 ° (dec.).

Analysis: Found: C 68.65 H 5.5 N 8.7 Theory: 68.8 5.3 8.9% (calculated for C ₂₃ H ₂₁ N ₃ OC ₄ H ₄ O ₄ )

Example 12

1.2.3.9- Preparation of tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one phosphate (1: 1)

0.61 g of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4 H -carbazol-4-one compound in 0.13 ml Dissolve in a hot mixture of 90% phosphoric acid and 10 ml of water, filter through hyflon and allow the solution to crystallize. This affords 0.5 g of the title compound, mp 225 ° Analysis Found: C 55.1 H 5.6 N 10.55 Calculated: 55.2 5.7 10.7% _(Ig C H ₁₉ N ₃ OH ₃ calculated on PO ₄ )

Example 13 2, 2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one citrate (2: 1) Production

0.89 g of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one 0.58 g. Add 20 g of citric acid to a hot solution of 20 ml of ethanol and allow to stand until crystallization. The resulting crystals were collected and recrystallized from 2: 1 acetone-water 2: 1 by dilution with 20 ml acetone. 4.6 g of the title compound are obtained, m.p. 162 °.

Example 11

1.2.3.9- Preparation of tetrahydro-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

To a solution of 2.θ g of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one in 30 ml of dry dimethylformamide was added 0.75 ml of methyl iodide with stirring. and the solution was stirred at room temperature for 30 minutes. A solution of 2 g of 2-propyl-1H-imidazole in 5 ml of dimethylformamide was added and the resulting solution was stirred at 100 ° C for 2 days, cooled, 150 ml of 2N sodium carbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water (100 mL), dried and evaporated in vacuo. The residue was purified by column chromatography using dichloromethane-ethanol-ammonia (400: 30: 3) as eluent. A solution of 1.2 g of the solid free base obtained in 0.2 g of abs. dissolved in ethanol, acidified with ethereal hydrogen chloride solution and ca. Dilute with 200 ml of dry ether (until oil is removed). It helps to crystallize the oil13

To scrape -13193592, scrape the container wall. 0.15 g of a solid is obtained, which is recrystallized from a mixture of methanol and isopropyl acetate. This gives 0.08 g of the title compound, m.p. 206-208 °.

Analysis: Found: C 65 H 6.8 N 12.0 Theory: 65.7 6.5 12.1% (calculated for C ₁₉ H ₂₁ N ₃ O · HCl · O ₂ H ₂ O) 1 H-NMR (CD ₃ SOCD ₃ ): δ: 0.94 (3H, t, CH ₃ ), 1.77 (2H, sx, CH ₂ CH ₂ CH ₃ ), 1.9-2.15 and 2.95-3.2 (7H , m), 4.32 and 4.71 (2H, ABX, CHCH ₂ N), 7.1-8.0 (6H, aromatic).

Example 15

1.2.3.9- Preparation of tetrahydro-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

A solution of 0.03 g of the compound of Example 3 in 15 ml of methanol was hydrogenated at room temperature and atmospheric pressure with 10% palladium on charcoal (50% aqueous suspension, 0.03 g) for 1 hour (hydrogen uptake: 5 g). mL). The catalyst was filtered off and the filtrate was concentrated in vacuo. The resulting oil was treated with ether to give 0.03 g of the title compound as a white solid, m.p. 199-203 °. The compound was identical to the compound of Example 14 by TLC and NMR.

Example 16

1.2.3.9- Preparation of tetrahydro-9-propyl-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

To a solution of 1.0 g of the compound of Example 14 in 20 ml of dry dimethylformamide was added sodium hydride (80% mineral oil suspension) with stirring under nitrogen, and the resulting suspension was stirred at room temperature for 30 minutes. Subsequently, 0.35 ml of 1-bromopropane was added and the resulting solution was stirred at 40 ° for 20 hours. To the solution was added 150 ml of 2N sodium carbonate solution and extracted twice with 100 ml of ethyl acetate. The combined extracts were washed with water (100 mL), dried and concentrated in vacuo. The resulting oil was purified by column chromatography using dichloromethane-ethanol-ammonia 100: 8: 1 as eluent. The free base is thus obtained as an oil which is dissolved in 5 ml of abs. dissolved in ethanol and acidified with ethereal hydrogen chloride solution and diluted with 200 ml of dry ether. The resulting oil was decanted off and replaced with 200 ml of an even drier ether. The mixture was allowed to stand at 0 ° C overnight and the precipitated crystals were collected. 0.53 g of the title compound is obtained, m.p. 144-147 °.

