2,5-disubstituted arylsulphonamide ccr3 antagonists

FIELD: chemistry.

SUBSTANCE: invention relates to 2,5 substituted arylsulphonamides of formula (Ia) or to their pharmaceutically acceptable salts, solvates, hydrates, stereoisomers or tautomers, where X represents S, SO or SO2; Y and Z represents (i) Y represents NR5; and Z represents =O, CO2R6 or C1-6alkyl; or (ii) Y represents CH2, CHF, CHCH3, O, S or SO2; and Z represents hydrogen or C1-6alkyl; R1 and R2 each independently represents halogen, C1-6alkyl or C1-6 halogenalkyl; R3 represents CN or NO2; R4 represents hydrogen or C1-6alkyl; R5 represents hydrogen or C1-6alkyl; and R6 represents hydrogen or C1-6alkyl. Invention also relates to compounds of formula (I) and (II), values of radicals of which are given in the invention formula, specific compounds, pharmaceutical composition based on compound of formula

,

and

,

method of modulating CCR3 activity.

EFFECT: obtained are novel compounds, possessing useful biological properties.

18 cl, 1 tbl, 3 ex

 

The technical field to which the invention relates

[0001] the Invention relates to 2,5-disubstituted arylsulfonamides that can be used for modulating CCR3 activity, and containing pharmaceutical compositions. The invention relates to methods of use thereof for the treatment, prevention or improvement of one or more symptoms of CCR3-mediated violation, the disease or condition.

Background of invention

[0002] Chemokinesis receptor CC 3 (CCR3) is a seven-transmembrane G protein - coupled receptor, which is associated with a variety of C-C chemokines, including eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). It is known that CCR3 is the main chemokine-recetaron expressed on allergic inflammatory cells, including eosinophils, basophils, mast cells and T-calpernia CD4+cell 2-type (Combadiere et al., J. Biol. Chem. 1995, 270, 16491-16494; Post et al., J. Immunol. 1995, 155, 5299-5305). Eosinophils are involved in the pathogenesis of a number of allergic diseases such as bronchial asthma (Durham and Kay, Clin. Allergy 1985, 15, 411-418; Kroegel et al., J. Allergy Clin. Immunol. 1994, 93, 725-734), allergic rhinitis (Durham, Clin. Exp. Allergy 1998, 28 Suppl. 2, 11-16), atopic dermatitis (Leung, J. Allergy Clin. Immunol. 1999, 104, S99-108) and eosinophilic gastroenteritis (Bischoff et al., Am. J. Gastro. 1999, 94, 3521-3529). It is shown that activated eosinophils wisweb who give major basic protein (MBP), which blocks muscarinic receptors M2 (M2Rs) on the nerves, increasing the release of acetylcholine and reinforcing vegasno-mediated bronchostenosis (Evans et al., J. Clin. Invest. 1997, 100, 2254-2262).

[0003] In numerous reports indicate that CCR3 plays an important role in allergic conditions. For example, it was reported that patients with atopic and diatopically asthma observed increased levels of both mRNA and protein CCR3 and its ligands - eotaxin, eotaxin-2, RANTES and MCP-4 (Ying et al., J. Immunol. 1999, 99, 6321-6329). It was also shown that deletion of the gene CCR3 reduces the increase in the number of eosinophils in acute model of experimental asthma (Humbles et al., Proc. Natl. Acad. Sci. USA 2002, 99, 1479-1484; Ma et al., J. Clin. Invest. 2002, 109, 621-628; Pope et al., J. Immunol. 2005, 175, 5341-5350; Fulkerson et al., Proc. Natl. Acad. Sci. USA 2006, 103, 16418-16423). In addition, studies have shown that antagonists of CCR3, such as anti-CCR3 monoclonal antibodies that block binding to CCR3-ligands with any of the CCR3 transfectants and eosinophils, thus blocking chemotaxis of eosinophils induced C-C chemokines, such as eotaxin, RANTES or MCP-3 (Heath et al., J. Clin. Invest. 1997, 99, 178-184; Grimaldi et al., J. Leukocyte Biol. 1999, 65, 846-853; Justice et al., Am. J. Physiol. 2003, 284, L168-L178). Accordingly, antagonists of CCR3 potentially can be used for the treatment of inflammatory diseases such as allergic rhinitis and allergic asthma. In addition, the antagonist of the CCR3 potentially also can be used to block infection of cells, expressing CCR3, some microorganisms, such as HIV, since it is known that CCR3 is an input coreceptor for some microorganisms.

The invention

[0004] the Invention relates to 2,5-disubstituted arylsulfonamides formula Ia:

or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer; where

X represents S, SO or SO2;

Y and Z represent

(i) Y represents NR5; and Z represents =O CO2R6or1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen; or

(ii) Y is CH2, CHF, CHCH3, O, S or SO2; and Z represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen;

R1and R2independently represent halogen, C1-6alkyl or C1-6halogenated;

R3represents CN or NO2;

R4represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen;

R5represents hydrogen or C1-6alkyl; and

R6represents hydrogen or C1-6alkyl.

[0005] from Britanie relates to 2,5-disubstituted arylsulfonamides formula I:

or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer; where

X represents S, SO or SO2;

Y and Z represent

(i) Y represents NR5; and Z represents =O or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen; or

(ii) Y is CH2, CHF, CHCH3, O, S or SO2; and Z represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen;

R1and R2independently represent halogen, C1-6alkyl or C1-6halogenated;

R3represents CN or NO2;

R4represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen; and

R5represents hydrogen or C1-6alkyl.

[0006] the invention relates to 2,5-disubstituted arylsulfonamides formula II or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer:

Y and Z represent

(i) Y represents NR5; and Z represents =O or C1-6alkyl, optionally substituted by aryl, hydroxy, ka is Boxing, alkoxy, carbamoyl or halogen; or

(ii) Y is CH2, CHF, CHCH3, O, S or SO2; and Z represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen;

R1and R2independently represent halogen, C1-6alkyl or C1-6halogenated;

R4represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen; and

R5represents hydrogen or C1-6alkyl;

provided that if Y is CH2at least one of Z and R4represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen.

[0007] the invention Also relates to pharmaceutical compositions comprising this compound, for example, the compound of formula Ia, formula I or formula II or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer in combination with one or more pharmaceutically acceptable carriers or excipients.

[0008] Further, the invention relates to a method of modulating CCR3 activity, comprising contacting CCR3 with a therapeutically effective amount of the compounds described herein, the example the compounds of formula Ia, formula I or formula II or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer.

[0009] furthermore, the invention relates to a method for treatment, prevention or improvement of one or more symptoms of a CCR3-mediated disorders, diseases or conditions in a subject comprising administration to the subject therapeutically effective amounts of compounds described herein, e.g. compounds of formula Ia, formula I or formula II or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer.

Detailed description of the invention

[0010] To facilitate understanding of the descriptions listed below are a number of terms.

[0011] Commonly used in the description of the item and described herein laboratory methods of organic chemistry, medicinal chemistry and pharmacology are those well known and commonly used in this field. If not specified other, all technical and scientific terms generally have the same meaning as that usually understood by ordinary specialist in the field to which the invention relates. In cases where there are many definitions used in the description of the term, it is dominated by the definitions in this section, if n is specified the other.

[0012] the Term "subject" refers to an animal, including, but not limited to, a Primate (e.g., human), cow, pig, sheep, goat, horse, dog, rabbit, rat or mouse. The terms "subject" and "patient" are used herein interchangeably when referring to, for example, the subject is a mammal, such as a subject-person, in one embodiment, human.

[0013] it is Implied that the terms "treat," "treating" and "treatment" include the relief or cessation, disease or condition, or the reduction or elimination of causes(s) of the disturbance, disease or condition.

[0014] it is Understood that the terms "prevent", "preventing" and "prevention" refer to the way the suspension and/or prevent the start of the disturbance, disease or condition and/or its attendant symptoms, preventing the subject of the emergence of disorders, diseases or condition or reducing a risk of the subject of disorders, diseases or conditions.

[0015] it is Implied that the term "therapeutically effective amount" includes the amount of compound that, when introduced, is sufficient to prevent development of or alleviate to some extent one or more symptoms of the disorders, the disease or condition being treated. Those who min "therapeutically effective amount" also refers to the number of connections, which is sufficient to cause the biological or medical response of a biological molecule (e.g., protein, enzyme, RNA or DNA), cell, tissue, system, animal or human that is meaningful from the point of view of the researcher, veterinarian, physician, or Clinician.

[0016] the Terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient," "physiologically acceptable carrier" or "physiologically acceptable excipient" refers to pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with other ingredients of a pharmaceutical product and suitable for use in contact with tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, corresponding to a reasonable value benefit/risk. Cm. Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company:2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004.

[0017] the Term "about" or "approximately" means the acceptable error for a particular value of a particular ordinary person skilled in the art, which depends partly on how you measure or determine this value. In some embodiments, the implementation, the term "about" or "approximately" is within 1, 2, 3, or 4 standard deviations. In some embodiments, the implementation, the term "about" or "approximately" is within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0,5% or 0.05% of a given value or range.

[0018] the Terms "active ingredient" and "active substance" refers to the compound that is administered to the subject separately or in combination with one or more pharmaceutically acceptable excipients, for the treatment, prevention and / or alleviate one or more symptoms of the condition, disorders or diseases. As used in this description, the terms "active ingredient" and "active substance" may refer to an optically active isomer of the described compounds.

[0019] the Terms "drug", "therapeutic agent" and "chemotherapeutic agent" refers to a compound or pharmaceutical composition that is administered to a subject to treat, prevent or ease the of one or more symptoms of the condition, disorders or diseases.

[0020] the Term "alkyl" refers to linear or branched saturated monovalent hydrocarbon radical, where alkylene optionally may be substituted as specified in this description. The term "alkyl" also encompasses both linear and branched alkali, unless otherwise stated. In some embodiments, implementation, alkyl is a linear saturated monovalent hydrocarbon radical, which contains 1-20 (C1-20), 1-15 (C1-15), 1-10 (C1-10) or 1-6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical that contains 3 to 20 (C3-20), 3-15 (C3-15), 3-10 (C3-10) or 3-6 (C3-6) carbon atoms. As used in this description, the terms "linear C1-6and branched C3-6alkyl group" also refers to "lower alkyl". Examples of alkyl groups include, but are not limited to specified, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, the term1-6alkyl refers to a linear saturated monovalent hydrocarbon radical of 1-6 carbon atoms or a branched saturated one who alertname hydrocarbon radical of 3-6 carbon atoms.

[0021] the Term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five carbon-carbon double bonds. Alkenyl optionally can be substituted, as described in this invention. The term "alkenyl" also embraces radicals having "CIS" or "TRANS" configuration or, alternatively, "Z" and "E" configuration, as understood in the usual experts in this field. As used herein, the term "alkenyl" encompasses both linear and branched of alkenyl, unless otherwise stated. For example, the term "C2-6alkenyl" refers to a linear unsaturated monovalent hydrocarbon radical of 2-6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3-6 carbon atoms. In some embodiments, implementation of alkenyl is a linear monovalent hydrocarbon radical of 2-20 (C2-20), 2-15 (C2-15), 2-10 (C2-10or 2-6 (C2-6) carbon atoms or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3-15 (C3-15), 3-10 (C3-10) or 3-6 (C3-6) carbon atoms. Examples alkenyl groups include, but are not limited to specified, ethynyl, propen-1-yl, propen-2-yl, allyl, butenyl and 4-methylbutanal.

[0022] the Term "quinil" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds. Quinil optionally can be substituted, as described in this invention. The term "quinil" also encompasses both linear and branched alkinyl, unless otherwise stated. In some embodiments, implementation, quinil is a linear monovalent hydrocarbon radical of 2-20 (C2-20), 2-15 (C2-15), 2-10 (C2-10or 2-6 (C2-6) carbon atoms or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3-15 (C3-15), 3-10 (C3-10) or 3-6 (C3-6) carbon atoms. Examples etkinlik groups include, but are not limited to specified, ethinyl (-C≡CH) and propargyl (-CH2C≡CH). For example, the term "C2-6quinil" refers to a linear unsaturated monovalent hydrocarbon radical of 2-6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3-6 carbon atoms.

[0023] the Term "cycloalkyl" refers to cyclic saturated bridge and/or bridge monovalent hydrocarbon radical, which optionally can be substituted, as described in this invention. In some embodiments, implementation, cycloalkyl contains from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10or from 3 to 7 (C 3-7) carbon atoms. Examples cycloalkyl groups include, but are not limited to specified, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decaline and substituted.

[0024] the Term "aryl" refers to monocyclic aromatic group and/or multicyclonic monovalent aromatic group which contains at least one aromatic hydrocarbon ring. In some embodiments, implementation, aryl contains from 6 to 20 (C6-20), from 6 to 15 (C6-15) or from 6 to 10 (C6-10) ring atoms. Examples of aryl groups include, but are not limited to specified, phenyl, naphthyl, fluorenyl, azulene, tenantry, pyrenyl, biphenyl and terphenyl. The term "aryl" also refers to a bicyclic or tricyclic carbon ring, where one of these rings is aromatic, and others may be saturated, partially saturated or aromatic, for example, dihydronaphtho, indenyl, indanyl or tetrahydronaphthyl (tetralinyl). In some embodiments, implementation, aryl optionally can be substituted, as described in this invention.

[0025] the Term "heteroaryl" refers to a monocyclic aromatic group and/or multicyclonic aromatic group that contains at least one aromatic ring, where at least one aromatic ring contains the Dean or several heteroatoms, independently selected from O, S, and N. Each ring of a heteroaryl group can contain one or two atoms Of one or two atoms S and/or one to four N atoms provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In some embodiments, implementation, heteroaryl contains from 5 to 20, 5 to 15 or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to specified, pyrrolyl, pyrazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolin, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to specified, indolyl, benzothiazolyl, benzoxazolyl, benzothiazyl, chinoline, tetrahydroisoquinoline, ethenolysis, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromones, coumarinyl, cinnoline, honokalani, indazoles, purinol, pyrrolopyridine, properidine, thienopyridines, dihydroisoquinolyl, and tetrahydroquinolines. Examples of tricyclic heteroaryl groups include, but are not limited to specified, carbazolyl, bunzendahl, phenanthrolines, acridines, phenanthridines and xantinol. In some valentinorossini, heteroaryl also optionally may be substituted as specified in this description.

[0026] the Term "heterocyclyl" or "heterocyclic" refers to a monocyclic non-aromatic ring system and/or multicyclonic ring system that contains at least one non-aromatic ring, where one or more of the atoms forming the non-aromatic ring are heteroatoms independently selected from O, S or N; and the remaining atoms are carbon atoms. In some embodiments, implementation, heterocyclyl or heterocyclic group contains from 3 to 20, 3 to 15, 3 to 10, 3 to 8, from 4 to 7 or 5 to 6 ring atoms. In some embodiments, implementation, heterocyclyl represents a monocyclic, bicyclic, tricyclic or tetracyclic system, which may include a condensed or bridged ring system, and in which the nitrogen atoms or sulfur may not necessarily be oxidized, the nitrogen atoms may not necessarily be quaternidinum, and some cycles may be partially or fully saturated or aromatic. Heterocyclyl can be attached to the main structure via any heteroatom or carbon atom which results in a stable compound. Examples of such heterocyclic radicals include, but are not ogranichivayutsya specified, acridines, azepine, benzimidazolyl, bunzendahl, benzisoxazole, benzisoxazole, benzodioxane, benzodioxole, benzofuranyl, benzopyranyl, benzenepropanal, benzopyranones, benzopyranyl, bettererererer, betterregulation, benzothiadiazoles, benzothiazolyl, benzothiophene, benzotriazolyl, benzothiophene, benzoxazines, benzoxazolyl, benzothiazolyl, β-carbolines, carbazolyl, bromanil, chromones, cinnoline, coumarinyl, decahydroquinoline, dibenzofurans, dihydromethysticin, dihydroergotoxine, dihydrofuran, dihydropyran, DIOXOLANYL, dihydropyrazine, dihydropyridines, dihydropyrazolo, dihydropyrimidines, dihydropyrrole, DIOXOLANYL, 1,4-ditional, furanones, furanyl, imidazolidinyl, imidazolyl, imidazolyl, imidazopyridines, imidazothiazoles, indazoles, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isobenzofurandione, isobenzofuranyl, isopropanol, isocoumarins, isoindolines, isoindolyl, ethenolysis, isothiazolinones, isothiazolin, isoxazolidine, isoxazolyl, morpholinyl, naphthyridine, octahedrally, activitiesunder, oxadiazolyl, oxazolidinyl, oxazolidinyl, oxazolopyridine, oxazolyl, oxiranyl, pyrimidinyl, phenanthridines, phenanthrolines, phenarsazine, phenazines, phenothiazines, phenoxazines, phthalazine, PIP is rasini, piperidinyl, 4-piperidinyl, pteridinyl, purinol, pyrazinyl, pyrazolidine, pyrazolyl, pyridazinyl, pyridinyl, pyridopyrimidines, pyrimidinyl, pyrrolidinyl, pyrrolyl, pyrrolyl, hintline, chinoline, honokalani, hinokitiol, tetrahydrofuryl, tetrahydropyranyl, tetrahydroisoquinoline, tetrahydropyranyl, tetrahydrofuryl, tetrazolyl, thiadiazolidine, thiadiazolyl, thiomorpholine, thiazolidine, thiazole, thienyl, triazinyl, triazolyl and 1,3,5-tritional. In some embodiments, implementation, heterocycle optionally may be substituted as specified in this description.

[0027] the Term "alkoxy" refers to a radical-OR where R represents, for example, alkyl, alkenyl, quinil, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is defined in this description. Examples of alkoxy groups include, but are not limited to specified, methoxy, ethoxy, propoxy, n-propoxy, 2-propoxy, n-butoxy, isobutoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzoxa and 2 naphthyloxy. In some embodiments, implementation, alkoxy optionally may be substituted as specified in this description. In some embodiments, implementation, alkoxy represents a C1-6alkyloxy.

