SI8910436A - Lactam derivatives, processes for obtaining them and their pharmaceutical preparations - Google Patents

Description

GLAXO GROUP LIMITED CLARLES HOUSE 6-12 CLARLES STREET LONDON W14 8DH ENGLISH

LACTAMUS DERIVATIVES, PROCEDURES FOR OBTAINING THEM AND THEIR

PHARMACEUTICALS

1. TECHNICAL FIELD

The present invention relates to the field of organic and pharmaceutical chemistry. According to the International Patent Classification it belongs to the group C 07 and A 6lK.

2. TECHNICAL PROBLEM

The present invention relates to lactar derivatives, processes for their preparation, pharmaceuticals. preparations containing them and for their medical use.

More specifically, the invention relates to. compounds which. are potent and selective 5-hydroxytryptamine (5-HT) antagonists. · at 5-HT keo receptors, which are those located at the ends of primary efferent nerves. Receptors of this type are now designated 5-HT4 receptors and are also present in the central nervous system. They are 5-HT. widespread in nerve pathways in the central nervous system and disruption of these pies containing 5-HT causes as is known changes in behavioral syndromes such as mood, psychomotor. activity, appetite and memory.

3. BACKGROUND OF THE INVENTION

The present invention describes novel compounds.

The present invention provides a tricyclic lactam of general formula (I):

// \ • · - · N | ii I • · · * vvv _ i ¹ (I) in which Im represents an imidazolyl group of the formula:

·.

\\ / a β ^{3 represents} a hydrogen atom or a C ^ _ ^ alkyl (eg. Methyl or n-propyl), C ^^ alkenyl (eg. Prop-2-enyl), C ^^ alkynyl (eg. prop-2-ynyl), C1-6cycloalkyl (e.g. cyclopentyl), C1-6cycloalkylmethyl (e.g. cyclopentylmethyl), benzyl, · phenylmethoxyethyl, N, K-diC ^ alkylcarboxamido (e.g. N, N- dimethylcarboxamido) group, and their physiologically acceptable salts and solvates.

Suitable physiologically acceptable salts of the compounds of general formula (I) include addition salts with acids formed with organic or inorganic acids, for example hydrochlorides, hydrobromides, sulfates, alkyl or aryl sulfonates (e.g. methanesulfonates or p-toluenesulfonates), phosphates, acetates , citrates, succinate, tartarates, fumarates and maleates. Solvates may, for example, be hydrates.

The invention encompasses all optical isomers of compounds of general formula (I) and mixtures thereof, including their

3.

racemic mixtures, and all geometric isomers of the compounds of formula (I).

, When R ^ represents a slkenyl or θ ^ -4 alkynyl group, the double or triple bond does not have to be adjacent to the nitrogen atom.

A particularly suitable group of compounds of formula (I) is one in which it represents a methyl, n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl or N, N-dimethylcarboxamido group. '

Strong and selective 5-HT antagonism to 5-HT ^ recipe. The compounds of the invention are shown by their ability to inhibit 3- (5-methyl-1H-imidazol-4-yl) -1- N -ethyl-tp-1H-indol-3-yl / 1-propanone. in rats on the entorhinal cortex homogenate. (according to the general method described by G. Kilpatrick et al. in Nature, 1987, ·· 330 «746) and / or their ability to prevent the 5-HT-induced depolarization of the rat isolated vagus nerve preparation.

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

A particularly advantageous compound of formula (I) in terms of both strength and length of action is 2,3,4,5-tetrahydro-5-methyl-2 / (5-methyl-1H-imidazol-4-yl) methyl / -1H- pyrido / 4,3-b / -indole-lon and its physiologically acceptable salts and solvates. The primary salts of this compound are hydrochloride:. and maleate.

Compounds of formula (I), which antagonize the effect of 5-HT on 5-HT3 receptors, are useful in treating conditions such as psychiatric disorders (e.g. schizophrenia and mania); fear; and nausea and vomiting, especially those related to chemotherapy and radiotherapy in cancer. The compounds of formula (I) au are also useful in treating gaatric arrest; symptoms of gastrointestinal dysfunction such as occur with dyspepsia, ulcer org ^^ s ^ digestion, reflux oesophagitis, bloating and irritatingVsyndrome; migraines; and pain. The compounds of formula (I) may also be used in the treatment of drug and substance abuse, depression and dementia. and other memory disorders.

According to the invention, the invention also provides 1 farm- / 'ceutaki product containing at least one compound ^2- branched from the compounds of general formula (I) and their compounds;

acceptable aoles and solvates (e.g., hydrates) for use in human or veterinary medicine, and formulated for administration / by any conventional means.

Such preparations may be formulated at a convention _; using one or more physiologically acceptable carriers, and / or inert fillers.

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

The proposed dose of the compound of the invention for use in humans (average body weight of 70 kg) is 0-, 001 to 100 mg, preferably 0.01 to 50 mg, more preferably 0.1 to 20 mg of the active ingredient per single dose expressed as the weight of the free base, which can be applied, 1 to 4 times per .ί day. It is understandable that routine dosage adjustments may be necessary depending on the age and condition of the patient. The dosage will also be appropriate for the route of administration.

Compounds of general formula (I) and their physiologically acceptable salts or solvates may be prepared by the general procedure--. ' cima which are later shown. In the following description, groups and Im are as defined for compounds of general formula (I).

According to the first general method (A), the compound of general formula (I) can be obtained by alkylation of the compound of formula (II):

// \ λ ___ a

II il »·« \\ / \ / \ / • N · (II)

5.

or a protected derivative thereof, aa by the compound of formula (III):

LCH ₂ -Im (III) r · or a protected derivative thereof, wherein L represents an atom or a leaving group, such as a halogen atom (e.g., chlorine, bromine or iodine), or an acyloxy group (e.g. trifluoroacetyloxy or acetoxy), or a sulfonyloxy group (e.g. trifluoromethanesulfonyloxy, N -toluenesulfonyloxy or methanesulfonyloxy); and then where necessary by removing any of the. protection groups. L is primarily a halogen atom (e.g., a chlorine atom).

The reaction may be carried out in an inert solvent such as ether (e.g. dimethoxyethane, diglyme or tetrahydrofuran), substituted amide (e.g. dimethylformamide or R-raethylpyrrolidone) an aromatic hydrocarbon (e.g. toluene) ', ketone (e.g. acetone), or dimethyl sulfoxide, at a temperature between room temperature and 100 ° C in the presence of a base. Suitable bases include alkali metal hydrides (e.g. sodium hydride), alkali metal carbonates (e.g. sodium carbonate), alkali metal amides (e.g. sodium amide), alkali metal alkoxides (e.g. potassium t-butoxide). or. alkali metal hydroxides (e.g. sodium or potassium hydroxide). '

According to another general method (B), compounds of general formula (I) can be prepared by reacting a compound of formula (II) or a protected derivative thereof, with a compound of formula (IV):

HOCHg-Im (IV) in the presence of acid at an elevated temperature and then where necessary by removing any protecting groups. The acid may be, for example, an echo mineral acid (e.g., chloro and hydrogen acid) or hydrocarbylsulfonic acid (e.g.

] 3-toluenesulfonic acid). The reaction can conveniently be carried out in aprotonic high boiling point polar solvent as

6.

such as N-methylpyrrolidinone or dimethylacetamide, at a temperature in the range of 100 to 200 ° C or in alcohol (not e.g. isopropanol) or water at the reflux temperature of the solvent.

