Chromenone analogues as sirtuin modulators

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

 

REFERENCE TO RELATED APPLICATION

This application claims the priority of provisional patent application U.S. No. 61/194576 registered on September 29, 2008, the content of which is contained in the description by reference.

The LEVEL of TECHNOLOGY

The family of gene regulators of silencing information (Silent Information Regulator (SIR)is a highly conserved group of genes present in the genomes of organisms, in a series of archaebacteria to eukaryotes. Coded SIR proteins involved in diverse processes from regulation of gene silencing prior to DNA repair. Proteins encoded by members of a gene family SIR demonstrate conservation of sequence in the core domain of 250 amino acids. Well-studied gene in this family is S. cerevisiae SIR2, which is involved in silencing of the locus HM, containing information that identifies the type of mating in yeast, the effects of the provisions of telomeres and senescence. Protein Sir2 in yeast belongs to the family of histone deacetylase. The homologue of Sir2, CobB, Salmonella typhimurium, performs the function ABOVE(NAD)(nicotinamide adenine dinucleotide)-dependent ADP-ribosyl transferase.

Protein Sir2 is deacetylase class III, which uses NAD as a substrate. Unlike other deacetylase, many of which are involved in the silencing of the gene, Sir2 is insensitive to inhibitors of histone dear tiles class I and II, such as trichostatin A (TSA).

The deacetylation of acetyl-lysine using Sir2 is closely associated with the hydrolysis OVER, producing nicotinamide and a new connection acetyl-ADP ribose. The activity of Sir2 in relation to OVER-dependent deacetylase is fundamental to its functions, which can bind to its biological role of cellular metabolism in yeast. The Sir2 homologues in mammals have activity against OVER-sensitive ristanovi deacetylase.

Biochemical studies have shown that Sir2 can easily deacetylate aminoterminal tails of histones H3 and H4, which leads to the formation of 1-O-acetyl-ADP-ribose and nicotinamide. Strains with extra copies of SIR2 is characterized by increased rDNA silencing and 30% longer life cycle. Recently it was shown that the extra copies of the SIR2 homologue in C. elegans, sir-2.1, and gene dSir2 D. melanogaster significantly increase the life span of these organisms. This suggests that SIR2-dependent regulatory pathway aging arose early in evolution and was highly conservative. Now consider that Sir2 genes appeared as a result of evolution with the aim of improving the health of the body and increase its resistance to stress, to increase its chance of survival in a hostile environment.

People have seven Sir2-like GE is s (SIRT1-SIRT7), which is divided between conservative catalytic domain of Sir2. SIRT1 is a nuclear protein with the highest degree of sequence similarity with Sir2. SIRT1 regulates by deacetylation a variety of cellular targets, including the tumor suppressor p53, factor NF-κB cell-signaling and transcription factor FOXO.

SIRT3 is a homologue SIRT1, which is conservative in prokaryotes and eukaryotes. SIRT3 protein targeted to the mitochondrial Krista using a unique domain located at the N-ends. SIRT3 is NAD+-dependent activity against protein deacetylase and everywhere expresses, in particular, in metabolically active tissues. Consider that when you transfer in the mitochondria, SIRT3 is split into smaller active form under the action of the mitochondrial matrix processorsa peptidases (MPP).

Caloric restriction is already known for more than 70 years as a way of improving health and increasing the life span of mammals. The lifespan of yeast, such as multicellular organisms, also increases as a result of interventions that are reminiscent of caloric restriction, such as lowering glucose. The discovery of the fact that yeast and flies to lack the gene SIR2 not live longer when restricting calories is docusates is in, that SIR2 genes are intermediates for the beneficial effect of a diet with caloric restriction on health. In addition, mutations that reduce the activity sensitive to glucose camp (adenosine 3',5'-monophosphate) - dependent (PKA) pathway of yeast, increase lifespan in wild-type cells but not in mutant strains of sir2, thus demonstrating that SIR2 is, apparently, the key following the path component of caloric restriction.

The INVENTION

The invention offers a new modulating sirtuin compounds and methods of their use.

In one aspect the invention provides modulating sirtuin compounds of structural formulas (I)-(IV), which are described in detail below.

In another aspect, the invention provides methods for applying modulating sirtuin compounds or compositions comprising modulating sirtuin connection. In specific embodiments, the implementation of modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used for a variety of therapeutic goals, including, for example, the increased life expectancy of the cell, and treating and/or preventing a wide range of diseases and disorders including, for example, diseases and disorders related to aging or stress, diabetes, obesity, n is rodegenerative disease, caused chemotherapy neuropathy, neuropathy associated with the phenomenon of ischemia, ocular diseases and/or disorders, cardiovascular disease, clotting disorders, inflammation, and/or hyperemia, and so on. Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be used to treat diseases or disorders in a patient, whose therapeutic effect is achieved through increased mitochondrial activity, to increase muscle activity, to increase the level of ATP in the muscles, or for treating or preventing muscle tissue damage associated with hypoxia or ischemia. In other embodiments, implementation of the modulating sirtuin compounds that decrease the level and/or activity of the protein of sirtuin, can be used for a variety of therapeutic goals, including, for example, increasing the sensitivity of cells to stress, increased apoptosis, treatment of cancer, stimulation of appetite and/or stimulation of weight gain, and so on. Described additionally below, the methods include the administration to the patient, if desired pharmaceutically effective amount of the modulating sirtuin connection.

In a particular aspect of modulating sirtuin compounds may be introduced themselves sludge is used in combination with other compounds, including other modulating sirtuin compounds, or other therapeutic agent.

DETAILED description of the INVENTION

1. Definition

Used in the description the following terms and phrases have the following values. If not specified otherwise, all the technical and scientific terms have the meanings conventional to a person skilled in this field.

The term "tool" used in the description to refer to chemical compounds, mixtures of chemical compounds, biological macromolecules, such as nucleic acid, antibody, protein, or portion thereof, e.g., a peptide) or extract derived from biological materials such as bacteria, plants, fungi, or cell or tissue of animals (particularly mammals). The activity of such tools allows you to use them as a "therapeutic agent", which is a biologically, physiologically, or pharmacologically active substance (or substances)that acts locally or systemically to the patient.

The term "bioavailable" in the connection is the definition adopted in the art, and refers to a form of connection that allows him or part of the input quantity of the compound to be absorbed, incorporated or otherwise physiologically available for the subject or patient, which egovedet.

"Biologically active portion of sirtuin" refers to the part of the protein of sirtuin having biological activity, such as the ability to deacetylation. Biologically active part of sirtuin may include nuclear domain of sirtuins. Biologically active part of SIRT1, deposited as GenBank Accession No. NP_036370 (room Deposit NP_036370 in GenBank), which cover the NAD+ binding domain and the substrate-binding domain, for example, may include, without limitation, amino acids 62-293 deposited as GenBank Accession No. NP_036370, which is encoded by nucleotides 237-932 deposited as GenBank Accession No. NM_012238. Therefore, this field is sometimes referred to as nuclear domain. Other biologically active part of SIRT1, also often referred to nuclear domains, include the region of amino acids 261-447 deposited as GenBank Accession No. NP_036370, which is encoded by nucleotides 834-1394 deposited as GenBank Accession No. NM_012238; the region of amino acids 242-493 deposited as GenBank Accession No. NP_036370, which is encoded by nucleotides 777-1532 deposited as GenBank Accession No. NM_012238; or amino acids 254-495 deposited as GenBank Accession No. NP_036370, which is encoded by nucleotides 813-1538 deposited as GenBank Accession No. NM_012238.

The term "pet" refers to cats and dogs. Used in the description of the term "dog(s)" means any member of the species Canis amiliaris (Dog home), belongs to a large number of different breeds. The term "cat(s)" refers to an animal of the cat family, including domestic cats and other members of the family Felidae (Cat), the genus Felis (Cats).

The term "diabetes" refers to high blood sugar or ketoacidosis, as well as chronic, General metabolic abnormalities resulting from a prolonged state of high blood sugar or reduced glucose tolerance. "Diabetes" encompasses both the form of the disease type I and type II (non-insulin-dependent diabetes mellitus or NIDDM). The risk factors for diabetes include the following factors: waist size over 40 inches (101.6 cm) for men, or 35 inches (88.9 cm) for women, blood pressure of 130/85 mm Hg or higher, triglycerides above 150 mg/deciliter, the content of the fasting blood glucose over 100 mg/deciliter or the content of high density lipoprotein less than 40 mg/deciliter in men or 50 mg/deciliter in women.

The term "ED50" refers to a generally accepted indicator of the effective dose. In specific embodiments, the implementation of the ED50means the dose of the drug that causes 50% of its maximum response or effect, or, alternatively, the dose that causes a given response in 50% of subjects the subject of the offering or in the case of 50% of the test drugs. The term "LD50" refers to a generally accepted indicator of a lethal dose. In specific embodiments, the implementation LD50means the dose of the drug that causes death in 50% of the test subjects. The term "therapeutic index" is a common term that refers to therapeutic index of the drug, defined as the ratio LD50/ED50.

The term "hyperinsulinemia" refers to the human condition, at which the level of insulin in the blood is higher than normal.

The term "insulin resistance" refers to the condition in which normal amounts of insulin causes inadequate response biological response compared with the response biological response in the subject that does not have insulin resistance.

Discussed in the description of "insulin resistant state" refers to any disease or condition which is caused by insulin resistance or which contributes to insulin resistance. Examples include diabetes, obesity, metabolic syndrome, syndrome of insulin resistance, syndrome X, insulin resistance, high blood pressure, hypertension, elevated levels of blood cholesterol, dyslipidemia, hyperlipidemia, atherosclerotic disease, including stroke, disease of oronary artery or myocardial infarction, hyperglycemia, hyperinsulinemia and/or hyperproinsulinemia, impaired glucose tolerance, delayed insulin secretion, diabetes complications, including coronary heart disease, angina, congestive heart failure, stroke, cognitive functions in dementia, retinopathy, peripheral neuropathy, nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis some types of cancer (such as endometrial, breast, prostate and colon), complications of pregnancy, poor female reproductive health (such as menstrual irregularities, infertility, irregular ovulation, polycystic ovary syndrome (PCOS)), lipodystrophy associated with cholesterol disorders, such as stones, gallbladder, cholecystitis and cholelithiasis, gout, obstructive sleep apnea and respiratory problems, osteoarthritis, and bone loss, such as, in particular, osteoporosis.

The term "livestock" refers to domesticated four-legged animals, which includes animals bred for meat and various byproducts, such as a ruminant, including cattle and other representatives of the genus Bos (These bulls), pig-like animal, including domestic pig and other representatives of the oil of the genus Sus (Pig), acceptanoe animal, including sheep and other representatives of the genus Ovis (sheep), domestic goats and other members of the genus Capra (goats); domesticated four-legged animals bred for special purposes, such as use as a pack animal such as a horse, including domestic horses and other members of the family Equidae (Horses) of the genus Equus (Horse).

The term "mammal" is a well-known term, and examples of mammals include humans, primates, livestock (including cows, pigs and so on), domestic animals (e.g. dogs, cats, and so on) and rodents (e.g. mice and rats).

"Full" individuals or individuals suffering from obesity, are usually individuals with a body mass index (BMI)of at least 25 or more. Obesity may be due or may not be associated with insulin resistance.

The terms "parenteral administration" and "parenteral introduced are common and are a way of introduction, different from enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, vnutrikapilliarnuu, intraorbitally, intracardially, intradermal, intraperitoneally, transtracheal, subcutaneous, Podkolokolny, NR is chrysostomou, pagkapanalo, subarachnoid, intraspinal and epigastric injection and infusion.

The term "patient", "subject", "individual" or "host" refers to either the person or do not belong to the human race animal.

The term "pharmaceutically acceptable carrier" is commonly used and refers to a pharmaceutically acceptable material, composition or environment, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in the transfer or transportation of any discussion of the composition or its components. Each carrier must be "acceptable" from the point of view of its compatibility with discuss composition and its components, and must not be dangerous for the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include : (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) the powder tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) auxiliary tools, such as cocoa butter and waxes for suppositories; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame Mac is on, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as etiloleat and tillaart; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic solution; (18) ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions and (21) other non-toxic compatible substances used in pharmaceutical preparations.

The term "prevention" is widely used in medicine, and when it is used in relation to the state, such as a local recurrence (e.g., pain), a disease such as cancer, complex syndromes, such as heart failure or any other medical condition, the value of this term is quite obvious, and it includes the introduction of a composition which reduces the frequency of, or delays the onset of symptoms of a clinical condition in a subject compared to a subject who does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable malignant tumors in the group of patients receiving prophylactic treatment compared to no treatment control group, and/or delay the occurrence of the detected slocate is to develop tumors in the group of patients being treated, in comparison with a control group of patients not undergoing treatment, for example, statistically and/or clinically significant amount. Prevention of infectious diseases include, for example, reducing the number of diagnoses of infectious diseases in the group of patients under treatment, in comparison with a control group of patients not undergoing treatment, and/or delay the onset of symptoms of communicable diseases in the group of patients under treatment, in comparison with a control group of patients not undergoing treatment. Prevention of pain includes, for example, reduction in force or, alternatively, delaying the pain experienced by patients in the group exposed to the treatment, in comparison with a control group of patients not undergoing treatment.

The term "prophylactic" or "therapeutic" treatment is a common and refers to the administration of a medicinal product in the host organism. If it is administered prior to clinical detection of an undesirable condition (e.g., disease or other unwanted state of an animal host), then the treatment is prophylactic, that is, it protects the host organism against developing the unwanted condition, but if it is introduced after the discovery of the undesirable condition, the treatment is terapeuticas is m (i.e., it aims to facilitate, improve or preserve the existing undesirable condition or side effects).

The term "pyrogen-free"composition refers to a composition that does not contain pyrogenic substance in a quantity that may cause the entity to which introduced the song, adverse effects (e.g., irritation, fever, inflammation, diarrhea, respiratory depression, endotoxic shock, and so on). For example, it is understood that this term encompasses compositions that do not contain, or contain virtually no, endotoxin, such as, for example, lipopolysaccharide (LPS).

"Replicative lifespan" of cells refers to the number of daughter cells produced individual "parent cell". On the other hand, "calendar age" and "calendar life expectancy" refers to the period of time during which the population of non-dividing cells remains viable in the absence of nutrients. "The increase in life expectancy cells" or "extension of the life span of cells," as applied to cells or organisms refers to the increase in the number of daughter cells produced by a single cell, improving the ability of cells or organisms to cope with stress and deal with injuries, for example, in the case of DNA, proteins; is/or enhancing the ability of cells or organisms to survive and to maintain all vital functions for a longer time when a specific condition, for example, under stress (e.g. heat shock, osmotic stress, high-energy radiation, stress caused by chemical substance, DNA damage, insufficient salt level, insufficient nitrogen or insufficient power). In the application described in the description of how the lifetime can be increased, at least about 10%, 20%, 30%, 40%, 50%, 60% or from 20% to 70%, from 30% to 60%, from 40% to 60% or more.

"Activating sirtuin connection" refers to a compound that increases the level of protein sirtuin and/or at least only increases the activity of the protein of sirtuin. In the example case for activating sirtuin connection may increase, at least, only the biological activity of the protein of sirtuin, at least about 10%, 25%, 50%, 75%, 100% or more. Examples of biological activity of proteins sirtuin include deacetylation, e.g., histones and p53; increased life expectancy; increased genomic stability; silencing transcription; and controlling segregation of oxidized proteins between mother and daughter cells.

"Protein sirtuin" refers to the representative of the family certainly protein deacetylase, or, preferably, to the sir2 family, which includes proteins Sir2 in yeast (GenBank Accession No. P53685),C. elegansSir-2.1 (GenBank Accession No. NP_501912), and lowecase SIRT1 (GenBank Accession No. NM_012238 and NP_036370 (or AF083106)) and SIRT2 (GenBank Accession No. NM_012237, NM_030593, NP_036369, NP_085096 and AF083107). Other members of the family include four additional similar to Sir2 genes of yeast, called "HST genes (homologues of Sir2) HST1, HST2, HST3 and HST4, and five other human homologue hSIRT3, hSIRT4, hSIRT5, hSIRT6 and hSIRT7 (Brachmann et al. (1995) Genes Dev. 9:2888 and Frye et al. (1999) BBRC 260:273). Preferred are sirtuins as well sirtuins as well that have more similarities with SIRT1, that is, hSIRT1, and/or Sir2 than with SIRT2, such as representatives of sirtuins, which have at least part of the N-terminal sequence present in SIRT1 and missing in SIRT2, such as SIRT3.

"SIRT1 protein" refers to the representative of the sir2 family of sirtuins deacetylase. In one embodiment, the protein SIRT1 includes yeast Sir2 (GenBank Accession No. P53685), C. elegans Sir-2.1 (GenBank Accession No. NP_501912), human SIRT1 (GenBank Accession No. NM_012238 or NP_036370 (or AF083106)), and its functional equivalents and fragments. In another embodiment, SIRT1 protein includes a polypeptide containing a sequence consisting of or mainly consisting of the amino acid sequence deposited as GenBank Accession Nos. NP_036370, NP_501912, NP_085096, NP_036369 or P53685. Proteins SIRT1 include polypeptides that contain all or part of the amino acid sequence deposited as GenBank Accession Nos. NP_036370, NP_501912, NP_085096, NP_036369 or P53685; the amino acid sequence deposited as enBank Accession Nos. NP_036370, NP_501912, NP_085096, NP_036369 or P53685, conservative substitution of amino acids in position 1 to about 2, 3, 5, 7, 10, 15, 20, 30, 50, 75 or more; an amino acid sequence that is at least on 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the deposited GenBank Accession Nos. NP_036370, NP_501912, NP_085096, NP_036369 or P53685, and their functional fragments. The polypeptides of the invention also include homologs (for example, orthologues and paralogy), variants, or fragments, deposited as GenBank Accession Nos. NP_036370, NP_501912, NP_085096, NP_036369 or P53685.

Used in the description "SIRT2 protein", "protein SIRT3", "SIRT4 protein", "protein SIRT 5", "protein SIRT6 and SIRT7 protein" refer to other proteins of the sirtuins as well deacetylase mammal, such as man, which are the homologues of the protein SIRT1, particularly in conservative catalytic domain of about 275 amino acids. For example, "SIRT3 protein " refers to the representative of the protein family of sirtuins deacetylase, which is a homolog of the protein SIRT1. In one embodiment, the protein includes a human SIRT3 SIRT3 (GenBank Accession No. AAH01042, NP_036371 or NP_001017524) or murine SIRT3 (GenBank Accession No. NP_071878) proteins and its functional equivalents and fragments. In another embodiment, SIRT3 protein includes a polypeptide containing a sequence consisting of or mainly consisting of the amino acid sequence deposited as GenBank Accession Nos. AAH01042, NP_036371, NP_00017524 or NP_071878. SIRT3 proteins include polypeptides that contain all or part of the amino acid sequence deposited as GenBank Accession AAH01042, NP_036371, NP_001017524 or NP_071878; the amino acid sequence deposited as GenBank Accession Nos. AAH01042, NP_036371, NP_001017524 or NP_071878, conservative substitution of amino acids in position 1 to about 2, 3, 5, 7, 10, 15, 20, 30, 50, 75 or more; an amino acid sequence that is at least on 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the deposited GenBank Accession Nos. AAH01042, NP_036371, NP_001017524 or NP_071878, and their functional fragments. The polypeptides of the invention also include homologs (for example, orthologues and paralogy), variants or fragments deposited as GenBank Accession Nos. AAH01042, NP_036371, NP_001017524 or NP_071878. In one embodiment, SIRT3 protein includes a fragment of SIRT3 protein, which is produced from the decomposition of using mitochondrial matrix peptidases processing (MPP) and/or mitochondrial intermediate peptidases (MIP).

The terms "system introduction, injected systemically", "peripheral introduction" and "peripheral input" are common and relate to the introduction discussed the composition, therapeutic or other material, but not directly into the Central nervous system, resulting in a composition, therapeutic or other material included in the system of the patient undergoes IU is abolism and other similar processes.

The term "therapeutic agent" is commonly used and refers to any chemical fragment that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject. The term also refers to any substance that is estimated for use to diagnose, cure, mitigate, treat, cure, or prevent disease or to enhance the desirable physical or mental development and/or condition of the animal or human.

The term "therapeutic effect" is commonly used and refers to a local or systemic effect in animals, particularly mammals, and more specifically, to people caused by pharmacologically active substance. The phrase "therapeutically active amount" means the amount of such substance that causes some desired local or systemic effect at a reasonable relation to the benefit/risk used in any type of treatment. A therapeutically effective amount of such a substance may depend on the subject and painful condition being treated, the weight and age of the subject, the severity of the disease condition, the method of administration and other such factors that can be easily determined by conventional expert in this area. For example, as described in the description of the concrete is e composition can be introduced in sufficient quantity to achieve the desired effect at an acceptable ratio of benefit/risk, used to such treatment.

"Treatment" of a condition or disease is to be cured, and to the relief of at least one symptom of a condition or disease.

The term "visual impairment" refers to vision impairment, which is often only partially can be restored or not restored in the treatment (for example, when the surgical treatment). Particularly severe visual impairment describe the terms "blindness or vision loss, which belong to a complete loss of vision, that is, the vision is worse than 20/200, which cannot be improved with corrective lenses, or visual field less than 20 degrees, on the basis of diameter (10 degrees based on the radius).

2. Modulators of sirtuin

In one aspect, the invention provides new modulating sirtuin compounds for the treatment and/or prevention of a wide range of diseases and disorders including, for example, diseases and disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, ocular diseases and disorders, cardiovascular disease, clotting disorders, inflammation, cancer, and/or hyperemia, and so on. Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be used to treat diseases or destroy the tion of the patient, whose therapeutic effect is achieved through increased mitochondrial activity, to increase muscle activity, to increase the level of ATP in the muscles or for treating or preventing muscle tissue damage associated with hypoxia or ischemia. Other disclosed in the description of the compounds may be used in pharmaceutical compositions and/or one or more disclosed in the description of the methods.