[0028] the Term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine and/or iodine.

[0029] it is Implied that the term "neo is Astelin substituted" means, that group, such as alkyl, Alchemilla, Alchemilla, cycloalkyl, aryl, heteroaryl, heterocyclic or alkoxy group may be substituted by one or more substituents, independently selected, for example, from (a) alkyl, alkenyl, quinil, cycloalkyl, aryl, heteroaryl and heterocyclyl, each of which optionally is substituted by one or more, in one embodiment, one, two, three or four substituents Q; and (b) halogen, cyano (-CN), nitro (-NO2), -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(NRa)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(=NRa)NRbRc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRcand-S(O)2NRbRcwhere each Ra, Rb, Rcand Rdindependently represents (i) hydrogen; (ii)1-6alkyl, C2-6alkenyl, C2-6quinil, C3-7cycloalkyl, C6-14aryl, heteroaryl or heterocyclyl, each is of which optionally is substituted by one or more, in one embodiment, one, two, three or four substituents Q; or (iii) Rband Rctogether with the N atom to which they are connected, form a heterocycle, optionally substituted by one or more, in one embodiment, one, two, three or four substituents Q. As used herein, all groups that can be substituted are "optionally substituted", unless otherwise stated.

[0030] In one embodiment, each Q is independently selected from the group consisting of (a) cyano, halogen and nitro; and (b) C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-7cycloalkyl, C6-14aryl, heteroaryl and heterocyclyl; and-C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(NRe)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(=NRe)NRfRg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORh, -NReC(O)NRfRg, -NReC(=NRh)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRgand-S(O)2NRfRg; where each Re, Rf, R gand Rhindependently represents (i) hydrogen; (ii) C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-7cycloalkyl, C6-14aryl, heteroaryl or heterocycle; or (iii) Rfand Rgtogether with the N atom to which they are connected, form heterocyclyl.

[0031] In some embodiments, implementation of the expression "optically active" and "active enantiomeric" refers to a collection of molecules, which has an enantiomeric excess of no less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, not less than approximately 99.5% or not less than about 99.8 per cent. In some embodiments, the implementation, the compound contains about 95% or more of the desired enantiomer and about 5% or less less preferred enantiomer is based on the total weight of the considered racemate.

[0032] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). Signs (+) and (-) are used to denote the optical rotation of the compound, i.e. the direction of the Oia, in which optically active compound rotates the plane of polarized light. Console (-) indicates that the connection is levogyrate, i.e. the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the connection is Pervouralsk, i.e. the compound rotates the plane of polarized light to the right or clockwise. However, the signs of optical rotation (+) and (-) does not refer to the absolute configuration of the molecule, R and S.

[0033] the Term "MES" refers to the developed invention the compound or its salt, which further includes a stoichiometric or non-stoichiometric amount of solvent bound non-covalent intermolecular forces. In the case where the solvent is a water, MES is a hydrate.

[0034] the Term "existing in nature" or "natural"when used in relation to biological substances such as nucleic acid molecules, polypeptides, host cells, and the like, refers to substances that are discovered in nature and is not controlled by men. Similarly, the term "does not exist in nature" or "unnatural" refers to a material that is not identified in nature, or that has been structurally modified or synthesized by man.

[0035] the Ermin "CCR3" refers to the chemokine receptor CC3 or its variant, which is able to mediate cellular responses to a variety of chemokines, including but not limited to, eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). Options CCR3 include proteins, essentially homologous natural CCR3, i.e. proteins having one or more deletions, insertions or substitutions of natural or unnatural amino acids (e.g., derivatives, homologues and fragments CCR3) compared to the amino acid sequence of natural CCR3. The amino acid sequence of the variant CCR3 is identical to at least 80%identical, at least 90% identical or at least 95% sequence natural CCR3.

[0036] the Term "CCR3 antagonist" refers to a connection that, for example, partially or fully blocks, reduces, prevents, inhibits and reduces the activity of CCR3. The term "CCR3 antagonist" also refers to a compound that binds, delay activation, inactivates or desensibilisation receptor CCR3. The CCR3 antagonist can act interfering with the interaction of the receptor CCR3 and its chemokine ligand, including, but not limited to, eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and/or RANTES (CCL5).

[0037] the Terms "CCR3-mediated disorder or disease" and "condition, disorder or disease mediated by CCR3" refers to a condition which, disturbance or disorder characterized by inappropriate, e.g., above or below normal, the activity of CCR3. Inappropriate functional activity of CCR3 may occur as a result of CCR3 expression in cells which normally do not Express CCR3, increased expression of CCR3 or degree of intracellular activation, leading, for example, inflammatory or associated with immune system disorders or diseases; or as a result of reduced expression of CCR3. CCR3-mediated condition, disorder or disease may be completely or partially mediated by inappropriate activity of CCR3. In particular, CCR3-mediated condition, disorder, or disease is a fact in which the modulation of receptor CCR3 leads to some effect on the underlying condition or disorder, for example, the antagonist or agonist results in some improvement in at least some patients under treatment.

Connection

[0038] the Invention relates to 2,5-disubstituted arylsulfonamides that can be used for modulating CCR3 activity. The invention relates to pharmaceutical compositions that include the compounds, and to methods of using compounds and compositions for treatment of CCR3-mediated disorders, diseases or conditions.

[0039] In one embodiment, the OS is supervising the invention relates to 2,5-disubstituted arylsulfonamides formula Ia:

or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer; where

X represents S, SO or SO2;

Y and Z represent

(i) Y represents NR5; and Z represents =O CO2R6or1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen; or

(ii) Y is CH2, CHF, CHCH3, O, S or SO2; and Z represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen;

R1and R2independently represent halogen, C1-6alkyl or C1-6halogenated;

R3represents CN or NO2;

R4represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen;

R5represents hydrogen or C1-6alkyl; and

R6represents hydrogen or C1-6alkyl.

[0040] In some embodiments, the implementation of formula Ia, X is S. In some embodiments, the implementation of formula Ia, X is a SO. In some embodiments, the implementation of formula Ia, X is a SO2.

[0041] In some embodiments, the implementation of formula Ia, Predstavljaet a NR 5. In the variants of implementation of the formula Ia where Y represents NR5Z represents =O or C1-6alkyl, optionally substituted. In one embodiment of formula Ia where Y represents NR5Z represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen. In one embodiment of formula Ia where Y represents NR5Z represents-CH3. In another embodiment of formula Ia where Y represents NR5Z represents CO2R6. In one embodiment of formula Ia where Y represents NR5and Z represents CO2R6, R6represents CH3. In one embodiment of formula Ia where Y represents NR5Z represents CO2CH3. In another embodiment of formula Ia where Y represents NR5Z is a =O. In different variants of implementation of the formula Ia where Y represents NR5, R5represents hydrogen or C1-6alkyl. In some embodiments, the implementation of formula Ia where Y represents NR5, R5represents a C1-6alkyl. In some embodiments, the implementation of formula Ia where Y represents NR5, R5the present is the focus of a hydrogen. In some embodiments, the implementation of formula Ia where Y represents NR5, R5represents methyl. In some embodiments, the implementation of formula I, where Y represents NR5, R5represents isopropyl.

[0042] In some embodiments, the implementation of formula Ia, Y is CH2, CHF, CHCH3, O, S or SO2. In the variants of implementation of the formula Ia where Y is CH2, CHF, CHCH3, O, S or SO2Z represents hydrogen or C1-6alkyl, optionally substituted. In some embodiments, the implementation of formula Ia where Y is CH2, CHF, CHCH3, O, S or SO2Z represents hydrogen. In some embodiments, the implementation of formula Ia where Y is CH2, CHF, CHCH3, O, S or SO2Z represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen. In some embodiments, the implementation of formula Ia where Y is CH2, CHF, CHCH3, O, S or SO2Z represents methyl. In some embodiments, the implementation of formula I, Y is CH2. In some embodiments, the implementation of formula Ia, Y is CHF. In some embodiments, the implementation of formula Ia, Y is a CHCH3. In some embodiments assests is of formula Ia, Y is O. In some embodiments, the implementation of formula Ia, Y is S. In some embodiments, the implementation of formula Ia, Y is SO2.

[0043] In some embodiments, the implementation of the formula Ia, R1represents a halogen, With1-6alkyl or C1-6halogenated. In some embodiments, the implementation of the formula Ia, R1represents a halogen. In some embodiments, the implementation of the formula Ia, R1represents fluorine or chlorine. In some embodiments, the implementation of the formula Ia, R1represents chlorine. In some embodiments, the implementation of the formula Ia, R1represents a C1-6alkyl. In some embodiments, the implementation of the formula Ia, R1represents methyl. In some embodiments, the implementation of the formula Ia, R1represents a C1-6halogenated. In some embodiments, the implementation of the formula Ia, R1represents trifluoromethyl.

[0044] In some embodiments, the implementation of the formula Ia, R2represents a halogen, With1-6alkyl or C1-6halogenated. In some embodiments, the implementation of the formula Ia, R2represents a halogen. In some embodiments, the implementation of the formula Ia, R2represents fluorine or chlorine. In some embodiments, the implementation of the formula Ia, R2is own the th chlorine. In some embodiments, the implementation of the formula Ia, R2represents a C1-6alkyl. In some embodiments, the implementation of the formula Ia, R2represents methyl. In some embodiments, the implementation of the formula Ia, R2represents a C1-6halogenated. In some embodiments, the implementation of the formula Ia, R2represents trifluoromethyl.

[0045] In some embodiments, the implementation of the formula Ia, R1and R2are different. In some embodiments, the implementation of the formula Ia, R1and R2are the same. In some embodiments, the implementation of formula Ia, both R1and R2represent chlorine. In some embodiments, the implementation of formula Ia, both R1and R2represent methyl. In some embodiments, the implementation of formula Ia, both R1and R2 represents trifluoromethyl.

[0046] In some embodiments, the implementation of the formula Ia, R3represents cyano. In some embodiments, the implementation of the formula Ia, R3represents nitro.

[0047] In some embodiments, the implementation of the formula Ia, R4represents hydrogen or C1-6alkyl, optionally substituted. In some embodiments, the implementation of the formula Ia, R4represents hydrogen. In some embodiments, the implementation of the formula Ia, R4represents a alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen. In some embodiments, the implementation of the formula Ia, R4represents methyl.

[0048] In another embodiment, the present invention relates to 2,5-disubstituted arylsulfonamides formula I or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer:

where

X represents S, SO or SO2;

Y and Z represent

(i) Y represents NR5; and Z represents =O or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen; or

(ii) Y is CH2, CHF, CHCH3, O, S or SO2; and Z represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen;

R1and R2independently represent halogen, C1-6alkyl or C1-6halogenated;

R3represents CN or NO2;

R4represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen; and

R5represents hydrogen or C1-6alkyl.

[0049] In some embodiments, the implementation of formula I, X is a small town is a place S. In some embodiments, the implementation of formula I, X represents SO. In some embodiments, the implementation of formula I, X represents the SO2.

[0050] In some embodiments, the implementation of formula I, Y represents NR5. In the variants of implementation of the formula I, where Y represents NR5Z represents =O or C1-6alkyl, optionally substituted. In one embodiment of formula I, where Y represents NR5Z represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen. In one embodiment of formula I, where Y represents NR5Z represents-CH3. In another embodiment, formula I, where Y represents NR5Z is a =O. In different variants of implementation of the formula I, where Y represents NR5, R5represents hydrogen or C1-6alkyl. In some embodiments, the implementation of formula I, where Y represents NR5, R5represents a C1-6alkyl. In some embodiments, the implementation of formula I, where Y represents NR5, R5represents hydrogen. In some embodiments, the implementation of formula I, where Y represents NR5, R5represents methyl. In some embodiments, Khujand the exercise of formula I, where Y represents NR5, R5represents isopropyl.

[0051] In some embodiments, the implementation of formula I, Y is CH2, CHF, CHCH3, O, S or SO2. In the variants of implementation of the formula I, where Y is CH2, CHF, CHCH3, O, S or SO2Z represents hydrogen or C1-6alkyl, optionally substituted. In some embodiments, the implementation of formula I, where Y is CH2, CHF, CHCH3, O, S or SO2Z represents hydrogen. In some embodiments, the implementation of formula I, where Y is CH2, CHF, CHCH3, O, S or SO2Z represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen. In some embodiments, the implementation of formula I, where Y is CH2, CHF, CHCH3, O, S or SO2Z represents methyl. In some embodiments, the implementation of formula I, Y is CH2. In some embodiments, the implementation of formula I, Y is CHF. In some embodiments, the implementation of formula I, Y represents CHCH3. In some embodiments, the implementation of formula I, Y is O. In some embodiments, the implementation of formula I, Y is S. In some embodiments, the implementation of formula I, Y isone SO 2.

[0052] In some embodiments, the implementation of formula I, R1represents a halogen, With1-6alkyl or C1-6halogenated. In some embodiments, the implementation of formula I, R1represents a halogen. In some embodiments, the implementation of formula I, R1represents fluorine or chlorine. In some embodiments, the implementation of formula I, R1represents chlorine. In some embodiments, the implementation of formula I, R1represents a C1-6alkyl. In some embodiments, the implementation of formula I, R1represents methyl. In some embodiments, the implementation of formula I, R1represents a C1-6halogenated. In some embodiments, the implementation of formula I, R1represents trifluoromethyl.

[0053] In some embodiments, the implementation of formula I, R2represents a halogen, With1-6alkyl or C1-6halogenated. In some embodiments, the implementation of formula I, R2represents a halogen. In some embodiments, the implementation of formula I, R2represents fluorine or chlorine. In some embodiments, the implementation of formula I, R2represents chlorine. In some embodiments, the implementation of formula I, R2represents a C1-6alkyl. In some embodiments, the implementation of formula I, R2is the Oh methyl. In some embodiments, the implementation of formula I, R2represents a C1-6halogenated. In some embodiments, the implementation of formula I, R2represents trifluoromethyl.

[0054] In some embodiments, the implementation of formula I, R1and R2are different. In some embodiments, the implementation of formula I, R1and R2are the same. In some embodiments, the implementation of formula I, both R1and R2represent chlorine. In some embodiments, the implementation of formula I, both R1and R2represent methyl. In some embodiments, the implementation of formula I, both R1and R2represent trifluoromethyl.

[0055] In some embodiments, the implementation of formula I, R3represents cyano. In some embodiments, the implementation of formula I, R3represents nitro.

[0056] In some embodiments, the implementation of formula I, R4represents hydrogen or C1-6alkyl, optionally substituted. In some embodiments, the implementation of formula I, R4represents hydrogen. In some embodiments, the implementation of formula I, R4represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen. In some embodiments, the implementation of formula I, R4is the Oh methyl.

[0057] In another embodiment, the present invention relates to 2,5-disubstituted arylsulfonamides formula II or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer:

where Y and Z represent

(i) Y represents NR5; and Z represents =O or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen; or

(ii) Y is CH2, CHF, CHCH3, O, S or SO2; and Z represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen;

R1and R2independently represent halogen, C1-6alkyl or C1-6halogenated;

R4represents hydrogen or C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen; and

R5represents hydrogen or C1-6alkyl;

provided that if Y is CH2at least one of Z and R4represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen.

[0058] In some embodiments, the implementation of formula II, Y is NR5. In variants of the implementation forms of the crystals II, where Y represents NR5Z represents =O or C1-6alkyl, optionally substituted. In one embodiment of formula II where Y represents NR5Z represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen. In one embodiment of formula II where Y represents NR5Z represents-CH3. In another embodiment, formula II where Y represents NR5Z is a =O. In different variants of implementation of the formula II where Y represents NR5, R5represents hydrogen or C1-6alkyl. In some embodiments, the implementation of formula II where Y represents NR5, R5represents a C1-6alkyl. In some embodiments, the implementation of formula II where Y represents NR5, R5represents hydrogen. In some embodiments, the implementation of formula II where Y represents NR5, R5represents methyl. In some embodiments, the implementation of formula II where Y represents NR5, R5represents isopropyl.

[0059] In some embodiments, the implementation of formula II, Y is CH2, CHF, CHCH3, O, S or SO2. In the variants of implementation of the formula II where Y is the Wallpaper CH 2, CHF, CHCH3, O, S or SO2Z represents hydrogen or C1-6alkyl, optionally substituted. In some embodiments, the implementation of formula II where Y is CH2, CHF, CHCH3, O, S or SO2Z represents hydrogen. In some embodiments, the implementation of formula II where Y is CH2, CHF, CHCH3, O, S or SO2Z represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen. In some embodiments, the implementation of formula II where Y is CH2, CHF, CHCH3, O, S or SO2Z represents methyl. In some embodiments, the implementation of formula II, Y is CH2. In the variants of implementation of the formula II where Y is CH2at least one of Z and R4represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen. In some embodiments, the implementation of formula II, Y is CHF. In some embodiments, the implementation of formula II, Y is CHCH3. In some embodiments, the implementation of formula II, Y is O. In some embodiments, the implementation of formula II, Y is S. In some embodiments, the implementation of formula II, Y is SO2.

[0060] In some embodiments, the implementation of formula II, R1represents a halogen, With1-6alkyl or C1-6halogenated. In some embodiments, the implementation of formula II, R1represents a halogen. In some embodiments, the implementation of formula II, R1represents fluorine or chlorine. In some embodiments, the implementation of formula II, R1represents chlorine. In some embodiments, the implementation of formula II, R1represents a C1-6alkyl. In some embodiments, the implementation of formula II, R1represents methyl. In some embodiments, the implementation of formula II, R1represents a C1-6halogenated. In some embodiments, the implementation of formula II, R1represents trifluoromethyl.

