New 5,7-disubstituted [1,3]thiazolo-[4,5-d]pyrimidin-2(3h)-one derivatives and their application in therapy

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

,

where R1 represents CH3; R2 represents halogeno or CN; R3 represents H or CH3; R4 represents H or CH3; n represents 0, 1 or 2; and to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition and to application of the compounds of formula (I) in preparing a drug exhibiting antagonist activity in relation to CX3CR1 receptor.

EFFECT: provided the compounds of formula (I) as CX3CR1 receptor antagonists.

20 cl, 1 tbl, 3 dwg, 10 ex

 

The scope of the invention

The present invention describes new 5,7-disubstituted derivatives [1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she, as well as methods for their preparation, pharmaceutical compositions containing them and their use in therapy.

Background of the invention

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 represent a growing superfamily of proteins by mass of 8-14 kDa characterized by conservative cysteine motif. Currently, the superfamily of chemokines contains four groups exhibiting structural characteristic motifs of the family of C-X-C, C-C, C-X3-C and XC. Family C-X-C and C-C have the similarity of sequences and differ from each other based on a single amino acid insertion between NH-proximal pair of cysteine residues. The family of C-X3-Differs from the other two families on the grounds that has a triple amino acid insertion between NH-proximal pair of cysteine residues. On the contrary, family members XC is missing one of the first two cysteine residues.

Chemokines of the C-X-C include several efficiency is tive of chemoattractants and activators of neutrophils, such as interleukin-8 (IL-8) and activating neutrophils peptide 2 (NAP-2, neutrophil-activating peptide 2).

Chemokines C-C include effective chemoattractant monocytes, lymphocytes and neutrophils. Examples include chemotactic proteins human monocytes 1-3 (MCP-1, MCP-2 and MCP-3, monocyte chemotactic proteins 1-3), RANTES (regulated upon activation, expressed and secreted normal T-cells, Regulated on Activation, Normal T Expressed and Secreted), eotaxin and inflammatory proteins macrophages 1α and 1β (WORLD-1α and MIP-1β).

Chemokine C-X3- (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 shown that the actions of chemokines is mediated by subfamilies of receptors associated with G-protein, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for a family of S-C); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for a family of C-X-C) and CX3CR1 for a family of C-X3-C. These receptors are good targets for drug development, because the agents that modulate these receptors, can be useful in the treatment of disorders and diseases such as those mentioned above.

In WO 01/25242 describes some derivatives thiazolo[4,5-d]pyrimidine, which are useful as antagon the ists receptors related families of chemokines C-X-C and C-C, in particular as antagonists of the CXCR2.

The present invention relates to a group of compounds that are related to the compounds described in WO 01/25242, but have structural type, specifically there is not described. Compared to the Examples described in WO 01/58907, the compounds of the present invention have unexpectedly useful properties as antagonists of the receptor CX3CR1.

Description of the invention

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

where:

R1represents CH3or CF3;

R2represents halogen, CN or C1-6alkyl;

R3represents N or CH3;

R4represents N or CH3;

n represents 0, 1 or 2;

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

In one embodiment of the proposed invention the compounds of formula (I), where n represents 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 invention the proposed soedineniya (I), where R2represents F or Cl.

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

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

In yet another embodiment of the proposed invention the compounds of formula (I), where the pyridine is attached by its position 5 and contains 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 CN contains 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 contains 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 contains 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 contains 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 contains F in position 3.

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

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

In yet another embodiment of the proposed invention the compounds of formula (I)chosen from:

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

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

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

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

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

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

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

5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)butyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she

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

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

The compounds of formula (I) can exist in stereoisomeric and/or tauto hernych forms. It should be understood that all enantiomers, diastereomers, racemates, tautomers and mixtures thereof are included in the scope of the invention.

Compared with the compounds described in WO 01/25242, the compounds of the present invention are characterized by the presence of branched thioalkalivibrio group in position 5 thiazolidinedione ring system. That is, the compounds of the present invention include the group of R1other than hydrogen.

According to the invention is also a method for obtaining compounds of formula (I) or its pharmaceutically acceptable salt, which includes:

a) interaction of the compounds of formula (II)

where R3and R4are as defined in formula (I)with the compound of the formula (III)

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

b) hydrolysis of compounds of formula (IV)

where R1, R2, R3, R4and n are as defined in formula (I);

and, when necessary, the conversion of the compounds of formula (I) or its salt in another of its pharmaceutically acceptable salt; or the conversion of the compounds of formula (I) into another compound of formula (I); and, when this is desirable, turning on the scientists of the compounds of formula (I) in its optical isomer.

In method (a) reagents (II) and (III) are combined 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 is carried out in the presence of a moderate reducing agent such as sodium borohydride. The interaction is carried out at a suitable temperature, typically between room temperature and the boiling temperature of the solvent. The reaction is usually continued for a period of time from about one hour to one week, or until such time as the analysis shows, that the formation of the target product is completed. Suitable leaving groups L1represent halogen, in particular chlorine or bromine. In one embodiment of the L1represents chlorine.

In method (b) reactant (IV) is subjected to acid catalyzed hydrolysis in a suitable organic solvent, such as 1,4-dioxane, tetrahydrofuran (THF), dimethylsulfoxide (DMSO) or 1-methyl-2-pyrrolidinone (NMP). Suitable acids include inorganic acids such as hydrochloric acid or Hydrobromic acid, or strong organic acids, such as triperoxonane acid. In aimogasta is carried out at a suitable temperature, usually between room temperature and the boiling temperature of the solvent. The reaction usually occurs within the period of time from about one hour to one day or until such time as the analysis shows, that the formation of the target product is completed.

Specialist in the art should be understood that in the above-described methods may be desirable or necessary to protect the amino group, hydroxy or other potentially reactive groups. Suitable protective groups and the details of how the introduction and removal of such groups in General are well known in the prior art (see, for example, "Protective Groups in Organic Synthesis", 3rd Edition (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 with organic or inorganic bases. Such salts are pharmaceutically acceptable, although the salt is pharmaceutically acceptable acids or bases can find application in the production and purification of the compounds being considered.

Salts of compounds of formula (I) can be obtained through the interaction of a free compound or its salt, enantiomer or racemate with one or more equivalents of the appropriate acid or base. The interaction may be OS the employees in the solvent or the environment, 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 in a mixture of solvents that can be removed under vacuum or by freeze-drying. This interaction can also be a metabolic process or may be performed on the ion-exchange resin.

The compounds of formula (II) can in General be obtained by known methods which are obvious to a person skilled in this field. One such suitable path shown in Scheme 1.

Scheme 1

The compounds of formula (III) are either commercially available or known from the literature or can be obtained using known methods that will be obvious to a person skilled in this field.

The compounds of formula (IV) are either known from, for example, WO 01/25242 or WO 05/33115, or can be obtained using known methods that will be obvious to a person skilled in this field. One such suitable path shown in Scheme 2.

Scheme 2

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

For example, the compounds of formula (V) and, accordingly, the compounds of formula (VI) can be obtained as shown in Scheme 3.

Scheme 3

Suitable specific methods for obtaining compounds of formula (II), (III), (IV), (V) and (VI) detailed in the Examples section of this application, and such methods are specific embodiment of the methods according to the invention.

Intermediate compounds may be used as such or in protected form. Suitable protective groups and particular ways of introduction and removal of such groups in General are well known in the prior art (see, for example, "Protective Groups in Organic Synthesis", 3rd Edition (1999), Greene and Wuts).

Compounds according to the invention and their intermediate compounds can be isolated from their reaction mixtures, and optionally subjected to additional purification using standard techniques.

The compounds of formula (I) can exist in stereoisomeric forms. Accordingly, 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. Alternatively, RA is ing optical isomers can be obtained directly by using optically active starting materials.

The compounds of formula (I) contain two stereogenic center and therefore can exist in four discrete 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 as purified enantiomers, diastereomers, racemates or mixtures.

In this description, the term "C1-6alkyl" includes both straight and branched chain and cyclic alkyl groups. With1-6alkyl has from 1 to 6 carbon atoms and may represent, without limitation them, methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, n-pentyl, out-of pentyl, tert-pentyl, neo-pentyl, n-hexyl, ISO-hexyl or cyclohexyl.

In this description, the term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The compounds of formula (I) and their pharmaceutically acceptable salts are useful because they possess pharmacological activity in which the quality antagonists CX 3CR1 receptor. In particular, compared with the compounds specifically disclosed in the examples in WO 01/25242, the compounds of formula (I) according to the present invention are significantly more pronounced ability in terms of inhibition CX3CR1 receptor and/or a reduced ability to inhibition of CXCR2 receptor. Preferred compounds of the present invention possess enhanced ability to inhibition CX3CR1 and lower potential for inhibition of 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 a positive antagonism against CX3CR1 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 disorders, diseases of the peripheral is such arteries, 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 rupture of plaques 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 transient damage of the Denia brain injury (TBI).

