SE460359B - 3-IMIDAZOLYLMETHYLTRAHYDROCARBAZOLONES, PROCEDURES FOR PREPARING THESE AND A PHARMACEUTICAL COMPOSITION - Google Patents

Description

460 559 2 is a potent and selective antagonist to neuronal 5HT receptors fulfilling this purpose.

A group of 3-imidazolylmethyltetrahydrocarbazolones has now been found which are potent and selective antagonists of neuronal SHT receptors. Thus, the present invention relates to a tetrahydrocarbazole of the general formula n R ** R3 a la \ / I OOíl // \ / \ / \ L * I o o-o o N I ll l! I \ // I I O I \\ / \ / \ / J..

(I) 2 W_-2 'JO-c wherein R 1 represents a hydrogen atom, a C 1-10 alkyl group, a C 3-7 cycloalkyl group, a C 3-6 alkenyl group, a phenyl group 3 or in phenyl-C 1-3 alkyl group, and wherein one of the symbols R R and R represent a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 2-6 alkenyl group or a phenyl-C 1-3 alkyl group, while the other two of the symbols R, R and R, which may be the same or different, each represents a hydrogen atom or a C 1-6 alkyl group; and physiologically acceptable salts and solvates, e.g. hydrate, hence.

When R 1 represents a C 3-6 alkenyl group, it should be understood that the double bond cannot be adjacent to the nitrogen atom.

The alkyl groups R 1, R 2, R 3 and R 4 in the general formula I may be straight-chain or branched alkyl groups, e.g. methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-2-yl, pentyl, pent-3-yl or hexyl. An alkenyl group can e.g. be a propenyl group. A phenyl-C 1-3 alkyl group may e.g. be a benzyl group, a phenethyl group or a 3-phenylpropyl group.

A cycloalkyl group can e.g. be a cyclopentyl group, a cyclohexyl group or a cycloheptyl group.

It should be appreciated that the carbon atom in the 3-position of the tetrahydrocarbazolone ring is asymmetric and may exist in the R or S configuration. The present invention encompasses both the individual isomeric forms of the compounds of formula I and all mixtures thereof, including racemic mixtures.

Suitable physiologically acceptable salts of the compounds of general formula I include acid addition salts formed with organic or inorganic acids, e.g. hydrochlorides, hydrobromides, sulphates, phosphates, citrates, fumarates and maleates.

The solvates can e.g. be hydrates.

A preferred class of compounds are those compounds of formula I, wherein R 1 represents a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group or a C 3-6 alkenyl group.

Another preferred class of compounds are those compounds of formula I, wherein one of the symbols R 2, R 3 and R 4 represents a C 1-3 alkyl group, a C 3-6 cycloalkyl group or a C 3-6 alkenyl group, and wherein each of the other two symbols, which may be the same or different, denotes a hydrogen atom or a C 1-3 alkyl group.

A further preferred class of compounds are those compounds of formula I, wherein R 1 represents a hydrogen atom, a C 1-6 alkyl group, a C 5-6 cycloalkyl group or a C 3-4 alkenyl group, and wherein either an R 2 represents a hydrogen atom and R 3 and / or R 4 represents a C 1-3 alkyl group, or R 2 represents a C 1-3 alkyl group and both R 3 and R 4 represent hydrogen atoms.

An especially preferred class of compounds of the invention are compounds having the following general formula wr _ // '\ ___ /' \ _ / '\ ¿_¿ (I \ _ |: zn | \ // a' \\ _ / Wherein R 1a represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, a prop-2-yl group, a prop-2-enyl group or a cyclopentyl group, wherein R 3a represents a hydrogen atom and wherein either R 2a represents a methyl group, an ethyl group, a propyl group or a prop-2-yl group and R 4a represents a hydrogen atom, or R 4a represents a hydrogen atom and R 4a represents a methyl group or an ethyl group, and physiologically acceptable salts and solvates (t. eg hydrate) thereof.

Particularly preferred compounds are listed below: 1,2,3,9-tetrahydro-3- [γ2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-enyl) -4H-carbazole-4- on; 9-cyclopentyl-1,2,3,9-tetrahydro-3- [γ2-methyl-1H-imidazol-1-yl) -methyl] -4H-carbazol-4-one; 1,2,3,9-tetrahydro-3- [γ2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazol-4-one; smt physiologically acceptable salts and solvates thereof. An especially preferred compound is 1,2,3,9-tetrahydro-9-methyl-1l; 3-(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one of the formula fl h '.f / \ .'_. / V Vi-Å (m Ä' I Ü ' V / \\ / \ / \ / lof? O H8 Me and physiologically acceptable salts and solvates (eg hydrates) thereof.

It should be understood that the invention also encompasses other physiologists. This compound is preferably in the form of hydrochloride-acceptable equivalents of the compounds of the invention, i.e. physiologically acceptable compounds that are converted in vivo to the parent compound of formula I.

The compounds of the invention are potent and selective antagonists to SHT-induced responses in vagus nerve preparations isolated from rats, and thus the compounds act as potent and selective antagonists to neuronal 5HT receptors present on primary afferent nerves.

The compounds of the invention are useful as analgesics, e.g. to relieve pain associated with migraines, headaches and many other forms of pain, for which AIBN is the endogenous mediator.

Animal experiments have shown that the compounds of the invention are also useful in the treatment of schizophrenia and other psychotic diseases. As stated above, SHT is commonly found in nerve pathways in the central nervous system, and disruption of these * pathways containing 5HT is known to alter many other behavioral syndromes, such as mood, appetite and memory. Since neuronal SHT receptors of the same type as those found at the ends of primary afferent nerves are also present in the central nervous system, the compounds of the invention may also be useful in the treatment of such conditions as anxiety, obesity and A mania. In particular, the compounds of the above formula Ia have been found to have a very selective and extremely potent action. These compounds are well absorbed from the gastrointestinal tract, and are therefore suitable for administration orally or rectally. The compounds of formula Ia do not prolong the sleep time of mice anesthetized with pentobarbitone, indicating that there is no undesirable interaction with drug metabolizing enzymes. In fact, the compounds show no effect on normal behavior, and they are non-toxic and do not produce adverse effects in mice at intravenous doses of up to 1 mg / kg.

The compound of formula Ib exhibits the same beneficial properties as the compounds of formula Ia, and when administered to humans it gives no adverse effects.

The compounds of the invention can thus be used for the treatment of an animal or a human suffering from a disease caused by a disorder of neuronal AI function. The compounds of the invention may e.g. be used to treat a person suffering from migraine pain or a psychotic illness, such as schizophrenia.

The invention also relates to a pharmaceutical composition intended for use in human medicine or veterinary medicine, which comprises at least one 3-imidazolylmethyltetrahydrocarbazolone derivative of the general formula I or a physiologically acceptable salt or solvate (eg hydrate) thereof. Such compositions may be prepared in the usual manner using one or more physiologically acceptable carriers or excipients.

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

For oral administration, the pharmaceutical compositions may be in the form of e.g. tablets or capsules prepared in a conventional manner using pharmaceutically acceptable excipients such as binders (eg pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (eg lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (eg magnesium stearate, talc or silica); disintegrants (eg potato starch or sodium starch glycolate); or wetting agents (eg sodium lauryl sulphate). The tablets can be coated according to well known methods. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be prepared as a dry product intended to be reconstituted with water or other suitable vehicle before use. Dy-like liquid preparations can be prepared in the usual way by means of pharmaceutically acceptable additives, such as suspending agents, W (eg sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (eg lecithin or acacia); non-aqueous vehicles (for example, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (eg methyl or propyl p-hydroxybenzoates or sorbic acid). The liquid preparations may also contain buffer salts, flavoring agents, coloring agents and sweetening agents, as appropriate.

Formulations for oral administration may conveniently be formulated in a form which provides controlled release of the active compound.

For buccal administration the compositions may take the form of tablets or small cakes prepared in a conventional manner.

The compounds of the invention may be formulated for parenteral administration by injection. Compositions intended to be injected may take the form of unit doses in, for example, ampoules, or may be multi-dose containers containing an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in the form of a powder, which is reconstituted with a suitable carrier before use, e.g. sterile pyrogen-free water.

* The compounds of the invention may also be used in rectal compositions, such as suppositories or retention enemas, e.g. containing common suppository bases, such as cocoa butter or other glycerides.

In addition to the compositions described above, the compounds of the invention may also be used in the form of depot preparations.

Such long-acting compositions may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, the compounds of the invention may be used in admixture with suitable polymeric or hydrophobic materials (for example, as an emulsion in a acceptable oil) or ion exchangers, or the compounds can be used in the form of sparingly soluble derivatives, e.g. a sparingly soluble salt. For administration by inhalation, the compounds of the invention are suitably used in the form of an aerosol composition in a pressure vessel or atomizer, using a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or any other suitable gas. When using an aerosol container under pressure, a dosing unit can be administered by means of a valve which provides a measured amount. Capsules and cartridges can also be produced from, for example, gelatin intended for use in an inhaler or insufflator. These capsules and cartridges may contain a powder mixture of a compound of the invention and a suitable powder base, such as lactose or starch.

A suggested dose of the compounds of the invention for administration to humans (having a body weight of about 70 kg) is 0.05-20 mg, preferably 0.1-10 mg, of active ingredient per unit dose, which may be administered e.g. 1-4 times a day. The dose depends on the route of administration and the patient's body weight. It should be understood that it may be necessary to vary the dose appropriately depending on the age and body weight of the patient and the severity of the condition being treated. A unit dose for oral administration preferably contains QS-10 mg of active ingredient.

