FI89484B - Process for preparing therapeutically active tetrahydro-2- /(imidazol-4-yl)methyl/pyrido(4,3-b)indole- and azepino- /4,3-b/indol-1-ones - Google Patents

Description

1 89484

Process for the preparation of therapeutically active tetrahydro-2 - [(imidazol-4-yl) methyl] pyrido (4,3-b) indole and azepino [4,3-b] indol-1-ones - For the preparation of therapeutically active substances The present invention relates to a process for the preparation of therapeutically active tetrahydro-2 - [(imidazol-4-yl) methyl] pyrido (4,3-b) indole and azepino- [4,3-b] indol-1-one. 2 - [(imidazol-4-yl) methyl] pyrido (4,3-b) indole and azepino [4,3-b] indol-1-ones of general formula (I)

O

Π— (i>% / A NJ— (CH 2, n where R 1 is a hydrogen atom or a group selected from C 1-6 alkyl, C 3-6 alkenyl, C 3-10 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, phenylC 1-3 alkyl, R -SO 2 R 4 (wherein R 2 and R 2, which may be the same or different, are each a hydrogen atom or a C 1-6 alkyl, provided that R 2 is not a hydrogen atom when R 1 is a group -so 2 R 5); R 1 and R 2 are independently a hydrogen atom or a C 1-6 alkyl group, n is 2 or 3, and their physiologically acceptable acid addition salts and solvates.

The compounds of formula (I) are potent and selective antagonists of 5-hydroxytryptamine (5-HT) at its type-2 89484 5-HT receptors located at the terminals of primary import nerves. These types of receptors are called S-HT 1A receptors and are also involved in the central nervous system. 5-hydroxytryptamine is widely found in the neuronal conduction pathways of the central nervous system. Disorder of these 5-HT-containing conduits is known to alter behavioral symptoms such as mood, psychomotor activity, appetite, and memory.

Compounds having antagonist activity at the δ-HT 1 receptor have been described previously.

Thus, for example, published UK patent publication no. 2153821A and in published European patent publications not. 191562, 219193 and 210840 disclose 3-imidazolylmethyltetrahydrocarbazolone and which can be represented by the general formula Q R1 * R3

Il I / Q · · · · - ·

N / \ / Λ / \ l — J

I II II I \ // • · · · · V V V 1>

R 1 wherein R 1 is a hydrogen atom or a group selected from the group consisting of C 1-10 alkyl, C 3-6 alkenyl, C 3-10 alkynyl »C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl, phenyl or phenylC 1-6 alkyl and in the case where Q is a hydrogen atom may be also -CO 2 R 5, -COR 5, -CONR 5 R 6 or -SO 2 R 5 (wherein R 5 and R 6, which may be the same or different, are each a hydrogen atom, a C 1-8 alkyl or C 3-7 cycloalkyl group, or a phenyl or phenyl-C 1-6 alkyl group in which the phenyl group is optionally substituted with one or more C 1-6 alkyl, C 1-4 alkoxy or hydroxy groups or a halogen atom, provided that R 1 is not a hydrogen atom when it is a group -CO 2 R 10 or -SC 2 R 4); 3 89484 one of H 2, R 3 and R 4 is a hydrogen atom or a C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl or phenylC 1-6 alkyl group, and each of the other two groups, which may be the same or different, is a hydrogen atom or _gal group; Q is a hydrogen atom or a halogen atom or a hydroxy, C 1-4 alkoxy, phenylC 1-3 alkoxy or C 1-4 alkyl group or a group -NR 7 R 8 or -CONR 7 R 8 (wherein R 7 and R 8, which may be the same or different, are each a hydrogen atom or a C 1-4 alkyl or C 3-4 alkenyl group. group, or together with the nitrogen atom to which they are attached form a saturated 5-7 membered ring); and their physiologically acceptable salts and solvates.

We have now discovered a new class of compounds which differ in structure from those previously described and which are potent antagonists of the action of 5-hydroxytryptamine at the 5-HT3 receptor.

The invention also provides compounds of formula (I) wherein R 1 * - is a hydrogen atom or selected from the group consisting of C 1-6 alkyl, C 3-8 alkenyl, C 3-7 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl or phenylC 1-3 alkyl (n, R 3 and R 4 has the same meaning as in formula (I), a selected group.

suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with organic or inorganic acids, e.g. hydrochlorides, hydrobromides, sulphates, alkyl or aryl sulphonates (e.g. methanesulphonates or p-toluenesulphonates), sulphonates, , succinates, tartrates, fumarates and maleates. The solvents can be, for example, hydrates.

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

Γ 4 89484

The following refers to the general formula (I). The alkyl group may be a straight-chain or branched alkyl group, e.g. methyl, ethyl, n-propyl, prop-2-yl, n-butyl, but-2-yl, 2-methylprop-2-yl, n-pentyl, pentyl. 3-yl or n-hexyl. The C 3-8 alkenyl group may be, for example, a propenyl or butenyl group. When R 1 is a C 3-8 alkenyl or C 3-10 alkynyl group, the double bond or the triple bond cannot be adjacent to the nitrogen atom. The phenylC3-3alkyl group may be, for example, a benzyl, phenethyl or 3-phenylpropyl group. The C 3-7 cycloalkyl group may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

In a well-liked class of compounds of formula (I), R 1 is hydrogen or C 1-4 alkyl (e.g. methyl, ethyl, n-propyl, prop-2-yl), C 3-4 alkenyl (e.g. prop-2-enyl), C 3-4 alkynyl (e.g. prop-2-ynyl), C 3-8 cycloalkyl (e.g. cyclopentyl), phenylC 1-6 alkyl (e.g. benzyl), phenylmethoxymethyl, N, N-diC 1-3 alkylcarboxamido (e.g.

N, N-dimethylcarboxamido) or a C 1-3 alkylsulfonyl (e.g. methylsulfonyl) group. R 1 is preferably C 1-4 alkyl (e.g. methyl or n-propyl), C 3-4 alkynyl (e.g. prop-2-ynyl), C 5-8 cycloalkyl (e.g. cyclopentyl), C 5-8 cycloalkylmethyl- (e.g. cyclopentylmethyl), phenylC 1-4 alkyl; - (e.g. benzyl), phenylmethoxymethyl or N, N-di-C 2-3 alkylcarboxamido (e.g. N, N-dimethylcarboxamido) group.

In another preferred class of compounds of formula (I), R 3 is a hydrogen atom or a C 1-3 alkyl (e.g. methyl) group, more preferably a hydrogen atom.

In another preferred class of compounds of formula (I), R 4 is a hydrogen atom or a C 1-3 alkyl (e.g. methyl or n-propyl) group. Most preferably R4 is a methyl group.

5 89484

When R 3 represents a hydrogen atom, R 4 is preferably C 1-6 alkyl.

In another preferred class of compounds of formula (I), n is 2.

In a preferred group of compounds of formula (I), R 1 is a hydrogen atom or a C 1-4 alkyl, C 3-4 alkenyl, C 3-4 alkynyl-C 5-6 cycloalkylmethyl, phenyl, C 1-6 alkyl, phenylmethoxymethyl, An N, N-diC 1-3 alkylcarboxamido or C 1-3 alkylsulfonyl group; and R 3 and R 4 are each a hydrogen atom or a C 1-3 alkyl group.

In a particularly preferred group of compounds of formula (I), R 1 is a methyl, n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl or N, N-dimethylcarboxamide group; R3 is a hydrogen atom; and R4 is a methyl group.

Of the above groups of compounds considered to be good and particularly good, in the particularly important group of compounds n is 2.

Preferred compounds of formula I are: 2.3.4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-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] 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] -1H-pyrido [4,3-b] indol-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; 2,3,4,5-tetrahydro-N, N-dimethyl-2 - [(5-methyl-lH-imidazol-4-yl) methyl] -l-oxo-5H-pyrido [4,3-b] indole -5-carboxamide; 6 8 9 4 G 4 2,3,4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propynyl) -1H-pyrido [4,3 b] indol-l-one; and their physiologically acceptable salts and solvates.

The effective and selective antagonism of 5-hydroxytryptamine at the 5-HT3 receptors by the compounds of the invention is demonstrated by the ability to inhibit 3- (5-methyl-1H-imidazol-4-yl) -1- [1- (methyl-t3) Binding of -1H-indol-3-yl] -1-propanone in rat entorinal cortex homogenates (following the general procedure: G. Kilpatrick et al., Nature, 1987, 330, 746) and / or their ability to prevent depolarization of a circulating nerve preparation isolated from rats, which is induced by 5-HT.

Due to both its efficacy and duration of action, one compound which is particularly preferred 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 its physiologically acceptable salts and solvates. Preferred salts of this compound include the hydrochloride and maleate.

Compounds of formula (I) which act against 5-hydroxytryptamine at the 5-HT3 receptor are useful in the treatment of conditions such as psychotic disorders (e.g. schizophrenia and mania); anxiety; and nausea and vomiting, especially when associated with cancer chemotherapy and radiotherapy. The compounds of formula (I) are also useful in the treatment of gastric block; . Gastrointestinaa-Lise signs of malfunction, for example, symptoms which occur in the gastrointestinal disorders, peptic ulcer, back-flow Vassa esophagus, flatulence and irritable bowel syndrome; migraine and pain. The compounds of formula (I) may also be used in the treatment of drug dependence and substance abuse, depression and dementia, as well as other cognitive disorders.

7 89484

The dose of the compounds of the invention proposed for administration to a human (weighing about 70 kg) is 0.001 to 100 mg, preferably 0.01 to 50 mg, even more preferably 0.1 to 20 mg of active ingredient per unit dose based on the weight of the free base. This dose can be given, for example, once or four times a day. It should be noted that it may be necessary to make routine adjustments to the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration.

The compounds of general formula (I) and their physiologically acceptable salts or solvates can be prepared by the general methods outlined below. In the following description, the groups R 1 -, n and Im have the same meaning as in the compounds of general formula (I), unless otherwise stated.

In the first general method (A), a compound of general formula (I) can be prepared by alkylating a compound of formula (II) or a protected derivative thereof.

O

ö (II). II - (CH2) n A1 by a compound of formula (III) LCH2-Im (III) or a protected derivative thereof, wherein L is a leaving atom or group such as halogen and Im in this formula and in the following represents p4 -m;

N NRJ

s 89484 followed, if necessary, by the removal of any protecting groups present.