In one embodiment, modulating sirtuin compounds of the invention are represented by structural formula (I):

or its salt, where

each of the Z1, Z2and Z3independently selected from N and CR, where

not more than one of the Z1, Z2and Z3is N; and

R is chosen from hydrogen, halogen, -OH, -C≡N, fluoro-substituted C1-C2of alkyl, -O-(C1-C2) fluoro-substituted alkyl, -S-(C1-C2) fluoro-substituted alkyl, C1-C4of alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) alkyl and C3-C7cycloalkyl;

---- represents an optional chemical bond,

W1selected from-O-, -NH - or-N=, so that when W1is-N=, W1associated with C(R2through a double chemical bond,

W2is-CR4=when W1is-NH - or-O-, so that when W2is-CR4=, Wsup> 2associated with C(R2through a double chemical bond; and W2is-NR4-when W1is-N=;

R1choose from carbocycle and heterocycle, where R1optionally substituted by one or two substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, =O, C3-C7cycloalkyl, fluoro-substituted C1-C4of alkyl, -O-R3, -S-R3, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4alkyl)-N(R3)(R3), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(R3and -(C1-C4alkyl)-C(O)-N(R3)(R3), and when R1is phenyl, R1also optionally substituted 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluoro-substituted 3,4-Ethylenedioxy, where

each R3independently selected from hydrogen and-C1-C4of alkyl; or two R3together with the nitrogen atom to which they are attached, form a 4-8-membered saturated a heterocycle, optionally containing one additional hetero-atomic fragment selected from NH, S, S(=O), S(=O)2and O, where alkyl optionally substituted by one or more-OH, fluorine, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -NH(CH2CH2OCH3or-N(CH2CH2OCH3 )2and rich heterocycle optionally substituted on the carbon atom of-OH, -C1-C4the alkyl, fluorine, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -NH(CH2CH2OCH3), or-N(CH2CH2OCH3)2;

R2choose from carbocycle and heterocycle, where R2optionally substituted by one or two substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, C3-C7cycloalkyl, C1-C2fluoro-substituted alkyl, -O-R3, -S-R3, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4alkyl)-N(R3)(R3), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(R3), -(C1-C4alkyl)-C(O)-N(R3)(R3), -O-phenyl, phenyl, and a second heterocycle, and when R2is phenyl, R2may also be optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluoro-substituted 3,4-Ethylenedioxy where any phenyl or second heterocyclic Deputy in R2optionally substituted with halogen; -C≡N; C1-C4the alkyl, fluoro-substituted C1-C2by alkyl, -O-(C1-C2) fluoro-substituted by alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) alkyl, -S-(C1-C2) tizamidine-alkyl, -NH-(C1-C4) alkyl and-N-(C1-C4)2- alkyl;

R4selected from hydrogen, C1-C4of alkyl, C1-C4fluoro-substituted alkyl, C1-C4alkyl-N(R7)(R7), C1-C4alkyl-C(O)-N(R7)(R7), C1-C4alkyl-O-R7and C1-C4alkyl-NR7-C(O)R7where each R7independently selected from hydrogen and C1-C4of alkyl;

X is chosen from-NH-C(=O)-†, -C(=O)-NH-†, -NH-C(=S)-†, -C(=S)-NH-†, -NH-S(=O)-†, -S(=O)-NH-†, -S(=O)2-NH-†, -NH-S(=O)2-†, -NH-S(O)2-NR5-†, -NR5-S(O)2-NH-†, -NH-C(=O)O-†, -OC(=O)NH-†, -NH-C(=O)NR5-†, -NR5-C(=O)NH-†, -NH-NR5-†, -NR5-NH-†, -O-NH-†, -NH-O-†, -NH-CR5R6-†, -CR5R6-NH-†, -NH-C(=NR5)-†, -C(=NR5)-NH-†, -C(=O)-NH-CR5R6-†, -CR5R6-NH-C(O)-†, -NH-C(=S)-CR5R6-†, -CR5R6-C(=S)-NH-†, -NH-S(O)-CR5R6-†, -CR5R6-S(O)-NH-†, -NH-S(O)2-CR5R6-†, -CR5R6-S(O)2-NH-†, -NH-C(=O)-O-CR5R6-†, -CR5R6-O-C(=O)-NH-†, -NH-C(=O)-NR5-CR5R6- † ,- CR5R6-NH-C(=O)-O-†, where

† indicates the place in which X is connected with R1; and

each R5and R6independently selected from hydrogen, C1-C4of alkyl, -CF3and (C1-C3alkyl)-CF3.

In specific embodiments, with the organisations of structural formula (I) are characterized by one or more of the following characteristics:

when each of the Z1, Z2and Z3is CR; W1is-O-, W2is-C=, R4is H; and X is-NH-CR5R6-† or-CR5R6-NH-†, then R2is optionally substituted pyridin-4-yl or unsubstituted morpholine-4-yl;

when each of the Z1, Z2and Z3is CH; W1is-O-; W2is-C=; R4is H or C1-C4by alkyl; R2is phenyl; and X is-C(=O)-NH-†, then R1is not 1H-benzimidazole-2-yl, 2,3-dihydro-2-oxo-1H-benzimidazole-5-yl, 4-methylpiperazin-1-yl, 6-(morpholine-4-yl)pyridine-3-yl, 5-(morpholine-4-yl)isoquinoline-8-yl, 5-chloro-2-(4-methyl-1-piperazinil) - phenyl, 7-fluoro-3,4-dihydro-4-oxo-6-hinazolinam, 1-methyl-1H-pyrazole-3-yl, 1H-pyrazole-3-yl, tetrazol-5-yl, 5-(1-methylethyl)-1,3,4-thiadiazole-2-yl, 5-(ethylthio)-1,3,4-thiadiazole-2-yl, 5-ethyl-1,3,4-thiadiazole-2-yl or 4-(pyrrolidin-1-ylmethyl)thiazol-2-yl;

when each of the Z1, Z2and Z3is CH; W1is-O-; W2is-C=; R4is H or C1-C4by alkyl; R2is phenyl; and X is-C(=O)-NH-†, then R1is not tetrazol-5-yl.

In specific embodiments, the implementation of the compound of structural formula (I) represented by the following structure:

In spiral the different variants of implementation of each of the Z 1, Z2and Z3independently represent CR. In specific embodiments, the implementation of one of the Z1, Z2or Z3is N, for example, Z1is N, or Z2is N, or Z3is N. In some of these embodiments, R is H, so in particular embodiments, the implementation of each of the Z1and Z2are-CH-, each Z1and Z3are-CH-, each Z2and Z3are-CH-, or Z1, Z2and Z3are-CH-.

In specific embodiments, the implementation of R is chosen from hydrogen, -(C1-C4) alkyl-N(R7)(R7), -(C1-C4) alkyl-C(O)-N(R7)(R7), -(C2-C4) alkyl-O-R7and -(C2-C4) alkyl-N(R7)-C(O)-R7. In specific embodiments, the implementation of R is hydrogen.

In specific embodiments, the implementation of the W1selected from-O-, -NH-, or-N=.

In specific embodiments, the implementation of the W2selected from-NR4or CR4=. In other embodiments, implementation, when W1is-N=, then W2selected from-NR4- and-CR4=. In specific embodiments, implementation, when W1is-O-, W2is-CR4=. In specific embodiments, implementation, when W1is-NH-, W2selected from-NR4- and-CR4=.

In specific embodiments, domestic the compound of structural formula (I) represented by the following structure:

In specific embodiments, the implementation, the compound of structural formula (I) represented by the following structure:

In specific embodiments, the implementation of R4selected from hydrogen, -C≡N, C1-C4the alkyl and fluoro-substituted C1-C4the alkyl. In specific embodiments, the implementation of R4is hydrogen. In specific embodiments, the implementation, where W1is-O - and W2is-CR4=, R4is hydrogen. In specific embodiments, implementation, when Z1, Z2and Z3are-CR-, R4is hydrogen.

In specific embodiments, the realization of X is-NH-C(=O) -†, or-C(=O)-NH-†. In specific embodiments, the realization of X is-NH-C(=O)-†. In the variant example of implementation, X is-NH-C(=O)-†, Z1, Z2and Z3are CR, and R and R4both are H. In specific embodiments, the implementation of the W1is-O - and W2is-CR4=, Z1, Z2and Z3all are CR, R and R4both are H and X is-NH-C(=O)-†.

In specific embodiments, the implementation of the compound of structural formula (I) represented by the following structure:

In specific embodiments, the implementation of R1choose from heterocycles (for example, heteroaryl), including the affected one or more heteroatoms, selected from N, O and S. In specific embodiments, the implementation of R1choose from heterocycles (for example, heteroaryl)comprising one or two nitrogen atom. In specific embodiments, the implementation of R1choose from heterocycles (for example, heteroaryl), comprising up to three heteroatoms selected from S and N. In other embodiments, implementation of R1choose from heterocycles (for example, heteroaryl), comprising up to three heteroatoms, selected from O and N.

Examples R1include

In specific such embodiments, the implementation of R1choose from

In the above embodiments, the implementation of R1optionally substituted by 1 or 2 substituents, independently selected from halogen, (C1-C4) alkyl and =O. In specific embodiments, the implementation of R1is thiazole or pyrazino, optionally substituted by one or more substituents selected from halogen and (C1-C4) alkyl. In specific embodiments, the implementation of R1is optionally substituted thiazole. In other embodiments, implementation of R1is optionally substituted by pyrazino, and X is-NH-C(=O)-†.

In specific embodiments, the implementation of R2is selected from aryl and heteros is aryl. In specific embodiments, the implementation of R2optionally substituted by one or two substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, C1-C2fluoro-substituted alkyl, -OR8where R8is alkyl, optionally substituted by one or more halogen substituents. In specific embodiments, the implementation of R2is phenyl, optionally substituted by one or more substituents selected from-Cl, -Br, -F, -C≡N, -CF3and-OCF3.

Typical examples R2include

In specific embodiments, the implementation of R2is meta-substituted relative to the place of attachment of R2to the rest of the connection, and where R2optional optionally substituted as described above. In specific embodiments, the implementation of R2choose from

In specific embodiments, the implementation of the Z1, Z2and Z3each independently selected from CR, W1selected from-O-, -N= and-N, W2is-CR4= or-NR4-, X is-NH-C(=O)-†, R1is optionally substituted thiazole or pyrazole and R2is optionally substituted by phenyl. In particular, the var is the ants implementation R is H.

In specific embodiments, the implementation of modulating sirtuin compounds of the invention are represented by structural formula (I)

or its salt, where W1, W2, R1, R4, Z1, Z2and Z3previously defined, and

---- represents an optional chemical bond,

R2choose from carbocycle and heterocycle, where R2optionally substituted by one or two substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, C3-C7cycloalkyl, C1-C2fluoro-substituted alkyl, -O-R3, -S-R3, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4alkyl)-N(R3)(R3), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(R3), -(C1-C4alkyl)-C(O)-N(R3)(R3), -O-phenyl, phenyl, and a second heterocycle, and when R2is phenyl, R2substituted by at least one Deputy, such as halogen, -C≡N, C1-C4alkyl, C3-C7cycloalkyl, C1-C2fluoro-substituted alkyl, -O-R3, -S-R3, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4alkyl)-N(R3)(R3), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(Rsup> 3), -(C1-C4alkyl)-C(O)-N(R3)(R3), -O-phenyl, phenyl, and a second heterocycle, 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluoro-substituted 3,4-Ethylenedioxy where any phenyl or second heterocyclic Deputy in R2optionally substituted with halogen, -C≡N, C1-C4the alkyl, fluoro-substituted C1-C2by alkyl, -O-(C1-C2) fluoro-substituted by alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) alkyl, -S-(C1-C2) fluoro-substituted by alkyl, -NH-(C1-C4) alkyl and-N-(C1-C4)2by alkyl;

X is chosen from-NH-C(=O)-†, -C(=O)-NH-†, -NH-C(=S)-†, -C(=S)-NH-†, -NH-S(=O)-†, -S(=O)-NH-†, -S(=O)2-NH-†, -NH-S(=O)2-†, -NH-S(O)2-NR5-†, -NR5-S(O)2-NH-†, -NH-C(=O)O-†, -OC(=O)NH-†, -NH-C(=O)NR5-†, -NR5-C(=O)NH-†, -NH-NR5-†, -NR5-NH-†, -O-NH-†, -NH-O-†, -NH-C(=NR5)-†, -C(=NR5)-NH-†, -C(=O)-NH-CR5R6-†, -CR5R6-NH-C(O)-†, -NH-C(=S)-CR5R6-†, -CR5R6-C(=S)-NH-†, -NH-S(O)-CR5R6-†, -CR5R6-S(O)-NH-†, -NH-S(O)2-CR5R6-†, -CR5R6-S(O)2-NH-†, -NH-C(=O)-O-CR5R6-†, -CR5R6-O-C(=O)-NH-†, -NH-C(=O)-NR5-CR5R6- †- CR5R6-O-C(=O)-NH-†, where

† indicates the place in which X is connected with R1; and

each R5and R6independently selected from hydrogen is, C1-C4of alkyl, -CF3and (C1-C3alkyl)-CF3.

In another embodiment, compounds of the invention are represented by structural formula (II):

or its salt, where

each R20independently selected from hydrogen, halogen, -C≡N, fluoro-substituted C1-C2of alkyl, -O-(C1-C2) fluoro-substituted alkyl, -S-(C1-C2) fluoro-substituted alkyl, C1-C4of alkyl, -S-(C1-C4) alkyl, C3-C7cycloalkyl, -(C1-C2) alkyl-N(R13)(R13), -O-CH2CH(OH)CH2OH, -O-(C1-C3) alkyl-N(R13)(R13and-N(R13)(R13);

R11choose from carbocycle and heterocycle, where R11optionally substituted by one or two substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, =O, C3-C7cycloalkyl, fluoro-substituted C1-C4of alkyl, -O-R13, -S-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), -O-(C1-C4alkyl)-N(R13)(R13), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R13)(R13), -C(O)-N(R13)(R13and -(C1-C4alkyl)-C(O)-N(R13)(R13), and when R11is phenyl, R11also optionally substituted 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedi the si, 3,4-Ethylenedioxy, fluoro-substituted 3,4-Ethylenedioxy, O-(saturated heterocycle), fluoro-substituted-O-(saturated heterocycle), or C1-C4alkyl substituted-O-(saturated heterocycle), where

each R13independently selected from hydrogen and-C1-C4of alkyl; or

two R13together with the nitrogen atom to which they are attached, form a 4-8-membered saturated a heterocycle, optionally containing one additional hetero-atomic fragment selected from NH, S, S(=O), S(=O)2and O, where

when R13is alkyl, alkyl optionally substituted by one or more substituents selected from-OH, fluorine, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -NH(CH2CH2OCH3and-N(CH2CH2OCH3)2and

when two R13together with the nitrogen atom to which they are attached, form a 4-8-membered saturated the heterocycle, saturated, a heterocycle optionally substituted on any carbon atom of-OH, -C1-C4the alkyl, fluorine, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -NH(CH2CH2OCH3or-N(CH2CH2OCH3)2and optionally substituted on any capable of substitution of the nitrogen atom-C1-C4the alkyl, fluoro-substituted C1-C4the alkyl or -(CH2)2-O-CH3;

R12 choose from carbocycle and heterocycle, which is not necessarily replaced by tetrazolium, where R12optionally substituted by one or more substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, C3-C7cycloalkyl, C1-C2fluoro-substituted alkyl, -O-R13, -S-R13, -S(O)-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), -O-(C1-C4alkyl)-N(R13)(R13), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R13)(R13), -C(O)-N(R13)(R13), -(C1-C4alkyl)-C(O)-N(R13)(R13), -O-phenyl, phenyl, and a second heterocycle, and when R12is phenyl, R12may also be optionally substituted 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy, or fluoro-substituted 3,4-Ethylenedioxy or-O-(substituted heterocycle), where any phenyl, second heterocycle or part from a saturated heterocycle, R12optionally substituted with halogen, -C≡N, C1-C4the alkyl, fluoro-substituted C1-C2by alkyl, -O-(C1-C2) fluoro-substituted by alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) alkyl, -S-(C1-C2) fluoro-substituted by alkyl, -NH-(C1-C4) alkyl and-N-(C1-C4)2by alkyl;

R14choose from Fodor is Yes, C1-C4of alkyl, C1-C4fluoro-substituted alkyl, C1-C4alkyl-N(R13)(R13), C1-C4alkyl-C(O)-N(R13)(R13), C1-C4alkyl-O-R13and C1-C4alkyl-NR13-C(O)R13; and

X1selected from-NH-C(=O)-†, -C(=O)-NH-†, -NH-C(=S)-†, -C(=S)-NH-†, -NH-S(=O)-†, -S(=O)-NH-†, -S(=O)2-NH-†, -NH-S(=O)2-†, -NH-S(O)2-NR15-†, -NR15-S(O)2-NH-†, -NH-C(=O)O-†, -OC(=O)NH-†, -NH-C(=O)NR15-†, -NR15-C(=O)NH-†, -NH-NR15-†, -NR15-NH-†, -O-NH-†, -NH-O-†, -NH-CR15R16-†, -CR15R16-NH-†, -NH-C(=NR15)-†, -C(=NR15)-NH-†, -C(=O)-NH-CR15R16-†, -CR15R16-NH-C(O)-†, -NH-C(=S)-CR15R16-†, -CR15R16-C(=S)-NH-†, -NH-S(O)-CR15R16-†, -CR15R16-S(O)-NH-†, -NH-S(O)2-CR15R16-†, -CR15R16-S(O)2-NH-†, -NH-C(=O)-O-CR15R16-†, -CR15R16-O-C(=O)-NH-†, -NH-C(=O)-NR15-CR15R16-†, -NH-C(=O)-CR15R16- †- CR15R16-NH-C(=O)-O-†, where

† indicates the place in which X1connected to R11; and

each R15and R16independently selected from hydrogen, C1-C4of alkyl, -CF3and (C1-C3alkyl)-CF3.

In specific embodiments, the implementation of the compounds represented by structural formula (II)can be characterized using one or more of the following is x characteristics:

when R14is H; and X1is-NH-CR15R16-† or-CR15R16-NH-†, then R12is optionally substituted pyridin-4-yl, optionally substituted pyridin-3-yl or unsubstituted morpholine-4-yl;

when R14is H; R12is phenyl; and X1is-C(=O)-NH-†, then R11is not 1H-pyrazole-3-yl or tetrazol-5-yl;

when R14is C1-C4the alkyl, R12is not optionally substituted phenyl;

each R20independently selected from hydrogen, halogen, -C≡N, fluoro-substituted C1-C2of alkyl, -O-(C1-C2) fluoro-substituted alkyl, -S-(C1-C2) fluoro-substituted alkyl, C2-C4of alkyl, -S-(C1-C4) alkyl, C3-C7cycloalkyl, -(C1-C2) alkyl-N(R13)(R13), -O-CH2CH(OH)CH2OH, -O-(C1-C3) alkyl-N(R13)(R13and-N(R13)(R13);

each R15and R16independently selected from hydrogen, C2-C4of alkyl, -CF3and (C1-C3alkyl)-CF3;

R11is optionally substituted piperidine or optionally substituted pyrrolidino;

R12choose from carbocycle and heterocycle having from 1 to 3 heteroatoms;

R12choose from carbocycle and heterocycle, having the th from 0 to 3 nitrogen atoms;

R12connected to the rest of the molecule via a ring carbon atom;

R12optionally substituted by one or two substituents;

when R12is phenyl, R12substituted by at least one Deputy;

X1selected from-NH-C(=O)-†, -C(=O)-NH-†, -NH-C(=S)-†, -C(=S)-NH-†, -NH-S(=O)-†, -S(=O)-NH-†, -S(=O)2-NH-†, -NH-S(=O)2-†, -NH-S(O)2-NR15-†, -NR15-S(O)2-NH-†, -NH-C(=O)O-†, -OC(=O)NH-†, -NH-C(=O)NR15-†, -NR15-C(=O)NH-†, -NH-NR15-†, -NR15-NH-†, -O-NH-†, -NH-O-†, -NH-C(=NR15)-†, -C(=NR15)-NH-†, -C(=O)-NH-CR15R16-†, -CR15R16-NH-C(O)-†, -NH-C(=S)-CR15R16-†, -CR15R16-C(=S)-NH-†, -NH-S(O)-CR15R16-†, -CR15R16-S(O)-NH-†, -NH-S(O)2-CR15R16-†, -CR15R16-S(O)2-NH-†, -NH-C(=O)-O-CR15R16-†, -CR15R16-O-C(=O)-NH-†, -NH-C(=O)-NR15-CR15R16-†, -NH-C(=O)-CR15R16- †- CR15R16NH-C(=O)-O-†;

X1selected from-NH-C(O) -†, and-C(O)-NH-†;

X1is-NH-C(O)-†;

R11choose from

R11choose from

R11choose from

R11optionally substituted by one or two substituents independently selected from halogen, C1-C4of alkyl, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13and-O-R13;

R12choose from

R12choose from

R12choose from

R12optionally substituted by one or more groups independently selected from halogen, C1-C4of alkyl, -(C1-C4alkyl)-N(R13)(R13), C1-C2fluoro-substituted alkyl, -O-R13, -SO2-R13, -N(R13)(R13and-O-(C1-C4alkyl)-N(R13)(R13); and

R12optionally substituted by one or two groups.

In specific embodiments implementing the invention provides a compound of structural formula III:

or its salt, where

X2selected from-NH-C(=O)-†, -C(=O)-NH-†, -NH-C(=S)-†, -C(=S)-NH-†, -NH-S(=O)-†, -S(=O)-NH-†, -S(=O)2-NH-†, -NH-S(=O)2-†, -NH-S(O)2-NR15-†, -NR15-S(O)2-NH-†, -NH-C(=O)O-†, -OC(=O)NH-†, -NH-C(=O)NR15-†, -NR15-C(=O)NH-†, -NH-NR15-†, -NR15-NH-†, -O-NH-†, -NH-O-†, -NH-C(=NR15)-†, -C(=NR15)-NH-†, -C(=O)-NH-CR15R16-†, -CR15R16-NH-C(O)-†, -NH-C(=S)-CR15R16-†, -CR15R16-C(=S)-NH-†, -NH-S(O)-CR R16-†, -CR15R16-S(O)-NH-†, -NH-S(O)2-CR15R16-†, -CR15R16-S(O)2-NH-†, -NH-C(=O)-O-CR15R16-†, -CR15R16-O-C(=O)-NH-†, -NH-C(=O)-NR15-CR15R16-†, -NH-C(=O)-CR15R16- †- CR15R16NH-(C=O)-O-†;

R21choose from carbocycle and heterocycle, which is not 1H-pyrazole-3-yl or tetrazol-5-yl, where R21optionally substituted by one or two substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, =O, C3-C7cycloalkyl, fluoro-substituted C1-C4of alkyl, -O-R13, -S-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), -O-(C1-C4alkyl)-N(R13)(R13), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R13)(R13), -C(O)-N(R13)(R13and -(C1-C4alkyl)-C(O)-N(R13)(R13), and when R11is phenyl, R11also optionally substituted 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy, fluoro-substituted 3,4-Ethylenedioxy, O-(saturated heterocycle), fluoro-substituted-O-(saturated heterocycle), or C1-C4alkyl substituted O-(saturated heterocycle);

R24selected from hydrogen, C1-C4fluoro-substituted alkyl, C1-C4alkyl-N(R13)(R13), C1-C4alkyl-C(O)-N(R13 )(R13), C1-C4alkyl-O-R13and C1-C4alkyl-NR13-C(O)R13; and

each of R12, R13, R15, R16and R20"†" are defined as for the compounds of formula II.

In specific embodiments, the implementation of the compounds represented by structural formula (II)can be characterized using one or more of the following characteristics:

each R20independently selected from hydrogen, halogen, -C≡N, fluoro-substituted C1-C2of alkyl, -O-(C1-C2) fluoro-substituted alkyl, -S-(C1-C2) fluoro-substituted alkyl, C2-C4of alkyl, -S-(C1-C4) alkyl, C3-C7cycloalkyl, -(C1-C2) alkyl-N(R13)(R13), -O-CH2CH(OH)CH2OH, -O-(C1-C3) alkyl-N(R13)(R13and-N(R13)(R13);

each R15and R16independently selected from hydrogen, C2-C4of alkyl, -CF3and (C1-C3alkyl)-CF3;

R12connected to the rest of the molecule via a ring carbon atom; and

R12choose from carbocycle and heterocycle having from 1 to 3 heteroatoms;

R12choose from carbocycle and heterocycle having from 0 to 3 nitrogen atoms;

R12optionally substituted by one or two substituents;

when R12is phenyl, R12/sup> substituted by at least one Deputy;

R21choose from carbocycle and heterocycle having 0, 1 or 3 nitrogen atom;

R21choose from carbocycle and heterocycle with the number of members 6 or 7, having 0-4 nitrogen atoms;

R21is optionally substituted piperidine or optionally substituted pyrrolidino;

X2selected from-NH-C(O) -†, and-C(O)-NH-†;

X2is-NH-C(O)-†;

R21choose from

R21choose from

R21choose from

R21optionally substituted by one or two substituents, independently selected from halogen, C1-C4of alkyl, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13and-O-R13;

R12choose from

R12choose from

R12choose from

R12optionally substituted by one or more groups independently selected from halogen, C1-C4of alkyl, -(C1-C4alkyl)-(R 13)(R13), C1-C2fluoro-substituted alkyl, -O-R13, -SO2-R13, -N(R13)(R13and-O-(C1-C4alkyl)-N(R13)(R13); and

R12optionally substituted by one or two groups.

