LU85743A1 - HETEROCYCLIC COMPOUNDS - Google Patents

Description

4 ",! φ *.

-1-

AT

The present invention relates to heterocyclic compounds, processes for their preparation, the pharmaceutical compositions containing them and their medical application. In particular, the invention relates to compounds which act on certain 3-hydroxytryptamine (5HT) receptors.

5HT, which is found endogenously in abundance in the peripheral nerves and in the; blood platelets, is known to cause pain in men by specific action on the 5HT receptors located on the ends of the primary nerves. Compounds which have an antagonistic action on the neuronal effects of 5HT have been shown to have analgesic activity, for example to relieve migraine pain. 5HT also causes depolarization of the pneumogastrious nerve preparation t isolated from rats by the same mechanism of the 5H receptor, and the inhibition of this effect is correlated with an analgesic effect in vivo.

20 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 "neuronal" 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 states like schizophrenia, chronic delusions and psychoses - delusional, anxiety, obesity in mania.

Treatments for such conditions 1 suffer from a number of drawbacks. Thus, for example, known treatments for migraine include the administration of a vasoconstrictor 4 -2-b like ergotamine, which is non-selective and produces vasoconstriction throughout the body. unwanted and potentially dangerous side effects. Migraine can also be treated by administering a pain reliever such as aspirin or paracetamol, usually in combination with an anti-emetic such as metaclopramide, but these treatments are only of limited value.

s Likewise, existing treatments for a r Ί 0 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 - impaired 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 "neural" 5HT receptors will fulfill such a role.

We have now found a group of 3-imida-zolylmethyltetrahydrocarbazolones which are potent and selective antagonists to "neutral" 5HT receptors.

. ** The invention provides a tetrahydrocarbazolone of general formula (ï): p 4 D 3 3C, v - · · · 'N \ I 11' l - r- 35 # · 4 * * ♦ · _ * ·. * sv - * v -3- * "*

"NOT

WHERE ~ η R represents a hydrogen atom or a C1 to C10 alkyl, a C3 to C7 cycloalkyl, a C3 to C6 alkenyl, a phenyl or a C1 to C3 phenyl-alkyl, and where 5 one of the groups represented by R2, RJ and R4 is a hydrogen atom or a C1 to C6 alkyl, a cycloalkyl to CJ to C7, a C2 to C6 alkenyl or a phenyl C1 to C3 alkyl and each of the two others groups, which may be the same or different, represents a hydrogen atom or a C1-C6 alkyl group; and its physiologically acceptable salts and solvates, for example hydrates.

It will be understood that when R1 represents an alkenyl group at 03 to 06, the double bond may not be adjacent to the nitrogen atom.

J Referring to the general formula (I), the alkyl groups represented by R1, R2, R3 and R4 T may be alkyl groups with a straight or branched chain, for example methyl, ethyl, propyl, prop-2 -20 yl, butyl, but-2-yl, 2-methylprop-2-yl, pentyl, pent-3-yl or hexyl.

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

Ά, ^

A cycloalkyl group can be, for example -. * Pie, a cyclopentyl, cyclohexyl or cycloheptyl group.

It will be appreciated that the carbon atom in position 30 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.

The appropriate physiologically acceptable salts of the indoles of general formula (I) are organic or inorganic, for example, hydrochlorides, hydrochlorides, sulfates, phosphates, citrates, fumarates and maleates. The solvates can for example be hydrates.

5 A ureferred class of compounds represented, Λ by the general formula (I) is that where R represents Λ a hydrogen atom or a C1 to C6 alkyl, a cyclom.

C3 to C6 alkyl or C3 to C6 alkenyl.

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 to C3 alkyl, C3 to C6 cycloalkyl or C3 alkenyl group. to C6 and each of the other two groups, which may be similar or different, represents a hydrogen atom or a C1 to C3 alkyl group.

Another preferred class of compounds represented by the general formula (I) is that in which R represents? has a hydrogen atom or a C1 to C6 alkyl, C5 to C6 cycloalkyl or C3 to 2 to C4 alkenyl group and or R represents a hydrogen atom and 3 4 '"R ^ and / or R represents a C1 to C3 alkyl group, or 2 v 3 although R represents a C1 to C3 alkyl group and Pr 4 and R both represent hydrogen atoms.

* A particularly preferred class of compounds according to the invention is that represented by the * * formula (la): s r; p4a p 3a I · * - * 30 / '%' y • · - · · \. - a, l li \ • · · · · / '' 'φ * 0 5 Î3.

7. 1b - x 1a '55 (where R represents a hydrogen atom or a group

. I

-5- ¾ methyl, ethyl, propyl, pro-2-yl, pro-2-enyl or cyclopentyl; E ^ a represents a hydrogen atom and either E ^ a represents a methyl, ethyl, propyl or prop-2-yl group and E represents a hydrogen atom, or E ^ represents a hydrogen atom hydrogen 4a and E represents a methyl or ethyl group) and their physiologically acceptable salts and solvates (for example * 1 hydrates).

The preferred compounds are as follows: iO 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl-J-9- (prop-2-enyl) -4H- carbazol-4-one; 9-cyclopentyl-1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) -methyll-4H-carbazol-4-one; and 1.2.3.9- tetrahydro-3- [2-methyl-1H-imidazol-1-yl) me-15 thyl] -9- (prop-2-yl) -4H-carbazol-4-one and their salts and products physiologically acceptable solvation.

A particularly preferred compound is 1.2.3.9- tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-2ô 1-yl) methyl] -4H-carbazol-4-one which can be represented by the formula (Ib); not ?! * · · «-1 // \ / \ / \! -: · · - · · N N rIfc: 25 i j] ;; ] \ / f • · · · ·. "- / \ / \ /! • N · Me

Me t and its physiologically acceptable salts and solvates (eg 30 hydrates). A preferred form of this compound is the hydrochloride dihydrate.

It will be appreciated that the invention extends to other physiologically acceptable equivalents of the compounds according to the invention, i.e. the physiologically acceptable compounds which are transformed into

"I

4 -6- • s »Γ- vivo into the parent compound of formula (I).

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 nerves. primary afferents.

The compounds of the invention are useful as * analgesics, for example to relieve 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 it is known that involvement with these pathways containing 5HT alters many other behavioral syndromes, such as , 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 the, * mania.

In particular, it has been found that the compounds of formula (Ia) 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 fia) do not prolong the duration of sleep in mice anesthetized with pentobarbiten, which indicates that there is no inter- -7-. "· -Desirable action 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 5 doses up to 1 mg / kg intravenously.

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

In another aspect, the invention provides a method of treating "a human or animal subject suffering from a condition caused by a" neuronal "5HT function disorder. Thus, for example, the invention provides a method of treating an human subject suffering from migraine pain or a psychotic disorder such as schizophrenia, chronic delusions and delusional psychoses.

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

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

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

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules conventionally prepared with pharmaceutically acceptable excipients such as binding agents (eg corn starch pregelatinized, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example lactose, microcrystalline cellulose or calcium acid phosphate); lubricants (for example magnesium stearate, talc or silica); Ί0 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 „15 for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product for the purpose of reconstitution with water or other vehicle. cule suitable 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 edible hydrogenated fats); emulsifying agents (for example lecithin or acacia); vehicles = * nonaqueous (for example almond oil, fatty 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, colorants and softeners as required.

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

* · "V _Q_ ✓’ ï "", For oral administration, the compounds may take the form of tablets or lozenges x formulated in a conventional manner.

The compounds of the invention can be formulated for parenteral administration by injection.

= ‘The injectable formulations can be presented K in unit dosage form, for example in ampoules or multi-dose containers, with the addition of a preservative. The compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending agents, stabilizers and / or dispersing agents. Alternatively, the active ingredient-15 may be in powder form for the purpose of 4. reconstitution with a suitable 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 as a depot preparation. These long-acting formulations can be administered. * very by implantation (for example by subcutaneous or intramuscular route) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example in the form of a sparingly soluble salt.

, 35 For administration by inhalation the corneas laid according to the invention are conveniently delivered in a presentation of aerosol spray liquid from pressurized packages or from a nebulizer, with use. of a suitable carrier, for example dichlorodifluoromethane, trichloro - "* fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of a pressurized aerosol the dosage unit can. * be determined by providing a valve to deliver a measured amount. Capsules and cartridges, for example of 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 friend 15.

