Quinazolinone, quinolone and related analogues as sirtuin modulators

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

 

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(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 deace the hole 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 has been highly conserved. 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 mitochondrial 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 that, and yeast, and fly with the lack of the gene SIR2 not live longer when restricting calories, is proof that the modern SIR2 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)to(V), 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 cells and 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, caused chemotherapy neuropathy, neuropathy associated with the phenomenon of ischemia, glasny the diseases and/or disorders, cardiovascular disease, bleeding disorders, inflammation and/or redness 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 alone or in combination with other compounds, including other modulating sirtuin compounds or other therapeutic medium spans the VA.

DETAILED description of the INVENTION

1. Definition

Used in the description the following terms and phrases have the following values. Unless otherwise noted, all used in the description of 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, such as 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 to whom it is administered.

"Biologically active portion of sirtuin" refers to the part of the protein C is Tuina, 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 familiaris (Dog home), applies to a large number of different the location. 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 the test subjects or in the case of 50% of the test drugs. The term "LD50refers 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, coronary artery disease or myocardial infarction, hyperglycemia, hyperinsulinism the Yu 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 the stones of the 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 by-products, for example, ruminant, including cattle and other representatives of the genus Bos (These bulls), pig-like animal, including domestic pig and other representatives of the genus Sus (Pig), acceptanoe animal, including the sheep and the 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, intra-articular, pagkapanalo, subarachnoid, intraspinal and nadrin the th 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 oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylenglycol the ü; (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 appearance of detectable malignant tumors in the group of patients under treatment, in comparison with the control gr is POI patients not treated, 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 therapeutic (i.e., it aims to facilitate, improve or preserve Westwego unwanted 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, and/or enhancing the ability of cells or organisms to survive and to maintain all vital functions for a longer BP is like 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; the silencing of transcription and the control of 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. elegans Sir-2.1 (GenBank Accession No. NP_501912), and the human is ical 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 GnBank 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_00107524 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 is exposed to meth is bolism 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 flushing 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 Rosstroy the VA 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=W 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 heteroatom selected from N, S, S(=O), S(=O)2and O, where alkyl optionally substituted by one or more-OH, fluorine, -NH2, -NH(C1-C4by alkyl), -N(C1-C4by alkyl)2, -NH(CH2CH2OCH3or-N(CH2CH2OCH3)2 and saturated heterocycle, optionally substituted at the carbon atom of-OH, -C1-C4the alkyl, fluorine, -NH2, -NH(C1-C4by alkyl), -N(C1-C4by alkyl)2, -NH(CH2CH2OCH3or-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, R2also optionally substituted 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) torsemide the NYM alkyl, -NH-(C1-C4) alkyl and-N-(C1-C4)2by 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; and

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; and

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 concr is the shaft 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, the implementation when W1is-N=, then W2selected from-NR4- and-CR4=. In specific embodiments, the implementation when W1is-O-, W2is-CR4=. In specific embodiments, the implementation when W1is-NH-, W2selected from-NR4- and-CR4=.

In specific embodiments, the implementation of connection is a group of structural formula (I) represented by the following structure:

In specific embodiments, the implementation of 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, the 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), enabling the x 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 heteroaryl. In specific embodiments, is sushestvennee R 2optionally 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 Halogens. In specific embodiments, the implementation of R2is phenyl, optionally substituted by one or more substituents independently selected from-Cl, -Br, -F, -C≡N, -CF3and-OCF3.

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 specific embodiments, the implementation of R is H.

In particular the x implementation 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)(R3), -(C1-C4alkyl)-C(O)-N(R3)(R3), -O-phenyl, phenyl, and a second heterocycle, 3,4-methylendioxy, fluorinated 34 methylendioxy, 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; and

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, C1-C4of alkyl, -CF3and (C1-C3alkyl)-CF3.

In another embodiment, the invention provides connection is out, represented by structural formula (II)

or its salt, where

each of the Z1, Z2and Z3independently selected from N and C(R9), where

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

each R9independently 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); and

represents the second chemical bond between either W2and C(R12), or W1and C(R12);

W1selected from-O-, -NH - or-N=, and

W2(R14) selected from-N(R14)- and-C(R14)=while

when W1is-O-, one of the Z1, Z2and Z3is N;

when W1is-O - or-NH-, W2(R14is-C(R14)= andrepresents the second chemical bond between W2and C(R12);

when W1is-N=, W2(R14is-N(R14), andrepresents the second chemical bond between W1and CR 12);

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-methylenedioxy, 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 heteroatom 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(C 1-C4the alkyl)2, -NH(CH2CH2OCH3and-N(CH2CH2OCH2)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 optionally substituted on any capable of substitution of the nitrogen atom-C1-C4the alkyl, fluoro-substituted C1-C4the alkyl or -(CH2)2-O-CH3;

R12choose from carbocycle and heterocycle, which is not 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 R12the C is a phenyl, R12also optionally substituted 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 of 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) alkyl, -S-(C1-C2) fluoro-substituted by alkyl, -NH-(C1-C4) alkyl and-N-(C1-C4) alkyl;

R14selected from hydrogen, 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 of structural formula (II) are characterized using one or more of the following characteristics:

the compound of structural formula (II) represented by structural formula (III), (IV) or (V)

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-CR15R6 -†, -NH-C(=O)-CR15R16- †- CR15R16-NH-C(=O)-O-†;

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

R11choose from

R11optionally substituted by one or two substituents, independently selected from halogen, C1-C4of alkyl, -(C1-C4the alkyl)-N(R13)(R13), =O, -N(R13)(R13and-O-R13;

R11choose from

R11choose 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);

R12choose from

R12choose from

R12choose from carbocycle and heterocycle having from 1 to 3 GE is eroatoms;

R12choose from carbocycle and heterocycle having 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;

W2(R14is-N(R14)and R14selected from hydrogen and -(C1-C4) alkyl;

W2(R14is-C(R14)and R14is hydrogen;

each of the Z1, Z2and Z3is C(R9); and

each of the Z1, Z2and Z3is-CH=.

Compounds of the invention, including the new compounds of the invention may also be used in the described 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 activity of deacetylase protein Sirte is on.

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 and aromatic 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 the ie 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 optionally substituted with 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, tetrahydrate is phenyl, 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, benzoxazole, 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, such as indole, through a sequence of atoms, for example, azabicyclo[2.2.1]heptane, and the position of one atom, such as spirits.

Bridging azabicyclo relates to bicyclic molecule, which contains a nitrogen atom and two condensed rings, where condensation occurs through the serial is inost 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" refers 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 it to is described in detail in the description of the objectives.

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 us Aasee the 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 inorganic acids 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, PI the reed, 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 other similar reasons. 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 using conventional techniques. Preferably, these compounds could simply be obtained from readily available starting materials.

Transformation and techniques C the Tethyan 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 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 practically nontoxic 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 5%, 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, the implementation of 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, the implementation of modulating sirtuin connection is activating 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 particular, the var is the ants implementation modulating sirtuin connection does not have any substantial ability to modulate the homologues of sirtuin. In one embodiment, the activator of the human protein 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 on), 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 that amount is and the IC 50when 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 SIRT1 modulator does not have any substantial ability to modulate 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 SIRT1 has no significant SPO is the functioning to modulate SIRT3 protein.

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 least 10 fold, 100 fold 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, the implementation of the Km values determined using OPI is " in the description of the 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 about 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 in comparison with this the e 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 activity of the 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 flushing and so on. Methods include introduction to the subject, if desired pharmaceutically effective amount of the modulating sirtuin connection, e.g. the measures 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 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 Sodnom 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), sirtinol 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 described in the description of therapeutic means is AMI); 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 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 the modulating sirtuin compound(I) and the other therapeutic agent(s) are in separate vessels). When using separate forms 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 may be raised to etka mammal by introducing into a cell of the mammal a nucleic acid, coding 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, such as protein SIRT1 and/or SIRT3. For example, nucleic acid encoding the protein may be at least about 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, such as protein SIRT1 and/or SIRT3. Stringent hybridization conditions may include hybridization and washing in 0.2 × SSC (solution of citrate and sodium chloride) at 65°C. 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 not tantoco type, preferably, 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 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, such as the ability to deacetylation, can be determined using known engineering methods.

In specific embodiments, the implementation of the relief options, before the rotation 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 using 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 deacetylation. For example, can be used mutant SIRT1 H363Y described, for example, Luo et al. (2001) Cell 107:137. Alternatively can 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 modulebus the m 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, e.g., 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 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 in the of epiderma 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 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, cell suspension, with the volove cells, cells in the bone marrow 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 removing 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 connection, the cat is itself 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 example case for the skin type in contact with the pharmaceutical or cosmetic composition, comprising 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 subjected to the treatment described in the present description means 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 is 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 burns. 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 PR is preventing the 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; the methods of treatment or prevention of diseases or conditions related to the proliferative capacity of cells; and methods of treating or preventing 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 using the described in the description of the connection is similar to the influence on the subject of hormesis, that is easy stress to the th 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. Other conditions that 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 m & e is Arda and impact; liver diseases 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 surgical operations, drug 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 an acute disease, such as 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 by means of modulating sirtuin compounds, which 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. In addition, under treatment or prevention using the described in the description of the 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 may be the evaluation of goty treatment with modulating sirtuin compounds, which 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, 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. 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 VA who ianthe implementation of 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.

Modulating sirtuin 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. May also be subjected to Le the structure of the benign growth of 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 be treated by introducing a modulating sirtuin connection viral infections 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 in the description of 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 in the description of modulating sirtuin connection as inducing the death of cells or reduce life expectancy or increase the susceptibility to article is the ECCA 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 unwanted cell proliferation.

Combination therapy includes modulating sirtuin connections and traditional chemotherapeutic agent, can be effective when applying the known technique 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 connection is receiving 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 compounds that increase the 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 m is ZGA 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, primary lateral sclerosis, 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 the death of the completion of brain cells in the part of the brain, which 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 brain 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, can be used to treat or prevent 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 which 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 to nerves 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 surgical intervention is elsto) or injury due to exposure to the environment (for example, 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 disorders of the 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 Spinnerei 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), spinal-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 is istemi 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 of any 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 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 is neither.

In one embodiment, the scheme of the combined drug treatment may include drugs or compounds for the treatment or prevention of neurodegenerative disorders or secondary conditions 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 dis is evani 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 provides anticoagulation and antithrombotic therapy aimed at inhibiting 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 t the tion include diseases or disorders, when there is adhesion of platelets and thrombus formation, and they can manifest as an increased tendency to thrombosis, such as increased numbers of 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, associated with the Gorm the us 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 who is in need of such treatment, can be a subject who is 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 respirato the problems, 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), 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 su the target, 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 once 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 the increase in the body weight associated with water retention in the body.

