Novel 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidine-2-(3h)-amine derivatives and use thereof in therapy

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1 denotes CH3; R2 denotes halogen or CN; R3 denotes H or CH3; R4 denotes H or CH3; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of compounds of formula (I) in preparing a medicinal agent, having CX3CR1 receptor antagonist activity.

EFFECT: compounds can be used as CX3CR1 receptor antagonists.

13 cl, 1 tbl, 10 ex

 

The scope of the invention

In the present invention discloses new 5-substituted derivatives of 7-amino-[1,3]thiazolo[4,5-d]pyrimidine, as well as methods for their preparation, pharmaceutical compositions containing them and their use in therapy.

Prior art

Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma, atherosclerosis, allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and multiple sclerosis. These small, secreted molecules are growing superfamily of 8-14 kDa proteins that differ conservative cysteine motif. Currently, the superfamily of chemokines includes four groups, having the characteristic structural motifs, a family of C-X-C, C-C and C-X3-C and XC. C-X-C and C-C family have sequence similarity and differ from each other by one amino acid insertion between NH-proximal pair of cysteine residues. C-X3With the family differs from the other two families that has an insertion of three amino acids between NH-proximal pair of cysteine residues. On the contrary, the members of the XC family is missing one of the first two cysteine residues.

C-X-C chemokines include several effective chemoattractants and the activator is in neutrophils, such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).

C-C chemokines include effective chemoattractant monocytes, lymphocytes and neutrophils. Examples include chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3) human monocytes, RANTES (regulated upon activation, expressed and secreted normal T-cells), eotaxin and macrophage inflammatory proteins 1α and 1β(Ì1Ð-1A and Ì1Ð-1β).

C-X3With chemokine (also known as fractalkine) is an effective chemoattractant and activator of microglia in the Central nervous system (CNS), as well as monocytes, T cells, NK cells and mast cells.

Studies have demonstrated that the actions of chemokines is mediated by subfamilies of receptors associated with G-proteins, including receptors, designated as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CP1 for C-X3With family. These receptors are good targets for drug development, because the agents that modulate these receptors will be useful in the treatment of disorders and diseases, such as mentioned above.

In WO 01/58907 revealed some 2-substituted derivatives of 4-aminothiazoline, which are useful as antagonists of receptors associated with families With-The-C and C-C chemokines, in particular as antagonists of the CXCR2 receptor.

The present invention relates to a group of compounds that are similar to the compounds disclosed in WO 01/58907, but have the type of structure, not specifically obtained there. Compared to the examples disclosed in WO 01/58907, the compounds of the present invention show unexpectedly beneficial properties as antagonists CX3CP1 receptor.

Description of the invention

In the present invention proposed the compounds of formula (I)

where R1represents CH3or CF3;

R2represents halogen, CN or C1-C6alkyl;

R3represents N or CH3;

R4represents N or CH3;

n is 0,1 or 2;

in the form of free base or its pharmaceutically acceptable salt, MES or MES salts thereof.

In one embodiment of the proposed invention the compounds of formula (I), where n is equal to 1.

In another embodiment of the proposed invention the compounds of formula (I), where R1represents CH3.

In yet another embodiment of the proposed invention the compounds of formula (I), where R2represents halogen or CN.

In yet another embodiment of the proposed invention the compounds of formula (I), where R2represents F or Cl.

In yet another embodiment from which retene proposed the compounds of formula (I), where R2represents CN.

In yet another embodiment of the proposed invention the compounds of formula (I), where n is equal to 1; R1represents CH3and R2represents F, Cl or CN.

In yet another embodiment of the proposed invention the compounds of formula (I), in which the pyridine is attached by its position 5 and is Cl in position 2.

In yet another embodiment of the proposed invention the compounds of formula (I), where the pyridine is attached by its position 2 and carries CN in position 4.

In yet another embodiment of the proposed invention the compounds of formula (I), where the pyridine is attached by its position 2 and assume F in position 5.

In yet another embodiment of the proposed invention the compounds of formula (I), where the pyridine is attached by its position 2 and is Cl in position 5.

In yet another embodiment of the proposed invention the compounds of formula (I), where the pyridine is attached by its position 2 and assume F in position 3.

In yet another embodiment of the proposed invention the compounds of formula (I), where the pyridine is attached by its position 4 and carries S1 in position 3.

In yet another embodiment of the proposed invention the compounds of formula (I), where R3represents N.

In yet another embodiment of the proposed invention the compounds of formula (I), where R4represents CH3.

In another embodied and the proposed invention the compounds of formula (I), selected from the

(2R)-2-[(2-amino-5-{[1-(5-herperidin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;

(2R)-2-[(2-amino-5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;

(2R)-2-[(2-amino-5-{[(1S)-1-(5-herperidin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;

(2R)-2-[(2-amino-5-{[1-(3-chloropyridin-4-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;

(2R)-2-[(2-amino-5-{[(1S)-1-(3-chloropyridin-4-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;

(2R)-2-[(2-amino-5-{[(1S)-1-(3-chloropyridin-4-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;

(2R)-2-[(2-amino-5-{[(1S)-1-(3-herperidin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;

(2R)-2-[(2-amino-5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)(methyl)amino]pentane-1-ol;

(2R)-2-[(2-amino-5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]pentane-1-ol and

2-{(1S)-1-[(2-amino-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-5-yl)thio]ethyl}isonicotinamide

in the form of free base or its pharmaceutically acceptable salt, MES or MES salts thereof.

The compounds of formula (I) can exist in stereoisomeric and/or tautomeric forms. It should be understood that all enantiomers, diastereomers, racemates, tautomers and the mixture is included in the scope of this invention.

Compared with the compounds disclosed in WO 01/58907, the compounds of the present invention are distinguished by the presence of branched dialkylphenol in position 5 triazolopyrimidine ring system. That is, the compounds of the present invention contain a group R1that is not hydrogen.

In accordance with the invention, the inventors also propose a method of obtaining the compounds of formula (I) or its pharmaceutically acceptable salt, which includes

a) interaction of the compounds of formula (II)

where R3and R4such as defined in formula (I)

with the compound of the formula (III)

(111) where R1, R2and n are such as defined in formula (I), and L1represents a leaving group, or

b) interaction of the compounds of formula (IV)

where R1, R2and n are such as defined in formula (I), and L2represents a leaving group,

with the compound of the formula (V)

where R3and R4such as defined in formula (I),

and, where necessary, converting the resulting compounds of formula (I), or other salts, its pharmaceutically acceptable salt or conversion of the compounds of formula (I) have the compound of formula (I) and where it is desirable that the conversion of the compounds of formula (I) in its optical isomer.

In method (a), the reactants (II) and (III) are combined together in a suitable organic solvent, such as dimethylsulfoxide (DMSO), acetonitrile or 1-methyl-2-pyrrolidinone (NMP). The interaction can be carried out in the presence of added organic or inorganic bases, such as triethylamine, N,N-diisopropylethylamine (DIPEA) or sodium hydride. The interaction can be carried out in the presence of a mild reducing agent such as sodium borohydride. The interaction is carried out at a suitable temperature, typically between room temperature and the boiling point of the solvent. Interaction in the General case continued throughout the period of time from one hour to one week or until the analysis indicated that the formation of the target product is finished.

In method (b) reactants (IV) and (V) are combined together in a suitable organic solvent, such as tetrahydrofuran, acetonitrile, dimethyl sulfoxide or 1-methyl-2-pyrrolidinone. The interaction can be carried out in the presence of added base. This base can be an organic base such as triethylamine or N,N-diisopropylethylamine, or inorganic base such as potassium carbonate. The interaction is carried out at a suitable those is the temperature, usually between room temperature and the boiling point of the solvent, but at higher temperatures when using a sealed reaction vessel. Interaction in the General case continued for a period of time from about one hour to one week or until the analysis indicated that the formation of the target product is finished.

Suitable leaving groups L1and L2are halogen, in particular chlorine or bromine. In one embodiment, each of the L1and L2represents chlorine.

Specialist in the art it is obvious that the above methods may be desirable or necessary to protect the amine, hydroxyl or other potentially reactive group. Suitable protective groups, and detail methods of attaching and removing such groups in General are well known in the art. See, for example, "Protective Groups in Organic Synthesis", 3rd ed. (1999), Greene and Wuts.

The present invention includes compounds of formula (I) in the form of salts. Suitable salts include salts formed with organic or inorganic acids, or organic or inorganic bases. Such salts are pharmaceutically acceptable, although salts of pharmaceutically unacceptable acids or bases can be used in the production and purification of interest is its compounds.

Salts of compounds of formula (I) can be formed by the interaction of a free compound or its salt, enantiomer or racemate, one or more equivalents of the appropriate acid or base. The interaction can be performed in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, such as water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents that can be removed under vacuum or by freeze drying. The interaction may also be a metabolic process or may be performed on the ion-exchange resin.

The compounds of formula (II) are either known from, for example, WO 01/58907, WO 01/25242 or WO 02/76990, or can be obtained using known methods, which are obvious to a person skilled in this technical field.

The compounds of formula (IV) can be obtained using methods similar to those described for example in WO 00/09511, or using other known methods, which are obvious to a person skilled in this technical field.

Compounds of formulas (III) and (V) are either commercially available or known in the literature or can be obtained using known methods, which are obvious to a person skilled in this technical field.

Suitable specific methods for obtaining the compounds of the Fort is str (II), (III), (IV) and (V) described in detail in the Examples section of this application, and such methods are specific embodiments of the methods according to the invention.

For example, the compounds of formula (II) and then the compounds of formula (I)can be obtained, as shown in figure 1:

Intermediate compounds can be used as such or in protected form. Suitable protective groups, and detail methods of attaching and removing such groups in General are well known in the art. See, for example, "Protective Groups in Organic Synthesis", 3rd ed. (1999), Greene and Wuts.

Compounds according to the invention and intermediate compounds can be isolated from reaction mixtures and, if necessary, further purified using standard techniques.

The compounds of formula (I) can exist in stereoisomeric forms. Therefore, all enantiomers, diastereomers, racemates and mixtures thereof are included in the scope of the invention. The various optical isomers may be isolated by separation of the stereoisomeric mixture of the compounds using conventional techniques such as fractional crystallization or HPLC. Alternative various optical isomers may be obtained directly by using optically active starting materials.

The compounds of formula (I) contain two stereogenic center is and can thus, to exist in four stereoisomeric forms, as shown in formulas (Ia)-(Id)

All these four stereoisomer or any mixture thereof is included in the scope of the invention. In one embodiment of compounds of formula (I) have the stereochemistry shown in formula (Ia). In another embodiment of the compounds of formula (I) have the stereochemistry shown in formula (Ib).

Intermediate compounds may also exist in stereoisomeric forms and can be used in the form of purified santomero, diastereomers, racemates or mixtures thereof.