1 H-NMR (CD ₃ SOCD ₃ ): δ 0.90 and 0.93 (6H, t + t, 2xMe), 1.65-2.2 and 2.9-3.25 (1 OH, 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: Found: C 66.6 H 7.7 N 10.0 Theory: 66.3 7.4 10.5% (calculated for C ₂₂ H ₂₇ N ₃ O · HCl · 0.7H ₂ O).

Example 17

1.2.3.9- Preparation of tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9-propyl-4H-carbazol-4-one maleate

0.86 g of the compound of Example 6 in 20 ml of abs. A solution of ethanol and 5 mL of dry dimethylformamide was hydrogenated at room temperature and atmospheric pressure with 0.1 g of 5% platinum on carbon (pre-hydrogenated in 10 mL of abs. ethanol) for 1 hour (70 mL of hydrogen uptake). The catalyst is filtered off, washed with ethanol and the filtrate is concentrated in vacuo to a volume of about 15 ml. Water (50 mL) was added to the remaining solution with stirring, and the precipitated solid was filtered, washed with water (3 x 15 mL) and dried. The resulting powder (0.73 g) was treated with 7 mL of hot abs. dissolved in ethanol, the solution was filtered and 0.25 g of maleic acid in 1 ml of hot abs. ethanol solution and diluted with 50 ml of dry ether with stirring. 0.84 g of the title compound is obtained, m.p. 150-151 °.

Analysis: Found: C, 65.8; H, 6.1; N, 9.3; 65.9, 6, 9.6% (calculated for C ₂₀ H ₂₃ N ₃ OC ₄ H ₄ O ₄ ).

Example 18

1.2.3.9- Preparation of 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

To a solution of the compound of Preparation 3 (1.90 g) in chloroform (15 ml) was added hydrogen ether (3.0 ml) under stirring and ice-cooling, and the resulting suspension was stirred in a sealed tube at room temperature for 16.5 hours. Concentration in vacuo gave 2.27 g of a solid residue. The residue was purified by column chromatography using chloroform as eluant to give 1.75 g of the title compound, m.p. 109-110.5 °. Recrystallization of part of the material from ethyl acetate gave partial decomposition.

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

0.50 g of 3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 2-methyl-1H-imidazole (1.60 g) in dry dimethyl formamide solution at 90 ° C for 3.75 hours and then poured into 25 ml of water. The resulting slurry was stirred for 1 hour, the solid filtered, washed with water (3 x 20 mL) and dried at 50 ° C in vacuo. The solid (0.53 g) was purified by column chromatography (eluent: dichloromethane: ethanol = 0.88, aqueous ammonia = 150: 10: 1) to give 0.45 g of the title compound, mp 228-229. °. The product thus obtained was identical to that of Example 7 by TLC and NMR.

-14193592

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

100 mg of compound of Preparation 4

A solution of 170 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 1.5 ml of tetrahydrofuran was added dropwise to a suspension of 3.5 ml of a mixture of tetrahydrofuran and 0.4 ml of water under stirring and ice-cooling under nitrogen. The resulting blue solution was stirred for 1.5 hours and then concentrated in vacuo. The residual solid was purified by column chromatography eluting with dichloromethane-ethanol-0.88 aqueous ammonia 150; Using a 10: 1 mixture of solvents gave 45 mg of the title compound, m.p. 227-2228.5 °. The product was identical to thin layer chromatography and NMR

Example 7.

Example 20 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl | Preparation of -4 H -carbazol-4-one

To a suspension of 100 mg of the compound of Preparation 5 in a mixture of 3.5 ml of tetrahydrofuran and 0.4 ml of water under stirring and ice-cooling, under nitrogen, 80 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone of dry tetrahydrofuran solution was added dropwise. The resulting blue solution was stirred for 1.5 hours, and the red suspension was concentrated in vacuo. The residual solid was purified by column chromatography using dichloromethane-ethanol-0.88 aqueous ammonia = 150: 10: 1 as eluent to give 0.47 g of the title compound as a white solid, m.p. 5-229 °. The product was identical to the compound of Example 7 by TLC and NMR.