According to another general procedure (C), a compound of general formula (I) can be obtained by cyclizing a compound of formula (V):, - ...... ----. -— ......— fl / \ / \ • N Im fl I • · / \ f *

• 'W V X / • ·

I! L • ♦ \\ / \ ·· V— ^Y dl (V) in which W represents a hydrogen atom and Y represents a group NH, or W represents a halogen atom and Y represents a bond, or 'its salts or protected derivative, and then where necessary by removing any of the protecting groups.

According to one embodiment (a) of process (C), the reaction is. is achieved with a compound of formula (V) in which W represents a hydrogen atom Y represents a group NH and cyclization can be carried out in aqueous or non-aqueous 0m medium in the presence of an acidic catalyst.

. It is understood that these compounds of formula (V) may exist in the corresponding tautomeric form of enol hydrazone.

When aqueous medium is used, it can be water or a mixture of water and an organic solvent such as alcohol (e.g. methanol, ethanol or isopropanol) or ether (e.g. dioxane _: or tetrahydrofuran). An acid catalyst may, for example, inorganic acids such as concentrated hydrochloric acid. or sulfuric acid. In some cases, the acid catalyst may 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 acids (e.g. acetic acid) or ester (e.g.

7.

ethyl acetate), the acid catalyst may alternatively be Lewis acid such as boron trifluoride, zinc chloride or magnesium chloride. The cyclization reaction may be suitable. '*> No. to be carried out at temperatures from 20 to 200 ° C, preferably from 20 to 125 ° C.

Alternatively, cyclization according to embodiment (a) of process (C) may be carried out in the presence of polyphosphate. . Esters in a reaction medium which may contain one or more organic solvents, preferably halogen hydrocarbons, are chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane, or mixtures thereof. Polyphosphate ester is a mixture of esters obtainable from phosphorus pentoxide, diethyl ether and chloroform according to the procedure described in “Reagents for Organic. Synthesis '', (Pieser and Pieser, John Wiley and Sons, 1967).

According to another embodiment (b) of process (C), the reaction is achieved with a compound of formula (V) in which W represents a halogen atom, for example a chlorine atom or more preferably a bromine or iodine atom, Y represents a bond, and cyclization which is achieved photochemically .

The reaction can be conveniently achieved by irradiation with mercury lamps, primarily medium or high pressure mercury lamps. 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 achieved in the presence of a base such as a tertiary amine (e.g. triethylamine). '

Compared to another General Procedure (D), a compound of general formula (I) can be converted to another compound of formula (I) using conventional techniques. Such conventional techniques include hydrogenation, alkylation, and acylation using protection and deprotection where necessary.

Thus, according to one embodiment of the interconversion process (D), the hydrogenation can be used to

8.

converted alkenyl or alkynyl substituent to alkyl substituent? tuent, or alkynyl to alkenyl substituent. Hydrogenation can also be used to replace phenylmethoxymethyl. * a group with a Hydrogen atom. Hydrogenation according to the general process (D) can be carried out using conventional methods, for example, to use hydrogen in the presence of a catalyst as described in the European Patent. Specification No.242> 73

The term "alkylation" according to general procedure (D) encompasses the addition of groups such as au cycloalkyl. alkenyl or benzyl groupC. Thus, 'for example, a compound of formula (I) in which R1. 'represents ®kyl, ^C 3-4 ®1' ^Λ θ ^η ϋ »alkynyl, g cycloalkyl, cycloalkylmethyl, benzyl or phenylmethoxymethyl group can be obtained by alkylation of a compound of formula (I) in which r1 represents a hydrogen atom, using conventional methods. for example as described in published European Patent Specification No. 1 242973. According to the invention, reactions can be achieved using a suitable alkylating agent of the formula R ^ Z (where R ^ is the group to be introduced and Z is the atom or group to be removed), preferably in the presence of a base.

According to another embodiment of general procedure (D), a compound of formula (I) in which R ¹ represents an N, N-di y alkyl-carboxamido group can be obtained by acylation of a compound of formula (I) in which R 1 represents a hydrogen atom. Reactions maybe. are achieved "using a suitable acylating agent according to conventional methods, for example, as described in published European Ratable Specification No. 210840.

It is understood that in the above transformations, it may be necessary or desirable to protect any of the sensitive groups in the molecule of the compound in question to prevent undesired side reactions. For example, it may be necessary to protect the nitrogen atom of indole I / or imidazole, for example with arylmethyl (e.g. trityl), arylmethoxymethyl (e.g. phenylmethoxymethyl), alkyl (e.g. t-butyl), alkoxymethyl

9.

(e.g. methoxymethyl), acyl (e.g. benzyloxycarbonyl) or <aulfonyl (e.g., Ν, di-diethylaminoaulfonyl or j-toluenesulfonyl) group.

In this way, according to another general procedure (E), a compound of general formula (I) can be obtained by removing any of the protecting groups from the protected form of the compound of formula (I). Deprotection can be achieved using conventional techniques such as those described in Protective Groups in Organic Synthesis by T.W. Greene's 1 (John Wiley and Sons, 1981).

For example, arylmethoxymethyl N-protecting groups may be present. to cleave hydrogenolysis in the presence of a catalyst (e.g., palladium on activated carbon). The trityl group can be cleaved by hydrolysis with an acid (e.g. using dilute hydrochloric or acetic acid). The alkoxyalkyl group may be removed using a mineral acid (e.g. dilute hydrochloric 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). Sulfonyl. the group may also be removed by alkaline or acid hydrolysis, and the N, N-dimethylaminosulfonyl group may also be removed (e.g. from the asot atom of imidazole) by photolysis.

.... The compounds of formula (II) can be obtained by Beckmann displacement of the oxime of formula (VI):

HO \

N II / Λ Λ • * · ·

I --1--1- | • · · · \\ / \ / • N (VI)

10.

or a protected derivative thereof. Bekmann transfer can be achieved using conventional methods, for example using kiaelin (eg phosphoric or euphoric acid, or a mixture of hydrochloric acid, acetic anhydride and sulfuric acid) in an inert solution such as ether (e.g. dioxane). , an amide (e.g. dimethylformamide) or a hydrocarbon (e.g. toluene or cyclohexane), at elevated temperature, for example, 5θ to 120 ° C. Alternatively, a hydroxy group; the oxime of formula (VI) 'may be methylated to a leaving group such as chloride (using for example phosphorus pentachloride) or hydrocarbylsulfonate (e.g. mesylate or tosylate) or trifluoroscetate group (using conventional acylation methods). Subsequently, it is heated to a temperature of, for example, 20 to 150 ° C, in an inert solvent such as. as described above, the compound of formula (II) is obtained.

The compounds of formula (VI) can be obtained from the corresponding tricyclic ketone of formula (VII):

// \ / \ • · - - · · ·

I and i I N (VII) or a protected derivative thereof using conventional methods, for example using hydroxylamine hydrochloride in a solvent such as pyridine.

Compounds of formula (V) in which W represents the hydrogen atom and Y represents the group NH can be obtained by the reaction of compounds of formula (Vlil)

11.

, // \ i i \\ / * \.

NR5H, (VIII) or salts thereof, having the compound of formula (IX):

• s • · / \ / \ • N Im (IX) • · // \ / or its protected derivative, in a suitable solvent such as aqueous alcohol (e.g. methanol) and at a temperature of ^ for example, from 20 to 100 ° C.

j '

A protected derivative of a compound of formula (IX) may, for example, have a protected keto carbonyl group (e.g. as ether. It is understood that when using a compound of formula (IX) in which the keto carbonyl group is protected, it may be necessary to remove a protecting group to react with the compound of formula (VIII) The deprotection can be carried out by conventional methods, for example by hydrolysis with acids (e.g. using dilute sulfuric or hydrochloric acid). to be executed in situ.

