NO164025B - ANALOGY PROCEDURE TE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 3-IMIDAZOLYLMETHYL-TETRAHYDROCARBAZOLONE DERIVATIVES. - Google Patents

Description

This invention relates to a method for the production of heterocyclic compounds which can be used in pharmaceutical preparations. In particular, the invention relates to the production of compounds that act on certain 5-hydroxytryptamine (5HT) receptors.

5HT, which occurs endogenously in abundant amounts in peripheral nerves and in blood platelets, is known to cause pain in humans through a specific action on 5HT receptors located at the ends of primary afferent nerves. Compounds that counteract the neuronal effects of 5HT have been shown to have analgesic properties, for example to relieve migraine pain. 5HT also causes depolarization of isolated rat vagus nerve preparations through the same 5HT receptor mechanism, and inhibition of this effect correlates with an analgesic effect in vivo.

5HT also occurs extensively in neuronal pathways

in the central nervous system and disruption of these pathways containing 5HT is known to alter behavioral syndromes, such as mood, psychomotor activity, appetite and memory. Since "neuronal" 5HT receptors of the same type as those found in primary afferent endings are also present in the central nervous system, it is believed that compounds that antagonize the neuronal effects of 5HT would be useful in the treatment of conditions such as schizophrenia, anxiety, severe obesity and mania.

Existing treatments for such conditions suffer

a number of disadvantages. Thus includes e.g. Known treatments for migraine include the administration of a vasoconstrictor such as ergotamine, which is non-selective and constricts blood vessels throughout the body. Ergotamine therefore has unwanted and potentially dangerous side effects. Migraine can also be treated by administering an analgesic such as aspirin or paracetamol, usually in combination with an antiemetic such as metoclopramide, but these treatments are only of limited value.

Similarly, existing treatments for psychotic disorders such as schizophrenia show a number of serious side effects such as extrapyramidal side effects.

There is thus a need for a safe and effective drug for the treatment of conditions in which disturbance of 5HT pathways is involved, such as migraine or psychotic disorders such as schizophrenia. It is believed that a compound which is a strong and selective antagonist at "neuronal" 5HT receptors would fulfill such a role.

We have now found a group of 3-imidazolylmethyl-tetrahydrogen-carbazolones which are strong and selective antagonists at "neuronal" 5HT_receptors.

The present invention provides a process for the preparation of a tetrahydrogencarbazolone with the general formula (I):

in which

R represents a hydrogen atom or a C 1 -C 1 -alkyl, C 1 -C 1 -cycloalkyl, C 1 -alkenyl, phenyl or phenyl-C 1 -alkyl group,

2 3 4

and one of the groups represented by R, R and R

is a hydrogen atom or a C 1-7 alkyl, C 1-7 cycloalkyl, C 2 galkenyl or phenyl-C 1-7 alkyl group and each of the other two groups", which may be the same or different,

represents a hydrogen atom or a C1-6 alkyl group;

and physiologically acceptable salts and solvates, e.g. hydrates thereof.

It must be clear that when R^ denotes a C^^alkenyl group, the double bond cannot be adjacent to the nitrogen atom.

With reference to the general formula (I), alkylgrup-12 3 4

represented by R , R , R and R are alkyl groups with straight chains or branched chains, for example methyl, ethyl propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-2-yl, pentyl, pent-3-yl or hexyl.

An alkenyl group can be, for example, a propenyl group.

A phenyl-C 1-2-alkyl group can, for example, be a benzyl, phenethyl or 3-phenylpropyl group.

A cycloalkyl group can e.g. be a cyclopentyl, cyclohexyl or cycloheptyl group.

It should be clear that the carbon atom in the 3-position of the tetrahydrocarbazalone ring is asymmetric and can exist in the R or S configuration. The present invention encompasses both the individual isomeric forms of the compounds of formula (I) and all mixtures, including racemic mixtures thereof.

Suitable physiologically acceptable salts of the indoles of general formula (I) include acid addition salts formed with organic or inorganic acids, e.g. hydrogen chlorides, hydrogen bromides, sulphates, phosphates, citrates, fumarates and maleates. The solvates can e.g. be hydrates.

A particularly preferred compound is 1,2,3,9-tetrahydrogen-9-methyl-3-2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, which can be represented by formula ( la) :

and the physiologically acceptable salts and solvates (eg hydrates) thereof. A preferred form of this compound is hydrogen chloride dihydrate.

US patents 3634420 and 3740404 describe, among other things, 3-methyltetrahydrocarbazol-4H-ones with a number of different N-linked substituents on the 3-methyl group. The substituents comprise N-linked heterocyclic groups (eg 3-pyrroline as in the product according to example 8 in US patent 3634420).

However, no mention is made of compounds where the N-linked substituent is an aromatic, heterocyclic group

and of course nothing about an imidazole group either.

Compounds produced according to the invention are strong and selective antagonists of 5HT-induced reactions in isolated vagus nerve preparations from rats and thus act as strong and selective antagonists at the "neuronal" 5HT receptor type which is localized to primary supplying nerves.

Compounds prepared according to the invention are useful as analgesics, e.g. for the relief of pain associated with migraine, headache and many other forms of pain for which 5HT is the endogenous mediator.

Experiments on animals have shown that the compounds produced according to the invention are also useful in the treatment of schizophrenia and other psychotic disorders. As indicated above, 5HT occurs to a large extent in nerve pathways in the central nervous system and disruption of these pathways containing 5HT is known to alter many other behavioral syndromes such as mood, appetite and memory. Since "neuronal" 5HT receptors of the same type as those present on primary afferent endings, also

is present in the central nervous system, the compounds prepared according to the compound may also be useful in the treatment of conditions such as anxiety, severe obesity and mania.

In particular, the compound of formula (Ia) as previously defined has been found to be very selective and extremely strong in its effect. It is easily absorbed from the gastrointestinal tract and is suitable for oral and rectal administration. The compound of formula (Ia) does not prolong the sleep time of mice anesthetized with pentobarbitone, indicating that there is no adverse reaction with drug-metabolizing enzymes. In fact, no adverse effects are shown in mice at doses up to 1 mg/kg intravenously.

As well as showing these excellent properties, the compound of formula (Ia) showed no adverse effects when administered to humans.

