Ether derivatives of 9-hydroxy-pyrido[1,2-a]pyrimidine-4-it, the retrieval method, the composition having antipsychotic activity and its preparation

 

(57) Abstract:

Ether derivatives of 9-hydroxy-pyrido[1,2-a]pyrimidine-4-it formula 1, where Alk - C1-4alcander; D is a heterocycle of formula (a) or (b), R1- C2-6alkenyl, C2-6alkenyl,1-19alkyl, possibly substituted C1-6alkoxy, siliciano; each of R2is hydrogen or C1-4alkyl, or isomers, or pharmaceutically acceptable additive salt of the acid possess antipsychotic activity. 10 C. p. F.-ly, 4 PL.

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The invention relates to new compounds of the formula

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to pharmaceutically acceptable additive salts of the acid and stereoisomers of these compounds, which are used as antagonists of mediators and have a high activity against Central nervous system.

In the patent US-4804663 described a number of 3-piperidinyl-1,2-benzisoxazoles, substituted, inter alia, 4H-pyrido [1,2-a]pyrimidine-4-novym radical and having antipsychotic activity.

In the patent EP-0368388-A describes the number of structurally close 3-piperidinyl-1,2-benzisoxazoles, substituted radical (6,7,8,9-tetrahydro-4-oxo-4H-pyrido[1,2-a] pyrimidine-3-yl), having a specific hydroxyl or C1-19

The present invention is new derivatives of 9-hydroxy-pyrido[1,2-a] pyrimidine-4-it, with enhanced activity against Central nervous system. This object is achieved with new ether derivatives of 9-hydroxy-pyrido[1,2-a]pyrimidine-4-it, which invariably have the ether substituent in the 9 position of the pyrido[1,2-a]pyrimidine-4-about fragment or 6,7,8,9-tetrahydro analog and have a high activity against Central nervous system.

The present invention relates to new compounds of the formula:

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to pharmaceutically acceptable additive to the acid salts of these compounds and their stereoisomers, where

Al-k represents a C1-4alcander,

D represents the bicyclic heterocycle of the formula:

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where each of R1independently represents a C2-6alkenyl; C2-6quinil; C3-6cycloalkyl, possibly substituted C1-4the alkyl, C1-19alkyl, C1-19alkyl, substituted C3-6-cycloalkyl, halogen, C1-6alkoxy or cyano;

each of R2independently represents water is further radicals with bivalent straight and branched chain, having from 1 to 4 carbon atoms, for example, methylene, 1,2-ethandiyl, 1,3-PROPANEDIOL and 1,4-butanediol; the term "C1-4alkyl" denotes a saturated hydrocarbon radicals, straight and branched chain, containing from 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl; the term "C1-6alkyl" denotes a C1-4alkyl radicals described above, and their higher homologues having from 5 to 6 carbon atoms, for example, pentyl and hexyl; the term "C1-6-alkyl" in the composite term "C1-6alkoxy" has the above meaning; the term "C1-12alkyl" means the above C1-6alkyl radicals, as well as their higher homologues having from 7 to 12 carbon atoms, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc; the term "C1-19alkyl" denotes a C1-12alkyl radicals described above, and their higher homologues having from 13 to 19 carbon atoms, for example, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, Needell, etc; the term "halogen" denotes fluorine, chlorine, bromine and iodine; the term "C3-6cycloalkyl" refers to cyclic hydrocarbon radicals having from 3 to 6 carbon atoms, for example, cyclopropyl, cyclob Svetlanas chain containing one double bond and having from 2 to 4 carbon atoms, for example, ethynyl, 2-propenyl, 3-butenyl, 2-butenyl, etc; the term "C2-6alkenyl" represents C2-4alkeneamine radicals described above, and their higher homologues having from 5 to 6 carbon atoms, for example, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, etc; the term "C2-4quinil" means hydrocarbon radicals c straight and branched chain, containing one triple bond and having from 2 to 4 carbon atoms, for example, ethyn, identical 2-PROPYNYL, 3-butynyl, 2-butynyl, etc; the term "C2-6quinil" represents C2-4alkyline radicals described above, and their higher homologues having from 5 to 6 carbon atoms, for example, 2-pentenyl, 3-pentenyl, 3-hexenyl etc.

