DK170506B1 - Pyrido and azepino-indole compounds, process for their preparation, pharmaceutical composition containing them and use of the compounds - Google Patents

Description

in DK 170506 B1

The present invention relates to pyrido and azepino-indole derivatives, processes for their preparation, pharmaceutical compositions containing the derivatives and their use in the manufacture of drugs.

In particular, the invention relates to compounds which are potent and selective antagonists of 5-hydroxytryptamine (5-HT) at 5-HT receptors of the type found at the terminals of primary afferent nerves. Receptors of this type are now referred to as 5-HT3 receptors and are also present in the central nervous system. 5-HT occurs widely in the neuronal pathways of the central nervous system, and disorders of these 5-HT-containing pathways are known to alter behavioral syndromes such as mood, psychomotor activity, appetite, and memory.

Compounds with antagonistic activity at 5-HT 3 receptors have been previously described.

Thus, for example, published GB 2153821A and published EP 191562, 219193 and 210840 disclose 3-imidazolylmethyltetrahydrocarbazolones, which may be denoted by the general formula: il i / 3 ν ^ γτΐ in 11 11 1 // // · · · · VVV > where R ^ - represents a hydrogen atom or group selected from C C--* alkyl, C3_g alkenyl, C3_ig alkynyl, C3_y cycloalkyl, C3-7 cycloalkyl-C ^. alkyl alkyl, phenyl or phenyl C 1 -C 3 alkyl and in the cases where Q represents a hydrogen atom, R 1 - may also represent -C 2 R 2, -COR 2, -CONR 2 R 2, or -SO 2 R 2 (where R 2 and R 2 which may be the same or different, each represents a hydrogen atom, a g-alkyl or C 3-7 cycloalkyl group or a phenyl or phenyl C 1-4 alkyl group, wherein the phenyl group is optionally substituted by one or more C 1-6 alkyl- C Cj ^ alkoxy or hydroxy groups or one or more halogen atoms, provided that R at does not represent a hydrogen atom when R ^ represents a -CO2R · 5- or -SO2R2 group); DK 170506 B1 is one of the groups R 2 and R 4 is a hydrogen atom or a C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkenyl or phenyl C 1-3 alkyl group, and each of the other two groups, which may be the same or different, represent a hydrogen atom or a C 1-6 alkyl group; Q represents a hydrogen atom or a halogen atom or a hydroxy,

Cj ^alk alkoxy, phenyl C ^ _3 alkoxy or Cj__g alkyl group or a group gruppeNR ^R® or -CONR ^R® (where R ^ and R®, which may be the same or different, each represent a hydrogen atom or a Cj ^alk alkyl or C3-4 al alkenyl group or together with the nitrogen atom to which they are attached form a saturated 5- to 7-membered ring); and physiologically acceptable salts or solvates thereof.

The above known compounds are ketones wherein the compounds of the invention are amides. In addition, the compounds of the prior art are N-linked imidazoles, wherein the compounds of the invention are 15 C-linked imidazoles.

A novel group of compounds which are different in structure from those previously described and which are potent antagonists of the action of 5-HT at 5-HT 3 receptors have now been found.

The present invention relates to tricyclic lactams, namely pyrido and azepino indoles of the general formula (I):

II

/ Λ Λ Λι »T ii — Ti I, (I>

• N

R1 wherein Im represents an imidazolyl group of the formula: p "R" / / * _ · _ · I-1, or I-1 \ r r \ / • ·

L L

R 2 DK 170506 B1 3 and rA represents a hydrogen atom or a group selected from C 1-6 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl, phenyl Cj__3 alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, -CC ^R ·, -COR ^, -CONR ^R R or -SO₂R "(where R ^ ^ and R ^, which are the same or different, each represent a hydrogen atom, a Cg-alkyl or C3_-cycloalkyl group or a phenyl or phenyl-C · alkyl alkyl alkyl group, wherein the phenyl group is optionally substituted by one or more C ^. alkyl alkyl, C ^. hydro alkoxy or hydroxy groups or one or more halogen atoms with the proviso that R 1 does not represent a hydrogen atom when R 1 represents a group - (^ R 2 or -SO 2 R 5); one of the groups R 1, R 2 and R 2 is a hydrogen atom or a Cj_.g alkyl, C3_7 cycloalkyl, C3_g alkenyl, phenyl or phenyl Cj_ alkyl alkyl group, and each of the other two groups which are the same or different, represent a hydrogen atom or a Cg-alkyl group; n represents the number 2 or 3; and physiologically acceptable salts and solvates thereof.

One aspect of the invention relates to lactam compounds of formula (I) wherein R 1 represents a hydrogen atom or a group selected from C 1-6 alkyl, C 3-8 alkenyl, C 3-6 alkynyl, C 3-7 cycloalkyl, C 3-7 -cycloalkyl-O 1-4 -alkyl, phenyl or phenyl-O-.3-alkyl (where n and Im have the meanings given in formula (I)).

Suitable physiologically acceptable salts of the lactam compounds of general formula (I) include acid addition salts formed with organic or inorganic acids, e.g., hydrochlorides, hydrobromides, sulfates, alkyl or arylsulfonates (e.g., methanesulfonates or p-toluenesulfonates), phosphates, acetates, , succinates, tartrates, fumarates and maleate. For example, the solvates may be hydrates.

The invention includes all optical isomers of lactam compounds 30 of general formula (I) and mixtures thereof, including racemic mixtures thereof and all geometric isomers of compounds of general formula (I).

DK 170506 B1 4

With respect to the general formula (I), an alkyl group may be a straight or branched alkyl group, e.g., methyl, ethyl, n-propyl, prop-2-yl, n-butyl, but-2-yl, 2-methylprop-2- yl, n-pentyl, pent-3-yl or n-hexyl. For example, a C3-6 alkenyl group may be a propenyl or butenyl group. When rA represents a C3-8 alkenyl or C3-8 alkynyl group, or represents a C3-6 alkenyl group, the double or triple bond cannot sit next to the nitrogen atom. For example, a phenyl- <3 -alkyl group may be a benzyl, phenethyl or 3-phenyl-propyl group. For example, a 3-7 cycloalkyl group may be a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

A preferred class of lactam compounds of general formula (I) is that wherein R 1 represents a hydrogen atom or a C 1-6 alkyl- (e.g., methyl, ethyl, n-propyl, prop-2-yl), C 3. β-alkenyl (e.g. prop-2-enyl), C 3-6 alkynyl (e.g. prop-2-ynyl), C5-6 cycloalkyl- (e.g. cyclopentyl), and C8-6 cycloalkylmethyl- (e.g. cyclopentylmethyl), and phenyl -C 2 -C 2 -alkyl (e.g. benzyl), a phenylmethoxymethyl, an N, N-di-C 1 -C 3 alkylcarboxamide (e.g., Ν, Ν-dimethycarboxamide) or a C 1-4 alkylsulfonyl (e.g. methylsulfonyl) group. R 1 represents in particular a C 1-4 alkyl- (e.g., methyl or n-propyl), a C 3-4 alkynyl- (e.g. prop-2-ynyl), and C5-6 cycloalkyl- (e.g., cyclopentyl), and a C5 - g -cycloalkylmethyl (eg cyclopentylmethyl), a phenyl-2'alkyl (eg benzyl), a phenylmethoxymethyl, or an N, N-di-C1-3 alkylcarboxamide (eg Ν, Ν-dimethylcarboxamide) group.

Another preferred class of lactam compounds of general formula (I) is that wherein R 1 represents a hydrogen atom or an O 3 to 25 alkyl (e.g. methyl) group, especially a hydrogen atom.

Another preferred class of lactam compounds of the general formula (I) is that wherein R 1 represents a hydrogen atom or an O 3 alkyl (e.g. methyl) group, especially a hydrogen atom.

A further preferred class of lactam compounds of general formula (I) is that wherein R 1 represents a hydrogen atom or an O 3 alkyl (e.g. methyl or n-propyl) group. Most preferably, R 1 represents a methyl group.

When and represents hydrogen atoms, R 1 is preferably C 1-6 alkyl, C 3-7 cycloalkyl, C 3. g -alkenyl or phenyl-C 2. 3-alkyl, especially C 1-6 alkyl.

A further preferred class of lactam compounds of general formula (I) is that where n represents the number 2.

A preferred class of lactam compounds of the general formula (I) is that wherein R ^ represents a hydrogen atom or a C ^. Alkyl alkyl, C3 _yl alkenyl, C3_4 alkynyl, C5_- cycloalkyl, Cg. g-cycloalkylmethyl, phenyl-C 2 -alkyl, phenylmethoxymethyl, N, N-di-C 1-4 alkylcarboxamide or C 1-6 alkylsulfonyl group; R 2 represents a hydrogen atom; and R 1 and R 1 each represent a hydrogen atom or a C 1-3 alkyl group.

