NO168772B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE IMIDAZOLYL-SUBSTITUTED TRICYCLIC LACTAMES - Google Patents

Description

This invention relates to methods of manufacture

of imidazolyl-substituted tricyclic lactam derivatives with therapeutic activity.

In particular, the invention applies to compounds which are strong 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 referred to as 5-HT3 receptors and are also present in central nervous

the system. 5-HT occurs to a large extent in the neuron pathways in the central nervous system and disturbances of these pathways that contain 5-HT are known to change behavioral traits such as mood, psychomotor activity, appetite and memory.

Compounds that have antagonist activity at 5-HT3-

the receptors have been previously described.

Thus mentions e.g. published UK patent description

No. 2153821A and Published European Patent Specifications Nos. 191562, 219193 and 210840, 3-imidazolylmethyltetrahydro-

carbazolones which can be represented by the general formula:

where R<1> denotes a hydrogen atom or a group selected from C1-10~alkv1' C3_6-alkenyl, C3_10-alkynyl, C3_7-cycloalkyl, <C>3_7-cycloalkyl-<C>1_4-alkyl, phenyl or phenyl-C1_3 -alkyl and i

in the case where Q denotes a hydrogen atom, R<1> can also

denote -C02R<5>, -C0R<5>, -CONR<5>R<6> or -S02R<5> (where R<5> and R<6>, which may be the same or different, both represent a hydrogen atom, a <C>1-6-alkyl- or <C>3-7-cycloalkyl group or a phenyl- or phenyl-C1-4-alkyl group, where the phenyl group is optionally substituted with one or more C^^-alkyl-,

C2_4~Alkoxy or hydroxy groups or halogen atoms, with

the proviso that R<5> does not denote a hydrogen atom when R<1>

denotes a group -CO2R<5> or -SO2R<5>);

one of the groups represented by R<2>, R<3> and R<4> is a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl-C1-3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a <C>1-g alkyl group;

Q denotes a hydrogen atom or a halogen atom or a hydroxy-, <C>1-4-alkyloxy-, phenyl-<C>1-3-alkyl- or C1-4-alkyl group or a group -NR<7>R<8> or -CONR <7>R8 (where R<7> and R<8>, which may be the same or different, both represent a hydrogen atom or a C1_4~<a>alkyl or C3_4-a<l>kenyl group, or form a saturated 5 - to the 7-membered ring together with the nitrogen atom to which they are attached);

and physiologically acceptable salts and solvates thereof.

We have now found a new group of compounds which differ in structure from those described previously and which are strong antagonists of the action of 5-HT at 5-HT3 receptors.

The present invention provides a tricyclic lactam with the general formula (I): where Im denotes an imidazolyl group with the formula:

and R<1> denotes a hydrogen atom or a group selected from C₁-g-alkyl, <C>3-6-alkenyl, <C>3-10-alkynyl, <C>3-7-cycloalkyl, C3-7<->cycloalkyl-C-L_4 -alkyl, phenyl-Ci_3-alkyl, phenylmethoxymethyl, -CONR<5>R<6> or -SO2R5 (where R<5> and R<6>, which may be the same or different, each represents a hydrogen atom or a C1_6-

alkyl group, with the proviso that R<5> does not denote a hydrogen atom when R<1> denotes a group -SO2R<5>);

R<3> and R<4> are each independently a hydrogen atom or a C 1-6 alkyl group;

n represents 2 or 3;

and physiologically acceptable salts and solvates thereof.

According to one aspect, the invention provides compounds of formula (I) wherein R<1> denotes a hydrogen atom or a group selected from C1-6-alkyl, C3-6-alkenyl, C3-10-<a>lkynyl» c3-7-cycloalkyl , C3-7-cycloalkyl-C1-4-alkyl or phenyl-C1-3-alkyl (n and Im are as defined in formula (I)).

Suitable physiologically acceptable salts of the compounds of the general formula (I) include acid addition salts formed with organic or inorganic acids, e.g. hydrogen chlorides, hydrogen bromides, sulfates, alkyl or aryl sulfonates (e.g. methane sulfonates or p_-toluene sulfonates), phosphates, acetates, citrates, succinates, tartrates, fumarates and maleates. The solvates can e.g. be hydrates.

With reference to the general formula (I), an alkyl group can be a straight chain or branched chain alkyl group, e.g. methyl, ethyl, n-propyl, prop-2-yl, n-butyl, but-2-yl, 2-methylprop-2-yl, n-pentyl, pent-3-yl or n-hexyl. A C3_6_alkenyl group can e.g. be a propenyl or butenyl group. When R<1> denotes a C3_6-alkenyl or C3_10-alkynyl group, the double or triple bond should not be adjacent to the nitrogen atom. A phenyl-C1_3~alkyl group can e.g. be a benzyl, phenethyl or 3-phenylpropyl group.

A C3_7-cycloalkyl group can e.g. be a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

A preferred class of compounds of formula (I) is that where R<1> denotes a hydrogen atom or a C1-6-alkyl- (e.g. methyl-, ethyl-, n-propyl-, prop-2-yl), C3_4-alkenyl-(eg prop-2-enyl), C3_4-alkynyl-(eg prop-2-ynyl), C5_6-<cy>chloroalkyl-(eg cyclopentyl), C5_6 -cycloalkylmethyl-(e.g. cyclopentylmethyl), phenyl-C1_2-alkyl-(e.g. benzyl), phenylmethoxymethyl-, N,N-di-C1_3-alkylcarboxamido-(e.g. N,N-dimethylcarboxamido) or C1-3 alkylsulfonyl (eg methylsulfonyl) group. More preferably R<1> denotes a C1-4~alkyl-(e.g. methyl- or n-propyl), C3-4~alkynyl- (e.g. prop-2-ynyl), <C>5-6-cycloalkyl- (f .e.g. cyclopentyl), C5-6-cycloalkyl-methyl- (e.g. cyclopentylmethyl), phenyl-C1-2-alkyl- (e.g. benzyl), phenylmethoxymethyl- or N,N-di-C1-3-alkylcarboxyamido-(e.g. eg N,N-dimethylcarboxamido) group.

Another preferred class of compounds of formula (I) is that where R<3> denotes a hydrogen atom or a C1-3 alkyl (eg methyl) group, more preferably a hydrogen atom.

A further preferred class of compounds of formula (I)

is that where R<4> denotes a hydrogen atom or a C 1-3 alkyl (e.g. methyl or n-propyl) group. Most preferably, R<4> denotes a methyl group.

When R<3> denotes a hydrogen atom, R<4> is preferably C1-6-alkyl.

A further preferred class of compounds of formula (I) is that where n denotes 2.

A preferred group of compounds of formula (I) is that where R<1> denotes a hydrogen atom or a C1_4-alkyl-, C3_4-alkenyl-, C3_4-<a>lkynyl-, C5_6-cycloalkyl-, C5_g-cycloalkyl-methyl- , phenyl-C1-2-alkyl-, phenylmethoxymethyl-, N,N-di-C1-3<->alkylcarboxamido- or C1-3-alkylsulfonyl group; and R<3> and R<4> both represent a hydrogen atom or a C 1-3 alkyl group.

A particularly preferred group of compounds of formula (I)

is that wherein R<1> denotes a methyl, n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl or N,N-dimethylcarboxamido group; R<3> denotes a hydrogen atom; and R<4>

denotes a methyl group.

Within the above preferred and particularly preferred groups of compounds, a particularly important group of compounds is that where n means 2.

Preferred compounds prepared according to the invention are: 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b] indol-1-one; 2,3,4,5-tetrahydro-5-(phenylmethyl)-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido[4,3-b]indole-1- on;

5-cyclopentyl-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido[4,3-b]indol-1-one;

2.3.4 ,5-tetrahydro-2-[2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-propyl-1H-pyrido[4,3-b]indol-1-one;

5-(cyclopentylmethyl)-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one ;

3.4.5 ,6-tetrahydro-6-methyl-2-[(5methyl-1H-imidazol-4-yl)methyl]-azepino[4,3-b]indol-1-(2H)-one;

2,3,4,5-tetrahydro-N,N-dimethyl-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1-oxo-5H-pyrido[4,3-b] indole-5-carboxamide; 2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-(2-propynyl)-1H-pyrido[4,3-b]indole-1 -on;

and their physiologically acceptable salts and solvates.

The strong and selective antagonism of compounds prepared according to the invention against 5-HT at 5-HT3~ receptors is shown by their ability to inhibit 3-(5-methyl-1H-imidazol-4-yl)-1-[1-( methyl-t3)-1H-indol-3-yl]-1-propanone linkage in rat entorhinal cortex homogenates (following the general procedure described by G. Kilpatrick et al., in Nature, 1987, 330, 746 ) and/or by their ability to inhibit 5-HT-induced depolarization of isolated rat vagus nerve preparations.

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

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

Compounds of formula (I) which antagonize the action of 5-HT at 5-HT 3 receptors are useful in the treatment of conditions such as psychotic disorders (eg schizophrenia and mania); anxiety, nausea and vomiting, especially those associated with chemotherapy and radiotherapy against cancer. Compounds of formula (I) are also useful in the treatment of gastric stasis; symptoms of dysfunction in the stomach and intestines, such as occur in dyspepsia, peptic ulcer, reflux oesophagitis, flatulence and irritable bowel syndrome, migraine and pain. Compounds of formula (I) can also be used in the treatment of dependence on drugs and substance abuse, depression and dementia and other cognitive disorders.

When comparing the biological data for the compounds prepared according to the invention with the data for the previously known compounds, 5-HT 3 antagonism can be illustrated in different ways. As indicated above, 5-HT3 can be detected on the basis of examinations of homogenates from rat entorhinal cortex and/or on preparations of isolated rat vagus nerve. The data in the following tabular overview for the compounds produced according to the invention were obtained by binding studies in homogenates from the entorhinal cortex by Kilpatrick et al in Nature, 1987, 330, 746, and the results obtained by this method are expressed as pK-j^ values. The data for the previously known compounds, on the other hand, were obtained with isolated rat vagus nerve preparations disclosed in GB-A-2153821, EP-A-191562 and EP-A-210840, and the relevant test method is described in Ireland et al, British Journal of Pharmacology, 1982, 75, 16P where the results are expressed as pA2 values. The pA2 values used in Ireland et al are defined as the negative logarithm of the molar concentration of antagonist required to reduce the effect by twice the ED50

for r-HT to the effect of ED50 in the absence of antagonists. The pA2 values from the preparation of isolated vagus nerve from rats can be compared with the pK^ values obtained in the binding studies in homogenates from the entorhinal cortex in rats as shown in figure l(b) on page 747 in the Kilpatrick et al article.

