DK169521B1 - 3-Imidazolylmethyltetrahydrocarbazolones, process for their preparation and pharmaceutical compositions containing the compounds - Google Patents

Description

DK 169521 B1

The present invention relates to heterocyclic compounds, processes for their preparation, and pharmaceutical compositions containing the compounds. The invention relates in particular to compounds acting on certain 5-hydroxytryptamine-5 (5HT) receptors.

5HT, which is endogenously high in peripheral nerves and platelets, is known to cause pain in humans through a specific effect on 5HT receptors located on terminals of primary supplying nerves. It has been shown that compounds that antagonize the neuronal effects of 5HT have analgesic effect, e.g., for the relief of migraine pain. 5HT also causes depolarization of an isolated rat vagus nerve preparation through the same 5HT receptor mechanism, and inhibition of this effect correlates with an analgesic effect in vivo.

5HT also occurs commonly in neuronal pathways of the central nervous system, and disruption of these 5HT-containing pathways is known to alter behavioral syndromes such as mood, psychomotor activity, appetite, and memory. Since "neuronal" 5HT-20 receptors of the same type as those present on the primary delivery terminals are also present in the central nervous system, it is believed that compounds that antagonize the neuronal effects of 5HT will be useful in the treatment of such conditions as schizophrenia, anxiety, obesity and 25 mania.

Existing treatments for such conditions have a number of drawbacks. Thus, for example, known treatments for migraine include the administration of a vasoconstrictor such as ergotamine, which is non-selective and contracts blood vessels throughout the body. Ergo-30 tamin therefore has undesirable and potentially dangerous side effects. Migraine can also be treated by giving an analgesic such as aspirin or paracetamol, usually in combination with an antiemetic such as metaclopramide, but these treatments have only limited value.

Similarly, existing treatments for psychotic disorders such as schizophrenia exhibit a number of serious side effects such as extrapyrimidal side effects.

Thus, there is a need for a safe and effective means of treating conditions in which disruption of 5HT-containing pathways is implicated such as migraine or psychotic conditions such as schizophrenia. It is believed that a compound that is a potent and selective antagonist at "neuronal" 5HT receptors will play such a role.

Applicants have now found a class of 3-imidazolylmethyltetra-hydrocarbazolones which are potent and selective antagonists of "neuronal" 5HT receptors.

The present invention provides a tetrahydrocarbazolone of the general formula I

0 R * R3 II \ / / uVn

15 i! “In V

\\ / \ / \ / I, • N · R2

R 1 wherein R 1 is hydrogen, alkyl, C 3-7 cycloalkyl, C 3-6 alkenyl, phenyl or phenyl C 1-3 alkyl, and one of the groups R2, R 3 and R 4 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C2-6 alkenyl or phenylC1-6 alkyl, and each of the other two, which may be the same or different, is hydrogen or C1-6 alkyl; and physiologically acceptable salts and solvates, e.g., hydrates thereof.

It will be understood that when R1 is C3-6 alkenyl, the double bond cannot sit next to the nitrogen atom.

DK 169521 B1 3

Referring to the general formula I, the alkyl groups represented by R 1, R 2, R 3 and R 4 can be straight or branched chain alkyl groups, for example methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop -2-yl, pentyl, pent-3-yl or hexyl.

For example, an alkenyl group may be propenyl.

For example, a phenyl-O-β-3-alkyl group may be benzyl, phenylethyl or 3-phenylpropyl.

For example, a cycloalkyl group may be cyclopentyl, cyclohexyl or cycloheptyl.

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

Suitable physiologically acceptable salts of the indoles of general formula I include acid addition salts formed with organic or inorganic acids, e.g., hydrochlorides, hydrobromides, sulfates, phosphates, citrates, fumarates and maleates. For example, the solvates may be hydrates.

A preferred class of compounds of general formula I are those wherein R 1 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 alkenyl.

Another preferred class of compounds of the general formula I are those wherein one of the groups R 2, R 3 and R 4 is C 3-3 cycyl, C 3-6 cycloalkyl or C 3-6 alkenyl, and each of the other two groups comprising may be the same or different, is hydrogen or C1-3 alkyl.

DK 169521 B1 4

Yet another preferred class of compounds of the general formula I are those wherein R 1 is hydrogen, C 1-6 alkyl, C 5,6 cycloalkyl or C 3-4 alkenyl and where either R 2 is hydrogen and R 3 and / or R 4 is C 1-3. -alkyl, or R 2 is C 1-3 alkyl, and both R 3 and R 4 are hydrogen.

A particularly preferred class of compounds of the invention are compounds of the general formula Ia R * a R ^ a / \ Λ Λπ

• --- · N N

I II II I \ // • · · · · -Lo.

\\ / \ / \ / L

• N · R2a

R 1® wherein R 11 is hydrogen, methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl; R 3a is hydrogen; and wherein either R 2a is methyl, ethyl, propyl or prop-2-yl, and R 4a is hydrogen or R 2a is hydrogen and R 4a is methyl or ethyl and physiologically acceptable salts and solvates (e.g. hydrates) thereof.

Preferred compounds are the following: 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-1-20yl) methyl] -4H-carbazol-4-one, and 1.2.3,9-tetrahydro-3- [ 2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazol-4-one and their physiologically acceptable salts and solvates.

A particularly preferred compound is 1,2,3,9-tetrahydro-9-25 methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one, which may be disclosed. by the formula Ib 8 DK 169521 B1 5 / Λ Λ / * \ ii

• · - · · N N

I II II I \ // Ib • · · · ·

\\ / \ / \ / I

• IjJ · Me

Me and physiologically acceptable salts and solvates (e.g. hydrates) thereof. 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 compounds of the invention, i. physiologically acceptable compounds which are converted in vivo to the original compound of general formula I.

Compounds of the invention are potent and selective antagonists for 5HT-induced responses in the isolated rat vagus nerve preparation and thus act as potent and selective antagonists of the "neuronal" 5HT receptor type located on primary supplying nerves.

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

Experiments in animals have shown that compounds of the invention are also useful in the treatment of schizophrenia and other psychotic disorders. As stated above, 5HT is common in the central nervous system neuronal pathways, and disruption of these 5HT-containing pathways is known to alter many other behavioral syndromes such as mood, appetite and memory. Since "neuronal" 5HT receptors of the same type as those present on primary supply terminals are also present in the central nervous system,

DK 169521 B1 I

6 of the invention may also be useful in treating such conditions as anxiety, obesity and mania.

From U.S. Patent Nos. 3,634,420 and 3,470,404 and R. Lit-tell, "Mannich bases of 2,3-dihydro-4 (1H) carbazolones as 5 potential psychotropic agents," Journal of Medicinal Chemistry, vol. 15, No. 8, 1971, pages 875-876, are known compounds which in some respects are structurally related to the present compounds. However, the known compounds are intrinsic tranquilizers which reduce locomotic activity, whereas no mention is made of the anxiolytic effects of the compounds.

In particular, the compounds of the general formula Ia as defined above have been found to be highly selective and highly potent in their action. They are well absorbed from the gastrointestinal tract and are suitable for oral or rectal administration. The compounds of the general formula Ia do not prolong dormancy in pentobarbitone-anesthetized mice, suggesting that there is no undesirable interaction with drug metabolizing enzymes. In fact, they show no effect on normal behavior, are non-toxic and exhibit no undesirable effects in mice at doses up to 1 mg / kg intravenously.

In addition to exhibiting the excellent properties seen in the compounds of the general formula Ia, the compounds of the general formula Ib, when administered to 25 people, show no adverse effects.

In another aspect, the invention enables a method of treating a human or animal suffering from a condition caused by a disorder of "neuronal" 5HT function. Thus, for example, the invention provides a method for treating people suffering from migraine pain or from a psychotic disorder such as schizophrenia.

Accordingly, the invention also provides a pharmaceutical composition comprising at least one compound selected from 3- imidazolylmethyltetrahydrocarbazolone derivatives of general formula I, their physiologically acceptable salts and solvates, e.g., hydrates, adapted for use in human or veterinary medicine, and formulated. for administration by any convenient route.

Such compositions may be formulated in conventional 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 insufflation (either by mouth or nose).

