ALKYL PIPERAZINE-1-CARBOXYLATE COMPOUNDS PROLYL HYDROXYLASE INHIBITORS AND PHARMACEUTICAL COMPOSITIO

专利摘要:
prolyl hydroxylase inhibitors. disclosed herein are prolyl hydroxylase inhibitors that can stabilize hypoxia-induced factor-1 alpha (hif-1a) as well as hypoxia-induced factor-2 (hif-2). pharmaceutical compositions comprising one or more of the disclosed compounds are also disclosed. methods of stimulating the cellular immune response in a mammal are also disclosed, such as increasing phagocytosis, for example, prolonging the life of phagocytes such as, among others, keratinocytes and neutrophils. in this way, the disclosed compounds provide methods of treating diseases related to the body's immune response.
公开号:BR112012010762B1
申请号:R112012010762-3
申请日:2010-11-05
公开日:2021-08-03
发明作者:Joseph H. Gardner；Robert Shalwitz
申请人:Aerpio Therapeutics Inc.；
IPC主号:

专利说明:

PRIORITY
[001] This order claims the benefit of Provisional Order Serial No. 61/258,914 and Provisional Order Serial No. 61/258,918, which were both filed on November 6, 2009, and the entire contents of the orders are hereby incorporated by reference. . DESCRIPTION FIELD
[002] Herein described are prolyl hydroxylase inhibitors that can stabilize hypoxia-induced alpha-factor-1 (HIF-1α) as well as hypoxia-induced alpha-factor-2 (HIF-2α). Also described herein are pharmaceutical compositions comprising one or more of the described compounds. Methods for stimulating the cellular immune response in a mammal are further described, such as increasing phagocytosis, for example, prolonging the life of phagocytes, inter alia, keratinocytes and neutrophils. In this way, the compounds described provide methods for treating diseases related to the body's immune response. SUMMARY
[003] The described compounds stabilize HIF-1α and HIF-2α, as well as other factors that are present in a compromised immune response or that are depleted or overloaded by the presence of a disease state and the manifestations of the disease state, inter alia, septicemia. The compounds described can be used to treat cancers and can be co-administered with other cancer treatment drugs. Furthermore, the disclosed compounds can be used to enhance the immune response by a mammal when co-administered with a vaccine, for example, influenza vaccines, malaria vaccines, yellow fever vaccines, cancer vaccines, and the like. BRIEF DESCRIPTION OF THE DRAWINGS
[004] Figure 1 depicts the normal metabolic pathway of HIF-1α during normoxia.
[005] Figure 2 depicts the increase in neutrophil death of S. aureus (Newman strain) with 50 μM and 200 μM of a compound described in Table VIII versus control (DMSO) at 60 and 90 minutes.
[006] Figure 3 depicts the increase in human monocyte cell lineage (U937) against S. aureus (Newman strain) by 10 µM of a compound described in Table VIII versus untreated samples.
[007] Figure 4 depicts the mean percentage of bacteria surviving in treated versus untreated U937 cells after infection with S. aureus (Newman strain) after 1 hour of pretreatment (black) or 2 hours of pretreatment (dashed) with 10 µM of a compound described in Table VIII.
[008] Figure 5 depicts the mean percentage of bacteria surviving in treated versus untreated U937 cells after infection with two strains of S. aureus, Newman (black) or methicillin-resistant S. aureus (MRSA) (dashed), after 1 hour of pretreatment with 10 µM of a compound described in Table VIII.
[009] Figure 6 depicts the mean percentage of surviving bacteria in treated versus untreated U397 cells after infection with two strains of S. aureus, Newman (black) or MRSA (dashed) and treatment with 10 μM of a compound described in the Table VIII.
[0010] Figure 7 depicts the mean percentage of bacteria surviving in treated versus untreated U937 cells after infection with two strains of S. aureus, Newman (dashed bars) or MRSA (black bars), after treatment with 100 mM of mimosin (A), 10 µM of a compound described in Table VIII (B), or 2 mg/ml vancomycin (C) within 2 hours of infection.
[0011] Figure 8 depicts the mean percentage of bacteria surviving in treated versus untreated U937 cells after infection with S. aureus (Newman) after no pretreatment, 1 hour pretreatment, or 2 hours pretreatment with 10 µM of a compound described in Table VIII.
[0012] Figure 9 depicts the mean percentage of bacteria surviving in HaCaT cells treated versus untreated infected with two strains of S. aureus, Newman (dashed bars) or MRSA (black bars) and pretreated for 1 hour with DMSO ( control), 800 μM of mimosin, 10 μM of a compound described in Table VIII, or 1 μg/mL of vancomycin. Data shown are from 2 hours post-treatment.
[0013] Figure 10 depicts the mean percentage of bacteria surviving in treated versus untreated HaCaT cells
[0014] infected with two strains of S. aureus, Newman (dashed bars) or MRSA (black bars), after pretreatment with 10 µM of a compound described in Table VIII.
[0015] Figure 11 depicts the upregulation of phosphoglycerate kinase (PGK) expression in wild-type murine embryonic fibroblasts as a result of treatment with a compound described in Table VIII at dosages of 1 μM (E), 10 μM (F ) and 50 μM (G) versus wild-type control (H) and the lack of up-regulation of PGK expression in HIF-1 inactivating cells as a result of treatment with a compound described in Table VIII at 1 μM dosages (A), 10 μM (B), and 50 μM (C) and HIF-1 inactivation control (D). Both cell types were treated for 7 hours.
Figure 12 depicts up-regulation of phosphoglycerate kinase (PGK) expression in wild-type murine embryonic fibroblasts as a result of treatment with the compound 1-(3-chlorobenzyl)-3-hydroxypyridin-2(1H)- ona at dosages of 1 μM (E), 10 μM (F), versus wild-type control (G) and the lack of up-regulation of PGK expression in HIF-1 inactivating cells as a result of treatment with a compound described in Table VIII in dosages of 1 μM (A), 10 μM (B) and 50 μM (C) and HIF-1 inactivation control (D).
[0017] Figure 13 depicts the upregulation of phosphoglycerate kinase (PGK) expression in wild-type murine embryonic fibroblasts as a result of treatment with a compound described in Table VIII at dosages of 1 μM (E), 10 μM (F ) and 50 μM (G) versus wild-type control (H) and the lack of up-regulation of PGK expression in HIF-1 inactivating cells as a result of treatment with a compound described in Table VIII at 1 μM dosages (A), 10 μM (B) and 50 μM (C) and HIF-1 inactivation control (D).
[0018] Figure 14 depicts the upregulation of vascular endothelial growth factor (VEGF) expression in wild-type murine embryonic fibroblasts as a result of treatment with a compound described in Table VIII at dosages of 1 μM (E), 10 μM (F), and 50 μM (G) versus control (H) and the lack of up-regulation of VEGF expression in HIF-1 inactivating cells treated with a compound described in Table VIII at dosages of 1 μM (A ), 10 μM (B), and 50 μM (C) and HIF-1 inactivation control (D). Both cell types were treated for 7 hours.
[0019] Figure 15 depicts the results of Example 11, where 3 groups of animals are treated with the antibiotic-sensitive Newman strain of Staphylococcus aureus. The data show the significant reduction in the size of skin lesions (wounds) for Group 1 animals (solid circles (•)) treated with 10 µM of a compound described in Table VIII versus the animal that received a DMSO bolus (squares solids (■)). Figure 15 depicts mice infected with the Newman strain of S. aureus followed by treatment with 10 μM of a compound described in Table VIII or DMSO (control) within 2 hours of infection. The data show the statistically significant reduction in the size of skin lesions (wounds) for animals treated with a compound described in Table VIII (solid circles (•)) or DMSO (solid squares (■)).
[0020] Figure 16 also depicts the results of Example 11 showing the reduction in size of skin lesions (wounds) for Group 1 animals (solid circles (•)) treated with 10 µM of a compound described in Table VIII versus animals that are not treated (solid triangles (▲)). Figure 16 depicts mice infected with the Newman strain of S. aureus followed by treatment with 10 µM of a compound described in Table VIII or no treatment within 2 hours of infection. The data show the reduction in the size of skin lesions (wounds) for animals treated with a compound described in Table VIII (solid circles (•)) or untreated (solid triangles (▲)).
Figure 17 is a graphical histogram depicting the results of Example 12, where 3 groups of animals are treated with the antibiotic-sensitive Newman strain of Staphylococcus aureus [ATCC #25904]. The data show the results for the untreated group plotted in (A), the results for the DMSO treated group plotted in (B) and the results for the group treated with 10 μM of a compound described in Table VIII plotted in (C ).
[0022] Figure 18 also depicts the results of Example 12, in which the number of colony-forming units in the kidney is represented for the various groups: the untreated group is represented in (A), the DMSO treated group is represented in (B) and the group treated with 10 µM of a compound described in Table VIII is represented in (C).
[0023] Figure 19 depicts the results of Example 13, where 2 groups of animals are treated with Streptococcus pyogenes NZ131 [strain M49]. The data show the reduction in the size of skin lesions (wounds) for Group 1 animals (solid triangles (▲)) treated with 0.5 mg/kg of a compound described in Table VIII versus animal treated with control vehicle (cyclodextran ) (solid circles (•)).
[0024] Figure 20 is a graphical histogram that also depicts the results of Example 12, in which the number of colony-forming units for skin lesions observed in animals treated with control vehicle (cyclodextran) is represented in (A) and the results for the group treated with 0.5 mg/kg of a compound described in Table VIII are shown in (B). DETAILED DESCRIPTION
[0025] In this descriptive report and in the attached claims, reference will be made to several terms that will be defined by the following meanings:
[0026] Throughout this descriptive report, unless the context indicates otherwise, the word "understand", or variations such as "comprises" or "comprising" suggest the inclusion of a stated integer or step or group of numbers integer steps, but not the exclusion of any other integer or step or group of integers or steps.
[0027] It should be noted that, as used in the descriptive report and in the appended claims, the singular forms "a", "an" and "o", "a", include the plural references unless clearly indicated otherwise. Thus, for example, reference to "a vehicle" includes mixtures of two or more such vehicles, and the like.
[0028] “Optional” or “optionally” means that the event or circumstance subsequently described may or may not occur, and that the description includes cases where the event or circumstance does occur and cases where it does not.
[0029] By "pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable, that is, material that can be administered to an individual together with the relevant active compound without causing clinically unacceptable biological effects or interacting in a harmful way with any of the other components of the pharmaceutical composition in which it is contained. Ranges may be expressed herein as "approximately" a particular value and/or even "approximately" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, using the antecedent “approximately”, it must be understood that the particular value forms another aspect. It should also be understood that the extreme points of each band are significant both in relation to the other extreme point and independently of the other extreme point.
[0030] The percentage by weight of a component, unless specifically stated otherwise, is based on the total weight of the formulation or composition in which the component is included.
By "effective amount" as used herein, means "an amount of one or more of the described HIF-1α prolyl hydroxylase inhibitors, effective at dosages and for periods of time necessary to achieve the desired or therapeutic result". An effective amount may vary according to factors known in the art, such as disease state, age, sex and weight of the human or animal being treated. Although particular dosing regimens can be described in examples herein, those skilled in the art will appreciate that the dosing regimen can be altered to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be scaled down as indicated by the requirements of the therapeutic situation. Furthermore, the compositions of this invention can be administered with any frequency necessary to achieve a therapeutic amount.
[0032] "Mixture" or "Mixture" generally means a physical combination of two or more different components.
"Excipient" is used herein to include any other compound that may be contained in or combined with one or more of the described inhibitors that is not a therapeutically or biologically active compound. Thus, an excipient must be pharmaceutically or biologically acceptable or relevant (for example, an excipient must generally be non-toxic to the individual). "Excipient" includes a single such compound and can also include a plurality of excipients.
[0034] As used herein, by an "individual" means a human individual. Thus, the “individual” may include domesticated animals (eg cats, dogs, etc.), livestock (cattle, horses, pigs, sheep, goats, etc.), laboratory animals (eg mice, rabbits, rats , guinea pigs, etc.), and birds. "Individual" can also include a mammal, such as a primate or a human.
[0035] By "prevent" or other forms of the word, such as "preventing" or "prevention", means the interruption of a particular event or feature, to stabilize or delay the development or progression of a particular event or feature, or to minimize the chances that a particular event or feature will occur. Prevention does not require comparison with a control as it is usually more absolute than, say, a reduction. As used here, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It should be understood that when reduction or prevention is used, unless specifically stated otherwise, the use of another word is also expressly described.
[0036] By "reducing" or other forms of the word, such as "reducing" or "reducing", we mean the lessening of an event or characteristic (eg, vascular leakage). It should be understood that this is normally in relation to some standard or expected value, in other words it is relative, but it is not always necessary for the standard or expected value to be referred to.
The term "treat" or other forms of the word, such as "treated" or "treatment", is used herein to mean that administration of a compound of the present invention alleviates a disease or disorder in a host and/or reduces, inhibits or eliminates a particular feature or event associated with a disorder (eg, infection caused by a microorganism). Therefore, the term “treatment” includes preventing a disorder from occurring in a host, particularly when the host is predisposed to acquiring the disease but has not yet been diagnosed with the disease; inhibition of the disorder; and/or alleviating or reversing the disorder. Although the methods of the present invention are directed towards preventing disorders, it should be understood that the term "prevention" does not always require that the disease state be completely frustrated. Preferably, as used herein, the term "prevention" refers to the ability of a person skilled in the art to identify a population that is susceptible to acquiring disorders, so that administration of the compounds of the present invention can occur prior to the onset of a disease. The term does not imply that the disease state is completely avoided.
Ranges may be expressed here as "about" a particular value, and/or "about" another particular value. When such a range is expressed, another aspect includes from a particular value and/or to another particular value. Likewise, when values are expressed as approximations, using the background "about", it will be understood that the particular value forms another aspect. It will also be understood that the assessment criteria for each of the ranges are significant in relation to the other assessment criteria, and independently of the other assessment criteria. It is also understood that there are a number of values described here, and that each value is also described here as "about" that particular value, in addition to the value itself. For example, if the value "10" is described, then "about 10" is also described. It is also understood that when the value is described, then "less than or equal to" the value, "greater than or equal to the value", and possible ranges between values are also described, as properly understood by the person skilled in the art. For example, if the value "10" is described, then "less than or equal to 10" as well as "greater than or equal to 10" are also described. It is also understood that throughout the order data is provided in a number of different formats and that this data represents evaluation criteria and starting points and ranges for any combination of information points. For example, if a particular information point "10" and a particular information point "15" are described, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered described as well as between 10 and 15. It is also understood that each unit between two particular units is also described. For example, if 10 and 15 are described, then 11, 12, 13 and 14 are also described. By "antimicrobial" is meant the ability to treat or control (for example, reduce, prevent, inhibit, break down or eliminate) the growth or survival of microorganisms at any concentration. Likewise, the terms "antibacterial", "antiviral" and "antifungal", respectively, mean the ability to treat or control (eg, reduce, prevent, inhibit, break or eliminate) bacterial, viral and fungal growth or survival in any concentration.
[0039] The term “anion” is a type of ion and is included in the meaning of the term “ion”. An “anion” is any molecule, portion of a molecule (eg, zwitterion), grouping of molecules, molecular complex, portion, or atom that contains a net negative charge or is likely to contain a net negative charge. The term “anion precursor” is used here to refer specifically to a molecule that can be converted to an anion through a chemical reaction (eg, deprotonation).
[0040] The term “cation” is a type of ion and is included in the meaning of the term “ion”. A "cation" is any molecule, portion of a molecule (eg, zwitterion), grouping of molecules, molecular complex, portion, or atom that contains a net positive charge or is likely to contain a net positive charge. The term “cation precursor” is used here to refer specifically to a molecule that can be converted to a cation through a chemical reaction (eg, protonation or alkylation).
[0041] "Chemotherapeutic agent" is used herein to include any other pharmaceutically active compound that can be used in conjunction with the described HIF-1α prolyl hydroxylase inhibitors, for example, cytotoxic drugs such as 6-hydroxymethylacylfulvene, cyclophosphamide, dacarbazine, carmustine, doxorubicin and methotrexate. Other chemotherapeutic agents also include anti-inflammatory drugs, that is, non-steroidal anti-inflammatory compounds such as aspirin.
[0042] Unless otherwise noted, a formula with chemical bonds shown only as solid lines rather than triangles or dashed lines encompasses every possible isomer, for example, every enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture.
[0043] The transcription factor Hypoxia-Induced Factor 1 (HIF-1) is one of the crucial regulators of oxygen homeostasis. It regulates physiological responses to low oxygen levels (hypoxia) and the pathophysiology of heart attack, cancer, stroke, and chronic lung disease. HIF-1 is a heterodimeric protein that consists of two subunits: HIF-1α and HIF-1β. While HIF-1β is constitutively expressed, HIF-1α expression is induced by oxygen concentrations below 6%. HIF-1 heterodimers bind to the hypoxia response element (HRE), a consensus sequence 5-RCGTG-3. Several dozen HIF-1-regulated genes have been identified to date, including genes that encode proteins involved in angiogenesis, energy metabolism, erythropoiesis, cell proliferation and viability, vascular remodeling, and vasomotor responses. Therefore, modulation of HIF activation in cells is critical for preventing, controlling, curing or otherwise affecting a wide range of diseases, disease states and conditions.
Hypoxia-induced transcription factor 1-alpha (HIF-1α) plays a central role in cellular adaptation to reduced oxygen availability. Under hypoxic stress, activated HIF-1α seeks oxygen homeostasis not only maintaining intracellular energy production through the induction of angiogenesis and glycolysis, but also limiting energy consumption due to inhibition of cell proliferation and DNA repair. Generally, HIF-1α activates its target genes, inter alia, EPO, VEGF, and PGK1, through binding to the hypoxia response element in the gene promoter (Wang, GL et al., J Biol Chem ( 1993); 268: 21513-21518).
[0045] HIF-1α under normal healthy conditions, where cells have a sufficient supply of oxygen, is converted to a degraded form by one of several enzymes 4-prolyl hydroxylase, inter alia, EGLN1 (herein referred to as HIFPH2). As stated above, when cells undergo hypoxia, this enzymatic transformation is slow or completely stopped and HIF-1α begins to accumulate in the cell. When this accumulation of HIF-1α occurs, this protein combines with HIF-1β to form the active transcription factor HIF-1 complex. This transcription factor then activates several biological pathways that are present as a response and as a means of alleviating the body's hypoxic state. These responses include, inter alia, angiogenic, erythropoietic (EPO), glucose (PGK) metabolism, matrix alteration, and the increased capacity of phagocytes to respond to pathogens.
[0046] Figure 1 summarizes the metabolism of HIF-1α during normal healthy conditions. HIF α-subunits are unstable under normoxic conditions; cells continually synthesize and degrade these proteins. The short half-life of HIF-1α is the by-product of a family of O2- and iron-dependent prolyl hydroxylases (PH1-3), whose action directs the HIF α-subunits to degradation via the ubiquitin-proteasome pathway in an interaction-dependent process with the Hippel-Lindau tumor suppressor protein (vHL). In Figure 1, the PDH's represent the prolyl hydroxylases that act in the presence of an asparaginyl hydroxylase to hydroxylate prolines 402 and 564, as well as asparagines 804. From that point on, as the hydroxylated HIF-1α it is also prevented from associating with the p300-CBP because of other factors, ubiquitin ligase begins to metabolize hydroxylated HIF-1α via the vHL pathway.
[0047] In patients who need to stimulate this response, for example, in patients who need more oxygen in tissues due to peripheral vascular disease (PVD), inhibition of HIF-1 enzymes, eg, Egl nine homologs 1 (HIFPH2), will stimulate the body's own angiogenic response without the consequences of oxygen deficiency. Furthermore, in ischemic diseases, inter alia, coronary artery disease (CAD) and anemia, stimulation of angiogenic, erythropoietic and metabolic adaptation may offer therapeutic benefits. Upregulation of HIF-1α also provides a method of enhancing immunity, for example, by increasing the capacity of phagocytes.
[0048] There is, therefore, a need for methods of controlling the activity of HIF-1α that can be efficiently carried out by compounds that inhibit the 4-prolyl hydroxylase enzymes that degrade HIF-1α. Such inhibition of the 4-prolyl hydroxylase enzymes, inter alia, HIFPH2 (also referred to herein as EGLN1 or PHD2) and HIFPH3 (also referred to herein as EGLN3 or PHD-3) thereby provides a method of increasing the concentration of HIF-1α in cells and therefore provide methods of treating a variety of diseases or disease states.
Described herein are methods of treating one or more diseases, conditions, syndromes, and the like that are affected by the level of hypoxia-induced transcription factors. The regulation of these factors both during hypoxia and during normoxia can provide methods to rebalance or regulate one or more biological pathways associated with abnormal conditions, inter alia, invasion of the body by pathogens, inter alia, bacteria, fungi, viruses and parasites, regulation abnormal cell, ie, ischemia from cancers, and side effects caused by vaccinations. Search for HIF1 stabilization in cells
[0050] HIF-1α is targeted for destruction through prolyl hydroxylation, an oxygen-dependent modification that signals recognition by the ubiquitin ligase E3 complex that contains the Hippel-Lindau tumor suppressor (VHL). Three prolyl hydroxylases, previously referred to in the literature as EGLN1, EGLN2 and EGLN3 (also known as, have been identified in mammals, including EGLN1 (also known as HIFPH2 or PHD2), and EGLN3 (also known as HIFPH3 or PHD3 ) are hypoxia-induced in their mRNA levels in a HIF-1α-dependent manner. HIF-1α levels are controlled by these polyl-4-hydroxylases through the hydroxylation of proline residues of HIF-1α Pro-402 and Pro -564 in humans (Ivan, M. et al., (2001) "HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing." Science 292, 464-468; Jaakkola, P. et al., (2001) "Targeting of HIF-1α to the von Hippel-Lindau ubiquitylation complex by O2- regulated prolyl hydroxylation." Science 292, 468-472; and Masson, N. et al., (2001) "Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation.” EMBO J. 20, 5197-5206). hypoxic ions, the activity of EGLN1 and EGLN3 is suppressed.
