PL164501B1 - Method of obtaining novel three-ring lactames - Google Patents

Abstract

A method of producing new tricyclic lactams Formula I wherein Im is an imidazolyl group of formula 2, Ri is atom hydrogen or a C1-C6-alkyl group, -CH2C2-Ca-alkynyl or C3-C7-cycloalkyl-Cs-C4-alkyl, n is 2 or 3, Q is a halogen atom or a hydroxyl group, phenyl-Ci-Ca-alkoxy, Ci-C6-alkyl or cyano and Q 'is hydrogen or fluoro and also the physiologically acceptable salts and solvates of these compounds characterized in that a) a compound of the general formula 3, wherein Ri, Q and Q 'and n are as defined above meaning, is alkylated with a compound of general formula XIm, where X is a group of formula -CH2L, w wherein L is a leaving atom or group separating, the reaction being carried out in the presence of a base or X is -CHiOH and the reaction is then carried out in the presence of an acid in elevated temperature, or is alkylated with the protected one a derivative of this compound, then optionally the protecting group or the protecting groups are removed when present, or b) the compound of Formula 1 is carried out transform into another compound of formula I, or c) from a protected one the compound of formula 1 in which (i) protected is the nitrogen atom on the indole and / or (ii) is protected a nitrogen atom in the imidazole and / or (iiii)

Description

The present invention relates to a process for the preparation of novel tricyclic lactams which are useful, in particular, in the treatment of psychotic disorders, anxiety, nausea and vomiting.

These compounds are potent and selective antagonists of the binding of 5-hydroxytryptamine (5-HT) to 5-HT receptors located at the endings of the main afferent nerves. These types of receptors are now called 5-HT3 receptors, and they are also present in the central nervous system. 5-HT is common in neural pathways in the central nervous system, and disruption of these 5-HT pathways is known to alter behavioral syndromes such as mood, psychomotor activity, appetite, and memory.

A new group of compounds, differing in structure from those described so far, and being potent and selective antagonists of 5-HT binding to 5-HT3 receptors has now been discovered. Some of these compounds have the advantage of showing a prolonged duration of action.

The process of the invention produces tricyclic lactams of the general formula 1, in which Im is an imidazolyl group of the formula 2, R 1 is a hydrogen atom or a C 1 -C 6 -alkyl group, -CH 2 C 2 -C 5 -alkynyl or a C 3 -C 6 -cycloalkyl group. C1-C4-alkyl, n is 2 or 3,

164 501

Q is halogen or hydroxy, phenyl-Ci-C6-alkoxy, Ci-C6-alkyl or cyano and Qi is hydrogen or fluorine, as well as physiologically acceptable salts and solvates of these compounds.

Suitable physiologically acceptable salts of compounds of formula I are acid addition salts with organic or inorganic acids, e.g., hydrochlorides, hydrobromides, sulfites, alkyl or arylsulfonates (e.g. methanesulfonates or toluenesulfonates), phosphates, acetates, citrates, succinates, tartrates, fumarates and maleates. Solvates can be, for example, hydrates.

Included within the scope of the invention are: all optical isomers of compounds of formula 1 and mixtures thereof, including racemates and all geometric isomers of compounds of formula 1. A particularly preferred group of compounds is formed by compounds of formula 1, wherein R is hydrogen or methyl, isopropyl, propyn-2-yl or cyclopentylmethyl, Q is fluoro or bromo or hydroxy, phenylmethoxy, methyl or cyano, Qi is hydrogen and n is 2.

Preferred compounds are 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazolyl-4) methyl] -1H-pyrido [4,3-6] indolone- 1,2,3,4,5-tetrahydro-5,6-dimethyl-2 - [(5-methyl-1Himidazolyl-4) methyl] -1H-pyrido [4,3-b] indolone-1,6, 9-difluoro-2,3,4,5-tetrahydro-5-methyl-2 [(5-methyl-1H-imidazolyl-4) methyl] -1H-pyrido [4,3-b] indolone-1,66 fluoro-2,3,4,5-tetrahydro-2 [(5-methyl-1H-imidazolyl-4) -methyl-5- (2-propynyl) -1H-pyrido [4,3-b] indolone- 1,2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazolyl-4) -methyl-1-keto-1H-pyrido [4,3-b] indole carbonitrile -6 and 6-fluoro-2,3,4,5-tetrahydro-5- (1-methylethyl) -2 - [(5-methyl-1H-imidazolyl-4) methylol 1H-pyrido [4,3-b] indolene-1 and their physiologically acceptable salts and solvates.

Compounds particularly advantageous for potency and duration of action are 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazolyl-4) methyl] -1H-pyrido [4 , 3-b] indolone-1 and its physiologically acceptable salts and solvates. The preferred salts are hydrochloride, maleate and benzoate. The compounds of formula 1 and their physiologically acceptable salts and solvates can be prepared by the methods described below, wherein R 1, Q, Q ', n and Im are as defined in formula 1.

According to process a) compounds of formula 1 can be prepared by alkylating a compound of formula 2 with a compound of formula X-Im in which X is a group of formula -CH2L. wherein L is a leaving atom such as a halogen atom (e.g. chlorine, bromine or iodine) or a leaving group such as an acyloxy group (e.g. trifluoroacetyloxy or acetoxy) or a sulfonyloxy group (e.g. trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or p-toluenesulfonyloxy) methanesulfonyloxy), the reaction is carried out in the presence of a base or X is a -CH 2 OH group and then the reaction is carried out in the presence of an acid at an elevated temperature or by alkylation with a protected derivative of this compound. After the alkylation reaction, the protecting group or groups, if present, are optionally removed.

According to the first variant of process a), a reaction is carried out with a compound of formula X-Im in which X is a group of formula -CH2L, in which L is preferably a halogen atom (e.g. chlorine). The reaction may be carried out in an inert solvent such as an ether (e.g. dimethoxyethane, diethylene glycol dimethyl ether or tetrahydrofuran), a substituted amide (e.g. dimethylformamide or N-methylpyrrolidone), an aromatic hydrocarbon (e.g. toluene), a ketone (e.g. acetone) or dimethylsulfoxide at room temperature to 100 ° C in the presence of a base. Suitable bases are 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 tert-butoxide) or metal hydroxides alkali (e.g. sodium or potassium hydroperoxide).

According to a second variant of process a), a reaction is carried out with a compound of formula X-Im in which X is -CH 2 OH in the presence of an acid. The acid can be, for example, a strong mineral acid (e.g. hydrochloric acid) or a hydrocarbon sulfonic acid (e.g. toluenesulfonic acid). The reaction may conveniently be carried out in a high boiling polar solvent such as N-methylpyrrolidinone or dimethylacetamide at an elevated temperature, e.g. 100-200 ° C. The reaction can also be carried out in water or an alcohol (e.g. isopropanol) at the reflux temperature of the solvent.

164 501

According to method b) a compound of the formula 1 can be converted into another compound of the formula 1 by following known procedures; for example by carrying out alkylation, optionally using protecting groups which are then cleaved off.

