CH664152A5 - DERIVATIVES OF TETRAHYDROCARBAZOLONES. - Google Patents

Description

DESCRIPTION

The present invention relates to heterocyclic compounds derived from tetrahydrocarbazolones, processes for their preparation and pharmaceutical compositions containing them. In particular, the invention relates to compounds which act on certain 5-hydroxytryptamine (5HT) receptors.

5HT, which is found endogenously in abundance in peripheral nerves and in blood platelets, is known to cause pain in humans by a specific action on the 5HT receptors located on the ends of primary afferent nerves. The compounds which have an action antagonizing the neuronal effects of 5HT have been shown to have analgesic activity, for example to relieve the pain of migraine. 5HT also causes depolarization of the rat pneumogastric nerve preparation by the same 5HT receptor mechanism, and inhibition of this effect is correlated with an analgesic effect in vivo.

There is also a lot of 5HT in the neuron pathways of the central nervous system (CNS) and it is known that a disorder of these 5HT pathways alters behavioral syndromes, such as mood, psychomotor activity, appetite and memory. Since the "neural" 5HT receptors of the same type as those present on the primary afferent ends are also present in the CNS, it is believed that compounds which are antagonistic to the neuronal effects of 5HT will be useful in the treatment of conditions such as schizophrenia, chronic delusions and delusional psychoses, anxiety, obesity and mania.

The existing treatments for such conditions suffer from a certain number of drawbacks. Thus, for example, known treatments for migraine include the administration of a vasoconstrictor such as ergotamine, which is non-selective and produces vasoconstriction throughout the body. Ergotamine therefore has unwanted and potentially dangerous side effects. Migraine can also be treated by using a pain reliever like aspirin or paracetamol, usually in combination with an antiemetic like metaclopramide, but these treatments are only of limited value. -

Similarly, existing treatments for psychotic disorders such as schizophrenia and chronic delusions and delusional psychoses have a number of serious side effects such as extra-pyramidal side effects.

There is therefore a need for a safe and effective drug for the treatment of conditions involving an attack of the pathways containing 5HT, such as migraine or psychotic disorders such as schizophrenia, chronic delusions and delusional psychoses. It is believed that a compound which is a potent and selective antagonist to “neuronal” 5HT receptors will fulfill such a role.

We have now found a group of 3-imidazolylmethyltetra-hydrocarbazolones which are potent and selective antagonists to 5HT receptors "neural".

The invention provides a tetrahydrocarbazolone of general formula (I):

"R1 'R3

AT / -

// \

i \ / \ r-

. ÏT

NOT

y y y

: v Ri

\ // l C1 to C6 alkyl group, and its physiologically acceptable salts and solvates, for example hydrates.

It will be understood that when R1 represents a C3 to C6 alkenyl group, the double bond may not be adjacent to the nitrogen atom. Referring to the general formula (I), the alkyl groups represented by R1; R2, R3 and R4 may be straight or branched chain alkyl groups, for example methyl, ethyl, propyl, prop-2-yIe, butyl, but-2-yl, 2-methylprop-2-yl, pentyl, pent- 3-yle or hexyl.

An alkenyl group can be, for example, a propenyl group. A C1-C3 phenylalkyl group may for example be a benzyl, phenethyl or 3-phenylpropyl group.

A cycloalkyl group can be, for example, a cyclo-pentyl, cyclohexyl or cycloheptyl group.

iy 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. The invention includes both the individual isomeric forms of the compounds of formula (I) and all of their mixtures, including racemic mixtures.

Suitable physiologically acceptable salts of the indoles of general formula (I) include the acid addition salts formed with organic or inorganic acids, for example hydrochlorides, hydrobromides, sulfates, phosphates, citrates, fumarates and maleates. The solvates can be, for example, hydrates.

A preferred class of compounds represented by the general formula (I) is that in which R1 represents a hydrogen atom or a C1 to C6 alkyl, a C3 to C6 cycloalkyl or a C3 alkenyl

to C6.

Another preferred class of compounds represented by the general formula (I) is that where one of the groups represented by R2, R3 and R4 represents a C1-C3 alkyl, C3-C6 cycloalkyl or C3-C6 alkenyl group. and each of the other two groups, which may be similar or different, represents a hydrogen atom or a C1-C3 alkyl group.

Another preferred class of compounds represented by the general formula (I) is that in which R1 represents a hydrogen atom or a C1 to C6 alkyl, C5 to C6 cycloalkyl or C3 to C4 alkenyl group or else R2 represents an atom of hydrogen and R3 and / or 40 R4 represent a C1 to C3 alkyl group, or else R2 represents a C1 to C3 alkyl group and R3 and R4 both represent hydrogen atoms.

A particularly preferred class of compounds according to the invention is that represented by formula (la):

// \

H,

/ "\ /» •

I I

■ ♦ .a

50

", • • •

v y \ /

• NOT •

Laugh

\ _ / \ | —Î

N N

\ //

"

I,

R2a

R3a

(the)

(I)

where R1 represents a hydrogen atom or a C1-C10 alkyl, a C3-C7 cycloalkyl, a C3-C6 alkenyl, a phenyl or a phenyl-C1-C3 alkyl, and where one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1 to C6 alkyl, a C3 to C7 cycloalkyl, a C2 to C6 alkenyl or a C1 to C3 phenylalkyl and each of the two other groups, which may be the same or different, represents a hydrogen atom or one in which R1 represents a hydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl group; R3a represents 55 a hydrogen atom and either R2a represents a methyl, ethyl, propyl or prop-2-yIe group and R4a represents a hydrogen atom, or else R2a represents a hydrogen atom and R4a represents a methyl or ethyl group and their physiologically acceptable salts and solvates (for example hydrates), n / a The preferred compounds are: 1,2,3,9-tetrahydro-3 - [(2-methyl-1 H-imidazol- 1 -yl) methyl] -9- (prop-2-enyl) -4H-carbazol-4-one; 9-cyclopentyl-1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol -l-yl) methyl] -4H-carbazol-4-one, and 1,2,3,9-tetrahydro-3- [2-methyl-1H-imidazol-1 -yl) methyl] -9- (prop- 2-yl) -4H-carbazol-4-one and their salts 65 and physiologically acceptable solvates.

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

664,152

4

ï

«•« o ■ - «

// \ / \ / \ l — I

. . . • K N

I II II I \ //

9 • 6 O “

VV \ / '

• N • Me

Me and its physiologically acceptable salts and solvates (eg hydrates). A preferred form of this compound is the hydrochloride dihydrate.

The compounds of the invention are powerful and selective antagonists of the 5HT-induced responses of the pneumogastric nerve preparation isolated from rats and thus act as powerful and selective antagonists of the 5HT "neuronal" receptor type located on the primary afferent nerves.

The compounds of the invention are useful as analgesics, for example to relieve the pain associated with migraine, headaches and many other forms of pain for which 5HT is the endogenous mediator.

Experiments in animals have shown that the compounds of the invention are also useful in the treatment of schizophrenia, chronic delusions and delusional psychoses and other psychotic disorders. As noted above, 5HT is widely distributed in the CNS neural pathways and involvement of these 5HT pathways is known to affect many other behavioral syndromes, such as mood, appetite and memory. Since the “neural” 5HT receptors of the same type as those present on the primary afferent ends are also present in the CNS, the compounds of the invention may also be useful in the treatment of conditions such as anxiety, obesity and mania.

In particular, it has been found that the compounds of formula (la) as defined above are very selective and extremely powerful in their action. They are well absorbed by the gastrointestinal tract and are suitable for oral or rectal administration. The compounds of formula (la) do not prolong the duration of sleep in mice anesthetized with pentobarbitone, which indicates that there is no undesirable interaction with the enzymes metabolizing the drug. In fact, they have no effects on normal behavior, are non-toxic and do not have undesirable effects on mice at doses up to 1 mg / kg intravenously.

While having the excellent properties of the compounds of formula (la), the compound of formula (Ib), when administered to humans, does not have harmful effects.

