NL8500202A - HETEROCYCLIC COMPOUNDS. - Google Patents

Description

* "1 -5 · 1 .¾ VO 7014

Heterocyclic compounds.

The present invention relates to heterocyclic compounds, to processes for their preparation, to pharmaceutical compositions containing these compounds and to their medical use. In particular, the invention relates to compounds that act on certain 5-hydroxytryptamines (5HT) receptors.

5HT, which is endogenous in abundance in peripheral nerves and platelets, is a known causative agent of human pain due to a specific action on 5HT receptors located at the ends of primary afferent nerves. The analgesic effect of compounds that counteract the neuronic effects of 5HT has been demonstrated, for example against migraine. 5HT also causes depolymerization of the vagus nerve preparations isolated from a rat by the same 5HT receptor mechanism, and inhibition of this effect is associated with an analgesic effect in vivo.

5HT is also common in neuron pathways in the central nervous system, and disruption in these 5HT-containing pathways is a known cause of changes in behavioral syndromes, such as mood, psychomotor activity, appetite and memory. Since neuron-20 5HT receptors of the same type as those present at the primary afferent ends are also present in the central nervous system, it is believed that compounds that counteract the neuronal effects of 5HT are useful for the treatment of conditions such as schizophrenia, anxiety, corpulence and mania.

Existing treatments for such conditions have a number of drawbacks. Known treatments for migraine include, for example, the administration of a vasoconstrictor such as ergotamine, which is non-selective and contracts blood vessels throughout the body.

Ergotamine therefore has unwanted and potentially dangerous side effects. Migraines can also be treated by administering a pain reliever such as aspirin or acetaminophen, usually in combination with an anti-emetic such as metaclopramide, but these treatments are 8500202 *. ί „* 2 are of limited value.

Likewise, existing treatments for psychotic confusions such as schizophrenia, exhibit some serious side effects such as extrapyramidal side effects.

There is therefore a need for a safe and effective drug for the treatment of conditions where interference from 5HT-containing pathways plays a role, such as migraine or psychotic confusion such as schizophrenia. It is believed that a compound which is a strong and selective antagonist on neurons 5HT receptors can fulfill such a role.

We have now found a group of 3-imidazolylmethyltetrahydrocarbazolones which are potent and selective antagonists at neurons 5HT receptors.

The present invention provides a tetrahydrocarbazolone of the general formula 1 of the formula sheet, wherein R * represents a hydrogen atom or a C 1-6 alkyl, C 1-6 cycloalkyl, C 1-6 alkenyl, phenyl or phenyl-C alkyl group, while one of the groups represented by R, RJ and R is a hydrogen atom or a C 1-8 alkyl, C 1-8 cycloalkyl, C 1-8 alkenyl or phenyl-C. alkyl group, and each of the other two Z-1-1-3 groups which may be the same or different represents a hydrogen atom or a C 1-8 alkyl group, and physiologically acceptable salts and solvates, such as hydrates thereof.

It will be clear that when R * represents a C 1-8 alkenyl group, the double bond may not be present next to the nitrogen atom.

With reference to the general formula 1, the alkyl groups represented by R1, R2, R3 and R4 may be either linear or branched alkyl groups, for example methyl, ethyl, propyl, prop-2-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.

For example, a phenyl-C 1-6 alkyl group may be a benzyl, phenethyl or 3-phenylpropyl group.

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

It will be appreciated that the carbon atom in the 3-position of the tetrahydrocarbazolone ring is asymmetric and may exist in 8500202 - * * * * *,! j 3 the R or S configuration. The present invention includes both the individual isomeric forms of the compounds of formula 1 and all mixtures thereof, including racemic mixtures.

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

A preferred group of compounds represented by the general formula 1 is that wherein R * represents a hydrogen atom or a

C 1-8 alkyl, cycloalkyl, or C 3-8 alkenyl group. j

Another preferred class of compounds represented by the general formula 1 is that, wherein one of the groups represented by R, R and R represents a C 1-3 alkyl, 5-cycloalkyl or alkenyl group, and each of the other two groups, which may be either the same or different, represents a hydrogen atom or a C 1-3 alkyl group.

A further preferred class of compounds represented by the general formula 1 is that wherein R * represents a hydrogen atom or a C 1-8 alkyl, C 8-8 cycloalkyl or C 3-8 alkenyl group, while either R 2 represents a hydrogen atom and R 3 and / or R4 represents an alkyl group 2 3 4 or R represents a and both R and R represent hydrogen atoms.

A particularly preferred class of compounds of the present invention is represented by the formula la of the formula sheet, wherein R * a represents a hydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl group, R represents a hydrogen atom and either R2a represents a methyl, ethyl, propyl or prop-2-yl group, and R4a represents a hydrogen atom or R2a represents a hydrogen atom, and R represents a methyl or ethyl group, as well as physiologically acceptable salts and solvates (such as hydrates) thereof. Preferred compounds are: 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-imidazcDl-1-yl) -methyl] -4H-carbazol-4-one; and 8500202 * Λ 4 1,2,3,9-tetrahydro-3- [2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazol-4-one and the physiologically acceptable salts and solvates thereof.

A more particularly preferred compound is 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazole-1-yl) methyl] -4H -carbazole-4-one, which compound may be represented by the formula Ib of the formula sheet, and its physiologically acceptable salts and solvates (such as hydrates). A preferred form of this compound is the hydrochloride dihydrate.

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

The compounds of the invention are strong and selective antagonists of 5HT-induced responses of the vagus nerve preparations isolated from the rat, and thus act as potent and selective antagonists of the neurons 5HT receptor type located on primary afferent nerves.

Compounds of the invention are useful as analgesics, for example, for the relief of migraine pain, headache and many other forms of pain for which 5HT is the endogenous mediator.

Animal experiments have also shown that compounds of the invention are also useful in the treatment of schizophrenia and other psychotic confusions. As noted above, 5HT is widely present in the neuron pathways in the central nervous system, and disruption of these 5HT-containing pathways is a known cause for alteration of many other behavioral syndromes such as mood, appetite and memory. Since neurons of 5HT receptors of the same type as di-e present on primary afferent ends are also present in the central nervous system, the compounds of the invention may also be useful in the treatment of conditions such as anxiety, obesity and mania.

In particular, compounds of formula la 35 as defined above are particularly selective and extremely potent in action. They are well absorbed from the gastrointestinal tract and 85 0 0 2 0 2 -v * «5 are suitable for oral or rectal administration. The compounds of formula la do not prolong sleep time in mice anesthetized with pentdbarbitone, indicating that there is no undesired interaction with drug metabolizing enzymes. Indeed, they show no effects on normal behavior, are non-toxic and show no undesirable effects in mice at doses up to 1 mg / kg intravenously.

The compound of formula Ib, like the excellent properties of compounds of formula la, shows no undesirable effects when the compound has been administered to humans.

In another aspect, the invention provides a method of treating a human or animal subject suffering from a condition caused by a disruption of neuron 5HT function. The invention therefore provides, for example, a method for the treatment of a human suffering from migraine or psychotic confusion such as schizophrenia.

Accordingly, the invention also provides a pharmaceutical composition containing at least one compund selected from 3-imidazolylmethyltetrahydrocarbazolone derivatives of general formula 1, its physiologically acceptable salts and solvates such as hydrates, adapted for use in human or animal medicines, and in a form brought for administration in any suitable manner.