In specific embodiments, the implementation of the compounds of the invention are represented by structural formula (IV):

or its salt, where

each R20independently selected from hydrogen, halogen, -C≡N, fluoro-substituted C1-C2of alkyl, -O-(C1-C2) fluoro-substituted alkyl, -S-(C1-C2) fluoro-substituted alkyl, C1-C4of alkyl, -S-(C1-C4) alkyl, C3-C7cycloalkyl, -(C1-C2)alkyl-N(R13)(R13), -O-CH2CH(OH)CH2OH, -O-(C1-C3) alkyl-N(R13)(R13and-N(R13)(R13);

R21choose from carbocycle and heterocycle, where R21optionally substituted by one or two substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, =O, C3-C7cycloalkyl, fluoro-substituted C1-C4of alkyl, -O-R13, -S-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), -O-(C1-C4alkyl)-N(R13)(R13), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R13)(R13), -C(O)-N(R13)(R13and -(C1-C 4alkyl)-C(O)-N(R13)(R13), and when R11is phenyl, R11also optionally substituted 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy, fluoro-substituted 3,4-Ethylenedioxy, O-(saturated heterocycle), fluoro-substituted-O-(saturated heterocycle), or C1-C4alkyl substituted O-(saturated heterocycle);

each R13independently selected from hydrogen and-C1-C4of alkyl; or two R13together with the nitrogen atom to which they are attached, form a 4-8-membered saturated a heterocycle, optionally containing one additional hetero-atomic fragment selected from NH, S, S(=O), S(=O)2and O, where

when R13is alkyl, alkyl optionally substituted by one or more substituents selected from-OH, fluorine, -NH2, -NH(C1-C4the alkyl), -N(C1-C4the alkyl)2, -NH(CH2CH2OCH3and-N(CH2CH2OCH3)2and

when two R13together with the nitrogen atom to which they are attached, form a 4-8-membered saturated the heterocycle, saturated, a heterocycle optionally substituted on any carbon atom of-OH, -C1-C4the alkyl, fluorine, -NH2, -NH(C1-C4by alkyl), -N(C1-C4by alkyl)2, -NH(CH2CH2OCH3or-N(CH2CH2OCH3)2and not necessarily samewe is on any capable of substitution of the nitrogen atom-C 1-C4the alkyl, fluoro-substituted C1-C4the alkyl or -(CH2)2-O-CH3;

R12choose from carbocycle and heterocycle having from 1 to 3 heteroatoms, where R12optionally substituted by one or more substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, C3-C7cycloalkyl, C1-C2fluoro-substituted alkyl, -O-R13, -S-R13, -S(O)-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), -O-(C1-C4alkyl)-N(R13)(R13), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R13)(R13), -C(O)-N(R13)(R13), -(C1-C4alkyl)-C(O)-N(R13)(R13), -O-phenyl, phenyl, and a second heterocycle, and when R12is phenyl, R12substituted by at least one Deputy, who may be additionally selected from 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy, or fluoro-substituted 3,4-Ethylenedioxy or-O-(saturated heterocycle), where any phenyl, second heterocycle or part from a saturated heterocycle substituent of R12optionally substituted with halogen, -C≡N, C1-C4the alkyl, fluoro-substituted C1-C2by alkyl, -O-(C1-C2) fluoro-substituted by alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) what Kilom, -S-(C1-C2) fluoro-substituted by alkyl, -NH-(C1-C4) alkyl and-N-(C1-C4)2by alkyl;

R24selected from hydrogen, C1-C4fluoro-substituted alkyl, C1-C4alkyl-N(R13)(R13), C1-C4alkyl-C(O)-N(R13)(R13), C1-C4alkyl-O-R13and C1-C4alkyl-NR13-C(O)R13; and

X2selected from-NH-C(=O)-†, -C(=O)-NH-†, -NH-C(=S)-†, -C(=S)-NH-†, -NH-S(=O)-†, -S(=O)-NH-†, -S(=O)2-NH-†, -NH-S(=O)2-†, -NH-S(O)2-NR15-†, -NR15-S(O)2-NH-†, -NH-C(=O)O-†, -OC(=O)NH-†, -NH-C(=O)NR15-†, -NR15-C(=O)NH-†, -NH-NR15-†, -NR15-NH-†, -O-NH-†, -NH-O-†, -NH-C(=NR15)-†, -C(=NR15)-NH-†, -C(=O)-NH-CR15R16-†, -CR15R16-NH-C(O)-†, -NH-C(=S)-CR15R16-†, -CR15R16-C(=S)-NH-†, -NH-S(O)-CR15R16-†, -CR15R16-S(O)-NH-†, -NH-S(O)2-CR15R16-†, -CR15R16-S(O)2-NH-†, -NH-C(=O)-O-CR15R16-†, -CR15R16-O-C(=O)-NH-†, -NH-C(=O)-NR15-CR15R16-†, -NH-C(=O)-CR15R16- †- CR15R16NH-C(=O)-O-†;

where

† indicates the place in which X1connected to R11; and

each of R15and R16independently selected from hydrogen, C1-C4of alkyl, -CF3and (C1-C3alkyl)-CF3.

Compounds of the invention, including the new compounds of the invention, that can the same be applied are described in the description of the methods.

Described in the description of the compounds and their salts also include their corresponding hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and the solvate. Typically suitable solvents to obtain the solvate and hydrate can be chosen by the expert in this field.

Compounds and their salts may be present in amorphous or crystalline (including cocrystallized and polymorphic) forms.

Modulating sirtuin compounds of the invention successfully modulate the level and/or activity of the protein of sirtuin, in particular, the deacetylase activity of the protein of sirtuin.

Separately or in addition to the above properties of a particular modulating sirtuin compounds of the invention practically does not possess one or more of the following types of activity: inhibition of PI3-kinase, inhibition elderadostone, inhibition of tyrosine kinase, transactivation of EGFR tyrosine kinase, coronary dilation or spasmolytic activity at concentrations of compounds that are effective for modulating the activity of protein sirtuin in respect of deacetylation (such as protein SIRT1 and/or SIRT3).

Carbocycle include a 5-7-membered monocyclic and 8-12 membered bicyclic ring, where the monocyclic or bicyclic ring selected from saturated, unsaturated, aromati the mini-rings. Carbocycle optionally substituted by one or more substituents, such as halogen, -C≡N, C1-C3alkyl, C1-C2fluoro-substituted alkyl, -O-(C1-C2) fluoro-substituted alkyl, -O-(C1-C3) alkyl, -S-(C1-C3) alkyl, -S-(C1-C2) fluoro-substituted alkyl, hydroxyl, amino, -NH-(C1-C3) alkyl and-N-(C1-C3)2alkyl. Examples of carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, substituted, phenyl and naphthyl.

Heterocycles include 4-7-membered monocyclic and 8-12 membered bicyclic ring, containing one or more heteroatoms, selected, for example, from the atoms N, O and S. In specific embodiments, the implementation of the heterocyclic group are selected from saturated, unsaturated, or aromatic groups. A heterocycle optionally substituted by one or more substituents, such as halogen, -C≡N, C1-C3alkyl, C1-C2fluoro-substituted alkyl, -O-(C1-C2) fluoro-substituted alkyl, -O-(C1-C3) alkyl, -S-(C1-C3) alkyl, -S-(C1-C2) fluoro-substituted alkyl, hydroxyl, amino, -NH-(C1-C3) alkyl and-N-(C1-C3)2alkyl.

Monocyclic rings include a 5-7 membered aryl or heteroaryl, 3-7-membered cycloalkyl and a 5-7 membered non-aromatic heterocyclyl. Monocyclic ring is not necessary for the emeny one or more substituents, such as halogen, cyano, lower alkoxy, lower alkyl, hydroxyl, amino, lower alkylamino and lower dialkylamino. Examples of monocyclic groups include substituted or unsubstituted heterocycles, or carbocycle, such as thiazolyl, oxazolyl, oxazinyl, triazinyl, dithienyl, dioxane, isoxazolyl, isothiazolin, triazolyl, furanyl, tetrahydrofuranyl, dihydrofurane, pyranyl, tetrazolyl, pyrazolyl, pyrazinyl, pyridazinyl, imidazolyl, pyridinyl, pyrrolyl, dihydropyrrole, pyrrolidine, piperidinyl, piperazinil, pyrimidinyl, morpholinyl, tetrahydrothiophene, thiophenyl, cyclohexyl, cyclopentyl, cyclopropyl, cyclobutyl, cycloheptyl, azetidine, oxetane, thiiranes, oxiranyl, aziridinyl and thiomorpholine.

Aromatic (aryl) groups include carbocyclic aromatic groups such as phenyl, naphthyl and antracol, and heteroaryl groups such as imidazolyl, thienyl, furyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl and tetrazolyl. Aromatic groups include condensed polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring fused with one or more other heteroaryl rings. Examples include benzothiazyl, benzofuran, indolyl, chinoline, benzothiazole, b is isoxazol, the benzimidazole, chinoline, ethenolysis and isoindolyl.

Azabicyclo relates to bicyclic molecule, which contains a nitrogen atom in the ring structure. Two rings of Bicycle can be condensed in the position of two mutually connected atoms, for example, indole, through a sequence of atoms, for example, azabicyclo[2.2.1]heptane and the position of one atom, for example, spirits.

Bridging azabicyclo relates to bicyclic molecule, which contains a nitrogen atom and two condensed rings, where condensation occurs through a sequence of atoms, that is, through the atoms in the head of the bridge. Bridge bicyclobutane include at least one bridge of one or more atoms connecting two atoms in the head of the bridge.

Fluoro-substituted compound includes from one forsometimes to full forsomeone. Example fluorinated C1-C2the alkyl includes-CFH2, CF2H, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH3and-CF2CHF2. Perversioni C1-C2alkyl includes, for example-CF3and-CF2CF3.

Provided by this invention, combinations of substituents and variables are only those combinations that result in the formation of stable compounds. Used in the description, the term "stable" relations is seeking to compounds, which possess stability sufficient for receiving the connection and to maintain the integrity of the compound for a sufficient period of time to apply for detailed purposes.

Disclosed in the description of the compounds also include partially and fully deuterated form. In specific embodiments, the implementation of the deuterated forms can be used for kinetic studies. Any expert in this field can choose places where there are such deuterium atoms.

In the present invention also includes salts, in particular pharmaceutically acceptable salt described in the description of the modelling certain compounds. Compounds of the present invention, which possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids with formation of salts. Alternatively, compounds that are of the nature of charge carriers, such as compounds with Quaternary nitrogen, can form a salt with an appropriate counterion (e.g., a halide such as bromide, chloride or fluoride, in particular, bromide).

Acids commonly used for the formation of acid additive salts are Neorganicheskie the acid, such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, phosphoric acid and other similar acids, and organic acids such as p-toluensulfonate acid, methanesulfonate acid, oxalic acid, p-bromophenylacetate acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and other similar acids. Examples of such salts include the sulfate, persulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, kaprilat, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacina, fumarate, maleate, Butin-1,4-diet, hexyne-1,6-diet, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, ecological, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other similar salts.

Basically additive salts include salts derived from inorganic bases, such as hydroxides of ammonium or alkali or alkaline earth metals, carbonates, bicarbonates, and others on the one Foundation. Such grounds suitable for obtaining salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and other similar reasons.

According to another variant implementation of the present invention provides methods of obtaining certain higher modulating sirtuin compounds. The compounds may be synthesized by conventional techniques. Preferably, these compounds could simply be obtained from readily available starting materials.

Transformation and techniques of synthetic chemistry used in the synthesis described in the description of modulating sirtuin compounds known in the field of engineering and include, for example, transformation and techniques described in R. Larock, Comprehensive Organic Transformations (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser''s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

In the example case for modulating sirtuin connection can penetrate the cytoplasmic membrane of the cell. For example, the connection may have cellular permeability of at least about 20%, 50%, 75%, 80%, 90% or 95%.

Described in the description of modulating sirtuin compounds can also have one or more of the following characteristics: the connection can be actually netaktichnym relation to the cell or subject; modulating sirtuin compound can be an organic molecule or a synthetic molecule with a mass of 2000 atomic units or less, 1000 atomic units or less; the connection may have a half-life under normal atmospheric conditions for at least about 30 days, 60 days, 120 days, 6 months or 1 year; the connection may have a half-life in solution, at least about 30 days, 60 days, 120 days, 6 months or 1 year; modulating sirtuin the connection can be more stable in solution than resveratrol, at least about 50%, 2 times, 5 times, 10 times, 30 times, 50 times or 100 times; modulating sirtuin connection can accelerate the deacetylation factor Ku70 DNA repair; modulating sirtuin connection can accelerate the deacetylation RelA/p65; the connection can increase the overall speed of the cell cycle and to increase the sensitivity of cells to apoptosis induced TNF (tumor necrosis factor).

In specific embodiments, implementation, modulating sirtuin connection does not have any substantial ability to inhibit discontiuation (HDAC) class I HDAC class II, or HDAC I and II, at concentrations (e.g.in vivo), is effective in modulating deacetylase activity sirtuin. For example, in preferred embodiments, implementation, modulating sirtuin connection is activate the her sirtuin connection, and it is chosen so that it had EC50when you activate deacetylase activity sirtuin at least 5 times less than EC50when the inhibition of HDAC I and/or II HDAC, and even more preferably at least 10 times, 100 times or even 1000 times less. Evaluation methods HDAC I and/or II HDAC activity are well known in the art and kits for carrying out such studies can be supplied by the relevant companies. See, for example, the website BioVision, Inc. (Mountain View, CA; www.biovision.com and Thomas Scientific (Swedesboro, NJ; www.tomassci.com).

In specific embodiments, the implementation of modulating sirtuin connection does not have any substantial ability to modulate the homologues of sirtuin. In one embodiment, the activator of the human protein of sirtuin may not have any significant ability to activate protein sirtuin lower eukaryotes, particularly yeast or human pathogens, at concentrations (e.g.in vivo), effective at activating deacetylase activity of human sirtuin. For example, activating sirtuin the connection can be chosen so that it had the value of EC50deacetylase activity when activated human sirtuin, such as SIRT1 and/or SIRT3, at least 5 times less than the value of EC50when you activate sirtuin yeast, such as Sir2 (such as Candida, S. cerevisiae, and so is her), and even more preferably at least 10 fold, 100 fold or even 1000 less. In another embodiment, the inhibitor protein of sirtuin lower eukaryotes, particularly yeast or human pathogens, does not have any substantial ability to inhibit protein sirtuin person at concentrations (e.g.in vivo), is effective in the inhibition deacetylase activity of the protein of sirtuin lower eukaryotes. For example, inhibition of sirtuin the connection can be chosen so that it had the value of the IC50when inhibition deacetylase activity of human sirtuin, such as SIRT1 and/or SIRT3, at least 5 times less than the value of the IC50when inhibition sirtuin yeast, such as Sir2 (such as Candida, S. cerevisiae, and so on), and even more preferably at least 10 times, 100 times or even 1000 times less.

In specific embodiments, the implementation of modulating sirtuin connection can possess the ability to modulate one or more homologues of protein sirtuin, such as, for example, one or more SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7 person. In one embodiment, modulating sirtuin connection has the ability to modulate as protein SIRT1 and SIRT3 protein.

In other embodiments, implementation of the modulator SIRT1 has no significant ability modelerov the ü other homologues of protein sirtuin, such as, for example, one or more SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7 person, at concentrations (e.g.in vivo), is effective in modulating deacetylase activity of SIRT1 person. For example, modulating sirtuin the connection can be chosen so that it had the value of the ED50when the modulation deacetylase activity of SIRT1 person at least 5 times less than the value of the ED50when modulating the one or more SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7 person, and even more preferably at least 10 fold, 100 fold or even 1000 less. In one embodiment, the modulator of SIRT1 does not have any substantial ability to modulate protein SIRT3.

In other embodiments, implementation of the modulator SIRT3 has no substantial ability to modulate other homologues of protein sirtuin, such as, for example, one or more SIRT1, SIRT2, SIRT4, SIRT5, SIRT6, or SIRT7 person, at concentrations (e.g.in vivo), is effective in modulating deacetylase activity of SIRT3 person. For example, modulating sirtuin the connection can be chosen so that it had the value of the ED50when the modulation deacetylase activity of SIRT3 person at least 5 times less than the value of the ED50when modulating the one or more SIRT1, SIRT2, SIRT4, SIRT5, SIRT6, or SIRT7 person, and even more preferably, at IU is e, 10 times, 100 times or even 1000 less. In one embodiment, the modulator SIRT3 has no substantial ability to modulate protein SIRT1.

In specific embodiments, the implementation of modulating sirtuin connection may have affinity for binding to the protein of sirtuin about 10-9M, 10-10M, 10-11M, 10-12M or less. Modulating sirtuin connection may lower (activator) or increase (inhibitor) seeming constant Km (Michaelis constant) of protein sirtuin for its substrate or NAD+ (or other cofactor), at least about 2, 3, 4, 5, 10, 20, 30, 50 or 100 times. In specific embodiments, implementation of the Km values determined using the described mass spectrometric studies. Preferred activating compounds reduce miles of sirtuin for its substrate or cofactor in more than caused by resveratrol at the same concentration, or reduce miles of sirtuin for its substrate or cofactor in the same degree, that is caused by resveratrol, at a lower concentration. Modulating sirtuin connection can increase the Vmax of protein sirtuin, at least about 2, 3, 4, 5, 10, 20, 30, 50 or 100 times. Modulating sirtuin connection can have a value of ED50when the modulation deacetylase activity of the protein SIRT1 and/or SIRT3 protein is less than about 1 nm, less than p is IMEMO 10 nm, less than about 100 nm, less than about 1 μm, less than about 10 microns, less than about 100 microns, or approximately in the range of 1-10 nm, approximately in the range of 10-100 nm, approximately in the range of 0.1 to 1 μm, approximately in the range of 1-10 μm, or approximately in the range of 10-100 μm. Modulating sirtuin connection can modulate deacetylase activity of the protein SIRT1 and/or SIRT3 protein, at least about 5, 10, 20, 30, 50, or 100 times, as measured by studies on cells or research-based cells. Activating sirtuin connection may cause a greater induction deacetylase activity of the protein of sirtuin, at least about 10%, 30%, 50%, 80%, 2 times, 5 times, 10 times, 50 times or 100 times compared with the same concentration of resveratrol. Modulating sirtuin connection can have a value of ED50when the modulation SIRT5, which is at least about 10 times, 20 times, 30 times, 50 times larger than the modulation of SIRT1 and/or SIRT3.

3. Examples of applications

In specific aspects the invention provides methods of modulating the level and/or activity of the protein of sirtuin and methods of its application.

In specific embodiments implementing the invention provides methods for applying modulating sirtuin compounds, in which the modulating sirtuin connection activate protein of sirtuin, for example, increase the level and/or aktivnosti protein of sirtuin. Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used for a variety of therapeutic applications including, for example, increase the life span of a cell, and treating and/or preventing a wide range of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, clotting disorders, inflammation, cancer, and/or hyperemia, and so on. Methods include introduction to the subject, if desired pharmaceutically effective amount of the modulating sirtuin connection, for example, activating sirtuin connection.

Without theory suggest that activators of the present invention can interact with sirtuins in the same location within the protein of sirtuin (e.g., active site or a site that affect the Km or Vmax of the active site). Believe that this is the reason why particular classes of activators and inhibitors of sirtuins can have significant structural similarities.

In specific embodiments, the implementation described in the description of modulating sirtuin connection can be used by themselves or in combination the with other compounds. In one embodiment, a mixture of two or more modulating sirtuin compounds can be administered to the subject, if desired. In another embodiment, modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be entered with one or more of the following compounds: resveratrol, butein, fisetin, piceatannol, or quercetin. In the example case for modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be introduced in combination with nicotinic acid. In another embodiment, modulating sirtuin compound that reduces the level and/or activity of the protein of sirtuin, can be entered with one or more of the following compounds: nicotinamide (NAM), suramin; NF023 (antagonist of G-protein); NF279 (antagonist of purinergic receptor); trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid); (-)-epigallocatechin (hydroxy provisions 3,5,7,3',4',5'); (-)-the effects of epigallocatechin (hydroxy in the provisions of 5,7,3',4',5' and gallaty ether at position 3); chloride cyanidin (3,5,7,3',4'-pentahydroxyflavone chloride; chloride delphinidin(3,5,7,3',4',5'-hexahydroquinoline chloride); myricetin (canalisation; 3,5,7,3',4',5'-hexahydronaphthalen); 3,7,3',4',5'-pentahydroxyflavone; gossipteen (3,5,7,8,3',4'-hexahydronaphthalen), zirtin is l; and splitomicin. In yet another embodiment, one or more modulating sirtuin compounds can be entered with one or more therapeutic agents in the treatment or prevention of various diseases, including, for example, cancer, diabetes, neurodegenerative diseases, cardiovascular disease, clotting disorders, inflammation, congestion, obesity, aging, stress and so on. In various embodiments, the implementation of combined therapy, including modulating sirtuin connection can relate to (1) pharmaceutical compositions that include one or more modulating sirtuin compounds in combination with one or more therapeutic agents (e.g., one or more of the described therapeutic agents); and (2) the joint introduction of one or more modulating sirtuin compounds in combination with one or more therapeutic means, where the modulating sirtuin connection and a therapeutic tool have not been prepared in the forms of the same songs (but may be present in the same set or packaging, such as a blister pack or other multi-cell package; in the United separately sealed containers (e.g. bags of foil), which can be separated by the user; or the set where Modulare the future of sirtuin compound(I) and the other therapeutic agent(s) are in separate vessels). When using separate forms, the modulating sirtuin the connection can be introduced simultaneously, intermittently, step, before, after or in combination with the introduction of another therapeutic agent.

In specific embodiments, the implementation modalities to relieve, prevent or treat diseases or disorders by modulating sirtuin compounds can also include an increase in the protein level of sirtuin, such as SIRT1, SIRT2 and/or SIRT3 person, or its homologues. Increased levels of protein can be achieved by introducing into the cell one or more copies of the nucleic acids that encode certain. For example, the level of sirtuin can be increased in a cell of a mammal by introducing into a cell of the mammal a nucleic acid encoding sirtuin, for example, increasing the level of SIRT1 by introducing a nucleic acid that encodes the amino acid sequence deposited as GenBank Accession No. NP_036370, and/or increasing the level of SIRT3 by introducing a nucleic acid that encodes the amino acid sequence deposited as GenBank Accession No. AAH01042.

