Derivatives of adenosine, pharmaceutical composition and method for correcting electrical disturbances in the heart of a mammal

 

(57) Abstract:

The invention includes optimally substituted N6-oxa-, thia-, dioxa and azacycloheptane substituted derivatives of adenosine, which are selective agonists of adenosine receptor type 1, and as such, they are potentially useful compounds for the treatment of cardiovascular diseases and disorders of the Central nervous system. Describes new derivatives of adenosine General formula 1, where R1represents a monocyclic heterocyclic group containing from 3 to 15 atoms, at least one of which is selected from the group consisting of N, O and SO2which may be mono - or polyamidine one or more substituents selected from the group consisting of a carbonyl group, hydroxyl, lower alkyl, substituted lower alkyl, acyl, or carboxyl group, where R1not a monocyclic-lactam or imide and where R1does not contain an epoxy group. also described pharmaceutical composition and method for correcting electrical disturbances in the heart of mammals. 5 C. and 7 C.p. f-crystals, 2 tab., 2 Il.

The invention includes optimally substituted N6-oxa-, t adenosine receptor type 1 and, as such, they are potentially useful compounds for the treatment of cardiovascular diseases and disorders of the Central nervous system.

Description modern technology.

There are two subtypes of adenosine receptors in the heart: A1and A2. Each subtype has diverse physiological functions. Stimulation of adenosine receptor A1causes two distinct physiological responses. The first is the inhibition of the stimulatory effect of catecholamine. Intermediate stage for this effect is the inhibition of the synthesis of cyclic AMP. The second effect, mediaready receptor A1is slowing the heart rate and the passage of impulses through the atrioventricular node. This effect does not depend on the metabolism of C - AMP, and it is associated with the activation of the adenosine receptor (A1internally reconfiguring channel+. This effect is unique to the receptor A1; the role of receptor-A2modulation of the function of this channel is absent. Stimulation of adenosine receptor A1accordingly shortens the duration and reduces the amplitude of the potential of DETA effects is to limit the number of impulses, passing from the Atria to the ventricles. This forms the basis for clinical use of agonists of receptor-A1for the treatment of supraventricular tachycardia, including atrial fibrillation, utter - flicker, reflexive tachycardia in the AV node.

Therefore, the clinical use of agonists A1you may be prompted for the treatment of acute and chronic disorders of heart rhythm, in particular, such diseases characterized by increased heart rate, when the frequency of contractions stimulated by disorders in the Atria. These violations include, but are not limited to, atrial fibrillation, supraventricular tachycardia and Torsade de pointes. The effects of agonists A1reduces the heart rate and the return of disturbed rhythm to its normal intensity, and thus restores blood flow with improved blood pressure.

Agonists A1due to its ability to inhibit the increase of the content of C - AMP-induced catecholamine, should have a beneficial effect in cardiac, when increased sinteticheski tone, the AI and sudden death.

Summary of invention.

The purpose of the present invention is new derivatives with heterocyclic substituents.

Another objective of the present invention is new derivatives of geterotsiklicheskikh substituted adenosine, which may be used as agonists of receptor-A1.

Another objective of the present invention are new geterotsiklicheskikh substituted derivatives of adenosine, which can be used for treatment of supraventricular tachycardia, including atrial fibrillation, utter-flicker and reflexive tachycardia in the AV node.

In one embodiment, the implementation of the present invention is a compound having the formula:

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where R1represents a monocyclic or polycyclic heterocyclic group containing from 3 to 15 atoms, at least one of which is N, O, S, P, and R1may be mono - or polygamist one or more compound selected from the group consisting of a halogen atom, carbonyl group, hydroxyl, lower alkyl, substituted lower alkyl, CNS, aryl, acyl, Allexinno, carbosilanes cycloalkyl, nitro, langroup and mixtures thereof, where R1does not contain an epoxy group.

In another embodiment, the implementation of the present invention is a method of stimulating cardiac activity of a mammal experiencing electrical disturbances in the heart that can be cured by stimulating adenosine receptor in heart for the mammal a therapeutically effective amount of the compounds described above.

In yet another variant implementation of the present invention is a pharmaceutical composition comprising as an active ingredient an effective amount of the compounds of the present invention and one or more pharmaceutical excipient.

Description of the figures.