According to the invention is also a method of treating or reducing the risk of diseases or conditions in which a positive antagonism against CX3CR1 receptor, which includes an introduction to the subject suffering from the specified disease or condition, or subject to it, therapeutically effective amounts of compounds of formula (I) or its pharmaceutically acceptable salt.

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 in a subject suffering from the specified disease or condition or affected by it, including an introduction to this subject a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

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

A method of treating or reducing the risk of atherosclerosis p is the 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 the subject, suffering from the specified disease or condition or affected by it, including an introduction to this subject a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

A method of treating or reducing the risk of atherosclerosis by changing the composition of the plaques with the aim of reducing the risk of rupture of plaques and atherothrombotic events in a subject suffering from the specified disease or condition or affected by it, including an introduction to this subject a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

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 a positive antagonism against CX3CR1 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 p is imeneniya 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 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 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.

The compounds may be used as monotherapy or in combination, as a prophylactic or therapeutic treatment of inflammatory conditions and diseases of the Central nervous system such as stroke or transient brain injury (TBI) (Soriano et al. J. Nuroimmunology 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 the treatment or prophylaxis of atherosclerosis by changing the composition of the plaques with the aim of reducing the risk of rupture of plaques 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 CX3CRI receptor. In particular, the compounds indicated for use in the treatment of neurodegenerative disorders or demyelinating disease in mammals, including humans. More specifically, these compounds are indicated for use in the treatment of multiple sclerosis. These compounds are also indicated for use in treatment of pain, rheumatoid arthritis, osteoarthritis, cardio - and cerebrovascular atherosclerotic disorders, peripheral artery disease and pulmonary arterial hypertension.

Conditions that may be specifically mentioned are: neurodegenerative diseases and dementia, for example Alzheimer's disease, amyotrophic lateral scle the oz and other diseases of the motor neurons, disease Creutzfeld-Jakob and other prion diseases, HIV (human immunodeficiency virus)-associated encephalopathy, Huntington's disease, frontotemporal dementia, dementia with calves Levi and vascular dementia; polyneuropathy, such as Guillain-Barre syndrome, chronic inflammatory demyelinizing polyradiculoneuropathy, multifocal motor neuropathy and plexopathy; demyelination of the CNS, such as acute disseminated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis; neuromuscular disorders, such as severe psevdomatematicheskoe male and syndrome of Lambert-Eaton; spinal disorders, such as tropical spastic prepares syndrome and muscle stiffness; paraneoplastic syndromes, such as cerebellar degeneration and encephalomyelitis; traumatic brain injury; headache; cancer; allograft rejection; systemic sclerosis; viral infection; - borne parasites diseases, such as malaria; periodontal disease; myocardial infarction; stroke; coronary heart disease; coronary heart disease; restenosis; rheumatoid arthritis; pulmonary diseases such as COPD; asthma and pain.

Compounds according to the invention are also indicated for use in the treatment of atherosclerosis by preventing the/or reduce 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 with the aim of reducing the risk of rupture of plaques and atherothrombotic events.

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

It is expected that prevention is particularly suitable for treating individuals who have had a previous episode, or that otherwise are considered to have an increased risk of the disease or condition. Individuals at risk of developing a particular disease or condition usually include individuals with a family history of the disease or condition and individuals who, through genetic testing or screening were identified as being particularly sensitive to the development of this disease or condition.

Enter the dosage for the above therapeutic indications, of course, will vary depending on the compound, route of administration and the desired treatment. However, in General satisfactory results are obtained when the compound is administered in a solid dosage form is between 1 mg and 2000 mg sutki.

The compounds of formula (I) and their pharmaceutically acceptable derivatives may be used by themselves or in the form of appropriate pharmaceutical compositions in which the compound or derivative is in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The introduction can be effected, without limiting them, parenteral (including oral, sublingual, or rectal), intranasal, intravenous, local or other parenteral routes. Conventional procedures for the selection and production of suitable pharmaceutical compositions are described, for example, in Pharmaceuticals - The Science of Dosage Form Designs", M.E.Aulton, Churchill Livingstone, 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, a method of manufacturing such pharmaceutical compositions, which comprises mixing the ingredients.

In addition, the invention relates to combination therapies, where the compound of formula (I) or its pharmaceutically acceptable salt or pharmaceutical composition or drug containing the compound of formula (I), is administered simultaneously or sequentially with therapy and/or agent for treatment of any cardio - or cerebrovascular atherosclerotic disorders and diseases the Oia peripheral arteries.

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

1) anti-inflammatory agents, for example

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

b) inhibitors of leukotriene synthesis (5-LO (5-lipoxygenase) inhibitor, for example AZD4407, zileuton (Zileuton), licofelone, CJ13610, CJ13454; FLAP (a protein that activates 5-lipoxygenase) inhibitors, such as BAY-Y-1015, DG-031, MC, MK, A; inhibitors of LTA4 (leukotriene A4) hydrolases, for example SC56938, SC57461A);

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

2) antihypertensive agents, for example

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

b) angiotensin converting enzyme inhibitors (such as captopril, ramipril, inapril, enalapril);

C) calcium channel blockers (e.g. verapamil, diltiazem, felodipine, amlodipine);

g) antagonists of angiotensin II receptors (for example, irbesartan, candesartan, telmisartan, losartan);

3) anticoagulants, such as

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

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

4) modulators of lipid metabolism, such as

activators of insulin sensitizers, such as PPAR agonists (nuclear receptor that is activated by proliferation peroxisome) (e.g., pioglitazone, rosiglitazone, halide (Galida), muraglitazar, getemail, phenobarbital);

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

b) inhibitors of cholesterol intake (for example, ezetimib);

in) IBAT inhibitors (transport of bile acids in the ileum, such as AZD-7806);

g) agonists, LXR (liver X receptors, such as GW-683965A, T-0901317);

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

e) inhibitors of phospholipase;

5) agents against angina, such as nitrates and nitrites;

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

The invention is illustrated in the following non-limiting examples.

Common methods

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

1H and13The NMR spectra were recorded the ri 400 MHz for proton and 100 MHz for carbon-13 NMR spectrometer Varian Unity+ 400, equipped with a 5 mm BBO probe with Z-gradients, or on the NMR spectrometer Bruker Avance 400, equipped with 60 ál of double inverse flow sensor with Z-gradients, or on the NMR spectrometer Bruker DPX400, equipped with a 4-nucleus probe with Z-gradients. 600 MHz1H NMR spectra were taken on a NMR spectrometer Bruker av600, equipped with a 5 mm BBI probe with Z-gradients. 300 MHz1H NMR spectra were taken on Varian Gemini 300 NMR, equipped with a 5 mm BBI probe. 500 MHz1H NMR spectra were taken on Varian Inova 500 Spectrometer operating at a magnetic field 11,74 T, equipped with a 5 mm probe with nuclear gradient. Unless specifically provided in the examples, the spectra were taken 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 (1H), the middle line CDCl3δ 77.16 (13C) (unless otherwise specified).

The enantiomeric excess (EE) was determined by GC (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 taken with the apparatus of the Waters LCMS, consisting of an Alliance 2795 (LC) and odnokletochnogo by weight of the spectrometer ZQ. The mass spectrometer was equipped with a source of ionization elektrorazpredelenie (ESI)operated in the positive mode or negative ions. The capillary voltage was 3 kV and the mass spectrometer was scanned in the range m/z 100-700 with a scan time of 0.3 or 0.8 sec. Separation was performed either on a Waters X-Terra MS C8 column (3.5 µm, 50 or 100 mm × 2.1 mm e)or ACE 3 AQ (100 mm × 2.1 mm e), obtained from ScantecLab. The column temperature was set equal to 40°C. was Applied a linear gradient, using a neutral or acidic mobile phase system, banishing from 0% to 100% of the organic phase for 4-5 minutes, flow rate 0.3 ml/min Neutral mobile phase system: acetonitrile/[10 mm NH4OAc (aq.) / MeCN (95:5)], or [10 mm NH4OAc (aq.) / MeCN (1/9)] / [10 mm NH4OAc (aq.) / MeCN (9/1)]. Acidic mobile phase system: [133 mm HCOOH (aq.) / MeCN (5/95)] / [8 mm HCOOH (aq.) / MeCN (98/2)]. Alternative mass SPECTA filmed on a mass spectrometer Micromass LCT with source ionization elektrorazpredelenie (ESI)operated in the positive ion mode.

Identification of compounds was performed on GC-MS (a combination of gas chromatography and mass spectroscopy, GC 6890, 5973N MSD)supplied by Agilent Technologies. The used column was a VF-5 MS, e, 0.25 mm × 30 m, 0.25 μm (Varian Inc.). A linear temperature gradient was applied starting from 40°C (kept for 1 min the Tu) and ending at 300°C (kept for 1 minute), 25°C/minute. MS was equipped EI (electron ionization) ion source. The MS was scanned between m/z 50-500, and the scan rate was 3.25 scans/sec Electronic voltage was set at 70 eV.

