Derivatives of lactam and a pharmaceutical composition, which is an antagonist of 5-oxitriptan /5-ht/ 5 - ht3the receptors or their physiologically acceptable salts and salawati

 

(57) Abstract:

The present invention relates to tricyclic lactams of General formula (1)

< / BR>
where Im represents an imidazole group of the formula

< / BR>
and R1represents a hydrogen atom or a C1-4alkyl, C3-4alkenyl,3-4quinil,5-6cycloalkyl,5-6cycloalkenyl, benzyl, phenylmethoxy or N, N-di1-3alkylcarboxylic or their physiologically acceptable salts and solvate. These compounds are potent and selective antagonists of 5-HT at 5-HT3the receptors and useful in the treatment of psychotic disorders, anxiety, nausea and vomiting. table 1.

The present invention relates to lactam derivative, pharmaceutical compositions containing these derivatives and their medical use.

In particular, the present invention relates to compounds, which are potent and selective antagonists of 5-oxitriptan (5-HT) on NT the receptors located on the endings of primary afferent nerves. Receptors of this type currently referred to as 5-HT3receptors are also present in Tsentralnoye those containing 5-HT pathways alters behavioral syndromes such as mood, psychomotor activity, appetite and memory.

The present invention provides tricyclic lactam of General formula (I)

< / BR>
where Im is imidazole group of the formula

< / BR>
and R1represents a hydrogen atom or a C1-4(alkyl) (for example, methyl or n-propyl)3-4alkenyl (for example, prop-2-enyl)3-4quinil (for example, prop-2-inyl)5-6cycloalkyl (for example, cyclopentyl)5-6cycloalkenyl (for example, cyclopentylmethyl), benzyl, phenylmethoxy, N,N-dis1-3alkylcarboxylic (for example, N,N-dimethylcarbamyl) group and its physiologically acceptable salt and solvate.

The corresponding physiologically acceptable salts of the compounds of formula (I) include acid additive salts formed with organic and inorganic acids, such as dichloride, hydrobromide, sulphates, alkyl - or arylsulfonyl (for example, methanesulfonate, or n-toluensulfonate), phosphates, acetates, citrates, succinate, tartratami, fumarate and maleate. The solvate may be, for example, hydrates.

All optical isomers of compounds of General formula (I) and their mixtures, including racemic mixtures, and all geometric isomers of the compounds f is C3-4alkylamino group, double or triple bond may not be adjacent to the nitrogen atom.

Partially preferred group of compounds of formula (I) is a group, where R1represents methyl, n-propyl, prop-2-inyl cyclopentyl, cyclopentylmethyl, benzyl or N-dimethylcarbamoyl.

Potential and selective antagonism NT on 5-HT3the receptors by compounds of the present invention as demonstrated by their ability to inhibit 3-(5-methyl-1H-imidazol-4-yl)-1-/-1 (tert)-1H-indol-3-yl/-propanoic communication intrageneric cortical homogenates of rats (General procedure described by G. Kilpatric et al in Nature, 1987, 330, 746) and/or their ability to block 5-HT-induced depolarization of isolated vagus nerve in rats.

In addition to their activity as a potential and selective antagonist of 5-HT at 5-HT3the receptors of some compounds of the present invention have the advantage of increased duration of their action.

In particular, the preferred compound of formula (I) in view 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/4,3-b/-indol-1-he and his physiologically premliminary formula (I), which counteract the effect of 5-HT at 5-HT3receptors, useful in the treatment of diseases such as psychotic disorders (schizophrenia and mania); anxiety and nausea and vomiting, particularly those that are associated with chemotherapy and radiotherapy for cancer. The compounds of formula (I) are also useful in the treatment of gastric stasis, symptoms of gastrointestinal dysfunction such that take place in dyspepsia, peptic ulcer, inflammation of the mucous membrane of the esophagus, flatulence and irritable bowel syndrome, migraine and Bolani. The compounds of formula (I) may also be useful in the treatment of dependence on drugs and substances of abuse, depression, dementia and other mental disorders.

Accordingly, the present invention also provides a pharmaceutical composition, which comprises at least one compound selected from compounds of General formula (I) and their pharmaceutically acceptable salts and solvate (e.g. hydrate) for use in human or veterinary medicine and prepared to accept any usual way.

Such compositions can be prepared in the usual way, using one or more physiologically acceptable carriers and/or ospring, alkaline, parenteral or rectal injection or in the form suitable for reception by inhalation, or by injection (through the mouth or nose).

A proposed dose of the compounds of the present invention for administration to man (of approximately 70 kg) is 0.001 to 100 mg, preferably 0.01 to 50 mg, more preferably 0.1 to 20 mg of the active ingredient in a unit dose, expressed as the weight of free base, which could be implemented, for example, 1 to 4 times per day. It is clear that can be made regular changes to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.

Compounds of General formula (I) and their physiologically acceptable salt or solvate can be prepared by conventional means, described below. In the following description, the groups R1and Im the same as those described for compounds of formula (I).

According to the method, the compound of General formula (I) can be obtained by alkylation of compounds of formula (II)

or a protected derivative, with a compound of formula (III)

LCH2-Im (III)

or a protected derivative, where L represents a leaving atom or group such as halogen atom (e.g. chlorine, bromine or iodine) or alloctype (such is sulfonyloxy or methansulfonate), followed, if necessary, removing any protective groups. L is preferably a halogen atom (e.g. chlorine atom).

The reaction can be carried out in an inert solvent such as an ether (for example, dimethoxyethane, diglyme or tetrahydrofuran), saturated amide (for example dimethylformamide or N-an organic, aromatic hydrocarbon (e.g. toluene), a ketone (e.g. acetone) or dimethylsulfoxide, at a temperature from ambient to 100oC in the presence of a base. Acceptable reasons include hydrides of alkali metals (e.g. sodium hydride), carbonates of alkali metals (e.g. sodium carbonate), amides of alkali metals (e.g. sodium amide), alkoxides of alkali metals (e.g. sodium hydroxide or potassium).

