Methods for increasing stabilisation of hypoxya induced factor-1 alpha

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: using a compound of formula (1) or its salt for preparing a drug for increasing HIF-1α stabilisation in a cell, as well as for preparing a drug enhancing the immune response in an individual, for preventive management of a wound to avoid an infection, for treatment of the microbial infection, for improvement of efficacy of a vaccine for management of the wound in the individual. What is presented is a pharmaceutical composition containing the above HIF-1α prolyl hydroxylase inhibitor and one or more additives. What is shown is achieving the declared applications by using the new compound of formula (1) with the HIF-1α prolyl hydroxylase (HIFPH2 (EGLN1)) inhibitor. It makes it applicable for treating HIF-1 alpha activity related diseases, conditions and/or syndromes.

EFFECT: preparing the drug for increasing HIF-1α stabilisation in a cell.

26 cl, 20 dwg, 8 tbl, 13 ex

This application claims priority based on provisional application serial number 61/258914 and provisional application serial number 61/258918 that have been entered in the register on 6 November 2009 and are included in the present description in its entirety as a reference.

The technical FIELD TO WHICH the PRESENT INVENTION

In the present invention are described inhibitors prolylhydroxylase that can stabilize hypoxia-induced factor-1 alpha (HIF-1α), and hypoxia-induced factor-2 alpha (HIF-2α). The present invention also describes pharmaceutical compositions containing one or more of the disclosed compounds. In addition, the present invention describes methods for the stimulation of cellular immune response in a mammal, such as enhancement of phagocytosis, for example, increasing the life expectancy of phagocytes, including keratinocytes, neutrophils. In this regard, the described connections provide methods for treating diseases that affect the immune response of the body.

The ESSENCE of the PRESENT INVENTION

Described compounds stabilize HIF-1α and HIF-2α, and other factors that are present in the damaged immune system, or the number of which is reduced, or that are excessively loaded by the presence of painful conditions and manifestations bresnen the condition, including sepsis. Described compounds can be used to treat cancer and it is possible to enter with other drugs for cancer therapy. In addition, the above compounds can be used to enhance the immune response in a mammal when combined with the introduction of vaccines, such as influenza vaccines, vaccines against malaria, yellow fever vaccines, vaccines against cancer and the like.

BRIEF DESCRIPTION of DRAWINGS

In Fig. 1 shows the normal metabolic pathway of HIF-1α when normoxia.

In Fig. 2 shows the increased destruction of neutrophils strain NewmanS. aureusin the processing of 50 μm and 200 μm of the compounds described in table VIII, in comparison with control (DMSO) after 60 and 90 minutes.

In Fig. 3 shows the gain cell lines of human monocytes (U937) with respect toS. aureus(strain Newman) in the processing of 10 μm of the compounds described in table VIII, in comparison with untreated samples.

In Fig. 4 shows the average percentage of surviving bacteria in the treated compared to untreated U937 cells after infectionS. aureus(strain Newman) after 1 hour pre-treatment (black) or 2 hours (shaded) pre-treatment of 10 μm of the compounds described in table VIII.

In Fig. 5 shows the average percentage of surviving bacteria in processed when Anenii with untreated U937 cells after infection with two strains of S. aureus, Newman (black) or methicillin-resistantS. aureus(MRSA) (shaded), after 1 hour pre-treatment of 10 μm of the compounds described in table VIII.

In Fig. 6 shows the average percentage of surviving bacteria in the treated compared to untreated U937 cells after infection with two strains ofS. aureus, Newman (black) or MRSA (shaded) and processing 10 μm of the compounds described in table VIII.

In Fig. 7 shows the average percentage of surviving bacteria in the treated compared to untreated U937 cells after infection with two strains ofS. aureus, Newman (shaded columns) or MRSA (black columns), after treatment with 100 mm mimosine (A), 10 μm of the compounds described in table VIII (B), or 2 mg/ml of vancomycin (C) within 2 hours after infection.

In Fig. 8 shows the average percentage of surviving bacteria in the treated compared to untreated U937 cells after infectionS. aureus(Newman) without pre-treatment, after 1 hour pretreatment or 2 hour pre-treatment of 10 μm of the compounds described in table VIII.

In Fig. 9 shows the average percentage of surviving bacteria in the treated compared to untreated HaCaT cells infected with two strains ofS. aureus, Newman (shaded columns) or MRSA (black columns) and pre-treated in t the value of 1 hour or DMSO (control), 800 μm mimosine, 10 μm of the compounds described in table VIII, or 1 μg/ml of vancomycin. Data shown represent the 2 hour post-processing.

In Fig. 10 shows the average percentage of surviving bacteria in the treated compared to untreated HaCaT cells infected with two strains ofS. aureusstrain Newman (shaded columns) or MRSA (black columns), after pre-treatment of 10 μm of the compounds described in table VIII.

In Fig. 11 shows a stimulating expression regulation phosphoglycerate (PGK) in embryonic fibroblasts wild-type mice as a result of processing by the connection described in table VIII at dosages of 1 μm (E), 10 μm (F) and 50 μm (G) compared with control wild-type (H) and the absence of incentive regulation PGK expression in HIF-1 knockout cells as a result of processing by the connection described in table VIII at dosages of 1 μm (A), 10 µm (B) and 50 μm (C) and HIF-1 knockout control (D). Both types of cells were treated for 7 hours.

In Fig. 12 shows a stimulating expression regulation phosphoglycerate (PGK) in embryonic fibroblasts wild-type mice as a result of processing by the connection 1-(3-Chlorobenzyl)-3-hydroxypyridine-2(1H)-one, at doses of 1 μm (E), 10 μm (F), in comparison with control wild-type (G) and the absence of incentive regulation PGK expression in HIF-1 knockout cells as a result of about what abode connection described in table VIII at dosages of 1 μm (A), 10 µm (B) and 50 μm (C) and HIF-1 knockout control (D).

In Fig. 13 shows a stimulating expression regulation phosphoglycerate (PGK) in embryonic fibroblasts wild-type mice as a result of processing by the connection described in table VIII at dosages of 1 μm (E), 10 μm (F) and 50 μm (G) compared with control wild-type (H) and the absence of incentive regulation PGK expression in HIF-1 knockout cells as a result of processing by the connection described in table VIII at dosages of 1 μm (A) , 10 µm (B) and 50 μm (C) and HIF-1 knockout control (D).

In Fig. 14 shows stimulatory regulation of expression of growth factor vascular endothelial (VEGF) in embryonic fibroblasts wild-type mice as a result of processing by the connection described in table VIII at dosages of 1 μm (E), 10 μm (F) and 50 μm (G) in comparison with control (H) and the absence of incentive regulation of VEGF expression in HIF-1 knockout cells treated with compound described in table VIII at dosages of 1 μm (A), 10 µm (B) and 50 µm (C), and HIF-1 knockout control (D). Both types of cells were treated for 7 hours.

In Fig. 15 shows the results of example 11, in which 3 groups of animals were treated sensitive to the antibiotic strain NewmanStaphylococcus aureus. The data show a significant decrease in the size of skin lesions (wounds) for animals in group 1 (filled diamonds (♦)), processing the data 10 μm compound, described in table VIII, in comparison with the animals, which were given bolus DMSO (filled squares (■)). Fig. 15 shows mice infected with strain NewmanS. aureus, followed by treatment of 10 μm of the compounds described in table VIII, or DMSO (control) 2 hours after infection. The data show a statistically significant decrease in the size of skin lesions (wounds) for animals treated with compound described in table VIII (filled diamonds (♦)or DMSO (filled squares (■)).

In Fig. 16 also shows the results of example 11, showing the reduction in size of skin lesions (wounds) for animals in group 1 (filled diamonds (♦)), treated with 10 μm of the compounds described in table VIII, in comparison with animals that were not treated (filled triangles (▲)). Fig. 16 shows mice infected with a strain of S. Aureus Newman, followed by treatment of 10 μm of the compounds described in table VIII, with or without treatment within 2 hours after infection. The data shows a decrease in the size of skin lesions (wounds) for animals treated with compound described in table VIII, (filled diamonds (♦)or untreated (filled triangles (▲)).

In Fig. 17 presents a histogram that shows the results of example 12, in which 3 groups of animals were treated sensitive to the antibiotic strain Newman Stahylococcus aureus [ATCC #25904]. Data show the results for the untreated group, built on (A), the results for the group treated with DMSO, built over (B), and the results for the group treated with 10 μm of the compounds described in table VIII, built over (C).

In Fig. 18 shows the results of example 12, in which the number of colony forming units in the Bud lay on the graph for different groups: untreated group delay over (A), the group treated with DMSO, lay over (B)and the group treated with 10 μm of the compounds described in table VIII, lay over (C).

In Fig. 19 shows the results of example 13, in which 2 groups of animals treated withStreptococcus pyogenesNZ131 [M49 strain]. The data shows a decrease in the size of skin lesions (wounds) for animals in group 1 (filled triangles (▲))treated with 0.5 mg/kg of the compounds described in table VIII, in comparison with animals treated with control medium (cyclodextrin) (filled squares (■)).

In Fig. 20 presents the histogram, which also shows the results of example 12, in which the number of colony forming units for the observed skin lesions in animals treated with control medium (cyclodextrin), lay on (A), and the results for the group treated with 0.5 mg/kg of the compounds described in table VIII, lay over (B).

DETAILED DESCRIPTION

In Dan is the first description and in the claims, next, referring to the number of terms, which, as will be defined, shall have the following meanings.

Throughout this description, unless the context requires otherwise, the word "comprise" or variations such as "includes" or "including"should be interpreted as having the value of including the specified integer or step or group of integers or steps, but not excluding any other integer or stage or group of integers or steps.

It should be noted that, as used in the description and the attached claims, the singular includes the plural, unless the context certainly does not dictate otherwise. Thus, for example, reference to "a carrier" includes a mixture of two or more data carriers and the like.

"Optional" or "optionally" means that the subsequently described event or circumstance may occur or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

By "pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable, i.e., the substance can enter the individual together with the corresponding active compound without causing clinically unacceptable biological effects or it does not interact adversely with other components Pharma is eticheskoi composition, in which it is contained. Ranges can be expressed in the present invention as from "about" one particular value and/or to "about" another particular value. In terms of range, another aspect includes from the one particular value and/or to the other particular value. Similarly, when the quantities are expressed in the form of approximate quantities, using the term "approximately", it is clear that the particular value forms another aspect. In addition, it is clear that the extreme values of each of the ranges are significant and relative to the other extreme of size and regardless of the other extreme value.

The weight percent of the component, unless specifically stated otherwise, are based on the total weight of the composition or of the composition containing the component.

By "effective amount", as used in the present invention, mean "one or more of the described inhibitors of HIF-1α of prolylhydroxylase, effective at dosages and for periods of time necessary to achieve the desired or therapeutic result." The effective amount may vary depending on factors known in the art, such as disease stage, age, gender and weight of a person or animal that is treated. Although specific dosing regimens can be is written in the examples in the present invention, specialists in the art it is clear that the dosage can be modified to provide the optimal therapeutic response. For example, several individual doses can be administered daily or the dose can be proportionally reduced as required for the needs of therapeutic situation. In addition, the compositions of the present description, you can enter as often as necessary to obtain therapeutic amounts.

"Mixture", usually used in the present invention, refers to the physical combination of two or more different components.

"Excipient" is used in the present invention to include any other compound that may be contained in or to be mixed with one or more of the described inhibitors, which is not therapeutically or biologically active compound. In this regard, the excipient must be pharmaceutically or biologically acceptable or appropriate (for example, the excipient should generally be non-toxic to the subject). "Excipient" includes this a single connection, and also implies that it includes several auxiliary substances.

As used in the present invention, the term "subject" means the individual. Thus, the "subject" can include domesticated animals (n is an example, cats, dogs etc), farm animals (e.g. cattle, horses, pigs, sheep, goats etc), laboratory animals (e.g., mouse, rabbit, rat, Guinea pig etc) and birds. "Subject" may also include a mammal such as a Primate or human.

Under the "prevention" or other forms of words, such as "preventing" or "prevention"means stopping the particular breach or condition, stabilization or slowing development or progression of specific violations or state or minimize the possibility that a particular disorder or condition will occur. Prevention does not require comparison with a control, as it is usually more absolutely than, for example, reduction. As used in the present invention, disorder or condition can be weakened, but not be prevented, but the violation or condition that weakens, can also be prevented. Similarly, violation or condition can be prevented, but not impaired, but the violation or condition that prevented can also be weakened. It is clear that the application of attenuation or prevention of, if not specifically stated otherwise, the use of other words also described explicitly.

Under the "weakening" or other forms of words, such as "weakening" or "oslabljeni the", imply a weakening of the violation or condition (for example, transudation of fluid through the vessels). Clearly, this usually refers to some standard or expected value, in other words, it is relative, but that is not always necessarily refer to a standard or relative value.

The term "treat" or other forms of words such as "cure" or "treatment", as used in the present invention refer to the fact that the introduction of the compounds of the present invention facilitates a disease or disorder in a recipient and/or relieves, inhibits, or eliminates a particular condition or disease associated with the disorder (for example, an infection caused by a microorganism). Thus, the term "treatment" includes preventing the occurrence of disorder of the recipient, particularly when the recipient is predisposed to acquiring the disease, but which have not yet diagnosed the presence of this disease; inhibiting the disorder; and/or relief or reversal of the disorder. Because the methods of the present invention is aimed at preventing disorders, it is clear that the term "prevent" does not require a painful condition completely undermined. Rather, as used in the present invention, the term prevention refers to the ability of a specialist in this allestimenti to detect population, which is prone to disturbances, so that the introduction of the compounds of the present invention can occur prior to the onset of the disease. The term does not imply that a painful condition completely reduced to nothing.

Ranges can be expressed in the present invention as from "about" one particular value and/or to "about" another particular value. In terms of range, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximate values, using the term "approximately", it is clear that the particular value forms another aspect. In addition, it is clear that the marginal value of each of the ranges are important and relative to the other limits and independently of the other thresholds. It is also clear that there are a number of variables, described in the present invention, and that each value also describe the present invention in the form of "approximately" this particular value in adding to the value. For example, if you describe the value of "10", then also describe "about 10". It is also clear that to describe any value, then also describe "less than or equal to the given value, greater than or equal to the given value and potential range is between values as, respectively, it is clear to a person skilled in the art. For example, if you describe the value of "10", then also describe "less than or equal to 10", and "greater than or equal to 10". It is also clear that throughout the application data are presented in several different formats and that these data represent limit values and the original values and ranges for any combination of private values. For example, if you describe a specific private value "10" and specific private value "15", it is clear that more than, greater than, or equal to, less than, less than or equal to and is equal to 10 and 15 are described, as well as the interval between 10 and 15. It is also clear that describe each a value between two specific integer values. For example, if you describe 10 and 15, also describe 11, 12, 13 and 14.

By "antimicrobial" refers to the ability to treat or control (e.g., reduce, prevent, inhibit, reduce or eliminate) the growth and viability of microorganisms at certain concentrations. Similarly, the terms "antibacterial", "antiviral" and "antifungal", respectively, denote the ability to treat or control (e.g., reduce, prevent, inhibit, reduce or eliminate) the growth and viability of bacteria, virus or fungus at a certain concentration.

The term "anion" PR is dstanley a type of ion and included in the meaning of the term "ion". "Anion" is any molecule, part of a molecule (for example, zwitterion), a cluster of molecules, molecular complex, fragment or atom, which contains the total negative charge or which can be obtained showing the total negative charge. The term "anionic precursor used in the present invention for the special link to a molecule that can be converted into the anion via a chemical reaction (for example, deprotonation).

The term "cation" is a type of ion and included in the meaning of the term "ion". "Cation" is any molecule, part of a molecule (for example, zwitterion), a cluster of molecules, molecular complex, fragment or atom, which contains the total positive charge or which can be obtained showing the total positive charge. The term "cationic precursor used in the present invention for the special link to a molecule that can be converted into a cation by a chemical reaction (e.g., protonation and alkylation).

"Chemotherapeutic agent" is used in the present invention to include any other pharmaceutically active compounds that can be used in combination with the described inhibitors of HIF-1α of prolylhydroxylase, such as cytotoxic drugs, such as the 6-hydroxymethylcellulose, cyclophosphamide, dacarbazine, carmustine, doxorubicin and methotrexate. Other chemotherapeutic agents also include anti-inflammatory drugs, i.e. non-steroidal anti-inflammatory compounds, such as aspirin.

Unless States otherwise, the formula with chemical bonds, only shown by solid lines and no wedges or dashed lines, assumes every possible isomer, for example, each enantiomer, diastereoisomer and metasediment and a mixture of isomers, such as racemic or kalamajska mixture.

Hypoxia-induced transcription factor 1 (HIF-1) is one of the key regulators of oxygen homeostasis. It regulates physiological response to low oxygen concentration (hypoxia) and the pathophysiology of myocardial infarction, cancer, stroke and chronic lung disease. HIF-1 is a heterodimeric protein that consists of two subunits, HIF-1α and HIF-1β. Whereas HIF-1β is expressed constitutively, the expression of HIF-1α is called the oxygen concentration below 6%. HIF-1 heterodimer contact sensitive to hypoxia element (HRE), 5-RCGTG-3 consensus sequence. Discovered already several dozen genes that regulate HIF-1, including genes encoding proteins involved in angiogenesis, energy metabolism, the EPO is h, cell proliferation and viability, vascular remodeling and vasomotor reactions. Therefore, the modulation of HIF activity in cells is crucial for the prevention, control, treatment, or, in other words, exposure to a wide range of diseases, illnesses and conditions.

Hypoxia-induced transcription factor 1-alpha (HIF-1α) plays a major role in cellular adaptation to low oxygen availability. In hypoxic stress activated HIF-1α is committed to oxygen homeostasis not only by maintaining intracellular energy production through induction of angiogenesis and glycolysis, but also limiting consumption of energy by inhibiting cell proliferation and DNA repair. In General, HIF-1α activates its target genes, includingEPO,VEGFandPGK1by linking sensitive to hypoxia element in the gene promoter (Wang, G.L. et al., J Biol Chem (1993); 268: 21513-21518).

HIF-1α in normal healthy condition in which cells have a sufficient supply of oxygen, is easily converted into a ruined form through one of the several 4-prolylhydroxylase enzymes, including EGLN1 (in the present invention is called HIFPH2). As described above, when the cells are exposed to hypoxia, this enzyme preframe the ie is slow or stopped completely and HIF-1α begins to accumulate in the cell. During the flow accumulation of HIF-1α this protein is combined with HIF-1β, forming an active transcription factor complex HIF-1. Then this transcription factor activates several biological pathways that are present in the form of responses and means of alleviating the condition of the body during hypoxia. These effects include, including angiogenesis, erythropoiesis (EPO), glucose metabolism (PGK), change hyaloplasm and increased the ability of phagocytes to respond to the pathogenesis.

Fig. 1 summarizes the metabolism of HIF-1α in normal healthy condition. HIF α-subunits are unstable under conditions of normal oxygen content; cells continuously synthesize and destroy their proteins. A short period of polurethane HIF-1α is a byproduct of the family, dependent O₂and iron prolylhydroxylase (PH1-3), whose activity is directed on HIF α-subunit for destruction by the ubiquitin-proteosomal path in a process dependent on the interaction with the protein is a tumor suppressor von Hippel-Lindau (vHL). In Fig. 1 PDH represent prolylhydroxylase that operate in the presence of asparaginases for hydroxylation of prolinol 402 and 564, and asparagine 804. From this moment, because other factors prevent the binding gidrauxilirovannogo HIF-1α with p300-CPB, ubiquitin-whether the Aza starts to metabolize gidroksilirovanii HIF-1α by vHL path.

Patients, when necessary stimulation for this reaction, for example in patients requiring increased oxygen to the tissues in the peripheral vascular disease (BPS), inhibition of HIF1 enzymes, for example, Egl nine homolog 1 (HIFPH2), will stimulate private angiogenic response of the body without the effects of oxygen deficiency. In addition, diseases ischemia, including coronary heart disease and anemia, stimulation of angiogenic, eritropoeticescoe and metabolic adaptation will bring therapeutic benefits. Incentive regulation of HIF-1α also provides a method for enhancing immunity, for example by increasing the capacity of phagocytes.

Therefore, there is a long felt need for methods of controlling the activity of HIF-1α, which can effectively be achieved by compounds that inhibit 4-prolylhydroxylase enzymes that destroy HIF-1α. Thus, the inhibition of 4-prolylhydroxylase enzymes, including HIFPH2 (also referred to in the present invention EGL1 or PHD2) and HIFPH3 (also referred to in the present invention EGLN3 or PHD-3), provides a method for increasing the concentration of HIF-1α in cells and, therefore, provides methods of treatment of diseases or medical conditions.

In the present invention describe methods of treating one or more diseases is s, conditions, syndromes and the like, which are affected by the concentration of hypoxia-induced transcription factors. Regulation of these factors and hypoxia, and when normoxia can provide ways to restore balance or regulate one or more biological pathways associated with abnormal conditions, including the introduction into the body of pathogens, including bacteria, fungi, viruses and parasites, impaired cellular regulation, i.e. cancer, ischemia and side effects caused by vaccination.

Directed HIF1 stabilization in cells

HIF-1α is targeted for destruction by prolylhydroxylase-dependent oxygen modifications, which signals the recognition E3 ubiquitinprotein complex containing oncosuppressor background Hippel-Lindau (VHL). Three prolylhydroxylase, previously referred to in the literature EGLN1, EGLN2, and EGLN3, have been found in mammals, among which EGLN1 (also known as HIFPH2 or PHD2) and EGLN3 (also known as HIFPH3 or PHD3), are induced by hypoxia in their mRNA concentrations of HIF-1α dependent manner. HIF-1α concentration is controlled by the data propyl-4-hydroxylase hydroxylation HIF-1α prolinnova residues Pro-402 and Pro-564 in humans (Ivan, M. et al., (2001) "HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O₂sensing." Science 292, 464-468; Jaakkola, P. et al., (2001) "argeting of HIF-1α to the von Hippel-Lindau ubiquitylation complex by O ₂-regulated prolyl hydroxylation." Science 292, 468-472; and Masson, N. et al., (2001) "Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation." EMBO J. 20, 5197-5206). In hypoxia EGLN1 and EGLN3 activity is suppressed.

Synthesis phosphoglycerate (PGK) and growth factor vascular endothelial (VEGF) stimulated an increase in the cellular concentration of HIF-1α. It was shown that stimulation of VEGF causes the formation of functional neocosmos in the cornea of mice and increases circulation models dogs c coronary artery disease. Inhibitors of HIF-1α of prolylhydroxylase of the present invention provide an increase in the expression of several hypoxia-induced genes, including VEGF, GAPDH and erythropoietin (EPO). In addition, inhibitors of HIF-1α of prolylhydroxylase of the present invention provide increased accumulation of HIF-1α in the cytoplasm and nucleus. Transgenic mice expressing constitutively active HIF-1α in the skin, increase skin vascularization and have a 13-fold increase in VEGF concentration.

Wounds

Chronic incurable wounds are a major cause of long-term morbidity in the population of older people. This, in particular, is a case in bedridden and diabetic patients who develop severe, incurable skin ulcers. In many of these cases, a delay of treatment is the result of inadequate cravenby the treatment or as a result of continuous pressure or blockages of blood vessels. Poor capillary circulation as a result of atherosclerosis of small arteries or venous stasis contributes to the inability to repair damaged tissue. These fabrics are often contaminated with microorganisms that proliferate without interfering with innate protective systems of the body that require well-vascularized tissue to effectively eliminate pathogenic organisms. As a result, most of therapeutic effects are based on restoring blood flow to ischemic tissues, by providing this access of nutrients and immunological factors in the wound area.

The present invention relates to methods for treating wounds and promote healing in a subject, comprising the introduction of required treatment to a subject an effective amount of one or more of the described compounds.

The present invention relates to the use of one or more of the described compounds for use in obtaining medications for the treatment of wounds and promote healing.

Antimicrobial drug

Sensitive to hypoxia transcription factor HIF-1α is important for regulation of inflammationin vivo. In this regard, it was discovered (C. Peyssonnaux et al., "HIF-1α expression regulates the bactericidal capacity of phagocytes" J. Clinical Investigation 115(7), pp 1808-1815 (205)), what bacterial infection induces HIF-1α expression in myeloid cells even under conditions of normal oxygen content and that HIF-1α regulates the synthesis of important molecular effectors of immune protection, including granular proteases, antimicrobial peptides, nitric oxide and TNF-α. Bacterial infection activates a subclass of HIF-1α of target genes specifically associated with the destruction of microbes, showing by this that HIF-1α has a vital function in innate immunity, non-hypoxic response. Therefore, HIF-1α function is important for the bactericidal activity of myeloid cells and the ability of the entity to limit the systemic spread of infection from the initial concentration in the tissue. Increased activity of HIF-1α way through vHL deletions promotes the synthesis of myeloid cells protective factors and increases bactericidal activity. Described compounds cause HIF-1α activity and may also contribute to the destruction of bacteria and NO-synthesis of HIF-1α-specific way. These findings provide ways of enhancing innate immune responses to microbial, e.g. bacterial, infection.

Not wishing to be bound by theory, the described compounds can increase the stabilization of HIF-1 protein, acting directly or indirectly on one who does more of cellular processes, acting destabilizers or which is subjected to metabolism cellular components, which stabilize the presence of HIF-1 protein, protects it from inhibition or increase the activity of the protein. Alternatively, the described compounds can increase the activity of HIF-1 protein by inhibiting or blocking the activity of compounds that inhibit the activity of HIF-1 protein. In this regard, in the present invention describe a method for improving the treatment of microbial infection by the introduction of a substance that increases the activity or the concentration of at least one HIF-1 protein in a subject suffering from microbial infection or exposed to great danger microbial infection.

In one aspect of the present invention describe methods of modulating the activity of at least one HIF-1 protein. In this regard, the described methods involve contact of at least one HIF-1 protein or a protein that interacts with HIF-1, with one or more of the above compounds which modulate the activity of HIF-1 protein, or the protein contact with the substance. In one embodiment, the contact isin vitro. In another embodiment, the contact isin vivo. In the following embodiment, the contact isexvivo.

