Alkylthiopyrimidines as crth2 antagonists

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new alkylthiopyrimidines of formula III or pharmaceutically acceptable salts thereof: In the compound III X represents a direct bond; R2 means hydrogen, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, -NR8aR8b or the group -SR3; each R3 independently represents (C1-C6)alkyl, optionally mono-, di- or trisubstituted by halogen; or (C3-C7)cycloalkyl; R4a and R4b represent hydrogen; R6 represents aryl; or heteroaryl; wherein aryl and heteroaryl are optionally substituted in a substituted position by one or more substitutes specified in a group consisting of (a) halogen; (b) cyano; (c) nitro; (a) hydroxy; (e) guanidino; (f) heteroaryl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy (k) -NR8aR8b; (1) -C(O)R9; (m)-C(O)NR8aR8b, (n) - OC(O)NR8aR8b; (o) -C(O)OR9; (p) -NR7C(O)0R9; (q) -NR7C(O)R9; (r) sulphamoyl; (s) (C1-C6) alkylsulphonyl; (t) (C1-C6)alkylaminosulphonyl; (i) di(C1-C6)alkylaminosulphonyl; (v) (C1-C6)alkyl, optionally mono-, di- or trisubstituted by halogen; (w) (C1-C6) alkoxy, optionally mono-, di- or trisubstituted by halogen; and (x)(C1-C6)alkylthio, optionally mono-, di- or trisubstituted by halogen R7 represents hydrogen. The other radical values are specified in the patent claim.

EFFECT: compounds possess CRTH2 (G-protein related chemoattractant receptor expressed on Th2 cells) antagonist activity and are applicable for treating and preventing the diseases related to CRTH2, including treating allergic diseases, eosinophil and basophile related diseases.

14 cl, 6 dwg, 1 tbl

 

The claim to priority

This application claims priority based on provisional application for U.S. patent No. 60/995386 called "Alkyldiphenylamine as CRTH2 antagonists", filed on 25 September 2007. The above application is included in context by reference in its entirety.

The technical field to which the invention relates.

In the context presented alkylthiophene pyrimidine derivatives having antagonistic activity against CRTH2 (receptor associated with G-protein chemoattractant expressed on Th2 cells) and applicable for the treatment or prevention of diseases associated with CRTH2 activity, including for the treatment of allergic diseases associated with eosinophils diseases and related basophils diseases.

The level of technology

CRTH2 receptor is associated with G-protein chemoattractant expressed on Th2 cells, eosinophils and basophils (Nagata et al., J. Immunol., 162: 1278-1286, 1999; Hiral et al., J. Exp. Med., 193: 255-261, 2001).

The Th2 polarization observed in allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis (Romagnani, S., Immunology Today, 18: 263-266, 1997; one et al., Blood, 98; 1135-1141, 2001). Cells regulate Th2 allergic disease by the production of Th2 cytokines, such as IL-4, IL-5 and IL-13 (Oriss et al., J. Immunol., 162; 1999-2007, 1999; Violaet al., Blood, 91: 2223-2230, 1998; Webb et al., J. Immunol., 165: 108-113, 2000; Dumont, F.J., Exp. Opin. Ther. Pat., 12: 341-367, 2002). These Th2 cytokines directly or indirectly cause the migration, activation, priming and prolonged survival of effector cells such as eosinophils and basophils, allergic diseases (Sanz et al., J. Immunol., 160: 5637-5645, 1998; Pope et al., J. Allergy Clin. Immunol., 108: 594-601, 2001; Teran, L.M., Clin. Exp. Allergy, 29: 287-290, 1999).

Prostaglandin D2(PGD2), the ligand for CRTH2, is produced from fat cells and other important effector cells in allergic diseases (Nagata et al., FEBS Lett., 459: 195-199, 1999; Hirai et al., J. Exp. Med., 193: 255-261, 2001). Activation of CRTH2 through PGD2induces the migration and activation of Th2 cells and eosinophils, suggesting that CRTH2 can play a proinflammatory role in allergic diseases (Hirai et al., J. Exp. Med., 193: 255-261, 2001; Gervais et al., J. Allergy Clin. Immunol., 108: 982-988, 2001). Therefore, antagonists that inhibit the binding of CRTH2 and PGD2should be applicable for the treatment or prevention of allergic diseases such as asthma caused by exercise asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis.

In addition, the experimental data showed the assistance of eosinophils to the emergence of sinusitis (Hamilos et al., Am. J. Respir. Cell and Mol. Biol., 15: 443-450, 1996; Fan et al., J. Allergy Clin. Immunol., 106: 551-558, 2000) and syndrome Cerca-Strauss Coffin et al., J. Allergy Clin. Immunol., 101: 116-123, 1998). In the tissues of these patients can be observed that the fat cells malokalinovka with eosinophils (Khan et al., J. Allergy Clin. Immunol., 106: 1096: 1101, 2000). This suggests that the production of PGD2from fat cells induces the recruitment of eosinophils. Therefore, antagonists of CRTH2 are also applicable to the treatment of other related eosinophils diseases such as syndrome Cerca-Strauss and sinusitis. Antagonists of CRTH2 can be applicable for the treatment of certain related basophils diseases, such as basophilic leukemia, chronic urticaria and basophilic leukocytosis, due to the high CRTH2 expression on basophils.

There is therefore a need for compounds with antagonistic activity against CRTH2 for the treatment or prevention mediated by CRTH2 disorders or diseases.

The invention

In the context presented alkylthiophene pyrimidine derivatives, which are CRTH2 antagonists, pharmaceutical compositions containing such compounds, and methods of their use. In some embodiments, the communication for use in the compositions and methods provided in the context, have the formula I

or are their pharmaceutically acceptable salts, solvate, hydrate, stereoisomer, or that what tamarama, where the symbols are selected so that the resulting compound had an activity as an antagonist of CRTH2.

In the context of the proposed pharmaceutical composition containing the compound of the above formula and a pharmaceutically acceptable carrier or excipient. Proposed methods of treatment or prevention mediated by CRTH2 diseases or their symptoms, including the proposed introduction in the context of the compounds or compositions.

In some embodiments, the implementation proposed in the context, there are ways modulation steps activity of CRTH2 receptor by contacting the receptor with the proposed in the context of a compound or composition. In one embodiment, the proposed context, suggests ways antagonistic effect against the activity of CRTH2 receptor by contacting the receptor with the proposed in the context of a compound or composition. In another embodiment, proposed in the context, there are ways of treating one or more symptoms of diseases or conditions associated with activity of CRTH2 receptor, including but not limited to the above, an allergic condition associated with eosinophils disease associated with basophils disease or inflammatory disease. In other embodiments, the implementation proposed in the context of Exte, there are methods of treatment or prevention of a disease or condition or symptom, where the disease or condition selected from the group consisting of asthma caused by exercise asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, syndrome Cerca-Strauss, sinusitis, basophilic leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, inflammatory bowel disease, ulcerative colitis, Crohn's disease, CORD (chronic obstructive pulmonary disease and arthritis.

Detailed description

Definition

If not stated otherwise, all technical and scientific terms used in the context, have the same meanings as they usually understand the average expert in the field to which this invention. All patents, applications, published applications and other publications are incorporated by reference in their entirety. Obviously, there are many definitions for the term in the context that this section prevail, unless otherwise specified.

Pharmaceutically acceptable salts include, but are not limited to, salts of amines, such as, but not limited to, N,N'-dibenziletilendiaminom, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyethylamino, Ethylenediamine, N-methylglycyl is on, of procaine, N-benzylpenicillin, 1-pair-of chlorbenzyl-2-pyrrolidin-1'-iletilerimde, diethylamine and other bonds alkylamines, piperazine and Tris(hydroxymethyl)aminomethane; alkali metal salts, such as, but not limited to lithium, potassium and sodium, salts of alkaline earth metals such as, but not limited to barium, calcium and magnesium; salts of transition metals, such as, but not limited to zinc; and other metal salts, such as, but not limited to, sodium phosphate and centripetal, and include, but are not limited to, salts of mineral acids, such as, but without limitation, hydrochloride and sulfates, and salts of organic acids, such as, but not limited to acetates, lactates, malaty, tartratami, citrates, ascorbates, succinate, butyrate, valerate and fumarate.

Pharmaceutically acceptable salts are proposed in the context of the compounds also include their salts of acids and bases.

Suitable acid additive salts are formed from acids which form non-toxic salts. Examples of salts include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, Etisalat, Eilat, formate, fumarate, gluceptate, gluconate, glucur the NAT, hexaflurophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isetionate, lactate, malate, maleate, malonate, mesilate, methyl sulfate, naftilan, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/phosphate/dihydrophosphate, Pyroglutamate, saharat, stearate, succinate, tannat, tartrate, tosylate, triptorelin and xinafoate.

Suitable salts of the bases are formed from bases which form non-toxic salts. Examples of salts include aluminium salts, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Used in the context of the term "MES" describes a molecular complex containing proposed in the context of the connection and one or more molecules pharmaceutically acceptable solvent, such as ethanol. The term "hydrate" is used when water is the solvent. Pharmaceutically acceptable solvate and hydrates are complexes of the compounds with one or more molecules of solvent or water, or from 1 to about 100, or from 1 to about 10, or from one to about 2, 3 or 4 molecules of solvent or water.

Used in context, the term "treatment is their" means any method, which decreases the intensity or other favorable changes one or more symptoms of diseases or disorders. Treatment also includes any pharmaceutical application in the context of compositions, such as use for the treatment mediated CTRH2 diseases or disorders, or diseases or disorders involving the CRTH2 activity.

Used in the context of the designation IC50refers to the amount, concentration or dosage of a particular test compound that causes 50% inhibition of the maximum response, such as modulation of CRTH2 activity, in the analysis that measures such response.

Used in the context of the expression "essentially pure" means sufficiently homogeneous substance, to be free of readily detectable impurities determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by the person skilled in the art for the analysis of such impurities, or pure enough substance so that additional cleaning couldn detektivami way change the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for cleaning connections for su is estu chemically pure compounds, well-known specialist in this field. However, essentially pure chemical compound may be a mixture of stereoisomers. In such cases, additional cleaning can increase the specific activity of the connection.

Used in the context of the term "in combination" means the administration of the compounds proposed in the context of one or more therapeutic agents, or both, together or sequentially with no specific time limits. In one embodiment, proposed in the context of the compound and the additional agent or agents are present in the cell or in the body of the subject at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, proposed in the context of the compound and the additional agent or agents are in the same composition or dosage form. In another embodiment, proposed in the context of the compound and the additional agent or agents are located in different compositions or dosage forms. In some embodiments, the implementation of the first compound or agent before you can enter (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 n the del, 6 weeks, 8 weeks or 12 weeks), simultaneously with or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks) administration of the second compound or agent.

Used in the context of the term "isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to existing in nature isotopic composition or prevalence for a given atom. Atoms containing their natural isotopic composition, may also be called "raw" atoms. Have in mind that, unless otherwise specified, the atoms of the compounds mentioned in the context, represent any stable isotope of this atom. For example, unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", it is clear that the position is represented by a hydrogen atom in its natural isotopic composition.

Used in the context of the term "isotopically enriched" refers to the atom having the isotopic composition other than the natural isotopic composition of the atom. "Isotopically enriched" can refer also to a compound containing at least one atom having the isotopic composition other than the natural isotopic comp is in this atom.

Used in the context of the term "isotopically enriched" refers to the percentage of the number of a certain isotope in a given atom in the molecule instead of the natural isotopic prevalence of this atom. For example, the deuterium enrichment of 1% in this position means that 1% of the molecules in the sample contain deuterium at the specified position. Due to the existing nature of the distribution of deuterium approximately 0,0156%, the enrichment of deuterium in any position in the compound synthesized using unenriched source substances, approximately 0,0156%. The isotopic enrichment of the compounds presented in context, can be determined using conventional analytical methods, well known to the average person skilled in the art, including mass spectrometry and spectroscopy nuclear magnetic resonance.

Used in the context of alkyl, alkeline and alkyline carbon chain, unless otherwise specified, contain from 1 to 20 carbon atoms or from 1 or 2 to 16 carbon atoms and are unbranched or branched. Alkeneamine carbon chain with the number of carbon atoms from 2 to 20, in some embodiments, the implementation contain 1 to 8 double bonds and alkeneamine carbon chain with the number of carbon atoms from 2 to 16 in some embodiments, the implementation contain 1-5 double tie the th. Alkyline carbon chain with the number of carbon atoms from 2 to 20, in some embodiments, the implementation contain 1-8 triple relations and alkyline carbon chain with the number of carbon atoms from 2 to 16 in some embodiments, the implementation contain 1-5 triple bonds. Exemplary alkyl, alkeline and alkyline group context include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, allyl (propenyl) and propargyl (PROPYNYL). Used in context, the terms "lower alkyl", "lower alkenyl" and "lower quinil" refers to carbon chains having from about 1 or about 2 carbon atoms to about 6 carbon atoms. Used in the context of the term "ALK(EN)(INF)Il" refers to an alkyl group containing at least one double bond and at least one triple bond.

Used in the context of "cycloalkyl" refers to a saturated mono - or polycyclic system containing in some embodiments, the implementation of 3-10 carbon atoms, in other embodiments, the implementation of 3-6 carbon atoms; cycloalkenyl and cycloalkenyl refer to mono - or polycyclic systems that respectively include at least one double bond and at least one triple bond. Cyclea keyline and cycloalkenyl group in some embodiments, the implementation contain 3-10 carbon atoms, and cycloalkenyl group in the following implementation options contain 4 to 7 carbon atoms and cycloalkenyl group in the following implementation options contain 8 to 10 carbon atoms. Cyclic system cycloalkyl, cycloalkenyl and cycloalkyl groups can consist of one ring or two or more rings, which can be connected to each other condensed, bridged or Spiro-connected fashion. "Cyclol(EN)(INF)Il" refers to cycloalkyl group containing at least one double bond and at least one triple bond.

Used in the context of the "aryl" refers to aromatic monocyclic or polycyclic group containing from 6 to 19 carbon atoms. Aryl groups include, but are not limited to such groups as the unsubstituted or substituted fluorenyl, unsubstituted or substituted phenyl and unsubstituted or substituted naphthyl.

Used in the context of "heteroaryl" refers to monocyclic or polycyclic aromatic system, in some embodiments, the implementation with the number of members from about 5 to about 15, where one or more, in one embodiment, 1 to 3 atoms in the cyclic system are heteroatoms, i.e. elements other than carbon atom, including, but not limited to, atom azo is a, oxygen or sulfur. Heteroaryl group may be optionally condensed with a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, triazolyl, chinoline and ethenolysis.

Used in the context of "heterocyclyl" refers to monocyclic or polycyclic non-aromatic system, in one embodiment, from 3 to 10 members, in another embodiment, 4-7 members, in the following embodiment, 5 or 6 members, where one or more, in some embodiments, the implementation of 1-3 atoms in the cyclic system are heteroatoms, i.e. elements other than carbon atom, including, but not limited to, nitrogen atom, oxygen or sulfur. In the variants of implementation, in which the heteroatom(s) is a nitrogen atom, a nitrogen atom optionally substituted by alkyl, alkenyl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylation, heterocyclisation, acyl, guanidino, or the nitrogen atom may be quaternity with the formation of the ammonium group in which the substituents selected from the above substituents.

Used in the context of "aralkyl" refers to an alkyl group, in the cat the Roy one of the hydrogen atoms of the alkyl substituted aryl group.

Used in the context of "heteroalkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl substituted heteroaryl group.

Used in the context of the "halogen" or "halide" refers to F, Cl, Br or I.

Used in the context of "halogenated" refers to an alkyl group in which one or more hydrogen atoms replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl, and 1-chloro-2-feratel.

Used in the context of "halogenoalkane" refers to RO-in which R represents halogenating group.

Used in the context of "sulfinil" or "tional" refers to-S(O)-.

Used in the context of "sulfonyl" refers to-S(O)2-.

Used in the context of "sulfamoyl" refers to-S(O)2NR2where each R independently represents hydrogen, aryl or alkyl, including lower alkyl.

Used in the context of the "carboxy" refers to-C(O)HE.

Used in the context of "aminocarbonyl" or "carbarnoyl" refers to-C(O)NH2.

Used in the context of "alkylaminocarbonyl" or "allylcarbamate" refers to-C(O)other, where R represents alkyl, including lower alkyl.

Used in the context of "dialkylaminoalkyl" or "dialkylamino" refers to-C(O)NR'r R, where R' and R independently represent alkyl, VK is uchumi lower alkyl; "carboxamide" refers to groups of the formula-NR'r COR, in which R' and R independently represent alkyl, including lower alkyl.

Used in the context of "cycloalkylcarbonyl" or "cycloalkylcarbonyl" refers to-C(O)other, where R represents cycloalkyl.

