N-substituted piperidineacetate, their n-oxide forms, pharmaceutically acceptable salt accession acids and stereochemical isomeric forms, methods for their preparation, pharmaceutical compositions on their basis and intermediate product

 

(57) Abstract:

The invention relates to new N-substituted piperidinylmethyl f-ly I, their N-oxide forms, isomers, and salts, where R1- halogen, C1-6alkylsulfonamides And divalent radical-CH2-CH2; -CH2-CH2-CH2- or-CH=CH-; R2is hydrogen or C1-6alkyloxy; L is a radical of formula-Alk-R4, -Alk-OR5, -Alk-NR6R7; Alk-C1-12alcander; R4is hydrogen, cyano, C1-6alkylsulphonyl,1-6allyloxycarbonyl etc. or the radical of f-crystals, II or III, where R8is hydrogen or C1-6alkyl; R5, R6and R7is hydrogen, C1-6alkyl, and other Compounds of formula I stimulate gastrointestinal peristalsis and can find application in medicine. 6 C. and 4 h.p. f-crystals, 4 PL.

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The invention relates to new derivatives of benzoate, pharmaceutical compositions containing these new compounds, methods of producing compounds and compositions and their use as pharmaceuticals, in particular in the treatment of conditions, including reduced peristalsis of the colon.

In our application EP-O 389 037-A, published on 26 September 1990, opisyvayuschie stimulating gastrointestinal motility properties. Our EP IS ABOUT 445 862-A, published on September 11, 1991, describes derivatives of N-(4-piperidinyl)(dihydrobenzofuran or dihydro-2H - benzopyran)carboxamide, also has a stimulating gastrointestinal motility properties. WO 93/03725 (SmithKline Beecham), published on March 4, 1993, describes in General use as antagonists of 5HT4receptors esters of General formula X-CO-Y-Z, in which X may be substituted by phenyl, Y can be oxygen, and Z may be the residue of substituted piperidine. WO 94/08995 (Smithkelne Beecham), published on April 28, 1994, in General describes, for example, substituted 7-benzophenoneoxymate also having 5HT4-antagonistic activity. The last two patent applications describe the use of 5HT4-antagonistic compounds in the treatment of irritable bowel syndrome (srtc), in particular, diarrhoeal species srtc.

Unexpectedly, we discovered that these new compounds show intestinal prokinetics activity. Therefore, described in this application connections demonstrate the usefulness in the treatment of conditions, including reduced peristalsis of the intestines, especially the colon.

This invention relates to new preeminene acids (acid additive salts) and stereochemical isomeric forms, where:

R1represents halogen or C1-6alkylsulfonamides;

A represents A bivalent radical of the formula:

-CH2-CH2(a)

-CH2-CH2-CH2(b)

-CH=CH- (c),

in the radicals (a), (b) and (c) one or two hydrogen atoms may be substituted C1-6by alkyl;

R2represents hydrogen or C1-6alkyloxy;

L is a radical of the formula:

Alk-R4(d)

-Alk-O-R5(e)

-Alk-NR6R7(f).

Alk is C1-12Alcantara,

R4represents hydrogen; cyano; C1-6alkylsulphonyl; C1-6allyloxycarbonyl; C3-7cycloalkyl; C1-6alkylsulfanyl; C1-6alkylsulfonyl; phenyl or phenyl substituted by halogen, C1-6the alkyl or C1-6alkyloxy; tetrahydrofuran; dioxolane; dioxolane substituted C1-6by alkyl; dioxane; dioxane, substituted C1-6by alkyl; pyridine; pyridine, substituted by halogen or C1-6by alkyl; pyridazin; pyridazin substituted by one or two substituents selected from halogen, C1-6of alkyl, hydroxy; or a radical of the formula:

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or

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where R8represents hydrogen or C1-6alkyl;

R5represents hydrogen or C< the number up to three, selected from halogen, C1-6of alkyl, C1-6alkyloxy;

R6represents hydrogen or C1-6alkyl,

R7represents hydrogen, C1-6alkyl, C1-6alkylsulphonyl; C1-6allyloxycarbonyl; pyridazin; pyridazin substituted by one or two substituents selected from halogen, C1-6of alkyl, hydroxy; pyrazin; pyrazin substituted by one or two substituents selected from halogen, C1-6of alkyl, hydroxy.

Used in the above definitions, the term halogen is a General term for fluorine, chlorine, bromine and iodine; C1-4alkyl defines saturated hydrocarbon radicals with normal or branched chain, having from 1 to 4 carbon atoms, such as for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-propylate and the like, it is assumed that C1-6alkyl includes C1-4alkyl and the higher its homologues having 5 or 6 carbon atoms, such as 2-methyl-butyl, pentyl, hexyl and the like; C3-7cycloalkyl is a General term for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C1-6alcander defines bivalent hydrocarbon radicals with the normal of the l, 1,4-butandiol, 1,5 - pentandiol, 1,6-hexandiol, 1,7-heptanediol, 1,8-octanediol, 1,9 - nonanediol, 1,10-decanediol, 1,11-undecanedioic, 1,12-dodecanediol and their branched isomers.