In another aspect described in the present invention is the manual treatment of the subject, contaminated or threatened with contamination microbial agent, comprising introducing to a subject a therapeutically effective amount of one or more of the described compounds. In one embodiment, the compound increases or activates HIF-1. In another embodiment, the microbial agent is a pathogen. Variants of this option implementation-related pathogens include bacteria, fungi, protozoa, viruses, yeasts and the like. Another variant of this aspect relates to a method of treatment of a subject infected or at risk of infection microbial agent, including increased activity, destroying microbial pathogen, the immune cells of the subject.

One way to enhance the stabilization of HIF-1 is the inhibition of the activity of 4-prolylhydroxylase enzymes that begin the cellular destruction of HIF-1α, preventing through this binding of HIF-1α with HIF-1β for the formation of HIF-1. In this regard, described in the present invention are methods of enhancing the cellular response to a painful condition, such as infection, i.e. the presence of a pathogen such as a bacterium, virus, parasite, yeast, fungus and the like, increased phagocytosis. The present invention also describe the methods of treatment of cancer by enhancing the cellular immune reactions is, for example, by stabilizing HIF-1, increasing by this the body's ability to reduce tumor size. In addition, in the present invention describe methods of treatment of diseases in which the immune response can be stimulated by vaccination.

The following chemical structure is used throughout the invention to describe and ensure the scope of the present invention and for specific instructions and clear statements of the fragments, which include the compounds of the present invention, however, unless specifically defined otherwise, the terms used in the present invention are the same as the terms are known to specialists in this field of technology. The term "hydrocarbon" refers to any fragment-based carbon atoms (organic molecule), and the aforementioned fragments optionally contain one or more organic functional groups, including salts containing inorganic atoms, including carboxylate salts, Quaternary ammonium. In a broad sense, the term "hydrocarbon" includes classes "acyclic hydrocarbon" and "cyclic hydrocarbon", where the term is used to distinguish hydrocarbonrich fragments on cyclic and acyclic classes.

As this applies to the following definitions, "cyclic gidrolabilna fragments can contain only atoms near the of Lerida in the ring (carbocyclic and aryl ring) or may contain one or more heteroatoms in the ring (the heterocyclic and heteroaryl). As for the "carbocyclic" rings, the smallest number of carbon atoms in the ring is 3 carbon atoms; cyclopropyl. As for the "aryl" of the rings, the smallest number of carbon atoms in the ring comprises 6 carbon atoms; phenyl. As for the "heterocyclic" rings, the smallest number of carbon atoms in the ring is 1 carbon atom; diazirines. The ethylene oxide contains 2 carbon atoms and represents a C₂a heterocycle. As for the "heteroaryl ring", the smallest number of carbon atoms in the ring is 1 carbon atom; 1,2,3,4-tetrazolyl. Below are non-limiting description of the term "acyclic hydrocarbon" and "cyclic hydrocarbon", as used in the present invention.

A. Substituted and unsubstituted acyclic hydrocarbon:

For the purposes of the present invention the term "substituted and unsubstituted acyclic hydrocarbon includes 3 categories of fragments:

1) linear or branched alkyl, non-limiting examples of which include methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), sec-butyl (C₄), isobutyl (C₄), tert-butyl (C₄), and the like; substituted linear or branched alkyl, non-limiting examples of which include hydroxymethyl (C₁), chloromethyl (C₁), triforma the Il (C ₁), aminomethyl (C₁), 1-chloroethyl (C₂), 2-hydroxyethyl (C₂), 1,2-dottorati (C₂), 3-carboxypropyl (C₃) and the like;

2) linear or branched alkenyl, non-limiting examples of which include ethynyl (C₂), 3-propenyl (C₃), 1-propanyl (2-methylethenyl) (C₃), isopropanol (2-mutilated-2-yl) (C₃), butene-4-yl (C₄) and the like; substituted linear or branched alkenyl, non-limiting examples of which include 2-chloranil (2-vinyl chloride) (C₂), 4-hydroxybutane-1-yl (C₄), 7-hydroxy-7-Metalock-4-EN-2-yl (C₉), 7-hydroxy-7-Metalock-3,5-Dien-2-yl (C₉) and the like;

3) linear or branched quinil, non-limiting examples of which include ethinyl (C2), prop-2-inyl (also propargyl) (C₃), propyne-1-yl (C₃) and 2-metrex-4-in-1-yl (C₇); substituted linear or branched quinil, non-limiting examples of which include 5-hydroxy-5-metrex-3-inyl (C₇), 6-hydroxy-6-methylhept-3-in-2-yl (C₈), 5-hydroxy-5-amilhat-3-inyl (C₉) and the like.

B. Substituted and unsubstituted cyclic hydrocarbon:

For the purposes of the present invention the term "substituted and unsubstituted cyclic hydrocarbon includes 5 categories fragments.

1) the Term "carbocyclic" is defined in this invention as "switch is in store rings, containing from 3 to 20 carbon atoms in which the atoms that form the above-mentioned ring, limited carbon atoms and, in addition, this ring can be independently substituted one or more fragments that can replace one or more hydrogen atoms". Below are non-limiting examples of "substituted and unsubstituted carbocyclic rings, which include the following categories of fragments:

i) carbocyclic ring containing one substituted or unsubstituted hydrocarbon ring, non-limiting examples of which include cyclopropyl (C₃), 2-methylcyclopropyl (C₃), cyclopropyl (C₃), cyclobutyl (C₄), 2,3-dihydroxycinnamate (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclopentadienyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cycloheptyl (C₇), cyclooctanol (C₈), 2,5-dimethylcyclopentene (C₅), 3,5-dichlorocyclohexyl (C₆), 4-hydroxycyclohexyl (C₆) and 3,3,5-trimethylcyclohex-1-yl (C₆);

ii) carbocyclic ring containing two or more substituted or unsubstituted condensed hydrocarbon rings, non-limiting examples of which include octahydrophenanthrene (C₈), octahydro-1H-indenyl (C₉), 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl (C₉), decaline (C₁₀, decahydronapthalene (C₁₀);

iii) carbocyclic ring which is substituted or unsubstituted bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo[2.1.1]hexanes, bicyclo[2.2.1]heptenyl, bicyclo[3.1.1]heptenyl, 1,3-dimethyl[2.2.1]heptane-2-yl, bicyclo[2.2.2]octenyl and bicyclo[3.3.3]undecane.

2) the Term "aryl" is defined in this invention as "fragments containing at least one phenyl or naphtalene ring and no heteroaryl or heterocyclyl rings, condensed with a phenyl or nafcillin ring, and each ring can be independently substituted one or more fragments, the ability to replace one or more hydrogen atoms." Below are non-limiting examples of "substituted and unsubstituted aryl rings", which include the following categories of fragments:

i) C₆or C₁₀substituted or unsubstituted aryl ring; phenyl and raftiline ring, substituted or unsubstituted, non-limiting examples of which include phenyl (C₆), naphtalen-1-yl (C₁₀), naphtalen-2-yl (C₁₀), 4-forfinal (C₆), 2-hydroxyphenyl (C₆), 3-were (C₆), 2-amino-4-forfinal (C₆), 2-(N,N-diethylamino)phenyl (C₆), 2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆), 3-methox is phenyl (C ₆), 8-hydroxynaphthalene-2-yl (C₁₀), 4,5-dimethoxyaniline-1-yl (C₁₀) and 6-cyanonaphthalene-1-yl (C₁₀);

ii) C₆or C₁₀aryl rings, condensed with 1 or 2 saturated rings, non-limiting examples of which include, bicyclo[4.2.0]OCTA-1,3,5-trienyl (C₈and indanyl (C₉).

3) the Terms "heterocyclic" and/or "getarticle" is defined in this invention as "fragments containing one or more rings containing from 3 to 20 atoms, in which at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O) or sulfur (S), or a mixture of N, O and S, and in which, furthermore, the ring contains a heteroatom, also not an aromatic ring. Below are non-limiting examples of "substituted and unsubstituted heterocyclic rings, which include the following categories of fragments:

i) heterocyclic fragments containing a single ring containing one or more heteroatoms, non-limiting examples of which include diazirines (C₁), aziridinyl (C₂), ursolic (C₂), azetidine (C₃), pyrazolidine (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃), isoxazolyl (C₃), diazolidinyl (C₃), isothiazoline (C₃), oxadiazolidine (C₃), oxazolidinones (C_{3 ), hydantoinyl (C3), tetrahydrofuranyl (C4), pyrrolidinyl (C4), morpholinyl (C4), piperazinil (C4), piperidinyl (C4), dihydropyran (C5), tetrahydropyranyl (C5), piperidine-2-IMT (valerolactam) (C5), 2,3,4,5-tetrahydro-1H-azepine (C6), 2,3-dihydro-1H-indole (C8) and 1,2,3,4-tetrahydroquinolin (C9);}

(ii) heterocyclic fragments containing 2 or more rings, one of which is a heterocyclic ring, non-limiting examples of which include hexahydro-1H-pyrrolizine (C₇), 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl (C₇), 3a,4,5,6,7,7a-hexahydro-1H-indolyl (C₈), 1,2,3,4-tetrahydroquinoline (C₉and decahydro-1H-cycloocta[b]pyrrolyl (C₁₀).

4) the Term "heteroaryl" is defined in the present invention as including one or more rings containing from 5 to 20 atoms, in which at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O) or sulfur (S), or a mixture of N, O and S and, moreover, in which at least one of the rings, which contains a heteroatom is an aromatic ring. Below are non-limiting examples of "substituted and unsubstituted heterocyclic rings, which include the following categories of fragments:

(i) heteroaryl rings containing their one ring non-limiting examples of which include 1,2,3,4-tetrazolyl (C₁), [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), triazinyl (C₃), thiazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl (C₃), isoxazolyl (C₃), isothiazole (C₃), furanyl (C₄), thiophenyl (C₄), pyrimidinyl (C₄), 2-phenylpyrimidine (C₄), pyridinyl (C₅), 3-methylpyridine (C₅4-dimethylaminopyridine (C₅);

ii) heteroaryl rings containing 2 or more condensed rings, one of which represents a heteroaryl ring, non-limiting examples of which include 7H-purinol (C₅), 9H-purines (C₅), 6-amino-9H-purines (C₅), 5H-pyrrolo[3,2-d]pyrimidinyl (C₆), 7H-pyrrolo[2,3-d]pyrimidinyl (C₆), pyrido[2,3-d]pyrimidinyl (C₇), 2-phenylbenzo[d]thiazole (C₇), 1H-indolyl (C₈), 4,5,6,7-tetrahydro-1H-indolyl (C₈), honokalani (C₈), 5-methylinosine (C₈), hintline (C₈), chinoline (C₉), 8-hydroxyquinoline (C₉and ethenolysis (C₉).

5) C₁-C₆United cyclic gidrolabilna fragments (carbocyclic fragments, C₆or C₁₀aryl fragments, heterocyclic fragments or heteroaryl fragments), which are connected with another fragment, block or skeleton of the molecule through a ₁-C₆alkalinous fragment. Non-limiting examples of the United cyclic hydrocarbonrich fragments include benzyl C₁-(C₆) formula:

in which R^ais an optional one or more independently selected substituents of hydrogen. Further examples include other aryl fragments, including (2 - hydroxyphenyl)hexyl C₆-(C₆); naphthalen-2-ylmethyl C₁-(C₁₀), 4-terbisil C₁-(C₆), 2-(3-hydroxyphenyl)ethyl C₂-(C₆), as well as substituted and unsubstituted C₃-C₁₀alkalinebatteries fragments, such as cyclopropylmethyl C₁-(C₃), cyclopentylmethyl C₂-(C₅), cyclohexylmethyl C₁-(C₆). Included in this category are substituted and unsubstituted C₁-C₁₀alkylenediamine fragments, such as 2-picalilly C₁-(C₆) fragment having the formula:

in which R^ais the same as defined above. In addition, C₁-C₁₂United cyclic gidrolabilna fragments include C₁-C₁₀alkylenediamine fragments and alkylenediamine fragments, non-limiting examples of which include aziridinyl C₁-(C₂and oxazol-2-ylmethyl Csub> 1-(C₃).

For the purposes of the present invention carbocyclic ring represents a C₃to C₂₀; aryl ring represents a C₆or C₁₀; heterocyclic rings are from C₁to C₉; and heteroaryl rings are from C₁to C₉.

For the purposes of the present invention and to ensure consistency of definitions present invention condensed ring fragments, as well as spirocycles rings, bicyclic rings and the like, which contain one heteroatom, will have to be called in the present invention are included in the circular collection, containing the corresponding heteroatom ring, although a specialist in this field of technology can have alternative definitions. For example, 1,2,3,4-tetrahydroquinolin formula:

consider, for the purposes of the present invention, the heterocyclic fragment. 6,7-dihydro-5H-cyclopentenopyridine formula:

consider, for the purposes of the present invention, heteroaryl fragment. When the condensed ring fragment contains heteroatoms, and in a saturated ring or heterocyclic ring) and the aryl ring or heteroaryl ring), aryl ring will play a major role, and define t the p category, to which the present invention is attributed to the ring for the purposes of describing the present invention. For example, 1,2,3,4-tetrahydro[1,8]naphthiridine formula:

consider, for the purposes of the present invention, heteroaryl fragment.

The term "substituted" is used throughout the description. The term "substituted" applied to the fragments described in this invention as "substituted block or fragment is hydrocarbonyl block or fragment, acyclic or cyclic, which contains one or more hydrogen atoms substituted by a Deputy or more substituents, as defined in the present invention below. Fragments, with the substitution of hydrogen atoms, the ability to replace one hydrogen atom, two hydrogen atoms or three hydrogen atoms hidrocarburos fragment at a time. In addition, these substituents may substitute two hydrogen atoms on two adjacent carbon atoms, forming referred to by the Deputy, the new slice or block. For example, substituted fragment, which requires the substitution of one hydrogen atom, contains halogen, hydroxyl and the like. The substitution of two hydrogen atoms include carbonyl, oximino and the like. The substitution of two hydrogen atoms from adjacent carbon atoms includes epoxy and the like. Replacement of three hydrogen atoms includes cyano similar. The term substituted is used throughout this description to denote that hydrocarbonyl fragment, including the aromatic ring, the alkyl chain may contain one or more substituents instead of hydrogen atoms. When a fragment is described as "substituted", it may be replaced by any number of hydrogen atoms. For example, 4-hydroxyphenyl represents a substituted aromatic carbocyclic ring (the aryl ring)" (N, N-dimethyl-5-amino)octanol represents a substituted C₈linear alkyl fragment, 3-guanidinopropionic represents a substituted C₃linear alkyl fragment and 2-carboxyphenyl is a "substituted heteroaryl fragment.

Below are non-limiting examples of fragments that can replace hydrogen atoms in the carbocyclic, aryl, heterocyclic or heteroaryl fragment:

i) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl; for example, methyl (C₁), chloromethyl (C₁), trifluoromethyl (C₁), aminomethyl (C₁), ethyl (C₂), hydroxymethyl 1-chloroethyl (C₂), 2-hydroxyethyl (C₂), 1,2-dottorati (C₂), n-propyl (C₃), isopropyl (C₃), 3-carboxypropyl (C₃), cyclopropyl (C₃), 2-IU is enciclopedy (C ₃), n-butyl (C₄), sec-butyl (C₄), isobutyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), 2,3-dihydroxycinnamate (C₄), pentyl (C₅), cyclopentyl (C₅), hexyl (C₆) and cyclohexyl (C₆) and the like;

ii) substituted or unsubstituted C₂-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkenyl; for example, ethynyl (C₂), 2-chloranil (2-vinyl chloride) (C₂), 3-propenyl (C₃), 1-propanyl (2-methylethenyl) (C₃), isopropanol (2-mutilated-2-yl) (C₃), butene-4-yl (C₄), 4-hydroxybutane-1-yl (C₄), cyclobutenyl (C₄), cyclopentenyl (C₅), cyclopentadienyl (C₅), cyclohexenyl (C₆), 7-hydroxy-7-Metalock-4-EN-2-yl (C₉) and 7-hydroxy-7-Metalock-3,5-Dien-2-yl (C₉) and the like;

iii) substituted or unsubstituted C₂-C₁₂linear or C₃-C₁₂extensive quinil; for example, ethinyl (C₂), prop-2-inyl (also propargyl) (C₃), propyne-1-yl (C₃), 2-methyl-Gex-4-in-1-yl (C₇); 5-hydroxy-5-metrex-3-inyl (C₇), 6-hydroxy-6-methylhept-3-in-2-yl (C₈), 5-hydroxy-5-amilhat-3-inyl (C₉) and the like;

iv) substituted or unsubstituted C₆or C₁₀aryl; for example phenyl, 2-chlorophenyl, 3-hydroxyphenyl, 4-nitrophenyl, 2-fluoro-4-were, 3,5-dinitrophenyl, 8-hydro is SYNAPT-1-yl, 6-sulfanilyl-2-yl and the like;

v) substituted or unsubstituted C₁-C₉a heterocycle; for example, as hereinafter defined in the present invention;

vi) substituted or unsubstituted C₁-C₁₁heteroaryl; for example, as hereinafter defined in the present invention;

vii) halogen; for example, fluorine, chlorine, bromine and iodine;

viii) -[C(R^23a)(R^23b)]_xOR¹⁰;

R¹⁰chosen from:

a) -H;

b) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

c) C₆or C₁₀substituted or unsubstituted aryl or alkylaryl;

d) C₁-C₉substituted or unsubstituted heterocycle;

e) C₁-C₁₁substituted or unsubstituted heteroaryl;

ix) -[C(R^23a)(R^23b)]_xN(R^11a)(R^11b);

each R^11aand R^11bindependently chosen from:

a) -H;

b) -OR¹²;

R¹²represents hydrogen or C₁-C₄linear alkyl;

c) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

d) C₆or C₁₀substituted or unsubstituted aryl;

e) C₁-C₉substituted or unsubstituted heterocycle;

f) C₁-C₁₁substituted or nezametno is about heteroaryl; or

g) R^11aand R^11btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

x) -[C(R^23a)(R^23b)]_xC(O)R¹³;

R¹³represents:

a) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

b) -OR¹⁴;

R¹⁴represents hydrogen, substituted or unsubstituted C₁-C₄linear alkyl, C₆or C₁₀substituted or unsubstituted aryl, C₁-C₉substituted or unsubstituted a heterocycle, C₁-C₁₁substituted or unsubstituted heteroaryl;

c) -N(R^15a)(R^15b);

each R^15aand R^15bindependently represents hydrogen, substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl, C₆or C₁₀substituted or unsubstituted aryl; C₁-C₉substituted or unsubstituted a heterocycle; C₁-C₁₁substituted or unsubstituted heteroaryl; or R^15aand R^15btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

R¹⁶represents:

a) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

b) -N(R^17a)(R^17b);

each R^17aand R^17bindependently represents hydrogen, substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl, C₆or C₁₀substituted or unsubstituted aryl; C₁-C₉substituted or unsubstituted a heterocycle; C₁-C₁₁substituted or unsubstituted heteroaryl; or R^17aand R^17btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

xii) -[C(R^23a)(R^23b)]_xNR¹⁸C(O)R¹⁹;

R¹⁸represents:

a) -H; or

b) substituted or unsubstituted C₁-C₄linear, C₃-C₄branched or C₃-C₄cyclic alkyl;

R¹⁹represents:

a) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

b) -N(R^20a)(R^20b);

each R^20aand R^20bindependently represents with the battle hydrogen, substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl, C₆or C₁₀substituted or unsubstituted aryl; C₁-C₉substituted or unsubstituted a heterocycle; C₁-C₁₁substituted or unsubstituted heteroaryl; or R^20aand R^20btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

xiii) -[C(R^23a)(R^23b)]_xCN;

xiv) -[C(R^23a)(R^23b)]_xNO₂;

xv) -[C(R^23a)(R^23b)]_xR²¹;

R²¹represents a C₁-C₁₀linear, C₃-C₁₀branched or C₃-C₁₀cyclic alkyl, substituted from 1 to 21 halogen atoms chosen from-F, -Cl, -Br or-I;

xvi) -[C(R^23a)(R^23b)]_xSO₂R²²;

R²²represents hydrogen, hydroxyl, substituted or unsubstituted C₁-C₄linear or C₃-C₄branched alkyl; substituted or unsubstituted C₆C₁₀or C₁₄aryl; C₇-C₁₅alkylaryl; C₁-C₉substituted or unsubstituted a heterocycle; or C₁-C₁₁substituted or unsubstituted heteroaryl;

each R^23aand R^23bregardless, not only is em a hydrogen or C ₁-C₄alkyl; and

the index x is an integer from 0 to 5.

Compounds described in the present invention include all salt forms, such as salts of basic groups, including amines, and salts of acidic groups, including carboxylic acids. Below are non-limiting examples of anions that can form salts with basic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate and the like. Below are non-limiting examples of cations that can form a salt of the acid group include sodium, lithium, potassium, calcium, magnesium, bismuth and the like.

For the purposes of the present invention, the terms "connection", "analog" and "chemical compound" equally well replace each other and include all enantiomeric forms, diastereomeric forms, salts and the like, and the terms "connection", "analog" and "chemical compound".

Inhibitors of HIF-1α of prolylhydroxylase

Described compounds have the following formula:

in which L is selected from CH₂or SO₂providing via this N-substituted benzyl - or N-substituted sulfonylureas-3-hydroxypyridine-2-(1H)-ones. Y, R¹and R²further what about the determine in the present invention below.

In the present invention describe N-substituted benzyl - and N-substituted sulfonylureas-4-aminomethyl-3-hydroxypyridine-2-(1H)-ones, which are inhibitors of HIF-1α of prolylhydroxylase having the formula:

in which R¹and R²further define the present invention below.

Alkyl piperazine-1-carboxylates

One category of these compounds belongs to C₁-C₄linear or branched alkyl 4-{[(1-N-(chloro - or fluoro-substituted)benzyl]-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl)methyl}piperazine-1-carboxylates of the formula:

in which Z represents a phenyl group which is substituted by 1 to 5 halogen atoms selected from chlorine and fluorine, and R¹and R²taken together, may form pieperazinove ring, which replaced alkylcarboxylic fragment in which R⁴selected from C₁-C₄linear or C₃-C₄branched alkyl, for example tert-butyl 4-{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

One aspect of R⁴fragments refers to compounds in which R⁴represents tert-butyl (C₄). Another aspect of R⁴fragments refers to compounds in which R⁴represents methyl (C ₁). The next aspect R⁴fragments refers to compounds in which R⁴represents ethyl (C₂). Still another aspect R⁴fragments refers to compounds in which R⁴selected from n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), sec-butyl (C₄and isobutyl (C₄). R⁴is not hydrogen, therefore, carboxylate fragment having the formula-CO₂H, is clearly excluded from this category, but may be included in other categories, as described in the present invention below.

Z represents phenyl, substituted by 1 to 5 Halogens chosen from fluorine and chlorine. One aspect Z fragments refers to compounds in which Z represents 4-chlorophenyl. Another aspect Z fragments refers to compounds in which Z is selected from 2-chlorphenyl, 3-chlorphenyl, 2-ftoheia, 3-ftoheia or 4-ftoheia. The next aspect Z fragments refers to compounds in which Z is selected from 2,3-dipthera, 2,4-dipthera, 2,5-dipthera, 2,6-dipthera, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl and 2,6-dichlorophenyl.

Below are non-limiting examples of compounds according to this categories:

methyl 4-{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

methyl 4-{[1-(2-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

ethyl 4-{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

ethyl 4-{[1-(3-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

ethyl 4-{[1-(2-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

tert-butyl 4-{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

tert-butyl 4-{[1-(3-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

tert-butyl 4-{[1-(2-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

methyl 4-{[1-(4-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

methyl 4-{[1-(3-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}PI is erasin-1-carboxylate of the formula:

methyl 4-{[1-(2-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

ethyl 4-{[1-(4-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

ethyl 4-{[1-(3-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

ethyl 4-{[1-(2-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

tert-butyl 4-{[1-(4-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

tert-butyl 4-{[1-(3-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

tert-butyl 4-{[1-(2-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate of the formula:

Another category of compounds relates to N-unsubstituted benzyl-4-aminomethyl-3-hydroxypyridine-2-(1H)-Onam, in which Z represents an unsubstituted phenyl group of the formula:

in which R¹and R²taken together, may form a substituted or unsubstituted of heteros licence or heteroaryl ring.

The first aspect of this category relates to compounds having the formula:

in which R¹and R²taken together, may form a substituted or unsubstituted heterocyclic or heteroaryl ring represented by ring A, containing from 2 to 20 carbon atoms and from 1 to 7 heteroatoms, and R²⁰⁰represents from 0 to 40 deputies of hydrogen. The index w is an integer from 0 to 40. Non-limiting examples of the rings include diazirines (C₁), 1,2,3,4-tetrazolyl (C₁), aziridinyl (C₂), ursolic (C₂), [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), azetidine (C₃), pyrazolidine (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃), isoxazolyl (C₃), isoxazolyl (C₃), diazolidinyl (C₃), isothiazole (C₃), isothiazoline (C₃), oxadiazolidine (C₃), oxazolidinones (C₃), hydantoinyl (C₃), 1H-imidazolyl (C₃), pyrrolidinyl (C₄), morpholinyl (C₄), piperazinil (C₄), piperidinyl (C₄), piperidine-2-IMT (valerolactam) (C₅), 7H-purinol (C₅), 9H-purines (C₅), 6-amino-9H-purines (C₅), 2,3,4,5-tetrahydro-1H-azepine (C₆), 5H-pyrrolo[3,2-d]pyrimidinyl (C₆), 7H-pyrrolo[2,3-d]pyrimidinyl (C₆) and 1,2,3,4-tetrahydroquinolin (C₉).