The antagonism of responses evoked by 5HT at "neuronal" 5HT receptors, by means of compounds prepared according to the invention can be determined in vitro by the method described in Ireland S.J., Straughan D.W.09Tyers M.B.; British Journal of Pharmacology, 75_, 16P, 1982. The results of such investigations are expressed as a pA2 value in the table below. This value is defined as the negative logarithm of the molar concentration of antagonist required to reduce the effect of twice the ED50 of 5HT to the effect of the ED50 in the absence of antagonist.

The antagonism of responses evoked by 5HT at "neuronal" 5HT receptors by means of compounds prepared according to the invention can be assessed in vivo by determining the effect of the compounds on the 5HT-evoked Bezold-Jarisch reflex. This test is described in Collins D.P., and Fortune R.H., British Journal of Pharmacology, 8J>»570P, 1983. The results are expressed below in the table as an ED50 which is the dose required to inhibit the 5HT-evoked reflex by 50% ( see Fozard, J.R., and Host M., British Journal of Pharmacology, 77, 520P, 1982).

According to the invention, the compounds of the general formula (I) and physiologically acceptable salts or solvates or physiologically acceptable equivalents thereof can be prepared by the general methods outlined hereafter.

According to the first general reaction (A), a compound of general formula (I) or a physiologically acceptable salt or solvate or a physiologically acceptable equivalent thereof can be prepared by reacting a compound of general formula (II): (whereR<1 > is as defined previously and Y represents a methylene group or group CH2Z where Z is a leaving group with an imidazole of general formula (III):

{in which R<2>, R<3> and R<4> are as previously defined) or a salt thereof.

Examples of compounds of formula (II) used as starting materials in reaction (A) include the compounds in which Y represents one group selected from a methylene group =CH 2 or a group of formula CH 2 Z where Z represents an atom or a group that readily substituents, such as a halogen atom, e.g. chlorine or bromine, an acyloxy group such as acetoxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy, a group -Sr<5>R<6>R<7>X~, where R5, R6 and R7 which may be the same or different, each represent lower alkyl, e.g. methyl, aryl, e.g. phenyl or arylalkyl, e.g. benzyl, or R and R together with the nitrogen atom to which they are attached may form a 5- to 6-membered ring, e.g. a pyrrolidine ring, and X represents an anion such as a halide ion, e.g. chloride, bromide or iodide, or a group -NR^R^ where R^ and R<6> are as defined above, e.g. -N(CH.j) 2 .

When Y represents the group =CH2, the reaction can conveniently take place in a suitable solvent, examples of sl. includes water, esters, e.g. ethyl acetate, ketones, e.g. act ton, or methyl isobutyl ketone, amides, e.g. dimethylformamide, alcohols, e.g. ethanol, and ethers e.g. dioxane or tetrahydrofuran, or mixtures thereof. The reaction can take place at a temperature of e.g. 20 to 100°C.

When Y represents the group CH2Z, where Z is a halogen atom or an acyloxy group, the reaction can conveniently take place

in a suitable solvent such as an amide, e.g. dimethylformamide, an alcohol, e.g. methanol or industrial methylated alcohol, or alkyl halide, e.g. dichloromethane, and at a temperature from -10 to 150°C, e.g. 20 to 100°C.

The reaction of a compound of formula (II) where Y stands for the group CH2Z where Z is the group -&R<5>R<6>R<7>X~ can conveniently take place in a suitable solvent such as water, an amide, e.g. e.g. dimethylformamide, a ketone, e.g. acetone or an ether, e.g. dioxane, and at a temperature from 20 to 150°C.

The reaction which comprises a compound of formula (II) where Y stands for the group -CH2Z where Z is the group -NR"<*>R^, can suitably take place in a suitable solvent such as water or an alcohol, for example methanol or a mixture thereof and at a temperature from 20 to 150°C.

According to another general reaction (B), a compound of formula (I) can be prepared by oxidizing a compound of formula (IV):

(where A means a hydrogen atom or a hydroxyl group and R<1>, R<2>, R<3> and R<4> are as previously defined) or a salt or

! |in a protected derivative thereof.

The oxidation process can be carried out using conventional methods and the reagents and reaction conditions should be selected

so that they do not cause oxidation of the indole group. Thus, the oxidation reaction is preferably carried out using a mild oxidizing agent.

When a compound of formula (IV) where A represents a hydrogen atom is to be oxidized, suitable oxidizing agents include quinones in the presence of water, e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3,5,6-tetrachloro-1,4-benzoquinone, selenium oxide, a cerium(IV) oxidizing agent such as cerium ammonium nitrate or a chromium ( VI) oxidizing agent, e.g. a solution of chromic acid in acetone (eg Jones' reagent) or chromium trioxide in pyridine.

When a compound of formula (IV) where A represents a hydroxyl group is to be oxidized, suitable oxidizing agents include quinones in the presence of water, e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3,5,6-tetrachloro-1,4-benzoquinone, ketones, e.g. acetone, methyl ethyl ketone or cyclohexanone, in the presence

of a base, e.g. aluminum t-butoxide, a chromium(VI) oxidizing agent, e.g. a solution of chromic acid in acetone (e.g. Jones reagent) or chromium trioxide in pyridine, an N-halosuccinimide, e.g. N-chlorosuccinimide or N -bromosuccinimide, a dialkylsulfoxide, eg dimethylsulfoxide, in the presence of an activating agent such as N,N'dicyclohexylcarbodiimide or an acyl halide, eg oxalyl chloride or tosyl chloride, pyridine-sulfur trioxide complex, or a dehydrogenating catalyst such as copper chromite, zinc oxide, copper or silver.

Suitable solvents can be chosen from ketones, e.g. acetone or butane, ethers, e.g. tetrahydrofuran or dioxane, amides, e.g. unmethylformamide, alcohols, e.g. methanol, hydrocarbons, e.g. benzene or toluene, halogenated hydrocarbons, e.g. dichloromethane, and water or mixtures thereof. The reaction is conveniently carried out at a temperature from -70 to 50°C. It must be clear that the choice of oxidizing agent will affect the preferred reaction temperature.

