Derivative azole and pharmaceutical composition with activity against serotonin (5-ht1d) receptor

 

(57) Abstract:

Derivatives of benzimidazole of the formula I, where R1, R7- H, C1-6-alkyl, C1-6-alkoxy; R2, R3R6, R11, R12- H, C1-6-alkyl; R4, R5- H or halogen; m and p are each 0, 1 or 2, n = 2; Z represents-O-, -S-, ; R9, R10- H1-6-alkyl or phenyl-C1-6-alkyl; X is oxygen; Y is a residue of formula (a) or (b) ; their salts and solvate possess activity against serotonin (5-HT1D) receptor and can be used in the treatment of obesity, bulimia, alcoholism, pain, depression. 3 s and 5 C. p. F.-ly.

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This invention relates to pharmaceutical compounds, their preparation and application.

The compounds of the invention corresponds to the formula

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in which R1and R7each represents halogen, trifluoromethyl, C1-C6-alkyl, C1-C6-alkoxygroup, optionally substituted phenyl, optionally substituted naphthyl or optionally substituted heteroaryl, R2and R3each represents hydrogen or C1-C6-alkyl, R4and R5each represents hydrogen, halogen, trifluoromethyl, C16represents hydrogen, C1-C6-alkyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, optionally substituted phenyl-C1-C6-alkyl or-CO2R8where R8represents an ester group, m and p each = 0, 1, 1, 3, or 4, n = 1, 2, 3 or 4, z represents a group of the formula

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where R9and R10each represents hydrogen, C1-C6is alkyl or optionally substituted phenyl-C1-C6-alkyl, X represents oxygen or sulfur, and Y represents a group of the formula

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where R11and R12each represents hydrogen, C1-C6-alkyl, trifluoromethyl, optionally substituted phenyl, optionally substituted naphthyl or optionally substituted heteroaryl; as well as salts and solvate of these compounds.

Compounds of the invention is shown for use in the treatment of diseases of the Central nervous system. The compounds exhibit activity in the test, indicating that serotonergic modulation.

The above formula (I) includes two groups of compounds

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and

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recommended the compounds of formula (II).

The group predpochtitelen methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, preferably methyl or ethyl. C1-C6-Alkoxygroup is an alkyl group that is attached to loop through an oxygen atom. The halogen atom is preferably represented by chlorine, bromine or fluorine, especially chlorine or fluorine.

Substituted phenyl group is a phenyl, substituted by one or more substituents, for example one to three substituents selected from, for example, C1-C4-alkyl, especially methyl, C1-C4-alkoxygroup, especially metoxygroup and ethoxypropan, hydroxy-group, nitro group, ceanography, halogen, especially chlorine and fluorine, trihalomethyl, especially trifloromethyl, carboxypropyl and C1-C4-alkoxy-carbonyl. Substituted phenyl C1-C6is an alkyl group has one or more of the above substituents in the phenyl cycle and preferably presents substituted benzyl. Substituted naphthyl or heteroaryl can also be substituted by one or more of the above substituents. Possibly substituted phenyl-C1-C6the alkyl is preferably represented by benzyl.

The ester group can be aliphatic or /SUB>C4-alkanols, especially methyl and ethyl esters.

The heteroaryl group may have one or more heteroatoms, selected, for example, from oxygen, nitrogen and sulfur, and preferably contains 5 to 10 carbon atoms. Preferably heteroaryl group corresponds to the formula

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where Q represents a group-O-, -S - or-NR - and R is hydrogen or C1-C6-alkyl. Or heteroaryl group may include a condensed benzene ring cycle, as, for example,

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Other heteroaryl groups include groups of the following formulas

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For preferred compounds include compounds characterized by one or more of the following characteristics:

(i) X is oxygen,

(ii) Z is a group and R9is hydrogen or C1-C6-alkyl,

(iii) R9is hydrogen,

(iv) R1- halogen, C1-C6-alkyl or C1-C6-alkoxygroup,

(v) m = 0, 1, or 2,

(vi) p = 0, 1, or 2,

(vii) R2and R3is hydrogen,

(viii) R4is hydrogen,

(ix) R5is hydrogen, trifluoromethyl, or C1-C6-alkyl,

(x) R5is hydrogen,

(xi) R6is hydrogen,

(xii) R7halogen, trifluoromethyl, C1-C6-alkyl III more than one R1or more than one of R7substituent, these substituents may be the same or different. In addition, when n = 2, 3 or 4 values of R2and R3attached to each carbon atom, but not necessarily identical.