Each R²⁰ fragment independently chosen from:

i) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl; for example, methyl (C₁), chlormethine (C₁), triptorelin (C₁), aminomethyl (C₁), ethyl (C₂), hydroxymethyl-1-chloroethyl (C₂), 2-hydroxyethyl (C₂), 1,2-deperately (C₂), n-propyl (C₃), isopropyl (C₃), 3-carboxypropyl (C₃), cyclopropyl (C₃), 2-methylcyclopropyl (C₃), n-butyl (C₄), sec-butyl (C₄), isobutyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), 2,3-dihydroxycinnamate (C₄), penttila (C₅), cyclopentyl (C₅), hexyl (C₆) and cyclohexyl (C₆) and the like;

ii) substituted or unsubstituted C₂-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkenyl; for example Attila (C₂), 2-chloranil (2-vinyl chloride) (C₂), 3-propenyl (C₃), 1-propanyl (2-methylethenyl) (C₃), isopropanol (2-mutilated-2-yl) (C₃), butene-4-yl (C₄), 4-hydroxybutane-1-yl (C₄), cyclobutenyl (C₄), cyclopentenyl (C₅), cyclopentadienyl (C₅), cyclohexenyl (C₆), 7-hydroxy-7-Metalock-4-EN-2-yl (C₉) and 7-hydroxy-7-Metalock-3,5-Dien-2-yl (C₉and the like;

iii) substituted or unsubstituted C₁-C₁₂linear or C₃-C₁₂branched quinil; for example, ethinyl (C₂), prop-2-inila (also propargyl) (C₃), propyne-1-yl (C₃), 2-methyl-Gex-4-in-1-Il (C₇); 5-hydroxy-5-metrex-3-inila (C₇), 6-hydroxy-6-methylhept-3-in-2-yl (C₈), 5-hydroxy-5-amilhat-3-inila (C₉) and the like;

iv) substituted or unsubstituted C₆or C₁₀aryl; for example, phenyl (C₆), naphtalen-1-yl (C₁₀), naphtalen-2-yl (C₁₀), 4-ftoheia (C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆), 2-amino-4-ftoheia (C₆), 2-(N,N-diethylamino)phenyl (C₆), 2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆), 3-methoxyphenyl (C₆), 8-hydroxynaphthalene-2-yl (C₁₀), 4,5-dimethoxyaniline-1-yl (C₁₀), 6-cyanonaphthalene-1-yl (C₁₀) and the like;

v) substituted or unsubstituted C₁-C₉heterocycle; for example diazirine (C₁), aziridinyl (C₂), Orsolya (C₂), azetidine (C₃), pyrazolidine (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃), isoxazolyl (C₃), isoxazolyl (C₃), thiazolidine (C₃), isothiazole (C₃), isothiazoline (C₃), oxadiazolidine (C₃), oxazolidinone (C₃), hydantoinyl (C₃), tetrahedr is furanyl (C ₄), pyrrolidinyl (C₄), morpholinyl (C₄), piperazinil (C₄), piperidinyl (C₄), dihydropyrrole (C₅), tetrahydropyranyl (C₅), piperidine-2-onila (valerolactam) (C₅) and the like;

vi) substituted or unsubstituted C₁-C₁₁heteroaryl; for example 1,2,3,4-tetrazolyl (C₁), [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), triazinyl (C₃), triazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl (C₃), furanyl (C₄), thiophenyl (C₄), pyrimidinyl (C₄), pyridinyl (C₅) and the like;

vii) halogen; for example,- F, -Cl, -Br or-I;

viii) -[C(R^37a)(R^37b)]_yOR²⁴;

R²⁴chosen from:

a) -Η;

b) substituted or unsubstituted C₂-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

c) substituted or unsubstituted C₆or C₁₀aryl or C₇or C₁₀alkylaryl; for example, phenyl or benzyl;

d) substituted or unsubstituted C₁-C₉heterocycle;

e) substituted or unsubstituted C₁-C₁₁heteroaryl;

for example-ΟΗ, -CH₂OH, -OCH₃, -CH₂OCH₃, -OCH₂CH₃, -CH₂OCH₂CH₃, -OCH₂CH₂CH₃and-CH₂OCH₂CH₂CH₃;

ix) -[C(R^37a)(R^37b)]_yN(R^{25a )(R25b);}

each R^25aand R^25bindependently chosen from:

a) -H;

b) -OR²⁶;

R²⁶represents hydrogen or C₁-C₄linear alkyl;

c) substituted or unsubstituted C₂-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

d) substituted or unsubstituted C₆or C₁₀aryl;

e) substituted or unsubstituted C₁-C₉heterocycle;

f) substituted or unsubstituted C₁-C₁₁heteroaryl; or

g) R^25aand R^25btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

for example-NH₂, -CH₂NH₂, -NHCH₃, -N(CH₃)₂, -NHOH, -NHOCH₃, -NH(CH₂CH₃), -CH₂NHCH₃, -CH₂N(CH₃)₂, -CH₂NH(CH₂CH₃) and the like;

x) -[C(R^37a)(R^37b)]_yC(O)R²⁷;

R²⁷represents:

a) substituted or unsubstituted C₂-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

b) -OR²⁸;

R²⁸represents hydrogen, substituted or unsubstituted C₁-C₄linear alkyl, substituted or unsubstituted C₆or C₁₀aryl, C is displaced or unsubstituted C ₁-C₉a heterocycle, substituted or unsubstituted C₁-C₁₁heteroaryl;

c) -N(R^29a)(R^29b);

each R^29aand R^29bindependently represents hydrogen, substituted or unsubstituted C₂-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl; substituted or unsubstituted C₆or C₁₀aryl, substituted or unsubstituted C₁-C₉a heterocycle, substituted or unsubstituted C₁-C₁₁heteroaryl; or R^29aand R^29btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

for example-COCH₃, -CH₂COCH₃, -OCH₂CH₃, -CH₂COCH₂CH₃, -COCH₂CH₂CH₃, -CH₂COCH₂CH₂CH₃and the like;

xi) -[C(R^37a)(R^37b)]_yOC(O)R³⁰;

R³⁰represents:

a) C₁-C₁₂substituted or unsubstituted linear, branched, or cyclic alkyl;

b) -N(R^31a)(R^31b);

each R^31aand R^31bindependently represents hydrogen, substituted or unsubstituted C₂-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl; substituted or unsubstituted C₆or C 10aryl, substituted or unsubstituted C₁-C₉a heterocycle, substituted or unsubstituted C₁-C₁₁heteroaryl; or R^31aand R^31btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

for example,- OC(O)CH₃, -CH₂OC(O)CH₃, -OC(O)NH₂, -CH₂OC(O)NH₂, -OC(O)NHCH₃, -CH₂OC(O)NHCH₃, -OC(O)N(CH₃)₂, -CH₂OC(O)N(CH₃)₂and the like;

xii) -[C(R^37a)(R^37b)]_yNR³²C(O)R³³;

R³²represents:

a) -H; or

b) substituted or unsubstituted C₁-C₄linear, C₃-C₄branched or C₃-C₄cyclic alkyl;

R³³represents:

a) substituted or unsubstituted C₂-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

b) -N(R^34a)(R^34b);

each R^34aand R^34bindependently represents hydrogen, substituted or unsubstituted C₂-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl; substituted or unsubstituted C₆or C₁₀aryl, substituted or unsubstituted C₁-C₉a heterocycle, substituted or unsubstituted C₁-C₁₁GE is Eroare; C₁-C₁₁substituted or unsubstituted heteroaryl; or R^34aand R^34btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

for example,- NHC(O)CH₃, -CH₂NHC(O)CH₃, -NHC(O)NH₂, -CH₂NHC(O)NH₂, -NHC(O)NHCH₃, -CH₂NHC(O)NHCH₃, -OC(O)N(CH₃)₂, -CH₂NHC(O)N(CH₃)₂and the like;

xiii) -[C(R^37a)(R^37b)]_yCN; for example,- CN, -CH₂CN and CH₂CH₂CN;

xiv) -[C(R^37a)(R^37b)]_yNO₂; for example-NO₂, -CH₂NO₂and-CH₂CH₂NO₂;

xv) -[C(R^37a)(R^37b)]_yR³⁵; for example,- CH₂F, -CHF₂, -CF₃, -CCl₃or-CBr₃;

R³⁵represents a C₁-C₁₀linear, C₃-C₁₀branched or C₃-C₁₀cyclic alkyl, substituted from 1 to 21 halogen atoms chosen from-F, -Cl, -Br or-I;

xvi) -[C(R^37a)(R^37b)]_ySO₂R³⁶;

R³⁶represents hydrogen, hydroxyl, substituted or unsubstituted C₁-C₄linear or C₃-C₄branched alkyl; substituted or unsubstituted C₆C₁₀or C₁₄aryl; C₇-C₁₅alkylene; substituted or unsubstituted C₁-C₉hetaeras the cycle; or substituted or unsubstituted C₁-C₁₁heteroaryl;

for example,- SO₂H, -CH₂SO₂H, -SO₂CH₃, -CH₂SO₂CH₃, -SO₂C₆H₅and CH₂SO₂C₆H₅; and

xv) two hydrogen atoms at the ring carbon atom can substitute to obtain =O,=S or =NH fragment;

each R^37aand R^37bindependently represents hydrogen or C₁-C₄alkyl; and

the index y is an integer from 0 to 5.

The first version of the implementation of this aspect relates to compounds in which R¹and R²taken together, may form a 5-membered substituted or unsubstituted C₁-C₄heterocyclic or substituted or unsubstituted C₁-C₄heteroaryl ring, non-limiting examples of which include a ring selected from:

The first version of this variant implementation relates to inhibitors of HIF-1α of prolylhydroxylase formula:

R²⁰⁰represents from 0 to 2 substituents for ring hydrogens, where the hydrogen substituents independently selected from:

i) C₁-C₄linear or C₃-C₄branched alkyl;

ii) C₁-C₄linear or C₃-C₄rasvet the Lenna alkoxy;

iii) hydroxyl;

iv) cyano;

v) nitro;

(vi) amino, methylamino or dimethylamino;

vii) carboxy, methylcarbamic or ethylcarboxyl;

viii) formyl, acetyl or propionyl;

ix) amido, methylamino or dimethylamino;

x) halogen;

xi) heterocycle, or

xii) heteroaryl.

Non-limiting examples of this variant include inhibitors of HIF-1α of prolylhydroxylase formula:

The following variant of this implementation relates to inhibitors of HIF-1α of prolylhydroxylase, in which R¹and R²taken together, may form a 5-membered substituted or unsubstituted heterocyclic or heteroaryl ring containing more than one heteroatom in the ring. Non-limiting examples include:

Another variant of this aspect relates to inhibitors of HIF-1α of prolylhydroxylase, in which R¹and R²taken together, may form a substituted or unsubstituted C₄-C₁₁heterocyclic or substituted or unsubstituted C₄-C₁₁heteroaryl ring, non-limiting examples of which are chosen from:

Non-limiting examples of implementation of this option include:

Another category of compounds has the formula:

in which R²⁰⁰and the index of w are the same as defined in the present invention above. R represents from 0 to 5 substituents hydrogen, where R is independently selected from:

i) C₁-C₁₂substituted or unsubstituted linear, branched, or cyclic alkyl; for example, methyl (C₁), chlormethine (C₁), triptorelin (C₁), aminomethyl (C₁), ethyl (C₂), hydroxymethyl-1-chloroethyl (C₂), 2-hydroxyethyl (C₂), 1,2-deperately (C₂), n-propyl (C₃), isopropyl (C₃), 3-carboxypropyl (C₃), cyclopropyl (C₃), 2-methylcyclopropyl (C₃), n-butyl (C₄), sec-butyl (C₄), isobutyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), 2,3-dihydroxycinnamate (C₄), penttila (C₅), cyclopentyl (C₅), hexyl (C₆) and cyclohexyl (C₆) and the like;

ii) C₂-C₁₂substituted or unsubstituted linear, branched or cyclic alkenyl; for example Attila (C₂), 2-chloranil (2-vinyl chloride) (C₂), 3-propenyl (C₃), 1-propanyl (2-methylethenyl) (C₃), isopropanol (2-mutilated-2-yl) (C₃), butene-4-yl (C₄), 4-hydroxybutane-1-yl (C₄), cyclobutenyl (C₄), cyclopent the Nile (C ₅), cyclopentadienyl (C₅), cyclohexenyl (C₆), 7-hydroxy-7-Metalock-4-EN-2-yl (C₉) and 7-hydroxy-7-Metalock-3,5-Dien-2-yl (C₉) and the like;

iii) C₂-C₁₂substituted or unsubstituted linear or branched quinil; for example, ethinyl (C₂), prop-2-inila (also propargyl) (C₃), propyne-1-yl (C₃), 2-metrex-4-in-1-Il (C₇); 5-hydroxy-5-metrex-3-inila (C₇), 6-hydroxy-6-methylhept-3-in-2-yl (C₈), 5-hydroxy-5-amilhat-3-inila (C₉) and the like;

iv) C₆or C₁₀substituted or unsubstituted aryl; for example, phenyl (C₆), naphtalen-1-yl (C₁₀), naphtalen-2-yl (C₁₀), 4-ftoheia (C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆), 2-amino-4-ftoheia (C₆), 2-(N,N-diethylamino)phenyl (C₆), 2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆), 3-methoxyphenyl (C₆), 8-hydroxynaphthalene-2-yl (C₁₀), 4,5-dimethoxyaniline-1-yl (C₁₀), 6-cyanonaphthalene-1-yl (C₁₀) and the like;

v) C₁-C₉substituted or unsubstituted heterocycle; for example diazirine (C₁), aziridinyl (C₂), Orsolya (C₂), azetidine (C₃), pyrazolidine (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃), isoxazolyl (C₃), isoxazolyl (C₃), thiazolidine (C₃), ittia Alila (C ₃), isothiazoline (C₃), oxadiazolidine (C₃), oxazolidinone (C₃), hydantoinyl (C₃), tetrahydrofuranyl (C₄), pyrrolidinyl (C₄), morpholinyl (C₄), piperazinil (C₄), piperidinyl (C₄), dihydropyrrole (C₅), tetrahydropyranyl (C₅), piperidine-2-onila (valerolactam) (C₅) and the like;

vi) C₁-C₁₁substituted or unsubstituted heteroaryl; for example 1,2,3,4-tetrazolyl (C₁), [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), triazinyl (C₃), triazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl (C₃), furanyl (C₄), thiophenyl (C₄), pyrimidinyl (C₄), pyridinyl (C₅) and the like;

vii) halogen; for example,- F, -Cl, -Br or-I;

viii) -[C(R^23a)(R^23b)]_xOR¹⁰;

R¹⁰chosen from:

a) -H;

b) C₁-C₁₂substituted or unsubstituted linear, branched, or cyclic alkyl;

c) C₆or C₁₀substituted or unsubstituted aryl or alkylaryl;

d) C₁-C₉substituted or unsubstituted heterocycle;

e) C₁-C₁₁substituted or unsubstituted heteroaryl;

for example-OH, -CH₂OH, -OCH₃, -CH₂OCH₃, -OCH₂CH₃, -CH₂OCH₂CH₃, -OCH₂CH₂CH₃and-CH₂OCH₂CH₂CHsub> 3;

ix) -[C(R^23a)(R^23b)]_xN(R^11a)(R^11b);

each R^11aand R^11bindependently chosen from:

a) -H;

b) -OR¹²;

R¹²represents hydrogen or C₁-C₄linear alkyl;

c) C₁-C₁₂substituted or unsubstituted linear, branched, or cyclic alkyl;

d) C₆or C₁₀substituted or unsubstituted aryl;

e) C₁-C₉substituted or unsubstituted heterocycle;

f) C₁-C₁₁substituted or unsubstituted heteroaryl; or

g) R^11aand R^11btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

for example-NH₂, -CH₂NH₂, -NHCH₃, -N(CH₃)₂, -NHOH, -NHOCH₃, -NH(CH₂CH₃), -CH₂NHCH₃, -CH₂N(CH₃)₂, -CH₂NH(CH₂CH₃) and the like;

x) -[C(R^23a)(R^23b)]_xC(O)R¹³;

R¹³represents:

a) C₁-C₁₂substituted or unsubstituted linear, branched, or cyclic alkyl;

b) -OR¹⁴;

R¹⁴represents hydrogen, substituted or unsubstituted C₁-C₄linear alkyl, C₆or C₁₀substituted or unsubstituted aryl, C₁-C₉for ewenny or the unsubstituted heterocycle, C₁-C₁₁substituted or unsubstituted heteroaryl;

c) -N(R^15a)(R^15b);

each R^15aand R^15bindependently represents hydrogen, C₁-C₁₂substituted or unsubstituted linear, branched or cyclic alkyl, C₆or C₁₀substituted or unsubstituted aryl; C₁-C₉substituted or unsubstituted a heterocycle; C₁-C₁₁substituted or unsubstituted heteroaryl; or R^15aand R^15btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; for example,- COCH₃, -CH₂COCH₃, -OCH₂CH₃, -CH₂COCH₂CH₃, -COCH₂CH₂CH₃, -CH₂COCH₂CH₂CH₃and the like;

xi) -[C(R^23a)(R^23b)]_xOC(O)R¹⁶;

R¹⁶represents:

a) C₁-C₁₂substituted or unsubstituted linear, branched, or cyclic alkyl;

b) -N(R^17a)(R^17b);

each R^17aand R^17bindependently represents hydrogen, C₁-C₁₂substituted or unsubstituted linear, branched or cyclic alkyl, C₆or C₁₀substituted or unsubstituted aryl; C₁-C₉substituted or unsubstituted a heterocycle; C₁-C₁₁zameshannyj the unsubstituted heteroaryl; or R^17aand R^17btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

xii) -[C(R^23a)(R^23b)]_xNR¹⁸C(O)R¹⁹;

R¹⁸represents:

a) -H; or

b) C₁-C₄substituted or unsubstituted linear, branched, or cyclic alkyl;

R¹⁹represents:

a) C₁-C₁₂substituted or unsubstituted linear, branched, or cyclic alkyl;

b) -N(R^20a)(R^20b);

each R^20aand R^20bindependently represents hydrogen, C₁-C₁₂substituted or unsubstituted linear, branched, or cyclic alkyl; C₆or C₁₀substituted or unsubstituted aryl; C₁-C₉substituted or unsubstituted a heterocycle; C₁-C₁₁substituted or unsubstituted heteroaryl; or R^20aand R^20btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; for example,- NHC(O)CH₃, -CH₂NHC(O)CH₃, -NHC(O)NH₂, -CH₂NHC(O)NH₂, -NHC(O)NHCH₃, -CH₂NHC(O)NHCH₃, - OC(O)N(CH₃)₂, -CH₂NHC(O)N(CH₃)₂and the like;

xiii) -[C(R^23a)(R^23b)] CN; for example,- CN, -CH₂CN and CH₂CH₂CN;

xiv) -[C(R^23a)(R^23b)]_xNO₂; for example-NO₂, -CH₂NO₂and-CH₂CH₂NO₂;

xv) -[C(R^23a)(R^23b)]_xR²¹; for example,- CH₂F, -CHF₂, -CF₃, -CCl₃or-CBr₃;

R²¹represents a C₁-C₁₀linear, branched or cyclic alkyl, substituted from 1 to 21 halogen atoms chosen from-F, -Cl, -Br or-I;

xvi) -[C(R^23a)(R^23b)]_xSO₂R²²;

R²²represents hydrogen, hydroxyl, substituted or unsubstituted C₁-C₄linear or branched alkyl; substituted or unsubstituted C₆C₁₀or C₁₄aryl; C₇-C₁₅alkylaryl; C₁-C₉substituted or unsubstituted a heterocycle; or C₁-C₁₁substituted or unsubstituted heteroaryl; for example,- SO₂H, -CH₂SO₂H, -SO₂CH₃, -CH₂SO₂CH₃, -SO₂C₆H₅and-CH₂SO₂C₆H₅;

each R^23aand R^23bindependently represents hydrogen or C₁-C₄alkyl; and

the index x is an integer from 0 to 5.

Non-limiting examples of this category include compounds of the formulas:

The next category of compounds refers to tamaseni N-benzyl-4-aminomethyl-3-hydroxypyridine-2-(1H)-Onam formula:

in which each R¹and R²independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₁₀linear, branched or cyclic alkyl;

iii) substituted or unsubstituted C₂-C₁₀linear, branched or cyclic alkenyl;

iv) substituted or unsubstituted C₂-C₁₀linear or branched quinil;

v) substituted or unsubstituted With₆or C₁₀aryl;

vi) substituted or unsubstituted C₁-C₉heterocycle; or

vii) substituted or unsubstituted C₁-C₉heteroaryl.

The first aspect of this category relates to inhibitors of HIF-1α of prolylhydroxylase, in which R²represents hydrogen and R¹represents a substituted or unsubstituted C₁-C₉a heterocycle or C₁-C₉heteroaryl. In the first embodiment, R¹represents a substituted heterocyclic group, non-limiting examples of which include aziridinyl (C₂), azetidine (C₃), pyrrolidinyl (C₄), morpholinyl (C₄), piperazinil (C₄), piperidinyl (C₄), piperidine-2-IMT (valerolactam) (C₅and azepin-2-IMT (caprolactam) (C₆), where R¹the fragment can be connected to the nitrogen atom in any position the Institute in the ring. In addition, C₁-C₉heterocyclic or C₁-C₉heteroaryl ring, you can substitute in any position when the ring carbon atom or ring heteroatom, for example a ring nitrogen. Non-limiting examples of this variant implementation include:

In another embodiment, R²represents hydrogen and R¹represents a substituted or unsubstituted C₃-C₁₂cycloalkyl in which cycloalkyl ring could be replaced at any ring position. Non-limiting examples of this variant implementation include:

Even the next category of compounds refers to unsubstituted N-benzyl-4-aminomethyl-3-hydroxypyridine-2-(1H)-Onam, having the formula:

each R¹and R²independently represents hydrogen or substituted or unsubstituted C₁-C₁₀linear or branched alkyl, where the alkyl part may be substituted by one or more fragments, independently selected from:

i) C₁-C₈linear, branched or cyclic alkoxy;

ii) hydroxy;

iii) halogen;

iv) cyano;

v) amino, C₁-C₈monoalkylamines, C₁-C₈dialkylamino;

vi) -SR⁴⁰; R^{40 represents hydrogen or C₁-C₄linear or branched alkyl;}

^{vii) substituted or unsubstituted With₆or C₁₀aryl;}

^{viii) substituted or unsubstituted C₁-C₉heterocycle; or}

^{ix) substituted or unsubstituted C₁-C₉heteroaryl.}

^{Non-limiting examples of this category include:}

^{Even the next category described compounds has the formula:}

^{in which R200and the index of w are the same as defined in the present invention above. R represents from 0 to 5 substituents hydrogen, where each R is independently selected from:}

i) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl; for example, methyl (C₁), chlormethine (C₁), triptorelin (C₁), aminomethyl (C₁), ethyl (C₂), hydroxymethyl-1-chloroethyl (C₂), 2-hydroxyethyl (C₂), 1,2-deperately (C₂), n-propyl (C₃), isopropyl (C₃), 3-carboxypropyl (C₃), cyclopropyl (C₃), 2-methylcyclopropyl (C₃), n-butyl (C₄), sec-butyl (C₄), isobutyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), 2,3-dihydroxycinnamate (C₄) pentile (C ₅), cyclopentyl (C₅), hexyl (C₆) and cyclohexyl (C₆) and the like;

ii) substituted or unsubstituted C₂-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkenyl; for example Attila (C₂), 2-chloranil (2-vinyl chloride) (C₂), 3-propenyl (C₃), 1-propanyl (2-methylethenyl) (C₃), isopropanol (2-mutilated-2-yl) (C₃), butene-4-yl (C₄), 4-hydroxybutane-1-yl (C₄), cyclobutenyl (C₄), cyclopentenyl (C₅), cyclopentadienyl (C₅), cyclohexenyl (C₆), 7-hydroxy-7-Metalock-4-EN-2-yl (C₉) and 7-hydroxy-7-Metalock-3,5-Dien-2-yl (C₉) and the like;

iii) substituted or unsubstituted C₂-C₁₂linear or C₃-C₁₂branched quinil; for example, ethinyl (C₂), prop-2-inila (also propargyl) (C₃), propyne-1-yl (C₃), 2-metrex-4-in-1-Il (C₇); 5-hydroxy-5-metrex-3-inila (C₇), 6-hydroxy-6-methylhept-3-in-2-yl (C₈), 5-hydroxy-5-amilhat-3-inila (C₉) and the like;

iv) substituted or unsubstituted With₆or C₁₀aryl; for example, phenyl (C₆), naphtalen-1-yl (C₁₀), naphtalen-2-yl (C₁₀), 4-ftoheia (C₆), 2-hydroxyphenyl (C₆), 3-were (C₆), 2-amino-4-ftoheia (C₆), 2-(N,N-diethylamino)phenyl (C_{6 ), 2-cyanophenyl (C6), 2,6-di-tert-butylphenyl (C6), 3-methoxyphenyl (C6), 8-hydroxynaphthalene-2-yl (C10), 4,5-dimethoxyaniline-1-yl (C10), 6-cyanonaphthalene-1-yl (C10) and the like;}

v) substituted or unsubstituted With₁-C₉heterocycle; for example diazirine (C₁), aziridinyl (C₂), Orsolya (C₂), azetidine (C₃), pyrazolidine (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃), isoxazolyl (C₃), isoxazolyl (C₃), thiazolidine (C₃), isothiazole (C₃), isothiazoline (C₃), oxadiazolidine (C₃), oxazolidinone (C₃), hydantoinyl (C₃), tetrahydrofuranyl (C₄), pyrrolidinyl (C₄), morpholinyl (C₄), piperazinil (C₄), piperidinyl (C₄), dihydropyrrole (C₅), tetrahydropyranyl (C₅), piperidine-2-onila (valerolactam) (C₅) and the like;

vi) substituted or unsubstituted C₁-C₁₁heteroaryl; for example 1,2,3,4-tetrazolyl (C₁), [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), triazinyl (C₃), triazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl (C₃), furanyl (C₄), thiophenyl (C₄), pyrimidinyl (C₄), pyridinyl (C₅) and the like;

vii) halogen; for example,- F, -Cl, -Br or-I;

viii) -[C(R^23a)(R^{23b )]_xOR10;}

R¹⁰chosen from:

a) -Η;

b) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

c) substituted or unsubstituted With₆or C₁₀aryl or C₇or C₁₀alkylaryl;

d) substituted or unsubstituted C₁-C₉heterocycle;

e) substituted or unsubstituted With₁-C₁₁heteroaryl;

for example-ΟΗ, -CH₂OH, -OCH₃, -CH₂OCH₃, -OCH₂CH₃, -CH₂OCH₂CH₃, -OCH₂CH₂CH₃and-CH₂OCH₂CH₂CH₃;

ix) -[C(R^23a)(R^23b)]_xN(R^11a)(R^11b);

each R^11aand R^11bindependently selected:

a) -H;

b) -OR¹²;

