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    • 专利摘要:
    compound, composition, method of inhibiting aoss / pav-1 amine oxidase activity, method of treating a disease associated with or modulated by aoss / pav-1 and use of a compound. the present invention relates to the preparation and use of substituted 3-haloalylamine derivatives as aoss / pav-1 inhibitors having the structure of formula i, as defined in the specification. the present invention also relates to methods of using the compounds of formula i or pharmaceutically acceptable salts or derivatives thereof for the treatment of a number of indications, for example, inflammatory diseases, eye diseases, fibrotic diseases, diseases induced by diabetes and cancer .
    公开号:BR112014027406B1
    申请号:R112014027406-1
    申请日:2013-04-05
    公开日:2020-09-24
    发明作者:Mandar Deodhar；Alison Dorothy Findlay；Jonathan Stuart Foot；Wolfgang Jarolimek；Ian Alexander Mcdonald；Alan Robertson；Craig Ivan Turner
    申请人:Boehringer Ingelheim International Gmbh；
    IPC主号:
    专利说明:

    [0001] [001] The present invention relates to new compounds that are capable of inhibiting certain enzymes amine oxidases. These compounds are useful for the treatment of a variety of indications, for example, the symptoms of inflammation and / or fibrosis in human patients, as well as in domestic animals and livestock, for the treatment of psychological diseases, neurodegenerative disorders and the like. In addition, the present invention relates to pharmaceutical compositions containing these compounds, as well as to various uses thereof. Background of the Invention
    [0002] [002] Semicarbazide-sensitive amine oxidase (AOSS), also known as primary amine oxidase, plasma amine oxidase and benzylamine oxidase, is identical in structure with the vascular adhesion protein-1 (PAV-1). In the discussion that follows, the term AOSS / PAV-1 is used to describe this protein. The role of this protein in inflammatory diseases has been reviewed (see, for example, Smith DJ and Vaino PJ, Targeting Vascular Adhesion Protein-1 to Treat Autoimmune and Inflammatory Diseases. Ann. NY Acad. Sci. 2007, 1110, 382- 388; and McDonald LA et al., Semicarbazide Sensitive Amine Oxidase and Vascular Adhesion Protein-1: One protein Being Validated as a Therapeutic Target for Inflammatory Diseases. Annual Reports in Medicinal Chemistry, 2008, 43, 229-241).
    [0003] [003] In most organisms, including humans, two families of mammalian amine oxidases metabolize various mono-, di- and polyamines produced endogenously or absorbed from exogenous sources. These include monoamine oxidases (MAO-A and MAO-B) which are present in the mitochondria of most cell types and use covalently linked flavin and adenine (FAD) dinucleotides as a cofactor. Polyamine oxidase is another FAD-dependent amine oxidase that oxidatively removes amine from sperm and spermidine. AOSS / PAV-1 belongs to the second family, which is copper dependent and uses other cofactors in addition to FAD, such as an oxidized tyrosine residue (abbreviated as TPQ or LTQ). MAO and AOSS / PAV-1 oxidatively remove amine from some common substrates that include monoamines such as dopamine, tyramine and benzylamine. AOSS / PAV-1 also oxidizes endogenous methylamine and aminoacetone.
    [0004] [004] Some of these enzymes were originally defined by the ability of certain compounds to inhibit their enzymatic activity. For example, MAO-A is selectively inhibited by clorgillin, MAO-B by L-deprenyl, while neither clorgillin nor L-deprenyl can inhibit AOSS / PAV-1 amine oxidase activity. AOSS / PAV-1 can be inhibited by semicarbazide, hence the name of semicarbazide-sensitive amine oxidase.
    [0005] [005] AOSS / PAV-1 is an ectoenzyme containing a very short cytoplasmic tail, a single transmembrane domain and a large highly glycosylated extracellular domain, which contains the active center for amine oxidase activity. AOSS / PAV-1 is also present in a soluble form that circulates in the plasma of some animals. This form has been shown to be a membrane-bound AOSS / PAV-1 cleavage product.
    [0006] [006] AOSS / VAP-1 appears to have two physiological functions: the first is the amine oxidase activity mentioned above and the second is cell adhesion activity. Both activities are associated with inflammatory processes. AOSS / PAV-1 has been shown to play an important role in the leakage of inflammatory cells from the circulation to sites of inflammation (Salmi M. and Jalkanen S., VAP-1: an adhesin and na enzyme. Trends Immunol. 2001, 22, 211 -216). PAV-1 protein antibodies have been shown to attenuate inflammatory processes by blocking the AOSS / PAV-1 protein adhesion site and, in conjunction with a substantial amount of evidence from in vitro and in vivo studies in knockouts, it is now clear that AOSS / PAV-1 protein is an important mediator of cellular inflammation. Transgenic mice lacking AOSS / PAV-1 exhibit reduced leukocyte adhesion to endothelial cells, reduced lymphocytes towards the lymph glands and a concomitant attenuated inflammatory response in a peritonitis model. These animals were healthy, grew normally, were fertile, and examination of various organs and tissues showed the normal phenotype. In addition, AOSS / V AP-1 amine oxidase activity inhibitors have been found to interfere with leukocyte rolling, adhesion and extravasation and, similar to AOSS / PAV-1 antibodies, have anti-inflammatory properties.
    [0007] [007] Inflammation is the immune system's first response to infection or irritation. The migration of leukocytes from the circulation to the tissues is essential for this process. Inappropriate inflammatory responses can result in local inflammation, otherwise healthy tissue, which can lead to disorders such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and respiratory diseases. Leukocytes first adhere to the endothelium by binding to adhesion molecules before they can begin the process of passing through blood vessel walls. Membrane-bound AOSS / PAV-1 is abundantly expressed in vascular endothelial cells, such as lymphoid high endothelial cell (VEA) cells and is also expressed in sinusoidal hepatic endothelial cells (CEHS), smooth muscle cells and adipocytes. The expression of AOSS / PAV-1 on the cell surface of endothelial cells is strictly regulated and is increased during inflammation. In the presence of AOSS / PAV-1 substrate (benzylamine), NFkB was activated in CEHSs along with the uptake of other adhesion molecules, E-selectin and chemokines CXCL8 (IL-8), in vitro. A recent study confirms this result, showing (by mutagenesis) that the transcription and translation of E-selectin and P-selectin is induced by the activity of the AOSS / PAV-1 enzyme. These results suggest an important role of AOSS / PAV-1 amine oxidase activity in the inflammatory response. AOSS / PAV-1 oxidase activity has been reported to induce endothelial E- and P-selectins and binding leukocytes (Jalkanen, S. et al., The oxidase activity of vascular adhesion protein-1 (VAP-1) induces endothelial E- and P-selectins and leukocyte binding (Blood 2007, 110, 1864-1870).
    [0008] [008] Excessive and chronic inflammatory responses have been associated with the symptoms of many chronic diseases, such as rheumatoid arthritis, multiple sclerosis, asthma and chronic obstructive pulmonary disease (COPD). Patients suffering from atopic eczema or psoriasis (or both chronic inflammatory skin diseases) have higher levels of AOSS / PAV-1 positive cells in their skin compared to the skin of healthy controls.
    [0009] [009] Asthma can be considered a disease that results from chronic inflammation of the airways that results in bronchoconstriction and excessive accumulation of mucus. Many patients can be treated appropriately with bronchodilators (eg, β2 agonists, leukotriene antagonists and with inhalable steroids). However, up to about 20% of patients suffer from severe asthma and do not respond well to these treatments. A subset of these patients are resistant to inhalable steroids and have high neutrophil counts in their lung fluids. AOSS / PAV-1 is expressed in the lungs and plays a role in neutrophil trafficking.
    [0010] [0010] Another subgroup of patients with asthma is extremely sensitive to viral airway infections; such infections exacerbate the underlying inflammation and can lead to attacks of severe asthma.
    [0011] [0011] It has recently been recognized that patients suffering from cystic fibrosis often suffer from persistent pulmonary inflammation, which can be independent of chronic lung infection. It has been argued that tissue damage in patients with cystic fibrosis is due to mediators released by neutrophils. While standard antibiotic treatment to eliminate bacterial infection would be expected to resolve the underlying inflammation, if the inflammation was solely due to the infection, data from recent studies demonstrate that this is not the case and that the airways are in a healthy state. inflammatory drug directed by neutrophils prepared for the excessive and prolonged inflammatory response to bacterial infection. See Rao S. and Grigg J., New insights into pulmonary inflammation in cystic fibrosis. Arch Dis Child 2006, 91: 786-788.
    [0012] [0012] AOSS / PAV-1 is also highly expressed in adipocytes, where it plays an important role in glucose transport regardless of the presence of insulin. Plasma levels of AOSS / PAV-1 have been observed to be increased in patients suffering from diabetes. Elevated plasma levels of AOSS / PAV-1 have been found in patients suffering from other diseases, such as congestive heart failure and liver cirrhosis. It has been suggested that AOSS / PAV-1 is associated with most, if not all, inflammatory diseases if the inflammation is a response to an immune response or subsequent to other events, such as occlusion and reperfusion of blood vessels.
    [0013] [0013] It has been recognized in recent years that AOSS / PAV-1 is expressed in sinusoidal endothelial cells of the liver and that this protein is believed to be associated with liver disease, in particular, liver fibrosis (Weston CJ and Adams DH, Hepatic consequences of vascular adhesion protein-1 expression, J Neural Transm 2011; 118: 1055-1064). In addition, an antibody from PAV-1 and a small molecule inhibitor has been found to attenuate fibrosis induced by carbon tetrachloride in rats. Thus, AOSS / PAV-1 inhibitors have the potential to treat fibrotic disease (WO 2011/029996). It has recently been reported that oxidation of methylamine by AOSS / PAV-1 in the presence of tumor necrosis factor α induces the expression of MAdCAM-1 in liver vessels, and that this is associated with the liver complications of inflammatory bowel disease (IBD) (Liaskou W. et al., Regulation of Mucosal Addressin Cell Adhesion Molecule 1 Expression in Human and Mice by Vascular Adhesion Protein 1 Amine Oxidase Activity, Hepatology 2011; 53, 661672).
    [0014] [0014] It has been reported that AOSS / PAV-1 inhibitors can attenuate angiogenesis and lymphangiogenesis and that these inhibitors offer a potential for the treatment of eye diseases, such as macular degeneration, corneal angiogenesis, cataracts and inflammatory conditions, such as uveitis (US 2009/0170770; WO 2009/051223; Noda K., et al., Inhibition of vascular adhesion protein-1 suppresses endotoxin-induced uveitis, FASEB J. 2008, 22, 1094-1103).
    [0015] [0015] Increased levels of AOSS / PAV-1 have been observed in the serum of patients suffering from hepatocellular carcinoma. In a murine melanoma model, small molecule AOSS / PAV-1 inhibitors have been shown to slow tumor growth, in contrast to PAV-1 antibodies that had no activity (Weston CJ and Adams DH, Hepatic consequences of vascular adhesion protein -1 expression, J Neural Transm 2011, 118, 1055-1064).
    [0016] [0016] AOSS / PAV-1 has been reported to play an important role in cancer biology (Marttila-Ichihara F. et al. Small-Molecule Inhibitors of Vascular Adhesion Protein-1 Reduce the Accumulation of Myeloid Cells into Tumors and Attenuate Tumor Growth in Mice, The Journal of Immunology, 2010, 184, 3164-3173). Small molecule AOSS / PAV-1 inhibitors reduced the number of myeloid Gr-1 + CD11b + pro-angiogenic cells in melanomas and lymphomas.
    [0017] [0017] During the catalytic cycle of amine oxidase AOSS / PAV-1 the covalently bound cofactor, TPQ, is first reduced and then reoxidated by oxygen in the presence of copper, with the generation of hydrogen peroxide as a by-product . It has been speculated that excess hydrogen peroxide concentrations may be harmful and may contribute to the pathology of various inflammatory processes and neurodegenerative diseases (Gotz ME, et al., Oxidative stress: Free radical production in neural degeneration. Pharmacol Ther 1994, 63, 37-122).
    [0018] [0018] Inflammation is believed to be an important feature of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and multiple sclerosis, and similarly, it is a feature of the pathophysiology that occurs after an occlusion event / cerebral reperfusion (Aktas, O. et al., Neuronal damage in brain inflammation. Arch Neurol 2007, 64, 185-9). Excessive AOSS / PAV-1 activity has been independently implicated in these processes (Xu, HL., Et al., Vascular Adhesion Protein-1 plays an important role in postischemic inflammation and neuropathology in diabetic, estrogen-treated ovariectomized. Journal Pharmacology and Experimental Therapeutics, 2006, 317, 19-26).
    [0019] [0019] Some known MAO inhibitors also inhibit AOSS / PAV-1 (for example, the MAO-B inhibitor mofegiline illustrated below). Mofegiline has been reported to inhibit experimental autoimmune encephalomyelitis (US 2006/0025438 A1). This inhibitor is a member of the haloalylamine family of MAO inhibitors; the halogen in mofegilina is fluorine. Fluoroalylamine inhibitors are described in US 4,454,158. There are reports of a chloroalylamine, MDL72274 (illustrated below), selectively inhibiting rat AOSS / PAV-1 compared to MAO-A and MAO-B:
    [0020] [0020] Additional fluoroalylamine inhibitors are described in US 4,699,928; the two compounds illustrated below have been described as selective MAO-B inhibitors:
    [0021] [0021] Other examples structurally related to mofegiline can be found in WO 2007/120528.
    [0022] [0022] Haloalylamine compounds that differ from mofegiline in core structure have been synthesized and shown to inhibit copper-dependent amine oxidase activity of a number of species (see Kim J., et al., Inactivation of bovine plasma amine oxidase by haloallylamines. Bioorg Med Chem 2006, 14, 1444-1453). These compounds were included in a patent application (WO 2007/005737):
    [0023] [0023] WO 2009/066152 describes a family of 3-substituted haloalylamines that are AOSS / PAV-1 inhibitors and are claimed as treatment for a variety of indications, including inflammatory disease. The following compounds are specifically described:
    [0024] [0024] References to the effects of AOSS / PAV-1 inhibitors in various animal models of disease can be found in the publication reviewed by McDonald IA et al., Semicarbazide Sensitive Amine Oxidase and Vascular Adhesion Protein-1: One Protein Being Validated as a Therapeutic Target for Inflammatory Diseases. Annual Reports in Medicinal Chemistry, 2008, 43, 229-241 and in the following publications, O'Rourke AM et al., Anti-inflammatory effects of LJP 1586 [Z-3-fluoro-2- (4-methoxybenzyl) allylamine hydrochloride] , an amine inhibitor of semicarbazide-sensitive amine oxidase activity. J. Pharmacol. Exp. Ther., 2008, 324, 867-875; and O'Rourke A. M. et al., Benefit of inhibiting SSAO in relapsing experimental encephalomyelitis. J. Neural. Trans., 2007, 114, 845-849. Brief Description of the Invention
    [0025] [0025] The present invention relates to substituted haloalylamine compounds that inhibit AOSS / PAV-1. Surprisingly, the modification of 2-substituted 3-haloalylamine structures described above has led to the development of new compounds that are potent inhibitors of the human AOSS / PAV-1 enzyme and that have much improved pharmacological and safety properties. These compounds are very potent in AOSS / PAV-1 and surprisingly they have been found to be very weak inhibitors of other members of the family, such as monoamine oxidase A, monoamine oxidase B, diamine oxidase, lysyl oxidase and lysyl similar to amine oxidase LOX1- 4 .
    [0026] [0026] A first aspect of the present invention provides a compound of Formula I:
    [0027] [0027] A second aspect of the present invention relates to a pharmaceutical composition that comprises a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient, carrier or diluent.
    [0028] [0028] A third aspect of the present invention relates to a method of inhibiting AOSS / PAV-1 amine oxidase activity in a patient in need thereof, said method comprising administering to said patient an effective amount of a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof, or a composition according to the second aspect of the present invention.
    [0029] [0029] A fourth aspect of the present invention relates to a method of treating a disease associated with or modulated by AOSS / PAV-1, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof, or a composition according to the second aspect of the present invention.
    [0030] [0030] A fifth aspect of the present invention relates to a method of treating a disease associated with or modulated by AOSS / PAV-1, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof, or a composition according to the second aspect of the present invention.
    [0031] [0031] A sixth aspect of the present invention relates to the use of a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a disease associated with or modulated by AOSS / PAV-1.
    [0032] [0032] A seventh aspect of the present invention relates to a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of a disease associated with or modulated by the AOSS / PAV- protein 1.
    [0033] [0033] In another aspect, the present invention describes the synthesis and use of compounds that inhibit AOSS / PAV-1 amine oxidase activity and describes the use of such inhibitors for the treatment of patients suffering from inflammatory diseases.
    [0034] [0034] The compounds of the present invention are useful for the treatment of symptoms of inflammation and / or fibrosis or in humans, as well as in domestic animals and livestock. Human inflammatory diseases contemplated for treatment include arthritis, Crohn's disease, irritable bowel disease, psoriasis, eosinophilic asthma, severe asthma, viral exacerbated asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, atherosclerosis, inflammation due to diabetes, destruction tissue mediated by inflammatory cells after stroke and the like. Human fibrotic diseases and disorders contemplated for treatment at present include idiopathic pulmonary fibrosis and other interstitial lung diseases, liver fibrosis, renal fibrosis, fibrosis of other organs and tissues, radiation-induced fibrosis and the like.