Compounds of formula (IX) can be prepared, for example, by reaction of compounds of formula (X):

and (X)

12.

or a protected derivative thereof, with a compound of formula (III) wherein L is as previously defined, or a protected derivative thereof, using the conditions described in process (A).

Compounds of formula (V) in which W represents a halogen atom and Y represents a bond may be obtained, for example, by reaction of a compound of formula (XI):

• W // \ / / • '· · NH

I fl I \\ Λ / '\ / • N (XI) in which W represents a halogen atom, or a protected derivative thereof, with a compound of formula (III) in which L is as previously defined, or a protected derivative thereof, using the conditions described in process (A).

Compounds of formula (XI) can be prepared by reacting compounds of formula (XII):

W .// λ, /! s (XII) with the compound of formula (X), at elevated temperature.

______ The compounds of formula (III) and their protected derivatives are either known or can be obtained, for example, by the methods described in the German Application (German Offenlegungsschrift)

Who. 3740352.

Compounds of formula (VII) may be prepared, for example, by methods or processes analogous to those described by H. Iida et al. in J. Org. Chem., 1980, 45, 2938.

13.

The compounds of formula (IV), (VIII), (X), and (XII) are either known or can be obtained from known compounds by conventional methods.

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

• Physiologically acceptable salts may also be obtained from other salts, including other physiologically acceptable salts, of the compounds of formula (I), using conventional methods.

The individual enantiomers of the compounds of the invention can be obtained by separating the mixture of enantiomers (e.g., racemic mixtures) using conventional means, 'such as optically active acid for separation; (see, for example,' Ereel Stereochemi8try of Carbon Compounds' (McGraw Hill, I962 ) and Tables of Resolving Agents SH Wilen.

The methods described above for preparing a compound of the invention can be used to introduce the desired groups at any of the trimming steps of the desired compounds, and it is understood that these methods can be combined in different ways in such multi-phase processes. The sequence of reactions in multi-phase processes must, of course, be so chosen that the reaction conditions used do not affect the groups in the molecule that are desirable in the final product.

The invention is further illustrated by the following Intermediates and Examples. All temperatures are in ° C. Thin layer chromatography (m.p.) was performed on silica and fLash chromatography (FCC) on silica (Merck 9385).

Solvent system (A) as used for 'chromatography' indicates dichloromethane: ethanol: 0.88 ammonia. The organic extracts were dried, where indicated, over magnesium sulfate or sodium sulfate. The following are used

14.

<abbreviations: DMP - dimethylformamide; THP-tetrahydrofuran:

Ί

DME - dimethoxyethane. H-N.mr. spectra were obtained at 250 MHz • for dilute solutions in d ^ -dimethyl sulfoxide.

INTERMEDIATE 1

3.4- Dihydro-4-methylcyclopent / b / indole-1 (2H) -one oxime

3.4- Dihydro-4-raethylcyclopent / b / indol-1 (2H) -one (1.7 g) and hydroxyamine hydrochloride (1.925 g) in pyridine are heated at 60 ° C for 18 hours and cooled. The reaction mixture was evaporated in vacuo to a residue which further added 8% sodium bicarbonate (150 ml). Extraction with ethyl acetate (300 ml) afforded the suspension in an organic layer; this layer and the solids ¹ that accompany it are separated from the aqueous layer. The aqueous layer was re-extracted with ethyl acetate (250 ml). The combined organic extracts (and suspended solids) were evaporated to a residue, which was boiled with a mixture of ethanol (150 ml) and methanol (15θ ^m l) and cooled to about 5θ ° 0. The residue is adsorbed from this solution on PCC silica and applied to the PCC column. Elution with ethyl acetate / 3-10% methanol afforded the title compound (1.69 g) mp 219-224 ° C (dec.).

INTERMEDIATOR 2

2,3,4,5-Tetrahydro-5-methyl-1H-pyrido / 4,3-b / indol-1-one

3.4- Dihydro-4-methylcyclopent / b / indole-1- (2H) -one oxime (1.53 g), polyphosphoric acid (40 g) and dioxane (15 ml) are heated to 110-120 ° C 2.2 hours under nitrogen. The reaction mixture was cooled and treated with 2N sodium carbonate solution (1 liter). The suspension was extracted with ethyl acetate (4 x 400 ml) and the combined extracts dried. Evaporation gave a solid (1.43 g) which was recrystallized from ethyl acetate / cyclohexane. This solid was * purified by PCC, eluting with system A (200: 10: 1) to give a solid (1.26) which recrystallized from ethanol to give the title compound (960 mg), m.p. 234r238 ° C

15.

INTERMEDIATE 3

5,6-Dichloro-4- (phenylamino) -1 (2H) -pyridinone

A mixture of 2,4-dioxopiperidine (1.13 g) and aniline (930 mg) was heated to 120 ° C under a stream of nitrogen for 15 minutes. The resulting solid was triturated with ether and filtered to give the title compound (1.74 g), mp 235238 ° C.

INTERMEDIATOR 4

2 _> 3,4,5-Tetrahydro-1H-pyrido / 4,3-b / indol-1-one

A solution of 5,6-dihydro-4- (phenylamino) -1 (2H) -pyridinone (1.5 g) and psladium acetate (150 mg) in dry DMF (50 ml) was treated with cupric acetate (3.2 g) ) and the resulting mixture was heated under nitrogen to 12O-13O ° G for 1.5 hours. The mixture was then concentrated in vacuo to give a solid which was triturated with 2N hydrochloric acid (250 ml). The acid was decanted, and the residual solid was extracted with ethyl acetate for 18 hours. The separated acid was basified with 2N sodium hydroxide and extracted with ethyl acetate (3 x 100 ml). These organic extracts are combined with earlier ethyl acetate extracts. and adsorbed on silica. Purification by PCC elution with system A (100: 8: 1) gave the title compound (874 mg), m.p. 212215 ° C

INTERMEDIATOR 5

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

A solution of 2,3,4,5-tetrahydro-1H-pyrido / 4,3-b / indol-1-one (1.12 g) in dry DMF (60 ml) was treated with sodium hydride (60% dispersion) in oil; 480 mg) and the resulting mixture was stirred under nitrogen

16.

until the violent gas release (penning) stops.

The mixture was then cooled to 0 ° C and benzyl (chloromethyl) ether (10% w / v solution in DMF; 0.835 ml) was added over 10 minutes. Stirring was continued for a further 5 minutes and then water (10 ml) was added. The reaction mixture was concentrated in vacuo to give an oil which was dissolved in ethyl acetate (100 mi) washed with water (3 x 100 ml). The organic phase is dried and adsorbed on FCC silica. Purification by FCC elution with system A (150: 8: 1) gave the title compound (1.1 g), m.p. 133-135 ° C.

Intermediates 6 and 7 were obtained in a similar manner to intermediate 5, i. by treating 2,3,4,5-tetrahydro-1H-pyrido / 4,3b / indol-1-one with sodium hydride and then with a suitable alkylating agent. Isolation and purification of the product was as described for Intermediate 5 unless otherwise specified

INTERMEDIATE 6? 4,5 > 4,5-Tetrahydro-5- (phenylmethyl) -1H-pyrido / 4,3-b / indol-1-one

2,3,4,5- ^T Etrahydro-1H-pyrido / 4,3-b / indol-1-one (559 mg) was treated with sodium hydride (73% dispersion in oil; 197 mg) and then mixed with benzyl bromide (513 mg) at room temperature for 30 minutes. Purification by FCC, eluting with dichloromethane: ethanol (80: 1) gave the title compound (347 mg), mp 209-212 ° C.