A unit dose for parenteral administration preferably contains 0.1-10 mg of active ingredient.

Aerosol compositions are preferably administered in such a manner that each metered dose or "puff" from a pressurized aerosol container contains 0.2-2 mg of a compound of the invention, and each dose administered via a capsule or cartridge in an insufflator or inhaler preferably contains 0.2-20 mg of a compound of the invention. The total daily dose for inhalation is from 0.4 to 80 mg. Administration can be performed several times a day, e.g. 2-8 times, each time giving e.g. 1, 2 or 3 doses.

If desired, the compounds of the invention may be administered in combination with one or more other therapeutic agents, such as antiseptics.

The compounds of the general formula I as well as physiologically acceptable salts or solvates or physiologically acceptable equivalents thereof can be prepared according to the methods described below.

(A) A compound of the general formula I or a physiologically acceptable salt or solvate or a physiologically acceptable equivalent thereof may be prepared by a compound of the general formula éšéß 559 8 Û I _ / \ / \ / 1 u R 1 Y (where R 1 has the meaning given above and Y represents a reactive substituent), or a protected derivative thereof, is reacted with an imidazole of the general formula HN N (III) ( where R 2, R 3 and R 4 have the meanings given above) or a salt thereof K As examples of the starting materials of formula II, there may be mentioned those compounds in which Y represents an alkenyl group = CH 2 or a group of the formula CH 2 Z, where Z represents an atom or a group which is easily displaced, such as a halogen atom, eg chlorine or bromine, an acyloxy group, eg acetoxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy, a group -R5R6R7X_, where R5, R6 and R7 , which may be the same or different, each denotes lower alkyl, eg methyl, aryl, eg f enyl, or aralkyl, e.g. benzyl, or where R 5 and R 5 together with the nitrogen atom to which they are attached may form a 5- or 6-membered ring, e.g. a pyrrolidine ring, and X represents an anion, such as a halide ion, e.g. chloride, bromide or iodide; or a group -NRSR 6, wherein R 5 and R 6 have the meanings given above, e.g. -N (CH3) 2.

When Y represents the group = CH 2, the process may conveniently be carried out in a suitable solvent, e.g. water; an ester, e.g. ethyl acetate; a ketone, e.g. acetone or methyl isobutyl ketone; an amide, e.g. dimethylformamide; an alcohol, e.g. ethanol; or an ether, e.g. dioxane or tetrahydrofuran; or in a mixture of such solvents. The process can be carried out at a temperature of, for example, 20-100 ° C. When Y represents gru a CH 2 Z, where Z is a halogen atom or PP 2 an acyloxy group, the process can be conveniently carried out in a suitable medium. solvent, such as an amide, e.g. dimethylformamide; an alcohol, e.g. methanol or industrial methylated spirits; or a haloalkane, e.g. dichloromethane, at a temperature from -10 ° C to + 1000 ° C, e.g. from + 20 ° C to + 100 ° C.

When using a compound of formula II, wherein Y represents the group CH 2 Z, where Z is the group -NR 5 R 6 R 7 X -, the reaction may conveniently be carried out in a suitable solvent, such as water; an amide, e.g. dimethylformamide; a ketone, e.g. acetone; or an ether, e.g. dioxane, and at a temperature of from 20 to 150 ° C.

When using a compound of formula II, wherein Y represents the group -CH 2 Z, where Z is the group -NRSRS, the reaction may conveniently be carried out in a suitable solvent, such as water or an alcohol, e.g. methanol, or any mixture thereof, and at a temperature of from 20 to 150 ° C.

(B) A compound of formula I may also be prepared by oxidation of a compound of formula A n "R 3 _ I \ / f / \ / \ / \ | I __ '| I x T g ET h \ An (I \.' uf \ / \ /. u. .fn (where A represents a hydrogen atom or a hydroxyl group, and where R1, R2, R3 and R4 have the meanings given above) or a salt or a protected derivative thereof.

The oxidation process can be carried out using conventional methods, and the reagents and reaction conditions should be selected so that the indole group is not oxidized. The oxidation process is therefore preferably carried out by means of a mild oxidizing agent.

When oxidizing a compound of formula IV, wherein A represents a hydrogen atom, quinones can be suitably used as oxidizing agents in the presence of water, e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3,5,6-tetrachloro-1,4-benzoquinone; selenium dioxide; an oxidizing cerium (IV) compound, such as cerium (IV) ammonium nitrate or an oxidizing chromium (VI) compound, e.g. a solution of chromic acid in acetone (such as Jones' reagent) or chromium trioxide in pyridine. 460 559 N When oxidizing a compound of formula IV, wherein A represents a hydroxyl group, quinones can be suitably used as oxidizing agents in the presence of water, e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3,5,6-tetrachloro-1,4-benzoquinone; ketones, e.g. acetone, methyl ethyl ketone or cyclohexanone, in the presence of a base, e.g. aluminum t-butoxide; an oxidizing chromium (VI) compound, e.g. a solution of chromic acid in acetone (such as Jones' reagent) or chromium trioxide in pyridine; and N-halosuccinimide, e.g. N-chlorosuccinimide or N-bromosuccinimide; a dialkyl sulfoxide, e.g. dimethyl sulfoxide, in the presence of an activating agent such as N, N-dicyclohexylcarbodiimide or an acyl halide, e.g. oxalyl chloride or tosyl chloride; pyridine-sulfur trioxide complex; or a dehydration catalyst, such as copper chromite, zinc oxide, copper or silver.

Suitable solvents are ketones, e.g. acetone or butanone; ethers, e.g. tetrahydrofuran or dioxane; amides, e.g. dimethylformamide; alcohols, e.g. methanol; hydrocarbons, e.g. benzene or toluene; halogenated hydrocarbons, e.g. dichloromethane; and water, and mixtures of such solvents.

The process is conveniently carried out at a temperature of from -70 ° C to + 50 ° C. It should be appreciated that the choice of oxidizing agent affects the preferred reaction temperature.

(C) A compound of formula I according to the invention or a salt or protected derivative thereof may also be converted into another compound of formula I using conventional methods. Such methods include alkylation, which may be carried out in any position of a compound of formula I, when one or more of the symbols R 1 and R 2 represents a hydrogen atom, and hydrogenation which may be used, for example, for the conversion of an alkenyl substituent to an alkyl substituent. The term "alkylation" also includes the introduction of other groups, such as cycloalkyl groups or alkenyl groups. Thus, a compound of formula I, wherein R 1 represents a hydrogen atom, can be converted to the corresponding compound, wherein R 1 represents a C 1-10 alkyl group, a C 3-7 cycloalkyl group PP, a C 3-6 alkenyl group or a C 1-6 alkyl-alkyl group.

The above alkylation reactions can be carried out using suitable alkylating agents of the formula Raxa, wherein Ra represents a C 1-10 alkyl group, a C 3-7 cycloalkyl group, a C 3-6 alkenyl group or a phenyl-C 1-3 alkyl group, and Xa represents a leaving group, such as a halide or such acyloxy group 9/11 460 359 as indicated above in connection with the definition of the symbol Y.

The alkylating agent may also be a sulphate of the formula The alkylation reaction is conveniently carried out in an inert organic solvent, such as an amide, e.g. dimethylformamide; an ether, e.g. tetrahydrofuran; or an aromatic hydrocarbon, e.g. toluene, preferably in the presence of a base. Suitable bases are e.g. alkali metal hydrides such as sodium hydride; alkali metal amides such as sodium amide; alkali metal carbonates such as sodium carbonate; and alkali metal alkoxides, such as sodium or potassium methoxide, ethoxide or t-butoxide. The reaction may conveniently be carried out at a temperature of from -20 ° C to + 100 ° C, preferably 0-50 ° C.

Hydrogenation according to the general procedure (C) can be carried out using conventional methods, e.g. using hydrogen in the presence of a noble metal catalyst, e.g. palladium, Raney nickel, platinum, platinum oxide or rhodium. The catalyst can be supported on, for example, charcoal, or a homogeneous catalyst can be used, such as tris (triphenylphosphine) rhodium chloride. The hydrogenation is usually carried out in a solvent, such as an alcohol, e.g. ethanol; an amide, e.g. dimethylformamide, an ether, e.g. dioxane, or an ester, e.g. ethyl acetate, and at a temperature from 220 ° C to + 100 ° C, preferably 0 ° C.

In some of the above transformations, it may of course be necessary or desirable to protect any sensitive groups in the compound in order to avoid undesired side reactions. The protecting groups used in the preparation of the compounds of formula I are suitably groups which can be readily cleaved off at a suitable stage of the reaction sequence, suitably in the last step.

During any of the reactions described above, for example, it may be necessary to protect the keto group, e.g. such as ketal or thioketal.

(D) Compounds of the general formula I can thus be prepared by removing any protecting groups from a protected form of a compound of formula I. The removal of protecting groups can be carried out according to conventional methods, such as the methods described in "Protective Groups". in Organic Chemistry ", Ed. J.F.W. McOmie (Plenum Press, 1973). Thus, a ketal group, such as an alkylene ketal group, can be removed by treatment with an inorganic acid, such as hydrochloric acid. A thioketal group can be cleaved by treatment with a mercury (II) salt, e.g. mercury (II) - 460 359 12 chloride, in a suitable solvent, such as methanol.

The compounds of formula I may be converted into physiologically acceptable salts thereof by conventional methods. Thus, the free base of a compound of formula I may be treated with a suitable acid, preferably with an equivalent amount of acid in a suitable solvent, e.g. aqueous ethanol.