HPLC analyses were performed on the system Agilent HP1000, consisting of microvacuum of G1379A degasser, binary pump G1312A, autosampler G1367A Wellplate, SO thermostatted column compartment and G1315B diode matrix detector. Column: X-Terra MS, Waters, and 4.6×50 mm, 3.5 µm. The column temperature was set equal to 40°C and a flow rate of 1.5 ml/minute. Diode matrix detector scanned in the range 210-300 nm, step and peak width was set equal to 2 nm and 0.05 minutes, respectively. Made linear gradient ran from 0% to 100% acetonitrile for 4 minutes. Mobile phase: acetonitrile/10 mm ammonium acetate in 5% acetonitrile in MilliQ Water.

Typical processing procedure after completion of the reaction consisted of extraction of the product with a solvent, such as ethyl acetate, washing with water, followed by drying the organic phase over MgSO4or Na2SO4and concentrating the solution in vacuo.

Thin-layer chromatographie (TLC) was performed on plates Merck TLC (silica gel 60 F254), and for visualization of the spots used ultraviolet light. Flash chromatography was performed by Combi Flash®Companion™using flash column with normal phase RediSep™, is whether Merck Silica gel 60 (0,040-0,063 mm). Typical solvents used for flash chromatography, was a mixture of chloroform/methanol, toluene/ethyl acetate and ethyl acetate/hexane.

Preparative chromatography was carried out on the installation Gilson auto-preparative HPLC with diode-array detector, using a column XTerra MS C8, 19×300 mm, 7 μm) and a gradient of acetonitrile/0.1 M ammonium acetate in 5% acetonitrile in MilliQ Water, chased from 20% to 60% acetonitrile in 13 minutes at a flow rate of 20 ml/minute, if the examples are not specified otherwise. Alternative purification was performed on prepreparation installation Shimadzu LC-8A HPLC with a Shimadzu SPD-10A UV-vis.-detector provided column Waters Symmetry®(C18,5 μm, 100 mm × 19 mm). A gradient of acetonitrile/0.1% of triperoxonane acid in MilliQ Water, chased from 35% to 60% acetonitrile in 20 minutes. Flow rate: 10 ml/minute. Alternative preparative HPLC was carried out on the installation of the Agilent 1100 with UV detection. Column: Kromasil-C18, 20×250 mm, 10 μm. Isocratic elution of mobile phase acetonitrile/MilliQ Water/formic acid (46/54/0,1). Flow rate: 19 ml/minute.

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

Used the following abbreviations: DCM = dichloromethane; de = diastereomeric excess; DIPCI = β-chlorodiisopinocampheylborane (DIP-Chloride™); 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.

Used original substances were either available from commercial sources, or were they received as described in the literature procedures, and they had the experimental data in accordance with what was reported. The following compounds are examples of starting substances, which have been received:

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

5-(benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidine-2-amine: WO 00/09511 (Examples 6 and 7);

5-herperidin-2-carbonitrile: WO 2005/066155 (Example 2);

1-(3-herperidin-4-yl)ethanol: Marsais, F. et al. Tetrahedron 1983, 39, 2009-2021 (Example 3);

2-acetyl-isonicotinamide: Citterio et al. J. Chem. Res. Synopses 1982, 10, 272-273 (Example 5);

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, R3and R4are as defined in formula (I); CH represents a possibly substituted pyridyl and LG represents a leaving group.

A common way And

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

A common way To

Conc. HCl (2.5 ml/mmol (VI)) was added to (VI) (1.0 equiv.) in CH3CN. The reaction mixture was cooled in an ice bath and was added dropwise sodium nitrite (2.0 equiv.), dissolved in a minimum amount of water. The reaction mixture was stirred at 0°C. until completion of reaction (monitored by LC-MS, HPLC or TLC) and then was poured into ice water, neutralized with sodium bicarbonate and was extracted with DCM or EtOAc. The combined organic phase was dried and concentrated in vacuum to obtain the product.

A common way To

Potassium hydroxide (2.0 equiv.), dissolved in methanol was added dropwise to a cooled (0°C.) solution of (VII) (1.0 equiv.) in methanol. The resulting mixture was stirred at 0°C. until completion of reaction (monitored by LC-MS, HPLC or TLC). The solvent is evaporated and the product was used on the next re is klonoa stage without additional purification.

General method D

A solution of concentrated HCl (1.0 equiv.) was added to a cooled (0°C) solution (IV) (1.0 equiv.) in 1,4-dioxane. The resulting mixture was stirred at 40°C. until completion of reaction (monitored by LC-MS, HPLC or TLC). The reaction mixture was neutralized with saturated NaHCO3(aq.) and the dioxane evaporated. The residue was dissolved in DCM or EtOAc, washed with brine, dried and concentrated in vacuum. The crude product is, if necessary, purified using preparative HPLC or by column flash chromatography.

General method E1

(VIII) (1.0 equiv.) in THF was added at 0°C to (+)-DIPCI (with receipt (IX)or (-)-DIPCI (receive (X)) (1.5 equiv.) in THF in an argon atmosphere. The reaction mixture was left to slowly warm to room temperature over night. The solvent is evaporated, followed by addition of Et2O and diethanolamine (2.2 equiv.). The mixture was stirred until completion of the reaction (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 is, if necessary, purified using preparative HPLC or by column flash chromatography.

General method E2

(R)-(+)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 0.1 to 1 equiv.) R who has storyli in THF and cooled to 0°C. Was added dropwise borane complex-metilsulfate (2 M in THF, 1 equiv.) and the reaction mixture was stirred for 1 h, the Reaction mixture was cooled to -10°C. and was added dropwise (VIII) (1 equiv.), dissolved in THF for 0.5 hours the mixture was stirred for 1 h or until completion of the reaction and the temperature was slowly raised to 10°C. to quench the reaction, was added 1 M aq. HCl. Was added saturated aq. NaHCO3up until the pH reached about 8. The product was extracted with DCM. The combined organic extracts were dried over Na2SO4and concentrated in vacuum to obtain (X). The product was purified by column chromatography.

A common way F1

Triphenylphosphine (1.3 equiv.) in THF was added at 0°C to NCS (1.3 equiv.) in THF in an argon atmosphere. The resulting mixture was stirred at ambient temperature for 30 minutes. At 0°C was added (IX) or (X) (1 equiv.) and the reaction mixture was stirred at ambient temperature until completion of the reaction (monitored by LC-MS, HPLC or TLC). The solvent is evaporated, after which was added hexane and the precipitate was removed by filtration. The filtrate was concentrated in vacuum and the crude product is, if necessary, purified using preparative HPLC or by column flash chromatography.

General the way F2

Cyanuric chloride (0.6 equiv.) was dissolved in ethyl acetate. Was added DMF (1.5 equiv.) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0°C. (IX) or (X) (1 equiv.) was dissolved in ethyl acetate and was added dropwise over 10 minutes. The resulting mixture was stirred at room temperature overnight. Added isopropanol (approx. 0.25 ml/mmol (IX) or (X)). The precipitate was filtered and washed with EtOAc. The filtrate was concentrated to obtain (XI) or (XII).

General method G

Sodium borohydride (1 to 2 equiv.) added to (II) (1.0 equiv.) in DMSO. After gas evolution was added (III) (2-2,5 equiv.). The resulting reaction mixture was stirred at 40°C. until completion of reaction (monitored by LC-MS, HPLC or TLC). Treatment, if necessary, was performed using preparative HPLC or by column flash chromatography.

Example 1

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

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

5-Chloropyridin-2-carbonitrile (10,71 g, 77 mmol) was dissolved in diethyl ether (65 ml) and THF (35 ml) under nitrogen atmosphere. The mixture was cooled to until inside the inner temperature did not reach -63°C. For 30 minutes was added magnesium bromide (3 M in THF, 35 ml, 105 mmol). The reaction mixture is then left to mix at -60°C for 45 minutes and then was heated to room temperature. For dissolution of precipitated precipitated substance was added 50 ml of THF. After 1 h at room temperature the completion of reaction was checked by HPLC. Added 2 M hydrochloric acid (aq., 100 ml) and the reaction mixture was stirred for 4 hours the pH was brought to 7 with sodium bicarbonate. The phases were separated and the product was extracted from the aqueous phase twice through DCM. The combined organic extracts were dried over sodium sulfate and concentrated in vacuum. The product was purified by column chromatography (eluent a gradient of heptane:ethyl acetate) to give 7.9 g (yield 64%) specified in the connection header.