When judging the biological data, it is important to take into account that the pA2 and pK^ values are both logarithmic and that a difference of +1 thus amounts to a tenfold increase in activity. The differences in activity between the compounds produced according to the invention and the comparable compounds according to the state of the art vary from 0.6 (when R<1> means the group CH2CECH) to 2.2 (when R<1> means a cyclopentyl group). The results thus show that a dramatic and surprising increase in activity is achieved (for a number of meanings of R<1>) when going from an N-linked (imidazol-l-yl) methyltetrahydrolarbazolone as in the known literature sources, to a C-linked ( imida2ol~4-yl) methyllactam as in the compounds produced according to the invention.

Compounds of general formula (I) and physiologically acceptable salts or solvates thereof can be prepared by the general methods indicated here later. In the following description, the groups R<1>, n and Im are as defined for compounds of general formula (I) unless otherwise indicated.

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

or a protected derivative thereof, where L denotes a "leaving" atom or group, such as a halogen atom (eg chlorine, bromine or iodine) or an acyloxy group (eg trifluoroacetyloxy or acetoxy) or a sulphonyloxy group (eg .eg trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy), followed if necessary by removal of any protecting groups. L is preferably a halogen atom (eg a chlorine atom).

The reaction can take place in an inert solvent such as

an ether (e.g. dimethoxyethane, diglyme or tetrahydrofuran),

a substituted amide (eg dimethylformamide or N-methylpyrrolidone), an aromatic hydrocarbon (eg toluene), a ketone (eg acetone) or dimethylsulfoxide, at a temperature between ambient and 100°C, in the presence of a base Suitable bases include alkali metal hydrides (e.g. sodium hydride), alkali metal carbonates (e.g. sodium carbonate), alkali metal amides (e.g. sodium amide), alkali metal alkoxides (e.g.

potassium t-butoxide) or alkali metal hydroxides, (e.g. sodium or potassium hydroxide).

According to another general method (B), a compound of general formula (I) where n means 2 can be prepared by hydrogenating a compound of formula (IV):

or a protected derivative thereof, followed if necessary by removal of any protecting groups.

Hydrogenation according to general method (B) can be carried out using common methods, e.g. using hydrogen in the presence of a noble metal catalyst (eg palladium, Raney nickel, platinum or rhodium). The catalyst can be coated on e.g. charcoal or aluminum oxide or alternatively a homogeneous catalyst such as tris(triphenylphosphine)rhodium chloride can be used. The hydrogenation usually takes place in a solvent such as an alcohol (e.g. methanol or ethanol), an ether (e.g. dioxane) or an ester (e.g. ethyl acetate) or in a mixture of an alcohol and either a hydrocarbon ( e.g. toluene) or a halogenated hydrocarbon (e.g. dichloromethane), at a temperature in the range -20 to +100°C, and at a pressure of from 1 to 10 atmospheres.

According to another general method (C), a compound of general formula (I) can be prepared by cyclization of a compound of formula (V):

where W denotes a hydrogen atom and Y denotes the group NH, or W denotes a halogen atom and Y denotes a bond, or a salt or protected derivative thereof, followed if necessary by removal of any protecting groups.

According to one design (a) of method (C), the reaction takes place with a compound of formula (V) where W denotes a hydrogen atom and Y denotes the group NH and the ring formation can take place in an aqueous or non-aqueous medium, in the presence of a acid catalyst.

It must be clear that these compounds of formula (V) can exist in the corresponding enol-hydrazone tautomeric forms.

When an aqueous medium is used, this can be water or a mixture of water and an organic solvent such as an alcohol (eg methanol, ethanol or isopropanol) or an ether (eg dioxane or tetrahydrofuran). The acid catalyst can e.g. be an inorganic acid such as concentrated hydrochloric or sulfuric acid. In some cases, the acid catalyst can also serve as a solvent in the reaction. In an anhydrous reaction medium, which may comprise one or more alcohols or ethers (e.g. as described above), carboxylic acids (e.g. acetic acid) or esters (e.g. ethyl acetate), the acid catalyst may alternatively be a Lewis acid such as boron trifluoride, zinc chloride or magnesium chloride. The ring formation reaction can suitably take place at temperatures from 20 to 200°C, preferably 20-125°C.

Alternatively, the ring formation according to design (a) of method (C) can take place in the presence of polyphosphate esters in a reaction medium which may comprise one or more organic solvents, preferably halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane or mixtures thereof. Polyphosphate ester is a mixture of esters which can be prepared from phosphorus pentoxide, diethyl ether and chloroform according to the procedure described in "Reagents for Organic Synthesis", (Fieser and Fieser, John Wiley and Sons, 1967).

According to another design (b) of method (C), the reaction takes place with a compound of formula (V) where W denotes a halogen atom, e.g. a chlorine atom or, more preferably, a bromine or iodine atom, Y denotes a bond and the ring formation is carried out photochemically.

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

According to another general method (D), a compound of general formula (I) where R<3> denotes a hydrogen atom can be prepared by reacting a compound of formula (VI):

or a protected derivative thereof, with formamide at a temperature in the range of 150 to 200°C, followed if necessary by deprotection.

According to another general method (E), a compound of general formula (I) can be prepared by reacting a compound of formula (VII) where G denotes a hydrogen atom or a protected derivative thereof, with phosgene in the presence of a Lewis acid; or by reacting a compound of formula (VII) where G denotes an iodine or bromine atom, or a protected derivative thereof, with carbon monoxide in the presence of palladium(II) salt, followed if necessary by removal of any protecting groups .

According to one embodiment of method (E), a compound of formula (VII) where G denotes a hydrogen atom is reacted with phosgene in the presence of a Lewis acid such as anhydrous aluminum trichloride or stannous (IV) chloride. The reaction can suitably take place in an inert solvent such as an aromatic hydrocarbon (e.g. toluene) or a halogenated hydrocarbon (e.g. dichloromethane) or mixtures thereof, and at a temperature between ambient and 100°C.

According to another design of method (E), is converted

a compound of formula (VII) where G denotes an iodine or bromine atom, with carbon monoxide in the presence of a palladium (II) salt (eg palladium acetate or palladium chloride) and preferably in the presence of triphenylphosphine. The reaction can suitably take place in a solvent such as a tertiary amine (e.g. tri-n-butylamine) optionally in the presence of another solvent such as ether (e.g. tetrahydrofuran) or an aromatic hydrocarbon (e.g. toluene), at a temperature in the range 100-150"C

and at atmospheric pressure.

According to another general method (F), a compound of general formula (I) can be transferred to another compound of formula (I) using conventional techniques.

Such common techniques include hydrogenation, alkylation and acylation using protection and deprotection where necessary.

Thus, according to one embodiment of conversion process F, hydrogenation can be used to transfer an alkenyl or an alkynyl substituent to an alkyl substituent or an alkynyl to alkenyl substituent. Hydrogenation can also be used to replace a phenylmethoxymethyl group with a hydrogen atom. Hydrogenation according to general method (F) can take place using common methods, e.g. by using hydrogen in the presence of a catalyst as described above in general procedure (B).

The term "alkylation", according to general method (F), includes the introduction of groups such as cycloalkyl, alkenyl or phenalkyl groups.

Thus, e.g. a compound of formula (I) where R1 denotes a C1-6-alkyl-, <C>3-6-alkenyl-, C3-10-alkynyl-, C3-7-cycloalkyl-, C3-17-cycloalkyl-C1-4-alkyl-, phenyl-C1-3~alkyl - or phenylmethoxymethyl group is prepared by alkylating a compound of formula (I) where R<1> denotes a hydrogen atom, or a compound where R<3> denotes a C 1-6 alkyl group can be prepared by alkylating the corresponding compound of formula (I) where R<3> denotes a hydrogen atom, using usual methods, e.g. as described in published

European patent description no. 242973. Thus, the reactions can take place using a suitable alkylating agent of formula R<7>Z

(where R<7> is the group to be introduced and Z is a "leaving" atom or group), preferably in the presence of a base.

According to another embodiment of general process (F), a compound of formula (I) wherein R<1> denotes -CONR<5>R<6 >or -SO2R<5> can be prepared by acylation or sulfonylation as appropriate, by a compound of formula (I) where R<1 >denotes a hydrogen atom. The acylation/sulfonylation reactions can take place using a suitable acylation/sulfonylation agent according to usual procedures, e.g. as described in published European Patent Specification No. 210840.

It must be clear that in the above conversions, it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question, in order to avoid unwanted side reactions. E.g. it may be necessary to protect indole and/or imidazole nitrogen atoms, e.g. with an arylmethyl- (e.g. trityl), arylmethoxymethyl- (e.g. phenylmethoxymethyl), alkyl- (e.g. t-butyl), alkoxymethyl- (e.g. methoxymethyl), acyl- (e.g. . benzyloxycarbonyl) or a sulfonyl (eg N,N-dimethylaminosulfonyl or p-toluenesulfonyl) group.

Thus, according to another general method (G), a compound of general formula (I) can be prepared by removing any protecting groups from a protected form of a compound of formula (I). Removal of protective groups can take place using common methods, e.g. those described in "Protective Groups in Organic Synthesis" by T.W. Greene (John Wiley and Sons, 1981).

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

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

where m means 1 or 2, or a protected derivative thereof. The Beckmann rearrangement can take place using common methods, e.g. when using an acid (e.g. polyphosphoric or sulfuric acid or a mixture of hydrochloric acid, acetic anhydride and

acetic acid) in an inert solvent such as an ether (eg dioxane), an amide (eg dimethylformamide) or a hydrocarbon (eg toluene or cyclohexane) at an elevated temperature of e.g. 50 to 120°C. Alternatively, the hydroxy group of the oxime of formula (VIII) can be transferred to a "leaving" group, such as a chloride (using e.g. phosphorus pentachloride) or a hydrocarbyl sulfonate (e.g. a mesylate or a tosylate) or a trifluoroacetate group (using conventional acylation procedures). Subsequent heating at a temperature of, for example, 20-150°C, in an inert solvent as described above, gives a compound of formula (II).

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

where m denotes 1 or 2 or a protected derivative thereof using common methods, e.g. using hydroxylamine hydrochloride in a solvent such as pyridine.

Compounds of formula (IV) can be prepared, e.g. by reacting a compound of formula (X):

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

Compounds of formula (X) can be prepared by heating a compound of formula (II) where n means 2, with a noble metal catalyst such as palladium, palladium oxide, platinum or nickel, at a temperature of e.g. 300-350°C. The catalyst can be imposed e.g. carbon or aluminum oxide, and the reaction can optionally be carried out in the presence of an inert solvent such as an aromatic hydrocarbon (eg p_-cymene).

