DD291765A5 - PROCESS FOR THE PREPARATION OF LACTAM DERIVATIVES - Google Patents

Abstract

The invention relates to processes for the preparation of lactam derivatives of the general formula wherein Im is an imidazolyl group of the formula and R 1 is a hydrogen atom or a group selected from C 1-16 -alkyl, C 2- C 2-5 -alkynyl and C 3-7 -cycloalkyl-C 1-4 -alkyl; n has the value 2 or 3; Q is a halogen atom or a group selected from hydroxy, phenyl C1-3 alkoxy, C1-6 alkyl and cyano; Q represents a hydrogen or a fluorine atom, and the physiologically acceptable salts and solvates thereof. The compounds prepared by methods known per se are potent and selective antagonists of the effect of 5-HT on 5-HT3 receptors, and they are suitable, for example, for the treatment of psychotic disorders, anxiety and nausea and vomiting. Equations {lactam-producing; pharmaceuticals; Treatment; Disturbance, psychotic; nausea; Vomit}

Description

b] indol-1-one; 6-fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propynyl) - 1H-pyrido [4,3-b] indol-1-one; 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1-oxo-1H-pyrido [4,3-b] indole 6-carbonitrile; 6-fluoro-2,3,4,5-tetrahydro-5- (1-methylethyl) -2 - [(5-rnethyI-1H-imidazol-4-yl) methyl) -1H-pyrido (4,3- b] indol-1-one, and their physiologically acceptable salts and solvates thereof.

Field of application of the invention

The invention relates to processes for the preparation of lactam derivatives which find use as active ingredient in pharmaceutical preparations.

Characteristic of the known state of the art

In particular, the compounds prepared according to the invention are compounds which are potent and selective antagonists of 5-hydroxytryptamine (5-HT) at 5-HT receptors of the type located at the ends of primary afferent nerves. Receptors of this type are now also referred to as% -HT ₃ receptors, and they are also present in the central nervous system.

5-HT occurs to a large extent in the neuronal pathways of the central nervous system. Disruption of these 5-HT-containing pathways is known to alter behavioral syndromes such as mood, psychomotor activity, appetite, and memory.

Object of the invention

With the erfindungsgc. .'ii produced lactam derivatives has now been found a new group of compounds which differ in structure from the compounds described above and are the potent antagonists of the effect of 5-HT at 5-HT ₃ receptors.

Explanation of the essence of the invention

The present invention has for its object to provide processes for the preparation of new, pharmaceutically active compounds.

According to the invention, a process for the preparation of an acyclic lactam of the general formula (I) is provided,

U 'U

1 \ ι Ij μ Lu

\ b ₀ i _{| t} (i)

4: < ^L

v / orin Im is an imidazolyl group of the formula:

~ a

and R ¹ represents a hydrogen atom or a group selected from C, _, _ ₄ alkyl, _e is alkyl, -CH ₂ C ₂ -6-alkynyl, and C ₃ -7-cycloalkyl-C;

η is 2 or 3;

Q is a halogen atom or a group selected from hydroxy, phenylC, ₃ -alkoxy, Ci_i ₆ -alkyl and cyano; Q 'represents a hydrogen or a fluorine atom, and the physiologically acceptable salts and solvates thereof.

Suitable physiologically acceptable salts of the compounds of the general formula (i) are, for example, acid addition salts formed with organic or inorganic acids, for example the hydrochlorides, hydrobromides, sulfates, alkyl or aryl sulfonates (for example methanesulfonates or p-toluenesulfonates), Phosphates, acetates, citrates, succinates, tartrates, fumarates and maleates. The solvates can be hydrates, for example.

All optical isomers of the compounds of the general formula (I) and their mixtures including the racemic mixtures and all geometric isomers of the compounds of the formula (I) are embraced by the invention.

A particularly preferred group of compounds of the formula (I) is characterized in that R ^{1 represents} a hydrogen atom or a methyl, isopropyl, prop-2-ynyl or cyclopentylmethyl group; Q is a fluorine or bromine atom or a hydroxy, phenylmethoxy, methyl or cyano group; Q 'is a hydrogen atom; and η is 2.

Preferred compounds according to the invention are:

6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) -methyll-1H-pyrido [4,3-b] indol-1 -one; 2,3,4,5-Tetrahydro-5,6-dimethyl-2 - [(5-methyl-1 H -imidazol-4-yl) -methyl] -1 H -pyrido (4,3-b] indole 1 -one; 6,9-Difluoro-2,3,4,5-tetrahydro-5-p-: 3-ethyl-2 - [(5-methyl-1 H -imidazol-4-yl) -methyl] -1H -pyrido (4,3-b] indole-1 -one; 6-fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] - 5- (2-propynyl) -1 H -pyrido [4,3-b] indole-1 -one; 2,3,4,5-tetrahydro-5-methyl-2 - [(b-methyl-1 H- imidazol-4-yl) -methyl] -1-oxo-1H-pyridoKS-blindol-beta-carbonitrile; 6-fluoro-2,3,4,5-tetrahydro-5- (1-methylethyl) -2- [ (5-methyl-1H-imidazol-4-yl) -methyl] -1H-pyrido [4,3-b] indol-1-one, and the physiologically acceptable salts and solvates thereof.

The potent and selective antagonism of 5-HT at 5-HT ₃ receptors by the compounds of the present invention has been demonstrated by their ability to produce 3- (5-methyl-1H-imidazol-4-yl) -1 - [1-10]. _(methyl-t3) -1 H-indol-3-yl) -1-propanone binding in rat entorhinal cortex homogenates (following by G. Kilpatrick et al. in Nature, 1987,330,746 general procedure described) and / or by their ability to inhibit 5-HT induced depolarization of the isolated rat vagus nerve preparation.

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

A compound particularly preferred for both potency and duration of action is 6-fluoro-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 are the hydrochloride, maleate and benzoate.

Compounds of formula (I) which antagonize the effect of 5-HT on 5-HT ₃ receptors are useful in the treatment of conditions such as psychotic disorders (e.g., schizophrenia and mania), anxiety and nausea, and vomiting.

They are particularly useful in the treatment of conditions associated with cancer chemotherapy and radiotherapy that occur postoperatively. Compounds of formula (I) are also useful for the treatment of gastric congestion, symptoms of gastrointestinal oysfunction associated with dyspepsia, peptic ulcers, reflux esophagitis, flatulence, and disturbed bowel syndromes. Furthermore, they are suitable for the treatment of migraine, obesity and conditions, such as bulimia, as well as pain. Compounds of formula (I) may also be used to treat dependence on drugs and abused substances, depression and dementia, as well as other cognitive disorders.

The invention therefore also provides a pharmaceutical composition containing at least one compound selected from compounds of the general formulas] (I) and their physiologically acceptable salts and solvates (for example hydrates) for use in human or veterinary medicine for administration by a suitable route.

Such preparations may be formulated conventionally using one or more physiologically acceptable carriers and / or excipients.

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

A proposed dose for the compounds of the present invention for human administration (having a body weight of about 70 kg) is 0.001 to 100 mg, preferably 0.01 to 50 mg, more preferably 0.1 to 20 mg, of active ingredient per unit dose in terms of Weight of the free base. For example, this dose could be administered one to four times daily. Of course, it may be necessary to routinely vary the dose according to the age and condition of the patient.

The dose also depends on the route of administration.