1H NMR (300 MHz, CDCl3): 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 E2, starting from 1-(5-chloropyridin-2-yl)ethanone (780 mg, 5 mmol). Purification by column flash chromatography gave 695 mg (yield 88%) specified in the connection header with 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]p is ridin

Specified in the title compound was obtained by the General method F2, starting with (1S)-1-(5-chloropyridin-2-yl)ethanol (695 mg, to 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, 3H); 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 (823 mg, of 2.75 mmol) and 5-chloro-2-[(1R)-1-chloroethyl]pyridine (less than 4.4 mmol). Purification by column flash chromatography (eluent gradient OSM:methanol) gave 350 mg (30%yield) specified in the connection header.

1H NMR (400 MHz, CD3OD): δ ppm 8.49 (d, 1H), 7.79 (dd, 1H), 7.66 (d, 1H), 5.22 (q, 1H), 4.46 (br s, 1H), 3.40-3.57 (m, 2H), 1.66-1.78 (m, 4H), 1.40-1.61 (m, 2H), 0.93-1.03 (m, 6H); MS (ESI) m/z 439 and 441 [M+1]+.

d) (2R)-2-[(2-Chloro-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 B, starting from (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 (340 mg, 0.77 mmol).

MS (ESI) m/z 458 and 460 [M+1]+.

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

Specified in the title compound was obtained from (2R)-2-[(2-chloro-5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol from the previous stage, using General method C, except that the reaction mixture was heated to 50°C for 1 h After completion of the reaction, the reaction mixture was diluted with water and the product was extracted with DCM (four times). The combined organic extracts were dried over sodium sulfate and concentrated in vacuum to obtain specified in the title compound, which was used in the next stage without purification.

MS (ESI) m/z 453 and 455 [M+1]+.

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

Specified in the title compound was obtained from (2R)-2-[(5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}-2-methoxy[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol from the previous stage, using General method D, except that the reaction mixture was stirred at 50°C for 2.5 h and then at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with brine and was extracted with DCM (three times). Merged the content of inorganic fillers extracts were dried over sodium sulfate and concentrated in vacuum. The product was purified flash chromatography (eluent gradient D:methanol) to give 160 mg. Additional purification by preparative HPLC (column: Chiralcel OJ, eluent: ethanol/heptane 30/70, flow rate: 12 ml/min) gave 82 mg specified in the connection header.

1H NMR (400 MHz, CD3OD): δ ppm 8.24 (d, 1H), 7.56 (dd, 1H), 7.38 (d, 1H), 4.90 (q, 1H), 4.19 (br s, 1H), 3.16-3.30 (m, 2H), 1.39-1.51 (m, 4H), 1.15-1.34 (m, 2H), 0.68-0.76 (m, 6H);1H NMR (DMSO-d6) δ ppm 12.36 (br s, 1H), 8.57 (d, 1H), 7.86 (dd, 1H); 7.57 (d, 1H); 7.23 (d, 1H); 5.03 (q, 1H); 4.69 (t, 1H); 4.29 (br s, 1H); 3.40-3.25 (m, 2H), 1.66 (d, 3H), 1.63-1.52 (m, 1H); 1.48-1.32 (m, 2H), 0.88 (d, 3H), 0.85 (d, 3H); MS (ESI) m/z 440 and 442 [M+1]+, 438 and 440 [M-1]+.

Example 2

5-{[(1S)-1-(5-Herperidin-2-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}][1,31]thiazolo[4,5-d]pyrimidine-2(3H)-he

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 an internal temperature -64°C. For 40 minutes was added magnesium bromide (3 M in THF, 105 ml, 315 mmol). The reaction mixture was stirred at -65°C for 1.5 h, then it was heated to room temperature. Added THF (50 ml) and the mixture was stirred for 3 hours was Added 2 M hydrochloric acid (aq., 100 ml) until then, until the mixture was slightly acidic, and the reaction mixture was stirred at room temperature is during the night. Then to neutralize the reaction mixture was added sodium bicarbonate. 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 by column flash chromatography to obtain 18 g (55%yield) specified in the connection header.

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 E2, starting from 1-(5-herperidin-2-yl)ethanone (3,18 g is 22.9 mmol). Purification by column flash chromatography gave 2,73 g (84%yield) specified in the connection header with 84%.

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 title compound with 80%was obtained by the General method F2, starting with (1S)-1-(5-herperidin-2-yl)ethanol (720 mg, 5.1 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 header is Obedinenie received a General way And, starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol (940 mg, 3.1 mmol) and 2-[(1R)-1-chloroethyl]-5-herperidin (0,81 g, 5.1 mmol). The product was purified flash column-chromatography to obtain 0.75 g (56%yield) 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), 0.88 (d, 3H), 0.85 (d, 3H); MS (ESI) m/z 423 [M+1]+.

d) (2R)-2-[(2-Chloro-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 using General method B, starting from (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 (750 mg, 1.77 mmol).

MS (ESI) m/z 442 and 444 [M+1]+.

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

Specified in the title compound was obtained from (2R)-2-[(2-chloro-5-{[(1S)-1-(5-herperidin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol from the previous stage, using General method C, except that the reaction mixture was heated to 50°C. for 1.5 hours After completion of the reaction, the reaction mixture was diluted with water and brine and the product was extracted with what cloroformo (three times). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuum to obtain specified in the title compound, which was used without purification.

MS(ESI) m/z 438 [M+1]+.

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

Specified in the title compound was obtained from (2R)-2-[(5-{[(1S)-1-(5-herperidin-2-yl)ethyl]thio}-2-methoxy[1,3]thiazolo[4,5-d]pyrimidine-7-yl)-amino]-4-methylpentan-1-ol from the previous stage, using General method D, except that the reaction mixture was stirred at 50°C for 3 hours After completion of the reaction, the reaction mixture was diluted with brine and was extracted with DCM (three times). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuum. The product was purified by flash chromatography (eluent a gradient of DCM:methanol). Additional purification by preparative HPLC (column Chiralcel OJ, eluent: ethanol, flow rate: 8 ml/min) gave 113 mg specified in the connection header.

1H NMR (CD3OD): δ ppm 8.19 (d, 1H), 7.46 (dd, 1H), 7.36 (dt, 1H), 4.97 (q, 1H), 4.26 (br s, 1H), 3.23-3.34 (m, 2H), 1.44-1.55 (m, 4H), 1.19-1.37 (m, 2H), 0.75 (dd, 6H);1H NMR (DMSO-d6) δ ppm 12.36 (br s, 1H), 8.52 (d, 1H), 7.66 (dt, 1H); 7.60 (dd, 1H), 7.23 (d, 1H); 5.07 (q, 1H); 4.69 (t, 1H); 4.30 (br s, 1H); 3.40-3.26 (m, 2H), 1.67 (d, 3H), 1.64-1.53 (m, 1H); 1.48-1.33 (m, 2H), 0.88 (d, 3H), 0.85 (d, 3H); MS (ESI) m/z 42 [M+1] +. OK

Example 3

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

a) 4-(1-Chloroethyl)-3-herperidin

1-(3-Herperidin-4-yl)ethanol (0.8 g, 5.7 mmol) was treated with thionyl chloride (5 ml) and the resulting mixture was heated up to 80°C for 2 hours was Added water (10 ml) and feast upon. sodium bicarbonate (aq., 10 ml). The product was extracted with DCM (three times). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuum. The crude product was purified flash column-chromatography (eluent a gradient of heptane:ethyl acetate) to give 0.36 g (39%yield) specified in the connection header.

1H NMR (300 MHz, CDCl3) 8.45 (m, 2H), 7.50 (m, 1H), 5.34 (q, 1H), 1.83 (d, 3H).

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

Specified in the title compound (370 mg, 47%yield) 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 (560 mg, of 1.87 mmol).

MS (ESI) m/z 423 [M+1]+.

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

Specified in the header of the connection is Uchali, using General method B, starting from (2R)-2-[(2-amino-5-{[1-(3-herperidin-4-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol (370 mg, 0.84 mmol).

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

Specified in the title compound was obtained from (2R)-2-[(2-chloro-5-{[1-(3-herperidin-4-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol from the previous stage, using General method C, except that the reaction mixture was heated to 50°C. for 1.5 hours After completion of the reaction, the reaction mixture was diluted with water and brine (1:1) and the product was extracted with DCM (twice). Then the pH of the aqueous phase was brought to 7 with ammonium chloride and the product was extracted with DCM (twice). The combined organic extracts were dried over sodium sulfate and concentrated in vacuum to obtain specified in the connection header.

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

Specified in the title compound was obtained starting from (2R)-2-[(5-{[1-(3-herperidin-4-yl)ethyl]thio}-2-methoxy[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-4-methylpentan-1-ol from the previous stage, using General method D, except that the reaction mixture was stirred at 50°C during the 2 hours After completion of the reaction, the reaction mixture was diluted feast upon. the sodium bicarbonate (aq.) and water (1:1) and was extracted with DCM (three times). The combined organic extracts were dried over sodium sulfate and concentrated in vacuum. The product was purified by column flash chromatography (eluent a gradient of heptane:ethyl acetate) to obtain specified in the title compounds as a mixture of diastereoisomers (194 mg).