Understood that pharmaceutically acceptable salts of the accession of the acids referred to above, contain forms therapeutically active non-toxic salts accession acids, which are capable of forming compounds of formula I. the Latter can conveniently be obtained by processing forms the Foundation of such a suitable acid. Suitable acids include, for example, inorganic acids such as kaleidostone acid: for example, hydrochloric or Hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultation, benzosulfimide, p-toluensulfonate, glutamic, salicylic, p-aminosalicylic, AMOVA and similar acids. The term salt accession used in the future, also includes a solvate, which is able to form compounds of formula (I) and their salts. To be honest by treatment with alkali in the form of a free base.

The term "stereochemical isomeric forms" as used here previously, defines all the possible isomeric forms, which can have compound of formula (I). If not specified or not specified, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms, and these mixtures containing all diastereomers and enantiomers of the basic molecular structure. More specifically, stereogenic centers may have the R - or S-configuration; substituents of the divalent cyclic (partially) saturated radicals may have the CIS or TRANS configuration. Clearly implied that the stereochemical isomeric forms of the compounds of formula (I) are included in the scope of this invention.

Some compounds of formula (I) may also exist in their tautomeric form. Assume that such forms, although they are certainly not indicated in the above formula, are included in the scope of this invention. For example, the compounds of formula (I), where R4is a 3 - or 6-hydroxypyridine or a radical of formula (g) or (h), where R8is hydrogen may exist in their corresponding tautomeric form.

Assume that the N-oxide forms of the compounds formed, particularly those N - oxides, where the nitrogen of the piperidine N-oxide.

R1is of interest halogen, preferably chlorine;

R2is of interest hydrogen or C1-4alkyloxy, preferably hydrogen or methoxy,

A is of interest bivalent radical of formula (a) or (b),

when A is substituted, preferably methyl Deputy;

when A is A bivalent radical of formula (a) or (b), preferably genialne dimethyl substitution, especially on the carbon atom adjacent to the oxygen atom;

when L is a radical of formula (d), R4preferably represents hydrogen, cyano, C1-6alkylsulphonyl, C1-6allyloxycarbonyl, C3-7cycloalkyl, C1-6alkylsulfonyl, tetrahydrofuran, dioxolane, substituted C1-6the alkyl, pyridine, a radical of formula (g), where R8is C1-6the alkyl, pyridazine substituted by halogen and hydroxy;

when L is a radical of formula (e), R5preferably represents hydrogen, C1-6alkyl, hydroxy, C1-6alkyl or phenyl, substituted by halogen or halogen);

when L is a radical of formula (f), Rpyridazin, substituted C1-6the alkyl, C1-6alkylcarboxylic.

Interesting compounds are those compounds of formula (I), where R1is chlorine.

The following interesting compounds are those compounds of formula (I), where R2is hydrogen or a methoxy group. More interesting compounds of formula (I) are those compounds where A is A bivalent radical of formula (a) or (b).

Preferred compounds of formula (I) are:

1-[(tetrahydro-2-furanyl)methyl] -4-piperidinyl-4-amino-5-chloro - 2,3-dihydro-7-benzophenoneoxymate;

1-[(tetrahydro-2-furanyl)methyl] -4-piperidinyl-5-amino-6-chloro - 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-8-carboxylate;

1-(3-methoxypropyl)-4-piperidinyl-4-amino-5-chloro-2,3-dihydro - 7-benzophenoneoxymate;

1-[3-(2-methyl-1,3-dioxolane-2-yl)propyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

1-[3-(1-methylethoxy)propyl] -4-piperidinyl-4-amino-5-chloro-2,3 - dihydro-7-benzophenoneoxymate;

1-[2-(2-hydroxyethoxy)ethyl] -4-piperidinyl-4-amino-5-chloro-2,3 - dihydro-7-benzophenoneoxymate;

1-[3-(3-chloro-6-oxo-1(6N)-pyridazinyl)propyl] -4 - piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

1-(4-oxobutyl)-4-PI is arbonyl] - oxy]-1-piperidinemethanol and

1-[2-(tetrahydro-2-furanyl)ethyl]-4-piperidinyl-4-amino-5-chloro - 2,3-dihydro-7-benzophenoneoxymate; all possible stereo chemically isomeric forms and pharmaceutically acceptable salts accession acids.

In order to simplify the structural image of the compounds of formula (I) and some raw materials and intermediate products, the radical of the formula

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next will be represented by the symbol D.

In the subsequent receive the reaction products can be isolated from the reaction mixture and, if necessary, further cleaned in accordance with methods generally known in this field, such as, for example, extraction, distillation, crystallization, grinding into powder and chromatography.

The compounds of formula (I) can be obtained N-alkylation of the piperidine of formula (II) an intermediate product of the formula (III), where W1is appropriate tsepliaeva group, such as for example, halogen, for example chlorine, bromine or iodine, or sulfonyloxy, for example, methanesulfonate, toluensulfonate and similar otsepleniya group. The reaction of N-alkylation (II) compound (III) is conveniently carried out in known in the field methods of alkylation.

the acid of formula (V) or its functional derivative, for example allelochemical, symmetrical or mixed anhydride or ester, preferably an activated ester, known in this field techniques.

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It may be appropriate to protect the amino - or hydroxy-group in the course of the reaction, to avoid unwanted side reactions. Amino - or hydroxyamino group is removed after the formation of the ether. Suitable protective groups include easily removable group, for example, C1-4alkylsulphonyl, C1-4allyloxycarbonyl, phenylmethyl and similar protective group.