A preferred group of compounds corresponds to the formula

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in which R9is hydrogen or C1-C6-alkyl, R1', R1", R7'and R7"each represents hydrogen, halogen, C1-C6-alkyl and C1-C6-alkoxygroup, R5is hydrogen or trifluoromethyl, and Y is a group of the formula

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as well as salts of these compounds.

It is obvious that the compounds of the invention can contain one or more asymmetric carbon atoms, the resulting isomers. Connection, usually obtained as racemic mixtures, and are usually used in this form, however, if desired, using standard techniques can be selected and the individual isomers. These racemic mixtures and individual optical isomers form part of the present invention. Recommended enantiomerically pure form.

Of course, can be obtained, and salts of compounds of the invention, and such salts are included within the scope of the twisted salts with acceptable acid, for example with inorganic acids such as: hydrochloric, Hydrobromic, nitric, sulphuric or phosphoric acids, or organic carboxylic acids, such as: glycolic, maleic, hydroxymaleimide, fumaric, malic, tartaric, citric, salicylic, o-acetoxybenzoic acids or organic sulphonic acids, for example: 2-hydroxyethanesulfonic, p-toluensulfonate or naphthalene-2-acid.

In addition to pharmaceutically acceptable salts in the scope of the invention include other salts. Such salts can serve as intermediates in the purification of target compounds or can be used for other, for example, pharmaceutically acceptable salts with acids, can also be used for identification, characterization or purification.

The invention also includes a solvate, for example, a solvate with ethers, for example the solvate formed with dioxane and tetrahydrofuran, or an alcohol solvate, such as, for example, a solvate with methanol and ethanol.

In addition, the scope of the invention includes a method of obtaining compounds of formula (I) comprising the reaction of compounds of formula

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where H is Y represent a group formulatinga formula

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where Q represents a leaving group, for example: halogen, mesilate or toilet, and Z, X, R1, R2, R3n and m take values above.

The reaction recommend in an inert organic solvent such as, for example: methyl isobutyl ketone or acetonitrile in the temperature range 80-110oC. the Reaction takes place under alkaline conditions in the presence of, for example: sodium carbonate or potassium carbonate.

The compounds of formula (V) are either known or can be synthesized by well-known experts methods. For example, the compounds of formula (V), which tetrahydropyridinium, in which H - Y is a group of the formula

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can be obtained by reaction of the corresponding hydrazine with an N-protected piperidine-3-one, for example, according to the following reaction equation:

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in the presence of potassium carbonate followed by treatment with acetic and hydrochloric acids and alkali. The removal of the protective group is carried out by hydrogenation in the presence of palladium on coal.

Intermediate tetrahydropyridine, in which H - Y represents a group of the formula

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can be obtained similarly by using the ACC is spodnie formula (VI) are either known compounds, or can be synthesized by standard methods, for example by reaction of compounds of formula

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with the compound of the formula Q'(CR2R3)nQ, where Q and Q' represent a leaving group.

An alternative way of obtaining compounds of the invention is similarly directed condensation of two major components of the molecule, for example, by reaction of compounds of formula

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with the compound of the formula

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where Q represents a leaving group.

Such reagents can be synthesized above or similar methods.

Obviously, if one or more R9, R10and R6different from hydrogen, the group can be entered into these terms by alkylation.

As mentioned above, the compounds of the invention possess useful activity against Central nervous system. Compounds active against serotonin (5-HT1D) receptor. Their ability to bind shown in the tests described in the work: Zgombick, J. M. and other Molecular Pharmacology, T. 40, 1992, pp. 1036-1042, and compounds of the invention are described in the following Examples, have the value of Ki in the range of 20 to 5000 nm. Some compounds, such as compounds of formula III, is azwani 5-HTA receptors as demonstrated in the tests described in: J. Leusen E. and other Molecular Pharmacology, T. 21, 1981, PP 301-314.

Due to their selective affinity to 5-HT receptors of the compounds of the present invention is shown for use in the treatment of various conditions, such as obesity, bulimia, alcoholism, pain, depression, hypertension, aging, memory loss, sexual dysfunction, anxiety, schizophrenia, disorders of the gastrointestinal tract, headache, cardiovascular disorders, habit of Smoking, addiction to narcotic drugs and vomiting.

Compounds of the invention are effective in a wide range of dosages. Real input dose depends on such factors as specific applicable connection that is subject to treatment condition, and the type and size of the subject to treatment of a mammal. However, the required dosage is usually covered by the interval of 0.01 - 20 mg/kg / day for the treatment of, for example, an adult may apply a dosage in the range of 0.5 to 100 mg per day.