The term "stereoisomers" in the text of this application refers to all possible isomers of the compounds of formula (1). Except where otherwise indicated, the chemical name of the compounds involves a mixture of all possible stereoisomers, and the mixture contains all diastereoisomers and enantiomers basic molecular structure. In particular, stereogenic centers may have the R - or S - configuration; substituents on bivalent cyclic saturated hydrocarbon radical isomers of compounds of formula (1) are covered by the scope of the present invention.

The compounds of formula (1) have basic properties and, consequently, they can be converted into pharmaceutically acceptable additive salt of the acid by treatment with appropriate acids such as inorganic acids, such as halogen acids, e.g. hydrochloric, Hydrobromic acid, etc., sulfuric acid, nitric acid, phosphoric acid and so on; or organic acids such as acetic, propanoic, exucuse, 2-oxopropanoic, 2-oxopropanoic, attentionwas, papandonatos, butandione, (Z)-2-butandione, (E)-2-butandione, 2-oxibutinina, 2,3-dioxaborinane, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, econsultancy, benzosulfimide, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-oksibenzoynoy, 4-amino-2-oksibenzoynoy, etc. on the Contrary, the salt can be converted to the free base by treatment with alkali.

Preferably, Alk was a C1-3alcander, especially 1,2-ethandiyl; each of R1independently represents a C1-12alkyl or C1-4alkyl, substituted C1-4alkoxy or cyano;

each of R2represented WITH1-4alkyl, especially methyl.battle C1-19alkyl or C1-19alkyl, substituted C1-6alkyloxy or cyano.

More interesting are those compounds of formula (1), where R1represents a C1-12alkyl, especially methyl; or C1-4alkyl, substituted C1-4alkyloxy or cyano, especially ethoxymethyl.

Of particular interest are those compounds of formula (1), where each of R1represents independently C2-6alkenyl or C2-6quinil.

A special group are the compounds of formula (1), where each of R1represents independently C2-4alkenyl, especially 2-propenyl; or C2-4quinil, especially 2-PROPYNYL.

Interesting group are those compounds of formula (1), where D represents a heterocycle of formula (a).

Another interesting group are those compounds of formula (1), where D represents a heterocycle of formula (b).

Preferred are those compounds of formula (1), where each R is a methyl.

The most preferred compounds are the following:

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] 6,7,8,9-tetrahydro-9-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimid,2-a]pyrimidine-4-one;

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] 9-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one;

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] 2-methyl-9-(2-propenyl-hydroxy)-4H-pyrido[1,2-a]pyrimidine-4-one;

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] 2-methyl-9-(2-PROPYNYL-hydroxy)-4H-pyrido[1,2-a]pyrimidine-4-one,

pharmaceutically acceptable additive, acid salts of these compounds and their stereoisomers.

The compounds of formula (1) are usually obtained by N-alkylation of 3-piperidinyl-1,2-benzisoxazole formula (II) an alkylating agent of the formula (III) using known methods N-alkylation.

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In the formula (III) and further in the text of the application D represents the above heterocycle, and W represents the corresponding active leaving group, such as chlorine-, bromine - or iodine-; sulfonylamino group, for example, methanesulfonate, 4-methylbenzenesulfonate, etc. leaving group. Mentioned N-alkylation can be accomplished by mixing the reagents in an inert to the reagents solvent, for example, water; an aromatic solvent such as benzene, methylbenzene, xylene and so on; alcohol, for example ethanol, 1-butanol, and so forth; ketone, the-dioxane, etc.; in bipolar aprotic solvent, e.g. N, N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and so on; or in mixtures of these solvents. To bind the acid which is formed during the reaction, you can add the corresponding base, for example, a carbonate of alkali or alkaline earth metal acid carbonate, hydroxide, oxide, carboxylate, the alkoxide, hydride or amide, e.g. sodium carbonate, potassium carbonate, etc. or organic compound, for example, tertiary amine, for example N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine, pyridine, etc., With stirring and somewhat higher temperatures, the reaction rate may increase.