Compounds of formula (V) where W denotes a hydrogen atom and Y denotes the group NH, can be prepared by reacting a compound of formula (XI): or a salt thereof, with a compound of formula (XII):

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

A protected derivative of a compound of formula (XII) can e.g. have the ketocarbonyl group protected (eg as an enol ether). It must be clear that when a compound of formula (XII) is used where the ketocarbonyl group is protected, it may be necessary to remove the protecting group in order for the reaction to proceed with the compound of formula (XI). Removal of the protection can be done by usual procedures, e.g. by acid hydrolysis (e.g. by using dilute sulfuric or hydrochloric acid). If desired, removal of protection can take place in situ.

Compounds of formula (XII) can be prepared, e.g. by reacting a compound of formula (XIII):

or a protected derivative thereof, with a compound of formula (III) where L is as previously defined, or a protected derivative thereof, using the conditions described in the method

(A) .

Compounds of formula (V) where W denotes a halogen atom

and Y denotes a bond, e.g. is produced by reacting a compound of formula (XIV):

where W denotes a halogen atom, or a protected derivative thereof, with a compound of formula (III) where L is as defined previously, or a protected derivative thereof, using the condition described in method (A).

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

with a compound of formula (XIII), at elevated temperature.

Compounds of formula (VI) can be prepared, e.g. by reacting a compound of formula (II) or a protected derivative thereof, with a compound of formula (XVI):

where L is as defined earlier, using the conditions described in method (A).

Compounds of formula (VII) where G denotes a halogen atom can be prepared, e.g. by reacting a compound of formula (VII) where G denotes a hydrogen atom, or a protected derivative thereof, with a suitable halogen and alkali metal halide (e.g. iodine and potassium iodide) in a suitable solvent such as an aqueous alcohol (e.g. aqueous ethanol).

Compounds with formula (VII) where G denotes a hydrogen atom can e.g. is produced by reacting a compound of formula (XVII):

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

IN

Compounds of formula (III) and protected derivatives

of which is either known or can be produced, e.g. by the methods described in German official document no. 3740352.

IN

Compounds of formula (IX) can be prepared, e.g. by the method or methods analogous to those described by H. lida et al., in J. Org. Chem., 1980, 45, 2938.

Compounds with the formulas (XI), (XIII), (XV), (XVI) and (XVII) are either known or can be prepared from known compounds by usual methods.

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

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

The methods described above for the production of compounds according to the invention can be used to introduce the desired groups at any step in the stepwise formation of the desired compounds, and it must be clear that these methods can be combined in different ways in such multi-step reactions. The order of the reactions in multi-step reactions should of course be chosen so that the reaction conditions used do not affect groups in the molecule that are desired in the final product.

The invention is further illustrated by the following intermediate products and examples. All temperatures are in "C. Thin layer chromatography (t.l.c.) was performed on silica and "flash" column chromatography (FCC) on silica (Merck 9385). Solvent system A used for chromatography means dichloromethane: ethanol: 0.88 ammonia solution. Organic extracts were dried, where indicated, over magnesium sulfate or sodium sulfate. The following abbreviations are used: DMF - dimethylformamide; THF - tetrahydrofuran; DME - dimethoxyethane. -^H-N.m. r. spectra were recorded at 250MHz for dilute solutions in dg- dimethyl sulfoxide.

Intermediate 1

4-(chloromethyl)-1-(triphenylmethyl)-1H-imidazole

Thionyl chloride (0.82 g) was added over 1 min. to a stirred suspension of 1-(triphenylmethyl)-1H-imidazole-4-methanol (1.3 g) in a mixture of dichloromethane (50 ml) and DMF (1.0 ml) at 23°. The resulting solution was stirred for 15 min. and extracted with 8% sodium bicarbonate solution (80 ml). The organic phase was washed with water (50 ml), dried and evaporated to give an oil which solidified. The solid was slurried in hexane and filtered to give the title compound (1.28 g),

m.p. 139-141°.

Intermediate product 2

4- formyl- N, N- dimethyl- 5- propyl- 1H- iroidazol- 1- sulfonamide

Dimethylsulfamoyl chloride (0.67 mL) was added to a stirred solution of 5-propyl-1H-imidazole-4-carboxaldehyde (860 mg) and triethylamine (0.87 mL) in dry dichloromethane (10 mL) under nitrogen. The solution was refluxed for 24 hours, allowed to cool, poured into water (50 mL) and extracted with dichloromethane (3x25 mL). The combined dried organic extracts were evaporated to give an oil (1.9 g) which was purified by FCC and eluted with ethyl acetate:hexane (1:1) to give the title compound (500 mg), m.p. 57-58 °.

Intermediate product 3

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

Sodium borohydride (139 mg) was added to a stirred solution of 4-formyl-N,N-dimethyl-5-propyl-1H-imidazole-1-sulfonamide (450 mg) in absolute ethanol (5 mL) under nitrogen. After 3 hours, the mixture was poured into water (30 mL) and extracted with dichloromethane (3x15 mL). The combined dried organic extracts were evaporated to give a solid (425 mg) which was triturated with ether

(2x10 ml) and gave the title compound (350 mg), m.p. 80-88°.

Intermediate product 4

4-(chloromethyl)- N.N.- dimethyl- 5- propyl- 1H- imidazole- 1- sulfonamide

A solution of thionyl chloride (0.12 ml) in dry dichloromethane (1.2 ml) was added dropwise to a cold (0°) stirred solution of 4-(hydroxymethyl)-N,N-dimethyl-5-propyl-1H-imidazole -1-sulfonamide (340 mg) in dry dichloromethane (7.5 mL) under nitrogen. After 1.5 h, the solution was washed with 8% sodium bicarbonate solution (2x15 mL) and the aqueous phase was extracted with dichloromethane (2x10 mL). The combined organic extracts were washed with water (15 ml), dried and evaporated to give the title compound (180 mg) as an oil, t.l.c. (ethyl acetate) Rf 0.68.

Intermediate 5

3, 4- dihydro- 4- methylcyclopent rb] indol- 1( 2H)- one- oxime

3,4-dihydro-4-methylcyclopent[b]indol-1(2H)-one (1.7 g) and hydroxylamine hydrochloride (1.925 g) in pyridine were heated at 60°

for 18 hours and cooled. The reaction mixture was evaporated in vacuo to a residue to which was added 8% sodium bicarbonate (150 ml). Extraction with ethyl acetate (300 mL) gave a suspension in the organic layer; this layer and associated solids were 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, boiled with a mixture of ethanol (150 ml) and methanol (150 ml) and cooled to approx. 50°. The residue was adsorbed from this solution onto FCC silica and applied to an FCC column. Elution with ethyl acetate/3-10% methanol gave the title compound (1.69 g),

m.p. 219-224° (decomp.).

Intermediate 6

2. 3, 4. 5- tetrahydro- 5- metvl- 1H- pyridor4. 3- b] indol- l- on

3,4-dihydro-4-methylcyclopent[b]indol-1(2H)-one-oxime

(153 g), polyphosphoric acid (40 g) and dioxane (15 ml) were heated at 110-120° for 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 (4x400 ml) and the combined extracts were dried. Evaporation gave a solid (1.43 g) which was recrystallized from ethyl acetate/cyclohexane. This solid was purified by FCC, washed out with System A

(200:10:1) to give a solid (1.26 g) which was recrystallized from ethanol to give the title compound (960 mg), m.p. 234-238°.

Intermediate product 7

3. 4, 5, 6- tetrahydro- 6- methylazepino[ 4, 3-b] indol- 1-(2H)-one

1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one-oxime (24 g) and polyphosphoric acid (600 g) in dioxane (500 ml) were treated according to the procedure described for Intermediate 6. The solid substance (22 g) obtained by evaporation of the organic extracts was recrystallized from ethyl acetate (300 ml) to give a solid (19.2 g). This was purified by FCC, eluting with System A (200:8:1) to give the title compound (5.5 g),

m.p. 212-215°.

Intermediate 8

5, 6-dihydro-4-(phenylamino)-1f2H)-pyridinone

A mixture of 2,4-dioxopiperidine (1.13 g) and aniline

(930 mg) was heated at 120° under a stream of nitrogen i

15 min. The resulting solid was triturated with ether and filtered to give the title compound (1.74 g), m.p. 235-238°.

Intermediate 9

2, 3. 4, 5- tetrahydro- 1H-pyrido\ 4, 3- blindol- 1- one

A solution of 5,6-dihydro-4-(phenylamino)-1(2H)-pyridinone (1.5 g) and palladium acetate (150 mg) in dry DMF (50 mL) was treated with copper(II) acetate ( 3.2 g) and the resulting mixture was heated under nitrogen at 120-130° for 1.5 hours. The mixture was then concentrated in vacuo to give a solid which was triturated with 2N hydrochloric acid (250 mL). The acid was decanted off and the remaining solid was extracted with ethyl acetate for 18 hours. The decanted acid was basified with 2N sodium hydroxide and extracted with ethyl acetate (3x100 mL). These organic extracts were combined with the previous ethyl acetate extracts and adsorbed on silicon oxide. Purification by FCC and elution with System A (100:8:1) gave the title compound (874 mg), m.p. 212-215°.

Intermediate 10 2, 3. 4. 5- tetrahydro- 5-[(phenylmethoxy) methyl]- 1H- pyridof4. 3- blindol- l- on

A solution of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (1.12 g) in dry DMF (60 mL) was treated with sodium hydride (60% dispersion in oil; 480 mg) and the resulting mixture was stirred under nitrogen until the effervescence stopped. The mixture was then cooled to 0° and benzyl (chloromethyl) ether (10% w/v solution in DMF; 0.835 mL) was added over 10 min. Stirring was continued for a further 5 min. 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 mL)

and washed with water (3x100 ml). The organic phase was dried and adsorbed on FCC silica. Purification by FCC and elution with System A (150:8:1) gave the title compound (1.1 g),

m.p. 133-135°.

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

Intermediate 11

5- ethyl- 2, 3, 4. 5- tetrahydro- 1H- pyrido[ 4, 3-b] indol- 1-one

2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (931 mg) was treated with sodium hydride (60% dispersion in oil; 400 mg) and then stirred with ethyl iodide ( 10% vol/vol solution in DMF 4 ml) and gave the title compound (758 mg), m.p. 203-204.5°.

Intermediate 12

2. 3. 4. 5-tetrahydro-5-(1-methylethyl)-1H-pyridof4. 3- b] indol- l- on

2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (931 mg) was treated with sodium hydride (73% dispersion in oil; 328 mg) and was then stirred with 2- bromopropane (615 mg) at room temperature for 72 hours. Purification by FCC and elution with System A (200:8:1) gave a foam (324 mg) which was further purified by recrystallization

from ethyl acetate:hexane (1:1) to give the title compound (294 mg), t.l.c. (System A, 100:8:1) Rf 0.58.

Intermediate 13 2.3.4,5-tetrahydro-5-(phenylmethyl)-1H-pyridof4,3-b]indol-1-one 2,3,,4,5-tetrahydro-1H-pyrido[4,3- b] indol-1-one (559 mg) was treated with sodium hydride (73% dispersion in oil; 197 mg) and was then stirred with benzyl bromide (513 mg) at room temperature for 30 min. Purification by FCC and eluting with dichloromethane:ethanol (80:1) gave the title compound (347 mg), m.p. 209-212°.