Compounds of the general formula (I) and the physiologically acceptable salts or solvates thereof can be prepared by the general methods given below. In the following description, the groups R ', Q, Q', η and Im are as defined for the compounds of general formula (I).

According to a first general process (A), a compound of the general formula (I) can be prepared by reacting a compound of the formula (II):

q I

Limit of a compound of formula (III):

X-Im (III)

or a protected derivative thereof alkyl, wherein X is a group -CH ₂ L and L is an exit atom or a leaving group, such as a halogen atom (for example chlorine, bromine or iodine), or an acyloxy group (for example Trifluorjcetyloxy or acetoxy) or oine Sulfonyloxy group (for example trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy) and the reaction is carried out in the presence of a base or X is the group -CH ₂ OH and the reaction in the presence of an acid at elevated temperature and, if necessary, followed by removal of any Protecting groups is performed.

According to one embodiment (a) of process (A), the reaction is carried out with a compound of formula (III), wherein X is the group -CH ₂ L and L is preferably a halogen (for example chlorine - / atom. The reaction may be carried out in an inert solvent such as an ether (for example dimethoxyethane, diglyme or tetrahydrofuran), a substituted amide (for example dimethylformamide or N-methylpyrrolidone), an aromatic hydrocarbon (for example toluene), a ketone (for example acetone). or dimethyl sulfoxide, be carried out at a temperature between ambient temperature and 10O ⁰ C and in the presence of a base. Suitable bases are, for example, 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 (for example, sodium or potassium hydroxide).

According to another embodiment (b) of process (A), the reaction is carried out with a compound of formula (III), wherein X is the group -CH ₂ OH, in the presence of an acid. The acid may be, for example, a strong mineral acid (for example hydrochloric acid) or a hydrocarbylsulfonic acid (for example p-toluene sulfonic acid).

The reaction may suitably be carried out in a high boiling point polar solvent such as N-methylpyrrolidinone or dimethylacetamide at elevated temperature, for example in the range of 100 to 200 ^° C. Alternatively, the reaction may suitably be carried out in water or an alcohol (for example isopropanol) at the reflux temperature of the solvent.

According to another general method (B), a compound of the general formula (I) can be prepared by reacting a compound of the formula (IV):

Q ¹ 0

I Il

/ Λ Λ Λ

• ·. N Im (IV)

, N-N

or a salt or protected derivative thereof, and if necessary, subsequently removing any protective groups.

Naturally, these compounds of formula (IV) may be present in the corresponding tautomeric enol-hydrazone form. The cyclization can be carried out in aqueous or nonaqueous media in the presence of an acidic catalyst. When using an aqueous medium, this may be water or a mixture of water and an organic solvent such as an alcohol (for example, methanol, ethanol or isopropanol) or an ether (for example, dioxane or tetrahydrofuran). The acidic catalyst may be, for example, an inorganic acid such as concentrated hydrochloric acid or sulfuric acid. In some cases, the acidic catalyst may also act as a reaction solvent. Alternatively, in an anhydrous reaction medium which may contain one or more alcohol or ethers (for example as described above), carboxylic acids (for example acetic acid) or esters (for example ethylarate acetate), the acidic catalyst may be a Lewis acid. such as boron trifluoride, zinc chloride or magnesium chloride. The cyclisation reaction may conveniently be carried out at temperatures of 20 to 200 ⁰ C, preferably 20 to 125 ° C, are carried out.

Alternatively, the cyclization according to embodiment (a) of process (B) may be carried out in the presence of polyphosphate ester in a reaction medium which may contain one or more organic solvents, preferably halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane or mixtures thereof. 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 another general method (C), a compound of the general formula (I) can be prepared by reacting a compound of the formula (V):

(V)

or a protected derivative thereof with formamide at a temperature in the range of 150 to 200 ⁰ C and, if necessary, subsequent removal of any protective groups are prepared.

According to another general method (D), a compound of general formula (I) can be converted to another compound of formula (I) using conventional techniques. Such conventional techniques include alkylation, with protection and deprotection removed as necessary

The term "alkylation" according to general procedure (D) includes the introduction of groups such as cycloalkylalkyl and alkynyl Thus, for example, a compound of formula (I) wherein R ^{1 is} a C 1-6 -alkyl, CH ₂ C ₂ _ ₆ alkynyl or C 1 -C ₆ cycloalkyl-C 1-4 alkyl group, can be prepared by reacting a compound of formula (I) wherein R ^{1 is} hydrogen by conventional procedures as described in U.S. Pat Thus, the reactions may be carried out using a suitable alkylating agent of the formula R ² Z (wherein R ^{2 is} the group to be introduced and Z is an exit atom or leaving group), preferably in the presence of a base ,

Naturally, conversions described above may be necessary or expedient to protect any sensitive groups in the molecule of the subject compound to avoid undesirable side reactions. Thus, for example, it may be necessary to use the indole and / or imidazole nitrogen atoms, for example, an arylmethyl (for example TrHyI), arylmethoxymethyl (for example phenylmethoxymethyl), alkyl (for example.-Butyl), Alkoxymethyl (for example, methoxymethyl), acyl (for example, benzyloxycarbonyl) or a sulfonyl (for example, Ν, Ν-dimethylaminosulfonyl or p-toluenesulfonyl lgruppe to protect.

If Q is a hydroxyl group then it may be necessary to protect the hydroxyl group, for example with an arylmethyl (for example benzyl or trityl) group.

Thus, according to another general method (E), a compound of the general formula (I) can be prepared by removing any protecting groups from a protected form of a compound of the formula (I). Cleavage of the protecting group (s) can be accomplished by conventional techniques such as described in "Protective Groups in Organic Synthesis" by T. W. Greene (John Wiley and Sons, 1981).

For example, an arylmethoxymethyl-N-protecting group can be cleaved off by hydrogenolysis in the presence of a catalyst (for example, palladium-on-charcoal). A trityl group can be cleaved by acid hydrolysis (for example, using dilute hydrochloric acid or acetic acid). An alkoxyalkyl group can be removed by using a mineral acid (for example, dilute hydrochloric acid or hydrobromic acid). An acyl group can be removed by hydrolysis under acidic or basic conditions (for example, using hydrogen bromide, dilute hydrochloric acid or sodium hydroxide solution). A sulfonyl group can also be removed by alkaline or acid hydrolysis. A Ν, Ν-dimethylaminosulfone group may also be removed by photolysis (for example, from an imidazole nitrogen atom.) An arylmethyl-OH protecting group may be prepared under acidic conditions (for example with dilute acetic acid, hydrobromic acid or boron tribromide) or by hydrogenolysis in the presence of a catalyst (for example, palladium-on-charcoal) are split off.

Precursors of the formula (II) in which R 'is a hydrogen atom can be synthesized, for example, by cyclization of a compound of the formula (VI):>

ΐ χ • Y η H NII • I Il • // \ / \ • · • I Q

wherein X is a hydrogen or halogen (for example bromine or iodine) atom, are prepared. The cyclization may be effected using methods analogous to those described by H. lida et al. in J. Org. Chem., 1980, 45, 2938.

Compounds of the formula (II) wherein R ^{1 is} a group other than a hydrogen atom may be prepared from a compound of the formula (II) wherein R ^{1 is} a hydrogen atom by conventional alkylation methods as described, for example, in the above interconversion process become.