Nucleic acid, which is injected into the cell to increase the protein level of sirtuin, can encode a protein that is at least about 80%, 85%, 90%, 95%, 98% or 99% identical to the sequence of sirtuin, for example, protein SIRT1 and/or SIRT3. E.g. the measures nucleic acid encoding a protein, can be at least approximately 80%, 85%, 90%, 95%, 98% or 99% identical to the nucleic acid that encodes a protein SIRT1 (e.g., GenBank Accession No. NM_012238) and/or SIRT3 protein (e.g., GenBank Accession No. BC001042). Nucleic acid can also be a nucleic acid that's hybrid, preferably under stringent conditions of hybridization, in nucleic acid encoding nematanthus type of sirtuin, for example, protein SIRT1 and/or SIRT3. Stringent hybridization conditions may include hybridization and washing in 0.2 × SSC (solution of citrate and sodium chloride) at 65ºC. When using a nucleic acid which encodes a protein that is different from the protein of sirtuin nematanthus type, such as a protein that is a fragment of sirtuin nematanthus type, it is preferable that the protein was biologically active, for example, capable of deacetylation. You only need to Express in the cell part of sirtuin, which is biologically active. For example, it is preferable that a protein that differs from nematanthus SIRT1 deposited as GenBank Accession No. NP_036370, contained his fibrillar center. Fibrillar center sometimes refers to the amino acids 62-293 deposited as GenBank Accession No. NP_036370, which is encoded by nucleotides 237-932 deposited as GenBank Accession No. NM_012238 that cover the see NAD binding, and substrate binding domains. Nuclear domain of SIRT1 may also refer to the amino acids around 261-447 deposited as GenBank Accession No. NP_036370, which is encoded by nucleotides 834-1394 deposited as GenBank Accession No. NM_012238; about amino acids 242-493 deposited as GenBank Accession No. NP_036370, which is encoded by nucleotides 777-1532 deposited as GenBank Accession No. NM_012238; or about amino acids 254-495 deposited as GenBank Accession No. NP_036370, which is encoded by nucleotides 813-1538 deposited as GenBank Accession No. NM_012238. Does protein or does not retain biological function, for example, the ability to deacetylation, can be determined using known engineering methods.

In specific embodiments, implementation, methods of relief, prevention or treatment of diseases or disorders by modulating sirtuin connection may also include the reduction of the protein level of sirtuin, such as SIRT1, SIRT2 and/or SIRT3 person, or its homologues. Lowering the protein level of sirtuin can be achieved by known engineering methods. For example, the cell can be expressed synthetic RNA, antisense nucleic acid or ribozyme targeting sirtuin. Can also be used a dominant negative mutant of sirtuin, for example, a mutant that is not able to diacetyl is the Finance. For example, can be used mutant SIRT1 H363Y described, for example, Luo et al. (2001) Cell 107:137. Alternatively, it may be used substances which inhibit transcription.

Methods of modulating protein levels of sirtuin also include methods of modulating the transcription of genes encoding sirtuins as well, stabilizing/destabilizing the corresponding messenger RNA, and others known in the field of engineering methods.

Aging/stress

In one embodiment, the invention provides a method of increasing the life expectancy of the cells, increase the proliferative potential of the cells, slowing the aging of cells, promote cell survival, delay cellular senescence in a cell, mimicking the effects of caloric restriction, increase the resistance of cells to stress or prevent apoptosis of cells by contacting the cells with a modulating sirtuin compound of the invention which increases the level and/or activity of the protein of sirtuin. In the variant example of implementation, the methods include contacting the cells with activating sirtuin connection.

Described in the description of the methods can be used to increase the length of time during which cells, particularly primary cells (i.e., cells derived from an organism, for example, human, can remain viable in cell culture. Embryonic stem (ES) cells and poly potent cells, and cells differentiated from them, can also be processed using modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, in order to keep the cells or their progeny in culture for longer periods of time. Such cells can also be used for transplantation to a subject, for example, afterex vivomodification.

In one embodiment, cells that are supposed to be preserved for long periods of time, can be processed using modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin. Cells may be in suspension (e.g., erythrocytes, serum medium for biological growth, and so forth) or in tissues or organs. For example, the blood taken from the individual with the purpose of transfusion, can be processed by modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, to save the blood for longer periods of time. In addition, the blood, which is used for forensic purposes, can also be saved by using modulating sirtuin compound that increases the em level and/or activity of the protein of sirtuin. Other cells that can be processed to lengthen their life expectancy or protection from apoptosis include cell for consumption, for example, mammalian cells, non-human (such as the cells of the meat), or plant cells (such as cells of vegetables).

Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be used during the phases of development and growth in mammals, plants, insects, microorganisms, in order, for example, to change, to slow down or speed up the process of development and/or growth.

In another embodiment, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used for treatment of cells used for transplantation or cell therapy, including, for example, transplantation of solid tissue, organ transplantation, suspension cells, stem cells, bone marrow cells, and so forth. Cells or tissue may be an autograft, allograft, ingratta or xenograft. Cells or tissue can be processed by modulating sirtuin connection before administration/implantation, simultaneously with introduction/implantation, and/or after insertion/implantation of the subject. Cells or tissue can be processed before the what Elenium cells from an individual donor, ex vivoafter removal of cells or tissue from an individual donor, or after implantation in the recipient. For example, the individual donor or the recipient may be subjected to systemic treatment with modulating sirtuin connection or may be a subpopulation of cells/tissue subjected to local processing with modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin. In specific embodiments, the implementation of cells or tissue (or individual donor/recipient) may optionally be subjected to treatment with another therapeutic agent used to extend the viability of the graft, such as, for example, an immunosuppressive agent, a cytokine, an angiogenic factor, and so on.

In some embodiments, the implementation of cells can be processed by modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin,in vivofor example, to increase their life or prevent apoptosis. For example, can be protected from aging skin (e.g. wrinkles, loss of elasticity, and so on) by treating the skin or epithelial cells modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin. In the variant example of implementation of the skin whodat contact with pharmaceutical or cosmetic composition, includes modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin. Examples of skin diseases or skin conditions that can be treated using the described methods include disorders and diseases relating to or caused by inflammation, damage from the sun or the natural aging process. For example, the compositions find use in the prevention or treatment of contact dermatitis (including irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis (also known as allergic eczema), actinic keratosis, disorders of keratinization (including eczema), disease epidermolysis epidermtm (including disease), exfoliative dermatitis, seborrheic dermatitis, eritem (including polymorphic erythema and nodoso erythema), damage caused by the sun or other light sources, discoid lupus erythematosus, dermatomyositis, psoriasis, skin cancer and the effects of natural aging. In another embodiment, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used in the treatment of wounds and/or burns to speed healing, including, for example, burns first, second or third degree and/or a thermal, chemical or electrical ago is I. Drugs can be tapicerki applied on the skin or tissue of the mucous membrane.

Topical medications, including one or more modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be used as a preventive, for example chemopreventive, compositions. When used in chemopreventive how sensitive the skin is subjected to processing before any obvious condition of a particular individual.

Modulating sirtuin compounds can be administered to the subject locally or systemically. In one embodiment, modulating sirtuin compound is administered topically to the tissue or organ of a subject by injection, topical medication, and so forth.

In another embodiment, modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be used to treat or prevent a disease or condition caused or aggravated by cellular senescence in a subject; methods of reducing the rate of aging of a subject, for example, after the onset of senescence; methods of increasing the life expectancy of a subject; methods of treatment or prevention of a disease or condition related to life expectancy; methods of treating or preventing the disease or condition treated is belonging to the proliferative capacity of cells; and the ways to treat or prevent a disease or condition resulting from damage or cell death. In specific embodiments, the implementation method is not affected by reducing the incidence of diseases that shorten the lifespan of the subject. In specific embodiments, the implementation method is not affected by reducing cases of mortality caused by disease, such as cancer.

In yet another embodiment, the modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be administered to the subject in order to increase the overall lifespan of its cells and to protect cells from stress and/or apoptosis. It is believed that treatment of the subject with the help of the described compounds is similar to the influence on the subject of hormesis, that is, light stress, which has a beneficial effect on organisms, and can increase their life expectancy.

Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be administered to the subject for the prevention of aging and aging-related consequences or diseases, such as stroke, heart disease, heart failure, arthritis, high blood pressure and Alzheimer's disease. Friend the e state, which can be treated include eye diseases, such as those associated with aging of the eye such as cataracts, glaucoma and macular degeneration. Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be introduced to subjects for the treatment of diseases, such as chronic diseases associated with cell death, in order to protect the cells from death. Examples of diseases include diseases associated with loss of nerve cells, neuronal dysfunction or death or dysfunction of muscle cells, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and muscular dystrophy; AIDS; fulminant hepatitis; diseases associated with degradation of the brain, such as disease Creutzfeldt-Jakob disease, retinitis pigmentosa and cerebellar degeneration; myelodysplasia, such as aplastic anemia; ischemic diseases such as myocardial infarction and stroke; liver disease such as alcoholic hepatitis, hepatitis B and hepatitis C; joint diseases, such as osteoarthritis; atherosclerosis; alopecia; skin damage in the UV radiation; planus; skin atrophy; cataract; and graft rejection. Cell death can also be a consequence of the surgery, the medication is therapy, chemical or radiation exposure.

Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin may also be administered to the subject suffering from acute diseases, for example, damage to the organ or tissue, for example, to a subject suffering from stroke or myocardial infarction, or to a subject suffering from spinal cord injuries. Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be used to restore affected by alcohol liver.

Cardiovascular disease

In another embodiment, the invention provides a method of treating and/or preventing cardiovascular diseases by introducing the subject, if desired modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin.

Cardiovascular disease, which can be subjected to treatment or prevention with modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin include cardiomyopathy or myocarditis; such as idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy. Also what about the, subjected to treatment or prevention with the help of the described compounds and methods are atheromatous disorders of the major blood vessels (macrovascular disease)such as the aorta, coronary arteries, carotid arteries, the cerebrovascular arteries, the renal arteries, iliac artery, femoral artery and popliteal artery. Other vascular diseases, which can be subjected to treatment or prevention include diseases related to platelet aggregation, the retinal arterioles, the glomerular arterioles, the vasa nervorum (small arteries that supply blood to the peripheral nerves), cardiac arterioles, and associated capillary beds of the eye, kidney, heart, and Central and peripheral nervous systems. Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be used to raise levels of HDL (high-density lipoprotein) in the blood plasma of an individual.

Another disorder that can be treated via modulation of sirtuin compounds that increase the level and/or activity of the protein of sirtuin include restenosis, for example in coronary intervention, and disorders related to abnormal cholesterol levels, high and low density.

In one embodiment, the fashion is yousee sirtuin connection, which increases the level and/or activity of the protein of sirtuin, can be introduced as part of a combined preparation with another cardiovascular agent. In one embodiment, modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be introduced as part of a combined preparation with antiarrhythmic agent. In another embodiment, modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be introduced as part of a combined preparation with another cardiovascular agent.

Cell death/cancer

Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be introduced to subjects who have recently received or are likely to receive a dose of radiation or toxin. In one embodiment, the dose of radiation or toxin receive as part of a work procedure or a medical procedure, for example, introduced as a preventive measure. In another embodiment, the radiation or toxin get unintentionally. In this case, it is preferable that the compound was administered as soon as possible after exposure in order to prevent apoptosis and the subsequent development of acute radiation syndrome.

Modulate is their certain compounds can also be used to treat and/or prevent cancer. In specific embodiments, the implementation of modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to treat and/or prevent cancer. Caloric restriction resulted in reduced incidence of age-related disorders, including cancer. Accordingly, increasing the level and/or activity of the protein of sirtuin can be used in the treatment and/or prevention of age-related disorders such as, for example, cancer. Examples of cancers that can be treated via modulation of sirtuin connections are brain cancer and kidney cancer; hormone-dependent cancers, including breast, prostate, testicular, and ovarian cancer; leukemia and lymphoma. Oncogene related to solid tumors, modulating compound can be injected directly into the tumor. Cancer of blood cells, such as leukemia, can be subjected to treatment by introducing a modulating compound in the blood or in the bone marrow. Can also be treated by the growth of benign cells, for example, warts. Other diseases that can be treated include autoimmune diseases such as systemic lupus erythematous, scleroderma and arthritis in which you want to delete autoimmune cells. In addition, can also is to be subjected to a treatment by introducing a modulating sirtuin connection viral infection, such as herpes, HIV, adenovirus, and associated with HTLV-1 (virus human T-cell leukemia) malignant disease and benign disease. Alternatively, cells can be taken from the subject, processedex vivoto remove specific unwanted cells, such as cancer cells, and put back the same entity or to another entity.

Chemotherapeutic agents can be co-introduced with the described modulating compounds as a means of having anticancer activity, for example, means that induce apoptosis, tools that reduce life expectancy, or tools, which give the cells susceptibility to stress. Chemotherapeutic agents can be applied by themselves together with the described modulating sirtuin connection as inducing the death of cells or reduce life expectancy or increase the susceptibility to stress and/or in combination with other chemotherapeutics. In addition to using traditional chemotherapeutics and described in the description of modulating sirtuin compounds can also be used with antisense RNA, the messenger RNA or other polynucleotide for inhibiting the expression of cellular components that contribute to n is desirable cell proliferation.

Combination therapy includes modulating sirtuin connections and traditional chemotherapeutic agent, can be effective in applying known in the technical field of combined therapies, as the combination can achieve greater effect at a lower dose of traditional chemotherapeutic agents. In a preferred embodiment, the effective dose (ED50for chemotherapeutic agents, or a combination of conventional chemotherapeutic agents when used in combination with the modulating sirtuin connection is at least 2 times smaller than the ED50only one chemotherapeutic drugs, and even more preferably 5-fold, 10 fold or even 25 fold less. Conversely, therapeutic index (TI) for such chemotherapeutic agents or combinations of such chemotherapeutic agents when used in combination with the described in the description of modulating sirtuin compound may be at least 2 times greater than the magnitude of TI to a treatment regimen only one traditional chemotherapeutic agent, and even more preferably 5-fold, 10 fold or even 25 times more.

Neuronally diseases/disorders

In a particular aspect of modulating sirtuin connection, which increases the t level and/or activity of the protein of sirtuin, can be used to treat patients suffering from neurodegenerative diseases and traumatic injuries or mechanical injury of the Central nervous system (CNS), spinal cord or peripheral nervous system (PNS). Neurodegenerative disease usually causes a decrease in the mass and volume of the human brain, which may be due to atrophy and/or loss of brain cells that occur to a much greater extent than in the case of cells of a healthy person, changes in which are attributed to aging. Neurodegenerative diseases may develop gradually after a long period of normal functioning of the brain due to progressive degeneration (e.g., dysfunction and neuronal cell death) specific areas of the brain. Alternatively, the neurodegenerative disease can have a rapid onset, such as neurodegenerative diseases associated with trauma or toxins. Clinical manifestation of degeneration of the brain may occur many years after the actual beginning of the degeneration of the brain. Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS; disease Lou Gehrig's disease (als), a disease diffuse Taurus Levi, chorey-acanthocytes, the primary side IC is Eros, eye diseases (ocular neuritis)caused chemotherapy neuropathy (e.g., vincristine, paclitaxel, bortezomib) - induced diabetic neuropathy and hereditary ataxia. Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to treat these disorders and other disorders described below.

Alzheimer's disease (AD) is a disorder of the Central nervous system, which leads to memory loss, unusual behavior, personality changes and the decline of intellectual abilities. These losses are caused by the death of specific cell types of the brain and severing ties and their supporting structures (e.g., glial cells) between them. The earliest symptoms include loss of short term memory, making wrong decisions and personality changes. Parkinson's disease (PD) is a disorder of the Central nervous system, which leads to uncontrolled body movements, rigidity, tremor, and dyskinesia and which is associated with loss of brain cells in the part of the brain that produces dopamine. Amyotrophic lateral sclerosis (ALS) (of upper motor neuron disease) is a disorder of the Central nervous system that affects the motor neurons, the components of the Central nervous system, which communicate m is ZGA with skeletal muscle.

Huntington's disease (HD) is another neurodegenerative disease that causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance areas. Disease Tay-Sachs disease Sandhoff are diseases of accumulation of the glycolipid in which GM2 of ganglioside and related glycolipid substrates for β-hexosaminidase accumulate in the nervous system and trigger acute neurodegeneration.

It is well known that apoptosis plays a role in the pathogenesis of HIV in the immune system. However, HIV-1 also induces neurological disease that can be treated via modulation of certain compounds of the invention.

Loss of neurons is also characteristic of prion diseases, such as disease of Creutzfeldt-Jakob disease in humans, BSE in cattle (BSE) in cattle (mad cow disease), prurigo in sheep and goats, and feline spongiform encephalopathy (FSE) in cats. Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used in the treatment or prevention of a loss of neurons, caused by the primary disease.

In another embodiment, modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, mo is et to be used for the treatment or prevention of any disease or disorder, including axonopathy. Distal axonopathy is a type of peripheral neuropathy that occurs as a result of some metabolic or toxic disorders of neurons of the peripheral nervous system (PNS). It is the most common response of nerves to metabolic or toxic disorders and therefore may be caused by metabolic diseases such as diabetes, kidney failure, failure syndromes, such as malnutrition and alcoholism, or the effects of toxins or drugs. Disease with distal axonopathy are typically symmetrical sensory-motor disorders by type "gloves-socks". In affected areas are lost or weakened deep tendon reflexes and functions of the autonomic nervous system (ANS).

Diabetic neuropathies are neuropathic disorders that are associated with diabetes. Relatively common condition that may be associated with diabetic neuropathy include paralysis of the third nerve; mononeuropathy; multiple manometric; diabetic amyotrophy; painful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy.

Peripheral neuropathy is the medical term for damage n the ditches of the peripheral nervous system, which may be caused either by diseases of the nerve or the side effects of a systemic disease. The main causes of peripheral neuropathy include epileptic seizures, malnutrition and HIV, although the most likely cause is diabetes.

In the example case for modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be used to treat or prevent multiple sclerosis (MS), including relapsing multiple sclerosis and monosymptomatic multiple sclerosis and other demyelinating conditions, such as, for example, chronic inflammatory demyelinizing polyneuropathy (CIDP) or associated symptoms.

In yet another embodiment, the modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be used for the treatment of nerve injury, including injury as a result of illness, injury (including surgery) or trauma due to exposure to the environment (e.g., neurotoxins, alcoholism, and so forth).

Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be used to prevent, treat or alleviate symptoms of various destroy the TV peripheral nervous system. The term "peripheral neuropathy" covers a wide range of disorders, in which were damaged peripheral nerves, i.e. the nerves outside the brain and spinal cord. Peripheral neuropathy may also be termed peripheral neuritis, or when affected by a large number of nerves, can be used the terms "PN" or "polyneuritis".

Diseases of the peripheral nervous system, subjected to treatment by modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin include diabetes, leprosy, the disease Charcot-Marie-Toot syndrome Guillaume-Barre and neuropathy of the brachial plexus (diseases of the cervical and first thoracic roots, nerve trunks, chords), and components of the peripheral nerves of the brachial plexus nerve.

In another embodiment, the activating sirtuin connection can be used to treat or prevent polyglutamine disease. Examples polyglutamine diseases include muscular atrophy spinal cord and medulla oblongata (Kennedy disease), Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (syndrome river Ho), spinal-cerebellar ataxia type 1 spinal-cerebellar ataxia type 2 spinal-cerebellar ataxia type 3 (disease Machado-Joseph), with inline-cerebellar ataxia type 6, spinal-cerebellar ataxia type 7 and spinal-cerebellar ataxia type 17.

In specific embodiments implementing the invention provides a method of treating cells of the Central nervous system to prevent damage due to reduced blood flow to the cells. Usually the severity of preventable damage may depend largely on the degree of reduction of blood flow to the cells and the duration of the period of decline. In one embodiment, can be prevented apoptotic or necrotic cell death. In one embodiment, can be prevented cell damage as a result of ischemia, such as cytoxicity swelling or anoxemia tissue of the Central nervous system. In each embodiment, the cells of the Central nervous system can be spinal cells or brain cells.

Another aspect covers the introduction activating sirtuin connection to a subject for treatment of an ischemic condition of the Central nervous system. The number of ischemic conditions of the Central nervous system can be treated using the described in the description activates sirtuin compounds. In one embodiment, the ischemic condition is stroke, which results in ischemic damage to the Central nervous system either is of type such as apoptotic or necrotic cell death, cytoxicity swelling or anoxemia tissue of the Central nervous system. A stroke can affect any area of the brain or can be caused by any known etiology, causing a stroke. In one alternative of this exercise, the stroke is a stroke within the brain stem. In another alternative of this exercise stroke is cerebellar stroke. In yet another embodiment, the embolic stroke is a stroke. In yet another embodiment, the stroke may be hemorrhagic stroke. In an additional embodiment, the stroke is thrombotic stroke.

In another aspect activating sirtuin the connection can be introduced to reduce infarct size and Central mass ischemic tissue after ischemic condition of the Central nervous system. In addition, activating sirtuin connection can also be successfully used to reduce the size of ischemic penumbra or transition zone after ischemic condition of the Central nervous system.

In one embodiment, the scheme of the combined drug treatment may include drugs or compounds for the treatment or prevented what I neurodegenerative disorders or secondary States, associated with these disorders. Therefore, the scheme of the combined drug treatment can include one or more activators of sirtuins and one or more agents against neurodegenerative disorders.

Disorders of blood coagulation

In other aspects modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to treat or prevent disorders of blood coagulation (or hemostatic disorders). Used in the description of the interchangeable terms "hemostasis, coagulation of blood" and "blood coagulation" refers to the control of bleeding, including the physiological properties of vasoconstriction and coagulation. Coagulation of the blood contributes to the preservation of the integrity of the blood of a mammal after injury, inflammation, disease, congenital pathology, dysfunction, or other disturbance. In addition, the formation of blood clots not only limits the bleeding in case of injury (hemostasis), but can cause serious damage and death of the body in case of atherosclerotic diseases caused by clogging important artery or vein. Therefore, the formation of a blood clot at the wrong time and in the wrong place is thrombosis.

Accordingly, the present invention offers anticoagula the ion and antithrombotic therapy, aimed at suppressing the formation of blood clots to prevent or treat disorders of blood coagulation, such as myocardial infarction, stroke, loss of limbs as the result of disease, peripheral artery, or embolism of the lungs.

Used in the description are interchangeable expressions modulation or modulation of hemostasis and control or regulation of hemostasis include induction (e.g., stimulation or enhancement) of hemostasis, as well as suppression (e.g., decrease or decrease) in hemostasis.

In one aspect the invention provides a method of reducing or suppressing hemostasis in a subject by introducing a modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin. Disclosed in the description of the compositions and methods are used for the treatment or prevention of thrombotic disorders. Used in the description of the term "thrombotic disorder" includes any disorder or condition characterized by excessive or undesirable coagulation or hemostatic activity, or hypercoagulable state. Thrombotic disorders include diseases or disorders for which there is adhesion of platelets and thrombus formation, and they can manifest as an increased tendency to form blood clots, for example, povyshen the th thrombosis, thrombosis at an early age, marital trends in relation to thrombosis and thrombosis in unusual places.

In another embodiment, the scheme of the combined drug treatment may include drugs or compounds for the treatment or prevention of disorders of blood coagulation or secondary conditions associated with these disorders. Therefore, the scheme of the combined drug treatment can include one or more modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, and one or more anticoagulant or antithrombotic funds.

The weight control

In another aspect, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to treat or prevent weight gain or obesity in a subject. For example, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used, for example, for the treatment or prevention of hereditary obesity, obesity due to diet, obesity-related hormones, obesity, associated with the introduction of the drug, to reduce the body weight of the subject, or for reducing or preventing weight gain in the subject. The subject, which is of WMD requires such treatment, the subject, who are obese, predisposed to obesity, has weight and is prone to be overweight. Subjects who are predisposed to obesity or extra weight, can be identified, for example, on the basis of family history, genetics, diet, activity level, take medication, or their various combinations.

In some embodiments, the implementation of modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be introduced to subjects suffering from other diseases and conditions that can be treated or prevented by accelerating loss of body weight in the subject. Such diseases include, for example, high blood pressure, hypertension, elevated levels of blood cholesterol, dyslipidemia, type 2 diabetes, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina, acute heart failure, stroke, gallstones, cholecystitis and cholelithiasis, gout, osteoarthritis, obstructive apnea during sleep and respiratory problems, some types of cancer (such as endometrial, breast, prostate and colon), complications of pregnancy, poor female reproductive health (such as menstru is further violations infertility, irregular ovulation), problems of bladder control (such as stress incontinence); uric acid nephrolithiasis; psychological disorders (such as depression, eating disorders, distorted bodily image and low self-esteem). Finally, patients, patients with AIDS may develop lipodystrophy or insulin resistance in response to combined therapy in the treatment of AIDS.