    [0035] [0035] The compounds of the present invention are also useful for the treatment of bacterial-induced lung inflammation associated with cystic fibrosis. Treatment can be either prophylactic or therapeutic. In addition, the compounds according to the present invention are useful for the treatment of other lung diseases induced by bacteria, such as sepsis, acute respiratory distress syndrome (RASD), acute lung injury (LPA), transfusion-induced lung injury ( TRALI) and the like.
    [0036] [0036] The compounds according to the present invention are also useful for the treatment of eye diseases, such as uveitis and macular degeneration.
    [0037] [0037] The compounds according to the present invention are also useful as an adjuvant therapy in the treatment of cancer. In combination with standard and novel chemotherapeutic agents, the compounds of the present invention can lead to better cancer control and to help reduce secondary metastatic cancers.
    [0038] [0038] Since small molecule inhibitors of AOSS / PAV-1 actively attenuate the levels of neutrophils in the lipopolysaccharide (LPS) mouse model of pulmonary neutrophilia, such molecules have the potential for the treatment of steroid-resistant asthma in patients humans. Accordingly, according to an aspect of the present invention, methods are provided for treating patients with an AOSS / PAV-1 inhibitor, either as a prophylactic or therapeutic agent to reduce neutrophil levels and treat the symptoms of severe asthma. .
    [0039] [0039] In accordance with another aspect of the present invention, methods are provided for treating patients with an AOSS / PAV-1 inhibitor, either as a prophylactic agent or as a therapeutic agent to treat the on-going disease.
    [0040] [0040] In accordance with yet another aspect of the present invention, methods are provided for using an AOSS / PAV-1 inhibitor to modulate the concentration of neutrophils in the airways and to treat the underlying cause of inflammation in patients suffering inflammation of the airways.
    [0041] [0041] In accordance with yet another aspect of the present invention, methods are provided for treating patients suffering from liver fibrosis with an AOSS / PAV-1 inhibitor.
    [0042] [0042] In accordance with a further aspect of the present invention, methods are provided for treating patients suffering from ocular surface diseases with an AOSS / PAV-1 inhibitor to treat the symptoms of the disease.
    [0043] [0043] Since AOSS / PAV-1 is expressed in various types of cancer, according to yet another aspect of the present invention, the use of AOSS / PAV-1 inhibitors is contemplated as adjunctive therapy for the treatment of patients suffering of cancers that express AOSS / PAV-1.
    [0044] [0044] In an embodiment of the methods and uses according to the present invention, the disease is inflammation. In another embodiment, the inflammation is associated with liver disease. In an additional embodiment, the inflammation is associated with respiratory disease. In yet another embodiment of the present invention, inflammation is associated with cystic fibrosis. In another embodiment, inflammation is associated with asthma or chronic obstructive pulmonary disease. In another embodiment, inflammation is associated with eye disease.
    [0045] [0045] In an embodiment of the methods and uses according to the present invention, the disease is a diabetes-induced disease selected from the group consisting of diabetic nephropathy, glomerulosclerosis, diabetic retinopathy, non-alcoholic fatty liver disease and choroidal neovascularization.
    [0046] [0046] In another embodiment of the methods and uses according to the present invention, the disease is a neuroinflammatory disease. In another embodiment of the methods and uses according to the present invention the disease is selected from the group consisting of liver fibrosis, liver cirrhosis, renal fibrosis, idiopathic pulmonary fibrosis and radiation-induced fibrosis. In yet another embodiment of the processes and use according to the present invention, the disease is cancer. Definitions
    [0047] [0047] The following are some definitions that may be useful for understanding the description of the present invention. These are intended for general definitions and should in no way limit the scope of the present invention to those terms alone, but are set out for a better understanding of the description that follows.
    [0048] [0048] Unless the context imposes a different interpretation or express indication to the contrary, whole numbers, steps or elements of the present invention recited here as singular whole numbers, steps or elements clearly cover the singular and plural forms of whole numbers, steps or recited elements.
    [0049] [0049] Throughout this specification, unless the context otherwise requires, the word "comprise" or variations such as "comprise" or "comprise", will be understood to imply the inclusion of a stated step or element or number integer or group of steps or elements or integers, but not the exclusion of any other element or step or integer or group of elements or integers. Thus, in the context of this specification, the term "comprising" means "including mainly, but not necessarily exclusive".
    [0050] [0050] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the present invention includes all such variations and modifications. The present invention also includes all the steps, characteristics, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or characteristics.
    [0051] [0051] As used herein, the term "alkyl" includes, within its meaning, monovalent ("alkyl") and bivalent ("alkylene") saturated hydrocarbon radicals with 1 to 6 carbon atoms, for example. example, 1,2, 3, 4, 5 or 6 carbon atoms (unless specifically defined). The straight or branched chain alkyl group is attached at any available point to produce a stable compound. In many embodiments, a lower alkyl is a straight or branched alkyl group containing from 1 to 6, 1 to 4 or 1 to 2 carbon atoms. For example, the term alkyl includes, but is not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, amyl, 1,2-dimethylpropyl, 1,1- dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1, 2,2-trimethylpropyl, 1,1,2-trimethylpropyl and the like.
    [0052] [0052] The term "alkoxy", as used herein, refers to straight or branched chain alkyloxy (i.e., O-alkyl) groups, where alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy.
    [0053] [0053] The term "cycloalkyl", as used herein, includes within its meaning monovalent ("cycloalkyl") and bivalent ("cycloalkylene") saturated, monocyclic, bicyclic, polycyclic or fused analogs. In the context of the present invention, the cycloalkyl group can have 3 to 10 or 3 to 7 carbon atoms. A fused analog of a cycloalkyl means a monocyclic ring fused to an aryl or heteroaryl group, where the point of attachment is in the non-aromatic portion. Examples of cycloalkyl and fused analogs of these include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
    [0054] [0054] The term "aryl" or variations such as "arylene", as used herein, refers to monovalent ("aryl") and bivalent ("arylene") simple, polynuclear, conjugated and fused aromatic hydrocarbon analogues with 6 to 10 carbon atoms. A fused aryl analog means an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group where the point of attachment is in the aromatic portion. Examples of fused aryls and analogues thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4-benzodioxanyl and the like. Examples of an arylene include phenylene and naphthylene. A "substituted aryl" is an aryl that is independently substituted with one or more, preferably 1, 2 or 3 substituents, attached to any available atom to produce a stable compound. A "substituted arylene" is an arylene that is independently substituted with one or more, preferably 1, 2 or 3 substituents, attached to any available atom to produce a stable compound.
    [0055] [0055] The term "alkylaryl", as used herein, includes within its meaning radicals of monovalent ("aryl") and divalent ("arylene") aromatic hydrocarbons, simple, polynuclear, conjugated and fused linked to alkylene radicals of straight or branched, simple and divalent chain. Examples of alkylaryl groups include, but are not limited to, benzyl.
    [0056] [0056] The term "heteroaryl" refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, where the heteroaryl contains one or more heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide from a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure, such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo [b] thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isotoxyl, isol, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl and indolyl. "Nitrogen containing heteroaryl" refers to heteroaryl in which any heteroatoms are N. A "substituted heteroaryl" is a heteroaryl that is independently substituted with one or more, preferably 1, 2 or 3 substituents, attached to any available atom to produce a stable compound.
    [0057] [0057] "Heteroarylene" refers to a bivalent monocyclic aromatic ring structure containing 5 or 6 atoms in the ring, where heteroarylene contains one or more heteroatoms independently selected from the group consisting of O, S, and N. Heteroarylene it is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroarylene ring structure to the substituents thereon, such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinylene, pyridazinylene, pyrazinylene, quinaoxalylene, indolizinylene, benzo [b] thienylene, quinazolinylene, purinylene, indolylene, quinolinylene, pyrimidinylene, pyrrolylene, oxazolylene, thiazolylene, thiazolene, thienylene, isothylene isothiazolylene, tetrazolylene, imidazolylene, triazinylene, furanylene, benzofurylene, and indolylene. "Nitrogen containing heteroarylene" refers to heteroarylene in which any heteroatoms are N. A "substituted heteroarylene" is a heteroarylene that is independently substituted with one or more, preferably 1, 2 or 3 substituents, attached to any available atom to produce a stable compound.
    [0058] [0058] The term "heterocyclyl" and variants, such as "heterocycloalkyl", as used herein, includes within its meaning monovalent ("heterocyclyl") and bivalent ("heterocyclylene"), saturated, monocyclic, bicyclic radicals , polycyclic or fused having 3 to 10 ring atoms, where 1 to 5 or 1 to 3 ring atoms are hetero atoms independently selected from O, N, NH or S, where the point of attachment can be carbon or nitrogen. A fused heterocyclyl analog means a monocyclic heterocycle fused to an aryl or heteroaryl group, where the point of attachment is in the non-aromatic portion. The heterocyclyl group can be C3-8 heterocyclyl. The heterocycloalkyl group can be C3-6 heterocyclyl. The heterocyclyl group can be C3-5 heterocyclyl. Examples of fused heterocyclic groups and analogs of these include aziridinyl, pyrrolidinyl, thiazolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro (2,3-b) pyridyl, benzoxazinyl, tetrahydroquinolinyl, dihydroindinyl, tetrahydroindinyl, quinidine , tetrahydrofuranyl, tetrahydropyranyl and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones bound via nitrogen or N-substituted uracils.
    [0059] [0059] The term "halogen" or variants, such as "halide" or "halo", as used herein refers to fluorine, chlorine, bromine and iodine.
    [0060] [0060] The term "heteroatom" or variants, such as "hetero" or "heterogroup" as used herein refers to O, N, NH and S.
    [0061] [0061] In general, "substituted" refers to an organic group, as defined herein (for example, an alkyl group), in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to carbon atom (s) or hydrogen (s) is (are) replaced by one or more bonds, including double or triple bonds, with a hetero atom. Thus, a substituted group will be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1,2, 3, 4, 5 or 6 substituents.
    [0062] [0062] The term "optionally substituted" as used herein means that the group to which this term refers may be unsubstituted or may be substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl , cycloalkenyl, heterocycloalkyl, halo, haloalkyl, haloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, NO2, NH (alkyl), N (alkyl) 2, nitroalkyl, nitroalkyl, nitro, alkyl, nitro, alkyl, nitro, alkyl, nitro, alkyl alkenylamine, alkynylamino, acyl, alkenyl, alkylino, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, heterocycloxy, heterocycloamino, haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acyl, alkyl containing phosphoryl, aryl, phosphoryl, aryl, phosphoryl, aryl heteroaryl, cyano, cyanate, isocyanate, CO2H, CO2alkyl, C (O) NH2, -C (O) NH (alkyl) andC (O) N (alkyl) 2. Preferred substituents include halogen, C1-C6 alkyl, C2C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, (C1-6) hydroxyalkyl, C3-C6 cycloalkyl, C (O) H, C (O) OH, NHC (O ) H, NHC (O) C1-C4 alkyl, C (O) C1-C4 alkyl, NH2, NHC1-C4 alkyl, N (C1-C4 alkyl) 2, NO2, OH and CN. Particularly preferred substituents include C1-3 alkyl, C1-3 alkoxy, halogen, OH, hydroxy (C1-3) alkyl (for example, CH2OH), C (O) C1-C4 alkyl (for example, C (O) CH3) and C1-3 haloalkyl (e.g., CF3, CH2CF3).
    [0063] The present invention includes within its scope all stereoisomeric and isomeric forms of the compounds disclosed herein, including all diastereomeric isomers, racemates, enantiomers and mixtures thereof. The compounds of the present invention can have asymmetric centers and can occur, except when specifically mentioned, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms included in the present invention. It is also understood that the compounds described by Formula I may be present as E and Z isomers, also known as cis and trans isomers. Thus, the present invention should be understood to include, for example, E, Z, cis, trans, (R), (S), (L), (D), (+) and / or (-) forms of the compounds , as appropriate in each case. When a structure has no specific stereoisomerism indicated, it should be understood that any and all possible isomers are encompassed. The compounds of the present invention can encompass all conformational isomers. The compounds of the present invention can also exist in one or more tautomeric forms, including both individual tautomers and mixtures of tautomers. Also included within the scope of the present invention are all polymorphs and crystalline forms of the compounds disclosed herein.
    [0064] [0064] The present invention includes in its scope isotopes of different atoms. Any atom not specifically designated as a specific isotope is used to represent any stable isotope for that atom. Thus, the present disclosure is to be understood as including deuterium and tritium isotopes of hydrogen.
    [0065] [0065] All references cited in this specification are specifically incorporated by cross-reference in their entirety. Any reference to these documents should not be construed as an admission that the document is part of common general knowledge or is state of the art.
    [0066] [0066] In the context of this specification, the term "administering" and variations of this term including "administering" and "administration", includes contacting, applying, releasing or supplying a compound or composition of the present invention to an organism or to surface by any suitable means. In the context of this specification, the term "treatment" refers to any and all uses that remedy a state of disease or symptoms, prevent the onset of the disease, or otherwise prevent, prevent, delay or reverse progression illness or other undesirable symptoms in any form whatsoever.
    [0067] [0067] In the context of the present specification, the term "effective amount" includes within its meaning a sufficient but non-toxic amount of a compound or composition of the present invention to provide a desired effect. Thus, the term "therapeutically effective amount" includes within its meaning a sufficient but non-toxic amount of a compound or composition of the present invention to provide the desired therapeutic effect. The exact amount needed will vary from patient to patient, depending on factors such as the species to be treated, sex, age and general condition of the patient, the severity of the condition being treated, the particular agent being administered, the mode of administration and so on. Thus, it is not possible to specify an exact "effective amount". However, in any case, an appropriate "effective amount" can be determined by a person skilled in the art using only routine experimentation. Brief Description of Drawings
    [0068] [0068] Figures 1A to 1E show the ability of compound 23 to inhibit the enzyme AOSS / PAV-1 in different tissues in rats after a single oral dose, with activity determined 24 hours after administration.
    [0069] [0069] Figures 2A to 2E show the ability of 2 mg / kg of compound 23 to inhibit the enzyme AOSS / PAV-1 in different tissues in rats after a single oral dose, with activity determined at various time points after administration .
    [0070] [0070] Figures 3A to 3E show the ability of compound 23 to inhibit the enzyme AOSS / PAV-1 in different tissues in rats after 5 days of repeated daily oral dosing, with activity determined 24 hours after the administration of the final dose.
    [0071] [0071] Figures 4A to 4D show the ability of compound 23 to reduce leukocyte migration to an inflamed air sac in a mouse model.
    [0072] [0072] Figures 5A and 5B show the ability of compound 23 to reduce leukocyte migration in the mouse cremaster microcirculation.
    [0073] [0073] Figures 6A and 6B show the ability of compound 23 to reduce leukocyte migration to the lung (6A) and to protect against mortality (6B) in a mouse model of systemic inflammation.
    [0074] [0074] Figures 7A to 7F show the ability of compound 9 to reduce neutrophil migration and microglial activation in a mouse model of neurodegeneration.
    [0075] [0075] Figures 8A to 8C show the ability of compound 9 to reduce neutrophil migration and activation in a mouse model of acute pulmonary inflammation.
    [0076] [0076] Figures 9A and 9B show the ability of compound 23 to reduce the migration of neutrophils to the lung (9A) and airway hyper-reactivity (9B) in a mouse model of allergic asthma.
    [0077] [0077] Figures 10A and 10B show the ability of compound 9 to reduce leukocyte migration to the lung (10A) and protect against mortality (10B) in a mouse model of lung infection.
    [0078] [0078] Figure 11 shows the ability of compound 23 to reduce the amount of soluble collagen in a mouse model with COPD.
    [0079] [0079] Figures 12A to 12E show the ability of compound 23 to improve renal function (12A and 12B), to reduce fibrosis (12C and 12E) and to reduce inflammation in a rat model of liver fibrosis.
    [0080] [0080] Figures 13A to 13D show the ability of compound 23 to reduce inflammation and fibrosis in a mouse model of fatty liver disease.
    [0081] [0081] Figures 14A and 14B show the ability of compound 23 to reduce eosinophil migration to the eye (14B) and to reduce clinical score (14A) in a mouse model of uveitis. Detailed Description of the Invention
    [0082] The present invention relates to substituted haloalylamine compounds that can inhibit AOSS / PAV-1.
    [0083] [0083] In accordance with the present invention, compounds with the structure of (Formula I) are provided:
    [0084] [0084] In one embodiment, the compounds of the present invention R1 and R4 are both hydrogen. In another embodiment of the compounds according to the present invention, R1 is hydrogen and R4 is optionally substituted C1-C6 alkyl. In another embodiment of the compounds of the present invention, R1 is optionally substituted C1-C6 alkyl and R4 is hydrogen. In another embodiment of the compounds of the present invention, R1 is hydrogen and R4 is methyl. In a further embodiment of the compounds of the present invention, R1 is a methyl group and R4 is hydrogen.
    [0085] [0085] In one embodiment of the compounds of the present invention, R2 and R3 are independently selected from the group consisting of hydrogen, chlorine and fluorine, provided that R2 and R3 are not hydrogen at the same time. In another embodiment of the compounds of the present invention, R2 and R3 are independently hydrogen or fluorine, provided that R2 and R3 are not hydrogen at the same time. In another embodiment of the compounds of the present invention, R2 and R3 are both fluorine. In another embodiment of the compounds of the present invention, R2 is hydrogen and R3 is fluorine. In a further embodiment of the compounds of the present invention, R2 is fluorine and R3 is hydrogen.