[0061] In some embodiments, the implementation of formula II, R2represents a halogen, With1-6alkyl or C1-6halogenated. In some embodiments, the implementation of formula II, R2represents a halogen. In some embodiments, the implementation of formula II, R2represents fluorine or chlorine. In some embodiments, the implementation of formula II, R2represents chlorine. In some embodiments, the implementation of formula II, R2represents a C1-6alkyl. In some embodiments, the implementation of formula II, R2is the Oh methyl. In some embodiments, the implementation of formula II, R2represents a C1-6halogenated. In some embodiments, the implementation of formula II, R2represents trifluoromethyl.

[0062] In some embodiments, the implementation of formula II, R1and R2are different. In some embodiments, the implementation of formula II, R1and R2are the same. In some embodiments, the implementation of formula II, both R1and R2represent chlorine. In some embodiments, the implementation of formula II, both R1and R2represent methyl. In some embodiments, the implementation of formula II, both R1and R2represent trifluoromethyl.

[0063] In some embodiments, the implementation of formula II, R4represents hydrogen or C1-6alkyl, optionally substituted. In some embodiments, the implementation of formula II, R4represents hydrogen. In some embodiments, the implementation of formula II, R4represents a C1-6alkyl, optionally substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl or halogen. In some embodiments, the implementation of formula II, R4represents methyl.

[0064] In some embodiments, the implementation, the invention relates to a compound selected from the group consisting of:

or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer.

[0065] it is Implied that developed in the invention compounds encompass all possible stereoisomers, unless a particular stereochemistry. In that case, when developed in the invention compounds contain alkenylphenol or alkenylamine group, the compound may exist as one or as a mixture of geometric CIS/TRANS (or Z/E) isomers. In the case where structural isomers are transformed into each other via a low energy barrier, the compound may exist as a single tautomer or as a mixture of tautomers. This may be the result of proton tautomerism in the compound, which contains, for example, an imino, keto, or oximo group; or so-called valence tautomerism in the compound containing the aromatic fragment. It follows that one connection can be more than one type of isomerism.

[0066] Developed in the invention compounds may be enantiomerically pure, for example, in the form of a single enantiomer is a or a single stereoisomer, or a stereoisomeric mixture, for example, a mixture of enantiomers, for example, a racemic mixture of two enantiomers, or a mixture of two or more diastereomers. Essentially, the person skilled in the art it will be clear that the introduction of the compound in its (R) form is equivalent, for compounds that undergo undergo epimerization in vivo, the introduction of the compound in its (S) form. Conventional methods of obtaining/separation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis of achiral starting substances or separation enatiomeric mixture, for example, chiral chromatography, recrystallization, division, education diastereomeric salt or converting to diastereomeric adducts with further separation.

[0067] Developed in the invention, the connection can also be isotopically labeled at one or more sites of the molecule. In some embodiments, implementation, developed in the invention compounds can be selectively Deuteronomy site, which slows the rate of metabolic deactivation, for example, to increase the circulation half-life in vivo.

[0068] When developed in the invention, the compound contains an acidic or basic fragment, it can also be obtained in the form of a pharmaceutically acceptable the Oli (see, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Properties, and Use," Stahl and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).

[0069] Suitable acids for use in obtaining pharmaceutically acceptable salts include, but are not limited to specified, acetic acid, 2,2-dichloracetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzosulfimide acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, Caproic acid, Caprylic acid, cinnamic acid, citric acid, reklamowy acid, cyclohexanesulfamic acid, dodecylthio acid, ethane-1,2-disulfonate acid, econsultancy acid, 2-hydroxy-econsultancy acid, formic acid, fumaric acid, galacturonic acid, entityname acid, glucoheptonate acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, Hydrobromic acid, hydrochloric acid, idiscovered acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, Euroway acid, maleic acid, (-)-L-malic acid, malonic acid,(±)-DL-almond acid, methansulfonate acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonate acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, Orotava acid, oxalic acid, palmitic acid, pambou acid, perchloro acid, phosphoric acid, L-pyroglutamic acid, sugar acid, salicylic acid, 4-amino-salicylic acid, sabotinova acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, ticinobuy acid, p-toluensulfonate acid, undecylenoyl acid and valeric acid.

[0070] Suitable bases for use in obtaining pharmaceutically acceptable salts include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide or sodium hydroxide; and organic bases such as primary, secondary, tertiary, and Quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, Diisopropylamine, 2-(diethylamino)ethanol, ethanolamine, ethylamine, Ethylenediamine, Isopropylamine, N-methyl-glucamine, geranamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)morpholine, methylamine, piperidine, piperazine, n is operamin, pyrrolidine, 1-(2-hydroxyethyl)pyrrolidine, pyridine, Hinkley, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propandiol and tromethamine.

[0071] Developed in the invention, the connection can also be obtained in the form of a prodrug, which is a functional derivative compounds, for example, formula I or formula II, and is easily converted into the original compound in vivo. Prodrugs are often used, because in some situations they can be easier to apply than the original compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not bioavailable. Procarta may also have a higher solubility in pharmaceutical compositions in comparison with the reference compound. The prodrug may be transformed into the original drug by different mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asgharnejad in "Transport Procsses in Pharmaceutical Systems," Amidon et al., Ed., Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc, Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

The synthesis methods

[0072] Developed in this invention the compound can be obtained, isolated or synthesized by any means known to the person skilled in the art. For example, the compound of formula Ia or formula I can be obtained according to synthetic scheme, as illustrated in figure 1. In the first stage nitrobenzene interacts with 1,3,5-triple-substituted benzene in the presence of a base (such as potassium carbonate or sodium hydride) in the reaction of aromatic substitution. Product - netrail, restore using a reducing agent (such as TiCl2or hydrosulfite sodium) aniline, which is then converted into sulphonylchloride reaction For which dmeyer. The compound of formula Ia or formula I is formed by the reaction of sulphonylchloride with a suitable nitrogen-containing heterocycle in the presence of a base such as triethylamine.

Scheme 1

[0073] the Compound of formula II can be obtained by the synthetic scheme as illustrated in figure 1.

[0074] the Compound of formula Ia or formula I can also be obtained by the synthetic scheme illustrated in scheme 2. In the first stage, aniline initially converted into sulphonylchloride by reaction of Sandmeyer. Subsequently, sulphonylchloride subjected to interaction with a suitable nitrogen-containing heterocycle in the presence of a base, such as triethylamine, with the formation of 2-chloro-5-substituted sulfonamida, which is then subjected to interaction with a suitable 1,3,5-triple-substituted benzene by reaction of aromatic substitution in the presence of a base such as potassium carbonate or sodium hydride, to form compounds of formula Ia or formula I.

Scheme 2

[0075] the Compound of formula II can be obtained by the synthetic scheme as shown in figure 2.

The pharmaceutical composition

[0076] the Invention relates to pharmaceutical compositions comprising developed izaberete the AI connection, for example, the compound of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer, as an active ingredient in combination with pharmaceutically acceptable vehicle, carrier, diluent or excipient or their mixture.

[0077] Developed in this invention, the connection can be entered by itself or in combination with one or more developed in this invention the compounds. Pharmaceutical composition, which includes developed in the invention, the connection, for example, the compound of formula Ia, formula I or formula II may be obtained in various preparative dosage forms for oral, parenteral or local administration. Pharmaceutical compositions can also be obtained in the form of a modified formulation of dosage forms, including preparative dosage form delayed, delayed, prolonged, continuous, pulsed, controlled, accelerated and rapid, directional, programmable release and held in the stomach preparative dosage forms. Data preparative dosage forms can be obtained in accordance with conventional methods known to experts in this field (see Remington: The Science and Practice of harmacy, above; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2003; Vol. 126).

[0078] In one embodiment, the pharmaceutical composition is designed in the form of preparative dosage forms for oral administration, which includes developed in the invention, the connection, for example, the compound of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer, and one or more pharmaceutically acceptable excipients or carriers.

[0079] In another embodiment, the pharmaceutical compositions obtained in preparative dosage form for parenteral administration, which includes developed in the invention, the connection, for example, the compound of formula Ia, formula I or formula II or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer and one or more pharmaceutically acceptable excipients or carriers.

[0080] In the following embodiment, the pharmaceutical compositions obtained in preparative dosage form for topical administration, which includes developed in the invention, the connection, for example, the compound of formula Ia, formula I or formula II or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer and one or more farmaci is almost acceptable excipients or carriers; and one or more pharmaceutically acceptable excipients or carriers.

[0081] Developed in this invention the pharmaceutical compositions can be obtained in a single preparative dosage forms or mnogochasovoj preparative dosage forms. The term "single preparative dosage form"as used herein, refers to physically discrete unit suitable for administration to a subject, human and animal, and packaged individually as is known in this field. Every single preparative dosage form contains a predetermined amount of the active ingredient(s)sufficient to provide the desired therapeutic effect, in combination with the required pharmaceutical carriers or excipients. Examples of individual preparative dosage forms include vials, syringe and individually packaged pill or capsule. Single preparative dosage form can be entered or to enter them a lot. Multiple preparative dosage form is a set of identical single preparative dosage forms packaged in a single container for administration in the form of a single formulation of dosage forms. Examples of multiple preparation the x dosage forms include bubble a bottle of pills or capsules or bottle of pints or gallons.

[0082] Developed in this invention the pharmaceutical composition can be injected once or many times over a period of time. It should be understood that the precise dosage and duration of treatment may vary with age, weight and condition of the patient being treated, and can be determined empirically using known testing protocols or by extrapolation of test data in vivo or in vitro or diagnostic data. Additionally, it should be understood that for any particular individual specific dose regimens should be adjusted over time in accordance with the need of the individual and the professional judgment of the specialist or monitoring medications.

A. Oral administration

[0083] Developed in this invention the pharmaceutical compositions can be obtained in solid, semi-solid or liquid formulation dosage forms for oral administration. As used in this description, oral administration also includes buccal, lingual and sublingual administration. Suitable oral formulations dosage forms include, but are not limited to specified, tablets, dissolving in the mouth tablets, Eveline pills, capsules, pills, pellets, lozenges, pills, pads, pellets, chewing gum with drug, bulk powders, effervescent or nishiuchi powders or granules, solutions, emulsions, suspensions, wafer, caramel chips, elixirs and syrups. In addition to the active ingredient(s) of the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, dezintegriruetsja agents, wetting agents, lubricants, glidant, dyes, inhibitors, change colors, sweeteners and flavorings.

[0084] Binders or granulators give the tablet binding capacity, guaranteeing tablets during pressing. Suitable binders or granulators include, but are not limited to specified, starches such as corn starch, potato starch, and pre-gelatinizing starch (such as STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, lemon balm, and lactose; natural and synthetic gums, such as gum Arabic, alginic acid, alginates, extract of Irish moss (carrageen), Povarovo gum, gum, ghatti, a mixture of solutions of gums husk isabgol, carboxymethylcellulose, methylcellulose, on vinylpyrrolidone (PVP), wigum, arabinogalactan from larch wood, powder tragacanth gum and guar gum; cellulose, such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hypromellose (HPMC); microcrystalline cellulose such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to specified, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrine, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizing starch and mixtures thereof. The binder and filler may be present in developed in the invention composition in an amount of from about 50 to about 99% by weight.

[0085] Suitable diluents include, but are not limited to specified, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, Inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Some diluents such as mannitol, lactose, sorbitol, sucrose and Inositol, when they are present in sufficient quantities, can give some properties extruded tablets, which give the possibility of destruction of mouth PR is chewing. Such molded tablets can be used as chewable tablets.

[0086] Suitable dezintegriruetsja agents include, but are not limited to specified, agar, bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resin; alginic acid; gums, such as guar gum and veegum HV; citrus pulp; cross-linked cellulose, such as croscarmellose; a cross-linked polymer such as crosspovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch and pre-generowanie starch; clays; lignins and their mixtures. The number dezintegriruetsja agent developed in the invention pharmaceutical compositions varies depending on the type of drug and is easily determined by conventional experts in this field. Developed in the invention compositions can contain from about 0.5 to about 15% or from about 1 to about 5% by weight dezintegriruetsja agent.

[0087] Suitable lubricants include, but are not limited to specified, calcium stearate; magnesium stearate; oil; light oil products; glycerin; sorbitol; mannitol; glycols, such as glycerinated and polyethylene who glycol (PEG); stearic acid; sodium lauryl sulfate; talc; gidrirovannoe vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; etiloleat; tillaart; agar; starch; Likopodija; silicon dioxide or silicagel, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. Developed in this invention the composition may contain from about 0.1 to about 5% lubricant by weight.

[0088] Suitable glidant (control flowability) include colloidal silica, CAB-O-SIL® (Cabot Co. of Boston, MA) and not containing asbestos talc. Dyes include any of the approved certified water soluble dyes, FD&C insoluble in water and dyes FD&C, suspended in the hydrate of alumina, colorful lacquers and mixtures thereof. Colorful nail Polish is a combination of adsorbed water-soluble dye in water heavy metal oxide, which leads to the formation of the insoluble form of the dye. Flavors include natural flavors extracted from plants such as fruits, and synthetic blends of compounds which give a feeling of pleasant flavor, such as peppermint oil and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrups, glycerin and art is natural sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, gum Arabic, tragacanth gum, bentonite, and surfactants, such as polyoxyethylenesorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80) and triethanolamine. Suspendresume and dispersing agents include carboxymethylcellulose sodium, pectin, tragacanth gum, veegum, gum Arabic, carbometalation sodium, hypromellose and polyvinylpyrrolidone. Preservatives include glycerin, methyl - and propylparaben, benzoic acid, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, servicemanual, monolaurate diethylene glycol and polyoxyethylene lauric simple ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids used in emulsions include oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[0089] it Should be understood that many carriers and excipients can perform several functions, even in the same drug.

[0090] Developed in this invention the pharmaceutical compositions can be obtained in the form of compressed tablets, powdered tablets, jewelleryfashion, fast dissolving tablets, compressed tablets complicated patterns or tablets with enteric shell, tablets by the sugar-coated or film-coated. Tablets with enteric shell are pressed tablets with substances that are resistant to the action of acid in the stomach, but dissolve and break down in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Shell dissolution in the intestine include, but are not limited to specified, fatty acids, fats, fenilsalitsilat, waxes, shellac, ammonioalkyl shellac and acetamidate cellulose. Tablets with sugar shell are pressed tablets, surrounded by a coating of sugar, which can be useful for masking unpleasant taste or odour, and to protect the tablet from oxidation. Tablet film-coating are pressed tablets that are coated with a thin layer or film of a water-soluble material. Film coating include, but are not limited to specified, hydroxyethyl cellulose, carboxymethyl cellulose sodium, polyethylene glycol 4000 and acetated cellulose. Film coating give the same General features as the sugar coating. Pressed tablets of complex structure, not only is jut a pressed tablet, received more than one pressing cycle, including layered tablets and tablets with the extruded coating or a dry floor.

[0091] the Preformed preparative dosage forms can be obtained from the active ingredient in powdered, crystalline or granular form, by itself or in combination with one or more described here, carriers or excipients, including binders, dezintegriruetsja substances control release polymers, lubricants, diluents and/or dyes. Flavors and sweeteners are especially useful in obtaining chewable tablets and lozenges.

[0092] Developed in this invention the pharmaceutical compositions can be obtained in the form of soft or hard capsules, which can be made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsule, also known as the dry capsule filling (SOC)consists of two sections, one moving over the other, thus placing in the shell of the active ingredient. Soft elastic capsule (IEC) is a soft, spherical shell, such as gelatin shell which is plasticized by the addition of glycerin, sorbitol, or a similar polyhydric alcohol. Soft gelatin shell which may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are described herein, including methyl - and propylparaben and sorbic acid. Developed in this invention a liquid, semi-solid and solid preparative dosage forms can be enclosed in a capsule. Suitable preparative liquid and semi-solid dosage forms include solutions or suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be obtained, as described in U.S. patent No. 4328245; 4409239 and 4410545. Capsules can also be coated, as is known to the person skilled in the art, to modify or maintain the dissolution of the active ingredient.

[0093] Developed in this invention the pharmaceutical compositions can be obtained in preparative liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsion is a two-phase system in which one liquid is dispersed as small globules in another liquid, and can be an oil-in-water or water-in-oil. The emulsion can include pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent and preservative. Suspension may include pharmaceutically acceptable suspendisse agent and preservative. Water distilling plants the ora may include pharmaceutically acceptable acetal, such as di(lower alkyl)acetal lower alkyl aldehyde, for example, diethylacetal acetaldehyde; and miscible with water, the solvent having one or more hydroxyl groups such as propylene glycol and ethanol. Elixirs are transparent and sweetened water-alcohol solution. Syrups are concentrated aqueous solutions of sugar, for example sucrose, and may also contain a preservative. Liquid preparative dosage form, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of pharmaceutically acceptable liquid carrier, e.g. water, to be able to conveniently measure in the introduction.

[0094] Other used preparative liquid and semi-solid dosage forms include, but are not limited to the specified form, containing developed in this invention the active ingredient(s) and dialkylamines mono - or poly-allenglish including, 1,2-dimethoxymethane, diglyme, trislim, tetralin, dimethyl ether of polyethylene glycol-350, dimethyl ether of polyethylene glycol-550, dimethyl ether of polyethylene glycol-750, where the numbers 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. These drugs may additionally include one or more antioxidants, such as botilony hydroc toluol (BHT), botilony hydroxyanisol (BHA), propylgallate, vitamin E, hydroquinone, getcustomerid, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamate.

[0095] Developed in this invention pharmaceutical compositions for oral administration can be presented as liposomes, micelles, microspheres or nanosystems. Micellar formulation of the dosage form can be obtained as described in U.S. patent No. 6350458.