Fig. 1 is a graphical representation of the influence of the concentration of the compound II of example 2 on vnutriepreserdna conductivity of the atrioventricular node for adenosine receptor (A1(- -) and adenosine receptor (A2(- O -)

Fig. 2 is a graphical depiction of the effect of concentration of compound I of example 2 on vnutriepreserdna conductivity of the atrioventricular node and specifically on the reaction adenosine what about the option of selling.

The present invention includes derivatives of adenosine, which are selective agonists of adenosine receptor type 1. Connection optimally substituted as described below.

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where R1represents a monocyclic or polycyclic heterocyclic group containing from 3 to 15 atoms, at least one (atom) of which is a heteroatom selected from the group consisting of N, O, P and S(O)0-2R1in turn may be mono - or polysuede a halogen atom, groups, oxo-, hydroxyl, lower alkyl, substituted lower alkyl, CNS, aryl, acyl, Allexinno, carboxyl, substituted aryl, heterocyclic, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro - and langroup. However, R1may not contain an epoxy group.

R1preferably represents a monocyclic, bicyclic or tricyclic group containing from 3 to 15 atoms, at least one of which is selected from the group consisting of O or S(O)0-2where R1may be mono - or polygamist one or more compound selected from the group comprised the school, acyl, Allexinno, carboxyl, substituted aryl, heterocyclic, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro-, langroup and mixtures thereof.

In a more preferred embodiment, the implementation of R1is:

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where R'1, R1, R"'1and R""1are individually selected from halogen atom, groups, oxo-, hydroxyl, lower alkyl, substituted lower alkyl, CNS, aryl, acyl, Allexinno, carboxyl, substituted aryl, heterocyclic, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro-, langroup and mixtures thereof, and X represents O or S (-O)0-2. Preferably R'1, R1, R"'1and R""1are individually selected from an H atom, groups, lower alkyl, substituted lower alkyl, CNS, aryl and substituted aryl. The term "individually selected" means that each of R'1, R1, R"'1and R""1may be different from the other component, each may be the same component that, for example, a hydrogen atom, or some of the components of the t a the above composition, R'1, R1, R"'1and R""1individually be selected from a H atom, groups, lower alkyl and substituted lower alkyl. R"'1and R""1can also be a single oxygen atom.

In an alternative implementation of R1is selected from the group consisting of:

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or

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where each R may be independently selected from the group consisting of H, groups, lower alkyl and substituted lower alkyl and where X represents O or S (-O)0-2. In the most preferred embodiment, the implementation of R1is selected from the group consisting of groups 3-tetrahydrofuranyl, 3-tetrahydrofuranyl, 4-Pernille and 4-tipirneni.

The following definitions relate to terms used here.

The term "halogen" refers to fluorine atoms, bromine, chlorine and iodine.

The term "oxo" refers to = O.

The term "hydroxyl" refers to the group - HE.

The term "lower alkyl" refers to a cyclic, branched or straight chain alkyl group with the number of carbon atoms from one to ten. This term is additionally illustrated by the examples of such groups as methyl, ethyl, n-through out-have, n-amilina, exilda and the like.

The term "substituted lower alkyl" refers to lower alkyl group, which has just been described, including one or more group such as hydroxyl group, tilina, alkylthiol, halogen atom, CNS group, amino-, amido-, carboxyl, cycloalkyl, substituted cycloalkyl, heterocyclic, cyclogeranyl, substituted cyclogeranyl, acyl, carboxyl, aryl, substituted aryl, azlocillin, heteroaryl, substituted heteroaryl, arylalkyl, heteroallyl, alkylalkoxysilane, alkylalkoxysilane, alkylcyclohexane, alkylcyclohexane and langroup. These groups can be attached to any carbon atom of the element lower alkyl groups.

The term "alkoxy" refers to the group - OR where R represents a group of lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, heteroallyl, cycloalkyl, substituted cycloalkyl, cyclogeranyl or substituted cyclogeranyl defined below.

The term "acyl" denotes the group - C(O)R, n aryl, the amino group and the like, are defined below.

The term "aryloxy" denotes the group - OAr, where Ar represents an aryl group, substituted aryl, heteroaryl or substituted heteroaryl, as defined below.

The term "amino" refers to the group NR2R'2where R2and R'2can be independently from each other hydrogen atom, the groups lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl as defined here.