The term "alkylation in method b) means the introduction of a group such as cycloalkylalkyl or alkynyl. Thus, for example, a compound of Formula 1 wherein R ¹ is C 1 -C 6 -alkyl, -CH 2, C 2 -C 5 -alkynyl or C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl may be prepared by alkylating a compound of Formula 1, in which R 1 is a hydrogen atom according to known methods, e.g., given in European Patent No. 242,973. This reaction can be performed using a suitable alkylating agent of the formula R ² Z (wherein R ² is the group to be introduced and Z is a leaving atom or a leaving group), preferably in the presence of a base.

It should be taken into account that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of a given compound in order to avoid undesirable side reactions. For example, it may be necessary to protect the nitrogen atoms of the indole and / or imidazole with a group such as arylmethyl (e.g., trityl), arylmethoxymethyl (e.g., phenylmethoxymethyl), alkyl (e.g., beta-butyl), alkoxymethyl (e.g., methoxymethyl) , acyl (e.g. benzyloxycarbonyl) or sulfonic (e.g. N, N-dimethylaminosulfonyl or p-toluenesulfonyl). When Q is hydroxy it may need to be protected with an arylmethyl group (e.g. benzyl or trityl).

Thus, according to process c), a compound of formula 1 may be prepared by cleavage of the protecting group or groups on the protected compound of formula 1. Protecting groups may be cleaved using known methods, e.g. as given in Protectove Groups in Organic Synthesis, TW Greene (John Wiley and Sons, 1981).

For example, an aryl methoxymethyl group protecting the nitrogen atom may be cleaved by hydrogenolysis in the presence of a catalyst (e.g. palladium on carbon). The trityl group can be cleaved by acid hydrolysis (e.g. using dilute hydrochloric or acetic acid). The alkoxyalkyl group can 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). The sulfonyl group can also be removed by acidic or basic hydrolysis, and the N, N-dimethylaminosulfonyl group (e.g., at the nitrogen atom in imidazole) can also be removed by photolysis. The arylmethyl group protecting the OH group can be cleaved under acidic conditions (e.g. by treatment with dilute acetic acid, hydrobromic acid or boron tribromide) or by hydrogenolysis in the presence of a catalyst (e.g. palladium on carbon).

If a compound of Formula 1 needs to be isolated as a salt, e.g. a physiologically acceptable salt, the salt can be prepared by treating the free base compound of Formula 1 with a suitable acid, preferably in an equivalent amount, in a suitable solvent such as an alcohol (e.g. ethanol). or methanol), an aqueous alcohol (e.g., aqueous ethanol), a halogenated hydrocarbon (e.g., dichloromethane), an ester (e.g., ethyl acetate), or an ether (e.g., tetrahydrofuran).

Physiologically acceptable salts can also be prepared from other salts, including the physiologically acceptable salts, of the compounds of Formula 1 using known methods. Certain diastereoisomers of compounds of formula I can be obtained by separating a mixture of enantiomers (e.g. a racemic mixture) by known methods, e.g. using an optically active acid [e.g. Stereochemistry of Carbon Compounds, E. L. Eliel (Me Graw Gill, 1962) and "Tables of Resolving Agents, S. H. Wilen].

The methods for the preparation of the compounds of Formula 1 described above may be used to introduce the desired groups at any stage of the multi-step process for producing the desired compounds, it being appreciated that the methods may also be combined in such a multi-step process. The sequence of reactions in a multistage process should of course be chosen such that the conditions used do not affect the groups in the molecule which are desired in the product.

The starting compounds of formula III in which R1 is hydrogen can be prepared, for example, by cyclization of a compound of formula IV in which X is hydrogen or halogen (e.g. bromine or iodine). The cyclization can be performed using methods analogous to that described by H. Iida et al. In J. Org Chem., 44, 2293, 1998.

164 501

Compounds of formula 3 in which R ¹ is not hydrogen can be prepared from a compound of formula 3 in which R 1 is hydrogen by known alkylation methods, e.g. as described for process b).

Compounds of formula 4 can be prepared by reacting a compound of formula 5, wherein X is as defined above, with a compound of formula 6 at elevated temperature.

The starting compounds of the formula X-Im and their protected derivatives can be prepared, for example, by methods analogous to the method described in European Patent No. 242,973. Compounds of the formulas 5 and 6 are known or can be prepared from known compounds by known methods.

The activity of compounds of formula 1 as potent and selective antagonists of 5-HT binding to 5-HT 3 receptors was demonstrated by determining their ability to inhibit 3 - ^. ^^^^ t: y ^ <^ -1Himidazolyl-4 / -1- [1 - / methyl-t3 / -1H-indolyl-3] propanone-1 in rat nasal homogenates (according to the method described by G. Kilpatrick et al. in Nature, 330, 746, 1987) and / or their ability to inhibit the induced 5-HT depolarization of an isolated rat vagus nerve preparation.

The compounds of formula I, which are antagonists of 5-HT binding to HT3 receptors, are useful in the treatment of conditions such as psychotic disorders (e.g., schizophrenia and psychosis), anxiety, nausea and vomiting, especially associated with chemotherapy and radiotherapy of neoplastic diseases and emerging in postoperative states. The compounds of formula I are also useful in the treatment of gastric congestion, symptoms of gastrointestinal dysfunction such as dyspepsia, peptic ulcer, retrograde esophagus, flatulence and irritable bowel syndrome, migraines, obesity and conditions such as sick hunger, and pain. The compounds of formula I can also be used in the treatment of drug dependence and excessive drug dependence, depression, dementia and other disturbances of consciousness.

Biological data.

The potent and selective antagonism of 5-HT 3 binding to 5-HT 3 receptors induced by the new compounds was determined in vitro, according to the method described by G. Kilpatrick et al in "Nature, 330, 746, 1987, their ability to inhibit 3- ( 5-methyl-1H-imidazolyl-4) -1- [1 (methyl-ts) -1H-indolyl-3] propanone-1 in rat nasal mucosa homogenates. The results of these trials were expressed in terms of pKi values. The compounds prepared in Examples 1 and ΙΙΙ-ΧΙΙ showed pKi values greater than 9.0.

The compounds according to the invention can be formulated as pharmaceuticals. These compositions contain at least one compound of the formula I or a physiologically acceptable salt or solvate (e.g. hydrate) thereof as active ingredient. These compositions are intended for human and veterinary use and are in a form suitable for administration by any route.

The antagonism of the 5-HT binding response to 5-HT3 receptors by the new compounds can be determined in vivo by determining the effect of these compounds on the 5-HT binding induced Bezold-Jarisch reflex in the cat. This test was carried out according to the method described by D. P. Collins and D. H. Fortune in British Journal Pharmacology, 1983, 80, 570P. The results are shown in the table below which gives the duration of action (DR5) with the compound administered intravenously (i. V.) At a dose of 1 µg / kg. The DR5 value is the approximate dose required to be developed

A 5-fold to the right of the dose response curve for 2-methyl-5-HT.

