CH674008A5 - - Google Patents

Description

DESCRIPTION

The present invention relates to heterocyclic compounds, a process for their preparation, and a pharmaceutical composition containing them. In particular, the invention relates to compounds which act on 5-hydroxytryptamine (5-HT) receptors of the type located on the ends of the primary afferent nerves.

Compounds having antagonistic activity to neuronal 5-HT receptors of the type located on the primary afferent nerves have previously been described.

Thus for example the British patent published under No. 2153821A describes tetrahydrocarbazolones of general formula

0 R4 R3

11 PH X— '

• A / "S

30

35

// \

NOT

\

"T

/

w / \ / \ / 12

• N • R2

R1 where R1 represents a hydrogen atom or a Q 45 to C 10 alkyl group, C 3 to C 7 cycloalkyl, C 3 to C 6 alkenyl, phenyl or C 1 to C 3 phenylalkyl, and one of the groups represented by R 2, R 3 and R4 is a hydrogen atom or a C alkyl group! to Cfi, C3 to C7 cycloalkyl, C2 to Cs alkenyl or C to phenylalkyl! to C3 and each of the other two groups, which may be the same or different, represent a hydrogen atom or a C 1 -C 6 alkyl group.

We have now found a new group of compounds whose structure differs from those described previously, and which are potent antagonists of the effect of 5-HT at the 5-HT neuronal receptors 55.

Thus, the invention provides a tetrahydrocarbazolone of general formula (I):

s r / 3

60 / A / \ / \ f î

• • • • NN

I II II l \ c \ // W

* • • “R •

W / \ / \ / L

• N • R2

where R1 represents a hydrogen atom or a group chosen from C 1 to C 10 alkyl, C 3 to C 7 cycloalkyl, cycloal-

3

674 008

C3 to C7 coyl-Q to C4 alkyl, C3 to Ce alkenyl, C3 to C10 alkynyl phenyl or phenyl Ct to C3, C02R6, —COR6, —CONR6R7 or - S02R6 (where R6 and R7, which may be identical or different, each represents a hydrogen atom, a C1-C6 alkyl or C3-C7 cycloalkyl group, or a phenyl or phenyl-C1-C4 group, in which the phenyl group is optionally substituted by one or more groups C1 to C6 alkyl, C1 to C4 alkoxy or hydroxy or halogen atoms, with the clarification that R6 does not represent a hydrogen atom when R1 represents a group —CO2R6, or —SO2R6);

one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1-C6 alkyl group, C3-C7 cycloalkyl, C2-C6 alkenyl or Cx-C3 phenylalkyl and each of the other two groups , which may be the same or different, represents a hydrogen atom or a Cx to C6 alkyl group, and

R5 represents a Ct to C6 alkyl group;

and its physiologically acceptable salts and solvates.

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

Referring to the general formula (I), the alkyl groups represented by R1, R2, R3, R4, R5, R6 and R7 may be straight or branched chain alkyl groups, for example methyl, ethyl groups , propyl, prop-2-yl, butyl, but-2-yl, 2-methyl-prop-2-yl, pentyl, pent-3-yl or hexyl.

A C3 to C6 alkenyl group may for example be a propenyl or butenyl group. A C3-C10 alkynyl group may for example be a prop-2-ynyl or oct-2-ynyl group. It will be appreciated that when R1 represents a C3-C6 alkenyl or C3-C6 alkynyl group, the double or triple bond respectively may not be adjacent to the nitrogen atom. A phenylalkyl group in Q to C3 can be, for example, a benzyl, phenethyl or 3-phe-nylpropyl group. A C3-C7 cycloalkyl group, alone or as part of a C3-C7 cycloalkyl-C1-C4 alkyl group, may be, for example, a cyclopropyl, cyclobutyl, cyclopen-tyle, cyclohexyl or cycloheptyl group.