Such compositions may be formulated in a conventional manner using one or more physiologically acceptable kare (s) - The compounds of the invention may be brought into a form suitable 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 be, for example, in the form of tablets or capsules made by known means using pharmaceutically acceptable carriers, such as binders (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (for example lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium 85 0 0 2 0 2 - ——— ^ s ^ · - tr · «6 trium starch glycollate); or wetting agents (e.g. sodium lauryl sulfate). The tablets may be coated using methods known above. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be in the form of a dry product which is made up with water or other suitable agent before use. Such liquid compositions can be prepared using known agents with pharmaceutically acceptable additives such as suspending agents (eg sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (for example lecithin or acacia) non-aqueous carriers (for example almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl p-hydroxybenzoate or sorbic acid). The compositions may also contain buffer salts, flavors, dyes and sweeteners as necessary.

Compositions for oral administration may also be suitably molded to effect a controlled release of the active compound.

For buccal administration, the compositions may be in the form of tablets or pellets formulated in a known manner.

The compounds of the invention may also be molded for parenteral administration by injection. Injection formulations may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous carriers and may contain formulating agents such as suspending agents, stabilizing agents and / or dispersing agents. It is also possible to present the active ingredient in powder form in order to prepare it with a suitable carrier, for example sterile pyrogen-free water, before use.

The compounds of the invention may also be formulated in rectal compositions, such as suppositories or retention enemas, which contain, for example, known suppository carriers such as cocoa butter or other glycerides.

85 0 0 2 0 2 f * <

7 I

In addition to the formulations described above, the compounds of the invention may also be in the form of a depot preparation. Such long acting formulations can be administered by implantation (for example, subcutaneous or intramuscular), or by intramuscular injection. The compounds of the invention can therefore be formulated with a suitable polymer or hydrophobic material (for example as an emulsion in an acceptable oil), or ion exchange resin or as sparingly soluble derivatives, for example as a sparingly soluble salt.

For administration by inhalation, the compounds of the invention are preferably administered in the form of an aerosol from a pressurized package or a nebulizer using a suitable propellant. Suitable propellants are, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by applying a valve delivering a metered amount.

Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator, may contain a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

A proposed dose of the compounds of the invention for administration to humans (from about 70 kg) is 0.05 to 20 mg, preferably 0.1 to 10 mg, of the active ingredient per unit dosage, which is, for example, 1 to 4 times can be administered per day. The dose will depend on the method of administration and the body weight of the patient. It is clear that it may be necessary to make routine dose deviations depending on the age and weight of the patient as well as the severity of the condition to be treated.

For oral administration, a dosage unit will generally preferably contain from 0.5 to 10 mg of the active ingredient.

A dosage unit for parenteral administration will preferably contain 0.1 to 10 mg of the active ingredient.

Aerosol formulations are preferably applied so that each metered dose or "puff" coming from a pressurized 8500202 aerosol container contains 0.2 to 2 mg of a compound of the invention, while each dose delivered via capsules and cartridges an insufflator or an inhaler, contains 0.2 to 20 mg of a compound of the invention. The total daily dose will be between 0.4 and 80 mg by inhalation. Administration can take place several times a day, for example from 2 to 8 times, for example, giving 1, 2 or 3 doses at a time.

The compounds of the invention may, 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, compounds of the general formula 1 and physiologically acceptable salts or solvated products or physiologically acceptable equivalents thereof can be prepared by the general methods outlined below.

According to a first general method (A), a compound of the general formula 1 or a physiologically acceptable salt or solvated product or a physiologically acceptable equivalent thereof can be prepared by reacting a compound of the general formula 2, which has the same meaning as defined above, and Y represents a reactive substituent, or a protected derivative 2 3 4 thereof with an imidazole of the general formula 3, wherein R, R and R have the same meaning as defined above, or a salt thereof.

25. Examples of compounds of formula 2 used such as starting material in the process (A) include compounds wherein Y represents a group selected from an alkenyl group or a group of the formula CH 2 Z wherein Z represents an easily removable atom or group such as a halogen atom, for example chlorine or bromine; an acyloxy group such as acetoxy, trifluoromethanesulfonyloxy, p- + 5 6 7 - toluenesulfonyloxy or methanesulfonyloxy; a group -NR RRX, wherein 5 6 7 R, R and R which may be either the same or different each have a lower alkyl, e.g. methyl, aryl e.g. phenyl or aralkyl, 5 6 e.g. benzyl, or R and R together with the nitrogen atom to which They are attached to form a 5- to 6-ring, for example a pyrrolidine ring, and X represents an anion such as a halide ion, for example 8500202 * 4 9 5 6 5 6 chloride, bromide or iodide; or a group -NR R where R and R have the same meaning as above, for example -N (CB3) 2

When Y represents the group = CH 2, the process may conveniently be conducted in a suitable solvent, examples of which are water, esters such as ethyl acetate, ketones such as acetone, or methyl isobutyl ketone; amides such as dimethylformamide; alcohols such as ethanol and ethers such as dioxane or tetrahydrofuran. It is also possible to use mixtures of these substances. The method comb can be performed at a temperature of, for example, 20 to 100 ° C.

When Y represents the group C 2 Z, wherein Z is a halogen atom or an acyloxy group, the process may conveniently be conducted in a suitable solvent, such as an amide, for example dimethylformamide, an alcohol such as methanol or industrial methylated alcohol, or a haloalkane, such as dichloromethane, and at a temperature from -10 to 150 ° C, for example 20 to 100 ° C.

The reaction of a compound of formula 2, where Y represents cis + 5 6 7 - group CH 2 Z, where Z is the grep -NR RRX, may conveniently be carried out in a suitable solvent such as water, an amide such as dimethylformamide, a ketone, for example acetone, or an ether, for example dioxane and at a temperature of 20 to 150 ° C.

The reaction comprising a compound of the formula 2, 5 6 where Y represents the group -C 2 Z, where Z is the group -NR R, may conveniently be conducted in a suitable solvent such as water or an alcohol, e.g. methanol or mixtures thereof , and at a temperature of 20 to 150 ° C.

According to another general method (8) a compound of the formula 1 can be prepared by oxidizing a compound of the formula 4, wherein A represents a hydrogen atom or a hydroxyl group and R, R, R and R the have significance given hereinbefore, or a salt or a protected derivative thereof.

The oxidation process can be carried out using known methods, while the reagents and reaction conditions must be chosen so as not to cause oxidation of the indole group. The oxidation is therefore preferably carried out using a mild oxidizer.

For oxidizing a compound of formula 4, 8500202 wherein A represents a hydrogen atom, suitable oxidizers 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-benzoquinone, selenium dioxide, a cerium (IV) oxidator such as cerium ammonium nitrate or a chromo-5 (Vl) oxidates, for example a solution of chromic acid in acetin (for example, Jones' reagent) or chromium trioxide in pyridine.

For oxidizing a compound of formula IV, wherein A represents a hydroxyl group, suitable oxidizers include quinones in the presence of water, for example, 2,3-dichloro-5,6-10 dicyano-1,4-benzoquinone or 2 3,5,6-tetrachloro-1,4-benzoquinone, ketones, for example acetone, methyl ethyl ketone or cyclohexanone, in the presence of a base such as aluminum t-butoxide, a chromium (IV) oxidator, for example a solution of chromic acid in acetone (eg, Jones reagent) or chromium trioxide in pyridine, an N-halosuccinimide, for example N-chlorosuccinimide or N-bromosuccinimide, a dialkyl sulfoxide such as dimethyl sulfoxide, in the presence of an activator such as N, N'-dicyclohexylcarbodiimide or an acyl halide such as oxalyl chloride or tosyl chloride, pyridine sulfurtrioxide complex, and a dehydrogenation catalyst such as copper chromite, zinc oxide, copper or silver.

Suitable solvents can be selected from ketones such as acetone or butanone, ethers such as tetrahydrofuran or dioxane; amides such as dimethylformamide, alcohols such as methanol, hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as dichloromethane and water or mixtures thereof.

