Derivatives of phenyl-oxo-alkyl-(4-piperidinyl) benzoate, methods for their preparation, pharmaceutical composition and method of reception and the intermediate connection

 

(57) Abstract:

The invention relates to new derivatives of phenyl-oxo-alkyl-(4-piperidinyl)benzoate of formula I, their N-oxide forms, salts and steric isomer forms, where R1- halogen, R2is hydrogen, R3- C1-6-alkyl, or R2and R3form together a bivalent radical of the formula -(CH2)2- or -(CH2)3-, Alk-C1-6-alcander, R4is hydrogen or C1-6-alkoxy, R5, R6and R7is hydrogen, halogen, C1-6-alkyl, C1-6-alkyloxy or R5and R6taken together , form a bivalent radical of the formula-NR8-C(O)-NR9- or-NH-C(NH-R10)=N-, where R8and R9is hydrogen, C1-6-alkyl, R10is hydrogen, C1-6-alkylsulphonyl, C1-6-allyloxycarbonyl. The compounds of formula I possess stimulating gastrointestinal peristalsis activity and can find application in medicine. 6 c. and 5 C.p. f-crystals, 1 PL.

This invention relates to new derivatives of benzoate, pharmaceutical compositions containing these compounds, methods of producing compounds and compositions and to their use as pharmaceuticals, in particular when l is th 26 September 1990, describes derivatives of N-(3-hydroxy-4-piperidinyl) dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide as having stimulating gastrointestinal motility properties. In EP 0445862, published on September 11, 1991, describes derivatives of H-(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 NT4-receptor complex esters of the General formula X-CO-Y-Z, where X can be substituted by phenyl, Y can be oxygen, and Z may be a fragment of a substituted piperidine. WO 94/08995 (Smithkline Beecham), published on 28 April 1994, describes in General, for example, substituted 7-benzophenoneoxymate also having NC4-antagonistic activity. The last two patent applications describe the use of ND4-antagonistic compounds in the treatment of irritable bowel syndrome (srtc), in particular diarrhoeal species srtc.

Unexpectedly, we discovered that new connections, o referred to, show intestinal prokinetics activity. So described in the present connection, the show is Noah (colon) cancer.

This invention relates to new derivatives of benzoate having the formula

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their N-oxide forms, the pharmaceutically acceptable acid additive salts and stereochemical isomeric forms, where

R1represents halogen or C1-6-alkylsulfonamides;

or R2represents hydrogen

and R3represents C1-6-alkyl, C2-6alkenyl or C2-6-quinil or R2and R3taken together form a bivalent radical of the formula

-CH=CH-, (a)

-(CH2)2-, (b) or

-(CH2)3(C) -

in the bivalent radicals of formula (a), (b) or (C) one or two hydrogen atoms may be substituted C1-6-alkyl;

A1k is C1-6-Alcantara;

R4is hydrogen or C1-6-alkyloxy;

each of R5, R6and R7independently represents hydrogen, halogen, C1-6-alkyl, C1-6-alkyloxy or R5and R6taken together may form a bivalent radical of the formula

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each of R8and R9independently represents hydrogen or C1-6-alkyl;

R10represents hydrogen, C1-6-alkylsulphonyl, C1-6-allyloxycarbonyl and

m t is shared by fluorine, chlorine, bromine and iodine; C1-6-alkyl defines saturated hydrocarbon radicals with normal or branched chain, having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylpropyl and the like; C2-6alkenyl determines hydrocarbon radicals with normal or branched chain, containing one double bond and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like; C2-6-quinil determines hydrocarbon radicals with normal or branched chain, containing one triple bond and having from 2 to 6 carbon atoms, such as, for example, ethinyl, 2-PROPYNYL, 3-butynyl, 2-butynyl, 2-pentenyl, 3-pentenyl, 3-hexenyl and the like; C1-6-alcander defines bivalent hydrocarbon radicals with normal or branched chain, containing from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentandiol, 1,6-hexandiol.