According to another general reaction (C), a compound of formula (I) in which R<1>represents a C1-10alkyl-, C3-7c<y>chloroalkyl-, c3-6al*enyl- or phenyl-C^alkyl group can be prepared by alkylation of a compound of formula (I)

where R represents a hydrogen atom. The term "alkylation" includes the introduction of other groups such as cycloalkyl-

or alkenyl groups.

The above alkylation reactions can be carried out using

the suitable alkylating agents selected from compounds of formula R<a>X<a>where Ra represents a C^^alkyl, C3_?cycloalkyl-, C3_galkenyl- or phenyl-C^<a>alkyl group, andX<a>represents a "leaving group" such as a halide or acyloxy group as previously defined for Z, or a sulfate of formula (R<a>)2S0^.

The alkylation reaction conveniently takes place in an inert organic solvent such as an amide, e.g. dimethylformamide, an ether, e.g. tetrahydrofuran or an aromatic hydrocarbon, e.g. toluene, preferably in the presence of a base. Suitable bases include e.g. alkali metal hydrides such as sodium hydride, alkali metal amides such as sodium amide, alkali metal carbonates such as sodium carbonate or an alkali metal alkoxide such as sodium or potassium methoxide, -ethoxide or -t-butoxide. The reaction can suitably be carried out at a temperature in the range -20 to 100°C, preferably 0 to 50°C.

According to another general method (D), can

a compound of formula (I) containing an alkyl substituent is prepared by hydrogenating a compound of formula (I) containing the corresponding alkenyl substituent.

Hydrogenation according to general reaction (D) can be carried out

using common methods, e.g. by using hydrogen in the presence of a noble metal catalyst, e.g. palladium, Raney nickel, platinum, platinum oxide or rhodium. The catalyst can be carried on e.g. charcoal or a homogeneous catalyst such as tris(triphenylphosphine)rhodium chloride can be used. The hydrogenation

will generally be carried out in a solvent such as an alcohol, e.g. ethanol, an amide, e.g. dimethylformamide, an ether, e.g. dioxane or an ester, e.g. ethyl acetate, and at a temperature in the range -20 to 100°C, preferably 0 to 50°C.

The compounds of formula (I) can be converted into their physiologically acceptable salts according to conventional methods. Thus, e.g. the free base of general formula (I) is treated with a suitable acid, preferably with an equivalent amount in a suitable solvent (eg aqueous ethanol).

Physiologically acceptable equivalents of a compound of formula (I) can be prepared according to conventional methods.

Individual enantiomers of the compounds prepared according to the invention can be obtained by resolving a mixture

of enantiomers (e.g. a racemic mixture) by conventional means, such as an optically active dissolving acid, see e.g. "Stereochemistry of Carbon Compounds" by E.I. Eliel (McGraw Hill 1962) and "Tables of Resolving Agents" by S.H.Wilen.

Examples of optically active dissolving acids that can be used to form salts with the racemic compounds include the (R) and (S) forms of organic carboxylic and sulfonic acids such as tartaric acid, di-p-toluoyltartaric acid, camphorsulfonic acid, and lactic acid. The resulting mixtures of isomeric salts can be separated, e.g. by fractional crystallization, in diastereoisomers and, if desired, the optically active isomers sought can be transferred to the free base. •

The procedures indicated above for manufacture

of the new compounds, can be used as the last essential step in the manufacturing sequence. The same general procedures can be used to introduce desired groups at an early stage in the stepwise formation of the desired compound, and it will also be clear that these general procedures can be variously combined in such multi-stage reactions. The order of the reactions in reactions with several steps should of course be chosen so that the reaction conditions used do not affect groups in the molecule that are desired in the final product!

tight.

The starting materials of formula (II) where Y represents the group =CH_ can be prepared from compounds of formula (II) where Y represents the group CF^N+ R 5 R 6 R 7 X~ — by reaction with a base in a suitable solvent. Examples of bases include alkali metal hydroxides, e.g. potassium hydroxide or alkali metal carbonates or hydrogen carbonates, e.g. sodium hydrogen carbonate.

The quaternary salts can be formed from the corresponding tertiary amines by reaction with an alkylating agent such as methyl iodide or dimethyl sulfate, if desired in a suitable solvent, e.g. dimethylformamide. The tertiary amines can be produced by reacting a tetrahydrogencarbazolone with the general formula (V):

with formaldehyde and the corresponding secondary amine, if desired in a suitable solvent such as an alcohol, e.g. ethanol.

Compounds of general formula (V) can be prepared,

for example by the method described by H. Iida et al. in J.Org. Chem. (1980) Vol. 45, No. 15, Pages 2938 - 2942.

The starting materials of general formula (II) where Y represents -CH2Z and where Z is a halogen atom or an acyloxy group, can be prepared from the corresponding hydroxymethyl derivative of general formula (VI):

which can be obtained by reacting the tetrahydrogencarbazolone of general formula (V) with formaldehyde, preferably in a suitable solvent

agent such as an alcohol, e.g. ethanol and preferably in the presence of a base.

Thus, one can get compounds where Z is a halogen atom

by reacting a compound of formula (VI) with a halogenating agent such as a phosphorus trihalide, e.g. phosphorus trichloride.

The compounds where Z is an acyloxy group can be prepared by reacting a compound of formula (VI) with a suitable acylating agent such as an anhydride or a sulfonyl halide such as sulfonyl chloride.

Compounds of formula (II) where Y represents -CH 2 Z

where Z is a halogen atom, can also be produced by reacting a compound of formula (II) where Y represents the group =CH2

with the appropriate hydrogen halide, e.g. hydrogen chloride, suitably in a suitable solvent such as an ether, e.g. diethyl ether.

Compounds of general formula (IV) can be prepared

by reacting a compound of formula (VII):

(where R and A are as defined previously and Z is an atom or a group that can easily be substituted, such as a halogen atom, an acyloxy group or the group -?]R^R^R7X~ as previously defined for Z) with an imidazole with formula (III) according to the procedure in reaction (A) which is described here.

Compounds of formula (VII) can be prepared by reducing compounds of formula (II) using e.g. lithium aluminum hydride or sodium borohydride.

Compounds of formula (VII) in which A represents a hydrogen atom can also be prepared by reacting a compound of formula (VII) in which A represents a hydroxyl group with a tosyl halide (eg tosyl chloride) and then reducing the resulting tosylate with lithium aluminum hydride.

