Tricyclic pyrazole derivatives, pharmaceutical composition

 

(57) Abstract:

Describes tricyclic pyrazole derivative represented by the General formula I, or its pharmaceutically acceptable salt, Het is a 5 - membered unsaturated heterocyclic ring containing a heteroatom selected from the group consisting of a sulfur atom or oxygen atom, or Het is isoxazol; And straight or branched lower Allenova group, R is a hydrogen atom, a lower alkyl group, halogen atom or lower alkoxygroup. Connection detect high affinity and selectivity for 5-HT2C-receptor and are useful for the treatment of diseases of the Central nervous system (e.g., sexual disorders, disturbances of appetite, anxiety, depression, sleep disorders and so on). 2 S. and 2 C.p. f-crystals, 4 PL.

The technical field

The invention relates to new tricyclic pyrazole derivative or its pharmaceutically acceptable salt. This invention relates also to pharmaceutical compositions, which include tricyclic pyrazole derivative or its salt and a pharmaceutically acceptable carrier, in particular pharmaceutical compositions, which are useful as medicines for before the appetite, anxiety or fear, depression, and sleep disturbance.

Prerequisites

With the progression of the aging society with regard to improvement and improve living conditions for older people, the focus was on the prevention and treatment of diseases, which are still not considered as a disease (e.g., sexual disorders, etc).

Although the role of the receptor 5-HT2Cthat was mainly distributed in the Central nervous system, has not been sufficiently clarified, believe that this receptor is associated with diseases of the Central nervous system, such as a sexual disorder, appetite disorder, anxiety or fear, depression, sleep disorders, etc., (Curr. Opin. Invest. Drugs, 2 (4), 317 (1993)). In the believe that the ligand of the receptor 5-HT2Ceffective for prevention or treatment of the above diseases, in particular diseases, which are still not considered as a disease for which no effective therapeutic method (e.g., sexual disorders, etc).

As for the tricyclic derivatives of pyrazole, which are agonists of the receptor 5-HT2Cthat was the message only about tricyclic derivative of p is izvozna of pyrazole, which is condensed with an unsaturated heterocyclic ring. In addition, the connection with tricyclic pyrazole nucleus, which is condensed with the ring of pyrazine, a pyridine ring, a thiophene ring, a furan ring or a pyrrole ring, reported in International Publication WO 96/13478, and in connection with tricyclic pyrazole nucleus nucleus condensed with an aromatic heterocyclic ring, and the substituents on the carbon atom of the pyrazole nucleus rings in this engine, it was reported in International Publication WO 95/07893. These references, however, do not describe the link in which the amine is associated with position 1 tricyclic pyrazole nucleus kernel through alkylenes chain, and also does not describe the relationship between the reported compounds and receptors 5-HT2c.

Description of the invention

As a result of intensive studies on compounds having 5-HT2Creceptor activity, the authors of this invention have discovered a new tricyclic derivative, having a high selectivity and high activity against 5-HT2C-receptor, and on the basis of this findings have completed this invention.

Thus, the present invention relates to novomesky selectivity and high affinity to 5-HT2C-receptor, or its pharmaceutically acceptable salt.

< / BR>
(each symbol in the above formula means the following:

the Het ring: 5-membered unsaturated heterocyclic ring containing 1-3 heteroatoms, each of which is selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom,

A: a straight or branched lower Allenova group, and

R: a hydrogen atom, a lower alkyl group, halogen atom, hydroxyl group or lower alkoxygroup).

The compound (I) of the present invention is characterized by its chemical structure, in which the amine is connected to position 1 tricyclic pyrosales nucleus condensed with a 5-membered unsaturated heterocyclic ring, always through alkylenes chain.

Among compounds (I) of the present invention, compounds in which a represents ethylene group or propylene group are preferable, and especially preferable are (S)-2-(lH-furo[2,3-g]indazol-l-yl)-1-methylethylamine, 2-(7-bromo-1H-thieno[2,3-g]indazol-1-yl) ethylamine, 2(7-iodine-1H-thieno[2, 3-g] indazol-1-yl) ethylamine 2-(7-methoxy-1H-thieno[2,3-g] indazol-1-yl)ethylamine, 2-(1H-furo[2,3-g]indazol-1-yl)ethylamine or their pharmaceutically priemel aziklicescoe pyrazole derivative or its salt and a pharmaceutically acceptable carrier. In particular, it relates to a pharmaceutical composition, which is a ligand 5-HT2Cand are useful as drugs for the prevention and treatment of diseases of the Central nervous system, such as sexual disorders, disturbances of appetite, anxiety (or worry or fear), depression, insomnia, etc.

The compound (I) of the present invention will be described hereinafter in detail.

The term "ligand 5-HT2C-receptor" refers to a compound that has an affinity to 5-HT2C-receptor and shows agonism or antagonism.

In the definition of the General formula, as applied to this application, unless otherwise indicated, the term "lower" means a straight or branched carbon chain having 1-6 carbon atoms.

Illustrative examples of the "lower alkalinous groups include methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene, hexamethylene and so on, of which preferred are ethylene and propylene.

Illustrative examples of "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl(amyl), isopentyl, neopentyl, tert-pentyl, hexyl, is preferred is methyl group.

Examples of the "halogen atom" include fluorine atom, chlorine atom, bromine atoms and iodine, of which preferred are bromine atoms and iodine.

The term "lower alkoxygroup" means oxygraph, substituted by the above lower alkyl group.

Illustrative examples of the "5-membered unsaturated heterocyclic ring containing 1-3 heteroatoms, each of which is selected from the group consisting of nitrogen atom, oxygen and sulfur atom" includes thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazol, isoxazol, triazole, thiadiazole, oxadiazole and so on, of which preferred are thiophene and furan.