M is tabolites 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 disorders such as insulin resistance, prediabetes status, 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 of the Oia 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 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 asthmatics diseases is e (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 the protein 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 disease (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 modulate their sirtuin connection which 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 are 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, implementation of 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, domestic is 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 that is causing the congestion, 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 the embodiment, modulating sirtuin connection which increase the level and/or activity of the protein of sirtuin, can be used to reduce the side effects such as hyperemia in the receiving 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 with etani (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 to reduce congestion 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 of pre is disgust, 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 derivative.

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, elect the TES prosthetic retina and transplantation of retinal pigment epithelium in age-related macular degeneration, acute multifocal Placido pigmentary epitheliopathy, acute retinal necrosis, a disease best, the side occlusion retinal artery occlusion retinal side veins, 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 detachment retinal 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 including the Ute eye bacterial infections (for example, conjunctivitis, keratitis, tuberculosis, syphilis, gonorrhea), viral infection (e.g., ocular herpes simplex, 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 of the Sabbath., if he needs such treatment, therapeutic doses disclosed in the description of the modulator of sirtuin. 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 the disorder. Therefore, the scheme of the combined drug treatment can include one or more activators of sirtuins 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. The methods include the introduction is the subject if desired a therapeutically effective amount of activating sirtuin connection. Increased mitochondrial activity means an increase in the activity of mitochondria while maintaining the total number of mitochondria (e.g., 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 ill the deposits 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 mediated by free radicals, leads to the degeneration of 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 is in. Examples of diseases or disorders include, for example, neuromuscular disorders (e.g., ataxia, muscular dystrophy, multiple sclerosis, etc.), disorders associated with neural instability (e.g., 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 muscle in patients 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 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 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 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 the percent 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 is involved in sport at any level and who strives to achieve high levels of strength, speed and endurance in the competition, such a person as, for example, bodybuilders, cyclists, distance runners, runners for a short distance, 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 mode, 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 have the effect to increase physical endurance and/or prevent physical fatigue of people who are involved in a wide 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 human papilloma) or as antifungal agents. In specific embodiments, the implementation of modulating sirtuin compounds that increase the level and/or and the efficiency of protein sirtuin, can be entered 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, non-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 connection is UNOSAT on 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 and/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, such as the brewing of beer, yogurt and bakery products such as 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 subject described in the description of the process

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 may be deposited on 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 have commercial 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 in the art method, which provides the biological uptake of the compounds by the larva of an insect, but not plants.

At least from the point of view of the relationship between reproduction and longevity, Modulare the common sirtuin connection which 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 agent under conditions 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 Ag-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 Bitterman 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. Because in the description it has been shown that activating compounds, 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, screening is the first 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 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.

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 environmenta who eat 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 in the description hereinafter. The method may additionally include the lizirovania cells for determining the level of acetylation of the substrate. The substrates can be added to cells at a concentration 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 is haunted 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 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 is whether localized introduction. 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 may 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 lyophilized 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). Tab is ETCI can be applied coatings with 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 (e.g., 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, such as dichlordifluormethane is a, 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 preparations for parenteral administration by injection e.g. 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, that is their as suppositories or retention enemas, for example, containing conventional suppozitornoj bases such as cocoa butter or other glycerides.

In addition to the above-described preparations of 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 (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 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 is epted, which 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 (caused by the infusion of mannitol solution into 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, cha is the surrounding area of the solution 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 forms are used 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 to the upnote particles of the active tool.

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 a topical formulation 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 in the u, 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 a specific basis, which should be used for the ointment, 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 usually are susp what semi solids, and they can 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 a cream as described in the above-mentioned monograph Remington's, is typically 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 (dujfasp the e system), the 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 benzophenone-3), camphor derivatives, cinnamates (for example, octylmethoxycinnamate), dibenzoylmethane (for example, butylperoxybenzoate), p-aminobenzoic acid (PABA) and its derivatives and salicylates (for example, octisalate).

In specific topical drugs 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 is treatment, 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 such as the anterior chamber, posterior chamber, vitreous 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, the RES is elatrol or its analogue may be prepared in a sealed capsule for oral administration, such as Capsugel Pfizer, Inc.

Cells, for example, 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 such as cyclosporine 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.

Toxicity and therapeutic efficacy of 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 n is zeleno delivers such compounds to the site of affected tissue, in order 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 initial 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(i.e. the concentration of 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 sets, such as sets for Ter the non-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 to those used in combined 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 PA the ethic of foil or other similar package) which 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, 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: 4,683,195; 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 Sprng 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-(3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-yl)picolinate (Connection239):

Stage 1. Getting 8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-4-she (3):

3-(trifluoromethyl)benzoyl chloride2(4,5 ml, 30.2 mmol) was added to a suspension of 2-amino-3-nitrobenzoic acid1(5.0 g, 27.5 mmol) in pyridine (65 ml). The reaction mixture was stirred at room temperature for 12 hours, then poured into a cooled ice H2O (300 ml). The precipitate was filtered off, washed with H2O and dried under vacuum to obtain compound3(5 g, 51% yield) as a yellow solid, which was used without further purification.

Stage 2. Obtaining 3-methyl-8-nitro-2-(3-(trifluoromethyl)phenyl)hinzelin-4(3H)-she (4):

A solution of methylamine (6.3 ml, 12.5 mmol) in THF was added to a suspension of 8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-4-it3(1.5 g, 4.2 mmol) in AcOH (18 ml). The reaction is th mixture gently boiled under reflux for 12 hours, then cooled to room temperature. Volatile components were removed under vacuum, and the residue was placed in EtOAc, washed with saturated aqueous NaHCO3, brine, dried (MgSO4) and concentrated. The residue was purified liquid chromatography medium pressure elwira using a mixture of pentane/EtOAc (0-75%) to obtain compound4(1.3 g, 89% yield) as a yellow solid.

Stage 3. Getting 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl)hinzelin-4(3H)-she (5):

Pd/C 10% wt. (100 mg) was added to a degassed solution of 3-methyl-8-nitro-2-(3-(trifluoromethyl)phenyl)hinzelin-4(3H)-it4(1.3 g, 3.7 mmol) in THF (35 ml). The mixture was first made using under pressure in the balloon of hydrogen for 12 hours. The catalyst was filtered and the solvent evaporated. The residue was purified liquid chromatography medium pressure elwira with pentane/EtOAc (0-50%), withconnection 5(1.1 g, 90% yield) as a yellow solid.

Stage 4. Obtaining N-(3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-yl)picolinate (Compound 239):

A mixture of 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl)hinzelin-4(3H)-it5(106 mg, 0.33 mmol), pyridine-2-carboxylic acid6(84 mg, of 0.68 mmol), HATU (263 mg, 0.69 mmol) and DIPEA (208 mg) in DMF heat and at 55°C for 2.5 hours, then poured in H2O. the precipitate was filtered off, washed with H2O, then Et2O obtaining connection239in the form of a yellow solid (130 mg, 93% yield). MS (ESI) calculated for C22H15F3N4O2: 424,11; found: 425 [M+H].

Example 2.Synthesis of N-(3-methyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)pyridine-3-sulfonamida (Connection361):

Pyridine-3-sulphonylchloride hydrochloride7(280 mg, 1.3 mmol) was added to a solution of 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl)hinzelin-4(3H)-it5(100 mg, 0,313 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 a mixture of CH2Cl2/MeOH (0-10%), recrystallized from CH3CN obtaining connection361(77 mg, 53% yield). MS (ESI) calculated for C21H15F3N4O3S: 460,08; found: 461[M+H].

Example 3.Synthesis of N-(4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-yl)picolinate (Connection231):

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

8-Nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-4-one3(150 mg, 0.45 mmol) was added to the ammonia solution (5.0 ml, 10 mmol) in IPA. The reaction mixture was gently boiled under reflux for 12 hours, then cooled to room temperature. The reaction mixture was poured into H2O and the precipitate was filtered off, washed with H2O and dried under vacuum. The crude residue was recrystallized from EtOAc to obtain the connection8(91 mg, 62% yield) as a yellow solid.

Stage 2. Getting 8-amino-2-(3-(trifluoromethyl)phenyl)hinzelin-4(3H)-it (9):

Connection9were obtained using a technique similar to the procedure described for 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl)hinzelin-4(3H)-it5,with 99% yield.

Stage 3. Obtaining N-(4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-yl)picolinate (Compound 231):

A mixture of 8-amino-2-(3-(trifluoromethyl)phenyl)hinzelin-4(3H)-it9(125 mg, 0.41 mmol), pyrazin-2-carboxylic acid10(102 mg, 0.82 mmol), HATU (342 mg, 0.90 mmol) and DIPEA (214 μl, 1.2 mmol) in DMAC (5 ml) was heated at 70°C for 12 hours, then poured in H2O. the Precipitate was filtered off, washed with H2O, and then recrystallized from EtOH to obtain the connection231(144 mg, 86% output is in the form of a white solid. MS (ESI) calculated for C20H12F3N5O2: 411,09; found: 412 [M+H].

Example 4.Synthesis of N-(2-(2,4-dimethylthiazol-5-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)pyrazin-2-carboxamide (Compound287):

Stage 1. Obtain methyl 2-amino-3-nitrobenzoate (11):

2-amino-3-nitrobenzoic acid1(5 g, a 27.4 mmol) was dissolved in methanol (100 ml)was added concentrated H2SO4. The mixture was heated at 100°C for 12 hours, concentrated to dryness and suspended in H2O (50 ml). The mixture was extracted with CH2Cl2(50 ml), dried (MgSO4) and concentrated. The crude residue was purified flash chromatography to obtain compound11(of 5.1 g, 95% yield).

Stage 2. Obtain methyl 2-(bis(tert-butoxycarbonyl)amino)-3-nitrobenzoate (12):

(Boc)2O (5 g, 23 mmol) was added to a solution of methyl 2-amino-3-nitrobenzoate11(4.5 g, 23 mmol) and DMAP (5 g, 46 mmol) in THF. The reaction mixture was stirred at room temperature for 6 hours, concentrated and purified flash chromatography to obtain compound12(6.4 g, 70% yield).

Stage 3. Obtain methyl 3-amino-2-(bis(tert-butoxycarbonyl)amino)benzoate (13):

Ni Raney (1 g) was added to a solution of methyl 2-(bis-(tert-butoxy arbonyl)amino)-3-nitrobenzoate 12(6 g, 27.5 mmol) in THF. The reaction mixture was first made using under pressure in the balloon of hydrogen for 4 hours. The catalyst was filtered and the solvent evaporated to obtain compound13(4.4 g, 80% yield).