In this case (and in other situations as below), the reaction products separated from the reaction medium and, if necessary, subjected to further purification using well-known methods, such as, for example, extraction, crystallization, titration and chromatography.

The compounds of formula (1) is also obtained by crystallization of the oxime of formula (IV), where Y represents a reactive leaving group, e.g. halogen or nitro-group. Preferably Y represents a halogen, in casinostates base, preferably in a suitable inert solvent, at a temperature of 20oC to 200oC, preferably from 50oC to 150oC, in particular at a temperature of distillation of the reaction mixture. Suitable bases for this reaction crystallization are, for example, carbonates of alkali and alkaline earth metals, acid carbonates, hydroxides, alkoxides or hydrides, such as sodium carbonate, acid sodium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydride, or organic bases, for example, N,N-diethylethanamine, 4-ethylmorpholine, etc. reasons. Suitable solvents are, for example, water; aromatic hydrocarbons, for example, methylbenzol, xylene and so on; halogenated hydrocarbons, for example, trichloromethane, 1,2-dichloroethane and so on; alcohols, such as ethanol, 1-butanol, etc; ketones, e.g. 2-propanone, 4-methyl-2-pentanone and so on; ethers, for example, 1,4-dioxane, tetrahydrofuran, etc.; bipolar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc., or mixtures of these solvents.

The compounds of formula (1) can be obtained by known reactions of O-alkylation of the intermediate compounds of formula (Y-is therefore, its, the compounds of formula (1) or (1-b). The compounds of formula (1-a) are those compounds of formula (1), where D represents a heterocycle of formula (a). The compounds of formula (1-b) are those compounds of formula (1), where D represents a heterocycle of formula (b).

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Specified O-alkylation is carried out by mixing the reagents in an inert solvent, for example, water; an aromatic solvent, e.g. benzene, methylbenzene, xylene and so on; in alcohol, for example ethanol, 1-butanol, and so forth; ketone, e.g. 2-propanone, 4-methyl-2-pentanone and so on ; in simple ether, for example, 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, etc.,; in bipolar aprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and so on; or in mixtures of these solvents.

To bind the acid which is formed during the reaction, you can add the corresponding base, for example a carbonate of alkali or alkaline earth metal acid carbonate, hydroxide, oxide, carboxylate, alkoxide, hydride or amide, e.g. sodium carbonate, potassium carbonate, etc. or organic base, such as tertiary amine, e.g. N,N-diethylethanamine,Oh reaction rate may increase.

Intermediate compounds of formula (V-a) are new.

The compounds of formula (1) can be converted one into another using known methods. For example, the compounds of formula (1) containing C2-6alkenylphenol or C2-6alkylamino group, can be converted into the corresponding compounds containing C2-6alkyl group, using known methods of hydrogenation.

Intermediate compounds of formula (III), where D represents a heterocycle of formula (a) and the specified intermediate compounds are described by formula (III-a), can be obtained by using Q-alkylation of the intermediate compounds of formula (VII-a) and subsequent conversion of the alcohol of formula (VIII-a) in the intermediate compound of formula (III-a). The specified reaction Q-alkylation carried out according to the method described above to obtain compounds of formula (1), using as starting compound intermediate compound of formula (V).

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Intermediate compounds of formula (III-a) can be further converted to intermediate compounds of the formula (III-b) using known methods of hydrogenation.

The stages of this reaction, starting from intermediate compounds of formula (VIII-a) to promezhutochnogo the subsequent hydrogenation, you can swap.