The term "alkylation" in accordance with the General method involves the introduction of groups such as cycloalkyl, alkenyl or bansalrupal.

Thus, for example, the compound of formula (I) in which R1represents alkenyl1-4C3-4quinil,5-6cycloalkyl,5-6cycloalkenyl, benzyl or formationtype, can be obtained by alkylation of compounds of formula (I) in which R1represents a hydrogen atom, ispolzuya, the reaction can be performed using the appropriate alkylating agent of formula R1(where R1is the group you want to enter, and Z-tsepliaeva group or atom), preferably in the presence of a base.

In accordance with another example of the General process of the compound of formula (I), where R1represents N,N-di1-3alkylcarboxylic, can be obtained by acylation of compounds of formula (I), where R1represents a hydrogen atom. These reactions can be performed using the appropriate allerease agent in accordance with the usual procedures, for example, as described in the published description of the European patent N210840.

It should be recognized that the above transformations may be necessary or desirable to protect any sensitive groups in the molecule compounds in order to avoid undesirable side reactions. For example, it may be necessary to protect the atoms of the indole and/or imidazolate, for example, arylmethyl (for example, trityl), helmetcity (for example, phenylmethoxy), alkyl (e.g., tributyl), alkoxymethyl (for example, methoxymethyl), acyl (e.g., benzyloxycarbonyl) or sulfonylureas (for example, n-toluensulfonyl).

Thus the Rupp from protected forms of compounds of formula (I), removing protection you can carry out by conventional means, such as described in Protective Groups in organic. Synthesis by T. W. Greene (John Wiley and Sons, 1981).

For example, helmetcity-N-protective group can be split by hydrogenolysis in the presence of a catalyst (e.g. palladium on coal). Trailguru can be split by acid hydrolysis (e.g. using dilute hydrochloric or acetic acid). Alkoxyalkyl can be removed, using a mineral acid (e.g. dilute hydrochloric or Hydrobromic acid). Allgraph can be removed by hydrolysis under acidic or basic conditions (for example, using hydrogen bromide, diluted hydrochloric acid or sodium hydroxide). Sulfonylurea you can also remove the basic or acidic hydrolysis and N, N-dimethylaminoacetonitrile you can also delete (for example, from the atom imidazolate) photolysis.

The compounds of formula (II) can be obtained by Beckmann rearrangement of the oxime of formula (VI)

< / BR>
or a protected derivative. The Beckmann rearrangement can be made using conventional methods, for example using an acid (for example, polyphosphoric or sulfuric acid or a mixture of hydrochloric, acetic anhydride and acetic acid) in an inert races the EP, toluene or cyclohexane) at a high temperature, for example 50 120oC).

On the other hand, hydroxylgroups of the oxime of formula (VI) can be converted to tsepliaeva group, such as chloride (using, for example, pathiakis phosphorus) or hydrocarboncontent (for example, mesilate or tosylate) or trifurcating (using traditional methods of acylation). Subsequent heating at a temperature of 20 150oC in an inert solvent, as described above, gives compound of formula (II).

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

< / BR>
or a protected derivative, using conventional methods, for example, using hydroxylaminopurine in a solvent such as pyridine.

The compounds of formula (III) or protected derivatives are either known or they can be obtained, for example, the methods described in the description of the patent Germany N3740352.

The compounds of formula (VII) can be obtained, for example, the method or methods similar to those described K. Iida et al in Org. Chem. 1980, 45, 2983.

Where it is necessary to allocate the connection of the present invention as a salt, for example, physiologically acceptable salt, this may be achieved by reaction of the numbers, in an acceptable solvent such as alcohol (e.g. ethanol or methanol), an aqueous alcohol (e.g. aqueous ethanol), halogenated hydrocarbon (e.g. dichloromethane), esters (e.g. ethyl acetate) or an ether (e.g. tetrahydrofuran).

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

Individual enantiomers of the compounds of the present invention can be obtained by separation of a mixture of enantiomers (e.g., racemic mixtures) using conventional means, such as separating optically active acid; see, for example, Stereo-Chemistry of Carbon Compaunds" by E. I. Elied (M. Grow Hill, 1962) and Tables of Resolving Agents" by S. H. Wiler.

The above-described methods for producing compounds of the present invention can be used for introduction of the desired groups at any stage in a stepwise formation of the desired compounds and it is clear that such methods can be combined in various ways in such multistage processes. The sequence of reactions in multistage processes should of course be chosen so that the used reaction conditions are not affected groups in the molecule, which is ediately and examples. All temperatures are given in degrees Celsius. Thin-layer chromatography (TLC) was performed on silica and evaporation column chromatography (ICH) on silica (Merck 9385). The solvent system And used for chromatography, means a solution of dichloromethane: ethanol, 0.88 ammonia. The organic extracts were obezvozhivani where indicated over magnesium sulfate or sodium. The following abbreviations are used: DMF-dimethylformamide, THF is tetrahydrofuran, DMZ-dimethoxyethan. 1H-NMR SPECTA were obtained for dilute solutions in d6-dimethylsulfoxide at 250 MHz.

Intermediate I

3,4-dihydro-4-methylcyclopentene (b) indol-1(2H)-ONEXIM.

3,4-dihydro-4-methylcyclopentene (b)-1(2H, he) (1.7 g) and hydroxylamine hydrochloride (1,925 g) in pyridine was heated at 60oWith 18 hours and cooled. The reaction mixture is boiled away in a vacuum to 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 the corresponding solid residue was separated from the aqueous layer. The aqueous layer was re-extracted with ethyl acetate (250 ml). The combined organic extracts (and suspended solid) boiled away to the residue boiled with a mixture was applied on the column ICH. Elution with ethyl acetate (3 with 10% methanol) has been specified in the title compound (1,69 g), etc., 219 - 224o(decomposition).

