Spyro(2h-1-benzopyrane-2,4'-piperidine) derivatives as glycine transport inhibitors

FIELD: pharmaceutical chemistry, in particular pharmaceutical compositions.

SUBSTANCE: new spyro(2H-1-benzopyrane-2,4'-piperidine) derivatives of general formula I

and pharmaceutically acceptable salts thereof are disclosed. In formula dotted line is optional bond; Y is 1-4 substituents independently selected from hydrogen, halogen, C1-C4-alkyl, optionally substituted with one or more halogen, C1-C6-alkyloxy, optionally substituted with halogen or C3-C6-cycloalkyl, C2-C6-alkenyloxy, C2-C6-alkinyloxy, C3-C6-cycloalkyloxy, C6-C12-aryloxy, arylalkyloxy, pyridilmethoxy, SR3, NR3R4, OSO2R5, and NR3SO2R4; or two Y together may form O-(CH2)n-O or O-(CF2)n-O, wherein n is 1 or 2: or Y is condensed C5-C6-aryl group; X is 1-3 substituents independently selected from hydrogen, halogen, hydroxyl, C1-C6-alkoxy, and C1-C4-alkyl; R1 is hydrogen, C1-C4-alkyl, or C6-C12-aryl; R2, R3, and R4 are independently hydrogen or C1-C4-alkyl; R5 is C6-C12-aryl. Also disclosed are pharmaceutical compositions including said derivatives and having activity in relation to CNS.

EFFECT: new compounds with valuable pharmacological action.

9 cl, 1 tbl, 83 ex

 

The present invention relates to derivatives of Spiro[2H-1-benzopyran-2,4’-piperidine], to pharmaceutical compositions comprising them, and to the use of these derivatives of Spiro[2H-1-benzopyran-2,4’-piperidine] in therapy.

The simplest αthe amino acid glycine, which has many important functions in the Central nervous system (CNS) of mammals. Together with γ-aminobutyric acid (GABA) is the primary post-synaptic inhibitor conduction of nerve impulses in the spinal cord and in the brain stem, through the ligand, located at the entrance of the ion channels. An antagonist of the interaction of glycine with these receptors may be the alkaloid strychnine. In this regard, these receptors are considered as glycine receptors, sensitive to strychnine”. Glycinergic neurotransmission important for the implementation and regulation of visual, auditory, and motor signal systems. Glycine is an obligatory coagonist acting together with the glutamate receptor N-methyl-D-aspartate (NMDA). Thus, glycine is used in the circuit of the conduction of nerve excitation modulating the action of glutamate is the main neurotransmitter in the circuit conduction in the Central nervous excitation. In addition, this amino acid plays a role in the metabolism of peptides and proteins, including the exchange of monochloro the data connections.

Regulation of the availability of glycine to participate in the above processes may influence their functioning and to provide a means for treating many diseases and conditions. One of the main processes controlling the concentration of free glycine near the strychnine-sensitive” and “strychnine-insensitive receptor glycine, is, in addition to metabolism, the functioning of selective vector control with high affinity to the glycine. These proteins can actively limit the spread of glycine beyond the immediate environment of the receptors, thus supporting the spatial and temporal accuracy activation of the receptor. Quick selection of a mediator in neuronal or glial cells using the vector also contributes to the conservation of glycine for the next release.

In the cloning vector glycine identified two main classes: GlyT-1 and GlyT-2. GlyT-1 is expressed by the entire brain, with the highest mRNA level detected in the caudal areas and cells are localized predominantly in glial area. Kim et al (Kirn et al., Molecular Pharm. 1994, 45, 608-617) identified three isoforms of GlyT-1: 1a, 1b, and 1C, resulting from differential splicing and use of the exon. Recently in the application for the European patent E Is 951543 (Allelix Neuroscience, Inc.) been disclosed cloning and expression of other human isoforms GlyT-1d.

According to immunochemical studies of the distribution of GlyT-2 clearly corresponds to the localization of the inhibitor “strychnine-sensitive glycine receptors, particularly in the spinal cord.

It can be expected that through the regulation of the level of glycine in the synapses, vector GlyT-1 and GlyT-2 will be selectively influence, respectively, on the activity of NMDA receptors and strychnine-sensitive glycine receptors.

Compounds that alter the functional activity of vectors glycine can lead to changes in the level of glycine in the tissues, and therefore can be used in the treatment of many painful conditions. Such painful conditions include those conditions that are associated with reduced or degraded functioning of NMDA receptors, namely:

psychosis, depression, dementia and other forms of violations cognitive abilities, such as a disorder of attention. The NMDA receptors are also involved in the pathogenesis of States arising from the death of neuronal cells and neurodegeneration, such as, for example, hemorrhage (head injury), Alzheimer's disease, Parkinson's disease and Huntington's disease. Increased inhibition glycinergic a nerve impulse that occurs when Engibarov the AI activity GlyT-2 or GlyT-1, can be used in the treatment of muscle hyperactivity associated with muscle spasticity, mioclauniei and epilepsy. Compounds that increase the level of glycine in the spinal cord, may also have analiticheskii properties.

Compounds that inhibit the glycine transport via vector Gly-T1 or Gly-T2, are disclosed in WO 97/45115 (Trophix Pharm. Inc.), in WO 97/45423 (Trophix Pharm. Inc.), in WO 99/34790 (Allelix Neuroscience Inc.) and in WO 00/07978 (Akzo Nodel N.V.) as compounds useful in the treatment of the above neurological and neuropsychiatric diseases. Based on the foregoing, there is a need for additional compounds suitable for treatment of mental and neurological diseases, particularly such compounds which have selective pharmacological profile.

It was found that derivatives of Spiro[2H-1-benzopyran-2,4'-piperidine], having a General formula I

where

the dotted line indicates an optional bond;

Y denotes 1-4 substituent, independently selected from hydrogen, halogen, (C1-6)alkyl (optionally substituted by one or more Halogens), (C1-6)alkyloxy (optionally substituted by one or more halogen or (C3-6)cycloalkyl), (C2-6)alkenylamine, (C2-6)alkyloxy, (C3-6)cycloalkane, (C6-12)aryloxy, (C7-15)Ari is alkyloxy, heteroaromatic, heteroarylboronic, SR3, NR3R4, OSO2R5and NR3SO2R4;

two substituent Y may together form O-(CH2)n-O or O-(CF2)n-O, where n is 1 or 2; or Y represents a condensed (C5-6)aryl group;

X denotes 1-3 substituent, independently selected from hydrogen, halogen, hydroxy, (C1-4)alkyloxy, SR3, NR3SO2R4and (C1-4)alkyl, optionally substituted with halogen;

r1denotes hydrogen, (C1-4)alkyl or (C6-12)aryl;

R2, R3and R4denote independently hydrogen or (C1-4)alkyl;

r5means (C1-4)alkyl (optionally substituted by one or more Halogens) or (C6-12)aryl (optionally substituted C1-4)alkyl);

or their pharmaceutically acceptable salt

selectively inhibit glycine transport via carrier GlyT-1 person, compared with participation of vector GlyT-2 people, and can be used in the treatment or prevention of schizophrenia, depression, dementia and other forms of violations cognitive or neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease, or muscle hyperactivity associated with muscle spasticness is about, mioclauniei and epilepsy.

The term "(C1-6)alkyl" in the context of the definition of formula I denotes an alkyl group branched or straight chain containing 1-6 carbon atoms, type exile, penttila, neopentyl, (2,2-dimethylpropyl), butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl. Similarly, the term (C1-4)alkyl refers to an alkyl group containing 1-4 carbon atoms.

The term "(C1-6)alkyloxy" (C1-6)alkyl means a branched or unbranched alkyl group defined above. (C1-6)alkyloxy group may be substituted by 1-3 Halogens, or (C3-6)cycloalkyl, which means a cyclic alkyl group containing 3 to 6 carbon atoms, type cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Examples of such substituted (C1-6)alkyloxy groups include cryptometrics, cyclopropylmethoxy.

The term “halogen” means F, Cl, Br or I. In the case where halogen represents the substituents on the alkyl group, preferred F. the Preferred halogen-substituted group is trifluoromethyl.

The term "(2-6)alkenyl", such as used in the term (C2-6)alkenylamine, means a branched or remotemachine alkenylphenol group containing 2-6 carbon atoms, such as ethynyl (vinyl), 2-propenyl allyl), Isopropenyl and 2-butenyl.

The term "(2-6)quinil", such as used in the term (C2-6)alkyloxy, means a branched or remotemachine alkylamino group containing 2-6 carbon atoms, such as propargyl.

The term "(6-12)aryloxy"used in the definition of formula I, (C6-12)aryl means an aromatic hydrocarbon group containing 6 to 12 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl. These aromatic groups may be substituted with halogen or (C1-4)alkyl or (C1-4)alkyloxy, where (C1-4)alkyl has the above meaning and may be substituted with halogen or (C1-4)alkyloxy.