A particularly preferred group of lactam compounds of general formula (I) is that wherein R 1 represents a methyl, n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl or N, N dimethyl carboxamide group; R 1 and R 2 each represent a hydrogen atom; and R 2 represents a methyl group.

Within the aforementioned preferred and particularly preferred groups of lactam compounds, a particularly important group of compounds is that wherein n represents the number 2.

Preferred lactam compounds of the invention are: 2.3.4.5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1- one; 2,3,4,5-tetrahydro-5- (phenylmethyl) -2 - [(5-methyl-1H-imidazol-4-yl) -methyl] -1H-pyrido [4,3-b] indol-1-one; 5-Cyclopentyl-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) -methyl] -1H-pyrido [4,3-b] indole-1- one; 2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5-propyl-1H-pyrido [4,3-b] indol-1-one; 5- (cyclopentylmethyl) -2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-30 yl) methyl] -1H-pyrido [4,3-b] indole-1 one; 3.4.5.6-tetrahydro-6-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -azepino [4,3-b] indol-1 (2H) -one; DK 170506 B1 6 2,3,4 »5-tetrahydro-N, N-dimethyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1-oxo-5H-pyrido [4, 3-b] indole-5-carboxamide; 2,3,4,5-tetrahydro-2 - [(5-methyl-lH-imidazol-4-yl) methyl] -5- (2-pro-propynyl) -ΙΗ-pyrido [4,3-b] indole-1 -one; 5 and physiologically acceptable salts and solvates thereof.

The strong and selective antagonism of 5-HT at 5-HT 3 receptors of lactam compounds of the invention has been demonstrated by their ability to inhibit 3- (5-methyl-1H-imidazol-4-yl) -1- [1- ( methyl-ββ-1H-indol-3-yl] -1-propanoribinding in entorhinal cortex homogenates from rats (according to the general procedure described by G. Kilpatrick et al. in Nature, 1987, 330. 746) and / or their ability to inhibit the 5-HT-induced depolarization of a vagus nerve preparation isolated from rats. The compounds of Examples 1, 3-9, 11, 12, 14, 15, and 16, when tested on entorhinal cortex homogenates 15 from rats, had pKværd values in the range 9.0-10.5.

In addition to their action as potent and selective antagonists of 5-HT at 5-HT 3 receptors, certain compounds of the invention have the advantage of an extended duration of action.

A particularly preferred lactam compound due to both its strength and duration of action is 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one and physiologically acceptable salts and solvates thereof. Preferred salts of this compound are the hydrochloride and maleate.

Lactam compounds of formula (I) which antagonize the action of 5-HT- by 5-HT3 receptors are useful in the treatment of conditions such as psychotic disorders (e.g., schizophrenia and mania); anxiety; and nausea and vomiting, especially those associated with cancer chemotherapy and radiotherapy. Compounds of formula (I) are also useful in the treatment of gastric stasis; symptoms of gastrointestinal dysfunction such as those with dyspepsia, peptic ulcer, reflux oesophagitis, flatulence and irritable bowel syndrome; migraine; and pain. Compounds of formula (I) may also be used in the treatment of drug and drug dependence, depression and dementia and other cognitive disorders.

DK 170506 B1 7

The compounds of the invention can be used to treat a human or animal suffering from a psychotic illness such as schizophrenia or mania; or of anxiety; nausea or vomiting; gastric stasis; symptoms of gastrointestinal dysfunction such as dyspepsia, reflux oesophagitis, peptic ulcer, flatulence and irritable bowel syndrome; migraine; or pain, by a method comprising administering an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.

Accordingly, the invention also relates to a pharmaceutical composition containing at least one compound selected from lactam compounds of general formula (I) and physiologically acceptable salts and solvates (e.g. hydrates) thereof with at least one physiologically acceptable carrier or excipient, preferably in a form adapted for oral or parenteral administration, for use in human or veterinary medicine and formulated for administration by any convenient route.

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

Thus, for example, the lactam 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 through the mouth or nose).

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared in a conventional manner with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); 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 glycollate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by known techniques. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups, or suspensions, or they may be in the form of a dry product for constitution with water or other suitable medium before use. Such liquid compositions may be prepared in a conventional manner with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia rubber); non-aqueous media (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-β-hydroxybenzoates or sorbic acid). The compositions may also contain buffered salts, flavors, dyes and sweeteners as required.

The compositions for oral administration may be conveniently formulated to provide controlled release of the active ingredient.

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

The lactam compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be in unit dosage form, for example in ampoules or in multi-dose containers, with added preservative. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous media and may contain formulation aids such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable medium, e.g. sterile pyrogen-free water, before use.

The lactam 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 formulations described above, the compound may 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 (eg as an emulsion in an acceptable oil) or ion exchange resins, or as weakly soluble derivatives, for example as a weakly soluble salt.

For administration by inhalation, the lactam compounds of the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packages or a nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or another gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing the container with a valve to deliver a metered amount. Capsules and 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.

For intranasal administration, the compounds of the invention can be formulated as solutions for administration via a suitable metered or unit dose device or alternatively as a powder mixture with a suitable carrier for administration using a suitable delivery device.

The lactam compounds of formula (I) may also be administered in conjunction with other therapeutic agents. For example, in the treatment of gastric stasis, symptoms of gastrointestinal dysfunction and nausea and vomiting, compounds of formula (I) may be administered in conjunction with antisecretory agents such as histamine β receptor antagonists (e.g. ranitidine, sufotidine, 1-methyl-5 - [[3 - [3- (1-piperidinylmethyl) p-henoxy] propyl] amino] -1H-1,2,4-triazole-3-methanol, cimetidine, famotidine, nizatidine or roxatidine) or H + K + ATPase inhibitors (e.g., omeprazole).

A suggested dose of the compounds of the invention for administration to humans (having a body weight of about 70 kg) is 0.001-100 mg, preferably 0.01-50 mg, especially 0.1-20 mg, active ingredient per day. unit dose expressed as the weight of free base which could be administered eg 1-4 times daily. It will be clear that routine dose variations may be necessary depending on the age and condition of the patient. The dose will also depend on the route of administration.

The invention also relates to the use of the compounds of formula (I) for the manufacture of a medicament for (a) treatment 5 of a condition caused respectively by a disorder of 5-HT by S-HT 2 receptors and b) treatment of nausea and vomiting; dyspepsia, reflux oesophagitis, irritable bowel syndrome and / or to promote gastric emptying.

Lactam compounds of the general formula (I) and physiologically acceptable salts or solvates thereof can be prepared according to the general methods described below. In the following, the groups rA, n and Im have the meanings for compounds of general formula (I) where nothing else is stated.

The invention also relates to a process for the preparation of the compounds of formula I as claimed in claim 9.

According to a first general method (A), a lactam compound of general formula (I) can be prepared by alkylating a compound of formula (II): Λ_Λη in ii ii L, \\ / \ / 2 n (H) ·

• N

With a compound of formula (III): LCH 2 -Im (III) or a protected derivative thereof, wherein L represents a leaving atom or a leaving entity such as a halogen atom (e.g. chlorine, bromine or iodine) or an acyloxy group (e.g. trifluoroacetyloxy or acet-oxy) or a sulfonyloxy group (e.g., trifluoromethanesulfonyloxy, DK 170506 B1 11 E-toluenesulfonyloxy or methanesulfonyloxy); followed where necessary by removal of the protecting groups. L is preferably a halogen atom (e.g., a chlorine atom).

The reaction may be carried out in an inert solvent such as an ether (e.g., dimethoxyethane, diglym or tetrahydrofuran), a substituted amide (e.g., dimethylformamide or N-methylpyrrolidone), an aromatic hydrocarbon (e.g., toluene), a ketone (e.g., acetone), or dimethylsulfoxide. at a temperature of between ambient temperature and 100 ° C in the presence of a base. Suitable bases include alkali metal hydrides (e.g., sodium hydride), alkali metal carbonates (e.g., sodium carbonate), alkali metal amides (e.g., sodium amide), alkali metal alkoxides (e.g., potassium t-butoxide), or alkali metal hydroxides (e.g., sodium or potassium hydroxide).

According to another general method (B), a lactam compound of general formula (I) can be converted to another compound of formula 15 (I) using conventional techniques. Such conventional techniques include hydrogenation, alkylation and acylation using protection and deprotection where necessary.

Thus, according to one embodiment of interconversion process (B), hydrogenation can be used to convert an alkenyl or an alkynyl substituent to an alkyl substituent or an alkynyl to an alkenyl substituent. Hydrogenation can also be used to replace a phenylmethoxymethyl group with a hydrogen atom. Hydrogenation according to the general process (B) can be carried out using conventional processes, for example using hydrogen in the presence of a catalyst as described in published EP 242973.