Assumes pharmaceutically acceptable acid additive salt (salt accession acids), mentioned here above, include Faure what I formula I. The latter can conveniently be obtained by processing the grounds for 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 here above, also includes a solvate, which is able to form compounds of formula (I) and their salts. These are solvate, for example, hydrates, alcoholate, and the like. On the contrary, the salt form can be converted 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 sidereally 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 a CIS - or TRANS-configuration, and C2-6-alkenilovyh radicals can have the E - or Z-configuration. Obviously meant that the stereochemical isomeric forms of the compounds of formula (I) is included in the scope of this invention.

Some compounds of formula (I) may also exist in their tautomeric forms. 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 R5and R6taken together form a bivalent radical of formula (d), where R8, R9or are both hydrogen, may exist in their corresponding tautomeric form.

Assume that the N-oxide forms of the compounds of formula (I) include those compounds of formula (I) in which one or more atoms of nitrogen oxidized in the so-called N-oxide, particularly those N-oxides, in which the nitrogen atom of the piperidine N-oxide.

R1is fluorine, chlorine or bromine, preferably R1is chlorine;

R3when he nsaty together preferred bivalent radical of formula (b);

A1k is 1,2-etandiola, 1,3-propandiol or 1,4-butandiol, preferably 1,3-propandiol;

R4is hydrogen or methoxy;

R5, R6and R7are hydrogen, C1-6-alkyl, C1-6-alkyloxy or chlorine, preferably the stands, methoxy or hydrogen; or

when R5and R6taken together, the preferred divalent radical of formula (d) or (e), in particular a radical of the formula (d).

Interesting compounds of formula (I) are the compounds of formula (I) in which R1is chlorine.

The following interesting compounds of formula (I) are those compounds of formula (I) in which R2and R3taken together form a bivalent radical of formula (b).

More interesting compounds are those compounds in which A1k is 1,3-propandiol.

The preferred compounds are more interesting compounds in which R5, R6and R7represent methoxy.

Preferred compounds are also more interesting compounds in which R7represents hydrogen and R5and R6integration is sustained fashion connections are connections, in which R5and R7are the stands and R6is methoxy.

The most preferred compounds are CIS-3-methoxy-1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl] -4 - piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate; 1-[4-oxo-4- (3,4,5-trimethoxyphenyl)butyl]-4-piperidinyl-4 - amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate; 1-[4-(2,3 - dihydro-2-oxo-1H-benzimidazole-5-yl) -4-oxobutyl]-4-piperidinyl - 4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate and

1-[4-(4-methoxy-3, 5dimethylphenyl)-4-oxobutyl] 4-piperidinyl-4 - amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

and their stereoisomeric forms and pharmaceutically acceptable salts accession acids.

In order to simplify the structural image of the compounds of formula (I) and some of their intermediates, the radical of the formula

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next will be represented by D, a radical

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will be hereinafter represented by the symbol L.

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


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W' in the intermediate product of the formula (II) is 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 compounds of formula (I) can also be obtained by esterification of the alcohol of formula (IV), where R4and L have the above definitions, the carboxylic acid of formula (V), where R1, R2and R3have the above definitions, or its functional derivatives, such as 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 group of the intermediate product of the formula (V) during the reaction, to avoid unwanted side reactions. Aminosidine group is removed after completion of the esterification. Suitable protective groups include easily removable group, for example, C1-4-alkylsulphonyl, C1-4-allyloxycarbonyl, phenylmethyl and similar protective group.

is represented by the formula (1-d), can be obtained by reaction of the intermediate product of the formula (VI) with 1,1'-carbonylbis-1H-imidazole or its functional derivatives by known in this field techniques

< / BR>
The compounds of formula (I) in which R5and R6taken together form a radical of formula (e), these compounds represented by the formula (1-e), can be obtained by reaction of the intermediate product of the formula (VI) in which R8and R9are both hydrogen (these intermediates are represented by formula (VI-a)) with an intermediate product of the formula (VII) are known in this field techniques

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The compounds of formula (I) can also be transformed into each other. For example, the compounds of formula (I) in which R10represents hydrogen, can be converted into compounds of formula (I) in which R10represents C1-6-alkylaryl or C1-6-allyloxycarbonyl known in this field by the reactions of N-acylation.