According to one aspect, the invention provides compounds of formula (I) in which R1 represents a hydrogen atom or a C1-C10 alkyl group, C3-C7 cycloalkyl, C3-C6 alkenyl, phenyl or C1-phenylalkyl C3, and R2, R3, R4 and R5 are as defined in formula (I).

A preferred class of compounds represented by the general formula (I) is that in which R1 represents a hydrogen atom or a Ct to C3 alkyl group (for example methyl), C3 to C6 cycloalkyl or C3 to C6 alkenyl.

Another preferred class of compounds represented by the general formula (I) is that in which one of the groups represented by R2, R3 and R4 represents a C 1-6 alkyl group! to C3, C3 to C6 cycloalkyl or C3 to C6 alkenyl and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1 to C3 alkyl group. When R2 represents a hydrogen atom, R3 and / or R4 preferably represent a C1 to C3 alkyl group (for example methyl). When R2 represents a C1-C3 alkyl group (for example methyl), R3 and R4 both preferably represent hydrogen atoms.

Another preferred class of compounds of formula (I) is that of compounds where R5 represents a C1 to C3 alkyl group (for example methyl).

A particularly preferred group of compounds of formula (I) is formed by those where R1 represents a methyl group, R2 represents a methyl group, R3 represents a hydrogen atom, R4 represents a hydrogen atom and R5 represents an alkyl group in Ci to C6.

A particular compound of the invention is 1,2,3,9-tetrahydro-3,9-dimethyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4- one and its physiologically acceptable salts and solvates.

The suitable physiologically acceptable salts of the compounds of general formula (I) include the acid addition salts formed with organic or inorganic acids, for example hydrochlorides, hydrobromides, sulfates, phosphates, citrates, succinates, tartrates, fumarates, maleates and p-toluenesulfonates. The solvating products can for example be hydrates.

It will be appreciated that the invention extends to other physiologically acceptable equivalents of the compounds according to the invention, namely physiologically acceptable compounds which are transformed in vivo into the parent compound of formula (I). The compounds of the invention are potent and selective antagonists of the 5-HT-induced depolarization of the pneumogastric nerve preparation isolated from the rat and thus act as potent and selective antagonists of the 5-HT neural receptors located on the nerves. primary afferents. Receptors of this type are now designated as 5-HT3 receptors. These receptors are also thought to be present in the central nervous system. 5-HT is very common in the neuronal pathways of the central nervous system and it is known that a disorder of these pathways containing 5-HT alters behavioral aspects such as mood, psychoactive activity, appetite and memory.

The compounds of formula (I), which act as an antagonist of the effect of 5-HT at the 5-HT3 receptors, are useful in the treatment of conditions such as psychotropic diseases (for example schizophrenia and mania ), anxiety, and nausea and vomiting. The compounds of formula (I) are also useful in the treatment of gastric stasis, symptoms of gastrointestinal dysfunction as found with dyspepsia, gastric ulcer, reflux esophagitis, flatulence and intestinal syndrome with irritation, migraine and pain.

Unlike the drug treatments available for these conditions, the compounds of the invention would not be expected, given their high selectivity for 5-HT3 receptors, to produce undesirable side effects. So, for example, neuroleptic drugs can exhibit mid-extrapyra-40 effects, such as tardive dyskinesia, and benzodiazepines can cause dependence.

The invention therefore therefore also provides a pharmaceutical composition which comprises at least one compound chosen from the compounds of general formula (I) and physiologically acceptable solvates, for example hydrates, suitable for application in human or veterinary medicine, and formulated for administration by any convenient route.

These compositions can be formulated conventionally using one or more physiologically acceptable carriers or excipients.

Thus, the compounds according to the invention can be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation (through the mouth or the nose).

For oral administration, the pharmaceutical compositions may take the form, for example, of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hy-droxypropylmethylcellulose); fillers (for example lactose, microcrystalline cellulose or calcium acid phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrating agents (for example potato starch 65 or sodium starch glycolate); or wetting agents (for example sodium lauryl sulfate). The compounds can be coated by methods well known to those skilled in the art. Liquid preparations for oral administration may

674 008

4

take the form, for example, of solutions, syrups or suspensions, or may be presented as a dry product for the purpose of reconstitution with water or any suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (eg methyl- or propyl-p-hydroxyben-zoates or sorbic acid). The preparations may also contain buffer salts, flavoring agents, colorants and softeners as required.