Intermediate 14

5- cyclopentylmethyl)- 2, 3, 4, 5- tetrahydro- 1H- pyridof 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 stirred with cyclopentanemethanol (methanesulfonate) (909 mg) at room temperature for 7 days. The solid (570 mg) obtained by FCC was further purified by slow evaporation from a solution in methanol to give the title compound, m.p. 179-181°.

Intermediate 15

2, 3, 4. 5-tetrahydro-2-f f5-methyl-1-(triphenylmethyl)-1H-imidazol-4-f11methyl]-1H-pyrido f4. 3- bl- 1- on

A solution of triphenylmethyl chloride (3.36 g) in dry DMF (40 mL) was added dropwise to a stirred solution of 2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl )methyl]-1H-pyrido[4,3-b]-indol-1-one (2.8 g) in dry DMF (50 mL) containing triethylamine (1.52 g). When addition was complete, the mixture was stirred overnight. The mixture was then poured into water (1000 mL) and the resulting suspension was extracted with ethyl acetate (3x300 mL). The combined organic extracts were washed with water (2x500 ml), dried and concentrated on silica. FCC elution with System A (100:8:1) gave the title compound (4.3 g), m.p. 235-236 °.

Intermediate 16

2, 3, 4. 5- tetrahydro- 5- methyl- 2- r[ 1-( triphenylmethyl)- 1H- imidazol-4- yl1methyl1- 1H- pyrido[ 4. 3- blindol- 1- one

A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido-[4,3-b]indol-1-one (0.3 g) and sodium hydride (80% dispersion in oil; 0, 05 g) in dry DMF (5 ml) was stirred under nitrogen at 50° until hydrogen evolution stopped (approx. 0.5 h). The mixture was cooled to 40° and a solution of 4-(chloromethyl)-1-(triphenylmethyl)-1H-imidazole (0.53 g) in dry THF (3 mL) was added. The mixture was stirred at 40° to 23° over 2 hours, poured into water (100 mL) and extracted with dichloromethane (3x100 mL). The dried organic phase was evaporated to give a semi-solid which was purified by FCC and eluting with dichloromethane:ethyl acetate:triethylamine (50:50:1) gave a solid. This was slurried in hexane and filtered to give the title compound (0.37 g), m.p. 205-210° (decomp.).

Intermediate 17

2. 5- dihydro- 5- methyl- lH- pvridof 4. 3- blindol- l- one

A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido-[4,3-b]indol-1-one (500 mg) and 10% palladium oxide on carbon catalyst (50% aqueous paste; 250 mg) was heated at 320° for 10 min. The cooled solid was triturated with ethanol (ca. 100 mL), filtered and the resulting filtrate was evaporated to give the title compound (470 mg), m.p. 242.5°.

Intermediate 18

2. 5- dihydro- 5- methyl- 2- r( 5- methyl- 1H- imidazol-4- yl) methyl]- 1H- pvrido\ 4, 3- blindol- 1- one- maleate

Sodium hydride (73% dispersion in oil; 80 mg) was added

a stirred suspension of 2,5-dihydro-5-methyl-1H-pyrido[4,3-b]-indol-1-one (440 mg) in dry dimethoxyethane (25 mL) under nitrogen and the mixture was heated at 50° for 6 hours. 4-(Chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (910 mg) was then added and stirring continued at 50° for 20 hours. Water (4.5 mL) and acetic acid (4.5 mL) were added and the solution heated at reflux for 5 hours. The mixture was poured into 8% bicarbonate solution (80 mL) and extracted with dichloromethane:ethanol

(10:1); 3x40 ml). The combined dried organic extracts were evaporated to give a solid (ca. 1.5 g) which was purified by FCC and eluting with System A (200:1:1) gave the free base of the title compound as a solid ( 384 mg). A sample of this solid (100 mg) was dissolved in absolute ethanol

(20 ml) and treated with a solution of maleic acid (40 mg) in absolute ethanol (1 ml). The solvent was removed in vacuo and the residue was triturated with dry ether (3x20 mL) to give a solid (115 mg) which was recrystallized from methanol/ethyl acetate to give the title compound (40 mg), m.p. 166-168°.

Intermediate 19

5, 6- dihydro- 4- methoxy- 1- r r 5- methyl- 1-( triphenylmethyl)-1H-imidazol- 4- yl1methyl- 2-( 1H)- pyridinone

Sodium hydride (80% dispersion in oil; 360 mg) was suspended in dry DME (50 mL) under nitrogen and 5,6-dihydro-4-methoxy-2-(1H)-pyridinone (1.27 g) in dry DME ( 20 ml) was slowly added. The resulting suspension was stirred at 20° for 1 hour. 4-(Chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (3.72 g) in dry DME (50 mL) was added and after the initial reaction had stopped, the mixture was warmed to 50 for 4 hours and then cooled. Methanol (5 mL) was added dropwise and the solvent was removed in vacuo. 8% aqueous sodium bicarbonate solution (300 mL) was added to the residue and the resulting solution was extracted with dichloromethane

(2x300 mL), dried and evaporated in vacuo to leave an oil which was purified by FCC and eluting with System A (200:8:1) to give the title compound (2.84 g), m.p. 181-184°.

Intermediate 20

2, 4-dioxo-l-f5-methyl-lH-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 THF (4 ml) was added hydrochloric acid (5M, 1 ml) and the mixture was stirred at 50° for 1 hour. The solvent was removed in vacuo, triethylamine (1 mL) was added and the mixture was again evaporated to dryness. FCC on the residue and eluting with ethyl acetate:methanol:triethylamine (8:4:1) gave the title compound (139 mg), m.p. 100-106° (decomp.).

Intermediate product 21

5, 6- dihydro- 1- r( 5- methyl- 1H- imidazol- 4- vl) methyl 1- 4-( 2- methyl- 2- phenylhydrazino)- 2( 1H)- pyridinone

2,4-dioxo-1-[(5-methyl-1H-imidazol-4-yl)methyl]piperidine

(20 mg) was dissolved in ethanol (2 ml) and 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 and eluting with System A (75:8:1) to give the title compound (24 mg) as a solid, t.l.c. (System A, 75:8:1) Rf 0.27.

Intermediate 22

N, N- 5- trimethyl- 4- r f( trimethylsilyl) oxyImethyl- 1H- imidazole- 1-sulfonamide

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 was stirred at room temperature over the night. Dimethylsulfamoyl chloride (14.3 g) was added and the reaction mixture was again stirred at room temperature overnight. The resulting suspension was filtered and the collected solid was washed with dichloromethane (100 mL). The filtrate was concentrated on silica and purification by FCC and eluting with hexane:ether (4:1) gave the title compound as an oil (7.2 g), m.p. (ether) Rf 0.5.

Intermediate 2 3

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

A solution of N,N,5-trimethyl-4-[[(trimethylsilyl)oxy]-methyl]-1H-imidazole-1-sulfonamide (2.59 g) in dry THF (50 mL) was treated with a solution of tetrabutylammonium fluoride (1M solution in THF; 10 mL) and THF was immediately removed in vacuo. The residue was partitioned between water (100 mL) and dichloromethane (100 mL) and the aqueous 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°.

Intermediate 24

4-( chloromethyl^- N, N, 5- trimethyl- 1H- imidazole- 1- sulfonamide

A suspension of 4-(hydroxymethyl)-N,N,5-trimethyl-1H-imidazole-1-sulfonamide (2.86 g) in dry dichloromethane (200 mL) containing DMF (0.5 mL) was treated dropwise with a solution of thionyl chloride (1.178 g) in dichloromethane (10 ml). The reaction mixture was cooled in ice during the addition and blanketed with nitrogen. When the addition was complete (about 5 min), stirring was continued at 0° for another 30 min. Water (200 ml)

was then added and the organic phase was separated,

washed with 8% sodium bicarbonate (100 mL), dried and concentrated to give the title compound (2.3 g) as a solid,

m.p. 115-118°.

Intermediate 2 5

5, 6- dihydro- 4-[(2- iodphenyl)methylaminol-2-(1H)- pyridinone

A mixture of 2-iodo-(N-methyl)aniline (1.17 g) and 2,4-dioxopiperidine (565 mg) was heated under a stream of nitrogen for 7 hours at 110-120°. After cooling, the reaction mixture was dissolved in methanol and the solution was adsorbed on FCC silica. Purification by FCC and elution with System A (150:8:1) gave the title compound (1.03 g), m.p. 163-164°.

Intermediate 2 6

N. N. 5- trimetvl- 4- ri, 2 . 3. 6-tetrahydro-4-r(2-iodophenyl)-methylaminol-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-imidazole-1-sulfonamide (832 mg) was then added and the resulting mixture was stirred at 60° overnight. After cooling, the reaction mixture was poured into water (100 mL) and the mixture was extracted with ethyl acetate (2x50 mL). The combined dried organic extracts were concentrated and the resulting solid was purified by FCC and eluting with System A (150:8:1) to give the title compound (712 mg), t.l.c.

(System A, 150:8:1) Rf 0.41.

Intermediate 27

N, N. 5- trimethyl- 4- r( 2. 3, 4. 5- tetrahydro- 5- methyl- 1- oxo- 1H-pyrido r 4, 3- b] indol- 2- yl) methyl 1- 1H- imidazole-l-sulfonamide

A solution of dimethylsulfamoyl chloride (0.107 mL) in dry dichloromethane was added to a stirred solution of 2,3,4,5-tetrahydro-5-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 heated at reflux for approx. 24 hours. After cooling, the solution was concentrated on FCC silica and purified by FCC and eluting with System A (150:8:1) gave an oil. This oil was triturated with ether to give a solid which was further purified by slow evaporation from a solution in ethyl acetate to give the title compound (122 mg),

m.p. 194-196°, m.p.c. (System A, 100:8:1) Rf 0.43.

Intermediate 28

Phenylmethyl- 5- methyl- 4- f( 2, 3. 4. 5- tetrahydro- 5- methyl- 1- oxo- 1H- pyridor 4, 3- b] indol- 2- yl) methyl]- 1H- imidazol- l-carboxylate

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

Intermediate product 29

2, 3, 4. 5- tetrahydro- 2-[ fl-( methoxymethyl)- 5- methyl- 1H- imidazol-4- 11- methyl]- 5- methyl- 1H- pyrido[ 4. 3- b] indole- 1- one and 2. 3, 4. 5-tetrahydro- 2-[[ 1-( methoxymethyl)- 4- methyl- 1H- imidazol- 5- yl]-methyl]- 5- methyl- 1H- pyridof 4. 3 - blindol- l- on

A solution of chloromethyl methyl ether (0.26 mL) in dichloromethane (10 mL) was added to a stirred solution of 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazole- 4-yl)methyl]-1H-pyrido[4,3-b]-indol-1-one (500 mg) and triethylamine (0.49 mL) in dichloromethane (50 mL) at 20° under nitrogen and the solution was stirred for 4 days. It was then partitioned between dichloromethane (50 mL) and sodium bicarbonate solution (2x50 mL). The organic extract was dried, concentrated on FCC silica and then purified by FCC and eluting with System A (100:8:1) to give the title compounds (139 mg). A portion of the title compounds (64 mg) was taken up in hot ethyl acetate and purified by slow evaporation from ethyl acetate to give the title compounds.

