Cache Methylhydrofumarate prodrugs, pharmaceutical compositions containing them and methods for using

Methylhydrofumarate prodrugs, pharmaceutical compositions containing them and methods for using


FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , which is a methylhydrofumarate (MHF) prodrug. In formula (I), radicals and symbols have the values specified in the patent claim. The invention also refers to a pharmaceutical composition containing the declared methylhydrofumarate drugs, to using the declared methylhydrofumarate drugs and the pharmaceutical composition containing them, for treating diseases, such as psoriasis, asthma, multiple sclerosis, inflammatory intestinal disease and arthritis, and to a method of treating the above diseases.

EFFECT: higher oral bioavailability and plasma MHF, dimethylfumarate and/or other metabolites.

47 cl, 1 tbl, 54 ex

 

The technical field to which the invention relates

This description reveals the prodrug of methylhydroquinone, pharmaceutical compositions comprising prodrugs of methylhydroquinone, and applications prodrug of methylhydroquinone and pharmaceutical compositions for the treatment of diseases such as psoriasis, asthma, multiple sclerosis, inflammatory bowel disease and arthritis.

The level of technology

The fumaric acid esters (PAE), approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis and proposed for use in the treatment of a wide range of immunological, autoimmune, and inflammatory diseases and conditions.

FAE and other fumaric acid derivatives proposed for use in the treatment of a variety of diseases and conditions, including immunological, autoimmune and inflammatory disorders, including psoriasis (Joshi and Strebel, WO 1999/49858; US 6277882; Mrowietz and Asadullah, Trends Mol. Med., 2005, 111(1), 43-48; and Yazdi and Mrowietz, Dermatology Clinics, 2008, 26, 522-526); asthma and chronic obstructive pulmonary disease (Joshi et al., WO 2005/023241 and US 2007/0027076); heart failure, including left ventricular insufficiency, myocardial infarction and angina (Joshi., WO 2005/023241; Joshi et al., US 2007/0027076); mitochondrial and neurodegenerative diseases such as Bo�of ESN Parkinson, Alzheimer's disease, Huntington's disease, pigmentary retinopathy and mitochondrial encephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659. US 6509376, US 6858750 and US 7157423); transplantation (Joshi and Strebel, WO 2002/055063, US 2006/0205659, US 6359003, US 6509376 and US 7157423; and Lehmann et al., Arch. Dermatol. Res., 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO 2002/055063, US 6509376, US 7157423 and US 2006/0205659), including multiple sclerosis (MS) (Joshi and Strebel, WO 1998/52549 and US 6436992; Went and Lieberburg, US 2008/008986; Schimrigk et al., Eur. J. Neurology, 2006, 13, 604-610; and Schilling et al., Clin. Experimental Immunology, 2006, 145, 101-107); ischemia and reperfusion injury (Joshi et al., US 2007/0027076); AGE-induced genome damage (Heidland, WO 2005/027899); inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; arthritis and other diseases (Nilsson et al., WO 2006/037342, and Nilsson and Muller, WO 2007/042034).

I believe that the mechanism of action of fumaric acid esters is mediated pathways associated with the immunological reaction. For example, FAE cause a shift of immune response from Th1 to Th2, favorably altering the cytokine profile; inhibit induced cytokine expression of adhesion factors, such as VCAM-1, ICAM-1 and E-selection, and by this decreases the dropping of immune cells; and reduce lymphocytes through apoptotic mechanisms (Lehmann et al., J. Investigative Dermatology, 2007, 127, 835-845; Gesser et al., J. Investigative Dermatology, 2007, 127, 2129-2137; Vandermeeren et al., Biochem. Biophys. Res. Commun., 1997, 234, 19-23; and Treumer et al., J. Invest. Dermatol. 2003, 121, 1383-1388).

Recent studies lead to the conclusion that FAE are inhibitors of the activation of NF-κ - transcription factor that regulates the inducible expression of mediators of prosopalgia (D'acquisto et al., Molecular Interventions, 2002, 2(1), 22-35). Accordingly, FAE proposed for use in the treatment of NF-κb-mediated diseases (Joshi et al., WO 2002/055066; and Joshi and Strebel, WO 2002/055063, US 2006/0205659, US 7157423 and US 6509376). It is also shown that inhibitors of the activation of NF-κ applicable in angiostatic therapy (Tabruyn and Griffioen, Angiogenesis, 2008, 11, 101 to 106), in inflammatory bowel disease (Atreya et al., J. Intern. Med., 2008, 263(6), 591-6); and, in animal models of diseases, including inflammation, including neutrophil alveolitis, asthma, hepatitis, inflammatory bowel disease, neurodegeneration, ischemia/reperfusion, septic shock, glomerulonephritis, and rheumatoid arthritis (D'acquisto et al., Molecular Interventions, 2002, 2(1), 22-35).

Studies also suggest that inhibition of NF-κ FAE may be mediated by interaction with the signal transmission of the tumor necrosis factor (TNF). Dimethyl fumarate inhibits induced TNF mRNA expression of tissue factor and protein and induced TNF DNA binding protein NF-κ, and inhibits induced TNF admission of activated protein NF-κ, and through this inhibited the activation of genes of inflammation (Loewe et al., J. Immunology, 2002, 168, 4781-4787). The way gear� TNF signals involved in the pathogenesis immunopositivity inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, psoriasis, psoriatic arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis (Tracey et al., Pharmacology & Therapeutics, 2008, 117, 244-279).

The enteric coated tablet Fumaderm®, containing a mixture of salts of monomethylfumarate and dimethylfumarate (DMF) (2), which rapidly hydrolyses to monomethylfumarate (MPR) (1), regarded as the main bioactive metabolite, was approved in Germany in 1994 for the treatment of psoriasis.

Fumaderm® is dosed TID for 1-2 g/day, administered for the treatment of psoriasis. Fumaderm® detects a high degree of variability from patient to patient with respect to the absorption of the drug, and food greatly reduces biological availability. Suppose that the absorption occurs in the small intestine with maximum levels achieved after 5-6 hours after oral administration. Significant side effect occurs in 70-90% of patients (Brewer and Rogers, Clin. Expt'l Dermatology, 2007, 32, 246-49; and Hoefhagel et al., Br. J. Dermatology, 2003, 149, 363-369). The side effects of modern FAE therapy include gastrointestinal disorders, including nausea, vomiting and diarrhea, and transient redness of the skin. Also DMF shows poor solubility in water.

In attempts to overcome the deficiencies of current FAE therapy developed derivatives of Umarov�th acid (Joshi and Strebel, WO 2002/055063, US 2006/0205659 and US 7157423 (amides and belowaverage conjugates); Joshi et al., WO 2002/055066, and Joshi and Strebel, US 6355676 (mono - and dialkylated); Joshi and Strebel, WO 2003/087174 (carbocyclic and exacerbations connection); Joshi et al., WO 2006/122652 (disuccinate);); Joshi et al., US 2008/0233185 (dialkyl and diarylethene) and salt (Nilsson et al., US 2008/0004344). Pharmaceutical compositions with controlled release comprising esters of fumaric acid, disclosed Nilsson and Muller, WO 2007/042034. Prodrug cycloamino esters described Nielsen and Bundgaard, J. Pharm. Sci, 1988, 77(4), 285-298.

Disclosure of the invention

Necessary Prodrug of the MPR with high the gastrointestinal liable to leakage and/or absorption, improved solubility, ordered by hydrolysis (i.e., the preferred cleavage of progroup) and minimal hydrolysis in the lumen of the intestine or enterocyte cytoplasm. Such Prodrugs of the MPR, which provide a higher oral bioavailability and levels in plasma MHF, DMF and/or other metabolites, may increase the efficacy/proportion of responders compared with existing esters of fumaric acid; to facilitate the use of lower doses, reduced frequency of dosing and standardized regimens; reduce the effect of food; to reduce gastrointestinal side effects/toxicity and reduce the variability of treatment from patient to patient. In the first aspect of the Fig�the notification relates to compounds of formula (I)

or their pharmaceutically acceptable salts, where in the formulae

R1and R2chosen independently from hydrogen, C1-6of alkyl and substituted C1-6-alkyl;

R3and R4chosen independently from hydrogen, C1-6of alkyl, substituted C1-6-alkyl, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S4-12-cycloalkenyl, substituted C4-12-cycloalkenyl, S7-12-arylalkyl and substituted C7-12-arylalkyl; or R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-10-heteroaryl, substituted C5-10-heteroaryl, S5-10-geterotsiklicheskie and substituted C5-10-geterotsiklicheskie; and

R5selected from methyl, ethyl and C3-6-alkyl;

where each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, -Oh, - NO2, benzyl, - C(O)NR112, - R11, - OR11, - C(O)R11, - COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl;

provided that when R5represents ethyl, then R3and R4chosen independently from hydrogen, C1-6of alkyl and substituted C1-6-alkyl.

In a second aspect, the invention relates to compounds of formula (II)

or their pharmaceutically acceptable salts, where in the formulae, R6selected from C1-6of alkyl, substituted C1-6-alkyl, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S3-8-cycloalkyl, substituted C3-8-cycloalkyl, S6-8-aryl, substituted C6-8-aryl and-OR10where R10selected from C1-6of alkyl, substituted C1-6-alkyl, C3-10-cycloalkyl, substituted C3-10-cycloalkyl, S6-10-aryl and substituted C6-10-aryl;

R7and R8chosen independently from hydrogen, C1-6of alkyl and substituted C1-6-alkyl;

and

R9selected from C1-6of alkyl and substituted C1-6-alkyl;

where each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, -Oh, -NO2, benzyl, -C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

In the third aspect of the invention relates to compounds of formula (III)

or their pharmaceutically acceptable salts, where in the formulae

R1and R2chosen independently from hydrogen, C1-6of alkyl and substituted C1-6-alkyl;

and

R3and R4chosen independently from hydrogen, C1-6-al�silt, substituted C1-6-alkyl, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S4-12-cycloalkenyl, substituted C4-12-cycloalkenyl, S7-12-arylalkyl and substituted C7-12-arylalkyl; or R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-10-heteroaryl, substituted C5-10-heteroaryl, S5-10-geterotsiklicheskie and substituted C5-10-geterotsiklicheskie;

where each group-Deputy independently chosen from halogen, -OH, -CN, -CF3,=O, -NO2, benzyl, -C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

In a fourth aspect of the invention relates to compounds of formula (IV)

or their pharmaceutically acceptable salts, where in the formulae, R6selected from C1-6of alkyl, substituted C1-6-alkyl, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S3-8-cycloalkyl, substituted C3-8-cycloalkyl, S6-8-aryl, substituted C6-8-aryl and-OR10where R10selected from C1-6of alkyl, substituted C1-6-alkyl, C3-10-cycloalkyl, substituted C3-10-cycloalkyl, S6-10-aryl and substituted C -aryl; and

R7and R8chosen independently from hydrogen, C1-6of alkyl and substituted C1-6-alkyl;

where each group-Deputy independently chosen from halogen, -OH, -CN, -CF3,=O, -NO2, benzyl, -C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl;

provided that

when one of R7and R8selected from ethyl and methyl, and the other of R7and R8represents hydrogen, then R is not-C(CH3)=CH2; and

when each of R7and R8represents hydrogen, then R6not chosen from-CH=CH2and 4-carboxyphenyl.

In the fifth aspect of the invention relates to pharmaceutical compositions comprising a compound of formulas (I) to(IV) and at least one pharmaceutically acceptable carrier.

In the sixth aspect of the invention relates to methods of treating diseases in a patient, comprising administering to a patient in need of such treatment, a pharmaceutical composition comprising a therapeutically effective amount of compounds of formulas (I) to(IV). In some embodiments the disease is selected from psoriasis, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease and arthritis.

In the seventh aspect of the invention relates to methods of inhibiting the activation of NF-κ the patient, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of compounds of formulas (I) to(IV).

In the eighth aspect of the invention relates to methods of inhibiting the function of TNF in a patient, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of compounds of formulas (I) to(IV).

The implementation of the invention

Definition

Dash ( " - " ) that is not between two letters or symbols is used to indicate the point of attachment to group substituent. For example, -CONH2attached via a carbon atom.

The term "alkyl" refers to a saturated or unsaturated branched or linear monovalent hydrocarbon radical obtained by removing one hydrogen atom from a single carbon atom source alkane, alkene or alkyne. Examples of alkyl groups include, but are not limited to, methyl; elite, such as etanol, ethenyl and ethinyl; cuts, such as propane-1-yl, propan-2-yl, prop-1-EN-1-yl, prop-1-EN-2-yl, prop-2-EN-1-yl (allyl), prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyl, such as butane-1-yl, butan-2-yl, 2-methyl-propane-1-yl, 2-methyl-propane-2-yl, but-1-ene-1-yl, but-1-EN-2-yl, 2-methyl-prop-1-EN-1-yl, but-2-EN-1-yl, but-2-EN-2-yl, buta-1,3-Dien-1-yl, buta-1,3-Dien-2-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc., and similar groups.

The term "alkyl" is specifically intended to include groups with any degree or level of substitution, i.e., groups with exclusively single carbon-carbon bonds, groups having one or several double carbon-carbon bonds, groups with one or more triple carbon-carbon bonds and groups with combinations of single, double and triple carbon-carbon bonds. When it is assumed a certain level of saturation, use the terms "alkenyl", "alkenyl" and "alkynyl". In some embodiments the alkyl group may have from 1 to 20 carbon atoms (C1-20), in some embodiments from 1 to 10 carbon atoms (C1-10), in some embodiments from 1 to 8 carbon atoms (C1-8), in some embodiments from 1 to 6 carbon atoms (C1-6), in some embodiments from 1 to 4 carbon atoms (C1-4and in some embodiments from 1 to 3 carbon atoms (C1-3)

The term "aryl" refers to monovalent aromatic hydrocarbon radical derived by removal of one hydrogen atom from a single carbon atom of the original aromatic cyclic system. Aryl includes monocyclic system, for example, benzene; bicyclic system, in which at least one cycle is carbocyclic and aromatic, for example, naphthalene, indane, and Tetra�in; and tricyclic systems in which at least one cycle is carbocyclic and aromatic, for example, fluorene. Aryl encompasses polycyclic system with at least one carbocyclic aromatic cycle is fused with at least one carbocyclic aromatic cycle, cycloalkenyl cycle or heteroseksualnymi cycle. For example, aryl includes phenyl cycle fused with a 5-7 membered heteroseksualnymi cycle containing one or more heteroatoms selected from N, O and S. In the case of such a condensed bicyclic systems in which only one of the cycles is aromatic carbocyclic cycle, the carbon atom of the radical may be in a carbocyclic aromatic cycle or geteroseksualen cycle. Examples of aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, Exacta, hexagen, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octazen, octavina, octalene, evalena, Penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pesantren, rubiana, triphenylene, Trenitalia etc. In some embodiments aryl �group can have from 6 to 20 carbon atoms (C 6-20), from 6 to 12 carbon atoms (C6-12), from 6 to 10 carbon atoms (C6-10), and in some embodiments from 6 to 8 carbon atoms (C6-8). However, the aryl covers and does not cover heteroaryl having this separate definition description.

The term "arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms associated with carbon atom, typically, terminal or sp3 carbon atom, is replaced by an aryl group. Examples arylalkyl groups include, but are not limited to, benzyl, 2-Penilaian-1-yl, 2-Penilaian-1-yl, naphthylmethyl, 2-Nettleton-1-yl, 2-naphthalate-1-yl, naphthalenyl, 2-naphthenate-1-yl and the like. When assumed certain alkyl groups, use the nomenclature arylalkyl, arylalkyl or arylalkyl. In some embodiments arylalkyl group is a C7-30-arylalkyl, for example, alkaneella, alkenyl or alkenyl part arylalkyl group is C1-10and the aryl part is a C6-20in some embodiments arylalkyl group is a C6-18-arylalkyl, for example, alkaneella, alkenyl or alkenyl part arylalkyl group is C1-8and the aryl part is a C6-10. In some embodiments arylalkyl group is a fun� 7-12-arylalkyl.

"Compounds" of formula (I) to(IV) disclosed herein include any specific compounds within these formulae. Compounds can be identified or based on their chemical structure and/or chemical name. Compounds called using Chemistry 4-D Draw Pro, version 7.01 C (Chemlnnovation Software, Inc., San Diego, CA). When the chemical structure and chemical name conflict, decisive for the identification of compounds is chemical structure. The compounds described herein, can include one or more chiral centers and/or double bonds and therefore may exist as stereoisomers, such as the double bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, any chemical structures within the scope of the description above, in whole or in part with related configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including stereochemical pure form (e.g., geometrically pure, enantiomerically pure or diastereomers pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be divided into their component enantiomers or stereoisomers using separation techniques or methods of chiral synthesis, well �known to specialists in this field of technology. Compounds of formulas (I) to(IV) include, but are not limited to, optical isomers of compounds of formulas (I) to(IV), their racemate and other mixtures thereof. In such embodiments the individual enantiomer or diastereoisomer, i.e. optically active form, can be obtained by asymmetric synthesis or cleavage of racemates. The splitting of racemates can be realized, for example, by conventional methods such as crystallization in the presence of a decomposing agent, or chromatography using, for example, chiral stationary phases. Notwithstanding the foregoing, in the compounds of formulas (I) to(IV) configuration of the double bond shown represents only the E-configuration (i.e., the TRANS-configuration).

Compounds of formulas (I) to(IV) may also exist in several tautomeric forms including the enol form, cecoforma and mixtures thereof. Accordingly, the chemical structures shown herein encompass all possible tautomeric forms of the compounds shown. Compounds of formulas (I)-(IV) also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be introduced into compounds disclosed herein include, but are not limited to,2H,3N,11C,13C 14C,15N,18Oh,17About etc.. Compounds may exist in resolutiony forms, as well as in solvated forms, including hydrated forms and N-oxides. In General, the compounds mentioned in this description may be a free acid, can be hydrated, solvated or N-oxides. Some compounds can exist in several crystalline, cocrystalline or amorphous forms. Compounds of formulas (I) to(IV) include their pharmaceutically acceptable salt or pharmaceutically acceptable solvate form of the free acid of any of the above forms, as well as crystalline forms of any of the above forms.

Compounds of formulas (I)-(IV) also include solvates. The term "solvate" refers to a complex connection with one or more solvent molecules in a stoichiometric or non-stoichiometric amounts. Such solvent molecules are solvents commonly used in the field of pharmacy which are known as harmless to patients, for example, water, ethanol and the like. Molecular complex connections or connection parts and solvent can be stable non-covalent intra-molecular forces such as, for example, electrostatic forces, van der Waals forces or hydrogen bonds. The term "GI�rat" refers to a solvate, in which one or more solvent molecules are water molecules.

In addition, when the structure of the compounds, the asterisk (*) indicates the point of attachment of the partial structure to the rest of the molecule.

The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl radical. When it is assumed a certain level of saturation, use the nomenclature "cycloalkenyl" or "cycloalkenyl". Examples cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane and the like. In some embodiments cycloalkyl group is a C3-15-cycloalkyl, S3-12-cycloalkyl, and in some embodiments With3-8-cycloalkyl.

The term "cycloalkenyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms associated with carbon atom, typically, limit or sp3carbon atom replaced by cycloalkyl group. When assumed certain alkyl part, use the nomenclature "cycloalkylcarbonyl", "cycloalkylcarbonyl" or "cycloalkylcarbonyl". In some embodiments cycloalkylation group is a C4-30-cycloalkenyl, for example, alkaneella, alkenyl or Alchemilla group cycloalkyl�the diesel group is a group of C 1-10and cycloalkyl group is a group With3-20and , in some embodiments cycloalkylation group is a C3-20-cycloalkenyl, for example, alkaneella, alkenyl or Alchemilla group cycloalkylation group is a group of C1-8and cycloalkyl group is a group With3-12. In some embodiments cycloalkylation group is a C4-12-cycloalkenyl.

The term "disease" refers to a disease, disorder, condition, or symptom of any of the above diseases.

The term "medicine" as defined in 21 U. S. C § 321(g)(l), means(A) articles recognized in the official Pharmacopoeia of the United States, official homeopathic Pharmacopoeia of the United States or official National Formulary, or any of their application; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in humans or other animals; and (C) articles (other than food), designed to impact on any function of the body of humans or other animals..."

The term "halogen" refers to fluorine atom, chlorine, bromine or iodine. In some embodiments, the term "halogen" refers to chlorine atom.

The term "heteroalkyl" by itself or as part of each�th Deputy refers to an alkyl group, in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced same or different heteroatomic groups. Examples of heteroatomic groups include, but are not limited to, -O-, -S-,-O-O-, -S-S-, -O-S-, -NR13, =N-N=, -N=N-, -N=N-NR13, -PR13, -P(O)2-, -POR13, -OP(O)2-, -SO-, -SO2-,-Sn(R13)2etc., where each R13chosen independently from hydrogen, C1-6of alkyl, substituted C1-6-alkyl, C6-12-aryl, substituted C6-12-aryl, S7-18-arylalkyl, substituted C3-7-arylalkyl, S3-7-cycloalkyl, substituted C3-7-cycloalkyl, S3-7-geterotsiklicheskie, substituted C1-6geterotsiklicheskie, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S6-12-heteroaryl, substituted C6-12-heteroaryl, S7-18-heteroaromatic or substituted C7-18-heteroallyl. Reference to, for example, C1-6-heteroalkyl mean C1-6-alkyl group in which at least one of the carbon atoms (and certain associated hydrogen atoms) is replaced with a heteroatom. For example, With1-6-heteroalkyl includes groups having five carbon atoms and one heteroatom, groups having four carbon atoms and two heteroatom, etc. In some embodiments, each R13chosen�up independently from hydrogen and C 1-3-alkyl. In some embodiments heteroatomic group selected from-O-, -S-, -NH-,-N(CH3)- and-SO2-; and in some embodiments heteroatomic group is a-O-.

The term "heteroaryl" refers to a monovalent heteroaromatic radical formed by removal of one hydrogen atom from a single atom of the original heteroaromatic cyclic system. Heteroaryl covers several cyclic systems having at least one heteroaromatic cycle, condensed with at least one other cycle which can be aromatic or non-aromatic. For example, heteroaryl covers bicyclic system in which one cycle is aromatic, and the second cycle is heteroseksualnymi cycle. In the case of such condensed cyclic heteroaryl systems in which only one of the cycles contains one or more heteroatoms, carbon radical may be aromatic cycle or in geteroseksualen cycle. In some embodiments, when the total number of atoms N, S and O in the heteroaryl group exceeds one, the heteroatoms are not adjacent to each other. In some embodiments the total number of heteroatoms in the heteroaryl group is not more than two.

Examples of heteroaryl groups include, but are not limited to Li�Clennam, groups derived from acridine, arsehole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochroman, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthiridine, oxadiazole, oxazole, pyrimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, PYRAN, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, chinazoline, quinoline, hemolysin, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, Xanten, thiazolidine, oxazolidine etc. In some embodiments the heteroaryl group is a 4 to 20-membered heteroaryl (C4-20), and in some embodiments 4-12-membered heteroaryl (C4-12). In some embodiments the heteroaryl group is a group derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole or pyrazine. For example, in some embodiments of the C5-heteroaryl can represent furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, isoxazolyl.

The term "heteroseksualci" refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and certain associated hydrogen atoms) are replaced nez�visimo same or different heteroatoms; or the source of the aromatic cyclic system, in which one or more carbon atoms (and certain associated hydrogen atoms) are replaced independently by identical or different heteroatoms, so that the cyclic system no longer contains at least one aromatic cycle. Examples of heteroatoms to replace the atom(s) carbon include, but are not limited to, N, R, O, S, Si, etc geterotsiklicheskikh groups include, but are not limited to, groups derived from epoxides, azirines, tyranov, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, hinoklidina etc. In some embodiments geteroseksualnoe group is a C5-10-heteroseksualci, S5-8-heteroseksualci, and in some embodiments With5-6-heteroseksualci.

"Leaving group" has the meaning normally associated with it in synthetic organic chemistry, i.e., is an atom or group capable to be replaced by a nucleophile and includes halogen, such as chlorine, bromine, fluorine and iodine, acyloxy (alkoxycarbonyl), such as acetoxy and benzyloxy, aryloxyalkyl, mesilate, tosyloxy, triftormetilfullerenov, aryloxy, such as 2,4-dinitrophenoxy, methoxy, N,O-dimethylhydroxylamine, p-nitrophenolate, imidazolyl, etc..

The definition of "Exodus�traveler aromatic cyclic system" refers to an unsaturated cyclic or polycyclic system with a system of conjugated π(PI) electrons. In the definition of "source of aromatic cyclic system" includes a condensed cyclic system in which one or several cycles are aromatic and one or more cycles are saturated or unsaturated, such as, for example, fluorene, indane, indene, finale etc. the original Examples of the aromatic cyclic systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, corona, fluoranthene, fluorene, exact, hexagen, hexalen, as-indocin, s-indocin, indane, indene, naphthalene, octazen, octave, octalin, oval, Penta-2,4-diene, pentacene, pentalene, Pentagon, fixed, finale, phenanthrene, pizen, plejaden, pyrene, pesantren, rubicin, triphenylene, triathalon, etc.

The definition of "source heteroaromatic cyclic system" refers to an aromatic cyclic system, in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatoms such a way that there is a continuous system of π-electrons characterizing the aromatic system, and the number of π-electrons outside the plane corresponding to the hückel rule (4n+2). Examples of heteroatoms to replace the carbon atoms include, but are not limited to, N, R, O, S, Si, etc. In the op�EDINENIE "source heteroaromatic cyclic system" is specifically included condensed cyclic system, in which one or more cycles are aromatic and one or more cycles are saturated or unsaturated, such as, for example, Arendal, benzodioxan, benzofuran, chroman, chroman, indole, indoline, Xanten, etc. Examples of source cyclic heteroaromatic systems include, but are not limited to, Arendal, carbazole, β-carboline, chroman, chroman, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochroman, isoindol, isoindoline, isoquinoline, isothiazole, isoxazole, naphthiridine, oxadiazol, oxazol, pyrimidin, phenanthridine, phenanthroline, fenesin, phthalazine, pteridine, purine, PYRAN, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, chinazoline, quinoline, hemolysin, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, Xanten, thiazolidin, oxazolidin, etc..

The term "patient" refers to a mammal, e.g., humans.

The definition of "pharmaceutically acceptable" refers to (material), approved or approved state regulatory authority or by the government or listed in the U.S. Pharmacopoeia or other approved Pharmacopoeia for use in animals, and in particular, for the people.

The definition of "pharmaceutically acceptable salt" refers to salts of a compound that has the desired pharmacologic�tion activity of the parent compound. Such salts include salts of joining acids, formed with inorganic acids such as hydrochloric acid, bromomethane acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, grape acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, mixture of Benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonate acid, 4-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionate acid, pivalic acid, tert-butiroksana acid, laurenzana acid, gluconic acid, glutamina acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid, etc.; and salts, formed by replacement of the acidic proton present in the source-sink�research Institute, a metal ion, e.g., alkali earth metal ion, an alkaline earth metal ion or an aluminum ion; or is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine etc. In some embodiments of the pharmaceutically acceptable salt is a hydrochloride. In some embodiments of the pharmaceutically acceptable salt is a sodium salt.

The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable diluent, a pharmaceutically acceptable adjuvant, pharmaceutically acceptable excipient, pharmaceutically acceptable carrier or a combination of any of the above materials with which the compound of the present invention can be administered to the patient, and which does not destroy the pharmacological activity and which are non-toxic when administered in doses sufficient to deliver a therapeutically effective amount of the compound.

The term "pharmaceutical composition" refers to a compound of formulas (I) to(IV) and at least one pharmaceutically acceptable carrier with which a compound of formulas (I) to(IV) is administered to the patient.

The definition of "substituted" refers to a group in which one or more hydrogen atoms are independently replaced with the same or different groups are alternates. � some embodiments each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, =O, -NO2, benzyl, -C(O)NH2, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl. In some embodiments each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, -NO2, benzyl, -R11, -OR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl. In some embodiments each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, =O, -NO2, benzyl, -C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl. In some embodiments each group-Deputy independently chosen from HE, C1-4-alkyl and-NH2.

The term "treat" or "treatment" of any disease refers to reversing, alleviating, stop or reduce the intensity of the disease or at least one of the clinical symptoms of the disease, reducing the risk of acquiring the disease or at least one of the clinical symptoms of the disease, suppression of the development of the disease or at least one of the clinical symptoms of the disease, or reducing the risk of disease development or at least �defined from the clinical symptoms of the disease. The term "treat" or "treatment" also refers to the suppression of disease physically (e.g., stabilization of explicit symptom), physiologically (e.g., stabilization of a physical parameter) or both and to suppress at least one physical parameter that may or may not be discernible by the patient. In some embodiments "treating" or "treatment" refers to delaying the onset of the disease or at least one or more of its symptoms in the patient, who can affect or who is predisposed to the disease, even if the patient still does not feel or does not show symptoms of the disease.

The definition of "therapeutically effective amount" refers to the amount of compound that, when introduced to a subject for treatment of the disease or at least one of the clinical symptoms of the disease, is sufficient to effect such treatment for the disease or symptom. "Therapeutically effective amount" can vary depending on, for example, compounds, diseases and/or symptoms of the disease, the severity of the disease and/or symptoms of the disease or disorder, age, weight and/or health of the patient being treated, and the decision of the attending physician. The corresponding amount in any given case can be set�been specialists in the art or can be determined by ordinary experimentation.

The definition of "therapeutically effective dose" refers to a dose that provides effective treatment of a disease or disorder in a patient. A therapeutically effective dose may vary from connection to connection and from patient to patient and may depend on such factors as the patient's condition and method of delivery. A therapeutically effective dose can be determined according to conventional pharmacological procedures known to those skilled in the art.

Now turning to the details of some embodiments of compounds, compositions and methods. Disclosed embodiments are not intended to limit the claims. On the contrary, it is assumed that the invention covers all alternatives, modifications and equivalents.