[0096] Developed in this invention the pharmaceutical compositions can be obtained in the form of nishiuchi or effervescent granules and powders for conversion to preparative liquid dosage form. Pharmaceutically acceptable carriers and excipients used in nishiuchi granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include an organic acid and a source of carbon dioxide.

[0097] the colors and flavors can be used in all of the above preparative dosage forms.

[0098] Developed in this invention the pharmaceutical compositions can be obtained in the form of formamidine or modified release including slow-motion, continuous, pulsed, controlled, directed and programmed release.

[0099] the Formulation developed in this invention the pharmaceutical compositions may be formulated together with other active ingredients which do not reduce the desired therapeutic action, or with substances that Supplement the desired action.

B. Injecting

[0100] Developed in this invention the pharmaceutical compositions can be entered parenterally by injection, infusion or implantation, for local or systemic administration. Parenteral administration, as the term is used in this description, includes intravenous, intraarterial, intraperitoneal, vnutrishkolnoe, vnutrepenialnymi, vnutriuretralnami, vnutrigrudne, intracranial, intramuscular, nutricionales, vnutrivaginalno and subcutaneous administration.

[0101] Developed in this invention the pharmaceutical compositions can be obtained in the form of any preparative dosage forms suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for obtaining solutions or suspensions in liquid prior to injection. Such preparation the e dosage forms can be obtained in accordance with customary methods, well-known specialists in the field of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).

[0102] the Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, water media, mixed water media, non-aqueous media, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, enhancers solubility, isotonic agents, buffering agents, antioxidants, local anesthetics, suspendresume and dispersing agents, wetting and emulsifying agents, complexing agents, insulating and chelating agents, cryoprotectants, bioprotector, thickeners, regulating pH agents and inert gases.

[0103] Suitable aqueous carriers include, but are not limited to specified, water containing salt solution, saline or phosphate buffered saline (PBS), sodium chloride solution for injection, ringer's solution for injection, isotonic dextrose injection, sterile water for injection containing dextrose and lactate ringer's solution for injection. Non-aqueous carriers include, but are not limited to a specified, fixed vegetable oils, castor oil is, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, gidrirovannoe soybean oil and triglycerides of medium length coconut oil and palm oil (seed). Mixed water media include, but are not limited to specified, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g. polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide and dimethylsulfoxide.

[0104] Suitable antibacterial agents and preservatives include, but are not limited to specified, phenols, Cresols, mercury drugs, benzyl alcohol, chlorobutanol, methyl - and propyl-p-hydrocyanate, thimerosal, benzalkonium chloride (e.g., chloride benzene) methyl - and propylparaben and sorbic acid. Suitable isotonic agents include, but are not limited to specified, sodium chloride, glycerin and dextrose. Suitable buffering agents include, but are not limited to specified, phosphate and citrate. Suitable antioxidants are mentioned in this description, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to the above, the hydrochloride, procaine. Suitable suspendresume and dispersing agents is predstavlyaet a given in this description, including carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Suitable emulsifying agents include specified herein, including polyoxyethylenesorbitan monolaurate, polyoxyethylenesorbitan monooleate 80 and triethanolamine. Suitable insulating or chelating agents include, but are not limited to specified, EDTA. Suitable regulating pH agents include, but are not limited to specified, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include, but are not limited to specified, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydrocerol-β-cyclodextrin, sulphobutylether β-cyclodextrin, sulfobutyl simple ether 7--β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

[0105] Developed in the present invention compositions can be obtained for administration in the form of single or multiple dosages. Drugs, containing a single dosage can be packaged in an ampoule, a vial or a syringe. Parenteral preparations containing multiple doses should contain an antibacterial agent in bacteriostatic or fungistatic concentrations. All parenteral drugs should be sterile, as is known and practiced in the field.

[0106] In one embodiment, the Khujand the exercise of, the pharmaceutical compositions obtained as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions obtained as a sterile dry soluble products, including liofilizovannye powders and tablets for subcutaneous injection, moisture content which restore using media before use. In another embodiment, the pharmaceutical compositions obtained as ready-to-use sterile suspensions. In another embodiment, the pharmaceutical compositions obtained as a sterile dry insoluble products, moisture content which restore using media before use. In the following embodiment, the pharmaceutical compositions obtained as ready-to-use sterile emulsions.

[0107] Developed in this invention the pharmaceutical compositions can be obtained in the form of immediate or modified release, including delayed -, sustained, pulsed, controlled, directed and programmed release.

[0108] the Pharmaceutical compositions can be obtained in the form of a suspension, a solid, semi-solid substances, or thixotropic liquid for administration as an implanted depot. In one embodiment, the wasp is estline developed in this invention the composition is dispersed in a solid inert matrix, which is surrounded by the outer polymeric membrane, which is not soluble in body fluids, but gives you the ability to diffuse through it to the active ingredient of pharmaceutical compositions.

[0109] Suitable internal matrix include polymethylmethacrylate, polybutylmethacrylate, plasticized or not plasticized polyvinyl chloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, copolymers of ethylene and vinyl acetate, silicone rubber, polydimethylsiloxane, siliconcarbide copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate.

[0110] Suitable external polymeric membranes include polyethylene, polypropylene, copolymers of ethylene/propylene, copolymers of ethylene/acrylate, copolymers of ethylene/vinyl acetate, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate, boutelou rubber, epichlorohydrine rubber, copolymer of ethylene/vinyl alcohol, terpolymer ethylene/vinyl acetate/vinyl, spirti copolymer of ethylene/vinylacetate.

C. Local introduction

[0111] Developed in this invention the pharmaceutical compositions can be applied topically on the skin, the holes of the internal organs or mucosa. Local introduction, as it is used herein, includes (inside)skin, conjunctive vnutrirodovoe, intraocular, ophthalmic, ear, cutaneous, nasal, vaginal, urethral, respiratory and rectal administration.

[0112] Developed in this invention the pharmaceutical compositions can be obtained in the form of any preparative dosage forms suitable for local injection for local or systemic action, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, apadravya powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, solutions for douching, sprays, suppositories, bandages, dermal patches. Local drugs developed in this invention the pharmaceutical compositions also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0113] Pharmaceutically acceptable carriers and excipients for use in local drugs developed in this invention include, but are not limited to the above, the water-carriers, miscible with water carriers, non-aqueous baranoski and, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, enhancers solubility, isotonic agents, buffering agents, antioxidants, local anesthetics, suspendresume and dispersing agents, specialsee or emulsifying agents, complexing agents, insulating or chelating agents, amplifiers permeability, cryoprotectants, bioprotector, thickeners and inert gases.

[0114] the Pharmaceutical compositions can also enter the local image using electroporation, iontophoresis, phonophoresis, sonophoresis, or using a microneedle or without needle injection, such as, for example, POWDERJECTTM(Chiron Corp., Emeryville, CA), and BIOJECTTM(Bioject Medical Technologies Inc., Tualatin, OR).

[0115] Developed in this invention the pharmaceutical compositions can be obtained in the form of ointments, creams and gels. Suitable carriers for ointments include oil or hydrocarbon carriers, including lard, betonirovannoy lard, olive oil, cottonseed oil and other oils, medical petrolatum, emulsifying or absorbent carriers, such as hydrophilic vaseline, hydroxystanozolol and anhydrous lanolin, removes water carriers, such as hydrophilic ointment; water-soluble carriers for ointments, including glycols with different molecular weight; amylcinnamaldehyde, or emulsion water-in-oil (W/M), or emulsion oil-in-water (M/V), including cetyl alcohol, glycerylmonostearate, lanolin and stearic acid (see Remington: The Science and Practice of Pharmacy, supra). The data vectors are softening means, but typically require the addition of antioxidants and preservatives.

[0116] Suitable basis for the cream can be emulsion oil-in-water or water-in-oil. Vectors cream can be washed off with water and contain an oil phase, an emulsifier and the aqueous phase. The oil phase is also called the "inner" phase, which is usually comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although this is not mandatory, exceeds the volume of the oil phase usually contains a humidifier. The emulsifier in a cream can be a nonionic, anionic, cationic or amphoteric surface-active substance.

[0117] the Gels are semisolid systems suspension type. Single-phase gels contain organic macromolecules distributed essentially uniformly in the liquid medium. Suitable gelling agents include crosslinked polymers of acrylic acid, such as carbomer, carboxypolymethylene, CARBOPOL®; hydrophilic polymers such as poecilonotini, copolymers of polyoxyethylene-polyoxypropylene and polyvinyl Speer is; cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate and gelatin. To obtain a homogeneous gel can be added dispersing agents such as alcohol and glycerin, or the gelling agent can be distributed by trituration, mechanical mixing and/or stirring.

[0118] Developed in the present invention compositions can be entered rectal, urethral, vaginal or perivaginal in the form of suppositories, pessaries, suppositories, poultices or dry poultices, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. Data preparative dosage forms can be produced using conventional methods, as described in Remington: The Science and Practice of Pharmacy, see above.

[0119] Rectal, urethral and vaginal suppositories are solid products for insertion into the holes of the body, which are solid at ordinary temperature but which melt or soften at body temperature, releasing the active(s) ingredient(s) inside the holes. Pharmaceutically acceptable carriers used in rectal is vaginal suppositories, include bases or carriers, such as giving rigidity agents, which provide a melting temperature in the region of body temperature and which enter into the composition developed in this invention pharmaceutical compositions, antioxidants described herein, including bisulfite and sodium metabisulfite. Suitable vectors include, but are not limited to specified, cocoa butter (dimethylxanthine oil), glycerin-gelatin, karbowski (polyoxyethyleneglycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di - and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethylmethacrylate, polyacrylic acid; glycerol gelatin. You can use a combination of different vectors. Rectal and vaginal suppositories can be obtained by pressing or molding. Typical weight rectal and vaginal suppositories is from about 2 to about 3,

[0120] Developed in this invention the pharmaceutical composition can be applied ophthalmologist in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for obtaining solutions, gels, eye inserts and implants.

[0121] Developed in this invention the pharmaceutical compositions can be entered vnutripuzarno or panostandalone in the respiratory tract. The pharmaceutical compositions can be obtained in the form of an aerosol or solution for the delivery of the pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to obtain the smallest aerosol or nebulizer, by themselves or in combination with a suitable propellant, such as 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3,3-Heptafluoropropane. Pharmaceutical compositions can also be obtained in the form of a dry powder for insufflation, alone or in combination with an inert carrier such as lactose, or a phospholipid; and nasal drops. For vnutripuzarnogo application of the powder may include bioadhesive agent, including chitosan, or a cyclodextrin.

[0122] the Solutions or suspensions for use in a pressurized container, pump, spreeta the atomizer, the atomizer or nebulizer can be obtained with a content of ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilization or prolonged allocation contained active ingredient of the propellant as the solvent and/or surfactant, such as sorbifolia, oleic acid or oligobrachia acid.

[0123] Developed in this invention the pharmaceutical composition can be crushed in microdisperse state size, suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of this size can be obtained using the method of grinding, known to specialists in this field, such as grinding in a spiral jet mill, grinding in a vortex mill with the liquefied layer, the processing in supercritical fluids for the formation of nanoparticles, homogenization under high pressure or spray drying.

[0124] Capsules, blisters and cartridges for use in an inhaler or insufflator can be obtained in such a way that they contained a powdery mixture developed in the invention pharmaceutical compositions, a suitable powder base such as lactose or starch; and the modifier operational properties, such as l-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. Developed in this invention is a pharmaceutical composition for inhalation/vnutripuzarnogo introduction can optionally contain suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.

[0125] R is srabotannye the present invention pharmaceutical compositions for topical application can be obtained for immediate release or modified release, including slow-motion, continuous, pulsed, controlled, targeted and programmed release.

D. Modified release

[0126] Developed in this invention the pharmaceutical compositions can be obtained in preparative dosage forms with modified release. As used herein, the term "modified release" refers to preparative dosage form, in which the rate or place of release of the active(s) ingredient(s) is different from that of preparative dosage form immediate release with the introduction of the same way. Preparative pharmaceutical form modified release include preparative dosage form delayed, delayed, prolonged, continuous, pulsed, controlled, accelerated and rapid, directional, programmable release and held in the stomach. Pharmaceutical compositions in preparative dosage forms of the modified release can be obtained using a variety of devices modified release and methods known to experts in this field, including, but not limited to, devices with a matrix-controlled release device is istwa with osmotically controlled release, consisting of many particles of a controlled release device, ion exchange resin, soluble in intestinal membranes, multilayer membranes, microspheres, liposomes, and combinations thereof. The rate of release of active ingredient(s) also can be modified by changing the particle size and polymorphism of active(s) ingredient(s).

[0127] Examples of modified release include, but are not limited to these described in U.S. patents№№: 3845770; 3916899; 3536809; 3598123; 4008719; 5674533; 5059595; 5591767; 5120548; 5073543; 5639476; 5354556; 5639480; 5733566; 5739108; 5891474; 5922356; 5972891; 5980945; 5993855; 6045830; 6087324; 6113943; 6197350; 6248363; 6264970; 6267981; 6376461; 6419961; 6589548; 6613358 and 6699500.

1. Matrix-controlled device release

[0128] Developed in this invention the pharmaceutical composition formulations pharmaceutical form modified-release can be fabricated using a matrix controlled device release, known to specialists in this field (see Takada et al. in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz Ed., Wiley, 1999).

[0129] In one embodiment, is developed in this invention the pharmaceutical composition formulations pharmaceutical form modified-release is obtained using erodirovannogo matrix device, which is nabukenya in the de, erodium or soluble polymers, including synthetic polymers, and natural polymers and their derivatives, such as polysaccharides and proteins.

[0130] the Materials used for education erodium matrix include, but are not limited to specified, chitin, chitosan, dextran and pullulan, agar gum, gum Arabic, Karay gum, gum carob, tragacanth gum, carrageen, gum, ghatti, guar gum, xanthan gum and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulose, such as ethylcellulose (EC), metilcellulose (YEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (SCE), hydroxypropylcellulose (GOC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), acetate-butyrate cellulose (tsab), DAC, Central, hypromellose (HPMC), HPMCP, PMCAS, acetate trimellitate hydroxypropylmethylcellulose (GPSCAT) and metilgidroxiatilzelllozu (AGEC); polyvinylpyrrolidon; polyvinyl alcohol; polyvinyl acetate; esters of glycerol and fatty acids; polyacrylamide; polyacrylic acid; copolymers metacrilato and methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactide; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable copolymers of lactic acid-glycolic acid; poly-D-(-)-3-hydroxybutanoic acid; and other derivatives of acrylic acid, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

[0131] In the following embodiments, the implementation of the pharmaceutical composition is obtained using aerodinamico matrix devices. Active(s) ingredient(s) dissolved or dispersed in an inert matrix, and they are released primarily by diffusion through an inert matrix after injection. Materials suitable for use in neurocinema matrix device include, but are not limited to specified, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinyl chloride, copolymers of methyl acrylate and methyl methacrylate, copolymers of ethylene and vinyl acetate, copolymers of ethylene/propylene, copolymers of ethylene/acrylate, copolymers of vinyl chloride with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate, bucilina rubber, epichlorhydrin rubber, copolyme the s ethylene/vinyl alcohol, terpolymer ethylene/vinyl acetate/vinyl alcohol copolymer ethylene/vinylacetate, polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, silicone rubber, polydimethylsiloxane, siliconcarbide copolymers and hydrophilic polymers, such as ethylcellulose, cellulose acetate, crosspovidone and cross-linked partially hydrolyzed polyvinyl acetate, and fatty compounds, such as Carnauba wax, microcrystalline wax, and triglycerides.

[0132] In matrix systems for the controlled release of the desired release kinetics can be controlled, for example, by the type of polymer, the viscosity of the polymer, the particle size of the polymer and/or active(s) ingredient(s), the ratio of active(s) ingredient(s) relative to the polymer and other excipients or carriers in the compositions.

[0133] Developed in this invention the pharmaceutical composition formulations pharmaceutical form modified-release can be obtained by methods known to experts in this field, including direct compression, dry or wet granulation followed by pressing, granulation in the melt, followed by pressing.

2. The osmotic device for the controlled release

[0134] there is given in the second invention the pharmaceutical composition formulations pharmaceutical form modified-release can be obtained using the osmotic device for the controlled release including single-chamber system, two-chamber system, asymmetric membrane technology (AMT) and systems with displaced nucleus (ECS). Typically, such devices have at least two components: (a) the core which contains an active(s) ingredient(s); and (b) a semipermeable membrane with at least one inlet. Semipermeable membrane controls the flow of water to the core from an aqueous environment of use so as to cause the release by displacement through the inlet(s) hole(s).

[0135] in Addition to the active ingredient(s) the core of the osmotic device optionally includes an osmotic agent, which creates the driving force for transport of water from the environment of use in the core of the device. One class of osmotic agents are vodosnabzhenie hydrophilic polymers, which are also referred to as "osmopolitan" and "hydrogels", including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropyleneglycol (BCP), poly(2-hydroxyethylmethacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), copolymers of PVA/PVP copolymers of PVA/PVP with hydrophobic monomers, such kammermeier and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageen, hydroxyethylcellulose (SCE), hydroxypropylcellulose (GOC), hypromellose (HPMC), carboxymethylcellulose (CMC) and karboksimetilcelljuloza (kets), sodium alginate, polycarbophil, gelatin, xanthan gum and picostreamer sodium.

[0136] Another class of osmotic agents are cosmogeny, which are able to absorb water for influencing the osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmotic agents include, but are not limited to specified, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulfate; sugars such as dextrose, fructose, glucose, Inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sabotinova acid, sorbic acid, adipic acid, adetola acid, glutamic acid, p-toluensulfonate acid, succinic acid and tartaric acid; urea and mixtures thereof.