Used in the context of "heterocyclizations" or "heterocyclisation" refers to-C(O)other, where R is heterocyclyl.

Used in the context of the "alkoxy" and "alkylthio" refers to RO - and RS-, where R represents alkyl, including lower alkyl.

Used in the context of "aryloxy and aaltio" refers to RO - and RS-, where R represents aryl, including lower aryl, such as phenyl.

Used in the context of "alkylene" refers to an unbranched, branched or cyclic, in some embodiments, the implementation of unbranched or branched divalent aliphatic hydrocarbon group, in one embodiment having from 1 to about 20 carbon atoms, in another embodiment having from 1 to 12 carbon atoms. In the following embodiment, alkylen includes a lower alkylene. In alkylenes group may be optionally inserted one or more oxygen atoms, sulphur, including the group S(=O) and S(=O)2or substituted or unsubstituted nitrogen atoms, including groups,- N - and-N +RR-where substituent(s), nitrogen atom is an alkyl, aryl, aralkyl, heteroaryl, heteroalkyl or COR'where R' represents alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, -OY or-NYY, where Y represents hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl. Alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-(CH2)3-), methylenedioxy (-O-CH2-O -), Ethylenedioxy (-O-(CH2)2"Oh-). The term "lower alkylene" refers to alkilinity groups having 1-6 carbon atoms. In some embodiments, the implementation alkylene groups are lower alkylene, including alkylen with 1-3 carbon atoms.

Used in the context of "amido" refers to the divalent group-C(O)NH-. "Thioamide" refers to the divalent group-C(S)NH-. "Acetamide" refers to the divalent group-OC(O)NH-. "Thioamide" refers to the divalent group-SC(O)NH-. "Dicyanamide" refers to the divalent group-SC(S)NH-. "Ureido" refers to the divalent group-HNC(O)NH-. "Touraid" refers to the divalent group-HNC(S)NH-.

When the number of any given substituent is not specified (for example, halogenated)may have one or more substituents. For example, "halogenated" may include one or more identical or different Atovulloev. As another example, "C1-3alkoxyphenyl" may include one or more identical or different alkoxygroup containing one, two or three carbon atom.

Used in the context of the group "alkyl", "alkenyl", "quinil", "cycloalkyl", "aryl", "heteroaryl", "heterocyclyl", "aralkyl", "heteroalkyl", "halogenated", "halogenoalkane", "carboxy", "aminocarbonyl", "carbarnoyl, alkylaminocarbonyl", "allylcarbamate", "dialkylaminoalkyl", "dialkylamino", "cycloalkylcarbonyl", "cycloalkylcarbonyl", "heterocyclizations", "heterocyclisation", "alkoxy", "alkylthio", "aryloxy", "aristeo", "alkylene", "amido", "thioamide", "acetamide", "teamid", "dicyanamide", "ureido and touraid do not contain deuterium at one or several positions, which contain hydrogen atoms, where the concentration of deuterium in the atom or atoms is other than the natural isotopic composition.

In addition, applied in the context of the group "alkyl", "alkenyl", "quinil", "cycloalkyl", "aryl", "heteroaryl", "heterocyclyl", "alkyl", "alkenyl", "quinil", "cycloalkyl", "aryl", "heteroaryl", "heterocyclyl", "aralkyl", "heteroalkyl", "halogenated", "halogenoalkane", "carboxy", "aminocarbonyl", "carbarnoyl, alkylaminocarbonyl", "allylcarbamate", "dialkylaminoalkyl", "dialkylamino", "cycloalkylcarbonyl", "cycloalkyl carbamoyl", "heterocyclizations", "heterocyclisation", "alkoxy", "alkylthio", "aryloxy", "aristeo", "alkylene", "amido", "thioamide", "acetamide", "teamid", "dicyanamide", "ureido and touraid do not contain carbon-13 in number, other than the natural isotopic composition.

Used in the context of the abbreviations for any protective groups, amino acids and other compounds, are, unless otherwise specified, in accordance with their ordinary usage, recognized abbreviations, or acronyms Commission IUPAC-IUB biochemical nomenclature (see (1972) Biochem. 11: 942-944).

Connection

In some embodiments, the communication for the application proposed in the context of the compositions and methods have the formula I

or are their pharmaceutically acceptable salts, solvate, hydrates, stereoisomers or tautomers, where

W represents a single bond, -(CH2)m-, -O-, -S(O)n-, -NR7-, -C(O)-, -C(O)O-, -C(O)NR7-, -NR7C(O)NR7- or-NR7C(O)O-;

R1represents-CO2R9-C(O)NR8aR8b, nitrile or tetrazolyl;

R2represents (a) hydrogen; b) halogen; (c) (C1-C6)alkyl; (d) (C1-C6)alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C1-C6)allylcarbamate di((C 1-C6)alkyl)carbamoyl, (C3-C7)cycloalkylcarbonyl or (C3-C7)heterocyclisation; (e) (C1-C6)alkyl, mono-, di - or tizamidine halogen; (f) (C3-C7)cycloalkyl; (g) -NR8aR8b; (h) -SR3or (i) (C1-C6)alkoxy, optionally mono-, di - or tizamidine halogen;

each R3independently represents (a) hydrogen; (b) (C1-C6)alkyl, mono-, di - or tizamidine halogen; (c) (C3-C7)cycloalkyl or (d) -C(O)R9;

R4aand R4bselected, each independently, from hydrogen or (C1-C6)alkyl;

each R5independently represents (a) hydrogen; b) halogen; (c) cyano; (d) nitro; (e) hydroxy; (f) phenyl; (g) phenyloxy; (h) benzyl; (i) benzyloxy; (j) guanidino; (k) heterocyclyl; (l) -NR8aR8b; (m) sulfamoyl; (n) (C1-C6)alkylsulfonyl; (o) (C1-C6)alkylaminocarbonyl; (p) di(C1-C6)alkylaminocarbonyl; (q) -C(O)R9; (r) -C(O)OR9; (s) -C(O)NR8aR8b; (t) -OC(O)NR8aR8b; (u) -NR7C(O)OR9; (v) -NR7C(O)R9; (w) (C2-C6)alkenyl; (x) (C1-C6)alkyl, optionally mono-, di - or tizamidine halogen; (y) (C1-C6)alkoxy, optionally mono-, di - or tizamidine halogen; or (z) a (C1-C6)alkylthio, long is ina mono-, di - or tizamidine halogen;

R6represents (a) hydrogen; (b) (C1-C6)alkyl; (c) (C2-C6)alkenyl; (d) (C2-C6)quinil; (e) (C3-C7)cycloalkyl; (f) (C1-C6)alkyl, substituted aryl or heteroaryl; (g) (C2-C4)alkenyl, substituted aryl or heteroaryl; (h) (C1-C6)alkyl, mono-, di - or tizamidine halogen; (i) (C1-C6)alkyl, substituted-C(O)R6a; (j) (C1-C6)alkoxy, mono-, di - or tizamidine halogen; (k) (C1-C6)alkylthio, mono-, di - or tizamidine halogen; (l) aryl; or (m) heteroaryl where these aryl and heteroaryl optionally substituted at substitutable position by one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) -NR8aR8b; (l) -C(O)R9; (m) -C(O)NR8aR8b; (n) -OC(O)NR8aR8b; (o) -C(O)OR9; (p) -NR7C(O)OR9; (q) -NR7C(O)R9; (r) sulfamoyl; (s) (C1-C6)alkylsulfonyl; (t) (C1-C6)alkylaminocarbonyl; (u) di(C1-C6)alkylaminocarbonyl; (v) (C1-C6)alkyl, optionally mono-, di - or trisemester halogen; (w) (C1-C6)alkoxy, optionally mono-, di - or triamese the aqueous halogen; and (x) (C1-C6)alkylthio, optionally mono-, di - or trisemester halogen;

R6arepresents (a) hydrogen; (b) (C1-C6)alkyl; (c) (C2-C6)alkenyl; (d) (C2-C6)quinil; (e) (C3-C7)cycloalkyl; (f) (C1-C6)alkyl, substituted aryl or heteroaryl; (g) (C2-C4)alkenyl, substituted aryl or heteroaryl; (h) (C1-C6)alkyl, mono-, di - or tizamidine halogen; (i) (C1-C6)alkoxy, mono-, di - or tizamidine halogen; (j) (C1-C6)alkylthio, mono-, di - or tizamidine halogen; (k) aryl or (l) heteroaryl where these aryl and heteroaryl optionally substituted at substitutable position by one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) -NR8aR8b; (l) -C(O)R9; (m) -C(O)NR8aR8b; (n) -OC(O)NR8aR8b; (o) -C(O)OR9; (p) -NR7C(O)OR9; (q) -NR7C(O)R9; (r) sulfamoyl; (s) (C1-C6)alkylsulfonyl; (t) (C1-C6)alkylaminocarbonyl; (u) di(C1-C6)alkylaminocarbonyl; (v) (C1-C6)alkyl, optionally mono-, di - or trisemester halogen; (w) (C1-C6)alkoxy, optionally mono-, di - or triseme the military halogen; and (x) (C1-C6)alkylthio, optionally mono-, di - or trisemester halogen;

R7represents (a) hydrogen; (b) (C1-C6)alkyl; (c) phenyl; (d) (C1-C6)alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C1-C6)allylcarbamate, di((C1-C6)alkyl)carbamoyl, (C3-C7)cycloalkylcarbonyl or (C3-C7)heterocyclisation; (e) (C1-C6)alkyl, mono-, di - or tizamidine halogen; or (f) (C3-C7)cycloalkyl;

in each case, R8aand R8bindependently selected from (i) or (ii) as follows:

(i) each of R8aand R8bindependently selected from (a) hydrogen; (b) (C1-C6)alkyl; (c) phenyl; (d) (C1-C6)alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C1-C6)allylcarbamate, di((C1-C6)alkyl)carbamoyl, (C3-C7)cycloalkylcarbonyl or (C3-C7)heterocyclisation; (e) (C1-C6)alkyl, mono-, di - or trisemester halogen, or (f) (C3-C7)cycloalkyl; or

(ii) each of R8aand R8btogether with the N to which they are linked, independently may form a 3-8-membered saturated or unsaturated ring, optionally containing one or more atoms are O or S or one or more of the additional N atoms;

each R9independently represents (a) hydrogen; (b) (C1-C6)alkyl; (c) phenyl or (d) (C1-C6)alkyl, substituted aryl, alkoxy or mono-, di - or tizamidine halogen;

k is 0, 1 or 2;

m is 1, 2, 3 or 4; and

n is 0, 1 or 2.

In one embodiment, R1represents-CO2N.

In another embodiment, R2represents-SR3.

In another embodiment, each R3independently is a (C1-C6)alkyl.

In another embodiment, R4aand R4brepresent, each independently, hydrogen, methyl or ethyl.

In one embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula II

or are their pharmaceutically acceptable salts, solvate, hydrates, stereoisomers or tautomers, where

W represents a single bond, -(CH2)m-, -O-, -S(O)n-, -NR7-, -C(O)-, -C(O)O-, -C(O)NR7-, -NR7C(O)NR7- or-NR7C(O)O-;

each R3independently is a (C1-C6)alkyl;

R4aand R4bselected, each independently, from hydrogen, methyl or ethyl;

each R5independently represents (a) hydrogen; b) halogen; c) cyano; (d) nitro; (e) hydroxy; (f) phenyl; (g) phenyloxy; (h) benzyl; (i) benzyloxy; (j) guanidino; (k) heterocyclyl; (l) -NR8aR8b; (m) sulfamoyl; (n) (C1-C6)alkylsulfonyl; (o) (C1-C6)alkylaminocarbonyl; (p) di(C1-C6)alkylaminocarbonyl; (q) -C(O)R9; (r) -C(O)OR9; (s) -C(O)NR8aR8b; (t) -OC(O)NR8aR8b; (u) -NR7C(O)OR9; (v) -NR7C(O)R9; (w) (C2-C6)alkenyl; (x) (C1-C6)alkyl, optionally mono-, di - or tizamidine halogen; (y) (C1-C6)alkoxy, optionally mono-, di - or tizamidine halogen; or (z) a (C1-C6)alkylthio, optionally mono-, di - or tizamidine halogen;

R6represents (a) hydrogen; (b) (C1-C6)alkyl; (c) (C2-C6)alkenyl; (d) (C2-C6)quinil; (e) (C3-C7)cycloalkyl; (f) (C1-C6)alkyl, substituted aryl or heteroaryl; (g) (C2-C4)alkenyl, substituted aryl or heteroaryl; (h) (C1-C6)alkyl, mono-, di - or tizamidine halogen; (i) (C1-C6)alkyl, substituted-C(O)R6a; (j) (C1-C6)alkoxy, mono-, di - or tizamidine halogen; (k) (C1-C6)alkylthio, mono-, di - or tizamidine halogen; (l) aryl; or (m) heteroaryl where these aryl and heteroaryl optionally substituted at substitutable position with one the or more substituents, selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) -NR8aR8b; (l) -C(O)R9; (m) -C(O)NR8aR8b; (n) -OC(O)NR8aR8b; (o) -C(O)OR9; (p) -NR7C(O)OR9; (q) -NR7C(O)R9; (r) sulfamoyl; (s) (C1-C6)alkylsulfonyl; (t) (C1-C6)alkylaminocarbonyl; (u) di(C1-C6)alkylaminocarbonyl; (v) (C1-C6)alkyl, optionally mono-, di - or trisemester halogen; (w) (C1-C6)alkoxy, optionally mono-, di - or trisemester halogen; and (x) (C1-C6)alkylthio, optionally mono-, di - or trisemester halogen;

R6arepresents (a) hydrogen; (b) (C1-C6)alkyl; (c) (C2-C6)alkenyl; (d) (C2-C6)quinil; (e) (C3-C7)cycloalkyl; (f) (C1-C6)alkyl, substituted aryl or heteroaryl; (g) (C2-C4)alkenyl, substituted aryl or heteroaryl; (h) (C1-C6)alkyl, mono-, di - or tizamidine halogen; (i) (C1-C6)alkoxy, mono-, di - or tizamidine halogen; (j) (C1-C6)alkylthio, mono-, di - or tizamidine halogen; (k) aryl or (l) heteroaryl where these aryl and heteroaryl optionally substituted at substitutable position with one or more what their deputies, selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) -NR8aR8b; (l) -C(O)R9; (m) -C(O)NR8aR8b; (n) -OC(O)NR8aR8b; (o) -C(O)OR9; (p) -NR7C(O)OR9; (q) -NR7C(O)R9; (r) sulfamoyl; (s) (C1-C6)alkylsulfonyl; (t) (C1-C6)alkylaminocarbonyl; (u) di(C1-C6)alkylaminocarbonyl; (v) (C1-C6)alkyl, optionally mono-, di - or trisemester halogen; (w) (C1-C6)alkoxy, optionally mono-, di - or trisemester halogen; and (x) (C1-C6)alkylthio, optionally mono-, di - or trisemester halogen;

R7represents (a) hydrogen; (b) (C1-C6)alkyl; (c) phenyl; (d) (C1-C6)alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C1-C6)allylcarbamate, di((C1-C6)alkyl)carbamoyl, (C3-C7)cycloalkylcarbonyl or (C3-C7)heterocyclisation; (e) (C1-C6)alkyl, mono-, di - or tizamidine halogen; or (f) (C3-C7)cycloalkyl;

in each case, R8aand R8bselected from (i) or (ii)as follows:

(i) each of R8aand R8bindependently selected from (a) hydrogen; (b) (C1-C6)alkyl; (c) Fe the sludge; (d) (C1-C6)alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C1-C6)allylcarbamate, di((C1-C6)alkyl)carbamoyl, (C3-C7)cycloalkylcarbonyl or (C3-C7)heterocyclisation; (e) (C1-C6)alkyl, mono-, di - or trisemester halogen, or (f) (C3-C7)cycloalkyl; or

(ii) each of R8aand R8btogether with the N to which they relate, independently may form a 3-8-membered saturated or unsaturated ring, optionally containing one or more atoms are O or S or one or more additional N atoms;

each R9independently represents (a) hydrogen; (b) (C1-C6)alkyl; (c) phenyl or (d) (C1-C6)alkyl, substituted aryl, alkoxy or mono-, di - or tizamidine halogen;

k is 0, 1 or 2;

m is 1, 2, 3 or 4; and

n is 0, 1 or 2.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula III

or are their pharmaceutically acceptable salts, solvate, hydrates, stereoisomers or tautomers, where

X represents a single bond, -O(CH2)p- or-NR9(CH2)p-;

R7represents hydrogen or (C1 -C6)alkyl;

p is 1, 2, 3, 4, 5 or 6 and

R2, R3, R4a, R4b, R6, R8aand R8bhave the meanings given in the context of this invention.