Compounds of the invention usually given orally or by injection, and for the purposes of the compounds usually applied in the form of pharmaceutical compositions. These drugs are produced by well-known is but the invention includes a pharmaceutical composition, containing as an active ingredient a compound of the formula (I) or its pharmaceutically acceptable salt, or MES in a mixture with a pharmaceutically acceptable filler. In the manufacture of the compositions of the invention the active ingredient is usually mixed with a carrier, or diluted by a carrier, or enclosed in a carrier, which may be in the form of a capsule, sachet, paper or other container. The filler may be solid, semi-solid or liquid product, the role of the carrier, excipient or medium for the active ingredient. Some examples of acceptable fillers include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, calcium phosphate, alginates, tragakant, gelatin, syrup, methylcellulose, methyl - and propyl-hydroxybenzoate, talc, magnesium stearate or oil. If desired, the compositions of the invention can be prepared in such a way as to ensure rapid, gradual or delayed release of active ingredient after its introduction to the patient.

Depending on the method of introduction of the above-mentioned composition can be obtained in the form of tablets, capsules or suspensions for oral and injectively solutions or suspensions for parenteral introduction, or in the form of a form contains 0.5 to 100, typically 1-100 mg of the active component.

The following examples illustrate the invention.

Example 1.

1-[2-(1,2,3,4-Tetrahydro-9H-pyrido[3,4-b] indol-2-yl)-1-ethyl] - 1,3-dehydrobenzperidol-2-he

In isobutyl ketone (50 ml) suspended 1,2,3,4-tetrahydro-9H-pyrido-[3,4-b] indole (1.5 g, 8.7 mmole). To the mixture was added 1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazole-2-it (1,958 g, 9,58 mmole) in a mixture with sodium carbonate (1,11 g, 10,45 mmole) and tetrabutylammonium (10 mg). The suspension is heated for 2 days at 90oC in inert (N2) atmosphere. The mixture is then concentrated to dryness in vacuo. Add water (70 ml) followed by addition of 2 N. HCl to pH 1. The mixture is extracted with CHCl3(2 x 70 ml), alkalinized to pH 10 by adding 5 N. NaOH and again extracted with CHCl3(3 x 70 ml). The organic solutions are combined, washed with brine, separated and dried over MgSO4). Purification of the obtained solid product by chromatography CHCl3, MeOH (2%)) receives a yellow substance with so pl. 214-216oC.

Example 2.

2-((3,3-Dimethyl)oxindoles)ethanol

In dry dimethylformamide is dissolved 3,3-dimethoxyindole (1.1 equivalent). Portions add sodium hydride (60% dispersion in mineral oil) (1.1 equivalent) is UNT) together with a catalytic amount of sodium iodide. The reaction mixture was stirred for 12 hours in a nitrogen atmosphere at 70oC, then the solvent is removed under reduced pressure. The oil obtained is distributed between ethyl acetate and water. The organic phase is dried (MgSO4), filtered and evaporated to dryness under reduced pressure. The oil obtained is transferred into methanol and stirred at room temperature with p-toluensulfonate. After eight hours the solvent is removed and replaced by ethyl acetate. The solution was washed (2 times), saturated sodium hydrogen carbonate solution, dried (MgSO4), filtered and evaporated to dryness. Column chromatography of the resulting oil on silica gel (eluent ethyl acetate: hexane, 1:1) to obtain 2-((3,3-dimethyl)oxindoles)ethanol.

1-(2-(1,2,3,4-Tetrahydro-9H-pyrido[3,4-b] indol-2-yl)-1-ethyl)- 1,3-dihydro-3,3-dimethyl-2H-indol-2-he

In dichloromethane was dissolved 2-((3,3-dimethyl)oxindoles)-ethanol (1.1 equivalent), cooled under stirring in nitrogen atmosphere to 0oC and add methanesulfonanilide (1 equivalent). The mixture is stirred for 30 minutes, washed with cold diluted hydrochloric acid, dried (MgSO4), filtered and concentrated to dryness. The oil obtained is dissolved in acetonitrile and added to a solution of tetrahydro- - carbonatebased three days in a nitrogen atmosphere. The solvent is removed under reduced pressure and the residue is transferred into ethyl acetate. The resulting solution was washed twice with water, dried (MgSO4), filtered and concentrated to dryness under reduced pressure. Chromatography on silica gel (eluent ethyl acetate: methanol) to obtain the oil, which is transferred to the ethyl acetate. Added maleic acid (1 equivalent). The solution is incubated for 12 hours in the refrigerator and after the separation of white crystals get 1-(2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl)-1-ethyl)- 1,3-dihydro-3,3-dimethyl-2H-indol-2-it is in the form of manumaleuna, melting point 156-158oC.