Stage 4. Obtain methyl 2-(bis-tert-butoxycarbonyl)amino)-3-(pyrazin-2-carboxamido)benzoate (14):

A solution of methyl 3-amino-2-(bis(tert-butoxycarbonyl)amino)benzoate13(3.8 g, 10.4 mmol), pyrazin-2-carboxylic acid10(1.54 g, 12.5 mmol), HATU (7.9 g, to 20.8 mmol) and DIPEA (2,68 g of 20.8 mmol) in DMF was heated at 50°C for 12 hours. The reaction mixture was poured into H2O, and the resulting precipitate was filtered and dried under vacuum. The crude residue was purified flash chromatography to obtain compound14(2,87 g, 58% yield)

Stage 5. Obtain methyl 2-amino-3-(pyrazin-2-carboxamido)benzoate (15):

Gaseous HCl was barbotirovany through a solution of methyl 2-(bis-(tert-butoxycarbonyl)amino)-3-(pyrazin-2-carboxamido)benzoate14(2.8 g, 5.9 mmol) in MeOH (50 ml) for 2 hours. Volatile components were removed under vacuum and added H2O (20 ml). the pH was adjusted to 7 with an aqueous solution of NaOH and the precipitate was filtered off, washed with H2O, and dried under vacuum to obtain compound15(of 1.37 g, 85% yield).

Stage 6. The floor is the group of 2-amino-3-(pyrazin-2-carboxamido)benzoic acid (16):

The mixture of aqueous NaOH solution (20 ml, 88,2 mmol) and methyl 2-amino-3-(pyrazin-2-carboxamido)benzoate15(1.2 g, to 4.41 mmol) in THF (20 ml) was stirred at room temperature for 4 hours. Volatile components were evaporated and the pH was adjusted to 4 with aqueous solution of HCl. The precipitate was filtered off, washed with H2O and dried under vacuum to obtain compound16(750 mg, 66% yield).

Stage 7. Obtaining N-(2-(2,4-dimethylthiazol-5-yl)-4-oxo-4H-benzo[d][1,3]oxazin-8-yl)pyrazin-2-carboxamide (18):

2,4-Dimethylthiazol-5-carbonylchloride17(104 mg, of 0.58 mmol) was added to a suspension of 2-amino-3-(pyrazin-2-carboxamido)benzoic acid16(100 mg, 0,39 mmol) in pyridine (5 ml). The reaction mixture was stirred at room temperature for 12 hours, then poured into a cooled ice H2O (30 ml). The precipitate was filtered off, washed with H2O and dried under vacuum to obtain compound18(110 mg, 81% yield).

Stage 8. Obtaining N-(2-(2,4-dimethylthiazol-5-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)pyrazin-2-carboxamide (Compound 287):

N-(2-(2,4-dimethylthiazol-5-yl)-4-oxo-4H-benzo[d][1,3]-oxazin-8-yl)pyrazin-2-carboxamid18(100 mg, 0.26 mmol) was dissolved in 30% of the mass. the solution of CH3NH2in methanol (10 ml). Reaction the second mixture was heated at 80°C for 12 hours. The precipitate was filtered and washed with DME obtaining connection287(32 mg, 31% yield). MS (ESI) calculated for C19H16F3N6O2S: 392,11; found: 393 [M+H].

Example 5.Synthesis of N-(3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-yl)-5-oxopyrrolidin-2-carboxamide (Compound339):

Thionyl chloride (83 mg, 0.7 mmol) was added to a solution of 5-oxopyrrolidin-2-carboxylic acid19(65 mg, 0.5 mmol) in THF (5 ml) at 0°C. was Added DMF (1 drop) and the solution warmed to room temperature for 3 hours, then was cooled to 0°C. was Added a solution of 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl)hinzelin-4(3H)-it5(65 mg, 0.2 mmol) and triethylamine (145 mg, 1.44 mmol) in THF (1 ml)and the reaction mixture was heated to room temperature and was stirred for 12 hours. The reaction mixture was concentrated to dryness and the crude residue was purified preparative thin-layer chromatography to obtain compound339. MS (ESI) calculated for C21H17F3N4O3: 430,1; found: 431 [M+H].

Example 6.Synthesis of 3-methyl-4-oxo-N-(pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-carboxamide (Compound212):

Stage 1. Obtain methyl 2-amino-3-(pyridine-2-ylcarbonyl)benzoate (22):

A solution of 2-am is but-3-(methoxycarbonyl)benzoic acid 20(1 g, 5.1 mmol), 2-aminopyridine21(723 mg, 7.7 mmol), HOBT (1.39 g, or 10.3 mmol), EDCI (1.9 grams, or 10.3 mmol) and DMAP (1.25 g, or 10.3 mmol) in DMF (40 ml) was stirred at 70°C for 12 hours. The reaction mixture was poured into H2O. the precipitate was filtered off, washed with H2O and dried under vacuum to obtain compound22(0.9 g, 58% yield).

Stage 2. Obtaining 2-amino-3-(pyridine-2-ylcarbonyl)benzoic acid (22):

LiOH-H2O (1.8 g, 42.8 mmol) was added to a solution of methyl 2-amino-3-(pyridine-2-ylcarbonyl)benzoate22(2.9 g, is 10.7 mmol) in THF (30 ml) and H2O (30 ml). The reaction mixture was heated at 60° for 5 hours. THF was removed under vacuum and added H2O (10 ml). the pH was adjusted to 4 with aqueous solution of HCl and the precipitate was filtered off, washed with H2O and dried under vacuum to obtain compound23(2.1 g, 76% yield).

Stage 3. Getting 4-oxo-N-(pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-8-carboxamide (25):

2-(Trifluoromethyl)benzoyl chloride24(180 mg, 0.88 mmol) was added to a suspension of 2-amino-3-(pyridine-2-ylcarbonyl)benzoic acid23(150 mg, of 0.58 mmol) in pyridine (8 ml). The reaction mixture was stirred at room temperature for 12 hours, then poured into a cooled ice H2O. the precipitate was filtered, amywali H 2O and dried under vacuum to obtain compound25(90 mg, 38% yield) as a white solid.

Stage 4. Obtaining 3-methyl-4-oxo-N-(pyridin-2-yl)-2-(2- (trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-carboxamide (Compound 212):

A solution of 30% wt. of methylamine (7 ml) in MeOH and 4-oxo-N-(pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]-oxazin-8-carboxamide25(90 mg, 0.22 mmol) was carefully heated under reflux for 1 hour, then cooled to room temperature. The precipitate was filtered off, washed with H2O and dried under vacuum to obtain compound212(20 mg, 22% yield) as a white solid. MS (ESI) calculated for C22H15F3N4O2: 424,11; found: 425 [M+H].

Example 7.Synthesis of 3-methyl-4-oxo-N-(pyridin-2-yl)-2-(4-(pyrrolidin-1-ylmethyl)phenyl)-3,4-dihydroquinazolin-8-carboxamide (Compound275):

Stage 1. Obtaining 2-(4-bromophenyl)-4-oxo-N-(pyridin-2-yl)-4H-benzo[d][l,3]oxazin-8-carboxamide (27):

2-(4-Bromophenyl)-4-oxo-N-(pyridin-2-yl)-4H-benzo[d][1,3]-oxazin-8-carboxamide27were obtained using a technique similar to the method described for 4-oxo-N-(pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-8-carboxamide25,with 91% yield.

Stage 2. Obtaining 2-(4-bromophenyl)-3-m is Tyl-4-oxo-N-(pyridin-2-yl)-3,4-dihydroquinazolin-8-carboxamide (28):

Connection28were obtained using a technique similar to the method described for 3-methyl-4-oxo-N-(pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-carboxamide compounds212,with 76% yield.

Stage 3. Obtaining 3-methyl-4-oxo-N-(pyridin-2-yl)-2-(4-(pyrrolidin-1-ylmethyl)phenyl)-3,4-dihydroquinazolin-8-carboxamide (Compound 275):

Degassed mixture of THF/H2O (4 ml, 10:1) was added into a vessel for carrying out reactions using microwave radiation, containing 2-(4-bromophenyl)-3-methyl-4-oxo-N-(pyridin-2-yl)-3,4-dihydroquinazolin-8-carboxamide28(100 mg, 0.23 mmol), Cs2CO3(224 mg, 0.69 mmol), Pd(OAc)2(1.5 mg, to 0.007 mmol), XPHOS (65 mg, 0.014 mmol) and potassium 1-triftoruranmetilidina (48 mg, 0.25 mmol). The reaction mixture was heated at 150°C in a microwave reactor for 30 minutes, poured into H2O and was extracted with EtOAc. The combined organic layers were washed with brine, dried, concentrated and the crude residue was purified liquid chromatography medium pressure elwira a mixture of CH2Cl2/MeOH (0-10%), with connection275(63 mg, 63% yield). MS (ESI) calculated for C26H25N5O2: 439,20; found: 440 [M+H].

Example 8.Synthesis of N-(3,4-acid)-3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydrogen the Olin-8-carboxamide (Compound 220):

In the vessel for carrying out reactions using microwave radiation was loaded N-carboxyanhydrides anhydride-2-carboxylic acid29(Clark, et al. J. Med. Chem. 1995, 38, 1493-1504) (115 mg, 0,555 mmol), 3,4-dimethoxyaniline30(102 mg, 0,666 mmol) and pyridine (2.0 ml). The reaction mixture was heated at 200°C using microwave radiation for 2 hours. Upon cooling, was added 3-(trifluoromethyl)benzoyl chloride2(120 ml HDI, 0.800 mmol) and the vessel was heated to 100°C for 1 hour. After cooling, the solution was added methylamine (1.0 ml, 2.0 mmol) in MeOH and the reaction mixture was heated to 100°C for another 1 hour. Volatile components were removed under vacuum, and the crude residue was purified liquid chromatography medium-pressure connection220(69 mg, 26% yield). MS (ESI) calculated for C25H20F3N3O4: 483,14; found: 484 [M+H].

Example 9.Synthesis of 3-methyl-4-oxo-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-carboxamide (Compound350):

Stage 1. Obtaining 2-amino-3-(methylcarbamoyl)benzoic acid (31):

Aqueous NaOH solution (to 23.4 ml, 46.8 mmol) was added to a solution of methylamine hydrochloride (3,52 g of 53.7 mmol) in H2O (37 ml). Added portions 2,4-dioxo-2,4-dihydro-1H-benzo[d]-[1,3]oxazin-8-karbonova the acid 29(3,23 g, 15.6 mmol). After complete addition the solution was stirred at ambient temperature for 1.5 hours. Added 6M HCl up until not established pH=3. The precipitate was filtered off, washed with H2O and dried to obtain compound31(2,60 g, 86% yield).

Stage 2. Obtaining 3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-carboxylic acid (33):

The sodium metabisulfite (of 3.56 g, to 18.7 mmol) was added to a solution of 2-amino-3-(methylcarbamoyl)benzoic acid31(2,80 g, 14.4 mmol) and 3-(trifluoromethyl)benzaldehyde32(of 2.51 g, 14.4 mmol) in DMAC (45 ml). The reaction mixture was stirred at 100°C for 21 hours. Added H2O (150 ml)and the precipitate was filtered off, washed with H2O and dried to obtain compound33(or 4.31 g, 84% yield).