^. A proposed dose of the compounds of the invention for administration to humans of approximately 70 kg (body weight) is 0.05 to 20 mg, preferably 0.1 to 10 mg of the active ingredient per unit dose. which can be administered, for example, 1-4 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 thus having 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 1 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 mg to 2 mg of a compound of the invention, and each dose administered with moven capsules and * -11- D * *

AT

cartridges in an insufflator or 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 per ^ ‘our, for example from 5 - 2 to 8 times, giving for example 1, 2 or 3 doses each time.

r

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 fl) 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 ):

25M

. "· · Y

\ / \ / • · - * ·] i (II j • · · · \ · / \ / \ / • "? · 30 Ri (where H is as defined above and Y represents a reactive substituent) or a of its derivatives protected with an imicazole of general formula (III): J * 4 -12- _ ""

AT

R1 * R3 \ / • - · - A N (Il l \ // 'llA'

5 T

D 2 '(where R, and 3 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 = CH ^ or a group of formula CH ^ Z where Z represents a easily displaceable atom or group such as a halogen atom, for example, chlorine or bromine; an acyloxy group such as acetoxy, trifluoromethanesulfonyloxy, p-toluenesulfo- -. nyloxy or metrianesulfonyloxy; a group -NR ^ E RfX, where R ^, R ^ and R ^, which may be similar or different, each represents a lower alkyl, for example a methyl, an aryl, for example a phenyl or an aralkyl, for example benzyl, or R ^ and R ^ 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 _ ** an ion halide, for example chloride, bromide or iodide; or a group -RR ^ R ^ where R ^ and R ^ are as defined above, for example

When Y represents the group -C 1, the process can conveniently be carried out in a suitable 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, dio- x10 or xanne or tetrahydrofuran; or their mixed. The "process can be carried out at a temperature of, for example, 20 to 100 ° C.

- When Y represents the group CH ^ Z, where Z

5 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 denatured industrial alcohol; or a haloalkane, for example dichloromethane, and at a temperature ranging from -10 to 150 ° C, for example +20 to + 100 ° C.

The reaction of a comnose of formula (II) in which Y represents the group + 5 6 7 - CBUjZ or Z is the group -KR RRX, may conveniently be carried out in a suitable solvent such as water, an amide, for example dimé-thylformamide; a ketone, for example acetone; or an ether, for example dioxane, and at a temperature ranging from 20 to 150 ° C.

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

According to another general method (B) it is possible. "prepare a compound of formula (I) by oxidizing a compound of formula (IV) * AP14 P3 i 'f • · · · _" 30 / \ / \ / \' t * -?? V r 'IV;

1! I

• · · · ·

v :. / '/ \ / I

• \ · R 2 D i i.

35 (where A represents a hydrogen atom or a hydroxyl group and R ^, R ^, R ^ and R ^ are as defined above) or one of its protected salts or derivatives.

The oxidation process can be carried out using conventional methods and the reagents and reaction conditions should be chosen carefully. * 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) 10 where A represents a hydrogen atom, the appropriate oxidizing agents include quinones in the presence of water, for example 2,3-dichloro-5,6-dicyano-1 , 4-benzoquinone or 2,5,5,6-tetrachloro-1,4-benzoquinone; selenium dioxide; an oxidizing reagent with cerium (IV) such as ceric ammonium nitrate or an *. chromium (VI) oxidizing agent, 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) in which A represents a hydroxyl group, the appropriate 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 the Jones'j reagent or chromium trioxide in r-vridine; a K-halosuccininide, for example h -chlcrcsuccinimide or IT-bromosuccinimide; a dialkyl sulfoxide, for example dimethyl sulfoxide in the presence of an activating agent such as K, I * '-dicyclohexylcarbodiimide or an acyl halide, for example oxalyl chloride or 35 chloride tosyle; the pyridine-trioxide complex of 4 * -15-. * Ί> * sulfur; or a dehydrogenation catalyst such as copper chromite, zinc oxide, copper or silver.

Suitable solvents can be selected from ketones, for example acetone or buta- - * none; ethers, for example tetrahvdrofuran or „dioxane; amides, for example aimethylformamide; alcohols, for example methanol; hydro-. · Carbides, 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 method (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 fl) where one or both of the radicals 1 2 E and E represents a hydrogen atom, and hydrogenation, which can, for example, be used to transform an alkyl substituent into an alkyl substituent. The term "alkylation" includes the introduction of other groups such as cycloalkyl or alkenyl groups. Thus, for example, it is possible to transform a compound of formula fl) where E represents a Λ pO atom d 'hydrogenated to the corresponding compound where E' represents a C1 to C10 alkyl, a C3 to C6 cycloalkyl, a CJ to C6 alkenyl or a C1 to C6 phenyl-alkyl group ;.

The above alkylation reactions can be carried out using the appropriate alkylating agent 4. "

If 3 3 chosen from the compounds of formula RX where R represents a C1 to C10 alkyl, a C3 to C7 cycloalkyl, a C3 to C6 alkenyl or a phenyl-C1 to C3 alkyl group, and X represents an leaving group such as a halide or an acyloxy group as defined above. - above for T, or a sulfate of formula (Ra ^ SO ^.

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. cuddles like sodium carbonate or an alkali metal alkoxide like methoxide, ethoxide or t-: - sodium or potassium 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 the general method (C) using conventional methods, for example using hydrogen in the presence of a noble metal catalyst such as palladium, Raney nickel, platinum, l platinum oxide or rhodium. The catalyst can be carried on, for example, charcoal or a homogeneous catalyst can be used such as tris (triphé-nylphosphine) 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 dioxarne: or an ester, for example ethyl acetate, and at a temperature ranging from -20 to -17- • "t * 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.

The compounds of form can thus be prepared. general mule (I) according to another general process (D), comprising the removal of any protective groups: - tuels of 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. publ. J.F.W McOmie (Plenum Press, 1973) · Thus, a ketal such as an alkyl ketal group can be removed 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, it is possible to treat the free base of general formula (I) with an appropriate acid, preferably with an equivalent amount in an appropriate solvent (for example aqueous ethanol).

Physiological equivalents can be prepared. • -18- • î »cally acceptable a compound of formula (I) according to conventional methods.

The individual enantiomers of the compounds of the invention can be obtained by splitting a mixture of enantiomers, for example of a racemic mixture, using conventional means, such as an optically active separating acid; see for example "Sterochemistru of Carbon Coumpounds" by E.L. Eliel, (McGraw Hill 1962) and "‘ Tables of Resolving Agents "by 10 S. H. Wilen.

Examples of optically active separating acids which can be used to form salts with racemic compounds include the forms (R) and (S) of organic carboxylic and sulfonic acids such as tartaric, di-p- toluoyltartrique, ï- camphosulfonique and lactic. It is possible to separate the mixtures of isomeric salts obtained, for example, by. fractional crystallization, to give the diastereoisomers and if desired gold can transform the optically active isomer 20 required 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 multistep methods . The reaction sequence in the multistage processes must be chosen in a way that the reaction conditions used do not affect the groups in the molecule which are desired in the final product.

The starting materials of "-19- -¾ formula (II) where Y represents the group = 0 ^ can be prepared from compounds of formula (II) where Y represents the group + 567-CïïïR R EX by reaction with a base in a solvent - suitable. Basic examples include alkali metal hydroxides, for example potassium hydroxide or acidic alkali metal carbonates or carbonates, for example sodium hydrogen carbonate.

The quaternary salts can be formed from paΓ-ΊΟ from the corresponding tertiary amine by reaction with an alkylating agent such as methyl iodide or dimethylsulfate, if it is preferred in an appropriate solvent, for example dimethylformamide (DHF). The tertiary amine can be prepared by reaction of a 1y tetrahydrocarbazolone of general formula (V): n • ·,. f \ / \ • · · ·! "(V) 2 °% / \, \ / • \ · h 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 prenared for example by the method described by H. Iida et al. , in J. Org. Chem. 'I960) Yol 4-5, 15, 50 pages 2958-29 ^ -2.

The starting materials of general formula (II) where Y represents -CI ^ Z where Z is a halogen atom or an acyloxy group can be prepared from the corresponding hydroxymethyl derivative of general formula (YI): 0 - 20- / \ Λ / Ch'2 ° ", î Π î

• · t I

C \\ / \ / \ / 2 · N '· i I.

R1 which can be obtained by reacting tetrahydro-, carbazolone 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 triha- *. phosphorus logenide, for example phosphorus trichloride.

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

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

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

_ I

-21- »Ί» *

• S

AT

- 'I, • · CH -iZ1 / \ _ / V' VII i: - I I! !! ! • · · · 5 \\ / \ / \ /; · N ·: · i>] i i; (where E and A are as defined above and Z is an easily displaceable atom or group such as a halogen atom, an acyloxy group or the group | -KS ^ E ^ R ^ X ”such as defined above for Z) with a! imidazole of formula (III) according to the procedure! of the 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.

