NL8701728A - HETEROCYCLIC COMPOUNDS. - Google Patents

Description

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a

VO 9236

Heterocyclic compounds.

The invention relates to heterocyclic compounds, to methods for their preparation, to pharmaceutical compositions containing them and to their medical use. In particular, the invention relates to compounds that act on 5-hydroxytrypt-5 amine (5-HT) receptors of the type located at endpoints of primary afferent nerves.

Compounds with antagonistic action on "neuronal" 5-HT receptors of the type located on primary afferent nerves have been previously described.

For example, published British Patent Publication 2,153,821A discloses tetrahydrocarbazolones of general formula 2, wherein R "* - is a hydrogen atom or an alkyl group of 1-10 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, an alkenyl group having 3-6 carbon atoms, a phenyl group or a phenylalkyl group in which the 2 2 alkyl group has 1-3 carbon atoms, and one of the groups represented by R 3, 3 R and R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, an alkenyl group of 2 to 6 carbon atoms or a phenylalkyl group in which the alkyl group has 1 to 3 carbon atoms and each of the other two groups, which may be the same or different, is a hydrogen atom or an alkyl group with 1 -6 represents carbon atoms.

A new group of compounds has now been found which differ in structure from the first described compounds, and which are strong antagonists of the effect of 5-HT on 5-HT "neuronal" receptors.

The present invention provides a tetrahydrocarbazolone of the general formula 1, wherein R 1 is a hydrogen atom or a group selected from C 1 alkyl, C 1 cycloalkyl, C 1 cycloalkyl C 1 alkyl, C 1 -1 U / -3 - /

alkenyl, C, alkynyl, phenyl or phenylC alkyl, CO R, -COR, -CQNR R

6 ^ 6 T ^ or ° s ° 2R (wherein R and R, which may be the same or different, represent a hydrogen atom, a C 1-4 alkyl or C 1-4 cycloalkyl group, or a phenyl or phenylC 1-6 alkyl group, wherein the phenyl group is optionally substituted by one or more C 1-6 alkyl, alkoxy or hydroxy groups or halogen atoms, with the proviso that R does not represent a 1 6 6 hydrogen atom when R represents a -CO R or - group SO R -35); 8701728 -2- ft Λ 2 3 4

one of the groups represented by R, R and R a hydrogen atom or a C. alkyl, C, cycloalkyl, C alkenyl or phenylC. .alkyl-1-o -— / ζ-Ό 1-J

group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C alkyl group; and 5 1-6 R represents a C 1-4 alkyl group; as well as physiologically acceptable salts and solvates thereof.

It will be understood that the carbon atom at the 3 position of the tetrahydrocarbazolone ring is asymmetric and may exist in the R or S configuration. All optical isomers of compounds of general formula 1 and their mixtures including the racemic mixtures, and all geometric isomers of compounds of formula 1 are included in the invention.

With reference to the general formula 1, the alkyl- .... ,. 1 2 3 4 5 6 7 groups represented by the symbols R, R, R, R, R, R and R are straight or branched chain alkyl groups such as, for example, methyl, ethyl, propyl, prop-2 -yl, butyl, but-2-yl, 2-methylprop-2-yl, pentyl, pent-3-yl or hexyl groups.

For example, a C 1-4 galkenyl group can be a propenyl or butenyl group. For example, a C3-3alkynyl group can be a prop-2-ynyl or oct-2-ynyl group. It will be clear that when R 1 represents a C 1 -alkenyl or C 3 -C-alkynyl group, the double and tri-double bonds, respectively, do not. next to the nitrogen atom. A phenylC1 -alkyl group can be, for example, a benzyl, phenethyl or 3-phenylpropyl group. For example, a C3-7cycloalkyl group, alone or as part of a C3-7cyclo-alkylalkylalkyl group, may be a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

In one aspect, the invention provides compounds of formula 1, wherein R is a hydrogen atom or a C alkyl, C cycloalkyl, C 1-10 3-7 234

alkenyl, phenyl or phenylC1-3 alkyl group, and R, R, R and R.

30 have the meanings defined for Formula 1.

A preferred class of compounds represented by the general formula 1 is that wherein R 1 is a hydrogen atom or a C 1 alkyl (eg methyl), C 1 cycloalkyl or C 1 alkenyl group for 1 - 3 3 - 0 3 - 0 sets.