The term "carboxyl" denotes the group - C(O)OR, where R may independently be a hydrogen atom, groups, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and the like, are defined here.

The term "aryl" or "Ar" refers to an aromatic carbocyclic group, which has at least one aromatic ring (such as phenyl or biphenylene group) or multiple condensed rings in which at least one ring is aromatic (e.g., groups 1,2,3,4-tetrahydronaphthalene, naftalina, antenna or phenantroline).

The term "zoé as a halogen atom, the group lower alkyl, lower CNS, lower alkylthio-, triptoreline, amino-, amido-, carboxyl, hydroxyl, aryl, azlocillin, heterocyclic, heteroaryl, substituted heteroaryl, nitro, cyan, alkylthio-, circularity and the like.

The term "heterocycle" refers to a saturated, unsaturated or aromatic carbocyclic group having a single ring (e.g., group morpholino-, perederina or furilla) or a lot of condensed rings (e.g., group afterdelay, khinoksalinona, hyalinella, indolizinyl or benzo [b] thienyl) and having at least one heteroatom, such as N, O or S, within the ring, which may or may not have substituents in the form of, for example, halogen atom, groups, lower alkyl, lower CNS, lower alkylthio-, triptorelin, amino-, amido-, carboxyl, hydroxyl, aryl, Allexinno, heterocyclic, heteroaryl, substituted heteroaryl, nitro, cyan, alkylthio-, Tilney, sulfa, and the like.

The term "heteroaryl" or "Garni" refers to a heterocycle in which at least one heterocyclic ring is aromatic.

the functional groups, for example, a halogen atom, groups, lower alkyl, lower CNS, lower alkylthio-, triptorelin, amino-, amido-, carboxyl, hydroxyl, aryl, Allexinno, heterocyclic, heteroaryl, substituted heteroaryl, nitro, cyan, alkylthio-, Tilney, sulfa, and the like.

The term "cycloalkyl" refers to a bivalent cyclic or polycyclic alkyl group containing 3 to 15 carbon atoms.

The term "substituted cycloalkyl" refers to cycloalkyl group containing one or more Deputy in the form of, for example, halogen atom, groups, lower alkyl, substituted lower alkyl, CNS, alkylthio-, aryl, Allexinno, heterocyclic, heteroaryl, substituted heteroaryl, nitro, cyan, alkylthio-, Tilney, sulfa, and the like.

Compounds of the present invention are useful as agonists of receptor-A1to ensure electrical disturbances in the heart, such as supraventricular tachycardia, including atrial fibrillation, Torsade de pointes, reflexive tachycardia atrioventricular node. The compounds can be administered orally, intravenously, through the epidermis x2">

The treatment method includes receiving an effective amount of the selected compound, preferably dispersed in a pharmaceutical carrier. Unit dosages of the active ingredient in the General case are selected from a range from 0.01 to 100 mg/kg, but they can easily be identified by specialists in the appropriate field depending on the route of administration, the age and condition of the patient. These unit doses may be accepted from one to ten times daily for acute and chronic disorders. When the compounds of the present invention will be made in accordance with the instructions of the present invention, there is no unacceptable Toxicological action.

In that case, if the target compound of the present invention will contain a basic group can be obtained additive salt of the acid. Additive salts of acids of these compounds are obtained in a standard manner in a suitable solvent from the parent compound and an excess of acid, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methansulfonate. Particularly useful is a salt of hydrochloric acid. In that case, if Ko is treated with an excess of an alkaline reagent, such as the hydroxide, carbonate or alkoxide, containing the appropriate cation. Such cations as Na+, K+Ca+2and NH4+provide examples of cations present in pharmaceutically acceptable salts. Some of the compounds form an internal salt or zwitter-ions, which can also be acceptable.

