Chemical compounds i

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl) piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsufonyl)phenyl]acetamide or its pharmaceutically acceptable salts. The invention also relates to a method for synthesis of the compound in paragraph 1, as well as to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with activity towards CCR5 (chemokine receptor 5).

6 cl, 6 ex, 2 tbl

 

The invention relates to heterocyclic derivatives having pharmaceutical activity, to methods for obtaining such derivatives, to pharmaceutical compositions containing such derivatives and to the use of such derivatives as active therapeutic agents.

Pharmaceutically active derivatives of piperidine derivatives are disclosed in WO 03/042205. It is necessary that pharmaceutical drugs were bioavailable, and compounds of the present invention exhibit better bioavailability and more selective (for example reduced muscarinic activity) compared with the compounds of WO 03/042205.

Chemokines are chemotactic cytokines that are released a variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils at sites of inflammation and also play a role in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules belong to a growing superfamily of proteins by mass of 8-14 kDa characterized by conservative motif of four cysteines. The chemokine supersymmetry is astwo can be divided into two main groups, with characteristic structural motifs: a family of Cys-X-Cys (C-X-C or α) and Cys-Cys (C-C or β). They are distinguished by the insertion of one amino acid between nearest to NH by a pair of cysteine residues and the similarity of sequences.

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

Chemokines C-C include powerful chemoattractant monocytes and lymphocytes, but not neutrophils, such as chemotactic proteins monocytes 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (regulated upon activation, expressed and secretory normal T-cells), eotaxin and inflammatory proteins macrophages 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of chemokines is mediated by subfamilies associated with G-protein receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors are good targets for drug development, as agents for modulation of these receptors will be useful in the treatment of disorders and diseases, such as disorders or diseases mentioned above.

The CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types. They detect and react n the several chemokines, mainly on "regulated upon activation, expressed and secretory normal T-cells" (RANTES), inflammatory proteins macrophages (MIP) MIP-1α and MIP-1β and protein-chemoattractant of monocytes 2 (MCP-2).

The result is the recruitment of immune cells to sites of disease. In many diseases these cells are cells expressing CCR5, which directly or indirectly contribute to the tissue damage. Therefore, inhibition of the recruitment of these cells is useful for a wide range of diseases.

CCR5 is also a coreceptor for HIV-1 (human immunodeficiency virus 1) and other viruses, allowing these viruses to enter cells. Blocking receptor CCR5 antagonist or inducing internalization of the receptor CCR5 agonist protects cells from viral infection.

According to the present invention proposed a compound of formula (I):

where

R1represents S(O)2R6, S(O)2NR10R11C(O)R7or C(O)other7;

R2represents 3,5-differenl, 3-triptoreline or 3-fluoro-5-chlorophenyl;

R3represents hydrogen or C1-4alkyl;

R4represents hydrogen, methyl, ethyl, allyl or cyclopropyl;

R5represents phenyl(C1-2)and the keel or phenyl(C 1-2alkyl)NH, where the phenyl ring may substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, a group S(O)k(C1-4alkyl), S(O)2NR8R9group NHS(O)2(C1-4alkyl), NH2group NH(C1-4alkyl), group N(C1-4alkyl)2, NHC(O)NH2C(O)NH2group C(O)NH(C1-4alkyl), a group S(O)N(C1-4alkyl)2group NHC(O)(C1-4alkyl), CO2N, a group of CO2(C1-4alkyl), - C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3;

k is 0, 1 or 2;

R6represents a C1-6alkyl [substituted C1-4alkoxy, phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3group (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, a group S(O)(C1-4alkyl) or a group S(O)2(C1-4alkyl)} or heteroaryl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3group (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, a group S(O)(C1-4alkyl) or a group S(O)2(C1-4alkyl)}], C3-7cycloalkyl, tetrahydropyranyl, phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF 3group (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, a group S(O)(C1-4alkyl) or a group S(O)2(C1-4alkyl)} or heteroaryl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3group (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, a group S(O)(C1-4alkyl) or a group S(O)2(C1-4alkyl)};

R7represents hydrogen, C1-6alkyl [substituted by halogen (e.g., fluorescent)1-4alkoxy, phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3group (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, a group S(O)(C1-4alkyl) or a group S(O)2(C1-4alkyl)} or heteroaryl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3group (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, a group S(O)(C1-4alkyl) or a group S(O)2(C1-4alkyl)}], C3-7cycloalkyl, tetrahydropyranyl, phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3group (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, a group S(O)(C1-4alkyl) or a group S(O)2(C1-4alkyl)} or heteroa the l {could be replaced by halogen, With1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3group (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, a group S(O)(C1-4alkyl) or a group S(O)2(C1-4alkyl)};

R8and R9independently represent hydrogen or C1-4alkyl, or together with the nitrogen atom or oxygen may be associated with the formation of 5 - or 6-membered ring which may be substituted With1-4the alkyl, C(O)H or a group S(O)(C1-4alkyl);

R10and R11independently represent hydrogen or C1-4alkyl, or may be associated with the formation of 5 - or 6-membered ring which may be substituted With1-4the alkyl or phenyl (where the phenyl ring may substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, a group S(O)mC1-4alkyl, S(O)2NH2, a group S(O)2NH(C1-4alkyl), a group S(O)2N(C1-4alkyl)2group NHS(O)2(C1-4alkyl), NH2group NH(C1-4alkyl), group N(C1-4alkyl)2, NHC(O)NH2C(O)NH2group C(O)NH(C1-4alkyl), a group NHC(O)(C1-4alkyl), CO2H, a group of CO2(C1-4alkyl), - C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3);

or its pharmaceutically acceptable salt.

Some connection to us is oedema invention may exist in different isomeric forms (such as enantiomers, diastereoisomers, geometric isomers or tautomers). The present invention includes all such isomers and mixtures thereof in all ratios.

Suitable salts include salts of joining acids, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, succinate, tartrate, citrate, oxalate, methanesulfonate or para-toluensulfonate.

Compounds according to the invention can exist in the form of a solvate (e.g. hydrate), and the present invention covers all such solvate.

Alkyl groups and groups are remotemachine or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl. Methyl sometimes shortened to Me.

Foralkyl includes, for example, from one to six, for example from one to three fluorine atoms and includes, for example, a group of CF3. Foralkyl represents, for example, CHF2CH2F, CF3or CH2CF3.

Cycloalkyl represents, for example, cyclopropyl, cyclopentyl or cyclohexyl.

Phenyl(C1-2alkyl)alkyl represents, for example, benzyl, 1-(phenyl)ETH-1-yl or 1-(phenyl)ETH-2-yl.

Phenyl(C1-2alkyl)NH represents, for example, benzylamino.

Heteroaryl represents an aromatic 5 - or 6-membered ring, possibly condensed with one or more che is one other ring, containing at least one heteroatom selected from the group comprising nitrogen, oxygen and sulfur; or an N-oxide or S-oxide or S-dioxide. Heteroaryl represents, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolin, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [1,2,4]-triazolyl, pyridinyl, pyrimidinyl, indolyl, benzo[b]furyl (also known as benzofuran), benzo[b]thienyl (also known as benzothiazyl or benzothiophene), indazole, benzimidazole, benzotriazole, benzoxazole, benzothiazole, 1,2,3-benzothiadiazoles, imidazopyridines (such as imidazo[1,2A]pyridinyl, thieno[3,2-b]pyridine-6-yl, 1,2,3-benzoxadiazole (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazole, benzofurazan (also known as 2,1,3-benzoxadiazole), honokalani, pyrazolopyrimidine (e.g., 1H-pyrazolo[3,4-b]pyridinyl), chinoline, ethenolysis, naphthyridines (for example [1,6]naphthyridine or [1,8]naphthyridine), benzothiazolyl or dibenzothiophene (also known as dibenzothiazyl); or N-oxide or S-oxide or S-dioxide. Heteroaryl can also be pyrazinyl. Heteroaryl represents, for example, pyridinyl, pyrimidinyl, indolyl or benzimidazolyl.

When R8and R9together with the nitrogen atom or oxygen associated with the formation of 5 - or 6-membered what about the ring, this ring represents, for example, piperazinilnom or morpholinyl ring.

When R10and R11associated with the formation of 5 - or 6-membered ring, then it formed a ring represents, for example, piperidine ring.

In one specific aspect of the present invention proposed a connection according to the invention, where R6represents a C1-6alkyl (for example, C1-4alkyl, such as methyl) or (C3-7cycloalkyl (such as cyclohexyl).

In another aspect of the present invention proposed a connection according to the invention, where R1represents S(O)2R6where R6such as defined above (e.g., R6represents a C1-4alkyl). For example, R1represents S(O)2CH3.

In another aspect of the present invention proposed a connection according to the invention, where R2represents 3,5-differenl.

In another aspect of the present invention proposed a connection according to the invention, where R3represents hydrogen.

In another aspect of the present invention proposed a connection according to the invention, where R4represents ethyl or cyclopropyl. In another aspect of the present invention proposed a compound of formula (I), where R4represents ethyl.

the another aspect of the present invention proposed a connection according to the invention, where R5represents phenyl(C1-2)alkyl (e.g. benzyl) or phenyl(C1-2alkyl)NH (e.g., benzylamino), where the phenyl ring is substituted (for example, in the para-position) by a group S(O)2(C1-4alkyl) (for example, a group S(O)2CH3).

In another aspect of the present invention proposed a connection according to the invention, where R5represents benzyl, where the phenyl ring is substituted in the para-position by a group S(O)2(C1-4alkyl) (for example, a group S(O)2CH3).

In another aspect of the present invention proposed pharmaceutically acceptable salt of the compounds according to the invention, for example the hydrochloride salt, hydrobromide, phosphate, acetate, fumarate, maleate, succinate, tartrate, citrate, oxalate, methanesulfonate or para-toluensulfonate compounds according to the invention (for example, salt is a fumarate or succinate).

The carbon atom marked with ^ the following formula (I)

always is chiral and has, for example, the absolute R-configuration. Thus, in another aspect of the present invention proposed a connection according to the invention, having an absolute R-configuration at the carbon atom ^identified above. In another aspect of the present invention proposed pharmaceutically acceptable salt of the compound invented by the Yu, with absolute R-configuration at the carbon atom ^identified above.