The term "alkylation" according to the general process (B) comprises the introduction of groups such as cycloalkyl, alkenyl or phenalkyl groups.

Thus, for example, a lactam compound of formula (I) may be prepared, wherein R · represents a C ^gg alkyl, C3. g-alkenyl-, C3-; L () - alkynyl-, ¢ 3.7-cycloalkyl, C3-7-cycloalkyl-, C1-6 -alkyl, phenyl-C1-3 -alkyl-, phenylmethoxymethyl-, phenoxyethyl - or phenoxymethyl group by alkylation of a compound of formula (I) wherein rA represents a hydrogen atom or a compound wherein R 1 represents a C 1-6 alkyl, C 3-6 cycloalkyl, C 3-8 alkenyl - or phenyl-C1-3 alkyl group, can be prepared by alkylating the corresponding compound of formula 5 (I), which represents a hydrogen atom, using conventional methods, for example as described in published EP 242973. The reactions can thus be carried out under using a suitable alkylating agent of formula R'Z (wherein R 'is the group to be introduced and Z is a leaving atom or leaving group) preferably in the presence of a base.

According to another embodiment of the general process (B), a lactam compound of formula (I) wherein R ^ represents -C ^R ", -COR ^, -CONR%, or -SO₂R" can be prepared by acylating or sulfonylating a compound of formula (I) wherein R 1 represents a hydrogen atom. The acylation / sulfonylation reactions can be carried out using a suitable acylation / sulfonylating agent according to conventional methods, for example as described in published EP 210840.

It should be clear that in the above-mentioned transformations it may be necessary or desirable to protect sensitive groups in the molecule of that compound, to avoid undesirable side reactions. For example, it may be necessary to protect the indole and / or imidazole nitrogen atoms, for example with an arylmethyl (e.g. trityl), arylmethoxymethyl (e.g. phenylmethoxymethyl), alkyl (e.g. t-butyl), alkoxymethyl (e.g. methoxymethyl) ), acyl (e.g. benzyloxycarbonyl) or a sulfonyl (e.g., Ν, Ν-dimethylaminosulfonyl or p-toluenesulfonyl) group.

Thus, according to another general method (C), a lactam compound of general formula (I) can be prepared by removing protecting groups from a protected form of a compound of formula (I).

Deprotection can be performed using conventional techniques such as those described in "Protective Groups in Organic Synthesis" by T. W. Greene (John Wiley and Sons, 1981).

For example, an arylmethoxymethyl-N protecting group may be cleaved by hydrogenolysis in the presence of a catalyst (e.g., palladium-on-charcoal). A DK 170506 B1 13 trityl group can be cleaved by acid hydrolysis (e.g. using dilute hydrochloric or acetic acid). An alkoxyalkyl group may be removed using a mineral acid (e.g., dilute hydrochloric or hydrobromic acid). An acyl group can be removed by hydrolysis under acidic or basic conditions (e.g. using hydrogen bromide, dilute hydrochloric acid or sodium hydroxide). A sulfonyl group may also be removed by alkaline or acidic hydrolysis, and an N, N-dimethylaminosulfonyl group may also be removed (e.g. from an imidazole nitrogen atom) by photolysis.

Compounds of formula (II) can be obtained by a Beckmann rearrangement of an oxime of formula (IV): H0

N

II

/ \ Λ • · · \ A / LicH2> m <IV> * \ R1 where m represents the number 1 or 2 or a protected derivative thereof. The Beckmann rearrangement may be carried out using conventional methods, for example using an acid (e.g. polyphosphoric or sulfuric acid or a mixture of hydrochloric acid, acetic anhydride and acetic acid) in an inert solvent such as an ether (e.g. dioxane), an amide ( (e.g., dimethylformamide) or a hydrocarbon (e.g., toluene or cyclohexane) at an elevated temperature of, e.g., 50-120 ° C. Alternatively, the hydroxy group of the oxime of formula (IV) can be converted to a leaving group such as a chloride (using, for example, phosphorus pentachloride) or a hydrocarbyl sulfonate (e.g., a mesylate or a tosylate) or a trifluoroacetate group (using conventional acylation methods). Subsequent heating at a temperature of, for example, 20-150 ° C in an inert solvent as described above gives a compound of formula (II).

DK 170506 B1 14

The compound of formula (IV) can be prepared from the corresponding tricyclic ketone of formula (V): 0

II

/ \ / \! ! Uch2> (V) W / \ / 2 m

• N

R1 wherein m represents the number 1 or 2 or a protected derivative thereof, 5 using conventional methods, for example using hydroxylamine hydrochloride in a solvent such as pyridine.

Compounds of formula (III) and protected derivatives thereof are either known or can be prepared, for example, by the methods described in DE A 3740352.

Compounds of formula (V) may be prepared, for example, by the method or methods similar to that described by H. Iida et al. in J. Org. Chem. 1980, 45, 2938.

Where it is desired to isolate a compound of the invention as a salt, e.g., a physiologically acceptable salt, this can be achieved by converting the compound of formula (I) in the form of the free base with an appropriate acid, preferably with an equivalent amount, in a suitable solvent such as an alcohol (e.g., ethanol or methanol), an aqueous alcohol (e.g., aqueous ethanol), a halogenated hydrocarbon (e.g., dichloromethane), an ester (e.g., ethyl acetate), or an ether (e.g., tetrahydrofuran).

Physiologically acceptable salts may also be prepared from other salts including other physiologically acceptable salts of the compound of formula (I) using conventional methods. <

Individual enantiomers of the compounds of the invention can be obtained by resolution of a mixture of enantiomers (e.g., a racemic mixture) using conventional means such as an optically active dissolving acid; see, e.g., "Stereochemistry of Carbon Compounds" by DK 170506 B1 15 E. L. Eliel (McGraw Hili, 1962) and "Tables of Resolving Agents" by S.

H. Wilen.

The above-described process for preparing the compounds of the invention can be used to introduce the desired groups at any stage of the stepwise formation of the required compounds, and it will be understood that these methods can be combined in various ways. in such multi-step processes.

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

The invention is further illustrated by the following intermediates and examples, thin layer chromatography (TLC) was performed on silica, and flash column chromatography (FCC) on silica (Merck 9385). Solvent A system as used for chromatography represents dichloromethane: -15 ethanol: 0.88-ammonia solution. Organic extracts were, where indicated, dried over magnesium sulfate or sodium sulfate. The following abbreviations are used: DMF - dimethylformamide; THF - tetrahydrofuran; DME - dimethoxyethane. 1 H NMR spectra were obtained at 250 MHz for dilute solutions in dg-dimethylsulfoxide.

Intermediate 1 4- (Chloromethyl) -1- (triphenylmethyl) -1H-imidazole

Thionyl chloride (0.82 g) was added over 1 minute to a stirred suspension of 1- (triphenylmethyl) -1H-imidazole-4-methanol (1.3 g) in a mixture of dichloromethane (50 ml) and DMF (1 , 0 ml) at 23 ° C. The thus obtained solution was stirred for 15 minutes and extracted with 8% sodium bicarbonate solution (80 ml). The organic phase was washed with water (50 ml), dried and evaporated to give an oil which solidified. The solid was slurried in hexane and filtered to give the title compound (1.28 g), m.p. 139-141 ° C.

DK 170506 B1

Intermediate 2 16 4- Formyl-N, N-dimethyl-5-propyl-1H-imidazole-1-sulfonamide

Dimethylsulfamoyl chloride (0.67 ml) was added to a stirred solution of 5-propyl-1H-imidazole-4-carboxaldehyde (860 mg) and triethylamine 5 (0.87 ml) in dry dichloromethane (10 ml) under nitrogen. The solution was heated at reflux for 24 hours, allowed to cool, poured into water (50 ml) and extracted with dichloromethane (3 x 25 ml). The combined dried organic extracts were evaporated to give an oil (1.9 g) which was purified by FCC with ethyl acetate: hexane (1: 1) as eluent to give the title compound (500 mg), m.p.

57-58 ° C.

Intermediate 3 4- (Hydroxymethyl) -N, N-dimethyl-5-propyl-1H-imidazole-1-sulfonamide

Sodium borohydride (139 mg) was added to a stirred solution of 4-formyl-N, N-dimethyl-5-propyl-1H-imidazole-1-sulfonamide (450 mg) in absolute ethanol (5 ml) under nitrogen. After 3 hours, the mixture was poured into water (30 ml) and extracted with dichloromethane (3 x 15 ml). The combined dried organic extracts were evaporated to give a solid (425 mg) which was triturated with ether (2 x 10 ml) to give the title compound (350 mg), m.p. 86-88 ° C.