The compound (I) of this invention may contain an asymmetric atom, depending on the types of groups. As a consequence, the concept of compound (I) of the present invention also includes a mixture or a dedicated form of optical isomers.

The compound (I) of the present invention may form an acid additive salt. These salts are also included in the concept of the connection of the present invention. Illustrative examples of salts include acid additive salts with inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, the slots (for example, formic acid, acetic, propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, tartaric, citric, methanesulfonic acid, econsultancy acid, etc.,), and acidic amino acids (such as aspartic acid, glutamic acid, etc.,).

In addition, compound (I) of this invention or its pharmaceutically acceptable salt can be isolated in the form of hydrates, various types of solvate (e.g., ethanol MES, etc.,) or polymorphic forms, and these different hydrate, solvate and polymorph forms are also included in the concept of the connection of the present invention.

(Production method)

The compound (I) of this invention can be obtained by applying various synthetic methods based on the use of the characteristic properties of its main core or deputies. Typical methods of obtaining described below.

The method of obtaining 1

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(In the above reaction scheme a ring Het, R and a have the above meanings and X denotes alkylenes group having the number of carbon atoms one atom less than the number of carbon atoms).

The compound (I) of this invention can be obtained by reduction under cooling or under heating, preferably at room temperature, using a suitable reducing agent in the presence or in the absence of a suitable inert solvent, such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, methylene chloride, benzene or toluene, preferably in ethers (e.g. tetrahydrofuran, etc.,), and, if necessary, in the presence of a suitable Lewis acid. As the Lewis acid can be used aluminum chloride or similar, as a reducing agent can be used a complex hydride, such as sociallyengaged or etc.

Alternatively, the reaction can be performed by catalytic hydrogenation at containing the metal catalyst, preferably a catalyst of palladium-carbon, platinum oxide, Raney Nickel or similar, using a suitable solvent, such as ethyl acetate, ethanol, tetrahydrofuran, dioxane, acetic acid or mixtures thereof.

The method of obtaining 2

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(In the above reaction scheme, a ring Het, R and a are as defined above meanings and Y represents a protected amino group, such as asiagraph, acetaminophe or similar.

Soy"ptx2">

When Y represents azido group, etc., recovery can be carried out under conditions of from cooling to heating conditions, preferably at room temperature, using a suitable reducing agent in the presence or in the absence of the same suitable inert solvent used in the method of obtaining 1, preferably in ethers (e.g. tetrahydrofuran, etc.,), and, if necessary, in the presence of a suitable Lewis acid such as aluminum chloride, etc. as a reducing agent or reductant you can use a complex hydride, such as sociallyengaged and so on). Alternatively, this reaction can be performed by catalytic hydrogenation with the catalyst metal, preferably a catalyst of palladium-carbon, platinum oxide, Raney Nickel or similar using a suitable solvent, such as ethyl acetate, ethanol, tetrahydrofuran, dioxane, acetic acid or their mixture, or using triphenylphosphine.

When Y represents an acetamido group, etc., you can use a method similar to those described in Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc. Preferably, the reaction can be performed in the condition is jinglian, dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane or alcohol (e.g. methanol, ethanol, propanol, isopropanol, etc.,), in the presence of a suitable base, such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, ammonia, sodium methoxide, ethoxide sodium, etc., preferably in the presence of a metal oxide, such as potassium hydroxide, sodium hydroxide or similar.

The source connection of each of the above methods of obtaining 1 and 2 can be easily obtained using the methods of reference examples and examples, which will be described below, either directly or with modification or using them.

The compound of the present invention, thus obtained, isolated in its free form or in the form of its salt. Salt of the compounds of this invention can be obtained confirmation of the compounds of this invention in free base form of the usual reactions of formation of salt.

The compound (I) of this invention or its salt can be isolated and purified in the form of a hydrate or MES or polymorphic form. Isolation and purification can be carried out usually using chemical pic, the various chromatographic techniques.

Different types of isomers can be separated by selecting the appropriate starting compound or by using the differences in the physical properties of the isomers. For example, optical isomers can be obtained in the form of pure stereochemical isomers using the selection of an appropriate material or may be separated by carrying out racemic separation of racemic compounds (for example, by using a method in which a compound is converted into diastereomer salts with conventional optically active acid and then subjected to optical separation).

Industrial applicability

Because the connection of the present invention have a high affinity and selectivity for 5-HT2creceptors and is effective in animal models, it is useful for the treatment of diseases of the Central nervous system, such as sexual dysfunction (eg, impotence and so on), obesity, disorders of appetite (for example, hyperphagia, hypophagia), anxiety, depression and insomnia.

The selectivity and affinity of the compounds of this invention in relation to 5-HT2C-receptor and its evaluation in animal models using the 5-HT2Areceptors: performed with the help of test binding of [3N] -5-HT according to method A. Pazos et. al. , Eur.J. Pharmacol., 106,539-546 (1985) or S. Havlik and S. J. Peroutka, Brain Res., 584, 191-196 (1992).

Using the above method to calculate the concentration of drug that inhibits 50% of the binding of the receptor with the ligand (the value of the IC50) and received the value of Ki, which represents the affinity towards the receptor, according to the following formula.

Ki = IC50/(1 + [L]/[K])

[L]: concentration of ligand, [Kd]: dissociation constant.

The results are presented in table 1.

Thus, the compound of this invention showed high affinity to 5-HT2c-receptor and approximately 20-fold higher selectivity in comparison with selectivity for 5-HT2A-receptor.