The term "additive salt of the acid used in this application also includes a solvate, which compounds of formula (1) can form, and these solvate included in the scope of the present invention. Examples of the solvate include, for example, hydrates, alcoholate, etc.,

Some compounds of formula (1) and some intermediate compounds of the present invention contain at least one asymmetric carbon atom. Pure stereoisomers of these compounds and intermediate compounds can be obtained using known methods. For example, diastereoisomer can be distinguished by physical methods such as selective crystallization or chromatographic methods, for example by counter current distribution, liquid chromatography, etc., Enantiomers can be obtained from racemic mixtures, and the racemic mixture first convert then reduced to diastereoisomeric salts or compounds using the appropriate peptization, for example, chiral acids; after that make the physical separation of these mixtures diastereoisomeric salts or compounds, for example, by selective crystallization or by chromatography, nresult into the corresponding enantiomers.

Pure stereoisomers of the compounds of formula (1) can also be obtained from the pure stereoisomers corresponding intermediates and starting materials, provided that these reactions take place in a stereospecific form. The scope of the present invention encompass both pure stereoisomers of the compounds of formula (1), and mixtures thereof.

The compounds of formula (1), as well as the intermediate compounds of formula (V), in particular, the intermediate compounds of formula (V-a) or (V-b), pharmaceutically acceptable additive acid salts and stereoisomers of these compounds are antagonists of mediators and, in particular, mediators serotonin. As antagonists of the mediator, these compounds inhibit or facilitate a variety of symptoms associated with symptoms caused by the release, in particular, excessive release of this mediator. Therapeutic indications for use of the compounds according to the present invention mainly relates to the field of diseases of the Central nervous system. However, the compounds according to the invention can also be used in the treatment of gastrointestinal and cardiovascular and other related diseases. The compounds of formula (1) is particularly effective Auda for the treatment of psychosis, aggressive behavior, anxiety, depression and migraine. Further, the compounds according to the invention can be applied to combat the autistic conditions. In addition, serotonin causes narrowing of the bronchi and blood vessels, therefore antagonists of the present invention can be used in hypertension and vascular diseases. In addition, antagonists of serotonin have a number of other properties, for example, they suppress the appetite and promote weight loss, so they can be used to combat obesity, as well as to alleviate withdrawal symptoms in those who are trying to quit drinking or Smoking.

As the results given in the examples related to pharmacology, the compounds according to the invention can easily penetrate into the Central nervous system and have increased activity in relation to it. The compounds of formula (1) have additional advantages are that they are relatively slowly eliminated from the body, so the action of these compounds for a long time. Therefore, the reception of the compounds of formula (1) can be assigned through a relatively large intervals, for example, in a few days or weeks; the duration of the intervals will depend on ozbolat be treated more effectively due to the fact, what compounds are excreted slowly in the plasma for a long time maintained a stable concentration of the drug at a non-toxic effective level, and the decrease in the number of techniques allows for more precise control of prescribed treatment regimen.

Given the pharmacological properties of the compounds according to the invention, one can produce medicines in various forms. In order to prepare a pharmaceutical composition of the present invention, an effective amount of a specific compound in the form of additive salts of acids or bases, as the active ingredient is mixed with a pharmaceutically acceptable carrier, which can be applied to a variety of compounds, depending on what the introduction is intended drug. Such pharmaceutical composition is preferably made in the form of single doses suitable for oral, rectal, percutaneous or parenteral destination. For example, for the manufacture of compositions for oral use can be used in any media, usually used for this purpose, for example, water, glycols, oils, alcohols, etc., (in those cases when eye as starches, sugars, kaolin, lubricants, binders, agents that cause decay, and so on (in those cases when they produce powders, pills, capsules and tablets). Due to the fact that tablets and capsules are the most easy to take, they are the most preferred form of pharmaceutical preparations according to the invention, for the manufacture of which, of course, use solid media. Carriers for parenteral compositions usually comprise sterile water, which represents at least a large part of the composition, although there may be other ingredients, for example, agents that increase the solubility. Can be manufactured, for example, solutions for injection, in which the media will include a salt solution, a glucose solution or a mixture of these solutions. Injectable solutions containing the compounds of formula (1), it is possible to produce in the form of oil solutions that will extend the period of validity of the compounds. For this purpose, suitable such oil, like peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. You can also make suspension for injection, for h is sonogo introduction, the carrier may contain an agent that enhances the penetration and/or a suitable wetting agent, the carrier may be mixed with suitable target additives of any nature, which are used in small quantities and which do not have significant adverse effects on the skin. These additives increase the efficiency of insertion through the skin and/or help to produce the desired composition. Such compositions can be applied in various ways, for example, putting them on separate areas of the skin, or to the particular skin, or in the form of ointments. Additive acid salt of compound (1) having a higher solubility compared to the ones better suited for the preparation of aqueous compositions.