_ „It is also possible to prepare the compounds of formula (VII) where A represents a hydrogen atom in 2C causing a compound of formula (VII) to react where A represents. feels a hydroxyl group with a tosyl halide (for example tosyl chloride) then reducing; tosylate obtained with lithium aluminum hydride.

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

The following examples illustrate the invention.

The temperatures are in ° C. χ, έ 0λ cena esr -pdioué, 30 the solutions are dried over IAPS04 and the solids are dried under vacuum over 5C * overnight. Chromatography is carried out using the technique described by VÎ.C. Still et al>. Org. Chem. 1978, 45, 2923-2925), on kieselgel 9385.

• a 4 -22- ·! ” PREPARATION 1

2,3,4,, 9-tetrahydro-N, N, N, N-triinethyl-4-oxo-1H-earbazole-3-methanaminiun iodide

A solution of 3 - [(dimethylamino; nethyl] -1,2,3,9-tetra-hydro-4H-carbazol-4-one (0.53 g) in iodomethane (15 is heated to reflux for 5 hours). ml) and evaporated to dryness, which gives the title compound in the form of a white solid (0.84 g '· mp 202-205 °.

10 PREPARATION 2

2,5,4,9-tetrahydro-N, N, N, N, 9-tetramethyl-4-oxo-1H-carhazole-5-inethanaminiuin iodide

A suspension of 3 - [(dimethylamino) methyl] -1,2,3,9-15 tetrahydro-9-methyl-4H-carbazol-4-one (3.80 g) in. 1 is stirred at reflux for 57 hours. '' iodomethane (100 ml). The solution obtained is concentrated under vacuum to give the title nethanaminium iodide - * in the form of a solid (5.72 g) mp 192 ° - 195 °.

20 PREPARATION 3 1,2,3i9-Tetrahydro-9-methyl-5-iaethylene-4H-carbazol-4-one

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

30 PREPARATION 4 2,3,4,9-Tetrahydro-5-methyl-5-L! / 2-methyl-1H-imidazol-1-yljmethyli-1H-carbazole naleate

Sodium hydrochloride (90 mg) is added under nitrogen to a stirred solution of the product of Example 35 (500 mg) in a mixture of methanol (3 ml) and J *

- I

-25- * * of chloroform (3 ml). Stirring is continued for 48 hours (more sodium borohydride (250 mg) is added after 17 1/2 hours and 42 hours), then the suspension is distributed between 5 N 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 dichloromethane, 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 e-ol thanol 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), mp 138.5 ° -140 °.

PREPARATION 5 2,5,4,9-Tetrahydro-9-methyl-3- [2-methyl-1H-imidazol-1-yl) methyli-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 hour and then cooled in ice. The suspension is carefully diluted with aqueous THF (15% (100%) and water (100 ml), concentrated in vacuo and the residual solid is extracted with dichloromethane (2 x 500 ml). The organic extracts are concentrated under vacuum and the residual solid (16.4 g) is purified by chromatography on a column with a short trajectory on silica (silica gel 60; Ilerck 7747; 35 500-g), eluting with a mixture of dichloromethane, • · -24- * »· • s of ethanol and 0.88 ammonia (150: 10: 1) to give the title compound as a foam (13.4 g). CCK silica, dichloromethane / ethanol / ammonia at 0.88 (150: 10: 1) Rf 0.34 and 0.36 (two pairs of diastereoisomers), UV detection. and iodine acid - platinum.

RM δ [CDCl ^ + CD, 0D (1 drop)] 1.6-2.3 and 2.6-3.0; a (5H, m), 2.32 and 2.40 (3H, s + s, Ke in 2 different isomers), 3.52 (3H, s, Kïïe), 3.65-4.3 (2H, m, CHCH2N), 4.75-4.85 (1H, m, CH-OH), 6.8-7.8 (CH, m, aromatic).

Example 1a

1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-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 3/4 hours. then let cool. The solid which crystallizes is filtered off, washed with ice-cold dry DKF (3 × 2 ml) and dry e-ther (2 × 10 ml) and then dried. The solid obtained is suspended (0.60 gN in a mixture of absolute ethanol (30 ml) and ethsolic-hydrochloric acid (1 ml), and the mixture is gently heated to obtain a solution, which is filtered while 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 under form of a solid (0.27 g), mp 186-187 ° * Analysis Found: C 61.9; H 6.4; K 11.8.

30 Cy, gold, HhQ. HCl.H30 requires ^ 1519b 2 C 62.3; H 6.1; K 12.1%.

The following compounds are prepared by a process analogous to that set out in detail in Table I: * S - -25-? ί

ΙΓηΤΤΤΤΤΤΓΓΤΤΤ ”J

* C0 · (, u C

- CC * · = I Ον «, <3; L, · Η f φ Ä,! ** i I ^; <f: fO £ CJ ι ί 1 rrt - 'Ci <*; r 'j v * i ^ ^; <J * ~ “Ι lt I Ï jj · i 8 U St =% \ T-1 Z i ~ j ^ i ^ i" 5 „• ^ z £ S ί - 01 j <= io '' as ce>> λ 1 ... ε "

C d £ H '(N 1 | Λ I O

<3 O i c "ό"! -C "^ I r- 'Π H

U £, 1 ^ ”(in - -“ - * • û *. ® · rfS 1 * “^ ^ H co ftj“ - <*. *, Θ'- .Τ'-j iŒ g! __1 __ ^ _ * = o: <^ i 5 o "u | i Ί:" ci "* 1 * N * fi. I τ '"! i -'! e "" I ml,. cj, η i — i 1 ^ 3 _ \ -, _>: = „j- cx = icxu H g .y ~ = œ * ·" Z ^ '2' -Z. O, 2 CS 05

w - c, * · σ; * a λ. x. λ · Ü C

;; O O CS r ~ J! \ £ '= ¾ _I. = J '*,. =. J I "f2-i G 1—’ ’S ~ ^ - ^ -. “^ O îü | q ä s; o i § 'ΙΛ "C i, Λ’ ‘° ® f- ^ c" u; - M-ί V - * O O C O | ^ i-l CL * '^' wîNiiO'C'C Ocrt ^ Λ w î V \ ΙΓ · | N &? \ Z. jT U * v ____ ~ ^ 1 ~ "- - 1 - ia rft -, 1 'Cl) J2. JÄ IO,, LPi LH" 1 ^ -5: - ^ ^! O; NC: m 03 ^ 33 ”c, · *;"; ·> - ->, a> p, ό c. ό w l-o, "-: o o o ^ -3 'a _ i B ^ H - £ xi _5i‘a: ir,' Ë g — i ο O içs I 3 3 O r * n · ** __ j ï! ! _> _ u -o <! ; ! jj o W · i j-j / - \ <'! '0; Vj ^ c I ’= U- - JJ & P3CC3Ë - iS = | <! -> .j £ -> ^ __ I_ | ___; _ 2 3 î: h ùi ÔTi j ‘! * 1 "'™’ g "c ° ί _ 1 ί; I * 5 CO -t — ί tvj eu * —i X “. θ '' CN \ C ^ y "S - -S 3 * =!" -: - ‘- *“ - - - - - - [- CTN Ό K 2 --N = co | N I 00: c 1 03 * 3 * 3 - - ^ i "o—! . . CL · r / s ^ ^ f-5 <* _®_ - u ^ -1 j! I i "-3 —i ._,% c j. _ => Ju \ ί j; - * a> r> I! £ ii s_ O - * 3 K =! F! = Ί =" * = '_ I dd - ·

U ^ - j - | - i J ü I- iJ

O ¢ 3 -; - - i = = - I p

Fm * * --- 1 ---; - p -: - r --------- - 0 3 0

rlj X ’X · 3Γ I l- I 1. j *. ** 05 K

0 <r c ό V "° i ·]„ r + <· * c · - 1 = 2. ^ i ~ λ ~ \ ~> -> - Oi

CN G U

1 »4 -26- TABLE I (Continued) NOTE 1

Compounds 1e and 1f are prepared in the same experiment and the isomers are separated by short path chromatography (D.F. Taber, J, Org.