Intermediate 2

2,3,4,5-tetrahydro-5-methyl-1H-pyrido (4,3-b) indole-1-he

3,4-dihydro-4-methylcyclopentene (b) indol-1(2H) ONEXIM (1,53 g), polyphosphoric acid (40 g) and dioxane (15 ml) was heated at 110 - 120o2.2 hours under nitrogen. The reaction mixture is cooled and treated with 2n. the sodium carbonate solution (1 liter). The suspension was extracted with ethyl acetate (4x400 ml) and the combined extracts were obezbedili. Evaporation gave a solid (1,43 g), which was recrystallization from ethyl acetate/cyclohexane. This solid is purified ICH, suirable system A (200:10:1) and obtained solid (1.26 g), which was recrystallization from ethanol to obtain the target compound) (960 mg), etc. 234 238o.

Intermediate 3

5,6-dihydro-4-(phenylamino)-1(2H)-pyridine.

A mixture of 2,4-dioxopiperidin (1.13 g) and aniline (930 mg) was heated at 120ounder a stream of nitrogen for 15 minutes the resulting solid was ground into powder with simple ether and filtered to obtain the target compound (1,74 g), i.e. 235 238o.

Intermediate 4

2,3,4,5-tetrahydro-1H-pyrido(4,3-b) indole-worked copper acetate (3.2 g) and the resulting mixture was heated under nitrogen at 120 130o1.5 hours. This mixture after concentrated in vacuo and the obtained solid substance was rubbed into powder with 2n. hydrochloric acid (250 ml). This acid decantation and the remaining solid was extracted with ethyl acetate for 18 hours. Desantirovaniya acid was converted into the base by means of 2n. sodium hydroxide and was extracted with ethyl acetate (CH ml). These organic extracts were combined with the previous an ethyl acetate extracts and absorbed on silica. Clean ICH with system A (100:8:1) to give the target compound (874 mg), etc. 212 215o.

Intermediate 5

2,3,4,5-tetrahydro-5-/(phenylmethoxy)methyl/-1H-pyrido (4,3-b)indole-1-it.

A solution of 2,3,4,5-tetrahydro-1H-pyrido (4,3-b)indole-1-he (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 stopped the rapid evolution of gas. This mixture then was cooled to 0oand added dibenzylamine ether (chloromethyl) (10% V/o solution in DMF; 08,835 ml) for 10 minutes Stirring continued for another 5 minutes and then added water (10 ml). The reaction mixture was concentrated in vacuum and the obtained oil was dissolved in ethyl acetate (100 ml) and washed with water (I ml). Organicheskoi EDINENIE (1.1 g), T. p. 133 135o.

Intermediates 6 and 7 was obtained analogously to intermediate 5, i.e., processing 2,3,4,5-tetrahydro-1H-pyrido(4, 3-b) indole-1-she sodium hydride followed by treatment of the appropriate alkylating agent. Isolation and purification of the products described in intermediate 5, unless otherwise noted.

Intermediate 6

2,3,4,5-tetrahydro-5-(phenylmethyl)-1H-pyrido(4,3-b)indole-1-it.

2,3,4,5-tetrahydro-1H-pyrido(4,3-b)indole-1-he (559 mg) was treated with sodium hydride (73% dispersion in oil; 179 mg) and then stirred with benzylbromide (513 mg) at room temperature for 30 minutes. Cleared ICH by elution with dichloromethane: ethanol in a ratio of (80:1) and obtained target compound (347 mg), etc. 209 212o.

Intermediate 7

5-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-pyrido(4,3-b) indole-1-it.

2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indole-1-he (950 mg) was treated with sodium hydride (60% dispersion in oil; 408 mg) and then mixed with Cyclopentanol (methylsulfonate) (909 mg) at room temperature for 7 days. Solid (570 mg), obtained using ICH, additionally purified by slow evaporation from a solution in methanol and got the target connection, etc. 179 181o.

Intermediate 8

oC.

Intermediate 9

5,6-dihydro-4-methoxy-1-/(5-methyl-1-(triphenylmethyl))- 1H-imidazol-4-yl)/-2(1H)-pyridinone.

Sodium hydride (80% dispersion in oil; 360 mg) suspended in dry DMF (50 ml) under nitrogen and 5,6-dihydro-4-methoxy-2(1H)-pyridine (1.27 g) in dry DMF (20 ml) was slowly added. The resulting suspension was stirred at 20oC for 1 hour. Added 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)- 1H-imidazole (and 3.72 g) in dry DMF (50 ml) and after reducing the initial reaction mixture was heated to 50o4 hours and then cooled. Dropwise added methanol (5 ml) and vacuum solvent removed. An aqueous solution of sodium bicarbonate (300 ml) was added to the residue and the resulting solution was extracted with dichloromethane (I ml), obezbedili was evaporated in vacuum and the obtained oil, which cleared ICH-elution with system A (200:8:1). Received cetyl/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 50oC for 1 hour. The solvent was removed under vacuum, was added triethylamine (1 ml) and the mixture was again evaporated to dryness. Elution of ICH residue in ethyl acetate: methanol: triethylamine (8:4:1) gives the target compound (139 mg), etc. 100 106oC (decomposition).

Intermediate 11

5,6-dihydro-1-/(5-methyl-1H-imidazol-4-yl)methyl/-4-(2-methyl-2 - phenylhydrazine)-2(1H)-pyridinone.

2,4-dioxo-1-/(5-methyl-1H-imidazol-4-yl)methyl/piperidine (20 mg) was dissolved in ethanol (2 mg) and added N-methylphenylhydrazine (26 mg). The mixture was stirred 1 hour and the solvent was removed in vacuum. The residue was purified ICH-elution with system A (75: 8:1) and obtained target compound (24 mg) as a solid, TLC (system a, 75:8:1), Rf 027.