1-(2-(2,3,4,5-Tetrahydro-1H-pyrido[4,3-b] indol-2-yl)-1-ethyl)- 1,3-dihydro-3,3-dimethyl-2H-indol-2-he

This compound was obtained from tetrahydro- -carboline and 2-((3,3-dimethyl)oxindoles)ethanol according to the aforementioned method and allocated in the form of manumaleuna, melting point 111-114oC.

1-(2-(1-Methyl-1,2,3,4-tetrahydro-2H-pyrido[3,4-b] indol-2-yl)- 1-ethyl)-1,3-dihydro-2H-benzimidazole-2-he

This compound was obtained from 1-chloritisation and tetrahydroharmine (ICS Perk I (1983) 265) by a standard method and allocated in the form of manumaleuna, melting point 174-176oC.

1-(2-(3-Methyl-1,2,3,4-tetrahydro-9H-pyrazolone and 3-methyl-1,2,3,4-tetrahydro- -carboline (Chem.Abs. 59 7501g) by a standard method and is allocated in the form of its hydrochloride, melting temperature 183-186oC.

Example 3.

6-Chloro-1-(2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol-2-yl)- 1-ethyl)-1,3-dihydro-2H-benzimidazole-2-he

To a mechanically stirred suspension of 6-chloro-1-(2-methyloxime)-1,3-dihydro-2H-benzimidazole-2-it (1G, 3,443 mmole) (U.S. patent 4,035,369) isobutylmethylxanthine (30 ml) is added potassium carbonate (0,403 g, 3.8 mmole) and heated with mechanical stirring for 24 hours to the boil under nitrogen atmosphere, cooled, the solvent is evaporated in vacuo, the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous layer was re-extracted with ethyl acetate (2 x 100 ml) are pooled, washed with water and dried (MgSO4). The magnesium sulfate and evaporation of the filtrate in vacuo get an orange-yellow residue, rinse which diethyl ether receives a yellow solid. Chromatography of this product pressurization chromatography on silica (MeOH-CHCl3with 5:95) get benzimidazole, melting point 138-140oC.

Example 4.

3-(Methyloxime)benzothiazolin-2-he

To 3-(2-hydroxyethyl)benzothiazolin-2-ONU (3.9 g, 20 mmol) (J. J. D'amico, F. G. Bollinger; J. Heterocy the AI methanesulfonanilide (1,625 ml, 2.4 g, 21 mmol) in dichloromethane (10 ml) and stirred for 1 hour at room temperature. Then the reaction mixture is washed with water, dried (MgSO4), filtered and evaporation of the solvent in vacuo get the title compound.

3-(2-(1,2,3,4-Tetrahydro-9H-pyrido[3,4-b]indol-2-yl)ethyl)-1,3 - dihydrobenzofuran-2-he

To a mixture of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (1,144 g of 6.65 mmole) and 3-(2-methyloxime)benzothiazolin-2-it (1,815 g 6,648 mmole) in acetonitrile (50 ml) is added potassium carbonate (1,105 g, 8 mmol) and the mixture is boiled for 24 hours with mechanical stirring in a nitrogen atmosphere. Excess acetonitrile is evaporated in vacuum to obtain a white solid product, which is distributed between ethyl acetate and water (150 ml, 1:1) and then divide. The aqueous layer was extracted with additional ethyl acetate (75 ml) and an ethyl acetate solutions are combined, washed with water and dried (MgSO4). The solvent (ethyl acetate) is evaporated in vacuum to obtain a yellow solid product by chromatography on which column with silica and elution with ethyl acetate to obtain compound, melting point 109-111oC.

Example 5.

3-(2-Methyloxime)benzoxazole-2-he

To a stirred solution of 3-(2-hydroc is methane (60 ml) add methanesulfonanilide (2,21 ml, 3,265 g, 28.5 mmole) and the mixture is stirred for three days at room temperature. The solvent is evaporated in vacuo and the residue partitioned between water and ethyl acetate, washed with hydrochloric acid (2M, 5 x 50 ml), sodium bicarbonate (2 x 20 ml), dried (MgSO4) and evaporation of the solvent in vacuo get the title compound.