Analysis found: C 67.3 H 6.9 N 16.5

C19<H>22N4°2 requires: C 67.4 H 6.6 N 16.6%.

Intermediate 3 0

2, 3. 4. 5- tetrahydro- 5- methyl- 2-\( 4- methyloxazol-5- yl) methyl 1- 1H-pyrido-

[ 4 . 3- blindol- l- on

Sodium hydride (60% dispersion in oil; 600 mg) was added to a stirred suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido-[4,3-b]indol-1-one (1, 5 g) in dry DME (150 ml) and then the mixture was stirred at 60° for 5 h under nitrogen. 5-Chloromethyl-4-methyloxazole (1.2 g) was added and the mixture was stirred overnight. An additional amount of sodium hydride (60% dispersion in oil; 600 mg) was added and the mixture was stirred at 60" for 4 hours, then carefully treated with water (100 mL). The mixture was extracted with dichloromethane containing methanol (ca. 1% ) (3x100 ml) and the combined extracts were evaporated in. The residue was purified by FCC and elution with System A (100:8:1)

gave the title compound (300 mg) as a solid, t.l.c.

(System A, 100:8:1) Rf 0.4.

Intermediate 31

N-[(1-methyl-1H-indol-2-yl)ethyl]trifluoroacetamide

A solution of 2-(1-methyl-1H-indol-2-yl)ethanamine

(3.48 g) in dry dichloromethane (50 ml) containing triethylamine (2.53 g) was cooled in an ice bath and trifluoroacetic anhydride (5.25 g) was added dropwise over 15 min. The mixture was then allowed to warm to room temperature and stirred for a further 3 hours. After this time, the reaction mixture was poured into water (100 ml), the organic phase was separated and the aqueous phase was washed with dichloromethane (2x50 ml). The combined dried organic extracts were concentrated on FCC silica and purification by FCC and washing with ether afforded the title compound (4.2 g) as a solid. A sample of this compound was further purified by slow evaporation from a solution in dichloromethane,

m.p. 124-126°.

Intermediate 32

N. N, 5-trimethyl-4- rr(1-methyl-1H-indole-2-yl)-N-trifluoroacetyl-aminol-ethyl-1-imidazole-1- sulfonamide

A solution of N-[(1-methyl-1H-indol-2-yl)ethyl]trifluoroacetamide (2.7 g) in dry DMF (100 mL) was treated with sodium hydride (60% dispersion in oil; 480 mg) and the mixture was stirred at room temperature for 30 min. 4-(Chloromethyl)-N,N,5-trimethyl-1H-imidazole-1-sulfonamide (2.37 g) was then added and the mixture was stirred at room temperature overnight. After this time, the reaction mixture was poured into water (500 ml) and the resulting suspension was extracted with ethyl acetate (2x100 ml). The combined organic extracts were washed with water (5x250 ml), dried and adsorbed on FCC silica. Purification by FCC and elution with System A (150:8:1) gave the title compound (1.9 g), m.p. 156-158°.

Intermediate 3 3

4- rr rfl- methyl- 1H- indole- 2- vl^ etvl1aminolmetvl1- N. N, 5- trimethvl-1H- imidazol- 1- sulfonamide

A mixture of N,N,5-trimethyl-4-[[(1-methyl-1H-indol-2-yl)-N-trifluoroacetylamino]ethyl]imidazole-1-sulfonamide (260 mg), methanol (10 mL) and saturated aqueous potassium carbonate solution (5 mL) was heated to 60° for 1.5 h. After cooling, the mixture was poured into water (50 mL) and the mixture was extracted with ethyl acetate (2x50 mL). The combined dried organic extracts were concentrated on FCC silica and purification by FCC and eluting with System A (150:8:1) afforded the title compound (140 mg) as an oil, m.p. (System A, 100:8:1) Rf 0.51.

Intermediate 34

4- f[[(3-iodo-l-methyl-lH-indole-2-vl)ethyl1trifluoroacetylaminol-methyl]- N,N,5-trimethyl-lH-imidazole-l- sulfonamide

A solution of 4-[[[(1-methyl-1H-indol-2-yl)ethyl]amino]-methyl]N,N,5-trimethyl-1H-imidazole-1-sulfonamide (471 mg) in methanol ( 25 ml) containing potassium carbonate (138 mg) was treated with a solution of iodine (254 mg) and potassium iodide (166 mg) in water (30 ml) over 30 min. When the addition was complete, the reaction mixture was stirred for an additional 2 hours. After this time, more methanol was removed in vacuo and the resulting suspension was extracted with ethyl acetate (3x25 mL). The combined organic extracts were concentrated on FCC silica and purification by FCC and eluting with System A (150:8:1) gave the title compound (367 mg), m.p. 141-143°.

Intermediate 3 5

4- r r rf3- iodo- l- metvl- lH- indol- 2- vl) etvl1amino1metvl1- N. N. 5-trimetvl- lH- imidazol- l- sulfonamide

4-t[[(3-iodo-1-methyl-1H-indol-2-yl)ethyl]trifluoroacetyl-amino]-methyl]-N,N,5-trimethyl-1H-imidazole-1-sulfonamide (199 mg ) was deprotected according to the procedure described in Intermediate 33 and this gave the title compound (50 mg) as an oil, t.l.c. (System A. 150:8:1) Rf 0.51.

Example 1

2. 3. 4, 5- tetrahydro- 5- methyl- 2- r( 5- methyl- 1H- imidazol- 4- vl)-methyl 1- 1H- pyrido[ 4, 3- b] indol- 1-one- maleate

A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido-[4,3-b]indol-1-one (0.6 g) and approx. 78% sodium hydride dispersion i

mineral oil (0.109 g) in dry DMF (15 mL) was stirred under nitrogen at 50° until hydrogen evolution stopped

(approx. 1.5 hours). The mixture was cooled to 40° and a solution of 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (1.12 g) in dry THF (15 mL) was added. The reaction mixture was then stirred at 40° for 3 hours, at 20° for 16 hours and another portion of 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (1.12 g) in dry THF ( 15 ml) was added. The resulting mixture was heated at 40° for 3 hours, quenched with water (20 mL) and acetic acid (20 mL), and the mixture was heated at 100° for 2 hours. The mixture was then concentrated in vacuo to approx. 60 ml, diluted with 1M hydrochloric acid (40 ml) and washed with ethyl acetate (3x50 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, 3x100 mL). The extracts were collected, dried and evaporated to give a brown gum (ca. 1 g). This gum was adsorbed on silica and purified by FCC and eluted with System A (100:8:1) to give a pale brown solid (0.8 g), m.p. 238-240° (decomp.). This solid was dissolved

into a mixture of hot ethanol and methanol (1:1; 100 ml) and treated with an ethanolic solution of maleic acid (318 g). The resulting solution was concentrated to ca. 20 ml and

diluted with dry diethyl ether (ca. 8 mL) to precipitate the title compound (0.75 g) as an off-white solid,

m.p. 160-162°.

Analysis found: C 61.6 H 5.5 N 13.6 C17<H>18N4°-C4H4°4 requires: C 61.5 H 5.4 N 13.8%.

Example 2

3. 4. 5. 6-tetrahydro-6-methyl-2-f(5-methyl-1H-imidazol-4-yl)-methyl 1-azepinof 4 . 3- b"| indole- 1 ( 2H) - on- maleate

3,4,5,6-tetrahydro-6-methylazepino[4,3-b]indol-1(2H)-one (0.64 g) was treated with sodium hydride (ca. 75-80% dispersion in oil; 0.108 g) and was then stirred with 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole as described in ex. 1. The reaction mixture was then poured into water (300 mL) and extracted with dichloromethane (4x250 mL). The combined dried organic extracts were evaporated to give a semi-solid (ca. 1.8 g) which was purified by FCC and washed with System A (200:8:1) to give a gum (0.7 g). This gum (0.7 g) was dissolved in a mixture of acetic acid, THF and water (1:1:1; ca. 70 ml) and heated on a steam bath for 1 hour. Processing as described in ex. 1 gave a gum (0.22 g) which on purification by FCC and washing with System A (200:8:1) gave a solid (0.11 g). Maleate formation gave a gum which was dried in vacuo giving a foam which was triturated with a mixture of ether and ethanol (50:1; ca. 25 mL)

and gave the title compound (0.145 g) as a solid, m.p. 132-133 °.

<1>H-N.m.r. indicated that 0.39 mol of ethanol was present. Water analysis found: 0.583% w/w = 0.14 mol H2O.

Analysis found: C 61.4 H 5.7 N 12.6 C18H2oN40.C4H404.0.39EtOH.O.14 H20

requires: C 61.4 H 6.0 N 12.6%.

Example 3

2, 3, 4, 5-tetrahydro-2-f(5-methyl-1H-imidazol-4-yl)methyl]-5-\(phenylmethoxy)methyl]-1H-pyrido|"4,3-b]indole - l- on- maleate

A suspension of 2,3,4,5-tetrahydrb-5-[(phenylmethoxy)methyl]-1H-pyrido[4,3-b]indol-1-one (920 mg) in dry DME (75 mL) was treated with sodium hydride (60% dispersion in oil; 180 mg) under nitrogen and the reaction mixture was stirred at 60" for 6 hours. 4-(Chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (1.11 g) was then added and the mixture was stirred at 60° overnight. Acetic acid (10 mL), water (10 mL) and THF (10 mL) were then added and the resulting solution was refluxed for 6 h. After cooling, 2N sodium hydroxide (100 mL) added and the resulting suspension extracted with dichloromethane (3x100 mL). The combined dried organic extracts were adsorbed onto FCC silica, and FCC and elution with System A (150:8:1) gave the free base of the title compound (1.08 g) as a foam.A small amount of this compound (200 mg) was dissolved in methanol (30 mL) and the resulting solution was treated with maleic acid

(58 mg). The solution was heated for 10 min., cooled and dry ether was added to precipitate the title compound (170 mg), m.p. 165-168 0 .

Water analysis found: 0.22% w/w = 0.06 mol H20.

Analysis found: C 64.5 H 5.6 N 10.7 <c>24H24N4°-c4H404-°'06 H2° requires: C 65.0 H 5.5 N 10.8%.