It is best to prepare the above composition in the form of individual doses, which will facilitate their introduction. The term "in the form of individual doses" in the text of the present description and claims refers to physically discrete units suitable for use as a separate doses, each of which contains a certain quantity of active ingredient calculated so that this number was producing the desired therapeutic effect, and is associated with the I grooved tablets and the pill wafers), capsules, pills, sachets of powder, pads, solutions or suspensions for injection, the dose of one teaspoon or tablespoon, etc.

Since the useful properties of the compounds according to the invention are manifested in the treatment of diseases associated with the release of mediators, in particular, in the treatment of psychotic diseases, the present invention provides a method of treating warm-blooded animals suffering from these diseases, in particular, psychotic disorders, and this method includes a systematic method of antipsychotic amount of a compound of formula (1) or pharmaceutically acceptable salt additive acid of the indicated compounds effective in the treatment of diseases associated with release of mediators, in particular, psychotic diseases. Doctors specializing in the treatment of such diseases can easily install an effective amount, using the results of the tests are presented below. In General it is believed that an effective antipsychotic amount is from 0.01 mg/kg to 4 mg/kg body weight, preferably from about 0.04 mg/kg to about 2 mg/kg of the body.

The following examples are intended to illustrate the crust is

A. the production of intermediate compounds

Example 1.

A mixture of 2-amino-3-pyridinol (0.9 mol), 3-acetylthio-2(3H)-furanone (0.8 mol), 4-methylbenzenesulfonic acid (1 g) and xylene (700 ml) was stirred and distilled during the night, using a water separator. The mixture is then cooled, and the resulting product was filtered and dried. The product was converted to the salt of hydrochloric acid in 2-propanol. Then the salt was filtered and dried, obtaining 120 g (58,4%) 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-monohydrochloride (intermediate compound 1).

Example 2.

a) a Mixture of 2-amino-3-pyridinol (0.10 mol), sodium hydroxide (50%) (30 mol), 1-hardtechno (0.20 mol) and methyl-three-octylamine chloride (8 g) in benzene (300 ml) was stirred overnight at 80oC. Then the reaction mixture was cooled, the organic layer was separated, washed with 2N NaOH, dried (MgSO4), filtered and the solvent evaporated. The residue was cooled and the resulting precipitate was filtered, washed with hexane, petroleum ether, and dried, obtaining 21 g (75%) of 3-(dodecyloxy)-2-pyridylamine (intermediate compound 2).

b) a Mixture of intermediate compound (2), (0,050 mol), 3-acetyld and during the night, using a water separator. The solvent is then evaporated. The residue was purified under silica gel on a glass filter (eluent: CH2Cl2/CH2OH 95/5). Pure fractions were collected and the solvent evaporated. The residue was led from acetonitrile. The precipitate was filtered and dried, obtaining 13 g(66,9%) 3-[1-[[3-(dodecyloxy)-2-pyridinyl] amino]ethylidene]dihydro-2(3H-)-furanone (intermediate compound 3).