Stage 3. Obtaining 3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-carbonylchloride (34):

A solution of thionyl chloride (10 ml) and 3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-carboxylic acid33(1,00 g, 2,87 mmol) was boiled under reflux for 1 hour. After cooling to room temperature, all volatile components were removed under vacuum to obtain compound34(of 1.05 g, 100% yield) as a white solid.

One hundred of the s 4. Obtaining 3-methyl-4-oxo-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-carboxamide (Compound 350):

The triethylamine (100 μl) and 6-pyrrolidin-1-espiridion-2-amine35(0,136 mmol) was added to a solution of 3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-carbonylchloride34(50 mg, 0,136 mmol) in dioxane (1 ml). The reaction mixture was stirred at 70°C for 2 days, after which was added 1N HCl (4 ml). The precipitate was filtered off, washed with 5 ml of H2O, 5 ml of pentane and dried under vacuum to obtain compound350(40 mg, 56% yield). MS(ESI) calculated for C26H22F3N5O2: 493,17; found: 494 [M+H].

Example 10.Synthesis of N-(4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-8-yl)pyrazin-2-carboxamide (Compound409):

Stage 1. Getting ethyl 8-nitro-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-3-carboxylate (36):

The solution Diisopropylamine (7,00 ml, 50.0 mmol) in THF (100 ml) was cooled to -78°C, was added n-BuLi (20,0 ml, 2.5 M in hexano, 50.0 mmol). After stirring for 20 minutes at -78°C was added ethyl acetate (5,72 ml, 58.6 mmol). The solution was stirred at -78°C for 10 minutes, warmed to 0°C and was stirred for 10 minutes, then was cooled to -78°C. was Added within 5 m of the nut a solution of 8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][l,3]oxazin-4-it 3(9,85 g of 29.3 mmol) in THF (100 ml) to a mixture of LDA/EtOAc. The reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature for 2 hours. Then was added 1N NaOH (50 ml) and the reaction mixture was intensively stirred over night. Added brine (50 ml) and separated the organic layer. The aqueous layer was extracted with ethyl acetate (2×100 ml)and the combined organic layers were dried MgSO4and concentrated under reduced pressure. The remaining material was purified liquid medium pressure chromatography (using a gradient from 20% to 50% EtOAc in pentane) to give the compound36(5,00 g, 42% yield).

Stage 2. Getting 8-nitro-2-(3-(trifluoromethyl)phenyl)quinoline-4(1H)-it (37):

In the vessel for carrying out reactions using microwave radiation was loaded 8-nitro-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-3-carboxylate36(1.0 g, 2,46 mmol), dioxane (8 ml) and 1N HCl (4 ml). The reaction mixture was heated at 190°C using microwave radiation for a period of 50 minutes. Volatile components were evaporated and the residue was dried under vacuum to obtain compound37(707 mg, 86% yield).

Stage 3. Getting 8-nitro-2-(3-(trifluoromethyl)phenyl)quinoline-4-ilaclama (38):

A solution of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinoline-4(1H)-it37(707 mg, 2,11 mmol), Treaty the amine (1 ml) and Ac 2O (0.7 ml) in CH2Cl2(10 ml) was stirred at room temperature for 16 hours. Was added a saturated aqueous solution of NaHCO3(10 ml)and the reaction mixture was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated to obtain compound38.

Stage 4. Getting 8-amino-2-(3-(trifluoromethyl)phenyl)quinoline-4-ilaclama (39):

Pd/C (300 mg) was added to a solution of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinoline-4-ilaclama38(2,11 mmol) in ethyl acetate (10 ml). After the reaction mixture was barbotirovany hydrogen gas for 10 minutes and then stirred the reaction mixture at a pressure of 1 ATM hydrogen for 16 hours. The catalyst was filtered through 10 g of silica. Was removed under vacuum of the solvent to obtain compound39(400 mg, 55% yield for both steps).

Stage 5. Getting 8-(pyrazin-2-carboxamido)-2-(3- (trifluoromethyl)phenyl)quinoline-4-ilaclama (41):

Pyrazin-2-carbonylchloride40(100 mg) was added to a solution of 8-amino-2-(3-(trifluoromethyl)phenyl)quinoline-4-ilaclama39(50 mg, 0,145 mmol) and triethylamine (0,20 ml) in dichloromethane (3 ml). The reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was poured into a diluted solution of NaHCO3(10 ml) and extragear the Wali 3×30 ml of dichloromethane. The combined organic layers were dried (MgSO4) and the solvent was removed under vacuum. The crude residue was purified liquid medium pressure chromatography (97:3 dichloromethane:methanol) to obtain compound41(33 mg, 50% yield).

Stage 6. Obtaining N-(4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-8-yl)pyrazin-2-carboxamide (Compound 409):

A solution of 8-(pyrazin-2-carboxamido)-2-(3-(trifluoromethyl)phenyl)quinoline-4-ilaclama41(33 mg, 0,073 mmol) in THF (2 ml) and 1N NaOH (0.5 ml) was heated at 60°C for 48 hours. The reaction mixture was cooled to room temperature and was added 1N HCl (5 ml). The precipitate was filtered off, washed with 3 ml of H2O and dried under vacuum to obtain compound409(21 mg, 70% yield). MS (ESI) calculated for C21H13F3N4O2: 410,10; found: 411 [M+H].

Example 11.Synthesis of 4-oxo-N-(pyridin-2-yl)-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-8-carboxamide (Compound401):

Stage 1. Obtain methyl 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-8-carboxylate (42):

To a solution of 2-amino-3-(methoxycarbonyl)benzoic acid20(1,16 g, 5,94 mmol) in pyridine (10 ml) was added 3-cryptomathematical2(of 0.90 ml, 5,94 mmol). The reaction mixture was stirred for 16 hours, poured in acadeny aqueous solution of NaHCO 3(50 ml), was extracted with dichloromethane (3×50 ml)and the combined organic layers were dried (MgSO4) and concentrated. Was added toluene (10 ml) and the solution was concentrated under vacuum. The crude residue was purified liquid chromatography medium pressure elwira using a mixture of pentane/EtOAc (10-50%), with connection42(1.45 g, 70% yield).

Stage 2. Obtaining 3-ethyl 8-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-3,8-in primary forms (43):

n-BuLi (4.4 ml, 2.5 M in hexano, 11.0 mmol) was added to a solution of Diisopropylamine (of 1.57 ml, and 11.2 mmol) in THF (30 ml) at -78°C. After stirring for 20 minutes was added EtOAc (1,09 ml, and 11.2 mmol). The solution was stirred at -78°C for 10 minutes, warmed to 0°C, stirred for 10 minutes, then was cooled to -78°C. To the reaction mixture was added over 5 minutes a solution of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-8-carboxylate42(2.00 g, 5,72 mmol) in THF (50 ml) and continued stirring at -78°C for 1 hour. Then the reaction mixture was heated to room temperature within 2 hours. Was added MeOH (50 ml), then solid NaOMe (of 1.62 g, 30 mmol) and the reaction mixture was intensively stirred for 12 hours at room temperature. The solution was concentrated to a total volume of 20 ml under vacuum, was added H2O (100 ml) and see what camping was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried (MgSO4) and concentrated under vacuum. The crude residue was purified liquid chromatography medium pressure elwira a mixture of pentane/EtOAc (10-50%) to give compound43(950 mg, 39% yield).

Stage 3. Getting 4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-8-carboxylic acid (44):

In a vessel with a capacity of 20 ml for carrying out reactions using microwave radiation was loaded 3-ethyl 8-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline to 3.8, in primary forms43(820 mg, a 1.96 mmol), dioxane (8 ml) and 1N HCl (4 ml). The reaction mixture was heated in a microwave reactor at 200°C for 25 minutes, then concentrated to dryness under vacuum to obtain compound44(585 mg, 90% yield).

Stage 4. Getting 4-oxo-N-(pyridin-2-yl)-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-8-carboxamide (Compound 401)

A mixture of 4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-8-carboxylic acid44(250 mg, 0,750 mmol), HATU (570 mg, 1.5 mmol), 2-aminopyridine21(141 mg, 1.5 mmol) and diisopropylethylamine (392 μl, 2.25 mmol) in DMAC (5 ml) was heated at 75°C for 16 hours. The reaction mixture was poured into H2O (25 ml) and the resulting precipitate was filtered. The crude residue was purified liquid medium pressure chromatography with recip is of the connection 401(102 mg, 33% yield). MS (ESI) calculated for C22H14F3N3O2: 409,10; found: 410 [M+H].

Example 12.Synthesis of 4-oxo-N-(thiazol-2-yl)-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthiridine-8-carboxamide (Compound449):

Stage 1. Getting 4-amino-5-bromonicotinic acid (46):

In a test tube with cap loaded 4-aminonicotinic acid45(8.00 g, to 57.9 mmol), acetic acid (75 ml) and water (75 ml). The reaction mixture was heated at 75°C and intensively stirred until the formation of homogeneous solution. After cooling to 50°C was added bromine (10.0 ml, 195 mmol) and continued stirring for 16 hours. After cooling to 0°C the obtained orange precipitate was filtered, washed with H2O and dried under vacuum to obtain compound46(10.5 g, 84% yield).

Stage 2. Obtain 8-bromo-2-(3-(trifluoromethyl)phenyl)-4H-pyrido[4,3-d][1,3]oxazin-4-it (47):

A mixture of 5-bromo-4-aminonicotinic acid46(of 10.5 g of 48.4 mmol) and pyridine (60 ml) was heated at 60°C until the formation of homogeneous solution. Was added 3-(trifluoromethyl)benzoyl chloride2(8.0 ml, to 53.0 mmol) and continued stirring for 2 hours. Added H2O (200 ml) and the mixture was cooled to 0°C. the yellow precipitate was filtered, washed with H2O (100 ml), then with pentane (100 is l), and dried under vacuum to obtain compound47(8,50 g, 47% yield).

Stage 3. Getting ethyl 8-bromo-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthiridine-3-carboxylate (48):

A mixture of THF (15 ml) and Diisopropylamine (of 1.40 ml, 10.0 mmol) was cooled to -78°C, was added n-BuLi (4.0 ml, 2.5 M in hexano, 10.0 mmol). After stirring at -78°C for 20 minutes was added ethyl acetate (1.0 l, 10.2 mmol) and stirring was continued for 5 minutes. Added 8-bromo-2-(3-(trifluoromethyl)phenyl)-4H-pyrido[4,3-d][1,3]oxazin-4-one47(990 mg, to 2.67 mmol). After 1 hour the reaction mixture was gradually warmed to room temperature. Added 1N NaOH (15 ml)and the reaction mixture was stirred for 24 hours. The mixture was poured into brine (50 ml), extracted with ethyl acetate (2×50 ml), dried (MgSO4) and concentrated under vacuum. The obtained solid was purified liquid chromatography medium-pressure connection48(910 mg, 77% yield).