Intermediate 4 4- (Chloromethyl) -N, N-dimethyl-5-propyl-1H-imidazole-1-sulfonamide

A solution of thionyl chloride (0.12 mL) in dry dichloromethane (1.2 mL) was added dropwise to a cold (0 ° C) stirred solution of 4- (hydroxymethyl-5,1-dimethyl-5-propyl) -IH-imidazole-1-sulfonamide (340 mg) in dry dichloromethane (7.5 ml) under nitrogen. After 1.5 hours, the solution was washed with 8% sodium bicarbonate solution (2 x 15 ml) and the aqueous phase extracted with dichloromethane (2 x 10 ml). The combined organic extracts were washed with water (15 ml), dried and evaporated to give the title compound (180 mg) as an oil, TLC (ethyl acetate) Rf 0.68.

Intermediate 5 3,4-Dihydro-4-methylcyclopent [b] indole-1 (2H) -one oxime 5,4-Dihydro-4-methylcyclopent [b] indole-1 (2H) -one (1.7 g ) and hydroxylamine hydrochloride (1.925 g) in pyridine were heated at 60 ° C for 18 hours and cooled. The reaction mixture was evaporated in vacuo to a residue to which 8% sodium carbonate (150 ml) was added. Extraction with ethyl acetate (300 ml) gave a suspension in the organic layer; this layer 10 and associated solids were separated from the aqueous layer. The aqueous layer was re-extracted with ethyl acetate (250 ml). The combined organic (and suspended solids) were evaporated to a residue, boiled with a mixture of ethanol (150 ml) and methanol (150 ml) and cooled to ca. 50 ° C. The residue was absorbed from this solution 15 onto FCC silica and applied to an FCC column. Elution with ethyl acetate / 3-10% methanol gave the title compound (1.69 g), m.p. 219-224 ° C (dec.).

Intermediate 6 2,3,4,5-Tetrahydro-5-methyl-1H-pyrido [3,4-b] indol-1-one 3,4-Dihydro-4-methylcyclopent [b] indole-1 (2H) -one oxime (1.53 g), polyphosphoric acid (40 g) and dioxane (15 ml) were heated at 110-120 ° C for 2.2 hours under nitrogen. The reaction mixture was cooled and treated with 2N sodium carbonate solution (1 L). The suspension was extracted with ethyl acetate (4 x 400 ml) and the combined extracts were dried. Evaporation gave a solid (1.43 g) which was recrystallized from ethyl acetate / cyclohexane. This solid was purified by FCC with system A as eluent (200: 10: 1) to give a solid (1.26 g) which was recrystallized from ethanol to give the title compound (960 mg '), m.p. 234-238 ° C.

DK 170506 B1

Intermediate 7 18 3.4.5.6- Tetrahydro-6-methyllazepino [4,3-b] indole-1 (2H) -one 1,2,3,9-Tetrahydro-9-methyl-4H-carbazol-4-one oxime (24 g) and polyphosphoric acid (600 g) in dioxane (500 ml) were treated according to the procedure described under intermediate 6. The solid (22 g) obtained by evaporation of the organic extracts was recrystallized from ethyl acetate (300 g). ml) to give a solid (19.2 g).

This solid was purified by FCC with system A as eluent (200: 8: 1) to give the title compound (5.5 g), m.p.

212-215 ° C.

Intermediate 8 5.6- Dihydro-4- (phenylamino) -1 (2H) -pyridinone

A mixture of 2,4-dioxopiperidine (1.13 g) and aniline (930 mg) was heated at 120 ° C under a stream of nitrogen for 15 minutes. The resulting solid was triturated with ether and filtered to give the title compound (1.74 g), m.p. 235-238 ° C.

Intermediate 9 2,3,4,5-Tetrahydro-1H-pyrido [4,3-b] indol-1-one

A solution of 5,6-dihydro-4- (phenylamino) -1 (2H) -pyridinone (1.5 g) and palladium acetate (150 mg) in dry DMF (50 ml) was treated with cupriacetate (3.2 g ) and the resulting mixture was heated under nitrogen at 120-130 ° C for 1.5 hours. The mixture was then concentrated in vacuo to give a solid which was triturated with 2N hydrochloric acid (250 ml). The acid was decanted and the remaining solid was extracted with ethyl acetate for 18 hours. The decanted acid was basified with 2N sodium hydroxide and extracted with ethyl acetate (3 x 100 mL). These organic extracts were combined with the ethyl acetate extracts previously and absorbed into silica. Purification by FCC using System A as eluent (100: 8: 1) gave the title compound (874 mg1), m.p. 212-215 ° C.

DK 170506 B1

Intermediate 10 2,3,4,5-Tetrahydro-5- [phenylmethoxy) methyl] -1H-pyrido [4,3-b] indol-1-one

A solution of 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (1.12 g) in dry DMF (60 ml) was treated with sodium hydride (60% dispersion). in oil; 480 mg) and the resulting mixture was stirred under nitrogen until the effervescence ceased. The mixture was then cooled to 0 ° C and benzyl (chloromethyl) ether (10% w / v solution in DMF; 0.835 ml) was added over 10 minutes. Stirring was continued for a further 5 minutes, after which water (10 ml) was added. The reaction mixture was concentrated in vacuo to give an oil which was dissolved in ethyl acetate (100 ml) and washed with water (3 x 100 ml). The organic phase was dried and absorbed onto FCC silica. The purification by FCC with system A as eluent 15 (150: 8: 1) afforded the title compound (1.1 g), m.p. 133-135 ° C.

Intermediates 11-14 were prepared in a similar manner to Intermediate 10, ie. by treatment of 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one with sodium hydride followed by a suitable alkylating agent. The isolation and purification of the products was as described for intermediate 10, unless otherwise stated.

Intermediate 11 5-Ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one 2,3,4,5-Tetrahydro-1H-pyrido [4,3-b] ] indol-1-one (931 mg) was treated with sodium hydride (60% dispersion in oil; 400 mg) and then stirred with ethyl iodide (10% by volume solution in DMF; 4ml) to give the title compound (758mg), mp. 203-204.5 ° C.

DK 170506 B1

Intermediate 12 2,3,4 '5-Tetrahydro-5- (1-methylethyl) -1H-pyrido [4,3-b] indo-1-one 2,3,4,5-Tetrahydro-1H-pyrido [4,3-b] b] indol-1-one (931 mg) was treated with sodium hydride (73% dispersion in oil; 328 mg) and then stirred with 2-bromopropane (615 mg) at room temperature for 72 hours. Purification by FCC with system A as eluent (200: 8: 1) gave a foam (324 mg) which was further purified by recrystallization from ethyl acetate: hexane (1: 1) to give the title compound Γ294 mg) TLC (system A, 100: 8: 1) Rf 0.58.

Intermediate 13 2.3.4.5-Tetrahydro-5- (1-phenylmethyl) -1H-pyrido [4,3-b] indo-1-one 2.3.4.5-Tetrahydro-1H-pyrido [4,3-b] indole 1-one (559 mg) was treated with sodium hydride (73% dispersion in oil; 197 mg) and then stirred with benzyl bromide (513 mg) at room temperature for 30 minutes.

Purification by FCC with dichloromethane: ethanol (80: 1) as eluent gave the title compound (347 mg), m.p. 209-212 ° C.

Intermediate 14 5- (Cyclopentylmethyl) -2,3,4,5-tetrahydro-ΙΗ-pyrido [4,3-b] indol-1-one 2.3,4,5-Tetrahydro-1H-pyrido [4,3-b] indole -l-one (950 mg) was treated with sodium hydride (60% dispersion in oil; 408 mg) and then stirred with cyclopentane methanol methanesulfonate (909 mg) at room temperature for 7 days. The solid (570 mg) obtained at FCC was further purified by slowly evaporating a solution in methanol to give the title compound, m.p. 179-181 ° C.

Intermediate 2,3,4,5-Tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indole-1 -on DK 170506 B1 21

A solution of triphenylmethyl chloride (3.36 g) in dry DMF (40 ml) was added dropwise with a stirred solution of 2,3,4,5-tetrahydro-2 - [[5-methyl-1H-imidazol-4-yl ] methyl] 1H-pyrido [4,3-b] indol-1-one (2.8 g) in dry DMF (50 ml) containing triethylamine (1.52 g). After the addition was complete, the mixture was stirred overnight. The mixture was then poured into water (1000 ml) and the resulting suspension 10 extracted with ethyl acetate (3 x 300 ml). The combined organic extracts were washed with water (2 x 500 ml), dried and concentrated on silica. FCC with system A as eluent (100: 8: 1) afforded the title compound (4.3 g), m.p. 235-236 ° C.