C. in vivo Test using rats

Induction of penile erection in rats: it is Known that the penile erection induced by stimulation of 5-HT2creceptor (Berendsen and Broekkamp, Eur. J. Pharmacol., 135, 179-184 (1987)). The test compound was administered to rats and the frequency of penile erection within 30 minutes after administration was measured to obtain the minimum effective dose at which the observed statistics, the data of the invention effectively on animal model using rats and therefore, it is useful for the treatment of diseases of the Central nervous system, such as sexual dysfunction (eg, impotence and so on).

Pharmaceutical composition that contains one or more compounds (I) of this invention, their pharmaceutically acceptable salt, hydrate, solvate, etc., as active ingredient, are prepared in the form of tablets, powders, fine granules, capsules, pills, solutions, injections, suppositories, ointments, adhesive preparations, etc. using pharmaceutical carriers, fillers and other additives and enter the oral (including sublingual) sublingual administration) or parenteral.

Clinical dose of the compound (I) of the present invention for a person is determined by the optional with regard to symptoms, weight, age, sex, etc. of each of the patient under treatment, and route of administration, etc. and oral compound may be usually in a dose of from 10 mg to 1000 mg, preferably from 50 mg to 200 mg, per day for an adult patient and the daily dose can be divided into 1 to several doses per day, or it can be administered via an intravenous injection, usually in a dose of from 1 mg to 500 mg, preferably from 5 mg to 100 mg per day for an adult is pennym infusion over 1 hour to 24 hours per day. Because the dose varies depending on various conditions, as described above, in many cases it may be sufficient to lower dose than the above interval.

Solid composition for use in oral administration according to this invention is used in the form of tablets, powders, granules, etc. In such solid compositions one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or silicate of aluminum-magnesium. Typically, the composition may contain other additives, in addition to the inert diluent, such as magnesium stearate or similar lubricant, glycolate, calcium cellulose or similar disintegrity agent, lactose or similar stabilizing agent and glutamic acid, aspartic acid or similar to facilitate solubilization agent. If necessary, tablets or pills may be coated with a sugar coating or a film of gastric or intercessor substances, such as sucrose, gelatin, hydroxypropylcellulose, phthalate-free hydroxypropylmethyl-cellulose or similar.

Injectable drugs for use in parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the diluent for use in aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of the diluent for use in non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, olive oil or a similar oil, ethanol or a similar alcohol, Polysorbate 80 (trade name), etc., Such a composition may optionally contain additional agents, such as agent toychest, antiseptics, wetting agent, emulsifier, dispersant, a stabilizing agent (for example, lactose is without restraint bacteria filter, mixing with germicidal or irradiation. Alternatively, they can be used by first cooking sterile solid compositions, followed by dissolving them in sterile water or a sterile solvent for injection before use.

The best way of carrying out the invention

Examples of the present invention are provided below for illustration but not for limitation. In this regard, the starting compound for use in the examples are described as reference examples.

Reference example 1

To a solution of tetrahydrofuran (80 ml) containing 7,29 g tertbutoxide potassium was added dropwise and with cooling with ice a solution of tetrahydrofuran (40 ml) containing 4.42 g of 6,7-dihydro-5H-benzofuran-4-it 10,47 ml ethylformate and the mixture was stirred for 1 hour. Then to the reaction solution was added 6,97 ml hydrazinoacetate, was added 1 N. hydrochloric acid for adjusting the pH to ~9 and then the mixture was stirred at room temperature for 17 hours. The reaction solution was podslushivaet the addition of an aqueous sodium hydroxide solution and then was extracted with chloroform. The organic layers were combined, washed with brine and then dried over betwedn silica gel (eluent: chloroform/methanol = 95/5) to obtain the 4,67 g of 2-(4,5-dihydro-1H-furo [2,3-g] indazol-1-yl)ethanol as a pale yellow solid.

Reference example 2

As described in reference example 1 was obtained 1,2-(4,5-dihydro-1H-furo[2,3-g] indazol-1-yl)ethanol.

Reference example 3

To a solution of tetrahydrofuran (20 ml) containing 2,95 g tertbutoxide, was added dropwise and under ice cooling a solution in tetrahydrofuran (10 ml) containing 2.00 g of 4-oxo-4,5,6,7-tetrabenzo[b]thiophene and the 3.89 ml ethylformate, and the mixture was stirred for 30 minutes. After completion of the reaction was added 26 ml of 1 N. hydrochloric acid. Then added while cooling with ice, and 3.16 g of hydrazinoacetate and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with methylene chloride. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the obtained filtrate was concentrated under reduced pressure to obtain 1.56 g of 2-(4,5-dihydro-1H-thieno [2,3-g]indazol-1-yl)ethanol as a pale yellow solid.

The connection reference of examples 4-7 were obtained as described in referential example 3.

Reference example 4: 2-(7-Bromo-4,5-dihydro-1H-thieno[2,3-g]indazol-1-yl)ethanol

Reference example 5: 2-(4,5-Dihydro-7-the l)ethanol

Reference example 7: 2-(7-Methoxy-4,5-dihydro-1H-thieno[2,3-g]indazol-1-yl)ethanol

Referential example 8:

2,04 g of 2-(4,5-dihydro-1H-thieno[2,3-g]indazol-1-yl)ethanol was dissolved in 40 ml of methylene chloride and added 4,18 ml of triethylamine and of 1.16 ml methanesulfonanilide and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and was extracted with chloroform. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the obtained filtrate was concentrated under reduced pressure obtaining of 3.23 g of 2-(4,5-dihydro-1H-thieno[2,3-g]indazol-1-yl)ethylmethanesulfonate.