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

In another general method (B), a compound of general formula (I) wherein n is 2 can be prepared by hydrogenating a compound of formula (IV)

O

Im (IV) cxo R1 or a protected derivative thereof, followed by removal of any protecting groups if necessary.

The hydrogenation according to the general process (B) can be carried out using conventional methods, e.g. using hydrogen, in the presence of a noble metal catalyst (e.g. palladium, Raney nickel, platinum or rhodium). The catalyst may be supported on e.g. carbon or alumina, or alternatively a homogeneous catalyst such as tris (triphenylphosphine) rhodium chloride may be used. The hydrogenation is generally carried out in a solvent such as an alcohol (e.g. methanol or ethanol), an ether (e.g. dioxane) or an ester (e.g. ethyl acetate) or a mixture of alcohol and either a hydrocarbon (e.g. toluene) or a halogenated hydrocarbon (e.g. dichloromethane). 1 temperature at -20 to + 100 ° and 1 to 10 atmospheric pressure.

In the general method (C), a compound of general formula (I) can be prepared by cyclizing a compound of formula (V)

O

'ί ^ Χ [] [Λ (V)} - (CH2) n

N-NH

R1 NH or a salt or protected derivative thereof, followed, if necessary, by the removal of the protecting groups present. The cyclization can be performed in aqueous or non-aqueous media in the presence of an acid catalyst.

It should be noted that these compounds of formula (V) may exist in the corresponding enolhydrazone tautomeric form.

When an aqueous medium is used, this may be water or a mixture of water and an organic solvent such as an alcohol (e.g. methanol, ethanol or isopropanol) or an ether (e.g. dioxane or tetrahydrofuran). The acid catalyst may be, for example, an inorganic acid such as hydrochloric acid or sulfuric acid. In some cases, the acid catalyst may also act as a reaction solvent. In an anhydrous reaction medium which may contain one or more alcohols or ethers (e.g. as described above), carboxylic acid (e.g. acetic acid) or ester (e.g. ethyl acetate), the acid catalyst may alternatively be a Lewis acid such as boron trifluoride, zinc chloride or magnesium chloride. The cyclization reaction may conveniently be carried out at temperatures of 20 to 200 ° C, preferably 20 to 125 ° C.

ίο 8 9 4 8 4

Alternatively, the cyclization according to process (C) may be carried out in the presence of a polyphosphate ester in a reaction medium which may contain one or more organic solvents, preferably a halogenated hydrocarbon such as chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane or mixtures thereof. A polyphosphate ester is a mixture of esters that can be prepared from phosphorus pentoxide, diethyl ether, and chloroform by the method described in Reagents for Organic Synthesis (Fieser and Fieser, John Wiley and Sons, 1967).

According to method (D), a compound of formula (XVIII) is cyclized

O

I ff Im (XVIII) ^ - (CH2) n

R1 wherein W is a halogen atom, or a salt or protected derivative thereof, followed, if necessary, by the removal of the protecting groups present.

The reaction may conveniently be carried out by irradiation with a mercury lamp, preferably a medium or high pressure mercury lamp. Suitable solvents include nitriles (e.g. acetonitrile), chlorinated hydrocarbons (e.g. carbon tetrachloride) and cyclic ethers (e.g. tetrahydrofuran or dioxane) and mixtures thereof. The reaction may conveniently be carried out in the presence of a base such as a tertiary amine (e.g. triethylamine).

In the general method (E), a compound of the general formula (I) in which R 3 is a hydrogen atom can be prepared by reacting a compound of the formula (VI) 11 89484 I il-I f li-f <VI)

Ux J— <cn2, n KJ

N R4

R1 or a protected derivative thereof to react with formamide at a temperature in the range of 150 to 200 ° C, after which, if necessary, any protecting groups are removed.

In the general method (F), a compound of general formula (I) can be prepared by reacting a compound of formula (VII)

G

_ /

II II (vh) ^> / "^ 'N / ^ ^' (CH2) nNHCH2Im Grain G has a hydrogen atom, or a protected derivative thereof, to react with phosphene in the presence of a Lewis acid.

According to method (F), a compound of formula (VII) wherein G is a hydrogen atom is reacted with phosgene in the presence of a Lewis acid such as anhydrous aluminum trichloride or stannous chloride. The reaction may conveniently be carried out in an inert solvent such as an aromatic hydrocarbon (e.g. toluene) or a halogenated hydrocarbon (e.g. dichloromethane) or a mixture thereof at a temperature ranging from ambient temperature to 100 ° C.

According to method (G), compound 12 of formula (VII) 89484

OnC (νιι) (CH2) nNHCH2 Im R1 wherein G is a bromine or iodine atom or a protected derivative thereof is reacted with carbon monoxide in the presence of a palladium (11) salt; after which, if necessary, the protecting groups present are removed.

In process (G), a compound of formula (VII) wherein G is an iodine or bromine atom is reacted with carbon monoxide in the presence of a palladium (11) salt (e.g. palladium acetate or palladium chloride) and preferably in the presence of triphenylphosphine. The reaction may conveniently be carried out in a solvent such as a tertiary amine (e.g. tri-n-butylamine), optionally in the presence of a co-solvent such as an ether (e.g. toluene) at a temperature between 100 and 150 ° C and atmospheric pressure.

The compound of general formula (I) may be converted into another compound of formula (I) by conventional techniques. Such conventional techniques include hydrogenation, alkylation, and acylation using shielding and deprotection, as appropriate.

In a conversion process (H) according to the invention for the preparation of a compound of formula (I) wherein R is a C 3-8 alkyl group, a compound of formula (I) wherein R 1 is a C 3-8 alkenyl group or a C 3-8 alkynyl group, or a protected derivative thereof, is hydrogenated; after which, if necessary, the protecting groups present are removed.

In one embodiment for the preparation of a compound of formula (I) wherein r! is a hydrogen atom, a compound of formula (I) 13 89484 is hydrogenated, R1 is a phenylmethoxymethyl group or a protected derivative thereof, followed, if necessary, by removal of the protecting groups present. The hydrogenation according to the general process (H) and (I) can be carried out by conventional methods, e.g. using hydrogen in the presence of the catalyst described above in connection with the general process (B).

In process (J) for preparing a compound of formula (I) wherein R 1 is C 1-6 alkyl, C 3-8 alkenyl, C 3-10 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, phenyl (C 1-6 alkyl) or phenylmethoxymethyl group, , containing a hydrogen atom, or a protected derivative thereof, followed, if necessary, by the removal of the protecting groups present.

In process (K) for preparing a compound of formula (I) wherein R 3 is C 1-6 alkyl, alkylating a compound of formula (I) wherein R 1 is a hydrogen atom, or a protected derivative thereof, and optionally then removing the protecting groups present. The alkylation can be carried out in a conventional manner, e.g. by the methods described in published European Patent Publication No. 242973. The reactions can thus be carried out using a suitable alkylating agent according to R 2 (wherein R is a group to be attached and Z is a leaving atom or group), preferably in the presence of a base.

In process (L) for the preparation of a compound of formula (I) wherein r 1 is -CONR 1 R 4 or -SC 2 R 4, by acylation of a compound of formula (I) wherein R * is a hydrogen atom, or a protected derivative thereof, optionally followed by removal of protecting groups. The acylation / sulfonation reactions can be performed using a suitable acylation / sulfonation agent by conventional methods, e.g., the methods described in published European Patent Publication No. 210,840.

It should be noted that in the above modifications, it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesired side reactions. For example, it may be necessary to protect indole and / or imidazole nitrogen atoms, e.g. arylmethyl (e.g. trityl), arylmethoxymethyl (e.g. phenyl-1-methoxymethyl), alkyl (e.g. t-butyl), alkoxymethyl (e.g. e.g. methoxymethyl), acyl (e.g. benzyloxycarbonyl) or sulfonyl (e.g. N, N-dimethylaminosulfonyl or p-toluenesulfonyl).

In the general process (M), a compound of general formula (I) can be prepared by removing any protecting groups from the protected form of a compound of formula (I). Deprotection can be accomplished using conventional methods, such as those described in "Protective Groups in Organic Synthesis", T.W. Greene (John Wiley and Sons, 1981).

The arylmethoxymethyl N-protecting group can be e.g. cleaved off by hydrogenolysis in the presence of a catalyst (e.g. palladium / carbon). The trityl group can be cleaved by hydrolysis with an acid (e.g., using dilute hydrochloric or acetic acid). The alkoxyalkyl group can be removed using a mineral acid (e.g., dilute hydrochloric acid or hydrobromic acid). The acyl group can be removed by hydrolysis under acidic or basic conditions (e.g., using hydrogen bromide, dilute hydrochloric acid, or sodium hydroxide). The sulfonyl group can be removed by alkaline or acid hydrolysis and the N, N-dimethylaminosulfonyl group can be removed (e.g., from an imidazole nitrogen atom) by photolysis.

Compounds of formula (II) may be obtained from an oxime of formula (VIII) via Beckmann rearrangement in H ° \

OF

II

M \ J \ (viii) 1! ! -LcH2) m

V V

R> is 894C4 where m is 1 or 2, or a protected derivative thereof. The Beckmann rearrangement can be performed by conventional methods, e.g. using an acid (e.g. polyphosphoric acid or sulfuric acid or a mixture of hydrochloric acid, acetic anhydride and acetic acid) in an inert solvent such as ether (e.g. dioxane), amide (e.g. dimethylformamide) or hydrocarbon. cyclohexane) at an elevated temperature (e.g. 50-120 ° C). The hydroxy group of the oxime of formula (VIII) may alternatively be converted to a leaving group such as chloride (e.g. phosphorus pentachloride) or hydrocarbyl sulphonate (e.g. mesylate or tosylate) or trifluoroacetate group. (using conventional acylation methods.) When then heated e.g.

At a temperature of 20 to 150 ° C in the inert solvent described above, a compound of formula (II) is obtained.

Compounds of formula (VIII) may be prepared from the corresponding tricyclic ketone of formula (IX)

II

/ Λ Λ i m i (ιχ) \\ Λ / - (ςΗΛ

• N

fl · where m is 1 or 2, or a protected derivative thereof using conventional methods, e.g. using hydroxylamine hydrochloride in a solvent such as pyridine.