Physiologically acceptable equivalents of a compound of formula I can be prepared according to conventional methods.

Individual enantiomers of the compounds of the invention may be obtained by dividing a mixture of enantiomers (eg a racemic mixture) by conventional means, such as an optically active dividing acid; see e.g. "Stereochemistry of Carbon Compounds" by E.L. Eliel (McGraw Hill 1962) and "Tables of Resolving Agents" by S. H. Wilen.

Examples of optically active dividing acids which can be used to form salts with the racemic compounds are the (R) and (S) forms of organic carboxylic acids and sulfonic acids, such as tartaric acid, di-p-toluoyltartaric acid, camphorsulfonic acid and lactic acid. The resulting mixture of isomeric salts can be split into the diastereoisomers, for example by fractional crystallization, and optionally the desired optically active isomer can be converted to the free base.

The methods described above for the preparation of the compounds of the invention can be used as the final main step in the preparation sequence. The same methods can also be used to introduce desired groups into an intermediate step of the stepwise preparation of the desired compound, and it should be understood that the methods described may be combined in various ways in such multi-step processes. The reaction sequence in multi-step processes should, of course, be chosen in such a way that the reaction conditions used do not affect such groups in the molecule as are desired in the final product.

The starting compounds of formula II, where Y represents the group = CH2, can be prepared by reacting compounds of formula II, where Y represents the group CH2 §R5R6R7X_, with a base in a suitable solvent. Examples of useful bases are alkali metal hydroxides, e.g. potassium hydroxide, and alkali metal carbonates or bicarbonates, e.g. sodium bicarbonate. The quaternary salts can be prepared by reacting the corresponding tertiary amine with an alkylating agent, such as methyl iodide or dimethyl sulfate, optionally in a suitable solvent, e.g. dimethylformamide. The tertiary amine can be prepared by reacting a tetrahydrocarbazolone of the general formula (I) with formaldehyde and the corresponding secondary amine. optionally in a suitable solvent, such as an alcohol, e.g. ethanol.

Compounds of general formula V may e.g. prepared according to the method described by H. Iida et al., in J. Org.

Chem. (1980) Vol 45, no. 15, pp.2938-2942.

The starting compounds of the general formula II, wherein Y represents -CH 2 Z, where Z is a halogen atom or an acyloxy group, can be prepared from the corresponding hydroxymethyl derivative of the general formula 'which can be obtained by reacting a tetrahydrocarbazolone of formula V with formaldehyde , preferably in a suitable solvent, such as an alcohol, e.g. ethanol, and preferably in the presence of a base.

The compounds where Z represents a halogen atom can thus be prepared by reacting a compound of formula VI with a halogenating agent, such as a phosphorus trihalide, e.g. phosphorus trichloride.

The compounds where Z represents an alkoxy group can be prepared by reacting a compound of formula VI with a suitable acylating agent, such as an anhydride or a sulfonyl halide, e.g. sulfonyl chloride. .60 (JJ E.

Compounds of formula II, wherein Y represents -CH 2 Z, where Z is the halogen atom, can also be prepared by reacting a compound of formula II, where Y represents the group = CH 2, with a suitable hydrogen halide, e.g. hydrogen chloride, preferably in a suitable solvent, such as an ether, e.g. diethyl ether.

Compounds of the general formula IV can be prepared by a compound of the formula? i cuzzl 'f \ / \ / (nn T f_? |' i / \ / \ / n ïi! o RI (where R1 and A have the meanings given above, and Z1 represents an atom or group that is easily displaced, such as a halogen atom, an acyloxy group or the group -§R 5 R 6 R 7 X- given above in connection with the definition of the symbol Z) is reacted with an imidazole of formula III according to the method (A) described above.

Compounds of formula VII may be prepared by reduction of compounds of formula II, e.g. using lithium aluminum hydride or sodium borohydride. Compounds of formula VII, wherein A represents a hydrogen atom, may also be prepared by a compound of formula VII, wherein A represents; draws a hydroxyl group, is reacted with a tosyl halide (eg tosyl chloride), after which the resulting tosylate is reduced with lithium aluminum hydride.

The compounds of formula IV are novel compounds which are also encompassed by the present invention.

The invention is illustrated by the following examples. In the examples, solutions have been dried over Na 2 SO 4, and solids have been dried in vacuo over PZOS at 50 ° C overnight. The chromatographies were performed on silica gel 9385 according to the method described by W.C. Still et al. (J. Org. Chem., 1978, YY, 2923-2925).

Preparation 1. 2,3,4,9-Tetrahydro-N, N, N-trimethyl-4-oxo-1H-carbazole-3-methanaminium iodide. One solution of 0.53 g of 3-(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one in 15 ml of iodomethane was refluxed. for 5 hours and then evaporated to dryness. This gave 0.84 g of the title compound as a white solid, m.p. 202 DEG-50 DEG. 460 559 Preparation 2. 2,3,4,9-tetrahydro-N, N, N, 9-tetramethyl-4-oxo-1H-carbazole-3-methanaminium iodide.

A suspension of 3.80 g of 3- [dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one in 100 ml of iodomethane was refluxed and stirred for 57 hours. The resulting suspension was concentrated in vacuo to give 5.72 g of the title compound as a solid, m.p. 192-195 ° C.

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

A solution of 5.0 g of the product prepared in Preparation 2 in 20 ml of water was treated with 6.55 ml of 2N sodium carbonate solution and heated at 35 ° C for 45 minutes. The resulting slurry was cooled to 0 ° C, and the solid was filtered off, washed with water and dried. This gave 2.8 g of the title compound, m.p. 127-129 ° C.

Preparation 4. 2,3,4,9-Tetrahydro-9-methyl-3- [γ2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazole maleate. 90 mg of sodium borohydride were added under nitrogen to a stirred solution of 500 mg of the product prepared in Example 7 in a mixture of 3 ml of methanol and 3 ml of chloroform. Stirring was continued for 48 hours, with an additional 250 mg of sodium borohydride being added after 17.75 hours and 42 hours, respectively. The suspension was then partitioned between 2N hydrochloric acid (15 ml) and chloroform (3 x 10 ml). The aqueous layer was alkalized with solid sodium carbonate and extracted with chloroform (3 x 10 ml), and the combined extracts were washed with water (2 x 10 ml) and with brine (10 ml), dried and concentrated in vacuo. The residual foam (557 mg) was subjected to column chromatography, eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 300: 10: 1. This gave 200 mg of a solid.

This substance was dissolved in 3 ml of refluxing absolute ethanol, after which a solution of 80 mg of maleic acid in 1 ml of refluxing absolute ethanol was added. The hot solution was filtered, stirred and diluted with 40 ml of dry ether. This gave 240 mg of the title compound, m.p. 138.5-140 ° C.

Preparation 5,5 2,3,4,5-tetrahyaro-9-methyl-3- [u-methyl-1H-imidazol-1-yl) methyl] -1H-carbazol-4-ol. 30.0 g of the product prepared in Example 7 were added under nitrogen to a stirred suspension of 7.75 g of lithium aluminum hydride in 750 ml of dry tetrahydrofuran. The reaction mixture was refluxed and stirred for 1 hour and then cooled in ice.

The suspension was carefully diluted with 100 mL of aqueous tetrahydrofuran (15% H 2 O) and with 100 mL of water, after which the mixture was concentrated in vacuo. The residual solid was extracted with dichloromethane (2 x 500 ml). The organic extracts were concentrated in vacuo, and the residual solid (16.4 g) was purified by short way column chromatography on silica (Kieselgel 60; Merck 7747; 500 g). Elution was carried out with a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 150: 10: 1. This gave 13.4 g of the title compound as a foam.

The product gave the Rf values of 0.34 and 0.36 (two pairs of diastereoisomers) by thin layer chromatography on silica using a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 150: 10: 1 as eluent. Ultraviolet light and iodoplatinic acid were used for the detection.

NMR: δ CDCl 3 + CD 3 OD (1 dropL): 1.6-2.3 and 2.6-3.0 (SH, m), 2.32 and 2.40 (3H, s + s, Me in two various isomers), 3.32 (BH, S, NMG), 3.65-4.3 (2H, m, CHCH 2 N), 4.75-4.85 (1H, m, gg-OH), 6.8 7.8 (CH 2 m, aromatic).

Example 1a. 1,2,30-tetrahydro-9-methyl-3- [γ2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride.

A solution of 2.0 g of the product prepared in Preparation 2 and 5.0 g of 2-methylimidazole in 30 ml of dry dimethylformamide was stirred under nitrogen at 95 ° C for 16.75 hours and then allowed to cool. The crystallized solid was filtered off, washed with ice-cold, dry dimethylformamide (3 x 2 ml) and with dry ether (2 x 710 ml) and then dried. The resulting solid (0.6O g) was suspended in a mixture of 30 ml of absolute ethanol and 1 ml of ethanolic hydrogen chloride. The suspension was gently heated to give a solution, which was filtered while hot.

The filtrate was then diluted with dry ether to precipitate a solid (0.6 g) which was recrystallized from absolute ethanol.

This gave 0.27 g of the title compound, m.p. 186-187 ° C.

Analysis for C 18 H 19 N 3 O.HCl.H 2 O Calculated: C, 62.3; H, 6.1; N, 12.1% (found: c, 61.9, - H, 6.4; N, 11.82.