MS (ESI) m/z 424 [M+1]+.

Example 4

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

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 to until the internal temperature did not reach -66°C. dropwise over 0.5 h was added utility (2.5 M in hexano, 26 ml, 65 mmol). The resulting reaction mixture was left at -65°C for 1 h For 10 minutes was added N,N-dimethylacetamide (6.5 ml, 70 mmol) and 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 by adding hydrochloric acid. The aqueous phase three times was extracted with diethyl ether. The joint is haunted organic phase was washed with brine, was dried over sodium sulfate and concentrated in vacuum. Purification by column flash chromatography (eluent a gradient of heptane:diethyl ether) gave 4.6 g (34%yield) 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 E2, starting from 1-(6-bromo-3-herperidin-2-yl)ethanone (1,76 g, 8,19 mmol). The product was purified by column flash chromatography (eluent a gradient of heptane:ethyl acetate) to give 1.31 g (73%yield) 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-H2O]+.

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 under hydrogen pressure of 2.5 ATM (253,25 kPa) at room temperature for 24 h the Mixture was filtered and the solid washed with DCM. The filtrate was washed with water and brine and dried over sodium sulfate and concentrated in VA is uume. The crude product was purified flash column-chromatography (eluent gradient D:methanol) to obtain 0.54 g (65%yield) 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 method F2, 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]pyrimidin-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). In the purification by column flash chromatography (eluent gradient D:methanol) was obtained 190 mg (47%yield) specified in the connection header with diastereomeric excess of 60%.

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); 3.45-3.30 (m, 2H), 1.69 (d, 3H), 1.66-1.58 (m, 1H), 1.50-1.35 (m, 2H), 0.88 (d, 3H), 0.85 (d, 3H); MS (ESI) m/z 423 [M+1]+. MS (ESI) m/z 423 [M+]+.

e) (2R)-2-[(2-Chloro-5-{[(1S)-1-(3-CFT is pyridin-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 B, starting from (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 (135 mg, 0.32 mmol).

MS (ESI) m/z 442 and 444 [M+1]+.

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

Specified in the title compound was obtained from (2R)-2-[(2-chloro-5-{[(1S)-1-(3-herperidin-2-yl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol from the previous stage, using General method C, except that the reaction mixture was heated to 50°C. for 1.5 hours After completion of the reaction, the reaction mixture was diluted with water and brine (2:1) and the product was extracted with chloroform (three times). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuum to obtain specified in the connection header.

MS (ESI) m/z 438 [M+1]+.

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

Specified in the title compound was obtained from (2R)-2-[(5-{[(1S)-1-(3-herperidin-2-yl)ethyl]thio}-2-methoxy[1,3]thiazolo[4,5-d]pyrimidine-7-yl)-amino]-4-methylpentan-1-ol using General method D, except that reaction the second mixture was heated to 50°C. for 1.5 hours After completion of the reaction, the reaction mixture was diluted with brine and was extracted with DCM (three times). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuum. The product was purified flash column-chromatography (eluent gradient D:methanol)and then preparative HPLC to obtain 20 mg specified in the connection header.

1H NMR (DMSO-d6) δ ppm 12.37 (br s, 1H), 8.41 (dt, 1H), 7.72 (m, 1H); 7.42 (m, 1H); 7.27 (br s, 1H); 5.43 (q, 1H); 4.67 (t, 1H); 4.30 (br s, 1H); 3.44-3.30 (m, 2H), 1.70 (d, 3H), 1.65-1.55 (m, 1H); 1.52-1.32 (m, 2H), 0.89 (d, 3H), 0.86 (d, 3H); MS (ESI) m/z 424 [M+1]+.

Example 5

2-{(1S)-1-[(7-[{(1R)-1-(Hydroxymethyl)-3-methylbutylamine}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-d]pyrimidine-5-yl)thio]ethyl}isonicotinamide

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

Specified in the title compound (1.13 g, 7,63 mmol) was obtained according to General method E1, starting from 2-acetyl-isonicotinamide (1.42 g, 9,72 mmol) and (-)-DIPCI (4,67 g of 14.57 mmol).

1H NMR (500 MHz, CDCl3) 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 header connection (to 32.2 mg, 0,19 mmol) was obtained in accordance with the General method F1, starting with 2-((S)-1-hydroxy-ethyl)-isonicotinamide (400 mg, 2.7 mmol).

1H NMR (500 MHz, CDCl3) δ 8.74 (d, 1H), 7.76 (s, 1H), 7.46 (dd, 1H), 5.16 (q, 1H), 1.88 (d, 3H).

C) (2R)-2-{2-Chloro-5-[2-chloro-7-((1R)-1-hydroxymethyl-3-methyl-butylamino)-thiazolo[4,5-d]pyrimidine-5-idealfor]-thiazolo[4,5-d]pyrimidine-7-ylamino}-4-methyl-pentane-1-ol

Sodium nitrite (5,19 g, 75 mmol) in water (25 ml) at 0°C was added dropwise to (2R)-2-[[2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl]-amino]-4-methylpentan-1-Olu (7.50 g, 25 mmol) in conc. hydrochloric acid (150 ml) and acetonitrile (150 ml). The reaction mixture was stirred for 18 h at 0-5°C and then poured into ice (500 ml) and was extracted with ethyl acetate. All remaining solid was filtered. The combined organic phases were washed sequentially with brine and saturated aqueous solution of bicarbona sodium. The organic phase was dried and evaporated and to it was added a pre-filtered solid. Total solid matter was dispersible in ethyl acetate, which after filtering has been specified in the title compound (6.3 g, 80%yield).

1H NMR (DMSO-d6) δ 8.25 (d, 2H), 4.19 (m, 2H), 3.35 (m, 4H), 1.40 (m, 4H), 1.21 (m, 2H), 0.68 (d, 6H), 0.51 (d, 6H); MS (ESI) m/z 635 [M+1]+.

g) (2R)-2-{5-[7-((1R)-1-Hydroxymethyl-3-methyl-butylamino)-2-methoxy-thiazolo[4,5-d]pyrimidine-5-idealfor]-2-methoxy-thiazolo[4,5-d]pyrimidine-7-ylamino}-4-methyl-pentane-1-ol

Potassium hydroxide (0,53 g, 9.4 mmol) in methanol (5 ml) we use the and at 0°C. to a solution of (2R)-2-{2-chloro-5-[2-chloro-7-((1R)-1-hydroxymethyl-3-methyl-butyl-amino)-thiazolo[4,5-d]pyrimidine-5-idealfor]-thiazolo[4,5-d]pyrimidine-7-ylamino}-4-methyl-pentane-1-ol (3.0 g, 4.7 mmol) in methanol (200 ml). The reaction was maintained at 0-5°C for 18 hours the Solvent is evaporated and the residue was transferred into a mixture of methanol/ethyl acetate (1:1). This solution was quickly chromatographically (eluent ethyl acetate) to obtain the specified title compound (2.0 g, 68%yield).

MS (ESI) m/z 627 [M+1]+.

e) 5-[7-{[(1R)-1-(Hydroxymethyl)-3-methylbutyl]amino}-[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one-5-idealfor]-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-he

A mixture of conc. hydrochloric acid (20 ml) and water (20 ml) was added to a solution of (2R)-2-{5-[7-((1R)-1-hydroxymethyl-3-methyl-butylamino)-2-methoxy-thiazolo[4,5-d]pyrimidine-5-idealfor]-2-methoxy-thiazolo[4,5-d]pyrimidine-7-ylamino}-4-methyl-pentane-1-ol (1.5 g, 2.4 mmol) in 1,4-dioxane (20 ml). This solution is then stirred at 45°C for 18 hours the Solvent is evaporated and the residue was transferred into ethyl acetate. All undissolved residue was collected by filtration. The filtrate was subjected to column flash chromatography (eluent is a mixture of ethyl acetate:methanol, 95:5). The solid residue and the product collected after chromatography, combined with obtaining specified in the title compound (600 mg, 42%yield).

1H NMR (DMSO-d6) δ 12.45 (s, 2H), 7.33 (d, 2H), 4.62 (t, 2H), 4.17 (br s, 2H), 1.48-1.31 (m, 4H), 1.25-1.14 (m, 2H), 0.72 (d, 6H), 0.56 (d, 6H); MS (ESI) m/z 599 [M+1]+.

e) 2-{(1S)-1-[(7-{[(1R)-1-(Hydroxymethyl)-3-IU is libutil]amino}-2-oxo-2,3-dihydro[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 G with the addition of DIPEA (2 equiv.), starting with the compound 5,5'-dithiobis[7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-he] (64 mg, 0,096 mmol) and 2-((R)-1-chloro-ethyl)-isonicotinamide (32 mg, 0,192 mmol). Specified in the title compound (39 mg) was obtained in the form of diastereomeric mixture. Purification by preparative HPLC (column: Kromasil-C18) gave 15 mg (36%yield) specified in the connection header with 98%de.