Compounds of formula (IV) may be prepared, for example, by reacting a compound of formula (X) ie 89 48 4 o / Λ Λ ί 1 ϊ Γ (X) • · · · \\ / \ / \ // • Ν · R1 or protected derivative, to react with a compound of formula (III) wherein L is as defined above or a protected derivative thereof under the conditions described in connection with method (A).

Compounds of formula (X) may be prepared by heating a compound of formula (II) wherein n is 2 with a noble metal catalyst such as palladium, palladium oxide, platinum or nickel at a temperature of e.g. 300-350 ° C. The catalyst may be supported on e.g. carbon or alumina, and the reaction may optionally be performed in the presence of an inert solvent such as an aromatic hydrocarbon (e.g. p-cymene).

Compounds of formula (V) may be prepared by reacting a compound of formula (XI) CX i <xi) nr1nh2 or a salt thereof with a compound of formula (XII) 89484 o

II

/ V \ m (ΧΠ) 1-icH2) // n

O

or a protected derivative thereof in a suitable solvent such as aqueous alcohol (e.g. methanol) and e.g. at 20-100 ° C.

In a protected derivative of a compound of formula (XII), for example, the ketocarbonyl group may be protected (e.g. as an enol ether). It should be noted that when using a compound of formula (XII) in which the ketocarbonyl group is protected, it may be necessary to remove the protecting group in order for the reaction with the compound of formula (XI) to take place. The protection can be removed by conventional methods, e.g. by hydrolysis with an acid (e.g. using dilute sulfuric or hydrochloric acid). If desired, the protection can be removed in situ.

Compounds of formula (XII) may be prepared, for example, by reacting a compound of formula (XIII) or a protected derivative thereof with a compound of formula (III) wherein L is as defined above, or a protected derivative thereof. using the conditions described in connection with method (A).

Compounds of formula (XVIII) in which W is halogen may be prepared, e.g., by reacting 89 (484 0 1) of formula (XIV).

• N Im (XII)

O

or a protected derivative thereof in a suitable solvent such as aqueous alcohol (e.g. jetanol) and e.g. at a temperature of 20-100 ° C.

In a protected derivative of a compound of formula (XII), for example, the ketocarbonyl group may be protected (e.g. as an enol ether). It should be noted that when using a compound of formula (XII) in which the ketocarbonyl group is protected, it may be necessary to remove the protecting group in order for the reaction with the compound of formula (XI) to take place. The protection can be removed by conventional methods, e.g. by hydrolysis with an acid (e.g. using dilute sulfuric or hydrochloric acid). If desired, the protection can be removed in situ.

Compounds of formula (XII) may be prepared, for example, by reacting a compound of formula (XIII) with a compound of formula (III) wherein L represents the same as above, or with a protected derivative thereof using the conditions described in connection with method (A).

Compounds of formula (V) in which M is a halogen atom and Y is a bond may be prepared, for example, by reacting a compound of formula (XIV) 89484 with a compound of formula XIV (XIV). ) \\ / \ / 2 n

• N

wherein W is a halogen atom, or a protected derivative thereof, to react with a compound of formula (III) wherein L is as defined above, or a protected derivative thereof, using the conditions described in method (A).

Compounds of formula (XIV) may be prepared by reacting a compound of formula (XV)

• W

/ V

I ί (XV) \\ Λ.

• NHR1 to react with a lid of a compound of formula (XIII) at elevated temperature.

Compounds of formula (VI) may be prepared, for example, by reacting a compound of formula (II) or a protected derivative thereof with a compound of formula (XVI) I I (XVI) • · J \ //

R1 * N

wherein L is as defined above, using the conditions described in Method (A).

Compounds of formula (VII) in which G is a halogen atom may be prepared, for example, by reacting a compound of formula (VII) in which G is a hydrogen atom or a protected derivative thereof with a suitable halogen or alkali metal halide (e.g. iodine or potassium iodide) in a suitable solvent such as in aqueous alcohol (e.g. aqueous ethanol).

Compounds of formula (VII) in which G is a hydrogen atom may be prepared, for example, by reacting a compound of formula (VXII) with a compound of formula (VII) (xvii) or a protected derivative thereof. , to react with a compound of formula (III) wherein L is as defined above, or a protected derivative thereof, using the conditions described in method (A).

The compounds of formula (III) or protected derivatives thereof are either known or can be prepared in German Offenlegungsschrift No. 3740352.

The compounds of formula (IX) may be prepared, e.g., by the method or methods described by H. Iida et al., J. Org. Chem., 1980, 45, 2938.

The compounds of formulas (XI), (XIII), (XV), (XVI) and (XVII) are either known or can be prepared from known compounds by conventional methods.

When it is desired to isolate a compound of the invention as a salt, e.g. a physiologically acceptable salt, this may be done by bringing the free base compound of formula (I) 2i 89 484 with a suitable acid, preferably in an equivalent amount, in a suitable solvent such as alcohol (e.g. ethanol or methanol), in an aqueous alcohol (e.g. aqueous ethanol), in a halogenated hydrocarbon (e.g. dichloromethane), in an ester (e.g. ethyl acetate) or in an ether (e.g. tetrahydrofuran).

Physiologically acceptable salts can also be prepared by conventional methods from other salts of the compound of formula (I), including other physiologically acceptable salts.

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

The methods described above for the preparation of the compounds of the invention can be used to attach the desired groups at any stage in the stepwise construction of the desired compounds. It should be noted that these methods can be combined in different ways in such multi-step methods. The order of the reactions in the multi-step methods should, of course, be chosen so that the reaction conditions do not affect the groups of the molecule desired in the final product.

The invention is further illustrated in the following intermediates and examples. All temperatures are in degrees Celsius. Thin layer chromatography (TLC) was performed on silica and flash column chromatography (FCC) on silica (Merck 9385). The solvent system A used for the chromatography is dichloromethane: ethanol: 0.88 ammonia solution. At the indicated positions, the organic extracts 22 8 9 4 8 4 were dried over magnesium sulfate or sodium sulfate. The following abbreviations have been used: DMF - dimethylformamide; THF -tetrahydrofuran; DME - dimethoxyethane. 1 HNM spectra were obtained at 250 MHz in dilute solutions in dimethyl sulfoxide.

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 dimethylformamide (1.0 ml) at 23 °. The solution thus obtained 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. The resulting oil solidified to a solid which was slurried in hexane and filtered to give the title compound (1.28 g), m.p. 139-141 °.

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

Dimethylsulfamoyl chloride (0.67 g) was added under nitrogen to a stirred solution of 5-propyl-1H-4-carboxaldehyde (860 mg) and triethylamine (0.87 ml) in dry dichloromethane (10 ml). 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 an oil (1.9 g) which was FCC purified by elution with ethyl acetate: hexane (1: 1) to give the title compound (500 mg), m.p. 57-58 °.

Intermediate 3 4- (hydroxymethyl) -N, N-dimethyl-5-propyl-1H-imidazole-1-sulfonamide 23 89404

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

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 cold (0 °) 4- (hydroxymethyl) -N, N-dimethyl-5-propyl-1H-imidazole-1-sulfonamide (340 mg). to a stirred solution in dry dichloromethane (7.5 ml) under nitrogen. After 1.5 h, the solution was washed with 8% sodium bicarbonate solution (2 x 15 mL) and the aqueous phase was 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] indol-1 (2H) -one oxime 3,4-Dihydro-4-methylcyclopent [b] indol-1 (2H) -one (1.7 g) and hydroxylamine hydrochloride (1.925 g) in pyridine was heated at 60 ° for 18 hours and cooled. The reaction mixture was evaporated in vacuo to a residue to which was added 8% sodium bicarbonate (ISO ml). Extraction with ethyl acetate (300 ml) gave a suspension in the organic layer; this layer and the associated solid were separated from the aqueous layer. The aqueous layer was re-extracted with ethyl acetate (250 mL). The combined organic extracts (and suspended solid) were evaporated to a residue, boiled with a mixture of ethanol (150 ml) and methanol (150 ml) and cooled to about 50 ° C. The residue was absorbed from this solution 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 ** (dec.).

Intermediate 6 2.3.4,5-Tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one 3,4-dihydro-4-methylcyclopentyl] indol-1 (2H) -one oxime (1, 53 g), polyphosphoric acid (40 g) and dioxane (15 ml) were heated under nitrogen at 110-120 ° C for 2.2 hours. 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 dried. Extraction gave a solid (1.43 g) which was recrystallized from ethyl acetate / cyclohexane. This solid was purified by FCC chromatography eluting with System A (200: 10: 1) to give a solid (1.26 g). This was recrystallized from ethanol to give the title compound (960 mg), m.p. 234-238 **.

Intermediate 7 3.4.5.6-Tetrahydro-6-methylazepino (4,3-b) indol-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 in the same way as described for intermediate 6.

The solid (22 g) obtained by evaporation of the organic extracts was recrystallised from ethyl acetate (300 ml) to give a solid (19.2 g). This was purified by FCC eluting with System A (200: 8: 1) to give the title compound (5.5 g), m.p. 212-215 **.

25 89484 Intermediate 8 -2.-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 ° for 15 minutes under a stream of nitrogen. below. The resulting solid was triturated with ether and filtered to give the title compound (1.74 g), m.p. 235-238 °.

Intermediate 9 2.3.4.5-Tetrahydro-1H-pyrido [4,3-b] indol-1-one 5,6-dihydro-4- (phenylamino) -1 (2H) -pyridone (1.5 g) and palladium acetate ( A solution of 150 mg) in dry dimethylformamide (50 ml) was treated with copper (II) acetate (3.2 g) and the resulting mixture was heated under nitrogen at 120-130 ° for 1.5 hours. The mixture was then concentrated in vacuo. The resulting solid 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). The organic extracts were combined with previous ethyl acetate extracts and adsorbed onto silica. FCC purification with System A (100: 8: 1) afforded the title compound (874 mg), m.p. 212-215 °.