Examples 4-7 were prepared in a similar way as in ex. 3.

Example 4

5-ethyl-2.3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl1-1H- pyridor4. 3- blindol- l- on- maleate

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

(500 mg) was treated with sodium hydride (60% dispersion in oil; 138 mg) and was then stirred with 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (927.5 mg) and the gave the free base of the title compound (320 mg) as a solid. Maleate formation gave the title compound (380 mg), m.p. 175.5-177°. Analysis found: C 62.1 H 5.7 N 13.0 <C>i8H20N4O.C4H4O4 requires: C 62.2 H 5.7 N 13.2%.

Example 5

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

Analysis found: C 62.6 H 6.0 N 12.6 C19<H>22<N>4°-C4H4°4 requires: C 63.0 H 6.0 N 12.8%.

Example 6

2, 3. 4, 5- tetrahydro- 5-( phenylmethyl)- 2 -\( 5- methyl- 1H- imidazol- 4-vl)- methyl]- 1H- pyridof4, 3- blindol- 1- one- maleate- monohydrate

2,3,4,5-tetrahydro-5-(phenylmethyl)-1H-pyrido[4,3-b]'indol-1-one (960 mg) was treated with sodium hydride (73% dispersion in oil; 132 mg ) and was then stirred with 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (1.3 g). The free base of the title compound (571 mg) appeared as a solid by FCC and elution with System A (175:8:1). Maleate formation gave the title compound (420 mg), m.p. 198-200°, m.p.c. (System A, 100:8:1) Rf 0.3.

Example 7

5-(cyclopentylmethyl)-2.3.4.5-tetrahydro-2- r(5-methyl-1H-imidazol-4-yl)methyl]-1H- pyridor4. 3- b] indole- l- on- maleate

5-(Cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indol-1-one (200 mg) was treated with sodium hydride (60% dispersion in oil; 60 mg) and was then stirred with 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (280 mg). The free base of the title compound was obtained as a solid (96 mg) by FCC and elution with System A (200:8:1). Maleate formation gave the title compound (60 mg), m.p. 81-83°, t.l.c.

(System A, 100:8:1) Rf 0.20.

Example 8

2, 3, 4, 5- tetrahydro- 5- methyl- 2- r( 5- propvl- 1H- imidazol- 4- yl)-methyl]- 1H- pyrido[ 4, 3- blindol- 1-one- maleate

Sodium hydride (60% dispersion in oil; 25 mg) was added to a stirred suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido-[4,3-b]indol-1-one (124 mg ) in dry DME (5 mL) under nitrogen. The mixture was heated at 50° for 7 hours and then treated with a solution of 4-(chloromethyl)-N,N-dimethyl-5-propyl-1H-imidazole-1-sulfonamide (165 mg) in dry DME (3 mL ) and stirring continued at 50° for 20 hours. 2N hydrochloric acid (5 mL) was added and the solution was heated at reflux for 6 h. The solution was poured into 8% sodium bicarbonate solution (50 mL) and extracted with dichloromethane (3x25 mL). The combined dried organic extracts were evaporated to give a solid (200 mg) which was purified by FCC and eluting with System A (200:10:1) to give the free base of the title compound (58 mg) as a solid. . This was dissolved in warm absolute ethanol (5 ml) and treated with a solution of maleic acid (21 mg) in ethanol (0.5 ml). The solvent was removed in vacuo and the residue was crystallized from ethanol:ether to give the title compound (58 mg), m.p. 137-138".

Analysis found: C 62.7 H 5.9 N 12.4 C19<H>22N4°-<C>4H4°4 requires: C 63.0 H 6.0 N 12.8%. Example 9

2,3,4 - 5-carboxamide maleate

A solution of 2,3,4,5-tetrahydro-2-[[5-methyl-1-(triphenyl-methyl)-1H-imidazol-4-yl]methyl]-1H-pyrido[4,3-b] indol-1-one (261 mg) in dry DMF (25 mL) was treated with sodium hydride (60% dispersion in oil; 30 mg) and the mixture was stirred at room temperature under nitrogen for 15 min. N,N-dimethylcarbamoyl chloride (1M solution in DMF; 1 mL) was then added and the solution was stirred at room temperature for a further 15 min. 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 (2x50 mL) and the combined organic extracts were washed with water (2x100 mL) and concentrated to give an oil. The oil was dissolved in a mixture of water (10 mL), glacial acetic acid (10 mL) and THF (10 mL) and the solution heated at reflux for 1.5 h. After cooling, the solution was basified by the addition of 2N sodium hydroxide (100 mL) and the resulting mixture was extracted with ethyl acetate (2x75 mL). The combined dried organic extracts were adsorbed onto FCC silica and the free base of the title compound (110 mg) was recovered as a solid by FCC and elution with System A (100:8:1). This was dissolved in dry methanol (10 ml) and heated with maleic acid (36 mg) on a steam bath for 5 min. On cooling, dry ether (3 mL) was added to precipitate the title compound (105 mg), m.p. 161-163°.

Water analysis found: 1.85% w/w = 0.49 mol H2O.

Analysis found: C 57.8 H 5.4 N 14.3 <C>19<H>21<N>5°2-C4H4°4'0'49 H20 requires: C 68.0 H 5.5 N 14 .7%.

Examples 10, 11 and 12 were prepared in a similar way as ex. 9 unless otherwise stated.

Example 10

2, 3, 4, 5- tetrahydro- 2- ff5- methyl- 1H- imidazol- 4- yl) methyne- 5-( methylsulfonyl)- 1H- pyrido[ 4, 3- b] indol- 1- one- maleate

2,3,4,5-tetrahydro-2-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-1H-pyrido[4,3-b]indol-1-one (261 mg) was treated with sodium hydride (60% dispersion in oil; 30 mg) and then stirred with methanesulfonyl chloride (1M solution in dry DMF; 1 mL) for 45 min. Deprotection, workup and purification afforded the free base of the title compound (60 mg) as a solid. Maleate formation gave the title compound (57 mg), m.p. 152-155°.

Analysis found: C 53.2 H 4.7 N 11.7 C17<H>18<N>4<0>3S-C4<H>4°4 requires: C 53.2 H 4.7 N 11.8 %.

Example 11

2, 3, 4, 5- tetrahydro- 2- f( 5- methyl- 1H- imidazol- 4- yl) methyl]- 5-( 2- propynyl)- 1H- pyrido[ 4, 3- blindol- 1- one - maleate

A suspension of 2,3,4,5-tetrahydro-2[[5-methyl-1-(triphenyl-methyl)-1H-imidazol-4-yl]methyl]-1H-pyrido[4,3-b]indole -1-one (522 mg) and potassium carbonate (276 mg) in dry acetone (75 mL) were treated with propargyl bromide (1M solution in acetone; 2 mL) and the mixture was refluxed overnight. After cooling, excess acetone was removed in vacuo to give an oil which was partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was washed with ethyl acetate (50 mL) and the combined organic extracts were concentrated in vacuo. Deprotection, workup and purification afforded the free base of the title compound (100 mg) as a solid. Maleate formation gave the title compound (89 mg), m.p. 202-205°, t.l.c.

(System A, 100:8:1) Rf 0.29.

Example 12

2. 3. 4, 5- tetrahydro- 2- r( 5- methyl- 1H- imidazol-4- yl) methyl]- 5-( 2 - propenyl)- 1H- pyridor4, 3- b] indol- 1- one - maleate

2,3,4,5-tetrahydro-2-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-1H-pyrido[4,3-b]indol-1-one (1.0 g) was treated with sodium hydride (60% dispersion in oil; 114 mg) and then stirred with allyl bromide (460 mg) for 1 hour. Deprotection, workup and purification gave the free base of the title compound (380 mg) as a solid. Maleate formation gave the title compound (160 mg) t.l.c. (System A, 100:8:1) Rf 0.3. Analysis found: C 63.2 H 5.5 N 12.5 C19<H>20N4°-<C>4H4°4 requires: C 63.3 H 5.5 N 12.8%.

Example 13

5- cyclopentyl- 2. 3, 4. 5- tetrahydro- 2- r( 5- methyl- 1H- imidazol- 4-yl) methyl]- 1H- pyridof4, 3- b] indol- 1-one maleate

A solution of 2,3,4,5-tetrahydro-2-[[5-methyl-1-(triphenyl-methyl)-1H-imidazol-4-yl]methyl]-1H-pyrido[4,3-b] indol-1-one (523 mg) in dry DMF (30 mL) was treated with sodium hydride (60% dispersion in oil; 46 mg) and stirred for 15 min. at 21° under nitrogen. Cyclopentyl bromide (298 mg) was then added dropwise and the mixture was stirred for 1 hour and then heated at reflux for 4 hours. The solution was allowed to stand at 21° 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 2N sodium hydroxide and extracted with dichloromethane (3x25 mL). The combined extracts were washed with water (2x50ml), concentrated in vacuo and purified by FCC and elution with System A (100:8:1) to give the free base of the title compound (42mg) as a solid. Maleate formation gave the title compound (38 mg), m.p. 180"

(decomp.), t.l.c. (System A, 100:8:1) Rf 0.3.

Example 14

2, 3, 4, 5- tetrahydro- 2-[(5- methyl- 1H- imidazol-4-yl) methyl- 5-propyl- 1H- pyridof4, 3-b] indol- 1-one- maleate

A solution of 2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-(2-propenyl)-1H-pyrido[4,3- b]indol-l-one (248 mg) in a mixture of ethanol (20 mL) and 2N hydrochloric acid (0.5 mL) was hydrogenated at room temperature and atmospheric pressure over prereduced 10% palladium oxide on carbon catalyst (50% aqueous paste ; 50 mg). The mixture was filtered and evaporated in vacuo. The residue was basified with 2N sodium hydroxide (10 mL) and extracted with dichloromethane (3x20 mL). The combined organic extracts were washed with water (30 mL) and evaporated to give the free base of the title compound (258 mg) as a solid. Maleate formation gave the title compound (345 mg), t.l.c.

(System A, 100:8:1) Rf 0.4.

Water analysis found: 1.13% w/w = 0.28 mol H20.

Analysis found: C 62.1 H 5.9 N 12.5 C19<H>22<N>4°-C4H4°4-0»28 H2° requires: C 62.2 H 6.0 N 12.6% .