In this application, the term "C1-C6-alkyl" includes an alkyl group with a straight or branched chain, and cyclic alkyl groups. With1-C6the alkyl contains from 1 to 6 carbon atoms and may consist of, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, isohexyl or cyclohexyl.

In this application, the term "halogen" or "halogen" refers to a fluorescent, chloro, bromo and iodide.

The compounds of formula (I) and their pharmaceutically acceptable salts are useful because they possess pharmacological activity as antagonists of the CX3 R1 receptors. In particular, compared with the compounds are given as specific examples in WO 01/58907, the compounds of formula (I) according to the present invention have significantly higher efficiencies in relation to inhibition CX3R1 receptor and/or reduced efficiencies in relation to inhibition of CXCR2 receptor. Preferred compounds of the present invention show improved efficacy in inhibiting CX3R1 and reduced efficacy in inhibiting CXCR2.

In one aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt for use as a medicine.

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicine for treatment or prevention of diseases or conditions in which useful antagonism CX3R1 receptor.

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicine for treatment or prevention of neurodegenerative disorders, demyelinating disease, cardio - and cerebrovascular atherosclerotic the Sam the properties, disease peripheral artery disease, rheumatoid arthritis, pulmonary diseases such as COPD (chronic obstructive pulmonary disease), asthma or pain.

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicine for treatment or prevention of multiple sclerosis (MS).

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicinal product for the treatment or prophylaxis of atherosclerosis by preventing and/or reducing the formation of new atherosclerotic lesions or plaques and/or by preventing or slowing the development of existing lesions and plaques.

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicinal product for the treatment or prophylaxis of atherosclerosis by changing the composition of the plaques with the aim of reducing the risk of plaque rupture and atherothrombotic events.

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicine for treatment or prevention of stroke or t is antidamage brain injury (TBI).

In accordance with the invention is also a method of treating or reducing the risk of diseases or conditions in which useful antagonism CX3CR1 receptor comprising the administration to a subject suffering from the specified disease or condition or having a risk for a specified disease or condition a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

Also, a method of treating or reducing the risk of neurodegenerative disorders, demyelinating disease, cardio - and cerebrovascular atherosclerotic disorders, peripheral artery disease, rheumatoid arthritis, pulmonary diseases such as COPD, asthma or pain, the subject suffering from the specified disease or condition or having a risk for a specified disease or condition comprising administration to the subject a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

Also, a method of treating or reducing the risk of multiple sclerosis (MS) in a subject suffering from the specified disease or condition or having a risk for a specified disease or condition including introduction to this subject a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

Also, a method of treating or reducing the risk of atherosclerosis by changing the composition of the plaques so as to reduce the risk of plaque rupture and atherothrombotic events in a subject suffering from the specified disease or condition or having a risk for a specified disease or condition comprising administration to the subject a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

Also proposed is a method of treating or reducing the risk of stroke or transient brain injury (TBI) in a subject suffering from the specified disease or condition or having a risk for a specified disease or condition comprising administration to the subject a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

The compounds can be used as monotherapy or in combination, either as a prophylactic or therapeutic treatment of inflammatory conditions and diseases of the Central nervous system such as stroke and transitor the th brain injury (TBI) (Soriano et al. J.Neuroimmunology 2002, 125, 59-65).

In another aspect of the invention proposed pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier for use in treating or preventing diseases or conditions in which useful antagonism CX3R1 receptor.

In another aspect of the invention proposed pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prevention of neurodegenerative disorders, demyelinating disease, cardio - and cerebrovascular atherosclerotic disorders, peripheral artery disease, rheumatoid arthritis, COPD, asthma or pain.

In another aspect of the invention proposed pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prevention of multiple sclerosis.

In another aspect of the present isobuteneisoprene pharmaceutical composition, containing a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the treatment or prophylaxis of atherosclerosis by preventing and reducing the formation of new atherosclerotic lesions and/or plaques and/or by preventing or slowing the development of existing lesions and plaques.

In another aspect of the present invention proposed a pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prophylaxis of atherosclerosis by changing the composition of the plaques so as to reduce the risk of plaque rupture and atherothrombotic events.

The compounds of formula (I) and their pharmaceutically acceptable salts are indicated for use in the treatment or prevention of diseases or conditions in which the desired modulation of the activity of the CX3R1 receptor. In particular, the compounds indicated for use in the treatment of neurodegenerative disorders or demyelinating disease in a mammal, including humans. More specifically, the compounds indicated for use in the treatment of asianova sclerosis. Connections are also shown as useful in the treatment of pain, rheumatoid arthritis, osteoarthritis, cardio - and cerebrovascular atherosclerotic disorders, peripheral artery disease and pulmonary arterial hypertension.

State, which can be specifically mentioned, are neurodegenerative diseases and dementia, for example Alzheimer's disease, amyotrophic lateral sclerosis and other diseases of the motor neuron disease Creutzfeldt-Jacobs and other prion diseases, HIV encephalopathy, Huntington's disease, frontotemporal dementia, dementia with calves Levi and vascular dementia; poly-neuropathies, such as Guillain-Barre syndrome, chronic inflammatory demyelinizing polyradiculopathy, multiple motor neuropathy and plexopathy; demyelination of the CNS (Central nervous system), such as acute disseminated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis; neuromuscular disorders, such as severe the male and the syndrome of Lambert-Eaton; spinal disorders, such as tropical spastic prepares syndrome and rigidity (stiff-man); paraneoplastic syndromes such as spinal cerebellar degeneration and encephalomyelitis; traumatic brain injury; headache; cancer; allograft rejection; the system is intelligent sclerosis; viral infections; diseases transmitted by parasites, such as malaria; periodontal disease; myocardial infarction; stroke; coronary heart disease; coronary heart disease; restenosis; rheumatoid arthritis; pulmonary diseases such as COPD, asthma or pain.

Compounds according to the invention are also indicated for use in the treatment of atherosclerosis by preventing and/or reducing the formation of new atherosclerotic lesions or plaques and/or by preventing or slowing the development of existing lesions and plaques.

Compounds according to the invention are also indicated for use in the treatment of atherosclerosis by changing the composition of the plaques so as to reduce the risk of plaque rupture and atherothrombotic events.

Compounds according to the invention are also indicated for use in treatment of inflammatory bowel disease (VG), such as Crohn's disease and ulcerative colitis by inducing remission and/or maintaining remission of IBD.

Prevention, as expected, is particularly relevant in the treatment of subjects who have suffered an earlier episode, or otherwise assessed as having an increased risk of the disease or condition. Subjects at risk of developing a particular disease or condition generally include subjects with a family history of et the disease or condition, or entities that have been identified by genetic testing or screening as particularly susceptible to developing the disease or condition.

For the above-mentioned therapeutic indications entered the dosage will, of course, vary depending on the compound, the route of administration and the desired treatment.

However, in General satisfactory results are obtained when the compound is injected with a solid dosage form from 1 mg to 2000 mg per day.

The compounds of formula (I) and their pharmaceutically acceptable derivatives can be used by themselves or in the form of suitable pharmaceutical compositions in which the compound or derivative is presented in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The introduction may occur, without limiting them, enteral (including oral, sublingual, or rectal), intranasal, intravenous, local or other parenteral routes. Traditional methods of selecting and obtaining a suitable pharmaceutical compositions are described, for example, in Pharmaceuticals - The Science of Dosage Form Designs", M.E.Aulton, Churchill Livingston, 1988. The pharmaceutical composition preferably contains less than 80% and more preferably less than 50% of the compounds of formula (I) or its pharmaceutically acceptable salt.

Also the method is auchenia such pharmaceutical compositions includes mixing ingredients.

The invention additionally relates to a combinational treatment, wherein the compound of formula (I) or its pharmaceutically acceptable salt or pharmaceutical composition, or a composition comprising a compound of formula (I), is administered simultaneously or sequentially with therapy and/or agent for the treatment of any cardio - and cerebrovascular atherosclerotic disorders and peripheral artery disease.

In particular, the compound of formula (I) or its pharmaceutically acceptable salt can be introduced together with compounds of one or more of the following groups:

1) anti-inflammatory agents, for example,

a) NSAID (non-steroidal anti-inflammatory drugs), such as acetylsalicylic acid, ibuprofen, naproxen, flurbiprofen, diclofenac, indomethacin);

b) inhibitors of leukotriene synthesis (5-LO inhibitors, for example AZD4407, zileuton, licofelone, CJ13610, CJ13454; FLAP inhibitors, such as BAY-Y-1015, DG-031, MK591, MC, A; inhibitors of LTA4-hydrolases, for example SC56938, SC57461A);

C) leukotriene receptor antagonists (for example, SR, amalasan, LY293111, accolate, MC);

2) antihypertensive agents, for example,

a) beta-blockers (e.g. metoprolol, atenolol, solatol);

b) inhibitors angiotensin-converting enzyme (for example, captopril, ramipril, Hina is the Rila, enalapril);

C) calcium channel blockers (such as verapamil, diltiazem, felodipine, amlodipine);

g) antagonists angiotensinogen receptor type II (e.g., irbesartan, candesartan, telmisartan, losartan);

3) anticoagulants, for example,

(a) thrombin inhibitors (e.g., ximelagatran), heparins, inhibitors of factor XA;

b) platelet aggregation inhibitors (eg, clopidogrel, ticlopidine, prasugrel, AZ4160);

4) modulators of lipid metabolism, for example,

(a) insulin sensitizers, such as PPAR agonists (receptors activated proliferation peroxisome) (e.g., pioglitazone, rosiglitazone, Halide, muraglitazar, getemail, phenobarbital);

b) inhibitors of HMG-CoA reductase, statins (such as simvastatin, pravastatin, atorvastatin, rosuvastatin, fluvastatin, pitavastatin);

V) inhibitors of cholesterol absorption (e.g. ezetimib);

d) IBAT inhibitors (transport of bile acids in the ileum) (for example, AZD-7806);

g) agonists, LXR (liver X receptor) (e.g., GW-683965A, T-0901317);

d) the FXR modulators (farnesiani X-receptor);

e) inhibitors of phospholipase;

5) antianginal tools, such as the nitrates and nitrites;

6) modulators of oxidative stress, such as antioxidants (probucol), inhibitors of myeloperoxidase.

The invention is illustrated, but the e as a limit, the following examples.

General methods

All used solvents were of analytical purity and reactions commonly used commercially available anhydrous solvents. Interaction is usually conducted in an inert atmosphere of nitrogen or argon.