The compounds of formula (I) can also be obtained by conversion of compounds of formula (I) into each other.

The compounds of formula (I), where L is a radical of formula (f), where R7is not hydrogen, these compounds represented by formula (I-f-2), can be obtained by reaction of compounds of formula (I), where R7is hydrogen, represented by formula (I-f-1), with a reagent of formula (VI), where W2is appropriate tsepliaeva group, such as for example, halogen, for example chlorine, bromine or iodine, or sulfonyloxy, for example, methanesulfonate, toluensulfonate and similar otsepleniya group, known in the field methods of reaction.

is cyano, can be obtained by reaction of the intermediate product of the formula (II) with Acrylonitrile known in this field techniques.

The compounds of formula (I), where L is a radical of formula (e), Alk is 1,2-etandiola and R5is hydrogen, can be obtained by reaction of the intermediate product of the formula (II) with oxirane known in this field techniques.

The compounds of formula (1), where L is a radical of formula (f), Alk is 1,3-propandiol and where R6and R7are hydrogen, can be obtained by hydrogenation of compounds of formula (I), where L is a radical of formula (d), Alk is 1,2-etandiola and R4is cyano.

The compounds of formula (I) can also be converted into the corresponding N-oxide forms known in the field methods for the conversion of trivalent nitrogen into its N-oxide form. The reaction of N-oxidation can be generally carried out by reaction of the starting material of the formula (I) with a suitable organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali metals or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; suitable organic benzoperylene acid, for example, 3-chlorobenzophenone acid, alcamovia nagkalat, for example, peracetic acid, alkylhydroperoxide, for example, tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

Intermediates of formula (II) can be obtained from the correspondingly substituted piperidine of formula (VII) by reaction with an intermediate acid of formula (V) or its functional derivatives by known in the field methods of education of ester and subsequent removal of the protective group P is known in this field techniques. P represents an easily removable protective group, for example, C1-4alkylsulphonyl, C1-4allyloxycarbonyl, phenylmethyl and similar protective group.

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Intermediate acids of formula (V) described in EP-O 389 037-A.

Intermediates of formula (VII'), where P1represents P, as well as hydrogen, can be obtained by recovering the intermediate product of formula (VIII) are known in this field techniques. what cnie products represented by formula (VII'), and where R2and 4-hydroxyl group have the CIS-configuration, it is possible to obtain the restoration of the intermediate product of formula (VII-a) with a reducing agent, such as substituted borhydride, for example, Tris-second-butylbromide lithium, Tris-second-butylbromide potassium, substituted alumoweld, three-tert-butoxylated lithium and the like. Using stereochemical pure reagents this recovery can be stereospecific way.

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CIS - and TRANS-diastereomeric the racemates of the compounds of formula (I) or any of the other intermediate products can also be divided into their optical isomers, CIS(+), CIS(-), TRANS(+) and TRANS(-), by applying well-known in this field techniques. Diastereoisomer can be divided by physical separation methods such as selective crystallization and chromatographic methods, for example, countercurrent distribution, and the enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with enantiomerically pure acids or their enantiomerically pure derivatives.

The compounds of formula (I) and the intermediates of formula (II), the N-oxide forms, the pharmaceutically acceptable. In particular, these compounds demonstrate significant increases peristalsis action on a thin and thick gut. The last property to prove the results of the test "Coaxial stimulation of the ileum of the Guinea pig and test the Motility of the colon from being in the mind of the dog. Both of these tests are described in further. Some compounds also show activity in Leguminosas testing on the dogs."

Because of their useful that increase peristalsis properties of the compounds of the invention can be prepared medicines in various forms for the purposes of introduction.

To obtain pharmaceutical compositions of this invention an effective amount of a compound, in the form of a base or salt accession acid, as the active ingredient is combined in intimate mixture with a pharmaceutically acceptable carrier, which may have different forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in a uniform dosage form (i.e., in the form of unit doses), a suitable, preferably, for administration orally, rectally or p the work any of the usual pharmaceutical media, such as for example, water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers, for example, starches, sugars, kaolin, lubricants, binders, dezintegriruetsja agents and the like in the case of powders, pills, capsules and tablets. Due to their ease of administration, tablets and capsules represent the most favorable oral unified dosage form, in this case explicitly use solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes sterile water, at least in the most part, although it can include other ingredients, for example, to facilitate solubility. Can be prepared, for example, injectable solutions, in which the medium contains a salt solution, a glucose solution or a mixture of saline and glucose solution. You can also prepare injectable suspension, in this case, you can use the appropriate liquid carriers, suspendresume tools and the like. In the compositions suitable for subcutaneous injection, the carrier may contain a tool that improves the penetration and/or a suitable wetting means is considerable worsening effect on the skin. These supplements can facilitate the introduction into the skin and/or may be useful for the preparation of the required compositions. These compositions can be administered in a number of ways, for example, in the form of a transdermal patch, in the form of the applied patches and ointments. Salts with acids (I) or (II) due to their high solubility in water compared with the appropriate form of the base, are obviously more suitable in the preparation of aqueous compositions. Particularly beneficial to prepare the above-mentioned pharmaceutical composition in a uniform dosage form to facilitate the introduction and constant dosage. The term uniform dosage form used here in the description and the claims refers to physically discrete units suitable as standardized doses, each unit contains a defined quantity of active ingredient calculated to produce therapeutic effects, in combination with the required pharmaceutical carrier. Examples of such standardized dosage forms are tablets (including tablets with grooves and coating), capsules, pills, sachets of powder, wafers, injectable solutions or suspensions, capacity to accept pidu their ability to stimulate peristalsis of the intestinal system and, in particular, their ability to increase peristalsis of the colon, the compounds of the invention are useful for normalization or improvement of the passage of contents through the intestine in subjects suffering from symptoms associated with impaired motility, for example, decreased peristalsis of the intestine and colon, or a combination of decreased peristalsis with delayed gastric emptying.