Stage 4. Getting 4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthiridine-8-carboxylic acid (49):

A mixture of ethyl 8-bromo-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthiridine-3-carboxylate48(910 mg, of 2.06 mmol), palladium acetate (22,4 mg, 0,100 mmol), XPhos (48,8 mg, is 0.102 mmol), copper cyanide(I) (450 mg, 5,02 mmol) and sodium carbonate (636 mg, 6,00 IMO the ü) in DMF (7.0 ml) was heated at 120°C for 16 hours. After cooling to room temperature the mixture was poured into methanol (100 ml), filtered through celite and concentrated under vacuum. The crude residue was dissolved in dioxane (10 ml) and 1N HCl (5 ml). The reaction mixture was heated at 190°C for 50 minutes in a microwave reactor. Volatile components were removed under vacuum and the residue was re-dissolved in methanol (10 ml) and 1N NaOH (5 ml). This solution was heated in a microwave reactor at 160°C for 1.5 hours, then was added 6N HCl (5 ml). The precipitate was filtered off, washed with H2O and dried under vacuum to obtain compound49(400 mg, 58% yield.)

Stage 5. Getting 4-oxo-N-(thiazol-2-yl)-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthiridine-8-carboxamide (Compound 449):

A mixture of 4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthiridine-8-carboxylic acid49(100 mg, 0,299 mmol) and carbonyldiimidazole (100 mg, 0,617 mmol) in dioxane (2 ml) was heated at 70°C for 1 hour. Was added 2-aminothiazol50(120 mg, 1.20 mmol) and the reaction mixture was stirred at 70°C for 16 hours. After cooling to room temperature was added 1N HCl (5 ml)and the resulting precipitate was filtered, washed with H2O (5 ml)and was purified preparative high performance liquid chromatography to obtain compound449as triptonic Tatnai salt (4.0 mg, 2.5% yield).

Additional compounds of the invention were synthesized in a similar manner by reaction of the corresponding carboxylic acid with the appropriate amine. The syntheses of various intermediate amine compounds and carboxylic acids, which are compounds of this invention listed in examples 13-51 below.

Example 13.Synthesis of 2-(deformity)of benzoyl chloride54:

Stage 1. Obtain methyl 2-(deformity)benzoate (52):

A solution of methyl 2-formylbenzoate51(10 g, 61 mmol) and [bis-(2-methoxyethyl)amino]sulfur TRIFLUORIDE (40,4 g, 183 mmol) in CH2Cl2boiled under reflux for 12 hours. The reaction mixture was cooled to room temperature, concentrated and distributed between EtOAc (500 ml) and H2O (300 ml). Added NaHCO3to adjust the pH value to 8. The organic phase was separated, washed with brine, dried and concentrated. The residue was purified flash chromatography to obtain compound52(7 g, 62% yield)

Stage 2. Getting 2-(deformity)benzoic acid (53):

A mixture of methyl 2-(deformity)benzoate52(7 g, 38 mmol) and 10% aqueous NaOH solution (100 ml) in MeOH (50 ml) was boiled under reflux for 30 minutes. Adjust the pH to 4 by addition of 3N HCl. The obtained solid substance from iltrovatore, washed H2O and dried to obtain compound53(6 g, 93% yield).

Stage 3. Getting 2-(deformity)of benzoyl chloride (54):

A solution of 2-(deformity)benzoic acid53(1.8 g, 10 mmol) in thionyl chloride (25 ml) was boiled under reflux for 3 hours. The reaction mixture was concentrated and dried under vacuum to obtain compound54. The crude acid chloride was used without further purification.

Example 14.Synthesis of 3-(deformity)of benzoyl chloride (56):

Connection56were obtained using a technique similar to the method described for 2-(deformity)of benzoyl chloride54,with a 32% yield.

Example 15.Synthesis of 6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pikolinos acid (59):

Solketal58(23,5 g, 178 mmol) was added to a suspension of NaH (7,1 g, 178 mmol, 60% of the mass. the dispersion in mineral oil) in THF (400 ml), cooled to 0°C. the Reaction mixture was stirred at room temperature for 1 hour and was added 6-bromopicolinic acid57(12 g, to 59.4 mmol). The reaction mixture is boiled under reflux for 1.5 hours. After cooling to room temperature was added H2O (50 ml) and adjusted pH to 3 by addition of 3N HCl. The mixture was poured into brine, and ek is was tragically EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The crude product is recrystallized from a mixture of pentane/EtOAc to obtain the connection59(10 g, 66% 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 16.Synthesis of 2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)nicotinic acid (61):

Connection61were obtained using a technique similar to the method described for 6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pikolinos acid59with 23% 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 17.Synthesis of 6-(morpholinomethyl)pikolinos acid65:

Stage 1. Getting 4-((6-bromopyridin-2-yl)methyl)research (64):

NaBH(OAc)3compared with 68.5 g, 0,323 mol) was added to a solution of 6-bronekollektsia62(40 g, 0.22 mol) and the research63(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, amywali brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified flash chromatography on silica gel, elwira a mixture of petroleum ether:ethyl acetate (10:1) to obtain the connection64(38 g, 68% yield).

Stage 2. Getting 6-(morpholinomethyl)pikolinos acid (65):

n-BuLi (56 ml, 0,140 mol) in THF was added to a solution of 4-((6-bromopyridin-2-yl)methyl)research64(30 g, 0.12 mol) in THF (500 ml) at -78°C. the Mixture was stirred for 30 minutes and the reaction mixture was barbotirovany CO2(gas) for 30 minutes. Volatile components were removed under vacuum and the residue was extracted with a mixture of CH2Cl2/MeOH (1:1). The solvent is evaporated and the residue was washed CH2Cl2getting connection65(11,0 g, 42% yield).

Example 18.Synthesis of 6-(pyrrolidin-1-ylmethyl)pikolinos acid70:

Stage 1. Obtain methyl 6-(chloromethyl)picolinate (67):

SOCl2(57 g, 0.48 mol) was added to a solution of methyl 6-(hydroxymethyl)picolinate66(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 to 9. The mixture was extracted with CH2Cl2, and the combined organic layers were washed brine is m, dried (Na2SO4) and concentrated under vacuum to obtain compound67(45 g).

Stage 2. Obtain methyl 6-(pyrrolidin-1-ylmethyl)picolinate (69):

K2CO3(66 g, 0.48 mol) was added to a solution of methyl 6-(chloromethyl)picolinate67(45,0 g) and pyrrolidine68(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 compound69(36 g).

Stage 3. Getting 6-(pyrrolidin-1-ylmethyl)pikolinos acid (70):

A mixture of methyl 6-(pyrrolidin-1-ylmethyl)picolinate69(36 g) and NaOH (40 g, 1.0 mol) in a mixture of 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 with a mixture of dichloromethane/methanol (3:1 by volume). The organic layer was dried with obtaining connection70(27 g, 55% yield).

Example 19.Synthesis of N-methylpropene72:

Connection72were obtained using a technique similar to the technique described in the publication J. Org. Chem. 2003, 66, 2652.

Example 20.Synthesis of 1-methyl-5-oxopyrrolidin the-2-carboxylic acid 73:

Connection73were obtained using a technique similar to the technique described in the publication J. Heterocyclic. Chem. 1991, 28, 1143.

Example 21.Synthesis of 3-(morpholinomethyl)aniline74:

Connection74were obtained using a technique similar to the method described in J. Med. Chem. 1990, 33(1), 327-36.

Example 22.Synthesis of 6-(pyrrolidin-1-ylmethyl)pyridine-2-amine81:

Stage 1. Obtain ethyl 6-aminopyridine (76):

To a solution of 2-amino-6-pyridineboronic acid75(6.0 g, to 43.5 mmol) in ethanol (150 ml) 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 compound76(5.5 g, 76% yield).

Stage 2. Obtain ethyl 6-(tert-butoxycarbonyl the Mino)picolinate (77):

To a solution of ethyl 6-aminopyridine76(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-tert-BUTYLCARBAMATE (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 compound77(11,0 g, 91% yield).

Stage 3. Obtain tert-butyl 6-(hydroxymethyl)pyridine-2-ylcarbamate (78):

To a stirred solution of ethyl 6-(bis(tert-butoxycarbonyl)amino)picolinate77(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 compound78(3.0 g, 41% yield).

Stage 4. Obtain (6-(tert-butoxycarbonylamino is)pyridine-2-yl)methyl methanesulfonate (79):

To a solution of tert-butyl 6-(hydroxymethyl)pyridine-2-ylcarbamate78(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 compound79with a quantitative yield.

Stage 5. Obtain tert-butyl 6-(pyrrolidin-1-ylmethyl)pyridine-2-ylcarbamate (80):

A mixture of (6-(tert-butoxycarbonylamino)pyridine-2-yl)methyl methanesulfonate79(of 1.30 g, 3.2 mmol), pyrrolidine68(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 NaHCO3the 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 compound80(0.75 g, 62% yield).

Stage 6. Getting 6-(pyrrole the n-1-ylmethyl)pyridine-2-amine (81):

To a solution of tert-butyl 6-(pyrrolidin-1-ylmethyl)pyridine-2-ylcarbamate80(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 with Na2SO4and concentrated under reduced pressure to obtain compound81(440 mg, 92% yield).

Example 23.Synthesis of 6-(morpholinomethyl)pyridin-2-amine82:

Connection82were obtained using a technique similar to the method described for 6-(pyrrolidin-1-ylmethyl)pyridine-2-amine81.

Example 24.Synthesis of (R)-6-((3-ftorpirimidinu-1-yl)methyl)pyridin-2-amine83:

Connection83were obtained using a technique similar to the method described for 6-(pyrrolidin-1-ylmethyl)pyridine-2-amine81.

Example 25.Synthesis of (S)-6-((3-ftorpirimidinu-1-yl)methyl)pyridin-2-amine84:

Connection84 were obtained using a technique similar to the method described for 6-(pyrrolidin-1-ylmethyl)pyridine-2-amine81.

Example 26.Synthesis of 6-(piperazine-1-ylmethyl)pyridine-2-amine85:

Connection85were obtained using a technique similar to the method described for 6-(pyrrolidin-1-ylmethyl)pyridine-2-amine81.