Compounds of the formula (VI) can be synthesized, for example, by reacting a compound of the formula (VII):

• ·

W / \ N

(viii

wherein X is as defined above, with a compound of formula (VIII):

Il

• MII (VIII)

be prepared at elevated temperature.

Compounds of formula (III) and the protected derivatives thereof are either known or may be prepared, for example, by methods analogous to those described in published European patent specification 242973.

Compounds of formulas (IV) and (V) can be prepared, for example, by methods analogous to those described in published European patent specification 306323A.

Compounds of formulas (VII) and (VIII) are either known or can be prepared from known compounds by conventional procedures.

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

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

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

The methods described above for the preparation of the compounds according to the invention can be used to introduce the desired groups in each step in the stepwise formation of the desired compounds.

Naturally, these methods can be combined in various ways, such as multi-step methods. The sequence of reactions in multistep processes should naturally be chosen so that the reaction conditions used do not affect groups in the molecule that are desired in the final product.

-7- 291765 embodiments

The invention is further illustrated by the following intermediates and examples. All temperatures are in ⁰ C. Thin layer chromatography (TLC) was performed on silica. Flash column chromatography (FCC) was performed on silica (Merck 9385). The solvent system A used for the chromatography is a dichloromethane / ethanol / O.ee ammonia solution. The organic extracts, if indicated, are dried over magnesium sulfate and sodium sulfate. The following abbreviations are used: DMF-dimethylformamide; THF tetrahydrofuran; DME - dimethoxyethane. The 'H NMR spectra were recorded at 250MHz for dilute solutions ^! nd ₆ -dimethylsulfoxide.

Intermediate 1

4- (2-fluorophenyl) amino-5,6-dihydro-2 (1H) -pyridinone

A mixture of 2-fluoroaniline (0.98g) and 2,4-dioxopiperidine (1.0g) was heated to 120 ° C for 2 hours. The cooled mixture was stirred with dry ether (5 x 40ml), and the solvent was decanted to give the title compound (1,495g), Fp.98 to 100 ⁰ C, remained.

Intermediate 2

5,6-dihydro-4 - [(2-methylphenyl) amino] -2 (1H) -pyrIdlnon

A mixture of o-toluidine (943mg) and 2,4-dioxopiperidine (1.0g) was heated at 120 ° C for 30 minutes. The oil was cooled, triturated with ether (30ml), and the solvent was decanted to give the title compound (1.74 g), mp. 158 ⁰ C was bis 155 was obtained.

Intermediate 3

4 - [(2,6-Dlbromphenyl) -amlno] -5,6-dihydro-2 (1H) -pyrldlnon

A mixture of 2,6-dibromoaniline (4.4 g) and 2,4-dioxopiperidine (2.0g) was heated at 12O ⁰ C for 2.5 hours, The mixture was then cooled (0 ⁰ C) and with ether ( 100 ml) to give a solid which was purified by FCC eluting with System A (100: 8: 1). Thus, the title compound (1.8 g), m.p. 240-243 ° C, was obtained.

Intermediate 4

4 - [(2,5-difluorophenyl) amino] -5,6-dihydro-2 (1H) -pyrldlnon

A mixture of 2,5-difluoroaniline (6.45g) and 2,4-dioxopiperidine (5.66g) was heated under nitrogen for 6 hours. The reaction mixture was then dissolved in ethanol (50 ml), adsorbed onto silica and purified by FCC eluting with System A (150: 8: 1). In this way, the title compound (2.3 g) mp. 252 to 255 ⁰ C, was obtained.

intermediate

3 - 2-cyclohexen-1-one [(2-fluorophenyl) -amlno]

2-Fluoroaniline (10g) and cyclohexane-1,3-dione (10g) were heated together under nitrogen to 120 ° C for 1 hour. The cooled mixture was stirred with ether and filtered to give the title compound (14.8g), m.p. 116-118 ° C.

intermediate

6-fluoro-2,3,4,5-tetrahydro-1H-pyro [4,3-b] indole-1-one

Copper (II) acetate (2.71 g) was added to a stirred solution of 4 - [(2-fluorophenyl) amino] -5,6-dihydro-2 (1 H) -pyridinone (1.4 g). and palladium (II) acetate (280mg) in dry DMF (28ml) under nitrogen. The mixture was heated at 130 ° C for 1.5 hours and the solvent was removed in vacuo. The residue was treated with hot methanol (50 ml) and the suspension was filtered and washed with hot methanol (3 x 50 ml). The combined filtrates were evaporated to give a gum (2.16 g) which was purified by FCC eluting with System A (200: 10: 1). In this manner, the title compound (490 mg), mp. 257 ⁰ C was bis 255 was obtained.

Intermediate 7

2,3,4,5-tetrahydro-e-methylm H -pyrido [4,3-b] indole-1-one

Copper (II) acetate (2.9g) was added to a stirred solution of 5,6-dihydro-4 - [(2-methylphenyl) amino] -2 (1H) -pyridinone (1.5g) and palladium dD. acetate (230 mg) in dry DMF (40 ml). The mixture was heated for 1 hour at 13O ⁰ C, eingetlampft in vacuo and the residue was extracted with methanol (250ml). This solution was concentrated in vacuo and the residue was purified by FCC eluting with System A (100: 8: 1). In this way, the title compound (360 mg), m.p. 300 to 302 ° C, was obtained.

Intermediate 8

6-bromo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one

4 - [(2,6-Dibromophenyl) amino] -5,6-dihydro-2 (1H) -pyridinone (0.5g) was cyclized by the method of Intermediate 7 to give the title compound (250mg), m.p. 268 to 270 ° C, was obtained.

intermediate

6,9-Difluoro-2,3,4,5-tetrahydro-1H-pyrodino [4, J-D] indole-1-one

4 - [(2,5-Difluorophenyl) amino] -5-C-dihydro-2 (1H) -pyridinone (2.24 g) was cyclized by the method of Intermediate 6 to give the title compound (900μτΐ (,) , Mp 221 to 223 ^° C.

Intermediate 10

8-fluoro-i, 2,3,9-tetrahydro-4H-carbazql-4-one

3 - ((2-fluorophenyl) amino] -2-cyfilohexen-1-one (14.8g), palladium (II) acetate (1g) and copper (II) acetate (29.5g) under nitrogen in DMF (100 -> il) for 2 hours to 14O ⁰ C. The solvent was removed in vacuo and the residue was purified by FCC, eluting with ether to give the title compound (10, 1 g), mp 222-224 ° C.

Intermediate 11

2,3,4,5-tetrahydro-6- (phenylmethoxy) -1-pyrldo [4,3-b] Indo! -1-one

A mixture of 2- (phenylmethoxy) aniline (7.6g) and 2,4-dioxopiperidine (4,5g) was heated for 3 hours under nitrogen to 12O ⁰ C. The mixture was then cooled and purified by FCC eluting with System A (100: 8: 1). In this way, a solid (5.4 g) was obtained. This solid was treated by the method of Intermediate 7 to give the title compound (4.0 g), m.p. 182 to 185 ° C.

Intermediate 12

6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrldo [4,3-b] indol-1-one

Sodium hydride (60% dispersion in oil, 196 mg) was added to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (500 mg). in dry DMF (10 ml) under nitrogen. After 30 minutes the solution was cooled (O ⁰ C) and treated with methyl iodide (0.153 ml). After stirring for 15 minutes, the suspension was poured into water (50 ml) and extracted with dichloromethane (3 x 25 ml). The combined, dried organic extracts were evaporated to give a solid (about 530 mg) which was purified by FCC eluting with System A (250: 10: 1). In this manner, the title compound (130 mg), mp. 242 ⁰ C was obtained.