Chem ,, 1982, 47, 1351) eluting with dichloromethane / ethanol / ammonia at 0.88 (300: 10: 1). We obtain * 1 the following RKN H data: 10 5? , this . Λ ', · Y. . y · ^ \ 31 T: î LT ru 7 \ Λ Λ / * 5> —y '• N · RC R3 8 p 1 1 15 d = doublet v „dd = doublet of doublets s = singlet:“ SPECTERS 1H BHN ( obtained at 250 KHz)

Solvent —-- 1 --—- Chemical displacements of selected protons (ô ppm and multiplicities jProtons of carbazolone Protons! Protons; - d * imida-imidazole; H-5,6,7,8 CHp-1 and CHp -2 zolyl: -! J Aromatic H-Jaliphatic: H * 2 '

1 H-5, U

1st A UMSO '7 2-8 ο- 2'9η- 1.75- 4.47 (dd> 9.20s 7.55s 1st d & -BriS0 | 7.2-8.0 ^, ^ 2.3 and • i! 4.64 (dd) _ i ____ 1f: GBC13! 7,15-ε, 05 2i% '^ C2rdd' £, l? 9j6,53s |; +!! Z&W. i! '_I__j_i_j____;!; entre other U.42 (dd)! i! Ί '-A ivcri tn pp': 2.9 ~ 1.6- 'and 7.61d.

1g d6-3KbC | 7.2 8, w, 2.2 -4.73 ^ (1) "and 7.70d -27- · * EXAMPLE 2 1,2,3,9-Tetrahydro-9-methyl-I-3 - [(2-methyl-1H-imidazol-1-yl) methyl ~ 1-4H-carbazol-4-one maleate. 1,2,3,9-tetrahydro- | 5-9-methyl is suspended -3- [(2-methylimidazol-1-yl) methyl-4H-carbazol-4-one (300 mg) in hot ethanol (5 ml) and treated with maleic acid ( The solution is cooled and the white crystalline solid is filtered off, and dried to give the title compound (300 mg), pE 132.3 °.

! EXAMPLE 3a! 1,2,3) 9-! Tetrah7dro-3- (1H-imidazol-1-ylmethyl) -4-H-car-! bazol-4-one j A solution of Preparation 1 (0.84 g) and imi-dazole (0.90 g) in DMP (25 ml) is heated at 103 ° for 6 hours ), 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 can be rified on a column of silica (Merck 7734), eluting with ethyl acetate / methanol ( 4: 1). By recrystallizing twice from ethyl acetate / metha- | nol the title compound is obtained (0.095 g) under I. form of a crystalline solid, mp 220-222 °.

; 25 -CCM silica, dichloromethane / ethanol / ammonia at 0.88 I - * (100: 8: 1) Rf 0.33, u.v detection. and acid iodoplati- | fuck.

The following compounds are prepared by an analogous method as described in detail in Table II.

The salification is carried out as described in Example 2.

i 2 5 Ml. ßgg -28- c. · * ο "ε or? 5 r '!! wo * v C1 ^»' »î rn ►“ * Ό vî r * I * - * îü O. 0) JJ - - V Û> S Tl 0) f '. 7. Γ-, II 1—1 • λ o 1 * "u ό" sy, in! "** g" i Æ -a0 w N <nn J - J <= - i; ï I s

r tt to | | ^ - S. Λ e «Ir ^ ttlO

WW C fl Sg fl ~ · _Γ ”_r-" * T! RT ^: Ό C tJ O "" P “- ~“, i ï “S 03 jj ε -“ t ·, f 01 Ί3 * rJ O -H CM,. R- Λ Ό OU - I 1 1 1 7. e 1 Îî Æ P- 13 PC I œ! OT; 1! »Gur“ - r -; ----— i. Jj jj · υ Ä w ta ^ - i'ojcjo) OW CO 0) 1 5 5 5 t! t - i "C ΐ I - -1¾ T 'K-Ir-ir-l ιλ c otj i — i>, 3 3 3 3- 3 33 ~ ^ tir tj, c, □ oo ^ 2 oS ^ jj cj ^ jj * L ^ • u ''! ^ jj ~ i «jjS j wjji I -jj 5! o o -5 w 2 £ ^ o S EÄ * * ® * i e‘w *! * a "I * ® *! * a * \ v * ° “3 o. -; - r —- i ---- -: -— -! κ n u c c itN 5 ·. i, ο i

"0) 0) C IC, γΊ I γμ I c: i, 7. _ 33 Ό W

£ ^ J2U "-h 7 7 7 S r-" · '! · ° owo jo t | 7. 7 œ ^ ^ "A! We, œ n L 2 - | - -3 ^ 3'" "ίφΈ - - -

S -ι-j -W VJ ^ ri "" * C S 5 CM

* -H-H 5 l · «« 7 7 J. τ '7 7V

- ° .s · - yes -! -: ~ - d: 5; here ?, | ,,! £; g | , s I g; - ÎJ 0) d c I ^ i = -! - - ° | O a * 1 U £ I ÜivO fl C) b * '* ’® e * U \

OR O * H Dl "C- '* r | J · J ® P V

a> saw jj c, m c o; ~! - - i - I - qj i-i C. Q 0i pu! | Vu-H: Γ- I Γ- * r »~ r, -! It’s H >> t. Lca — _ ,. i c «u_I_ I I. I u .c - _; ; ; -; - j - ι-ό 53 ^ I! ! i c. a '"uiti ο ly œ H ^ ^ ° Ο I, ^, (o! * ο Φ ûj. f Pm ί *?" C s - fN IC * Λ ir * "j | n> o Û) ÇÎ M! l, I, iw "wc! "! <"Cc c U> CÖ

- "ö --i - = - = - 1 =: - = - = _ 7-! .7_—, 6 ^ X

03! ^ I i! 1 <U AJ u

St i j i 5? - i Sie; - * srej ^ vo. n Ο Ή ^ κ i, ^ Vu - ·, S o a μ 3 ut c = c i o! => o "totjo PJ ΙΟ. Ό Ο.Ό ^ I] i i — 1 O. ··

S -: --------—, - j-- '0) Φ O

~ 'you ^ ~ ^ ", I j. I ί ο) μ jo> -ιε a "œ ΐ Œ = i ^ Q)! J, ς · '1' S, .t .i 'ο I CO JJ - MO se ô ~ - j = j Ό Pu' Qj o

"W = i i ë $ 1 idÜO

0d V i "-! - s—" | sw • S o; i no- ·· .2 ^ ê ^ C! CS j 1-S O F.

fl S άου ς 1 u ç ξ! ί! «O 5 r '~ S s Ä I S I a s I S! QJ [i Q V JJ ^ ^ I t j CO ce O 03 \ —H ~ | __; _ o o) co: r-1 "! -,>" • I JJ! I:! 'Ο Λ te o

r-i r-ι C - i! 1 W E

ooro— ^ us c-i us, 0: cojjæ o

-> W> 3 ^ ~ i 1 r,, c. W -C DD

VS ; "R-J-s —- 1 -! - i -; __ · E -W c o c - -z-r Q> I I". i; o c c 0 / ûALTV ^ if -a-j ^ ios ^ t ί o w "- {or w

- B O Î-J'Q) O c 1 i U '0) ci' U

s— ”w -r-ï te Ca — s c; i cr, r- <* »> w / *> W Γ3- C C.). · r- C I“ 7. 'O! occ ~ • f a 3 -— Π3 and £ 3. -! - i - cm j C! · - CiOC C,

\ --i _! _ '_! - H K

- P1 w C ci E it, ~ 5— "r c- es - £ 0_ \ y 7) 7. I c | = 'x"! "- &. C> - V · - PL, u ^ - -c , ir »i κ-„ '; ce ό w -m.

- ---- r ------ CLKI— ·

I ^ „H a- jt i J'Q) X C C

I _ = - n: ^ en 3Γ r * x ï - PjCcîC "*" ---- 1-1 ---! - 1 ----- J PU O £ C Qi u, \ o) - il ^ - - M · m -j and EIX ί X i GI = <»j C JJ O JJ J3

"—P -s —-; - 1 -—) ---: - J C Ci NJ Ό C

* "I | = |:; -13 W. j ts I a. Ί j> _ ·· o" sT ^ i:;! Ci fï-, t- j CI χ_ 1 __ ^ | x 'j ^' - ' .. ^ 1 ^ 1 = 1 = 1 = i =! S fi 2 ^ ° __- issjss | nzo -29- * EXAMPLE 4- 1,2,3,9-TetrahYdro-9-methyl-3- [^ - methyl-1H-imidazcl-1-yl) methyl ~! -4-H-carbazol - ^ - one

A solution of 1,2,3,9-tetrahydrc-3-L (2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-e - one 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 ), at the end of 1/2 hour, dimethyl sulphate f0 (p4 ml) is added, and the solution is stirred at room temperature (Ta) laying down. The solid obtained is filtered off, washed with dry ice DMF (2 × 5 ml) and dry ether (3 × 13 ml) and dried to give the title compound in the form of a solid (C, 2p g), mp 225_224 ° (dec.).

silica, chlor0for3e / Qôth.anol (93/7),

Rf 0.27 u.v. detection and iodoplatinic acid, identical to the product of exeanle 1a.