1H and13The NMR spectra were recorded at 400 MHz for proton and 100 MHz for carbon-13 or on a Varian Unity+400 NMR spectrometer equipped with a 5 mm BBO probe with Z-gradients, or BrukerAvance 400 NMR spectrometer equipped with a 60 ál of double probe for the inverse flow with Z-gradients, or a Bruker DPX400 NMR spectrometer, equipped with a 4-nucleus probe equipped with Z-gradients. 600 MHz1H NMR spectra were recorded on a Bruker av600 NMR spectrometer equipped with a 5 mm BBI probe head with Z-gradients. 300 MHz1H NMR spectra were recorded on a Varian Gemini 300 NMR equipped with a 5 mm W probe head. If the examples are not specifically indicated, the spectrum was recorded at 400 MHz for proton and 100 MHz for carbon-13. Used the following reference signals: the middle line DMSO-d6δ 2.50 (1N), δ 39.51 (13C); the middle line CD3OD δ 3.31 (1N) or δ 49.15 (13C); acetone-d62.04 (1N), 206.5 (13C), and CDCl3δ (7.26 (1N), the middle line CDCl377.16 (13C) (unless otherwise specified).

The enantiomeric excess (EE) was determined by GC (g is gas chromatography) column (Cyclodex B (isothermal elution 100°C) or column Cyclosil B (temperature gradient 110-130°C). Diastereomeric excess (de) was determined by HPLC (high performance liquid chromatography).

Mass spectra were recorded on a Waters LCMS, consisting of an Alliance 2795 (LC) and ZQ odnokletochnogo mass spectrometer. The mass spectrometer was equipped with electrospray ion source (ESI)operating in positive mode or negative ions. The capillary voltage was 3 kV and the mass spectrometer scanned m/z 100-700 with a scan time of 0.3 or 0.8 C. Separation was performed either on a Waters X-Terra MS C8-columns (3.5 µm, 50 or 100 mm (2.1 mm EXT. D. (inside diameter), or ScatecLab's ACE 3 AQ column (100 mm (2.1 mm VND). The column temperature was set at 40°C. was Applied a linear gradient, using a neutral or acidic system of the mobile phase, passing from 0% to 100% of the organic phase for 4-5 minutes, flow rate 0.3 ml/min Neutral mobile phase: acetonitrile/[10 mm NH4OAc (aq.)/N (95:5)], or [10 mm NH4OAc (aq.)/N (1/9)]/ [10 mm NH4OAc (aq.)/MESM (9/1)]. Sour system of the mobile phase: [133 mm HCOOH (aq.) / MeCN (5/95)]/[8 mm HCOOH (aq.) / MeCN (98/2)].

Alternative mass spectra were recorded on a GC-MS (GC 6890, 5973N MSD, Agilent Technology), using a column VF-5 MS (EXT. D. 0.25 mm ×30 m, 0.25 μm (Varian Inc.)). Applied linear temperature gradient (40°C-300°C), 25°C/min. MS was equipped with a CI (chemical ionization) ion source, and d is gennym gas was methane. The MS was scanned between m/z 50-500 and set the scan rate to 3.25 scans/sec HPLC analysis was performed on Agilent NR system consisting of G1379A Micro Vacuum Degaser, G1312A binary pump, G1367A Wellplate automatic sampler, SO thermostatted column compartment and G1315B diode matrix detector. Column: X-Terra MS, Waters, and 4.6×50 mm, 3.5 µm. Set the column temperature 40°C and a flow rate of 1.5 ml/min Diode matrix detector scanned at 210-300 nm, step and peak width was set to 2 nm and 0.05 min, respectively. Applied linear gradient, passing from 0% to 100% acetonitrile for 4 min Mobile phase: acetonitrile/10 mm ammonium acetate in 5%acetonitrile in MilliQ water.

A typical method of processing after the interaction consisted in the extraction of the product with a solvent, such as ethyl acetate, washing with water, followed by drying the organic phase over MgSO4or Na2SO4and the concentration of the solution in vacuum.

Thin-layer chromatography (TLC) was performed on Merck TCX plates (silica gel 60 F254and for visualization of the spots used UV (ultraviolet light). Flash chromatography was performed by Combi Flash® Companion™using ReadyStep™ flash column with normal phase or on Merck Silica Gel 60 (0,040-0,063 mm). Typical solvents used for flash chromatography were mixtures of chloroform/methanol, toluene/ethyl acetate and ethyl acetate/g is Xana.

Preparative chromatography was performed on a Gilson autoproperties HPLC with diode-array detector, using a column Hagga MS (C8, 19×300 mm, 7 μm), and a gradient of acetonitrile/0.1m ammonium acetate in 5% acetonitrile in MilliQ water, flowing from 20% to 60% acetonitrile over 13 min, flow rate 20 ml/min, if the examples are not specified otherwise. Alternative purification was performed on prepreparation Shimadzu LC-8A HPLC with a Shimadzu SPD-10A UV-vis.-detector equipped with a Waters Symmetry® column (C18, 5 μm, 100 mm (19 mm). A gradient of acetonitrile/0.1% of triperoxonane acid in MilliQ water, run 35%-60% acetonitrile in 20 min flow Rate 10 ml/min

The recrystallization step is typically carried out in solvents or mixtures of solvents, such as ether, ethyl acetate/heptane and methanol/water.

Used the following abbreviations: DCM=dichloromethane; de=diastereomeric excess; DIPCI=β-chlorodiisopinocampheylborane (DIP-Chlorid™); DIPEA=N,N-diisopropylethylamine; DMF=N,N-dimethylformamide; DMSO=dimethyl sulfoxide; it=enantiomeric excess; NCS=N-chlorosuccinimide; NMP=1-methyl-2-pyrrolidinone; THF=tetrahydrofuran; aq.=water; conc.=concentrated.

The source of substance used or possessed for sale, or were obtained in accordance with known literature methods and had experimental data corresponding to announce. Below are examples of source materials, which have been received:

(2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol: WO 02/076990 (Examples 1-5 and 8);

5-(benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidine-2-amine: WO 00/09511 (Example 8);

5-fluoro-2-formylpyridine: WO 2005/066155 (Example 1);

5-Herperidin-2-carbonitril WO 2005/066155 (Example 3);

1-(3-Chloropyridin-4-yl)alanon: Marsais, F. et al. J.Organometal. Chem. 1981, 216, 139-147 (Example 4);

2-acetyl-isonicotinamide: Citterio et al. J. Chem. Res. Synopses 1982, 10, 272-273 (Example 8), and

1-(6-chloropyridin-3-yl)alanon: Lee, C. et al. J. Med. Chem. 2001, 44, 2133 (Examples 6 and 7).

In General the methods that follow, PN represents a possibly substituted pyridyl.

A common Way And

Sodium borohydride (0.1 equiv.) DIPEA (1.5 EQ.) and the compound of General formula (III), (1.2 EQ.) was added to the compound of General formula (II) (1.0 EQ.) in DMSO under nitrogen atmosphere. The resulting reaction mixture was stirred at 40°C. until the reaction has ended (monitored by LC-MS, HPLC or TLC). The mixture was poured into ice water and the product was extracted with DCM or tO. The combined organic phase was dried and concentrated in vacuum. The crude product, if necessary, purified using preparative HPLC or by column flash chromatography.

A common Way B1

The compound (VI) (1.0 EQ.) in THF was added at 0°C to (+)-DIPCI (with receipt (VII)or (-)-DIPCI (with receipt (VIII)) (1.5 EQ.) in THF in an argon atmosphere. R is the promo and the mixture was left to slowly reach room temperature over night. The solvent is evaporated, then add EtαO and diethanolamin (2.2 EQ.). The mixture was stirred until the reaction has ended (monitored by LC-MS, HPLC or TLC). The precipitate was filtered off, washed with Et2O and the filtrate was concentrated in vacuum. The crude product, if necessary, purified using preparative HPLC or by column flash chromatography.

A common way B2

(R)-(+)-2-Methyl-S-oxazaborolidine (1 M in toluene, 0.1 to 1 EQ.) was dissolved in THF and cooled to 0°C. was added dropwise borane complex-metilsulfate (2 M in THF, 1 EQ.) and the reaction mixture was stirred for 1 h, the Reaction mixture was cooled to -10°C. and was added dropwise (VI) (1 EQ.), dissolved in THF, for 0.5 h the mixture was stirred for 1 h or until the end of the reaction, and the temperature was slowly raised to 10°C. was Added 1 M HCl aq., to quench the reaction. Was added a saturated Panso3aq., until the pH was approximately 8. The product was extracted with DCM. The combined organic extracts were dried over Na2SO4and concentrated in vacuum to obtain (VIII). The product was purified column chromatography.

A common Way C1

Triphenylphosphine (1.3 EQ.) in THF was added at 0°C to NCS (1.3 EQ.) in THF in an argon atmosphere. The resulting mixture premesis is whether at ambient temperature for 30 minutes (VII) or (VIII) (1 EQ.) was added at 0°C and the reaction mixture was stirred at ambient temperature until the interaction was not complete (monitored by LC-MS, HPLC or TLC). The solvent is evaporated, and then hexane was added and the precipitate was removed by filtration. The filtrate was concentrated in vacuum to obtain (IX) or (X). The crude product, if necessary, purified using preparative HPLC or by column flash chromatography.

A common way C2

The acid chloride cyanuric acid (0.6 EQ.) was dissolved in ethyl acetate. Was added DMF (1.5 EQ.) and the mixture was stirred at room temperature for 10 minutes, the Reaction mixture was cooled to 0°C. (VII) or (VIII) (1 EQ.) was dissolved in ethyl acetate and added dropwise within 10 minutes the resulting mixture was stirred at room temperature overnight. Added isopropanol (approximately 0.25 ml/mmol (VII) or (VIII)). The precipitate was filtered and washed tO. The filtrate was concentrated to obtain specified in the header of the compound (IX) or (X).

Example 1

(2R)-2-[2-Amino-5-{[1-(5-herperidin-2-yl)ethyl]thio}[1.3] triazolo[4,5d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol

a) 1-(5-Herperidin-2-yl)ethanol

To a solution of 5-fluoro-2-formylpyridine (0.66 g, 5.3 mmol) in THF (20 ml) with a temperature of -78°C was added dropwise metallic the nd (1.6 M in diethyl ether, 4,0 ml). After stirring for 1.5 h at -78°C was added a saturated solution of ammonium chloride (25 ml), then water (25 ml). The mixture was extracted with chloroform, the organic phase was dried over magnesium sulfate and concentrated in vacuum. The residue was purified flash column-chromatography (eluent: chloroform : methanol 98:2) to obtain the specified title compound (0.25 g, yield 33%).