    [0086] [0086] In one embodiment of the compounds of the present invention, R5 is an optionally substituted arylene group. In another embodiment of the compounds of the present invention, R5 is an unsubstituted arylene group. In a further embodiment of the compounds of the present invention, R5 is an optionally substituted phenylene group. In another embodiment of the compounds of the present invention, R5 is an unsubstituted phenylene group. In one embodiment of the compounds of the present invention, R5 is a phenylene group optionally substituted by one or more groups independently selected from alkyl, halo, alkoxy and haloalkyl. In another embodiment of the compounds of the present invention, R5 is a phenylene group optionally substituted by one or more groups independently selected from methyl, fluorine, chlorine, bromine, OCH3 and CF3.
    [0087] [0087] In one embodiment of the compounds of the invention, R6 is selected from:
    [0088] [0088] In another embodiment of compounds of the present invention R6 is
    [0089] [0089] In a further embodiment of the compounds of the present invention R6 is
    [0090] [0090] In one embodiment of the compounds of the present invention, R7 and R8 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl and optionally substituted C3-C7 cycloalkyl. In another embodiment of the compounds according to the present invention, R7 and R8 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl and optionally substituted C3-C7 cycloalkyl. In another embodiment of the compounds of the present invention, R7 and R8 are independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl. In a further embodiment of the compounds of the present invention, R7 and R8 are both hydrogen. In a further embodiment of the compounds of the present invention, R7 and R8 are both C1-C6 alkyl. In a further embodiment of the compounds according to the present invention, R7 is hydrogen and R8 is C1-C6 alkyl. In yet another additional embodiment, R7 and R8 are independently selected from the group consisting of hydrogen, tert-butyl, methyl, ethyl, isopropyl and 2-butyl.
    [0091] [0091] In one embodiment of the compounds of the present invention, X is CH2, oxygen, sulfur or SO2. In another embodiment of the compounds of the present invention, X is CH2, oxygen or sulfur. In a further embodiment of the compounds of the present invention, X is oxygen.
    [0092] [0092] In a particular embodiment of the present invention, a compound having the structure of (Formula II) is provided, as follows:
    [0093] [0093] According to an embodiment of the present invention, the presently preferred compounds include compounds of Formulas I and II in which R3 is fluorine and X is oxygen.
    [0094] [0094] It is understood that the compounds described by Formulas I or II can be administered in a prodrug form, wherein the R1 substituent can be selected from such functional groups, such as -C (O) alkyl, -C (O) aryl, -C (O) -arylalkyl, C (O) heteroaryl, -C (O) -heteroarylalkyl or the like.
    [0095] [0095] The compounds described by Formula I can exist as acid addition salts when a basic amino group is present or as metal salts when an acid group is present.
    [0096] [0096] Examples of compounds according to the present invention include the compounds shown in Table 1:
    [0097] [0097] The compounds of the present invention can be prepared in a variety of ways, such as, for example, the procedures described in US 4,454,158; US 4,699,928; and US 4,650,907.
    [0098] [0098] An alternative way to prepare the compounds described by Formula I in which X = O or S employs the synthetic protocol described in Scheme 1, below. This is similar to the procedures described in WO 2007/120528.
    [0099] [0099] A compound represented by Formula III is either directly used in a substitution reaction (method A), such as a Mitsunobu reaction, to obtain the compound represented by Formula IV, or is first converted to a compound represented by Formula V, which contains a leaving group (LG), such as bromide, chloride or iodide, by procedures well known in the art (Method B). Alternatively, alcohol can be activated directly with the tosyl protector / activation group (P2 = tosyl in Scheme 2, Formula VIII, see below). The activated compound described by Formula V is then treated with a nucleophilic reagent to provide the compound represented by Formula IV (Method C).
    [0100] [00100] Mitsunobu's reaction conditions are well described in the scientific and patent literature (available on the internet at en.wikipedia.org/wiki/Mitsunobu_reaction and Mitsunobu, O. in The use of diethyl and treiphenylphosphine in synthesis and transformation of natural Synthesis 1981, 1-28) and proceed by contacting an alcohol with an appropriately substituted phenolic or thiophenolic group or a substituted phthalimide in the presence of a dialkyl and triphenylphosphine nitrodicarboxylate in an organic solvent, such as tetrahydrofuran (THF) or CH2Cl2 (CH2Ch).
    [0101] [00101] The conversion of the alcohol group in Formula III to the corresponding bromide, chloride or iodide is achieved by any number of commonly used processes (see, for example, J. March in Advanced Organic Synthesis, John Wiley & Sons, Third Edition 1985 ), including treatment with PBr3 in toluene or CBr4 and triphenylphosphine in an organic solvent, such as CH2Cl2. The resulting halide can be treated with nucleophiles, such as substituted alcohols, phenols, amines or thiols to obtain the compound represented by Formula IV.
    [0102] [00102] There are many well-established chemical processes for deprotecting the compounds described by Formula IV to the compounds of the present invention described by Formula I (Method J; see Scheme 2). For example, if P1 is a BOC protecting group, the compounds described by Formula IV can be treated with an acidic substance, such as dry hydrogen chloride in a solvent such as diethyl ether to provide the compounds described by Formula I in the form of hydrochloride salt. In general, free amino compounds are converted to acid addition salts for ease of handling and for improved chemical stability. Examples of acid addition salts include, but are not limited to, hydrochloride, hydrobromide and methanesulfonate salts.
    [0103] [00103] The preparation of the compounds described by Formula III is simple both for the commercially available and for the easily accessible aminodiol illustrated by Formula VI (see Scheme 3).
    [0104] [00104] The first step is the selective protection of the primary amine, preferably as the tert-butyl carbamate (BOC) (P1 = BOC in Formula VII), followed by selective protection of the primary alcohol to obtain the alcohol described by Formula IX. Selective protection methods (Method E) are well known in the art of synthetic chemistry. For example, primary alcohol can be selectively reacted with tert-butyl- (chlorine) dimethylsilane in the presence of imizadol to provide the protected tert-butyldimethylsilyl alcohol (Formula VII). Secondary alcohol oxidation is best achieved under Swern oxidation conditions (Method F), resulting in the ketone represented by Formula VIII. The haloalkene functional group in Formula X is introduced by the reaction of Wittig or Horner-Wadsworth-Emmons. When R2 and R3 are F and H in the structure described by Formula I, the reaction of the ketone described by Formula VIII with fluoromethyl (triphenyl) phosphonium tetrafluoroborate in the presence of a strong base, such as sodium bis (trimethylsilyl) amide produces the fluoroalkene as a mixture of E and Z isomers (described by Formula X). These isomers can be separated by chromatographic procedures to obtain the individual E and Z isomers. The removal of the protecting group in the compounds described by Formula X can be easily achieved (Method H). The choice of deprotection reagent is determined by the nature of the protecting groups P1 and P2. When P2 is tert-butyldimethylsilyl and P1 is the BOC group, selective removal of P2 is achieved with TBAF to provide the alcohol described by Formula III. Therapeutic uses and formulations
    [0105] [00105] The present invention provides methods for using the compounds described by Formulas I and II to inhibit membrane-bound AOSS / PAV-1 and solubilize AOSS / PAV-1. The relative inhibitory potencies of the compounds can be determined by the amount needed to inhibit AOSS / PAV-1 amine oxidase activity in a variety of ways, for example, in an in vitro assay with recombinant human protein or recombinant non-human enzyme in cell assays that express the normal rodent enzyme, in cell assays that have been transfected with the human protein, in in vivo tests on rodents and other mammalian species and the like.
    [0106] [00106] The present invention also discloses methods for using the compounds described by Formulas I and II to inhibit AOSS / PAV-1 in patients suffering from an inflammatory disease, as well as methods for the treatment of inflammatory diseases. Human inflammatory diseases include arthritis, Crohn's disease, irritable bowel disease, psoriasis, asthma, chronic obstructive pulmonary disease, bronchiectasis, atherosclerosis, inflammation due to diabetes and inflammatory cell destruction after stroke.
    [0107] [00107] Thus, in one aspect, the present invention relates to methods of inhibiting an amine oxidase enzyme in a patient in need thereof, said methods comprising administering to said patient an effective amount of a compound of Formula I or Formula II to cause a positive therapeutic response.
    [0108] [00108] In another aspect, the present invention relates to methods of treating a disease associated with an amine oxidase enzyme, said methods comprising administering to a patient in need of a therapeutically effective amount of a compound of Formula I or Formula II.
    [0109] [00109] In yet another aspect, the present invention relates to methods of treating a disease modulated by AOSS / PAV-1, said methods comprising administering to a patient in need of a therapeutically effective amount of a compound of Formula I or Formula II.
    [0110] [00110] The methods described above are applicable when the disease is inflammation. As used herein, "inflammation" encompasses a wide variety of indications, including arthritis (including juvenile rheumatoid arthritis), Crohn's disease, ulcerative colitis, inflammatory bowel diseases (eg, irritable bowel disease), psoriasis, asthma, inflammation pulmonary, chronic obstructive pulmonary disease (COPD), bronchiectasis, skin inflammation, eye disease, contact dermatitis, liver inflammation, autoimmune liver diseases, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, arteriosclerosis, chronic heart failure, congestive heart failure, ischemic diseases, stroke and its complications, myocardial infarction and its complications, destruction of inflammatory cells after stroke, synovitis, systemic inflammatory sepsis and the like.
    [0111] [00111] The methods described above are also applicable when the disease is type I diabetes and its complications, type II diabetes and its complications and the like.
    [0112] [00112] The methods described above are also applicable when the disease is macular degeneration and other eye diseases.
    [0113] [00113] The methods described above are also applicable when the disease is fibrosis. As used herein, "fibrosis" includes diseases such as cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, including non-alcoholic fatty liver disease, such as non-alcoholic steatohepatitis (NASH) and alcohol-induced fibrosis leading to liver cirrhosis, renal fibrosis , scleroderma, radiation-induced fibrosis and other diseases in which excessive fibrosis contributes to the pathology of the disease.
    [0114] [00114] The methods described above are also applicable when the disease is a neuroinflammatory disease. As used at present, "neuroinflammatory diseases" cover a variety of indications, including stroke, Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis, chronic multiple sclerosis and the like.
    [0115] [00115] The methods described above are also applicable when the disease is cancer. In one embodiment, the cancer is selected from the group consisting of lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and biliary tract carcinoma; esophageal carcinoma; non-Hodgkin's lymphoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medullary blastoma and other brain tumors; kidney cancer; head and neck cancer; stomach cancer; multiple myeloma; testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; carcinoids of the gastrointestinal tract, breast and other organs; seal ring carcinoma; mesenchymal tumors, including sarcomas, fibrosarcomas, hemangioma, angiomatosis, hemangiopericytoma, pseudoangiomatous stromal hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastic tumor, lipoma, angiolipoma, granular tumor, neurofibroma, leiomyoma, angiosoma, rabies, schwanoma Pharmaceutical and / or therapeutic formulations
    [0116] [00116] In another embodiment of the present invention, compositions are provided comprising a compound of Formula I or Formula II and at least one excipient, carrier or pharmaceutically acceptable diluent therefor. The compounds of Formula I can also be present in the form of appropriate salts, including pharmaceutically acceptable salts.
    [0117] [00117] The term "pharmaceutically acceptable carrier" refers to any carrier known to those skilled in the art as being suitable for the particular mode of administration. In addition, the compounds can be formulated as the only pharmaceutically active ingredient in the composition or can be combined with other active ingredients.
    [0118] [00118] The phrase "pharmaceutically acceptable salt" refers to any salt preparation that is suitable for use in a pharmaceutical application. By pharmaceutically acceptable salt is meant those salts that, within the scope of a suitable medical evaluation, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the art and include acid and base addition salts. Hemisals of acids and bases can also be formed. Pharmaceutically acceptable salts include amine salts of mineral acids (for example, hydrochlorides, hydrobromides, sulfates and the like); and amine salts of organic acids (e.g., formats, acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, maleates, butyrates, valerates, fumarates and the like).
    [0119] [00119] For compounds of formula (I) that have a basic site, pharmaceutically acceptable salts can be acid addition salts. For example, suitable pharmaceutically acceptable salts of such compounds can be prepared by mixing a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, citric acid or with the compounds of the present invention.
    [0120] [00120] SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, cyclopentanopropionate, dodecylsulfate, ethanesulfonate, glycoside, glycate, glycolate, glycolate , hexanoate, hydrobromide, hydrochloride, iodhydrate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, phalate, oxalate, phalate, oxalate, phalate, oxalate, phalate, oxalate, phalate, oxalate, phalate, oxalate persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzatin, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, triethanolamine and the like.
    [0121] i. Por reação do composto de fórmula I com o ácido ou base desejada; ii. Por meio da remoção de um grupo protetor ácido ou base-lábil de um precursor adequado do composto de fórmula I ou por abertura de anel de um precursor cíclico adequado, por exemplo, uma lactona ou lactama, utilizando o ácido ou base desejada; ou iii. Por meio da conversão de um sal do composto de fórmula I em um outro por meio de reação com um ácido ou base apropriados ou por meio de uma coluna de troca iônica adequada. [00121] Pharmaceutically acceptable salts of the compounds of formula I can be prepared by methods known to those skilled in the art including, for example: i. By reacting the compound of formula I with the desired acid or base; ii. By removing an acid or labile protecting group from a suitable precursor of the compound of formula I or by ring opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or iii. By converting a salt of the compound of formula I into another by reacting it with an appropriate acid or base or through a suitable ion exchange column.
    [0122] [00122] The above reactions (i) - (iii) are typically carried out in solution. The resulting salt can precipitate and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized.
    [0123] [00123] Thus, for example, suitable pharmaceutically acceptable salts of compounds according to the present invention can be prepared by mixing a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, citric acid or with the compounds of the invention. The pharmaceutically acceptable salts of the compounds of the present invention, therefore, include acid addition salts.
    [0124] [00124] The compounds of the present invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the present invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when the solvent is water.
    [0125] [00125] In one embodiment, the compounds of Formula I can be administered in the form of a "prodrug". The term "prodrug" refers to a compound which, after administration in vivo, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound. Prodrugs can be prepared by modifying the functional groups present in the compound, such that the modifications are cleaved, either in routine manipulation or in vivo, from a compound described herein. For example, prodrugs include compounds of the present invention in which a hydroxy, amino or sulfhydryl group is attached to any group that, when administered to a mammal, can be cleaved to form a free hydroxyl, free amino or free sulfhydryl, respectively . Representative prodrugs include, for example, amides, esters, enol ethers, enol esters, acetates, formats, benzoate derivatives and the like of alcohol and amine functional groups in the compounds of the present invention. By virtue of their knowledge of pharmacodynamic processes and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, for example, Nogrady (1985) in Medicinal Chemistry Biochemical Approach, Oxford University Press, New York, pages 388-392).
    [0126] [00126] The compositions described herein comprise one or more compounds provided herein. The compounds are, in one embodiment, formulated in suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for administration by route parenteral as well as for the preparation of transdermal patch and dry powder inhalers. In one embodiment, the compounds described above are formulated in pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel in Introduction to Pharmaceutical Dosage Forms, 4th Edition 1985, 126).
    [0127] [00127] In the compositions, the effective concentrations of one or more pharmaceutically acceptable compounds or derivatives, is (are) mixed with a suitable pharmaceutical carrier. The compounds can be derived as the corresponding enol salts, esters, ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemicetals, acids, bases, solvates, hydrates or prodrugs as described above. The concentrations of the compounds in the compositions are effective for releasing an amount, upon administration, which treats, prevents or improves or one or more of the symptoms of the diseases or disorders to be treated.
    [0128] [00128] In one embodiment, the compositions are formulated for single dose administration. To formulate a composition, the weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is alleviated, avoided or one or more symptoms are improved.
    [0129] [00129] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects in the treated patient. The therapeutically effective concentration can be determined empirically by testing the compounds in vitro and in vivo systems described in this and international publication WO 04/018997 and then extrapolated from there for dosages for humans.
    [0130] [00130] The concentration of the active compound in the pharmaceutical composition will depend on the absorption, inactivation and excretion rates of the active compound, the physical-chemical characteristics of the compound, the dosage schedule and the amount administered, as well as other factors known to those skilled in the art. subject matter.
    [0131] [00131] In one embodiment, a therapeutically effective dose should produce an active ingredient serum concentration of about 0.1 ng / ml to about 50-100 pg / ml. The pharmaceutical compositions, in another embodiment, should provide a dose of about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Single dose pharmaceutical forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or 2000 mg and, in one embodiment, from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients as a single dose.
    [0132] [00132] The dose can occur in intervals of minutes, hours, days, weeks, months or years or continuously over any of these periods. Appropriate doses are within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dose. The dose is preferably in the range of 1 pg to 1 g per kg of body weight per dose, as it is in the range of 1 mg to 1 g per kg of body weight per dose. Suitably, the dose is in the range of 1 pg to 500 pg per kg of body weight per dose, such as from 1 pg to 200 mg per kg of body weight per dose or 1 pg to 100 mg per kg of body weight per dose. Other suitable doses may be in the range of 1 mg to 250 mg per kg of body weight, including 1 mg to 10, 20, 50 or 100 mg per kg of body weight per dose or 10 pg to 100 mg per kg of body weight per dose.
    [0133] [00133] The amounts of suitable doses and dosage regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition, as well as the patient's general health, age and weight.
    [0134] [00134] The active ingredient can be administered at once or it can be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dose and duration of treatment is a function of the disease being treated and can be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentrations and dose values may also vary with the severity of the condition being relieved. It should also be understood that for any particular patient, specific dosage regimens must be adjusted over time, according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are examples only and are not intended to limit the scope or practice of the claimed compositions.