The term "(C7-15)arylalkyl"used in the definition of formula I means arylalkyl group containing from 7 to 15 carbon atoms, and specified an alkyl group represents a (C1-6)alkyl group and the above aryl group is (C6-12)aryl, as defined previously. Phenyl(C1-6)alkyl groups are preferably arylalkyl groups such as benzyl.

The term “heteroaryl”used in the term heteroaromatic, means a substituted or unsubstituted aromatic group containing 6 to 12 carbon atoms and comprising at least one heteroatom selected from N, O and S type, for example, imidazolyl, teinila, bastianini, chinoline and indolyl. Heteroaryl group may bear substituents described for the aryl group.

Heteroallyl groups are similar (7-15)arylalkyl groups comprising at least one heteroatom selected from N, O and S.

In the definition of formula I Y may denote condensed (C5-6)aryl group, which means that Y is a 5 - or 6-membered aromatic ring condensed with the benzene ring to which X is attached to education (C11-12) aromatic ring system, like naphthalene or indene ring.

In addition to the definition of R1, O-R1group in formula I can be any other group, from which can be obtained (in vivo) free acid (R1denotes hydrogen). In the technique known such alternative predecessors acid or prodrugs, such as ester or amide derivatives, which are included in the scope of the present invention.

Derivatives of Spiro [2H-1-benzopyran-2,4’-piperidine] of the formula I and their salts may contain one or more stereogenic centers and can exist as stereoisomers. In the scope of the present invention included these stereoisomers and enantiomers of compounds of formula I and their sole is, which is essentially free of the other enantiomer, i.e. contain less than 5%, preferably less than 2%, and especially less than 1%, as well as mixtures of such stereoisomers in any ratio, including a racemic mixture, which contains essentially equal amounts of the two enantiomers.

Preferred are derivatives of Spiro[2H-1-benzopyran-2,4’-piperidine] of the formula I, in which the dotted line indicates the relationship, and more preferred are those compounds in which, in addition, R1and R2both represent hydrogen.

Especially preferred derivatives of Spiro[2H-1-benzopyran-2,4’-piperidine] according to the present invention and their salts correspond to the compounds of the formula I, in which the dotted line represents a bond, R1and R2denote hydrogen and Y represents a substituent in the para-position, selected from chlorine, bromine, (C1-4)alkyloxy, (C1-4)alkenylamine, (C1-4)alkyloxy and NR3R4and 1 or 2 substituent in the meta position selected from halogen, while preferred is fluorine. Specific examples of the preferred substitution for Y include: 3-fluoro-4-methyl, 3-fluoro-4-chloro, 3-fluoro-4-dimethylamino and 3.3-debtor-4-dimethylamino. Especially preferred compounds of formula I in which Y represents 3-fluoro-4-alkyloxy, in particular 3-fluoro-4-n-propoxy and 3-FPO is-4-n-butoxy, and 3,5-debtor-4-alkyloxy.

Derivatives of Spiro[2H-1-benzopyran-2,4’-piperidine] the General formula I can be obtained by using the sequence of reactions in which the 2’-hydroxyacetophenone derivatives of the formula II, where X has the above values are used as starting materials, and which are either readily available commercially or can be obtained by synthesis using methods known to experts in the field of organic synthesis. Carry out the condensation of 2’-hydroxyacetophenone derivatives II with 1-methyl-4-piperidone [R denotes methyl; alternatively, can be used 1-benzyl-4-piperidone (R denotes benzyl), benzyl group is often easier removed than a methyl group (see diagram C)] in methanol solution in the presence of pyrrolidine to obtain derivatives of N-methyl-Spiro[2H-1-benzopyran-2,4’-piperidine]-4(3H)-she, having the formula III, shown As:

Scheme A.

Spiro-keto derivatives of the formula III. then processed, as shown in the diagram, using a Grignard reagent of the formula IV where Y has the above meaning, in a suitable solvent, such as tetrahydrofuran, to obtain after treatment with acid derivatives of 4-aryl-N-methyl - or N-benzyl-Spiro[2H-1-benzopyran-2,4’-piperidine] formula V.

The scheme of the Century

Alternatively, the compounds of formula V can be obtained by transformation of Spiro-keto derivatives of the formula III, where R denotes H, methyl or benzyl, in inatitute derivative III’ followed by the binding assays Suzuki derived from phenylboronic acid IV (the scheme’).

Scheme”.

N-dezalkilirovania compounds of formula V using 1-chloroethylphosphonic in a chlorinated solvent such as 1,3-dichloropropan or dichloromethane, leads to the production of the intermediate in the form of derivatives of 4-aryl-Spiro[2H-1-benzopyran-2,4’-piperidine] of the formula VI, which is then subjected to alkylation reaction with HalCH2R2-COOR1where R1can imagine (With1-4)alkyl or (C6-12)aryl, R2has the previously mentioned meaning and Hal represents halogen, preferably bromine, to obtain the derivatives of 4-aryl-Spiro[2H-1-benzopyran-2,4’-piperidine] formula I, as shown in the diagram, ester group which is hydrolyzed to form compounds of the formula I, where R1denotes hydrogen.

Scheme C.

In the case when the desired Grignard reagent of the formula IV is not available commercially, it is produced from the corresponding pomarina using standard procedures (The Handbook of Grignard Regents, ed. G.S. Silverman and P.E. Rakita, 1996, Marcel Dekker, New York).

Compounds according to the present invention can be used in the treatment of schizophrenia, depression, dementia and other forms of violations cognitive abilities, for the treatment or prevention of neurodegenerative disorders that occur after hemorrhage(stroke or head injury, for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington, to treat muscle hyperactivity associated with muscular spasticity, mioclauniei and epilepsy, for the treatment or prevention of pain, mood disorders or disorders associated with impaired learning ability.

Compounds according to the present invention may have one or more stereogenic centers and can be obtained in the form of pure stereoisomers or mixtures of stereoisomers. The level technique known methods of asymmetric synthesis, resulting in pure stereoisomers and which include, for example, synthesis of chiral induction, enantioselective enzymatic hydrolysis of ester, the crystallization of salts derived from optically active acids and racemic mixtures, separation of stereoisomers or enantiomers by chromatography on chiral environments or chromatography in direct phase or reversed phase. Indicated which these methods are described, for example, in Chirality in Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley).

Pharmaceutically acceptable salts of compounds of formula I can be obtained by treating the free base of the compounds of formula I with a mineral acid, such as hydrochloric acid, phosphoric acid, sulfuric acid, preferably hydrochloric acid, or organic acid, such as, for example, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonate acid and other

Pharmaceutically acceptable salts of the compounds of formula I in which R1denotes hydrogen, can be obtained by treating acid or zwitterionic forms of these compounds with an organic base or inorganic base, such as sodium hydroxide, potassium or lithium.

Another object of the invention are pharmaceutical compositions comprising a derivative of Spiro[2H-1-benzopyran-2,4’-piperidine] of the formula I or its pharmaceutically acceptable salt in a mixture with pharmaceutically acceptable additives.

Pharmaceutical compositions applicable in accordance with the present invention include derived Spiro[2H-1-benzopyran-2,4’-piperidine] of the formula I or the pharmacist who Cesky acceptable salt in a mixture with pharmaceutically acceptable additives and optionally other therapeutic agents. The term “acceptable” means compatible with this agent with other ingredients of the composition and emissions of the recipient. The composition can be obtained using standard techniques, such as, for example, described in the standard manual Gennaro et al., Remington''s Pharmaceutical Science, (18 th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture).

Compositions include, for example, such compositions, which are suitable for oral, sublingual, intranasal, subcutaneous, intravenous, intramuscular, topical and rectal and other introduction, in the form of a standard dosage forms.

For the case of oral administration the active ingredient may be presented as discrete units such as tablets, capsules, powders, granular, tools, solutions and suspensions.

For the case of parenteral administration of the pharmaceutical composition according to the present invention can be represented as a single dose or in the form of containers with multiple dose, in particular for the injection of liquids in predetermined amounts, for example, in sealed vials and vials and may be stored in a freeze dried (lyophilized) form, which requires only the addition of sterile liquid carrier, for example water, before use.

Compounds according to the present izobreteny may be people in a dose of 0.001 to 50 mg per kg of body weight, preferably, in a dose of 0.01 to 20 mg per kg of body weight.

The present invention also includes a pharmaceutical composition specified above, in combination with packaging material suitable for this composition, and this package includes instructions for use of the composition with the aim described above is applied.

The invention is illustrated using the following examples.

Basic notes.

All mass spectrometric analyses are conducted either using devices PE SCIEX API 150EX, or PE SCIEX API

365. The melting point is not corrected and were determined using either of the devices of the Leica Galen III or Leica VMHB System Kofler.

