FR2601951A1 - NOVEL TETRAHYDROCARBAZOLONES, PHARMACEUTICAL COMPOSITION CONTAINING SAME AND PROCESS FOR PREPARING THE SAME - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS TETRAHYDROCARBAZOLONES OF FORMULA I: (CF DRAWING IN BOPI) R REPRESENTS H OR A GROUP OF CAC ALCOHOL, CAC CYCLOALCOYL, CA CYCLOALCOYL C-ALCOYL EN CYNAC, ALCENYL, PHYLEN CAC, CAC ALCENYL -ALCOYL EN CAC, -COR, -COR, -CONRR OR -SOR (OR R AND R, WHICH MAY BE THE SAME OR DIFFERENT, EACH REPRESENTS A HYDROGEN ATOM, A CAC ALCOHOL GROUP OR A CAC CYCLOALCOYL OR A PHENYL GROUP OR PHENYL-ALCOYL IN CAC IN WHICH THE PHENYL GROUP IS POSSIBLE SUBSTITUTED BY ONE OR MORE GROUPS OF CAC ALCOHYL, CAC ALCOXY OR HYDROXY OR HALOGEN ATOMS, WITH THIS PRECISION THAT R DOES NOT REPRESENT A REPRESENT OF HORSYD ATOMES A -COR OR -SOR GROUP); ONE OF THE GROUPS REPRESENTED BY R, R AND R IS H OR A GROUP ALCOYL IN C A C, CYCLOALCOYL IN C A C, ALCENYL IN C A C OR PHENYL-ALCOYL IN C A C AND EACH OF THE TWO OTHER GROUPS REPRESENTS INDEPENDENTLY A C A C HYDROALCOYL; R REPRESENTS A C A C ALCOHYL, AND THEIR PHYSIOLOGICALLY ACCEPTABLE SALTS AND SOLVATION PRODUCTS. THE COMPOUNDS ARE POWERFUL AND SELECTIVE ANTAGONISTS OF THE EFFECT OF 5-HT IN 5-HT RECEPTORS AND ARE USEFUL, FOR EXAMPLE, IN THE TREATMENT OF PSYCHOTROPIC DISEASES, ANXIETY, AND NAUSEA AND VOMITING . THE PRESENT INVENTION ALSO CONCERNS A PHARMACEUTICAL COMPOSITION CONTAINING THEM AND A PROCESS FOR THEIR PREPARATION.

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 at the "neuronal" -HT receptors of the type located on the primary afferent nerves have been previously described. For example, British Patent Publication No. 2153821A discloses tetrahydrocarbazolones of the general formula

O R4 R3

// \ H.

i he he t * d

\\ / CH \ \ / \ /

R

  R represents a hydrogen atom or a C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, phenyl or C 1 -C 3 phenylalkyl group, and one of the groups represented by R 2, R 3 and R 4; is a hydrogen atom or a C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl or C1-C3 phenyl-alcoyl group 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. A new group of compounds whose structure differs from those previously described, and which are potent antagonists of the effect of 5-HT at the neuronal "at the -HT. Thus, the invention provides a tetrahydrocarbazolone of the general formula (I):

I R 4 R 3

  ## STR2 ## represents a hydrogen atom or a group selected from the group consisting of C 1 to C 10 alkyl, C 3 to C 7 cycloalkyl, C 3 to C 7 cycloalkyl C 1 to C 4 alkyl groups. C3 to C6 alkenyl, C3 to C3 alkynyl phenyl or phenyl C1 to C4 alkyl,

610 6 6 \ 7 6

  CO 2, -COR 2, -CONRR or -SO 2 R (oR 6 and R which may be the same or different, each represent a hydrogen atom, a C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl group, or a phenyl or phenyl C 1 -C 7 alkyl group. at C4, wherein the phenyl group is optionally substituted by one or more C1-C4 alkyl, C1-C4 alkoxy or hydroxy or halogen atoms, with the proviso that R6 does not represent a hydrogen atom when R is CO 2 R 6, or -SO 2 R 6); One of the groups represented by R 2, R 2 and R 3 is a hydrogen atom or a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl or phenyl C 1 -C 3 alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-C6 alkyl group; and R5 is (C1-C6) alkyl; i 6 '

  and its physiologically acceptable salts and solvates.

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

  general formula (I) are included in the invention.