3-(2-(1,2,3,4-Tetrahydropyrido[3,4-b]indol-2-yl)ethyl)benzoxazole-2-he

A mixture of potassium carbonate (0.828 g, 6 mmol), 3-(2-methyloxime) benzoxazole-2-it (1,494 g 5,814 mmole) and 1,2,3,4-tetrahydropyrido [3,4-b]indole (1 g, 5,814 mmole) in acetonitrile (30 ml) is boiled for 16 hours under nitrogen atmosphere. The solvent is evaporated in vacuo and the residue distributed between ethyl acetate (80 ml) and water (30 ml). The water is separated and add hydrochloric acid (0.5 M, 40 ml). The resulting white precipitate is filtered off, suspended in sodium hydroxide solution (2 M, 60 ml) and washed with chloroform (3 x 50 ml). The combined chloroform extracts washed with water (30 ml), dried (MgSO4), filtered and the solvent evaporated in vacuum. After treatment of the residue with a mixture of diethyl ether-ethyl acetate (3:1, 40 ml) receive small flocculent precipitate. The resulting filtrate is evaporated in vacuo and chromatography of the residue on silica (ethyl acetate-PE is 2">

2-tert-Butoxycarbonyl-1,2,3,4-tetrahydropyrido[3,4-b]indole

To 2-phase mixture of 1,2,3,4-tetrahydropyrido[3,4-b]indole (5 g, 29,07 mmole), 2 M sodium hydroxide solution (100 ml) and dichloromethane (80 ml) is added di-tert-BUTYLCARBAMATE (6,35 g, 29,09 mmole) and the mixture is stirred for 20 hours at room temperature. The dichloromethane layer is separated, the aqueous layer was extracted with dichloromethane (120 ml). The aqueous layer was separated, the dichloromethane layers combine, washed with 1 M hydrochloric acid (100 ml), sodium hydrogen carbonate solution and dried (MgSO4). The magnesium sulfate and evaporation of the filtrate in vacuo get protected beta carboline.

2-tert-Butoxycarbonyl-9-methyl-1,2,3,4-tetrahydropyrido[3,4-b]indole

To a suspension of sodium hydride in the form of a dispersion in oil (50%, 0,388 g, 0,194 g; 8,088 mmole) under nitrogen atmosphere was added dropwise and stirring 2-tert-butoxycarbonyl-1,2,3,4-tetrahydropyrido[3,4-b] indole (2 g, 7,353 mmole) in THF (25 ml). After one hour add DMF (5 ml), the mixture is stirred for 30 minutes, then add logmean (0,546 ml, 1,245 g 8,088 mmole). After two hours add an additional number of iodomethane (2 ml, 4,56 g 29,626 mmole) and the mixture is stirred for 16 hours at room temperature. The mixture is then partitioned between water (150 ml)together, washed with diluted hydrochloric acid (1M, 2 50 ml), water and dried (MgSO4). The magnesium sulfate and evaporation of the filtrate in vacuo get methylated beta-carbolin.

9-Methyl-1,2,3,4-tetrahydropyrido[3,4-b]indole

To a solution of 2-tert-butoxycarbonyl-9-methyl-1,2,3,4-tetrahydropyrido[3,4-b]indole (of 1, 848 g, 6,461 mmole) in dichloromethane (25 ml) add triperoxonane acid (3.5 ml, 45,23 mmole) and the mixture is stirred for 3 hours at room temperature. The mixture is then diluted with dichloromethane (125 ml), washed with 2 M sodium hydroxide solution (2 x 50 ml), water and dried (MgSO4). The magnesium sulfate and evaporation of the filtrate in vacuo get the title compound.

9-Methyl-1-(2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol-2-yl)-ethyl)- 1,3-dihydro-2H-benzimidazole-2-he

To a mechanically stirred mixture of 9-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole (1.08 g, of 5.81 mmole), 1-(2-chloro-ethyl)-1,3-dihydro-2H-benzimidazole-2-it (1,14 g of 5.81 mmole), sodium carbonate (0,6625 g of 6.25 mmole) and isobutylmethylxanthine (30 ml) was added Tetra-n-butylammonium (100 ml) and heated for 24 hours at 90oC, cooled and left for 48 hours. The solvent is evaporated in vacuo and the residue partitioned between water and ethyl acetate. The ethyl acetate susanou GHUR (60% acetonitrile, 40% water, 0.1% of NH3and get the product with a melting point 166-167oC (toluene).

Example 7.