The following compounds are prepared by a similar assigned prc-20 using the appropriate alkylating agent as described in detail in Table III.

-30- | e I ir 'i θ' \ ir. J œ {- {c "il, vf Ci -stvC j vs (v I *> <U 2 -" * 'θ' i * "" œ j: ¾; o]% ^ j ® ί: i '~; ·· »C> (vC (O- <- .a. L ·" 'IW 2 1 O> ^' v; ~! Rn ^ 'N * »i ^ nC> C> r- r * iw% 0. in 1 ^ α> ί; |, "fcsÇ çj | r - ip ^ vî rsj · ^> o r- 1 *: * Γ ·.

u! = -1-1 κΓ · ^ ^ i ^ I έ "In; - S _; _y„ ___ * · _ ^ 1 jC j · £ ·> c * o ω j- = t-. Î J f ^ | ^ ; £ ~ = - · £ -! -I "; i: - 1"> - · - ">; -: -"! - 'T i;; *! <—I' · "* -" *, ό ! σ ·. c ~ - v.

I 5 5 2 ί S5 - · I \ C! * \ * y - »Γ- Γ '1 <3 O j I i> r. NC "} -j i; i it. \! w I t-j r · - · ^ - "·" <i - <l * r "r ^ · | o

j “* · | · * I *.} ".} -V (- -: O

t t— * <T I O · j tT-sO ”. f ~ v | O * * "C? IT <_ | _C_J_Ο I O 1 vQ i _ ^ _ i ^ _I_c I i

! have ! jf i ~ i j! i · »j I

i U 1 j S S =, I =, I | i ^ I -> i i! = i = s I ^! r û; ί crt · '"" i ^ i t I, _ î ", · JZ j c- i c_ i c. 2r; (_ t · 4 m * CL »» * - <lc: ·· î ·, 'I · I.Cwi * θ | CC' JZ-! r— "" 3 i C f »Ci, C · C» cja · IC "" i ~ c? Z- ga 5 1 jT: 2 "·!: 3" 's | "; V 11 z * - *, r" = -: = 1- = -: i ": = * ! x ”i sT = j · 2— · OO .er - - C 'θ'. j · j <-î l ^ xl KI« - «

S \ J [V, C j - t_ f J _.0 <<N i fN J- i fN i O

• er ^ ^ 1 'wJ x · w w' _u. u. ! _w c_ o l._ ”• Z '! <t j î 'i ö {, j 5. Ο; CC. ··!,! o. i o; w χ ^ .Μ-Ιΐ .ι »λ: _i in ir • es- · î Dj;» C jC.5o .ji wrv î i 1 i | S> .- 'fi - «rv * *' ^ cr ' c - ^ * cc σ ^ ιΐτ> ci 2— "" r C. - O- 2 * \ O '* rs i (^ fSÎ'S · - - - —.— i / *? -’L * C * ί - o! ^ I

^ ^. U 1 4—1 ^ Nfi * e I I »·« 3 * | ^ r fVi I

ί · Η ο · η ^ '- "' _r: =.! t -L:

| OQJî-i3 &ac;.“.“; , ί 2.. these are I

- j Cl · Ό Cl * 73 v— / | _______________; __ H φ! I 1 'il i ’î' <ί I - e- i □ I -1" -! "!.?’.?. ·· 1 -f,? 1 *! r-: M - a; o'ai | r; -i - ’z \ Z -, = 'x' ►,‘ B W Ë | .It 3 - 3. 3 3 "t P‘ -i. 3; · Ε - r t r x o i g 1 ^ ^ i; ; ! -! vs ; your "? 'OJ C ä I j! ^ ·! Γ ~ ί rj I ç io 3 '(l · · * * Vt · “* t C *. 4 tj J-ι M Ο / -“ I * i * £ 1 * r 1 r · * tλ; <, M aa; -h, cö c I! ';, s; ^, ¾ 1 ΡΌ Ü I - 1 - I i I 1' „1 r ~~ 1:: ij 3 1 '_' x, ~ çSl. Ij _ύΐ__ = _ [_ = __ î X xi XX _ x _x "> - 'ί ji ~ i TI 1'“! - 1 <V c.! s: x!!!: z: £ ο:! - i _ C = . ^ - _1? J? "; Î:?" J = Ë "-: L.", i ί!..? II: v.

** -: I i έ! · * "✓ ·: f 1: 1 '5’ 5 I "f · I 4 · TJ *! f U I r * ~ t ‘I ~~ J-iJ- ^ t & ί x Λ. SX ·! C O * O î c t fx ’O X C ·

‘Cï ü * · î Λ: V,. r "- - SX

^ 1 ^ "x w, -. ^ O e 1?>" "X · x; , at. u a. - * · - c O i! î · I? ο i: ί c r «

I T— i i, ^ "* J

I ^! I! i; : ί IU i Γ ". 1 T: iii \ vo <" S 'it r5 -i! e. -s &. I "-; cr. j:> ^ ^ t <r; -c *" 3- ^ ^ <τί · σ -tf -31- Λ TABLE III (Continued) NOTE 1

The following PMN data are obtained: π p '5 5 ’ü ·' 2. . . .2-

! ' \ /> 5 / \ / V

C \ i '-tb · · - · · \ \ 3, ji> II, ·' n 'V ΡΛ R3 SJ: 10 1 d = doublet dd = doublet of doublets s = singlet I bPETERS ^ H 2KN Γ obtained s at 250 MHz) i__v -.

15 ° olva: rt Chemical displacements of selected protons (δ ppm) and multiplicities

Carbazolone protons Frotonsj Imidazole imida-j protons ---- ‘zolyl -i-: H-5,6,7,8 CH -, - 1 and CHP-2 methylene H-2 'H-4‘

'2 7! ! 1> t / 0VL

20, Aliphatic AromaticsH-3 | -i ---—------! - j 4g | dfi-DKS017,15-8,1 2,9-5,2 1,9-2,2 ^ '29 (dd) - 7, 55d! ; 6.68 (dd) 7165di

i 1 I

4hid6-0MS0 7.2 -8.1 -2.9-5.5 1.5-2.2 | ^ 26 (dd ^ - \ ^ 42d; 6.65 (dd) i: 7.57d _1. _J_ ,> 'EXAMPLE 5 9-0yclouent: / l-1,2,3,9-tetrahydro-3- [i2-nethyl-1H-30 imidazol-1-yl ^ ethyl -] - 4H-carbazol-4-one naleate

A solution of 1,2,3,9-teters hydro- 5 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (1.20 g) is added in dry BMP (9 ml) in an ice-cold and stirred suspension of sodium hydride (80% in oil; 0.14 g) in dry BMP (2 ml) under nitrogen, * "-52-

AT

and we keep shaking for 1/4 hour. Bromocyclopentane (0.51 ml) is added and the stirred solution is heated to 100 ° for 18 1/2 hours. The solution is allowed to cool and then it is distributed between water 5 (100 ml) and ethyl acetate (5 x 70 ml). The combined organic extracts are washed with 2 N sodium carbonate (2 x 50 ml), water (2 x 50 ml) and brine (50 ml), dried, evaporated to dryness and purified 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 2ÿ ml) and the mother liquors and the combined washing waters are left to stand. The solid which crystallizes out from the solution is filtered off, washed with dry ether (3 x 5 ml) and dried to give the title salt as a white crystalline solid ( 0.058 g), mp 104.5-106 °.

; . Analysis Found: C 65.95; H 6.4; N 8.6.

25 022 ^ 2 ^^ 0.0 ^ 11 ^ 0 ^ .0.61120 requires _ - C 65.8; H 6.4; R 8.9% EXAMPLE 6 1,2,5,9- ^ etrahydro-5-L (2-methyl-1H-imidazol-1-yl) methyl -9- (2 - propenyl) -4H- carbazol-4-one maleate 30 Add a solution of 1,2,5,9-tetrahydro- 3 - ['^ 2-mé t hy 1-1 H-imid a zo 1-1-y 1) mé thy 1 ] -4H-ca rb az ο 1-4-one (1.0 g) in dry DKF (6 ml) in an ice-cold suspension and stirred with sodium hydride (80% in oil; 0, 12 g) in dry DKF (2 ml). After 35 of 1/4 hour, add allyl bromide, stir: “4 -i: - -33- -¾ To

U

Ila solution at 0 ° for 1/4 hour, and at room temperature for 20 hours before dividing between water (75 ml) and ethyl acetate (3 x 50 ml). The combined organic extracts are washed with water (2 x 50 ml), brine (30 ml), dried, and concentrated in vacuo and purified by chromatography eluting with a mixture of dichloromethane, etha-; * nol and 0.88 ammonia (200: 10: 1) to give a solid (0.4-3 g). This solid was dissolved in absolute ethanol at reflux (2 ml) and a solution of a-

Maleic acid (0.18 g) in absolute ethanol at reflux · - (1 ml). The hot solution is filtered, diluted with dry ether (4 ml ') and the crystallized solid is filtered off, washed with dry ether (3x5 π 15 ml) and dried to give the compound of title in the form of a white solid. (0.48 g), pi1 150.5 ° -151 ° * Analysis Found: G 66.3; H 5.75; N 9.6.