Example 15

2. 3, 4, 5-tetrahydro-2- f(5-methyl-1H-imidazol-4-yl)methyl1-1H-pyrido\4,3-b]indol-1-one maleate

A suspension of 2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-5-[phenyl(methoxymethyl)]-1H-pyrido[4,3- b]-indol-l-one (400 mg) in ethanol (20 mL) and glacial acetic acid (5 mL) was hydrogenated overnight at room temperature and atmospheric pressure over pre-reduced 10% palladium oxide on carbon catalyst (50% aqueous paste; 100 mg ). The reaction mixture was filtered and the residue was washed with ethanol (100 mL). The filtrate was concentrated in vacuo to give an oil to which was added 2N sodium hydroxide (50 ml). The resulting suspension was extracted with dichloromethane (2x50 mL) and the combined dried organic extracts were evaporated to give a solid. This was purified by FCC and elution with System A (75:8:1) to give the free base of the title compound as a solid (240 mg) which was then dissolved in dry methanol (50 mL). Maleate formation gave the title compound (261 mg), t.l.c. (System A, 75:8:1)

Rf 0.2.

Analysis found: C 60.3 H 5.2 N 13.8 C16<H>16N4°-C4H4°4 requires: C 60.6 H 5.1 N 14.1%.

Example 16

2. 3. 4, 5- tetrahydro- 5- methyl- 2- r( 1. 5- dimethyl- 1H- imidazol- 4- yl)-methyl 1- 1H- pyrido[ 4. 3- blindol- 1- one- maleate

Sodium hydride (73% dispersion in oil; 40 mg) was added to a stirred suspension of 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]- 1H-pyrido[4,3-b]indol-1-one (300 mg) in dry DMF (3 mL) under nitrogen. After 30 min. the suspension was cooled to 0° and iodomethane (0.076 mL) was added dropwise. The mixture was now brought to room temperature, stirred for 1.5 hours, then poured into water (30 ml) and extracted with dichloromethane (3x15 ml).

The combined dried organic extracts were evaporated to give an oil (ca. 545 mg) which was purified by FCC and washing with System A (200:8:1) gave a solid (95 mg). A portion of this material (90 mg) was dissolved in absolute ethanol (3 ml) and treated with a solution of maleic acid (35 mg) in absolute ethanol (1 ml). The solvent was removed in vacuo and the residue was triturated with dry ether (3x5 mL) to give the title compound (122 mg), m.p. 178-180°.

Analysis found: C 62.1 H 5.7 N 13.1 C18<H>20<N>4°-C4H4°4 requires: C 62.3 H 5.7 N 13.2%.

Example 17

2. 3. 4, 5-tetrahydro-2-f(1H-imidazol-4-yl)methyl1-5-methyl-1H-pvridor4. 3- b] indole- l- on- dimaleate

A solution of 2,3,4,5-tetrahydro-5-methyl-2-[[1-(triphenyl-methyl)-1H-imidazol-4-yl]methyl]-1H-pyrido[4,3-b] indol-l-one

(0.22 g) in a mixture of acetic acid, THF and water (1:1:1; 10 ml) was heated on a steam bath for 30 min. The resulting suspension was diluted with 1N hydrochloric acid (20 ml) and washed with ethyl acetate (3x20 ml). The acidic aqueous phase was basified with solid

sodium carbonate and extracted with dichloromethane:methanol (9:1; 3x20 ml). The combined dried organic extracts were evaporated to give a foam which was dissolved in methanol (5 ml) and treated with a solution of maleic acid (0.15 g) in methanol (5 ml). The clear solution was evaporated to give a gum which on trituration with ether gave the title compound (0.17 g) as a solid, m.p. 117-118°.

Analysis found: C 56.1 H 4.3 N 10.5 C16<H>16N40.2C4H404 requires: C 56.2 H 4.7 N 10.9%.

Example 18

2.3.4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-! H- pyridor4 , 3- b") indol- l-one- hydrochloride

2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido[4,3-b]indol-1-one ( 1.00 g) was suspended in ethanol (40 mL) and concentrated hydrochloric acid (1.00 mL) was added. The mixture was heated to 40° and charcoal (0.25 g) was added. The resulting suspension was stirred and heated for 5 min. and then filtered. The filtrate was evaporated in vacuo to approx. 20 ml and allowed to cool to 20°. Ether (40 ml) was added with stirring over 5 min. and the mixture was stored at 4° overnight. The resulting precipitate was filtered off, washed with ether (2x10 ml), dried in vacuo at room temperature for 2 hours and then at 70° for 7 hours to give the title compound (0.95 g), m.p. 288-291°.

Analysis found: C 61.4 H 5.8 N 16.7 Cl 10.7 <C>17<H>18N40.HC1 requires: C 61.7 H 5.8 N 16.9 Cl 10.7%.

Example 19

2. 3, 4, 5-tetrahydro-5-methyl-2-f(5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido\A . 3-b] indole-l-one-sulphate

2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido[4,3-b]indol-1-one ( 0.81 g) was suspended in absolute ethanol (6 ml) and was heated at 50° with concentrated sulfuric acid (0.15 ml). More ethanol (4 mL) was added and the mixture was stirred with charcoal (0.1 g). The suspension was then filtered and the collected solid was washed with ethanol (ca. 3 mL). The resulting filtrate was stirred for 1 hour

at room temperature, tert-butyl methyl ether (10 ml) was added slowly and the mixture was stirred for 20 min. The precipitate was filtered off, washed with ethanol:tert-butyl methyl ether (1:1; 6 ml), then with tert-butyl methyl ether (6 ml) and dried in vacuo at 40° for 4 days to give the title compound (0.4 g), m.p. 205-209°.

Analysis found: C 49.5 H 5.6 N 13.5 S 8.4 C17<H>18N40.1.1 H2S04 requires: C 49.9 H 5.4 N 13.3 S 8.4%.

Example 2 0

2. 3. 4, 5- tetrahydro- 5- methyl- 2- f( 5- methyl- 1H- imidazol- 4- yl)-methyl]- 1H- pyrido r 4. 3- b] indol- 1- one

A suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido-[4,3-b]indol-1-one (400 mg) in dry DME (50 mL) was treated with sodium hydride (60 % dispersion in oil; 100 mg) and the mixture was stirred at 60° under nitrogen for 6 hours. 4-(Chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (474 mg) was added and the reaction mixture was stirred at 60° under nitrogen overnight. 2N hydrochloric acid (10 mL) and water (10 mL) were then added and the mixture was refluxed for 6 h. After cooling, the mixture was basified with 2N sodium hydroxide and the resulting mixture was extracted with ethyl acetate (2x50 mL).

The combined, dried organic extracts were concentrated on FCC silica and purified by FCC and eluted with System A

(150:8:1) gave the title compound (352 mg) as a solid, m.p. (System A, 100:8:1) Rf 0.28.

<1->H-N.m.r.: c 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 (IH.dd), 7.94-8.03 (1H,dd ).

Example 21

2. 3, 4 , 5- tetrahydro- 5- methyl- 2- r( 5- methyl- 1H- imidazol- 4- yl)-methyl1- 1H- pyrido r 4. 3- blindol- l- one

A mixture of 2,5-dihydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido[4,3-b]indol-1-one (50 mg) and 10% palladium oxide on carbon catalyst (50% aqueous paste; 25 mg) in absolute ethanol (10 ml) was heated at 80° in a hydrogen atmosphere at 5.52 x 10<5> Pa (80 p.s.i.) for 24 hours. The suspension was filtered and the filtrate was evaporated to give an oil (49 mg) which was purified by short path column chromatography on silica gel (Merck 7739) and eluting with System A (150:10:1) gave the title compound (8 mg) as a solid, t.l.c. (System A, 150:10:1) Rf 0.36. ^-H-N.m.r. data obtained for this material were consistent with those obtained for the product from ex. 20.

Example 22

2, 3, 4, 5- tetrahydro- 5- methyl- 2- f (5- methyl- 1H- imidazol-4- yl)■-methyl]- 1H- pyrido f 4, 3- b] indol- 1- one

A solution of 2,3,4,5-tetrahydro-2-[[5-methyl-1-(triphenyl-methyl)-1H-imidazol-4-yl]methyl]-1H-pyrido[4,3-b] indol-1-one (261 mg) in dry DMF (25 mL) was treated with sodium hydride (60% dispersion in oil; 30 mg) and the mixture was stirred at room temperature under nitrogen for 15 min. Iodomethane (0.5M solution in DMF; 2 mL) was then added and stirring continued for a further 15 min. The reaction mixture was then poured into water (100 ml) and the resulting suspension was extracted with ethyl acetate (2x50 ml). The combined organic extracts were washed with water (2x100 mL), dried and concentrated to give a solid. This was dissolved in a mixture of water (10 mL), THF

(10 ml) and glacial acetic acid (10 ml) and heated at reflux for 2 hours. After cooling, residual THF was removed in vacuo and the remaining solution was made basic (to pH 14) by addition of 2N sodium hydroxide. The resulting suspension was extracted with ethyl acetate (2x50 mL) and the combined dried organic extracts were concentrated on silica (Merck 7385). FCC and elution with System A (100:8:1) gave the title compound (81 mg) as a solid. <1>H-N.m.r. and t.l.c. data recorded for this material were consistent with those recorded for the product from e.g. 20.

Example 23

2, 3, 4, 5- tetrahydro- 5- methyl- 2- f( 5- methyl- 1H- imidazol- 4- yl)-methyl1- 1H- pyrido[ 4. 3- b] indol- 1- one

5,6-dihydro-1-[(5-methyl-1H-imidazol-4-yl)methyl]-4-(2-methyl-2-phenylhydrazino)-2(1H)-pyridinone (20.0 mg) was dissolved in 98% sulfuric acid (1 ml) and the solution was stirred at 25° for 5 min. The mixture was carefully poured into 8% aqueous sodium bicarbonate solution (60 mL) and extracted with 10% methanol:dichloromethane (2x60 mL). The combined dried organic extracts were evaporated in vacuo to leave an oil which was purified by FCC and eluting with System A (100:8:1) to give the title compound (13.5 mg) as a solid. ^-H-N.m.r. and t.l.c. data recorded for this material were consistent with those that appeared for the product from ex. 20.

Example 24

2. 3. 4. 5-tetrahydro-5-methyl-2- r(5-methyl-1H-imidazol-4-yl)-methyl-1H-pyridof4. 3- blindol- l- on

A solution of N,N,5-trimethyl-4-[[1,2,3,6-tetrahydro-4-[(2-iodophenyl)methylamino]-6-oxo-1-pyridinyl]methyl]-1H-imidazole -1-Sulfonamide (264 mg) in a mixture of dioxane and acetonitrile (2:1; 200 mL) containing triethylamine (2 mL) was irradiated in a pyrex immersion chamber with a medium pressure 125W mercury lamp at room temperature for 24 hours. The reaction mixture was then concentrated on FCC silica and purification by FCC and eluting with System A (150:8:1) gave the title compound (87mg)

as a solid substance. ^-N.m.r. and t.l.c. data recorded for this material were consistent with those recorded for the product from ex. 20.