Pharmaceutical compositions containing the compounds of the present invention, and/or their derivatives, can be obtained in the form of solutions or liofilizovannyh powders for parenteral administration. The composition of the powders can be changed by adding before the use of a suitable diluent or another pharmaceutically acceptable carrier. Being used in liquid form, the compositions of the present invention preferably are entered in the buffer, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, a standard 5% dextrose in water and buffer solution of sodium acetate or ammonium acetate. Such liquid compositions suitable for parenteral administration, but can also be used for oral administration. It may be desirable to add exogrid sodium, sodium citrate or any other excipient, well-known specialists in the field of pharmaceutical compositions including the compounds of the present invention. In the alternative case, the pharmaceutical compounds can be in the form of capsules, tablets or prepared in an emulsion or syrup for oral administration. In order to improve or stabilize the composition, or to facilitate the acquisition of the composition, can be added pharmaceutically acceptable solid or liquid carriers. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, Teff Alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a substance providing a prolonged selection of the drug, such as glycerol monostearate or distearate glycerol, alone or together with wax. The amount of solid media is changing, but, preferably, it is in the range from about 20 mg to about 1 gram per unit dosage. Pharmaceutical dosing is carried out using conventional techniques, such kalyanee, mixing and filling for hard gelatin capsule forms. When used carrier liquid is received in the form of a syrup, elixir, emulsion, or aqueous or non-aqueous suspensions. Such liquid compositions can be made directly, or they may be filled in soft gelatin capsules.

The examples below serve to illustrate the invention. Examples in no way imply a limitation of the scope of claims of the present invention, but are provided to show how to make and use the compounds of the present invention. In the examples all temperatures are measured in degrees Celsius.

Example 1.

Compounds of the present invention can be obtained by conventional methods of organic chemistry. The sequence of reactions shown below, is a General method suitable for producing compounds of the present invention.

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In accordance with this method, oxacyclopropane acid is heated in a mixture of dioxane, diphenylphosphinite triethylamine for 1 hour. To this mixture is added benzyl alcohol and the reaction mixture is additionally heated in accordance with the make a concentrated HCl, Pd/C and the mixture is placed in a nitrogen atmosphere at a pressure of 1 ATM. The mixture is stirred over night at room temperature and filtered. The residue is recrystallized with the formation of intermediate compound 2. Add riboside 6 - chloropurine and the mixture is a compound 2 dissolved in methanol and treated with triethylamine. The reaction mixture is heated at 80oC for 30 hours. Separation and purification yield compound 3.

Example 2.

Compounds of the present invention obtained in accordance with the method of example 1, were tested for the two functional models that are specific to the functions of the agonist adenosine receptor (A1. The first model represents the inhibition by receptor-A1accumulation of C - AMP stimulated by isoproterenol cells DDT. AS for each derivative are shown in table 1. Table 1 shows the ability of each derivative to stimulate the formation of C - AMP in cells RS, the function of stimulating agonist adenosine receptors (A2. The ratio of the relative performance of each of the compounds to stimulate action or receptor A1or receptor A2izvozna relatively selectively as an agonist of the receptor of A1. Using measurements of parameters of metabolism of C - AMP to analyze the functions of adenosine receptor A1it has been described previously (Scammells, P., Baker, S., Belardinelli, L., and Olsson, R. , 1994, Substituted 1,3-dipropylxanthines as irreversible antagonists of A1adenosine receptors. J. Med.Chem., 2794-2712, 1994).

Compounds were also tested for the model of the whole body, describing the activation of receptor-A1in relation to the function of the Atria and function of the atrioventricular node. In this model, the hearts of Guinea pigs were isolated and then watered with saline containing compound, the frequency of contractions of the Atria and the time of conduction in the atrioventricular node was evaluated by carrying out electrophotographic measurement of the cycle duration of the atrial and atrio-ventricular intervals as described in detail in the work Belardinelli, L., Lu, J., Dennis, D., Martens, J. , and Shryock, J. (1994); The cardiac effects of a novel A - adenosine receptor agonist in guinea pig isolated heart. J. Pharm. Exp. Therap. 271: 1371- 1382(1994). As shown in Fig 1, each derivative was effective for lowering the frequency of contractions of the Atria and longer conductivity of the atrioventricular node to the spontaneous heart rate, and the concentration dependence is nature, Denom heart.

Example 3.

Obtaining N-benzyloxycarbonyl - 4-aminopyrene.