Intermediate 12

N, N-5-trimethyl-4-//(trimethylsilyl)oxy/methyl/-1H-imidazole-1 - sulfonamide.

A suspension of 4-(oxymethyl)-5-methylimidazolidine (14.9 g) in dry dichloromethane (500 ml) containing triethylamine (50 mg), was processed chloride trimethylsilyl (21,7 g) and the reaction mixture was stirred overnight at room temperature. Added deleterous suspension was filtered and the collected solid was washed with dichloromethane (100 ml). The filtrate was concentrated onto silica and purified using ICH elution with hexane: simple ether (4:1), which gave the target compound in the form of oil (7.2 g), TLC (ether), Rf 0.5 in.

Intermediate 13

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

A solution of N,N,5-trimethyl-4-//(trimethylsilyl)oxy/Metin-imidazol-1-sulfonamida (2,59 g) in dry THF (50 ml) was treated with a solution of tetrabutylammonium fluoride (1M solution in THF; 10 ml) and THF immediately removed in vacuum. The remainder was divided between water (100 ml) and dichloromethane (100 ml) and the aqueous layer was extracted with dichloromethane (100 ml). United dehydrated organic fraction was concentrated and the obtained target compound (1.63 g) as a solid, T. p. 134 136oC.

Intermediate 14

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

A suspension of 4-(oxymethyl))-N,N,5-trimethyl-1H-imidazol-1-sulfonamida (2.86 g) in dry dichloromethane (200 ml) containing DMF (0.5 ml), treated dropwise with a solution of chloride of tonila (1,178 g) in dichloromethane (10 ml). The reaction mixture was cooled on ice while adding and covered with nitrogen. When the addition was complete (approximately 5 minutes), stirring was continued at 0oanother 30 minutes. For what was narrowly and got a target compound (2.3 g) as a solid, T. p. 115 118oC.

Intermediate 15

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

A mixture of 2-iodide-(N-methyl)aniline (1,17 g) and 2,4-dioxopiperidin (565 mg) was heated under steam of nitrogen for 7 hours at 110 120oC. After cooling, the reaction mixture was dissolved in methanol and the solution was absorbed on the silica ICH by elution with system A (150:8:1) and obtained the target connection (1,03 g), T. p. 163 164oC.

Intermediate 16

N,N,5-trimethyl-4-/1,2,3,6-tetrahydro-4-/(2-iodophenyl)-methyl-amino/ -6-oxo-1-pyridine/methyl-niridazole-1-sulfonamide.

A suspension of 5,6-dihydro-4-/(2-iodophenyl)methylamino/-2-(1H-pyridinone) (984 mg) in dry DMF (50 ml) was treated with sodium hydride (60% dispersion in oil; 140 mg) and the mixture was stirred under nitrogen for 6 hours. Then added 4-(chloromethyl)-N, N, 5-trimethyl-1H-imidazole-1-sulfonamide (832 mg) and the resulting mixture was stirred at 60othe whole night. After cooling, the reaction mixture was poured into water (100 ml) and the mixture was extracted with ethyl acetate (CH ml). Combined, dehydrated extracts were concentrated, the resulting solid residue was purified ICH by elution with system A (150:8:1) and obtained target compound (712 mg), TLC, system a (150:8:1), Rf 0,41.

Intermediate 17

N, N,solution of chloride of dimethylsulphamoyl (0,107 ml) in dry dichloromethane was added a mixed solution of 2,3,4,5-tetrahydro-5-methyl-2/(5-methyl-1H-imidazol-4-yl)methyl/-nerida/4,3-b/indole-1-it (0,294 g) and triethylamine (0.2 ml) in dry dichloromethane (30 ml) under nitrogen and the mixture was heated at the temperature of reflux distilled for about 24 hours. After cooling, the solution was concentrated on silica ICH, cleaned ICH by elution with system A (150:8:1) and got the oil. This oil is rubbed into powder with simple ether and received solid, which was further purified by slow evaporation from a solution in ethyl acetate, and the obtained target compound (122 mg), TLC (system a, 100:8: 1), Rf of 0.43.

Intermediate 18

Phenylmethyl 5-methyl-5/(2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido/4,3 - b/indol-2-yl)methyl-1H-imidazole-1-carboxylate.

The solution benzylphosphonate (of 0.28 ml) in dichloromethane (10 ml) was added to stirred solution of 2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl)methyl-nerida/4,3-b/indole-1-she (294 mg) and triethylamine (0.5 ml) in dichloromethane (30 ml) at 20ounder nitrogen and the mixture was stirred overnight. Then it was concentrated on silica ICH, cleaned ICH-elution with system A (100:8:1) and obtained target compound (62 mg), TLC (system a, 100:8:1), Rf 0.50 in.

Intermediate 19

2,3,4,5-tetrahydro-2-//1-(methoxymethyl)-5-methyl-1H-imidazol-4 - yl/methyl/-5-methyl-1H-pyrido/4,3-b/-indol-1-he 2-3-4-5-tetrahydro-2-//1-(methoxymethyl)-4-methyl-1H-imidazol-yl/methyl//-5-methyl-1H-pyrido/4,3-b/indole-1-it.

The solution chloromethylmethylether ether (of 0.26 ml) in dichloromethane (10 ml) add the g) and triethylamine (0,49 ml) in dichloromethane (50 ml) at 20ounder nitrogen and the solution was stirred for 4 days. Then it was divided between dichloromethane (50 ml) and sodium bicarbonate solution (g ml). The organic extract was obezbedili, concentrated on silica ICH, cleaned then ICH by elution with system A (100: 8: 1) and obtained target compound (139 mg). Part of the target compounds was placed (64 mg) in hot ethyl acetate and purified by slow evaporation from ethyl acetate and obtained target compound.