1-Phenylmethyl-3-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl 1-ethyl] -1,3-dihydro-2H-benzimidazole-2-it monohydrochloride

In DMF (10 ml) is dissolved 1-[2-(1,2,3,4-tetrahydro-9-H-pyrido [3,4-b] indol-2-yl)-1-ethyl] -1,3-dihydro-2H-benzimidazole-2-he (1 g, 3 mmole). To the solution was added 60% sodium hydride (0,132 g, 3.3 mmole) and the mixture is stirred for 10 minutes at room temperature in a nitrogen atmosphere. Add benzylbromide (0,39 ml of 3.31 mmole) and the solution stirred for 24 hours at room temperature.

After concentrating the mixture in vacuo, water is added (50 ml), the precipitate is extracted with chloroform (3 x 50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained solid product is transferred into ethyl acetate (20 ml) and the solution propulsive hydrogen chloride. By recrystallization of the resulting precipitate from methanol-diethyl ether to obtain a cream-colored substance with melting point 215-217oC.

The following compound is obtained in a similar way:

1-Methyl-3-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol-2-yl)-1-ethyl] -1,3-dihydro-2H-benzimidazole-2-it, melting point 182-184o<
In 9 ml of water is dissolved hydrochloride 6-fortitudine (0,511 g of 2.38 mmole). Add the Glyoxylic acid monohydrate (0,241 g 2,618 mmole) followed by the addition of KOH (0,129 g, 2,31 mmole). The resulting precipitate is stirred for one hour at room temperature, after which one portion add concentrated HCl (0.6 ml). The mixture is boiled for 30 minutes, add the additional amount of concentrated hydrochloric acid (0.6 ml) and the mixture is boiled for another 15 minutes. The mixture is cooled to room temperature and add 5 n sodium hydroxide solution is alkalinized to pH 12. The mixture is then extracted with chloroform (4 x 75 ml), separated, dried over magnesium sulfate, filtered and concentrated in vacuo get snowy-white solid.

In a similar way the following compounds (see also the Application for the European patent N 94302608.8, Publication 0 620 222):

7-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,

7-methyl-8-bromo-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,

6-methyl-8-chloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,

6-fluoro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole.

1-[2-(6-Methoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol-2-yl) ethyl]-1,3-dihydro-2H-benzimidazole-2-he

In 35 ml of isobutyl ketone suspended 6-methoxy-1,2,(1,605 g, 8,16 mmole), sodium carbonate (0,944 g, 8,904 mmole) and tetrabutylammonium iodide (0.03 g). The mixture is heated for two days in a nitrogen atmosphere at 90oC. the mixture is Then concentrated in vacuo, transferred into water (75 ml) and extracted with chloroform (3 x 50 ml). The mixture is dried over MgSO4, filtered and concentrated in vacuo. Purification of the obtained oil pressure chromatography on silica with elution with a mixture of chloroform-methanol receives a yellow substance with a melting point 116-117oC.

Similarly receive the following connections:

1-[2-(6-fluoro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol-2-yl)- 2-ethyl]-1,3-dihydro-2H-benzimidazole-2-it, melting point 115-117oC,

1-[2-(8-bromo-7-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol - 2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazole-2-it, melting point 141-143oC,

1-[2-(8-chloro-6-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol - 2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazole-2-it, melting point 188-189oC,

1-[2-(7-fluoro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol-2-yl)- 2-ethyl]-1,3-dihydro-2H-benzimidazole-2-it, melting point 104-106oC.

Example 9.

6-Hydroxymethylene

In dried over sodium tetrahydrofuran (150 ml) suspended socialiniai the l-(indol-6-yl)methanoate (8 g, 45,7 mmole) and the solution added dropwise to a suspension of sociallyengaged. The mixture is stirred for three hours at room temperature. Add water (10 ml) dropwise followed by addition of 2 N. hydrochloric acid (30 ml). Extraction of the mixture with diethyl ether (3 x 150 ml) receive light purple oil.

6-Methylindol

In ethanol (70 ml) was dissolved 6-hydroxymethylene (6,135 g, 41,69 mmole). In acetic acid (70 ml) suspended 10% Paladiy coal (0,61 g) and the suspension is added to the ethanol solution (70 ml). The mixture is placed in a device for hydrogenation at high pressure and hydronaut at 60 psi (414 kPa). After 20 hours the mixture is filtered through a zeolite and the resulting solution was concentrated in vacuo. Purification of the mixture pressure chromatography using as solvent chloroform receive a colorless oil.