In one embodiment, each R3independently is a (C1-C6)alkyl.

In another embodiment, R2represents-S(C1-C6)alkyl and R7and R9represent, each independently, hydrogen.

In another embodiment, R6represents aryl or heteroaryl where these aryl or heteroaryl optionally substituted at substitutable position by one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) -NR8aR8b; (f) -C(O)R9; (g) -C(O)NR8aR8b, (h) -OC(O)NR8aR8b; (i) -NR7C(O)OR9; (j) -NR7C(O)R9; (k) -C(O)OR9; (l) guanidino; (m) heterocyclyl; (n) phenyl; (o) phenyloxy; (p) benzyl; (q) benzyloxy; (r) sulfamoyl; (s) (C1-C6)alkylsulfonyl; (t) (C1-C6)alkylaminocarbonyl; (u) di(C1-C6)alkylaminocarbonyl; (v) (C1-C6)alkyl, optionally mono-, di - or trisemester halogen; (w) (C1-C6)alkoxy, optionally mono-, di - or trisemester halogen; and (x) (C1-C6)alkylthio, optionally mono, di - or trisemester halogen.

In another embodiment, R7, R8aand R8brepresents, each independently, hydrogen or (C1-C6)alkyl.

In one embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula IV

or are their pharmaceutically acceptable salts, solvate, hydrates, stereoisomers or tautomers, where

each R3independently is a (C1-C6)alkyl;

each R10independently represents (a) halogen; (b) cyano, (c) nitro; (d) hydroxy; (e) -NR8aR8b; (f) -C(O)R9; (g) -C(O)NR8aR8b; (h) -OC(O)NR8aR8b; (i) -NR7C(O)OR9; (j) -NR7C(O)R9; (k) -C(O)OR9; (l) guanidino; (m) heterocyclyl; (n) phenyl; (o) phenyloxy; (p) benzyl; (q) benzyloxy; (r) sulfamoyl; (s) (C1-C6)alkylsulfonyl; (t) (C1-C6)alkylaminocarbonyl; (u) di(C1-C6)alkylaminocarbonyl; (v) (C1-C6)alkyl, optionally mono-, di - or tizamidine halogen; (w) (C1-C6)alkoxy, optionally mono-, di - or tizamidine halogen; and (x) (C1-C6)alkylthio, optionally mono-, di - or tizamidine halogen;

q is 0, 1, 2, 3, 4 or 5 and

R4a, R4band X have the meanings defined Lennie in the context of this invention.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula V

or are their pharmaceutically acceptable salts, solvate, hydrates, stereoisomers or tautomers, where

R2represents hydrogen or halogen;

R3is a (C1-C6)alkyl;

each R10independently represents (a) halogen; (b) cyano, (c) nitro; (d) hydroxy; (e) -NR8aR8b; (f) -C(O)R9; (g) -C(O)NR8aR8b; (h) -OC(O)NR8aR8b; (i) -NR7C(O)OR9; (j) -NR7C(O)R9; (k) -C(O)OR9; (l) guanidino; (m) heterocyclyl; (n) phenyl; (o) phenyloxy; (p) benzyl; (q) benzyloxy; (r) sulfamoyl; (s) (C1-C6)alkylsulfonyl; (t) (C1-C6)alkylaminocarbonyl; (u) di(C1-C6)alkylaminocarbonyl; (v) (C1-C6)alkyl, optionally mono-, di - or tizamidine halogen; (w) (C1-C6)alkoxy, optionally mono-, di - or tizamidine halogen; and (x) (C1-C6)alkylthio, optionally mono-, di - or tizamidine halogen;

q is 0, 1, 2, 3, 4 or 5 and

R4a, R4band X have the meanings defined in the context of this invention.

In one embodiment, R4aand R4brepresent, each independently, vodor the doctor

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula VI

or are their pharmaceutically acceptable salts, solvate, hydrates, stereoisomers or tautomers, where R10, X and q have the meanings defined in the context of this invention.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula VII

or are their pharmaceutically acceptable salts, solvate, hydrates, stereoisomers or tautomers, where R2, R10, X and q have the meanings defined in the context of this invention.

In some embodiments, the implementation of each R10independently represents (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) -NH2; (f) -NH(C1-C6)alkyl; (g) -N((C1-C6)alkyl)2; (h) -C(O)(C1-C6)alkyl; (i) -CO2H; (j) -NHC(O)(C1-C6)alkyl; (k) -C(O)O(C1-C6)alkyl; (l) phenyl; (m) phenyloxy; (n) benzyl; (o) benzyloxy; (p) sulfamoyl; (q) (C1-C6)alkylsulfonyl; (r) (C1-C6)alkylaminocarbonyl; (s) di(C1-C6)alkylaminocarbonyl; (t) (C1-C6)alkyl, optionally mono-, di - or tizamidine halogen (u) (C 1-C6)alkoxy, optionally mono-, di - or tizamidine halogen; or (v) (C1-C6)alkylthio, optionally mono-, di - or tizamidine halogen.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula VIII

or are their pharmaceutically acceptable salts, solvate, hydrates, stereoisomers or tautomers, where X has the values defined in the context of this invention.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula IX

or are their pharmaceutically acceptable salts, solvate, hydrates, stereoisomers or tautomers, where

R2represents a hydrogen or halogen and

X has the values defined in the context of this invention.

In another embodiment, X represents a single bond, -co2- or-NH-.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and method of the x have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the present context is omposite and how have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the proposed in this context, the compositions and methods have the formula

.

In another embodiment, compounds for use in the present context is omposite and how have the formula

.

Proposed in the context of connections can exist in a continuum solid States ranging from fully amorphous to fully crystalline. The term "amorphous" refers to a state in which a substance has no long-range order structure on the molecular level and, depending on the temperature can be physical properties of solids and liquids. Such substances usually do not give the characteristic x-rays and, although and possess properties of solids, more formally described as fluid. When heated to change the properties of solids properties of liquids, which is characterized by change of state, usually the second order ("vitrification"). The term "crystalline" refers to a solid phase, in which the substance has a regular ordered structure at the molecular level and gives a characteristic x-ray with defined peaks. Such substances at sufficient heat will also reveal the properties of the liquid, but the transformation from the solid to the liquid phase is characterized by the transformation, usually the first order ("melting point").

Proposed in the context of the compounds may also exist in resolutiony and solvated forms. Proposed in the context of the shape of the MES includes the t, for example, hydrates. Currently accepted classification system for organic hydrates is a classification system that defines and hydrates with isolated areas, channel hydrates and hydrates, coordinated with a metal ion - see Polymorphism in Pharmaceutical Solids, K. R. Morris (Ed. H. G. Brittain, CRC, 1999). Hydrate with isolated areas are hydrates, in which water molecules are isolated from direct contact with each other a location between organic molecules. In channel hydrates, the water molecules are located in the channels of the crystal lattice, where they are adjacent to other water molecules. In the hydrates, coordinated with a metal ion, water molecules are bound with a metal ion.

When the solvent or water is bound tightly, the complex will have a well-characterized, independent of the stoichiometry of humidity. However, when the solvent or water are weakly coupled, as in channel solvate and hygroscopic compounds, water content/the MES will depend on humidity and drying conditions. In such cases, the nonstoichiometry is the norm.

In the scope of this description also includes metabolites proposed in the context of connections, that is, compounds formed in vivo after administration proposed in the context of the connection. Some examples proposed in the context of what those metabolites include

(i) when the compound contains a methyl group, it hydroxymethylpropane (-CH3-> CH2HE);

(ii) when the compound contains alkoxygroup, its hydroxy (-OR -> -OH);

(iii) when the compound contains a tertiary amino group, its derivative with a secondary amino group (-NR1R2-> -other1or other2);

(iv) when the compound contains a secondary amino group, it is derived from the primary amino group (-other1-> -NH2);

(v) when the compound contains phenyl part, its phenolic derivative (-Ph- > - PhOH); and

(vi) when the compound contains aminogroup, its carboxylic acid derivative (-CONH2-> -COOH; -COOR -> -COOH).

Proposed connection context may contain chiral centers. Such chiral centers can be either (R)-or (S)-configuration, or may be mixtures thereof. Thus, the proposed connection context may be enantiomerically pure, or may be stereoisomeric or diastereomeric mixtures.

When offered in the context of the connection contains alkenylphenol or alkenylamine group, possible geometric CIS/TRANS (or Z/E)-isomers. When structural isomers are vzaimoprevrascheny via a low energy barrier, may be tautomeric isomerism ('tautomerism)". This isomerism may take the form of proton the th tautomerism in compounds, containing, for example, imino, keto-or axiograph, or so-called valence tautomerism in compounds which contain aromatic portion. This means that one connection can be more than one type of isomerism.

It should be clear that the chiral centers of the compounds proposed in the context, can be subjected to epimerization in vivo. Essentially, the person skilled in the art it should 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.

In the scope of the present description include all stereoisomers, geometric isomers and tautomeric forms proposed in the context of compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more such isomers. Also included are salts of acids or bases, in which the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

CIS/TRANS-isomers can be divided conventional methods, well known to the person skilled in the art, for example, chromatography and fractional crystallization.

Conventional methods for receiving/separation of individual enantiomers include chiral synthesis from a suitable optically pure PressTV is nice or separation of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, alcohol, or when the compound of formula I contains acidic or basic part, base or acid, such as 1-phenylethylamine or tartaric acid. Formed diastereomer mixture can be separated by chromatography and/or fractional crystallization, and one or both of diastereoisomeric to turn in the corresponding pure enantiomer(s) in the manner well known specialist in this field.

Proposed in the context of chiral compounds (and chiral precursors) can be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, including heptane or hexane, containing from 0 to 50% vol. isopropanol in one embodiment, from 2% to 20% in another embodiment, and from 0 to 5% vol. the alkylamine, in one embodiment, 0.1% diethylamine. Concentration of the eluate gives a rich mixture.

When any racemate crystallizes, the formation of crystals of two different types. The first type is a racemic compound (true racemate), referenced above,in this case, get one homogeneous form of the crystal, containing both enantiomers in equimolar amounts. The second type is a racemic mixture, or conglomerate, in this case, get two forms of crystal in equimolar amounts, and each contains a single enantiomer.

When both of crystal shapes present in the racemic mixture, have identical physical properties, they may have physical properties that differ from the physical properties of the true racemate. Racemic mixtures can be divided by using common methods known to the person skilled in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).

In the context of the proposed enriched with isotope alkylthiophene derivatives of pyrimidine.

Isotopic enrichment (e.g., deuterium) pharmaceutical products to improve the pharmacokinetics ("PK"), pharmacodynamic ("PD") profile and toxicity was shown earlier on some classes of drugs. See, for example, Lijinsky et al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et al., Mutation Res. 308: 33 (1994); Gordon et al., Drug Metab. Dispos., 15: 589 (1987); Zello et al., Metabolism, 43: 487 (1994); Gately et al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999).

The isotopic enrichment of the medicinal product can be applied, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life period "parent" Lekarstvo the th tools from the body, (3) a reduction in the number of doses needed to achieve the desired action, (4) reducing the number of doses needed to achieve the desired action, (5) increasing the formation of active metabolites, if any are formed, and/or (6) reduce the production of harmful metabolites in certain tissues and/or education more effective drugs and/or safe drugs for combination therapy, regardless of whether combination therapy intentional or not.

Replacement of an atom to one of its isotopes can often lead to a change in the reaction rate of a chemical reaction. This phenomenon is known as the kinetic isotope effect (KIE"). For example, if the connection With the-N is broken during which determines the speed stage in a chemical reaction (i.e. the stage with the highest energy transition state), replacement of the hydrogen atom with deuterium can cause a decrease in the reaction rate, and the process may be slow. This phenomenon is known as the kinetic isotope effect of deuterium ("DKIE"). (See, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 [in Russian] (1999)).

The magnitude DKIE can be expressed as the ratio between the velocity of this reaction, in which the connection With the-N is broken, and the same reaction, in which hydrogen is replaced by deuterium. DKIE can be is in the range from about 1 (no isotope effect) to very large numbers, such as 50 or more, this means that the reaction may be fifty or more times slower when hydrogen is replaced by deuterium. High values DKIE may be due, in part, by the phenomenon known as tunneling effect, which is a consequence of the uncertainty principle. The tunneling effect is attributed to the small mass of the hydrogen atom, and it occurs because the transition States, including the proton, can sometimes be formed in the absence of the required activation energy. Because deuterium has a greater mass than hydrogen, it is statically significantly less likely to be susceptible to this phenomenon.

Tritium (T) is a radioactive isotope of hydrogen used in the study, fusion reactors, neutron generators and radiopharmaceutical products. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most usually found in the form of T2O. Tritium decays slowly (half-life = 12.3 years) and emits beta particles of low energy, which cannot pass through the outer layer of human skin. The impact on the internal organs is the main risk associated with this isotope, however, it must be internalized in balticconnector, to create a significant health risk. Compared with deuterium must be absorbed fewer tritium before it reaches dangerous levels. Replacement of hydrogen with tritium (T) leads to an even stronger connection than that of deuterium, and induces numerically larger isotope effects. Similarly, replacement of other items on isotopes, including, but not limited to, listed,13C or14C for carbon,33S34S or36S to sulfur,15N for nitrogen and17O or18O for oxygen, will cause similar kinetic isotope effects.

For example, DKIE used to reduce the hepatotoxicity of halothane gas presumably by limiting the production of reactive compounds, such as cryptomaterial. However, this method may not be applicable for all classes of drugs. For example, the incorporation of deuterium can lead to metabolic shutdown. The concept of metabolic shutdown argues that xenogene when sequestration enzymes of phase I may contact temporarily and re-bound in different conformations before the chemical reaction (e.g. oxidation). This hypothesis is confirmed by the relatively large size of the binding pockets in many enzymes of phase I and heterogeneous nature of many metabolicheskii. Metabolic switching can potentially lead to different quantitative ratios of known metabolites, and in General new metabolites. This new metabolic profile may give greater or lesser toxicity.

The body of the animal expresses a variety of enzymes to eliminate foreign substances, such as therapeutic tools of his cardiovascular system. Examples of such enzymes include enzymes of the cytochrome P450 ("CYP"), esterase, protease, oxidoreductase, dehydrogenase and monoamine oxidase, they react with these alien substances and turn them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds include oxidation of carbon-hydrogen (C-H) or in the relationship of carbon-oxygen (C-O), or PI-bond carbon-carbon (C-C). The resulting metabolites may be stable or unstable under physiological conditions and can have essentially the pharmacokinetic, pharmacodynamic profiles and profiles of acute and prolonged toxicity other than such profiles "parent" compounds. For many drugs such oxidation are fast. For such medicines, so they often require the introduction of many or high is their daily doses.

Therefore, the isotopic enrichment in some of the provisions proposed in the context of the connection will provide the detected KIE, which will affect the pharmacokinetic, pharmacologic and/or toxicologic profiles proposed in the context of connections, compared to the same connection with natural isotopic composition.

Getting connections

Proposed in the context of the compounds are commercially available or can be obtained by usual chemical reactions known to the person skilled in the art. General scheme for obtaining approximate compounds are illustrated below.

Scheme 1: preparation of derivatives of bis-alkyldiphenylamine

Methyl-2-(4-nitrobenzyl)-4,6-bis-dimethylpyrimidin-5-ylacetic (1)

To a suspension of methyl-4,6-dichloro-2-(4-nitrobenzyl)pyrimidine-5-ilaclama (10,00 g, 28,08 mmol) in ethanol (100 ml) was added thiourea (6.42 per g, 84,30 mmol) and the resulting suspension was heated under reflux for 2 hours and then cooled to room temperature before keeping at 4°C for 18 hours. The resulting thick reddish-brown suspension was filtered and collected on the filter cake suspended in diisopropyl the simple ether (100 ml), was filtered and dried in the air. Thus obtained bright yellow intermediate product, the hydrochloride tiourine, suspended in water (40 ml) and was treated with 3 n sodium hydroxide solution to obtain a clear solution (30 ml). Introduced logmean (the 5.25 ml, 84,30 mmol) and the resulting reaction mixture was vigorously stirred at room temperature for 18 hours. The resulting grey suspension was filtered and the filter residue was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the filtrate was treated with diisopropyl simple ether until until no longer observed precipitation. Separated solid was collected by suction and washed with diisopropyl ether, thus obtaining methyl-2-(4-nitrobenzyl)-4,6-bis-dimethylpyrimidin-5-ylacetic (1) in the form of a white powder (6,87 g, 86%).