C) phosphorus Oxychloride (75 ml) was added to the intermediate compound (3) (0,025 mol) with stirring. The mixture was stirred and distilled for 6 hours. The solvent is then evaporated. The residue was stirred in ice water and the mixture was podslushivaet ammonia. This mixture was extracted with dichloromethane. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5) Pure fractions were collected and the solvent evaporated. The residue was led from a mixture of 2,2'-oxybisethane/acetonitrile. The crystals were filtered and dried, obtaining 8.5 g (83.5 per cent) of 3-(2-chloroethyl)-9-(dodecyloxy)- 2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one (intermediate compound 4).

Example 3.

a) Dimethylsulfate (0,020 m), the additive is produced by cooling in ice water. The reaction mixture was stirred for 15 minutes at room temperature, then heated for 1 hour in a warm water bath. Then the reaction mixture was cooled, and then was extracted with dichloromethane. The separated aqueous layer contained a precipitate, which was filtered and was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH 97/3). Pure fractions were collected and the solvent evaporated. The residue was led from acetonitrile. The crystals were filtered and dried, obtaining 2 g (42%)

3-(2-hydroxyethyl)-9-methoxy-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-it (intermediate compound 5).

b) Methanesulfonanilide (0,013 mol) drop by drop) was added with stirring to a chilled (5oC) a mixture of intermediate compound (5) (0,0115 mol) and N,N-diethylamine (0,013 mol) in dichloromethane (50 ml). The reaction mixture was stirred for 2 hours at room temperature. Then the reaction mixture was washed with water. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The residue was led from acetonitrile. The crystals were filtered and dried, obtaining 2.9 g (80%) of 9-methoxy-2-methyl-3-[2-[(metals.

Example 4.

a) a Mixture of intermediate (1) (0,050 mol) and potassium carbonate (by 0.055 mol) in N,N-dimethylformamide (50 ml) was stirred for 1 hour at 60-70oC. Then the mixture was cooled to room temperature and one drop was added 1-methoxy-2-iodata (by 0.055 mol). The reaction mixture was stirred for 4 hours at 60-70oC. the Solvent is evaporated. The residue was stirred in water and was added dichloromethane. This resulted in the crystallization. The precipitate was filtered and recrystallize from acetonitrile. The precipitate was filtered and dried, obtaining of 9.2 g (66%) of 3-(2-hydroxyethyl)-9-(2-methoxyethoxy)- 2-methyl-4H-pyrido[1,2-a] pyrimidine-4-it (intermediate compound 10).

b) a Mixture of intermediate (10) (0,0179 mol) in phosphorus oxychloride (50 ml) was stirred and distilled for 2 hours. The solvent is evaporated. The residue was stirred in water and the mixture was podslushivaet ammonia. This mixture was extracted with dichloromethane. The separated organic layer was dried, filtered and the solvent evaporated. The residue was led from a mixture of 2,2'-oxybisethane/acetonitrile. The precipitate was filtered and dried, obtaining 3 g (57%) of 3-(2-chloroethyl)-9-(2-methoxyethoxy)-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-it (propanole (250 ml) was first made at the 50oC when using as a catalyst of palladium on carbon (10%), 2 g After uptake of hydrogen (2 EQ.) the catalyst was filtered. The filtrate is evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH 95/5). Pure fractions were collected and the solvent evaporated to give 10 g (71%)

()-6,7,8,9-tetrahydro-3-(2-hydroabietyl)-9-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-it (intermediate compound 12).

b) Methanesulfonanilide (0,030 mol) drop by drop) was added with stirring to a chilled (ice bath) mixture of intermediate (12) (0,029 mol) and N, N-diethylethanamine (0,030 mol) in dichloromethane (50 ml). The reaction mixture was stirred for 2 hours at room temperature. Then the reaction mixture was washed with water. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated, receiving 8 g (84%) () -6,7,8,9-tetrahydro-9-methoxy-2-methyl-3-[2-[(methylsulphonyl)-oxy] ethyl]-4H-pyrido[1,2-a]pyrimidine-4-it (intermediate compound 13).