Connection

Some embodiments relate to the compound of formula (I)

or its pharmaceutically acceptable salt, where in the formulae

R1and R2chosen independently from hydrogen, C1-6of alkyl and substituted C1-6-alkyl;

R3and R4chosen independently from hydrogen, C1-6of alkyl, substituted C1-6-alkyl, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S4-12-cycloalkenyl, substituted C4-12-cycloalkenyl, S7-12-arylalkyl � substituted C 7-12-arylalkyl; or R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-10-heteroaryl, substituted C5-10-heteroaryl, S5-10-geterotsiklicheskie and substituted C5-10-geterotsiklicheskie; and

R5selected from methyl, ethyl and C3-6-alkyl;

where each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, =O, -NO2, benzyl, - C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl;

provided that when R5represents ethyl, then R3and R4selected from hydrogen, C1-6of alkyl and substituted C1-6-alkyl.

In certain embodiments of a compound of formula (I) each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, - R11, - OR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl. In some embodiments each group-Deputy independently chosen from-HE and-COOH.

In certain embodiments of a compound of formula (I) each group-Deputy independently chosen from =O, C1-4-alkyl and -- COOR11where each R11selected from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (I) ka�each of R 1and R2represents hydrogen.

In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2represents C1-4-alkyl.

In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2is methyl.

In certain embodiments of a compound of formula (I) R3and R4chosen independently from hydrogen and C1-6-alkyl.

In certain embodiments of a compound of formula (I) R3and R4chosen independently from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (I) R3and R is chosen independently from hydrogen, methyl and ethyl.

In certain embodiments of a compound of formula (I) each of R3and R4represents hydrogen; in certain embodiments, each of R3and R4is methyl; and in some embodiments each of R3and R4represents ethyl.

In certain embodiments of a compound of formula (I) R3is a fun� hydrogen, and R4selected from C1-4of alkyl, substituted C1-4-alkyl, where the group is the Deputy selected from =O, -OR11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (I) R3represents hydrogen, and R4selected from C1-4-alkyl, benzyl, 2-methoxyethyl, carboxymethyl, carboxypropyl, 1,2,4-tiedostolla, methoxy, 2-methoxycarbonyl, 2-oxo(1,3-oxazolidinyl), 2-(methylethoxy)ethyl, 2-ethoxyethyl, (tert-butoxycarbonyl)bromide (ethoxycarbonyl)bromide, carboxymethyl, (methylethyl)oxycarbonyl and ethoxycarbonylmethyl.

In certain embodiments of a compound of formula (I) R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-6-geterotsiklicheskie, substituted C5-6-geterotsiklicheskie, S5-6-heteroaryl and substituted C5-6-heteroaryl. In certain embodiments of a compound of formula (I) R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-geterotsiklicheskie, substituted C5-geterotsiklicheskie, S5-heteroaryl and substituted C5-heteroaryl. In certain embodiments of a compound of formula (I) R3and R4together with the nitrogen atom to which they are linked, form a cycle, �selected from C 6-geterotsiklicheskie, substituted C6-geterotsiklicheskie, S6-heteroaryl and substituted C6-heteroaryl. In certain embodiments of a compound of formula (I) R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from piperazine, 1,3-oxazolidinyl, pyrrolidinones and morpholino cycle.

In certain embodiments of a compound of formula (I) R3and R4together with the nitrogen atom to which they are linked, form a C5-10-heteroseksualci.

In certain embodiments of a compound of formula (I) R5is methyl.

In certain embodiments of a compound of formula (I) R5represents ethyl.

In certain embodiments of a compound of formula (I) R5represents C3-6-alkyl.

In certain embodiments of a compound of formula (I) R5selected from methyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

In certain embodiments of a compound of formula (I) R5selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2represents C1-6-alkyl; R3represents hydrogen; R4selected from hydrogen, C1-6 -alkyl and benzyl.

In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2represents C1-6-alkyl; R3represents hydrogen; R4selected from hydrogen, C1-6-alkyl and benzyl; and R5is methyl.

In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl; and each of R3and R4represents C1-6-alkyl.

In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl; each of R3and R4represents C1-6-alkyl; and R5is methyl. In certain embodiments of a compound of formula (I) each of R1and R2represents hydrogen; each of R3and R4represents C1-6-alkyl; and R5is methyl.

In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-4-alkyl; R3represents hydrogen; R4selected from C1-4of alkyl, substituted�wow 1-4-alkyl, where the group is the Deputy selected from =O, -OR11, - COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl; and R5is methyl. In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2is methyl; R3represents hydrogen; R4selected from C1-4of alkyl, substituted C1-4-alkyl, where the group is the Deputy selected from =O, - OR11, - COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl; and R5is methyl. In certain embodiments of a compound of formula (I) each of R1and R2represents hydrogen; R3represents hydrogen; R4selected from C1-4of alkyl, substituted C1-4-alkyl, where the group is the Deputy selected from =O, - OR11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl; and R5is methyl.

In certain embodiments of a compound of formula (I) R3and R4together with the nitrogen atom to which they are linked, form a C5-10-heteroseksualci.

In certain embodiments of a compound of formula (I) one of R1and R2is a fun� hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl; R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-6-geterotsiklicheskie, substituted C5-6-geterotsiklicheskie, S5-6-heteroaryl and substituted C5-6-heteroaryl; and R5is methyl. In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2is methyl; R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-6-geterotsiklicheskie, substituted C5-6-geterotsiklicheskie, S5-6-heteroaryl and substituted C5-6-heteroaryl; and R5is methyl. In certain embodiments of a compound of formula (I) each of R1and R2represents hydrogen; R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-6-geterotsiklicheskie, substituted C5-6-geterotsiklicheskie, S5-6-heteroaryl and substituted C5-6-heteroaryl; and R5is methyl.

In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl; and R3and R4/sup> together with the nitrogen atom to which they are linked, form a cycle selected from morpholine, piperazine and N-substituted piperazine.

In certain embodiments of a compound of formula (I) one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl; and R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from morpholine, piperazine and N-substituted piperazine; and R5is methyl.

In certain embodiments of a compound of formula (I) R5not is methyl.

In certain embodiments of a compound of formula (I) R1represents hydrogen, and in some embodiments R2represents hydrogen.

In certain embodiments of a compound of formula (I) compound is selected from the group consisting of

(N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat;

methyl-[N-benzylcarbamoyl]methyl(2E)but-2-ene-1,4-diat;

methyl-2-morpholine-4-yl-2-oxoethyl(2E)but-2-ene-1,4-diat;

(N-butylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat;

[N-(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diat;

2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetylamino}acetic acid;

4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetylamino}butane acid;

methyl-(N-(1,3,4-thiadiazole-2-yl)carbamoyl)methyl(2E)but-2-ene-1,4-dia�;

(N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat;

(N-methoxy-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat;

bis[(2-methoxyethylamine)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diat;

[N-(methoxycarbonyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diat;

4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetylamino}butane acid, sodium salt;

methyl-2-oxo-2-piperazinylmethyl(2E)but-2-ene-1,4-diat;

methyl-2-oxo-2-(2-oxo-1,3-oxazolidin-3-yl)ethyl(2E)but-2-ene-1,4-diat;

{N-[2-(dimethylamino)ethyl]carbamoyl}methyl methyl(2E)but-2-ene-1,4-diat;

methyl-2-(4-methylpiperazine)-2-oxoethyl(2E) but-2-ene-1,4-diat;

methyl-{N-[(propylamino)carbonyl]carbamoyl}methyl(2E)but-2-ene-1,4-diat;

2-(4-acetylpiperidine)-2-oxoethyl-methyl(2E)but-2-ene-1,4-diat;

{N,N-bis[2-(methylethoxy)ethyl]carbamoyl}methyl methyl(2E)but-2-ene-1,4-diat;

methyl-2-(4-benzylpiperazine)-2-oxoethyl(2E)but-2-ene-1,4-diat;

[N,N-bis(2-ethoxyethyl) carbamoyl]methyl methyl(2E)but-2-ene-1,4-diat;

2-{(2S)-2-[(tert-butyl)oxycarbonyl]pyrrolidinyl}-2-oxoethyl-methyl(2E)but-2-ene-1,4-diat;

1-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetyl}-(2S)-pyrrolidin-2-carboxylic acid;

(N-{[(tert-butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat;

{N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methyl methyl(2E)but-2-ene-1,4-diat;

methyl-1-methyl-2-morpholine-4-yl-2-oxoethyl(2E)but-2-ene-,4-diat;

(N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl(2E)but-2-ene-1,4-diat;

(N,N-dimethylcarbamoyl)ethyl methyl(2E)but-2-ene-1,4-diat;

2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]-N-methylacetamide}acetic acid;

(N-{[(tert-butyl)oxycarbonyl]methyl}carbamoyl)methyl methyl(2E)but-2-ene-1,4-diat;

methyl-(N-methyl-N-{[(methylethyl)oxycarbonyl]methyl}carbamoyl)methyl(2E)but-2-ene-1,4-diat;

{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methyl methyl(2E)but-2-ene-1,4-diat;

{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}ethyl methyl(2E)but-2-ene-1,4-diat;

{N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}ethyl methyl(2E)but-2-ene-1,4-diat;

(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl-methyl(2E)but-2-ene-1,4-diat;

(1S)-1-[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl(2E)but-2-ene-1,4-diat;

(1R)-1-(N,N-diethylcarbamoyl)ethyl methyl(2E)but-2-ene-1,4-diet and pharmaceutically acceptable salt of any of the foregoing compounds.

In certain embodiments of a compound of formula (I) compound is selected from the group consisting of

(N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat;

methyl-[N-benzylcarbamoyl]methyl(2E)but-2-ene-1,4-diat;

methyl-2-morpholine-4-yl-2-oxoethyl(2E)but-2-ene-1,4-diat;

(N-butylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat;

[N-[-(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diat;

2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetylamino}acetic acid;

HR-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetylamino}butane acid;

methyl-(N-(1,3,4-thiadiazole-2-yl)carbamoyl)methyl(2E)but-2-ene-1,4-diat;

(N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat;

(N-methoxy-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat;

bis(2-methoxyethylamine)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diat;

[N-(methoxycarbonyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diat;

methyl-2-oxo-2-piperazinylmethyl(2E)but-2-ene-1,4-diat;

methyl-2-oxo-2-(2-oxo-1,3-oxazolidin-3-yl)ethyl(2E)but-2-ene-1,4-diat;

{N-[2-(dimethylamino)ethyl]carbamoyl}methyl methyl(2E)but-2-ene-1,4-diat;

{N-[(methoxycarbonyl)ethyl]carbamoyl}methyl methyl(2E)but-2-ene-1,4-diat;

2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetylamino}propane acid and

pharmaceutically acceptable salt of any of the foregoing compounds. In certain embodiments of a compound of formula (I) R3and R4chosen independently from hydrogen, C1-6of alkyl, substituted C1-6-alkyl, C6-10-aryl, substituted C6-10-aryl, S4-12-cycloalkenyl, substituted C4-12-cycloalkenyl, S7-12-arylalkyl, substituted C7-12-arylalkyl, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S6-10-heteroaryl, substituted C6-10-heteroaryl, S4-12-geterotsiklicheskie, substituted C4-12-GE�of eroticaarchiveangie, With7-12-heteroaromatic, substituted C7-12-heteroallyl; or R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-10-heteroaryl, substituted C5-10-heteroaryl, S5-10-geterotsiklicheskie and substituted C5-10-geterotsiklicheskie.

Some embodiments relate to the compound of formula (II)

(II) or its pharmaceutically acceptable salt, where in the formulae

R6selected from C1-6of alkyl, substituted C1-6-alkyl, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S3-8-cycloalkyl, substituted C3-8-cycloalkyl, S6-8-aryl, substituted C6-8-aryl and-OR10where R10selected from C1-6of alkyl, substituted C1-6-alkyl, C3-10-cycloalkyl, substituted C3-10-cycloalkyl, S6-10-aryl and substituted C6-10-aryl;

R7and R8chosen independently from hydrogen, C1-6of alkyl and substituted C1-6-alkyl;

and

R9selected from C1-6of alkyl and substituted C1-6-alkyl;

where each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, =O, -NO2, benzyl, -C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R11liberalization from hydrogen and C 1-4-alkyl.

In certain embodiments of a compound of formula (II) each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, -R11, -OR11and-NR112where each R11chosen independently from hydrogen, C1-4-alkyl.

In certain embodiments of a compound of formula (II) each group-Deputy independently chosen from =O, C1-4-alkyl and -- COOR11where R11selected from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (II) one of R7and R8represents hydrogen, and the other of R7and R8represents C1-6-alkyl. In some embodiments of a compound of formula (II) one of R7and R8represents hydrogen, and the other of R7and R8represents C1-4-alkyl.

In certain embodiments of a compound of formula (II) one of R7and R8represents hydrogen, and the other of R7and R8selected from methyl, ethyl, n-propyl and isopropyl. In certain embodiments of a compound of formula (II) each of R7and R8represents hydrogen.

In certain embodiments of a compound of formula (II) R9selected from substituted C1-6-alkyl and-OR11where R11represents independently C1-4-alkyl.

In certain embodiments of a compound of formula (II) R9 represents C1-6-alkyl, in some embodiments, R9represents C1-3-alkyl; and in certain embodiments, R9selected from methyl and ethyl.

In certain embodiments of a compound of formula (II) R9is methyl.

In certain embodiments of a compound of formula (II) R9is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

In certain embodiments of a compound of formula (II) R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

In certain embodiments of a compound of formula (II) R6represents C1-6-alkyl; one of R7and R8represents hydrogen, and the other of R7and R8represents C1-6-alkyl; and R9selected from C1-6of alkyl and substituted C1-6-alkyl.

In certain embodiments of a compound of formula (II) R6is a-OR10.

In certain embodiments of a compound of formula (II) R10selected from C1-4of alkyl, cyclohexyl and phenyl.

In certain embodiments of a compound of formula (II) R6selected from methyl, ethyl, n-propyl and isopropyl; one of R7and R8represents hydrogen, and the other of R7and R8selected from methyl, ethyl, n-propyl and isopropyl.

In some waples�the deposits of a compound of formula (II) R 6is a substituted C1-2-alkyl, where each of the one or more groups of substituents selected from-COOH, -NHC(O)CH2NH2and-NH2.

In certain embodiments of a compound of formula (II) R6selected from ethoxy, methylethoxy, isopropyl, phenyl, cyclohexyl, cyclohexyloxy, -CH(NH2)CH2COOH, -CH2CH(NH2)COOH, -CH(NHC(O)CH2NH2)-CH2COOH and-CH2CH(NHC(O)CH2NH2)-COOH.

In certain embodiments of a compound of formula (II) R9selected from methyl and ethyl; one of R7and R8represents hydrogen, and the other of R7and R8selected from hydrogen, methyl, ethyl, n-propyl and isopropyl; and R6selected from C1-3of alkyl, substituted C1-2-alkyl, where each of the one or more groups of substituents selected from-COOH, -NHC(O)CH2NH2and-NH2, -OR10where R10selected from C1-3-alkyl and cyclohexyl and phenyl.

In certain embodiments of a compound of formula (II) compound is selected from the group consisting of

ethoxycarbonylmethyl-methyl(2E)but-2-ene-1,4-diat;

methyl-(metalelectronics)ethyl(2E)but-2-ene-1,4-diat;

(cyclohexyloxycarbonyloxy)ethyl methyl(2E)but-2-ene-1,4-diet and

pharmaceutically acceptable salt of any of the foregoing compounds.

In certain embodiments of a compound of formula (II) with�connection selected from the group which includes

methyl-(2-methylpropyloxy)ethyl(2E)but-2-ene-1,4-diat;

methyl phenylcarbonylamino(2E)but-2-ene-1,4-diat;

cyclohexylcarbodiimide-methyl(2E)but-2-ene-1,4-diat;

[(2E)-3-(methoxycarbonyl)prop-2-enolase]ethyl methyl(2E)but-2-ene-1,4-diat;

methyl-2-methyl-1-phenylcarbonylamino(2E)but-2-ene-1,4-diet and

pharmaceutically acceptable salt of any of the foregoing compounds.

In certain embodiments of a compound of formula (II) compound is selected from the group consisting of

ethoxycarbonylmethyl-methyl(2E)but-2-ene-1,4-diat;

methyl-(metalelectronics)ethyl(2E)but-2-ene-1,4-diat;

methyl-(2-methylpropyloxy)ethyl(2E)but-2-ene-1,4-diat;

methyl phenylcarbonylamino(2E)but-2-ene-1,4-diet and

cyclohexylcarbodiimide-methyl(2E)but-2-ene-1,4-diat;

[(2E)-3-(methoxycarbonyl)prop-2-enolase]ethyl methyl(2E)but-2-ene-1,4-diat;

(cyclohexyloxycarbonyloxy)ethyl methyl(2E)but-2-ene-1,4-diat;

methyl-2-methyl-1-phenylcarbonylamino(2E)but-2-ene-1,4-diat;

3-({[(2E)-3-(methoxycarbonyl)prop-2-enolase]methyl}oxycarbonyl)(3S)-3-aminopropanoic acid, 2,2,2-triptorelin;

3-({[(2E)-3-(methoxycarbonyl)prop-2-enolase]methyl}oxycarbonyl)(2S)-2-aminopropanoic acid, 2,2,2-triptorelin;

3-({[(2E)-3-(methoxycarbonyl)prop-2-enolase]methyl}oxycarbonyl)(3S)-3-(2-aminoethylamino)propane acid, 2,2,2-�referatai;

3-{[(2E)-3-(methoxycarbonyl)prop-2-enolase]ethoxycarbonyl}(2S)-2-aminopropanoic acid, chloride; and

pharmaceutically acceptable salt of any of the foregoing compounds.

The compounds presented in the disclosure of the present invention include compounds of formula (III) and formula (IV). Compounds of the formula (III) and formula (IV) can be obtained with the metabolism in vivo of the compounds of formula (I) and formula (II), respectively; or they can be administered to the patient.

Accordingly, some embodiments relate to the compound of formula (III)

or its pharmaceutically acceptable salt, where in the formulae

R1and R2chosen independently from hydrogen, C1-6of alkyl and substituted C1-6-alkyl; and

R3and R4chosen independently from hydrogen, C1-6of alkyl, substituted C1-6-alkyl, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S4-12-cycloalkenyl, substituted C4-12-cycloalkenyl, S7-12-arylalkyl and substituted C7-12-arylalkyl; or R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-10-heteroaryl, substituted C5-10-heteroaryl, S5-10-geterotsiklicheskie and substituted C5-10-geterotsiklicheskie;

where each group choose a Deputy netavis�mo from halogen, -OH, -CN, -CF3, =O, -NO2, benzyl, -C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R" is independently chosen from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (III) each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, -R11, -OR11, -C(O)R11and NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (III) each group-Deputy independently chosen from =O, C1-4-alkyl and -- COOR11where each R11selected from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (III) each of R1and R2represents hydrogen.

In certain embodiments of a compound of formula (III) one of R1and R2represents hydrogen, and the other of R1and R represents C1-4-alkyl.

In certain embodiments of a compound of formula (III) one of R1and R2represents hydrogen, and the other of R1and R2selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

In certain embodiments of a compound of formula (III) one of R1and R2represents hydrogen, and the other of R1and R2is a m�Teal.

In certain embodiments of a compound of formula (III) R3and R4chosen independently from hydrogen and C1-6-alkyl.

In certain embodiments of a compound of formula (III) R3and R4chosen independently from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (III) R3and R4chosen independently from hydrogen, methyl and ethyl.

In certain embodiments of a compound of formula (III) each of R3and R4represents hydrogen; in certain embodiments of a compound of formula (III) each of R3and R4is methyl; and in certain embodiments of a compound of formula (III) each of R3and R4represents ethyl.

In certain embodiments of a compound of formula (III) R3represents hydrogen; and R4selected from C1-4of alkyl, substituted C1-4-alkyl, where the group is the Deputy selected from =O, -OR11, -COOR11and NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (III) R3represents hydrogen; and R4selected from C1-4-alkyl, benzyl, 2-methoxyethyl, carboxymethyl, carboxypropyl, 1,2,4-tiedostolla, methoxy, 2-methoxycarbonyl, 2-oxo(1,3-oxazolidinyl), 2-(methylethoxy)ethyl, 2-ethoxyethyl, (tert-butyloxycarbonyl)IU�silt, (ethoxycarbonyl)bromide, carboxymethyl, (methylethyl)oxycarbonyl and ethoxycarbonylmethyl.

In certain embodiments of a compound of formula (III) R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-6-geterotsiklicheskie, substituted C5-6-geterotsiklicheskie, S5-6-heteroaryl and substituted C5-6-heteroaryl. In certain embodiments of a compound of formula (III) R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-geterotsiklicheskie, substituted C5-geterotsiklicheskie, S5-heteroaryl and substituted C5-heteroaryl. In certain embodiments of a compound of formula (III) R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C6-geterotsiklicheskie, substituted C6-geterotsiklicheskie, S6-heteroaryl and substituted C6-heteroaryl. In certain embodiments of a compound of formula (III) R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from piperazine, 1,3-oxazolidinyl, pyrrolidinones and morpholino cycle.

In certain embodiments of a compound of formula (III) R3and R4together with the nitrogen atom to which they are linked, form a C5-10-heteroseksualci.

In some of volumemeasurement of formula (III) one of R 1and R2represents hydrogen, and the other of R1and R2represents C1-6-alkyl; R3represents hydrogen; R4selected from hydrogen, C1-6-alkyl and benzyl.

In certain embodiments of a compound of formula (III) one of R1and R2represents hydrogen, and the other of R41and R2represents C1-6-alkyl; and each of R3and R4represents C1-6-alkyl. In certain embodiments of a compound of formula (III) each of R1and R2represents hydrogen; and each of R3and R4represents C1-6-alkyl. In certain embodiments of a compound of formula (III) one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-4-alkyl; R3represents hydrogen; and R4selected from C1-4of alkyl, substituted C1-4-alkyl, where the group is the Deputy selected from =O, -OR11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl. In certain embodiments of a compound of formula (III) one of R1and R2represents hydrogen, and the other of R1and R2is methyl; R3represents hydrogen; and R4selected from C1-4of alkyl, substituted C1-4-�of Lila, where the group is the Deputy selected from =O, - OR11, - COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl. In certain embodiments of a compound of formula (III) each of R1and R2represents hydrogen; R3represents hydrogen; and R4selected from C1-4of alkyl, substituted C1-4-alkyl, where the group is the Deputy selected from =O, -OR11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (III) R3and R4together with the nitrogen atom to which they are linked, form a C5-10-heteroseksualci.

In certain embodiments of a compound of formula (III) one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl; and R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-6-geterotsiklicheskie, substituted C5-6-geterotsiklicheskie, S5-6-heteroaryl and substituted C5-6-heteroaryl. In certain embodiments of a compound of formula (III) one of R1and R2represents hydrogen, and the other of R1and R2is methyl; and R3and R4together with the nitrogen atom to which they are linked, the way�t cycle, selected from C5-6-geterotsiklicheskie, substituted C5-6-geterotsiklicheskie, S5-6-heteroaryl and substituted C5-6-heteroaryl. In certain embodiments of a compound of formula (III) each of R1and R2represents hydrogen; and R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-6-geterotsiklicheskie, substituted C5-6-geterotsiklicheskie, S5-6-heteroaryl and substituted C5-6-heteroaryl.

In certain embodiments of a compound of formula (III) one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl; and R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from morpholine, piperazine and N-substituted piperazine.

In certain embodiments of a compound of formula (III) R3and R4chosen independently from hydrogen, C1-6of alkyl, substituted C1-6-alkyl, C6-10-aryl, substituted C6-10-aryl, S4-12-cycloalkenyl, substituted C4-12-cycloalkenyl, S7-12-arylalkyl, substituted C7-12-arylalkyl, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S6-10-heteroaryl, substituted C6-10-heteroaryl, S4-12-geterotsiklicheskie, substituted C4-12-g�of eroticaarchiveangie, With7-12-heteroaromatic, substituted C7-12-heteroallyl; or R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from C5-10-heteroaryl, substituted C5-10-heteroaryl, S5-10-geterotsiklicheskie and substituted C5-10-geterotsiklicheskie.

In certain embodiments of a compound of formula (III) R1represents hydrogen, and in some embodiments R2represents hydrogen.

In certain embodiments of a compound of formula (III) compound is selected from the group consisting of

(2E)-3-[(2-morpholine-4-yl-2-oxoethyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-{[(N,N-diethylcarbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-({[N-benzylcarbamoyl]methyl}oxycarbonyl)prop-2-ANOVA acid;

(2E)-3-{[(N-butylcarbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-{[(N-methoxy-N-methylcarbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

bis[(2-methoxyethylamine)carbamoyl]methylprop-2-ANOVA acid;

(N,N-dimethylcarbamoyl)methylprop-2-ANOVA acid;

(2E)-3-({[N-(3-carboxypropyl)carbamoyl]methyl} oxycarbonyl)prop-2-ANOVA acid;

methyl(N-(1,3,4-thiadiazole-2-yl)carbamoyl)methylprop-2-ANOVA acid;

(2E)-3-[(2-{(2S)-2-[(tert-butyl)oxycarbonyl]pyrrolidinyl}-2-oxoethyl)oxycarbonyl]prop-2-ANOVA acid;

1-[2-((2E)-3-carboxypropyl-2-eno�lksi)acetyl]-(2S)-pyrrolidin-2-carboxylic acid;

(2E)-3-[({N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-{[(N-{[(tert-butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-[(1-methyl-2-morpholine-4-yl-2-oxoethyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-({[N,N-bis(2-methoxyethyl)carbamoyl]ethyl}oxycarbonyl)prop-2-ANOVA acid;

(2E)-3-{[(N,N-dimethylcarbamoyl)ethyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-[({N,N-bis[(2-methylethoxy)ethyl]carbamoyl}methyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-({[N,N-bis(2-ethoxyethyl)carbamoyl]methyl}oxycarbonyl)prop-2-ANOVA acid;

(2E)-3-{[2-(4-acetylpiperidine)-2-oxoethyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-({2-oxo-2-[4-benzylpiperazine]ethyl}oxycarbonyl)prop-2-ANOVA acid;

(2E)-3-{[(N-{[(tert-butyl)oxycarbonyl]methyl}carbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-{[(N-methyl-N-{[(methylethyl)oxycarbonyl]methyl}carbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-[({N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-[({N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl} ethyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-[({N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}ethyl)oxycarbonyl]prop-2-ANOVA acid and

pharmaceutically acceptable salt of any of the foregoing compounds.

NEK�which embodiments relate to the compound of formula (IV)

or its pharmaceutically acceptable salt, where in the formulae

R6selected from C1-6of alkyl, substituted C1-6-alkyl, C1-6-heteroalkyl, substituted C1-6-heteroalkyl, S3-8-cycloalkyl, substituted C3-8-cycloalkyl, S6-8-aryl, substituted C6-8-aryl and-OR10where R10selected from C1-6of alkyl, substituted C1-6-alkyl, C3-10-cycloalkyl, substituted C3-10-cycloalkyl, S6-10-aryl and substituted C6-10-aryl; and

R7and R8chosen independently from hydrogen, C1-6of alkyl and substituted C1-6-alkyl; where each group-Deputy independently chosen from halogen, -OH, -CN, -CF3, -Oh, -NO2, benzyl, -C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl;

provided that

when one of R7and R8selected from ethyl and methyl, and the other of R7and R8represents hydrogen, then R6is not-C(CH3)=CH2; and

when each of R7and R8represents hydrogen, then R6not chosen from-CH=CH2and 4-carboxyphenyl.

In certain embodiments of a compound of formula (IV) each group-Deputy SEL�play independently from halogen, -OH, -CN, -CF3, -R11, -OR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (IV) each group-Deputy independently chosen from =O, C1-4-alkyl and -- COOR11where R11selected from hydrogen and C1-4-alkyl.

In certain embodiments of a compound of formula (IV) one of R7and R8represents hydrogen, and the other of R7and R8represents C1-6-alkyl. In certain embodiments of a compound of formula (IV) one of R7and R8represents hydrogen, and the other of R7and R8represents C1-4-alkyl.

In certain embodiments of a compound of formula (IV) one of R7and R8represents hydrogen, and the other of R7and R8selected from methyl, ethyl, n-propyl and isopropyl. In certain embodiments of a compound of formula (IV) each of R7and R8represents hydrogen.

In certain embodiments of a compound of formula (IV), R6represents C1-6-alkyl; and one of R7and R8represents hydrogen, and the other of R7and R8represents C1-6-alkyl.

In certain embodiments of a compound of formula (IV), R6is a-OR10.

In certain embodiments of a compound of formula(IV), R 10selected from C1-4of alkyl, cyclohexyl and phenyl.

In certain embodiments of a compound of formula (IV), R6selected from methyl, ethyl, n-propyl and isopropyl; one of R7and R8represents hydrogen, and the other of R7and R8selected from methyl, ethyl, n-propyl and isopropyl.

In certain embodiments of a compound of formula (IV), R6is a substituted C1-2-alkyl, where each of the one or more groups of substituents selected from-COOH, -NHC(O)CH2NH2and-NH2.

In certain embodiments of a compound of formula (IV), R6selected from ethoxy, methylethoxy, isopropyl, phenyl, cyclohexyl, cyclohexyloxy, -CH(NH2)CH2COOH, -CH2CH(NH2)COOH, -CH(NHC(O)CH2NH2)-CH2COOH and-CH2CH(NHC(O)CH2NH2)-COOH.

In certain embodiments of a compound of formula (IV) one of R7and R8represents hydrogen, and the other of R7and R8selected from hydrogen, methyl, ethyl, n-propyl and isopropyl; and R6selected from C1-3of alkyl, substituted C1-2-alkyl, where each of the one or more groups of substituents selected from-COOH, -NHC(O)CH2NH2and-NH2, -OR10where R10selected from C1-3-alkyl and cyclohexyl and phenyl.

In certain embodiments of a compound of formula (IV) compound is selected from g�uppy, which includes

(2E)-3-{[(2-methylpropyloxy)ethyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-({[(methylethyl)oxycarbonyl]ethyl}oxycarbonyl)prop-2-ANOVA acid;

2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetic acid and pharmaceutically acceptable salt of any of the foregoing compounds.