Preparations for oral administration may conveniently be formulated to give a controlled release of the active compound.

For oral administration, the compounds may take the form of tablets or lozenges formulated in a conventional manner.

The compounds of the invention can be formulated for parenteral administration by injection. The injectable formulations can be presented in unit dosage form, for example in ampoules or in multidose containers with the addition of a preservative. The compositions can take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with an appropriate vehicle, for example sterile pyrogen water, before use.

The compounds of the invention can also be formulated in rectal compositions such as suppositories or enemas to keep, for example containing bases of conventional suppository such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds of the invention can also be formulated in the form of depot preparations. Such long-acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (for example in the form of an emulsion in an acceptable oil) or ion exchange resins, or in the form of derivatives little soluble, for example in the form of a sparingly soluble salt.

For administration by inhalation, the compounds of the invention are conveniently administered in the form of a presentation of sprayed liquid aerosol from pressurized packaging or a nebulizer, with the use of a suitable rector, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a measured amount. The capsules and cartridges, for example of gelatin, for use in an inhaler or insuffilator can be formulated so as to contain a pulverulent mixture of a compound of the invention and of a suitable powder base such as lactose or starch .

A proposed dose of the compounds of the invention for administration to humans (weighing approximately 70 kg) is 0.05 to 100 mg, preferably 0.1 to 50 mg of the active ingredient per unit dose as '' For example, 1-4 times a day can be administered. It will be appreciated that routine variations in dosage may be necessary, depending on the age and condition of the patient. The dosage also depends on the mode of administration.

The compounds of general formula (I) and their physiologically acceptable salts or solvates can be prepared by the general methods presented below. In the following description, the groups R1 to Rs are as defined for the compounds of general formula (I), unless otherwise indicated.

According to a first general process (A) according to the invention, a compound of formula (I) can be prepared by alkylating a compound of s formula (II)

\ "/ R3

(II)

20

25

A A / "\ F = I

i Mi i \ / • • • • “

W / \, / \ / I,

• N • R2

or a protected salt or derivative thereof, using an alkylating agent and then, if necessary, removing any protective groups.

Alkylating agents which can be used in the above process according to the invention include the compounds of formula R5Z, where Z represents an atom or group leaving as a halogen atom (for example chlorine, bromine or iodine), a group acyloxy (eg trifluoroacetyloxy or acetoxy), or a sulfonyloxy group (eg trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy), or a sulphate of formula (Rs) 2SO4.

The alkylation reaction is conveniently carried out in an inert organic solvent such as a substituted amide (for example dimethylformamide), an ether (for example tetrahydrofuran) or an aromatic hydrocarbon (for example 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 alkoxy (e.g. example sodium or potassium methoxide, ethoxide or t-butoxide). The reaction can conveniently be carried out at a temperature in the range of -80 to + 100 ° C, pre-3 d ference -80 to + 25 ° C.

It will be appreciated that when it is desired to prepare a compound of formula (I) where R1 represents a hydrogen atom by process (A), it is necessary to protect the nitrogen atom from the carbazolone in order to prevent it from 'be alkylated by the alkylating agent. The protecting group can be a conventional protecting group such as those described in "Protective Groups in Organic Synthesis" by Theodora W. Green (John Wiley and Sons of 1981), mentioned below.

The compounds of formula (II) can be prepared by the processes described in British Patent No. 2153821A and methods analogous to those described therein.

According to another general method (B), a compound of general formula (I) or one of its protected salts or derivatives can be transformed into another compound of formula (I) using conventional techniques. These conventional techniques include hydrogenation, alkylation and acylation.