[0051] Stimulated by an increase in the cellular concentration of HIF-1α is the production of Phosphoglycerate Kinase (PGK) and Vascular Endothelial Growth Factor (VEGF). It has been shown that VEGF stimulation induces the formation of functional neo-vessels in the mouse cornea and increased blood flow in a canine model of coronary artery disease. The HIF-1α prolyl hydroxylase inhibitors of the present invention provide increased expression of multiple hypoxia-inducible genes, including VEGF, GAPDH and erythropoietin (EPO). In addition, the HIF-1α prolyl hydroxylase inhibitors of the present invention provide an increase in accumulation of HIF-1α in the cytoplasm and nucleus. Transgenic mice that expressed a constitutively active HIF-1a in the skin had increased dermal vascularity and had a 13-fold increase in VEGF levels. wounds
[0052] Chronic wounds, which do not heal, are a major cause of prolonged morbidity in the aging human population. This is especially the case for bedridden or diabetic patients who develop severe skin ulcers that do not heal. In many of these cases, the delay in healing is the result of an inadequate blood supply as a result of continued pressure or vascular blockage. Poor capillary circulation, due to small arterial atherosclerosis or venous stasis, contributes to the lack of repair of damaged tissues. These tissues are often infected with microorganisms that proliferate unchecked by the body's innate defense systems that require well-vascularized tissues for effective elimination of pathogenic organisms. As a result, much of the therapeutic intervention focuses on restoring blood flow to ischemic tissues, thus allowing nutrients and immunological factors to access the wound site.
The present invention relates to methods of treating wounds and promoting wound healing in an individual comprising administering to an individual in need of treatment an effective amount of one or more of the compounds described.
[0054] The present invention relates to the use of one or more of the compounds described for use in the manufacture of a medicament for the treatment of wounds and the promotion of wound healing. Antimicrobian activity
The hypoxia-responsive transcription factor HIF-1α is essential for the regulation of inflammation in vivo. Thus, it was found (Peyssonnaux C. et al., “HIF-1α expression regulates the bactericidal capacity of phagocytes” J. Clinical Investigation 115(7), pp 1808-1815 (2005)) that bacterial infections induce HIF expression -1a in myeloid cells even under normoxic conditions, and that HIF-1a regulates the generation of crucial molecular effectors of immune defense including granular proteases, antimicrobial peptides, nitric oxide and TNF-α. Bacterial infection induces a subset of HIF-1a target genes specifically related to microbial killing, thereby demonstrating that HIF-1a has an essential role in innate immunity distinct from the hypoxic response. Therefore, the function of HIF-1a is critical for bactericidal activity on myeloid cells and for the host's ability to limit systemic spread of infection from an early tissue focus. The increased activity of the HIF-1α pathway through the elimination of vHL enhances the production in myeloid cells of defense factors and improves bactericidal activity. The described compounds induce the activity of HIF-1α and may also enhance bacterial killing and NO production in a way specific to HIF-1a. These findings provide methods for enhancing innate immune responses to microbial, eg bacterial, infections.
[0056] Without intending to limit the discussion to theory, the compounds described can increase the stabilization of the HIF-1 protein by acting directly or indirectly on one or more cellular processes that act to destabilize or metabolize cellular components that stabilize the presence of the protein of HIF-1, protect it from inhibition, or increase the activity of the protein. Alternatively, the compounds described can increase the activity of the HIF-1 protein by inhibiting or otherwise blocking the activity of compounds that inhibit the activity of the HIF-1 protein. Thus, described herein is a method of improving the treatment of microbial infections by administering a substance that increases the activity or level of at least one HIF-1 protein in an individual suffering from a microbial infection or in increased risk of microbial infection.
[0057] In one aspect, methods of modulating the activity of at least one HIF-1 protein are described herein. Thus, the described methods comprise contacting at least one HIF-1 protein or a protein that interacts with HIF-1 with one or more of the compounds described that modulate the activity of the HIF-1 protein, or effecting contact between the protein and the substance. In one modality, contact is made in vitro. In another modality, contact is made in vivo. In yet another modality, contact is made ex vivo.
[0058] In another aspect, described herein is a method of treating an individual infected or at risk of infection by a microbial agent comprising administering to an individual a therapeutically effective amount of one or more of the compounds described. In one embodiment, the compound increases the amount or activity of HIF-1. In another modality, the microbial agent is a pathogen. Pathogen-related iterations of this modality include bacteria, fungi, protozoa, viruses, yeasts, and the like. Another iteration of this aspect relates to a method of treating an individual infected or at risk of infection by a microbial agent comprising increasing the killing activity of microbial pathogens in the individual's immune cells.
[0059] One method of enhancing the stabilization of HIF-1 is to inhibit the activity of 4-prolyl hydroxylase enzymes that initiate cell disruption of HIF-1α, thereby preventing HIF-1α from combining with HIF-1β to form the HIF-1. Thus, described herein are methods for increasing the cellular response to disease states, such as infections, i.e., presence of a pathogen, such as a bacterium, a virus, a parasite, a yeast, a fungus, and the like by augmenting of phagocytosis. Also described herein are methods of treating cancer by enhancing the cellular immune response, for example, by stabilizing HIF-1, thereby enhancing the body's ability to reduce tumor size. Further described herein are methods of treating diseases in which an immune response can be stimulated by vaccination.
[0060] The following chemical hierarchy is used throughout the specification to describe and expose the scope of the present invention, and particularly to specifically indicate and claim the units comprising the compounds of the present invention; however, unless specifically defined otherwise, the terms used herein are the same as those skilled in the art. The term "hydrocarbyl" represents any unit based on carbon atom (organic molecule), said units optionally containing one or more organic functional groups, including inorganic atom comprising salts, inter alia, carboxylate salts, and quaternary ammonium salts. Within the broad meaning of the term "hydrocarbyl" are the classes "acyclic hydrocarbyl" and "cyclic hydrocarbyl", which terms are used to divide hydrocarbyl units into cyclic and non-cyclic classes.
[0061] With reference to the following definitions, "cyclic hydrocarbyl" units may comprise only ring carbon atoms (carbocyclic and aryl rings) or may comprise one or more ring heteroatoms (heterocyclic and heteroaryl). For “carbocyclic” rings, the smallest number of carbon atoms in a ring is 3 carbon atoms; cyclopropyl. For “aryl” rings, the smallest number of carbon atoms in a ring is 6 carbon atoms; phenyl. For "heterocyclic" rings, the smallest number of carbon atoms in a ring is 1 carbon atom; diazirinyl. Ethylene oxide comprises 2 carbon atoms and is a C2 heterocycle. For "heteroaryl" rings, the smallest number of carbon atoms in a ring is 1 carbon atom; 1,2,3,4-tetrazolyl. The following is a non-limiting description of the terms "acyclic hydrocarbyl" and "cyclic hydrocarbyl" as used herein. A.Substituted and unsubstituted acyclic hydrocarbyl:
[0062] For the purposes of the present invention, the term "substituted and unsubstituted acyclic hydrocarbon" encompasses three categories of units: 1) Linear or branched alkyl, non-limiting examples of which include methyl (C1), ethyl (C2), n- propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), iso-butyl (C4), tert-butyl (C4), and the like; substituted linear or branched alkyl, non-limiting examples of which include hydroxymethyl (C1), chloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), 1-chloroethyl (C2), 2-hydroxyethyl (C2), 1,2-difluoroethyl (C2), 3-carboxypropyl (C3), and the like. 2) Linear or branched alkenyl, non-limiting examples of which include ethenyl (C2), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2-methylethen-2-yl) (C3) , buten-4-yl (C4), and the like; linear or branched substituted alkenyl, non-limiting examples of which include 2-chloroethenyl (also 2-chlorovinyl) (C2), 4-hydroxybuten-1-yl (C4), 7-hydroxy-7-methyloct-4-en-2-yl ( C9), 7-hydroxy-7-methyloct-3,5-dien-2-yl (C9), and the like. 3) Linear or branched alkynyl, non-limiting examples of which include ethynyl (C2), prop-2-ynyl (also propargyl) (C3), propyn-1-yl (C3), and 2-methyl-hex-4-yn-1 -yl(C7); linear or branched substituted alkynyl, non-limiting examples of which include 5-hydroxy-5-methylhex-3-ynyl (C7), 6-hydroxy-6-methylhept-3-yn-2-yl (C8), 5-hydroxy-5 -ethylhept-3-ynyl (C9), and the like. B. Substituted and unsubstituted cyclic hydrocarbyl
[0063] For the purposes of the present invention, the term "substituted and unsubstituted cyclic hydrocarbyl" encompasses five categories of units: 1) The term "carbocyclic" is defined herein as "encompassing rings comprising from 3 to 20 carbon atoms, wherein the atoms composing such rings are limited to carbon atoms, and furthermore, each ring may be independently replaced by one or more moieties capable of replacing one or more hydrogen atoms”. The following are non-limiting examples of "substituted and unsubstituted carbocyclic rings" covering the following categories of units: i) Carbocyclic rings having a single substituted or unsubstituted hydrocarbon ring, which non-limiting examples include cyclopropyl (C3), 2 -methyl-cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), 2,3-dihydroxycyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclopentadienyl (C5), cyclohexyl (C6 ), cyclohexenyl (C6), cycloheptyl (C7), cyclooctanyl (C8), 2,5-dimethylcyclopentyl (C5), 3,5-dichlorocyclohexyl (C6), 4-hydroxycyclohexyl (C6), and 3,3,5-trimethylcyclohex -1-yl (C6). ii) Carbocyclic rings having two or more substituted or unsubstituted fused hydrocarbon rings, non-limiting examples of which include octahydropentalenyl (C8), octahydro-1H-indenyl (C9), 3a,4,5,6,7,7a-hexahydro -3H-inden-4-yl (C9), decalinyl (C10), decahydroazulenyl (C10). iii) Carbocyclic rings which are substituted or unsubstituted bicyclic hydrocarbon rings, non-limiting examples of which include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl [2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanil. 2) The term "aryl" is defined herein as "units which encompass at least one phenyl or naphthyl ring and in which there are no heteroaryl or heterocyclic rings fused to the phenyl or naphthyl ring, and furthermore each ring may independently be substituted by one or more moieties capable of replacing one or more hydrogen atoms”. The following are non-limiting examples of “substituted and unsubstituted aryl rings” covering the following categories of units: i) C6 or C10 substituted or unsubstituted aryl rings; substituted or unsubstituted phenyl and naphthyl rings, non-limiting examples of which include phenyl (C6), naphthylene-1-yl (C10), naphthylene-2-yl (C10), 4-fluorophenyl (C6), 2-hydroxyphenyl (C6 ), 3-methylphenyl (C6), 2-amino-4-fluorophenyl (C6), 2-(N,N-diethylamino)phenyl (C6), 2-cyanophenyl (C6), 2,6-di-tert-butylphenyl (C6), 3-methoxyphenyl (C6), 8-hydroxynaphthylene-2-yl (C10), 4,5-dimethoxynaphthylene-1-yl (C10), and 6-cyano-naphthylene-1-yl (C10). ii) C6 or C10 aryl rings fused with 1 or 2 saturated rings, non-limiting examples of which include bicyclo[4.2.0]octa-1,3,5-trienyl (C8), and indanyl (C9). 3) The terms "heterocyclic" and/or "heterocycle" are defined herein as "units comprising one or more rings having from 3 to 20 atoms, wherein at least one atom in at least one ring is a selected heteroatom from nitrogen (N), oxygen (O) or sulfur (S), or mixtures of N, O and S, and in which the ring comprising the heteroatom is also not an aromatic ring”. The following are non-limiting examples of "substituted and unsubstituted heterocyclic rings" covering the following categories of units: i) heterocyclic units that have a single ring that contains one or more heteroatoms, non-limiting examples of which include diazirinyl (C1), aziridinyl (C2), urazolyl (C2), azetidinyl (C3), pyrazolidinyl (C3), imidazolidinyl (C3), oxazolidinyl (C3), isoxazolinyl (C3), thiazolidinyl (C3), isothiazolinyl (C3), oxathiazolidinonyl (C3), oxazolidinonyl (C3), hydantoinyl (C3), tetrahydrofuranyl (C4), pyrrolidinyl (C4), morpholinyl (C4), piperazinyl (C4), piperidinyl (C4), dihydropyranyl (C5), tetrahydropyranyl (C5), piperidin-2-onyl ( valerolactam) (C5), 2,3,4,5-tetrahydro-1H-azepinyl (C6), 2,3-dihydro-1H-indole (C8), and 1,2,3,4-tetrahydro-quinoline (C9 ). ii) heterocyclic moieties having 2 or more rings, one of which is a heterocyclic ring, non-limiting examples of which include hexahydro-1H-pyrrolizinyl (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-tetrahydroquinolinyl (C9), and decahydro-1H-cycloocta[b ]pyrrolyl (C10). 4) The term "heteroaryl" is defined herein as "encompassing one or more rings comprising from 5 to 20 atoms, wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O) or sulfur (S), or mixtures of N, O and S, and in which at least one of the rings comprising a heteroatom is an aromatic ring”. The following are non-limiting examples of "substituted and unsubstituted heterocyclic rings" covering the following categories of units: i) Heteroaryl rings containing a single ring, which non-limiting examples 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 ), isothiazolyl (C3), furanyl (C4), thiopheneyl (C4), pyrimidinyl (C4), 2-phenylpyrimidinyl (C4), pyridinyl (C5), 3-methylpyridinyl (C5), and 4-dimethylaminopyridinyl (C5). ii) Heteroaryl rings which contain two or more fused rings, one of which is a heteroaryl ring, non-limiting examples of which include 7H-purinyl (C5), 9H-purinyl (C5), 6-amino-9H-purinyl (C5), 5H-pyrrolo[3,2-d]pyrimidinyl (C6), 7H-pyrrolo[2,3-d]pyrimidinyl (C6), pyrido[2,3-d]pyrimidinyl (C7), 2-phenylbenzo[d]thiazolyl (C7), 1H-indolyl (C8), 4,5,6,7-tetrahydro-1-H-indolyl (C8), quinoxalinyl (C8), 5-methylquinoxalinyl (C8), quinazolinyl (C8), quinolinyl (C9 ), 8-hydroxy-quinolinyl (C9), and isoquinolinyl (C9). 5) C1-C6 bonded cyclic hydrocarbyl units (be it carbocyclic units, C6 or C10 aryl units, heterocyclic units, or heteroaryl units) which are connected to another portion, unit or nucleus of the molecule via a C1-C6 alkylene unit. Non-limiting examples of tethered cyclic hydrocarbyl units include C1-(C6) benzyl having the formula:
where Ra is optionally one or more independently selected substitutions for hydrogen. Additional examples include other aryl moieties, inter alia, C6-(C6) (2-hydroxyphenyl)hexyl; naphthalen-2-ylmethyl C1-(C10), 4-fluorobenzyl C1-(C6), 2-(3-hydroxy-phenyl)ethyl C2-(C6), as well as substituted and unsubstituted C3-C10 alkylenecarbocyclic units, by example, cyclopropylmethyl C1-(C3), cyclopentylethyl C2-(C5), cyclohexylmethyl C1-(C6). Included in this category are substituted and unsubstituted C1-C10 alkylene-heteroaryl units, for example, a 2-picolyl C1-(C6) unit having the formula:
where Ra has the same definition given above. In addition, C1-C12 bonded cyclic hydrocarbyl units include C1-C10 alkyleneheterocyclic units and alkyleneheteroaryl units, non-limiting examples of which include C1-(C2) aziridinylmethyl and C1-(C3) oxazol-2-ylmethyl.
[0064] For the purposes of the present invention, carbocyclic rings are from C3 to C20; aryl rings are C6 or C10; heterocyclic rings are from C1 to C9; and heteroaryl rings are from C1 to C9.
[0065] For the purposes of the present invention, and to have congruence in the definition of the present invention, the fused ring units, as well as the spirocyclic rings, bicyclic rings, and the like, which comprise a single heteroatom, will be characterized and referred to herein as falling within the cyclic family corresponding to the ring containing the heteroatom, although those skilled in the art may have alternative characterizations. For example, 1,2,3,4-tetrahydroquinoline having the formula:
is, for the purposes of the present invention, considered to be a heterocyclic unit. A 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:
is, for the purposes of the present invention, considered to be a heteroaryl moiety. When a fused ring unit contains heteroatoms in both a saturated ring (heterocyclic ring) and an aryl ring (heteroaryl ring), the aryl ring will predominate and determine the type of category the ring belongs to here for the purposes of describing the invention. For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:
is, for the purposes of the present invention, considered to be a heteroaryl moiety.
[0066] The term “replaced” is used throughout this descriptive report. The term "substituted" is applied to units described herein as "substituted unit or moiety is a hydrocarbyl unit or moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined hereinafter" . Units, when replacing hydrogen atoms, are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a given time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety, or unit. For example, a substituted unit that requires a replacement of a single hydrogen atom includes halogen, hydroxyl, and the like. A two hydrogen atom substitution includes carbonyl, oximino, and the like. A replacement of two hydrogen atoms from adjacent carbon atoms includes epoxy, and the like. A substitution of three hydrogen atoms includes cyano, and the like. The term "substituted" is used throughout this specification to indicate that a hydrocarbyl moiety, inter alia, an aromatic ring, an alkyl chain, may have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as "substituted", any number of hydrogen atoms can be replaced. For example, 4-hydroxyphenyl is a "substituted aromatic carbocyclic ring (aryl ring)", (N,N-dimethyl-5-amino)octanyl is a "substituted linear C8 alkyl unit", 3-guanidinopropyl is a "C3 alkyl unit substituted linear", and 2-carboxypyridinyl is a "substituted heteroaryl moiety".
[0067] The following are non-limiting examples of units that can replace hydrogen atoms in a carbocyclic, aryl, heterocyclic or heteroaryl unit: i) C1-C12 linear, substituted or unsubstituted, C3-C12 branched, or C3-C12 alkyl cyclic,; for example, methyl (C1), cchloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), ethyl (C2), hydroxymethyl 1-chloroethyl (C2), 2-hydroxyethyl (C2), 1,2-difluoroethyl (C2 ), n-propyl (C3), iso-propyl (C3), 3-carboxypropyl (C3), cyclopropyl (C3), 2-methyl-cyclopropyl (C3), n-butyl (C4), sec-butyl (C4) , iso-butyl (C4), tert-butyl (C4), cyclobutyl (C4), 2,3-dihydroxycyclobutyl (C4), pentyl (C5), cyclopentyl (C5), hexyl (C6), cyclohexyl (C6), and similar; ii) substituted or unsubstituted linear C2-C12, branched C3-C12, or cyclic C3-C12 alkenyl; for example, ethenyl (C2), 2-chloroethenyl (also 2-chlorovinyl) (C2), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2-methylethen-2-yl) ( C3), buten-4-yl (C4), 4-hydroxybuten-1-yl (C4), cyclobutenyl (C4), cyclopentenyl (C5), cyclopentadienyl (C5), cyclohexenyl (C6), 7-hydroxy-7-methyloct -4-en-2-yl (C9), and 7-hydroxy-7-methyloct-3,5-dien-2-yl (C9), and the like; iii) substituted or unsubstituted linear C2-C12 or branched C3-C12 alkynyl; for example ethynyl (C2), prop-2-ynyl (also propargyl) (C3), propyn-1-yl (C3), 2-methylhex-4-yn-1-yl (C7); 5-hydroxy-5-methylhex-3-ynyl (C7), 6-hydroxy-6-methylhept-3-yn-2-yl (C8), 5-hydroxy-5-ethylhept-3-ynyl (C9), and similar; iv) C6 or C10 substituted or unsubstituted aryl; for example, phenyl, 2-chlorophenyl, 3-hydroxyphenyl, 4-nitrophenyl, 2-fluoro-4-methylphenyl, 3,5-dinitrophenyl, 8-hydroxynaphth-1-yl, 6-sulfonylnaphth-2-yl, and the like; v) C1-C9 substituted or unsubstituted heterocyclic; for example, as defined hereinafter; vi) C1-C9 substituted or unsubstituted heteroaryl; for example, as defined hereinafter; vii) halogens; for example, fluorine, chlorine, bromine, and iodine; viii) - [C(R23a)(R23b)]xOR10; R10 is selected from: a) -H; b) C1-C12 linear substituted or unsubstituted, C3-C12 branched, or C3-C12 cyclic alkyl; c) C6 or C10 substituted or unsubstituted aryl or alkylenearyl; d) C1-C9 substituted or unsubstituted heterocyclic; e) C1-C11 substituted or unsubstituted heteroaryl; ix) -[C(R23a)(R23b)]xN(R11a)(R11b); R11a and R11b are each independently selected from a) -H; b) -OR12; R12 is hydrogen or linear C1-C4 alkyl; c) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; d) C6 or C10 substituted or unsubstituted aryl; e) C1-C9 substituted or unsubstituted heterocyclic; f) C1-C11 substituted or unsubstituted heteroaryl; or g) R11a and R11b may together form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; x) - [C(R23a)(R23b)]xC(O)R13; R13 is: a) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; b) -OR14; R14is hydrogen, substituted or unsubstituted linear C1-C4 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; c) -N(R15a)(R15b); R15a and R15b are each independently hydrogen, substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R15a and R15b may together form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; xi) -[C(R23a)(R23b)]xOC(O)R16; R16 is: a) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; b) -N(R17a)(R17b); R17a and R17b are each independently hydrogen, linear substituted or unsubstituted C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R17a and R17b may together form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; xii) - [C(R23a)(R23b)]xNR18C(O)R19; R18 is: a) -H; or b) substituted or unsubstituted linear C1-C4, branched C3-C4, or cyclic C3-C4 alkyl; R19 is: a) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl,; b) -N(R20a)(R20b); R20a and R20b are each independently hydrogen, substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R20a and R20b may together form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; xiii) — [C(R23a)(R23b)]xCN; xiv) — [C(R23a)(R23b)]xNO02; xv) — [C(R23a)(R23b)]xR21; R21 is a linear C1-C10, branched C3-C10, or cyclic C3-C10 alkyl, substituted by 1 to 21 halogen atoms selected from -F, -Cl, -Br or -I; xvi) - [C(R23a)(R23b)]xSO2R22; R22is hydrogen, hydroxyl, substituted or unsubstituted linear C1-C4 or C3-C4 branched alkyl, substituted or unsubstituted C6, C10 or C14 aryl; C7-C15 alkylenearyl; substituted or unsubstituted C1-C9 heterocyclic; or substituted or unsubstituted C1-C11 heteroaryl; R23a and R23b are each independently hydrogen or C1-C4 alkyl; and the index x is an integer from 0 to 5.
The compounds described herein include all salt forms, e.g. salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, carboxylic acids. The following 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. The following are non-limiting examples of cations that can form salts of acidic groups: sodium, lithium, potassium, calcium, magnesium, bismuth, and the like.
[0069] For purposes of the present invention, the terms "compound", "analog" and "composition of matter" are synonymous and include all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms "compound", " analogue”, and “composition of matter”. HIF-1α prolyl hydroxylase inhibitors
[0070] The compounds described have the following formulas:
wherein L is selected from CH2 or SO2, thereby providing N-substituted benzyl or N-substituted sulfonylaryl-3-hydroxypyridin-2-(1H)-ones. Y, R1 and R2 are further defined hereinafter.
Described herein are N-substituted benzyl and N-substituted sulfonylaryl-4-aminomethylene-3-hydroxypyridin-2-(1H)-ones which are HIF-1α prolyl hydroxylase inhibitors having the formula:
where R1 and R2 are defined hereinafter. Alkyl piperazine-1-carboxylates
[0072] One category of these compounds refers to linear or branched C1-C4 alkyl 4-{[(1-N-(chloro- or fluoro-substituted)-benzyl]-3-hydroxy-2-oxo-1,2- dihydropyridin-4-yl)methyl}piperazine-1-carboxylates having the formula:
wherein Z is a phenyl group which is substituted with 1 to 5 halogen atoms which are selected from chlorine and fluorine, and R1 and R2 together form a piperazine ring which is substituted with an alkylcarboxy moiety, wherein R4 is selected to from linear C1-C4 or branched C3-C4 alkyl, eg tert butyl 4{[1-(4chlorobenzyl)-3-hydroxy-2-oxo1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate having the formula:

[0073] One aspect of R4 units refers to compounds wherein R4 is tert-butyl (C4). Another aspect of R4 units relates to compounds where R4 is methyl (C1). A further aspect of R4 units relates to compounds where R4 is ethyl (C2). Yet another aspect of R4 units relates to compounds wherein R4 is n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), and iso-butyl (C4) . R4 is not hydrogen; therefore, a carboxylate moiety having the formula: -CO2H is expressly excluded from this category, but may be included in other categories as described hereinafter.
[0074] Z is phenyl substituted with 1 to 5 halogens selected from fluorine and chlorine. One aspect of Z units relates to compounds where Z is 4-chlorophenyl. Another aspect of Z units pertains to compounds where Z is selected from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl. Another aspect of Z units relates to compounds, wherein Z is selected from 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, and 2,6-dichlorophenyl.
[0075] The following are non-limiting examples of compounds according to that category: methyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl} -piperazine-1-carboxylate having the formula:
methyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
methyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
ethyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
ethyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
ethyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
tert-butyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
tert-butyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
methyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
methyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
methyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
ethyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
ethyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
ethyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
tert-butyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
tert-butyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate having the formula:
tert-butyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate having the formula:

[0076] Another category of compounds refers to N-unsubstituted-benzyl-4-aminomethyl-3-hydroxypyridin-2-(1H)-ones, where Z is an unsubstituted phenyl group, having the formula:
wherein R1 and R2 together form a substituted or unsubstituted heteroaryl or heterocyclic ring.
[0077] A first aspect of this category concerns compounds having the formula:
wherein R1 and R2 together form a substituted or unsubstituted heteroaryl or heterocyclic ring represented by ring A having from 2 to 20 carbon atoms and from 1 to 7 heteroatoms, and R200 represents from 0 to 40 substitutions from hydrogen. The index w is an integer from 0 to 40. Non-limiting examples of rings include diazirinyl (C1), 1,2,3,4-tetrazolyl (C1), aziridinyl (C2), urazolyl (C2), [1,2 ,3]triazolyl (C2), [1,2,4]triazolyl (C2), azetidinyl (C3), pyrazolidinyl (C3), imidazolidinyl (C3), oxazolidinyl (C3), isoxazolinyl (C3), isoxazolyl (C3), thiazolidinyl (C3), isothiazolyl (C3), isothiazolinyl (C3), oxathiazolidinonyl (C3), oxazolidinonyl (C3), hydantoinyl (C3), 1H-imidazolyl (C3), pyrrolidinyl (C4), morpholinyl (C4), piperazinyl (C4 ), piperidinyl (C4), piperidin-2-onyl (valerolactam) (C5), 7H-purinyl (C5), 9H-purinyl (C5), 6-amino-9H-purinyl (C5), 2,3,4, 5-tetrahydro-1H-azepinyl (C6), 5H-pyrrolo[3,2-d]pyrimidinyl (C6), 7H-pyrrolo[2,3-d]pyrimidinyl (C6), and 1,2,3,4- tetrahydroquinoline (C9).
[0078] Each R200 unit is independently selected from: i) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; for example, methyl (C1), (C1), chloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), ethyl (C2), hydroxymethyl 1-chloroethyl (C2), 2-hydroxyethyl (C2), 1,2 -difluoroethyl (C2), n-propyl (C3), iso-propyl (C3), 3-carboxypropyl (C3), cyclopropyl (C3), 2-methyl-cyclopropyl (C3), n-butyl (C4), sec- butyl (C4), iso-butyl (C4), tert-butyl (C4), cyclobutyl (C4), 2,3-dihydroxycyclobutyl (C4), pentyl (C5), cyclopentyl (C5), hexyl (C6), and cyclohexyl (C6), and the like; ii) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkenyl; for example, ethenyl (C2), 2-chloroethenyl (also 2-chlorovinyl) (C2), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2-methylethen-2-yl) ( C3), buten-4-yl (C4), 4-hydroxybuten-1-yl (C4), cyclobutenyl (C4), cyclopentenyl (C5), cyclopentadienyl (C5), cyclohexenyl (C6), 7-hydroxy-7-methyloct -4-en-2-yl (C9), and 7-hydroxy-7-methyloct-3,5-dien-2-yl (C9), and the like; iii) C1-C12 linear substituted or unsubstituted, C3-C12 branched alkynyl; for example ethynyl (C2), prop-2-ynyl (also propargyl) (C3), propyn-1-yl (C3), 2-methylhex-4-yn-1-yl (C7); 5-hydroxy-5-methylhex-3-ynyl (C7), 6-hydroxy-6-methylhept-3-yn-2-yl (C8), 5-hydroxy-5-ethylhept-3-ynyl (C9), like similar; iv) C6 or C10 substituted or unsubstituted aryl; for example, phenyl (C6), naphthylene-1-yl (C10), naphthylene-2-yl (C10), 4-fluorophenyl (C6), 2-hydroxyphenyl (C6), 3-methylphenyl (C6), 2-amino -4-fluorophenyl (C6), 2-(N,N-diethylamino)phenyl (C6), 2-cyanophenyl (C6), 2,6-di-tert-butylphenyl (C6), 3-methoxyphenyl (C6), 8 -hydroxynaphthylene-2-yl (C10), 4,5-dimethoxynaphthylene-1-yl (C10), 6-cyano-naphthylene-1-yl (C10), like the like; v) C1-C9 substituted or unsubstituted heterocyclic; for example, diazirinyl (C1), aziridinyl (C2), urazolyl (C2), azetidinyl (C3), pyrazolidinyl (C3), imidazolidinyl (C3), oxazolidinyl (C3), isoxazolinyl (C3), isoxazolyl (C3), thiazolidinyl ( C3), isothiazolyl (C3), isothiazolinyl (C3), oxathiazolidinonyl (C3), oxazolidinonyl (C3), hydantoinyl (C3), tetrahydrofuranyl (C4), pyrrolidinyl (C4), morpholinyl (C4), piperazinyl (C4), piperidinyl ( C4), dihydropyranyl (C5), tetrahydropyranyl (C5), piperidin-2-onyl (valerolactam) (C5), and the like; vi) C1-C11 substituted or unsubstituted heteroaryl; for example, 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), furanyl (C4), thiopheneyl (C4), pyrimidinyl (C4), pyridinyl (C5), and the like; vii) halogen; for example, -F, -Cl, -Br, or -I; viii) - [C(R37a)(R37b)]yOR24; viii) is selected from: a) -H; b) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; c) C6 or C10 substituted or unsubstituted aryl or C7 or C10 alkylenearyl; for example, phenyl or benzyl; d) C1-C9 substituted or unsubstituted heterocyclic; e) C1-C11 substituted or unsubstituted heteroaryl; for example, -OH, -CH2OH, -OCH3, -CH2OCH3, -OCH2CH3, -CH2OCH2CH3, -OCH2CH2CH3, and -CH2OCH2CH2CH3; ix)-[C(R37a)(R37b)]yN(R25a)(R25b); R25a and R25b are each independently selected from: a) -H; b) -OR26; R26is hydrogen or linear C1-C4 alkyl; c) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; d) C6 or C10 substituted or unsubstituted aryl; e) C1-C9 substituted or unsubstituted heterocyclic; f) C1-C11 substituted or unsubstituted heteroaryl; or g) R25a and R25b together form a substituted or unsubstituted ring having 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(R37a)(R37b)]yC(O)R27; R27 is: a) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; b) -OR28; R28 is hydrogen, substituted or unsubstituted C1-C4 linear alkyl, substituted or unsubstituted C6 or C10 aryl, substituted or unsubstituted C1-C9 heterocyclic, substituted or unsubstituted C1-C11 heteroaryl; c) -N(R29a)(R29b); R29a and R29b are each independently hydrogen, substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R29a and R29b together form a substituted or unsubstituted ring having 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, -CH2COCH2CH2CH3, and the like; xi) -[C(R37a)(R37b)]yOC(O)R30; R30 is: a) C1-C12 linear substituted or unsubstituted, branched or cyclic alkyl; b) -N(R31a)(R31b); R31a and R31b are each independently hydrogen, substituted or unsubstituted linear C1-C12, branched C3C12, or cyclic C3-C12 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R31a and R31b together form a substituted or unsubstituted ring having 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)2, and the like; xii) -[C(R37a)(R37b)]yNR32C(O)R33;R32 is: a) -H; or b) substituted or unsubstituted linear C1-C4, branched C3-C4, or cyclic C3-C4 alkyl; R33 is: a) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; b) -N(R34a)(R34b); R34a and R34b are each independently hydrogen, substituted or unsubstituted linear C1-C12, branched C3C12, or cyclic C3-C12 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; substituted or unsubstituted C1-C11 heteroaryl; or R34a and R34b together form a substituted or unsubstituted ring having 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)2, and the like; xiii) - [C(R37a)(R37b)]yCN; for example; -CN, -CH2CN, and -CH2CH2CN; xiv) -[C(R37a)(R37b)]yNO2; for example; -NO2, -CH2NO2, and -CH2CH2NO2; xv) -[C(R37a)(R37b)]yR35; for example, -CH2F, -CHF2, -CF3, -CCl3, or -CBr3; R35 is linear C1-C10, branched C3-C10, or substituted cyclic C3-C10 alkyl of 1 to 21 halogen atoms selected from -F, -Cl, -Br, or -I; xvi) -[C(R37a)(R37b)]ySO2R36; R36is hydrogen, hydroxyl, substituted or unsubstituted linear C1-C4 or substituted or unsubstituted C3-C4 branched alkyl, C6, C10, or C14 aryl; C7-C15 alkylenearyl; substituted or unsubstituted C1-C9 heterocyclic; or substituted or unsubstituted C1-C11 heteroaryl; for example, -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; and xv) two hydrogen atoms in a carbon atom ring may be substituted to form a unit of =O, =S, or =NH; R37a and R37b are each independently hydrogen or C1-C4 alkyl; and index y is an integer from 0 to 5.
[0079] A first embodiment of this aspect relates to compounds, wherein R1 and R2 together form a five-membered substituted or unsubstituted C1-C4 heterocyclic or a substituted or unsubstituted C1-C4 heteroaryl ring, non-limiting examples of which include a ring selected from:


[0080] A first iteration of this modality refers to HIF-1α prolyl hydroxylase inhibitors having the formula:
R200 represents from 0 to 2 substitutions for a hydrogen ring, where the substitutions for the hydrogen are independently selected from: i) linear C1-C4 or branched C3-C4 alkyl; ii) C1-C4 linear or C3-C4 branched alkoxy; iii) hydroxyl; iv) cyano; v) nitro; vi) amino, methylamino, or dimethylamino; vii) carboxy, methyl carboxy; or ethyl carboxy; viii) formyl, acetyl, or propionyl; ix) starch, methyl starch, or dimethyl starch; x) halogen; xi) heterocyclic; or xii) heteroaryl.
[0081] Non-limiting examples of this iteration include HIF-1α prolyl hydroxylase inhibitors having the formula:

[0082] Another iteration of this embodiment relates to HIF-1α prolyl hydroxylase inhibitors, wherein R1 and R2 together form a heterocyclic or substituted heteroaryl ring members with more than one heteroatom in the ring. Examples not

[0083] Another modality of this aspect relates to HIF-1α prolyl hydroxylase inhibitors, in which R1 and R2 form from


[0084] Non-limiting examples of this modality


[0085] Another category of compounds has the formula:
where R200 and the index w are the same as defined above. R represents from 0 to 5 substitutions for hydrogen, where each R is independently selected from: i) C1-C12 linear substituted or unsubstituted, branched, or cyclic alkyl; for example, methyl (C1), chloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), ethyl (C2), hydroxymethyl 1-chloroethyl (C2), 2-hydroxyethyl (C2), 1,2-difluoroethyl (C2 ), n-propyl (C3), iso-propyl (C3), 3-carboxypropyl (C3), cyclopropyl (C3), 2-methyl-cyclopropyl (C3), n-butyl (C4), sec-butyl (C4) , iso-butyl (C4), tert-butyl (C4), cyclobutyl (C4), 2,3-dihydroxycyclobutyl (C4), pentyl (C5), cyclopentyl (C5), hexyl (C6), and cyclohexyl (C6), and the like; ii) C2-C12 linear substituted or unsubstituted, branched, or cyclic alkenyl; for example, ethenyl (C2), 2-chloroethenyl (also 2-chlorovinyl) (C2), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2-methylethen-2-yl) (C3), buten-4-yl (C4), 4-hydroxybuten-1-yl (C4), cyclobutenyl (C4), cyclopentenyl (C5), cyclopentadienyl (C5), cyclohexenyl (C6), 7-hydroxy-7- methyloct-4-en-2-yl (C9), and 7-hydroxy-7-methyloct-3,5-dien-2-yl (C9), and the like; iii) substituted or unsubstituted C2-C12 linear or branched alkynyl; for example ethynyl (C2), prop-2-ynyl (also propargyl) (C3), propyn-1-yl (C3), 2-methylhex-4-yn-1-yl (C7); 5-hydroxy-5-methylhex-3-ynyl (C7), 6-hydroxy-6-methylhept-3-yn-2-yl (C8), 5-hydroxy-5-ethylhept-3-ynyl (C9), and similar; iv) C6 or C10 substituted or unsubstituted aryl; for example, phenyl (C6), naphthylene-1-yl (C10), naphthylene-2-yl (C10), 4-fluorophenyl (C6), 2-hydroxyphenyl (C6), 3-methylphenyl (C6), 2-amino -4-fluorophenyl (C6), 2-(N,N-diethylamino)phenyl (C6), 2-cyanophenyl (C6), 2,6-di-tert-butylphenyl (C6), 3-methoxyphenyl (C6), 8 -hydroxynaphthylene-2-yl (C10), 4,5-dimethoxynaphthylene-1-yl (C10), 6-cyano-naphthylene-1-yl (C10), and the like; v) C1-C9 substituted or unsubstituted heterocyclic; for example, diazirinyl (C1), aziridinyl (C2), urazolyl (C2), azetidinyl (C3), pyrazolidinyl (C3), imidazolidinyl (C3), oxazolidinyl (C3), isoxazolinyl (C3), isoxazolyl (C3), thiazolidinyl ( C3), isothiazolyl (C3), isothiazolinyl (C3), oxathiazolidinonyl (C3), oxazolidinonyl (C3), hydantoinyl (C3), tetrahydrofuranyl (C4), pyrrolidinyl (C4), morpholinyl (C4), piperazinyl (C4), piperidinyl ( C4), dihydropyranyl (C5), tetrahydropyranyl (C5), piperidin-2-onyl (valerolactam) (C5), and the like; vi) C1-C11 substituted or unsubstituted heteroaryl; for example, 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), furanyl (C4), thiopheneyl (C4), pyrimidinyl (C4), pyridinyl (C5), and the like; vii) halogen; for example, -F, -Cl, -Br, or -I; viii) - [C(R23a)(R23b)]xOR10; R10 is selected from: a) -H; b) C1-C12 linear substituted or unsubstituted, branched, or cyclic alkyl;; c) C6 or C10 substituted or unsubstituted aryl or alkylenearyl; d) C1-C9 substituted or unsubstituted heterocyclic; e) C1-C11 substituted or unsubstituted heteroaryl; for example, -OH, -CH2OH, -OCH3, -CH2OCH3, -OCH2CH3, CH2OCH2CH3, -OCH2CH2CH3, and -CH2OCH2CH2CH3; ix) - [C(R23a)(R23b)]xN(R11a)(R11b); R11a and R11b are each independently selected from a) -H; b) -OR12; R12 is hydrogen or linear C1-C4 alkyl; c) C1-C12 linear substituted or unsubstituted, branched or cyclic alkyl;; d) C6 or C10 substituted or unsubstituted aryl; e) C1-C9 substituted or unsubstituted heterocyclic; f) C1-C11 substituted or unsubstituted heteroaryl; or g) R11a and R11b may together form a substituted or unsubstituted ring having 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(R23a)(R23b)]xC(O)R13; R13 is: a) C1-C12 linear substituted or unsubstituted, branched or cyclic alkyl;,; b) -OR14; R14is hydrogen, substituted or unsubstituted linear C1-C4 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; c) -N(R15a)(R15b); R15a and R15b are each independently hydrogen, C1-C12 linear substituted or unsubstituted, branched or cyclic alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R15a and R15b together form a substituted or unsubstituted ring having 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, -CH2COCH2CH2CH3, and the like xi) — [C(R23a)(R23b)]xOC(O)R16; R16 is: a) C1-C12 linear substituted or unsubstituted, branched or cyclic alkyl;; b) -N(R17a)(R17b); R17a and R17b are each independently hydrogen, C1-C12 linear substituted or unsubstituted, branched, or cyclic alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R17a and R17b together form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; xii) - [C(R23a)(R23b)]xNR18C(O)R19; R18 is: a) -H; or b) substituted or unsubstituted linear C 1 -C 4 , branched or cyclic alkyl; R 19 is: a) substituted or unsubstituted linear C 1 -C 12 , branched or cyclic alkyl; b) -N(R20a)(R20b); R20a and R20b are each independently hydrogen, substituted or unsubstituted linear C1-C12, branched, or cyclic alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R20a and R20b together form a substituted or unsubstituted ring having 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)2, and the like; xiii) -[C(R23a)(R23b)]xCN; for example; -CN, -CH2CN, and -CH2CH2CN; xiv) -[C(R23a)(R23b)]xNO2; for example; -NO2, -CH2NO2, and -CH2CH2NO2; xv) -[C(R23a)(R23b)]xR21; for example, -CH2F, -CHF2, -CF3, -CCl3, or -CBr3; R21 is C1-C10 linear, branched or cyclic alkyl substituted by 1 to 21 halogen atoms selected from -F, -Cl, -Br or -I; xvi) -[C(R23a)(R23b)]xSO2R22; R22 is hydrogen, hydroxyl, substituted or unsubstituted C1-C4 linear or branched alkyl, substituted or unsubstituted C6, C10 or C14 aryl; C7-C15 alkylenearyl; substituted or unsubstituted C1-C9 heterocyclic; or substituted or unsubstituted C1-C11 heteroaryl; for example, -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; R23a and R23b are each independently hydrogen or C1-C4 alkyl; and the index x is an integer from 0 to 5.
[0086] Non-limiting examples of this category include compounds having the formula:

[0087] Another category of compounds refers to unsubstituted N-benzyl-4-aminomethyl-3-hydroxypyridin-2-(1H)-ones having the formula:
wherein R1 and R2 are each independently selected from i) hydrogen; ii) C1-C10 linear substituted or unsubstituted, branched, or cyclic alkyl; iii) C2-C10 linear substituted or unsubstituted branched, or cyclic alkenyl; iv) substituted or unsubstituted C2-C10 linear or branched alkynyl; v) C6 or C10 substituted or unsubstituted aryl; vi) C1-C9 substituted or unsubstituted heterocyclic; or vii) C1-C9 substituted or unsubstituted heteroaryl.
[0088] The first aspect of this category relates to HIF-1α prolyl hydroxylase inhibitors, where R2 is hydrogen and R1 is C1-C9 substituted or unsubstituted heterocyclic or or C1-C9 heteroaryl. In a first embodiment, R1 is a substituted heterocyclic group, non-limiting examples of which include aziridinyl (C2), azetidinyl (C3), pyrrolidinyl (C4), morpholinyl (C4), piperazinyl (C4), piperidinyl (C4), piperidin-2 -onyl (valerolactam) (C5), and azepan-2-onyl (caprolactam) (C6), in which the R1 moiety can be attached to the nitrogen atom at any position on the ring. Furthermore, the C1-C9 heterocyclic or C1-C9 heteroaryl ring can be substituted at any position if a carbon ring or a heteroatom ring, for example, a nitrogen ring. Non-limiting examples of this modality include:

[0089] In another embodiment, R2 is hydrogen and R1 is substituted or unsubstituted C3 C12 cycloalkyl, wherein the cycloalkyl ring may be substituted at any position on the ring. Non-limiting examples of this modality include:

[0090] Yet another category of compounds refers to unsubstituted N-benzyl-4-aminomethyl-3-hydroxypyridin-2-(1H)-ones having the formula:
R1 and R2 are each independently substituted or unsubstituted hydrogen, linear or branched C1-C10 alkyl, wherein the alkyl unit may be substituted by one or more units independently selected from: i) C1-C8 linear, branched , or cyclic alkoxy; ii) hydroxy; iii) halogen; iv) cyano; v) amino, C1-C8 mono-alkylamino, C1-C8 di-alkylamino; vi) -SR40; R40is hydrogen or linear or branched C1-C4 alkyl; vii) C6 of C10 substituted or unsubstituted aryl; viii) C1-C9 substituted or unsubstituted heterocyclic; or ix) substituted or unsubstituted C1-C9 heteroaryl.
[0091] Non-limiting examples of this category include:

[0092] Another category of the compounds described has the formula:
where R200 and the index w are the same as defined here above. R represents from 0 to 5 substitutions for hydrogen, where each R is independently selected from: i) substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; for example, methyl (C1), C1), chloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), ethyl (C2), hydroxymethyl 1-chloroethyl (C2), 2-hydroxyethyl (C2), 1,2- difluoroethyl (C2), n-propyl (C3), iso-propyl (C3), 3-carboxypropyl (C3), cyclopropyl (C3), 2-methyl-cyclopropyl (C3), n-butyl (C4), sec-butyl (C4), iso-butyl (C4), tert-butyl (C4), cyclobutyl (C4), 2,3-dihydroxycyclobutyl (C4), pentyl (C5), cyclopentyl (C5), hexyl (C6), and cyclohexyl ( C6), and the like; ii) substituted or unsubstituted linear C2-C12, branched C3-C12, or cyclic alkenyl C3-C12; for example ethenyl (C2), 2-chloroethenyl (also 2-chlorovinyl) (C2), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2-methylethen-2- il) (C3), buten-4-yl (C4), 4-hydroxybuten-1-yl (C4), cyclobutenyl (C4), cyclopentenyl (C5), cyclopentadienyl (C5), cyclohexenyl (C6), 7-hydroxy- 7-methyloct-4-en-2-yl (C9), and 7-hydroxy-7-methyloct-3,5-dien-2-yl (C9), and the like; iii) substituted or unsubstituted linear C2-C12 or branched C3-C12 alkynyl; for example ethynyl (C2), prop-2-ynyl (also propargyl) (C3), propyn-1-yl (C3), 2-methylhex-4-yn-1-yl (C7); 5-hydroxy-5-methylhex-3-ynyl (C7), 6-hydroxy-6-methylhept-3-yn-2-yl (C8), 5-hydroxy-5-ethylhept-3-ynyl (C9), and similar; iv) C6 or C10 substituted or unsubstituted aryl; for example, phenyl (C6), naphthylene-1-yl (C10), naphthylene-2-yl (C10), 4-fluorophenyl (C6), 2-hydroxyphenyl (C6), 3-methylphenyl (C6), 2-amino -4-fluorophenyl (C6), 2-(N,N-diethylamino)phenyl (C6), 2-cyanophenyl (C6), 2,6-di-tert-butylphenyl (C6), 3-methoxyphenyl (C6), 8 -hydroxynaphthylene-2-yl (C10), 4,5-dimethoxynaphthylene-1-yl (C10), 6-cyano-naphthylene-1-yl (C10), and the like; v) C1-C9 substituted or unsubstituted heterocyclic; for example, diaziridinyl (C1), aziridinyl (C2), urazolyl (C2), azetidinyl (C3), pyrazolidinyl (C3), imidazolidinyl (C3), oxazolidinyl (C3), isoxazolinyl (C3), isoxazolyl (C3), thiazolidinyl ( C3), isothiazolyl (C3), isothiazolinyl (C3), oxathiazolidinonyl (C3), oxazolidinonyl (C3), hydantoinyl (C3), tetrahydrofuranyl (C4), pyrrolidinyl (C4), morpholinyl (C4), piperazinyl (C4), piperidinyl ( C4), dihydropyranyl (C5), tetrahydropyranyl (C5), piperidin-2-onyl (valerolactam) (C5), and the like; vi) C1-C11 substituted or unsubstituted heteroaryl; for example, 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), furanyl (C4), thiopheneyl (C4), pyrimidinyl (C4), pyridinyl (C5), and the like. vii) halogen; for example, -F, -Cl, -Br, or -I; viii) - [C(R23a)(R23b)]xOR10; R10 is selected from: a) -H; b) substituted or unsubstituted linear C1-C12, branched C3-C12 or cyclic C3-C12 alkyl; c) C6 or C10 aryl or substituted or unsubstituted C7 or C10 alkylenearyl; d) C1-C9 substituted or unsubstituted heterocyclic; e) C1-C11 substituted or unsubstituted heteroaryl; for example, -OH, -CH2OH, -OCH3, -CH2OCH3, -OCH2CH3, -CH2OCH2CH3, -OCH2CH2CH3, and -CH2OCH2CH2CH3; ix) -[C(R23a)(R23b)]xN(R11a)(R11b); R11a and R11b are each independently selected from a) -H; b) -OR12; R12 is hydrogen or linear C1-C4 alkyl; c) substituted or unsubstituted linear C1-C12, branched C3-C12 or cyclic C3-C12 alkyl; d) C6 or C10 substituted or unsubstituted aryl; e) C1-C9 substituted or unsubstituted heterocyclic; f) C1-C11 substituted or unsubstituted heteroaryl; or g) R11a and R11b together form a substituted or unsubstituted ring having 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(R23a)(R23b)]xC(O)R13; R13 is: a) substituted or unsubstituted linear C1-C12, branched C3-C12 or cyclic C3-C12 alkyl; b) -OR14; R14is hydrogen, substituted or unsubstituted linear C1-C4 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; c) -N(R15a)(R15b); R15a and R15b are each independently hydrogen, substituted or unsubstituted linear C1-C12, branched C3-C12, or cyclic C3-C12 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R15a and R15b together form a substituted or unsubstituted ring having 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, -CH2COCH2CH2CH3, and the like; xi) -[C(R23a)(R23b)]xOC(O)R16; R16 is: a) substituted or unsubstituted linear C1-C12, branched C3-C12 or cyclic C3-C12 alkyl; b) -N(R17a)(R17b); R17a and R17b are each independently hydrogen, substituted or unsubstituted linear C1-C12, branched C3-C12 or cyclic C3-C12 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R17a and R17b may together form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; xii) - [C(R23a)(R23b)]xNR18C(O)R19; R18 is: a) -H; or b) substituted or unsubstituted linear C1-C4, branched C3-C4 or cyclic C3-C4 alkyl; R19 is: a) substituted or unsubstituted linear C1-C12, branched C3-C12 or cyclic C3-C12 alkyl; b) -N(R20a)(R20b); R20a and R20b are each independently hydrogen, substituted or unsubstituted linear C1-C12, branched C3-C12 or cyclic C3-C12 alkyl; substituted or unsubstituted C6 or C10 aryl; substituted or unsubstituted C1-C9 heterocyclic; substituted or unsubstituted C1-C11 heteroaryl; or R20a and R20b may together form a substituted or unsubstituted ring having 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)2, and the like; xiii) - [C(R23a)(R23b)]xCN; for example; -CN, -CH2CN, and -CH2CH2CN; xiv) -[C(R23a)(R23b)]xNO2; for example; -NO2, -CH2NO2, and -CH2CH2NO2; xv) -[C(R23a)(R23b)]xR21; for example; -CH2F, -CHF2, -CF3, -CCl3, or -CBR3; R21 is C1-C10 linear, branched or cyclic alkyl substituted by 1 to 21 halogen atoms selected from -F, -Cl, -Br or -I; xvi) -[C(R23a)(R23b)]xSO2R22; R22is hydrogen, hydroxyl, substituted or unsubstituted linear C1-C4 or C3-C4 branched alkyl, substituted or unsubstituted C6, C10 or C14 aryl; C7-C15 alkylenearyl; substituted or unsubstituted C1-C9 heterocyclic; or substituted or unsubstituted C1-C11 heteroaryl; for example, -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; R23a and R23b are each independently hydrogen or C1-C4 alkyl; and the index x is an integer from 0 to 5.
[0093] One aspect of this category relates to HIF-1α prolyl hydroxylase inhibitors, wherein R1 and R2 together form a substituted or unsubstituted five-membered C1-C4 heterocyclic or a substituted or unsubstituted C1-C4 heteroaryl ring, which non-limiting examples include a ring selected from: i)

iii)
[0094] Another aspect of this category relates to HIF-1α prolyl hydroxylase inhibitors, wherein R1 and R2 together form a substituted or unsubstituted C4-C11 heterocyclic heteroaryl ring or a substituted or unsubstituted C4-C11 heteroaryl ring

[095] Non-limiting examples of this category include compounds having the formula:

[0096] Another category of compounds described has the formula:
wherein R represents from 1 to 5 optional substitutions for a phenyl ring hydrogen atom, R 1 and R 2 are each independently hydrogen or substituted or unsubstituted linear or branched C 1 -C 10 alkyl, wherein the alkyl moiety may be substituted by one or more units independently selected from: i) C1-C8 linear, C3-C8 branched, or C3-C8 cyclic alkoxy; ii)hydroxy; iii) x) halogen; iv) cyano; v) amino, C1-C8 mono-alkylamino, C1-C8 di-alkylamino; vi)-SR40; R40 is hydrogen or linear or branched C1-C4 alkyl; vii) C6 of C10 substituted or unsubstituted aryl; viii) C1-C9 substituted or unsubstituted heterocyclic; or ix) substituted or unsubstituted C1-C9 heteroaryl.
[0097] Non-limiting examples of this category include:

[0098] Yet another category of HIF-1α prolyl hydroxylase inhibitors refers to compounds having the formula:
wherein R1 and R2 together form a substituted or unsubstituted piperazine ring, the ring substitutions as defined for R200 hereinabove.
[0099] Yet another category of HIF-1α hydroxylase inhibitors described has the formula:
wherein R1 and R2 may together form a substituted or unsubstituted heterocyclyl or heteroaryl ring having from 2 to 20 carbon atoms and from 1 to 7 heteroatoms, wherein the rings formed exclude a piperazine ring.
Also described herein are N-substituted benzyl or N-substituted sulfonylaryl-3-hydroxypyridin-2-(1H)-ones having the formula:
that can be used to stimulate the cellular immune response in an individual. For these compounds, Z and L are the same as described here above. Non-limiting examples of these compounds include: 1-(4-chlorobenzyl)-3-hydroxypyridin-2(1H)-one having the formula:
1-(3-chlorobenzyl)-3-hydroxypyridin-2(1H)-one having the formula:
1-(2-chlorobenzyl)-3-hydroxypyridin-2(1H)-one having the formula:

Further described herein are N-substituted benzyl or N-substituted sulfonylaryl-5-substituted-3-hydroxypyridin-2-(1H)-ones having the formula:
x wherein Y is substituted or unsubstituted phenyl, Z and L are the same as defined herein above.
[00102] An aspect of Y of this refers to a phenyl group which is substituted with 1 to 5 halogen atoms, for example Y is chosen from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl. Another aspect of Y units relates to compounds, wherein Y is chosen from 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3-dichlorophenyl, 2 ,4-dichlorophenyl, 2,5-dichlorophenyl, and 2,6-dichlorophenyl.
[00103] A non-limiting example of compounds under this category includes 1-(4-chlorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one having the formula:

[00104] Other non-limiting examples include: 1-(2-chlorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(2-chlorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(2-chlorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-chlorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-chlorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-chlorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(4-chlorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(4-chlorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(2-fluorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(2-fluorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(2-fluorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-fluorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-fluorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-fluorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(4-fluorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(4-fluorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one 1-(4-fluorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H) -one 1-(2-chlorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(2-chlorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(2-chlorobenzyl)-5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-chlorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-chlorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-chlorobenzyl)-5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(4-chlorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(4-chlorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(4-chlorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one 1-(2-fluorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H) -one; 1-(2-fluorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(2-fluorobenzyl)-5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-fluorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-fluorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(3-fluorobenzyl)-5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(4-fluorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one; 1-(4-fluorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one; and 1-(4-fluorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one.
[00105] The described compounds are organized into various categories for the strictly non-limiting purpose of descriptive alternatives to synthetic strategies for the preparation of subgenus compounds within the scope of the described compounds that are not expressly exemplified herein. This mental organization into categories implies nothing with respect to increased or decreased biological effectiveness with respect to any of the matter described herein.
[00106] Category I of the described HIF-1 prolyl hydroxylase inhibitors described refers to compounds having the formula:
wherein A is a substituted or unsubstituted heterocyclic or heteroaryl ring of 2 to 20 carbon atoms and 1 to 7 heteroatoms, R200 represents from 0 to 40 hydrogen substitutions, R represents from 1 to 5 hydrogen substitutions as defined herein above , and the index n is from 1 to 5. Table I provides representative examples of compounds according to this category. TABLE I


[00107] The described compounds of this category can be prepared by the procedure outlined herein below in Scheme 1 and described in Example 1. Scheme I
Reagents and conditions: (a) TBDMSCl, imidazole, DMF: room temperature (rt), 30 min.
Reagents and conditions: (b) (4-chloro)benzyl chloride, Cs2CO3, THF; rt.
Reagents and conditions: (c) 5M HCl, EtOH; 30 min. Reagents and conditions: (d)(i) H2CHO, AcOH, t-Boc-piperazine, EtOH; 3 days.
EXAMPLE 1 tert-Butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate (4)
[00108] Preparation of 3-(tert-butyldimethylsilanyloxy)-1H-pyridin-2-one (1): 3-hydroxypyridin-2(1H)-one (15 g, 135 mmoles) and imidazole (23 g, 338 mmoles) were suspended in dimethylformamide (200 ml) under inert atmosphere. A solution of tert-butyldimethylsilyl (20.5 g, 136 mmol) in dimethylformamide (200 mL) is added dropwise at room temperature over 30 minutes. The reaction was then allowed to stir overnight. The resulting solution was then poured into water (300ml) and the mixture extracted with tert-butyl methyl ether (3x500ml). The combined organic layer was washed with water (300 mL), brine (300 mL), then dried over Na2SO4. The solvent is removed under reduced pressure and the crude product crystallized from heptanes to provide 16.3 g (53% yield) of the desired product. 1H NMR (250 MHz, CDCl 3 ) δppm 12.98 (1H, m); 6.91 (1H, dd, J = 1, Hz, J = 6.8 Hz); 6.81 (1H, dd, J = 1.8 Hz, J = 7.2 Hz); 6.02 - 6.007 (1H, m); 0.90 (9H, s), and 0.17 (6H, s).
[00109] Preparation of 3-(tert-butyldimethylsilanyloxy)-1-(3-chlorobenzyl)-1H-pridin-2-one (2): At 0°C under an inert atmosphere, a solution of 4-chlorobenzyl chloride ( 4.44 mmoles) in THF (10 mL) was added dropwise to a solution of 3-(tert-butyldimethylsilanyloxy)-1H-pyridin-2-one, 1 (1 g, 4.44 mmoles) and CsCO3 (2 .17 g, 6.66 mmol) in THF (10 mL). The reaction solution was allowed to warm to room temperature and stirring continued overnight. The resulting solution was diluted with water (40ml) and then extracted with EtOAc (3x30ml). The combined organic layer was washed with brine (30 mL) then dried over Na2SO4. The solvent is removed under reduced pressure and the crude product purified over silica (EtOAc:heptane 4:1) to furnish the desired product as a white solid.
[00110] Preparation of 1-(4-chlorobenzyl)-3-hydroxypyridin-2(1H)-one (3): To a solution of 3-(tert-butyldimethylsilanyloxy)-1-(3-chlorobenzyl)-1H-pridin -2-one, 2, (2.36 g, 10 mmol) in EtOAc (25 mL) was added 5 M HCl (25 mL) with vigorous stirring at room temperature. The reaction was monitored by TLC for the disappearance of starting material and completed within 30 minutes. The organic layer was decanted and the aqueous phase was extracted with dichloromethane (2x50ml). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was recrystallized from dichloromethane. The yield was almost quantitative. 1H NMR (360 MHz, DMSO-d6) δ ppm 5.12 (2H, s); 6.13 (1H, t, J = 7.04); 6.71 (1H, dd, J = 7.04, 1.59); 7.23-7.28 (2H, m); 7.36-7.43 (2H, m); 9.10 (1H, br.s).
[00111] Preparation of tert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydro-pyridin-4-yl]methyl}piperazine-1-carboxylate (4): tert-butyl piperazine-1-carboxylate (97.6 mmoles), formaldehyde (8 ml of a 37% solution, 97.6 mmoles) and acetic acid (8 ml) were dissolved in ethanol (350 ml) and the solution was stirred for 1 hour at room temperature. A solution of 1-(4-chlorobenzyl)-3-hydroxypyridin-2(1H)-one, 3, (48.8 mmoles) in ethanol (350 mL) was added dropwise over 30 minutes. After 3 days of stirring, formaldehyde (3 ml) was added and the reaction was heated to 50°C after the reaction solution was concentrated under reduced pressure to approximately 500 ml. The desired product is obtained by crystallization from ethanol. 1H NMR (250 MHz, CDCl 3 ) d ppm 1.46 (s, 9H); 2.38-2.57 (m, 4H); 3.40-3.49 (m, 4H); 3.51 (s, 2H); 5.13 (s, 2H); 6.13 (d, J = 7.16 Hz), 1H); 6.79 (d, J = 7.16 Hz, 1H); 7.20-7.41 (m, 4H); 8.33-8.85 (m, 1H). The biological data described refer to A41.
[00112] Category II of the prolyl hydroxylase inhibitors described for compounds having the formula:
wherein A is a substituted or unsubstituted heterocyclic or heteroaryl ring of 2 to 20 carbon atoms and 1 to 7 heteroatoms, and R200 represents from 0 to 40 substitutions from hydrogen. Table II provides representative examples of compounds according to this category. TABLE II


Compounds according to Category II can be prepared according to the procedure described in Scheme I and described in Example 1. The following are further examples of inhibitors according to Category II.