The analysis showed: C 67,3 H 6,9 N 16,5

C19H22N4O2requires C 67,4 H 6,6 16,6 N%

Example 1.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl) methyl/-1H-pyrido/4,3-b/indole-1-he maleate.

A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido/4,3-b/indole-1-she (0.6 g) and about 78% dispersion of sodium hydride in mineral oil (0,109 g) in dry DMF (15 ml) was stirred under nitrogen at 50ountil it was ended by the release of nitrogen (approximately 1.5 hours). The mixture was then cooled to 40oand added the solution of 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (1.12 g) in dry THF (15 ml). The reaction mixture was then stirred at 40o3 hours, at 20o16 hours and added an additional portion of 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (1.12 g) in dry is th (20 ml) and was heated at 100o2 hours. This mixture is then concentrated in vacuum to 60 ml, was diluted with 1M hydrochloric acid (40 ml) and washed with ethyl acetate (CH ml). The organic phase was discarded and the acidic aqueous phase was transferred to a base (pH 9) with sodium carbonate and was extracted with ethyl acetate: ethanol (20:1, 3x100 ml). The extracts were combined, obezbedili, steamed and got a brown resin (approximately 1 g). This resin was absorbed on silica and purified ICH by elution with system A (100:8:1) and received a light brown solid (0.8 g), etc. 238 240o(decomposition). This solid was dissolved in a mixture of hot ethanol and methanol (1:1, 100 ml) and treated with an ethanol solution of maleic acid (318 g). The resulting mixture was concentrated to 20 ml, diluted with dry diethyl ether (about 8 ml) and besieged the target compound (0.75 g) as off-white solids, etc. 160 162oC.

Analysis found: C 61,6 H 5,5 N 13,6

C17H18N4OC4H4O4calculation 61,5 C H 5,4 N 13,8%

Example 2.

2,3,4,5-tetrahydro-2/(5-methyl-1H-imidazol-4-yl)methyl/- 5-/(phenylmethoxy)methyl/-1H-pyrido/4,3-b/indole-1-omelet.

A suspension of 2,3,4,5-tetrahydro-5-/(phenylmethoxy)methyl/- 1H-pyrido-/4,3-b/indole-1-she (920 mg) in dry DMF (75 m is o 6 hours.

Then added 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (1,11 g) and the mixture was stirred overnight at 60o. Then added acetic acid (10 ml), water (10 ml) and THF (10 ml) and the resulting solution was heated at the temperature of reflux distilled 6 hours. After cooling, was added 2n. sodium hydroxide (100 ml) and the resulting suspension was extracted with dichloromethane (I ml). Combined, dehydrated organic extracts were absorbed on the silica ICH and ICH elution with system A (150:8:1) gives the free base of the target 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 minutes, cooled, added dry ether and besieged the target compound (170 mg), etc. 165 168oC. Analysis of water established 0,22 about. 0.06 mol H2O.

Analysis found: C 64,5 H 5,6 N 10,7

C24H24N4OC4H4O40,06 H2O calculation of C 65,0 H 5,5 N 10,8%

Examples 3 and 4 was obtained analogously to example 2.

Example 3.

2,3,4,5-tetrahydro-5-(phenylmethyl)-2-/(5-methyl-1H-imidazol-4-yl)- methyl/-1H-pyrido/4,3-b/indole-emulatormanager.

2,3,4,5-tetrahedrally with 4-(chloromethyl-5-methyl-1-(triphenylmethyl)-1H-imidazole (1.3 g). The free base of the target compound was obtained as a solid substance ICH by elution with system A (175:8:1).Education maleate gives the target compound (420 mg), etc., 198 200oC, TLC (system a, 100:8:1), Rf of 0.3.

Example 4.

5-(cyclopentylmethyl)-2,3,4,5-tetrahydro-2-/(5-methyl-1H-imidazol-4 - yl)methyl/-1H-pyrido/4,3-b/indole-1-omelet.

5-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-pyrido/4,3-b/indole-1-he (200 mg) was treated with sodium hydride (60% dispersion in oil; 60 mg) and then stirred with 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (280 mg). The free base of the target compound was obtained as a solid substance ICH by elution with system A (200:8:1). Education maleate gives the target compound (60 mg), T. p. 81 83oC, TLC (system a, 100:8:1), Rf 0,20.

Example 5.

2,3,4,5-tetrahydro-N, N-dimethyl-2-/(5-methyl-1H-imidazol-4-yl)methyl/-1 - oxo-5H-pyrido/4,3-b/indole-5-carboxamidine.

A solution of 2,3,4,5-tetrahydro-2-//5-methyl-1-(triphenylmethyl)-1H-imidazol-4 - yl/methyl/-1H-pyrido/4,3-b/indole-1-she (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 minutes. Then added N,N-dimethylcarbamoyl (1M solution in DMF; 1 ml) and a solution of ilili in water (100 ml). The resulting mixture was extracted with ethyl acetate (CH ml) and the combined organic extracts were washed with water (I ml), concentrated and got the oil. This oil was dissolved in a mixture of water (10 ml), glacial acetic acid (10 ml) and THF (10 ml) and the solution was heated at the temperature of reflux distilled 1.5 hours. After cooling the solution is made the basis of the addition of 2n. of sodium hydroxide (100 ml) and the resulting mixture was extracted with ethyl acetate (CH ml). Combined, dehydrated organic extracts were absorbed on ICH silica and got ICH by elution with system A (100:8:1) free base of the target compound (110 mg) as a solid. It was dissolved in dry methanol (10 ml) and was heated with maleic acid (36 ml) on a steam bath for 5 minutes. When cooled, added simple dry ether (3 ml) and besieged the target compound (105 mg), etc., 161 163oC.

Analysis of water established 1,85 about. 0.49 mol H2O.