Thus, for example, hydrogenation can be used to convert an alkenyl or alkynyl substituent to an alkyl substituent, or an alkynyl substituent to an alkenyl substituent. 55 The hydrogenation according to the general method (B) can be carried out using conventional methods, for example using hydrogen in the presence of a noble metal catalyst (for example palladium, Raney nickel, platinum or rhodium). The catalyst can be on a support, for example carbon, or alternatively one can use a homogeneous catalyst such as tris (triphenulphosphine) rhodium chloride. The hydrogenation is generally carried out in a solvent such as an alcohol (for example ethanol), an ether (for example dioxane), or an ester (for example ethyl acetate), and at a temperature situated in the range from 65 - 20 to + 100 ° C, preferably 0 to 50 ° C.

The acylation according to the general method (B) can be carried out for example on a compound of formula (I) where one of the radicals R1 and R2, or both, represent a hydrogen atom.

5

674 008

The term "alkylation" also includes the introduction of other groups such as cycloalkyl or alkenyl groups. Thus, for example, it is possible to transform a compound of formula (I) where R1 represents a hydrogen atom into the corresponding compound where R1 represents a C1-C10 alkyl group, C3-C7 cycloalkyl, C3-C6 alkenyl, C3 to C10 alkynyl, C3 to C7 cycloalkyl-C alkyl! to C4 or phenylalkyl to Cx to C3.

The above alkylation reactions can be carried out using the appropriate alkylating agent chosen from the compounds of formula R8Z where R8 represents a C1-C10 alkyl, C3-C7 cycloalkyl, C3-Cs alkenyl, C3-alkynyl C3 to C10, C3 to C7 cycloalkyl-Ct to C4 alkyl or phenylalkyl to Q to C3, and Z represents an atom or leaving group such as a halogen atom or an acyloxy or sulfonyloxy group as defined above for Z , or a sulfate of formula (R8) 2SO4.

The alkylation reaction is conveniently carried out in an inert organic solvent such as a substituted amide (for example di-methylformamide), an ether (for example tetrahydrofuran) or an aromatic hydrocarbon (for example toluene), preferably 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), alkali metal carbonates (e.g. sodium carbonate) or an alkali metal alkoxy (e.g. sodium or potassium methoxide, ethoxide or t-butoxide). The reaction can conveniently be carried out at a temperature in the range of from -20 to + 100 ° C, preferably 0 to 50 ° C.

The acylation according to the general process (B) can be used to prepare compounds of formula (I) where R1 represents —C02R6, —COR6, - CONR6R7 or - S02Rs, starting from a compound of formula (I) where R1 represents a hydrogen atom. The acylation reactions can be carried out according to conventional methods using an appropriate acylating agent. -

It should be appreciated that, in the above transformations, it may be necessary or desirable to protect any possible sensitive group in the molecule of the compound in question to avoid undesirable side reactions. For example, it may be necessary to protect the keto group, for example in the form of a ketal or a thioketal. It may also be necessary to protect the nitrogen atom of the carbazolone, for example with an arylmethyl group (for example benzyl or trityl).

Thus, according to another general process (C), a compound of formula (I) can be prepared by the removal of two optional protecting groups from a protected form of a compound of formula (I). Deprotection can be accomplished using standard techniques such as those described in "Protective Gxoups in Organic Synthesis" by Theodora W. Greene (John Wiley and Sons, 1981).

For example, a ketal such as an alkyl-necetal group can be removed by treatment with a mineral acid such as hydrochloric acid. A thioketal group can be cleaved by treatment with a mercuric salt (for example 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 (for example palladium on charcoal), and a trityl group can also be cleaved by acid hydrolysis (for example by using hydrochloric acid or diluted acetic acid).

When it is desired to isolate a compound of the invention in the form of a salt, for example a physiologically acceptable salt, this can be done by treating the free base of general formula (I) with an appropriate acid, preferably with a equivalent amount, in a suitable solvent such as an alcohol (for example ethanol or methanol), an ester (for example ethyl acetate) or an ether (for example tetrahydrofuran).