In another aspect of the present invention proposed a compound of formula (Ia)

where R1, R2and R4such as defined above, and X represents CH2or NHCH2. In another aspect of the present invention proposed pharmaceutically acceptable salt of the compounds of formula (Ia)where R1, R2and R4such as defined above, and X represents CH2or NHCH2.

In another aspect of the present invention proposed a compound of formula (I)having the absolute R-configuration at the carbon atom ^, identified above, where:

R1represents S(O)2R6[where R6such as defined above (e.g., R6represents a C1-4alkyl, such as methyl)];

R2represents 3,5-differenl;

R3represents hydrogen;

R4represents ethyl or cyclopropyl [for example, R4represents ethyl];

R5represents phenyl(C1-2)alkyl or phenyl(C1-2alkyl)NH, where the phenyl ring is substituted (for example, in the para-position) by a group S(O)2(C1-4alkyl) (for example, a group S(O)2CH3) [for example, R5represents benzyl, where Fe is strong ring substituted in the para-position by a group S(O) 2(C1-4alkyl) (for example, a group S(O)2CH3)];

or pharmaceutically acceptable salt of the compounds of formula (I) [for example, salt is hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, succinate, tartrate, citrate, oxalate, methanesulfonate or para-toluensulfonate (for example, salt is a fumarate or succinate)].

In another aspect of the present invention proposed a compound of formula (Ia)having the absolute R-configuration identified above, the carbon atom ^where:

R1represents S(O)2R6[where R6is as defined above (e.g., R6represents a C1-4alkyl, such as methyl)];

R2represents 3,5-differenl;

R4represents ethyl or cyclopropyl [for example, R4represents ethyl];

X represents CH2or NHCH2[for example, X represents CH2];

or pharmaceutically acceptable salt of the compounds of formula (Ia) [for example, salt is hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, succinate, tartrate, citrate, oxalate, methanesulfonate or para-toluensulfonate (such as salt fumarate or succinate)].

In another aspect of the present invention proposed a connection:

N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidine-4-yl)-N-ethyl-2-[4-(meth sulfonyl)phenyl]ndimethylacetamide;

the succinate salt of N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidine-4-yl)-N-ethyl-2-[4-(methylsulphonyl)phenyl]ndimethylacetamide;

the fumarate salt of N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidine-4-yl)-N-ethyl-2-[4-(methylsulphonyl)phenyl]ndimethylacetamide; or

N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidine-4-yl)-N-ethyl-2-[3-(methylsulphonyl)phenyl]ndimethylacetamide.

The compounds listed in Table I, illustrate the invention.

TABLE I
Table I includes compounds of formula (Ia)
Connection # StereochemistryR1R2R4x
1Rmethanesulfonyl3,5-differenlEthylCH2
2Rmethanesulfonyl3,5-di is terfenol EthylNHCH2
3Rmethanesulfonyl3-CF3-phenylEthylCH2
4Rmethanesulfonyl3,5-differenlcyclopropylCH2
5Rmethanesulfonyl3-fluoro-5-chlorophenylEthylCH2
6Rmethanesulfonyl3-forfinalEthylCH2

In another aspect of the invention proposed each individual link that is listed in Table I.

Compounds according to the invention can be obtained with the use or modification of techniques, methods, diagrams, or examples of WO 03/042205.

Thus, the connection according to the invention can be obtained by reacting compounds of the forms of the crystals of (II):

where R2, R3, R4and R5such as defined above,

depending on the compounds according to the invention, which is preferably obtained in the reaction with:

a) an acid of formula R1CO2H in the presence of a suitable agent combinations (for example, PyBrOP [bromo-Tris-pyrrolidinone hexaphosphate] or HATU [O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate]) in the presence of a suitable base (such as three(C1-6alkyl)amine, for example, diisopropylethylamine) in a suitable solvent (for example, N-methylpyrrolidinone or chlorinated solvent such as dichloromethane) at room temperature (for example 10-30°C); or

b) an acid chloride of formula R1C(O)Cl or sulphonylchloride formula R1S(O)2Cl in the presence of a suitable base (such as three(C1-6alkyl)amine, such as triethylamine or diisopropylethylamine) in a suitable solvent (for example, chlorinated solvent such as dichloromethane) at room temperature (for example 10-30°C).

The alternate connection according to the invention can be obtained by combining the compounds of formula (III):

where R1, R2, R3and R4such as defined above, with:

a) an acid of formula R5CO2H in the presence of suitably is about agent combinations (for example, PyBrOP or HATU) in the presence of a suitable base (such as three(C1-6alkyl)amine, for example, diisopropylethylamine) in a suitable solvent (for example, N-methylpyrrolidinone or chlorinated solvent such as dichloromethane) at room temperature (for example 10-30°C); or

b) an acid chloride of formula R5C(O)Cl in the presence of a suitable base (such as three(C1-6alkyl)amine, such as triethylamine or diisopropylethylamine), in a suitable solvent (for example, chlorinated solvent such as dichloromethane) at room temperature (for example 10-30°C).

The connection according to the invention can be obtained by reductive amination of compounds of formula (IV):

the compound of the formula (V):

in the presence of NaBH(OAc)3(where AC represents C(O)CH3) and acetic acid in a suitable solvent (such as C1-6aliphatic alcohol, e.g. ethanol) at room temperature (for example 10-30°C).

The compound of formula (V) can be obtained by removal of the protective group (PG) from compounds of formula (VI). For example, when PG is benzyloxycarbonyl or benzyl, removal may be effected by hydrogenation (e.g., with hydrogen in the presence of palladium catalyst on carbon); when PG a tert-butyloxycarbonyl, removal can be effected by treatment with acid (such as hydrochloric acid or triperoxonane acid)

The connection according to the invention can also be obtained by alkylation of compounds of formula (V) compound of formula (VII):

where R1, R2and R3such as defined above, and IG represents a leaving group such as halide, mesilate, toilet or triflate), in the presence of a suitable base (such as potassium carbonate or a tertiary amine (for example, the base Hunga or triethylamine)in a suitable solvent (such as acetonitrile or tetrahydrofuran (THF)at room temperature (for example 10-30°C.). The compounds of formula (VII) can be obtained by methods described in the patent or scientific literature, or by routine adaptation of these methods.

In the described methods suitable protective group and details of how to add and remove such groups can be found in "Protective Groups in Organic Synthesis", 3rd Edition (1999) by Greene and Wuts.

The source materials for these methods are commercially available or can be obtained by known literature methods, adapting known from the literature methods or in accordance with the description of WO 03/042205.

In another aspect of the invention the methods of obtaining compounds f is rmula (I) or (Ia). Many intermediate compounds in these methods are new and proposed as additional aspects of the invention.

The connection according to the invention, or its pharmaceutically acceptable salt, can be used in the treatment of the following diseases:

1) respiratory tract: obstructive diseases of the respiratory tract, including asthma, including bronchial, allergic, endogenous, exogenous, caused by the physical stress caused by drugs (including aspirin and non-steroidal anti-inflammatory drugs (NSAID)and is caused by dust asthma, as alternating and constant and of all degrees of severity, and other causes of hyperactively respiratory tract; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; lung "farmer" and related diseases; hypersensitive pneumonitis; fibrosis of the lung, including endogenous fibrous alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-tumor therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitis and thrombotic disorders of the vascular network of the lung and pulmonary hypertension; antitussive activity is here, including treatment of chronic cough associated with inflammatory and secretory conditions of the Airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis drug and vasomotor rhinitis; year-round and seasonal allergic rhinitis, including nervous rhinitis (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS (SARS)and adenovirus;

2) bones and joints: skin rashes, rheumatic or gouty origin, associated with osteoarthritis/osteoarthrosis or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, back pain, and neck pain; rheumatoid arthritis and of still's disease; seronegative of spondyloarthropathies, including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondyloarthropathy; septic arthritis and other infectious arthropathies and bone disorders such as tuberculosis, including Pott disease and syndrome Ponce; acute and chronic synovitis caused by crystals, including urate gout, a disease associated with deposits of calcium pyrophosphate is, and inflammation of the tendons, bags and synovial inflammation associated with deposits of calcium Apatite; Behcet's disease; primary and secondary Sjogren syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed disease of connective tissue, and undifferentiated disease of connective tissues; inflammatory myopathies including dermatomyositis and polymyositis; polymyalgia rheumatica; juvenile arthritis including idiopathic skin rash rheumatic or gouty origin any zone of innervation of the joint and associated syndromes, and rheumatic fever and its systemic complications; vasculitides, including giant cell arteritis diagnostics, Takayasu's arteritis, granulomatous allergic anghit, Nowotny polyarteritis, microscopic polyarteritis and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulinemia and paraproteins; lumbar pain; familial Mediterranean fever syndrome Make Wales and Irish family fever, Kikuchi disease; caused by drugs arthralgia, tendonitis and myopathy;

3) pain and remodeling of connective tissue in the musculoskeletal disorders due to injury [for example sports injury] or disease: skin rash rheumatic or gouty what about the origin (e.g., rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as degeneration of the intervertebral disc or degeneration of the temporomandibular joint (TMJ), bone remodeling (e.g., osteoporosis, Paget's disease or osteonecrosis), polyhedric, scleroderma mixed disorder of connective tissue, spondyloarthropathies or periodontal disease (such as periodontitis);

4) skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and hypersensitivity reactions delayed type; phyto - and photodermatitis; subarray dermatitis, dermatitis herpetiformis, lichen planus, sclerotic and atrophic lichen, pyoderma pyoderma, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, congenital bullous bullosa, urticaria, angioedema, vasculitides, toxic erythema, dermal eosinophilia, alopecia areata, male alopecia, sweet syndrome, syndrome, Weber-Christian, erythema multiforme; infectious and non-infectious cellulitis; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; caused by drug disorders, including local drug rash;

5) eyes: blepharitis; conjunctivitis, including chronic and vernal allergic conjunctivitis; Iran is; early and late uveitis; chorioidea; autoimmune disease; degenerative or inflammatory disorders affecting the retina; ophthalmic, including sympathetic ophthalmic; sarcoidosis; infections including viral, fungal and bacterial infections;

6) gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, anal itching; disease of the abdomen, irritable bowel syndrome and food allergies which may have effects far from the gut (for example migraine, rhinitis or eczema);

7) abdominal: hepatitis, including autoimmune, alcoholic and viral hepatitis; fibrosis and cirrhosis of the liver; cholecystitis; acute and chronic pancreatitis;

8) genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and ulcer of Hanner; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both men and women);

9) graft rejection: acute and chronic post-transplantation, such as kidney, heart, liver, lung, bone marrow, skin or cornea or following the overflow of the Oia blood; or chronic disease graft-versus-host;

10) Central nervous system: Alzheimer's disease and other causes of dementia disorders, including disease Creutzfeldt Jakob (CJD) and new variant disease Creutzfeldt Jakob disease (nvCJD); amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis diagnostics; asthenic bulbar paralysis; acute and chronic pain (acute, intermittent or persistent, Central or peripheral origin)including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, pain in joints and bones, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post herpetic, and HIV-associated neuropathy; neurosarcoidosis; complications of malignant, infectious or autoimmune processes in the Central and peripheral nervous system;

11) other autoimmune and allergic disorders, including Hashimoto's thyroiditis, toxic goiter, Addison disease, diabetes mellitus, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, Hyper-IgE syndrome, antiphospholipid syndrome;

12) other disorders with an inflammatory or immunological component, including the syndrome acquired is of immunodeficita (AIDS), leprosy, syndrome Cesari and paraneoplastic syndromes;

13) cardiovascular system: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoidosis; ischaemic reperfusion injuries; endocarditis, valvular and aortic, including infective (for example syphilitic) aortic; vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14) Oncology: treatment of common cancers, including tumors of the prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain and zlokacestvennosti affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as jackinsky and non-Hodgkin lymphoma, including prevention and treatment of metastasis and tumor recurrence, and paraneoplastic syndromes; or

15) gastrointestinal tract: a disease of the abdomen, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, interspersed colitis, disorder irritable bowel syndrome irritable Ki is Ki, non-inflammatory diarrhea, food allergies, which affect far from the intestine, for example migraine, rhinitis and eczema;

warm-blooded animal such as man.

Compounds according to the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) activity of chemokine receptors (e.g. CCR5), and can be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or diseases mediated by the immune system (including rejection of transplanted organs or tissues and acquired immunodeficiency syndrome (AIDS)).

Compounds of the present invention are also useful in the inhibition of penetration of viruses (such as human immunodeficiency virus (HIV)in target cells and, thus, useful for the prevention of infection by viruses (such as HIV), treatment of viral infections (such as HIV), and prevention and/or treatment of acquired immunodeficiency syndrome (AIDS).

According to the invention proposed compound of formula (I) or (Ia) or its pharmaceutically acceptable salt for use in the method of treating a warm-blooded animal (such as man) by therapy (including prophylaxis).

According to the present invention p is idlogin method of modulating the activity of a chemokine receptor (e.g., the activity of the receptor CCR5) in a warm-blooded animal, such as man, in need of such treatment, comprising the introduction of a specified animal an effective amount of the compounds of the present invention or its pharmaceutically acceptable salt.

According to the present invention has also proposed the use of the compounds of formula (I) or (Ia) or its pharmaceutically acceptable salt as medicines, such as medicines for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (e.g. rheumatoid arthritis). [Respiratory disease represents, for example, COPD, asthma {such as bronchial, allergic, endogenous, exogenous or dust asthma, particularly chronic or inveterate asthma (for example late asthma or Hyper-reactive Airways)} or rhinitis {acute, allergic, atrophic rhinitis or chronic rhinitis including caseous chronic rhinitis, chronic hypertrophic rhinitis, purulent rhinitis, dry rhinitis or rhinitis medication; membranous rhinitis including croupous, fibrinous or pseudobinary rhinitis or scrupulously rhinitis; seasonal rhinitis including nervous rhinitis (hay fever) or vasomotor rhinitis}; and in particular asthma or rhinitis].

In another aspect of this is part II of the invention it is proposed to use the compounds of formula (I) or (Ia) or its pharmaceutically acceptable salts in the manufacture of a medicinal product for use in therapy (for example, modulating the activity of chemokine receptors (e.g., the activity of the receptor CCR5 (e.g., rheumatoid arthritis)) in a warm-blooded animal, such as man).

According to the invention also suggested that the compound of formula (I) or (Ia) or its pharmaceutically acceptable salt for use as medicines, such as medicines for the treatment of rheumatoid arthritis.

In another aspect of the present invention proposed the use of the compounds of formula (I) or (Ia) or its pharmaceutically acceptable salts in the manufacture of a medicinal product for use in therapy (for example modulating the activity of chemokine receptors (e.g., the activity of the receptor CCR5 (for example rheumatoid arthritis)) in a warm-blooded animal, such as man).

According to the invention also suggested the use of the compounds of formula (I) or (Ia) or its pharmaceutically acceptable salts in the manufacture of a medicinal product for use in the treatment of the following diseases:

1) respiratory tract: obstructive diseases of the respiratory tract, including asthma, including bronchial, allergic, endogenous, exogenous, caused by the physical stress caused by drugs (including aspirin and nonsteroidal anti-inflammatory drugs (NSAID)and is caused by dust asthma as AC is gaysauna, and constant and of all degrees of severity, and other causes of hyperactively respiratory tract; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; lung "farmer" and related diseases; hypersensitive pneumonitis; lung fibrosis, including endogenous fibrous alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-tumor therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitis and thrombotic disorders of the vascular network of the lung and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the Airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis drug and vasomotor rhinitis; year-round and seasonal allergic rhinitis, including nervous rhinitis (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS (SARS)and adenovirus;

2) bones and joints skin rashes revelations the CSO or gouty origin, associated with osteoarthritis/osteoarthrosis or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, back pain and neck pain; rheumatoid arthritis and of still's disease; seronegative of spondyloarthropathies, including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondyloarthropathy; septic arthritis and other infectious arthropathies and bone disorders such as tuberculosis, including Pott disease and syndrome Ponce; acute and chronic synovitis caused by crystals, including urate gout, a disease associated with sediments pyrophosphate calcium, and inflammation of the tendons, bags and synovial inflammation associated with deposits of calcium Apatite; Behcet's disease; primary and secondary Sjogren syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed disease of connective tissue, and undifferentiated disease of connective tissues; inflammatory myopathies including dermatomyositis and polymyositis; polymyalgia rheumatica; juvenile arthritis including idiopathic skin rash rheumatic or gouty origin any zone of innervation of the joint and associated syndromes, and rheumatic fever and e is about systemic complications; vasculitides, including giant cell arteritis diagnostics, Takayasu's arteritis, granulomatous allergic anghit, Nowotny polyarteritis, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulinemia and paraproteins; lumbar pain; familial Mediterranean fever syndrome Make Wales and Irish family fever, Kikuchi disease; caused by drugs arthralgia, tendonitis and myopathy;

3) pain and remodeling of connective tissue in the musculoskeletal disorders due to injury [for example sports injury] or disease: skin rash rheumatic or gouty origin (for example, rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as degeneration of the intervertebral disc or degeneration of the temporomandibular joint (TMJ), bone remodeling (e.g., osteoporosis, Paget's disease or osteonecrosis), polyhedric, scleroderma mixed disorder of connective tissue, spondyloarthropathies or periodontal disease (such as periodontitis);

4) skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and hypersensitivity reactions delayed type; phyto - and photodermatitis; semoran the th dermatitis, herpetiformis dermatitis, lichen planus, sclerotic and atrophic lichen, pyoderma pyoderma, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, congenital bullous bullosa, urticaria, angioedema, vasculitides, toxic erythema, dermal eosinophilia, alopecia areata, male alopecia, sweet syndrome, syndrome, Weber-Christian, erythema multiforme; infectious and non-infectious cellulitis; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; caused by drug disorders, including local drug rash;

5) eyes: blepharitis; conjunctivitis, including chronic and vernal allergic conjunctivitis; iritis; early and late uveitis; chorioidea; autoimmune disease; degenerative or inflammatory disorders affecting the retina; ophthalmic, including sympathetic ophthalmic; sarcoidosis; infections including viral, fungal and bacterial infections;

6) gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, anal itching; disease of the abdomen, irritable bowel syndrome and food allergies which may have effects far from the intestine (e.g. the, migraine, rhinitis or eczema);

7) abdominal: hepatitis, including autoimmune, alcoholic and viral hepatitis; fibrosis and cirrhosis of the liver; cholecystitis; acute and chronic pancreatitis;

8) genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and ulcer of Hanner; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both men and women);

9) graft rejection: acute and chronic post-transplantation, such as kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic disease graft-versus-host;

10) Central nervous system: Alzheimer's disease and other causes of dementia disorders, including disease Creutzfeldt Jakob (CJD) and new variant disease Creutzfeldt Jakob disease (nvCJD); amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis diagnostics; asthenic bulbar paralysis; acute and chronic pain (acute, intermittent or persistent, Central or peripheral origin)including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, pain in the composition and bones, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post herpetic, and HIV-associated neuropathy; neurosarcoidosis; complications of malignant, infectious or autoimmune processes in the Central and peripheral nervous system;

11) other autoimmune and allergic disorders, including Hashimoto's thyroiditis, toxic goiter, Addison disease, diabetes mellitus, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, Hyper-IgE syndrome, antiphospholipid syndrome;

12) other disorders with an inflammatory or immunological component, including acquired immunodeficiency syndrome (AIDS), leprosy, syndrome Cesari and paraneoplastic syndromes;

13) cardiovascular system: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoidosis; ischaemic reperfusion injuries; endocarditis, valvular and aortic, including infective (for example syphilitic) aortic; vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14) Oncology: treatment of common the Idov cancer, including tumors of the prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain and zlokacestvennosti affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as jackinsky and non-Hodgkin lymphoma, including prevention and treatment of metastasis and tumor recurrence, and paraneoplastic syndromes; or

15) gastrointestinal tract: a disease of the abdomen, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, interspersed colitis, disorder irritable bowel, irritable bowel syndrome, non-inflammatory diarrhea, food allergies, which affect far from the intestine, for example migraine, rhinitis and eczema; warm-blooded animal such as man.