Analysis found: C 57,8 H 5,4 N 14,3

C19H21N5O2C4H4O40,49 H2O calculation of C 68,0 H 5,5 N 14,7%

Unless otherwise specified, examples 6 and 7 receive analogously to example 5.

Example 6.

2,3,4,5-tetrahydro-2/(5-methyl-1H-imidazol-4-yl)methyl/-5-(2-about the ol-4 - yl/methyl/-1H-pyrido/a 4.3 N/indole-1-it (522 mg) and potassium carbonate (276 mg) in dry acetone (75 ml) was treated with propargylamine (1M solution in acetone; 2 ml) and the mixture overnight was heated at the temperature of reflux distilled. After cooling, the excess acetone was removed in vacuum and got the oil which separated 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 vacuum. Removing protection, finishing and cleaning give the free base of the target compound (100 mg) as a solid. Education maleate provides the target compound (89 mg), etc. 202 205oC, TLC (system a, 100:8: 1), Rf of 0.29.

Example 7.

2,3,4,5-tetrahydro-2-/(5-methyl-1H-imidazol-4-yl)methyl/-5- (2-propenyl)-1H-pyrido/4,3-b/indole-1-omelet.

2,3,4,5-tetrahydro-2-//5-methyl-1-(triphenylmethyl)-1H-imidazol-4 - yl/methyl/-1H-pyrido/4,3-b/indole-1-he (1.0 g) was treated with sodium hydride (60% dispersion in oil; 114 mg) and then stirred with methyl-allyl (460 mg) for 1 hour. Removing protection, finishing and cleaning give the free base of the target compound (380 mg) as a solid. Education maleate provides the target compound (160 mg), TLC (system a, 100:8:1), Rf of 0.3.

Analysis found: C 63,2 H 5,5 12,5 N

C19H20N4OC4H4O4the calculation of C 63,3 H 5,5 N 12,8

Example 8.

5-cyclo of pentyl-2,3,4,5-tet-(triphenyl-methyl)-1H-imidazol-4 - yl/1H-pyrido//4,3-b/Indo-1-it (523 mg) in dry DMF (30 ml) was treated with sodium hydride (60% dispersion in oil; 46 mg) and stirred for 15 minutes at 21ounder nitrogen. After this dropwise added bromine cyclopentyl (298 mg) and the mixture was stirred 1 hour and then was heated at the temperature of reflux distilled for 4 hours. This solution was left in the 21ofor 2 days and then treated with a mixture of acetic acid (7 ml), water (7 ml) and THF (8 ml). The resulting solution was heated at the temperature of reflux distilled for 4 hours, then was turned into a basis of 2n. sodium hydroxide and was extracted with dichloromethane (I ml). The combined extracts were washed with water (I ml), concentrated in vacuo, purified ICH by elution with system A (100:8:1) and obtained the free base of the target compound (42 mg) as a solid. Education maleate gives the target compound (38 mg), etc., 180oC (decomposition), TLC (system a, 100:8: 1), Rf of 0.3.

Example 9.

2,3,4,5-tetrahydro-2-/5-methyl-1H-imidazol-4-yl/methyl/-5 - propyl-1H-pyrido/4,3-b/indole-1-omelet.

A solution of 2,3,4,5-tetrahydro-2-/(5-methyl/1H-imidazol-4-yl)methyl/-5-(2-propenyl) -1H-pyrido/4,3-b/indole-1-she (248 mg) in ethanol (20 ml) and 1N. hydrochloric acid (0.5 ml) was hydrogenatable at room temperature and atmospheric pressure on the pre-restored 10% palladium oxide on coal (50% aqueous paste; 50 mg). Was stragically dichloromethane (3h20 ml). The combined organic extracts were washed with water (30 ml), evaporated and the obtained free base of the target compound (258 mg) as a solid. Education maleate provides the target compound (345 mg), TLC (system a, 100:8:1), Rf of 0.4.

Analysis of water established 1,13 about. 0.28 mol H2O.

Analysis found: C 62,1 H 5,9 12,5 N

C19H22N4OC4H4O40,28 H2O calculation of C 62,2 H 6,0 N 12,6%

Example 10.

2,3,4,5-tetrahydro-2-/(5-methyl-1H-imidazol-4-yl)methyl/-nerida/4,3-b/indole-1-omelet.

A suspension of 2,3,4,5-tetrahydro-2-/(5-methyl-1H-imidazol-4-yl)methyl/-5 -/phenyl(methoxymethyl)/-1H-pyrido/4,3-b/indole-1-she (400 mg) in ethanol (20 mg) in glacial acetic acid (5 ml) was hydrogenatable overnight at room temperature and atmospheric pressure over pre recovered catalyst 10% palladium oxide on coal (50% aqueous paste; 100 mg). The reaction mixture was filtered and the residue washed with ethanol (100 ml). The filtrate was concentrated in vacuum and the obtained oil, to which was added 2n. sodium hydroxide (50 ml). The resulting suspension was extracted with dichloromethane (I ml), combined, dehydrated organic extracts were evaporated and the obtained solid substance. It o then dissolved in dry methanol (50 ml). Education maleate provides obtaining the target compound (261 mg), TLC (system a, 75:8:1), Rf of 0.2.

Analysis found: C, 60,3 H 5,2 N 13,8

C16H16N4OC4H4O4the calculation C of 60.5 N 5,1 N 14,1%

Example 11.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl)methyl/-1H-pyrido/4,3-b/indole-1-anhydrobiotic.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl)methyl/-1H-pyrido/4,3-b/indole-1-he (1.0 g) is suspended in ethanol (40 ml) and added concentrated hydrochloric acid (1.0 ml). The mixture was heated to 40oC and added charcoal (0.25 g). The resulting suspension was mixed and heated for 5 minutes and then filtered. The filtrate was evaporated in vacuo to 20 ml and allowed to cool to 20oC. Under stirring for 5 minutes was added ether (40 ml) and the mixture kept at 4oC all night. The resulting precipitate was filtered, washed with ether (2x10 ml), obezbedili in vacuum at room temperature for 2 hours and then at 70o7 hours and got a target compound (0.95 g), etc., 288-291oC.