R¹²represents hydrogen or C₁-C₄linear alkyl;

c) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

d) substituted or unsubstituted With₆or C₁₀aryl;

e) substituted or unsubstituted C₁-C₉heterocycle;

f) substituted or unsubstituted C₁-C₁₁heteroaryl; or

g) R^11aand R^11btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and is t 0 to 3 heteroatoms, selected from oxygen, nitrogen and sulfur;

for example-NH₂, -CH₂NH₂, -NHCH₃, -N(CH₃)₂, -NHOH, -NHOCH₃, -NH(CH₂CH₃), -CH₂NHCH₃, -CH₂N(CH₃)₂, -CH₂NH(CH₂CH₃) and the like;

x) -[C(R^23a)(R^23b)]_xC(O)R¹³;

R¹³represents:

a) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

b) -OR¹⁴;

R¹⁴represents hydrogen, substituted or unsubstituted C₁-C₄linear alkyl, substituted or unsubstituted With₆or C₁₀aryl, substituted or unsubstituted C₁-C₉a heterocycle, substituted or unsubstituted C₁-C₁₁heteroaryl;

c) -N(R^15a)(R^15b);

each R^15aand R^15bindependently represents hydrogen, substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl; substituted or unsubstituted With₆or C₁₀aryl; substituted or unsubstituted C₁-C₉a heterocycle; substituted or unsubstituted C₁-C₁₁heteroaryl; or R^15aand R^15btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatom is in, selected from oxygen, nitrogen and sulfur;

for example-COCH₃, -CH₂COCH₃, -OCH₂CH₃, -CH₂COCH₂CH₃, -COCH₂CH₂CH₃, -CH₂COCH₂CH₂CH₃and the like;

xi) -[C(R^23a)(R^23b)]_xOC(O)R¹⁶;

R¹⁶represents:

a) substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

b) -N(R^17a)(R^17b);

each R^17aand R^17bindependently represents hydrogen, substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl; substituted or unsubstituted With₆or C₁₀aryl; substituted or unsubstituted C₁-C₉a heterocycle; substituted or unsubstituted C₁-C₁₁heteroaryl; or R^17aand R^17btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

xii) -[C(R^23a)(R^23b)]_xNR¹⁸C(O)R¹⁹;

R¹⁸represents:

a) -H; or

b) substituted or unsubstituted C₁-C₄linear, C₃-C₄branched or C₃-C₄cyclic alkyl;

R¹⁹represents:

a) is replaced by the military or unsubstituted C ₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl;

b) -N(R^20a)(R^20b);

each R^20aand R^20bindependently represents hydrogen, substituted or unsubstituted C₁-C₁₂linear, C₃-C₁₂branched or C₃-C₁₂cyclic alkyl; substituted or unsubstituted With₆or C₁₀aryl; substituted or unsubstituted C₁-C₉a heterocycle; substituted or unsubstituted C₁-C₁₁heteroaryl; or R^20aand R^20btaken together, may form a substituted or unsubstituted ring containing from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;

for example,- NHC(O)CH₃, -CH₂NHC(O)CH₃, -NHC(O)NH₂, -CH₂NHC(O)NH₂, -NHC(O)NHCH₃, -CH₂NHC(O)NHCH₃, -OC(O)N(CH₃)₂, -CH₂NHC(O)N(CH₃)₂and the like;

xiii) -[C(R^23a)(R^23b)]_xCN; for example,- CN, -CH₂CN and CH₂CH₂CN;

xiv) -[C(R^23a)(R^23b)]_xNO₂; for example-NO₂, -CH₂NO₂and-CH₂CH₂NO₂;

xv) -[C(R^23a)(R^23b)]_xR²¹; for example,- CH₂F, -CHF₂, -CF₃, -CCl₃or-CBr₃;

R²¹represents a C₁-C₁₀linear, branched or cyclic alkyl, substituted on the 1 to 21 halogen atoms, selected from-F, -Cl, -Br or-I;

xvi) -[C(R^23a)(R^23b)]_xSO₂R²²;

R²²represents hydrogen, hydroxyl, substituted or unsubstituted C₁-C₄linear or C₃-C₄branched alkyl; substituted or unsubstituted C₆C₁₀or C₁₄aryl; C₇-C₁₅alkylene; substituted or unsubstituted C₁-C₉a heterocycle; or a substituted or unsubstituted C₁-C₁₁heteroaryl; for example,- SO₂H, -CH₂SO₂H, -SO₂CH₃, -CH₂SO₂CH₃, - SO₂C₆H₅and-CH₂SO₂C₆H₅;

each R^23aand R^23bindependently represents hydrogen or C₁-C₄alkyl; and

the index x is an integer from 0 to 5.

One aspect of the case for this category relates to inhibitors of HIF-1α of prolylhydroxylase, in which R¹and R²taken together, may form a 5-membered substituted or unsubstituted C₁-C₄heterocyclic or substituted or unsubstituted C₁-C₄heteroaryl ring, non-limiting examples of which include a ring selected from:

Another aspect of this category relates to inhibitors of HIF-1α of prolylhydroxylase, in which R¹ and R ²taken together, may form a substituted or unsubstituted C₄-C₁₁heterocyclic or substituted or unsubstituted C₄-C₁₁heteroaryl ring, non-limiting examples of which are chosen from:

Non-limiting examples of this category include compounds of formula:

The next category described compounds has the formula:

in which R represents from 1 to 5 optional substituents for the hydrogen atoms of the phenyl ring, each R¹and R²independently represents hydrogen or substituted or unsubstituted C₁-C₁₀linear or branched alkyl, in which alkyl fragment, you can replace one or more fragments, independently selected from:

i) C₁-C₈linear, C₃-C₈branched or C₃-C₈cyclic alkoxy;

ii) hydroxy;

iii) halogen;

iv) cyano;

v) amino, C₁-C₈monoalkylamines, C₁-C₈dialkylamino;

vi) -SR⁴⁰; R⁴⁰represents hydrogen or C₁-C₄linear or branched alkyl;

vii) substituted or unsubstituted With₆or C₁₀aryl;

viii) substituted or unsubstituted C 1-C₉heterocycle; or

ix) substituted or unsubstituted C₁-C₉heteroaryl.

Non-limiting examples of this category include:

Even the next category is described inhibitors of HIF-1α of prolylhydroxylase refers to compounds having the formula:

in which R¹and R²taken together, may form a substituted or unsubstituted pieperazinove ring, the substituents in the ring are as defined for R²⁰⁰in the present invention above.

Even the next category is described inhibitors of HIF-1α of prolylhydroxylase has the formula:

in which R¹and R²taken together, may form a substituted or unsubstituted heterocyclic or heteroaryl ring containing from 2 to 20 carbon atoms and from 1 to 7 heteroatoms, in which the formed ring exclude pieperazinove ring.

Also in the present invention describe N-substituted benzyl or N-substituted sulfonylureas-3-hydroxypyridine-2-(1H)-ones having the formula:

you can apply for stimulation of the cellular immune response in the subject. For these compounds Z and L are the same as described in the present invention above. Non-limiting approx the market these compounds include:

1-(4-Chlorobenzyl)-3-hydroxypyridine-2(1H)-he of the formula:

1-(3-Chlorobenzyl)-3-hydroxypyridine-2(1H)-he of the formula:

1-(2-Chlorobenzyl)-3-hydroxypyridine-2(1H)-he of the formula:

Further, in the present invention describe N-substituted benzyl - or N-substituted sulfonylureas-5-substituted-3-hydroxypyridine-2-(1H)-ones having the formula:

in which Y represents a substituted or unsubstituted phenyl, Z and L are the same as defined in the present invention above.

One aspect of Y refers to a phenyl group which is substituted by 1 to 5 halogen atoms, for example, Y is selected from 2-chlorphenyl, 3-chlorphenyl, 2-ftoheia, 3-ftoheia or 4-ftoheia. The next aspect Y fragments refers to compounds in which Y is selected from 2,3-dipthera, 2,4-dipthera, 2,5-dipthera, 2,6-dipthera, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl and 2,6-dichlorophenyl.

Non-limiting examples of compounds according to this category include 1-(4-Chlorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridine-2(1H)-he of the formula:

The following non-limiting examples include:

1-(2-Chlorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(2-Chlorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(2-chloro shall ensil)-5-(4-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(3-Chlorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(3-Chlorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(3-Chlorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(4-Chlorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(4-Chlorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(2-terbisil)-5-(2-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(2-terbisil)-5-(3-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(2-terbisil)-5-(4-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(3-terbisil)-5-(2-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(3-terbisil)-5-(3-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(3-terbisil)-5-(4-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(4-terbisil)-5-(2-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(4-terbisil)-5-(3-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(4-terbisil)-5-(4-chlorophenyl)-3-hydroxypyridine-2(1H)-he;

1-(2-Chlorobenzyl)-5-(2-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(2-Chlorobenzyl)-5-(3-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(2-Chlorobenzyl)-5-(4-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(3-Chlorobenzyl)-5-(2-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(3-Chlorobenzyl)-5-(3-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(3-Chlorobenzyl)-5-(4-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(4-Chlorobenzyl)-5-(2-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(4-Chlorobenzyl)-5-(3-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(4-Chlorobenzyl)-5-(3-forfinal)-3-gidroksipinan the h-2(1H)-he;

1-(2-terbisil)-5-(2-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(2-terbisil)-5-(3-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(2-terbisil)-5-(4-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(3-terbisil)-5-(2-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(3-terbisil)-5-(3-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(3-terbisil)-5-(4-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(4-terbisil)-5-(2-forfinal)-3-hydroxypyridine-2(1H)-he;

1-(4-terbisil)-5-(3-forfinal)-3-hydroxypyridine-2(1H)-he; and 1-(4-terbisil)-5-(3-forfinal)-3-hydroxypyridine-2(1H)-he.

The described connections are distributed across multiple categories for strictly non-limiting purposes of the description of alternatives for synthetic techniques for the subgroups of compounds within the scope of the described connections that are not explicitly illustrated by examples in the present invention. This mental organization by categories does not imply anything regarding increased or decreased biological activity in respect of any of the compounds or compositions described in this invention.

Category I described inhibitors of HIF-1α of prolylhydroxylase relates to compounds of the formula:

in which A represents a substituted or unsubstituted heterocyclic or heteroaryl ring containing from 2 to 20 carbon atoms and up to 7 heteroatoms, R²⁰⁰represents from 0 to 40 substituents hydrogen, R represents from 1 to 5 substituents hydrogen, as defined in the present invention above, and the index n is from 1 to 5. Table I shows typical examples of compounds according to this category.

Described compounds in this category can be obtained by the method presented in this invention in the following scheme I and described in example 1.

Reagents and conditions: (a) TBDMSCl, imidazole, DMF: room temperature, 30 minutes.

Reagents and conditions: (b) (4-chloro)benzylchloride, Cs₂CO₃, THF, room temperature.

Reagents and conditions: (C) 5M HCl, EtOH; 30 minutes.

Reagents and conditions: (d)(i) H₂CHO, AcOH, tert-Boc-piperazine, EtOH; 3 days.

EXAMPLE 1

tert-Butyl{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate (4)

Obtaining 3-(tert-butyldimethylsilyloxy)-1H-pyridine-2-she (1): 3-Hydroxypyridine-2(1H)-one (15 g, 135 mmol) and imidazole (23 g, 338 mmol) suspended in dimethylformamide (200 ml) in an inert atmospherehandler tert-butyldimethylsilyloxy (20.5 g, 136 mmol) in dimethylformamide (200 ml) was added dropwise at room temperature within 30 minutes. Then the reaction mixture was stirred over night. Then the resulting solution was poured into water (300 ml)and the mixture was extracted with tert-butylmethylamine ether (3×500 ml). The combined organic layer was washed with water (300 ml), brine (300 ml), then dried over Na₂SO₄. The solvent was removed under reduced pressure, and the crude product was led from heptane to obtain 16.3 g (53% yield) of the desired product.¹H NMR (250 MHz, CDCl₃) δ ppm 12,98 (1H, m); 6,91 (1H, DD, J=1 Hz, J=6,8 Hz); for 6.81 (1H, DD, J=1.8 Hz, J=7.2 Hz); 6,02-6,007 (1H, m); of 0.90 (9H, s) and 0.17 (6H, s).

Obtaining 3-(tert-butyldimethylsilyloxy)-1-(3-Chlorobenzyl)-1H-pyridine-2-she (2): At 0°C in an inert atmosphere a solution of 4-chlorobenzylchloride (of 4.44 mmol) in THF (10 ml) was added dropwise to a solution of 3-(tert-butyldimethylsilyloxy)-1H-pyridine-2-it, 1, (1 g, of 4.44 mmol) and Cs₂CO₃(2.17 g of 6.66 mmol) in THF (10 ml). The reaction solution was heated to room temperature and stirring continued overnight. The resulting solution was diluted with water (40 ml) and then was extracted with EtOAc (3×30 ml). The combined organic layer was washed brine (30 ml), then dried over Na₂SO₄. The solvent was removed under reduced pressure, and the crude product PTS who attended on silica gel (EtOAc:heptane 4:1) to obtain the desired product in the form of a solid white color.

Obtaining 1-(4-Chlorobenzyl)-3-hydroxypyridine-2(1H)-she (3): To a solution of 3-(tert-butyldimethylsilyloxy)-1-(3-Chlorobenzyl)-1H-pyridine-2-it, 2, (a 2.36 g, 10 mmol) in EtOAc (25 ml) was added 5 M HCl (25 ml) under vigorous stirring at room temperature. The reaction was controlled by TLC for disappearance of starting substances, and it was completed within 30 minutes. The organic layer decantation and the aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over Na₂SO₄, and the solvent was removed under reduced pressure. The crude product was recrystallized from dichloromethane. The output was close to quantitative.¹H NMR (360 MHz, DMSO-d₆) δ ppm 5,12 (2H, s); 6,13 (1H, t, J=? 7.04 baby mortality; of 6.71 (1H, DD, J=7,04, 1,59); 7,23-7,28 (2H, m); of 7.36-the 7.43 (2H, m); 9,10 (1H, USS).

Obtain tert-butyl{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate (4): tert-Butyl piperazine-1-carboxylate (97,6 mmol), formaldehyde (8 ml of 37% solution, which is 97.6 mmol) and acetic acid (8 ml) was dissolved in ethanol (350 ml)and the solution was stirred for 1 hour at room temperature. A solution of 1-(4-Chlorobenzyl)-3-hydroxypyridine-2(1H)-it, 3, (48.8 mmol) in ethanol (350 ml) was added dropwise within 30 minutes. After 3 days stirring was added formaldehyde (3 ml)and the reaction was heated to 50°C, after which the reaction solution was concentrated under pengendalian to approximately 500 ml. The desired product was obtained by crystallization from ethanol.¹H NMR (250 MHz, CDCl₃) δ ppm 1,46 (c, 9H); 2,38-to 2.57 (m, 4H); 3.40 in-3,49 (m, 4H); 3,51 (c, 2H); 5,13 (c, 2H); 6,13 (d, J=7,16 Hz, 1H); 6,79 (d, J=7,16 Hz, 1H); 7,20-7,41 (m, 4H); 8,33 cent to 8.85 (m, 1H). Described biological data refer to A41.

Category II described inhibitors prolylhydroxylase refers to compounds having the formula:

in which A represents a substituted or unsubstituted heterocyclic or heteroaryl ring containing from 2 to 20 carbon atoms and from 1 to 7 heteroatoms, and R²⁰⁰represents from 0 to 40 deputies of hydrogen. Table II shows typical examples of compounds according to this category.

Compounds according to category II can be obtained according to the method shown in scheme I and described in example 1. Below are some additional examples of inhibitors according to category II.

1-Benzyl-3-hydroxy-4-(piperidine-1-ylmethyl)pyridine-2(1H)-he:¹Η NMR (300 MHz, CD₃OD) δ is 1.81 (m, 6H), of 3.07 (m, 2H), 3,51 (m, 2H), 4,23 (c, 2H), 5,24 (c, 2H), of 6.31 (d, J=6,9 Hz, 1H), 7,35 (m, 6H);¹⁹F NMR (252 MHz, CD₃OD) δ 85,5;¹³C NMR (75 MHz, DMSO) δ 21,3, 22,7, 51,8, 52,5, 53,1, 106,4, 117,4, 127,7, 128,0, 128,2, 128,9, 137,3, 147,4, 158,0; ES MS(M+1) 299,12; HRMS. Calculated for C₁₈H₂₂N₂O₂, 298,38. Found (M+1) 299,17.

1-Benzyl-3-hydroxy-4-(morpholine-4-ylmethyl)pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ of 3.25 (m, 4H), 3,81 (m, 4H), 4,18 (c, 2H), 5,17 (c, 2H), of 6.31 (d, J=6,9 Hz, 1H), 7,35 (m, 6H);¹⁹F NMR (300 MHz, DMSO) δ 88,5;¹³C NMR (300 MHz, DMSO) δ 51,6, 51,8, 53,4, 63,5, 107,9, 119,1, 127,8, 128,0, 128,2, 128,9, 137,3, 147,5, 158,3; ES MS(M+1) 301,12; HRMS. Calculated for C₁₇H₂₀N₂O₃, 300,35.

1-Benzyl-3-hydroxy-4-(thiomorpholine-4-ylmethyl)pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ of 2.92 (m, 4H), to 3.38 (m, 4H), 4,17 (c, 2H), 5,16 (c, 2H), 6,29 (d, J=7.5 Hz, 1H), 7,34 (m, 6H), becomes 9.97 (c, 1H);¹⁹F NMR (300 MHz, DMSO) δ 88,4;¹³C NMR (75 MHz, DMSO) δ 24,3, 51,9, 53,4, 53,7, 107,9, 110,9, 127,8, 128,0, 128,2, 128,8, 137,2, 147,6, 157,6; ES MS (M+1) 317,14; HRMS. Calculated for C₁₇H₂₀N₂O₂S, 316,42. Found: (M+1) 317,13.

1-Benzyl-3-hydroxy-4-(thiazolidin-3-ylmethyl)pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ to 3.09 (t, J=6.3 Hz, 2H), 3,42 (t, J=6.3 Hz, 2H), 4,03 (c, 2H), 4,29 (c, 2H), 5,16 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), 10,48 (USS, 1H);¹⁹F NMR (300 MHz, DMSO) δ 87,9;¹³C NMR (75 MHz, DMSO) δ 28,3, 48,3, 50,1, 56,3, 57,0, 107,4, 122,1, 127,8, 128,2, 128,8, 137,4, 146,3, 157,6; ES MS (M+1) 303,08; anal. calculated for C₁₈H₁₉N₂O₄SF, C, 51,92; H, 4,60; N, 6.73 X; S, 7,70. Found: C, 51,67; H, 4,48; N, 6,69; S, 7,65.

1-Benzyl-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridine-2(1H)-he:¹Η NMR (300 MHz, DMSO) δ 1,96 (c, 4H), and 3.16 (c, 2H), 3.43 points (c, 2H), 4,23 (c, 4H), 5,17 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H);¹⁹ F NMR (252 MHz, DMSO) δ 88,7;¹³C NMR (75 MHz, DMSO) δ 22,8, 50,9, 51,8, 53,7, 107,3, 118,0, 128,0, 128,2, 128,9, 137,3, 146,7, 157,6; ES MS (M+1) 285,13; anal. calculated for C₁₉H₂₁F₃N₂O₄C, 57,28; H, 5,31; N, 7.03 IS. Found: C, 57,10; H, 5,11, N, 7,02.

1-Benzyl-3-hydroxy-4-(4-benzylpiperidine-1-ylmethyl)pyridine-2(1H)-he:¹H NMR (DMSO) δ USD 1.43 (m, 2H), 1,72 (m, 4H), 2,96 (m, 2H), 3,41 (m, 3H), 4.09 to (c, 2H), 5,16 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,35 (m, 11H);¹⁹F NMR (252 MHz, DMSO) δ 88,8;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 389,21; HRMS. Calculated for C₂₅H₂₈N₂O₂, 388,50. Found (M+1) 389,22.

1-Benzyl-3-hydroxy-4-(4-benzylpiperazine-1-ylmethyl)pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 3,11 (USS, 4H), 3,81 (c, 2H), 4,18 (c, 2H), 5,15 (c, 2H), 6,24 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), 7,46 (m, 5H);¹⁹F NMR (252 MHz, DMSO) δ 88,2;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 390,21; HRMS. Calculated for C₂₄H₂₇N₃O₂, 389,49. Found (M+1) 390,21.

1-Benzyl-3-hydroxy-4-[(3-hydroxypyrrolidine-1-yl)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 1,90 (m, 1H), 3,18 (m, 2H), 3,47 (m, 3H), 4,24 (c, 2H), 4,43 (c, 1H), 5,17 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H);¹⁹F NMR (252 MHz, DMSO) δ 89,0;¹³C NMR (75 MHz, DMSO) δ 51,8, 52,6, 61,3, 68,6, 107,4, 117,9, 128,0, 128,2, 128,9, 137,3, 146,7, 157,6; ES MS(M+1) 301,13; HRMS. Calculated for C₁₇H₂₀N₂O₃, 300,35. Found: (M+1) 301,15.

1-Ben the Il-3-hydroxy-4-(l,4-dioxa-8 azaspiro[4,5]Dec-8-ylmethyl)pyridine-2(1H)-he :¹H NMR (300 MHz, DMSO) δ 1,90 (m, 4H), 3,11 (m, 2H), 3.43 points (m, 2H), 3,93 (c, 4H), 4,19 (c, 2H), 5,16 (c, 2H), 6,34 (d, J=12 Hz, 1H), 7,34 (m, 6H), 10,01 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,3;¹³C NMR (75 MHz, DMSO) δ 31,7, 50,7, 51,9, 52,5, 64,5, 101,1, 108,0, 116,5, 127,8, 128,0, 128,3, 128,9, 137,3, 147,5 157,6; ES MS(M+1) 357,19; HRMS. Calculated for C₂₀H₂₄N₄O₂, 356,42. Found (M+1) 357,18.

1-Benzyl-3-hydroxy-4-azepin-1-iletileri-2(1H)-he:¹Η NMR (300 MHz, DMSO) δ to 1.61 (m, 4H), of 1.80 (m, 4H), 3,20 (m, 4H), 4,17 (c, 2H), 5,16 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H);¹⁹F NMR (252 MHz, DMSO) δ 88,9;¹³C NMR (75 MHz, DMSO) δ 22,8, 26,4, 51,8, 53,4, 54,4, 107,6, 117,2, 127,9, 128,0, 18,2, 128,9, 137,3, 147,2, 157,6; ES MS(M+1) 313,18; HRMS. Calculated for C₁₉H₂₄N₂O₄, 312,41. Found (M+1) 313,19.

1-Benzyl-3-hydroxy-4-(asokan-1-ylmethyl)pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ equal to 1.59 (m, 10H), 3,18 (m, 2H), 3,38 (m, 2H), 4,17 (c, 2H), 5,16 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H);¹⁹F NMR (252 MHz, DMSO) δ 88,9;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 327,2; HRMS. Calculated for C₂₀H₂₆N₂O₂, 326,43. Found (M+1) 327,20.

1-Benzyl-3-hydroxy-(1,4'-bipiperidine-1'-ylmethyl)pyridine-2(1H)-he:¹Η NMR (300 MHz, DMSO) δ 1,43-to 1.98 (m, 10H), of 2.21 (m, 2H), 3,01 (m, 4H), 3.43 points (m, 3H), 4,12 (c, 2H), 5,16 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), 9,85 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,7;¹³C NMR (75 MHz, DMSO) δ 21,6, 22,9, 23,8, 49,6, 50,5, 51,8, 53,0, 59,5, 108,0, 127,8, 128,0, 128,2, 18,9, 137,3, 147,5, 157,6; ES MS(M+1) 382,4; HRMS. Calculated for C₂₃H₃₁N₃O₂(M+1) 383,51. Found (M+1) 382,25.

1-Benzyl-3-hydroxy-4-[(3,4-dihydroquinoline-1(2H)-yl)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ of 3.13 (t, J=6.3 Hz, 2H), 3,52 (m, 2H), 4,28 (c, 2H), to 4.41 (c, 2H), 5,18 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7.23 percent-7,41 (m, 10H), 10,15 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,9;¹³C NMR (75 MHz, DMSO) δ 25,4; 49,3, 51,8, 52,7, 52,9, 107,6, 11,6, 116,8, 126,9, 127,0, 127,9, 128,0, 128,1, 128,2, 128,8, 128,9, 131,7, 137,3, 147,3, 157,6; ES MS(M+1) 347,40; HRMS. Calculated for C₂₂H₂₂N₂O₂, 346,42. Found (M+1) 347,17.

Methyl 1-[(1-benzyl-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl)methyl]pyrrolidin-2-carboxylate:¹H NMR (300 MHz, DMSO) δ a 2.01 (m, 3H), of 2.45 (m, 1H), 3,26 (m, 1H), 3,53 (m, 1H), 3,69 (c, 3H), 4,30 (m, 3H), 5,17 (c, 2H), 6,27 (d, 6.9 Hz, 1H), 7,35 (m, 6H),¹⁹F NMR (252 MHz, DMSO) δ 88,3;¹³C NMR (75 MHz, DMSO) δ; ES MS (M+1) 343,20; HRMS. Calculated for C₁₉H₂₂N₂O₄,342,39. Found (M+1).

1-Benzyl-3-hydroxy-4-{[2-(methoxymethyl)pyrrolidin-1-yl]methyl}pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 1,71 (m, 1H), of 1.84 (m, 1H), 1,99 (m, 1H), 2,15 (m, 1H), 3,19 (m, 1H), 3,30 (c, 3H), 3,41 (m, 1H), 3,62 (m, 2H), of 3.77 (m, 1H), 4,15 (m, 1H), 4,39 (m, 1H), 5,17 (c, 2H), 6,34 (d, J=7,2 Hz, 1H), 7,34 (m, 6H); 9,60 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,3;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 329,2; HRMS. Calculated for C₁₉H₂₄N₂O₃, 328,41. Found (M+1.