The compounds of formula (I) in which R3is C2-6-alkenyl or C2-6-quinil, can be converted into compounds of formula (I) in which R3is the corresponding saturated alkyl radical, known in the field by means of hydrogenation.

Soedinenii to convert 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; appropriate organic peroxides may include nagkalat, such as, for example, benzoperylene acid or halogen-substituted benzoperylene acid, such as 3-chlorobenzophenone acid, alcamovia nagkalat, for example peracetic acid, alkylhydroperoxide, for example tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alkanols, such as ethanol and the like, hydrocarbons such as toluene, ketones, such as 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 (VIII) and the intermediate acid of formula (V) or its functional derivative of the known in the field methods of education of ester followed by removal of the protective group P in salciccioli, C1-4-allyloxycarbonyl, phenylmethyl and similar protective group

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Intermediate acids of formula (V) described in EP 0389037-A.

Intermediates of formula (VI-a) can be obtained by recovering the intermediate product of formula (IX) with a suitable reducing agent, such as for example, a combination of platinum on charcoal and hydrogen, in an inert reaction solvent such as, for example, tetrahydrofuran,

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Intermediates of formula (IX) can be obtained N-alkylation of the piperidine of formula (II) an intermediate product of the formula (X), where W' is appropriate tsepliaeva group, such as, for example, halogen atom, in the same way as the compounds of formula (I) is obtained from the intermediates (II) and (III)

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Intermediates of formula (VIII), in which P1is P with the above values, as well as hydrogen, can be obtained by recovering the intermediate product of formula (XI) are known in this field techniques. In particular, intermediates of formula (VIII) in which R4is C1-6- alkyloxy (these intermediates are represented by formula (VIII')) and where R4and hydroxyl group are ctel such as substituted borohydride, for example Tris-second-butylbromide lithium, Tris-second-butylbromide potassium, substituted alumoweld, three-tert-butoxylated lithium and the like, in an inert reaction solvent such as, for example, tetrahydrofuran. A positive reaction carried out at low temperature, preferably at a temperature below -70oC. When using stereochemical pure reagents this recovery may undergo 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 known in this field techniques. Diastereoisomer can be divided by physical separation methods such as selective crystallization and chromatographic methods, such as 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 formulae (II) and (VI), their N-oxide forms, pharmaceutically postami. In particular, these compounds show significantly increases peristalsis effect on small and large intestines. The last property to prove the results obtained in the test "Coaxial stimulation of the ileum of the Guinea pig and test "Peristalsis 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 present 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 a mixture with a pharmaceutically acceptable carrier, which may take different forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in the dosage form in the form of single doses, preferably suitable for administration orally, rectally or in the form of parentlabel 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 such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja agents and the like in the case of powders, pills, capsules and tablets. Due to ease their introduction of tablets and capsules represent the most advantageous oral unit dosage form, in this case explicitly use solid pharmaceutical carriers. For parenteral compositions, the carrier usually contains sterile water, at least in most parts, 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 administration, the carrier optionally includes a tool that improves the penetration and/or a suitable wetting Soro not have a significant deteriorating 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. 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. Salt accession acid compounds (I), (II) or (VI) because of their increased solubility in water as compared with the corresponding shape of the base are obviously more suitable in the preparation of aqueous compositions. Especially advantageous to prepare the above pharmaceutical composition in unit dosage form for ease of administration and constant dosage. Dosage form in the form of single doses used in the description and the claims refers to physically discrete units suitable as unit doses, each unit contains a defined quantity of active ingredient calculated to provide therapeutic activities, in combination with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including tablets with grooves and coating), capsules, pills, sachets of powder, wafers, injectable solutions or suspensions, a container with a volume of teaspoons, table is histolytica intestinal system and, in particular, their ability to increase peristalsis of the colon 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 peristalsis, such as 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 is the 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, the slow passage of contents through the colon. This method provides a 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) in the quality of the funds to CSOs 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 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 of introduction from two to four times a day.