The following examples illustrate the invention. The temperatures are in °C. Where indicated, solutions were dried over Na 2 SO 4 and solids were dried in vacuo at ?2°5ve<^ 50°C overnight. Chromatography was performed using the technique described by W.C. Still et al. (J.Org.Chem., 1978, 43, 2923 - 2925), on silica gel 9385.("tetrahydrogen"="tetrahydro").

MANUFACTURE 1

2, 3, 4, 9- tetrahydroqen- N, N, N- trimethyl- 4- oxo- 1H- carbazole- 3- methyl ammonium iodide

A solution of 3-[(dimethylamino)methyl-1,2,3,9-tetrahydrogen-4H-carbazol-4-one (0.53 g) in methyl iodide (15 ml) was heated at reflux for 5 hours and evaporated to dryness to give the title compound as a white solid (0.84 g). melting point

202 - 205°C.

MANUFACTURE 2

2, 3, 4, 9- tetrahydrogen- N, N, N, 9- tetramethyl- 4- oxo- 1H- carbazole-3- methylammonium iodide

A suspension of 3-£(dimethylaminojmethyl}-1,2,3,9-tetrahydrogen-9-methyl-4H-carbazol-4-one (3.80 g) in methyl iodide (100 ml)

was stirred under reflux for 57 hours. The resulting suspension was concentrated in vacuo to give the title methylammonium iodide as a solid (5.72 g), mp 192-195°C.

MANUFACTURE 3

1, 2, 3, 9- tetrahydrogen- 9- methyl- 3- methylene- 4H- carbazol- 4- one

A solution of the product from Preparation 2 (5.0 g)

in water (20 mL) was treated with 2N sodium carbonate (6.55 mL)

and heated at 35°C for 45 min. The resulting slurry was cooled to 0°C and the solid was filtered off, washed with water and dried to give the title compound (2.8g), mp 127-129°C.

EXAMPLE la

1, 2, 3, 9- tetrahydrogen- 9- methyl- 3- T( 2- methyl- 1H- imidazol- 1- yl)-methyl"] - 4H- carbazol- 4- one- hydrogen chloride

A solution of the product from Preparation 2 (2.0 g)

and 2-methylimidazole (5.0 g) in dry dimethylformamide (30 mL) was stirred under nitrogen at 95°C for 16.75 hours and then allowed to cool. The solid that crystallized was filtered off, washed with ice-cold dry dimethylformamide (3 x 2 mL) and dry ether (2 x 10 mL) and then dried. The resulting solid (0.60 g) was suspended in a mixture of absolute ethanol (30 ml) and ethanolic hydrogen chloride (1 ml), and heated

carefully to obtain a solution which was filtered while hot. The filtrate was then diluted with dry ether and a solid precipitated (0.6 g9 which was recrystallized from absolute ethanol to give the title compound as a solid (0.27 g) mp 186-187°C.

Analysis Found C, 61.9; H, 6.4; N, 11.8<C>18H19N30,HC1'H2° requires c'62'3; H'N» 12.1%

The following compounds were prepared by a similar procedure as detailed in Table I:

Table 1 continued:

NOTICE 1

Compounds 1e and 1f were prepared in the same experiment

and the isomers were separated by short path chromatography (D.F. Taber, J.Org.Chem., 1982, 47, 1351) eluting with dichloromethane/ethanol/0.88 ammonia (300:10:1). The following 'H n.m.r. data was captured.

EXAMPLE 2

1, 2, 3, 9-tetrahydroqen-9- methyl- 3- r(2- methyl-TH-imidazol-1-yl)-methyl]- 4H-carbazol-4-one maleate

1,2,3,9-tetrahydrogen-9-methyl-3-£(2-methylimidazol-1-yl)methyl3-4H-carbazol-4-one (300 mg) was suspended in hot ethanol (5 ml) and treated with maleic acid (116 mg). The solution was cooled and the white crystalline solid was filtered off and dried to give the title compound (300 mg), mp 132.3°C.

EXAMPLE 3a

1, 2, 3, 9- tetrahydrogen- 3-( 1H- imidazol- 1- ylmethyl)- 4H- carbazol-4- one

A solution of the product of Preparation 1 (0.84 g) and imidazole (0.90 g) in dimethylformamide (25 mL) was heated at 105°C for 6 hours, cooled, added to water (200 mL) and extracted six times with ethyl acetate. The combined extracts were washed, dried and evaporated to give a solid which was purified on a silica column (Merck 7734) eluted with ethyl acetate/methanol (4:1). Recrystallization twice from ethyl acetate/methanol gave the title compound (0.095 g) as a crystalline solid, mp 220-222°C.

T.l.c. Silicon oxide, dichloromethane/ethanol/0.88 ammonia (100: 8:1) Rf 0.33, detection u.v. and iodoplatinic acid.

The following descriptions were produced by a similar method as described in Table II. The salt formation took place as described in example 2.

Note 1 to Table II

Compounds 3e and 3f were prepared in the same experiment and the isomers were separated by preparative "h.p.l.c" on Zorbax sieve and washing with hexane/ethyl acetate/ethanol/0.88 ammonia (400:100:100:0.6) . In the table, the positions of the protons are numbered with reference to the formula below

The symbols in table II have the following meanings: d = doublet, dd = doublet of doublets, s =» singlet. Y represents the group

EXAMPLE 4

1, 2, 3, 9- tetrahydrogen- 9- methyl- 3- r( 2- methyl- 1H- imidazol- 1- yl)-methylJ- 4H- carbazol- 4- one

A solution of 1,2,3,9-tetrahydrogen-3-Q2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (1.0 g) in dry dimethylformamide (10 ml) was added dropwise under nitrogen to a stirred ice-cooled suspension of sodium hydride (80% in oil; 0.11 g) in dry dimethylformamide (5 mL). After 0.5 h, dimethyl sulfate (0.34 mL) was added and the solution was stirred at room temperature

for 4 hours. The resulting solid was filtered off, washed with ice-cold dry dimethylformamide (2 x 5 mL) and dry ether (3 x 15 mL) and dried to give the title compound as a solid (0.25 g) mp 223 - 224°C ( dec.).