Example 1

Hydrochloride of 1’-carboxymethyl-7-methoxy-4-perspire[2H-1-benzopyran-2,4’-piperidine]

Stage A: 7-methoxy-N-methylspiro[2H-1-benzopyran-2,4’-piperidine]-4(3H)-he

To a stirred solution of 2-hydroxy-4-methoxyacetophenone (4,08 g, 24,58 mmol) in anhydrous methyl alcohol (60 cm3) in a dry nitrogen atmosphere was added 1-methyl-4-piperidinol (3 cm3, 24,58 mmol) and then pyrrolidine (4 cm3, 47,92 mmol) and the solution is heated to the boiling temperature under reflux. After 7 hours, add another portion of 1-methyl-4-piperidine (0.6 cm3, 4.76 mmol) and the mixture is heated to boiling point under reflux for a further 4.5 hours. Then CME and allow to cool to room temperature, then volatile fractions are removed under reduced pressure. The resulting oil is treated with dichloromethane (100 cm3), washed with water (5×100 cm3) and dried over anhydrous sodium sulfate to obtain a dark viscous oil (6,33 g of 24.25 mmol), which partially crystallizes upon standing for a long period of time.

Stage: 7-methoxy-N-methyl-4-perspire[2H-1-benzopyran-2,4'-piperidine]

To a stirred solution of 7-methoxy-N-methylspiro[2H-1-benzopyran-2,4’-piperidine]-4(3H)-she (to 6.19 g, 23,72 mmol) in anhydrous tetrahydrofuran (80 cm3) in an atmosphere of anhydrous nitrogen is added dropwise a solution of panelbased magnesium in tetrahydrofuran (40 cm3, 1.0 M, 40 mmol), maintaining the reaction temperature below 30°C. After complete addition, the reaction mixture was stirred at room temperature for 2.5 hours, by this time, the reaction is not yet completed, but the Grignard reagent is missing. Next, carefully add even a portion of panelbased magnesium (13,3 cm3) and the reaction mixture was stirred over night. Add water (30 cm3and then a saturated aqueous solution of ammonium chloride (30 cm3). In vacuum to remove volatile products and then the resulting material is treated with diethyl ether (100 cm3) and water (100 cm3). Separate the organic layer and the water part extragere the t diethyl ether (2× 100 cm3). The combined extracts washed with water (3×100 cm3), dried over sodium sulfate and the ether removed in vacuo. The residue is triturated with a little diethyl ether and the resulting crystals are separated by filtration under vacuum (of 4.57 g, 12, and 15 mmol), 51%). The solid material absorb ethanol (75 cm3) and treated with hydrochloric acid (75 cm3, 2 h), then begin heating to the boiling temperature under reflux for 1.5 hours. The solution is concentrated under reduced pressure until the onset of crystallization. The mixture is then cooled and the solid material is separated by filtration under vacuum. Then the material is treated with a mixture of water (300 cm3), a saturated aqueous solution of potassium bicarbonate (50 cm3) and diethyl ether (650 cm3and shake. The aqueous layer was separated and extracted with diethyl ether (2×100 cm3) and then the combined extracts washed with water (3×250 cm3), dried over sodium sulfate and the volatile products are removed under vacuum to obtain specified in the connection header (3,91 g, 12,18 mmol, 51% of ketone).

Stage C: 7-methoxy-4-perspire[2H-1-benzopyran-2,4’-piperidine]

To a stirred solution of 7-methoxy-N-methyl-4-perspire[2H-1-benzopyran-2,4’-piperidine] (3,76 g, 11,71 mmol) in anhydrous 1,2-dichloropropane (150 cm ) add potassium carbonate (Android 4.04 g, 29,23 mmol) and the resulting suspension cooled in an ice bath, and then added dropwise 1-chloroethylphosphonic (1,58 cm3, 14,64 mmol). The reaction mixture is heated at the boiling point under reflux over night and add another portion of 1-chloroethylphosphonic (0.8 cm3, 7.4 mmol) and the mixture is heated to boiling point under reflux for a further 24 hours. Upon cooling, the reaction mixture was filtered through a cotton filter, which is subsequently washed with dichloromethane (50 cm3) and volatile fractions removed in vacuo. The resulting intermediate is treated with methyl alcohol (200 cm3) and the mixture is heated at boiling temperature under reflux overnight. Upon cooling, the volatile products are removed under vacuum, after which the resulting solid material dissolved in a mixture of dichloromethane (150 cm3) and aqueous sodium carbonate (5%, 30 cm3). The organic layer was separated, washed with water (2×50 cm3), dried over sodium sulfate and the solvent is removed in vacuum to obtain specified in the title compound as a gum (3,93 g).

Stage D: ethyl 7-methoxy-4-perspire[2H-1-benzopyran-2,4’-piperidine]-1’-acetate

To a solution of 7-methoxy-4-perspire[2H-1-benzopyran-2,4’-piperidine] (3,85 g, 12,54 mmol) in anhydrous N,N (75 cm 3) add potassium carbonate (4,32 g, 31,30 mmol) and then ethylbromoacetate (1,39 cm3, of 12.53 mmol) and the mixture is heated to 100°C in nitrogen atmosphere for 2 hours. The resulting mixture was poured into water (600 cm3) and extracted with ethyl acetate (3×150 cm3). The combined organic extracts washed with water (3×300 cm3), dried over sodium sulfate and the volatile products are removed under vacuum. Specified the crude product is purified by chromatography on a column (silica gel, with elution with a mixture of dichloromethane-ethyl acetate in the ratio of from 9:1 to 4:1), giving the pure ethyl ester (3.51 g, 71%).

Stage E:

A mixture of ethyl 7-methoxy-4-perspire[2H-1-benzopyran-2,4’-piperidine]-1’-acetate (3,38 g, 8.60 mmol), ethanol (250 cm3) and an aqueous solution of lithium hydroxide (2 n, 6,44 cm312,88 mmol) heated at boiling temperature under reflux for 3.5 hours. Upon cooling the mixture is treated with hydrochloric acid (5 n, 70 cm3and a certain amount of ethyl alcohol is removed prior to the deposition of sediment. The mixture is then cooled to 4°until then, until crystallization. The solid material removed by filtration under vacuum obtaining specified in title product as white solids, Tpl.195-230°; positive ion ESI (M+H)+366,4.

Below preprogram the Oia get a similar manner using the appropriate derivative of 2’-hydroxyacetophenone formula II (Scheme a) and the Grignard reagent of the formula IV (Scheme):

Example 2: the Hydrochloride of 1’-carboxymethyl-4-(4-chlorophenyl)-Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.259-265°; positive ion ESI (M+H)+370,0.

Example 3: 4-(4-forfinal)Spiro[2H-1-benzopyran-2,4’-piperidine]-1'-acetate lithium:

The lithium salt obtained using the procedure similar to that described in example 1 (stage E) except that the hydrolysis of complex ethyl ester is carried out with the use of 1.02 molar equivalents of an aqueous solution of lithium hydroxide (2.0 n) and the completion of the reaction, volatile products are removed under vacuum. Tpl.285-291° (Razlog.); positive ion ESI (M+H)+354/2.

Example 4: the Hydrochloride of 1’-carboxymethyl-4-(4-were)-Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.247-249°; positive ion ESI (M+H)+352,2.

Example 5: 6-Fluoro-4-perspire[2H-1-benzopyran-2,4’-piperidine]-1’-acetate lithium: Tpl.293-298° (Razlog.); negative ion ESI (M+H)+354,2.

Example 6: the Hydrochloride of 1’-carboxymethyl-6-methyl-4-perspire[2H-1-benzopyran-2,4’-piperidine]: Tpl.240-244°; positive ion ESI (M+H)+350,2.

Example 7: the Hydrochloride of 1’-carboxymethyl-7-fluoro-4-perspire[2H-1-benzopyran-2,4’-piperidine]: Tpl.237-242°; positive ion ESI (M+H)+354,2.

Example 8: the Hydrochloride of 1’-carboxymethyl-4-(4-chloro-3-forfinal)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.263-24° With; positive ion ESI (M+H)+388,2.

Example 9: the Hydrochloride of 1’-carboxymethyl-4-(1-naphthyl)-Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.237-252°; positive ion ESI (M+H)+385,9.

Example 10: the Hydrochloride of 1’-carboxymethyl-4-(2-naphthyl)-Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.253-264°; positive ion ESI (M+H)+386,2.

Example 11: the Hydrochloride of 1’-carboxymethyl-4-(3-fluoro-4-methoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine] Tpl.252-261°; positive ion ESI (M+H)+384,2.

Example 12: the Hydrochloride of 1’-carboxymethyl-4-(4-tert-butylphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+392,2.

Example 13: the Hydrochloride of 1’-carboxymethyl-4-(3-forfinal)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+354,4.