Example 21

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

To a solution of 0.5 g of the compound of Example 7 in 30 ml of hot methanol was added a hot solution of 0.7 g of (+) - di-p-toluoyl-D-tartaric acid monohydrate in 10 ml of methanol and the resulting solution crystallized overnight. forget it. 0.68 g of the desired salt is obtained. The salt was dissolved in 20 ml of hot dimethylformamide and diluted with 10 ml of hot water and allowed to crystallize overnight. The precipitate was filtered off and dried in vacuo. 0.23 g of (+) -di-p-toluoyl-D-tartaric acid salt, m.p. 231-233 °, are obtained in approximately 90% pure S-enantiomer (NMR-serine). To 0.15 g of this salt was added 25 ml of 8% sodium bicarbonate solution and extracted twice with 25 ml of chloroform. The combined extracts were dried and evaporated in vacuo. This gives 0.07 g of pure free base which is dissolved in 5 ml of methanol and 0.03 g of maleic acid is added. The salt was precipitated with 80 ml of dry ether and filtered. 0.062 g of the title compound is obtained, m.p. 142-145 °. TLC: silica gel plate, dichloromethane - ethanol - 0.88 ammonia, 100: 8: 1, Rf = 0.3, UV and iodine-platinum acid detection. The S: R = 93: 7 Enantiomeric Ratio was determined by NMR. The sample of the maleate salt had no significant optical rotation in methanol: [α] ²⁵ = -14 ° (c 0.19 MeOH).

Example 22

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

To a solution of 0.5 g of the compound of Example 7 in 30 ml of hot methanol was added a hot solution of 0.7 g of (-) - di-p-toluoyl-L-tartaric acid monohydrate in 10 ml of methanol and the resulting solution was allowed to crystallize overnight. . 0.8 g of the desired salt is obtained. The salt was dissolved in hot dimethylformamide (20 mL) and diluted with hot water (10 mL) and allowed to crystallize for 3 days. The precipitate was filtered off and dried in vacuo. There was thus obtained 0.26 g of (-) - di-p-toluoyl-L-tartaric acid salt, approximately 95% pure, according to NMR, with a melting point (NMR) of 0.26 g (-) - Di-p-toluoyl-L-tartaric acid salt is obtained, m.p. 170-172 °. To 0.2 g of this salt is extracted with 25 ml of chloroform. The combined extracts were dried and evaporated in vacuo. 0.12 g of pure free base are obtained, which is dissolved in 5 µl of methanol and 0.045 g of maleic acid is added. The salt was triturated with 80 mL of dry ether and filtered. 0.08 g of the title compound is obtained, m.p. 142-145 °.

TLC: silica gel plate, dichloromethane-ethanol-0.88 ammonia = 100: 8: 1, Rf = 0.3, UV and iodine-platinum acid detection. The R: S enantiomer ratio is> 95: 5. The sample of the maleate salt has no significant optical rotation in methanol. Optical rotation of the base liberated from the maleate salt: [α] ²⁵ = + 16 ° (c 0.34, MeOH).

The invention is further illustrated by the following pharmaceutical preparation examples wherein the active ingredient is 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-. carbazol-4-one hydrochloride dihydrate (1.25 g hydrochloride dihydrate 1.00 g free base) was used. The other compounds of the invention may be formulated into pharmaceutical compositions in a similar manner. Preparation of tablets for oral administration

Tablets may be prepared by conventional means such as direct compression or wet granulation.

The tablet may be film-coated with suitable film-forming materials, e.g.

-15193592 µl hydroxypropyl 1-methyltululose 1 - prepared in a conventional manner. Alternatively, a sugar coated tablet may be prepared.

Direct compression

Tablet mg / tablet agent 4.688 28.125 Kálciumhidrogén-phosphate i BP 83.06 87.75 Tablet mg / tablet Croscarmellose nátri- um, NF 1.8 1.8 Magnesium stearate BP 0.45 0.45 Press weight 90.0 118.0

* direct compression quality The active ingredient is passed through a 50 mesh screen, mixed with calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. The resulting blends are compressed into tablets using a Manesty F3 5.5 mm flat tabbed machine with a bevelled edge stamp.

Sublingual (sublingual mg / tablet gual) tablet

Active ingredient 2.5

Pressable sugar, NF 62.5

Magnesium stearate, BP 0.5

Press weight 65.0

The active ingredient is sieved through a suitable sieve, mixed with the fillers and pressed with a suitable stamp. Other strength tablets may be made by varying the active ingredient / filler ratio or compression weight and using appropriate stamps.