[0137] the Osmotic agents with different speed solution which deposits can be used to influence, how quickly the active(s) ingredient(s) originally delivered from preparative dosage forms. For example, amorphous sugars, such as MANNOGEMTMEZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to provide the desired therapeutic effect in the shortest time and the gradual and continuous release of the remaining portion to maintain a desired level of therapeutic or preventive actions throughout the extended period of time. In this case, the active(s) ingredient(s) is released with such speed, to replace the quantity of active ingredient which has been subjected to metabolism and withdrawn from the body.

[0138] the Core may also include a large variety of other excipients and carriers, as described herein, to enhance the effect of preparative dosage forms or to promote stability or handling.

[0139] the material used for the formation of semi-permeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives, which are permeable and insoluble in water at physiologically relevant pH, or become insoluble in water by chemical modification, such as stitching. Examples of podhodyashaya, used for the formation of coatings include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, acetate-butyrate cellulose (tsab), ethylcarbamate CA, DAC, methylcarbamate CA, succinate CA, acetate trimellitate cellulose (Central), dimethylaminoacetyl CA, ethylcarbonate CA, CHLOROACETATE CA, ethylacetat CA, methylsulfonate CA, butylsulfonyl CA, p-toluensulfonate CA, acetate agar, amylose triacetate, acetate, beta-glucan, triacetate, beta-glucan, dimethylacetal acetaldehyde, triacetate gum fruit carob, gidroksilirovanii ethylene-vinyl acetate, EC, PEG, BCPs, copolymers of PEG/BCP PTS SEC, GOC, CMC, CMAC, GPMC, HPMCP, PMCAS, GEMCUT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkene, polyethers, polysulfones, polyether sulfones, polystyrenes, polyvinylchloride, polyvinyl complex and ethers, natural waxes and synthetic waxes.

[0140] a Semi-permeable membrane may also be a hydrophobic microporous membrane, where the pores are essentially filled with gas and is not wetted by the water environment, but are permeable to water vapor, as described in U.S. patent No. 5798119. Such hydrophobic, what about permeable to water vapour membranes usually consist of hydrophobic polymers, such as polyalkene, polyethylene, polypropylene, polytetrafluoroethylene, derivatives of polyacrylic acid, polyethers, polysulfones, polyether sulfones, polystyrenes, polyvinylchloride, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0141] the Input(s) hole(s) in a semi-permeable membrane can be obtained after coating using mechanical or laser drilling. Input(s) hole(s) can also be obtained in situ by erosion stubs water-soluble material or due to rupture of the thinner portion of the membrane over the recesses in the kernel. In addition, the inlet can be obtained during the coating process, as in the case of asymmetric membrane membranes of the type described in U.S. patent No. 5612059 and 5698220.

[0142] the Total amount of the released active(s) ingredient(s) and the rate of release of the substance can be modulated due to the thickness and porosity of the semipermeable membrane, the composition of the nucleus and the number, size and position openings.

[0143] the Pharmaceutical compositions of the formulations dosage forms with osmotically controlled release can optionally include additional conventional excipients or carriers as described herein, to t the th, to facilitate performance or processing of the composition.

[0144] the Preparative dosage forms with osmotically controlled release can be obtained in accordance with conventional methods known to experts in this field (see Remington: The Science and Practice of Pharmacy, above; Santus and Baker, J. Controlled Release 1995, 55, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

[0145] In some embodiments, the implementation developed in this invention the pharmaceutical composition is manufactured in the form of preparative dosage forms with AMT controlled-release, which contains asymmetric osmotic membrane that coats a core comprising active(s) ingredient(s) and other pharmaceutically acceptable excipients or carriers. (See U.S. patent No. 5612059 and WO 2002/17918). Preparative dosage forms with AMT controlled-release can be obtained in accordance with conventional methods known to experts in this field, including direct compression, dry granulation, wet granulation and method of coating by immersion processing.

[0146] In some embodiments, the implementation developed in this invention the pharmaceutical compositions obtained as preparative Lakers the governmental form ESC-controlled-release, which includes an osmotic membrane that coats a core comprising active(s) ingredient(s), hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

3. Devices controlled release, consisting of many particles

[0147] Developed in this invention the pharmaceutical composition in the form of preparative pharmaceutical form modified-release can be obtained in the form of a controlled release device, consisting of many particles, which includes a multitude of particles, granules or pellets, ranging in size from about 10 microns to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm in diameter. So many particles can be obtained by methods known to experts in this field, including wet and dry granulation, extrusion/spheronization, roller compaction, melting-freezing and using the coating is sprayed on the embryonic nucleus. (See for example, Multiparticulate Oral Drug Delivery, Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology, Marcel Dekker: 1989).

[0148] Other excipients or carriers as described herein, can be mixed with pharmaceutical compositions to assist in the processing and the formation of multiple particles. The obtained particles themselves are the devices of the set of particles or they can be covered with various film-forming materials, such as enteric polymers, nabukenya in water and water-soluble polymers. Many of the particles may be further processed to obtain tablets or capsules.

4. Targeted delivery

[0149] Developed in this invention the pharmaceutical compositions can also be formulated in such a way as to be directed to a particular tissue, receptor, or in another area of the body of the subject being treated, including delivery systems based on liposomes released red blood cells and antibodies. Examples include, but are not limited to these U.S. patents№№ 6316652; 6274552; 6271359; 6253872; 6139865; 6131570; 6120751; 6071495; 6060082; 6048736; 6039975; 6004534; 5985307; 5972366; 5900252; 5840674; 5759542 and 5709874.

Applications

[0150] In one embodiment, the invention relates to a method for treatment, prevention or improvement of symptoms of disorders, diseases or conditions associated with CCR3, the subject, which includes an introduction to the subject a therapeutically effective amount developed in the invention compounds, for example, the compounds of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human the ESA.

[0151] In another embodiment, the invention relates to a method for treatment, prevention or improvement of symptoms of disorders, diseases or conditions, giving the response to the modulating CCR3 activity, subject, comprising administration to the subject a therapeutically effective amount developed in the invention compounds, for example, the compounds of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0152] in Another embodiment, the invention relates to a method for treatment, prevention or improvement of symptoms of disorders, diseases or conditions mediated recetaron CCR3, subject, comprising administration to the subject a therapeutically effective amount developed in the invention compounds, for example, the compounds of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0153] in Another embodiment, the invention relates to what the manual treatment prevention or improvement of symptoms associated with eosinophils disorders, diseases or conditions in a subject comprising administration to the subject a therapeutically effective amount developed in the invention compounds, for example, the compounds of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0154] In the following embodiment, the invention relates to a method for treatment, prevention or improvement of symptoms associated with basophils disorders, diseases or conditions in a subject comprising administration to the subject a therapeutically effective amount developed in the invention compounds, for example, the compounds of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0155] in Another embodiment, the invention relates to a method for treatment, prevention or improvement of symptoms associated with mast cell disorders, diseases or condition is of the subject, includes introduction to the subject a therapeutically effective amount developed in the invention compounds, for example, the compounds of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0156] in Another embodiment, the invention relates to a method for treatment, prevention or improvement of symptoms of inflammatory disease in a subject comprising administration to the subject a therapeutically effective amount developed in the invention compounds, for example, the compounds of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0157] Violations of the disease or condition being treated with the help of the developed in the invention compounds, for example, the compounds of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer include, but are not limited to specified, (1) inflammatory or allerg the ical diseases, including anaphylaxis and related hypersensitivity diseases, atopic dermatitis, urticaria, drug allergies, allergies to insect bites, food allergies (including coeliac disease and the like), and mastocytosis; (2) inflammatory bowel diseases, including Crohn's disease, ulcerative colitis, REIT and enteritis; (3) vasculitis and syndrome Bechet; (4) psoriasis and inflammatory dermatoses, including dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral cutaneous pathologies including derivatives of human papilloma virus, HIV or RSV (respiratory syncytial virus)bacterial, fungal and other parasitic skin diseases and cutaneous lupus erythematosus; (5) asthma and respiratory allergic diseases, including allergic asthma caused by exercise asthma, allergic rhinitis, otitis media, allergic conjunctivitis, associated with hypersensitivity lung diseases and chronic obstructive pulmonary disease; (6) autoimmune diseases, including arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, diabetes type I, bulbospinal palsy, multiple sclerosis, grave's disease and glomerulonephritis; (7) graft rejection (including rejection homotransplantation and reaction transpla the tat-versus-host), for example, rejection of transplanted skin, rejection of transplanted solid organ transplant rejection, bone marrow; (8) fever; (9) cardiovascular disorders, including acute heart failure, hypotension, high blood pressure, angina, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, a disease of the coronary arteries, restenosis, and vascular stenosis; (10) cerebral-vascular disorders, including traumatic brain injury, stroke, ischemic reperfusion injury and aneurysm; (11) cancer of the breast, skin, prostate, neck, uterus, ovaries, testicular, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid, blood, and lymphatic system; (12) fibrosis, a disease of the connective tissue and sarcoidosis, (13) a morbid state of the genitals and reproductive system, including erectile dysfunction; (14) gastrointestinal disorders, including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15) neurological disorders, including Alzheimer's disease; (16) sleep disorders, including insomnia, narcolepsy syndrome sleep apnea syndrome and picwik; (17) pain; (18) renal disorders; (19) eye diseases, the key glaucoma; and (20) infectious diseases, including HIV.

[0158] In some embodiments, implementation, disorder, disease or condition selected from the group consisting of asthma, allergic asthma caused by exercise asthma, allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, contact dermatitis, conjunctivitis, allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mastocytosis syndrome Hyper IgE, systemic lupus erythematosus, psoriasis, acne, multiple sclerosis, transplant rejection, reperfusion injury, chronic obstructive pulmonary disease syndrome Jurga-Strauss, sinusitis, basophilic leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, COPD (chronic obstructive pulmonary disease), arthritis, rheumatoid arthritis, psoriatic arthritis and osteoarthritis.

[0159] In some embodiments, implementation, disorder, disease or condition is an asthma caused by physical activity, asthma, allergic rhinitis, atopic dermatitis, chronic obstructive pulmonary disease or allerg the ical conjunctivitis.

[0160] In some embodiments, implementation, disorder, disease or condition is an inflammatory or immunoregulative disease. In some embodiments, implementation, disorder, disease or condition is a asthma, rhinitis, allergic disease or autoimmune pathology. In some embodiments, implementation, disorder, disease or condition is a HIV, lung granuloma or Alzheimer's disease.

[0161] In various embodiments, the implementation of the methods of treatment of the above disorders, diseases or conditions include treatment of the subject with a pharmaceutical composition comprising developed in the invention, the connection, for example, the compound of formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer in combination with one or more pharmaceutically acceptable excipients or carriers.

[0162] depending on the violation, the disease or condition to treat and condition of the subject, developed in the invention, the compounds or pharmaceutical compositions can be introduced through oral, parenteral (for example, intramuscularly, intraperitoneally, intravenously, intracerebrally using vnutriuretralnami injection or infusion, subcutaneous injection, or implant), in Aracinovo, nasal, vaginal, rectal, sublingual, or local (e.g., transcutaneous or local) routes of administration and can be obtained individually or together, in suitable dosage forms, with pharmaceutically acceptable excipients, carriers, auxiliary substances and carriers suitable for each of the pathways of introduction. The invention relates to the introduction developed in the invention compounds or compositions in the form of depo-preparations in which the active ingredient is released over a certain period of time.

[0163] For the treatment, prevention or improvement of one or more symptoms of asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer or other conditions, disorders or diseases associated with receptor CCR3, a suitable dosage level generally ranges from about 0.001 to 100 mg per kg of body weight of the subject per day (mg/kg / day), from about 0.01 to about 75 mg/kg in day, from about 0.1 to about 50 mg/kg / day, from about 0.5 to about 25 mg/kg / day or from about 1 to about 20 mg/kg / day, which can be entered into the IDE single or multiple dosages. Within this range the dosage may range from about 0.005 to about 0.05, from about 0.05 to about 0.5, from about 0.5 to about 5.0 and from about 1 to about 15, from about 1 to about 20, or from about 1 to about 50 mg/kg / day. In some embodiments, the implementation, the level of dosage ranges from about 0.001 to about 100 mg/kg / day. In some embodiments, the implementation, the dose level ranging from about 0.01 to about 75 mg/kg / day. In some embodiments, the implementation, the level of dosage ranges from about 0.1 to about 50 mg/kg / day. In some embodiments, the implementation, the dose level ranging from about 0.5 to about 25 mg/kg / day. In some embodiments, the implementation, the level of dosage ranges from about 1 to about 20 mg/kg / day.

[0164] For oral administration developed in the invention compositions can be obtained in the form of tablets containing about 1.0 to about 1000 mg of the active ingredient, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900 and about 1000 mg of the active ingredient for the symptomatic adjustment dosage for the patient p is vergemoli treatment. The pharmaceutical compositions can be entered in the mode from 1 to 4 times a day, including one, two, three times and four times a day.

[0165] it Should however be understood that the specific dose level and frequency of the dose for any particular patient may vary and will depend on factors including the activity of the specific compound, the metabolic stability and length of action of this compound, the age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the owner, being treated.

[0166] the present invention Also relates to methods of modulating CCR3 activity, comprising contacting the receptor CCR3 with the invention the connection, for example, a compound of formula Ia, formula I or formula II, including its enantiomer, mixture of enantiomers, a mixture of two or more diastereomers, tautomer or a mixture of two or more tautomers, or pharmaceutically acceptable salt, MES, hydrate or prodrug. In one embodiment, the receptor CCR3 is expressed by the cell.

[0167] Developed in this invention compounds, for example, the compound of formula Ia, formula I or formula II, or its pharmaceutically acceptable salt, MES, hydrate, wiped isomer or tautomer, can also be combined and used in combination with other agents used in the treatment, prevention or to improve one or more symptoms of disorders, diseases or conditions in which you can use designed in the invention compounds, including asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer, infectious diseases, and the above-mentioned pathology.

[0168] In some embodiments, the implementation developed in this invention the compounds may be combined with one or more steroid drugs are known in this field, including, but not limited to the specified group, including aldosterone, beclomethasone, betamethasone, hypertension acetate, fludrocortisone, hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone.

[0169] In some embodiments, implementation, developed in the invention compounds can be combined with one or more antibacterial agents known in this field, including, but not limited to, the group including amikacin, and oxacillin, ampicillin, arsphenamine, azithromycin, aztreonam, azlotillin, bacitracin, carbenicillin, cefaclor, cephalo-Smoking, cefamandole, Cefazolin, cephalexin, cefdinir, cefditoren, cefepime, cefixime, cefoperazone, Cefotaxime, tsefoksitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, Ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clindamycin, cloxacillin, colistin, dalfopristin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, ertapenem, ethambutol, Flucloxacillin, fosfomicin, furazolidone, Gatifloxacin, gagamitin, gentamicin, herbimycin, imipenem, isoniazid, kanamycin, levofloxacin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, Meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oxytetracycline, penicillin, piperacillin, platensimycin, polymyxin b, prontosil, pyrazinamide, quinupristin, rifampin, roxithromycin, spectinomycin, streptomycin, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, tetracycline, tikarcillin, tobramycin, trimethoprim, troleandomycin, trovafloxacin and vancomycin.

[0170] In some embodiments, implementation, developed in the invention compounds may be joint who are satisfied with one or more antifungal agents, known in this field, including, but not limited to, the group consisting of amorolfine, amphotericin b, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, Itraconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxiconazole, ravuconazole, Posaconazole, rimoldi, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole and voriconazole.

[0171] In some embodiments, implementation, developed in the invention compounds can be combined with one or more anticoagulants, known in this field, including, but not limited to, the group comprising acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin and ximelagatran.

[0172] In some embodiments, implementation, developed in the invention compounds can be combined with one or more thrombolytic drugs, known in this field, including, but not limited to, the group comprising anistreplase, reteplase, t-RA (activase alteplase), streptokinase, tenecteplase and urokinase.

[0173] In some embodiments, implementation, developed in the invention compounds can be combined with one or more nonsteroidal protivovospalitel the entrusted agents, known in this field, including, but not limited to, aceclofenac, acemetacin, aloxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, helenmary salicylate, diclofenac, diflunisal, etodolac, etoricoxib, filamin, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, Ketoprofen, Ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, marennikova acid, meloxicam, Metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylsalicylic, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, tolmetin.

[0174] In some embodiments, implementation, developed in the invention compounds can be combined with one or more antiplatelet agents, known in the field, including, but not limited to, abciximab, Cilostazol, clopidogrel, dipyridamole, ticlopidine and tirofiban.