Intermediate 13

2,3,4,5-tetrahydro-5,6-dimethyMH-pyrldo [4,3-b] indol-1-one

Sodium hydride (60% dispersion in oil, 140 mg) was added to a stirred solution of 2,3,4,5-tetrahydro-6-methyl-1H-pyrido [4,3-b] indol-1-one (350 mg ) in dry DMF (15ml) at 21 ⁰ C under nitrogen. After 15 minutes the solution was cooled (0 ⁰ C) and treated dropwise with a 10% (vol./vol.) Solution of methyl iodide in DMF (1,14ml) was added. After 10 minutes, water (100m) was added and the mixture was extracted with ethyl acetate (2 χ SOmI). The combined organic extracts were washed with water (100 ml) and brine (100 ml) and then evaporated to give a solid which was purified by FCC eluting with dichloromethane / ethanol (80: 1). In this way the Titelverb'ndung (190mg), mp. 298-300 ⁰ C, was obtained.

Intermediates 14 and 15 were prepared in a manner similar to Intermediate 13, d. H. by methylation of the corresponding 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one using sodium hydride and methyl iodide in DMF.

Intermediate 14

6-bromo-2,3,4,5-tetrahydro-5-methyl-1H-pyrldo [4,3-b] indol-1-one

The methylation of 6-bromo-2,3,4,5-tetrahydro-1 H-pyrido [4,3-b] indol-1-one (200mg) gave the title compound (80 mg), mp 212-214 ⁰ C.

Intermediate 15

6,9-difluoro-2,3A5-tetrahydro-5-methyl-1H-pyrldj [4,3-bHndoM-one

Methylation of 6,9-difluoro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole-1-one (900mg) afforded the title compound (110mg), mp 226-229 ° C. (The FCC eluant was System A (150: 8: 1).)

Intermediate 16

yy

To a suspension of sodium hydride (80% dispersion in oil, 1.15 g) in dry THF (50 ml) under nitrogen was added e-fluoro-1: 5-tetrahydro-1-carbazol-1-one (6.5 g) dry THF (50ml) and the mixture was stirred for 1h. Methyl iodide (4.1 ml) was added and the mixture was stirred for 3 hours. The mixture was then poured into brine (300 ml) and extracted with ether (2 × 300 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (5.77g), mp 126-128 ° C.

Intermediate 17

2,3,4,5-Tetrahydro-5-methyl-6- (phenylmethoxy) -1H-pyrido [4,3-b] indol-1-one 2,3,4,5-tetrahydro-6- (phenylmethoxy ) -1 H-pyridoI4,3-b] indol-1 -one (2.0g) was methylated according to the method of intermediate 12 to give the title compound (950mg), mp. 201 ⁰ C was bis 199 was obtained. (The FCC eluant was System A

Intermediate 18

6-fluoro-2,3,4,5-tetrahydro-5 - [(phenylmethoxy) methyl] -1H-pyrido [4,3-bl r!. ^r ! ol-1-one 6-fluoro-2,3,4,5-tetrahydro-1H-pyridoI4,3-b] indol-1-one (800 mg) was treated with benzyl chloromethyl ether (0.55 ml) by the method of Intermediate 12 to give the title compound (220mg), mp. 130 to 132 ⁰ C, was obtained. (The FCC eluant was System A [300: 10: 1].)

Intermediate 19

2,3A5-Tetrahydro-6- (phenylmethoxy) -5- [(phenylmethoxy) -methyl] -1H-pyrido [4,3-b] indom-2,3,4,5-tetrahydro-e- (phenylmethoxy) - 1 H-pyridoI4,3-blindol-1 -one (1.8 g) was alkylated with benzylchloromethyl ether (0,86ml) by the method of intermediate 13, to give the title compound (600mg), mp. 189 to 19O ⁰ C was obtained (The FCC eluant was System A [100: 8: 11.]

Intermediate 20

6-fluoro-2,3,4,5-tetrahydro-5- (1-methylethyl) -1H-pyrldo- [4,3-b] indol-1-one

A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (1.006 g) in dry DMF (50 ml) was treated with sodium hydride (73 , 2% dispersion in oil, 333 mg) and stirred under nitrogen for 1 hour. Isopropyl bromide (663 mg) was then added and the solution was stirred at room temperature for 30 minutes and then at 5O ⁰ laiig C12 hours. Another portion of the isopropyl bromide (150mg) was then added and the reaction mixture was then stirred under nitrogen at 50 ° C for 60 hours, the mixture was then cooled to room temperature and added to water (300ml), the mixture was then washed with dichloromethane (3 x 200 ml), adsorbed on silica and purified by FCC eluting with System A (150: 8: 1) to give a solid (240 mg) which was stirred with ether to give the title compound (130mg), mp. 184 ⁰ C was bis 183 was obtained.

Intermediate 21

5- (Cy-Jopentylmethyl) -6-fluoro-2,3,4,5-tetrahydro-1H-pyrldo [4,3-b] indole-1-one A stirred solution of 6-fluoro-2,3 4,5-tetrahydro-1H-pyrido-4.3-b) indol-1-one (1.023g) in dry DMF (50ml) was treated with sodium hydride (73.2% dispersion in oil, 331mg) and hui Stirred at room temperature for? 0 minutes under nitrogen.

A solution of cyclopentylmethyl-ethylsulfonate) (893 mg) in dry DMF (20 ml) was then added over 15 minutes and stirring was continued for 5 days. Water (20 ml) was added to the reaction mixture, which was then concentrated in vacuo to give a solid. This was dissolved in ethyl acetate (300 ml) and methanol (1 ml), and the resulting solution was washed with saturated sodium chloride solution (3 x 100 ml) and then adsorbed on silica. Purification by FCC eluting with System A (150: 8: 1) provided a solid (283mg) which was recrystallised from ethyl acetate to give the title compound (237mg), m.p. 175-176 ° C.

Intermediate 22

e-FluoM.i.S.iMetrahydro S methyMH-carbazoM-on-oxlm

A mixture of e-FluoM ^ .S ^ -tetrahydro-g-methyl ^ H-carbazoM-on (3.0g) and Hyo. .xylamine hydrochloride (2.92 g) in pyridine. 35 ml) was heated to 60 ^° C. for 3 hours. The solution was then concentrated in vacuo and then azeotropically dried with toluene (2 × 10 ml). The residue was treated with 8% sodium bicarbonate solution (125ml) and extracted with ethyl acetate (3x100ml). The combined extracts were filtered and concentrated in vacuo to give the title compound (1.8 g) as a solid. TLC (System A, 100: 8: 1), Rf 0.66.

