Phenoxyphenylalkane sulfonates and medicinal agent based on thereof as cannabinoid receptor agonist

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to phenoxyphenylalkane sulfonates of the general formula (I): wherein R3 means alkyl group comprising from 4 to 7 carbon atoms and this group can be substituted from one to some times with fluorine or chlorine atom; A means oxygen atom or NH-group. Also, invention describes a method for preparing compounds of the formula (I) and medicinal agent based on thereof. Compounds can be used in treatment of pain syndromes and neurodegenerative diseases.

EFFECT: valuable medicinal properties of compounds.

7 cl, 3 tbl, 30 ex

 

The invention relates to new esters of sulfonic acid, more particularly to phenoxybenzenesulfonyl and medicinal product based on them as a cannabinoid receptor.

Among the substances contained in the hemp plant (Cannabis sativa) is the most important in pharmacological attitude is Δ9-tetrahydrocannabinol, which causes the main effects of cannabis on the Central nervous system of a person. Potential historical and contemporary therapeutic applications of drugs include hemp along with other analgesia, vomiting, anorexia, glaucoma and disorders of motor functions.

To date we have identified two subtypes of cannabinoid receptors and one option with a combination of functions. SW and SW receptors have seven transmembrane regions and belong to the family of receptors associated with G-proteins.

SW-Receptor and the option of combining the functions of SWA localized predominantly in the Central nervous system. SW-Receptor is found predominantly in peripheral tissues, particularly in leukocytes, the spleen and macrophages.

Up to the present time have been known for many structural classes of agonists Kanna-binidng receptors: the classical cannabinoids, such as Δ9-Tetra-hydrocannabinol, t is the cue non-classical cannabinoids, as, for example, aminoalkyl-indoles, and eicosanoids. The latter is endogenous agonist SW-receptors, anandamide.

In the international patent applications No. And-98/37061, No.-00/10967 and # A-00/10968 describes certain aryloxypropanolamine as agonists can nabinoid receptors for the treatment of neurodegenerative diseases.

In U.S. patent No. 3462473, articles Biochem. Pharmacol. 1972, 21, 1127-1134, Fed. Proc. Fed. Amer. Soc. Exp. Biol. 1971, 30, 841-847, and J. Pharm. Sci. 1973, 62, 1780-1784 discloses certain n-phenoxybenzenesulfonyl and their hypocholesterolemic or hypolipidemic action.

In addition, certain known phenoxybenzenesulfonyl and their use as herbicides (1), antimicrobial agents (2), means for reducing adhesion (3), sensitizers for thermal paper (4) and synthetic intermediates (5): (1) the application for the European patent No. 0023725; U.S. patent No. 3929903; U.S. patent No. 4415354; Chem. Abstr. 1979, 91, 175034 (Japan patent No.-54066631); Chem. Abstr. 1981, 94, 156552 (Japan patent No.-55154953); Chem. Abstr. 1981, 95, 168773 (Japan patent No. A-56046859); Chem. Abstr. 1981, 95, 168789 (Japan patent No. A-56079665); Chem. Abstr. 1989, 111, 2678 (Japan patent No.-63104903); (2) the application for the Federal Republic of Germany patent No.-1493 776; patent application Germany No. And-2131754; U.S. Patent No. 3629477; U.S. patent No. 3772445; U.S. patent No. 3850972; patent application Switzerland no In-450347; patent application Switzerland no In-459656; Chem. Abstr. 1975, 83, 72725 the Japan patent No.-50003375); (3) U.S. patent No. 3346612; (4) U.S. patent No. 4837197; (5) Chem. Abstr. 1997, 727, 26629 (Japan patent No. A-09087210); Tetrahedr. 1990, 46, 4161-4164; J. Am. Chem. Soc. 1998, 39, 435-436.

The present invention was to obtain agonists of cannabinoid receptors with improved action.

This task is solved corresponding to the invention of new connections.

In accordance with this present invention relates to new compounds of General formula (I)

where

R1means a hydrogen atom, alkyl group with carbon atoms of from one to four halogen atom, triptorelin group, cryptometer, panograph or nitrogroup,

R2means halogen atom, triptorelin group, cryptometer, cyano or nitro-group,

R3means alkyl group with the number of carbon atoms from four to seven, which can be from one to several times substituted by fluorine atoms or chlorine,

R4means a hydrogen atom or halogen and

A represents an oxygen atom or NH group.

Corresponding to the invention compounds can exist in stereoisomeric forms which differ both an image and its mirror reflection (enantiomers) or do not like an image and its mirror reflection (diastereomers). The invention relates both to the enantiomers is whether the diastereomers, and any of their mixtures. These mixtures of enantiomers or diastereomers can be separated by known methods on stereoisomers homogeneous components.

Corresponding to the invention compounds can also be in the form of their salts. In the General case it should be called salt with organic or inorganic bases or acids.

In the framework of the present invention preference is given priority concerns from a physiological point of view salts. Acceptable from the physiological standpoint, salt corresponding to the invention compounds can be represented by the salts corresponding to the invention substances with mineral acids, carboxylic acids or sulphonic acids. Especially preferred, for example, salts with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, econsultation, toluensulfonate, benzosulfimide, naphthalenedisulfonate, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Acceptable from the physiological standpoint salts can be salts corresponding to the invention of compounds with metals or their ammonium salts. Especially preferred, for example, n is travie, potassium, magnesium or calcium salts, and also ammonium salts which are proizvodnje ammonia or organic amines such as, for example, ethylamine, di - or, respectively, triethylamine, di - or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or 2-phenylethylamine.

The present invention also include ammonium compounds, which can be obtained by conversion of the free amines by alkylation.

In the framework of the present invention, the substituents in the General case we have the following value.

Alkyl group with the number of carbon atoms one to four in the framework of the invention means a linear or branched alkyl residue with the number of carbon atoms one to four. As an example, should be called methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, isobutylene, Deut.-boutelou and tert.-boutelou group.

Alkyl group with the number of carbon atoms from four to seven in the framework of the invention means a linear or branched alkyl residue with the number of carbon atoms from four to seven. As an example, should be called n-boutelou, isobutylene, Deut.-boutelou, tert.-boutelou, isopentanol, n-pentelow, hexoloy or heptylene group. Preference is given to n-butilkoi, n-PE is a stylish and n-hexylene groups.

The notion of halogen in the framework of the invention include fluorine atoms, chlorine, bromine and iodine. Preference is given to chlorine atoms or fluorine.

Preference is given to compounds of the General formula (I), where

R1means a hydrogen atom, fluorine, chlorine, methyl group, triptorelin group, cryptometer, cyano or nitro-group,

R2means a fluorine atom, triptorelin group, cryptometer, cyano or nitro-group,

R3means n-boutelou, n-pentelow group, 4,4,4-triflorum-1-ilen group or 5,5,5-triterpen-1-ilen group,

R4means a hydrogen atom, and

A represents an oxygen atom.

Particular preference is given to compounds of the formula (I),

where

R1, R2, R3, R4and a have the above meaning, and in the phenyl nucleus by substituents R1and R2the hydrogen atom is in position 4.

This may be reflected in the following formula:

The most preferred compounds of General formula (I),

where

R1, R2, R3, R4and a have the above meaning, while R1and R2take in the phenyl nucleus position 2 and 3.

R1and R2in the phenyl nucleus can be represented by the following formula

<> Similarly, the most preferred compounds of General formula (I),

where

R1, R2, R3, R4and a have the above meaning, while

And is in position with the benzene residue.

Position in the benzene residue may be reflected by the following formula:

The most preferred compounds of General formula (I),

where

R1, R2, R3, R4And have the above meaning, while

R1and R2take a phenyl ring position 2 and 3, and

And is in position with the benzene residue.

R1, R2and can be represented by the following formula:

In addition, a method of obtaining compounds of General formula (I), characterized in that the compound of General formula (II)

where R1, R2, R4and a have the above meaning, in an inert solvent in the presence of a suitable base and, if necessary, in the presence of the phase transfer catalyst is introduced into reaction with the compound of General formula (III),

where

X1means suitable leaving group, and

R3has the above value.

Compounds of General formula (II) is the returns by analogy with the well-known methods in the result of the interaction of compounds of General formula (IV) with a compound of General formula (V)

where

R1, R2and R4have the above meaning,

a) Y represents a hydroxyl group and X is a suitable leaving group,

or Vice versa

b) Y represents a suitable leaving group, and X means a hydroxyl group,

and

E means the nitro-group or a group of the formula-O-R5,

where

R5means suitable protective group for hydroxyl group,

when this interaction is carried out in an inert solvent in the presence of a suitable base and, if necessary, in the presence of compounds of monovalent copper or divalent copper, receiving a first compound of General formula (VI)

where R1, R2, R4and E have the above meaning,

and then

[And] this substance in the case where E means the nitrogroup, in suitable conditions, conventional ways to restore with the formation of compounds of General formula (IIa)

where R1, R2and R4have the above meaning,

or

[B] in the case where E means a group of the formula-O-R5in suitable conditions, conventional ways to remove the protective group R5with the formation of compounds of General formula (IIB)

where

R1, R2and R4have the above value.

Compounds of General formula (II) can be also obtained by the interaction of compounds of General formula (IV) with a compound of General formula (VII)

where

R1, R2, R4And, X and Y have the above meaning,

when this interaction is carried out in an inert solvent in the presence of a suitable base and, if necessary, in the presence of compounds of monovalent copper or divalent copper.