Experimental part A. the production of intermediate products

Example 1

a) sodium Borohydride (7.7 g) was added in portions to stirred solution of 3-methoxy-1-(phenylmethyl)-4-piperidone (44,8 g) in ethanol (610 ml). When you are finished adding all of the content was cooled to room temperature and stirring was continued for 3 h at room temperature. The reaction mixture was concentrated to a volume of about 150 ml of the concentrate was added water (300 ml), and all traces of ethanol evaporated. After cooling, the mixture was extracted with diethyl ether. The extract was washed with water, dried, filtered and evaporated. The oily residue was purified column chromatography on silica gel (eluent: CHCl3/CH3OH, 96/4). Collected pure fractions, and the eluent is evaporated. The residue was divided by column chromatography on silica gel (eluent: hexane/CHCl the XI-1-(phenylmethyl)-4-piperidinol (intermediate 1). Collected second fraction, and the eluent evaporated, receiving of 7.7 g (17,1%) of CIS-3-methoxy-1-(phenylmethyl)-4-piperidinol (intermediate 2).

a') a Solution of 3-methoxy-1-(phenylmethyl)- 4-piperidone (4.4 g) in tetrahydrofuran was cooled to -75oC. was added dropwise Tris-second-butylbromide lithium and the reaction mixture was stirred for 2 h at -70oC. is added dropwise at room temperature was added 10% acetic acid (100 ml). The organic solvent evaporated. The aqueous residue was podslushivaet NH4OH, and then was extracted two times with diisopropyl ether. The separated organic layer was washed with water, dried over MgSO4, was filtered, and the solvent evaporated. The residue was purified by chromatography on a short column of silica gel (eluent: CH2Cl2/CH3HE 95/5 increasing to 98/2) to give 1.3 g (29,4%) of CIS-3-methoxy-1-(phenylmethyl)-4-piperidinol (intermediate 2).

b) a Mixture of 11.5 g of the intermediate product (2) and 150 ml of methanol was first made at normal pressure and room temperature with 2 g of catalyst palladium on coal (10%). After consumption of the calculated amount of hydrogen the catalyst was separated by filtration, and the filtrate evaporated. The residue was purified column of chromemoly, getting 3.6 g (53%) of CIS-3-methoxy-4-piperidinol in the form of oil residue (intermediate 3).

C) a Solution of bis(1,1'- dimethylethyl)dicarbonate (65,5 g) in CHCl3(100 ml) was added dropwise to a solution of intermediate (3) (34 g) in trichloromethane (350 ml) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was washed with water and ammonia, and then with water. The separated organic layer was dried over MgSO4, was 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 4).

d) sodium Hydride (4 g) was added to a solution of intermediate (4) (19,4 g) in tetrahydrofuran (400 ml). The mixture was stirred and boiled under reflux for 3 h (solution 1). 1,1'-Carbonylbis-1H-imidazole (13,6 g) was added to a suspension of 4-amino-5 - chloro-2,3-dihydro-7-benzofuranol acid (18 g) in acetonitrile (400 ml) and the mixture was stirred for 2 h at room temperature. The solvent is evaporated. The mod is creative (I), and the reaction mixture was stirred for 2 h 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 32 g ()-CIS-1-[(1,1-dimethylmethoxy) carbonyl] -3-methoxy-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7 - benzophenoneoxymate (87%) (intermediate 5).

e) a Mixture of intermediate (5) (32 g) in tetrahydrofuran (500 ml) and hydrochloric acid (50 ml) was stirred and boiled under reflux for 30 minutes, the Reaction mixture was cooled and podslushivaet NH4HE. The layers were separated. The aqueous layer was extracted with tetrahydrofuran. The separated organic layer evaporated. 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 led from acetonitrile. The precipitate was filtered and power (26%) (intermediate 6).