T.l.c. Silicon oxide, chloroform/methanol (93:7) Rf 0.27 detection u.v. and iodoplatinic acid, identical to the product from example la.

The following compounds were prepared by a similar procedure using the appropriate alkylating agents as described in Table III.

Table III continued:

NOTICE 1

The following 'H n.m.r. data was captured.

EXAMPLE 5

9- cyclopentyl- 1, 2, 3, 9- tetrahydrogen- 3- Q2- methyl- IH- imidazol-1- yl) methyl 1- 4H- carbazol- 4- one- maleate

A solution of 1,2,3,9-tetrahydrogen-3-(N2-methyl-1H-imidazol-1-yl)methyl3-4H-carbazol-4-one (1.20 g) in dry dimethylformamide (9 ml) was added to a stirred, ice-cooled suspension of sodium hydride (80% in oil; 0.14 g) in dry dimethylformamide

(2 mL) under nitrogen, and stirring continued for 0.25 h. Bromocyclopentane (0.51 mL) was added and the stirred solution was heated at 100°C for 18.5 hours. The solution was allowed to cool and was then separated between water (100ml)

and ethyl acetate (3 x 70 mL). The combined organic extracts were washed with 2N sodium carbonate (2 x 50 ml), water (2 x 50 ml) and sodium chloride solution (50 ml), dried, evaporated to dryness and purified by chromatography and eluting with a mixture of dichloromethane, ethanol, 0.88 ammonia (150:10:1) and gave an oil (0.27 g). This oil was dissolved in refluxing absolute ethanol (7 ml) and a solution of maleic acid (0.10 g) in refluxing absolute ethanol (0.5 ml) was added. The hot solution was filtered, stirred and diluted with dry ether (20 mL). The resulting yellow gum was washed with dry ether (7 x 25 mL), and the combined mother liquors and washings were allowed to stand. The solid that crystallized from the solution was filtered off, washed with dry ether (3 x 5 mL) and dried to give the title salt as a white crystalline solid (0.058 g), mp 104.5-106°C. Analysis Found C, 65.95; H, 6.4; N, 8.6 C22<H>25<N>3<O>'C4H4°4,0'6H2° requires C'65'8> H»6'4?N» 8»9%

EXAMPLE 6

1, 2, 3, 9- tetrahydrogen- 3- C( 2- methyl1- 1H- imidazol- 1- yl) methyl]-9-( 2- propenyl)- 4H- carbazol- 4- on- maleate

A solution of 1,2,3,9-tetrahydrogen-3-j2-methyl-1H-imidazol-1-yl)methyl3-4H-carbazol-4-one (1.0 g) in dry dimethylformamide (6 ml) was added to a stirred, ice-cooled suspension of sodium hydride : ("8~6%l\.jL\ol je; 0.12 g) in dry dimethylformamide (2 ml)'.. After 0.25 hours^ allyl bromide was added, the solution was stirred at 0°C for 0.25 h and at room temperature for 20 h before partitioning between water (75 mL) and ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 x 50 mL ), sodium chloride solution (50 mL) dried and concentrated in vacuo and purified by chromatography eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (200:10:1) to give a solid (0.43 g) This solid was dissolved in refluxing absolute ethanol (2 mL) and a solution of maleic acid (0.18 g) in refluxing absolute ethanol (1 mL) was added. was filtered, diluted with dry ether (4 mL) and crystallized e solid was filtered off, washed with dry ether (3 x 5 mL) and dried to give the title compound as a white solid (0.48 g), mp 150.5 - 151°C. Analysis Found: C, 66.3; H, 5.75; N, 9.6 C20<H>21<N>3O,C4H4°4requires C'66'2?H'5'8; N'9'65%

EXAMPLE 7

1, 2, 3, 9- tetrahydrogen- 9- methyl- 3- f( 2- methyl- 1H- imidazol- 1- yl)-methyl"] - 4H- carbazol- 4-one

A solution of 3-[{dimethylamino)methyl]-1,2,3,9-tetrahydrogen-9-methyl-4H-carbazol-4-one hydrogen chloride (1.7 g) in water (17 ml) was treated with 2-methyl-imidazole (1.4 g) and then heated under reflux for 20 hours. The cooled mixture was filtered and the residue was washed with water (3 x 15 ml) to give the pure product (1.7 g), mp 221-221.5°C. This material was recrystallized from methanol to give the title compound (1.4 g), mp 231-232°C, identical at t.l.c. with the product from example 4.

EXAMPLE 8

1, 2, 3, 9- tetrahydrogen- 9- methyl- 3- C( 2- methyl- 1H- imidazol- 1- yl)-methyl] - 4H- carbazol- 4- one

A suspension of the product from Preparation 3 (0.5 g)

and 2-methylimidazole (0.4 g) in water (5 ml) was refluxed for 20 hours. The cooled reaction mixture was filtered and the residue washed with water (3 x 10 ml), dried and recrystallized from methanol (18 ml) to give the title compound (0.3 g), mp 232-234°C (dec.), identical at t.l.c. with the product from example 4.

EXAMPLE 9

1, 2, 3, 9- tetrahydrogen- 9-( 1- methylethyl)- 3- D2- methyl- 1H- imidazol-1- yl) methyl] - 4H- carbazol- 4- one- hydrogen chloride

Sodium hydride (80% dispersion in oil, 0.208 g) was added to a stirred solution of 1,2,3,9-tetrahydrogen-3-[2-methyl-1H-imidazol-1-yl]methyl}-4H-carbazole-4 -one (1.93 g) at 0 °C in DMF (35 mL) and the resulting suspension was stirred at 0 °C for 0.25 h. 2-Bromopropane (0.78 mL) was then added and stirring continued at room temperature overnight, followed by 4 hours at 40°C. The reaction mixture was partitioned between sodium carbonate (2N; 200 mL) and ethyl acetate (2 x 150 mL). The combined organic extracts were washed with water (3 x 75 mL), dried, and evaporated in vacuo and the product was purified by chromatography, eluting with dichloromethane:ethanol:ammonia (100:8:1) to give an oil.This oil was dissolved in ethanol (3 mL), acidified with ethereal hydrogen chloride and diluted with dry ether, and the title compound was precipitated as a white solid (0.13 g), mp 230-232°C.