Intermediate 23

7-fluoro-3,4,5,6-tetrahydro-6-methylazeplno [4,3-b] indol-1 (2H) -one

A mixture of 8-fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one oxime (1.8 g) and polyphosphoric acid (ca 20 ml) in dioxane (30 ml) was added Nitrogen for 1 hour at 100 to 110 ⁰ C stirred. After cooling, the reaction mixture was poured into ice-water (11) and the resulting suspension was extracted with dichloromethane. The organic extract was concentrated in vacuo to give a solid which was taken up in methanol and adsorbed onto silica. Purification by FCC eluting with System A (200: 8: 1) afforded the title compound (850mg), mp 233 bis

Intermediate 24

2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrldo [4,3-b] INDC! -6-carbonitrll

A mixture of 6-bromo-2,3,4,5-t3-tetrahydro-5-methyl-1H-pyrido [4,3-blindol-1-one (1.1 g) and copper (1) cyanide (1 , 0g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (30ml) was heated at 180 ° C for 24 hours. The mixture was poured onto ice (about 500 ml) and iron (III) chloride (20 g) and stirred for 1 hour. It was then extracted with dichloromethane (3 x 300 ml) and the combined organic extracts were washed with water (2 x 300 ml) and concentrated in vacuo. The residue was extracted with hexane (250ml), then with a mixture of ether / hexane (50:50; 100 ml) and finally with ether (60ml) stirred, to give the title compound (620 mg), mp 230-231 ⁰ C is obtained. ,

Intermediate 25

6-Fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1 H -imidazol-4-yl) -methyl] -5 - [(phenylmethoxy) -methyl] -1 H-pyr! do [4,3-b] indole-1-one sodium hydride (60% dispersion in oil, 28 mg) was added to a standard solution of 6-fluoro-2,3,4,5-tetrahydro-5- [ (phenylmethoxy) methyl] -1H-pyrido [4,3-b] indol-1-one (190mg) in dry DME (10ml). The mixture was heated for 6 hours at 5O ⁰ C and then treated with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (261 mg). Stirring was continued under nitrogen for 18 hours. Water (2 ml) and acetic acid (2 ml) were added and the solution was heated at reflux for 2.5 hours. The solution was poured into 8% sodium bicarbonate solution (50 ml) and extracted with dichloromethane (3 × 25 ml).

The combined, dried organic extracts were evaporated to give an oil (about 750 mg) which was purified by FCC eluting with System A (200: 10: 1). Thus, the title compound (188 mg), TLC (System A, 200: 10: 1), Rf 0.33, was obtained.

Intermediate 2β

e-fluoro-2,3,4,5-tetrahydro-2 - [[5-methYM- (tri-phenylmethyl) H-imidazol-1-methyl-H-pyrido [4,3-b] indole-1-one

A solution of triphenylmethyl chloride (0.625g) in dry DMF (10mL) was added dropwise to a stirred solution of

6-Fluoro-2,3,4,5-tetrahydro-2-l (5-methyl-1 H -imidazol-4-yl) -methyl-1 H -pyrido [4,3-b] indole-1-one (530mg) in dry DMF (20ml) containing triethylamine (0.25g).

The reaction mixture was then stirred at room temperature for 20 hours, added to water (500 ml) and washed with Extracted ethyl acetate (3 χ 20OmI). The combined organic extracts were washed with water (2 × 300 ml),

dried and adsorbed on silica. Purification by FCC eluting with System A (150: 8: 1) provided the

Title compound (509mg), mp. 252-253 ⁰ C. Intermediate 27

2,3,4,5-tetrahydro-2 - [(5-methyl-1H-lmldazol-4-yl) methyl] -E- (phenylmeUioxy) -S - [(phenylmethoxy) methyl] -1H-pyrldo- [4,3-b] Indom-on

2,3,4,5-Totrahydro-6- (phenylmethoxy) -5 - [(phenylmethoxy) methyl] -1H-pyrido [4,3-b] indol-1-one (500 mg) was treated with 4- (chloromethyl) -S-methyM- (triphenylrnethyl) -1H-imidazole (671 mg) was reacted according to the method of intermediate 25, whereby the Titelvei compound (340 mg), mp. 170 to 172 ⁰ C was obtained. (The FCC eluant was System A [100: 8: 1].)

Intermediate 28

4-Amino-5,6-dihydro-1 - [(S-methyl-1H-imidazol-4-yl) -methyl] -2 (1H) -pyrldinone To a solution of 5,6-dihydro-4- Methoxy-1 - [(5-methyl-1H-imidazil-4-yl) -methyl] -2 (1 "pyridinone (1.00g) in THF (10ml) was added with hydrochloric acid (4.3ml) and the mixture became The mixture was stirred at 25 ° C. for 24 hours

Vacuum removed. The residue was dissolved in methanol (10 ml), adsorbed on silica and eluted with FCC by FCC System A (50: 8: 1) to give the title compound (286mg) as a solid, mp was 268-271 ⁰ C, was obtained.. Intermediate 29

4- [2- (2-Fluorophenyl) -2-methylhydrazine] -S, 6-dihydro-1 - [(S-methyl-1H-imidazol-4-yl) methyl] -2 (1H) -pyrldinon

A mixture of 1- (2-fluorophenyl) -1-methylhydrazine (57 mg) and 4-amino-5,6-dihydro-1-l (5-methyl-1H-imidazol-4-yl) -methyll-

2 (1 H) -pyridinone (70 mg) in ethanol (3 ml) was incubated for 4 hours at room temperature and then for 20 hours

Reflux temperature stirred. The solvent was removed in vacuo and the residue was purified by FCC eluting

with System A (75: 10: 1) to give the title compound (85mg) as an oil. TLC (System A, 200: 10: 1), Rf

Intermediate 30

6-Fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(4-methyloxazol-5-yl) -methyl] -1H-pyrido [4,3-b] indole-1-one sodium hydride ( 73% dispersion in oil, 167 mg) was added to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1 H -pyrido [4,3-b] indol-1-one (500mg) in dry DME (150ml), and the suspension was stirred for 6 hours at 6O ⁰ C under nitrogen. 5-Chloromethyl 4-methyloxazole (440 mg) was then added and the mixture was stirred at 60 ° C overnight. An additional amount of sodium hydride (73% dispersion in oil, 84 mg) was added and the mixture was stirred for 3 hours and then cooled ( ⁰ ° C.). Water (200ml) was added and the mixture was extracted with dichloromethane (3 x 200ml). The combined organic extracts were concentrated in vacuo and the residue was purified by FCC eluting with System A (100: 8: 1) to give the title compound (550mg) as Feststoft, mp was 158-161 ⁰ C, was obtained..

Intermediate 31

Phenylmethyl ^ -tie-fluoro ^ .SAS-tetrahydro-S-methyl-i-oxo-IH-pyridyl-KS-indol-1-yl-methyl-S-methyl-imidazoM · carboxylate

A solution of benzyl chloroformate (0.47 ml) in dichloromethane (1 ml) was added to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H ] indol-1-one (496mg) and triethylamine (0,67ml) (50 ml) was added 4,3-b in dry dichloromethane at 20 ⁰ C under nitrogen | imidazol-4-yl-methyl] -1 H -pyrido The mixture was stirred overnight The cooled reaction mixture was then added to 2N sodium hydroxide solution (100 ml) and extracted with dichloromethane (2 × 100 ml) The combined dried organic extracts were adsorbed onto silica and eluted by FCC with System A (200: 8: 1) to give the title compound (442 mg) as a solid A sample was recrystallized from hot ethyl acetate and the resulting solid was stirred with ether to give a crystalline solid, m.p. 128 ⁰ C, was obtained.

example 1

e-fluoro-.SAS-tetrahydro-S-methyl ^ -tfS-methyl-IH-imidazole ^ -d-methyl-1-pyridyl-S-t-indol-1-one-maleate sodium hydride (60% dispersion in oil; 25 mg) to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indole-1-one (115 mg) in dry DME (7.5 ml) given under nitrogen. The mixture was heated to 5O ⁰ C for 6 hours and then with 4- (chloromethyl) (triphenylmothyl) -1H-imidazole (236 mg) treated -5-methyl-1-. It was further stirred at 50 ^° C. for 18 hours. Water (1.25ml) and acetic acid (1.25ml) were added and the solution was heated at reflux for 6 hours. The mixture was poured into 8% sodium bicarbonate solution (40 ml) and extracted with dichloromethane (3 × 20 ml). The combined, dried organic extracts were evaporated to give a solid (375 mg) which was purified by FCC eluting with System A (200: 10: 1). In this way, the free base of the title compound was obtained as a solid (147 mg). This was dissolved in dichloromethane (3 ml) and treated with a solution of maleic acid (55 mg) in absolute ethanol (0.5 ml). The solvent was removed in vacuo, and the residue was stirred with dry ether (3 x 5ml) to give the title compound (185 mg), mp. 178 to 18O ⁰ C was obtained.