Synthesis

Compounds disclosed in the present description, can be obtained by synthetic methods shown in schemes 1-9. General synthesis methods applicable to the synthesis of compounds described in this description, are available in the art. The initial substance, applicable upon receipt of the compounds and intermediate compounds for them and/or ways of implementation, described herein, are commercially available or can be obtained by well-known methods of synthesis. The methods presented in the schemes, are explanatory and not exhaustive. For specialists in the art should be obvious that in practice can be done many modifications in both materials and methods without departing from the scope of disclosure.

Some unsubstituted, 1-monosubstituted or 1,1-benzamidine halogenated, is applicable for the producing compounds of formula (I), are available from commercial sources. Commercially available unsubstituted, 1-monosubstituted or 1,1-benzamidine halogenated applicable for �of Holocene compounds of formula (I), and the intermediate can be obtained by well-known methods of synthesis, such as described in schemes 1 and 2.

Containing functional group 1-halogenated applicable to obtain the prodrug of acetamido the MPR formula (I) can be obtained according to scheme 1

where X and Y represent leaving groups such as halogen, and R1, R2, R3and R4have the meanings given in the description. In some embodiments of scheme 1, X represents chlorine, Y represents chlorine or O-utilization.

Chemical activation of the carboxylic acid to the corresponding acid chloride of the carboxylic acid as shown in scheme 1, can be achieved by interaction with chlorination agents such as thionylchloride (SOCl2), oxaliplatin (C2O2Cl2) or phosphorus pentachloride (PCl5), optionally in the presence of a suitable catalyst such as N,N-dimethylformamide (DMF), and either in substance (absence of solvent) or in an inert organic solvent, such as dichloro methane (DCM) at an appropriate temperature such as from about 0°C to about 70°C. Chemical activation of the carboxylic acid can carry out in situ and without isolation of the activated substrate prior to the subsequent stage of aminolysis. Uncut�optionally activated carboxylic acid can be isolated and/or purified using the methods well known in the art, for example, fractional distillation.

On the other hand, for formation of the activated carboxylic acid derivative can be used agents of dehydration carbodiimide, such as N,N'-diisopropylcarbodiimide (DIC), N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC, EDC), optionally in the presence of catalytic or stoichiometric amount of a suitable additive such as 4-(N,N-dimethylamino)pyridine (DMAP) (esterification conditions on Steglich), 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-asobancaria (HOAt), or N-hydroxysuccinimide (NHS); salts Urania or phosphonium with dinucleophiles anions, such as hexaphosphate N-[(1H-benzotriazole-1-yl)(dimethylamino)methylene]-N-methylmethanamine (HBTU), N-oxide hexaflurophosphate N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanamine (HATU), tetrafluoroborate N-[(1H-benzotriazole - yl)(dimethylamino)methylene]-N-methylmethanamine (TBTU) or hexaphosphate the benzotriazole-1-electroparadise (PyBOP). Also optional, you can use an organic tertiary base such as triethylamine (TEA) or diisopropylethylamine (DIEA). The formation of the activated carboxylic acid derivative can occur in an inert solvent such as dichloro methane (DCM), N,N-dimethylformamide (DMF), N-methylpyrrolidone� (NMP), N,N-dimethylacetamide (DMA, DMAc), or mixtures of any of the above solvents at suitable temperatures, such as from about 0°to about 40°C.

Aminals obtained in situ or selected derivatives of carboxylic acids with amine derivatives with functional groups (HNR3R4) (figure 2) can occur in the presence of a suitable base, such as an organic tertiary base, i.e., triethylamine (TEA), diethylaminoethylamine (DIEA), pyridine or a mixture of any of the above solvents, optionally in the presence of suitable additives, such as a nucleophilic acylation catalysts, i.e., 4-(N,N-dimethylaminopyridine (DMAP), and in another or the same inert solvent that was used at the stage of activation, such as dichloro methane (DCM), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA, DMAc), or mixtures of any of the foregoing solvents, at suitable temperatures, such as from about 0°C to about 70°C.

Functionalized 1-hydroxyacetamido applicable to obtain the prodrug of acetamido the MPR formula (I) can be obtained according to scheme 2

in which PG represents a protective group for hydroxyl group; Y represents a leaving group such as chlorine or the radical, images�from nny O-isomotion; and R1, R2, R3and R4have the meanings given in the description.

Some of functionalized and activated derivatives of 1-hydroxiacetic commercially available, for example, benzyloxycarbonyl acid and tert-butiloxinazola acid. Methods of introduction of protective groups for hydroxyl (PG) is well known in the art. The applicable protective groups for temporary blocking of the hydroxyl group functionalized 1-hydroxysuccinic acids include some alkali, such as (substituted) benzyl ethers, tert-butyl esters, trailovic ether or different Silovye esters, such as tert-butyldimethylsilyloxy ether, triisopropylsilyl ether or tert-butyldiphenylsilyl the air.

Some contain a protective group of the functionalized and activated derivative of 1-hydroxiacetic commercially available, for example, benzyloxyacetophenone. On the other hand, chemical activation containing protective groups functionalized derivative of 1-hydroxiacetic to the corresponding activated derivative of 1-hydroxyoctanoic acid, i.e., carboxylic acid chloride, O-allodapini,. activated esters, etc., can be achieved using reaction procedures and conditions similar to those described in scheme 1 for Akti�ation functionalized derivatives of 1-halogenases acid.

Aminals obtained in situ or dedicated derivative containing a protective group of the functionalized and activated derivatives of 1-hydroxiacetic functionalized amines (HNR3R4) can take place using reaction procedures and conditions similar to those described in scheme 1 for aminolysis functionalized and activated derivatives of 1-halogenases acid with a protective group.

Orthogonal (or ordered) the removal of protecting groups containing a protective group derived 1-hydroxiacetic frees the corresponding hydroxyl group. Methods, procedures and practical implementation of the removal of the protective groups are well known in the art.

In some embodiments, the protective group may be an alkyl group such as tert-butyl group. The removal of protective group can be carried out by contacting containing protective tert-butyl group acetamide derivative with an excess of strong acid Bronsted, such as trifluoroacetic acid (TFA) or hydrochloric acid (HCl) in an inert solvent, such as dichloro methane (DCM), diethyl ether (Et2O), 1,4-dioxane or a mixture of any of the foregoing solvents, at suitable temperatures, such as from about 0°to about 40°C.

In some�which embodiments of the protective group can be selected from alkyl groups, such as benzyl group. When the protective group is a benzyl group, removing the protective group can be effected by interaction of the functional sirovanga 1-hydroxyacetamido derivative with hydrogen gas (Hi) in prisutstvie heterogeneous catalyst, e.g., 5-10 wt.% palladium (activated or wet) coal, in a solvent such as methanol (MeOH), ethanol (EtOH), ethyl acetate (EtOAc) or any mixture of the above solvents, optionally in the presence of a small amount of activator, such as 1 N hydrochloric acid, at suitable temperatures, such as from about 0°to about 40°C and in an atmosphere of hydrogen at a pressure of from about 103,4 kPa (15 lb/d2) to about 413,7 kPa (60 f/d2).

Prodrug of acetamido the MPR formula (I) can be obtained according to scheme 3

in which X represents a leaving group such as halogen, and R1, R2, R, R and R5have the meanings given in the description. In some embodiments of scheme 3 X represents a chlorine, and R5represents alkyl, such as methyl.

Nucleophilic substitution monoalkylphenol acid functionalized 1-halogenation (scheme 1), shown in scheme 3, can occur in the presence of inorganic bases, such as carbon� alkali metal, such as cesium bicarbonate (CsHCO3), cesium carbonate (Cs2CO6) or potassium carbonate (K2CO3). Optional you can use organic tertiary base such as triethylamine (TEA), diisopropylethylamine (DIEA) or amidine; the grounds on the basis of guanidine, such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG); silver salt such as silver oxide(1) (Ag2O) or silver carbonate(1) (Ag2CO3); or other acceptors Slovenia known in the art. The corresponding salts of alkali metals, three - and tetraalkylammonium, amidine or guanidine of monoalkylamines can be obtained in situ or, on the other hand, can be obtained separately. Interference may occur in an inert solvent, such as N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA, DMAC), dimethylsulfoxide (DMSO), thetraitour (THF), toluene or a mixture of any of the foregoing solvents, at suitable temperatures, such as from about room temperature to about 70°C.

Progcast of acetamide MHF formula (I) can also be obtained according to scheme 4

where Y is an appropriate leaving group such as halogen, O-utilization, various triazoline group or other �the group; and R1, R2, R3, R4and R5have the meanings given in the description. In some embodiments of scheme 4 Y represents chlorine, and R5represents alkyl, such as methyl.

Chemical activation of the carboxylic acid to the corresponding acid chloride of the carboxylic acid as shown in scheme 4, may be accomplished by interaction with a chlorination agent, such as thionylchloride (SOCl2), oxaliplatin (C2O2Cl2), phosphorus pentachloride (DCS or others, optionally in the presence of a catalyst such as N,N-dimethylformamide (DMF), and either in substance (absence of solvent) or in an inert organic solvent, such as dichloro methane (DCM) at an appropriate temperature such as from about 0°C to about 70°C. Chemical activation of the carboxylic acid as shown in scheme 4 can be carried out in situ without isolation of the activated substrate prior to the subsequent stage of aminolysis. Optional activated acid chloride of the carboxylic acid can be isolated and/or purified using methods well known in the art, for example, fractional distillation.

On the other hand, for formation of the activated derivative monoalkylamines you can use the agents of dehydration carbodiimide, such as N,N'-diisopropylcarbodiimide (DIC), N,N'-Diez�logaccessdenied (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC, EDC), optionally in the presence of catalytic or stoichiometric amount of an additive such as 4-(N,N-dimethylamino)pyridine (DMAP) (esterification conditions on Steglich), 1-hydroxybenzotriazol (HOBt), 1-hydroxy-7-asobancaria (HOAt), or N-hydroxysuccinimide (HOSu); salt Urania or phosphonium with dinucleophiles anions, such as hexaphosphate N-[(1H-benzotriazole-1-yl)(dimethylamino)methylene]-N-methylmethanamine (HBTU), N-oxide of hexaflurophosphate N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanamine (HATU), tetrafluoroborate N-[(1H-benzotri eazol-1-yl)(dimethylamino)methylene]-N-methylmethanamine (TBTU) or hexaphosphate the benzotriazole-1-electroparadise (PyBOP). Also optional, you can use an organic tertiary base such as triethylamine (TEA) or diethylaminoethylamine (DIEA). The formation of activated monoalkylamines may occur in an inert solvent such as dichloro methane (DCM), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA, DMAc), or mixtures of any of the above solvents at suitable temperatures, such as from about room temperature to about 70°C.

Alcoholysis of activated derivative of monoalkylamines using the functionality Pirovano hydroxyacetamido derivative (scheme 2) can occur in the presence of OS�hardware, for example, an organic tertiary base such as triethylamine (TEA), diethylaminoethylamine (DIEA), or pyridine, optionally in the presence of additives, such as a nucleophilic acylation catalyst such as 4-(N,N-dime ylamino)pyridine (DMAP) (esterification conditions on Steglich), and in another or the same inert solvent that was used at the stage of activation, such as dichloro methane (DCM), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA, DMAc), or mixtures of any of the foregoing solvents, at suitable temperatures, such as from about 0°C to about 70°C.

Prolekarstva of acetamido the MPR formula (I) can also be obtained according to scheme 5

which And is or a leaving group such as halogen, or a nucleophilic group of a combination, such as hydroxyl; Y is an appropriate leaving group such as halogen, O-utilization, various triazoline group or other group; PG represents a protective group for carboxyl group; and R1, R2, R3, R4and R5have the meanings given in the description. In some embodiments of scheme 5 X represents bromine, and PG is a tert-butyl group, each of R1and R2represents hydrogen, and electrofilm is �pet-butylbromide. In some embodiments of scheme 5, Y represents chlorine or O-utilization obtained from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), and R5represents alkyl, such as methyl.

The reaction of nucleophilic substitution monoalkylphenol acid containing protective and functional groups derived from 1-halogenases acid, for example, commercially available tert-butylbromide or other derivatives, may take place using reaction procedures and conditions similar to those described in scheme 3 for the direct formation of functionalized prodrug of acetamido IVTHF of formula (I) from monoalkylphenol acid and accordingly Fung tionalizing 1-halogenated.

Alkalis intermediate activated derivative monoalkylphenol acids and contains protective and functional groups derived 1-hydroxiacetic can take place using reaction procedures and conditions similar to those described in scheme 4 for the direct formation of functionalized MHF prodrug-acetamides of formula (I) from monoalkylphenol acid and an appropriately functionalized 1-gidroksilaza Hamid.

Orthogonal (or ordered) the removal of protecting groups containing a protective group derived monoalkylphenol to�slots functionalized derivative of acetic acid releases the corresponding free intermediate ester monoalkylamines, containing a free carboxyl group. When the protective group is a tert-butyl group, removing the protective group can be carried out by contacting containing protective tert-butyl group fumaric acid derivative with an excess of strong acid Bronsted, such as trifluoroacetic acid (TFA) or hydrochloric acid (HCl) in an inert solvent, such as dichloro methane (DCM), diethyl ether (Et2O), 1,4-dioxane or a mixture of any of the foregoing solvents, at suitable temperatures, such as from about 0°to about 40°C.

Chemical activation exempt derivative of monoalkylamines-functional siromoney hydroxyoctanoic acid (carboxylic acid) to the corresponding activated carboxylic acid derivative, i.e., carboxylic acid chloride, 0-utilization, activated esters, etc., can be accomplished using reaction procedures and conditions similar to those described in scheme 4 to activate monoalkylphenol acid, the direct formation of functionalized prodrug of acetamido the MPR formula (I) from monoalkylphenol acid and suitably functionalized hydroxyacetamido.

Aminals obtained in situ activated or selected functionalized derivatives of hidroxi�ssnoi acid monoalkylamines with functionalized amines (HNR^ 4can happen with used it reaction procedures and conditions similar to those described in schemes 1 and 2 to aminolysis containing protective groups, respectively functionalized and activated derivatives hydroxiacetic.

Some of functionalized 1-halogencarboxylic (1-aryloxyalkanoic) or functionalized 1-, is applicable for the producing compounds of formula (II), are available from commercial sources. Commercially available 1-halogenocarboxylic (1-aryloxyalkanoic) or functionalized 1- can be obtained by methods well known in the art and are briefly described in schemes 6 and 7.

1-Aryloxyalkanoic applicable to obtain the prodrug of the MPR formula (II) can be obtained according to scheme 6

in which X represents a leaving group such as halogen; and R6, R7and R8have the meanings given in the description. In some embodiments of scheme 6 X represents a chlorine, and R6represents a 2-[methyl-(2E)-but-2-ene-4-at]Il; one of R7and R8represents hydrogen, and the other of R7and R8represents alkyl.

Functionalized 1-halogenocarboxylic�s (1-aryloxyalkanoic) can be obtained by contacting the functionalized carboxylic acid halide, such as the acid chloride of carboxylic acids with functionality fazirovannym carbonyl compound such as aldehyde, in the presence of a catalyst of a Lewis acid such as anhydrous zinc chloride (ZnCl2), in an inert solvent such as dichloro methane (DCM) at a temperature of from about -10°C to room temperature. 1-Chlorellaceae (1-aryloxyalkanoic) can be used directly or can be extracted and purified by methods well known in the art, such as fractional distillation or column chromatography on silica gel.

1-Alkoxy - and 1- applicable to obtain a MHF prodrug of formulae (II), can be obtained according to scheme 7

in which X represents a leaving group such as halogen; and R7, R8and R10have the meanings given in the description. In some embodiments of scheme 7 X represents a chlorine, and R10together with the oxygen atom to which it is linked, is equivalent to R6with the values specified in this specification.

Functionalized 1-alkoxy - or 1- can be obtained by contacting the functionalized halogenallylacetic, such as the functionalized chloroalkyl - or allglorious, with functionality�with alcohol or phenol (HOR 10) in the presence of base, such as an organic secondary and tertiary base, such as dicyclohexylamine (DCHA), triethylamine (TEA), diisopropylethylamine (DIEA, base Hunya), pyridine, in an inert solvent such as dichloro methane (DCM) at a temperature of from about -10°C to room temperature. 1-Alkoxy - and 1- can be used directly or can be extracted and purified by methods well known in the art, such as fractional distillation or column chromatography on silica gel.

Prodrug aryloxyalkyl and alkoxycarbonylmethyl the MPR formula (II) can be obtained be obtained according to scheme 8

in which X represents a leaving group such as halogen; and R7, R, R9and R10have the meanings given in the description.

Nucleophilic substitution monoalkylphenol acid functionality sirbanum 1-halogen... (scheme 1), as shown in scheme 8, can occur in the presence of inorganic bases such as alkali metal carbonate, for example, cesium bicarbonate (CsHCO3), cesium carbonate (Cs2CO3) or potassium carbonate (K2CO3). On the other hand, you can use organic secondary and tertiary bases, such as dicyclohexylamine (DCHA), triethyl�min (TEA), diisopropylethylamine (DIEA), amidine, or the grounds on the basis of guanidine, such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,1,3,3-tetramethylguanidine (TMG); silver salt such as silver oxide(1) (Ag2O) or silver carbonate(1) (Ag2CO3); or other halide acceptors known in the art. The corresponding salts of alkali metals, three - and tetraalkylammonium, amidine or guanidine of monoalkylamines can be obtained in situ or, on the other hand, can be obtained separately. Interference may occur in an inert solvent, such as N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA, DMAC), dimethylsulfoxide (DMSO) or tetrahydrofuran (THF), toluene or a mixture of any of the foregoing solvents, at suitable temperatures, such as from about room temperature to about 70°C.

Monotony amides of glycolic acid fumaric acid of formula (III) or monetary aryloxyalkyl - and alkoxy - or acid of formula (IV) can be obtained according to scheme 9

where X is an appropriate leaving group such as halogen; and R1, R2, R3, R4, R6, R7, R8and R9and have the values listed in this description. In some embodiments� scheme 9 X represents chlorine, and R9selected from hydrogen or tert-butyl (tert-Bu), and the fumaric acid derivative is a or fumaric acid, or tert-butylfuran.

The combination of fumaric acid or of monoalkylamines, for example, mono-tert-butylformamide, functionalized with 1-halogenated derivatives, functional yserowanej 1-halogenocarboxylic (1-allocationally) or 1-alkoxy - or can take place using reaction procedures and conditions similar to those described in schemes 3 and 8 for the direct formation of functionalized prodrug acetamide the MPR formula (I) (scheme 3) or a prodrug aryloxyalkyl - or MHF formula (II) (scheme 8).

In some embodiments, where R9represents alkyl, such as tert-butyl, orthogonal (or ordered) the removal of protective group (or the release of free carboxylic acid) from the corresponding functionalized acetamide or aryloxyalkyl - or alkoxy-/aryloxypropanolamine-tert-butylparabe can be accomplished using reaction procedures and conditions similar to those described in scheme 5.

The pharmaceutical composition

Pharmaceutical compositions of the present invention may include a therapeutically effective�th number of compounds of formulas (I) to(IV) together with a suitable amount of one or more pharmaceutically acceptable carriers, to provide a composition for proper administration to the patient. Suitable pharmaceutical carriers are described in the technique.

In some embodiments the compound of formulas (I) to(IV) may be included in pharmaceutical compositions for oral administration. Oral administration of such pharmaceutical compositions may result in uptake of the compounds of formulas (I) to(IV) through the intestine and entry into the systemic circulation. Such oral compositions can be obtained by means known in the field of pharmacy, and they include a compound of formulas (I) to(IV) and at least one pharmaceutically acceptable carrier. Oral pharmaceutical compositions may include a therapeutically effective amount of compounds of formulas (I) to(IV) and a suitable amount of pharmaceutically acceptable carrier so as to provide the appropriate form for administration to a patient.

Compounds of formulas (I) to(IV) can be included in the pharmaceutical composition introduced by any other suitable means of administration, including intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation or topical administration.

Pharmaceutical compositions comprising a compound of formulas (I) to (IV can be obtained through the ordinary processes of mixing, dissolution, granulation, to obtain pellets, grinding, emulsification, insulinopenia, capture or lyophilisate. Pharmaceutical compositions may be formulated in conventional manner using the inclusion of one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate processing of compounds of formulas (I) to(IV) or its crystalline form and one or more pharmaceutically acceptable media in the drug that can be used for pharmaceutical purposes. The right drug depends on the selected method of administration. Pharmaceutical compositions of the present invention may take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, and preparations with delayed release, suppositories, aerosols, sprays or any other form suitable for administration to a patient.

Pharmaceutical compositions of the present invention can be obtained in a standard dosage form. The definition of "standard dosage form" refers to physically discrete unit suitable as a single dose for patients undergoing treatment, with each unit contains a pre-ustanovlennomu compounds of formulas (I) to(IV), calculated to obtain the intended therapeutic effect. Standard dosage form can be a dose for one administration per day, for the introduction of 2 times a day, or one of multiple daily doses, e.g. 3 or more times a day. When using multiple daily doses, a standard dosage form can be the same or different for each dose. One or more dosage forms may include the dose that can be administered to the patient at one time or over a time interval.

Pharmaceutical compositions comprising a compound of formulas (I) to(IV) can be obtained for immediate release.

In some embodiments of the oral dosage form of the present invention may be a dosage form with controlled release. Technology adjustable delivery can improve the absorption of the drug in a certain area or areas of the gastrointestinal tract. System controlled drug delivery can be created for delivery of the drug in such a way that the level of drug is maintained at a therapeutically effective window, and effective and safe blood levels persist during the period of such duration as the system continues to deliver Les�arctonoe tool with a specific release profile in the gastrointestinal tract. Adjustable delivery drugs can give essentially constant levels of the drug in the blood for some period of time in comparison with the oscillations observed with dosage forms with immediate-release. For certain dosage forms, the ongoing concentration in the blood and tissues during treatment is the most desirable method of treatment. Immediate release drugs can cause levels in the blood, exceeding required for the identification of the desired reactions that can become unproductive consumption of the drug and may cause or exacerbate toxic side effects. Adjustable delivery of the drug can lead to optimal treatment and can not only reduce the frequency of doses, but may also reduce the severity of side effects. Examples of dosage forms with controlled release system include adjustable dissolution system with adjustable diffusion, ion exchange resins, osmotically controlled systems, systems with erodible matrix, pH-independent drugs, the system of retention in the stomach and similar systems.

The appropriate oral dosage form for a particular farmatsevticheskii compositions of the present invention may depend�et, at least in part, on the properties of absorption in the GI tract compounds of formulas (I) to(IV), the stability of the compounds of formulas (I) to(IV) in the gastrointestinal tract, the pharmacokinetics of the compounds of formulas (I) to(IV) and the intended therapeutic profile. For certain compounds of formulas (I) to(IV) can be selected corresponding oral dosage form with controlled release. For example, oral dosage forms with retention in the stomach may be appropriate for compounds absorbed primarily from the upper gastrointestinal tract, and oral dosage form extended-release may be appropriate for compounds absorbed primarily from the lower gastrointestinal tract. Some compounds are absorbed mainly from the small intestine. In General, the compounds undergo the small intestine for about 3-5 hours. In the case of compounds which are not easily absorbed in the small intestine or are hardly dissolved, the window for the absorption of the active substance in the small intestine may be too short to obtain the desired therapeutic action.

In some embodiments, the pharmaceutical compositions of the present invention can be used with dosage forms adapted to provide prolonged you�of volodine compounds of formulas (I-(IV) after oral administration. Oral dosage form slow release can be used to release medication over a long period of time and is applicable when it is desirable that the drug or dosage form is delivered to the lower gastrointestinal tract. Oral dosage form extended-release include any dosage form that maintains therapeutic concentration of the drug in biological fluids such as plasma, blood, cerebrospinal fluid, or tissue or organ for a long period of time. Oral dosage form extended-release cover systems with variable diffusion, such as the device reservoir and the device with a matrix system with adjustable dilution, osmotic systems and systems with controlled demolition. Oral dosage form extended-release and methods for their preparation are well known in the art.

The appropriate dose of a compound of formulas (I) to(IV) or pharmaceutical compositions comprising a compound of formulas (I) to(IV) may be determined according to any one of several standard protocols. For example, to determine the appropriate dose of the pharmaceutical compounds can be used issledovaniya animals such as studies using mice, rats, dogs and/or monkeys. The results of animal studies can be extrapolated to determine doses for use by other species, such as, for example, people.

Application

Compounds of formulas (I) to(IV) are prodrugs of the MPR. Thus, the compounds of formulas (I) to(IV) and pharmaceutical compositions comprising them, can be administered to the patient suffering from any disease including a disorder, condition or symptoms for which it is known that the MPR is therapeutically effective, or it would be revealed later. Readings, in which case the prescribed MHF, and, consequently, in which case it is also expected that the compound of formulas (I) to(IV) or pharmaceutical compositions comprising it, can be effective include psoriasis. Other indications in which the compounds of formulas (I) to(IV) may be therapeutically effective include multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease and arthritis.

Ways of treating disease in a patient according to the present invention comprise administration to a patient in need of such treatment, a therapeutically effective amount of a prodrug of the MPR formula (I) to(IV). Compounds of formulas (I) to(IV) or pharmaceutical compositions with them after the introduction of the patient can provide�ü therapeutic or prophylactic concentration of MHF in the blood plasma and/or blood.

MHF prodrug of formulae (I) to(IV) can be included in the pharmaceutical composition and/or dosage form adapted for oral administration, although the MHF prodrug of formulae (I) to(IV) can also be entered by any other appropriate means, such as, e.g., injection, infusion, inhalation, transdermal path, or absorption through epithelial or mucous membranes (for example, mucosa of the oral cavity, rectum and/or bowel).

MHF prodrug of formulae (I) to(IV) can be administered in amount and using regimens appropriate for the treatment of a particular disease. Daily doses of a MHF prodrug of formulae (I) to(IV) can range from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 50 mg/kg, from about 1 mg/kg to about 50 mg/kg, and in some embodiments, from about 5 mg/kg to about 25 mg/kg. In some embodiments, the MHF prodrug of formulae (I) to(IV) can be entered during these limits in the dose of from 1 mg to about 5 g per day, from about 10 mg to about 4 g per day, and in some embodiments, from about 20 mg to about 2 g per day. The appropriate dose of a MHF prodrug of formulae (I) to(IV) can be determined on the basis of several factors, including, for example, body weight and/or the condition of the patient to be treated, the severity of the disease, which treat the cases and/or the severity pomocnog� operation, the method of administration and the decision of the attending physician. Appropriate dosing intervals may be measured by methods known to those skilled in the art.

MHF prodrug of formulae (I) to(IV) before applying for people can be analyzed in vtro and in vivo for the desired therapeutic or prophylactic activity. Tests in vivo, for example using appropriate animal models, can also be used to determine whether the introduction of a MHF prodrug of formulae (I) to(IV) therapeutically effective.

In some embodiments a therapeutically effective dose of a MHF prodrug of formulae (I) to(IV) may provide a beneficial therapeutic effect without causing substantial toxicity including adverse effects. The toxicity of the MHF prodrug of formulae (I) to(IV) and/or their metabolites can be determined using standard pharmaceutical procedures and may be fixed by the specialists in this field of technology. The ratio between toxic dose and therapeutic effect is a therapeutic index. Dose MHF prodrug of formulae (I) to(IV) may be in the interval in which you can establish and maintain a therapeutically effective concentration in the circulating plasma and/or blood of a MHF prodrug of formulae (I) to(IV), which shows little toxicity or lack �oxyconti.

MHF prodrug of formulae (I) to(IV) can be used to treat any of the above diseases, disorders, conditions and symptoms for which it is known that MHF provides therapeutic blagoprijatstviju or it will show up later. It is known that MHF is effective in the treatment of psoriasis, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease and arthritis. Consequently, the MHF prodrug of formulae (I) to(IV) can be used to treat any of these diseases and disorders. The etiology underlying any of the foregoing diseases that are treated, can have many sources. In addition, in some embodiments a therapeutically effective amount of one or more compounds of formulas (I) to(IV) may be injected into a patient, such as a person, as a preventative measure against various diseases or disorders. Thus, a therapeutically effective amount of one or more compounds of formulas (I) to(IV) can be introduced as a preventive measure for patients with a predisposition to and/or history of immunological, autoimmune and/or inflammatory diseases including psoriasis, asthma and chronic obstructive pulmonary disease, heart failure, including left ventricular't�dostatochnosti, myocardial infarction and angina, mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, pigmentary retinopathy and mitochondrial encephalopathy, graft rejection, autoimmune diseases, including multiple sclerosis, ischemia and reperfusion injury, damage to the genome caused by AGE, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; and diseases mediated NF-κ.

Psoriasis

Psoriasis is characterized by hyperkeratosis and thickening of the epidermis, as well as an increased presence of blood vessels and infiltration of cells in areas of inflammation in the dermis. Psoriasis vulgaris is manifested in the form of silvery scale-shaped erythematous plaques typically on the hairy part of the scalp, elbows, knees and buttocks. Guttate psoriasis occurs in the form of damages as discontinuous droplets.

Esters of fumaric acid is recognized for the treatment of psoriasis, and dimethylfumarate approved in Germany for the systemic treatment of psoriasis (Mrowietz and Asadullah, Trends Mol. Med., 2005, 11(1), 43-48; and Mrowietz et al., Br. J. Dermatology, 1999, 141,424-429).

The efficacy of MHF prodrug for the treatment of psoriasis can be determined using animal models and clinical trials.

Inflammatory arthritis

Inflammatory arthritis includes�t diseases such as rheumatoid arthritis, juvenile rheumatoid arthritis (juvenile idiopathic arthritis), psoriatic arthritis and ankylosing spondylitis, causing inflammation of the joints. I believe that the pathogenesis immunopositive diseases, including inflammatory arthritis, involves ways of TNF signaling and NF-κ (Tracey et al., Pharmacology & Therapeutics, 2008, 117, 244-279). It is shown that DMF inhibits TNF and, because they believe that inflammatory diseases, including inflammatory arthritis, involve signaling of TNF and NF-κ, therefore, may be useful in the treatment of inflammatory arthritis (Lowewe et al., J. Immunology, 2002, 168, 4781-4787).