Example 27.Synthesis of tert-butyl 4-((6-aminopyridine-2-yl)methyl)piperazine-1-carboxylate86:

To a solution of 6-(piperazine-1-ylmethyl)pyridine-2-amine85in THF was added di-tert-BUTYLCARBAMATE (1 EQ.) and 4-(dimethyl)aminopyridine (catalytic amount). The reaction mixture was stirred at room temperature for 18 hours. Then it was concentrated under reduced pressure. Added pentane, and the resulting solid was filtered and dried to obtain compound86. Protective Boc group can be removed after the reaction in combination with a corresponding carboxylic acid by treatment with TFA/CH2Cl2within 12 hours.

Example 28.Synthesis of 4-(morpholinomethyl)thiazol-2-amine of triptoreline91:

Stage 1. Obtain ethyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate (88):

Ethyl 2-aminothiazol-4-carboxylate87(10.0 g, to 58.1 mmol) were placed in 150 ml bezvodno the THF together with di-tert-BUTYLCARBAMATE (12,67 g, to 58.1 mmol) and 4-(dimethyl)aminopyridine (DMAP) (10 mg, 0,082 mmol). The reaction mixture was stirred at 50°C for 4 hours and then at room temperature for 18 hours. Then it was concentrated under reduced pressure to obtain a viscous oil. Added pentane and the resulting crystalline substance was filtered and dried to obtain compound88(10.5 g, 66% yield).

Stage 2. Obtain tert-butyl 4-(hydroxymethyl)thiazol-2-ylcarbamate (89):

Ethyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate88(10,5 g, and 38.6 mmol) was dissolved in 300 ml of anhydrous THF and cooled in a bath of dry ice-acetonitrile. Then the solution was added 1M Super Hydride™ in THF (85 ml) for 10 minutes. The resulting reaction mixture was stirred at -45°C for 2 hours. Then added another portion of 1M Super Hydride™ in THF (35 ml) and the reaction mixture was stirred for another 2 hours at -45°C. the Reaction was stopped at -45°C by adding 50 ml of brine. After warming up to room temperature the reaction mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried Na2SO4and concentrated under reduced pressure. The obtained residue was purified by chromatography to obtain compound89(6,39 g, 72% yield).

b> Stage 3. Obtain tert-butyl 4-(morpholinomethyl)thiazol-2-ylcarbamate (90):

Tert-butyl 4-(hydroxymethyl)thiazol-2-ylcarbamate89(2.00 g, 8,68 mmol) were placed in 25 ml of CH2Cl2together with Et3N (1,82 ml of 13.05 mmol) and cooled to 0°C. was Added methanesulfonamide of 0.85 ml, 10,88 mmol) and the resulting reaction mixture was stirred at 0°C for 60 minutes. Then was added morpholine63(3.0 ml, 35 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was placed in EtOAc and washed with dilute aqueous solution of NaHCO3, brine, dried Na2SO4and concentrated under reduced pressure. This substance was purified by filtration through a short column with silica gel. The filtrate was concentrated to obtain compound90(1.88 g, 69% yield).

Stage 4. Getting 4-(morpholinomethyl)thiazol-2-amine of triptoreline (91):

Tert-butyl 4-(morpholinomethyl)thiazol-2-ylcarbamate90(1.88 g, 6,28 mmol) was treated with 20 ml of 25% triperoxonane acid in CH2Cl2within 18 hours at room temperature. Then was removed the solvent by concentration and drying under vacuum, the resulting residue was treated with a mixture of pen is an/EtOAc to obtain the connection 91(1,96 g, 100% yield) as a white solid.

Example 29.Synthesis of 4-(pyrrolidin-1-ylmethyl)thiazol-2-amine of triptoreline92:

Connection92were obtained using a technique similar to the method described for 4-(morpholinomethyl)thiazol-2-amitriptyline91.

Example 30.Synthesis of 5-(morpholinomethyl)thiazol-2-amitriptyline93:

Connection93were obtained using a technique similar to the method described for 4-(morpholinomethyl)thiazol-2-amitriptyline91.

Example 31.Synthesis of 5-(pyrrolidin-1-ylmethyl)thiazol-2-amitriptyline94:

Connection94were obtained using a technique similar to the method described for 4-(morpholinomethyl)thiazol-2-amitriptyline91.

Example 32.Synthesis of 4-(piperazine-1-ylmethyl)thiazol-2-amitriptyline95:

Connection95were obtained using a technique similar to the method described for 4-(morpholinomethyl)thiazol-2-amitriptyline91.

Example 33.Synthesis of tert-butyl 4-((2-aminothiazol-4-yl)methyl)piperazine-1-carboxylate96:

Connection96were obtained using a technique similar to the method described for tert-bout the l-4-((6-aminopyridine-2-yl)methyl)piperazine-1-carboxylate 86. Protective group Boc can be strangled after the reaction combination with the corresponding carboxylic acid by treatment with a mixture of TFA/CH2Cl2within 12 hours.

Example 34.Synthesis of 2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyrimidine-4-amine98:

To a solution of solketal58(34.4 g, 260 mmol) in THF (150 ml) was added NaH (10.4 g, 260 mmol) at room temperature and the mixture was stirred for 1 hour. Then added 2-chloro-4-aminopyrimidine97(15.0 g, 115 mmol) and the mixture was stirred at 70°C for 48 hours. The reaction mixture was concentrated and the crude residue was purified flash chromatography (dichloromethane:methanol = 15:1-10:1) to obtain the connection98(18.2 g, 70% yield) as oil. 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 35.Synthesis of 6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyrazin-2-amine99:

Connection99were obtained using a technique similar to the method described for 2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyrimidine-4-amine98. The acetonide protective group can be removed after the reaction combination with the corresponding aniline by treatment with EtOH/3N HCl (4:1) at kipac the Institute under reflux for 12 hours.

Example 36.Synthesis of (S)-6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-2-aminopyridine100:

Connection100were obtained using a technique similar to the method described for 2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyrimidine-4-amine98. 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 37.Synthesis of (R)-6-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-2-aminopyridine101:

Connection101were obtained using a technique similar to the method described for 2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyrimidine-4-amine98. 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 38.Synthesis of (R)-3-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)aniline105:

Stage 1. Receive (R)-2,2-dimethyl-4-((3-nitrophenoxy)methyl)-1,3-dioxolane (104):

A mixture of 3-NITROPHENOL102(2.00 g, 14.4 mmol), potassium carbonate (4,96 g, or 35.9 mmol) and (5)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane103(2.55 ml, to 18.7 mmol) in DMF (20 ml) was heated in a microwave reactor at 160°C in t the value of 4 hours. The crude reaction mixture was poured into H2O and was extracted with dichloromethane (3×15 ml). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by chromatography using ethyl acetate:pentane, obtaining (R)-2,2-dimethyl-4-((3-nitrophenoxy)methyl)-1,3-dioxolane104(1.90 g, 52% yield) as oil amber color.

Stage 2. Obtaining (R)-3-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)aniline (105):

A mixture of Fe powder (2.38 g, 42,5 mmol), NH4Cl (2,27 g, 42,5 mmol) and (R)-2,2-dimethyl-4-((3-nitrophenoxy)methyl)-1,3-dioxolane104(1.80 g, to 7.09 mmol) in isopropanol (30 ml)/H2O (10 ml) was boiled under reflux for 18 hours. The crude substance was filtered through a layer of celite and the filtrate was concentrated under reduced pressure. The resulting aqueous layer was extracted with dichloromethane (3×15 ml). The combined organic layers were dried Na2SO4and concentrated under reduced pressure to obtain compound105(1.25 g, 76% 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 39.Synthesis of 3-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)aniline106 :

Connection106were obtained using a technique similar to the method described for (R)-3-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)aniline105. 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 40.Synthesis of (S)-3-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)aniline107:

Connection107were obtained using a technique similar to the method described for (R)-3-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)aniline105. 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 41.Synthesis of 4-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)aniline108:

Connection108were obtained using a technique similar to the method described for (R)-3-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)aniline105. 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 42.Synthesis of 2-(pyrrolidin-1-yl)pyridine-4-amine10 :

A mixture of 2-chloro-4-aminopyridine109(to 2.29 g, 17.8 mmol) and pyrrolidine68(5.0 ml) was heated at 200°C in a microwave reactor for 10 minutes. After cooling to room temperature, the solid was filtered and washed with dichloromethane (10 ml×3). The filter cake was dissolved in an aqueous solution of K2CO3and was extracted with CH2Cl2(40 ml×3). The combined organic layers were dried over Na2SO4and concentrated to obtain compound110(2.30 g, 79% yield).

Example 43.Synthesis of 2-morpholinopropan-4-amine111:

Connection111were obtained using a technique similar to the method described for 2-(pyrrolidin-1-yl)pyridine-4-amine110.

Example 44.Synthesis of 6-morpholinopropan-2-amine112:

Connection112were obtained using a technique similar to the method described for 2-(pyrrolidin-1-yl)pyridine-4-amine110.

Example 45.Synthesis of 6-(pyrrolidin-1-yl)pyridine-2-amine35:

Connection35were obtained using a technique similar to the method described for 2-(pyrrolidin-1-yl)pyridine-4-amine110.

Example 46.Synthesis of (S)-5-((3-ftorpirimidinu-1-yl)methyl)pyridin-2-amine120:

Stage 1. Receiving the s ethyl 6-aminonicotinate (114):

To a solution of 2-amino-5-pyridineboronic acid113(150 g, of 1.09 mol) in ethanol (2 l) was added thionyl chloride (259 g, 2,18 mol) at 0°C. the Mixture was boiled under reflux for 12 hours. The solvent was removed under reduced pressure. Was added a saturated aqueous solution of Na2CO3to adjust the pH to 9, and the obtained solid substance was filtered off, washed with H2O and dried to obtain compound114(160 g, 88% yield).

Stage 2. Obtain ethyl 6-(bis(tert-butoxycarbonyl)amino)nicotinate (115):

To a solution of ethyl 6-aminonicotinate114(160 g, 963 mmol) in tert-BuOH (1.7 l) and acetone (560 ml) was added DMAP (2.38 g, 19,1 mmol) and di-tert-BUTYLCARBAMATE (420 g, 1.92 mol). The reaction mixture was stirred at room temperature overnight. The solvent was removed and added hexane/dichloromethane (2.5 l, 3:1). The mixture was cooled to -20°C within 2 hours. The solid was filtered and dried under vacuum to obtain compound115(300 g, 85% yield).

Stage 3. Obtain tert-butyl 5-(hydroxymethyl)pyridine-2-ylcarbamate (116):

To a stirred solution of ethyl 6-(bis(tert-butoxycarbonyl)amino)nicotinate115(300 g, 819 mmol) in THF (1.2 l) was added LiAlH4of 57.6 g and 1.51 mol) in THF (3 l) for 30 minutes is ri 0°C. The reaction mixture was stirred for 6 hours and added H2O (30,0 ml) and 10% NaOH solution (60,0 ml). The solids were filtered off and the filtrate was dried (Na2SO4) and concentrated. The crude residue was purified flash chromatography (CH2Cl2:MeOH = 40:1) to obtain the connection116(85,0 g, 46% yield).