  With reference to the general formula (I), the alkyl groups represented by R 1, R 2, R 3, R 4, R 5, R 6 and R 7 may be straight or branched chain alkyl groups, for example methyl or ethyl groups. ,

  propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-2yl, pentyl, pent-3-yl or hexyl.

  C 3 -C 6 alkenyl may be, for example, propenyl or butenyl. C3-C10 alkynyl may be, for example, prop-2-ynyl or oct-2-ynyl. It will be appreciated that when R 1 is C 1 -C 6 alkenyl or

3 6

  C3-C10 alkynyl, the double or triple bond respectively may not be adjacent to the nitrogen atom. Phenyl-C 1 -C 3 alkyl may be, for example, benzyl, phenethyl or 3-phenylpropyl. A C 3 -C 7 cycloalkyl group, alone or as part of a C 3 to C C 7 alkyl cycloalkyl group, may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

or cycloheptyl.

  According to one aspect, the invention provides compounds of formula (I) wherein R represents a hydrogen atom or a C1-C10 alkyl, C3-C7 cycloalkyl, C3-C6 alkenyl, phenyl or phenyl-alkyl group in C1 to C3, and R, R3, R and R5 are

  as defined in formula (I).

  A preferred class of compounds represented by the general formula (I) is where R 1 is hydrogen, C 1 -C 3 alkyl (eg methyl), C 3 -C 6 cycloalkyl or

C3-C6 alkenyl.

  Another preferred class of compounds represented by the general formula (I) is where one of R 2, R 3 and R 4 is C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 alkenyl and each of the other two groups, which may be the same or different, represent a hydrogen atom or a C 1 -C 3 alkyl group. When R2 represents an atom

13 3 4

  of hydrogen, R and / or R is preferably

  C1-C3 alkyl group (for example methyl).

  When R2 represents a C1 to C3 alkyl group

3 4 3

  (eg methyl) R and R both represent

  preferably hydrogen atoms.

  Another preferred class of compounds of formula (I) is that of the compounds where R 5 represents a C 1 to C 3 alkyl group (for example methyl). A particularly preferred group of compounds of formula (I) is those where R 1 is methyl, R 2 is methyl, R 3 is hydrogen, R 4 is hydrogen and R 5 is alkyl in C1 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 salts and physiologically acceptable solvates. Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with organic or inorganic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, citrates, succinates, tartrates, fumarates, maleates and p-toluenesulphonates. Solvates

  can be for example 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 to the parent compound of formula (I).

  The compounds of the invention are potent and selective antagonists of the 5-HT induced depolarization of the rat-isolated pneumogastric nerve preparation and thus act as potent and selective "neuronal" receptor antagonists.

  at the 5-HT located on the primary afferent nerves.

  Receptors of this type are now referred to as 5HT3 receptors. These receptors are also thought to be present in the central nervous system. 5-HT is widespread in the neuronal pathways of the central nervous system and it is known that a disorder of these 5-HT containing pathways alters aspects of behavior such as mood, psychomotor activity,

appetite and memory.

  Compounds of formula (I), which antagonize the effect of 5-HT at 5-HT3 receptors, are useful in the treatment of condition such as psychotropic diseases (eg 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, esophagitis

  reflux, flatulence and intestinal syndrome with irritation; migraine; and pain.

  In contrast to existing drug treatments for these conditions, it would not be expected that the compounds of the invention, given their high selectivity for 5-HT3 receptors, produce undesirable side effects. Thus, for example, neuroleptic drugs may exhibit extrapyramidal effects, such as tardive dyskinesia, and benzodiazepines may

to provoke an addiction.

  The invention therefore also provides a pharmaceutical composition which comprises at least one compound selected from the compounds of general formula (I) and physiologically acceptable solvates, for example hydrates, adapted for application in human or veterinary medicine, and formulated for

  administration by any convenient way.

  These compositions may be formulated in conventional manner using one or more carriers

  or physiologically acceptable excipients.

  Thus compounds according to the invention can be formulated for oral, oral, 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 by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (eg lactose, microcrystalline cellulose or calcium acid phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (eg sodium lauryl sulphate). The tablets may be coated by methods well known to those skilled in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product for reconstitution with water or any suitable vehicle prior to use. . Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example lecithin or acacia); non-aqueous vehicles (eg, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring agents, coloring agents and the like.

softeners as needed.

  Preparations for oral administration can 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 classical way.

  The compounds of the invention may be formulated for parenteral administration by injection. Injectable formulations may be presented in unit dosage form, for example in ampoules or multidose containers with the addition of a preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as

  suspension, stabilization and / or dispersion.