Table

Relationship by example Duration of DRs AND 52 II 87 IV 63

Toxicity

The toxicity of the new compounds was determined by intravenous administration of these compounds to mice. The compounds prepared in Examples I, III, VIII, IX and X, when administered in doses of 3 mg / kg, showed no side effects.

164 501

The pharmaceutical compositions can be manufactured in known manner using one or more physiologically acceptable carriers and / or excipients. Thus, the compounds of formula I may be formulated for oral, buccal, parenteral or rectal administration, or in the form of formulations suitable for administration by inhalation or insufflation (through the mouth or nose).

The proposed dose, when administered to a human (about 70 kg body weight), is 0.001-100 mg, preferably 0.01-50 mg, especially 0.1-20 mg of active ingredient, based on the free base, per dosage form and may be administer e.g. 1-4 times a day. It should be understood that the dosage can be changed routinely depending on the age and condition of the patient. The dosage will also depend on the route of administration.

The invention is illustrated by the following Examples, with Examples XVHI-XLV relating to the preparation of the starting compounds.

Thin layer chromatography (TLC) was performed using silica and flash column chromatography (FCC) was performed using silica (Merck 9385). System A used for chromatography was a mixture of dichloromethane, ethanol and ammonia solution (density 0.88 g / ml). The organic extracts were dried, when indicated, over magnesium sulfate or sodium sulfate. The abbreviations used have the following meanings: DMF - dimethylformamide, THF - tetrahydrofuran, DME - dimethoxyethane, m.p. - melting temperature. 1 H-NMR spectra were obtained at 250 MHz with dilute solutions in dimethylsulfoxide.

Example I. Preparation of 6-nuoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazolyl-4) methyl] -1H-pyrido [4,3-b] maleate -indolone-1.

To a stirred suspension of 115 mg of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indolone-1 in 7.5 ml of DME was added under a nitrogen atmosphere 25 mg of 60 % sodium hydride dispersion in oil. The mixture was heated at 50 ° C for 6 hours, and after adding 236 mg of 4-chloromethylt5-methyl-1-triphenylmethyl-1H-imidazole, stirring was continued at 50 ° C for 18 hours. After adding 1.25 ml of water and 1.25 ml of acetic acid, the solution was refluxed for 6 hours. The mixture was poured into 40 mL of 8% aqueous sodium bicarbonate solution and extracted with dichloromethane (3 X 20 mL). The combined, dried organic extracts were evaporated to give 375 solids. The material was purified by FCC using system A (200: 10: 1) as eluent to give 147 mg of the free base as a solid corresponding to the title compound. This material was dissolved in 3 mL of dichloromethane, and a solution of 55 mg of maleic acid in 95 mL of absolute ethanol was added to the solution. The solvent was removed in vacuo and the residue was triturated with anhydrous ether (3 x 5 mL). 185 mg of the title compound at 1.178-180 ° C were obtained.

Elemental analysis for C17H17FN 4'C4H4O4 Found: C 59.0, H 5.0, N 12.85

Calculated: C, 58.9, H 4.9, N 13.1%

The products of Examples 2 through 9 were prepared in a similar manner to that of Example 1 by reacting the appropriate lactam with 4-chloromethyl-5-methyl-1-triphenylethyl-1-H-thimidazole (called compound X) in DME in the presence of sodium hydride.

The protecting groups were removed by treatment with acetic acid and water, and then the solution was basified with 2N sodium hydroxide solution, not with 8% sodium bicarbonate solution. The basic solution was extracted with dichloromethane (or ethyl acetate in examples 4 and 8) and the combined, dried extracts were evaporated in vacuo. The residue was purified by FCC using the system A as eluent [Examples II, IV, V, VIII, IX (150: 8: 1) and Examples III, VI, VII (100: 8: 1)] to obtain a free base corresponding to the title compound . Maleate was prepared as in Example 1, except that methanol (instead of ethanol) was used as solvent for recrystallization and the mixture was heated in a bath for 10 minutes. The product was obtained from the methanol solution by evaporation to dryness in vacuo and then trituration of the residue with ether (Examples III, VI) or by recrystallization of the residue from a mixture of methanol and ether (Example VII) or the product was precipitated from the methanol solution by adding ether (Examples II, IV) , V, VIII, IX).

164 501 Ί

Example II. Preparation of 2,3,4,5-tetrahydro-5,6-dimethyl-2 - [(5-methyl-1Himidazolyl-4) methyl] -1H-pyrido [4,3-b] indolone-1 maleate

Reaction of 150 mg of 2,3,4,5-tetrahydro-5,6-dimethyl-1H-pyrido [4,3-b-indolone-1 with 260 mg of compound X yielded 120 mg of the free base corresponding to the title compound. After the maleate preparation 110 mg of the title compound was obtained. TLC (system A, 150: 8: 1) Rf = 0.3 ¹ H-NMR δ 2.35 (3H, s), 2.75 (3H, s), 3.08 (2H, t), 3, 64 (2H, t), 3.93 (3H, s), 4.62 (2H, s), 6.07 (2H, s), 6.90 (1H, brd), 7.01 (1H, t ), 7.88 (1H, brd), 8.73 (1H, brs).

Exemplary. Preparation of 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazolyl-4) methyl] -1H-pyrido [4,3-b] indolone-1 maleate

In the reaction of 140 mg of 6-bromo-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidaz.olyl-4) methyl] -1H-pyrido [4,3-b ] indolone-1 with 280 mg of compound X yielded 130 mg of the free base corresponding to the title compound. After formation of the maleate, 170 mg of the title compound were obtained, m.p. 155 ° C.

Water content

Found: 2.86 wt.% = 0.79 mol of H 2 O

Elemental analysis for C17HrzBrN4O · C4H404.0.79 H2O Found: C 501, H 4.4, N 10.7

Calculated: C 50.1, H 4.5, N 11 119%

Example IV. Preparation of 6,9-difuoro-2,3,4,5-tetrahydro-5-methyl-2 [(5-methyl-1H-imidazolyl-4) methyl] -1H-pyrido [4,3-b] indolone-1 maleate

By reacting 1.0 g of 6,9-difluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indolone-1 with 1.7 g of compound X, 846 mg of the free base was obtained corresponding to the title compound. After formation of the maleate, 920 mg of the title compound were obtained, m.p. 206-208 ° C.

Elemental analysis for C17H16N4O.C4H4O4 Found: C56.1, H 4.6, N 12.6

Calculated: C 56.5, H 4.5, N 11.6%

Example 5 Preparation of 7-ffuoro-3,4,5,6-tetrahydro-6-methyl-2 - [(5-methyl-1H-imidazolyl-4) methyl] -2H-azepino [4,3-b] indolone maleate -1

Reaction of 850 mf 7-fluoro-3,4,5,6-tetrahydro-6-methyl-2H-azepino [4,3-b] indolone-1 with 1.46 g of compound X gave 358 mg of the free base corresponding to the title compound. After formation of the maleate, 383 mg of the title compound were obtained, m.p. 143-145 ° C.