The efficacy of MHF prodrug for the treatment of inflammatory arthritis can be determined using animal models and in clinical trials.

Multiple sclerosis

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the Central nervous system caused by autoimmune attack against the insulating aksonnogo myelin layers of the Central nervous system. Demyelination leads to the destruction of conductivity and severe disease with destruction of local axons and irreversible necrosis of neurons. Symptoms of MS vary greatly with each individual patient, showing a particular pattern of movement disorders, feelings and sensitivity. MS typically pathologically prowl�is many foci of inflammation, plaques of demyelination, gliosis and aksonnogo lithology in brain and spinal cord, all of which contribute to clinical manifestations of neurological disability (see, for example, Wingerchuk, Lab. Invest, 2001, 81, 263-281; and Virley, NeuroRx, 2005, 2(4), 638-649). Although random events that accelerate MS, are not completely understood, evidence links the autoimmune etiology with environmental factors and specific genetic predispositions. Functional impairment, disability and disadvantages are expressed in the form of paralysis, sensory and activitywhich (octinitive) disorders, spasticity, tremor, lack of coordination and visible deterioration, affecting the quality of life of the individual. The clinical course of MS can vary from individual to individual, but invariably the disease can be classified in three forms; relapsing-remitting, secondary progressive and primary progressive.

Studies confirm the effectiveness of the FAE for the treatment of MS and are in phase II clinical validation (Schimrigk et al., Eur. J. Neurology, 2006, 13, 604-610; and Wakkee and Thio, Current Opinion Investigational Drugs, 2007, 8(11), 955-962).

The assessment of treatment efficacy in MS clinical trials can be carried out using tools such as the Expanded Disability Status Scale and the MS Functional, and imaging of pathological napr�narrow method of magnetic resonance imaging biomarkers and self-assessment of quality of life. Animal models of MS shown as applicable to identify and validate potential therapeutic agents include eksperimentalnye rodent model of autoimmune/allergic encephalomyelitis (EAE), which mimics the clinical and pathological manifestations of MS and EAE model primates, non-human beings.

Inflammatory bowel disease (Crohn's disease, ulcerative colitis)

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and in some cases, the small intestine, including Crohn's disease and ulcerative colitis. Crohn's disease, characterized by areas of inflammation with areas of healthy pavement between them, may affect any part of the gastrointestinal tract from mouth to anus. The main gastrointestinal symptoms are abdominal pain, diarrhea, constipation, vomiting, weight loss and/or weight gain. Crohn's disease can also cause redness of the skin, arthritis and eye inflammation. Ulcerative colitis is characterized by ulcers or open lesions in the large intestine or colon. The main symptom of ulcerative colitis is typically persistent diarrhea with blood impurities, begin gradually. �other types of inflammatory bowel disease include collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, eosinophilic colitis and Behcet nondeterministic colitis.

FAE are inhibitors of the activation of NF-κ and can therefore be used in the treatment of inflammatory diseases such as Crohn's disease and ulcerative colitis (Atreya et al., J. Intern. Med., 2008,263(6), 59106).

The efficacy of MHF prodrug for the treatment of inflammatory bowel disease may be assessed using animal models and clinical trials. Applicable animal models of inflammatory bowel disease known.

Asthma

Asthma is a reversible airway obstruction, in which the airway occasionally compressed, become inflamed and are covered with an excess of mucus. Symptoms of asthma include shortness of breath, stridor, tightness in the chest area and coughing. Episodes of asthma can be caused airborne allergens, food allergies, medications, inhaled irritants, physical exercise, respiratory infection, psychological stress, hormonal changes, cold weather or other factors.

As inhibitors of the activation of NF-κ, and as shown in animal studies (Joshi et al., US 2007/0027076), FAE can be used in the treatment of lung diseases such as asthma and chronic obstructive �Olesen lungs.

The effectiveness of a MHF prodrug of formulae (I) to(IV) for the treatment of asthma can be assessed using animal models and clinical trials.

Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD), also known as chronic obstructive airway disease, is a group of diseases characterized by the pathological limitation of airflow in the airway that is not fully reversible, and includes conditions such as chronic bronchitis, emphysema, and lung disorders such as asbestosis, pneumoconiosis and cancer of the lungs (see, for example, Bames, Pharmacological Reviews, 2004, 56(4), 515-548). Airflow limitation is usually progressive and associated with abnormal inflammatory response of the lungs to noxious particles and gases. COPD is characterized by shortness of breath, lasting for months or years, possibly accompanied by stridor, and persistent cough with production of sputum. COPD is most often caused by Smoking, although it can also be due to other airborne irritants such as coal dust, asbestos, urban pollution or solvents. COPD encompasses chronic obstructive bronchiolitis S. fibrosis and obstruction of small Airways, and emphysema with enlargement of gaps and des�the modernization of the parenchyma of the lungs, loss of lung elasticity and closure of small Airways.

The efficiency of introducing at least one compound of formulas (I) to(IV) for the treatment of chronic obstructive pulmonary disease may be assessed using animal models of chronic obstructive pulmonary disease and clinical research. For example, a well-known mouse model of chronic obstructive pulmonary disease.

Neurodegenerative disorders

Neurodegenerative diseases such as Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis, are characterized by progressive dysfunction and necrosis of neurons. As a therapeutic target in the case of neurodegenerative diseases proposed inhibition of NF-κb (Camandola and Mattson, Expert. Opin. Ther. Targets, 2007, 11(2), 123-32).

Parkinson's disease

Parkinson's disease is a gradually progressive, degenerative disorder of the nervous system characterized by tremor when muscles are at rest (resting tremor), slowness of voluntary movements and increased muscle tone (rigidity). In Parkinson's disease nerve cells in the basal nuclei, for example, a black substance, degenerate and thereby reduce the production of dopamine and the number of connections between nerve cells in the basal nuclei. In Reza�adds the basal nucleus is unable to movement of smooth muscles and coordinate changes in posture as normal, that leads to tremor, discoordination and delayed weakened movement (bradykinesia) (Blandini et al., Mol. Neurobiol., 1996, 12, 73-94).

The efficacy of compounds of formulas (I) to(IV) for the treatment of Parkinson's disease can be assessed using animal and human models of Parkinson's disease and in clinical trials.

Alzheimer's disease

Alzheimer's disease is a progressive loss of mental function characterized by degeneration of brain tissue, including loss of nerve cells and the development of senile plaques and neurofibrillary weaves. In Alzheimer's disease parts of the brain degenerate, and nerve cells are destroyed, and decreases the sensitivity of the remaining neurons to neurotransmitters. Of abnormality in brain tissue consist of senile or senile plaques, for example, aggregates of dead nerve cells containing abnormal insoluble protein called amyloid, and neurofibrillary weaves twisted chains of insoluble proteins in the nerve cell.

The efficacy of compounds of formulas (I) to(IV) for the treatment of Alzheimer's disease can be assessed using animal and human models of Alzheimer's disease and in clinical trials.

Huntington's

Huntington's disease is an autosomal until�inante neurodegenerative disorder, where in the new striped body (neostriatum) and the cerebral cortex occurs specific cell death (Martin, N. Engl. J. Med., 1999, 340, 1970-80). Start is usually in the fourth or fifth decade of life with an average expiration period of the beginning of 14-20 years. Huntington's disease is usually fatal, and effective treatment does not exist. Symptoms include a characteristic movement disorder (Huntington's chorea), cognitive dysfunction and psychiatric symptoms. The disease is caused by a mutation encoding an abnormal buildup coded CAG polyglutamine repeats in the protein huntingtin.

The efficacy of compounds of formulas (I) to(IV) for the treatment of Huntington's disease can be assessed using animal and human models of Huntington's disease and in clinical trials.

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by a progressive and specific loss of motor neurons in the brain, the brain stem and spinal cord (Rowland and Schneider, N. Engl. J. Med., 2001, 344, 1688-1700). ALS begins with weakness, often in the hands and less often in the feet, which usually progresses to the shoulder or lower leg. Over time, the weakness increases, and spasticity develops, characterized by muscle cramps and �aparently, with subsequent muscle spasms and possible tremor. The average age of onset is 55 years, and the average duration of life after clinical beginning is 4 years. The only recognized treatment for ALS is riluzole, which can extend the life of only about three months.

The efficacy of compounds of formulas (I) to(IV) for treating ALS may be assessed using animal and human models of ALS and in clinical studies.

Other diseases

Other diseases and conditions, treatment which you can apply the compounds of formulas (I) to(IV) include rheumatic diseases, granuloma annulare, lupus, autoimmune carditis, eczema, sarcoidosis, and autoimmune diseases, including acute dissimilitude encephalomyelitis, Addison's disease, alopecia alopecia, ankylosing spondylitis, antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune disease of the inner ear, bullous pemphigoid, Behcet's disease, celiac disease, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, diabetes mellitus type I, endometriosis, goodpasture's syndrome, graves ' disease, syndrome Gillina-Barr, Hashimoto's disease, suppurative hydradenitis, Kawasaki disease, IgA-neuropathy, idiopathic thrombocytopenic purple, interst�social cystitis, lupus erythematosus, mixed connective tissue disease, morphea, scleroderma, multiple sclerosis, severe myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, rheumatoid arthritis, schizophrenia, scleroderma, Sjogren's syndrome, stiff person, temporal arthritis, ulcerative colitis, vasculitis, vitiligo and Wegener's granulomatosis.

Introduction

Prodrug of the MPR formula (I) to(IV) and pharmaceutical compositions can be administered orally or by any appropriate means, e.g., by inhalation or bolus injection, by absorption through epithelial or mucocutaneous membranes (for example, the mucous membranes of the mouth, rectum, and small intestine, etc.). Other appropriate ways of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation or topical administration.

Administration may be systemic or local. There are various delivery systems, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc.) that can�about to use for administration of the compounds and/or pharmaceutical compositions.

The number of MHF prodrug of formulae (I) to(IV), which will be effective in the treatment of disease in a patient will depend, in part, on the nature of the condition, and may be determined by standard clinical techniques known in the art. In addition, to help identify optimal dosing intervals can be used tests in vitro or in vivo. A therapeutically effective amount of a MHF prodrug of formulae (I) to(IV) for administration may also depend on, among other factors, the subject being treated, the weight of the subject, the severity of the disease, the route of administration and the decision of the treating physician.

For system the introduction of a therapeutically effective dose possible at first to figure in in vitro tests. For example, in animal models it is possible to estimate the dose to achieve a favorable range of concentrations in the bloodstream. Initial doses can also be estimated from in vivo data, e.g., animal models, using techniques that are known in the art. Such information can be used to more accurately determine the applicable doses for humans. Specialist in the art can optimize administration to humans based on the results for the animals.

The dose can be administered in a single dosage form or multiple dosage forms. When using multiple dosage forms, the number of connections, �terjadinya in each dosage form, may be the same or different. The number of MHF prodrug of formulae (I) to(IV) contained in a dose may depend on the method of administration and is also treated and if the disease in the patient effectively urgent or continuous administration, or a combination of term and permanent administration.

In some embodiments of the administered dose less than the toxic dose. Toxicity of the compositions described in this description, you can define standard pharmaceutical procedures in cell cultures or experimental animals, e.g., determining the LD50(the dose lethal to 50% of the population) or LD100(the dose lethal to 100% of the population). The ratio between toxic dose and therapeutic effect is a therapeutic index. In some embodiments, the prodrug of the MPR may show a high therapeutic index. Data obtained from such analyses in cell cultures and animal studies can be used in the preparation of the dosing interval, which is not toxic for human use. Dose MHF prodrug of the present invention may be in the range of circulating concentrations in for example, blood, plasma, or Central nervous system that include the effective dose and which show weak toxicity or lack thereof. Dose can ismenias� in the specified range depending on the dosage form and the route of administration. Some embodiments may be given to increasing the dose.

Combination therapy

The methods of the present invention also include the introduction of one or more pharmaceutically active compounds in addition to the MHF prodrug of formulae (I) to(IV). Such compounds may be provided to treat the same disease, which treat the MHF prodrug of formulae (I) to(IV), or other disease.

In some embodiments, the MHF prodrug of formulae (I) to(IV) can be used in combination with at least one other therapeutic agent. In some embodiments, the MHF prodrug of formulae (I) to(IV) can be administered to the patient together with another compound for treating diseases and conditions, including immunological, autoimmune and/or inflammatory processes, including psoriasis; asthma; chronic obstructive pulmonary disease and arthritis; cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina; mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, pigmentary retinopathy and mitochondrial encephalopathy; transplant rejection; autoimmune diseases, including multiple sclerosis (MS); ischemia and reperfusion injury (damage to the genome caused by AGE); and others. In some �uplasenih a MHF prodrug of formulae (I) to(IV) can be administered to the patient together with another compound for the treatment of psoriasis, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease and arthritis.

The MHF prodrug of formulae (I) to(IV) and at least one other therapeutic agent can act additively or, in certain embodiments, synergistically. At least one additional therapeutic agent may be included in the same dosage form as that of a MHF prodrug of formulae (I) to(IV), or may be provided in a separate dosage form. The methods of the present invention can also include, besides the introduction of a MHF prodrug of formulae (I) to(IV), the introduction of one or more therapeutic agents effective for treating the same disease, which treat the MHF prodrug of formulae (I) to(IV), or other disease. The methods of the present invention include the introduction of a MHF prodrug of formulae (I) to(IV) and one or more therapeutic agents provided that the combined introduction does not inhibit therapeutic efficacy of MHF prodrugs and/or typically leads to substantial and/or significant side-effect of the combination.

In some embodiments the dosage form comprising a MHF prodrug of formulae (I) to(IV) can be introduced simultaneously with the introduction of another therapeutic agent, which may be part of the same drug� form, or other dosage forms, what form that includes a MHF prodrug of formulae (I) to(IV). The MHF prodrug of formulae (I) to(IV) can be entered before or after administration of another therapeutic agent. In some embodiments of combination therapy may involve the alternation of the introduction of a MHF prodrug of formulae (I) to(IV) and a composition comprising another therapeutic agent, e.g., to minimize adverse effects associated with a particular drug. When the MHF prodrug of formulae (I) to(IV) is administered concurrently with another therapeutic agent that potentially can cause side effect of the medicine, including, but not limited to, toxicity, the other therapeutic agent can be advantageous to introduce at a dose that is below the threshold at which the detected adverse reaction to the drug.

In some embodiments the dosage form comprising a MHF prodrug of formulae (I) to(IV) can be introduced with one or more substances to enhance, modulate and/or control release, bioavailability, therapeutic efficacy, therapeutic potency, stability, etc. MHF prodrug of formulae (I) to(IV). For example, to enhance therapeutic efficacy of the ligand MHF prodrug of formulae (I) to(IV) a dosage form comprising a prodrug MHF (I) to(IV), may include, or a MHF prodrug of formulae (I) to(IV) can be entered together with one or more active substances, which increase the absorption or diffusion of a MHF prodrug of formulae (I)-(IV) from the gastrointestinal tract into the General circulation or inhibit the expansion of a MHF prodrug of formulae (I) to(IV) in the patient's blood. In some embodiments, the MHF prodrug of formulae (I) to(IV) can be entered together with the active substance having a pharmacological effect, which enhances therapeutic efficacy of MHF prodrugs of formulae (I) to(IV).

In some embodiments, the MHF prodrug of formulae (I) to(IV) or pharmaceutical composition can be administered to the patient to treat psoriasis in combination with a therapy or another therapeutic agent known or believed they are effective in the treatment of psoriasis. Medicines, applicable for the treatment of psoriasis include steroids, such as flurandrenolide, fluocinonide, alclometasone, amcinonide, desonide, halcinonide, triamcinolone, clobetasol, clocortolone, mometasone, desoximetasone and halobetasol; Antirheumatic agents, such as etanercept, infliximab and adalimumab; immunosuppressive agents such as cyclosporine, alefacept and efalizumab; psoralens, such as methoxsalen; and other tools such as calcipotriene, methotrexate, hydrocorti�he/pramoxine, acitretin, betamethasone/calcipotriene, tazarotene, benzocaine/pyrilamine/zinc oxide and ustekinumab.

In some embodiments, the MHF prodrug of formulae (I) to(IV) or pharmaceutical composition can be administered to the patient for the treatment of inflammatory arthritis, such as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, in combination with a therapy or another therapeutic agent known or suspected of being effective in the treatment of inflammatory arthritis, such as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

Medicines, applicable to the treatment of arthritis include NSAIDs, such as ibuprofen, Ketoprofen, salicylate, diclofenac, nabumetone, naproxen, meloxicam, sulindac, flurbiprofen, indomethacin, tolmetin, piroxicam, fenoprofen, oxaprozin and etodolac; Antirheumatic agents, such as etanercept, adalimumab, infliximab, hydroxychloroquine, Leflunomide, azathioprine, penicillamine, methotrexate, anakinra, auranofin, rituximab, aurothioglucose, tocilizumab and golimumab; inhibitors of Cox-2 such as celecoxib and widechars; corticosteroids such as triamcinolone; glucocorticoids, such as methylprednisolone prednisone; other means, such as sulfasalazin.

Medicines, applicable to the treatment of juvenile rheumatoid arthritis include adalimumab, abatacept and infliximab.

Medicines, applicable for the treatment of psoriatic arthritis include etanercept, adalimumab, triamcinolone, cortisone, infliximab and golimumab.

Medicines, applicable for the treatment of ankylosing spondylitis include adalimumab, celecoxib, diclofenac, etanercept, golimumab, indomethacin, infliximab, naproxen, olsalazine, salicylates, sulindac and triamcinolone.

In some embodiments, the MHF prodrug of formulae (I) to(IV) or pharmaceutical composition can be administered to the patient. for the treatment of psoriatic arthritis in combination with a therapy or another therapeutic agent known or suspected of being effective in the treatment of psoriatic arthritis. Medicines, applicable for the treatment of psoriatic arthritis include etanercept, adalimumab, triamcinolone, cortisone, infliximab and golimumab.

In some embodiments, the MHF prodrug of formulae (I) to(IV) or pharmaceutical composition can be administered to the patient for the treatment of autoimmune diseases such as lupus, in combination with a therapy or another therapeutic agent known or u�apologiesa, they are effective in the treatment of autoimmune diseases such as lupus. Pharmaceuticals applicable to the treatment of lupus include hydroxylated, triamcinolone, salicylate, azathioprine and abetimus.

In some embodiments, the MHF prodrug of formulae (I) to(IV) or pharmaceutical composition can be administered to the patient for the treatment of multiple sclerosis in combination with a therapy or another therapeutic agent known or suspected of being effective in the treatment of multiple sclerosis. Medicines available for treating multiple sclerosis include interferon-β-1a, interferon-β-1b, Tatars EP, modafinil, azathioprine, prednisolone, mycophenolate, mitoxantrone and natalizumab. Other examples of drugs that are applicable for the treatment of MS include corticosteroids, such as methylprednisolone, IFN-β, such as IFN-β1a and IFN-β1b; glatiramer acetate; monoclonal antibodies that bind to the integrin very late antigen-4 (VLA-4), such as natalizumab; immunomodulatory agents such as modulator synagogen-1-phosphate FTY 720, and inhibitors of COX-2, such as BW755c, piroxicam, and feniton; and neuroprotective agents, including inhibitors of excitotoxicity and iNOS, scavengers of free radicals and blockers of cation channels; memantine; AMPA antagonists such as topiramate; and antagonist� site of the NMDA glycine.

In some embodiments, the MHF prodrug of formulae (I) to(IV) or pharmaceutical composition can be administered to the patient for the treatment of inflammatory bowel disease in combination with a therapy or another therapeutic agent known or believed they are effective in the treatment of inflammatory bowel disease. Medicines, applicable to the treatment of inflammatory bowel disease include cromolyn and mercaptopurine; and, especially for the treatment of Crohn's disease include certolizumab, budesonide, azathioprine, sulfasalazine, metronidazole, adalimumab, mercaptopurine, infliximab, mesalamine and natalizumab; and for the treatment of ulcerative colitis include balsalazide, infliximab, azathioprine, mesalamine and cyclosporine.

In some embodiments, the MHF prodrug of the present invention and pharmaceutical compositions can be administered to the patient for the treatment of asthma in combination with a therapy or another therapeutic agent known or suspected of being effective in the treatment of asthma or, in some embodiments, the disease, disorder or condition associated with asthma. Examples of drugs that are applicable for the treatment of asthma include albuterol, theophylline, beclomethasone, bitolterol, budesonide, cromolyn, ephedrine, epinephrine, �linezolid, fluticasone, formoterol, hydrocortisone, isoproterenol, levalbuterol, methylprednisolone, prednisolone, prednisone, pirbuterol, metaproterenol, racepinephrine, omalizumab, oxtriphylline, mometasone, montelukast, nedocromil, oxtriphylline, salmeterol, terbutaline, theophylline, triamcinolone, zafirlukast and zileuton.

In some embodiments, the MHF prodrug of the present invention and pharmaceutical compositions can be administered to the patient for the treatment of chronic obstructive pulmonary disease in combination with a therapy or another therapeutic agent known or suspected of being effective in the treatment of chronic obstructive pulmonary disease or, in some embodiments, the disease, disorder or condition associated with an obstructive lung disease. Examples of drugs that are applicable for the treatment of obstructive lung disease include albuterol, arformoterol, azithromycin, bitolterol, epinephrine, fluticasone, formoterol, ipratropium, isoproterenol, levalbuterol, metaproterenol, pirbuterol, racepinephrine, salmeterol and Tiotropium. Medicines, applicable to the treatment of chronic obstructive pulmonary disease, also include bronchodilators such as β2 agonists such as salbutamol, bambuterol, clenbuterol, fenoterol, and formoterol; anti-m�Skarina M3, such as ipratropium; leukotriene antagonists such as montelukast, pranlukast and zafirlukast; chromone, such as cromoglycate and nedocromil; xanthines such as theophylline; corticosteroids such as beclomethasone, mometasone and fluticasone; and TNF antagonists, such as infliximab, adalimumab and etanercept. Other ways treat chronic obstructive pulmonary disease include oxygen therapy and lung rehabilitation.

In some embodiments, the prodrug of the present invention and pharmaceutical compositions can be administered to the patient for the treatment of angiogenesis in combination with a therapy or another therapeutic agent known or suspected of being effective in the treatment of angiogenesis. Medicines, applicable for the treatment of angiogenesis include angiostatin, endostatin, vitaxin, bevacizumab, thalidomide, batimastat, marimastat, carboxamidates, TNP-470, 101 CM, IFN-a, IL-12, platelet factor 4, suramin, SU5416, thrombospondin, VEGFR, angiostatic steroids, the factor of inhibition of angiogenesis cartilage, inhibitory matrix metalloproteinases, 2-methoxyestradiol, tecogen, prolactin, inhibitors of αvβ3and linomide.

In some embodiments, the prodrug of the present invention and pharmaceutical compositions can be administered to the patient for treatment Attori�of graft in combination with a therapy or another therapeutic agent, known or suspected of being effective in the treatment of transplant rejection. Medicines, applicable to the treatment of transplant rejection include inhibitors calcineurin, such as cyclosporine and tacrolimus, mTOR inhibitors such as sirolimus and everolimus, antiproliferative agents such as azathioprine and mycophenolic acid; corticosteroids, monoclonal antibodies against the receptor IL2Rα, including basiliximab and impact; and pelikaanimies anti-T-cell antibodies, including antithymocyte globulin and antilimfocitarnyi globulin.

In some embodiments, the prodrug of the present invention and pharmaceutical compositions can be administered to the patient for the treatment of transplant rejection in combination with a therapy or another therapeutic agent known or suspected of being effective in the treatment of transplant rejection. Medicines, applicable to the treatment of transplant rejection, include corticosteroids, such as dexamethasone, prednisolone and prednisone; globulins, such as antithymocyte globulin and antilimfocitarnyi globulin; macrolide immunodepressant, such as sirolimus, tacrolimus and everolimus; inhibitors of mitosis, such as azathiprine, cyclophosphamide, and methotrexate; monoclonal antibodies, �which as basiliximab, impact, infliximab, muromonab; fungal metabolites, such as cyclosporine; and other agents such as glatiramer and mycophenolate.

In some embodiments, the prodrug of the present invention and pharmaceutical compositions can be administered to the patient to treat heart failure in combination with a therapy or another therapeutic agent known or suspected of being effective in the treatment of heart failure. Pharmaceuticals applicable to the treatment of heart failure include antianginalnaya agents, diuretics, such as furosemide, bumetanide, gidrohlortiazid chlorthalidone, chlorothiazide, spironolactone, eplerenone; beta-blockers such as bisoprolol, carvedilol and metoprolol; positive inotropy, such as digoxin, milrinone and dobutamine; alternative vasodilatatory, such as isosorbide dinitrate/hydralazine; antagonists aldosterone receptors; recombinant neuroendocrine hormones, such as nesiritide; and antagonists vasopressin receptors, such as tolvaptan and conivaptan.

In some embodiments, the prodrug of the present invention and pharmaceutical compositions can be administered to the patient for the treatment of mitochondrial diseases, such as neurodegenerative disorder, with�etani with a therapy or another therapeutic agent, known or suspected of being effective in the treatment of mitochondrial diseases, such as neurodegenerative disorder. In some embodiments the neurodegenerative disorder is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

A therapeutic agent for the treatment of Parkinson's disease include precursors of dopamine, such as levodopa, dopamine agonists such as bromocriptine, pergolid, pramipexol and ropinirole, MAO inhibitors, such as selegiline, anticholinergic medications, such as benztropine, trihexyphenidyl, tricyclic antidepressants such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, amantadine and trimipramine, some antihistamines, such as diphenhydramine; antiviral drugs such as amantadine; and beta-blockers, such as propranolol.

Applicable drugs for the treatment of Alzheimer's disease include rosiglitazone, raloxifene, vitamin E, donepezil, tacrine, rivastigmine, galantamine and memantine.

Applicable drugs for the treatment of Huntington's disease include antipsychotics such as haloperidol, chlorpromazine and�Antipin, to combat the hallucinations, delusions and violent outbursts; antidepressants such as fluoxetine, sertraline and nortriptyline to treat depression and obsessive-compulsive behavior; tranquilizers such as benzodiazepines, paroxetine, inflexion and beta-blockers to deal with anxiety and chorea; mood stabilizers such as lithium, valproate and carbamazepine, to combat addictions and bipolar disorder; and botulinum toxin to fight dystonia and jaw clenching. Applicable medicines to treat the symptoms of Huntington's disease also include selective inhibitors of re-uptake of serotonin (SSRI) such as fluoxetine, sertraline, ESCITALOPRAM, citalopram, fluvastatin; inhibitors of re-uptake of norepinephrine and serotonin (NSRI) such as venlafaxine and DULOXETINE, benzodiazepines such as clonazepam, alprazolam, diazepam and lorazepam, tricyclic antidepressants such as amitriptyline, nortriptyline, and imipramine; atypical antidepressants such as buspirone, bupropion and mirtazapine, to treat the symptoms of anxiety and depression; Atomoxetine dextroamphetamine, perhaps, and modafinil for the treatment of symptoms of apathy; amantadine, memantine and tetrabenazine to treat the symptoms of chorea; citalopram, Atomoxetine, memantine, rivastigmine and donepezil for the treatment of cogni�active symptoms; lorazepam and trazedone for the treatment of insomnia; valproate, carbamazepine and lamotrigine for the treatment of symptoms of ratnajyoti; SSRI antidepressants such as fluoxetine, paroxetine, sertaline and fluvoxamine, NSRI antidepressants, such as venlafaxine, and other tools, such as mirtazepine, clomipramine, lamotrigine, gabapentin, allroad, carbamazepine, olanzapine, risperidone and quetiapine, to treat symptoms of obsessive-compulsive disorder; haloperidol, quetiapine, clozapine, risperidone, olanzapine, ziprasidone and aripiprazole for the treatment of psychosis; and pramipexole, levodopa and amantadine for the treatment of rigidity.

Applicable drugs for the treatment of ALS include riluzole. Other drugs, the potential for use in the treatment of ALS include memantine, tamoxifen, thalidomide, Ceftriaxone, phenylbutyrate sodium, celecoxib, glatiramer acetate, buspiron, creatine, minocycline, coenzyme Q10, Oxandrolone, IGF-1, topiramate, xaliproden and indinavir. Medicines such as baclofen and diazepam, can be used in the treatment of spasticity associated with ALS.

In some embodiments, the MHF prodrug of formulae (I) to(IV) or pharmaceutical composition can be administered to the patient in combination with a therapy or another therapeutic agent known or believed they effect�wny the inhibition of TNF function.

Examples of drugs known to inhibit the function of TNF include infliximab, adalimumab. Etanercept, certolizumab, golimumab, pentoxifylline, canillejas, thalidomide, flavonoids, such as naringenin, resveratrol and quecertin, allodi, such as lycorine, terpenes, such as acanthus acid, fatty acids such as 13-NOAH, and retinoids such as retinoic acid.

Examples

The following examples describe in detail the synthesis of a MHF prodrug of formulae (I) to(IV), the properties of a MHF prodrug of formulae (I) to(IV) and the use of a MHF prodrug of formulae (I) to(IV). For specialists in the art it will be obvious that in practice can be done many modifications in both materials and methods, without departing from the scope of disclosure.

Common protocols of experiments

All reagents and solvents purchased from commercial suppliers, and used without further purification or manipulation procedures.