[00114] 1-Benzyl-3-hydroxy-4-(piperidin-1-ylmethyl)pyridin-2(1H)-one: 1H NMR (300 MHz, CD3OD) δ 1.81 (m, 6H), 3.07 (m, 2H), 3.51 (m, 2H), 4.23 (s, 2H), 5.24 (s, 2H), 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.

[00115] 1-Benzyl-3-hydroxy-4-(morpholin-4-ylmethyl)pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 3.25 (m, 4H), 3.81 (m, 4H), 4.18 (s, 2H), 5.17 (s, 2H), 6.31 (d, J = 6.9 Hz, 1H), 7.35 (m, 6H); 19FRMN (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.

[00116] 1-Benzyl-3-hydroxy-4-(thiomorpholin-4-ylmethyl)pyridin-2(1H)-one: 1HRMN(300MHz, DMSO) δ2.92(m, 4H), 3.38(m) , 4H), 4.17 (s, 2H), 5.16 (s, 2H), 6.29 (d, J = 7.5Hz, 1H), 7.34 (m, 6H), 9.97 (s, 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.

[00117] 1-Benzyl-3-hydroxy-4-(thiazolidin-3-ylmethyl)pyridin-2(1H)-one: 1HNMR (300 MHz, DMSO) δ 3.09 (t, J = 6.3 Hz, 2H), 3.42 (t, J = 6.3 Hz, 2H), 4.03 (s, 2H), 4.29 (s, 2H), 5.16 (s, 2H), 6.34 ( d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 10.48 (broad s, 1H); 19FRMN (300 MHz, DMSO) δ 87.9; 13CRMN (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; S, 7.70. Found: C, 51.67; H, 4.48; N, 6.69; S, 7.65.

[00118] 1-Benzyl-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.96 (s, 4H), 3.16 (s, 2H), 3.43 (s, 2H), 4.23 (s, 4H), 5.17 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7 .34 (m, 6H); 19F 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 C19H21F3N2O4, C, 57.28; H, 5.31; N, 7.03. Found: C, 57.10; H, 5.11, N, 7.02.

[00119] 1-Benzyl-3-hydroxy-4-(4-benzylpiperidin-1-ylmethyl)pyridin-2(1H)-one: 1H NMR (DMSO) δ 1.43 (m, 2H), 1.72 ( m, 4H), 2.96 (m, 2H), 3.41 (m, 3H), 4.09 (s, 2H), 5.16 (s, 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.

[00120] 1-Benzyl-3-hydroxy-4-(4-benzylpiperazin-1-ylmethyl)pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 3.11 (broad s, 4H), 3.81 (s, 2H), 4.18 (s, 2H), 5.15 (s, 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 (75 MHz, DMSO) δ; ES MS(M+1) 390.21; HRMS calculated for C24H27N3O2, 389.49. Found (M+1) 390.21.

[00121] 1-Benzyl-3-hydroxy-4-[(3-hydroxypyrrolidin-1-yl)methyl]pyridin-2(1H)-one: 1HNMR (300 MHz, DMSO) δ 1.90 (m, 1H) , 3.18 (m, 2H), 3.47 (m, 3H), 4.24 (s, 2H), 4.43 (s, 1H), 5.17 (s, 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.

[00122] 1-Benzyl-3-hydroxy-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylmethyl)pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO δ 1.90 (m, 4H), 3.11 (m, 2H), 3.43 (m, 2H), 3.93 (s, 4H), 4.19 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 10.01 (broad s, 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.

[00123] 1-Benzyl-3-hydroxy-4-azepan-1-ylmethylpyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.61 (m, 4H), 1.80 (m, 4H), 3.20 (m, 4H), 4.17 (s, 2H), 5.16 (s, 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.

[00124] 1-Benzyl-3-hydroxy-4-(azocan-1-ylmethyl)pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.59 (m, 10H), 3.18 (m, 2H), 3.38 (m, 2H), 4.17 (s, 2H), 5.16 (s, 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.

[00125] 1-Benzyl-3-hydroxy-(1,4'-bipiperidinyl-1'-ylmethyl)pyridin-2(1H)-one: 1HO NMR (300 MHz, DMSO) δ 1.431.98 (m, 10H) ), 2.21 (m, 2H), 3.01 (m, 4H), 3.43 (m, 3H), 4.12 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 9.85 (broad s, 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, 128.9, 137.3, 147.5, 157.6; ES MS(M+1) 382.4; HRMS calculated for C23H31N3O2, 383.51. Found (M+1) 382.25.

[00126] 1-Benzyl-3-hydroxy-4-[(3,4-dihydroquinolin-1(2H)-yl)methyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 3, 13 (t, J = 6.3 Hz, 2H), 3.52 (m, 2H), 4.28 (s, 2H), 4.41 (s, 2H), 5.18 (s, 2H), 6.34 (d, J = 7.2Hz, 1H), 7.23-7.41 (m, 10H), 10.15 (broad s, 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.

[00127] Methyl 1-[(1-benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methyl]pyrrolidine-2-carboxylate: 1H NMR (300 MHz,DMSO) δ 2.01 (m, 3H), 2.45 (m, 1H), 3.26 (m, 1H), 3.53 (m, 1H), 3.69 (s, 3H), 4.30 (m, 3H) , 5.17 (s, 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).

[00128] 1-Benzyl-3-hydroxy-4-{[2-(methoxymethyl)pyrrolidin-1-yl]methyl}pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.71 ( m, 1H), 1.84 (m, 1H), 1.99 (m, 1H), 2.15 (m, 1H), 3.19 (m, 1H), 3.30 (s, 3H), 3.41 (m, 1H), 3.62 (m, 2H), 3.77 (m, 1H), 4.15 (m, 1H), 4.39 (m, 1H), 5.17 (s , 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H); 9.60 (broad s, 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).

[00129] 1-Benzyl-3-hydroxy-4-{[2-(pyrdin-2-yl)pyrrolidin-1-yl]methyl}pyridin-2(1H)-one: 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), 6.15 (d, J = 6.9 Hz, 1H), 7.33 (m, 6H), 7.44 (m, 1H), 8.05 (d, J = 8.1 Hz, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.74 (s, 1H); 19F NMR (252 MHz, DMSO) δ 88.0; ES MS(M+1) 362.22; HRMS calculated for C22H23N3O2, 361.44. Found (M+1).

[00130] 1-Benzyl-3-hydroxy-4-[4-(6-chloropyridazin-3-yl)piperazin-1-ylmethyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 3 .18 (m, 2H), 3.48 (m, 4H), 4.19 (s, 2H), 4.46 (m, 2H), 5.16 (s, 2H), 6.62 (d, J = 7.2 Hz, 1H), 7.35 (m, 6H), 7.48 (m, 1H), 7.68 (m, 1H), 11.5 (broad s, 1H); 13 C 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 C21H22ClN5N3O2, 411.88. Found (M+1) 412.76.

[00131] 1-Benzyl-3-hydroxy-4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]pyridin-2(1H)-one:1H NMR (300 MHz, DMSO) δ 2.95 (m , 2H), 3.30 (m, 2H), 3.48 (m, 4H), 3.80 (s, 3H), 4.25 (s, 2H), 5.18 (s, 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 of the described prolyl hydroxylase inhibitors refer to compounds having the formula: R1 I.N, R R2 X^/OH^N^O
wherein R1 and R2 are each independently hydrogen or substituted or unsubstituted linear or branched C1-C10 alkyl, wherein the alkyl moiety may be substituted by one or more moieties independently selected from: i) C1-C8 linear , C3-C8 branched, or C3-C8 cyclic alkoxy; ii) hydroxy; iii) halogen; iv) cyano; v) amino, C1-C8 mono-alkylamino, C1-C8 di-alalkylamino; vi) -SR40; R40 is hydrogen or linear C1-C4 or branched C3-C4 alkyl; vii) C6 of C10 substituted or unsubstituted aryl; viii) C1-C9 substituted or unsubstituted heterocyclic; or ix) substituted or unsubstituted C1-C9 heteroaryl.
[00133] Table III below provides non-limiting examples of compounds falling under this category. TABLE III


The compounds described in this category can be prepared by the procedure outlined here below in Scheme II and described in Example 2.
Scheme II Reagents and conditions: (a)(i) HCHO, EtOH; 0.5 h (ii) 3-(1-H-imidazol-1-yl)propan-1-amine; 2 h. EXAMPLE 2 1-Benzyl-3-hydroxy-4-{[3-(1-H-imidazol-1-yl)propylamino]methyl}-pyridin-2(1H)-one (6)
[00135] N-Benzyl-3-hydroxypyridin-2(1H)-one (5) can be prepared according to Example 1, substituting benzyl bromide or benzyl chloride in step (b) for (4-chloro) benzyl chloride.
[00136] 1-Benzyl-3-hydroxy-4-{[3-(1-H-imidazol-1-yl)propylamino]methyl}pyridin-2(1H)-one (6): N-Benzyl-3- hydroxypyridin-2(1H)-one (5) (250 mg, 1.23 mmol) and formaldehyde (200 mg, 273 eq.) are combined in aqueous ethanol (10 mL) and stirred for 30 minutes. 3-(1H-imidazol-1-yl) propan-1-amine (340 mg, 2.7 mmol) is then added and the reaction stirred for 12 hours. The solvent is removed by evaporation and the residue dissolved in methanol (2 ml) and purified via preparative HPLC eluting with water/acetonitrile to furnish the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO) δ 2.19 (m, 2H), 2.97 (m, 2H), 4.02 (s, 2H), 4.30 (t, J = 6.6 Hz, 2H ); 5.17 (s, 2H), 6.30 (d, J = 6.9 Hz, 1H), 7.36 (m, 6H), 7.26 (s, 1H), 7.76 (s, 1H ), 9.03 (s, 1H), 9.11 (s, 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 0.9, 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.
[00137] The following are non-limiting examples of this aspect of the described HIF-1α prolyl hydroxylase inhibitors.

[00138] 1-Benzyl-3-hydroxy-4-(benzylaminomethyl)pyridin-2(1H)-one: 1HNMR (300 MHz, DMSO) δ 4.01 (s, 2H), 4.20 (s, 2H) , 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.36 (m, 11H), 9.16 (broad s, 1H); 19FRMN (252 MHz, DMSO) δ 88.6; 13C NMR (75 MHz, DMSO) δ; ES MS(M+1) 321.16; Anal. calculated for C22H21F3N2O4, C, 60.83; H, 4.87; N, 6.45. Found: C, 60.75; H, 4.56; N, 6.34.

[00139] 1-Benzyl-3-hydroxy-4-{[(2-(pyridin-2-yl)ethylamino]methyl}pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 3.26 (m, 2H), 3.37 (m, 2H), 4.08 (s, 2H), 5.17 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7 .38 (m, 6H), 7.86 (d, J = 5.7Hz, 2H), 8.84 (m, 2H), 9.32 (broad s, 1H); 19FRMN (252MHz, 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.

[00140] 1-Benzyl-3-hydroxy-4-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.56 (m, 1H), 1.86 (m, 2H), 1.99 (m, 1H), 2.92 (m, 1H), 3.05 (m, 1H), 3.80 (m, 2H), 4. 09 (m, 3H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H); 8.91 (broad s, 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.

[00141] 1-Benzyl-3-hydroxy-4-[(2-methoxyethylamino)methyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 3.13 (broad s, 2H), 3 .30 (s, 3H), 3.59 (t, J = 5.4 Hz, 2H), 4.02 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 8.91 (broad s, 1H); 19F NMR (252 MHz, DMSO) δ 88.4; 13C NMR (252 MHz, DMSO) δ; ES MS(M+1) 289.13; HRMS calculated for C16H20N2O3, 288.34. Found (M+1) 289.15.

[00142] 1-Benzyl-3-hydroxy-4-[(1-hydroxy-2-methylpropan-2-ylamino)methyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.27 (s, 6H), 3.49 (s, 2H), 3.95 (s, 2H), 5.17 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7 .34 (m, 6H), 8.47 (broad s, 2H), 9.94 (broad s, 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-[(pyridin-4-ylmethylamino)methyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 4.07 (s, 2H), 4.32 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H); 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.

[00144] 1-Benzyl-3-hydroxy 4-{[(furan-2-ylmethyl)amino]methyl}pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 4.00 (s, 2H) ), 4.28 (s, 2H), 5.16 (s, 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 (broad s, 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).

[00145] 1-Benzyl-3-hydroxy-4-{[2-(methylthio)ethylamino]methyl}pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 2.10 (s, 3H) , 2.74 (t, J = 6.9 Hz, 2H), 3.16 (t, J = 8.1 Hz, 2H), 4.05 (s, 2H), 5.17 (s, 2H) , 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 19F NMR (252 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-methoxybenzylamino)methyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 3.70 (s, 3H), 3. 98 (s, 2H), 4.13 (s, 2H), 5.16 (s, 2H), 6.28 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 9 0.0Hz, 4H), 7.34 (m, 6H); 9.07 (broad s, 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.

[00147] 1-Benzyl-3-hydroxy-4-[(1-phenylethylamino)methyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.59 (d, J = 7.2 Hz, 3H), 3.71-3.93 (m, 2H), 4.45 (m, 1H), 5.15 (s, 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.

[00148] 1-Benzyl-3-hydroxy-4-(cycloheptylaminomethyl)pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.55 (m, 10H), 2.03 (m, 2H) ), 3.18 (s, 1H), 3.99 (m, 2H), 5.17 (s, 2H), 6.32 (d, J = 6.9 Hz, 1H), 7.35 (m , 6H), 8.65 (broad s, 2H), 9.98 (broad s, 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.

[00149] 1-Benzyl-3-hydroxy-4-[(4-methylcyclohexylamino)methyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 0.93 (d, J = 6.9 Hz, 3H), 1.38 (m, 4H), 1.74 (m, 4H), 2.05 (m, 1H), 3.10 (m, 1H), 4.01 (s, 2H), 5.17 (s, 2H), 6.31 (m, 1H), 7.34 (m, 6H), 8.05 (broad s, 2H), 9.98 (broad s, 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.

[00150] 1-Benzyl-3-hydroxy-4-[(1-benzylpiperidin-4-ylamino)methyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.77 (m, 2H) ), 2.31 (m, 2H), 2.98 (m, 2H), 3.30 (m, 3H), 3.46 (m, 2H), 4.03 (s, 2H), .29 ( s, 2H), 5.16 (s, 2H), 6.30 (d, J = 7.5 Hz, 1H), 7.34 (m, 6H), 7.49 (s, 5H), 9. 12 (broad s, 1H), 10.05 (broad s, 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.

[00151] 3-[(1-Benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methylamino]azepan-2-one: 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 (s, 2H), 4.2 (m, 1H), 5.17 (s, 2H), 6.33 (d, J = 7.5 Hz, 1H), 7.34 (m, 6H) ), 8.31 (t, J = 5.4 Hz, 1H), 9.07 (broad s, 2H), 9.90 (broad s, 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.

[00152] 1-Benzyl-3-hydroxy-4-[(1-benzylpyrrolidin-3-ylamino)methyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 2.22 (m, 2H) ), 2.42 (m, 1H), 3.39 (m, 3H), 3.68 (m, 1H), 4.06 (s, 2H), 4.39 (s, 2H), 5.17 (s, 2H), 6.33 (d, J = 7.5Hz, 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.

[00153] (R)-1-Benzyl-3-hydroxy-4-[(1- calculated for C21H22N2O2, 334.41. Found (M+1) 335.31.

[00154] 1-Benzyl-3-hydroxy-4-[([1,3]dioxolan-2-ylmethylmethylamino)methyl]pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 2.81 ( s, 3H), 3.35 (d, J = 3.9 Hz, 2H), 3.89 (m, 2H), 4.01 (m, 2H), 4.21 (m, 2H), 5. 17 (s, 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.
[00155] Category IV of the described prolyl hydroxylase inhibitors formula:
where A represents a ring optionally substituted by one or more units of R200. Table IV provides non-limiting examples of this category. TABLE IV


The compounds described in this category can be prepared by the procedure outlined below in Scheme III and described in Example 3. Scheme III
Reagents and conditions: (a) (i) n-BuLi, TsCl, THF; -78°C at rt, 1 h; (ii) HCl, MeOH; rt, 1 h.
EXAMPLE 3
[00157] 1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridin-2(1H)-one (8) 1-(4'-Methylbenzenesulfonyl)-3-hydroxypyridin-2 (1H)-one (7): To a stirred solution of 3-[(tert-butyldimethylsilyl)oxy]pyridin-2(1H)-one (1) (4.66 g, 20.7 mmoles) in dry THF (150 mL) kept at -78°C under a dry nitrogen atmosphere is added n-butyllithium (1.6 M solution in hexane, 21.0 mmoles). After 20 minutes, 4-methyl-benzenesulfonyl chloride (3.95 g, 20.7 mmol) is added as a solution of THF. The solution is allowed to warm to room temperature over one hour, water (10 mL) is added and the contents of the reaction vessel are extracted with EtOAc (3x), washed with brine (1x), dried over Na 2 SO 4 and concentrated. The combined organic layers are dried over Na2SO4 and concentrated. The residue is taken up in ethanol (10 ml) and treated with concentrated HCl (2 ml). The mixture is allowed to stir for 1 hour and the solvent is removed under reduced pressure to furnish the desired compound as a white solid. 1H NMR (300 MHz, DMSO) δ 2.43 (s, 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).
[00158] 1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridin-2(1H)-one (8): 1-(4'-Methylbenzenesulfonyl)-3-hydroxypyridin- 2(1H)-one (7) (250 mg, 0.94 mmol) and formaldehyde (200 mg, 2.07 mmol) are combined in aqueous ethanol (10 mL) and stirred for 30 minutes. Pyrrolidine (149 mg, 2.07 mmol) is then added and the reaction stirred for 12 hours. The solvent is removed by evaporation and the residue dissolved in methanol (5 ml) and purified via preparative HPLC eluting with water/acetonitrile to furnish the desired product. 1H NMR (300 MHz, DMSO) δ 1.87 (m, 2H), 1.99 (m, 2H), 2.44 (s, 3H), 3.09 (m, 2H), 3.40 (m , 2H), 4.19 (s, 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), 9.93 (broad s, 1H); 19F NMR (252 MHz, DMSO) δ 88.4; 13C NMR (75 MHz, DMSO) δ21.5, 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.
[00159] The following are non-limiting examples of prolyl hydroxylase inhibitors according to this category.

[00160] 1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-thiazolidin-3-ylmethylpyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 2.43 (s, 3H), 2 .94 (t, J = 6.6 MHz, 2H), 3.18 (t, J = 6.0 Hz, 2H), 3.66 (s, 2H), 4.12 (s, 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.

[00161] 1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-azocan-1ylmethylpyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.59 (m, 10H), 2.44 (s, 3H), 3.17 (m, 2H), 3.32 (m, 2H), 4.15 (s, 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)-pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 2.43 ( s, 3H), 3.13 (m, 8H), 3.43 (s, 2H), 6.47 (d, J = 7.5 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 7.21 9m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 7.8 Hz, 1H), 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.