Example 2

a) a Mixture of 4-amino-5-chloro-2,3-dihydro-7-benzofuranol acid (4.3 g) in thionyl chloride (100 ml) and CHCl3(200 ml) was stirred and boiled under reflux for 2 hours the Mixture was cooled, and the solvent evaporated. Added toluene and again evaporated, receiving 4.8 g of 4 - amino-5-chloro-2,3-dihydro-7-benzotrichloride (100% of the crude residue) (intermediate 7).

b) a Solution of 1,1-dimethylethyl-4-hydroxy-1-piperidine-carboxylate (as 4.02 g) and N, N-dimethyl-4-pyridylamine (3.7 g) in dichloromethane (200 ml) was stirred at room temperature. This solution was poured a solution of intermediate (7) (4.8 g) in CH2Cl2(200 ml). The reaction mixture was stirred for 3 h at room temperature. The mixture was washed with water, 5% NaOH solution and again with water. The organic layer was separated, dried over MgSO4, was filtered, and the solvent evaporated. The balance of 7.4 g) was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH, 98/2). Pure fractions were collected and the solvent evaporated, gaining 4.7 grams of 1,1-dimethylethyl-4- [(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl) carbonyl] oxy] -1-piperidinecarboxylate (59%) (intermediate 8).

(C) a Mixture of intermediate product shall receive 2 hours The reaction mixture was cooled and podslushivaet NH4HE. The organic layer was separated by decantation and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/-(CH3HE/NH3), 92/8). Pure fractions were collected and the solvent evaporated. The residue (5.5 g) was re-purified by high-performance liquid chromatography (column: 200 g of kromasil; 10 μm; 100 , eluent: (0.5% solution of salt NH4O-acetyl in water/methanol 70/30). Pure fractions were collected and was extracted with NH3/CH2Cl2. The extract evaporated. The residue was led from acetonitrile. The precipitate was separated by filtration and dried (vacuum: 70oC) receiving 2,60 g of 4-piperidinyl - 4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate (54%) (intermediate 9).

Example 3

a) a Mixture of cyclopropyl-(4-amino-3-nitrophenyl)methanone (80 g), obtained as described in U.S. patent 3657267, and concentrated HCl (420 ml) was stirred and boiled under reflux for 30 minutes, the Reaction mixture was cooled and added to water. The precipitate was separated by filtration, washed with water and dried, obtaining 80 g (84,5%) 1-(4-amino-3-nitrophenyl)-4-chloro-1 - butanone; so pl. 150oC (intermediate 10).

b) a Mixture of mamide (150 ml) was stirred for 20 h at 70oC. the Solvent is evaporated. The residue was diluted with water, and the mixture was extracted twice CH2Cl2. The separated organic layer was washed with water, dried over MgSO4, was filtered, and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH, 90/10). The desired fractions were collected and the solvent evaporated. The residue (10 g) was led from diisopropyl ether. The precipitate was separated by filtration and dried, obtaining 8,3 g(33%) 1-(4-(4-amino-3-nitrophenyl)-4-oxobutyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate (intermediate 11).

(C) a Mixture of intermediate (11) (8,2 g) in tetrahydrofuran (150 ml) was first made using platinum on charcoal (5%) as catalyst. After absorption of H2(3 equiv.) the catalyst was separated by filtration through dicalite, and the filtrate evaporated. The residue was diluted with water, and the mixture was extracted twice CH2Cl2. The separated organic layer was washed with water, dried over MgSO4, was filtered, and the solvent evaporated. The residue (8 g) was purified column chromatography on silica gel (eluent: CH2Cl2/(CH3HE/NH3), 92/8). Pure fractions of the m and dried, getting 5,43 g(70,5%) 1-[4-(3,4-diaminophenyl) -4-oxobutyl] -4-piperidinyl-4-amino-5-chloro-2,3 - dihydro-7-benzophenoneoxymate; so pl. 173,4oC (intermediate 12).