In another aspect of the invention also suggested the use of the compounds of formula (I) or (Ia) or its pharmaceutically acceptable salts in the manufacture of a medicinal product for use in the treatment of:

1) (the respiratory tract) obstructive respiratory diseases, including chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, endogenous, exogenous or paleaaesina, particularly chronic or inveterate asthma (for example late asthma or Hyper-reactive Airways)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis or rhinitis medication; membranous rhinitis including croupous, fibrinous or pseudobinary rhinitis or scrupulously rhinitis; seasonal rhinitis including nervous rhinitis (hay fever) or vasomotor rhinitis}; sarcoidosis; diseases of the lung "farmer" and related diseases; nasal polyposis; pneumosclerosis or idiopathic interstitial pneumonia;

2) (bone and joints) arthritis, including rheumatic, infectious, autoimmune, seronegative of spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or disease Reiter), disease behceta syndrome Sjogren's syndrome or systemic sclerosis;

3) (eye and skin) psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatitis, sebrango dermatitis, flat shingles, water, medical pemphigoid, congenital bullous of bullosa, urticaria, angioblasts, erythema of vasculitides, skin eosinophilia, uveitis, alopecia areata or vernal conjunctivitis;

4) (gastrointestinal to the muscle path) diseases of the abdominal cavity, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease or food allergies, which have far from the gut (for example migraine, rhinitis and eczema);

5) (graft rejection) acute and chronic, for example after transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; and chronic graft versus host; and/or

6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus (such as systemic lupus erythematosus or systemic lupus), eritematoso, thyroiditis Hashimoto, severe myasthenia gravis, diabetes type I, nephrotic syndrome, eosinophilic fasciitis, Hyper-IgE syndrome, leprosy (such as lepromatosis leprosy), periodontal disease, syndrome Cesari, idiopathic thrombocytopenic purpura or disorders of the menstrual cycle;

warm-blooded animal such as man.

According to the present invention a method of treatment of a pathological state mediated by chemokines (e.g., a painful condition mediated CCR5) in a warm-blooded animal, such as man, comprising the administration to a mammal, n is gaudemus for such treatment, effective amounts of compounds of formula (I) or (Ia) or its pharmaceutically acceptable salt.

For application of the compounds according to the invention or its pharmaceutically acceptable salts for therapeutic treatment of warm-blooded animal, such as man, in particular for modulating the activity of chemokine receptors (e.g., the CCR5 receptor), in accordance with standard pharmaceutical practice usually prepare a drug specified ingredient in the form of pharmaceutical compositions.

Thus, in another aspect of the present invention proposed a pharmaceutical composition comprising a compound of formula (I) or (Ia) or its pharmaceutically acceptable salt (active ingredient) and a pharmaceutically acceptable adjuvant, diluent or carrier. In another aspect of the present invention, a method for preparation of a specified composition, comprising mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the method of administration of the pharmaceutical composition should contain from 0.05 to 99 wt.% (mass percent), for example from 0.05 to 80 wt.%, for example from 0.10 to 70 wt.% (for example from 0.10 to 50 wt.%) the active ingredient, and all weight percents are calculated on the total weight of the composition.

The pharmaceutical compositions according to image meniu you can enter standard for painful conditions, which is treated by the method, for example by local (such as in the lung and/or Airways or to the skin), oral, rectal or parenteral administration. For these purposes can be prepared preparations of the compounds according to the invention by methods known in this field, in the form of, for example, aerosols, dry powder preparations, tablets, capsules, syrups, powders, granules, aqueous or oil solutions or suspensions (liquid), emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

A suitable pharmaceutical composition according to the invention is a composition suitable for oral administration in a standard dosage form, for example in the form of tablets or capsules, which contains from 0.1 mg to 1 g of the active ingredient.

In another aspect the pharmaceutical composition according to the invention is a composition suitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, intravenous, subcutaneous or intramuscular dose of from 0.01 to 100 mg/kg compound, for example in the range from 0.1 to 20 mg/kg, and the composition is administered 1 to 4 times per day. Intravenous, subcutaneous and intramuscular dose may be introduced by injection of a bolus. Alternate the VNO intravenous dose may be entered by continuous infusion over a certain period of time. Alternative every patient should receive the daily dose for oral administration, which is approximately equivalent to the daily parenteral dose, and the composition is administered 1 to 4 times per day.

The following are examples of pharmaceutical dosage forms containing the compound of formula (I) or (Ia) or its pharmaceutically acceptable salt (hereafter compound X), for therapeutic or prophylactic use in humans:

(a)

Tablet Img tablet
Compound X100
Lactose, the European Pharmacopoeia179
Sodium crosscarmelloseto 12.0
Polyvinylpyrrolidone6
Magnesium stearate3,0

(b)

Tablet IImg tablet
Compound X50
Lactose, the European Pharmacopoeia229
Sodium crosscarmelloseto 12.0
Polyvinylpyrrolidone6
Magnesium stearate3,0

(in)

Tablet IIImg tablet
Connection X1,0
Lactose, the European Pharmacopoeia92
Sodium crosscarmellose4,0
Polyvinylpyrrolidone2,0
Magnesium stearate1,0

(g)

Capsulemg/capsule
Connection X10
Lactose, the European Pharmacopoeia389
Sodium crosscarmellose100
Magnesium stearate1,0

(d)

Injection I(50 mg/ml)
Compound X5.0 masses./vol.%
Isotonic aqueous solutionUp to 100%

As auxiliary substances for the preparation of drugs can be used buffers, pharmaceutically acceptable co-solvents, such as glycol, polypropyleneglycol, glycerol or ethanol, or complexing agents, such as hydroxypropyl-β-cyclodextrin.

These drugs can be obtained by standard techniques, well known in the pharmaceutical field. The tablets (a)-(C) can be covered intersolubility shell by conventional methods, for example methods to ensure the coatings of phthalate cellulose acetate.

The invention also relates to a combination therapy, in which treatment of one or more than one or more of the listed conditions connection according to the invention or its pharmaceutically acceptable salt or pharmaceutical composition or drug containing the compound according to the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents.

In particular, for Leche is of inflammatory diseases, such as (but not limited to, rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel disease, the compounds according to the invention can be combined with the agents listed below.

Nonsteroidal anti-inflammatory agents (hereinafter NSAIDs)including non-selective cyclo-oxygenase inhibitors MOR-1/SOH-2, applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, Ketoprofen and ibuprofen, fenamate, such as mefenamovaya acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective inhibitors MOR-2 (such as meloxicam, celecoxib, rofecoksib, valdecoxib, lumiracoxib, parecoxib, etoricoxib); inhibiting cyclooxygenase donors of nitric oxide (CINOD); glucocorticosteroids (entered local, oral, intramuscular, intravenous or intra-articular path); methotrexate; Leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral drugs based on gold; analgesics; diacerein; intra-articular drugs, such as derivatives of hyaluronic acid; and nutritional supplements such as glucosamine.

The present invention t is the train refers to the combination of compounds according to the invention or its pharmaceutically acceptable salt together with a cytokine, or agonist or antagonist of cytokine function, (including agents that act on cytokine signalling pathways such as modulators system SOCS (suppressors of cytokine signaling), including alpha-, beta - and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL), including IL 1-17, and antagonists or inhibitors interleukins, such as anakinra; inhibitors of tumor necrosis factor alpha (TNF-a), such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and antagonists of TNF receptors, including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxifylline.

In addition, the invention relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt with a monoclonal antibody against b-lymphocytes (such as CD20 (rituximab), MRA-alL16R and T-lymphocytes, CTLA4-Ig, HuMax II-15).

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt with a modulator of the function of the chemokine receptor, such as an antagonist of 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 CX3CP1 for a family of C-X3-S.

The present invention also relates to combinations of compounds according to the invention or the th pharmaceutically acceptable salt inhibitor of matrix metalloprotease (DFID), i.e. stromelysins, collagenases and gelatinases and aggrecanases, such as collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3 (MMP-11 and MMP-9 and MMP-12, including such agents as doxycycline.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and inhibitor of leukotriene biosynthesis, an inhibitor of 5-lipoxygenase (5-LO) or antagonist of a protein that activates 5-lipoxygenase (FLAP), such as zileuton; ABT-761; Finlayson; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylbenzothiazole; methoxyethylamine, such as Zeneca ZD-2138; the compound SB-210661; pyridinylamino 2-cyanonaphthalene connection, such as L-739010; 2-cyanohydrine connection, such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886 and BAYx1005.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and a leukotriene receptor antagonist (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of phenothiazines-3-1, for example L-651392; amidinopropane, such as CGS-25019c; benzoxazepine, such as ontazolast; benzoperoxide, such as BIIL 284/260; and of compounds such as zafirlukast, ABLOY to provide the AST, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP A) and BAYx7195.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and inhibitor of phosphodiesterase (PDE), such as methylxanthines, including theophylline and aminophylline; selective inhibitor of PDE isoenzyme, including PDE4 inhibitor, an inhibitor of the isoform PDE4D, or a PDE5 inhibitor.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and antagonist of histamine receptor type 1, such as cetirizine, loratadine, desloratadine, Fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine or mizolastine applied orally, topically or parenterally.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and proton pump inhibitor (such as omeprazole) or gastroprotective antagonist histamine receptor type 2.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and antagonist of histamine receptor type 4.

The present invention also relates to combinations of compounds according to the invention or its headlight is asepticheski acceptable salts and agonist alpha-1/alpha-2 adrenergic receptors which vasoconstrictor sympathomimetic such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, nafazolina hydrochloride, Oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, Xylometazoline hydrochloride, tramazoline hydrochloride or Ethylmorphine hydrochloride.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and anticholinergic agents including muscarinic antagonist receptor (M1, M2 and M3), such as atropine, hyoscine, glycopyrrolate, ipratropium bromide, Tiotropium bromide, oxytrope bromide, pirenzepine or telenzepine.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and agonist beta adrenergic receptors (including subtypes 1-4 beta-receptors), such as izoprenalin, salbutamol, formoterol, salmeterol, terbutaline, ortsiprenalin, bitolterol mesilate or pirbuterol or chiral enantiomer.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and chromone, such as cromoglycate sodium or nedocromil sodium.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt is a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt with an agent that modulates nuclear receptor hormones, such as receptor-activated peroxisomal proliferation (PPAR).