Another preferred class of compounds represented by the general formula 1 is that wherein one of the groups represented by R, 8701728% -3- 3 4 R, R represents a C alkyl, C cycloalkyl, 3-6 or C 1-6 alkenyl group and each of the other two groups, which may be the same or 3-6 different, represents a hydrogen atom or a C alkyl group 2 1-3 3 4. When R represents a hydrogen atom, R and / or R preferably represent a C 1, alkyl (e.g. methyl) group. When R represents a C 1-4 1-3 alkyl (e.g., methyl) group, R and R preferably both represent hydrogen atoms.

Yet another preferred class of compounds of formula 1 are those wherein R 1 represents a C 1-6 alkyl (e.g. methyl) group.

A particularly preferred group of compounds of formula 1 2 1 are those in which R represents a methyl group, R represents a methyl group-3 4, R represents a hydrogen atom, R represents a hydrogen atom and R5 represents a C 1-4 alkyl group.

A particularly preferred compound according to the invention is the compound 1,2,3,9-tetrahydro-3,9-dimethyl-3 - [(2-methyl-1H-imida-zol-1-yl) methyl] -4H- carbazoi-4-one as well as its physiologically acceptable salts and solvates.

Suitable physiologically acceptable salts of the compounds of the general formula 1 include acid addition salts formed with organic or inorganic acids, for example hydrochlorides, hydrobromides, sulfates, phosphates, citrates, sucinates, tartrates, fumarates, maleates and p-toluenesulfonates. The solvates can be, for example, hydrates.

It will be understood that the invention extends to other physiologically acceptable equivalents of the compounds of the invention, ie physiologically acceptable compounds which are converted into the parent compound of formula 1 in vivo.

Compounds of the invention are strong and selective antagonists of 5-HT-induced depolarization of the rat-isolated wandering nerve preparation and thus act as strong and selective antagonists of the "neuronal" 5-HT receptor type located on primary posterior nerves . Receptors of this type are currently referred to as 5-HT receptors. It is believed that such receptors are also present in the central nervous system. 5-HT is common in the neuronal pathways in the central nervous system, and disruption of these 5-HT-containing pathways is known to alter behavioral aspects such as mood, psychomotor activity, appetite and memory.

8701728 »-4- • ί

Compounds of formula 1 which antagonize the effect of 5-HT at 5-HT receptors are useful in the treatment of conditions such as psychotic disorders (e.g. schizophrenia and mania); fears; and nausea and vomiting. Compounds of formula 1 are also useful in the treatment of gastric stasis; gastrointestinal dysfunction symptoms such as occur with dispepsia, gastric ulcer, reflux oesophagitis, flatulence and irritated bowel syndrome; migraine; and pain.

Unlike existing drug treatments for these states, the compounds of the invention are not expected to cause undesirable side effects due to their high selectivity to 5-HT receptors. For example, neuroleptic drugs can exhibit extrapyramidal effects such as tardive diskinesia and benzodiazepines can cause dependence.

In another aspect, the invention provides a method of treating a human or animal subject suffering from psychotic disorder such as schizophrenia or mania; or fears; nausea or vomiting; gastric stasis; gastrointestinal dysfunction symptoms such as dispepsia, reflux esophagitis, stomach ulcers, flatulence and irritated bowel syndrome; migraine; or pain, comprising administering an effective amount of a compound of formula 1 or a physiologically acceptable salt or solvate thereof.

The invention therefore also provides a pharmaceutical composition comprising at least one compound selected from compounds of the general formula 1, as well as their physiologically acceptable salts and solvates, for example hydrates, adapted for use in human or veterinary medicine and molded for administration by any suitable route.

Such compositions can be brought into a dosage form in a conventional manner, using one or more physiologically acceptable carriers or excipients.

The compounds of the invention can therefore be presented in a form for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation (by mouth or nose).

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared according to known means using pharmaceutically acceptable excipients such as binders (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); Lubricants (e.g. magnesium stearate, talc or silicon oxide); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulfate). The tablets can be coated by methods known per se. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product to be prepared for use with water or other suitable vehicle. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol-15 syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl hydroxybenzoates or sorbic acid). The formulations may also contain buffer salts, flavors, dyes and sweeteners as required.