The process is suitably carried out at a temperature from -70 to + 50 ° C. It is clear that the selection of the oxidator influences the preferred reaction temperature.

According to another general method (C), a compound of the formula 1 according to the invention or a salt or a protected derivative thereof can be converted into another compound of the formula 1 using conventional techniques. Such known techniques include alkylation, which can be performed at any location 1 2 in a compound of formula 1, where one or more of R and R represents a hydrogen atom, and hydrogenation, which can be used, for example, to convert an alkenyl substituent in an alkyl substituent. The term "alkylation" also includes the introduction of other groups, such as cycloalkyl or alkenyl groups. Thus, for example, it is possible to convert an 8500202 11 compound of the formula 1 wherein R * represents a hydrogen atom to * 1 into the corresponding compound wherein R is a C 1 -C 5 alkyl, C 1 -C y cycloalkyl, C 1 -C alkenyl or phenyl C. - - - alkyl group.

3-b 1 l-o

The above-mentioned alkylation reactions can be carried out using suitable alkylating agents selected from 9L & 3 from compounds of the formula RX where R represents a C 1-4 alkyl, a cycloalkyl, alkenyl or phenyl-C 1-6 alkyl, while X represents a leaving group such as a halide or an acyloxy group as defined above for Y or a sulfate of the formula (Ra) 2 · 10 The alkylation reaction may be carried out, for example, 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 of -20 to + 100eC, preferably 0 to 50eC.

Hydrogenation according to general method C can be carried out by conventional methods, for example by using hydrogen in the presence of a noble metal catalyst, for example palladium, Raney nickel, platinum, platinum oxide or rhodium. The catalyst can be applied to, for example, carbon, but it is also possible to use a homogeneous catalyst such as tris (tri-phenylphosphine) rhodium chloride. The hydrogenation will generally be 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 of -20 to 100 ° C , preferably 0 to 50 ° C.

It will be understood that in some of the transformations described above, the. necessary or desirable comb. are to protect certain sensitive groups in the compound in order to avoid undesired side reactions. Preferably, the protecting groups used in the preparation of compounds of formula 1 are groups which can be readily cleaved at an appropriate stage in the reaction sequence, most preferably at the final stage. For example, during some of the reaction sequences described above, it may be necessary to protect the keto group, for example, as a ketal or thioketal.

Thus, compounds of the general formula 1 can be prepared according to another general method (D), which is the removal. protecting groups of a protected form of a compound of the formula 1. Association of protecting groups can be accomplished using known techniques, such as those described in "Protective Groups in Organic Chemistry" Ed. J.F.W. McOmie (Plenum Press, 10 1973). A ketal such as an alkylene ketal group can therefore be removed by treatment with a mineral acid such as hydrochloric acid. The thio ketal group can be cleaved by treatment with a mercury salt, for example mercury chloride, in a suitable solvent such as ethanol.

The compounds of formula 1 can be converted into their physiologically acceptable salts using known methods. Thus, the free base of formula 1 can, for example, be treated with a suitable acid, preferably with an equivalent amount in a suitable solvent (e.g. aqueous ethanol).

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

Individual enantiomers of the compounds of the invention can be obtained by separation of a mixture of enantiomers (e.g. a racemic mixture) using known means such as an optically active separating acid; see, for example, "Stereochemistry of carbon compounds" by E.L. Eliel (McGraw Hill 1962) and "Tables of Resolving Agents" by S.H. Wilen.

Examples of optically active separating acids that can be used to form salts with the racemic compounds include the (R) and (S) forms of organic dicarboxylic acids and sulfonic acids such as tartaric acid, di-p-toluoyl tartaric acid, camphor sulfonic acid, and lactic acid. The resulting mixture of isomeric salts can be cleaved, for example by fractional crystallization, into the diastereoisomers and, if desired, the desired optically active isomer can be converted to the free base.

The above indicated method for preparing the compounds of the invention may be used as the last 8500202 13th main stage in the preparative order. The same general methods can be used for the introduction of the desired groups during an intermediate step in the stepwise formation of the desired compound and it will be appreciated that these general methods can be combined in different ways in such multistage processes. The order of the reactions in multistage processes should, of course, be chosen so that the reaction conditions employed do not affect groups in the molecule that are desired in the final product.

The starting materials of formula 2, wherein Y represents the group = CH 2, can be prepared from compounds of formula 2, + 5 6 7 - where Y represents the group CH 2 NR R R X, by reaction with a base in a suitable solvent. Examples of bases include alkali metal hydroxide such as potassium hydroxide or alkali metal carbonates or hydrogen carbonates such as sodium hydrogen carbonate.

The quaternary salts can be formed from the corresponding tertiary amine by reaction with an alkylating agent such as methyl iodide or dimethyl sulfate, if desired in a suitable solvent such as dimethylformamide. The tertiary amine can be prepared by reacting a tetrahydrocarbazolone of the general formula 5 with formaldehyde and the corresponding secondary amine, if desired in a suitable solvent such as an alcohol, for example ethanol.

»

Compounds of general formula 5 can be prepared, for example, by the method described by H. Iida et al., In 25 J. Qrg. Chem. (1980) vol. 45, No. 15, p. 2983-2942.

The starting materials of general formula 2, wherein Y represents a group -CH 2 Z, wherein Z represents a halogen atom or an acrylic oxy group, can be prepared from the corresponding hydroxy-methyl derivative of general formula 6, which can be obtained by reacting tetrahydrocarbazolone of general formula 5 with formaldehyde, preferably in a suitable solvent such as an alcohol, for example ethanol, and preferably in the presence of a base.

The compounds in which Z is a halogen atom can be obtained by reacting a compound of formula 6 with a halogenating agent, such as a phosphorus trihalide, for example phosphorus trichloride.

8500202 14

The compounds wherein Z is an acyloxy group can be prepared by reacting a compound of formula 6 with a suitable acylating agent such as an anhydride or a sulfonyl halide such as sulfonyl chloride.

Compounds of formula 2, wherein Y represents -CH_z where * Δ wherein Z is a halogen atom, may also be prepared by reacting a compound of formula 2, wherein Y represents the group “CH 2” with the appropriate hydrogen halide, for example hydrogen chloride, preferably in a suitable solvent such as an ether, for example diethyl ether.

Compounds of general formula 4 can be prepared by a compound of formula 7, wherein R * and A have the meanings given above and Z1 is an easily removable atom or a group such as a halogen atom, an acyloxy group or the group -NR ^ R ^ R ^ X as previously defined for Z *, represents reacting with an imidazole of the formula 3 according to the method of Method A described herein.

Compounds of formula 7 can be prepared by reducing compounds of formula 2 using, for example, lithium aluminum hydride or sodium borohydride.

Compounds of formula 7 wherein A represents a hydrogen atom may also be prepared by reacting a compound of formula 7 wherein A represents a hydroxyl group with a tosyl halide (eg tosyl chloride) followed by reduction of the resulting tosylate with lithium aluminum hydride.

Compounds of the formula IV are new compounds, and as such constitute a new further elaboration of the invention.

The following examples illustrate the invention. Temperatures are given in ° C. Where indicated, solutions are dried over sodium sulfate, and solids are dried in vacuo over P2 <0g at 50 ° C overnight. Chromatography was performed using the technique described by W.C. Still et al. (J. Org.

Chem., 1978, 43, 2923-2025) on silica gel 9385.