Corresponding to the invention methods can be illustrated, for example, by the following reaction scheme:

Inert solvents in the context of the invention are those solvents which do not undergo transformations in the selected conditions of reactions or changed slightly.

Suitable for the method (II)+(III)→(I) inert solvents, for example, such ethers, such as diethyl ether, mono - or dimethyl ether glycol, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or the products of distillation, or such halogen-substituted hydrocarbons like dichloromethane, chloroform, carbon tetrachloride,as well as dimethylsulfoxide, dimethylformamide, HEXAMETHYL-tramadom phosphoric acid, ethyl acetate, pyridine, triethylamine or picoline. You can also use a mixture of these solvents, including water. Particular preference is given dichlormethane, dichlormethane with water, tetrahydrofuran, dioxane and dioxane with water.

As bases for the reaction (II)+(III)→(I) suitable organic amines, in particular such trialkylamine with the number of carbon atoms in the alkyl groups of from one to six, as, for example, triethylamine or diisopropylethylamine, or such heterocycles as pyridine, methylpiperidine, piperidine or N-methylmorpholin such hydroxides or carbonates of alkali or alkaline earth metals, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or alcoholate such as, for example, sodium methylate or sodium ethylate. Particular preference is given to triethylamine, pyridine and sodium hydroxide.

In General the base is introduced into the reaction in amounts of from 0.1 mole to 5 moles, preferably from 1 mol to 3 mol, in each case based on 1 mol of the compounds of General formula (II).

If necessary, the method (II)+(III)→(I) can be implemented in the presence of a phase transfer catalyst. As the phase transfer catalyst is suitable, for example, and Quaternary ammonium, the preferred bromide, Tetra-butylamine.

As the leaving group X1suitable, for example, the halogen preferably is chlorine.

Interactions can be carried out at normal pressure but also at elevated or reduced pressure (for example, in the range from 0.5 to 3 bar). In General if the work is carried out at normal pressure.

Method (II)+(III)→(I) implement, in the temperature range from 0 to 100°C, preferably from 0 to 30°C.

In the role of suitable inert solvents for methods (IV)+(V)→(VI) and (IV)+(VII)→(II) justified the use of such compounds: such organic solvents, such as diethyl ether, mono - or dimethyl ether glycol, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or the products of distillation, or halogen-substituted hydrocarbons like dichloromethane, chloroform, carbon tetrachloride and dimethyl sulfoxide, dimethylformamide, N-organic, hexamethylene phosphoric acid, utilitate, pyridine, triethylamine or picoline. You can also use a mixture of these solvents, including water. Particular preference is given to pyridine, N-organic, dimethylformamide and dimethylsulfoxide.

If necessary, the methods (IV)+(V)→(VI) and (IV)+(VII)→ (II) can also be realized in the presence of compounds of monovalent or divalent copper. The preferred monovalent iodide copper and oxide of divalent copper.

The role of the grounds for methods (IV)+(V)→(VI) and (IV)+(VII)→(II) suitable carbonates and bicarbonates of alkali metals, in particular sodium carbonate and potassium hydroxides of alkali metals, in particular sodium hydroxide, or organic amines, in particular such trialkylamine with the number of carbon atoms in the alkyl groups of from one to six, as, for example, triethylamine. Particular preference is given to potassium hydroxide, sodium hydroxide and potassium carbonate.

In General the base is introduced into the reaction in amounts of from 0.1 mole to 5 moles, preferably from 1 mol to 3 mol, in each case based on 1 mol of the compounds of General formula (IV) or (V).

For the role of the leaving group X in method (IV)+(V)→(VI) in option a) and, respectively, Y in method (IV)+(V)→(VI) option b) is suitable, for example, halogen or a sulphonate group, as, for example, tripleta. Preference is given to fluorine, chlorine or bromine.

Interactions can be carried out at normal pressure but also at elevated or reduced pressure (for example, in the range from 0.5 to 5 bar). In General if the work is carried out at normal pressure.

Receiprocal in the temperature interval from 20 to 200° C, preferably from 100 to 160°C.

Methods for recovering aromatic nitro group stage of the process (IV)→(IIa) are known (for example, it R.C.Larock, "Comprehensive Organic Transformations", new York, 1989, s-415, and cited in the source literature).

The introduction of protective groups for hydroxyl functions, as well as methods for their removal are known (for example, T.W.Green, P.G.M.Wuts, "Protective Groups in Organic Synthesis", 2nd ed. New York. 1991, and references cited in this source literature; J. Org. Chem. 1999, 64, 9719-9721).

As a protective group, R5for the reaction sequence (IV)+(V)→(VI)→(11b) are suitable, for example, methyl, benzyl, allyl, methoxymethyl, 2-trimethylsilyl-ethoxymethylene or trimethylsilyl group. Preference is given to methyl and benzyl groups.

Compounds of General formula (III) can be purchased commercially, they are known from the literature or can be synthesized by known literature methods (see, for example, J. Chem. Soc. Since 1968, 1265; Chem. Ber. 1967, 100, 1696; fluorinated chlorides alkanesulfonyl can be obtained, for example, in accordance with the application for international patent # A-98/37061 or with the application for the Federal Republic of Germany patent No.-1942264).

Compounds of General formula (IV), (V) and (VII) are known or they can be obtained by known methods.

Compounds of General formula (IV) and (V) can be obtained kom erteschik by, they are known from the literature or they can be obtained by analogy with the known literature methods (see, for example, J.March, "Advanced Organic Chemistry", 4th ed., Wylie, 1992, S. 531-534 and 1295, and, accordingly, cited in the source literature, Synthesis 1990. 1145-1147).

In an unexpected way relevant to the invention compounds showed valuable spectrum of pharmacological activities that were not anticipated in advance.

They are as highly effective agonists of cannabinoid receptors with high metabolic stability and with high bioavailability when taken through the mouth. Accordingly, they are particularly suitable for oral therapy.

As single drugs or in combination with other drugs, they can be used for the prevention and treatment of acute and/or chronic pain syndromes (their classification is shown in the "Classification of Chronic Pain, Descriptions of Pain Syndromes and Definitions of Pain Terms, 2nd ed., ed. Meski, Bagdat, lASP-Press, Seattle, 1994), as well as neurodegenerative diseases, in particular for the treatment of pain caused by cancer, and chronic neuropathic pain, such as diabetic neuropathy, postherpetic neuralgia, peripheral nerve injuries, Central pain (for example, as a consequence of cerebral who enoy ischemia) and trigeminal neuralgia, and at such other chronic pain, such as lumbago, back pain (low back pain) or rheumatic pain. Along with this, these substances are also suitable for the treatment of primary acute pain of any origin and derives from them a secondary pain syndromes, as well as for the treatment of acute pain syndromes that have fallen into chronic.

For combining with the relevant invention compounds for the treatment of acute and/or chronic pain are suitable, for example, opiates such as tramadol, morphine, Dihydrocodeine, dextropropoxyphene, tricyclic antidepressants, such as amitriptyline, anticonvulsants, such as carbamazepine, gabapentin, non-steroidal anti-inflammatory drugs, such as aspirin, ibuprofen, naproxen, including MOR-2 inhibitors, such as rofecoksib, celecoxib.

Similarly, appropriate to the invention of compounds for therapy of primary and/or secondary pathological States of the brain, for example, during or after cerebral vascular spasms, migraine, spasticity, hypoxia and/or anoxia, which do not have the above-named Genesis, perinatal asphyxia, autoimmune diseases, diseases associated with metabolism, or diseases that can be derived from brain damage, and brain damage due to primary ill the deposits in the brain, for example, convulsive States, utero and/or arteriosclerotic changes. Corresponding to the invention compounds are also suitable for the treatment of such chronic or psychiatric illnesses, such as depression, stomach ulcers, neurodegenerative diseases such as, for example, Alzheimer's disease, Parkinson's or Huntington's, multiple sclerosis, amyotrophic lateral sclerosis, degeneration of the nerves in the acute and/or chronic viral or bacterial infections and multi-infarct dementia.

In addition, they can be used in medicines for the treatment of vomiting, nausea, glaucoma, asthma, anorexia, convulsions, rheumatism, delayed and impaired movement.

Corresponding to the invention, the substances are also suitable for treating diseases caused by bacterial and/or viral infection, based on direct and/or indirect changes in the immune system or, respectively, for violations of the regulation with the participation of the immune system, for example, when local or systemic autoimmune diseases (e.g. lupus erythematosus Lupus erythematodes in all its variants), inflammatory and/or having autoimmunological the origin of diseases of the joints (for example, primary chronic polyarthritis, due to injuries, vospolenie the x), in inflammatory and/or having autoimmunological the origin of the diseases of the skeletal and muscular system, inflammatory and/or having autoimmunological the origin of the painful processes in internal organs (for example, Crohn's disease, ulcerative colitis, glomerulonephritis), external bodies (for example, when allergic reactions coming from the air antigens) and in the Central nervous system (e.g. multiple sclerosis, Alzheimer's disease, psychiatric diseases), as well as in the organs of senses, primary and/or secondary and/or autoimmunological diseases of the haematopoietic system and the immune system (for example, when rejection reactions, AIDS)and skin diseases inflammatory and/or immunological origin in humans and animals. In addition, these substances have an effect in indirect symptoms of these diseases, such as pain.

Preferably they are used to treat pain, spasticity, cerebral ischemia and injury of the skull/brain.