A mixture of 4 - perenesennoy acid (2.28 g, 20 mmol), diphenylphosphinite (or 4.31 ml, 20 mmol), triethylamine (2,78 ml, 20 mmol) in dioxane (40 ml) is heated in an oil bath at 100oC in dry nitrogen atmosphere for 1 hour. Add benzyl alcohol (2.7 ml, 26 mmol) and continue heating at 100oC for 22 hours. The mixture is cooled, filtered from the white precipitate and concentrate. The residue is dissolved in 2 n HCl and extracted twice using EtOAc. The extracts are washed with water, sodium bicarbonate, brine and then dried over MgSO4, then concentrate to obtain the oil, which solidifies upon standing. The oil is passed through the chromatograph (from 30% to 60% EtOAc/Hex), which gives 1.85 g of a white solid (40%).

Getting 4 - aminopyrene.

N-benzyloxycarbonyl-4-aminopyrene (1.85 g, 7.87 mmol) dissolved in MeOH(50 ml) with concentrated HCl and PdC (10%, 300 mg). The vessel is filled with hydrogen at a pressure of 1 ATM and the mixture is left to mix for 18 hours at room temperature. The mixture is filtered on pad of brownmillerite and concentrate. The residue is evaporated twice together with MeOH/EtOAc and ptx2">

Getting riboside 6-(4-aminopyrine) - purine.

A mixture of riboside 6-chloropurine (0,318 g, 1.1 mmol), 4-aminopurin - HCl (0,220 mg, 1.6 mmol) and triethylamine (0,385 ml, 2.5 mmol) in methanol (10 ml) is heated at 80oC for 30 hours. The mixture is cooled, concentrated and the residue passed through a chromatograph (90:10:1, CH2Cl2/MeOH/PrNH2). The appropriate fractions are collected and again chromatographic on chromatotron (plate 2 mm, 90:10:1, CH2Cl2/MeOH/PrNH2), which are whitish foam, (0,37 g, 95%).

Example 4.

Obtaining N-benzyloxycarbonyl-3-aminotetrahydrofuran.

A mixture of 3-tetrahydrofuranate acid (3.5 g, 30 mmol), diphenylphosphinite (6,82 ml, 32 mmol), triethylamine (5 ml, 36 mmol) in dioxane (35 ml) was stirred at room temperature for 20 minutes and then heated in an oil bath at 100oC in dry nitrogen atmosphere for 2 hours. Add benzyl alcohol (4,7 ml, 45 mmol) and continue heating at 100oC for 22 hours. The mixture is cooled, filtered from the white precipitate and concentrate. The residue is dissolved in 2 n HCl and extracted twice using EtOAc. The extracts are washed with water, sodium bicarbonate, brine, was passed through the chromatograph (from 30% to 60% EtOAc/Hex) that gave 3.4 g of an oil (51%).

Obtaining 3 - aminotetrahydrofuran.

N - benzyloxycarbonyl - 3 - aminotetrahydrofuran (3.4 g, 15 mmol) dissolved in Meon (50 ml) with concentrated HCl and Pd-C (10%, 300 mg). The vessel is filled with hydrogen at a pressure of 1 ATM and the mixture is left to mix for 18 hours at room temperature. The mixture is filtered on pad of brownmillerite and concentrate. The residue is evaporated twice together with MeOH/EtOAc and recrystallized from MeOH/EtOAc to obtain 1.9 g of a yellow solid.

Getting riboside 6-(3-aminotetrahydrofuran) purine.

A mixture of riboside 6 - chloropurine (0.5 g, of 1.74 mmol), 3 - aminotetrahydrofuran (0,325 g, 2.6 mmol) and triethylamine (0,73 ml, with 5.22 mmol) in methanol (10 ml) is heated at 80oC for 40 hours. The mixture is cooled and concentrated. The residue is filtered over a short column with silica gel, loireau a 90/10/1 mixture of (CH2Cl2/MeOH/PrNH2containing the product fractions are combined and focus. The remainder chromatographic on chromatotron (plate 2 mm 92,5/7,5/1, CH2Cl2/MeOH/PrNH2). The resulting white solid is recrystallized from MeOH/EtOAc, resulting in a gain of 0.27 g of hydrochloride 3-aminotetrahydrofuran.

A mixture of the hydrochloride of 3 - aminotetrahydrofuran (0.5 g, 4 mmol) and chloride (S)-()-10-camphorsulfonate (1.1 g, 4.4 mmol) in pyridine (10 ml) is stirred for 4 hours at K. T. and then concentrated. The residue is dissolved in EtOAc and washed with 0.5 n HCl solution, sodium bicarbonate and saline. The organic layer is dried over MgSO4, filtered and concentrated, giving 1,17 g brown oil (97%), which is passed through the chromatograph with a column with silica gel (25% to 70%, EtOAc/Hex). The obtained white solid precipitate was repeatedly recrystallized from acetone and the crystals and the supernatant combine until then, until you get using 1H NMR gain, more than 90%.