Water content

Found: 1.19 wt.% = 0.296 mol of H 2 O

Elemental analysis for C1eH19N4OF.C4H4O4.0.296 H 2O Found: C 59.2, H 5.6, N 12.1

Calculated: C 59.0, H 5.3 NI 2 <%

Example VI. Preparation of 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1Himidazolyl-4) methyl] -6-phenylmethoxy-1H-pyrido [4,3-b] indolone-1 maleate

Reaction of 900 mg 2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indolone-1 with 1.6 g of the compound X gave 800 mg of the free base corresponding to the title compound. An aliquot of the free base (90 mg) was treated with maleic acid to give 90 mg of the title compound, m.p. 158-160 ° C. TLC (system A, 100: 8: 1) Rf = 0.2.

Example VII. Preparation of 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1Himidazolyl-4) methyl] -1-keto-1H-pyrido [4,3-b] indole-carbonitrile-6 maleate

The reaction of 550 mg 2,3,4,5-tetrahydro-5-methyl-1-keto-1H-pyrido [4,3-b] indole carbonitrile-6 with 1.3 g of compound X yielded 410 mg of the free base corresponding to the title compound . An aliquot of the free base (100 mg) was treated with maleic acid to give 50 mg of the title compound. TLC (A system, 100: 8: 1) R f = 0.2.

Elemental analysis for CisH17N5O · C4H4O4 Found: C 60.4, H 4.8, N NS!

Calculated: C ^ 0.7, H 4.9, N 16.0%

Example VIII. Preparation of 6-fluoro-2,3,4,5-etrahydro-5- (1-methylethyl) -2 [(5-methyl-1H-imidazolyl-4) methyl] -1H-pyrido [4.3] maleate -b] indolone-1

164 501

The reaction of 130 mg of 6-fluoro-2,3,4,5-tetrahydro-5- (1-methylethyl) -1H-pyrido [4,3-b] indolone-1 with 295 mg of compound X yielded 69 mg of the free base corresponding to title compound. An aliquot of the free base (66 mg) was treated with maleic acid to give 79 mg of the title compound, m.p. 185-187 ° C.

Elemental analysis for C19H21FN4O · C4H4O4 Found: C 66.2, H 5.6, N 12.0

Calculated: C 66.2, H 5.5, N 62.33%

Example IX. Preparation of 5-cyclopentylmethyl-6-fluoro-2,3,4,5-tetrahydro-2 [(5-methyl-1H-imidazolyl-4) methyl] -1H-pyrido [4,3-b] indolone- maleate 1

Reaction of 222 mg of 5-cyclopentylmethyl-6-ffuoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolone-1 with 317 mg of compound X gave 100 mg of the free base corresponding to the title compound. After formation of the maleate, 85 mg of the title compound were obtained, m.p. 164-166 ° C.

Elemental analysis for C22H25FN4O · C4H4O4 Found: C 62.2, H 5.9, N21.1

Calculated: C 62.9, H 5.9, N 61.23%

Example X. Preparation of 2-fluoro-2,3,4,5-tetrahydrot2-t [(5-methyl-1H-imidazolyl-4) methyl J-5- (2-propynyl) -1H-pyrido [4,3-b] indolone maleate -1

To a stirred solution of 228 mg of 6-fluoro-2,3,4,5-tetrahydro-2t [(5-methyl-1-triphenylmethyl-1H-thimidazolyl-4) methyl] -1H-pyrido [4,3-b] indolone-1 in 40 ml of anhydrous acetone with the addition of 116 mg of anhydrous potassium carbonate was added 1 ml of a 10% v / v propargyl bromide solution in acetone and the mixture was refluxed overnight. After cooling, excess acetone was removed in vacuo and the residue was partitioned between 100 ml of water and 100 ml of ethyl acetate. The organic phase was washed with water (2 X 50 ml) and the combined aqueous extracts were washed with ethyl acetate (50 ml). The combined organic extracts were concentrated in vacuo and the residue was dissolved in a mixture of 100 ml of water and 10 ml of glacial acetic acid and 15 ml of THF, and the solution was refluxed for 2 hours. The cooled solution was basified with 2N sodium hydroxide solution (about 100 ml) and extracted with ethyl acetate (2 X 100 ml). The combined, dried organic extracts were loaded onto silica and purified by FCC using system A (100: 8: 1) as eluent. 95 mg of the free base corresponding to the title compound was obtained. The base was dissolved in a minimum amount of hot anhydrous methanol, and 32 mg of maleic acid was added to the solution. The solution was warmed up and allowed to cool. After the addition of ether to precipitate the product, 80 mg of the title compound were obtained, m.p. 123-124 ° C.

Elemental analysis for C19H17FN4O · C4H4O4 Found: C 60.9, H 4.7, N 22.1

Calculated: C 61.1, H4.7, N 12.4%

Example XI. Preparation of 2-fluorot2,3,4,5 tetrahydro-2t [(5-methylth1Himidazolylth4) methyl] -1H-piiydo [4,3-b] indole maleate 1

Solution of 175 mg of 2-fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-thimidazolyl-4) mttyl] --- phenylmethoxymtryl-1H-pyrido [4,3-b] indolone-1 in 10ml absolute ethanol with 2.5 ml of acetic acid was hydrogenated for 20 hours at room temperature under atmospheric pressure in the presence of 10% palladium on carbon (45 mg of 50% aqueous paste) as a catalyst in 2 ml of absolute ethanol. After addition of an additional 45 mg of catalyst, stirring was continued for 20 hours. The mixture was filtered and the filtrate was evaporated to dryness. 50 mL of 8% sodium bicarbonate solution was added to the residue, and the mixture was extracted with dichloromethane (3 X 25 mL). The combined, dried organic extracts were evaporated to about 130 mg of an oil. The oil was purified by FCC using A system (150: 10: 1) as eluent to give 102 mg of the free base corresponding to the title compound. The base was dissolved in about 2 ml of ethanol, and 42 mg of maleic acid in 0.5 ml of ethanol was added to the solution. The solvent was removed in vacuo and the residue was triturated with anhydrous ether (5 X 5 mL). 120 mg of the title compound were obtained, m.p. 186-188 ° C.