[00163] 1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-[1,4']Bipiperidinyl-1'-ylmethylpyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 1.43 (m, 1h), 1.67 (m, 2H), 1.82 (m, 4H), 2.19 (m, 2H), 2.44 (s, 3H), 2.94 (m, 4H) , 3.39 (m, 2H), 3.54 (m, 3H), 4.06 (s, 2H), 6.47 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.73 (d, 7.8 Hz, 1H), 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.

[00164] 1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-[4-(6-chloropyridazin-3-yl)piperazin-1-ylmethyl]pyridin-2(1H)-one: 1H NMR (300 MHz , DMSO) δ2.44 (s, 3H), 3.17 (m, 2H), 3.46 (m, 4H), 4.17 (s, 2H), 4.45 (m, 2H), 6. 77 (d, J = 7.8 Hz, 1H), 7.04 (m, 1H), 7.53 (m 2H), 7.68 (m, 2H), 7.98 (m, 2H), 11 .3 (broad s, 1H), ES MS(M+1) 476.92. HRMS calculated for C21H25ClN5O4S, 475.95. Found (M+1) 476.11.
[00165] Category V of HIF-1α prolyl inhibitors refers to compounds having the formula:
R represents from 1 to 5 optional substitutions for a phenyl ring hydrogen atom, R 1 and R 2 are each independently hydrogen or substituted or unsubstituted linear or branched C 1 -C 10 alkyl, wherein the alkyl moiety may be replaced by a or more units independently selected from: i) C1-C8 linear, C3-C8 branched, or C3-C8 cyclic alkoxy; ii) hydroxy; iii) halogen; iv) cyano; v) amino, C1-C8 mono-alkylamino, C1-C8 di-alkylamino; vi) -SR40; R40 is hydrogen or linear C1-C4 or branched C3-C4 alkyl; vii) C6 of C10 substituted or unsubstituted aryl; viii) C1-C9 substituted or unsubstituted heterocyclic; or ix) substituted or unsubstituted C1-C9 heteroaryl.
[00166] Table V provides non-limiting examples of this category of HIF-1α prolyl hydroxylase inhibitors. TABLE V



The compounds described in this category can be prepared by the procedure outlined below in Scheme IV and described in Example 4. Scheme IV
Reagents and conditions: (a) benzyl bromide, HCHO, H2O/EtOH; rt, 12 h. EXAMPLE 4
[0168] 1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-[(benzylamino)methyl]-pyridin-2(1H)-one (9) 1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4 -(benzylaminomethyl)pyridin-2(1H)-one (9): 1-(4'-Methylbenzenesulfonyl)-3-hydroxypyridin-2(1H)-one (7) (250mg, 0.94mmol) and formaldehyde ( 200 mg, 2.07 mmol) are combined in aqueous ethanol (10 mL) and stirred for 30 minutes. Benzylamine (229 mg, 2.07 mmol) is then added and the reaction stirred for 12 hours. The solvent is removed by evaporation and the residue dissolved in methanol (5ml) and purified via preparative HPLC eluting with water/acetonitrile to furnish the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO) d 2.44 (s, 3H), 3.96 (s, 2H), 4.16 (s, 2H), 6.69 (d, J = 8.1 Hz), 7.40 (m, 7H), 7.52 (m, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 9.71 (broad s, 2H), 10.44 (broad s, 1H); ES MS(M+1) 396.67; HRMS calculated for C20H20N2O4S, 384.45. Found (M+1) 385.12. The following is a non-limiting example of this category of HIF-1a prolyl hydroxylase inhibitors.

[00169] 1-(4'-Methylbenzenesulfonyl)-3-hydroxy-4-[(2-methoxyethylamino)methyl]-pyridin-2(1H)-one: 1H NMR (300 MHz, DMSO) δ 2.43 (s , 3H), 3.12 (m, 2H), 3.29 (s, 3H), 3.56 (t, J = 5.1 Hz, 2H), 3.99 (s, 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.
[00170] Category VI of HIF-1α prolyl hydroxylase inhibitors refers to compounds having the formula:
wherein L is selected from CH2 or SO2 and Z is substituted or unsubstituted phenyl. Non-limiting examples of inhibitors according to this category are described in Table VI below. TABLE VI


Compounds falling under this category can be prepared according to Scheme I and Z equals CH2 according to Scheme III for Z equals SO2. pharmaceutically acceptable salts
The described HIF-1α prolyl hydroxylase inhibitors described may be in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts can be used by the formulator to provide a form of the described inhibitor that is more consistent with the intended administration of the inhibitor to an individual or for formulation compatibility.
The following are examples of procedures for preparing the pharmaceutically acceptable salt of the described inhibitor, tert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4- yl]methyl}piperazine-1-carboxylate.
A suspension of tert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate (242 mg, 0 .56 mmol) in MeOH (15 mL) heated to reflux until a homogeneous solution was obtained. Heating was stopped and 0.1 N HCl (6.7 mL, 1.2 eq.) was added while still hot and the solution was cooled to room temperature. Volatiles were evaporated under reduced pressure and the amorphous residue was crystallized from acetone (5ml). The solid was collected by filtration.
A suspension of tert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate (217 mg, 0 .5 mmol) in MeOH (15 mL) was heated to reflux until a homogeneous solution was obtained. Heating was stopped and methanesulfonic acid (115.2 mg, 1.2 eq.) was added while still hot and the solution was cooled to room temperature. Volatiles were evaporated under reduced pressure and the amorphous residue was crystallized from acetone (5ml). The solid was collected by filtration.
[00176] Table VII herein below provides examples of pharmaceutically acceptable salts of tert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine- 1-carboxylate formed from organic and inorganic acids. TABLE VII
* HPLC analysis
[00177] 1H NMR analyzes were used to determine the salt form, for example, where the mesylate salt formed here above has the following formula:

[00178] 1H NMR analyzes were used to determine which site of the salt molecule formation occurred. Chemical shifts for the methylene group protons binding the piperazine and pyridinone rings shifted from 3.59 ppm free base to 4.31 ppm salt. Furthermore, the piperazine methylene groups adjacent to the tertiary amine shifted from 2.50 ppm to approximately 3.60 ppm. Chemical shifts to the remaining protons were virtually unchanged. These data indicate that the tertiary amine nitrogen of the piperazine ring is protonated to salt forms. Furthermore, the integration of the methyl protons of the sulfonyl methane unit in relation to the core compounds identifies the presence of an acid equivalent.
[00179] The formulator can determine the solubility of the pharmaceutically acceptable salts of the described inhibitors by any desirable method. The following is a non-limiting example of a procedure for evaluating the solubility of a salt of an inhibitor described. A suspension of methanesulfonate tert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate (26.6 mg) in deionized distilled water (3.0 ml) is sonicated for 20 min with the water bath temperature less than 25°C. The suspension is filtered to remove any insoluble salt. The clear filtered solution (200 μL) is diluted with deionized, distilled water (800 μL) and subjected to HPLC analysis. Below are the results for the pharmaceutically acceptable salts described in Table VII above.

* HPLC analysis
[00180] The following are non-limiting examples of other acids that can be used to form pharmaceutically acceptable salts of the described inhibitors: acetate, citrate, maleate, succinate, lactate, glycolate, and tartrate.
[00181] Further described herein is a process for preparing the described HIF-1α prolyl hydroxylase inhibitors, comprising: a) protecting the hydroxyl portion of hydroxypyridin-2(1H)-one to prepare a protected pyridone having the formula:
where W represents a protecting group. b) reacting the protected pyridone with a compound having the formula:
where R represents from 1 to 5 hydrogen substitutions as defined herein, the index n is an integer from 0 to 5 years, Q is a leaving group to form an O-protected N-benzyl pyridone or N-sulfonylphenyl pyridone having the formula:
c) removing the protecting group from the O-protected N-benzyl pyridone or N-sulfonylphenyl pyridone to form an N-benzyl pyridone or N-sulfonylphenyl pyridone having the formula:
d) reacting an amine having the formula: R1 IH R2 wherein R1 and R2 are the same as defined herein, with formaldehyde to form an N-formylamine having the formula:
e) reacting the N-formylamine formed in step (d) with the N-benzyl pyridone or N-sulfonylphenyl pyridone formed in step (c) to form a compound having the formula:
Step (a) Preparation of an O-protected hydroxypyridin-2(1H)-one
[00182] Step (a) refers to the formation of O-protected hydroxypyridin-2(1H)-one having the formula:

[00183] W can be any protection group. Non-limiting examples of protecting groups include m-carbamates, for example, tert-butoxycarbonyl and methoxycarbonyl, alkylsilanes, for example, trimethylsilyl and tert-butyldimethylsilyl, and the like. Step (b): Preparation of an O-protected N-benzyl hydroxypyridin-2(1H)-one or O-protected N-sulfonylphenyl hydroxypyridin-2(1H)-one
[00184] Step (b) refers to the formation of an O-protected N-benzyl hydroxypyridin-2(1H)-one or O-protected N-sulfonylphenyl hydroxypyridin-2(1H)-one having the formula:

The protected hydroxypyridin-2(1H)-one formed in step (a) is reacted with a compound having the formula:
wherein Q is a leaving group capable of being eliminated by the nitrogen ring of protected hydroxypyridin-2(1H)-one. Step (c): Preparation of N-benzyl-3-hydroxypyridin-2(1H)-one or N-sulfonylphenyl-3-hydroxypyridin-2(1H)-one
[00186] Step (c) refers to the formation of N-benzyl-3-hydroxypyridin-2(1H)-one or N-sulfonylphenyl-3-hydroxypyridin-2(1H)-one having the formula:

wherein the O-protected N-benzyl hydroxypyridin-2(1H)-one or O-protected -N-sulfonylphenyl hydroxypyridin-2(1H)-one formed in step (b) is reacted with one or more suitable reagents for removing the protecting group W in a form compatible with any substitution of R for hydrogen on the phenyl ring. Step (d): Preparation of an N-formylamine synthon
[00188] Step (d) refers to the formation of an N-formylamine synthon having the formula:
N-formylamine is formed by reaction of amine R1 I 2 having the formula:
with formaldehyde or a reagent capable of generating formaldehyde in situ. Step (e): Preparation of the described HIF-1a prolyl hydroxylase inhibitors
[00189] Step (e) refers to the final descriptions having the formula:

[00190] by the reaction of N-formylamine formed in step (d) with the N-benzyl-3-hydroxypyridin-2(1H)-one or N-sulfonylphenyl-3-hydroxypyridin-2(1H)-one formed in step ( ç). FORMULATIONS Medicines and Pharmaceutical Compositions
[00191] The present invention further relates to compositions or formulations that are useful for the manufacture of a medicine or a pharmaceutical composition. The described medicaments or described pharmaceutical compositions comprising the described human protein HIF-1α prolyl hydroxylase inhibitors may comprise: a) an effective amount of one or more HIF-1α prolyl hydroxylase inhibitors according to the present invention; and b) one or more excipients.
[00192] Diseases or conditions affected by increased stabilization of HIF-1 by inhibition of HIF-1 α prolyl hydroxylase include PVD, CAD, heart failure, ischemia, anemia, wound healing, antimicrobial activity, increased phagocytosis, anticancer activity, and increased effectiveness of vaccines.
[00193] For the purposes of the present invention, the terms "excipient" and "vehicle" are used interchangeably throughout the specification of the present invention and said terms are defined herein as, "ingredients that are used in the practice of formulating a safe and effective pharmaceutical composition".
[00194] The formulator will understand that excipients are primarily used to serve in the delivery of a safe, stable and functional pharmaceutical product, serving not only as part of the entire vehicle for delivery but also as a means to achieve effective absorption by the ingredient container active. An excipient can fill a role as simple and straightforward as being an inert filler material, or an excipient as used herein can be part of a pH coating stabilization system to ensure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact that the compounds of the present invention have improved cellular potency, pharmacokinetic properties as well as improved 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 HIF-1α human protein prolyl hydroxylase inhibitors according to the present invention; and b) one or more excipients.
Another example according to the present invention relates to the following compositions: a) from about 0.01 mg to about 100 mg of one or more inhibitors of HIF-1α prolyl hydroxylase of human protein according to the present invention; and b) one or more excipients.
[00197] Another example according to the present invention relates to the following compositions: a) from about 0.1 mg to about 10 mg of one or more human protein HIF-1α prolyl hydroxylase inhibitors according to the present invention; and b) one or more excipients.
Yet another example of compositions according to the present invention comprises: a) an effective amount of one or more inhibitors of HIF-1α human protein prolyl hydroxylase according to the present invention; and b) one or more chemotherapeutic agents or chemotherapeutic compounds as described herein.
A still further example of the compositions according to the present invention comprises: a) an effective amount of one or more inhibitors of HIF-1α human protein prolyl hydroxylase according to the present invention; and b) one or more vaccines for the treatment of an infectious disease.
[00200] The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for the treatment of anemia.
[00201] The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for the treatment of enhanced cellular immunity.
[00202] The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for the treatment of cancer.
The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament to enhance the stabilization of HIF-1.
The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for the treatment of anemia.
The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for the treatment of peripheral vascular disease.
The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for the treatment of wounds.
[00207] The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament which is an antimicrobial agent.
The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for the treatment of atherosclerotic lesions.
The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for the treatment of diabetes.
[00210] The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for the treatment of hypertension.
[00211] The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for treating diseases affected by the level of vascular endothelial growth factor (VEGF), glyceraldehyde 3 - phosphate dehydrogenase (GAPDH), and erythropoietin (EPO).
[00212] The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for the described treatment of a disorder selected from Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis , rheumatoid arthritis, hemangiomas, Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, and terminal blood tumors and acquired immunodeficiency syndrome.
[00213] The present invention further relates to the use of one or more of the HIF-1a prolyl hydroxylase inhibitors described herein for the manufacture of a medicament for treating a disorder selected from diabetic retinopathy, macular degeneration, cancer, anemia of sickle cell, sarcoid, syphilis, pseudoxanthoma elastic, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitreitis, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retinopathy of prematurity, disease of Eales, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma and post complications. laser, diseases associated with rubeosis and proliferative vitreoretinopathy.
The described compositions and the form of pharmaceutical preparations comprising the HIF-1la± prolyl hydroxylase inhibitors alone, or in combination with another drug or other therapeutic agent, inter alia, chemotherapeutic agent or chemotherapeutic compound, may vary according to the route of intended administration.
Orally administered preparations may be in the form of solids, liquids, emulsions, suspensions or gels, or in unit dosage form, for example as tablets or capsules. Tablets can be combined with other commonly used ingredients such as tale, vegetable oils, polyols, gums, gelatin, starch, and other vehicles. HIF-1αprolyl hydroxylase inhibitors can be dispersed in or combined with a suitable liquid vehicle in solutions, suspensions, or emulsions.
[00216] Parenteral compositions intended for injection, or subcutaneous, intramuscular, or intravenous injection, may be prepared as liquid or solid forms for solution in liquid prior to injection, or as emulsions. Such preparations are sterile, and fluids to be injected intravenously must be isotonic. Suitable excipients are, for example, water, dextrose, saline, and glycerol.
[00217] Administration of the pharmaceutically acceptable salts of the substances described herein is included within the scope of this description. Such salts can be prepared from pharmaceutically acceptable non-toxic bases including organic bases and inorganic bases. Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, and the like. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary, and tertiary amines, basic amino acids, and the like. For a useful discussion of pharmaceutical salts, see S.M. Berge et al., Journal of Pharmaceutical Sciences 66:1-19 (1977), the description of which is incorporated herein by reference.
[00218] Substances for injection can be prepared in unit dosage form in ampoules, or in multi-dose containers. The HIF-1α prolyl hydroxylase inhibitors or compositions comprising one or more HIF-1α prolyl hydroxylase inhibitors to be administered may be present in such forms as suspensions, solutions, or emulsions in oil or, preferably, aqueous vehicles. Alternatively, the HIF-1α prolyl hydroxylase inhibitor salt may be in lyophilized form for reconstitution at the time of administration with a suitable vehicle, such as sterile pyrogen-free water. Both liquids, as well as lyophilized forms which are to be reconstituted, will comprise agents, preferably buffers, in amounts necessary to properly adjust the pH of the injected solution. For any parenteral use, particularly if the formulation is to be administered intravenously, the total concentration of solutes must be controlled to make the preparation isotonic, hypotonic, or weakly hypertonic. Nonionic materials, such as sugars, are preferred to adjust tonicity, and sucrose is particularly preferred. Any of these forms may further comprise suitable formulating agents such as starch or sugar, glycerol or saline. Unit dosage compositions, whether liquid or solid, can contain from 0.1% to 99% of the polynucleotide material. METHODS Methods related to HIF-1 stabilization
[00219] Eradication of invading microorganisms depends initially on preexisting innate immune mechanisms in all individuals that act within minutes of infection. Phagocytic cell types, including macrophages and neutrophils, play a crucial role in innate immunity because they can recognize, ingest and destroy many pathogens without the aid of an adaptive immune response. The effectiveness of myeloid cells in innate defense reflects their ability to function in low-oxygen environments. While in normal tissues oxygen tension is generally 20 - 70 mm HG (ie 2.5 - 9% oxygen), much lower levels (< 1% oxygen) have been described in wounds and foci of necrotic tissues (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)). It has also been shown (Zinkernagel AS et al., "Pharmacologic Augmentation of Hypoxia-Inducible Factor-1α with Mimosine Boosts the Bactericidal Capacity of Phagocytes" J. Infectious Diseases (2008):197: 214-2) that HIF1-α against mimosin can enhance the ability of human phagocytes and whole blood to kill the major pathogen Staphylococcus aureus in a dose-dependent fashion and reduce the size of lesions in a murine model of S. aureus skin infection.
[00220] Macrophages are a population of effector cells involved in immune responses. Its role in natural immunity includes the mediation of phagocytosis, as well as the release of cytokines and cytotoxic mediators. They also facilitate the development of acquired immunity through antigen presentation and the release of immunomodulatory cytokines. Although macrophages are immune effectors, they are also susceptible to infections by agents such as bacteria, protozoa, parasites, and viruses (The Macrofage, CE Lewis & J.O'D. McGee. eds., IRL Press at Oxford University Press, New York, NY, 1992). Viruses capable of infecting macrophages include several RNA viruses, such as measles virus (MV) (eg, Josef 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 Macrofage Biology and Activation, SW Russell and S. Gordon, eds., SpringerVerlag, New York, NY, pp. 239-263(1992: Potts et al., Virology 175, 465-476, 1990).
[00221] Described herein is a method of enhancing the stabilization of HIF-1 in a cell, comprising contacting a cell in vivo, in vitro or ex vivo with an effective amount of one or more of the described inhibitors of HIF-1α prolyl hydroxylase described.
Also described herein are methods of increasing the cellular immune response of a human or mammal in need of enhanced cellular immunity, comprising administering to a human or mammal in need thereof an effective amount of one or more of the HIF inhibitors -1a prolyl hydroxylase described.
[00223] Further described herein are methods for enhancing the cellular immune response of a human or mammal diagnosed with medical conditions that cause diminished cellular immunity, comprising administering to a human or mammal in need thereof an effective amount of one or more of the HIF-1a prolyl hydroxylase inhibitors.
[00224] Further described herein are methods for enhancing the cellular immune response of a human or mammal diagnosed with medical conditions that cause diminished cellular immunity, comprising administering to a human or mammal in need thereof an effective amount of one or more HIF-1a prolyl hydroxylase inhibitors described.
[00225] Further described herein are methods for enhancing the cellular immune response of a human or mammal having a medical condition that causes diminished cellular immunity, comprising administering to a human or mammal in need thereof an effective amount of one or more HIF-1a prolyl hydroxylase inhibitors described.
As such, the one or more HIF-1a prolyl hydroxylase inhibitor and any co-administered compounds can be administered or contacted with a cell topically, buccally, orally, intradermally, subcutaneously, mucosa in the eye, vaginal, rectum , and nose, intravenously, intramuscularly. Methods related to Cancer Treatment
[00227] As referred to here, cancer is defined as "an abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, metastasize." As such, both types of cancer, non-metastatic and metastatic, can be treated with the methods described.
Described are methods of treating cancer in a human or mammal, comprising administering to a human or mammal having a cancer with an effective amount of one or more of the described HIF-1α prolyl hydroxylase inhibitors.
[00229] Also described herein are methods for treating diagnosed in a human or mammal with cancer, co-administration to a human or mammal of one or more chemotherapeutic agents or chemotherapeutic compounds in conjunction with one or more of the prolyl HIF-1a inhibitors hydroxylases described.
[00230] The following are non-limiting examples of malignant and non-malignant cancers: acute lymphoblastic; acute myeloid leukemia, adrenocortical carcinoma; adrenocortical carcinoma, childhood cancer, appendix cancer, basal cell carcinoma, bile duct cancer, extrahepatic, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brainstem glioma, , adult childhood brain tumor; brainstem glioma, infantile brain tumor, atypical central nervous system teratoid//rhabdoid tumor, infantile, embryonic central nervous system tumours; cerebellar astrocytoma, cerebral astrocytoma/malignant glioma; craniopharyngioma; ependymoblastoma; ependymoma; medulloblastoma; medulloepithelioma; intermediate-differentiated pineal parenchymal tumors; primitive supratentorial neuroectodermal tumors and pineoblastoma; via visual and hypothalamic glioma, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, carcinoid tumor, gastrointestinal; atypical central nervous system teratoid/rhabdoid tumor; embryonic central nervous system tumors, central nervous system lymphoma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, infantile, cervical cancer, chordoma, infantile, chronic lymphocytic leukemia; chronic myelogenous leukemia, chronic myeloproliferative diseases; colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, esophageal cancer, Ewing's family of tumors, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, eye cancer , retinoblastoma; gallbladder cancer, Cancer gastric (stomach) gastrointestinal carcinoid tumor; gastrointestinal stromal tumor (GIST); germ cell tumor, extracranial, germ cell tumor, extragonadal; germ cell tumor, ovary, gestational trophoblastic tumor, glioma, glioma, infant brainstem; glioma, infantile cerebral astrocytoma, glioma, infantile visual pathway and hypothalamic; hairy cell leukemia, head and neck cancer; hepatocellular cancer (liver), histiocytosis, Langerhans cells, Hodgkin's lymphoma, hypopharyngeal cancer, Glioma of the hypothalamic and visual pathway, intraocular melanoma; islet cell tumors, kidney (kidney cell) cancer; Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic; leukemia, , acute myeloid; leukemia, chronic lymphocytic; leukemia, chronic myelogenous; leukemia, hair cells, oral and lip cavity cancer; liver cancer, lung cancer, non-small cell, lung cancer, small cell, lymphoma, AIDS-related; Burkitt's lymphoma, cutaneous T-cell lymphoma, lymphoma, Hodgkin's lymphoma, lymphoma, non-Hodgkin's lymphoma, primary central nervous system; macroglobulinemia, Waldenstrom, malignant fibrous bone histiocytoma and osteosarcoma, medulloblastoma, melanoma, melanoma, intraocular (eye); Merkel cell carcinoma; , mesothelioma; metastatic squamous neck cancer with occult primary, mouth cancer, multiple endocrine (infant) syndrome; multiple myeloma neoplasm/plasma cell, fungoid mycosis, myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases; chronic myeloid leukemia; acute adult myeloid leukemia, acute infantile myeloid leukemia; myeloma, multiple; myeloproliferative disorders, chronic; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer, oral cancer; oral cavity cancer; oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, low potential ovarian malignant tumor, pancreatic cancer, pancreatic cancer, islet cell tumors, papillomatosis, cancer parathyroid, penile cancer, pharyngeal cancer, pheochromocytoma; intermediate differentiation pineal parenchymal tumors, primitive supratentorial pineoblastomae neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma; primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney), renal pelvis and ureter cancer, transitional cell cancer, respiratory tract carcinoma involving the NUT gene on chromosome 15; retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's tumor family, Kaposi's sarcoma, sarcoma, soft tissue, sarcoma, uterine, Sézary syndrome, skin cancer (non-melanoma); skin cancer (melanoma); skin carcinoma, Merkel cells, small cell lung cancer, small bowel cancer, soft tissue sarcoma; squamous cell carcinoma, squamous neck cancer with occult primary, metastatic, gastric (gastric) cancer, primitive supratentorial neuroectodermal tumors, T-cell lymphoma, skin, testicular cancer, throat cancer; Thymoma and thymus carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, gestational, urethral cancer, uterine cancer, endometrial; uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia; and Wilms' tumor.
Also described herein are methods of treating cancer in a human or mammal, comprising co-administration to a human or mammal, together with one or more chemotherapeutic agents or chemotherapeutic compounds, one or more of the HIF-inhibitors. 1α prolyl hydroxylase described.
Also described herein are methods for treating a human or mammal diagnosed with cancer, co-administering to a human or mammal, in conjunction with one or more chemotherapeutic agents or chemotherapeutic compounds, one or more of the HIF-1a inhibitors prolyl hydroxylase described.
A "chemotherapeutic agent" or "chemotherapeutic compound" is a chemical compound useful in the treatment of cancer. Chemotherapeutic cancer agents that can be used in combination with the described HIF-1a inhibitors include, but are not limited to, mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine, vindesine and Navelbine™ (vinorelbine, 5'-noranhydroblastine). In still other embodiments, chemotherapeutic cancer agents include topoisomerase I inhibitors, such as camptothecin compounds. As used herein, "camptothecin compounds" include Camptosar™ (irinotecan HCl), Hycamtin™ (topotecan HCl) and other compounds derived from camptothecin and its analogs. Another category of chemotherapeutic cancer agents that can be used in the methods and compositions described herein are podophyllotoxin derivatives, such as etoposide, teniposide, and mitopodozide. The present invention further encompasses other chemotherapeutic cancer agents known as alkylating agents, which alkylate genetic material in tumor cells. These include, without limitation, cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramidae, carmustine, busulfan, chlorambucil, belustine, uracil mustard, clomafazin, and dacarbazine. The description encompasses antimetabolites as chemotherapeutic agents. Examples of these types of agents include cytosine arabinoside, fluorouracil, methotrexate, mercaptopurine, azathioprine and procarbazine. An additional category of chemotherapeutic cancer agents that can be used in the methods and compositions described herein include antibiotics. Examples include, without limitation, doxorubicin, bleomycin, dactinomycin, daunorubicin, mitramycin, mitomycin, mitomycin C, and daunomycin. There are numerous commercially available liposomal formulations for these compounds. The present invention further encompasses other chemotherapeutic cancer agents including, without limitation, anti-tumor antibodies, dacarbazine, azacitidine, amsacrine, melphalan, ifosfamide and mitoxantrone.
The HIF-1α prolyl hydroxylase inhibitors described herein can be administered in combination with other antitumor agents, including cytotoxic/antineoplastic agents and antiangiogenic agents. Cytotoxic/anti-neoplastic agents are defined as agents that attack and kill cancer cells. Some cytotoxic/anti-neoplastic agents are alkylating agents, which alkylate genetic material in tumor cells, for example, cis-platinum, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, clomafazin, and dakabazine. Other cytotoxic/antineoplastic agents are antimetabolites to tumor cells, for example, cytosine arabinoside, fluorouracil, methotrexate, mercaptopyrin, azathioprime, and procarbazine. Other cytotoxic/anti-neoplastic agents are antibiotics, for example, doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C, and daunomycin. There are numerous commercially available liposomal formulations for these compounds. Still other cytotoxic/anti-neoplastic agents are mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine, and etoposide. Various cytotoxic/antineoplastic agents include taxol and its derivatives, L-asparaginase, anti-tumor antibodies, dacarbazine, azacitidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone and vindesine.
[00235] Anti-angiogenic agents are well known to those skilled in the art. Suitable anti-angiogenic agents for use in the described methods and compositions include anti-VEGF antibodies, including chimeric and humanized 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 metalloproteinase-1 and -2. (TIMP-1 and -2). Small molecules, including topoisomerases, such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity, can also be used.
[00236] Other anticancer agents that can be used in combination with the described HIF-1a inhibitors include, but are not limited to: acivicin, aclarubicin; acodazole hydrochloride; acronine, adozelesin; aldesleucine; altretamine; ambomicin; amethantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; nitrogenomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate, sodium brequinar; bropyrimine; busulfan; cactinomicin; calusterone; characmid; carbtimer; carboplatin, carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemicin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinocin; daunorubicin hydrochloride, decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostalonone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidin; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine, estramustine sodium phosphate; ethanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; phosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea, idarubicin hydrochloride; ifosfamide; ilmofosin; interleukin II (including recombinant interleukin II, or rIL2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-I a, interferon gamma I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaryl; mercaptopurine; methotrexate; sodium methotrexate; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomicin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamicin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomicin sulfate; perphosphamide; pipobroman; piposulfan; pyroxantrone hydrochloride; plicamicin; plomestane; porfimer sodium; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; roglethimide; safingol; safingol hydrochloride; semustina; simtrazene; sodium sparphosate; sparsomicin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporphine; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; thiazofurin; tirapazamine, toremifene citrate; trestolone acetate; triciribin phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinlicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anticancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethinyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adozelesin; aldesleucine; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrografolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostate carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid, ara-CDP-DL-PTBA, arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol, batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine, beta lactam derivatives; beta-aletin; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafid; bistratene A; bizelesin; breflate; bropyrimine; budotitane; butionine sulfoximine; calcipotriol; calfostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagen; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cipemicin; cytarabine ocphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexyphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxyfluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelphosine; edrecolomab; eflornithine; element; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; ethanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide;, filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunounicin hydrochloride; forphenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; hydramantone; ilmofosin; ilomastat; imidazoacridones; imiquimod; immunostimulating peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iodoxorubicin; ipomanol, 4-; iroplact; irsogladin; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte interferon alpha; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; Ipophilic disaccharide peptide; lipophilic platinum compounds; lyssoclinamide 7; lobaplatin; lombrichine; lometrexol; lonidamine; losoxantrone; lovastatin; loxobin; lurtotecan; texaphyrin lutetium; lysophyllin; lytic peptides; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaryl; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; myrimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafid; mitotoxin fibroblast growth factor saporin; mitoxantrone; mopharotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; lipid A monophosphoryl + mycobacterial cell wall sk; mopidamol; multiple drug resistance gene inhibitor; therapy1 based multiple tumor suppressor 1; mustard anticancer agent; micaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavin; nafterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamicin; nitric oxide modulators; nitroxide antioxidant; nitrullin; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomicin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrizoxin; pamidronic acid; panaxytriol; panomiphene; parabactin; pazelliptin; pegaspargase; peldesin; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perphosphamide; peryl alcohol; phenazinomicin; phenylacetate; phosphatase inhibitors; picibanil, pilocarpine hydrochloride, pirarubicin; pyritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds, platinum-triamine complex; porfimer sodium; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase inhibitor C; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; glitters; pyrazoloacridine; pyridoxylated polyoxyethylene hemoglobin conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated retelliptin; rhenium Re 186 etidronate; rizoxin; ribozymes; RII retinamide; roglethimide; rohituccine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; SDI 1 mimetics; semustina; deescence-derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizophiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; soluble; somatomedin binding protein; sonermin; sparphosic acid; espamicin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; hyperactive vasoactive intestinal peptide antagonist; Suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrilium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastin; thiochoralin; thrombopoietin; thrombopoietin mimetic; thymalfasin; timopoietin receptor agonist; timotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; tricribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; Velaresol; veramine; verdins, verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and stimalamer zinostatin. In one embodiment, the anticancer drug is 5-fluorouracil, taxol, or leucovorin. Methods related to the treatment of conditions involving microorganisms
A method of prophylactically treating a human or a mammal against infection by a microorganism is disclosed, comprising administering to a human or mammal an effective amount of one or more of the described HIF-1a prolyl hydroxylase inhibitors.
Further described is a method of decreasing the virulence of a microorganism when a human or mammal is infected with a microorganism, comprising administering to a human or mammal an effective amount of one or more of the HIF-1a prolyl hydroxylase inhibitors described.
[00239] However, described is a method of treating an infection in a human or mammal caused by a microorganism, comprising administering to a human or mammal an effective amount of one or more of the described HIF-1α prolyl hydroxylase inhibitors.
Further described is a method of treating a human or mammal diagnosed with an infection caused by a microorganism, comprising administering to a human or mammal an effective amount of one or more of the described HIF-1α prolyl hydroxylase inhibitors.
Also described is a method for preventing the transmission of a disease caused by a microorganism from a human or mammal to a human or mammal, comprising administering to a human or mammal an effective amount of one or more of the inhibitors of HIF-1α prolyl hydroxylase described.
Further described is a method of preventing infection of a human or a mammal during a surgical procedure, comprising administering to a human or mammal an effective amount of one or more of the described HIF-1α prolyl hydroxylase inhibitors.
[00243] The microorganism can be any benign or malignant microorganism, for example, bacteria, viruses, yeasts, fungi, or parasites. The following are non-limiting examples of microorganisms that can be affected by the described HIF-1α prolyl hydroxylase inhibitors. By the term "affected" is meant, the virulence of the microorganism is reduced, diminished or eliminated. The cause of the reduction, decrease, or removal of virulence may be from stabilization of HIF-1 and/or from the level of phagocytosis due to administration of one or more of the HIF-1α prolyl hydroxylase inhibitors described.
00244 Bacteroides vulgatus, Bordetella bronchiseptica, Bordetella parapertussis, Bordetella pertussis, Borrelia burgdorferi, Branhamella catarrhalis, Brucella melitensis, Burkholderia cepacia, Burkholderia pseudomallei, Campylobacter coli, Campylobacterfetus, Campylobacterfetus,Campylobacter,Clobacter,Difficule,Cylobacter Corynebacterium glutamicum, Corynebacterium ulcerans, Edwardsiella tarda, Enterobacter aerogenes, Erwinia chrysanthemi, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Francisella tularensi s, Gardnerella vaginalis, Haemofilus ducreyi, Haemofilus haemolyticus, Haemofilus influenzae Haemofilus parahaemolyticus, Haemofilus parainfluenzae, Helicobacter pylori, Klebsiella oxytoca, Klebsiella pneumoniae, cryocrescens Kluyvera, 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 , P. , Pseudomonas alcaligenes, Pseudomonasfluorescens, 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 saprofyticus, 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
Described herein are methods of increasing the efficacy of a vaccine, comprising co-administering to a human or mammal a vaccine in combination with one or more HIF-1a prolyl hydroxylase inhibitors.
[00246] Non-limiting examples of vaccines are those to raise antibodies against hepatitis, flu, measles, rubella, tetanus, polio, rabies, and the like.
[00247] Therefore, the methods described include the administration, or in the case of cell contact in vitro, in vivo or ex vivo, of one or more HIF-1α prolyl hydroxylase inhibitors and any compounds co-administered topically, buccally, orally , intradermal, subcutaneous, ocular, vaginal, rectal, and nasal, intravenous and intramuscular mucosa. PROCEDURES EGLN-1 Activity Assay
[00248] The activity of the enzyme EGLN-1 (or EGLN-3) is determined using mass spectrometry (matrix-assisted laser desorption ionization, time-of-flight EM, EM MALDI-TOF). Recombinant human EGLN-1-179/426 is prepared as described above and in the Supplemental Data. Recombinant full-length human EGLN-3 is similarly prepared; however, it is necessary to use the His-MBP-TVMV-EGLN-3 fusion for the assay because of the instability of the cleaved protein. For both enzymes, the HIF-1α peptide corresponding to residues 556-574 is used as substrate. The reaction is conducted in a total volume of 50 μl containing TrisCl (5 mM, pH 7.5), ascorbate (120 μM), 2-oxoglutarate (3.2 μM), HIF-1α (8.6 μM), and bovine serum albumin (0.01%). The enzyme, in an amount predetermined to hydroxylate 20% of substrate in 20 minutes, is added to start the reaction. When inhibitors are used, compounds are prepared in dimethyl sulfoxide at 10x the final assay concentration. After 20 minutes at room temperature, the reaction is stopped by transferring 10 μl of the reaction mixture to 50 μl of a mass spectrometry matrix solution (α-cyano-4-hydroxycinnamic acid, 5 mg/mL in 50% acetonitrile /0.1% TFA, 5 mM NH4PO4). 2 microliters of the mixture is poured onto a MALDI-TOF EM target plate for analysis with a 4700 Proteomics Analyzer MALDI-TOF MS from Applied Biosystems (Foster City, California, USA) equipped with a Nd:YAG laser (355 nm, width of 3 ns pulse, 200 Hz repetition rate). The hydroxylated peptide product is identified from the substrate by the gain of 16 Da. Data defined as percent substrate to product conversion is analyzed in GrafPad Prism 4 to calculate IC50 values. VEGF ELISA Assay
[00249] HEK293 cells were germinated in poly-lysine-coated 96-well plates at 20,000 cells per well in DMEM (10% FBS, 1% NEAA, 0.1% glutamine). After overnight incubation, cells are washed with 100 µl of Opti-MEM (Gibco, Carlsbad, CA) to remove serum. Compound in DMSO is serially diluted (starting at 100 µM) in Opti-MEM and added to the cells. Conditioned media is analyzed for VEGF with a Quantikine human VEGF immunoassay kit (R&D Systems, Minneapolis, MN). Optical density measurements at 450 nm are recorded using Spectra Max 250 (Molecular Devices, Sunnyvale, CA). Data defined as percent DFO stimulus is used to calculate EC50 values with GraphPad Prism 4 software (San Diego, CA). Study of ischemic hind limbs in mice
[00250] All work with animals is conducted in accordance with the guidelines in the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences; Copyright ©1996). 9 - 10 week old male C57B1/6 mice from the Charles River Laboratory (Portage, MI) were used in these experiments. The mice received oral dosage with vehicle (aqueous carbonate buffer, 50 mM; pH 9.0) or with compound to be tested in vehicle at 50 mg/kg or 100 mg/kg. The animals were dosed three times: on Day 1 at 8:00 am and at 5:00 pm, and on Day 2 at 8:00 am. One hour after the first dose, a unilateral arterial ligation is performed under anesthesia using isoflurane. The femoral artery is connected proximally to the origin of the popliteal artery. The contralateral limb undergoes a sham surgical procedure. Binding is performed alternately between the right and left hind limbs. Two hours after the 8:00 h dosing on Day 2, blood is obtained by ventricular swab while the mice are anesthetized with isoflurane. Serum samples for EPO analysis are obtained using serum and clot gel separation tubes. Heart, liver, and gastronemic muscles are harvested, snap frozen in liquid nitrogen, and stored at -80°C until use. Mouse Serum EPO Assay
Mouse serum EPO is detected using the Mouse Quantikine Erythropoietin ELISA kit from R&D Systems according to the manufacturer's instructions. Western Blot Analysis of HIF in Mouse Tissues
[00252] Tissues from mice stored at -80°C are powdered with a mortar and pestle cooled with liquid nitrogen. Nuclear extracts are prepared using an NE-PER kit (Pierce Biotechnology). For immunoprecipitation, nuclear extract is added to monoclonal antibody to HIF1-α (Novus, Littleton, CO) at a tissue to antibody ratio of 200:1. The suspension is incubated in a micro conical centrifuge tube for 4 hours at 4°C. Protein A/G-coupled agarose beads (40 µl of a 50% suspension) are then added to the tube. After stirring overnight at 4°C, the beads are washed three times with ice-cold phosphate-buffered saline. Beads are then prepared for SDS-PAGE with 40 µl of Laemmli sample buffer. Proteins separated on SDS-PAGE are transferred onto nitrocellulose slides with the XCell-II Blot Module system (Invitrogen, Carlsbad, CA). Blots are blocked with 5% BSA prior to incubation with a rabbit antibody to HIF1-α at a 1:100 dilution (Novus). Blots are then washed with Tris/Tween-20 saline buffer and incubated with horseradish peroxidase-conjugated goat anti-rabbit secondary antibodies (Pierce, Rockford, IL). Blots are developed with ECL reagent (Amersham, Piscataway, NJ). Spot images are captured with an Epson Expression 1600 scanner.
[00253] Table VIII below provides non-limiting examples of the in vivo response for compounds according to the present invention, for example, the inhibition of HIFF2 (EGLN1) and the stimulation of VEGF. TABLE VIII