Getting hydrochloride 3-(S)-aminotetrahydrofuran.

The sulfonamide (170 mg, 0,56 mmol) is dissolved in a concentrated mixture of HCl/AcOH (2 ml for each component), for 20 hours at room temperature, stirred, and then washed three times using CH2Cl2(10 ml) and concentrated to dryness, giving 75 mg(quantitative) of a white solid.

Getting riboside 6-(3-(S)-aminotetrahydrofuran)purine.

A mixture of riboside 6 - chloropurine (30 mg, 0.10 mmol), hydrochloride of 3-(S)-aminotetrahydrofuran (19 mg the support, concentrate and chromatographic using 95/5 (CH2Cl2/MeOH) to give 8 mg (24%) of a white solid.

An example of a composition for intravenous injection

1000 nm active compound in the solution containing (mm): NaCl - 117,9, KCl - 4,8, CaCl2- 2,5, MgSO4- 1,18, KH2PO4- 1,2, NaEDTA - 0,5, ascorbic acid is 0.14, glucose - 5,5, pyruvic acid and 2.0, and NaHCO3a-2.5, pH to 7.4. The solution is administered intravenously.

Test of competitive binding

Striatum (striped body) pigs homogenized in 50 mm Tris buffer (5 volumes to the tissue mass, pH of 7.4). After centrifugation at 19 000 rpm for 25 minutes atoC, the supernatant discarded, and the procedure repeated twice. Compounds according to the invention are tested to determine their affinity for the receptor, A1in membrane preparations of pig striatum. Briefly, 0.2 mg membrane striatum pigs treated with adenoidectomies and 50 mm Tris buffer (pH= 7,4), followed by mixing. The membranes add 2 ml of serially diluted DMSO initial solution of the compounds according to the invention, having a concentration of from 100 μm to 10 nm. The control contains 2 μl of DMSO, then add the antagonist of the striatum pigs - [3H] 8-cyclopentylamine (CPX, the 2 hours the solution is filtered, using harvester (collector) membranes and multiple (triple) washing of the membranes. Calculation of filter discs is carried out in a scintillation mixture, allowing you to determine the number of substitutions tritium-labeled CPX or due to competitive binding of the compounds according to the invention. Curves constructed on the basis of more than 5 points were used to determine the IC50. The results are presented in table 2.

VI. (3S)-3-({9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl) oxolan-2-yl]purine-6-yl}amino)-3,4,5-trihydrogen-2-it:

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VII. 4-({ 9-[(4S, 3R,5R)-3,4-DigiTrace-5-(hydroxymethyl) oxolan-2-yl] purine-6-yl}amino)-1,1-dissociation:

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X. (4S,3R,5R)-5-(hydroxymethyl)-2-[6-(pyrrolidin-3 - ylamino)purine-9-yl] oxolan-3,4-diol:

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XI. (4S, 3R, 5R)-5-(hydroxymethyl)-2-[6-(3-piperidylamine) purine-9-yl] oxolan-3,4-diol:

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XII. 8-({ 9-[(4S, 3R,5R)-3,4-dihydroxy-5-(hydroxymethyl) oxolan-2-yl] purine-6-yl}amino)-3-oxabicyclo[3,3,0]Octan-2-he

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XIV. (4S, 3R,5R)-5-(hydroxymethyl)-2-(6-{[1-benzyl (4-piperidyl)]amino} - purine-9-yl]oxolan-3,4-diol:

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XV. (4S, 3R, 5R)-5-(hydroxymethyl)-2-[6-(4-piperidylamine) purine-9-yl] oxolan-3,4-diol:

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XVI. 2-{ 6-[((3R)pyrrolidin-3-yl)amino] purine-9-yl} -(4S, 3R, 5R)-5-(hydroxymethyl)oxolan-3,4-diol:

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XVII XVIII. [4-({9-[(43,3 R,5R)-3,4-dihydroxy-5-(hydroxymethyl) oxolan-2-yl] purine-6-yl}amino)piperidyl]-N-benzylcarbamoyl:

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XIX. 4-({ 9-[(4S, 3R,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl] purine-6-yl}amino)-1-[(4 - were)sulfonyl]piperidine:

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XX. 4-({ 9-[(4S, 3R, 5R)-3,4-dihydroxy-5-(hydroxymethyl) oxolan-2-yl] purine-6-yl}amino)piperidinylmethyl:

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XXI. Phenylmethyl 3-({9-[(4S,3R,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl]purine-6-l}amino) pyrrolidinecarboxylic:

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XXII. 3-({ 9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl) oxolan-2-yl] purine-6-yl}amino)pyrrolidine-2-itfeel-ketone:

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XXIII. (4S, 3R,5R)-2-{6-[((3S,4R)-4-hydroxyanisole-3-yl)amino] purine-9-yl}-5-(hydroxymethyl)oxolan-3,4-diol:

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XXV. Ethyl 4-({9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl) oxolan-2-yl]purine-6-yl}amino)(3S,4R)-3-hydroxypyrrolidine:

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XXVI. (4S,3R,5R)-5-(hydroxymethyl-2-{6-[(7-oxabicyclo- [2,2,1]hept-2-yl)amino]purine-9-yl}oxolan-3,4-diol

1. Derived adenosine formula

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where R1represents a monocyclic heterocyclic group containing from 3 to 15 atoms, at least one of which is selected from the group consisting of N, O and SO2which may be mono - or polyamidine one or more mixing is alkyl, acyl or carboxyl group, and where1not a monocyclic-lactam or imide, and where R1does not contain an epoxy group.

2. Derived adenosine formula

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where R1represents a monocyclic, bicyclic or tricyclic cycloalkyl group containing from 3 to 15 atoms, at least one of which is oxygen, which may be mono - or polyamidine one or more substituents selected from the group consisting of a carbonyl group, hydroxyl, lower alkyl or substituted lower alkyl groups.

3. Connection on p. 1, where R1is selected from the group consisting of

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or

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where each R may be independently selected from the group consisting of H atom, a lower alkyl group and a substituted lower alkyl group, and where X represents O or SO2.

4. Connection on p. 1, where R1is selected from the group consisting of 3-tetrahydrofuranyl, 3-tetrahydrofuranyl, 4-pyranyl and 4-dipiradol.

5. Connection PP.1 to 4, having the properties of agonist adenosine receptor type I.

6. The correction method of electrical disturbances in the heart of a mammal papatayin therapeutically effective amount of the compounds under item 1.

7. The method according to p. 6, characterized in that a therapeutically effective amount of the compounds on p. 1 of approximately from 0.01 to 100 mg/kg weight of the mammal.

8. The method according to p. 6, characterized in that the electrical disturbance in the heart may be supraventricular tachycardia, atrial fibrillation, Torsade de pointes and age tachycardia atrioventricular node.

9. The method according to p. 6, characterized in that the mammal is man.

10. Pharmaceutical composition for correction of electrical disturbances in the heart of mammals that contains the connection on p. 1 and one or more pharmaceutical excipient.

11. The pharmaceutical composition under item 10 in the form of a solution.

12. The pharmaceutical composition under item 10 in the form of tablets.

 

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The invention relates to O6substituted derivatives of guanine, method of their production and to their use for the treatment of tumor cells

The invention relates to derivatives of adenosine General formula I, where R1is a hydrogen atom, halogen atom, lower alkyl, lower-alkyl, lower S-alkyl or phenyl, and may be in the 2 - or 5-position of the indole; n = 0, 1, and 2, R2- lower alkyl, lower alkenyl, lower quinil,3-C7-cycloalkyl or lower-alkyl, phenyl, possibly substituted by 1-4 substituents selected from a halogen atom, nitro, lower alkyl or O-alkyl groups or a group-NR6R7where R6and R7a hydrogen atom, lower alkyl; pyridyl; thienyl, naphthyl, and in the case when n = 2, R2group-NR8R9where R8and R9at the same time are lower alkyl or form together with the nitrogen atom to which they are attached, a heterocycle selected from the research, piperidine; R3and R4the same or different, is a hydrogen atom or lower alkyl, exhibiting analgesic and antihypertensive activity