[0175] Developed in this invention compounds can also be entered in combination with other classes of compounds, including, but not limited to, inhibitors of endothelin converting enzyme (ECE), such as phosphoramidon; antagonists thromboxane receptor, such as petrobas; modulators of potassium channels; inhibi the ora of thrombin, such as hirudin; inhibitors of growth factor, such as modulators of the activity of the PDGF; antagonists of platelet-activating factor; antiplatelet agents, such as blockers GPIIb/IIIa (e.g., abciximab, eptifibatide, and tirofiban), P2Y antagonists(AC) (e.g., clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, such as warfarin; heparin, low molecular weight, such as enoxaparin; inhibitors of factor VIIa and factor Xa inhibitors; renin inhibitors; inhibitors of neutral endopeptidase (NEP); inhibitors of vasopeptidase (dual inhibitors of NEP-ACE)such as omapatrilat and gemopatrilat; inhibitors of HMG CoA reductase, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nicastrin or nicastrin) and ZD-4522 (also known as rosuvastatin, itavastatin or visitation); inhibitors stvalentines; fibrates; substances that increase the excretion of bile acids, such as questran; Niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP inhibitors; calcium channel blockers such as amlodipine; activators of potassium channels; alpha-adrenergic agents; beta-adrenergic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide Ben is roflumilast, methylchlorothiazide, trichlormethiazide, polythiazide, benzothiazyl, ethacrynic acid, ticrynafen, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride and spironolactone; thrombolytic agents such as plasminogen the tissue activator (tPA), recombinant tPA, streptokinase, urokinase, the PUK and Antilibanus complex activator plasmonpolariton (APSAC); anti-diabetic agents such as biguanides (e.g. Metformin), glucosidase inhibitors (e.g. acarbose), insulin, meglitinide (for example, Repaglinide), sulfonylureas (e.g., glimepiride, glyburide and glipizide), thiazolidinedione (for example, troglitazone, rosiglitazone and pioglitazone) and agonists of PPAR-gamma; antagonists mineralocorticoid receptor, such as spironolactone and eplerenone; stimulators of growth hormone secretion; aP2 inhibitors; phosphodiesterase inhibitors, such as inhibitors of PDE III (for example, Cilostazol) and inhibitors of PDE V (e.g., sildenafil, tadalafil and vardenafil); inhibitors proteincontaining; anti-inflammatory agents, antiproliferative agents such as methotrexate, FK506 (tacrolimus), mycophenolate mofetil; chemotherapeutic agents; immunosuppressant; anticancer agents and cytotoxic agents (e.g., alkylating agents, such as chlormethine, alkyl sulphonates, nitrosoanatabine, ethyl is niminy and triazine); antimetabolites, such as volatie antagonists, purine analogues, and pyrimidine analogues; antibiotics such as anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; enzymes such as L-asparaginase; inhibitors farnesyl-proteincenter; hormonal agents such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and antagonists of luteinizing hormone-releasing hormone and octreotidesee; destructive microtubule agents such as ecteinascidins; stabilizing microtubule agents such as paclitaxel, docetaxel and epothilones A-F; products of vegetable origin, such as the Vinca alkaloids, epipodophyllotoxins and taxanes; and topoisomerase inhibitors; inhibitors prenyl-proteincenter; cyclosporin a; steroids such as prednisone and dexamethasone; cytotoxic drugs, such as azathioprine and cyclophosphamide; inhibitors of TNF-alpha, such as tenidap; antibodies against TNF or soluble TNF receptors, such as etanercept, rapamycin, and Leflunomide; and inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib and rofecoksib; and mixed agents, such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine; gold compounds, coordination complexes of platinum, such as cisplatin, satraplatin and CT is Platin.

[0176] Such other agents or drugs can be entered by using the route of administration and in quantities normally used for them, simultaneously or sequentially with the invention compounds, for example, a compound of formula Ia, formula I or formula II, including a single enantiomer, mixture of enantiomers, or a mixture of diastereomers; or its pharmaceutically acceptable salt, MES or prodrug. When developed in the invention the connection is used simultaneously with one or more other drugs, you can use a pharmaceutical composition containing such other drugs in addition to developed in the invention, but it is not mandatory. Accordingly, developed in this invention the pharmaceutical compositions include those that also contain one or more other active ingredients or therapeutic agents, in addition to the developed invention for the connection.

[0177] the Weight ratio developed in the invention the connection to the second active ingredient may vary and will depend upon the effective dose of each ingredient. Typically, you will use the effective dose of each of them. For example, when developed in the invention, the connection combined with NSPs, Novoe the ratio of connections to NSPs can range from about 1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinations developed in the invention compounds and other active ingredients will generally also be within the aforementioned range, but in each case you should use an effective dose of each active ingredient.

[0178] Developed in this invention, the connection can also be provided in the form of product production using packaging materials that are well known to specialists in this field. (See, for example, U.S. patent No. 5323907; 5052558 and 5033252). Examples of pharmaceutical packaging materials include, but are not limited to specified, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for the selected drug and the proposed route of administration and treatment.

[0179] the Present invention also relates to kits that are using the practitioner can facilitate the introduction of the subject of appropriate amounts of active ingredients. In some embodiments, the implementation developed in this invention, the kit includes a container and preparative dosage form developed in the invention compounds, for example, the compounds of formula Ia, formula I or formula II or its pharmaceutically acceptable salt, MES, hydrate, Stere the isomer or tautomer.

[0180] In some embodiments, the implementation, the kit includes a container containing preparative dosage form developed in the invention compounds, for example, the compounds of formula Ia, formula I or formula II or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer, the container contains one or more other therapeutic agents mentioned in this description.

[0181] Developed in this invention, the kits may further include devices that are used to introduce active ingredients. Examples of such devices include, but are not limited to the above, the syringe, without needle injection packages for droppers, patches and inhalers. Developed in this invention, the kits may also include condoms for the introduction of active ingredients.

[0182] Developed in this invention, the kits can optionally include pharmaceutically acceptable carriers that can be used for introducing one or more active ingredients. For example, if the active ingredient is in solid form, moisture content which must be restored for parenteral administration, the kit may include a hermetically sealed container with a suitable carrier which can be dissolved active ingredient formed for the I not containing particles of a sterile solution, which is suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to the specified water carriers, including, but not limited to, water for injection, corresponding to the Pharmacopoeia of the United States, the sodium chloride solution for injection, ringer's solution for injection, dextrose injection, dextrose and sodium chloride for injection and lactate ringer's solution for injection; miscible with water carriers, including, but not limited to, ethyl alcohol, polyethylene glycol and polypropyleneglycol; and non-aqueous media, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, etiloleat, isopropylmyristate and benzyl benzoate.

[0183] a Description will be further understood by the following non-limiting examples.

EXAMPLES

[0184] As used herein, the symbols and conventions used in these ways, the schemes and the examples, regardless of whether specifically defined certain reduction, match those used in the contemporary scientific literature, for example, in the journal of the American chemical society (Journal of the American Chemical Society or the journal of biological chemistry Journal of Biological Chemistry). In particular, but without the exhaust gas is anichini, the following abbreviations may be used in the examples and throughout the text of this specification: g (grams); mg (milligrams); ml (milliliters); μl (Microlitre); mm (millimolar); μm (micromolar); nm (nanomolar); equiv. (equivalent); Hz (Hertz); MHz (megahertz); mmol (millimole); h or h (hours); min (minutes); MC (mass spectrometry); ESI (ionization method elektrorazpredelenie); TLC (thin layer chromatography); Rt(retention time); SiO2(silicon dioxide); THF (tetrahydrofuran); CDCl3(deuterated chloroform); DHM (dichloromethane); DMF (dimethylformamide); DMSO (dimethylsulfoxide); EtOAc (ethyl acetate); CHCl3(chloroform); DMF (N,N-dimethylformamide); MeOH (methanol); HCl (hydrochloric acid); LiOH (lithium hydroxide); MgSO4(magnesium sulfate); NaH (sodium hydride); NaOH (sodium hydroxide); NaHCO3(sodium bicarbonate); DIPEA (N,N-diisopropylethylamine); tea (triethylamine); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); CDI (carbonyldiimidazole); TBTU (tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea); Me (methyl); Et (ethyl); tBu (tert-butyl); Boc (tert-butoxycarbonyl); Bn (benzyl); TsO (toilet); DIAD (diisopropylcarbodiimide), DEAD (diethylazodicarboxylate), PPh3(triphenylphosphine), PNBA (p-nitrobenzoic acid) and PNB (p-nitrobenzoyl).

[0185] In all the following examples, you can use the standard methods of processing and purification, known special is the specialists in this field. Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). All reactions were carried out at room temperature unless otherwise stated. Illustrated in this description of the synthetic methodology is intended to illustrate applied chemistry for use in the specific examples and do not indicate the scope of the invention.

EXAMPLE 1

Obtaining the compound (9)

[0186] 1) preparation of 4-(3,5-dichlorophenylthio)-3-nitrobenzonitrile. - 3,5-Dichlorothiophene (11,772 g, 65,74 mmol) was dissolved in THF (80 ml), cooled in an ice bath was added NaH (2,629 g, 109,56 mmol). Thus obtained reaction mixture was stirred for 5 minutes, after which was added 4-chloro-3-nitrobenzonitrile (10,000 g, 54,78 mmol), then stirred additionally for 15 minutes and then heated to room temperature. After 3 days the reaction mixture are condensed in vacuo to remove organic solvent. The resulting suspension was filtered and the filtered solid washed with water, receiving the product as a yellow powder (17,200 g, 86.5% of purity according to HPLC, 96,6% yield).1H-NMR: (500 MHz, DMSO-d6) 8,77 (d, J=1 Hz, 1H), to 7.99 (DD, J1=8 Hz, J1=2 Hz, 1H), 7,89 (t, J1=J2=1 Hz, 1H), 7,80 (d, J=2 Hz, 2H), 7,13 (d, J=9 Hz, 1H).

[0187] 2) Obtaining 4-(3,5-dichlorophenylthio)-3-aminobenzonitrile. Hydro is unfit sodium (35,000 g, 201,02 mmol) was dissolved in minimum amount of water (150 ml)to which was added a solution of 4-(3,5-dichlorophenylthio)-3-nitrobenzonitrile (17,200 g, 52,90 mmol) in THF (200 ml). Thus obtained reaction mixture was heated and kept at 90°C for 18 hours, after which the volatile components were removed in vacuum. The separated solids were collected by filtration under pressure and washed with water, receiving the product as a yellow powder. (15,387 g, 93,3% purity according to HPLC, 98.5% of the output).1H-NMR: (500 MHz, DMSO-d6) 7,51 (d, J=8 Hz, 1H), 7,43 (t, J1=J2=1 Hz, 1H), 7,14 (d, J=1 Hz, 1H), 7,07 (d, J=1 Hz, 2H), of 6.96 (DD, J1=8 Hz, J2=2 Hz, 1H), 6,02 (s, 2H).

[0188] 3) Obtaining 5-cyano-2-(3,5-dichlorophenylthio)benzene-1-sulphonylchloride. - 4-(3,5-Dichlorophenylthio)-3-aminobenzonitrile (8,000 g, 27,10 mmol) suspended in a mixture consisting of 50 ml each of water and concentrated HCl, and then was cooled in an ice bath. To a stirred suspension of the acid was added dropwise a solution of sodium nitrite (5,610 g, 81,30 mmol) in 50 ml of water. Thus obtained reaction mixture was stirred for one hour in an ice bath. In a separate container SO2was barbotirovany in acetic acid (150 ml) for one hour, to which was then added chloride copper (II) (2,310 g, 13,55 mmol). A solution of copper (II) and then was stirred for 10 minutes, the solution became blue-green, indicating the comprehensive saturation. Blue-green reaction mixture was cooled in an ice bath. The first reaction mixture (solution diazocompounds) was added dropwise to the second reaction mixture (saturated acetic acid)through which there barbotirovany SO2. The source of gaseous SO2removed, thus obtained reaction mixture was stirred for one hour until gas evolution stops and then slowly poured the solution into the intensively stirred ice water. The resulting suspension is then filtered and the filtered solid washed with water, receiving the product as a yellow powder (6,850 g, 90% purity for1H NMR, 66,8% yield).1H-NMR: (500 MHz, DMSO-d6) with 8.05 (d, J=2 Hz, 1H), 7,72 (t, J1=J2=1 Hz, 1H), to 7.64 (DD, J1=8 Hz, J2=2 Hz, 1H), 7,54 (d, J=1 Hz, 2H), 6,97 (d, J=8 Hz, 1H).

[0189] 4) Obtaining the compound (9 - a Solution of 5-cyano-2-(3,5-dichlorophenyl-thio)benzene-1-sulphonylchloride (1,500 g of 3.96 mmol) in 20 ml of CH2Cl2was added dropwise with speed 0,200 ml/min to a stirred solution of 2-piperazinone (0,396 g of 3.96 mmol) and triethylamine (0,823 ml, 5,94 mmol) in 5 ml of CH2Cl2. Thus obtained reaction mixture was stirred for 17 hours, with a brown solution was formed a white precipitate. The solid was filtered and washed with a minimum amount of CH2Cl2getting joint is 9 in the form of a white powder (1,071 g, 92,3% purity according to HPLC, to 61.2% yield).1H-NMR: (500 MHz, DMSO-d6) to 8.34 (d, J=2 Hz, 1H), 8,13 (s, 1H), to 7.93 (DD, J1=8 Hz, J2=2 Hz, 1H), to 7.84 (t, J1=J2=2 Hz, 1H), of 7.75 (d, J=2 Hz, 2H), 7,14 (d, J=8 Hz, 1H), 3,90 (s, 2H), 3,60 (m, 2H), 3,21 (m, 2H). ESI-Mass spectrum: 414 (M+1)+.

EXAMPLE 2

Obtaining compounds 24

[0190] 1) preparation of 2-chloro-5-nitrobenzene-1-sulphonylchloride. To a solution of 2-chloro-5-nitroaniline (5,000 g, 28,97 mmol) in 45 ml of acetic acid was added 35 ml of HCl. The resulting solution was cooled in an ice bath and to it under stirring solution was added sodium nitrite (5,997 g, 86,91 mmol) in 15 ml of water. Thus obtained reaction mixture was stirred in an ice bath for 1 hour. In a separate container SO2was barbotirovany in acetic acid (40 ml). After 30 minutes, was added copper chloride (II) (1,435 g, 14,49 mmol), and the solution became dark blue-green, indicating full saturation. Blue-green reaction mixture was cooled in an ice bath. The first reaction mixture (solution diazocompounds) was added dropwise to the second reaction mixture (saturated acetic acid)through which there barbotirovany SO2. The source of gaseous SO2removed, thus obtained reaction mixture was stirred for one hour until gas evolution stops and then slowly poured into the solution in Encino stir the ice water. The resulting solution was then stirred until the ice melting and filtered, getting a pink powder. The powder was washed with plenty of water, getting the product as a pale pink powder. (4,902 g, 87.3 per cent purity according to HPLC, 66,2% yield).1H-NMR: (500 MHz, DMSO-d6) 8,61 (d, J=3 Hz, 1H), 8,16 (DD, J1=9 Hz, J2=3 Hz, 1H), of 7.70 (d, J=9 Hz, 1H).

[0191] 2) Obtaining 4-(2-chloro-5-nitrophenylacetic)thiomorpholine. To a solution of 2-chloro-5-nitrobenzene-1-sulphonylchloride (0,200 g, 0.78 mmol) in 8 ml of CH2Cl2added thiomorpholine (0,111 ml of 1.17 mmol) and triethylamine (rate £ 0.162 ml of 1.17 mmol). Thus obtained reaction mixture was stirred at room temperature for 18 hours and was purified column chromatography (8%-->15%-->20% EtOAc in hexano). The fractions containing the desired product were combined and are condensed in vacuo, then triturated with EtOAc and hexane. The solid was filtered, receiving the product as a pale yellow powder. (0,139 g, with 99.6% purity according to HPLC, 55.2% of the output).1H-NMR: (500 MHz, DMSO-d6) to 8.62 (d, J=3 Hz, 1H), of 8.47 (DD, J1=9 Hz, J2=3 Hz, 1H), 8,01 (d, J=9 Hz, 1H), 3,54 (m, 4H), to 2.65 (m, 4H).

[0192] 3) Obtaining the compound 24. A solution of 3,5-dichlorothiophene (0,047 g, 0.26 mmol) in 8 ml of THF was cooled in an ice bath. To this solution was added NaH (0,011 g, 0.44 mmol). The solution then was stirred for 5 minutes, after which was added 4-(2-chlorine is-5-nitrophenylacetic)thiomorpholine (0,0700 g, 0.22 mmol). Thus obtained reaction mixture was stirred for 10 minutes, heated to room temperature and then was stirred additionally for 18 hours. The reaction mixture are condensed in vacuo and triturated with EtOAc and hexane. The solids were filtered off, getting the product as a white powder (0,096 g, 97.1% of purity according to HPLC, 93.7% of the output).1H-NMR: (500 MHz, DMSO-d6) charged 8.52 (d, J=1 Hz, 1H), 8,29 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,88 (t, J1=J2=1 Hz, 1H), 7,78 (d, J=1 Hz, 2H), 7.23 percent (d, J=9 Hz, 1H)and 3.59 (m, 4H), 2,70 (m, 4H).

EXAMPLE 3

Physical characteristics

[0193] the following compounds were obtained by methods similar to the above for compounds 9 and 24.

[0194] the Compound 1 -1H-NMR: (500 MHz, DMSO-d6) by 8.22 (d, J=1 Hz, 1H), to $ 7.91 (DD, J1=7 Hz, J2=1 Hz, 1H), to 7.84 (t, J1=J2=1 Hz, 1H), 7,71 (d, J=1 Hz, 2H), 7,12 (d, J=8 Hz, 1H), 3,26 (m, 4H), and 1.56 (m, 4H), for 1.49 (m, 2H). ESI-Mass spectrum: 427 (M+1)+.

[0195] the Compound 2 -1H-NMR: (500 MHz, DMSO-d6) of 8.47 (d, J=8 Hz, 1H), 8,40 (DD, J1=7 Hz, J2=1 Hz, 1H), with 8.33 (d, J=1 Hz, 1H), 7,83 (t, J1=J2=1 Hz, 1H), of 7.75 (d, J=1 Hz, 2H), 3,19 (m, 4H), and 1.54 (m, 4H), of 1.46 (m, 2H). ESI-Mass spectrum: 358 (M+1)+.

[0196] the Compound 3 -1H-NMR: (500 MHz, DMSO-d6) 8,71 (d, J=8 Hz, 1H), 8,48 (DD, J1=7 Hz, J2=1 Hz, 1H), 8,42 (d, J=1 Hz, 1H), 8,03 (t, J1=J2=1 Hz, 1H), of 7.90 (d, J=1 Hz, 2H), 3.27 to (m, 4H), 1,50 (m, 6H), ESI-Mass spectrum: 45 (M+1) +.