Referential example 9:

of 3.23 g of 2-(4, 5-dihydro-1H-furo[2,3-g] indazol-l-yl)ethylmethanesulfonate was dissolved in 20 ml of dimethylformamide, was added 1,95 ml of sodium azide and the mixture was stirred at 70oC for 17 hours. The reaction solution was cooled, poured into ice water and then was extracted with ether. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure and Pol,64 g of 1-(2-azidoethyl)-4,5-dihydro-1H-furo[2,3-g]indazole

Reference example 10:

1.35 g of 2-(4,5-dihydro-1H-furo[3,2-g]indazol-1-yl)ethanol was dissolved in 20 ml of methylene chloride, was added 2.76 ml of triethylamine and 0.77 ml methanesulfonanilide and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into a mixture of ice water and then was extracted with chloroform. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, the obtained residue was dissolved in 20 ml of dimethylformamide. Then was added 1.29 g of sodium azide and the mixture was stirred at 80oC for 5 hours. After cooling, the reaction solution was poured into ice water and then was extracted with ether. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure obtaining of 1.30 g of 1-(2-azidoethyl)-4,5-dihydro-lH-furo[3,2-g]indazole.

Referential example 11:

5.10 g of 2-(4,5-dihydro-1H-thieno [2,3-g]indazol-1-yl)ethanol was dissolved in 50 ml of 1,2-dichloroethane was added at 0oFrom 7.74 ml triethylamin the ice water and then was extracted with chloroform. The organic layers were combined and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the obtained residue was dissolved in 30 ml of dimethylformamide. Then added a 3.01 g of sodium azide and the mixture was stirred at 80oC for 3 hours. The reaction solution was cooled, poured into ice water and then extracted with ethyl acetate. The organic layers were combined, washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent:toluene/ethyl acetate = 5) obtaining 3,39 g of 1-(2-azidoethyl)-4,5-dihydro-1H-thieno[2,3-g]indazole in the form of a yellow oil.

Reference example 12:

to 1.00 g of 1-(2-azidoethyl)-4,5-dihydro-1H-thieno[2,3-g]indazole was dissolved in 30 ml of dioxane, was added at room temperature 2,80 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the mixture was heated under reflux for 8 hours. The reaction solution was cooled, poured into aqueous sodium bicarbonate solution and then was extracted with chlorofo the filtration the solvent was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent:toluene/ethyl acetate = 6) to obtain 0.73 g of 1-(2-azidoethyl)-1H-thieno[2,3-g]indazole in the form of a pale brown oil.

Reference example 13:

In the same manner as described in reference example 10 was obtained 1-(2-azidoethyl)-7-bromo-4,5-dihydro-1H-thieno[2,3-g]-indazole.

Reference example 14:

In the same manner as described in reference example 12, was obtained 1-(2-azidoethyl)-7-bromo-1H-thieno[2,3-g]indazol.

Reference example 15:

In the same manner as described in reference example 10 was obtained 1-(2-azidoethyl)-4,5-dihydro-7-iodine-1H-thieno[2,3-g]-indazole.

Reference example 16:

In the same manner as described in reference example 12, was obtained 1-(2-azidoethyl)-7-iodine-1H-thieno[2,3-g]indazol.

Compounds of reference examples 17 and 18 were obtained as described in referential example 10.

Reference example 17: 1-(2-Azidoethyl)-7-chloro-4,5-dihydro-1H-thieno[2,3-g] indazol.

Reference example 18: 1-(2-Azidoethyl)-7-methoxy-4,5-dihydro-1H-thieno[2,3-g]indazol

Reference example 19:

0.51 g of sociallyengaged suspended in 20 ml of tetrahydrofuran in an argon atmosphere. Under ice cooling to the suspension was added 1.55 g of 1-(2-azidoethyl)-4,5-dihydro-1H-furo [2,3 g]indazole and the mixture was stirred for 1 hour. For the destruction of excess sociallyengaged to the reaction solution was added methanol and then added 0.51 ml of water, ivali within 30 minutes, added anhydrous sodium sulfate and celite, and then the mixture was stirred for another 30 minutes. The obtained insoluble material was removed by filtration through celite, and the obtained filtrate was concentrated and the obtained residue was purified column chromatography on silica gel (eluent: chloroform/methanol = 9/1) to give 1.26 g of 2-(4,5-dihydro-1H-furo[2,3-g] indazol-1-yl)ethylamine. 0.11 g of 2-(4,5-dihydro-1H-furo[2,3-g] indazol-1-yl) ethylamine was dissolved in a mixture of ethanol and ethyl acetate. Then added 4 N. hydrochloric acid in ethyl acetate and the precipitate was collected by filtration and dried under reduced pressure to get 0,092 g of the hydrochloride of 2-(4,5-dihydro-1H-furo[2,3-g]indazol-l-yl) ethylamine.

Reference example 20:

In the same manner as described in reference example 19 was obtained 2-(4,5-dihydro-1H-furo[2,3-g] indazol-1-yl)-ethylamine.

Reference example 21:

of 1.15 g of 2-(4,5-dihydro-1H-furo[2,3-g]indazol-1-yl)ethylamine was dissolved in 40 ml of methylene chloride, was added of 0.64 ml of acetic anhydride, at 1.91 ml of triethylamine and 30 mg dimethylaminopyridine and the mixture was stirred at room temperature for 18 hours. The solvent is evaporated and the obtained residue was purified column chromatography on silica gel (eluent:glory example 22:

As described in reference example 21 was obtained N-[2-(4,5-dihydro-1H-furo[3,2-g]indazol-1-yl)ethyl]ndimethylacetamide.

Reference example 23:

1.24 g of N-[2-(4,5-dihydro-1H-furo[2,3-g] indazol-1-yl)ethyl] ndimethylacetamide was dissolved in 20 ml of dioxane, was added to 1.16 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the mixture was heated under reflux for 4 hours.