Methyl-2-(4-aminobenzyl)-4,6-bis-dimethylpyrimidin-5-ylacetic (2)

A suspension of compound 1 (0.50 g, 1,32 mmol) in methanol (15 ml) was treated with ammonium chloride (0.27 g, equal to 4.97 mmol), zinc powder (0,93 g, 14,20 mmol) and water (1 ml). The resulting gray suspension was heated at 80°C for 1 hour and she was allowed to cool to room temperature. Added a spatula celite and the mixture is then filtered through a layer of celite. The residue was washed with methanol and the filtrate conc who was narrowly in vacuum, while receiving a white paste which was dissolved in ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain the crude product as a pale brown oil. Chromatography on silica gel with elution with 20% ethyl acetate in hexano gave a thick oil, which was aterials upon standing at room temperature. Rubbing with ethyl acetate and hexane gave methyl 2-(4-aminobenzyl)-4,6-bis-dimethylpyrimidin-5-ylacetic (2) in the form of a white powder, which was collected by suction (0,43 g, 93%).

(4,6-bis-thiomethyl-2-(4-(4-trifloromethyl)aminobenzyl)pyrimidine-5-yl)acetic acid (3)

A solution of compound 2 (0.14 g, 0.40 mmol) in dichloromethane (5 ml) was treated with triethylamine (0.06 ml, 0.44 mmol) and then cooled in an ice bath. To the solution was added dropwise 4-cryptomathematical (0,07 ml, 0.44 mmol) and the resulting reaction mixture was allowed to warm to room temperature. After stirring for 1 hour at room temperature the reaction mixture was distributed between dichloromethane and water. The separated organic layer was washed sequentially with saturated sodium bicarbonate solution, water and saturated salt solution, dried over anhydrous sodium sulfate, filtered and conc the Wali in vacuum, while receiving the crude product as a white powder, which was washed with dichloromethane and diisopropyl simple ether and collected by suction. An aliquot of this product (0.11 g) was dissolved in tetrahydrofuran (8 ml) and treated with 1 n sodium hydroxide (2 ml) followed by treatment a sufficient amount of methanol to obtain a homogeneous mixture (approximately 0.5 ml). After stirring for 18 hours at room temperature the volatile components were removed in vacuum and the thus obtained white suspension was diluted with water (1 ml), cooled in an ice bath and acidified 3 n hydrochloric acid to weak acid reaction (pH ~5). The thus obtained separated solid substance was collected by suction, washed with water and dried under vacuum, thus obtaining (4,6-bis-thiomethyl-2-(4-(4-trifloromethyl)aminobenzyl)pyrimidine-5-yl)acetic acid (3) (0.08 g, 80%) as a white powder.

Scheme 2: obtain the unsymmetrical derivatives of bis-alkyldiphenylamine

The compounds of formula 6 can be obtained by reaction of compound 4 with thiourea in boiling under reflux methanol, handling of product 1 n NaOH (aqueous), followed by acidification of the Asón with the formation of compound 5. Alkalinization of compounds 5, subsequent processing of 1 equivalent each is from a different alkylating agents must give unbalanced connection, in which R3a≠ R3b. Subsequent reaction according to the above scheme 1 to give the final compounds of formula 6.

Scheme 3: preparation of derivatives of 4-amino-6-dipyrimidine

The compounds of formula 9 can be obtained in the following stages. Reaction of compound 4 with an amine of the formula HNR7R8in acetonitrile at room temperature gives the compounds of formula 7 can be transformed into compounds of formula 8 (thiourea, Meon, boiling under reflux; then 1 n NaOH, an alkylating agent) and the compounds of formula 9, as shown in schemes 1 and/or 2.

Figure 4: additional derivatives of 4-substituted 6-dipyrimidine

The compounds of formula 12 can be obtained by replacing (CH3CO2)2CHCH2CO2CH3a compound of formula 10 in the first stage of scheme 1. The reaction of compounds of formula 11 according to the other stages of scheme 1 can provide compounds of formula 12.

Obtaining enriched isotopes connections

Enriched isotope analogs of compounds proposed in the context, can in General be obtained according to the following methods, in which one or more of the reagents replace enriched isotope reagent. Enriched isotope R the agents are commercially available or can be obtained conventional chemical reactions, well-known specialist in this field. General scheme to obtain a sample enriched in the isotopes of the compounds are illustrated below.

Figure 5: getting deuterated analogs

The compound of formula 15 can be obtained, for example, the conversion of esterification of commercially available compound 13 compound 14 with subsequent reaction of compound 14 with diethylmalonate.

Deuterated derivatives of bis-alkyldiphenylamine then get a replacement (CH3CO2)2CHCH2CO2CH3the connection 15 in the first stage of scheme 1, as shown below.

Alternatively, deuterated derivatives of bis-alkyldiphenylamine can be obtained from commercially available iodomethane-d3 or brometane-d3 at appropriate stages of scheme 1, as shown below.

Deuterium can also enter into compounds proposed in the context, in different positions, having exchangeable proton (such as amine N-H and hydroxyl O-N) through the equilibrium exchange proton-deuterium. Methods of introduction of deuterium through the exchange of proton-deuterium are known in this field.

Scheme 6: production of carbon-13-analogs

The is a group of formula 18 can be obtained, for example, the conversion of esterification of commercially available compound 16 compound 17 with subsequent reaction of compound 17 with diethylmalonate.

Carbon-13-analogues derivatives of bis-alkyldiphenylamine proposed in the context, then received a replacement (CH3CO2)2CHCH2CO2CH3compound 18 in the first stage of scheme 1, as shown below.

Alternatively, the method of scheme 6 can be used for additional carbon-13 analogues derivatives of bis-alkyldiphenylamine proposed in the context, using the following commercially available reagents:

The methods of schemes 5 and 6 are only examples of methods that can be applied for the production of enriched isotope analogues proposed in the context of the connection. Additional enriched isotope analogs of compounds proposed in the context, can be obtained using conventional chemical reactions of the enriched isotope reagents that are commercially available and/or which can be obtained conventional chemical reactions known to the person skilled in the field.

The pharmaceutical composition

In the context of the proposed pharmaceutical composition, which is holding proposed in the context of the compound or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer as the active pharmaceutical ingredient in combination with one or more pharmaceutically acceptable carriers or excipients. The choice of excipient to a large extent depends on such factors as the specific route of administration, the effect of excipient on the solubility and stability of the active ingredient and the nature of the dosage form.

Pharmaceutical compositions proposed in the context can be represented in the form of dosage forms or dosage forms for multiple injections. The term "dosage form"is used in context, refers to physically discrete doses suitable for administration to a human - and animal-the subjects and packaged individually as is known in this field. Each standard dose contains a predetermined quantity of active ingredient(s)sufficient to induce the desired therapeutic effect, in combination with the required pharmaceutical carriers or excipients. Examples of dosage forms include capsules, syringes and individually Packed tablets and capsules. Dosage forms can be entered as parts of a single dose or multiple doses. Dosage form multiple doses of a drug the Orme with many identical doses, Packed in one container, which is administered in the form to be a segregated school dosage forms. Examples of dosage forms for multiple injections include ampoules, bottles of tablets or capsules or bottles a few pints or gallons.

Proposed connection context can be entered separately or in combination with one or more proposed in the context of other compounds, one or more other active ingredients. Pharmaceutical compositions that contain proposed in the context of a connection can be made in the form of various dosage forms for oral, parenteral or local administration. Pharmaceutical compositions can also be manufactured in the form of dosage forms with modified release, including dosage forms with detainees, stretched, extended, bravely supported, pulse, adjustable, rapid and quick release, targeted release, programmed-release, and dosage forms with delayed stomach. These dosage forms can be obtained according to conventional methods and techniques known to the person skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126).

Farmaceuticas is their composition, proposed in the context, you can enter once or many times with time intervals. It is clear that the exact dose and duration of treatment can vary depending on age, weight and condition being treated patient can be determined empirically using known testing protocols or by extrapolation from data testing in vivo or in vitro or diagnostic data. In addition, it is clear that for any individual specific medication should be adjusted over time as needed for individual and professional assessment of the person introducing or governing the administration of drugs.

A. Oral administration

Pharmaceutical compositions proposed in the context, can be represented in the form of solid, semi-solid or liquid dosage forms for oral administration. Used in the context of oral administration includes transbukkalno, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, tortillas, flavored tablets, porridge, beads containing drug chewing gum granules, powders in the total mass, effervescent or nishiuchi gas bubbles powders or granules which, solutions, emulsions, suspensions, solutions, pills, compositions for spraying, 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 the above, binders, fillers, diluents, dezintegriruetsja agents, wetting agents, lubricants, chemicals, giving a slide, coloring agents, inhibitors of migration of the colorant, sweetening agents and corrigentov.

Binder or means for granulating give the tablet binding capacity, to ensure that the tablet remain intact after pressing. Suitable binders or means for granulating include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (swelling in cold water) (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as Arabian gum, alginic acid, alginates, extracts Cartagena, Panwar gum, gum, ghatti, gum from the husk nuts, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), wigum, erbogachan larch, on the Sabbath.osteopathy tragakant and guar gum; cellulose, such as ethylcellulose, acetate cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose (NES), hydroxypropylcellulose (LDCs), hypromellose (receiver array); 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, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrine, kaolin, mannitol, silicic acid, sorbitol, starch, starch, swelling in cold water, and mixtures thereof. Binder or filler in pharmaceutical compositions proposed in the context, may be present in an amount of from about 50 to about 99% of the mass.

Suitable diluents include, but are not limited to, 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 that allow them to disintegrates in the mouth during chewing. Such molded tablets can be used is as chewable tablets.

Suitable dezintegriruetsja agents include, but are not limited to, 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; lemon 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 (sodium salt starch glycolate); potassium salt of polacrilin; starches such as corn starch, potato starch, tapioca starch and starch swelling in cold water; glues; algini and mixtures thereof. The number dezintegriruetsja agent in the pharmaceutical compositions proposed in the context varies depending on the type of drug and can easily be determined by the average person skilled in the art. Pharmaceutical compositions proposed in the context, can contain from about 0.5 to about 15% of the mass. or from approximately 1 to approximately 5% of the mass. dezintegriruetsja agent.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; Sorbi is; mannitol; glycols, such as Behinat of glycerol and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated 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; silica or silica gels, such as AEROSIL®200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL®(Cabot Co. of Boston, MA), and mixtures thereof. Proposed in the context of the pharmaceutical compositions can contain from approximately 0.1 to approximately 5% of the mass. lubricant.

Appropriate means, give the slip, include colloidal silica, CAB-O-SIL®(Cabot Co. of Boston, MA), and asbestos-free talc. Coloring agents include any of the permitted, certified, water-soluble dyes, FD&C and water-insoluble dyes, FD&C, suspended on the hydrate of aluminum oxide and coloring lacquers and mixtures thereof. Coloring lacquer is a combination obtained by the absorption of water-soluble dye in water heavy metal oxide with the formation of the insoluble form of the dye. The corrigentov include natural corrigentov extracted from plants, such as fruits, and synthetic blends of compounds which provide a feeling of pleasant taste, tcog is how the taste of peppermint, and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin and artificial sweetening agents such as saccharin and aspartame. Suitable emulsifying agents include gelatin, Arabic gum, tragakant, bentonite, and surfactants, such as monooleate of polyoxyethylenesorbitan (TWEEN®20), monooleate of polyoxyethylenesorbitan 80 (TWEEN®80) and triethanolamine oleate. Suspendresume and dispersing agents include sodium carboxymethyl cellulose, pectin, tragakant, Wigan, Arabian gum, sodium salt of carbometalation, hypromellose and polyvinylpyrrolidone. Preservatives include glycerin, methyl - and propylparaben, benzoic acid, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, monooleate sorbitan, monolaurate diethylene glycol and polyoxyethyleneglycol ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids used in the emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

It should be clear that many carriers and excipients can perform several functions, even in the same preparation of the same.

Pharmaceutical compositions proposed in the context, can be represented in the form of compressed tablets, pills, pounded into powder, chewing bread, fast dissolving tablets, multilayer pressed pellets or tablets with intersolubility coated tablets coated with sugar or glaze. Tablets with intersolubility coating are compressed tablets coated with substances that are resistant to gastric acid, but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Intersolubility coatings include, but are not limited to, fatty acids, fats, fenilsalitsilat, waxes, shellac, ammonioalkyl shellac and acetate-phthalate cellulose. Covered sugar tablets are compressed tablets, surrounded by sugar coating, which can be beneficial when masking an unpleasant taste or odor and protect tablets from oxidation. Film-coated tablets are compressed tablets are coated with a thin layer or film of water-soluble material. Film coating include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and acetate-phthalate C is lulzy. Film coating gives the same General characteristics as the sugar coating. Multilayer molded tablets are compressed tablets made by more than one cycle of pressing, including layered tablets and coated tablets pressing, or coated tablets drying.

Tablet dosage forms can be obtained from the active ingredient in powdered, crystalline or granular forms, alone or in combination with one or more described in the context of carriers or excipients, including binders, dezintegriruetsja agents, polymers with controlled release, lubricants, diluents and/or colorants. The corrigentov and sweetening agents are particularly applicable when receiving chews and biscuits.

Pharmaceutical compositions proposed in the context, can be represented 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 filled with dry substance capsule (DFC), consists of two sections, one slides into the other, thus completely closing the active ingredient. Soft elastic capsule (SEC) has the soft, spherical shell, such as gelatin shell which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. Soft gelatin shell may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are preservatives that are described in this context and including methyl - and propylparaben and sorbic acid. Proposed in the context of liquid, semi-solid and solid dosage forms can be encapsulated in capsules. Suitable 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. The capsules can also be covered, as known to the person skilled in the art, to modify or steadfastly supported the dissolution of the active ingredient.

Pharmaceutical compositions proposed in the context, can be represented in the form of 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 in the form of small balls throughout the other liquid and which may be of type oil-in-water or water-in-oil. The emulsion may include farmaci is almost acceptable non-aqueous liquid or solvent, emulsifying agent and preservative. Suspension may include pharmaceutically acceptable suspendisse agent and preservative. Aqueous alcoholic solutions may include pharmaceutically acceptable acetal, such as di(lower alkyl)acetal lower alkylenediamine, for example, diethylacetal acetaldehyde, and mixed with water, the solvent having one or more hydroxyl groups such as propylene glycol and ethanol. Elixirs are clear, sweetened and water-alcohol solutions. Syrups are concentrated aqueous solutions of sugar, for example sucrose, and may also contain a preservative. Liquid dosage form, such as a solution in polyethylene glycol, can be diluted with a sufficient amount of pharmaceutically acceptable liquid carrier, e.g. water, so that it can be measured appropriately in the introduction.

Other applicable liquid and semi-solid dosage forms include, but are not limited to, pharmaceutical form, containing proposed in the context of the active ingredient(s) and dialkylamines mono - or polyalkyleneglycol, including 1,2-dimethoxymethane, diglyme (dimethyl ether of diethylene glycol), trislim, tetralin, dimethyl ether of polyethylene glycol-350, dimethyl ether of polyethylene glycol-550, dimethyl ether of polyethylene glycol-750, where 50, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. These preparations can additionally contain one or more antioxidants, such as bottled hydroxytoluene (EIT), bottled hydroxyanisol (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamate.

Proposed in the context of pharmaceutical compositions for oral administration may be presented in the form of liposomes, micelles, microspheres or nanosystems. Micellar pharmaceutical form can be obtained, as described in U.S. patent No. 6350458.

Proposed in the context of pharmaceutical compositions may be presented in the form of effervescent or nishiuchi granules and powders, which recreate in 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 effervescent granules or powders may include an organic acid and a source of carbon dioxide.

Coloring agents and corrigentov can p is to change any in any of the above dosage forms.

Proposed in the context of pharmaceutical compositions for oral administration can be produced in the form of dosage forms for immediate or modified release, including forms with detainees, bravely supported, pulsed, controlled release, release in target and programmed release.

Proposed in the context of the pharmaceutical compositions can be manufactured in conjunction with other active ingredients which do not weaken the desired therapeutic action, or with substances that Supplement the desired action, such as antacids, proton pump inhibitors and antagonists of N2-receptor.

C. Injecting

Proposed in the context of the pharmaceutical compositions can be entered parenterally by injection, infusion or implantation for local or systemic administration. Used in the context of parenteral administration includes intravenous, intraarterial, intraperitoneal, vnutriobolochechnoe, intraventricular, be, vnutrigrudne, intracranial, intramuscular, intra-articular and subcutaneous administration.

Proposed in the context of the pharmaceutical compositions can be manufactured in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for the preparation of solutions or suspensions in liquid prior to injection. Such dosage forms can be obtained according to conventional methods known to the expert in the field of pharmaceutical science (see above Remington: The Science and Practice of Pharmacy).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including but not limited to the above, water fillers, mixed with water, fillers, organic fillers, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, means of improving the solubility, isotonic agents, buffering agents, antioxidants, local anesthetics, suspendresume and dispersing agents, wetting or emulsifying agents, complexing agents, requestrefuse or chelating agents, createsite agents, lisamarie agents, thickening agents, agents regulating pH, and inert gases.