Intermediate 10 2.3.4.5-Tetrahydro-5 - [(phenylmethoxy) methyl] -1H-pyrido [4,3-b] indol-1-one 2.3.4.5-Tetrahydro-1H-pyrido [4,3-b] indole A solution of 1-one (1.12 g) in dry dimethylformamide (60 ml) was treated with sodium hydride (60% dispersion in oil; 480 mg) and the resulting mixture was stirred under nitrogen until effervescence ceased. The mixture was then cooled to 0 ° and benzyl (chloromethyl) ether (10 w / v in DMF; 0.835 ml) was added over 10 minutes. Stirring was continued for a further 5 minutes and then water (10 ml) was added. The reaction mixture was concentrated in vacuo.

The resulting oil was dissolved in ethyl acetate (100 mL) and kept with water (3 x 100 mL). The organic phase was dried and adsorbed onto FCC silica. FCC purification with System A (150: 8: 1) afforded the title compound (1.1 g), m.p. 133-l3Se.

Intermediates 11-IA were prepared according to intermediate 10, i. by treating 2,3,5,5-tetrahydro-1H-pyrido [3,3-b] indol-1-one with sodium hydride followed by a suitable alkylating agent. The products were isolated and purified in the same manner as for intermediate 10, unless otherwise stated.

Intermediate 11 5-Ethyl-2,3,5,5,5-tetrahydro-1H-pyrido [1,3-b] indol-1-one 2,3,5,5-tetrahydro-1H-pyrido [1,3-b] indol-1-one -one (931 mg) was treated with sodium hydride (60% dispersion in oil; A00 mg) and then stirred with ethyl iodide (10 v / v% solution in DMF; A ml) to give the title compound (758 mg), m.p. 203-20A **.

Intermediate 12 2.3, A, 5-Tetrahydro-5- (1-methylethyl) -1H-pyrido [A, 3-b] indol-1-one 2.3, A, 5-Tetrahydro-1H-pyrido [A, 3-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) for 72 hours at room temperature. The FCC was purified by System A (200: 8: 1) to give a foam (32A mg) which was further purified by recrystallization from ethyl acetate: hexane (1: 1) to give the title compound (29A mg), TLC (System A, 100: 8: 1) Rf 0.58.

27 89404 Intermediate 13 2.3.4.5-Tetrahydro-5- (phenylmethyl) -1H-pyrido [4,3-b] indol-1-one 2.3.4.5-Tetrahydro-1H-pyrido-4,3-b] indol-1-one (559 mg) was treated with sodium hydride (73% dispersion in oil; 197 mg) and then stirred with benzyl bromide (513 mg) for 30 minutes at room temperature. FCC purification by extraction with dichloromethane: ethanol (80; 1) afforded the title compound (347 mg), m.p. 209-212 °.

Intermediate 14 5- (Cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one 2.3.4,5-Tetrahydro-1H-pyrido [4,3-b] indole -1-one (950 mg) was treated with sodium hydride (60% dispersion in oil; 408 mg) and then stirred with cyclopentyl (methylsulfonate) (909 mg) at room temperature for 7 days. The solid obtained by FCC chromatography (570 mg) was further purified by slow evaporation from methanol to give the title compound, m.p. 179-181 °.

Intermediate 15 2.3.4,5-Tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indol-1-one

A solution of triphenylmethyl chloride (3.36 g) in dry dimethylformamide (40 ml) was added dropwise 2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido To a stirred solution of [4,3-b] indol-1-one (2.8 g) and dry dimethylformamide (50 ml) containing triethylamine (1.52 g). After the addition, the mixture was stirred overnight. The mixture was then poured into water (1000 ml) and the resulting suspension was extracted with ethyl acetate (3 x 300 ml). The combined organic extracts 28 89404 were washed with water (2 x 500 mL), dried and concentrated with herring. FCC purification with System A (100: 8: 1) afforded the title compound (A, 3 g), m.p. 235-236 °.

Intermediate 16 2.3, A, 5-Tetrahydro-5-methyl-2 - [[1- (triphenylmethyl) -1H-imidazol-A-yl] methyl] -1H-pyrido [A, 3-b] indol-1-one 2.3 A mixture of 3,5-tetrahydro-5-methyl-1H-pyrido [A, 3-b] indol-1-one (0.3 g) and sodium hydride (807 dispersion in oil; 0.05 g) in dry dimethylformamide ( 5 ml) was stirred under nitrogen at 50 ° until hydrogen evolution ceased (about 0.5 hours). The mixture was cooled to 0 ° and a solution of N- (chloroethyl) -1- (diphenylmethyl) -1H-imidazole (0.53 g) in dry tetrahydrofuran (3 ml) was added. The mixture was stirred for 2 hours at -23 ° AO, poured into water (100 ml) and extracted with dichloromethane (3 x 100 ml). The dried organic phase was evaporated and the resulting semi-solid was purified by FCC chromatography eluting with dichloromethane-ethyl acetate: triethylamine (50: 50: 1). The resulting solid was slurried in hexane and filtered to give the title compound (0.37 g), m.p. 205-210 ° (decomposes).

Intermediate 17 2,5-Dihydro-5-methyl-1H-pyrido [A, 3-b] indol-1-one 2,3, A, 5-tetrahydro-5-methyl-1H-pyrido [A, 3-b] indole-1 -one (500 mg) and 10% palladium oxide / carbon catalyst (50% aqueous paste; 250 mg) were heated at 320 ° for 10 minutes. After cooling, the solid was triturated with ethanol (ca. 100 ml), filtered and the resulting filtrate evaporated to give the title compound (A70 mg), m.p. 2A2,5 °.

Intermediate 18 2,5-Dihydro-5-methyl-2 - ((5-methyl-1H-imidazol-A-yl) methyl] -2,848,800] -1H-pyrido [4,3-b] indol-1-one maleate

Sodium urahydride {73% dispersion in oil; 80 mg) was added to a stirred suspension of 2,5-dihydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (440 mg) in dry dimethoxyethane (25 ml) under nitrogen and the mixture was heated at 50e for 6 hours: in. Then N- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (910 mg) was added and stirring was continued for 20 hours at 50e. Water (4.5 ml) and acetic acid (4.5 ml) were added and the solution was heated at reflux for 5 hours. The mixture was poured into 8% sodium bicarbonate solution (80 mL) and extracted with dichloromethane: ethanol (10: 1; 3 x 40 mL). The combined dried organic extracts were evaporated. The resulting solid (ca. 1.5 g) was purified by FCC chromatography eluting with System A (200: 10: 1) to give the free base of the title compound as a solid (384 mg). A sample (100 mg) of this solid was dissolved in absolute ethanol (20 ml) and treated with a solution of maleic acid (40 mg) in absolute ethanol (1 ml). The solvent was removed in vacuo and the residue was triturated with dry ether (3 x 20 mL). The resulting solid (115 mg) was recrystallized from methanol-ethyl acetate to give the title compound (40 mg), m.p. 166-168 °.

Intermediate 19 2,5-Dihydro-4-methoxy-1 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -2 (1H) -pyridinone

Sodium hydride (80% dispersion in oil; 360 mg) was suspended in dry dimethoxyethane (50 ml) under nitrogen and 5,6-dihydro-4-methoxy-2 (1H) -pyridone (1.27 g) in dry dimethoxyethane (20 ml) was added slowly. . The resulting suspension was stirred for 1 hour at 20 °. 4- (Chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-iridazole (3.72 g) in dry dimethoxyethane (50 ml) was added and after the initial reaction was quenched, the mixture was heated for 4 hours. At 50 ° and then cooled. Methanol (5 ml) was added dropwise and the solvent was removed in vacuo. An 8% aqueous solution of sodium bicarbonate (300 ml) was added to the residue and the resulting solution was extracted with dichloromethane (2 x 300 ml), dried and evaporated in vacuo. The residual oil was purified by FCC eluting with System A (200: 8: 1) to give the title compound (2.84 g), m.p. 181-184 °.

Intermediate 20 2,4-Dioxo-1 - ((5-methyl-1H-imidazol-4-yl) methyl] piperidine 5,6-dihydro-4-methoxy-1 - [[5-methyl-1- (triphenylmethyl) -1H -imidazol-4-yl] methyl] -2 (1H) -pyridinone (500 mg) in tetrahydrofuran (4 ml) was added hydrochloric acid (5M; 1 ml) and the mixture was stirred for 1 hour at 50 ° C. The solvent was removed in vacuo, triethylamine (1 ml) and evaporated to dryness again FCC treatment of the residue eluting with ethyl acetate: methanol: triethylamine (8: 4: 1) afforded the title compound (139 mg), mp 100-106 ° (dec).

Intermediate 21 5.6-Dihydro-1 - ((5-methyl-1H-imidazol-4-yl) methyl) -4- (2-methyl-2-phenylhydrazino) -2 (1H) -pyridinone 2,4-dioxo-1 - [ (5-Methyl-1H-imidazol-4-yl) methyl] piperidine (20 mg) was dissolved in ethanol (2 ml) and added to N-methylphenylhydrazine (26 mg). The mixture was stirred for 1 hour and the solvent was removed in vacuo. The residue was FCC purified by elution with System A (75: 8: 1) to give the title compound (24 mg) as a solid, TLC (System A, 75: 8: 1) Rf 0.27.

Intermediate 22 N, N, 5-Trimethyl-N - [[(trirethylsilyl) oxy] methyl] -1H-imidazole-1-sulfonamide 31 8 9 484 A- (hydroxymethyl) -5-methylimidazole hydrochloride (IA, 9 g) and a suspension of dry dichloroethane (500 ml) containing triethylamine (50 g) was treated with trimethylsilyl chloride (21.7 g) and the reaction mixture was stirred overnight at room temperature. Dimethylsulfamoyl chloride (IA, 3 g) was added and the reaction mixture was stirred again overnight at room temperature. The resulting suspension was filtered and the recovered solid was washed with dichloromethane (100 mL). The filtrate was concentrated on silica and FCC purified by eluting with hexane-ether (A: 1) to give the title compound as an oil (7.2 g), TLC (ether) Rf 0.5.

Intermediate 23 N- (hydroxymethyl) -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide N, N, 5-trimethyl-N - [[(trirethylsilyl) oxy] methyl] -1H-imidazole-1 A solution of -sulfonamide (2.59 g) in dry tetrahydrofuran (50 ml) was treated with a solution of tetrabutylammonium fluoride (1M solution in tetrahydrofuran and 10 ml) and the THF was removed immediately in vacuo. The residue was partitioned between water (100 ml) and dichloromethane (100 ml) and the aqueous layer extracted with dichloromethane (100 ml). The combined dried organic fractions were concentrated to give the title compound (1.63 g) as a solid, m.p. 13A-136 **.