The action of the corresponding compounds in vitro on the cannabinoid receptors may be illustrated by the following further biological experiments.

1. Experience in CB1-luciferase reporter gene in rats

The main crops Reporter cell line rat - SNOW get described in the application between Narodny patent No.-98/37061, p.55 FF. method.

For screening substances use the following sequence of experimental operations. The main crops grown in 50% modified Dulbecco environment Needles / 50% F-12 (DMEM/F12) with 10% FCS at 37°in an atmosphere of 10% carbon dioxide, and in each case upon the expiration of the period of two to three days divide them as 1:10. Experimental cultures were seeded at 5000 cells per cell, using plates with 96 cells, and dormivit them for 70 hours at 37°C. After the culture gently washed with saline phosphate buffer and lead to its original state with the help of free serum medium Ultra-SNO (Bio-Whittaker). Dissolved in dimethyl sulfoxide substances once diluted in the medium with a pipette and added to the test cultures (maximal final concentration of dimethylsulfoxide in the study of the mixture equal to 0.5%). After 20 minutes add Forskolin and after that incubated the culture for three hours in the chamber to grow at 37°C. Then remove supernatant, and the cells are lysed with 25 μl of lyse reagent (25 mmol/l triphosphate, pH to 7.8 with 2 mmol/l dithiothreitol, 10% glycerol, 3% Triton X100). Immediately after this, add a solution of a substrate for luciferase (2.5 mmol/l ATP, 0.5 mmol/l of luciferin, 0.1 mmol/l coenzyme A, 10 mmol/l of trizina, 1.35mm the l/l of magnesium sulfate, 15 mmol/l dithiothreitol, pH 7,8), quickly shaken and determine the luciferase activity in the camera system to Hamamatsu.

For inactivation of Gi-proteins in experimental culture before the experiment, treated for 16 hours with 5 ng/ml (final concentration) of toxin pertussis.

The concentrations inhibiting IC50calculated using GraphPadPrism (hill Equation, version: one-site competition).

The substance according to example 17 shows in this experiment the value of the IC50equal to 0.81 nmol/L.

2. Experience on h2-luciferase reporter gene in rats

Spend a stable transfection of cells Ol9 SW-receptor of human rights. TRANS-infection, the selection of clones and growing experimental material is carried out by analogy with the work on SW-receptor in rats. For pharmacological characterization of cells for test substances using the following sequence of experimental operations.

The main crops grown in 50% modified Dulbecco environment Needles / 50% F-12 (DMEM/F12) with 10% FCS at 37°in an atmosphere of 10% carbon dioxide, and in each case upon the expiration of the period of two to three days divide them as 1:10. Experimental cultures were seeded at 5000 cells per cell, using plates with 96 cells in DMEM/F12 with 5% FCS and dormivit them for 70 hours at 37°C. After that, the culture is separated from the media and replace it free of serum environment Ultra-CHO (Bio-Whittaker). Dissolved in dimethyl sulfoxide substance (final concentration 200) with a pipette and added to the test cultures (maximal final concentration of dimethylsulfoxide in the study of the mixture equal to 0.5%) and after 20 minutes add Forskolin. After that incubated the culture for three and a half hours in the chamber to grow at 37°C. Then remove supernatant, and the cells are lysed with 25 μl of lyse reagent (25 mmol/l triphosphate, pH to 7.8 with 2 mmol/l dithiothreitol, 10% glycerol, 3% Triton X100). Immediately after that, add 50 µl of substrate solution for luciferase double concentration (5 mmol/l ATP, 1 mmol/l of luciferin, 0.2 mmol/l of coenzyme A, 10 mmol/l of trizina, 1.35 mmol/l of magnesium sulfate, 15 mmol/l dithiothreitol, pH 7,8), quickly shaken and determine the luciferase activity in the measuring chamber system with photomultiplier (Hamamatsu).

The concentrations inhibiting IC50calculated using GraphPadPrism™ (hill Equation, version: one-site competition).

3. Binding to cortical membranes of rats

By standard techniques prepare a membrane protein from different tissues or cells. Use the eyedropper to get a mixture of buffer, labeled ligand, dimethyl sulfoxide or the analyte, then add 100 μg of protein,mix well the mixture and incubated in a water bath for 60 minutes at 30° C. after the incubation time the reaction is stopped by adding to each tube cooled in ice incubation buffer. After filtration is washed using 3/4 ml incubation buffer. The filters are transferred into miniplane, the radioactivity determined in a liquid scintillation counter.

Metabolic stability corresponding to the invention compounds can be illustrated by the following in vitro experiments.

4. The study of microsomal stability

Metabolic stability corresponding to the invention compounds can be determined using liver microsomes of rats (by analogy with J. Pharmacol. Exp. Ther. 1997, 283, 46-58).

To determine microsomal stability and calculation based on the effect of primary transformations in the liver (reaction phase I) maximum bioavailability (Fmax) incubated substance in small concentration of microsomal protein within 15 minutes with the addition of cofactors at 37°C.

Incubation and sampling carried out on a modified repetiruem machine company Canberra Packard.

As shown by the comparison with the example of the application of international patent No.-98/37061 corresponding to the invention in this connection the experience is more metabolically stable.

Table 1
R1R2Fmax [%]
Example 304 of the application for international patent # A-98/3 7061CH3CH32
Example 15ClCH34
Example 17HOCF340

Bioavailability relevant to the invention compounds, and other pharmaco-kinetic parameters can be determined in vivo following way.

5. Pharmacokinetics in the rat

a) Intravenous infusion

The substance is injected through Branly directly into the bloodstream via the lateral tail vein for 15 minutes. For the exact implementation of the selected dose and volume using a calibrated syringe 20 ml For infusion using a pump manufacturing Braun Melsungen No. 152440/1.

b) Oral administration

The dose of the substance administered in the form of a bolus through the gastric tube.

C) sampling and analysis of blood and plasma

Blood samples taken from animals with catheter (jugular vein in heparinized tubes. The blood is centrifuged and accordingly prepare plasma for analytical studies (liquid chromatography with mass-SP is ctroscopy, mass spectroscopy). To analyze the plasma stored at a temperature of less than -15°C.

g) the Results of pharmacokinetic studies

Microsomal data (liver microsomes rat) suggest possible bioavailability of 100%.

Obtained in experiments in vivo (rats) pharmacokinetic parameters for example 22:

Oral data (dose 3 mg/kg): AUCnorm- is 0.102 kg·h/l, Cmax,norm- 0,0198 kg/l, tmax- 2.29 h, t1/2- 2,36 h, F - 33%.

Intravenous data (dose 0.3 mg/kg): AUCnom- 0,307 kg·h/lmax,norm- 0,5978 kg/l, Vss- 4,12/kg, t1/2to 1.6 hours

Legend:

AUCnorm- brought to a dose of 1 mg/kg surface under the curve plasma concentration from time to time;

Withmax,norm- brought to a dose of 1 mg/kg maximum concentration in plasma after a single injection;

tmaxthe time during which the maximum plasma concentration after a single injection;

t1/2- the end time of half-transformation;

F - bioavailability, in this case, the fraction of the dose in percent, which has a systemic effect compared with intravenous;

Vsseffective volume of distribution at steady state (steady state).

The effect of in vivo relevant to the invention of compounds b is to be presented, for example, in the following experiments on animals.

6. Hypothermia (rats)

The effect of agonism in vivo in SW-receptor is demonstrated in the experiment on Hypo-termio on a rat.

Five minutes after the definition of rectal body temperature using a temperature probe Esophagus administered (oral) test substance. The control group receives oral only solvent for the investigated substances (Cremophore EL 1-10% + distilled water). Body temperature is measured after 120 and 240 minutes after oral administration. The number of groups for each dose is 5-7 animals (rats).

Hypothermia in rats - effect of agonism

ExampleED-1°Ca)[mg/kg]
2210

a)Effective dose to reduce the body temperature by 1°

The ability to use relevant to the invention of compounds for the treatment of pain syndromes can be demonstrated by the following further experiments on animals.

7. Axotomy branches of the sciatic nerve in rats (a model of chronic pain)

During anaesthesia using pentobarbital dissect trifurcation sciatic nerve after nerve ligature near acetamidophenyl plot axotomized branch is small the crural nerve and tibial nerve. In control animals perform simulation operations. After the operation, acetominoven animals develop chronic mechanical hyperalgesia. This hyperalgesia determined using a pressure sensor (electronic anesthesiometer Freya production PTS Inc.-Life Science Instruments, Woodland Hills, CA, USA) in comparison with the animals on which the operation was only simplerules.

Introduction of substances is carried out in different points of time before measuring pain effect in various routes of administration (intravenous, intraperitoneal, oral, i.t., i.c.v., through the skin).

The substance according to example 22 reduces hyperalgesia in the modeling experience with a minimum effective dosage of 1 mg/kg, oral (is an introduction, for 60 minutes before the experience).

The ability to use relevant to the invention of compounds, for example, for the treatment of neurodegenerative diseases can be shown in the model experience permanent focal cerebral ischemia in rats (MCA-O) or in the modeling experience subdural hematoma in the rat (SDH) (application for an international patent No.-98/37061, p.60 FF.).

The new active substances can be converted by known methods in such a conventional dosage forms such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, suitable with farmac ticheskoj standpoint substances carriers or solvents. To do this, therapeutically effective compound in each case should be at a concentration of from about 0.5 to 90 wt.% of the total mixture, i.e. in amounts which are sufficient to achieve the specified limits dosing.