Suitable water fillers include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), injectable solution of sodium chloride, injectable RA is creative ringer, isotonic injectable dextrose, sterile water injection solution, dextrose and lactationally injection ringer's solution. Organic fillers include, but are not limited to, non-volatile vegetable oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, sunflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and having an average chain length triglycerides of coconut oil and palm oil. Mix with water fillers include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g. polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, Cresols, mercury compounds, benzyl alcohol, chlorobutanol, methyl - and propyl-para-hydroxybenzoate, thimerosal, benzalkonium chloride, chloride benzene, methyl - and propylparaben and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin and dextrose. Suitable buffering agents include, but are not limited which are listed, phosphate and citrate. Suitable antioxidants are antioxidants described in the context, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, hydrochloride, procaine. Suitable suspendresume and dispersing agents are described in the context of suspendresume and dispersing agents include sodium salt of the carboxymethyl cellulose, hypromellose and polyvinylpyrrolidone. Suitable emulsifying agents include described in the context of emulsifying agents, including monolaurate of polyoxyethylenesorbitan, monooleate of polyoxyethylenesorbitan 80 and triethanolamine oleate. Suitable requestrefuse or chelating agents include, but are not limited to specified, EDTA. Suitable agents regulating the pH include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether beta-cyclodextrin and sulfobutyl ether 7-beta-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

Proposed in the context of the pharmaceutical compositions can be manufactured is o be catching in the form of a single dose or multiple doses of. Preparations for a single injection is packaged in an ampoule, a vial or a syringe. Preparations for repeated parenteral administration should contain an antimicrobial agent in bacteriostatic or fungistatic concentrations. All parenteral drugs should be sterile, as is known and practiced in the field.

In one embodiment, the proposed pharmaceutical composition in the form of a ready to use sterile solutions. In another embodiment, the proposed pharmaceutical composition in the form of a sterile dry soluble products, including liofilizovannye powders and hypodermal pills that recreate with filler before applying. In another embodiment, the proposed pharmaceutical composition in the form of a ready to use sterile suspensions. In another embodiment, the proposed pharmaceutical composition in the form of a sterile dry insoluble products that recreate with filler before applying. In another embodiment, the proposed pharmaceutical composition in the form of a ready to use sterile emulsions.

Proposed in the context of the pharmaceutical compositions can be manufactured in the form of dosage forms for immediate or modified release, is with a form with the detainees, steadfastly supported, pulsed, controlled release, release in target and programmed release.

The pharmaceutical compositions can be manufactured in the form of a suspension, solid, semi-solid substances, or thixotropic liquid for administration as an implanted depot. In one embodiment, proposed in the context of the pharmaceutical composition is dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows you to diffuse through it to the active ingredient in pharmaceutical compositions.

Suitable internal matrix include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, copolymers of ethylene and vinyl acetate, silicone rubber, polydimethylsiloxane, copolymers of silicone and carbonate, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, crosslinked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene, copolyme the s of ethylene and propylene, copolymers of ethylene and ethyl acrylate, copolymers of ethylene and 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, butyl rubber, epichlorohydrine rubbers, copolymers of ethylene and vinyl alcohol, terpolymer ethylene, vinyl acetate, vinyl alcohol, and copolymers of ethylene and vinyloxyethyl.

C. Local introduction

Proposed in the context of the pharmaceutical compositions can enter the local way into the skin, holes or mucous membrane. Used in the context of local introduction includes (inside)skin, conjunctival, vnutrirodovoe, intraocular, ophthalmic, ear, percutaneous, nasal, vaginal, ureter, respiratory and rectal administration.

Proposed in the context of the pharmaceutical compositions can be manufactured in any dosage forms that are suitable for local introduction for local or systemic action and include emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, liquids for washing, sprays, suppositories, bandages, dermal patches. Local prep the ATA proposed in the context of pharmaceutical compositions may also contain liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use in the proposed in the context of topical drugs include, but are not limited to, water fillers, mixed with water, fillers, organic fillers, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, agents that increase the solubility, isotonic agents, buffering agents, antioxidants, local anesthetics, suspendresume and dispersing agents, wetting or emulsifying agents, complexing agents, requestrefuse or chelating agents, agents improving the penetration, createsite agents, lisamarie agents, thickening agents, and inert gases.

Pharmaceutical compositions can also enter the local way by electroporation, iontophoresis, phonophoresis, sonophoresis and microholes or needleless injection, such as POWDERJECT™ (Chiron Corp., Emeryville, CA), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, OR).

Proposed in the context of the pharmaceutical compositions can be presented in the forms of ointments, creams and gels. Suitable fillers for ointments include oily or hydrocarbon bases, including lard, betonirovannoy lard, olive oil, cottonseed oil, white petrolatum and plastic; analginum the e or absorbed by the base, such as hydrophilic vaseline, the sulfate hydroxystyrene and anhydrous lanolin; sadogashima bases such as hydrophilic ointment; water-soluble bases ointments, including polyethylene glycols of various molecular weights; emulsion bases, emulsion type water-in-oil (W/O)or emulsion of the type oil-in-water (O/W), including cetyl alcohol, glycerylmonostearate, lanolin and stearic acid (see above Remington: The Science and Practice of Pharmacy). These fillers are softening means, but typically require the addition of antioxidants and preservatives.

A suitable cream base can be emulsion oil-in-water or water-in-oil. Fillers creams can be washed with water and contain an oil phase, an emulsifier and the aqueous phase. The oil phase is also called the "dispersed phase", which usually contains petrolatum and a fatty alcohol series, such as cetyl or stearyl alcohol. The aqueous phase usually, though not necessarily, exceeds the oil phase in volume, and usually contains a wetting agent. The emulsifier in the preparation of the cream can be nonionic, anionic, cationic or amphoteric surface-active substance.

Gels are semisolid systems such as suspensions. Single-phase gels contain organic macromolecules distributed essentially uniformly throughout the liquid carrier. Under adamie gelling agents include crosslinked polymers of acrylic acid, such as carbomer, carboxypolymethylene, Carbopol®; hydrophilic polymers such as polyethylene oxides, copolymers of polyoxyethylene and polyoxypropylene and polyvinyl alcohol; cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose and methylcellulose; gums, such tragacanth and xanthan gum; sodium alginate and gelatin. To obtain a homogeneous gel can be added dispersing agents such as alcohol or glycerin, or the gelling agent can be atomized by rubbing, mechanical mixing and/or stirring.

Proposed in the context of the pharmaceutical compositions can be entered rectal, urethral, vaginal or perivaginal in the form of suppositories, vaginal suppositories, sticks, hot compresses or poultices, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional methods, as described in Remington: The Science and Practice of Pharmacy, see above.

Rectal, urethral and vaginal suppositories are solid bodies for insertion into the bore of the body and are solid at ordinary temperature, but melt or soften the ri body temperature with the release of the active ingredient(s) inside the holes. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include fillers such as giving firmness agents that provide a melting point approximately at body temperature when making proposed in the context of pharmaceutical compositions, and described in the context of antioxidants, including bisulfite and sodium metabisulfite. Suitable fillers include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (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, treated with glycerol gelatin. You can apply a combination of different fillers. Rectal and vaginal suppositories can be obtained by way of pressing or molding. Rectal and vaginal suppositories usually have a weight of approximately 2-3 g

Proposed in the context of the pharmaceutical compositions can be entered ophthalmic way in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, eye inserts and implants.

Proposed in the context of the pharmaceutical compositions can be intranasal is or inhalation into the respiratory tract. The pharmaceutical compositions can be presented in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics for the formation of fine aerosol or spray, alone 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 presented as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose, or a phospholipid, and nasal drops. For intranasal use, the powder may contain bioadhesive agent, including chitosan, or a cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be produced so that they contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilization or prolonged release of the active ingredient, proposed in the context of the propellant as the solvent and/or surfactant, such as triolein sorbitan, oleic acid or oligobrachia acid.

Proposed in the context of the pharmaceutical compositions can be ekranizirovat to size, under tamago for delivery by inhalation, such as 50 micrometers or less, or 10 micrometers or less. Particles of such sizes can be obtained by using the grinding method known to the person skilled in the art, such as a method using a spiral jet mill, jet mill for grinding in the fluidized bed, the method in the conditions of the supercritical fluid with the formation of the nanoparticles, homogenization under high pressure or spray drying.

Capsules, blisters and cartridges for use in an inhaler or insufflator can be made so that they contained a powdery mixture proposed in the context of pharmaceutical compositions, a suitable powder base, such as lactose or starch; and the modifier actions, such as l-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or may be in the form of a monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. Proposed in the context of pharmaceutical compositions for inhalation/intranasal may optionally contain a suitable corrigent, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium salt of saccharin.

Proposed in the context of pharmaceutical compositions for local injection can be manufactured by Garrett, Borg who were so so they were compositions immediate-release or modified release, including delayed, bravely supported, pulsed, modified release, the release in the target and programmed release.

D. Modified release

Proposed in the context of the pharmaceutical compositions can be manufactured in the form of dosage forms with modified release. Used in context, the term "modified release" refers to the dosage form, in which the rate or place of release of the active ingredient(s) different from the speed or release dosage form immediate-release with the introduction in the same way. Dosage forms with modified release include dosage forms with detainees, stretched, extended, bravely supported, pulsed or pulse, adjustable, rapid and quick release, release in the target programmed-release, and dosage forms with delayed stomach. Pharmaceutical compositions in dosage forms with modified release can be made using various devices and methods for providing modified release, well-known specialist in this is blasti, including but not limited to the above, a matrix device for the controlled release osmotic device for the controlled release device with many particles for controlled release ion-exchange resin, intersolubility coating, multilayer coatings, microspheres, liposomes, and combinations thereof. The rate of release of active ingredient(s) can also be modified by varying the particle size and polymorphism of active ingredient(s).

Examples of modified release include, but are not limited to, modified-release, 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 devices controlled release

Proposed in the context of the pharmaceutical composition in dosage forms with modified release can be fabricated using a matrix device for the controlled release is known to the person skilled in the art (see Takada et al. in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz ed., Wiley, 1999).

In one embodiment, proposed in the context of the pharmaceutical composition in dosage forms with modified what Svobodnye made using erodirovannogo matrix device, which is Nauheim, erodible or water soluble polymer, including synthetic polymers and existing in the nature of the polymers and their derivatives, such as polysaccharides and proteins.

Substances used in the manufacture erodium matrix include, but are not limited to, chitin, chitosan, dextran & pullulan; gum agar, Arabic gum, gum karaya, gum carob, tragacanth gum, carragenan, 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 and cellulose, such as ethylcellulose (EU), metilcellulose (MONTHS), carboxymethylcellulose (CMC), COMPOUNDS, hydroxyethylcellulose (NES), hydroxypropylcellulose (LDCs), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), acetate-butyrate cellulose (CAB), cap, CAT, hypromellose (receiver array), WRMSR, HPMCAS, acetate-trimellitate hydroxypropylmethylcellulose (NRSET) and metilgidroxiatilzelllozu (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; esters of glycerol and fatty acids; polyacrylamide; polyacrylic acid; copolymers metacrilato acid or methacrylic acid (EUDRAGIT®, Rohm America,Inc., Piscataway, NJ); poly(2-hydroxyethylmethacrylate); polylactide; copolymers of L-glutamic acid and ethyl-L-glutamate; destructible copolymers of lactic acid and glycolic acid; poly-D-(-)-3-hydroxybutiric 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)methacrylamide.

In another embodiment, the pharmaceutical composition is made from indestructible matrix device. Active ingredient(s) dissolved or dispersed in an inert matrix and is released primarily by diffusion through an inert matrix after injection. Substances suitable for use as a nondestructive matrix devices include, but are not limited to, 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 and propylene, a copolymer of ethylene and ethyl acrylate, copolymers of vinyl chloride with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrine rubbers, a copolymer of ethylene and vinyl alcohol, terpolymer ethylene, vinyl acetate and vinyl alcohol and a copolymer of ethylene and vinyloxyethyl, polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, silicone rubbers, polydimethylsiloxane, copolymers of silicones and carbonates and hydrophilic polymers, such as ethylcellulose, cellulose acetate, crosspovidone and cross-linked partially hydrolyzed polyvinyl acetate; and compounds of the fatty series, such as Carnauba wax, microcrystalline wax, and triglycerides.

In the matrix system with adjustable release, the desired release kinetics can be adjusted, for example, by the type of polymer, the viscosity of the polymer, the particle size of the polymer and/or active ingredient(s), the relationship of the active ingredient(s) to the polymer and other excipients in the composition.

Proposed in the context of the pharmaceutical composition in dosage forms with modified release can be obtained by methods known to the person skilled in the art, including direct compression, dry or wet granulation followed by extrusion, melt granulation followed by compression.

2. The osmotic device for the controlled release

Proposed in the context of the farm is septicemia composition in the form of dosage forms with modified release can be made with the use of the osmotic device for the controlled release including single-chamber system, two-chamber system, technology asymmetric membrane (AMT) and the system ekstruderede core (ECS). In General, such devices have at least two components: (a) a core containing the active ingredient(s) and (b) a semipermeable membrane with at least one aperture for delivery, which capsulebuy the core. A semi-permeable membrane regulates the flow into the water in the core from an aqueous environment of the body so as to cause the release of a medicinal product by extrusion through hole(s) for delivery.

In addition to the active ingredient(s) the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for water transfer from the environment of the organism in the core of the device. One class of osmotic agents are nabukenya in water hydrophilic polymers, which are also called "cosmopolitanly" and "hydrogels", including but not limited to the above, the hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (REO), polyethylene glycol (PEG), polypropyleneglycol (PPG), poly-(2-hydroxyethylmethacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), copolymers of PVA/PVP, polimery PVA/PVP with hydrophobic monomers, such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large blocks of REO, sodium salt croscarmellose, carrageenan, hydroxyethyl cellulose (NES), hydroxypropylcellulose (LDCs), hypromellose (receiver array), carboxymethylcellulose (CMC) and carboximetilzellulozu (SES), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium salt starch glycolate.

Another class of osmotic agents are cosmogeny, which are able to absorb water, thereby influencing the osmotic pressure gradient across the barrier of the surrounding coating. Suitable omogeni include, but are not limited to, 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, ethylenediaminetetraacetic acid, glutamine acid, p-toluensulfonate acid, succinic acid and tartaric acid; urea is their mixtures.

Osmotic agents with different rates of dissolution can be used to influence how quickly the active ingredient(s) is supplied from the first dosage form. For example, amorphous sugars, such as managem EZ (SPI Pharma, Lewes, ED) can be used to allow faster feed during the first two hours for the rapid achievement of the desired therapeutic effect, and gradually and continually release other amounts to maintain the desired level of therapeutic or preventive actions over a long period of time. In this case, the active ingredient(s) is released with such speed, to replace the quantity of the active ingredient, metabolized and excreted.

The core may include a large variety of other described in the context of excipients and carriers to improve the efficiency of the dosage form or stability or improvement of technological process of manufacture.

Substances, applicable in the manufacture of semi-permeable membranes include high, polyvinyl, ethers, polyamides, polyesters, and cellulose derivatives of various grades (marks), which are photopolymerizable and water-insoluble at physiological relevant pH values or are the Xia susceptible to giving vodorastvorimostew chemical transformation, such as stitching. Examples of suitable polymers applicable in the formation of coatings include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, acetate-butyrate cellulose (CAB), ethylcarbamate SA, SAR, methylcarbamate SA, succinate SA, acetate-trimellitate cellulose (CAT), dimethylaminoacetyl SA, ethylcarbonate SA, CHLOROACETATE, SA, ethylacetat SA, methylsulfonate SA, butylsulfonyl SA, p-toluensulfonate SA, acetate agar, amylose triacetate, acetate, beta-glucan, triacetate, beta-glucan, dimethylacetal acetaldehyde, triacetate gum carob, gidroksilirovanii the ethylene vinyl acetate, EU, PEG, PPG, copolymers of PEG/PPG, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and their esters and poly(methacrylic acid) and their esters and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkylene, polyethers, polysulfones, poly(simple ether)sulfones, polystyrenes, polyvinylchloride, polyvinyl esters and ethers, natural waxes and synthetic waxes.

A semi-permeable membrane may also be a hydrophobic microporous membrane, the pores of which are essentially filled with gas and which is not wetted by the aqueous medium, but is permeable to water vapor, as described in PA is inthe U.S. No. 5798119. Such hydrophobic, but permeable to water vapor membranes usually consist of hydrophobic polymers, such as polyalkene, polyethylene, polypropylene, polytetrafluoroethylene, derivatives of polyacrylic acid, polyethers, polysulfones, poly(simple ether)sulfones, polystyrenes, polyvinylchloride, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes and synthetic waxes.