1H NMR (400 MHz, CDCl3): δ ppm 8.38 (d, 1 H), 7.42 (dt, 1 H), 7.33 (dd, 1 H), 4.90 (q, 1 H), 3.90 (s, 1 H), 1.50 (d, 3 H); MS (ESI) m/z 142 [M+1]+.

b) 2-(1-Chloroethyl)-5-herperidin

A mixture of triphenylphosphine (0,92 g, 3.5 mmol) and CCL4(4 ml) was stirred for 10 minutes and Then was added a solution of 1-(5-herperidin-2-yl)ethanol (0.25 g, 1.7 mmol) in DCM (2 ml). After 18 h was added pentane (20 ml), the solid was removed by filtration and the filtrate was concentrated in vacuum. The residue was purified flash column-chromatography (eluent: heptane : ethyl acetate 3:1) to obtain the specified title compound (8 mg, yield 3%).

1H NMR (400 MHz, CDCl3): δ ppm 8.35 (d, 1 H), 7.44 (dd, 1 H), 7.36 (dt, 1 H). 5.09 (q,1 H),1.81 (d,3H).

C) (2R)-2-[(2-Amino-5-{[1-(5-herperidin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol

Specified in the title compound was obtained in accordance with the General method a starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimi the in-7-yl)amino]-4-methylpentan-1-ol (21 mg, 0,072 mmol) and 2-(1-chloroethyl)-5-herperidin (8 mg, 0,048 mmol). In the purification by preparative HPLC received 4 mg (21% yield) specified in the title compounds as a mixture of diastereoisomers.

1H NMR (400 MHz, DMSO-d6): δ ppm 8.44 (t, 1H), 7.91 (s, 2H), 7.55-7.64 (m, 1H), 7.47-7.55 (m, 1H), 6.83 (d, 1H), 4.99-5.11 (m, 1H), 4.59 (q, 1H), 3.41-3.28 (m, 2H), 1.60 (dd. 3H), 1.48-1.57 (m, 1H), 1.25-1.42 (m, 2H), 0,72 is 0.86 (m, 6H); MS (ESI) m/z 423 [M+1]+.

Example 2

(2R)-2-[(2-Amino-5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}[1.3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol

a) 1-(5-Chloropyridin-2-yl)alanon

5-Chloropyridin-2-carbonitrile (10.7 g, 77 mmol) was dissolved in diethyl ether (65 ml) and THF (35 ml) under nitrogen atmosphere. The mixture was cooled until the internal temperature did not reach -63°C. was Added methylmagnesium (3 M in THF, 35 ml, 105 mmol) for 30 minutes, the Reaction mixture is then left to mix at -60°C for 45 min and then was heated to room temperature. Added THF (50 ml) to dissolve any precipitated substances and the reaction mixture was stirred for 1 h was Added 2 M HCL aq. (100 ml) and the reaction mixture was stirred for 4 hours the pH is then brought to 7 with sodium bicarbonate. The phases were separated and the product was extracted with DCM from the aqueous phase. The combined organic extracts were dried over sodium sulfate and concentrated in vacuum is. The product was purified flash column-chromatography (eluent: heptane : tO, gradient) to give 7.9 g (64% yield) specified in the connection header.

1H NMR (300 MHz, Dl3) δ ppm at 8.62 (m, 1H); 8.00 (m, 1H); 7.80 (m, 1H); 2.70 (s. 3H).

b) (1S)-1-(5-Chloropyridin-2-yl)ethanol

Specified in the title compound was obtained by the General method B2, starting from 1-(5-chloropyridin-2-yl)ethanone (780 mg, 5 mmol). After purification column flash chromatography was received 695 mg (88% yield) specified in the connection header with its 92%.

1H NMR (300 MHz, CDCl3): 8.47 (s, 1H); 7.65 (d, 1H); 7.26 (d, 1H); 4.87 (q, 1H); 3.87 (br s, 1H); 1.47 (d, 3H); MS (ESI) m/z 140 and 142 [M+1]+.

C) 5-Chloro-2-[(1R)-1-chloroethyl]pyridine

Specified in the title compound was obtained by the General method C2, starting from (1S)-1-(5-chloropyridin-2-yl)ethanol (695 mg, 4.41 mmol). The crude product was used in the next stage without purification.

1H NMR (400 MHz, CDCl3): δ ppm 8.46 (d, 1H), 7.64 (dd, 1H), 7.41 (d, 1H), 5.08 (q, 1H), 1.80 (d. 3 H); MS (ESI) m/z 176 and 178 [M+1]+.

g) (2R)-2-[(2-Amino-5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]]pyrimidine-7-yl)amino]-4-methylpentan-1-ol

Specified in the title compound was obtained by the General method a starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol (572 mg, at 1.91 mmol) and 5-chloro-2-[(1R)-1-chloroethyl]PI is Idina (376 mg, 2.1 mmol). After purification preparative HPLC got 99 mg (12% yield) specified in the connection header.

1H NMR (400 MHz, CD3D): (ppm 8.49 (d, 1H), 7.79 (dd, 1H), 7.66 (d, 1H), 5.22 (q, 1H), 4.46 (br s, 1H), 3.57-3.40 (m, 2H), 1.78-1.66 (m, 4H), 1.61-1.40 (m, 2H), 1.03-0.93 (m, 6H); MS (ESI) m/z 439 and 441 [M+1]+.

Example 3

(2R)-2-[(2-Amino-5-{[(1S)-1-(5-herperidin-2-yl)ethyl]thio}[1,3]thiazolo[4.5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol

a) 1-(5-Herperidin-2-yl)alanon

5-Herperidin-2-carbonitrile (29 g, 240 mmol) was dissolved in THF (150 ml) under nitrogen atmosphere. The reaction mixture was cooled to the temperature of the mixture -64°C. Methylmagnesium (3 M in THF, 105 ml, 315 mmol) was added within 40 minutes the Reaction mixture was stirred at -65°C for 1.5 h, then was heated to room temperature. Added THF (50 ml) and the mixture was stirred another 3 hours was Added 2 M hydrochloric acid (aq., 100 ml)until the mixture was slightly acidic, and the reaction mixture was stirred at room temperature overnight. Then add sodium bicarbonate to neutralize the reaction mixture. The phases were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuum. The crude product was purified flash column-chromatography to obtain 18 g (55% yield) specified in C is the coupling head.

1H NMR (300 MHz, CDCl3): 8.50 (m, 1H); 8.10 (m. 1H); 7.52 (m, 1H); 2.70 (s, 3H).

b) (1S)-1-(5-Herperidin-2-yl)ethanol

Specified in the title compound was obtained by the General method B2, starting from 1-(5-herperidin-2-yl)ethanone (2.70 g, and 19.4 mmol). After purification column flash chromatography was obtained 0.85 g (31% yield) specified in the header of the connection with 94% EE.

1H NMR (300 MHz, CDCl3): 8.38 (m, 1H); 7.5-7.2 (m. 2H); 4.89 (q, 1H); 3.9 (br s,1H);1.49(d,3H).

a) 2-[(1R)-1-Chloroethyl]-5-herperidin

Specified in the header connection with its 87% received General way C2, starting from (1S)-1-(5-herperidin-2-yl)ethanol (407 mg, 2.9 mmol). The crude product was used in the next stage without purification.

1H NMR (300 MHz, CDCl3): 8.44-8.40 (m, 1H); 7.6-7.4 (m, 2H); 5.16 (q, 1H), 1.86(d,3H).

g) (2R)-2-[(2-Amino-5-{[(1S)-1-(5-herperidin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol

Specified in the title compound was obtained by the General method a starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol (550 mg, 1.8 mmol) and 2-[(1R)-1-chloroethyl]-5-herperidin (0,46 g, 2.9 mmol). The product was purified column flash chromatography, then preparative HPLC (column: Reprosil, eluent: isopropanol : heptane 20:80, flow 16 ml/min), collecting the first eluruumis isomer, with the receipt of 135 mg (yield 18% specified in the connection header.

1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (d, 1H), 7.98 (s, 2H), 7.65 (dt, 1H); 7.58 (dd, 1H); 6.88 (d, 1H); 5.12 (q, 1H); 4.66 (t, 1H); 4.27 (br s, 1H); 3.41-3.27 (m, 2H), 1.66 (d, 3H), 1.65-1.55 (m, 1H); 1.48-1.35 (m, 2H), from 0.88 (d, 3H)to 0.85 (d, 3H); MS(ESI) m/z 423 [M+1]+.

Example 4

(2R)-2-[(2-Amino-5-{[-(3-chloropyridin-4-yl)ethyl]thio}[1.3]thiazolo[4.5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol

a) (1S)-1-(3-Chloropyridin-4-yl)ethanol

Specified in the header connection with its 90% was obtained using General method B1, starting from 1-(3-chloropyridin-4-yl)ethanone (0,90 g, 5,78 mmol).

1H NMR (300 MHz, CDCl3) 8.47 (s, 1H); 7.65 (d, 1H); 7.26 (d, 1H); 4.87 (q, 1H); 3.87 (br s, 1H); 1.47 (d, 3H); MS (ESI) m/z 158 and 160 [M+1]+.

b) 3-Chloro-4-[(1R)-1-chloroethyl]pyridine

Specified in the title compound was obtained using General method C2, starting from (1S)-1-(3-chloropyridin-4-yl)ethanol (570 mg, 3.62 mmol). The crude product was used in the next stage without purification.

MS (ESI) m/z 176 and 178 [M+1]+.

C) (2R)-2-[(2-Amino-5-{[1-(3-chloropyridin-4-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol (isomer 1 and isomer 2)

Specified in the title compound was obtained using General method a starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol (860 mg, 2,87 mmol) and 3-chloro-4-[(1R)-1-chloroethyl]pyridine with the previous stage. After the cleaning flash chromatography got mentioned in the title compound (105 mg, yield 8%) as diastereomeric mixture.

MS (ESI) m/z 439 and 441 [M+1]+.

Example 5

(2R)-2-[(2-Amino-5-{[(1S)-1-(3-herperidin-2-yl)ethyl]thio}[1.3] thiazolo[4.5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol

a) 1-(6-Bromo-3-herperidin-2-yl)alanon

2-Bromo-5-herperidin (11 g, 62.5 mmol) was dissolved in diethyl ether at room temperature in a nitrogen atmosphere. The reaction mixture was cooled until the internal temperature did not reach -66°C. Utility (2.5 M in hexano, 26 ml, 65 mmol) was added dropwise over 0.5 hours the reaction mixture was left at -65°C for 1 h N,N-Dimethylacetamide (6.5 ml, 70 mmol) was added within 10 minutes

The reaction mixture was stirred at -65°C for 2 hours was Added 1 M hydrochloric acid aq. (50 ml) and the mixture was heated to room temperature. the pH was brought to 7 additional amounts of hydrochloric acid. The aqueous phase was extracted with diethyl ether three times. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuum. After purification column flash chromatography (eluent: heptane : diethyl ether gradient) was obtained 4.6 g (yield 34%) specified in the connection header.