In another embodiment, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to suppress lipogenesis or differentiation of fat cells, orin vitroorin vivo. Such methods can be used to treat or prevent obesity.

In other embodiments, implementation of the modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to reduce appetite and/or increase feelings of satiety, thereby causing weight loss or preventing weight gain. A subject who is in need of such treatment may be a subject who is overweight, obese, or entity that has a predisposition to the presence of overweight or obesity. The method may include introduction to the subject daily, or every other day, or times a week dose, for example, in the form of pills. The dose may be a "dose that reduces the appetite."

In the example case for modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be entered as a combination therapy for treating or preventing weight gain or obesity. For example, one or more modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be introduced in combination with one or more anti-obesity.

In another embodiment, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be introduced to reduce the weight gain caused by the intake of the medicine. For example, modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be entered as a combination therapy with drugs that can stimulate the appetite or cause weight gain, in particular, increased body weight is associated with water retention in the body.

Metabolic disorders/diabetes

In another aspect, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to treat or prevent metabolic the ski disorder, such as insulin resistance, pre-diabetic condition, type II diabetes and/or its complications. Introduction modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can increase insulin sensitivity and/or lower the levels of insulin in the subject. A subject who is in need of such treatment, is a subject that is resistant to insulin or other preceding symptom of type II diabetes, which is diabetes type II or who are predisposed to the development of any of these States. For example, the subject may be a subject having insulin resistance, for example, have high levels of circulating insulin, and/or associated conditions such as hyperlipidemia, dissipates, hypercholesterolemia, impaired glucose tolerance, high levels of glucose (sugar) in the blood, other manifestations of syndrome X, hypertension, atherosclerosis, and lipodystrophy.

In the example case for modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be entered as a combination therapy for the treatment or prevention of metabolic diseases. For example, one or more modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be introduced in combination the with one or more antidiabetic drugs.

Inflammatory disease

In other aspects modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to treat or prevent diseases or disorders associated with inflammation. Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be introduced before the start of inflammation during inflammation or after the onset of inflammation. When used in prevention is preferable to enter the connection before the onset of the inflammatory response or symptom. Introduction compounds can prevent or mitigate inflammatory responses or symptoms.

In another embodiment, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to treat or prevent allergies and respiratory conditions, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen poisoning, emphysema, chronic bronchitis, acute respiratory distress syndrome and any chronic obstructive pulmonary disease (COPD). The compounds may be used for the treatment of chronic hepatitis, including hepatitis B and hepatitis C.

In addition, modulating sirtuin compounds that increase the level and/or activity of proteins is of sirtuin, can be used to treat autoimmune diseases and/or inflammation associated with autoimmune diseases such as arthritis, including rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, as well as autoimmune diseases of the organs-tissues (such as Raynaud's syndrome), ulcerative colitis, Crohn's disease, mucositis mucous membranes of the oral cavity, scleroderma, myasthenia gravis, transplant rejection, endotoxin bacterial-toxic shock, sepsis, psoriasis, eczema, dermatitis, multiple sclerosis, autoimmune thyroiditis, uveitis, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular diseases also known as autoimmune polyglandular syndrome) and graves ' disease.

In specific embodiments implement one or more modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used by themselves or in combination with other compounds used to treat or prevent inflammation.

Hyperemia

In another aspect, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to reduce the incidence or severity of flushing and/or paroxysmal sensations of heat, which is s are the symptoms of the disease. For example, the method includes the use of modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, by themselves or in combination with other drugs to reduce the incidence or severity of flushing and/or paroxysmal sensations of heat in cancer patients. In other embodiments, the implementation, the method proposes the use of a modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, to reduce the incidence or severity of flushing and/or paroxysmal sensations of heat in women in menopause and post-menopausal period.

In another aspect, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used as a therapeutic agent for reducing the incidence or severity of flushing and/or paroxysmal sensations of heat, which are the side effects of other drug therapies, for example, hyperemia caused by the use of a medicinal product. In specific embodiments implement a method of treating and/or preventing congestion caused by the use of a medicinal product, includes an introduction to the patient if it is necessary, the preparation comprising at least one connection, call the state of hyperemia, and at least one modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin. In other embodiments implement a method of treating congestion caused by the use of a medicinal product, includes separate introduction of one or more compounds that cause hyperemia, and one or more modulating sirtuin compounds, for example, when modulating sirtuin connection, and means causing hyperemia, were not prepared in the same compositions. Using the separate drugs modulating sirtuin connection can be entered (1) simultaneously with the introduction of the tool, causing redness, (2) periodically with the introduction of money, which is causing the congestion, (3) alternately on the introduction of money, which is causing the congestion, (4) before the introduction of the tool, causing redness, (5) after insertion, causing the redness, and (6) in their various combinations. Examples of substances that cause the blood include, for example, Niacin, raloxifene, antidepressants, neuroleptics, chemotherapeutic drugs, calcium channel blockers and antibiotics.

In one embodiment, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to reduce the side effects in the form of hyperemia is as a result of taking vasodilator or antilipemics funds (including hypocholesterolemic tools and lipotropic agents. In the example case for modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be used to reduce the redness associated with the introduction of Niacin.

In another embodiment, the invention provides a method of treating and/or preventing hyperlipidemia in reducing the side-effects in the form of hyperemia. In another typical embodiment, the method includes the use of modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, to reduce the side effects such as hyperemia from taking raloxifene. In another typical embodiment, the method includes the use of modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, to reduce the side effects such as hyperemia from taking antidepressants or neuroleptics. For example, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used in combination (when administered separately or together) with the inhibitor of the reuptake of serotonin or antagonist 5HT2 receptor.

In specific embodiments, the implementation of modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used for mind is nisene hyperemia as part of therapy with an inhibitor of serotonin reuptake (SRI). In another typical embodiment, the modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to reduce side effects such as hyperemia from the use of chemotherapeutic agents such as cyclophosphamide and tamoxifen.

In another embodiment, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to reduce side effects such as hyperemia from the use of calcium channel blockers, such as amlodipine.

In another embodiment, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to reduce side effects such as hyperemia from taking antibiotics. For example, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used in combination with levofloxacin.

Eye disorders

One aspect of the present invention is a method for the prevention, recovery or treatment of visual impairment by introducing the patient a therapeutic dose of a modulator of certain selected from disclosed in the description of the compounds, or pharmaceutically acceptable salt, prodrug or a metabolic production is Oh.

In a particular aspect of the invention, the visual impairment caused by damage to the optic nerve or the Central nervous system. In specific embodiments, the implementation of damage to the optic nerve caused by high intraocular pressure, such as pressure caused by glaucoma. In other specific embodiments, the implementation of damage to the optic nerve caused by swelling of the nerve, which is often associated with infection or immune (such as autoimmune) response, such as with neuritis of the optic nerve.

In a particular aspect of the invention, the visual impairment caused by retinal damage. In specific embodiments, the implementation of the retinal damage caused by impaired blood flow to the eye (for example, arteriosclerosis, vasculitis). In specific embodiments, the implementation of the retinal damage caused by the destruction of the macula (e.g., exudative or nonexudative macular degeneration).

Examples of retinal diseases include exudative age-related macular degeneration, nonexudative age-related macular degeneration, electronic retinal prosthesis and transplantation of retinal pigment epithelium in age-related macular degeneration, acute multifocal Placido pigmentary epitheliopathy, acute retinal necrosis, a disease best, occlusion of the retinal side and the criteria, the side occlusion of the retinal vein, associated and related to cancer autoimmune retinopathy, occlusion of Central retinal artery occlusion Central retinal vein, Central serous the horioretinopatia, disease ILSA, epimacular membrane, lattice degeneration of the retina, microaneurysm, diabetic macular edema, macular edema Irvine-Gass, macular hole, subretinal neovascular membrane, diffuse unilateral subacute neuroretinitis, cystic macular edema without artiphakia, the alleged syndrome ocular histoplasmosis, exudative retinal detachment, post-operative retinal detachment, proliferative retinal detachment, regmatogenous retinal detachment, tractional retinal detachment, retinitis pigmentosa, cytomegalovirus retinitis, retinoblastoma, retinopathy of prematurity, tablewindow retinopathy associated with diabetic retinopathy, proliferative diabetic retinopathy, retinopathy due to hemoglobinopathy, retinopathy Porcher, Valsalva retinopathy, juvenile retinoschisis, senile retinoschisis, syndrome Terson and syndromes white dots.

Other examples of diseases include ocular bacterial infection (e.g., conjunctivitis, keratitis, tuberculosis, syphilis, gonorrhea), viral infection (e.g., eye Viru is herpes simplex, the varicella-zoster virus, cytomegalovirus retinitis, human immunodeficiency virus (HIV)and progressive outer retinal necrosis in the context of HIV and other HIV-related and other-related immunodeficiency eye diseases. In addition, eye diseases include fungal infections (such as Candida choroiditis, histoplasmosis), protozoal infections (e.g. toxoplasmosis) and others, such as ocular toxocariasis and sarcoidosis.

One aspect of the invention is a method for the prevention, recovery or treatment of visual impairment in a subject being treated with a chemotherapeutic drug (e.g., a neurotoxic agent, medicine that raises intraocular pressure, such as a steroid), by introducing the subject, if he needs that kind of treatment, therapeutic doses disclosed in the description of the modulator of sirtuin.

Another aspect of the invention is a method for the prevention, recovery or treatment of visual impairments in the subject subjected to surgery, including eye or other operations performed in the supine position on the abdomen, such as surgery on the spinal cord, by introducing the subject, if he needs that kind of treatment, therapeutic doses disclosed in the description of the modulator sirtuin is. Eye operations include cataracts, iridotomy and lens replacement.

Another aspect of the invention is the treatment, including prevention and prophylactic treatment of age-related eye diseases, which include cataracts, dry eyes, senile macular degeneration (AMD), retinal damage and other similar diseases, by introducing the subject, if he needs that kind of treatment, therapeutic doses disclosed in the description of the modulator of sirtuin.

Another aspect of the invention is the prevention or treatment of eye damage caused by stress, chemical damage or ionizing radiation, by introducing the subject, if he needs that kind of treatment, therapeutic doses disclosed in the description of the modulator of sirtuin. Radiation or electromagnetic eye damage may include damage caused by radiation from cathode ray tubes or exposed to sunlight or UV radiation.

In one embodiment, the scheme of the combined drug treatment may include drugs or compounds for the treatment or prevention of ocular disorders or secondary conditions associated with these disorders. Therefore, the scheme of the combined drug treatment can include one or more activate the s of sirtuin and one or more therapeutic agents for the treatment of eye disorders.

In one embodiment, the modulator of sirtuin can be introduced in combination with a therapeutic tool for lowering intraocular pressure. In another embodiment, the modulator of sirtuin can be introduced in combination with a therapeutic tool for the treatment and/or prevention of glaucoma. In yet another embodiment, the modulator of sirtuin can be introduced in combination with a therapeutic tool for the treatment and/or prevention of optic neuritis. In one embodiment, the modulator of sirtuin can be introduced in combination with a therapeutic tool for the treatment and/or prevention of cytomegalovirus retinopathy. In another embodiment, the modulator of sirtuin can be introduced in combination with a therapeutic tool for the treatment and/or prevention of multiple sclerosis.

Diseases and disorders associated with mitochondrial activity

In specific embodiments implementing the invention provides methods for treating diseases or disorders, which has a therapeutic effect increased mitochondrial activity. Methods include introduction to the subject, if desired therapeutically effective amount of activating sirtuin connection. Increased mitochondrial activity means an increase in AK is Yunosti mitochondria while maintaining the total number of mitochondria (for example, mitochondrial mass), increasing the number of mitochondria, resulting in increased mitochondrial activity (for example, by stimulating mitochondrial biogenesis) or their combination. In specific embodiments, the implementation of diseases and disorders, which has a therapeutic effect increased mitochondrial activity, include diseases and disorders associated with mitochondrial dysfunction.

In specific embodiments, the implementation of the methods of treatment of diseases or disorders, which has a therapeutic effect increased mitochondrial activity may include the identification of a subject suffering from mitochondrial dysfunction. Methods of diagnosing mitochondrial dysfunction may include molecular genetic studies, the analysis of the pathology and/or biochemical studies. Diseases and disorders associated with mitochondrial dysfunction include diseases and disorders for which insufficient activity of the respiratory chain of mitochondria contributes to the development of the pathophysiology of such diseases or disorders in a mammal. Diseases or disorders that may have a therapeutic effect increased mitochondrial activity, usually include, for example, diseases in which oxidative damage, oborudova the Noah free radicals, leads to degeneration of the tissue; diseases in which cells in unacceptably high risk of apoptosis; diseases in which cells are unable to undergo apoptosis.

In specific embodiments implementing the invention provides methods of treating diseases or disorders that may have a therapeutic effect increased mitochondrial activity, which include introduction to the subject, if desired, one or more activating sirtuin compounds in combination with another therapeutic agent, such as, for example, an agent used for the treatment of mitochondrial dysfunction, or the tool used to reduce the manifestation of a symptom associated with a disease or disorder, including mitochondrial dysfunction.

In examples of embodiments, the invention provides methods for treating diseases or disorders that may have a therapeutic effect increased mitochondrial activity, by introducing to the subject a therapeutically effective amount of activating sirtuin connection. Examples of diseases or disorders include, for example, neuromuscular disorders (e.g., ataxia, muscular dystrophy, multiple sclerosis, etc.), disorders associated with neural instability (in the example, epileptic disorders, migraine and so on), delay in development, neurodegenerative disorders (such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and so forth), ischemia, renal tubular acidosis, age related neurodegeneration and cognitive disturbance, fatigue during chemotherapy, age or caused by chemotherapy menopause or menstrual cycle or ovulation, mitochondrial myopathy, mitochondrial damage (for example, accumulation of calcium excitotoxicity, effects of nitric oxide, hypoxia, and so on) and mitochondrial deregulation.

Muscular dystrophy refers to a family of diseases, including depletion of neuromuscular structure and function, often leading to atrophy of skeletal muscle and myocardial dysfunction, such as muscular dystrophy of Duchenne. In specific embodiments, the implementation of the activating sirtuin connections can be used to reduce the degree of depletion of the functional capacity of muscles and to improve the functional state of muscles in patients with muscular dystrophy.

In specific embodiments, the implementation of modulating sirtuin connection can be used for the treatment of mitochondrial myopathies. Mitochondrial myopathy include a range from moderate slowly developing is the existing weakening of the external muscles of the eye to severe fatal childhood myopathies and Multisystem encephalomyopathy. Identified some symptoms, which to some extent overlap each other. Installed syndromes muscles include progressive external ophthalmoplegia, syndrome Kearns-Sara (ophthalmoplegia, pigmentary retinopathy, heart defects conductivity, cerebellar ataxia, and sensorineural deafness), MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and insulinopenia attacks), MERFF syndrome (myoclonic seizures and torn red fibers), distributed weakness of the muscles of the shoulder girdle and infant myopathy (benign or severe and fatal).

In specific embodiments, the implementation of the activating sirtuin connections can be used to treat patients suffering from toxic damage to the mitochondria, such as toxic damage due to the accumulation of calcium excitotoxicity, effects of nitric oxide, toxic damage caused by the drug, or hypoxia.

In specific embodiments, the implementation of the activating sirtuin connections can be used to treat diseases or disorders associated with mitochondrially deregulation.

Muscle activity

In other embodiments implementing the invention provides methods for enhancing muscle de the activity by introducing a therapeutically effective amount of activating sirtuin connection. For example, activating sirtuin connections can be used to increase physical endurance (for example, the ability to perform a task to perform physical work, such as exercise, physical labor, sports and so on), to slow down or prevent physical fatigue, increase oxygen levels in the blood, increasing physical activity in healthy people, improve performance and endurance, reduce muscle fatigue, reduce stress, strengthen the heart and cardiovascular function, improve sexual performance, increase levels of ATP in the muscles and/or reducing the amount of lactic acid in the blood. In specific embodiments, the implementation methods include the introduction of a number of activating sirtuin compound that increases mitochondrial activity, increases mitochondrial biogenesis and/or increases mitochondrial mass.

Sports refer to the ability of the athlete to muscle work when participating in sports activities. Increased sports activity, strength, speed and endurance measure to increase the force of muscle contraction, the increase in the amplitude of muscle contraction, reducing the reaction time muscle from the moment of initiation to the date of reduction. An athlete is someone who occupies the tsya sport at any level and who strives to achieve a higher level of force, speed and endurance in the competition, such a person, as for example, bodybuilders, cyclists, distance runners, runners for short distances, and so on. Increased sports activity is characterized by the ability to overcome muscle fatigue, the ability to sustain activity for longer periods of time and more effective workouts.

For muscular activity of the athlete, it is desirable to create conditions that allow for competition or training at higher levels of endurance over an extended period of time.

It is assumed that the methods of the present invention will also be effective in the treatment connected with muscles of pathological conditions, including acute sarcopenia, for example, atrophy of the muscles and/or cachexia associated with burns, bed regime, the fixation of the limb by applying gypsum; or major thoracic, abdominal and/or orthopedic surgery.

In specific embodiments implementing the invention offers new food compositions comprising modulators of sirtuin, the method of their preparation and method of using the compositions to improve the outcome of sporting activities. Accordingly, the available therapeutic compositions, foods and beverages, which areas shall indicate the action to increase physical endurance and/or prevent physical fatigue people, related in the broadest sense of the word, with physical exercise, including sports requiring endurance and effort, requiring repeated muscular contractions. Such food compositions may additionally include electrolytes, caffeine, vitamins, carbohydrates and so on.

Other applications

Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be used to treat or prevent viral infections, such as infections as a result of infection by the influenza virus, herpes virus, or HPV), or as antifungal agents. In specific embodiments, the implementation of modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be introduced as part of multidrug therapy with another therapeutic agent for the treatment of viral diseases. In another embodiment, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be introduced as part of multidrug therapy with another antifungal agent.

Entities that can be subjected to the above treatment include eukaryotes, such as mammals, for example humans, sheep, cattle, horses, pigs, dogs, cats, not p is engliash to the human race of primates, mice and rats. Cells that can be treated include eukaryotic cells such as the cells described above subject, plant cells, yeast cells and prokaryotic cells such as bacterial cells. For example, the modulating compounds may be introduced livestock to improve their ability to withstand the conditions of their detention in agriculture over a longer period.

Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be used to increase longevity, resistance to stress and resistance to apoptosis in plants. In one embodiment, the compound is applied to plants, for example, periodically, or fungi. In another embodiment, plants genetically modified with the aim of producing their connection. In another embodiment, plants and fruits treated with compounds before harvest and transportation to improve the resistance to damage during transport. Plant seeds may also be subjected to the engagement described in the description of the compounds, for example, for their protection.

In other embodiments, implementation of the modulating sirtuin compounds that increase the level of is/or activity of the protein of sirtuin, can be used to modulate life span of yeast cells. Situations where it may be desirable to increase the life span of yeast cells include any process that uses yeast, for example, the brewing of beer, yogurt and baked goods, e.g. bread. Using yeast with increased life expectancy may lead to using less yeast or give the opportunity to keep active yeast for longer periods of time. Yeast or other mammalian cells used for recombinant obtain proteins, may also be subjected to the described treatment.

Modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be used to increase longevity, resistance to stress and resistance to apoptosis insects. In this embodiment, the compounds can be applied to beneficial insects such as bees and other insects, which are involved in the pollination of plants. In a specific embodiment, the compound may be applied to bees producing honey. Usually described in the description of the methods can be applied to any organism, such as eukaryotes, which may be of p is aisleway value. For example, they can be applied to fish (fish farm) or birds (e.g. chickens and hens).

Higher doses modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can also be used as a pesticide, preventing regulation "off" genes and the regulation of apoptosis in the development process. In this embodiment, the connection can be applied to the plants using known technologies manner that provides biological uptake of compounds by the larva of an insect, but not plants.

At least from the point of view of the relationship between reproduction and longevity, modulating sirtuin compounds that increase the level and/or activity of the protein of sirtuin, can be applied for infringement of the reproduction of organisms, such as insects, animals and microorganisms.

4. Research

Another offer in the description of the methods include methods of identifying compounds or drugs that modulate sirtuins as well. Medicine can be a nucleic acid, such as aptamers. Research can be conducted in cell type or cell-free version. For example, the study may include incubation (or contacts) of sirtuin with the test tool andforming, in which sirtuin may be subjected to modulation by using a tool known as capable of modulating sirtuin, and monitoring or determining the level of modulation of sirtuin in the presence of the test assets in comparison with the case of absence of the test tools. The level of modulation of sirtuin can be measured by determining its ability to deacetylate substrate. Examples of substrates are acetylated peptides, which can be provided by the company BIOMOL (Plymouth Meeting, PA). Preferred substrates include p53 peptides, such as peptides containing acetylated K382. Particularly preferred substrate is a Fluor de Lys-SIRT1 (BIOMOL), i.e. acetylated peptide Arg-His-Lys-Lys. Other substrates are peptides of human histone H3 and H4 and acetylated amino acid. The substrates can be florogenetic. Sirtuins can be SIRT1, Sir2, SIRT3 or part of them. For example, recombinant SIRT1 may be provided by the company BIOMOL. The reaction can be carried out for about 30 minutes and stopped, for example, using nicotinamide. For determining the level of acetylation may be used set to research/identify drugs by fluorescent HDAC activity (discontiuation) (AK-500, BIOMOL Research Laboratories). Similar studies are described in the publication Btterman et al. (2002) J. Biol. Chem. 277:45099. The level of modulation of sirtuin in the study can be compared with the level of modulation of sirtuin in the presence of one or more (separately or simultaneously) described in the description of compounds that can serve as positive or negative control. Sirtuins as well for use in research can be reprezentirovanii proteins by sirtuins as well or their parts. As was shown in the description, activating connections, apparently react with the N-end SIRT1 proteins for use in research include the N-terminal part of sirtuins, such as near amino acids 1-176 or 1-255 SIRT1; near amino acids 1-174 or 1-252 Sir2.

In one embodiment, a screening study includes (i) contacting sirtuin with the test tool and acetylated substrate under conditions in which sirtuin able to deacetylate substrate in the absence of the test facility; and (ii) determining the level of acetylation of the substrate, where a lower level of acetylation of the substrate in the presence of the test assets in comparison with the level of acetylation in the absence of the test means indicates that the test agent stimulates deacetylation under the influence of sirtuin, while a higher level of acetylation of the substrate in the presence of the test environments is tion in the level of acetylation in the absence of the test means indicates that the test agent inhibits the deacetylation under the influence of sirtuin.