    [0135] [00135] In cases where the compounds exhibit insufficient solubility, methods can be used to solubilize the compounds. Such methods are known to those skilled in the art and include, but are not limited to, the use of cosolvents, such as dimethyl sulfoxide (DMSO), using surfactants such as TWEEN®, dissolving in aqueous sodium bicarbonate, the formulation of the compounds of interest as nanoparticles and the like. Derivatives of the compounds, such as prodrugs of the compounds, can also be used in the formulation of effective pharmaceutical compositions.
    [0136] [00136] After mixing or adding the compound (s), the resulting mixture can be a solution, suspension, emulsion or the like. The form of the resulting mixture depends on a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to improve the symptoms of the disease, disorder or condition being treated and can be empirically determined.
    [0137] [00137] The pharmaceutical compositions are provided for administration to humans and animals in single dose forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions and oral solutions or suspensions, and oil-water emulsions containing amounts compounds or pharmaceutically acceptable derivatives. The pharmaceutically and therapeutically active compounds and their derivatives are, in one embodiment, formulated and administered in single dose or multiple dose forms. Single dose forms as used herein refer to physically discrete units suitable for human and animal patients and individually packaged as is known in the art. Each single dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required carrier, vehicle or pharmaceutical diluent. Examples of single dose forms include ampoules and syringes and individually packaged tablets or capsules. Single dose forms can be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical single dose forms packaged in a container to be administered in a separate single dose form. Examples of multiple dose forms include vials, bottles of pills or capsules or bottles of pints or gallons. Thus, the multiple dose form is a multiple of single doses that are not separated into packages.
    [0138] [00138] The current methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th edition, 1975.
    [0139] [00139] Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% (% by weight) with the balance made from a non-toxic vehicle can be prepared. The methods for preparing these compositions are known to those skilled in the art. The contemplated compositions may contain from 0.001% to 100% (% by weight) of active ingredient, in an embodiment of 0.1 to 95% (% by weight) and, in another embodiment, from 75 to 85% (% by weight) ). Administration Modes
    [0140] [00140] Convenient modes of administration include injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, topical creams or gels or powders and vaginal or rectal administration. Depending on the route of administration, the formulation and / or the compound may (s) be coated with a material to protect the compound from the action of enzymes, acids and other natural conditions that may inactivate the compound's therapeutic activity. The compound can also be administered parenterally or intraperitoneally. Compositions for oral administration
    [0141] [00141] Oral pharmaceutical dosage forms are both solid, as well as liquid or liquid. Solid dosage forms are tablets, capsules, granules and bulk powders. Oral tablet types include tablets, chewable tablets and tablets that can be enteric-coated, sugar-coated or film-coated. The capsules can be hard or soft gelatin capsules, while granules and powders can be supplied in non-effervescent or effervescent form with a combination of other ingredients known to those skilled in the art. Solid compositions for oral administration
    [0142] [00142] In certain embodiments, formulations are solid dosage forms, in one embodiment, capsules or tablets. Tablets, pills, capsules, lozenges and the like may contain one or more of the following ingredients or compounds of a similar nature: a binder; a lubricant; a diluent; a slider; a disintegrating agent; a dye; a sweetening agent; a flavoring agent; a wetting agent; an emetic coating; and a film coating. Examples of binders include microcrystalline cellulose, tragacanth gum, glucose solution, gum arabic mucilage, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidones, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Gliders include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved water-soluble FD and C dyes and mixtures thereof; FD and C dyes insoluble in water and suspended in alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents, such as saccharin and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants, such as fruits and synthetic mixtures of compounds that produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniacal shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
    [0143] [00143] The compound or a pharmaceutically acceptable derivative thereof can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other ingredient.
    [0144] [00144] When the single dose form is a capsule, it may contain, in addition to the materials of the above type, a liquid vehicle such as a fatty oil. In addition, single dose forms may contain various other materials that modify the physical form of the single dose, for example, sugar coatings and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, spray, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, pigments and dyes and flavors.
    [0145] [00145] The active materials can also be mixed with other active materials that do not harm the desired action or with materials that supplement the intended action, such as antacids, H2 blockers and diuretics. The active ingredient is a pharmaceutically acceptable compound or derivative thereof, as described herein. Higher concentrations, up to about 98% by weight of the active ingredient, can be included.
    [0146] [00146] In all embodiments, the tablet and capsule formulations can be coated as is known to those skilled in the art, in order to modify or maintain the dissolution of the active ingredient. Thus, for example, they can be coated with a conventional enteric digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate. Liquid compositions for oral administration
    [0147] [00147] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are oil-in-water or water-in-oil.
    [0148] [00148] Pharmaceutically administrable liquid compositions can, for example, be prepared by dissolving, dispersing or otherwise by mixing an active compound as defined above and optional pharmaceutical adjuvants in a vehicle, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrin derivatives , sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate and other such agents.
    [0149] [00149] Elixirs are sweet and clear hydroalcoholic preparations. Pharmaceutically acceptable vehicles used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which a liquid is dispersed as small blood cells over another liquid. Pharmaceutically acceptable vehicles used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted in a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted in a liquid oral dosage form, include organic acids and a source of carbon dioxide. Dyes and flavorings are used in all of the above dosage forms.
    [0150] [00150] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia gum, tragacanth, bentonite and surfactants, such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and gum arabic. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include baking soda and sodium carbonate. Dyes include any of the approved certified water-soluble FD and C dyes and their mixtures. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic mixtures of compounds that produce a pleasant taste sensation.
    [0151] [00151] For a solid dosage form, the solution or suspension, for example propylene carbonate, vegetable oils or triglycerides, is, in one embodiment, encapsulated in a gelatinous capsule. Such solutions and their preparation and encapsulation are disclosed in US Patents 4,328,245; US 4,409,239; and US 4,410,545. For a liquid dosage form, the solution, for example, in a polyethylene glycol, for example, can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, for example, water, to be easily measured for administration.
    [0152] [00152] Alternatively, oral liquid or semi-solid formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (eg propylene carbonate) and other such vehicles, and by encapsulating these solutions or suspensions in hard or soft gelatin capsules. Other useful formulations include those set forth in US Patents RE28,819 and US 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or polyalkylene glycol, including, but not limited to, methyl 1,2-dimethoxymethane, diglyme, triglyme, tetraglime polyethylene glycol ether-350, methyl polyethylene glycol-550 ether, methyl polyethylene glycol-750 ether, where 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol, and one or more antioxidants, such as butylhydroxytoluene (BHT ), butylhydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephaline, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.
    [0153] [00153] Other formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. The alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents with one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di (lower alkyl) acetals of lower alkyl aldehydes, such as diethyl acetaldehyde. Injectables, solutions and emulsions
    [0154] [00154] Parenteral administration, in an embodiment characterized by injection, whether subcutaneous, intramuscular or intravenous, is also contemplated in the present. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid before injection, or as emulsions. Injectables, solutions and emulsions can also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers and other agents of this type, such as example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
    [0155] [00155] The implementation of a slow-release or sustained-release system, so that a constant dose level is maintained (see, for example, US patent 3,710,795), is also contemplated in the present. Briefly, a compound provided herein is dispersed in a solid interior matrix, for example, of polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized ethylene polyether phthalate, natural rubber, polyisoprene, polyisobutylene, polybutylene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol and partially hydrolyzed polyvinyl acetate which is partially hydrolyzed, crosslinked is surrounded by an outer polymeric membrane, for example, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol copolymer, and copolymer of ethylene / vinyloxy ethanol, which is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a step of controlling the release rate. The percentage of active compound contained in such parenteral compositions is highly dependent on its specific nature, as well as the activity of the compound and the needs of the patient.
    [0156] [00156] Parenteral administrations of the compositions include intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent immediately before use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready for use be combined with a vehicle immediately before use and sterile emulsions. The solutions can be aqueous or non-aqueous.
    [0157] [00157] If administered intravenously, suitable vehicles include saline or phosphate buffered serum (PBS) and solutions containing thickeners and solubilizing agents, such as glucose, polyethylene glycol and polypropylene glycol and mixtures thereof.
    [0158] [00158] Pharmaceutically acceptable vehicles used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
    [0159] [00159] Examples of aqueous vehicles include sodium chloride injection, Ringer injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations should be added to parenteral preparations packaged in multiple dose containers, which include phenols or cresols, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent for metal ions, including EDTA. Pharmaceutical vehicles also include ethyl alcohol, polyethylene glycol and propylene glycol for water-miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
    [0160] [00160] The concentration of the pharmaceutically active compound is adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
    [0161] [00161] Single dose parenteral preparations are packaged in an ampoule, vial or syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.
    [0162] [00162] Illustratively, intravenous or intra-arterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as needed to produce the desired pharmacological effect.
    [0163] [00163] Injectables are designed for local and systemic administration. In one embodiment, a therapeutically effective dose is formulated to contain a concentration of at least about 0.1% w / w to about 90% w / w or more, in certain embodiments, more than 1% w / w of the compound active for the treated tissue (s).
    [0164] [00164] The compound can be suspended in micronized or other suitable form or it can be derived to produce a more soluble active product or to produce a prodrug. The resulting mixing form depends on a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to improve the symptoms of the condition and can be determined empirically. Freeze dried powders
    [0165] [00165] Of interest in the present are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. they can also be reconstituted and formulated as solids or gels.
    [0166] [00166] The sterile lyophilized powder is prepared by dissolving a compound provided herein or a pharmaceutically acceptable derivative thereof in a suitable solvent. The solvent may contain an excipient that improves the stability or other pharmacological component of the powder or reconstituted solution prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other buffer known to those skilled in the art at, in one embodiment, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those skilled in the art provides the desired formulation. In one embodiment, the resulting solution will be distributed among the vials for lyophilisate. Each vial will contain a single dose or multiple doses of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4 ° C to room temperature.
    [0167] [00167] The reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or another suitable carrier. The precise amount depends on the selected compound. This amount can be determined empirically. Topical administration
    [0168] [00168] Topical mixtures are prepared as described for local and systemic administration. The resulting mixture can be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, dressings, plasters dermal or any other formulations suitable for topical administration.
    [0169] [00169] The pharmaceutically acceptable compounds or derivatives thereof can be formulated as aerosols for topical application, such as by inhalation (see, for example, US Patents 4,044,126, US 4,414,209 and US 4,364,923, which describe aerosols for release of a steroid useful for the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will, in one embodiment, have diameters less than 50 microns, in one embodiment, less than 10 microns.
    [0170] [00170] The compounds can be formulated for local or topical application, such as for topical application to the skin and mucous membranes, as in the eye, in the form of gels, creams and lotions and for application to the eyes or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
    [0171] [00171] These solutions, particularly those intended for ophthalmic use, can be formulated as 0.01% to 10% (volume%) of isotonic solutions, pH of about 5 to 7, with appropriate salts. Compositions for other routes of administration
    [0172] [00172] Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated in the present.
    [0173] [00173] Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those skilled in the art. For example, such patches are described in US Patents 6,267,983, US 6,261,595, US 6,256,533, US 6,167,301, US 6,024,975, US 6,010,715, US 5,985,317, US 5,983,134, US 5,948,433 and US 5,860,957.
    [0174] [00174] For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. The rectal suppositories used in the present mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmacologically acceptable substances used in suppositories are bases or vehicles and agents for raising the melting point. Examples of bases include cocoa butter (Theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases can be used. Agents for raising the melting point of suppositories include spermaceti and wax. Rectal suppositories can be prepared by either the compression method or by molding. The weight of a rectal suppository, in one embodiment, is about 2 to 3 g.
    [0175] [00175] Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration. Target formulations
    [0176] [00176] The compounds provided in the present or its pharmaceutically acceptable derivatives can also be formulated to target a tissue, receptor or other particular area of the patient's body to be treated. Many of these targeting methods are well known to those skilled in the art. All of these targeting methods are contemplated herein for use in the compositions of the present invention. For examples of non-limiting targeting methods, see, for example, US patents 6,316,652, US 6,274,552, US 6,271,359, US 6,253,872, US 6,139,865, US 6,131,570, US 6,120. 751, US 6,071,495, US 6,060,082, US 6,048,736, US 6,039,975, US 6,004,534, US 5,985,307, US 5,972,366, US 5,900,252, US 5,840,674, US 5,759. 542 and US 5,709,874.
    [0177] [00177] In one embodiment, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in US patent 4,522,811. Briefly, liposomes, such as multilamellar vesicles (VML) can be formed by transporting phosphatidylcholine from the egg and phosphatidylserine from the brain (7: 3 molar ratio) inside a bottle. A solution of a compound provided in the present in phosphate buffered saline without divalent cations (PBS) is added to the flask and stirred until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compost, pelletized by centrifugation and then resuspended in PBS. Co-administration with other drugs
    [0178] [00178] In accordance with another aspect of the present invention, it is contemplated that the compounds as described herein can be administered to a patient in need of it in combination with the medication considered by those skilled in the art to be the current standard of care for the condition of interest. Such combinations provide one or more advantages for the patient, for example, requiring reduced doses to achieve similar benefit, obtaining the desired palliative effect in less time and the like.
    [0179] [00179] The compounds according to the present invention can be administered as part of a therapeutic regimen with other drugs. It may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition. Thus, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of Formula (I) according to the present invention, can be combined in the form of a kit suitable for the co-administration of the compositions .
    [0180] [00180] In one embodiment of the methods of the present invention, a compound of formula I can be administered with a second therapeutic agent. In one embodiment, the second therapeutic agent is selected from the group consisting of an anti-cancer agent, an anti-inflammatory agent, an anti-hypertensive agent, an anti-fibrotic agent, an anti-angiogenic agent, an anti-diabetic agent and an immunosuppressive agent.
    [0181] [00181] When two or more active ingredients are co-administered, they can be administered simultaneously, sequentially or separately. In one embodiment, the Formula I compound is co-administered simultaneously with a second therapeutic agent. In another embodiment, the compound of Formula I and the second therapeutic agent are administered sequentially. In a further embodiment, the compound of Formula I and the second therapeutic agent are administered separately.
    [0182] [00182] The present invention will now be described in greater detail with reference to the following non-limiting examples. The examples are intended to serve to illustrate the present invention and are not to be construed as limiting the generality of the disclosure of the description throughout this specification. Examples Example 1 Preparation of (Z) -tert-butyl 2- (bromomethyl) -3-fluoroalylcarbamate and (E) -tert-butyl 2- (bromomethyl) -3-fluoroalylcarbamate syntones
    [0183] [00183] To a stirred solution of 3-amino-1,2-propanediol (10.0 g, 0.11 mol) and triethylamine (23 ml, 0.17 mol) in MeOH (200 ml) at room temperature was added di-tert-butyl dicarbonate (26.4 g, 0.12 mol). The resulting solution was left to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and then co-evaporated with toluene to renew all MeOH. The crude residue was taken up in CH2Cl2 and, after cooling to 0 ° C, imidazole and tert-butyl- (chloro) dimethylsilane were added sequentially. The resulting mixture was left to stir at this temperature for 2h. The reaction mixture was partitioned between water (100 ml) and CH2Cl2 (70 ml) and the aqueous layer was extracted with additional CH2cl2 (2 x 70 ml). The combined organics were dried over Na2SO and concentrated in vacuo. The crude residue was purified on silica gel eluting with n-hexane followed by 10% ethyl acetate in hexanes to produce tert-butyl 3- (tert-butyldimethylsilyloxy) -2-hydroxypropylcarbamate (32.6 g, 97.3%) like a colorless oil. 1H-NMR (300 MHz, CDCl3) δppm: 0.09 (6 H, s), 0.91 (9 H, s), 1.46 (9 H, s), 2.86 (1 H, br d , J 4.2 Hz), 3.13 (1 H, ddd, J 14.1, 6.7, 5.3 Hz), 3.30 - 3.43 (1 H, m), 3.54 ( 1 H, dd, J 10.1, 6.2 Hz), 3.66 (1 H, dd, J 10.1, 4.5 Hz), 3.70 - 3.80 (1 H, m), 4.98 (1 H, br s). Preparation of tert-butyl 3- (tert-butyldimethylsilyloxy) -2-oxopropylcarbamate
    [0184] [00184] To a stirred solution of oxalyl chloride (13.6 ml, 0.16 mol) in dry CHCl2 (150 ml) at -78 ° C under N2 atmosphere was added DMSO (15.2 ml, 0, 21 mol) dropwise over 30 min. After the addition was complete, the resulting solution was stirred at -78 ° C for 1 h. A solution of tert-butyl 3- (tert-butyldimethylsilyloxy) -2-hydroxypropyl (32.6 g, 0.11 mol) in CH2Cl2 (50 ml) was then added dropwise over 20 min. Stirring was continued for an additional 1 hour, at which time triethylamine (59.6 ml, 0.43 mol) was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was partitioned between water (100 ml) and CH2Cl2 (70 ml) and the aqueous layer was extracted with more CH2Cl2 (2 x 70 ml); the combined organics were dried over Na2SO4 and concentrated under a stream of nitrogen gas. The crude residue was purified on silica gel eluting with 5% ethyl acetate in n-hexane to generate tert-butyl 3- (tert-butyldimethylsilyloxy) -2-oxopropylcarbamate (29.8 g, 92%) as a pale yellow oil . 1H-NMR (300 MHz; CDCI3) δρρm: 0.11 (6 H, s), 0.94 (9 H, s), 1.47 (9 H, s), 3.92 (2 H, s) , 4.26 (2 H, d, J 4.6 Hz), 5.22 (1 H, br s). Preparation of tert-butyl 2 - ((tert-butyldimethylsilyloxy) methyl) -3-fluoroalylcarbamate
    [0185] [00185] To a suspension with vigorous stirring of fluoromethyl (triphenyl) -phosphonium tetrafluoroborate (18.9 g, 49.4 mmol) in dry THF (190 ml) at -20 ° C under N2, bis (trimethylsilyl) was added ) sodium amide (1.0 M in THF, 49.4 ml, 49.4 mmol) slowly over 10 min. The resulting dark orange solution was allowed to stir at this temperature for 15 min. A solution of tert-butyl 3- (tert-butyldimethylsilyloxy) -2-oxopropylcarbamate (10.0 g, 33.0 mmol) in THF (10 ml) was then added slowly over 10 min. After complete addition, stirring was continued for an additional 1 h, during which time the reaction was allowed to warm slowly to room temperature. The reaction was quenched by the addition of water (5 ml) and the reaction mixture was concentrated in vacuo. The residue was partitioned between water (100 ml) and diethyl ether (100 ml) and the aqueous layer was extracted with more diethyl ether (2 x 100 ml). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified on silica gel eluting with n-hexane followed by 6% ethyl acetate in n-hexane to generate tert-butyl 2 - ((tert-butyldimethylsilyloxy) methyl) -3-fluoroalylcarbamate as a mixture of double isomers E / Z (E / Z = 1: 1; 9.9 g, 94%). The isomers were not separated at this stage. Preparation of (E) -tert-butyl 3-fluoro-2- (hydroxymethyl) allylcarbamate and (Z) -tert-butyl 3-fluoro-2- (hydroxymethyl) allycarbamate
    [0186] [00186] To a stirring solution of tert-butyl 2 - ((tert-butyldimethylsilyloxy) methyl) -3-fluoroalylcarbamate (E / Z = 1: 1, 12.0 g, 37.6 mmol) in THF (30 ml ) at room temperature, TBAF (1.0 M in THF; 45.1 ml, 45.1 mmol) was added. The resulting solution was left to stir for 30 min. The reaction mixture was partitioned between water (70 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organics were washed with saturated aqueous NH4Cl solution (70 ml), followed by brine (70 ml). After drying over Na2SO4, the organic extracts were concentrated in vacuo. Purification of the crude material over silica gel eluting with 20% ethyl acetate and 5% THF in n-hexane yielded (Z) -tert-butyl 3-fluoro-2- (hydroxymethyl) allycarbamate (0.5 g, 6 , 5%), (E) -tert-butyl 3-fluoro-2- (hydroxymethyl) allycarbamate (1.2 g, 15.6%) and a mixture of the E / Z isomers (5.5 g, 71.4 %).