Analysis found: C: 59.0; H: 5.0; N: 12.80

theoretical values>

for C ₁₇ H ₁₇ FN ₄ O.C ₄ H ₄ O ₄ C: 58.9; H: 4.9; N: 13.1%.

Examples 2 to 9 were carried out in a similar manner as Example 1, d. H. in the Woise, the corresponding lactam was reacted with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (hereinafter referred to as compound (X)) in DME in the presence of sodium hydride The solution was then made alkaline with 2N sodium hydroxide solution instead of 8% sodium bicarbonate solution, the basic solution was then washed with dichloromethane (or ethyl acetate in the case of Examples 4 and 8). The combined dried organic extracts were evaporated in vacuo Purification of the residue was performed by FCC under Elutior with System A (Examples 2,4,5,8,9 [150: 8: 1] and Examples 3,6, 7 (100: 8: 11) to give the free base of the title compound The maleate formation was carried out as described in Example 1, except that methanol (in place of ethanol) was used as the recrystallization solvent and that the mixture was heated on a steam bath for 10 minutes. The product was obtained from this methanolic solution either by evaporation in vacuo to dryness and subsequent stirring of the resulting residue with ether (Examples 3.6) or recrystallization of the residue from a mixture of methanol and ether (Example 7), or the product was precipitated the methanolic solution precipitated by the addition of ether (Examples 2,4,5,8,9).

Example 2

2,3,4,5 · tetrahydro · 5, δ · dimethethyl · 2 · t (5 · methyl · 1H · imidazole · 4 vl) · n · ethyl · · 1H phryl [4,3 · b] indole 1-one The reaction of 2,3,4,5-tetrahydro-5,6-dimethyl-1H-pyrido [4,3-b] indol-1-one (150 mg) with compound (X) (260 mg) afforded the free base of the title compound (120mg). Maleate formation afforded the title compound (110mg), TLC (System A, 150: 8: 1), Rf

¹ H-NMRO 2.35 (3H, s); 2.75 (3H, s); 3.08 (2H, t); 3.64 (2H, t); 3.93 (3H, s); 4.62 (2H, s); 6.07 (2 H, s); 6.90 (1H, brd); 7.01 (1H, t); 7.88 (1H, brd); 8.73 (1H, brs).

Example 3

e-Bromo ^ .S ^ .B-tetrnhydro-S-methyl ^ -dS-methyl-imldazol ^ -ylmethyl-IH-pyrido ^ .s-Blindy-i-one-maleate The reaction of 6-bromo-2 3,4,5-Tetrahydro-5-methyl-1 H -pyrido [4,3-b] indole-1-one (140 mg) with Compound X (280 mg) afforded the free base of the title compound (130 mg). Maleate formation afforded the title compound (170mg), mp 155 ° C.

Water analysis found: 2.86% w / w. = 0.79 mol H ₂ O

Analysis found: C: 50.1; H: 4.4; N: 10.7 theoretical values for

C ₁₇ H ₁₇ BrN ₄ OC ₄ H ₄ O ₄ 0.79H ₂ O: C: 50.1; H: 4.5; N: 11.1%. Example 4

6,9-Difluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1 H -imidazol-4 L) -methyl] -1 H -pyrido [4,3-b] indole 1-on-maleate The rearrangement of 6,9-difluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido (4,3-b) indol-1-one (1.0 g) with Compound (X) (1.7 g) afforded the free base of the title compound (846 mg). Maleate formation gave the title compound (920 mg), mp. 206 to 208 ⁰ C.

Analysis found: C: 56.1; H: 4.6; N: 12,6

theoretical values for

C ₁₇ H ₁₆ N ₄ OC ₄ H ₄ O _4: C: 56.5; H: 4.5; N: 12.6%.

Beisplel5

7 · fluorine · 3,4,5,6-tθ-tetrahydro · 6 · mθthyl · 2 · [(5 · methyl-1H-imidazole · 4 · yl) · mθthyl] · azθplno [4,3-b] indole-1 (2H) On maleate The reaction of 7-fluoro-3,4,5,6-tetrahydro-6-methylazepino [4,3-b] indol-1 (2H) -one (850 mg) with compound (X) (1, 64g) provided the free base of the title compound (358mg). Maleate formation gave the title compound (383mg), mp. 143 to 145 ⁰ C.

Water analysis found: 1.19% w / w. s 0.296 mol H ₂ O.

Analysis Found: C: 59.2; H: 5.6; N: 12.5 theoretical values for

C ₁₈ H ₁₉ N ₄ OF • C ₄ H ₄ O ₄ · 0,296H ₂ O: C: 59.0; H5,3; N: 12.5%.

Examples

2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-lmldazol-4-yl / -methyl] -e- (phenylmethoxy) -1H-pyrldo [4,3-b] -lndol-1-one maleate The reaction of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido-4,3-b! indol-1-one (900 mg) with compound (X! (1.6g) gave the free base of the title compound (800mg). A portion of the free base (90mg) was treated with maleic acid to give the title compound (90mg), mp. was 158 to 16O ⁰ C, was obtained. TLC (system A , 100: 8: 1), Rf 0.2.

Example 7

The reaction of 2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3-b] indole-6-carbonitrile (550 mg) with compound (X) (1.3 g) provided the free base of the title compound (410mg). A portion of the free base (100 mg) was treated with maleic acid to give the title compound (50 mg). TLC (System A, 100: 8: 1), Rf 0.2.

Analysis found; C: 60.4; H: 4.8; N: 15.6

theoretical values for

C ₁₈ H ₁₇ N ₆ OC ₄ H ₄ O _4: C: 60.7; H: 4.9; N: 16.0%.

Examples

Reaction of B-fluoro-2,3,4,5-ietrahydro-5- (1-n.-ethyl) -1H-pyrido [4,3-b] indol-1-one (130 mg) with Compound (X) (295 mg) afforded the free base of the title compound (69 mg). A portion of the free base (66 mg) was treated with maleic acid to give the title compound (79 mg), m.p. 185-187 ° C.

Analysis Found: C: 60.2; H: 5.6; N: 12.0

theoretical values for

C ₁₉ H ₂₁ FN ₄ O-C ₄ H ₄ O ₄ : C: 60.5; H: 5.5; N: 12.3%.