The compounds according to the invention allow the treatment of a human or animal subject suffering from a condition caused by a “neuronal” 5HT function disorder, for example the treatment of a human subject suffering from migraine pain or 'a psychotic disorder like schizophrenia, chronic delusions and delusional psychoses.

The invention therefore therefore also provides a pharmaceutical composition comprising at least one compound chosen from 3-imidazolylmethyltetrahydrocarbazolone derivatives of general formula (I), their physiologically acceptable salts and solvates, for example hydrates, suitable for application in human medicine or veterinary, and formulated for administration by any convenient route.

These compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.

Thus, the compounds of the invention can be formulated 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 can take the form of tablets or capsules prepared in a conventional manner with pharmaceutically acceptable excipients such as binding agents (for example pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose) ; fillers (e.g. lactose, microcrystalline cellulose or calcium acid phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium starch glycolate); or wetting agents (for example sodium lauryl sulfate). The tablets can be coated by methods well known to those skilled in the art. Liquid preparations for oral administration may take the form of solutions, syrups or suspensions, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. These 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 (eg almond oil, fatty esters, ethyl alcohol or fractionated vegetable oils), and preservatives (eg methyl or propyl p-hydroxybenzoates or acid sorbic). The preparations may also contain buffer salts, flavoring agents, colorants and softeners as required.

Preparations for oral administration can be conveniently 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 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 agents, stabilizing agents and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with an appropriate vehicle, for example sterile pyrogen-free 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 conventional suppository bases 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 preparation. These 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 sparingly soluble derivatives, for example in the form of a sparingly soluble salt.

For administration by inhalation, the compounds according to the invention are conveniently supplied in the form of an aerosol spray liquid from pressurized packaging or from a nebulizer, with the use of an appropriate vector, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafiuoroethane, 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. Capsules and cartridges, for example gelatin, can be formulated for application in an inhaler or insufflator containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

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A proposed dose of the compounds of the invention for administration to humans of approximately 70 kg of body weight is 0.05 to 20 mg, preferably 0.1 to 10 mg, of the ingredient. active per unit dose which can be administered, for example, 1 to 4 times a day. The dose depends on the mode of administration and the patient's body weight. It will be appreciated that it may be necessary to make routine dosage variations depending on the age and weight of the patient, as well as on the severity of the condition to be treated.

For oral administration, a unit dose preferably contains 0.5 to 10 mg of the active ingredient. A unit dose for parenteral administration preferably contains 0.1 to 10 mg of the active ingredient.

The aerosol formulations are preferably arranged so that each measured or "puff" dose delivered from a pressurized aerosol contains from 0.2 to 2 mg of a compound of the invention, and each dose administered to the means of capsules and cartridges in an insufflator or an inhaler contains from 0.2 to 20 mg of a compound of the invention. The overall daily dose by inhalation is in the range of 0.4 to 80 mg. The administration can be done in several times a day, for example from 2 to 8 times, giving for example 1, 2 or 3 doses each time.

The compounds of the invention can, if desired, be administered in combination with one or more other therapeutic agents, such as anti-nausea agents.

According to another aspect of the invention, the compounds of general formula (I) and their physiologically acceptable salts or solvates or their physiologically acceptable equivalents can be prepared by the general methods presented below.

According to a first general process (A), a compound of general formula (I) or one of its physiologically acceptable salts or solvates or one of its physiologically acceptable equivalents can be prepared by reacting a compound of general formula (II)

"• ■ • ©

I II II I (n)

• 0 0. •

vvv

Rl where R1 is as defined above and Y represents a reactive substituent, or one of its derivatives protected with an imidazole of general formula (III)

R * 4 'K3

\ /

• •.

HK N (IH)

\ //

>

where R2, R3 and R4 are as defined above, or a salt thereof.

Examples of compounds of formula (II) used as starting materials in process (A) include compounds where Y represents a group selected from an alkenyl group = CH2 or a group of formula CH2Z where Z represents an easily displaceable atom or group as a halogen atom, for example of chlorine or of bromine, an acyloxy group As acetoxy, trifiuoromé-thanesulfonyloxy, p-toluènesulfonyloxy or méthanesulfonyloxy; a group - + NR5R <SR7X ~, where R5, R® and R7, which may be similar or different, each represents a lower alkyl, for example a methyl, an aryl, for example a phenyl or an aral-coyl, for example benzyl, or R5 and R6 together with the nitrogen atom to which they are attached can form a 5 or 6-membered ring, for example a Pyrrolidine ^ ring and X represents an anion as a halide ion, for example chloride, bromide or iodide; or a group —NRSR6 where R5 and R6 are as defined above, for example — N (CH3) 2.

When Y represents the group - CH2, the process can conveniently be carried out in an appropriate solvent, examples of which include water; esters, for example ethyl acetate, ketones, for example acetone or methyl isobutyl ketone; amides, for example dimethylformamide; alcohols, for example ethanol; and ethers, for example dioxane or tetrahydrofuran or mixtures thereof. The process can be carried out at a temperature of, for example, 20 to 100 ° C.

When Y represents the CH2Z group, where Z is a halogen atom or an acyloxy group, the process can be conveniently carried out in a suitable solvent such as an amide, for example dimethylformamide; an alcohol, for example methanol or industrial denatured alcohol or a haloalkane, for example dichloromé-thane, and at a temperature ranging from -10 to 150 ° C, for example +20 to + 100 ° C.

One can conveniently carry out the reaction of a compound of formula (II) where Y represents the group CH2Z, where Z is the group - + NRSR6R7X ~, in a suitable solvent such as water, an amide, for example dimethylformamide; a ketone, for example acetone; or an ether, for example dioxane, and at a temperature ranging from 20 to 150 ° C.

The reaction can conveniently be carried out including a compound of formula (II) where Y represents the group - CH2Z, where Z is the group --NR5R6, in a suitable solvent such as water or an alcohol, for example methanol, or mixtures thereof , and at a temperature ranging from 20 to 150 ° C.

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

A R, "R3

1

// * \ / \ / AI — î (iv]

• • • ® N N

I II there i Y // \ / \ / \ / i,

• N • R2

R1

where A represents a hydrogen atom or a hydroxyl group, and R1, R2, R3 and R4 are as defined above or one of its protected salts or derivatives.

The oxidation process can be carried out using conventional methods, and the reactants and reaction conditions should be chosen such that they do not cause oxidation of the indole group. Thus, the oxidation process is preferably carried out using a mild oxidizing agent.

When oxidizing a compound of formula (IV) where A represents a hydrogen atom, the suitable oxidizing agents include quinones in the presence of water, for example 2,3-dichloro-5,6-dicyano-1 , 4-benzoquinone or 2,3,5,6-tetrachloro-1,4-benzoqui-none; selenium dioxide; an oxidizing reagent to cerium (IV) such as ceric ammonium nitrate or an oxidizing agent to chromium (VI), for example a solution of chromic acid in acetone (for example Jones reagent) or chromium trioxide in Pyridine.

When oxidizing a compound of formula (IV) where A represents a hydroxyl group, the suitable oxidizing agents include quinones in the presence of water, for example 2,3-dichloro-5,6-dicyano-1,4 benzoquinone or 2,3,5,6-tetrachloro-1,4-benzoqui-none; ketones, for example acetone, methyl ethyl ketone or cyclohexanone, in the presence of a base, for example aluminum t-butoxide; a chromium (VI) oxidizing agent, for example a solution of chromic acid in acetone (for example Jones' reagent) or chromium trioxide in pyridine; an N-halosuccini-mide, for example N-chlorosuccinimide or N-bromosuccinimide; a dialkyl sulfoxide, for example dimethyl sulfoxide in the presence of an activating agent such as N, N'-dicyclohexylcarbodiimide or an acyl halide, for example oxalyl chloride or tosyl chloride; pyridine-sulfur trioxide complex; or a catalyst

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dehydrogenation such as copper chromite, zinc oxide, copper or silver.

The suitable solvents can be chosen from ketones, for example acetone or butanone; ethers, for example tetrahydrofuran or dioxane; amides, for example dimethylformamide; alcohols, for example methanol; hydrocarbons, for example benzene or toluene; halogenated hydrocarbons, for example dichloromethane, and water or their mixtures.