Preparations for oral administration can be suitably introduced into a dosage form that provides controlled release of the active compound.

For buccal administration, the compositions may be in the form of tablets or lozenges formed in a conventional manner.

The compounds of the invention can be brought into a form for parenteral administration by injection. Injection preparations can be presented in dosage units, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may have forms such as suspensions, solutions or emulsion in oily or aqueous vehicles, and may contain formulating agents such as suspending agents, stabilizing agents and / or dispersing agents. Also, the active ingredient may be in powder form to be prepared before use with a suitable vehicle, for example sterile pyrogen-free water.

The compounds of the invention may also be administered in a dosage form for rectal preparations such as suppositories or 87 0 1 "/ 2 &"

J

Retention enemas, for example, containing conventional suppository base such as cocoa butter or other glycerides.

In addition to the preparation forms described above, the compounds according to the invention can also be carried out as depot preparations. Such long acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, the compounds of the invention can be processed, for example, with suitable polymers or hydrophobic materials (eg, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For administration by inhalation, the compounds of the invention are preferably delivered in the form of an erosol spray presentation from pressure packages or a nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized erosol, the dosage unit can be determined by a valve delivering a measured amount. For example, capsules and cartridges of gelatin 20 for use in an inhaler or insufflator may be formulated to contain a powdered mixture of a compound of the invention and a suitable powder base such as lactose or starch.

A proposed dose of the compounds of the invention for administration to humans (approximately 70 kg body weight) is 0.05-100 mg, preferably 0.1-50 mg of the active ingredient per unit dose containing, for example, 1- Could be administered 4 times a day. It will be understood that routine dose variations may be required depending on the age and condition of the patient. The dosage will also depend on the route of administration.

According to another aspect of the invention, compounds of the general formula 1 and physiologically acceptable salts or solvates thereof can be prepared by the general methods described below.

In the following description, the groups have the meanings mentioned previously for the compounds of the general formula 1 unless otherwise indicated.

8701726 -7- *

According to a first general method (A) ,. a compound of formula 1 can be prepared by alkylating a compound of formula 2 or a salt or a protected derivative thereof using an alkylating agent, followed if necessary by removing any protecting groups.

Alkylating agents which can be used in the above process of the invention include compounds of the formula R2, wherein Z represents a leaving atom or leaving group such as a halogen atom (eg, chlorine, bromine or iodine), an acyloxy group (eg trifluoroacetyloxy or acetoxy), or a sulfonyloxy group (eg, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy); 5 or a sulfate of the formula (R J ^ SO ^.

The alkylation reaction is conveniently conducted in an inert organic solvent such as a substituted amide (e.g. dimethylformamide), an ether (e.g. tetrahydrofuran) or an aromatic hydrocarbon (e.g. toluene), and in the presence of a base. Suitable bases include, for example, alkali metal hydrides (e.g. sodium hydride), alkali metal amides (e.g. sodium amide or lithium diisopropylamide), and alkali metal alkoxides (e.g. sodium or potassium methoxide, ethoxide or t-butoxide).

The reaction may conveniently be carried out at a temperature in the range of -80 to + 100 ° C, preferably -80 to + 25 ° C.

It will be understood that if one wishes to prepare a compound of formula 1 in which a hydrogen atom represents by the above method (A), the carbazolone nitrogen atom must be protected to prevent it from being alkylated by the alkylating agent. The protecting group may be a conventional protecting group as described in "Protective Groups in Organic Synthesis" by Theodora W. Greene (John Wiley and Sons 1981).

The compounds of formula 2 can be prepared by methods described in British Patent Publication 2,153,821A and by methods analogous to the methods described therein.

According to another general method (B), a compound of the general formula 1 or a salt or protected derivative thereof can be converted into another compound of formula 1 using conventional techniques. Such conventional techniques include hydrogenation, alkylation and acylation.

8701728

a

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For example, hydrogenation can be used to convert an alkenyl or an alkynyl substituent to an alkyl substituent, or to convert an alkynyl to an alkenyl substituent.