Elemental analysis for CieH 15 FN4O · C4H4O4 Found: C 57.8, H 4.7, N 12, 1

Calculated: C 58.0, H 4.6, N 11.5%

164 501 9

Example XII. Preparation of 2,3,4,5-tetrahydrof-6-eyaroxy-2 - [(5-methyl-1Himiaazolyl-4) methyl] -1H-pyrido [4,3-b] indolone-1 maleate

Solution 600 mg 2,3,4,5-etraeydro-2 - [(5-methyl-1H-imidaz.olylf-4) methyl] -6-phenylmethoxy-5-fcnylmethoxymethyl-1H-pyrido [4,3-b] indolone -1 in 80 ml of absolute ethanol with the addition of 4 ml of acetic acid was hydrogenated for 24 hours at room temperature under atmospheric pressure in the presence of 10% palladium on carbon (100 mg of 50% aqueous paste) as a catalyst. The mixture was filtered and the filtrate was concentrated in vacuo. About 150 ml of 8% sodium bicarbonate solution was added to the residue and the mixture was filtered. The filtered solid was washed with about 100 mL of water, dissolved in 200 mL of ethanol, and the solution was concentrated in vacuo to give 320 mg of a solid. This material was purified by FCC using system A (100: 8: 1) as eluent to give 100 ml of the free base corresponding to the title compound. 39 mg of maleic acid was added to a solution of 100 mg of the free base in 20 ml of methanol. The solution was heated on the steam bath for 10 minutes and concentrated in vacuo. After dissolving the residue in 2 ml methanol and added to a solution of 80 ml of ether to give 100 mg of the title compound, mp 130 ^o C. TLC (System A, 100: 8: 1, twice elution) Rf = 0.3.

Example XIII. Preparation of e-fluoro-2,3,4,5-tetraeya-5-methyl-2 - [(5-methyl-1H-imidazolyl-methyl] -1H-pyrido [4,3-b] inaolone-1 hydrochloride

For a solution of 260 mg 6-fluoro-2,3,4,5-tetrahyarf-5-methyl-2 - [(5-methyl-1H-imiaazolyl-4) methyl] -1H-pyrido [4,3-b] indolone- 1 in 10 ml of methanol, ethereal hydrogen chloride was added and the mixture was concentrated in vacuo. The residue was triturated with 15 ml of ether to give 230 mg of the title compound as a solid, m.p. 275-278 ° C.

Water content

Found: 3.73 wt.% = 0.75 moles of H 2 O

Elemental analysis for C17H17FN4O · HCl · 0.75 H2O Found: C 55.8, H 5.3, N 15.2

Calculated: C 56.3, H 4.4, N 15.4%

Example XIV. Preparation of e-fluoro-2,3,4,5-tetrahydro-5-methyl-2 [(5-methyl-1H-imidazolyl-2-methyl] -1H-pyrrolo [4,3-b] indolone-1 benzoate

For a solution of 170 mg of 6-fluorph-2,3,4,5-tetraeyaro-5-methyl-2 - [(5-methyl-1H-imidazolyl-4) methyl] -1H-pyrido [4,3-b] mdolone -1 in 10 ml of methanol 66 mg of benzoic acid was added. After about 20 ml was added, the precipitated solid was filtered off to give 220 mg of the title compound, m.p. 169-171 ° C.

Elemental analysis for C17H17FN4O · C7H6O2 Found: C 66.3, H 4.4, N 12.8

Calculated: C ^^, 3, H 5.3, N 12.9%

Example XV. Preparation of 6-nuoro-2,3,4,5-tetraeydro-5-methyl-2 - [(5-methyl-1Himidazolyl-methyl] -1H-pyrido-^^ - blindolone-1

To a solution of 100 mg of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indolone-1 in 10 ml of N-methylpyrrolidinone was added 17 mg of p-toluenesuffonic acid monohydrate and 37 mg of 4-hydroxymethyl-5-methyloomidazole hydrochloride. The mixture was heated to 125 ° C for 18 hours during which time an additional 3 portions of 37 mg of N-hydroxymethylf-5-methylphimidazflu hydrochloride were added after 1, 2 and 3 hours, respectively. The solution was poured into 100 mL of 8% sodium bicarbonate solution and the mixture was extracted with dichloromethane (3 x 100 mL). The combined extracts were concentrated in vacuo and N-methylpyrrolidinone was distilled off at 100 ° C. The residue was purified by FCC using the A system (200: 8: 1) as eluent to give 100 mg of the title compound.

TLC (A system, 100: 8: 1) R _f = 0.3,

1H-NMR δ 2.36 (3H, s), 3.12 (2H, t), 3.67 (2H, t), 3.90 (3H, s), 4.66 (2H, s), 6 . 07 (2H, s), 6.95-7.2 (2H, m), 7.80 (1H, d), 8.80 (1H, s).

Example XVI. Preparation of 6-fluorph> -2,3,4,5-tetrahydro-5-methylf-2 - [(5-methyl-1H-imidazolyl-4) methylf] -1H-pyrido [4,3-b] indolone- 1

To a stirred solution of 100 mg of 6-flufro-2,3,4,5-tetraeyarΌ-2 - [(5-methyl-1-triphenylphenyl-1H-imiaazolyl-4) methyl] -1H-pyrrolo [4,3-b] indolphne- 1 in 15 ml of DMF was added 10.5 mg of a 73.2% dispersion of sodium hydride in oil, and the mixture was stirred under a nitrogen atmosphere under

164 501 room temperature for 20 minutes. After adding 1 ml of a 2.3 vol.% Solution of methyl iodide in dry DMF, the solution was stirred for an additional 20 minutes. The reaction mixture was added to 100 mL of water and extracted with ethyl acetate (2 X 50 mL). The combined organic extracts were washed with water (2 X 100 mL), dried and concentrated in vacuo. The resulting solid was dissolved in a mixture of 10 mL of THF, 10 mL of water, and 10 mL of acetic acid, and the solution was refluxed for 3 hours. THF was removed in vacuo and the remaining solution was added to 2N sodium hydroxide solution (pH ~ 14) and the mixture was extracted with ethyl acetate (3 X 50 ml). The combined, dried organic extracts were loaded onto silica and purified by FCC using system A (100: 8: 1) as eluent. 45 mg of the title compound were obtained, m.p. 234-235 ° C.

The 1 H-NMR spectrum of this product was consistent with that of the product obtained in Example XV.

Example XVII. Preparation of 6-methyl-1H-imidazole.quant.4) methyl] -1H-pyrido [4,3b] indolone

A solution of 100 mg of 4 - [(6-fluoro-2,3,4,5-tetrahydro-5-methyl-oxyceto-1H-pyrido [4,3b] indolyl-2 / methyl] dimethyl-1H-imidazolecarboxylate-isphenylmethyl in 20 ml ethanol and 10 ml 2n The hydrochloric acid solution was heated on the steam bath for 10 minutes The cooled reaction mixture was added to 5 mL of water and 20 mL of 2N sodium hydroxide solution and the mixture was extracted with ethyl acetate (2 X 75 mL). The combined, dried organic extracts were loaded onto silica and purified by FCC. Using system A (100: 8: 1) as eluent, trituration of the resulting solid with ether gave 50 mg of the title compound, mp 232-233 ° C.

The ¹ H-NMR spectrum of this product was consistent with that of the product obtained in Example XV.