INTERMEDIATE 7

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 / indol-1-one (950 mg) was treated with sodium hydride (60% dispersion in oil; 408 mg) and then mixed with cyclopentyl (methylsulfonate) (909 mg) at room temperature for 7 days. Solids obtained ^ aa FCC is further purified by gentle evaporation from solution

17.

in methanol to give the title compound, m.p. 179181 ° C.

INTERMEDIATE 8

2,3,4,5-Tetrahydro-2 - [(5-niethyl-1- (trphenylmethyl) -1H-imidazol4-yl) methyl] -1H-plrido / 4,3-b / indol-1-one

A solution of triphenylmethyl chloride, (3.36 g), in dry DMF (40 ml), was added dropwise to a solution of 2,3,4,5-tetrahydro-2 - [(5methyl-1-yl] -imide-zol-4-yl). ) π-ethyl / -1H-pyrido / 4,3 “b / indol-1-one (2.8 g) in dry DMF (50 ml) · containing triethylamine (1.52 g), which was miscible. When the addition is complete, the mixture is stirred overnight. The mixture was then poured into water (1000 ml) and the resulting suspension extracted with ethyl acetate (3 x 300 ml). The combined organic extracts were washed with water (2 x 500 ml), dried and concentrated on silica. FCC elution with system A (100: 8 τ l) gave the title compound (4.3 g), m.p. Mp 235-236 ° C. .

INTERMEDIATOR 9

5.6- Dihydro-4-methoxy-1- [5-methyl-1- (triphenylmethyl) -1Himidazol-4-yl] methyl] -2 (1H) -pyridinone

Sodium hydride (8% dispersion in oil; 36 ° mg) was suspended in dry DME (50 ml) under nitrogen and added gently.

5.6-Dihydro-4-methoxy-2 (1H) -pyridinone (1.27 g) in dry DME (20 ml). The resulting suspension was stirred for 1 hour at 20 ° C. 4- (Chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidezole (3.72 g) in dry DME (50 ml) was added and after the initial reaction had dropped, the mixture was heated at 50 ° C for 4 hours and then cool. Methanol (5 ml) was added dropwise and the solvent was removed in vacuo. An 8% aqueous sodium bicarbonate solution (300 ml) was added and the residue and the resulting solution was extracted with dichloroipetane (2 x 300 ml), dried and evaporated in vacuo to give an oil which was purified by FCC elution with system A (200: 8: 1) to give the title compound (2.84 g), mp 181-184 ° C.

18.

INTERMEDIOR 10

- —— ✓

2.4- Dloflo-1 - [(5-methyl-1H-imidazol-4-yl) methyl / piperidine

To a solution of 5,6-dihydro-4-methoxy-1- [5-methyl-1- (triphenylmethyl) 1H-imidazol-4-yl] methyl / -2 (1H) pyridinone (500 mg) in THP (4 ml ) hydrochloric acid (5M; 1 ml) was added and the mixture was stirred for 1 hour at 50 ° C. The solvent was removed in vacuo, triethylamine (1 ml) added and the mixture was evaporated to dryness again. FCC of the residue Eluting with ethyl acetate: methanol: triethylamine (8: 4 with 1) yes.1 the title compound (139 mg), m.p. 100-10 (? C (raap.).

INTERMEDIOR 11

5,6-Dihydro-1 - [(5-methyl-1H-imidazol-4-yl) methyl] -4- (2-methyl2-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 N-methylphenylhydrazine (26 mg) was added. The mixture was stirred for 1 hour and the solvent was removed in vacuo. The residue was purified by FCC elution with the system

A (75: 8: 1) to give the title compound (24 mg) as a solid, m.p. (System A, 75: 8: 1) Rf 0.27.

INTERMEDIATOR 12

N _t N, 5-Trimethyl-4 - [(trimethylsilyl) oxy / methylZ-1H-imidazol-lsulfonamide ~

A suspension of 4- (hydroxymethyl) -5-methylimidazole hydrochloride (14.9 g) in dry dichloromethane (500 ml) containing triethylamine (50 g) was treated with trimethylsilyl chloride '(21.7 g) and the reaction mixture stirred at room temperature. overnight. . Dimethylsulfamoyl chloride (14.3 g) was added and the reaction mixture was stirred again overnight at room temperature. The resulting suspension was filtered and the collected solid was washed with dichloromethane (100 ml). The filtrate was concentrated on silica and purified by FCC eluting with hexane: ether (4: 1) afforded the title compound as an oil (7.2 g), m.p.c. (ether) Rf 0.5.

ICTERMEDIER 13

4- (Hydroxymethyl) -N, K, 5-trimethyl-1H-imidazole-1-sulfonamide

A solution of N, N, 5-trimethyl-4 - [(trimethylsilyl) oxy / methyl / -1Himidazole-1-sulfonamide (2.59 g) in dry THP (50 ml) was treated with tetrabutylammonium fluoride solution (IM solution in THP (10 ml) and THP was immediately removed in vacuo. The residue was partitioned between water (loo ml) and dichloromethane (loo ml) .., .. ... and aqueous. The layer was 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. 134-136 ° C.

IKTERMEDIER 14.

4- (Chloromethyl) -N, N, 5-trimethyl-1H-imidazole-1-sulfonamide

Suspension. 4- (hydroxymethyl) -K, N, 5-trimethyl-1H-imidazole-lsulfonamide (2.86 g) in dry dichloromethane (200 ml) containing DMP (θ, 5 ml) was treated dropwise with a solution of thionyl chloride (1.178 g) in dichloromethane (10 ml), - the reaction mixture is cooled in ice as it is added and is under nitrogen. When the addition is complete (about 5 minutes) · stirring is continued for another 3θ minutes at 0 ° C. Then water (200 ml) was added and the organic phase was separated, washed with 8% sodium bicarbonate solution (100 ml), dried and concentrated to give the title compound (2.3 g) as a solid, m.p. 115-118 ° C.

IKTERMEDIER 15

5,6-Dihydro-4 - / (2-iodophenyl) methylamino / - (1H) -pyridinone

A mixture of 2-iodo- (K-methyl) aniline (1.17 g) and 2,4-dioxopiperidine (565 mg) was heated under a stream of nitrogen for 7 hours at 110-120 ° C. After cooling, the reaction mixture was dissolved in methanol and the solution was adsorbed on FCC silica. Purification

20.

PCC elution with system A (150: 8: 1) gave the title compound (1.03 g), m.p. Mp 163-164 ° C.

INTERMEDIATE 16

N, N, 5-Trinethyl-4- [1,2,3,6-tetrahydro-4 - [(2-iodophenyl) - _: methylamino] -6-oxo-1-pyridinyl] methyl-1H-imidazol-1- sulfonamide

A suspension of 5,6-dihydro-4 - / (2-iodophenyl) methylamino / -2 (1H) pyridinone (984 mg) in dry DME (50 ml) was treated with sodium hydride (60% dispersion in oil; 140 mg). and the mixture was stirred under nitrogen for 6 hours, 4- (Chloromethyl) -N, N, 5-trimethyl-1H-imidazol-1-. sulfonamide (832 mg) was added and the mixture was stirred overnight at 60 ° C. After cooling, the reaction mixture was poured into water (100 ml) and the mixture extracted with ethyl acetate (2 x 50 ml). The combined, · dried, organic extracts were concentrated and the resulting solid was purified by PCC elution with system A (150: 8: 1) to give the title compound (712 ing), m.p. (System A, 150: 8: 1) Rf 0.41

INTERMEDIATE 17

N, N, 5-Trimethyl - / (2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido-N- [b / ind] -

A solution of dimethylsulfamoyl chloride (0.107 ml) in dry dichloromethane was added to a solution miscible with 2,3,4,5-tetrahydro5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] - 1H-pyrido / 4,3-b / indol-1-one (0.294 g) and triethylamine (0.2 ml) in dry dichloromethane (30 ml) under nitrogen, and the mixture was refluxed. After cooling, the solution was concentrated on PCC silica and purified by PCC elution with system A (150: 8: 1) to give an oil. This oil was triturated with ether to give a solid which was further purified by gentle evaporation from a solution in ethyl acetate to give the title compound (122 mg), m.p. 194 - 196 ° C, m.p. (System A, 100: 8: 1) Rf 0.43.