Hole(s) for delivery (active ingredient) on a semi-permeable membrane can be created after coating by mechanical or laser drilling. Hole(s) for delivery can also be created in situ erosion of the tubes of the water-soluble substance or the rupture of a thinner portion of the membrane over the hole in the core. In addition, the holes for delivery can be formed during the coating process, as in the case of asymmetric membrane coatings of the type described in U.S. patent No. 5612059 and 5698220.

The total amount of the released active ingredient(s) and the rate of release can be significantly modulated by regulating the thickness and porosity of the semipermeable membrane, the composition of the core and the number, size and position of holes for delivery.

Pharmaceutical compositions in the form of a dosage form with an osmotic controlled release can Supplement the sustained fashion to contain additional conventional excipients, described in the context, to promote efficiency or technological process of manufacturing of the drug.

Dosage form osmotic controlled release can be obtained according to conventional methods and techniques known to the person skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21 ; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

In some embodiments, the implementation proposed in the context of the pharmaceutical composition is made in the form of a dosage form with AMT controlled-release, which contains asymmetric osmotic membrane that coats a core containing the active ingredient(s) and other pharmaceutically acceptable excipients. Cm. U.S. patent No. 5612059 and WO 2002/17918. Dosage forms with AMT-controlled release can be obtained according to conventional methods and techniques known to the person skilled in the art, including direct compression, dry granulation, wet granulation and method of coating by dipping.

In some embodiments, the implementation proposed in the context of the pharmaceutical composition is made in the form of a dosage form with ESC-adjustable release, which contains an osmotic membrane which covers the core, stereoselectively ingredient(s), hydroxyethyl cellulose and other pharmaceutically acceptable excipients.

3. The device of the set of particles with controlled release

Proposed in the context of the pharmaceutical composition in dosage forms with modified release can be made in the form of the device of the set of particles with controlled release, which contains many particles, granules or balls the size of constituting from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to 1 mm in diameter. So many particles can be produced by methods known to the person skilled in the art, including wet and dry granulation, extrusion/stereopathy, rolling-extrusion, melt-solidification and formation of the coating on the core particles applied by spray. Cm. for example, Multiparticulate Oral Drug Delivery, Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology, Marcel Dekker: 1989.

To help process and formation device in the form of a set of particles of the pharmaceutical composition can be mixed with other excipients described in the context. The resulting particles can themselves be a device from the set of particles or can be covered with various film-forming substances, such as intersolubility polymers, Nauheim the e in water and water-soluble polymers. Many particles can be further processed to obtain tablets or capsules.

4. Aimed at a target delivery

Proposed in the context of the pharmaceutical compositions can also manufacture to delivery to which target a particular tissue, receptor, or other area of the body being treated of the subject, including pharmaceutical compositions in the form of systems for delivery based on liposomes, red blood cells and antibodies. Examples of such systems include systems, but is not limited to that described in U.S. patent№6316652; 6274552; 6271359; 6253872; 6139865; 6131570; 6120751; 6071495; 6060082; 6048736; 6039975; 6004534; 5985307; 5972366; 5900252; 5840674; 5759542 and 5709874.

Applications

In one embodiment, a method for treatment, prevention or reduction of the intensity of one or more symptoms of disorders or diseases associated with CRTH2 and/or one or more other receptors PGD2introduction to a subject who has or who assumes such a condition or disease, a therapeutically effective amount proposed in the context of the compound or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer or pharmaceutical compositions.

In another embodiment, in the context of a method for treatment, prevention or decrease in the ensenaste one or more symptoms of the disorders or diseases, susceptible to modulation of CRTH2 and/or one or more other receptors PGD2containing an introduction to a subject that has or is suspected of having such a condition or disease, a therapeutically effective amount of one or more proposed in the context of the compounds or compositions.

In another embodiment, in the context of a method for treatment, prevention or reduction of the intensity of one or more symptoms of disorders or diseases mediated by CRTH2 and/or one or more other receptors PGD2containing an introduction to a subject that has or is suspected of having such a condition or disease, a therapeutically effective amount of one or more proposed in the context of the compounds or compositions.

In another embodiment, in the context of a method for treatment, prevention or reduction of the intensity of one or more symptoms associated with eosinophils disease, containing an introduction to the subject a therapeutically effective amount proposed in the context of the compound or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer or pharmaceutical compositions.

In another embodiment, in the context of the proposed method of treatment, pre the prevention or reduction of the intensity of one or more symptoms associated with basophils disease, introducing to the subject a therapeutically effective amount proposed in the context of the compound or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer or pharmaceutical compositions.

In another embodiment, in the context of a method for treatment, prevention or reduction of the intensity of one or more symptoms of the inflammatory disease, containing an introduction to the subject a therapeutically effective amount proposed in the context of the compound or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer or tautomer or pharmaceutical compositions.

Disorders and diseases that can be treated by one or more proposed in the context of compounds include, but are not limited to, (1) inflammatory or allergic diseases, including systemic anaphylaxis and violation type hypersensitivity, atopic dermatitis, urticaria, drug allergies, allergies caused by insect bites, food allergies (including abdominal disease and the like), and mastocytosis; (2) inflammatory bowel diseases, including Crohn's disease, ulcerative colitis, REIT and enteritis; (3) vasculitis, and Bechet syndrome; (4) psoriasis and inflammatory dermatosis, vkljuchajuwih the dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral cutaneous pathologies including pathology, caused by the human papillomavirus, HIV or RLV, 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, allergic lung disease and chronic obstructive pulmonary disease; (6) autoimmune diseases, including arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, diabetes type I, severe myasthenia, multiple sclerosis, grave's disease and glomerulonephritis; (7) graft rejection (including allograft rejection and disease graft-versus-host), such as the rejection of the skin graft, graft rejection, solid organ transplant rejection, bone marrow; (8) fever; (9) cardiovascular disorders, including acute heart failure, hypotension, hypertension, angina, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary arterial disease, restenosis, and vascular stenosis; (10) cerebrov the molecular violations including traumatic brain injury, "shock", ischemic damage in reperfusion injury and aneurysm; (11) a cancerous disease of the breast, skin, prostate, neck, uterine, ovarian, 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) genital and reproductive disorders, 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) ocular disorders, including glaucoma, and (20) infectious diseases, including disease caused by HIV.

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

In some embodiments, the implementation of disease is asthma caused by exercise asthma, allergic rhinitis, atopic dermatitis, chronic obstructive pulmonary disease or allergic conjunctivitis.

In some embodiments, implement disease is a syndrome Cerca-Strauss or sinusitis.

Depending on the exposed treatment of diseases and conditions of the subject proposed in the context of the compounds or compositions can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracavitary injection or infusion, subcutaneous injection, or implant), inhalation, nazalnam, vaginal the YM, rectal, sublingual, or local (e.g., transdermal or local) by introducing and can be manufactured separately or together, in the form of a suitable standard dose with pharmaceutically acceptable carriers, adjuvants and fillers suitable for each route of administration. Suggested introduction proposed in the context of the compounds in the composition of the drug depot, in which the active ingredient is released over a predetermined period of time.

In the treatment, prevention or reduction of the intensity of one or more asthma symptoms caused by exercise 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 CRTH2 and/or one or more other receptors PGD2suitable level of dose is usually about 0.001 to 100 mg per kg of body weight of the patient per day (mg/kg / day), from about 0.01 to about 75 mg/kg / 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 bring the LNA 20 mg/kg / day, with this number you can enter as a single or multiple doses. In this range the dosage may be from 0.005 to 0.05, 0.05 to 0.5 or 0,5-5,0, 1-15, 1-20 or 1-50 mg/kg / day. In some embodiments, the implementation level of dose is about 0.001 to 100 mg/kg / day. In some embodiments, the implementation level of doses is from about 0.01 to about 75 mg/kg / day. In some embodiments, the implementation level of doses is from about 0.1 to about 50 mg/kg / day. In some embodiments, the implementation level of doses is from about 0.5 to about 25 mg/kg / day. In some embodiments, the implementation level of doses is from about 1 to about 20 mg/kg / day.

For oral administration the pharmaceutical compositions may be presented in the form of tablets containing 1.0 to 1000 mg of active ingredient, especially 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 dose for exposed treatment the patient. The composition can be used to the regimen of 1-4 times a day, including one, two, three times and four times a day.

Must be, however, it is clear that a certain level of doses and frequency of dosage for any particular patient may be varied and will depend on various factors including the activity of a used compound, the metabolic stability and length of action of that compound, the age, body weight, General health, sex, method and time of administration, excretion rate, combination of drugs, the severity of the condition and the subject under treatment.

Combination therapy

A method of modulation of CRTH2 and/or one or more other receptors PGD2containing the contacting of the receptor(s) with one or more proposed in the context of the compounds or compositions. In one embodiment, the receptor(s) expressed in the cell.

Proposed in the context of the connection can also be combined or used in combination with other therapies used in the treatment, prevention or reduction of the intensity of one or more symptoms of diseases or conditions for which the proposed connection context are applicable and which include asthma, you are the private exercise asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer and pathology, above.

Other active funds, which are used in combination with the proposed in the context of compounds include, but are not limited to, inactivating antibodies (e.g. monoclonal or polyclonal) against interleukins (such as IL-4 and IL-5 (see, e.g., Leckie et al. Lancet 2000 356:2144)); soluble receptors chemokines (e.g., recombinant soluble IL-4 receptor ((Steinke and Borish 2001 Respiratory Research 2:66)); receptor modulators of chemokine, including but not limited to antagonists CCRl (for example, CP-481715 (Gladue et al. J. Biol. Chem. 278:40473)), CCR3 (for example, UCB35625 (Sabroe et al. J. Biol. Chem. 2000 275:25985) and CCR5; antagonists/antihistamines receptor histamine H1 (i.e. any compound capable of blocking, inhibiting, reducing or otherwise interfere with the interaction between histamine and its receptor)including but not limited to the above, astemizol, acrivastine, antazoline, astemizole, azatadine, azelastine, brompheniramine, carbinoxamine, carebastine, cetirizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine at, descarboethoxyloratadine is h, dexchlorpheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, Bastin, efletirizine, epinastine, Fexofenadine, hydroxyzine, hydroxyzine, ketotifen, levocabastine, levocetirizine, levocetirizine, loratadine, meclizine, mequitazine, methdilazine, mianserin, mizolastine, doberstyn, northerntel, erastamisel, Pheniramine, ecumest, promethazine, pyrilamine, temelastine, terfenadine, trimeprazine, tripelennamine and triprolidine; receptor antagonists leukotriene D4/leukotriene antagonists/LTD4 antagonists (i.e. any compound capable of blocking, inhibiting, reducing or otherwise interfere with the interaction between leukotrienes and the receptor Cys LTI)including, but not limited to the above, zafirlukast, montelukast, montelukast sodium (Singulair®), pranlukast, iralukast and pobilukast; PGD2 receptor antagonists including, but not limited to the above, compounds with antagonistic activity against PGD2; antagonists of VLA-4; corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, triamcinolone, dexamethasone, fluticasone, flunisolide and hydrocortisone, and analogues corticosteroids, such as budesonide; immunosuppressants, such as cyclosporine (cyclosporine a, Candimmyne® Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®), etc is affected immunosuppressants type FK-506 and mycophenolat, for example, mycophenolat mofetil (CellCept®); the nonsteroidal Antiasthmatic, such as beta-2 agonists (e.g., terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, salmeterol, bitolterol and pirbuterol) and a combination of beta-2-agonist-steroid (eg, salmeterol-fluticasone (Advair®), formoterol-budesonide (Symbicort®)), theophylline, kromolin, cromolyn sodium, nedocromil, atropine, ipratropium, ipertrofia bromide, inhibitors of leukotriene biosynthesis (zileuton, BAY1005); nonsteroidal anti-inflammatory agents (NSAID), such as propionic acid derivatives (for example, alminoprofen, benoxaprofen, belokrilova acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, Ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), derivatives of acetic acid (e.g., indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, enclosinga acid, fentiazac, furofenac, ibufenac, isoxepac, exping, sulindac, tiopinac, tolmetin, zidometacin, zomepirac)derived Funambol acid (for example, floranova acid, meclofenamate acid, mefenamovaya acid, niflumova acid and telenova acid), derivatives biphenylcarbonic acid (for example, diflunisal and flufenisal), oxicam (for example, from the xicam, piroxicam, sudoxicam and tenoxicam), salicylates (for example, acetylsalicylic acid and sulfasalazin) and the pyrazolones (e.g., Amazon, baseperiod, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); inhibitors of cyclooxygenase-2 (MOR-2), such as celecoxib (Celebrex®), rofecoksib (Vioxx®), valdecoxib, etoricoxib, parecoxib and lumiracoxib; inhibitors of phosphodiesterase type IV (PDE-I); opioid analgesics, such as codeine, fentanyl, hydromorphone, Levorphanol, meperidine, methadone, morphine, oxycodone, Oxymorphone, propoksifen, buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine; antithrombotic agents, such as thrombolytic agents (e.g. streptokinase, alteplaza, anistreplase and reteplase), heparin, hirudin and derivatives of warfarin, beta-blockers (eg, atenolol), beta-adrenergic agonists (e.g., isoproterenol), ACE inhibitors and vasodilators (e.g., sodium nitroprusside, nicardipine hydrochloride, nitroglycerin and enalaprilat); anti-diabetic agents such as insulin and insulin mimetics, derivatives of insulin, such as Lantus®, derivatives, sulfonylureas (e.g., gliburid, maglinte, tolbutamide, glibenclamide, glipizide or glimepiride), biguanides, such as Metformin (Glucophage®), meglitinide (for example, Repaglinide), oxadiazolidine, glucosidase inhibitors (e.g. the measures miglitol or acarbose), insulin sensitizers, including but not limited to those listed derivative of thiazolidinone (for example, rosiglitazone (Avandia®), troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) and englitazone); glucagon antagonists; agonists of GLP-1; on the basis 4; akenaten; potassium channels openers; inhibitors of HMGCoA reductase inhibitors (e.g. simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin and tseriwastatina); inhibitors of cholesterol absorption (e.g., ezetimibe, tiqueside and pemaquid); fibrates, such as, for example, fenofibrate, clofibrate, and bezafibrat; rosuvastatine preparations of interferon beta (interferon-beta,I-alpha, interferon-beta, (I-beta); gold compounds such as auranofin and aurothioglucose; TNF inhibitors, such as etanercept (Enbrel®), therapeutic antibodies, such as orthoclone (OCT), daclizumab (Zenapax®), basiliximab (Simulex®), infliximab (Remicade®), and antibody TNF D2E6; lubricants or emollients such as petrolatum and lanolin, keratolytic agents, 3-substituted derivatives of vitamin D (for example, calcipotriene and calcipotriol (Dovonex®)), PUVA, anthralin (Drithrocreme®), etretinate (Tegison®) and isotretinoin; therapeutic agents for the treatment of multiple sclerosis, such as interferon-beta,I-beta (Betaseron®), interferon beta, I-beta (Avonex®), azathioprine (imurek®, imuran®), glatiramer acetate (ka is axon®), glucocorticoid (e.g., prednisolone) and cyclophosphamide and other compounds, 5-aminosalicylic acid and its prodrugs, DNA-alkylating agents (e.g. cyclophosphamide, ifosfamide), antimetabolites (e.g., azathioprine, 6-mercaptopurine, methotrexate, a folate antagonist and 5-fluorouracil, a pyrimidine antagonist), the agents of the destruction of microtubules (e.g., vincristine, vinblastine, paclitaxel, colchicine, nocodazole and vinorelbine), DNA intercalators (e.g., doxorubicin, daunomycin and cisplatin), inhibitors of DNA synthesis, such as hydroxyurea, DNA cross-linking agents for example, mitomycin C, hormones used in therapy (e.g., tamoxifen, and flutamide), and cytostatic agents, for example, imatinib (ST1571, Gleevec®) and rituximab (Rituxan®).