1H NMR (300 MHz, DMSO-d6): 8.0-7.8 (m, 2H); 2.57 (s, 3H); MS (ESI) m/z 218 and 220 [M+1]+.

b) (1S)-1-(6-Bromo-3-herperidin-2-yl)ethanol

Specified in the title compound was obtained using General method B2, starting from 1-(6-bromo-3-herperidin-2-yl)ethanone (1,76 g, 8,19 mmol). The product was purified flash column-chromatography (eluent: heptane : ethyl acetate, gradient) to give 1.31 g (yield 73%) specified in the connection header with 80%.

1H NMR (300 MHz, CDCl3): 7.38 (m, 1H); 7.26 (m, 1H); 5.06 (q, 1H); 3.38 (br s, 1H); 1.47 (d, 3H); MS (ESI) m/z 220 and 222 [M+1]+the m/z 202 [M-H2-O]+.

C) (1S)-1-(3-Herperidin-2-yl)ethanol

(1S)-1-(6-Bromo-3-herperidin-2-yl)ethanol (1.3 g, 5.9 mmol), triethylamine (1.6 ml, 11.5 mmol) and palladium on carbon (0.64 g, 0.34 mmol) were mixed in DCM (25 ml). The flask was evacuated/filled with gaseous hydrogen for 4 cycles and then left when the pressure of the hydrogen gas 2.5 ATM (0.25 MPa) at room temperature for 24 h the Mixture was filtered and the solid washed with DCM. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated in vacuum. The crude product was purified flash column-chromatography (eluent D : methanol, gradient) to obtain 0.54 g (yield 65%) specified in the connection header.

1H NMR (300 MHz, CDCl3): 8.38 (m, 1H); 7.39 (m, 1H); 7.26 (m, 1H); 5.11 (q, 1H);4.16 (br s,1H);1.49(d,3H).

g) 2-((R)- 1-Chloroethyl)-3-herperidin

Specified in the title compound (0.24 g) was obtained using General is th way C2, starting with (1S)-1-(3-herperidin-2-yl)ethanol (254 mg, 1.8 mmol).

1H NMR (300 MHz, CDCl3): 8.46 (m, 1H); 7.47 (m, 1H); 7.34 (m, 1H); 5.48 (q, 1H), 1.94 (d, 3H); MS (ESI) m/z 160 and 162 [M+1]+.

d) (2R)-2-[(2-Amino-5-{[(1S)-1-(3-herperidin-2-yl)ethyl]thio}-[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol

Specified in the title compound was obtained using General method a starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol (348 mg, of 1.16 mmol) and 2-((R)-1-chloroethyl)-3-herperidin (240 mg, 1.5 mmol). After purification column flash chromatography (eluent: DCM : methanol, gradient) received 190 mg (yield 47%) specified in the connection header with diastereomeric excess of 60%. 55 mg of the substance was further purified by preparative HPLC. Last eluruumis isomer was collected to obtain 21 mg specified in the connection header.

1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (dt, 1H), 7.98 (s, 2H), 7.70 (m, 1H), 7.40 (m, 1H); 6.92 (d, 1H); 5.45 (q, 1H); 4.65 (t, 1H); 4 27 (br s, 1H); 345-3 .30 (m, 2H), 1.69 (d, 3H), 1.66-1.58 (m, 1H), 1.50-1.35 (m, 2H), from 0.88 (d, 3H)to 0.85 (d, 3H); MS (ESI) m/z 423 [M+1]+.

Example 6

(2R)-2-[(2-Amino-5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio{[1.3] thiazolo[4.5-d]pyrimidine-7-yl)(methyl)amino]pentane-1-ol

a) (1S)-1-(6-Chloropyridin-3-yl)ethanol

Specified in the title compound was obtained in accordance with the General CSP is obom B1, using (-)and DIPCI 1-(6-chloropyridin-3-yl)alanon (0,80 g, 5,14 mmol), to obtain 0.71 g (yield 88%) specified in the connection header.

1H NMR (CDCl3) δ ppm 8.40-8.28 (m, 1H), 7.75-7.63 (m, 1H), 7.35-7.24 (m, 1H), 5.04-4.79 (m, 1H), 1.63-1.45 (m, 3H); MS (ESI) m/z 158 and 160 [M+1]+.

b) 2-Chloro-5-[(1R)-1-chloroethyl]pyridine

Specified in the title compound was obtained in accordance with the General method of C1 using (1S)-1-(6-chloropyridin-3-yl)ethanol (0.20 g, of 1.27 mmol), to obtain 0.16 g (yield 72%) specified in the connection header.

1H NMR (CDCl3) δ ppm 8.45-8.35 (m, 1H), 7.79-7.70 (m, 1H), 7.39-7.29 (m, 1H), 5.07 (q, 1H), 1.85-1.78 (m, 3H); MS (ESI) m/z 176 and 178 [M+1]+.

C) N-(Etoxycarbonyl)-D-Norvaline

D-Norvaline (10.0 g, 85.3 mmol) was dissolved in aqueous sodium hydroxide solution (4 M, 25 ml). Ethylchloride a (10.6 ml, 111 mmol) and aqueous sodium hydroxide (4M, 25 ml) was added over 15 min at 0°C. the Reaction mixture was heated to room temperature and stirred at this temperature for 4 hours, the Reaction mixture was washed with diethyl ether three times and then acidified aqueous hydrochloric acid (2M). The product was extracted with diethyl ether three times. The combined organic phases were dried over magnesium sulfate and concentrated in vacuum to obtain specified in the connection header with a quantitative yield.

1H NMR (CDCl3 ) δ ppm 6.43 (br s, 1H). 5.22 (d, 1H), 4.37 (q, 1H), 4.13 (q, 2H), 1.84 (m, 1H), 1.68 (sextet, 1H), 1.42 (sextet, 1H), 1.25 (t, 3H), of 0.95 (t, 3H); MS (CI) 144 (100%),190 [M+1]+.

g) (2R)-2-(Methylamino)pentane-1-ol

Alumoweld lithium (6.5 g, 171 mmol) suspended in THF at 0°C under nitrogen atmosphere. N-(Etoxycarbonyl)-D-Norvaline was dissolved in THF and added dropwise at 0°C. the Reaction mixture is boiled under reflux during the night. After cooling to room temperature was added a saturated aqueous sodium sulfate with suspension. The resulting mixture was filtered through alitte substance washed with DCM until the entire product has not been extracted. The combined filtrate was dried over sodium sulfate and concentrated in vacuum. In the distillation from the flask into the flask" (bulb-to-bulb distiltion) at 0.1 mbar (10 PA), collecting the fraction at 75-85°C, received and 7.1 g (yield 71%) specified in the connection header.

1H NMR (CDCl3) 3.63 (dd, 1H); 3.30 (dd, 1H); 2.51 (m, 1H); 2.41 (s, 3H); 2.09 (br s, 2H); 1.50-1.28 (m, 4H); of 0.93 (t, 3H); MS (CI) 86 (100%), 118 [M+1]+.

d) (2R)-2-{[2-Amino-5-(benzylthio)[1,3]thiazolo[4,5-d]pyrimidine-7-yl](methyl)amino}pentane-1-ol

5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidine-2-amine (6.0 g, with 19.4 mmol) was dissolved in NMP (25 ml). Added DIPEA (6.8 ml, to 38.8 mmol) and (2R)-2-(methylamino)pentane-1-ol (3.4 g, of 29.1 mmol) and the mixture was heated to 120°C for 3 days. Additionally added is (2R)-2-(methylamino)pentane-1-ol (350 mg, to 2.99 mmol) and DIPEA (1 ml, 5,74 mmol) and the reaction mixture was heated for 6 h at 120°C. After cooling to room temperature the mixture was poured into ice. The precipitated product was collected by filtration and was purified flash column-chromatography (eluent: DCM : ethyl acetate, gradient) to obtain specified in the connection header (5,74 g, yield 76%).

1H NMR (DMSO-d6) 7.98 (br s, 2H), 7.41 (m, 2H), 7.29 (m, 2H), 7.22 (m, 1H), 4.73 (t, 1H), 4.54 (br s, 1H), 4.33 (m, 2H), 3.55-3.40 (m, 2H), 3.01 (s, 3H), 1.52-1.44 (m, 2H), 1.25-1.10 (m. 2H), from 0.84 (t, 3H); MS (ESI) m/z 390 [M+1]+.

e) (2R)-2[(2-Amino-5-mercapto[1,3]thiazolo[4,5-d]]pyrimidine-7-yl)(methyl)amino]pentane - 1-ol

A round bottom flask equipped with a fridge with a mixture of dry ice-ethanol and immersed in a cooling bath of dry ice-ethanol. Ammonia (200 ml) are condensed into the flask, then added (2R)-2-{[2-amino-5-(benzylthio)[1,3]thiazolo[4,5-d]pyrimidine-7-yl](methyl)amino}pentane-1-ol (5,43 g, a 13.9 mmol). The resulting mixture was left to warm to -33°C and added small pieces of sodium metal, yet did not appear and was not saved within 30 seconds blue staining. The reaction is then extinguished, adding a spoonful of solid ammonium chloride. Ammonia is evaporated and to the residue was added water (250 ml). The resulting mixture was neutralized 1 M hydrochloric acid (aq.). The precipitated product was collected by filtration, washed with water and acetonitrile and dried in vacuum p is the receiving 3,38 g (yield 81%) specified in the connection header.

1H NMR (DMSO-d6) 12.81 (br s, 1H); 8.45 (br s. 2H), 4.84 (br s. 1H), 3.55-3.40 (m, 2H), 3.02 (s. 3H), 1.48 (m, 2H), 1.21 (m, 2H), of 0.87 (t, 3H); MS (ESI) m/z 300 [M+1]+.

W) (2R)-2-[(2-Amino-5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)(methyl)amino]pentane-1-ol

Specified in the title compound was obtained using General method a starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)(methyl)amino]pentane-1-ol (96 mg, 0.32 mmol) and 2-chloro-5-[(1R)-1-chloroethyl]pyridine (85 mg, 0.48 mmol). After purification column flash chromatography (eluent: OSM : ethyl acetate) received 22 mg (16% yield) specified in the connection header.

1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (d, 1H), 7.99 (br s, 2H), 7.96 (dd, 1H), 7.45 (d, 1H); 4.98 (q, 1H); 4.73 (t, 1H); 4.46 (br s, 1H); 3.53-3.38 (m, 2H), 2.97 (s, 3H), 1.66 (d, 3H), 1.48 (m, 2H), 1.17 (m, 2H), from 0.84 (t, 3H); MS (ESI) m/z 439 and 441 [M+1]+.