Stage 4. Obtain tert-butyl 5-(chloromethyl)pyridine-2-ylcarbamate (117):

To a solution of tert-butyl 5-(hydroxymethyl)pyridine-2-ylcarbamate116(85,0 g, 379 mmol) and diisopropylethylamine (296 g of 2.27 mol) in THF (850 ml) was added methanesulfonamide (130 g, 1,14 mol) over 30 minutes at 0°C. the Mixture was stirred for 12 hours at room temperature, then washed with H2O (2×100 ml) and dried over Na2SO4. The mixture was concentrated and the crude residue was purified flash chromatography (petroleum ether:ethyl acetate=10:1) to obtain the connection117(30 g, 63% yield).

Stage 5. Obtain (S)-tert-butyl 5-((3-ftorpirimidinu-1-yl)methyl)pyridine-2-ylcarbamate (119):

A mixture of tert-butyl 5-(chloromethyl)pyridine-2-ylcarbamate117(9.5 g, 39,1 mmol), (S)-3-terpinolene118(4,19 g, and 47.0 mmol), potassium carbonate (16.2 g, 117 mmol) and sodium iodide (0,586 g, 3,91 mmol) in DMF (150 ml) was stirred at 60°C for 2 hours. The reaction mixture was filtered and the filtrate concentration is Aravali under vacuum. Added H2O (250 ml) and the resulting solid substance was filtered off, washed with H2O and dried to obtain compound119(7,00 g, 61% yield).

Stage 6. Obtain (S)-5-((3-ftorpirimidinu-1-yl)methyl)pyridin-2-amine (120):

To a solution of (S)-tert-butyl 5-((3-ftorpirimidinu-1-yl)methyl)pyridine-2-ylcarbamate119(7,00 g, with 23.7 mmol) in dichloromethane (70 ml) was added TFA (15.5 g, 142 mmol). The mixture was stirred for 12 hours at room temperature. The solvent was removed under vacuum and added a saturated aqueous solution of Na2CO3. The mixture was extracted with dichloromethane, dried (MgSO4) and concentrated to obtain compound120(4,50 g, 97% yield).

Example 47.Synthesis of 5-(morpholinomethyl)pyridin-3-amine121:

Connection121were obtained using a technique similar to the method described for (S)-5-((3-ftorpirimidinu-1-yl)methyl)pyridin-2-amine120.

Example 48.Synthesis of 6-(morpholinomethyl)pyridin-3-amine122:

Connection122were obtained using a technique similar to the method described for (S)-5-((3-ftorpirimidinu-1-yl)methyl)pyridin-2-amine120.

Example 49.Synthesis of 2-(morpholinomethyl)pyrimidine-4-amine127:

Stage 1. Getting dihydrochloride 2-chloroacetamide (124):

2-chloroacetonitrile123(300 g, 4.0 mol) was added to a solution of sodium (10.0 g, 0.43 mol) in methanol (1000 ml), keeping the temperature below 20°C. the Mixture was stirred at room temperature for 2 hours. Added NH4Cl (234 g, 4,37 mol) in 5 portions and continued stirring for another 2 hours. The solvent was removed to obtain compound124(525 g, 79% yield), which was directly used in the next stage without additional purification.

Stage 2. Getting 2-(chloromethyl)pyrimidine-4-amine (126):

The solution of the dihydrochloride of 2-chloroacetamide124(250,0 g and 1.51 mol), 2-chloroacrylonitrile125(171 g, 1,95 mol) and triethylamine (490 g, 4.8 mol) in anhydrous ethanol (600 ml) was boiled under reflux for 30 minutes. The solvent was removed under vacuum and the residue was purified flash chromatography (dichloromethane:methanol=30:1) to obtain the connection126(39,0 g, 18% yield).

Stage 3. Getting 2-(morpholinomethyl)pyrimidine-4-amine (127):

A solution of 2-(chloromethyl)pyrimidine-4-amine126(30.0 g, 209 mmol), the research63(23.7 g, 272 mmol) and triethylamine (42,3 g, 418 mmol) in anhydrous ethanol (250 ml) was heated under reflux for 16 hours. The solvent was removed under vacuum and added to methanol (400 ml), H2O (100 is l) and sodium bicarbonate (25,0 g). Stirring was continued for 30 minutes. The mixture was concentrated and purified flash chromatography (dichloromethane:methanol:triethylamine=100:8:0,5) to obtain the connection127(25,0 g, 62% yield).

Example 50.Synthesis of tert-butyl 4-((4-aminopyrimidine-2-yl)methyl)piperazine-1-carboxylate128:

Connection128were obtained using a technique similar to the method described for 2-(morpholinomethyl)pyrimidine-4-amine127. Protective Boc group can be removed after the reaction in combination with a corresponding carboxylic acid by treatment with TFA/CH2Cl2within 12 hours.

Example 51.Synthesis of 2-(pyrrolidin-1-ylmethyl)pyrimidine-4-amine129:

Connection129were obtained using a technique similar to the method described for 2-(morpholinomethyl)pyrimidine-4-amine127.

Example 52.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. PEFC is 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 subsequent mass spectral studies. Determination of the mass of the peptide substrate allows to accurately determine the degree of acetylation (i.e. source 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 connecting to the op is adelene 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 for 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 connection, which Aktivera the Ali SIRT1, and they are listed below in tables 1 and 2. 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
Compounds where W1is-N= and W2is N
Connection
No.
[M+H]+StructureEC1,5,
mcm
The increase in activation
%
200447BB

201431AB
202426AA
203447 CIn
204442AAnd
205431InIn

206425AAnd
207441AA
208425CB
209442BA
210357 BB

211441CB
212425BA
213441BA
214349CB
215435CB

216442CB
217442 BA
218411AA
219426AA
220484AA

221435BA
222435BA
223358CB
224335CB
225364CB

226378BB
227361CB
228361BB
229431BB
230429AA

231412CB
232440AA
233454AA
234468AA
235509BA

236428BA
237425BB
238428BA
239425 AA
240425BA

241426CB
242391BB
243391BB
244391CB
245426AA

246428 AA
247428BB
248428AA
249426AA
250415CB

251426BB
252442CB
253382B
254382CB
255358CB

256358CB
257359CB
258359CB
259359CB
260359CB
/p>

261361CB
262361CB
263361CB
264361B
265425BA

266425BA
267454AA
268428CB
269439BB
270453CB

271467InIn
272508BB
273514AA
274442AA
275 440CB

276440BB
277359CB
278359BB
279359CIn
280360CB

281360CB
282 360CB
283365CB
284379BA
285362BB

286514AA
287393BA
288362CB
289362 CB
290362CB

291362CB
292362CB
293510AA
294460AA
295442CB

296445 BB
297488AA
298459AA
299432BA
300524BA

301524BA
302523AA
303426B A
304510AA
305429BA

306453AA
307525BA
308530BA
309530AA
310408AA

311394CIn
312424AA
313410AA
314408AA
315424AA

316410CB
317412AA
318 428AA
319393CB
320427AA

321411BA
322407BA
323407CB
324393AA
325409 CB

326423AA
327423BA
328409BA
329394AA
330509AA

331431BB
332524 AA
333508AA
334515BA
335515AA

336511AA
337493CB
338523AA
339431C B
340445CB

341510AA
342494AA
343445CB
344524AA
345526AA

346526A A
347524AA
348523AA
349494AA
350494BB

516
351508AA
352526AA
353515AA
354AA
355516AA

356515AA
357514AA
358514BA
359509BA
360514AA

361 461CB
362461CB
363514AA
364507BA
365445BA

366529AA

In specific embodiments, the implementation of the connection of this invention are selected from any one of the compounds 201, 202, 204, 206, 207, 218, 219, 220, 230, 232, 233, 234, 239, 245, 246, 248, 249, 267, 273, 274, 286, 293, 294, 297, 298, 302, 304, 306, 309, 310, 312, 313, 314, 315, 317, 318, 320, 324, 326, 329, 330, 332, 333, 335, 336, 338, 341, 342, 344, 345, 346, 347, 348, 349, 351, 35, 353, 354, 355, 356, 357, 360, 363 and 366 table 1. In one aspect, the compound is chosen from any one of the compounds 201, 202, 204, 218, 220, 230, 239, 245, 248, 249, 274, 286, 293, 309, 310, 312, 313, 314, 315, 317, 318, 329, 330, 332, 333, 335, 336, 341, 344, 345, 346, 349, 352, 354, 355, 357 and 360.

Table 2
Compounds where W1is N and W2is C
Connection
No.
[M+H]+StructureEC1,5,
mcm
The increase in activation
%
400445AA

401410AA
402410AA
403411A A
404416AA
405416AA

406414AA
407427AA
408410AA
409411AA
410427AA

411416AA
412417BA
413417BB
414442BA
415411AA

416416AA
417411AA
418 411AA
419410AA
420413AA

426382AA
427416AA
428414AA
429432AA
430432AA
431398AA

432393AA
433382AA
434377AB
435398BA
436414AA
437410A

438392BA
439426AA
440408AA
441376BA
442427AA

443408AA
444416 AA
445411AA
446382BA
447377AA

448509AA
449417AA

In specific embodiments, the implementation of the connection of this invention are selected from any one of the compounds 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 415, 416, 417, 418, 419, 420, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 436, 437, 439, 442, 443, 444, 445, 447, 448 and 449 table 2. In one aspect, the compound of this invention are selected from any one of the compounds 400, 401, 402, 403, 404, 405, 406, 408, 409 410, 415, 417, 418, 420, 423, 424, 425, 428, 431, 432, 434, 442, 443, 445 and 448.

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 such 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 given in the description by reference as if each individual publication or patent was 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 is to the 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).http://www.wipo.int/portal/en/scam_warning.html

1. The compound having a structure described by structural formula (II):

or its salt, where
each of the Z1, Z2and Z3independently selected from N and C(R9), where
not more than one of the Z1, Z2and Z3is N;
each R9represents hydrogen; and
represents the second chemical bond between either W2and C(R12), or W1and C(R12);
W1represents-N=, and
W2(R14) selected from-N(R14)- and - C(R14)=, choosing so that when W1is-N=, W2(R14is-N(R14- andrepresents the second chemical bond between W1and C(R12);
R11selected from phenyl and heterocycle chosen from saturated or aromatic 5-6 membered monocyclic ring comprising one, or two, or three heteroatoms selected from N, O and S, or an 8-membered bicyclic ring, containing one or more heteroatoms selected from N, O and S, where R11optionally substituted by one or two substituents, independently selected, is passed from halogen, C1-C4of alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where
each R13independently selected from-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 heteroatom selected from NH and 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 5-6-membered saturated the heterocycle, saturated, a heterocycle optionally substituted on any carbon atom with fluorine;
R12selected from phenyl, 4-6 membered monocyclic saturated ring and heterocycle selected from aromatic 5-6 membered monocyclic ring comprising one or two heteroatoms, selected from N and S, where R12optionally substituted by one or more substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, C1-C2fluoro-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13);
R14selected from hydrogen, C1-C4of alkyl, C1-C4fluoro-substituted alkyl, C1-C4alkyl-N(R )(R13), C1-C4alkyl-C(O)-N(R13)(R13); and
X1selected from-NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where
† indicates the place in which X1connected to R11.