Example 1b-1g. In the same manner as above, the compounds listed in Table I below were prepared. The table also states the preparation conditions and the properties of the compounds produced. 460 559 17. . PHCF uCC fl QÜÛCÜ- ~ wÅ ~ Lm ~ I ~ E> ~ CMJ m U._1 _ .. CAVE_EÜ æ fl. C ÃLÛ: vCw-uæß M _,:. MQÜELÉV_J: V> C CE .HCCCÜHÃ CU ÉÜE ÜÜCLC: FC C71: FC C71 v> LC> MA Pn-.Mw M ~ Næï ~ M .EQÃU. ÜLC - T ~ LCÃÜLM -.._. »N: .g GL TSG GEÖHX lwnwmxruhnvx ÉÛCUÜ Wmvmu fi wknvx-Glßmw ÉCLUkÜF-Cwww: UC M Xmwmu / .Lmwu CEECW _ WOT ~ m fi wmF-wwåk .__. : LC fl. CCLCHVCWCULÛß. ~ C ~ uo_cEmS: mr «: E: nmm mUCcm> cm una ~ SmO40EE: fi: MEæcm # UE | mx fi ONmQucx |: PlCXC | v | ~> ~ oEmuQQMIZMZMZMo1CuM>: m»; ; .._ U:., M. @. MmM.MMæw «. = _. Mm.MMæ @ uMnM- @ fM M. = MQ:: M @ ._ = .M = = fi g 2 U.

. .CmZßNZMNU O i M M M M cf_m.M M @. = _. W.w, M.MM m. = M. Mwæ.MM M MM, M p> M | => _ M =. = 1: M: Q = = Ü: MM .C 2 __ MMMM M., @. @ MMO = w; .. MU = M M . @ MM @. ». M @ @. .MM _. @ M_.M @ M MM: MM ~« M _- = MM MM.c MQ: = 2; : M = M; Q.

.C 2 ._ U M M M cM = m. =. MQ = u = M =. M MM._MM @ .w m.mw ~ .MM, ß.wM @. «@ M OM c.M Mu: GM @ .M M.M =: Mm; M: U v.

.QMZM = Q | @> M,.

M M M @ M = M. @., @, =, U U. MMM M M M w. @ .ØMw.>. «W @ .o. =. @ Mw. «@ M .M MM cw. = Mm @ MM = M @ .G @. =. = L: QI: U UM .Q 2 __ U IMMM MMMM = M = @. @. MQ = M5M . = cM _. _ M M.MM. @. M.w.Mw> .MM.M.M.m @ .M @ M MM MM @ M. = MM:: M DM M om M = =:: M LM .L 2 = M -M.M @.

Amy 2 __ M 2 __ U wwww Mm. ßmww ||| «| - M. , M: M: Mm _: umczmuwm @w === @ Mmapow .mew .mv | wm: M = MMMMMMEM um = m @ wa | M> xwMo: ømzme ~ Mmw | mmM M. EMM IM: M MMV w> MM = <Iaxsßøup »~ @ MMm E> Mo> umcmz @@ = mz M Mweuoh L = @ l¿ B. wx flfi wnma 18 1 H NMR data were obtained, where d means doublet, 460 359 * The dd given below means doublet of doublets and s means singlet.

Rz »r 1 | E2 | \\ Nl / \\ Nl3, '.ínu' m / 'ZS / \ n' ° H3 ß 'ä 6 /' \ 3 / '\ 1 - - k 250 MHz l Lösnmgsr H NMR spa tra () šnedel Chemical displacements for protons (6 ppm) and signal types ia farbazolone ottotones Imidazolyl- Imidazole protons É - 1 Líí-ï-methylene-; Chromatic Aliphatic Protons Q H-2 '; H-4 'ochí ¿i * H-5,6,7,8 CH -1och g ¿eller H-D' å e * o GHz-z H-3 f 'u! 2 - 1e 'aS-nmso š7,2-a, os ïz, 91-3, _zs 4,47 (dä), 9,20s'' IUSSS i -; 5.75-2.3 and. = å É 4.64 (dd) '1 f §cnc13 + é o * f: DMSO ¿7.15-8.05; 2.6-3.05 4.02 (dd) 8.175 «5.935 g: i1, 7s-2,1 and -> i «4,63 (aa) 1g: aö-nmso š7,2-s, os. Including 4,42 (ad) ''; 7.61d 'É; 2.9-3; 3 och 1 i Och f g í1.6-2.2 4.73 (ad) g; 7.70 d E Example 2. 1,2,3,9-Tetrahydro-9-methyl-3- [2H-methyl-1H-imidazol-1-yl) -methyl] -4H-carbazol-4-one maleate. 300 mg of 1,2,3,9-tetrahydro-9-methyl-3- [γ2-methylimidazol-1-yl) -methyl] -4H-carbazol-4-one was suspended in 5 ml of hot ethanol and treated with 116 mg maleic acid. The solution was cooled, and the white crystalline solid was filtered off and dried. This gave 300 mg of the title compound, m.p. 132.3 ° C.

Example 3a. 1,2,3,9-Tetrahydro-3- (1H-imidazol-1-ylmethyl) -4H-carbazol-4-one.

A solution of 0.84 a .a of the product prepared in Preparation 1 and 0.90 g of imidazole in 25 ml of dimethylformamide was heated at 105 ° C for 6 hours, then cooled and added to 200 ml of water. ten. The mixture was extracted six times with ethyl acetate. The extracts were washed, dried and evaporated to a solid, which was purified on a column of silica (Merck 7734), eluting with a 4: 1 mixture of ethyl acetate and methanol. The product was recrystallized twice in a mixture of ethyl acetate and methanol. This gave 0.095 g of the title compound as a crystalline solid, m.p. 220 DEG-222 DEG.

The product gave an Rf value of 0.33 by thin layer chromatography on silica using a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 100: 8: 1 as eluent. Ultraviolet light and iodoplatinic acid were used for the detection.

Example 3b-33. The compounds listed in Table II below were prepared in a similar manner. The salt formation was carried out in the manner described in Example 2. 20 59 460 _ .ccucoïccpuocv ~ _oncrå _.._ w _... 5w = _> _ .. c> __ "« _ «. Å _._ Q_____m. Mæd: oo Hocfo .u fi uumï fl wo .cmxoz> æ vcwcøcmi.: U OzEÉEW fl o_uu ___ macïo __. a Esmmw: m5 ÉPÉ> _ Éwnxmauou ma.

QÉ:> wumummc <ä_ Eocmv møcmuwummom mcšfaêcm fi: co Equal .. .šämw __. mov fi mumšmuu um: m0 mm mcummc fl conwm uêë 2.356 _ 0.2 .: _: om. | : oo 172.- WTÉN 047 .... 2 .: ...___ __.:\._~ = ~ ._._: ___ __ ___ __ 3 ... m fi ß ... S fi é | ~ í Ü. _: Éíé 9 :: _. fe ... ana ... S00 cqwxcßÅ cwåncå wcÄTÉ ... ac ... ... ršcz _ .C _. : __ .R .___._ e ~ .. ~ Ai nå ... m ~. ~ E ..: Éëé n WE: nä ... 3%:: oo 2.72 .. 2.7 .... 2472 ... ._ E ... _32: __., ___, _ __ __ 3 ._._._____.._ 1 :: _52 .. 2.325 92: _: oo | zoo É. ~ -__._ _. ~ | É. ~ Éél fl š 3 .: _.:;..__ ... zëå Û ... än ___: __ __ ..._ 32 __ __ »_._. ..; ._._.___ ~ .._ -Éš _: Sá _ .Es fi é UQYL _ .S00 | _ ... OO NÄÅM ... mwårcl »... cénwfß me ... 15.5. mmš: wß cwé .. cc .. ___: n: u ~: u __ om: Sš ._._._ ~ ».._ Ani .. uGé ._. u __ \ .._.._ 0.1.2 : oo 1 ... uo Néëà »Nëèä Ééåé ___._. = _.._, ._ = __: Eš fi ï m» 3.2: fw __ __ J: __ _:: RH ._._._ ~. ~ .._ in .. .må »__ .då .m fi ow .cmï Hwšño m ~ 1 ~ ___, _: v07 ... Éwilz .E .U Év ... amg zm-u fi š fi -wwmz .___» __ ~ __ __; Hmm 31: är: uæcøwou ._mv.m _._ .. mw fl9 ~ min. _.ë = .. <..__., __ w ... mama "ämm iëwmšv fl u- nëz fl qm flfi mšm fi nm acw .. Lä _ Lä. .få 1 __. _ Lä. Dä. b _ lä. àwvmmwn fl vw fi nn. _> ÉÉ ___ .. __ umcoßounTco fi oum fl nwz .Esncpmwmwv fifl m wmcc fl uxmmz ÉSO> .Ü ._ mmcmï .Ü .Q fi oßf _ _ uëudnEw-. fi w: oo _ .Emm 2 .nwcouOum .Anu umm m uw fifl cuz fifl uv. : _ ~ @ _ _w. fi_ un_mlzzz | __.

HH Hawßm ... 21 460 359 The positions of the protons given in the table are shown in the following structural formula: n R2 5 H 11121 6/7 \ ._ «/ \ f / \ a / X3 '1 uu 12, 1__¿ ,, VN . / '\ /' \ / y "_ \ a N I R a lll 1 The symbol d in Table II means doublet, dd means doublet of doublets, and s means singlet.

Example 4. 1,2,3,9-Tetrahydro-9-methyl-3-Z11-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one.

RB A solution of 1.0 g of 1,2,3,9-tetrahydro-3- [γ2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in 10 ml of dry dimethylformamide was added dropwise under nitrogen to a stirred, ice-cold suspension of sodium hydride (80% in oil; 0.11 g) in 5 ml of dry dimethylformamide.