1-Benzyl-3-hydroxy-4-{[2-(pyridin-2-yl)pyrrolidin-1-yl]methyl}pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 2,12 (m, 4H), 3,39 (m, 1H), 3,63 (m, 1H), 4,07 (m, 2H), 4,60 (m, 1H), 5,10 (m, 2H), x 6.15 (d, J=6,9 Hz, 1H), 7,33 (m, 6H), 7,44 (m, 1H), with 8.05 (d, J=8,1 Hz, 1H), 8,59 (d, J=4,8 Hz, 1H), a total of 8.74 (c, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,0; ES MS(M+1) 362,22; HRMS. Calculated for C₂₂H₂₃N₃O₂, 361,44. Found (M+1).

1-Benzyl-3-hydroxy-4-[4-(6-chloropyridin-3-yl)piperazine-1-ylmethyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 3,18 (m, 2H), 3,48 (m, 4H), 4,19 (c, 2H), 4,46 (m, 2H), 5,16 (c, 2H), 6,62 (d, J=7.2 Hz, 1H), 7,35 (m, 6H), of 7.48 (m, 1H), 7,68 (m, 1H), 11,5 (USS, 1H);¹³C NMR (75 MHz, DMSO) δ 42,1, 50,3, 51,9, 52,5, 108,2, 116,2; 118,0, 128,0, 128,2, 128,9, 129,8, 137,3, 147,4, 157,6, 158,8; ES MS(M+1) 476,09. HRMS. Calculated for C₂₁H₂₂ClN₃O₂, 411,88. Found (M+1) 412,76.

1-Benzyl-3-hydroxy-4-[4-(2-methoxyphenyl)piperazine-1-ylmethyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 2,95 (m, 2H), 3,30 (m, 2H), 3,48 (m, 4H), 3,80 (c, 3H), 4.25 in (c, 2H), 5,18 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 6,93 (m, 2H), 7,01 (m, 2H), 7,34 (m, 6H);¹⁹F NMR (252 MHz, DMSO) δ 88,5;¹³C NMR (75 MHz, DMSO) δ 47,2, 51,8, 53,0, 55,3, 108,1, 112,2, 114,8, 116,2, 118,6, 121,2, 123,8, 127,8, 128,0, 128,9, 137,3, 139,6, 147,5, 152,2, 157,6; ES MS(M+1) 405,82; HRMS. Calculated for C₂₄H₂₇N₃O₃, 405,49. Found (M+1) 406,21.

Category III described inhibitors prolylhydroxylase refers to compounds having the formula:

Each R¹and R²independently represents hydrogen or substituted or unsubstituted C₁-C₁₀linear or branched alkyl, in which alkyl fragment, you can replace one or more fragments, independently selected from:

i) C₁-C₈linear, C₃-C₈branched or C₃-C₈cyclic alkoxy;

ii) hydroxy;

iii) halogen;

iv) cyano;

v) amino, C₁-C₈monoalkylamines, C₁-C₈dialkylamino;

vi) -SR⁴⁰; R⁴⁰represents hydrogen or C₁-C₄linear or C₃-C₄branched alkyl;

vii) substituted or unsubstituted With₆or C₁₀aryl;

viii) substituted or unsubstituted C₁-C₉heterocycle; or

ix) substituted or unsubstituted C₁-C₉heteroaryl.

In table III in the present invention, the following are non-limiting examples of compounds included in this category.

Described compounds in this category can be obtained by the method shown in the present invention in the following scheme II and described in example 2.

Reagents and conditions: (a)(i) HCHO, EtOH; 0.5 hour (ii) 3-(1H-imidazol-1-yl)propan-1-amine; 2 hours.

EXAMPLE 2

1-Benzyl-3-is hydroxy-4-{[3-(1H-imidazol-1-yl)propylamino]methyl}pyridine-2(1H)-he (6)

N-Benzyl-3-hydroxypyridine-2(1H)-he (5) can be obtained according to example 1, replacing (4-chloro)benzylchloride benzylbromide or benzylchloride at the stage (b).

1-Benzyl-3-hydroxy-4-{[3-(1H-imidazol-1-yl)propylamino]methyl}pyridine-2(1H)-he (6):N-Benzyl-3-hydroxypyridine-2(1H)-he (5) (250 mg, of 1.23 mmol) and formaldehyde (200 mg, 273 EQ.) mixed in aqueous ethanol (10 ml) and was stirred for 30 minutes. Then added 3-(1H-imidazol-1-yl)propan-1-amine (340 mg, 2.7 mmol)and the reaction mixture was stirred for 12 hours. The solvent was removed by evaporation, and the residue was dissolved in methanol (2 ml) and purified by preparative HPLC, elwira a mixture of water/acetonitrile to obtain the desired product in the form of triptoreline salt.¹H NMR (300 MHz, DMSO) δ 2,19 (m, 2H), 2,97 (m, 2H), was 4.02 (c, 2H), 4,30 (t, J=6.6 Hz, 2H); 5.17 to (c, 2H), 6,30 (d, J=6,9 Hz, 1H), was 7.36 (m, 6H), 7,26 (c, 1H), 7,76 (c, 1H), 9,03 (c, 1H), 9,11 (c, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,5;¹³C NMR (75 MHz, DMSO) δ 26,5, 44,0, 46,0, 51,8, 106,8, 118,7, 120,5, 122,2, 127,9, 128,2, 128,9, 135,8, 137,4, 146,0, 158,2; ES MS (M+1) 339,05; HRMS. Calculated for C₁₉H₂₂N₄O₂, 338,44. Found (M+1) 339,18.

Below are additional non-limiting examples of this aspect are described inhibitors of HIF-1α of prolylhydroxylase.

1-Benzyl-3-hydroxy-4-(benzylamino)pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 4,01 (c, 2H), 4,20 (c, 2H), 5,16 (c, 2H), 6,34 (who, J=7.2 Hz, 1H), was 7.36 (m, 11H), 9,16 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,6;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 321,16; Anal. Calculated for C₂₂H₂₁F₃N₂O₄C, 60,83; H, TO 4.87; N, 6,45. Found: C, 60,75; H, 4,56; N, 6,34.

1-Benzyl-3-hydroxy-4-{[(2-(pyridin-2-yl)ethylamino]methyl}pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 3,26 (m, 2H), 3,37 (m, 2H), 4,08 (c, 2H), 5,17 (c, 2H); 6,34 (d, J=7.2 Hz, 1H), 7,38 (m, 6H), 7,86 (d, J=5.7 Hz, 2H), 8,84 (m, 2H), to 9.32 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,6;¹³C NMR (75 MHz, DMSO) δ 31,5, 44,1, 46,3, 51,8, 106,9, 114,8, 127,1, 128,1, 128,8, 137,4, 143,8, 146,1, 155,3, 157,5, 158,4; ES MS (M+1) 336,18; HRMS. Calculated for C₂₀H₂₁N₃O₂, 335,40. Found: 336,16.

1-Benzyl-3-hydroxy-4-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ of 1.56 (m, 1H), to 1.86 (m, 2H), 1,99 (m, 1H), 2,92 (m, 1H), 3,05 (m, 1H), 3,80 (m, 2H), 4.09 to (m, 3H), 5,16 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H); 8,91 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,5;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 315,16; HRMS. Calculated for C₁₈H₂₂N₂O₃, 314,38. Found (M+1) 315,16.

1-Benzyl-3-hydroxy-4-[(2-methoxyethylamine)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 3,13 (USS, 2H), 3,30 (c, 3H)and 3.59 (t, J=5.4 Hz, 2H), was 4.02 (c, 2H), 5,16 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), 8,91 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,4;¹³C NMR (252 MHz, DMSO) δ; ES MS(M+1) 289,13; HRMS. Calculated for C₁₆H₂₀N ₂O₃, 288,34. Found (M+1) 289,15.

1-Benzyl-3-hydroxy-4-[(1-hydroxy-2-methylpropan-2-ylamino)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 1,27 (c, 6H), 3,49 (c, 2H), 3,95 (c, 2H), 5,17 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), of 8.47 (USS, 2H), 9,94 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,7;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 303,19; HRMS. Calculated for C₁₇H₂₂N₂O₃, 302,37. Found (M+1) 303,17.

1-Benzyl-3-hydroxy-4-[(pyridine-4-ylmethylamino)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 4,07 (c, 2H), 4,32 (c, 2H), 5,16 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H); a 7.62 (d, J=5.7 Hz, 2H), 8,71 (d, J=4.5 Hz, 2H);¹⁹F NMR (252 MHz, DMSO) δ 88,0;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 322,17; HRMS. Calculated for C₁₉H₁₉N₃O₂, 321,37. Found (M+1) 322,15.

1-Benzyl-3-hydroxy-4-{[(furan-2-ylmethyl)amino]methyl}pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 4,00 (c, 2H), 4,28 (c, 2H), 5,16 (c, 2H), 6,27 (d, J=6,9 Hz, 1H), 6,54 (m, 1H), 6,65 (m, 1H), 7,34 (m, 6H), 7,80 (m, 1H), 9,27 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,3;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 323,15; HRMS. Calculated for C₁₈H₁₈N₂O₃, 310,35. Found (M+1).

1-Benzyl-3-hydroxy-4-{[2-(methylthio)ethylamino]methyl}pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 2,10 (c, 3H), 2,74 (t, J=6.9 Hz, 2H), and 3.16 (t, J=8,1 Hz, 2H), 4,05 (c, 2H), 5,17 (c, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H),¹⁹F NMR (25 MHz, DMSO) δ 89,0; ES MS(M+1) 305,14, HRMS. Calculated for C₁₆H₂₀N₂O₂S, 304,41. Found (M+1).

1-Benzyl-3-hydroxy-4-[(4-methoxybenzylamine)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 3,70 (c, 3H), 3,98 (c, 2H), 4,13 (c, 2H), 5,16 (c, 2H), 6,28 (d, J=7.5 Hz, 1H), 7,00 (d, J=9.0 Hz, 4H), 7,34 (m, 6H); 9,07 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 89,0; ES MS(M+1) 351,10; HRMS. Calculated for C₂₁H₂₂N₂O₃, 350,41. Found (M+1) 351,17.

1-Benzyl-3-hydroxy-4-[(1-phenylethylamine)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ equal to 1.59 (d, J=7.2 Hz, 3H), 3,71-3,93 (m, 2H), of 4.45 (m, 1H), 5,15 (c, 2H), 6,28 (d, J=7.5 Hz, 1H), 7,34 (m, 11H);¹⁹F NMR (252 MHz, DMSO) δ 88,9;¹³C NMR (75 MHz, DMSO) δ 19,6, 42,5, 51,7, 58,0, 106,8, 119,3, 128,0, 128,1, 128,2, 128,9, 129,3, 129,4, 137,3, 145,9, 158,3; ES MS(M+1) 335,13; HRMS. Calculated for C₂₁H₂₂N₂O₂, 334,41. Found (M+1) 335,17.

1-Benzyl-3-hydroxy-4-(cycloheptylmethyl)pyridine-2(1H)- he:¹H NMR (300 MHz, DMSO) δ of 1.55 (m, 10H)2,03 (m, 2H), 3,18 (c, 1H), 3,99 (m, 2H), 5,17 (c, 2H), 6,32 (d, J=6,9 Hz, 1H), 7,35 (m, 6H), 8,65 (USS, 2H), 9,98 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,6;¹³C NMR (75 MHz, DMSO) δ 23,0, 27,2, 30,4, 41,6, 51,7, 58,9, 107,0, 111,7, 127,9, 128,0, 128,2, 128,8, 137,4, 146,0, 157,5; ES MS(M+1) 327,13; HRMS. Calculated for C₂₀H₂₆N₂O₂, 326,43. Found (M+1) 327,20.

1-Benzyl-3-hydroxy-4-[(4-methylcyclohexylamine)methyl]pyridine-2(1H)-on the Sabbath. :¹H NMR (300 MHz, DMSO) δ of 0.93 (d, J=6.9 Hz, 3H), of 1.38 (m, 4H), of 1.74 (m, 4H), of 2.05 (m, 1H), 3,10 (m, 1H), 4,01 (c, 2H), 5,17 (c, 2H), of 6.31 (m, 1H), 7,34 (m, 6H), 8,05 (USS, 2H), 9,98 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,9; ES MS(M+1) 327,14; HRMS. Calculated for C₂₀H₂₆N₂O₂, 326,43. Found (M+1) 372,20.

1-Benzyl-3-hydroxy-4-[(1-benzylpiperidine-4-ylamino)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 1.77 in (m, 2H), 2,31 (m, 2H), 2,98 (m, 2H), 3,30 (m, 3H), 3.46 in (m, 2H), 4,03 (c, 2H), 29th (c, 2H), 5,16 (c, 2H), 6,30 (d, J=7.5 Hz, 1H), 7,34 (m, 6H), 7,49 (c, 5H), 9,12 (USS, 1H), of 10.05 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,8;¹³C NMR (75 MHz, DMSO) δ 27,1, 43,4, 51,8, 52,1, 54,2, 54,7, 57,6, 106,9, 118,5, 128,0, 128,1, 128,8, 129,3, 129,8, 130,7, 131,3, 137,3, 146,2, 157,4; ES MS(M+1) 404,56; HRMS. Calculated for C₂₅H₂₈N₃O₂, 403,52. Found (M+1) 404,23.

3-[(1-Benzyl-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl)methylamino]azepin-2-he:¹H NMR (300 MHz, DMSO) δ 1,25 (m, 1H), 1,59 (m, 2H), 1,74 (m, 1H), 1,92 (m, 1H), 2,10 (m, 1H), 3,18 (m, 3H), 4,03 (c, 2H), 4,2 (m, 1H), 5,17 (c, 2H), 6,33 (d, J=7.5 Hz, 1H), 7,34 (m, 6H), 8,31 (t, J=5.4 Hz, 1H), 9,07 (USS, 2H), 9,90 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,4;¹³C NMR (75 MHz, DMSO) δ 27,0, 27,2, 28,4, 43,4, 51,7, 59,3, 107,1, 118,9, 127,8, 127,9, 128,1, 128,9, 137,4, 146,0, 157,5, 166,3; ES MS(M+1) 342,01; HRMS. Calculated for C₁₉H₂₃N₃O₃, 341,40. Found (M+1) 342,18.

1-Benzyl-3-hydroxy-4-[(1-benzylpyrrolidine-3-ylamino)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ2,22 (m, 2H), 2,42 (m, 1H), 3,39 (m, 3H), 3,68 (m, 1H), 4,06 (c, 2H), 4,39 (c, 2H), 5,17 (c, 2H), 6,33 (d, J=7.5 Hz, 1H), 7,30-7,52 (m, 11H);¹⁹F NMR (252 MHz, DMSO) δ 88,5;¹³C NMR (75 MHz, DMSO) δ 27,1, 43,4, 51,8, 52,1, 54,2, 54,7, 57,5, 106,9, 118,5, 128,0, 128,8, 129,3, 129,8, 130,7, 131,3, 137,3, 146,2, 157,5; ES MS(M+1) 390,14; HRMS. Calculated for C₂₄H₂₇N₃O₂, 389,49. Found (M+1) 390,21.

(R)-1-Benzyl-3-hydroxy-4-[(1-phenylethylamine)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 1,58 (d, J=6.9 Hz, 3H), 3,74 (m, 2H), of 4.44 (m, 1H), 5,14 (c, 2H), 6,23 (d, J=7.2 Hz, 1H), 7,35 (m, 6H);¹⁹F NMR (252 MHz, DMSO) δ 89,4;¹³C NMR (75 MHz, DMSO) δ 19,6, 42,6, 51,7, 58,0, 106,9, 18,7, 128,0, 128,1, 128,8, 129,3, 129,4, 137,2, 137,4, 145,9, 157,5; ES MS(M+1) 335,13; Anal. Calculated for C₂₁H₂₂N₂O₂, 334,41. Found (M+1) 335,31.

1-Benzyl-3-hydroxy-4-[([1,3]dioxolane-2-iletilmedigini)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 2,81 (c, 3H), 3,35 (d, J=3,9 Hz, 2H), with 3.89 (m, 2H), 4,01 (m, 2H), 4,21 (m, 2H), 5,17 (c, 2H); 5,27 (t, J=3,9 Hz, 1H), 6,34 (d, J=7.2 Hz, 1H), 7,35 (m, 6H);¹⁹F NMR (252 MHz, DMSO) δ 88,5;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 331,18; HRMS. Calculated for C₁₈H₂₂N₂O₄, 330,38. Found (M+1) 331,16.

Category IV describes inhibitors prolylhydroxylase relates to compounds of the formula:

in which A is a ring, optionally substituted by one or more R²⁰⁰the fragments. Table IV presents Neogen is to provide examples of this category.

Described compounds in this category can be obtained by the method shown in the present invention in the following scheme III and described in example 3.

Scheme III

Reagents and conditions: (a) (i) n-BuLi, TsCl, THF; -78°C to room temperature, 1 h; (ii) HCl, MeOH, room temperature, 1 hour.

Reagents and conditions: (b) pyrrolidin, HCHO, H₂O/EtOH, room temperature, 12 hours.

EXAMPLE 3

1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridine-2(1H)-he (8)

1-(4'-Methylbenzenesulfonyl)-3-hydroxypyridine-2(1H)-he (7): To a stirred solution of 3-[(tert-butyldimethylsilyl)oxy]pyridine-2(1H)-it (1) (of 4.66 g of 20.7 mmol) in anhydrous THF (150 ml)maintained at -78°C in dry nitrogen atmosphere, was added n-utility (a 1.6 M solution in hexane, to 21.0 mmol). After 20 minutes was added 4-methylbenzenesulfonate (3,95 g of 20.7 mmol) in THF solution. The solution was heated to room temperature over 1 hour, was added water (10 ml) and the contents of the reaction vessel was extracted with EtOAc (3×), washed with brine (1×), dried over Na₂SO₄and concentrated. The combined organic layers were dried over Na₂SO₄and concentrated. The residue was dissolved in ethanol (10 ml) and treated with concentrated HCl (2 ml). A mixture of TRANS who massively for 1 hour and the solvent was removed under reduced pressure to obtain the desired compound in the form of a solid white color. ¹H NMR (300 MHz, DMSO) δ 2,43 (c, 3H), 6,14 (t, J=6,9 Hz, 1H), 6,76 (DD, J=7,65 Hz, 1.5 Hz, 1H), 7,18 (DD, J=6,6 Hz, 1.8 Hz, 1H), 7,32 (d, J=7,3 Hz, 2H), 7,98 (d, J=7.9 Hz, 2H).

1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridine-2(1H)-he (8):1-(4'-methylbenzenesulfonyl)-3-hydroxypyridine-2(1H)-he (7) (250 mg, of 0.94 mmol) and formaldehyde (200 mg, 2,07 mmol) were mixed in aqueous ethanol (10 ml) and was stirred for 30 minutes. Then add pyrrolidine (149 mg, 2,07 mmol) and the reaction mixture was stirred for 12 hours. The solvent was removed by evaporation, and the residue was dissolved in methanol (5 ml) and purified by preparative HPLC, elwira a mixture of water/acetonitrile, to obtain the desired product.¹H NMR (300 MHz, DMSO) δ of 1.87 (m, 2H), 1,99 (m, 2H), 2,44 (c, 3H), to 3.09 (m, 2H), 3,40 (m, 2H), 4,19 (c, 2H), 6,51 (d, J=7.5 Hz, 1H), 7,51 (d, J=8,4 Hz, 1H), 7,76 (d, J=7.5 Hz, 1H), 7,98 (d, J=8,1 Hz, 1H), to 9.93 (USS, 1H);¹⁹F NMR (252 MHz, DMSO) δ 88,4;¹³C NMR (75 MHz, DMSO) δ 21,5, 22,7, 50,5, 53,7, 108,7, 118,6, 119,4, 128,4, 129,7, 130,1, 133,1, 146,8, 147,7, 156,2; ES MS(M+1) 349,25; HRMS. Calculated for C₁₇H₂₀N₂O₄S, 348,42. Found (M+1) 349,42.

Below are additional non-limiting examples of inhibitors prolylhydroxylase under this category.

1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-thiazolidin-3-iletileri-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 2,43 (c, 3H), equal to 2.94 (t, J=6.6 MHz, 2H), 3,18 (t, J=6.0 Hz, 2H), 3,66 (c, 2H), 4,12 (c, 2H), 6,51 (d, J=7,5 Hz, 1H), 7,51 (d, J=8,4 Hz, 1H), 7,76 (d, J=7.5 Hz, 1H), 7,98 (d, J=8,1 Hz, 1H),¹⁹F NMR (252 MHz, DMSO) δ 87,9;¹³C NMR (75 MHz, DMSO) δ 21,5, 21,9, 24,6, 25,8, 50,3, 51,6, 108,7, 118,6, 120,8, 129,7, 130,1, 133,1, 146,9, 148,1, 156,1, 158,4, 158,8; ES MS(M+1) 367,18; HRMS. Calculated for C₁₆H₁₈N₂O₄S₂, 366,46. Found (M+1) 367,43.

1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-asokan-1-iletileri-2(1H)-he:¹H NMR (300 MHz, DMSO) δ equal to 1.59 (m, 10H), 2,44 (c, 3H), 3,17 (m, 2H), 3,32 (m, 2H), 4,15 (c, 2H), 6,51 (d, J=7.5 Hz, 1H), 7,51 (d, J=8,4 Hz, 1H), 7,76 (d, J=7.5 Hz, 1H), 7,98 (d, J=8.1 Hz);¹⁹F NMR (252 MHz, DMSO) δ 88,7;¹³C NMR (75 MHz, DMSO) δ 21,5, 21,9, 23,7, 24,6, 25,8, 50,3, 51,6, 108,7, 118,9, 120,8, 129,8, 130,1, 133,1, 146,9, 148,2, 156,1; ES MS(M+1) 391,18; HRMS. Calculated for C₂₀H₂₆N₂O₄S, 390,18. Found (M+1) 391,23.

1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-(4-phenylpiperazin-1-ylmethyl)pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 2,43 (c, 3H), of 3.13 (m, 8H), 3.43 points (c, 2H), 6,47 (d, J=7.5 Hz, 1H), 6,78 (t, J=7.2 Hz, 1H), 7,21 (m, 2H), 7,50 (d, J=8.1 Hz, 2H), to 7.67 (d, J=7.8 Hz, 1H), of 7.97 (d, J=8,4 Hz, 2H);¹³C NMR (75 MHz, DMSO) δ 21,5, 42,6, 45,6, 46,2, 50,8, 51,9, 109,6, 116,4, 116,8, 117,7, 120,6, 121,1, 129,5, 129,6, 129,8, 130,1, 133,2, 146,8, 149,5, 156,1; ES MS(M+1) 440,15; HRMS. Calculated for C₂₃H₂₅N₃O₅S, 439,53. Found (M+1) 440,16.

1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-[1,4']bipyridinyl-1'-iletileri-2(1H)-he:¹H NMR (300 MHz, DMSO) δ USD 1.43 (m, 1H), 1,67 (m, 2H), equal to 1.82 (m, 4H), 2,19 (m, 2H), 2,44 (c, 3), to 2.94 (m, 4H), 3,39 (m, 2H), 3,54 (m, 3H), 4,06 (c, 2H), 6,47 (d, J=8,1 Hz, 1H), 7,51 (d, J=8.1 Hz, 2H), 7,73 (d, 7.8 Hz, 1H), to 7.99 (d, J=8,4 Hz, 2H);¹⁹F NMR (252 MHz, DMSO) δ 88,7;¹³C NMR (75 MHz, DMSO) δ 21,4, 22,9, 23,6, 48,4, 49,5, 59,4, 109,3, 114,8, 117,6, 120,5, 122,7, 129,7, 130,1, 133,1, 146,9, 148,6, 156,2; ES MS(M+1) 446,19; HRMS. Calculated for C₂₃H₃₁N₃O₄S, 445,58. Found (M+1) 446,21.

1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-[4-(6-chloropyridin-3-yl)piperazine-1-ylmethyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 2,44 (c, 3H), 3,17 (m, 2H), 3.46 in (m, 4H), 4,17 (c, 2H), 4,45 (m, 2H), 6,77 (d, J=7.8 Hz, 1H),? 7.04 baby mortality (m, 1H), 7,53 (m, 2H), 7,68 (m, 2H), 7,98 (m, 2H), 11,3 (USS, 1H), ES MS(M+1) 476,92. HRMS. Calculated for C₂₁H₂₅ClN₅O₄S, 475,95. Found (M+1) 476,11.

Category V inhibitors of HIF-1α of prolylhydroxylase relates to compounds of the formula:

R represents from 1 to 5 optional substituents for the hydrogen atoms of the phenyl ring, each R¹and R²independently represents hydrogen or substituted or unsubstituted C₁-C₁₀linear or branched alkyl, in which alkyl fragment, you can replace one or more fragments, independently selected from:

i) C₁-C₈linear, C₃-C₈branched or C₃-C₈cyclic alkoxy;

ii) hydroxy;

iii) halogen;

iv) cyano;

v) amino, C₁-C₈monoalkyl is but C₁-C₈dialkylamino;

vi) -SR⁴⁰; R⁴⁰represents hydrogen or C₁-C₄linear or C₃-C₄branched alkyl;

vii) substituted or unsubstituted With₆or C₁₀aryl;

viii) substituted or unsubstituted C₁-C₉heterocycle; or

ix) substituted or unsubstituted C₁-C₉heteroaryl.

Table V presents non-limiting examples of this class of inhibitors of HIF-1α of prolylhydroxylase.

Described compounds in this category can be obtained by the method described in this invention in the following scheme IV and described in example 4.

Scheme IV

Reagents and conditions: (a) benzylbromide, HCHO, H₂O/EtOH, room temperature, 12 hours.