21.

INTERMEDIATOR 18

Phenylmethyl 5-methyl-4 - [(2,3,4,5-tetrahydro-5-methyl-1-oxo-1Hpyrido / 4,3-b / indol-2-yl) methyl] -1H-imidazol-1- carbokilate ~~

A solution of benzyl chloroformate (0.28 ml) in dichloromethane (10 ml) was added to a solution miscible with 2,3,4,5-tetrahydro-5methyl-2- [(5-methyl-1H-imidazol-4-yl) methyl / -1H-pyrido / 4,3-b / indol-1-one (294 mg) - and triethylamine (o, 4 ml) in dichloromethane (30 ml at.30 ° C under nitrogen, and the mixture stirred over Z Then, concentrate on FCC silica and purify · with PCC elution with system A (200: 8: 1) to give the title compound (62 mg), tlc, (system A, 100: 8: 1)

Rf 0.50.

IKTERMEDIJER_19 '

2.3.4.5- TetahahidO-2 - // 1- (methoxymethyl) -5-methyl-1H-imidazol-N-1-methyl 1 / -5-methyl-1K-pyrido / 4,3-b / indole-1 -on and ~

2.3.4.5- Tetrahydro-2 - // 1- (methoxymethyl) -4-niethyl-1H-imidazol5-yl / methyl / -5-methyl-1H-pyrido / 4,3-b / indol-1-one ~~

A solution of chloromethyl methyl ether (0.26 ml) in dichloromethane (10 ml) was added to a solution of 2,3,4,5-tetrahydro-5-methyl-2 / (5-methyl-1H-imidazol-4-yl) methyl 1 H -pyrido / 4,3-b / indole-lone (500 mg) and triethylamine (0.49 ml) in dichloromethane (50 ml) at 20 ° C, stirred and kept under nitrogen, and the solution stirred 4 days. It was then partitioned between dichloromethane (50 ml) and sodium bicarbonate solution (2 x 50 ml). The organic extra was dried, concentrated on FCC silica, and then purified by FCC elution with system A (100: 8: 1) to give. the title compounds (139 mg). One portion of the title compounds (64 mg) was taken up with warm ethyl acetate and purified by slow evaporation from ethyl acetate whereby the title compounds would be purified.

22.

Found: C 67.3; H, 6.9; N, 16.5;

^C 19 ^H 22 ^N 4 ° 2 P ° ^{needed σ} 67,4; H, 6.6; N 16,6%

EXAMPLE 1

2,3> 4 »5-Tetrahydro6-5-methyl-2 - [(5-niethyl-1H-indolazol-4-yl) methyl] -1H-pyrido / 4,3-b / indol-1-one maleate ~

A mixture of N, N-S-tetrahydro-S-methyl-1H-pyrido / N-b / indole-lone (0.6 g) and about 78% of the dispersions of sodium hydride in mineral oil (0.109 g) in dry DMP (15 ml) stirred under nitrogen at 50 ° C until hydrogen release ceases (about 1.5 hours). The mixture was cooled to 40 ° C and a solution of 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (1.12 g) in dry THP (15 ml) was added. The reaction was stirred for 3 hours at 40 ° C, 16 hours at 20 ° C and a further portion of 4- (chloromethyl) -5-methyl-1 (triphenylmethyl) -1H-imidazole (1.12 g) was added in dry THP (15 ml). The resulting mixture was heated at 40 [deg.] C. for 3 hours, quenched with water (20 ml) and etheracetic acid (20 ml) and heated at 100 [deg.] C. 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 (resin) (about 1 g). This resin was adsorbed on silica and purified with PCC eluting with system A (100: 8: 1) to give a light brown solid (0.8 g) m.p. 238-24 ° C (dec.). This solid was dissolved in a mixture of warm ethanol and methanol (1: 1; 100 ml) and treated with an ethanolic solution of maleic acid (318 g). The resulting solution was concentrated to approximately 20 ml and diluted with a dry diet! ether (about 8 ml) to precipitate the title compound (0.75 g) as an off-white solid, m.p. 160-162 ° C.

23.

Found: C, 61.6; H 5 ·, 5; N, 13.6;

' ^C 17 ^H 13 ^N 4 ° * ^C 4 ^H 4 ° 4 do you ^{need c 6l} «5i ^H 5,4? N, 13.8%.

f

EXAMPLE 2

2,3,4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5 / (phenyl-methoxy) methyl / -1H-plrido74,3-b / indole-1 -on-maleate

Suspensions-2,3,4,5-tetrahydro-5 - [(phenylmethoxy) methyl7-1Hpyrido / 4,3-b / indol-1-one (-920 mg) in auve DME (75 ml) was treated with sodium hydride (60% dispersion in oil; 180 mg) under nitrogen and the reaction mixture was stirred for 6 hours at 60 ° C.

Then 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1Himidazole (1.11 g) was added and the mixture was stirred overnight at 60 ° C.

Acetic acid (10 ml), water (10 ml) and THP (10 ml) were then added and the resulting solution was refluxed for 6 hours. After cooling, 2N sodium hydroxide solution (loo ml) was added and the resulting suspension was extracted with dichloromethane (3 x 100 ml). ^s ' combined, dried organic extracts were adsorbed on PCC silica and PCC was eluted 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 ml) and the resulting solution was treated with melaic acid (58 mg). The solution was heated for 10 minutes, cooled and dry ether added to precipitate the title compound (170 mg), mp 165-168 ° C.

Analysis of water found 0.22% w / w = 0.06 mol H ^ O.

Found: C 64.5; H, 5.6; N, 10.7;

^C 24 ^ 24 ^N 4 ° * ^C 4 ^ 4®4 · ⁰ ' ⁰ ^ Hg ⁰ required: .0 65.0; H, 5.5; R 10.8%. Examples 3 and 4 were done in a similar manner to Example 2.

EXAMPLE 3

2.3.4.5- Tetrahydro-5- (phenylmethyl) -2 - [(5-methyl-1H-imidazol4-yl) -methyl] -1H-pyrido / 4,3-b / indol-1-one maleate monohydrate

2.3.4.5- ^ Etrahydro-5- (phenylmethyl)-)-pyrido / 4,3-indol-1-one (960 mg) was treated with sodium hydride (73% dispersion in oil; 132 mg) and then ae mixed 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 PCC eluting with system A (175 ^: 8: 1). Maleate cropping gave the title compound (420 fng), mp 198-200 ° C, t. 1 · c. (System A 100: 8: 1) Rf 0.3.

EXAMPLE 4

5- (Cyclopentylmethyl) -2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido / 4,3-b / indol-1- he mateaT

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 ) and then mixed with 4- (chloromethyl) 5-methyl-1- (triphenylmethyl) -1H-imidazole (280 mg). Free base title. Compounds ae obtained as Solids (96 mg) by PCC eluting with system A (200: * S: 1). Maleate treatment gave the title compound (60 mg) m.p. 81-83 C,. t.i.c. (System A, 100: 8: 1) Rf 0.20.