After 0.5 hours, 0.34 ml of dimethyl sulfate was added, and the resulting solution was stirred at room temperature for 4 hours. The resulting solid was filtered off, washed with ice-cold, dry dimethylformamide (2 x 5 ml) and with dry ether (3 x 15 ml) and dried. This gave 0.25 g of the title compound as a solid, melting at 223-224 ° C with decomposition.

The product gave an Rf value of 0.27 by thin layer chromatography on silica using a mixture of chloroform and methanol in a volume ratio of 93: 7 as eluent. Ultraviolet light and iodoplatinic acid were used for the detection. The product was identical to the product prepared in Example 1a.

Examples 4b-4i. The compounds listed in Table III below were prepared according to a similar method using suitable alkylating agents. _ _: _54 vill ..___.:. § ._ ... E: ___ ._ .__. T_ 37 :. ~ _.__: ___ E .___ _23. \ / _ _ __. .____. = ~ z: __ 2u __ ._.__ __ __ J: _51. 1 ~ __.___: ~ G / K \\ ___ 050 __ l C: fi. C. . J cC fi mv fl xá m n \ / N ß N m .___ J: .få __. ~ _ _: 9.3 S1 ___. ___.__ __._: _..__ f. __ __ _: ___-. 1 å: _ __: ___ .___ ._c ~ __ ~ uc ~ zï ___ ~ u Q. ._ // f |. \\ _ __ ~ __ ~ .__... o .___.___ fi äñä _.__ S6 .ßaæ .___ .Qnfñßw .___ z__ ~ __... ~ Q -ä: ___ ... EE 2A __ __: ___ _____ ~ __.:._,_ ..._ u ° S_ i 1: H __. __ .fw ._92 S. .f fi Fswßw .___.___._ u .___.___._ ~ __2u __: E .. .___..__.___ 3. » __ __: __ _ _..._ ~ ________.._ ___ 0.3.3 .. __ .. 2 _.___ ¿._23 mm .____.._._..__ ¿._ .___.___.___ .__.__ 2 __ .. J -EL ____._ _._..._.___ mñm __ __ ___... .___ ~ ______._ 8 _ U = Cw ~ __._ t _..._._. ._ê¿_ m __._..__: _.._ ï ._.._ .___..__.: _.__ ~ ___ ~ __2 .._ å: Sá _52: Û. __ __: __ ..._ 22 .___ .___..__..., _ 93 .: _ 5 .: .Q ..._ »___ ...__ ._ _.... \ .__. _. ~ _._ .__ ~ = 2 __ .. ~ _ -..__ Nä: _. = _____._ __ __ __ ..._ 32 _ .___.... ~ ____ ...__ ______ .. __._____ now; ...__. \ w .._._ ~ .._._ ___:: äw ._._...___ _ ____ z_ ~ ___._.._ ir ..: __ _ ,, ___ _. .___ __ __ 2: 3 .... .wmw .___ __ __ .._ __ __., _. fr. . 1.5 ..-. .!: - I- |. |% I! ! l .E .ämm .fi ïmuâšu dm w umcxmuwm umccsf .. ï fi ßwlïw fi öw .mEw Uacä: .få 1315 ___... .___ ___ “__ fi w flfi cmmc fi uw fi æx fi <1 vâ f 23 _ .. |, + =. : _: Ém .fi wccwuzm fl š Û / O _ wH_ __ @ nmm 23 46Û 559 The following 1 H NMR data were obtained, where d means doublet, dd means doublet of doublets and s means singlet. 0 R2 o E 12 'sm, f \ 3 / \ / \\ o ø - o g N M3' l '.' '.' i -l 'n f \\ / \ / \ / 2 55-3 0 N o R s ål 1 R3 TH-N fi rspektra (250 Mz) lausnings- Tnedel ^. _. _. HRS _ .

- Chemical displacements for protons (c pmm) and signal types! ,.

. ; Carbazolone protons Imidazolyl ~ Imidazole protons I 1 methylene- ie: I 'Aromatic Aliphatic protons H-2' H-4 'and / or A ln-5,6,7, s caz-1 and cnz-2 Hs' f * _ Ha I 4 g dö-DMSO; 7.15-8.1 2.9-3.2 1.9-2.2 6-29 ("d) 7.55d ii and - and 2 6.68 (dd) '= 7.65d 4 ht d6- DMSO; 7.2-8.1 2.9-3.3 1.8-2.2 6.26 (dd) '7.42d in å 1 and' - and I; 1 6.65 (dd) Z 7.57d Example 5. 9-Cyclopentyl-1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one maleate.

A solution of 1.20 g of 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in 9 ml of dry dimethylformamide was added to a stirred, ice-cold sodium hydride suspension (80% in oil; 0.14 g) in 2 ml of dry dimethylformamide under nitrogen, after which stirring was continued for 0.25 hours. Then 0.51 ml of bromocyclopentane was added, and the stirred solution was heated at 100 ° C for 18.5 hours. After allowing the solution to cool, it was partitioned between water (100 ml) and ethyl acetate (3 x TO ml). The combined organic extracts were washed with ZN sodium carbonate solution (2 x 50 ml), with water (2 x 50 ml) and with brine (50 ml), dried and evaporated to dryness. The residue was purified by chromatography eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 150: 10: 1. This gave 0.27 g of an oil. This oil was dissolved in 7 ml of refluxing absolute ethanol, and a solution of 0.10 g of maleic acid in 0.5 ml of refluxing absolute ethanol was added. The hot solution was filtered, stirred and diluted with 20 ml of dry ether. The resulting yellow gum was washed with dry ether (7 x 25 ml), and the mixture of mother liquor and washing solutions was allowed to stand. The solid crystallized out was filtered off, washed with dry ether (3 x 5 ml) and dried. This gave 0.058 g of the title salt as a white crystalline solid, m.p. 104.5-106 ° C.

Analysis for C 22 H 25 N 3 O.C 4 H 4 O 4 .6H 2 O Calculated: C, 65.8; H, 6.4; N, 8.9% Found: C, 65.95; H, 6.4; N, 8.6% Example 6. 1,2,3,9-Tetrahydro-3- [γ-methyl-1H-imidazol-1-yl) methyl] -9- (2-propenyl) -4H-carbazole-4 -on-maleat.

A solution of 1.0 g of 1,2,3,9-tetrahydro-3- [γ2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in 6 ml of dry dimethylformamide was added to a stirred, ice-cold suspension of sodium hydride (80% in oil; 0.12 g) in 2 ml of dry dimethylformamide. After 0.25 hours, allyl bromide was added, and the resulting solution was stirred at 0 ° C for 0.25 hours and then at room temperature for 20 hours.

The solution was then partitioned between water (75 ml) and ethyl acetate (3 x 50 ml). The combined organic extracts were washed with water (2 x 50 ml) and with brine (50 ml), dried and concentrated in vacuo. The residue was purified by chromatography eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 200: 10: 1. This gave 0.43 g of a solid, which was dissolved in 2 ml of refluxing absolute ethanol. To the solution was added a solution of 0.18 g of maleic acid in 1 ml of refluxing absolute ethanol. The hot solution was filtered and diluted with 4 ml of dry ether. The crystallized solid was filtered off, washed with dry ether (3 x 5 ml) and dried.

This gave 0.48 g of the title compound as a white solid, m.p.

Analysis for C 20 H 21 N 3 O.C 4 H 4 O 4: Calculated: C, 66.2; H, 5.8; N, 9.65% Found: C, 66.3; H, 5.75; N, 9.6% Example 7. 1,2,39-Tetrahydro-9-methyl-3- [γ-methyl-1H-imidazol-1-yl) methyl] -4-carbazol-4-one. A solution of 1.7 g of 3-(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride in 17 ml of water was treated: V 460 559 with 1.4 g of 2-methylimidazole, after which the reaction mixture was refluxed for 20 hours. The cooled mixture was filtered, and the residue was washed with water (3 x 15 ml). 1.7 g of a crude product with a melting point of 221-221.5 ° C were obtained. This material was recrystallized from ethanol to give 1.4 g of the title compound, m.p. 231-232 ° C. Using thin layer chromatography, the product was shown to be identical to the product prepared in Example 4.

Example 8. 1,2,39-Tetrahydro-9-methyl-3- [YZ-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one.

A suspension of 0.5 g of the product prepared in Preparation 3 and 0.4 g of 2-methylimidazole in 5 ml of water was refluxed for 20 hours. The cooled reaction mixture was filtered, and the residue was washed with water (3 x 10 ml), dried and recrystallized from 18 ml of methanol. This gave 0.3 g of the title compound, which melted at 232-234 ° C with decomposition. Using thin layer chromatography, the product was shown to be identical to the product prepared in Example 4.

Example 9. 1,2,3β-Tetrahydro-9- (1-methylethyl) -3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride.

Sodium hydride (80% dispersion in oil; 0.208 g) was added to a stirred solution of 1.93 g of 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl ] -4H-carbazol-4-one in 35 ml of DMF at 0 ° C, whereupon the resulting suspension was stirred at 0 ° C for 0.25 hours. Then 0.78 ml of 2-bromopropane was added, and stirring was continued at room temperature overnight and then at 40 ° C for 4 hours.