Wet granules

Usual tablet mg / tablet

Active ingredient 2.5

I. aciosis, BP 151.5

Starch, BP 30.0

Pregelatinised maize starch, BP 15.0

Magnesium stearate, BP 1.5

Press weight 200.0

The active ingredient is sieved through a suitable sieve, mixed with lactose, starch and pregelatinised corn starch. An appropriate volume of purified water is added to the mixture and granulated. After drying, the granulate is screened and mixed with magnesium stearate. The granules are then pressed into tablets with a 7 mm diameter stamp.

Pills of other strengths, either by varying the active ingredient-lactose ratio or by compression weight and appropriate stamps

application. Can be placed under the tongue (sub g / tablett gual) tablets agent 2.5 Mannitol, BP 56.5 Hydroxypropyl methylcellulose 5.0 Magnesium stearate, BP 1.5 Press weight 65.5

lake

The active ingredient is sieved through a suitable sieve, mixed with mannitol and hydroxypropylmethylcellulose. An appropriate volume of purified water is added and granulated. After drying, the granules are screened and tabletted with suitable stamps.

Other strength tablets may be prepared using either the drug-mannitol ratio or the compression weight and the appropriate stamps.

Capsules mg / tablet

Active ingredient 2.5 * Starch 1500 97.0

Magnesium Stearate, BP 1.0

Filling weight 100.0 * direct pressable starch

The active ingredient is sieved and mixed with the fillers. The mixture is filled into a size 2 hard gelatin capsule with a suitable structure. Other doses may be made by varying the filling: weight and, if necessary, the capsule size.

Syrup

The syrup composition may be a beet sugar or beet sugar free preparation.

A. Sugar beet syrup mg / 5 ml dose

Active ingredient 2.5

Beet Sugar, BP 2750.0

Glycerin, BP 500.0

A. Sugar beet syrup mg / 5 ml dose

Buffer / flavoring /

Coloring. / as desired

Preservative /

Purified water, BP up to 5.0 ml

The active ingredient, buffer, flavoring, coloring and preservative are dissolved in a little water and glycerol is added. The remaining water is heated to dissolve the beet sugar and then cooled. Combine the two solutions, make up to volume and mix. The syrup was clarified by filtration.

B. Sugar free beet syrup mg / 5 ml dose

Active ingredient 2.5

Hydroxypropylmethylcellulose, L'SP 22.5 (Viscosity 4000)

Buffer /

Flavoring /

Coloring / on request

Preservative /

Sweetener /

Purified water, BP up to 5.0 volumes

The hydroxypropylmethyl-target hyalodoxypropyl methyl is dissolved in boiling water, cooled and mixed with an aqueous solution containing the active ingredient and the other syrup ingredients. The resulting solution was adjusted to the volume indicated and stirred. The syrup was clarified by filtration.

Injection preparation

The injection may be administered intravenously or subcutaneously.

-16193592

Injection

Active ingredient Diluted hydrochloric acid, BP Sodium chloride injection, BP pg / ml

800 to pH 3.5 = 1 mL

The active ingredient is dissolved in an appropriate volume of sodium chloride injection (BP) and the resulting solution is adjusted to pH 3.5 with dilute hydrochloric acid (BP). The volume is then adjusted by injection of sodium chloride (BP) and mixed thoroughly. The solution

Type 1 is filled into 5 ml clear glass ampoules by thawing the glass previously sealed with aeration. It is then sterilized at 120 ° C for at least 15 minutes.

Measured dose pressurized aerosol Suspension aerosol mg / dose bottle unit

Active ingredient, micronized 0.250 66 mg

Oleic acid, BP 0.020 5.28mg

Trichlorofluoromethane, BP 23.64 5.67 g Dichlorodifluoromethane,

BP 61.25 14.70g

The active ingredient is micronized to a fine particle size in a liquid energy mill. The oleic acid is mixed with trichlorofluoromethane at 10-15 ° C and the micronized active ingredient is mixed with the solution by means of a shredder mixer. The suspension is weighed into an aluminum aerosol can and fitted with a suitable metering valve of 85 mg suspension and filled with dichlorodifluoromethane via pressure into the package.

Solution aerosol mg / dose bottle

unit agent 0.25 30,0mg Ethanol, BP 7,500 l, 80g Trichlorofluoromethane, BP 18.875 4,35g Dichloro-difluoromethane, BP 48.525 11,65g

(Oleic acid (BP) may also be present on a suitable surfactant such as Span 85 times (sorbitan triolate)).