Intermediate 2A

N- (chloromethyl) -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide N- (hydroxymethyl) -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide (2.86 g) and dry a suspension of dichloromethane (200 ml), 32 89484 containing dimethylformamide (0.5 ml), was treated dropwise with a solution of thionyl chloride (1.178 g) in dichloromethane (10 ml). The reaction mixture was cooled with ice during the addition and protected with nitrogen. After the addition was complete (ca. 5 minutes), stirring was continued at 0 ° for an additional 30 minutes. Water (200 ml) was then added and the organic phase was separated, washed with 8% sodium bicarbonate (100 ml), dried and concentrated to give the title compound (2.3 g) as a solid, m.p. 115-118 °.

Intermediate 25 5.6-Dihydro-4 - [(2-iodophenyl) methylamino] -2 (1H) -pyridinone A mixture of 2-iodo- (N-methyl) aniline (1.17 g) and 2,4-dioxopiperidine (565 mg) heated under a stream of nitrogen for 7 hours at 110-120 °. After cooling, the reaction mixture was dissolved in methanol and the solution was absorbed onto FCC silica. FCC purification by elution with System A (150: 8: 1) afforded the title compound (1.03 g), m.p. 163-164 °.

Intermediate 26 N, N, 5-Trimethyl-4- [1,2,3,6-tetrahydro-4 - [(2-iodophenyl) methylamino] 6-oxo-1-pyridinyl] methyl-1H-imidazole-1- sulfonamide A suspension of 5,6-dihydro-4 - [(2-iodophenyl) methylamino] -2 (1H-pyridinone (984 mg) in dry dimethoxyethane (50 ml) was treated with sodium hydride (60% dispersion in oil; 140 mg) and the mixture stirred under nitrogen for 6 hours. 4- (Chloromethyl) -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide (832 mg) was added and the resulting mixture was stirred overnight at 60. After cooling, the reaction mixture was poured into water (100 ml) and extracted. ethyl acetate (2 x 50 mL) The combined dried organic extracts were concentrated and the resulting solid was purified by FCC eluting with System A (150: 8: 1) to give 33 8 9 4 0 4 to give the title compound (712 mg) by TLC (System A, 150: 8: 1) Rf 0.41.

Intermediate 27 N, N, 5-Trimethyl - [{2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3-b] indol-2-yl) methyl] -1H imidazole-l-sulfonamide

A solution of dimethylsulfamoyl chloride (0.107 ml) in dry dichloromethane under nitrogen was added 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido- To a stirred solution of [4,3-b] indol-1-one (0.294 g) and triethylamine (0.2 ml) in dry dichloromethane (30 ml) and the mixture was heated at reflux for about 24 hours. After cooling, the solution was concentrated to FCC silica and purified by FCC eluting with System A (150: 8: 1). The resulting oil was triturated with ether to give a solid which was further purified by slow evaporation from ethyl acetate to give the title compound (122 mg) m.p. 194-196 °, TLC (System A, 100: 8: 1) Rf 0.43.

Intermediate 28

Phenylmethyl-5-methyl-4 - [(2,3,4,5-tetrahydro-5-methyl-l-oxo-lH-pyrido [4,3-b] indol-2-yl) methyl] -lH-imidazole -1-carboxylate

A solution of benzyl chloroformate (0.28 ml) in dichloromethane (10 ml) was added 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido. To a solution of [4,3-b] indol-1-one (294 mg) and triethylamine (0.4 ml) in dichloromethane (30 ml) in 20e under nitrogen and the mixture was stirred overnight. It was then concentrated on FCC silica and purified by FCC eluting with System A (200: 8: 1) to give the title compound (62 mg), TLC (System A, 100: 8: 1) Rf 0.50.

3 * 89484 Intermediate 29 2,3,4,5-Tetrahydro-2 - [[1- (methoxymethyl) -5-methyl-1H-imidazol-4-yl] methyl] -5-methyl-1H-pyrido [4, 3-b] indol-1-one and 2,3,4,5, -tetrahydro-2 - [[1- (methoxymethyl) -4-methyl-1H-imidazol-5-yl] -5-methyl-1H- pyrido [4,3-b] indol-i-one

A solution of chloromethyl methyl ether (0.26 ml) in dichloroethane (10 ml) was added under nitrogen 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H To a stirred solution of pyrido [4,3-b] indol-1-one (500 mg) and triethylamine (0.49 ml) in dichloromethane (50 ml) at 20 ° C and the solution was stirred for 4 days. It was then partitioned between dichloromethane (50 ml) and sodium bicarbonate solution (2 x 50 ml). The organic extract was dried, concentrated on FCC silica and then FCC purified by elution with System A (100: 8: 1) to give the title compounds (139 mg). A portion of the title compounds (64 mg) was taken up in hot ethyl acetate and purified by slow evaporation from ethyl acetate to give the title compound.

Analysis calculated for C 67.3 H 6.9 N 16.5: C 67.4 H 6.6 N 6.6.6.

Intermediate 30 2.3.4.5-Tetrahydro-2 - [(4-methyloxazol-5-yl) methyl] -1H-pyrido [4,3-b] indol-1-one

Sodium hydride (60% dispersion in oil; 600 mg) was added to a stirred suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (1.5 g) in dry dimethoxyethane (150 ml). and then the mixture was stirred at 60e for 5 hours under nitrogen. 5-Chloromethyl-4-methyloxazole (1.2 g) was added and the mixture was stirred overnight. Additional sodium hydride (607 dispersion in oil; 600 mg) was added and the mixture was stirred for 4 hours at 60e, then carefully treated with water (100 ml).

35 89484

The mixture was extracted with dichloromethane containing methanol (ca.

17.) (3 x 100 ml), and the combined extracts were evaporated. The residue was FCC purified by elution with System A (100: 8: 1) to give the title compound (300 mg) as a solid, TLC (System A, 100: 8: 1) Rf 0.4.

Intermediate 31 N - [(1-methyl-1H-indol-2-yl) ethyl] trifluoroacetamide 2- (1-methyl-1H-indol-2-yl) ethanamine (3.48 g) and dry dichloromethane (50 ml) a solution of triethylamine (2.53 mg) was cooled in an ice bath and trifluoroacetic anhydride (5.25 g) was added dropwise over 15 minutes. The mixture was then allowed to warm to room temperature and stirred for a further 3 hours. After this time, the reaction mixture was poured into water (100 mL), the organic phase was separated and the aqueous phase was washed with dichloromethane (2 x 50 mL). The combined dried organic extracts were concentrated onto FCC silica and purified by FCC eluting with ether to give the title compound (4.2 g) as a solid. A sample of this compound was further purified by slow evaporation from dichloromethane solution, m.p. 124-126e.

Intermediate 32 N, N, 5-Trimethyl-4 - [[1-methyl-1H-indol-2-yl) -N-trifluoroacetylamino] ethyl] imidazole-1-sulfonamide N - [(1-methyl-1H A solution of -indol-2-yl) ethyl] trifluoroacetamide (2.7 g) in dry dimethylformamide (100 ml) was treated with sodium hydride (607, dispersion in oil; 480 mg) and the mixture was stirred at room temperature for 30 minutes. 4- (Chloromethyl) -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide (2.37 g) was then added and the mixture was stirred at room temperature overnight. After this time, the reaction mixture was poured into water (500 mL) and the resulting suspension was extracted with ethyl acetate 36 89484 (2 x 100 mL). The combined organic extracts were washed with water (5 x 250 mL), dried and adsorbed onto FCC silica. FCC was purified by elution with System A (150: 8: 1) to give the title compound (1.9 g), m.p. 156-158 °.

Intermediate 33 4 - [[[(1-methyl-1H-indol-2-yl) ethyl] amino] methyl] -N, N, 5-trimethyl-1H-imidazole-1-sulfonaride N, N, 5-trimethyl- 4 - [[(1-methyl-1H-indol-2-yl) -N-trifluoroacetylamino] ethyl] imidazole-1-sulfonamide (260 mg), methanol (10 ml) and saturated aqueous sodium carbonate solution (5 ml) ) the mixture was heated at 60e for 1.5 hours. After cooling, the mixture was poured into water (50 ml) and the mixture was extracted with ethyl acetate (2 x 50 ml). The combined dried organic extracts were concentrated on FCC silica and purified by FCC eluting with System A (150: 8: 1) to give the title compound (143 mg) as an oil, TLC (System A, 100: 8: 1) Rf 0.51. .

Intermediate 34 4 - [[((3-iodo-1-methyl-1H-indol-2-yl) ethyl] trifluoroacetylamino] methyl] -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide 4 - ([[(1-methyl-1H-indol-2-yl) ethyl] amino] methyl] -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide (471 mg) and methanol (25 ml) a solution of potassium carbonate (138 mg) was treated with a solution of iodine (254 mg) and potassium iodide (166 mg) in water (30 ml) for 30 minutes, after which time the reaction mixture was stirred for a further 2 hours, after which time the added methanol was removed in vacuo and the resulting suspension extracted with ethyl acetate (3 x 25 mL) The combined organic extracts were concentrated to FCC silica and FCC purified by elution with System A (150: 8: 1) to give the title compound (367 mg), mp 141-143 °.

37 894C4 Intermediate 35 4 - [[[(3-iodo-1-methyl-1H-indol-2-yl) ethyl] amino] methyl] -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide 4- [[[[(3-iodo-1-methyl-1H-indol-2-yl) ethyl] trifluoroacetylamino] methyl] -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide (199 mg) deprotection by the method described in Intermediate 33 to give the title compound (50 mg) as an oil, TLC (System A, 150: 8: 1) Rf 0.51.