The reaction mixture was partitioned between 2N sodium carbonate solution (200 ml) and ethyl acetate (2 x 150 ml). The combined organic extracts were washed with water (3 x 75 ml), dried and evaporated in vacuo. The resulting product was purified by chromatography, eluting with a mixture of dichloromethane, ethanol and ammonia in a volume ratio of 100: 8: 1. This gave an oil which was dissolved in 3 ml of ethanol. The solution was acidified with an ethereal solution of hydrogen chloride and diluted with dry ether to precipitate the title compound. This gave 0.13 g of the title compound as a white solid, m.p. 230-232 ° C.

Analysis for C H N O.HCl.0.5H 2 O: Calculated: C, 65.4; H, 6.9; N, 11.45% Fu + and C = 65.3; H, 6.6; N, 11.1% 460 359 za 1Example 10. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imiazol-1-yl) methyl] afecafbazo-4-an-hyafaciaride áihydrat. 18.3 g of 1,2,3,9-tetrahydro-9-methyl-3- [T2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in a hot mixture of 90 ml of isopropa nol and 18.3 ml of water were treated with 6.25 ml of concentrated hydrochloric acid. The hot mixture was filtered, and the filtrate was diluted with 90 ml of isopropanol. The mixture was stirred at room temperature for 17 hours and then cooled to 2 ° C. 21.6 g of a solid were filtered off. A sample thereof (6 g) was recrystallized from a mixture of 6 ml of water and 10 ml of isopropanol. This gave 6 g of the title compound as a white crystalline solid, m.p. 178.5-179.5 ° C.

Analysis for C 12 H 19 N 3 O.HCl 1.2H 2 O = Calculated: C, 59.1; H, 6.6; N, 11.5% Found: C, 59.45; H, 6.45; N, 11.5% Water content: C H N 3 O.HCl.2H 2 O: 12 19 6 Calculated: _ 9.85% 1 Found: 10.23%.

Example 11, 1,2,3,9-Tetrahydro-3- [2H-methyl-1H-imidazol-1 + yl) methyl] -9-phenyl-4H-carbazol-4-one maleate. (i) 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one hydrochloride.

A solution of 3.90 g of 1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one, 1.50 g of dimethylamine hydrochloride and 0.60 g of paraformaldehyde in glacial acetic acid was boiled under reflux and with stirring in nitrogen gas. moss sphere for 42 hours, after which it was allowed to cool and 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 hours. The resulting solid was filtered off, washed with dry ether (4 x 30 ml) and dried. 4.2 g of the title compound were obtained. A portion of it (1.0 g) was recrystallized twice in 10 ml of absolute ethanol. This gave 0.39 g of the title compound as a light yellow-brown powder, melting at 193-194 ° C with decomposition. (ii) 1,2,3,9-Tetrahydro-3 - 1- (2-methyl-1H-imidazol-1-yl) -methyl] -9-phenyl-4H-carbazol-4-one maleate. 1.4 g of 2-methyl-1H-imidazole was added under nitrogen to a stirred suspension of 2.0 g of 3 - [(dimethylamino) methylz-1,2,3,4-tetrahydro-9-phenyl-4H-carbazole-4 -one hydrochloride in 20 ml of water. Mixture 2, 460 559 was deheated at 90 ° C for 43 hours, after which the solvent was decanted from the light tan solid. Chloroform was added to the solid, the suspension was filtered through hyflo, the filtrate was dried and concentrated in vacuo. The remaining light tan foam (2.04 g) was subjected to chromatography, eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 200: 10: 1. 1.1 g of a white foam were obtained. A solution of this foam in 3 ml of ethanol was treated with 0.4 g of maleic acid in 1 ml of ethanol and then with 40 ml of dry ether.

The resulting gum was triturated with dry ether (2 x 40 ml). This gave 1.37 g of the title compound as a cream solid, melting at 165-166 ° C with decomposition.

Analysis for C 23 H 21 N 3 O.C 4 H 4 O 4: Calculated: C, 68.8; H, 5.3; N, 8.9% Found: C, 68.65; H, 5.5; N, 8.7% Example 12. 1,2,3,9-Tetrahydro-9-methyl-3-Al 2 -methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one phosphate (1: 1). 0.61 g of 1,2,3,9-tetrahydro-9-methyl-3- [γ2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one was dissolved in a hot mixture of phosphorus acid (90%; 0.13 ml) and 10 ml of water. The solution was filtered through hyflo, after which crystallization took place. This gave 0.5 g of the title compound, m.p. 225 ° C.

Analysis for C H N 0.H 3 PO 4: Calculated: C, 55.2; H, 5.7; N, 10.7% Found: C, 55.1; H, 5.6; N, 10.55% Example 13. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one -citrate (2: 1). 0.89 g of 1,2,3, e-tetranyaro-e-methyl-s- (2-methyl-ox-imiaazol-1-yl) methyl] -4H-carbazol-4-one was dissolved in a hot solution of 0, 58 g of citric acid in 20 ml of ethanol, after which crystallization took place.

The resulting crystalline solid was recrystallized by dissolving in 2 ml of a 2: 1 by volume mixture of acetone and water, then diluting with 20 ml of acetone. This gave 0.6 g of the title compound, m.p. 162 DEG.

Example 14. 1,2,3,9-Tetrahydro-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride. 0.75 ml of iodomethane was added to a stirred solution of 2.9 g of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one in 30 ml of dry DMF, after which the resulting the solution was stirred at room temperature for 30 minutes. A solution of 2 g of 2-propyl-1H-imidazole in 5 ml of DMF was added, and the resulting solution was stirred at 100 ° C for 2 days, then cooled and partitioned between 2N sodium carbonate solution (150 ml) and ethyl acetate (2 x 100 ml). The combined extracts were washed with 100 ml of water, dried and evaporated in vacuo. The residue was purified by column chromatography eluting with a mixture of dichloromethane, ethanol and ammonia in a volume ratio of 400: 30: 3. This gave 1.2 g of the free base as a solid. A sample thereof (0.2 g) was dissolved in 5 ml of absolute ethanol, after which the solution was acidified with an ethereal solution of hydrogen chloride and diluted with about 200 ml of dry ether. The oil thus formed crystallized on scraping, whereby 0.15 g of the salt was recrystallized from a mixture. This gave 0.08 g of the title compound, m.p. 206-208 ° C. of a solid was obtained. methanol and isopropyl acetate.

Analysis for C 19 H 21 N 3 O.HCl · 0.2H 2 O: Calculated: C, 65.7; H, 6.5; N, 12.1% Found: C, 65.6; H, 6.8; N, 12.0% NMR: δ (CD 3 SOCD 3): 0.94 (3H, t, CH 3), 1.77 (2H, Sextet, CH 2 Cl 2 CH 3), 1.9-2.15 and 2.95-3 , 2 (7H, m), 4.32 and 4.71 (ZH, §§X, CHQEZN), 7.1-8.0 (6H, aromatic).

Example 15. 1,2,3,9-Tetrahydro-3- [72-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride.

A solution of 0.03 g of the product prepared in Example 3g in 15 ml of methanol was hydrogenated at room temperature and atmospheric pressure over a catalyst consisting of 10% palladium oxide on charcoal (50% aqueous paste; 0.03 g) for 4 hours (hydrogen uptake was 5 ml). The catalyst was filtered off, and the filtrate was evaporated in vacuo to an oil. When this oil was triturated with ether, 0.03 g of the title compound was obtained as a white solid, m.p. 199 DEG-23 DEG.

Using thin layer chromatography and NMR spectrum, this product was shown to be identical to the product prepared in Example 14.

Example 16. 1,2,3,9-Tetrahydro-9-propyl-3- [K2-propyl-1H-imidazel-1-yl] methyl] -4H-carazazol-4-onephyaracioria. Sodium hydride (80% dispersion in oil) was added under nitrogen to a stirred solution of 1.0 g of the F product prepared in Example 14 in 20 ml of dry dimethylformamide. The resulting suspension was stirred at room temperature for 30 minutes. Then 0.35 ml of 1-bromopropane was added, after which the reaction mixture was stirred at 40 ° C for 20 hours. The resulting solution was partitioned between 2N sodium carbonate solution (150 ml) and ethyl acetate (2 x 100 ml). The combined extracts were washed with 100 ml of water, dried and evaporated in vacuo to an oil. This oil was purified by column chromatography, eluting with a mixture of dichloromethane, ethanol and ammonia in a volume ratio of 100: 8: 1.

This gave a pure free base such as an oil. This oil was dissolved in 5 ml of absolute ethanol, after which the solution was acidified with an ethereal solution of hydrogen chloride and diluted with 200 ml of dry ether. The ether was decanted from the resulting oil and replaced with another 200 ml of dry ether. When the oil was allowed to stand at 0 ° C overnight, it crystallized to give 0.53 g of the title compound, m.p. 144-147 ° C.

NMR: δ (CD 3 SOCD 3): 0.90 and 0.93 (6H, t + t, 2xMe), 1.65-2.2 and 2.9-3.25 (10H, m), 4.19 (ZH , t. CH2g§2N), 4.32 and 4.71 (2H, ABX, CH2§§2N), 7.15-8.1 (6H, aromatic).

Analysis for C 22 H 27 N 3 O.HCl, 0.7H 2 O: Calculated: C, 663 ,; H, 7.4; N, 10.5% Found: C, 66.6; H, 7.7; N, 10.0% Example 17. 1,2,5-Sα-tetrahyaro-s-fl-methyl-na-imiaazol-1-yl) methyl [9-propyl-4H-carbazol-4-one maleate.