[0197] the Compound 4 -1H-NMR: (500 MHz, DMSO-d6) 8,18 (d, J=1 Hz, 1H), a 7.85 (DD, J1=7 Hz, J2=1 Hz, 1H), 7.23 percent (s, 3H), 6,92 (d, J=8 Hz, 1H), 3,26 (m, 4H), 2,32 (s, 6H), and 1.56 (m, 4H), 1,50 (m, 2H). ESI-Mass spectrum: 343 (M+1)+.

[0198] the Compound 5 -1H-NMR: (500 MHz, DMSO-d6) 8,19 (d, J=2 Hz, 1H), a 7.85 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,22 (s, 3H), 6,93 (d, J=8 Hz, 1H), 3,78 (m, 2H), was 2.76 (m, 2H), 2,32 (s, 6H), by 1.68 (m, 2H), 1,49 (m, 1H), 1,13 (m, 2H), 0,89 (d, J=7 Hz, 3H). ESI-Mass spectrum: 441 (M+1)+.

[0199] the Compound 6 -1H-NMR: (500 MHz, DMSO-d6) 8,23 (d, J=1 Hz, 1H), 7,92 (DD, J1=7 Hz, J2=1 Hz, 1H), to 7.84 (s, 1H), 7,69 (s, 2H), 7,15 (d, J=8 Hz, 1H), of 3.77 (m, 2H), 2,78 (m, 2H), 1.69 in (m, 2H), 1,47 (m, 1H), 1,10 (m, 2H), from 0.88 (d, J=7 Hz, 3H). ESI-Mass spectrum: 441 (M+1)+.

[0200] the Compound of the 71H-NMR: (500 MHz, DMSO-d6) of 8.27 (d, J=1 Hz, 1H), 7,92 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,85 (t, J1=J2=1 Hz, 1H), 7,73 (d, J=1 Hz, 2H), 7,13 (d, J=8 Hz, 1H), 4,87 (m, 0,5H), 4,78 (m, 0,5H), 3,40 (m, 4H), of 1.94 (m, 2H), 1,79 (m, 2H). ESI-Mass spectrum: 335 (M+1)+.

[0201] the Compound 8 -1H-NMR: (500 MHz, DMSO-d6) 8 compared to 8.26 (d, J=1 Hz, 1H), to $ 7.91 (DD, J1=5 Hz, J2=1 Hz, 1H), to 7.84 (t, J1=J2=1 Hz, 1H), 7,68 (d, J=1 Hz, 2H), 7,14 (d, J=8 Hz, 1H), 3,74 (m, 2H), 2,32 (t, J1=J2=12 Hz, 2H), 1.70 to (m, 1H), 1,61 (m, 2H), 0,84 (d, J=7 Hz, 6H), of 0.68 (m, 1H). ESI-Mass spectrum: 455 (M+1)+.

[0202] the Compound 10 -1H-NMR: (500 MHz, DMSO-d6) 8,29 (d, J=1 Hz, 1H), 8,14 (s, 1H), 7,88 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,24 (s, 2H), 7,22 (s, 1H), 6,93 (d, J=8 Hz, 1H), 3,90 (s, 2H)and 3.59 (m, 2H), 3,20 (m, 2H), 2,32 (s, 6H). ESI-the ACC-range: 443 (M+1) +.

[0203] Compound 11 -1H-NMR: (500 MHz, DMSO-d6) of 8.33 (d, J=1 Hz, 1H), 8,13 (DD, J1=7 Hz, J2=1 Hz, 1H), 8,11 (s, 1H), EUR 7.57 (t, J1=J2=1 Hz, 1H), 7,40 (d, J=1 Hz, 2H), 7,30 (d, J=9 Hz, 1H), 3,81 (s, 2H), 3,52 (m, 2H), 3,11 (m, 2H). ESI-Mass spectrum: 467 (M+1)+.

[0204] the Compound 12 -1H-NMR: (500 MHz, DMSO-d6) 8,23 (s, 1H), 7,94 (d, J=10 Hz, 1H), a 7.85 (s, 1H), to 7.77 (s, 2H), 7,14 (d, J=8 Hz, 1H), 3,66 (m, 4H), of 3.27 (m, 4H). ESI-Mass spectrum: 369 (M+1)+.

[0205] the Compound 13 -1H-NMR: (500 MHz, DMSO-d6) compared to 8.26 (d, J=1 Hz, 1H), 7,92 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,85 (t, J1=J2=1 Hz, 1H), of 7.75 (d, J=1 Hz, 2H), 7,14 (d, J=8 Hz, 1H), to 3.58 (m, 4H), 2,68 (m, 4H).

[0206] the Compound 14 -1H-NMR: (500 MHz, DMSO-d6) to 8.34 (d, J=1 Hz, 1H), 7,94 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,85 (t, J1=J2=1 Hz, 1H), 7,79 (d, J=1 Hz, 2H), 7,16 (d, J=8 Hz, 1H), 3,84 (m, 4H), 3,29 (m, 4H). ESI-Mass spectrum: 475 (M-1)-.

[0207] Compound 15 -1H-NMR: (500 MHz, DMSO-d6) 8,19 (s, 1H), 7,88 (d, J=10 Hz, 1H), 7,26 (s, 2H), 7.23 percent (s, 1H), 6,94 (d, J=8 Hz, 1H), 3,66 (m, 4H), 3,26 (m, 4H), 2,33 (m, 6H). ESI-Mass spectrum: 343 (M+1)+.

[0208] the Compound 16 -1H-NMR: (500 MHz, DMSO-d6) by 8.22 (d, J=1 Hz, 1H), 7,87 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,24 (s, 2H), 7,22 (s, 1H), 6,94 (d, J=8 Hz, 1H), to 3.58 (m, 4H), 2,69 (m, 4H), 2,32 (s, 6H). ESI-Mass spectrum: 343 (M+1)+.

[0209] the Compound 17 -1H-NMR: (500 MHz, DMSO-d6) 8,30 (d, J=1 Hz, 1H), 7,89 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,26 (s, 2H), 7.23 percent (s, 1H), of 6.96 (d, J=8 Hz, 1H), 3,83 (m, 4H), 3,30 (m, 4H), 2,32 (s, 6H). ESI-Mass spectrum: 500 (M+1)+.

<> [0210] the Compound 18 -1H-NMR: (500 MHz, DMSO-d6) at 8.36 (s, 2H), 8,31 (s, 1H), compared to 8.26 (d, J=1 Hz, 1H), 7,92 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,14 (d, J=8 Hz, 1H), 3,66 (m, 4H), 3,29 (m, 4H).

[0211] the Compound of 191H-NMR: (500 MHz, DMSO-d6) of 8.33 (s, 2H), 8,30 (m, 2H), to $ 7.91 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,16 (d, J=8 Hz, 1H), 3,60 (m, 4H), 2,70 (m, 4H).

[0212] the Compound of the 201H-NMR: (500 MHz, DMSO-d6) of 8.37 (m, 3H), 8,31 (s, 1H), to 7.93 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,17 (d, J=8 Hz, 1H), 3,86 (m, 4H), 3,30 (m, 4H).

[0213] the Compound of the 211H-NMR: (500 MHz, DMSO-d6) 8,28 (d, J=1 Hz, 1H), 8,12 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,56 (t, J1=J2=1 Hz, 1H), 7,38 (d, J=1 Hz, 1H), 7,32 (d, J=9 Hz, 1H), 3,48 (m, 4H), to 2.65 (m, 4H).

[0214] the Connection of the 221H-NMR: (500 MHz, DMSO-d6) 8,24 (d, J=1 Hz, 1H), 8,03 (DD, J1=7 Hz, J2=1 Hz, 1H), 6,99 (m, 2H), 6,84 (s, 2H), 3,50 (m, 4H), to 2.65 (m, 4H), of 2.30 (s, 6H). ESI-Mass spectrum: 327 (M+1)+.

[0215] the Compound of the 231H-NMR: (500 MHz, DMSO-d6) of 8.33 (d, J=1 Hz, 1H), 8,14 (DD, J1=7 Hz, J2=1 Hz, 1H), EUR 7.57 (t, J1=J2=1 Hz, 1H), 7,42 (d, J=1 Hz, 2H), 7,33 (d, J=9 Hz, 1H), to 3.73 (m, 4H), 3,26 (m, 4H). ESI-Mass spectrum: 526 (M+1)+.

[0216] the Compound 25 -1H-NMR: (500 MHz, DMSO-d6) charged 8.52 (d, J=1 Hz, 1H), 8,27 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,27 (s, 2H), 7,24 (s, 1H),? 7.04 baby mortality (d, J=9 Hz, 1H)and 3.59 (m, 4H), 2,70 (m, 4H), of 2.33 (s, 6H). ESI-Mass spectrum: 363 (M+1)+.

[0217] Compound 26 -1H-NMR: (500 MHz, DMSO-d6) 8,29 (d, J=1 Hz, 1H), with 8.05 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,02 (d, J=9 Hz, 1H), 6,98 (s, 1H), 6,85 (s, 2H), and 3.7 (m, 4H), 3,26 (m, 4H), of 2.30 (s, 6H). ESI-Mass spectrum: 484 (M+1)+.

[0218] the Compound of the 271H-NMR: (500 MHz, DMSO-d6) 8,23 (d, J=1 Hz, 1H), 7,92 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,85 (t, J1=J2=1 Hz, 1H), of 7.70 (d, J=1 Hz, 2H), 7,14 (d, J=8 Hz, 1H)and 3.59 (m, 2H), 2.91 in (m, 1H), to 2.67 (m, 3H), 2,32 (m, 1H), and 2.26 (m, 1H), 0,95 (d, J=6 Hz, 3H). ESI-Mass spectrum: 442 (M+1)+.

[0219] the Compound of the 301H-NMR: (500 MHz, DMSO-d6) to 8.57 (d, J=1 Hz, 1H), 8,31 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,89 (t, J1=J2=1 Hz, 1H), 7,83 (d, J=1 Hz, 1H), 7,24 (d, J=9 Hz, 1H), 3,86 (m, 4H), 3,30 (m, 4H). ESI-Mass spectrum: 495 (M-1)-.

[0220] Compound 31 -1H-NMR: (500 MHz, DMSO-d6) by 8.22 (s, 1H), 7,92 (DD, J1=8 Hz, J2=1 Hz, 1H), 7,83 (s, 1H), 7,72 (s, 1H), 7,13 (d, J=8 Hz, 1H), 3,25 (s, 3H), and 3.16 (m, 2H), 2,92 (s, 1H), 2,73 (m, 2H), 1,23 (m, 2H). ESI-Mass spectrum: 469 (M+1)+.

[0221] Compound 32 -1H-NMR: (500 MHz, DMSO-d6) compared to 8.26 (d, J=1 Hz, 1H), to 7.93 (DD, J1=7 Hz, J2=1 Hz, 1H), 7,86 (t, J1=J2=1 Hz, 1H), 7,73 (d, J=1 Hz, 2H), 7,13 (d, J=8 Hz, 1H)and 3.59 (m, 1H), only 3.57 (s, 3H), of 3.28 (m, 1H), 3,23 (m, 1H), 3,13 (m, 1H), 2,98 (m, 1H), and 2.83 (m, 1H), 2,68 (m, 1H). ESI-Mass spectrum: 376 (M-1)-.

EXAMPLE 4

Analysis of the binding of the receptor CCR3

[0222] Cells were washed once with PBS and re-suspended in binding buffer (25 mm HEPES, pH of 7.6, 5 mm MgCl2, 1 mm CaCl2, 0,5% BSA, 0,1% NaN3). 100 ml of cell suspension (2×105cells/well) and 0.1 nm [125I]-labeled eotaxin/CCL11 person (specific activity 2000 CI/mmol) were mixed in 96-Luna the nom polypropylene plate with U-bottom, and incubated for 60 minutes at room temperature to the reaction of binding. The suspension of cells is then transferred to a tablet for filtering (#MAFB, Millipore) and washed 3 times with binding buffer containing 0.5 M NaCl, was added to the scintillator and the radioactivity was counted on a TopCount (Packard). To determine nonspecific binding of cell suspension and [125I]-labeled eotaxin/CCL11 person incubated in the presence of 500 nm unlabeled eotaxin/CCL11 person. Cm. During closing et al., "Molecular cloning and functional characterization of cynomolgus monkey (Macaca fascicularis) CC chemokine receptor, CCR3," Cytokine 2002, 19, 276-286.

[0223] the Biological results are summarized in table 1, where A represents the value of not more than 50 nm, and B represents a value greater than 50 nm but not more than 500 nm, C represents a value greater than 500 nm but not more than 5 μm, and D represents a value greater than 5 microns.

Table 1

[0224] the above examples are provided to give the ordinary person skilled in the art for full details and description of how to obtain and use the claimed embodiments of, and are not intended to limit the scope disclosed in the present description information. It is assumed that the modifications which are obvious to experts in this field, enter the amount of n is ieslegusi claims. All publications, patents and patent applications, cited herein, are incorporated into it by reference as if each such publication, patent or patent application were specifically and individually indicated as included in this description by reference.

1. The compound of formula Ia or pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer:

where
X represents S, SO or SO2;
Y and Z represent
(i) Y represents NR5; and Z represents =O, CO2R6or C1-6alkyl; or
(ii) Y is CH2, CHF, CHCH3, O, S or SO2; and Z represents hydrogen or C1-6alkyl;
R1and R2each independently represent halogen, C1-6alkyl or C1-6halogenated;
R3represents CN or NO2;
R4represents hydrogen or C1-6alkyl;
R5represents hydrogen or C1-6alkyl; and
R6represents hydrogen or C1-6alkyl.

2. The compound of formula I or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer:

where
X represents S, SO or SO2;
Y and Z represent
(i) Y represents NR5; and Z represents =O or C alkyl; or
(ii) Y is CH2, CHF, CHCH3, O, S or SO2; and Z represents hydrogen or C1-6alkyl;
R1and R2each independently represent halogen, C1-6alkyl or C1-6halogenated;
R3represents CN or NO2;
R4represents hydrogen or C1-6alkyl; and
R5represents hydrogen or C1-6alkyl.

3. The compound according to claim 1 or 2, where X represents S.

4. The compound according to claim 1 or 2, where R3represents CN.

5. The compound according to claim 1 or 2, where R3represents NO2.

6. The compound of formula II or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer:

where
Y and Z represent
(i) Y represents NR5; and Z represents =O; or
(ii) Y is S or SO2; and Z represents hydrogen;
R1and R2each independently represent a halogen or C1-6alkyl;
R4represents hydrogen;
R5represents hydrogen.

7. The connection according to claim 6, where Y represents NR5.

8. The connection according to claim 6, where Y is S.

9. The connection according to claim 6, where Y represents the SO2.

10. The connection according to claim 6, where R1and R2represent Cl.

1. The connection according to claim 6, where R1and R2represent CH3.

12. A compound selected from the group consisting of:
















or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer.

13. Pharmaceutical composition for treating, preventing, or alleviating one or more symptoms associated with CCR3 disorders, disease or condition, comprising the compound according to any one of claims 1, 2 and 6, and one or more pharmaceutically acceptable carriers and excipients.

14. A method of treating, preventing or alleviating one or more symptoms associated with CCR3 disorders, diseases or conditions in a subject comprising administration to the subject a therapeutically effective amount of a compound according to any one of claims 1, 2 and 6.

15. The method according to 14, where the violation or disease is aboveexplained or immunoregulative violation or disease.

16. The method according to 14, where the violation or disease is a asthma, rhinitis, allergic disease or autoimmune pathology.

17. The method according to 14 where the compound or composition is administered orally, parenterally or topically.

18. Method of modulating CCR3 activity, comprising contacting the receptor CCR3 with the compound according to any one of claims 1, 2 and 6.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to N-hydroxylsulphonamide derivatives of formula or , where R1 is H; R2 is H; n is 0; b is an integer in the range of 1-4; R3, R4, R5, R6 and R7 are independently selected from H, halogen, carboxyl, carboxyl ester selected from a group including -C(O)O-morpholino, -C(O)O-C1-C8alkyl and -C(O)O-substituted C1-C8alkyl, where the substitute is morpholino; acylamino, which is a -C(O)NRaRb group, where Ra and Rb are independently C1-C8alkyl, or Ra and Rb together with a nitrogen atom to which they are bonded form morpholino; and sulphonylamino, which is a SO2NR2 group, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; R8 is selected from halogen and carbonylamino, selected from a -CONH-substituted C1-C8alkyl, where the substitute is morpholino; and -CONR2, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; C is a heteroaromatic ring which contains cyclic fragments Q9, Q10, Q11, Q12, Q13 and Q14, which are independently selected from C, CH and S, under the condition that at least one of the fragments Q9, Q10, Q11, Q12, Q13 and Q14 is S. The invention also relates to a method of modulating nitroxyl levels, a method of treating diseases which respond to treatment with nitroxyl, a treatment set and a pharmaceutical composition containing compounds of formula (I) or (III).

EFFECT: compounds of formula (I) or (III) for treating diseases which respond to treatment with nitroxyl.

20 cl, 5 ex, 4 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to spirocyclic nitriles of formula (1a): wherein the radicals A, B, C, X, Y, R24, R25, R26 and R27 are presented in cl.1 of the patent claim, inhibiting thiol proteases, particularly cathepsins, a method for preparing and using them as a drug for treating the diseases directly or indirectly mediated by cathepsins.

EFFECT: preparing the agent for treating the diseases directly or indirectly mediated by cathepsins.

12 cl, 2 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely new organic compounds, namely N,N'-substituted piperazines of general formula (I), wherein R1, R2: linear or branched alkoxy (C1÷C4), CH3C(=O)O; n=1-5; m=0-3; Z: C=O, SO2; X:C(=NH)NH2, C(=NH)NHC(-NH)NH2, G is low-molecular organic or mineral acid, sodium, potassium, ammonium cations or water influences the haemostasis system, showing antiagregant, anticoagulant and vasodilator properties, and to a method for preparing N,N'-substituted piperazines of formula 1 by reaction of N-substituted piperazines of general formula wherein R1, R2; linear or branched alkoxy (C1÷C4), CH3C(=O)O; n=1-5; m=0-3; Z: C=O, SO2; and 1H-pyrazole-1-carboxamidine, dicyane diamide and their salts in organic solvents or water at temperature 10-50°C in the presence of bases.