The process is conveniently carried out at a temperature ranging from -70 to + 50 ° C. It will be understood that the choice of the oxidizing agent has an influence on the preferred reaction temperature.

According to another general process (C), a compound of formula (I) according to the invention or one of its protected salts or derivatives can be transformed into another compound of formula (I) using conventional techniques. These conventional techniques include alkylation, which can be carried out at any position in a compound of formula (I) where one or both of the radicals R1 and R2 represents a hydrogen atom, and hydrogenation, which can, for example, be used to transform an alkenyl substituent into an alkyl substituent. The term "alkylation" includes the introduction of other groups such as cycloalkyl or alkenyl groups. Thus, a compound of formula (I) in which R1 represents a hydrogen atom can be transformed into the corresponding compound in which R1 represents a C1 to C10 alkyl, a C3 to C7 cycloalkyl, a C3 to C6 alkenyl or a phenyl group. - C1 to C3 alkyl.

The above alkylation reactions can be carried out using the appropriate alkylating agent chosen from the compounds of formula RaXa where Ra represents a C1 to C10 alkyl, a C3 to Cl cycloalkyl, a C3 to C6 alkenyl or a phenyl-C1-C3 alkyl group, and X "represents an leaving group such as a halide or an acyloxy group as defined above for Y, or a sulfate of formula (Ra) 2SO4.

The alkylation reaction is conveniently carried out in an inert organic solvent such as an amide, for example dimethylformamide; 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 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 conveniently be carried out at a temperature in the range of from -20 to + 100 ° C, preferably from 0 to 50 ° C.

The hydrogenation can be carried out according to general method (C) using conventional methods, for example using hydrogen in the presence of a noble metal catalyst such as palladium, Raney nickel, platinum, platinum oxide or rhodium. The catalyst can be carried on charcoal for example, or one can use a homogeneous catalyst such as tris (triphenylphosphine) rhodium chloride. The hydrogenation is generally carried out in a solvent such as an alcohol, for example ethanol; an amide, for example dimethylformamide; an ether, for example dioxane; or an ester, for example ethyl acetate, and at a temperature in the range of from -20 to 100 ° C, preferably from 0 to 50 ° C.

It should be appreciated that, in some of the above transformations, it may be necessary or desirable to protect the sensitive groups possibly present in the compound to avoid undesirable side reactions. It is desirable that the protecting groups used in the preparation of compounds of formula (I) are groups which can be readily separated at an appropriate step in the reaction sequence, conveniently at the last step. Thus, during any of the reaction sequences described above, it may be necessary to protect the keto group, for example in the form of a ketal or a thioketal.

It is thus possible to prepare the compounds of general formula (I) according to another general process (D), comprising the removal of any protective groups from a protected form of a compound of formula (I). Deprotection can be carried out using conventional techniques such as those described in “Protective Groups in Organic Chemistry” dir. pubi. J.F.W. McOmie (Plenum Press, 5 1973). Thus, one can remove a ketal such as an alkylene group by treatment with a mineral acid such as hydrochloric acid. The thioketal group can be cleaved by treatment with a mercuric salt, for example mercuric chloride, in a suitable solvent, such as ethanol.

The compounds of formula (I) can be transformed into their physiologically acceptable salts according to conventional methods. Thus, for example, the free base of general formula (I) can be treated

with a suitable acid, preferably with an equivalent amount in a suitable solvent (for example aqueous ethanol). 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 separating acid; cf. for example "Ste-rochemistry of Carbon Compounds" by E.L. Eliei (McGraw Hill 1962) and "Tables of Resolving Agents" by S.H. Wilen.

Examples of optically active separating acids which the oe can use to form salts with racemic compounds include the forms (R) and (S) of organic carboxylic and sulfonic acids such as tartaric acids, di-p -toluoyltartrique, cam-phosulfonique and lactic. The isomeric salt mixtures obtained can be separated, for example, by fractional crystallization, to give the diastereoisomers and, if desired, the required optically active isomer can be converted into the free base.

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. Of course, the sequence of reactions must be chosen in multi-step processes, so that the reaction conditions used do not affect the groups in the molecule which are desired in the final product.

The starting materials of formula (II) where Y represents the group = CH2 can be prepared from compounds of formula (II), where Y represents the group CH2 + NR5R6R7X "by reaction with a base in an appropriate solvent. basic examples include alkali metal hydroxides, for example potassium hydroxide or alkali metal carbonates or acid carbonates, for example sodium hydrogen carbonate.

The quaternary salts can be formed from the corresponding tertiary amine 50 by reaction with an alkylating agent such as methyl iodide or dimethylsulfate, if preferred in a suitable solvent, for example dimethylformamide (DMF). The tertiary amine can be prepared by reaction of a tetrahydrocarbazolone of general formula (V)

ï

/ A A (V)

e e. o e \ * /

I II II I

0000

vvv

R1 with formaldehyde and the corresponding secondary amine, if desired in a suitable solvent such as an alcohol, for example ethanol.

The 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.

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

I II II î (VI)

vw

El which can be obtained by reacting the tetrahydrocarbazolone of general formula (V) with formaldehyde, preferably in a suitable solvent such as an alcohol, for example ethanol, and preferably in the presence of a base.

Thus, the compounds where Z is a halogen atom can be obtained by reacting a compound of formula (VI) with a halogenating agent such as a phosphorus trihalide, for example phosphorus trichloride.

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

One can also prepare the compounds of formula (II) where Y represents - CH2Z, where Z is a halogen atom by reacting a compound of formula (II) where Y represents the group = CH2 with the appropriate hydrohalic acid, by example hydrochloric acid; conveniently in a suitable solvent such as an ether, for example diethyl ether.

The compounds of general formula (IV) can be prepared by reacting a compound of general formula (VII)

• ♦ ■ ■■ - • • V

I II II I

• • • - a vw

R1 where R1 and A are as defined above and Z1 is an easily displaceable atom or group such as a halogen atom, an acyloxy group or the group - H "NR5R6R7X as defined above for Z1, with an imidazole of formula (UI) according to the operating method of process (A) described here.

The compounds of formula (VII) can be prepared by reducing compounds of formula (II) using for example lithium aluminum hydride or sodium borohydride.

The compounds of formula (VII) where A * represents a hydrogen atom can also be prepared by reacting a compound of formula (VII) where A represents a hydroxyl group with a tosyl halide (for example tosyl chloride), then reducing the tosylate obtained with lithium aluminum hydride.

The compounds of formula (IV) are new compounds, and as such provide another feature of the invention.

The following examples illustrate the invention. The temperatures are in ° C. Where indicated, the solutions are dried over Na2SO4 and the solids are dried under vacuum P2Os at 50 ° C overnight. Chromatography was carried out using the technique described by W.C. Still et al. (J. Org. Chem. 1978, 43, 2923-2925), on kieselgel 9385.

Preparation 1

2,3,4,9-tetrahydro-N, N, N-trimethyl-4--xo-1H-carbazoy-3-methanaminium lodide

A solution of 3 - [(dimethyl-amino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one (0.53 g) in iodomethane is heated at reflux for 5 h. ml) and evaporated to dryness, which gives the title compound as a white solid (0.84 g), mp 202-205 °.

Preparation 2

2,3,4,9-tetrahydro-N, N, N, 9, tetramethyl-4-oxo-1H-carbazo-le-3-methanaminium lodide

A suspension of 3 - [(dimethyl-amino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (3.80 g) in 1 h is stirred at reflux for 57 h. '' iodomethane (100 ml). The solution obtained is concentrated in vacuo to give the title methanaminium iodide as a solid (5.72 g), m.p. 192-195 °.

Preparation 3

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

A solution of the product of preparation 2 (5.0 g) in water (20 ml) is treated with 2N sodium carbonate (6.55 ml) and the mixture is heated at 35 ° for 45 min. The slurry obtained is cooled to 0 ° and the solid is filtered off, washed with water and dried to give the title compound (2.8 g), m.p. 127-129 °.

