New compounds for mental disorders, preparing and using them

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I), its optical isomer or pharmaceutically acceptable salt, R is specified in cl.1 of the patent claim. The compounds may be presented both as an optical isomer, and as a racemic substance, and may be used for mental disorders, such as schizophrenia.

EFFECT: higher efficacy of using the compounds.

8 cl, 4 tbl, 3 dwg, 7 ex

 

The technical FIELD TO WHICH the INVENTION RELATES

The present invention relates to the compound of formula (I) and its salts, method thereof, pharmaceutical compositions and their use for the treatment or adjunctive treatment of mental disorders.

The LEVEL of TECHNOLOGY

It was reported that the compound [formula (II)] 3-{2-[4-(6-toranzo[d]isoxazol-3-yl)piperidine-1-yl]-ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one; or according to the IUPAC nomenclature: 3-[2-[4-(6-toranzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-7-hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]DECA-3,5-Dien-2-he; CAS No. 144598-75-4; molecular weight (MW) 426,48; "Paliperidone", or "9-Oh-risperidone"or "9-hydroxyrisperidone"] is a derivative of benzisoxazole and one of the new generation of antipsychotic funds. The compound [formula (II)] is a selective monoaminergic antagonist with unique properties, and has a high affinity for serotonergic 5-HT2 receptor and dopamine D2 receptor. The compound [formula (II)] can also communicate with α1-adrenergic receptor, and binds to histaminergic H1 receptor and α2-adrenoceptors with relatively low affinity. The compound [formula (II)] is not associated with cholinergic receptor. The compound [formula is (II)] is a potent D2 antagonist and can improve the positive symptoms of schizophrenia, but it may cause less inhibition of motor function and catalepsy than classical antipsychotics. Its balanced antagonistic effects on serotonin and dopamine in the Central nervous system can reduce the possibility of extrapyramidal side effects, and therapeutic effect can be extended to negative symptoms and emotional symptoms of schizophrenia.

The compound [formula (II)] represents the new generation of psychotropic drugs relative to Risperidone. The management under the control over products and medicines of the USA sanctioned the sale of oral composition of extended release with the compound [formula (II)] (INVEGA), developed by JANSSEN Pharmaceuticals, Inc., in December 2006 for the treatment of mental disorders. Because the hydroxyl group in the compound causes an increase in hydrophilicity, rate of absorption in oral introduction decreases and the absolute bioavailability of INVEGA is only 28%, which is much less than for Risperidone (at least 70%), so the daily dose of the compounds significantly increased, which, in turn, leads to an increase in presystemic side effects possible unabsorbed drug. In international patent publication WO99/25354 was described ester connect the of [formula (II)] with long-chain aliphatic acid, but he is metabolized in vivo very slowly with the formation of compound [formula (II)] and not able to achieve the appropriate level of therapeutic effect. In order to remedy the aforementioned shortcomings associated with the compound [formula (II)] and its esters with aliphatic acids was synthesized a series of derivatives of compounds [formula (II)] (compounds of formula (I)), used as prodrugs of the compound [formula (II)], and typed in smaller quantities due to rapid metabolism in vivo with the formation of compound [formula (II)], thereby achieving therapeutic effects.

The INVENTION

The purpose of the present invention is to develop a new compound that is a prodrug for the treatment of mental disorders. The following compounds of formula (I)thus obtained by the authors of the present invention, have the advantage of the rapid metabolism in vivo with the formation of compound [formula (II)], thereby providing enhanced bioavailability and reduced presystemic side effects caused by possible unabsorbed drug, facilitating the regulation of dosage and therapeutic effects, reducing side effects and the risk of interactions with other medicines.

On toadie the invention relates to the connection, represented by formula (I), its optical isomer or pharmaceutically acceptable salt, which is a prodrug for the treatment of mental disorders

in which,

chiral center (*) may have the R configuration or S, or RS (racemic mixture);

R represents aryl having 6-20 carbon atoms; or a saturated alkoxygroup having 1-20 carbon atoms, or unsaturated alkoxygroup having 2-20 carbon atoms, or cycloalkyl group having 4-20 carbon atoms, or arylalkyl group having 6-20 carbon atoms; or an amino group of the following formula having 1-20 carbon atoms:

in which the radicals R2 and R3 independently represent hydrogen, a saturated alkyl having 1-10 carbon atoms, or unsaturated alkyl having 2-10 carbon atoms, or aryl having 6-10 carbon atoms.

R represents aryl having 6-20 carbon atoms, preferably, but not limited to such:

in which the radicals R4 and R5 independently represent hydrogen, saturated alkyl or CNS group having 1-6 carbon atoms, unsaturated alkyl or CNS group having 2-6 carbon atoms, HE, Cl, F, CN, carboxyl and ester group; preferably, but not about rancevas such hydrogen, methyl, ethyl, metaxylene, ethoxyline group, fluorine or carboxyl.

R represents a saturated alkoxygroup having 1-20 carbon atoms, or unsaturated alkoxygroup having 2-20 carbon atoms, or cycloalkyl group having 4-20 carbon atoms, preferably, but not limited to, metaxylene, amoxilina, propoxyimino, isopropoxyphenol, betaxolol, isobutoxy, tert-butoxyl, pentoxil, cyclohexylamino group; or arylalkyl group having 6-20 carbon atoms, preferably, but not limited to such:

in which the radicals R6 and R7 independently represent hydrogen, saturated alkyl or CNS group having 1-6 carbon atoms, unsaturated alkyl or CNS group having 2-6 carbon atoms, HE, Cl, F, CN, carboxyl and ester group; preferably, but not limited to, hydrogen, methyl, ethyl, metaxylene, ethoxyline group, fluorine or carboxyl.

R represents an amino group of the following formula having 1-20 carbon atoms:

in which the radicals R2 and R3 independently represent hydrogen, a saturated alkyl having 1-10 carbon atoms, or unsaturated alkyl having 2-10 carbon atoms, preference for the equipment, but not limited to, methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, tert-boutelou group; or aryl having 6-10 carbon atoms, preferably, but not limited to:

in which the radicals R4, R5 independently represent hydrogen, saturated alkyl or CNS group having 1-6 carbon atoms, unsaturated alkyl or CNS group having 2-6 carbon atoms, HE, Cl, F, CN, carboxyl and ester group; preferably, but not limited to, hydrogen, methyl, ethyl, metaxylene, ethoxyline group, fluorine or carboxyl.