Example XVIII. Preparation of 4- / 2-fluorophenylamine Os5, (6-dihydro-1H-pyridinone Us2

A mixture of 0.98 g of 2-fluoroaniline and 1.0 g of 2,4-dimetopyridine was heated at 120 ° C for 2 hours. The cooled mixture was triturated with anhydrous ether (5 X 40 mL) and the solvent was decanted. 1.495 g of the title compound are obtained, m.p. 98-100 ° C.

Example XIX. Preparation of 5,6-di.hydroxy4- (2-methylphenylamino) -1H-pyridinoneUś2

A mixture of 943 mg of o-toluidine and 1.0 g of 2,4-dimetopiperidine was heated at 120 ° C for 30 minutes. The oil was cooled, triturated with 30 mL of ether and the solvent was decanted. 1.74 g of the title compound were obtained, m.p. 155-158 ° C.

Example XX. Preparation of 4-(2,6-dibromophenylamino) -5,6-dihydro-1H-pyridinone-2

A mixture of 4.4 g 2,6-dibromoaniline and 2.0 g 2,4-dimo-piperidine was heated at 120 ° C for 2.5 hours. The mixture was cooled (0 ° C) and triturated with 100 mL of ether. The resulting solid was purified by FCC using system A (100: 8: 1) as eluent. 1.8 g of the title compound are obtained, m.p. 240 - 243 ° C.

Example XXI. Preparation of 4- (2,5-difuorophenylamino) -5,6-dihydro-1H-pyridinone-2

A mixture of 6.45 g of 2,5-bis-difluoroaniline and 1.56 g of 2,4-dimetopiperidine was heated under nitrogen for 6 hours. The reaction mixture was dissolved in 50 ml of ethanol, the solution was loaded on silica and purified by FCC using system A (150: 8: 1) as eluent. 2.3 g of the title compound are obtained, m.p. 252-255 ° C.

Example XXII. Preparation of 3- (2-Fluorophenylamino) cyclohexen-2-one-1 g of 2-fluoroaniline and 10 g of 1,3-cyclohexanedione were heated under nitrogen at 120 ° C for 1 hour. The cooled mixture was triturated with ether and filtration gave 14.8 g of the title compound, m.p. 116-118 ° C.

Example XXIII. Preparation of 6-fluoro-2,3,4,5-syirahydro-1H-pyrido [4,3-b] -ndolone-1

To a stirred solution of 1.4 g 4- (2-uorophenylamino) ś 5,6-dihydro-1H-pyridinone-2 and 280 mg of palladium (II) acetate in 28 ml of anhydrous DMF was added 2.71 g of cupric acetate under nitrogen. The mixture was heated at 130 ° C for 1.5 hours and the solvent was removed in vacuo. The residue was triturated with 50 mL of hot methanol and the suspension was filtered and washed with hot methanol (3 X 50 mL). The combined filtrates were evaporated to give 2.16 g of a resin. The resin was purified by FCC using system A (200: 10: 1) as eluent. 490 mg of the title compound were obtained, m.p. 255-257 ° C.

164 501

Example XXIV. Preparation of 2,3,4,5-tetrahydro-6-methyl-1H-pyrido [4,3-b] -indolone-1

To a stirred solution of 1.5 g of 5,6-dihydro-4- (2-methyloffnylamino) -1H-pyridinone-2 and 230 mg of palladium (II) acetate in 40 ml of DMF, 2.9 g of cupric acetate was added. The mixture was heated at 130 ° C for 1 hour and evaporated in vacuo and the residue was extracted with 250 ml of methanol. The solution was concentrated in vacuo and the residue was purified by FCC using the A system (100: 8: 1). 360 mg of the title compound were obtained, m.p. 300-302 ° C.

Example XXV. Preparation of 6-bromo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] -indolone-1

0.5 g of 4- (2,6-dibromophenylamino) -5,6-dihydro-1H-pyridinone-2 was cyclized as described in Example 24. 250 mg of the title compound were obtained, m.p. 265-270 ° C.

Example XXVI. Preparation of 6,9-difluoro-2,3,4,5-tetrahydro-1H-pyrido- ² [4,3-b] -indolone-1

2.24 g of 4- (2,5-di-difluorophenylamino) -5,6-dihydro-1H-pyridinone-2 was cyclized as described in Example 23. 900 mg of the title compound were obtained, m.p. 221-223 ° C.

Example XXVII. Preparation of 8-Fluoro-1,2,3,9-tetrahydro-4H-carbazolone-4

14.8 g of 3- (2-fluorophenylamino) cyclohexen-2-one-1, 1 g of palladium (II) acetate and 29.5 g of copper (II) acetate were heated together in 100 ml of DMF under nitrogen at 140 ° C for 2 hours. The solvent was removed in vacuo and the residue was purified by FCC using ether as eluent. 10.1 g of the title compound are obtained, m.p. 222-224 ° C.

Example XXVIII. Preparation of 2,3,4,5-tetrahydro-6-phenylmethoxy-1H-pyrido [4,3-b] indolone-1

A mixture of 7.6 g of 2- (phenylmethoxy) aniline and 4.5 g of 2,4-dimetopiperidine was heated at 120 ° C under nitrogen for 3 hours. The mixture was cooled and purified by FCC using A (100: 8: 1) as eluent to afford 5.4 g of a solid. This material was treated as described in Example 24. 4.0 g of the title compound are obtained, m.p. 182-185 ° C.

Example XXIX. Preparation of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indolone-1

To a stirred suspension of 500 mg of 6-fluoro-2,3,4,5-ietrahydro-1H-pyrido [4,3b] indolone-1 in 10 ml of DMF was added 196 mg of 60% sodium hydride-oil dispersion under nitrogen. After 30 minutes, the solution was cooled (0 ° C) and 0.153 ml of methyl iodide was added thereto. After stirring for 15 minutes, the suspension was poured into 50 mL of water and the mixture was extracted with dichloromethane (3 X 25 mL). The combined and dried organic extracts were evaporated to give about 530 mg of a solid. This material was purified by FCC using A system (250: 10: 1) as eluent. 130 mg of the title compound were obtained, m.p. 242 ° C.

Example XXX. Preparation of 2,3,4,5-tetrahydro-5,6-dimethyl-1H-pyrido [4,3-b] indolone-1

To a stirred solution of 350 mg of 2,3,4,5-tetrahydro-6-methyl-1H-pyrido [4,3b] indolone-1 in 15 ml of DMF was added at 21 ° C under nitrogen atmosphere 140 mg of 60% sodium hydride dispersion in oil. After 15 minutes, the solution was cooled (0 ° C) and 1.14 ml of a 10% by volume solution of methyl iodide in DMF was added dropwise thereto. After 10 minutes, 100 mL of water was added and the mixture was extracted with ethyl acetate (2 X 50 mL). The combined organic extracts were washed with 100 ml of water and 100 ml of brine then evaporated. The resulting solid was purified by FCC using a mixture of dichloromethane and ethanol (80: 1) as eluent. 190 mg of the title compound were obtained, m.p. 298-300 ° C.

The products of Examples XXXI and XXXII were prepared in a similar manner to the product of Example XXX by methylating the appropriate 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolone-1 with sodium hydride and methyl iodide in DMF .