EFFECT: new substance are promising for prevention and treatment of the disturbed haemostasis system.

12 cl, 10 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I: where Y1 and Y2 are independently selected from N and CR10, where R10 is selected from group, including hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, R1 is selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and pyperasinyl, substituted up to 2 radicals C1-C6alkyl, R2 and R5 are independently selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino, R3 and R4 are independently selected from group, including hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, or R1 and R5 with phenyl, to which they are bound, form C5-C10heteroaryl, R6 and R7 are independently selected from group, including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, on condition that R6 and R7 both do not represent hydrogen, R8 is selected from group, including hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, R9 is selected from -S(O)2R11, -C(O)R11, -NR12aR12b and -R11, where R11 is selected from group, including aryl, cycloalkyl and heterocycloalkyl, R12a and R12b are independently selected from (C1-C6)alkyl and hydroxy(C1-C6)alkyl, and said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in composition of R9 optionally contain as substituents from 1 to 3 radicals, independently selected from group, including (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heterocycloalkyl, where said arylalkyl substituent in composition of R9 optionally contains as substituents from 1 to 3 radicals, independently selected from group, including halogen, cyano, (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methyl-pyperasinyl, as well as to its pharmaceutically acceptable salts, hydrates, solvates and isomers. In addition, invention relates to method of inhibiting hedgehog pathway in cell and to method of inhibiting undesirable cell proliferation, when cell contacts with compound described above.

EFFECT: obtained and described are novel compounds, which can be applied in medicine.

13 cl, 153 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to use of existing and novel N-sulfamoyl- N'-arylpiperazines and their physiologically compatible acid-addition salts of formula I , where Ar denotes a monocyclic or bicyclic C6-C10aryl in which ring carbon atoms are optionally substituted with 1-3 nitrogen or oxygen atoms, and/or where the C6-C10aryl ring system optionally contains 3-5 double bonds, and/or where the C6-C10aryl ring system is optionally substituted with 1 or 2 substitutes which can be identical or different and which can be selected from a group containing halogen, trifluoromethyl, cyano group, nitro group, C1-C4alkyl, C1-C4alkoxy group, C1-C4alkylsulfonyl; and two oxygen atoms which are bonded to two neighbouring carbon atoms of the C6-C10aryl ring system and are bonded by a C1-C2alkylene bridge; or where the C6-C10aryl ring system is substituted with phenyl which can optionally be substituted in the phenyl ring by one substitute which can be selected from a group containing halogen; for preventing or treating obesity and related diseases.

EFFECT: design of a method of obtaining the said compounds and a pharmaceutical composition based on the said compounds.

25 cl, 9 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed N-hydroxyformamide compound of formula (I) or its pharmaceutically acceptable salt where ring B represents phenyl, pyridinyl or pyrimidinyl; R2 represents the group chosen from C1-6alkyl, phenyl or naphthyl where the specified group is substituted with one or more fluoro group; n is equal to 1, 2 or 3; and R1 represents tetrahydropyranyl, 2-pyrimidinyl-CH2CH2-, 2-pyrimidinyl-CH2CH2CH2-, SF-2-pyrimidinyl-CH2CH2-, C1-6alkyl or phenyl.

EFFECT: compounds are metalloproteinase inhibitors.

6 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: description is given of amides of piperazinyl- or piperidinylaminesulphoamic acid with genera formula (I) , in which R1 and R2 together with a nitrogen atom, to which they are bonded, represent a 6-member aliphatic heterocyclyl, containing two atoms of nitrogen as heteroatoms. The indicated extra atom of nitrogen is substituted with radical R, where R represents COOR', and R' represents (C1-C6)alkyl or benzyl, or phenyl, substituted with trifluoromethyl and aminocarbonyl, or R1 represents hydrogen, and R2 represents a group with formula , in which R9 represents (C1-C8)alkoxycarbonyl or phenyl, substituted with haloid(C1-C6)alkyl or aminocarbonyl; R3 represents phenyl or phenyl(C1-C4)alkyl, containing two substitutes, chosen from halogen and haloid(C1-C6)alkyl. Description is given of the use of formula (I) compounds as inhibitors of steroid sulphatase.

EFFECT: compound has inhibition effect to steroid sulphatase.

7 cl, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein n = 1 or 2; R1 represents chlorine, fluorine, bromine atom, methyl or methoxy-group; R2 is taken among of one the following groups: (i) halogen atom, nitro-, hydroxy- amino- or cyano-group; (ii) -X1-R5 wherein X1 represents -O-, -S-, -SO-, -SO2-, NR6-, -CO-, -CONR6-, -NR6CO- wherein R6 represents hydrogen atom and R5 is taken among (C1-C6)-alkyl optionally substituted with one or some A, and so on; (iii) 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom and so on; R3 represents (C1-C6)-alkyl optionally substituted with one or some A and so on; A is taken among hydroxy-, amino-group, halogen atom, carboxy-, N-(C1-C4-alkyl)-amino-, N,N-di-(C1-C4-alkyl)-amino-group, carbamoyl and (C1-C6)-alkoxy-group; D is taken among: (i) -Xa-Rc wherein Xa represents -SO2, -CO-, -NRdCO-, -NRd- or -CONRd-; (iv) cyano-group or halogen atom; (v) -XcRf wherein Xc represents -C(O)- and Rf represents 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom with optionally additional heteroatom taken independently among oxygen atom (O), optionally substituted at ring carbon atom by the hydroxy-group, halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or cyano-group; G represents (C1-C6)-alkanoyl; R4 represents hydrogen or fluorine atom; or to its pharmaceutically acceptable salt or its ester hydrolyzed in vivo. Also, invention proposes a method for preparing compound of the formula (I). Also, invention proposes pharmaceutical composition enhancing activity of pyruvate dehydrogenase comprising substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I) or its pharmaceutically acceptable salt or ester hydrolyzed in vivo in combination with pharmaceutically acceptable vehicle or carrier. Invention provides preparing derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 1 tbl, 85 ex

The invention relates to new compounds, levogyrate and programada, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -4-[(were)sulfonyl]-piperazine of the formula I:

< / BR>
the method of production of these compounds, their use as levogyrate and programalso, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -piperazine

FIELD: chemistry.

SUBSTANCE: invention relates to low-molecular inhibitors of N-terminus activation of androgen receptors of formula B: or pharmaceutically acceptable salts thereof, where: X denotes N; Y denotes O; R1 denotes OJ, where J denotes a linear or branched, saturated C1-10alkyl; R2 denotes a linear or branched, saturated, optionally substituted C1-10alkyl, where the optional substitute denotes one or more: F, Cl, Br and I; R3 denotes H; R4 denotes H, linear or branched, saturated C1-4alkyl, optionally substituted, where the optional substitute denotes one or more: F, Cl, Br and I; R5 denotes a linear or branched, saturated C1-10alkyl, optionally substituted, where the optional substitute denotes one or more: F, Cl, Br and I; Z denotes Bu, Pr, Et or Me; denotes a double bond; and under the condition that the compound is not: .

EFFECT: compound exhibits inhibiting activity on AR, which allows use thereof to treat various diseases, including prostate cancer.

26 cl, 9 dwg, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing protected (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid of formula 2, as shown on dwg 1, and a dipeptidyl peptidase-IV inhibitor intermediate compound. The method involves: (step a) obtaining a compound of formula 6 by opening the epoxide ring in compound 5, using Grignard reagent; (step b) obtaining a compound of formula 7 by reacting the compound of formula 6 with sodium azide; (step c) obtaining a compound of formula 8 by reacting the compound of formula 7 with triphenyl phosphine and adding an amine protective group (PG); (step d) obtaining a compound of formula 9 by opening the aziridine ring in compound 8 using a cyanogens-based reagent; and (step e) obtaining a compound of formula 2 by hydrolysis of the compound of formula 9 using a base; [Reaction scheme 1] , where X denotes a halogen and PG denotes a protective group. Novel intermediate compounds are described.

EFFECT: improved method.

12 cl, 3 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: method is demonstrated on the scheme Method includes the following steps: (step 1) preparing a compound represented by chemical formula 4 by bonding a compound represented by chemical formula 2 and a compound represented by chemical formula 3 with peptide bond by reacting them using isobutyl chloroformate and a base in the presence of a reaction solvent; and (step 2) preparing a compound represented by chemical formula 1 by removing an amine protective group from the compound represented by chemical formula 4 obtained at step 1. On the reaction scheme, PG is a protective group; X is OR1, where R1 is a lower C1-C5alkyl; HY is a free acid. The invention also relates to a method of producing a compound represented by chemical formula 2, and an intermediate compound used to produce a compound represented by chemical formula 3.

EFFECT: method increases output of dipeptidyl peptidase-IV inhibitor, represented by chemical formula 1.

12 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described fumaryl diketopiperazin (FDKP) formulations and microparticles with the particular amount of trans-isomer making approximately 45% to approximately 65%. The FDKP microparticles can contain a drug such as endocrine hormone including a peptide, including insulin, glucagon, parathyroid hormone, and can be used to prepare a powder for pulmonary drug delivery.

EFFECT: fumaryl diketopiperazin (FDKP) microparticles with the above amount of trans-isomer show the improved aerodynamic properties.

27 cl, 6 dwg, 6 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new method for preparing anti-cancer compounds of formula (I) by cycling alkyl esters of tetra acetic acids of formula (II) in the presence of ammonium and formamide, as well as to compounds of formula (ROOCCH2)2N-CHCH3-CH2-N(CH2COOR)2 (II) used in the presented method, wherein R means alkyl.

EFFECT: what is presented is a new effective method for preparing biologically active compounds.

7 cl, 5 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: present invention describes substituted amides which inhibit Btk. Described are pharmaceutical compositions containing at least one of the compounds along with at least one pharmaceutically acceptable medium selected from carriers, auxiliary components and filler materials. Described are methods of treating patients suffering from several diseases which are sensitive to inhibition of activity of Btk and/or activity of B-cells. Described are methods of determining presence of Btk in a sample.

EFFECT: improved method.

58 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: maleic acid derivatives having general formula

have metallo-β-lactamase inhibiting activities. It is possible to recover anti-bacterial activities of β-lactam antibiotics against metallo-β-lactamase producing bacteria by combining the compound of general formula (I) with β-lactam antibiotics. The metallo-β-lactamase inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 denotes C2-6-alkyl; C3-7-cycloalkyl, where said cycle can be substituted with a hydroxyl group or can be condensed with an aryl; hydroxymethyl; - C1-3-alkylene phenyl, where said phenyl group can be substituted with a hydroxyl group, C1-6-alkyl group, hydroxymethyl group, a -COOM group, where M denotes a hydrogen atom or a pharmaceutically acceptable cation, a -CO-NR22R23 group, where R22 and R23, which can be identical or different, denote a hydrogen atom or C1-6-alkyl, wherein the alkyl can additionally be substituted with an aminocarbonyl, or R22 and R23, together with a nitrogen atom with which they are bonded, can form a five- or six-member saturated heterocyclic ring containing 1-2 oxygen or nitrogen atoms, and the heterocycle can be substituted with a hydroxyl group or a C1-6-alkanoyloxy group, a -O-R24 group, where R24 denotes C1-6-alkyl, wherein the alkyl is optionally substituted with an aminocarbonyl, an amine group, a guanidine group or a five- or six-member saturated heterocycle, having 1-2 nitrogen atoms, -COOM, where M denotes a hydrogen atom, C1-6-alkyl or a pharmaceutically acceptable cation, or a five- or six-member unsaturated heterocycle, having 1-2 nitrogen atoms; - C0-1 alkylene heterocycle, where said heterocycle is a five- or six-member saturated or unsaturated heterocycle containing one nitrogen or oxygen atom and can be substituted with a hydroxyl group; - O-C1-6-alkyl; or - S-C1-6-alkyl, R2 denotes C1-6-alkyl, C3-7-cycloalkyl, where said cycle can be substituted with a hydroxyl group or can be condensed with an aryl; or - C1-3-alkylene phenyl, each M1 independently denotes a hydrogen atom, a pharmaceutically acceptable cation.

EFFECT: new metallo-β-lactamase inhibitor acts as a medicament for inhibiting inactivation of β-lactam antibiotics and recovering anti-bacterial activities.

18 cl, 3 tbl, 98 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I)

wherein: A means a ring selected from phenyl group or heteroaryl group, Q means oxygen atom or a link -CH2-, X, Y and Z mean carbon atoms; R1 and R2, identical or different are selected from the following atoms and groups: hydrogen, halogen, -CF3, (C1-C6)alkyl, Alk, (C1-C6)alkoxy, (C1-C6)alkyl-O-(C1-C6)alkyl, -(CH2)m-SO2-(C1-C6)alkyl with m equal to 0, 1 or 2, benzyl, pyrazolyl, -CH2-triazolyl and -L-R12 wherein L represents a link or a bridge -CH2- and/or -CO- and/or -SO2-, and R12 means (C3-C8)cycloalkyl or group of formula ,

wherein: n=0 or 1, R13 means one-three groups, identical or different, selected from hydrogen atom and hydroxyl, (C1-C4)alkyl, oxo and phenyl, R14 means hydrogen atom or is selected from groups - NR18R19, -NR18-COOR19, -NR18-Alk-R20 and -R21, wherein R18, R19, R20, R21 and Alk have the values as specified below, R14' means -CO-(C1-C6)alkyl, R15 is selected from groups -Alk, -R20, -Alk-R20, -Alk-R21, -CO-Alk, -CO-R20, -CO-R21, -Alk-CO-NR18R19, (C3-C8)cycloalkyl and -CO-(C3-C8)cycloalkyl, wherein R18, R19, R20, R21 and Alk has the values as specified below, R16 means hydrogen atom or group Alk, wherein Alk has the values as specified below, R17 means group -Alk, -Alk-R20 or -Alk-R21, wherein Alk, R20 and R21 have the values as specified below, -CO-(C1-C6)alkyl, -CO-(C3-C8)cycloalkyl, R18 and R19, identical or different, mean hydrogen atom or (C1-C6)alkyl, R20 means phenyl or heteroaryl group (such as pyridinyl, pyrazolyl, pyrimidinyl or benzimidazolyl), which is optionally substituted by one (C1-C6)alkyl, R21 means heterocycloalkyl group optionally substituted by one or more halogen atoms or (C1-C6)alkyl, hydroxyl or (C1-C4)alkoxy groups, and Alk means (C1-C6)alkyl which is linear or branched and which is optionally substituted by one or two groups, identical or different, selected from hydroxyl, phenyl, (C1-C4)alkoxy and -NR18R19, wherein R18 and R19 have the values as specified above, R3 means linear (C1-C10)alkyl which is optionally substituted by one-three groups, identical or different, selected from halogen atoms and (C1-C4)alkoxy groups, R4 means hydrogen atom, R5 and R6 independently mean hydrogen atom or (C1-C5)alkyl, R7 and R8 independently mean hydrogen atom or (C1-C5)alkyl, R9 and R10 independently mean hydrogen atom, or R9 and R10 together form linear (C2-C3)alkylene chain, thereby forming 6-merous ring with nitrogen atom whereto attached with said alkylene chain optionally substituted by one-three groups selected from (C1-C4)alkyl, oxo, R11 means hydrogen atom or (C1-C8)alkyl which is optionally substituted by one-three groups selected from halogen atoms, hydroxyl, (C1-C6)alkoxy, -NR18R19, - or pyridinyl, wherein R18 and R19 have the values as specified above; wherein 'heterocyclic group' means saturated 5- or 6-member ring containing one or two heteroatoms selected from oxygen, nitrogen and sulphur atoms; 'heteroaryl group' means aromatic cyclic group containing 5-11 ring atoms selected from carbon, nitrogen and sulphur atoms with heteroaryl groups to be monocyclic or bicyclic, in this case at least one of two cyclic fragments are aromatic; in the form of a free base or an additive acid salt or base. Also, the invention refers to methods for preparing such compounds and to a based drug showing rennin inhibitory activity.

EFFECT: compounds can find application in medicine for preparing the drug for treating and preventing hypertension, cardiac damages, myocardial infraction, cardiac failure, cardiac and vascular hypertrophy, left ventricular dysfunction, restenosis, glaucoma, renal conditions, diabetic complications.

26 cl, 3 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

where X represents OR1, SR1 or NR1R2 where R1 and R2 independently represent C1-C5 lower alkyl, and R1 and R2 in NR1R2 can form a 5-7-members ring including an O heteroatom; or to its stereoisomer, to a pharmaceutically acceptable salt, hydrate or solvate. Besides, the invention refers to a method for making thereof and to a based pharmaceutical composition exhibiting DPP-IV inhibitor activity.

EFFECT: new compounds which can find application in medicine for prevention or treatment of the DPP-IV associated diseases, such as diabetes or obesity are produced.

12 cl, 1 tbl, 2 dwg, 18 ex

FIELD: medicine.

SUBSTANCE: invention relates to novel compounds of formula or to its pharmaceutically acceptable salts, where n is 0 or 1; R1 represents H or F; R2 represents C1-4alkyl; R7 represents H or C1-4alkyl; and Z represents hydroxyl C1-6alkyl or C1-6alkoxycarbonyl, or 5- or 6-member heteroaromatic ring, which belongs to aromatic rings which have given number of atoms, of which at least one is N, O or S, the remaining being carbon atoms, and which also optionally has methyl substituting group. Invention also relates to pharmaceutical composition, to application of compounds, as well as to method of obtaining formula I compounds.

EFFECT: obtaining novel biologically active compounds, possessing activity of receptor 5-HT2A antagonists.

9 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

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