Preparation 4

2,3,4,9-Tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl) methyl] -IH-carbarole maleate

Sodium borohydride (90 mg) is added under nitrogen to a stirred solution of the product of Example 7 (500 mg) in a mixture of methanol (3 ml) and chloroform (3 ml). Stirring is continued for 48 h (additional sodium borohydride (250 mg) is added after 17 h lA and 42 h), then the suspension is divided between 2N hydrochloric acid (15 ml) and chloroform (3 x 10 ml). The aqueous layer is made basic with solid sodium carbonate, extracted with chloroform (3 x 10 ml), and the combined extracts are washed with water (2 x 10 ml) and brine (10 ml) , dried and concentrated in vacuo. Column chromatography of the residual foam (557 mg) eluting with a mixture of dichlo-romethane, ethanol and 0.88 ammonia (300: 10: 1) gives a solid (200 mg). This material is dissolved in absolute ethanol at reflux (3 ml) and a solution of maleic acid (80 mg) in absolute ethanol at reflux (1 ml) is added. The hot solution is filtered, stirred, and diluted with dry ether (40 ml) to give the title compound (240 mg), m.p. 138.5-140 °.

Preparation5

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

The product of Example 7 is added, under nitrogen, to a stirred suspension of lithium aluminum hydride (7.75 g) in dry tetrahydrofuran (THF) (750 ml). The mixture is stirred at reflux for 1 h and then cooled in ice. The suspension is carefully diluted with aqueous THF (15% H 2 O; 100 ml) and water (100 ml), concentrated in vacuo and the residual solid is extracted with dichloromethane (2 x 500 ml). The organic extracts are concentrated in vacuo and the residual solid (16.4 g) is purified by column chromatography on a short trajectory on silica (silica gel 60; Merck 7747; 500 g), eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (150: 10: 1) to give the title compound as a foam (13.4 g). TLC silica, dichloromethane / ethanol / ammonia at 0.88 (150: 10: 1), Rf 0.34 and 0.36 (two pairs of diastereoisomers), u, v detection. and iodo-platinic acid.

NMR 8 [CDC13 + CD3OD (1 drop)] 1.6-2.3 and 2.6-3.0 (5H, m), 2.32 and 2.40 (3H, s + s, Me in 2 isomers different), 3.32 (3H, s, NMe), 3.65-4.3 (2H, m, CHCH2N), 4.75-4.85 (1H, m, CH-OH), 6.8- 7.8 (CH, m, aromatic).

5

10

15

20

25 "

30

35

40

45

50

55

60

65

664,152

Example the

1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imida-zol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

A solution of the product of preparation 2 (2.0 g) and 2-methylimidazole (5.0 g) in dry dimethylformamide (30 ml) is stirred under nitrogen at 95 ° for 1 h 3A, then allowed to cool. The solid which crystallizes is filtered off, washed with ice-cold dry DMF (3x2 ml) and dry ether (2x10 ml) and then dried. The solid obtained (0.60 g) is suspended in a mixture of absolute ethanol (30 ml) and ethanolic hydrochloric acid (1 ml), and the mixture is gently heated to obtain a solution which is filtered while she is hot. The filtrate is then diluted with dry ether to deposit a solid (0.6 g) which is recrystallized from absolute ethanol to give the title compound in the form of a solid (0.27 g ), pf 186-187 °.

Analysis for Cj 8H19N30 • HCl • H20:

Calculated: C 62.3 H 6.1 N12, l%

Found: C 61.9 H 6.4 Nll, 8%

The following compounds are prepared by a process analogous to that set out in detail in Table I: - "

Example 2

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

1,2,3,9-tetrahydro-9-methyl-3 - [(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one (300 mg) is suspended in ethanol hot (5 ml) and treated with maleic acid (116 mg). The solution is cooled and the white crystalline solid is filtered off, and dried to give the title compound (300 mg), m.p. 132.3

Example 3a

1,2,3,9-Tetrahydro-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 DMF (25 ml) is heated at 105 ° for 6 h, cooled, poured into water (200 ml) and extracted 6 times with ethyl acetate. The combined extract is washed, dried and evaporated to give a solid which is purified on a column of silica (Merck 7734) eluting with ethyl acetate / methanol (4: 1). By recrystallizing 2 times from ethyl acetate / methanol, the title compound (0.095 g) is obtained in the form of a crystalline solid, m.p. 220-222 °.

TLC silica, dichloromethane / ethanol / ammonia at 0.88 (100: 8: 1), Rf 0.33, detection u.v. and iodoplatinic acid.

The following compounds are prepared by an analogous method as described in detail in Table II. Salification is carried out as described in Example 2.

Example 4

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

A solution of 1,2,3,9-tetra-hydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (1) is poured dropwise under nitrogen. , 0 g) in dry DMF (10 ml) in an ice-cold and stirred suspension of sodium hydride (80% in oil; 0.11 g) in dry DMF (5 ml). After 1 h, dimethyl sulfate (0.34 ml) is added, and the solution is stirred at room temperature (RT) for 4 h. The solid obtained is filtered off, washed with ice-cold dry DMF (2x5 ml) and dry ether (3x15 ml) and dried to give the title compound as a solid (0.25 g), pf 223-224 ° (dec.).

TLC silica, chloroform / methanol (93/7), Rf 0.27, UV detection and iodoplatinic acid, identical to the product of Example la.

The following compounds are prepared by an analogous method using the appropriate alkylating agent as detailed in Table III.

9

664152

Table I (continued)

Note 1

Compounds lc and lf are prepared in the same experiment and the isomers are separated by short trajectory chromatography (DF 5 Taber, J. Org. Chem., 1982,47,1351), eluting with dichlorome thane / ethanol / ammonia. 0.88 (300: 10: 1). The following XH NMR data are obtained:

5 "1? §

6 / \ / V / \) '{\ î il — il î 1 f' 7 * W A A / '2

ï * 1

R3

d = doublet dd = doublet of doublets s = singlet

Solvent

SPECTRUM 1H NMR (obtained at 250 MHz)

Chemical movements of selected protons (5 ppm and multiplicities)

Carbazolone protons

Methylene imidazolyl protons

Imidazole protons

H-5,6,7,8 aromatic

. CH2-1 and CH2-2 H-3 aliphatic

H-2 '

H-4 'and / or H-5'

the de-DMSO

7.2-8.05

2.91-3.25 1.75-2.3

4.47 (dd) and 4.64 (dd)

9.20s

. 7.55s lf

CDCI3 + DMSÖ

7.15-8.05

2.6-3.05 1.75-2.1

4.02 (dd) and 4.63 (dd)

8.17s

6.93s

1g d6-DMSO

'7.2-8.05

among others 2.9-3.3 1.6-2.2

4.42 (dd) and 4.73 (dd)

-

7.61d and 7.70d

Example 5

9-Cyclopentyl-1,2,3,9-tetrahydro-3- [(2-methyl-1H-imidazol-1-yl) methyl-4H-carbazol-4-onemaleate

A solution of 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4-H-carbazol-4-one (1.20 g) is added in dry DMF (9 ml) in an ice-cold and stirred suspension of sodium hydride (80% in oil; 0.14 g) in dry DMF (2 ml) under nitrogen, and stirring is continued for Go h. Bromocyclopentane (0.51 ml) is added and the stirred solution is heated at 100 ° for 18 h Vi. The solution is allowed to cool and then it is distributed between water (100 ml) and ethyl acetate (3 x 70 ml). The combined organic extracts are washed with 2N sodium carbonate (2 x 50 ml), water (2 x 50 ml) and brine (50 ml), dried, evaporated to dryness and purify by chromatography eluting with a mixture of dichloromethane, ethanol, 0.88 ammonia (150: 10: 1) to give an oil (0.27 g). This oil is dissolved in absolute ethanol at reflux (7 ml) and a solution of maleic acid (0.10 g) in absolute ethanol at reflux (0.5 ml) is added. The hot solution is filtered, stirred and diluted with dry ether (20 ml). The yellow gum obtained is washed with dry ether (7 x 25 ml) and the mother liquors and the combined washings are left to stand. The solid which crystallizes from the solution is filtered off, washed with dry ether (3 x 5 ml) and dried to give the title salt in the form of a white crystalline solid (0.058 g), m.p. 104.5-106 °.