The active ingredient, together with the oleic acid or surfactant, if used, is dissolved in ethanol and the resulting solution is placed in a suitable aerosol container and trichlorofluoromethane is added. A suitable measuring valve is provided to fill the bottle with dichlorodifluoromethane under pressure. Inhalation cartridge mg / cartridge

Micronized active ingredient 0.5

Lactose, supplemented with BP 25.00 mg

The active ingredient is micronized to a finely divided liquid energy mill and then mixed with high quality lactose in a high energy mixer.

The powder mixture is filled into size 3 hard gelatin capsules using a suitable kap32 melting apparatus. The contents of the cartridge are administered by inhalation.

The compounds of the invention were tested in vitro for antagonizing the 5HT-induced response at neuronal 5HT receptors by Ireland SJ, Straughan DW and Tyers HB; British Journal of Pharmacology, 75, 16P, 1982. The results are given in the following table with pA ₂ values. The pA ₂ of the antagonist CPM of the negative logarithm of the molar concentration of which is required to the effect of 5-HT ED ₅₀ -value is reduced by twice the ED _50, no antagonistic effect.

The number of specimens of the production rat isolated by the planetary nerve was calculated as pA2 ~

9

8.6

8.5

8.7

9.1

The compounds of the present invention were tested in vivo for their ability to antagonize the 5HT-induced response to the 5HT-induced Bezold-Jarisch reflex at neuronal 5HT receptors. The assay is described in Collins DP and Fortuna RH, British Journal of Pharmacology, 80, 570P, 1982. The results are shown in the following table with ED ₅₀ values. This is the dosage amount required for 50% inhibition of 5HT-induced reflex (Fozard JR and Host M., British Journal of Pharmacology, 77, 520P, 1982).

Example number of production ED50

1a 7

3.2

2.5

11.6

Claims (14)