Because of the usefulness of the compounds of the present invention, a method of treating warm-blooded animals suffering from intestinal disorders, such as, for example, a higher, pseudoprobability, intestinal atony, postoperative intestinal atony, irritable bowel syndrome (srtc) induced drug slow the passage of contents through the intestine and, in particular, weakened by the passage of contents through the colon. This method involves the systematic introduction of effective, stimulating the intestines amount of the compounds of formula (I), its N-oxide, pharmaceutically acceptable salt accession acid or a possible stereoisomeric form of warm-blooded animals. Therefore, the use of the compounds of formula (I) as lacasta to treat conditions, including reduced peristalsis of the colon.

In General it is assumed that therapeutically effective amount is from about 0.001 mg/kg to about 10 mg/kg body weight, preferably from about 0.02 mg/kg to about 5 mg/kg of body weight. The treatment method may also include the introduction of the active ingredient according to the scheme with the introduction of two to four times a day.

The following examples are intended to illustrate and not limit the scope of the present invention in all its aspects. In the future, "THF" means tetrahydrofuran and DIPA" refers to diisopropyl ether.

Experimental part

A. Obtaining an intermediate product

Example 1

a) a Solution of 3-methoxy-1-(phenylmethyl)-4-piperidone (4.4 g) in THF was cooled to -70oC. was added dropwise Tris-second - butylbromide lithium and the reaction mixture was stirred for 2 hours at -70oC. At room temperature was added dropwise 10% acetic acid (100 ml). The organic solvent evaporated. The aqueous residue was podslushivaet NH4OH, and then was extracted two times with THF. The separated organic layer was washed with water, dried over MgSO4, was filtered, and the solvent evaporated. The residue was purified is aluca 1.3 g (29,4%) of CIS-3-methoxy-1-(phenylmethyl)-4 - piperidinol (intermediate 1).

b) a Mixture of intermediate (1) (11.5g) and methanol (150 ml) was first made at normal pressure and room temperature with 2 g of palladium catalyst on charcoal, 10%. After absorption of the calculated amount of hydrogen the catalyst was separated by filtration, and the filtrate evaporated. The residue was purified column chromatography on silica gel (eluent: CHCl3/(CH3OH/NH3), 85/15). Pure fractions were collected and the eluent is evaporated, getting 3.6 g (53%) of CIS-3-methoxy-4-piperidinol in the form of oil residue (intermediate 2).

C) a Solution of bis (1,1'-dimethylethyl)carbonate (65,5 g) in CHCl3(100 ml) was added dropwise to a solution of intermediate (2) (34 g) in CHCl3(350 ml) and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was washed with water and ammonia, and then with water. The separated organic layer was dried over MgSO4was filtered and the solvent evaporated. The remainder (79 g) was purified column chromatography on silica gel (eluent: CHCl3/(CH3OH/NH3), 97/3, increasing to 95/5). Pure fractions were collected and the solvent evaporated, receiving 58 g ()-1,1-dimethylethyl-CIS-4-hydroxy - 3-methoxy-1-piperidinecarboxylate (94% crude residue) (intermediate 3) shivali and boiled under reflux over a stream of nitrogen for 3 hours, then cooled (solution I). 1,1'-Carbonylbis-1H-imidazole (21 g) was added to a solution of 4-amino-5-chloro-2,3 - dihydro-2,2-dimethyl-7-benzofuranol acid (of 31.4 g) in acetonitrile (1000 ml) and the mixture was stirred for 2 hours at room temperature. The solvent is evaporated. The residue was dissolved in THF (1000 ml) to give solution II. At room temperature the solution (II) was poured into the solution (I), and the reaction mixture was stirred for 2 hours at room temperature. The solvent is evaporated. The residue was distributed between CH2Cl2and H2O. the Organic layer was separated, and the aqueous layer was extracted twice CH2Cl2. The separated organic layer was dried over MgSO4, was filtered, and the solvent evaporated. The residue was purified by chromatography on a short column of silica gel (eluent: CH2Cl2/CH3OH, 98/2). The desired fractions were collected and the solvent evaporated, receiving 50 g ()-dimethylethyl-CIS-4-[[(4-amino-5-chloro - 2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonyl]oxy]- 3-methoxy-1-piperidinecarboxylate (85%) (intermediate 4).

e) a Mixture of intermediate (4) (50 g) in THF (600 ml) and hydrochloric acid (60 ml) was stirred and boiled under reflux for 30 minutes. Reacciona ivali, and the residue was purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3), 93/7). Pure fractions were collected and the solvent evaporated. The residue was stirred in boiling DIPA. The mixture was cooled and the resulting precipitate was separated by filtration, was dissolved in 2-propanol and converted into salt tangiwai acid (1:1) reaction with anandibai acid (0.6 g). The mixture is boiled, cooled and the resulting precipitate was separated by filtration and dried, obtaining 16 g of candiota (1:1) ()-CIS-3-methoxy-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-2,2 - dimethyl-7-benzophenoneoxymate (33%), so pl. 193,2o(intermediate 5).