: ^ 20 ^ 21 ^ 5 ° ’C ^ H ^ O ^ requires; C 66.2; H 5, S; K 9.65%.

EXAMPLE 7 d: 1,2,3,9-Tetrahydro-9-methyl-3- [(2-nethyl-1H-imidazol-1-yl) methyll-4H-carbazol-4-one:] A | .j hydrochloride solution. 3- [(dimethylamino) methyl] -1,2,5,9-tetrahydro-9-methyl- 4H-carbazol-4-one (1.7 g) in water (17 ml) with 2-methylimidazole (1.4 g) then heated to reflux! for 20 hours. The cooled mixture is filtered and | the residue is washed with water (3 x 15 ml) to give i- the crude product (1.7 g), ρΡ 221-221.5 °. This material is recrystallized from methane to give the i = title compound (1.4 g). mp 231-252 °, identical by j, TLC to the product of Example 4.

! EXAMPLE 8: 1,2,5,9-Tetrahydro-9-methyl-5 - [(2-methyl-1H-imidazoI- j · 35 1 -yl) methyl 1 -4H-ca rb a zo 1 -4 -one d -54- D * I *

A suspension of the product of preparation 3 (0.5 g) and 2-methylimidazole (0.4 g) in water (5 ml) is heated at reflux for 20 hours. Or-filter the cooled reaction mixture and wash the residue t 5 with water (3 x 10 ml), dry and recrystallized from methanol 08 ml) to give the title compound (C, 3 g), mp 232-234 ° (dec.), Identical by CCM to the product of example 4.

EXAMPLE 9 10,2,3,9-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. 15 h, 2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) mé-thyl] -4H-carhazcl-4-one (1.93 g) at 0 ° C in DKF (35 ml) and the suspension obtained is stirred at 0 ° C for 1/4 hour. 2-bromopropane (0.78 ml) is then added and stirring is continued at room temperature overnight, then for 4 hours at 40 ° C.

The reaction mixture is distributed between sodium carbonate (2IT; 200 ml) and ethyl acetate (2 x 150 ml). The combined organic extracts are washed with water (3 × 75 ml), dried, and evaporated in vacuo and the product is purified by chromatography, eluting with dichloromethane: ethanol: ammonia (100: 8 : 1) 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 Found: G 65.3; H 6.6; 11.1%.

C ^ qH ^ J ^ O.HCl.O ^ HpG requires C 65.4; H 6.9; 11.45%.

4 ”-¾ -35- • 4 a EXAMPLE 10

1,2,5,9-tetrahydro-9-methyl-3-Tf2-methyl-1H-imidazol-'l -yl) methyll-4H-carbazol-4-one hydrochloride dihydrate 5 3,9-tetrahydro-9-methyl-. 3- [(2-methyl-dH ~ imidazol-1-yl'l, niethyl] -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), filter the hot mixture 10 and dilute the filtrate with isopropanol (90 ml) and stir at room temperature for 17 hours, it is cooled to 2 ° and the solid is separated by filtration (21.6 g) and recrystallized from a mixture of water (6 ml) and isopropanol (10 ml) to give the title compound as a white crystalline solid (6 g) mp 178.5-179.5 °.

Analysis Found: C 59, ^ 5; H 6.4-5; N 11.5 · ^ 12 ^ 19 ^ 0- ^ 01.2 ^ 0 requires C 59.1; E H, 6; ïï 11.5%.

Water determination: Found: 10.23%.

C ^ gH ^ N ^ O.HCl ^ H ^ O requires 9.85% ·; EXAMPLE 11 1,2,3,9-Tetrahydro-3-r (2-methyl-1H-imidazol-1-yl) methyl ~ | -9-phenyl-4H-carbazol-4-one maleate 25 i) Hydrochloride of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-nhenyl-4H-carbazol-4-one

A solution of 1,2,3,9-tetrahydrc-9-rhenyl-4H-carbazol-4-one (3.90 g) of diaethyl-amine hydrochloride (1.50) is stirred at reflux under nitrogen for 42 hours. g) and paraformaldehyde (0.60 g) 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 1/4 hour, and the mixture is filtered off. solid obtained, washed • • s - ___ * • "-36- *> with dry ether (4 x $ 0 ml) and dried to give the title compound (4.2 g). Recrystallization twice a fraction of this solid (1.0 g) from absolute ethanol (10 ml) to give the title compound as a tawny powder (0.59 g), mp 193-194 ° ( Dec.) ii) 1,2,5,9-tetrahydro-3- [i2-methyl-1H-lmidazol-1-yl) -methylj-9-i> hényl-4H-carbazol-4-one, maleate

2-methyl-1H-inidazole (1.4 g), added under nitrogen, is added to a stirred suspension of 3-L (dimethylanino) methyl hydrochloride -1,2,3,9-tetrahydro-9-phenyl - - 4H-carbazol-4-one (2.0 g) in water (20 ml). The mixture is heated at 90 ° for 43 hours and the solvent is separated by decantation from the tawny solid. Chloroform is added to the solid, the suspension is filtered through fluoride, 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 mixture is triturated. gum obtained with dry ether (2 x 40 ml) to give the title compound as a cream solid (1.3? g), ρϊ1 165-166 ° (dec). Analysis Found: C 68, &5; H 5.5; K 8.7.

C23H21K30 * C4H4 ° 4 requires C 68.8; H 5.3; K 8.9%. EXAMPLE 12 1,2,3,9-Tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one-phosphate (1: 1 )

1,2,3,9-Tetrahydro-9-methyl-3 - ['2-methyl-12-imid a z01-1-y1vmethy11-4H-carbazol-4-one (0.61 g) is dissolved in a hot mixture of phosphorous acid (90%, 0.13 ml) and water (10 ml), filtered to -37- • <! " Λ - through Hyflo and allowed to crystallize to give the title compound (0.5 g), mp 225 °

Analysis Found: C 55.1; H 5.6; N 10.55 · C ^ gK ^ NjO.H ^ PO ^ requires 5 C 55.2; H 5.7; K 10.7%.

EXAMPLE 15 1,2,3,9- ™ etrahydro-9-methyl-3 - [(2-methyl-1H-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] -4-ïï-carbazol-4-one (0, 89 g) 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), mp 162 °.

EXAMPLE 14

1,2,3,9-Tetrahydro-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -e-H-carbazol-4-one hydrochloride Iodomethane (0, 75 ml) to a stirred solution of 3 - [(dimethylanino'methyl] -1,2,3,9-tetrahydro-4-H-carbazol-4 ~ one (2.9 g) in dry DMF i'30 ml ) and the solution is stirred at room temperature for 30 minutes. A solution of 2-propyl-1H-imidazcle (2 g) in DîfF (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 (4-00: 30: 3) to give the free base in the form of a solid (1.2 g).

A sample (0.2 g) is dissolved in abso-35 lu ethanol (5 ml), acidified with hydrochloric acid - tt -38- ΐ »ethereal and diluted with dry ether (about 200 ml) to give an oil. When scraped, the oil crystallizes to give a solid (0.15 g) · The salt is crystallized from a mixture of inethanol and isopropyl acetate to give the title compound (0.08 g) mp 206 ° -208 ° C.

Analysis Found: C 65.6; H 6.8; N 12.0.

C ^ cHo ^ N70.HC1 0.2Ho0 requires' 5 2 0 65.7; H 6.5i H 12.1%.

10 RM ô (CD5S0CD5) 0.94 (3H, t, CH5), 1.77 (2H, sextet, CH2CH2CH5), 1.9-2.15 and 2.95-3.2 (7H, m), 4 , 32 and 4.71 "(2H, ABX, CHCHgN), 7.1-8.0 (6H, aromatic).

EXAMPLE 15

1,2,5,9-tetrahydro-5 - [(2-propyl-1H-15 imidazol-1-yl'methyl! -4H-carbazol-4-one hydrochloride

A solution of the product of Example 3g is hydrogenated at ambient pressure and temperature. = (0.03 g) in methanol (15 ml) on 10% palladium oxide on charcoal (50% aqueous paste, 0.03 g) for 4 hours (absorption of H ^, 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), mp 199 ° -203 °.