Example 14: Hydrochloride of 4-(1,3-benzodioxole)-1’-carboxymethylthio[2H-1-benzopyran-2,4’-piperidine]: Tpl.260-265°; positive ion ESI (M+H)+380,4.

Example 15: the Hydrochloride of 1’-carboxymethyl-4-(3,4-dimetilfenil)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.224-234°; positive ion ESI (M+N)+361,9.

Example 16: the Hydrochloride of 1’-carboxymethyl-4-(3,4-dichlorophenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+404,0.

Example 17: the Hydrochloride of 1’-carboxymethyl-4-(3,4-acid)Spiro[2H-1-benzopyran-2,4’-piperidine]: ogically ion ESI (M+H) +396,2.

Example 18: Hydrochloride of 1’-carboxymethyl-4-(3,4,5-tryptophanyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.242-250°; positive ion ESI (M+H)+390,1.

Example 19: Hydrochloride of 1’-carboxymethyl-7-fluoro-4-(4-were)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.153-163°; positive ion ESI (M+H)+368,0.

Example 20: the Hydrochloride of 1’-carboxymethyl-4-(4-methoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+399,6.

Example 21: Hydrochloride of 1’-carboxymethyl-4-(3-chlorophenyl)-Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+370,2.

Example 22: the Hydrochloride of 1’-carboxymethyl-4-(3-methoxy-phenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+N)+366,4.

Example 23: Hydrochloride of 1’-carboxymethyl-4-(3-were)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+350,0.

Example 24: the Hydrochloride of 1’-carboxymethyl-4-[4-(N,N-dimethylamino)phenyl]Spiro[2H-1-benzopyran-2,4’-piperidine]

The specified connection is obtained using methods described in example 1, except that the hydrolysis reaction at the final stage E is carried out with 1.5 equivalents of an aqueous solution of sodium hydroxide (1 M). Once the reaction is finished, most of the ethanol is removed and the resulting crystals are collected by filtration. Obtained the solid is treated with excess methanolic solution of hydrogen chloride for 1 hour at room temperature. Methyl alcohol is removed in vacuo, and the resulting product is treated with a mixture of 2-propanol/methanol (1:1) and added dropwise diethyl ether until precipitation of the product. The specified product is separated by filtration and dried; Tpl.238-250°; positive ion ESI (M+H)+379,4.

Example 25: the Hydrochloride of 1’-carboxymethyl-4-(4-ethylphenyl)-Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+N)+364,4.

Example 26: the Hydrochloride of 4-(4-biphenyl)-1’-carboxymethyl-Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+N)+412,2.

Example 27: the Hydrochloride of 1’-carboxymethyl-4-(4-phenoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+428,2.

Example 28: the Hydrochloride of 1’-carboxymethyl-4-(3-fluoro-4-were)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+N)+368,2.

Example 29: Hydrochloride of 1’-carboxymethyl-7-chloro-4-phenyl-Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+370,2.

Example 30: the Hydrochloride of 1’-carboxymethyl-6-chloro-4-phenyl-Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+N)+370,2.

Example 31: the Hydrochloride of 1’-carboxymethyl-7-chloro-4-(4-ethylphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+N)+398,2.

Example 32: the Hydrochloride of 1’-carboxymethyl-7-chloro-4-(4-propylphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positively the nd ion ESI (M+N) +412,2.

Example 3 3: Hydrochloride of 1’-carboxymethyl-4-(2,2-debtor-1,3-benzodioxole)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.248-250°; positive ion ESI (M+H)+416,2.

Example 34: Hydrochloride of 1’-carboxymethyl-4-(2,3,5-tryptophanyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.206-210°; positive ion ESI (M+H)+RUR 390.4.

Example 35: Hydrochloride of 1’-carboxymethyl-7-chloro-4-(3-fluoro-4-were)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+402,3.

Example 36: Hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-methoxyphenyl)Spiro[2H-1-benzopyran-2,4'-piperidine]: positive ion ESI (M+H)+402,2 4-bromo-2,6-differenital, the source material for the preparation of the Grignard reagent of the formula IV (scheme V), is obtained from 4-bromo-2,6-differenoe. To a solution of phenol (49,0 g, 234 mmol) in anhydrous acetone (980 cm3) add methyliodide (29,4 cm3, 468 mmol) and then potassium carbonate (USD 80.85 g, 585 mmol). Stir the mixture heated at boiling temperature under reflux for 2 hours, then allow the mixture to cool. The resulting solid material is filtered off and the filtrate is evaporated in vacuum. The residue is transferred in diethyl ether (1000 cm3) and the solution washed with water (3×300 cm3), dried (Na2SO4and removing the ether in vacuo to obtain the crude product, which is exploited to obtain the desired Grignard reagent without further purification (49,4 g, 222 mmol, 95%).

Example 37: Hydrochloride of 1’-carboxymethyl-4-(4-dimethylamino-3-forfinal)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.231-239°; positive ion ESI (M+H)+397,4.

Example 38: the Hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-dimethylaminophenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.231-242°; positive ion ESI (M+H)+415,0.

Example 39: Hydrochloride of 4-(4-bromo-3-forfinal)-1’-carboxymethyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+N)+432,5.

Example 40: Hydrochloride of 1’-carboxymethyl-4-(3-bromo-4-methoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+444,1.

Example 41: Hydrochloride of 1’-carboxymethyl-4-(3,5-differenl)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.230-264°; positive ion ESI (M+H)4372,2.

Example 42: Hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-ethoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]:

Stage A: the hydrobromide of 1’-carboxymethyl-4-(3,5-debtor-4-hydroxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]

A mixture of methyl ester (2.35 g) in acetic acid (15 cm3) and 47% Hydrobromic acid was stirred at 120°C for 40 hours. The resulting suspension is cooled in a water bath with ice and then add water (30 cm3). The solid material is separated by filtration, washed with acetic acid and then water, the donkey then dried in vacuum.

Stage b: Ethyl (3,5-debtor-4-hydroxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate

The hydrobromide of 1’-carboxymethyl-4-(3,5-debtor-4-hydroxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine] (1.7 g, obtained by the method described in stage A) are suspended in a solution of hydrogen chloride in ethanol (120 cm3) and the mixture is heated at boiling temperature under reflux for 16 hours. Upon cooling, the volatile materials are removed under vacuum to obtain a solid residue, which is distributed between ethyl acetate (100 cm3) and a mixture of water (100 cm3) and a saturated aqueous solution of potassium bicarbonate (30 cm3). The aqueous layer was extracted with ethyl acetate (2×50 cm3), then the combined extracts washed with water (2×50 cm3) and dried (Na2SO4). The crude material was filtered through silica gel, using as eluent ethyl acetate, which is then evaporated to obtain a solid product (1.54 g).

Stage C: Ethyl-(3,5-debtor-4-ethoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate

To ethyl (3,5-debtor-4-hydroxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate (350 mg), cesium carbonate (412 mg) and sodium iodide (13 mg) is added N,N-dimethylformamide (9 cm3and then Iodate (a 1.7 molar equivalent). The resulting mixture is heated with stirring to 65°C for 3 cha is impressive. Upon cooling, the reaction mixture was diluted with ethyl acetate (90 cm3) and then washed with water (5×35 cm3) and dried (Na2SO4). The specified solution of the crude material is then filtered through a layer of silica gel, after which the solvent is removed in vacuum to obtain a homogeneous product.

Stage D: ethyl (3,5-debtor-4-ethoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate according to the procedure described in example 1, to obtain the hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-ethoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+416,5.

The specified method will also get the following connections:

Example 43: Hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-n-propoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+430,3.

Example 44: the Hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-n-butoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+444,4.

Example 45: the Hydrochloride of 1’-carboxymethyl-4-(4-benzyloxy-3,5-differenl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+478/0.

Example 46: Hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-ISO-pentyloxide)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.211 to 215°; positive ion ESI (M+H)+458,5.

Example 47: Hydrochloride of 1’-carboxymethyl-4-(4-ethoxy-3-forfinal)the pyro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H) +398,2.

Example 48: Hydrochloride of 1’-carboxymethyl-4-(3-fluoro-4-n-propoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+412,0.

Example 49: Hydrochloride of 1’-carboxymethyl-4-(3-fluoro-4-n-butoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+426,1.

Example 50: Hydrochloride of 1’-carboxymethyl-4-(4-benzyloxy-3-forfinal)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+460,3.

Example 51: Hydrochloride of 1’-carboxymethyl-4-(3-fluoro-4-ISO-pentyloxide)Spiro-[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+440,2.

Example 52: Hydrochloride of 1’-carboxymethyl-4-(3-fluoro-4-methoxyethoxymethyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+N)+428,2.

Example 53: Hydrochloride of 1’-carboxymethyl-4-(3-fluoro-4-ISO-butylacetyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+425,8.

Example 54: Hydrochloride of 1’-carboxymethyl-4-[3-fluoro-4-methoxybenzyloxy)phenyl]Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+490,0.