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

The individual enantiomers of the compounds of the invention can be obtained by splitting a mixture of enantiomers (for example a racemic mixture) using conventional means, such as an optically active splitting acid; see for example “Stereo-5 chemistry of Carbon Compounds” by E.L. Eliei (McGraw Hill 1962) and “Tables of Resolving Agents” by S.H. Wilen.

The methods indicated above for preparing the compounds of the invention can be used as the last main step in the preparation sequence. The same general methods can be used for the introduction of the desired groups at an intermediate stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-process. steps. The sequence of reactions in multi-step processes should, of course, be chosen so that the reaction conditions used do not affect the groups in the molecule which are desired in the final product.

The following example specifies the invention. All temperatures are in ° C.

Example 1

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

N-butyllithium (1.37 ml of a 1.53M solution in hexane) is poured dropwise at -78 °, under nitrogen, with stirring, into a solution of diisopropylamine (0.30 ml) in dry tetrahydrofuran (5 ml) and the solution is stirred between -5 and 0 ° for 30 30 minutes. The solution is cooled to -78 ° and added using a cannula to 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1 -yl) methyl] -4H-carbazol-4-one (500 mg) at -78 ° under nitrogen while stirring. After 51/2 h at -78 °, iodo-methane (0.13 ml) is added and stirring is continued at -78 ° for 2 h, then at room temperature for 13 h. The mixture is treated with saturated aqueous ammonium chloride (30 ml), extracted with chloroform (5 x 30 ml), and the combined and dried organic extracts (Na2SO4) are evaporated. The residue is combined with the residues obtained for three other identical reactions and crystallized from ethyl acetate. The precipitate is separated by filtration and discarded, and the mother liquors are evaporated. The residual foam is purified by HPLC (high pressure liquid chromatography) (using a 170 x 8 mm column of 5 µm Spheri-sorb silica gel and a gilson Autoprep machine), eluting with Phexane / chloroform / ethanol / 0.8880 ammonia (476: 476: 481: 1) to give the free base of the title compound (172 mg). A hot solution of 4-methylbenzenesulfonic acid monohydrate (104 mg, 0.55 mmol) in ethanol (2 ml) is added and, when it cools, the title compound crystallizes in the form of white needles 50 fines (180 mg), for example 115-120 °.

Analysis for C19H21N30-C7Hs03S-0.84 C2H60 -0.18 ^ 0:

Calculated: C 63.8 H 6.7 N 8.0%

Found: C 63.75 H 6.65 N8, 1%

55 Water dosage found: 0.62% w / w = 0.18 mol of H2O.

The following examples specify the pharmaceutical formulations according to the invention. The term "active ingredient" is used herein to represent a compound of formula (I).

60

Tablets for oral administration

Tablets can be prepared by normal methods such as direct compression or wet granulation. Award winning com-65s can be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard techniques. Alternatively, the tablets can be coated with sugar.

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6

Direct compression

Tablet mg / tablet

Active ingredient 5.00

Calcium acid phosphate BP * 82.75

Croscarmellose sodium NF 1.8

Magnesium stearate BP 0.45

Compression weight 90.0

* of quality suitable for direct compression.

The active ingredient is passed through a 0.250 ml mesh screen, mixed with calcium acid phosphate, Croscarmellos sodium and magnesium stearate. The resulting mixture is compressed into tablets using a Manesty F3 compression machine fitted with 5 mm flat punches with a beveled edge.

Tablets of different strengths can be made by changing the ratio of the active ingredient to the excipients or the compression weight and using suitable punches.

Injection for intravenous administration mg / ml

Active ingredient 0.5

Sodium chloride BP ad libitum

5 BP injectable water q.s.p. 1.0 ml

Sodium chloride can be added to adjust the tone of the solution and the pH can be adjusted, using an acid or a base, to that of optimal stability and / or to facilitate dissolution of the active ingredient. Alternatively, suitable buffer salts can be used.