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

EXAMPLE 16

1,2,3,9-tetrahydro-9-r-ro-Dyl-5-i (2-υ ropvl-1 H-imida zo 1-1 -y 1} métn hydrochloride: »Tl '-4H-carba zc 1 on 30 Gn adds, under nitrogen, sodium hydride (80% dispersion in oil), to a stirred solution of the product of Example 14 (1.0 g) in DKF dry (20 ml) and stir the suspension at room temperature for 30 minutes, add 1-bromopro-35 pane (0.35 ml), and stir the solution at 40 ° C for · * -¾ -39 -

• I

" 20 hours. The solution is divided 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 under; In the form of 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 com-. 15 set title ^ 0.53 g) P? 144 ° -147 ° C.

RMN ÔÇCD ^ SOCD ^) 0.90 and 0.93 (6H, t + t, 2xMe), 1.65-2.2 and 2.9-3.25 f'10H, m), 4.19'2H , t, CHpCI ^ N), 4.52 and 4.71 (2H, ABX, CH ^ CHqN), 7.15-8.1 (6H, m, aromatic)

Analysis Found: 0 66.6 ·, H 7.7; N 10.0.

20 ¢ 22 ^ 27 ^ 30 requires C 66.3; H 7.4; N 10.5%.

EXAMPLE 17 1,2,5,9-Tetrahydro-5 - [(2-methyl-1H-imidazol-1-yl) mes-thyl) -9-propyl-4H-carbazol-4-one maleate 25 Hydrogenation is carried out under pressure and room temperature a solution of the product of Example 6 (0.86 g) in a mixture of absolute ethanol (20 ml) and dry dimethylformamide (5 ml) on 5% platinum on carbon [(0 , 1 g), pre-reduced in absolute ethanol (10 ml)] 30 for 1 hour. (Absorption of H ^: 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 55 is filtered off, washed with water (3 x 15 ml) and dried for

• I

-40- * r.

j »give a powder ($ 0.7 g).

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

Analysis Found C 65.8; H 6.1; N 9.3; C ^ qH ^ -N ^ O.C ^ H ^ O ^ requires 10 C 65.9; H 6.2; N 9.6%.

EXAMPLE 18 1,2,5,9-Tetrahydro-9-methyl - $ - [(2-methyl-1H-imidazol- "1-ylvmethyl] -4H-carbazol-4-one (i) $ -fChloromethyl) -1 , 2,3,9-tetrahydro-9-methyl-4H-15 carbasol-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 re-container closed at room temperature for 16 1/2 hours, 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 screen a fraction of this material from ethyl acetate results in partial decomposition.

(ii) 1,2,5,9-Tetrahydro-9-methyl-5 - [(2-methyl-1S-imidazol-1 -? 'l) methyl1-4H-carba zol-4-one 30 Agitation is carried out under nitrogen at 90 ° for 3 3/4 "a solution of 3- (chloromethyl) -1,2,3,9-tetra- -hydro-9-methyl-4H-carbazol-4-one (0.50 g) and of 2-methyl-1H-imidazole (1.60 g) in dry DKF, then poured into water (2 ml). The suspension is stirred for 1 hour, and the solid is filtered off. , i * mi • Λ -41- * · <, wash with water (3 x 20 ml) and dry under vacuum at 50 ° C. 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), mp 228-229 ° C. This material is identical to the product of 1 'example 7 by COM and ïtÆ.

EXAMPLE 19 1.2.3.9- Letrah7 / dro-9-methyl-3- [(2-aethyl-1H-imidazol-1-7yl) methvl] -4H-carbazol-4-one

A solution of 2,3-dichloro-5,6-dicyano-1,4 - 'benzoquinone (170 mg in dry THF 0.5 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 µl) and water (0.4 ml). The blue solution obtained is stirred for 1 hour 1/2, then concentrated in vacuo. Column chromatography of the residual solid, eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (d50: 10: 1) gives the title compound (4-5 mg). mp 227-228.5 °. This material is identical to the product of Example 7 by CGM and SMK.

EXAMPLE 20 1.2.3.9- Tetrahydro-9-methyl-3 - [(2-methyl-dH-imidazol-1-yl) methyll-4H-carhazol-4-one

A solution of 2,3-dichloro-5,0-dicyano-1,4-henzoquinone (80 mg) in dry THF (1.5 ml) under nitrogen is added dropwise to a stirred, ice-cold suspension of the product. 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 hour and a half, 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 under the title as a white solid (0.47 g), mp 227.5-229 °. This material is identical to the product of Example 7 by CCW and RKN.

EXAMPLE 21 5 3S-1,2,5,9-getrahydro-5-L (2-methylimidazol-1-yl) methyl ~ j-9-methyl-4H-carbazol-4-one, maleate

A solution of the product from e- = example 7 (0.5 g) is dissolved in 30 ml of hot methanol and treated with a hot solution of (+) - di-p-10 toluoyl-D-tartaric acid. monohydrate (0.7 g) in methanol (10 ml) and the solution obtained is allowed to crystallize overnight to give the desired salt (0.68 g). This salt is dissolved in hot DME (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 (+) - di-p-toluoyl-I> -tartaric acid enantiomerically pure at about 90% (as seen by RKN) (0 , 23 g), pE 231-233 °. A sample of the salt (0.15 g) is partitioned between 8% sodium bicarbonate (25 ml) and 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 dry ether (80 µl) to give the title compound ( 0.062 g), pE 142-145 °.

TLC silica, dichiorornethane / ethanol / ammonia-only at 0.88 (100: 8: 1), Rf 0.3, u.v detection. and iodoplatinic acid, identical to the product of Example 7A.

The enantiomeric ratio, determined by ‘H RLE 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, 55 gives; ra] fp -14 ° (c 0.19; MeOH).

-¾ -43- ί ki '' f EXAMPLE 22 * 3H-1, 2,3 ^ -Tetrahydro-9-methyl-3- [(2-methyl-1H-imida- zol-1-yl) methyl ~ l- 4H-carbazol-4-one maleate

Dissolve a solution of the product of e-5 xample 7 (0.5 g) in hot methanol (30 ml) and we! treats with a hot solution of acid (-) - di-p-! toluoyl-L-tartriaue monohydrate (0.7 g) in metha- | nol (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. separate product by | filtration, and dried under vacuum to give the salt

i acid (-) - di-p-toluoyl-L-tartriaue (0.26 g), pF

15 170-172 °. A sample of the salt (0.2 g) ^ is divided between the b% 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 [20 (5 ml) acidified with maleic acid (0.045 g) and the salt is precipitated by adding an excess of dry ether rf (80 ml) to give the title compound ( 0.08 g), p3? 142-145 °.

CGM Silica, dichloromethane / ethanol / ammonia at 0.88; 25 (100: 8: 1), Rf 0.3, UV detection and iodoplati- acid! nic, identiaues to the product of Example 7. The ratio j ^ r η enantiomeric, determined by Ή NMR, is greater than i - 95: 5 * A sample of the maleate salt shows no significant optical rotation in methanol. The | Free base, regenerated from the maleate salt, gives j v + 16 ° (c 0.34; Me OH).

i, t The following examples specify formulas; pharmaceuticals according to the invention, containing 1,2,3,9-tetrahydro-9-ifiethyl-3- ['2-35 methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4 hydrochloride -one • 1 * -44- ·; " "

AT

as active ingredient (1.25 g of dihy-draté hydrochloride contains 1.00 g of the free base). Other compounds of the invention can be formulated analogously.

5 TABLETS FOR ORAL ADPIKISPRATION

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

The tablets can be coated with a film 10 with suitable film-forming materials, such as hydroxypropyl methylcellulose, using standard techniques. Sugar tablets can also be coated.

Direct compression 15 mg / tablet tablet - - Active ingredient 4,688 28,125

Calcium acid phosphate BP * 85.06 87.75

Croscarmellose sodium RP 1.8 1.8

Magnesium stearate BP 0.45 0.45 20 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 Manesty B5 compression machine equipped with 5.5 mm punches with a bevelled flat edge.

Sub-lingual tablet mg / tablet 50 Active ingredient 2.5 - Compressible sugar KF 82.5 ^ Magnesium stearate BP 0.5

Compressed weight 65.0

The active ingredient is sieved through an appropriate sieve, mixed with the excipients and -4-5- * 1 Λ -¾ 'compressed using suitable punches. Tablets of other strengths can be made by modifying either the ratio of the active ingredient to the excipients or the compression weight and by using appropriate punches.