  Alternatively, the active ingredient may be in the form of a powder for reconstitution with a suitable vehicle, eg pyrogen water

sterile, before use.

  The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as

  cocoa butter or other glycerides.

  In addition to the formulations described above, the compounds of the invention may also be formulated as delayed preparations. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or resins.

  ion exchangers, or in the form of poorly soluble derivatives, for example in the form of a poorly soluble salt.

  For administration by inhalation the compounds of the invention are conveniently administered in the form of an aerosol sprayed liquid presentation from a pressure container or nebulizer, using a suitable rector, for example, dichlorodifluoro methane, 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 for delivering a measured amount. Capsules and cartridges of eg gelatin for use in an inhaler or insufflator may be formulated containing a powder 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 (weighing about 70 kg) is 0.05 to 100 mg, preferably 0.1 to 50 mg of the active ingredient per unit dose than it can be administered, for example from 1 to 4 times a day. It will be appreciated that routine variations in dosage may be required depending on the age and condition of the patient. The dosage also depends on

administration mode.

  According to another aspect of the invention, it is possible to prepare the compounds of general formula (I) and their salts or solvates physiologically.

  acceptable by the general procedures presented below. In the following description, the groups R 1 to R 5 are as defined for the compounds of the general formula (I) unless otherwise indicated.

  According to a first general method (A), a compound of formula (I) can be prepared by alkylating a compound of formula (II)

/ R4 R3

r. 1 N N (II)

\\ / \ \ / \ / - 2

  eRN1 * R2 R1 or a protected salt or derivative thereof, using an alkylating agent and, if necessary, removing the

possible protective groups.

  Alkylating agents which can be used in the above process according to the invention include compounds of the formula R 5 Z, where Z represents an atom or leaving group such as a halogen atom (for example chlorine, bromine or iodine), a group Acyloxy (for example trifluoroacetyloxy or acetoxy),

  or a sulphonyloxy group (for example trifluoromethanesulphonyloxy, ptoluenesulphonyloxy or methanesulphonyloxy); or a sulphate of formula (R5) 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 based. 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 (eg example methoxide, ethoxide or t-butoxide

  sodium or potassium). The reaction can be conveniently conducted at a temperature in the range of -80 to +100 ° C, preferably -80 to +25 ° C.

  It will be appreciated that when it is desired to prepare a compound of formula (I) wherein R 1 represents a hydrogen atom by the process (A) above, it is necessary to protect the nitrogen atom from carbazolone.

  to prevent it from being alkylated by the alkylating agent.

  The protecting group may be a conventional protecting group such as those described in "Protective Groups in Organic Synthesis" by Theodora W. Greene (John Wiley

  and Sons 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 converted 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 substituent or

  alkynyl to an alkyl substituent, or an alkynyl substituent to an alkenyl substituent.

  The hydrogenation according to the general method (B) can be carried out using conventional methods, for example using hydrogen in the presence

  a noble metal catalyst (for example palladium dium, Raney nickel, platinum or rhodium).

  The catalyst may be supported on, for example, charcoal, or a homogeneous catalyst such as tris (triphenylphosphine) rhodium chloride may be used. 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 within a range of -20 to +100 C, from

preferably 0 to 50 C.

  The alkylation according to the general process (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.

  The term "alkylation" also includes the introduction of other groups such as cycloalkyl or alkenyl groups. Thus, for example, a compound of formula (I) wherein R1 is hydrogen may be converted to the corresponding compound wherein R1 is C1-C10 alkyl, C3-C7 cycloalkyl, C3-C6 alkenyl C3-C10 alkynyl,

  C3-C7 cycloalkyl-C1-C4 alkyl or phenyl-C1-C3 alkyl.

  The above alkylation reactions may be carried out using the appropriate alkylating agent selected from the compounds of the formula R 8 wherein R 8 is C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, alkynyl C 3 to C 10, C 3 to C 7 cycloalkyl-C 1 to C 4 alkyl or phenyl C 1 to C 3 alkyl, and Z represents an outgoing atom or group such as a halogen atom or an acyloxp or sulphonyloxy group as defined above for

  Z; or a sulphate of formula (R8) 2SO4.

  The alkylation reaction is conveniently carried out in an inert organic solvent such as a substituted amide (eg dimethylformamide), 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 hydride), alkali metal amides (eg, sodium amide or lithium diisopropylamide), alkali metal carbonates (e.g. sodium carbonate) or an alkali metal alkoxy (for example, sodium or potassium methoxide, ethoxide or t-butoxide). The reaction may be conveniently conducted at a temperature in the range of -20 to +100 C, preferably

0 to 50 C.