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt with immunoglobulin (Ig)or Ig drug, or an antagonist or antibody modulating the function Ig, such as anti-IgE antibody (e.g. omalizumab).

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and other anti-inflammatory agent used systemically or topically, such as thalidomide or its derivative, a retinoid, dithranol or calcipotriol.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salts and combinations aminosalicylates and sulfapiridina, such as sulfasalazin, mesalazine, balsalazide, and olsalazine, and immunomodulatory agents, such as thiopurine and corticosteroids, such as budesonide.

The present invention also Rel is referring to the combination of the compounds according to the invention or its pharmaceutically acceptable salt with an antibacterial agent, such as a derivative of penicillin, tetracycline, macrolide, beta-lactam, a fluoroquinolone, metronidazole, inhalation of aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir and saxinger; nucleoside reverse transcriptase inhibitors, such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside inhibitor of reverse transcriptase inhibitors such as nevirapine or efavirenz.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and a cardiovascular agent such as a calcium channel blocker, blocker beta-adrenergic receptors, angiotensin-converting enzyme (ACE)receptor antagonist of angiotensin-2; agent for reducing the level of lipid, such as a statin or fibrate; modulator morphology of blood cells, such as pentoxifylline; thrombolytic agent or an anticoagulant, such as an inhibitor of platelet aggregation.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and an agent acting on the Central nervous system (CNS), such as and tidepressant (such as sertraline), antiparkinsonian drug (such as deprenyl, L-DOPA, ropinirole, pramipexol, inhibitor IAIA (monoamine oxidase), such as selgin, rasagiline, inhibitor comP (oligomeric matrix protein cartilage), such as tasmar, inhibitor-2, an inhibitor of the reuptake of dopamine antagonist of the NMDA (N-methyl-D-aspartic acid), the agonist nicotine, dopamine agonist or inhibitor of neuronal synthase nitric oxide, or drug against Alzheimer's disease, such as donepezil, rivastigmine, taken, inhibitor SOH-2, propentofylline or metrifonate.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and agent for the treatment of acute or chronic pain, such as an analgetic Central or peripheral actions (for example an opioid or its derivative), carbamazepine, phenytoin, sodium valproate, amitryptiline or other antidepressants, paracetamol or non-steroidal anti-inflammatory agent.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt together with applicable parenterale or local (including inhalation) local anesthetic agent such as lignocaine or its derivative.

The compound of the present invention or its farmaci is almost acceptable salt can also be applied in combination with the tool against osteoporosis, including hormonal agent such as raloxifene, or biphosphonate, such as alendronate.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt together with: (1) a tryptase inhibitor; (2) an antagonist of platelet activating factor (PAF); (3) the inhibitor of the interleukin converting enzyme (ICE); (4) the inhibitor insertunorderedlist (IMPDH); (5) inhibitors of adhesion molecules, including antagonist VLA-4; (6) a cathepsin; (7) a kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example gefitinib or imatinib mesilate), serine/ser / thr kinase (such as an inhibitor of MAP kinase, such as R, JNK, protein kinase a, b or C, or IKK), or a kinase involved in cell cycle regulation (such as cyclin-dependent kinase); (8) an inhibitor of glucose-6-phosphate dehydrogenase; (9) an antagonist of kinin-B.sub1.- or .sub2-receptor; (10) protivopodagricakih agent, for example colchicine; (11) an inhibitor of xanthine oxidase, for example allopurinol; (12) an agent that promotes the excretion of uric acid, for example probenecid, sulfinpirazonom or benzbromarone; (13) secretagogue growth hormone; (14) transforming growth factor (TGFβ); (15) platelet-derived growth factor (PDGF); (16) fibroblast growth factor for example basic fibroblast growth factor (bFF); (17) granulocyte-macrophage colony-stimulating factor (GM-CSF); (18) capsaicinoid cream; (19) antagonist thickening NK.sub1. or NK.sub3. receptor, such as NKP-608C, SB-233412 (talnetant) or D-4418; (20) elastase inhibitor such as UT-77 or ZD-0892; (21) an inhibitor of TNF-alpha converting enzyme (TACE); (22) an inhibitor of the inducible synthase nitric oxide (iNOS); (23) molecule homologue of the receptor of chemoattractants expressed on cells IN (such as a CRTH2 antagonist); (24) inhibitor R; (25) agent modulating the function of Toll-like receptors (TLR); (26) agent modulating the activity of purinergic receptors such as RH; or (27) inhibitor activation of transcription factors such as NFκB, API, or STATS.

The connection according to the invention or its pharmaceutically acceptable salt can also be used in combination with existing therapeutic agent for the treatment of cancer; suitable agents include for example:

(1) antiproliferative/antineoplastic drug, or combination thereof, which is used in medical Oncology, such as alkylating agent (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen analogue of mustard, melphalan, chlorambucil, busulfan or nitrosoanatabine); an antimetabolite (for example, antifolate, for example, ftorpirimidinu, such as 5-fluorouracil or tegafur, raltitrexed, m is Turksat, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); antitumor antibiotics (for example, anthracycline, such as adriamycin, bleomycin, doxorubicin, minomycin, epirubicin, idarubitsin, mitomycin-C, dactinomycin or mithramycin); antimitoticescoe agent (for example, Vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or taxoid, such as Taxol or Taxotere); or a topoisomerase inhibitor (e.g., epipodophyllotoxins, such as etoposide, teniposide, amsacrine, topotecan or camptothecin);

(2) cytotoxic agent, such as an antiestrogen (e.g., tamoxifen, toremifene, raloxifene, droloxifene or idoxifene), a negative regulator of estrogen receptor (for example fulvestrant), an antiandrogen (for example, bikalutamid, flutamide, nilutamide or ciproteron acetate), a LHRH antagonist (releasing factor, luteinizing hormone or LHRH agonist (for example goserelin, leiprorelina or buserelin), a progestogen (for example, megestrol acetate), aromatase inhibitor (for example, anastrozole, letrozole, varsol or exemestane) or an inhibitor of 5α-reductase such as finasteride;

(3) an agent which inhibits invasion by cancer cells (for example, the inhibitor of metalloproteinases, such as marimastat or inhibitor of receptor function urokinase plasminogen activator);

(4) inhibi the PR function growth factor, for example, an antibody against growth factor (for example the anti-erbb2 antibody trastuzumab or the anti-erbb1 antibody cetuximab [S]), inhibitor farnesyltransferase, a tyrosine kinase inhibitor or inhibitor of serine/trionychinae, inhibitor family of epidermal growth factors (e.g., an inhibitor of protein tyrosine kinase EGFR, such as N-(3-chloro-4-forfinal)-7-methoxy-6-(3-morpholinopropan)hinzelin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)hinzelin-4-amine (erlotinib, OSI-774) or 6-acrylamide-N-(3-chloro-4-forfinal)-7-(3-monolinoleate)hinzelin-4-amine (CI 1033)), an inhibitor of a family of platelet-derived growth factor or inhibitor of a family of growth factors hepatocyte;

(5) an antiangiogenic agent such as an agent that will inhibit the effects of vascular endothelial growth factor (for example, an antibody against vascular endothelial growth factor bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that acts by a different mechanism (e.g., linomide, representing an inhibitor of the function of integrin αvβ3 or angiostatin);

(6) an agent that destroys vascular cells, such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;

(7) an agent used in antisense therapy, for example, the agent is directed acting on one of the targets listed above, such as ISIS 2503, an anti-ras antisense agent;

(8) an agent used in gene therapy, for example to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (proletarienne therapy gene-directed enzyme), for example using citizendiumat, timedancing or bacterial nitroreductase, and to increase the tolerance of the patient to chemotherapy or radiotherapy such as gene therapy using gene multilocational resistance;

(9) an agent used in immunotherapy, for example ex vivo and in vivo increase the immunogenicity of tumor cells of a patient, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, to decrease T-cell anergy, using transfected immune cells such as cytokine-transfetsirovannyh dendritic cells using cytokine-transfected lines of tumor cells and using antiidiotypic antibodies; or

(10) the compound used in the treatment of AIDS and/or HIV infection, for example an agent that prevents or inhibits the capture of viral protein Dr the host-cell CD4 {for example, soluble CD4 (recombinant); anti-CD4 antibody (or a modified/recombinant antibody), such as PRO542; ntitle against a group of 120 (or modified/recombinant antibody); or another agent that prevents the binding group 120 with CD4, for example, BMS806}; an agent that prevents the binding of the chemokine receptors other than CCR5 used by the HIV virus {such as agonist or antagonist of CXCR4 or anti-SHSR antibody}; a compound that interferes with the fusion of the membrane of the HIV virus with the cell membrane {such as antibody against group 41; enfuvirtide (T-20 or T-1249}; inhibitor of DC-SIGN (specific for dendritic cells neinteen, exciting intracellular adhesion molecule-1, also known as CD209) {such as anti-DC-SIGN antibody or inhibitor binding to DC-SIGN}; nucleoside reverse transcriptase inhibitors, which represents a nucleoside/nucleotide analogue {for example, zidovudine (Z), nevirapine, didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir, adefovir, or tenofovir (for example, in free base form or in the form fumarata of disoproxil)}; non-nucleoside reverse transcriptase inhibitors {e.g., nevirapine, delavirdine or efavirenz}; protease inhibitor {for example, ritonavir, indinavir saxinger (for example, in free base form or in the form mesilate salt), nelfinavir (for example, in free base form or in the form mesilate salt), APV, lopinavir or atazanavir (for example, in free base form or in the form of a sulfate salt)}; inhibitor of ribonucleo tidey inhibitors {e.g., hydroxyurea}; or antiretroviral agent {e.g., emtricitabine}.