Analysis for C22H2SN30 ■ G4.H4.O4 • 0.6H20:

Calculated: C65.8 H 6.4 N8.9%

Found: C 65.95 H 6.4 N 8.6%

Example 6

1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methylJ-9- (2-propenyl) -4H-carbazol-4-one maleate

A solution of 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-One (1.0 g) is added in DMF dry (6 ml) to an ice-cold, stirred suspension of sodium hydride (80% in oil; 0.12 g) in dry DMF (2 ml). After 1 h, allyl bromide is added, the solution is stirred at 0 ° for 1 h and at room temperature for 20 h before dividing between water

30 (75 ml) and ethyl acetate (3 x 50 ml). The combined organic extracts are washed with water (2 x 50 ml), brine (50 ml), dried, concentrated in vacuo and purified by chromatography eluting with a mixture of dichloromethane, 0.88 ethanol and ammonia (200: 10: 1) to give a solid (0.43 g). This solid was dissolved in absolute ethanol at reflux (2 ml) and a solution of maleic acid (0.18 g) in absolute ethanol at reflux (1 ml) was added. The hot solution is filtered, diluted with dry ether (4 ml) and the crystallized solid is filtered off, washed with dry ether (3 x 5 ml) and dried to give the title compound 40 as a white solid (0.48 g), mp 150.5-151 °.

Analysis for C20H21N3O • C4H404:

Calculated: C66.2 H 5.8 N9.65%

Found: C66.3 H 5.75 N9.6%

Example 7

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

50 A solution of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (1.7 g) is treated with water (17 ml) with 2-methylimidazole (1.4 g) and then heated to reflux for 20 h. The cooled mixture is filtered and the residue is washed with water (3 x 15 ml) to give the crude product (1.7 g), m.p. 55 221-221.5 °. This material is recrystallized from methanol to give the title compound (1.4 g). P.f. 231-232 °, identical by CCM to the product of Example 4.

Example 8

60

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

A suspension of the product of preparation 3 (0.5 g) and 2-methylimidazole (0.4 g) in water 65 (5 ml) is heated at reflux for 20 h. The cooled reaction mixture is filtered and the residue is washed with water (3 x 10 ml), dried and recrystallized from methanol (18 ml) to give the title compound (0.3 g), m.p. 232-234 ° (dec.), Identical by TLC to the product of Example 4.

Table II

'H NMR spectra (obtained at 250 MHz in d6DMSO)

Chemical waste of selected protons (ppm) and multiplicities

Ex. No.

Formula (I)

Weight S.M. (g)

Weight of suitable imidazole

(at)

Flight. solvent (ml)

Reaction time / temp. (h./°C)

Salt formed

Product weight (g)

P.f.

Carbazolone protons

Methylene imidazolyl protons

Imidazole protons

R1

R2

R3

R4

H-5,6,7,8 aromatic

CH2-1 and CH2-2 H-3 aliphatic

H-2 '

H-4 'and / or H-5'

3b

H

ch3

H

H

6.60

17.00

75

17.25 / 100

Maleate

0.40

155-156 °

7.1-8.05

3.0-3.25 1.9-2.2

4.29 (dd) and 4.69 (dd)

-

7.57d and 7.67d

3h

ch2ch3

H

H

7.00

10.50

75

18/85

Maleate

0.48

154.5-156 °

7.15-8.05

3.0-3.25 1.9-2.2

4.32 (dd) and 4.72 (dd)

-

7.61d and 7.69d

3d h

CH2Ph

H

H

3.00

3.10

25

24/100

Maleate

0.61

100.5-102 °

7.15-8.05

2.85-3.1 1.8-2.05

4.28 (dd) and 4.71 (dd)

-

7.59d and 7.7 Id

3rd

H

h ch3

H

1.00

2.2

5

18/95

Maleate

0.16

144-145.5 °

7.15-8.05

3.0-3.20 1.75-2.25

4.48 (dd) and 4.62 (dd)

8.97s

7.46s

3f h

h h

ch3

Maleate

0.09

143-144 °

7.15-8.05

3.0-3.20 1.90-2.20

4.29 (dd) and 4.74 (dd)

8.93s

7.41s

3g

H

y h

H

1.80

1.0

20

20/100

HCl

0.11

142-146 °

7.1-8.0

2.9-3.2 1.75-2.1

6.32 (dd) and 6.70 (dd)

-

7.75d and 7.83d

WE

o \

• fe.

I — k Ul K>

NOTE 3

Compounds 3e and 3f are prepared in the same experiment and the isomers are separated by preparative HPLC on Zorbax-sil, eluting with hexane / ethyl acetate / ethanol / ammonia at 0.88 (400: 100: 100: 0.6)

In the table, y represents: / -

CH3

Table III

d = doublet dd = doublet doublet s = singlet

Ex. No.

Alkylating

R2

R3

R4

Reaction time (at RT)

(h)

Salt formed

Product weight

P.f.

Molecular formula

Analysis (%)

Find

Calculated

C H N

C H N

4b

Me2S04

CH2CH3

H

H

0.5

HCl

0.13

211-212 °

C19H2IN30-HC10,5H20

64.7

6.5

11.8

64.7

6.6

11.9

4c

Me2S04

CH2Ph

H

H

4

Maleate

0.32

143-145 °

c24h23n3o-c4h4o4

69.35

5.5

8.5

69.3

5.6

8.65

4d

Et2S04

ch3

H

H

6.5

Maleate

0.67

159-160 °

c19h21n3oc4h4o4

65.15

6.1

9.85

65.25

5.95

9.9

4th

PhCH2Br ch3

H

H

5.75

Maleate

1.00

150-151.5 °

C24H23N30 • C4H404

69.1

5.65

8.55

69.3

5.6

8.65

4f

CH3 (CH2) 5I

ch3

h

H

7.25

Maleate

1.16

118-119 °

C23H29N30 • C4H404

67.4

6.9

8.7

67.6

6.9

8.8

4g

Ph (CH2) 3Br ch3

H

H

5.75

Maleate

0.84

95-96.5 °

c26h27n3o • c4h4o4 o, 2H2o

69.5

5.9

8.0

69.7

6.1

8.1

4h ch3 (ch2) 9oso2 y> -cn3

ch3

h h

4

(at 50 ° C)

Oxalate

0.14

50-51 °

C27H37N3O • C2H2O4 • 0.3H20

66.7

7.8

7.8

66.6

7.8

8.0

4i

Et2CH0S02 - <^ ^> - CH3

ch3

H

h

14 (at 40 ° C)

HCl

0.12

131-133 °

C22H27N30 • HCl ■ 1.1H20

65.8

7.9

10.3

65.4

7.5

10.4

11

664152

Note 1

The following NMR data are obtained:

Table III (continued) 5

0

.11

h

• -, • 1 • 1 21

f W \ ..A

fY-s ï \ r X,

7 \ A A r v - * \

• N • R ^ R3 8 ^ - 1

d = doublet dd = doublet of doublets s = singlet

Solvent

SPECTRUM * H NMR (obtained at 250 MHz)

Chemical displacements of selected protons (5 ppm) and multiplicities

Carbäzolone protons

Methylene imidazolyl protons

Imidazole protons

H-5,6,7,8 aromatic

CH2-1 and CH2-2 H-3 aliphatic

H-2 '

H-4 'and / or H-5'

4g d6-DMSO

7.15-8.1

2.9-3.2 1.9-2.2

6.29 '(dd) and 6.68 (dd)

-

7.55d and 7.65d

4h d6-DMSO

7.2-8.1

2.9-3.3 1.8-2.2

6.26 (dd) and 6.65 (dd)

-

7.42d and 7.57d

Example 9

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

Sodium hydride (80% oil dispersion, 0.208 g) is added to a stirred solution of 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1- yl) methyl] -4H-carbazol-4-one (1.93 g) at 0 ° C in DMF (35 ml) and the suspension obtained is stirred at 0 ° C for 1 h. 2-bromopropane (0.78 ml) is then added and stirring is continued at room temperature overnight, then for 4 h at 40 ° C.