    [0187] [00187] (Z) -tert-butyl 3-fluoro-2- (hydroxymethyl) allycarbamate: 1H-NMR (300 MHz; CDCl2) δppm: 1.46 (9 H, s), 3.41 (1 H, br s), 3.74 (2 H, dd, J 6.5, 3.1 Hz), 4.28 (2 H, dd, J 6.0, 2.3 Hz), 4.87 (1 H, br s), 6.53 (1 H, dd, J 83.5).
    [0188] [00188] (E) -tert-butyl-3-fluoro-2- (hydroxymethyl) allycarbamate: 1H-NMR (300 MHz; CDCb) δppm, 1.47 (9 H, s), 3.78 (1 H, t, J 6.4 Hz), 3.93 - 4.02 (4 H, m), 4.94 (1 H, br s), 6.63 (1 H, d, J 83.6 Hz). Preparation of (Z) -tert-butyl 2- (bromomethyl) -3-fluoroalylcarbamate
    [0189] [00189] To a stirred solution of (Z) -tert-butyl 3-fluoro-2- (hydroxymethyl) -alylcarbamate (0.50 g, 2.44 mmol) in acetone (15 ml) at 0 ° C under atmosphere of N2 was added sequentially triethylamine (0.51 ml, 3.65 mmol) and methanesulfonyl chloride (0.23 ml, 2.92 mmol). The resulting mixture was stirred at this temperature for 30 min. The reaction mixture was filtered to remove precipitated salts and the filter cake was washed with more acetone (10 ml). The filtrate was charged with lithium bromide (1.06 g, 12.18 mmol) and the resulting suspension was stirred at room temperature for 1 h. The reaction mixture was partitioned between water (25 ml) and ethyl acetate (25 ml) and the aqueous layer was extracted with more ethyl acetate (25 ml). The combined organics were washed with brine (25 ml), dried over Na2SO4 and concentrated in vacuo to generate (Z) -tert-butyl-2 (bromomethyl) -3-fluoroalylcarbamate as a pale yellow oil (0.63 g, 96% ). 1H-NMR (300 MHz; CDCI2) δppm: 1.47 (9 H, s), 3.80 (2 H, br s), 4.09 (2 H, d, J 2.6 Hz), 4, 75 (1 H, br s), 6.65 (1 H, d, J 81.9 Hz). Preparation of (E) -tert-butyl 2- (bromomethyl) -3-fluoroalylcarbamate
    [0190] [00190] To a stirring solution of (E) -tert-butyl-3-fluor-2- (hydroxymethyl) -alylcarbamate (1.20 g, 5.85 mmol) in acetone (20 ml) at 0 ° C under N2 atmosphere was added sequentially triethylamine (1.22 ml, 8.77 mmol) and methanesulfonyl chloride (0.54 ml, 7.02 mmol). The resulting mixture was stirred at this temperature for 30 min. The reaction mixture was filtered to remove precipitated salts and the filter cake was washed with more acetone (10 ml). The filtrate was charged with lithium bromide (2.54 g, 29.24 mmol) and the resulting suspension was stirred at room temperature for 1 h. The reaction mixture was partitioned between water (25 ml) and ethyl acetate (25 ml) and the aqueous layer was extracted with more ethyl acetate (25 ml). The combined organics were washed with brine (25 ml), dried over Na2SO4 and concentrated in vacuo to generate (E) -tert-butyl 2- (bromomethyl) -3-fluoroalylcarbamate as a pale yellow oil (1.46 g, 93% ). 1H-NMR (300 MHz; CDCl3) δppm 1.47 (9 H, s), 3.97 (2 H, dd, J 3.5, 0.7 Hz), 4.02 (2 H, br d, J 6.1 Hz), 4.78 (1 H, br s), 6.79 (1 H, d, J 81.1 Hz). Example 2 Procedure A: Preparation of (Z) -tert-butyl 2 - ((4- (dimethylcarbamoyl) phenoxy) -methyl) -3-fluoroalylcarbamate
    [0191] [00191] To a vigorously stirred suspension of (Z) -tert 2-butyl- (bromomethyl) -3-fluoroalylcarbamate (430.0 mg, 1.60 mmol) and potassium carbonate (332.5 mg, 2.41 mmol) in dry DMF (2.0 ml) at room temperature under N2, 4-hydroxy-N, N-dimethylbenzamide (291.4 mg, 1.76 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water (40 ml) and ethyl acetate (20 ml) and the aqueous layer was extracted with more ethyl acetate (2 x 20 ml). The combined organics were washed with saturated aqueous NH4Cl solution (40 ml), brine (40 ml), dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude material on silica gel eluting with 60% ethyl acetate in n-hexane followed by 75% ethyl acetate in n-hexane generated (Z) -tert-butyl 2 - ((4- (dimethylcarbamoyl) phenoxy) methyl) -3-fluoroalylcarbate (520.0 mg, 92%) as a colorless oil. 1H-NMR (300 MHz; CDCl3) δppm: 1.44 (9 H, s), 3.07 (6 H, br s), 3.78 (2 H, br s), 4.74 (2 H, dd, J 2.7, 0.8 Hz), 4.80 (1 H, br s), 6.75 (1 H, d, J 82.7 Hz), 6.95 (2 H, d, J 8.9 Hz), 7.42 (2 H, d, J 8.8 Hz). Procedure B: Preparation of (Z) -4- (2- (aminomethyl) -3-fluoroalyloxy) -N, N-methyl-benzamide hydrochloride (Compound 18)
    [0192] [00192] To a stirred solution of (Z) -tert-butyl 2 - ((4- (dimethylcarbamoyl) -phenoxy) methyl) -3-fluoroalylcarbamate (520.0 mg, 1.48 mmol) in CH2Cl2 (8.0 ml) at room temperature, trifluoroacetic acid (2.0 ml) was added. The resulting mixture was stirred at room temperature for 30 minutes. All volatiles were removed in vacuo and the residue was co-evaporated with CH2Cl2 (2 x 20 ml) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3.0 ml) and then ethereal HCl (2.0 M in diethyl ether, 1.0 ml, 2.0 mmol) was added. The formed precipitate was isolated and dried under reduced pressure to generate (Z) -4- (2- (aminomethyl) -3-fluoroalkyloxy) -N, N-dimethylbenzamide hydrochloride (301 mg, 71%) as a pale yellow solid; mp 135 to 137 ° C; 1H-NMR (300 MHz; MeOD) δppm: 3.06 (3 H, br s), 3.10 (3 H, br s), 3.71 (2 H, d, J 3.0 Hz), 4 , 88 (2 H, dd, J 2.8, 0.8 Hz), 7.1 1 (2 H, d, J 8.9 Hz), 7.13 (1 H, d, J 80.8 Hz ), 7.45 (2 H, d, J 8.9 Hz). Procedure C: Preparation of (Z) -tert-butyl 2 - ((4 (N, N-dimethylsulfamoyl) phenoxy) methyl) -3-fluoroalylcarbamate
    [0193] [00193] To a vigorously stirred suspension of (Z) -tert-butyl 2- (bromomethyl) -3-fluoroalylcarbamate (232.0 mg, 0.87 mmol) in dry DMF (2.0 ml) at room temperature under N2 was added sequentially potassium carbonate (300.0 mg, 2.16 mmol) and 4-hydroxy-N, N-dimethylbenzamide (174.0 mg, 0.87 mmol). The resulting suspension was left to stir at room temperature for 2 h. The reaction mixture was partitioned between saturated aqueous NH4Cl solution (40 ml) and ethyl acetate (20 ml) and the aqueous layer was extracted with more ethyl acetate (20 ml). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude material over silica gel eluting with 50% ethyl acetate in n-hexane generated 2 - ((4- (N, N-dimethylsulfamoyl) phenoxy) methyl) -3-fluoroalylcarbamate (279.0 mg, 83%) like a colorless oil. 1H-NMR (300 MHz; CDCl3) δppm: 1.42 (9 H, s), 2.69 (6 H, s), 3.79 (2H, br s), 4.76 (2H, d, J 2.7 Hz), 4.81 (1H, br s), 6.76 (1H, d, J 82.6 Hz), 7.04 (2H, d, J 8.9 Hz), 7.72 ( 2H, d, J 9.0 Hz). Process D: Preparation of (Z) -4- (2- (aminomethyl) -3-fluoroalyloxy) hydrochloride -W, W-dimethyl-benzenesulfonamide (Compound 10)
    [0194] [00194] To a stirred solution of (Z) -tert-butyl 2 - ((4- (N, N-dimethylsulfamoyl) phenoxy) methyl) -3-fluoroalylcarbamate (279.0 mg, 0.72 mmol) in CH2Cl2 trifluoroacetic acid (1.0 ml) was added (4.0 ml) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. All volatiles were removed in vacuo and the residue was co-evaporated with CH2 Cl2 (2 x 20 ml). The resulting oil was taken up in ethyl acetate / MeOH (5: 1, 3.0 ml) and then ethereal HCl (2.0 M in diethyl ether, 0.5 ml, 1.0 mmol) was added. The formed precipitate was isolated and dried under reduced pressure to generate (Z) -4- (2- (aminomethyl) -3-fluoroalyloxy) -N, N-dimethylbenzenesulfonamide hydrochloride (196.0 mg, 84%) as a white solid ; mp 185 to 187 ° C; 1H-NMR (300 MHz, d 6 -DMSO) δppm: 3.39 (6 H, br s), 3.54 (2H, br s), 4.81 (2H, d, J 2.3 Hz), 7.16 (2H, d, J 9.0 Hz), 7.24 (1H, d, J 82.3 Hz), 7.25 (2H, br s), 7.77 (2H, d, J 9 , 0 Hz). Example 3
    [0195] [00195] The following compounds were prepared according to procedures A and B as indicated in Example 2.
    [0196] [00196] (Z) -4- (2- (aminomethyl) -3-fluoroalyloxy) -N-tert-butylbenzamide hydrochloride (Compound 1):
    [0197] [00197] (Z) -4- (2- (aminomethyl) -3-fluoroalyloxy) -3-fluoro-Ν, Ν-dimethyl-benzamide hydrochloride (Compound 4):
    [0198] [00198] (Z) -4- (2- (aminomethyl) -3-fluoroalyloxy) -3-chloro-Ν, Ν-dimethyl-benzamide hydrochloride (compound 6):
    [0199] [00199] (Z) -4- (2- (aminomethyl) -3-fluoroalyloxy) -3-bromo-N, N-dimethyl-benzamide hydrochloride (Compound 20):
    [0200] [00200] 4- (2- (Aminomethyl) -3-fluoroalkylthio) -N, N-dimethylbenzamide hydrochloride as a mixture of R and Z isomers (compounds 8E and 8Z):
    [0201] [00201] (E) -4- (2- (aminomethyl) -3-fluoroalyloxy) -N-isopropylbenzamide trifluoroacetate (Compound 39):
    [0202] [00202] (E) -4- (2- (aminomethyl) -3-fluoroalyloxy) -N-tert-butylbenzamide hydrochloride (Compound 23):
    [0203] [00203] (E) -4- (2- (aminomethyl) -3-fluoroalkyloxy) -N, N-diethylbenzamide hydrochloride (Compound 24):
    [0204] [00204] (E) -4- (2- (aminomethyl) -3-fluoroalkyloxy) -N-methylbenzamide hydrochloride (Compound 25):
    [0205] [00205] (2) -4 (2- (aminomethyl) -3-fluoroalyloxy) benzamide hydrochloride (Compound 2):
    [0206] [00206] (E) -4- (2- (aminomethyl) -3-fluoroalyloxy) benzamide hydrochloride (Compound 3):
    [0207] [00207] (E) -4- (2- (aminomethyl) -3fluoroalyloxy) -N, N-dimethylbenzamide hydrochloride (Compound 13):
    [0208] [00208] (Z) -4- (2- (aminomethyl) -3-fluoroalkyloxy) -N, N, 2-trimethylbenzamide hydrochloride (Compound 26):
    [0209] [00209] 4- (2- (Aminomethyl) -3-fluoroalyloxy) -3-methoxy-Ν, Ν-dimethylbenzamide hydrochloride as a mixture of E and Z isomers (compounds 7E and 7Z):
    [0210] [00210] The following compounds were prepared according to procedures C and D, as set out in Example 2.
    [0211] [00211] (E) -4- (2- (aminomethyl) -3-fluoroalyloxy) -benzenesulfonamide hydrochloride (Compound 26): Colorless solid; mp 107 to 110 ° C; 1H-NMR (300 MHz; MeOD) δppm: 3.85 (2 H, d, J 2.0 Hz) 4.71 (2 H, dd, J3.6, 0.8 Hz), 7.16 (2 H, d, J9.0 Hz), 7.27 (1 H, d, J 81.5 Fiz), 7.88 (2 H, d, J 9.0 Hz).