The invention is illustrated by the following non-limiting Examples in which, unless stated otherwise:

1) temperatures are given in degrees Celsius (°C.); operations were carried out at room temperature or at ambient temperature, i.e. at temperatures in the range of 18-25°C.;

2) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out on a rotary evaporator under reduced pressure (600-4000 PA; a 4.5-30 mmHg) with a bath temperature up to 60°C;

3) if not stated otherwise, chromatography is a flash chromatography on silica gel; thin layer chromatography (TLC) was performed on silikagelevye plates; if the mentioned column "Bond Elut", we mean a column containing 10 g or 20 g of silicon dioxide with a particle size of 40 microns, and the silicon dioxide is in a disposable syringe 60 ml on a substrate constituting the porous disk, from Varian, Harbor City, California, USA, under the name of "Honey Bond Elut SI". If you mention "column Isolate™ SCX", they mean the column containing benzosulfimide acid (nezadelannyh end), from International Sorbent Technology Ltd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan 30, UK. If you mention "PS-Tris-amine acceptor resin Argonaut™"refers to Tris(2-aminoet is)aminopenicillin resin from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, California, USA.

4) as a rule, the reaction was controlled by TLC and reaction times are given for illustration only;

5) outputs, if they are given are for illustration only and not necessarily it will be the outputs that can be obtained as a result of persistent development of the way; if you wanted more material, the procedures for obtaining repeated;

6) data1H NMR, if they are given in the form of Delta values for major diagnostic protons in ppm (m-1regarding tetramethylsilane (TMS) as internal standard, determined at 300 MHz using, unless otherwise stated, predeterminado DMSO (dimethyl sulfoxide) (CD3SOCD3) as solvent; the binding constants (J) are given in Hz;

7) chemical symbols have their usual meanings; used units and symbols SI;

8) the ratio of the solvents indicated in percent by volume;

9) mass spectra (MS) were recorded with an electron energy of 70 electron volts in the chemical mode of ionization at atmospheric pressure (head) using a direct exposure of the sample; where indicated ionization was carried elektrorazpredelenie (ER); if the values of m/z, then they are given, generally only ions which indicate the source mass, and, if not decree what about the other given the mass ion is the positive mass ion - (M+N)+;

10) characterization of LC-MS (liquid chromatography/mass spectrometry) was performed using a pair of pumps Gilson 306 with the sampler Gilson 233 XL and mass spectrometer Waters ZMD4000. LC was performed on a column of Water Symmetry Of 4.6×50 C18 with a particle size of 5 microns. Eluent represented: A, water with 0.05% of formic acid and B, acetonitrile with 0.05% of formic acid. The gradient of eluent was held from 95% a to 95%

B for 6 minutes. There where indicated ionization was carried elektrorazpredelenie (ER); if the values of m/z, then they are given, generally only ions which indicate the source mass, and, if not stated otherwise, the given mass ion is the positive mass ion - (M+N)+; and

11) used the following abbreviations:

DMF N,N-dimethylformamide;

TPL melting point;

TMEDA (N,N,N',N'-tetramethylethylenediamine;

THF tetrahydrofuran.

EXAMPLE 1

This example illustrates the obtaining N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidine-4-yl)-N-ethyl-2-[4-(methylsulphonyl)phenyl]ndimethylacetamide (Compound 1 in Table I)

Triacetoxyborohydride sodium (2.5 g) was added to a solution of (3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propanal (1.98 g) and N-e is Il-2-[4-(methylsulphonyl)phenyl]-N-piperidine-4-ylacetamide (1,94 g) in dichloromethane (100 ml), and this mixture was stirred for 2 hours, then washed with 2M NaOH (2×100 ml) and dried. Organic matter was applied to a 50 g cartridge SCX2 and suirable with methanol (6×50 ml) and 1M methanolic ammonia (7×50 ml). The combined methanol-ammonia washing liquid evaporated to dryness to obtain specified in the title compound as a white foam, yield 2,6, NMR (CDCl3): 1.2-2.1 (m, 19H), 2.3-2.7 (m, 3H), 2.75 (s, 3H), 2.8-2.9 (m, 2H), 3.0 (s, 3H), 3.3 (q, 2H), 3.7-3.9 (m, 4H), 6.65 (m, 3H), 7.4 (m, 2H), 7.9 (d, 2H).

EXAMPLE 2

This Example illustrates obtaining succinate salt of N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidine-4-yl)-N-ethyl-2-[4-(methylsulphonyl)phenyl]ndimethylacetamide.

A hot solution of succinic acid (59 mg) in ethanol (3 ml) was added to a hot solution of N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidine-4-yl)-N-ethyl-2-[4-(methylsulphonyl)phenyl]ndimethylacetamide (640 mg) in ethanol (16 ml) and the mixture was allowed to cool. After 24 hours the mixture was ground with a spatula and left to stand for another 24 hours. The solid was filtered and dried, TPL 175-175,5°C. This solid was recrystallized from ethanol (14 ml) to obtain specified in the connection header, TPL 177-177,5°C.

EXAMPLE 3

This example illustrates the obtaining of fumaric salt of N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidin-yl)-N-ethyl-2-[4-(methylsulphonyl)phenyl]ndimethylacetamide.

A hot solution of fumaric acid (55 mg) in methanol (3 ml) was added to a hot solution of N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidine-4-yl)-N-ethyl-2-[4-(methylsulphonyl)phenyl]ndimethylacetamide (300 mg) in methanol (4 ml) and the mixture was allowed to cool. The mixture was then cooled in an ice bath and left to stand in a refrigerator for 14 hours. The solid was filtered and dried at 60°C in vacuum for 2 hours, TPL 164-166,5°C.

EXAMPLE 4

This example illustrates the obtaining N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidine-4-yl)-N-ethyl-2-[3-(methylsulphonyl)phenyl]ndimethylacetamide.

3-(Methylsulphonyl)phenylacetic acid (96 mg) was dissolved in dichloromethane (5 ml) was added carbonyldiimidazole (73 mg). The reaction mixture was stirred at room temperature for 3 hours. Was added N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propyl}piperidine-4-yl)-N-ethylamine (200 mg) in dichloromethane (5 ml) and the reaction mixture was left to stand at room temperature for 72 hours. Added PS-isocyanate resin (1 mm/g) (0.5 g) and the reaction mixture was stirred at room temperature for 2 hours, then filtered and evaporated. The residue was purified column chromatography, elwira a mixture of ethyl acetate-20% methanol/acilac the tat with obtaining specified in the title compound as a foam (105 mg).

NMR CDCl3: 1.0-2.1 (m, 21 H), 2.3-2.6 (m, 3H), 2.65 (s, 3H), 2.9 (s, 3H), 3.3 (m, 2H), 3.65 (d, 1H), 3.7 (m, 2H), 3.75 (d, 1H), 6.6 (m, 3H), 7.5 (m, 2H), 7.75 (m, 2H).

Method And

Obtain (3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propanal

Stage 1. Obtain (2E)-3-[1-(methylsulphonyl)piperidine-4-yl]akriloilkhlorida

Oxalicacid (5,1 g) was added to a solution of (2E)-3-[1-(methylsulphonyl)piperidine-4-yl]acrylic acid (9.4 g) in dichloromethane containing 2-3 drops of DMF and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture is evaporated to dryness and directly obtained residue was used in the next stage.

Stage 2. Obtain (4R,5S)-1,5-Ib-3-{(2E)-3-[1-(methylsulphonyl)piperidine-4-yl]prop-2-enoyl}-4-phenylimidazoline-2-it

Bis(trimethylsilyl)amide lithium (8 ml 1M solution in THF) was added dropwise to a suspension of (4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidinone (1.52 g) in THF (20 ml) in an argon atmosphere at -10°C. the Reaction mixture was stirred at -10°C for 10 minutes, gave her the opportunity to warm up to 0°C and kept at this temperature for 10 minutes, then re-cooled to -10°C. was added dropwise a solution obtained in stage 1 of the acid chloride (2 g dissolved in 10 ml dichloromethane), the reaction mixture gave the opportunity heated the Xia to room temperature and washed with water (100 ml). The aqueous extract was extracted with ethyl acetate (3×50 ml), an ethyl acetate extracts were dried and the residue was passed through a 90 g Biotage column, elwira gradient solvents (50% ethyl acetate/isohexane - 70% ethyl acetate/isohexane). Output 1,89, LC-MS MN+406, NMR (CDCl3): 0.8 (d, 3H), 1.5-1.6 (m, 3H), 1.9 (m, 2H), 2.3 (m, 1H), 2.7 (m, 2H), 2.75 (s, 3H), 2.8 (s, 3H), 3.75 (m, 2H), 3.9 (m, 1H), 5.3 (d, 1H), 6.85 (d-d, 1H), 7.1 (d, 1H), 7.2-7.35 (m, 3H), 7.45 (d,1H).

Stage 3. Receipt of (4S,5R)-1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propanoic}-3,4-dimethyl-5-phenylimidazole-2-it

Stage And

TMEDA (11.6 g) was added to a suspension of copper iodide (19,4 g) in THF (240 ml) in an argon atmosphere, and the mixture was stirred for 45 minutes, then cooled to -70°C. for 10 minutes was added a solution of 3,5-differentialalgebraic in THF (201,1 ml of 0.5m solution in THF)and the mixture was stirred at -70°C for 30 minutes.

Stage B

Triplet di-n-butylboron (100,7 ml of 1M solution in dichloromethane) was added to a suspension of (4R,5S)-1,5-dimethyl-3-{(2E)-3-[1-(methylsulphonyl)piperidine-4-yl]prop-2-enoyl}-4-phenylimidazoline-2-it (20,41 g) [stage 2] in THF, supported at -40°C, and stirring was continued for 10 minutes, the mixture was cooled to -70°C. and added via cannula to a suspension of cuprate, obtained in stage A. the Reaction mixture was stirred at -70°C for 1 hour and gave her the opportunity to warm up to anatoy temperature, then was added a saturated solution of ammonium chloride (200 ml). THF is evaporated and added ethyl acetate (200 ml). Through this mixture for 1 hour let in the air. An ethyl acetate layer was collected and the aqueous layer was extracted with ethyl acetate (2×100 ml). United an ethyl acetate extracts were washed with a saturated solution of ammonium chloride (2×100 ml), dried and evaporated to dryness. The residue was purified by chromatography on silica, elwira gradient solvent of ethyl acetate-isohexane (1:1) to pure ethyl acetate to obtain specified in the title compounds as white solids, exit 25, NMR (CDCl3) 0.78 (d, 3H), 1.2-1.6 (m, 6H), 1.9 (m, 1H), 2.4-2.65 (m, 2H), 2.75 (s, 3H), 2.85 (s, 3H), 3-3 .2 (m, 2H), 3.7-3.9 (m, 4H), 5.2 (d, 1H), 6.6 (m, 3H), 6.85 (m, 2H), 7.2 (m, 3H).