Example 1 2.3.4.5-Tetrahydro-5-methyl-2 - [(methyl-1H-imidazol-4-yl) methyl] -ΙΗ-pyrido [4,3-b] indol-1-one maleate 2.3.4.5 - A mixture of tetrahydro-5-methyl-1H-pyrido-4,3-b] indol-1-one (0.6 g) and sodium hydride (ca. 78¾ dispersion in mineral oil, 0.109 g) in dry dimethylformamide (15 ml) was stirred under nitrogen for 50e. until the evolution of hydrogen ceased (about 1.5 hours). The mixture was cooled to 0e and a solution of 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-iridazole (1.12 g) in dry tetrahydrofuran (15 ml) was added. The reaction mixture was then stirred for 3 hours at 40 °, 16 hours at 20 ° C and a new portion of 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (1.12 g) in dry tetrahydrofuran ( 15 ml). The resulting mixture was heated at 40 ° C for 3 hours, quenched with water (20 mL) and acetic acid (20 mL) and heated at 100 ° for 2 hours. The mixture was then concentrated in vacuo to about 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, 3 x 100 ml). The extracts were combined, dried and evaporated to give a brown gum (ca. 1 g). This gum was adsorbed onto silica and FCC purified by elution with System A (100: 8: 1) to give a light brown solid (0.8 g) (0.8 g), m.p. 238-240 ° (decomposes). This solid was dissolved in a mixture of hot ethanol and methanol (1: 1; 100 ml) and treated with an ethanolic solution of maleic acid (318 g). The resulting solution was concentrated to about 20 mL and diluted with dry diethyl ether (ca. 8 mL). This precipitated the title compound (0.75 g) as an off-white solid, m.p. 160-162 °.

Analysis for C 17 H 16 N 2 O 2. C 11 H 18 N 2 O requires: C 61.6 H 5.5 N 13.6 Calculated: C 61.5 H 5.4 N 13.8%.

Example 2 3.4.5.6-Tetrahydro-6-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] azepino [4,3-b] indol-1 (2H) -one maleate 3.4 .5.6-Tetrahydro-6-methylazepino [4,3-b] indol-1 (2H) -one (0.64 g) was treated with sodium hydride (ca. 75-80% dispersion in oil; 0.108 g) and then stirred in Example 1. as described with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole. 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. The resulting semi-solid (ca. 1.8 g) was FCC purified by elution with System A (200: 8: 1) to give a gum (0.7 g). This gummy substance (0.7 g) was dissolved in a mixture of acetic acid, tetrahydrofuran and water (1: 1: 1; about 70 nl) and heated on a steam bath for 1 hour. Further work-up was performed as described in Example 1 to give a gum (0.22 g) which was FCC purified by elution with System A (200: 8: 1) to give a solid (0.11 g). The formation of the maleate gave a gummy substance which was dried in vacuo. The resulting foam 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. 132-133 °.

Based on 1 H-NMR, 0.39 mol of ethanol is present.

39 89 48 4

Water analysis, obtained 0.583 wt% s 0.14 mol HOO.

Analysis of CleHaON. * 0. CUH- * CU. 0.39EtOH. 0.14HaO found: C 61.4 H 5.7 N 12.6 calculated: C 61.4 H 6.0 N 12.6%.

Example 3 2.3.4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5-t (phenylmethoxy) methyl] -1H-pyrido [4,3-b] indole-1- onion maleate 2.3.4.5-Tetrahydro-5 - [(phenylmethoxy) methyl] -1H-pyrido [4,3-b] indol-1-one (920 mg) in dry dimethoxyethane (75 ml) was treated with sodium hydride under nitrogen. (60% dispersion in oil; 180 mg) and the reaction mixture was stirred for 6 hours at 60 °. Then 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (1.11 g) was added and the mixture was stirred overnight at 60 °. Acetic acid (10 ml), water (10 ml) and tetrahydrofuran (10 ml) were then added and the resulting solution 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 adsorbed onto FCC silica and FCC purified by eluting with System A (150: 8: 1) to give 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 mg) and the resulting solution was treated with maleic acid (58 mg). The solution was heated for 10 minutes, cooled and stirred with dry ether to give the title compound (170 mg), m.p. 165-168 °. Water analysis, obtained 0.22 wt% s.0.06 mol HaO.

Analysis Ca ^ Ha ^ N ^ .0. C * H. * Cu. 0.06 HaO obtained: C 64.5 H 5.6 N 10.7 calculated: C 65.0 H 5.5 N 10.8%.

Examples 4-7 were prepared as in Example 3.

i0 89484

Example 4 5-Ethyl-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) -methyl] -1H-pyrido [4,3-b] indol-1- onion 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) followed by was mixed with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (927.5 mg) to give the free base of the title compound (320 mg) as a solid. Formation of the maleate gave the title compound (380 mg), m.p.

175.5-177®.

Analysis Οι · ΗζοΝ ^ Ο obtained: C 62.1 H 5.7 N 13.0 calculated: C 62.2 H 5.7 N 13.2%.

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-S- (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 for 4 hours. - (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (371 mg) to give the free base of the title compound (180 mg) as a solid. Formation of the maleate gave the title compound (172 mg), m.p. 203-205 °.

Analysis Ci »H3» N. * 0. C * HU Cu found: C 62.6 H 6.0 N 12.6 calculated: C 63.0 H 6.0 N 12.8%.

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 41 89424 2.3.4.5-Tetrahydro-5- (phenylacetyl) -1H-pyrido [4,3-b] indol-1-one (960 mg) was treated with sodium hydride (73% dispersion in oil; 132 mg) and then stirred With 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (1.3 g). The free base of the title compound (571 mg) was obtained as a solid by eluting with FCC; 11a System A (175: 8: 1). Formation of the maleate gave the title compound (420 mg), m.p. 198-200®, TLC (System A, 100: 8: 1) Rf 0.3.

Example 7 5- (Cyclopentylmethyl) -2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1 -one maleate 5- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (200 mg) was treated with sodium hydride (60% dispersion in oil; 60 mg) then mixed with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (280 mg). The free base of the title compound was obtained as a solid (96 mg) by FCC eluting with System A (200: 8: 1). Formation of the maleate gave the title compound (60 mg), m.p. 81-83 °, 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 under nitrogen to a stirred suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (124 mg) in dry dimethoxyethane. (5 ml). The mixture was heated at 50 ° for 7 hours then treated with a solution of 4- (chloromethyl) -N, N-dimethyl-5-propyl-1H-imidazole-1-sulfonamide (165 mg) in dimethoxyethane (3 ml) and stirring was continued for 20 hours. 50® ° C. 2N Hydrochloric acid (5 ml) was added and the solution was heated at reflux for 6 hours. The solution was poured into 8% sodium bicarbonate solution (50 42 8 9 48 4 ml) and extracted with dichloromethane (3 x 25 ml). The combined dried organic extracts were evaporated. The resulting solid (200 mg) was purified by FCC eluting with System A (200: 10: 1) to give the free base of the title compound (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 recrystallized from ethanol: ether to give the title compound (58 mg), m.p. 137-138e.

Analysis for C 16 H 19 N 3 O 4 C 4 H 4 O 4 found: C 62.7 HS, 9 N 12.4 calculated: C 63.0 H 6.0 N 12.8%.

Example 9 2.3.4,5-Tetrahydro-N, N-dimethyl-2 - [(S-methyl-1H-imidazol-4-yl) methyl] -1-oxo-5H-pyrido [4,3-b] indole-5 Carboxamido maleate 2,3,4,5-Tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indol-1-one A solution of (261 mg) in dry dimethylformamide (25 ml) was treated with sodium hydride (60% dispersion in oil; 30 mg) and the mixture was stirred at room temperature under nitrogen for 15 minutes. N, N-Dimethylcarbamoyl chloride (1M solution in DMF; 1 ml) was then added and the solution was stirred at room temperature for a further 15 minutes. Water (1 ml) was carefully 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 an oil. The oil was dissolved in a mixture of water (10 ml), glacial acetic acid (10 ml) and tetrahydrofuran (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 adsorbed onto FCC silica and the free base of the title compound (110 mg) was obtained by FCC eluting with System A (100: 8: 1) as a solid. This was dissolved in dry methanol (10 ml) and heated with maleic acid (36 mg) for 5 minutes on a steam bath. After cooling, dry ether (3 ml) was added to precipitate the title compound (105 mg), m.p. 161-163 «.

Water analysis, obtained 1.85 wt% = 0.49 mol Ha0.

Analysis CivHziNoOz C4Ο4 0.49 HzO

found: C 57.8 H5.4 N 14.3 calculated: C 68.0 H 5.5 N 14.7%.

Examples 10, 11 and 12 were prepared in the same manner as Example 9 unless otherwise stated.

Example 10 2.3.4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (methylsulfonyl) -ΙΗ-pyrido [4,3-b] indol-1-one 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) followed by stirring with methanesulfonyl chloride (1M solution in dry dimethylformamide; 1 mL) for deprotection, work-up and purification to give the free base of the title compound (60 mg) as a solid. title compound (57 mg), mp 152-155 «.

Analysis Cx-rHxehUOoS. C * H * CU

found: C 53.2 H 4.7 N 11.7 calculated: C 53.2 H 4.7 N 11.8%.

Example 11 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 8 9 4 C 4 2,3, A, 5-tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3- b] A suspension of indol-1-one (522 mg) and potassium carbonate (276 mg) in dry acetone (75 ml) was treated with propargyl bromide (1M solution in acetone; 2 ml) and the mixture was heated at reflux overnight. partitioned between water (100 ml) and ethyl acetate (100 ml), the aqueous phase washed with ethyl acetate (50 ml) and the combined organic extracts concentrated in vacuo to remove deprotection, work-up and purification to give the free base of the title compound (100 mg) as a solid. Θ9 mg), mp 202-205 *, TLC (System A, 100: 8: 1) Rf 0.29.

Example 12 2.3.4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propenyl) -1H-pyrido [4,3-b] indol-1-one maleate 2.3.4,5-Tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido (4,3-b] indol-1-one (1 , 0 g) was treated with sodium hydride (dispersion 607 in oil; 114 mg) followed by stirring with allyl bromide (460 mg) for 1 hour Deprotection, work-up and purification to give the free base of the title compound (380 mg) as a solid. 160 mg), TLC (System A, 100: 8: 1) Rf 0.3.

Analysis Ci »H = toN 2 O. C «H« Q «found: C 63.2 H5.5 N 12.5 calculated: C 63.3 H 5.5 N 12.87 ..