EXAMPLE 4

1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-[(benzylamino)methyl]- pyridine-2(1H)-he (9)

1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-(benzylamino)pyridine-2(1H)-he (9):1-(4'-Methylbenzenesulfonyl)-3-hydroxypyridine-2(1H)-he (7) (250 mg, of 0.94 mmol) and formaldehyde (200 mg, 2,07 mmol) were mixed in aqueous ethanol (10 ml) and was stirred for 30 minutes. Then add benzylamine (229 mg, 2,07 mmol) and the reaction mixture was stirred for 12 hours. The solvent was removed by evaporation, and the residue was dissolved in methanol (5 ml) and the imali by preparative HPLC, elwira a mixture of water/acetonitrile, to obtain the desired product in the form of triptoreline salt.¹H NMR (300 MHz, DMSO) δ 2,44 (c, 3H), 3.96 points (c, 2H), 4.16 the (c, 2H), 6,69 (d, J=8.1 Hz), 7,40 (m, 7H), 7,52 (m, 1H), 7,73 (d, J=8,1 Hz, 1H), of 7.97 (d, J=8,1 Hz, 1H), 9,71 (USS, 2H), 10,44 (USS, 1H); ES MS(M+1) 396,67; HRMS. Calculated for C₂₀H₂₀N₂O₄S, 384,45. Found (M+1) 385,12.

Below are additional non-limiting example of this class of inhibitors of HIF-1α of prolylhydroxylase.

1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-[(2-methoxyethylamine)methyl]pyridine-2(1H)-he:¹H NMR (300 MHz, DMSO) δ 2,43 (c, 3H), of 3.12 (m, 2H), 3,29 (c, 3H), of 3.56 (t, J=5,1 Hz, 2H), 3,99 (c, 2H), 6,51 (d, J=7.5 Hz, 1H), 7,51 (d, J=8,4 Hz, 1H), 7,76 (d, J=7.5 Hz, 1H), 7,98 (d, J=8.1 Hz);¹⁹F NMR (252 MHz, DMSO) δ 88,6;¹³C NMR (75 MHz, DMSO) δ 21,5, 43,8, 46,2, 46,5, 58,5, 67,2, 106,7, 119,2, 120,2, 123,9, 128,4, 129,7, 130,1, 133,1, 146,8, 147,0, 156,0; ES MS(M+1) 353,12. HRMS. Calculated for C₁₆H₂₀N₂O₅S, 352,41. Found (M+1) 353,11.

Category VI inhibitors of HIF-1α of prolylhydroxylase relates to compounds of the formula:

in which L is selected from CH₂or SO₂and Z represents a substituted or unsubstituted phenyl. Non-limiting examples of inhibitors according to the categories described in table VI below.

Compounds included in this category, can be obtained according to the scheme Dla Z, represents CH₂and according to scheme III to Z, representing the SO₂.

Pharmaceutically acceptable salts

Described inhibitors of HIF-1α of prolylhydroxylase can be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts may be used by the specialist to obtain the forms described inhibitor, which is more compatible with the intended method of delivery to the subject or the compatibility of the composition.

The following are examples of ways to obtain pharmaceutically acceptable salt described inhibitor, tert-butyl{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate.

A suspension of tert-butyl{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate (242 mg, 0,56 mmol) in MeOH (15 ml) was boiled under reflux until a homogeneous solution. Heating was stopped and added 0,1N. HCl (6,7 ml, 1.2 EQ.), while the solution was still hot, and the solution was cooled to room temperature. Volatile components were evaporated under reduced pressure, and the amorphous residue was led in acetone (5 ml). The solid residue was collected by filtration.

A suspension of tert-butyl{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate (217 mg, 0.5 mmol) in MeOH (15 ml) was boiled under reflux to the teachings of the homogeneous solution. Heating was stopped and added methansulfonate (115,2 mg, 1.2 EQ.), while the solution was still hot, and the solution was cooled to room temperature. Volatile components were evaporated under reduced pressure, and the amorphous residue was led in acetone (5 ml). The solid residue was collected by filtration.

In table VII in the present invention the following are examples of pharmaceutically acceptable salts of tert-butyl{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate formed from organic and inorganic acids.

¹H NMR analysis was used to determine the form of salts, for example, mutilata salt obtained in the present invention above, has the following formula:

¹H NMR analysis was used to determine which part of the molecule is the formation of salts. The chemical shifts of the protons in the methylene group connecting pieperazinove and pyridinone ring, shifted from 3,59 hours/million in free base or 4.31 PM/million of salt. In addition, pieperazinove methylene group adjacent to the tertiary amine, shifted from 2.50 PM/m to approximately 3,60 hours/million Chemical shifts of the remaining protons basically unchanged. These data show that the nitrogen of the tertiary amine piperazinovogo ring is protonated in SOLEV the sixth form. In addition, the integration of the methyl protons methanesulfonyl of a fragment relative to the compound shows the presence of one equivalent of acid.

The specialist can determine the solubility of the pharmaceutically acceptable salts described inhibitors in the desired manner. Below is a non-limiting example of a method of increasing the solubility of the salts described inhibitor. The suspension methansulfonate tert-butyl{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate (26.6 mg) in distilled deionized water (3.0 ml) was treated with ultrasound for 20 minutes in a water bath at 25°C. the Suspension was filtered to remove insoluble salts. A clear solution of the filtrate (200 ál) was diluted with distilled deionized water (800 μl) and subjected to HPLC analysis. Below are the results for the pharmaceutically acceptable salts listed in table VII above.

Below are non-limiting examples of other acids that can be used to obtain pharmaceutically acceptable salts of the described inhibitors: acetate, citrate, maleate, succinate, lactate, piconet and tartrate.

Further described in the present invention is a method of obtaining the described inhibitors of HIF-1α of prolylhydroxylase, on the make:

a) protection of the hydroxyl fragment of hydroxypyridine-2(1H)-it is to obtain a secure pyridone of the formula:

in which W represents a protective group;

b) reaction of the protected pyridone with the compound of the formula:

in which R represents from 1 to 5 substituents hydrogen, as defined in the present invention, the index n is an integer from 0 to 5, Q represents a leaving group, to obtain O-protected N-benzylpyridine or N-sulfonylhydrazide formula:

c) removing the protective group of the O-protected N-benzylpyridine or N-sulfonylhydrazide to obtain N-benzylpyridine or N-sulfonylhydrazide formula:

d) reaction of the amine of the formula:

in which R¹and R²are the same as defined in the present invention, with formaldehyde to obtain the N-formylamino formula:

e) reaction of N-formylamino obtained in stage (d), N-benzylpyridine or N-sulfonylhydrazide obtained in stage (c), to obtain compounds of the formula:

Stage (a) Receiving O-protected hydroxypyridine-2(1H)-it

Stage (a) apply the receivable O-protected hydroxypyridine-2(1H)-she formulas:

W may be any protective group. Non-limiting examples of protective groups include carbamates, for example, tert-butoxycarbonyl and methoxycarbonyl, alkylsilane, for example, trimethylsilyl and tert-butyldimethylsilyl and the like.

Stage (b) Receiving O-protected N-benzylhydroxylamine-2(1H)-or O-protected N-sulfonylhydrazide-2(1H)-it

Stage (b) relates to the production of O-protected N-benzylhydroxylamine-2(1H)-or O-protected N-sulfonylhydrazide-2(1H)-it formula

Protected hydroxypyridine-2(1H)-he obtained in stage (a), is reacted with a compound of the formula:

in which Q represents a leaving group, is able to leave the ring nitrogen is protected hydroxypyridine-2(1H)-it.

Stage (c) Obtaining N-benzyl-3-hydroxypyridine-2(1H)-or N-sulfanilyl-3-hydroxypyridine-2(1H)-it

Stage (c) relates to the production of N-benzyl-3-hydroxypyridine-2(1H)-or N-sulfanilyl-3-hydroxypyridine-2(1H)-she formulas:

in which O-protected N-benzylhydroxylamine-2(1H)-or O-protected N-sulfonylhydrazide-2(1H)-he obtained in stage (b), reacts with one or more reagents suitable for removal Pro is based groups W way compatible with any R Deputy hydrogen in the phenyl ring.

Stage (d) obtaining the N-formylamino Cinchona

Stage (d) relates to the production of N-formylamino Sinton formula:

N-formylamino is formed by the reaction of an amine of the formula:

with formaldehyde or with a reagent capable of generating formaldehydein situ.

Stage (e) obtaining the described inhibitors of HIF-1α of prolylhydroxylase

Stage (e) relates to the production end of the described compounds of the formula:

reaction of N-formylamino obtained in stage (d), with N-benzyl-3-hydroxypyridine-2(1H)-one or N-sulfanilyl-3-hydroxypyridine-2(1H)-one, obtained in stage (c).

COMPOUNDS

Medicines and pharmaceutical composition

In addition, the present invention relates to compositions or formulations which are suitable for receiving the medicament or pharmaceutical composition. Described drugs or pharmaceutical compositions containing the described inhibitors prolylhydroxylase human protein HIF-1α, may contain:

a) an effective amount of one or more inhibitors of HIF-1α of prolylhydroxylase according to the present invention and

b) one or more auxiliary is a recreational substances.

Disease or condition that can be influenced by increasing the stability of HIF-1 inhibition of HIF-1α of prolylhydroxylase include BPS, ischemic heart disease, heart failure, ischemia, anemia, wound healing, antimicrobial activity, increased phagocytosis, anticancer activity and increase the effectiveness of vaccination.

For the purposes of the present invention, the term "excipient" and "carrier" are used interchangeably throughout the description of the present invention, and referred to the terms defined in this invention as ingredients, which are used in obtaining safe and effective pharmaceutical compositions.

Specialist clear that the excipients used primarily for the fact that they contributed to the delivery of safe, stable and functional medicines, which serves not only as part of a total environment for the delivery, but also as a means to achieve efficient absorption recipient of the active ingredient. The excipient may play a role simply and directly inert filler or excipient as used in the present invention, may be part of a pH stabilizing systems or coatings to ensure delivery of safe ingredients in the stomach. The specialist may also use the fact that soy is inane of the present invention possess increased cell efficiency, pharmacokinetic properties, and high oral bioavailability.

Non-limiting examples of compositions according to the present invention include:

a) from about 0.001 mg to about 1000 mg of one or more inhibitors prolylhydroxylase human protein HIF-1α in accordance with the present invention and

b) one or more auxiliary substances.

Another example according to the present invention includes the following songs:

a) from about 0.01 mg to about 100 mg of one or more inhibitors prolylhydroxylase human protein HIF-1α in accordance with the present invention and

b) one or more excipients.

The following example according to the present invention includes the following songs:

a) from about 0.1 mg to about 10 mg of one or more inhibitors prolylhydroxylase human protein HIF-1α in accordance with the present invention and

b) one or more excipients.

The following example compositions according to the present invention includes:

a) an effective amount of one or more inhibitors prolylhydroxylase human protein HIF-1α in accordance with the present invention and

b) one or more chemotherapeutic agents or chemotherapeutic compounds, as described in us is oasam the invention.

The following example compositions according to the present invention includes:

a) an effective amount of one or more inhibitors prolylhydroxylase human protein HIF-1α in accordance with the present invention; and

b) one or more vaccines for the treatment of infectious diseases.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product for the treatment of anemia.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product for the treatment of increased cellular immunity.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, to obtain drugs for cancer treatment.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product to increase HIF-1 stabilization.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in this and the finding, to obtain drugs for the treatment of anemia.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product for the treatment of peripheral vascular disease.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product for the treatment of wounds.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product, which is an antimicrobial drug.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product for the treatment of atherosclerotic lesions.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product for the treatment of diabetes.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α prelinger is xylase, described in the present invention, for obtaining a medicinal product for the treatment of hypertension.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product for the treatment of a disease that is affected by the concentration of growth factor vascular endothelial (VEGF), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and erythropoietin (EPO).

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product for the treatment of diseases selected from Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangioma, disease Osler-Weber-Rend or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome.

In addition, the present invention relates to the use of one or more inhibitors of HIF-1α of prolylhydroxylase described in the present invention, for obtaining a medicinal product for the treatment of diseases selected from diabetic retinopathy, muscle degeneration, cancer, sickle cell anemia, sarcoid, syphilis, elastic pseudoxanthoma, disease P the jet, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitrite, mycobacterial infections, Lyme disease, systemic lupus erythematosis, retinopathy of prematurity, illness ILSA, disease behceta, infections causing retinitis or hareidit, probable syndrome ocular histoplasmosis, a disease of the best, myopia, congenital pit of the optic nerve, diseases of Stargardt, intermediario uveitis, chronic retinal detachment, syndrome of increased blood viscosity, toxoplasmosis, trauma and complications after surgery using laser, diseases associated with rubeosis iris, and proliferative vitreoretinopathy.

Describes the composition and form of pharmaceutical preparations containing only inhibitors of HIF-1α of prolylhydroxylase or in combination with another drug or other therapeutic agent, including, chemotherapeutic agent or a chemotherapeutic compound, can vary depending on the intended route of administration.

Orally administered drugs can be in the form of solids, liquids, emulsions, suspensions or gels, or in the form of a unit dosage forms, e.g. tablets or capsules. Tablets can be in combination with other commonly used ingredients such as talc, vegetable m is s'la, polyols, gums, gelatin, starch and other media. Inhibitors of HIF-1α of prolylhydroxylase can be atomized in or mixed with a suitable liquid carrier to obtain solutions, suspensions or emulsions.

Parenteral compositions intended for injection, or subcutaneous, intramuscular, or intravenous, can be obtained in liquid or solid form to be dissolved in liquid prior to injection, or as emulsions. These drugs are sterile, and fluid will be injected intravenously, should be isotonic. Suitable excipients are, for example, water, dextrose, saline and glycerin.

The introduction of pharmaceutically acceptable salts of the substances of the present invention is included in the scope of the present invention. These salts can be obtained from pharmaceutically acceptable non-toxic bases, including organic bases and inorganic bases. Salts derived from inorganic bases include salts of sodium, potassium, lithium, ammonium, calcium, magnesium and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, basic amino acids and the like. For a useful parsing salts drugs, see S.M. Berge et al., Journal of Pharmaceutical Sciences, 66: 1-19 (1977),the disclosure of which is introduced in the present invention by reference.

Substances for injection can be obtained in a unit dosage form in ampoules, or in containers containing multiple doses. Inhibitors of HIF-1α of prolylhydroxylase or compositions containing one or more inhibitors of HIF-1α of prolylhydroxylase, which will be introduced, may be in such forms as suspensions, solutions or emulsions in oily or preferably aqueous media. Alternatively, the salt of the inhibitor of HIF-1α of prolylhydroxylase can be in lyophilized form for dilution at the time of delivery, a suitable vehicle such as sterile pyrogen-free water. Liquid and lyophilized forms, which will be diluted, will contain the agents, preferably the buffers in the quantities necessary to bring the pH of the injectable solution to an appropriate value. For any parenteral application, particularly if the composition is administered intravenously, the total concentration of dissolved substances must be controlled in order to make the drug isotonic, gipotonikam or slightly hypertonic. Non-ionic substances such as sugar, are preferred for control toychest, and sucrose is particularly preferred. Any of these forms may additionally contain suitable agents for the formulation, such as starch or sugar, glizer is h or saline. Composition per dose, liquid or solid, may contain from 0.1% to 99% polynucleotide substances.

WAYS

Way related to stabilization of HIF-1

The destruction of invading microorganisms depends initially on innate immune mechanisms that pre-exist in all individuals and act in the moment of infection. Types of phagocytic cells, including macrophages and neutrophils, play a key role in innate immunity, as they learn, absorb and destroy many pathogens without the aid of the adaptive immune response. The effectiveness of myeloid cells in innate protection reflects their ability to function in environments with low oxygen content. Whereas in healthy tissue oxygen pressure is usually 20-70 mm HG (i.e. 2.5 to 9% oxygen), lower concentrations (<1% oxygen) is described for wounds and lesions of necrotic tissue (Arnold et al., Br J Exp Pathol 68, 569 (1987); Vogelberg & Konig, Clin Investig 71, 466 (1993); Negus et al., Am J Pathol 150, 1723 (1997)). Also shown (Zinkernagel, A. S. et al, "Pharmacologic Augmentation of Hypoxia-Inducible Factor-1α with Mimosine Boosts the Bactericidal Capacity of Phagocytes" J. Infectious Diseases (2008): 197: 214-217)that HIF-1α agonist, mimosin, can increase the ability of human phagocytes and whole blood to kill the main pathogenStaphylococcus aureusin a dose-dependent manner to reduce the amount of damage in a murine model of cutaneous infection.

Macrophages represent one population of effector cells involved in the immune response. Their role in natural immunity involves the mediation of phagocytosis, and the release of cytokines and cytotoxic mediators. They also facilitate the development of acquired immunity through antigen presentation and release of immunomodulatory cytokines. Although macrophages are immune effectors, they are also susceptible to infection with agents such as bacteria, protozoa, parasites, and viruses (The Macrophage, C. E. Lewis & J.O'D. McGee. eds., IRL Press at Oxford University Press, New York, N.Y., 1992). Viruses capable of infecting macrophages include several RNA viruses, such as measles virus (MV) (e.g., Joseph et al, J. Virol. 16, 1638-1649, 1975), respiratory syncytial virus (RSV) (Midulla et al, Am. Rev. Respir. Dis. 140, 771-777, 1989) and human immunodeficiency virus type 1 (HIV-1) (Meltzer and Gendelman, in Macrophage Biology and Activation, S. W. Russell and S. Gordon, eds., Springer-Verlag, New York, N.Y., pp. 239-263(1992: Potts et al, Virology 175, 465-476, 1990).

Described in the present invention is a method of increasing HIF-1 stabilization in the cell, including the contact cellsin vivo,in vitroorex vivowith an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Also in the present invention describe methods of enhancing the cellular immune response of a human or mammal in need on the Sabbath. asenna immunity, involving the introduction of a needy person or mammal an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

In addition, in the present invention describe methods of enhancing the cellular immune response of a human or mammal, who has been diagnosed with a disease that causes a decrease in cellular immunity, including the introduction of a needy person or mammal an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

In addition, in the present invention describe methods of enhancing the cellular immune response of a human or mammal diagnosed as having disease that causes a decrease in cellular immunity, including the introduction of a needy person or mammal an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

In addition, in the present invention describe methods of enhancing the cellular immune response of a human or mammal having a disease that causes a decrease in cellular immunity, including the introduction of a needy person or mammal an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

In this regard, one or more inhibitors of HIF-1α of prolylhydroxylase and Liu is haunted jointly introduced compound can be entered or brought into contact with the cell locally, buccal, oral, intradermally, subcutaneously, on the mucous membranes of the eye, vaginal, rectal and nasal, intravenous and intramuscular injection.

Methods relating to cancer treatment

As used in the present invention, cancer is defined in this invention as "impaired growth of cells which tend to proliferate uncontrolled way and, in some cases, to metastasize." In this regard, and cancer metastasis, and cancer without metastases can be treated with the methods.

Described are methods of treatment of cancer in human or mammal, comprising the administration to a human or mammal suffering from cancer, an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Also in the present invention describe methods of treatment of a human or mammal, who has been diagnosed with cancer, joint introduction of a human or mammal one or more chemotherapeutic agents or chemotherapeutic compounds together with one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Below are non-limiting examples of malignant and benign cancer. Acute lymphoblastic leukemia; acute malacitana leukemia; adrenocortical carcinoma; children adrenocortical carcinoma; cancer of the Appendix; basal the o-cell carcinoma; extrahepatic cancer of the bile duct; bladder cancer; bone cancer; osteosarcoma and malignant fibrous histiocytoma; children stem glioma brain; brain tumor, adult; brain tumor, glioma, brain stem, children; brain tumor, atypical teratoma/rathena tumor of the Central nervous system, children; embryonal tumors of the Central nervous system; astrocytoma cerebellar; astrocytoma of cerebellum/malignant glioma; craniopharyngioma; ependymoblastoma; ependymoma; medulloblastoma; medulloepithelioma; pineal parenchymal tumor of intermediate differentiation; supratentorial primitive neuroectodermal tumor, pineoblastoma; glioma of the optic pathway, and hypothalamus; tumors of the brain and spinal cord; breast cancer; bronchial tumors; Burkitt's lymphoma; carcinoid tumor; carcinoid tumor, gastrointestinal; atypical teratoma/rathena tumor of Central nervous system embryonal tumors of the Central nervous system, lymphoma of the Central nervous system; cerebral astrocytoma, cerebral astrocytoma/children malignant glioma; cervical cancer; chordoma, children; chronic lymphocytic leukemia; chronic granulocyte leukemia; chronic myeloproliferative disease; colon cancer; cancer abadon the th and rectum; craniopharyngioma; cutaneous T-cell lymphoma; cancer of the esophagus; the family of Ewing tumors; sneganna germ cell tumor; extrahepatic cancer of the bile passage; of an eye cancer, intraocular melanoma; cancer of the eye, retinoblastoma; gallbladder cancer; gastric cancer; gastrointestinal carcinoid tumor; gastrointestinal stromal tumor (GIST); germ cell tumor, extracranial; germ cell tumor, sneganna; germ cell tumor, ovarian; gestational USSR disease; glioma; glioma, pediatric brain stem; glioma, children cerebral astrocytoma; glioma, children of the visual pathway and hypothalamic; hairy cell leukemia; cancer of the head and neck; liver cancer; histiocytosis, Langerhans cells; Hodgkin lymphoma; hypopharyngeal cancer; glioma hypothalamic and visual pathway; intraocular melanoma; tumor of the islets of the pancreas; kidney cancer (kidney); Langerhans cell histiocytosis; larynx cancer; acute lymphoblastic leukemia; acute myeloid leukemia; chronic lymphocytic leukemia; chronic myelogenous leukemia; hairy cell leukemia; cancer of the lip and oral cavity; liver cancer; non-small cell lung cancer; small cell lung cancer; lymphoma, AIDS-related; lymphoma, Burkitt; lymphoma, codna T-cell; jackinsky lymphoma; non-Hodgkin if the Foma; primary lymphoma of the Central nervous system; macroglobulinemia, waldenstrom; malignant fibrous histiocytoma bone and osteosarcoma; medulloblastoma; melanoma; melanoma, intraocular (eye); carcinoma from Merkel cells; mesothelioma; metastatic squamous neck cancer of unknown source; oral cancer; the syndrome of multiple endocrine neoplasia, (children); multiple myeloma/neoplasma plasma cells; mushroom avium; myelodysplasia syndromes; myelodysplastic/ myeloproliferative diseases, chronic myelogenous leukemia; acute myeloid leukemia in adults; children with acute myeloid leukemia; myeloma, multiple; myeloproliferative disorders, chronic; cancer of the nasal cavity and sinuses; nasopharyngeal cancer; neuroblastoma; non-small cell lung cancer; oral cancer; oral cancer; cancer of the oropharynx; osteosarcoma and malignant fibrous histiocytoma bone; ovarian cancer; epithelial ovarian cancer; germ cell tumor, ovarian; borderline tumour of the ovary; pancreatic cancer; pancreatic cancer, a tumor of the pancreatic islets; papillomatosis; parathyroid cancer; penile cancer; cancer of the pharynx; pheochromocytoma; pineal parenchymal tumor staging differential and; pineoblastoma and supratentorial primitive neuroectodermal tumors; pituitary tumor; tumor of plasma cells/multiple myeloma; pulmonary blastoma; primary lymphoma of the Central nervous system; prostate cancer; rectal cancer; kidney cancer; renal pelvis and ureter cancer "transitional cells"; cancer of the respiratory tract, including the NUT gene on chromosome 15; retinoblastoma; rhabdomyosarcoma; cancer of the salivary gland cancer; sarcoma family of tumors Ewing's sarcoma; sarcoma, Kaposi's; sarcoma, soft tissue; sarcoma, uterine; syndrome Cesari; skin cancer (not melanoma); skin cancer (melanoma); carcinoma of skin, Merkel cells; small cell lung cancer; cancer of the small intestine; sarcoma, soft tissue; squamous cell carcinoma, squamous neck cancer of unknown origin, metastatic; stomach cancer; supratentorial primitive neuroectodermal tumors; lymphoma, T-cell, cutaneous; testicular cancer; throat cancer; thymoma and limosna carcinoma; thyroid cancer; cancer transitional cell renal pelvis and ureter; USSR disease, gestational; urethral cancer; uterine cancer, endometrial; sarcoma of the uterus, cancer of the vagina; vaginal cancer; macroglobulinemia waldenstrom; and Wilms tumor.

In addition, in the present invention describe methods of treatment of cancer in human or mammal, including joint is e introduction human or mammal, together with one or more chemotherapeutics or chemotherapeutic compounds, one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Also in the present invention describe methods of treatment of a human or mammal, who has been diagnosed with cancer, joint introduction of a human or mammal, together with one or more chemotherapeutics or chemotherapeutic compounds of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

"Chemotherapeutic agent" or "chemotherapeutic compound" is a chemical compound suitable for the treatment of cancer. Chemotherapeutic agents that can be used in combination with the described inhibitors of HIF-1α, include, but are not limited to, mitotic inhibitors (Vinca alkaloid). They include vincristine, vinblastine, vindesine, navelbine™ (vinorelbine, 5'-orangebreasted). In still other embodiments, the implementation of chemotherapeutic agents include inhibitors of topoisomerase I, such as camptothecine connection. As used in the present invention, "camptothecin compounds include camptosar™ (irinotecan HCl), Cosmegen™ (topotecan HCl) and other compounds derived from camptothecin and its analogues. Another category of chemotherapeutic cf the of funds, which can be used in the methods and compositions of the present invention includes derivatives podofillotoksina, such as etoposide, teniposide and etoposide. In addition, the present invention includes other chemotherapeutic drugs known as alkylating funds, which alkylate genetic material in the tumor cells. They include, without limitation, cisplatin, cyclophosphamide, nitrogen mustard, triethylenethiophosphoramide, carmustine, busulfan, chlorambucil, blustin, uramustine, hamarain and dacarbazine. The present invention includes antimetabolites as chemotherapeutic agents. Examples of these types of funds include citizenoriented, fluorouracil, methotrexate, mercaptopurine, azathioprine and procarbazine. An additional category of chemotherapeutic agents that can be used in the methods and compositions described in this invention, includes antibiotics. Examples include, without limitation, doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C and daunomycin. There are many liposomal formulations commercially available for these compounds. In addition, the present invention includes other chemotherapeutic agents, including, without limitation, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, phosphamide and mitoxantrone.