Intermediate 16 2,3,4,5-Tetrahydro-5-methyl-2 - [[1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indole pay

A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (0.3 g) and sodium hydride (80% dispersion in oil; 0.05 g) in dry DMF (5 ml) was stirred under nitrogen at 50 ° C until hydrogen evolution 20 ceased (about 0.5 hour). The mixture was cooled to 40 ° C and a solution of 4- (chloromethyl) -1- (triphenylmethyl) -1H-imidazole (0.53g) in dry THF (3ml) was added. The mixture was stirred at 40-23 ° C for 2 hours, poured into water (100 ml) and extracted with dichloromethane (3 x 100 ml). The dried organic phase was evaporated to give a partial solid which was purified by FCC with dichloromethane: ethyl acetate: triethylamine (50: 50: 1) as the eluent to give a solid. This was slurried in hexane and filtered to give the title compound (0.37 g), m.p. 205-210 ° C (dec.).

2,3,4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one maleate Example 170506 B1 EXAMPLE 1 22

A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one 5 (0.6 g) and ca. 78% sodium hydride dispersion in mineral oil (0.109g) in dry DMF (15ml) was stirred under nitrogen at 50 ° C until hydrogen evolution ceased (about 1.5 hours). The mixture was cooled to 40 ° C and a solution of 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (1.12 g) in dry THF (15 ml) was added. The reaction mixture was then stirred at 40 ° C for 3 hours, at 20 ° C for 16 hours, and an additional portion of 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (1 , 12 g) in dry THF (15 ml) was added. The resulting mixture was heated at 40 ° C for 3 hours, quenched by the addition of water (20 ml) and acetic acid (20 ml), and the mixture was heated at 100 ° C for 2 hours. The mixture was then concentrated in vacuo to ca. 60 ml, diluted with 1M hydrochloric acid (40 ml) and washed with ethyl acetate (3 x 50 ml). The organic phase was discarded and the acidic aqueous phase was basified (pH 9) with potassium carbonate and extracted with ethyl acetate: ethanol (20: 1, 20 x 3 x 100 mL). The extracts were combined, dried and evaporated to give a brown gum (about 1 g). This gum was absorbed into silica and purified by FCC with system A as eluent (100: 8: 1) to give a light brown solid (0.8 g), m.p. 238-240QC (decomposition). This solid was dissolved in a mixture of warm ethanol and methanol (1: 1; 100 ml) and treated with an ethanolic solution of maleic acid (318 g). The resulting solution was concentrated to ca. 20 ml and diluted with dry diethyl ether (about 8 ml) to precipitate the title compound (0.75 g) as an off-white solid, m.p. 160-162 ° C.

Analysis: Calculated for C 17 H 18 N 4 O 4 C 4 H 4 O 4: C, 61.5; H, 5.4; N, 13_, 8%; found: C, 61.6; H, 5.5; N, 13.6.

EXAMPLE 2 23 2.3.4.5 - Tetrahydro-6-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -azepino [4,3-b] indole-1 (2H) - on-maleate 3.4.5.6- Tetrahydro-6-methyllazepino [4,3-b] indole-1 (2H) -one (0.64 g) was treated with sodium hydride (about 75-80% dispersion in oil; 0.108 g) and then stirred with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole as described in Example 1. The reaction mixture was then poured into water (300 ml) and extracted with dichloromethane (4). x 250 ml). The combined dried organic extracts were evaporated to give a partial solid (about 1.8 g) which was purified by FCC with system A as eluent (200: 8: 1) to give a gum (0.7 g). This gum (0.7 g) was dissolved in a mixture of acetic acid, THF and water (1: 1: 1; about 70 ml) and heated on a steam bath for 1 hour. Workup, as described in Example 1, gave a gum 15 (0.22 g) which was purified by FCC with system A as eluent (200: 8: 1) to give a solid (0.11 g). Maleate formation afforded a gum which was dried in vacuo to give a foam which was triturated with a mixture of ether and ethanol (50: 1; about 25 ml) to give the title compound (0.145 g) as a solid, m.p.

Mp 132-133 ° C.

1 H NMR showed that 0.39 moles of ethanol was present.

Water analysis found 0.583% by weight = 0.14 mol H2O.

Analysis: Calculated for C ^ gH₂ON40O · C ^H ^O ^ * 0.39 EtOH * 0.14 H₂O: C, 61.4; H, 6.0; N, 12.6%; found: C, 61.4; H, 5.7; N, 12.6.

EXAMPLE 3 2,3,4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5 - [(phenylmethoxy) methyl] -1H-pyrido [4,3- b] indol-1-one maleate A suspension of 2,3,4,5-tetrahydro-5 - [(phenylmethoxy) methyl] -1H-pyrido [4,3-b] indol-1-one (920 mg ) in dry DME (75 ml) was treated with DK 170506 B1 24 sodium hydride (60% dispersion in oil; 180 mg) under nitrogen and the reaction mixture was stirred at 60 ° C for 6 hours. 4- (Chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (1.11 g) was then added and the mixture was stirred at 60 ° C overnight. Acetic acid 5 (10 ml), water (10 ml) and THF (10 ml) were then added and the resulting mixture was heated at reflux for 6 hours. After cooling, 2N sodium hydroxide (100 ml) was added and the resulting suspension was extracted with dichloromethane (3 x 100 ml). The combined dried organic extracts were absorbed on FCC silica and 10 FCC with system A as eluent (150: 8: 1) gave the free base of the title compound (1.08 g) as a foam. A small amount of this compound (200 mg) was dissolved in methanol (30 ml) and the resulting mixture was treated with maleic acid (58 mg). The solution was heated for 10 minutes and cooled, and dry ether was added to precipitate the title compound (170 mg), m.p. 165-168 ° C.

Water analysis 0.22% by weight = 0.06 mol H2O.

Analysis: Calculated for C 24 H 24 N 4 O · 04 · 04 · 0.06 · 0: C, 65.0; H, 5.5; N.10,8%; found: C, 64.5; H, 5.6; N, 10.7.

Examples 4-7 were prepared in a similar manner to Example 3.

Example 4 5-Ethyl-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one -Maleate 5-Ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (500 mg) was treated with sodium hydride (60% dispersion in oil; 138 mg) and then stirred with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (927.5 mg) to give the title compound free base (320 mg) as a solid. Maleate formation gave the title compound (380 mg), m.p. 175.5 to 177 ° C.

DK 170506 B1 25

Analysis: Calculated for C, 62.2; H, 5.7; N, 13.2%; found: C, 62.1; H, 5.7; N, 13.0.

EXAMPLE 5 2,3,4,5-Tetrahydro-5- (1-methylethyl) -2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b ] indol-1-one maleate 2.3.4.5- Tetrahydro-5- (1-methylethyl) -1H-pyrido [4,3-b] indol-1-one (228 mg) was treated with sodium hydride (60% dispersion in oil; 60 mg) and then stirred with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (371 mg) to give the title compound free base (180 mg) as a solid . Maleate formation gave the title compound (172 mg), m.p. 203-205 ° C.

Analysis: Calculated for 0 ^ 9 ^ 2 ^ 0 ^ C4 H4 O4: C, 63.0; H, 6.0; N, 12.8%; Found: C, 62.6; H, 6.0; N, 12.6.

Example 6 2.3.4.5- Tetrahydro-5- (phenylmethyl) -2 - [(5-methyl-1H-imidazol-4-yl) -methyl] -1H-pyrido [4,3-b] indol-1-one maleate monohydrate 2.3.4.5- Tetrahydro-5- (phenylmethyl) -1H-pyrido [4,3-b] indol-1-one (960 mg) was treated with sodium hydride (73% dispersion in oil; 132 mg) and was then stirred with 4- (chloromethyl) -5-methyl-1- (tri-phenylmethyl) -1H-imidazole (1.3 mg). The free base of the title compound (571 mg) was obtained as a solid at FCC with system A as eluent (175: 8: 1). Maleate formation gave the title compound 25 (420 mg), m.p. 198-200 ° C, TLC (System A, 100: 8: 1) Rf 0.3.

5- (Cyclopentylmethyl) -2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one EXAMPLE 7 26 5- (Cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-pyridof4,3-b] indol-1-one (200 mg) was treated with sodium hydride (60% dispersion) in oil; 60 mg) and then stirred with 4- (chloromethyl) -5-methyl-1- (tri-phenylmethyl) -1H-imidazole (280 mg). The free base of the title compound (96 mg) was obtained as a solid at FCC with system A as eluent (200: 8: 1). Maleate formation saw the title compound (60 mg), 10 m.p. 81-83 ° C, TLC (System A, 100: 8: 1) Rf 0.20.