C. obtain the final compounds

Example 4

A mixture of intermediate (6) (2.3 g) 4-chloro-1-(3,4,5 - trimethoxyphenyl)-1-butanone (2 g), sodium carbonate (2.1 g) and potassium iodide (catalytic amount) in 4-methyl-2-pentanone (150 ml: pre-dried over MgSO4) was stirred and boiled under reflux during the night. The reaction mixture was cooled, washed with water, dried over MgSO4, was filtered, and the filtrate evaporated. The residue was purified column chromatography on silica gel (eluent: gradient from CH2Cl2until CH2Cl2/(CH3HE/NH3), 97/3). Pure fractions were collected and the solvent evaporated. The residue was dissolved in methanol and converted into salt tangiwai acid treatment tangiwai acid (0.6 g). The mixture is boiled, then cooled, and the precipitate was separated by filtration and recrystallize from 2-propanol. The residue was dissolved in a mixture of aqueous NH4OH/CH2Cl2. The organic layer was separated, dried over MgSO4, was filtered, and the solvent evaporated. The residue was stirred in boiling disap is 1.10 g () -CIS-3-methoxy-1-[4-oxo-4-(3,4, 5-trimethoxyphenyl)butyl] -4 - piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate (28%); so pl. 132,3oC (compound 1).

A similar method was also received:

tandikat(1: 1) 1-[4-oxo-4-(3,4,5-trimethoxyphenyl) butyl]-4-piperidinyl-4-amino-5-chloro-2,3-dihydro - 7-benzophenoneoxymate; so pl. of 177.8oC (compound 2);

1-[4- (4-ethylphenyl)-4-oxobutyl-4-piperidinyl-4-amino-5-chloro-2,3 - dihydro-7-benzophenoneoxymate; so pl. 121,3oC (compound 3);

1-[4-(3,5-dichlorophenyl)-4-oxobutyl] -4-piperidinyl-4-amino-5-chloro - 2,3-dihydro-7-benzophenoneoxymate; so pl. 122,6oC (compound 4);

1-[4-(3,4-acid)-4-oxobutyl] -4-piperidinyl-4-amino - 5-chloro-2,3-dihydro-7-benzophenoneoxymate; so pl. 156,3oC (compound 5);

1-[4-(4-methoxyphenyl)-4-oxobutyl] -4-piperidinyl-4-amino - 5-chloro-2,3-dihydro-7-benzophenoneoxymate; so pl. to 136.4oC (compound 6);

(E)-2-butenedioate(1: 1) 1-[4-(4-methoxy - 3, 5dimethylphenyl)-4-oxobutyl] -4-piperidinyl-4-amino-5-chloro-2,3 - dihydro-7-benzophenoneoxymate; so pl. 171,2oC (compound 7).

Example 5

4-(4-Hydroxy-1-piperidinyl)-1-(3, 4, 5- trimethoxyphenyl)-1-butanone (3.3 grams) was added to a solution of sodium hydride (0.4 g) in tetrahydrofuran (100 ml) (solution 1) current N2. A mixture of 5-amino-6-CHL is eremetical for 2 h at room temperature, and the solvent evaporated. The residue was dissolved in tetrahydrofuran (100 ml) (solution 11). At room temperature the solution (11) was poured into a solution of (1), and the reaction mixture was stirred for 4 h at room temperature. The solvent is evaporated. The residue was diluted with water and was extracted twice CH2Cl2. The separated organic layer was washed with water, dried over MgSO4, was filtered, and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/hexane/(CH3HE/NH3, 50/42/3). The desired fractions were collected and the solvent evaporated. The residue (2.3 g) was purified by high-performance liquid chromatography on silica gel (eluent: CH2Cl2/CH3OH, 90/10). Pure fractions were collected and the solvent evaporated. The residue (1.2 g) was led from diisopropyl ether. The precipitate was separated by filtration and dried, obtaining 0,93 g 1-14-oxo-4-(3,4,5-trimethoxyphenyl) butyl]-4-piperidinyl-5-amino-6-chloro-3,4-dihydro-2H-benzopyran-8 - carboxylate (17%); so pl. 112,7oC (compound 8).