EXAMPLE 5

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

Solution 2,3 »4,5-tetrahydro-2 - [(5-methyl-1- (triphenylmethyl) -1Himidazol-4-yl] methyl] -1H-pyrido / 4,3-b / indol-1-one ( Teg mg) in dry DMF (25 ml) was treated with sodium hydride (60% · dispersion in oil; 3θ mg) and the mixture was stirred at room temperature under nitrogen for 15 minutes. N, N-dimethylcarbamoyl chloride (1 M solution in DMF; 1 ml) was then added and the solution stirred at

25.

room temperature for another 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.times.50 ml) The combined organic extracts are per _u with water (2 x 100 mL) and concentrated to provide an oil. The θνο oil was dissolved in a mixture of water (10 ml) of glacial acetic acid (10 ml) and THF (10 ml) and the solution was heated at reflux for 1.5 hours. After cooling, the solution was made basic with the addition of 2N sodium hydroxide (100 ml) and the resulting mixture was extracted with et.il. acetate. .... (2 x 75 ml). The combined dried organic extracts were adsorbed on FCC silica and the free base of the title compound (110 mg) was obtained by PCC 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) in a steam bath for 5 minutes. After cooling, dry ether (3 ml) was added to precipitate the title compound (lo5 mg), mp 161-163 ° C.

Analysis of water found 1.85% w / w = 0.49 mol H ^ O.

Found: C 57.8; H, 5.4; N 14,3 » ^C 19 ^Ii 21 ^N 5 ° 2 * ^C 4 ^ 4 ° 4 * θ» 49. ^Η 2 ° Funeral: C 68.0; H, 5.5; N, 14.7%.

Examples 6 and 7 would be similar to Example 5 unless otherwise indicated.

EXAMPLE 6

2,3,4,5-Jetrahydro-2 - [(5-methyl-1H-ynidazol-4-yl) methyl] -5- (2'-propynyl) -1H-pyrido / 4,3-b / indole -l-he maleate

Suspension of 2,3 »4,5-tetrahydro-2 - // 5-methyl-1- (triphenylmethyl) 1H-imidazol-4-yl / methyl / -1H-pyrido / 4,3-b / indol-1-one (522 mg) and potassium carbonate (276 mg) in dry acetone (75 ml) was treated with propargyl bromide (LM solution in acetone "2 ml) and the mixture was heated at reflux overnight ^with i. After cooling, the excess acetone is removed in vacuo whereby. an oil was obtained which was partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was washed with ethyl acetate (5θ ml) and the combined organic extracts were concentrated in vacuo.

Deprotection, treatment and purification give the free base of the title compound (loo mg) as a solid. Maleate trimming gave the title compound (89 mg) m.p.

202-2O5 ° C, m.p. (System A, 100: 8: 1) Rf 0.29.

EXAMPLE 7

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- ^τ τrahydro-2 - // 5-methyl-1- (triphenylmethyl) -1H-imidazol4-yl / methyl / -1H-pyrido / 4,3-b / indol-1-one (1.0 g ) was treated with sodium hydride (60% dispersion in oil; 114 mg) and then mixed with allyl bromide (460 mg) for 1 hour. Release of. · - · · Protection, treatment and purification give the free base of the title compound (380 mg) as a solid. Maleate education gives the title compound (l60 mg) tic (system A, 100: 8: 1)

Rf 0.3.

Analysis found: C 63.2; H, 5.5; N, 12.5;

^C 19 ⁱⁱ 2 ^{O N} 4 ^{O, C} 4 ^H 4 ° 4 P ° ^needed: C 63.3; H, 5.5; N, 12.8%.

EXAMPLE 8

5- Cyclopentyl-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4yl) methyl] -1H-pyrido / 4,3-b / indol-1-one maleate ~

A solution of 2,3,4,5-tetrahydro-2 - [(5-methyl-1- (triphenylmethyl) -1Himidazol-4-yl] methyl] -1K-pyrido / 4,3-b / indol-1-one ( 523 g) in dry DMF (30 ml) was treated with sodium hydride (60% dispersion in oil; 46 mg) and stirred for 15 minutes at 21 ° G under nitrogen. Cyclopentyl bromide (298 mg) was then added dropwise, and the mixture was stirred for 1 hour and then refluxed for 4 hours. The solution was left at 21 ° C for 2 days and then treated with a mixture of acetic acid (7 ml), water (7 ml) * and THF (8 ml). The resulting solution was refluxed for 4 hours then basified with 2 N sodium hydroxide and extracted with dichloromethane (3x25 ml). The combined extracts are washed with water

27.

J (2 × 5θ ml) was concentrated in vacuo and purified by PCC eluting with system A (100: 8: 1) to give the free base of the title compound (42 mg) as a solid. Maleate formation gives the title compound (38 mg), mp 180 ° C (dec.), Tlc (system A _? 100 s 8: 1)

Rf 0.3.

EXAMPLE 9 '.......

2.3.4.5- Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5-propyl-1H-plrido / 4,3-b / indole-1-one maleate

Solution of 2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propenyl) -1H-pyrido / 4,3-b / indole- 1-one (248 g) in a mixture of ethanol (20 ml) and 2N hydrochloric acid (0.5 ml) was hydrogenated at room temperature and at atmospheric pressure, above pre-reduced 10% palladium oxide on carbon as catalyst (50%) water paste; 5θ mg). The mixture was filtered and evaporated in vacuo. The residue was basified with 2N sodium

Ve ^ eiiRsa ^ 0¾ ³ ^ m ° ff ^a and * ^ski evaporated to give the free base of the title compound (258 mg) as a solid. Maleate education gives the title compound (345 mg) tlc (System A 100: 8: 1)

Rf 0.4. '' '

Analysis of water found 1.13% w / w = 0.28 mol HgO.

Analysis found: C 62.1; H, 5.9; N, 12.5;

^ 19 ^ 22 ^Ν 4θ * θ4 ^ 4θ4 θ · ^ θ required: C 62.2; H, 6.0; N, 12.6%.

EXAMPLE 10

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

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

Analysis found: C, 60.3; H, 5.2; N, 13.8;

^C 16 ^H 16 ^K 4 ° - ^C 4 ^H A required: C 60.6; H, 5.1; N, 14.1%.

EXAMPLE 11.

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- Etrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) -. Methyl / -1H-pyrido / 4,3-b / indol-1-one (1.00 g) was suspended in ethanol (40 ml) and concentrated hydrochloric acid (1.00 ml) was added. The mixture was heated to 40 ° C and activated 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 with about 20 ml and allowed to cool to 20 ° C. Ether is added. (40 ml) was stirred for 5 minutes and the mixture was stored overnight at 4 ° C. The resulting precipitate was filtered, washed with ether (2 x 10 ml), dried in vacuo. at room temperature for 2 hours and then at 70 ° C for 7 hours to give the title compound (0.95 g>, mp 288-291 ° C.

Analysis found: c 61.4; H, 5.8; ' N, 16.7; Cl 10.7;

^C 17 ^H 18 ^N 4 ^{O, HCl} P ° required ^: C 61.7; H, 5.8; N, 16.9; Cl 10.7 '%.

29.