The reaction mixture is distributed between sodium carbonate (2N; 200 ml) and ethyl acetate (2 x 150 ml). The combined organic extracts are washed with water (3; x 75 ml), dried, and evaporated in vacuo and the product is purified by chromatography eluting with dichloromethane / ethanol / ammonia (100: 8: l) to give an oil. This oil is dissolved in ethanol (3 ml), acidified with ethereal hydrochloric acid and diluted with dry ether to deposit the title compound as a white solid (0.13 g ), pf 230-232 °.

Analysis for C20H23N3O- HCl • 0.5H20:

Calculated: C 65.4 - H 6.9 N 11.45%

Found: C65.3 H 6.6 M 11.1%

Example 10

1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imid-azol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate

1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (18.3 g) in a hot mixture of isopropanol (90 ml) and water (18.3 ml) with concentrated hydrochloric acid (6.25 ml). The hot mixture is filtered and the filtrate is diluted with isopropanol (90 ml) and stirred at room temperature for 17 h, cooled to 2 ° and the solid is filtered off (21.6 g). Recrystallized from a mixture of water (6 ml) and isopropanol (10 ml) to give the title compound as a white crystalline solid (6 g), m.p. 178.5-179.5 °.

Analysis for C12H.lgN3Ö-HCl-2H20:

Calculated: C 59.1 H 6.6 N 11.5%

Found: C 59.45 H 6.45 N 11.5%

Analysis for C18H19N30 ■ HG1 • 2H20 (water dosage): Calculated: 9.85%

30 Found: 10.23%

Example 11

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

I) 3 - [(dimethylaminojmethylj-1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one hydrochloride

Stirred at reflux under nitrogen for 42 h a solution of 1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one (3.90 g), dimethylamine hydrochloride (1.50 g) and paraformaldehyde (0.60 g) 40 in glacial acetic acid, allowed to cool and concentrated in vacuo. The residual brown gum is stirred with water (50 ml), ethyl acetate (50 ml) and brine (20 ml) for Va h, and the solid obtained is filtered off, washed with dry ether (4 x 30 ml) and dry to give the title compound (4.2 g). A fraction of this solid (1.0 g) is recrystallized twice from absolute ethanol (10 ml) to give the title compound as a tawny powder (0.39 g), m.p. 193-194 ° (dec.).

ii) 1,2,3,9-Tetrahydro-3- [(2-methyl-1H-imidazol-1-yl) -methyl] -9-50 phenyl-4H-carbazol-4-one maleate

2-methyl-1H-imidazole (1.4 g) is added, under nitrogen, to a stirred suspension of 3 - [(dimethylaxnino) methyl] -1,2,3,9-tetrahydro-9-phenyl- hydrochloride 4H-carbazol-4-one (2.0 g) in water (20 ml). The mixture is heated at 90 ° for 43 h and the solvent is separated by decantation from the tawny solid. Chloroform is added to the solid, the suspension is filtered through Hyflo, the filtrate is dried and concentrated in vacuo. Chromatography of the residual fawn foam (2.04 g) eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (200: 10: 1) gives a white foam (1.1 g) . A solution of this foam in ethanol (3 ml) is treated with maleic acid (0.4 g) in ethanol (1 ml) then with dry ether (40 ml) and the triturated gum obtained with dry ether (2 x 40 ml) to give the title compound as a cream solid (1.37 g), mp 165-166 ° (dec.).

65 Analysis for C23H21N30 • C4H404:

Calculated: C68.8 H 5.3 N8.9%

Found: C 68.65 H 5.5 N 8.7%

664,152

12

Example 12

1,2,3,9-Tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-I-yl) methylJ-4H-carbazol-4-one phosphate (1: 1)

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

Analysis for C18H19N30H3P04:

Calculated: C 55.2 H 5.7 N 10.7%

Found: C55.1 H 5.6 N 10.55%

Example 13

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

1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (089 g) is dissolved in a hot solution of citric acid (0.58 g) in ethanol (20 ml) and allowed to crystallize. The crystalline solid obtained is recrystallized by dissolving it in acetone / water (2: 1.2 ml) and diluting with acetone (20 ml) to give the title compound (0.6 g), m.p. 162 °.

Example 14

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

Iodomethane (0.75 ml) is added to a stirred solution of 3- [dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one (2.9 g) in the DMF dry (30 ml) and the solution is stirred at room temperature for 30 min. A solution of 2-propyl-1H-imidazole (2 g) in DMF (5 ml) is added, and the solution is stirred at 100 ° C. for 2 days, cooled and partitioned between sodium carbonate (2N. 150 ml) and ethyl acetate (2 x 100 ml). The combined extracts are washed with water (100 ml), dried and evaporated in vacuo. The residue is 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) is dissolved in absolute ethanol (5 ml), acidified with ethereal hydrochloric acid and diluted with dry ether (about 200 ml) to give an oil. When it is scraped, the oil crystallizes to give a solid (0.15 g). The salt is crystallized from a mixture of methanol and isopropyl acetate to give the title compound (0.08 g), m.p. 206-208 °.

Analysis for C19H2iN3OHC10,2H20:

Calculated: C 65.7 H 6.5 N12, l%

Found: C 65.6 H 6.8 N 12.0%

NMR 5 (CD3S0CD3) 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-tetrahydro-3 - [(2-propyl-1H-imidazoI-1-yl) methyl] -4H-carbazol-4-one hydrochloride

A solution of the product of Example 3 (0.03 g) in methanol (15 ml) is hydrogenated at ambient pressure and temperature on 10% palladium oxide on charcoal (50% aqueous paste, 0 , 03 g) for 4 h (absorption of H2, 5 ml). The catalyst is filtered off, and the filtrate is evaporated in vacuo to give an oil. Trituration with ether gives the title compound as a white solid (0.03 g), m.p. 199-203 °.

This material is identical according to the TLC and the NMR to the product of Example 14.

Example 16

1,2,3,9-tetrahydro-9-propyl-3- [(2-propyl-1H-imid-azol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

Sodium hydride (80% oil dispersion) is added under nitrogen to a stirred solution of the product of Example 14 (1.0 g) in dry DMF (20 ml) and stir the suspension at room temperature for 30 min. 1-Bromopropane (0.35 ml) is added, and the solution is stirred at 40 ° C for 20 h. The solution is distributed between sodium carbonate (2N, 150 ml) and ethyl acetate (2 x 100 ml). The combined extracts are washed with water (100 ml), dried and evaporated in vacuo to give an oil. The oil is purified by column chromatography eluting with dichloromethane: ethanol: ammonia (100: 8: 1) to give the pure free base as an oil. The oil is dissolved in absolute ethanol (5 ml), acidified with ethereal hydrochloric acid, and diluted with dry ether (200 ml). The ether is removed by decantation of the residual oil and replaced by a larger quantity of dry ether (200 ml). When stored at 0 ° C overnight, the oil crystallizes to give the title compound (0.53 g), m.p. 144-147 °.

NMR 5 (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 , CH2CH2N), 4.32 and 4.71 82H, ABX, CH2CH2N), 7.15-8.1 (6H, m, aromatic).

Analysis for C22H27N30 ■ HCl -0.7H20:

Calculated: C 66.3 H 7.4 N 10.5%

Found: C 66.6 H 7.7 N 10.0%

Example 17

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

A solution of the product of Example 6 (0.86 g) in a mixture of absolute ethanol (20 ml) and dry dimethylformamide (5 ml) is hydrogenated at ambient pressure and temperature on 5% platinum on charcoal [( 0.1 g), prereduced in absolute ethanol (10 ml)] for 1 h. (Absorption of H2: 70 ml.) The catalyst is filtered off, washed with ethanol, and the filtrate is concentrated in vacuo to about 15 ml. The residual solution is stirred, diluted with water (50 ml) and the precipitated solid is filtered off, washed with water (3 x 15 ml) and dried to give a powder (0.73 g ).