Methods of identifying an agent that modulates, for example, stimulates sirtuins as wellin vivomay include (i) contacting the cells with the test agent and the substrate, which is able to penetrate into the cell in the presence of an inhibitor of HDAC class I and class II under conditions in which sirtuin able to deacetylate substrate in the absence of the test facility; and (ii) determining the level of acetylation of the substrate, where a lower level of acetylation of the substrate in the presence of the test assets in comparison with the level of acetylation in the absence of the test means indicates that the test agent stimulates deacetylation under the influence of sirtuin, while a higher level of acetylation of the substrate in the presence of the test assets in comparison with the level of acetylation in the absence of the test means indicates that the test agent inhibits the deacetylation under the influence of sirtuin. The preferred substrate is an acetylated peptide, which is also, preferably, florogenetic, as described below. The method may additionally include the lizirovania cells for determining the level of acetylation of the substrate. The substrates can be added to the cells the REE concentrations of from about 1 μm to 10 mm, preferably, from about 10 μm to 1 mm, more preferably, from about 100 μm to 1 mm, such as about 200 μm. The preferred substrate is an acetylated lysine, for example, ε-acetylized (Fluor de Lys, FdL) or Fluor de Lys-SIRT1. A preferred inhibitor of HDAC class I and class II is trichostatin A (TSA), which can be used at concentrations in the range of from about 0.01 to 100 microns, preferably from about 0.1 to 10 microns, such as 1 μm. Incubation of the cells with the test compound and a substrate can be carried out for from about 10 minutes to 5 hours, preferably for about 1-3 hours. As TSA inhibits all HDAC class I and class II, and due to the fact that concrete substrates, for example, Fluor de Lys is a poor substrate for SIRT2 and even more minor substrate for SIRT3-7, such a study can be used to identify modulators of SIRT1in vivo.

5. The pharmaceutical composition

Described in the description of modulating sirtuin compounds can be prepared in the traditional way drugs using one or more physiologically or pharmaceutically acceptable carriers or excipients. For example, modulating sirtuin compounds and their pharmaceutically acceptable salts and solvate can be prepared the drugs for administration by, for example, injection (e.g. subcutaneously, intramuscularly, administered intraperitoneally), inhalation or insufflation (either through the mouth or through the nose), or by oral, buccal, sublingual, transdermal, nasal, parenteral or rectal administration. In one embodiment, modulating sirtuin connection can be entered locally, i.e. in the place where the target cells, i.e., in a specific tissue, organ or fluid (e.g. blood, cerebrospinal fluid, and so forth).

Of modulating sirtuin compounds can be prepared medicines for various routes of administration, including systemic and topical or localized administration. In General, information about the methods and dosage forms can be found in Remington''s Pharmaceutical Sciences, Meade Publishing Co., Easton, PA. In the case of parenteral administration is preferred injection, including intramuscular, intravenous, intraperitoneal, and subcutaneous injection. In the case of injections, the compounds can be prepared in the form of liquid solutions, preferably in physiologically compatible buffers such as solution Khanka or ringer's solution. In addition, the compounds can be prepared in solid form and re-dissolved or suspended immediately prior to use. It also includes lyophilizer the private form.

In the case of oral administration the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by traditional methods with pharmaceutically acceptable excipients such as binding agents (for example, pre-Galatasaray corn starch, polyvinylpyrrolidone or hypromellose); fillers (e.g. lactose, microcrystalline cellulose or hydrogenphosphate calcium); sliding substances (for example, magnesium stearate, talc or silica); disintegrating agents (e.g., potato starch or sodium starch glycolate); or wetting means (for example, sodium lauryl sulphate). The tablets can be coated with coating by using well-known engineering methods. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may represent a dry product for reconstitution in water or other suitable medium before use. Such liquid preparations can be prepared by traditional methods with pharmaceutically acceptable additives such as suspendresume means (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or Arabian gum); non-aqueous environment (such as the er, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid). The preparations may also contain buffer salts, substance, corrective taste and smell, coloring and sweetening substances, if necessary. Preparations for oral administration can be suitably prepared for the controlled release of active compounds.

In the case of administration by inhalation (for example, pulmonary administration) modulating sirtuin compounds may be conveniently introduced in the form of the produced aerosol jet from the spray pressure or a nebulizer with the use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of an aerosol under pressure single dose can be determined by setting valve for supplying a measured quantity. For use in the inhaler or insufflator can be prepared, for example, from gelatin, capsules and cartridges containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

Of modulating sirtuin compounds can be prepared drugs for parenteral the nogo administration by injection, for example, by bolus injection or continuous infusion. Preparations for injection can be a standard dosage form, for example in the form of ampoules or packings for repeated administration, with added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous medium, and may contain tools such as suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable environment, for example, sterile pyrogen-free water.

Of modulating sirtuin compounds can also be prepared rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppozitornoj bases such as cocoa butter or other glycerides.

In addition to the above drugs, modulating sirtuin compounds can also be prepared with drug depot effect. These long-acting drugs can be introduced by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. So, for example, modulating sirtuin compounds can be prepared with the appropriate polymeric or hydrophobic materials is (for example, in the form of an emulsion in the corresponding oil) or ion exchange resins, or as slowly soluble derivatives, for example, in the form of a slowly soluble salts. Dosage form with controlled release also includes the patches.

In specific embodiments, implementation of the features described in the description of the compounds can be prepared preparations for introduction into the Central nervous system (CNS) (described in Begley, Pharmacology & Therapeutics 104: 29-45 (2004)). Traditional approaches for the introduction of drugs into the Central nervous system include neurosurgical techniques (for example, intracerebrally injection or intracerebral-ventricular infusion); the molecule manipulation tools (e.g., producing the chimeric fused protein, which includes transport peptide that has affinity to molecules on the surface of endothelial cells in combination with a tool, which in itself is not able to pass through the blood-brain barrier (BBB)when you try to use one of the endogenous transport pathways BBB; pharmacological approaches aimed at increasing the lipid solubility means (for example, water-soluble compound of funds from lipid or cholesterol carriers); and transient violation of the integrity of the BBB by hyperosmotic destruction (due to what puzia solution of mannitol in the carotid artery or the use of biologically active products, such as angiotensin-peptide).

Liposomes are another delivery system of the medicinal product, which is easy to be injected. Accordingly, in the method of the invention the active compounds can also be introduced in the form of a liposomal delivery system. Liposomes are well known to the expert in this area. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine of phosphatidylcholine. Used in the method of the invention liposomes cover all types of liposomes, including, but not limited to, small manelmellado vesicles, large manelmellado vesicles and multilamellar vesicles.

Another method of preparation of the drug, in particular the solution of the modulator of sirtuin, such as resveratrol or its derivative, is the use of cyclodextrin. Under the cyclodextrin mean α-, β - or γ-cyclodextrin. Cyclodextrins are described in detail in patent document Pitha et al., U.S. Pat. No. 4727064, the content of which is contained in the description by reference thereto. Cyclodextrin are cyclic oligomers of glucose; these compounds form inclusion complexes with any drug whose molecule can be built in possessing lipophilic affinity cavity of the cyclodextrin molecules.

Rapidly disintegrating or dissolving dosage is army apply for quick absorption, in particular, buccal and sublingual absorption of pharmaceutically active agents. Fast dissolving dosage forms are preferred for patients, such as elderly people and children who have difficulty swallowing conventional solid dosage forms such as capsules and tablets. In addition, quick-dissolving dosage forms do not have drawbacks, for example, chewable dosage forms, for which the duration of the location of the active funds in the mouth of the patient is highly dependent determination of the amounts, correcting the taste and smell of medicines, and the degree of intolerance of the patient influence on the throat size of the particles of active funds.

Pharmaceutical compositions (including cosmetic preparations may contain from about 0,00001%to 100%, for example, from 0.001 to 10% or from 0.1% to 5% by weight, of one or more described in the description of modulating sirtuin compounds. In other embodiments, the implementation of the pharmaceutical composition comprises (i) from 0.05 to 1000 mg of the compounds of the invention or its pharmaceutically acceptable salt, and (ii) from 0.1 to 2 grams of one or more pharmaceutically acceptable auxiliary substances.

In one embodiment described in the description of modulating sirtuin compound is administered in topical drugs the at, containing a topical carrier that is commonly used for topical administration of medical preparations and includes any such known in the field of engineering material. Topical carrier may be selected so that it gave the opportunity to obtain a composition in the desired form, for example, in the form of ointment, lotion, cream, microemulsion, gel, oil, mud, or other such forms, and it may consist of material, either natural or artificial origin. Preferably, the selected media did not adversely affect the active agent or other components of the topical preparation. Examples suitable for use in the description of topical carriers include water, alcohols and other non-toxic organic solvents, glycerin, mineral oil, silicone, petroleum jelly, lanolin, fatty acids, vegetable oils, parabens, waxes and other similar materials.

Drugs can be colorless odorless ointments, lotions, creams, microemulsions and gels.

Modulating sirtuin connections can be put into ointments, which are usually semi-solid preparations and which is usually made on the basis of mineral oil or other oil derivatives. For professionals in this field is obvious that the particular basis which should be used for ointments, is a framework that can ensure the optimal delivery of drugs and, preferably, can provide other desired characteristics as well, for example, softening or other similar properties. As in the case of other media or environments, the materials should be inert, stable, non-irritating and desensibiliziruyuschey.

Modulating sirtuin connections can be put into lotions, which are usually preparations for application to the skin surface without friction, and are typically liquid or semiliquid preparations in which there are solid particles, including the active agent, in an aqueous or alcohol-based. Lotions are usually suspensions of solids, and they may include a liquid oil emulsion of the type oil-in-water.

Modulating sirtuin connections can be put into creams, which are usually viscous liquid or semisolid emulsions, either of type oil-in-water or water-in-oil. Basics creams washed with water and contain an oil phase, an emulsifier and the aqueous phase. The oil phase usually consists of paraffin oil and fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, though not necessarily, exceeds the oil phase in volume, and usually contains a water-retaining substance. The emulsifier in the formulation of the cream, as this description is about in the above mentioned monograph Remington's, is usually non-ionic, anionic, cationic or amphoteric surface-active substance.

Modulating sirtuin compounds may be introduced into microemulsions, which generally are thermodynamically stable isotope clear dispersions of two immiscible liquids such as oil and water, stabilized by using interfacial film of molecules of surface-active substances (Encyclopedia of Pharmaceutical Technology (New York: Marcel Dekker, 1992), volume 9).

Modulating sirtuin compounds may be introduced into the gel-like drugs, which generally are semisolid systems consisting of either suspensions made with fine inorganic particles (two-phase system)or large organic molecules, distributed almost uniformly in the liquid medium (single-phase gels). Although usually in gels using liquid aqueous media, alcohols and oils can also be used as a liquid medium.

Other means may also be included in the preparations, for example, other anti-inflammatory agents, analgesics, antimicrobial agents, antifungal agents, antibiotics, vitamins, antioxidants, and sunscreen, usually present in sunscreen preparations, including, but not limited to, anthranilate, benzophenone (in particular, benzothieno is -3), derivatives of camphor, cinnamate (for example, octylmethoxycinnamate), dibenzoylmethane (for example, butylperoxybenzoate), p-aminobenzoic acid (PABA) and its derivatives, salicylates (for example, octisalate).

In specific topical preparations, the active agent is present in an amount in the range of from about 0.25% wt. up to 75% of the mass. by weight of the preparation, preferably in the range of from about 0.25% wt. up to 30% of the mass. by weight of the drug, more preferably in the range of from approximately 0.5% of the mass. up to 15% of the mass. by weight of the drug, and most preferably in the range of from about 1.0% of the mass. up to 10% of the mass. by weight of the drug.

The eye condition may be subjected to treatment or prevention, for example, by systemic, topical, intraocular injections modulating sirtuin connection or by introducing a device with a slow release, which releases the modulating sirtuin connection. Modulating sirtuin compound that increases the level and/or activity of the protein of sirtuin, can be entered in a pharmaceutically acceptable ophthalmic environment, so that the connection is maintained in contact with the ocular surface for a sufficient period of time to ensure that the connection could penetrate the corneal and internal parts of the eye, as for example, front camera, rear camera, the stack is Vidnoe body, intraocular fluid, the liquid part of the vitreous, cornea, iris/eyelashes, lenses, vascular sheath/retina and sclera. Pharmaceutically acceptable ophthalmic environment may, for example, be ointment, vegetable oil, or encapsulating material. Alternatively, compounds of the invention can be injected directly into the vitreous body of the eye and watery fluid of the eye. In another embodiment, compounds can be introduced systemically, e.g. by intravenous infusion or injection, for the treatment of eyes.

Described in the description of modulating sirtuin connections can be stored in nestorgames oxygen environment. For example, resveratrol or its analogue may be prepared in a sealed capsule for oral administration, such as Capsugel Pfizer, Inc.

Cells, such as processedex vivousing modulating sirtuin compounds can be introduced in accordance with the methods of introduction of the graft to the subject, which can be, for example, the introduction of the immunosuppressant, e.g., cyclosporin A. with regard to the General principles of creation of a drug, they are described in Cell Therapy: Stem Cell Transplantation, Gene Therapy, and Cellular Immunotherapy, by G. Morstyn &W. Sheridan eds, Cambridge University Press, 1996; and Hematopoietic Stem Cell Therapy, E. D. Ball, J. Lister &P. Law, Churchill Livingstone, 2000.

Toxicwaste therapeutic efficiency modulating sirtuin compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. LD50is lethal dose for 50% of the subjects. ED50is the dose that is therapeutically effective in 50% of subjects. The ratio of toxic dose to therapeutic dose (LD50/ED50) is a therapeutic index. Modulating sirtuin compounds that are characterized by a high therapeutic indices are preferred. Because they can be used for modulation of sirtuin compounds, which are characterized by toxic side effects, should be taken to create a delivery system that purposefully delivers such compounds to the site of affected tissue to minimize potential damage to uninfected cells and, thereby, reduce side effects.

Data obtained in studies on cell cultures and animals, can be used to determine the interval dosing when used on people. The dosage of such compounds may be in the range of circulating concentrations that include the ED50with little toxicity or no toxicity. The dosage may vary within this interval depending on the dosage form and used as a way of introduction. For any connection, therapeutically effective dose can be estimated recognize the but studies on cell cultures. The dose can be determined in animal models with obtaining interval circulating plasma concentration, which includes the value of the IC50(that is, the concentration of the test compound that achieves a half-maximal inhibition of symptoms)as defined in cell culture. Such information can be used to more accurately determine the most appropriate for people of doses. Levels in plasma may be measured, for example, by high performance liquid chromatography.

6. Sets

In addition, in the description of the available kits, for example, kits for therapeutic purposes or kits for modulating the life span of cells or modulation of apoptosis. The set can include one or more modulating sirtuin compounds, for example, predefined doses. The kit can optionally include a device for contacting cells with links and instructions for use. Devices include syringes, stents, and other devices for introducing modulating sirtuin connection to the subject (for example, into a blood vessel of the subject) or applying it on the skin of the subject.

In yet another embodiment, the invention provides a composition of substances, comprising a modulator of sirtuin of this invention and another therapeutic agent (similar the th same time, used in combination therapies and combination compositions) in separate dosage forms, but are related to each other. Used in the description, the term "connected" means that the separate dosage forms are packaged together or attached to each other, so there is no doubt that the separate dosage forms are intended for sale and introduction as part of the same treatment regimen. Preferably, the means and the modulator of sirtuin were packaged together in a blister pack or other packaging with many cells, or if they are attached to each other, separately sealed containers (such as bags made of foil or other similar packaging)that can be disconnected by the user (for example, by breaking along the lines of incision between the two containers).

In yet another embodiment, the invention provides a kit comprising in separate containers (a) a modulator of sirtuin of this invention; and (b) another therapeutic agent, such as therapeutic agents, which are described in any location in the description of the request.

The implementation of these methods can be used, unless otherwise indicated, conventional methods of Cytology, cell culture, molecular biology, transgenic biology and, Microbiology, recombinant DNA and immunology, which are known in the art. Such methods are described in detail in the literature. See, for example, Molecular Cloning A Laboratory Manual, 2ndEd., ed. Sambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press: 1989); DNA Cloning, Volumes I and II (D. N. Glover ed., 1985); Oligonucleotide Synthesis (M. J. Gait ed., 1984); Mullis et al. U.S. Patent No: 4683195; Nucleic Acid Hybridization (B. D. Hames &S. J. Higgins eds. 1984); reduced And Translation (B. D. Hames &S. J. Higgins eds. 1984); Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); the treatise, Methods In Enzymology (Academic Press, Inc., N. Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D.M. Weir and C.C. Blackwell, eds., 1986); Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y., 1986).

EXAMPLES

Described in General terms, the invention will be easier to understand with the help of the following examples which are given only for the purpose of illustration, specific aspects and embodiments of the present invention and are in no way limit the invention.

Example 1.Synthesis of N-(4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-yl)thiazole-4-carboxamide (Compound 204).

Stage 1. Getting 8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-it (2):

1-(2-Hydroxy-3-nitrophenyl)alanon<> 1(1.2 g, is 6.61 mmol) were placed in 20 ml of pyridine with 3-triftoratsetilatsetonom48(1.2 ml, 7.9 mmol) and DBU (2,9 ml, 14.5 mmol). The reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was diluted with EtOAc and washed with diluted hydrochloric acid (1N HCl. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (1:1 pentane/EtOAc) gave 300 mg of the compound2. MS (ESI) calculated for C16H8F3NO4: 335,04; found: 336 [M+H].

Stage 2. Getting 8-amino-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-it (178):

8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one2(300 mg, 0.90 mmol) were placed in 10 ml of MeOH. Added a hydrate of sodium hydrosulfide (250 mg, 4.5 mmol) in solution in 4 ml of H2O. the Reaction mixture was stirred while boiling under reflux for 45 minutes. Then it was cooled to room temperature and concentrated under reduced pressure. The resulting aqueous mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to obtain 240 mg of the compound178. MS (ESI) calculated for C16H10F3NO2: 305,07; found: 306 [M+H].

Stage 3. P the receive N-(4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-yl)thiazole-4-carboxamide:

8-amino-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one (178) (70 mg, 0.23 mmol) were placed in 2 ml of DMF together with the thiazole-4-carboxylic acid3(30 mg, 0.23 mmol), ΗATU (175 mg, 0.46 mmol) and DIEA (80 μl, 0.46 mmol). The reaction mixture was stirred at room temperature for 18 hours. Then it was diluted with 5 ml of H2O. the obtained solids were filtered off, washed successively with diluted solution of NaHCO3/MeOH (1:1), aqueous MeOH, diluted with 1N HCl/MeOH (1:1), aqueous MeOH, and then pure MeOH. After drying under high vacuum, received 28 mg connection204as not quite white solid. MS (ESI) calculated for C20H11F3N2O3S: 416,04; found: 417 [M+H].

Example 2.Synthesis of N-(4-oxo-2-(pyridin-3-yl)-4H-chromen-8-yl)thiazole-4-carboxamide (Compound 215):

Stage 1. Getting 2-acetyl-6-nitrophenyl the nicotinate (5):

A mixture of 1-(2-hydroxy-3-nitrophenyl)ethanone1(1.0 g, 5.5 mmol), nicotinic acid4(0.8 g, 5.8 mmol), DCC (2.4 g, 11.6 mmol) and DMAP (0.7 g, 5.8 mmol) in CH2Cl2(30 ml) was stirred at room temperature for 12 hours. After cooling to 0°C, precipitated dicyclohexylphosphino was removed by filtration and the filtrate was concentrated. The crude residue was purified flash chromatography, elwira with pentane/EtOAc (10:1) with what rucenim connection 5(1.3 g, 81% yield).

Stage 2. Getting 8-nitro-2-(pyridin-3-yl)-4H-chromen-4-it (6):

2-acetyl-6-nitrophenylacetic5(1.3 g, 4.4 mmol) was dissolved in pyridine (10 ml) and heated to 50°C. was Added in small portions finely powdered KOH (3.4 g, 6.1 mmol). After cooling to room temperature the reaction mixture was concentrated to dryness. Added concentrated H2SO4(0.4 g, 4.4 mmol) and AcOH (3 ml), and the mixture was heated up to 80°C for 2 hours. The reaction mixture was concentrated to dryness and the crude residue was purified flash chromatography, elwira with pentane/EtOAc (5:1) to obtain the connection6(410 mg, 35% yield).

Stage 3. Getting 8-amino-2-(pyridin-3-yl)-4H-chromen-4-it (7):

8-amino-2-(pyridin-3-yl)-4H-chromen-4-one7received from 78% yield, using a technique similar to the technique used in example 1, step 2, to obtain compounds178.

Stage 4. Obtaining N-(4-oxo-2-(pyridin-3-yl)-4H-chromen-8-yl)thiazole-4-carboxamide (Compound 215):

Compound 215 was obtained from 23% yield, using a technique similar to the technique used in example 1, stage 3, for connection 204.

Example 3.Synthesis of N-(4-oxo-2-(2-(trifluoromethyl)phenyl)-4H-chromen-8-yl)thiazole-4-carboxamide (Compound 227):

Stage 1. Obtaining (E)-1-(2-hydroxy-3-nitrophenyl)-3-(2- (trifluoromethyl)phenyl)prop-2-EN-1-it (9):

A solution of 1-(2-hydroxy-3-nitrophenyl)ethanone1(788 mg, 4.4 mmol), 2-(trifluoromethyl)benzaldehyde8(1.1 g, 6.5 mmol) and 25% aqueous KOH (90 ml) in EtOH (90 ml) was stirred for 12 hours at room temperature. The reaction mixture was poured into ice water, and adjusting the pH to 2 with concentrated HCl. The precipitate was filtered off, washed with H2O and dried under vacuum to obtain compound9in the form of a yellow solid (1.4 g, 95% yield).

Stage 2. Getting 8-nitro-2-(2-(trifluoromethyl)phenyl)-4H-chromen-4-it (10):

A solution of (E)-1-(2-hydroxy-3-nitrophenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-EN-1-it9(1.4 g, 4.2 mmol) and SeO2(1.4 g, 12.5 mmol) in DMSO/dioxane (35 ml, 1:15) was boiled under reflux for 12 hours. After cooling to room temperature the reaction mixture was passed through a filter and the filtrate was concentrated to dryness. The crude residue is suspended in H2O and filtered to obtain compound10in the form of a yellow solid (1.3 g, 92% yield).

Stage 3. Getting 8-amino-2-(2-(trifluoromethyl)phenyl)-4H-chromen-4-it:

Connection11received from 58% yield by the Yu techniques similar to the technique used in example 1, step 2, to obtain compounds178.

Stage 4. Obtaining N-(4-oxo-2-(2-(trifluoromethyl)phenyl)-4H-chromen-8-yl)thiazole-4-carboxamide:

Compound 227 was obtained with 60% yield, using a technique similar to the technique used in example 1, stage 3, for connection 204. MS (ESI) calculated for C20H11F3N2O3S: 416,04; found: 417 [M+H].

Example 4.Synthesis of N-(4-oxo-2-(2-(trifluoromethyl)phenyl)-4H-chromen-8-yl)pyridine-3-sulfonamida (Compound 326):

Hydrochloride pyridine-3-sulphonylchloride12(280 mg, 1.3 mmol) was added to a solution of 8-amino-2-(2-(trifluoromethyl)phenyl)-4H-chromen-4-it11(100 mg, 0,328 mmol) in pyridine (5 ml). The reaction mixture was heated at 80°C for 12 hours. The pyridine was removed under vacuum. The residue was placed in CH2Cl2, washed with saturated aqueous NaHCO3, dried (MgSO4) and concentrated. The crude residue was purified liquid chromatography medium pressure elwira using CH2Cl2/MeOH (0-10%), and then recrystallized from CH3CN obtaining connection326(46 mg, 31% yield). MS (ESI) calculated for C21H13F3N2O4S: 446,1; found: 447 [M+H].