For oral administration, the pharmaceutical compositions may be in the form of, for example, tablets or capsules prepared in a conventional manner with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, 25 solutions, syrups or suspensions, or they may be in the form of a dry product for constitution with water or another suitable carrier prior to use. Such liquid preparations can be prepared in a conventional manner by pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous carriers (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The compositions may also contain buffer salts, flavors, dyes and sweeteners as required.

Compositions for oral administration may conveniently be formulated to provide controlled release of the active compound.

For buccal administration, the compositions may be in the form of tablets or pills formulated in conventional manner.

The compounds of the invention may be formulated for parenteral administration by injection. Formulation for injection may be presented in unit dosage form, for example in ampoules or in multi-dose containers as well as with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers and may contain formulation agents such as suspending agents, stabilizers and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable carrier, e.g., sterile pyrogen-free water, prior to use.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention layers, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the previously described formulations, the compounds of the invention can also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymers or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as heavily soluble derivatives, e.g., as a heavily soluble salt.

DK 169521 B1 9

For administration by inhalation, the compounds of the invention may conveniently be disclosed in the form of an aerosol spray formulation from pressure seals or a nebulizer using an appropriate propellant, e.g. For a pressure aerosol, the metering unit can be determined by using a valve that delivers a metered amount. Capsules or cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

A suggested dose of the compound of the invention for administration to humans (with a body weight of about 70 kg) is from 0.05 mg to 20 mg, preferably from 0.1 mg to 10 mg of the active ingredient per day. unit dose, which can be administered, for example, 1-4 times daily. The dose will depend on the route of administration and the patient's body weight. It will be clear that routine variations 20 of the dose may be required depending on the age and weight of the patient as well as the severity of the condition to be treated.

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

Aerosol formulations are preferably arranged such that each metered dose or "breath" delivered from a pressure aerosol contains from 0.2 mg to 2 mg of a compound of the invention and each dose administered via capsules and cartridges in an insufflator or an inhaler contains from 0 , 2 mg to 20 mg of a compound of the invention. The total daily dose by inhalation will range from 0.4 mg to 80 mg. Administration can be done several times daily, for example from 2 to 8 times, with, for example, 1, 2 or 3 doses given each time.

DK 169521 B1 10

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 yet another aspect of the invention, compounds of general formula I and physiologically acceptable salts or solvates or physiologically acceptable equivalents thereof can be prepared by the general methods set forth below.

According to a first general process (A), a compound 10 of the general formula I or a physiologically acceptable salt or solvate or a physiologically acceptable equivalent thereof can be prepared by a compound of the general formula II

0

II

• · Y

// \ / \ / I il ii I ii • · · · v \ / \ / \ / • N.

R1

(wherein R 1 is as previously defined and Y is a reactive substituent) or a protected derivative thereof, reacted with imidazole of the general formula III

R1 * R3 \ _ / HN lil

\ // III

1a (wherein R 2, R 3 and R 4 are as previously defined) or a salt thereof.

Examples of compounds of general formula II used in process (A) as starting material include compounds wherein Y is a group selected from alkenyl = CH 2 or a group of general formula CH 2 Z wherein Z is an easily leaving atom or group such as halogen, for example chlorine or bromine, acyloxy such as acetoxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy; a group - + NR5R6R7X 'wherein R5, R6 and R7, which may be the same or different, are each lower alkyl, for example methyl, aryl, eg phenyl, 5 or aralkyl, eg benzyl, or R5 and R6 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 is an anion such as a halide ion, e.g., chloride, bromide or iodide; or a group -NR5R6 wherein R5 and R6 are as defined above, for example 10 -N (CH3) 2.

If Y is the group = CH 2, the process may conveniently be carried out in a suitable solvent, examples of which include water; esters, e.g., ethyl acetate; ketones, e.g., acetone; or methyl isobutyl ketone; amides, e.g., dimethylformamide; alcohols, e.g., ethanol; and ethers, e.g., dioxane or tetrahydrofuran; or mixtures thereof. The process can be carried out at a temperature of, for example, 20-100 ° C.

If Y is the group CH 2 Z where Z is halogen or acyloxy, the process may conveniently be carried out in a suitable solvent such as an amide, for example dimethylformamide; an alcohol, for example ethanol or industrial denatured alcohol; or a halo-alkane, for example dichloromethane, and at a temperature of from -10 ° C to 150 ° C, for example from 20 ° C to 100 ° C.

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

The reaction comprising a compound of the general formula II wherein Y is the group -CH 2 Z, where Z is the group -NR 5 R 6 may conveniently be carried out in a suitable solvent such as water or an alcohol, eg methanol, or mixtures thereof, and in a temperature of from 20 ° C to 150 ° C.

DK 169521 B1 12

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

A R k R 3 I \ / / \ Λ Λι- in the π * i \ / iv • · · · · VVV in 5 * R 1 (where A is hydrogen or hydroxy, and R 1, R 2, R 3 and R 4 are as previously defined), 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 chosen so as not to cause oxidation of the indole group. Thus, the oxidation process is preferably carried out using a mild oxidizing agent.

When oxidizing a compound of general formula IV wherein A is hydrogen, suitable oxidizing agents include quinones in the presence of water, for example 2,3-dichloro-5,6-dicyanone-1,4-benzoquinone or 2,3,5,6-tetrachloro-1,4-benzoquinone; selenium dioxide; a cerium (IV) oxidizer such as cerium (IV) ammonium nitrate or a chromium (VI) oxidizer, e.g., a solution of chromic acid in acetone (e.g. Jones's reagent) or chromium trioxide in pyridine.

When oxidizing a compound of general formula IV wherein A is hydroxy, suitable oxidizing agents include quinones in the presence of water, e.g., 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3, 5,6-tetrachloro-l, 4-benzoquinone; ketones, for example acetone, methyl ethyl ketone or cyclohexanone in the presence of a base, e.g. aluminum tert-butoxide; a chromium (VI) oxidizer, e.g., a solution of chromic acid in acetone (e.g., Jones's reagent) or chromium trioxide in pyridine; an N-halo-succinimide, e.g., N-chlorosuccinimide or N-bromosuccinimide; a dialkyl sulfoxide, for example, dimethyl sulfoxide, in the presence of an activating agent such as N, Ν'-dicyclohexylcarbodiimide or an acyl halide, for example oxalyl chloride or tosyl chloride; pyridin-svovltrioxidcomplex; or a dehydrogenation catalyst such as copper chromite, zinc oxide, copper or silver.

Suitable solvents may be selected from ketones, for example acetone or butanone; ethers, eg tetrahydrofuran or dioxane; amides, e.g., dimethylformamide; alcohols, e.g., methanol; hydrocarbons, for example benzene or toluene; halogenated hydrocarbons, for example dichloromethane and water or mixtures thereof.

The process is conveniently carried out at a temperature of from -70 ° C to + 50 ° C. It will be clear that the choice of oxidant will affect the preferred reaction temperature.

According to yet another general process (C), a compound of general formula I according to the invention or a salt or protected derivative thereof can be converted to another compound of general formula I using conventional techniques. Such conventional techniques include alkylation which can be carried out in any position in connection with the general formula I wherein one or more of R 1 and R 2 is hydrogen, and hydrogenation which can be used, for example, to convert an alkenyl substituent to an alkyl substituent. The term "alkylation" includes the introduction of other groups such as cycloalkyl or alkenyl. Thus, for example, a compound of the general formula I wherein R 1 is hydrogen can be converted to the corresponding compound wherein R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, C 3-6 alkenyl or phenyl - C x. 3-alkyl.

The above alkylation reactions can be carried out using a suitable alkylating agent selected from the compounds of the general formula RaXa wherein Ra is C 1-6 alkyl, C 3-7 cycloalkyl, C 3-6 alkenyl or phenyl C 1-4 -alkyl, and Xa is a leaving group such as a halide or acyloxy group as previously defined for Z, or a sulfate of the general formula (Ra) 2 SO4.

DK 169521 B1 14

The alkylation reaction is conveniently carried out in an inert organic solvent such as an amide, e.g., dimethyl formamide; an ether, e.g., 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 tert-butoxide. The reaction may conveniently be carried out at a temperature in the range 10 from -20 ° C to + 100 ° C, preferably from 0 ° C to 50 ° C.