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

Analysis for C20H23N3O • C4H404:

Calculated: C 65.9 H 6.2 N9.6%

Found: C 65.8 H 6.1 N 9.3%

Example 18

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

Ethereal hydrochloric acid (3.0 ml) is added to an ice-cold stirred solution of the product of preparation 3 (1.90 g) in chloroform (15 ml), and the suspension obtained is stirred in a closed container at room temperature for 16 h 'A, concentrated in vacuo and the residual solid (2.27 g) is purified by column chromatography eluting with chloroform to give the title compound (1.75 g), mp 109-110.5 °. An attempt to crystallize a fraction of this material from ethyl acetate results in partial decomposition.

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ii) 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) me-

thyl] -4H-carbazol-4-one

A solution of 3- (chlo-romethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (0.50 g) is stirred under nitrogen at 90 ° for 3 h 3A. of 2-methyl-1H-imidazole (1.60 g) in dry DMF, then poured into water (25 ml). The suspension is stirred for 1 h, and the solid is filtered off, washed with water (3 x 20 ml) and dried under vacuum at 50 °. Column chromatography of this solid (0.53 g) eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (150: 10: 1) gives the title compound (0.45 g) , pf 228-229 °. This material is identical to the product of Example 7 by TLC and NMR.

Example 19

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

A solution of 2,3-dichlo-ro-5,6-dicyano-1,4-benzoquinone (170 mg) in dry THF (1.5 ml) is added dropwise under nitrogen to a stirred and ice-cold suspension. of the product of preparation 4 (100 mg) in a mixture of THF (3.5 ml) and water (0.4 ml). The blue solution obtained is stirred for 1 h 'A, then concentrated in vacuo. Column chromatography of the residual solid eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (150: 10: 1) gives the title compound (45 mg), m.p. 227-228.5 °. This material is identical to the product of Example 7 by TLC and NMR.

Example 20

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

A solution of 2,3-dichloro-5,6-dicya-no-1,4-benzoquinone (80 mg) in dry THF (1.5 ml) under nitrogen is added dropwise to a stirred ice-cold suspension. product of preparation 5 (100 mg) in a mixture of THF (3.5 ml) and water (0.4 ml). The blue solution obtained is stirred for 1 h XA, then the red suspension is concentrated under vacuum.

Column chromatography of the residual solid eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (150: 10: 1) gives the title compound as a white solid (0.47 g), pf 227.5-229 °. This material is identical to the product of Example 7 by TLC and NMR.

Example 21

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

A solution of the product of Example 7 (0.5 g) is dissolved in 30 ml of hot methanol and treated with a hot solution of (-t -) - di-p-toluoyl-D-tartaric monohydrate ( 0.7 g) in methanol (10 ml) and the solution obtained is left to crystallize overnight to give the desired salt (0.68 g). This salt is dissolved in hot DMF (20 ml), diluted with hot water (10 ml) and allowed to crystallize overnight. The product is separated by filtration, and dried under vacuum to give the salt of (90%) enantiomerically pure (-t-) - di-p-toluoyl-D-tartaric acid.

(as seen by NMR) (0.23 g), m.p. 231-233 °. A sample of the salt (0.15 g) is distributed between the 8% sodium bicarbonate (25 ml) and the chloroform (2 x 25 ml). The combined extracts are dried and evaporated in vacuo to give the pure free base (0.07 g). The base is dissolved in methanol (5 ml) acidified with maleic acid (0.03 g) and the salt is precipitated by adding an excess of ether (80 ml) to give the title compound (0.062 g) , pf 142-145 °.

TLC silica, dichloromethane / ethanol / ammonia at 0.88 (100: 8: 1), Rf 0.3, u.v detection. and iodoplatinic acid, identical to the product of Example 7. The enantiomeric ratio, determined by * H NMR is 93: 7 (S: R). A sample of the maleate salt does not show significant optical rotation in methanol. The free base, regenerated from the maleate salt, gave [a] "-14 ° (c 0.19; MeOH).

Example 22

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

A solution of the product of Example 7 (0.5 g) is dissolved in hot methanol (30 ml) and treated with a hot solution of (-) - di-p-toluoyl-L-tartaric acid monohydrate ( 0.7 g) in methanol (10 ml) and the solution obtained is left to crystallize overnight to give the desired salt (0.8 g). This salt is dissolved in hot DMF (20 ml), diluted with hot water (10 ml) and allowed to crystallize for 3 days. The product is separated by filtration, and dried in vacuo to give the salt of (-) - di-p-toluoyl-L-tartaric acid (0.26 g), m.p. 170-172 °. A sample of the salt (0.2 g) is divided between the 8% sodium bicarbonate (25 ml) and the chloroform (2 x 25 ml). The combined extracts are dried and evaporated in vacuo to give the pure free base (0.12 g). The base is dissolved in methanol (5 ml) acidified with maleic acid (0.045 g) and the salt is precipitated by adding an excess of dry ether (80 ml) to give the title compound (0.08 g ), pf 142-145 °.

TLC silica, dichloromethane / ethanol / ammonia at 0.88 (100: 8: 1), Rf 0.3, u.v detection. and iodoplatinic acid, identical to the product of Example 7, The enantiomeric ratio, determined by XH NMR, is greater than 95: 5. A sample of the maleate salt shows no significant optical rotation in methanol. The free base, regenerated from the maleate salt, gives [a] o + 16 ° (c 0.34; MeOH).

The following examples specify pharmaceutical formulations according to the invention, containing 1,2,3,9-tetrahy-dro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl hydrochloride] -4H-carbazol-4-one as active ingredient (1.25 g of hydrochloride dihydrate contains 1.00 g of the free base). Other compounds of the invention can be formulated analogously.

Tablets for oral administration

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

The tablets may be coated with a film with suitable film-forming materials, such as hydroxypropyl methylcellulose, using standard techniques. Sugar tablets can also be coated.

Direct compression

Tablet mgj tablet

Active ingredient 4,688 28,125

Calcium acid phosphate BP * 83.06 87.75

Croscärmellöse sodium NF 1.8 1.8

Magnesium stearate BP 0.45 0.45

Compressed weight 90.0 118.0

* Of suitable quality for direct compression.

The active ingredient is passed through a 0.250 mm mesh screen, mixed with calcium acid phosphate, croscarmellose sodium and magnesium stearate. The mixture obtained is compressed into tablets using a Manestry F3 compression machine equipped with 5.5 mm punches with a beveled flat end.

Sublingual mg mg tablet

Active ingredient 2.5

Compressible sugar NF • 62.5

Magnesium stearate BP 0.5

Compressed weight • 65.0

The active ingredient is sieved through a suitable sieve, mixed with the excipients and compressed using suitable punches. Tablets of other strengths can be made

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by modifying either the ratio of the active ingredient to the excipients, or the compression weight and by using appropriate punches.

Wet granulation

Classic tablet

Active ingredient Lactose BP Starch BP

Pregelatinized corn starch BP Magnesium stearate BP Compressed weight

mgj tablet

2.5 151.5 30.0 15.0

L5

200.0

The active ingredient is sieved through an appropriate sieve and mixed with lactose, starch and pregelatinized corn starch. Appropriate volumes of purified water are added and the powders are granulated. After drying, the granules are sieved and mixed with the magnesium stearate. The granules are then compressed into tablets using punches 7 mm in diameter.

Tablets of other strengths can be made by changing the ratio of the active ingredient to lactose or the compression weight and using appropriate punches.

Sublingual tablet

Active ingredient Mannitol BP

Hydroxypropyl methylcellulose Magnesium stearate BP Compressed weight

mg tablets

2.5 56.5 5.0

U5

65.5

The active ingredient is sieved through an appropriate sieve and mixed with mannitol and hydroxypropylmethylcellulose. Appropriate volumes of purified water are added and the powders are granulated. After drying, the granules are sieved and mixed to give tablets using appropriate punches.

Tablets of other strengths can be made by changing the ratio of the active ingredient to mannitol or the compression weight and using appropriate punches.

Mg / capsule capsules

Active ingredient 2.5

* Starch 1500 97.0 Magnesium stearate BP 1.0

Filling weight 100.0

* Directly compressible starch form.