i. Process for the preparation of compounds of the formula I, their physiologically acceptable salts and solvates - in the formula I R ¹ is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-6 alkenyl, phenyl or phenyl (C 1-3 alkyl), One of R ² , R ³ and R ⁴ is hydrogen or C 1-6 alkyl, C 3-7 cycloalkyl, -17193592 C2-C6 alkenyl or phenyl (C1-C3 alkyl) and the other two groups, which may be the same or different, are hydrogen or C1-C6 alkyl, characterized in that one of the compounds of formula II reacting a compound of formula II wherein Y is a methylene group, in this case a double bond to the carbazolone ring, or a -CH ₂ Z group wherein Z is an easily cleaved atom or group, with an imidazoate derivative of formula III or a salt thereof; and, if desired, alkylating, alkenylating or aralkylating the compound of formula (I) wherein R 'is hydrogen or phenyl, and optionally yielding (I) a compound of formula (I) wherein R ¹ is other than hydrogen and phenyl; general The free base of Formula I is converted into a physiologically acceptable salt. Priority: 25.01.1984. 2. A process for the preparation of compounds of formula I, their physiologically acceptable salts and solvates thereof, wherein R ¹ is hydrogen or C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, phenyl or phenyl (C1-C3) alkyl, and One of R ² , R ³ and R ⁴ is hydrogen or C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl or phenyl (C 1-3 alkyl) and the other two - which may be the same or different - are hydrogen or (C 1 -C 6) -alkyl - characterized in that a compound of formula (II) - in formula (II) - Y is a methylene - in this case is double bonded to the carbazolone ring - or -CH _{2 is} reacted with an imidazole derivative of general formula (III) or a salt thereof and optionally substituted with an R ¹ substituent other than hydrogen and phenyl as described above. obtained with R ¹ in the form of hydrogen ( The compound of formula (I) is alkylated, alkenylated or aralkylated and / or, if desired, to form a compound of formula (I) wherein R ', R ² , R ³ and / or R ^{4 are C} 2 -C 6 alkyl. Hydrogenating the compound of formula I having R ² , R ³ and / or R ⁴ substituted with C 2 -C 6 alkenyl18 and optionally converting the resulting free base of formula I into a physiologically acceptable salt. Priority: 15.10.1984. 3. Process for the preparation of compounds of the formula I, their physiologically acceptable salts and solvates and their optically active enantiomers - in the formula I R ¹ is hydrogen or C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, phenyl or phenyl (C 1 -C 3 alkyl), and One of R ² , R ³ and R ⁴ is hydrogen or C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl or phenyl (C 1-3 alkyl) and the other two - which may be different - is hydrogen or (C 1 -C 6) -alkyl, characterized in that a) a compound of formula II, wherein Y is a methylene group in formula II, in which case it is double bonded to the carbazolone ring, or a group of formula -CH ₂ Z wherein Z is an easily cleaved atom or group; with an imidazole derivative of the general formula (II) or a salt thereof, or b) oxidizing a compound of formula IV, wherein A represents a hydrogen atom or a hydroxy group, or a salt thereof, and optionally, where R ¹ is a substituent other than hydrogen, to produce a compound of formula I as described above the resulting compound of formula (I) wherein R 'is hydrogen is alkylated, alkenylated or aralkylated and / or, if desired, the compound of formula (I) wherein R ¹ , R ² , R ³ and / or R ⁴ is C 2 -C 6 hydrogenating the compound of formula (I) wherein R ¹ , R ² , R ³ and / or R ^{4 are C} 2 -C 6 alkenyl, as hereinbefore obtained, and if desired, preparing the optically active enantiomer, a racemic compound of formula (I) resolution and / or the resultant (I) optionally converting the free base of Formula I to a physiologically acceptable salt. Priority: 25.01.1985. The process of claim 1 wherein R ¹ is hydrogen, C 1-6 alkyl, For the preparation of compounds of formula I having from 3 to 6 carbon atoms cycloalkyl or from 3 to 6 carbon atoms alkenyl, characterized in that they are suitably substituted -18193592 (Π) and starting materials (III). Priority: 25.01.1984. A process for the preparation of a compound of formula (I) according to claim 1 or 4, wherein any of R ² , R ³ and R ⁴ is C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 carbon atoms. and the other two groups, which may be the same or different, are hydrogen or (C 1 -C 3) -alkyl, characterized in that the appropriately substituted starting compounds (II) and (III) are used. Priority: 25.01.1984. A process for the preparation of a compound of formula (I) according to claim 1 wherein R ¹ is hydrogen or C 1-6 alkyl, C 5-6 cycloalkyl or C 3-4 alkenyl, and either Ic is hydrogen and R ^α and / or R ⁴ is C 1 -C 3 alkyl or R ² is C 1 -C 3 alkyl and both R ³ and R ⁴ are hydrogen, characterized in that the appropriately substituted starting compounds of formulas II and III compounds. Priority: 25.01.1984. 7. A process according to claim 1 for the preparation of compounds of formula (Ia), their physiologically acceptable salts and solvates thereof, R10 is hydrogen or methyl, ethyl, propyl, 2-propyl, 2-propenyl or cyclopentyl, R ³ 'is hydrogen, and either R ^5a is methyl, ethyl, propyl or 2-propyl and R ⁴ 'is hydrogen or R ^2a is hydrogen and R ⁴ 'is methyl or ethyl, characterized in that the appropriately substituted starting compounds of formulas II and III are used. Priority: 25.01.1984. The process according to claim 1, 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one , for the preparation of a physiologically acceptable salt and solvate thereof, characterized in that the appropriately substituted starting materials of the formulas II and III are used. Priority: 25.01.1984. The process according to claim 1, which is 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazole) 36 -1-yl) methyl] -4H-carbazol-4-one hydrochloride, characterized in that the appropriately substituted starting materials of the formulas II and III are used. 5 Priority: 25.01.1984. The process according to claim 1, which is 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one- hydrochloride dihydrate, wherein the appropriately substituted starting compounds of formulas II and III are used. Priority: 25.01.1984. The process according to claim 1, which is 1,2,3,915-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9- (2-propenyl) -4H-carbazole-4- on, 9-cyclopentyl-1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one, 1,2,3, 9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] 9- (2-propyl) -4H-carbazol-4-one, physiologically acceptable for the preparation of their salts and solvates, using appropriately substituted starting compounds of formulas II and III. ²⁵ Priority: 25.01.1984. 12. A process for the preparation of a pharmaceutical composition for use in the central nervous system, comprising the preparation of a compound of formula I according to claim ¹ , wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1, , a physiologically acceptable salt or solvate thereof, is converted into a pharmaceutical formulation commonly used in the manufacture of pharmaceuticals. 35 Priority: 25.01.1984. 13. A process for the preparation of a pharmaceutical composition for use in the central nervous system, comprising the preparation of a compound of formula I according to claim ² , wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 2, the physiologically acceptable salt or solvate thereof is converted into a pharmaceutical composition by the customary pharmaceutical excipients. 45 Priority: 15.10.1984. 14. A process for the preparation of a pharmaceutical composition for use in the central nervous system, wherein the compound of formula (I) according to claim 3, wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 3, a physiologically acceptable salt or solvate or an optically active enantiomer thereof, in a pharmaceutical preparation with the usual excipients.