According to the present invention, the term "optical isomer" is R - or S-optical isomer, or RS-racemic mixture of compounds of formula (I) or a pharmaceutically acceptable salt.

According to the present invention is illustrative of the compounds of formula (I) include:

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-benzoate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-methylbenzoate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-methylbenzoate,

3-{2-[4-(6-fluoro-1,2-benzoato Sasol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methylbenzoate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-methoxybenzoate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-methoxybenzoate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methoxybenzoate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-perbenzoate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-perbenzoate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-perbenzoate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-carboxybenzoyl,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-methylcarbonate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-ethylcarbonate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-propylmalonate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidine is]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-isopropylcarbonate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-BUTYLCARBAMATE,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-isobutylketone,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-tert-BUTYLCARBAMATE,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-methylbutylamine,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-n-intercabinet,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-intercabinet,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-intercabinet,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-isopentylamine,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-neopentylene,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-hexylcaine,

3-{2-[4-(6-fluoro-1,2-benzo oxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-cyclohexylcarbamate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-phenylcarbamate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-methylphenylcarbinol,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-methylphenylcarbinol,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methylphenylcarbinol,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-methoxyphenylacetone,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-methoxyphenylacetone,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methoxyphenylalanine,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-tortenelmebol,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-tortenelmebol,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-florfenicol ONAT,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-N,N-dimethylcarbamate,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-N,N-diethylcarbamyl,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-N,N-dipropylamine,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-N,N-Diisopropylamine,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-N,N-dibutylformamide,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-N,N-diisobutylamine,

3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-N,N-di-tert-BUTYLCARBAMATE

and a variety of salts and optical isomers thereof.

According to well-known methods of producing pharmaceutical compositions of the compound of formula (I) according to the present invention, including its optical isomers and racemic mixtures and pharmaceutically acceptable salts, may be incorporated into the dosage forms suitable for oral, injectable, transdermal, II andstc the nasal, mucosal administration and by inhalation, and the like. Dosage forms suitable for oral administration may be either in the form of solid tablets, capsules, soft capsules or tablets, or solutions, suspensions, emulsions or powders and can be a conventional dosage form, the dosage form with a slow-release form of drug delivery to specific tissues, dosage forms quick release or dosage forms with oral cleft. Injection may be intravenous injection, hypodermic injection, intramuscular injection or intraperitoneally injection, and suitable dosage forms for this can be solutions, suspensions or emulsions, or traditional dosage forms or any long-term effects, such as implants, microspheres or gels. Dosage form suitable for transdermal administration, can be a percutaneous patches, gels or other dosage forms for percutaneous introduction. Dosage form suitable for nasal administration and by inhalation may be in the form of solutions, suspensions, emulsions or powders. Dosage forms suitable for mucosal injection, can be represented as solutions, suspensions, emulsions, powders or soup is sicarii.

The present invention also relates to pharmaceutical compositions comprising an effective amount of the compounds of formula (I) and a compatible and pharmaceutically acceptable carrier or diluent. The carrier may be any inert organic or inorganic substance, such as water, gelatin, cellulose, starch, biodegradable polymer excipients, such as polyesters or polycarbonates or copolymers of any two or three of the components thereof, other pharmaceutically active substance and commonly used additives, such as stabilizers, wetting means, emulsifiers, flavour and buffer reagents.

The compound of formula (I) according to the present invention, including its optical isomers, racemic mixtures and pharmaceutically acceptable salts, as antagonists of neurotransmitters, may be used to treat mental disorders such as schizophrenia, and his daily dose may be from 0.01 to 100 mg, which may be entered as single or multiple doses.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows the absorption and metabolism of the compound [formula (II)] and its compounds proletarienne 1, 2, 3, 5, 6, 7 and the connection 8 when tested in hound dog (Beagle):

A. changes in the concentration of AK the active metabolite, the compounds of formula (II), for compounds 1, 2 and 3 (ig, intragastric administration) and the compound [formula (II)] (iv, intravenous) in the blood;

C. changes in the concentration of the active metabolite, the compounds of formula (II), for compounds 5, 6, 7 and 8 (ig) and the compound [formula (II)] (iv) in the blood;

C. measure the concentrations of prototype compounds 1, 2, 3, 5, 6, 7 and 8 for connections 1, 2, 3, 5, 6, 7 and 8 (ig) in the blood.

SPECIFIC embodiments of the INVENTION

The present invention is illustrated by the following examples which are not to be construed as limiting the scope of the invention in any way.

A. Synthesis of compound [formula (II)]

1. Obtaining 3-(2-chloroethyl)-2-methyl-9-benzyloxy-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-it

In the reaction flask was placed 1500 ml of toluene, 120 g (of 0.65 mole) 2-amino-3-benzyloxypyridine, 114 ml of 1.05 mol) of 2-acetyl-γ-butyrolactone and dropwise added 300 ml (3,21 mole) of phosphorus oxychloride. The reaction was carried out at a temperature of 90-93°C for 5 hours. The solvent was distilled under reduced pressure, the residue was poured into pinned ice, the pH was brought to 9 by the addition of 25%ammonia solution, was extracted three times with chloroform (100 ml each time), the extract washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, the residue in the still hot sauce is the right was dissolved in 100 ml of isopropanol and left to stand over night. The crystalline precipitate was filtered, washed with isopropanol and dried with the formation of 65.0 g of pale pink crystals (yield 31%). Melting point: 139,9-140,9°C.

2. Obtaining 3-(2-chloroethyl)-2-methyl-9-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-it

In a three-neck flask with a capacity of 250 ml at room temperature was placed 4.0 g (0,0122 mole) of 3-(2-chloroethyl)-2-methyl-9-benzyloxy-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-she added 80 ml of methanol and then dropwise added concentrated hydrochloric acid (about 25 drops) with stirring to bring the pH to 3.0. After complete dissolution of the added 1.8 g of wet 5%palladium on coal (Pd/C) (water content: 56%) (weight ratio: 10/1), three times he lost the installation of gaseous argon for creating inert atmosphere, three times he lost the installation of gaseous hydrogen to displace inert atmosphere, the reaction was carried out at 27°C for about 36 hours and to determine dibenzylamino product used thin-layer chromatography (TLC) (eluent a mixture of ethyl ether:n-hexane:methanol:triethylamine=2 ml:0.5 ml:6 drops:6 drops"). The reaction was stopped after using up all of the original materials.