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

It will be understood that, in some of the above conversions, it may be necessary or desirable to protect any sensitive groups in the compound to avoid undesirable side reactions. Protective groups used in the preparation of the compounds of general formula I are preferably groups which can be readily cleaved off at an appropriate step in the reaction sequence, conveniently at the last step. For example, during any of the reaction sequences described above, it may be necessary to protect the keto group, for example as a ketal or a thioketal.

Thus, compounds of general formula I can be prepared according to yet another general method (D) which comprises removing any protecting groups from a protected form of a compound of general formula I. Deprotection DK 169521 B1 can be carried out using conventional techniques such as those described in "Protecting Groups in Organic Chemistry", edited by JFW McOmie (Plenum Press, 1973). Thus, a ketal such as an alkylene ketal can be removed by treatment with a mineral acid such as hydrochloric acid. The thioketal group may be cleaved by treatment with a mercuric salt, e.g., mercuric chloride, in a suitable solvent such as ethanol.

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

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

Individual enantiomers of the compounds of the invention can be obtained by cleavage of a mixture of enantiomers (e.g., a racemic mixture) using conventional methods such as an optically active resolving acid; cf. e.g., "Stereochemistry of Carbon Compounds" by E.L. Eliel (McGraw Hiil 1962) and "Tables of Resolving Agents" by S.H. Wilen.

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

The above-described methods for preparing the compounds of the invention can be used as the last step in the preparation sequence. The same general methods can be used to introduce the desired groups at an intermediate step in the stepwise formation of the desired compound, and it will be clear that these general methods can be combined in different ways in such multi-step process. 5 cesses. Of course, the order of the reactions in multi-step processes should be chosen such that the reaction conditions do not affect groups in the molecule desired in the final product.

The starting materials of general formula II wherein Y is the group = CH 2 can be prepared from compounds of general formula II wherein Y is the group - CH 2 + NR 5 R 6 R 7 "by reaction with a base in a suitable solvent. Examples of bases include alkali metal hydroxides. , for example, potassium hydroxide, or alkali metal carbonates or hydrogen carbonates, for example sodium bicarbonate.

The quaternary salts can be formed from the corresponding tertiary amine by reaction with an alkylating agent such as methyl iodide or dimethyl sulfate and, if preferred, in a suitable solvent, for example, dimethylformamide. The tertiary 20 amine can be prepared by a tetrahydrocarbazolone of the general formula V

0

II

/ \ Λ • · - · · I II II I v

V V V

R 1 is reacted with formaldehyde and the corresponding secondary amine if desired in a suitable solvent such as an alcohol, eg ethanol.

Compounds of general formula V can be prepared by the method described by H. Iida et al., J. Org. Chem. . 45, no.

15. pp. 2938-2942, 1980.

DK 169521 B1 17

The starting materials of general formula II wherein Y is -CH 2 Z, where Z is halogen or acyloxy can be prepared from the corresponding hydroxymethyl derivative of general formula VI

0

Λ A / CH2 ° H

5 i! ! N · R1 which can be obtained by reacting the tetrahydrocarbazolone of the general formula V with formaldehyde, preferably in a suitable solvent such as an alcohol, eg ethanol, and preferably in the presence of a base.

Thus, the compounds wherein Z is halogen can be obtained by reacting a compound of general formula VI with a halogenating agent such as a phosphorus trihalide, e.g., phosphorus trichloride.

The compounds wherein Z is acyloxy can be obtained by reacting a compound of general formula VI with an appropriate acylating agent such as an anhydride or a sulfonyl halide such as sulfonyl chloride.

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

Compounds of general formula IV can be prepared by providing a compound of general formula VII

DK 169521 B1 18

A

A Λ / CM2Zl will • · - · ·

I II ί! IN

• · · · \\ / \ / \ / • N ·

R 1 (where R 1 and A are as previously defined and Z 1 is an easily leaving atom or group such as halogen, acyloxy or the group - + NR 5 R 6 R 7 'as defined previously for Z) is reacted with an imidazole of the general formula III according to the process ( A) described earlier.

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

Compounds of general formula VII wherein A is hydrogen may also be prepared by reacting a compound of general formula VII wherein A is hydroxy with a tosyl halide (e.g. tosyl chloride) and then reducing the resulting tosylate by lithium aluminum hydride.

Compounds of general formula IV are novel compounds and therefore constitute yet another aspect of the invention.

The antagonistic effects of the compounds of the invention against responses induced by 5-HT at "neuronal" 5-HT receptors can be determined in vitro by the method described by S.J. Ireland, D.W. Straughan and M.B. Tyers; British Journal of Pharmacology, 75, 16P, 1982. The results of such tests are expressed as a pA2 value in the table below. This value is defined as the negative logarithm of the molar concentration of antagonist needed to reduce the effect of twice the ED50 of 5-HT to the ED50 value in the absence of antagonist.

DK 169521 B1 19

Compound of Example No. Isolated vagus nerve from rats

Calculated pA2 5 la 8.6 le 8.9 ld 8.0 lg 6.4 3c 8.6 10 4d 8.7 4th 8.2 4f 7.7 5 8.5 6 8.7 15 9 9.1 11 8.8

The compounds of the invention antagonism to responses induced by 5-HT at "neuronal" 5-HT receptors 20 can be evaluated in vivo by determining the effect of the compounds on the 5-HT-induced Bezold-Jarisch reflex. This test is described by D.P. Collins and R.H. Fortune in British Journal of Pharmacology j80, 570P, 1983. The results are expressed in the following table as an ED 50 value, which is the 25 dose needed to inhibit the 5-HT induced reflex by 50% (cf. JR Fozard and M. Host, British Journal of Pharmacology, TT_, 52OP, 1982).

Compound of Example No. ED50 (µg / kg) 30 Ia 7 5 3.2 6 2.5 9 11.6 35 DK 169521 B1 20

The invention is illustrated by the following examples. Where indicated, solutions were dried over Na 2 SO 4 and solids were dried in vacuo over P 2 O 5 at 50 ° C overnight. Chroma graphing was performed using the technique described 5 by W.C. Still et al. (J. Orq. Chem. M, pp. 2923-2925, 1978) on Kieselgel 9385.

PREPARATION 1 2.3.4.9- Tetrahydro-N, N, N-trimethyl-4-oxo-1H-carbazole-3-methanaminium iodide A solution of 0.53 g of 3- [(dime thylamino) methyl] -1, 2,3,9-tetrahydro-4H-carbazol-4-one in 15 ml of iodomethane was refluxed for 5 hours and evaporated to dryness to give the title compound as 0.84 g of a white solid, mp 202-205 ° C.

PREPARATION 2 2.3.4.9- Tetrahydro-N, N, N, 9-Tetramethyl-4-oxo-1H-carbazole-3-methanium 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 stirred at reflux for 57 hours. The resulting suspension was concentrated in vacuo to give 5.72 g of the title compound as a solid, mp 192-195 ° C.

PREPARATION 3 1.2.3.9- Tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one 25 A solution of 5.0 g of the product of Preparation 2 in 20 ml of water was treated with 6.55 ml of 2N sodium carbonate and heated at 35 ° C for 45 minutes. The resulting slurry was cooled to 0 ° C and the solid filtered off and washed with water to give 2.8 g of the title compound, mp 127-129 ° C.

PREPARATION 4 2,3,4,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) -5methyl] -1H-carbazole maleate 90 mg of sodium borohydride was added to a stirred nitrogen solution of 500 mg of the product of Example 7 in a mixture of 3 ml of methanol and 3 ml of chloroform. Stirring was continued for 48 hours (an additional 250 mg of sodium borohydride 10 was added after 17.75 hours and 42 hours) and the suspension was then partitioned between 15 ml of 2N hydrochloric acid and 3 x 10 ml of chloroform. The aqueous phase was made basic with solid sodium carbonate and extracted with 3 x 10 ml of chloroform, and the combined extracts were washed with 2 x 10 ml of water and 10 ml of brine, dried and concentrated in vacuo. Column chromatography of the residual foam (557 mg) eluted with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (300: 10: 1) gave 200 mg of a solid. This material was dissolved in 3 ml of refluxing absolute ethanol and 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 to give 240 mg of the title compound, mp 138.5-140 ° C.