In a similar way received the following connections:

()-9-(ethoxyethoxy)-6,7,8,9-tetrahydro-2-methyl-3- [2-[(methylsulphonyl)oxy] ethyl] -4H-pyrido[1,2-a] pyrimidine-4-one (intermediate compound 14).omegaton connection 15).

Example 6.

A mixture of intermediate compound (4) (0,010 mol) in methanol (250 ml) and hydrochloric acid in 2-propanol (to acid) was first made when using as a catalyst of palladium on carbon (10%), 2 g After uptake of hydrogen (2 EQ.) the catalyst was filtered and the filtrate is evaporated, receiving 4.5 g (100% crude residue)

()-3-(2-chloroethyl)-9-(dodecyloxy)-6,7,8,9-tetrahydro-2 - methyl-4H-pyrido[1,2-a]pyrimidine-4-it (intermediate compound 16).

In a similar way received the following connection:

()-3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-(2-methoxyethoxy)- 2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one (intermediate compound 17).

Example 7.

A mixture of 9-(ethoxyethoxy)-3[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 1-piperidinyl] ethyl]-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-it (0,008 mol) in 12N hydrochloric acid (25 ml) and ethanol (100 ml) was stirred and distilled for 6 hours. Then the reaction mixture was cooled and the precipitate was filtered and dried, receiving 4 g(95,7%) 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] -9-hydroxy-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-it is the hydrochloride, sesquihydrate; melting point 288,3oC (intermediate compound 18).

B. Receiving end soudamini)-1,2-benzisoxazole (0,009 mol) and sodium carbonate (0,025 mol) in N,N-dimethylformamide (50 ml) was stirred for 6 hours at 80-90oC. the Reaction mixture was cooled to room temperature and the precipitate was filtered, stirred in water and was filtered again. The solid was bicrystalline from a mixture of N,N-dimethylformamide/H2O. the Crystals were filtered and dried, obtaining 1.9 g (48%).

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] -9-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-it;

melting point 209,3oC (compound 1).

Example 9.

A mixture of intermediate (13) (0.012 mol), monohydrochloride 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (0,010 mol) and sodium carbonate (0,025 mol) in N,N-tiliifolia (50 ml) was stirred for 6 hours at 80-90oC. the Reaction mixture was filtered, and the filtrate evaporated. To the residue was added water, and the mixture was extracted with dichloromethane. The separated organic layer was dried (MgSO4), filtered, and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: CH2CL2/CH3OH 95/5). Pure fractions were collected, the solvent evaporated. The residue was led from a mixture of acetonitrile/2,2'-oxybisethane. The crystals were filtered and dried, obtaining 1.6 g (36%)

()-3-[2-[4-(6-fluoro-1,2-benzisoxazol-C-and theoC (compound 7) .

C. Pharmacological example

Example 10.

Antipsychotic activity of the compounds according to the invention support the experimental data obtained at least one of two different tests: combined test on rats using apomorphine (APO), tryptamine (TRY) and norepinephrine (NOR) and test with the use of apomorphine in dogs.

The specified combined test with the use of apomorphine, tryptamine and norepinephrine, are described in Arch/Int Pharmacodyn., 227, 238-253 (1977) and allows to obtain an empirical evaluation of the relative specificity with which drugs can affect specific mediators in the Central and peripheral nervous system. In particular, the test demonstrates that the tested compounds of the formula (1) had antagonistic activity towards dopamine (preventing symptoms caused by apomorphine, which is a dopamine agonist), serotonin (preventing the symptoms of lesions of the Central and peripheral nervous system (convulsions, hyperemia caused by serotonin or tryptamine), and norepinephrine (preventing the breath after the introduction of the d21959) and allows to measure the duration of action of the tested compounds. The tests are carried out according to the method described in EP-A - 0,196,132, and experimental data are summarized in table 4.

D. Examples of songs

The term "active ingredient" in the text of these examples relates to compounds of formula (1). Pharmaceutically acceptable additive salts of the acid and stereoisomers of these compounds.