Hydrogenation according to the general method (B) can be carried out according to conventional procedures, for example with hydrogen in the presence of a precious metal catalyst (eg palladium, Raney nickel, platinum or rhodium). The catalyst can be a supported catalyst, for example charcoal or it is also possible to use a homogeneous catalyst such as tris (triphenylphosphine) rhodium chloride. The hydrogenation will generally be carried out in a solvent such as an alcohol (eg ethanol), an ether (eg dioxane), or an ester (eg ethyl acetate), and at a temperature in the range of -20 to + 100 ° C. , preferably 0 to 50 ° C.

Alkylation according to the general method (B) can for instance be carried out on a compound of formula 1 in which one or both 1 of the groups R and R represent hydrogen.

The term "alkylation" also includes the introduction of other groups such as cycloalkyl or alkenyl groups. For example, a compound of formula 1 wherein R represents a hydrogen atom can be converted to the corresponding compound wherein R 1 is an alkyl, cycloalkyl, C alkenyl, C alkynyl, C cycloalkylC alkyl or phenyl C alkyl. "6 o-lU .3" / I "4 J." j represents group.

The above alkylation reactions can be carried out using a suitable alkylating agent selected from compounds 8 8 of the formula R 2 wherein R represents a C 1 -alkyl-cycloalkyl, C-alkenyl, C-alkynyl, C-2 -cycloalkylC. alkyl or phenyl C. .alkyl group, and Z represents a leaving atom or leaving group such as a halogen atom or an acyloxy or sulfonyloxy group as previously defined for Z; or a sulfate of the formula (R 30) The alkylation reaction is conveniently conducted in an inert organic solvent such as a substituted amide (eg dimethyl formamide), an ether (eg tetrahydrofuran) or an aromatic hydrocarbon (eg toluene), preferably in the presence of a base Suitable bases include, for example, alkali metal hydrides (eg sodium 35 hydride), alkali metal amides (eg sodium amide or lithium diisopropylamide), alkali metal carbonates (eg sodium carbonate) or an alkali metal

870 1 7 2P

-9-metal alkoxide (e.g. sodium or potassium methoxide, ethoxide or t-butoxide). The reaction may conveniently be conducted at a temperature in the range of -20 to + 100 ° C, preferably 0 to 50 ° C.

Acylation according to the general method (B) can be used to prepare compounds of formula 1 wherein R ^ represents 6 6 6 7 6 -CO R, -COR, -CONR R or -SO.R, from a compound of formula 1 2 1 2. wherein R represents a hydrogen atom. The acylerms reactions can be carried out according to conventional procedures using an appropriate acylating agent.

It should be noted that in the above-mentioned transformations, protection of any sensitive groups in the molecule of the compound in question may be necessary or desirable to avoid undesired side reactions. For example, it may be necessary to protect the keto group, for example, as a ketal or a thio ketal. It may also be necessary to protect the carbazolone nitrogen atom, for example, with an arylmethyl (e.g. benzyl or trityl) group.

According to another general method (C), a compound of formula 1 can be prepared by removing any protecting groups from a protective form of a compound of formula 1. Deprotection can be performed by conventional techniques as described in "Protective Groups in Organic Synthesis "by Theodora W. Greene (John Wiley and Sons, 1981).

For example, a ketal such as an alkylene ketal group can be removed by treatment with an inorganic acid such as hydrogen chloride. A thio ketal group can be cleaved off by treatment with a mercury salt, (e.g. mercuric chloride), in a suitable solvent, such as ethanol. An arylmethyl N-protecting group can be cleaved by hydrogenolysis in the presence of a catalyst (eg palladium on charcoal) and a trityl group can also be cleaved by acid hydrolysis (eg using dilute hydrochloric or acetic acid).

If one wishes to isolate a compound according to the invention as a salt, for example a physiologically acceptable salt, this can be carried out by treating the free base of the general formula 1 with a suitable acid, preferably with an equivalent amount thereof, in a suitable solvent such as an alcohol (eg ethanol 8701728

V

4-10 or methanol), an ester (e.g. ethyl acetate) or an ether (e.g. tetrahydrofuran).

Physiologically acceptable equivalents of a compound of formula 1 can be prepared by conventional methods.

Individual enantiomers of the compounds of the invention can be obtained by separating a mixture of enantiomers (e.g. a racemic mixture) by conventional means, for example, using an optically active separating acid; see, for example, "Stereochemistry of Carbon Compounds" by E.L. Eliel 10 (MCGraw Hill 1962) and "Tables of Resolving Agents" by S.H. Wanting.