After filtration with suction received light green liquid and drove under reduced pressure to remove the solvent and produce a dark green viscous liquid. Added about 16 ml of distilled water, stimulated dissolution using ultrasonic treatment, lowered the temperature to 5°C. using a bath of ice water, and brought the pH to 10-11 by addition of 2-normal aqueous sodium hydroxide solution to precipitate a large amount of white precipitate when the pH value was almost reached its final value. White precipitate was filtered under reduced pressure. The filtrate was extracted with dichloromethane (2×20 ml). The organic layers were combined and washed twice with a saturated aqueous solution of sodium chloride (NaCl) (10 ml each time), dried over anhydrous magnesium sulfate. After removal of the solvent obtained pale-yellow solid. The obtained solids were combined and dried with the formation of 2.14 g of product (yield: 72.6 per cent). Melting point: 100,8-102,7°C.

3. Obtain 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl}-2-methyl-9-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-it (the compound [formula (II)])

In the reaction flask was placed 100 ml of methanol, 10,27 g (0,04 mole) of the hydrochloride of 6-fluoro-3-piperidine-4-yl-1,2-benzisoxazole, 9,17 g (of 0.04 mole) of 3-(2-chloroethyl)-2-methyl-9-benzyloxy-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-it, 10 ml of Diisopropylamine and the reaction was conducted at 60°C for 14 hours. The solvent was distilled under reduced pressure, bavili water and chloroform (in sufficient quantity, q.s.), the pH was brought to 8 by adding 10%NaOH solution, the obtained chloroform extract is washed three times with water and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure with the formation of a viscous product, the dissolution of which at this point was added 100 ml of isopropanol, and the mixture is left to stand overnight. The crystalline precipitate was filtered to obtain 9.0 g of crude product.

Purification using column chromatography: column chromatography on silica gel using a mixture of chloroform-methanol (100:2)as eluent was carried out to obtain the pure product, the compound [formula (II)], in the amount of 5.6 g (yield: 32,8%), melting point: 174,7-178,3°C.

C. Synthesis of esters of compound [formula (II)] with aromatic carboxylic acids

General methods

The reaction scheme:

in which the fragment X represents aryl having 6-20 carbon atoms, such as phenyl, tolyl, methoxyphenyl, etc.

To 10 ml of anhydrous pyridine was added of 0.43 g (1 mmol) of the compound [formula (II)], dissolved under stirring at room temperature, dropwise added the acid chloride of an aromatic acid (2 mmol) and the reaction is carried out until the spot of the original substance will not disappear on thin-layer the chromatogram (TLC). The reaction mixture is poured into water, brought the pH to 9 by adding 10%aqueous NaOH solution and was extracted with chloroform three times (15 ml each time). The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure to obtain the product. The product was dissolved in 2 ml of anhydrous ethanol, and dropwise added 3 ml of a saturated solution of hydrogen chloride (HCl) in anhydrous ethanol and the mixture is left to stand overnight. The solid precipitate was filtered, washed with ethyl acetate, dried to obtain the hydrochloride aromatic 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-carboxylate.

The following compounds were synthesized and characterized, respectively, the above reaction scheme.

EXAMPLE 1:Synthesis of ester [formula (III)] of the compound [formula (II)] with aromatic carboxylic acids

3-{2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-benzoate below as an example.

To 10 ml of anhydrous pyridine was added of 0.43 g (1 mmol) of the compound [formula (II)], dissolved under stirring at room temperature, dropwise added 0.28 g (2 mmol) of benzoyl chloride and the reaction was carried out until the spot of the original substance is not isce what does thin the chromatogram (TLC). The reaction mixture is poured into water, brought the pH to 9 by adding 10%aqueous NaOH solution and was extracted with chloroform three times (15 ml each time). The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure to obtain the product. The product was dissolved in 2 ml of anhydrous ethanol, dropwise added 3 ml of a saturated solution of hydrogen chloride (HCl) in anhydrous ethanol and the mixture is left to stand overnight. The solid precipitate was filtered, washed with ethyl acetate, dried to obtain 0.33 g of the dihydrochloride of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-benzoate. The product was converted to the receipt of 0.30 g of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine-1-yl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-benzoate. Melting point is 138,6 is 140.7°C.

The following compounds were synthesized and characterized according to this method.

Connection 1.3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-benzoate

1H-NMR(CDCl3): 2,10-2,27 (8H, m,-CH2-), to 2.29 (3H, s,-CH3), 2,58, 2,78, 3,18 (6H, t, t, t, >N-CH2-), 3,91, 4,11 (2H, m, m, -CON-CH2-), 3,10 (1H, m,-≥-CH-), of 6.02 (1H, t, ≥-CH-O-), 7,02-8,06 (8H, m, Ar-H).

sup> 13SAMR: 20,61, 22,90, 23,79, 27,69(2C), 33,66, 34,27, 42,65, 48,73(2C), 50,74, 79,57, 99,70, 107,36, 114,31, 118,63, 126,83, 129,07(2C), 130,09(2C), 130,97, 133,02, 141,91, 143,75, 155,11, 157,00, 163,78, 165,58, 166,57.

Connection 2.3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methylbenzoate

Reaction conditions were essentially the same, except that instead of benzoyl chloride used 4-methylbenzoate to obtain 0.36 g of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methylbenzoate.

Melting point: 112,1-113,5°C.

1H-NMR (CDCl3): 2,04-2,34(8H, m, -CH2-), is 2.40(6H, s, -CH3), 2,56, 2,80, only 2.91 (6H, t, t, t, >N-CH2-), up 3.22(1H,m, -≥-CH-), 3,91, 4,11 (2H,m,m, -CON-CH2-), 5,96 (1H, t,≥-CH-O-), 6,98-7,99 (7H, m, Ar-H).