Example 5.Synthesis of 5-oxo-N-(4-oxo-2-(2-(trif ormetal)phenyl)-4H-chromen-8-yl)pyrrolidin-2-carboxamide (Compound 313):

Thionyl chloride (236 mg, 2.0 mmol) was added to a solution of 5-oxopyrrolidin-2-carboxylic acid120(170 mg, of 1.32 mmol) in THF (5 ml) at 0°C. was Added DMF (1 drop), and the solution warmed to room temperature for 2 hours, then was cooled to 0°C. was Added a solution of 8-amino-2-(2-(trifluoromethyl)phenyl)-4H-chromen-4-it11(100 mg, 0.33 mmol) and pyridine (0.5 ml) in THF (1 ml)and the reaction mixture was heated to room temperature and was stirred for 2 hours. The reaction mixture was concentrated to dryness, dissolved in EtOAc, washed with saturated aqueous NaHCO3, brine, and dried (Na2SO4). The crude residue was purified preparative thin-layer chromatography, elwira EtOAc, obtaining connection313. MS (ESI) calculated for C21H15F3N2O4: 416,1; found: 417 [M+H].

Example6.Synthesis of N-(2-(2-(methylsulphonyl)phenyl)-4-oxo-4H-chromen-8-yl)thiazole-4-carboxamide (Compound 241):

Stage 1. Obtaining (E)-1-(2-hydroxy-3-nitrophenyl)-3-(2- (methylthio)phenyl)prop-2-EN-1-it (15):

(E)-1-(2-hydroxy-3-nitrophenyl)-3-(2-(methylthio)phenyl)prop-2-EN-1-he15received with 100% yield, using a technique similar to the technique used in example 3, step 1, to obtain (E)-1-(2-hydroxy-3-nitrophenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-EN-1-it9

Stage 2. Obtaining(E)-1-(2-hydroxy-3-nitrophenyl)-3-(2- (methylsulphonyl)phenyl)prop-2-EN-1-she (16):

A solution of OXONE (3.7 g, 6 mmol) in H2O (15 ml) was added dropwise to a solution of (E)-1-(2-hydroxy-3-nitrophenyl)-3-(2-(methylthio)phenyl)prop-2-EN-1-it15(315 mg, 1.0 mmol) in THF/MeOH (35 ml, 1:1) at room temperature. The reaction mixture was stirred for 12 hours. Volatile components were removed under reduced pressure, and the precipitate was filtered off, washed with H2O and dried under vacuum. The crude residue was purified flash chromatography, elwira using CH2Cl2/MeOH (0-1%) to obtain compound16in the form of a yellow solid (200 mg, yield 58%).

Stage 3. Obtaining 2-(2-(methylsulphonyl)phenyl)-8-nitro-4H-chromen-4-it (17):

2-(2-(methylsulphonyl)phenyl)-8-nitro-4H-chromen-4-one17received from 45% yield, using a technique similar to the technique used in example 4, step 2, to obtain compounds10.

Stage 4. Getting 8-amino-2-(2-(methylsulphonyl)phenyl)-4H-chromen-4-it (18):

8-amino-2-(2-(methylsulphonyl)phenyl)-4H-chromen-4-one18received from 93% yield, using a technique similar to the technique used in example 1, step 2, to obtain compounds178.

Stage 5. Obtaining N-(2-(2-(METI sulfonyl)phenyl)-4-oxo-4H-chromen-8-yl)thiazole-4-carboxamide (Compound 241):

Connection241received 26% yield, using a technique similar to the technique used in example 1, step 3, to obtain N-(4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-yl)thiazole-4-carboxamide compounds204.

Example 7.Synthesis of N-(4-oxo-2-o-tolyl-4H-chromen-8-yl)pyrazin-2-carboxamide (Compound 273):

Stage 1. Obtaining (E)-1-(2-hydroxy-3-nitrophenyl)-3-o-lolipop-2-EN-1-it:

(E)-1-(2-hydroxy-3-nitrophenyl)-3-o-lolipop-2-EN-1-he21received from 88% yield, using a technique similar to the technique used in example 3, step 1, to obtain (E)-1-(2-hydroxy-3-nitrophenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-EN-1-it9.

Stage 2. Getting 8-nitro-2-o-tolyl-4H-chromen-4-it (22):

A mixture of (E)-1-(2-hydroxy-3-nitrophenyl)-3-o-lolipop-2-EN-1-it21(250 mg, 0.88 mmol), I2(471 mg, of 1.86 mmol), DMSO (0.5 ml) and 1,4-dioxane (10 ml) was boiled under reflux for 5 hours. The reaction mixture was concentrated and added H2O. the precipitate was filtered off, washed with pentane/EtOAc (1:1) and dried under vacuum to obtain compound22in the form of a yellow solid.

Stage 3. Getting 8-amino-2-o-tolyl-4H-chromen-4-it (23):

8-amino-2-o-tolyl-4H-chromen--he 23received with 40% yield in two stages using a technique similar to the technique used in example 1, step 2, to obtain compounds178.

Stage 4. Obtaining N-(4-oxo-2-o-tolyl-4H-chromen-8-yl)pyrazin-2-carboxamide (Compound 273):

Connection273received from 53% yield, using a technique similar to the technique used in example 1, stage 3, for connection204.

Example 8.Synthesis of N-(4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-8-yl)pyrazin-2-carboxamide (Compound 306):

Stage 1. Obtain 1-(2-hydroxy-3-nitrophenyl)-3-(2-(trifluoromethyl)pyridin-3-yl)propane-1,3-dione (26):

DBU (334 mg, 2.2 mmol) was added to a solution of 1-(2-hydroxy-3-nitrophenyl)ethanone1(181 mg, 1 mmol) and 2-(trifluoromethyl)-pyridine-3-carbonylchloride25(1.1 mmol) in pyridine (3 ml). The mixture was stirred at 70°C for 12 hours, poured into 2N HCl (20 ml) and was extracted with EtOAc. The organic layers were dried over Na2SO4concentrated and was purified preparative thin-layer chromatography (CH2Cl2/EtOAc, 10:1) to obtain the connection26in the form of a yellow solid (135 mg, 38% yield).

Stage 2. Getting 8-nitro-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-4-it (27):

A mixture of 1-(2-hydroxy-3-nitrophenyl)-3-(2 - (trifluoromethyl)pyridin-3-yl)propane-1,3-dione 26(135 mg, 0.38 mmol), concentrated HCl (0.2 ml) and AcOH (5 ml) was stirred at 100°C for 3.5 hours. The reaction mixture was concentrated and added a saturated aqueous solution of Na2CO3. The obtained solid was filtered to obtain compound27in the form of a yellow solid, which was used in the next stage without additional processing.

Stage 3. Getting 8-amino-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-4-it (28):

A mixture of 8-nitro-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-4-it27(118 mg, 0.38 mmol), Fe (96 mg, 1.7 mmol), saturated aqueous solution of NH4Cl (7 ml) and MeOH (14 ml) was stirred at 90°C for 2 hours. After cooling to room temperature the reaction mixture was poured into EtOAc and the layers were separated. The organic layer was dried (MgSO4) and concentrated to obtain compound28in the form of a yellow solid (90 mg, 77% yield in two stages).

Stage 4. Obtaining N-(4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-8-yl)pyrazin-2-carboxamide (Compound 306):

Connection306received 28% yield, using a technique similar to the technique used in example 1, stage 3, for connection204.

Example 9.Synthesis of 4-oxo-N-(pyridin-3-yl)-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-Carbo is samida (Compound 224):

Stage 1. Getting 2-acetoxy-5-bromobenzoyl acid (30):

To a well stirred mixture of 5-bromosalicylic acid29(200 g, of 0.92 mol) and acetic anhydride (210 ml) was added concentrated H2SO4(0.5 ml). After a few minutes the reaction mixture was hardened and suspended in H2O (1 l). The solid was filtered and washed with H2O. White solid was dissolved in ethyl acetate (3 l), washed with brine, dried (Na2SO4) and concentrated to obtain compound30(210 g, 88% yield).

Stage 2. Obtaining 3-acetyl-5-bromo-2-hydroxybenzoic acid (31):

2-acetoxy-5-bromobenzoyl acid30(100 g of 0.39 mol) and AlCl3(159 g, 1.20 mol) was mixed in a three-neck flask with a capacity of 3 liters and heated to 160°C under mechanical stirring. After 3 hours the reaction mixture was cooled to room temperature, crushed in a mortar and poured into 800 g of ice containing concentrated HCl (200 ml). The suspension was extracted with ethyl acetate, washed with 1N HCl, brine, dried (Na2SO4) and concentrated. The crude residue was washed with dichloromethane to obtain compound31(50 g, 50% yield).

Stage 3. Obtaining 3-acetyl-2-hydroxybenzoic acid (32):

3-acetyl-5-bromo-2-hydroxybenzoic acid31(50 g, to 0.19 mol) was dissolved in 250 ml of ethanol. After adding 5.0 g of 10% Pd/C, the reaction mixture was first made at a pressure of H215 ATM and room temperature for 6 hours. The catalyst was filtered and the solvent evaporated. The residue was poured into H2O and was extracted with CH2Cl2. The combined organic phase was dried and solvent was removed to obtain compound32(28 g, 85% yield).

Stage 4. Obtaining (E)-2-hydroxy-3-(3-(3-(trifluoromethyl)phenyl)acryloyl)benzoic acid (34):

3-acetyl-2-hydroxybenzoic acid32(0.9 g, 5 mmol) and 3-(trifluoromethyl)benzaldehyde33(0.96 g, 5.5 mmol) was dissolved in 100 ml of ethanol. After adding the same volume of 25% aqueous KOH, the reaction mixture was stirred for 24 hours. The mixture was poured into ice water, and adjusting the pH to 2 using concentrated HCl. The precipitate was filtered off, washed with H2O and dried to obtain compound34(0.8 g, 47% yield)

Stage 5. Getting 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-carboxylic acid (35):

A mixture of (E)-2-hydroxy-3-(3-(3-(trifluoromethyl)phenyl)acryloyl)benzoic acid34(0.8 g, 2.4 mmol), SeO2(0,79 g, 7.1 mmol) and DMSO (5 ml) in dioxane (150 ml) was heated with reverse Kholodilin the com for 1 hour. The black solid was filtered and the dioxane evaporated. The remaining oil suspended in H2O, filtered and dried to obtain compound35(0.56 g, 76% yield).

Stage 6. Getting 4-oxo-N-(pyridin-3-yl)-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-carboxamide (Compound 224):

A mixture of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-carboxylic acid35(0.5 g, 1.5 mmol), 3-aminopyridine36(0.28 g, 3 mmol), HATU (1,14 g, 3 mmol) and DIPEA (0,78 g, 6 mmol) in DMF (4 ml) was stirred at room temperature for 12 hours. The reaction mixture was filtered and the solid is washed with H2O and dried under vacuum to obtain compound224in the form of a yellow solid (0,13 g, 23% yield). MS (ESI) calculated for C22H13F3N2O3: 410,09; found: 411 [M+H].

Example 10.Synthesis of 4-oxo-N-(6-(pyrrolidin-1-ylmethyl)pyridine-2-yl)-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-carboxamide (Compound 243):

Stage 1. Getting 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-carbonylchloride (37):

Axillare (285 mg, 2,24 mmol) was added to a solution of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-carboxylic acid35(250 mg, 0.75 mmol) in CH2Cl2(15 ml), then was added DMF (1 drop). The reaction mixture was stirred at room temperature during the 12 hours. Volatile components were concentrated and the crude residue was dissolved in CH2Cl2. The solvent is evaporated and the crude product was dried under vacuum and used without further purification.

Stage 2. Getting 4-oxo-N-(6-(pyrrolidin-1-ylmethyl)pyridine-2-yl)-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-carboxamide (Compound 243):

DIPEA (125 ml, 0,705 mmol) was added to a solution of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-carbonylchloride37(83 mg, 0,235 mmol) and hydrochloride of 6-(pyrrolidin-1-ylmethyl)pyridine-2-amine49(75 mg, 0,353 mmol) in CH3CN (15 ml). The reaction mixture was heated at 60°C for 12 hours, cooled to room temperature and poured into H2O. the Mixture was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified liquid chromatography medium pressure elwira using CH2Cl2/MeOH (0-10%), with connection243(46 mg, 40% yield). MS (ESI) calculated for C27H22F3N3O3: 493,16; found: 494 [M+H].

Example 11.Synthesis of N-(5-methylthiazole-2-yl)-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-8-carboxamide (Compound 305):

Stage 1. Obtain methyl 3-acetyl-2-hydroxybenzoate (38):

To a solution of 3-acetyl-2-hydroxyl what Noynoy acid 32(3 g, and 16.7 mmol) in MeOH (50 ml) was added concentrated H2SO4(3.0 ml). The reaction mixture is boiled under reflux for 12 hours. After concentration under vacuum, the crude residue was diluted with H2O, podslushivaet to pH=8 water NaHCO3and was extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to obtain compound38in the form of a white solid (550 mg, 20% yield).

Stage 2. Obtain methyl 2-hydroxy-3-(3-oxo-3-(2-(trifluoromethyl)pyridin-3-yl)propanol)benzoate (39):

2-(trifluoromethyl)pyridine-3-carbonylchloride25(300 mg, of 1.46 mmol) was added to a mixture of methyl 3-acetyl-2-hydroxybenzoate38(183 mg, of 1.46 mmol) and DBU (446 mg, of 2.92 mmol) in pyridine at 0°C. the Reaction mixture was heated at 80°C for 12 hours. The resulting mixture was poured into H2O and was extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated to obtain compound39(600 mg)which was used without further purification.

Stage 3. Obtain methyl 4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-8-carboxylate (40):

A mixture of 2-hydroxy-3-(3-oxo-3-(2-(trifluoromethyl)pyridin-3-yl)propanol)benzoate39(600 mg, of 1.46 mmol) and concentrated HCl (1 ml) in acetic acid (5 ml) was heated is at 100°C for 4 hours. The reaction mixture was concentrated, and added a saturated aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated. The crude residue was purified flash chromatography to obtain compound40(120 mg, 23% yield).

Stage 4. Getting 4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-8-carboxylic acid (41):

LiOH-H2O (28 mg, 0.64 mmol) was added to a solution of methyl 4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-8-carboxylate40(120 mg, 0.32 mmol) in H2O/THF/MeOH (5 ml, 1:2:2). The reaction mixture was stirred at ambient temperature for 12 hours, poured into H2O, adjust pH value to 3. The mixture was extracted with ethyl acetate, dried (MgSO4) and concentrated to obtain compound41(120 mg)which was used without further purification.

Stage 5. Obtaining N-(5-methylthiazole-2-yl)-4-oxo-2-(2- (trifluoromethyl)pyridin-3-yl)-4H-chromen-8-carboxamide (Compound 305):

A mixture of 4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-8-carboxylic acid41(210 mg, 0.6 mmol), 5-methyl-1,3-thiazol-2-ylamine47(68 mg, 0.6 mmol), HATU (274 mg, to 0.72 mmol), and DIPEA (155 mg, 1.2 mmol) in DMF (4 ml) was stirred at 55°C for 12 hours. The reaction mixture was wiliwili H 2O (25 ml) and was extracted with ethyl acetate. The organic layer was concentrated and purified flash chromatography to obtain compound305(85 mg, 32% yield). MS (ESI) calculated for C20H12F3N3O3S: 431,06; found: 432 [M+H].

Example 12.Synthesis of N-(5-methylthiazole-2-yl)-4-oxo-2-(pyridin-4-yl)-4H-chromen-8-carboxamide (Compound 248):

Stage 1. Getting 2-acetyl-6-(methoxycarbonyl)phenylisocyanate (43):

Pyridine-4-carbonylchloride42(705 mg, 5 mmol) was added to a solution of methyl 3-acetyl-2-hydroxybenzoate38(650 mg, 3.6 mmol) and DIEA (932 mg, 7.2 mmol) in CH3CN (10 ml). The reaction mixture was stirred at room temperature for 12 hours, poured into H2O (20 ml) and was extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and concentrated. The residue was purified preparative high performance liquid chromatography to obtain the product as yellow solid (855 mg, 83% yield).

Stage 2. Obtain methyl 2-hydroxy-3-(3-oxo-3-(pyridin-4-yl)propanol)benzoate (44):

A solution of t-BuOK (3,03 ml, 7.5 mmol) in THF was added to a solution of 2-acetyl-6-(methoxycarbonyl)phenylisocyanate43(850 mg, 2.5 mmol) in THF (50 ml) at 0°C. the Reaction mixture was stirred at room temperature for the of 12 hours, then concentrated to dryness to obtain compound44.

Stage 3. Obtain methyl 4-oxo-2-(pyridin-4-yl)-4H-chromen-8-carboxylate (45):

Methyl 4-oxo-2-(pyridin-4-yl)-4H-chromen-8-carboxylate45received from 43% yield, using a technique similar to the technique used in example 11, stage 3, for connection40.

Stage 4. Getting 4-oxo-2-(pyridin-4-yl)-4H-chromen-8-carboxylic acid (46):

4-oxo-2-(pyridin-4-yl)-4H-chromen-8-carboxylic acid46received from 63% yield, using a technique similar to the technique used in example 11, step 4, to obtain 4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-8-carboxylic acid41.

Stage 5. Obtaining N-(5-methylthiazole-2-yl)-4-oxo-2-(pyridin-4-yl)-4H-chromen-8-carboxamide (Compound 248):

Connection248received 30% yield, using a technique similar to the technique used in example 11, step 5, to obtain N-(5-methylthiazole-2-yl)-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-8-carboxamide compounds305. MS (ESI) calculated for C19H13N3O3S: 363,07; found: 364 [M+H].

Additional compounds in table 1 and in the scope of the invention can be obtained using similar methods by the reaction of a combination of sootvetstvujushej carboxylic acid and amine intermediates. Examples of additional compounds of carboxylic acid and amine intermediates below.

Example 13.Synthesis of 2-(deformity)benzaldehyde (52):

Stage 1. Obtain 1-bromo-2-(deformity)benzene (51):

DAST (8.7 g, 54.1 mmol) was added to a mixture of 2-bromobenzaldehyde50(5.0 g, of 27.0 mmol) in dichloromethane (100 ml) at 0°C. the Reaction mixture was stirred at room temperature for 12 hours, poured into saturated aqueous solution of NaHCO3and was extracted with EtOAc. The organic layer was concentrated to obtain compound51(5,4 g, 96% yield)which was used in the next stage without additional purification.

Stage 2. Getting 2-(deformity)benzaldehyde (52):

A solution of n-BuLi (4,2 ml, 10.6 mmol) in THF was added to a solution of 1-bromo-2-(deformity)benzene51(2.0 g, 9.7 mmol) in THF (50 ml) at -78°C. the Reaction mixture was stirred for 30 minutes and was added DMF (1.4 g, and 19.3 mmol). Stirring was continued for 1 hour at -40°C, and the reaction was stopped by adding a saturated aqueous solution of NH4Cl. The crude mixture was extracted with Et2O, dried (MgSO4) and concentrated to obtain compound52(1.7 g, 94% yield).

Example 14.Synthesis of (R)-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)nicotinic acid is ( 55):

(R)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol54(1.8 ml, 14.9 mmol) was added at room temperature to a suspension of NaH (392 mg, 16.3 mmol) in THF (30 ml). The reaction mixture was stirred at room temperature for 30 minutes and was added 2-bromonicotinic acid 53 (1 g, of 4.95 mmol). The reaction mixture is boiled under reflux for 12 hours. After cooling to room temperature, adjust pH to 3 by addition of 3N HCl. The mixture was poured into brine and was extracted with EtOAc. The combined organic layers were dried and concentrated. The crude product was recrystallized from pentane/EtOAc to obtain the connection55(1.2 g, 92% yield). The acetonide protective group can be removed after the reaction combination with the corresponding aniline by treatment with EtOH/3N HCl (4:1) by boiling under reflux for 12 hours.

Example 15.Synthesis of (R)-6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pikolinos acid (57):

(R)-6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pikolinos acid57received from 74% yield, using a technique similar to the technique used in example 14 to obtain the connection55. The acetonide protective group can be removed after the reaction combination with the corresponding aniline by treatment with EtOH/3N Cl (4:1) by boiling under reflux for 12 hours.

Example 16.Synthesis of (R)-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)isonicotinic acid (59):

(R)-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)isonicotinoyl acid59received with 72% yield using a technique similar to the technique used in example 14 to obtain the connection55. The acetonide protective group can be removed after the reaction combination with the corresponding aniline by treatment with EtOH/3N HCl (4:1) by boiling under reflux for 12 hours.

Example 17.Synthesis of (R)-6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)nicotinic acid (61):

(R)-6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)nicotinic acid61received with 60% yield, using a technique similar to the technique used in example 14 to obtain the connection55. The acetonide protective group can be removed after the reaction combination with the corresponding aniline by treatment with EtOH/3N HCl (4:1) by boiling under reflux for 12 hours.

Example 18.Synthesis of 6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pikolinos acid (64):

6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pikolinos acid64received from 66% yield using a technique similar to the technique used in example 14 to receive the connection 55. The acetonide protective group can be removed after the reaction combination with the corresponding aniline by treatment with EtOH/3N HCl (4:1) by boiling under reflux for 12 hours.

Example19.Synthesis of 2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)nicotinic acid (65):

2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)nicotinic acid65received 23% yield, using a technique similar to the technique used in example 14 to obtain the connection55. The acetonide protective group can be removed after the reaction combination with the corresponding aniline by treatment with EtOH/3N HCl (4:1) by boiling under reflux for 12 hours.

Example 20.Synthesis of 6-(morpholinomethyl)pikolinos acid (69):

Stage 1. Getting 4-((6-bromopyridin-2-yl)methyl)research (68):

NaBH(OAc)3compared with 68.5 g, 0,323 mol) was added to a solution of 6-bronekollektsia66(40 g, 0.22 mol) and the research67(20,9 g, 0.24 mol) in 1,2-dichloroethane (500 ml). The mixture was stirred at room temperature for 16 hours. Was added a saturated solution of NaHCO3(500 ml)and the mixture was extracted with EtOAc, washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified flash chromatography on silica gel, elwira sociopathology ether:ethyl acetate (10:1) to obtain the connection 68(38 g, 68% yield).

Stage 2. Getting 6-(morpholinomethyl)pikolinos acid (69):

n-BuLi (56 ml, 0,140 mol) in THF was added to a solution of 4-((6-bromopyridin-2-yl)methyl)research68(30 g, 0.12 mol) in THF (500 ml) at -78°C. the Mixture was stirred for 30 minutes and was barbotirovany CO2(gas) through the reaction mixture for 30 minutes. Volatile components were removed under vacuum, and the residue was extracted with CH2Cl2/MeOH (1:1). The solvent is evaporated, the residue was washed CH2Cl2getting connection69(11,0 g, 42% yield).

Example 21.Synthesis of 6-(pyrrolidin-1-ylmethyl)pikolinos acid (74):

Stage 1. Obtain methyl 6-(chloromethyl)picolinate (71):

SOCl2(57 g, 0.48 mol) was added to a solution of methyl 6-(hydroxymethyl)picolinate70(40,0 g, 0,239 mol) (Chem. Eur. J. 2006, 12, 6393-6402) in dichloromethane (500 ml) at room temperature. The mixture was stirred at 40°C for 1 hour and added a saturated aqueous solution of K2CO3to adjust the pH value to 9. The mixture was extracted with CH2Cl2, and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated under vacuum to obtain compound71(45 g).

Stage 2. Obtain methyl 6-(pyrrolidin-1-ylmethyl)picolinate (73):

K2CO3(66 g, 0.48 mol) was added to a solution of methyl 6-(chloromethyl)picolinate71(45,0 g) and pyrrolidine72(34 g, 0.48 mol) in DMF (300 ml). The reaction mixture was heated at 80°C for 12 hours. Added H2O (300 ml)and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under vacuum to obtain compound73(36 g).