Stage 4. Obtain (3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propan-1-ol

Borohydride lithium (48 ml of a 2M solution in THF) was added to a solution of (4S,5R)-1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propanoic}-3,4-dimethyl-5-phenylimidazole-2-it (25 g) in THF (200 ml), the mixture was heated at 70°C for 3 hours, then gave her an opportunity to cool to room temperature, stirring was continued for 16 hours. Caution was added ethanol (20 ml) and the reaction mixture was acidified to pH 4 by addition of 2M HCl. THF is evaporated, the residue was dissolved in dichloromethane (100 ml), p is washed with water (100 ml) and dried. The solvent was removed and product was purified by chromatography on Biotage column 65, eluruumi a mixture of 1:1 ethyl acetate/isohexane. Exit 13, NMR (CDCl3): 1.2-1.8 (m, 5H), 1.95-2.2 (m, 2H), 2.5-2.7 (m, 3H), 2.75 (s, 3H), 3.3-3.6 (m, 2H), 3.7-3.9 (m, 2H), 6.65 (m, 3H).

Stage 5. Obtaining specified in the connection header

Periodinane dess-Martin (5,09 g) was added to a solution of (R) 3-(N-methanesulfonamido-4-yl)-3-(3,5-differenl)propanol (4.0 g) in dichloromethane (100 ml) and the mixture was stirred for 1.5 hours. The reaction mixture was washed with 2M NaOH (2×100 ml) and dried. The solution specified in the connection header in dichloromethane was used in the subsequent reactions.

Method B

N-ethyl-2-[4-(methylsulphonyl)phenyl]-N-piperidine-4-ylacetamide

Stage 1: obtain the dihydrochloride of 1-phenylmethyl-4-Ethylenediamine

To a solution of 1-phenylmethyl-4-piperidone (25,0 g, 132 mmol) in THF (250 ml) was added ethylamine hydrochloride (12.0 g, 147 mol) and methanol (50 ml), the mixture was stirred at room temperature for 10 minutes Portions was added triacetoxyborohydride sodium (40 g, 189 mmol), the mixture was stirred at room temperature for 1 h was Added 2M sodium hydroxide solution (250 ml), the mixture was extracted with diethyl ether. The organic extracts were dried (K2CO3) and was evaporated with the doctrine 1-phenylmethyl-4-Ethylenediamine in the form of oil. It was dissolved in ethanol (500 ml)was added concentrated hydrochloric acid (20 ml). The resulting crystals were collected, washed with diethyl ether and dried to yield (38 g); NMR: (CDCl3): 1.10 (t, 3H), 1.40 (m, 2H), 1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3.75 (m, 1H), 7.2-7.4 (m, 5H); MS: 219 (MH+).

Stage 2: Obtain N-(1-benzylpiperidine-4-yl)-N-ethyl-2-[4-(methylsulphonyl)phenyl]ndimethylacetamide

To a solution of dihydrochloride of 1-phenylmethyl-4-Ethylenediamine (32,0 g, 110 mmol) in DHM (500 ml) under stirring to ensure complete dissolution was added N,N-diisopropylethylamine (60 ml). Added 4-methanesulfonylaminoethyl acid (25,0 g, 117 mmol), 4-dimethylaminopyridine (2.0 g) and dicyclohexylcarbodiimide (25,0 g, 121 mmol), the mixture was stirred at room temperature for 20 hours the Precipitate was removed by filtration, the resulting solution was then washed 2 N. aqueous HCl, water, and 1 N. aqueous NaOH, dried (gSO4) and was evaporated. The residue was purified by chromatography on silica gel (eluent: 10% Meon/ethyl acetate) to obtain specified in the subtitle compound (35 g, 76%); NMR: 1.00 and 1.14 (t, 3H), 1.45 and 1.70 (m, 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.33 (q, 2H), 3.45 (s, 2H), 3.80 and 3.87 (s, 2H), 3.70-4.10 (m, IH), 7.2-7.3 (m, 5H), 7.48 (m, 2H), 7.82 (m, 2H); MS: 415 (MH+).

Stage 3: Obtaining specified in the connection header

To a solution of N-(1-benzylpiperidine-4-yl)-N-ethyl-2-[4-(METI sulfonyl)phenyl]ndimethylacetamide (34 g, 82 mmol) in ethanol (600 ml) was added ammonium formate (40 g). The mixture was purged with argon and added 30% Pd on carbon (4,2 g). The resulting mixture was stirred while boiling under reflux for 4 h, then gave her an opportunity to cool and was filtered through a hard-shelled land. The filtrate was evaporated to a thick oil which hardened on standing, giving specified in the header connection (24,9 g, 94%). NMR: 1.02 and 1.15 (t, 3H), 1.4-1.6 (br m, 4H), 2.45 (m, 2H), 2.93 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.32 (q, 2H), 3.72 and 4.18 (m, 1H), 3.80 and 3.87 (s, 2H), 7.50 (m, 2H), 7.85 (m, 2H); MS: 325 (MH+).

EXAMPLE 5

The ability of compounds to inhibit the binding of RANTES was evaluated by analysis of binding of radioligand in vitro. Membranes were obtained from ovary cells Chinese hamster expressing recombinant human CCR5 receptor. These membranes were incubated with 0.1 nm iodinated RANTES granules for scintillation proximal analysis and various concentrations of the compounds according to the invention in 96-well plates. The number of iodized RANTES, contacting the receptor was determined by counting the scintillations. Built competitive curves for connections and calculates the concentration of the compounds, which displaced 50% associated iodized RANTES (IC50). The compounds of formula (I)with IC50less than 50 μm, form another aspect of the invention.

EXAMPLE 6

The ability of compounds inhibit is to bind MIP-1α was assessed by analysis of binding of radioligand in vitro. Membranes were obtained from ovary cells Chinese hamster expressing recombinant human CCR5 receptor. These membranes were incubated with 0.1 nm iodinated MIP-1α granules for scintillation proximal analysis and various concentrations of the compounds according to the invention in 96-well plates. The amount of iodinated MIP-1α, contacting the receptor was determined by counting the scintillations. Built competitive curves for connections and calculates the concentration of the compound, displacing 50% associated iodized MIP-1α (IC50). The compounds of formula (I)with IC50less than 50 μm, form another aspect of the invention.

The results of this test for some of the compounds according to the invention are presented in Table II, where these results are presented as Pic50 values. The Pic50 value represents the negative logarithm (base 10) of the IC50so IC501 μm (1×10-6M) gives Pic50 equal to 6. If the connection is tested more than once, the following data represent the mean value of the results of confirmatory tests.

Table II
Connection # Table No.Pic50
1I9,5
2I9,3
3I8,45
4I8,8
5I9,4
6I9

1. The compound N-(1-{(3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl) piperidine-4-yl]propyl}piperidine-4-yl)-N-ethyl-2-[4-(methylsulphonyl) phenyl]ndimethylacetamide or its pharmaceutically acceptable salt.

2. The compound according to claim 1, which represents its salt, fumarate or succinate.

3. A method of obtaining a compound according to claim 1, including restorative amination of (3R)-3-(3,5-differenl)-3-[1-(methylsulphonyl)piperidine-4-yl]propanal N-ethyl-2-[4-(methylsulphonyl)phenyl]-N-piperidine-4-ylacetamide in the presence of NaBH(SLA)3(where AC represents C(O)CH3) and acetic acid in a suitable solvent at room temperature.

4. Pharmaceutical composition having activity against CCR5 (chemokine receptor 5), containing the compound according to claim 1 or its pharmaceutically acceptable salt and supplied with the ski acceptable adjuvant, the diluent or carrier.

5. The compound according to claim 1 or its pharmaceutically acceptable salt for use as a drug for the treatment of disease conditions mediated CCR5.

6. The compound according to claim 1 or its pharmaceutically acceptable salt in the manufacture of a medicine for the treatment of disease conditions mediated CCR5.



 

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FIELD: medicine.

SUBSTANCE: invention concerns derivatives of thiazolidine-4-one of general formula (I) and general formula (II), to their isomers and pharmaceutically acceptable salts which can be used as a medical product with immunosuppressive activity. In formulae (I) and (II), R1 and R14 independently represent lower alkyl, lower alkenyl; cycloalkyl; 5,6,7,8-tetrahydronaphth-1-yl; phenyl group or phenyl group independently mono- or disubstituted with lower alkyl, halogen, lower alkoxy or group -CF3; R2 and R15 independently represent lower alkyl; allyl; cyclopropyl; or di- lower alkylamino; R3 represents -NR5R6 or -O-CR7R8-CR9R10-(CR11R12)n-O-R13; R23 represents hydrogen; hydroxycarbonyl-lower alkyl or 1-glyceryl. Values of the other radicals are specified in the patent claim. The invention also concerns application of one or more compounds of general formula (I) or (II) for preparation of a medical product with immunosuppressive activity.

EFFECT: agent exhibits improved efficiency.

24 cl, 1 tbl, 157 ex

FIELD: medicine.