PREPARATION 5 2,3,4,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazol-4-ol 30.0 g of the product from Example 7, nitrogen was added to a stirred suspension of 7.75 g of lithium aluminum hydride in 750 ml of dry tetrahydrofuran. The mixture was stirred under reflux for 1 hour and then cooled in ice. The suspension was gently diluted with 100 ml of aqueous tetrahydrofuran (15% H2 O) and 100 ml of water and concentrated in vacuo, and the residual solid was extracted with 2 x 500 ml of dichloromethane. The organic extracts were concentrated in vacuo and the residual solid (16.4 g) was purified by short silica gel column chromatography (Kiesel-5 gel® 60, Merck 7747, 500 g) eluted with a mixture of dichloromethane , ethanol and 0.88 aqueous ammonia (150: 10: 1) to give 13.4 g of the title compound as a foam. Thin layer chromatography, silica gel, dichloromethane (ethanol / 0.88 ammonia (150: 10: 1), Rf value 0.34 and 0.36 (two pairs of diastereoisomers), UV detection and iodoplatinic acid).

NMR Spectrum [CDCl3 + CD3OH (1 drop)]: δ (ppm) = 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), 6.8-7.8 (CH, m, aromatic).

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

A solution of 2.0 g of the product of Preparation 2 and 5.0 g of 2-methylimidazole in 30 ml of dry dimethylformamide was stirred under 95 nitrogen at 95 ° C for 16.75 hours and then allowed to cool. The solid which crystallized out was filtered off, washed with 3 x 2 ml ice-cold dry dimethylformamide and 2 x 10 ml dry ether and then dried. The resulting solid (0.60 g) was suspended in a mixture of 30 ml of absolute ethanol and 1 ml of ethanolic hydrogen chloride and gently heated to obtain a solution which was filtered hot. The filtrate was then diluted with dry ether to give a solid (0.6 g) which was recrystallized from absolute ethanol to give the title compound as a solid (0.27 g), mp 186-187 ° C .

Analysis:

Calcd for C 18 H 9 N 3 O · HCl-H 2 O: C 62.3 H6, 1.1 N 12.1

Found: C 61.9 H 6.4 N 11.8 DK 169521 B1 23 The following compounds were prepared by a similar procedure, as detailed in Table I.

TABLE I

5 Ex. Formula I Weight Weight Vol. Salt Weight No. R1 R2 R3 R4 ed. of addition. solution preparation, imidazole net cloth (g) (g) agent (g) (ml) 10-lb CH3 η η H 2.00 4.10 HCl 0.78

Melting point 199.5-200.5 ° C Analysis for C17H17N3O * HCl * 0.8H2O:

Calculated: C 61.8 H 5.9 N 12.7 Found: C 62.05 H 5.5 N 12.7 lc CH 3 H CH 3 CH 3 0.8 0.6 5 maleate 0.50

Melting point 151-152 ° C

Analysis for ε19Η21Ν30 · <34Η404 · 0.2H2O: Calculated: C 64.7 H6.0 N 9.8

Found: C 64.6 H 6.0 N 9.8 ld CH3 iPr Η H 3.2 2.9 40 HCl 1.0

Melting point 178-182 ° C Analysis for C20H23N3O-HC1-0.5H2O:

Calculated: C 65.5 H 6.9 N 11.45

Found: C 64.9 H 6.9 N 11.2 DK 169521 B1 TABLE 1 continued 24 le * Me H CH2Ph H 0.8 1.2 5 HCl 0.25

Melting point 130-135 ° C Analysis for ε24Η23Ν30 · Η (Ι1 · 0.5Η20:

Calculated: C 69.5 H6, N N 10.1

Found: C 69.1 H6, N N 9.9

If * Me Η H CH2Ph 0.8 1.2 5 - 0.05

Melting point 170-174 ° C

Analysis for ^ 24 ^ 23 ^ 3 ^ * 1:

Calculated: C 72.7 H 6.6 N 10.6

Found: C 72.8 H 6.2 N 10.5 15 µg * Me 2 H 1.0 1.0 HCl 0.3

Melting point 150-155 ° C

Analysis for C23H27N3O * HCl-0.3H2O:

Calculated: C 68.4 H 7.15 N 10.4

Found: C 68.5 H 7.55 N 10.4 20 TABLE 1 continued * 2,3,4,9-tetrahydro-9, N, N, N-tetramethyl-4-oxo-1H-carbazole-3 - methane aluminum methosulfate is used as starting material. In Table 25, f represents cyclohexyl.

Note 1

Compounds 1e and 1f were prepared by the same experiment and the isomers were separated by short-circuit chromatography (DF Taber, J. Orq. Chem. 47. p. 1351, 1982) by elution with dichloromethane / ethanol / 0.88 ammonia (300 : 10: 1). The following 1 H NMR data were obtained.

^^ ........

DK 169521 B1 25 O R2 5 *, l, • · · 1 'e 2i, // \ / \ 3 / \ / \\ 6 # · -. · N No. I II I! L .1_lu, d = duplicate 7 · · · »2 ς · - · '\ / \ / \ / / dd = duplicate of duplicates • N · Ru R3 8 ^ 1 s = singlet

Resolution NMR spectra (obtained at 250 MHz) 5 Selected Proton Chemical Shifts (δρρηα) mean and multiplicities

Carbazolone protons Imidazo- Imidazole-

Aromatic Aliphatic Lyl Methyl Protons 10 H-5,6,7,8 CH2-1 and CH2-2 Len Protons H-2 'H-4' H-3 and / or H-5 '4.47 (dd) 15 le 7 , 2-8.05 2.91-3.25 1.75-2.3 and 9.20s 7.55s d6-DMSO 4.64 (dd) 4.02 (dd) lf 7.15-8.05 2.6-3.05 1.75-2.1 and 8.17s 6.93s CHCl3 + DMSO 4.63 (dd) i.a. 4.42 (dd) 7.61d lg 7.2-8.05 2.9-3.3 1.6-2.2 and - and d5-DMSO 4.73 (dd) 7.70d ______ EXAMPLE 2 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-3-one maleate DK 169521 B1 26 300 mg 1 , 2,3,9-1etrahydro-9-methyl-3 - [(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one was suspended in 5 ml of hot ethanol and treated with 116 mg of maleic acid. The solution was cooled and the white crystalline solid filtered off and dried to give 300 mg of the title compound, mp 132.3 ° C.

Example 3a 1,2,3,9-Tetrahydro-3- (1H-imidazol-1-ylmethyl) -4H-carbazol-4-one A solution of 0.84 g of the product of Preparation 1 and 0.90 g of imidazole in 25 ml of dimethylformamide was heated to 105 ° C for 6 hours, cooled, added to 200 ml of water and extracted six times with ethyl acetate. The combined extracts were washed, dried and evaporated to give a solid which was purified on a silica gel column (Merck® 7734) eluted with ethyl acetate / methanol (4: 1). Twice recrystallization of ethyl acetate / methanol gave 0.095 g of the title compound as a crystalline solid, mp 220-222 ° C.

Thin layer chromatography: Silica gel, dichloromethane / ethanol / 0.88 ammonia (100: 8: 1), Rf value 0.33, UV detection and iodoplatinic acid.

The following compounds were prepared by a similar procedure as described in detail in Table II. Salt formation was performed as described in Example 2.