Example 8 2,3,4,5-Tetrahydro-5-methyl-2 - [(5-propyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one maleate

Sodium hydride (60% dispersion in oil; 25 mg) was added to a stirred suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (124 mg ) in dry DME (5 ml) under nitrogen. The mixture was heated at 50 ° C for 7 hours and then treated with a solution of 4- (chloromethyl) -N, N-dimethyl-5-propyl-1H-imidazole-1-sulfonamide (165 mg) in dry DME (3 ml ) and stirring was continued at 50 ° C for 20 hours. 2N hydrochloric acid (5 ml) was added and the solution was heated at reflux for 6 hours. The solution was poured into 8% sodium hydrogen carbonate solution (50 ml) and extracted with dichloromethane (3 x 25 ml). The combined dried organic extracts were evaporated to give a solid (200 mg) which was purified by FCC with System A as eluent (200: 10: 1) to give the title compound free base (58 mg) as a solid . This was dissolved in warm absolute ethanol (5 ml) and treated with a solution of maleic acid (21 mg) in ethanol (0.5 ml). The solvent was removed in vacuo and the residue was crystallized by ethanol: ether to give the title compound (58 mg), m.p. 137-138 ° C.

DK 170506 B1 27

Analysis: Calculated for C ^ glH ^N ^O * C ^H ^O ^: C, 63.0; H, 6.0; N, 12.8%; found: C.62.7; H, 5.9; N.12,4.

EXAMPLE 9 2,3,4,5-Tetrahydro-N, N-dimethyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1-oxo-5H-pyrido [4, 3-b] indole-5-carboxamide maleate

A solution of 2,3,4,5-tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indole 1-one (261 mg) in dry DMF (25 ml) was treated with sodium hydride (60% dispersion in 10 oil; 30 ml) and the mixture was stirred at room temperature under nitrogen for 15 minutes. Ν, Ν-Dimethylcarbamoyl chloride (1M solution in DMF; 1ml) was then added and the solution was stirred at room temperature for an additional 15 minutes. Water (1 ml) was gently added and the reaction mixture was then poured into water (100 ml). The resulting mixture was extracted with ethyl acetate (2 x 50 ml) and the combined organic extracts were washed with water (2 x 100 ml) and concentrated to give an oil. The oil was dissolved in a mixture of water (10 ml), glacial acetic acid (10 ml) and THF (10 ml), and the solution was heated at reflux for 1.5 hours. After cooling, the solution was basified by the addition of 2N sodium hydroxide (100 mL) and the resulting mixture was extracted with ethyl acetate (2 x 75 mL). The combined dried organic extracts were absorbed on FCC silica and the free base of the title compound (110 mg) was obtained as a solid at FCC with System A as eluent 25 (100: 8: 1). This was dissolved in dry methanol (10 ml) and heated with maleic acid (36 mg) on a steam bath for 5 minutes. On cooling, dry ether (3 ml) was added to precipitate the title compound (105 mg), m.p. 161-163 ° C.

Water analysis 1.85% w / w s 0.49 mol H2O.

Analysis: Calculated for δ ^ 112 ^ 502 ^ / 0.491 ° C: C, 68.0; H, 5.5; N, 14.7%; Found: C, 57.8; H, 5.4; N, 14.3.

DK 170506 B1 28

Examples 10, 11 and 12, unless otherwise stated, were carried out in a similar manner to Example 9.

EXAMPLE 10 2.3.4.5- Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (methylsulfonyl) -1H-pyrido [4,3-b] indole-1- on-maleate 2.3.4.5- Tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indol-1-one ( 261 mg) was treated with sodium hydride (60% dispersion in oil; 30 mg) and then stirred with methanesulfonyl chloride (1M solution in dry TMF; 1 ml) for 45 minutes. Deprotection, reprocessing and purification gave the title compound's free base (60 mg) as a solid. Maleate formation gave the title compound (57 mg), m.p. 152-155 ° C.

Analysis: Calculated for C CHH ^ gNNC ^S'C ^H ^P ^: C, 53.2; H, 4.7; N, ll, 8%; Found C, 53.2; H, 4.7; N, D, 7th

Example 11 2.3.4.5- Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propynyl) -1H-pyrido [4,3-b] indole-1 -one maleate

A solution of 2,3,4,5-tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -20H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indole -l-one (522 mg) and potassium carbonate (276 mg) in dry acetone (75 ml) were treated with propargyl bromide (1M solution in acetone; 2 ml) and the mixture was heated at reflux overnight. After cooling, excess acetone was removed in vacuo to give an oil which was partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was washed with ethyl acetate (50 ml) and the combined organic extracts were concentrated in vacuo. Deprotection, work-up and purification gave the title compound's free base (100 mg) as a solid. Maleate formation gave the title compound (89 mg), m.p. 202-205 ° C, TLC (system 30 A, 100: 8: 1) Rf 0.29.

EXAMPLE 12 29 2.3.4.5- Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propynyl) -1H-pyrido [4,3-b ] indol-1-one maleate 2.3.4.5- Tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-5-yl] methyl] -1H-pyrido [4,3-b] indol-1-one (1.0 g) was treated with sodium hydride (60% dispersion in oil; 114 ml) and then stirred with allyl bromide (460 mg) for 1 hour. Deprotection, work-up and purification gave the title compound's free base (380 mg) as a solid. Maleate formation gave the title compound (160 mg), TLC (system A, 100: 8: 1) Rf 0.3.

Analysis calculated for C ^^ q q ^OCC ^O ^C, 63.3; H, 5.5; N, 12.8%; found: C, 63.2; H, 5.5; N, 12.5.

EXAMPLE 13 5-Cyclopentyl-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1 -one maleate

A solution of 2,3,4,5-tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indole 1-one (523 mg) in dry DMF (30 ml) was treated with sodium hydride (60% dispersion in oil; 46 mg) and stirred for 15 minutes at 21 ° C under nitrogen. Cyclopentyl bromide (298 mg) was then added dropwise and the mixture was stirred for 1 hour and then heated at reflux for 4 hours. The solution was kept at 21 ° C for 2 days and then treated with a mixture of acetic acid (7 ml), water (7 ml) and THF (8 ml). The resulting solution was heated at reflux for 4 hours, then acidified with 2N sodium hydroxide and extracted with dichloromethane (3 x 25 ml). The combined extracts were washed with water (2 x 50 ml), concentrated in vacuo and purified by FCC with system A as eluent (100: 8: 1) to give the title compound free base (42 mg) as a solid. Maleate formation gave the title compound (38 mg), m.p. 180 ° C (dec.), TLC (system A, 100: 8: 1) 0.3.

EXAMPLE 14 2,3,4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5-propyl-1H-pyrido [4,3-b] indole 1-one maleate

A solution of 2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propynyl-1H-pyrido [4,3- b] indol-1-one (248 mg) in a mixture of ethanol (20 ml) and 2N hydrochloric acid (0.5 ml) was hydrogenated at room temperature and atmospheric pressure over a reduced 10% palladium moxide-on-carbon catalyst. (50% aqueous paste; 50 mg). The mixture was filtered and evaporated in vacuo. The residue was made basic with 2N sodium hydroxide (10 ml) and extracted with dichloromethane (3 x 20 ml). 30 ml) and evaporated to give the title compound free base (258 mg) as a solid Maleate formation gave the title compound (345 mg), TLC (system A, 100: 8: 1) Rf 0.4.

Water analysis 1.13% w / w = 0.28 mol H2O.

Analysis: calculated for 0.281 ° C: 62.2; H, 6.0; N, 12.6%; found: C, 62.1; H, 5.9; N, 12.5.

EXAMPLE 15 2,3,4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one maleate

A mixture of 2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- [phenyl (methoxymethyl)] - 1H-pyrido [4,3- b] indol-1-one (400 mg) in ethanol (20 ml) and glacial acetic acid (5 ml) was hydrogenated overnight at room temperature and atmospheric pressure over a pre-reduced 10% palladium oxide-on-carbon catalyst (50% aqueous paste; 100 mg). The reaction mixture was filtered and the residue was washed with ethanol (100 ml). The filtrate was concentrated in vacuo to give an oil to which 2N sodium hydroxide (50 ml) was added. The resulting suspension was extracted with dichloromethane (2 x 50 ml) and the combined dried organic extracts were evaporated to give DK 170506 B1 a solid. This was purified by FCC using System A as eluent (75: 8: 1) to give the title compound free base as a solid (240 mg) which was then dissolved in dry methanol (50 ml). Maleate formation gave the title compound (261 mg), TLC (system A, 75: 8: 1) Rf 0.2.

Analysis: Calculated for C 16 H 16 N 4 O 4 C 4 H 4 O 4: C, 60.6; H, 5 L; N.14,1%; found: C, 60.3; H, 5.2; N, 13.8.

EXAMPLE 16 2,3,4,5-Tetrahydro-5-methyl-2 - [(5-dimethyl-1H-imidazol-4-yl) methyl] -1-pyrido [4,3-b] indole-1 one maleate

Sodium hydride (73% dispersion in oil; 40 mg) was added to a stirred suspension of 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one (300 mg) in dry DMF (3 ml) under nitrogen. After 30 minutes, the suspension was cooled to 0 ° C and iodomethane (0.76 ml) was added dropwise. The mixture was allowed to reach room temperature, stirred for 1.5 hours, then poured into water (30 ml) and extracted with dichloromethane (3 x 15 ml). The combined dried organic extracts were evaporated to give an oil (about 545 mg) 20 which was purified by FCC with system A as eluent (200: 8: 1) to give a solid (95 mg). A portion of this material (90 mg) was dissolved in absolute ethanol (3 ml) and treated with a solution of maleic acid (35 mg) in absolute ethanol (1 ml). The solvent was removed in vacuo and the residue was triturated with dry ether (3x5 ml) to give the title compound (122 mg), m.p. 178-180 ° C.