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EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invented compounds have antagonist properties towards CB1 receptors. In formula (I) , R1 is a lower alkoxy, (lower alkyl amino)-(lower alkoxy) or -N(Ra)Rb; Ra is hydrogen, lower alkyl, carbamoyl-(lower alkyl), hydroxy-(lower alkyl), dihydroxy-(lower alkyl), lower alkynyl, lower alkoxy, (lower alkoxy)-(lower alkyl), di-(lower alkylamino)-(lower alkyl), C3-6cycloalkyl; or Ra is a phenyl-(lower alkyl) group, where the phenyl fragment can be optionally mono-substituted, independently, by lower alkyl, lower alkoxy or halogen; or Ra is a 5- or 6-member heteroaromatic ring system, containing one or two nitrogen atoms in the ring, where the said heteroaromatic ring system is bonded to the remaining part of the molecule by lower alkylene; or Ra is a 5-, 6- or 7-member saturated heterocyclic ring system, containing one nitrogen heteroatom, where the said heterocyclic ring system is optionally mono-substituted by lower alkyl; Rb is hydrogen, lower alkyl or (lower alkoxy)-(lower alkyl); or Ra and Rb together with a nitrogen atom to which they are bonded, for a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring system, optionally containing an extra heteroatom, which is chosen from nitrogen, oxygen or sulphur, where the said heterocyclic ring system is optionally mono- or disubstituted, independently, by lower alkyl, hydroxy group, hydroxy-(lower alkyl), lower alkoxy, (lower alkoxy)-(lower alkyl) group, cyano group, halogen, phenyl and/or benzyl; R2 is hydrogen or lower alkyl; R3 is phenyl, mono- or disubstituted, independently, by lower alkoxy, halogen, or perfluoro-(low alkoxy) group; and R4 is phenyl, which is mono- or disubstituted with a halogen.

EFFECT: new compounds have useful biological properties.

18 cl, 195 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) or pharmaceutically acceptable salts thereof, where R1 is chosen from a group containing optionally substituted C1-C6alkyl, lower alkoxy group, (lower)alkoxy(lower)alkyl, cycloalkyoxy(lower)alkyl, lower thioalkyl, (lower)alkylthio(lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R2 is chosen from a group containing optionally substituted (lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R3 is chosen from a group containing halogen, cyano group, optionally substituted (lower alkyl, lower thioalkyl, aryl, aryl(lower)alkyl, lower alkenyl, lower alkynyl); R4 is chosen from a group containing hydrogen, halogen, cyano group, hydroxyl group, optionally substituted (lower alkyl, lower alkoxy group, aryl, pyridyl, aryl(lower)alkyl, heteroaryl, which is an aromatic mono- or bicyclic hydrocarbon, containing from 5 to 9 ring atoms, from which one or more is a heteroatom, chosen from O, N or S, and an amino group) and a group, with formula R8-Z-(CH2)n-; where Z is a single bond or chosen from a group consisting of O, NH, CH2, CO, SO, SO2 or S; where R8 is chosen from a group containing optionally substituted (aryl, pyridyl); and where n=0, 1 or 2; R5 represents hydrogen; R6 is chosen from a group containing halogen, optionally substituted lower alkoxy group; R7 is one or more substitutes, independently chosen from a group containing hydrogen, optionally substituted lower alkoxy group; where the optional substitute or substitutes when R1-R8 are independently chosen from a group containing halogen, hydroxyl group, lower alkyl, mono- or di(lower)alkylamino group, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di(lower)alkylaminocarbonyl, amino group, carboxyl group, lower alkoxy group, C3-C12cycloalkyl, (lower)alkylcarbonyl, (lower)alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted with one or more substitutes, chosen from a group containing halogen, hydroxyl group, lower alkyl, sulfinyl, sulfonyl, sulfanyl, amino group, carboxyl group, lower alkoxy group, carbamoyl. Invention also relates to formula (I'), to a pharmaceutical composition, as well as use of formula (I) compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds, for preventing or treating bone diseases, associated with very low or resorption of calcium.

6 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds with formula I where R1, R2, R3 and Y together with a formula I residue, are compounds, chosen from a group given in the formula of invention, or to their pharmaceutically used and split esters, or to their acid-additive salts, which promote release of parathyroid hormone.

EFFECT: compounds can be used for making medicinal agents, with antagonistic properties towards calcium sensitive parathyroid gland receptor for treating diseases mediated by effect of parathyroid hormone.

7 cl, 179 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I): (I) where: R1 represents either direct or branched (C1-C7)alkyl, or (C2-C4)alkenyl; R2 represents piridinyl, thienyl, thiazol; R3 represents one or more substitutes chosen from halogen atoms and following groups; trifluoromethyl, direct or branched (C1-C6)alkyl; as free base or additive salt with acid. Additionally, the invention concerns medical product, pharmaceutical composition, and application.

EFFECT: production of new biologically active compounds active to specific inhibitors of glycine glyt 1 and/or glyt 2 carriers.

6 cl, 2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) or pharmaceutically acceptable salts thereof, where R1 is chosen from a group containing optionally substituted C1-C6alkyl, lower alkoxy group, (lower)alkoxy(lower)alkyl, cycloalkyoxy(lower)alkyl, lower thioalkyl, (lower)alkylthio(lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R2 is chosen from a group containing optionally substituted (lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R3 is chosen from a group containing halogen, cyano group, optionally substituted (lower alkyl, lower thioalkyl, aryl, aryl(lower)alkyl, lower alkenyl, lower alkynyl); R4 is chosen from a group containing hydrogen, halogen, cyano group, hydroxyl group, optionally substituted (lower alkyl, lower alkoxy group, aryl, pyridyl, aryl(lower)alkyl, heteroaryl, which is an aromatic mono- or bicyclic hydrocarbon, containing from 5 to 9 ring atoms, from which one or more is a heteroatom, chosen from O, N or S, and an amino group) and a group, with formula R8-Z-(CH2)n-; where Z is a single bond or chosen from a group consisting of O, NH, CH2, CO, SO, SO2 or S; where R8 is chosen from a group containing optionally substituted (aryl, pyridyl); and where n=0, 1 or 2; R5 represents hydrogen; R6 is chosen from a group containing halogen, optionally substituted lower alkoxy group; R7 is one or more substitutes, independently chosen from a group containing hydrogen, optionally substituted lower alkoxy group; where the optional substitute or substitutes when R1-R8 are independently chosen from a group containing halogen, hydroxyl group, lower alkyl, mono- or di(lower)alkylamino group, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di(lower)alkylaminocarbonyl, amino group, carboxyl group, lower alkoxy group, C3-C12cycloalkyl, (lower)alkylcarbonyl, (lower)alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted with one or more substitutes, chosen from a group containing halogen, hydroxyl group, lower alkyl, sulfinyl, sulfonyl, sulfanyl, amino group, carboxyl group, lower alkoxy group, carbamoyl. Invention also relates to formula (I'), to a pharmaceutical composition, as well as use of formula (I) compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds, for preventing or treating bone diseases, associated with very low or resorption of calcium.

6 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds with formula I where R1, R2, R3 and Y together with a formula I residue, are compounds, chosen from a group given in the formula of invention, or to their pharmaceutically used and split esters, or to their acid-additive salts, which promote release of parathyroid hormone.

EFFECT: compounds can be used for making medicinal agents, with antagonistic properties towards calcium sensitive parathyroid gland receptor for treating diseases mediated by effect of parathyroid hormone.

7 cl, 179 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of pyridinecarboxamides with formula (I), where the descriptions of radicals are given in the formula of the invention and its salts.

EFFECT: compounds exhibit insecticide activity.

7 cl, 5 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (Z)-methyl-16-(5-oxo-2-phenyl-oxazol-4-ilidenmethyl)-15,16-epoxy-8(17),13(16),14-labdatrien-18-oate of formula (I) (I). Compound (I) possesses high antioxidative, hepatoprotective and hemostimulatng activity and can be used for correction of side effects, arising with introduction of highly toxic medications used in anti-tumor therapy.

EFFECT: obtaining compound, which possesses high antioxidative, hepatoprotective and hemostimulatng activity.

1 cl, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new piperidine derivative, with the following general formula (I) where R1 - R4 each stands for any of the univalent groups, indicated below: R1 stands for a hydrogen atom, halogen atom, inferior alkyl, which can be substituted with a halogen atom or OH; -O-inferior alkyl, which can be substituted with a halogen atom; -O-aryl, aryl, -C(=O)-inferior alkyl, COOH, -C(=O)-O-inferior alkyl, -C(=O)-NH2, -C(=O)NH-inferior alkyl, -C(=O)N-(inferior alkyl)2, OH, -O-C(=O)-inferior alkyl, NH2, -NH-inferior alkyl, -N-(inferior alkyl)2, NH-C(=O)- inferior alkyl, CN or NO2; R2 and R3 each stands for a hydrogen atom; and R4 stands for any of the univalent groups (a), (b) and (c), shown below in formula 2 where in the above indicated groups (a), (b) and (c), A stands for a pyrrolidine, piperidine, morpholine, piperizine or oxazepane ring; B stands for a pyrrolidine or piperidine ring; R5 and R8-R11 can be identical or different from each other and each stands for a hydrogen atom, -C(=O)-O-inferior alkyl, cycloalkyl or tetrahydropyrane; R6 stands for a hydrogen atom, -C(=O)-O-inferior alkyl, OH, -inferior alkylene-OH or -C(=O)-pyridine; and R7 stands for a hydrogen atom. The invention also pertains to pharmaceutical salts of the piperidine derivative, as well as medicinal compositions.

EFFECT: obtaining new biologically active compounds and a medicinal composition, based on these compounds, which is a sodium channel inhibitor.

10 cl, 91 ex, 22 tbl

FIELD: chemistry.

SUBSTANCE: new method is described for producing new derivatives in the series 5-amino-2,4-dihydro-3N-1,2,4-triazole-3-thiones, and specifically to a method of producing 4,5-disubstituted 2,4-dihydro-3N-1,2,4-triazole-3-thiones with general formula I: , where R1=C1-C6 alkylphenyl, haloid phenyl, thienyl, furanyl or pyrrolyl; R2= phenyl C1-C6 alkyl, naphthyl C1-C6 alkyl, anthryl C1-C6 alkyl, C1-C6 alkoxyphenyl, which involves reaction of corresponding acylisothiocyanates, obtained from acylchlorides R1-C(O)Cl and ammonium rhodanide, with 4-R2- thiosemicarbazides R2-NH-C(S)-NH-NH2 and subsequent cyclisation of N-[2-(R2- carbamothioyl) hydrazinocarbonothioyl]acylamides in a medium of high-boiling aliphatic alcohols.

EFFECT: desired product, which is obtained with high output and purity, can be used in medicine.

1 cl, 8 ex

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