Example XXXI. Preparation of 6-bromo-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indolone-1

Methylation with 200 mg of 6-bromo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolone-1 gave 80 mg of the title compound, m.p. 212-214 ° C.

Example XXXII. Preparation of 6,9-difluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indolone-1

164 501

Methylation of 900 mg of 6,9-difluoro-2,3,4,5-tetrahydro-1H-plido [4.3tb] indolone1 gave 110 mg of the title compound, m.p. 226-229 ° C. For FCC purification, system A (150: 8: 1) was used as eluent.

Example XXXIII. Preparation of 8-fluoro-1,2,3,9-tetrahydrot-9-methyl-4H-carbazolone-4 To a suspension of 1.15 g of an 80% sodium hydride dispersion in oil and 50 ml of THF was added 6.5 g of 8-fluoro 1,2,3,9-tetrahydrot4H-carbazolone in 50mL anhydrous THF and the mixture was stirred for 1 hour. The mixture was poured into 300 mL of brine and extracted with ether (2X300 mL). The combined, dried extracts were evaporated in vacuo. 5.77 g of the title compound are obtained, m.p. 126-128 ° C.

Example XXXIV. Preparation of 2,3,4,5-tetrahydrot5-methyl-6-phenylmethoxy-1H-pyrido [4.3tb] t indolone-1

2.0 g of 2,3,4,5-tetrahydro-6-phenylmethoxy-1H-pyrido [4,3-b] indolone-1 was methylated as in Example XXIX to give 950 mg of the title compound, m.p. 199-201 ° C. System A (100: 8: 1) was used as the eluent for FCC purification.

Example XXXV. Preparation of 6-fluoro-2,3,4,5-terahiydro-5-phenylmethoxymethyl-1H- ^ f) ^ iy ^ c ^ c ^ [4,3 ^ 3)} indolone-1

800 mg of 6-luoro-2,3,4,5-tetrahydro-1H- [4,3-b] indole-1 was alkylated with 0.55 ml of benzylchloromethyl ether following the procedure described in Example XXIX. 220 mg of the title compound were obtained, m.p. 130-132 ° C. For FCC purification, system A (300: 10: 1) was used as the eluent.

Example XXXVI. Preparation of 2,3,4,5-tetrahydro-6-enylmethoxy-tphenylmethoxymethyl-1 Htpyrido [4.3 tb] indolone-1

1.8 mg of 2,3,4, -ttetrahydro-6-phenylmethoxy-1H-piI · yido [4,3-b] indolonut-1 was alkylated with 0.86 ml of benzylchloromethyl ether following the procedure described in Example XXX. 600 mg of the title compound were obtained, m.p. 188-190 ° C. System A (100: 8: 1) was used as the eluent for FCC purification.

Example XXXVII. Preparation of 6-fluorote 2,3,4, - tetrahydrot - (1-methylethyl) t1H-pyrido [4.3tb} indolone-1

To a stirred solution of 1.006g of 6-Ωuoro-2,3,4,5-etrahydro-1H-tplido [4,3b] indolone-1 in 50 ml of anhydrous DMF was added 330 mg of a 73.2% dispersion of sodium hydride in oil, and the mixture was stirred for 1 hour. After adding 663 mg of isopropyl bromide, the solution was stirred at room temperature for 30 minutes and then at 50 ° C for 12 hours. After adding 150 mg of isopropyl bromide, the mixture was stirred under nitrogen at 50 ° C for 60 hours. The mixture was cooled to room temperature and 300ml was added. The mixture was extracted with dichloromethane (3X200ml), loaded onto silica and purified by FCC using system A (150: 8: 1) as eluent. 240 mg of a solid are obtained, trituration with ether gives 130 mg of the title compound, m.p. 183-184 ° C.

Example XXXVIII. Preparation of 5-cyclopentylmethyl-6-Ωuoro-2,3,4,5 --- t-ahydro-1Ht pyrido [4,3-b] indolone-1

To a stirred solution of 1.023 g of e-Ωuoro-2,3,4,5 - etΓahydro-1H-pyrido [4.3t b] indolone-1 in 50 ml of anhydrous DMF was added 331 mg of a 73.2% dispersion of sodium hydride in oil and the mixture stirred under nitrogen at room temperature for 30 minutes. A solution of 893 mg of cyclopentylmethyl methylsulfonate was added to the mixture over 15 minutes, and stirring was continued for 5 days. After adding 20 ml of water, the mixture was concentrated in vacuo. The resulting solid was dissolved in 300 mL of ethyl acetate with the addition of 1 mL of methanol, the resulting solution was washed with saturated sodium chloride solution (3 X 100 mL) and applied to silica. Purification by FCC using A system (150: 8: 1) as eluent gave 283 mg of a solid and recrystallization from ethyl acetate gave 237 mg of the title compound, m.p. 175-176 ° C.

Example XXXIX. Preparation of 8-fluo fluO-1,2,3,9 - e-rahydro-9tme-ylot4Hcarbazolone-4 oxime

A mixture of 3.0 g of 8-Ωuoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazolonut 4 and 2.92 g of hydroxylamine hydrochloride in about 35 ml of pyridine was heated at 60 ° C for 3 hours. Solution

The 164 501 was concentrated in vacuo then dried by azeotroping with toluene. 125 mL of 8% sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate (3 X 100 mL). The combined extracts were filtered and concentrated in vacuo. 1.8g of the title compound was obtained as a solid. TLC (A system, 100: 8: 1) Rf = 0.66.

Example XL. Preparation of 7-Fluorph-3,4,5,6-tetahydro-6-methyl-1H-az_epinf- [4,3-b] lnaolone-1

A mixture of 1.8 g of 8-fluorf-1,2,3,9-tetrahyaro-9-methyl-4H-carbazolone-4 oxime and about 20 ml of polyphosphoric acid in 30 ml of dioxane was stirred under nitrogen at 100-110 ° C for 1 hour. After cooling, the reaction mixture was poured into 1 liter of ice-water and the resulting suspension was extracted with dichloromethane. The organic extract was concentrated in vacuo, the resulting solid was taken up in methanol and the mixture was loaded onto silica. Purification by FCC using system A (200: 8: 1) as eluent gave 850 mg of the title compound, m.p. 233-235 ° C.

Example XLI. Preparation of 2,3,4,5-tetraeydro-5-methyl-1-keto-1H-pyridine [4,3-b] lnaphthalene nitrile-6

A mixture of 1.1 g of 6-nromo-2,3,4,5-tetraeyaro-5-methyl-1H-pyrido [4,3-b] indolone-1 and 1.0 g of cuprous cyanide in 30 ml of 1,3-avumethyl 3,4,5,6-tetrahydro-1H-pyrimiaon-2 was heated at 180 ° C for 24 hours. The mixture was poured into about 500 ml of ice and 20 g of iron (III) chloride and stirred for 1 hour. The mixture was extracted with dichloromethane (3 X 300 mL) and the combined organic extracts were washed with water (2 X 300 mL) and concentrated in vacuo. The residue was triturated successively with 250 mL of hexane, 100 mL of 50:50 ether / hexane and 60 mL of ether. 620 mg of the title compound were obtained, m.p. 230 - 231 ° C.