  The acylation according to the general method (B) can be used to prepare compounds of formula (I) where R1 represents -CO2R6, -COR6, CONR6R7 or -SO2R6, from a compound of formula ( I) o R

  represents a hydrogen atom. Acylation reactions can be conducted according to conventional methods using a suitable acylating agent.

  It should be appreciated that in the above transformations it may be necessary or desirable to protect any susceptible groups 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 thioketal.-It can also be

  It is necessary to protect the nitrogen atom from carbazolone, for example with an arylmethyl group (for example benzyl or trityl).

  260195i Thus according to another general method (C), a compound of formula (I) can be prepared by removing two possible protecting groups from a protected form of a compound of formula (I). Deprotection can be performed using standard techniques such as those described in "Protective Groups in Organic Synthesis" by Theodora W. Greene (John Wiley

and Sons, 1981).

  For example, a ketal may be removed as an alkylenecetal group 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 (eg palladium on charcoal) and a trityl group can also be cleaved by acid hydrolysis (e.g.

  dilute hydrochloric or 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, it can be done by treating the free base of general formula (I) with a suitable acid, preferably with a equivalent amount in a suitable solvent such as an alcohol (eg ethanol or methanol), an ester (eg ethyl acetate) or an ether (eg

for example tetrahydrofuran).

  Physiologically acceptable equivalents of a compound of formula (I) can be prepared

according to 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 "Stereochemistry of Carbon Compounds" by E.L. Eliel (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 major step in the preparation sequence. The same general methods can be used for introducing the desired groups at an intermediate stage into the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multistep processes. The sequence of the reactions in the multistep processes will naturally be chosen so that the reaction conditions used do not affect the groups in the molecule that 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-ylmethyl) -4H-carbazol-4-one 4-methylbenzenesulfonate N-Butyllithium (1 g. , 37 ml of a 1.53M solution in hexane) at -78, under nitrogen, with stirring, in a solution of diisopropylamine (0.30 ml) in dry tetrahydrofuran (5 ml) and the solution is shaken. between -5 and 0 for 30 minutes The solution was cooled to -78 and added via 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 with stirring After 5 h and half to -78 iodomethane (0 13 ml) and continue to dry at -78 for 2 h and then at room temperature for 13 h The mixture is treated with saturated aqueous ammonium chloride (30 ml) and extracted with chloroform (5x30 ml) ) and the combined and dried organic extracts are evaporated (Na2SO4).

  the residues obtained for three other identical reactions and crystallized from ethyl acetate.

  The precipitate is filtered off and discarded, and the mother liquors are evaporated. Residual foam was purified by HPLC (high pressure liquid chromatography) (using a

  x 8 mm of 5 gm Spherisorb silica gel and a Gilson Autoprep machine), eluting with hexane-chloroform-ethanol-ammonia at 0.8880 (476: 476: 481: 1) to give the free base of the compound of the title (172 mg).

  A hot solution of 4-methylbenzenesulphonic acid monohydrate (104 mg, 0.55 mmol) in ethanol (2 ml) is added and the compound is cooled

  The title crystallizes as fine white needles (180 mg), for example, 115-120.

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

C9H21N3O.C7H803S.O.84 C2H60O.18H20

  requires: C, 63.75; H, 6.65; N, 8.1%. Determination of water found: 0.62% w / w E0.18 mol H20.

  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).

  TABLETS FOR ORAL ADMINISTRATION

  Tablets can be prepared by normal methods

  like direct compression or wet granulation.

  The tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard techniques. Other solution, tablets

can be coated with sugar.

  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 appropriate quality for direct compression.

  The active ingredient is passed through a 0.250 ml mesh sieve, mixed with calcium acid phosphate, Croscarmellos sodium, and magnesium stearate. The resulting mixture is compressed into tablets using a Manesty F3 compression machine equipped with punches

plates of 5 mm bevelled edge.

  Tablets of different concentration can be prepared by varying the ratio of the active ingredient to the excipients or the compression weight and employing appropriate poisons.

  INJECTION FOR INTRAVENOUS ADMINISTRATION

  mg / ml Active Ingredient 0.5 Sodium Chloride BP ad libitum Injectable Water BP qs 1.0 ml Sodium Chloride can be added to adjust the tonicity of the solution and the pH can be adjusted using an acid or base at that of optimal stability and / or facilitate dissolution

  of the active ingredient. Alternatively, suitable buffer salts may be used.