[00254] Compound F2 was further tested in the mouse serum EPO assay described here above, and showed an EPO of EC50 = 14 μM. increased neutrophil activity
[00255] One aspect of the invention relates to the increased neutrophil activity and increased neutrophil life that the described compounds can offer. The following are methods and examples of increased phagocytosis by the described compounds. In the examples below, the cell strain of Newman Staphylococcus aureus is ATCC #25904, and the methicillin resistant strain of Staphylococcus aureus is ATCC #33591, and the cell lineage U937 is ATCC #CRL-1593.2. HaCaT cells were generated by the procedure of Boukamp P et al., "Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line." J Cell Biol. (1988) Mar:106(3):761-71.
[00256] For bacterial assays, S. Aureus (ATCC 33591) can be grown in Todd-Hewitt broth (THB) until logarithmic phase (OD600 of 0.4 or ~5 x 107 cfu/ml) and then pelleted, washed and resuspended in PBS or RPMI 1640 tissue culture medium to the desired concentration. Venous blood from healthy volunteers can be used for isolation of whole blood and neutrophils. Neutrophils can be purified using the PolyMorfPrep kit (Axis Shield) according to the manufacturer's instructions. The human monocytic cell line U937 can be propagated in RPMI 1640 plus 10% fetal bovine serum, 1 mmol/L NaPyr, 10 mmol/L HEPES, and glucose. Whole blood or phagocytic cells can be pre-incubated with mimosin (Sigma-Aldrich) (0 - 500 µmol/L) for 2 - 4 hours, then challenged with S. Aureus (105 cfu in 100 µl added to 300 μl of whole blood or at an MOI of 1 bacterium/cell for isolated phagocytes). Aliquots are then placed on THB agar after 30 (whole blood and neutrophils) or 60 (U937) minutes for enumeration of surviving S. aureus colony-forming units. EXAMPLE 5
[00257] Isolated human neutrophils were pre-incubated for 1 hour at 37°C with a control consisting of dimethyl sulfoxide (DMSO), 50 μM and 200 μM of a compound described in Table VIII. Staphylococcus aureus (Newman's strain) was then added to the neutrophils at an MOI of approximately 0.1 (1 bacteria for every 10 neutrophils). Samples were collected at 60 and 90 minutes, where neutrophils were lysed with water, and the remaining total bacteria were enumerated on Todd-Hewitt broth (THB) agar plates.
[00258] Figure 2 illustrates the efficacy of a compound described in Table VIII in providing an increased killing of S. aureus (Newman strain) at concentrations of 50 μM and 200 μM versus control. As can be seen in Figure 2, at 90 minutes post-infection, approximately half of the colony-forming units are absent at a concentration of 200 μM. EXAMPLE 6
[00259] Cells of the human monocytic cell line U937 were pre-incubated for 2 hours at 37°C under an atmosphere of 5% CO2 with a control consisting of DMSO and 10 µM of a compound described in Table VIII. Staphylococcus aureus (virulent Newman strain) was then added to the cells at an MOI of approximately 1 (1 bacteria for every 1 cell). Samples were collected at 30, 60, 90 and 120 minutes post-infection. U937 cells were lysed with TritonTM, and the amount of bacteria remaining was enumerated on THB agar plates.
As illustrated in Figure 3, a 4-prolyl hydroxylase inhibitor compound described in Table VIII is effective in killing S. aureus compared to a control (DMSO). After 120 minutes, a compound described in Table VIII produces an 84% kill of the Newman S. aureus strain when monocytic cells are treated with 10 µM of a compound described in Table VIII, thus showing increased phagocytosis due to the lifetime of the extended neutrophil. EXAMPLE 7
[00261] Two cell samples from the human monocytic cell line U937 were pretreated with 10 µM of a compound described in Table VIII. One sample was pre-incubated for 1 hour, and the other sample was pre-incubated for 2 hours, both at 37°C under an atmosphere of 5% CO 2 . S. aureus (virulent Newman strain) was then added to the cells at an MOI of approximately 1 - 2 (1 - 2 bacteria for each cell). Aliquots of cells were removed from each sample at 30, 60, 90 and 120 minutes post-infection, U937 cells were immediately lysed with TritonTM, and total remaining bacteria were enumerated on THB agar plates.
[00262] As illustrated in Figure 4, U937 monocytic cells pretreated with 10 µM of a compound described in Table VIII for 1 hour (black bars) did not contain any colony forming units present at 120 minutes post-infection, while that cells pretreated 2 hours before infection had approximately 15% colony forming units present compared to cells that were not treated. In addition, Figure 4 indicates that within 1 hour after U937 monocytic cells were exposed to S. aureus (Newman's strain), the number of colony-forming units present was significantly reduced relative to cells that did not receive S. aureus inhibitor. HIF-1α. EXAMPLE 8
Two cell samples from the human monocytic cell line U937 were pretreated with 10 µM of a compound described in Table VIII for 1 hour at 37°C under an atmosphere of 5% CO2. S. aureus (Newman's strain) was added to one sample, and to the other, methicillin-resistant S. aureus (MRSA) was added. Both bacteria were added at an MOI of approximately 2 - 3 (2 - 3 bacteria for every 1 cell). Aliquots of cells were removed from each sample at 30, 60, 90 and 120 minutes post-infection. U937 cells were immediately lysed with Triton™, and total remaining bacteria were enumerated on THB agar plates.
[00264] As illustrated in Figure 5, at 120 minutes post-infection, cells infected with MRSA had only 25% of the mean percentage of colony forming units present compared to the control as represented by the black bars. As also illustrated in Figure 5, at 60 minutes post-infection, the Newman strain of S. aureus had only approximately 12% of the mean percentage of colony-forming units present compared to the control, and almost no colony-forming units were present. present at 120 minutes post-infection as represented by the dashed bars. EXAMPLE 9
Two cell samples from the U937 human monocytic cell line treated with 10 µM of a compound described in Table VIII were infected with S. aureus (Newman's strain) or with methicillin-resistant S. aureus (MRSA). Both bacteria were added at an MOI of approximately 2 - 3 (2 - 3 bacteria for every 1 cell). Aliquots of cells were removed from each sample at 30, 60, 90 and 120 minutes post-infection. U937 cells were immediately lysed with Triton™, and total remaining bacteria were enumerated on THB agar plates.
[00266] As illustrated in Figure 6, even without pretreatment with a compound described in Table VIII, within 60 minutes of post-infection, the Newman strain of S. aureus had only 25% of the mean percentage of colony forming units present compared to the control as represented by the black bars. The MRSA strain was reduced to less than approximately 40% of the mean percentage of colony forming units present compared to the control as represented by the dashed bars. EXAMPLE 10
[00267] Three cell samples from the U937 human monocytic cell line were treated with 100 µM mimosin, 2 µg/ml vancomycin, or 10 µM of a compound described in Table VIII. Each sample was infected with either S. aureus (Newman strain) or methicillin-resistant S. aureus (MRSA). Both bacteria were added at an MOI of approximately 2 - 3 (2 - 3 bacteria for every 1 cell). Within 120 minutes of post-infection, aliquots were removed from all six samples and U937 cells were immediately lysed with TritonTM, and total remaining bacteria were enumerated on THB agar plates.
[00268] As illustrated in Figure 7, 10 µM of a compound described in Table VIII increased the killing of both bacterial strains, ie, S. aureus, Newman (dashed bars) or MRSA (black bars), compared to the cells treated with mimosin. With reference to the dashed bars representing the Newman strain, as further illustrated in Figure 7, the sample treated with 10 µM of a compound described in Table VIII had a lower mean percentage of colony forming units present than cells treated with vancomycin . MRSA-infected U937 cells (black bars) had approximately 40% colony forming units present versus untreated cells and less than half the number of those treated with minosin.
[00269] Figure 8 depicts the average percentage of colony-forming units present (Newman strain) versus control for human monocytic cells (U937) at 30, 60, 90 and 120 minutes post-infection when treated with 10 μM of a compound described in Table VIII. Black bars represent treatment with a compound described in Table VIII starting at the time of infection with S. aureus, dashed bars represent cells pretreated with a compound described in Table VIII, and white bars represent cells pretreated two hours before infection with S. aureus.
[00270] Figure 9 depicts the mean percentage of colony forming units present at 120 minutes post-infection versus DMSO (control) when HaCaT cells are pretreated for 1 hour according to the examples above with 800 μM of mimosin, 10 µM of a compound described in Table VIII, or 1 µg/ml vancomycin, followed by inoculation with S. aureus (Newton's strain, dashed bars) and methicillin resistant S. aureus (MRSA, black bars).
[00271] Figure 10 depicts the average percentage of colony-forming units present at 30, 60, 90 and 120 minutes post-infection for the Newton strain of S. aureus (dashed bars) and MRSA (black bars) when HaCaT cells are pretreated for 1 hour according to the above examples with 10 µM of a compound described in Table VIII.
[00272] Figure 11 depicts the upregulation of phosphoglycerate kinase (PGK) expression in wild-type murine embryonic fibroblasts as a result of treatment with a compound described in Table VIII at dosages of 1 μM (E), 10 μM (F ), and 50 μM (G) versus wild-type control (H), and the absence of up-regulation of PGK expression in HIF-1 inactivating cells as a result of treatment with a compound described in Table VIII at dosages of 1 μM (A), 10 μM (B), and 50 μM (C) and HIF-1 inactivation control (D). Both cell types were treated for 7 hours.
[00273] Figure 12 depicts the upregulation of phosphoglycerate kinase (PGK) expression in wild-type murine embryonic fibroblasts as a result of treatment with a compound described in Table VIII at dosages of 1 μM (E), 10 μM (F ), versus wild-type control (G) and the absence of up-regulation of PGK expression in HIF-1 inactivating cells as a result of treatment with a compound described in Table VIII at dosages of 1 μM (A), 10 µM (B), and 50 µM (C) and HIF-1 inactivation control (D).
[00274] Figure 13 depicts the upregulation of phosphoglycerate kinase (PGK) expression in wild-type murine embryonic fibroblasts as a result of treatment with a compound described in Table VIII at dosages of 1 μM (E), 10 μM (F ), and 50 μM (G) versus wild-type control (H) and the absence of up-regulation of PGK expression in HIF-1 inactivating cells as a result of treatment with a compound described in Table VIII at dosages of 1 µM (A), 10 µM (B), and 50 µM (C) and HIF-1 inactivation control (D).
[00275] The Vascular Endothelial Growth Factor (VEGF) is dependent on the presence of HIF-1 in cells. Figure 14 depicts the upregulation of vascular endothelial growth factor (VEGF) expression in wild-type murine embryonic fibroblasts as a result of treatment with a compound described in Table VIII at dosages of 1 μM (E), 10 μM (F ), and 50 μM (G) versus control (H), and the absence of up-regulation of VEGF expression in HIF-1 inactivating cells treated with a compound described in Table VIII at dosages of 1 μM (A), 10 µM (B), and 50 µM (C) and HIF-1 inactivation control (D). Both cell types were treated for 7 hours. As seen in Figure 14, VEGF is increased when receiving doses of 10 μM (F) and 50 μM (G). In HIF-1 knockout cells, there is no increase in PGK upregulation when HIF-1 knockout cells receive doses of 1 µM (A), 10 µM (B), and 50 µM (C) compared to the wild type control (H) and with the HIF-1 inactivation control (D). Healing wounds EXAMPLE 11
[00276] Twenty-four (24) mice were divided into three groups. Animals in Group 2 were given bacterial inoculum (antibiotic-sensitive Newman strain of Staphylococcus aureus [ATCC #25904]) by subcutaneous injection on Day 0 and received 10 µM of a compound described in Table VIII for 6 days starting at 2 hours of post-infection (Days 0 - 5). Group 1 received subcutaneous injections of DMSO. Group 3 served as a control group and received no treatment. The size of the lesions was monitored daily during the study. Only open wounds were considered injuries; lumps and white spots without an open wound were not measured for lesion size. On Day 7, the final lesion size was measured and mice were sacrificed for the determination of bacterial load on the skin and kidneys. On Day 7 post-infection, mice were sacrificed after the final lesion size measurement and the injured skin tissues and both kidneys were collected. Skin and kidneys were homogenized in phosphate-buffered saline, serially diluted, and placed on Todd-Hewitt agar plates to enumerate bacterial colony-forming units.
[00277] Figure 15 shows the significant reduction in the size of skin lesions (wounds) for Group 1 animals (solid circles (•)) treated with 10 µM of a compound described in Table VIII versus animals treated with DMSO ( solid squares (■)). As illustrated in Figure 15, mice infected with the Newman strain of S. aureus followed treatment with 10 μM of a compound described in Table VIII or DMSO (control) within 2 hours post-infection. The data show the statistically significant reduction in the size of skin lesions (wounds) for animals treated with a compound described in Table VIII (solid circles (•)) or DMSO (solid squares (■)).
[00278] Figure 16 shows the significant reduction in the size of skin lesions (wounds) for Group 1 animals (solid circles (•)) treated with 10 µM of a compound described in Table VIII versus untreated animals (triangles solids (▲)). As illustrated in Figure 16, mice infected with the Newman strain of S. aureus followed treatment with 10 µM of a compound described in Table VIII or no treatment within 2 hours of post-infection. The data show the reduction in the size of skin lesions (wounds) for animals treated with a compound described in Table VIII (solid circles (•)) or untreated (solid triangles (▲)). EXAMPLE 12
[00279] Twenty-four (24) mice were divided into three groups. Animals in Group 1 were administered bacterial inoculum (antibiotic-sensitive Newman strain of Staphylococcus aureus [ATCC #25904]) by subcutaneous injection on Day 0 and received 10 µM of a compound described in Table VIII for 6 days starting at 2 hours post-infection (Days 0 - 5). Group 2 received subcutaneous injections of DMSO. Group 3 served as a control group and received no treatment. The size of the lesions was monitored daily during the study. Only open wounds were considered injuries; lumps and white spots without an open wound were not measured for lesion size. On Day 7 post-infection, mice were sacrificed after the final lesion size measurement and the injured skin tissues and both kidneys were collected. Skin and kidneys were homogenized in phosphate-buffered saline, serially diluted, and placed on Todd-Hewitt agar plates to enumerate bacterial colony-forming units.
[00280] Figure 17 is a histogram in which the number of colony forming units observed per gram of skin tissue is shown. Straight lines indicate the average value for each group. The results for the untreated group are plotted under (A), the results for the DMSO treated group are plotted under (B), and the results for the group treated with 10 µM of a compound described in Table VIII are plotted under ( Ç).
[00281] Figure 18 is a graph of the observed bacterial colony-forming units found in the kidneys of animals. The results for the untreated group are plotted under (A), the results for the DMSO treated group are plotted under (B), and the results for the group treated with 10 µM of a compound described in Table VIII are plotted under ( Ç). As can be seen from these data, half of the animals treated with the HIF-1a prolyl hydroxylase inhibitor described in Table VIII had no bacteria in the kidneys, indicating that the compound described in Table VIII was able to systematically prevent the spread of wound infection to the kidneys. EXAMPLE 13
[00282] Twenty (20) mice were divided into two groups. Animals in Group 1 given bacterial inoculum (Streptococcus pyogenes NZ131 [strain M49]) by subcutaneous injection on Day 0 were pretreated with a compound described in Table VIII once daily for 4 days starting at 2 hours pre- infection (Days 0 - 3). The compound described in Table VIII was formulated in cyclodextran and diluted in distilled water before subcutaneous injection, at a dose of 0.5 mg/kg. Lesion size was monitored daily throughout the study. Only open wounds were considered injuries; lumps and white spots without an open wound were not measured for lesion size. On Day 4 post-infection, mice were sacrificed after the last lesion size measurement, and the injured skin tissues and both kidneys were collected. Skin and kidneys were homogenized in phosphate-buffered saline, serially diluted, and placed on Todd-Hewitt agar plates to enumerate bacterial colony-forming units.
[00283] Figure 19 depicts the results of Example 13, where two groups of animals are treated with Streptococcus pyogenes NZ131 [strain M49]. The data show the reduction in size of skin lesions (wounds) for Group 1 animals (solid triangles (▲)) treated with 0.5 mg/kg of a compound described in Table VIII versus animals treated with vehicle control (cyclodextran ) (solid circles (•)). Figure 20 is a histogram that also depicts the results of Example 12, in which the number of colony-forming units for skin lesions observed in animals treated with vehicle control (cyclodextran) is labeled under (A), and the results for the group treated with 0.5 mg/kg of a compound described in Table VIII are plotted under (B). KITS
Kits comprising HIF-1α prolyl hydroxylase inhibitors to be administered to a human, mammal or cell are also described. Kits can comprise one or more packaged dosage units of a composition comprising one or more HIF-1α prolyl hydroxylase inhibitors to be delivered to a human, mammal, or cell. Dosage unit ampoules or multiple dose containers, in which the HIF-1α prolyl hydroxylase inhibitors to be administered are packaged before use, may comprise a hermetically sealed container containing an amount of polynucleotide or solution containing a substance suitable for a pharmaceutically effective dose thereof, or multiples of an effective dose. The HIF-1a prolyl hydroxylase inhibitor can be packaged as a sterile formulation, and the hermetically sealed container is designed to preserve the sterility of the formulation until use.
[00285] The HIF-1a prolyl hydroxylase inhibitors described may also be present in liquids, emulsions or suspensions for the administration of active therapeutic agents in aerosol form in body cavities, such as the nose, throat or bronchial passages. The ratio of HIF-1a prolyl hydroxylase inhibitors to the other component agents in these preparations will vary depending on the dosage form required.
[00286] Depending on the desired mode of administration, the pharmaceutical compositions may be in solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams , gels, or the like, preferably in a unit dosage form suitable for the single administration of a precise dose. The compositions will include, as indicated above, an effective amount of the HIF-1α prolyl hydroxylase inhibitor in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
[00287] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceuticals of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Pharmaceutically administrable liquid compositions may, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine acetate sodium, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, referred to above.
[00288] Parenteral administration, if used, is usually characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to injection, or as emulsions. A more recently revised approach to parenteral administration involves the use of a slow-release or extended-release system so that a constant dosage level is maintained. See, for example, U.S. Patent No. 3,710,795, which is incorporated herein by reference.
[00289] When HIF-1α prolyl hydroxylase inhibitors are administered to a mammal other than a human, the mammal may be a non-human primate, horse, pig, rabbit, dog, sheep, goat, cat, guinea pig. -Indian or rodent. The terms "human" and "mammal" do not denote a particular age or sex. Therefore, adult and newborn individuals, as well as fetuses, whether male or female, are covered. A patient, individual, human or mammal refers to an individual afflicted with a disease or disorder. The term "patient" includes both human and veterinary individuals.
[00290] Although particular embodiments of the present invention have been illustrated and described, it will be obvious to those skilled in the art that various other changes and alterations can be made without departing from the spirit and scope of the invention. Therefore, it is intended to cover in the appended claims all such modifications and alterations which are within the scope of this invention.

权利要求:
Claims (21)
[0001]
1. Compound, characterized by having the formula:
[0002]
2. Compound according to claim 1, characterized in that R4 is methyl.
[0003]
3. Compound according to claim 1, characterized in that R4 is ethyl.
[0004]
4. Compound according to claim 1, characterized in that R4 is tert-butyl.
[0005]
5. Compound according to any one of claims 1 to 4, characterized in that Z is 4-chlorophenyl.
[0006]
6. Compound according to any one of claims 1 to 4, characterized in that Z is selected from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.
[0007]
7. Compound according to any one of claims 1 to 4, characterized in that Z is selected from 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2, 3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, and 2,6-dichlorophenyl.
[0008]
A compound according to any one of claims 1 to 7, characterized in that it is tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate.
[0009]
A compound according to any one of claims 1 to 7, characterized in that it is selected from: Methyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4- yl]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; and tert-Butyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate.
[0010]
10. Compound according to any one of claims 1 to 9, characterized in that the compound is a pharmaceutically acceptable salt of an anion selected from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, hydrogen sulfonate, p-toluenesulfate, methanesulfonate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, glycolate or citrate.
[0011]
11. Pharmaceutical composition, characterized in that it comprises: a) one or more compounds, as defined in any one of claims 1 to 10; and b) one or more pharmaceutically acceptable excipients.
[0012]
12. Composition according to claim 11, characterized in that R4 is methyl.
[0013]
13. Composition according to claim 11, characterized in that R4 is ethyl.
[0014]
14. Composition according to claim 11, characterized in that R4 is tert-butyl.
[0015]
15. Composition according to any one of claims 11 to 14, characterized in that Z is 4-chlorophenyl.
[0016]
16. Composition according to any one of claims 11 to 14, characterized in that Z is selected from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.
[0017]
17. Composition according to any one of claims 11 to 14, characterized in that Z is selected from 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2, 3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, and 2,6-dichlorophenyl.
[0018]
18. Composition according to claim 11, characterized in that it comprises tert-butyl 4-{[1-(4-chloro-benzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4- yl]methyl}piperazine-1-carboxylate.
[0019]
19. Composition according to claim 11, characterized in that it comprises one or more compounds selected from: Methyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridine -4-yl]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; or tert-Butyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate.
[0020]
20. Composition according to any one of claims 11 to 19, characterized in that the compound is a pharmaceutically acceptable salt of an anion selected from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, hydrogen sulfonate, p-toluenesulfonate, methanesulfonate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, glycolate or citrate.
[0021]
21. Composition according to any one of claims 11 to 20, characterized in that the composition further comprises an antimicrobial agent.

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法律状态:
2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-10-15| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-10-06| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-11-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-02-23| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2021-06-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-08-03| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/11/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

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申请号 | 申请日 | 专利标题

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US25891809P| true| 2009-11-06|2009-11-06|

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US25891409P| true| 2009-11-06|2009-11-06|

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US61/258,914|2009-11-06|

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US61/258,918|2009-11-06|

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PCT/US2010/055694|WO2011057115A1|2009-11-06|2010-11-05|Prolyl hydroxylase inhibitors|

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