A similar method was also received:

4-piperidinyl-4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7 - benzophenoneoxymate; so pl. 161,0o(intermediate 6), ()-CIS-3-methoxy-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-2,2 - dimethyl-7-benzophenoneoxymate (intermediate 7), 4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate, so pl. 161,0o(intermediate 8).

C. the final product

Example 2

A mixture of 1-[3-(1-methylethoxy)propyl] -4-piperidinol (2.5 g) and N,N-dimethyl-4-pyridylamine (2 g) in dichloromethane (100 ml) was stirred at room temperature. Decenia 72 hours at room temperature. The solvent is evaporated, and the residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH, 95/5). The desired fractions were collected and the solvent evaporated.

The residue (3.2 g) was dissolved in THF (100 ml) and treated with hydrochloric acid (10 ml). The reaction mixture was stirred and boiled under reflux for 2 hours. The mixture was cooled and podslushivaet NH4OH. The organic layer is evaporated and the aqueous residue twice was extracted with CH2Cl2. The separated organic layer was dried over MgSO4was filtered, and the solvent evaporated. The residue was purified by chromatography on a short column of silica gel (eluent: CH2Cl2/CH3OH/NH3), 97/3). The desired fractions were collected and the solvent evaporated. The residue (2.9 g) was purified by high-performance liquid chromatography (eluent: CH2Cl2/(CH3OH/NH3)/CH3OH, 97/1/2). Pure fractions were collected and the solvent evaporated. The residue was dissolved in 2-propanol and converted into the salt of hydrochloric acid (1: 1) mixture of HCl/2-propanol. The mixture is boiled, then cooled. The residue was separated by filtration and dried (vacuum, 80oC) to give 0.50 g of monohydrochloride 1-[3-(1-methylethoxy)propyl]-4-piperidinyl-4 a Mixture of intermediate (8) (3 g), 2-(3-chlorpropyl)-2-methyl-1,3-dioxolane (2.5 g), sodium carbonate (2.1 g) and potassium iodide (catalytic amount) in 4-methyl-2-pentanone (150 ml) was stirred and boiled under reflux during the night. The mixture was cooled, washed with water, dried (MgSO4), filtered, and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2the gradient until CH2Cl2/(CH3OH/NH3), 97/3). Pure fractions were collected and the solvent evaporated. The residue was stirred in boiling DIPA, cooled, stirred, filtered and recrystallize from CH3CN/DIPE. The precipitate was separated by filtration and dried, obtaining of 1.00 g of 1-[3-(2-methyl-1,3-dioxolane-2-yl)propyl]-4-piperidinyl-4 - amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate (24%); so pl. 128,1oC (compound 6).

Example 4

A mixture of intermediate (5) (10 g) and 2-propenenitrile (2 ml) in 2-propanol (150 ml) was stirred and boiled under reflux during the night. Was added 2-propenenitrile (1 ml) and the reaction mixture was stirred and boiled under reflux for 20 hours. The solvent is evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH, was stirred and the resulting precipitate was separated by filtration and dried (vacuum, 80oC) to give 10.7 g ()-CIS-1-(2-cyanoethyl)-3-methoxy-4 - piperidinyl-4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7 - benzophenoneoxymate (94%), so pl. 180,3o(Compound 27).

Example 5

At room temperature oxiran (gas) was barbotirovany through a solution of intermediate (6) (3.3 grams) in methanol (80 ml) for 3 hours, keeping the temperature below 30oC. the Solvent is evaporated, and the residue was purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3), 97/3). Pure fractions were collected and the solvent evaporated. The residue was stirred in boiling DIPA, cooled to room temperature and the precipitate was separated by filtration and dried (vacuum, 80oC) to give 1.66 g of 1-(2-hydroxyethyl)-4-piperidinyl-4-amino-5 - chloro-2,3-dihydro-2,2-dimethyl-7-benzophenoneoxymate (45%), so pl. 166,3o(Compound 21).

Example 6

A mixture of compound (6) (2 g) in THF (50 ml) and hydrochloric acid (5 ml) was stirred and boiled under reflux for 30 minutes. The reaction mixture was cooled and podslushivaet NH4OH. The separated aqueous layer was extracted with THF. The combined organic layers evaporated, and the OST is taken fractions were collected, and the solvent evaporated. The residue was stirred in boiling DIPA. The precipitate was separated by filtration and was dried and further purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH, 90/10). Pure fractions were collected and the solvent evaporated, receiving of 0.90 g of 1-(4-oxobutyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate (47%), so pl. 104,8o(Compound 8).