Example 9

5 × (cyclop-β-nylmethyl) -fluo-2,3,35-tetrahydro-2 × [(5 × methyl-1H-imid-1-ol-4-yl) -methyl] -1H-pyridine [4,3 × b] indole · 1 × on maleate Reaction of S-cyclopentylmethoxy-e-fluoro-i.SAS-tetrahydro-iH-pyrido [4,3-b] indol-1-one (222mg) with Compound X (317mg) the free base of the title compound (100 mg). Maleate formation gave the title compound (85 mg), mp. 164 to 166 ⁰ C.

Analysis found: C: 62.5; H: 5.9; N: 11.0

theoretical values for

C ₂₂ H ₂₅ FN ₄ OC ₄ H ₄ O _4: C: 62.9; H: 5.9; N: 11.3%.

Example 10

6-fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-lmldazol-4-yl) methyl] -5- (2-proplnyl) -1H-pvrldo [4,3- b] -Indol-1-one-maleate A stirred solution of e-fluoro-.SAS-tetrahydro-1-sil-methyl-i-1-triphenylmethy-1H-imidazol-1-methyl-1H-pyridoKS-b] indole-1 -one (228mg) in dry acetone (40ml) and anhydrous potassium carbonate (116mg) was treated with propargyl bromide (10% (v / v) solution in dry acetone, 1ml) and heated at reflux overnight. After cooling, excess acetone was removed in vacuo and the residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with water (2 x 50 ml) and the combined aqueous extracts were washed with ethyl acetate (50 ml). The combined organic extracts were then concentrated in vacuo and the residue was dissolved in a mixture of water (10ml), glacial acetic acid (10ml) and THF (15ml) and heated at reflux for 2 hours. The cooled solution was then basified with 2N sodium hydroxide solution (ca 100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined, dried organic extracts were adsorbed on silica and purified by FCC eluting with System A (100: 8: 1) to give the free base of the title compound (95mg). This was dissolved in the minimum amount of hot dry methanol and maleic acid (32 mg) added. The solution was heated and then allowed to cool. Ether was added to precipitate the title compound (80mg), m.p. 123-124 ° C.

Analysis found: C: 60.9; H: 4.7; N: 12.0

theoretical values for

C ₁₉ H ₁₇ FN ₄ OC ₄ H ₄ O ₄ : C: 61.1; H: 4.7; N: 12.4%.

Example 11

6-fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-lmldazol-4-yl) methyl] -1H-pyrldo [4,3-b] indol-1-one maleate A solution of 6-fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) -methyl] -5- (phenylmethoxymethyl) -1 H -pyrido- [4,3-b] indol-1-one (175mg) in absolute ethanol (10ml) and acetic acid (2.5ml) was added at room temperature and atmospheric pressure to 10% palladium on carbon 6 catalyst (50% aqueous paste; 45mg) in absolute ethanol (2ml) for 20 hours. Additional catalyst (45 mg) was added and stirring was continued for 20 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was washed with 8% sodium bicarbonate solution (50 ml) and extracted with dichloromethane (3 × 25 ml). The combined, dried organic extracts were evaporated to give an oil (about 130 mg) which was purified by FCC eluting with System A (150: 10: 1). In this way, the free base of the title compound (102 mg) was obtained. This was dissolved in ethanol (about 2 ml) and treated with a solution of maleic acid (42 mg) in ethanol (0.5 ml). The solvent was removed in vacuo and the residue was triturated with dry ether (5x5ml) to give the title compound (120mg), m.p. 186-188 ° C.

Analysis found: C: 57.8; H: 4.7; N: 13.2

theoretical values for

C ₁₆ Hi ₅ FN ₄ OC ₄ H ₄ O _4: C: 58.0; H: 4.6; N: 13.5%.

Example 12

A solution of 2,3,4,5-tetrahydro-2- (5-methyl-1H-imidazol-4-yl) -methyl] -6- (phenylmethoxy) -5 - [(phenylmethoxy) -methyl] - 1 H-pyrido [4,3-b] indol-1-one (600mg) in absolute ethanol (80ml) and glacial acetic acid (4ml) was added at room temperature and atmospheric pressure to 10% palladium on carbon catalyst (50% aqueous Paste; 100 mg) for 24 hours. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was treated with 8% sodium bicarbonate solution (ca 150 ml) and filtered. The filtered solid was then washed with water (ca 100 ml), dissolved in ethanol (200 ml) and concentrated in vacuo to give a solid (320 mg) which was purified by FCC eluting with System A (100: 8: 1). was cleaned. In this way, the free base of the title compound (100 mg) was obtained. A solution of the free base (100 mg) in methanol (20 ml) was treated with maleic acid (39 mg). The solution was heated on a steam bath for 10 minutes and concentrated in vacuo. A solution of the residue in methanol (2ml) was treated with ether (ca 80ml) to give the title compound (100mg), mp 130 ° C. TLC (System A, 100: 8: 1) (2x elution), Rf 0.3.

Example 13 6-Fluoro-2,3,4,5-t-tetrahydro-5-metroyl · 2 - [(5-methyl-1H-imidazol-4-yl) -methyl} 1H-pyrido [4,3-b] indole A solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methylm H -imidazol-4-yl) -methyl] -1 H -pyrido [4, 3-b] indol-1-one (260 mg) in methanol (10 ml) was treated with ethereal hydrogen chloride and the mixture was concentrated in vacuo. The residue was stirred with ether (15ml) to give the title compound (230mg) as a solid, mp. 278 ⁰ C was bis 275 was obtained.

Water analysis found: 3.73% w / w = 0.75 mol H ₂ O

Analysis Found: C: 55.8; H: 5.3; N: 15.2 theoretical values for

C ₁₇ H ₁₇ FN ₄ O HCI 0.75H ₂ OC: 56.3; H: 5.4; N: 15.4%. Example 14

6-fluoro-2,3,4,5tetrahydro-5-methyl-2 - [(? 5-methyl-1H-lmld IZOL-4-yl) methyl] -1H-pyrldo [4,3-b] indole 1-on-benzoate

A solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2- (5-methyl-1H-imidazol-4-yl) -methylMH-pyrido (4.3- b) indol-1-one

(170mg) in methanol (10ml) was treated with benzoic acid (63mg). Ether (about 20 ml) was added to a Feststoffauszufällen which was filtered off to give the title compound (222mg), mp. Was 169 to 171 ⁰ C, was obtained.

Analysis found: C: 66.3; H: 5.4; N: 12,8

theoretical values for

C, ₇ H, ₇ FN O · C ₇ H ₆ O _2: C: 66.3; H: 5.3; N: 12.9%. Example 15

6-fluoro-2,3,4,5-tetrahydro-S-methyl-1-tlB-methyl-1H-imldazole ^ -d-methyl-1H-pyridoKS-blindol-i-one

A solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (100 mg) in N-methylpyrrolidinone (10 ml)

was treated with 4-toluenesulfonic acid monohydrate (17 mg) and 4-hydroxymethyl-5-methylimidazole hydrochloride (37 mg).

The mixture was then heated at 125 ^° C. for 18 hours, during which time three more portions of 4- Hydroxymethyl-5-methylimidazole hydrochloride (3 mg) were added after 1.2 and 3 hours, respectively. The solution was then in

Pour in 8% sodium bicarbonate solution (100ml) and extract with dichloromethane (3 χ 100ml). The combined

Extracts were concentrated in vacuo and the N-methylpyrrolidinone was distilled at 100 ⁰ C. The residue was through FCC eluting with System A (200: 8: 1) to give the title compound (100mg). TLC (System A,

100: 8: 1), Rf 0.3.