Example 13 5-Cyclopentyl-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl) -1H-pyrido [4,3-b] indol-1-one maleate 2.3.4,5-Tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-458 9 4 8 4 imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indole A solution of 1-one (523 mg) in dry dimethylformamide (30 ml) was treated with sodium hydride (60¾ dispersion in oil; 46mg) and stirred for 15 minutes at 21e under nitrogen. Cyclopentyl bromide (292 mg) was then added dropwise and the mixture was stirred for 1 hour and then heated at reflux for 4 hours. The solution was allowed to stand for 2 days at 21- and then treated with a mixture of acetic acid (7 ml), water (7 ml) and tetrahydrofuran (8 ml). The resulting solution was heated at reflux for 4 hours, then basified 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 eluting with System A (100: 8: 1) to give the free base of the title compound (42 mg) as a solid. Formation of the maleate gave the title compound (38 mg), m.p. 180e (decomposes), TLC (System A, 100: 8: 1) Rf 0.3.

Example 14 2.3.4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5-propyl-1H-pyrido [4,3-b] indol-1-one maleate 2.3. 4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propenyl) -1H-pyrido [4,3-b] indol-1-one (248 mg) a solution in a mixture of ethanol (20 ml) and 2N hydrochloric acid (0.5 ml) was hydrogenated at room temperature and atmospheric pressure with a pre-reduced 10¾ palladium oxide / carbon catalyst (50¾ water paste; 50mg). The mixture was filtered and evaporated in vacuo. The residue was basified with 2N sodium hydroxide (10 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic extracts were washed with water (30 ml) and evaporated to give the free base of the title compound (258 mg) as a solid. Formation of the maleate gave the title compound (345 mg), TLC (System A, 100: 8: 1) Rf 0.4.

Water analysis, obtained 1.13 p-7, = 0.28 mol H * 0.

Analysis CiCl.% H4Ο4 0.2ΘΗ2Ο 46 8 9 4 C4 obtained: C 62.1 H5.9 N 12.5 calculated: C 62.2 H 6.0 N 12.6¾.

Example 15 2.3.4.5-Tetrahydro-2 - [(S-methyl-1H-imidazol-4-yl) methyl] -ΙΗ-pyrido [4,3-b] indol-1-one maleate 2.3.4.5-Tetrahydro-2-yl Suspension of 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) were hydrogenated overnight at room temperature and atmospheric pressure with pre-reduced 10¾ palladium oxide / carbon catalyst (50¾ water paste; 100mg). The reaction mixture was filtered and the residue was washed with ethanol (100 ml). The filtrate was concentrated in vacuo. To the resulting oil was added 2N sodium hydroxide (50 mL). The resulting suspension was extracted with dichloromethane (2 x 50 ml) and the combined dried organic extracts evaporated to a solid. This FCC was purified by elution with System A (75: 8: 1) to give the free base of the title compound as a solid (240 mg) which was then dissolved in dry methanol (50 mL). Formation of the maleate gave the title compound (261 mg), TLC (System A, 75: 8: 1) Rf 0.2.

Analysis for C 10 H 11 N 3 O found: C 60.3 H 5.2 N 13.8 calculated: C 60.6 H 5.1 N 14.1¾.

Example 16 2.3.4,5-Tetrahydro-5-methyl-2 - [(1,5-dimethyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one maleate

Sodium hydride (73¾ dispersion in oil; 40 mg) was added under nitrogen to 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido (4 To a stirred suspension of 3-b] indol-1-one (300 mg) in dry dimethylformamide (3 mL) After 30 minutes, the suspension was cooled to 0e and iodirethane (0.076 mL) was added dropwise. The mixture was allowed to warm to room temperature, stirred for 1 h. 5 hours and then poured into water (30 ml) and extracted with dichloromethane (3 x 15 ml) The combined dried organic extracts were evaporated to an oil (ca. 545 mg) which was FCC purified by elution with System A (200: 8: 1) to give A solid (95 mg) was obtained, a portion of which (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 removed in vacuo and the residue triturated with dry ether (3 x 5 ml). to give the title compound (122 mg), mp 178-180 °.

Analysis CxeH ^ oN ^ O. CUhUCU

Found: C 62.1 H 5.7 N 13.1 Calculated: C 62.3 H 5.7 N 13.27.

Example 17 2.3.4.5-Tetrahydro-2 - [(1H-iridazol-4-yl) methyl] -5-methyl-1H-pyrido [4,3-b] indol-1-one dimaleate 2.3.4.5-Tetrahydro-2-yl A solution of 5-methyl-2 - [[1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indol-1-one (0.22 g) in acetic acid, tetrahydrofuran and the mixture of 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 solid sodium carbonate and extracted with dichloromethane: methanol (9: 1; 3 x 20 ml). The combined dried organic extracts were evaporated. The resulting oil 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. The resulting gum was triturated with ether to give the title compound (0.17 g) as a solid, m.p. 117-118 °.

Analysis CxeHieN, * 0. 2C.J-UCU

found: C 56.1 H 4.3 N 10.5 calculated: C 56.2 H 4.7 N 10.9¾.

48 8 9 4 G 4

Example 18 2.3.4.5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one 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 40e 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 about 20 ml and allowed to cool to 20 °. Ether (40 mL) was added over 5 minutes with stirring and the mixture was kept overnight at 4 °. 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 ° for 7 hours to give the title compound (0.95 g), m.p. 288-291 * ».

Analysis Ci- ^ HiehUO. HCl found: C 61.4 H 5.8 N 16.7 Cl 10.7 calculated: C 61.7 H 5.8 N 16.9 Cl 10.77.

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 sulfonate 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) was suspended in absolute ethanol ( 6 ml) and heated at 50 ° with concentrated sulfuric acid (0.15 ml), more ethanol (4 ml) was added and the mixture was stirred with charcoal (0.1 g), then the suspension was filtered and the recovered solid was washed with ethanol (0.1 ml). The resulting filtrate was stirred for about 1 hour at room temperature, tert-butyl methyl ether (10 ml) was added slowly and the mixture was stirred for 20 minutes, the precipitate was filtered off, washed with ethanol and tert-butyl methyl ether (1: 1; 6 ml). ) followed by tert-4β 8 9 4 G 4 butyl ethyl acetate (6 mL) and dried in vacuo at 40 ° for 4 days to give the title compound (0.4 g), mp 205-209 °. O. 1. IH3SO. * found: C 49.5 H 5.6 N 13.5 S 8.4 calculated: C 49.9 H 5.4 N 13.3 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] indol-1-one 2.3.4.5- A suspension of tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (400 mg) in dry dimethoxyethane (50 ml) was treated with sodium hydride (60% dispersion in oil; 100 mg) and the mixture was stirred at 60 ° under nitrogen for 6 hours. 4- (Chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (474 mg) was added and the reaction mixture was stirred under nitrogen at 60 ° overnight. Then 2N hydrochloric acid (10 ml) and water (10 ml) were 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 was extracted with ethyl acetate (2 x 50 ml). The combined dried organic extracts were concentrated on FCC silica and purified by FCC eluting with System A (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: δ 2.2 (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).

Example 21 2.3.4,5-Tetrahydro-5-methyl-2 - ((S-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one 2,5-dihydro- 5-Methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one (50 mg) and 10% palladium oxide / carbon catalyst (50% aqueous paste; 25 mg) in absolute ethanol (10 ml) was heated at 80 ° for 24 hours at 5.6 kp / cm 2 under hydrogen pressure, the suspension was filtered and the filtrate was evaporated. mg) was purified by short path column chromatography on silica gel (Merck 7739) eluting with system A (150: 10: 1) to give the title compound (8 mg) as a solid, TLC (system A, 150: 10: 1) Rf 0.36 The 1 H-NMR values obtained for this material were consistent with those obtained for the product of Example 20.

Example 22 2.3.4.5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido (4,3-b] indol-1-one 2.3.4.5- solution of tetrahydro-2 - [[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indol-1-one (261 mg) in dry dimethylformamide ( 25 ml) was treated with sodium hydride (dispersion 607 in oil; 30 mg) and the mixture was stirred at room temperature under nitrogen for 15 minutes, then iodomethane (0.5M solution in dimethylformamide; 2 ml) was added and stirring was continued for a further 15 minutes. 100 ml) and the resulting suspension was extracted with ethyl acetate (2 x 50 ml) The combined organic extracts were washed with water (2 x 100 ml), dried and concentrated to a solid which was dissolved in water (10 ml), tetrahydrofuran (10 ml) and glacial acetic acid (10 ml). ml) and heated at reflux for 2 h.After cooling, the THF was removed in vacuo and the residual solution was basified. (to pH 14) by adding 2N sodium hydroxide. The resulting suspension was extracted with ethyl acetate (2 x 50 mL) and the combined dried organic extracts were concentrated on silica (Merck 7385). The FCC was purified by elution with System A (100: 8: 1) to give the title compound (81 mg) as a solid. The 1 H-NMR and TLC values obtained for this material were consistent with those obtained for the product of Example 20.

si 8 9 484

Example 23 2,3, A, 5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one 5,6-Dihydro-1 - [(5-methyl-1H-imidazol-4-yl) methyl] -4- (2-methyl-2-phenylhydrazino) -2 (1H) -pyridinone (20.0 mg) was dissolved. 98% sulfuric acid (1 mL) and the solution was stirred for 5 minutes at 25e. The mixture was carefully poured into 8% aqueous sodium bicarbonate (60 mL) and extracted with 10% raethanol: dichloromethane (2 x 60 mL). The combined dried organic extracts were evaporated in vacuo. The residual oil was purified by FCC eluting with System A (100: 8: 1) to give the title compound (13.5 mg) as a solid. The 1 H-NMR and TLC values obtained for this material were consistent with those obtained for the product of Example 20.

Example 24 2.3.4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one N, N, 5-Trimethyl-4- [1,2,3,6-tetrahydro-4 - [(2-iodophenyl) methylamino] -6-oxo-1-pyridinyl] methyl-1H-imidazole-1-sulfonamide (264 mg) a solution in a mixture of dioxane and acetonitrile (2: 1; 200 ml) containing triethylamine (2 ml) was irradiated in a submerged pyrex bath with a medium pressure 125W mercury lamp at room temperature for 24 hours. The reaction mixture was then concentrated to FCC silica and FCC purified by elution with System A (150: 8: 1) to give the title compound (87 mg) as a solid. The 1 H-NMR and TLC values obtained for this material were consistent with those obtained for the product of Example 20.