Example 7

A mixture of compound (9) (8.5 g) in THF (500 ml) was first made with the use of Raney Nickel (catalytic amount) as catalyst. After absorption of H2(2 equiv.) the catalyst was separated by filtration, and the filtrate evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3), 90/10). Pure fractions were collected and the solvent evaporated. The residue was stirred in boiling DIPE, then cooled and the resulting precipitate was separated by filtration and dried, obtaining of 5.2 g ()-CIS-1-(2-amino-ethyl)-3-methoxy - 4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate (61%), so pl. 133,9o(Compound 11).

Example 8

A mixture of compound (11) (4 g), 2-chloro-3-methylpyrazine (2.8 g) and N,N-diethylethanamine (2.8 ml) was stirred for 24 hours at 120oC. the Mixture on silica gel (eluent: CH2Cl2/(CH3OH/NH3), 95/5). Pure fractions were collected and the solvent evaporated. The residue was stirred in boiling DIPA, cooled and the resulting precipitate was separated by filtration and dried, obtaining of 0.53 g ()-CIS-3-methoxy-1-/2- [(3-methyl-2-pyrazinyl)amino]ethyl]-4-piperidinyl-4-amino-5-chloro-2,3 - dihydro-7-benzophenoneoxymate (11,5%), so pl. of 124.1oWith (compound 12).

Example 9

A mixture of compound (38) (4.5 g), 2-chloro-3-methylpyrazine (3.3 grams) and N,N-diethylethanamine (2.1 ml) was stirred for 20 hours at 120oC. the Reaction mixture was cooled and purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3), 95/5). The desired fractions were collected and the solvent evaporated. The residue was again purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3), 90/10). Pure fractions were collected and the solvent evaporated. The residue was hardened in DIPE. The precipitate was separated by filtration and dried, obtaining of 2.10 g of 1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-4-piperidinyl-4 - amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate (38%), so pl. 108,6o(Compound 39).

In tables 1-3 lists the compounds that were obtained by the same way one visheupomyanutoi Guinea pigs

Guinea pigs Dunkin Harley both sexes (weight 500 g) were killed by decapitation. The terminal ileum was separated and washed heated and saturated oxygen solution of Krebs-Henseleit. Non-end segments of the intact ileum length 4.5 cm Guinea pigs vertically hung with end-diastolic pressure of 1 g in 100 ml of Krebs-Henseleit (37,5oC) saturated with a mixture of 95% O2and 5% CO2. Transmural stimulation caused along the length of the segment of the ileum by means of two platinum electrodes, the anode threaded through the cavity of the ileum, the cathode was in the bath solution. The drug was filed by a rectangular stimulus [1 MS; 0.1 Hz; submaximal response (current, resulting in 80% of the maximum response)] from the programmable stimulator. Reduction was measured isometrically. During the stabilization period of 30 min, the strips several times stretched to a tension of 2 g in order to obtain the tension of the stationary state 1, Before the electrical stimulation received cumulative curve depending on the dose of acetylcholine (curve dose-response). Electrical stimulation was started at sirmixalot current to determine the maximum amplitude of atalecio to get 80% of the maximum response as long while the response of muscle contractions were constant for at least 15 minutes, after which the liquid bath was added a single dose of the test compound. The amplitude response of muscle contractions five minutes after administration of the test compounds is compared with the amplitude before the introduction of the test compounds. Connection 1, 4, 6-8, 14-16, 32-36, 39, 46 and 50 show the increase of the amplitude response of muscle contractions by more than 5% at a concentration of 310-9M

Example 11: Peristalsis of the colon have in mind dogs

Females breed Beagle with lots 7-17 kg implanted isometric force sensors under General anesthesia and aseptic conditions. To study the motility of the colon sensors were sewn on the colon at a distance of 8, 16, 24 and 32 cm from the ileocecal valve. Dogs left on the recovery period of at least two weeks. Experiments were started after a period of fasting for 20 hours, during which water was available on demand. During the experiments, the dogs were able to move freely in their cages by using telemetry (wireless) system. Cells were constructed in a special code as the dog could not see the observer. Through this system it was possible to observe behavioral changes in dogs and to determine the cases of defecation. Information from the sensors is transmitted to the converted digital form small, specially constructed box-transmitter. This box was placed in the jacket worn by the dog. The signals received through the microphone located above each cell, and transmitted to the Central computer system. One of the parameters in this test is a defecating dog. During the first three hours after administration of the test compounds was observed, was there and when he was defecating in dogs. The compounds of this invention caused a bowel movement in the test animals during the first three hours.

D). Examples of compositions

The following ready preparative forms are examples of typical pharmaceutical compositions in a uniform dosage form suitable for systemic or local injection of warm-blooded animals in accordance with this invention.

"Active ingredient" (A. I.) used throughout these examples relates to a compound of formula I, its N-oxide form, pharmaceutically acceptable salt accession acid or a stereochemical isomeric form was dissolved in 4 l of boiling purified water. In 3 l of this solution were dissolved first 10 g of 2,3-dihydroxybutanedioate acid and then 20 g of A. I. Last solution was mixed with the remaining part of the first solution and, in addition, was added to 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g of sodium salt of saccharin was dissolved in 0.5 l of water was added 2 ml essences of raspberry and 2 ml essences gooseberry. The last solution was mixed with the first, adding water as needed, up to a volume of 20 l, receiving oral solution containing 5 mg A. I. in teaspoonful (5 ml). The resulting solution is filled into suitable containers.

