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Nitric Oxide Releasing Amino Acid Ester

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(19) TZZ ¥ __T (11) EP 2 342 175 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 229/08 (2006.01) A61K 31/197 (2006.01) 27.05.2015 Bulletin 2015/22 A61P 39/06 (2006.01) (21) Application number: 09815530.2 (86) International application number: PCT/CA2009/001355 (22) Date of filing: 24.09.2009 (87) International publication number: WO 2010/034118 (01.04.2010 Gazette 2010/13) (54) NITRIC OXIDE RELEASING AMINO ACID ESTER COMPOUND, COMPOSITION AND METHOD OF USE STICKOXIDFREISETZENDE AMINOSÄUREESTERVERBINDUNG SOWIE ZUSAMMENSETZUNGEN DAMIT UND VERWENDUNGSVERFAHREN DAFÜR COMPOSÉ D’ESTER D’ACIDE AMINÉ LIBÉRANT UN OXYDE NITRIQUE, COMPOSITION ET PROCÉDÉ D’UTILISATION (84) Designated Contracting States: (74) Representative: Kling, Simone AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Lavoix Munich HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL Bayerstrasse 83 PT RO SE SI SK SM TR 80335 München (DE) (30) Priority: 24.09.2008 US 99616 P (56) References cited: WO-A1-2008/071421 WO-A2-2005/030135 (43) Date of publication of application: WO-A2-2008/095841 WO-A2-2009/106471 13.07.2011 Bulletin 2011/28 CA-A1- 2 370 412 CA-A1- 2 370 425 CA-A1- 2 677 387 (73) Proprietor: Nitrogenix Inc. Tortola (VG) Remarks: Thefile contains technical information submitted after (72) Inventor: FARBER, Michael the application was filed and not included in this Montreal, Québec H3X 2K4 (CA) specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 342 175 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 342 175 B1 Description (a) Field 5 [0001] The subject matter disclosed generally relates to novel amino acid ester compounds comprising at least one nitric oxide releasing group and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one amino acid ester compound comprising at least one nitric oxide releasing group and/or at least one therapeutic agent. [0002] The invention relates to the subject-matter as defined in the claims, which involves the amino acid compound 2’-nitrooxyethyl 2-amino-3-methylbutanoate; the following description is subject to this definition. 10 [0003] The invention also provides novel compositions comprising at least the amino acid ester compound and/or at least one therapeutic agent. The invention also provides novel kits comprising at least the amino acid ester compound and at least one therapeutic agent. The invention also provides methods for (a) treating cardiovascular diseases; (b) treating renovascular diseases; (c) treating diabetes; (d) treating diseases resulting from oxidative stress; (e) treating endothelial dysfunctions; (f) treating diseases caused by endothelial dysfunctions; (g) treating cirrhosis; (h) treating pre- 15 eclampsia; j) treating osteoporosis; (k) treating nephropathy; (I) reperfusing injury following ischemia; and/or (m) pre- serving tissues, organs, organ parts and/or limbs. (b) Related Prior Art 20 [0004] Normal metabolic processes in vascular cells are associated with the generation of reactive oxygen interme- diates that must be neutralized in order to limit oxidative damage and cellular dysfunction. In the setting of common disorders or in the presence of common risk factors for numerous diseases reactive oxygen species (ROS) are generated in abundance and their rate of synthesis and flux typically exceeds the capacity of endogenous antioxidant mechanisms. For example, hypercholesterolemia, hyperglycemia (Keaney et al, Circulation, 99: 189-191 (1999)), cigarette smoking, 25 hyperhomocysteinemia, hypertension, and atherosclerosis are all accompanied by an increase in plasma and tissue ROS generation. [0005] Numerous drugs for vasodilation act through a nitric oxide creating effect, for examples nitroglycerin for angina pectoris, isosorbide mono and dinitrates for long term prevention and relief of angina pectoris, sodium nitroprusside for eclempsia, and phosphodiesterase inhibitors for erectile dysfunction. However most of these molecules have fairly high 30 levels of toxicity and or other problems with limited efficacy or side effects. Nitric oxide donating esters of amino acids have high bioavailability, low toxicity levels and their release profiles can be modified through either the length of the ester linkage (n = 1to 10) or the amino acid selected. SUMMARY 35 [0006] In a first embodiment there is disclosed the novel amino acid ester compound 2’-nitrooxyethyl 2-amino-3- methylbutanoate and pharmaceutically acceptable salts thereof. [0007] The subject matter herein disclosed further relates to compositions for increasing nitric oxide physiological levels in a subject whether by itself or in conjunction with another therapeutic agent whereby the combination reduces 40 negative side effects such as hypertension or gastric ulceration or has other positive effects on the outcome of the therapy of the therapeutic agent when combined with a nitric oxide source from the nitric oxide donating ester amino acids. [0008] The subject matter is also based on the discovery that administering the amino acid ester compound comprising at least one nitric oxide releasing group, or pharmaceutically acceptable salts thereof, can be used for the delivery of nitric oxide at the targeted site. Nitric oxide donors include, for example, S-nitrosothiols, nitrites, nitrates, N-oxo-N- 45 nitrosamines, SPM 3672, SPM 5185, SPM 5186 and analogues thereof, and substrates of the various isozymes of nitric oxide synthase. Thus, another embodiment of the invention provides compositions comprising at least the amino acid ester compound comprising a nitric oxide releasing group. The invention also provides for such compositions in a pharmaceutically acceptable carrier. [0009] The invention provides compositions comprising at least the amino acid ester compound and at least one 50 therapeutic agent, including, but not limited to, aldosterone antagonists, alpha-adrenergic receptor antagonists, angi- otensin R antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β-adrenergic antagonists, calcium channel block- ers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H 2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel block- 55 ers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof. In a preferred embodiment the at least one therapeutic agent is selected from the group consisting of an aldosterone antagonist, an angiotensin II antagonist, an angiotensin- converting enzyme (ACE) inhibitors, a β-adrenergic antagonist, a digitalis, a diuretic, and a hydralazine compound. The invention also 2 EP 2 342 175 B1 provides for such compositions in a pharmaceutically acceptable carrier. [0010] Another embodiment of the invention provides compositions comprising a therapeutically effective amount of at least the amino acid ester compound comprising a nitric oxide releasing group of the invention, and at least one therapeutic agent selected from the group consisting of an aldosterone antagonist, an angiotensin II antagonist, an 5 angiotensin-converting enzyme (ACE) inhibitor, a β-adrenergic antagonist, a diuretic and a hydralazine compound. The invention also provides for such compositions in a pharmaceutically acceptable carrier. [0011] The invention provides methods for (a) treating cardiovascular diseases; (b) treating renovascular diseases; (c) treating diabetes; (d) treating diseases resulting from oxidative stress; (e) treating endothelial dysfunctions; (f) treati ng diseases caused by endothelial dysfunctions; (g) treating cirrhosis; (h) treating pre-eclampsia; (j) treating osteoporosis; 10 (k) treating nephropathy; (I) reperfusing injury following ischemia; and/or (m) preserving tissues, organs, organ parts and/or limbs in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least the amino acid ester compound comprising at least one nitric oxide releasing group, and, optionally, at least one therapeutic agent, such as, for example, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic com- 15 pounds, antioxidants, antithrombotic and vasodilator compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel block- ers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof. 20 [0012] The method optionally further comprises the administration of at least one nitric oxide donor compound. In this embodiment of the invention, the methods can involve (i)
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  • Adrenoreceptors F