Example 2 5

2. 3, 4, 5- tetrahydro- 5- methyl- 2-[( 5- methyl- 1H- imidazol- 4- vl)-methyl 1- 1H- pyrido r 4. 3- blindol- 1- one

A solution of N,N,5-trimethyl-4-[(2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido[4,3-b]indol-2-yl)methyl ]-1H-imidazole-1-sulfonamide (86 mg) in 2N hydrochloric acid (10 mL) and absolute ethanol (2 mL) was heated at 100-110" for 4 hours. The reaction mixture was then cooled and 2N sodium hydroxide (50 mL) was was added. The resulting solution was extracted with dichloromethane (2x50 mL) and the combined dried organic extracts were concentrated on FCC silica and purification by FCC and eluting with System A (100:8:1) afforded a solid (36 mg).

This was taken up in hot ethyl acetate and purified by slow evaporation to give the title compound (12 mg). <1>H-N.m.r.- and t.l.c. data taken for this material were consistent with those taken for the product from e.g. 20.

Example 26

2 3

A solution of N,N,5-trimethyl-4-[(2,3,4,5-tetrahydro-5-methyl-1-oxo-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) was irradiated at room temperature with a medium pressure mercury lamp for 24 hours. The reaction mixture was then concentrated in vacuo on FCC silica and purification by FCC and eluting with System A (100:8:1) afforded the title compound (203 mg) as a solid. % N.m.r. and t.l.c. data taken for this material were consistent with those taken for the product from e.g. 20.

Example 27

2. 3. 4. 5- tetrahydro- 5- methyl- 2- r( 5- methyl- 1H- imidazol- 4- yl)-methyl]- 1H- pyrido f 4, 3- b] indol- 1- one

A solution of phenylmethyl 5-methyl-4-[(2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido[4,3-b]indol-2-yl)methyl-1H- imidazole-1-carboxylate (134 mg) in a mixture of absolute ethanol and 2N hydrochloric acid (2:1; 30 ml) was heated on a steam bath for 15 min. After cooling, the solution was concentrated in vacuo to ca. 20 ml and diluted with water (40 ml). The mixture was then washed with ethyl acetate (2x40 mL) and the acidic aqueous layer was basified with potassium carbonate solution. The solution was then extracted with ethyl acetate (3x50 mL) and the combined dried organic extracts were concentrated on FCC silica and purification by FCC and washing with System A (150:8:1) gave a solid. This was dissolved in hot methanol and triturated with ether to give the title compound (69 mg). -^H-N.m.r.- and t.l.c. data recorded for this material were consistent with those taken for the product from ex. 20.

Example 28

2, 3, 4, 5- tetrahydro- 5- methyl- 2- r( 5- methyl- 1H- imidazol- 4- yl)-methyl]- 1H- pyrido f 4. 3- b] indol- 1- one

A solution of 2,3,4,5-tetrahydro-2-[[1-methoxymethyl)-5-methyl-1H-imidazol-4-yl]methyl]-5-methyl-1H-pyrido[4,3-b ]indol-1-one and 2,3,4,5-tetrahydro-2-[[1-(methoxymethyl)-4-methyl-1H-imidazol-5-yl]methyl]-5-methyl-1H-pyrido[ 4,3-b]indol-1-one (34 mg) in 49% hydrobromic acid (2 ml) was heated on a steam bath for approx. 3 hours. After cooling, the reaction mixture was basified by the addition of potassium carbonate solution and extracted with ethyl acetate (3x50 mL). The combined dried organic extracts were concentrated in vacuo to give the title compound (6 mg) as a solid. <1>H-N.m.r.- and t.l.c. data recorded for this material were consistent with those recorded for the product from e.g. 20.

Example 29

2, 3, 4, 5- tetrahydro- 5- methyl- 2-\(5- methyl- 1H-imidazol-4- yl)-methyl]- 1H- pyridor4, 3- blindol- 1- one

A mixture of 2,3,4,5-tetrahydro-5-methyl-2-[(4-methyloxazol-5-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (100 mg ) in formamide (20 ml) was heated at 180° for 24 h. The mixture was then cooled, diluted with water (100 mL) and extracted with dichloromethane (3x100 mL). The combined organic extracts were concentrated in vacuo and the residue was purified by FCC and eluting with System A (100:8:1) to give the title compound (40 mg) as a solid. -^H-N.m.r.- and t.l.c. data for this material were consistent with those taken for the product from ex. 20.

Example 3 0

2. 3. 4, 5-tetrahydro-5-methyl-2- r(5-methyl-1H-imidazol-4-yl)-methyl-1H- pyridof 4,3-b]indol-1-one

A solution of 4-[[[(1-roethyl-1H-indol-2-yl)ethyl]amino]-methyl]-N,N-,5-trimethyl-1H-imidazole-1-sulfonamide (140 mg) in dry dichloromethane (15 mL) was cooled to 5° and the mixture was stirred under nitrogen while phosgene (12% w/w solution in toluene; 1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, aluminum trichloride (60 mg) was powdered and added and stirring was continued overnight.

After this time, methanol (1 mL) was added and the reaction mixture was adsorbed on FCC silica and purification by FCC and eluting with System A (150:8:1) gave the protected derivative of the title compound (42 mg) as a solid, identical (at t.l.c. and m.p.) with the product from Intermediate 27. Removal of the protection as described in one of Examples 25 or 26 gives the title compound.

Example 31

2. 3, 4, 5- tetrahydro- 5^ methyl- 2-\( 5- methyl- 1H-imidazol-4- yl)-methyl- 1H- pyridof 4 , 3-b") indol- 1-one

A mixture of 4-[[[(3-iodo-1-methyl-1H-indol-2-yl)ethyl]-amino]-methyl]-N,N,5-trimethyl-1H-imidazole-1-sulfonamide ( 70 mg), triphenylphosphine (52 mg) and palladium acetate (22 mg) in tri-n-butylamine (5 ml) and dry THF (1 ml) were heated under an atmosphere of carbon monoxide at 120° for 1 hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid (50 mL) and the resulting mixture was extracted with ethyl acetate (2x50 mL; discarded). The acidic solution was then basified with 2N potassium carbonate and the resulting basic suspension was extracted with ethyl acetate (2x50 mL). The combined dried organic extracts were concentrated in vacuo and an oil and residual tri-n-butylamine were removed by distillation to leave a solid. This was adsorbed on FCC silica and purification by FCC and elution with System A (150:8:1) gave the protected derivative of the title compound (21 mg) as a solid, identical (at t.l.c. and m.p.) to the product from Intermediate 27 Deprotection as described in either Examples 25 or 26 provides the title compound.

Example 3 2

2, 3, 4. 5- tetrahydro- 5- methyl- 2- r( 5- methyl- 1H- imidazol- 4- vl)-methyl]- 1H- pyridof 4, 3- b] indol- 1- one

5,6-dihydro-1-[(5-methyl-1H-imidazol-4-yl)methyl]-4-(2-methyl-2-phenylhydrazino)-2(1H)-pyridinone (60 mg) was dissolved in glacial acetic acid (4 ml). Anhydrous zinc chloride (600 mg) was added and the mixture was heated at 85° for 1.5 hours. The cooled mixture was poured into 8% aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate:methanol (10:1) (2x100 mL). The combined, dried organic extracts were evaporated into

vacuum leaving a solid which on purification by FCC and eluting with System A (100:8:1) gave the title compound (26 mg). ^-H-N.m.r. and t.l.c. data taken for this material were consistent with those taken for the product from ex. 20.

Claims (2)

1. Analogy method for the preparation of therapeutic active compounds of general formula (I) where Im denotes an imidazolyl group of formula: and R<1> denotes a hydrogen atom or a group selected from C1-6-alkyl, <C>3-6-alkenyl, C3-10-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-<C>1-4-alkyl, phenyl-C1-3-alkyl , phenylmethoxymethyl, - CONR<5>R<6> or -SO2R5 (wherein R5 and R<6>, which may be the same or different, each represents a hydrogen atom or a C2_6~ alkyl group, with the proviso that R<5> does not denotes a hydrogen atom when R<1> denotes a group -SO2R<5>); R<3> and R<4> are each independently a hydrogen atom or a C 1-6 alkyl group; n represents 2 or 3; and physiologically acceptable salts and solvates thereof; characterized by: (A) alkylation of a compound of formula (II) with a compound of formula (III) or a protected derivative thereof, wherein L represents a leaving atom or group, followed if necessary by removal of any protecting groups present; or (B) for the preparation of a compound of formula (I) where n is 2, hydrogenating a compound of formula (IV) or a protected derivative thereof, followed if necessary by removal of any protecting groups present; or (C) ring formation in a compound of formula (V) wherein W represents a hydrogen atom and Y represents the group NH, or W represents a halogen atom and Y represents a bond, or a salt or protected derivative thereof, followed if necessary by removal of any protecting groups present; or (D) for the preparation of a compound of formula (I) where R<3 >denotes a hydrogen atom, reaction of a compound with formula (VI) or a protected derivative thereof, with formamide, followed if necessary by removal of any protecting groups present; or (E) conversion of a compound of formula (VII) where G represents a hydrogen atom or a protected derivative thereof, with phosgene in the presence of a Lewis acid; or where G represents a bromine or iodine atom or a protected derivative thereof, with carbon monoxide in the presence of a palladium(II) salt; followed if necessary by removal of any protecting groups present; or (F)(i) for the preparation of a compound of formula (I) where R-1- means a C3-g-alkyl group, hydrogenation of a compound of formula (I) where R<1> means a C3-g-alkenyl group or a C3-6 -alkynyl group or a protected derivative thereof, optionally followed by removal of any protecting groups present; (F)(ii) for the preparation of a compound of formula (I) where R-L means a hydrogen atom, hydrogenation of a compound of formula (I) where R<1> means a phenylmethoxymethyl group, or a protected derivative thereof, optionally followed by removal of any groups present; (F)(iii) for the preparation of a compound of formula (I) where R-L means a C-16-alkyl-, <C>3-6-alkenyl-, C3-10-alkynyl-, C3-7-cycloalkyl-, C3-7-<cy >chloroalkyl-C1-4-alkyl-, phenyl-C1-3-alkyl- or phenylmethoxymethyl group, or a compound where R<3 >means a C1-6-alkyl group, alkylation of a compound of formula (I) where one or both groups R< 1> and R<3> means a hydrogen atom, or a protected derivative thereof, optionally followed by removal of any protecting groups present; (F) (iv)' for the preparation of a compound of formula (I) where R<1> means -CONR<5>R<6> or -SO2R<5>, acylation of a compound of formula (I) where R <1> means a hydrogen atom, or a protected derivative thereof, optionally followed by removal of any groups present; or (G) removal of protecting group(s) from a protected form of a compound of formula (I); and where the compound of formula (I) is in the form of a free base, possibly transferring the free base to a salt. 2. Process according to claim 1 for the preparation of the 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 physiologically acceptable salts and solvates thereof, characterized by the use of corresponding starting materials.