Analysis Found: C,65.3; H, 6.6; N, 11.1%<C>2Q<H>23<N>3<0>.HC1.0.5 H2O requires C, 65.4; H, 6.9; N, 11.45%

EXAMPLE 10

1, 2, 3, 9- tetrahydroqen- 9- methyl- 3-[( 2- methyl- 1H- imidazol- 1- yl)-methyl]- 4H- carbazol- 4- one- hydrogen chloride- dihydrate

1,2,3,9-tetrahydrogen-9-methyl-3-C(2-methyl-1H-imidazol-1-yl)methyl3-4H-carbazol-4-one (18.3 g) in hot solution of isopropanol (90 mL) and water (18.3 mL) were treated with concentrated hydrochloric acid (6.25 mL). The hot mixture was filtered and the filtrate diluted with isopropanol (90 ml) and stirred at room temperature for 17 hours, cooled to 2°C and the solid filtered off (21.6 g). A sample (6 g) was recrystallized from a mixture of water (6 ml) and isopropanol (10 ml) to give the title compound as a white crystalline solid (6 g), mp 178.5 - 179.5°C.

EXAMPLE 11

1, 2, 3, 9- tetrahydroqen- 3-(( 2- methyl- 1 H- imidazol- 1- yl) methyl? - 9- phenyl- 4H- carbazol- 4- one- maleate

i) 3- f( dimethylamino) methyl) - 1, 2, 3, 9- tetrahydrogen-9- phenyl- 4H- carbazol- 4- one- hydrogen chloride

A solution of 1,2,3,9-tetrahydrogen-9-phenyl-4H-carbazol-4-one (3.90 g), dimethylamine hydrogen chloride (1.50 g) and paraformaldehyde (0.60 g) in glacial acetic acid was stirred by heating

refluxed under nitrogen for 42 hours, allowed to cool and concentrated in vacuo. The remaining brown gum was stirred with water (50 mL), ethyl acetate (50 mL) and sodium chloride solution (20 mL) for 0.25 h, and the resulting solid was filtered off, washed with dry ether (4 x 30 mL) and dried to give the title compound (4.2 g). A portion of this solid (1.0g) was recrystallized twice from absolute ethanol (10ml) to give the title compound as a light brown powder (0.39g), mp 193-194°C (dec.).

ii) 1, 2, 3, 9- tetrahydrogen- 3-[( 2- methyl- 1H- imida2ol-1- yl) methyl]- 9- phenyl- 4H- carbazol- 4- one- maleate 2-methyl- 1H- imidazole (1.4 g) was added under nitrogen to a stirred suspension of 3-[(dimethylamino)methyl^-1,2,3,9-tetrahydrogen-9-phenyl-4H-carbazol-4-one hydrogen chloride (2 .0 g). The mixture was heated at 90°C for 43 hours and the solvent was decanted from the light brown solid. Chloroform was added to the solid, the suspension was filtered through Hyflo, the filtrate was dried and concentrated in vacuo. Chromatography of the remaining pale brown foam (2.04 g), eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (200:10:1) gave a white foam (1.1 g). A solution of this foam in ethanol (3 ml) was treated with maleic acid (0.4 g) in ethanol (1 ml) followed by dry ether (40 ml) and the resulting gum triturated with dry ether (2 x 40 ml) to give the title compound as a cream-colored solid (1.37 g), m.p. 165 - 166°C (dec.).

Analysis found: C, 68.65; H, 5.5; N, 8.7 C23H21N30,C4H4°4 requires C'68.8; H, 5.3; N, 8.9%

EXAMPLE 12

1, 2, 3, 9- tetrahydrogen- 9- methyl- 3- C( 2- methyl- 1H- imidazol- 1- yl)-methyl- 4H- carbazol- 4- one- phosphate ( 1:1)

1,2,3,9-tetrahydrogen-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (0.61 g) was dissolved in a hot mixture of phosphoric acid (90%, 0.13 ml) and water (10 ml), filtered through Hyflo and allowed to crystallize gave the title compound (0.5 g) m.p. 225°C.

Analysis Found: C,55.1; H, 5.6; N, 10.55 C18Hl9N3O.H3PO4 requires C.55.2; H, 5.7; N, 10.7*

EXAMPLE 13

1, 2, 3, 9- tetrahydrogen- 9- methyl - 3- f_( 2- methyl- 1H- imidazol- 1- yl) - methyl]- 4H- carbazol- 4- one- citrate ( 2:1)

1,2,3,9-tetrahydrogen-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (0.89 g) was dissolved in a hot solution of citric acid (0.58 g) in ethanol (20 mL) and allowed to crystallize.The resulting crystalline solid was recrystallized by dissolving it in acetone/water (2:1 2 mL) and diluting it with acetone (20 ml) and gave the title compound (0.6 g) m.p. 162°C.

EXAMPLE 14

1, 2, 3, 9- tetrahydrogen- 3- C( 2- propyl- 1 H- imidazol- 1 - yl) methyl*]-4H- carbazol- 4- one-hydrogen chloride

Iodomethane (0.75 mL) was added to a stirred solution of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydrogen-4H-carbazol-4-one (2.9 g) in dry DMF ( 30 ml) and the solution was stirred at room temperature for 30 minutes. A solution of 2-propyl-1H-imidazole (2 g) in DMF (5 mL) was added and the solution was stirred at 100°C for 2 days, cooled and partitioned between sodium carbonate (2N, 150 mL) and ethyl acetate (2 x 100ml). The combined extracts were washed with water (100 ml), dried and evaporated in vacuo. The residue was purified by column chromatography eluting with dichloromethane:ethanol:ammonia (400:30:3) to give the free base as a solid (1.2 g). A sample (0.2 g) was dissolved in absolute ethanol (5 ml), acidified with ethereal hydrogen chloride and diluted with dry ether (ca. 200 ml) to give an oil. On scraping, the oil crystallized to give a solid (0.15 g). The salt was recrystallized from a mixture of methanol and isopropyl acetate to give the title compound (0.08 g), mp 206-208°C.