In one embodiment, proposed in the context of the connection, you can type in combination with an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757. In another embodiment, proposed in the context of the connection, you can type in combination with an inhibitor of the absorption of bile acids (see, for example, U.S. patent No. 6245744 or U.S. patent No. 6221897), such as, for example, HMR 1741; inhibitor SETR, such as, for example, JTF-705; absorbent polymeric bile acid, such as, for example, cholestyramine, colesevelam; inductor of the LDL receptor (see, for example, U.S. patent No. 6342512) such as, for example, HMR1171, HMR1586; ACAT inhibitor, such as, for example, avasimibe; an antioxidant, such as, for example, OPC-14117; inhibitor of lipoprotein lipase activity, such as, for example, NO-1886; inhibitor of ATP-citrate lyase, such as, for example, SB-204990; inhibitor of stvalentines, such as, for example, BMS-188494; antagonist lipoprotein, such as, for example, CI-1027; nicotinic acid; a lipase inhibitor, such as orlistat (xenical®, Alli); immunosuppressive drugs, such as cyclosporine A, substituted xantina (for example, methylxanthines, such as pentoxifylline), tacrolimus, rapamycin (and its derivatives), Leflunomide (or its main active metabolite A or its analogues, named malononitrile), mycofenolate acid and its salts (including sodium salt, sold under the trade name mofetil®); adrenocorticoid steroids (eg, dexamethasone, methylprednisolone, methotrexate, prednisone, prednisolone, triamcinolone and their pharmaceutically acceptable salts), azathioprine, brachyura, gusperimus, 6-mercaptopurine, mizoribine, chloroquine, hydroxychloroquine and monoclonal antibodies with immunosuppressive properties; immunomodulators, such as acemannan, amiprilose, bucillamine, ditiocarb sodium, imiqimod, inosine pranobex (isoprinosine®, yanover®, Affairs of man®), interferon-beta, interferon-gamma, lentinan, levamisole, pidotimod, romantic, platonis, procodazole, propagermanium, thymomodulin, thymopentin and ubenimex.

In another embodiment, proposed in the context of the connection, you can type in combination with a therapeutic agent used to treat asthma or caused by physical exertion asthma, and including but not limited to the above, albuterol (accuneb®, ProAir HFA®, proventil®, ventolin®, vosper®), beclomethasone (kvar®), budesonide (pulmicort®), kromolin (Intal®), terbutaline (bretin®), metaproterenol (alupent®), theophylline (quibron-T®, elixophyllin®, uniphyl®), theophylline Ethylenediamine (aminophylline®), ephedrine, epinephrine, flunisolide (aerobid®), fluticasone (flovent®), levalbuterol (Hortex®), mometazon (asmanex®), montelukast sodium (singulair®), nedocromil (tiled®), triamcinolone (asmacort®), fenoterol, isoetharine, salmeterol, bitolterol, Tefillin (dilor®, delix®, lufyllin®), Tefillin/guaifenesin (CORD®, lufyllin-GG®, Ed-Bron G®), primatene asthma®, pirbuterol (maxair®), zafirlukast (assalat®) or zileuton (zyflo®).

In another embodiment, proposed in the context of the connection, you can type in combination with a therapeutic agent used for the treatment of multiple sclerosis, including, but not ogranichivaemsya listed, betametha is n (celestone®), hydrocortisone (a-hydrocort®, cortef®), hydrocortisone nutriceutical (solu-cortef®), corticotropin (aktar®), methylprednisolone (metaprel®, medrol®, depo-medrol®, marelon®), methylprednisolone nutriceutical (solu-medrol®), dexamethasone (dexpak®, texacort®), triamcinolone (kenalog®), triamcinolone acetonide, prednisolone (prelone®, orapred®, sterapred®, pediapred®), interferon beta-1A (Avonex®, Rebif®), interferon beta-1b (Betaseron®), baclofen (kemstro®, lioresal®), glatiramer (Copaxone®), dantrolene sodium (dantrium®), mitoxantrone, mitoxantrone hydrochloride (Novantrone®), natalizumab (TYSABRI®), tizanidine (zanaflex®, sirdalud®), amantadine, toxin Clostridium botulinum (Botox®), cyclophosphamide (neosar®, cytoxan®) or cycloheptadiene.

In another embodiment, proposed in the context of the connection, you can type in combination with a therapeutic agent used for the treatment of inflammatory bowel disease, including but not limited to the above, adalimumab (Humira®), loperamide (diamond®, immodium®, kaopectate 1-D®, Maalox®, imperil®, Pepto diarrhea control®), azathioprine (imuran®), betamethasone (celestone®), hydrocortisone (a-hydrocort®, cortef®), corticotropin (Astar®), methylprednisolone (metaprel®, medrol®, depo-medrol®, marelon®), dexamethasone (dexpak®, texacort®), salasin(dipentum®), kromolin (gastrocrom®), triamcinolone (kenalog®, aristocort®, triacet®), mercaptopurine (purinethol®) or prednisolone (prelone®, orapred®, sterapred®, pediapred®).

In another embodiment, proposed in the context of the connection, you can type in combination with a therapeutic agent used for the treatment of transplant rejection, including but not limited to the above, betamethasone (celestone®), hydrocortisone (a-hydrocort®, cortef®), corticotropin (aktar®), methylprednisolone (metaprel®, medrol®, depo-medrol®, marelon®), dexamethasone (dexpak®, texacort®), triamcinolone (kenalog®, aristocort®, triacet®), cyclosporine (Neoral®, Sandimmune®, gengraf®), muromonab (orthoclone OKT®), tacrolimus (prograf®) or prednisolone (prelone®, orapred®, sterapred®, pediapred®).

Such other therapeutic agent or drug can be administered by and in quantities normally used to them, simultaneously or sequentially with the proposed in the context of a compound or composition. When offered in the context of a connection, use in conjunction with one or more other drugs, can be applied pharmaceutical composition containing such other drugs in addition to the proposed connection context, but not necessarily. According to this, FA the pharmaceutical composition, proposed context include compositions that contain one or more other active ingredients or therapeutic agents, in addition to the proposed connection context.

The mass ratio proposed in the context of the connection to the second active agent can be varied, and it would depend upon the effective dose of each ingredient. Usually apply effective dose of each. For example, when offered in the context of connection combined with NSAID, the mass ratio proposed in the context of the connection to the NSAID may be in the range from about 1000:1 to about 1:1000, or from about 200:1 to about 1:200. The combination proposed in the context of compounds and other active ingredients are also usually located in the aforementioned range, but in each case it is necessary to apply an effective dose of each active ingredient.

EXAMPLES

Obtaining methyl-2-(4-nitrobenzyl)-4,6-bis-dimethylpyrimidin-5-ilaclama (1)

To a suspension of methyl-4,6-dichloro-2-(4-nitrobenzyl)pyrimidine-5-ilaclama (10,00 g, 28,08 mmol) in ethanol (100 ml) was added thiourea (6.42 per g, 84,30 mmol) and the resulting suspension was heated under reflux for 2 hours and then was cooled to room temperature before cooling at 4°C for 18 hours. Education is bassous thick reddish-brown suspension was filtered and collected by filtration the precipitate suspended in diisopropyl simple ether (100 ml), was filtered and dried in the air. Thus obtained bright yellow intermediate product hydrochloride toronja suspended in water (40 ml) and was treated with 3 n sodium hydroxide solution to obtain a clear solution (30 ml). Introduced logmean (the 5.25 ml, 84,30 mmol) and the resulting reaction mixture was vigorously stirred at room temperature for 18 hours. The resulting grey suspension was filtered and the filter residue was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the filtrate was treated with diisopropyl ether to until no longer observed precipitation. The separated solids were collected by suction and washed with diisopropyl ether, thus obtaining methyl-2-(4-nitrobenzyl)-4,6-bis-dimethylpyrimidin-5-ylacetic (1) in the form of a white powder (6,87 g, 86%).

Obtaining methyl-2-(4-aminobenzyl)-4,6-bis-dimethylpyrimidin-5-ilaclama (2)

A suspension of compound 1 (0.50 g, 1,32 mmol) in methanol (15 ml) was treated with ammonium chloride (0.27 g, equal to 4.97 mmol), powdered zinc (0,93 g, 14,20 mmol) and water (1 ml). The resulting gray suspension was heated at 80°C for 1 hour and allowed it to cool to room temperature. Added a spatula celite and then filtered through a layer of celite. The residue was washed with methanol and filtercontrol in vacuum, while receiving a white paste which was dissolved in ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum, thus obtaining the crude product as light brown oil. Chromatography on silica gel with elution with 20% ethyl acetate in hexano gave a thick oil, which was aterials upon standing at room temperature. Rubbing with ethyl acetate and hexane gave methyl 2-(4-aminobenzyl)-4,6-bis-dimethylpyrimidin-5-ylacetic (2) in the form of a white powder, which was collected by suction (0,43 g, 93%).

Receiving (4,6-bis-thiomethyl-2-(4-(4-trifloromethyl)aminobenzyl)pyrimidine-5-yl)acetic acid (3)

A solution of compound 2 (0.14 g, 0.40 mmol) in dichloromethane (5 ml) was treated with triethylamine (0.06 ml, 0.44 mmol) and then cooled in an ice bath. To the mixture was added dropwise 4-cryptomathematical (0,07 ml, 0.44 mmol) and the resulting reaction mixture was allowed to warm to room temperature. After stirring for 1 hour at room temperature the reaction mixture was distributed between dichloromethane and water. The separated organic layer was washed sequentially with saturated sodium bicarbonate solution, water and saturated salt solution, dried over anhydrous sodium sulfate, filtered and Ko is centered in the vacuum, while receiving the crude product as a white powder, which was washed with dichloromethane and diisopropyl ether and collected by suction. An aliquot of the product (0.11 g) was dissolved in tetrahydrofuran (8 ml) and treated with 1 n sodium hydroxide (2 ml) followed by treatment a sufficient amount of methanol to obtain a homogeneous mixture (approximately 0.5 ml). After stirring for 18 hours at room temperature the volatile components were removed in vacuum and the thus obtained white suspension was diluted with water (1 ml), cooled in an ice bath and acidified 3 n hydrochloric acid to weakly acid reaction (pH ~5). Thus obtained separated solid substance was collected by suction, washed with water and dried under vacuum, thus obtaining (4,6-bis-thiomethyl-2-(4-(4-trifloromethyl)aminobenzyl)pyrimidine-5-yl)acetic acid (3) (0.08 g, 80%) as a white powder.

APPLICATION

TABLE 1.
ConnectionKi (nmConnectionKi (nm)
23598
4845
7832

ConnectionKi (nmConnectionKi (nm)
168033
1635
27310
8.08.3

Connection Ki (nmConnectionKi (nm)
1314
7188
13630
626.0

ConnectionKi (nmConnectionKi (nm)
528.2
1740
img src="https://img.russianpatents.com/1147/11470232-s.jpg" height="46" width="61" /> 18334
288398

ConnectionKi (nmConnectionKi (nm)
2728
1778
2828
242502

ConnectionKi (nmConnectionKi (nm)
277912
1652494
5.81.2
1.659

ConnectionKi (nmConnectionKi (nm)
4142
120.4
4.4 5.8
0.90.4

ConnectionKi (nmConnectionKi (nm)
1.2128
2.59.1

1. The compound having the formula III

or its pharmaceutically acceptable salt, where X represents a direct bond;
R2means hydrogen, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, -NR8aR8bor group-SR3;
each R3independently is a (C1-C6)alkyl, optionally mono-, di - or tizamidine halogen; or (C3-C7)cycloalkyl;
R4aand R4brepresent hydrogen;
R6represents aryl; or heteroaryl; the de aryl and heteroaryl optionally substituted at substitutable position by one or more substituents, selected from the group consisting of (a) halogen; (b) cyano; (C) nitro; (a) hydroxy; (e) guanidino; (f) heteroaryl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) -NR8aR8b; (l) -C(O)R9; (m) -C(O)NR8aR8b(n) -OC(O)NR8aR8b; (o) -C(O)OR9; (p) -NR7C(O)OR9; (q) -NR7C(O)R9; (g) sulfamoyl; (s) (C1-C6)alkylsulfonyl; (t) (C1-C6)alkylaminocarbonyl; (u) di(C1-C6)alkylaminocarbonyl; (v) (C1-C6)alkyl, optionally mono-, di - or trisemester halogen; (w) (C1-C6) alkoxy, optionally mono-, di - or trisemester halogen; and (x)(C1-C6)alkylthio, optionally mono-, di - or trisemester halogen;
R7represents hydrogen;
in each case, R8aand R8bindependently selected from (i) or (ii) as follows:
(i) each of R8aand R8bindependently selected from (a) hydrogen;
(b) (C1-C6)alkyl; (C) phenyl; (d) (C1-C6)alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C1-C6)allylcarbamate, di((C1-C6)alkyl)carbamoyl, (C3-C7)cycloalkylcarbonyl or (C3-C7)heterocyclisation; (e) (C1-C6)alkyl, mono-, di - or trisemester halogen, or (f) (C3-C7)cycloalkyl; Il the
(ii) each of R8aand R8btogether with the N to which they are linked, independently may form a 3-8-membered saturated or unsaturated ring, optionally containing one or more atoms are O or S or one or more additional N atoms;
each R9independently represents (a) hydrogen; (b) (C1-C6)alkyl; (C) phenyl or (d) (C1-C6)alkyl, substituted aryl, alkoxy or mono-, di - or tizamidine halogen; K is 0; and
where each aryl independently represents an aromatic monocyclic or bicyclic group containing from 6 to 10 carbon atoms; and each heteroaryl independently represents a monocyclic or bicyclic aromatic 5-to 10-membered ring system, where 1-3 atoms in the cyclic system are heteroatoms, each of which is independently selected from a nitrogen atom, oxygen or sulfur.

2. The compound according to claim 1, where each R3independently is a (C1-C6)alkyl.

3. The compound according to claim 1, where
R2represents-S(C1-C6)alkyl and
R7and R9each represents hydrogen.

4. The compound according to claim 1, where
R7and R9each represents hydrogen.

5. The compound according to claim 1 having formula IV

or its pharmaceutically acceptable salt,
where is jdy R 3independently is a (C1-C6)alkyl;
each R10independently represents (a) halogen; (b) cyano; (C) nitro; (d) hydroxy; (e) -NR8aR8b; (f) -C(O)R9; (g) -C(O)NR8aR8b, (h) -OC(O)NR8aR8b; (i) -NR7C(O)OR9; j) -NR7C(O)R9; (k) -C(O)OR9; (l) guanidino; (m) phenyl; (n) phenyloxy; (o) benzyl; (p) benzyloxy; (q) sulfamoyl; (r) (C1-C6)alkylsulfonyl; (s) (C1-C6)alkylaminocarbonyl; (t) di(C1-C6)alkylaminocarbonyl; (u) (C1-C6)alkyl, optionally mono-, di - or tizamidine halogen; (v) (C1-C6)alkoxy, optionally mono-, di - or tizamidine halogen; or (w) (C1-C6)alkylthio, optionally mono-, di - or tizamidine halogen; q is 0, 1, 2, 3, 4 or 5.

6. The compound according to claim 1, having the formula V

or its pharmaceutically acceptable salt, where
R2is a halogen;
R3is a (C1-C6)alkyl;
each R10independently represents (a) halogen; (b) cyano; (C) nitro; (d) hydroxy; (e) -NR8aR8b; (f) -C(O)R9; (g) -C(O)NR8aR8b, (h) -OC(O)NR8aR8b; (i) -NR7C(O)OR9; (j) -NR7C(O)R9; (k) -C(O)OR9; (l) guanidino; (m) phenyl; (n) phenyloxy; (o) benzyl; (p) benzyloxy; (q) sulfamoyl; (r) (C1 6)alkylsulfonyl; (s) (C1-C6)alkylaminocarbonyl; (t) di(C1-C6)alkylaminocarbonyl; (u) (C1-C6)alkyl, optionally mono-, di - or tizamidine halogen; (v) (C1-C6)alkoxy, optionally mono-, di - or tizamidine halogen; or (w) (C1-C6)alkylthio, optionally mono-, di - or tizamidine halogen; q is 0, 1, 2, 3, 4 or 5.

7. The compound according to claim 1, where
each R10independently represents (a) halogen; (b) cyano; (C) nitro; (a) hydroxy; (e) -NH2; (f) -NH(C1-C6)alkyl; (g) -N((C1-C6)alkyl)2; (h) -C(O)(C1-C6)alkyl; (i) -CO2H; (j) -NHC(O)(C1-C6)alkyl; (k) -C(O)O(C1-C6)alkyl; (l) phenyl; (m) phenyloxy; (n) benzyl; (o) benzyloxy; (p) sulfamoyl; (q) (C1-C6)alkylsulfonyl; (r) (C1-C6)alkylaminocarbonyl; (s) di(C1-C6)alkylaminocarbonyl; (t) (C1-C6)alkyl, optionally mono-, di - or tizamidine halogen; (u) (C1-C6)alkoxy, optionally mono-, di - or tizamidine halogen; or (v) (C1-C6)alkylthio, optionally mono-, di - or tizamidine halogen.

8. The compound according to claim 1, having the formula VIII

or its pharmaceutically acceptable salt, where X represents a direct link.