Example 7

(2R)-2-[(2-Amino-5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]pentane-1-ol

a) (2R)-2-{[2-Amino-5-(benzylthio)[1,3]thiazolo[4,5-d]pyrimidine-7-yl]amino}pentane-1-ol

5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidine-2-amine (6.0 g, with 19.4 mmol) was dissolved in NMP (30 ml). Added DIPEA (8,4 ml of 48.5 mmol) and 2-amino-(2R)-1-pentanol (3.5 g, to 33.9 mmol), the mixture was heated to 110°C for 4 days. After cooling to room temperature the mixture was poured into water (200 ml). The precipitated product was collected by filtration, washed in the water and used for the next stage without additional purification (7.0 g, yield 97%).

MS (ESl) m/z 376 [M+1]+.

b) (2R)-2-[(2-Amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]pentane-1-ol

A round bottom flask equipped with a fridge with a mixture of dry ice-ethanol and immersed in a cooling bath of dry ice-ethanol. Ammonia (250 ml) are condensed into the flask, then added (2R)-2-{[2-amino-5-(benzylthio)[1,3]thiazolo[4,5-d]pyrimidine-7-yl]amino}pentane-1-ol (6.8 g, to 18.1 mmol). The resulting mixture was left to warm to -33°C and added small pieces of sodium metal, yet did not appear and was not saved within 30 seconds blue staining. The reaction then put a spoon of solid ammonium chloride. Ammonia is evaporated and to the residue was added water (250 ml). The resulting mixture was neutralized 1 M hydrochloric acid (aq.). The precipitated product was collected by filtration, washed with water and dried in vacuum to obtain 4.15 g (yield 80%) specified in the connection header.

MS(ESI) m/z 286 [M+1]+.

C) (2R)-2-[(2-Amino-5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]pentane-1-ol

Specified in the title compound was obtained using General method a starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]eremein-7-yl)amino]pentane-1-ol (70 mg, 0,245 mmol) and 2-chloro-5-[(1R)-1-chloroethyl]pyridine (Example 6b, 52 mg, 0.29 mmol). After purification preparative HPLC on what Uchali 23 mg (22% yield) specified in the connection header.

1H NMR (400 MHz, DMSO-d6) 8.50 (d, 1H); 7.99 (br s, 2H); 7.95 (dd, 1H); 7.44 (d, 1H); 6.91 (d, 1H); 4.95 (q, 1H); 4.11 (m, 1H); 3.41 (dd, 1H); 3.31 (dd, 1H); 1.64 (d, 3H); 1.56 (m, 1H); 1.41 (m, 1H); 1.4-1.2 (m, 2H); of 0.85 (t, 3H); MS (ESI) m/z 425 and 427 [M+1]+.

Example 8

2-{(1S)-1-[(2-Amino-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-5-yl)thio]ethyl}isonicotinamide

a) 2-((S)-1-Hydroxyethyl)isonicotinamide

Specified in the title compound was obtained in accordance with the General method B, starting from 2-acetyl-isonicotinamide (2.00 g, 13.7 mmol) and (-)-DIPCI (6,58 g, 20,53 mmol) to obtain the specified title compound (625 mg, 4,22 mmol) with its 90%.

1H NMR (CDCI3) δ 8.72 (d, 1H), 7.62 (s, 1H), 7.44 (dd, 1H), 4.96 (q, 1H), 1.54 (d, 3H).

b) 2-((R)-1-Chloroethyl)isonicotinamide

Specified in the title compound was obtained from 2-((S)-1-hydroxyethyl)isonicotinamide (620 mg, 4,18 mmol) according to General method C, except that used 1,0 EQ. NCS and 1.0 EQ. PPh3. After 24 h of interaction was added to 0.2 EQ. each of the NCS and PPh3and the temperature was raised to 30°C for 12 hours After treatment and purification column flash chromatography got mentioned in the title compound (46 mg, 7% yield with 82%.

1H NMR (CDCl3) δ 8.74 (d, 1H), 7.76 (s, 1H), 7.46 (dd, 1H). 5.16 (q, 1H), 1.88 (d. 3H).

a) 2-{(1S)-1-[(2-Amino-7{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-5-yl)thio]ethyl}isonicotinamide

Specified in the title compound was obtained in accordance with the General Method a starting from 2-((R)-1-chloroethyl)isonicotinamide (46 mg, 0.28 mmol) and (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol (69 mg, 0.23 mmol). After cleaning chiral HPLC (column: Chiralpak AD 50×150 mm, eluent: heptane : isopropanol 85:15), flow rate 60 ml/min) has been specified in the title compound (20 mg, yield 20%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (d, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.72 (m, 1H), 6.90 (m, 1H), 5.14 (q, 1H), 4.64 (t, 1H), 4.23 (br s, 1 H), 3.23-3.41 (m, 2H), 1.67 (d, 3H), 1.64 - 1.52 (m, 1H), 1.32-1.48 (m, 2H), of 0.87 (dd, 6H); MS (ESI) m/z430 [M+1]+.

Example 9

Example 9a

(2R)-2-[(2-Amino-5-{[(1R)-1-(3-chloropyridin-4-yl)ethyl]thio}[1,3] thiazolo[4.5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol and

Example 9D

(2R)-2-[(2-Amino-5-{[(1S)-1-(3-chloropyridin-4-yl)ethyl]thio}[1.3] thiazolo[4.5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol

Diastereomer a mixture of (2R)-2-[(2-amino-5-{[1-(3-chloropyridin-4-yl)ethyl]thio}[1,3]thiazolo[4,5d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol (105 mg) from Example 4 was separated by preparative HPLC to obtain 14 mg of the first aliremove isomer (Example 9a).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.48 (d, 1H), 8.00 (s, 2H), 7.68 (d, 1H); 6.93 (d, 1H); 5.27 (q, 1H); 4.63 (t, 1H); 4.16 (br s, 1H); 3.42-3.30 (m, 2H), 1.64 (d, 3H), 1.58-1.30 (m, 3H), from 0.84 (d, 3H), of 0.74 (d, 3H); MS (ESI) m/z 439 and 441 [M+1]+.

Also recip is there 15 mg last aliremove isomer (Example 9b).

1H NMR (400 MHz, DMSO-d6) δ m D. 8.60 (s, 1H), 8.48 (d, 1H), 8.00 (s, 2H), 7.67 (d, 1H); 6.92 (d, 1H); 5.28 (q, 1H); 4.56 (t, 1H); 4.22 (br s, 1H); 3.33-3.12 (m, 2H), 1.62 (d, 3H), 1.60-1.30 (m, 3H), from 0.88 (d, 3H), of 0.85 (d, 3H); MS (ESI) m/z 439 and 441 [M+1]+.

Pharmacological screening

Substances

Recombinant fractalkine person (hCX3CL1) and recombinant interleukin-8 person (IL-8 or hCXCL8) was purchased from PeproTech Inc., UK. Recombinant [125|]-fractalkine (man) and [125|] hlL-8 with specific activity 2200 CI/mmol was purchased from NEN® Life Science Products, Inc., UK. Fluo4-AM was purchased from Molecular Probes, US. All other chemical reagents were of analytical purity.

Cells

Full cDNA CX3CR1 human (GenBank number U20350) were extracted mRNA from human brain (Superscript, Life Technologies) and ligated into pCR-Blunt II TORO vector (InVitrogen). Insert the appropriate h3CP1 was isolated and additionally was subcloned into the pcDNA3.1zeo. Plasmid DNA was obtained using Plasmid Mini Kit (Qiagen). Using Superfect Transfection Reagent (Qiagen) according to the manufacturer's Protocol, the expression plasmid for hCX3CR1 is then introduced into the suspension cell line kidney of human embryos (HEKS) 293 containing the vector for stable expression of a chimeric G-protein Gαqi5. A stable clone was obtained using selection with seosenok (500 µg/ml) and hygromycin (100 µg/ml). For future applications of cells maintained in medium Needle, modify the new, Dulbecco/nutrient mixture ham F12 (DMEM/F12), containing pyridoxine with the addition of 10% (vol./about.) fetal bovine serum, 2 mm L-glutamine, 100 U/ml penicillin and 100 mg/ml streptomycin, 250 μg/ml of zeocin and 100 μg/ml of hygromycin.

Cells expressing human CXCR2 received from AstraZeneca Charnwood, cultivated in EMEM containing Glutamax with the addition of 10% FBS (PAA, Austria), 1% essentially amino acids (NEAA), 100 U/ml penicillin and 100 µg/ml streptomycin (PEST) and 500 μg/ml of geneticin/G418.

Membrane preparation

Cells are grown at 37°C and 5% CO2and collect at 60-80% confluence in a buffer containing 10 mm Tris-HCl, pH 7.4, 5 mm EDTA (etilendiamintetrauksusnoy acid), 0.1 mg/ml bacitracin. Cells are centrifuged at 300X for 10 min, the precipitate resuspended in the buffer to collect (10 mm Tris-HCl, pH 7.4, 5 mm ethylenediaminetetraacetic acid (EDTA) and 0.1 mg/ml bacitracin)are pooled and homogenized using a Dounce homogenizer. The homogenate was centrifuged at HD for 10 min and resuspended in the buffer for collecting, using Ultra-Turrax T8. Aliquots of membranes stored at -80°C. the protein Concentration was determined in microtiter tablets, as described in Harrington (1990, Anal. Biochem. 186,285-287).

In vitro analysis of the binding of receptors

Studies of competitive binding [125|]fractalkine was performed in 2 ml 96-well tablets with deep holes (Beckman, Germany) in a total volume of 1000 μl/well and Each well contained 10 PM [ 125I]-fractalkine and an equivalent amount of the membrane to the concentration of receptor 1 PM in the analytical buffer (50 mm HEPES-KOH, pH 7.4, 10 mm MgCl2, 1 mm EDTA, 0.1% (wt./about.) gelatin). Ten concentrations (2 points/Iog unit) of the tested compounds was pre-dissolved in DMSO and was added to achieve a final concentration of 1% (vol./about.) DMSO. The analysis was started with the addition of membranes and incubated at 25°C for 24 h the Reaction was stopped by rapid filtration through Whatman GF/B glass fiber filters pre-treated with 0.3% polyethylimine, and subsequent washing with a mixture of ice-cold buffer (10 mm HEPES-KOH, pH 7.4, 500 mm NaCl)using a Brandel harvester for receptor binding. Added to scintillation cocktail and radioactivity was determined in a Packard 2500TR liquid scintillation counter (Perkin Elmer, USA).