Preparation 1 35 2,3,4,9-Tetrahydro-NN, N-trimethyl-4-oxo-1H-carbazol-3-methanaminium iodide 85 0 0 2 0 2 Εβη ° ^ oss ^ n ^ of 3 - [( dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one (0.53 g) in iodomethane (15 ml) was heated under reflux for 5 hours and evaporated to dryness. title compound as a white solid (0.84 g), mp 202-205 °. Preparation 2 5 2,3,4,9-Tetrahydro-N, N, N, 9-tetramethyl-4-oxo-1H-carbazol-3-methanamine amino iodide

A suspension of 3 - [(dimethylamino) methyl] -1,2,3,9-te-trahydro-9-methyl-4H-carbazol-4-one (3.80 g) in iodomethane (100 ml) was refluxed stirred for 57 hours. The resulting suspension was concentrated in vacuo to give the title compound as a solid (5.72 g), mp 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) was treated with 2N sodium carbonate (6.55 ml) and heated at 35 ° for 45 minutes. The resulting slurry was cooled to 0 ° C and the solid filtered, washed with water and dried to give the title compound (2.8 g), mp 127-9 °.

Preparation 4 2.3.4.9- Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazole maleate

Sodium borohydride (90mg) was added under nitrogen to a stirred solution of the product of Example 7 (500mg) in a mixture of methanol (3ml) and chloroform (3ml). Stirred for 48 hours while sodium borohydride (250 mg) was added after 17.75 hours and 42 hours. The suspension was partitioned between 2N hydrochloric acid.

(15 ml) and chloroform (3 x 10 ml). The water layer was raised to pH with solid sodium carbonate, extracted with chloroform (3 x 10 ml) and the combined extracts 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 dichloro-0 methane, ethanol and 0.88 normal aqueous ammonia (300/10/1) gave 200 mg of a solid. This material was dissolved in reflux in the absolute ethanol (3 ml) and a solution of maleic acid (80 mg) in reflux in the absolute ethanol (1 ml) was added. The hot solution became 8500202 t

• I

16 filtered, stirred and diluted with dry ether (40 ml) to give the title compound (240 mg), mp 138.5-140 ° C.

Preparation 5 5 2,3,4,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazol-4-ol

The product of Example 7 (30.0 g) was fed under nitrogen to a stirred suspension of lithium aluminum hydride (7.75 g) in dry tetrahydrofuran (750 ml). The mixture was stirred under reflux for 1 hour and then cooled in ice. The suspension was diluted gently with aqueous tetrahydrofuran (15% H 2 O; 100 ml), and water (100 ml), concentrated in vacuo. The residual solid was extracted with dichloromethane (2 x 500ml). The organic extracts were concentrated in vacuo, and the residual solid 15 (16.4 g) was purified by short path column chromatography on silica (silica gel 60, Merck 7747, 500 g), eluting with a mixture of dichloromethane, ethanol and 0.88 normal aqueous ammonia (150/10/1) to give the title compound as a foam (13.4 g).

Thin layer chromatographies of silica, dichloromethane / ethanol / 0.88 NH ^ (150/20 10/1) Rf 0.34 and 0.36 (two pairs of diastereoisomers), detection u.v. and iodoplatinic acid.

N.m.r. S [CDCl ^ + CD ^ OD (1 drop)] 1.6 - 2.3 and 2.6 - 3.0 (5H, m), 2.32 and 2.40 (3H, s + s, Me in two different isomers), 3.32 (3H, s, NMe), 3.65 - 4.3 (2H, m, CHCH2N), 4.75 - 4.85 (1H, m, CH-OH), 6, 8-25 7.8 (CH, m, aromatic).

Example Ia 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-earbazole-4-one hydrochloride

A solution of the product of preparation 2 (2.0 g) and 2-methylimidazole (5.0 g) in dry DMP (30 ml) was stirred under nitrogen at 95 ° for 16.75 hours and the mixture was allowed to cool . The crystallized solid was filtered off, washed with ice cold dry DMF (3x2 ml) and dry ether (2 x 10 ml) and then dried. The resulting solid (0.60 g) was suspended in a mixture of absolute ethanol (30 ml) and ethanolic hydrochloric acid (1 ml) and heated gently to obtain a solution which was filtered hot 8500202 17. The filtrate was then diluted with dry ether to precipitate a solid (0.6 g) which was recrystallized from absolute ethanol to yield the title compound as a solid (0.27 g), the melting point of the substance was 186 - 187 ° C.

5 Analysis: G 61.9? H 6.4? N 11.8.

C18H19N3 ° HCl * H2 ° requires: C 62.3, H 6.1; N 12.1%.

The following compounds were prepared using a similar procedure as shown in Table 1.

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Note 1 to Table 1;

Compounds ie and if were prepared in the same experiment, and the isomers were cleaved by short path chromatography (DF Taber, J. Org. Chem., 1982, 47_ (1351), eluting with dichloro-5 methane / ethanol / 0 .88 NH 4 (300/10/1) The following 1 H nmr data were obtained (see also Formula 8).

10 TABLE 1a * H NMR SPECTRA (obtained at 250 MHz)

Some chemical shifts of protons (& ppta) and Solvents-Pll-ci-agents

Carbazolone Protons Imidazolyl Imidazole Protons ........ ...........- Methylene i —------ -

Aromatic Aliphatic Protons H-2 'H-4' and / or H-5,6,7,8 CH2-1 and CH2-2 H-5 'H-3 * 4,47 (dd)

Ie 7.2-8.05 2.91-3.25 1.75-2.3 and 9.20s 7.55s dg-DMSO '4.64 (dd) 4.02 (dd) 2f CDC13 7.15 -8.05 2.6-3.05 1.75-2.1 and 8.17s 6.93s + DMS0 4.63 (dd) inter alia 4.42 (dd) 7f61d

Ig 7.2-8.05 en - and d6-DMS0 2.9-3.3 1.6-2.2 4.73 (dd) 7r70d d = doublet dd = doublet of doublets s = singlet 8500202 20

Example II

1,2,3,9-Tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl) methyl 3 -4H-carbazol-3-one-maleate 1,2,3,9-Tetrahydro- 9-methyl-3- [(2-methylimidazol-1-yl) -5 methyl-4H-carbazol-4-one (300mg) was suspended in hot ethanol (5ml) and treated with maleic acid (116mg). The solution was cooled and the white crystalline solid filtered off and dried to give the title compound (300 mg), mp 132.3 ° C. Example lilac 10 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 dimethylformamide (25 ml) was heated at 105 ° C for 6 hours, cooled, added to water (200 ml) and six times with ethyl acetate extracted. The combined extract was washed, dried and evaporated to give a solid which was purified on a silica column (Merck 7734) and eluted with ethyl acetate / methanol (4/1). The title compound (0.095 g) was obtained after recrystallization twice from ethyl acetate / methanol, as a crystalline solid, mp 220-222 ° C.

20 Thin layer chromatography on silica, with dichloromethane / ethanol / 0.88 ammonia (100/8/1): Rf 0.33, detection: u.v. and iodoplatinic acid.

The following compounds were prepared using a similar method as shown in Table 2. The salt formation was performed as described in Example II.

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t

S

8500202 22]

Note 1 to Table 2 continued

In the table, the locations of the protons are numbered with reference to formula 8.

The symbols have the same meaning as in table 1a, 5 while γ is the group represented by formula. 9.

Example IV

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

A solution of 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (1.0 g) in dry DMF (10 ml) was added dropwise under nitrogen to a stirred ice-cooled suspension of sodium hydride (80% in oil; 0.11 g) in dry DMF (5 ml). After 1 hour, dimethyl sulfate (0.34 ml) was added and the solution was stirred at room temperature for 4 hours. The resulting solid was filtered, washed with ice cold dry DMF (2x5ml) and dry ether (3x15ml) and dried to give the title compound as a solid (0.25g), mp 223 -, 224eC (dec.).