Example 55: Hydrochloride of 4-(4-allyloxy-3,5-differenl)-1’-carboxymethyl)Spiro[2H-1-benzopyran-2,4’-piperidine]:

Stage A: N-benzyl-4-(3,5-debtor-4-allyloxyphenyl)Spiro-[2H-1-benzopyran-2,4’-piperidine]

To a mixture of N-benzyl-4-(3,5-debtor-4-hydroxyphenyl)Spiro-[2H-1-benzopyran-2,4’-piperidine] (750 mg, 1,79 IMO the ü; received in accordance with the procedures described in examples 1 and 42), cesium carbonate (1,1 molar equivalent) and anhydrous N,N-dimethylformamide (15 cm3) is added dropwise allylbromide (to 1.1 molar equivalent). After stirring for 2 hours at room temperature does not remain the source material. The reaction mixture was diluted with ethyl acetate (50 cm3) and treated with water (100 cm3), after which the aqueous layer was separated and re-extracted with ethyl acetate (2×25 cm3). The combined organic extracts washed with water (4×100 cm3) and then dried (Na2SO4and remove volatile materials in vacuo to obtain the desired material of high purity (60%).

Stage b: 4-(3,5-debtor-4-allyloxyphenyl)Spiro[2H-1-benzopyran-2,4 ' -piperidine]

Spend dibenzylamine in accordance with the procedure stage With example 1 with the following changes: in the solvent used dichloromethane (which is not specially dried) and the reaction does not lead in an inert atmosphere. In some examples, the decomposition of the intermediate carbamate ineffective when heated at the boiling point under reflux in the presence of methyl alcohol. In such cases, you need to add excess 10h aqueous potassium hydroxide with heating during the night when the temperature of the bales in the deposits under reflux.

Next, the amine is transformed into the final product in accordance with the procedures described in example 1: Tpl.221-225°; positive ion ESI (M+N)+428,2.

Example 56: Hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-ISO-proproxyphene)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.241 to 243°; positive ion ESI (M+N)+430,3.

Example 57: Hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-propargyloxy)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.211-217°; positive ion ESI (M+N)+426,1.

Example 58: Hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-cyclopropylmethoxy)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.225-231°; positive ion ESI (M+H)+442,0.

Example 59: Hydrochloride of 1’-carboxymethyl-4-(3,5-debtor-4-triptracker)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.244-251°; positive ion ESI (M+N)+470,2.

Example 60: Hydrochloride of 1’-carboxymethyl-4-(3-fluoro-4-ISO-proproxyphene)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.>260°; positive ion ESI (M+N)+412,4.

Example 61: Hydrochloride of 1’-carboxymethyl-4-(3-fluoro-4-triptracker)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.230-235°; positive ion ESI (M+N)+452,2.

Example 62: Hydrochloride of 1’-carboxymethyl-4-(3-fluoro-4-phenoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]: Tpl.160-180°positive ion ESI (M+H) +446,0.

Example 63: 4-perspire[2H-1-benzopyran-2,4’-piperidine]-1’-acetate lithium: Tpl.280-281°; positive ion ESI (M+N)+336,2.

Example 64: 4-(4-triptoreline)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate lithium: positive ion ESI (M-Li+2H)+404,4.

Example 65: Ethyl 4-(4-ethylphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate: Tpl.119-121°; positive ion ESI (M+N)+392,3.

Example 66: Phenyl 4-(4-ethylphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate: Tpl.104-105°; positive ion ESI (M+H)+440,3.

Example 67: Hydrochloride of 1’-carboxymethyl-4-(4-isopentylamine)Spiro[2H-1-benzopyran-2,4’-piperidine]: positive ion ESI (M+H)+422,0.

Example 68: [4-(2-pyridylmethylene)phenyl]Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate of sodium; it is produced in accordance with the procedure of example 42 using the hydrochloride of 2-picolylamine. The final hydrolysis is carried out in accordance with the procedure of example 1 except that the use of sodium hydroxide; positive ion ESI (M+H)+443,4.

Example 69: Hydrochloride of 1’-carboxymethyl-4-[4-(4-methylphenylsulfonyl)phenyl]Spiro[2H-1-benzopyran-2,4’-piperidine]:

Stage A: Ethyl ester of 1’-carboxymethyl-4-[4-(4-methylphenylsulfonyl)phenyl]Spiro[2H-1-benzopyran-2,4 ' -piperidine]

To stir at -5°With a mixture of ethyl 4-hydroxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate (182 mg, 0.5 mmol; obtained according to the procedure of example 42), dichloromethane (13 cm3) and pyridine (158 mg, 2.0 cm3carefully add a solution of p-toluensulfonate (288 mg, 1.5 mmol) in dichloromethane (13 cm3). Then the reaction mixture was allowed to warm to ambient temperature, stirred for a further 2 hours, after which the solution is left to stand overnight. To the mixture is added water (7 cm3) and after stirring for 10 minutes the solvent is evaporated to obtain the product as a gum, which solidified upon standing. Specified product break a spatula, filtered and washed with water (20 cm3). The resulting cake is sucked off almost to dryness and then dried in vacuum at 65°With receipt of the product (300 mg); (M+N)+534,2 m/z.

The specified ester hydrolyzing in accordance with the procedure described in example 1, except that the hydrolysis is carried out in n-butanol: positive ion ESI (M+N)+506,2.

Example 70: Hydrochloride of 1’-carboxymethyl-8-fluoro-4-perspire[2H-1-benzopyran-2,4’-piperidine]

In the case where the desired source 2’-hydroxyacetophenone not commercially available, it can be obtained as follows:

Stage A: (2-forfinal)acetate

To a stirred mixture of 2-terfenol (60,0 g, 535 mmol) and an aqueous solution of sodium hydroxide (4 n, 214 cm3, 856 mmol) PR is 0° With added acetic anhydride (81 cm3, 856 mmol). After stirring the reaction mixture for 30 minutes, the aqueous layer was separated from the organic part and washed with dichloromethane (150 cm3). The combined organic extracts washed with aqueous solution of sodium hydroxide (4 N, 150 cm3and then with saturated salt solution (100 cm3). The organic phase is dried (Na2SO4) and the solvent is evaporated in vacuum to obtain specified in the connection header (84,9 g, >100%.

Stage b: 1’-hydroxy-3’-peracetate

Finely ground trichloride aluminum (32,0 g, 239 mmol) are added to (2-forfinal)acetate (23,0 g, 149 mmol) and the mixture is heated to 180°C for 1 hour. Upon cooling to room temperature the reaction mixture is carefully poured into a mixture of ice/water and the product extracted with dichloromethane (150 cm3). Separate the organic layer, wash it with a saturated solution of salt (150 cm3), dried (Na2SO4) and the solvent is removed in vacuum. Untreated(raw), the reaction mixture was purified by chromatography on a column (silica gel, dichloromethylsilane alcohol 99:1) to obtain the specified title compound (3.1 g, 14%).

Further, the acetophenone is transformed into the final product using the procedure described in example 1: Tpl.180-182°; positive ion ESI (M+N)+354,0.

In soo is according to the specified method are the following connections:

Example 71: Hydrochloride of 1’-carboxymethyl-7-chloro-6-fluoro-4-perspire[2H-1-benzopyran-2,4’-piperidine]; Tpl.275-293°; positive ion ESI (M+N)+387,7.

Example 72: Hydrochloride of 1’-carboxymethyl-5-fluoro-4-perspire[2H-1-benzopyran-2,4’-piperidine]

The necessary source 2’-hydroxyacetophenone not commercially available, due to which it is obtained the following way:

Stage A: 2’-fluoro-6’-methoxyacetophenone

A mixture of 2-fluoro-6-methoxybenzonitrile (15,94 g of 105.5 mmol) and the solution under the conditions of magnesium in diethyl ether (3 M, 46,0 cm3, 137 mmol) was heated to 100°C for 18 hours. Upon cooling to room temperature, add aqueous solution of hydrochloric acid (3 M 94 cm3) and the mixture is heated to boiling point under reflux for 4 hours. As soon as the reaction mixture cooled to room temperature, separate the organic layer and the aqueous phase extracted with ethyl acetate (100 cm3). The combined organic extracts washed with saturated salt solution (100 cm3) and then dried (Na2SO4). The solvent is removed in vacuum to obtain specified in the title compound as oil (117,7 g, 100%).

Stage b: 2’-fluoro-6’-hydroxyacetophenone

The solution tribromide boron in dichloromethane (69,0 g, to 69.6 mmol) is added dropwise during 25 minutes at a temperature of -78°to races the thief 2’-fluoro-6 methoxyacetophenone (17,72 g, of 105.5 mmol) in dichloromethane (150 cm3). After increasing the temperature of the reaction mixture to 0°the reaction is quenched by addition of water (100 cm3) and the product extracted with dichloromethane (100 cm3). The organic solution was washed with water (100 cm3), saturated salt solution (150 cm3) and then dried (Na2SO4). Evaporation of the solvent in vacuo gives the crude product, which is used further without additional purification.