TABLE II

DK 169521 B1 27

Ex. Formula I Weight Weight Vol. Reak. Salt Weight No. R1 R2 R3 R4 ed. of addition. dissolved formate, imidazole temp., net cloth (g) (g) mean time / (g)

(ml) ° C

3b H CH3 Η H 6.60 17.00 75 17.25 / 100 maleate 0.40

Mp 155-156 ° C

3c H CH2 - Η H 7.00 10.50 75 18/85 maleate 0.48 CH3

Melting point 154.5-156 ° C

15 _________ 3d H CH2- Η H 3.00 3.10 25 24/100 maleate 0.61

Ph

Melting point 100.5-102 ° C

20 3rd Η H CH3 H 1.0 2.2 5 18/95 maleate 0.16

Melting point 144-145.5 ° C

3f Η Η H CH3 1.00 2.2 5 18/95 maleate 0.09

Melting point 143-144 ° C

25 _ 3g H 7 Η H 1.80 1.0 20 20/100 HCl 0.11

Melting point 7.1-8.0 DK 169521 B1 TABLE II continued 28

Ex. H NMR Spectra (obtained at 250 MHz) No. Selected Proton Chemical Shifts (5ppm) and Multiplicities 5__

Carbazolone protons Imidazo- Imidazole-

Aromatic Aliphatic Lyl Methyl Protons H-5,6,7,8 CH2-1 and CH2-2 Len H-2 'H-4' H-3 and / or 10 H-5 '4.29 (dd) 7.57d 3b 7.1-8.05 3.0-3.25 1.9-2.2 and - and 4.69 (dd) 7.67d - 4.32 (dd) 7.6ld 3c 7.15- 8.05 3.0-3.25 1.9-2.2 and 4.72 (dd) 7.69d 20 4.28 (dd) 7.59d 3d 7.15-8.05 2.85 -3.1 1.8-2.05 and - and 4.71 (dd) 7.71d 4.48 (dd) 25 3rd 7.15-8.05 3.0-3.20 1.75-2 , 25 and 8.97s 7.46s 4.62 (dd) 4.29 (dd) 3f 7.15-8.05 3.0-3.20 1.90-2.20 and 8.93s 7.41s 3.74 (dd) 6.32 (dd) 7.75d 3g 7.1-8.0 2.9-3.2 1.75-2.1 and - and 6.70 (dd) 7, 83d 35 _ DK 169521 Pg 29

Note 1

Compounds 3e and 3f were prepared by the same experiment and the isomers were separated by preparative HPLC on Zorbax-Sil eluted with hexane / ethyl acetate / ethanol / 0.88 ammonia-ac (400: 100: 100: 0.6). the positions of the protons numbered as given in the formula below, 0 R2 5 n ,, I, 6 // \ / W \ / \\, I Ί! IN! I2, 1_U.

7 w / \ / \ / V \, • N · R * R3 8 il 1

The symbols in Table II have the following meanings d = doubled, dd = doubled by doublets, s = singlet 10 γ denotes the group / -λ 'CH3 EXAMPLE 4 1,2,3,9-Tetrahydro-9-methyl-3 [(2- methyl-1H-imidazol-1-yl) -methyl] -4H-carbazol-4-one A solution of 1.0 g, 2,3,9-tetrahydro-3 [(2-methyl-1H-imidazole-1) -yl) methyl] -4H-carbazol-4-one in 10 ml of dry dimethylformamide was added dropwise under nitrogen to a stirred ice-cooled suspension of 0.11 g of sodium hydride (80% in oil) in 5 ml of dry dimethylformamide. After 1/2 hour, 0.34 ml of dimethyl sulfate was added and the solution was stirred at room temperature for 4 hours. The resulting solid was filtered off, washed with 2 x 5 ml ice-cold dry dimethyl formamide and 3 x 15 ml dry ether and dried to give 0.25 g of the title compound as a solid, m.p. 224 ° C (dec.).

Thin layer chromatography: silica gel, chloroform / methanol (93: 7), Rf value 0.27, detection of UV and iodoplatinic acid, identically with the product of Example 1a.

The following compounds were prepared by a similar process using the corresponding alkylating agent as described in detail in Table III.

TABLE III

10 Ex. Alkyl is reagent R2 R3 R4 Hour / Weight No. ° C ** Product (g) 4b Me2SO4 CH2CH3 Η H 0.5 0.13 15 Formed salt, HCl, mp 211-212 ° C Analysis for C19H21N30 · HC1 · 0, 5H20:

Calculated: C 64.7 H 6.6 N 11.9

Found: C 64.7 H 6.5 N 11.8 20 4C Me 2 SO 4 CH 2 Ph Η H 0.32

Formed salt, maleate, m.p. 143-145 ° C. Analysis for C24H23N30-C4H404:

Calculated: C, 69.3; H, 5.6; N, 8.65

Found: C 69.35 H 5.5 N 8.5 _____ 4d Et 2 SO 4 CH 3 Η H 6.5 0.67

Salt, maleate, m.p. 159-160 ° C. Analysis for C19H21N3O * C4H4O4:

Calculated: C 65.25 H 5.95 N 9.9 Found: C 65.15 H 6.1 N 9.85 TABLE III continued DK 169521 B1 31 4th PhCH2Br CH3 Η H 5.75 1.00

Formed salt, maleate, m.p. 150-151.5 ° C. Analysis for C24H23N30-C4H404:

Calculated: C, 69.3; H, 5.6; N, 8.65

Found: C 69.1 H 5.65 N 8.55 4f CH3 (CH2) 5I CH3 Η H 7.25 1.16 Formed salt, maleate, m.p. 118-119 ° C Analysis I for C23H2gN30-C4H404:

Calculated: C 67.6 H 6.9 N 8.8

Found: C 67.4 H 6.9 N 8.7 4g Ph (CH 2) 3 Br CH 3 Η H 5.75 0.84

Formed salt, maleate, m.p. 95-96.5 ° C Analysis for C26H27N30-C4H404.0.2H2O:

Calculated: C 69.7 H 6.1 N 8.1

Found: C 69.5 H 5.9 N 8.0 20 4 H CH 3 (CH 2) 90 SO 2 - ^) - CH 3 CH 3 Η H 4 at 0.14

50 ° C

Formed salt, oxalate, m.p. 50-51 ° C Analysis for C27H37N30-C2H2O4.0.3H2O: Calculated: C 66.6 H 7.8 N 8.0

Found: C 66.7 H 7.8 N 7.8 t · 4

4i Et, CHOSO? VCH, CH3 Η H 14 at 0.12 t 40 ° C

Formed salt, HCl, mp 131-133 ° C Analysis for C22H27N30-HCl-1.1H2O:

Calculated: C 65.4 H 7.5 N 10.4

Found: C 65.8 H 7.9 N 10.3 DK 169521 B1 32 ** Reaction time (hours) at reaction temperature Note 1 The following 1 H-NMR data were obtained

5 * I

// \ / \ 3 / \ / w, 6 * · - · · NN3 'd = doubled I II H I I L auJ31et 5 y · ^ * 2 bt * - ^ = dtiblet of doublets • N · R R3 s = singlet 8 1

Ex. Resolve 1 H NMR Spectra (obtained at 250 MHz No. Selected Proton Chemical Shifts Values (δ Mean ppm) and Multiplicities 10

Carbazolone protons Imidazo- Imidazole-

Aromatic Aliphatic Lyl Methyl Protons H-5,6,7,8 CH2-1 and CH2-2 Lenpro- H-2 'H-4' H-3 Tones and / or 15 H-5 'dg-DMSO 6.29 ( dd) 7.55d 4g 7.15-8.1 2.9-3.2 1.9-2.2 and - and 6.68 (dd) 7.65d 20 dg-DMSO 6.26 (dd) 7 , 42d 4h 7.2-8.1 2.9-3.3 1.8-2.2 and 6.65 (dd) 7.57d EXAMPLE 5 9-Cyclopentyl-1,2,3,9 tetrahydro-3 [(2-methyl-IH-imidazol-1-yl) methyl] -4H-carbazol-4-one maleate

A solution of 1.20 g, 2,3,9-tetrahydro-3 [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in 9 ml of dry dimethyl-DK 169521 B1 33 formamide was added to a stirred ice-cooled suspension of 0.14 g of sodium hydride (80% in oil) in 2 ml of dry dimethylformamide under nitrogen and stirring was continued for 0.25 hour. 0.51 ml of bromocyclopentane was added and the stirred solution 5 was heated to 100 ° C for 18.5 hours. The solution was allowed to cool and was then partitioned between 100 ml of water and 3 x 70 ml of ethyl acetate. The combined organic extracts were washed with 2 x 50 ml of 2N sodium carbonate, 2 x 50 ml of water and 50 ml of brine, dried, evaporated to dryness and purified by chromatography, eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia. (150: 10: 1) to give 0.27 g of an oil. This oil was dissolved in 7 ml of reflux absolute ethanol and a solution of 0.10 g of maleic acid in 0.5 ml of reflux absolute ethanol was added. The hot solution 15 was filtered, stirred and diluted with 20 ml of dry ether. The resulting yellow rubber was washed with 7 x 25 ml of dry ether and the combined mother liquors and washing phases allowed to stand. The solid which crystallized from the solution was filtered off, washed with 3 x 5 ml of dry ether and dried to give 0.058 g of the title salt as a white crystalline solid, mp 104.5-106 ° C.