1H NMR (500 MHz, CD3OD) δ 8.71 (d, 1H), 7.92 (s, 1H), 7.56 (d, 1H), 5.17 (q, 1H), 4.4 (s, 1H), 3.40-3.52 (m, 2H), 1.72 (d, 3H), 1.60-1.71 (m, 1H), 1.38-1.54 (m, 2H), 0.90-0.98 (m, 6H); MS (ESI+m/z 431 [M+H]+.

Example 6

5-{[(1S)-1-(6-Chloropyridin-3-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)butyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-he

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) and the mixture was heated to 110°C for 4 days. After cooling to room temperature the mixture was poured into water (200 ml). Precipitated precipitated product was collected by filtration, washed with water and used in the next stage without further clear and (7.0 g, 97%yield).

MS (ESI+) m/z 376 [M+H]+.

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

A round bottom flask was supplied with the refrigerator dry ice-ethanol and immersed in a cooling bath of dry ice-ethanol. In the flask are condensed ammonia (250 ml)and then was 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 allowed to warm up to -33°C and in small pieces was added sodium metal until, until you appear blue staining, which was maintained for 30 seconds. Then the reaction was suppressed by adding 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.). Precipitated precipitated product was collected by filtration, washed with water and dried in vacuum to obtain 4.15 g (80%yield) specified in the connection header.

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

C) (2R)-2-{2-Chloro-5-[2-chloro-7-((1R)-1-hydroxymethylamino)-thiazolo[4,5-d]pyrimidine-5-idealfor]-thiazolo[4,5-d]pyrimidine-7-ylamino}-pentane-1-ol

(2R)-2-[(2-Amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)amino]-pentane-1-ol (4.0 g, 14 mmol) was dissolved in acetonitrile (100 ml) and concentrated hydrochloric acid (150 ml). Sodium nitrite (1,93 g, 28 mm is l) was dissolved in water (10 ml) was added at 0°C. The reaction mixture was left at 0°C for 2 days prior to the completion of the reaction according to the LCMS. The reaction mixture was poured on ice and precipitated precipitated product was collected by filtration. The solid was dried in vacuum to obtain 3.3 g (78%yield) specified in the connection header.

1H NMR (DMSO-d6) δ 8.27 (d, 1H), 4.32-3.81 (m, 2H), 3.50-3.23 (m, 2H), 1.37-1.19 (m, 2H), 1.10-0.93 (m, 1H), 0.94-0.78 (m, 1H), 0.49 (t, 3H); MS (ESI) m/z 607 [M+1]+.

g) (2R)-2-{5-[7-((1R)-1-Hydroxyethylamino)-2-methoxy-thiazolo[4,5-d]pyrimidine-5-idealfor]-2-methoxy-thiazolo[4,5-d]pyrimidine-7-ylamino}-pentane-1-ol

Potassium hydroxide (495 mg, 8,8 mmol) was added to (2R)-2-{2-chloro-5-[2-chloro-7-((1R)-1-hydroxymethylamino)-thiazolo[4,5-d]pyrimidine-5-idealfor]-thiazolo[4,5-d]pyrimidine-7-ylamino}-pentane-1-Olu (2,68 g, to 4.41 mmol) in methanol (200 ml) at 0°C. the Reaction mixture was stirred at 0°C during the night and then the methanol is evaporated. The residue was poured into water and the resulting precipitate was collected by filtration. Crude wet product was used in the next stage without additional purification.

MS (ESI) m/z 599 [M+1]+.

e) 5-[7-{[(1R)-1-(Hydroxymethyl)]amino}-[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one-5-idealfor]-7-{[(1R)-1-(hydroxymethyluracil]amino}[1,3]-thiazolo[4,5-d]pyrimidine-2(3H)-he

Crude (2R)-2-{5-[7-((1R)-1-hydroxyethylamino)-2-methoxy-thiazolo[4,5-d]pyrimi the in-5-idealfor]-2-methoxy-thiazolo[4,5-d]pyrimidine-7-ylamino}-pentane-1-ol (to 4.41 mmol) from the previous stage was dissolved in 1,4-dioxane (100 ml). Added conc. hydrochloric acid (2 ml) and water (2 ml) and the resulting mixture was stirred at 45°C during the night. The solvent is evaporated in vacuum and the product precipitated with addition of water. The precipitate was collected by filtration and washed with water. The crude product was purified flash column-chromatography (eluent a gradient of DCM:ethyl acetate) to obtain 1.5 g (59%yield over two stages) specified in the connection header.

1H NMR (DMSO-d6) δ 12.46 (s, 1H), 7.33 (d, 1H), 4.61 (t, 1H), 4.10 (br s, 1H), 3.35 (t, 2H), 1.37-1.20 (m, 2H), 1.13-1.10 (m, 1H), 0.96-0.82 (m, 1H), 0.59 (t, 3H); MS (ESI) m/z 571 [M+1]+.

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

Specified in the title compound was obtained in accordance with the General method E1, using 1-(6-chloropyridin-3-yl)alanon (0,80 g, 5,14 mmol), to obtain 0.71 g (88%yield) 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]+.

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

Specified in the title compound was obtained in accordance with the General method F1 using (1S)-1-(6-chloropyridin-3-yl)ethanol (0.20 g, of 1.27 mmol), to obtain 0.16 g (72%yield) 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) 5-{[(1S)-1-(6-Chloropyridin-3-yl)what Teal]thio}-7-{[(1R)-1-(hydroxymethyl)butyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-he

Specified in the title compound was obtained according to General method G, using 5-[7-{[(1R)-1-(hydroxymethyl)]amino}-[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one-5-idealfor]-7-{[(1R)-1-(hydroxymethyluracil]-amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-he (0.10 g, 0,175 mmol), 2-chloro-5-[(1R)-1-chloroethyl]pyridine (0,069 g 0,39 mmol) and sodium borohydride (0,040 g, 1.05 mmol), obtaining by 0.055 g (37%yield) specified in the connection header.

1H NMR (CDCl3) δ ppm 8.52-8.38 (m, 1H), 7.87-7.72 (m, 1H), 7.30-7.26 (m, 1H), 4.91-4.81 (m, 1H), 4.74-4.65 (m, 1H), 4.29-4.17 (m, 1H), 3.68-3.52 (m, 2H), 1.69-1.64 (m, 3H), 1.56-1.46 (m, 2H), 1.46-1.32 (m, 2H), 0.98-0.90 (m, 3H);

MS (ESI) m/z 426 and 428 [M+1]+.

Example 7

5-{[(1S)-1-(6-Chloropyridin-3-yl)ethyl]thio}-7-[[(1R)-1-(hydroxymethyl)butyl](methyl)amino][1,3]thiazolo[4,5-d]-pyrimidine-2(3H)-he

a) N-(Etoxycarbonyl)-D-Norvaline

D-Norvaline (10.0 g, 85,3 mmol) was dissolved in aqueous sodium hydroxide (4 M, 25 ml). For 15 minutes at 0°C was added ethylchloride a (10.6 ml, 111 mmol) and aqueous sodium hydroxide (4 M, 25 ml). 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 (2 M). The product was extracted with diethyl ether three times. The combined organic phases were dried over su is hatom magnesium and concentrated in vacuum to obtain specified in the connection header with a quantitative yield.

1H NMR (CDl3) 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), 0.95 (t, 3H); MS (Cl) 144 (100%), 190 [M+1]+.

b) (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 was 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 the formation of the suspension. The resulting mixture was filtered through celite. The solid is washed with DCM until then, until the whole was extracted with the product. The combined filtrates were 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) for collecting the fraction between 75-85°C was received and 7.1 g (71%yield) 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); 0.93 (t, 3H); MS (Cl) 86 (100%), 118 [M+1]+.

C) (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[4,5d]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 on revali up to 120°C for 3 days. Added additional amount of (2R)-2-(methylamino)pentane-1-ol (350 mg, 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 on ice. Precipitated precipitated product was collected by filtration and was purified flash column-chromatography (eluent a gradient of DCM:ethyl acetate) to obtain specified in the connection header (5,74 g, 76%yield).

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), 0.84 (t, 3H); MS (ESI) m/z 390 [M+1]+.