The above-mentioned methods of preparing the compounds of the invention can be used as the last major step in the synthesis procedure. The same general methods can be used to introduce the desired groups into an intermediate step of cascading the required compound, and it will be appreciated that these general methods can be combined in such multistage procedures in various ways.

The order of the reactions in multistage procedures 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.

The invention is elucidated by means of the following example. All temperatures are expressed in ° C.

EXAMPLE I

1,2,3,9-Tetrahydro-3,9-dimethyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -25 4H-carbazol-4-one 4-methylbenzenesulfonate

N-butyl lithium (1.37 ml of a 1.53 M solution in hexane) was added dropwise at -78 ° C under nitrogen and with stirring to a solution of 0.30 ml diisopropylamine in 5 ml dry tetrahydrofuran and stirred the solution at -5 to 0 ° C for 30 minutes. The solution was cooled to -78 ° C and added via cannula at -78 ° C under nitrogen and with stirring to 500 mg of 1,2,3,9-tetrahydro-9-methyl-3-C (2-methyl- 1H-imidazol-1-yl) methyl] -4H-carbazol-4-one. After 5.5 hours at -78 ° C, 0.13 ml of iodomethane was added and stirring was continued for 2 hours at -78 ° C and then for 13 hours at room temperature. The mixture was treated with saturated aqueous ammonium chloride (30 ml), extracted with chloroform (5x30 ml), and the 87 0 1.7 2 8 & n-combined organic extracts dried over Na 2 O 2 were evaporated . The residue was combined with the residues obtained from three other identical reactions and crystallized from ethyl acetate. The precipitate was filtered off and discarded, and the mother liquids were evaporated. The residual foam was purified by HPLC (using a 170x8 mm column of 5 µl Spherisorb silica gel and a Gilson Autoprep machine) eluting with hexane-chloroform-ethanol-880 ammonia (476: 476: 481: 1 ) to give the free base of the title compound (172 mg). A hot solution of 4-methylbenzenesulfonic acid monohydrate (104mg, 0.55mmol) in 2ml of ethanol was added and on cooling the title compound crystallized as fine white needles (180mg), mp 115-120pc.

Analysis found: C: 63.8, H: 6.7, N: 8.0.

CHN 0.0 ^ 0.5.0.84 Ο, Η, Ο.Ο, ΙδΗ ,, Ο calculated: C: 63.75, H: 6.65, N: 8.1% I? 21 3/8 3 2 o 2 15 Water analysis, found: 0.62% w / w = 0.18 mol H 2 O.

The following examples illustrate pharmaceutical preparations according to the invention. The term "active ingredient" used herein represents a compound of the formula 1.

TABLETS FOR ORAL ADMINISTRATION

Tablets can be prepared by normal methods such as direct compression or wet granulation.

The tablets can be film-coated using suitable film-forming materials such as hydroxypropylmethyl cellulose, using standard techniques. On the other hand, the tablets can also be dressed with sugar.

Direct compression

Tablet mg / tablet active ingredient 5.00 calcium hydrogen phosphate BP * 82.75 30 croscarmellose sodium NF 1.8 magnesium stearate BP 0.45 compression weight 90.0 * of a quality suitable for direct compression 8701720 -12- ¥ *

The active ingredient was passed through a 0.25 mm mesh sieve mixed with calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. The resulting mixture was compressed into tablets using a Manesty F3 tablet machine fitted with 5 5.5 mm flat stamps with beveled edges.

Tablets of other strengths can be obtained by changing the ratio of the active ingredient to excipients or the compression weight and using suitable stamps.

INJECTION FOR INTRAVENOUS ADMINISTRATION 10 mg / ml active ingredient 0.5 sodium chloride BP as needed water for injection BP up to 1.0 ml

Sodium chloride could be added to adjust the tonicity of the solution and the pH adjusted with acid or alkali to that of optimum stability and / or to facilitate dissolution of the active ingredient. On the other hand, suitable buffer salts can be used.

The solution was prepared, clarified and filled into suitable sized ampoules which were sealed by melting the glass.

The injection preparation was sterilized by autoclaving by one of the accepted methods. The solution could also be sterilized by filtration and packaged in sterile ampoules under aseptic conditions. The solution can be packaged under an inert atmosphere of nitrogen or other suitable gas.