Dosage forms get, for example, by dilution of the active compounds with solvents and/or substances native to the application, if necessary, emulsifying and/or dispersing funds, and in the case of using, for example, as diluent water may also be used organic solvents as solubilization.

Introduction carried out by conventional means, preferably by mouth, through the skin, or parenteral, in particular through language or intravenously. It is also possible inhalation introduction through the mouth or nose, for example, by aerosol, or externally through the skin.

In the General case, it turned out that to achieve effective results it is best to introduce substances in amounts from about 0.001 to 10 mg/kg, with the introduction through the mouth, preferably from about 0.005-1 mg/kg of body weight.

However in some cases it may be necessary to deviate from these quantities, namely depending on the body weight or, respectively, of a way of introduction, from individual attitudes towards drug to its generic the military form and from time to time or from time interval, which is his introduction. For example, in some cases, you can take less than a specified minimum amount, whereas in other cases it is necessary to exceed the above mentioned upper limit. In the case of high amounts can recommend their distribution into several individual doses over the day.

Determination of the retention time of the parent compounds and derived substances using HPLC is carried out in the following conditions:

Column: Kromasil 18 60*2; volume of injected sample µl 1,00; feed rate of 0.75 ml/min; eluent: A=0.01 mol/l of phosphoric acid in water, B = acetonitrile; gradient [t(min) - A/B]: 0-90/10; 0.5 to 90/10; 4,5-10/90, 6,5-10/90, 7.5 to 90/10.

Abbreviations

DHMdichloromethane
EAthe ethyl acetate
DHcyclohexane
IERelectrospray ionization
EVIionization by electronic impact
PHIdirect chemical ionization
Rfthe rate of retention in thin-layer chromatography
Rtretention time (HPLC)
MMmolecular weight

Original soy is inane Example I

3-Methoxy-1-(3-methyl-2-nitrophenoxy)benzene

(Synthesis of diphenyl ethers, method A)

To approximately 600 ml of pyridine are added to 14.7 g (96,0 mmol) 3-methyl-2-NITROPHENOL, 53,9 g (288 mmol) of 3-bromoanisole and 18.3 g (96,0 mmol) of potassium carbonate and heated to a temperature of about 140°C. the Mixture to give a little back to cool and add to 18.3 g (96 mmol) of iodide monovalent copper. The reaction mass is stirred for about 60 hours at a temperature of approximately 140°C. After removal of the solvent in vacuo the residue is dissolved in toluene and again evaporated. The residue is dissolved in dichloromethane and filtered through infusorial the ground. After washing, a small amount of dichloromethane sequentially washed with 5 G. hydrochloric acid, 2 N. a solution of sodium hydroxide, 5 N. hydrochloric acid, water and sodium chloride solution. After drying over magnesium sulfate evaporated in vacuo and purify the resulting crude product by distillation with ball reflux.

Yield 3.50 g (13%; purity according to HPLC 94%).

The value of Rf0,28 (cyclohexane/ethyl acetate 5:1).

Mass spectrum (ionization by electronic impact): 259 (100%, [M]+).

HPLC: retention time 4,94 minutes

1H-NMR (300 MHz, deuterochloroform): δ (ppm) = 2,37 (C., 3H), 3,78 (C., 3H), 6,1-of 6.65 (m, 2H), 6,67-6,74 (m, 1H), 6.83 (D., J=8 Hz, 1H), 6,99 (D., J=8 Hz, 1H), 7,14-to 7.32 (m, 2H).

Example II

3-Methoxy-1-[2-(trifluoromethyl)phenoxy]Ben is ol

(Synthesis of diphenyl ethers, method B)

To about 450 ml of pyridine was added 50.0 g (222 mmole) of 2-bromobenzonitrile, of 27.6 g (222 mmole) 3-methoxyphenol and 30.7 g (222 mmole) of potassium carbonate and briefly heated at a temperature of about 100°C. Give a little back to cool and add to 17.7 g (222 mmole) of oxide of divalent copper. The reaction mass is stirred for about 48 hours while heating under reflux (bath temperature 140°). After removal of the solvent in vacuo the residue is dissolved in dichloromethane and shaken with 2 N. hydrochloric acid. After that, the organic phase is washed with 1 N. a solution of sodium hydroxide and water. After drying over magnesium sulfate evaporated in vacuo and purify the resulting crude product by distillation with ball reflux.

The output is 37.2 g (62%; purity according to HPLC 98%).

The value of Rf0,47 (cyclohexane/ethyl acetate 5:1).

Mass spectrum (ionization by electronic impact): 268 (100%, [M]+).

HPLC: retention time 5,14 minutes

1H-NMR (200 MHz, deuterochloroform): δ (ppm) = 3,79 (C., 3H), 6,56-of 6.65 (m, 2H), of 6.71 (DDD, J=8 Hz. 2 Hz, 1 Hz, 1H), 6,97 (D., J=8 Hz, 1H), 7,17 (t, J=8 Hz, 1H), 7.25 (t, J=8 Hz, 1H), 7,46 (so, J=8 Hz. 1 Hz, 1H), 7,66 (D., J=8 Hz, 1H).

Example III

1-[2-Cyano-3-(trifluoromethyl)phenoxy]-3-methoxybenzoyl

(Synthesis of diphenyl ethers, method)

In an argon atmosphere to anhydrous di is malformed added 10.7 g (52.1 mmole) of 2-chloro-6-(trifluoromethyl)benzonitrile [example 5 in the application for the Federal Republic of Germany patent No.-3836159; 2-chloro-6-(trichloromethyl)benzonitrile can be obtained from 2,6-dimethylbenzonitrile according to example 3 in the application for the Federal Republic of Germany patent No.-2214058], add 7,19 g (52.1 mmole) of potassium carbonate and 6,46 g (52.1 mmole) 3-methoxyphenol and stirred for 5 hours at 100°C. then add 500 ml of 2 n sodium hydroxide and 200 ml of saturated solution of sodium chloride. Extracted twice with ether approximately 300 ml, dried the combined organic phases over magnesium sulfate, evaporated in vacuum and hold flash chromatography on 450 g of silica gel, using as mobile phase toluene. The fractions with the product evaporated to dryness and add the remaining butter a little ether, leave for crystallization, is sucked off and washed with pentane.

Output 9,36 g (57%; purity according to HPLC 96%).

The value of Rf0,39 (toluene).

Melting point 68°

HPLC: retention time 4,89 minutes

1H-NMR (200 MHz, deuterochloroform): δ (ppm) = 3,72 (C., 3H), 6,62-6,87 (m, 3H), 7,08 (D., J=8 Hz, 1H), 7,33 (t, J=8 Hz, 1H), 7,44 (D., J=8 Hz, 1H), EUR 7.57 (t, J=8 Hz, 1H).

Example IV

1-[2-Chloro-3-(trifluoromethyl)phenoxy]-3-nitrobenzene

(Synthesis of diphenyl ethers, method D)

In an argon atmosphere to 10 ml of dimethylformamide was added to 1.00 g (5,09 mmole) of 2-chloro-3-(trifluoromethyl)phenol, 0,72 g (5,09 mmole) of cryptomaterial and 0.70 g (5,09 mmole) of potassium carbonate. The mixture boil for approximately 16 hours with inverse x is Hladilnika. After cooling, was added to the reaction mass 50 ml of 2 n sodium hydroxide and stirred for further one hour, then add 20 ml of sodium chloride solution and stirred for further 30 minutes. Then extracted with dichloromethane, the organic phase is dried over magnesium sulfate and evaporated in vacuum. Cleaning is performed chromium-togetheranal on silica gel, using as mobile phase cyclohexane/ethyl acetate 20:1, get 0,69 g (42%; purity according to HPLC 100%) of target compound.

The value of Rf0,39 (cyclohexane/ethyl acetate 2:1).

Mass spectrum (ionization by electronic impact): 317 (100%, [M]+).

HPLC: retention time 5,22 minutes

1H-NMR (300 MHz, d6-dimethylsulfoxide): δ (ppm) = 7,51 (Shostakovich, J=8 Hz, 2 Hz, 1H), 7,56-7,83 (m, 5H), with 8.05 (DD, J=8 Hz, 2 Hz, 1H).

The following examples V-XIII receive similar schemes in accordance with the methods of obtaining the source compounds a or B from the corresponding original products.

Table I
Example No.The target connectionMMWay / exit %Purity according to HPLC in %/Rtin minutesThe value of Rf(the mobile phase)Mass spectrum
V 293,2B/1594/5 .550,53 (TT/EE 20:1)PHI/NH3: 293 (100%, [M+H]+)
VI259,3A/5996/5,050.31 (CG/AA:1)EVI: 259 (100%, [M]+)
VII268,2B/6298/5,140,47 (TT/EE 5:1)EVI: 268 (100%, [M]+)
VIII269,1A/4578/5,360,51 (CG/AA:1)EVI: 268 (90%, [M]+)
IX248,7A/7096/5,540,55 (CG/AA:1)EVI: 248 (100%, [M]+)
X234,7A/6173/5,090,46 (TT/EE 2:1)PHI/NH3: 235 (100%, [M+H]+)
XI360,3B/4596/5,670,53 (TT/EE 5:1)IER: 361 (100%, [M+H]+)
XII302,7A/7789/5 .360,55 (TT/EE 2:1)EVI: 302 (100%, [M]+)
XIII360,3B/5796/5,830,14 (TT/EE 2:1)EVI: 360 (26%, [M]+)

Example XIV

3-(3-Methyl-2-nitrophenoxy)phenol

(Cleavage of a methyl group in a simple ether, method A)

In an argon atmosphere for 2 ml of anhydrous dichloromethane are added 500 mg (1,93 mmole) of 1-methoxy-3-(3-methyl-2-nitrophenoxy)benzene and cooling the solution to -20°C. At this temperature was added 5.8 ml of a solution of tribromide boron in dichloromethane to a concentration of 1 mol/L. the Temperature is allowed to rise to 0°C and stirred for 1 hour. After adding water three times extracted with dichloromethane. The combined organic phases are washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuum. After cleaning chromatographytandem on silica gel with a mixture of cyclohexane/ethyl acetate 30:1 as mobile phase receive 424 mg (89%) of target compound.