Then added 0,58 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the mixture was further heated under reflux for 17 hours. The reaction solution was cooled, poured into aqueous sodium bicarbonate solution and then was extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 1/4) to obtain of 0.53 g of N-[2-lH-furo[2,3-g]indazol-1-yl)ethyl]ndimethylacetamide.

Reference example 24:

of 0.44 g of sociallyengaged suspended in 50 ml of tetrahydrofuran in an argon atmosphere, was added dropwise a solution of tetrahydrofuran (10 ml) containing 2,60 g (1H-furo[2,3-g]indazol-1-yl)ethyl acetate, and the MCA is ulali methanol to destroy excess sociallyengaged and then added to 0.44 ml of water, of 0.44 ml of 15% aqueous sodium hydroxide solution and 1,30 ml of water in a specified sequence. The resulting mixture was stirred for 30 minutes, was added anhydrous magnesium sulfate and celite, and then the mixture was stirred additionally for 30 minutes. After removal of insoluble material by filtration through celite, and the obtained filtrate was concentrated under reduced pressure to get to 1.82 g of 2-(1H-furo[2,3-g]indazol-1-yl)ethanol.

Reference example 25:

The solution in dimethyl sulfoxide (15 ml) containing 4,20 ml of triethylamine and 4,74 g complex SO3-pyridine, was added to the solution in dimethyl sulfoxide containing 1.80 g of 2-(1H-furo[2,3-g]indazol-1-yl)ethanol, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, acidified 1 N. hydrochloric acid and then was extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 1) obtaining 0,89 g (lH-furo[2,3-g]indazol-1-yl)acetamide,00 g 1H-furo[2,3-g]indazole, was added dropwise to the solution in dimethylformamide (10 ml) containing 0.27 g of sodium hydride, in an argon atmosphere and the mixture was stirred for 30 minutes. To the reaction solution under ice cooling was added to the value of 0.52 ml of propylene oxide and the mixture was stirred at room temperature for 41 hours. The reaction solution was poured into a mixture of ice water and was extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the obtained residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 2) receipt of 0.59 g of 1-(1H-furo[2,3-g]indazol-1-yl)propan-2-ol.

Reference example 27:

In argon atmosphere, 5 ml of 1.0 M solution ethylacetamide in tetrahydrofuran was diluted in 5 ml of tetrahydrofuran, was added dropwise a solution in tetrahydrofuran (5 ml) of 0.30 g of (1H-furo[2,3-g]indazol-1-yl)acetaldehyde and the mixture was stirred at room temperature for 3 days. The reaction solution was poured into an aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After evaporation of the solvents is of 0.29 grams of 1-(1H-furo[2,3-g] indazol-1-yl)butanol.

Compounds of reference examples 28 and 29 were obtained as described in reference example 27.

Reference example 28: 1-(lH-Furo[2,3-g]indazol-l-yl)pentanol.

Reference example 29: 1-(1H-Furo [2,3-g]indazol-1-yl)-3-methyl-2-butanol.

Compounds of reference examples 30-32 received as described in reference example 8.

Reference example 30: 2-(1H-Furo[2,3-g]indazol-1-yl)-1-metiletilgeksanon

Reference example 31: 1-(1H-Furo[2,3-g]indazol-1-ylmethyl)butylmalonate

Reference example 32: 1-(lH-furo[2,3-g]indazol-1-ylmethyl) -2-methylpropanesulfonate

Reference example 33:

As described in reference example 9 was obtained 1-(2-azithromy)-1H-furo[2,3-g]indazol.

Reference example 34:

As described in reference example 10 was obtained 1-(2-azidomethyl)-lH-furo[2,3-g] indazol.

Reference example 35:

As described in reference example 3 was obtained 2-(8-methyl-4,5-dihydro-1H-pyrazolo [3,4-e]benzisoxazol-1-yl) ethanol.

Reference example 36:

As described in reference example 10 was obtained 1-(2-azidoethyl)-8-methyl-4,5-dihydro-1H-pyrazolo[3,4-e] [1,2]benzisoxazole.

Reference example 37:

As described in reference example 12, was obtained 1-(2-and mawali hexane in an argon atmosphere was added 5 ml of dimethylformamide. While cooling with ice was gradually added 0.50 g of 1H-furo[2,3-g]indazol in 5 ml of dimethylformamide and the mixture was stirred for 1 hour. To the reaction solution under ice cooling was added 0.33 ml of 2-bromopropionitrile and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a mixture of ice water and was extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the obtained residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 4) to obtain 0.45 g of 2-(1H-furo[2,3-g]indazol-1-yl)propiononitrile.

Reference example 39:

As described in the reference examples 26 and 10, was obtained (S)-1-(2-azithromy)-1H-furo[2,3-g]indazol.

Example 1

1,60 g of potassium hydroxide was added to the solution in ethylene glycol (20 ml) containing 0.51 g of N-[2-(1H-furo[2,3-g]indazol-1-yl)ethyl]acetamide", she and the mixture was stirred at 170oC for 2 hours. The reaction solution was cooled, diluted with water and then was extracted with ethyl acetate. The organic layers were combined, washed with water and brine and then dried over anhydrous magnesium sulfate. After removed the offered by chromatography on silica gel (eluent:chloroform/methanol = 95/5) to obtain 2-(1H-furo[2,3-g] indazol-1-yl)ethylamine. Obtained 2-(1H-furo[2,3-g] indazol-1-yl)ethylamine was dissolved in a mixture of ethanol and ethyl acetate, the resulting solution was added 4 N. hydrochloric acid in ethyl acetate and the precipitate was collected by filtration and dried under reduced pressure to obtain 0.06 g of the hydrochloride of 2-(1H-furo [2,3-g]indazol-1-yl)ethylamine.