Analysis for C 22 H 25 N 3 O · C 4 H 4 O 4 · 0.6H 2 O:

Calculated: C 65.95 H 6.4 N8.6

Found: C 65.8 H 6.4 N 8.9.

EXAMPLE 6 1,2,3,9-Tetrahydro-3- [(2-methyl-1H-imidazol-1-yl) methyl] -9- (2-propenyl) -4H-carbazol-4-one maleate

A solution of 1.0 µl, 2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one in 6 ml of dry dimethylformamide was added to a stirred ice-cooled suspension of 0.12 g of sodium hydride (80% in oil) in 2 ml of dry dimethylformamide. After 0.25 h, allyl bromide was added and the solution was stirred at 0 ° C for 0.25 h at room temperature for 20 h before partitioning between 75 mL of water and 3 x 50 mL of ethyl acetate. The combined organic extracts were washed with 2 x 50 ml water and 50 ml brine, dried and concentrated in vacuo and purified by chromatography eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (200: 10: 1), giving 0.43 g of a solid. This solid was dissolved in 2 ml of refluxing absolute ethanol and a solution of 0.18 g of maleic acid in 1 ml of refluxing absolute ethanol was added. The hot solution was filtered and diluted with 4 ml of dry ether and the crystallized solid was filtered off, washed with 3 x 5 ml of dry ether and dried to give 0.48 g of the title compound as a white solid, mp 150 , from 5 to 151 ° C.

Analysis for C20H2N3 ° C4H4 ° 4:

Calculated: C 66.2 H 5.8 N 9.65 Found: C 66.3 H 5.75 N 9.6.

Example 7 1.2.3.9- Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) -methyl] -4H-carbazol-4-one

A solution of 1.7 g of 3 [(dimethylamino) methyl] -1,2,3,9-tetra-20-hydro-9-methyl-4H-carbazol-4-one hydrochloride in 17 ml of water was treated with 1 4 g of 2-methylimidazole and then refluxed for 20 hours. The cooled mixture was filtered and the residue was washed with 3 x 15 ml of water to give 1.7 g of crude product, mp 221-221.5 ° C. This material was recrystallized from ethanol to give 1.4 g of the title compound, mp 231-232 ° C, identical by TLC with the product of Example 4.

Example 8 1.2.3.9- Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) -methyl] -4H-carbazol-4-one DK 169521 B1

A suspension of 0.5 g of the product of Preparation 3 and 0.4 g of 2-methylimidazole in 5 ml of water was heated at reflux for 20 hours. The cooled reaction mixture was filtered and the residue was washed with 3 x 10 ml water, dried and recrystallized from 18 ml ethanol to give 0.3 g of the title compound, mp 232-234 ° C (dec.) Identical to TLC with the product of Example 4.

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

The reaction mixture was partitioned between 200 ml of 2N sodium carbonate and 2 x 150 ml of ethyl acetate. The combined organic extracts were washed with 3 x 75 ml of water, dried and evaporated in vacuo, and the product was purified by chromatography eluting with dichloromethane / ethanol / ammonia (100: 80: 1) to give an oil. This oil was dissolved in 3 ml of ethanol, acidified with ethereal hydrogen chloride and diluted with dry ether to give 0.13 g of the title compound as a white solid, mp 230-232 ° C.

Analysis for C20H23N3 ° * HC1-0 / 5H2O:

Calculated: C 65.4 H 6.9 N 11.45

Found: C 65.3 H 6.6 N 11.1.

EXAMPLE 10 DK 169521 B1 36 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate 18.3 gl, 2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-5-1-yl) methyl] -4H-carbazol-4-one in a hot mixture of 90 ml of isopropanol 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, stirred at room temperature for 17 hours and cooled to 2 ° C, and the solid was filtered off (21.6 g). A sample of 6 g was recrystallized from a mixture of 6 ml of water and 10 ml of isopropanol to give 6 g of the title compound as a white crystalline solid, mp 178.5-179.5 ° C.

Analysis for C 12 H 19 N 3 · HCl · 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 found: 10.23% 0ι8Ηι9Ν30 · Η01 * 2H 2 O calculated: 9.85% Example 11 20 1,2,3,9-Tetrahydro-3 - [(2-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, 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 stirred at reflux. under nitrogen for 42 hours, 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 h, and the resulting solid was filtered off, washed with 4 x 30 ml of dry ether and dried, gave 4.2 g of the title compound. A portion of this solid (1.0 g) was recrystallized twice by 10 ml of absolute ethanol to give 0.39 g of the title compound as a light brown powder, mp 193-194 ° C (dec.).

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

Under nitrogen, 1.4 g of 2-methyl-1H-imidazole was added to a stirred suspension of 2.0 g of 3 - [(dimethylamino) methyl] -1,2,3,9-10 tetrahydro-9-phenyl-4 carbazol-4-one hydrochloride in 20 ml of water. The mixture was heated to 90 ° C for 43 hours and the solvent was decanted from the light brown solid. Chloroform was then added to the solid, the suspension was filtered through Hyflo®, the filtrate dried and concentrated in vacuo. Chromatography of the remaining pale brown foam (2.04 g) eluted with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (200: 10: 1) gave 1.1 g of a white foam. A solution of this foam in 3 ml of ethanol was treated with 0.4 g of maleic acid in 1 ml of ethanol followed by 20 of 40 ml of dry ether and the resulting gum was triturated with 2 x 40 ml of dry ether to give 1.37 g of the title compound as a cream solid, mp 165-166 ° C (dec.).

Analysis for C23H2N3O-C4H4O4: 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 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one phosphate (1: 1) 1 0.61 g, 2,3,9-tetrahydro-9-methyl - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one, was dissolved in a hot mixture of 0.13 ml 90% phosphoric acid and 10 ml water filtered through DK 169521 B1 38

Hyflo® and allowed to crystallize to give 0.5 g of the title compound, mp 225 ° C.

Analysis for 018Η19Ν30 · Η3Ρ03:

Calculated: C 55.2 H5.7 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 , 2,3,9-Tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-10-yl) methyl] -4H-carbazol-4-one was dissolved in a hot solution of 0.58 g of citric acid in 20 ml of ethanol, and allowed to crystallize. The resulting crystalline solid was recrystallized by dissolving in 2 ml of acetone / water (2: 1) and diluting with 20 ml of acetone to give 0.6 g of the title compound, m.p. 162 ° C.

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 20 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one in 30 ml of dry DMF and 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 solution was stirred at 100 ° C for 2 days, cooled and partitioned between 150 ml of 2N sodium carbonate and 2 x 100 ml of ethyl acetate. The combined extracts were washed with 100 ml of water, dried and evaporated in vacuo. The residue was purified by column chromatography eluting with dichloromethane / ethanol / ammonia (400: 30: 3) to give 1.2 g of the free base as a solid. A sample of 0.2 g of this was dissolved in 5 ml of absolute ethanol, acidified with ethereal hydrogen chloride and diluted with ca. 200 ml of ether, which gave an oil. Upon scraping, the oil crystallized to give 0.15 g of a solid. The salt was crystallized from a mixture of ethanol and isopropyl acetate to give 0.08 g of the title compound, mp 206-208 ° C.

Analysis for C19H21N3O * HCl · 0.2H2O:

Calculated: C 65.7 H 6.5 N 12.1

Found: C 65.6 H 6.8 N 12.0.

NMR Spectrum (CD 3 SOCD 3): δ (ppm) = 0.94 (3H, t, CH 3), 1.77 (2H, sextet, CH 2 CH 2 CH 3), 1.9-2.15 and 2.95-3.2 ( 7H, m), 4.32 and 4.71 (2H, ABX, CHCH 2 N), 7.1-8.0 (6H, aromatic).

Example 15 1.2.3.9- Tetrahydro-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

A solution of 0.03 g of the product of Example 3g in 15 ml of 15 methanol was hydrogenated at room temperature and pressure over 0.03 g of 10% palladium oxide on charcoal (50% aqueous paste) for 4 hours (5 ml H2 uptake). The catalyst was filtered off and the filtrate was evaporated in vacuo to give an oil. Trituration with ether gave 0.03 g of the title compound as a white solid, mp 199-203 ° C.