20 Thin layer chromatography on silica, with chloroform / methanol (93/7): Rf 0.27; detection u.v. and iodoplatinic acid, identical to the product of Example 1a. The following compounds were prepared using a similar procedure using the appropriate alkylating agents, as detailed in Table 3.

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Note 1 buttock Table 3:

The following 'H n.m.r. data was obtained with reference to Formula 8.

Table 3a 'H NMR SPECTRA (obtained at 250 MHz)

Solvent chemical shifts of protons (ppm) and ^ multiplicity

CarbazoLon Protons Imidazolyl Imidazol Protons —......... --Γ .......... —..... .....— Methylene -----

Aromatic Aliphatic Protons H-2 'H-4' and / or H-5,6,7,8 CH2-1 and CH2-2 H-5 'H-3 6.29 (dd) 7.55d IVg 7.15 -8.1 2.9-3.2 1.9-2.2 and - and c! $ - rMSC 6.68 (dd) 7.65d 6.26 (dd) 7.42d 7.2-8, 1 2.9-3.3 1.8-2.2 and - and d6-D! *! S0 6.85 (dd) 7.57d d = doublet dd = doublet of doublets s = singlet 8500202 25

Example V

9-Cyclopentyl-1,2,3,9-tetrahydro-3- [(2-methyl-1H-imidazol-1-yl) methyl] -4B-carbazole-4-one maleate

A solution of 1,2,3,9-tetrahydro-3 - [(2-methyl-1B-5 imidazol-1-yl) methyl] -4H-carbazol-4-one (1.20 g) in dry dimethyl formamide (9ml) was added to a stirred, ice-cooled, suspension of sodium hydride (80% in oil; 0.14g) in dry dimethylformamide (2ml) under nitrogen, and stirring was continued for 0.25 hours continued. 0.51 ml of bromocyclopentane was added and the stirred solution was heated at 100 ° C for 18.5 hours. The solution was allowed to cool and partitioned between water (100ml) and ethyl acetate (3 x 70ml). The combined organic extracts were washed with 2N sodium carbonate (2 x 50ml), water (2 x 50ml) and brine (50ml), dried, evaporated and purified by chromatography eluting with a mixture of dichloromethane, ethanol 0.88 ammonia (150 / 10/1) to give 0.27 g of an oil. This oil was dissolved in refluxing absolute ethanol (7 ml) and a solution of maleic acid (0.10 g) in refluxing absolute ethanol (0.5 ml) was added. The hot solution was filtered, stirred and diluted with dry ether (20 ml). The resulting yellow gum was washed with dry ether (7 x 25 ml), and the combined mother liquors and washes were left to stand. The solid which crystallized from the solution was filtered off, washed with dry ether (3x5 ml) and dried to give the title salt as a white crystalline solid (0.058 g), mp 104.5-25 106 ° C.

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

C22H25N3 ° C4H404 "0.6H2 O requires: c 65-8 H 6.4; N 8.9%.

Example VI

1,2,3,9-Tetrahydro-3- [(2-methyl-1H-imidazol-1-yl) methyl 3 -9- (2-propenyl) -30 4H-carbazole-4-one maleate

A solution of 1,2,3,9-tetrahydro-3 - [(2-methyl-1B-imidazol-1-yl) methyl] -4H-carbazol-4-one (1.0 g) in dry dimethylformamide (6 ml) was added to a stirred ice-cooled suspension of sodium hydride (80% in oil; 0.12 g) in dry dimethylformamide 35 (2 ml). After 0.25 hours, allyl bromide was added, the solution was stirred at 0 ° C for 0.25 hours and at room temperature for 20 hours. 8500202) 26

Before the solution was partitioned between water (75 ml) and ethyl acetate (3 x 50 ml). The combined organic extracts were washed with water (2 x 50 ml), brine (50 ml), dried, and concentrated in vacuo and purified by chromatography eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous. ammonia (200/10/1) to yield a solid (0.43 g). This solid was dissolved in reflux in the absolute ethanol (2 ml) and a solution of maleic acid (0.18 g) in refluxing absolute ethanol (1 ml) was added.

The hot solution was filtered, diluted with dry ether (4ml) and the crystallized solid was filtered off, washed with dry ether (3x5ml) and dried to give the title compound as a solid (0.48g). The melting point was 150.5 - 151 ° C.

Analysis found: C 66.3; H 5.75; N 9.6.

C, nH, S, 0.C.HO. Requires: C 66, 2; H 5.8; N 9.65%.

20 21 3 444 15 Example Vil 1.2.3.9- Tetrahydro-9-methyl-3-f (2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

A solution of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one hydrochloride (1.7 g) in water 20 (17 ml) was treated with 2-methylimidazole (1.4 g) and then heated under reflux for 20 hours. The cooled mixture was filtered and the residue washed with water (3 x 15 ml) to obtain a crude product (1.7 g), mp 221-221.5 ° C. This material was recrystallized from methanol to give the title compound (1.4 g), mp 231-232 ° C. This product was identical to the product of Example IV according to the low chromatography.

Example VIII

1.2.3.9- Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one 30 A suspension of the product of preparation 3 (0.5 g ) and 2-methylimidazole (0.4 g) in 5 ml of water was heated under reflux for 20 hours. The cooled reaction mixture was filtered and the residue washed with water (3 x 10ml), dried and recrystallized from methanol (18ml) to give the title compound (0.3g), mp -322-234 ° C ( decomposition), which product was identical to the product of Example IV by thin layer chromatography.

8500202 4 27

Example IX

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

An 80% oil dispersion of sodium hydride (0.208 g) 5 was added to a stirred solution of 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H -carbazole-4-one (1.93 g) at 0 ° C in 35 ml DMF, after which the resulting suspension was stirred at 0 ° C for 0.25 hours. 2-Bromopropane (0.78 ml) was then added and stirred at room temperature overnight. Then 10 was stirred at 40 ° C for 4 hours.

The reaction mixture was partitioned between sodium carbonate (2N; 200ml) and ethyl acetate (2 x 150ml). The combined organic extracts were washed with 3 x 75 ml water, dried and evaporated in vacuo, after which the product was purified by chromatography eluting with dichloromethane / ethanol / ammonia (100/8/1) to give an oil. This oil was dissolved in 3 ml of ethanol, acidified with a hydrochloric acid solution in ether and diluted with dry ether to precipitate the title compound as a solid (0.13 g), mp 230-232 ° C.

Analysis found: C 65.3; H 6.6; N 11.1%.

C20H23N3O.HC1.0.5H2O requires: C 65.4; H 6.9; N 11.45%.

Example X.

1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4-one hydrochloride dihydrate 1,2,3, 9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-25-yl) methyl] -4H-carbazol-4-one (18.3 g) in a hot mixture of isopropanol (90 ml) and water (18.3 ml) treated with concentrated hydrochloric acid (6.25 ml). The hot mixture was filtered and the filtrate was diluted with 90 ml of isopropanol and stirred at room temperature for 17 hours; the product was cooled to 2 ° C and the solid filtered off (21.6 g). A sample (6 g) was recrystallized from a mixture of 6 ml of water and 10 ml of isopropanol to give the title compound as a white crystalline solid (6 µg, melting point 178.5 -179.5 ° C).

Analysis found: C 59.45; H 6.45; N 11.5.

C12 H19 N3 O · HC1.2H2 O requires: C 59.1; H 6.6; N 11.5%.

Water content found: 10.23%.

8500202 28 i C18H19N3 ° * HCl * 2H2 ° required 9/85%.