Example 2

0,94 g of N-[2-(4,5-dihydro-1H-furo[3,2-g] indazol-l-yl)ethyl] ndimethylacetamide was dissolved in 20 ml of dioxane, was added 0,86 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the mixture was heated under reflux for 4 hours. Then added 0,86 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the mixture was heated under reflux for 17 hours. The reaction mixture was cooled, poured into aqueous sodium bicarbonate solution and then was extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the obtained filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane = 4) to give 0.075 g of N-[2-(1H-furo[3,2-g]indazol-1-yl)ethyl] ndimethylacetamide. It was dissolved in 10 ml of ethylene glycol was added 0.40 g of hydroxide is then extracted with ethyl acetate. The organic layers were combined, washed with water and brine and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the obtained filtrate was concentrated and the obtained residue was purified column chromatography on silica gel (eluent:chloroform/methanol = 95/5) to obtain 2-(1H-furo[3,8] indazol-1-yl)ethylamine. Obtained 2-(1H-furo[3,8]indazol-1-yl)ethylamine was dissolved in a mixture of ethanol and ethyl acetate, the resulting solution was added 4 N. hydrochloric acid in ethyl acetate and the precipitate was collected by filtration and dried under reduced pressure to obtain 0.03 g of the hydrochloride of 2-(1H-furo [3,2-g] indazol-1-yl)ethylamine.

Connection examples 3 and 4 were obtained as described in reference example 19.

Example 3: the Hydrochloride of 2-(1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine

Source connection: 1-(2-Azithromy)-1H-furo[2,3-g]indazol

Example 4: the Hydrochloride of 1-ethyl-2-(1H-furo[2,3-g]indazol-1-yl)ethylamine

Source connection: 1-(2-Azidomethyl)-(1H-furo[2,3-g]indazol

Example 5:

0,045 g of sodium azide was added to 0,088 g of 1-(1H-furo[2,3-g]indazol-1-ylmethyl)butylmalonate in 5 ml of dimethylformamide and the mixture was stirred at 80oC for 16 hours. The reaction is applicable, washed with brine and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the obtained filtrate was concentrated under reduced pressure to get 0,063 g of 1-(2-azidophenyl)-1H-furo[2,3-g]indazole. In an argon atmosphere 0,018 g sociallyengaged suspended in 5 ml of tetrahydrofuran, to the resulting suspension under ice cooling was added to the solution in tetrahydrofuran (5 ml) containing 0,063 g of 1-(2-azidophenyl)-1H-furo[2,3-g] indazole, and the resulting mixture was stirred for 30. minutes. To the reaction solution was added methanol to destroy excess sociallyengaged. Then added 0,018 ml of water, 0,018 ml of 15% aqueous sodium hydroxide solution in a specified sequence, and the resulting mixture was stirred for 30 minutes. Then was added anhydrous sodium sulfate and celite, and the mixture was additionally stirred for 30 minutes. The obtained insoluble material was removed by filtration through celite, and the obtained filtrate was concentrated, and then the obtained residue was purified column chromatography on silica gel (eluent:chloroform/methanol = 95/5) to obtain 1-(1H-furo [2,3-g]indazol-1-ylmethyl)butylamine. The obtained 1-(1H-furo[2,3-g]indazol-1-ylmethyl)butylamine were dissolved VI the precipitate was collected by filtration and dried under reduced pressure to obtain 0.04 g of the hydrochloride of 1-(1H-furo[2,3-g]indazol-1-ylmethyl)butylamine.

Example 6

In the same way as described in example 5 was obtained the hydrochloride of 1-(1H-furo [2,3-g] indazol-1-ylmethyl) -2-methylpropylamine of 1-(1H-furo[2,3-g]indazol-1-ylmethyl)-2 - methylpropanesulfonate.

Example 7

As described in reference example 19 was obtained the hydrochloride of 2-(1H-thieno[2,3-g] indazol-1-yl)ethylamine 1-(2-azidoethyl)-1H-thieno[2,3-g] indazole.

Example 8

of 0.91 g of triphenylphosphine was added to 0,93 g of 1-(2-azidoethyl)-7-bromo-1H-thieno[2,3-g] indazole dissolved in 20 ml of tetrahydrofuran, and the solution was heated under reflux for 1.5 hours. Then was added 0.08 g of water and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled, concentrated under reduced pressure and then diluted with a mixture of methanol and methylene chloride. The resulting solution was acidified by addition of 1 N. hydrochloric acid, washed with chloroform, and the resulting aqueous layer was podslushivaet 40% aqueous sodium hydroxide solution and was extracted again with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the obtained filtrate was concentrated under reduced pressure and the obtained residue was purified kolonen the,73 g of 2-(7-bromo-1H-thieno[2,3-g]indazol-1-yl)ethylamine as a pale yellow oil. Obtained 2-(7-bromo-1H-thieno[2,3-g]indazol-1-yl)ethylamine was dissolved in 8 ml of ethanol, to the solution was added 0.6 ml 4 N. hydrochloric acid in ethyl acetate and the precipitate was collected by filtration and dried under reduced pressure to get a 0.59 g of the hydrochloride of 2-(7-bromo-1H-thieno[2,3-g]indazol-1-yl)ethylamine.

Example 9

In the same way as described in example 8, the hydrochloride of 2-(7-iodine-1H-thieno [2,3-g] indazol-1-yl)ethylamine was obtained from 1-(2-azidoethyl)-(7-iodine-1H-thieno[2,3-g] indazole.