2. The compound according to claim 1, where the compound has a structure represented by the structural formula:
or
.

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 halogen, C1-C4of alkyl, -(C1-C4alkyl)-N(R13)(R13), =O, -N(R13)(R13and-O-R13.

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




















and.

6. The compound according to claim 5, where R11choose from
+








and.

7. The connection of claim 1, where R12choose from
,
where 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)(R13).

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













,

9. The connection of claim 8, where R12choose from,

and.

10. The compound according to claim 1, where W2(R14is-N(R14)and R14selected from hydrogen and -(C1-C4) alkyl.

11. The compound according to claim 1, where W2(R14is-C(R14)and R14is hydrogen.

12. The compound according to claim 1, where the compound is chosen from any one of compounds




















and
.

13. The connection section 12, where the compound is chosen from any one of compounds











and
.

14. The compound according to claim 1, where the compound is chosen from any one of compounds













and.

15. The connection 14, where the compound is chosen from any one of compounds








and.

16. Pyrogen-free pharmaceutical composition having sirtuin modulating activity, including pharmaceutically acceptable carrier or diluent and a compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt.

17. 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 composition according to item 16.

18. A method of increasing insulin sensitivity in a subject, comprising the administration to a subject, if desired, the composition according to item 16.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 11-(piperazin-1-yl) dibenzo[b,f[1,4]oxazapine compounds of general formula specified below wherein the radicals are presented in the description, to their pharmaceutically acceptable salts and pharmaceutical compositions. There are also described methods for preparing said compounds.

EFFECT: compounds may be used for treating disorders, such as schizophrenia, resistant schizophrenia, bipolar disorder, psychotic depression, resistant depression, depressive conditions related to schizophrenia, treating resistant OCD, autism, senile dementia, psychotic dementia, L-DOPA-induced psychotic disorder, psychogenic polydipsia, psychotic symptoms of neurological disorders, sleeping disorders.

39 cl, 25 ex, 8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) wherein R4 represents a group of formula (II) and R1, R2, R3, R5 and X are those as specified in the patent claim.

EFFECT: preparing the pharmaceutical composition applicable in treating chronic obstructive pulmonary disease and containing the compound of formula (I).

8 cl, 3 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: pharmacology.

SUBSTANCE: invention refers to the compound of formula(I) or to is salt where R1 is -H or C1-6 alkyl; R2 is bridged aza-ring chosen out of group including formula and where ring hydrogen atom in bridged aza-ring may be substituted by one or several groups of R22; m, n and p have respective values 1 or 2; r has the value 0 or 1; R21 is C1-6 alkyl, -C1-6 alkyl-O-phenyl or -C1-6 alkyl-phenyl; R22 is C1-6 alkyl-cycloalkyl or -C1-6 alkyl-phenyl; R2 is thienyl, phenyl, pyridyl, pyranzinyl, thiazolyl or pyrazolyl, each of which can be substituted by one or several R31; R31 is the halogen, -OH, -CN, -CF3, C1-6 alkyl or -O-C1-6 alkyl; ring A is the group consisting of thiophene, thiazole, isothiazole, thidiazole, oxazole, isooxazole, cyclohexan, norboran, benzothiophene and 5,6-dihydro-4H-cyclopentathiophene, each of which can be substituted by the group chosen out of the group consisting out of one or several RA1; where RA1 is a halogen, -CN, -NH2, C1-6 alkyl, -O-C1-6 alkyl, CONH2, - HN-C1-6 alkyl, -HN-C1-6 alkyl-O-C1-6 alkyl-phenyl, -HN-C1-6 alkyl-phenyl or -HN-C1-6 alkyl-OH where C1-6 alkyl can be substituted with one or several halogen atoms; V is -NH- or -O-; W is -(CH2)q-; q has the value 0.1 or 2; X is the counteranion and is an ordinary bond; on condition when in case ring A is cyclohexane, R3 is phenyl which can be replaced with one or several R31. The invention also refers to pharmaceutical composition that has antagonistic effect on muscarine receptor M3, on the basis of said compound.

EFFECT: production of new compound and pharmaceutical composition on its basis, which can be applied in the medicine as an active substance for preventive and/or therapeutic drug for treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like.

14 cl, 60 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 1-azabicyclo[2.2.2]oct-3(R)yl ether of 2-hydroxy-2,2-dithien-2-ylacetic acid and 3-phenoxypropyl bromide, where the reaction takes place in a solvent or mixtures of solvents, having boiling point ranging from 50 to 210°C and selected from a group comprising ketones and cyclic ethers, preferably in acetone, dioxane and tetrahydrofuran.

EFFECT: efficient method of obtaining the compounds.

12 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (R)- quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate or salt thereof, involving: 1) converting a compound which is 4-amino-3-methoxypiperidine-1-carboxylate to a salt; 2) converting the ethyl 4-amino-3-methoxypiperidine-1-carboxylate salt into ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate 3) treating ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate with hydroxide or hydride of an alkali metal to obtain 3-methoxy-N,N-diphenylpiperidine-4-amine 4) obtainijng a chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine by bringing 3-methoxy-N,N-diphenylpiperidine-4-amine into contact with a chiral splitting agent and extracting the obtained chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine; optional recrystalisation of product 4; converting product 4 or 5 to a base to obtain product 4 or 5 in form of a free base; 7) bringing product 6 into contact with ethyl 6-bromohexanoate to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 8) esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate using (R)-quinuclidin-3-ol with a Lewis acid to obtain (R)- quinuclidin-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 9) removing protection from the 4-amine group of product 8 to obtain (R- quinuclidin-3-yl 6- [(3S,4R)-4-amino-3-methoxypiperidin-1-yl)hexanoate; 10) acylation of product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)- quinuclidin-3-yl 6-((38,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate; 11) optional conversion of product 10 into a salt.

EFFECT: method increases output of the end product and reduces content of impurities.

7 cl, 3 ex, 6 tbl, 3 dwg

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: chemistry.

SUBSTANCE: invention relates to compound of formula I in which R1 represents halogen, methoxy group or cyano group; each of Y1 and Y2 represents CH, and one or two from U, V, W and X represent N, and each remaining one represents CH, or in case X, cam also represent CRa, or Ra represents halogen; A represents CH2CH(OH), CH2CH(NH2), CH(OH)CH(NH2) or CH(NH2)CH2, B represents CH2CH2, CH2NH or CONH, and D represents CH2, or A represents CH(OH)CH2, and B represents CH2NH, N(R2)CO or CONH, and D represents CH2, or B represents N(R2a)CH2, and D represents CH(OH), or A represents CH(OH)CH(OH), B represents CH2NH or CONH and D represents CH2, or A represents CH2CH2, and B represents CH2CH2, CH2NR3, NHCO, CONR4, CH2O, COCH2 or CH2CH2NH, and D represents CH2, or B represents CH2NH, and D represents CO, or A also represents CH2CH2, B represents NR4bCH2 and D represents CH(OH), or A represents CH=CH, B represents CH2NR5 or CONR6, and D represents CH2, or A represents C≡C, B represents CH2NH and D represents CO, or A represents COCH2, B represents CONH and D represents CH2, or A represents CH2N(R7), and B represents CH2CH2, a D represents CH2, or B represents CH2CH(OH), a D represents CH(OH), or A represents NHCH2, and B represents CH2NH, a D represents CH2, or B represents CH2NH, a D represents CO, or A represents NHCO, B represents CH(R8)NH or CH2CH2, and D represents CH2, or A represents OCH2, B represents CH=CH or CONH, and D represents CH2; R2 represents (C1-C4)alkyl; R2a represents hydrogen; R3 represents hydrogen, CO-(CH2)p-COOR3', (CH2)p-COOR3, (C2-C5)acyl or amino(C1-C4)alkyl, or also R3 represents (C1-C4)alkyl, which can be one or two times substituted with hydroxygroup, p stands for integer number from 1 to 4, and R3 represents hydrogen or (C1-C4)alkyl; R4 represents hydrogen or (C1-C4)alkyl; R4b represents hydrogen; R5 represents hydrogen or (C2-C5)acyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents hydrogen or (C1-C4)alkyl, which can be one or two times substituted with group, independently selected from hydroxygroup and aminogroup, R8 represents hydrogen or (C1-C4)alkyl; E represents one of the following groups (a-a1) where Z represents CH or N, and Q represents O or S, or E represents phenyl group, which is one or two times substituted in meta- and/or para-position with substituents, each of which is independently selected from group, including halogen, (C1-C3)alkyl and trifluoromethyl; or pharmaceutically acceptable salt of such compound. Formula I compound or its pharmaceutically acceptable salt is applied for obtaining medication or pharmaceutical composition for prevention or treatment of bacterial infection.

EFFECT: derivatives of oxazolidine antibiotics for obtaining medication for treatment of bacterial infections.

15 cl, 2 tbl, 214 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where "----" denotes a bond or is absent; R1 is a C1-4alkoxy group or halogen; R1b is H or C1-3alkyl; U and V each independently denote CH or N; W is CH or N, or, if "----" is absent, W is CH2 or NH; under the condition that at least one of U, V and W is CH or CH2; A is -CH2-CH(R2)-B-NH-* or -CH(R3)-CH2-N(R4)-[CH2]m-*; where asterisks indicate a bond which binds said fragments through a CH2-group with an oxazolidinone fragment; B is CH2 or CO; and R2 is hydrogen, OH or NH2; R3 and R4 both denote hydrogen, or R3 and R4 together form a methylene bridge; m equals 0, 1 or 2; and G is a phenyl which is monosubstituted in position 3 or 4, or disubstituted in positions 3 and 4, where each substitute is independently selected from a group comprising C1-4alkyl, C1-3alkoxy group and halogen; or G is a group selected from groups G1 and G5 where M is CH or N; Q' is S or O; Z1 is N, Z2 is CH and Z3 is CH; or Z1 is CH, Z2 is N and Z3 is CH or N; or Z1 is CH, Z2 is CR5 and Z3 is CH; or Z1 is CH, Z2 is CH and Z3 is N; and R5 is hydrogen or fluorine; or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof are used as a medicinal agent for preventing or treating bacterial infections.

EFFECT: oxazolidinone derivatives used as antimicrobial agents.

15 cl, 2 tbl, 44 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

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