A solution of 0.86 g of the product prepared in Example 6 in a mixture of 20 ml of absolute ethanol and 5 ml of dry dimethylformamide was hydrogenated at room temperature and atmospheric pressure over a catalyst consisting of 5% platinum on carbon (0.1 pre-reduced in 10 ml of absolute ethanol) for 1 hour (hydrogen uptake was 70 ml). The catalyst was filtered off and washed with ethanol, and the filtrate was concentrated in vacuo to a volume of about 15 ml. The residual solution was stirred and diluted with 50 ml of water, and the precipitated solid was filtered off, washed with water (3 x 15 ml) and dried to give 0.73 of a powder.

This material was dissolved in 7 ml of refluxing ethanol. The solution was filtered, and a solution of 0.25 g of maleic acid in 1 ml of refluxing absolute ethanol was added. The stirred solution was diluted with 50 ml of dry ether. This gave 0.84 g of the title compound, m.p. 150-151 ° C. Analysis for C 20 H 23 N 3 O.C 4 H 4 O 4: Calculated: C, 65.9; H, 6.2; N, 9.6% Found: C, 65.8; H, 6.1; N, 9.3% Example 18. 1, α, 3,9-tetrahydro-β-methyl-3- [γ-methyl-1H-imidazol-1-yl) methyl] -4H-carbarol-α-one. (i) 3- (Chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazole-E 3.0 ml of an ethereal solution of hydrogen chloride was added to a stirred, ice-cooled solution of 1.90 g of the product prepared in Preparation 3 in 15 ml of chloroform, after which the resulting suspension was stirred in a closed vessel at room temperature for 16.5 hours.

Then the suspension was concentrated in vacuo, and the residual solid (2.27 g) was purified by column chromatography, eluting with chloroform. This gave 1.75 g of the title compound, m.p. 109-110.5 ° C. An attempt to crystallize a portion of this material in ethyl acetate resulted in partial decomposition. (ii) 1,2,3,9-Tetrahydro-9-methyl-3- [T2-methyl-1H-imidazol-1-yl) methyl-Lznecarbazole-fa-qn. A solution of 0.50 g of 3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (0.50 g) and 1.60 g of 2-methyl- 1H-imidazole in dry dimethylformamide was stirred under nitrogen at 90 ° C for 3.75 hours and then poured into 25 ml of water. The resulting suspension was stirred for 1 hour, then the solid was filtered off, washed with water (3 x 20 ml) and dried in vacuo at 5000. This solid (0.53 g) was purified by column chromatography, eluting with with a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 150: 10: 1. This gave 0.45 g of the title compound, m.p. 228-229 ° C. Using thin layer chromatography and NMR spectrum, this product was shown to be identical to the product prepared in Example 7. Example 19. 1,2,3,9-Tetrahydro-8-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one.

A solution of 170 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 1.5 ml of dry tetrahydrofuran was added dropwise under nitrogen to a stirred, ice-cold suspension of 100 mg of the preparation prepared in Preparation 4. the product in a mixture of 3.5 ml of tetrahydrofuran and 0.4 ml of water. The resulting blue solution was stirred for 1.5 hours and then concentrated in vacuo. The residual solid was purified by column chromatography eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 150: 10: 1. This gave 45 mg of the title compound, m.p. 227-228.5 ° C. Using thin layer chromatography and NMR spectra, this product was found to be identical to the product of Example 7. Example 20. 71,2,3,9-Tetrahydro-9-methyl-3- [72-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one.

A solution of 80 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 1.5 ml of dry tetrahydrofuran was added dropwise under nitrogen to a stirred, ice-cold suspension of 100 mg of the product prepared in Preparation 5 in a mixture of 3.5 ml of tetrahydrofuran and 0.4 ml of water. The resulting blue solution was stirred for 1.5 hours, after which the red suspension was concentrated in vacuo.

The residual solid was purified by column chromatography eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 150: 10: 1. This gave 0.47 g of the title compound as a white solid, m.p. 227.5-279 ° C. Using thin layer chromatography and NMR spectrum, this product was shown to be identical to the product prepared in Example 7.

Example 21. 3S-1,2,3,9-Tetrahydro-3 - [(2-methylimidazol-1-yl) methyl] -9-methyl-4H-carbazol-4-one maleate.

A solution of 0.5 g of the product prepared in Example 7 in 30 ml of hot methanol was treated with a hot solution of 0.7 g of (+) - di-p-toluoyl-D-tartaric acid monohydrate in 10 ml of methanol. The resulting solution was allowed to crystallize overnight to give 0.68 g of the desired salt. This salt was dissolved in 20 ml of hot dimethylformamide. The solution was diluted with 10 ml of hot water and allowed to crystallize overnight. The product was filtered off and dried in vacuo. This gave 0.23 g of (+) - di-p-toluoyl-D-tartaric acid salt, m.p. 231-233 ° C. Using the NMR spectrum, it was shown that the enantiomeric purity of the product was about 90%. A sample of this salt (0.15 g) was partitioned between 8% sodium bicarbonate solution (25 ml) and chloroform (2 x 25 ml). The combined extracts were dried and evaporated in vacuo to give 0.07 g of pure free base. The base was dissolved in 5 ml of methanol, the solution was acidified with 0.03 g of maleic acid, and the salt precipitated by adding an excess of dry ether (80 ml). This gave 0.062 g of the title compound, m.p. 142-145 ° C. 460 559 2 32 The product gave an Rf value of 0.3 by thin layer chromatography on silica using a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 100: 8: 1 as eluent. Ultraviolet light and iodo-platinum acid were used for the detection. The product was identical to the product prepared in Example 7. The enantiomer ratio S: R, determined by 1 H-NMR, was 93: 7. A sample of the maleate salt showed no significant optical rotation in methanol. The free base regenerated from the maleate salt exhibited the following optical vtidaiag = fdjšs. = -14 ° (e 0.19, MeOH).

Example 22. 3R-1,2,3,9-Tetrahydro-9-methyl-3- [γ2-methyl-1H-imidol-1-yl) methyl] -4H-carbazol-4-one maleate.

A solution of 0.5 g of the product prepared in Example 7 in 30 ml of hot methanol was treated with a hot solution of 0.7 g of (-) - di-p-toluoyl-L-tartaric acid monohydrate in 10 ml of methanol. The resulting solution was allowed to crystallize overnight to give 0.8 g of the desired salt. This salt was dissolved in 20 ml of hot dimethylformamide. The solution was diluted with 10 ml of hot water and allowed to crystallize for 3 days. The product was filtered off and dried in vacuo. This gave 0.26 g of (-) - di-p-toluoyl-L-tartaric acid salt, m.p. 170 DEG-172 DEG. using the Niin spectrum, the enantiomeric purity of the product was shown to be about 95%. A sample of this salt (0.2 g) was partitioned between 8% sodium bicarbonate solution (25 ml) and chloroform (2 x 25 ml). The combined extracts were dried and evaporated in vacuo to give 0.12 g of pure free base.

The base was dissolved in 5 ml of methanol, the solution was acidified with 0.045 g of maleic acid, and the salt precipitated by adding an excess of dry ether (80 ml). This gave 0.08 g of the title compound, m.p. 142-145 ° C.

The product gave an Rf value of 0.3 by thin layer chromatography on silica using a mixture of dichloromethane, ethanol and 0.88 ammonia in a volume ratio of 100: 8: 1 as eluent. Ultraviolet light and iodoplatinic acid were used for the detection. The product was identical to the product prepared in Example 7. The enantiomer ratio, determined by 1 H-NMR, was 95: 5.

A sample of the maleate salt showed no significant optical rotation in methanol. The free base regenerated from the maleate salt showed the following optical rotation: [à 1234 = + 16 ° (e 0.34, meon). The following examples illustrate pharmaceutical compositions of the invention containing 1,2,9-tetrahydro-9-methyl-3- [γ2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4- on-hydrochloride dihydrate as active ingredient (1.25 g of hydrochloride dihydrate contains 1.00 g of free base). Other compounds of the invention may be used for the preparation of compositions in a similar manner.

Tablets for oral administration Tablets may be prepared by conventional methods, such as direct compression or wet granulation. The tablets may be film-coated with suitable film-forming materials, such as hydroxypropyl methylcellulose, using standard methods. Alternatively, the tablets can be sugar coated.

Direct compression Tablet mg / tablet active ingredient 4,688 28,125 calcium hydrogen phosphate BP (quality suitable for direct compression) 83.06 87.75 croscarmellose sodium NF 1.8 1.8 magnesium stearate BP 0.45 0.45 total weight 90.0 118, The active ingredient was sieved through a 0.25 mm orifice sieve and then mixed with calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. The resulting mixture was compressed into tablets using a Manesty F3 tablet machine equipped with 5.5 mm flat tablet punches with bevelled edges.

Sublingual tablet mg / tablet active ingredient 2.5 compressible sugar NH 62.5 magnesium stearate BP 0.5 total weight 65.0 The active ingredient is sieved through a suitable sieve and mixed with the excipients. The resulting mixture is compressed into tablets using suitable punches. Tablets of different strengths can be prepared by changing the ratio of active ingredient to excipient or changing the total weight and using appropriate punches. 460 359 34 Wet granulation ordinary tablet mg / tablet active ingredient 2.5 lactose BP 151.5 starch BP 30.0 pregenatinized maize starch BP 15.0 magnesium stearate BP 1.5 tøtai weight 2oo, o The active ingredient is sieved through a suitable sieve and mixed with lactose, starch and pregelatinized corn starch.

Appropriate volumes of purified water are added, and the resulting mixture is granulated. After drying, the granules are sieved and mixed with the magnesium stearate. The granules are then compressed into tablets using a 7 mm diameter tablet punch.