The value of Rf0,18 (cyclohexane/ethyl acetate 2:1).

Mass spectrum (ionization by electronic impact): 245 ([M]+).

HPLC: retention time 4,40 minutes

1H-NMR (300 MHz, deuterochloroform): δ (mill the district shares) = 2,37 (C., 3H), 4,88 (sh, 1H), 6,54 (t, J=2 Hz, 1H), 6,57 of 6.66 (m, 2H). 6,85 (D., J=8 Hz, 1H), 7,01 (D., J=8 Hz, 1H), 7,19 (t, J=8 Hz, 1H), 7,27 (t, J=8 Hz, 1H).

Example XV

3-[2-Cyano-3-(trifluoromethyl)phenoxy]-phenol

(The removal of metal of the group in a simple ether, method B)

In an argon atmosphere in anhydrous dichloromethane was dissolved 10.0 g (34.1 mmole) 1-(2-qi-ANO 3-triptoreline)-3-methoxybenzene and gain of 13.9 g (37.5 mmole) of iodide n-tetrabutylammonium. Cooled to -78°and slowly added dropwise to 120 ml of trichloride boron in dichloromethane to a concentration of 1 mol/l, keeping the temperature not higher than -70°C. for two hours, allowed to warm to room temperature. The reaction mixture is poured into 300 ml of ice water, three times extracted with a mixture of dichloromethane, the organic phase is twice washed with saturated sodium bicarbonate solution and once with sodium chloride solution. Dried over magnesium sulfate and perform purification via flash chromatography on approximately 400 g of silica gel with dichloromethane. To the obtained oily product was added pentane and left for crystallization.

The output of 7.75 g (96%, purity according to HPLC 96%).

The value of Rf0,16 (dichloromethane).

Melting point 108°C.

HPLC: retention time to 4.41 min

1H-NMR (300 MHz, deuterochloroform): δ (ppm) = 5,13 (S., 1H), 6,59-of 6.78 (m, 3H), 7,11 (D., J=8 Hz, 1H), 7,28 (t, J=8 Hz, 1H) 7,45 (doctor, J=8 Hz, 1H), 7,58 (t, J=8 Hz, 1H).

Example XVI

3-[2-Chloro-3-(trifluoromethyl)phenoxy]phenol

(Cleavage of a methyl group in a simple ether method)

In 6 ml of glacial acetic acid dissolve 600 mg (1.98 mmole) of 3-methoxy-1-[2-chloro-3-(trifluoromethyl)phenoxy] benzene, gain of 3.60 ml of 48%aqueous Hydrobromic acid and 4 hours refluxed. After cooling, diluted with water and extracted with ethyl acetate. The organic phase washed three times with water, dried over magnesium sulfate and evaporated in vacuum. Chromatographytandem on silica gel with a mixture of dichloromethane/cyclohexane 2:1 as mobile phase receive 484 mg (81%, purity according to HPLC 96%) of target compound.

The value of Rf0,39 (cyclohexane/ethyl acetate 2:1).

Mass spectrum (ionization by electronic impact): 288 ([M]+).

HPLC: retention time 4,80 minutes

1H-NMR (300 MHz, d6-dimethylsulfoxide): δ (ppm) = 6,37 (t, J=2 Hz), 6,44 (DDD, J=8 Hz, 2 Hz, 1 Hz, 1H), 6,59 (DDD, J=8 Hz, 2 Hz, 1 Hz, 1H), 7,20 (t, J=8 Hz, 1H), 7,39 (DD, J=8 Hz, 1 Hz, 1H), 7,56 (t, J=8 Hz, 1H), 7,68 (DD, J=8 Hz, 1 Hz, 1H), RS 9.69 (S., 1H).

Example XVII

3-[3-(Trifluoromethyl)phenoxy]phenol

(The removal of benzyl groups in a simple ether, method G)

In the apparatus for hydrogenation in 135 ml of tetrahydrofuran and 15 ml of ethanol is suspended 1.70 g (4,72 mmole) of 3-benzyloxy-1-[3-(trifluoromethyl)phenoxy]benzene and the settlement of the e addition of 170 mg of 10%palladium on coal during the night hydronaut at normal temperature and hydrogen pressure of 1 ATM. To highlight the product is filtered off the catalyst through infusorial the earth, the filtrate evaporated and flash chromatographic on 130 g of silica gel with a gradient cyclohexane/ethyl acetate 10:1 to 1:1.

Upon removal of solvent receive 1.27 g (99%, purity according to HPLC 95%) of target compound.

The value of Rf0,28 (cyclohexane/ethyl acetate 5:1).

Mass spectrum (ionization by electronic impact): 270 ([M]+).

HPLC: retention time 4,78 minutes

1H-NMR (200 MHz, deuterochloroform): δ (ppm) = equal to 4.97 (SD, 1H), 6,53 (t, J=2 Hz, 1H), 6,56 is 6.67 (m, 2H), 6,85-7,01 (m, 3H), 7,22 (t, J=8 Hz, 1H), 7,34 (t, J=8 Hz, 1H).

The following examples XVIII-XXV receive similarly, in accordance with the methods And, or,

Table II
Example No.The target connectionMMWay / exit %Purity according to HPLC in %/Rtin minutesThe value of Rf(the mobile phase)Mass spectrum
XVIII279,1In/7992/4,930,21 (TT/EE 10:1)EVI: 278 (100%, [M]+)
XIX245,2In/75100/4,460,24 (CHEE 5:1) PHI/VD: 263 (100%, [M+NH4]+)
XX254,2In/9998/4,560,56 (TT/EE 2:1)EVI: 254 (100%, [M]+)
XXI255,1In/4991/4,720,20 (TT/EE 5:1)EVI: 254(43%, [M]+)
XXII220,7In/8094/4,440,21 (TT/EE 5:1)EVI: 220 (61%, [M]+)
XXIII245,2A/8999/4,40,18 (CG/AA:1)PHI/NH3: 263 (100%, [M+NH4]+)
XXIV234,7In/6496/4,830,39 (TT/EE 2:1)EVI: 234 (100%, [M]+)
XXV270,2G/9895/4,650,29 (CG/AA:1)EVI: 270 (100%, [M]+)

Example XXVI

3-[2-Chloro-3-(trifluoromethyl)phenoxy]-aniline

In an argon atmosphere to 7 ml of methanol was added 630 mg (1.98 mmole) 1-[2-chloro-3-(tri-permitil)phenoxy]-3-nitrobenzene is, 625 mg (a 9.09 mmole) of ammonium formate and 31.5 mg 10-aqueous palladium on coal as a catalyst. A mixture of two hours, heated under reflux. After cooling, filtered through infusorial earth, washed with methanol and the filtrate evaporated. Again dissolved in dichloromethane, extracted three times with water, dried the organic phase over magnesium sulfate and again evaporated. Chromatographic purification on silica gel with a mixture of cyclohexane/ethyl acetate 6:1 as mobile phase receive 458 mg (72%according to HPLC purity 90%) of target compound.

The value of Rf0,48 (cyclohexane/ethyl acetate 1:1).

Mass spectrum (ei when elektrorazpredelenie): 288 (22%, [M+H]+).

HPLC: retention time to 4.41 min

1H-NMR (300 MHz, d6-dimethylsulfoxide): δ (ppm) = 5,28 (S., 2H), 6,11-to 6.19 (m, 2H). 6,38 (DDD, J=8 Hz, 2 Hz, 1 Hz, 1H), 7,03 (t, J=8 Hz. 1H), 7,33 (Shostakovich, J=8 Hz, 1 Hz, 1H), 7.54 (t, J=8 Hz, 1H), 7,63 (Shostakovich, J=8 Hz, 1 Hz).

Example XXVII

1-[2-Cyano-3-(trifluoromethyl)phenoxy]-3-hydroxybenzoyl

(Synthesis of diphenyl ether according to the method D)

In 170 ml of N-methylpyrrolidone partially dissolve to 44.0 g (0.4 mole) of resorcinol, add the potassium hydroxide [not less than 85%, of 34.5 g (of 0.52 mole)] and then add 2-chloro-6-(trifluoromethyl)benzonitrile [of 20.5 g (0.1 mol)]. This mixture is stirred for 2.5 hours at 60-65°C. After addition of 300 ml of toluene and 400 ml of water separated water is ABC and again extracted with 300 ml of toluene. The combined organic phases are dried over magnesium sulfate and after filtration, evaporated. After extraction of the oily residue 150 ml of water, filtering and drying receive slightly brownish crystals.