This material was identical to the product of Example 14 by TLC and NMR.

Example 16 1.2.3.9- Tetrahydro-9-propyl-3 - [(2-propyl-1H-imidazol-1-yl) -methyl] -4H-carbazol-4-one hydrochloride

Under nitrogen, sodium hydride (80% dispersion in oil) was added to a stirred solution of 1.0 g of the product of Example 14 in 20 ml of dry DMF and the suspension was stirred at room temperature for 30 minutes. 0.35 ml of 1-bromopropane was added and the solution was stirred at 40 ° C for 20 hours. The solution was partitioned between 150 ml of 2N sodium carbonate and 2 x 100 ml of ethyl acetate. The combined extracts were washed with 100 ml of water, 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% absolute ethanol, acidified with ethereal hydrogen chloride and diluted with 200 ml of dry ether. The ether was decanted from the resulting oil and replaced with an additional 200 ml of dry ether. After standing at 0 ° C overnight, the oil crystallized to give 0.53 g of the title compound, mp 144-147 ° C.

NMR Spectrum (CD3 SOCD3): δ (ppm) = 0.90 and 0.93 (6H, t + t, 2xMe), 1.65-2.2 and 2.2.9-3.25 (10H, m) , 4.19 (2H, t, CH 2 CH 2 N), 4.32 and 4.71 (2H, MX, CH 2 CH 2 N), 7.15-8.1 (6H, m aromatic).

Analysis for C22H27N3O · HCl · 0.7H2O:

Berenet: C 66.3 H 7.4 N 10.5

Found: C 66.6 H 7.7 N 10.0.

EXAMPLE 17 1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9-propyl-4H-carbazol-4-one maleate

A solution of 0.86 g of the product of 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 0.1 g of 5% platinum on carbon (reduced in 10 ml of absolute ethanol) for 1 hour. 70 ml of H2 was taken up. The catalyst was filtered off and washed with ethanol, and the filtrate was concentrated in vacuo to ca. 15 ml. The residual solution was stirred and diluted with 50 ml of water and the 30 precipitated solid was filtered off, washed with 3 x 15 ml of water and dried to give 0.73 g of a powder.

DK 169521 Pg 41

This material was dissolved in 7 ml of refluxing absolute ethanol and 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 to give 0.84 g of the title compound, mp 150-151 ° C.

Analysis for C20H23N3O * C4H4O4:

Calculated: C 65.9 H 6.2 N 9.6

Found: C 65.8 H 6.1 N 9.3.

Example 18 10 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one i) 3- (Chloromethyl ) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one 3.0 ml of ethereal hydrogen chloride was added to a stirred ice-cooled solution of 1.90 g of the product of Preparation 3 in 15 ml of chloroform and the resulting suspension was stirred in a closed container at room temperature for 16.5 hours and then concentrated in vacuo and the residual solid (2.27 g) was purified by column chromatography eluting with chloroform to give 1.75 g of the title compound, mp 109-110.5 ° C. An attempt to crystallize some of this material of 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 0.50 g of 3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 1.60 g of 2-methyl-1H-imidazole in dry DMF was obtained. stirred under nitrogen at 90 ° C for 3.75 hours and then poured into 25 ml of water. 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 of this solid (0.53 g) eluted 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 . This material was identical to the product of Example 7 as determined by TLC and NMR.

EXAMPLE 19 1,2,3,9-Tetrahydro-9-methyl-3- ((2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

A solution of 170 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 1.5 ml of dry tetrahydrofuran was added dropwise and under 10 nitrogen to a stirred ice-cooled suspension of 100 mg of the product of preparation. 4 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. Column chromatography of the residual solid eluted with a mixture of dichloromethane, ethanol and 0.88 ammonia (150: 10: 1) afforded 45 mg of the title compound, mp 227-228.5 ° C. This material was identical to the product of Example 7 as determined by TLC and NMR.

EXAMPLE 20 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-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 and under nitrogen to a stirred ice-cooled suspension of 100 mg of the product of 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 and the red suspension was then concentrated in vacuo. Column chromatography of the residual solid eluted with a mixture of dichloromethane, ethanol and 0.88 ammonia (150: 10: 1) afforded 0.47 g of the title compound as a white solid, mp 227.5-229 ° C. This material was identical to the product of Example 7 as determined by TLC and NMR.

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

A solution of 0.5 g of the product of Example 7 was dissolved in 30 ml of hot ethanol and treated with a warm solution of 0.7 g of (+) - di-p-toluoyl-D-tartaric acid monohydrate in 10 ml of methanol, and 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 (DMF), diluted with 10 ml of hot water and allowed to crystallize overnight. The product was filtered off and dried in vacuo to give 0.23 g of ca. 90% enantiomerically pure (as detected by NMR) (+) - di-p-toluoyl-D-tartaric acid salt, mp 231-233 ° C. A sample of 0.15 g of the salt was partitioned between 25 ml of 8% sodium hydrogen carbonate and 2 x 25 ml of chloroform. The combined extracts were dried and evaporated in vacuo to give 0.07 g of the pure free base. The base was dissolved in 5 ml of methanol acidified with 0.03 g of maleic acid and the salt precipitated by adding an excess of dry ether (80 ml) to give 0.062 g of the title compound, mp 142-145 ° C.

TLC Silica, dichloromethane / ethanol / 0.88 ammonia (100: 8: 1) Rf 0.3, detection of UV and iodoplatinic acid, identical to the product of Example 7. The enantiomer ratio determined by 1 H-NMR was 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] 25 D -14 ° (c = 0.19 in methanol).

EXAMPLE 22 3R-1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one maleate 1

A solution of 0.5 g of the product of Example 7 was dissolved in 30 ml of hot methanol and treated with a warm solution of 0.7 g of (-) - di-p-toluoyl-L-tartaric acid monohydrate in 10 ml of methanol, DK 169521 B1 44 and the resulting solution were allowed to crystallize overnight to give 0.8 g of the desired salt. This salt was dissolved in 20 ml of warm dimethyl formamide (DMF), diluted with 10 ml of warm water and allowed to crystallize for 3 days. The product was filtered off and dried in vacuo to give 0.26 g of ca. 95% enantiomerically pure (as detected by NMR) (-) - di-p-toluoyl-L-tartaric acid salt, mp 170-172 ° C. A sample of 0.2 g of the salt was partitioned between 25 ml of 8% sodium hydrogen carbonate and 2 x 25 ml of chloroform. The combined extracts 10 were dried and evaporated in vacuo to give 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 the addition of excess dry ether (80 ml) to give 0.08 g of the title compound, mp 142-145 ° C.

TLC silica, dichloromethane / ethanol / 0.88 ammonia (100: 8: 1), Rf 0.3, UV detection and iodoplatinic acid, identical to the product of Example 7. The enantiomer ratio, as determined by 1 H NMR, was 95: 5th A sample of the maleate salt showed no significant optical rotation in methanol. The free base regenerated from the maleate salt gave [α] 24 D + 16 ° (c = 0.34 in methanol).

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

TABLES FOR ORAL ADMINISTRATION

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

The tablets may be film-coated with suitable film-forming materials, e.g., hydroxypropylmethylcellulose, using standard techniques. Alternatively, the tablets may be sugar coated.

Direct pressing

Tablet mg / tablet 5

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

Pressure weight 90.0 118.0 * of a quality suitable for direct pressing.

The active ingredient was passed through a 0.25 mm sieve and mixed with calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. The resulting mixture was pressed into tablets using a Manesty F3 tablet machine equipped with 5.5 mm flat rims with a ragged edge.

Sublingual tablet mg / tablet Active ingredient 2.5

Compressible sugar NF 62.5

Magnesium stearate BP 0.5

Pressure Weight 65.0 25 The active ingredient is sieved through a suitable sieve, mixed with the excipients and pressed using appropriate pistons. Tablets with other strengths can be prepared by changing either the ratio of active ingredient to excipient or the press weight and by using 30 suitable pistons.