In the future, the acetophenone is transformed into the final product using the procedures described in example 1: Tpl.252-254°; positive ion ESI (M+H)+354,2.

Example 73: Hydrochloride of 1’-carboxymethyl-4-[4-(2-ethoxypropane)phenyl]Spiro[2H-1-benzopyran-2,4’-piperidine]. Obtained using the methods described in example 42, by alkylation of the corresponding phenol hydrochloride of 4-(2-chloroethyl)of the research; positive ion ESI (M+2N)+465,2.

Example 74: Hydrochloride of 1’-carboxymethyl-6-hydroxy-4-perspire[2H-1-benzopyran-2,4’-piperidine]. Obtained using the methods described in examples 1 and 42, the positive ion ESI (M+N)+352,2.

Example 75: Hydrochloride of 1’-carboxymethyl-7-methylthio-4-perspire[2H-1-benzopyran-2,4’-piperidine].

Stage A: 7-fluoro-N-methylspiro[2H-1-benzopyran-2,4’-piperidine]-4(3H)-he

Stir a solution of 4’-fluoro-2’-hydroxyacetophenone the (15,97 g), 1-methyl-4-piperidone (12,74 cm3and pyrrolidine (4,325 cm3) in methyl alcohol (250 cm3) is heated to the boiling point under reflux in a nitrogen atmosphere. After 0.5 hours, add another portion of pyrrolidine (4,33 cm3), then another portion through the following 0.5 hour and the solution is allowed to cool. After that the reaction mixture is evaporated under reduced pressure to obtain oil, which was dissolved in dichloromethane (400 cm3). The solution was washed with water (3×400 cm3), dried (Na2SO4) and evaporated to obtain an oil (25,7 g). Flash chromatography on silica gel (elution with a mixture of dichloromethane:methyl alcohol:33% aqueous ammonia = 380:20:1) to give the purified product in the form of oil (14,41,

Stage: 7-methylthio-N-methylspiro[2H-1-benzopyran-2.4 ' piperidine]-4(3H)-he

To a stirred solution of 7-fluoro-N-methylspiro [2H-1-benzopyran-2,4’-piperidine]-4 (3H)-she (4,54 g) in dimethylformamide (20 cm3in nitrogen atmosphere add thiamethoxam sodium (1.40 g). The mixture is stirred at room temperature for 1.25 hours at 60° - for 4.5 hours and then allow to cool and stand overnight at room temperature. Next, this mixture is stirred and heated at 130°C for 2.5 hours, then allow to cool and stand overnight at room temperature, after CEG is poured into water with stirring (140 cm 3). The solid product is filtered off, washed with water and dissolved in dichloromethane. The solution is dried (Na2SO4) and evaporated to obtain the product as a gum (4.44 g).

The next 7-methylthio-N-methylspiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-he converted into the target compound using the procedure described in example 1, in which the following changes: when conducting stage demethylation target secondary amine is suddenly transformed into a less polar compound which is treated with an aqueous solution of potassium hydroxide (10 n) in methyl alcohol at the boiling point under reflux with the formation of the target amine; (M+H)+= 382,0.

Example 76: Hydrochloride of 1’-carboxymethyl-4-(4-Cryptor-methoxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]

Stage A: ester triftormetilfullerenov acid-4-[1’-phenylmethylene(2N-1-benzopyran-2,4’-piperidine)]

To a stirred cooled solution (-78° (C) N-benseler[2H-1-benzopyran-2,4’-piperidine]-4-(3H)-she (1.54 g, 5 mmol; obtained according to the method of example 1) in dry tetrahydrofuran (40 cm3) add hexamethyldisilazide lithium (1 M solution in hexane, 7.5 cm3, 7.5 mmol) dropwise over about 5 minutes. After stirring at the same temperature for 1 hour add the sulfonamide N-phenyltrichlorosilane (2,68 g, 7.5 mmol) in the ne portion and the resulting reaction mixture is left to mixed and slowly heated during the night. The reaction is quenched with water (10 cm3) and extracted with ethyl acetate (2×50 cm3). The organic portion was washed with saturated aqueous ammonium chloride (50 cm3), saturated aqueous sodium chloride (50 cm3) and water (50 cm3) and then dried (Na2SO4) and concentrate. The product was then purified column chromatography on silica gel (3:1 heptane-ethyl acetate) to give the desired material (1,75 g, 80%), which is either immediately used or stored in an inert atmosphere at -20°C.

Stage b: N-benzyl-4-(4-trifloromethyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-4(3H)-he

A mixture of {N-benseler[2H-1-benzopyran-2,4’-piperidine]}-4-(phenyl-4-triftormetilfullerenov) (1,69 g, 3,86 mmol), 4-triftormetilfullerenov acid (1.25 EQ.), dimethoxyethane (40 cm3), lithium chloride (2.5 EQ.), tetrakis(triphenylphosphine)palladium (0) (2.5 mol%) and aqueous 2 n solution of sodium carbonate (2 equiv.) heated at boiling temperature under reflux for 12 hours. Upon cooling the mixture is treated with water (75 cm3) and ethyl acetate (75 cm3). After shaking, the organic layer is separated and washed with water (2×100 cm3), dried (Na2SO4) and the solvent is removed to obtain the desired product (96%), which is used in the next stage without additional purification.

Further N-gasoline is-4-(4-trifloromethyl)Spiro [2H-1-benzopyran-2,4’-piperidine]-4 (3H)-he converted into the target compound using the procedures described in example 1: Tpl.233-237°; (M+H)+= 420,2.

Example 77: Hydrochloride of 1’-carboxymethyl-4-(4-methylthio-phenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]. Obtained using the method described in example 76; positive ion ESI (M+N)+352,2.

Example 78: Hydrochloride of 1’-carboxymethyl-4-[4-(N-methyl-N-methylsulfonylamino)phenyl]Spiro[2H-1-benzopyran-2,4’-piperidine]

Stage A: ethyl 4-(4-hydroxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate

To a mixture of 1’-carboxymethyl-4-(4-hydroxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’ acetate (432 mg, 1 mmol, obtained by the procedure of example 42), sodium hydrogen carbonate (176 mg, 2.1 mmol) in dry N,N-dimethylformamide (25 cm3) add ethyliodide (0,088 cm3, 1.1 mmol) and the mixture is heated to 80°C for 2 hours. Upon cooling, this mixture was diluted with ethyl acetate (100 cm3) and washed with water (5×100 cm3). Then the organic solution is dried over sodium sulfate, then the solvent is removed in vacuum. Next, the crude material is passed through a small layer of silica gel using first dichloromethane (which is then discarded) and then ethyl acetate. The solvent is removed to obtain the desired product (194 mg, 51%).

Stage b: Complex ethyl ester triftormetilfullerenov acid-{1’-carboxymethyl-4-perspire[2H-1-benzopyran-2,’-piperidine]

To a chilled mix (-20° (C) suspension of ethyl 4-(4-hydroxyphenyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate (158 mg, 4,16×10-4mol) in anhydrous dichloromethane (10 cm3in an inert atmosphere add triethylamine (0,065 cm3, 4,6×10-4mol). After 10 minutes, added dropwise within about 5 minutes the solution triftormetilfullerenov anhydride (0,077 cm3, 4,6×10-4mol) in dichloromethane (7.7 cm3). For about the next 20 minutes of solid material disappears. However, analysis using thin-layer chromatography shows that the reaction is not completed yet, so add another portion of triftormetilfullerenov anhydride (0.25 EQ.). After about 20 minutes the reaction mixture was diluted with ethyl acetate (60 cm3), washed with water (3×60 cm3), then dried (Na2SO4) and the solvent is removed in vacuum. The crude product is purified by chromatography on a column of silica gel (dichloromethane: ethyl acetate, 3:1) to give the desired material (154 mg, 75%).

Stage C: Ethyl ester of 4-[4-(diphenylamino)phenyl]-Spiro[2H-1-benzopyran-2,4’-piperidine]-1-acetic acid

Specified in the title compound was produced using the modified methods of Buchwald et al. (Buchwald et al. Tetrahedron Letters, 1997, 38, 6367).

To a solution of triftormetilfullerenov acid-{1’-carboxy shall ethyl-4-perspire[2H-1-benzopyran-2,4’-piperidine]-ethyl ester} (421 mg, 8,43×10-4mol) in dry tetrahydrofuran (25 cm3during stirring at room temperature in a dry nitrogen atmosphere add Imin benzophenone (1.2 EQ., 0,283 cm3). Then add palladium acetate (1.25 mol%), (R)-(+)-2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (3.75 mol%) and cesium carbonate (1,40 EQ., 385 mg). The mixture is heated to boiling point under reflux for 24 hours and then allow it to cool to room temperature. The mixture is diluted with diethyl ether (not dry) (250 cm3), filtered through filter pad and removed in vacuo volatile products. The residue is purified column chromatography on silica gel (heptane:ethyl acetate, 1:1) to give the desired material (547 mg, mixed with benzophenone imine).