    Adrenoreceptors F

    Stimulation of in vitro ovulation and contraction of brook trout (Salvelinus fontinalis) follicles by adrenaline through \g=a\-adrenoreceptors F. W. Goetz and J. A. Bradley University of Notre Dame, Department of Biological Sciences, Notre Dame, ID 46556, USA The effects of adrenaline and adrenoreceptor antagonists on ovulation and follicle wall contraction were investigated in brook trout (Salvelinus fontinalis) follicles using in vitro incubation systems. Adrenaline significantly stimulated a dose-dependent increase in ovu- lation and follicle contraction at concentrations between 1.0 and 100 \g=m\moll \m=-\1 The ovulatory and contractile effects of 10 \g=m\mol adrenaline l \m=-\1 could be blocked by the \g=a\1-adrenoreceptorantagonists WB-4101 and benoxathian, and by the \g=a\2-antagonist yohim- bine. WB-4101 was the most potent blocker, significantly inhibiting ovulation and con- traction at 1.0 \g=m\mol l\m=-\1. In contrast, the \g=b\-antagonistpropranolol (100\p=n-\0.001\g=m\moll\m=-\1) was totally ineffective in blocking adrenaline-induced ovulation and follicle contraction. The results indicate that there is a strong correlation between the effects of adrenaline on ovulation and contraction. In addition, the antagonist studies indicate that adrena- line stimulates ovulation and follicle contraction of brook trout follicles through \g=a\-adrenoreceptors. Introduction follicles in smaller mammals has not been reported. In addition, while the perfused ovary system may be free of extraovarian Evidence that catecholamines play a direct role in the control of influences, it is still possible that the effects of certain agents in vertebrate ovulation comes from a variety of investigations this system act through vascular changes in the follicle rather (Goetz et al, 1991).