Example 25 2.3.4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-iridazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one 52 89484 N, n, 5-trimethyl [2,3,4,5-tetrahydro-5-methyl-l-oxo-lH-pyrido [4,3-b] indol-2-yl) methyl] -lH-imidazole-L- a solution of the sulfonamide (86 mg) in 2N hydrochloric acid (10 ml) and absolute ethanol (2 ml) was heated at 100-110 ° for 4 hours. The reaction mixture was then cooled and 2N sodium hydroxide (50 ml) was added. The resulting solution was extracted with dichloromethane (2 x 50 mL) and the combined dried organic extracts were concentrated to FCC-silica and purified by FCC eluting with System A (100: 8: 1) to give a solid (36 mg). This was taken up in hot ethyl acetate and purified by slow evaporation to give the title compound (12 mg). The 1 H-NMR and TLC values obtained for this material were consistent with those obtained for the product of Example 20.

Example 26 2.3.4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one N, N, 5-trimethyl - [(2,3,4,5-tetrahydro-5-methyl-l-oxo-lH-pyrido [4,3-b] indol-2-yl) methyl] -lH-imidazole-1-sulfonamide A solution of (401 mg) in a mixture of dioxane (150 ml) and acetonitrile (150 ml) containing triethylamine (1 ml) was irradiated at room temperature for 24 hours with a medium pressure mercury lamp. The reaction mixture was then concentrated in vacuo to FCC yeast and FCC purified by elution with System A (100: 8: 1) to give the title compound (203 mg) as a solid. The 1 H-NMR and TLC values obtained for this material were consistent with those obtained for the product of Example 20.

Example 27 2.3.4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one

Phenylmethyl-5-methyl-4 - [(2,3,4,5-tetrahydro-5-methyl-l-oxo-lH-pyrido [4,3-b] indol-2-yl) methyl] -lH- A solution of imidazole-1- 53 β 94 S 4 carboxylate (134 mg) in a mixture of absolute ethanol and 2N hydrochloric acid (2: 1; 30 ml) was heated on a steam bath for 15 minutes. After cooling, the solution was concentrated in vacuo to about 20 mL and diluted with water (40 mL). The mixture was then washed with ethyl acetate (2 x 40 mL) and the acidic aqueous layer was basified with potassium carbonate solution. The solution was then extracted with ethyl acetate (3 x 50 mL) and the combined dried organic extracts were concentrated to FCC silica and FCC purified by elution with System A (150: 8: 1) to give a solid. This was dissolved in hot methanol and triturated with ether to give the title compound (69 mg). The 1 H-NMR and TLC values obtained for this material were consistent with those obtained for the product of Example 20.

Example 28 2.3.4.5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one 2.3.4.5- tetrahydro-2 - [[1- (methoxymethyl) -5-methyl-1H-imidazol-4-yl] methyl] -5-methyl-1H-pyrido [4,3-b] indol-1-one and 2.3 .4.5-tetrahydro-2 - [[1- (methoxymethyl) -4-methyl-1H-imidazol-5-yl] methyl] -5-methyl-1H-pyrido [4,3-b] indole-1- A solution of onion (34 mg) in 49% hydrobromic acid (2 mL) was heated on a steam bath for about 3 hours. After cooling, the reaction mixture was basified by the addition of potassium carbonate solution and extracted with ethyl acetate (3 x 50 ml). The combined dried organic extracts were concentrated in vacuo to give the title compound (6 mg) as a solid. The 1 H-NMR and TLC values obtained for this material were consistent with those obtained for the product of Example 20.

Example 29 2.3.4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one

Si 8 9 40 4 2.3, A, 5-tetrahydro-2 - [(A-methyloxazol-5-yl) methyl] -1H-pyrido (A, 3-b] indol-1-one (100 mg) in formamide ( 20 mL) was heated at 180e for 2A h, then the mixture was cooled, diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL), the combined organic extracts were concentrated in vacuo and the residue was FCC purified by elution with System A (100: 8 : 1) to give the title compound (AO mg) as a solid, the 1 H-NMR and TLC values of this material being consistent with those obtained for the product of Example 20.

Example 30 2.3, A, 5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-A-yl) methyl] -1H-pyrido [A, 3-b) indol-1-one A- A solution of [CC (1-methyl-1H-indol-2-yl) ethyl] amino] methyl] -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide (1A0 mg) in dry dichloromethane (15 ml) was cooled to 5 ° C. The mixture was stirred under nitrogen while phosgene (12 w / w solution in toluene; 1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, powdered aluminum trichloride (60 mg) was added and stirring was continued overnight. After this time, methanol (1 mL) was added and the reaction mixture was adsorbed onto FCC silica and FCC purified by elution with System A (150: 8: 1) to give the protected derivative of the title compound (A2 mg) as an identical solid (TLC and melting point) with 27 intermediate products. Deprotection in either Example 25 or Example 26 affords the title compound.

Example 31 2.3, A, 5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-A-yl) methyl] -1H-pyrido [A, 3-b) indol-1-one A- [[[3-iodo-1-methyl-1H-indol-2-yl) ethyl] amino] methyl] -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide (70 mg), tri-SS 8 9 4 G A mixture of 4-phenylphosphine (52 mg) and palladium acetate (22 mg) in tri-n-butylamine (5 ml) and dry tetrahydrofuran (1 ml) was heated in carbon monoxide gas at 120 x 883 for 1 hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid (50 ml) and the resulting mixture was extracted with ethyl acetate (2 x 50 ml); was thrown away. The acidic solution was then basified with 2N potassium carbonate and the resulting basic suspension was extracted with ethyl acetate (2 x 50 ml). The combined dried organic extracts were concentrated in vacuo to an oil and the remaining tri-n-butylamine was removed by distillation. The residual solid was adsorbed onto FCC silica and FCC purified by elution with System A (150: 8: 1) to give the protected derivative of the title compound (21 mg) as an solid that was identical by TLC and m.p. ) with 27 intermediate products. Deprotection as described in either Example 25 or 26 afforded the title compound.

Example 32 2,3,4,5-Tetrahydro-5-methyl-2 - [(S-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one 5,6-Dihydro-1 - [(5-methyl-1H-imidazol-4-yl) methyl] -4- (2-methyl-2-phenylhydrazino) -2 (1H) -pyridone (60 mg) was dissolved in glacial acetic acid ( 4 ml). Anhydrous zinc chloride (600 mg) was added and the mixture was heated at 85e for 1.5 hours. The cooled mixture was poured into 8% aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate: methanol (10: 1) (2 x 100 mL). The combined dried organic extracts were evaporated in vacuo. The residual solid was purified by FCC eluting with System A (100: 8: 1) to give the title compound (26 mg). The 1 H-NMR and TLC values obtained for this material were consistent with those obtained for the product of Example 20.

Claims (2)

A process for the preparation of therapeutically active tetrahydro-2 - [(imidazol-4-yl) methyl] pyrido (4,3-b) indole and azepino [4,3-b] indole-1-ones with the general formula (I) N '- ICH2> n ™ 1 where R 1 is a hydrogen atom or any of the following groups: C 1-6 alkyl, C 3 -SC ^R ^ (where R ^ and R ^, which may be the same or different, are both a hydrogen atom or C ^galkyl, provided that R ^ is not a hydrogen atom, since R ^ · is the group -SCCR ^ ); R 2 and R 2 are independently a hydrogen atom or C 1-6 alkyl group, n is 2 or 3; and their physiologically acceptable acid addition salts and solvates, characterized in that (A) a compound of formula (II) is alkylated with a compound of formula (III) LCH 2-Im (III) or its protected derivative, in which Formula L is a leaving atom or group, such as halogen and Im in this formula, and in the following refers to the group R4N NR · 3 and, if necessary, any present protecting groups are removed; or (B) for preparation. of a compound of formula (I), where n is 2, a compound of formula (IV) is imidated with (i) Im (IV) A i.1 or its protected derivative, whereupon, if necessary, protecting groups are removed; or (C) a compound having the formula (V) O h A- If P Im (V) / - (CH 2) n N-Nil II 63 89484 or its salt or protected derivatives, is cyclized, where necessary, protecting groups present are removed; or * (D) a compound having the formula (XVIII) A ^ [I * Im (XVIII) A A A ^ - (CH₂) n N n halogen atom, or its salt or protected derivative, is cyclized, where necessary protecting groups of 1 are removed; or (E) for the preparation of a compound of formula (I), which is a hydrogen atom, a compound of formula (VI) removed; or (F) a compound of formula (VII) G IIA II (vh) nNHCH2lm 64 6440 4 or its protected derivative, reacted with phosgene in the presence of Lewis acid; or (G) a compound of the formula (VII) GI 1 [I) ^ (VIT) ^ '' '(CH2) nNHCH2Im R a palladium (11) salt, where necessary protecting groups are removed; or (H) to prepare a compound of formula (I) wherein R is a C3 alkyl group, a compound of formula (I) is hydrogenated, wherein R 1 is a C or C3-6 alkynyl group, or its protected derivative; where appropriate, protecting groups are removed; (I) to prepare a compound of formula (I) wherein R 1 is a hydrogen atom, a compound of formula, R (J) for the preparation of a compound of formula (I) wherein R 1 is C 1-6 alkyl, C 3-6 galkenyl, C 3-10 alkynyl, C 3-7 cycloalkyl, C 3 -methyl group, a compound of formula (I) is alkylated, wherein R 2 (K) for the preparation of a compound of formula (I), wherein R 1 is C 1-6 alkyl, by alkylating a compound of formula (I), wherein there is a hydrogen atom, or its protected derivative, and if necessary subsequently removed protecting groups; (L) to prepare a compound of formula (I) wherein R 1 is -CONR 2 R 2 or -SC 2 R 4, by acylating a compound of formula (I) wherein R 1 is a hydrogen atom , or its protected derivative, which is followed when required by presence of protecting groups; (M) removing the protecting group (s) from a protected form of a compound of formula (I); and when a compound of formula (I) is obtained as an enantiomeric mixture, the mixture is optionally separated so that the desired enantiomer is obtained; and / or when a compound of formula (I) exists as a free base, the free base is optionally converted into a site. 2. A process according to claim 1, characterized in that 2,3,4,5-tetrahydro-5-methyl-2- [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [ 4,3-b] indole-1-one; and its physiologically acceptable salts and solvates. A process according to claim 1, characterized in that the compound is prepared as hydrochloride or maleate salt.