Example XI

1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) -methyl-9-phenyl-4H-carbazole-4-one-inalate 5 '!) 3- [ (Dimethylamino) methyl] -1,2,3,9-tetrahydro-9-phenyl-4H-carbazole-4-one hydrochloride

A solution of 1,2,3,9-tetrahydro-9-phenyl-4H-carbazole-4-one (3.90 g of dimethylamine hydrochloride (1.50 and paraformaldehyde (0.60 g) in glacial acetic acid was reflux stirred for 42 h on nitrogen, then the product was allowed to cool then concentrated in vacuo The remaining brown gum was stirred with 50 ml of water, 50 ml of ethyl acetate and 20 ml of brine for 0.25 h after which the remaining solid The substance was filtered off, washed with 4 x 30 ml dry ether and dried to give the title compound (4.2 g). Part of this solid (1.0 g) was recrystallized twice from absolute ethanol. (10 ml) to provide the title compound as a tan powder (0.39 g), mp 193-194 ° C (decomposition).

ii) 1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl 3-9-phenyl-4H-carbazole-4-one maleate 2-Methyl-1H- imidazole (1.4 g) was added under nitrogen to a stirred suspension of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-phenyl-4H-carbazole-4-one hydrochloride (2 .0 g) in water (20 ml). The mixture was heated at 90 ° C for 43 hours and the solvent was poured off the tan solid. Chloroform was added to the solid, the suspension was filtered through hyflo, the filtrate was dried and concentrated in vacuo. Chromatography of the remaining tan brown foam (2.04.04 g) eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (200/10/1) gave a white foam (1.1 g). A solution of this foam in ethanol (3 ml) was treated with maleic acid (0.4 g) in ethanol (1 ml) followed by dry ether (40 ml) and the remaining gum was triturated with 2 x 40 ml dry ether to provide the title compound as a cream-colored solid (1.37 g), mp 165-166 ° C (decomposition).

Analysis found: C 68.65; N 5.5; N 8.7.

C0_H-.N.O.C.B.0. requires: C 68.8; N 5.3; N 8.9%.

23 21 3 444 8500 202 29

Example XII

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-1H-imidazol-5'-yl) methyl] -4H-carbazol-4-one (0.61 g) was dissolved in a hot mixture of phosphoric acid (90%, 0, 13 ml) and water (10 ml), filtered through hyflo and crystallized to give the title compound (0.5; g), mp 225 ° C.

Analysis found: C 55.1? H 5.6; N 10.55.

10 C18HigN30.H3PO4 requires: C 55.2; H 5.7; N 10.7%.

Example Kill 1,2,3> 9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4-one citrate (2 ': 1) 1.2.3.9- Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-15 yl) methyl] -4H-carbazol-4-one (0.89 g) was dissolved in hot solution of citric acid (0.58 g) in 20 ml of ethanol and then crystallized. The resulting crystalline solid was recrystallized by dissolving it in acetone / water (2: 1.2 ml) and diluting with 20 ml of acetone to give the title compound (0.6 g), mp 162 ° C.

Example XIV

1.2.3.9- Tetrahydro-3- [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride 0.75 ml Methane iodide was added to a stirred solution of 3- [(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one (2 ', 9 g) in dry DMP (30 ml), and the solution was stirred at room temperature for 30 minutes. A solution of 2-propyl-1H-imidazole (2 g) in 5 ml DMF was added, and the solution was 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 were washed with 100 ml of water, dried, and evaporated to dryness in vacuo. The residue was 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) was dissolved in absolute ethanol (5 ml), acidified with a solution of hydrochloric acid in ether and diluted with dry ether (ch. 200 ml) to give an oil of 8500202. After scratching, the oil crystallized to a solid (0.15> g). The salt was crystallized from a mixture of methanol and isopropyl acetate to give the title compound (0.08.0 g), mp 206-208 eC.

5 Analysis found: C 65.6; H 6.8; N 12.0.

C19H21N30, HCl ° -2H2 ° required 65'7 '* H 6.5} N 12.1%.

N. m.r. S (CD3SOCD3) 0.94 (3H, t, CH3), 1.77 (2H, sextet, CH2CH2CH3), 1.9 - 2.15 and 2.95 - 3.2 (7S, m), 4.32 and 4.71 (2H, ABX, CHCH2N), 7.1-8.0 (6H, aromatic).

Example XV

1,2,3,9-Tetrahydro-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4-one hydrochloride * |

A solution of the product of Example III (0.03 g) in 15 ml of methanol was hydrogenated at room temperature and normal pressure over a 10% palladium oxide on carbon catalyst (50% aq. Paste, 0.03 fg ) for 4 hours (H2 uptake, 5 ml). The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo to yield an oil. Trituration with ether gave the title compound as a white solid (0.03 sg), mp 199-203 ° C.

According to thin layer chromatography and n.m.r., this product was identical to the product of Example XIV. j

Example XVI

1,2,3,9-Tetrahydro-9-propyl-3 - [(2-propyl-1H-imldazol-1-yl) methyl3-45-carbazole-4-one hydrochloride

An 80% dispersion in oil of sodium hydride was added under J

Nitrogen was added to a stirred solution of the product of Example XIV (1.0 µg) in 20 ml of dry DMF, and the suspension was stirred at room temperature for 30 minutes. 1-Bromopropane (0.35 ml) was added, and the solution was stirred at 40 ° C for 20 hours. The solution was partitioned between sodium carbonate (2N, 150ml) and ethyl acetate (2 x 100ml). The combined extracts were washed with water (100 ml), dried and evaporated in vacuo to give an oil. The oil was purified by column chromatography, eluting with dichloromethane: ethanol: ammonia (100: 8: -1) to give the pure free base as an oil. The oil was dissolved in 5 ml absolute ethanol, acidified with a solution of hydrochloric acid in ether and diluted with 8500202 t 31 with 200 ml dry ether. The ether was decanted from the residual oil and replaced with more dry ether (20 ml). When stored at 0 ° C overnight, the oil crystallized to yield the title compound (0.53> g), mp 144-147 ° C.

5 N.m.r. & (CD3SOCD3) 0.90 and 0.93 (6H, t + t, 2 x Me), 1.65 - 2.2 and 2.9 - 3.25 (1ÜH, a), 4.19 (2fi, t, CH2CH2N), 4.32 and 4.71 (2H, ABX, CH2CH2; N), 7.15-8.1 (6E, m, aromatic)

Analysis found: C 66.6; H 7.7; N 10.0.

C22H27N3O.HC1.0.7H2O requires: C 66.3; H 7.4; N · 10.5%.

Example XVII · 1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9-propyl-4H-carbazole-4-one maleate

A solution of the product of Example VI (01.86; g), in a mixture of 20 ml of absolute ethanol and 5 ml of dry DMF, was hydrogenated at room temperature and normal pressure over a 5% platinum-on-carbon catalyst (0.1 g, pre-reduced in 10 ml of absolute ethanol) for 1 hour. (H2 uptake = 70 ml). The catalyst was filtered off, washed with ethanol, and the filtrate concentrated in vacuo to about 15 ml. The remaining solution was stirred, diluted with 50 ml of water and the precipitated solid was filtered off, washed with 3 x 15 ml of water and dried, yielding a powder (0.73 g).

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

Analysis found: C 65.8; B 6.1; N 9.3; C2qH23N30.C4H4 O4 requires: C 65.9; H 6.2; N 9.6%.

Example XVIII

1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-1midazol-1-yl) methyl] -4H-carbazol-4-one (ii) 3- (Chloromethyl) - 1,2,3,9-Tetrahydro-9-methyl-4H-carbazol-4-one 3.0 ml Hydrochloric acid in ether was added to a stirred ice-cooled solution of the product of preparation 3 (1 ', 90 g ) 35 in 15 ml of chloroform, and the resulting suspension was stirred in a sealed vessel at room temperature for 16.5 hours, concentrated in vacuo 8500202 µl 32 and the residual solid (2.27 g) was purified by means of column chromatography, elution with chloroform to give 1.75 g of the title compound (mp 109-110.5eC). An attempt to un-crystallize some of this material from ethyl acetate resulted in partial decomposition.