Research [125I]-hIL-8 competitive binding was carried out in a single copy in white 96-well isoplanatic with a transparent bottom for a final volume of 200 µl to each well contained 150 PM [125I]-hIL-8 (specific activity 2200 CI/mmol), drug membrane-SPA, equivalent to 20 gr receptors, and 1.5 mg of SPA-granules in analytical buffer [50 mm HEPES-KOH, pH 7.4, 10 mm MgCl2, 1 mm EDTA, and 0.5% (wt/vol.) gelatin]. The tested compounds were processed as described above. Nonspecific binding was determined in the presence of 500 nm unlabeled hIL-8. Agonist hIL-8 (curve concentration - response from 3 PM to 30 nm) is used as a reference compound in each test. Peptide curve does not contain DMSO. The binding reaction start by adding 140 μl of drug membrane-SPA and the samples incubated in the dark at room temperature for 4 hours Analytical tablets cheated in a liquid scintillation counter (Wallac MicroBeta® TriLux 1450 jn PerkinElmer, USA).

[35S]GTPγS binding

Research [35S]GTPγS binding was performed in microtiter tablets with a glass bottom in two Parallels with 10 concentrations of inhibitor (2 conc./log unit), diluted with DMSO (final concentration 1%) and at room temperature. Membranes expressing hCX3CR1 receptor (final concentration 20 μg protein/well)was added together with SPA-granules (final concentration 1 mg/well), all suspended in GTPγS binding buffer (50 mm Tris-HCl, 100 mm NaCl, 0.1% gelatin, 15 μg saponin/ml and 3 μm GDP (guanosine-5'-diphosphate), pH 7.4 at room temperature). Membrane, SPA pellets and medicines pre-incubated for 30 min, then was added 310 PM, fractalkine for maximum stimulation. The source activity was defined as activity without detectable stimulation fractalkine (GTPγS binding buffer). After another 30 min the reaction was started by addition of [35S]GTPγS to ejnoy a concentration of 0.1 nm and the final analytical volume of 0.2 ml. The experiment was finished after 30 minutes by centrifugation at 2000 rpm for 2×5 minutes (different directions) and radioactivity was determined in a liquid scintillation counter (Wallac MicroBeta® TriLux 1450).

Results

Typical CX3R1 Ki values for compounds of the present invention are in the range of from about 0.1 to about 1000 nm. Other values CX3R1 Ki are in the range of from about 0.1 nm to about 500 nm. Other values CX3W1 Ki are in the range of from about 0.1 nm to about 25 nm. Results in vitro analysis h3R1 binding for the target compounds are shown in the table.

ExampleKi(nm)
121
26.2
36.5
4not tested*
523
6203
7149
881
9a not tested
9b35
*) Example 4 a mixture of diastereoisomers which are separated in Example 9.

Compounds of the present invention, where R1represents Me (containing branched dialkylamino group in position 5), are more effective antagonists CX3CP1 receptor, and/or less effective antagonists of the CXCR2 receptor than the corresponding reference compound, where R1represents N. This improved selectivity for antagonism CX3CR1 receptor is expected to bring significant therapeutic benefit.

1. The compound of formula (I)

where R1represents CH3;
R2represents halogen or CN;
R3represents N or CH3;
R4represents N or CH3;
n represents 1;
in the form of free base or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R2represents F or Cl.

3. The compound according to claim 1, where R2represents CN.

4. The compound according to claim 1, where R2represents F, CL or CN.

5. The compound according to claim 1, where R3represents N.

<> 6. The compound according to claim 1, where R4represents CH3.

7. A compound selected from:
(2R)-2-[(2-amino-5-{[1-(5-herperidin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]-pyrimidine-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}[1,3]thiazolo-[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-(5-herperidin-2-yl)ethyl]thio}[1,3]thiazolo-[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-(3-chloropyridin-4-yl)ethyl]thio}[1,3]thiazolo[4,5-d]-pyrimidine-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-(3-chloropyridin-4-yl)ethyl]thio}[1,3]thiazolo-[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1R)-1-(3-chloropyridin-4-yl)ethyl]thio}[1,3]thiazolo-[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-(3-herperidin-2-yl)ethyl]thio}[1,3]thiazolo-[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}[l,3]thiazolo-[4,5-d]pyrimidine-7-yl)(methyl)amino]pentane-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}[1,3]thiazolo-[4,5-d]pyrimidine-7-yl)amino]pentane-1-ol; and
2-{(1S)-1-[(2-amino-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-[1,3]thiazolo[4,5-d]pyrimidine-5-yl)thio]ethyl}isonicotinamide;
in the form of free base or its pharmaceutically acceptable salt.

8. The compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt for use as a drug Leche for the treatment or prevention of diseases or conditions, which is favorable antagonism against CX3CR1 receptor.

9. Pharmaceutical composition having antagonistic activity against CX3CR1 receptor containing a therapeutically effective amount of a compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable diluent or carrier.

10. The use of the compounds of formula (I)as defined in any one of claims 1 to 7, or its pharmaceutically acceptable salts in the manufacture of a medicinal product for the treatment or prevention of demyelinating disease, cardio - and cerebrovascular atherosclerotic disorders, disease, peripheral artery disease, rheumatoid arthritis, or asthma.

11. The use of the compounds of formula (I)as defined in any one of claims 1 to 7, or its pharmaceutically acceptable salts in the manufacture of a medicine for treatment or prevention of multiple sclerosis.

12. The use of the compounds of formula (I)as defined in any one of claims 1 to 7, or its pharmaceutically acceptable salts in the manufacture of a medicinal product for the treatment or prophylaxis of atherosclerosis by changing the composition of the plaques with the aim of reducing the risk of plaque rupture and atherothrombotic events.

13. The use of the compounds of formula (I)as defined in any which one of claims 1 to 7, or its pharmaceutically acceptable salts in the manufacture of a medicine for treatment or prevention of diseases or conditions in which a positive antagonism against CX3CR1 receptor.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I), which can be used as a medicinal agent having PI3-kinase inhibiting properties. In general formula (I)

,

A denotes N, Ra denotes C1-C8alkyl, phenyl substituted with 1-2 residues selected from a group comprising halogen and C1-C6halogenalkyl, Rb denotes hydrogen, R1 denotes hydrogen or C1-C8alkyl, R2 denotes hydrogen or a substitute selected from a group comprising: C1-C8alkyl, substituted with one substitute selected from C1-C6alkoxy group, -(CO)-O-C1-C6alkyl, N(C1-C6alkyl)2; 6-member heterocycloalkyl containing a nitrogen atom as a heteroatom, substituted with 1-2 substitutes selected from an oxo group and phenyl; (5-6-member heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen)-C1-C4alkyl, optionally substituted with 1-2 substitutes independently selected from -(CO)-O-C1-C6alkyl, C1-C6alkyl, -(CO)-O-benzyl, oxo group, benzyl substituted with C1-C6alkyl, 6-member heteroaryl containing 2 nitrogen atoms as heteroatoms; phenyl which is optionally substituted with 1 substitute selected from a 6-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, optionally substituted with -(CO)-O-C1-C6alkyl, (5-6-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with C1-C6alkyl)-C1-C4alkyl, optionally substituted with an oxo group, -(C1-C4alkyl)-NR7-(CO)O-C1-C6alkyl; phenyl-C1-C5alkyl, optionally substituted with 1-2 substitutes selected from NH2, N(C1-C6alkyl)2, C1-C6alkyl, N(C1-C6alkyl)2-C1-C6alkyl, OR7, OCF3, haloC1-C6alkyl, CN, SO2R7, NR7COR8, CONH2, NR7-(CO)O-C,-C6alkyl; -(C1-C4alkyl)-NR7-(CO)O-C1-C6alkyl, 5-member heteroaryl containing 2 nitrogen atoms as heteroatoms, (5-6-member heterocycloalkyl containing 1-2 heteroatoms independently selected from nitrogen and oxygen), optionally substituted with an oxo group, (5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms substituted with 1-3 substitutes independently selected from oxo group, C1-C6alkyl)-C1-C4alkyl, -C(O)-NH-(C3-C8cycloalkyl), -C(O)-NH-(C1-C6alkyl), -C(O)-N(C1-C6alkyl)2, COR7, NR7(CO)NR8R9; (5-6-member heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, sulphur and oxygen)-C1-C6alkyl, optionally substituted with 1-2 substitutes selected from C1-C6alkyl, C3-C8cycloalkyl, CN and OH; (9-member heteroaryl containing a nitrogen atom as a heteroatom)-C1-C4alkyl; C3-C8cycloalkyl, optionally substituted with a 5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with an oxo group; C3-C8cycloalkyl-C1-C4alkyl, optionally substituted with 1 substitute selected from C1-C4alkyl-(CO)OR8, NR (CO)OR8; 1,3-benzodioxole-C1-C4alkyl; 1,4-benzodioxane-C1-C4alkyl; isoindoline-C1-C4alkyl substituted with 1 CO-NH2 substitute; or R1 and R2 together form a 5- or 6-member saturated ring which optionally contains an additional heteroatom selected from oxygen and nitrogen, and optionally substituted with 1-3 substitutes independently selected from OH, C1-C6alkyl, (CO)OR8, (C1-C4alkyl)-(CO)OR8, NR7(CO)OR8, -(C1-C4alkyl)-NR7(CO)OR8, NR7COR8, -(C1-C4alkyl)-NR7COR8, -NH-C(O)CF3, -CH(OH)-phenyl, NR7(CO)NR8R9, NR7(CO)CH2NR8R8, -NR7(SO2)R8, phenyl, optionally substituted C1-C6alkoxy, OH, 9-10-member bicyclic heteroaryl containing 1-2 nitrogen atoms as heteroatoms, optionally substituted with a phenyl oxo group, substituted with a hydroxy group, -CH2-isoquinoline, substituted with an oxo group, 5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with an oxo group, -CH2-O-(phenyl, substituted with 3 substitutes independently selected from halogen and amino); or R1 and R2 together form a saturated 9-11-member spirocyclic system with 1-2 additional nitrogen heteroatoms, substituted with 1-2 substitutes independently selected from -C1-C6alkyl, OH, oxo group and phenyl; or R2 denotes a residue selected from a group of residues of general formulae:

, , , , , and , where X denotes C1-C7alkylene, Q denotes C1-C7alkylene, R3, R4 have identical or different values and denote hydrogen or a substitute selected from a group comprising C1-C8alkyl, 9-member bicyclic heteroaryl containing 2 nitrogen atoms as heteroatoms, substituted with C1-C6alkyl, phenyl substituted with C1-C4alkyl, 6-member heteroaryl containing 2 nitrogen atoms as heteroatoms, 5-member heterocyclyl containing 1 nitrogen atom as a heteroatom, (C3-C8cycloalkyl)-C1-C4alkyl-, or R3, R4 together form a 6-member saturated ring containing an oxygen atom as an additional heteroatom, R7, R8, R9 have identical or different values and denote hydrogen or a substitute selected from a group comprising C1-C8alkyl, 5-6-member heterocycloalkyl containing 1-2 heteroatoms independently selected from nitrogen and oxygen, C3-C8cycloalkyl, C1-C6haloalkyl, C3-C8cycloalkyl- C1-C4alkyl-, C1-C4alkoxy-C1-C4alkyl-.