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

A round bottom flask was supplied with the refrigerator dry ice-ethanol and immersed in a cooling bath of dry ice-ethanol. In the flask are condensed ammonia (200 ml)and then was 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 in small pieces was added sodium metal until, until you appear blue staining, which was maintained for 30 seconds. Then the reaction was suppressed by adding 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 issue is Chille precipitated product was collected by filtration, washed with water and acetonitrile and dried in vacuum to obtain to 3.38 g (81%yield) 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), 0.87 (t, 3H); MS (ESI) m/z 300 [M+1]+.

d) (2R,2'R)-2,2'-{Dithiobis[(2-chloro[1,3]thiazolo[4,5-d]pyrimidine-5,7-diyl)(methylimino)]}dipenta-1-ol

(2R)-2-[(2-Amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidine-7-yl)(methyl)-amino]pentane-1-ol (1.0 g, to 3.34 mmol) was dissolved in acetonitrile (25 ml) and concentrated hydrochloric acid (40 ml). Sodium nitrite (461 mg, to 6.67 mmol) was dissolved in water (2 ml) was added at 0°C. the Reaction mixture was stirred at 0°C for three days. The reaction mixture was poured on ice and precipitated precipitated product was collected by filtration and washed with water. Drying under vacuum gave specified in the title compound (800 mg, 75%yield).

MS (ESI) m/z 635 and 637 [M+1]+.

(e) (2R,2'R)-2,2'-{Dithiobis[(2-methoxy[1,3]thiazolo[4,5-d]pyrimidine-5,7-diyl)(methylimino)]}dipenta-1-ol

Potassium hydroxide (210 mg, 3.75 mmol)dissolved in methanol (20 ml)was added to (2R,2'R)-2,2'-{dithiobis[(2-chloro[1,3]thiazolo[4,5-d]pyrimidine-5,7-diyl)(methylimino)]}dipenta-1-Olu (795 mg, 1.25 mmol) in methanol (40 ml) at 0°C. the Reaction mixture was stirred at 0°C over night and then the methanol is evaporated. The residue was poured on ice and received what I precipitate was collected by filtration. The filtrate was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo, and the residue was combined with the previously collected solid with obtaining specified in the title compound, which was used in the next stage without any further purification.

MS (ESI) m/z 627 [M+1]+.

g) 5-[7-{[(1R)-1-(Hydroxymethyl)](methyl)amino}-[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one-5-idealfor]-7-{[(1R)-1-(hydroxymethyluracil]-amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-he

Crude (2R,2'R)-2,2'-{dithiobis[(2-methoxy[1,3]thiazolo[4,5-d]pyrimidine-5,7-diyl)(methylimino)]}dipenta-1-ol (1.25 mmol) from the previous stage was dissolved in 1,4-dioxane (25 ml). Added conc. hydrochloric acid (0.5 ml) and water (0.5 ml) and the resulting mixture was stirred at 45°C during the night. The dioxane is evaporated in vacuo and the residue poured into ice deposition product, which was collected by filtration. Drying under vacuum gave 590 mg (78%yield over two stages) specified in the connection header.

MS (ESI) m/z 599 [M+1]+.

g) 5-{[(1S)-1-(6-Chloropyridin-3-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)butyl](methyl)amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-he

Specified in the title compound was obtained in accordance with the General method G, using 5-[7-{[(1R)-1-(hydroxymethyl)](methyl)amino}-[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one-5-yl who sulfanyl]-7-{[(1R)-1-(hydroxy-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-he (0.10 g, 0,167 mmol), 2-chloro-5-[(1R)-1-chloroethyl]pyridine (Example 6(e), 0,065 g and 0.37 mmol) and sodium borohydride (0,038 g, 1.00 mmol), getting to 0.060 g (41%yield) specified in the connection header.

1H NMR (CDCl3) δ ppm 8.56-8.38 (m, 1H), 7.87-7.73 (m, 1H), 7.28-7.26 (m, 1H), 4.86 (q, 1H), 4.75-4.62 (m, 1H), 3.76-3.55 (m, 3H), 3.03 (s, 3H), 1.70-1.63 (m, 3H), 1.53-1.45 (m, 2H), 1.26-1.21 (m, 2H), 0.95-0.88 (m, 3H);

MS (ESI) m/z 440 and 442 [M+1]+.

Example 8

Example 8A

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

Example 8b

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

and

Diastereomer a mixture of 5-{[1-(3-herperidin-4-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she (179 mg) from Example 3 were separated by preparative HPLC to obtain 25 mg of the first eluruumideta isomer:

1H NMR (DMSO-d6) δ ppm 12.31 (br s, 1H), 8.51 (m, 1H), 8.38 (d, 1H); 7.62 (m, 1H); 6.97 (br s, 1H); 5.16 (q, 1H); 4.66 (t, 1H); 4.12 (m, 1H); 3.44-3.30 (m, 2H, obscured by water signal), 1.66 (d, 3H), 1.61-1.27 (m, 3H), 0.84 (d, 3H), 0.74 (d, 3H);

MS (ESI) m/z 424 [M+1]+;

and 45 mg eluruumideta last isomer:

1H NMR (DMSO-d6) δ ppm 12.35 (br s, 1H), 8.52 (d, 1H), 8.38 (d, 1H); 7.62 (dd, 1H); 7.12 (br s, 1H); 5.15 (q, 1H); 4.62 (t, 1H); 4.21 (m, 1H); 3.35-3.15 (m, 2H, partially obscured by water signal), 1.65 (d, 3H), 1.63-1.29 (m, 3H), 0.88 (d, 3H), 0.85 (d, 3H); MS (ESI) mz 424 [M+1] +.

Pharmacological screening

Materials

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

Cells

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

Cells expresarse human CXCR2 received from AstraZeneca Charnwood, cultivated in EMEM containing glutamax and supplemented with 10% FBS (fetal calf serum, PAA, Austria), 1% nonessential amino acids (NEAA), 100 units/ml penicillin and 100 µg/ml streptomycin (PEST) and 500 μg/ml of geneticin/G418.

Obtaining membranes

Cells are grown at 37°C and 5% CO2and gather at the confluence of 60-80% in buffer containing 10 mm Tris-HCl, pH of 7.4, 5 mm EDTA, 0.1 mg/ml bacitracin. Cells are centrifuged at 300×g for 10 minutes and 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 48000×g for 10 minutes 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 receptor binding

Studies of competitive binding [125I]-fractalkine performed in tablets with 96 deep wells in 2 ml (Beckman, Germany) in a total volume of 1000 µl/well. Each well contained 10 PM [125I]-fractalkine and membrane in an amount equivalent to the concentration of receptor 1 PM, in the buffer for analysis (50 mm Hepes-KOH, pH of 7.4, 1 mm MgCl 2, 1 mm EDTA, 0,1% (wt./about.) gelatin). Ten concentrations (2 points/log 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 initiated by addition of membranes and incubated at 25°C for 24 h the Reaction was stopped by rapid filtration through filters with glass fiber Whatman GF/B, pre-treated with 0.3%by polyethylimine and then washed with chilled on ice buffer (10 mm Hepes-KOH, pH of 7.4, 500 mm NaCl)using a harvester for binding to receptors Brandel. Added scintillation mixture and the radioactivity was determined in a liquid scintillation counter Packard 2500TR (Perkin Elmer, USA).

Studies of competitive binding [125I]-hIL-8 perform one 96-well white isoplanatic with a transparent bottom for a final volume of 200 μl, and each well contains 150 PM [125I]-hlL-8 (specific activity 2200 CI/mmol), drug membrane-SPA (SPA - analysis of scintillation proximity), equivalent to 20 gr receptors, and 1.5 mg of SPA beads in buffer for analysis [50 mm HEPES-KOH pH of 7.4, 10 mm MgCl2, 1 mm EDTA, and 0.5% (wt./about.) gelatin]. The tested compounds were processed as previously. The nonspecific binding determined in the presence of 500 nm unlabeled hIL-8. As a reference compound in each case used agonist hIL-8 (curve concentration on the response from 3 PM to 30 nm). Peptide curve does not contain DMSO. The binding reaction initiated by the addition of 140 μl of the preparation of the membrane-SPA and the samples incubated in the dark at KG over 4 hours the Tablets for analysis cheated in a liquid scintillation counter (Wallac MicroBeta®TriLux 1450 from PerkinElmer, USA).

[35S]GTPγS binding

Research [35S]GTPγS binding was performed in microtiter tablets with a glass bottom in two replications with 10 concentrations of inhibitor (2 conc./log units), dissolved in DMSO (final concentration 1%) and at room temperature. Membranes expressing hCX3CR1 receptor (final concentration 20 μg protein/well)was added together with SPA-beads (final concentration 1 mg/well). All suspended in the buffer for the binding of GTPγS (50 mm Tris-HCl, 100 mm NaCl, 0.1% gelatin, 15 μg saponin/ml) and 3 μl of GDP (guanosine-5'-diphosphate), a pH of 7.4 when K.T.). Membrane, SPA beads and medicines were subjected to pre-incubation for 30 minutes before adding 310 gr of fractalkine for maximum stimulation. Baseline activity was defined as activity is detected without stimulation fractalkine (buffer for the binding of GTPγS). After another 30 minutes the reaction was initiated by addition of [35S]GTPγS to a final concentration of 0.1 nm and finite volume analysis of 0.2 ml of the Experiment was finished after 30 minutes centrifugation PR is 2000 rpm/min for 2×5 minutes (in different directions) and radioactivity was determined in a liquid scintillation counter (Wallac MicroBeta® TriLux 1450).