DK 169521 B1 46 Wet granulation

Conventional Tablet mg / tablet

Active ingredient 2.5 Lactose BP 151.5

Starch BP 30.0

Pregelatinised corn starch BP 15.0

Magnesium stearate BP 1.5 10 Pressure weight 200.0

The active ingredient is sieved through a suitable sieve and mixed with lactose, starch and pregelatinized corn starch. Appropriate volumes of pure water are added and the powder granulated. After drying, the granules are sieved and mixed with the magnesium stearate. The granules are then compressed into tablets using pistons 7 mm in diameter.

Tablets with other strengths can be prepared by changing either the ratio of active ingredient to lactose or the press weight and using corresponding pistons.

Sublingual tablet mg / tablet

Active ingredient 2.5

Mannitol BP 56.5 Hydroxypropylmethylcellulose 5.0

Magnesium stearate BP 1.5

Pressure weight 65.5

The active ingredient is screened through a suitable screen and mixed with mannitol and hydroxypropylmethyl cellulose.

Appropriate volumes of pure water are added and the powder granulated. After drying, the granules are sieved and pressed into tablets using appropriate pistons.

Tablets with other strengths can be prepared by either changing the ratio of active ingredient to mannitol or the press weight and corresponding pistons.

Capsules mg / capsule

Active ingredient 2.5 * Starch 1500 97.0 10 Magnesium stearate BP 1.0 Filling weight 100.0 * a form of direct compressible starch.

The active ingredient is sieved and mixed with the excipients.

The mixture is filled into size 2 hard gelatin capsules using appropriate machinery. Other doses can be prepared by changing the filling weight and, if necessary, by changing the capsule size accordingly.

Syrup 20 This can either be a sucrose preparation or a sucrose free preparation.

A. Sucrose syrup mg / 5 ml dose

Active ingredient 2.5 Sucrose BP 2750.0

Glycerin BP 500.0

Buffer)

Flavoring)

Dye) 30 Preservative) as needed

Purified water BP up to 5.0 ml DK 169521 B1 48

The active ingredient, buffer, flavor, color and preservative are dissolved in some of the water and the glycerine is added. The rest of the water is heated to dissolve the sucrose and then cooled. The two solutions are combined, adjusted to 5 volumes and mixed. The syrup is clarified by filtration.

B. Sucrose-free mg / 5 ml dose

Active ingredient 2.5

Hydroxypropyl methyl cellulose USP 10 (viscosity type 4000) 22.5

Buffer)

Flavoring)

Dye)

Preservative) As required 15 Sweetener)

Purified water up to 5.0 ml

The hydroxypropylmethyl cellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the preparation. The resulting solution is adjusted to volume and mixed. The syrup is clarified by filtration.

Injection preparation

Injections may be administered by intravenous or subcutaneous route.

25 Injection preparation Mg / ml

Active ingredient 50 800

Dilute hydrochloric acid BP to pH 3.5 to pH 3.5

Sodium Chloride Injection Solution BP to 1 ml to 1 ml

The active ingredient was dissolved in a suitable volume of sodium chloride injection solution BP, the resulting solution pH was adjusted to pH 3.5 using dilute hydrochloric acid BP, then the solution was filled to volume with sodium chloride injection solution BP and mixed thoroughly. The solution was filled into 5 ml clear Type 1 vials, which were sealed under a peak volume of air by melting the glass followed by sterilization by autoclaving at 120 ° C for not less than 15 minutes.

Pressure aerosol for metered dose

Suspension aerosol mg / metered dose Pr. can 10

Active ingredient, micronized 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 micronized in a fluid energy mill to a fine particle size range. The oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 ° C and the micronized substance is mixed into the solution by means of a high shear mixer. The suspension is measured in aluminum aerosol cans and suitable metering valves delivering 85 mg of suspension are shrunk on the cans and the dichlorodifluoromethane is pressurized on the cans through the valves.

Solution aerosol mg / metered dose Pr. can 25

Active ingredient, 0.250 30.0 mg

Ethanol BP 7.500 1.80 g

Trichlorofluoromethane BP 18.875 4.35 g

Dichlorodifluoromethane BP 48.525 11.65 g 1 (oleic acid BP or a suitable surfactant, e.g. Span® 85 (sorbitan trioleate) may also be included).

Claims (16)

10 Lactose BP up to 25.00 The active ingredient is micronized in a fluid energy mill to a particle size range prior to mixing in a high-energy tablet of normal tableting quality. The powder mixture is filled into hard gelatin capsules # 3 on a suitable sealing machine. The contents of the cartridges are administered using a powder inhaler. 1. 3 - Imidazolylmethyltetrahydrocarbazolones of the general formula I>> / 3 / wVYi ! Wherein R1 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, phenyl or phenyl-Cx. 3-alkyl, and one of the groups R 2, R 3 and R 4 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl or phenyl-C 1-6 alkyl, and each of the other two groups which can be be the same or different, is hydrogen or C 1-6 alkyl; DK 169521 B1 or physiologically acceptable salts and solvates thereof. A compound according to claim 1, characterized in that R 1 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 alkenyl. A compound according to claim 1 or 2, characterized in that one of the groups R 2, R 3 and R 4 is C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 alkenyl, and each of the other two groups which may be the same or various, are hydrogen or C 1-6 alkyl. A compound according to claim 1, characterized in that R1 is hydrogen, C1-6 alkyl, C5-6 cycloalkyl or C3-4 alkenyl, and that either R2 is hydrogen and R3 and / or R4 is -31-3 alkyl, or R 2 is <3 -alkyl and both R 3 and R 4 are hydrogen. 5. Compound of the general formula lajj R ^ a R3a i \ Λ Arn Ia I II II I \ // • · · · · w \ / \ / 12a • N · R2a Ria wherein R1a is hydrogen, methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl; R 3a is hydrogen; and wherein either R 2a is methyl, ethyl, propyl or prop-2-yl, and R 4a is hydrogen or R 2a is hydrogen and R 4a is methyl or ethyl; and physiologically acceptable salts and solvates thereof. Compound according to claim 1, characterized in that it is 1,2,3,9-tetrahydro-9-25 methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole -4-on and physiologically acceptable salts and solvates thereof. DK 169521 B1 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-carbazole 4-one in the form of a hydrochloride salt. 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-carbazole. 4-one hydrochloride dihydrate. Compound according to Claim 1, 10, characterized in that it is 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2- enyl) -4H-carba zol-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-1H-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazol-4-one, or physiologically acceptable salts and solvates thereof. Process for the preparation of a compound of the general formula I as defined in claim 1 or a physiologically acceptable salt or solvate thereof, characterized in that A) a compound of the general formula II A / I II II In 11, N · R1 (wherein R1 is as defined in claim 1 and Y is a reactive substituent) or a protected derivative thereof, is reacted with an imidazole of the general formula III B1 Rh R3 / H III / R2 (wherein R2, R3 and R4 are as defined in claim 1) or a salt thereof; or B) a compound of the general formula IV A R 1 R 3 R 3 - wherein R is hydrogen or hydroxy; and R 1, R 2, R 3 and R 4 are as defined in claim 1) or a salt or a protected derivative thereof is oxidized; or C) a compound of general formula I or a salt or a protected derivative thereof is converted to another compound of general formula I; or D) removing one or more protecting groups from a protected form of a compound of general formula I; and, if a compound of general formula I is obtained as a mixture of enantiomers, the mixture is optionally digested to give the desired enantiomer; and / or, if the compound of general formula I is in the form of a free base, the free base is optionally converted into a salt. DK 169521 B1 Process according to claim 10 (A), characterized in that Y is an alkenyl group = CH 2 or a group of the general formula CH 2 Z, wherein Z is an easily leaving atom or a leaving group. Process according to claim 10 (C), characterized in that a compound of the general formula I or a salt or protected derivative thereof is converted to another compound of the general formula I by alkylation or hydrogenation. Pharmaceutical composition, characterized in that it comprises at least one compound of general formula I as defined in claim 1 or a physiologically acceptable salt or solvate thereof together with at least one physiologically acceptable carrier or excipient. Composition according to claim 13, characterized in that it contains 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. Composition according to claim 13, characterized in that it contains 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl) methyl] -4H carbazol-4-one hydrochloride. Preparation according to claim 13, 25, characterized in that it contains 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl) methyl] -4H carbazol-4-one hydrochloride hydrate.