¹ H-NMRO 2.36 (3H, s); 3,12 (2H, t); 3.67 (2H, t); 3.90 (3H, s); 4.66 (2H, s); 6.07 (2H, s); 6.95-7.2 (2H, m); 7.80 (1H, d); 8.80 (1 H, s). Example 16

4-I2- (2-fluorophenyl) -2-methylhydrazinol-5,6-dihydro-1 - [(5-methyl-1 H -imidazol-4-yl) -methyl] -2 (1 H) -pyridinone (65 mg ) was treated with concentrated sulfuric acid (0.5 ml) and allowed to stand for 5 minutes. The solution was then neutralized with 8% sodium bicarbonate solution (30 ml) and then extracted with dichloromethane / ethanol (5: 1) (3 x 15 ml). The combined, dried organic extracts were evaporated to give an oil (52 mg) which was purified by FCC eluting with System A (200: 10: 1). In this way, the title compound (3 mg) was obtained. TLC (System A, 200: 10: 1), Rf 0.28

 The 'H NMR values obtained for this material were consistent with those of the product of Example 15.

Example 17

6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrldo [4,3-b] indole 1-one

A mixture of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2- [(4-methyloxazol-5-yl) -methyl] -1 H -pyrido [4,3-b] indole 1-on (180mg) and Formamide (20 ml) was heated at 180 ° C. for 18 hours and the solution was then cooled (O ⁴ C) with water (100 ml).

diluted and extracted with dichloromethane (3 x 100ml). The combined extracts were concentrated in vacuo and purified by FCCunter eluting with System A (100: 8: 1) to give the title compound (110 mg) was Fp.230 to 233 ⁰ C, was obtained.

The 'H NMR values obtained for this material were consistent with those of the product of Example 15.

Example of construction 18

6 · fluoro-2,3,4,5-tβ-tetrahydro · 5 · mβthvl · 2 ^ I (5 · mθthvl-1H · lmldazol4 · yl) · mβthγl] -1Hpyr: dot4,3 b] indole · 1-one

A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-2- | I5-methyl-1- (triphenylmethyl) -1H-imidazoM-yl-methylj-iH-pyrido [4,3-

b] indol-1-one (100mg) in dry DMF (15m) was treated with sodium hydride (73.2% dispersion in oil, 10.5mg) and stirred under nitrogen at room temperature for 20 minutes. Methyl iodide (2.3% v / v) solution in dry DMF; 1 ml) was added and the solution was stirred for a further 20 minutes. The reaction mixture was then added to water (100 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were washed with water (2 x 100 ml), dried and concentrated in vacuo to give a solid. This solid was in

THF (10 ml), water (10 ml) and glacial acetic acid (10 ml) were dissolved and heated at reflux for 3 hours. THF was in a vacuum

and the remaining solution was added to 2N sodium hydroxide solution (pH -> 14) and extracted with ethyl acetate (3 x 50 ml). The combined, dried organic extracts were adsorbed on silica and purified by FCCunti elution with System A (100: 8: 1) to give the title compound (45 mg), m.p. 234-235 °.

The Ή NMR values obtained for this material were consistent with those of the product of Example 15. Example 19

6-Huoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1 H -imidazol-4-yl) -methyl] -1 H -pyrido [4,3-b] indole -1 -on

A solution of phenylmethyl 4 - [(6-fluoro-2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3-b] indol-2-yl) -methyl ] -5-methyl-1H-

imidazole-1-carboxylate (100mg) in ethanol (20mL) and 2N hydrochloric acid (10mL) were heated on a steam bath for 10 minutes, the cooled reaction mixture was then added to water (5mL) and 2N sodium hydroxide solution (20mL) and extracted with ethyl acetate ( The combined, dried organic extracts were adsorbed on silica and purified by FCC eluting with System A (100: 8: 1) to give a solid which was triturated with ether.

In this way the title compound (50 mg), mp 232-233 ° C, was obtained.

The 'H NMR values obtained for this material were consistent with those of the product of Example 15.

The following Bei «·; iel describes a pharmaceutical preparation according to the invention, the 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1 H-imidazol-1-yl) methyl] -1 H-pyrido [4,3-b] indol-1-one as an active ingredient. Physiologically acceptable salts and / or solvates of this compound as well as other compounds of formula (I) and their physiologically acceptable salts and / or solvates may be formulated in a similar manner.

Tablets for oral administration

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

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

direct compression

Tablet mg / tablet

active substance 1.00 anhydrous lactose USNF 79,00 microcrystalline cellulose USNF 19.55 Magnesium Stearate BP 0.45

Compaction weight 90.00

* a degree suitable for oil compression.

The active ingredient is passed through a 60-mesh sieve and mixed with the anhydrous lactose, the microcrystalline cellulose and the magnesium stearate. The resulting mixture is compressed into tablets using a suitable tabletting machine provided with punches of 5.5mm diameter. Tablets of other strengths can be prepared by altering the ratio of active ingredient to lactose or the weight of the compaction and adjusting the punches accordingly.

Claims (4)

claims: 1. Process for the preparation of lactam derivatives of the general formula (I): ID where Im is an imidazolyl group of the formula: and R ^{1 is} a hydrogen atom or a group selected from C ₁ -I ₆ - and C3-7 cycloalkyl-C ₁ _4-alkyl group; η 'is 2 or 3; Q is a halogen atom or a group selected from hydroxy, phenylC ^ alkoxy, C ^ alkyl and cyano stands;
Q 'is a hydrogen or a fluorine atom, and the physiologically acceptable salts and Solvates thereof, characterized in that (A) a compound of the formula (II): (ID Q Κ " with a compound of the formula (I! I): X-In (III) or a protected derivative thereof, wherein X represents a group -CH ₂ L and L represents an exit atom or a leaving group and the reaction is carried out in the presence of a base or wherein X represents the group CH ₂ OH and the reaction in the presence of an acid at elevated Temperature is carried out, and if necessary, followed by removal of any existing Fichutzgruppen; or that one
(B) a compound of formula (IV): (IV) ¹ Vn or cyclizing a salt or protected derivative thereof, followed if necessary by removal of any protective groups present; or (C) a compound of formula (V): or reacting a protected derivative thereof with formamide followed, if necessary, by removal of any protective groups present; or that one (D) converting a compound of general formula (I) into another compound of formula (I) using conventional techniques; or (E) protecting groups of a protected form are removed from the compound of formula (I); and when the compound of formula (I) is obtained as a mixture of enantiomers, optionally the mixture dissolves to obtain the desired enantiomer; and / or, when the compound of formula (I) is in the free base form, optionally converting the free base to a salt. 2. The method according to claim 1, characterized in that compounds of formula I are prepared in which R ^{1 is} a hydrogen atom or a methyl, isopropyl, prop-2-inyl or cyclopentylmethyl group; Q is a fluorine or bromine atom or a hydroxy, phenylmethoxy, methyl or cyano group; Q 'is a hydrogen atom; and η is 2. 3. The method according to claim 1, characterized in that the compound 6-fluoro-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 thereof. 4. The method according to claim 1, characterized in that the following compounds are prepared:
2,3,4,5-tetrahydro-5,6-dimethyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1