Example XLII. Preparation of 6-flufro-2,3,4,5-tetΓahyaro-2 - [(5-methyl-1H-imidazflylf-4) methyl] -5 -: ^^^^ l <^ 1 H-pyrido ^^ - blindolone -1

To a stirred solution of 190 mg of 6-fluoro-2,3,4,5-tetraeyarf-5-phenylmethoxymethyl-1H-pyriphyl [4,3-b] -indolone-1, 28 mg of a 60% sodium hydride-oil dispersion was added. The mixture was heated at 50 ° C for 6 hours, then 261 mg of 4-celoromethyl-5-methyl-1-triphenylmethyl-1H-imidazole was added thereto, and stirring was continued under nitrogen for 18 hours. After adding 2 ml of water and 2 ml of acetic acid, the solution was refluxed for 2.5 hours. The solution was poured into 50 mL of 8% sodium bicarbonate solution and the mixture was extracted with dichloromethane (3 X 25 mL). The combined, dried organic extracts were evaporated to give about 750 mg of an oil. Purification by FCC using system A (200: 10: 1) as eluent gave 188 mg of the title compound. TLC (A system, 200: 10: 1) Rf = 0.33.

Example XLIII. Preparation of 6-fluoro-2,3,4,5-tetrahydro-2 - [(5-methylf-1-triphenylphmethyl-1H-imiaazflylf-4) methyl] -1H-pyr / dol / lJ-blindolone-1

A solution of 0.625 g of triphenylmethyl chloride in 10 ml of DMF was added dropwise to a stirred solution of 530 mg of 6-flufen-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazphyl-4) methyl] -1H-pyrrolo [4 , 3-b] naphthenium-1 in 20 ml of DMF with the addition of 0.25 g of triethylamine. The reaction mixture was stirred at room temperature for 20 hours and added to 500 mL of water, extracted with ethyl acetate (3 X 200 mL). The combined organic extracts were washed with water (2 X 300 mL), dried, and loaded onto silica. Purification by FCC using system A (150: 7: 1) as eluent gave 509 mg of the title compound, m.p. 252-253 ° C.

Example XLIV. Preparation of 2,3,4,5-tetrahydrof-2 - [(5-methyl-1H-imlaazolyl-4) methyl] 6-phenylmethfxy-5-phenylmethyl-1H-pyriph [4,3-b] inaolone-1

500 mg 2,3,4,5-tetiahydro-2 - [(5-methyl-1H-imidazflyl-4- (methylf] -6-phenylmethoxy-5-p'enylmethoxymethylf-1H-pyridine [4,3-b] indo] fnu-1 was reacted with 671 mg of 4-celfrphmethyl-5-methyl-1-triphenylmythyl-1H-imidazflu following the procedure of Example XLII to give 340 mg of the title compound, mp 170-172 ° C. Purification by FCC was eluted using the system A (100: 8: 1).

Example XLV. Preparation of 4 - [(6-ffuoro-2,3,4,5-tetrahydro-5-methyl-1-ketf-1H-pyriphyl [4,3-b] inaolyl-2) methyl] -5-methyl-1H -phenylmethyl-imidazole-1-carboxylate.

A solution of 0.47 ml of benzyl chloroformate in 1 ml of avucelfromethane was added to the stirred solution of 496 mg of 6-fluorph-2,3,4,5-tetrahydif-5-methylf-2 - [(5-methyl-1H-imida14).

164 501 zolyl-4) methyl] -1H-pyrido [4,3-b] indolone-1 and 0.67 ml of triethylamine in 50 ml of dichloromethane at 20 ° C under nitrogen atmosphere and the mixture was stirred overnight. The cooled reaction mixture was added to 100 mL of 2N sodium hydroxide solution and extracted with dichloromethane (2 X 100 mL). The combined, dried organic extracts were loaded onto silica and purified by FCC using system A (200: 8: 1) as eluent. 442 mg of the title compound were obtained as a solid. A recrystallization of a sample of the product from hot ethyl acetate and trituration of the resulting solid with ether gave a crystalline solid, m.p. 126-128 ° C.

164 501

Pattern 5 o

II

Ie

- (CH ₂ ) _n

Formula 6

Publishing Department of the UP RP. Circulation of 90 copies. Price: PLN 10,000

Claims (3)

Patent claims A method for the preparation of new tricyclic lactams of the general formula I, in which Im is an imidazolyl group of the formula 2, R ¹ is a hydrogen atom or a C 1 -C 6 -alkyl group, -CH 2 C 2 -C 8 -alkynyl or a C 3 -C 7 -cycloalkyl-C 1- C4-alkyl, n is 2 or 3, Q is halogen or hydroxy, phenyl-Ci-C3-alkoxy, C-C6-alkyl or cyano, and Q 'is hydrogen or fluorine, as well as physiologically acceptable salts and solvates of these compounds, characterized in that a) a compound of general formula 3 in which R 1, Q and Q 'and n are as defined above, is alkylated with a compound of general formula X-Im in which X is a group of formula -CH 2L where L is a leaving atom or a leaving group, the reaction is carried out in the presence of a base, or X is a -CH 2 OH group and then the reaction is carried out in the presence of an acid at elevated temperature or is alkylated with a protected derivative of the compound, optionally by removing the protecting group or protecting groups if present, or b) a compound of formula 1 is converted into another compound of formula 1, or c) from a protected compound of formula 1 wherein (i) the indole nitrogen is protected and / or (ii) the nitrogen atom in the imidazole is protected and / or (iii) when Q is a hydroxyl group, the hydroxyl group is protected, the protecting group or protecting groups are removed, and when the compound of formula 1 is obtained as a mixture of enantiomers, then the mixture is optionally separated to the enantiomers desired and / or when the compound of formula 1 is obtained as the free base, then optionally converting the free base to a salt. 2. The method according to p. A compound according to claim 1, characterized in that the compound of formula 3, in which R1 is hydrogen or methyl isopropyl, propyn-2-yl or cyclopentylmethyl, Q is fluoro or bromo or hydroxy, phenylmethoxy, methyl or cyano, Q 'is hydrogen, and n is 2 is alkylated with a compound of formula X-Im, and / or a compound of formula 1 is converted to another compound of formula I, optionally followed by removal of the protecting group or protecting groups. 3. The method according to p. 2. The process of claim 1, wherein in the preparation of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazoyl-4) methyl] -1H-pyrido [4, 3-b] indolone-1-u, as well as physiologically acceptable salts and solvates of this compound, 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indolone-1- 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole is alkylated, followed by removal of the triphenylmethyl protecting group and, when obtained as a free base, the free base is converted to a salt or a solvate.