Results

Typical values CX3CR1 Kifor compounds of the present invention are in the range of from about 0.1 to about 1000 nm. Other values for CX3CR1 Kirange from approximately 0.1 nm to approximately 500 nm. Other values for CX3CR1 Kiare in the range of from about 0.1 nm to about 25 nm. The results of in vitro assays hCX3CR1 binding for a number of compounds shown in Table 1.

Table 1
# ExampleKi(nm)
15,8
220
3Not tested*
418
5Not tested **
621,4
7440
8A97
8b1,5
*) diastereomeric compounds of examples 8A and 8b.
**not available in sufficient quantities for testing in the in vitro assays hCX3CR1 binding.

Compounds of the present invention, where R1represents Me (containing branched dialkylamino group in position 5), are more effective antagonists CX3CR1 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 H or CH3;
R4represents H or CH3;
n represents 0, 1 or 2;
in the form of free base or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where n represents 1.

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

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

5. The compound according to claim 1, where n represents 1; and R2represents F, Cl or CN.

6. The compound according to claim 1, where the pyridine is attached at its the th position 5 and contains Cl in position 2.

7. The compound according to claim 1, where the pyridine is attached by its position 2 and CN contains in position 4.

8. The compound according to claim 1, where the pyridine is attached by its position 2 and contains F in position 5.

9. The compound according to claim 1, where the pyridine is attached by its position 2 and contains Cl in position 5.

10. The compound according to claim 1, where the pyridine is attached by its position 2 and contains F in position 3.

11. The compound according to claim 1, where the pyridine is attached by its position 4 and contains F in position 3.

12. The compound according to claim 1, where R3represents H.

13. The compound according to claim 1, where R4represents CH3.

14. A compound selected from:
5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she;
5-{[(1S)-1-(5-herperidin-2-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she;
5-{[1-(3-herperidin-4-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she;
5-{[(1S)-1-(3-herperidin-4-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she;
5-{[(1R)-1-(3-herperidin-4-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she;
5-{[(1S)-1-(3-herperidin-2-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she;
2-{(1S)-1-[(7-{[(1R)-1-(hydroxym the Teal)-3-methylbutyl]amino}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-d]pyrimidine-5-yl)thio]ethyl}isonicotinamide;
5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}-7-{[(1R)-1-(hydroxymethyl)butyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-it
5-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]thio}-7-[[(1R)-1-(hydroxymethyl)butyl](methyl)amino][1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she;
in the form of free base or pharmaceutically acceptable salt.

15. The compound according to any one of claims 1 to 14 or its pharmaceutically acceptable salt for use as a drug for treatment or prevention of diseases or conditions in which a positive antagonism against CX3CR1 receptor.

16. Pharmaceutical composition having antagonistic activity against CX3CR1 receptor containing a therapeutically effective amount of a compound according to any one of claims 1 to 14 or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable diluent or carrier.

17. The use of the compounds of formula (I)as defined in any one of claims 1 to 14, 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, peripheral artery disease, rheumatoid arthritis, or asthma.

18. The use of the compounds of formula (I)as defined in any one of claims 1 to 14, or its pharmaceutically receiving the emnd salt in the manufacture of a medicine for treatment or prevention of multiple sclerosis.

19. The use of the compounds of formula (I)as defined in any one of claims 1 to 14, 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 rupture of plaques and atherothrombotic events.

20. The use of the compounds of formula (I)as defined in any one of claims 1 to 14, 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.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) where the bond b represents a double bond; X represents -S-; each Z1 and Z3 independently represents a direct bond, -N(R5) - or - (CH2)q; Z2 represent -C(O)- or -C(S)-; m represents an integer equal to 1; n represents an integer equal to 1; each of q independently represents an integer varying within 1 to 4; R0 represents hydrogen, halogen, hydroxy, unsubstituted C1-C3alkyl or unsubstituted C1-C3alkoxy; R1 is independently selected from a group consisting of halogen, optionally substituted C1-C3alkyl, -R6OR7, -R6N(R7)2, -R6C(O)R7, -R6C(O)OR7, -R6C(O)N(R7)R9N(R7)2, -R6OC(O)R8, -R6C(O)N(R7)2 or -R6OR9N(R7)2; R2 represents hydrogen; R4 is selected from a group consisting of morpholine, isoxazolyl, thiazolyl, oxazolyl, benzisoxazolyl, benzothiazolyl, dioxynyl, dioxolyl, and optionally substituted phenyl. Also, the invention refers to pharmaceutically acceptable salts of the compounds of formula (I) and to a pharmaceutical composition exhibiting antiproliferative activity and containing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) exhibiting antiproliferative activity.

21 cl, 11 dwg, 5 tbl, 19 ex

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

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

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 inventions refers to a new crystalline form of tetomilast hydrate of the X-ray powder diffraction spectrum having characteristic peaks at the angle 20=10.6°, 12.9°, 21.1°, 22.3° and 25.0°, to a new crystalline form of anhydrous tetomilast type C of the X-ray powder diffraction spectrum having characteristic peaks at the angle 2θ=4.2°, 8.2°, 12.0°, 16.4°, 24.7° and 25.9°, to a new crystalline form of acetonitrile tetomilast solvate of the X-ray powder diffraction spectrum having characteristic peaks at the angle 2θ=3.6°, 7.1°, 10.6°, 14.2° and 24.8°, to based pharmaceutical compositions and to methods for preparing.

EFFECT: new crystalline forms shows useful processing characteristics with relation to preparing pharmaceutical drugs of them.

13 cl, 14 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine, in particular to device for transdermal bisoprolol introduction, which includes base and layer of sensitive to pressure adhesive, which contains bisoprolol, which is layered on one base surface, where maximal value of bisoprolol release in time period immediately from application on skin within 24 hours constitutes 30 mcg/cm2/hour or less; and where velocity of bisoprolol release 24 hours after application on skin constitutes 10 mcg/cm2/hour or less.

EFFECT: device for transdermal introduction reduces skin irritation, especially in case of layering, and can constantly introduce into living organism therapeutically or preventively efficient amount of bioprolol.

5 cl, 3 tbl, 3 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is a coformulated drug for treating various ischemic pathologies containing succinic acid and 2-ethyl-3-(N,N-dimethylcarbamoyloxy)-6-methylpyridine salts with succinic or hydrochloric acid of general formula I where HX is salt-forming succinic or hydrochloric acid, m + 0.1-3.0; showing antihypoxic, antiamnestic and anticonvulsant activity characterised by the fact the relation in I between 2-ethyl-3-(N,N-dimethylcarbamoyloxy)-6-methylpyridine salts and the second component providing a 'synergistic' (potentiating) pharmacological effect by succinic acid makes 1:>0.3. It is shown that succinic acid potentiates declared action of the compound of formula I. It is a reason to create the coformulated drugs exceeding common preparations of 3-oxypyridine groups in pharmacological activity: emoxypin and mexidol, used for treating ischemic pathologies, particularly in diseases accompanied by cerebral ischemia.

EFFECT: preparation of new pharmaceutical compositions for treating ischemic pathologies.

5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diazepane of formula , where A, X, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, n and m have values, given in description and formula of invention, as well as their physiologically acceptable salts. Said compounds are antagonists of chemokine receptors CCR-2, CCR-5 and/or CCR-3 receptor and can be used in medicine as medications.

EFFECT: obtaining novel diazepane derivatives.

20 cl, 505 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically cardiology and concerns treating ischemic heart disease (IHD). For this purpose, the standard integrated drug treatment involving statin is added with administration of the biologically active additive MARISTIM 4.5 mg/day.

EFFECT: method provides higher clinical effectiveness of statins in the given group of patients due to elimination of their inhibitory effect on enzymes of a mitochondrial respiratory chain.

2 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method of treating hypertension, congestive cardiac failure, stenocardia, myocardial infarction, atherosclerosis, stroke. A method of treating involves introduction to a patient requiring such treatment of the solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in which the active ingredient makes more than 46 wt % of total weight of the oral dosage form. The oral dosage form is presented in the form of a tablet or a film-coated tablet and produced by methods other than wet granulation with excipients by means of water and/or a water solution of a binding agent.

EFFECT: realisation of the specified purpose.

12 cl, 2 ex

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

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, pharmaceutics.

SUBSTANCE: what is described a new compound representing (2R)-5'-[5-(morpholin-4-ylmethyl)-3-furyl]-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridine and a pharmaceutical composition binding with alpha-7 nicotinic receptors and containing them which can find application in medicine.

EFFECT: preparing the new pharmaceutical composition.

2 cl, 16 ex

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