    [0212] [00212] (E) -4- (2- (aminomethyl) -3-fluoroalkyloxy) -N, N-dimethylbenzenesulfonamide hydrochloride (Compound 14):
    [0213] [00213] (Z) -3- (2- (aminomethyl) -3-fluoroalyloxy) -N, N-dimethylbenzenesulfonamide hydrochloride (Compound 15):
    [0214] [00214] (E) -4- (2- (aminomethyl) -3-fluoroalyloxy) -N-methylbenzenesulfonamide hydrochloride (Compound 28):
    [0215] [00215] (Z) -4- (2- (aminomethyl) -3-fluoroalkyloxy) -N-methylbenzenesulfonamide hydrochloride (Compound 29):
    [0216] [00216] (E) -4- (2- (aminomethyl) -3-fluoroalkyloxy) -N-ethylbenzenesulfonamide hydrochloride (Compound 30):
    [0217] [00217] (Z) -4- (2- (aminomethyl) -3-fluoroalyloxy) -N-ethylbenzenesulfonamide hydrochloride (Compound 31):
    [0218] [00218] (E) -4- (2- (aminomethyl) -3-fluoroalyloxy) -N-isopropylbenzenesulfonamide hydrochloride (Compound 32):
    [0219] [00219] (Z) -4- (2- (aminomethyl) -3-fluoroalyloxy) -N-isopropyl-benzenesulfonamide hydrochloride (Compound 33):
    [0220] [00220] (Z) -4- (2- (aminomethyl) -3-fluoroalyloxy) benzenesulfonamide hydrochloride (Compound 9):
    [0221] [00221] The inhibitory effects of all compounds of Formula I were tested against recombinant human AOSS / PAV-1 using the coupled colorimetric method as described for monoamine oxidase, amines oxidases containing copper and related enzymes (Holt AM and Palcic M. , A peroxidise-coupled continuous absorbance plate-reader assay for flavin monoamine oxidases, copper-containing amine oxidases and related enzymes. Nat. Protocol. 2006, 1, 24982505). Briefly, a cloned cDNA model corresponding to residues 34-763 of human AOSS / PAV-1 and incorporating a mouse Ig kappa (κ) signal sequence, an N-terminal signal epitope marker and a virus cleavage site tobacco mosaic (VMT), were brought together in a mammalian expression vector (pLO-CMV) by GeneArt AG. This vector containing human AOSS / PAV-1 was transfected to waste a CHO-K1 glycosylating mutant cell line, Lec 8. A clone stably expressing human AOSS / PAV-1 was isolated and cultured on a large scale. Active human AOSS / PAV-1 was purified and recovered using immunoaffinity chromatography. This was used as a source for AOSS / PAV-1 activity. A high yield colorimetric assay was developed using a 96 or 384 well format. Briefly, in a 96 well plate assay of 50 μl of purified human AOSS / PAV-1 (0.25 Hg / ml) was added to each 0.1 M NaPO4 buffer well (pH 7.4). The test compounds were dissolved in DMSO and tested on a concentration response curve (CRC) with data points from 4 to 9, typically in the micromolar or nanomolar range after incubation with human AOSS / PAV-1 for 30 minutes at 37 ° C . After 30 minutes of incubation, 50 μΙ of the reaction mixture containing 600 μΜ benzylamine (Sigma Aldrich), Red Amplexa 120 μΜ (Sigma Aldrich) and horseradish peroxidase at 1.5 U / ml (Sigma Aldrich) prepared in buffer 0.1 M NaPO4 (pH 7.4) was added to the corresponding well. The fluorescence unit (RFU) was read every 2.5 minutes for 30 minutes at 37 ° C at 565 nm excitation and 590 emission (Optima, BMG labtech). The kinetic slope for each well was calculated using the MARS data analysis software (BMG labtech) and this value was used to deduce the IC50 value (Dotmatics). The results are shown in Table 2. Table 2 Inhibitory activities of AOSS / PAV-1, MAO-B and DAO of examples of compounds of the present invention and compounds comparative
    [0222] [00222] AOSS / PAV-1 activity was determined using a method similar to that described in Example 5, except for the human AOSS / PAV-1 source. pcDNA-DEST40-hAOSS / PAV-1 was transfected into HMEC cells using lipofectamine (Invitrogen Ltda.). A clone stably expressing human AOSS / PAV-1 was selected and was stored in liquid nitrogen until cell lysate was needed for the colorimetric assay. Briefly, the cell expressing human HMEC AOSS / PAV-1 was cultured in several 10 cm Petri dishes. Once the cells reached 100% confluence, the cells were collected and the homogenates were prepared. The cells were washed twice with 5 ml of refrigerated HES buffer (20 mM HEPES, 1 mM EDTA, 250 mM sucrose, pH 7.4). HES buffer containing 1x protease inhibitors (Sigma Aldrich) was added and the cells were incubated on ice for 3 minutes. The buffer was removed and the cells were scraped and transferred to a centrifuge tube. Cell lysates were prepared by passing through a G 23 needle 10 times and followed by a 27 G needle 10 times. Alternatively, cell lysates were prepared using IKA Ultra-Turrax T 10 homogenizer for 3 minutes for each 10 ml of cell suspensions. The cells were then centrifuged for 5 min at 300xg. The clear supernatant was transferred to a new centrifuge tube and stored at -80 ° C until the colorimetric assay was performed. Before the assay, 0.5 mM pargyline was added to inhibit any residual MAO activity. The assay was performed as described in Example 5. In summary, 50 µl of cell lysate was incubated with the test compounds for 30 minutes at 37 ° C. Reaction mixtures were added and kinetics were read as described in detail in Example 5. Table 2 shows data for various compounds of Formula I. Example 7 Method for determining the ability of Formula I compounds to inhibit AOSS / PAV-1 in mouse and fat rat homogenate
    [0223] [00223] Abdominal fat from BALB / c mice, Wistar rats or Sprague-Dawley rats, which are tissues enriched with AOSS / PAV-1, has been surgically removed. For each gram of abdominal fatty tissue of the animals, 1 ml of 0.1 M NaPO4 (pH 7.4) was added. The tissues were homogenized using IKA Ultra-Turrax T 10 homogenizer for 3 minutes and the homogenate was centrifuged for 15 minutes at 3000xg. The middle layer (clear supernatant) was removed without disturbing the top layer (high fat content) or debris at the bottom of the tube. AOSS / PAV-1 activity was determined by checking the fluorescent signal. Km / Vmax values were measured and the fat homogenate was aliquoted and stored at -80 C until the tests were performed. The assay was performed in a similar manner as for human AOSS / PAV-1 (Example 5), except that the substrate concentrations (benzylamine) used for mouse fat homogenate and mouse fat rat homogenate were 80 μΜ and 30 μΜ, respectively. The results are shown in Table 2. Example 8 Method for determining the ability of Formula 1 compounds to inhibit recombinant human MAO-B
    [0224] [00224] The specificity of the compounds of the present invention was tested by determining their ability to inhibit MAO-B activity in vitro. Recombinant human MAO-B (0.06 mg / ml; Sigma Aldrich) was used as a source of MAO-B enzyme activities. The assay was performed in a similar manner as for human AOSS / PAV-1 (Example 5), with the exception of the fact that benzylamine substrate was used at 100 μΜ. Table 2 presents the data for various compounds of formula I. Example 9 Method for determining the ability of Formula I compounds to inhibit recombinant human diamine oxidase
    [0225] [00225] Three human genes are found to encode copper-containing amine oxidases. Diamine oxidase (DAO) is one of the enzymes produced by the AOC1 gene, named for its preference for substrates for diamines. The specificity of the compounds of Formula I was tested by determining their ability to inhibit DAO activity in vitro. Recombinant human DAO (2.4 µg ml) was used as a source of DAO enzyme activities. The assay was performed as described in the method for human AOSS / PAV-1 (Example 5), except that the substrate used was 200 μΜ putrescine and the control wells contained 10 μΜ aminoguanidine instead of mofegiline. Table 2 presents the data for various compounds of formula I. Example 10 Method for determining the ability of Formula I compounds to inhibit lysyl oxidase
    [0226] [00226] Lysyl oxidase (LOX) is an extracellular copper-dependent enzyme that oxidizes peptidyl lysine and hydroxylisin residues in collagen and lysine residues in elastin to produce alpha-aminoadipic-delta-semialdehyde peptidyl. This catalytic reaction can be irreversibly inhibited by β-aminopropionitrile (βΑΡΝ) that binds to the active site of LOX (Tang SS, Trackman PC and Kagan HM, Reaction of aortic lysyl oxidase with beta-aminoproprionitrile. J. Biol. Chem. 1983, 258, 4331-4338). There are five members of the LOX family; these are LOX, LOXL1, LOXL2, LOXL3 and LOXL4. The specificity of the compounds of formula I was tested by determining their ability to inhibit different sources of the LOX family in vitro.
    [0227] [00227] Two sources of enriched LOX were prepared using (1) supernatant of normal human lung fibroblasts (NHLF) and (2) rat skin homogenate. Briefly, NHLF was grown in complete medium containing supplements of SingleQuot with 5% FBS (Lonza Australia Pty Ltd.) and medium FGM-2 (Lonza Australia Pty Ltd.) in a T175 flask up to 60% to 80% confluence. Once the optimal confluence was reached, the cells were washed twice with phosphate saline buffer and replaced with medium containing 0.1% FBS and medium FGM-2. Two to four days later, the supernatant was collected and centrifuged for 5 minutes at 300xg. Cell debris was removed and LOX proteins were enriched using Amicon® Ultra-4 centrifugal filter units, with a 10 kDa cut (Millipore Ltd). Briefly, the samples were added to the columns and centrifuged at 4000xg, 4 ° C until a final volume of 1 ml was obtained. During the centrifugation process, the buffer was changed using sodium borate buffer (1.2 M urea; 0.05 M sodium borate, pH 8.2). Different substrates were tested in the enriched LOX supernatant and the fluorescence signals were measured using a colorimetric assay. The substrate specificities and pharmacological properties of the enriched supernatant have been corroborated with published literature. The enriched supernatant was aliquoted and stored at -80 ° C.
    [0228] [00228] LOX proteins are found highly expressed in the skin (Rucker et al., 1995), so rat skin homogenates were used as a second source to determine the activities of the LOX enzyme. Briefly, for each gram of finely chopped rat skin, 3 ml of phosphate buffered saline was added. The tissues were then homogenized using IKA Ultra Turrax T-10 homogenizer for 3 minutes. This and all subsequent homogenizations were performed on ice. The homogenate was centrifuged (20817xg, 30 minutes) at 4 ° C and the supernatant was discarded. The tissues were resuspended using 4.2 M sodium borate-urea buffer and homogenized for about 3 minutes (2.5 ml buffer / g). The homogenate was incubated overnight at 4 ° C. The sample was centrifuged (20817xg, 30 minutes) and the supernatants were collected. Cell pellets were subjected to two homogenization cycles and the supernatant from each process was collected. All supernatants were pooled and LOX proteins in rat skin homogenate were enriched using Amicon® Ultra-4 centrifugal filter units, with a 10 kDa cut. The sample was subjected to a buffer change until a 1.2 M urea concentration was reached. Different substrates were tested in the enriched LOX skin homogenate and fluorescence signals were measured using a colorimetric assay. Substrate specificity and pharmacological properties were determined. The enriched skin homogenate was aliquoted and stored at -80 ° C.
    [0229] [00229] The specificity of the Formula 1 compounds was tested using two different sources of LOX supernatant from normal human lung fibroblasts (NHLF) and rat skin homogenate. The tests were performed as described in the method for human AOSS / PAV-1 (Example 5), except that these two sources were treated with pargyline (0.5 mM), the substrate used was 10 mM putrescine, the control wells contained βΑΡΝ at 10 μΜ instead of mofegiline and was read at 45 ° C. Table 2 presents the data for several compounds of formula I. Example 11 Method for determining the ability of Formula I compounds to inhibit AOSS / PAV-1, when administered to mice and rats
    [0230] [00230] Mice and rats were administered either orally (p.o.) or intravenously (i.v.) the compounds of the present invention at various concentrations in the range from 0.1 mg / kg to 100 mg / kg. The control group was given the same vehicle volume p.o. or i.v. Abdominal, plasma and lung, liver and aorta tissues were collected at various time points ranging from 0 to 96 hours.
    [0231] [00231] Each tissue was homogenized in HES buffer with 1x phosphatase inhibitor (Sigma Aldrich) and 1x protease inhibitor (5 ml / g for rats and 20 ml / g for mice). The homogenate was used to measure AOSS activity as described in human AOSS / PAV-1 (Example 5), except that the mouse and rat homogenates were further diluted with 0.1 M NaPO4 (pH 7, 4) the ratio of 1: 5 and 1:20, respectively. The substrate concentrations (benzylamine) used for mouse fat homogenate and for rat fat homogenate were 80 μΜ and 30 μΜ, respectively. The kinetic slope for each well was calculated using MARS data analysis software. The percentage response was calculated using AOSS activity from animal tissue treated normalized with control animals. The graphs were constructed using the GraphPad Prism Software. The method described by Yu, PH et al., Involviment of SSAO-mediated deamination in adipose glucose transport and weight gain in obese diabetic KKay mice, Am J Physiol Endocrinol Metab 2004, 286: E634-E64 was used to determine the degree of inhibition of AOSS / PAV-1 in the plasma. Figures 1A to 1E, 2A to 2E and 3A to 3E show the dose-response profile for compound 23 in all tissues using different administration protocols. Example 12 Inhibition of carrageenan-induced rat paw edema
    [0232] [00232] Carrageenan-induced rat paw edema is a test widely used to determine the anti-inflammatory activity of various therapeutic agents and is a useful experimental system for evaluating the effectiveness of compounds to relieve acute inflammation. Inflammation is induced by intraplantar injection of 20 µL of carrageenan suspension (1% in saline) as described (see Roussin, A. et al. Neutrophil-associated inflammatory responses in rats are inhibited by phenylarsine oxide. Eur. J. Pharmacol 1997 , 322, 91-96 and Wise, LE et al., Evaluation of fatty acid amides in the carrageenan-induced paw edema model (Neuropharmacology, 2008. 54, 181-188). The test compound (0.1 to 100 mg / kg) is administered 1 hour before the administration of carrageenan. Paw thickness is measured with electronic digital calipers before 1, 3, 5, 6 and 24 hours after carrageenan injection, to demonstrate more than 50% edema inhibition when compared to control animals. Example 13 Efficacy in a systemic inflammation model
    [0233] [00233] Evaluation of the efficacy of the compounds of the present invention is carried out in an endotoxemia model consisting of intraperitoneal injection of a high dose of lipopolysaccharide (LPS) (5 mg / kg) (see Schabbauer, G. et al. In PI3K , -Akt pathway suppresses coagulation and inflammation in endotoxemic mice. Arterioscler. Thromb. Vessel. Biol, 2004, 24, 1963-1969 and Lentsch, AB et al. In STAT4 and STAT6 regulate systemic inflammation and protect against lethal endotoxemia. J. Clin Invest., 2001, 108, 1475-1482). Blood samples (50 ml) are collected at 0, 1, 2, 4, and 8 hours after LPS injection and used for blood smears and cytokine evaluation. Plasma concentrations of TNF-α, IL-6, MCP-1 and KC in mice treated with the compound (0.1 to 100 mg / kg) are reduced by 20 to 80%, as measured by ELISA. Animal survival rates are recorded for the next 3 days and mice treated with the compounds show a 20% higher survival rate. Example 14 Inhibition of inflammation in the air sac in the rat
    [0234] [00234] The injection of carrageenan induces inflammation and the bag serves as a reservoir of cells and mediators that can be easily measured in the fluid that accumulates at the site.
    [0235] [00235] The animals were anesthetized and 6 ml of sterile air was injected subcutaneously as described (see Romano, M. et al. Carrageenan-induced acute inflammation in the mouse air pouch synovial model. Role of tumor necrosis factor. Mediators Inflamm , 1997. 6, 32-38). After 3 days, the bags were discarded with 3 ml of sterile air. On day 6, controls received 1 ml of vehicle; controls treated with 10 mg / kg dexamethasone and the Compound 23 group received 2 mg / kg. 1 hour after treatment, the mice were injected with 1 ml of carrageenan solution in the air bag. After 4 hours after the injection of carrageenan, the animals were sacrificed and the bags were washed with saline solution. Exudates were used for cell counting, as well as cytokine measurement. Compound 23 treated rats showed a reduction in inflammation, with a significant reduction in the volume of exudate and neutrophil infiltration, as well as significantly decreased TNF-α and 1L-6 (Figure 4). Example 15 Inhibition of leukocyte migration in microcirculation
    [0236] [00236] The mouse cremaster preparation was used to study the inhibition of leukocyte migration to the microcirculation and adjacent connective tissue, as described (see Pinho, V. et al. Tissue- and Stimulus-Dependent Role of Phosphatidylinositol 3 -inase Isoforms for Neutrophil Recruitment Induced by Chemoattractants In Vivo. J Immunol 2007; 179: 7891-7898 and Nanhekhan, LV, Microcirculatory hemodynamics of the rat cremaster muscle flapin reduced blood flow states. Ann Plast Surg. August, 2003; 51 (2 ): 182-8).
    [0237] [00237] In summary, an incision was made in the skin of the scrotum to expose the left cremaster muscle, which was then carefully removed from the associated front panel. A longitudinal incision was made on the ventral surface of the cremaster muscle using a cautery. The testis and epididymis were separated from the underlying muscle and were transferred into the abdominal cavity. The muscle was then distributed over an optically clear viewing pedestal and was fixed along the extremities with a suture. The tissue was exposed to superfusion with warm saline solution buffered with bicarbonate. Single unbranched cremastolic venules (25-40 μm in diameter) were selected and, to minimize variability, the same section of the cremasteric venule was observed throughout the experiment. The number of rolling, adherent and migrating leukocytes by stimulation of KC or LPS was determined offline during video playback analysis. Rolling leukocytes were defined as cells that move at a slower rate than erythrocytes within a given container. The flow of rolling cells was measured as the number of rolling cells passing through a given point in the venule per minute. A leukocyte was considered adherent if it remained stationary for at least 30 seconds and total leukocyte adhesion was quantified according to the number of adherent cells within a 100 μm length of venule. Compound 23 (6 mg / kg) was administered 1 hour before stimulus administration. Compound 23 demonstrated> 50% inhibition of rolling and adhesion when compared to the control group (Figure 5). Example 16 Inhibition of inflammation in inducing cecal connection and perforation insult (CLP)
    [0238] [00238] The CLP procedure involved a laparotomy and ligation of the cecum, distal to the ileocecal valve, as described (see Martin, E. et al. In Phosphoinositide-3 Kinase γ Activity Contributes to Sepsis and Organ Damage by Altering Neutrophil Recruitment. Am. J. Respir. Crit. Care Med. September 2010, 182 (6) 762-773 and Lutterloh, CE, Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection. Crit Care. 2007; 11 (6 ): R122).
    [0239] [00239] The cecum was punctured with a needle to induce moderate sepsis; after the puncture, a small amount of fecal matter was extruded from each puncture. Sham animals received a laparotomy without manipulation of the cecum. Compound 23 was administered 6 hours before puncture. After ligation and puncture, the cecum was returned to the abdomen, the peritoneal wall and skin incisions were closed and the animals were allowed to recover. Eighteen hours after CLP / simulated surgery, a proportion of animals in each group were sacrificed and the lungs were washed. The wash was centrifuged to isolate the inflammatory cells for differential cell analysis, while a separate aliquot was used to count the total number of living cells using a hemocytometer and light microscopy. Survival was monitored over 7 days. In comparison with the vehicle-treated group that showed a 50% lethality incidence, mice treated with the compound resulted in a statistically significant reduction in 90% lethality of the surviving mice on day 7 (Figure 6B). In addition, the inhibitory effect of the compound on the inflammatory component of the disease was observed by the total reduction of leukocytes in BAL (Figure 6A). Example 17 Inhibition of chemically induced colitis
    [0240] [00240] This procedure is used to screen for compounds that inhibit the development of colitis compared to the control using the TNBS-induced colitis model (see Maslowski, KM et al. In Regulation of inflammatory responses by gut microbiota and chemoattractant GPR43 Nature, 2009. 461, 1282-1286). Briefly, the mice were sensitized by applying a mixture of acetone / olive oil (50:50) with TNBS (50:50, in total) on the shaved skin between the shoulder blades. Seven days later, the mice are challenged intrarectally with 2.5 mg of TNBS with 50% ethanol, 3.5 cm from the anal margin. The mice are fed during the night before the intrarectal challenge and given 5% dextrose in the drinking water. The mice are analyzed three days after the challenge with TNBS.