Proton NMR spectra (400 MHz) and carbon NMR (125 MHz) recorded on NMR spectrometer Varian AS 400, equipped with an automatic sampler and data processing software. As solvents used CDCl3(99,8% D), DMSO-d6(The 99.9% D) or MeOH-d4(99,8+% D) and acetonitrile-d3if not specified otherwise. The signals of the solvent CHCl3, DMSO-d5or MeOH-d3use DL� calibration of the individual spectra. Analytical thin-layer chromatography (TLC) carried out using TLC Whatman, Schleicher & Schuell, and silica gel plates MK6F (2.5 x 7.5 cm, layer thickness: 250 µm). The melting point recorded in glass capillaries using the system Stanford Research Systems (SRS) Optimelt Automated Melting Point, S/N 78047. Analytical LC/MS carried out on the separation module Waters 2790, equipped with a mass spectrometer Waters Micromass QZ, a photo diode array detector Waters 996 and analytical column (Merck Chromolith UM2072-027 or Phenomenex Luna C-18. Cleaning mass (mass-guided) preparative HPLC of the final compounds is carried out using a device equipped with a controller, Waters 600, micromass-ZMD spectrometer, detector with photodiode matrix Waters 2996 and device control samples Waters 2700. A mixture of acetonitrile/water gradient containing 0.05% formic acid, used in the experiments as allentow in both analytical and preparative HPLC. The selection of compounds from aqueous mixtures of solvents, e.g., acetonitrile/water/0.05% of formic acid is carried out by primary lyophilization (drying) of a frozen solution under reduced pressure at room temperature using different freeze-dryers, such as Heto Drywinner DW 6-85-1, Heto FD4, or VIRTIS Freezemobile 25 ES, equipped with high vacuum pumps. When the allocated connection �has ionizable functional groups, such as the amino group or carboxyl group, the lyophilization is carried out in the presence of a small excess odnomestnoi (1 M) hydrochloric acid, and get purified compound in the form of relevant hydrochloride (HCl salt) or the corresponding protonated free carboxylic acids. When secreted the compound has ionizable functional groups such as carboxyl group, the lyophilization is carried out in the presence of equimolar amounts of sodium bicarbonate (NaHCO3and receive the purified compound in the form of the corresponding sodium salts (Na salt). Optional selected substances further purified column flash chromatography on silica gel, optionally, using pre-filled with silica gel cartridges biotage AB. Suitable organic solvents, such as ethyl acetate (EtOAc), hexane (HXN), n-heptane (Hptn) mixtures and/or gradients are used as allentow, and after evaporation of the solvents get the target compound as colorless viscous oils or solids. Chemical name prepared by program Chemistry 4-D Draw Pro Version 7.01 C (Draw Chemical Structures Intelligently® 1993-2002) from Chemilnnovation Software, Inc., San Diego, USA.

Commercially available respectively functionalized or substituted 2-halogenated, derivatives of 2-halogenase �of islote, 2-hydroxyacetamido, derivatives of 2-hydroxiacetic, aryloxyalkanoic or alkoxy - or synthesized from commercially available starting materials and by adapting methods well known in the art.

General synthetic methods

General method A: nucleophilic substitution of 1-halogenated or derivatives of 1-halogenases acid monomethylfumarate

(2E)-3-(Methoxycarbonyl)prop-2-envoy acid (methylhydroquinone, MPR), (2E)-3-(tert-butoxycarbonyl)prop-2-envoy acid (tert-butylhydroquinone) or fumaric acid (FA) (1.0 equivalent) was dissolved in 5-10 ml/3.0 mmol inert solvent, such as N-methylpyrrolidone (NMP), N,N-dimethylformamid (DMF), N,N-dimethylacetamide (DMA, DMAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), toluene or mixtures thereof. To the solution was added 0.8 to 1.2 equivalents of the appropriate inorganic bases such as cesium bicarbonate (CsHCO3), cesium carbonate (Cs2CO3) or potassium carbonate (K2CO3). On the other hand, you can use 0.8 to 1.2 equivalent of silver salt such as silver oxide(1) (Ag2O) or silver carbonate(1) (Ag2CO3); organic secondary or tertiary base such as dicyclohexylamine (DCHA), triethylamine (TEA), diisopropylethylamine (DIEA) hydroxide, Tetra�of telamonia (TWAIN), the amidine; or the basis on the basis of guanidine, such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,1,3,3-tetramethylguanidine (TMG). You can also obtain the corresponding salt of an alkali metal, silver, di-, tri - and tetraalkylammonium, amidine or guanidine of monoalkylamines. The solution was stirred for 10-60 min at room temperature, and then add 0.8 to 1.2 equivalent, respectively functionalizing 1-halogenated derived 1-halogenases acid, aryloxyalkanoic or alkyl - or . The reaction mixture was stirred overnight at a temperature of from 40 to 100°C. After cooling to room temperature, insolubles can optionally be filtered, and the reaction mixture was diluted odnomestnoi (1 M) hydrochloric acid (HCl) and an appropriate organic solvent such as methyl tert-butyl ether (MTBE), diethyl ether (Et2O), ethyl acetate (EtOAc), or mixtures thereof. After phase separation, the aqueous phase is extracted several times with the same solvent. The combined organic extracts were washed with water and brine and dried over anhydrous magnesium sulfate (MgSO4). After filtration, the organic solvents were removed under reduced pressure using a rotary evaporator. If necessary �Irie the reaction products were further purified by a well-known purification methods, such as flash column chromatography on silica gel (i.e., biotage AB), mass preparative HPLC with reversed phase/lyophilization, precipitation or crystallization.

General method B1: activation of carboxylic acid derivatives by dehydration agents for aminolysis or alcoholysis

(2E)-3-(Methoxycarbonyl)prop-2-envoy acid (methylhydroquinone, MHF), [(2E)-3-(methoxycarbonyl)prop-2-enolase]acetic acid (23) or [(2E)-3-(methoxycarbonyl)prop-2-enolase]propane acid (24) (1.0 equivalent) at a temperature from ca. 0°C (ice bath) to room temperature is injected into interaction with the agent of the dehydration carbodiimides, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC, EDC), N,N'-diisopropylcarbodiimide (DIC), N,N-dicyclohexylcarbodiimide (DCC), in an inert solvent such as dichloro methane (DCM), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP or N,N-dimethylacetamide (DMA, DMAc) (ca. 3 ml/mmol). At temperatures from ca. 0°C to room temperature, add 1.0 to 1.5 equivalent, respectively, functionalized amine, or 2-hydroxyacetamido dissolved in the same solvent, and optionally in the presence of catalytic or stoichiometric amount of 4-(N,N-dimethylamino)pyridine (DMAP). When Amin is in salt form, can be added an equimolar amount of tertiary organic bases, such as three!�ylamine (TEA) or Diisopropylamine (DIEA), to free base amine in front of the stage combinations. The reaction mixture was stirred for 4-12 hours at room temperature. Optionally, an organic base is removed under reduced pressure using a rotary evaporator, and the residue was diluted with a suitable extraction solvent such as diethyl ether (Et2O), methyl tert-butyl ether (MTBE), ethyl acetate (EtOAc), or other solvent. For isolation and purification of the reaction product can be used the procedures described in method A.

General method B2: activation of carboxylic acid derivatives chlorinating agents and aminals

[(2E)-3-(Methoxycarbonyl)prop-2-enolase]acetic acid (23) or [(2E)-3-(methoxycarbonyl)prop-2-enolase]propane acid (24) (1.0 equivalent) at a temperature of ca. 0°C (ice bath) was injected into interaction with oxalylamino (1.0 to 1.5 equivalent) in anhydrous dichloromethane (DCM), ca. 3 ml/mmol in the presence of a catalytic amount of N,N-dimethylformamide (DMF) for 1-3 hours. The solvents were removed under reduced pressure using a rotary evaporator, and the crude material was dissolved in anhydrous dichloromethane (DCM), ca. 3 ml/mmol. When ca. 0°C (ice bath) was added dropwise a solution of 1.0-1.5 equivalents, respectively, of the functionalized nucleophile (primary or secondary amine or alcohol) � anhydrous dichloromethane (DCM), ca. 3 ml/mmol, optionally in the presence of a catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP). When the amine component is in salt form, is added an equimolar amount of base, such as triethylamine (TEA), Diisopropylamine (DIEA) or more, to free base amine in front of the stage combinations. The reaction mixture was stirred overnight with warming to ambient temperature, optionally, the solvents were removed under reduced pressure using a rotary evaporator and the residue is diluted with a suitable extraction solvent such as diethyl ether (Et2O), methyl tert-butyl ether (MTBE), ethyl acetate (EtOAc), or other solvent. For isolation and purification of the reaction product can be used the procedures described in method A.

Example 1

(N,N-Diethylcarbamoyl)methyl(2E)but-2-ene-1,4-diat (1)

Following the General method a, methylhydroquinone (MPR) is 0.39 g, 3.00 mmol) dissolved in NMP, ca. 55°C is injected into interaction with 2-chloro-N,N-diethylacetamide (of 0.44 g, 3.00 mmol) in the presence CsHCO3(0,69 g, of 3.60 mmol) and after purification column chromatography on silica gel (biotage AB) using as eluent a mixture of ethyl acetate (EtOAc) and hexane (1:1) gain of 0.37 g (yield 51%) named in the title compound (1). So a MP 53-56°C.1H NMR (CDCl3 , 400 MHz): δ 6,99-6,90 (m, 2H), a 4.83 (s, 2H), 3,80 (s, 3H), 3,39 (K, J=7,2 Hz, 2H), 3,26 (K, J=7,2 Hz, 2H), 1,24 (t, J=7,2 Hz, 3H), 1.14 in (t, J=7,2 Hz, 3H). MS (ESI): m/z 244,13 (M+H)+.

Example 2 Methyl[N-benzylcarbamoyl]methyl(2E)but-2-ene-1,4-diat (2)

Following the General method a, methylhydroquinone (MHF) (0.50 g, of 3.85 mmol) dissolved in NMP, ca. 55°C is injected into the interaction with N-benzylglycine (0.84 g, USD 4.61 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol) and after purification mass preparative HPLC (biotage AB) and lyophilization receive 0.56 g (yield 53%) named in the title compound (2) as a white solid.1H NMR (CDCl3, 400 MHz): δ of 7.36-7,26 (m, 5H), 6,94-to 6.88 (m, 2H), 6,19 (Ushs, 1H), 4,73 (s, 2H), 4,51 (d, J=5.6 Hz, 2H), 3,81 (s, 3H). MS (ESI): m/z 278,04 (M+H)+.

Example 3

Methyl-2-morpholine-4-yl-2-oxoethyl(2E)but-2-ene-1,4-diat (3)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, ca. 55°C is injected into interaction with 4-(chloroacetyl)morpholine (0.75 g, USD 4.61 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol) and after purification mass preparative HPLC (biotage AB) and lyophilization get 0,34 g (yield 35%) named in the title compound (3) as a white solid. So a MP 124-126°C.1H NMR (CDCl3, 400 MHz): δ 6.97 in-6,91 (m, 2H), 4,84 (s, 2H), 3,82 (s, 3H), and 3.72-3,70 (m, 4H), 3,64-3,62 (m, 2H), 3.46 in-to 3.41 (m, 2H). MS (ESI): m/z 258,04 (M+H)+.

Example 4

(-Butylcarbamoyl)methylethyl(2E)but-2-ene-1,4-diat (4)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, ca. 55°C is injected into the interaction with N-butylchloride (0,69 g, USD 4.61 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol) and after purification mass preparative HPLC (biotage AB) and lyophilization gain of 0.19 g (yield 21%) named in the title compound (4) as a white solid.1H NMR (CDCl3, 400 MHz): δ 6,98-at 6.92 (m, 2H), 6,09 (Ushs, 1H), 4,68 (s, 2H), 3,82 (s, 3H), 3,34-3,29 (2H, J=6,4 Hz), 1,54-of 1.48 (m, 2H), 1,38-1,32 (m, 2H), 0,956-0,920 (t, J=7,6 Hz, 3H). MS (ESI): m/z 244,04 (M+H)+.

Example 5

[N-(2-Methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diat (5)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, ca. 55°C is injected into interaction with N-(2-methoxyethyl)chloracetamide (0,69 g, 4,60 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol) and after purification mass preparative HPLC and lyophilization get 0.07 g (yield 8%) named in the title compound (5) as a white solid.1H NMR (CDCl3, 400 MHz): δ 6.94 per-at 6.92 (m, 2H), of 6.46 (Ushs, 1H), 4,68 (s, 2H), 3,83 (s, 3H), 3,52-of 2.46 (m, 4H), 3,36 (s, 3H). MS (ESI): m/z 245,98 (M+H)+.

Example 6

2-{2-[(2E)-3-(Methoxycarbonyl)prop-2-enological} acetic acid (6)

Following the General method a, methylhydroquinone (MHF) (0,68 g, 526 mmol), dissolved in NMP, ca. 55°C is injected into interaction with tert-butyl-2-(2-chloroacetamido)acetate (0,91 g, of 4.38 mmol) in the presence CsHCO3(1.19 g, 6,13 mmol) (with education) intermediate compounds with protective tert-butyl group, followed by purification column chromatography on silica gel (biotage AB) using as eluent a mixture of ethyl acetate (EtOAc) and hexane(1:2-2:3-1:1). The purified product is treated with 50% trifluoroacetic acid (TFA) in dichloromethane (DCM). Removal of solvent gives 0.13 g (yield 12%) named in the title compound (6).1H NMR (CD3OD, 400 MHz): δ 6,96-6,93 (m, 2H), 4,74 (s, 2H), 3,98-3,95 (m, 2H), 3,81 (s, 3H). MS (ESI): m/z 246,00 (M+H)+, 244,02 (M-N)-.

Example 7

4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetylamino}butane acid (7)

Following the General method a, methylhydroquinone (MHF) (0.56 g, 4,33 mmol) dissolved in NMP, with sa. 55°C is injected into interaction with tert-butyl-4-(2-chloroacetamido)butanoate (0.85 g, 3,61 mmol) in the presence CsHCO3(0,98 g, to 5.05 mmol) (with education) intermediate compounds with protective tert-butyl group, followed by purification column chromatography on silica gel (biotage AB) using as eluent a mixture of ethyl acetate (EtOAc) and hexane (1:1). The purified product is treated with 50% trifluoroacetic acid (TFA) in dichloromethane (DCM). Removal� solvent gives 0.45 g (yield 46%) named in the title compound (7). 1H NMR (CD3OD, 400 MHz): δ 6.94 per-6,91 (m, 2H), a 4.65 (s, 2H), 3,81 (s, 3H), or 3.28 (t, J=6,8 Hz, 2H), 2,33 (t, J=7,2 Hz, 2H), is 1.81 (t, J=7,1 Hz, 2H). MS (ESI): m/z 274,03 (M+H)+, 272,06 (M-H)-.

Example 8

Methyl(N-(1,3,4-thiadiazole-2-yl)carbamoyl)methyl(2E)but-2-ene-1,4-diat (8)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, with sa. 55°C is injected into interaction with 2-chloro-N-1,3,4-thiadiazole-2-ylacetamide (0,81 g, USD 4.61 mmol) in the presence CsCHO3(0.89 g, 4.61 record mmol). The precipitated crude material was washed several times with dichloromethane (DCM) for further purification, and get 0.12 g (yield 12%) named in the title compound (8) as a white solid.1H NMR (CD3OD, 400 MHz): δ 9,06 (s, 1H), 6,95-6,91 (m, 2H), 4,99 (s, 2H), 3,82 (s, 3H). MS (ESI): m/z 272,07 (M+H)+.

Example 9

(N,N-Dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat (9)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, with sa. 55C injected into interaction with N,N-dimethylacetamide (0.56 g, USD 4.61 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol). The raw material ejected from a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (1:1), and receive a white solid. Then, the resulting solid was dissolved in dichloromethane (DCM) and the organic layer was washed with water. After removal of solvents 0.55 g (�ith the release of 67%) named in the title compound (9) as a white solid. 1H NMR (CDCl3, 400 MHz): 5 6,98-6,90 (m, 2H), 4,84 (s, 2H), 3,80 (s, 3H), 2,99-of 2.97 (2 s, 6H). MS (ESI): m/z 216 (M+H)+.

Example 10

(N-Methoxy-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat (10)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, with sa. 55C injected into interaction with N-methyl,N-hydroxymethylglycinate (0,63 g, USD 4.61 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol). The raw material ejected from a concentrated solution in ethyl acetate (EtOAc). The solid is filtered off and dried under vacuum, and the gain of 0.54 g (yield 61%) named in the title compound (10) as a white solid.1H NMR (CD3OD, 400 MHz): 6 at 6.92-6,89 (m, 2H), 5,01 (s, 2H), 3,80 (s, 3H), of 3.78 (s, 3H), 3,20 (s, 3H).

MS (ESI): m/z 232,06 (M+H)+.

Example 11

Bis-[(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diat (11)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, with sa. 55C injected into interaction with bis-(2-methoxyethyl)chloracetamide (0.96 g, USD 4.61 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol) and after purification mass preparative HPLC and lyophilization gain of 0.53 g (yield 46%) named in the title compound (11) as a white solid. T. PL. 79-82C.1H NMR (CDCl3, 400 MHz): 5 6,98-to 6.88 (m, 2H), to 4.98 (s, 2H), and 3.8 (s, 3H), 3,57-

3,50 (�, 8H), 3,41 (s, 3H), and 3.31 (s, 3H). MS (ESI): m/z 304,14 (M+H)+.

Example 12

[N-(Methoxycarbonyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diet (12)

Following General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, ca. 55°C is injected into interaction with methyl-N-(2-chloroacetyl)carbamate (0,69 g, USD 4.61 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol). The crude material was precipitated out of solution in diethyl ether (Et2O). The solid is filtered off, washed several times with dichloromethane (DCM) and dried under vacuum, and the gain of 0.19 g (yield 21%) named in the title compound (12) as a white solid.1H NMR (CDCl3, 400 MHz): δ 6,99-6,91 (m, 2H), 5,23 (s, 2H), 3,81 (s, 6H). MS (ESI): m/z 246,09 (M+H)+, 268,00 (M+Na)+.

Example 13

[N-(2-{2-[(2E)-3-(Methoxycarbonyl)prop-2-enolase]acetylamino}ethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diat (13)

Following the General method a, methylhydroquinone (MHF) (0.73 g, 5,61 mmol) dissolved in NMP, ca. 55°C is injected into the interaction of N-(2-[2-chloroacetyl]aminoethyl)-2-chloracetamide (0.50 g, 2.34 mmol) in the presence CsHCO2(1,08 g, 5,61 mmol). The raw material ejected from a concentrated solution in diethyl ether (Et2O). The solid is filtered off, washed several times with dichloromethane (DCM) and dried under vacuum, and the gain of 0.90 g (yield 96%) n�called in the header connection (13) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8,23 (Ushs, 2H), of 6.96-at 6.92 (m, 4H), 4,58 (s, 4H), 3,79 (s, 6H), 3,16 (m, 4H). MS (ESI): m/z 401,05(M+H)+.

Example 14

Hydrochloride methyl-2-oxo-2-piperazinyl(2E)but-2-ene-1,4-dioate (14)

Following the General method a, methylhydroquinone (MHF) (1.00 g, to 7.68 mmol) dissolved in NMP, ca. 55°C is injected into interaction with 1-(tert-butyloxycarbonyl)-4-chloracetophenone (2.42 g, 9,22 mmol) in the presence CsHCO3(1.78 g, 9,22 mmol). After treatment and removal of solvent produced the crude material as a white solid. Solid at room temperature is injected into interaction with 15 ml of 4 molar (4 M) solution of hydrogen chloride (HCl) in 1,4-dioxane. After removal of the solvent the solid hydrochloride is further purified preparative HPLC mass, and after lyophilization of the solvents in the presence of excess 1-normal (1 N) hydrochloric acid get 0,93 g (yield 41%) named in the title compound (14) as a white solid.1H NMR (D2O, 400 MHz): δ 6,93-6,86 (m, 2H), to 4.92 (s, 2H), 3,70-3,63 (m, 7H), of 3.32 (t, J=5,2 Hz, 2H), 3,17 (t, J=6 Hz, 2H). MS (ESI): m/z 257,13 (M+H)+.

Example 15

Methyl-2-(4-benzylpiperazine)-2-oxoethyl(2E)but-2-ene-1,4-diat (15)

Hydrochloride methyl-2-oxo-2-piperazinyl-(2E)but-2-ene-1,4-dioate (14) (0.50 g, 1,71 mmol) in ca. 0°C was injected into the interaction with Benzi�bromide (BnBr) (0,243 ml 0.35 g, 2,05 mmol) and diisopropylethylamine (DIEA) (1,00 ml, 0.74 g, or 5.76 mmol) in dichloromethane (DCM) followed by heating to room temperature. After treatment with water the crude reaction product is purified preparative HPLC mass, and receive 0.18 g (yield 27%) named in the title compound (15) as a white solid.1H NMR (CDCl3, 400 MHz): δ 7,08-7,01 (m, 5H), 6,72-6,71 (m, 2H), 4,60 (s, 2H), 3,58 is 3.57 (s, 3H), 3,23-3,19 (Ushs, 2H), 3,30 (s, 2H), 3,19-3,11 (Ushs, 2H), 2,23 (Ushs, 4H); MS (ESI): m/z 347,13 (M+H)+.

Example 16

2-(4-Acetylpiperidine)-2-oxometalates(2E)but-2-ene-1,4-diat (16)

Hydrochloride methyl-2-oxo-2-piperazinyl-(2E)but-2-ene-1,4-dioate (14) (0.20 g, of 0.68 mmol) was injected into interaction with acetylurea (AcCl) (0,60 ml, 0.66 g, 0,84 mmol) and diisopropylethylamine (0,70 ml, 0.52 g, 4.0 mmol) in dichloromethane (DCM). After treatment with water the crude reaction product is purified flash chromatography on silica gel, and get 0.12 g (yield 54%) named in the title compound (16) as a white solid.1H NMR (CDCl3, 400 MHz): δ 6,98-6,93 (m, 2H), with 4.86 (s, 2H), 3,83 (s, 3H), 3,66-3,63 (m, 4H), 3,50-3,40 (m, 4H), 2,14 (s, 3H). MS (ESI): m/z 299,12 (M+H)+.

Example 17

Methyl-2-oxo-2-(2-oxo-1.3-oxazolidin-3-yl)ethyl(2E)but-2-ene-1.4-diat (17)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, ca. 55°C is introduced in the interaction�a journey of 3-(chloroacetyl)-1,3-oxazolidin-2-one (0.75 g, USD 4.61 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol) and after purification mass preparative HPLC and lyophilization get 0.30 g (yield 30%) named in the title compound (17) as a white solid.1H NMR (CDCl3, 400 MHz): δ 6.97 in-at 6.92 (m, 2H), 5,32 (s, 2H), a 4.53 (t, J=8 Hz, 2H), of 4.05 (t, J=8,0 Hz, 2H), 3,82 (s, 3H). MS (ESI): m/z 258,20 (M+H)+.

Example 18

{N-[2-(Dimethylamino)ethyl] carbamoyl} methyl methyl(2E)but-2-ene-1,4-diat (18)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, ca. 55°C is injected into interaction with N,N- (0.75 g, USD 4.61 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol) and after purification mass preparative HPLC and lyophilization get 0.02 g (yield 2%) named in the title compound (18) as a white solid.1H NMR (D2O, 400 MHz): δ 8,27 (s, 1H), 6,87-6,78 (m, 2H), 4,63 (s, 2H), 3,68 (s, 3H), 3,51 (t, J=6,2 Hz, 2H), 3,17 (t, J=6,0 Hz, 2H), to 2.76 (s, 6H). MS (ESI): m/z 259,14(M+H)+.

Example 19

Methyl-{N-[(propylamino)carbonyl]carbamoyl}methyl(2E)but-2-ene-1,4-diet (19)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, ca. 55°C is injected into interaction with 1-(2-chloroacetyl)-3-preprocesing (0,82 g, 4,60 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol), and get 0.02 g (yield 2%) named in the title with�unity (19) as a white solid. The addition of methanol (MeOH) to give 0.49 g (yield 49%) of white solids.1H NMR (CDCl3, 400 MHz): δ 6,90-of 6.99 (m, 2H), of 4.77 (s, 2H), 3,82 (s, 3H), 3,25-3,24 (K, 2H, J=5,6 Hz), 1,57-of 1.55 (K, 2H, J=7,2 Hz), 0,95-of 0.91 (t, 3H, 7=7,6 Hz). MS (ESI): m/z 273,08 (M+H)+.

Example 20

2-{(2S)-2-[(tert-Butyl)oxycarbonyl]pyrrolidinyl}-2-oxometalates(2E)but-2-ene-1,4-diet (20)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, ca. 55°C is injected into interaction with tert-butyl-(2S)-1-(2-chloroacetyl)pyrrolidin-2-carboxylate (0,82 g, 4,60 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol) and after purification mass preparative HPLC and lyophilization gain of 0.44 g (yield 34%) named in the title compound (20) as a white solid.1H NMR (CDCl3400 MHz processor, all rotamer): δ 6.97 in-6,90 (m, 2H), 4,91-4,55 (m, 2H), of 4.44-4,29 (m, 1H), 3,80 (s, 3H), 3,61-3,58 (m, 2H), 2,23-2,03 (AG, 4H), 1,54-of 1.46 (s, 9H). MS (ESI): m/z 342,16 (M+H)+, 364,09 (M+Na)+.

Example 21

N-{[(tert-Butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diat(21)

Following the General method a, methylhydroquinone (MHF) (0.50 g, 3,84 mmol) dissolved in NMP, ca. 55°C is injected into interaction with tert-butyl-2-(2-chloro-N-methylacetamide)acetate (1.02 g, 4,60 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol) and after purification flash chromatography on silica gel (biotage AB) semi�up with 0.24 g (yield 21%) named in the title compound (21) as a white solid. 1H NMR (CDCl3400 MHz processor, all rotamer): δ 7,00-6,93 (m, 2H), 4,90-4,79 (2C, 2H), 4,03-3,89 (2C, 2H), 3,80 (s, 3H), 3,04-to 2.99 (2s, 3H), 1,45 (s, 9H). MS (ESI): m/z 316,13 (M+H)+.

Example 22 N-[(Ethoxycarbonyl)methyl]-N-methylcarbamoyl))methyl methyl(2E)but-2-ene-1.4-diat(22)

Following the General method a, methylhydroquinone (MPR) (0.50 g, 3,84 mmol) dissolved in NMP, ca. 55°C is injected into interaction with ethyl-2-(2-chloro-N-methylacetamide)acetate (0.89 g, 4,60 mmol) in the presence CsHCO3(0.89 g, 4.61 record mmol) and after purification flash chromatography on silica gel (biotage AB) are obtained 0.30 g (yield 27%) named in the title compound (22) as a white solid.1H NMR (CDCl3400 MHz processor, all rotamer): δ 7,00-6,93 (m, 2H), 4,90-4,79 (2C, 2H), 4,03-3,89 (2C, 2H), 3,80 (s, 3H), 3,04-to 2.99 (2s, 3H), 1,45 (s, 9H). MS (ESI): m/z 316,13 (M+H)+.

Example 23 2-[(2E)-3-Methoxycarbonyl)prop-2-enolase]acetic acid (23)

Following the General method a, methylhydroquinone (MPR) (6,91 g 53,12 mmol) dissolved in NMP, ca. 55°C is injected into interaction with tert-butyl-2-Chloroacetic acid (9,48 ml, 10.0 g, to 66.4 mmol) in the presence CsHCO3(Of 15.41 g, 79,68 mmol), and after deposition from a concentrated solution in diethyl ether (Et2O) receive 13,11 g (yield 81%) of the intermediate ester as a white solid. The substance has a sufficient purity for use in the next step.1H NMR (CDCl3, 40 MHz): δ 6,95-at 6.92 (m, 2H), USD 4.61 (s, 2H), 3,81 (s, 3H), of 1.47 (s, 9H). The substance is dissolved in 50 ml of 50 vol.% trifluoroacetic acid (TFA) in dichloromethane (DCM), and the reaction overnight at room temperature. After removal of solvent the crude material periostat from a mixture of acetone and hexane (1:3), and get 12.3 g (yield 92%) named in the title compound (23) as a white solid.1H NMR (CDCl3, 400 MHz): δ 7,02-6,90 (m, 2H), 4,79 (s, 2H), 3,82 (s, 3H). MS (ESI): m/z 189,07 (M+H)+.

Example 24 RAC-2-[(2E)-3-(Methoxycarbonyl)prop-2-enolase]propane acid (24) Following the General method a, methylhydroquinone (MPR) (4,68 g, 36,0 mmol) dissolved in NMP, ca. 55°C is injected into interaction with the RAC-tert-butyl-2-bromopropionic acid (to 4.98 ml, 6,27 g, 30.0 mmol) in the presence CsHCOs (6,40 g, of 33.0 mmol), and get the intermediate ester. The substance has a sufficient purity for use in the next step.1H NMR (CDCh, 400 MHz): δ 6,93-to 6.88 (m, 2H), 5,02 (K, J=7,2 Hz, 2H), 3,79 (s, 3H), 1,49 (d,.7=7,2 Hz, 3H), of 1.44 (s, 9H). The substance is dissolved in 25 ml of 50 vol.% trifluoroacetic acid (TFA) in dichloromethane (DCM), and the reaction overnight at room temperature. After removal of the solvents named in the title compound (24) as a white solid which is sufficiently pure for use in subsequent stages.1H NMR (CDCl3, 400 MHz): δ 6.97 in-at 6.92 (m, 2H), 5,22 (K, J=7,2 �C, 2H), 3,82 (s, 3H), 1,60 (d, J=7,2 Hz, ZN).

Example 25 Methyl 2-(4-methylpiperazine)-2-oxoethyl(2E)but-2-ene-1,4-diat (25)

Following the General method B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetic acid (23) (0.50 g, 2.65 mmol) at ca. 0°C to activate the hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDAC) (0,60 g, 3,18 mmol) in 10 ml of dichloromethane (DCM). To the activated carboxylic acid was added N-methylpiperazine (0,353 ml, 0.31 g, 3,18 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3,18 mmol). After processing and separation and purification preparative HPLC mass, and after lyophilization, get 0.09 g (yield 13%) named in the title compound (25) as a white solid.1H NMR (CDCl3, 400 MHz): δ 6,93-6,78 (m, 2H), of 4.77 (s, 2H), 3,73 (s, 3H), 3,56-3,54 (m, 2H), 3,35-of 3.25 (m, 2H), 2,37-2,33 (m, 4H), 2,31 (s, 3H). MS (ESI): m/z 271,13 (M+H)+.