Wet granulation

Classic mg / tablet

Active ingredient 2.5

Lactose BP 151.5 iO Starch BP 30.0

Pregelatinized corn starch BP 15.0

Magnesium stearate BP 1.5

Compressed weight 200.0

The active ingredient is sieved through an appropriate sieve and mixed with lactose, friend-don and pregelatinized corn starch. Add appropriate volumes of purified water and granulate the powders. 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 prepared by changing the ratio of the active ingredient to lactose or the compression weight and using appropriate punches.

Sub-lingual tablet mg / tablet

Active ingredient 2.5

Mannitol BP 56.5

Hydroxypropylmethylceilulose 5.0 50 Magnesium stearate BP 1.5 r Compressed weight 65.5 * The active ingredient is sieved through an appropriate sieve and mixed with mannitol and hydroxypropylmethylceilulose. Appropriate volumes of purified water are added and the powders are granulated.

\ -46- * *

After drying, the granules are sieved and mixed to give tablets using suitable punches.

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

CAPSULES mg / capsule

Active ingredient 2.5 10 * Starch 1500 97.0

Magnesium stearate BP 1.0

Filling weight 100.0 * Form of directly compressible starch.

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 25 Active ingredient 2.5

Sucrose BP 2750.0

Glycerin BP 500.0

Buffer ·

Q taste agent

30 Dye \

Preservative

Purified water BP asp 5.0 ml & ^ The active ingredient, buffer, flavoring agent, colorant and preservative are dissolved in part of the water and the glycerol is added. "* · Φ ·· -47- rine. 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.

5 B. Without sucrose mg / 5 ml dose

Active ingredient 2.5

Hydroxypropylmethylcellulos e USP (viscosity type 4000) 22.5

Buffer ", 10 Taste agent

Colorant γ q.s.

Preservative Softener J

Purified water BP asp 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.

Injection ^ ug / ml 25 Active ingredient 50,800

Diluted hydrochloric acid BP at pH 5.5 at pH 3.5 Injection of sodium chloride BP at 1 ml to 1 ml

The active ingredient is dissolved in a suitable injection volume of sodium chloride BP, the pH of the solution obtained is adjusted to 5.5 with dilute hydrochloric acid BP and then the solution is completed. - * - tion by volume with an injection of sodium chloride BP and mixed thoroughly. The solution 55 is poured into 5 ml vials of type 1 clear glass which -¾ -48- are sealed under a point of air by melting the glass έ and then sterilized by autoclaving at 120 ° for at least 15 minutes.

! AEROSOL UNDER PEESSIOIT A PC MEASURES

5 Aerosol in excess mg / dose per measured container

Active ingredient micronized 0.250 66 mg

Oleic acid BP 0.020 5.28 mg

Trichlorofluoromethane BP 23.64 5.67 g 10 Dichlorodifluoromethane BP 61.25 14.70 g

The active ingredient is micronized in a liquid phase micro-nizer at a fine particle size interval. Oleic acid is mixed with tri-chlorofluoromethane at a temperature of 10-15 ° C and the micronized drug in the solution is mixed with a high shear mixer. The suspension is poured into aluminum aerosol cans and the appropriate measuring valves providing 85 mg of suspension are fixed by embossing, then the dichlorodifluoromethane is poured through the valves under pressure.

Aerosol solution mg / dose per measured tank

Active ingredient 0.25 30.0 mg 25 Ethanol BP 7.500 1.80 g

Trichlorofluoromethane BP 18.875 4-, 35 B

Dichlorodifluoromethane BP 48.525 11.65 g (BP oleic acid can also be included on an appropriate surfactant, for example Span 85 30 (soroitan trioleate)).

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

Inhalation cartridges mg / cartridge | 5 Active ingredient (micronized) 0.5

Lactose BP asp 25.00

The active ingredient is micronized in a liquid phase micro-nizer at a fine particle size interval before mixing with normal quality lactose for tablet in a high energy mixer. Pour the mixture of powder in hard gelatin capsules No. 5 in a suitable encapsulator. The contents of the cartridges are administered using a powder inhaler.

j! "î l Γ j j; r“ II 'U- r p-'j i-lr u

Claims (11)

1. Compound of general formula (I) ^ L, —J CXXJ vh R “R 10 where“ j R represents a hydrogen atom or a C1 to G10 alkyl, a C3 to C7 cycloalkyl, a C3 to alkenyl C6, phenyl or phenyl C1 to C3 alkyl, and where 2 3 4 one of the groups represented by R, R and R is a hydrogen atom or C1 to C6 alkyl, a cycloalkyl at C3 to C7, a C2 to C6 alkenyl or a C1-C3 alkyl p-S-nyl and each of the other two groups, which may be similar or different, represents a hydrogen atom or an alkyl group in C1 to C6: 20 and its physiologically acceptable salts and solvates. 2. A compound according to claim 1 wherein R represents a hydrogen atom or a C1 to C6 alkyl, a C5 to C6 cycloalkyl or a C3 to ~ 06 alkenyl. 3. A compound according to claims 1 and 2 -2 3 4 wherein one of the groups represented by it, E and H represents a C1 to C3 alkyl group, C3 to C6 cycloalkyl or C3 to 06 alkenyl and each of the two au-30 very groups, which may be similar or different, "represents a hydrogen atom or a C1-C3 alkyl group. η 4. Compound according to claim 1, in which R represents a hydrogen atom or a C1 to C6 alkyl group, C5 to C6 cycloalkyl or C3 to C4 alkenyl 2% 3 and / or R represents a hydrogen atom and R ^ and / or R ^ represents a C1 to C3 alkyl group, or 2 x 3 v well R represents a C1 to C3 alkyl group and R 4. and R both represent atoms of hydrogen. 5 I .. _rV: R1 10 (where R is as defined in claim 1 and T - represents a reactive substituent) or one of its derivatives protected with an imidazole of general formula (III) 15 p4, 3 x _ / - <h ::; iIIi R2 ' R 2 3 4 (where R, R and R are as defined in claim 1) or a salt thereof; or (B) a compound of formula (IV) is oxidized 25 A ^ F.3 I N î: il · ;; kX.lJ Ύ R 30 (where A represents a hydrogen atom or a hy- i ?? Ί 2 X h droxyl group and R, R, R ^ and R are as defined in • s of claim 1) or a its protected salts or derivatives; or 35 (G) a compound of formula (I) or one of its protected salts or derivatives is transformed into another compound of formula (I); or (D) removing one or more protecting groups from a protected form of a compound of formula (I); And when the compound of formula (I) is obtained in the form of a mixture of enantiomers, the mixture is optionally split to obtain the desired enantiomer; and / or when the compound of formula (I) is in the form of a free base, optionally the free base is converted into a salt. 5. Compound of general formula (la): j J '"*" ’i - a. R, a R2a (where R ^ a represents a hydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or 5a cyclopentyl group; R ^ represents a hydrogen atom and 2 * either R ^ 3 represents a methyl, ethyl, pro- ^ 4 pyle or pro-2-yl group and R represents a hydro- 2a ~ - gene, or else R represents a hydrogen atom and ** 4a R represents a methyl or ethyl group; and its physiologically acceptable salts and solvates. 6 - 1,2,3,9-etrahydro-9-Eiethyl-5 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one and its salts and physiologically solvates acceptable 25 tables. 7 - 1,2,3,9-etrahydro-3 - [(2-methyl-1H-imida-zol-1-yl) methyl] -9- (p? Op-2-enyl) -4H-carbazol-4 -one; 9-Cyclopentyl-1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imida-zol-yl) methyl] -4H-c & rbazol-4-one: 1,2,5,9- Tetrahydro-3-L2-methyl-1H-imidazol-1-yl) methylj- ^ 9- (prop-2-yl) -4H-carbazol-4-one, v and their salts and physiological solvates- V. ment acceptable. 8. Process for the preparation of a compound of P5 general formula (I) as defined in the claim! -52-! ” tion 1 or of a salt or solvate thereof - physiologically acceptable, process in which:> (A) a compound of general formula (II) is reacted 9. The method of claim 8 (A) wherein Y represents an alkenyl group = 01 ^ or a group of formula CE ^ Z where Z represents an atom or group easily. 15 movable. 10. The method of claim 8 (C) wherein ** a compound of formula (I) or one of its *, protected derivatives is transformed into another compound of formula (I) by alkylation or hydrogenation. 20 11 - Pharmaceutical composition comprising at least one compound of general formula (I) as defined in claim 1 or one of its physiologically acceptable salts or solvates with at least one physiologically acceptable carrier or excipient. 1 Λ. /; \