Stage D: ethyl 4-(4-AMINOPHENYL)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate

Specified in the header of the connection get method

Buchwald et al. (Buchwald et al., Tetrahedron Letters, 1997, 38, 6367).

To a stirred solution of ethyl 4-(4-benzothioneyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate (542 mg, 1 mmol) in methyl alcohol (25 cm3) add sodium acetate (198 mg, 2.4 mmol) and then hydroxylamine hydrochloride (125 mg, 1.8 EQ.) and the reaction mixture was stirred at room temperature for 30 minutes. Methyl alcohol is removed in vacuo, then the residue is apredeljat between dichloromethane (25 cm 3) and an aqueous solution of sodium hydroxide (0.1 M, 25 cm3). Separate the organic layer and the volatile products are removed under vacuum, after which the product was then purified column chromatography (silica gel, ethyl acetate) (220 mg, 69% of the triflate).

Stage E: ethyl 4-(methyl 4-phenylsulfonyl)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate

Specified in the header connection receive according to the method of Sandberg et al. (R.J. Sundberg et al., Journal of Organic chemistry, 1984, 49, 249).

A flask containing a mixture of ethyl 4-(4-AMINOPHENYL)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate (214 mg, 0,566 mmol), pyridine (3 EQ., 0,137 cm3) and anhydrous dichloromethane (10 cm3) is stirred in a bath containing ice/methyl alcohol. After 10 minutes at the same temperature is added dropwise within about 5 minutes the solution methanesulfonamide (1.5 EQ., of 0.066 cm3) in dry dichloromethane (0,66 cm3). After stirring for 2 hours the reaction mixture was poured into a saturated aqueous solution of potassium bicarbonate (10 cm3). The organic layer was washed with water (3×50 cm3) and the solvent is removed in vacuum. Add toluene (30 cm3and then delete it in the vacuum (the specified procedure is repeated up until the smell will disappear pyridine) and then add methyl alcohol (30 cm3) and remove it. The rest is a homogenous material (234 mg, 91%).

Stage F: ethyl 4-(methyl 4-phenyl-N-metalsalt-named)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate

To a solution of ethyl 4-(methyl 4-phenylsulfonyl)Spiro[2H-1-benzopyran-2,’piperidine]-1’-acetate (108 mg, 0,236 mmol) in methyl alcohol (10 cm3) add without stirring solution trimethylsilyldiazomethane (2 M in hexano, 5 cm3). Immediately adding celebrated the release of nitrogen. After incubation for 1 hour at room temperature, volatile products are removed under vacuum, then the residue purified by chromatography on a column (silica gel, ethyl acetate) to obtain a homogeneous product (74 mg, 67%).

Example 79 Hydrochloride of 1’-carboxymethyl 4-(N-methyl-4-phenyl-N-methylsulfonyl)Spiro[2H-1-benzopyran-2,4’-piperidine]

In further synthesis is carried out according to the method described in example 1; positive ion ESI (M+N)+= 443,2

Example 80: Dihydrochloride of 1’-carboxymethyl-4-(4-amino-3,5-dipropenyl)Spiro[2H-1-benzopyran-2,4’-piperidine] (4-bromo-2,5-differenl)-2,5-dimethylpyrrole receive, following the methodology of Brockelman et al. (Bruekelmann et al., J. Chem. Soc., Perkin Trans. 1, 1984, 2801).

This material is transformed into the corresponding Grignard reagent and conduct the reaction with N-methylspiro[2H-1-benzopyran-2,4’-piperidine]-4(3H)-one according to the method of example 1, except that the receive undivided mixture of pirolli and freed from the protective groups of Ani is in. This mixture is subjected to N-dezalkilirovania as described in example 1 (together with the conduct of the accompanying unprotect aniline group) to obtain 4-(4-amino-3,5-differenl)Spiro-[2H-1-benzopyran-2,4’-piperidine]. Next, the resulting alkylate amine by ethylbromoacetate and the resulting ester hydrolyzing according to the method of example 1; positive ion ESI (M+H)+387,1.

Example 81: Hydrochloride of 1’-carboxymethyl-3,4-dihydro-4-(4-were)Spiro[2H-1-benzopyran-2,4’-piperidine]

Stage A: ethyl 3,4-dihydro-4-(4-were)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate

To a solution of ethyl 4-(4-were)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate (730 mg, 0,194 mmol) in ethanol (125 cm3) add 10% palladium on coal. This mixture is heated to 40°C for 7 hours in an atmosphere of hydrogen (4 bar) and then filtered warm and the resulting filter cake washed with hot ethanol (3×50 cm3). The solvent is removed in vacuo and the resulting connection is re-crystallized from ethyl alcohol (67%). The specified ester hydrolyzing the procedure of example 1; Tpl.247-249°; (M+N)+= 352,2.

The specified method will also get:

Example 82: 3,4-dihydro-4-(4-forfinal)Spiro[2H-1-benzopyran-2,4’-piperidine]-1’-acetate lithium: Tpl.274-278° (Razlog.); negative and the n ESI (M-Li) -354,40.

Example 83:

The method of determining the absorption of glycine in Cho cells, heterologic expressing a Transporter GlyT-1b person.

A: Cloning: cDNA get by PCR according to the method described by Kim et al, (Kirn K.-M. et al., Mol. Pharmacol. 1994, 45, 608-617). The sequence confirmed by the method of dimethoxyisoquinoline using DNA sequencing machine ALF DNA sequencer™ (Pharmacia) and clone in expressing the construct pcDNA3 (Invitrogen).

In: Transfection: Transfection of hGlyT-1b in Cho cells performed by standard calcium-phosphate method described by Sambruna et al. (Sumbrook, J. et al., (1989) in Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

With: Selection: Hold the selection of stably transfected cells for 1 week in a growth medium containing 1 mg/cm3geneticin. Select individual clones for further analysis and conduct positive passages, as described below.

D: the cultivation Conditions: Cells, stably expressing the gene hGlyT-1b, cultivated at 37°C in an atmosphere containing 5% CO2in the DMEM-NUT.MIX.F12 and with Glutamax-1 (Gibco)containing geneticin (0.5 mg/cm3, Gibco) and with the addition of 10% Fetalclone II (Hyclone). Culture support in the standard ventilated flasks 80 cm2(2×10-6m filter, Nunc) and cells at the point of merge subcultured with trypsin (Sigma).

E: Proced the RA analysis: Cells used in studies of absorption, placed in 96-well plates (17,000 cells per well) without geneticin and cultured for 48 hours before use. To determine the level of transport of glycine, the cells are washed twice with balanced salt solution Hanks (HBSS), preheated to 37°and then the excess liquid is removed with a subsequent payment of the investigated compounds dissolved in 0,200 cm3HBSS. Tablets incubated at 37°C for 5 minutes, then add [3H]glycine (0,050 cm3, 150×10-6M, 248 Bq/nmol1, NEN) and continue incubation for another 10 minutes. Absorption is stopped by washing cells chilled icy environment HBSS, and then remove the excess liquid, and to each well add 0,200 cm3scintillation cocktail. Tablets are close by adhesive film, shaken to achieve homogeneity of the samples and conduct scintillation account counter for tablets.

F: data Analysis: the data Obtained is analyzed by constructing standard curves to calculate the value of plC50(where l50denotes the negative logarithm of the concentration of tested compound causing 50% inhibition of uptake).

G: Results: Compounds according to the present invention selectively inhibit transport the tons of glycine vector GlyT-1b person in comparison with vector GlyT-2 (molecular cloning and functional expression vector GlyT-2 person described by morrow et al. (Morrow, J.A. et al., FEBS letters 1998, 439, 334-340).

Table 1 shows the values plC50for a number of compounds according to the present invention

1. Derived Spiro[2H-1-benzopyran-2,4’-piperidine], having a General formula I

where the dotted line indicates an optional bond;

Y denotes 1-4 substituent, independently selected from hydrogen, halogen, (C1-6)alkyl (optionally substituted by one or more Halogens), (C1-6)alkyloxy (optionally substituted by one or more halogen or (C3-6)cycloalkyl), (C2-6)alkenylamine, (C2-6)alkyloxy, (C3-6)cycloalkane, (C6-12)aryloxy, arylalkyl, pyridyloxy, SR3, NR3R4, OSO2R5and NR3SO2R4;

2 substituent Y may together form O-(CH2)n-O or O-(CF2)n-O, where n is 1 or 2; or Y represents a condensed (C5-6)aryl group;

X denotes 1-3 substituent, independently selected from hydrogen, halogen, hydroxy, (C1-6)alkyloxy, and (C1-4)alkyl;

R1denotes hydrogen, (C1-4)alkyl or (C6-12)aryl;

R2, R3 and R 4denote independently hydrogen or (C1-4)alkyl;

R5means (C1-4)alkyl (optionally substituted by one or more Halogens) or (C6-12)aryl (optionally substituted (C1-4)alkyl); or its pharmaceutically acceptable salt.