The active ingredient is sieved and mixed with the excipients. The mixture is poured into size 2 hard gelatin capsules using suitable equipment. Other doses can be prepared by modifying the filling weight and, if necessary, by modifying the size of the capsule as appropriate.

Syrup

It can be a presentation with or without sucrose. A. Sucrose syrup mg / 5 ml dose

Active ingredient 2.5

2,750.0

Sucrose BP Glycerin BP Buffer

Dye flavoring agent

Preservative agent Purified water BP q.s.p.

The active ingredient, the buffer, the flavoring agent, the colorant and the preservative are dissolved in part of the water and the glycerin is added. The rest of the water is heated to dissolve the sucrose and then cooled. The two solutions are combined, adjusted to volume and mixed. The syrup is clarified by filtration.

mg / 5 ml dose 2.5

22.5

q.s.

B. Without sucrose

Active ingredient Hydroxypropylmethylcellulose USP (viscosity type 4000)

5 Taste Agent I Colorant f

Preservative J Softener

10 BP purified water q.s.p. 5.0 ml

The hydroxypropyl methylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation. The solution obtained is adjusted to volume and mixed. The syrup is clarified by filtration.

Injection

The injection can be administered intravenously or subcutaneously.

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Ssgjml injection

Active ingredient 50,800

Diluted hydrochloric acid BP at pH 3.5 at pH 3.5

Sodium chloride injection BP 1 ml to 1 ml

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The active ingredient is dissolved in an appropriate volume of BP sodium chloride injection, the pH of the solution obtained is adjusted to 3.5 with BP hydrochloric acid, then the solution is made up to volume with an injection of sodium chloride BP and mixed thoroughly. The solution is poured into vials of 5 ml in type 1 clear glass which is sealed under a point of air by melting the glass and then sterilized by autoclaving at 120 ° for at least 15 min .

Pressure metered dose aerosol

Aerosol suspension mg / dose per container

measured

Micronized active ingredient

0.250

66 mg

BP oleic acid

0.020

5.28 mg

Trichlorofluoromethane BP

23.64

5.67 g

Dichlorodifluoromethane BP

61.25

14.70 g

The active ingredient is micronized in a liquid phase micronizer at a fine particle size range. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C and the micronized drug is mixed in the solution with a high shear mixer. By measuring the suspension, it is poured into aluminum aerosol containers and by embossing suitable measuring valves supplying 85 mg of suspension are fixed, then the dichlorodifluoromethane is poured under pressure into the containers through the valves.

500.0

q.s.

5.0 ml

Aerosol in solution

55 Active ingredient Ethanol BP

Trichlorofluoromethane BP Dichlorodifluoromethane BP

mgd dose measured

0.25 7.500 14.875 48.525

per tank

30.0 mg 1.80 g 4.35 g 11.65 g

60 [BP oleic acid can also be included on an appropriate surfactant, for example Span 85 (sorbitan trioleate).]

The active ingredient is dissolved in ethanol with oleic acid or the surfactant if used. The alcoholic solution is poured by measuring it into suitable aerosol containers, and then the trichlorofluoromethane is put there. Appropriate measurement valves are fixed to the containers and the dichlorodifluoromethane is pressurized through the valve.

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Inhalation cartridges mg / cartridge

Active ingredient (micronized) 0.5,

Lactose BP q.s.p. 25.00

The active ingredient is micronized in a liquid phase micronizer at a fine particle size range before mixing with normal grade lactose for tablet in a high energy blender. The powder mixture is poured into No. 3 hard gelatin capsules in a suitable wrapper. The contents of the cartridges are administered using a powder inhaler.

Claims (3)

664,152 CLAIMS 1. Compound of general formula (I) (I) (the) where Rla represents a hydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl group; R3a represents a hydrogen atom and either R2a represents a methyl, ethyl, propyl or prop-2-yl group and R4a represents a hydrogen atom, or else R2a represents a hydrogen atom and R4a represents a methyl group or ethyl and its physiologically acceptable salts and solvates. 6. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one according to claim 1 and its salts and physiologically acceptable solvates. 7. Salt according to claim 6, consisting of the hydrochloride. 8. Salt according to claim 6, consisting of the hydrochloride dihydrate. 9. 1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-enyl) -4H-carbazol-4-one, 9 -cyclopentyl-1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidaol-yl) methyl] -4H-carbazol-4-one, 1,2,3,9-té-trahydro- 3 - [(2-methyl-1 H-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazol-4-one, according to claim 1, and their salts and solvates physiologically acceptable. 10. Process for the preparation of a compound of general formula (I) according to claim 1 or of a physiologically acceptable salt or solvate thereof, process in which a compound of general formula (II) is reacted (II) where R1 represents a hydrogen atom or a C1-C10 alkyl, a C3-C7 cycloalkyl, a C3-C6 alkenyl, a phenyl or a phenyl-C1-C3 alkyl, and where one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1-C6 alkyl, a C3-C1 cycloalkyl, a C2-C6 alkenyl or a C1-C3 phenylalkyl and each of the other two groups, which may be similar or different, represents a hydrogen atom or a C1 to C6 alkyl group and its physiologically acceptable salts and solvates. 2. A compound according to claim 1 wherein R1 represents a hydrogen atom or a C1 to C6 alkyl, a C3 to C6 cycloalkyl or a C3 to C6 alkenyl. 3. A compound according to claims 1 and 2 wherein one of the groups represented by R2, R3 and R4 represents a C1-C3 alkyl, C3-C6 cycloalkyl or C3-C6 alkenyl group and each of the other two groups, which may be similar or different, represents a hydrogen atom or a C1 to C3 alkyl group. 4. Compound according to claim 1, in which R1 represents a hydrogen atom or a C1 to C6 alkyl, C5 to C6 cycloalkyl or C3 to C4 alkenyl group and or R2 represents a hydrogen atom and R3 and / or R4 represents a C1 to C3 alkyl group, or R2 represents a C1 to C3 alkyl group and R3 and R4 both represent hydrogen atoms. 5. Compound of general formula (la) according to claim 1 where R1 is as defined in claim 1 and Y represents a reactive substituent or one of its protected derivatives, in which case the protective group is removed after reaction, with an imidazole of general formula (III) HN fiali) where R2, R3 and R4 are as defined in claim 1 or one of its salts, the compound being, if desired, isolated as a salt acceptable for therapeutic use, or transformed into another acceptable salt. 11. Method according to claim 10, characterized in that Y represents an alkenyl group = CH2 or a group of formula CH2Z where Z represents an easily displaceable atom or group. 12. Process for the preparation of a compound of general formula (I) according to claim 1 or of one of its physiologically acceptable salts or solvates, characterized in that a compound of formula (IV) is oxidized (IV) where A represents a hydrogen atom or a hydroxyl group and R1, R2, R3 and R4 are as defined in claim 1 or a 40 of its protected salts or derivatives, in which case the protective group is eliminated, the compound being, if desired, isolated as an acceptable salt for therapeutic use, or transformed into another acceptable salt. 13. Process for the preparation of a compound of general formula (I) according to claim 1 or of a salt or sol product thereof 45 physiologically acceptable vation, characterized in that a compound of formula (I) or one of its protected derivatives is transformed, in which case the protective group is removed after reaction, into another compound of formula (I) by alkylation, the compound being, if desired, isolated as an acceptable salt for therapeutic use, or transformed into another acceptable salt. 14. Process for the preparation of a compound of general formula (I) according to claim 1 or of one of its physiologically acceptable salts or solvates, characterized in that a compound of formula (I) or one of its protected derivatives, 55 in which case the protective group is removed after reaction, into another compound of formula (I) by hydrogenation, the compound being, if desired, isolated as a salt acceptable for therapeutic use, or transformed into another acceptable salt. 15. Preparation process according to claim 10,12,13 or 60 14, characterized in that the racemic mixture is split to obtain the desired enantiomer, the compound being, if desired, isolated as an acceptable salt for therapeutic use , or made into another acceptable salt. 16. Pharmaceutical composition comprising at least one 65 compound of general formula (I) according to claim 1 or one of its physiologically acceptable salts or solvates with at least one physiologically acceptable carrier or excipient. 3 664152