6-Methylindol-3-carboxaldehyde

To dimethylformamide (26 ml) for ten minutes added dropwise at -5oC oxychloride phosphorus (3.2 ml, 34.3 mmole). To the resulting solution was added over 10 minutes a solution of 6-methylindole (3,307 g, 25.2 mmole) in dimethylformamide (32 ml). The mixture is slowly warmed to room temperature and then four hours, heated at 50ois s, then to the brown solution is added dropwise a solution of sodium hydroxide (6 g) in water (22 ml). The resulting yellow precipitate is boiled and filtered in hot condition. The filtrate is cooled to room temperature and then to 5oC. the Precipitate is filtered off and washed with water (800 ml), dried under reduced pressure, and after further drying in vacuum at 50oC for 16 hours to obtain a yellow solid product.

6-Methyl-3-(2-nitroethylene)-1H-indole

In nitromethane (60 ml) suspended 6-methylindol-2-carboxaldehyde (3.5 g, 21,99 mmole), add ammonium acetate (0,562 g, 7.3 mmole) and the mixture is boiled for three hours under nitrogen atmosphere. The mixture is cooled and add a further quantity of ammonium acetate (0,762 g of 9.9 mmole). The mixture is boiled for another nine hours and then leave for 13 hours at room temperature. The mixture is optionally cooled in a bath of ice, filtered under vacuum, sucked dry after additional drying in vacuum at 50oC get the orange solid product.

6-Methyltryptamine

In dried over sodium tetrahydrofuran (95 ml) suspended sociallyengaged (3,993 g, 105 mmol) and the suspension cooled in a bath of ice. Within 15 minutes added dropwise 6-methyl-who promote to room temperature and then further cooled in a bath of ice. To the mixture is added dropwise water (120 ml). Add ethyl ether (200 ml) and the organic solution is decanted. The aqueous phase is extracted with diethyl ether (2 x 200 ml). The ether solutions are combined and washed with 2 N. hydrochloric acid (2 x 200 ml). The aqueous layer was separated and alkalinized 50% sodium hydroxide solution to pH 12. The aqueous layer was extracted with diethyl ether (2 x 200 ml), separated, dried over magnesium sulfate, filtered and after concentration in vacuo get a solid cream color.

1-[2-(7-Methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol-2-yl)- 1-ethyl]-1,3-dihydro-2H-benzimidazole-2-he

In N-organic (5 ml) was dissolved 7-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole (0.4 g, with 21.4 mmole). To this mixture was added 1-chloroethyl-1,3-dihydro-2H-benzimidazole-2-he (0,454 g, 2,31 mmole), potassium carbonate (0,739 g's, 5.25 mmole) and sodium iodide (0,385 g, to 2.57 mmole). These components are heated for three hours in a nitrogen atmosphere at 80oC. the Mixture is cooled to room temperature and transferred onto ice (20 g). The formed precipitate is filtered off and washed with water (3 x 20 ml). The precipitate is dried in vacuum at 50oC and after cleaning pressure chromatography on silica with elution with a mixture of chloroform-methanol receives a yellow substance with the chloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol-2-yl)- 1-ethyl]-1,3-dihydro-2H-benzimidazole-2-it, melting point 110-112oC.

1-[2-(7-methoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indol-2-yl)- 1-ethyl] -1,3-dihydro-2H-benzimidazole-2-it, melting point 105-107oC.

Example 10.

7-Fluoro-2,3,4-tetrahydro-1H-pyrido[4,3-b]indole

In ethanol (80 ml) contribute monohydrate hydrochloride 4-piperidone (4,55 g) hydrochloride and 3-forfamilies (4,85 g) and the mixture is boiled for one hour. The mixture propulsive hydrogen chloride and boiling continued for another 1.5 hours. The solution is cooled to 0oC, hydrochloride is filtered off, washed with ethanol, dissolved in boiling water, discolor activated charcoal and filtered. To the warm solution was added 2 M sodium hydroxide solution until neutral reaction of the indicator paper. Pale cream precipitate is filtered off, washed with water and dried. By recrystallization from acetonitrile receive a white solid, a mixture of 7-fluoro - 9-personera 86:14, respectively ghvd).

This technique is applied (J. Chm. Soc. (C), 1968, 1235-1243) to obtain the following known compounds:

8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole, melting point 210oC (U.S. Patent 3,419,568) (from the hydrochloride of 4-forfamilies),

2,3,4,5-tetrahydro-1>6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole, melting point 220oC (2-forfamilies hydrochloride).