13C-NMR: 20,61, 21,40, 22,90, 23,79, 27,69(2C), 33,66, 34,27, 42,65, 48,73(2C), 50,74, 79,57, 99,70, 107,36, 114,35, 118,63, 125,84, 126,43, 127,21(2C), 129,23(2C), 141,90, 141,91, 143,75, 155,11, 157,00, 163,78, 165,58, 166,57.

Connection 3.3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methoxybenzoate

Reaction conditions were essentially the same, except that instead of 4-methylbenzylamine used 4-methoxybenzophenone to obtain 0.26 g of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrim the DIN-9-yl-4-methoxybenzoate, melting point 96,1-98,0°C.

1H-NMR(CDCl3): 2,08-2,22(6H,m,-CH2-), of 2.28(3H,c-CH3), 2,39(2H,t,-CH2-), 2,65, 2,82, with 3.27 (6H,t,t,t,>N-CH2-), 3,14(1H, m, -≥-CH-), 3,83(3H,c-OCH3), 3,89, 4,10 (2H,m,m, -CON-CH2-), to 5.93(1H,t, ≥-CH-0-), 6,91-8,10 (7H,m,Ar-H ).

13C-NMR: 20,61, 22,90, 23,79, 27,69(2C), 33,66, 34,27, 42,65, 48,73(2C), 50,74, 55,25, 79,57, 99,70, 107,36, 114,24(2C), 114,35, 118,63, 121,80, 125,84, 130,82(2C), 141,91, 143,75, 155,11, 157,00, 162,50, 163,78, 165,58, 166,57.

Connection 4.3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-perbenzoate

Reaction conditions were essentially the same, except that instead of 4-methylbenzylamine used 4-perbenzoate.

1NAMR: δ 1,94-2,12(6H, m,-CH2-), 2,19 (3H c CH3), 2,20-2,30(4H t-NCH2-), 2,48(2N t-CH2-), of 2.54(2H, t,-CH2N-), 2,58(1H, m >CH-), 2,61 was 2.76(2H, m-CH2-), 3,43-3,55 (2N t-CH2N), to 5.85(1H t>CHOC(C=O)-), is 6.61(1H, m, Ar-H), 7,17-8,03(6N m, Ar-H).

13C-NMR: 20,61, 22,90, 23,79, 27,69(2C), 33,66, 34,27, 42,65, 48,73(20, 50,74, 79,57, 99,70, 107,36, 114,31, 115,86(20, 118,63, 125,84, 126,36, 130,25(2C), 141,91, 143,75, 155,11, 157,00, 163,87, 164,88, 165,58, 166,57.

Melting point: 226,1-227,6°C (hydrochloride).

EXAMPLE 2: Synthesis of esters (carbonates) (formula (IV)) of the compound [formula (II)] with carbonic acid

A. General methods

The reaction scheme:

in which the Y fragment is from the battle saturated alkyl, having 1-20 carbon atoms, or unsaturated alkyl having 2-20 carbon atoms, or cycloalkyl having 4-20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and a variety of isomers, cyclohexyl, etc; or aryl having 6-20 carbon atoms, such as phenyl, tolyl, methoxyphenyl, etc.

The connection 5. Hydrochloride 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-ethylcarbonate

To 30 ml of anhydrous dichloromethane and 3 ml of anhydrous pyridine was added 2.0 g (4,69 mmol) of the compound [formula (II)], dissolved under stirring at room temperature, and then dropwise added 1.0 g (9,38 mmol) ethylchloride and the reaction led to the disappearance of spots of source materials on the thin layer of the chromatogram (TLC). The reaction mixture was poured in enough water, brought the pH to 9 by adding 10%aqueous NaOH solution and was extracted three times with dichloromethane (30 ml each time). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The residue was dissolved in 5 ml of anhydrous ethanol and then dropwise added 5 ml of a saturated solution of hydrogen chloride (HCl) in anhydrous ethanol. After standing overnight the solid precipitate was filtered, washed with ethyl acetate and yashili with the formation of 1.60 g of the hydrochloride of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-ethylcarbonate, melting point: 229,0-of 229.5°C.

1H-NMR(CDCl3): of 1.32(3H, t, -CH3), 2,02-2,60(8H,m,-CH2-), 2,39(3H,s,Ar-CH3), 2,40-3,47(6H,m, >N-CH2-), up 3.22(1H,m,-≥-CH-), 3,91, 4,11(2H,m,m,-CON-CH2-), to 4.23(2H,m,-OCH2-), 5,96(1H,t,≥-CH-O-), 7,01-7,22(3H,m,Ar-H ).

13SAMR: 13,93, 20,61, 22,90, 24,02, 27,69(2C), 32,10, 34,27, 42,65, 48,73(2C), 50,74, 62,40, 81,82, 99,70, 107,36, 114,31, 118,63, 120,82, 126,83, 148,20, 150,05, 155,11, 163,78, 165,08, 166,57.

Connection 6.The dihydrochloride of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-isobutylketone

To 30 ml of anhydrous dichloromethane and 3 ml of anhydrous pyridine was added 2.0 g (4,69 mmol) of the compound [formula (II)], dissolved under stirring at room temperature, and then dropwise added 1.29 g (9,38 mmol) isobutylphthalate and the reaction led to the disappearance of spots of source materials on the thin layer of the chromatogram (TLC). The reaction mixture was poured in enough water, brought the pH to 9 by adding 10%aqueous NaOH solution and was extracted three times with dichloromethane (30 ml each time). The extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The residue was dissolved in 5 ml of anhydrous ethanol and then dropwise added 5 ml of a saturated solution of hydrogen chloride (HCl) in anhydrous ethanol. After standing in the course is their nights solid precipitate was filtered, was washed with ethyl acetate and dried with the formation of 1.65 g of the dihydrochloride of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-isobutylketone, melting point: 242,1-243,5°C.

1H-NMR (DO-d6): to 0.88(6H,d,-<), 1,92-2,40 (9H,m,-CH2-, >CH-in), 2.25(3H,s, Ar-CH3), 2,99-of 3.12 (6H,m, >N-CH2-), 3,50(1H,m, -≥-CH-), 3,70, of 3.97 (6H,m,m, -CON-CH2-, -OCH2-, Ar-CH2-), of 5.55(1H,t, ≥-CH-O-), 6,56(1H, user., HCl), 7,31-8,18 (3H,m,Ar-H ), 11,02 (1H,user.,HCl).