9. The compound according to claim 1 them the abuser formula IX

or its pharmaceutically acceptable salt, where
R2represents a halogen and
X represents a direct link.

10. The compound according to claim 1, having the formula

or its pharmaceutically acceptable salt.

11. The compound according to claim 1, having the formula

or its pharmaceutically acceptable salt.

12. The compound according to claim 1, having the formula

or its pharmaceutically acceptable salt.

13. The compound according to claim 1, having the formula

or its pharmaceutically acceptable salt.

14. Pharmaceutical composition having a modulating effect on the activity of CRTH2 receptor containing an effective amount of a compound according to any one of claims 1 to 13 and one or more pharmaceutically acceptable carriers or excipients.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula (I-a), having the capacity to simulate axonal growth coupled with the capacity to stimulate angiogenesis and can be used in treating spinal chord damage, damage to the central nervous system as a result of head injuries, ischaemic stroke, ischemic heart disease, peripheral arterial occlusive disease, vascular dementia, cerebrovascular dementia or senile dementia. In the compound of formula (I-a): R0 is a group where R3 and R4 denote a hydrogen atom; R1 is a methyl group; R2 is a methyl group; R5 is a hydrogen atom; R6 is a hydrogen atom; R7 is a methyl group; E is an oxygen atom; is a benzyl group, a cyclohexyl methyl group, an isobutyl group, a cyclohexane carbonyl group, an acetyl group, a phenylsulphonyl group, a cyclohexyl group, a piperidine-1-carbonyl group, a methylbenzyl group, a phenyl group, a fluorobenzyl group, a methoxybenzyl group or a trifluorobenzyl group; or a pharmaceutically acceptable salt thereof.

EFFECT: high efficiency of using the compounds.

4 cl, 16 dwg, 27 tbl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to specific derivatives of bicyclic amides disclosed in the claim, as well as a pharmaceutical composition.

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13 cl, 115 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new acid dihydrogenphosphate of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyrimidine-4-yl}phenyl)-2-methylpropionic acid of formula optionally in a crystalline form exhibiting cAMP inhibitor properties. Also, the invention refers to a pharmaceutical composition.

EFFECT: compound can find application for treating the diseases associated with cell expression of prostaglandin D2 in such diseases, as allergic rhinitis, bronchial asthma, allergic conjunctivitis, etc.

3 cl, 12 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula I, as well as to their diastereoisomers, enentiomers and/or pharmaceutically acceptable salts, which possess inhibiting action with respect to cyclin-dependent kinases and/or tyrosinekinases of VEGF receptor. In compound of general formula (I) Q stands for group where D, E, G, L, M and T in each case represent carbon, R1 represents hydrogen, halogen or CF3, R2 represents C1-C10-alkyl, which can optionally be disrupted with one group-C(O), C2-C10-alkinyl, C3-C10-cycloalkyl or phenyl, which is optionally substituted in one or more places in similar or different way by hydroxyl, halogen, C1-C6-alkoxy, C1-C6-alkyl, C3-C10-cycloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl or -COR8, X represents oxygen, sulphur or group -NH-, R3 represents hydroxy, halogen, CF3 or C1-C6-alkoxy, m represents 0-4, R4 represents hydrogen or group -COR8, NO2 or -SO2R7, or represents C1-C10-alkyl or C3-C10-cycloalkyl, R5 represents C1-C10-alkyl, which can be optionally substituted in one or more places, in similar or different way, by hydroxyl or C3-C10-cycloalkyl, or C3-C10-cycloalkyl, R7 represents C1-C10-alkyl, which is optionally substituted by group trimethylsilanyl (TMS), R8 represents C1-C6-alkyl, C1-C6-alkoxy. Invention also relates to intermediate compounds.

EFFECT: compounds can be applied for obtaining medication intended for treatment of cancer, selected from Kaposhi's sarcoma, Khodgkin's disease, leukemia or solid tumour, such as carcinoma of mammalian gland, kung, large intestine or prostate gland, autoimmune disease, such as psoriasis, and/or proliferative diseases, such as hemangioma or angiofibroma.

21 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents 3-10-member non-aromatic heterocyclic group, where group is limited by group containing nitrogen as ring-constituting atom, and nitrogen, having additional bond, or group represented by formula -NR11aR11b, where R11a and R11b can be similar or differ from each other, and each represents hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10-member heteroaryl or 4-10-member non-aromatic heterocyclic group, and R11a and R11b can be substituted with substituent selected from group of substituents A or group of substituents B, and R1 can be substituted with substituent selected from group of substituents A or group of substituents B; R2 and R3 represent hydrogen; R4, R5, R6 and R7 can be similar or differ from each other, and each represents hydrogen, halogen, C1-6 alkyl; R8 represents hydrogen or C1-6 alkyl; R9 represents 3-10-member non-aromatic heterocyclic group, where group is limited by group containing nitrogen as ring-constituting atom, and nitrogen, having additional bond, or group represented by formula -NR11aR11b, where R11a and R11b have the same values as described above; n represents integer 1 or 2; and X represents group, represented by formula -C(R10)=, or nitrogen, where R10 represents hydrogen; where group of substituents A consists of halogen, hydroxyl and oxogroup; where group of constituents B consists of C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10-member heteroaryl, 3-10-member non-aromatic heterocyclic group, C1-6 alkoxy, 5-10-member heteroaryloxy, 4-10-member non-aromatic heterocyclic oxygroup and group represented by formula -T1-T2-T3, and each group in group of substitutes B can be substituted with substituent selected from group of substituents C, where T1 represents direct bond or C1-6 alkylene, T2 represents group represented by formula -NRT1-, T3 represents hydrogen or C1-6 alkyl, and RT1 represents hydrogen or C1-6 alkyl; and where group of substutuents C consists of hydroxyl, C1-6 alkyl, 3-10-member non-aromatic heterocyclic group and di-C1-6 alkylaminogroup, to pharmaceutical composition possessing anti-tumor activity, to inhibitors of: hepatocyte growth factor receptor, angiogenesis and cancer dissemination, as well as to anti-tumor medication.

EFFECT: obtaining novel compounds which demonstrate anti-tumor activity.

31 cl, 111 ex, 18 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for improved synthesis of pharmacologically active compound of the formula (A): Method involves the following steps: (a) interaction of compound of the formula (I): with alkaline metal nitrite in the presence of suitable acid to yield compound of the formula (VII): (b) coupling compound of the formula (VII) with compound of the formula (VI): to yield compound of the formula (V): and (c) removal of protection from compound of the formula (V) to yield compound of the formula (A). Compound of the formula (A) possesses property of antagonist of R2T receptors, high metabolic stability and bioavailability. Also, invention relates to a novel intermediate substance of the formula (I) and methods for its synthesis, and to novel intermediate substances used in its synthesis.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

12 cl, 4 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

The invention relates to an improved process for the preparation of compounds of formula (I), where each of the residues X and Y independently of one another denotes hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxygroup or (C1-C4)-allylthiourea, each of the last three residues is unsubstituted or substituted by one or more residues from the group comprising halogen, (C1-C4)-alkoxygroup or (C1-C4)-allylthiourea, means or di[(C1-C4)alkyl]-amino, (C3-C6-cycloalkyl, (C3-C5)-alkenyl, (C3-C5)-quinil, (C3-C5)-alkenylacyl or (C3-C5)-alkyloxy, in which the compound of formula (II) or salts thereof, where X and Y are specified in the formula (I) values are subjected to interaction with 1-6 moles of phosgene per 1 mol of the compounds of formula (II) in the presence of 2-3,5 molar equivalents of an organic aminoaniline per mole of the compounds of formula (II) and in the presence of an aprotic organic solvent at the reaction temperature in the range from -30 to +60oWith

The invention relates to new derivatives of phenylsulfonylacetate General formula (I), which are herbicide and regulating plant growth properties and can find application in agriculture

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 2-S-benzylpyrimidine derivatives having CRTH2 receptor antagonist activity. In formula 1: R1 means -CO2H; R4a and R4b mean hydrogen; W means -C(O)NR7-; R2 and R3, each independently mean F; Cl; Br;-NR10R11 or (C1-C6)alkoxy, optionally substituted by 1-3 halogen atoms; R5 means hydrogen; R6 means (C1-C6)alkyl; (C6-C19)aryl or (5-15)-member heteroaryl containing nitrogen, oxygen or sulphur atoms as heteroatoms, wherein above aryl and heteroaryl are optionally substituted by one or more substitutes specified in a group consisting of halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; and (C1-C6)alkoxy optionally substituted by one, two or three halogen atoms; R7 means hydrogen; R10 and R11, each independently mean (C1-C6)alkyl; or R10 and R11, together with N, whereto attached form a 3-8- member saturated or unsaturated ring optionally containing one or more O or S atoms, or one or more additional N atoms in the ring; k is equal to 0; m is equal to 1.

EFFECT: invention also refers to using the above compounds for preparing a drug for treating allergic and inflammatory diseases mediated by CRTH2 receptor activity, such as asthma, atopic dermatitis, allergic conjunctivitis, Churg-Strauss disease, sinusitits, basophilic leukaemia, and recurrent urticaria.

27 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (I) X=N or C-R3; R1 stands for proton, saturated or unsaturated linear alkoxy radical, which has 2-5 carbon atoms; cycloalkyloxy radical, which has to 6 carbon atoms, saturated linear alkylmercapto radical, which has 1-3 carbon atoms; amino radical, having 1-10 carbon atoms, selected from saturated or unsaturated linear mono- or dialkylamino radical, or cycloalkylamino radical, cyclic amino radical, and each of cyclic groups can be substituted with 1-2 metal groups, or benzylaminogroup; R2 represents proton, saturated or unsaturated, linear alkyl radical, which has 1-5 carbon atoms, or cyclic aliphatic radical, which has to 6 carbon atoms, trifluoromethyl, stiryl or methylmercaptogroup; R3 stands for trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyanogroup or alkoxycarbonyl sunstituent, which has 1-3 carbon atoms in alkoxygroup.

EFFECT: obtaining novel 2-nitroheterylthiocyanates of general formula (I), or their pharmaceutically acceptable additive salts with acids or bases, probably in crystalline form, possessing activity with respect to strains of fungi, causative agents of fungal infections, their application for treatment of fungal infections, as well as obtaining based on them pharmaceutical composition.

8 cl, 3 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing optically pure voriconazole via: a) coupling reaction of 1-(2,4-difluorophenyl)-2(1H-1,2,4-triazol-1-yl)ethanone with 4-(1-bromoethyl)-6-(4-chlorophenylsulphanyl)-5-fluoropyrimidine in Reformatsky reaction conditions to obtain the desired (2R,3S)/(2S,3R) enantiomeric pair, b) splitting the thiol fragment from the enantiomer to obtain racemic voriconazole; and c) extracting the desired optically pure voriconazole via optical separation of the enantiomer using an optically active acid.

EFFECT: improved method.

4 cl, 7 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 4-aminocarbonylpyrimidine of formula (I).

EFFECT: invention is applicable as P2Y12 receptor antagonists for treatment and/or prevention of diseases or disease states of peripheral vessels, as well as vessels, supplying internal organs, vessels of liver and kidneys, in treatment and/or prevention of cardiovascular and cerebrovascular diseases and states, associated with aggregation of platelets, including thrombosis in humans and mammals.

26 cl, 500 ex

FIELD: medicine.

SUBSTANCE: invention refers to compound of formula I wherein X represents -S- or -NH-; R1 represents C1-12alkyl, C2-12alkenyl, phenyl C1-12alkel, phenyl C2-12alkenyl or phenyl-O-C1-12alkyl and wherein said phenyl groups are optionally substituted with one or two assistants chosen from the group consisting of lower C1-7alkyl, C C1-7alkoxy and halogen C1-7alkyl; R2 represents hydrogen, lower C1-7alkyl or C3-6cycloalkyl; R3/R4 together with N-atom whereto attached, form nonaromatic 5,6-members heterocyclic ring system which optionally contains in addition to N-atom one additional heteroatom chosen from the group, consisting of O or N and where the ring system is optionally substituted group lower C1-7alkyl, lower C1-7alkoxy, -NR2, -CONR2; or R3/R4 together with N-atom whereto attached, can form heterocyclic ring system which contains at least two rings and which optionally contains one or two additional heteroatoms chosen from group, consisting of N and O; R represents hydrogen or lower C1-7alkyl; R5 represents hydrogen or lower C1-7alkyl; or to pharmaceutically acceptable additive salts with acid of this compound. The invention also concerns a medical product.

EFFECT: improved clinical effectiveness.

16 cl, 4 dwg, 3 tbl, 43 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes compound of the general formula (3): wherein R15 represents a heterocyclic group chosen from 3-7-membered saturated or 4,7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom, or 7-14-membered polycyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R16 represents a cycloalkyl group comprising 3-7 carbon atoms, monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms, or heterocyclic group chosen from 3-7-membered saturated or 4-7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R17 represents a monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms or heterocyclic group chosen from 4-7-membered saturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R18 represents hydrogen atom or (C1-C)-alkyl group; X represents -S-, -SO- or -SO2; or N-oxide or S-oxide of this compound; their salt; or solvate of above described compound. Proposed compounds possess the inhibitory activity against producing/secretion of β-amyloid protein and can be used in treatment of such diseases as Alzheimer's disease, Down's disease and other diseases associated with amyloid deposition.

EFFECT: valuable medicinal properties of inhibitors.

7 cl, 1 tbl, 410 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1,2-diaminopentane of the formula (I): wherein R1 means hydrogen atom, (C1-C6)-alkyl; R2 means phenyl-(C1-C6)-alkyl wherein phenyl is substituted with halogen atom; R3 means hydrogen atom; R4 means -W-X-Y-Z wherein W is absent or means (C1-C6)-alkylene; X is absent or means -S(O)n- or -N(Ra)-; Y means arylene or heteroarylene; Z means hydrogen atom, aryl; Ra means hydrogen atom; n = 0 under condition that this enumeration doesn't involve trans-3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]benzamide and trans-N-methyl-3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]benzamide, or its pharmaceutically acceptable salt. Also, invention proposes a pharmaceutical composition possessing antagonistic activity with respect to CCR-3 receptors and comprising the effective amount of compound of the formula (I) or its salt and excipient. Invention provides using derivatives of 1,2-diaminopentane inhibiting binding eotaxine with CCR-3 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 1 tbl, 17 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel retinoid compounds of the structural formula (I) or their pharmaceutically acceptable salts and pharmaceutical compositions possessing agonistic activity with respect to retinoid receptors and comprising indicated compounds wherein n = 1; d = 0 or 1; B means -CR7=CR8-, -CH2O- wherein R7 and R8 each means independently hydrogen atom; X means phenyl optionally substituted with halogen atom, or 5-membered heteroaryl comprising sulfur atom (S) as a heteroatom; R1 means -C(=O)-R9 wherein R9 means alkyl, hydroxyl, amino-, heteroaryloxy-group comprising oxygen atom (O) or 6-membered heterocyclyl comprising nitrogen atom (N) as a heteroatom; R2 means: (a) -(CR10R11)m-Yp-R12; m means a whole number from 1 to 10; p means 0 or 1; R10 and R11 mean hydrogen atom; Y means -O-, -S- or -NR13-; R13 means hydrogen atom; R12 means hydrogen atom, alkyl, cycloalkyl, phenyl, 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom, 5- or 6-membered heteroarylalkyl comprising atoms N, S, O as a heteroatom, heteroalkyl comprising atoms N, S, O as a heteroatom, 5- or 6-membered heterocyclyl comprising atoms N, S, O as a heteroatom, or 5- or 6-membered heterocyclylalkyl comprising atoms N, S, O as a heteroatom under condition that when p means 0 then R12 doesn't mean hydrogen atom or alkyl; (b) 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom; (c) -Z-L wherein Z means -CR14=CR15-, -C≡C-, -C(=O) or -S-; R14 and R15 mean hydrogen atom; L means 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom; (d) -CR14=CR15-L1 wherein L1 means -S(O)2R17 or -SO2NR18R19 wherein R17 means alkyl; R18 and R19 mean hydrogen atom; each R3 means independently hydrogen atom, hydroxyl or oxo-group; t means 1 or 2.

EFFECT: valuable medicinal properties of compounds and compositions.

59 cl, 10 tbl, 54 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to derivatives of aminodicarboxylic acids of the general formula (I) and a medicinal agent able to stimulate activity of soluble guanylate cyclase being independently of the presence of the heme group comprising in it and able to cause relaxation of vessels and comprising at least one compound of the general formula (I). Agent is designated for treatment of cardiovascular diseases and for treatment of the central nervous system diseases characterizing by disorder of the system NO/cGMP, and shows high bioavailability and effectiveness.

EFFECT: improved and valuable medicinal properties of agent.

7 cl, 232 ex

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on
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