8701728

Claims (2)

1. Compounds of general formula 1 wherein: R1 represents a hydrogen atom or a group selected from: C, alkyl, C, cycloalkyl, C cycloalkylC. alkyl, C 1 -alkenyl, C 3-10 alcynyl, phenylC 1 -3 alkyl, -CO 2 Rb, -COR, -CONRk, or -SO 2Rb 5 (where Rb and R 2, which may be the same or different, each represent a hydrogen atom, a C 2 ^ alkyl, or C 3-7 cycloalkyl group, or a phenyl phenyl C 1-4 alkyl group, wherein the phenyl group is optionally substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, or hydroxy groups or halogen atoms, provided that Rb does not represent a hydrogen atom 1 6 6 10 when R represents a group -CO R or -SO R); ^ 2 2 3 4 one of the groups represented by the symbols R, R and R represents a hydrogen atom or a C 1 -alkyl, C-cycloalkyl, 10 / C-alkenyl or phenylalkyl group and each of the other two 2-6-10 groups, which may be the same or different, represents a hydrogen atom or a C.alkyl group? and 1-6 R represents a C 1 alkyl group; 1—6 and physiologically acceptable salts and solvates thereof. 2. Compounds according to claim 1, wherein R 1 in the general formula 1 represents a hydrogen atom or a C 1-6 alkyl, C 1-4 cycloalkyl or C 1-6-5-6 alkenyl group. Compounds according to claim 1, wherein in the general formula 2 3 4 1, one of the groups represented by R, R and R represents a C, alkyl, C 7 cycloalkyl, or C, alkenyl group and each of the two 1-6-6-6 other groups, which may be the same or different, represent a hydrogen atom or a C 1-3 alkyl group. Compounds according to claim 1 or 3, wherein in the general formula 1, R represents a 3alkyl group and R and R both represent hydrogen atoms. Compounds according to claim 1, wherein in the general formula 1, R 5 represents a C 1 alkyl group. 1—3 6. Compounds according to claim 1, wherein in the general formula 1 2 3 1, R represents a methyl group, R represents a methyl group, R represents a hydrogen atom, R represents a hydrogen atom and R represents a c-alkyl group. 1-6 870172 »-14- to if 7. 1,2,3,9-Tetrahydro-3,9-dimethyl-3 [(2-methyl-1H-imidazol-1-yl) -methyl] -4H-carbazole -4-one as well as physiologically acceptable salts and solvates thereof. A pharmaceutical composition comprising at least one compound 5 selected from compounds of the general formula 1 as defined in claim 1, as well as their physiologically acceptable salts and solvates, together with one or more physiologically acceptable carriers or excipients. 9. A process for preparing a compound of the general formula [I] as defined in claim 1 or a salt thereof, comprising: (A) alkylating a compound of the general formula [II] 12 3 4 (wherein R, R , R and R have the meanings set forth in claim 1), or a salt or a protected derivative thereof; or (B) subjecting a compound of the general formula 1 as defined in claim 1 or a salt or a protected derivative thereof to a conventional conversion reaction wherein another compound of the general formula 1 is formed as defined in claim 1, or a salt or protected derivative thereof; or (C) subjecting a protected derivative of a compound of the general formula 1 or a salt thereof to a reaction to remove the protecting group or groups; and, if necessary and / or optionally, subjecting the compound obtained in step A, B or C to one or more further reactions including: (1) removing any protecting group or groups; (2) converting the obtained compound of the general formula 1 or a salt thereof into a physiologically acceptable salt or solvate thereof; and (3) if the compound of the general formula 1 is obtained as a mixture of enantiomers, optionally separating the mixture to obtain the desired enantiomer. Compounds according to claim 1, wherein in the general formula 1, R 1 represents a hydrogen atom or a C 1-4 alkyl, C 3-7 cycloalkyl, C alkenyl, phenyl or phenyl C alkyl group, and R 2, R 3, R 3, and R 3 de in 3-6 1-3 claim 1 have listed meanings. 870 1 728 I * * I O R "r3 ΠηΛ ^ ν II R2 R1" "I4 R3 'η' i R2 R1 ^ 7 Ö 1 7 2 Θ Glaxo Group Limited