Example 26 {N,N-Bis[2-(methyl)ethoxyethyl]carbamoyl}methyl methyl(2E)but-2-ene-1,4-diat (26)

Following the General method B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetic acid (23) (0.50 g, 2.65 mmol) at ca. 0°C to activate the hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDAC) (0,60 g, 3,18 mmol) in 10 ml of dichloromethane (DCM). To the activated carboxylic acid is added bis(2-isopropoxyphenyl)amine (0,60 g, 3,18 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3,18 mmol). After processing and separation and cleaning� column flash chromatography on silica gel (biotage AB) using ethyl acetate (EtOAc) and hexane (1:1), and after freezing, get 0.30 g (yield 32%) named in the title compound (26) as a white solid.1H NMR (CDCl3, 400 MHz): δ 6,95-6,86 (m, 2H), to 4.98 (s, 2H), 3,76 (s, 3H), 3,50-3,47 (m, 10H), 1,10-of 1.05 (m, 12H). MS (ESI): m/z 360,16 (M+H)+.

Example 27 [N,N-Bis(2-ethoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diet (27)

Following the General method B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetic acid (23) (0.80 g, 6,14 mmol) at ca. 0°C to activate the hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDAC) (1.40 g, value of 7, 37 mmol) in 20 ml of dichloromethane (DCM). To the activated carboxylic acid is added the hydrochloride of bis(2-ethoxyethyl)amine (1.18 g, value of 7, 37 mmol) and diisopropylethylamine (DIEA) (1.34 ml, 0,99 g, 7.67 per mmol). After processing and separation and purification column flash chromatography on silica gel (biotage AB) using ethyl acetate (EtOAc) and hexane (1:1) are obtained 0.30 g (yield 15%) named in the title compound (27) as a white solid.1H NMR (CDCl3, 400 MHz): δ 6,97 (d, J=1.6 Hz, 1H), 5,01 (s, 2H), 3,80 (s, 3H), 3,56-of 3.43 (m, 12H), 1,19 (K, J=7,6 Hz, 6H). MS (ESI): m/z 332,20 (M+H)+.

Example 28 Methyl-1-methyl-2-morpholine-4-yl-2-oxoethyl(2E)but-2-ene-1,4-diet

Following the General method B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]propane acid (24) (0,48 g, 2,40 mmol) at ca. 0°C to activate the hydrochloride of N-(3-dimethylamino�sawdust)-N-ethylcarbodiimide (EDAC) (0.64 g, 3,36 mmol) in 10 ml of dichloromethane (DCM). To the activated carboxylic acid is added morpholine (0.25 ml, 0.25 g, is 2.88 mmol). After processing and separation and purification preparative HPLC mass, and after lyophilization, get 0.22 g (yield 33%) named in the title compound (28) as a white solid. So a MP 70-73°C.1H NMR (CDCl3, 400 MHz): δ 6,95-6,89 (m, 2H), of 5.45 (K, J=6,8 Hz, 1H), 3,80 (s, 3H), 3,71-3,68 (m, 4H), 3,58-3,54 (m, 4H), of 1.48 (d, J=7,2 Hz, 3H). MS (ESI): m/z 272,13 (M+H)+.

Example 29 N,N-Bis(2-methoxyethyl)carbamoyl]ethyl methyl(2E)but-2-ene-1,4-diet (29)

Following the General method B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]propane acid (24) (0,48 g, 2,40 mmol) at ca. 0°C to activate the hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDAC) (0.64 g, 3,36 mmol) in 10 ml of dichloromethane (DCM). To the activated carboxylic acid is added bis(2-methoxyethyl)amine (0.42 ml, 0,37 g, is 2.88 mmol). After processing and separation and purification preparative HPLC mass, and after lyophilization, gain of 0.29 g (yield 38%) named in the title compound (29) as a white solid.1H NMR (CDCl3, 400 MHz): δ 6.94 per-to 6.88 (m, 2H), 5,52 (K, J=6,8 Hz, 1H), 3,80-3,79 (s, 3H), 3,57-3,49 (m, 8H), 3,33-3,31 (2s, 6H), of 1.48 (d,7=6,4 Hz, 3H). MS (ESI): m/z 318,13 (M+H)+.

Example 30 (N-Dimethylcarbamoyl)ethyl methyl(2E)but-2-ene-1N-diat (30)

Following the General method B2, 2-[(2E)-3-(meth�xianbei)prop-2-enolase]propane acid (24) (0,48 g, 2,40 mmol) at ca. 0°C to activate the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDAC) (0.64 g, 3,36 mmol) in 10 ml of dichloromethane (DCM). To the activated carboxylic acid is added the hydrochloride of N,N-dimethylamine (0,23 g, is 2.88 mmol) and diisopropylethylamine (DIEA) (0.63 ml, 0,467 g 3,61 mmol). After processing and separation and purification preparative HPLC mass, and after lyophilization, get 0.25 g (yield 46%) named in the title compound (30) as a white solid.1H NMR (CDCl3, 400 MHz): δ 6,93-6,86 (m, 2H), 5,46 (K, J=6,8 Hz, 1H), 3,79. (s, 3H), 3,06-of 2.97 (2s, 6H), of 1.47 (d, J=6,4 Hz, 3H). MS (ESI): m/z 2230,13 (M+H)+.

Example 31

(1S)-1-Methyl-2-morpholine-4-yl-2-oxoethyl-methyl(2E)but-2-ene-1,4-diet (31)

Following the General method B2, (2E)-3-(methoxycarbonyl)prop-2-envoy acid (methylhydroquinone, MHF) (0.50 g, 3,84 mmol) at ca. 0°C to activate the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDAC) (0,81 g, 4.20 mmol) in 10 ml of dichloromethane (DCM). To the activated carboxylic acid is added to (28)-2-hydroxy-1-morpholine-4-improper-1-he (0,48 g, of 3.07 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3,18 mmol). After processing and separation and purification column flash chromatography on silica gel (biotage AB) using ethyl acetate (EtOAc) and hexane (ca. 3:2) are obtained 0.42 g (yield 51%) named in the title compound (31) as a white solid. So a MP 79-82°C;1 H NMR (CD3CN, 400 MHz): δ 6,90-is 6.81 (m, 2H), 5,44 (K, J=6,8 Hz, 1H), of 3.78 (s, 3H), 3,65-of 3.60 (m, 4H), 3,51-3,50 (m, 4H), of 1.42 (d, J=6,8 Hz. 3H). MS (ESI): m/z 272,05 (M+H)+.

Example 32

(1S)-1-[N,N-Bis(2-methoxyethyl)carbamoyl]ethyl methyl(2E)but-2-ene-1,4-diet (32)

Following the General method B2, (2E)-3-(methoxycarbonyl)prop-2-envoy acid (methylhydroquinone, MPR) (0.50 g, 3,84 mmol) at CA. 0°C to activate the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDAC) (0.88 g, 4,60 mmol) in 20 ml of dichloromethane (DCM). To the activated carboxylic acid is added (2S)-2-hydroxy-N,N-bis(2-methoxyethyl)propanamide (0,63 g, of 3.07 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3,18 mmol). After processing and separation and purification column flash chromatography on silica gel (biotage AB) using ethyl acetate (EtOAc) and hexane (2:1) are obtained 0.16 g (yield 14%) named in the title compound (32) in the form of a clear oil.1H NMR (CDCl3, 400 MHz): δ 6,93-was 6.77 (m, 2H), 5,53 (K, J=6,4 Hz, 1H), 3,80 (s, 3H), 3,58-3,50 (m, 8H), 3,47-of 3.32 (2 s, 6H), 1,49 (d, J=6,8 Hz, 3H). MS (ESI): m/z 318,05 (M+H)+.

Example 33

(1S)-1-(N,N-Diethylcarbamoyl)ethyl methyl(2E)but-2-ene-1,4-diet (33)

Following the General method B2, (2E)-3-(methoxycarbonyl)prop-2-envoy acid (methylhydroquinone, MHF) (0.50 g, 3,84 mmol) at ca. 0°C to activate the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDAC) (0.88 g, 4,60 mmol) in 12 ml of dihormati�and (DCM). To the activated carboxylic acid is added (2S)-N,N-diethyl-2-hydroxypropane (0,44 g, of 3.07 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3,18 mmol). After processing and separation and purification preparative HPLC mass/lyophilization and column flash chromatography on silica gel (biotage AB) using ethyl acetate (EtOAc) and hexane receive 0.17 g (yield 18%) named in the title compound (33) in the form of a clear oil.1H NMR (CDCl3, 400 MHz): δ 6,95-6,87 (m, 2H), 5,43 (K, J=6,8 Hz, 1H), 3,80 (s, 3H), 3,50-3,26 (m, 4H), 1,49 (d, J=6,4 Hz, 3H), of 1.26 (t, J=6,8 Hz, 3H), of 1.12 (t, J=7,6 Hz, 3H). MS (ESI): m/z 258,06 (M+H)+.

Example 34

(N-{[(tert-Butyl)oxycarbonyl]methyl}carbamoyl)methyl methyl(2E)but-2-ene-1,4-diat (34)

Following the General method B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetic acid (23) (0.50 g, 2.65 mmol) at ca. 0°C to activate oxaliplatin (0,30 ml, 0.40 g, 3,18 mmol) in dichloromethane (DCM) and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). The solution just obtained the crude acid chloride in DCM at ca. 0°C (ice bath) was injected into interaction with the tert-butyl ester of glycine (H-GlyO-tert-Bu) (0,53 g, 3,18 mmol) in DCM and in the presence of 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3,18 mmol). After treatment with water and extraction and purification flash chromatography on silica gel get 0.16 g (yield 20%) named in the title compound (3) in the form of semi-solid substances. 1H NMR (CDCl3400 MHz processor, all rotamer): δ 6,95-6,69 (m, 2H), 6,63 (AG, 1H), 4,73 (s, 2H), 3,99 (d, J=4,8 Hz, 2H), 3,83 (s, 3H), of 1.48 (s, 9H). MS (ESI): m/z 324,05 (M+Na)+.

Example 35

Methyl-[N-methyl-N-{[(methylethyl)oxycarbonyl]methyl} carbamoyl)methyl(2E)but-2-ene-1,4-diet (35)

Following the General method B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetic acid (23) (0.50 g, 2.65 mmol) at CA. 0°C to activate oxaliplatin (0,30 ml, 0.40 g, 3,18 mmol) in dichloromethane (DCM) and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). The solution just obtained the crude acid chloride in DCM at CA. 0°C (ice bath) was injected into interaction with isopropyl ether sarcosine (H-Sar-O-isorg) (0,41 g, 3,18 mmol) and diisopropylethylamine (DIEA) (0,41 ml, 0,304 g, 2.35 mmol) in DCM and in the presence of 4-(N,N-dimethyl)aminopyridine (DMAP) (0.10 g, 0,82 mmol). After treatment with water and extraction and purification flash chromatography on silica gel get 0,214 g (yield 27%) named in the title compound (35) in the form of a pale yellow solid.1H NMR (CDCl3400 MHz processor, all rotamer): δ 6.94 per-6,90 (m, 2H), 5,09-4,99 (m, 1H), 4,89-4,79 (2C, 2H), 4,07-of 3.95 (2s, 2H), of 3.78 (s, 3H), of 3.04-2.98 mm (2 s, 3H), of 1.27-to 1.21 (m, 6H). MS (ESI): m/z 302,04 (M+H)+.

Example 36

{N-[(Ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methyl methyl(2E)but-2-ene-1,4-diat (36)

Following the General method B2, 2-[(2E)-3-(metoxia�bonyl)prop-2-enolase]acetic acid (23) (0.50 g, 2.65 mmol) at CA. 0°C to activate oxaliplatin (0,27 ml, 0.40 g, 3,15 mmol) in dichloromethane (DCM) and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). The solution just obtained the crude acid chloride in DCM at CA. 0°C (ice bath) was injected into interaction with the ethyl ester of N-benzylglycine (Bn-Gly-OEt) (0,61 g, 3,18 mmol) in DCM and excess of diisopropylethylamine (DIEA) in the presence of a catalytic amount of 4-(N,N-dimethyl)aminopyridine (DMAP). After treatment with water and extraction and purification flash chromatography on silica gel get 0.12 g (yield 13%) named in the title compound (36) as a white solid.1H NMR (CDCl3400 MHz processor, all rotamer): δ value of 7, 37-7,20 (m, 5H), 6,97-6,86 (m, 2H), 4,94-4,83 (2C, 2H), 4,63-4,55 (2C, 2H), 4,18-to 4.14 (m, 2H), 4,04-3,88 (2 s, 2H), 3,79 (s, 3H), 1,24-of 1.20 (m, 3H). MS (ESI): m/z 364,15 (M+H)+.

Example 37

{N-[(Ethoxycarbonyl)methyl]-N-benzylcarbamoyl}ethyl methyl(2E)but-2-ene-1,4-diet (37)

Following the General method B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]propane acid (24) (0.50 g, 2,47 mmol) at CA. 0°C to activate oxaliplatin (0.25 ml, 0.35 g, 2,71 mmol) in dichloromethane (DCM) and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). The solution just obtained the crude acid chloride in DCM at CA. 0°C (ice bath) was injected into interaction with the ethyl ester of N-benzylglycine (Bn-Gly-OEt)(0.56 g, 2,90 mmol) in DCM and diisopropylethylamine (DIEA) (0,506 ml 0,376 g, 2,90 mmol) in the presence of a catalytic amount of 4-(N,N-dimethyl)aminopyridine (DMAP). After treatment with water and extraction and purification flash chromatography on silica gel get 0.31 g (yield 33%) named in the title compound (37) as a white solid.1H NMR (CDCl3400 MHz processor, all rotamer): δ value of 7, 37-7,17 (m, 5H), to 6.88-was 6.77 (m, 2H), 5,49 (K, J=6,4 Hz, 0,75 H), is 5.33 (K, J=6,4 Hz, 0,25 N), 4,7-4,27 (m, 3H), 4,16-4,13 (m, 2H), 3,83-3,63 (m, 4H), of 1.53 (d, J=6,8 Hz, 3H), 1,21 (t, J=4.0 Hz, 3H). MS (ESI): m/z 378,10 (M+H)+.

Example 38

{N-[(Ethoxycarbonyl)methyl]-N-methylcarbamoyl}ethyl methyl(2E)but-2-ene-1,4-diet (38)

Following the General method B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]propane acid (24) (0.50 g, 2,47 mmol) at CA. 0°C to activate oxaliplatin (0.25 ml, 0.35 g, 2,71 mmol) in dichloromethane (DCM) and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). The solution just obtained the crude acid chloride in DCM at CA. 0°C (ice bath) was injected into interaction with the ethyl ester of sarcosine (H-Sar-OEt) (0,43 g, 2,90 mmol) and diisopropylethylamine (DIEA) (0,506 ml 0,376 g, 2,90 mmol) in DCM in the presence of a catalytic amount of 4-(N,N-dimethyl)aminopyridine (DMAP). After treatment with water and extraction and purification flash chromatography on silica gel get 0.30 g (yield 39%) named in the title compound (38)as a white solid. 1H NMR (CDCl3400 MHz processor, all rotamer): δ to 6.88-is 6.81 (m, 2H), 5,47 (K, 0,75 H, J=6,8 Hz), 5,32 (a, 0,25 H, J=6,8 Hz), 4,40-of 4.33 (m, 1H), 4,16-4,11 (m, 2H), 3,94-of 3.75 (m, 4H), 3,10 (s, 2.25 H), 2,96 (s, 0.75 H), 1,50-of 1.44 (DD, 3H), 1,26-of 1.20 (m, 3H). MS (ESI): m/z 302,09 (M+H)+.

Example 39

Ethoxycarbonylmethyl-methyl(2E)but-2-ene-1,4-diet (39)

Following the General method a, methylhydroquinone (0,39 g, 3.0 mmol) in NMP (8 ml) was injected into interaction with CsHCO3(0,69 g, 3,6 mmol) and ethyl(chloroethoxy)formate (0.64 g, 4.2 mmol), and after separation and purification gain of 0.63 g (yield 85%) named in the title compound (39).1H NMR (CDCl3, 400 MHz): δ 6,89 (d, J=15,6 Hz, 1H), about 6,82 (d, J=15,6 Hz, 1H), 6.84 (K, J=5,6 Hz, 1H), 4,23 (K, J=7,2 Hz, 3H), 3,81 (s, 3H), 1,58 (d, J=5.6 Hz, 3H), 1,32 (t, J=7,2 Hz, 3H). MS (ESI): m/z 247,01 (M+H)+.

Example 40

Methyl-(metalelectronics)ethyl(2E)but-2-ene-1,4-diat (40)

Following the General method a, methylhydroquinone (0,39 g, 3.0 mmol) in NMP (8 ml) was injected into interaction with CsHCO3(0,69 g, 3,6 mmol) and methylethyl(chloroethoxy)formate (0.70 g, 4.2 mmol), and after separation and purification gain of 0.71 g (yield 91%) named in the title compound (40).1H NMR (CDCl3, 400 MHz): δ 6,89 (d, J=15,6 Hz, 1H), 6,84 (K, J=5,2 Hz, 1H, overlap), about 6,82 (d, J=15,6 Hz, 1H, overlap). 4,90 (septet, J=6,2 Hz, 3H), 3,81 (s, 3H), of 1.57 (d, J=5,2 Hz, 3H), 1,32 (d, J=6.2 Hz, 3H), of 1.31 (d, J=6.2 Hz, 3H). MS (ESI): m/z 261,02 (M+H)+.

Example 41

(Cyclohexyloxy�bonelace)ethyl methyl(2E)but-2-ene-1,4-diet(41)

Following the General method a, methylhydroquinone (0.50 g, of 3.85 mmol) in NMP (8 ml) at CA. 55°C is injected into interaction with CsHCO3(1.1 g, 5,716 mmol) and chloroethylnitrosourea (1.03 g, 4,99 mmol) and after purification mass preparative HPLC and lyophilization get to 0.94 g (yield 821%) named in the title compound (41).1H NMR (CDCl3, 400 MHz): δ 6,91-of 6.79 (m, 3H), 4,67-4,62 (m, 1H), 3,81 (s, 3H), 1,94-of 1.91 (m, 2H), 1,77-of 1.73 (m, 2H), 1,57 (d, J=5.6 Hz, 3H). 1,53-1,46 (m, ZN), 1,39-of 1.33 (m, 3H). MS (ESI): m/z 301,10 (M+H)+.

Example 42

Methyl-(2-methylpropyloxy)ethyl(2E)but-2-ene-1,4-diet (42)

Following the General method a, methylhydroquinone (0,39 g, 3.0 mmol) in NMP (8 ml) was injected into interaction with CsHCO3(0,69 g, 3,6 mmol) and chloroethyl-2-methylpropanoate (0,63 g, 4.2 mmol), and after separation and purification receive 0.65 g (yield 89%) named in the title compound (42).1H NMR (CDCl3, 400 MHz): δ 6,93 (K, J=5,2 Hz, 1H), to 6.88 (d, J=16,0 Hz, 1H), is 6.81 (d, J=15,6 Hz, 1H), 3,81 (s, 3H), by 2.55 (septet, J=6,8 Hz, 3H), 1,54 (d, J=5,2 Hz, 3H), of 1.18 (d, J=6,8 Hz, 6H). MS (ESI): m/z 245,05 (M+H)+.

Example 43

Methylphenylcarbinol(2E)but-2-ene-1,4-diet (43)

Following the General method a, methylhydroquinone (0.42 g, 3.3 mmol) in NMP (6 ml) was injected into interaction with CsHCO3(0,69 g, 3,6 mmol) and chloritisation (0.55 g, 3.0 mmol) and after purification column flash chrome�ografia on silica gel (biotage AB) using as eluent a mixture of ethyl acetate (EtOAc) and hexane (1:8) are obtained 0.2 g (yield 24%) named in the title compound (43). 1H NMR (CDCl3, 400 MHz): 5 8,08-8,02 (m, 2H), 7,63-7,56 (m, 1H), 7,49-of 7.42 (m, 2H), 7,21 (K, J=5,2 Hz, 1H), at 6.92 (d, J=16,0 Hz, 1H), of 6.85 (d, J=16,0 Hz, 1H), 3,81 (s, 3H), 1,69 (d, J=5,2 Hz, 3H). MS (ESI): m/z 278,99 (M+H)+.

Example 44

Cyclohexylcarbodiimide-methyl(2E')but-2-ene-1,4-diat (44)

Following the General method a, methylhydroquinone (1.00 g, to 7.68 mmol) at CA. 55°C is injected into interaction with CsHCO30(2.22 g, to 11.52 mmol) and (2,16 g, 9,98 mmol) and after purification mass preparative HPLC and lyophilization receive 1.2 g (yield 50%) named in the title compound (44) in the form of a clear oil.1H NMR (CDCl3, 400 MHz): δ 6,90-was 6.77 (m, 3H), 3,81 (s, 3H), 2,34-of 2.28 (m, 1H), 1,91-of 1.88 (m, 2H), 1,82-of 1.73 (m, 4H), 1.65 V-1,62 (m, 2H), 1,47-of 1.39 (m, 4H), 1,29-1,23 (m, 2H), and 0.98 to 0.94 (t, 3H). MS (ESI): m/z 313,09 (M+H)+.

Example 45

[(2E)-3-(Methoxycarbonyl)prop-2-enolase]ethyl methyl(2E)but-2-ene-1,4-diat (45)

Adapting methods and procedures according to Iyer et al., Synth. Commun., 1995, 25(18), 2739, get chloroethyl-methyl(2E)but-2-ene-1,4-diet from methylhydroquinone (MHF), acetaldehyde and anhydrous zinc chloride(P) in anhydrous dichloromethane (DCM).1H NMR (CDCl3, 400 MHz): δ 6,95 (d, J=16,0 Hz, 1H), of 6.85 (d, J=16,0 Hz, 1H), 6,60 (K, J=5,2 Hz, 1H), 3,81 (s, 3H), 1,83 (d, J=5,2 Hz, 3H).

Following the General method a, methylhydroquinone (0.22 g, 1.7 mmol) in NMP (4 ml) was injected into interaction with CsHCO3(0,38 g, 1.9 mmol) � chlorethylene-(2E)but-2-ene-1,4-diatom (0.27 g, 1,4 mmol) and after purification flash chromatography on silica gel (biotage AB) using a mixture of ethyl acetate (EtOAc) and hexane (1:3) get 0,068 g (yield 17%) named in the title compound (45).1H NMR (CDCl3, 400 MHz): δ 7,03 (K, J=5,2 Hz, 1H), 6.90 (d, J=16,0 Hz, 1H), about 6,82 (d, J=16,0 Hz, 1H), 3,82 (s, 3H), 1,60 (d, J=5,2 Hz, 3H).

Example 46

Methyl-2-methyl-1-phenylcarbonylamino(2E)but-2-ene-1,4-diet (46)

Following the General method a, methylhydroquinone (0.50 g, 3,82 mmol) at CA. 55°C is injected into interaction with CsHCO3(Or 5.76 mmol) and chloridebucinnazine (1.1 g, 5.17 mmol) and after purification flash chromatography on silica gel (biotage AB) using a mixture of ethyl acetate (EtOAc) and hexane (1:7) are obtained 0.18 g (yield 15%) named in the title compound (46).1H NMR (CDCl3, 400 MHz): δ 8,04-8,01 (m, 2H), 7,58-to 7.55 (m, 1H), 7,45-7,41 (m, 2H), 6,98 (d, J=4,8 Hz, 1H), 6,90 (d, J=16,0 Hz, 1H), at 6.84 (d, J=16,0 Hz, 1H), of 3.78 (s, 3H), 2,25-of 2.21 (m, 1H), 1,10-of 1.07 (m, 6H). MS (ESI): m/z 307,11 (M+H)+.

Example 47

(2E)-3-[(2-Morpholine-4-yl-2-oxoethyl)oxycarbonyl]prop-2-ANOVA acid (47)

Following the General method A, fumaric acid (1.00 g, at 8.60 mmol) at CA. 100°C is injected into interaction with chloroacetylation (1.4 g, 8,6 mmol) and Ag2O (4.2 g, for 9.47 mmol) in N-methylpyrrolidinone. Reacciona the mixture is cooled to room temperature, filtered through celite®, and the residue on the filter is washed �tracedata (EtOAc). The combined organic filtrates treated with an aqueous acid, and the crude material is purified preparative HPLC mass, and receive 0.50 g (yield 24%) named in the title compound (47) as a white solid.1H NMR (CD3CN, 400 MHz): δ of 6.85-6,80 (m, 2H), is 4.85 (s, 2H), 3,64-of 3.60 (m, 4H), 3,57-3,54 (t, J=4,8 Hz, 2H), 3,42-3,39 (t, J=5,2 Hz, 2H). MS (ESI): m/z 244,06 (M+H)+242,07 (M-N)-.

Example 48

(2E)-3-{[(N,N-Diethylcarbamoyl)methoxy] oxycarbonyl} prop-2-ANOVA acid (48)

Following the General method A, mono-tert-butylfuran acid (0.70 g, 4,06 mmol) at CA. 55°C is injected into interaction with N,N-diethylformamide (0,55 ml to 0.60 g, 4,06 mmol) and CsHCO3(0,93 g, 4,87 mmol) in N-methylpyrrolidinone (NMP). After extraction and purification of the crude material is injected into interaction with 50 vol.% trifluoroacetic acid (TFA) in dichloromethane (DCM). Free acid is purified preparative HPLC mass, and get 0,051 g (yield 6%) named in the title compound (48) as a white solid.1H NMR (CD3CN, 400 MHz): δ 6,90-about 6,82 (m, 2H), of 4.88 (s, 2H), 3,40-of 3.32 (K, J=6,8 Hz, 2H), 3,31-3,27 (K, J=6,8 Hz, 2H), 1,22-of 1.18 (t, J=7,6 Hz, 3H), 1,11-of 1.07 (t, J=6,8 Hz, 3H). MS (ESI): m/z 230,03 (M+H)+228,07 (M-N)-.

Example 49

(2E)-3-{[[Methylpropanoate)ethoxy]oxycarbonyl}prop-2-ANOVA acid (49)

Following the General method A, chloroethyl-2-methylprop�anoat (0.24 g, 1,58 mmol) at CA. 100°C is injected into interaction during the night with a preformed salt of ridicilously (DCHA) fumaric acid (FA) (0.50 g, of 1.26 mmol) in N-methylpyrrolidinone (NMP). The crude substance was purified preparative HPLC mass, and receive (0.035 g, yield 12%) named in the title compound (49) in the form of a waxy semi-solid substance.1H NMR (CD3CN, 400 MHz): δ 6,89-6,83 (K, J=5,6 Hz, 1H), about 6,82-is 6.81 (d, J=16,0 Hz, 1H), 6,73-6,69 (d, J=16,0 Hz, 1H), 2,58-2,49 (septet, J=6,8 Hz, 1H), 1,49-of 1.47 (d, J=5.6 Hz, 3H), of 1.12 (d, J=7,2 Hz, 3H), of 1.09 (d, J=6,8 Hz, 6H); MS (ESI): y/z 239,0 l(M-H)-.

Example 50

(2E)-3-({[(Methylethyl)oxycarbonyl]ethyl}oxycarbonyl)prop-2-ANOVA acid (50)

Following the General method A, chloroethyl(methylethoxy)formate (0.25 g, 1,50 mmol) at CA. 100°C is injected into interaction during the night with a preformed salt of ridicilously (DCHA) fumaric acid (FA) (0.50 g, of 1.26 mmol) in N-methylpyrrolidinone (NMP). The crude substance was purified preparative HPLC mass, and receive (0.030 g, yield 10%) named in the title compound (50) in the form of a waxy semi-solid substance.1H NMR (CD3CN, 400 MHz): δ 6,86 (K, J=5,6 Hz, 1H), is 6.81 (d, J=16,0 Hz, 1H), 6,73 (d, J=16,0 Hz, 1H), 2,57-2,50 (septet, J=7,2 Hz, 1H), of 1.48 (d, J=5,6 Hz, ZN), of 1.13 (m, 6H). MS (ESI): m/z=244,99 (M-H)-.

Example 51

Alkyloxy - and aryloxypropanolamine-alkylhydroperoxide Perechisleny�e next alkyloxy and obtained using the methods described in examples 1-50 and adapting General synthetic methods A, B1 and B2:

(2E)-3-({[N-benzylcarbamoyl]methyl}oxycarbonyl)prop-2-ANOVA acid;

(2E)-3-[(2-morpholine-4-yl-2-oxoethyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-{[(N-butylcarbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-{[(N-methoxy-N-methylcarbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

bis[(2-methoxyethylamine)carbamoyl]methylprop-2-ANOVA acid;

(N,N-dimethylcarbamoyl)methylprop-2-ANOVA acid;

2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetic acid;

(2E)-3-({[N-(3-carboxypropyl)carbamoyl]methyl} oxycarbonyl)prop-2-ANOVA acid;

methyl-(N-(1,3,4-thiadiazole-2-yl)carbamoyl)methylprop-2-ANOVA acid;

(2E)-3-[(2-{(28)-2-[(tert-butyl)oxycarbonyl]pyrrolidinyl}-2-oxoethyl)oxycarbonyl]prop-2-ANOVA acid;

1-[2-((2E)-3-carboxypropyl-2-enolase)acetyl]-(2S)-pyrrolidin-2-carboxylic acid;

(2E)-3-[({N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-{[(N-{[(tert-butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-[(1-methyl-2-morpholine-4-yl-2-oxoethyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-({[N,N-bis(2-methoxyethyl)carbamoyl]ethyl}oxycarbonyl)prop-2-ANOVA acid;

(2E)-3-{[(N,N-dimethylcarbamoyl)ethyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-[({N,N-bi�[(2-methylethoxy)ethyl]carbamoyl}methyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-({N,N-bis(2-ethoxyethyl)carbamoyl]methyl}oxycarbonyl)prop-2-ANOVA acid;

(2E)-3-{[2-(4-acetylpiperidine)-2-oxoethyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-({2-oxo-2-[4-benzylpiperazine]ethyl}oxycarbonyl)prop-2-ANOVA acid;

(2E)-3-{[(N-{[(tert-butyl)oxycarbonyl]methyl}carbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-{[(N-methyl-N-{[(methylethyl)oxycarbonyl]methyl}carbamoyl)methyl]oxycarbonyl}prop-2-ANOVA acid;

(2E)-3-[({N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methyl)oxycarbonyl]prop-2-ANOVA acid;

(2E)-3-[({N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}ethyl)oxycarbonyl]prop-2-ANOVA acid and

(2E)-3-[({N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}ethyl)oxycarbonyl]prop-2-ANOVA acid.