EXAMPLE 12

2.3.4.5- Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido / 4,3-b / indole-1-one sulfate

2.3.4.5- Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido / 4,3-b / indol-1-one (o, 81 g) was suspended in absolute ethanol (6 ml) and warmed to 50 ° C with concentrated sulfuric acid (0.15 ml). More ethanol (4 ml) was added and the mixture was mixed with activated charcoal (0.1 g). The suspension was then filtered and the collected solid was washed with ethanol (about 3 ml). The resulting filtrate was stirred for about 1 hour at room temperature, tert-butyl methyl ether (10 mL) was added gently and the mixture was stirred for 20 minutes. The tslog was filtered, washed with ethanol: tert. butyl methyl ether (1: 1; 6 ml) then tert. butyl methyl ether (6 ml) and dried in vacuo at 40 ° C for 4 days to give the title compound (0.4 g), m.p. 2O5-2O9 ° C.

Analysis found: C 49.51 'H 5.6; N, 13.5; S 8.4;

^C 17 ^H 18 ^N 4 ° * ^{1,1 H} 2 ^SO 4 P ° required ^c 49.9; ^H, 5.4; N, 13.3; With 8.4%. EXAMPLE 13

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

A suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido / 4,3-b / Indoll-one (400 mg) in dry DME (50 ml) was treated with sodium hydride (60% dispersion in oil; 100 mg) and the mixture was stirred at 60 ° C under nitrogen for 6 hours 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H imidazole (474 mg) was added and the reaction mixture was stirred overnight at 60 2 N hydrochloric acid (10 ml) and water (10 ml) are added, the mixture is stirred and refluxed for 6 hours. After cooling, the mixture is basified with 2N sodium hydroxide and the resulting mixture is extracted with ethyl acetate (2 × 5θ ml) .The combined dried organic extracts were concentrated on FCC silica.

30.

. and purified by PCC elution aa system A (150: 8: 1) to give the title compound (352 mg) as a solid, m.p.c. (system A, 100: 8: 1) Rf 0.28.

2.2 (3H, s), 3.04 (2H, t), 3.62 (2H, t), 3.72 (3H, s), 4.53. (2H, s), 7.1-7.28 (2H, m), 7.43 (1H, s), 7.47-7.55 (1H, dd), 7.94-8.03 (1H, dd).

EXAMPLE 14

2,3,4,5-Ietrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido / 4,3-b / indol-1-one " . Solution 2,3,4,5-tetrahydro-2 - // 5-methyl-1- (triphenylmethyl) -1Himidazol-4-yl / methyl / -1H-pyrido / 4,3-b / indol-1-one ( 261 mg) in dry DMP (25 ml) was treated with sodium hydride (60% dispersion in oil; 30 mg) and the mixture was stirred at room temperature under esotor for 15 minutes. Iodomethane (0.5M solution in DMP; 2 ml) was then added and stirring continued for 15 minutes. The reaction mixture was then poured into water (100 ml) and the resulting suspension extracted with ethyl acetate (2 χ 5θ ml). The combined organic extracts were washed with water (2 x 100 ml), dried and concentrated to give a solid. This was dissolved in a mixture of water (10 ml), THP (10 ml) and glacial vinegar (10 ml) and refluxed for 2 hours. After cooling, the residual THP is removed in vacuo and the residual solvent is made alkaline (at pH 14) by the addition of 2N sodium hydroxide. The resulting suspension was extracted with ethyl acetate (2 x SC ml and the combined, dried organic extracts were concentrated on silica (Merck 7335). PCC elution with system A (100: 8: 1) gave the title compound (81 mg) as a sol * stu substance. ^ Hn.mr and tlc results obtained for this material were in agreement with those obtained for the product of Example 13.

EXAMPLE 15

2,3,4,5-Etrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrrolidin-4,3-b / indol-1-one *

5,6-Dihydro-1 - /. (5-methyl-1H-imidazol-4-yl) raethyl / -4- (2-methyl2-phenylhydrazino) -2 (1H) -pyridinone (20, about mg) was dissolved. in 98% sulfuric acid (1 ml) and the solution is stirred for 5 minutes at 25¾ The mixture is carefully poured into an 8% aqueous solution of .ria'trium bicarbonate (60 'ml) and extracted with 10% methanol: dichloromethane (2 x 60 ml). The combined dried organic extracts were evaporated in vacuo to leave an oil which was purified by PCC elution with system A (100: 8: 1) to give the title compound (13.5 mg) as a solid. ^ H-n.m.r. and so.c. the results obtained for this material are consistent with those obtained for the product of Example 13.

EXAMPLE 16

2,3,4,5-Etrahydro-5-tnetyl-2 - [(5-tnetyl-1H-imidazol-4-yl) methyl] -1H-pyrido / 4,3-b / indol-1-one

Solution N ₁ N, 5-Trimethyl-4- [1,2,3,6-tetrahydro-4 - [(2-odophenyl) methylamino] -6-oxo-1-pyridinyl] methyl-1H-imidazole-1-sulfonamide (264 mg) in a mixture of dioxane and acetonitrile (2: 1;

200 ml) containing 'triethylamine (2 ml) was irradiated in a' pyrex immersion vessel with 125 W mercury lamp at room temperature for 24 hours. The reaction mixture was then concentrated on PCC silica and purified by PCC elution with system A (150 : 8: 1) To give the title compound (87 mg) as a solid. ^ H-n.m.r and t.l.c. the results obtained for this material were in agreement with those obtained for the product of Example 13v and

EXAMPLE 17

2t3,4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-plrido / 4,3-b / indol-1-0n "

Solution of N, N, 5-trimethyl - / (2,3 »4,5-tetrahydro-5-methyl-1-oceanol-pyrido / 4,3-b / indol-2-yl) methyl / -1H-imidazole- l-8ulfon _am i _{(i a} (86 mg) in 2N hydrochloric acid (10 ml) and absolute ethanol (2 ml) was heated at 100-110 ° C for 4 hours. tteakciona mixture is then cooled down and added to 2N sodium hydroxide ( The resulting solution was extracted with dichloromethane (2 x 50 ml) and the combined, dried organic extracts were concentrated on · PCC silica and purified by PCC elution with system A (100: 8: 1) to afford obtained solid (36 mg) This was taken up with warm ethyl acetate and purified by slow evaporation to give the title compound (12 mg) AH-nmr and tlc results obtained for this material were in accordance with those obtained for the product of the example 13 ·

EXAMPLE ~ 18

2,3,4,5- ^T Etrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido (4,3-b) -indol-1-one ^-

A solution of N, N, 5-trimethyl- / 2,3,4,5-tetrahydro-5-methyl-1-oxo-1.

1H pyrido / 4,3-b / indol-2-yl) methyl / -1H-imidazole-1-sulfonamide (401 mg) in a mixture of dioxane (150 ml) and acetonitrile (150 ml) containing triethylamine (1 ml) irradiates at room temperature with a medium pressure mercury lamp for 24 hours. The reaction mixture was then concentrated in vacuo on FCC silica and purified by FCC elution with system A (100: 8: 1) to give the title compound (203 mg) as a solid. ^ H-n.m.r. and t.l.c results for <

this material was consistent with those obtained for the product of Example 13.

33.

EXAMPLE 19

2,3 »4,5- ^T etrahydro-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-lso-1H-pyrido / 4,3-b / indol-2-yl) methyl / -1H-imidazol-1- carboxylate (134 mg) in a mixture of absolute ethanol and 2N hydrochloric acid (2: l 30 ml). heat in the 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 on PCC silica and purified by PCC elution with system A (150: 8: 1) to give a solid. This is dissolved in warm methanol and triturated with. ether to give the title compound (69 mg). ^ H-n.m.r. and so.c. the age results for this material were consistent with those obtained for the product of Example 13.

EXAMPLE 20 ......