    [0241] [00241] Colitis is also induced by sodium dextran sulfate salt (DSS), as described (see Vieira, EM et al. In Treatment with a novel chemokine-binding protein or eosinophil lineage-ablation protects mice from experimental colitis. Am. J. Pathol, 2009 175 23822891). The mice received 4% DSS (w / v) in their drinking water ad libitum for 7 days, then switched to autoclaved drinking water. The compounds are administered throughout the experimental period at 0.1 to 100 mg / kg. The mice are sacrificed on the seventh day and the colon is analyzed. For survival studies, mice are followed for 25 days after starting DSS treatment. The compounds inhibit disease progression, as assessed by less weight loss (20%) and reduce clinical symptoms. They also delay the presence of blood in the stool and loss of firmness. Histological analysis of colon sections shows> 30% less inflammation. The cytokine measurement shows up to 70% inhibition of IL5, IL6 and TNF production. Example 18 Inhibition of ConA-induced liver injury in mice
    [0242] [00242] Autoimmune liver disease includes autoimmune hepatitis (AIH), a distinct form of acute and chronic inflammatory liver disease, in which immune reactions against host antigens have been found to be the main pathological mechanisms. AIH can lead to severe liver disease, such as liver cirrhosis. Specific ConA-induced liver injury in mice is an experimental animal model that has been well studied in the pathogenesis of liver injury. T cell-mediated immunity and the subsequent release of TNF-α are considered to play an important role in this disease.
    [0243] [00243] 10 mg / kg of concanavalin A (ConA) are administered intravenously in saline. Control mice are injected with saline. Transaminase and alkaline phosphatase in the blood and liver are reduced> 40% by the compound by 0.1 to 100 mg / kg. Cytokines, such as IL-6, TNF-α and IL-5, are significantly reduced, showing a reduction of up to 75% when compared to the control. Hepatic histopathology demonstrates decreased inflammation and tissue damage in the compound-treated group (see Hu, XD et al., Preventive effects of 1,25- (OH) 2VD3 against ConA-induced mouse hepatitis through promoting vitam D receptor gene expression. Acta Pharmacol Sin, 2010, 31, 703-708; Zhang, XL et al., Protective effetcs of cyclosporine A on T-cell dependent ConA-induced liver injury in Kunming mive. World J. Gastroenterol., 2001, 7,569-571; Erhardt, A. et al., IL-10, regulatory T cells, and Kupffer cellsmediate tolerance in concanavalin A-induced liver injury in mice. Hepatology, 2007, 475-485). Example 19 Inhibition of Parkinson's disease pathology in rats
    [0244] [00244] Model A: Systemic exposure to LPS to promote neurodegeneration
    [0245] [00245] Parkinson's disease is an age-related neurodegenerative disorder, pathological, characterized by a progressive and specific degeneration of dopaminergic neurons. Exposure to peripheral LPS, a potent inducer of inflammation in rodents, has been shown to result in neuroinflammation, persistent, delayed microglia activation and progressive loss of dopamine neurons in the substantia nigra, similar to that seen in Parkinson's disease. Recent evidence has implicated inflammation in the neurodegeneration of nigrostriatal dopaminergic neurons and LPS has been shown to promote it (see Qin, L. et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration, 2007 Glia, 453-462).
    [0246] [00246] Long-Evans rats were administered intraperitoneally (i.p.) 2 mg / kg of Compound 9 or vehicle 1 hour before the first (0 hour time) and the third (24 hour time) LPS injection. At time 0, the animals received a dose of 10 mg / kg of LPS. At 6 and 24 hours, the animals were treated with 3 mg / kg of LPS solution, i.p. 30 hours after the first LPS injection, the animals received i.p. of letabarb and were perfused transcardially with 400 ml of PBS at 4 ° C, followed by 400 ml of 4% paraformaldehyde (PFA). The brains were post-fixed overnight in 4% PFA at 4 ° C, followed by a 20% sucrose solution for 24 hours. 30 μm sections were collected and stained for immunofluorescence, immunohistochemistry and Western blot analysis. The group treated with compound 9 showed a reduction in neutrophil infiltration in the striated back and hippocampus, and a reduction in the recruitment of microglia cells and activation (length, surface and volume of dendrites) in the substantia nigra and dorsolateral striatum (Figure 7).
    [0247] [00247] Model B: localized exposure to LPS to promote neurodegeneration
    [0248] [00248] Direct injection of LPS into selected areas of the brain can be performed in order to induce a localized inflammatory response in the brain. Dopaminergic neurons are more vulnerable to neurotoxicity-based inflammation, and injections of local LPS into relevant areas, such as the substantia nigra and striatum, have been used as a model for Parkinson's disease (see Liu, M., & Bing, Lipopolysaccharide animal models for Parkinson's disease, 2011, 327,089; Choi, DY et al. Striatal neuroinflammation promotes Parkinsonism in rats. PLoS One, 2009, 4 (5), e5482). LPS has also been shown to promote negral dopaminergic neuron degeneration (see Machado, R. et al., Inflammatory animal model for Parkinson's Disease: The intranigral injection of LPS induced the inflammatory process along with the selective degeneration of nigrostriatal dopaminergic neurons. ISRN Neurologia, 201 1, 1-16).
    [0249] [00249] A solution containing 2 μΙ of 1 mg / ml LPS is injected into the left black substance of previously anesthetized female rats. The animals are treated with 0.1 to 100 mg / g of compound and the results show that up to 80% decrease in inflammation with less activation of the microglia compared to the control animals. Vehicle-treated animals are accompanied by loss of dopaminergic neurons and decreased intracellular dopamine content (AD), effects that are significantly inhibited by the compound. The average loss of the dopaminergic system in vehicle-treated groups is about 35%, while in the compound-treated group it is <20%. Example 20 Inhibition of inflammation associated with stroke in mice
    [0250] [00250] The development of brain tissue damage in stroke is composed of an immediate component followed by an inflammatory response, with secondary tissue damage after reperfusion. The ischemia / reperfusion model reproduces tissue damage as well as an inflammatory component (see Hase, Y. et al., Cilostazol, a phosphodiesterase inhibitor, prevents no-reflow and haemorrhage in mice with focal cerebral ischemia. Exp. Neurol, 2012 , 233 (1), 523). The mice are submitted to occlusion / reperfusion surgery of the middle cerebral artery through the introduction of a nylon monofilament in the right common carotid artery (CCA). It is carefully advanced to 11 mm from the bifurcation of the carotid artery and a proximal occlusion of the right middle cerebral artery is established. After 90 minutes of occlusion, the filament is removed to allow reperfusion for another 22.5 hours. The animals are treated with 0.1 to 100 mg / kg of the compound and show a reduction of up to 50% in the platelet aggregation and leukocyte connection in the micro vessels. Treatment significantly reduces the mortality rate with> 80% animal survival. Example 21 Inhibition of acute pulmonary inflammation in the LPS-driven model
    [0251] [00251] Inflammation was induced by instillation of LPS into the lungs of mice using a tracheal surgery challenge method (see Innate immune responses to LPS in mouse lung are suppressed and reversed by neutralization of GM-CSF via repression of TLR- 4. Am. J. Physiol. Lung Cell. Mol. Physiol., 2004, L877-85; and Harrod, KS, AD Mounday and JA Whitsett, Adenoviral E3-14.7K protein in LPS-induced lung inflammation. Am J. Physiol Lung Cell, Mol. Physiol., 2000, 278, L631-9). Briefly, 1 hour after treatment with 10 mg / kg dexamethasone or 2 mg / kg Compound 9, the mice were anesthetized, a midline incision was made in the neck, the muscle layers separated by blunt dissection, and 1 ml / kg of LPS (20 mg kg) or vehicle injected into the trachea. The incision was closed with wound clips and the rats returned to the cages.
    [0252] [00252] Six hours after the injection of LPS / saline solution, the mice were anesthetized, the wound clips removed, the trachea was cannulated with a 23-gauge needle and the lungs were washed eight times with 0.5 ml of serum heparinized physiological. The wash was pooled, gently inverted and a sample retained by differential analysis of white blood cells (CBS). The rest of the wash was centrifuged and the supernatant was used for cytokine analysis. Compound 9 demonstrated a significant reduction in neutrophil infiltration and a decrease in IL-6 and TNF-α compared to controls (Figure 8). Example 22 Inhibition of allergic pulmonary inflammation in mice infected with virus
    [0253] [00253] Early-life respiratory viral infections, mainly with respiratory syncytial virus (RSV), increase the risk of later development of childhood asthma. Infection with the mouse pneumonia virus (PVM), which belongs to the same family (Paramyxoviridae) and gender (Pneumovirus) as RSV, provides a model of RSV disease (see Rosenberg, HF et al., The pneumonia virus of mice infection model for severe respiratory syncytial virus infection: identifying novel targets for therapeutic intervention. Pharmacol Ther, 2005, 105, 1-6). Allergic airway inflammation, including recruitment of eosinophils, is prominent in animals that are infected with neonatal PVM and challenged with OVA antigen (see Siegle, JS et al., In Early-life viral infection and allergen exposure interact to induce an asthmatic phenotype in mice Respir. Res., 2010, 11, 14).
    [0254] [00254] On both days 1 and 2 of life, the rats are inoculated intranasally with 2 UFP (line PVM J3666 ~ 1 χ 105 UFC / ml) in phosphate buffered saline solution at 5 pl (PBS) in the external nostrils . Control animals are sham-infected with PBS only. Intranasal sensitization to OVA is performed either on days 1 and 2 of life or on days 28 and 29 with OVA at 5 µg / PBS at 5 µl or 100 mg / 40 µl, respectively. The mice receive a low level aerosol challenge with ovoalbumin (mass concentration of 3 ~ mg / m3 of ovoalbumin for 30 min / day, 3 days / week for 4 weeks). This is followed by a single moderate level challenge (~ 30 mg / m3 for 30 minutes) to induce changes in an acute exacerbation. The aim of this study is to evaluate the anti-inflammatory effect of the compound (0.1 to 100 mg / kg) in mice that are predisposed to the development of asthma characteristics due to early life infection.
    [0255] [00255] Bronchoalveolar lavage (BAL) is performed for the recovery of airway luminal cells. This procedure is achieved by intratracheal instillation of 800 μl of PBS / mouse. The total number of leukocytes is counted using a hemocytometer. Cytocentrifuged slides are prepared from the LBA fluid and then stained with Wright-Giemsa for differential cell count. The cells are classified into mononuclear cells, eosinophils, neutrophils and lymphocytes, according to standard morphological criteria and at least 200 cells were counted per slide under light microscopy. For lung histology, the lungs are perfused, inflated and fixed in 10% buffered formalin, before immunohistochemistry analysis. The extent of the leukocyte infiltrate is scored as 0, minimal or no inflammation; 1, mild inflammation, only perivascular or peribronchiolar; 2, moderate inflammation, some involvement of the parenchyma; 3, marked inflammation, generalized parenchyma involvement; 4, severe inflammation as previously described. The compounds are administered at 0.1 mg / kg to 100 mg / kg and the animals showed a 40 to 80% reduction in neutrophil infiltration, a decrease of IL-6 and TNF-α of up to 30% compared to controls . Example 23 Inhibition of exacerbation in an APC-induced asthma model
    [0256] [00256] Respiratory infections, which are predominantly caused by rhinovirus in people with asthma, aggravate airway inflammation and still contribute to the disease burden and health costs. The exacerbated house dust mite rhinovirus (APC) model was used to study the effect of compound 23 in the allergic asthma model (Collison, A. et al. The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity, Nat Med 2013, 19 (2): 232-7).
    [0257] [00257] The mice were sensitized and challenged intranasally, exposing them to a crude APC extract (50 µg per day on days 0, 1 and 2, followed by four exposures of APC at 5 pg daily from day 14 to the day 17, delivered in 50 μΙ of sterile saline). The animals were infected (day 18, 1 day after the last APC extract challenge) with 50 μl infectious or inactivated UV1B41 ultraviolet (UV) light (2.5 x 106 median infectious tissue culture dose) intranasally. The compounds were dosed at 0.1 to 100 mg / kg 1 hour before the rhinovirus challenge. The mice were killed 24 hours after the last allergen or rhinovirus challenge. Cytocentrifuged slides were prepared from bronchoalveolar lavage and then stained with Wright-Giemsa for differential cell count. The cells are classified into mononuclear cells, eosinophils, neutrophils and lymphocytes, according to standard morphological criteria and at least 200 cells were counted per slide under light microscopy. Animals treated with Compound 23 at 6 mg / kg showed a significant reduction in neutrophils infiltrating the BAL (Figure 9A) and reduced airway hyperresponsiveness in response to methacholine challenge back to the control group (Figure 9B) . Example 24 Inhibition of skin inflammation in the SCID mouse model of psoriasis
    [0258] [00258] Psoriasis is a common inflammatory skin disease characterized by
    [0259] [00259] abnormal epithelial differentiation, extensive capillary formation in the papillary dermis, and accumulation of inflammatory leukocytes including T lymphocytes, NK lymphocytes and granulocytes. Human skin transplantation in immunocompromised rats (severe combined immunodeficiency [SCID] mice) provides a model for studying psoriasis. Using this approach, epidermal thickening, extensive pin formation, and the presence of inflammatory cells are maintained for a prolonged period in the transplanted skin (see Zeigler, M. et al. In Anti-CDl la ameliorates disease in the human psoriatic skin-SCID mouse transplant model: comparison of antibody to CDl la with Cyclosporin A and clobetasol propionate.Lab Invest, 2001, 81, 1253-1261 and Nickoloff, BJ et al, Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model. Am. J. Pathol., 1995, 146, 580-588).
    [0260] [00260] SCID mice (6 to 8 weeks old) are prepared for orthotopical skin xenografts. Human skin xenografts (measuring 1.5 x 1.5 x 0.05 cm) are sutured to the flank area of each SCID mouse with absorbable Dexon suture. The dressings are changed every 2 days and the animals are kept throughout the study free of pathogens. Human skin / chimera from SCID mice are sacrificed at 4 or 6 weeks after xenograft transplantation (as this period of time has ensured adequate acceptance and healing). Xenograft biopsies are processed by cytokine ELISA, as well as histopathological analysis. After transplantation, the compound treated group (0.1 to 100 mg / kg) showed a 20 to 50% reduction in inflammation in the dermis and epidermis, compared to the vehicle treated group. In addition, cytokines, such as IL-6 and TNF-α, are inhibited by up to 80% by treatment with the compound. Example 25 Antimicrobial activity - Klebsiella pneumoniae infection
    [0261] [00261] The efficacy of the compound was investigated in a model of lung infection caused by a Gram-negative bacterium Klebsiella pneumoniae. The results are the differences between the control and the compound in lethality, bacterial counts and inflammatory indices after lung infection in mice (see Soares, CA et al., Dual function of the long pentraxin PTX3 in resistance against pulmonary infection with Klebsiella pneumoniae in transgenic mice. Microbes infect., 2006, 8, 1321-1329.).
    [0262] [00262] BALB / c mice (8 weeks old) were divided into three groups; 2 infected and one uninfected. Infected groups: Group A, the animals were administered vehicle orally; Group B, the animals were administered 2 mg / kg of compound orally; and Group C the animals were not infected. Bronchooalveolar lavage fluid (BAL) was collected to determine the total number of leukocytes. Cytocentrifuged slides were prepared from BAL and then stained with Wright-Giemsa for differential cell count. The cells are classified into mononuclear cells, eosinophils, neutrophils and lymphocytes, according to standard morphological criteria and at least 200 cells were counted per slide under light microscopy. For bacterial counts, the lung was homogenized, diluted in series and placed on MacConkey agar plates. Colony forming units were counted after 24 hours of incubation at 37 ° C. Animal survival rates were recorded for the next 10 days.
    [0263] [00263] Compared to the vehicle-treated group, which showed a 45% lethality incidence, mice treated with compound 23 showed a statistically significant reduction in lethality, with 100% of surviving mice (p = 0.0597 ) after 8 days (Figure 10A). In addition, the inhibitory effect of Compound 23 on the inflammatory component of the disease was observed in reduced leukocyte infiltrate to infiltrate BAL (Figure 10B). Example 26 Inhibition of Chronic Obstructive Pulmonary Disease
    [0264] [00264] Chronic obstructive pulmonary disease (COPD) is a debilitating disease of the lung. The disease is characterized by chronic inflammation of the airways, hypersecretion of mucus, remodeling of the airways and emphysema, which lead to reduced lung function and shortness of breath. Airflow limitation is generally progressive and associated with an abnormal inflammatory response of the lungs to toxic gases and particles. Cigarette smoke causes a repetitive inflammatory insult that is believed, through the action of mediators, such as proteases, to lead to structural and functional changes in the lung. In addition, COPD patients are more susceptible to respiratory tract infections (see Beckett, EL in A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis. J Allergy Clin Immunol 2013 Mar; 131 (3): 752-762.e7; Guerassimov, A., The Development of Emphysema in Cigarette Smoke-exposed Mice Is Strain Dependent. Am J. Respir. Crit. Care Med. November 2004 (170) 974-980 and Morris, A., Comparison of CIgarette Smoke-Induced Acute Inflammation in Multiple Strains of Mice and the Effect of a Matrix Metalloproteinase Inhibitor on These Responses. JPET December 2008 (327) 851862).