Example 13: Capsules

20 g A. I., 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate vigorously stirred together. The resulting mixture is then filled into 1000 suitable hard gelatin capsules, each capsule contains 20 mg A. I.

Example 14: Tablets film-coated

Obtain core tablets

A mixture of 100 g A. I., 570 g lactose and 200 g starch mix well and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The mixture in the form of a moist powder proceviat, dried and sieved again. Then add 100 g of microcrystallite the traveler 10,000 tablets, moreover, each contains 10 mg of active ingredient.

Floor

In a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol grind and dissolve in 75 ml of dichloromethane. The last solution is added first and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye and all homogenized. Core tablets cover the thus obtained mixture in the device coating.

Example 15: Injectable solution

1.8 g of methyl-4-hydroxybenzoate and 0.2 g of propyl-4 - hydroxybenzoate was dissolved in about 0.5 l of boiling water for injection. After cooling to about 50oC was added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g of A. I. the Solution was cooled to room temperature and supplemented with water for injection, as needed, up to a volume of 1 l, obtaining a solution of 4 mg/ml A. I. the Solution was sterilized by filtration (USP XVII, page 811) and filled in sterile containers.

Example 16: Suppositories

3 g A. I. was dissolved in a solution of 3 g of 2,3-dihydroxybutyl ride, how much to 300, the Latest the mixture was well mixed with the first solution. Thus obtained mixture was poured into moulds at a temperature of 37-38oC to 100 medical education candles, each containing 30 mg of active ingredient.

All compounds of the present invention were tested for toxicity screening test in rats. This test involves injecting rats of the test compound in a dose of 40 mg/kg None of the tested compounds did not show acute toxicity at the tested dose, based on which the indicator LD50for all compounds is more than 40 mg/kg

In the following table 4 lists the data responses in test "Coaxial stimulation of the ileum in Guinea pigs", carried out as described in example 10 of this application at a concentration of 310-7M

1. N-substituted piperidineacetate having the formula I

< / BR>
their N-oxide forms, pharmaceutically acceptable salt accession acids and stereochemical isomeric forms,

where R1represents halogen or1-6alkylsulfonamides;

A represents a bivalent radical of the formula:- odored can be replaced WITH1-6by alkyl;

R2represents hydrogen or C1-6alkyloxy; L represents a radical of the formula: -Alk-R4(d), -Alk-O-R5(e)- Alk-NR6R7(f);

Alk represents a C1-12alcander;

R4represents hydrogen; cyano; C1-6alkylsulphonyl; C1-6allyloxycarbonyl; C3-7cycloalkyl; C1-6alkylsulfanyl; C1-6alkylsulfonyl; phenyl or phenyl substituted WITH halogen1-6the alkyl or C1-6alkyloxy; tetrahydrofuran, dioxolane; dioxolane substituted WITH1-6by alkyl; dioxane; dioxane, substituted C1-6by alkyl; pyridine; pyridine, substituted with halogen or1-6by alkyl; pyridazin; pyridazin substituted by one or two substituents selected from halogen, C1-6of alkyl, hydroxy; or a radical of the formula

< / BR>
or

< / BR>
in which R8represents hydrogen or C1-6alkyl;

R5represents hydrogen; C1-6alkyl; hydroxy1-6alkyl; C1-6alkylsulphonyl; phenyl or phenyl substituted by substituents in the number to three, selected from halogen, C1-6of alkyl, C1-6alkyloxy;

R6represents hydrogen or C1-6alkyl;

R7represents hydrogen; C1-the two alternates, selected from halogen, C1-6of alkyl, hydroxy; pyrazin; pyrazin substituted by one or two substituents selected from halogen, C1-6of alkyl, hydroxy.

2. Connection on p. 1, in which R4represents hydrogen; cyano; C1-6alkylsulphonyl; C1-6alkylsulfanyl; C1-6alkylsulfonyl; phenyl or phenyl substituted by halogen, C1-6the alkyl or C1-6alkyloxy; tetrahydrofuran, dioxolane; dioxolane substituted WITH1-6by alkyl; dioxane; dioxane, substituted C1-6by alkyl; pyridine; pyridine, substituted with halogen or1-6by alkyl; pyridazin; pyridazin substituted by one or two substituents selected from halogen, C1-6of alkyl, hydroxy; or a radical of the formula

< / BR>
or

< / BR>
in which R8represents hydrogen or C1-6alkyl.

3. Connection on p. 1, in which R1is chlorine.

4. Connection on p. 1, in which R2represents hydrogen or methoxy.

5. Connection on p. 1, selected from the following:

1-[(tetrahydro-2-furanyl)methyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

1-[(tetrahydro-2-furanyl)methyl] -4-piperidinyl-5-amino-6-chloro-3,4-dihydro-2,2-dimethyl-2H-is at;

1-[3-(2-methyl-1,3-dioxolane-2-yl)propyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

1-[3-(1-methylethoxy)propyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

1-[2-(2-hydroxyethoxy)ethyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

1-[3-(3-chloro-6-oxo-1(6N)-pyridazinyl)propyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

1-(4-oxopent-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

ethyl-4-[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]oxy]-1-piperidinemethanol;

1-[2-(tetrahydro-2-furanyl)ethyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate,

their stereochemical isomeric forms, or pharmaceutically acceptable salt accession acids.