2.3.4.5- Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido / A, 3-b / indol-1-one "

Solution 2,3,4,5-tetrahydro-2 - [1- (methoxymethyl) -5-methyl / -1Himidazol-4-yl] methyl] -5-methyl-1H-pyrido / 4,3-b / indole -l-she and

2.3.4.5-Tetrahydrop-2 - [1- (methoxyniethyl) -4-methyl-1H-imidazol5-yl / methyl / -5-methyl-1H-pyrido / 4,3-b / indol-1-one (34 mg) in 49% hydrochloric acid (2 ml) is heated in a steam bath for about 3 hours, After cooling, the reaction. The mixture was triturated with 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. ^ Ή-η.ω.Γ.

34.

and so.c. the results obtained for this material were in agreement with those obtained for the product of Example 13.

EXAMPLE 21

2,3,4,5-Tetrahydro-5-methyl-11 - [(5-methyl-1H-imidazol-4-yl) ethyl] -1H-pyrido / 4,3-b / indol-1-one

5,6-Lihydro-1 - [(5-methyl-1H-imidazol-4-yl) methyl] -4- (2-methyl2-phenylhydrazino) -2- (1H) -pyridinone (.6.0_mg) was dissolved in glacial acetic acid (4 ml). Anhydrous zinc chloride (600 mg) was added and the mixture was heated to 85 ° C for 1.5 hours.

The cooled mixture was poured into an 8% aqueous solution. sodium bicarbonate (100 ml) and extracted with ethyl acetate: methanol (10: 1) (2 x 100 ml). The combined, dried organic extracts were evaporated in vacuo to leave a solid which was purified by FCC elution with system A (100: 8: 1) to give the title compound (26 mg). ^ H-n.m.r. and so.c. the results obtained for this material were in agreement with those obtained for the product of Example 13.

EXAMPLE 22

2,3, A, 5-T _e trahidro-5-methyl-2 - / (5-methyl-lH-imidazol-4-yl) methyl / -lH-pyrido / 4,3-b / indol-l-one

A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido / 4,3-b / indole -one (49.97 g), p-toluenesulfonic acid monohydrate (9.50 g) and 4-hydroxymethyl 1-5-Methylimidazole hydrochloride. In R-methylpyrrolidinone (25O ml) was stirred and heated at 125 ° C (for 1 hour). The reaction was then heated to 125-13 ° C for 4.5 hours, during which time two further portions of 4-hydroxymethyl-5-methylimidazole hydrochloride (17.51 g and 6.88 g) were added.

The reaction mixture was washed with water (100 ml), and the stirred mixture was lightly treated with 8% aqueous sodium bicarbonate solution (75θ ml). The resulting suspension was stirred in an ice bath for 1 hour and then filtered to give a solid (57.64 g). One part of this solid (11.09 g) was dissolved in dichloromethane (307 ml) and ethanol (166 ml), boiled with decolourisation for 10 minutes and filtered. Dichloromethane is distilled at atmospheric pressure. while the temperature of the mixture was 65 C. The stirred mixture was cooled and the resulting precipitate was filtered to give the title compound (9.28 g)., so.c. (system A,: 8: l) Rf 0.55, ^ H-n.m.r. the results for this material were in agreement with those obtained for the product of Example 13. ·

EXAMPLE 23

2,3,4,5-Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) ethyl] -1H-pyrido / 4,3-b / indol-1-one · ^-

Hydrogen chloride gas <1 g) was introduced into 1 K-methylpyrrolidinone (10 ml). To this solution was added 2,3,4,5-tetrahydro-5methyl-1H-pyrido / 4,3-b / indol-1-one (2 g) and 4-hydroxymethyl-5methyl-imidazole hydrochloride (0.74 g ), and the solution is heated ra. about 130 ° C under nitrogen. After 3θ minutes, further 4-hydroxymethyl-5-methyl-imidazole (0.74 g) was added and heating continued for another 4 hours. The solution was allowed to cool, water (3θ ml) and 1N sodium bicarbonate solution (40 ml) were added to pH 7-8. After stirring for 2 hours, the precipitated solid which was filtered was washed with water (2 x 10 ml) and dried in vacuo at 40 ° C to give the title compound (1.3 g), m.p. (System A, 5θ J 8: 1) Rf 0.59. ^ H-n.m.r. the results for this material were consistent with those obtained for the product of Example 13.

36.

The following example illustrates a pharmaceutical composition of the invention containing 2,3,4,5-tetrahydro-5-methyl-2 / (5-methyl-1H-imidazol-1-yl) methyl / -1H-pyrido / 4,3- b / indol-l-one as the active component. The physiologically acceptable salts and / or solvates of this compound, and other compounds of formula (I) and their physiologically acceptable salts and / or solvates can be incorporated in a similar manner.

ORAL APPLICATION TABLETS

I

The tablets can be produced by normal processes such as direct compression or wet granulation.

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

Direct pressing

Mg / tablet

Active component 0.50

Calcium hydrophosphate BP ^X 87.25

Croscarmellose sodium NF 1,80

Magnesium stearate BP · 0.45

Compression weight 90,00 ϊ type suitable for direct pressing.

The active component is sieved through a 60 mesh sieve, mixed with calcium hydrophosphate, croscarmallose sodium and magnesium stearate. The resulting mixture was compressed into tablets using a Manesty P3 tablet equipped with 5.5 mm straight bevelled holes.

Claims (6)

A process for the preparation of compounds of general formula (I) wherein Im represents an imidazolyl group of the formula: H CH ₃ and R ¹ represent a hydrogen atom or a C ₁₄ alkyl, C _{3 4} alkenyl, C _{3 4} alkynyl, C _{5 6} cycloalkyl, C _{5 6} cycloalkylmethyl, benzyl, phenylmethoxymethyl or a Ν, di-di-C ₁ alkylcarboxamide group and their physiological acceptable salts and solvates; characterized in that it comprises: (A) alkylation of a compound of formula (II) O (II) or a protected derivative thereof with a compound of formula (III) LCH ₂ -Im (III) or a protected derivative thereof, wherein L represents a leaving atom or leaving group and then, if necessary, removing any protecting groups present; or -3ί (B) reaction of a compound of formula (II) or a protected derivative thereof with a compound of formula (IV) HOCH ₂ -Im (IV) in the presence of an acid at elevated temperature and then, if necessary, removing any protecting groups present; (C) cyclization of a compound of formula (V) (V) in which W represents a hydrogen atom and Y represents a NH group, or W represents a halogen atom and Y represents a bond ah its salts or protected derivative and then, if necessary, removing any protecting groups present; or (D) converting a compound of general formula (I) to another compound of formula (I) using conventional techniques; or (E) removing the protecting group (s) from the protected form of the compound of formula (i); and when the compound of formula (I) is obtained as a mixture of enantiomers, optionally separating the mixture to give the desired enantiomer; and / or wherein the compound of formula (I) is in the form of a free base, optionally converting the free base into a salt. Process according to claim 1, characterized in that it is used for the preparation of compounds in which R ¹ represents a methyl, n-propyl, prop-2-inyl, cyclopentyl, cyclopentylmethyl, benzyl or a Ν, et dimethylcarboxamide group. Process according to claim 1, characterized in that it is used to obtain compound 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. -394. Process according to any one of claims 1 to 3, characterized in that it is used to obtain a compound of formula (I) in the form of hydrochloride, hydrobromide, sulfate, alkylsulfonate, arylsulfonate, phosphate, acetate, citrate, succinate, tartrate, fumarate ah maleate . A process according to claim 3, characterized in that it is used to obtain a compound in the form of hydrochloride soh. Process according to claim 3, characterized in that it is used to obtain a compound in the form of maleate soh.