13C NMR: 19,12(2C), 20,61, 22,90, 24,02, 27,83, 27,69(2C), 32,10, 34,27, 42,65, 48,73(2C), 50,74, 70,66, 81,82, 99,70, 107,36, 114,31, 118,63, 120,82, 126,83, 148,20, 150,05, 155,11, 163,78, 165,08, 166,57.

Connection 7.The dihydrochloride of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-n-intercorporate

To 30 ml of anhydrous dichloromethane and 3 ml of anhydrous pyridine was added 2.0 g (4,69 mmol) of the compound [formula (II)], dissolved under stirring at room temperature, and then dropwise added 1.42 g (9,38 mmol) intelcorporation and the reaction led to the disappearance of spots of source materials on the thin layer of the chromatogram (TLC). The reaction mixture was poured in enough water, brought the pH to 9 by adding 10%aqueous NaOH solution and was extracted three times with dichloromethane (30 ml each time). The extracts washed in the Oh, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The residue was dissolved in 5 ml of anhydrous ethanol and then dropwise added 5 ml of a saturated solution of hydrogen chloride (HCl) in anhydrous ethanol. After standing overnight the solid precipitate was filtered, washed with ethyl acetate and dried with education 1,72 g of the dihydrochloride of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-n-intercorporate, melting point: reach 232.5-233,6°C.

1H-NMR (DCO-d6): 0,86(3H,d,-CH3), 1,30-to 1.61(8H, m, -CH2-), 1,97-2,48 (8H,m,-CH2-), 2,32(3H,s, Ar-CH3), 2,99-3,71 (6H, m, >N-CH2-), 3,71 (3H, m, -≥-CH-Ar-CH2-), 3,50, 3,90 (6H, m, m, -CON-CH2-), of 4.16 (2H, m, -och2-),), of 5.55 (1H, t, ≥-CH-O-), 7,32-OF 8.25 (3H, m, Ar-H), 8,46 (1H, user., HCl), 22,26 (1H, user., HCl).

1SAMR: 13,99, 20,61, 22,42, 22,90, 24,02, 27,69(2C), 28,23, 28,48, 32,10, 34,27, 42,65, 48,73(2C), 50,74, 64,64, 81,82, 99,70, 107,36, 114,31, 118,63, 120,82, 126,83, 148,20, 150,05, 155,11, 163,78, 165,08, 166,57.

Connection 8.Hydrochloride 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-phenylcarbamate

To 10 ml of anhydrous dichloromethane and 1 ml of anhydrous pyridine was added 2.0 g (4,69 mmol) of the compound [formula (II)], dissolved under stirring at room temperature, and then dropwise added 1.48 g (9,38 mm is l) phenylcarbamate and the reaction led to the disappearance of spots of source materials on the thin layer of the chromatogram (TLC). The reaction mixture was extracted three times with dichloromethane (15 ml each time). The extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The residue was dissolved in 2 ml of anhydrous ethanol and then dropwise added 3 ml of a saturated solution of hydrogen chloride (HCl) in anhydrous ethanol. After standing overnight the solid precipitate was filtered, washed with ethyl acetate and dried with the formation of 1.51 g of the hydrochloride of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-phenylcarbamate. Melting point: 186,7-187,8°C.

1H-NMR (CDCl3): 2,03-2,60(8H,m,-CH2-), 2,43(3H,s,Ar-CH3), of 3.07, 3,11(6H,m, >N-CH2-), of 3.46(1H, m, -≥-CH-), 3,88, 3,98(2H, m,-CON-CH2-), the 5.65(1H, t, ≥-CH-O-), 6,78-7,40 (8H, m, Ar-H), 7,95 (1H, user., HCl).

13SAMR: 20,61, 22,90, TO 24.02, 27,69(2C), 32,10, 34,27, 42,65, 48,73(2C), 50,74, 81,82, 99,70, 107,36, 114,31, 118,63, 120,82, 121,48(2C), 125,60, 127,92, 130,09(2C), 142,58, 150,05, 150,35, 155,11, 163,78, 165,08, 166,57.

Melting point: 249,2-251,5°C.

Connection 9.Hydrochloride 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-para-nitrophenylarsonic

To 10 ml of anhydrous dichloromethane and 1 ml of anhydrous pyridine was added 2.0 g (4,69 mmol) of the compound [formula (II)], dissolved under stirring at room themes is the temperature value, then dropwise added at 1.91 g (9,38 mmol) para-nitrophenylphosphate and the reaction was carried out until the disappearance of the spots of source materials on the thin layer of the chromatogram (TLC). The reaction mixture was extracted three times with dichloromethane (15 ml each time). The extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The residue was dissolved in 2 ml of anhydrous ethanol and then dropwise added 3 ml of a saturated solution of hydrogen chloride (HCl) in anhydrous ethanol. After standing overnight the solid precipitate was filtered, washed with ethyl acetate and dried with education 1,69 g of the hydrochloride of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-para-nitrophenylarsonic.

1H-NMR (CDCl3): 1,78-2,47 (8H, m, -CH2-), to 2.35 (3H, s, Ar-CH3), 2,60, 2,95, to 3.36 (6H, m, >N-CH2-), or 3.28 (1H, m, -≥-CH-), 3,83 (1H, s, HCl), 3,95, a 4.03 (2H, m, -CON-CH2-), to 5.58 (1H, t, ≥-CH-0-), 6,93-8,10 (8H, m, Ar-H), 7,95 (1H, user., HCl).

13SAMR: 20,61, 22,90, TO 24.02, 27,69(2C), 32,10, 34,27, 42,65, 48,73(2C), 50,74, 81,82, 99,70, 107,36, 114,31, 118,63, 120,82, 122,18(2C), 125,18(2C), 127,92, 145,38, 148,20, 150,05, 155,11, 155,47, 163,78, 165,08, 166,57.