1-[2-(2,3,4,5-(Tetrahydro-1H-pyrido[4,3-b] indol-2-yl)-1-ethyl] - 1,3-dihydro-2H-benzimidazole-2-he

In dry acetonitrile (150 ml) dissolved 2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole (2.15 g). To the solution was added a catalytic amount of sodium iodide, sodium carbonate (2.25 g) and 1-chloroethyl-1,3-dihydro-2H-benzimidazole-2-he (2.8 g). The mixture is boiled for 48 hours with stirring, the hot solution filtered from inorganic substances and evaporated in vacuum. The residue is rinsed with ethanolic hydrogen chloride. The hydrochloride is filtered off, washed with ethanol, dissolved in hot water, filtered and alkalinized 50% sodium hydroxide solution. The precipitate is filtered off, washed with water and dried. The crude solid product was dissolved in 5% methanol in chloroform, passed through a layer of silicon dioxide in displacement chromatography, evaporate and rinsed with acetonitrile. The precipitate is filtered and washed with ethanol. By recrystallization of the precipitate from dioxane get monoricinoleate with a melting point 114-117oC.

In a similar way the following compounds:

1-[2-(8-fluoro-/SUP>C (8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]- indole),

1-[2-(6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indol-2-yl)- 1-ethyl]-1,3-dihydro-2H-benzimidazole-2-it, melting point 214-216oC (6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indole,

1-[2-(7-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indol-2-yl] - 1-ethyl]-1,3-dihydro-2H-benzimidazole-2-it, melting point 125-127oC. the Compound contains 6-10% of 9-isomer (7-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (+14% 9-isomer).

Example 11.

Tablets, each containing 10 mg of the active component, was obtained as follows.

Active ingredient 10 mg

Starch - 160 mg

Microcrystalline cellulose 100 mg

Polyvinylpyrrolidone (as 10% solution in water) - 13 mg

Natrocarbonatite - 14 mg

Magnesium stearate 3 mg

Just 300 mg

The active ingredient, starch and cellulose are thoroughly mixed. The solution of polyvinylpyrrolidone is mixed with the obtained powder and sift through a sieve. The resulting granules are dried and again passed through a sieve. To the pellet add natrocarbonatite and magnesium stearate and after mixing pressed into teletrauma car and get the pills, each of which knowest ucaut as follows.

The active ingredient 20 mg

The dried starch - 178 mg

Magnesium stearate 2 mg

Only 200 mg

The active ingredient, starch and magnesium stearate is sifted through a sieve and the obtained mixture in an amount of 200 mg fill hard gelatin capsules.

1. Derived Azola General formula I

< / BR>
in which R1and R7each represents halogen, C1- C6alkyl, C1- C6alkoxy; R2and R3each represents hydrogen or C1- C6alkyl; R4and R5each represents hydrogen or halogen; R6represents hydrogen or C1- C6alkyl; m and p are each 0, 1 or 2, n is 2; Z is a

< / BR>
where R9and R10each represents hydrogen, C1- C6alkyl or phenyl-C1- C6alkyl; X is oxygen; Y is

,

where R11and R12each represents hydrogen, C1- C6alkyl, and salts thereof and a solvate.

2. Connection on p. 1 of General formula

< / BR>
where R1, R2, R3, R4, R5, R6, R7, R11, R12, X, Z, m, n, p taking the values defined in paragraph 1.

3. Connection on p. 2, in which X Prieur> represents hydrogen or C1- C6-alkyl.

5. Connection on p. 1, in which Z represents a group

< / BR>
X represents oxygen,

where R9represents hydrogen or C1- C6-alkyl, m is 0, 1 or 2, n is 2, R4, R5and R6each represents hydrogen.

6. A derivative of benzimidazole of General formula Ia

< / BR>
in which R9represents hydrogen or C1- C6-alkyl, R1', R1", R7'and R7"each represents hydrogen, halogen, C1- C6alkyl or C1- C6alkoxygroup, R5represents hydrogen, Y represents a

< / BR>
and its salts.

7. Pharmaceutical composition having activity against serotonin (5-HT1D) receptor containing an effective amount of the compounds under item 1 or its pharmaceutically acceptable salt, or MES in a mixture with a pharmaceutically acceptable diluent or carrier.

8. The compound of formula I under item 1 or its pharmaceutically acceptable salt, or MES, possessing activity against serotonin (5-HT1D) receptor.

Priority points:

02.06.95 on PP.1 to 3, 7 and 8;

12.09.94 on the Sabbath.

 

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