Stage 3. Getting 6-(pyrrolidin-1-ylmethyl)pikolinos acid (74):

A mixture of methyl 6-(pyrrolidin-1-ylmethyl)picolinate73(36 g) and NaOH (40 g, 1.0 mol) in ethanol/H2O (320 ml) was stirred at 75°C for 16 hours. The pH was adjusted to 7 3N HCl and was extracted with EtOAc. The aqueous layer was concentrated to dryness and extracted using dichloromethane/methanol (3:1 by volume). The organic layer was dried with obtaining connection74(27 g, 55% yield).

Example 22.Synthesis of N-methylpropene (76):

Connection76were obtained using a technique similar to the technique described in the publication J. Org. Chem. 2003, 66, 2652.

Example 23.Synthesis of 6-(pyrrolidin-1-ylmethyl)pyridine-2-amine (49):

Stage 1. Obtain ethyl 6-aminopyridine (78):

To a solution of 2-amino-6-pyridineboronic acid77(6.0 g, to 43.5 mmol) in ethanol (150 is l) was added thionyl chloride (12.0 g, 101 mmol) at 0°C. the resulting reaction mixture was stirred while boiling under reflux for 12 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. Was added a saturated aqueous solution of Na2CO3up until the pH of the solution reached 9. The mixture was concentrated under reduced pressure, and the obtained residue was added dichloromethane (150 ml). The mixture was intensively stirred at room temperature for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure to obtain compound78(5.5 g, 76% yield).

Stage 2. Obtain ethyl 6-(tert-butoxycarbonylamino)picolinate (79):

To a solution of ethyl 6-aminopyridine78(5.5 g, 33 mmol) in tert-BuOH (120 ml) and acetone (40 ml) was added 4-dimethylaminopyridine (0.08 g, 0.66 mmol) and di-tributilphosphat (10.8 g, a 49.5 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed by concentration under reduced pressure was added a mixture of hexane/dichloromethane (180 ml, 3:1). The resulting mixture was cooled to -20°C within 2 hours. The obtained solid was filtered and dried to obtain compound79(11,0 g, 91% yield).

Stage 3. Obtain tert-butyl 6-(hydroxymethyl)pyrid is n-2-ylcarbamate (80):

To a stirred solution of ethyl 6-(bis(tert-butoxycarbonyl)amino)picolinate79(11,0 g, 33 mmol) in THF (120 ml) under nitrogen atmosphere was added LiAlH4(3.80 g, 100 mmol) in THF (60 ml) for 30 minutes at 0°C. the Reaction mixture was stirred at 0°C for 6 hours, and stopped the reaction by careful addition of H2O (2.0 ml) and 10% NaOH solution (4.0 ml) at 0°C. the Reaction mixture was filtered and the filtrate was dried (Na2SO4) and concentrated under reduced pressure. The obtained residue was purified by chromatography (1:1 petroleum ether:ethyl acetate) to obtain compound80(3.0 g, 41% yield).

Stage 4. Obtain (6-(tert-butoxycarbonylamino)pyridine-2-yl)methylmethanesulfonate (81):

To a solution of tert-butyl 6-(hydroxymethyl)pyridine-2-ylcarbamate80(3.0 g, a 13.4 mmol) and diisopropylethylamine (5.0 g, 40 mmol) in acetonitrile (30 ml) was added methanesulfonamide (2.0 g, to 17.4 mmol) for 30 minutes at 0°C, and the mixture was stirred for 2 hours at room temperature. The reaction was stopped by adding a saturated aqueous solution of NaHCO3and were extracted with ethyl acetate (3×60 ml). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to get crude compound81with kolichestvennymi output.

Stage 5. Obtain tert-butyl 6-(pyrrolidin-1-ylmethyl)pyridine-2-ylcarbamate (82):

A mixture containing (6-(tert-butoxycarbonylamino)pyridine-2-yl)methylmethanesulfonate81(of 1.30 g, 3.2 mmol), pyrrolidin72(0,46 g, 6.4 mmol) and K2CO3(of 1.30 g, 9.6 mmol) in acetonitrile (15 ml)was stirred at room temperature for 12 hours. Was added a saturated aqueous solution of NaHCO3and the mixture was concentrated under reduced pressure. The resulting aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to obtain compound82(0.75 g, 62% yield).

Stage 6. Getting 6-(pyrrolidin-1-ylmethyl)pyridine-2-amine (49):

To a solution of tert-butyl 6-(pyrrolidin-1-ylmethyl)pyridine-2-ylcarbamate82(750 mg, a 2.71 mmol) in dichloromethane (10 ml) was added triperoxonane acid (4.0 ml) at room temperature. The resulting reaction mixture was stirred at room temperature for 6 hours and then concentrated under reduced pressure. To the obtained residue was added a saturated aqueous solution of Na2CO3up until the pH of the solution reached 9. Then the mixture was extracted with ethyl acetate (3×25 ml). The combined organic layers were dried Na2SO4, and concentrated under reduced pressure to obtain compound 49(440 mg, 92% yield).

Example24.Biological activity

To identify modulators of the activity of SIRT1 used research-based mass spectrometry. In the study on the basis of mass spectrometry applied to a peptide having 20 the following amino acid residues: Ac-EE-K(Biotin)-GQSTSSHSK(Ac)NleSTEG-K(5TMR)-EE-NH2 (SEQ ID NO: 1) where K(Ac) is an acetylated lysine residue and Nle is norleucine. The peptide have been labelled with the fluorophore 5TMR (excitation 540 nm/emission 580 nm) C-ends. The sequence of the peptide substrate based on p53 with various modifications. In addition, methionine balance, by nature present in the sequence was replaced with norleucine as methionine may be susceptible to oxidation in the process of synthesis and purification.

Mass-spectrometric study carried out as follows: a 0.5 μm peptide substrate and 120 μm βNAD+incubated with 10 nm SIRT1 for 25 minutes at 25°C in reaction buffer (50 mm Tris-acetate pH 8, 137 mm NaCl, 2.7 mm KCl, 1 mm MgCl2, 5 mm DTT, 0.05% of BSA). Compound can be added to the above reaction mixture. The SIRT1 gene clone in the T7-promoter-containing vector, and transformed into BL21(DE3). After 25 minutes of incubation with SIRT1 add 10 μl of 10% formic acid to stop the reaction. The reaction mixture is sealed and frozen for p the following mass spectral studies. Determination of the mass of the peptide substrate allows to accurately determine the degree of acetylation (i.e., starting material) compared to deacetylating peptide (product).

Control of inhibiting the activity of sirtuin carried out by adding 1 μl of 500 mm nicotinamide as a negative control at the beginning of the reaction (for example, to determine the maximum inhibition of sirtuin). Control activation activity of sirtuin carried out by using 10 nm protein of sirtuin with 1 ál of DMSO instead of compound to determine the degree of deacetylation of the substrate in a given time within the linear area of study. This time is the same as the time used for the tested compounds, and within the linear region of the end point is the change in velocity.

For the above research SIRT1 protein expressed and purified as follows. SIRT1 gene cloned in a T7-promoter-containing vector, and transformed into BL21(DE3). The protein expressed by induction with 1 mm IPTG as an N-terminal hybrid protein His-tag at 18°C during the night and collected at 30,000 × g. Cells were literally with lysozyme to lyse buffer (50 mm Tris-HCl, 2 mm Tris[2-carboxyethyl]phosphine (TCEP), 10 μm ZnCl2, 200 mm NaCl) and then treated with ultrasound within 10 minutes for complete lysis. The protein was purified on Ni-NTA column (Amersham), and the fractions containing pure protein were pooled, concentrated and passed through a classifier column (Sephadex S200 26/60 global). The peak containing the soluble protein was collected and passed through an ion exchange column (MonoQ). Gradient elution (200 mm-500 mm NaCl) gave pure protein. This protein was concentrated and deliberately relatively dialysis buffer (20 mm Tris-HCl, 2 mm TCEP) during the night. Take an aliquot of the protein and froze it at -80°C until further use.

Using the above studies were identified modulating sirtuin compounds that activated SIRT1, and they are listed below in table 1. The values of EC1,5for activating compounds denoted by A (EC1,5<1,0 µm), B (EC1,51-25 μm), C (EC1,5>25 μm). The maximum percentage increase activation denoted by A (increase activation >200%) or B (increased activation <200%).

Table 1
Connection
No.
[M+H]+StructureEC1,5,
mcm
The increase in activation
%
200349 CIn
201344CB
202433CB
203428BB
204417BB

205412CB
206417CB
207411C B
208434CB
209428CB

350
210433CB
211427CB
212434BA
213428CB
214429BB
215CB

216344CB
217345CB
218421BB
219422CB
220427CB

221421CB
222 427CB
223442CB
224411CB
225411CB

226411CB
227417AA
228417CB
229434 CB
230428CB

231428AA
232428CB
233428CB
234428AA
235431CB

236442 CB
237442BB
238364CB
239364CB
240434BA

241421BA
242421CB
243494B A
244501BA
245501CB

246501BB
247501CB
248364CB
249421CB
250414AA

251411AA
252412AA
253412AA
254374CB
255379CB

256414AA
257414AA
258 411BA
259414BA
260412CB

261412AA
262411BB
263410CB
264415CB
265422 CB

266427BB
267417BA
268415AA
269414BA
270397CB

271381CB
272401 BA
273358AA
274363CB
275447CB

276431CB
277414BA
278362CB
279367C B
280378AA

281383AA
282394AA
283399AA
284413CB
285405CB

286386A A
287391BA
288380BB
289385CB
290380CB

429
291385BB
292380CB
293385CB
294BB
295399CB

296396AA
297401BA
298396BB
299401CB
300396CB

301 401CB
302412BA
303417BA
304441CB
305432CB

306413BA
307418AA
308413 BA
309418BA
310432BB

311495BA
312479BA
313417BA
315510AA
316497A A

317417BB
318501AA
319463AA
320494AA
321501BA

322496AA
323480A A
324462AA
325446AA
326447CB

476
327460AA
328509BA
329445AA
330475BA
331AA

332467BA
333459BA
334467AA
335378AA
336461BA

337380AA
338 483AA
339492AA

In one embodiment, the compound of this invention are selected from any one of compound numbers 227, 231, 234, 250, 251, 252, 253, 256, 257, 261, 268, 273, 280, 281, 282, 283, 286, 296, 307, 315, 316, 318, 319, 320, 322, 323, 324, 325, 327, 329, 331, 334, 335, 337, 338 or 339 from the above table. In one aspect, the compound of this invention are selected from any one of compound numbers 227, 231, 234, 251, 252, 253, 257, 261, 280, 296, 315, 323 or 337 in the above table.

EQUIVALENTS

The present invention provides, in particular, activating sirtuin compounds and methods of their use. Although in the description of the application were discussed specific embodiments of the present invention, the above description of the application is an illustration, not limitation. When reading the description of the application for professionals in this field may become apparent that many embodiments of the invention. The full scope of the invention should be determined on the basis of claims along with their full scope of equivalents, and descriptions together with the akimi options.

Inclusion IN the DESCRIPTION of the INVENTION INFORMATION BY REFERENCE

The content of all mentioned in the description of publications and patents, including the list below, are by reference as if each individual publication or patent would be specifically and individually listed in the description. In case of conflict, the present application, including any in her determination, will be taken into account in the first place.

In addition, in the description provides polynucleotide and polypeptide sequences by reference to the number of Deposit linked to the entry in a public database, such as database, supported by the Institute for genomic research (the Institute for Genomic Research (TIGR)) (www.tigr.org and/or the National center for biotechnology information (National Center for Biotechnology Information (NCBI)) (www.ncbi.nlm.nih.gov).

1. The compound of formula (II):
;
or its pharmaceutically acceptable salt, where
each R20is hydrogen;
R11selected from phenyl and 5-6-membered saturated or aromatic heterocycle comprising one or two heteroatoms selected from N, O or S, where R11optionally substituted by one or two substituents, independently selected from C1-C4of alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13 13), where
each R13independently selected from hydrogen and-C1-C4of alkyl; or
two R13together with the nitrogen atom to which they are attached, form a 5-6-membered saturated, a heterocycle, optionally containing one additional O, where:
when R13is alkyl, alkyl optionally substituted by one or more substituents selected from-OH, fluorine, and
when two R13together with the nitrogen atom to which they are attached, form a 6-membered saturated the heterocycle, saturated, a heterocycle optionally substituted on any carbon atom of the-C1-C4by alkyl;
R12selected from phenyl and pyridyl, where R12optionally substituted by one or more substituents, independently selected from halogen, C1-C4of alkyl, C1-C2fluoro-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13);
R14selected from hydrogen; and
X1selected from-NH-C(=O)-†, -C(=O)-NH-†, - S(=O)2-NH-†, where
† indicates the place in which X1connected to R11;
when R14is H; R12is phenyl; and X1is - C(=O)-NH-†, then R11is not 1H-pyrazole-3-yl.

2. The compound according to claim 1, where R12connected to the rest of the molecule via a ring carbon atom; and R11don't I have is optionally substituted piperidine or optionally substituted pyrrolidines.

3. The compound according to claim 1, where X1selected from-NH-C(O) -†, and-C(O)-NH-†.

4. The compound according to claim 1, where R11choose from
,
,
,
and

where R11optionally substituted by one or two substituents, independently selected from C1-C4of alkyl, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13and-O-R13.

5. The compound according to claim 4, where R11choose from,
,
,
,
,
,
,
,
,
,
,
,

6. The compound according to claim 5, where R11choose from
,
,
,
and
and X1is-NH-C(O)-†.

7. The compound according to claim 1, where R12choose from
,
where R12optionally substituted by one or more groups independently in the swear from halogen, C1-C4of alkyl, -(C1-C4alkyl)-N(R13)(R13), C1-C2fluoro-substituted alkyl, -O-R13, -SO2-R13N(R13)(R13).

8. The connection according to claim 7, where R12choose from,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,

9. The connection of claim 8, where R12choose from,
,
and; and X1= NH-C(O)- †

10. The compound according to claim 1, selected from any one of compounds









11. The compound of claim 10 selected is passed from any one of compounds



and.

12. The compound of formula (III):
;
or its pharmaceutically acceptable salt, where
each R20independently selected from hydrogen;
R21selected from phenyl and 5-6-membered saturated or aromatic heterocycle comprising one or two heteroatoms selected from N, O or S, non 1H-pyrazole-3-yl, where R21optionally substituted by one or two substituents, independently selected from C1-C4of alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13);
each R13independently selected from hydrogen and-C1-C4of alkyl; or two R13together with the nitrogen atom to which they are attached, form a 5-6-membered saturated, a heterocycle, optionally containing one additional hetero-atomic fragment selected from O, where
when R13is alkyl, alkyl optionally substituted by one or more substituents selected from-OH, fluorine, and
when two R13together with the nitrogen atom to which they are attached, form a 6-membered saturated the heterocycle, saturated, a heterocycle optionally substituted on any carbon atom of the-C1-C4by alkyl;
R12/sup> selected from phenyl and pyridyl, where R12optionally substituted by one or more substituents, independently selected from halogen, C1-C4of alkyl, C1-C2fluoro-substituted alkyl, -O-R13, S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13);
R24selected from hydrogen; and
X2selected from-NH-C(=O)-†, -C(=O)-NH-†, - S(=O)2-NH-†; where:
† indicates the place in which X2connected to R21.

13. The compound of formula (IV):
;
or its pharmaceutically acceptable salt, where
each R20independently selected from hydrogen;
R21selected from phenyl and 5-6-membered saturated or aromatic heterocycle comprising one or two heteroatoms selected from N, O or S, where R21optionally substituted by one or two substituents, independently selected from C1-C4of alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13);
each R13independently selected from hydrogen and-C1-C4of alkyl; or two R13together with the nitrogen atom to which they are attached, form a 5-6-membered saturated, a heterocycle, optionally containing one additional hetero-atomic fragment selected from O, where
when R13is alkyl, alkyl optionally substituted od is them or more substituents, selected from-OH, fluorine, and
when two R13together with the nitrogen atom to which they are attached, form a 6-membered saturated the heterocycle, saturated, a heterocycle optionally substituted on any carbon atom of the-C1-C4by alkyl;
R12selected from phenyl and pyridyl, where R12optionally substituted by one or more substituents, independently selected from halogen, C1-C4of alkyl, C1-C2fluoro-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13);
R24selected from hydrogen; and
X2selected from-NH-C(=O)-†, -C(=O)-NH-†, -S(=O)2-NH-†;
where † denotes the place in which X2connected to R21.

14. Pharmaceutical composition having sirtuin-modulating activity, comprising a pharmaceutically acceptable carrier or diluent and a compound according to any one of claims 1 to 13 or its pharmaceutical salt.

15. The method of treatment of a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or its complications, including introduction to the subject, if desired, the compositions of 14.

16. A method of increasing insulin sensitivity in a subject, comprising the administration to a subject, if desired, the compositions of 14.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1.0:

,

where Q represents tetrahydropyridinyl ring substituted. R5, R1 are selected from: (1) pyridyl, substituted with substituent, selected from group, consisting of: -O-CH3, -O-C2H5, -O-CH(CH3)2, and -O-(CH2)2-O-CH3, R2 is selected from group, consisting of: -OCH3 and -SCH3; and R5 is selected from (a) substituted triazolylphenyl-, where triazolyl is substituted with one or two alkyl groups, selected from group, consisting of: -C1-C4alkyl, (b) substituted triazolylpheenyl-, wheretriazolyl is substituted on nitrogen atom with -C1-C4alkyl, (c) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2alkylene-O-C1-C2alkyl, (d) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2-C4alkylene-O-CH3, and (e) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with hydroxy-substituted -C1-C4alkyl, and where phenyl is optionally substituted with from 1 to 3 substituents, independently selected from group, consisting of halogen; and their pharmaceutically acceptable salts and solvates, which are claimed as ERK inhibitors.

EFFECT: obtaining pharmaceutically acceptable salts and solvates, claimed as ERK inhibitors.

15 cl, 2 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

Organic compounds // 2518462

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and

,

where X represents S or O, one of X1 and X2 represents CR3' and second represents N or independently CR3', n represents integer number 1, 2 or 3; R1 represents C1-6 halogenalkyl, R2 is selected from halogen and C1-C6-halogenalkyl; R3' represents H, C1-C6-alkyl, halogen, cyanogroup, or phenyl, non-substituted or substituted with halogen, C1-C6-alcoxygroup, C1-C6-halogenalcoxygroup, C1-C6-halogenalkyl group; Z represents halogen, Q radical or group -C(O)-NR5R6; R5 represents H or C1-C4-alkyl, R6 represents H; Q', C1-C6-alkyl, non-substituted or substituted with halogen, cyanogroup, C1-C4-alcoxygroup, C1-C4-alkoxycarbonyl, C2-C4-alkanoyl, aminocarbonyl, N-mono- or N,N-di-C1-C2-alkylaminocarbonyl, C1-C4-alkylthiogroup, group -C(O)NHR7 or radical Q"; or C3-C6-cycloalkyl, substituted with group -C(O)NHR7; or C2-C4-alkinyl; Q, Q' and Q" are such as given in the invention formula; R7 represents C1-C6-alkyl, which is non-substituted or substituted with halogen, cyanogroup, pyridyl; or represents C2-C4-alkinyl. Invention also relates to composition for fighting ectoparasites, containing compound of formula (Ia) or (Ib), and to application of compounds of formula (Ia) or (Ib) for composition production.

EFFECT: compounds of formula (Ia) and (Ib), possessing activity against ectoparasites.

11 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: biotechnologies.

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

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of treating or relieving severity of disease in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease. Methods include introduction of effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or pharmaceutical composition, containing said compound, to patient.

EFFECT: treatment of relief of disease severity in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease.

16 cl, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazine derivatives represented by general formula (I): 0, where R1 is a hydrogen atom; C1-C6 alkyl; COR5; SO2R5; CO(CH2)mOR6; (CH2)mR6; (CH2)mCONR7R8; (CH2)nNR7R8; (CH2)nOR6; CHR7OR9; (CH2)mR10; m assumes values from 1 to 6; n assumes values from 2 to 6; R2 is phenyl; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, phenylpyridine or a benzene ring condensed with a saturated or unsaturated monocyclic heterocycle containing 5-7 atoms and consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, other than indole, R3 is methyl or ethyl; R4 and R′4 are identical or different and denote a hydrogen atom; a halogen atom; C1-C6 alkyl; NR7R8; SO2Me; as well as stereoisomers, salts and solvates thereof, for therapeutic use and which are capable of inhibiting 11β-HSD1 on an enzymatic and cellular level.

EFFECT: obtaining benzothiazine derivatives.

17 cl, 197 ex

FIELD: medicine, pharmaceutics.

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

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

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining N-(1,5,3-dithiazonan-3-yl)amides of general formula (1): where R=p-C5H4N (a), (CH3)3CO (b), m-C5H4N (c), which consists in the following: hydrazides of general formula RC(O)NHNH2 (R=mentioned above) undergo interaction with 1,4-butanedithiol, preliminarily mixed at 20°C with water formaldehyde solution, in presence of catalyst crystallohydrate of copper chloride CuCl2·2H2O with molar ration 1,4-butanedithiol: CH2O : RC(O)NHNH2 : CuCl2·2H2O = 10:20:10:(0.3-0.7) at 75-85°C and atmospheric pressure for 44-52 h.

EFFECT: elaborated is method of obtaining novel compounds, which can be applied as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-[methylenebis(1,4-phenylene)]-, 3,3'-[oxybis(1,4-phenylene)]- and 3,3'-(3,3'-dimethoxybiphenyl-4, 4'-diyl)-bis-1,5,3-dithiazepinanes of general formula (1): R=4-C6H4-CH2-C6H4-4/, 4-C6H4-O-C6H4-4/, 4-H3COC6H3-C6H3OCH3-4/ which consists in the following: arylamines [diaminodiphenylmethane, diaminodiphenyloxide, dimethoxybenzidine] undergo interaction with N-tert-butyl-1,5,3-dithiazepinane in presence of catalyst Sm(NO3)3·6H2O in argon atmosphere with molar ratio arylamine:N-tert-butyl-1,5,3-dithiazeoinane: Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) at temperature ~20°C in system of solvents ethanol-chloroform for 2.5-3.5 h.

EFFECT: increased efficiency of applying compound as antibacterial, antifungal and antiviral agents, biologically active complexants, selective sorbents and extractants of precious metals, special reagents for suppressing bacterial vital activity in different technical media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining 3,3'-[oxa(thia)alkane-α,ω-diyl]-bis-1,5,3-dithiazepinanes of general formula (1) R=CH2CH2OCH2CH2, (CH2CH2O)2CH2CH2, (CH2CH2S)2 , which consists in the following: oxa(thia)alkane-α,ω-diamine (3-oxapentane-1,5-diamine, 3,6-dioxaoctane-1,8-diamine, 3,4-dithiahexane-1,6-diamine) undergoes interaction with 1-oxa-3,6-dithiacycloheptane in ethanol-chloroform system of solvents in argon medium in presence of catalyst SmCl3·6H2O with molar ratio oxa(thia)alkane-α,ω-diamine: 1-oxa-3,6-dithiacycloheptane: SmCl3·6H2O = 10 : 20 : (0.3-0.7) at room (~20°C) temperature for 2.5-3.5 h.

EFFECT: elaborated is method of obtaining novel compounds which can be applied as selective sorbents and extractants of precious metals, preparations for protection of leather, fur, fabrics against biodamage, biologically active substances with respect to various microorganisms and sulfate-reducing bacteria.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to piridazine derivatives of formula II

,

in which radicals and symbols have determinations, given in the invention formula, or to their pharmaceutically acceptable salts.

EFFECT: compounds of formula II demonstrate inhibiting effect with respect to proteinkinases such as c-met, ron, or ALK, or chimeric proteins, and can be useful for treatment of disorders, associated with abnormal activity of proteinkinases, such as cancer.

7 cl, 1 tbl, 30 ex

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