Example 11. Drops for oral intake

500 g of active ingredient was dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60-80oC. After cooling to 30 40oC added 35 l of polyethylene glycol and the mixture is well mixed. Then added a solution of 1750 g of saccharin sodium 2.5 l of purified water and while stirring was added 2.5 liters of coconut flavor and polyethylene glycol to a volume of 50 l, having the solution drops for oral administration containing 10 mg/ml of active ingredient. The resulting solution was poured into suitable bottles.

Example 12. Solution for oral administration

9 g of methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate 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 the active ingredient. The resulting solution was combined with estabseveral in 0.5 l of water and added 2 ml of raspberry and 2 ml of gooseberry family essences. The resulting solution was combined with the first solution was added water up to a volume of 20 l, having a solution for oral administration containing 5 mg of active ingredient in a teaspoon (5 ml). The resulting solution was poured into appropriate containers.

Example 13. Tablets, coated surface

Preparation of core tablets

A mixture of 100 g of the active ingredient, 570 g lactose and 200 g starch is well stirred and then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture was sieved, dried and again sieved. Then added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All together thoroughly mixed and compressed into tablets having 10,000 tablets each containing 10 mg of active ingredient.

Shell

In a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol was added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol was melted and dissolved in 75 ml of dichloromethane. The last solution is added first, and then added 2.5 g of octadecanoate magnesium, 5 g polyvinylpyrrolidon the received mixture in a special apparatus.

Example 14. Injection

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 50 added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g of active ingredient. The solution was cooled to room temperature and added water for injection to a total volume of 1 l, obtaining a solution containing 4 mg/ml of active ingredient. The solution was sterilized by filtration and filled in sterile containers.

Ether derivatives of 9-hydroxy-pyrido[1,2-a]pyrimidine-4-she formulas (1)

< / BR>
or its isomers or its pharmaceutically acceptable additive salt of the acid,

where Alk represents a C1-4alcander;

D represents a heterocycle of the formula

< / BR>
where each of R1independently represents C2-6alkenyl; C2-6quinil; C1-19alkyl, possibly substituted C1-6alkoxy or cyano;

each of R2independently represents hydrogen or C1-4alkyl.

2. Connection on p. 1, where R2represents methyl.

3. Connection on p. 2, where Alk represents a C1-3alcander, R1represents a C1-12alkyl or C1-2
alcander.

5. Connection on p. 2, where Alk represents a C1-3alcander, R1represents a C2-4alkenyl or C2-4quinil.

6. Connection on p. 5, where Alk represents a C1-2alcander.

7. Connection on p. 1, where the compound is:

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-9-methoxy-2-methyl--pyrido[1,2-a]pyrimidine-4-one;

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-9-propoxy--pyrido[1,2-a]pyrimidine-4-one;

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl]-9-methoxy-2-methyl--pyrido[1,2-a]pyrimidine-4-one;

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl]-2-methyl-9-(2-propenyl-hydroxy)--pyrido[1,2-a]pyrimidine-4-one;

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl]-2-methyl-9-(2-PROPYNYL-hydroxy)--pyrido[1,2-a]pyrimidine-4-one,

its pharmaceutically acceptable additive acid salt or stereoisomer.

8. The composition having antipsychotic activity, including pharmaceutically acceptable carrier and an active ingredient, wherein the active ingredient contains an effective amount of a compound according to any one of paragraphs.1-eat, what pharmaceutically acceptable carrier mixed with an effective amount of a compound according to any one of paragraphs.1 - 7 until a homogeneous mixture.

10. Compounds according to any one of paragraphs.1 - 7 with antipsychotic activity.

11. A method of obtaining a connection on p. 1, characterized in that the conducting N-alkylation of 3-piperidinyl-1,2-benzisoxazole formula (II) an alkylating agent of the formula (III), where W represents a reactive leaving group and D has the values specified in paragraph 1.



 

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FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

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