Described in this invention, the inhibitors of HIF-1α of prolylhydroxylase you can type in combination with other antitumor means, including cytotoxic/ antineoplastic tools and antiangiogenic funds. Cytotoxic/antineoplastic funds are defined as funds that attack and destroy cancer cells. Some cytotoxic/antineoplastic agents are alkylating agents that alkylate the genetic material of cancer cells, for example, cisplatin, cyclophosphamide, nitrogen mustard, triethylenethiophosphoramide, carmustine, busulfan, chlorambucil, blustin, uramustine, hamarain and databasen. Other cytotoxic/antineoplastic funds are antimetabolites for tumor cells, for example, citizenoriented, fluorouracil, methotrexate, mercaptopurine, azathioprine and procarbazine. Other cytotoxic/antineoplastic agents are antibiotics, such as doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C and daunomycin. There are a large number of liposomal formulations commercially available for these compounds. Other cytotoxic/antineoplastic agents are mitotic inhibitors (Vinca alkaloids). They include vincristine, vinblastine is etoposide. Mixed cytotoxic/antineoplastic agents include Taxol and its derivatives, L-asparaginase, antitumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

Antiangiogenic agents are well known to specialists in this field of technology. Suitable antiangiogenic tools for use in the described methods and compositions include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense-oligonucleotides. Other known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 (including α and β) interleukin 12, retinoic acid, and tissue inhibitors of metalloprotease-1 and -2 (TIMP-1 and -2). You can also apply small molecules, including inhibitors of topoisomerases, such as razoxane, a topoisomerase II inhibitor with antiangiogenic activity.

Other anti-cancer tools that can be used in combination with the described inhibitors of HIF-1α, include, but are not limited to: acivicin; aclarubicin; acidsolitaire; Acronis; adozelesin; aldeslakin; altretamine; ambomycin; ametantrone; aminoglutethimide; amsacrine; anastrozole; astromicin; asparaginase; aspirin; azacytidine; asettaa; azotomycin; batimastat; benzodepa; bikalutamid; bestrengthened; bis is afid dimesilate; bizelesin; bleomycins; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carouselmicrowave; carzelesin; Cedeira; chlorambucil; cirolemycin; cisplatin; cladribine; crysatal mesilate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin; decitabine; decompletion; deazaguanine; deazaguanosine; diazinon; docetaxel; doxorubicin; doxorubicininduced; droloxifene; droloxifene; dromostanolone; deatomizer; edatrexate; floridageorgia; elsamitrucin; anoplate; enpromate; epirubicin; epirubicinol; arbolada; atropineiphenoxylate; estramustine; estramustine sodium; etanidazole; etoposide; etoposide; atopen; patronagebased; fazarabine; fenretinide; floxuridine; fludarabine; fluorouracil; ferritin; poquito; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubitsin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alpha-2a; interferon Alfa-2b; interferon Alfa-n1; interferon Alfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecanbased; lanreotide; letrozole; leuprolide; lioresallioresal; lometrexol sodium; lomustin; looks ntron hydrochloride; masoprocol; maytansine; macroeconomically; magistralata; melengestrol; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; Matorin; matureup; maintain; metatarsi; mitotropin; mitogillin; mitomycin; mitomycin; mitosis; mitotane; mitoxantrone; mycophenolate acid; nocodazole; nogalamycin; ormaplatin; oxysure; paclitaxel; pegaspargase; polymycin; pentamycin; palomilla; perforated; pipobroman; piposulfan; piroxantrone; plicamycin; plomelin; porfimer sodium; porfiromycin; prednimustine; processesinvolved; puromycin; parameterizable; pyrazofurin; ibuprin; regitered; safingol; categorydownload; semustine; contrast; Cartosat sodium; sparsomycin; spirogermanium hydrochloride; spiramycin; spiroplatin; streptonigrin; streptozocin; alienor; talisayan; tecogen sodium; tegafur; alexandragirard; ]; teniposide; teraxion; testolactone; timipre; tioguanin; thiotepa; teatterin; tirapazamine; toremifene; trestolone; triciribine; trimetrexate; trimetrexate the glucuronate; triptorelin; tubulosa hydrochloride; uramustine; uredepa; vapreotide; verteporfin; vinblastine; vincristina; vindesine; indesignserver; beneficialfor; singlecontroller; Villareal is at; vinorelbine; winnresidential; ventricular; vorozole; senility; zinostatin; Zarubezhenergoproekt. Other anti-cancer tools include, but are not limited to, 20-EPI-1,25 dihydroxyvitamin D3; 5-itinerarary; abiraterone; aclarubicin; allfusion; Adelina; adozelesin; aldeslakin; ALL-TK antagonists; altretamine; ambamustine; amidax; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; Andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; entrelacs; anti-dorsalization morphogenetic protein-1; antiandrogen; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; gene modulators of apoptosis; regulators of apoptosis; apurinovaya acid; ara-CDP-DL-PTBA; argininemia; Bulacan; atamestane; attemptin; achinstein 1; achinstein 2; achinstein 3; azasetron; anatoxin; asteroid; derivatives baccatin III; balana; batimastat; BCR/ABL antagonists; benzocaine; benzoyltartaric; beta-lactam derivatives, beta-alamin; butaclamol B; Betulinol acid; bFGF inhibitor; bikalutamid; bisantrene; besuseradminclient; bisnafide; bitraten A; bizelesin; Brevet; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; derivatives camptothecin; canarypox IL-2; capecitabine; carboxamidine; carbox aminotriazol; CaRest M3; CAR 700; inhibitor of cartilage; carzelesin; inhibitors caseinline (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; floridacarinsurance; cicaprost; CIS-porphyrin; cladribine; clomifene analogues; clotrimazole; collision a; collision B; combretastatin A4; analogues of combretastatin; convenin; kambezidis 816; crysatal; cryptophycin 8; derivatives cryptophycin a; curacin a; cyclopentadecanone; cyclopean; suremilk; cytarabine ocfosfate; cytolytic factor; cytostatin; daclizumab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; Taxifolin; dexrazoxane; dexverapamil; diazinon; didemnin B; detox; diethylnitrosamine; dihydro-5-azacytidine; 9-dihydroxy; dioxazine; diphenylpyraline; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; elastin; edelfosine; edrecolomab; eflornithine; elements; Amateur; epirubicin; epristeride; similar estramustine; agonists of estrogen; estrogen antagonists; etanidazole; etoposide; exemestane; fadrozole; fazarabine; phenetidine; filgrastim; finasteride; flavopiridol; fileselection; fluasterone; fludarabine; fortunatelythe; forenames; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; Galitsin; ganirelix; inhibitors gelatinase; gemcitabine; inhibitors is of glutathione; HaSulam; heregulin; hexamethyleneimine; hypericin; ibandronate acid; idarubitsin; idoxifene; Idamante; ilmofosine; ilomastat; imidazolidone; imiquimod; immunostimulating peptides; inhibitor of receptor insulin-like growth factor-1; interferon agonists; interferons; interleukins; iobenguane; iododeoxyuridine; 4-ipomeanol; ireplace; irsogladine; isomerases; solomakhin B; fusetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; linamarin; lenograstim; rentenanstalt; leptostachys; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leiprorelina; levamisole; lioresal; linear polienovy similar; lipophilic disaccharide glycosides peptide; lipophilic platinum compounds; lysocline 7; lobaplatin; lubricin; lometrexol; lonidamine; losoxantrone; lovastatin; doxorubin; lurtotecan; texasfury lutetium; lisofylline; lytic peptides; maytansine; sandostatin a; marimastat; masoprocol; maspin; inhibitors matrilysin; inhibitors of matrix metalloprotease; menogaril; merbanan; peterlin; methionine; metoclopramide; MIF inhibitor; mifepristone; miltefosin; Miramistin; double-stranded RNA with complementary areas; mitoguazone; mitolactol; analogues of mitomycin; mitonafide; mycotoxicosis growth factor f is broblast-saporin; mitoxantrone; Maarten; molgramostim; monoclonal antibody, human chorionic gonadotropic hormone; monophosphoryl lipid A+skeleton wall of mycobacteria; mopidamol; inhibitor gene in multiple drug resistance; therapy on the basis of multiple oncosuppressor 1; iprange an anti-cancer agent; megaproxy B; extract walls of mycobacteria; mylapore; N-azetidinone; N-substituted benzamide; nafarelin; Agresti; naloxone+pentazocine; nipawin; Natterer; nartograstim; nedaplatin; nemorubicin; Nejdanov acid; neutral endopeptidase; nilutamide; nizamettin; modulators of nitric oxide; nitroxyl antioxidant; nitrolon; O6-benzylguanine; octreotide; okizeme; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral inducer of cytokines; ormaplatin; asteron; oxaliplatin; axiomized; paclitaxel; analogues of paclitaxel, derivatives of paclitaxel; palyulin; palmitoylation; pamidronovu acid; panaxytriol; promife; pyrabactin; panelitem; pegaspargase; peltatin; pentosanpolysulfate sodium; pentostatin; petrosal; perflubron; perforated; parallelly alcohol; fansinating; phenylacetate; inhibitors of phosphatase; picibanil; procurementrelated; pirarubicin; piritrexim; placedin a; placein B; inhibitor of plasminogen activator; platinum to the complex; platinum compounds; platinum-criminaly complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridan; prostaglandin J2; proteasome inhibitors; immune modulator based on A protein; inhibitor of protein kinase C, inhibitors of protein kinase C, microalgal; inhibitors patientinitiated; phosphorylase inhibitors of purine nucleoside; purpurin; pyrazoloacridine; paradoxrecovery haemoglobin polyoxyethylene conjugate; PAF antagonists; raltitrexed; ramosetron; inhibitors of ras farnesyltransferase; ras inhibitors; ras-GAP inhibitor; reality demetilirovanny; rhenium Re-186 etidronate; rhizoxin; ribozymes; RII retinamide; reglated; rohitukine; romantic; roquinimex; religion B1; robaxin; safingol; sintobin; SarCNU; sarcophyton A; sargramostim; Sdi1 mimetics; semustine; inhibitor 1, derived from senescent cells; sense oligonucleotides; inhibitors of signal transduction; modulators of signal transduction; single-stranded antigennegative protein; sizofiran; sobuzoxane; borocaptate sodium; sodium phenylacetate; solvera; somatomedin-binding protein; sonarmen; smartsieve acid; spicamycin D; spiramycin; splenopathy; spongistatin 1; squalamine; inhibitor of stem cells; inhibitors of the division of stem cells; stipend; inhibitors stromelysin; solifenacin; the antagonist overactiv the CSOs vasoactive putting peptide; coralista; suramin; swainsonine; synthetic glucosaminoglycans; tallimustine; tamoxifen methiodide; terramycin; tazarotene; tecogen sodium; tegafur; tolerability; telomerase inhibitors; ]; temozolomide; teniposide; tetrachlorodecaoxide; tetrasomy; teleblaster; thiocoraline; thrombopoietin; mimetic of thrombopoetin; thymalfasin; agonist of the receptor of thymopoietin; timorian; thyroid stimulating hormone; utilityperson tin; tirapazamine; titanocene bichloride; topsentin; toremifene; the totipotent stem cell factor; inhibitors broadcast; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostin; UBC inhibitors; ubenimex; inhibitory growth factor from the urogenital sinus; antagonists of the receptor for urokinase; vapreotide; variolin B; vector system, erythrocyte gene therapy; valarezo; vermin; verdini; verteporfin; vinorelbine; Wincanton; vitaxin; vorozole; sonotron; senility; salaskar; and zinostatin stimulater. In one embodiment, the anticancer agent is 5-fluorouracil, Taxol or leucovorin.

Methods relating to the treatment of conditions associated with microorganisms

Described is a method of prophylactic treatment of a human or mammal from infection, the microorganism is m, involving the introduction of a human or mammal an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Also described is a method of reducing virulence of the microorganism, when a person or a mammal infected with a microorganism, comprising the administration to a human or mammal an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Also described is a method of treating infection in a human or mammal caused by a microorganism, comprising the administration to a human or mammal an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Also described is a method of treatment of a human or mammal, who has been diagnosed with an infection caused by a microorganism, comprising the administration to a human or mammal an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Also described is a method of preventing the transmission of diseases caused by microorganism, from human or mammal to a human or mammal, comprising the administration to a human or mammal an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

In addition, opican the m is a method of preventing the infection of a human or mammal in surgical operations, involving the introduction of a human or mammal an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The microorganism may be any benign or virulent microorganism, for example, bacteria, viruses, yeast, fungi, or parasites. Below are non-limiting examples of microorganisms that can affect the described inhibitors of HIF-1α of prolylhydroxylase. The term "influence" understand that the virulence of the microorganism is reduced, decreased or eliminated. The reason of decrease, reduce or eliminate virulence may be the stabilization of HIF-1 and/or increased the degree of phagocytosis as a result of introduction of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Aeromonas hydrophilia, Agrobacterium tumefaciens, Bacillus anthracis, Bacillus halodurans, Bacillus subtilis, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides fragilis, Bacteroides ovalus, Bacteroides 3452A group homology, Bacteroides splanchnicus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Bordetella bronchiseptica, Bordetella parapertussis, Bordetella pertussis, Borrelia burgdorferi, Branhamella catarrhalis, Brucella melitensis, Burkholderia cepacia, Burkholderia pseudomallei, Campylobacter coli, Campylobacter fetus, Campylobacter jejuni, Caulobacter crescentus, Citrobacter freundii, Clostridium difficile, Clostridium perftingens, Corynebacterium diphtheriae, Corynebacterium glutamicum, Corynebacterium ulcerans, Edwardsiella tarda, Enterobacter aerogenes, Erwinia chrysanthemi, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Francisella tularensis, Gardnrella vaginalis, Haemophilus ducreyi, Haemophilus haemolyticus, Haemophilus influenzae, Haemophilus parahaemolyticus, Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella oxytoca, Klebsiella pneumoniae, Kluyvera cryocrescens, Legionella pneumophila, Listeria innocua, Listeria monocytogenes, Listeria welshimeri, Methanosarcina acetivorans, Methanosarcina mazei, Morganella morganii, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Mycobacterium tuberculosis, Mesorhizobium loti, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella haemolytica, Pasteurella multocida, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Proteus mirabilis, Proteus vulgaris, Pseudomonas acidovorans, Pseudomonas aeruginosa, Pseudomonas alcaligenes, Pseudomonas fluorescens, Pseudomonas putida, Ralstonia solanacearum, Salmonella enterica subsp. enteridtidis, Salmonella enterica subsp. paratyphi, Salmonella enterica, subsp. typhimurium, Salmonella enterica, subsp. typhi, Serratia marcescens, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Sinorhizobium meliloti, Staphylococcus aureus, Streptococcus criceti, Staphylococcus epidemmidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus hyicus, Staphylococcus intermedius, Stenotrophomonas maltophilia, Staphylococcus saccharolyticus, Staphylococcus saprophyticus, Staphylococcus sciuri, Streptomyces avermitilis, Streptomyces coelicolor, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes Sulfobalblobus soffiataricus, Thermotoga maritima, Vibrio cholerae, Vibrio parahaemolyticus, Vogesella indigofera, Xanthomonas axonopodis, Xanthomonas campestris, Yersinia enterocolitica, Yersinia intermedia, Yersinia pestis and Yersinia pseudotuberculosis

Methods related to vaccination or inoculation

In the present invention describe methods for improving the efficiency of the vaccine, including the joint introduction of a human or mammal vaccine in combination with one or more inhibitors of HIF-1α of prolylhydroxylase.

Non-limiting examples of vaccines include vaccines for which stimulirovania antibodies against hepatitis, influenza, measles, rubella, tetanus, polio, rabies and such.

Non-limiting examples of vaccines include vaccines for stimulating antibodies against hepatitis, influenza, measles, rubella, tetanus, polio, rabies and such.

Therefore, the described methods include the introduction, or in the case of contact cellsin vitro, in vivo or ex vivo, one or more inhibitors of HIF-1α of prolylhydroxylase and any conjunction of input connections, local, buccal, oral, intradermally, subcutaneously, on the mucous membranes of the eye, vaginal, rectal and nasal, intravenous and intramuscular injection.

Below are non-limiting examples of methods according to the present invention.

The way to increase HIF-1 stabilization in the cell, including the contact cells in vivoin vitroor ex vivo with an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Method of enhancing the cellular immune response of a subject in need of increased cellular immunity, including the introduction of the needy to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Method of enhancing the cellular immune response of a subject diagnosed as having disease that causes a decrease in cellular immunity, including the introduction of needy subject effective the amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Method of enhancing the cellular immune response of a subject who has been diagnosed with a disease that causes a decrease in cellular immunity, including introduction to the subject an effective amount of one or more described HIF-1α inhibitors.

Method of enhancing the cellular immune response of a subject having a disease that causes a decrease in cellular immunity, and the above-mentioned method includes the introduction of the needy to the subject an effective amount of one or more described HIF-1α inhibitors.

A method of treating cancer in a subject comprising the administration to a subject suffering from a cancer, an effective amount of one or more described HIF-1α inhibitors.

The method of treatment of a subject who has been diagnosed with cancer, by stabilizing the concentration of cellular HIF-1, increasing by this immune response in a subject, comprising the administration to a subject who has been diagnosed with cancer, an effective amount of one or more HIF-1α inhibitors.

The method of treatment of a subject who has been diagnosed with cancer, by stabilizing the concentration of cellular HIF-1, increasing by this immune response in a subject, comprising the administration to a subject who has been diagnosed with cancer, an effective amount of a composition containing one or more chemotherapeutic agents or chemotherapeutic compounds is one or more inhibitors of HIF-1α of prolylhydroxylase.

A method of treating cancer in a subject by stabilizing the concentration of cellular HIF-1, increasing by this immune response in a subject, comprising the administration to a subject suffering from a cancer, an effective amount of one or more HIF-1α inhibitors.

A method of treating cancer in a subject by stabilizing the concentration of cellular HIF-1, increasing by this immune response in the subject, and the above method includes an introduction to the subject an effective amount of a composition containing one or more chemotherapeutic agents or chemotherapeutic compounds and one or more inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of a subject who has been diagnosed with cancer, comprising the administration to a subject who has been diagnosed with cancer, an effective amount of one or more HIF-1α inhibitors.

The method of treatment of a subject who has been diagnosed with cancer, comprising the administration to a subject who has been diagnosed with cancer, an effective amount of a composition containing one or more chemotherapeutic agents or chemotherapeutic compounds and one or more inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of a subject who has been diagnosed with cancer, a joint introduction to the subject one or more chemotherapeutic agents or chemotherapeutic compounds and one or Bo what it described inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of a subject suffering from cancer, a joint introduction to the subject one or more chemotherapeutic agents or chemotherapeutic compounds and one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

A method of prophylactic treatment of infection in a subject comprising administration to the subject an effective amount of one or more described HIF-1α inhibitors.

A method of treating infection in a subject caused by a microorganism, comprising an introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of the subject of the infection caused by a pathogen selected from bacteria, viruses, yeast, fungi or parasites, including the introduction of an infected subject an effective amount of one or more HIF-1α inhibitors.

The method of treatment of a subject who has been diagnosed with an infection caused by a microorganism, comprising an introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The way to prevent the spread of diseases caused by microorganism from one entity to another entity, including an introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The way to increase the effectiveness of the vaccine, on the expectation of the joint introduction to the subject of vaccine in combination with one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The way to increase the effectiveness of the vaccine, including introduction to a subject a composition comprising a vaccine in combination with one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The method of inhibition of 4-prolylhydroxylase activity against hypoxia-induced factor-1 alpha (HIF-1α) in a subject by stabilizing the concentration of cellular HIF-1, which includes an introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α 4-prolylhydroxylase.

The method of modulating the cellular concentration of hypoxia-induced factor-1 alpha (HIF-1) in a subject comprising contacting the subject with an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The method of increasing the cellular concentration of HIF-1 in the subject able normoxia, including introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

A method of treating anemia in a subject comprising administration to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of a subject who has been diagnosed with anemia, including introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Method of strengthening Angie is ESA the subject, includes introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of a subject in need of enhanced angiogenesis, comprising an introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

A method of treating sepsis in a subject comprising administration to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of a subject who has been diagnosed with sepsis, including introduction to the subject an effective amount of one or more inhibitors of HIF-1α of prolylhydroxylase.

A method of treating peripheral vascular disease in a subject comprising administration to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of a subject who has been diagnosed with a disease of the peripheral vessels, including introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

A method of treating a wound in a subject comprising administration to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of a subject having a wound, comprising an introduction to the subject an effective amount of one or the more of the described inhibitors of HIF-1α of prolylhydroxylase.

A method of preventing contamination of a wound in a subject comprising administration to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

A method of treating diabetes in a subject comprising administration to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of a subject who has been diagnosed with diabetes, including an introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

A method of treating hypertension in a subject comprising administration to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

The method of treatment of a subject who has been diagnosed with hypertension, including introduction to the subject an effective amount of one or more of the described inhibitors of HIF-1α of prolylhydroxylase.

Also described are the following:

The application of one or more of the described inhibitors of HIF-1α of prolylhydroxylase to obtain drugs for the treatment of wounds.

The application of one or more of the described inhibitors of HIF-1α of prolylhydroxylase to obtain drugs for cancer treatment.

The application of one or more of the described inhibitors of HIF-1α of prolylhydroxylase to obtain drugs is to enhance cellular immunity in a subject with reduced cellular immunity.

The application of one or more of the described inhibitors of HIF-1α of prolylhydroxylase to obtain drugs to enhance the immune response in the subject with a weakened immune response.

The application of one or more of the described inhibitors of HIF-1α of prolylhydroxylase to obtain drugs for the treatment of infection.

The application of one or more of the described inhibitors of HIF-1α of prolylhydroxylase to obtain drugs, which oseltamivir prevents the subject has an infection caused by a pathogen.

TECHNIQUES

EGLN-1 activity analysis

EGLN-1 (or EGLN-3) enzyme activity determined using mass spectrometry (matrix-activated laser desorption/ionization, time-of-flight MS, MALDI-TOF MS).

Recombinant human EGLN-1-179/426 received, as described above in reference data. Human recombinantly full EGLN-3 was obtained in a similar way, but you need to apply His-MBP-TVMV-EGLN-3 conjugate to analyze due to the instability of the split protein. For both enzymes HIF-1α peptide corresponding to residues 556-574, used as a substrate. The reaction is carried out in a total volume of 50 µl containing TrisCl (5 mm, pH 7.5), ascorbate (120 μm), 2-oxoglutarate (3.2 mm), HIF-1α (8,6 mm) and bovine serum albumin (0.01 per cent). The amount of enzyme, which as before is artelino defined, hydroxylase 20% of the substrate for 20 minutes, was added to the original reaction. When inhibitors compounds were obtained in dimethyl sulfoxide at 10 times the final concentration for analysis. After 20 minutes at room temperature the reaction was stopped by transferring 10 μl of the reaction mixture to 50 μl of the solution matrices for mass spectrometry (α-cyano-4-hydroxyurea acid, 5 mg/ml in 50% acetonitrile/0.1% of TFA, 5 mm NH₄PO₄). Two microliters of the mixture was applied in the form of drops on MALDI-TOF MS plate for analysis Applied Biosystems (Foster City, CA) 4700 Proteomics Analyzer MALDI-TOF MS, equipped with a Nd:YAG laser (355 nm, 3 NS pulse width, 200 Hz repetition frequency). Gidroksilirovanii peptide products were detected from the mass of the substrate increase of 16 Da. Data is defined as the percentage conversion of substrate into product, were analyzed in GraphPad Prism 4 for calculating IC₅₀values.

VEGF ELISA analysis

HEK293 cells were planted in 96-well tablets, coated polylysine at 20,000 cells per well in DMEM (10% FBS, 1% NEAA, 0.1% glutamine). After incubation overnight, the cells were washed in 100 μl of Opti-MEM (Gibco, Carlsbad, CA) to remove serum. The compound in DMSO was sequentially diluted (starting with 100 μm) in Opti-MEM and added to the cells. The conditioned medium were analyzed for VEGF using the Quantikine human VEGF kit immunoassay (R&D Systems, Minneapolis, MN). The total optical PL is in the surrounding area at 450 nm was recorded, using Spectra Max 250 (Molecular Devices, Sunnyvale, CA). Data defined as % DFO stimulation, was used to calculate EC₅₀values using GraphPad Prism 4 software (San Diego, CA).

Studies of ischemic hind limbs in mice

All manipulations with animals were conducted according to the guidelines for the content and use of laboratory animals (National Academy of Sciences; Copyright ©1996). Used in these experiments were 9-10-week-old male C57B1/6 mice from Charles River Laboratory (Portage, MI). Mice orally they dosaged environment (water carbonate buffer, 50 mm; pH 9,0) or compound that experience, in an environment at 50 mg/kg or 100 mg/kg, the Animals were injected dose three times: day 1 - 8 hours and 17 hours, and day 2 - 8 hours. One hour after the first dose was performed unilateral ligation of the artery under anesthesia using isoflurane. The femoral artery is ligated proximally to the beginning of the popliteal artery. The contralateral limb was subjected to sham surgery. Ligation was performed alternating manner between the right and left hind limbs. Two hours after dosing in 8 hours on day 2 received blood ventricular fence, while mice were shot by isoflurane. Serum samples for EPO analysis was obtained using a test tube with a coagulation activator for separation of serum. Heart, liver and gastrocnemius muscle were collected, quickly frozen in liquid nitrogen and kept at -80°C until use.

EPO serum of mice

Mouse serum EPO was detected using Quantikine ELISA kit for determination of erythropoietin in mice from R&D Systems according to the manufacturer's instructions.