  The solution is prepared, clarified and poured into appropriately sized ampoules sealed by melting the glass. We sterilize the injection26'01951

  by heating in an autoclave using one of the acceptable cycles. Alternatively, the solution can be sterilized by filtration and poured into sterile ampoules under aseptic conditions. The solution can be conditioned under an atmosphere

  inert nitrogen or other suitable gas.

Claims (10)

  1. Compounds of general formula (I): O R4 R3 R R   (R) o R1 represents a hydrogen atom or a group selected from C1 to C10 alkyl, C3 to C7 cycloalkyl, C3 to C7 cycloalkyl (C1 to C4) alkyl, (C3 to C6) alkenyl, (C3 to C6) alkynyl; , phenyl, phenyl-C1-C3 alkyl, -CO2R6, -COR, -CONR R7 or -SO2R (o R and R, which may be identical or different, each represent a hydrogen atom, a C1-alkyl group; C 6 -C 8 cycloalkyl or phenyl or phenyl-C 1 -C 4 alkyl, wherein the phenyl group was optionally substituted with one or more C 1 -C 4 alkyl, C 1 -C 4 alkoxy or hydroxy groups; halogen atoms, with the proviso that R6 does not represent a hydrogen atom when R1 is -CO R6 or -SO2R6); one of the groups represented by 2 2 3 42   R 2, R 3 and R 3 are hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl or phenyl C 1 -C 3 alkyl and each of the other two groups, which may be identical or different, represents a hydrogen atom or a C1-C6 alkyl group; and R5 is C1-C6 alkyl;   and their physiologically acceptable salts and solvates. 260 1951   2. Compounds according to claim 1, characterized in that, in the general formula (I) R represents a   hydrogen atom or a C1-C3 alkyl, C3-C6 cycloalkyl or C3-C6 alkenyl group.   3. Compounds according to claim 1, characterized in that in the general formula (I) one of the groups 2 3 4   R 1, R 3 and R 3 are C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 alkenyl and each of the other two groups, which may be identical or different, represents a hydrogen atom or a hydrogen atom. C1 to C3 alkyl group.   4. Compounds according to claim 1 or 3, characterized in that in the general formula (I) R2 represents   C1 to C3 alkyl and R and R are both hydrogen.   5. Compounds according to claim 1, characterized in that in the general formula (I) R5 represents a C1 to C3 alkyl group.   6. Compounds according to claim 1, characterized in that in the general formula (I) R1 represents a   methyl group, R represents a methyl group, R represents a hydrogen atom, R4 represents a hydrogen atom and R5 represents a C1-C6 alkyl group.   7. 1,2,3,9-Tetrahydro-3,9-dimethyl-31 (2-methyl-1H-25-imidazol-1-yl) methyl-4H-carbazol-4-one and its salts and   physiologically acceptable solvates.   8. Pharmaceutical composition characterized in that   it comprises at least one compound selected 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. Process for preparing a compound of formula   general (I) as defined in one of claims 1 to 7 or a salt thereof, characterized in that   (A) alkylating a compound of the general formula (II): O R4 XX N N R1 R2 (II)   i 2 3 4 (o R 1, R, R and R are as defined in one of   Claims 1 to 7), or a protected salt or derivative thereof; or   (B) subjecting a compound of the general formula (I) as defined in claim 1 or a protected salt or derivative thereof to a conventional interconversion reaction to form another compound of the general formula (I) as defined in claim 1, or a salt or protected derivative thereof; or (C) subjecting a protected derivative of a compound of general formula (I) or a salt thereof to a reaction to remove the protecting group or groups; and if necessary and / or if desired, subjecting the compound obtained from step (A), (B) or (C) to one or more other reactions comprising (1) removing any possible protecting group; (2) converting the resulting compound of general formula (I) or a salt thereof into a physiologically acceptable salt or solvate; and (3) when the compound of the general formula (I) is obtained in the form of a mixture of enantiomers, the mixture is optionally divided to give the desired enantiomer.   10. Compounds according to claim 1, characterized in that in the general formula (I) R represents a hydrogen atom, or a C1-C10 alkyl, C3-C7 cycloalkyl, C3-C6 alkenyl, phenyl or phenyl group. C1-C3 alkyl, and R2 ,, R3 Ret R5 are such   as defined in claim 1.