Yield 22 g (79% of theory; compare with example XV).

Examples retrieve

Example 1

3-[2-Cyano-3-(triptoreline]phenyl-4,4,4-Cryptor-1-butanesulfonate

(Synthesis of esters of sulfonic acids, method A)

In an argon atmosphere in 60 ml of dichloromethane is dissolved of 7.70 g (27.6 mmole) of 3-[2-cyano-3-(trifluoromethyl)phenoxy] phenol, then to this solution was added 4,32 g (13.1 mmole) of tetrabutylammonium bromide, and 3.95 ml of 45%sodium hydroxide solution. At a temperature of 0°immediately poured the solution 6,64 g (31.5 mmole) 4,4,4-triptorelin-1-sulfochloride in 20 ml of dichloromethane. The solution is painted in color from yellow to orange, stirred for one hour. Then diluted with water and extracted three times with dichloromethane. The combined organic phases are washed with sodium chloride solution and dried over magnesium sulfate. The cleaning is performed using flash chromatography 360 g of silica gel using a step gradient of concentrations of the mobile phase cyclohexane/dichloromethane 1:1 to 1:4. After evaporation on a rotary evaporator remains oily residue, which crystallized after to the Alenia pentane.

Output: the first fraction of 9.21 g (74%, purity according to HPLC 100%),

the second faction to 2.29 g (18%, purity according to HPLC 97%).

The value of Rf0,56 (dichloromethane).

The melting point of 60-61°C.

Mass spectrum (electrospray ionization): 454 ([M+H]+).

HPLC: retention time 5,08 minutes

1H-NMR (300 MHz, deuterochloroform): δ (ppm) = of 2.2-2.5 (m, 4H), 3,39 (t, J=7 Hz, 2H), 7,0-to 7.3 (m, 4H), to 7.50 (t, J=8 Hz, 1H), 7,53 (d, J=8 Hz, 1H), to 7.64 (d, 1=8 Hz).

Example 2

3-(3-Methyl-2-nitro-phenoxy)phenyl-n-pentanesulfonate

(Synthesis of esters of sulfonic acids, method B)

To 200 mg (of 0.82 mmole) of 3-(3-Methyl-2-nitro-phenoxy)phenol in 5 ml of dichloromethane at room temperature first, add 1 ml of 40%aqueous hydroxide solution tet-rautalampi, then after stirring for five minutes to give 153 mg (from 0.90 mmole) of n-pentasulphide. After stirring for 1.5 hours, add 0.5 ml of 10%sodium bicarbonate solution, filtered the mixture through an Extrelut cartridge (3 g) (Merck, Darmstadt, order 115095) and washed several times with cartridge dichloromethane. When chromatographic purification on silica gel with a mixture of cyclohexane/ethyl acetate 30:1 as mobile phase obtain 255 mg (82%according to HPLC purity 99%) of target compound.

The value of Rfof 0.35 (cyclohexane/ethyl acetate 2:1).

The mass spectrum of the (electrospray ionization): 380 (100%, [M+H]+).

HPLC: retention time of 5.29 minutes

1H-NMR (300 MHz, deuterochloroform): δ (ppm) = 0,93 (t, J=7 Hz, 3H), 1.30 and is 1.51 (m, 4H), 1,89-2,02 (m, 2H), 2,39 (C., 3H), 3.18 of 3.28 (m, 2H), 6,85-7,42 (m, 7H).

Example 3

N-{3-[2-Chloro-3-(trifluoromethyl)phenoxy]phenyl}-4,4,4-triptorelin-1-sulfonamide (the Synthesis of amide sulfonic acids, method)

In an argon atmosphere in 1 ml of dichloromethane was dissolved 100 mg (0.35 mmole) of 3-[2-chloro-3-(trifluoromethyl)phenoxy]aniline. Give 106 mg (1.04 million mmole) of triethylamine and a solution of 77 mg (0.37 mmole) of 4,4,4-triptorelin-1-sulfochloride in 1 ml of dichloromethane and stirred at room temperature. After 4 days add another 0.3 equivalent of 4,4,4-tripersonality and stirred for three days. After the reaction mass three times extracted with 2 N. hydrochloric acid and once with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and evaporated in vacuum. When chromatographic purification on silica gel with a mixture of dichloromethane/cyclohexane 7:2 as the mobile phase obtain 96 mg (54%according to HPLC purity 90%) of target compound.

The value of Rf0,33 (cyclohexane/ethyl acetate 2:1).

Mass spectrum (direct chemical ionization/NH3): 479 (100%, [M+NH4]+).

HPLC: retention time to 8.34 minutes

1H-NMR (300 MHz, d6-dimethylsulfoxide): 4 (ppm) = 1,80-of 1.93 (m, 2H), 2,31-of 2.50 (m, 2H), 3,25 (t, J=8 Hz, 2H), 6.75 in (Shostakovich, J=8 Hz, 2 Hz, 1H), 6,85 (t, J=2 Hz, 1H), 7,03 (DD, J=8 Hz, 1 Hz), 7,38 (t, J=8 Hz, 1H), 7,43 (Shostakovich, J=8 Hz, 1 Hz. 1H), 7,58 (t, J=8 Hz, 1H), 7,72 (Shostakovich, J=8 Hz, 1 Hz, 1H), 10,04 (S., 1H).

The following examples 4 to get 24 similarly, in accordance with examples for methods a, B or C from the appropriate starting compounds.

Table III
Example No.The target connectionMMWay / exit %Purity according to HPLC in %/Rtin minutesThe value of Rf(the mobile phase)Mass spectrum
4453,3A/6197/5,150,33 (TT/EE 5:1)IER: 453 (79%, [M+H]+)
5379,4A/7694/5,360,63 (CG/AA:1)PHI/NH3: 397(100%, [M+N]+)
6419,4B/78100/5,120.69 (toluene/ EA:1)IER: 420 (100%, [M+H]+)
7413,3 A/10389/5,830,52 (TT/EE 2:1)PHI/NH3:430 (100%, [M+NH]+)
8428,4A/6797/5,240.32 (TT/EE 2:1)IER: 451 (100%. [M+NaD, IER: 429 (89%, [M+H]+)
9of 388.4A/7994/5,470,53 (TT/EE 2:1)IER: 349 (35%, [M+H]+)
10354,9B/6381/5,440,45 (CG/AA:1)PHI/NH3: 372 (100%, [M+NH4]+)
11349,8B/6781/5,20,37 (TT/EE 2:1)PHI/NH3: 412 (100%, [M+NH4]+)
12389,3B/76100/5,640,48 (TT/EE 2:1)PHI/NH3: 406 (100%, [M+NH4]+)
13429,2B/7297/5,380,31 (CG/AA:1)PHI/NH3: 446 (100%, [M+NH4]+)
14 368,9B/8493/5,770,49 (TT/EE 2:1)PHI/NH3: 386 (100%, [M+NH4]+)
15408,9B/6992/5,50,38 (CG/AA:1)PHI/NH3: 426 (100%, [M+NH4]+)
16419,4B/8198/5,070,23 (TT/EE 2:1)IER: 420 (100%, [M+H]+)
17444,4A/9193/5,330.25 (TT/EE 5:1)IER: 445 (100%, [M+H]+)
18404,4A/1798/5,65PHI/NH3: 422 (100%, [M+NH4]+)
19444,4A/2996/5,40,26 (TT/EE 5:1)IER: 445 (57%, [M+H]+)
20404,4A/2470/5,7PHI/NH3: 422 (100%, [M+NH4]+)
21 413,4A/95100/5,10,33 (DHM/ Meon 100:3)IER: 414 (100%, [M+H]+)
22462,8A/8697/5,40,36 (CG/DHM 2:1)IER: 463 (80%, [M+H]+)
23422,9A/97100/5,620,49 (TT/EE 2:1)PHI/NH3:440 (100%, [M+NH4]+)
24421,9In/4891/7,940,42 (TT/EE 2:1)PHI/NH3: 439 (100%, [M+NH4]+)

The above examples are characterized by the following further data spectra1H NMR.

ExampleSpectra1H NMR (300 MHz): δ/millionths
17Deuterochloroform; 2,17-to 2.42 (m, 4H); to 3.33 (t, J=7 Hz, 2H); to 6.88 (t, J=2 Hz; 1H); 6,92-to 6.95 (m, 1H); 7,01-7,05 (DDD, J=8 Hz, 2 Hz, 0.5 Hz; 1H); 7,09 (Shostakovich, J=8 Hz, 2 Hz, 1H); 7.18 in-7,39 (m, 4H).
21d6-Dimethylsulfoxide; 0,86 (t, J=7 Hz, 3H); 1,24 was 1.43 (m, 4H); 1,80 (the Queen., 2H); of 3.56 (t, J=7.5 Hz, 2H); 7.29 trend-7,38 (m, 4H); to 7.61 (t, J=8 Hz, 1H); to 7.77 (d, J=7.5 Hz, 1H); 7,88 (t, J=8 Hz, 1H).
22d6-Dimethyls epoxid; 2,02 (the Queen., 2H); to 2.46 (m, 2H); of 3.69 (t, J=7.5 Hz, 2H); 7,02-was 7.08 (m, 3H); 7,17-7,20 (Shostakovich, J=8 Hz, 2 Hz, 1H); of 7.48-7,63 (m, 3H): 7,72 to 7.75 (Shostakovich, J=8 Hz, 1 Hz, 1H).
23d6-Dimethylsulfoxide; 0,86 (t, J=7 Hz, 3H); of 1.33 (m, 4H); 1,78 (the Queen., 2H); to 3.52 (t, J=7.5 Hz, 2H); 7,02-7,06 (m, 2H); 7,15-to 7.18 (m, 1H); of 7.48-to 7.64 (m, 3H); 7,72 to 7.75 (Shostakovich, J=8*Hz, 1 Hz, 1H).