Example 10

1.48 g of 1-(2-azidoethyl)-7-methoxy-4,5-dihydro-1H-thieno[2,3-g] indazole was dissolved in 20 ml of dioxane, was added at room temperature 3,66 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the resulting mixture was heated under reflux for 8 hours. The reaction solution was cooled and poured into aqueous sodium bicarbonate solution obtained insoluble material was removed by filtration through celite and then the filtrate was extracted with ethyl acetate. The organic layers were combined, washed with saline, was mixed with activated carbon and then dried over anhydrous magnesium sulfate. After removal of insoluble material by filtration, the obtained filtrate was concentrated under reduced davleniya at 50oC for 30 minutes. Then was added 0.18 g of water and the mixture was further heated at 50oC for 1 hour. After cooling, to the resulting solution was added 1 ml of 4 N. hydrochloric acid and the precipitate was collected by filtration and dried under reduced pressure. The resulting product was recrystallized from ethanol to obtain hydrochloride of 2-(7-methoxy-1H-furo[2,3-g]indazol-1-yl) ethylamine as a white powder.

Example 11

In the same way as described in example 10, was obtained the hydrochloride of 2-(7-chloro-1H-thieno[2,3-g] indazol-1-yl)ethylamine 1-(2-azidoethyl)-7-chloro-4,5-dihydro-1H-thieno[2,3-g]indazole.

Example 12

In the same way as described in example 8, the hydrochloride of 2-(8-methyl-1H-pyrazolo[3,4-e] [1,2] benzisoxazole-1-yl) ethylamine was obtained from 1-(2-azidoethyl)-8-methyl-1H-pyrazolo[3,4-e][1,2]benzisoxazole.

Example 13

In an argon atmosphere 0.08 g of sociallyengaged suspended in 20 ml of tetrahydrofuran were added under ice cooling 0.29 grams of aluminum chloride and the mixture was stirred for 15 minutes. To the suspension was added a solution in tetrahydrofuran (5 ml) at 0.42 g of 2-(lH-furo[2,3-g]indazol-1-yl)propiononitrile under ice cooling and the mixture was stirred at room temperature for 30 minutes. To reactiond sodium and then the mixture was stirred for 10 minutes. The obtained insoluble material was removed by filtration through celite and then the organic layers were combined and dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent evaporated and the obtained residue was purified column chromatography on silica gel (eluent:chloroform/methanol/saturated aqueous ammonia = 10/1/0,1) to obtain 0.39 g of 2-(1H-furo[2,3-g]indazol-1-yl) Propylamine. Obtained 2-(1H-furo[2,3-g]indazol-1-yl)Propylamine was dissolved in ethanol, the resulting solution was added 4 N. hydrochloric acid in ethyl acetate and the precipitate was collected by filtration and dried under reduced pressure to get to 0.22 g of the hydrochloride of 2-(1H-furo[2,3-g]indazol-1-yl)Propylamine in the form of a white solid.

Example 14

As described in reference example 19, hydrochloride, (S)-2-(1H-furo[2,3-g] indazol-1-yl) methylethylamine was obtained from (S)-1-(2-azithromy)-1H-furo[2,3-g]indazole.

Chemical structural formula (formula) and physico-chemical properties of the compounds obtained in reference examples and examples shown in the following table.

Each of the symbols used in the tables, indicates the following:

Rf.: reference example

Ex.:) :

S - singlet,

d - doublet,

dd = double doublet,

t - triplet,

m - multiplet,

bzs - wide singlet,

m/z Data of mass spectrometry (m/z),

Me: Methyl group,

Et: Ethyl group,

RG: Sawn group,

iPr: Isopropyl group.

An example of the finished formulation composition

Composition 3 mg tablets

The compound of the present invention is 3 mg

D-mannitol - 89,8 mg

Corn starch is 22.4 mg

Hydroxypropylcellulose 3.6 mg

Magnesium stearate 1.2 mg

Just 120 mg

The way to obtain 3 mg tablets

Using the device to obtain granules with a coating fluidized bed thoroughly mixed with the compound of the present invention (15 g), D-mannitol (449 g) and corn starch (112 g). Then sprayed with a 10% aqueous solution of hydroxypropylcellulose, and the mixture granularit. After drying, the granules were sieved through 20 mesh, add magnesium stearate (6 g) and the mixture tabletirujut using a rotary teletrauma machine with punch 7 mm x 8.4 R, receiving tablets, each contains 3 mg of the compound of the present invention.

1. Three cyclic pyrazole derivative of the General formula I

< / BR>
in which Het p or oxygen, or Het is isoxazol;

A represents a straight or branched alkylenes group;

R represents a hydrogen atom, a lower alkyl group, halogen atom or lower alkoxygroup,

or its pharmaceutically acceptable salt.

2. (S)-2-(1H-Furo[2,3-q] indazol-1-yl)-1-methylethylamine, 2-(7-bromo-1H-thieno[2,3-q] indazol-1-yl)ethylamine, 2(7-iodine-1H-thieno-[2,3-q] indazol-1-yl)ethylamine, 2-(7-methoxy-1H-thieno[2,3-q] indazol-1-yl)ethylamine 2-(1H-furo[2,3-q]indazol-1-yl)ethylamine or their pharmaceutically acceptable salts.

3. Pharmaceutical composition having affinity to T2Cthe receptor, which contains a connection on p. 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to p. 3, represents a therapeutic drug for impotence.