Analysis found: C,65.6; H, 6.8; N, 12.0

CigH 2 1 N 3 O.HCl 0.2 H 2 O requires C, 65.7; H, 6.5; N, 12.1% N.m.r. 5(cD3SOCD3) 0.94 (3H, t,CH3>, 1.77 (2H, sextet, CH2CH2CH3), 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- tetrahydrogen- 3- f*( 2- propyl - 1 H- imidazol- 1 - yl) methyl] - 4H- carbazol- 4- one- hydrogen chloride

A solution of the product from example 3g (0.03 g)

in methanol (15 mL) was hydrogenated at room temperature and pressure over 10% palladium acid on charcoal (50% aqueous paste, 0.03 g)

for 4 hours (H2 uptake, 5 ml). The catalyst was filtered off and the filtrate was evaporated in vacuo to give an oil. Trituration with ether gave the title compound as a white solid (0.03 g), mp 199 - 203°C.

This material was at t.l.c. and n.m.r. identical to the product from example 14.

EXAMPLE 16

1, 2, 3, 9- tetrahydrogen- 9- propyl- 3- [( 2- propyl- 1H- imidazol- 1-yl) methyl]- 4H- carbazol- 4- one- hydrogen chloride

Sodium hydride (80% dispersion in oil) was added under nitrogen to a stirred solution of the product from Example 14 (1.0 g) in dry DMF (20 mL) and the suspension was stirred at room temperature for 30 minutes. 1-Bromopropane (0.35 mL) was added and the solution stirred at 40°C for 20 hours. The solution was partitioned between sodium carbonate (2N, 150 mL) and ethyl acetate (2 x 100 mL). The combined extracts were washed with water (100 mL), dried and evaporated in vacuo to give an oil. The oil was purified by column chromatography eluting with dichloromethane : ethanol : ammonia (100:8:1) to give pure free base as an oil. The oil was dissolved in absolute ethanol (5 mL), acidified with ethereal hydrogen chloride and diluted with dry ether (200 mL). The ether was decanted from the resulting oil and replaced with more dry ether (200ml). On standing at 0°C overnight, the oil crystallized and gave the title compound (0.53 g) m.p. 144-147°C.

N.M.R. i(CD3SOCD3) 0.90 and 0.93 (6H, t+t, 2xMe) 1.65 - 2.2

and 2.9 - 3.25 (10H, m), 4.19 (2H, t, CH2£H2N), 4.32 and 4.71 (2H, ABX; CH2ch_2N), 7.15 - 8.1 ( 6H, m, aromatic).

Analysis Found: C, 66.6: H, 7.7; N, 10.0<C>22<H>27N30-HC1'°'7H20 requires c- fi6.3; H, 7.4; N, 10.5%

EXAMPLE 17

1, 2, 3, 9- tetrahydrogen- 3- C( 2- methyl- 1H- imidazol- 1- yl) methyl] - 9- propyl- 4H- carbazole- 4- one- maleate

A solution of the product from Example 6 (0.86 g) i

a mixture of absolute ethanol (20 mL) and dry dimethylformamide (5 mL) was hydrogenated at room temperature and pressure over 5% platinum on carbon ((0.1 g, pre-reduced in absolute ethanol (10 mL)) for 1 h .(H2 uptake = 70 ml). The catalyst was filtered off, washed with ethanol and the filtrate was concentrated in vacuo to about 15 ml. The remaining solution was stirred, diluted with water (50 ml) and the precipitate was filtered off, washed with water (3 x 15 mL) and dried to give a powder (0.73 g).

This material was diluted in refluxing absolute ethanol (7 ml), filtered and a solution of maleic acid (0.25 g) in refluxing absolute ethanol (1 ml) was added. The stirred solution was diluted with dry ether (50ml) to give the title compound (0.84g), mp 150-151°C.

Analysis Found: C, 65.8; H, 6.1; N, 9.3 C20H23N3°*C4H4°4 requires C'65'9»*H»6'2; N'9'6%

EXAMPLE 18

1, 2, 3, 9- tetrahydrogen- 9- methyl- 3- C( 2- methyl- 1H- imidazol- 1- yl)-methyl]- 4H- carbazol- 4- one

i) 3-(chloromethyl)-1,2,3,9-tetrahydroqen-9-methyl-4H-carbazol-4-one

Ethereal hydrogen chloride (3.0 mL) was added to a stirred, ice-cooled solution of the product of Preparation 3 (1.90 g) in chloroform (15 n in ) and the resulting suspension was stirred in a sealed vessel at room temperature for 16.5 hours, concentrated in vacuo and the residual solid (2.27 g) purified by column chromatography and eluting with chloroform to give the title compound (1.75 g), mp 109 - 110.5° C. An attempt to crystallize out a portion of this material from ethyl acetate resulted in partial decomposition.

ii) 1,2,3,9-tetrahydrogen-9-methyl-3-f(2-methyl-1H-imidazol-1-yl)methyl"!-4H-carbazol-4-one

A solution of 3-(chloromethyl)-1,2,3,9-tetrahydrogen-9-methyl-4H-carbazol-4-one (0.50 g) and 2-methyl-1H-imidazole (1.60 g) in dry DMF was stirred under nitrogen at 90°C for 3.75 h and then poured into water (25 mL). The suspension was stirred for 1 hour and the solid was filtered off, washed with water (3 x 20 mL) and dried in vacuo at 50°C. Column chromatography of this solid (0.53 g) eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (150:10:1) gave the title compound (0.45 g), mp 228 - 229°C . This material was identical to the product from Example 7 at t.l.c. and n.m.r.

EXAMPLE 19

1, 2, 3, 9- tetrahydrogen- 9- methyl- 3- L( 2- methyl- 1H- imidazol- 1- yl)-methyl"! - 4H- carbazol- 4- one

A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (170 mg) in dry tetrahydrofuran (1.5 mL) was added dropwise under nitrogen to a stirred ice-cooled suspension of 2,3,4 ,9-tetrahydrogen-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl")-1H-carbazole maleate (100 mg) in a mixture of tetrahydrofuran was stirred for 1.5 hours and then concentrated in vacuo Column chromatography of the resulting solid, eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (150:10:1) gave the title compound (45 mg), mp 227-228.5°C. This material was identical to the product from Example 7 at t.l.c. and n.m.r.