The solution is prepared, clarified and poured into appropriately sized vials sealed by melting the glass. The injection is sterilized by heating in an autoclave using one of the acceptable cycles. Another solution is to sterilize the solution by filtration and pour it into sterile ampoules under aseptic conditions. The solution can be conditioned under an inert atmosphere of nitrogen or another suitable gas.

r

Claims (9)

674 008 ? CLAIMS 1. Compounds of general formula (I): 0 R1 * It \ • • • ■ * // \ / \ / \ I I • “• • NN I he II l \ c \ // / \\ / \ / \ / • NOT . fieri C3 to C6, phenyl or phenylalkyl to C, to C3, and R2, R3, R4 and R5 are as defined in claim h 10. Process for the preparation of a compound of general formula (I) according to one of claims 1 to 7 or of a salt thereof, character-ized in that an alkyl compound of general formula (II) : (I) or R1 represents a hydrogen atom or a group chosen from C1-C10 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-Ct-C4 alkyl, C3-C6 alkenyl, C3-C10 alkynyl, phenyl, phenylalkyl Ct to C3, —C02R6, —COR6, —CONR6R7 or -S02Rs, where R6 and R7, identical or different, each represent a hydrogen atom, a C1-C6 alkyl or C3-C7 cycloalkyl group, or a phenyl or phenyl-Ct-C4 group, in which the phenyl group was optionally substituted by one or more C alkyl groups! to C4, Cx to C4 alkoxy or hydroxy or halogen atoms, with the clarification that R6 does not represent a hydrogen atom when R1 represents a group - C02R6 or --SO2R6; one of the groups represented by R2, R3 and R4- is a hydrogen atom or a C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl or Cx-C3 phenylalkyl, and each of the two other groups, identical or different, represents a hydrogen atom or a Cx to C6 alkyl group, and Rs represents a Ct to C6 alkyl group; and their physiologically acceptable salts and solvates. 2. Compounds according to claim 1, characterized in that, in the general formula (I), R1 represents a hydrogen atom or a C 1-6 alkyl group! to C3, C3 to C5 cycloalkyl or C3 to C6 alkenyl. 3. Compounds according to claim 1, characterized in that, in the general formula (I), one of the groups represented by R2, R3 and R4 represents a C1-C3 alkyl, C3-C7 cycloalkyl or C3-C6 alkenyl group, and each of the two other groups, identical or different, represents a hydrogen atom or a Q to C3 alkyl group. 4. Compounds according to claim 1 or 3, characterized in that, in the general formula (I), R2 represents a C 1 to C 3 alkyl group and R 3 and R 3 and R 4 both represent hydrogen atoms. 5. Compounds according to claim 1, characterized in that, in the general formula (I), R5 represents a C1-C3 alkyl group. 6. Compounds according to claim 1, characterized in that, in the general formula (I), R1 represents a methyl group, R2 represents a methyl group, R3 represents a hydrogen atom, R4 represents a hydrogen atom and R5 represents a Cx to C6 alkyl group. 7. I, 2,3,9-tetrahydro-3,9-dimethyl-2 - [(2-methyl-1H-imidazol-ly!) Methyl] -4H-carbazol-4-one according to claim 1 and its salts and physiologically acceptable solvates. 8. Pharmaceutical composition, characterized in that it comprises at least one compound chosen from the compounds of general formula (I) as defined in one of claims 1 to 7, and their physiologically acceptable salts and solvates, with one or more physiologically acceptable carriers or excipients. 9. Compounds according to claim 1, characterized in that, in the general formula (I), R1 represents a hydrogen atom, or a C 1-6 alkyl group! to C10, C3 to C7 cycloalkyl, alkenyl (II) where R1, R2, R3 and R4 are as defined in one of claims 1 to 7, or one of its protected salts or derivatives; in which case the protective group is removed, the compound being, if desired, split or isolated as an acceptable salt or solvate for therapeutic use, or transformed into another acceptable salt or solvate.