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

A solution of 3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (0.50 g) and 2-methyl-1H-imidazole (1.60 g) in dry DMF was stirred under nitrogen at 90 ° C for 3.75 hours and then poured into water (25 ml). The suspension was stirred for 1 hour, and the solid filtered off, washed with 3 x 20 ml water and dried in vacuo at 50 ° C. Column chromatography on this solid (0.53 g), eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (150: 10; 1) gave 0.45 g of the title compound, mp 228-229 ° C). According to thin layer chromatography and n.m.r. this material was identical to the product of Example VII.

Example XIX

1.2.3.9- Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl3-4H-20 carbazol-4-one

A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (170 mg) in dry tetrahydrofuran (1.5 ml) was added dropwise under nitrogen to a stirred, ice-cooled suspension of the product of preparation 4 (100 mg) in a mixture of 3.5 ml tetra-25 hydrofuran and 0.4 ml water. The resulting blue solution was stirred for 1.5 hours and then concentrated in vacuo. Colon chromatography of the obtained solid, elution with a mixture of dichloromethane, ethanol and 0.88 ammonia (150: 10: 1) gave 45 g of the title compound (mp 227-228.5 ° C). According to thin layer chroma-30 tography and n.m.r. this material was identical to the product of Example VII.

Example XX

1.2.3.9- Tetrahydro-9-methyl-3 - [(2-methyl-1H-1midazol-1-yl) methyl3-4H-carbazol-4-one 35 A solution of 2,3-dichloro-5,6-dicyano 1,4-benzoquinone (80 mg) in dry tetrahydrofuran (1, 5 ml) was added dropwise under nitrogen to a stirred ice-cooled suspension of the product of preparation 5 (100 mg) in a mixture of 3 .5 ml of tetrahydrofuran and 0.4 ml of water were added. The resulting blue solution was stirred for 1.5 hours and then the red suspension was concentrated in vacuo.

Column chromatography, eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (150 s 10 s) of the resulting solid, afforded the title compound as a white solid (0.47 g), mp 227, 5-229 ° C. This material is identical to the product of Example Vil by thin layer chromatography and n.m.r.

10 Example XXI

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

A solution of the product of Example VII (0.5 g) was dissolved in hot methanol (30 ml) and treated with a hot solution of (i +) - di-p-toluoyl-D-tartaric acid monohydrate ( Q ', 7 g) in 10 ml of methanol, and the resulting solution was allowed to crystallize overnight to yield the desired salt (0.68 g). This salt was dissolved in hot dimethyl formaldehyde (DMF, 20 ml), diluted with 10 ml of hot water and crystallized overnight. The product was filtered off and dried in vacuo to give approximately 90% enantiomerically pure (by nmr) (> +) - di-p-toluoy 1-D-tartaric acid salt (0.23 g), mp 231-233 ° C ,supply. A sample of the salt (0.15 g) was partitioned between 8% sodium bicarbonate (25 ml) and chloroform (2 x 25 ml). The combined extracts were dried and evaporated to dryness in vacuo to give the pure free base (0.07 g). The base was dissolved in 5 ml of methanol, acidified with 0.03 g of maleic acid, and the salt was precipitated by adding excess dry ether (80 ml) to yield 0.062 g of the title compound (mp 142-145e: C ).

30 Thin layer chromatography; silica; dichloromethane / ethanol / 0.88 ammonia (10; 8::): Rf 0.3

Detection u.v. and iodoplatinic acid, identical to the product of Example VII. The enantiomer ratio according to proton n.m.r. 93: 7 (S: R). A sample of the maleate salt showed no significant optical rotation in methanol. The free base regenerated from the maleate salt gave [α] 14-14 (c 0.19, MeOH).

8,500 202 34

Example xxil 3R-1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-1-midazol-1-yl) methyl] -4H-carbazole-4-one maleate

A solution of the product of Example VII (0.5 g) 5 was dissolved in 30 ml of methanol and treated with a hot solution of 0-) di-p-toluoyl-L-tartaric acid monohydrate (0.7 g) in 10 ml of methanol and the resulting solution were crystallized overnight to give the desired salt (0.8 g). This salt was dissolved in hot dimethyl fozamide (20 nd), diluted with 10 ml of hot water and crystallized for 3 days. The product was filtered off and dried in vacuo to give about 95% enantiomerically pure (by nmr) (t -) - di-p-toluoy 1-L-tartaric acid salt (0.26 g), mp 170-172 ° C to deliver. A sample of the salt (0.2 ') was partitioned between 8% sodium bicarbonate (25ml) and chloroform (2 x 25ml). The combined extracts were dried and evaporated in vacuo to yield 0.12 g of the pure free base. The base was dissolved in 5 ml of methanol, acidified with 0.045 g of maleic acid, and the salt precipitated by adding excess dry ether (80 ml) to yield 0.08 g of the title compound (mp 142-145 ° C).

20 Thin layer chromatography; silica; dichloromethane / ethanol / 0.88 ammonia (100/8/1) Rf 0.3

Detection u.v. and iodoplatinic acid, identical to the product of Example VII. The enantiomer ratio according to proton n.m.r. 95: 5.

A sample of the maleate salt showed no significant optical rotation in methanol. The free base regenerated from the maleate salt gave 24 [a] + 16 ° (c 0.34, MeOH).

The following examples illustrate pharmaceutical compositions of the invention which, as active ingredient, 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole -30 containing 4-on hydrochloride dihydrate (1.25 g of the hydrochloride dihydrate contains 1.00 g of the free base). Other compounds of the invention can be formulated in a similar manner.

Tablets for oral administration

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

The tablets may be coated with a suitable coating using suitable materials, such as hydroxypropyl methylcellulose using standard methods. It is also possible to coat the tablets with sugar.

Direct pressing 5 Tablet mq / tablet active ingredient 4,688 28,125 calcium hydrogen phosphate BP * 83.06 87.75 croscarmellose sodium NF 1.8 1.8 magnesium stearate BP 0.45 0.45 10 press weight 90.0 118.0 χ suitable for direct pressing .

The active ingredient was sieved through a sieve with 0.25 mm (60 mesh) sieve openings, mixed with the calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. The resulting mixture was pressed into tablets using a Manesty-F3 tableting machine fitted with 5.5 mm flat beveled stamps.

Sub-lingual tablet mg / tablet active ingredient 2.5 compressible sugar NF 62.5 20 magnesium stearate BP 0.5 press weight 65.0

The active ingredient is sieved with a suitable screen, mixed with the carriers and compressed using suitable stamps. Tablets of other strengths can be prepared by changing either the active ingredient to carrier ratio, or the press weight, using stamps suitable therefor.

Wet granulation

Ordinary tablet mg / tablet 30 active ingredient 2.5 lactose BP 151.5 starch BP 30.0 pre-gelatinized corn starch BP 15.0 magnesium stearate BP 1.5 35 press weight 200.0 8500 202 36

The active ingredient is sieved using a | suitable sieve and mixed with lactose, starch and pre-gelatinized corn starch. Appropriate amounts of purified water are added and the powders are granulated. After drying, the granulate is sieved and mixed with magnesium stearate. The granulate is dam pressed into tablets using 7 mm diameter punches.

Tablets of other strengths can be prepared by changing the ratio of the active ingredient to lactose, or the press weight, using suitable stamps.