The invention relates to new compounds of formula I Nu-O-Fa, where O is oxygen, Nu is a nucleoside or nucleoside analogue, including such nitrogen base, as adenine, Esenin, cytosine, uracil, thymine; Fa - acyl monounsaturated C18YPD C20-9-fatty acids, which fatty acid etherification hydroxyl group in 5-position of the sugar portion of the nucleoside or nucleoside analog, or a hydroxyl group, an acyclic chain of an analogue of the nucleoside

d-arabinofuranosyl)-n-purine, method for their preparation and use and pharmaceutical composition" target="_blank">

The invention relates to mono-, di - or tri-esters of 2-amino-6-(C1-C5-alkoxy)-9-(-D-arabinofuranosyl)-N-purine General formula (I)

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where arabinofuranosyl residue substituted for 2'-, 3'- or 5'-positions, and esters formed by carboxylic acids, in which decarbonising part selected from n-propyl, tert-butyl, n-butyl, methoxymethyl, benzyl, phenoxymethyl, phenyl, methanesulfonyl and succinyl

The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula I:

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where R is C1-C4-alkyl, does not necessarily substituted by one or more groups, or R is:

< / BR>
a benzyl, robotjam, 2-deoxyribosyl or (CH2)n-OR1where n is 1 or 2, and R1is CH2CH2OH or< / BR>
or their salts

The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula

(l) where R is a C1-C4-alkyl, optionally substituted by one or more hydroxyl groups, or R is

a benzyl, ribosom, 2-deoxyribosyl or (CH2)n-OR SIG1where n is 1 or 2, and R1is CH2CH2HE or CHor their salts

The invention relates to a method for producing derivatives of S-adenosylmethionine (HIMSELF), General formula

< / BR>
where R is benzene, p-toluensulfonyl or linear aliphatic acyl radical containing 2-6 carbon atoms; R1H or benzoyl or linear aliphatic acyl containing 2 to 6 carbon atoms; R and R1same or different when R1has a value other than hydrogen; n is 1-5; And is the equivalent of the acid with PKandless than 2.5

The invention relates to certain substituted purine to arabinoside and acceptable from the physiological standpoint derivatives, in particular esters and their use for the treatment of certain DNA-viral diseases

The invention relates to medicine, specifically to composition antiarrhythmic drugs, including amiodarone hydrochloride, lactose, polyvinylpyrrolidone, talc powder, potato starch, microcrystalline cellulose, calcium stearate at a certain ratio

The invention relates to new chemical compounds, specifically to the derivatives of amino acids, which exhibit antiarrhythmic activity and can be used in medical practice as anti-arrhythmic drugs

The invention relates to 4-mercapto-benzoylpyridine formula (I), where R1denotes A; R2means And, unsubstituted or substituted by F, Cl, Br, phenyl, pyridyl; And - alkyl with 1-6 C-atoms, and their physiologically acceptable salts, methods for their production and pharmaceutical compositions based on them

The invention relates to new heterocyclic condensed to benzoylpyridine General formula I, where R1and R2denote independently from each other H or A; X denotes CR4R5; C=Z or O, Y represents CR6R7Z denotes O or CH2, R4, R5, R6or R7denote independently from each other H, A, HE or OA, or R5and R6or R7and R8indicate link together, with each molecule may receive a maximum of only one such bond, or R4and R5indicate together O-(CH2)2-O or O-(CH2)3-O, or R8and R9denote independently from each other H or A; And denotes alkyl with 1 to 6 C-atoms; n represents 0 or 1, and their physiologically acceptable salts

The invention relates to substituted benzosulfimide formula I

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where mean:

R(1) - alkyl with 1, 2, 3, 4, 5 or 6 C-atoms;

R(2) - alkoxy with 1, 2, 3, 4, 5 or 6 C-atoms;

R(3) - hydrogen;

R(4), R(5) R(6) - independently from each other hydrogen, aryl or alkyl with 1, 2, 3, 4, 5 or 6 C-atoms;

E - sulfur;

X is oxygen;

Y - CH2group,

and their pharmaceutically tolerable salts

The invention relates to methods for treating diseases caused by hepatitis B virus (also known as HBV and Epstein-Barr (also known as EBV, which include the introduction of an effective amount of one or more of the active compounds disclosed here, or farmatsevticheskii acceptable derivatives or prodrugs of one of these compounds
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