EXAMPLE 3: Test compounds, metabolisable with the formation of the active component, 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]feast midin-4-it, (compound [formula (II)]), in liver cells

40 μg of Compound 1 of Example 1 (or Compound 2, or Compound 3, or Compound 5 or Compound 6 or Compound 7 or Compound 8, or the Compound (9) was dissolved in 0,01M buffer solution of potassium phosphate (containing 1 mm NADPH (NADP.N), mixed with 25 μl of cells in human liver S9 (20 mg protein/ml, N), cultivated at 37°C for 2 hours, and then the mixture is put out of concentrated perchloric acid. After precipitation of the proteins were removed by centrifugation, the pH of the resulting solution supernatant is brought to 3 by adding a concentrated solution of potassium phosphate and again centrifuged. The obtained supernatant was directly injected into the HPLC instrument (HPLC, high performance liquid chromatography) analysis.

The results of metabolism are shown in Table 1. The extent of metabolism metabolisable compounds in the liver cells for 2 hours with the formation of the active component 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-it (the compound [formula (II)]) varied from 70% to 95%, depending on various ester groups.

Table 1
The extent of metabolism of the compounds in the cells of pécs is no
within 2 hours
ConnectionMetabolic rates (%)
Connection 189
Connection 278
Connection 387
Connection 595
Connection 692
Connection 793
Compound 894
Connection 989

EXAMPLE 4:The absolute bioavailability of the Test hound dog (Beagle) compound [formula (II)] and its prodrugs, compounds 1, 2, 3, 5, 6, 7 and 8

Twenty-one hound dog breed (Beagle), weighing about 10 kg, were divided into 7 groups, and introduced intragastrically connection 1, 2, 3, 5, 6, 7 and 8 in the dosage of 9.4 mmol/dog respectively. At predefined points in time took blood samples and measured the concentration of the active metabolite (compound [formula (II)]) and prodrugs in the blood. Meanwhile, three dogs (Beagle), weighing about 10 kg, intravenously introduced the compound [formula (II)] dose the information, equimolar to the prodrug, as a control group, and the measured concentration of the compound [formula (II)] in the blood.

The results are shown in Figure 1 and Table 2. Prodrugs in the body of the dog (Beagle) immediately metabolizability almost completely with the formation of the active metabolite, compound [formula (II)], parenteral, and concentrations of the parent compounds were very low (see: Figs). The results also showed that the indicators of the bioavailability of the prodrugs of the compound [formula (II)] were significantly higher than those for drug Invega (28%). In particular, prodrug carbonate type showed significant improvement in bioavailability.

EXAMPLE 6:Obtaining standard tablets for oral administration

Ingredients:
Compound 1, or Compound 6 or Compound 76%
Microcrystalline cellulose72%
The hypromellose8%
The dihydrate of the calcium hydrogen phosphate12%
Stearate mA is of 0,8%
Colloidal anhydrous silica1,2%

Tablets obtained by direct pelletizing, and each tablet contains 6 mg of the active ingredient (expressed for the compound [formula (II)]). Standard tablets for oral administration were subjected to dissolution tests, and the results are shown below in Table 3.

Table 3
The dissolution of standard tablets for oral administration
The time of dissolution (hours)248
The percentage of dissolution of the active ingredient (%)Connection 1356792
Connection 6437998
Connection 7457693

EXAMPLE 7: Getting capsules delayed release for oral introduction the Oia

A. Granules:
Compound 1, or Compound 6 or Compound 75%
Microcrystalline cellulose91%
The hypromellose4%

The granules obtained using a standard fluidized bed.

C. Coating:
Ethylcellulose85%
The hypromellose15%

After drying of the coating the coated pellets were placed in hard gelatin capsules, each capsule contained 6 mg of the active ingredient (expressed for the compound [formula (II)]), and the degree of coverage was 6%. The capsules were subjected to dissolution tests according to the method specified in the Pharmacopoeia of the people's Republic of China. The results are shown below in Table 4.

Table 4
Dissolving capsules delayed visualaid is ment for oral administration with Compound 1
The time of dissolution (hours)2481224
The percentage of dissolution of the active ingredient (%)Connection 18,926607694
Connection 68,819426889
Connection 75,322415982

1. The compound of formula (I),

where the chiral center (*) may have the R configuration or S, or RS (racemic mixture);
R is an aryl having the formula:

where the radicals R4 and R5 independently represent hydrogen, a saturated alkyl having 1-6 carbon atoms or alkoxy having 1-6 carbon atoms, unsaturated alkyl having 2-6 carbon atoms, HE, Cl, F, CN, is karboksilnuyu and ester group; preferably, hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine or carboxyl,
rich alkoxygroup having 1-20 carbon atoms, or unsaturated alkoxygroup having 2-20 carbon atoms, or cycloalkyl group having 4-20 carbon atoms, or arylalkyl group having the formula:

where R6 and R7 independently represent hydrogen, saturated alkyl group having 1-6 carbon atoms, or CNS group having 1-6 carbon atoms, unsaturated alkyl group having 2-6 carbon atoms, HE, Cl, F, CN, carboxyl and ester group; preferably, hydrogen, methyl, ethyl, metaxylene, ethoxyline group, fluorine or carboxyl; or
its optical isomer or pharmaceutically acceptable salt.

2. The compound of formula (I) according to claim 1, characterized in that the compound of formula (I),
R represents a saturated alkoxy having 1-10 carbon atoms or unsaturated alkoxy having 2-10 carbon atoms or cycloalkane having 4-10 carbon atoms.

3. Salt of the compounds of formula (I) according to claim 1, wherein the salt compound is a hydrochloride, sulfate, maleate, succinate, and other salts formed with pharmaceutically acceptable acid.

4. The compound according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of:
3-{-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-benzoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-methylbenzoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-methylbenzoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methylbenzoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-methoxybenzoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-methoxybenzoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methoxybenzoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-perbenzoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-perbenzoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-perbenzoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-carboxybenzoyl,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-methylcarbonate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-ethylcarbonate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-propylmalonate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-isopropylcarbonate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-BUTYLCARBAMATE,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-isobutylketone,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-tert-BUTYLCARBAMATE,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-9-yl-2-methylbutanoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-n-intercorporate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-intercorporate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-intercorporate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)--piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-isopentylamine,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-neopentanoate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-exercebant,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-cyclohexylcarbamate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-phenylcarbamate,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-methylphenylcarbinol,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-methylphenylcarbinol,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methylphenylcarbinol,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-methoxyphenylalanine,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-methoxyphenylalanine,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-methoxyphenylalanine,
3-{-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-2-ftorhinolonami,
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-3-ftorhinolonami, and
3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-9-yl-4-ftorhinolonami, and
their various salts and optical isomers.