10 Sub-lingual tablet mg / tablet active ingredient 2.5 mannitol BP 56.5 hydroxypropylmethylcellulose 5.0 magnesium stearate BP 1.5 15 press weight 65.5

The active ingredient is sieved through a suitable sieve and mixed with the mannitol and hydroxypropylmethylcellulose. Appropriate amounts of purified water are added and the powders are granulated. After drying, the granulate is screened and mixed into tablets using suitable punches.

Tablets of other strengths can be prepared by changing the active ingredient to mannitol ratio or the press weight, using suitable stamps.

Capsules mg / capsule 25 active ingredient 2.5 x starch 1500 97.0 magnesium stearate BP 1.0 fill weight 100.0 χ directly pressable starch 30 The active ingredient is sieved and mixed with the carriers. The mixture is filled into No. 2 hard gelatin capsules using an appropriate device. Other doses can be prepared by changing the fill weight and if necessary changing the capsule size.

8,500 202 37

Syrup

This can be either a sucrose or a sucrose-free form.

A. Sucrose syrup mg / 5 ml dose 5 active ingredient 2.5 sucrose BP 2750.0 glycerol BP 500.0 buffer) flavoring) as necessary 10 color:) preservative) agent) purified water BP up to 5.0 ml

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

20 B. Sucrose-free mg / 5 ml dose of active ingredient ^ 2.5

hydroxypropylmethyl cellulose USP

(viscosity type 4000) 22.5 buffer i) 25 flavor ') colorant ·) preservative if necessary) sweetener:) purified water BP to 5.0 ml 30 The hydroxypropylmethylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution which contain the active ingredient and the other components of the composition. The resulting solution is made up to volume and mixed, the syrup is clarified by filtration.

35 Injection

The injection can be administered intravenously or subcutaneously.

8,500 202 38

Injection, µg / ml active ingredient 50 800 dilute hydrochloric acid BP BP to pH 3.5 to pH 3.5 sodium chloride injection BP to 1 ml to 1 ml 5 The active ingredient was dissolved in an appropriate amount of sodium chloride injection BP, the The pH of the resulting solution was adjusted to 3.5 with dilute hydrochloric acid BP, after which the solution was made up to volume with sodium chloride injection BP and mixed thoroughly. The solution was placed in a type 1 clear glass 10 ampoule sealed with a free air space, by melting the glass, after which the ampoule was sterilized by autoclaving at 120 ° C for no less than 15 minutes.

Dose dose of pressure aerosol

Suspension aerosol mg / metered dose per container 15 active ingredient micronized 0.250 66 mg oleic BP BP 0.020 5.28 mg trichlorofluoromethane BP 23.64 5.67 g dichlorodifluoromethane BP 61.25 14.70 g 20 The active ingredient is micronized in a "fluid energy mill" to very fine particles. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C, and the micro-drug is mixed into this solution using a high shear mixer. The slurry is metered into aluminum aerosol containers and suitable metering valves delivering 85 mg of the suspension are shrunk onto the containers and the dichlorodifluoromethane is pressurized into the containers.

Aerosol solution mg / metered dose per container 30 active ingredient 0.25 30.0 mg ethanol BP 7,500 1.80 g trichlorofluoromethane BP 18.875 4.35 g dichlorodifluoromethane BP 48.525 11.65 g oleic BP, or a suitable surfactant such as Span 85 (sorbitol trioleate) can also be used.

8500202 ll 39

The active ingredient is dissolved in ethanol together with the oleic acid or surfactant when used. The alcoholic solution is measured in suitable aerosol containers followed by the trichlorofluoromethane. Suitable trim valves are crimped onto the containers and dichlorodifluoromethane is introduced into the containers under pressure through the valves.

Inhalation cartridges mg / cartridge active ingredient (micronized) 0.5 10 lactose BP to 25.00

The active ingredient is micronized in a "fluid energy mill" to very small particles before being mixed with a normal tableting type lactose in a high energy mixer. The powder mixture is placed in No. 3 hard gelatin capsules using a suitable encapsulation device The contents of the cartridges are administered using a powder inhaler 1 8500202 ♦

Claims (11)

A compound of the general formula 1, wherein R 1 represents a hydrogen atom or a C 1-8 alkyl, C 1-4 cycloalkyl, C 1-6 alkenyl, phenyl or phenyl-C. alkyl group, while 3-7 3-0 2 3 4 ^ is one of the groups represented by R, R and R is a hydrogen atom 5 or a C 1-8 alkyl, C 1-6 cycloalkyl, C 2-8 alkenyl or a phenyl-C 8 alkyl group, and any of the other two groups which may be either the same or different, represents a hydrogen atom or a C 1-8 alkyl group, and physiologically acceptable salts and solvates thereof. A compound according to claim 1, wherein R represents a hydrogen atom or a C 1-8 alkyl, C 1-8 cycloalkyl or C 1-8 alkenyl group. A compound according to claim 1 or 2, wherein one of the 2 3 4 groups represented by R, R and R represents a C 1-3 alkyl, C 3-8 cycloalkyl, or C 1-8 alkenyl group and any of the other two groups thus, the same or different can be a hydrogen atom and represents a C - alkyl group. A compound according to claim 1, wherein R represents a hydrogen atom or a C 1 -alkyl, C 1 -cycloalkyl or C 1 -alkenyl-2 1-6 b-b 3 group and either R represents a hydrogen atom and R and / or R represents a C1-8 alkyl group or R represents a C1alkyl group and both R4 and R represent hydrogen atoms. A compound of the general formula la, wherein Ria represents a hydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl group; R ^ a represents a hydrogen atom, and either R2a represents a methyl, ethyl, propyl or propa 4a 2a 2-yl group and R represents a hydrogen atom or R represents a hydrogen atom and R represents a methyl or ethyl group and physiologically acceptable salts and solvates thereof. 6. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-30-yl) methyl] -4H-carbazol-4-one and its physiologically acceptable salts and solvates . 7. 1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-enyl) -4H-carbazol-4-one, 8500202 X 41 9-cyclopentyl-1,2,3,9-tetrahydro-3- [(2-methyl-1H-imidazol-yl) methyl 3 -4H-carbazol-4-one, 1,2,3,9-tetrahydro -3- [2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazol-4-one 5 and physiologically acceptable salts and solvates thereof. A process for the preparation of a compound of the general formula 1, as defined in claim 1 or a physiologically acceptable salt or solvate thereof, which process comprises: A) reacting a compound of the general formula 10, wherein R 1 is the has definition, as in claim 1, and Y represents a reactive substituent or a protected derivative thereof, having an imlda 2 3 4 sole of the general formula 3, wherein R, R and R have the meaning given in claim 1, or a salt thereof; or ®) oxidizing a compound of formula 4, 1 2 15 wherein A represents a hydrogen atom or a hydroxyl group, and R, R, 3 4 R and R have the same meaning as in claim 1, or a salt or a protected derivative thereof; or C) converting a compound of the general formula 1 or a salt or a protected derivative thereof into another compound of the formula 1; or> D) removing a protecting group or groups * of a protected form of a compound of the formula 1; and in case a compound of formula 1 has been obtained as a mixture of enantiomers, optionally cleaving the mixture to obtain the desired enantiomer; and / or in case the compound of formula 1 is in the form of a free base, optionally converting the free base to a salt. 9. Process according to claim 8, characterized in that Y represents an alkenyl group (= CH 2) or a group of the formula CH 2, wherein 2 Z represents an easily removable atom or group. 10. Process according to claim 8, characterized in that a compound of formula 1 or a salt or a protected derivative thereof is converted into another compound of formula 1 by alkylation or hydrogenation. 11. Pharmaceutical composition comprising at least one 8500202 ** X-I? A compound of the general formula 1 as defined in claim 1 or a physiologically acceptable salt or solvate thereof, together with at least one physiologically acceptable carrier. 1 8500202