Analysis found: C 61,4 H 5,8 N 16,7 Cl 10,7

C17H18N4OHCl calculation C 61,7 H 5,8 N 16,9 Cl 10.7% of

Example 12.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl)methyl/- 1H-Piri is he (0,81 g) suspended in absolute ethanol (6 ml) and heated at 50owith concentrated sulfuric acid (0.15 ml). Added ethanol (4 ml) and the mixture was stirred with charcoal (0.1 g). Then the suspension was filtered and the collected solid filtrate was washed with ethanol (3 ml). The resulting filtrate was stirred 1 hour at room temperature, was slowly added tertBUTYLPEROXY ether (10 ml) and the mixture was stirred for 20 minutes. The precipitate was filtered, washed with a mixture of ethanol: tertbutylamine ether 1:1.6 ml, then tertBUTYLPEROXY ether (6 ml), was obezbedili in vacuum at 4o4 days and got a target compound (0.4 g), etc., 205 - 209oC.

Analysis found: C 49,5 H 5,6 13,5 N S 8,4

C17H18N4O1,1 H2O4the calculation of C to 49.9 H 5,4 N 13,3 S 8,4%

Example 13.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl)methyl/- 1H-pyrido/4,3-b/indole-1-it.

A suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido/4,3-b/- indol-1-she (400 mg) in dry DME (50 ml) was treated with sodium hydride (60% dispersion in oil; 100 mg) and the mixture was stirred at 60ounder nitrogen for 6 hours. Added 4-(chloromethyl)-5-methyl-1- (triphenylmethyl)-1H-imidazole (474 mg) and the reaction mixture was stirred at 60ounder nitrogen overnight. Then added 2n. hydrochloric acid (10 ml) and water (10 ml) and the mixture was heated at the temperature of the camping was extracted with ethyl acetate (CH ml). Combined, dehydrated organic extracts were concentrated on ICH silica, cleaned ICH by elution with system A (150:8:1) and obtained target compound (352 mg) as a solid, TLC (system a, 100:8:1), Rf 0.28 in.

1H NMR 2,2 (3H, c), totaling 3.04 (2H, t), 3,62 (2H, t), 3,82 (3H, s), a 4.53 (2H,s), 7,1 7,28 (2H, s), the 7.43 (1H, s), 7,47 of 7.55 (1H, DV.D.) 7,94 8,03 (1H, DD).

Example 14.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl)methyl/1H - pyrido/4,3-b/indole-1-it.

A solution of 2,3,4,5-tetrahydro-2-/(5-methyl-1-(triphenyl-methyl)-niridazole-4-yl/methyl/-1H-pyrido/4,3-b/indole-1-she (261 mg) in dry DMF (25 ml) was treated with sodium hydride (60% dispersion in oil; 30 mg), the mixture was stirred at room temperature under nitrogen for 15 minutes. Then added iodomethane (0.5 M solution in DMF): 2 ml) and stirring continued for another 15 minutes. The reaction mixture was then poured into water (100 ml) and the resulting suspension was extracted with ethyl acetate (CH ml). The combined organic extracts were washed with water (I ml), obezbedili, concentrated and the obtained solid substance. It was dissolved in a mixture of water (10 ml), THF (10 ml) and glacial acetic acid (10 ml) and was heated at the temperature of reflux distilled for 2 hours. After cooling, the residual THF was removed in vacuum and the remaining solution is the Etat (g ml) and the combined dehydrated organic extracts was concentrated on silica (Merck 7385). ICH by elution with system A (100: 8: 1) to give the target compound (81 mg) as a solid. Data1H NMR and TLC received for this product, coincide with those obtained for the product in example 13.

Example 15.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl)methyl/-nerida/4,3-b/indole-1-it.

5,6-dihydro-1/(5-methyl-1H-imidazol-4-yl)methyl/-4- (2-methyl-2-phenylhydrazine)-2-(1H)-pyridinone (20.0 mg) was dissolved in 98% sulfuric acid (1 ml) and the solution was stirred at 25o5 minutes. The mixture is carefully poured into 8% aqueous sodium bicarbonate solution (60 ml) and was extracted with a mixture of 10% methanol:dichloromethane (I ml). Combined, dehydrated organic extracts were evaporated in vacuum and the obtained oil, which cleared ICH by elution with system A (100: 8: 1) and obtained target compound (13.5 mg) as a solid. Data1H NMR and TLC obtained for this substance is identical with the data obtained for the product of example 13.

Example 16.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl) methyl/-1H-pyrido/4,3-b/indole-1-it.

A solution of N, N,5-trimethyl-4-/1,2,3,6-tetrahydro-4-/(2-iodophenyl)- methylamino/-6-ox is ylamine (2 ml), were irradiated in pyrexia imensional reservoir mercury medium pressure lamp 125 W at room temperature for 24 hours. Then the reaction mixture was concentrated on ICH silica, cleaned ICH by elution with system A (150:8:1) and obtained target compound (87 mg) as a solid.

Data1H NMR and TLC obtained for this substance is identical with the data obtained for the product of example 13.

Example 17.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl) methyl/-1H-pyrido/4,3-b/indole-1-it.

A solution of N, N, 5-trimethyl-/(2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido/4,3-b/ indol-2-yl)-1H-imidazol-1-sulfonamida (86 mg) in 2n. hydrochloric acid (10 ml) and absolute ethanol (2 ml) was heated at 100 110o4 hours. Then the reaction mixture is cooled and added 2n.sodium hydroxide (50 ml). The resulting solution was extracted with dichloromethane (I ml), combined, dehydrated organic extracts were concentrated on ICH silica, cleaned ICH by elution with system A (100:8:1) and obtained solid (36 mg). He was placed in hot ethyl acetate, purified by slow evaporation and the obtained target compound (12 mg). Data1H NMR and TLC obtained for this substance is identical with the data, semi-yl) methyl/-1H-pyrido/4,3-b/indole-1-it.