5. Pharmaceutical composition for treatment of mental disorders, comprising a compound according to any one of claims 1 to 4, or its optical isomer, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, in which the composition is injected oral, injectable, transdermal, intranasal or mucosal by injection or by inhalation.

7. The pharmaceutical composition according to claim 5, which is represented in the dosage form in tablet form for oral administration, capsules delayed release.

8. The use of compounds according to any one of claims 1 to 4, or an optical isomer or pharmaceutically acceptable salts, for the manufacture of a medicinal product as an antagonist of neurotransmitters to ensure appropriate mental disorders such as schizophrenia.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted heteroaryl derivatives of general formula I: , wherein: A means N, CR7-10, with A at the most twice meaning N; W means O, S or NR4, the values B, C, R7-10 are presented in clause 1 of the patent claim. The method for preparing the compound I is described.

EFFECT: compounds show analgesic activity that enables using them for a variety of diseases, especially acute pain, neuropathic, chronic or inflammatory pain.

16 cl, 2 tbl, 307 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are produced new diazepane substituted compounds representing various heterocyclic systems, including condensed, pharmaceutical compositions containing said compounds.

EFFECT: producing the compounds and compositions for preventing and treating neurological and mental disorders and diseases with involved orexin receptors.

13 cl, 1 tbl

New compounds // 2458920

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or to its pharmaceutically acceptable salts wherein -A-(R1)a means a group; -B-(R2)b means a group specified in the patent claim 1, R3 means hydrogen; X means CH2 or O; and Y means CH2. Also, the invention refers to a pharmaceutical composition exhibiting FGFR inhibitor activity on the basis of the declared compound.

EFFECT: there are produced new compounds and based pharmaceutical composition which can find application in medicine for preparing a cancer drug.

8 cl, 1 tbl, 180 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to to new compounds of formula (1) or their pharmaceutically acceptable salts, optionally in the form of (1S)-isomers showing the properties of polo-like kinase (serine-threonine kinase) PLK1 inhibitor. In the compounds of formula (1) , R1 represents a halogen atom; a lower alkyl group having 1-2 carbon atoms, which can be substituted by 3 fluorine atoms; or a cyclopropyl group; R2 represents a hydrogen atom; one of R3 and R4 represents a hydrogen atom while the other one of R3 and R4 represents: a) a lower alkyl group substituted by NRaRb wherein each Ra and Rb, which can be identical or different, represent a lower alkyl group, or each Ra and Rb, which can be different, represent a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3-6 carbon atoms wherein a cycloalkyl group can be substituted by one ore more substitutes which can be identical or different and specified in a group 1): a lower alkyl; b) a 4-6-member aliphatic heterocyclic group specified in an azetidinyl group, a pyrrolidinyl group and a piperidinyl group; c) a lower alkyl group substituted by a 4-6-member aliphatic heterocyclic group specified in an azetidinyl group, a pyrrolidinyl group and a piperidinyl group; d) a 6-member aromatic heterocyclic group specified in a pyridyl group wherein each of an aliphatic heterocyclic group and an aromatic heterocyclic group can be substituted by substitutes specified in a group 1) described above; R5 represents a hydrogen atom, a cyano group, a halogen atom or a lower alkyl group.

EFFECT: compounds can find application in treating oncological diseases.

10 cl, 4 dwg, 8 tbl, 42 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new 1H-pyrrolo[3,4-b]quinoline-3,9(2H, 4H)-dione derivatives of general formula 1

wherein R1=Alk, Ar; R2=H, Alk, halogen; R3=H, Alk, halogen; R4=H, Alk, halogen; R5=H, Alk, halogen; R6=CH2Ar, R7=Ar, Also, the invention refers to a method for preparing them.

EFFECT: there are prepared new 1H-pyrrolo[3,4-b]quinoline-3,9(2H, 4H)-dione derivatives possessing anti-tuberculosis activity.

3 cl, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel azaindole derivatives, having JAK-2 and JAK-3 kinase inhibiting activity, or pharmaceutically acceptable salts thereof. In formula (I): R3 denotes H; X1 denotes N or CR4; R2 denotes H, COOH, COOR' or CONHR'; R4 denotes H, F, R, OH, OR', COR', COOH, COOR', CONH2 or CN; or R2 and R4, taken together, form a benzene ring optionally substituted with 1-2 R10; R' denotes C1-3-alkyl or C1-3-alkenyl, each optionally substituted 1-2 R5; each R5 is independently selected from CN, unsubstituted C1-2alkyl, or two groups R5 together with a carbon atom with which they are bonded form a cyclopropyl ring; each R10 is independently selected from halogen, OCH3 or OH; R1 denotes or , R is H or denotes C1-2alkyl, optionally substituted with 1-3 R11; R6 denotes C1-4alkyl, optionally substituted with 1-5 R12; values of radicals R7 -R9, ring A, R11 -R14. The invention also relates to a pharmaceutical composition containing said compounds and a method of treating or reducing severity of a pathological condition such as allergy, asthma, amyotrophic lateral sclerosis, multiocular sclerosis, graft rejection, rheumatoid arthritis, solid malignant tumour, haematologic malignant disease, leukaemia, lymphoma and myeloproliferative disorders.

EFFECT: high efficiency of using the compounds.

41 cl, 6 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula , where R1 denotes OH, OPO3H2 or OCOR5; R2 denotes H, OH or OPO3H2; A denotes N or CR6; R3 denotes fluorine; R4 denotes H, C1-3alkyl or C3-6cycloalkyl; R5 denotes an alanine residue; R6 denotes H, C1-6alkoxy group or halogen; and n=0 or 1; and to pharmaceutically acceptable salts of compounds of formula I. The invention also relates to a pharmaceutical composition having antibacterial activity, and to use of compounds of formula I to obtain a medicinal agent for preventing or treating bacterial infections.