Example 52

Methods for determining the stability of the prodrug in vitro

In the case of a prodrug may be desirable that the prodrug was left intact (i.e. not hydrolyzed) is still in the bloodstream and hydrolethalus (i.e., released the original medicinal product) in the target tissue. On the other hand, it may be desirable that the prodrug was left intact (i.e. pagedropdown) is still in the gastro-intestinal tract and hydrolethalus (i.e., released the original drug) after intake or absorption from the gastrointestinal lumen, such�EP, or in the enterocytes lining the gastrointestinal lumen, or blood. Applicable level of resistance can be at least partially determined by the mechanism and pharmacokinetics of the prodrug. Typically, prodrugs that are more stable in the analysis of Pancreatin or lavage of the colon and is more labile drugs in rat plasma, human plasma, rat liver S9, and/or human liver S9, can be used as a prodrug, administered orally. Typically, prodrugs that are more stable in preparations of rat plasma, human plasma, rat liver S9, and/or human liver S9, and which are more labile in preparations of cell homogenate, such as drugs SASO S9, can be used as a prodrug, administered systemically, and/or may be more effective in the delivery of the prodrug to the target tissue. Typically, prodrugs that are more stable in the pH range of physiological buffers (pH 6.0-pH 8.5), may be more useful as a prodrug. Typically, prodrugs that are more labile in preparations of cell homogenate, such as drugs SASO S9, can be hydrolyzed intracellularly with the original release of the drug to the target tissue. The results of such tests, as described in this example, to determine the enzymatic or chemical g�of tolisa prodrug in vitro can be used to select prodrug length tests in vivo.

The stability of the prodrug can be assessed in one or more in vitro systems using a variety of preparations following methods known in the art. For example, this description describes techniques used to determine the stability of the prodrug in the homogenate preparations SASO S9 rat liver S9, plasma, rat, porcine Pancreatin, flush the colon of the rat and the buffer pH 8.0.

Homogenate SASO S9 prepared using the following procedure. Cells SASO grown in culture for 21 days prior to collection. Culture medium was removed from culture vessel, and the monolayer washed twice with 10-15 ml of chilled PBS buffer. The PBS buffer (7-10 ml) was added into the flask, and the cells scraped from the surface on which they grew, and transferred to the centrifuge tube. Cells precipitated by centrifugation at 1500 rpm for 5 min at 4°C. the Supernatant is removed, and the cell precipitate was washed with chilled PBS on ice and re-pelleted by centrifugation. Supernatant removed and the cell pellet resuspended in the buffer for lysis (0.15 M KCl and 10 mm matrifocality buffer, pH 7.4). Cells lisarow by sonication at 4°C using an ultrasonic disintegrator samples. Then the lysed cells are transferred into vials and centrifuged at 1600 rpm for 10 min at 4°C to remove intact cells, the poison� and large cellular debris. The supernatant is removed and transferred to a test tube for centrifugation at 8600 rpm for 20 min at 4°C. After centrifugation, the obtained Supernatant, representing the fraction S9 homogenate of cells SASO, carefully remove and dispense the aliquots in vials for storage at -80°C until use. While using lysate SASO S9 diluted to 0.5 mg/ml in 0.1 M Tris buffer, pH 7.4.

S9 rat liver (XenoTech, Lenexa, K. S; R1000.S9, 20 mg/ml) was diluted to 0.5 mg / ml in 0.1 M califorina buffer at pH 7.4 and 1 mm of the cofactor NADPH.

The rat plasma (Pel-Freez Biologicals, Rogers, AR; 36150) use the same as what you get from the vendor.

Pork Pancreatin (Sigma Aldrich, St. Louis, MO; P1625-100G) was diluted to 10 mg/ml in 0.1 M Tris buffer, pH 7.4.

In order to get the wash from the large intestine of the rat, userswindows excised rat colon between the ceacum and the rectum. At 0°C (ice bath) pour five to 10 ml of PBS buffer, pH 7.4 (depending on the weight of the rat) in the lumen of the colon and collected in 250-ml glass beaker. Flushing the colon transferred into 10-ml conical tubes using a syringe equipped with a filter. The samples in 0.5 ml of flushing the colon stored at -80°C until use. They are used without dilution.

Tests for the enzymatic stability of the prodrug in SACO S9, S9 rat liver, the plasma of rats, swine Pancreatin and the colon of the rat vol�lnewt using the following procedure. Lysate distribute the aliquots on ninety (90) μl into labeled tubes (tubes) on the multi-well plates. The lysate is pre-incubated for 10 min at 37°C. except For the time t(0) in several holes, representing different times of incubation, add 10 μl of 400 μm solution of test compound in 0.1 M Tris buffer, pH 7.4. The samples were incubated at 37°C. At each time point the reaction was quenched by adding 300 ál of 100% ethanol. The samples are thoroughly mixed, the tubes transferred to a plate with a hole with a V-shaped bottom and stored at -20°C. For a time t(0) lysate quenched with 300 μl of chilled on ice 100% ethanol, mix thoroughly, add 10 μl of 400 μm solution of the test compound and mixed, and the tube with the sample is transferred to a plate with a hole with a V-shaped bottom and stored at -20°C. For analysis of 180 µl of each sample was transferred to a 96-well plate with holes with a V-shaped bottom and sealed. After collecting samples for all time points the tablet was centrifuged for 10 min at 5600 rpm at 4°C. Then, a hundred and fifty (150) μl from each well is transferred to a 96-well plate with round bottom wells. Samples analysed using LC/MS/MS to determine the concentrations of the prodrug and the source of the drug.

For studies of stability at pH 8.0 190 μl of 150 mm NaH2PO4BU�EPA pH 8.0, is added to each tube with the sample. In each tube add 10 ál of 10 mm solution of the test compounds and mix. The samples were incubated for 60 min at 37°C. After incubation, the samples are transferred into the conditions of room temperature, and to each tube was added 800 µl of 50% ACN solution in water. Samples analysed using LC/MS/MS to determine the concentrations of the prodrug and the source of the drug.

Analysis of LC-MS/MS for the MPR performed using an API 4000 equipped with Agilent 1100 HPLC and by the autosampler from Leap Technologies. Used HPLC column Phenomenex Onyx Monolithic 18 (Cho-7644) at a temperature of 35°C, flow rate 2.0 ml/min, injection volume of 30 µl and the passing time of 3 min. Mobile phase AI represents 0.1% formic acid in water and mobile phase EN represents 0.1% formic acid in acetonitrile. The gradient is 98% AI/2% AII at time 0; 98% AI/2% AII at time of 0.1 min; 5% AI/95% AII at time of 1.4 min; 5% AI/95% AII at time of 2.2 min; 98% AI/2% EN at the time of 2.3 min; 98% AI/2% AII at time of 3.0 min. Content MHF determined using negative ion type (01 128,94; Q2 71).

The stability of the prodrug DMF and MHF some of the present invention in various environments is shown in table 1.

Table 1.
The stability of the MHF prodrug in biological fluids
T1/2the initial hydrolysis of the prodrug (min)
Conn.SACOCu. liverCu. plasmaSt. PancreatinFlushing the colon of the CD.pH 8.0s
DMF2120>600
103114>6042
452123340
249912517
98 614>6047
18218>6063
5301023>6053
3562218>6053
8522361527141
§ The percentage of DMF or prodrug remains after 60 minutes.

Example 53

The biological availability of methylhydroquinone after oral administration of the prodrug of methylhydroquinone

Rats obtained from commercial sources and pre-cannulated in the jugular vein. Animals during the experiment are in sosn�research Institute. All the animals were not fed during the night and within 4 hours after dosing of a prodrug of formula (I).

Blood samples of rats (0.3 ml/sample) are collected from all animals prior to dosing and at various time points up to 24 h after giving the dose in tubes containing EDTA. Two aliquots (100 µl each) was quenched with 300 μl of methanol and stored at -20°C until analysis.

In order to get the standards for analysis, 90 ál of blood rats quenched with 300 μl of methanol, then 10 µl of fixing (spiking) of the standard and/or 20 µl internal standard. The tubes with samples shaken for at least 2 min and then centrifuged at 3400 rpm for 20 min, Then the supernatant is transferred into the injection flask or tablet for analysis by LC-MS-MS.

In order to obtain samples for analysis, 20 µl of internal standard added to each tube with quenched sample. The tubes with samples shaken for at least 2 min and then centrifuged at 3400 rpm for 20 min, Then the supernatant is transferred into the injection flask or tablet for analysis by LC-MS-MS.

Analysis of LC-MS / MS is performed using an API 4000 (12 MS) equipped with Agilent 1100 HPLC and by the autosampler from Leap Technologies. Use the following columns: column HPLC, Onyx Monolithic 18 Phenomenex (PN Cho-7644), 35°C; flow rate 2.0 ml/min; injection volume 30 μl; time pass�Yes 3 min; mobile phase A: 0.1% formic acid in water; mobile phase B: 0.1% formic acid in acetonitrile (ACN): the gradient of 98% A/2% at the time of 0.0 min; 98% A/2% for a time of 0.1 min; 5% A/95% at the time of 1.4 min; 5% A/95% at the time of 2.2 min; 98% A/2% at the time of 2.3 min; and 98% A/2% In a time of 3.0 min. MPR control using negative ion type.

Compartmentally analysis is carried out using the software WinNonlin (V. 3.1 Professional Version, Pharsight Corporation, Mountain View, California) on individual animal profiles. The summary statistics for the estimation of key parameters to perform Cmax(peak concentration observed after dosing), Tmax(the time to maximum concentration is the time at which the observed maximum concentration), AUC(0-t)(area under the curve plasma concentration from time from time zero to time of last selection, evaluate using trapezoidal log-linear method), AUC(0-∞)(area under the curve plasma concentration from time from time zero to infinity, evaluate using trapezoidal log-linear method to the time of the last sampling with extrapolation to infinity) and t1/2,z(end half-life).

Prodrug of the MPR or DMF is administered orally via gavage to groups of izchisti adult male rats Sprague-Dawley (approximately 250 g). Animals during the experiment are in the mind. Prodrug of the MPR or DMF is administered orally or through the large intestine 3.4% fatale at a dose of 70 mg-equivalents of MHF per kg of body weight.

The relative bioavailability of the MPR, in percent (R%), determined by comparing the area under curve of concentration of the MPR versus time (AUC) after administration orally or via the colon Prodrug of the MPR or DMF with the AUC under the curve based on the concentration of MHF after intravenous administration of the MPR in the normalized dose.

MHF prodrug(41), (3), (9) and (11), when administered orally to rats at a dose of 30 mg/kg MHF-equivalents in 50 mm sodium acetate solution, pH 4.6, find the absolute bioavailability (relative to IV), ranging from about 43% to about 60%, with an average bioavailability of approximately 51%.

Example 54

Animal model EAE for assessing therapeutic efficacy of MHF prodrug for the Treatment of multiple sclerosis

Animals and induction of EAE

Female mice C57BL/6 at the age of 8-10 weeks (Harlan Laboratories, Livermore, CA) immunize subcutaneously in the flanks and mid-scapular region of 200 µg of glycoprotein peptide of myelin oligodendrocyte (MOG35-55) (synthesized by Invitrogen), emulsified (volume ratio 1:1) with the complete adjuvant of franda (CFA) containing 4 mg/ml Mycobacterium tuberculosis). The emulsion is produced by extrusion through a syringe with POM�using two glass syringes Luer-Lock, United 3-way stopcock. The mice are also given intraperitoneal injection of 200 ng pertussis toxin (List Biological Laboratories, Inc., Campbell, CA) on the day of immunization and the second day after immunization. Mice are weighed and checked daily for clinical signs of experimental autoimmune encephalomyelitis (EAE). Food and water was given ad libitum, and as soon as the animals begin to show disease, the food served at the bottom of the cage. All experiments authorized Instititional Animal Care and Use Committee.

Clinical evaluation

Mice evaluated daily starting at day 7 after immunization. Scale clinical assessments is as follows (Miller and Karplus, Current Protocols in Immunology, 2007, 15.1.1-15.1.18): 0 = normal; 1 = limp tail and weakness of hind limbs (determined by the sliding of the legs between the bars of the top of the cage during movement); 2 = limp tail and weakness of hind limbs; 3 = partial hind limb paralysis (determined by the absence of load on the hind legs, but still to some extent have the ability to move one or both hind limbs); 4 = complete hind limb paralysis; 5 = state of agony (includes paralysis of the forelimbs) or death.

Treatment

The DMF or prodrug of MHF dissolved in a mixture of 0.5% metallovozy/0.1% tween 80 in distilled water and administered orally via gavage twice a day, �ince in 3 days after immunization until the end. Dexamethasone was dissolved in IX PBS buffer and injected subcutaneously once a day. Group processing the following: one medium, 15 mg/kg prodrug DMF, 20 mg/kg prodrug of MHF and 1 mg/kg of dexamethasone.

Description 1

Using animal models to evaluate the effectiveness in the treatment of psoriasis

Murine model of severe combined immunodeficiency (SCID) can be used to evaluate the effectiveness of the compounds for the treatment of psoriasis in humans (Boehncke, Ernst Shering Res. Found Workshop, 2005, 50, 213-14; and Bhagavathula et al., J. Pharmacol. Expt'l Therapeutics, 2008, 324(3), 938-947).

The SCID mice are used as recipients of the fabric. One biopsy of each healthy volunteers with psoriasis or transplanted on the surface of the back of the mouse. Treatment begin within 1-2 weeks after transplantation. Animals with grafts of human skin is divided into the treatment group. Animals are treated twice daily for 14 days. At the end of the treatment of animals are photographed and then killed. Transplantirovannam human tissue along with the surrounding mouse skin removed surgically and fixed in 10% formalin, and receive samples for microscopy. Measure the thickness of the epidermis. The tissue sections were stained with antibodies to associate with the proliferation antigen Ki-67 and anti-human monoclonal antibodies CD3+for the detection of human T-lymphocytes in transplanted�bath tissue. Slicers are also probing with antibodies to C-myc and β-catenin. A positive response to treatment is reflected in the reduction of the average thickness of the epidermis of psoriatic grafts skin grafts. A positive reaction is also associated with reduced expression of Ki-67 in keratinocytes.

Description 2

Animal model for assessing therapeutic efficacy of MHF prodrug for the Treatment of multiple sclerosis

Experiments are conducted on female mice aged 4-6 weeks belonging to the line C57BL/6, weighing 17-20 g. Experimental autoimmune encephalomyelitis (EAE) is actively causing using synthetic peptide glycoprotein myelin oligodendrocyte (MOG35-55, MEVGWYRSPFSRWHLYRNGK). Each mouse was anesthetized and she gets 200 μg of MOG peptide and 15 μg of saponin extract from secondary bark Quilija emulsified in 100 µl phosphate-buffered saline. Volume of 25 µl was injected subcutaneously over four flank areas. Mice are also injected intraperitoneally with 200 ng of the cough toxin in 200 µl PBS. A second identical injection cough toxin yield after 48 h.

The MHF prodrug is administered in various doses. Control animals receive 25 μl DMSO. Daily the treatment lasts from day 26 to day 36 after immunization. Clinical assessment receive daily from day 0 after immunization until day 60.

Clinical recognized�and evaluate using the following Protocol: 0 - no visible signs; 0.5 to dullness of the tip of the tail, charleneli and immobility; 1 - Limper tail; 1,5 - flaccidity of the tail and weakness of hind limbs (unsteady gait and poor control of hind limbs); 2 - unilateral partial hind limb paralysis; 2.5 to bilateral hind limb paralysis; 3 - complete bilateral hind limb paralysis; 3.5 to full hind limb paralysis and unilateral paralysis of forelimbs; 4 - total paralysis of the hind limbs and forelimbs (Eugster et al., Eur. J. ImmunoL, 2001, 31, 2302-2312).

Inflammation and demyelination evaluate histologically in sections of the CNS of mice with EAE. Mice were sacrificed after 30 or 60 days, all animals recovered to the spinal cord and placed in a 0.32 M solution of sucrose at 4°C overnight. Tissue dissect and make the cuts. Dye fast blue buff non treated buff used to monitor demyelination. Staining with hematoxylin and eosin are used to highlight the areas of inflammation by a darker staining of the nuclei of mononuclear cells. Immune cells, stained with H&E and counted in a light field in an optical microscope. Sections are divided into gray and white matter, and every sector manually cheated before combining to produce an overall result for the slice. Labeled T cells of the immune method monoclonal antibodies p�of otiv CD3+. After washing, sections were incubated with goat anticrisisnye secondary antibodies HPR. Then sections were washed and kontrobersyal methyl green. Splenocytes recovered from mice at 30 and 60 day after immunization, treated with a lysing buffer to remove red blood cells. Then the cells was resuspended in PBS and believe. Cells at a density of about 3×106cells/ml were incubated overnight with 20 μg/ml of MOG peptide. The supernatants from stimulated cells to assess protein levels of IFN-y using the corresponding system of immunoassay the murine IFN-Y.

Description 3

Using animal models to evaluate the effectiveness in the treatment of

inflammatory bowel disease

Animal models of inflammatory bowel disease described in Jurjus et al., J. Pharmacol. Toxicol. Methods, 2004, 50, 81-92; Villegas et al., Int'l Immunopharmacol., 2003, 3, 1731-1734; and Murakami et al.. Biochemical. Pharmacol., 2003, 66, 1253-1261. For example, to evaluate the effectiveness of a compound for the treatment of inflammatory bowel disease you can use the following Protocol.

Using female ICR mice. Mice are divided into treatment group. Groups receive or water (control), given 5% DSS in tap water for the start of the experiment to induce colitis or various concentrations of the test compounds. After the introduction of the test compounds for 1 week also introducing� 5% DSS in tap water groups receiving the test compound for 1 week. At the end of the experiment all mice were sacrificed, and remove the colon. Receive samples of the mucosa of the colon and homogenize them. Quantify Pro-inflammatory mediators (e.g., IL-1α, IL-1β, TNF-α, PGE2 and Pgf2á) and protein concentration. Every isecheno the colon check and histologically evaluate the damage of the colon.

Description 4

A clinical trial to evaluate the effectiveness in the treatment of asthma Register adult subjects (non-smokers) with stable mild-moderate asthma (see, for example. Van Schoor and Pauwels, Eur. Respir. J., 2002, 19, 997-1002). Use randomized double-blind and placebo-controlled two-periodic cross plan. On the day of screening 1 patients subjected to introduction of metacholine (<8 mg/ml). Baseline forced expiratory volume in 1 second (FEV1) before each subsequent administration should be within 15% of skanirovannaja baseline FEV1 obtained at the first visit. After 24-72 hours in a day screening 2 enter neurokinin (1×10-6mol/ml). The study period after the second visit lasts between 10 days. First, the introduction of methacholine and neurokinin-A (NKA) performed on days 1 and 0, respectively. The fourth visit is administered the test compound in the appropriate dose and in those�Linux appropriate period of time. In the last 2 days of the treatment period, repeat the introduction of methacholine and NKA. After the treatment period one there is a cancellation period of about 5 weeks, after which patients switching to another medication or placebo in the study period two, which is identical to the one period. The lung function tests carried out using a spirometer. The introduction of methacholine carried inhalation doubled concentrations of methacholine up until FEV1 will not be >20% of postdiluent baseline FEV1 of that date, as described in Cockcroft et al., Clin. Allergy, 1977, 7, 235-243. Introduction NKA perform the inhalation of increasing concentrations of NKA, as described in Van Schoor et al., Eur. Respir. J., 1998, 12, 17-23. The effect of treatment on the sensitivity of the respiratory tract is determined using appropriate statistical methods.

Description 5

Using animal models to evaluate the effectiveness in the treatment of chronic obstructive pulmonary disease

Animal model using mice chronically exposed to from Smoking cigarettes, can be used to assess the effectiveness in the treatment of emphysema (see, e.g., Martorana et al., Am. J. Respir. Crit. Care Med., 2005, 172, 848-835; and Cavarra et al., Am. J. Respir. Crit. Care Med., 2001, 164, 886-890). Use a six-week male mice C57B1/6J. In the study with a sharp exposure of mice exposed to either room air or d�mA from five cigarettes for 20 minutes. In a study of chronic exposure of mice exposed to either room air or smoke from three cigarettes a day for 5 days a week for 7 months.

For studies with dramatic effects mice divided into three groups of 40 animals each. Then these groups are divided into four subgroups of 10 mice each as follows: (1) no treatment/exposure to air; (2) no treatment/exposure; (3) the first dose of the test compound plus the effects of smoke; (4) the second dose of the test compound. In the first group at the end of exposure in the wash bronchoalveolar fluid evaluate the antioxidant capacity equivalent to trolox. In the second group in the wash bronchoalveolar fluid determine the cytokines and chemokines in 4 hours using a commercial panel of cytokines; and in the third group estimate the number of cells in bronchoalveolar wash fluid for 24 hours.

For studies with chronic exposure to use five groups of animals: (1) no treatment/exposure to air; (2) the first dose of the test compound plus exposure to air; (3) no treatment/exposure; (4) the second dose of the test compound plus the effects of smoke; and (5) the first dose of the test compound plus the effects of smoke. After seven months of constant exposure to room �ozdoba or cigarette smoke for 5 to 12 animals from each group were sacrificed, and easy fix intrathecal formalin. Lung volume measured by water displacement. Light paint. Assessment of emphysema includes the average linear intercept and the internal surface area. Bulk density of macrophages labeled immunohistochemically intimissimi monoclonal antibody Wt-3, determine the point count. The mouse is seen as having baclofenbaclofen dysplasia, when at least one or more medium size bronchi/lungs show a positive periodic acid staining dye by Schiff. To determine desmosine fresh lungs homogenized, processed and analyzed by high-performance liquid chromatography.

Description 6

Animal models for assessing therapeutic efficacy of MHF prodrug for the treatment of Parkinson disease

Neurotoxicity caused MRTR

MRTR or 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine is a neurotoxin that causes parkinsonovy syndrome as humans and experimental animals. Studies of the mechanism of neurotoxicity MRTR show that it involves the generation of the main metabolite MPP+formed due to the activity of monoamine oxidase in relation MRTR. The monoamine oxidase inhibitors block the neurotoxicity MRTR for both mice and primates. OK�called, the specificity of the neurotoxicity of MPP+in relation to dopaminergic neurons is due to the absorption MPP+synaptic dopamine Transporter. Blockers such carrier prevents the neurotoxicity of MPP+. It is shown that MPP+is a relatively specific inhibitor of the activity of mitochondrial complex I by binding to complex I in the binding site rotenone and reducing oxidative phosphorylation. In vivo studies show that MRTR can reduce the concentration of ATP in the striatum in mice. It is shown that MPP+introduced intrastriatal rats causes a significant depletion of ATP and increased lactate concentration, held in the striatum, at the injection site. Compounds that enhance the production of ATP, can protect mice from toxic effects MRTR.

The prodrug of formulae (I) to(IV) are administered to animals, such as mice or rats for three weeks before treatment MRTR. MRTR administered in appropriate dose at the appropriate interval dosing and the appropriate method of enforcement for 1 week before the killing. The control group receive normal saline or one hydrochloride MRTR. After killing quickly excised two striped body and placed in chilled 0.1 M perchloro� acid. Then the fabric is treated with ultrasound, and analyze aliquots for protein content using fluorometric analysis. Also determine quantitatively dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and gomovanilinovoi acid (HVA). Concentrations of dopamine and metabolites expressed as nmol/mg protein.

Prodrug of formulae (I) to(IV) that protect against DOPAC depletion induced MRTR, exhaustion HVA and/or dopamine, are neuroprotectors and can therefore be used for the treatment of Parkinson's disease.

Hypolocomotion caused by haloperidol

Discusses the ability of compounds to reverse in rodents, behavioral depressurise the action of dopamine antagonists such as haloperidol, and effective method of screening pharmaceuticals for possible antiparkinsonian action (Mandhane et al., Eur. J. Pharmacol., 1997, 328, 135-141). Hence the ability of the prodrug of formulae (I) to(IV) block caused by haloperidol deficiencies in locomotor activity in mice can be use to assess the effectiveness of in vivo and potential antiparkinson efficiency.

Mice used in the experiments, kept in a controlled environment and allow it to acclimate before use in experiments. For one and a half (1,5) hours before testing, mice are administered 0.2 mg/kg haloperidol is the dose that decreases base Luo�amatarou activity, at least 50%. The test compound is administered over 5-60 min before testing. Then the animals were placed individually in clear cell polycarbonate flat lid with holes. Horizontal locomotor activity is determined by placing the cells in a frame containing a matrix of 3×6 solar cells, associated with the computer for the tab interrupts the beam. Mice don't bother to study for 1 hour, and the number of interruptions of the beam occurring within a specified period, serves as an indicator of locomotor activity, which is compared with data for control animals for statistically significant differences.

Animal model with 6-hydroxydopamine

Neurochemical defects obvious in Parkinson's, can be played by local injection of the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in brain areas containing or cell body or aksonnogo fiber neurons efferent connection of the black substance with a striped body. Due to the unilateral lesions of the way of the efferent connection of the black substance with a striped body on only one side of the brain see behavioral asymmetry in the suppression of the movement. Although animals with unilateral damage is still mobile and capable of autonomy, remaining sensitive to dopamine not�Rhone on the affected side become hypersensitive to irritation. This is demonstrated by the observation that after systemic administration of dopamine agonists such as apomorphine, the animals show a clear rotation in the direction opposite to the side of the injury. It is shown that the ability of compounds to induce contralateral rotations in rats damaged by 6-OHDA, is a sensitive model for predicting the effectiveness of drugs in the treatment of Parkinson's disease.

Male rats Sprague-Dawley contain in a controlled environment and allow it to acclimate before use in experiments. Fifteen minutes before surgery, the animals given intraperitoneal injection of the inhibitor re-absorption of noradrenaline desipramine (25 mg/kg) to prevent damage negovanovic neurons. Then the animals are placed in a chamber for anesthesia and anesthetized using a mixture of oxygen and izoflurana. Once the animals lose consciousness, they are transferred to the stereotactic frame, where the anesthesia support through the mask. The upper part of the head shaved and sterilized using a solution of iodine. Once dry, make the cut Dina 2 cm along the midline of the scalp, and the skin pulled and fixed on the back for the impact on the skull. Then drill a small hole in the skull above the injection site. To damage the path of efferent connection of the black substances�and striped body the injection cannula is gradually lowered to the position right above the middle forebrain bundle on falling 3.2 mm more forward, 1.5 mm laterally from the middle of bregma and to a depth of 7.2 mm below the Dura mater. Two minutes after immersion give cannula infusion of 6-OHDA at a rate of 0.5 μl/min for 4 min to ensure a final dose of 8 μg. The cannula before it is removed, left in place for 5 min to facilitate diffusion. Then connect the skin suture, the animal removed from the stereotaxic frame and return to the place of detention. Rats allowed to recover from surgery for two weeks before behavioral testing.

Rotational behavior was measured using rotametricheskoy system with stainless steel rollers (diam. 45 cm×15 cm height), closed with transparent plexiglass around the end of the video and continued to a height of 29 cm in order to assess rotation, rats are placed in a fabric cover attached to the elastic tether which is connected to roller located above the optical rotameter, which assesses movement to the left or right or as a partial (45°) or full (360°) rotation.

In order to reduce stress during the introduction of the test compounds, rats are first placed in the apparatus for 15 minutes four days in a row. On the day of the test, the rats given the test compound on�reamer, the prodrug of formulae (I) to(IV). Immediately before the test animals are given a subcutaneous injection of a subthreshold dose of apomorphine and then placed in the bracket, and record the number of rotations within one hour. The total number of full contralateral rotations over time of the test period serves as an index antiparkinson efficacy of the medicine.

Description 7

Animal model for assessing the effectiveness of the MHF prodrug for the treatment of Alzheimer's disease

As an animal model of Alzheimer's disease using heterozygous transgenic mice expressing Swedish mutant gene AD hAPPK670N, M671L (Tg2576; Hisao, Learning & Memory, 2001, 8, 301-308). Animals kept in standard conditions with a light cycle light/dark 12:12, and free access to feed and water. Since the age of 9 months, the mice are divided into two groups. The first two groups of animals receive increasing doses of MHF prodrugs for six weeks. The remaining control group receives, within six weeks of saline injection on a daily basis.

Behavioral testing is performed at each dose of the drug using the same sequence within two weeks in all experimental groups: (1) changes in the learning space, (2)locomotion, (3) fear conditioning � (4) sensitivity to shock.

Purchase example of spatial learning and change learning checks during the first five days of the introduction of the test compounds using a water T-maze, as described in Bardgett et al., Brain Res. Bull., 2003, 60, 131-142. Mice were placed in a water T-maze for 1-3 days, and the perception of task starts on day 4. On day 4 the mice are trained to find and rescue platform within the selected branch of the maze until then, until it is done 6-8 consecutive correct choices in the tests. Then on day 5 spend the phase changes learning. During the phase change of training mice are trained to search and rescue platform in a selected branch, opposite to the location and rescue of the platform on day 4. Use the same Executive criteria and test intervals, and that during the perception task.

Large displacement estimate in order to detect changes in the learning space does not impact the ability to walk after surgery. After a period of rest in two days horizontal movement, eliminating vertical movement and fine motor skills, assessed at day 8 in the chamber, provided with a grate, which is sensitive to the displacement of the detectors. The number of movements accompanied by the simultaneous locking and unlocking of the detector in the horizontal direction by measuring�t for the period of one hour.