2. Derived Spiro[2H-1-benzopyran-2,4’-piperidine] of General formula I according to claim 1, in which the dotted line indicates the connection.

3. Derived Spiro[2H-1-benzopyran-2,4’-piperidine] according to claim 2, in which R1and R2denote hydrogen.

4. Derived Spiro[2H-1-benzopyran-2,4’-piperidine] according to claim 3, in which Y denotes a substituent in the para-position, selected from chlorine, bromine, (C1-4)alkyloxy, (C2-4)alkenylamine, (C2-4)alkyloxy and NR3R4, and 1 or 2 substituent in the meta position selected from halogen.

5. Derived Spiro[2H-1-benzopyran-2,4’-piperidine] according to claim 4, in which the substituents in the meta-position is represented by fluorine.

6. Derived Spiro(2H-1-benzopyran-2,4’-piperidine] according to claim 5, in which X is hydrogen.

7. Derived Spiro[2H-1-benzopyran-2,4’-piperidine] according to any one of claims 1 to 6, with activity against Central nervous system.

8. Pharmaceutical composition having activity against Central nervous system, including derived Spiro[2H-1-benzopyran-2,4’-piperidine] the General formula I or its pharmaceutically acceptable salt, mixed with Pharm is citiesi acceptable additives.

9. Derived Spiro[2H-1-benzopyran-2,4’-piperidine] according to claim 1 or its pharmaceutically acceptable salt as an active ingredient of drugs having activity against Central nervous system.



 

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The invention relates to new derivatives of galantamine General formula I:

where R1-R5, G1-G3and W have the meanings indicated in the claims, and the invention relates to a method for producing these compounds, medicinal product and the method of its production

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FIELD: medicine, obstetrics.

SUBSTANCE: the present innovation deals with three types of species of medicinal plants to prevent late gestoses in pregnant women out of high-risk group: for pregnant women in case of affected dream the suggested species contains flowers of camomile and calendula, leaves of Bergenia and balm, hops collective fruits, and dogrose fruits taken at a certain ratio; for pregnant women in case of chronic urinary infection and neurocirculatory dystonia it contains flowers of camomile and calendula, mountain ash and dogrose fruits, fruits and seeds of Schizandra, leaves of Bergenia and bearberry taken at a certain quantitative ratio; for pregnant women in case of thyroid dysfunction and affected metabolism it contains flowers of camomile and Filipendula, bearberry leaves, Bupleurum grass, fennel seeds, valerian rhizome and roots, hops collective fruits, fruits of black currant taken at a certain quantitative ratio. Species of medicinal plants efficiently prevents and treats at development of both early and late gestoses in pregnant women.

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3 cl, 3 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical neuroleptics according to titration scheme and tricyclic antidepressants. Neuroleptics are applied according to titration scheme in the morning and tricyclic antidepressants are introduced as intravenous drop-by-drop infusion in the evening in combination with per os application of atypic neuroleptic risperidon. After having given 12-14 intravenous infusions, strategic supporting risperidon psychopharmacotherapy in combination with tricyclic antidepressants during 4-6 months.

EFFECT: enhanced effectiveness in overcoming pharmacological resistance; accelerated schizo-affective syndrome relief.

FIELD: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

FIELD: organic chemistry, biochemistry, biology.

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7 cl, 1 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry, biology.

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or its salt with pharmacologically acceptable acid as an active component taken in pharmaceutically effective amount wherein X means oxygen (O) or sulfur (S) atom; R1 and R2 represent independently of one another hydrogen atom, inert substitute taken among the group including low- or non-reactive and optionally substituted radical, such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, (C7-C12)-heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, heterocyclyl; optionally substituted hydroxy-(C1-C5)-alkyl group; R3, R4, R5 and R6 represent independently of one another hydrogen, halogen atom, -CF3, -CN, inert substitute taking among the group including low- or non-reactive and optionally substituted radical, optionally substituted hydroxyl group, optionally substituted hydroxy-(C1-C5)-alkyl group, optionally substituted amino-group, optionally substituted amino-(C1-C7)-alkyl group, optionally substituted carboxy-(C1-C7)-alkyl group, optionally substituted (C1-C6)-alkylcarboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group, optionally substituted (C1-C6)-alkylcarbamoyl group, optionally substituted sulfamoyl group. Also, invention relates to applying compounds of the formula (1) for preparing pharmaceutical composition and experimental study (in vitro and in vivo) processes associated with apoptosis.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of composition.

7 cl, 1 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry, biology.

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or its salt with pharmacologically acceptable acid as an active component taken in pharmaceutically effective amount wherein X means oxygen (O) or sulfur (S) atom; R1 and R2 represent independently of one another hydrogen atom, inert substitute taken among the group including low- or non-reactive and optionally substituted radical, such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, (C7-C12)-heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, heterocyclyl; optionally substituted hydroxy-(C1-C5)-alkyl group; R3, R4, R5 and R6 represent independently of one another hydrogen, halogen atom, -CF3, -CN, inert substitute taking among the group including low- or non-reactive and optionally substituted radical, optionally substituted hydroxyl group, optionally substituted hydroxy-(C1-C5)-alkyl group, optionally substituted amino-group, optionally substituted amino-(C1-C7)-alkyl group, optionally substituted carboxy-(C1-C7)-alkyl group, optionally substituted (C1-C6)-alkylcarboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group, optionally substituted (C1-C6)-alkylcarbamoyl group, optionally substituted sulfamoyl group. Also, invention relates to applying compounds of the formula (1) for preparing pharmaceutical composition and experimental study (in vitro and in vivo) processes associated with apoptosis.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of composition.

7 cl, 1 dwg, 2 tbl, 5 ex

FIELD: pharmacology.

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7 cl, 2 dwg, 8 tbl

FIELD: organic chemistry, medicine, pharmacy.

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wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to nootropic, cerebroprotective medicinal agents as tablets. Tablet of a medicinal agent comprises thiotriazoline and piracetam as active components and accessory components used for formation of core and applying an envelope on it. Invention provides elevating rate and power of a medicinal agent effect on the brain blood supply, expanding spectrum of its pharmacological effect and excludes negative adverse effects.

EFFECT: improved and valuable medicinal properties of agent.

6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying substituted benzenesulfonylureas and -thioureas of the formula (I) for preparing a medicinal agent used for treatment and prophylaxis of disturbances in vegetative nervous system. In particular, invention relates to treatment and prophylaxis of disturbances associated with vagus nerve, for example, in cardiovascular diseases, and to applying compounds of the formula (I) in combination with beta-receptor blocking agents. Also, invention relates to products and pharmaceutical compositions that comprise at least one substance among compounds of the formula (I) and at least one beta-receptor blocking agent, and to new compounds also. Invention provides enhancing effectiveness in treatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

22 cl, 2 tbl, 6 ex

The invention relates to derivatives of 5-areolation formula I, where a represents-CH2-, -C(O)- or-S(O)2-; Z denotes a group of formula b or D:

< / BR>
where X is O or S; R6and R7independently from each other selected from the group including hydrogen, C1-C6alkyl, CF3WITH1-C6alkylthio,1-C6alkoxy, halogen, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen or C1-C6alkyl; R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy2-C6alkyloxy, hydroxy, halogen, cyano, carboxy, co2SOP(CH3)2, -СОNR9R10, -ОСОNR9R10or ОSO2R11where R9and R10have the meanings indicated above, and R11means1-C6alkyl or CF3; R3means-SO2R12or-SO2NR13R14where R12means1-C6alkyl; R13means hydrogen or C1-C6alkyl, and R14means hydrogen, C1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, hydroxy SS1-C6alkyl, benzyl, phenethyl, naphtalate, acyl, morpholino-C1-C6alkyl, pyrrolidino-C1-C6alkyl, pyridyl-C1-C6alkyl, furanyl-C1-C6alkyl, or R13and R14together with the nitrogen atom to which they are attached, optionally form heterocyclization selected from piperidino, morpholino, di-(C1-C6alkyl)morpholino, pyrrolidino, methylpiperazine, phenylpiperazine, forfilipino; and their pharmaceutically acceptable salts or their esters or carbamates, individual isomers and mixtures of isomers and method thereof

The invention relates to a new method of obtaining diastereomeric mixture piperidinylmethyl-tripterocalyx cyclic ethers of the formulae Ia and Ib and their pharmaceutically acceptable salts, where R1is C1-C6the alkyl, R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl, R3is hydrogen or halogen; m = 0, 1 or 2, in which said mixture is enriched compound of formula Ia
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