For C 18 H 20 N 4 O. C 4 H 4 O 4: C, 62.3; H, 5.7; N, 13.2%; found: C, 62.1; H, 5.7; N, 13, l.

EXAMPLE 17 DK 170506 B1 32 2.3.4.5-Tetrahydro-2 - [(1H-imidazol-4-yl) methyl] -5-methyl-1H-pyrido [4,3-b] indol-1-one dimaleate

A solution of 2,3,4,5-tetrahydro-5-methyl-2 - [[1- (triphenylmethyl) -5H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole -l-one (0.22 mg) in a mixture of acetic acid, THF and water (1: 1: 1; 10 ml) was heated on a steam bath for 30 minutes. The suspension thus obtained was diluted with 1M hydrochloric acid (20 ml) and washed with ethyl acetate (3 x 20 ml).

The acidic aqueous phase was basified with sodium carbonate and extracted with dichloromethane: methanol (9: 1; 3 x 20 ml). The combined dried organic extracts were evaporated to give a foam which was dissolved in methanol (5 ml) and treated with a solution of maleic acid (0.15 g) in methanol (5 ml). The clear solution was evaporated to give a gum which after trituration with ether gave the title compound CO.17 g) as a solid, m.p. 117-118 ° C.

Analysis: Calculated for C ^ gH ^ gNNO ^C ^H ^O ^: C, 56.2; H, 4.7; N, 10.9%; found: C, 56.1; H, 4.3; N, 10.5.

EXAMPLE 18 2,3,4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1 on hydrochloride 2.3.4.5- Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one (1, 00 g) was suspended in ethanol (40 ml) and concentrated hydrochloric acid (1.00 ml) was added. The mixture was heated to 40 ° C and charcoal (0.25 g) was added. The resulting suspension was stirred and heated for 5 minutes and then filtered. The filtrate was evaporated in vacuo to ca. 20 ml and allow to cool to 20DC. Ether (40 ml) was added with stirring over 5 minutes and the mixture was kept at 4 ° C overnight. The resulting precipitate was filtered off, washed with ether (2 x 10 ml), dried in vacuo at room temperature for 2 hours and then at 70 ° C for 7 hours to give the title compound (0.95 g ), m.p. 288-291 ° C.

Analysis: Calculated for C 17 H 18 N 4 O · HCl: C, 61.7; H, 5.8; N, 16.9; Cl, 10.7%; Found: C, 61.4; H, 5.8; N, 16.7; Cl, 10.7.

Example 19 2.3.4.5- Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one sulfate 2.3. 4.5- Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one (0.81 g) suspended in absolute ethanol (6 mL) and heated at 50 ° C with concentrated sulfuric acid (0.15 mL). Additional ethanol (4 ml) was added and the mixture was stirred with charcoal (0.1 g). The suspension was then filtered and the combined solid washed with ethanol (about 3 ml). The resulting filtrate was stirred for ca. 1 hour at room temperature, tart. butyl methyl ether (10 ml) was slowly added and the mixture was stirred for 20 minutes. The precipitate was filtered off, washed with ethanol: tert.butyl methyl ether (1: 1; 6 mL), then with tert.butyl methyl ether (6 mL) and dried in vacuo at 40 ° C for 4 days to give the title compound (0.4 g) , m.p. 205-209 ° C.

Analysis: Calculated for C 17 H 18 N 4 O · 1.1H 2 O: C, 49.9; H, 5.4; N, 13.3; S, 8.4%; found: C, 49.5; H, 5.6; N.13,5; S, 8.4.

EXAMPLE 20 2,3,4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1 on

A suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (400 mg) in dry DME (50 ml) was treated with sodium hydride (60% Dispersion in oil; 100 ml) and the mixture was stirred at 60 ° C under nitrogen for 6 hours. 4- (Chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (474 mg) was added and the reaction mixture was stirred at 60 ° C under nitrogen overnight. 2N hydrochloric acid (10 ml) and 5 water (10 ml) were then added and the mixture was heated at reflux for 6 hours. After cooling, the mixture was basified with 2N sodium hydroxide and the resulting mixture extracted with ethyl acetate (2 x 50 ml). The combined dried organic extracts were concentrated on FCC silica and purified by FCC with system A as eluent (150: 8: 1) to give the title compound (352 mg) as a solid, TLC (system A, 100: 8: 1) Rf 0.28. 1 H-NMR: 52.2 (3H, s), 3.04 (2H, t), 3.62 (2H, t), 3.72 (3H, s), 4.53 (2H, s), δ , 1-7.28 (2H, m), 7.43 (1H, s), 7.47-7.55 (1H, dd), 7.94-8.03 (1H, dd).

The following examples illustrate pharmaceutical formulations of the invention containing 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-1/4-yl) methyl] -1H-pyrido [4 , 3-b] indol-1-one as the active ingredient. Physiologically acceptable salts and / or solvates of this compound and other compounds of formula (I) and physiologically acceptable salts and / or solvates thereof may be similarly formulated.

BIOLOGICAL DATA

For the compounds of Examples 1, 2, 6 and 9, DR5 duration is determined, cf. The following: The antagonism of the responses induced by 5-HT at 5-HT 3 receptors using compounds of the invention can be determined in vivo by determining the effect of the compounds on the 5-HT induced Bezold-Jarisch reflex in cats. This test was performed according to the method described by D.P. Collins and D.H. Fortune, British Journal of Pharmacology, 1983, 80, 570P. The results are expressed in the table below as the duration of DR5 when the compounds are administered intraduodenally (i.d.) or intravenously (i.v.). The DR5 value is the approximate dose required to produce a right-sided offset of the 5-dose dose-response curve relative to 2-methyl.-5HT.

Table

Compound, Ex- Dose, (pg / kg) Duration of DR5 Sample No. (minutes) 1 3 i.d. > 180 2 3 i.d. 48 6 1 i.v. 57 9 3 i.v. 24

Tablets for oral administration

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

The tablets can be coated with a film with suitable film-forming materials such as hydroxypropylmethyl cellulose using standard techniques. Alternatively, the tablets may be coated with sugar.

Direct pressing 10 Tablet mg / tablet

Active ingredient 0.50

Calcium Hydrogen Phosphate BP "87.25

Croscarmellose sodium NF 1.80

Magnesium stearate BP 0.45

Pressure weight 90.00 * of a quality suitable for direct pressing.

The active ingredient was passed through a 250 μτη (60 mesh) screen mixed with calcium hydrogen phosphate, croscarmellose sodium and 20 magnesium stearate. The resulting mixture is pressed into tablets with a Manesty F3 tableting machine equipped with 5.5 mm flat pistons with jagged edges.

DK 170506 B1 36

Sublingual tablet mg / tablet

Active ingredient 0.5

Compressible sugar NF 64.5

Magnesium stearate BP 0.5 5

Pressure weight 65.00

The active ingredient is sieved through a suitable sieve, mixed with the excipients and pressed using suitable 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 appropriate pistons.

Wet granulation

Conventional tablet mg / tablet

Active ingredient 0.5 Lactose BP 153.5

Starch BP 30.0

Pre-laminated corn starch BP 15.0

Magnesium stearate BP 1.5 20 Pressure weight 200.0

The active ingredient is sieved through a suitable sieve and mixed with lactose, starch and pregelatinized corn starch. Pure water is added in a suitable volume and the powders are granulated. The granules are sieved after drying and mixed with the magnesium stearate. The granules are then pressed into tablets using pistons 7 mm in diameter.

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

DK 170506 B1 37

Sublingual tablet mg / tablet

Active ingredient 0.5

Mannitol BP 58.5

Hydroxypropyl methylcellulose 5.0 Magnesium stearate BP 1.0

Pressure weight 65.0

The active ingredient is sieved through a suitable sieve and mixed with mannitol and hydroxypropyl methyl cellulose. Pure water in an appropriate volume is added and the powders are granulated. The granules are sieved after drying and mixed into tablets using suitable pistons.

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

15 Capsules mg / capsule

Active ingredient 0.5 Λ Starch 1500 98.5

Magnesium stearate BP 1.0 20 Filling weight 100.0 "is 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 suitable machinery. Other doses can be prepared by changing the fill weight 25 and, if necessary, changing the capsule size to fit.

DK 170506 B1 38

Syrup

This can be either with or without sucrose.