1. Phenoxybenzenesulfonyl General formula (I)

where R1means a hydrogen atom, alkyl group with carbon atoms of from one to four halogen atom, triptorelin group, cryptometer, cyano or nitro-group,

R2means halogen atom, triptorelin group, cryptometer, cyano or nitro-group,

R3means alkyl group with the number of carbon atoms from four to seven and this group can be from one to several times substituted by fluorine atoms or chlorine,

R4means a hydrogen atom or halogen and

A represents an oxygen atom or NH group.

2. Compounds according to claim 1, and

R1means a hydrogen atom, fluorine, chlorine, methyl group, triptorelin group, cryptometer, cyano or nitro-group,

R2means a fluorine atom, triptorelin group, cryptometer, cyano or nitro-group,

R3 is n-boutelou, n-pentelow group, 4,4,4-triflorum-1-ilen group or 5,5,5-triterpen-1-ilen group,

R4means a hydrogen atom, and

A represents an oxygen atom.

3. Compounds according to claim 1 or 2, and

R1, R2, R3, R4and have given in claim 1 or 2, the value in the phenyl nucleus by substituents R1and R2the hydrogen atom is in position 4.

4. Compounds according to claim 1 or 2,

and

R1, R2, R3, R4and have given in claim 1 or 2, the value, and

R1and R2take a phenyl ring position 2 and 3.

5. Compounds according to one of claims 1 to 3, and

R1, R2, R3, R4and And are given in claims 1 to 4, the value, and

And is in position with the benzene residue.

6. Method of preparing compounds according to claim 1, characterized in that the compound of General formula (II)

where R1, R2, R4and have given in claim 1 value

in an inert solvent in the presence of a suitable base and, if necessary, in the presence of the phase transfer catalyst is introduced into reaction with the compound of General formula (III)

where X1means suitable leaving group, and

R3has specified what use value.

7. Medicine as a cannabinoid receptor containing at least one of the compounds according to one of claims 1 to 5 in a mixture with at least one pharmaceutically acceptable mainly non-toxic carrier or diluent.



 

Same patents:

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new compounds of formula

,

wherein A and B are independently CH or CR3; X is C=O or (CR4aR4b)m, (m = 1 or 2); Y is S(O)n-R2 (n = 1 or 2), S(O)n-NR2R2, or S(O)n-OR2; N1 and N2 are nitrogen atoms; Q and R1 are independently 1) optionally substituted C1-C10-alkyl; 2) optionally substituted aralkyl containing C6-C10-aryl, attached to C1-C10-alkyl; 3) optionally substituted aralkenyl containing C5-C10-aryl, attached to C1-C10-alkenyl; 4) optionally substituted C6-C10-aryl; 5) optionally substituted aryl, containing 5-10 ring atoms, selected from carbon and sulfur; each R2 and R3 are hydrogen; R4a, R4b, R5, and R6, are independently hydrogen; R2 and R3 are independently hydrogen or C1-C6-alkyl; as well as acid and base additive salts thereof. Also disclosed are method for production of claimed compounds, pharmaceutical composition inhibiting serine protease enzymes and therapeutic method based thereon.

EFFECT: new compounds and pharmaceutical composition for thrombosis preventing or abnormal thrombosis treatment.

11 cl, 7 tbl, 15 ex

The invention relates to new derivatives and analogs 3-arylpropionic acid having the General formula (I), and their stereo and optical isomers and racemates, as well as their pharmaceutically acceptable salts, wherein in the formula And is located in the meta - or para-position and represents a

where: R represents hydrogen;

-ORawhere Rarepresents hydrogen, alkyl, phenyl or alkylphenyl;

-NRaRbwhere Raand Rbare the same or different and represent hydrogen, alkyl, phenyl, alkylphenyl, cyano;

R1represents alkyl, cyano;

-ORewhere Rerepresents alkyl, phenyl or alkylphenyl;

-O-(CH2]m-ORfwhere Rfrepresents alkyl, and m is an integer of 1-2;

-SRdwhere Rdrepresents an alkyl or phenyl;

-SO2ORawhere Rarepresents alkyl, phenyl or alkylphenyl;

-COORdwhere Rdrepresents alkyl;

R2represents hydrogen or alkyl;

R3and R4

D is situated in the ortho-, meta - or para-position and represents a

-OSO2Rdwhere Rdrepresents alkyl, phenyl or alkylphenyl;

-OCONRfRawhere Rfand Rarepresent hydrogen, alkyl, phenyl or alkylphenyl;

-NRcCOORdwhere Rcrepresents hydrogen or alkyl and Rdrepresents alkyl, phenyl or alkylphenyl;

-NRcCORawhere Rcrepresents hydrogen or alkyl, and Rarepresents hydrogen, alkyl, phenyl or alkylphenyl;

-NRcRdwhere Rcand Rdrepresent hydrogen, alkyl, phenyl or alkylphenyl;

-NRcSO2Rdwhere Rcrepresents hydrogen or alkyl, and Rdrepresents alkyl, phenyl or alkylphenyl;

-NRcCONRaRkwhere Rcrepresents hydrogen, Raand Rkare the same or different and each represents hydrogen, alkyl, phenyl or alkylphenyl;

-NRcCSNRaRkwhere Rcrepresents hydrogen, Raand Rkare the same or different and each represents hydrogen, phenyl иLASS="ptx">-SRcwhere Rcrepresents alkyl, phenyl or alkylphenyl;

-SO2ORawhere Rarepresents alkyl, phenyl or alkylphenyl;

-CN;

-CONRcRawhere Rcrepresents hydrogen or alkyl, and Rarepresents hydrogen or alkyl;

D’ is located in the meta-position and represents-ORfwhere Rfrepresents alkyl; or is located in the ortho-, meta - or para-position and represents hydrogen;

D’ is located in the ortho - or para-position and represents-NO2, -ORfwhere Rfrepresents alkyl; or is located in the ortho-, meta - or para-position and represents hydrogen;

where specified, the alkyl means a straight or branched alkyl group having from 1 to 6 carbon atoms, or cyclic alkyl having from 3 to 6 carbon atoms, with the specified alkyl may be substituted by one or more than one group of alkyl, alkoxy, halogen or phenyl; where the specified phenyl may be substituted by one or more than one group of alkyl, alkoxy, nitro, thiol, or halogen; the invention also relates to a method of their production, pharmaceutical preparations containing them, the Sabbath.

The invention relates to new substituted bicyclic compounds of General formula I: R1-A-D-E-G-L-R2(I) where R1means naphthyl or a residue of formula:

< / BR>
< / BR>
< / BR>
< / BR>
where a = 1 or 2, R3means H, C2-C6alkenyl, C1-C6alkyl or C1-C6acyl and all of the above ring systems and the remains unsubstituted or substituted optionally gemenele, one or more, same or different substituents selected from the group: halogen, carboxyl, hydroxy, phenyl, C1-C6alkoxy, a group of the formula -(CO)b-NR4R5where b = 0 or 1, R4and R5the same or different and independently of one another denote hydrogen, phenyl, C1-C6acyl, C4-C7cyclacel, benzene C1-C6alkyl and the other dialkylamino, where alkyl with 1-6 carbon atoms, a and E are the same and different and mean a connection or C1-C4alkylene, D is-O - or a residue of formula-S(O)c- or-N(R9)- , THE 2-5T.GIF" ALIGN="ABSMIDDLE">< / BR>
and the other, G means double-linked aryl with 6-10 carbon atoms, or double-linked 5-7 membered aromatic heterocycle containing up to 3 heteroatoms from the series of sulfur, nitrogen and/or oxygen, which may be substituted by one or more identical or different substituents, R2means6-C10aryl or a 5-7 membered saturated or aromatic heterocycle containing up to 3 heteroatoms from the series of sulfur, nitrogen and/or oxygen, unsubstituted or substituted by one or more identical or different substituents with the exception of compounds of the formula I, where R1means of naphthas-1-yl, unsubstituted or substituted in position 3 C1, C1-C4the alkyl and in position 4 chlorine or phenyl; a and E indicate the relationship, D is-O-; G means 1,4-phenyl, unsubstituted or substituted C1-C4by alkyl; L is-O-; R2means of CH3and except for the connection m-bis-(1-naphthyloxy)benzene