EFFECT: high efficiency of using the disclosed compounds in preparing a medicinal agent.

10 cl, 1 tbl, 299 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where R1 denotes a lower alkyl; R2 denotes phenyl or a 5- or 6-member heteroaryl containing 1-2 N atoms or 1 N atom and 1 S atom as heteroatoms, which may be unsubstituted or substituted with a substitute selected from halogen or lower alkyl; R3 denotes hydrogen, phenyl or a 5-6-member heteroaryl containing 1-2 N atoms and 1 O atom as heteroatoms, which can be unsubstituted or substituted with a substitute selected from 1-2 halogen atoms, lower alkyl or a S(O)2-lower alkyl group; as well as pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, having metabotropic glutamate receptor mGluR5 antagonist properties, which contains the compound of formula (I) as active component and pharmaceutically acceptable excipients.

EFFECT: possibility of using said derivatives as mGluR5 receptor antagonists.

25 cl, 2 dwg, 1 tbl, 30 ex

FIELD: chemistry.

SUBSTANCE: described are novel substituted naphthyridines of general formula E: (radicals R1 and R3 are described in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, and use of the novel compounds to prepare a medicinal agent for treating or preventing malignant tumours in mammals.

EFFECT: compounds inhibit Akt acitivity, in particular, the compounds selectively inhibit one or two isoforms of Akt and can be used in medicine.

5 cl, 14 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein Q together with carbon and nitrogen atoms whereto attached forms a 5-6-members monocyclic heteroaromatic ring; or Q together with carbon and nitrogen atoms whereto attached forms a 9-10-members bicyclic heterocycle; R1 and R2 independently mean hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup substituted by alkoxygroup, alkylthiogroup, sulphonyl, free or etherified carboxygroup, carbamoyl, sulohamoyl, morpholinyl or pyridinyl; or R2 is absent; R3 means (C3-C6)cycloalkyl; R4 means hydrogen, halogen, lower alkyl or lowest alkyl substituted by one or more halogen; R5 means (C3-C6cycloalkyl, (C6-C10) aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl; R6 means free or etherified carboxygroup; and n is an integer equal to 1-6; or to its enanthiomer, or a mixture of its enanthiomers, or its pharmaceutically acceptable salt. Besides, the invention refers to a method of glucokinase activation in mammals, to a method of treating pathological conditions associated with glucokinase activation in mammals and impaired glucose tolerance, as well as to a pharmaceutical composition based on these compounds and to application of said compositions for preparing a drug.

EFFECT: there are produced and described new compounds which are activators and can be used as therapeutic agents for treating the glucokinase mediated pathological conditions.

31 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a derivative of 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine of formula

and its optical isomers and pharmaceutically acceptable salts where R1 represents CH3 or CH3CH2; R2 represents H, 2-F, 2-Cl, 3-F, 3-OCN3, 3-CN, 3-CF3, 3-CONH2 or 3-SO2CH3; R3 represents H or CH3; R4 represents H or CH3; and R5 represents H; or when R4 represents CH3, R5 represents H or F. Also, the invention refers to methods for producing the compounds of formula (I) and to pharmaceutical compositions exhibiting CX3CR1 receptor antagonist properties containing the compounds of formula (I).

EFFECT: production of 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine as selective CX3CR1 receptor antagonists.

15 cl, 2 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds (la) of formula applied as tyrosine kinase c-Met inhibitors. , where: LA is selected from ,

or ; RA is selected from:

or each RA2 and RA6 represents hydrogen; RA3 represents RAr; or RA3, RA4 and carbon atoms whereto attached form 6-members aryl, optionally substituted, in the amount up to 4 by independent groups RAr, or a 5-6-members heterocyclyl or heteroaryl ring containing at least one O, N or S atom; R represents -OH; RA5 represents hydrogen or RAr; LB represents a covalent bond or -N(R*)-; RB represents halogen, NH2 or C1-8aliphatic group, optionally substituted by R; a 6-10-members aryl ring; a 3-7-members carbocyclyl ring, a 5-10-members heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, where each said aryl or heteroaryl ring is optionally substituted, in the amount up to five by independent groups RAr; R represents halogen, -R°, -SR°, Ph, optionally substituted R° or -C(O)OR°; each RAr is independently selected from halogen, -R°, -OR°, -SR°, Ph, optionally substituted in the amount up to five by independent groups -R°, -CN, -N(R°)2 or -C(O)OR°; or two adjacent groups RAr taken together, represent 1,2-methylenedixy or 1,2-ethylenedixy; each R* represents hydrogen; and each R° represents independently hydrogen, an optionally substituted C1-6aliphatic radical or an unsubstituted 5-6-members heteroaryl or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms.

EFFECT: invention refers to pharmaceutically acceptable compositions containing the compounds under the invention, and methods of application of the compositions in treatment of various proliferative disorders.

10 cl, 4 tbl, 548 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel sulphonamidethiazole pyrimidine derivatives of formula (I)

, which are glucokinase activators or to their enantiomers, mixture of enantiomers or pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on the novel compounds, use of the compounds to prepare a medicinal agent and to a method of activating glucokinase. In formula (I) R1 denotes (C1-C10)alkoxy, R2 denotes (C3-C6)cycloalkyl, R3 denotes hydrogen, and values of substitutes R4 and R5 are given in the formula of invention.

EFFECT: more effective use of the compounds.

33 cl, 166 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of binuclear sulphur-nitrosyl complex of anion type iron of formula Na2[Fe2(S2O3)2(NO)4]·4H2O as vasodepressor means for obtaining medication for treatment of ischemic diseases.

EFFECT: invention ensures extension of arsenal of cardiotropic medications with improved activity spectrum based on said iron complex, which is non-toxic water-soluble NO donor.

2 cl, 4 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: modelling a myocardial infraction is followed by intravenous introduction of the immune corrector tamerite 3 mg/kg in an animal every days for seven days. The histological results of the myocardial tissue presented after the first, third and seventh days show the sufficiency and efficacy of the therapy.

EFFECT: effective therapy of the acute myocardial infraction ensured by reducing the intensity of an acute inflammatory reaction, providing faster granulation tissue formation.

2 tbl

FIELD: medicine.

SUBSTANCE: modelling a myocardial infraction is followed in a rat is followed by intravenous introduction of the immune corrector tamerite 3 mg/kg. The preparation is injected daily for seven days. The histological results of the myocardial tissue presented after the first, third and seventh days show the sufficiency and efficacy of the therapy.

EFFECT: effective therapy of the acute myocardial infraction with high possibility of cure ensured by reduced manifestations of systemic inflammation response syndrome, faster granulation tissue formation and necrotic zone replacement by cicatricial tissue.

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to purulent surgery, and can be used for treating patients with critical ischemia of lower extremities. For this purpose, standard medical therapy is additionally combined with single-step wound layered infiltration of soft tissues by Perftoran at 3 cm from wound edges in dose 10-15 ml if the wound is localised on a feet, and 40-50 ml if the wound is localised on a leg or a hip every second day in amount 8-10 procedures.

EFFECT: method allows reducing length of treatment and managing pain syndrome, accelerating wound cleansing and healing in higher intensity of repair processes ensured by constant maximally effective active Perftoran concentration in the wound zone.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns creation of a pharmaceutical composition with a wide spectrum of pharmacological activity, namely exhibiting antihypoxic, neuroprotective and antiamnestic activity, and also showing an ergogenic nature. The declared pharmaceutical composition contains semax and choline. The outcome of experiments proves that the offered pharmaceutical composition containing semax and choline, mutually intensifies an effect of each of them.

EFFECT: composition can find application in creation of the new drug preparations exhibiting neuroprotective activity in a combination with antihypoxic and antiamnestic activity and the ergogenic nature and used for treatment of various pathologies of the central nervous system.

12 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a therapeutic and diagnostic agent used in treatment or diagnostics of a cerebral disease caused by a mitochondrial dysfunction, or in a method for prevention within a surgical intervention and an intravascular surgery, and also to a diagnostic technique for cerebral diseases. The therapeutic agent contains an iron compound and δ-aminolevulinic acid or its salt by formula R2R1NCH2COCH2CH2COR3 (1) where each R1 and R2 independently represents hydrogen atom, and R3 represents a hydroxyl group or C1-24 alkoxy group. The diagnostic agent contains 8-aminolevulinic acid or its salt by formula specified above. The diagnostic technique for the cerebral disease caused by mitochondrial dysfunction, involves a stage of introduction of the specified diagnostic agent followed by a stage of exposure of a diagnosed brain region to light, capable to excite protoporphyrin IX, accompanied by emission of red light, and a stage of diagnostics of the involved brain by the detected emission of red light.

EFFECT: higher diagnostic efficiency.

7 cl, 4 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular, to pharmacy. As medical substance composition contains therapeutically effective quantity of trimetazidine dihydrochloride, as prolonging agent - interpolymer complex of polyacrylic acid and polyethylenglucol. As additional substances composition includes: bibasic calcium phosphate, monocrystalline cellulose, basic calcium carbonate, group of sliding substances - stearic acid and/or its salts. Composition can be made in form of pills, covered with coating, contains optimal quantity of additional substances, makes it possible to sufficiently release medical substance and ensures its high bio-availability.

EFFECT: obtaining prolonged pharmaceutical composition, which has antianginal action.

16 cl, 6 tbl, 6 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of pharmaceutics and medicine and pharmaceutical composition for treatment of reperfusion disorders, which contains inert auxiliary substances and as active component compounds of general formula I-Iva.

EFFECT: obtaining pharmaceutical composition for treatment of reperfusion disorders.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel flavonoid compounds of formula 1 where R1-R5 assume values given in the description. The invention also relates to a pharmaceutical composition based on said compounds and a treatment and prevention method. Such compounds and corresponding pharmaceutically acceptable derivatives and/or salts are used in pharmaceutical, veterinary and nutraceutical fields.

EFFECT: compounds and compositions have antioxidant properties and are especially effective in treating ischemic and reperfusion injury.

39 cl, 19 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to rheumatology. Method of rheumatoid arthritis treatment includes therapy by non-steroid anti-inflammatory medications, glucocorticosteroids and cytostatics, and patient is additionally prescribed selenase 1 time per day in form of intravenous drop infusions in dose 2 ml (100 mcg), diluted in 200 ml of physiologicalsolution, during 10 days, with following transfer to per oral application of selenase in dose 2 ml (100 mcg of selenium) 1 time per day, course lasting to 6 months.

EFFECT: invention ensures increase of rheumatoid arthritis treatment efficiency and correction of autoimmune processes in case of said disease, makes it possible to reduce clinical symptoms of rheumatoid arthritis, reduce treatment terms, improve immunity properties and life quality of said category of patients.

2 ex

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