A. Sucrose syrup mg / 5 ml dose;

Active ingredient 0.5 Sucrose BP 2750.0.

Glycerin BP 500.0

Buffer)

Flavoring)

Dye) as required 10 Preservative)

Pure water BP to 5.0 ml

The active ingredient, buffer, flavor, dye and preservative are dissolved in a little of the water and glycerine is added. The rest of the water is heated to dissolve the sucrose and then cooled. The two solutions -15 are combined, adjusted in volume and mixed. The syrup is clarified by filtration.

B. Sucrose-free syrup with / 5 ml dose

Active ingredient 0.5

Hydroxypropylmethylcellulose USP

20 (viscosity type 4000) 22.5

Buffer)

Flavoring)

Dye) as needed

Preservative) 25 Sweetener)

Pure water BP to 5.0 ml

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

DK 170506 B1 39

Injection preparation for intravenous administration mg / ml

Active ingredient 0.05 0.5

Sodium chloride BP as needed as needed 5 Water for injection BP to 1.0 ml 1.0 ml

Sodium chloride can be added to adjust the tonicity of the solution and the pH can be adjusted using acid or alkali to a pH for optimum stability and / or to facilitate dissolution of the active ingredient. Alternatively, suitable buffer salts may be used.

10 The solution is prepared, clarified and filled into ampoules of appropriate size which are sealed by melting the glass. The injection is sterilized by heating in an autoclave using one of the acceptable cycles. Alternatively, the solution can be sterilized by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen or other suitable gas.

Cross-dose dose aerosol

Suspension aerosol mg / metered dose per container

Micronized Active Ingredient 0.050 12.0mg 20 Oleic Acid BP 0.020 4.8mg

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 the trichlorofluoromethane at a temperature of 10-15 ° C and the micronized drug is mixed in the solution with a high shear mixer. The suspension is metered into aluminum aerosol containers and suitable metering valves delivering 85 mg of the suspension are placed on the containers and dichlorofluoromethane is pressurized into the containers through the valves.

DK 170506 B1 40

Solution aerosol mg / metered dose per container

Active ingredient 0.5 mg 12.0 mg

Ethanol BP 7.500 1.80 g Trichlorofluoromethane BP 18.875 4.53 g

Dichlorodifluoromethane BP 48.525 11.65 g

Oleic acid BP or a suitable surfactant, for example Span 85 (sorbitan tetrioleate) may also be included.

The active ingredient is dissolved in the ethanol with the oleic acid or surfactant, if used. The alcoholic solution is measured in suitable aerosol containers followed by the trichlorofluoromethane. Suitable metering valves are put on the containers and dichlorodifluoromethane is pressurized in them through the valves.

Inhalation cartridges 15 mg / cartridge

Active ingredient (micronized) 0.05

Lactose BP for 25.00

The active ingredient is micronized in a fluid energy mill to a fine particle size range before mixing with tablet-grade normal lactose in a high shear mixer. The powder mixture is filled into size 3 hard gelatin capsules on a suitable encapsulating machine. The contents of the cartridges are administered using a powder inhaler.

Suppository 25 Active ingredient 0.5 mg * Witepsol H15 to 1.0 g * * Witepsol H15 is a commercial grade of Adeps Solidus Ph. Eur.

A suspension of the active ingredient is prepared in the molten Witepsol, which, using suitable machinery, is filled into suppository molds of equal size of 1 g.

Claims (11)

1. Pyrido and azepino-indole compounds of the general formula (I) O -r ^ f _ £ CH 2) n characterized in that Im represents an imidazolyl group of the formula: r4 N NR3 or ΓIS / r3n. TY and R 1 represents a hydrogen atom or group selected from C 1-6 alkyl, C 3-8 alkenyl, C 3-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4. 4-alkyl, phenyl, phenyl - C 3-alkyl, phenylmethoxymethyl, phenoxy-10-ethyl, phenoxymethyl, -CO 2 R 3, -COR 3, -CONR 2 R 2 or -SO 2 R 3 (where R 3 and R 2, which are the same or different, each represent a hydrogen atom, a C -alkyl or C 3-6 cycloalkyl group or a phenyl or phenyl C 1-4 alkyl group, wherein the phenyl group is optionally substituted by one or more C 1-4 alkyl, C 1-4 alkoxy or hydroxy groups or one or more halogen atoms with provided that R3 does not represent a hydrogen atom when R4 represents a group -CO2R3 or -SO2R5); one of the groups R 1, R 3 and R 2 is a hydrogen atom or a C 1-6 alkyl, C 3-7 cycloalkyl, C 3-8 alkenyl, phenyl or phenyl C 1-3 alkyl group. 20 pe, and each of the other two groups, which are the same or different, represents a hydrogen atom or a C1-6 alkyl group; DK 170506 B1 42 n represents the number 2 or 3; and physiologically acceptable salts and solvates thereof. Compounds according to Claim 1, characterized in that rA represents a C ^ ^alk alkyl, C alk. Alk alkynyl, C5_g cycloalkyl, Cj.g cycloalkylmethyl, phenyl C C₂2 alkyl is phenylmethoxymethyl or an NN-di-C 1-6 alkylcarboxamide group. Compounds according to claim 1 or 2, characterized in that R 1 and R 2 each independently represent a hydrogen atom or a C 1-6 alkyl group. Compounds according to claim 1, characterized in that a hydrogen atom or a Cjjj * alkyl, C3.4ken alkenyl, C3_yl alkynyl, C5_g cycloalkyl, C5.g cycloalkylmethyl, phenyl-C 3-alkyl, phenylmethoxymethyl-N, N-di-C 1-6 alkylcarboxamide or C 1-4 alkylsulfonyl group; R 1 represents a hydrogen atom; and R 1 and R 2 each represent a hydrogen atom or a 3-alkyl group, preferably such compounds wherein R 1 represents a methyl, n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl, or Ν, Ν-dimethylcarboxamide group; R 1 and R 2 each represent a hydrogen atom; and R 2 represents a methyl group. Compounds according to claim 4, characterized in that n represents the number 2. 6. 2,3,4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -LH-pyrido [4,3-b] indol-1-one; and physiologically acceptable salts and solvates thereof. 7.2,3,4,5-Tetrahydro-5- (phenylmethyl) -2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1 -one; 5-cyclopentyl-2,3,4,5-tetrahydro-2 - [(5-methyl-lH-imidazol-4-yl) methyl] -ΙΗ-pyrido [4,3-b] indol-1-one; 2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5-propyl-1H-pyrido [4,3-b] indol-1-one; 5- (cyclopentylmethyl) -2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1-pyrido [4,3-b] indole 1- on; 3,4,5,6-tetrahydro-6-methyl-2 - [(5-methyl-111-imidazol-4-yl) methyl] -azepino [4,3-b] indol-1 (2H) -one ; 2,3,4,5-tetrahydro-N, N-dimethyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1-oxo-5H-pyrido [4,3- b] indole-5-carboxamide; 2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propynyl) -1H-pyrido [4,3-b] indole -1-one; and physiologically acceptable salts and solvates thereof. Compounds according to any one of claims 1-7, characterized in that the compound of formula (I) is in the form of a hydrochloride, hydrobromide, sulfate, alkylsulfonate, arylsulfonate, phosphate, acetate -, citrate, succinate, tartrate, fumarate or maleate salt, preferably such compounds which are in the form of a hydrochloride salt or a maleate salt. Process for the preparation of compounds of general formula (I) as defined in any one of claims 1-8 or a physiologically acceptable salt or solvate thereof, characterized in that 20 (A) is a compound of formula (II) N -alkyl with a compound of formula (III) LCH 2 -Im (III) or a protected derivative thereof, wherein L represents a leaving atom or leaving group , followed if necessary by the removal of any protecting groups present; or (B) a compound of general formula (I) is converted to another compound of formula (I) using conventional techniques; or * (C) a protecting group or groups are removed from a protected form of a compound of formula (I); and when the compound of formula (I) is obtained as a mixture of enantiomers, the mixture is optionally separated, thereby obtaining the desired enantiomer; and / or wherein the compound of formula (I) is in the form of a free base, the free base is optionally converted into a salt. 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, preferably a pharmaceutical composition, which is in a form adapted for oral or parenteral administration. Pharmaceutical composition according to claim 10, characterized in that the active ingredient is 2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5-propyl -1H-pyrido- [4,3-b] indol-1-one or a physiologically acceptable salt or solvate thereof. * Use of a compound of general formula (I) as defined in any one of claims 1-8 or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a condition caused by a disorder of -HT at 5-HT3 receptors. DK 170506 B1 45 Use of a compound of general formula (I) as defined in any one of claims 1-8 or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of nausea and vomiting, dyspepsia, reflux oesophagitis. 5 tis, irritable bowel syndrome and / or to promote gastric emptying.