Tablets of different strengths can be prepared by changing the ratio of active ingredient to lactose or changing the total weight and using suitable punches.

Sublingual tablet mg / tablet active ingredient 2.5 mannitol BP 56.5 hydroxypropylmethylcellulose 5.0 magnesium stearate BP 1.5 total weight 65.5 The active ingredient is sieved through a suitable sieve and mixed with the mannitol and hydroxypropylmethylcellulose. Appropriate volumes of purified water are added, and the resulting mixture is granulated. After drying, the granules are sieved and mixed with the magnesium stearate. The granules are then compressed into tablets using suitable tablet punches.

Tablets of different strengths can be prepared by changing the ratio of active ingredient to mannitol or changing the total weight and using suitable punches.

Capsules mg / capsule active ingredient 2,5 ïstäreklse 1500 (a form of directly compressible starch) 7 97.0 magnesium stearate BP> '1,0 total weight 100,0 35 460 359 The active ingredient is sieved and mixed with the excipients. The mixture is filled into No. 2 hard gelatin capsules using a suitable machine. Other doses can be prepared by changing the total weight and possibly changing the capsule size.

E22 The syrup can be either sucrose-containing or sucrose-free.

(A) Sucrose-containing syrup mg / 5 ml dose active ingredient 2.5 sucrose BP 2750, D glycerol BP 500.0 buffer, flavoring, coloring and preservative as needed purified water BP to 5.0 ml The active ingredient, buffer, flavoring, the dye and preservative are dissolved in a 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, and the volume of the mixture is set to the desired value. The syrup is clarified by filtration.

(B) Sucrose-free syrup mg / 5 ml dose active ingredient 2.5 hydroxypropoylmethylcellulose USP (viscosity type 4000) 22.5 buffer, flavoring, coloring, preservative and sweetener as needed * purified water BP to 5.0 ml The hydroxypropylmethylcellulose is dispersed in hot water, after which the dispersion is cooled and mixed with an aqueous solution containing the active ingredient and the other components of the composition. The volume of the resulting solution is then set to the desired value. The syrup is clarified by filtration.

Injection formulation The injection formulation can be administered intravenously or subcutaneously. Ä _ _ leo 509 36 2219; active ingredient 50 800 dilute hydrochloric acid BP to pH 3.5 to pH 3.5 sodium chloride solution for injection BP to 1 ml to 1 ml The active ingredient is dissolved in a suitable volume of sodium chloride solution for injection, after which the pH of the resulting solution is adjusted to 3.5 with dilute hydrochloric acid. The volume of the solution is then adjusted to the desired value with sodium chloride solution for injection, and the solution is mixed thoroughly.

The solution is poured into 5 ml clear glass ampoules of type 1, which are sealed under air by fusing the glass. The vials are then sterilized by autoclaving at 120 ° C for at least 15 minutes.

Aerosol in pressure vessel for metered dose Suspension aerosol mg / metered dose atomized active ingredient 0.250 66 mg oleic acid BP »0.020 5.28 mg trichlorofluoromethane BP 23.64 5.67 g dichlorodifluoromethane BP 61.25 14.70 g The active ingredient is finely divided a fluid energy mill to a fine particle size. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C, and the finely divided active ingredient is mixed into the solution by means of a high shear mixer. The suspension was measured in aluminum aerosol containers. Suitable measuring valves, which give 85 mg of suspension, are shrunk on the containers. The dichlorodifluoromethane is then pressurized on the containers through the valves.

Solution aerosol 7 mg / metered dose of active ingredient 0.25 _ 30.0 mg ethanol BP in 7,500 1.80 g trichlorofluoromethane BP _ 18.875 4.35 g dichlorodifluoromethane BB 48.525 11.65 g The composition may also contain oleic acid BP or a suitable surfactant, e.g. Span 85 (sorbitan trioleate).

The active ingredient is dissolved in the ethanol together with any oleic acid or surfactant used. The alcohol solution is measured in suitable aerosol containers, after which the trichlorofluoromethane Per container Per container .fl

Claims (16)

Lu \ J 460 359 is added. Suitable measuring valves are shrunk on the containers, after which the dichlorodifluoromethane is pressurized on the containers through the valves. Inhalation Gatrons may / Eatron atomized active ingredient 0.5 lactose BP to 25.00 The active ingredient is atomized in a fluid energy mill to a fine particle size, after which it is mixed with ordinary tablet grade lactose in a high energy mixer. The powder mixture is filled into No. 3 hard gelatin capsules using a suitable machine. The contents of the cartridges are administered using a powder inhaler. P a t e n t k r a v A compound of the general formula O wherein R1 represents a hydrogen atom, a C1-10 alkyl group, a C3-7 cycloalkyl group, a C3-6 alkenyl group, a phenyl group or a phenyl C 1-3 alkyl group, and wherein one of the symbols R, R and R represents a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 2-6 alkenyl group or a phenyl-C 1-3 alkyl group, and each of the other two symbols , which may be the same or different, denotes a hydrogen atom or a C 1-6 alkyl group; and physiologically acceptable salts and solvates thereof. _ A compound according to claim 1, characterized in that R represents a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C3-6 alkenyl group. A compound according to claim 1 or 2, characterized in that one of the symbols R 2, R 3 and R 4 represents a C 1-6 alkyl group, Y 1-3 1 a C 3-6 cycloalkyl group or a C 3-6 alkenyl group, and each of the the other two symbols, which may be the same or different, denote a hydrogen atom or a C 1-3 alkyl group. 4. A compound according to claim 1, wherein R 1 represents a hydrogen atom, a C 1-6 alkyl group, a C 5-6 cycloalkyl group or a C 4-4 alkenyl group, and either R 2 represents a hydrogen. 2 atoms and R and / or R 4 represent a C 1-3 alkyl group, or R represents a C 1-3 alkyl group and both R 3 and R 4 represent hydrogen atoms. A compound according to claim 1, characterized in that it has the general formula o R "a n3a in IN .N (IB) YN å1a RÉE where R1a represents a hydrogen atom, a methyl group, an ethyl group, a propyl group prop-2-yl group, a prop-2-enyl group or a cyclopentyl group, wherein R 3a represents a hydrogen atom, and wherein either R 2a represents a methyl group, an ethyl group, a propyl group or a prop-2-yl group and R 4a represents a hydrogen atom, or R a represents a hydrogen atom and R 4a represents a methyl group or an ethyl group; and physiologically acceptable salts and solvates thereof. Compound according to Claim 1, characterized in that it is 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H- carbazol-4-one or a physiologically acceptable salt or solvate thereof. A compound according to claim 1, characterized in that it is 1,2,3,9, -tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in the form of a hydrochloride salt. Compound according to Claim 1, characterized in that it is 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H -carbazol-4-one hydrochloride dihydrate. Compound according to Claim 1, characterized in that it is 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-imidazol-1-yl) methyl] -4H-carbazol-4-one; 1,2,3,9-tetrahydro-3 - [(2-methyl-TH-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazol-4-one; (dk 39 460 359 or a physiologically acceptable salt or solvate of any of these compounds. Process for the preparation of a compound of general formula I according to claim 1 or a physiologically acceptable salt or solvate thereof, characterized in that (A) a compound of general formula O (II) N 1 H 1 (wherein R 1 has the meaning given in claim 1, and Y represents a reactive substituent), or a protected derivative thereof, is reacted with an imidazole of the general formula RL 'H3 \ I (III) HN \ T7N H2 (where R2, R3 and R4 have the the meanings given in claim 1) or a salt thereof; or (B) oxidizing a compound of formula 3 11. A RA R (IV) MW ”N | R 1 R (where A represents a hydrogen atom or a hydroxyl group, and R 1, R 2, R 3 and R 4 have the meanings given in claim 1) or a salt or a protected derivative thereof; or (C) a compound of formula I, or a salt or a protected derivative thereof, is converted to another compound of formula I; or (D) one or more protecting groups are removed from a protected form of a compound of formula I; 460 559 40 f., Wherein, when a compound of formula I is obtained as a mixture of enantiomers, this mixture is optionally divided to form the desired enantiomer; I and / or wherein, if the compound of formula I is in the form of a free base, this free base is optionally converted to a salt. In that Y represents an alkenyl group = CH2 or a group with Process according to claim 10, alternative (A), the formula CHZZ, wherein Z represents an atom or group which is easily displaced. A compound of formula I, or a salt or a process according to claim 10, alternative (C), characterized by a protected derivative thereof, is converted to another compound of formula I by alkylation or hydrogenation. Pharmaceutical composition, characterized in that it comprises at least one compound of the general formula wherein R 1 represents a hydrogen atom, a C 1-10 alkyl group, a C 3-7 cycloalkyl group, a C 3-6 alkenyl group, a phenyl group or a phenyl-C 1-3 alkyl group, and wherein one of the symbols R, R and R represents a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 2-6 alkenyl group or a phenyl-C 1-3 alkyl group. alkyl group, and each of the other two symbols, which may be the same or different, denotes a hydrogen atom or a C 1-6 alkyl group or a physiologically acceptable salt or solvate thereof, together with at least one physiologically acceptable carrier or at least one physiologically acceptable excipients. That it comprises 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imide composition according to claim 13, characterized by zol-T-yl) methyl] -4H- carbazol-4-one or a physiologically acceptable salt or solvate thereof. 15. * that it comprises 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imida-Composition according to claim 13, characterized by 4 * 460 359 zol-1-yl) methyl] -4H-carbazol-4-one in the form of a hydrochloride salt. Composition according to Claim 13, characterized in that it comprises 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole -4-one hydrochloride dihydrate.