The ability of the animal to contextual and approximate memorization test using the example of fear conditioning, since day 9. The test is carried out in a chamber in which is contained a piece of absorbent cotton soaked in emitting the smell of the solution, such as peppermint extract, placed below the slatted floor. For training animals injected on day 9 on feet sound shocking series of 3 tests and 5 min at 80 dB, 2800 Hz. On day 10 check memorization of context, returning each mouse in the chamber without exposure to sound and shock on the legs, and register the presence or absence of a behavior constraint every 10 seconds for 8 minutes. Stiffness is defined as the absence of motion, such as the ability to move, sniff, or stereotype, other than breathing.

Day 11 check the reaction of the animal to the changed context and auditory examples. Extract coconut is placed in a Cup and represent the sound at 80 dB, but the shock on the paws will not be served. Then determine the presence or absence of stiffness in response to the changed context in the first 2 minutes of the test. Then the sound is present continuously for the remaining 8 minutes of the test, and determine the presence or absence of the constraint.

Day 12 animals have to assess their sensitivity to the conditioning stimulus,i.e., the shock on his paws.

After the last day of behavioral testing of the animals was anesthetized, and then extract the brain, will fix it over night, and make slices through the hippocampus. Sections were stained for obtaining images of β-amyloid plaques.

Data analysed using appropriate statistical methods.

Description 8

Animal model of therapeutic efficacy of MHF prodrug for the treatment of Huntington's disease

A neuroprotective effect in a transgenic mouse model of Huntington's disease

Transgenic mice line HD N171-82Q and non-transgenic pups at the age of 10 weeks treated with a prodrug of formula (I) to(IV) or carrier. Mice are placed on a rotating beam ("rotarod" ("rotarod")). The duration of the period over which the mouse falls from rotarod, recorded as a measure of motor coordination. Total distance, elapsed mouse also recorded as a measure of General locomotion. The mice that were injected prodrug of formulae (I) to(IV), which are neuroprotective agents in a transgenic mouse model of HD N171-82Q remain on rotarod for a longer period of time and "travel" further than the mice that were injected with the carrier.

Maloata model of Huntington's disease

A number of reversible and irreversible acting inhibitors of enzymes involved in the way of energy generation is used for �of Holocene animal models for neurodegenerative diseases such as Parkinson's and Huntington's. In particular, for obtaining a model of Huntington's disease using inhibitors of succinate dehydrogenase, the enzyme which affects the homeostasis of cellular energy.

In order to evaluate the effect of the MHF prodrug of formulae (I) to(IV) of this malonate model of Huntington's disease, a prodrug of formulae (I) to(IV) administered to male rats Spargue-Dawley in appropriate doses, with appropriate dosing interval and in the appropriate manner. A prodrug is administered within two weeks before the introduction of malonate and then another during the week before the killing. Malonate dissolved in distilled deionized water, and pH was adjusted to 7.4 with 0.1 M HCl. Intrastriatal injection of 1.5 μl, 3 mmol solution of malonate doing in the left striatum at the level of bregma 2.4 mm laterally from the midline and 4.5 mm ventral to the Dura mater. Animals were sacrificed at 7 days by decapitation and the brain rapidly removed and placed in a chilled ice of 0.9% saline. Brains excised at intervals of 2 mm in the appropriate form. Then the slices were placed posterior side down in a 2% solution of chloride 2,3,5-triphenyltetrazolium. Sections were stained in the dark at room temperature for 30 min and then removed and placed in 4% paraformaldehyde, pH 7.3. Damage, note on weak akrasian�Yu, assess on the rear surface of each slice. The measurements confirm the comparison with the measurements obtained on adjoining sections, Nissl stained. Compounds exhibiting neuroprotective action and are therefore potentially applicable in the treatment of Huntington's disease, show a decrease of damages caused by malonate.

Description 9

Animal model of therapeutic efficacy of MHF prodrug for the treatment of amyotrophic lateral sclerosis

Developed murine model of ALS-associated SOD1 mutation, in which mice Express superoxiddismutase (SOD) mutation of human glycine→alanine at residue 93 (SOD1). Such mice with SOD1 find the dominant growth of harmful properties of SOD, and they develop degeneration of motor neurons and dysfunction, with similar dysfunction in people with ALS. Transgenic mice with SOD1 show signs of weakness of the hind limbs at the age of about 3 months and die in 4 months. Signs common to ALS person, including astrocytosis, microglia, oxidative stress, increased levels of cyclooxygenase/prostaglandin and disease development, a profound loss of motor neurons.

Studies performed on transgenic mice, sverkhekspressiya mutations in human Cu/Zn-SOD G93F (B6SJL-TgN (SOD1-G93A) 1 Gur) and non-transgenic mice (B6/SJL and their babies wild type. Mice with�this software collection, with 12-hour cycle of daylight and (since the age of 45 days) provide free access or to feed with the addition of the test compound or, as a control, to cold prasowania the stern of conventional composition, processed in an identical pellets. Genotyping can be performed at the age of 21 days, as described in Gumey et al., Science, 1994, 264(5166), 1772-1775. Mice with SOD1 divided into groups and treated with the test compound, e.g., a prodrug of the MPR, or used as control.

Mice are inspected daily and weekly weighed. In order to assess the state of health of mice weekly weighed and checked for changes in lacrimation/salivation, closing of the eyelids, twitching of the ears and pupillary reactions, the orientation of the hairs, postural reflexes and installation and overall assessment of the condition of the body. General pathological examinations carried out during the killing.

For the coordination of movements of animals can be assessed by one or more methods known to those skilled in the art. For example, coordination can be assessed using the neurological evaluation. Neurological assessment neurological control indicator each limb and register according to 4 - point scale: 0 - normal reflex in the hind limbs (animal wraps its hind limbs when lifted by the tail); 1 - abnormal reflex of the hind limbs (loss of the ability �otvorachivanie hindquarters, when the animal is lifted by the tail); 2 - abnormal reflex of the hind limbs and signs of paralysis; 3 - loss of reflex and paralysis; and 4 - the inability to stand up straight when lying on your side, 30 seconds, or found dead. The primary endpoint is survival with secondary endpoints neurological evaluation and body weight. Observe for neurologic assessments and body mass and register them five times a week. The data analysis is carried out using appropriate statistical methods.

In the test on rotator assess the ability of the animal to remain on a rotating pin, giving the opportunity to assess motor coordination and proprioceptive sensitivity. The device is a rod with a diameter of 3 cm with automatic rotation, for example, at a speed of 12 rpm In the test rotatori determine how long a mouse can stay on the rod and not fall. The test can be terminated after an arbitrary limit at 120 C. the Animal may fall earlier than 120 s, the action register and perform two additional tests. Calculate the average time of 3 trials. The lack of motility shown to reduce time walks.

In the test with a lattice mice are placed on a lattice (length 37 cm, width 10.5 cm, hole size 1×1 cm2) installed�ing above a flat support. The number of times the mouse gets his hands against the bars, celebrate, and this serves as a measure of motor coordination.

In the test by hanging assess the ability of the animal to hang on the wire. The device is a wire stretched horizontally at a height of 40 cm above the table. The animal is attached to the wire with its front paws. The time it takes the animal to grasp the wire with their hind paws, record (max. 60 s) in three consecutive experiments.

Electrophysiological measurements (EMG) can also be used to assess the status of physical activity. Electromyographic indicators are registering using an electromyograph device. During the EMG control mice was anesthetized. The measured parameters are the amplitude and latent period of action potential connections on the muscles (SMARA). SMAR measured in the gastrocnemius muscle after stimulation of the sciatic nerve. The reference electrode is inserted near the Achilles tendon, and the active needle is placed in the base of the tail. Needle grounding is inserted into the lower back of the mouse. Sciatic nerve irritate one pulse of 0.2 MS with extreme intensity (a 12.9 mA). Measure the amplitude (mV) and latent period of the reaction (MS). Amplitude is a measure of units of active movement, while distal�th latent period reflects the conduction velocity of motor nerve.

The effectiveness of the test compounds can also be evaluated using biomarker analysis. To assess the regulation of protein biomarkers in SOD1 mice during the onset of deterioration of motor skills samples of the lumbar part of the spinal cord (protein extracts) is applied to the matrix with ProteinChip changing chemical/biochemical properties of the surface and analyze, for example, time-of-flight mass spectrometry with ionization surface-enhanced laser desorption. Then the data, using methods of analysis of the integrated profile of the protein mass, is used to compare the protein expression profiles of the different treatment groups. The analysis can be performed using appropriate statistical methods.

Finally, it should be noted that there are alternative ways to perform the embodiments disclosed in this description. Accordingly, the presented embodiments should be considered as illustrative and not restrictive, and the claims should not limited to the details given in this description, which may be modified within the scope and equivalents.

1. The compound of formula (I)

or its pharmaceutically acceptable salt, where in the formulae
R1and R2chosen independently from hydrogen, C1-6-alkyl and the Deputy�enny C 1-6-alkyl;
R3and R4chosen independently from hydrogen, C1-6of alkyl, substituted C1-6-alkyl, methoxy, methoxycarbonyl, methoxyethyl, S4-12-cycloalkenyl, substituted C4-12-cycloalkenyl, S7-12-arylalkyl, substituted C7-12-arylalkyl, thiadiazolyl and groups-CH2CH2NHC(O)CH2OC(O)CH=CHCOOCH3;
or R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from substituted oxazolidine, substituted pyrrolidine, morpholine, piperazine and N-substituted piperazine; and
R5is methyl,
where each group-Deputy independently chosen from halogen, -CN, -CF3,=O, -NO2, benzyl, - C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

2. The compound of claim 1, wherein each of R1and R2represents hydrogen.

3. The compound of claim 1, wherein one of R1and R2represents hydrogen and the other of R1and R2selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

4. The compound according to claim 1, where R3and R4chosen independently from hydrogen and C1-6-alkyl.

5. The compound according to claim 1, where R3and R4together with at�IOM nitrogen, to which they are linked, form a cycle of morpholine.

6. The compound of claim 1, wherein one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl, and R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from morpholine, piperazine and N-substituted piperazine.

7. The compound of claim 1, wherein one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl, R3represents hydrogen; R4selected from hydrogen, C1-6-alkyl and benzyl.

8. The compound according to claim 1, selected from the group consisting of
(N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diet;
methyl-[N-benzylcarbamoyl]methyl(2E)but-2-ene-1,4-diet;
methyl-2-morpholine-4-yl-2-oxoethyl(2E)but-2-ene-1,4-diet;
(N-butylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diet;
[N-(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diet;
2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetylamino}acetic acid;
4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enolase]acetylamino}butane acid;
(N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diet;
bis[(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diet;
[N-(methoxycarbonyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diet;
methyl-2-oxo-2-(2-oxo-1,3-oxazolidin-3-yl)ethyl(2E)but-2-ene-1,4-�ioat;
{N-[2-(dimethylamino)ethyl]carbamoyl}methyl methyl(2E)but-2-ene-1,4-diet;
methyl-2-(4-methylpiperazine)-2-oxoethyl(2E)but-2-ene-1,4-diet;
methyl-{N-[(propylamino)carbonyl]carbamoyl}methyl(2E)but-2-ene-1,4-diet;
2-(4-acetylpiperidine)-2-oxoethyl-methyl(2E) but-2-ene-1,4-diet;
{N,N-bis[2-(methylethoxy)ethyl]carbamoyl}methyl methyl(2E)but-2-ene-1,4-diet;
methyl-2-(4-benzylpiperazine)-2-oxoethyl(2E)but-2-ene-1,4-diet;
[N,N-bis(2-ethoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diet;
2-{(2S)-2-[(tert-butyl)oxycarbonyl]pyrrolidinyl}-2-oxoethyl-methyl(2E)but-2-ene-1,4-diet;
(N-{[(tert-butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diet;
{N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methyl methyl(2E)but-2-ene-1,4-diet;
methyl-1-methyl-2-morpholine-4-yl-2-oxoethyl(2E)but-2-ene-1,4-diet;
[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl(2E)but-2-ene-1,4-diet;
(N,N-dimethylcarbamoyl)ethyl methyl(2E)but-2-ene-1,4-diet;
(N-{[(tert-butyl)oxycarbonyl]methyl}carbamoyl)methyl methyl(2E)but-2-ene-1,4-diet;
methyl-(N-methyl-N-{[(methylethyl)oxycarbonyl]methyl}carbamoyl)methyl(2E)but-2-ene-1,4-diet;
{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methyl methyl(2E)but-2-ene-1,4-diet;
{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}ethyl methyl(2E)but-2-ene-1,4-diet;
{N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}ethyl methyl(2E)but-2-ene-1,4-diet;
(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl-methyl(2E)but-2-ene-1,4-dio�t;
(1S)-1[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl(2E)but-2-ene-1,4-diet;
(1S)-1-(N,N-diethylcarbamoyl)ethyl methyl(2E)but-2-ene-1,4-diet.

9. The compound of formula (II)

or its pharmaceutically acceptable salt, where in the formulae, R6selected from C1-6of alkyl, substituted C1-6-heteroalkyl, S3-8-cycloalkyl, S6-8-aryl and-OR10where R10selected from C1-6-alkyl and C3-10-cycloalkyl;
R7and R8chosen independently from hydrogen and C1-6-alkyl; and R9is methyl,
where each group-Deputy independently chosen from halogen, -CN, -CF3,=O, -NO2, benzyl, -C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

10. The connection according to claim 9, where one of R7and R8represents hydrogen and the other of R7and R8selected from methyl, ethyl, n-propyl and isopropyl.

11. The connection according to claim 9, where each group-the under is a-OR11where each R11represents C1-4-alkyl.

12. The connection according to claim 9, where R6represents C1-6-alkyl and one of R7and R8represents hydrogen, the other of R7and R8represents C1-6alkyl.

13. The connection according to claim 9, where R6is a-OR10where R10selected from C1-4-alkyl and cyclohexyl.

14. The connection according to claim 9, where R6selected from methyl, ethyl, n-propyl and isopropyl, and one of R7and R8represents hydrogen, and the other of R7and R8selected from methyl, ethyl, n-propyl and isopropyl.

15. The connection according to claim 9, selected from the group consisting of
ethoxycarbonylmethylene(2E)but-2-ene-1,4-diet;
methyl-(metalelectronics)ethyl(2E)but-2-ene-1,4-diet;
methyl-(2-methylpropyloxy)ethyl(2E)but-2-ene-1,4-diet;
methyl phenylcarbonylamino(2E)but-2-ene-1,4-diet;
cyclohexyloxycarbonyloxy-methyl(2E)but-2-ene-1,4-diet;
[(2E)-3-(methoxycarbonyl)prop-2-enolase]ethyl methyl(2E)but-2-ene-1,4-diet;
(cyclohexyloxycarbonyloxy)ethyl methyl(2E)but-2-ene-1,4-diet;
methyl-2-methyl-1-phenylcarbonylamino(2E)but-2-ene-1,4-diet; and
3-({[(2E)-3-(methoxycarbonyl)prop-2-enolase]methyl}oxycarbonyl)(2S)-2-aminopropanoic acid, 2,2,2-triptorelin.

16. The compound according to claim 1, where R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from piperazine, substituted 1,3-oxazolidinyl, substituted pyrrolidine and morpholine.

17. The compound of claim 1, wherein one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C 1-6-alkyl and each of R3and R4represents C1-6-alkyl.

18. The compound of claim 1, wherein each of R1and R2represents hydrogen and each of R3and R4represents C1-6-alkyl.

19. The compound of claim 1, wherein one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-4-alkyl, R3represents hydrogen and R4selected from C1-4of alkyl and substituted C1-4-alkyl, where the group is the Deputy selected from =O, -OR11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

20. The compound of claim 1, wherein one of R1and R2represents hydrogen, and the other of R1and R2is methyl, R3represents hydrogen and R4selected from C1-4of alkyl and substituted C1-4-alkyl, where the group is the Deputy selected from =O, -OR11, -COOR11and-NR112where each R11chosen independently from hydrogen and C1-4-alkyl.

21. The compound of claim 1, wherein each of R1and R2represents hydrogen, R3represents hydrogen; and R4selected from C1-4of alkyl and substituted C1-4-alkyl, where the group is the Deputy selected from =O, -OR11, -COOR11and-N 112where each R11chosen independently from hydrogen and C1-4-alkyl.

22. The compound of claim 1, wherein one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl and R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from substituted oxazolidine, substituted pyrrolidine, morpholine, piperazine and N-substituted piperazine.

23. The compound of claim 1, wherein one of R1and R2represents hydrogen, and the other of R1and R2is bromide and R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from substituted oxazolidine, substituted pyrrolidine, morpholine, piperazine and N-substituted piperazine.

24. The compound of claim 1, wherein each of R1and R2represents hydrogen and R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from substituted oxazolidine, substituted pyrrolidine, morpholine, piperazine and N-substituted piperazine.

25. The compound of claim 1, wherein one of R1and R2represents hydrogen, and the other of R1and R2selected from hydrogen and C1-6-alkyl, and R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from morpholine, Piper�ina and N-substituted piperazine.

26. The compound according to claim 1, where R3and R4together with the nitrogen atom to which they are linked, form a cycle selected from piperazine, substituted 1,3-oxazolidinyl, pyrrolidine and morpholine.

27. The compound according to claim 1, which is a (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diet.

28. The compound according to claim 1 which is methyl-2-morpholine-4-yl-2-oxoethyl(2E)but-2-ene-1,4-diet.

29. The compound according to claim 1, which is a (N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-diet.

30. The compound according to claim 1, which is bis(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-diet.

31. The connection according to claim 9, selected from the group consisting of:
methyl-(2-methylpropyloxy)ethyl(2E)but-2-ene-1,4-diet;
methyl phenylcarbonylamino(2E)but-2-ene-1,4-diet;
cyclohexyloxycarbonyloxy-methyl(2E)but-2-ene-1,4-diet;
[(2E)-3-(methoxycarbonyl)prop-2-enolase]ethyl methyl(2E)but-2-ene-1,4-diet; and
methyl-2-methyl-1-phenylcarbonylamino(2E)but-2-ene-1,4-diet.

32. The connection according to claim 9, selected from the group consisting of:
ethoxycarbonylmethyl-methyl(2E)but-2-ene-1,4-diet;
methyl-(metalelectronics)ethyl(2E)but-2-ene-1,4-diet; and
(cyclohexyloxycarbonyloxy)ethyl methyl(2E)but-2-ene-1,4-diet.

33. The connection according to claim 9, which is a
methyl-2-methyl-1-phenylcarbonylamino(2E)but-2-e�-1,4-diet.

34. The connection according to claim 9, which is a [(2E)-3-(methoxycarbonyl)prop-2-enolase]ethyl methyl(2E)but-2-ene-1,4-diet.

35. Pharmaceutical composition for the manufacture of medicinal products for the treatment of immunological diseases and conditions, autoimmune diseases and conditions, inflammatory diseases and conditions, containing a therapeutically effective amount of a compound according to any one of claims. 1-34 and at least one pharmaceutically acceptable carrier.

36. Pharmaceutical composition according to claim 35, representing the oral dosage form.

37. Pharmaceutical composition according to claim 35, representing an oral dosage form with controlled release.

38. Pharmaceutical composition according to claim 35, representing the oral dosage form extended-release.

39. Pharmaceutical composition according to claim 35, where the diseases and conditions selected from the group consisting of: psoriasis, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease and arthritis.

40. Pharmaceutical composition according to claim 35, where the diseases and conditions selected from the group consisting of: psoriasis, asthma, chronic obstructive pulmonary disease, heart failure, left ventricular failure, infer�t of the myocardium, angina, Parkinson's disease, Alzheimer's disease, Huntington's disease, pigmentary retinopathy, mitochondrial encephalopathy, graft rejection, multiple sclerosis, ischemia, reperfusion injury, damage to the genome caused by AGE, inflammatory bowel disease, Crohn's disease and ulcerative colitis.

41. Method of treating disease in a patient, comprising administering to a patient in need of such treatment, a therapeutically effective amount of the pharmaceutical composition according to any one of claims. 35-40, where the disease is selected from the group consisting of: psoriasis, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease and arthritis.

42. Method of treating disease in a patient, comprising administering to a patient in need of such treatment, a therapeutically effective amount of the pharmaceutical composition according to any one of claims. 35-40, where the disease is selected from the group consisting of: psoriasis, asthma, chronic obstructive pulmonary disease, heart failure, left ventricular failure, myocardial infarction, angina, Parkinson's disease, Alzheimer's disease, Huntington's disease, pigmentary retinopathy, mitochondrial encephalopathy, graft rejection, multiple sclerosis, ischemia, reperfusion p�the damaging, damage to the genome caused by AGE, inflammatory bowel disease, Crohn's disease and ulcerative colitis.

43. Use of a compound according to any one of claims. 1-34 or a pharmaceutical composition according to any one of claims. 35-40 for the manufacture of a medicine for the treatment of psoriasis, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease or arthritis.

44. Use of a compound according to any one of claims. 1-34 or a pharmaceutical composition according to any one of claims. 35-40 for the manufacture of a medicine for the treatment of psoriasis, asthma, chronic obstructive pulmonary disease, heart failure, left ventricular failure, myocardial infarction, angina, Parkinson's disease, Alzheimer's disease, Huntington's disease, pigmentary retinopathy, mitochondrial encephalopathy, transplant rejection, multiple sclerosis, ischemia, reperfusion injury, damage to the genome caused by AGE, inflammatory bowel disease, Crohn's disease or ulcerative colitis.

45. Use of a compound according to any one of claims. 1-34 or a pharmaceutical composition according to any one of claims. 35-40 for the manufacture of a medicine for the treatment of psoriasis.

46. Use of a compound according to any one of claims. 1-34 or a pharmaceutical composition according to any�at PP. 35-40 for the manufacture of a medicine for the treatment of multiple sclerosis.

47. Use of a compound according to any one of claims. 1-34 or a pharmaceutical composition according to any one of claims. 35-40 for the manufacture of medicinal products for the treatment of alopecia areata.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a peptide, a peptide mimetic or an amino acid derivative, which contain di-substituted β-amino acid, wherein each of substituting group in the β-amino acid, which can be identical or different, contains at least 7 non-hydrogen atoms, is lipophilic and contains at least one cyclic group; one or more cyclic groups in the substituting group can be bound or condensed with one or more numbers of cyclic groups in the other substituting groups, and when the cyclic groups are fused so that an aggregate total number of non-hydrogen atoms for these two substituting groups makes at least 12, wherein the above peptide, peptide mimetic or amino acid derivative consist of 1-4 amino acids or length-equivalent sub-units.

EFFECT: preparing the peptide, peptide mimetic or amino acid derivative, which contain the di-substituted β-amino acid.

17 cl, 4 dwg, 10 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining secondary amides. Method is realised by carbonylation of respective tertiary amines by means of carbon monoxide in presence of catalyst, containing less than 750 parts per million (ppm) of palladium, and halogen-containing promoter.

EFFECT: increased catalytic activity of catalyst with reduction of palladium concentration and increase of reaction selectivity.

39 cl, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of short-chain fatty acids, in particular derivatives of butyric acid, having physicochemical characteristics suitable for an easy oral administration, being devoid of the unpleasant organoleptic properties that characterise butyrate.

EFFECT: novel compounds have an easily weighable form, are stable to acids and alkalis and are capable of releasing the acid in the small and large intestines continuously over a long time.

7 cl, 5 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-(azacycloalkyl)benzene-1,3-diol compounds of general formula (I) given below:

,

where: R1 is: - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom or a trifluoromethyl group, - aralkyl radical, - C1-C5-alkoxy radical, -amine radical, having the structure (a):

,

where R2 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6- cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical of the structure (b):

,

where p is equal to 1 or 2, - a radical of the structure (c):

,

where R4 is: - carboxymethyl, -COOCH3, or carboxyethyl, -COOEt, radical, - C1-C3-alkyl radica, - hydrogen, and R5 is: - an unsubstituted aryl radical or an aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, fluorine atom or a trifluoromethyl group, - C3-C6-cycloalkyl radical, - pyridyl, and R3 is: - hydrogen, - C1-C5-alkyl radical; or R1 can also be a radical of formula (d):

,

where R6 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical, R7 is: - hydrogen, - C1-C5-alkyl radical, and R8 is: - hydrogen, - hydroxyl, - amine radical, - C1-C3-alkoxy radical; Y is hydrogen or fluorine, and m and n are equal to 0, 1 or 2, as well as isomeric and enantiomeric forms of compounds of formula (I). The invention also relates to use of said compounds as a drug for treating pigmentation disorders.

EFFECT: novel compounds, which can be used in pharmacology or cosmetology to treat or prevent pigmentation disorders, are obtained and described.

6 cl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) or to its stereoisomers, or to a pharmaceutically acceptable salt, wherein Ra represents H or (C1-C6)alkyl; Rb is specified in an optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroaryl, -(CH2)n-(C3-C8) cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8) cycloalkylaryl; or Ra and Rb taken together with a nitrogen atom form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl; Y is specified in an an optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, -NH-(CH2)n-heterocyclyl, wherein NH is attached to carbonyl, and -heterocyclylaryl, wherein heterocyclyl is attached to carbonyl; and n is equal to 0, 1 or 2; wherein each heterocyclyl represents an independent non-aromatic ring system containing 3 to 12 ring atoms, and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; wherein each heteroaryl represents an independent non-aromatic ring system containing 3 to 12 ring atoms and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; and wherein the optional substitutes are independently specified in a group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl. The invention also describes a pharmaceutical composition having chemokine receptor antagonist activity and a method of treating such diseases, such as rheumatoid arthritis, psoriasis, lupus, etc.

EFFECT: there are prepared and described new chemical compounds that can be used as chemokine receptor antagonists and, as such, may be used in treating certain pathological conditions and diseases, particularly inflammatory pathological conditions and diseases and proliferative disorders and conditions, eg rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

23 cl, 59 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new crystalline modifications of N-α-(2,4,6-triisopropylphenylsulphonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazide and/or its salts. Such crystalline modifications have high stability particularly at low hygroscopicity compared to known amorphous forms of the compound.

EFFECT: invention relates to a method of obtaining such new crystalline modifications, to pharmaceutical compositions containing these new crystalline modifications and their use as an anti-tumour agent.

26 cl, 7 tbl, 13 ex, 20 dwg

FIELD: chemistry, pharmaceutical.

SUBSTANCE: invention pertains to compounds with formula I , where: n is an integer equal 1 or 2; p is an integer from 1 to 7; A is chosen from one or more radicals X and/or Y; X represents methylene group, substituted when necessary by one or two C1-6-alkyl groups; Y represents C2-alkenyl, C2-alkenyl; G represents a single bonds, oxygen or C=O. The compound can be used as ferment FAAH inhibitor for pain killing, inflammation or nerve-degenerative diseases. Description is given of the method of obtaining compounds, pharmaceutical compositions based on them and their use.

EFFECT: design of a method of obtaining alkylhomopiperazinecarboxylates and their use for pain killing, treating inflammation or nervous degenerative diseases.

11 cl, 2 tbl, 7 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, novel biologically active substances of the class of N-hetarylamides of 4-aryl-2,4-dioxobutanoic acids, and specifically to 2-(5-ethyl-1,3,4-thiadiazolyl)amide of 2-(4-bromophenyl)-4-oxo-4-phenyl-2-butenoic acid. The compound is obtained by reacting 4-bromophenyl-5-aryl-3-imino-3H-furan-2-one with 2-amino-5-ethyl-1,3,4-thiadiazole with equimolar ratio of reactants in a medium of anhydrous toluene while boiling, followed by separation of the end product.

EFFECT: obtaining compounds having analgesic effect, as well as low toxicity

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition possessing anti-inflammatory, broncholytic and anti-tuberculosis activity, which represents N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-nitrobenzamide. Obtained results of pharmacological study showed that claimed compound possesses high anti-inflammatory, broncholytic and anti-tuberculosis activity, which are not worse and in some cases is better than known applied in medicine preparations. Elaborated is solid dosed pharmaceutical composition based on claimed compound, made in form of tablets, or capsules, or in form of powder for preparation of suspension for drinking.

EFFECT: obtaining possibility to apply claimed pharmaceutical compositions based on claimed compound for prevention and treatment of inflammatory, bronchopulmonary (bronchitis, pneumonia, bronchial asthma) diseases, tuberculosis.

4 cl, 10 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 5-amino-3-(2-nitroxipropyl)-1,2,4-thiadiazoles of general formula , where R1, R2 can be similar or different and independently represent hydrogen, substituted or non-substituted aryl or heteroaryl or aralkyl, alkyl, cycloalkyl, and R1 + R2 can represent heteroaryl (optionally substituted piperasin and piperidin).

EFFECT: obtained are novel compounds, which can be applied in medicine for treatment of neurodegenerative diseases.

1 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

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

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

31 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel biologically active substances of the class of complex compounds of N-heterylamides of 4-aryl-2,4-dioxobutanoic acids. The invention discloses bis{3-phenyl-1-[2-(5-methyl-1,3,4-thiadiazolyl)]carboxamido-1,3-propanedionato}manganese having anti-inflammatory and analgesic activity and formula: .

EFFECT: high output of compounds with pronounced anti-inflammatory and analgesic activity, as well as low toxicity.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to N-[2-(5-ethyl-1,3,4-thiadiazolyl)]amide of 2-(2-hydroxyphenyl)-2-oxoethane acid, which has anti-inflammatory and analgesic activity, of formula: .

EFFECT: compound has low toxicity.

1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to bis{3-phenyl-1-[2-(5-ethyl-1,3,4-thiadiazol or carboxamido-1,3-propanedionato}cadmium, possessing hypoglycemic activity, of formula: .

EFFECT: compound has low toxicity.

1 tbl, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2,5-diamino-1,3,4-triazole. Method involves interaction at heating of dithiourea with hydrogen peroxide in its concentration 24-26% and excess for 0.04-0.18 g-mole followed by decomposition of hydrogen peroxide excess with gaseous hydrogen sulfide up to onset of detecting sulfide ions in the solution. Proposed method provides preparing the end product with the yield 79-98% being without formation of colored by-side substances.

EFFECT: improved method of synthesis.

1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

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