EXAMPLE 20

1, 2, 3, 9- tetrahydrogen- 9- methyl- 3- [( 2- methyl- 1H- imidazol- 1- yl)-methyl""- 4H- carbazol- 4- one

A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

(80 mg) in dry tetrahydrofuran (1.5 mL) was added dropwise under nitrogen to a stirred, ice-cooled suspension of 2,3,4,9-tetrahydrogen-9-methyl-3-((2-methyl-1H-imidazole -1-yl)methyl-1H-carbazol-4-ol (100 mg) in a mixture of tetrahydrofuran (3.5

ml) and water (0.4 ml). The resulting blue solution was stirred for 1.5 h, and then the red suspension was concentrated in vacuo. Column chromatography of the resulting solid and eluting with a mixture of dichloromethane, ethanol and 0.99 ammonia (150:10:1) gave the title compound as a white

solid (0.47 g), mp 227.5-229°C. This material was identical to the product from Example 7 at t.l.c. and n.m.r.

EXAMPLE 21

3S- 1 , 2 , 3 , 9- tetrahydrogen- 3- C( 2- methylimidazol- 1 - yl) methyl") - 9-methyl- 4H- carbazol- 4-one- maleate

A solution of the product from Example 7 (0.5 g) was

dissolved in hot methanol (30 ml) and treated with a hot solution of (+)-di-p-toluoyl-D-tartaric acid monohydrate (0.7 g)

in methanol (10 mL), and the resulting solution was allowed to crystallize overnight to give the desired salt (0.68 g). This salt was dissolved in hot dimethylformamide (DMF, 20ml), diluted with hot water (10ml) and allowed to crystallize overnight. The product was filtered off and dried in vacuum and gave approx. 90% enantiomerically pure (shown by n.m.r.) (+)-di-p-toluoyl-D-tartaric acid salt (0.23 g), mp 231 - 233°C. A sample of the salt (0.15 g) was partitioned between 8% sodium bicarbonate (25 mL)

and chloroform (2 x 25 mL). The combined extracts were dried and evaporated in vacuo to give pure free base (0.07 g). The base was dissolved in methanol (5 ml), acidified with maleic acid (0.3 g)

and the salt precipitated on addition of excess dry ether (80 ml) to give the title compound (0.062 g), mp 142-145°C.

T.l.c.Silica, dichloromethane/ethane/0.88 ammonia (100:

8:1) Rf 0.3 detection etc. and iodoplatinic acid, identical to the product from Example 7. The ratio of the enantiomers, determined by 'H n.m.r. was 93:7 (S:R). A sample of the maleate salt did not show any significant turning in methanol. The free base, regenerated from the maleate salt, gave [d]^-1 4° (cO, 19, MeOH).

EXAMPLE 2 2

3R-1,2,3,9-tetrahydrogen-9-methyl-3-f(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one maleate

A solution of the product from Example 7 (0.5 g) was dissolved in hot methanol (30 ml) and treated with a hot solution of (-)-di-p-toluoyl-L-tartaric acid monohydrate (0, 7g)

in methanol (10 mL) and the resulting solution allowed to stand

and crystallize overnight to give the desired salt (0.8 g). This salt was dissolved. in hot dimethylformamide (DMF, 20 ml), diluted with hot water (10 ml) and allowed to stand and crystallize for 3 days. The product was filtered off and dried in vacuo,

and gave approx. 95% enantiomerically pure (as shown by n.m.r.) (-)-di-p-toluoyl-L-tartaric salt (0.26 g), mp 170 - 172°C.

A sample of the salt (0.2 g) was partitioned between 8% sodium bicarbonate (25 mL) and chloroform (2 x 25 mL). The combined extracts were dried and evaporated in vacuo to give pure free base (0.12 g). The base was dissolved in methanol (5 ml), acidified with maleic acid (0.045 g) and the salt was precipitated by addition of excess dry ether (80 ml) to give the title compound (0.08 g), m.p. 142 - 145°C.

T.l.c. Silica, dichloromethane/ethanol (0.88 ammonia (100: 8:1), Rf 0.3 detection etc. and iodoplatinic acid, identical to the product from example 7. The ratio between the enantiomers, determined by 'H n.m.r., was 95:5. A sample of the maleate salt showed no significant optical rotation in methanol.The free base, regenerated from the maleate salt, gave £*]d<4>+ 16° (c 0.34, MeOH) .

Claims (4)

1. Analogous process for the preparation of a therapeutically active compound of the general formula (I) where R<1> denotes a hydrogen atom or a C 1-4 alkyl, C 3-7 cycloalkyl, <C> 3-6 alkenyl, phenyl or phenyl-C 1-3 alkyl group, and one of the groups represented by R<2>, R<3> and R<4>is a hydrogen atom or a C-3 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl C1 alkyl group and each of the other two groups, which may be the same or different, denotes a hydrogen atom or a C 1-6 alkyl group; or a physiologically acceptable salt or solvate thereof, and the enantiomeric forms, characterized by (A) reaction of a compound with the general formula (II) where Y denotes a methylene group or a group CH2Z, where z is a leaving group, with an imidazole of the general formula (III) or a salt thereof; or (B) oxidation of a compound of formula (IV) where A denotes a hydrogen atom or a hydroxyl group, or a salt thereof, or (C) for the preparation of compounds of formula I where R<1>is a Cj^q alkyl-, C3-7cycloalkyl-, <C>3-6alkenyl- or phenyl-Ci_3 -alkyl group, a compound of formula I where R<1>is hydrogen is alkylated with a suitable alkylating agent, or (D) for the preparation of compounds of formula I containing an alkyl substituent, a compound containing a corresponding alkenyl substituent is hydrogenated, and when a compound of formula (I) appears as a mixture of enantiomers, possibly dissolving the mixture to obtain the desired enantiomer, and/or where the compound is in the form of a free base, possibly transferring the base to a salt. 2. Process according to claim 1 for the production of 1,2,3,9-tetrahydrogen-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4- on or a physiologically acceptable salt or solvate thereof, characterized in that corresponding starting materials are used. 3. Method according to claim 2, characterized in that the hydrochloride of the compound is produced. 4. Process according to claims 2 and 3, characterized by preparing the hydrochloride-dihydrate of the compound.