A similar method was also received:

1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl] -4 - piperidinyl-4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7 - benzophenoneoxymate; so pl. 154,2ooC (compound 10);

1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl] -4-piperidinyl-4-amino-5 - chloro-2-methyl-7-benzophenoneoxymate; so pl. of 128.6oC (compound 11).

Example 6

A mixture of intermediate (12) (2.4 g) and hydrochloric acid (few drops) in water (50 ml) was stirred at room temperature. Solution was added potassium isocyanate (2.5 g) in water (50 ml) and the resulting reaction mixture was stirred and boiled under reflux for 2 hours, the Reaction mixture was cooled, was podslushivaet NH4OH and then was extracted twice CH2Cl2. The separated organic layer was dried over MgSO4, was filtered, and the solvent evaporated. The residue (2.5 g) was mixed with 1,1'-carbonylbis-1H-imidazole (0,93 g) in tetrahydrofuran (80 ml). The reaction mixture was stirred and boiled under reflux for 2 hours the Solvent is evaporated. The residue was diluted with water, and the mixture was extracted twice CH2Cl2. The separated organic layer was washed with water, dried over MgSO4, was filtered, and the solvent evaporated. The residue was led from a mixture of 2-propanol/methanol. The precipitate was separated by filtration and dried, obtaining of 0.53 g of 1-[4-(2,3-dihydro-2-oxo-1H-benzimidazole-5-yl)-4 - oxobutyl] -/P> Example 7

A mixture of intermediate (12) (1.8 g), methyl(-imino-methoxymethyl)carbamate (0.5 g) and acetic acid (0.75 ml) in CHCl3(100 ml) was stirred and boiled under reflux for 2 days. The reaction mixture was podslushivaet NH4OH. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, dried over MgSO4, was filtered, and the solvent evaporated. The residue was led twice from methanol. The precipitate was separated by filtration and dried, gaining 0.4 g of monohydrate 1-[4-[2-[(methoxycarbonyl)amino]-1H-benzimidazole - 5-yl] -4-oxobutyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7 - benzophenoneoxymate (18,7%); so pl. 201,6oC (compound 13).

C. Pharmacological example

Example 8: Coaxial stimulation of the ileum of the Guinea pig

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) what's intestine 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, leading to 80% of maximum response)] from the programmable stimulator. The 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 responses of the muscle contractions. When these responses were stable, gave a submaximal stimulation to obtain 80% of the maximum response up until a response the 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 in 5 min after injection of the test compounds is compared with the amplitude before the introduction of the test compounds. Compounds 1, 2, 7 and 13 is played.

Example 9: Peristalsis of the colon have in mind dogs

Females breed Beagle with lots 7-17 kg implanted isometric force sensors under General anesthesia in 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 20 hours, during which water was available on demand. During the experiments, the dogs were able to move freely in their cages, where used telemetry (wireless) system. Cells were constructed in a special room with glass permeable to light in the same direction, i.e., the observer could see the dogs, while dogs 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 was transmitted converted in digital form small specially constructed box-transmitter. The box was placed in the jacket worn by the dog. The signals received through the microphone located above each cell, and transferred to zeeweg 3 h after injection of the test compounds was observed, was there and when he was defecating in dogs. Compounds 1, 2, 5, 6, 12, and 13 caused a bowel movement at least 50% of the test animals at doses 0,31 mg/kg during those first 3 hours

D. Examples of songs

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

Active ingredient (AI) 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.

Example 10: Oral solution

9 g of methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate 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 AI. The 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% aqueous 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 cloke (5 ml). The resulting solution is filled into suitable containers.

Example 11: Capsules

20 g AI, 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 containing 20 mg of AI.

Example 12: Tablets film-coated

Obtain core tablets

A mixture of 100 g AI, 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 sieved, dried and sieved again. Then add 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All well mixed and pressed into tablets, receiving 10,000 tablets, 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 is melted and dissolved in 75 ml of dichloromethane. The last solution is added first and then on the CE homogenized. Core tablets cover the thus obtained mixture in the device coating.

Example 13: 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 AI. 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 with 4 mg/ml A. I. the Solution was sterilized by filtration (USP XVII, page 811) and filled in sterile containers.