The invention relates to the derivatives of aminophenylamino formula I

< / BR>
where R is phenyl, substituted C1-C6by alkyl; R1represents hydrogen; X represents -(CH2)3-Y, cyclopropyl or tetrahydro-2-oxo-3-furoyl; Y represents chlorine, bromine or hydroxy,

or their acid additive salts

The invention relates to alkyl substituted cyclic amines of the formula I, where X and Y are in position 5, 6 or 7, where (i) n = 1, X represents (CH2)mCONR4R5, (CH2)mNR4CONR5, (CH2)mNHSO2R3(where m = 0 or 1, except that when m = 0, then Y cannot be hydrogen and Y is hydrogen or or6; (ii) n = 0 or 1, then X and Y are in the 0-position relative to each other and together form a: a) -C(O)NR10C(O)-, b) -C(O)NR4(CH2)xNR10C(O)- (where x = 0 or 1); (C) -CH2NR10C(O)-; d) -(CH2)NR10C(O) -, (e) -CH2C(O)NR10, g) -N(R3)-C(O)-O-, j) -CH2N(R8)CH2-; (iii) n = 0, and Y represents OR9then X is (CH2)mCONR4R5, (CH2)mNHCOR3(where m = 0 or 1); R1and R2represent, independently, WITH1-C8-alkyl, R3is1-C8-alkyl, aryl; R4and R5represent, independently, H, C1-C8-alkyl, C1-C6-alkylaryl or aryl; R6is1-C8-alkyl, R8is1-C8-alkyl, SO2R4(provided that R4is not hydrogen); R10is H, C is phenyl, possibly replaced by stands, nitro, chlorine, fluorine, bromine, amino, CN, carboxamido, acetyl; or represents thiophenyl, isoxazolyl, imidazolyl

The invention relates to analogs of 2-aminoindane General formula I, where R1and R2independently represent hydrogen, C1-C8alkyl; X is CH2R3or NHSO2R4; Y represents hydrogen, NHSO2R4, SO2(Ph); R3is NHSO2R4,

SO2R4, CONR1R2; R4represents C1-C8alkyl, phenyl or phenyl, substituted by-CN or-CF3; and their pharmaceutically acceptable salts, active receptor Dopamine D3

The invention relates to a new method of obtaining sulfur-containing imidazole derivatives of the formula I

R4-C6H4-C6H4-CH2NC4R, R2R3,

characterized in that the compound of formula (A)

Hal-C6H4-C6H4R'4< / BR>
enter into reaction with the oxidizing agent to obtain a compound of the formula (B)

CHO-C6H4-C6H4-R41,

which is then injected into the reaction with the compound of the formula (II)

H2N-CH(CN)-R31,

where possible functional groups can be protected to obtain a compound of formula (C)

R31-CH(CN)-NH-CH2-C6H4-C6H4-R41,

which enter into reaction with the compound of the formula (III)

R11-CO-Hal

to obtain the compounds of formula (D)

R31-CH(CN)-N(COR1CH2-C6H4C6H4-R41,

which undergoes the reactions proceed on the CN radical with a reagent able to enter the substituent R21where possible functional groups can be protected to obtain a compound of formula (E)


,

after which the compound of formula (E) and the compound of formula (L) is subjected to cyclization reaction to obtain compounds of formula (I)

FIELD: chemistry of surface-active substances, chemical technology.

SUBSTANCE: invention relates and describes a method for preparing sodium lauryl sulfate of high purity degree. Method involves the sulfatization reaction of lauryl alcohol with chlorosulfonic acid, desorption of hydrogen chloride by vacuum evaporation at temperature 35-40°C and gradual declining pressure up to 30-35 mm of mercury column for 15 min, neutralization sulfomass after vacuum evaporation with an aqueous-acetone solution of sodium hydroxide at water content 18-24% to pH = 8.5 at temperature 55-57°C followed filtering off hot aqueous-acetone solution at temperature 45-50°C, not less, and crystallization of sodium lauryl sulfate for three stages at gradual declining temperature and constant stirring, washing out sodium lauryl sulfate crystals with acetone at temperature 30-35°C. Proposed method provides preparing the end product of high purity degree with the yield 76% of stoichiometry and by simplified technology. The end product can be used for using in medicine, pharmaceutical, cosmetic and steel foundry industry and for scientific investigations.

EFFECT: improved preparing method, enhanced purity of product.

3 cl, 1 tbl, 1 ex

FIELD: medicine, neurology, in particular treatment of disseminated sclerosis.

SUBSTANCE: complex therapy includes plasma exchange, interferonotherapy, administration of copaxon, cytostatics, symptomatic and bracing agents, and cyclosporin A. Administration of steroids is excluded. Additionally ceruloplasmine intravenously drop-by-drop in dose of 100 mg and cerebrolysate intramuscularly in dose of 10 ml for 10 days are administered. Claimed method provides stable remission up to 12 months for 89.2 % of patients.

EFFECT: decreased invalidisation due to reconstitution of regulatory relationship between nervous and immune systems.

1 ex, 1 tbl

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition stimulating adenosine receptors and comprising one or some compounds of the formula (I) and new compounds of the formula (II) . The composition provides the effective modulation of the adenosine system.

EFFECT: valuable properties of modulators.

12 cl, 541 ex

FIELD: organic chemistry, neurology, medicine.

SUBSTANCE: invention relates to a new medicinal agent used in treatment of feeble-mindedness comprising a derivative of 2-aryl-8-oxodihydropurine, namely, a derivative of 2-aryl-8-oxodihydropurine that comprises acetamide group at position 7 or 9 of purine ring. Invention proposes compounds of formulae (Ia) and (Ib) wherein radicals X1, Y1, R12, R13, R22, R23, R32, R42 and R43 have the corresponding values, or their pharmaceutically acceptable acid-additive salt. Also, invention proposes using compounds of the formulae (Ia) and (Ib) or their pharmaceutically acceptable acid-additive salt for preparing a medicinal agent used in treatment or prophylaxis of feeble-mindedness wherein feeble-mindedness represents deterioration of the teaching process, dysmnesia, dysmnesia-based disorientation, mental dysfunction, Alzheimer's disease, cerebrovascular feeble-mindedness and/or senile feeble-mindedness, and in treatment or prophylaxis of higher cerebral dysfunction. Invention provides the development of a medicinal preparation for prophylaxis or treatment of feeble-mindedness symptoms associated with diseases that can induce feeble-mindedness and higher cerebral dysfunction.

EFFECT: valuable medicinal properties of agents.

12 cl, 3 tbl, 5 ex

FIELD: medicine, neurology, therapy, pharmacy.

SUBSTANCE: invention relates to pharmaceutical preparations used in treatment of neurological disorders. Preparations comprise eicosapentaenoic acid and arachidonic acid and shoes at least 90% of purity and taken as components of the preparation in the ratio from 1:1 to 20:1. Also, invention relates to methods for treatment of neurological disorders. Invention discloses the positive effect of the preparation on pathological neurodegenerative process. Invention provides the combined using eicosapentaenic and arachidonic acids in treatment of neurological disorders.

EFFECT: valuable medicinal properties of preparation.

11 cl, 3 tbl, 1 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: claimed method includes blending of active base and auxiliary ingredients to form tablet corn, representing composition of sugar powder, monocrystalline cellulose, vinylpyrrolidone and calcium stearate; humidifying of obtained mixture; drying of obtained granules; dry granulation through granulator with standardized holes; pelletization of standardized granules to produce tablet corn; and coating. Mixture is humidified with 5-7 % starch mucilage in starch mucilage/humidifying mixture mass ratio of 1:25-30, wherein mixture is blending with starch mucilage for homogeneous distribution wet in whole mass.

EFFECT: tablets with increased hardness and enhanced pharmacological activity.

2 cl, 2 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a new agent with expressed selective activity with respect to central muscarinic acetylcholine receptors belonging to subtype M1. Agent represents 1-phenyl-1-(1'-methylcyclopentyl)-4-piperidino-2-butyne-1-ol hydrochloride of the formula (1) known early as low toxic cholinolytic. Agent expands a set of ligands used in research of mechanisms of the central nervous system function. Agent shows high capacity for penetration through blood-brain barrier, low toxicity and high effectiveness.

EFFECT: valuable medicinal properties of agent.

1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-hydroxypiperidine of the general formula (I): wherein R means (a): -C(O)(CH2)nC(O)OH; (b): wherein R1 means -N(R2)(R3); each R2 and R3 means hydrogen atom, lower alkyl or cyclic tertiary amine; (c): -P(O)(OH)2 or (d): -C(O)(CH2)n and -NHC(O)(CH2)nN(R2)(R3) wherein n means a whole number 1-4. Indicated compounds can be used as prodrugs in preparing medicinal agents used in treatment of diseases associated with blocking agents for receptors of subtype NMDA.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 1 tbl, 20 ex

FIELD: medicine, pediatrics, psycho-neurology.

SUBSTANCE: the present innovation deals with applying preparation that normalize energy exchange. For this purpose it is necessary to introduce L-carnitine at the dosage of 20-30 mg/kg/d in three stages, coenzyme Q10 at the dosage of 30-60 mg/d once and limontar at the dosage of 10 mg/kg/d once during the first half of the day for 2 mo twice annually. The present innovation provides improved values for nervous-psychic development due to correcting mitochondrial alterations.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: organic chemistry of heterocyclic compounds, biology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of the general formula (1): or (2): or their pharmaceutically acceptable salts, N-oxides or hydrate possessing physiologically active properties, in particular, eliciting ability to induce apoptosis in tumor cells causing their death. In the general formula (1) or (2) X represents sulfur or oxygen atom; Y represents sulfur atom, group -SO, group -SO2, group -NH or group -NR6; R1 represents aryl, substituted aryl, heteroaryl; R2 and R5 represent hydrogen atom, alkyl, allyl, substituted benzyl, group -CH2-C(O)R3, group -CH2-C(O)NR3R4 wherein R3, R4 and R6 represent inert substitute. Also, invention relates to new combinatory libraries for search compound-leaders and candidates for medicinal compounds preparing by screening the combinatory libraries.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 9 ex

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