A solution of N,N,5-trimethyl-/(2,3,4,5-tetrahydro-5-methyl-1-oxo-nerida/4,3-b/indol-2-yl)methyl/-1H-imidazol-1-sulfonamida (401 mg) in a mixture of dioxane (150 ml) and acetonitrile (150 ml) containing triethylamine (1 ml) were irradiated at room temperature mercury lamp, medium pressure for 24 hours. The reaction mixture was then concentrated in vacuo on silica ICH, cleaned ICH by elution with system A (100:8:1) and obtained target compound (203 mg) as a solid. Data1H NMR and TLC obtained for this substance is identical with the data obtained for the product in example 13.

Example 19.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl) methyl/-1H-pyrido/4,3-b/indole-1-it.

The solution phenylmethyl 5-methyl-4-/(2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido/4,3-b/indol-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 the steam bath for 15 minutes. After cooling, the solution was concentrated in vacuo to 20 ml and diluted with water (40 ml). The mixture was then washed with ethyl acetate (2x40 ml) and the acidic aqueous layer was turned into a base solution of potassium carbonate. The solution was then extracted with ethyl acetate (CH ml), combined, dehydrated extracts were concentrated on ICH credit is canola and rubbed into powder with ether and the obtained target compound (69 mg). Data1H NMR and TLC for this substance is identical with the data obtained for the product of example 13.

Example 20.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl) methyl/-1H-pyrido/4,3-b/indole-1-it.

A solution of 2,3,4,5-tetrahydro-2-//1-(methoxymethyl)-5-methyln-imidazol-4-yl/methyl/-5-methyl-1H-pyrido/4,3-b/indole-1-she 2,3,4,5-tetrahydro-2-//1-(methoxymethyl)-4-methyl-1H-imidazol-5 - yl/methyl/-5-methyl-1H-pyrido/4,3-b/indole-1-she (34 mg) in 49% Hydrobromic acid (2 ml) was heated on the steam bath for 3 hours. After cooling, the reaction mixture turned into a base by adding potassium carbonate solution and extracted with ethyl acetate (CH ml). Combined, dehydrated organic extracts were concentrated in vacuum and the obtained target compound (6 mg) as a solid. Data 1H NMR and TLC obtained for this substance is identical with the data obtained for the product of example 13.

Example 21.

2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-4-yl)methyl/- 1H-pyrido/4,3-b/indole-1-it.

5,6-dihydro-1-/(5-methyl-1H-imidazol-4-yl)methyl/-4-(2-methyl-2 - phenylhydrazine)-2-(1H)-pyridinone (60 mg) was dissolved in glacial acetic acid (4 ml). Added anhydrous zinc chloride (600 mg) and the mixture was heated at 851H NMR and TLC obtained for this substance is identical with the data obtained for the product of example 13.

The following example illustrates a pharmaceutical composition in accordance with the present invention, containing 2,3,4,5-tetrahydro-5-methyl-2-/(5-methyl-1H-imidazol-1-yl) methyl/-1H-pyrido/4,3-b/indole-1-he as an active ingredient. Physiologically acceptable salt and/or solvate of this compound and other compounds of formula (1) and/or a physiologically acceptable salt and solvate of these compounds can be used in the same way.

Tablets for oral administration

Tablets can be prepared by conventional means, such as direct pressing or wet granulation.

These tablets can be coated with a film of the respective film-forming substances, such as hypromellose, using standard methods. On the other hand, these tablets can be coated with sugar.

Direct pressing

Tablet mg/tablet

Active ingredie BP 0,45

Weight pressing 90,00

xor varieties suitable for direct compression.

The active ingredient is passed through a sieve of 60 mesh, is mixed with a secondary acid calcium phosphate, croscarmellose and magnesium stearate. The resulting mixture is pressed into tablets using a tabletting machine Manesty 73, equipped flat with the removed facet stamps 5,5 mm

Appendix 1

Data for biological studies

In continuation of the characteristics of the activity of the compounds of the first test results are expressed as values RK. All of the compounds of examples 1 to 10 have RK, the largest in excess of 9.0.

Marked antagonism can be assessed in vivo by determining the effects of compounds on reflex Bezold-Arish in cats induced by 5-HT. The experience carried out in accordance with the methodology described A. Butler al. in the literature, British Journal of Pharmacology, 1988, 94, p.397.

In the table below the results obtained are expressed in terms of length R5when this compound is administered intraduodenally (12-duodenum). R5represents an approximate dose required for 5-fold shift to the right of the curve "dose response" to 2-methyl-5-HT (see table).

2. Connection on p. 1, wherein R1hydrogen or methyl, N-propyl, prop-2-enyl, prop-2-inyl, cyclopentyl, cyclopentylmethyl, benzyl, phenylmethoxy or N,N-dimethylcarbamate.

3. Connection under item 1 or 2, characterized in that the connection predstavljaet a physiologically acceptable salt and solvate.

4. Compounds according to any one of paragraphs. 1 to 3, characterized in that the compound of General formula I is the hydrochloride, sulfate, alkylsulfonate, arylsulfonate, phosphate, acetate, nitrate, succinate, tartrate, fumarate, or maleate.

5. Connection on p. 1, characterized in that represent 2,3,4,5 - tetrahydro-5-methyl-2-[1(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido [4,3-b]indol-1-one or its pharmaceutically acceptable salt, or MES, or cleaners containing hydrochloride salt.

6. Formative substance and a pharmaceutically acceptable carrier, characterized in that the active substance contains a compound of General formula I in an effective amount.

 

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