EFFECT: compounds of formula I, having antibacterial activity.

14 cl, 3 dwg, 2 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention offers compounds presented by general formula (I): or their pharmaceutically acceptable salts wherein R1, R2, R3 and R4 are presented in the description and exhibit substantial COMT inhobotory activity. Besides, the present invention described pharmaceutical compositions inhibiting catechol-O-transferase activity which contain the compound or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier.

EFFECT: there are declared pharmaceutical combinations for treatment or prevention of Parkinson's disease which contain (1) the pharmaceutical composition containing the compound under any cl 1-8 or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier, and (2) at least one compound specified in L-dope or carbidole.

10 cl, 9 ex, 17 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (VI): or its pharmaceutically acceptable salts; wherein n is equal to 0, 1, 2 or 3; R1 means -OH, H; R2a means OH, -CH3, provided at least one of R1 and R2a means -OH;R3 means Cl, Br, cyclopropyl, branched C3-5alkyl R4a means H; R8 means H; wherein the fragment: may be one of the groups B8, B35, B36, B37, B38, B39, B40, B41, B42, B43, B45, B46, B48, B54, B56, B58, B59, B61, B62, B71, B72, B74, B75, B76, B77, B78, B79, B80, B81, B82, B84, B86, B87, B88, B89, B90, B91, B93, B94, B95, B96, B97, B98, B99, B100 and B101 wherein the values are disclosed in the patent claim 1.

EFFECT: compounds show Hsp90 inhibitory activity that enables using them for treating the diseases caused by abnormal cell growth in mammals.

26 cl, 8 dwg, 2 tbl, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine-3-yl derivatives of formula (I)

wherein A represents *-CONH-CH2-, *-CO-CH=CH-, *-CO-CH2CH2-, or wherein asterisks specify a link which binds with a pyridine group of formula (I); R1 represents hydrogen, C1-4alkyl or chlorine; R2 represents C1-5alkyl or C1-4alkoxy group; R4 represents hydrogen or C1-4alkyl; R4 represents hydrogen, C1-4alkyl; C1-4alkoxy group or halogen; R5 represents -CH2-(CH2)n- CONR51R52, -CO-NHR51, 1-(3-carboxyazetidinyl)-2-acetyl, hydroxy group, hydroxyC2-5alkoxy group, di-(hydroxy C1-4alkyl) C1-4alkoxy group, 2,3-dihydroxypropoxy group, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxy group, -OCH2-CH(OH)-CH2-NR51R52 or -OCH2-CH(OH)-CH2-NHCOR54; R51 represents hydrogen, C1-3alkyl, 2-hydroxyetyl, 2-hydroxy-1-hydroxymethyletyl or 2,3-dihydropropyl; R52 represents hydrogen; R54 represents hydroxymethyl; n represents 0 or 1; and R6 represents hydrogen, C1-4alkyl or halogen; and a salt of said compound. Also the invention describes a pharmaceutical composition for prevention or treatment of diseases or conditions associated with activated immune system, on the basis of the compound of formula I and application of said compounds for preparing said pharmaceutical composition.

EFFECT: there are produced and described new compounds which are especially active as immunomodulatory agents.

18 cl, 92 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I):

, where: R=NO2, or and Het denotes an azolyl radical selected from nitroazolyl and tetrazolyl radicals; except 3- and nitro-4-(4-nitro-1,2,3-triazol-1-yl)furazan. The invention also describes a method of producing a compound of formula I and an energy composition based on said compounds.

EFFECT: compounds have high energy characteristics, low sensitivity and high thermal stability.

11 cl, 7 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound with formula (I): where the values of radicals Q, R1, R2, R3, R4, X and Y are as specified in Clause 1 of the patent claim or to a pharmaceutically acceptable salt of such compound or a compound ether hydrolysed in vivo provided such compound is not: {(3S)-1-[5-(adamantan-1-ylcarbamoyl)pyridine-2-yl] piperidine-3-yl} acetic acid or {(3S)-1-[5-(cyclohexylcarbamoyl)-6-(piperazine-1-yl) pyridine-2-yl] piperidine-3-yl} acetic acid or a pharmaceutically acceptable salt thereof or a compound ether hydrolysed in vivo. Additionally, the invention relates to a pharmaceutical composition containing a compound with formula I for treatment of metabolic syndrome, Type II diabetes, adiposity etc and to application of such compound with formula I for manufacture of a medication to be applied for causing an inhibition effect with regard to 11βHSD1 with a homoiothermal animal.

EFFECT: produced and described is a new compound possessing inhibition activity with regard to Type 1 human 11-β-hydroxisteroiddehydrohenase enzyme (11βHSD1).

15 cl, 187 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formulae (I) and (III), as well as isomers or pharmaceutically acceptable salts thereof: where the values of radicals are given in claim 1 and 5. The invention also relates to a pharmaceutical composition based on said compounds, which has vanilloid receptor antagonist activity, use of said compounds to produce a medicinal agent for preventing or treating a condition which is associated with aberrant expression and/or aberrant activation of the vanilloid receptor. Described also is a method of producing a compound of formula III.

EFFECT: novel compounds which can be used as vanilloid receptor antagonists, for preventing or treating diseases are obtained and described.

40 cl, 281 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula

wherein A, R1, R2, R3, R4, R5 and R6 are presented in the description, preparing and using them as pharmaceutically active compounds as immunomodulatory agents.

EFFECT: preparing the pharmaceutical composition showing agonist activity with respect to S1P1/EDG1 receptor and using it for prevention and treatment diseases or disorders associated with activated immune system.

20 cl, 244 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I, as well as to their physiologically acceptable salts wherein: X means NH; R1 means (C1-C6)-alkyl; R2 means OH; R2' means H; R5' means (C1-C6)-alkylene-O-S(O)2-R6; R3, R3', R4, R4' and R5 independently mean H, OH, (C1-C6)-alkylene-O-S(O)p-R6, O-(CH2)m-phenyl; at least one of the radicals R3, R3', R4, R4' and R5 has the value -O-(CH2)m-phenyl; R6 means OH; m=1; p=2.

EFFECT: compounds can find application in medicine, eg as lipid-lowering agents.

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