6. Pharmaceutical composition having stimulating gastrointestinal peristalsis activity comprising a therapeutically effective amount of the compounds on p. 1 and a pharmaceutically acceptable carrier.

7. Connection on p. 1 with stimulating gastrointestinal motility activity.

8. The intermediate compound of formula VII'-a

< / BR>
in which P1is hydrogen ITIL and similar protective group; R2is1-6alkyloxy, and R2and hydroxyl group are CIS-configuration, or its enantiomer.

9. The method of obtaining compounds on p. 1, wherein the piperidine of the formula H-D II in which D represents a group of the formula

< / BR>
in which R1, R2and a have the meanings given in paragraph 1,

N-alkylate the intermediate compound of the formula L-W1(III) in which L has the meaning as defined in paragraph (1; W1is the right of the deleted group, and optionally the compounds of formula I transform into each other through the reaction for the conversion of functional groups and, if desired, the compound of the formula I is converted into a therapeutically active non-toxic salt accession acid, or Vice versa, salt accession acid is transformed into the free base by the action of alkali and/or receive a stereochemical isomeric form.

10. The method of obtaining compounds on p. 1, characterized in that the alcohol of formula IV

< / BR>
subjected to reaction with a carboxylic acid of formula V

< / BR>
or its functional derivatives, such as allalone, symmetrical or mixed anhydride or ester, in the above formulas, R1, R2L is eacli conversion of functional groups, and if desired, the compound of the formula I is converted into a therapeutically active non-toxic salt accession acid or, on the contrary, salt accession acid is transformed into the free base by the action of alkali and/or receive a stereochemical isomeric form.

 

Same patents:

The invention relates to derivatives of benzimidazole and their use in therapy, in particular for the treatment or prophylaxis of viral infections such as caused by herpes viruses

The invention relates to novel 2,6-dimethylaniline N - cyclopropylmethyl-2-carboxylic acid f-ly I, where R is cyclopropyl or methylcyclopropyl in the form of a racemic mixture or the individual enantiomers or their salts, which exhibit increased antiarrhythmic and local anestesiologia properties and can find application in medicine

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to a method for producing (+) (2R)-endo-norbornene and (-)-(2S)-endo-norbornene and their subsequent transformations, respectively, in pharmaceuticals, 5-(3-[(2S)-endo-norbornene and their subsequent transformations, respectively, in pharmaceuticals, 5-(3-[(2S)-Exo-bicyclo [2.2.1] gate-2-yloxy] - 4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2 (1H)he is of the formula:

,

and its enantiomer, 5-(3- [(2R.) -Exo-bicyclo [2.2.1.]hept-2 - yloxy]- 4 - methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2 (1H)-he, of the formula:

The invention relates to new derivatives isoindoline General formula:

< / BR>
in which the radicals R represent hydrogen atoms or together form a single bond; the radical R' represents a hydrogen atom or easily removable and the radicals R" are identical, represent phenyl radicals which may be substituted by a halogen atom or a methyl radical in the ortho - or meta-position, as well as their salts

The invention relates to derivatives of 3-(piperidinyl-1)-chroman-5,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)alkanol General formula I or their pharmaceutically acceptable salts accession acid, in which (a) R2and R5taken individually and R1, R2, R3and R4independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7and R5represents methyl; or (b) R2and R5taken together form a ring chroman-4-ol, a R1, R3and R4each independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7; R7represents methyl; and R6represents a substituted piperidinyl or 8-azabicyclo[3,2,1]octenidine derived; provided that (a) if R2and R5taken separately, at least one of R1, R2, R3and R4is not hydrogen; and (b) if R2and R5taken together, at least one of R1, R3and R4is not hydrogen, with the property that the NMDA antagonist

The invention relates to new fluorine-containing organic compounds, more specifically to an amine derivative having biological activity

The invention relates to new derivatives of piperidine and piperazine of the formula I

< / BR>
where Ind is unsubstituted or one - or twofold substituted by Oh, OA, CN, Hal, COR2or CH2R indol-3-ilen balances;

R1is unsubstituted or once substituted with CN, CH2OH, CH2OA or COR2benzofuran-5-yl, 2, 3-dihydrobenzofuran-5-yl-, chroman-6-yl, chroman-4-one-6-yl, 3-chromen-6-yl or chromen-4-one-6-yl;

Q-CmH2m;

Z is N or CR3;

A is alkyl with 1-6 C-atoms;

Hal is F, Cl, Br or I;

R2-OH, OA, NH2, NHA or NA2;

R3Is H, OH or OA;

m is 2, 3 or 4,

and their physiological acceptable salts

The invention relates to the field of organic chemistry and pharmaceuticals, namely heterobicyclic compounds and pharmaceutical compositions based on them, as well as methods of producing these compounds

The invention relates to stereoisomerism forms of Itraconazole (X=CL) and saperconazole (X= F), which can be represented by the formula CIS-(I) that are listed in the text of the description, their pharmaceutically acceptable acid additive salt forms, and methods of producing these stereoisomeric forms and their complexes with cyclodextrin derivatives and pharmaceutical compositions containing the above-mentioned complexes with anti-fungal activity

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory organs and areas of the brain

The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine

The invention relates to substituted azetidinone General formula I listed in the description
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