Example 14: Suppositories

3 g AI was dissolved in a solution of 3 g of 2,3-dihydroxybutanedioate acid in 25 ml of polyethylene glycol-400. Together melted 12 g surfactants and triglycerides, as necessary, 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 with a content of 30 mg of the active ingredient.

The test results of the compounds obtained are presented in the table.

1. Derivatives of phenyl-oxo-alkyl-(4-piperidinyl)Ben is the slot or a stereochemical isomeric form,

where R1represents halogen;

R2represents hydrogen;

R3represents C1-6alkyl, or R2and R3taken together form a bivalent radical of the formula

-(CH2)2- (b)

or

-(CH2)3(c)

or divalent radicals of the formula (b) or (C) one or two hydrogen atoms may be substituted C1-6-alkyl;

Alk represents a C1-6-alcander;

R4represents hydrogen or C1-6-alkoxy;

each of R5, R6and R7is independently hydrogen, halogen, C1-6-alkyl, C1-6-alkyloxy; or R5and R6taken together may form a bivalent radical of the formula

< / BR>
or

< / BR>
each of R8and R9is independently hydrogen or C1-6-alkyl;

R10represents hydrogen, C1-6-alkylsulphonyl, C1-6-allyloxycarbonyl.

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

3. Connection on p. 1, in which R2and R3taken together form a bivalent radical of formula (b).

4. Connection on p. 1 in which Alk is 1,3-propandiol.

5. Connection on p. 1, which pre is furancarboxylic;

1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

1-[4-(2,3-dihydro-2-oxo-1H-benzimidazole-5-yl)-4-oxobutyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

1-[4-(4-methoxy-3, 5dimethylphenyl)-4-oxobutyl] -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzophenoneoxymate;

their stereoisomeric 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. A method of obtaining a pharmaceutical composition, as stated in paragraph 6, characterized in that the connection on p. 1 is mixed with a pharmaceutically acceptable carrier.

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

9. The intermediate compound of the formula

< / BR>
and its N-oxide form, pharmaceutically acceptable salt accession acid or a stereochemical isomeric form, where R1- R4, R7and Alk have the meanings given in paragraph 1.

10. The way of gaining the discharge formula

L-W' (III)

where L represents a radical of the formula

< / BR>
in which Alk and R5- R7have the meanings given in paragraph 1;

D represents a radical of the formula

< / BR>
in which R1- R4have the meanings given in paragraph 1,

and optionally the compounds of formula I transform into each other through the reaction for the conversion of functional groups; and/or, if desired, the compound of formula I is transformed into a pharmaceutically acceptable salt, or, on the contrary, the additive salt of the acid is transformed into the form of the free base with alkali, and/or get it stereochemical isomeric form.

11. The method of obtaining the compounds stated in paragraph 1, wherein the alcohol of the formula IV

< / BR>
in which L and R4have the meanings given in paragraph 10, is subjected to reaction with a carboxylic acid of formula V

< / BR>
in which R1- R3have the meanings given in paragraph 10,

or its functional derivatives, such as allelochemical, symmetrical or mixed anhydride or ester, and optionally the compounds of formula I transform into each other through the reaction for the conversion of functional groups; and/or, if desired, the compound of the formula I is converted into pharmaceutically p the Chi, and/or get it stereochemical isomeric form.

 

Same patents:

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

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 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

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

The invention relates to certain CIS - and TRANS-benzopyrane having substituted benzamide in position C-4, and to their use for the treatment and/or prevention (prophylaxis) of certain CNS disorders

The invention relates to an improved process for the preparation of 4-(4'-forfinal)-3-hydroxyethylpiperazine f-ly I, where R3represents hydrogen; C1-C6-alkyl or C1-C6-alkylaryl, the recovery of the corresponding piperidine 2,6-dione f-crystals II, where R3have the above values, R4- C1-C6-alkyl, in the presence of a reducing agent - DIBORANE in an inert solvent, such as tetrahydrofuran or dimethoxyethane
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