 

Same patents:

The invention relates to compounds of formula (I):

< / BR>
where

-A= B-C= D - represents-CH=CH-CH=CH-group, in which 1 or 2 CH may be replaced by nitrogen;

Ar denotes phenyl or naphthyl, unsubstituted or one-, two - or three-fold substituted with H, Gal, Q, alkenyl with the number of C-atoms up to 6, Ph, OPh, NO2, NR4R5, NHCOR4, CF3, OCF3CN, OR4, COOR4, (CH2)nCOOR4, (CH2)nNR4R5, -N=C=O or NHCONR4R5phenyl or naphthyl;

R1, R2, R3each independently from each other, are absent or represent H, Gal, Q, CF3, NO2, NR4R5, CN, COOR4or CHCOR4;

R4, R5each independently of one another denote H or Q, or together also denote-CH2-(CH2)N-CH2-;

Q denotes alkyl with 1-6 C-atoms;

Ph denotes phenyl;

X denotes O or S;

Gal denotes F, Cl, Br or I;

"n" represents 1, 2 or 3;

and their salts, except 4-methyl-N-(2,1,3-benzothiadiazole - 5-yl)benzosulfimide, 4-nitro-N-(2,1,3-benzothiadiazole-5-yl)- benzosulfimide and 4-amino-N-(2,1,3-benzothiadiazole-5-yl)- benzolsulfonat

The invention relates to the field of production of new heterocyclic O-dicarbonitriles, which can be used to achieve different hexatriene, useful as active media of liquid and solid lasers, scintillators, for the transformation of shortwave radiation in the long wavelength in the transmission of information through fiber-optic communication lines and so on

The invention relates to medicine and relates to a method of inhibiting tyrosine kinase receptor, epidermal growth factor, for example, Erb-b2, Erb-b3, or Erb-b4, by introducing to a mammal in need, an effective amount of nitrogen-containing heterocyclic compounds, which is that as the nitrogen-containing heterocyclic compounds used as a compound of formula I, where R1-R9are specified in the claims value, or its pharmaceutically acceptable salt, or hydrate, thereof the pharmaceutical composition and the contraceptive composition based on them

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula II, where R1, R2are primocane C1-6alkyl group; R4represents unsubstituted phenyl; R5and R8represent hydrogen; R6represents methoxy or bromo; R7arepresents methoxy, hydroxy or trifluoromethyl; R9and R10represent hydrogen, salts, solvate or physiologically functional derivatives, and method of production thereof

The invention relates to compounds of the following formula I which inhibit the enzyme glycinamide ribonucleotide the formyl transferase (GARFT)

The invention relates to new heterocyclic compounds with biological activity, more specifically, to the derivatives of benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone, the pharmaceutical composition having inhibitory cell adhesion or HIV activity, method of inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it and the method of treating mammals infected with HIV

The invention relates to compounds of formula (I):

< / BR>
where

-A= B-C= D - represents-CH=CH-CH=CH-group, in which 1 or 2 CH may be replaced by nitrogen;

Ar denotes phenyl or naphthyl, unsubstituted or one-, two - or three-fold substituted with H, Gal, Q, alkenyl with the number of C-atoms up to 6, Ph, OPh, NO2, NR4R5, NHCOR4, CF3, OCF3CN, OR4, COOR4, (CH2)nCOOR4, (CH2)nNR4R5, -N=C=O or NHCONR4R5phenyl or naphthyl;

R1, R2, R3each independently from each other, are absent or represent H, Gal, Q, CF3, NO2, NR4R5, CN, COOR4or CHCOR4;

R4, R5each independently of one another denote H or Q, or together also denote-CH2-(CH2)N-CH2-;

Q denotes alkyl with 1-6 C-atoms;

Ph denotes phenyl;

X denotes O or S;

Gal denotes F, Cl, Br or I;

"n" represents 1, 2 or 3;

and their salts, except 4-methyl-N-(2,1,3-benzothiadiazole - 5-yl)benzosulfimide, 4-nitro-N-(2,1,3-benzothiadiazole-5-yl)- benzosulfimide and 4-amino-N-(2,1,3-benzothiadiazole-5-yl)- benzolsulfonat

The invention relates to compounds of the formula I, their pharmaceutically acceptable salts and stereoisomeric forms, where R is hydrogen or C1-6-alkyl; R2is hydrogen; C1-6-alkyl; trihalomethanes; C1-6-alkyl, substituted carboxyla,1-6-alkylcarboxylic,1-6-allyloxycarbonyl, or R1and R2taken together with the nitrogen atom to which they are attached, may form a ring morpholinyl or optionally substituted heterocyclic radical; R3- R10each independently represents hydrogen; R8, R9independently represent hydrogen or halogen; R11and R12is hydrogen; n= 1, 2, 3, 4, 5 or 6; X Is O, S, S(=O)

The invention relates to new chemical compounds, in particular derivatives (1,2,3-triazolyl)-1,2,5-oxadiazole General formula I, where R = NH2or< / BR>
and, if R1= N, R2lowest hydroxyalkyl, or, if R1- lower alkyl, lower hydroxyalkyl, aryl, R2= N, the lower hydroxyalkyl or a radical of General formula-C(O)R3where R3= HE, NH2, lower alkyl or lower alkoxyl, potentiating NO-dependent activation of the soluble form of guanylate cyclase (RGC)

The invention relates to new chemical compounds with valuable biological properties, in particular to derive hinolan and naphthyridinone acids with antibacterial activity, as well as to the isoindole derivative as starting compounds for obtaining the derivatives hinolan and naphthyridinone acid

The invention relates to new heterocyclic compounds with biological activity, more specifically, to the derivatives of benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone, the pharmaceutical composition having inhibitory cell adhesion or HIV activity, method of inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it and the method of treating mammals infected with HIV

The invention relates to new derivatives of guanidine and their pharmaceutically acceptable salts, used as medicines

The invention relates to vysokomernoa tritium 2-methyl-4-(4-methyl-1-piperazinil)-10H-thieno[2,3-b] [1,5] benzodiazepine, which can be used
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