    [0265] [00265] BALB / c mice were simultaneously exposed to cigarette smoke (twelve 3R4F reference cigarettes [University of Kentucky, Lexington, KY], twice a day and five times a week for 1 to 12 weeks), using a custom design and purpose built for nose only, directed flow inhalation and smoke-exposure system (CH Technologies, Westwood, NJ) housed in a laminar flow and fume hood. Each exhibition lasted 75 minutes. Exposure through the nose was only achieved through specialized containment tubes that released smoke and normal air directly to the animal's nose. This protocol allowed for more intensive smoke release than full-body exposure systems. During the first two days, the mice were exposed to a smoking session with 12 puffs of each cigarette to allow acclimatization. The smoke was released in 2-second breaths, with 30 seconds of normal air between each breath. After day 2, the mice underwent two sessions in which they were exposed to smoke from 12 cigarettes (in the morning and in the afternoon, separated by a recovery period). Compound 23 was given at 2 mg / kg from week 6 weeks of the experimental procedure and collagen content in the lung significantly inhibited (Figure 11). Example 27 Inhibition of liver fibrosis induced by CCI4
    [0266] [00266] An analysis of the use of AOSS / PAV-1 inhibitors for the treatment of inflammatory / fibrotic diseases is performed through the use of a CCU induced model of liver fibrosis. Liver damage is often followed by regeneration of the complete parenchyma due to the regenerative power of hepatocytes. However, concomitant activation of fat storage cells leads to the accumulation of extracellular matrix accompanied by recurrent hepatocyte necrosis, inflammation and regenerative processes, and causes liver fibrosis and, consequently, liver cirrhosis (see Natsume, M. et al. In Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice. J. Leukoc. Biol, 1999, 66, 601-608.).
    [0267] [00267] Liver fibrosis in male Sprague Dawley (SD) rats was induced by oral application of CCl4 (2.5 μl / g of CCl4 olive oil solution, 3 times a week). Vehicle (PBS) and positive control of imatinib mesylate (2.5 mg kg) were given to rats from day 1 to day 28, and Compound 23 (6 mg / kg) was administered to rats from day 14 to day day 28. Compound 23 demonstrated a clear tendency to decrease levels of fibrous tissue, as represented by a decrease in Sirius red staining (Figure 12C). In addition, Compound 23 showed protective effects of liver function and a reduction in inflammation, which were significantly evidenced by decreased serum ALT and AST levels (Figure 12A and 12B) and a reduction in inflammatory score (12D), when compared with the CCI4 group only. Example 28 Inhibition of non-alcoholic steatohepatitis (ENA) induced liver fibrosis
    [0268] [00268] An analysis of the use of AOSS / PAV-1 inhibitors for the treatment of inflammatory / fibrotic diseases is performed using a model of liver fibrosis induced by non-alcoholic steatohepatitis (ENA). The ENA STAM model was induced in 30 male mice by a single subcutaneous injection of streptozotocin solution two days after birth and fed a high fat diet (CKD, 57 kcal fat%) after 4 weeks of age and 10 weeks old. From 7 weeks of age the mice were administered orally the daily dose of vehicle (PBS), Compound 23 (6 mg / kg) or the positive control telmisartan (10 mg / kg) for 3 weeks. Compound 23 reduced inflammation and scores of non-alcoholic fatty liver disease (NAFLD) after clinical examination (Figures 13A and 13B). Fibrosis, as evidenced by a reduction in the red-positive Sirius area (Figure 13C) was also reduced. Example 29 Inhibition of uveitis
    [0269] [00269] This procedure is for determining the inhibition of uveitis by the compound (s) according to the present invention. Uveitis is a complex inflammatory eye disease that can lead to blindness. It can affect any part of the eye and is characterized by the accumulation of leukocytes in the eye tissues. Current therapies for uveitis include corticosteroids and chemotherapeutic agents to reduce inflammation. However, the serious side effects of these drugs, such as increased intraocular pressure or cytotoxicity limit their use (see Moorthy, RS et al. In Glaucoma associated with uveitis. Surv. Ophthalmol. Surv. Ophthalmol., 1997, 41, 361 -394 and Lightman, S., New therapeutic options in uveitis (Eye 1997, 11,222-226).
    [0270] [00270] Thirty (30) albino Lewis rats were divided into four (4) groups. For three groups of 4, eye inflammation was induced by a single injection in the paw of 1 mg / kg of lipopolysaccharide (Salmonella typhimurium LPS). Compound 23 (2 mg / kg) and vehicle were administered by forced oral feeding (1 ml / kg) 1 hour before induction (day 0). Reference substance (dexamethasone, 2 mg / kg) was administered by intravenous injection (2.5 ml / kg) only after induction (day 0). Ocular inflammation was assessed by clinical examination and quantification of neutrophils, eosinophils and proteins in aqueous humor, 24 hours after induction.
    [0271] [00271] Clinical examination of inflammation; The animals were examined with a slit lamp at the baseline (Day 1), then 24 hours after induction (day 1). Inflammation in each animal was classified using a described scoring system (Devos A. et al., Systemic antitumor necrosis factor antibody treatment exacerbates Endotoxin Induced Uveitis in the rat. Exp. Eye. Res. 1995; 61: 667-675). Enlargement, miosis and hippopotamus were marked by absence (0) or presence (1), the hyperemia iris and cells in the anterior chamber were marked by absence (0) or mild (1) or severe presence (2). The maximum score (sum of the five parameter scores) is 7. In the group treated with compound 23, a 33% reduction in the severity of eye inflammation, compared to the result observed for the vehicle group, was detected 24 hours after induction and 25 hours after oral administration (Figure 14A).
    [0272] [00272] At the end of the clinical evaluation (24 hours) after induction, the animals were anesthetized by an intramuscular injection of a mixed solution of Rompun® (xylazine) and Imalgene® 1000 (ketamine) and sacrificed by cardiac injection of pentobarbital overdose . The aqueous humor was immediately collected for each eye.
    [0273] [00273] Quantification of cellular infiltration in aqueous humor; Neutrophils and infiltrated eosinophils were counted manually in the cytological preparation of aqueous humor samples diluted 10 times with PBS before Giemsa staining. A significant decrease in eosinophils (mean ± SEM: 8.9 ± 1.7 cells / µl, n = 20) was observed for the group treated with Compound 23 compared to the group treated with the vehicle (p = 0.033) (Figure 14B). Example 30 Inhibition of macular degeneration
    [0274] [00274] Age-related macular degeneration (AMD) is the main cause of blindness and occurs in two main forms. The first is a form of geographic atrophy ("dry"), which is defined by a degeneration of photoreceptors and the retinal pigmented epithelium (RPE) near the macula, the accumulation of lipofuscin (A2E), and the formation of druses. The second is a "wet" form, which is associated with choroidal neovascularization (see Randazzo, J. et al. In Orally active multi-functional antioxidants are neuroprotective in a rat model of light-induced retinal damage. PLoS One, 201, 6 e21926 and Davis, SJ et al., The Effect of Nicotine on Anti-Vascular Endothelial Growth Factor Therapy in a Mouse Model of Neo vascular Age-Related Macular Degeneration (Retina, 2011). Model A: Light Model
    [0275] [00275] After two weeks of adaptation to the dark, rats from each group are exposed to harmful light for three hours at 1000 1x of white light (damaged light rats, LD). Control rats in each group are also placed inside the light box apparatus for three hours, but not exposed to light (damaged non-light mice, NLD). Oxidative stress markers were evaluated immediately after exposure to light. Animals treated with 0.1 - 100 mg / kg compounds show a> 20% reduction in oxidative stress, as seen by assessing neural retinas, which are dissected after euthanasia of the enucleated eye. For functional and morphological evaluation, the rats are returned to the dark environment after exposure and the function of the retina is evaluated by ERG, 5 to 7 days later. After ERG analysis, the rats are sacrificed and the eyes enucleated and processed immediately for quantitative morphology. The compound-treated group demonstrates a reduction in disease severity, as seen by reductions in eye morphological changes when compared to control animals. Model B: Laser Model
    [0276] [00276] CNV is induced by laser photocoagulation in mice with an argon laser (spot size, 50 mm; duration, 0.05 seconds, strength, 260 mW). Three laser points are placed in each eye close to the optic nerve. The production of a vaporization bubble at the laser confirms the rupture of BM. Animals from each group were sacrificed on days 1, 3, 5 and 7 post-laser. In comparison to the control, the rats treated with the compound (0.1 to 100 mg / kg) showed a significant reduction in size (by 20%) and the incidence of CNV (> 40%), as determined by microscopy. Example 31 Inhibition of cancer progression
    [0277] [00277] B16F10 melanoma cells (4 x 105 cells / animal) were injected into the scraped abdominal region of the animal, as described in Marttila-Ichihara, F. et al. Small-Molecule Inhibitors of Vascular Adhesion Protein-1 Reduce the Accumulation of Myeloid Cells into Tumors and Attenuate Tumor Growth in Mice. The Journal of Immunology, 2010, 184, 3164-3173. The growth of the tumor is followed by measuring the dimensions, using electronic calibrators. Tumor progression is decreased in treated animals (compounds 0.1 to 100 mg / kg), with up to 25% less tumor growth, when compared to the control group. Groups of treated compounds show an attenuated accumulation of myeloid cells in tumors, showing> 40% less cell infiltrate; in addition, treated mice demonstrate inhibited neoangiogenesis.
    [0278] [00278] All patents and other references cited in the specification are indicative of the level of expertise of those technicians in the subject to which the invention belongs and are incorporated by reference in their entirety, including any figures and tables, to the same extent as if each had been incorporated by reference in its entirety individually.
    [0279] [00279] A person skilled in the art will readily understand that the present invention is well adapted to obtain the mentioned purposes and advantages, as well as those inherent to it. The methods, variations and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended to be limitations on the scope of the present invention. Changes and other uses will occur to those skilled in the art, which are included within the scope of the invention, are defined by the scope of the claims.
    [0280] [00280] It will be easily apparent to a person skilled in the art that various substitutions and modifications can be made to the invention described in the present without departing from the scope and spirit of the invention. For example, variations can be made to provide additional compounds of Formula I and / or various methods of administration can be used. Thus, these additional realizations are within the scope of the present invention and claims that follow.
    [0281] [00281] The invention described herein by way of illustration can be properly practiced in the absence of any element or elements, limitations or limitations that are not (are) specifically disclosed (s). The terms and expressions that have been used are used as terms of description and not of limitation, and there is no intention, in the use of such terms and expressions, to exclude any equivalents of the features presented and described or their portions, but it is recognized that they are possible various modifications within the scope of the claimed invention. Thus, it should be understood that, although the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and variations of the concepts disclosed herein can be invoked by those skilled in the art and such modifications and variations are considered to be within the scope of present invention, as defined by the appended claims.
    [0282] [00282] Furthermore, where the features or aspects of the present invention are described in terms of Markush groups or another group of alternatives, those skilled in the art will recognize that the present invention is therefore also described in terms of any individual member or subgroup of members of the Markush group or another group.
    [0283] [00283] Furthermore, unless otherwise indicated, when several numerical values are provided for realizations, additional realizations are described taking any two different values as the parameters of a range. Such bands are also within the scope of the described invention.
    [0284] [00284] Thus, further realizations are within the scope of the present invention and within the scope of the following claims.
    权利要求:
    Claims (18)
    [0001]
    Compound, characterized by the fact that it presents Formula II:
    [0002]
    Compound according to claim 1, characterized by the fact that R5 is an unsubstituted phenylene group or a phenylene group substituted with one or more groups selected independently from methyl, fluorine, chlorine, bromine, OCH3 and CF3.
    [0003]
    Compound according to claim 1 or 2, characterized by the fact that R7 and R8 are both hydrogen, R7 and R8 are both C1-C6alkyl or R7 is hydrogen and R8 is C1-C6alkyl.
    [0004]
    Compound according to any one of claims 1 to 3, characterized by the fact that R6 is
    [0005]
    Compound according to any one of claims 1 to 3, characterized in that R6 is where R7 and R8 are defined in claim 1 or 3.
    [0006]
    Compound, according to claim 1, characterized by the fact that said compound is selected from the group consisting of:
    [0007]
    Compound, characterized by the fact that it is: (E) -4- (2- (aminomethyl) -3-fluoroalyloxy) -N-fer-butylbenzamide, or a pharmaceutically acceptable salt or solvate thereof.
    [0008]
    Compound, characterized in that it is a pharmaceutically acceptable salt of the compound as defined in any one of claims 1 to 7.
    [0009]
    Compound according to claim 8, characterized in that it is an acid addition salt.
    [0010]
    Compound according to claim 9, characterized by the fact that the acid addition salt is selected from the group consisting of hydrochlorides, hydrobromides, sulfates, formats, acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, maleates , butyrates, valerates and fumarates.
    [0011]
    Compound according to claim 10, characterized in that the acid addition salt is a hydrochloride salt.
    [0012]
    Compound, characterized by the fact that it is the pharmaceutically acceptable (E) -4- (2- (Aminomethyl) -3-fluoroalyloxy) -N-tert-butylbenza-mida hydrochloride salt.
    [0013]
    Composition, characterized in that it comprises a compound as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt, as defined in any one of claims 8 to 12, or solvate thereof, and at least one pharmaceutically acceptable excipient , vehicle or thinner.
    [0014]
    Use of a compound, as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, or of a composition as defined in claim 13, characterized in that it is for the manufacture of a medicament for the treatment of a disease associated with or modulated by AOSS / PAV-1 protein, in which the disease is inflammation, fibrosis, diabetes-induced disease, neuroinflammatory disease or cancer.
    [0015]
    Use according to claim 14, characterized by the fact that said inflammation is associated with liver disease, respiratory disease, cystic fibrosis, asthma or chronic obstructive pulmonary disease or eye disease.
    [0016]
    Use, according to claim 14, characterized by the fact that the disease is a diabetes-induced disease selected from the group consisting of diabetic nephropathy, glomerulosclerosis, diabetic retinopathy, non-alcoholic fatty liver disease and choroidal neovascularization.
    [0017]
    Use, according to claim 14, characterized by the fact that the disease is selected from the group consisting of cystic fibrosis, liver fibrosis, liver cirrhosis, renal fibrosis, scleroderma, idiopathic pulmonary fibrosis and radiation-induced fibrosis.
    [0018]
    Use according to claim 17, characterized by the fact that the disease is a non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH) or alcohol-induced fibrosis, leading to liver cirrhosis.
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    同族专利:
    公开号 | 公开日
    HRP20180953T1|2018-07-27|
    HUE038437T2|2018-10-29|
    HK1245237A1|2018-08-24|
    RS57086B1|2018-06-29|
    PL2844637T3|2018-09-28|
    KR20200030126A|2020-03-19|
    US20190071396A1|2019-03-07|
    WO2013163675A1|2013-11-07|
    US20180086698A1|2018-03-29|
    JP6182595B2|2017-08-16|
    KR20150014926A|2015-02-09|
    MX2014013294A|2015-05-08|
    CA2871793A1|2013-11-07|
    JP6602802B2|2019-11-06|
    SG10201707020TA|2017-10-30|
    ME03063B|2019-01-20|
    AU2013203655B2|2017-02-02|
    US20150158813A1|2015-06-11|
    PT2844637T|2018-04-17|
    US20160244406A1|2016-08-25|
    EP3438087A1|2019-02-06|
    JP2020019810A|2020-02-06|
    ES2668300T3|2018-05-17|
    US9815782B2|2017-11-14|
    HK1203477A1|2015-10-30|
    CA2871793C|2020-09-15|
    EP2844637A1|2015-03-11|
    AU2013255103A1|2014-11-06|
    CN104520268B|2017-05-24|
    EP2844637B1|2018-03-28|
    SG11201406948PA|2014-11-27|
    NO2842608T3|2018-07-21|
    BR112014027406A2|2017-06-27|
    DK2844637T5|2018-08-13|
    CY1120334T1|2019-07-10|
    JP2015521167A|2015-07-27|
    TR201807453T4|2018-06-21|
    EP2844637A4|2015-12-09|
    US10160723B2|2018-12-25|
    AU2013203655A1|2013-11-21|
    CN107266332A|2017-10-20|
    CN104520268A|2015-04-15|
    KR102089935B1|2020-03-18|
    JP2017132767A|2017-08-03|
    CN107266332B|2020-07-24|
    DK2844637T3|2018-04-23|
    CA3086105A1|2013-11-07|
    LT2844637T|2018-05-10|
    US9302986B2|2016-04-05|
    MX360634B|2018-11-12|
    SI2844637T1|2018-07-31|
    AU2013255103B2|2016-09-29|
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    CA3122623A1|2019-01-11|2020-07-16|Nanjing Transthera Biosciences Co., Ltd.|Halo-allylamine compounds and use thereof|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-02-27| B25A| Requested transfer of rights approved|Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH (DE) |
    2018-12-04| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-01-07| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-06-23| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-09-24| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/04/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    2021-08-10| B25A| Requested transfer of rights approved|Owner name: PHARMAXIS LTD (AU) |
    优先权:
    申请号 | 申请日 | 专利标题
    US201261641814P| true| 2012-05-02|2012-05-02|
    US61/641,814|2012-05-02|
    PCT/AU2013/000356|WO2013163675A1|2012-05-02|2013-04-05|Substituted 3-haloallylamine inhibitors of ssao and uses thereof|
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