HIF Western blot analysis tissue of mice

Tissue of mice contained at -80°C, was ground into powder in a mortar with pestle cooled with liquid nitrogen. Nuclear extracts were obtained using NE-PER kit (Pierce Biotechnology). For thus the nuclear extract was added to the monoclonal antibody to HIF-1α (Novus, Littleton, CO) in the tissue with antibodies against 200:1. The suspension was kept in a conical microcentrifuge tube for 4 hours at 4°C. Then was added to a test tube agarose pellets associated with protein A/G (40 μl of 50% slurry). After rotation overnight at 4°C, pellets were washed 3 times with ice-cold saline solution with phosphate buffer. Then the pellets were prepared for SDS-PAGE using 40 μl of the buffer, Lemly. Proteins separated on SDS-PAGE, transferred to nitrocellulose plate with XCell II Blot Module (Invitrogen, Carlsbad, CA). Spots were blocked by 5% BSA before keeping with the antibody rabbit to HIF-1α at 1:100 dilution (Novus). Then the spots were washed in Tris-buffered saline /Tween-20 buffer and kept with goat anti-rabbit secondary antibodies, konjugierte is related to horseradish peroxidase (Pierce, Rockford, IL). Spots showed ECL reagent (Amersham, Piscataway, NJ). Image spots were obtained using Epson Expression 1600 scanner.

In table VIII shows non-limiting examples of in vivo reactions for compounds according to the present invention, for example, HIFPH2 (EGLN1) inhibition and VEGF stimulation.

Connection F2 additionally experienced in EPO analysis of mouse serum, as described in the present invention above, and found that it has EPO EC₅₀=14 ám.

Increased activity of neutrophils

One aspect of the present invention relates to increased activity of neutrophils and increased life of neutrophils, which can provide the described connections. The following are the methods and examples enhance phagocytosis described compounds. In the examples below cell strain NewmanStaphylococcus aureusrepresents ATCC # 25904, and methicillin-resistant strain ofStaphylococcus aureusrepresents ATCC # 33591, and U937 cell line is a ATCC # CRL-1593.2. HaCaT cells were obtained by way Boukamp P, et al., "Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line." J Cell Biol. (1988) Mar: 106(3):761-71.

For bacterial analysisS. aureus(ATCC 33591) can be grown in broth Todd-Hewitt (THB) to logarithmic phase (OD₆₀₀0.4 or ~5×10⁷To the E/ml) and then precipitated by centrifugation, rinse and re-suspended in PBS or RPMI 1640 medium for growing tissue to the desired concentration. Venous blood of healthy volunteers can be used for whole blood and excretion of neutrophils. Neutrophils can be cleaned by applying a set of PolyMorphPrep (Axis-Shield) according to the manufacturer's instructions. Line human monocytic leukocytes U937 can be propagated in RPMI 1640 plus 10% fetal calf serum, 1 mmol/l NaPyr, 10 mmol/l HEPES and glucose. Whole blood or phagocytes you can withstand with mimosine (Sigma-Aldrich) (0-500 µmol/l) for 2-4 hours, then activateS. Aureus(or 10⁵CFU in 100 μl added to 300 µl of whole blood or MOI of 1 bacterium/cell for the selected phagocytes). Then aliquots were applied to THB agar after 30 (whole blood and neutrophils) or 60 (U937 monocytes) minutes to calculate survivalS. Aureuscolony forming units.

EXAMPLE 5

Dedicated human neutrophils previously kept for 1 hour at 37°C with a control consisting of dimethyl sulfoxide (DMSO), 50 μm and 200 μm of the compounds described in table VIII. Then added,Staphylococcus aureus(strain Newman) to neutrophils at MOI of approximately 0.1 (1 bacterium per 10 neutrophils). The samples were taken after 60 and 90 minutes, in which neutrophils were literally water, and the total balance of bacteria were recorded n the agar plates with the broth Todd-Hewitt (THB).

Fig. 2 shows the effectiveness of the compounds described in table VIII, to secure enhanced destructionS. aureus(strain Newman) at concentrations of 50 μm and 200 μm relative to the control. As can be seen in Fig. 2 through 90 minutes after infection, approximately half of colony forming units was absent at a concentration of 200 ám.

EXAMPLE 6

Cell line human monocytes U937 previously kept for 2 hours at 37°C in an atmosphere of 5% CO₂with control, consisting of DMSO and 10 μm of the compounds described in table VIII. Then added Staphylococcus aureus (virulent strain Newman) to the cells at MOI of approximately 1 (1 bacterium per 1 cell). The samples were taken after 30, 60, 90 and 120 minutes after infection. U937 cells were literally Triton™, and the number of remaining bacteria were recorded on THB agar plates.

As is shown in Fig. 3, the inhibitor 4-prolylhydroxylase, the connection is described in table VIII, is effective to killS. aureuswhen compared with control (DMSO). After 120 minutes the connection is described in table VIII, has 84% destruction of the strain of S. aureus Newman, when monocytes treated with 10 μm of the compounds described in table VIII, showing through this enhanced phagocytosis resulting in increased lifespan of neutrophils.

EXAMPLE 7

Two samples of CL is current from the line of human U937 monocytes pre-treated with 10 μm compound, described in table VIII. One sample had previously stood for 1 hour, and the other sample had previously stood for 2 hours, both at 37°C in an atmosphere of 5% CO₂. Then added to the cellsS. aureus(virulent strain Newman) at MOI of approximately 1-2 (1-2 bacteria per 1 cell). Aliquots of cells were collected from each sample after 30, 60, 90 and 120 minutes after infection, U937 cells were immediately literally Triton™, and the total number of remaining bacteria were recorded on THB agar plates.

As shown in Fig. 4, U937 monocytes pre-treated with a 10 μm compounds described in table VIII, within one hour (black columns) had almost no colony forming units present within 120 minutes after infection, while cells pre-treated for two hours before infection, had approximately 15% of attendees colony forming units, compared with cells that were worked. In addition, Fig. 4 shows that within 1 hour after U937 monocytes were subjected toS. aureus(strain Newman), the number of people present colony forming units was significantly reduced, relative to cells not treated with HIF-1α inhibitor.

EXAMPLE 8

Two sample cells from the line of human U937 monocytes pre-treated with 10 μm of the is to be placed, described in table VIII, for 1 hour at 37°C in an atmosphere of 5% CO₂. Was added to one sampleS. aureus(strain Newman) and another was added methicillin-resistantS. aureus(MRSA). Both bacteria were added at MOI of approximately 2-3 (2-3 bacteria per 1 cell). Aliquots of cells were collected from each sample after 30, 60, 90 and 120 minutes after infection. U937 cells were immediately literally Triton™, and the total number of remaining bacteria were recorded on THB agar plates.

As shown in Fig. 5 through 120 minutes after infection MRSA infected cells had only 25% of the average percent present colony forming units when compared with the control, represented by black columns. Also shown on Fig. 5 through 60 minutes after infection - strain NewmanS. aureushad only approximately 12% of the average percent present colony forming units when compared with control and almost did not contain the present colony forming units through l20 minutes after infection, as shown by the shaded columns.

EXAMPLE 9

Two sample cells from the line of human U937 monocytes treated with 10 μm of the compounds described in table VIII, infected orS. aureus(strain Newman), or methicillin-resistantS. aureus(MRSA). Both bacteria were added at MOI of approximately 2-3 (2-3 bacteria per 1 glue the cu). Aliquots of cells were collected from each sample after 30, 60, 90 and 120 minutes after infection. U937 cells were immediately literally Triton™, and the total number of remaining bacteria were recorded on THB agar plates.

As shown in Fig. 6, even without pre-treatment with compound described in table VIII, through 60 minutes after infection, the strain NewmanS. aureushad only 25% average percent present colony forming units when compared with the control, as represented by black columns. MRSA strain was decreased to less than approximately 40% of the average percent present colony forming units when compared with the control, as shown by the shaded columns.

EXAMPLE 10

Three samples of cells from the line of human U937 monocytes were treated with 100 μm mimosine, 2 μg/ml of vancomycin or 10 μm of the compounds described in table VIII. Each sample was contaminated orS. aureus(strain Newman), or methicillin-resistantS. aureus(MRSA). Both bacteria were added at MOI of approximately 2-3 (2-3 bacteria per 1 cell). After 120 minutes after infection were selected aliquots from all six samples, and U937 cells were immediately literally Triton™, and the total number of remaining bacteria were recorded on THB agar plates.

As shown in Fig. 7, 10 μm of the compounds described in table VIII, strengthened uni is the subject of both bacterial strains, ieS. aureusNewman (shaded columns) or MRSA (black columns), when compared with cells treated with mimosine. Referring to the shaded columns represent the strain Newman, as additionally shown in Fig. 7, the sample treated with 10 μm of the compounds described in table VIII, had a lower average percentage of the present colony forming units than cells treated with vancomycin. U937 cells infected with MRSA (black columns), had approximately 40% of attendees colony forming units compared to the untreated cells and less than half the value for cells treated with mimosine.

Fig. 8 shows the average percentage of present colony forming units (strain Newman) relative to the control for human monocytes (U937) after 30, 60, 90 and 120 minutes after infection, the treatment of 10 μm of the compounds described in table VIII. Black columns represent the processing of the connection described in table VIII, which began at the time of infectionS. aureusshaded columns represent cells, pretreated with compound described in table VIII, and white columns represent cells pre-treated for two hours before infectionS. aureus.

Fig. 9 shows the average percentage of present colony forming units after 120 minutes after infection relative activities is but DMSO (control), when HaCaT cells pretreated for 1 hour according to the above examples, 800 μm mimosine, 10 μm of the compounds described in table VIII, or 1 μg/ml of vancomycin after the introduction ofS. aureus(strain Newman, shaded columns) and methicillin-resistantS. aureus(MRSA, black columns).

Fig. 10 shows the average percentage of present colony forming units 30, 60, 90 and 120 minutes after exposure to strain NewmanS. aureus(shaded columns) and MRSA (black columns), when HaCaT cells pretreated for 1 hour according to the above examples, 10 μm of the compounds described in table VIII.

Fig. 11 shows a stimulating expression regulation phosphoglycerate (PGK) in embryonic fibroblasts wild-type mice, as a result of processing by the connection described in table VIII at dosages of 1 μm (E), 10 μm (F) and 50 μm (G) relative to the control wild-type (H) and the absence of incentive regulation PGK expression in HIF-1 knockout cells, as a result of processing by the connection described in table VIII at dosages of 1 μm (A), 10 µm (B) and 50 μm (C) and HIF-1 knockout control (D). Both types of cells were treated for 7 hours.

Fig. 12 shows a stimulating expression regulation phosphoglycerate (PGK) in embryonic fibroblasts wild-type mice, as a result of processing by the connection described in table VIII at dosages of 1 μm (E), 10 μm (F), relative to control wild-type (G), and the absence of incentive regulation PGK expression in HIF-1 knockout cells, as a result of processing by the connection described in table VIII at dosages of 1 μm (A), 10 µm (B) and 50 μm (C) and HIF-1 knockout control (D).

Fig. 13 shows a stimulating expression regulation phosphoglycerate (PGK) in embryonic fibroblasts wild-type mice, as a result of processing by the connection described in table VIII at dosages of 1 μm (E), 10 μm (F) and 50 μm (G) relative to the control wild-type (H), and the absence of incentive regulation PGK expression in HIF-1 knockout cells, as a result of processing by the connection described in table VIII at dosages of 1 μm (A), 10 µm (B) and 50 μm (C) and HIF-1 knockout control (D).

Growth factor vascular endothelial (VEGF) depends on the presence of HIF-1 in cells. Fig. 14 shows stimulating the regulation of expression of growth factor vascular endothelial (VEGF) in embryonic fibroblasts wild-type mice, as a result of processing by the connection described in table VIII at dosages of 1 μm (E), 10 μm (F) and 50 μm (G) relative to the control (H), and the absence of incentive regulation of VEGF expression in HIF-1 knockout cells treated with compound described in table VIII at dosages of 1 μm (A), 10 µm (B) and 50 μm (C) and HIF-1 knockout control (D). Both types of cells were treated for 7 hours. As can be seen in Fig. 14, VEGF increases at doses of 10 m is M (F) and 50 μm (G). In HIF-1 knockout cells no increase PGK incentive regulation, when HIF-1 knockout cells treated with 1 μm (A), 10 µm (B) and 50 μm (C) when compared with control wild-type (H) and HIF-1 knockout control (D).

Wound healing

EXAMPLE 11

Twenty-four (24) mice were divided into three groups. Animals of group 2 were injected bacterial inoculum (sensitive to the antibiotic strain Newman Staphylococcus aureus [ATCC #25904]) by subcutaneous injection on day 0 and injected 10 μm of the compounds described in table VIII, for 6 days, starting 2 hours after infection (days 0-5). Group 1 was administered subcutaneous injections of DMSO. Group 3 served as the control group and was not processed. The lesion size was monitored daily during the study. Only open wounds believed lesions; tumors and white spots without open wound not researched on the size of the damage. On day 7 was measured by the size of the damage, and mice were killed for determination of bacterial contamination in the skin and kidney. On day 7 after infection mice were killed after measuring the final lesion size, and collected the damaged skin tissue and both kidneys. The skin and kidneys homogenized in physiological solution with phosphate buffer, serially diluted and placed on agar plates Todd-Hewitt to count kolonialismus the units of bacteria.

Fig. 15 shows a significant reduction of damage to the skin (wounds) for animals in group 1 (filled diamonds (♦)), treated with 10 μm of the compounds described in table VIII relative to the animal treated with DMSO (filled squares (■)). As shown in Fig. 15, mice infected with strain NewmanS. aureus, followed by treatment of 10 μm of the compounds described in table VIII, or DMSO (control) 2 hours after infection. The data show a statistically significant decrease in the size of skin lesions (wounds) for animals treated with compound described in table VIII (filled diamonds (♦)or DMSO (filled squares (■)).

Fig. 16 shows a significant reduction in the size of skin lesions (wounds) for animals in group 1 (filled diamonds (♦)), treated with 10 μm of the compounds described in table VIII, relative to untreated animals (filled triangles (▲)). As shown in Fig. 16, mice infected with strain NewmanS. aureus, followed by treatment of 10 μm of the compounds described in table VIII, with or without treatment within 2 hours after infection. The data shows a decrease in the size of skin lesions (wounds) for animals treated with compound described in table VIII (filled diamonds (♦)), or untreated (filled triangles (▲)).

EXAMPLE 12

Twenty-four (24) mouse section is whether the three groups. Animals of group 1 were injected bacterial inoculum (sensitive to the antibiotic strain Newman Staphylococcus aureus [ATCC #25904]) by subcutaneous injection on day 0 and injected 10 μm of the compounds described in table VIII, for 6 days, starting 2 hours after infection (days 0-5). Group 2 was administered subcutaneous injections of DMSO. Group 3 served as control and was not processed. The lesion size was monitored daily during the study. Only open wounds believed lesions; tumors and white spots without open wound not researched on the size of the damage. On day 7 after infection mice were killed after measuring the final lesion size, and collected the damaged skin tissue and both kidneys. The skin and kidneys homogenized in physiological solution with phosphate buffer, serially diluted and placed on agar plates Todd-Hewitt for counting colony-forming units of bacteria.

Fig. 17 is a histogram showing the number of observed colony forming units per gram of skin tissue. Straight lines show the average for each group. The results for the untreated group is based on (A), the results for the group treated with DMSO, built over (B), and the results for the group treated with 10 μm of the compounds described in table VIII, built over (C).

Fig. 18 before the hat is a graph of the observed colony forming units of bacteria, found in the kidneys of animals. The results for the untreated group is based on (A), the results for the group treated with DMSO, built over (B), and the results for the group treated with 10 μm of the compounds described in table VIII, built over (C). As can be seen from these data, half of the animals treated with the inhibitor of HIF-1α of prolylhydroxylase described in table VIII, had no bacteria in the kidney, showing that the connection is described in table VIII, was able to systemically prevent the spread of infection from a wound in the kidney.

EXAMPLE 13

Twenty (20) mice were divided into two groups. Mice of group 1 were injected bacterial inoculum (Streptococcus pyogenes NZ131 [M49 strain]) by subcutaneous injection on day 0 and was pre-treated with compound described in table VIII, once a day for 4 days, starting 2 hours after infection (days 0-3). The connection is described in table VIII, formulated in cyclodextrine and diluted in distilled water prior to subcutaneous injection at a dose of 0.5 mg/kg of the lesion Size was monitored daily during the study. Only open wounds believed lesions; tumors and white spots without open wound not researched on the size of the damage. On day 4 after infection, mice were killed after measuring the final lesion size and collected the damaged skin tissue and both almost the I. The skin and kidneys homogenized in physiological solution with phosphate buffer, serially diluted and placed on agar plates Todd-Hewitt for counting colony-forming units of bacteria.

Fig. 19 shows the results of example 13, in which 2 groups of animals were treated Streptococcus pyogenes NZ131 [M49 strain]. The data shows a decrease in the size of skin lesions (wounds) for animals in group 1 (filled triangles (▲))treated with 0.5 mg/kg of the compounds described in table VIII relative to the animal treated with control medium (cyclodextrin) (filled squares (■)). Fig. 20 is a histogram, which also shows the results of example 12, in which the number of colony forming units for the observed skin lesions in animals treated with control medium (cyclodextrin), lay on (A), and the results for the group treated with 0.5 mg/kg of the compounds described in table VIII, lay over (B).

SETS

Also described are kits containing inhibitors of HIF-1α of prolylhydroxylase, which will be introduced human, mammal or in a cage. Kits can contain one or more packaged unit doses of a composition containing one or more inhibitors of HIF-1α of prolylhydroxylase, which will be introduced human, mammal or in a cage. The ampoule is in a single dose or mnogorazovye containers, in which, before the application is Packed inhibitors of HIF-1α of prolylhydroxylase that will type, may include a sealed container containing a number of polynucleotide or a solution containing a substance that is suitable for its pharmaceutically effective dose, or more effective doses. Inhibitor of HIF-1α of prolylhydroxylase can be packaged in a sterile composition and to create a sealed container to maintain sterility of the composition before use.

Described inhibitors of HIF-1α of prolylhydroxylase may also be present in the form of liquids, emulsions or suspensions for delivery of active therapeutic agents in aerosol form in the body cavity, such as the nose, larynx, or bronchial paths. The ratio of inhibitors of HIF-1α of prolylhydroxylase to other components in the mixture in these drugs will vary depending on the requirements of the dosage form.

Depending on the intended method of administration, the pharmaceutical compositions can be in solid, semi-solid or liquid dosage form, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels or the like, preferably in unit dosage form suitable for single administration of precise dosages. The song will be containing the e l e C as noted above, an effective amount of an inhibitor of HIF-1α of prolylhydroxylase in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, excipients, diluents, etc.

As for solid compositions, conventional nontoxic solid carriers include, for example, mannitol, lactose, starch, magnesium stearate, saccharin sodium, talc, cellulose, glucose, sucrose, magnesium carbonate and the like, pharmaceutical grade. Liquid pharmaceutical compositions which can be entered, can be obtained, for example, by dissolving, dispersing, etc., active compounds described in the present invention, and optional excipients for pharmaceuticals in the media, such as, for example, water, aqueous salt dextrose, glycerol, ethanol and the like, getting through this solution or suspension. If desired, the pharmaceutical composition, which will type, can also contain minor amounts of nontoxic auxiliary substances such as wetting agents or emulsifying agents, agents regulating the pH, and the like, for example, sodium acetate, sorbitanoleat, triethanolaminato sodium, triethanolamine etc. Specific ways to get these dosage forms JW is Auda known or obvious to experts in the art; for example, see Remington's Pharmaceutical Sciences, referenced above.

Parenteral administration, if used, is generally characterized by injection. Injections can be obtained in the form of conventional form or in the form of liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Recently revised method for the parenteral administration includes the use of systems with slow or delayed release, so that a constant degree of dosing. See, for example, U.S. patent No. 3710795, which is introduced in the present invention by reference.

When inhibitors of HIF-1α of prolylhydroxylase will be administered to a mammal other than human, a mammal can be a non-human Primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, Guinea pig or rodent. The terms man and mammal does not define a specific age or gender. Thus, it is assumed that included adult and newborn subjects, as well as embryos, male or female. The patient, a subject, person or mammal refers to a subject suffering from a disease or disorder. The term "patient" includes human and subjects of veterinary medicine.

While specific options for this and is gaining illustrated and described, specialists in the art it is clear that various other changes and modifications can be made without going beyond the scope and essence of the present invention. Therefore, it is assumed that the appended claims include all such changes and modifications are included within the scope and essence of the present invention.

1. The use of compound or its pharmaceutically acceptable salt to obtain drugs to enhance HIF-1 stabilization in the cell, where the compound has the formula:

in which
R represents from 0 to 5 substituents hydrogen, where the substituents selected from chlorine and fluorine;
R⁴selected from C₁-C₄linear or C₃-C₄branched alkyl;
the index n is an integer from 0 to 5.

2. The use of compound or its pharmaceutically acceptable salt for a drug to enhance the immune response in the subject, where the compound has the formula:

in which
R represents from 0 to 5 substituents hydrogen, where the substituents selected from chlorine and fluorine;
R⁴selected from C₁-C₄linear or C₃-C₄branched alkyl;
the index n is an integer from 0 to 5.

3. The use of compounds or E. what about the pharmaceutically acceptable salts to obtain drugs for prophylactic treatment of wounds, preventing infection, where the compound has the formula:

in which
R represents from 0 to 5 substituents hydrogen, where the substituents selected from chlorine and fluorine;
R⁴selected from C₁-C₄linear or C₃-C₄branched alkyl;
the index n is an integer from 0 to 5.

4. The use of compound or its pharmaceutically acceptable salt for a medicinal product for the treatment of infections caused by microorganism, the subject, where the compound has the formula:

in which
R represents from 0 to 5 substituents hydrogen, where the substituents selected from chlorine and fluorine;
R⁴selected from C₁-C₄linear or C₃-C₄branched alkyl; the index n is an integer from 0 to 5.

5. The use according to claim 4, where the infection caused by a pathogen selected from bacteria, viruses, yeast, fungi and parasites.

6. The use of compound or its pharmaceutically acceptable salt for a drug to increase the effectiveness of the vaccine, where the compound has the formula:

in which
R represents from 0 to 5 substituents hydrogen, where the substituents selected from chlorine and fluorine;
R⁴selected from C₁-C₄linear or ₃-C₄branched alkyl; the index n is an integer from 0 to 5.

7. The use according to claim 6, where the vaccine is a vaccine against hepatitis, influenza, measles, rubella, tetanus, polio, or rabies.

8. The use of compound or its pharmaceutically acceptable salt for a medicinal product for treatment of wounds in a subject, where the compound has the formula:

in which
R represents from 0 to 5 substituents hydrogen, where the substituents selected from chlorine and fluorine;
R⁴selected from C₁-C₄linear or C₃-C₄branched alkyl; the index n is an integer from 0 to 5.

9. The use according to any one of claims 1 to 8, in which the compound is a salt containing an anion selected from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarata and citrate.

10. The use according to any one of claims 1 to 8, in which the compound is a salt containing a cation selected from ammonium, sodium, lithium, potassium, calcium, magnesium, and bismuth.

11. The use according to any one of claims 1 to 10, in which R⁴represents methyl.

12. The use according to any one of claims 1 to 10, in which R⁴PR is dstanley an ethyl.

13. The use according to any one of claims 1 to 10, in which R⁴represents tert-butyl.

14. The use according to any one of claims 1 to 10, in which Z represents 4-chlorophenyl.

15. The use according to any one of claims 1 to 10, in which Z is selected from 2-chlorphenyl, 3-chlorphenyl, 2-ftoheia, 3-ftoheia or 4-ftoheia.

16. The use according to any one of claims 1 to 10, in which Z is selected from 2,3-dipthera, 2,4-dipthera, 2,5-dipthera, 2,6-dipthera, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl and 2,6-dichlorophenyl.

17. The use according to any one of claims 1 to 10, in which the compound is selected from tert-butyl 4-{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate or its pharmaceutically acceptable salt selected from the cleaners containing hydrochloride salt, bisulfate salt, sulfate salt, p-toluensulfonate salt, methanesulfonate salts and mixtures thereof.

18. The use according to any one of claims 1 to 10, in which the compound is selected from the following compounds:
methyl 4-{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
methyl 4-{[1-(3-Chlorobenzyl)-3-hydroxy-2-oxo-1,2 - dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
methyl 4-{[1-(2-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
ethyl 4-{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2 - dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
ethyl 4-{[1-(3-Harbin who yl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
ethyl 4-{[1-(2-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
tert-butyl 4-{[1-(3-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
tert-butyl 4-{[1-(2-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
methyl 4-{[1-(4-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
methyl 4-{[1-(3-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
methyl 4-{[1-(2-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
ethyl 4-{[1-(4-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
ethyl 4-{[1-(3-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
ethyl 4-{[1-(2-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate;
tert-butyl 4-{[1-(4-terbisil)-3-hydroxy-2-oxo-1,dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;
tert-butyl 4-{[1-(3-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate and
tert-butyl 4-{[1-(2-terbisil)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate.

19. Pharmaceutical composition containing:
a) an inhibitor of HIF-1α of prolylhydroxylase, representing a compound of the formula

in which
R represents from 0 to 5 substituents hydrogen,
where substituents selected from chlorine and fluorine;
the index n is an integer from 0 to 5;
R⁴selected from C₁-C₄linear or C₃-C₄branched alkyl;
or its pharmaceutically acceptable salt; and
b) one or more auxiliary substances.

20. The composition according to claim 19, in which R⁴represents methyl.

21. The composition according to claim 19, in which R⁴represents ethyl.

22. The composition according to claim 19, in which R⁴represents tert-butyl.

23. The composition according to claim 19, in which Z represents 4-chlorophenyl.

24. The composition according to claim 19, in which Z is selected from 2-chlorphenyl, 3-chlorphenyl, 2-ftoheia, 3-ftoheia or 4-ftoheia.

25. The composition according to claim 19, in which Z is selected from 2,3-dipthera, 2,4-dipthera, 2,5-dipthera, 2,6-dipthera, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl and 2,6-dichlorophenyl.

26. The composition according to claim 19 in which the compound is selected from tert-butyl 4-{[1-(4-Chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridines-4-yl]methyl}piperazine-1-carboxylate or its pharmaceutically acceptable salt selected from the cleaners containing hydrochloride salt, bisulfate salt, sulfate salt, p-toluensulfonate salt, methanesulfonate salts and mixtures thereof.